Self-Immolative System
for Disclosure of Reactive
Electrophilic Alkylating Agents: Understanding the Role of the Reporter
Group
The development of stable, efficient chemoselective self-immolative systems, for use in applications such as sensors, requires the optimization of the reactivity and degradation characteristics of the self-immolative unit. In this paper, we describe the effect that the structure of the reporter group has upon the self-immolative efficacy of a prototype system designed for the disclosure of electrophilic alkylating agents. The amine of the reporter group (a nitroaniline unit) was a constituent part of a carbamate that functioned as the self-immolative unit. The number and position of substituents on the nitroaniline unit were found to play a key role in the rate of self-immolative degradation and release of the reporter group. The position of the nitro substituent (meta- vs para-) and the methyl groups in the ortho-position relative to the carbamate exhibited an influence on the rate of elimination and stability of the self-immolative system. The ortho-methyl substituents imparted a twist on the N–C (aromatic) bond leading to increased resonance of the amine nitrogen’s lone pair into the carbonyl moiety and a decrease of the leaving character of the carbamate group; concomitantly, this may also make it a less electron-withdrawing group and lead to less acidification of the eliminated β-hydrogen.
Introduction<!>Results and Discussion<!><!>Results and Discussion<!><!>Results and Discussion<!><!>Results and Discussion<!><!>Results and Discussion<!><!>Results and Discussion<!><!>Conclusions<!>General Information<!>Synthesis of N,2,6-Trimethyl-4-nitroaniline
(10)<!>General Procedure 1: Synthesis of N-Methylated
Anilines (11–14)<!>Synthesis
of N,2-Dimethyl-4-nitroaniline (11)<!>Synthesis of N,2-Dimethyl-5-nitroaniline (12)<!>Synthesis of N,2,6-Trimethyl-3-nitroaniline
(13)<!>Synthesis of N,2,4,6-Tetramethyl-3-nitroaniline
(14)<!>General Procedure 2: Synthesis of Carbamoyl
Chlorides (1–9)<!>Synthesis
of Methyl(4-nitrophenyl)carbamic Chloride (1)31<!>Synthesis
of Methyl(2-methyl-4-nitrophenyl)carbamic Chloride
(2)<!>Synthesis of (2,6-Dimethyl-4-nitrophenyl)(methyl)carbamic Chloride
(3)<!>Synthesis of Methyl(3-nitrophenyl)carbamic Chloride (4)33<!>Synthesis of Methyl(2-methyl-5-nitrophenyl)carbamic Chloride
(5)34<!>Synthesis
of (2,6-Dimethyl-3-nitrophenyl)(methyl)carbamic Chloride
(6)<!>Synthesis of Methyl(2,4,6-trimethyl-3-nitrophenyl)carbamic Chloride
(7)<!>Synthesis of Methyl(phenyl)carbamic
Chloride (8)31<!>Synthesis
of Mesityl(methyl)carbamic Chloride (9)33<!>General Procedure 3: Synthesis of Self-Immolative
Systems (15–23)<!>Synthesis of 2-(Diphenylphosphanyl)ethyl
Methyl(4-nitrophenyl)carbamate
(15)23<!>Synthesis of 2-(Diphenylphosphanyl)ethyl Methyl(2-methyl-4-nitrophenyl)carbamate
(16)<!>Synthesis
of 2-(Diphenylphosphanyl)ethyl (2,6-Dimethyl-4-nitrophenyl)(methyl)carbamate
(17)<!>Synthesis of 2-(Diphenylphosphanyl)ethyl
Methyl(3-nitrophenyl)carbamate
(18)<!>Synthesis of 2-(Diphenylphosphanyl)ethyl Methyl(2-methyl-5-nitrophenyl)carbamate
(19)<!>Synthesis of 2-(Diphenylphosphanyl)ethyl
(2,6-Dimethyl-3-nitrophenyl)(methyl)carbamate
(20)<!>Synthesis
of 2-(Diphenylphosphanyl)ethyl Methyl(2,4,6-trimethyl-3-nitrophenyl)carbamate
(21)<!>Synthesis of 2-(Diphenylphosphanyl)ethyl
Methyl(phenyl)carbamate
(22)<!>Synthesis of 2-(Diphenylphosphanyl)ethyl
Mesityl(methyl)carbamate
(23)<!>General Procedure 4 for the Synthesis of Carbamate
Model Compounds (24–28)<!>Synthesis of Naphthalen-2-ylmethyl Methyl(4-nitrophenyl)carbamate
(24)<!>Synthesis
of Naphthalen-2-ylmethyl Methyl(2-methyl-4-nitrophenyl)carbamate
(25)<!>Synthesis
of Naphthalen-2-ylmethyl (2,6-Dimethyl-4-nitrophenyl)(methyl)carbamate
(26)<!>Synthesis
of Naphthalen-2-ylmethyl Methyl(3-nitrophenyl)carbamate
(27)<!>Synthesis
of Naphthalen-2-ylmethyl Methyl(phenyl)carbamate (28)<!>General Procedure
for the Alkylation Reactions of Self-Immolative
Systems (15–23)<!>General Procedure for the β-Elimination Reactions of Self-Immolative
Systems 15a–23a<!>General Procedure for the “One-Pot”
Reactions
of Self-Immolative Systems 18–20<!><!>Accession Codes<!>
<p>Stimuli-responsive
compounds,1−3 such as self-immolative molecules
and polymers,4−7 have become significant targets in organic-based material development
as systems of this type offer enormous potential in a diverse range
of applications that span drug delivery,8−10 biological and chemical
sensors,11,12 diagnostics,13 and degradable polymers or degrade-on-demand adhesives.14−19 The seminal report by Katzenellenbogen and co-workers,20 based upon the "prodrug" concept
discussed by Albert,21 set in place the
key molecular design for self-immolative materials that have been
explored and refined by several groups in recent years, one in which
a substrate-specific trigger is coupled via a degradable linker group
to a reporter moiety. Activation or deprotection of the trigger moiety,
by either nucleophiles4 or electrophiles,22−24 renders the immolative linker unit labile via generation of an electron-rich
center that then initiates a cascade of electrons and culminates in
the release of the reporter group from the linker group. When designing
a self-immolative system for a specific application, the delicate
balance of reactivity and stability of each of the key components
(i.e., trigger, linker, reporter) must be assessed
and optimized. The system must feature a selective trigger unit to
react with the desired substrate; equally, the linker to the reporter
group must be sufficiently stable to withstand unwanted side reactions
(such as environment-induced degradation) that can lead to "false-positive"
results. The effect of the structure of the linker group upon self-immolative
pathway and degradation rates has been shown to be pivotal in this
design rationale.25,26 In a detailed study, Phillips
and co-workers have elegantly shown27 the
effect that the structure of aromatic self-immolative linkers has
on a self-immolative process and were able to tune the controlled
release of phenols under neutral conditions.</p><p>In a recent communication,23 we reported
the first examples of selective solution-phase self-immolative systems
triggered by a nonacidic electrophilic species, such as methyl, allyl,
and benzylic halides, to afford a facile colorimetric visual disclosure
of toxic electrophilic alkylating agents (Scheme 1).</p><p>These systems, based upon the rarely utilized carbamate-based 2-(methylthio)ethoxycarbonyl
(Mteoc) protecting group developed28 by
Kunz and the phosphorus analogue advanced by Verducci et al.,29 afforded a visual colorimetric response to such
electrophiles following exposure to mild, basic conditions. A diphenylphosphine
nucleophile was used as it offered the best balance between reactivity
toward electrophiles while also offering reasonable stability toward
aerobic oxidation. Recently, a related approach for detection of alkylating
agents has been reported using a Förster resonance energy-transfer
(FRET)-based profluorescent probe.24 In
this system, alkylation of the probe results in the formation of a
quaternary ammonium salt, which increases its leaving group capacity
allowing the probe to facilitate the 1,6-elimination of the self-immolative
process. When the elimination proceeds, the fluorophore is no longer
quenched and can emit a fluorescence signal.</p><p>To the best of
our knowledge, a systematic study on the effect
of the structure of the reporter group (red moiety in Scheme 1) on self-immolative processes,
embracing conformational and basicity variations, has not been reported
in the literature. Indeed, in Katzenellenbogen's seminal paper,20 and in a later paper by Shabat,4b the nature of the reporter group was considered to have
only a limited impact on the rate of self-immolative elimination of
their carbamate systems. A related observation was made in respect
of carbonate linkers highlighted by Schmidt and Jullien; interestingly,
consideration was also given to conformational effects in the leaving
group.4c Hay has varied the substituent
in the para-position of an aniline reporter group
that fragmented from a 4-hydroxylaminobenzyl alcohol linker, observing
that the extent of release was not affected by its leaving group ability,
but rather by its subsequent reactions.4d In this paper, we describe a systematic study that reveals valuable
information on the role of the reporter group in relation to how this
key component influences the self-immolative molecule's stability
and degradation rate.</p><!><p>In view of
employing self-immolative systems in real-world environments
for the specific disclosure of toxic alkylating agents, it is important
that these materials possess suitable shelf-lives and are resistant
toward fluctuations in ambient conditions (such as moisture and/or
temperature) while stored. We have recently reported a novel self-immolative
system23 for the selective disclosure of
reactive electrophilic alkylating agents that is stable in solution
(>72 h in CD3CN) and when exposed to water (10% D2O in CD3CN). However, disappointingly, release
of the
reporter group was observed when stored in the bulk. To study the
influence of the reporter group structure on the stability and reactivity
of the self-immolative system, a variety of analogue structures were
prepared; these analogues have been designed to probe both electronic
and steric effects. To this end, carbamoyl chloride precursors 1–9 were first synthesized (see Figure 1).</p><!><p>Structure of carbamoyl
chlorides 1–9.</p><!><p>Carbamoyl chloride 3, substituted by a nitro group
in the para-position relative to the carbamoyl group,
was synthesized according to the route displayed in Scheme 2.30,31 Protection of the amine group using 4-toluenesulfonyl chloride (TsCl)
was carried out prior to nitration to promote regioselective reaction para- to the N-tosylate group. The carbamoyl
chloride 3 was then obtained via a two-pot, three-step
process; that involved initial N-methylation of the
protected aniline followed by deprotection of the tosylate group under
acidic conditions to yield 10, which was then converted
to the corresponding carbamoyl chlorides using triphosgene (see Figures S1–S4 in the Supporting Information
(SI) for analytical data for 10 and 3).</p><p>The carbamoyl chlorides 2 and 5–7 were synthesized utilizing an alternative
synthetic pathway
(Scheme 3). Regioselective
nitration of the anilines leading to 5–7 afforded the corresponding meta-derivatives (2-methyl-4-nitroaniline
was purchased), and then selective monomethylation was carried out
according to the procedure reported by Lebleu et al.,32 using methyl triflate as an alkylating agent in hexafluoroisopropanol
(HFIP), affording the desired N-methylated aniline
products (11–14) in yields ranging
from 68 to 83%. As in the case of 3, the carbamoyl chlorides 2 and 5–7 were then obtained
by reaction of the N-methylated aniline derivatives
with triphosgene (see Figures S5–S20 in the SI for analytical data for 11–14 and 2, 5–7). The carbamoyl chlorides 1, 4, 8, and 9 were
obtained using procedures reported previously (see Figures S21–S28 in the SI for analytical data for 1, 4, 8, and 9).31,33,34</p><p>The target self-immolative systems were obtained
by conjugation
of 2-diphenylphosphinoethanol to the N-methyl carbamoyl
chloride derivatives 1–9 using 4-dimethylaminopyridine
(DMAP) in a catalytic amount and heating under reflux in tetrahydrofuran
(THF): this procedure afforded the self-immolative systems 15–23 (Scheme 4; see Figures S29–S60 in the SI for analytical data for 15–23).23</p><p>NMR spectroscopic analysis of the different self-immolative systems
containing one or two methyl groups ortho- to the
carbamate revealed the presence of two rotamers as a result of restricted
rotation about their carbamate C–N bonds (see Scheme 5), and it is evident that the
rotamer ratios for these disclosure systems were perturbed by changing
the solvent (e.g., compound 19; see Figure 2).a In addition, the rotameric ratio increased with the number
of electron-donating methyl groups present on the aromatic ring (see Table 1: 19 vs 20 vs 21).35</p><!><p>VT 1H NMR spectroscopic analysis of self-immolative
system 19: rotamer ratio 62/38 recorded in DMSO-d6 (500 MHz).</p><p>Rotameric
ratio is not determined
as the coalescence temperature is below 22 °C.</p><p>The observed degradation occurs
within the first 24 h, after which the physical state of the neat
liquid changes to a paste-like consistency.</p><!><p>Since the energy barrier to free rotation of the C–N
bonds
of the carbamate group can be overcome at elevated temperatures, variable-temperature
(VT) 1H and 31P NMR spectroscopic studies were
conducted on 16, 19, and 20 to specifically facilitate two pairwise comparisons, 16/19 and 19/20 (see Figures S61–S65). The pair 16/19 was selected to evaluate the relative effect of
a para- and meta-positioned nitro
group on the double-bond character of the nominally C–N single
bond of the carbamate, whereas 19/20 permitted
the effect of one vs two ortho-methyl groups to be
assessed. These results could then be correlated to the observed stability/reactivity
of the systems. Thus, 16 and 19 were analyzed
in DMSO-d6 in increments between 25 and
90 °C: Figure 2 shows the 1H NMR spectra obtained for the self-immolative
system 19 at four selected temperatures. The resonances
at 2.98–3.12 ppm (c, CH3–N), 4.06–4.25 ppm (b, CH2–O), and 8.06 ppm (f and g, CHAr) began to broaden as the temperature
was increased and eventually coalesced by ca. 50
°C into two single broad resonances. Meanwhile, the resonances
corresponding to the aromatic protons CHArf and g sharpened from a broad signal
to a doublet for proton f and a doublet of doublets for
proton g. Upon heating to 90 °C, the resonances
corresponding to the protons CH3–N
and CH2–O sharpened into a singlet
and an apparent quartet, respectively. Compound 16 showed
similar spectroscopic changes but with coalescence being achieved
at ca. 40 °C (see Figures S62 and S63). The determination of the coalescence temperature
(Tc), in addition to the value of the
rotamer population difference (ΔP) and the
limiting chemical shift difference (Δν), obtained from
spectra at temperatures below coalescence for both 16 and 19 allowed the calculation of the free energy of
activation (ΔG‡) for the
rotational equilibrium of 16 and 19 by treating
the data as an exchange between two unequally populated sites (see eqs S1–S6 in the SI).36 Lower values of the energy barriers were found for 16 (ΔGC,rotamer A‡ = 65.2 kJ·mol–1 and ΔGC,rotamer B‡ = 64.0 kJ·mol–1, respectively) when compared to 19 (ΔGC,rotamer A‡ = 67.8 kJ·mol–1 and ΔGC,rotamer B‡ = 66.5 kJ·mol–1, respectively), showing the influence of the nitro group position
(para- vs meta-) on the carbamate
C–N rotation equilibrium. As anticipated, the ability of the
nitrogen lone pair to resonate into the carbamate increases when the
nitro group was moved from the para- to the meta-position, consistent with the change in coalescence
temperature.</p><p>In contrast to 19, 20 revealed only broadening
of the key resonances (see Figures S64 and S65), without coalescence at 100 °C, indicating a greater resonance
of the nitrogen lone pair into the carbamate carbonyl and a larger
steric barrier to rotation (ΔGC,rotamer A‡ > 79.3 kJ·mol–1 and ΔGC,rotamer B‡ > 77.3 kJ·mol–1, respectively) when compared
to 19. A similar trend was observed by comparing the
VT 1H and 31P NMR spectroscopic analysis obtained
for 16 and 17 (with the nitro group in the para-position) (see Figures S62–S63 and S66–S67). The reduced resonance into the aromatic
ring arises from a substantial torsion angle between the ring and
the carbamate group (Figure 3).</p><!><p>Resonance structures contributing to the stability of the leaving
groups of 15 and 17.</p><!><p>To investigate the thermal stability of these self-immolative systems,
the solutions were then cooled down from 100 to 25 °C and the
sharp, well-resolved resonances observed at an elevated temperature
for 16, 17, 19, and 20 returned to their original shape, indicating their thermal stability
across this temperature range (see Figures S68–S75). In addition, the different self-immolative systems 15–23 were found to be stable at both 0.1 and 0.025
M (reaction conditions for the self-immolative study) solutions in
CD3CN over >72 h at 22 °C (see Figures S76–S84). However, a small amount of oxidation
to the corresponding phosphine oxide was noted.</p><p>The stability
of the different self-immolative systems as neat
liquids was then investigated (see Table 1). The stability of 15, bearing
a nitro group in the para-position relative to the
carbamate group, was first assessed. When left to stand at room temperature
as a neat liquid, it proved to be unstable and release of the reporter
group (N-methyl-para-nitroaniline)
was observed, with 32% degradation evident after 24 h (see Figure S85). Lowering the storage temperature
to −20 °C was ineffective in preventing degradation. The
instability of 15 was attributed to the structure of
the N-methyl-para-nitroaniline reporter
unit; in particular, the resonance of the nitrogen lone pair into
the aromatic ring and nitro group rendered the carbamate less electron-rich
and more electrophilic. In contrast, the self-immolative system 18, with the nitro group in the meta-position
(wherein its influences are limited to inductive and field effects),
proved more stable. However, while the stability of 18 improved relative to 15, the observed release of 4%
of the reporter group (N-methyl-meta-nitroaniline) over 72 h would still risk a false-positive response
if used in real-world applications (see Figure S86). Removal of the nitro group afforded phenyl carbamate 22 that proved to be stable under identical conditions (see Figure S87). These observations indicated the
influence of the presence of the nitro group on the carbamate unit
stability. However, as a colorimetric response is required for visual
disclosure, the presence of the nitro group was essential in the reporter
moiety. Therefore, an alternative route to enhance the stability of
the self-immolative system was investigated that involved the introduction
of methyl groups in the ortho-position of the reporter
unit (relative to the carbamate linkage). Introduction of the methyl
groups in the ortho-position of the reporter group
should impart a twist on the N–C (aromatic) bond, reducing
the ability of the lone pair of the carbamate nitrogen to resonate
into the aromatic ring (Figure 3). Indeed, resonance into a carbamate anion was noted by Johnson
as significant in determining the pKa of
its conjugate acid.37</p><p>When added
to the increase in steric size of the reporter group,
this should have the effect of reducing the carbamate's electrophilicity.
Regarding the self-immolative system 16, featuring a
single ortho-methyl group and the nitro group in
the para-position, relative to the carbamate group,
a decrease of degradation rate was observed when compared to 15. However, after 72 h, a similar amount of reporter group
release was observed for 16 and 15 (see Figures S85 and S88). In contrast, regarding
the self-immolative system 19, with the nitro group located
in the meta-position and a single methyl group in
the ortho-position, relative to the carbamate group,
degradation was not observed after 72 h (see Figure S89). In the cases of the self-immolative systems 17, 20, 21, and 23, substituted
by two ortho-methyl groups, degradation was not observed
at room temperature after 72 h (see Figures S90–S93). These results highlight the strong influence of the presence of
the methyl groups in the ortho-position, relative
to the carbamate group, on the stability of the self-immolative system.</p><p>These effects will also bear upon the ability of the carbamate
to function as a leaving group in the manner identified in Schemes 1 and 8 and Figure 5. However, it is worth noting that such effects
will be attenuated as compared to the leaving group ability of the
aniline itself. Johnson has noted that while the pKaH+ of the amine in a carbamate can vary by
as much as 8 pKa units, the corresponding
carbamic acids vary by around 1 pKa unit.37 However, though the differences are attenuated,
they do vary in the same direction as the amine pKaH+.</p><p>To quantify the torsion angle imparted
on the CCNC moiety, as highlighted
in red (Scheme 6),
the model compounds 24–28 that possess
similar structures to the self-immolative systems 15, 16, 17, 18, and 22 were
synthesized. 2-Naphthalenemethanol was selected as a result of its
crystalline nature. Crystalline carbamates were obtained via the conjugation
of 2-naphthalenemethanol to N-methyl-carbamoyl chloride
derivatives 1–4 and 8 using sodium hydride (NaH) in dimethylformamide (DMF) (see Figures S94–S103).</p><p>The solid-state structures
of 22–28 were obtained using X-ray
crystallographic analysis. Partial structures
are shown in Figure 4 to emphasize the CCNC torsion angle (for full structures, see Figures S104–S110 and Tables S2–S8).b</p><!><p>Partial solid-state structures of model compounds 22–28.</p><!><p>The analysis showed no significant changes in geometry when the
nitro group was located in either the para- or the meta-position, with torsion angles of 41(1) and 44(1)°
for 24 and 27, respectively. However, when
the nitro group was not present (e.g., 28), a higher torsion angle of 57(1)° was observed. In the cases
of 24 and 27, the torsion angles reflect
the ability of the CCNC linkage to adopt a more planar geometry as
a consequence of electronic effects when the electron-withdrawing
nitro group is present. These results are in good agreement with the
stability profiles observed for the self-immolative systems 15, 18, and 22 in their neat liquid
form. In contrast to 24 and 27, the solid-state
structures of 25 and 26 that possess one
and two ortho-methyl groups, respectively, revealed
an increase in the torsion angle to 72(1)° for 25 and 81(1) or 88(1)° for 26 (two conformers were
evident in the unit cell). Assuming that the solid-state data of the
model carbamates translates to the self-immolative system in their
liquid form, the additional twist imparted on the N–C (aromatic)
bond by the presence of ortho-methyl groups should
lead to a reduction in the electrophilicity of the carbamate linker.
These effects could serve to explain the improved stability, in their
neat liquid forms, of the self-immolative systems 17 when
compared to that of 15 as well as the improved stability
of 19 and 20 when compared to that of 18.</p><p>The solid-state structures of the self-immolative
systems 22 and 23 were also obtained. The
CCNC torsion
angle for 23 (that features two ortho-methyl groups but no nitro residue) was determined to be 73(1) or
78(1)° (two conformers were evident in the unit cell), comparable
in value relative to that of the model carbamate 26 (81(1)
or 88(1)°). However, the CCNC torsion angle of the phenyl carbamate 22 (78(1)°) was found to be higher than expected when
compared to that of the model compound 28; the difference
between the torsion angles values could be attributed to crystal packing
forces involving the planar aromatic units.</p><p>To assess the ability
of the different self-immolative systems
to disclose the presence of reactive electrophilic alkylating agents
via a two-step process involving alkylation followed by elimination/decarboxylation
(Scheme 1), the reactivity
of 15–23 toward alkylation was first
investigated, using benzyl bromide as the alkylating agent (Scheme 7).38,39</p><p>Cognizant that these are type II SN2 reactions,38,39 alkylation of self-immolative
systems 15–23 was conducted by dissolution
of the self-immolative system
in the polar aprotic solvent CD3CN, followed by the addition
of 10 molar equiv of benzyl bromide and recording the 1H NMR spectra at regular time intervals at 20 °C (see Figures S111–S119). Following analysis
of the reactions under these pseudo-first-order conditions, it was
found that the introduction of different substituents on the aromatic
ring of the reporter moiety had no dramatic influence on the alkylation
rate, with half-life times (t1/2) measured
between 10.4 and 28.6 min (see Table 2 and Figure S120). Given
that there is a developing positive charge at the phosphorus center,
during alkylation, it is understandable that self-immolative systems
with otherwise equivalent reporter groups, but with the nitro group meta- to the carbamate alkylate faster than those with it
in the para-position, e.g., 18 vs 15. Incorporation of ortho-methyl groups relative to the carbamate slowed the rate of alkylation, e.g., 18 vs 19, vs 20. Also evident was the slower alkylation of the nitro-substituted
aromatic derivatives in comparison to those systems without nitro
substituents, e.g., 22 vs 18. Whether this arises purely by a charge–dipole interaction
between the developing phosphonium center and the carbamate, or a
more specific alignment of the developing σ*(C–P) orbital
is not clear.</p><!><p>Percentage of β-elimination
after 24 h.</p><!><p>The β-elimination
of the alkylated systems 15a–23a was
then performed using 2 molar equiv of N,N-diisopropylethylamine (DIPEA) (see Figures S121–S131). All compounds underwent
the expected elimination to produce the reporter unit and CO2 (Scheme 8). When the elimination of 21 was conducted
in D2O/CD3CN, at partial conversion, no incorporation
of deuterium was observed (1H NMR) in the PCH2CH2 resonance of residual 21 or
the vinyl group of phosphonium salt 29. However, both
species were deuterated at the benzylic methylene. This limits the
mechanism to either E2, E1cB (anion), or E1cB (irreversible).</p><p>In contrast to the
alkylation profiles, the rate of elimination
dramatically changed with respect to the structure of reporter groups
(see Table 2). The
highest elimination rates were observed for the reporter groups most
able to withdraw electron density from the carbamate nitrogen, thus
affording both the best leaving group and, concomitantly, acidifying
the β-hydrogen removed during the elimination reaction. Therefore,
for equivalently substituted reporter groups bearing the same substituents
but located in different positions on the aromatic ring, a para-nitro substituent is more effective than a meta-substituent, e.g., 15a vs 18a, whereas additional methyl groups slowed the
elimination, e.g., 18a vs 19a vs 20a. In addition, these methyl groups are modestly
electron donating and would be expected to restrict solvation of the
leaving group. Other solvents were investigated to enhance the sensitivity
of the alkylation and β-elimination pathways using 19 (see Figures S132–S136). The rate
of alkylation varied with the solvent, with the observed order being
DMSO-d6 > 10% MeOD/CD3CN
>
CD3CN > DMF; however, β-elimination was observed
at a respectable rate in CD3CN in comparison to DMSO-d6 and DMF-d7. The
variation in the rate of elimination in these three solvents may relate
to changes in the pKaH+ for iPr2EtNH+ in them. For
example, pKaH+ Et3NH+ (CH3CN) > pKaH+ Et3NH+ (DMSO).40</p><p>The rate of elimination was enhanced using 10% MeOD
as a cosolvent
with CD3CN in comparison to neat CD3CN;27 however, for consistency within these studies,
alkylation and elimination experiments were conducted in CD3CN.</p><p>In addition, under the pseudo-first-order conditions used,
depending
on the reporter group structure, it was observed that post degradation
of the self-immolative system, alternative alkylation pathways could
occur involving the excess benzyl bromide present. Therefore, three
distinct reporter group categories have been determined: (i) partial
alkylation of the carbamate leaving group was observed for the reporter
groups featuring two ortho-methyl groups leading
to the formation of Cbz-protected amines (observed for 17, 20, 21, and 23; see Figures S123, S126–S127, S129, and S130), (ii) full N-alkylation of the reporter group was observed for 22 after the release of N-methylaniline (see Figures S128 and S131), and (iii) in the case
of reporter groups possessing either one or no ortho-methyl groups and a nitro substituent, alkylation was not observed
(15, 16, 18, and 19; see Figures S121–S122 and S124–S125). As a result of increasing the steric bulk of the reporter groups
(case (i): 17, 20, 21, and 23), the lifetime of the carbamate anion generated upon initial
degradation was sufficient to permit its alkylation. In the case of
(ii), the increased nucleophilicity of N-methylaniline
released from 22a led to rapid N-alkylation with the
excess benzyl bromide present. The optimum degradation pathway was
obtained in the case of (iii), whereby the reporter units featured
a nitro substituent and either a hydrogen or a single methyl group
in the ortho-position. Since slow decarboxylation
and subsequent alkylation lead to loss of the color of the reporter
group, this is an important design point for this self-immolative
system.</p><p>In the light of the stability of 19 in
both the neat
and solution forms, taken together with its reactivity profile, this
self-immolative system was selected for degradation studies, whereby
the disclosure system and base were present and then exposed to the
alkylating agent. As a result, a one-pot alkylation–elimination
sequence was carried out by mixing system 19 with 2 molar
equiv of DIPEA before the addition of benzyl bromide. From the plot
shown in Figure 5, it can be observed that after addition
of 10 molar equiv of benzyl bromide the reporter group N-methyl-2-methyl-5-nitroaniline was released, demonstrating the viability
of this one-pot alkylation–elimination process (see Figure S137 and Table S10). Furthermore, an intense
yellow coloration was evident within 15 min following the addition
of the alkylating agent. In addition, identical degradation studies
conducted on self-immolative systems 18 and 20 confirmed the viability of the one-pot alkylation–elimination
process as well as the relative reactivities of these compounds relative
to 19 (e.g., 18 > 19 > 20; see Figures S138–S139 and Tables S9 and S11). In addition to these degradation studies,
self-immolative system 19 was further studied via UV–visible
spectroscopy, utilizing a solution of alkylated 19 and
in relation to an external calibration plot. In an analogous one-pot
study, the concentration of both 19 and benzyl bromide
was decreased 10-fold and the release of the reporter group was monitored
with respect to time (see Figures S140–S143).</p><!><p>Top: reaction schematic of the self-immolative degradation of disclosure
systems 18–20. Bottom: reaction kinetics
calculated from the 1H NMR spectra (20 °C) obtained
following the addition of 10 molar equiv of benzyl bromide to 18–20 and N,N-diisopropylethylamine (DIPEA) in a one-pot approach (18–20, blue diamonds; 18a–20a, red squares; reporter groups, yellow triangles). Errors
associated with the integral values for these 1H NMR studies
were ±5%.</p><!><p>In summary, a range
of selective self-immolative systems, triggered
by a nonacidic electrophilic alkylating agent to afford a facile colorimetric
visual disclosure, have been synthesized. The effect of the structure
of the reporter group upon the rate of degradation and stability of
the compounds has been determined. A significant influence on both
the stability and the rate of elimination was determined in relation
to the position of the nitro substituent (meta- vs para-) on the aniline reporter group. In addition, both
the stability and reactivity of the self-immolative system could be
tuned by the introduction of methyl groups in the ortho-position relative to the carbamate moiety of the reporter group.
The ortho-methyl groups were found to have imparted
an increased twist on the N–C (aromatic) bond, which led to
a reduction of the ability of the carbamate nitrogen's lone
pair to resonate within the aromatic ring, resulting in a decrease
of the leaving character of the carbamate group. Additionally, this
should render the carbamate less electron withdrawing and so less
able to acidify the β-hydrogen undergoing elimination. This
study revealed that the structural modifications to the reporter group
had a modest influence on the alkylation rate, with similar half-lives
being observed for the benzylation of self-immolative systems 15–23. In contrast, the β-elimination
rates were affected by both the position of the nitro group on the
aromatic ring (pKa) and the introduction
of ortho-methyl groups relative to the carbamate
group (conformation). The position and nature of the substituents
on the reporter group have led to these being divided into three groups,
depending on their fate post release. Additionally, the rate of the
present 1,2-elimination appears to be more substantially affected
by the nature of the reporter group than the original 1,6-elimination
reported by Katzenellenbogen, and by Hay and 1,4- and 1,6- examples
reported by Shabat.4b,20,4d From the series of self-immolative disclosure systems synthesized, 19 was selected as the candidate for the disclosure of reactive
alkylating agents, as it exhibited the optimum balance between stability
and reactivity. Owing to the potential of these self-immolative systems
to offer a practical route for the selective disclosure of reactive
electrophilic species, such as chemical warfare agents, outside of
the laboratory environment and without need for instrumentation, further
studies are currently underway to produce clear and robust disclosure
events for a broader range of electrophiles.</p><!><p>All chemical reagents were purchased
from Sigma-Aldrich and used as received, without purification. 2-Diphenylphosphinoethanol41,42 and N-(2,6-dimethyl-4-nitrophenyl)-4-methylbenzenesulfonamide30 were synthesized by modifications of literature
procedures. Solvents were purchased from Fisher Scientific except
for ethyl acetate and hexane, which were purchased from Sigma-Aldrich.
All solvents were used as supplied except for THF that was distilled
under argon from sodium and benzophenone prior to use. Fisher Scientific
Silica 60A (particle size 35–70 μm) was used to perform
column chromatography. Thin-layer chromatography (TLC) was performed
on aluminum sheets coated with Merck 5735 Kieselgel 60 F254. Developed plates were air-dried and stained using a potassium permanganate
solution. 1H (400 MHz), 31P{1H} (162
MHz), and 13C{1H} (100 MHz) NMR spectra were
recorded at 20 °C on a Bruker Nanobay 400 MHz (9.39 T) or a Bruker
DPX 400 (9.39 T) instrument. 1H (500 MHz), 31P{1H} (203 MHz), and 13C{1H} (125
MHz) variable-temperature NMR (VT-NMR) were recorded on a Bruker Avance
III 500 MHz instrument (11.74 T). This instrument was calibrated at
installation with ethylene glycol with an associated error of ±0.1
°C. 1H NMR spectra recorded in CDCl3 were
referenced to tetramethylsilane (TMS) as the internal standard, whereas
those recorded in CD3CN, DMF-d7, or DMSO-d6 were referenced to residual
solvent. Chemical shifts (Î´) are reported in parts per million
(ppm) from low to high field. Coupling constants (J) are reported in hertz (Hz). Standard abbreviations indicating multiplicity
are used as follows: br. = broad, s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, and app. = apparent. Fourier transform
infrared (FTIR) spectra were recorded on a PerkinElmer Spectrum FTIR
directly using a diamond ATR sampling accessory. Mass spectrometry
was conducted using a ThermoFisher Scientific Orbitrap XL LCMS. The
sample was introduced by liquid chromatography, and sample ionization
was achieved by electrospray ionization (ESI). Elemental microanalyses
of 2, 3, 6, and 7 were performed by MEDAC Ltd. Melting points were recorded using
a Stuart MP10 melting point. UV–visible spectra were measured
with a Varian Cary 300 spectrophotometer using a 10 mm inner width
Quartz cuvette in the wavelength range of 250–800 nm.</p><p>Crystals of 22, 23, 24, 25, 26, 27, and 28 were mounted
under paratone-N oil and flash-cooled to either 100 K (22, 23, 26, 27, 28) or 150 K (24, 25) under nitrogen in an
Oxford Cryosystems Cryostream. Single-crystal X-ray intensity data
were collected using either an Agilent Gemini S Ultra diffractometer
(Mo Kα radiation (λ = 0.71073 Å)) (24, 25) or a Rigaku XtaLAB Synergy diffractometer (Cu
Kα radiation (λ = 1.54184 Å)) (22, 23, 26, 27, 28). The
data were reduced within CrysAlisPro software.43 The structures were solved using the program Superflip,44 and all nonhydrogen atoms were located. Least-squares
refinements on F were carried out using the CRYSTALS
suite of programs.45 The nonhydrogen atoms
were refined anisotropically. All of the hydrogen atoms were located
in difference Fourier maps and then placed geometrically with a C–H
distance of 0.95 Å and a Uiso of
1.2 times the value of Ueq of the parent
C atom. The hydrogen atoms attached to C were then refined with riding
constraints. The crystallographic details for compounds 22–28 are presented in the Supporting Information.</p><!><p>N-(2,6-Dimethyl-4-nitrophenyl)-4-methylbenzenesulfonamide30 (4.0 g, 12.49 mmol) was dissolved in THF (20
mL) and cooled to room temperature. Upon cooling, 60% sodium hydride
dispersion in mineral oil (0.55 g, 13.73 mmol) was added followed
by iodomethane (1.17 mL, 18.73 mmol) and left to stir overnight. The
volatiles were removed in vacuo to yield a white
crystalline solid and used without further purification. N-(2,6-Dimethyl-4-nitrophenyl)-N-4-dimethylbenzenesulfonamide
was dissolved in H2SO4 (15 mL) and water (1
mL) and warmed at 40 °C (using an aluminum heating block) for
16 h. The reaction mixture was poured slowly into an ice/water/NaOH
mixture. This was extracted with ethyl acetate, dried over MgSO4, filtered, and the solvent was removed in vacuo to yield yellow crystals (1.89 g, 84%). Mp 90–92 °C. 1H NMR (CDCl3, 400 MHz) δ 7.86 (s, 2H), 3.88
(br. s, 1H), 3.06 (s, 3H), 2.33 (s, 6H). 13C{1H} NMR (CDCl3, 100 MHz) Î´ 153.8, 139.4, 125.4, 124.9,
24.9, 19.6. FTIR (ATR/Î½max) 3425, 2920, 2383, 1592,
1525, 1421, 1352, 1254, 1235, 1153, 1107, 1029 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C9H13O2N2 181.0972;
found 181.0972.</p><!><p>To a solution of HFIP
(hexafluoroisopropanol) (10 equiv) and aniline (1 equiv) was added
methyl trifluoromethanesulfonate (MeOTf) (1.5 equiv). The mixture
was stirred for 1 h at room temperature and then quenched by a solution
of 2 N HCl. Volatiles were evaporated in vacuo. The
resulting mixture was neutralized with a saturated aqueous solution
of NaHCO3 and extracted with CH2Cl2 (3 × 30 mL). The organic phases were dried over MgSO4, filtered, and the solvent was removed in vacuo. The crude product was further purified by column chromatography.</p><!><p>Following general procedure 1, 2-methyl 4-nitroaniline
(2.0 g, 13.14 mmol) was treated with HFIP (13.8 mL, 131.45 mmol) and
MeOTf (2.16 mL, 19.72 mmol) to provide 11 (1.58 g, 72%)
as a yellow solid after silica-gel column chromatography (THF/hexane
10/90). Mp 138–140 °C. 1H NMR (CDCl3, 400 MHz) δ 8.09 (dd, 3J = 9.0
Hz, 4J = 2.5 Hz, 1H), 7.99–7.96
(d, 4J = 2.5 Hz, 1H), 6.53 (d, 3J = 9.0 Hz, 1H), 4.37 (br. s, 1H), 3.00 (d, 3J = 5.0 Hz, 3H), 2.17 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) Î´ 152.6, 137.6,
126.0, 124.9, 121.0, 107.4, 30.5, 17.3. FTIR (ATR/Î½max) 3378, 2908, 1608, 1587, 1541, 1486, 1463, 1407, 1386, 1290, 1261,
1189, 1118, 1094, 1036, 1001 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C8H11O2N2 167.0815; found 167.0810.</p><!><p>Following general procedure 1, 2-methyl-5-nitroaniline
(2.0 g, 13.14 mmol) was treated with HFIP (13.8 mL, 131.45 mmol),
and MeOTf (2.16 mL, 19.72 mmol) to provide 12 (1.49 g,
68%) as a yellow solid after silica-gel column chromatography (THF/hexane
10/90). Mp 110–112 °C. 1H NMR (CDCl3, 400 MHz) δ 8.31 (dd, 3J = 8.0
Hz, 4J = 2.5 Hz, 1H), 7.37 (d, 4J = 2.5 Hz, 1H), 7.13 (d, 3J = 8.0 Hz, 1H), 3.85 (br. s, 1H), 2.96 (d, 3J = 4.0 Hz, 3H), 2.19 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) Î´ 148.0, 147.9, 130.0, 129.3, 111.9, 103.1,
30.7, 17.7. FTIR (ATR/Î½max) 3429, 2923, 2801, 1621,
1524, 1498, 1336, 1284, 1162, 1093, 1067 cm–1. HRMS
(ESI) m/z: [M + H]+ calcd
for C8H11O2N2 167.0815;
found 167.0816.</p><!><p>Following general procedure 1, 2,6-dimethyl-3-nitroaniline
(2.0 g, 12.04 mmol) was treated with HFIP (12.64 mL, 120.35 mmol)
and MeOTf (1.97 mL, 18.05 mmol) to provide 13 (1.67 g,
77%) as a yellow oil after silica-gel column chromatography (THF/hexane
10/90). 1H NMR (CDCl3, 400 MHz) Î´ 7.39
(d, 3J = 8.5 Hz, 1H), 7.07 (d, 3J = 8.5 Hz, 1H), 3.23 (br. s, 1H), 2.80 (s, 3H),
2.42 (s, 3H), 2.33 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) Î´ 150.2, 149.5, 134.4, 128.3, 124.3, 117.6,
35.5, 18.9, 14.9. FTIR (ATR/Î½max) 3407, 2953, 1599,
1465, 1376, 1293, 1260, 1229, 1144, 1158, 1013 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C9H13O2N2 181.0972;
found 181.0970.</p><!><p>Following general procedure 1, 2,4,6-trimethyl-3-nitroaniline
(2.0 g, 11.10 mmol) was treated with HFIP (11.66 mL, 110.98 mmol)
and MeOTf (1.82 mL, 16.65 mmol) to provide 14 (1.79 g,
83%) as a yellow solid after silica-gel column chromatography (THF/hexane
10/90). Mp 59–60 °C. 1H NMR (CDCl3, 400 MHz) δ 6.89 (app. s, 1H), 2.98 (br. s, 1H), 2.75 (s,
3H), 2.27 (s, 3H), 2.20 (s, 6H). 13C{1H} NMR
(CDCl3, 100 MHz) Î´ 151.6, 146.5, 131.8, 130.7, 122.3,
121.2, 35.6, 18.4, 16.9, 13.3. FTIR (ATR/Î½max) 3407,
2930, 1582, 1507, 1476, 1432, 1377, 1356, 1309, 1281, 1249, 1216,
1151, 1063, 1038, 1013 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C10H15O2N2 195.1128; found
195.1123.</p><!><p>To a solution of triphosgene
(2 equiv)
in dry hexane (10 mL), aliquat 336 (0.5 equiv) was added and left
to stir at room temperature for 16 h. A solution of the N-methylated aniline derivative (1 equiv) and triethylamine (2 equiv)
in THF (20 mL) was added dropwise to the solution at 0 °C. After
stirring the solution at room temperature for 2 h, the precipitate
was filtered and the solvent was removed in vacuo. The crude product was further purified by column chromatography.</p><!><p>Following the general procedure
2, N-methyl-4-nitroaniline (0.77 g, 5.05 mmol) was
treated with triphosgene (3.00 g, 10.11 mmol), aliquat 336 (1.00 g,
2.53 mmol), and triethylamine (1.41 mL, 10.11 mmol) to provide 1 (0.91 g, 84% yield) as a white solid after silica-gel column
chromatography (10 → 20% EtOAc/hexane) followed by a recrystallization
from EtOAc/hexane (9/1 v/v). Mp 101–103 °C. 1H NMR (CDCl3, 400 MHz) δ 8.31 (app. d, 2H), 7.48
(app. d, 2H), 3.48 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) Î´ 143.3, 142.9, 141.6 (br.), 122.5, 119.7,
35.3 (br.). FTIR (ATR/νmax) 3111–3081, 1726,
1594, 1512, 1495, 1418, 1342, 1255 cm–1.</p><!><p>Following the general procedure 2, 11 (0.84 g, 5.05 mmol) was treated with triphosgene (3.00
g, 10.11 mmol), aliquat 336 (1.00 g, 2.53 mmol), and triethylamine
(1.86 mL, 13.30 mmol) to provide 2 (0.89 g, 76% yield)
as a white solid with an 83:17 mixture of rotamers A/B after silica-gel
column chromatography (10 → 20% EtOAc/hexane). Mp 85–87
°C. 1H NMR (CDCl3, 400 MHz) δ 8.23–8.17
(s, 1H, rotamer A + rotamer B), 8.17–8.10 (m, 1H, rotamer A
+ rotamer B), 7.37 (app. d, 1H, rotamer A + rotamer B), 3.46 (s, 3H,
rotamer B), 3.32 (s, 3H, rotamer A), 2.42 (s, 3H rotamer A), 2.38
(s, 3H rotamer B). 13C{1H} NMR (CDCl3, 100 MHz) Î´ 149.1, 148.5, 147.7, 147.4, 147.1, 147.0, 138.1,
137.3, 129.4, 127.9, 126.6, 122.9, 122.7, 41.3, 39.0, 17.9, 17.8.
FTIR (ATR/νmax) 3081–2932, 1724, 1586, 1529,
1513, 1491, 1344, 1304, 1252, 1113, 1085 cm–1. Anal.
calcd for C9H9ClN2O3:
C, 47.28; H, 3.97; N, 12.25. Found: C, 46.97; H, 3.75; N, 11.97.</p><!><p>Following the general procedure 2, 10 (0.91 g, 5.05 mmol) was treated with triphosgene (3.00
g, 10.11 mmol), aliquat 336 (1.00 g, 2.53 mmol), and triethylamine
(1.86 mL, 13.30 mmol) to provide 3 (0.97 g, 72% yield)
as a white solid with an 88:12 mixture of rotamers A/B after silica-gel
column chromatography (10 → 20% EtOAc/hexane). Mp 124–126
°C. 1H NMR (CDCl3, 400 MHz) δ 8.02
(s, 1H, rotamer A), 8.00 (s, 1H, rotamer B), 3.37 (s, 3H, rotamer
B), 3.26 (s, 3H, rotamer A), 2.39 (s, 6H, rotamer A), 2.36 (s, 6H,
rotamer B). 13C{1H} NMR (CDCl3, 100
MHz) Î´ 148.8, 147.4, 146.0, 138.1, 137.2, 124.0, 39.7, 37.3,
18.1 (×2). FTIR (ATR/νmax) 3086–2966,
1744, 1587, 1516, 1473, 1348, 1299, 1238, 1118, 1090 cm–1. Anal. calcd for C10H11ClN2O3: C, 49.50; H, 4.57; N, 11.54. Found: C, 49.13; H, 4.60; N,
11.18.</p><!><p>Following the general procedure
2, N-methyl-3-nitroaniline (0.77 g, 5.05 mmol) was
treated with triphosgene (3.00 g, 10.11 mmol), aliquat 336 (1.00 g,
2.53 mmol), and triethylamine (1.41 mL, 10.11 mmol) to provide 4 (0.75 g, 70% yield) as a white solid after silica-gel column
chromatography (10 → 20% EtOAc/hexane). Mp 92–94 °C. 1H NMR (CDCl3, 400 MHz) δ 8.26 (m, 1H), 8.18
(s, 1H), 7.76–7.58 (m, 2H) 3.47 (br. s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ 148.8, 143.9, 133.8
(br.), 130.6, 123.3 (br.), 40.4. FTIR (ATR/Î½max)
3073, 1727, 1532, 1480, 1418, 1352, 1252 cm–1.</p><!><p>Following the
general procedure 2, 12 (0.84 g, 5.05 mmol) was treated
with triphosgene (3.00 g, 10.11 mmol), aliquat 336 (1.00 g, 2.53 mmol),
and triethylamine (1.86 mL, 13.30 mmol) to provide 5 (1.01
g, 87% yield) as a colorless oil with an 83:17 mixture of rotamers
A/B after silica-gel column chromatography (10 → 20% EtOAc/hexane). 1H NMR (CDCl3, 400 MHz) δ 8.16 (dd, 3J = 8.5 Hz, 4J = 2.5
Hz, 1H rotamer A), 8.11 (dd, 3J = 8.5
Hz, 4J = 2.5 Hz, 1H, rotamer B), 8.09–8.05
(m, 1H, rotamer A + rotamer B), 7.49 (d, 3J = 8.5 Hz, 1H, rotamer A), 7.46 (d, 3J = 8.5 Hz, 1H, rotamer B), 3.48 (s, 3H, rotamer B), 3.33 (s, 3H,
rotamer A), 2.40 (s, 3H, rotamer A), 2.36 (s, 3H, rotamer B).13C{1H} NMR (CDCl3, 100 MHz) Î´
149.4 (rotamer B), 148.8 (rotamer A), 147.1 (rotamer A), 147.0 (rotamer
B), 144.0 (rotamer A), 143.3 (rotamer B), 142.5 (rotamer A), 142.1
(rotamer B), 132.3 (rotamer A), 132.2 (rotamer B), 123.9 (rotamer
A), 123.5 (rotamer A), 123.4 (rotamer B), 122.3 (rotamer B), 41.4
(rotamer B), 39.1 (rotamer A), 17.9 (rotamer B), 17.8 (rotamer A).
FTIR (ATR/νmax) 2923–2852, 1733, 1520, 1480,
1347, 1325, 1270, 1253 cm–1.</p><!><p>Following the general procedure 2, 13 (1.20 g, 6.67 mmol) was treated with triphosgene (3.95
g, 13.30 mmol), aliquat 336 (1.32 g, 3.33 mmol), and triethylamine
(1.86 mL, 13.30 mmol) to provide 6 (1.20 g, 74% yield)
as a white solid with an 87:13 mixture of rotamers A/B after silica-gel
column chromatography (10% EtOAc/hexane). Mp 64–66 °C. 1H NMR (CDCl3, 400 MHz) δ 7.88 (d, 3J = 8.5 Hz, 1H, rotamer A), 7.84 (d, 3J = 8.5 Hz, 1H rotamer B), 7.30 (d, 3J = 8.5 Hz, 1H, rotamer A + rotamer B), 3.38 (s,
3H, rotamer B), 3.26 (s, 3H, rotamer A), 2.45 (s, 3H, rotamer A),
2.44 (s, 3H, rotamer B), 2.36 (s, 3H, rotamer A), 2.34 (s, 3H, rotamer
B). 13C{1H} NMR (CDCl3, 100 MHz)
Î´ 151.5, 146.4, 131.7, 130.5, 122.2, 121.1, 40.0, 37.5, 18.3,
14.2. Anal. calcd for C10H11ClN2O3: C, 49.50; H, 4.57; N, 11.54. found: C, 49.38; H, 4.40; N,
11.38.</p><!><p>Following the general procedure 2, 14 (0.55 g, 2.84 mmol) was treated with triphosgene (1.68
g, 5.67 mmol), aliquat 336 (0.56 g, 1.42 mmol), and triethylamine
(0.79 mL, 5.67 mmol) to provide 7 (0.97 g, 72% yield)
as a colorless oil with an 88:12 mixture of rotamers A/B after silica-gel
column chromatography (10% EtOAc/hexane). 1H NMR (CDCl3, 400 MHz) Î´ 7.09 (s, 1H, rotamer A), 7.07 (s, 1H, rotamer
B), 3.35 (s, 3H, rotamer B), 3.23 (s, 3H, rotamer A), 2.30 (s, 3H,
rotamer A), 2.28 (s, 3H, rotamer A), 2.27 (s, 3H, rotamer B), 2.26
(s, 3H, rotamer B), 2.19 (s, 3H, rotamer A), 2.17 (s, 3H, rotamer
B). 13C{1H} NMR (CDCl3, 100 MHz)
Î´ 150.9, 149.4, 139.3, 138.4, 137.5, 131.3, 130.2, 129.9, 128.0,
40.1, 37.6, 17.7, 17.4, 12.9. FTIR (ATR/Î½max) 2931,
1734, 1524, 1477, 1415, 1366, 1350, 1330, 1304, 1219, 1119, 1058,
1015 cm–1. Anal. calcd for C11H13ClN2O3: C, 51.47; H, 5.10; N, 10.91. Found:
C, 51.48; H, 5.11; N, 10.78.</p><!><p>Following
the general procedure
2, N-methylaniline (0.77 g, 7.19 mmol) was treated
with triphosgene (4.27 g, 14.40 mmol), aliquat 336 (1.00 g, 2.53 mmol),
and triethylamine (2 mL, 14.4 mmol) to provide 8 (0.91
g, 84% yield) as a white solid after silica-gel column chromatography
(10% EtOAc/hexane) followed by a recrystallization from hexane. Mp
88–90 °C. 1H NMR (CDCl3, 400 MHz)
δ 7.50–7.32 (m, 3H), 7.32–7.18 (m, 2H), 3.35 (br.
s, 3H). 13C{1H} NMR (CDCl3, 100 MHz)
Î´ 149.2, 143.3, 129.6, 128.5, 127.4, 40.4. FTIR (ATR/Î½max) 2942, 1727, 1598, 2587, 1497, 1454, 1418, 1360, 1329,
1263, 1160, 1113, 1071, 1034, 1018 cm–1.</p><!><p>Following the general procedure
2, N-methyl-2,4,6-trimethylaniline (1.0 g, 6.70 mmol)
was treated with triphosgene (3.98 g, 13.40 mmol), aliquat 336 (1.65
g, 3.34 mmol), and triethylamine (1.9 mL, 13.62 mmol) to provide 9 (1.10 g, 50% yield) as a white solid with a 90:10 mixture
of rotamers A/B after silica-gel column chromatography (10% EtOAc/hexane)
followed by a recrystallization from hexane. Mp 73–75 °C. 1H NMR (CDCl3, 400 MHz) δ 6.94 (m, 2H rotamer
A), 6.92 (m, 2H, rotamer B), 3.34 (s, 3H, rotamer B), 3.23 (s, 3H,
rotamer A), 2.30 (s, 3H, rotamer A), 2.27 (s, 3H rotamer B), 2.22
(s, 6H, rotamer A + rotamer B). 13C{1H} NMR
(CDCl3, 100 MHz) Î´ 150.0, 138.6, 138.4, 135.2, 129.5,
37.6, 21.0, 17.5. FTIR (ATR/Î½max) 2920, 1727, 1483,
1409, 1379, 1354, 1333, 1302, 1248, 1169, 1100, 1035, 1011 cm–1.</p><!><p>Carbamoyl chloride (1
equiv), 2-(diphenylphosphino)ethanol
(1 equiv), 4-dimethylaminopyridine (0.1 equiv), and triethylamine
(2 equiv) were dissolved in THF (20 mL), and the solution was heated
(using an aluminum heating block) under reflux overnight. The solvent
was removed in vacuo, and the crude product was purified
via column chromatography.</p><!><p>Following
the general procedure 3, 1 (0.30 g, 1.40 mmol) was treated
with 2-(diphenylphosphino)ethanol (0.32 g, 1.40 mmol), 4-dimethylaminopyridine
(0.018 g, 0.14 mmol), and triethylamine (0.38 mL, 2.80 mmol) to provide 15 (0.40 g, 73%) as a pale yellow oil after silica-gel column
chromatography (hexane/EtOAc 75/25). 1H NMR (CDCl3, 400 MHz) δ 8.18 (2H, AA′XX′), 7.48–7.38
(m, 6H), 7.38–7.28 (m, 6H), 4.35 (dt, J =
9.5, 7.0 Hz, 2H), 3.25 (s, 3H), 2.48 (t, J = 7.0
Hz, 2H). 13C{1H} NMR (CDCl3, 100
MHz) Î´ 154.5, 148.8, 144.3, 137.6 (d, 1JCP = 12.0 Hz), 132.6 (d, 2JCP = 19.0 Hz), 128.9, 128.6 (d, 3JCP = 7.0 Hz), 124.4, 124.2, 64.2 (d, 2JCP = 23.3 Hz), 36.8, 28.1 (d, 1JCP = 14.4 Hz). 31P{1H}
NMR (CDCl3, 162 MHz) −22.27. FTIR (ATR/νmax) 3051–2954, 1705, 1593, 1513, 1498, 1433, 1325,
1254, 1151, 1103 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C22H22N2O4P 409.1312; found 409.1304.</p><!><p>Following the general procedure 3, 2 (0.30 g, 1.31 mmol) was treated with 2-(diphenylphosphino)ethanol
(0.30 g, 1.31 mmol), 4-dimethylaminopyridine (0.016 g, 0.13 mmol),
and triethylamine (0.37 mL, 2.62 mmol) to provide 16 (0.38
g, 69%) as a colorless oil after silica-gel column chromatography
(hexane/EtOAc 75/25). 1H NMR (CDCl3, 400 MHz)
δ 8.18–7.95 (m, 2H rotamer A + rotamer B), 7.55–7.15
(m, 11H, rotamer A + rotamer B), 4.44–4.29 (m, 2H, rotamer
B), 4.29–4.11 (m, 2H, rotamer A), 3.20 (s, 3H, rotamer A),
3.06 (s, 3H, rotamer B), 2.59–2.18 (m, 5H, rotamer A + rotamer
B). 13C{1H} NMR (CDCl3, 100 MHz)
δ 154.9, 147.5, 146.7, 137.7, 132.6 (d, 1Jcp =18.5 Hz), 129.1–128.1 (m, 7C), 126.2,
122.2, 63.9 (d, 2J = 25.0 Hz), 37.2, 28.2
(d, 1Jcp = 15.0 Hz), 18.0 (br.). 31P{1H} NMR (CDCl3, 162 MHz) Î´
−22.08 (rotamer B), −22.80 (rotamer A). FTIR (ATR/νmax) 3070–2925, 1704, 1586, 1520, 1492, 1433, 1345,
1154, 1086 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C23H24O4N2P 423.14468; found 423.1459.</p><!><p>Following the general procedure 3, 3 (0.30 g, 1.24 mmol) was treated with 2-(diphenylphosphino)ethanol
(0.29 g, 1.24 mmol), 4-dimethylaminopyridine (0.015 g, 0.12 mmol),
and triethylamine (0.35 mL, 2.48 mmol) to provide 17 (0.37
g, 68%) as a colorless oil after silica-gel column chromatography
(hexane/CH2Cl2 1/1 → hexane/EtOAc 75/25). 1H NMR (CDCl3, 400 MHz) δ 7.95 (s, 2H, rotamer
B), 7.91 (s, 2H rotamer A), 7.52–7.27 (m, 10H, rotamer A +
rotamer B), 4.36 (dt, J = 9.5, 7.5 Hz, 2H, rotamer
B), 4.18 (m, 2H, rotamer A), 3.13 (s, 3H, rotamer A), 2.99 (s, 3H,
rotamer B), 2.53 (t, 2J = 7.5 Hz, 2H,
rotamer B), 2.33–2.24 (m, 8H rotamer A + rotamer B). 13C{1H} NMR (CDCl3, 100 MHz) δ 155.1 (rotamer
A), 154.5 (rotamer B), 146.7 (rotamer B), 146.6 (rotamer A), 146.5
(rotamer B), 146.0 (rotamer A), 138.2 (rotamer B), 137.9 (rotamer
A), 137.8 (d, 1Jcp = 12.0 Hz,
rotamer B), 137.7 (d, 1Jcp =
12.5 Hz, rotamer A), 132.8 (d, 2Jcp = 19.0 Hz, rotamer B), 132.6 (d, 2Jcp = 19.0 Hz, rotamer A), 129.0 (rotamer B), 128.9 (rotamer
A), 128.7 (d, 3Jcp = 7.0 Hz,
rotamer B), 128.6 (d, 3Jcp =
7.0 Hz, rotamer A), 123.7 (rotamer B), 123.6 (rotamer A), 63.9 (d, 2Jcp = 25.5 Hz, rotamer A), 63.8
(d, 2Jcp = 24.0 Hz, rotamer
B), 35.6 (rotamer B), 35.4 (rotamer A), 28.5 (d, 1Jcp = 14.5 Hz, rotamer B), 28.3 (d, 1Jcp = 15.0 Hz, rotamer A), 18.2 (rotamer
A and rotamer B). 31P{1H} NMR (CDCl3, 162 MHz) δ −22.17 (rotamer B), −22.99 (rotamer
A). FTIR (ATR/νmax) 2923–2852, 2361, 1702,
1591, 1520, 1478, 1433, 1389, 1345, 1298, 1153, 1090 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C24H26O4N2P 437.162; found 437.1621.</p><!><p>Following the general procedure 3, 4 (0.30 g, 1.40 mmol) was treated with 2-(diphenylphosphino)ethanol
(0.32 g, 1.40 mmol), 4-dimethylaminopyridine (0.018 g, 0.14 mmol),
and triethylamine (0.38 mL, 2.80 mmol) to provide 18 (0.40
g, 73%) as a colorless oil after silica-gel column chromatography
(hexane/CH2Cl2 1/1 → hexane/EtOAc 75/25). 1H NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 8.03
(d, J = 8.0 Hz, 1H), 7.61 (d, J =
8.0 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.42 (m, 4H),
7.33 (m, 6H), 4.34 (q, 3J = 7.0 Hz, 2H),
3.24 (s, 3H), 2.46 (t, 2J = 7.0 Hz, 2H). 13C{1H} NMR (CDCl3, 100 MHz) Î´
154.9, 148.5, 144.3, 137.7 (d, 1JCP = 12.1 Hz), 132.8 (d, 2JCP = 19.0 Hz), 131.3, 129.5, 129.0, 128.7 (d, 3JCP = 6.9 Hz), 120.4, 120.0, 64.2 (d, 2JCP = 23.4 Hz), 37.2, 28.2 (d, 1JCP = 14.3 Hz). 31P{1H} NMR (CDCl3, 162 MHz) δ −22.3. FTIR (ATR/νmax) 3071–2954, 1702, 1526, 1481, 1433, 1386, 1342,
1261, 1154, 1126 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C22H22N2O4P 409.1312; found 409.1312.</p><!><p>Following the general procedure 3, 5 (0.32 g, 1.40 mmol) was treated with 2-(diphenylphosphino)ethanol
(0.32 g, 1.40 mmol), 4-dimethylaminopyridine (0.018 g, 0.14 mmol),
and triethylamine (0.38 mL, 2.80 mmol) to provide 19 (0.18
g, 30%) as a colorless oil with a 65:35 mixture of rotamers A/B after
silica-gel column chromatography (hexane/acetone 95/5). 1H NMR (CDCl3, 400 MHz) Î´ 8.04 (app. d, 3J = 8.5 Hz, 1H, rotamer A + rotamer B), 7.99 (s,
1H, rotamer B), 7.94 (s, 1H, rotamer A), 7.59–7.27 (m, 10H,
rotamer A + rotamer B), 4.38 (br. s, 2H, rotamer B), 4.28–4.10
(m, 2H, rotamer A), 3.21 (s, 3H, rotamer A), 3.06 (s, 3H, rotamer
B), 2.54 (br. s, 2H, rotamer B), 2.30 (br. s, 2H, rotamer A), 2.30
(s, 3H, rotamer A + rotamer B). 13C{1H} NMR
(CDCl3, 100 MHz) Î´ 155.2 (rotamer A), 155.0 (rotamer
B), 146.9 (rotamer A + rotamer B), 144.3 (rotamer B), 143.1 (rotamer
A), 143.0 (rotamer B), 142.5 (rotamer A), 138.0–137.5 (m, rotamer
A + rotamer B), 133.1–132.4 (m, rotamer A + rotamer B), 131.8
(rotamer B), 131.7 (rotamer A), 128.8 (d, 2Jcp = 22.5 Hz, rotamer A + rotamer B), 128.6 (rotamer A
+ rotamer B), 123.1 (rotamer A + rotamer B), 122.5 (br. s, rotamer
A + rotamer B), 64.0 (d, 2Jcp = 25.5 Hz, rotamer A + rotamer B), 37.4 (rotamer A), 37.3 (rotamer
B), 28.4 (d, 1Jcp = 15.0 Hz,
rotamer B), 28.3 (d, 1Jcp =
14.5 Hz, rotamer A), 18.1 (rotamer A + rotamer B). 31P{1H} NMR (CDCl3, 162 MHz) δ −21.8 (rotamer
B), −23.1 (rotamer A). FTIR(ATR/νmax) 3071–2954,
1702, 1519, 1433, 1340, 1153, 1123 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C23H24N2O4P 423.1468; found
423.1463.</p><!><p>Following the general procedure 3, 6 (0.34 g, 1.40 mmol) was treated with 2-(diphenylphosphino)ethanol
(0.32 g, 1.40 mmol), 4-dimethylaminopyridine (0.018 g,
0.14 mmol), and triethylamine (0.38 mL, 2.80 mmol) to provide 20 (0.10 g, 33%) as a colorless oil with a 72:28 mixture of
rotamers A/B after silica-gel column chromatography (hexane/acetone
95/5). 1H NMR (CDCl3, 400 MHz) Î´ 7.77
(app. d, J = 8.5 Hz, 1H, rotamer A + rotamer B),
7.54–7.27 (m, 10H, rotamer A + rotamer B), 7.21 (app. d, J = 8.5 Hz, 1H rotamer B), 7.20 (app. d, 3J = 8.5 Hz, 1H, rotamer A), 4.38 (dt, 3JHP = 8.5 Hz, 3J =
7.5 Hz, 2H, rotamer B), 4.23–4.13 (m, 2H, rotamer A), 3.14
(s, 3H rotamer A), 3.00 (s, 3H, rotamer B), 2.55 (t, J = 7.5 Hz, 2H, rotamer B), 2.34–2.29 (m, 2H, rotamer A), 2.28
(s, 3H, rotamer A), 2.27 (s, 3H, rotamer B). 13C{1H} NMR (CDCl3, 100 MHz) Î´ 155.3 (rotamer A), 154.7
(rotamer B), 149.1 (rotamer B), 149.0 (rotamer A), 142.6 (rotamer
B), 142.4 (rotamer B), 142.3 (rotamer A), 141.9 (rotamer A), 141.3
(rotamer A), 137.85 (d, 1Jcp = 12.5 Hz, rotamer B, Ph′ or Ph″), 137.84 (d, 1Jcp = 12.5 Hz, rotamer B, Ph′
or Ph″), 137.66 (d, 1Jcp = 12.5 Hz, rotamer A, Ph″), 137.64 (d, 1Jcp = 12.5 Hz, rotamer A, Ph′), 132.74
(d, 2Jcp = 18.0 Hz, rotamer
B, Ph′ or Ph″), 132.72 (d, 2Jcp = 18.5 Hz, rotamer B, Ph′ or Ph″), 132.60
(d, 2Jcp = 18.5 Hz, rotamer
A, Ph″), 132.56 (d, 2Jcp = 18.5 Hz, rotamer A, Ph′), 132.0 (rotamer B), 131.7 (rotamer
A), 128.9 (rotamer B), 128.8 (rotamer A), 128.74 (d, 3Jcp = 6.0 Hz, rotamer B), 128.70 (d, 3Jcp = 7.5 Hz, rotamer A), 128.5 (rotamer
A + rotamer B), 123.8 (rotamer B), 123.7 (rotamer A), 63.7 (d, 3Jcp = 26.0 Hz, rotamer A), 63.6
(d, 3Jcp = 23.0 Hz, rotamer
B), 35.8 (rotamer B), 35.7 (rotamer A), 28.4 (d, 3Jcp = 14.5 Hz, rotamer B), 28.3 (d, 3Jcp = 15.0 Hz, rotamer A), 18.43 (rotamer
A), 18.40 (rotamer B), 14.3 (rotamer A + rotamer B). 31P{1H} NMR (CDCl3, 162 MHz) δ −22.15
(rotamer B), −23.37 (rotamer A). FTIR (ATR/νmax) 3081–2932, 1724, 1586, 1529, 1513, 1491, 1422, 1344, 1304,
1252, 1113, 1085 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C24H26N2O4P 437.1625; found 437.1624.
As an example of signal NMR assignment for these self-immolative systems,
further NMR analyses were carried out for 20 (see Figures S44–S51).</p><!><p>Following the general procedure 3, 7 (0.36 g, 0.82 mmol) was treated with 2-(diphenylphosphino)ethanol
(0.32 g, 1.40 mmol), 4-dimethylaminopyridine (0.018 g, 0.14 mmol),
and triethylamine (0.38 mL, 2.80 mmol) to provide 21 (0.11
g, 30%) as a colorless oil with a 74:26 mixture of rotamers A/B after
silica-gel column chromatography (hexane/acetone 95/5). 1H NMR (CDCl3, 400 MHz) δ 7.50–7.27 (m, 10H,
rotamer A + rotamer B), 7.01 (s, 1H, rotamer B), 6.99 (s, 1H, rotamer
A), 4.35 (dt, 2H, 3JHP = 9.5
Hz, 3J = 7.5 Hz rotamer B), 4.16 (AA′BB′,
2H, rotamer A), 3.11 (s, 3H, rotamer A), 2.97 (s, 3H, rotamer B),
2.52 (app. t, 3J = 8.0 Hz, 3H rotamer
B), 2.31 (app. t, 3J = 8.0 Hz, 2H, rotamer
A), 2.27 (s, 3H, rotamer A), 2.26 (s, 3H, rotamer B), 2.19 (s, 3H,
rotamer A + rotamer B), 2.12 (s, 3H, rotamer A), 2.11 (s, 3H, rotamer
B). 13C{1H} NMR (CDCl3, 100 MHz)
Î´ 155.5 (rotamer A), 154.9 (rotamer B), 151.0 (rotamer B), 150.9
(rotamer A), 139.6 (rotamer B), 139.1 (rotamer A), 138.8 (rotamer
B), 138.6 (rotamer A), 137.90 (d, 1Jcp = 12.0 Hz, rotamer B, Ph′ or Ph″), 137.87
(d, 1Jcp = 12.0 Hz, rotamer
B, Ph′ or Ph″), 137.72 (d, 1Jcp = 12.0 Hz, rotamer A, Ph′ or Ph″), 137.68
(d, 1Jcp = 12.0 Hz, rotamer
A, Ph′ or Ph″), 132.85 (d, 2JCP = 18.0 Hz, rotamer B, Ph′ or Ph″), 132.82
(d, 2JCP = 19.0 Hz, rotamer
B, Ph′ or Ph″), 132.77 (d, 2Jcp = 18.0 Hz, rotamer A, Ph″), 132.69 (d, 2Jcp = 18.5 Hz, rotamer A, Ph′),
131.0 (rotamer B), 130.9 (rotamer A), 129.0–128.5 (m, 7C),
128.3 (rotamer B), 128.0 (rotamer A), 63.74 (d, 2Jcp = 25.5 Hz, rotamer A), 63.68 (d, 2Jcp = 24.0 Hz, rotamer B), 36.0 (rotamer
B), 35.9 (rotamer A), 29.2 (d, 1Jcp = 14.5 Hz, rotamer B), 28.4 (d, 1Jcp = 15.0 Hz, rotamer A), 18.0 (rotamer A), 17.9 (rotamer
B), 17.5 (rotamer A), 17.4 (rotamer B), 13.1 (rotamer A + rotamer
B). 31P{1H} NMR (CDCl3, 162 MHz)
δ −22.1 (rotamer B), −23.3 (rotamer A). FTIR (ATR/νmax) 3054–2932, 1702, 1524, 1480, 1454, 1433, 1388,
1345, 1311, 1284, 1220, 1152, 1124, 1095, 1027 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C25H28N2O4P 451.1781; found 451.1766.</p><!><p>Following the general procedure 3, 8 (0.24 g, 1.40 mmol) was treated with 2-(diphenylphosphino)ethanol
(0.32 g, 1.40 mmol), 4-dimethylaminopyridine (0.018 g, 0.14 mmol),
and triethylamine (0.38 mL, 2.80 mmol) to provide 22 (0.30
g, 59%) as a white solid after silica-gel column chromatography (hexane/EtOAc
95/5 → 90/10) followed by crystallization via vapor diffusion
using a mixture of n-hexane and ethyl acetate to
obtain colorless single crystals. Mp 53–55 °C. 1H NMR (CDCl3, 400 MHz) δ 7.47–7.37 (m, 4H),
7.37–7.29 (m, 8H), 7.25–7.17 (m, 3H), 4.27 (q, J = 7.5 Hz, 2H), 3.22 (s, 3H), 2.44 (t, J = 7.5 Hz, 2H). 13C{1H} NMR (CDCl3, 100 MHz) δ 155.5, 143.3, 137.9 (d, 1JCP = 12.2 Hz), 132.8 (d, 2JCP = 18.9 Hz), 128.9 (×2), 128.7 (d, 3JCP = 6.7 Hz), 126.1, 125.8, 63.5 (d, 2JCP = 25.0 Hz), 37.7, 28.4 (d, 1JCP = 14.0 Hz). 31P{1H} NMR (CDCl3, 162 MHz) δ −22.5. FTIR
(ATR/νmax) 3066–2961, 1688, 1595, 1493, 1451,
1433, 1393, 1351, 1307, 1295, 1283, 1151, 1040 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C22H23NO2P 364.1461;
found 364.1458.</p><!><p>Following the general procedure 3, 9 (0.26 g, 1.40 mmol) was treated with 2-(diphenylphosphino)ethanol
(0.32 g, 1.40 mmol), 4-dimethylaminopyridine (0.018 g, 0.14 mmol),
and triethylamine (0.38 mL, 2.80 mmol) to provide 23 (0.20
g, 35%) as a white solid after silica-gel column chromatography (hexane/acetone
95/5) followed by crystallization via vapor diffusion using a mixture
of n-hexane and ethyl acetate to obtain colorless
single crystals. Mp 93–95 °C. 1H NMR (CDCl3, 400 MHz) δ 7.53–7.23 (m, 10H, rotamer A + rotamer
B), 6.88 (s, 2H, rotamer A + rotamer B), 4.33 (AA′BB′,
2H, rotamer B), 4.15 (AA′BB′, 2H, rotamer A), 3.11 (s,
3H, rotamer A), 2.98 (s, 3H, rotamer B), 2.52 (AA′BB′,
2H, rotamer B), 2.33 (AA′BB′, 2H, rotamer A), 2.28 (s,
3H, rotamer A), 2.26 (s, 3H, rotamer B), 2.14 (s, 6H, rotamer A +
rotamer B). 13C{1H} NMR (CDCl3, 100
MHz) Î´ 156.0 (rotamer A) 155.0 (rotamer A), 138.2 (rotamer A
+ rotamer B), 137.9 (d, 1Jcp = 12.5 Hz, rotamer A), 137.7 (d, 1Jcp = 12.5 Hz, rotamer B), 137.7 (rotamer A), 137.1 (br. s,
rotamer A + rotamer B), 135.4 (rotamer B), 135.3 (rotamer A), 132.8
(d, 2Jcp = 19.0 Hz, rotamer
B), 132.7 (d, 2Jcp = 19.0 Hz,
rotamer A), 129.3 (rotamer B), 129.1 (rotamer A), 128.8 (rotamer B),
128.7 (rotamer A), 128.6 (d, 3Jcp = 7.0 Hz, rotamer B), 128.5 (d, 3Jcp = 6.5 Hz, rotamer A), 63.3 (d, 2Jcp = 28.0 Hz, rotamer A), 63.2 (d, 2Jcp = 23.0 Hz, rotamer B), 35.99 (rotamer B),
35.97 (rotamer A), 28.5 (d, 1Jcp = 14.5 Hz, rotamer B), 28.3 (d, 1Jcp = 14.5 Hz, rotamer A), 21.11 (rotamer A), 21.06 (rotamer
B), 17.75 (rotamer A), 17.72 (rotamer B). 31P{1H} NMR (CDCl3, 162 MHz) δ −22.0 (rotamer
B), −23.1 (rotamer A). FTIR (ATR/νmax) 3049–2915,
1707, 1655, 1584, 1483, 1454, 1432, 1390, 1348, 1308, 1277, 1217,
1172, 1148, 1097, 1070, 1027 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C25H29NO2P 406.1924; found 406.1930.</p><!><p>Sodium hydride
(NaH, 60% dispersion in mineral oil, 1.1 equiv) was added to a solution
of 2-naphthalenemethanol (1 equiv) in anhydrous DMF (10 mL) at 0 °C
and left to stir for 15 min. Carbamoyl chloride (1 equiv) was added,
and the mixture was left to stir overnight. The salts formed were
filtered off, and volatiles were removed in vacuo. The crude product was further purified by column chromatography,
followed by recrystallization via vapor diffusion using a mixture
of n-hexane and ethyl acetate to obtain colorless
single crystals.</p><!><p>Following the general procedure 4, 2-naphthalenemethanol
(0.122 g, 0.77 mmol) was treated with NaH (0.034 g, 0.85 mmol) and 1 (0.166, 0.77 mmol) to provide 24 (0.200 g,
77%) as a white solid after silica-gel column chromatography (hexane/EtOAc
75/25). Mp 109–111 °C. 1H NMR (CDCl3, 400 MHz) δ 8.21 (d, J = 9.0 Hz, 2H), 7.88–7.80
(m, 4H), 7.67–7.34 (m, 5H), 5.38 (s, 2H), 3.42 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ
154.8, 149.0, 144.6, 133.31, 133.28, 128.6, 128.1, 127.9, 127.7, 126.6,
125.9, 124.7, 124.4, 68.5, 37.2. FTIR (ATR/Î½max)
3057–2963, 1709, 1602, 1590, 1512, 1442, 1329, 1257, 1160,
1104 cm–1. HRMS (ESI) m/z: [M + Na]+ calcd for C19H16O4N2Na 359.1002; found 359.0999.</p><!><p>Following the general procedure 4, 2-naphthalenemethanol
(0.122 g, 0.77 mmol) was treated with NaH (0.034 g, 0.85 mmol) and 2 (0.176 g, 0.77 mmol) to provide 25 (0.197 g,
73%) as an off-white solid after silica-gel column chromatography
(hexane/EtOAc 75/25). Mp 99–101 °C. 1H NMR
(CDCl3, 400 MHz) Î´ 8.08 (br. s, 1H, rotamer A + rotamer
B), 8.09–8.04 (m, 1H, rotamer A + rotamer B), 7.90–7.71
(m, 3H, rotamer A + rotamer B), 7.63 (br. s, 1H, rotamer A + rotamer
B), 7.55–7.44 (m, 2H, rotamer A + rotamer B), 7.38–7.27
(m, 2H, rotamer A + rotamer B), 5.43–5.18 (m, 2H, rotamer A
+ rotamer B), 3.24 (br. s, 3H, rotamer A + rotamer B), 2.32 (s, 3H,
rotamer B), 2.24 (s, 3H, rotamer A). 13C{1H}
NMR (CDCl3, 100 MHz) Î´ 154.8, 147.4, 146.6, 137.7,
133.5, 133.0, 128.4, 128.3, 127.9, 127.7, 127.4, 127.1, 126.3, 126.3,
126.0, 125.8, 125.5, 122.2, 67.9, 37.3, 17.9. FTIR (ATR/νmax) 3070–2956, 1698, 1582, 1514, 1431, 1304, 1155,
1088 cm–1. HRMS (ESI) m/z: [M + Na]+ calcd for C20H18O4N2Na 373.1159; found 373.1155.</p><!><p>Following the general procedure 4, 2-naphthalenemethanol
(0.100 g, 0.63 mmol) was treated with NaH (0.028 g, 0.70 mmol) and 3 (0.153 g, 0.63 mmol) to provide 26 (0.178 g,
77%) as an off-white solid after silica-gel column chromatography
(hexane/EtOAc 75/25). Mp 87–89 °C. 1H NMR (CDCl3, 400 MHz) δ 7.97 (s, 2H, rotamer B), 7.95 (s, 2H, rotamer
A), 7.91–7.84 (m, 1H, rotamer A + rotamer B), 7.82–7.79
(m, 1H, rotamer A + rotamer B), 7.77 (app. d, J =
8.0 Hz, 1H, rotamer A + rotamer B), 7.74–7.72 (m, 1H, rotamer
A + rotamer B), 7.62 (s, 1H, rotamer A), 7.55 (s, 1H, rotamer B),
7.54–7.44 (m, 2H, rotamer A + rotamer B), 7.28–7.23
(m, 1H, rotamer A + rotamer B), 5.40 (s, 2H, rotamer B), 5.25 (s,
2H, rotamer A), 3.18 (s, 3H, rotamer B), 3.15 (s, 3H, rotamer A),
2.30 (s, 6H, rotamer B), 2.22 (s, 6H, rotamer A). 13C{1H} NMR (CDCl3, 100 MHz) Î´ 155.0, 154.6, 146.7,
146.1, 138.2, 138.0, 133.7, 133.3, 133.2, 133.2, 128.6, 128.4, 128.1,
128.1, 127.9, 127.8, 127.4, 127.2, 126.5, 126.5, 126.4, 126.4, 125.9,
125.7, 123.7, 123.6, 68.0, 67.8, 35.8, 35.4, 18.1. FTIR (ATR/νmax) 3052–2928, 1693, 1602, 1518, 1479, 1435, 1303,
1168, 1088 cm–1. HRMS (ESI) m/z: [M + Na]+ calcd for C21H20O4N2Na 387.1315; found 387.1316.</p><!><p>Following the general procedure 4, 2-naphthalenemethanol
(0.122 g, 0.77 mmol) was treated with NaH (0.034 g, 0.85 mmol) and 4 (0.166 g, 0.77 mmol) to provide 27 (0.160 g,
62%) as a white solid after silica-gel column chromatography (hexane/EtOAc
75/25). Mp 85–87 °C. 1H NMR (CDCl3, 400 MHz) δ 8.19 (app. t, J = 2.0 Hz, 1H),
8.06 (dd, J = 8.0, 2.0 Hz, 1H), 7.87–7.78
(m, 4H), 7.65 (d, J = 8.0 Hz, 1H), 7.54–7.41
(m, 4H), 5.36 (s, 2H), 3.41 (s, 3H). 13C{1H}
NMR (CDCl3, 100 MHz) Î´ 155.1, 148.6, 144.4, 133.4,
133.3, 131.3, 129.6, 128.6, 128.2, 127.9, 127.5, 126.5, 126.5, 125.9,
120.6, 120.3, 68.3, 37.5. FTIR (ATR/νmax) 3090–2925,
1703, 1615, 1579, 1528, 1486, 1443, 1348, 1336, 1251, 1169, 1122,
1026 cm–1. HRMS (ESI) m/z: [M + Na]+ calcd for C19H16O4N2Na 359.1002; found 359.0998.</p><!><p>Following the general procedure 4, 2-naphthalenemethanol
(0.122 g, 0.77 mmol) was treated with NaH (0.034 g, 0.85 mmol) and 8 (0.131 g, 0.77 mmol) to provide 28 (0.180 g,
80%) as a white solid after silica-gel column chromatography (hexane/EtOAc
75/25). Mp 93–95 °C. 1H NMR (CDCl3, 400 MHz) δ 7.84–7.70 (m, 4H), 7.50–7.45 (m,
2H), 7.44–7.39 (m, 1H), 7.39–7.32 (m, 2H), 7.25–7.19
(m, 3H), 5.32 (s, 2H), 3.34 (s, 3H). 13C{1H}
NMR (CDCl3, 100 MHz) Î´ 155.6, 143.4, 134.2, 133.3,
133.1, 129.0, 128.3, 128.1, 127.8, 126.9 (br. s), 126.3 (br. s), 126.2,
126.0 (br. s), 125.7, 67.5, 38.0. FTIR (ATR/Î½max)
3060–2946, 1697, 1597, 1438, 1397, 1362, 1337, 1261, 1180,
1119 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C19H18O2N 292.1332; found 292.1332.</p><!><p>1H NMR spectroscopic
studies were conducted by dissolution of the various disclosure systems
(15–23) in MeCN-d3 (0.5 mL, [disclosure system]0 = 0.025 mol·L–1), followed by the addition of 10 molar equiv of benzyl
bromide (BnBr) directly to the NMR tube. The 1H NMR spectra
were recorded at regular time intervals. The area of the singlet resonance CH3N of 15–23 was standardized to the area of the MeCN solvent resonance
at 1.94 ppm and was used to calculate the percentage of disclosure
system that remained nonalkylated over time with respect to the initial
area of the methyl resonance (i.e., before the addition
of the alkylating agent, time point = 0). The same procedure was employed
for the solvent screening of self-immolative system 19.</p><!><p>1H NMR spectroscopic
studies were conducted by addition of 2 molar equiv of N,N-diisopropylethylamine (DIPEA) to the corresponding
alkylated disclosure system (15a–23a) directly to the NMR tube. The percentage of alkylated disclosure
system 15a–23a remaining over time
was calculated by comparison of the integrations of the CH3N or aromatic ortho- aromatic proton
of the reporter moiety prior to β-elimination and standardized
to the area of the MeCN solvent resonance at 1.94 ppm. The same procedure
was employed for the solvent screening of self-immolative system 19a.</p><!><p>1H NMR spectroscopic studies were conducted by addition of
10 molar equiv of benzyl bromide to a solution of the corresponding
self-immolative disclosure system 18–20 (V = 0.5
mL, [disclosure system] = 0.025 mol·L–1) and
2 molar equiv of DIPEA directly to the NMR tube. The 1H
NMR spectra were recorded at regular time intervals. The area of the
singlet CH3N for the
self-immolative disclosure systems 18 and 20, the area of the singlet CHAr for the
self-immolative disclosure system 19, the area of the
multiplet resonance CH2P+ for
the self-immolative alkylated disclosure system 18a–20a as well as the area for the vinyl proton corresponding
to the phosphonium salt 29 were used to calculate the
percentage of the different species remaining over time (i.e., before the addition of BnBr, time point = 0).</p><!><p>1H NMR, 13C NMR, and 31P spectra; calculations of rotational
barriers; and X-ray crystallographic
data of CCDC 1980913 (22), 1962710 (23), 1908144 (24), 1908143 (25), 1908145 (26), 1908146 (27), and 1980598 (28) (PDF)</p><p>jo1c00996_si_001.pdf</p><!><p>CCDC 1908143–1908146, 1962710, 1980598, and 1980913 contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.</p><!><p>The authors declare no
competing financial interest.</p>