The Dark Side of Isocyanides:
Visible-Light Photocatalytic
Activity in the Oxidative Functionalization of C(sp3)–H
Bonds
The possibility to harness aromatic isocyanides as visible-light photocatalysts in the α-amino C(sp3)–H functionalization is herein presented. Actually, the three-component cross-dehydrogenative coupling of aromatic tertiary amines with isocyanides and water leads to amide products under very mild conditions in high yields and with a good substrate scope. While the reaction with aromatic isocyanides proceeds upon direct photoexcitation, aliphatic isocyanides are able to form a photoactive electron–donor–acceptor complex with aromatic amines. Moreover, the use of a catalytic loading of an aromatic isocyanide promotes the oxidative coupling of N-phenyl-1,2,3,4-tetrahydroisoquinoline with an array of different (pro)nucleophiles in good to excellent yields, thus providing the proof-of-concept for the development of a new highly tunable class of organic visible-light photocatalysts.
Introduction<!><!>Introduction<!><!>Introduction<!>Direct
Photoexcitation of Aromatic Isocyanides<!><!>Direct
Photoexcitation of Aromatic Isocyanides<!><!>Reaction of Aliphatic Isocyanides<!><!>Reaction of Aliphatic Isocyanides<!><!>Catalytic Role of Aromatic Isocyanides: Proof-of-Concept<!>Michael-Type
Addition Promoted by Isocyanide 1 as a
Photocatalyst<!>Catalytic Role of Aromatic Isocyanides: Proof-of-Concept<!>Conclusions<!>General Methods<!>General Procedure for the
Preparation of Compounds 2–16<!>N-([1,1′-Biphenyl]-4-yl)-2-(methyl(phenyl)amino)acetamide
(2)<!>N-(4-Chlorophenyl)-2-(methyl(phenyl)amino)acetamide
(3)36<!>2-(Methyl(phenyl)amino)-N-(4-nitrophenyl)acetamide
(4)44<!>N-(3,5-Dimethylphenyl)-2-(methyl(phenyl)amino)acetamide
(5)<!>N-(4-Methoxyphenyl)-2-(methyl(phenyl)amino)acetamide
(6)45<!>N-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-2-(methyl(phenyl)amino)-acetamide
(7)<!>2-(Methyl(phenyl)amino)-N-(naphthalen-1-yl)acetamide
(8)44<!>N-([1,1′-Biphenyl]-3-yl)-2-(methyl(phenyl)amino)acetamide
(9)<!>N-([1,1′-Biphenyl]-2-yl)-2-(methyl(phenyl)amino)acetamide
(10)<!>N-([1,1′-Biphenyl]-4-yl)-2-((4-bromophenyl)(methyl)amino)-acetamide
(11)<!>N-([1,1′-Biphenyl]-4-yl)-2-(methyl(p-tolyl)amino)acetamide (12)<!>N-([1,1′-Biphenyl]-4-yl)-2-(methyl(m-tolyl)amino)acetamide (13)<!>N-([1,1′-Biphenyl]-4-yl)-2-((4-methoxyphenyl)(methyl)-amino)acetamide
(14)<!>N-([1,1′-Biphenyl]-4-yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline-1-carboxamide
(15)<!>N-([1,1′-Biphenyl]-4-yl)-4-phenylmorpholine-3-carboxamide
(16)<!>General Procedure for the
Preparation of Compounds 18, 20–31<!>N-Cyclohexyl-2-(methyl(phenyl)amino)acetamide
(18)36<!>2-(Methyl(phenyl)amino)-N-pentylacetamide (20)45<!>N-Benzyl-2-(methyl(phenyl)amino)acetamide
(21)36<!>N-((Methyl(phenyl)amino)methyl)pivalamide (22)36<!>N-((3s,5s,7s)-Adamantan-1-yl)-2-(methyl(phenyl)amino)acetamide
(23)<!>Ethyl N-Methyl-N-phenylglycylglycinate
(24)36<!>2-(Methyl(phenyl)amino)-N-(tosylmethyl)acetamide
(25)36<!>2-((4-Bromophenyl)(methyl)amino)-N-(tosylmethyl)acetamide
(26)46<!>2-((3-Bromophenyl)(methyl)amino)-N-(tosylmethyl)acetamide
(27)36<!>2-((3,5-Dimethylphenyl)(methyl)amino)-N-(tosylmethyl)-acetamide
(28)36<!>2-((4-Methoxyphenyl)(methyl)amino)-N-(tosylmethyl)-acetamide
(29)45<!>4-Phenyl-N-(tosylmethyl)morpholine-3-carboxamide
(30)<!>2-(Ethyl(phenyl)amino)-N-(tosylmethyl)acetamide
(31)36<!>General Procedure for the Preparation of Compounds 32, 33, and 36<!>Diethyl 2-(2-Phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)malonate
(32)39<!>2-Phenyl-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile
(33)40<!>Dimethyl
(2-Phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phosphonate
(36)42<!>1-(Nitromethyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline
(34)41<!>2-(2-Phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)malononitrile
(35)39<!>
<p>Isocyanides
represent a class of very complex and fascinating compounds,
thanks to their chameleonic electronic properties, which have been
enabling, in the last decades, the development of well-defined and
stimulating research areas.1 Accordingly,
their unique reactivity features have been widely exploited in isocyanide-based
multicomponent reactions2−4 (nucleophile/carbene reactivity, Figure 1a) and in Lewis acid-catalyzed
migratory insertions into nucleophiles5−8 (electrophile reactivity, Figure 1b). Furthermore, their ability
to form complexes with π-electron-releasing transition metals
has been shown as key to promote imidoylative cross couplings, with
isocyanides undergoing 1,1-migratory insertions into either σ-
or π-bonds.9−14 On the other hand, the presence of a lone pair on the (carbenic)
isocyanide carbon atom makes them excellent geminal radical acceptors
in reactions involving the formation of open-shell species (somophile
reactivity, Figure 1c).15−18</p><!><p>Reactivity
modes of isocyanides.</p><!><p>Recently, with the advent
of the visible-light photocatalysis era,19−22 the somophile reactivity has
been investigated in a plethora of
transformations involving intramolecular cyclization of 2-isocyanobiphenyls
and related analogues,16,17,23 as well as in two- or multicomponent reactions leading to amides,
keto-amides, and other interesting molecular scaffolds.24−26 More in detail, these processes involve the formation of an imidoyl
radical intermediate upon the addition of a radical species to isocyanide
(Figure 1c). The imidoyl
radical, depending on the reaction conditions and the species involved,
can meet different fates such as oxidation to nitrilium ions, α-fragmentation
(α-FGM) to give back isocyanide and the radical species, β-fragmentation
(β-FGM) to nitrile (Figure 2a), and intramolecular interception of a radical acceptor
(e.g., phenyl ring in the ortho-position of 2-isocyanobiphenyl, Figure 2b).</p><!><p>Possible reaction pathways
of imidoyl radicals.</p><!><p>While most of the current
literature is based on these reactivity
profiles, mainly triggered by either metal-based or organic visible-light
photocatalysts as well as by thermal initiators (e.g., ditert-butyl peroxide, DTBP; tert-butyl hydroperoxide,
TBHP; and so forth), processes involving the formation of imidoyl
radical anions have been marginally reported (Figure 1d). The latter are indeed considered quite
unstable,27 albeit a recent involvement
of their generation has been accounted upon photoinduced single-electron
transfer (SET) from arylsulfinate anions following the formation of
an EDA complex (EDA: electron donor–acceptor).28</p><p>Following our interest in isocyanide-involving photochemical
reactions,29,30 we wondered whether the exploitation
of such isocyanide radical
anions could lead to developing new useful chemical transformations
proceeding via EDA complex formation.31−35 Accordingly, a screening of possible electron donors
endowed with different redox potentials (i.e., carboxylic and boronic
acids and dimethylaniline, DMA) was performed. Interestingly, the
test reaction of isocyanide 1 with DMA in MeCN at room
temperature and under irradiation with 30 W blue light-emitting diodes
(LEDs), open in air and in the presence of 10 equivalents of water,
led to the formation of amide 2 in 20% yield (Scheme 1).36</p><!><p>Intrigued
by the mechanism underlying its formation and with the aim to gain
information useful to optimize reaction conditions, the UV–vis
absorption spectra of 1, DMA, and a mixture of both were
recorded to check the presence of an EDA complex. While no bathochromic
shift was observed for the mixture of 1 and DMA, we noticed
that the absorption spectrum of 1 was characterized by
two bands with Î»max at 265 and 360 nm (Figure S1, Supporting Information). This observation prompted
us to propose a mechanistic hypothesis entailing a catalytic role
of isocyanide 1 upon its direct photoexcitation with
visible light (Scheme 2).</p><p>More in detail, 1, upon light absorption,
reached
an electronically excited state, thus acting as a photocatalyst: a
SET from DMA to 1* led to the formation of the imidoyl
radical anion 1•– and the radical
cation of dimethylaniline DMA•+. Molecular oxygen
was then able to regenerate isocyanide 1, while forming
a superoxide radical anion O2•–, which abstracted a hydrogen atom from DMA•+,
thus leading to the formation of the iminium ion DMA+.
The latter was then intercepted by the ground-state isocyanide 1, to afford a nitrilium ion I, and eventually,
after the addition of water, the amide 2. Overall, formation
of amide 2 proceeded via a radical/polar crossover pathway.</p><p>Experimental data further supporting this mechanistic hypothesis
were provided by Stern–Volmer quenching of 1 with
increasing amounts of DMA (Figure 3) and by the formation of product 2–18O in the presence of H218O, as detected by means of high-resolution mass
spectrometry (HRMS) analysis of the crude reaction mixture (Figure
S2, Supporting Information). Taken together,
such results provided a rational basis to identify optimum reaction
conditions. Changing the ratio of 1:DMA as well as the
reaction times or the light source did not improve the yield of amide 2 (Table S1, Supporting Information). Therefore, we wondered if the poor yield of 2 could
be ascribed to a very short half-life of imidoyl radical anion 1•–, which would lead to a back-electron
transfer (BET) event to isocyanide 1 and DMA, thus preventing
a quantitative oxidation of DMA to DMA+.</p><!><p>(a) Fluorescence spectra
of 1 in the absence and presence
of DMA (10 equiv) at 25 °C and an excitation wavelength of 265
nm and (b) Stern–Volmer fluorescence quenching of 1* with increasing amounts of DMA at 25 °C and an excitation
wavelength of 360 nm.</p><!><p>In light of these observations,
we reasoned that the use of a σ-electron
acceptor, such as a Lewis acid, could promote the stabilization of
such imidoyl radical anion, thus preventing unproductive BETs. Actually,
the reaction performed in the presence of 30 mol % of Yb(OTf)3 afforded amide 2 in 95% isolated yield.37 While the irradiation with black light did not
change the yield, no product was obtained when the light was carefully
excluded, proving the photocatalytic nature of the transformation.
Other Lewis acids such as silver, lanthanum, and copper triflates
as well as transition metals and different ytterbium sources showed
to have either no or poorer catalytic activity (Table S1, Supporting Information). A further survey of
the minimum amount of Yb(OTf)3 required to get optimum
yields revealed that a 10 mol % equivalent was effective with a reaction
time of 20 h. A tentative scaling up to 0.25 and 0.8 mmol afforded
41 and 23% yields, respectively, with a recovery of about 50% of the
starting isocyanide. Interestingly, the use of 30 W blue LEDs was
crucial to the transformation, as when the reaction was performed
under irradiation with 1 W blue LEDs, only traces of 2 could be detected.</p><p>With the optimized conditions in hand,
the substrate scope of both
aromatic isocyanides and amines was investigated. As shown in Figure 4, both electron-poor
(3, 4) and electron-rich isocyanides (5–7) gave excellent yields, with the para- and meta-substitution patterns not
affecting the formation of the desired products. Interestingly, even ortho-isocyanobiphenyl, usually reacting intramolecularly
when involved in the formation of imidoyl radical intermediates, gave
the linear amide 10 in 94% yield, thus supporting the
radical/polar crossover mechanistic hypothesis. As for the amine partners,
both electron-poor (11) and electron-rich (12–14) N,N-dimethylanilines
were competent starting materials, as well as cyclic tertiary aromatic
amines (15 and 16). Heteroaromatic dimethylanilines,
such as N,N-dimethyl aminopyridine,
as well as N-methyldiphenylamine, secondary anilines,
tertiary aliphatic amines, and amides, were all unsuccessful substrates.
These results were in accordance with related existing reactions.38</p><!><p>Substrate scope for aromatic isocyanides and amines [awithout Yb(OTf)3; b5 d; c48 h; d72 h].</p><!><p>With the aim of further
expanding the isocyanide scope to aliphatic ones and to prove the
ability of aromatic isocyanides to act as photocatalysts, a test reaction
involving cyclohexylisocyanide 17, DMA, a catalytic 20
mol % loading of isocyanide 1 and 10 mol % of Yb(OTf)3 was performed (Scheme 3). After 20 h, the desired amide 18 was obtained
in 16% yield. Optimization of reaction conditions (Table S2, Supporting Information) surprisingly led to the
formation of product 18 in 53% yield in the absence of
both 1 and Yb(OTf)3 (Scheme 3).</p><p>In order to shed light on the nature of this
unexpected outcome,
UV–Vis absorption spectra of DMA alone and in combination with
an aliphatic nonvolatile isocyanide such as 1-adamantyl isocyanide 19 were recorded. As apparent from Figure 5, such experiments indicated a charge-transfer
band due to the formation of an EDA complex between DMA and 19, thus leading to propose the mechanistic hypothesis shown
in Scheme 4. More in
detail, visible-light excitation of the EDA complex II triggered a SET from DMA (the donor) to the isocyanide 17 (the acceptor), thus forming the radical cation DMA•+ and the isocyanide radical anion 17•–.</p><!><p>UV–Vis absorption spectra at 25 °C of 19, DMA alone, and in combination with 19. For comparison,
spectra of isocyanide 1 alone and upon the addition of
DMA were also reported.</p><!><p>The latter, similar to the pathway proposed for aromatic
isocyanide 1 (Scheme 2), was oxidized back to 17 by molecular
oxygen furnishing
a superoxide radical anion O2•–, which was responsible for hydrogen atom abstraction from DMA•+, eventually affording the iminium ion DMA+. As stated above, overall, the formation of product 18 proceeded via a radical-polar crossover mechanism.</p><p>As for
the generality of this transformation, as shown in Figure 6, it proved to be
efficient with electron-rich aliphatic primary, secondary, and bulky
tertiary isocyanides (20–23), while
excellent yields were obtained with isocyanides bearing electron-withdrawing
groups (24 and 25). When p-toluenesulfonylmethyl isocyanide (TosMIC) was reacted with different N,N-dimethylanilines, excellent yields
were observed in the presence of electron-withdrawing substituents
regardless of the para- or meta-substitution
pattern (26 and 27, Figure 6), while electron-donor substituents (28 and 29, Figure 6) as well as cyclic tertiary aromatic amines (30, Figure 6) led to yields from good to moderate. When nonsymmetrical N-ethyl-N-methylaniline was reacted as
the starting amine, the selective formation of regioisomer 31 was obtained in 30% yield (Figure 6).</p><!><p>Substrate scope of aliphatic isocyanides (a48 h; b20 h; and c72 h).</p><!><p>If the unearthing of EDA complex formation between aliphatic isocyanides
and tertiary aliphatic amines contributed to explain the mechanism
underlying the generation of amide derivatives 18, 20–31 (Figure 6), on the other hand, the need for further
proving the catalytic role of aromatic isocyanides, for example 1, was still disappointed.</p><p>Accordingly, in order to
investigate whether this unexplored catalytic reactivity of isocyanides
could be harnessed at a more general level, a range of both carbon
and hetero-atom (pro)nucleophiles, such as diethyl malonate (Mannich-type
reaction),39 cyanotrimethylsilane (Strecker-type
reaction),40 nitromethane (aza-Henry reaction),41 malononitrile,39 and dimethyl phosphite,42 were made to react with N-phenyl-1,2,3,4-tetrahydroisoquinoline
in the presence of a 20 mol % loading of isocyanide 1 (Scheme 5).</p><!><p>1H NMR yields; in
parentheses isolated yields.</p><!><p>Here, the resonance-stabilized
carbanions (Michael donors) were
formed upon deprotonation by the in situ formed hydroperoxide
anion HO2–, without requiring the addition
of any further base. As shown in Scheme 5, all the (pro)nucleophiles gave the cross
dehydrogenative coupling adducts in good to excellent yields; note
that the reaction between N-phenyl-1,2,3,4-tetrahydroisoquinoline
and diethyl malonate performed in the absence of 1 afforded
a 4% yield of product 32. Cyanotrimethylsilane and nitromethane
led to the Strecker and aza-Henry products 33 and 34 in 98 and 69% yields, respectively.
Malononitrile showed to be effective as a Michael donor under standard
reaction conditions leading to a mixture of α-aminonitrile 33 and adduct 35. These results were consistent
with previous reports in the literature.38 Similarly, dimethyl phosphite afforded phosphonylated product 36 in 92% yield.</p><!><p>In conclusion, the possibility
to trigger completely new reactivities
by enlightening a dark side of isocyanide was herein disclosed. Indeed,
aromatic isocyanides proved able to act as photocatalysts triggering
the oxidation of α-amino C(sp3)–H bonds. When
stoichiometric amounts of aromatic isocyanides were used, the self-catalyzed
reaction led to the formation of amide derivatives upon the radical/polar
crossover reaction in good to excellent yields and with a wide substrate
scope. Aliphatic isocyanides proved to form photoactive EDA complexes
with aromatic amines and when combined with water, they were able
to provide amide adducts under very mild and, to our knowledge, unprecedented,
metal-free oxidative conditions. Importantly, it was also shown that
a catalytic loading of an aromatic isocyanide can promote the cross
dehydrogenative coupling of a tertiary aromatic amine, such as N-phenyl-1,2,3,4-tetrahydroisoquinoline, with a range of
(pro)nucleophiles affording Mannich, Strecker, aza-Henry, Michael-addition, and phosphonylated adducts in good to excellent
yields. As a whole, the experimental data provided evidence of the
potential exploitation of aromatic isocyanides as a new class of highly
tunable organic photocatalysts. Worth of note, isocyanides are nowadays
considered a class of widely accessible compounds, with thousands
of derivatives endowed with no or limited toxicity reported in the
literature and readily synthesizable from the corresponding amines.43,44 Actually, the addition of electron-withdrawing or electron-donor
groups on their aromatic moiety, as well as the ring expansion to
polycyclic scaffolds, could lead to easily accessible and fine modulation
of their redox and optical properties, which could expand the substrate
scope to a broader range of C(sp3)–H bonds. Such
investigations are currently in progress in our laboratories.</p><!><p>Commercially available reagents and
solvents were used without further purification. Photochemical reactions
were carried out using a PhotoRedOx Box (EvoluChem) with a 30 W blue
LED (EvoluChem, model: HCK1012-01-008, wavelength 450 nm, LED: CREE
XPE; for the emission spectrum of the light source see: https://www.hepatochem.com/photoreactors-leds-accessories/led-evoluchem/). A holder suitable for 4 mL scintillation vials (45 × 14.7
mm) has been fitted within the box: this allows a fixed sample placement
distance from the light source. All NMR spectra were obtained using
a Bruker AVANCE NEO 400 or 700 MHz instrument. Experiments for structure
elucidation were performed in CDCl3 at 25 °C with
a RT-DR-BF/1H-5 mm-OZ SmartProbe. High-resolution electrospray ionization
mass spectrometry (ESI-MS) spectra were recorded on a Thermo LTQ Orbitrap
XL mass spectrometer. The spectra were recorded by infusion into the
ESI source using MeOH as the solvent. Chemical shifts (Î´) are
reported in parts per million (ppm) relative to the residual solvent
peak. Column chromatography was performed on silica gel (70–230
mesh ASTM) using the reported eluents. Thin-layer chromatography (TLC)
was carried out on 5 × 20 cm plates with a layer thickness of
0.25 mm (Silica gel 60 F254) to monitor the reaction by
using UV as the revelation method.</p><!><p>To a 4
mL colorless screw-cap glass vial equipped with
a magnetic stir bar were added isocyanide (0.08 mmol) and Yb(OTf)3 (0.008 mmol, 0.1 equiv). Then, 800 Î¼L of dry MeCN (0.1
M), 14.4 Î¼L of microfiltered water (0.8 mmol, 10 equiv), and
the aniline derivative (0.16 mmol, 2 equiv) were added into the reaction
vial via a syringe. The resulting mixture was stirred open flask in
a Photoredox box (EvoluChem), under 30 W blue LED irradiation, at
room temperature, until the completion of the reaction, as monitored
by TLC (specific reaction times are available for each compound).
Then, the solvent was removed under vacuum and the crude mixture was
purified by silica gel chromatography.</p><!><p>The crude material (reaction time: 20 h)
was purified by column chromatography (n-hexane/ethyl
acetate 97:3) to give the product as a light pink solid [23.0 mg,
91% yield; 62.6 mg, 23% when the reaction was performed on a 0.8 mmol
scale, with a recovery of 51% (76 mg) of the starting isocyanide (reaction
time: 5dd); 41% NMR yield when the reaction was performed on a 0.25
mmol scale, with 50% of unreacted 4-isocyanobiphenyl (reaction time:
5dd)]. 1H NMR (700 MHz, CDCl3): Î´ 8.50
(br s, −NH), 7.61 (d, J =
8.5 Hz, 2H), 7.57–7.56 (m, 4H), 7.43 (t, J = 7.6 Hz, 2H), 7.34–7.31 (m, 3H), 6.92 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 7.9 Hz, 2H), 3.99 (s,
2H), 3.10 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): Î´ 168.8, 149.5, 140.5, 137.5, 136.5, 129.6, 128.8,
127.6, 127.2, 126.9, 120.2, 119.5, 113.8, 60.1, 40.1; HRMS (ESI) m/z: calcd [M + H]+ for C21H21N2O+, 317.1648; found,
[M + H]+ 317.1650.</p><!><p>The crude material
(reaction time: 20 h) was purified by column chromatography (n-hexane/ethyl acetate 97:3) to give the product as a pink
solid (16.7 mg, 76% yield). 1H NMR (400 MHz, CDCl3): δ 8.43 (br s, −NH), 7.49–7.47 (m, 2H), 7.33–7.27
(m, 4H), 6.91 (t, J = 7.3 Hz, 1H), 6.83 (d, J = 8.0 Hz, 2H), 3.96 (s, 2H), 3.08 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): Î´ 168.8,
149.4, 135.8, 129.6, 129.6, 129.0, 121.2, 119.6, 113.8, 60.1, 40.2;
HRMS (ESI) m/z: calcd [M + H]+ for C15H16ClN2O+, 275.0946; found, [M + H]+ 275.0943.</p><!><p>The crude material
[reaction performed without Yb(OTf)3; reaction time: 5
days] was purified by column chromatography (n-hexane/ethyl
acetate 94:6) to give the product as a yellow amorphous solid (11.5
mg, 50% yield). 1H NMR (700 MHz, CDCl3): Î´
8.78 (br s, −NH), 8.21–8.20 (m, 2H),
7.73–7.72 (m, 2H), 7.32 (dd, J = 8.7, 7.4
Hz, 2H), 6.93 (t, J = 7.3 Hz, 1H), 6.84 (d, J = 8.1 Hz, 2H), 3.99 (s, 2H), 3.10 (s, 3H); 13C{1H} NMR (176 MHz, CDCl3): Î´ 169.5,
149.3, 143.8, 142.9, 129.7, 125.1, 120.0, 119.3, 114.0, 60.3, 40.4;
HRMS (ESI) m/z: calcd [M + H]+ for C15H16N3O3+, 286.1186; found, [M + H]+ 286.1185.</p><!><p>The crude material (reaction time: 20 h)
was purified by column chromatography (n-hexane/ethyl
acetate 97:3) to give the product as a brownish solid (20.7 mg, 96%
yield). 1H NMR (700 MHz, CDCl3): Î´ 8.32
(br s, −NH), 7.32–7.29 (m, 2H), 7.16
(s, 2H), 6.90 (t, J = 7.3 Hz, 1H), 6.83 (d, J = 8.0 Hz, 2H), 6.77 (s, 1H), 3.94 (s, 2H), 3.07 (s, 3H),
2.29 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3): Î´ 168.5, 149.5, 138.8, 137.1, 129.5, 126.3, 119.4,
117.6, 113.7, 60.1, 40.0, 21.3; HRMS (ESI) m/z: calcd [M + H]+ for C17H21N2O+, 269.1648; found, [M + H]+ 269.1647.</p><!><p>The crude material
(reaction time: 20 h) was purified by column chromatography (n-hexane/ethyl acetate 95:5) to give the product as a brown
solid (19.6 mg, 91% yield). 1H NMR (700 MHz, CDCl3): δ 8.32 (br s, −NH), 7.43–7.41
(m, 2H), 7.32–7.29 (m, 2H), 6.89 (t, J = 7.4
Hz, 1H), 6.86–6.83 (m, 4H), 3.95 (s, 2H), 3.78 (s, 3H), 3.08
(s, 3H); 13C{1H} NMR (101 MHz, CDCl3): Î´ 168.5, 156.7, 149.5, 130.4, 129.5, 121.8, 119.3, 114.2,
113.7, 59.9, 55.5, 40.1; HRMS (ESI) m/z: calcd [M + H]+ for C16H19N2O2+, 271.1441; found, [M + H]+ 271.1439.</p><!><p>The crude material (reaction time: 20 h)
was purified by column chromatography (n-hexane/ethyl
acetate 85:15) to give the product as a brownish solid (22.0 mg, 92%
yield). 1H NMR (400 MHz, CDCl3): Î´ 8.25
(br s, −NH), 7.32–7.28 (m, 2H), 7.17
(d, J = 2.5 Hz, 1H), 6.90–6.86 (m, 2H), 6.83–6.77
(m, 3H), 4.24–4.21 (m, 4H), 3.93 (s, 2H), 3.06 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ
168.4, 149.5, 143.5, 140.7, 130.9, 129.5, 119.3, 117.2, 113.7, 113.6,
109.8, 64.4, 64.3, 59.9, 40.1; HRMS (ESI) m/z: calcd [M + H]+ for C17H19N2O3+, 299.1390; found, [M + H]+ 299.1390.</p><!><p>The crude material
(reaction time: 20 h) was purified by column chromatography (n-hexane/ethyl acetate 96:4) to give the product as a brown
solid (21.3 mg, 92% yield). 1H NMR (400 MHz, CDCl3): δ 8.96 (br s, −NH), 8.08 (d, J = 7.5 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H),
7.68 (d, J = 8.2 Hz, 1H), 7.49 (t, J = 7.9 Hz, 1H), 7.45–7.42 (m, 2H), 7.38–7.34 (m, 3H),
6.97–6.92 (m, 3H), 4.12 (s, 2H), 3.21 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 168.9,
149.3, 134.1, 131.7, 129.7, 128.8, 126.6, 126.4, 126.0, 125.8, 125.6,
120.0, 120.0, 119.6, 113.9, 59.9, 40.4; HRMS (ESI) m/z: calcd [M + H]+ for C19H19N2O+, 291.1492; found, [M + H]+ 291.1489.</p><!><p>The crude material (reaction time: 20 h)
was purified by column chromatography (n-hexane/ethyl
acetate 98:2) to give the product as a reddish solid (23.5 mg, 93%
yield). 1H NMR (400 MHz, CDCl3): Î´ 8.50
(br s, −NH), 7.73–7.72 (m, 1H), 7.59–7.55
(m, 3H), 7.44–7.40 (m, 3H), 7.38–7.29 (m, 5H), 6.91
(t, J = 7.3 Hz, 1H), 6.86 (d, J =
8.0 Hz, 2H), 3.98 (s, 2H), 3.10 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): Î´ 168.8, 149.5, 142.2,
140.6, 137.7, 129.6, 129.4, 128.7, 127.5, 127.2, 123.4, 119.5, 118.8,
118.7, 113.8, 60.2, 40.1; HRMS (ESI) m/z: calcd [M + H]+ for C21H21N2O+, 317.1648; found, [M + H]+ 317.1648.</p><!><p>The crude material (reaction time: 20 h)
was purified by column chromatography (n-hexane/ethyl
acetate 98:2) to give the product as a reddish sticky solid (23.8
mg, 94% yield). 1H NMR (400 MHz, CDCl3): Î´
8.65 (br s, −NH), 8.46 (d, J = 8.1 Hz, 1H), 7.33–7.29 (m, 1H), 7.18–7.04 (m, 7H),
7.00–6.98 (m, 2H), 6.77 (t, J = 7.3 Hz, 1H),
6.48 (d, J = 8.0 Hz, 2H), 3.74 (s, 2H), 2.58 (s,
3H); 13C{1H} NMR (101 MHz, CDCl3):
Î´ 168.6, 148.7, 137.6, 134.6, 131.9, 129.8, 129.2, 129.0, 128.8,
128.5, 127.6, 124.1, 119.9, 118.8, 113.2, 59.6, 39.4; HRMS (ESI) m/z: calcd [M + H]+ for C21H21N2O+, 317.1648; found,
[M + H]+ 317.1646.</p><!><p>The crude material (reaction time: 5 days)
was purified by column chromatography (n-hexane/ethyl
acetate 95:5) to give the product as an off-white solid (12.1 mg,
38% yield). 1H NMR (700 MHz, CDCl3): Î´
8.31 (br s, −NH), 7.59–7.55 (m, 6H),
7.43 (t, J = 7.7 Hz, 2H), 7.40–7.38 (m, 2H),
7.33 (t, J = 7.4 Hz, 1H), 6.71 (d, J = 9.0 Hz, 2H), 3.96 (s, 2H), 3.09 (s, 3H); 13C{1H} NMR (176 MHz, CDCl3): Î´ 168.2, 148.4, 140.4,
137.7, 136.3, 132.3, 128.8, 127.7, 127.2, 126.9, 120.2, 115.3, 111.8,
59.9, 40.3; HRMS (ESI) m/z: calcd
[M + H]+ for C21H20BrN2O+, 395.0754; found, [M + H]+ 395.0753.</p><!><p>The crude
material (reaction time: 48 h) was purified by column chromatography
(n-hexane/ethyl acetate 97:3) and preparative TLC
(dichloromethane) to give the product as a light pink solid (12.1
mg, 46% yield). 1H NMR (700 MHz, CDCl3): Î´
8.57 (br s, −NH), 7.61 (d, J = 8.6 Hz, 2H), 7.57–7.55 (m, 4H), 7.42 (t, J = 7.7 Hz, 2H), 7.33 (t, J = 7.4 Hz, 1H), 7.12 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.5 Hz, 2H),
3.93 (s, 2H), 3.06 (s, 3H), 2.29 (s, 3H); 13C{1H} NMR (176 MHz, CDCl3): Î´ 169.0, 147.4, 140.5,
137.4, 136.6, 130.0, 129.0, 128.8, 127.6, 127.2, 126.9, 120.2, 114.1,
60.5, 40.4, 20.3; HRMS (ESI) m/z: calcd [M + H]+ for C22H23N2O+, 331.1805; found, [M + H]+ 331.1806.</p><!><p>The crude
material (reaction time: 48 h) was purified by column chromatography
(n-hexane/ethyl acetate 98:2) to give the product
as a light pink solid (16.9 mg, 64% yield). 1H NMR (700
MHz, CDCl3): δ 8.51 (br s, −NH), 7.62–7.61 (d, 2H), 7.57–7.56 (m, 4H), 7.43 (t, J = 7.7 Hz, 2H), 7.33 (t, J = 7.4 Hz, 1H),
7.22–7.19 (m, 1H), 6.74 (d, J = 7.5 Hz, 1H),
6.67–6.66 (m, 2H), 3.97 (s, 2H), 3.08 (s, 3H), 2.35 (s, 3H); 13C{1H} NMR (176 MHz, CDCl3): δ
168.9, 149.6, 140.5, 139.5, 137.5, 136.5, 129.4, 128.8, 127.7, 127.2,
126.9, 120.4, 120.2, 114.6, 111.0, 60.2, 40.1, 21.8; HRMS (ESI) m/z: calcd [M + H]+ for C22H23N2O+, 331.1805; found,
[M + H]+ 331.1806.</p><!><p>The crude material (reaction performed
with 3 equiv of 4-methoxy-N,N-dimethylaniline;
reaction time: 48 h) was purified by column chromatography (n-hexane/ethyl acetate 95:5) to give the product as a dark
green solid (10.5 mg, 38% yield). 1H NMR (700 MHz, CDCl3): δ 8.71 (br s, −NH), 7.63–7.62
(m, 2H), 7.57–7.56 (m, 4H), 7.43 (t, J = 7.7
Hz, 2H), 7.33 (t, J = 7.4 Hz, 1H), 6.89–6.88
(m, 2H), 6.84–6.82 (m, 2H), 3.88 (s, 2H), 3.78 (s, 3H), 3.02
(s, 3H); 13C{1H} NMR (176 MHz, CDCl3): Î´ 169.0, 153.6, 144.0, 140.5, 137.4, 136.6, 128.8, 127.6,
127.1, 126.9, 120.1, 115.9, 114.9, 61.0, 55.7, 41.0; HRMS (ESI) m/z: calcd [M + H]+ for C22H23N2O2+, 347.1754;
found, [M + H]+ 347.1750.</p><!><p>The crude material (reaction time: 48 h)
was purified by column chromatography (n-hexane/ethyl
acetate 98:2) to give the product as an off-white solid (24.0 mg,
74% yield). 1H NMR (400 MHz, CDCl3): Î´
8.89 (br s, −NH), 7.69 (d, J = 7.2 Hz, 1H), 7.60–7.52 (m, 6H), 7.43 (t, J = 7.6 Hz, 2H), 7.39–7.27 (m, 5H), 7.21 (d, J = 7.1 Hz, 1H), 7.06 (d, J = 8.2 Hz, 2H), 6.98 (t, J = 7.3 Hz, 1H), 5.13 (s, 1H), 4.00–3.95 (m, 1H),
3.47–3.41 (m, 1H), 3.19–3.03 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3): δ 170.6, 149.4,
140.5, 137.3, 136.8, 134.5, 132.1, 129.6, 129.1, 128.7, 127.8, 127.7,
127.5, 127.1, 126.8 (3 C), 120.4, 120.1, 115.3, 66.4, 45.4, 28.8;
HRMS (ESI) m/z: calcd [M + H]+ for C28H25N2O+, 405.1961; found, [M + H]+ 405.1957.</p><!><p>The crude material (reaction time: 72 h)
was purified by column chromatography (n-hexane/ethyl
acetate 95:5) to give the product as a light purple solid (15.0 mg,
52% yield). 1H NMR (700 MHz, CDCl3): Î´
8.17 (br s, −NH), 7.53 (d, J = 7.3 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 7.41 (t, J = 7.7 Hz, 2H),
7.36–7.30 (m, 3H), 7.07 (d, J = 8.1 Hz, 2H),
7.00 (t, J = 7.3 Hz, 1H), 4.20–4.19 (m, 1H),
4.16–4.15 (m, 1H), 4.10–4.09 (m, 1H), 3.96–3.89
(m, 2H), 3.53–3.50 (m, 1H), 3.32–3.29 (m, 1H); 13C{1H} NMR (176 MHz, CDCl3): δ
168.5, 149.6, 140.4, 137.5, 136.5, 129.9, 128.8, 127.6, 127.2, 126.9,
122.2, 120.2, 117.7, 67.7, 66.5, 62.0, 49.0; HRMS (ESI) m/z: calcd [M + H]+ for C23H23N2O2+, 359.1754; found,
[M + H]+ 319.1754.</p><!><p>To a 4 mL colorless screw-cap
glass vial equipped with a magnetic stir bar were added isocyanide
(0.08 mmol), 800 Î¼L of dry MeCN (0.1 M), 14.4 Î¼L of microfiltered
water (0.8 mmol, 10 equiv), and the aniline derivative (0.16 mmol,
2 equiv). The resulting mixture was stirred open flask in a Photoredox
box (EvoluChem), under 30 W blue LED irradiation, at room temperature,
until the completion of the reaction, as monitored by TLC (specific
reaction times are available for each compound). Then, the solvent
was removed under vacuum and the crude mixture was purified by silica
gel chromatography.</p><!><p>The crude
material (reaction time: 72 h) was purified by column chromatography
(n-hexane/ethyl acetate 9:1) to give the product
as an off-white solid (10.4 mg, 53% yield). 1H NMR (400
MHz, CDCl3): δ 7.29–7.25 (m, 2H), 6.84 (t, J = 7.3 Hz, 1H), 6.74 (d, J = 8.1 Hz, 2H),
6.44 (br d, −NH), 3.87–3.78 (m, 1H),
3.83 (s, 3H), 2.99 (s, 3H), 1.86–1.82 (m, 2H), 1.67–1.56
(m, 3H), 1.40–1.28 (m, 2H), 1.16–1.03 (m, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ
169.3, 149.5, 129.3, 118.7, 113.3, 59.2, 47.8, 39.7, 33.0, 25.4, 24.7;
HRMS (ESI) m/z: calcd [M + H]+ for C15H23N2O+, 247.1805; found, [M + H]+ 247.1804.</p><!><p>The crude material
(reaction time: 48 h) was purified by column chromatography (n-hexane/ethyl acetate 9:1) to give the product as an off-white
amorphous solid (6.0 mg, 32% yield). 1H NMR (700 MHz, CDCl3): δ 7.29–7.26 (m, 2H), 6.84 (t, J = 7.3 Hz, 1H), 6.74 (d, J = 8.3 Hz, 2H), 6.57 (br
t, −NH), 3.85 (s, 2H), 3.27 (q, J = 9.4 Hz, 2H), 3.01 (s, 3H), 1.46 (m, 2H), 1.30–1.22 (m,
4H), 0.85 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (176 MHz, CDCl3): Î´ 170.2, 149.3,
129.4, 118.6, 113.1, 59.0, 39.8, 39.2, 29.3, 29.0, 22.3, 14.0; HRMS
(ESI) m/z: calcd [M + H]+ for C14H23N2O+, 235.1805;
found, [M + H]+ 235.1808.</p><!><p>The crude
material
(reaction time: 48 h) was purified by column chromatography (n-hexane/ethyl acetate 9:1) to give the product as a brownish
solid (6.7 mg, 33% yield). 1H NMR (400 MHz, CDCl3): δ 7.31–7.24 (m, 5H), 7.21–7.19 (m, 2H), 6.90
(br t, −NH), 6.84 (t, J =
7.3 Hz, 1H), 6.74 (d, J = 8.2 Hz, 2H), 4.49 (d, J = 6.0 Hz, 2H), 3.92 (s, 2H), 3.00 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): Î´ 170.4,
149.3, 138.0, 129.4, 128.7, 127.5, 127.5, 118.8, 113.3, 59.0, 43.1,
39.9; HRMS (ESI) m/z: calcd [M +
H]+ for C16H19N2O+, 255.1492; found, [M + H]+ 255.1496.</p><!><p>The crude material
(reaction time: 48 h) was purified by column chromatography (n-hexane/ethyl acetate 96:4) to give the product as an off-white
amorphous solid (6.9 mg, 39% yield). 1H NMR (400 MHz, CDCl3): δ 7.29–7.25 (m, 2H), 6.85 (t, J = 7.3 Hz, 1H), 6.74 (d, J = 8.0 Hz, 2H), 6.38 (br
s, −NH), 3.73 (s, 2H), 2.98 (s, 3H), 1.33
(s, 9H); 13C{1H} NMR (176 MHz, CDCl3): Î´ 169.6, 149.5, 129.3, 118.7, 113.4, 59.9, 50.9, 39.8, 28.7;
HRMS (ESI) m/z: calcd [M + H]+ for C13H21N2O+, 221.1648; found, [M + H]+ 221.1654.</p><!><p>The crude material (reaction time: 48 h)
was purified by column chromatography (n-hexane/ethyl
acetate 9:1) to give the product as an off-white solid (6.7 mg, 28%
yield). 1H NMR (400 MHz, CDCl3): δ 7.29–7.25
(m, 3H), 6.84 (t, J = 7.3 Hz, 1H), 6.74 (d, J = 8.0 Hz, 2H), 6.25 (br s, −NH), 3.71 (s, 2H), 2.98 (s, 3H), 2.06 (s, 3H), 1.96 (d, J = 2.8 Hz, 6H), 1.67–1.65 (m, 6H); 13C{1H} NMR (101 MHz, CDCl3): δ 169.2, 149.5, 129.3,
118.7, 113.4, 59.9, 51.6, 41.6, 39.7, 36.3, 29.4; HRMS (ESI) m/z: calcd [M + H]+ for C19H27N2O+, 299.2118; found,
[M + H]+ 299.2117.</p><!><p>The crude
material (reaction time: 48 h) was purified by column chromatography
(n-hexane/ethyl acetate 85:15) to give the product
as a yellow solid (19.6 mg, 98% yield). 1H NMR (400 MHz,
CDCl3): δ 7.30–7.26 (m, 2H), 7.05 (br t, −NH), 6.85 (t, J = 7.3 Hz, 1H), 6.78 (d, J = 8.1 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H),
4.06 (d, J = 5.7 Hz, 2H), 3.91 (s, 2H), 3.04 (s,
3H), 1.26 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3): Î´ 171.0, 169.5,
149.4, 129.4, 118.8, 113.4, 61.5, 58.8, 41.0, 39.7, 14.1; HRMS (ESI) m/z: calcd [M + H]+ for C13H19N2O3+, 251.1390;
found, [M + H]+ 251.1391.</p><!><p>The crude
material (reaction time: 20 h) was purified by column chromatography
(n-hexane/ethyl acetate 85:15) to give the product
as a white solid (17.8 mg, 67% yield). 1H NMR (400 MHz,
CDCl3): Î´ 7.72 (d, J = 8.2 Hz, 2H),
7.34–7.29 (m, 4H), 6.89 (t, J = 7.3 Hz, 1H),
6.67 (d, J = 8.2 Hz, 2H), 4.68 (d, J = 6.9 Hz, 2H), 3.75 (s, 2H), 2.98 (s, 3H), 2.46 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): Î´ 170.3,
149.0, 145.5, 133.8, 129.9, 129.5, 128.8, 119.3, 113.5, 59.9, 58.5,
40.1, 21.8; HRMS (ESI) m/z: calcd
[M + H]+ for C17H21N2O3S+, 333.1267; found, [M + H]+ 333.1267.</p><!><p>The crude
material (reaction time: 48 h) was purified by column chromatography
(n-hexane/ethyl acetate 7:3) to give the product
as an off-white solid (23.7 mg, 72% yield). 1H NMR (700
MHz, CDCl3): Î´ 7.69 (d, J = 8.2
Hz, 2H), 7.34–7.33 (m, 4H), 7.24 (br t, −NH), 6.52–6.50 (m, 2H), 4.68 (d, J = 6.9 Hz,
2H), 3.73 (s, 2H), 2.97 (s, 3H), 2.46 (s, 3H); 13C{1H} NMR (176 MHz, CDCl3): Î´ 169.8, 148.0,
145.7, 133.7, 132.2, 130.0, 128.8, 115.0, 111.4, 59.8, 58.3, 40.2,
21.8; HRMS (ESI) m/z: calcd [M +
H]+ for C17H20BrN2O3S+, 411.0373; found, [M + H]+ 411.0373.</p><!><p>The crude
material (reaction time: 48 h) was purified by column chromatography
(n-hexane/ethyl acetate 75:25) to give the product
as a beige solid (29.5 mg, 90% yield). 1H NMR (700 MHz,
CDCl3): Î´ 7.71 (d, J = 8.2 Hz, 2H),
7.35 (d, J = 8.2 Hz, 2H), 7.24 (br t, −NH), 6.99–6.97 (m, 1H), 6.98 (d, J = 7.9 Hz, 1H), 6.81–6.80 (m, 1H), 6.56 (dd, Ja = 8.4, Jb = 2.5 Hz, 1H), 4.67 (d, J = 6.9
Hz, 2H), 3.75 (s, 2H), 2.96 (s, 3H), 2.45 (s, 3H); 13C{1H} NMR (176 MHz, CDCl3): Î´ 169.7, 150.2,
145.7, 133.7, 130.7, 130.1, 128.8, 123.6, 121.9, 116.1, 111.8, 59.9,
57.9, 39.9, 21.8; HRMS (ESI) m/z: calcd [M + H]+ for C17H20BrN2O3S+, 411.0373; found, [M + H]+ 411.0377.</p><!><p>The crude
material (reaction time: 48 h) was purified by column chromatography
(n-hexane/ethyl acetate 8:2) to give the product
as a beige sticky solid (18.1 mg, 63% yield). 1H NMR (700
MHz, CDCl3): Î´ 7.72 (d, J = 8.2
Hz, 2H), 7.35–7.32 (m, 3H), 6.55 (s, 1H), 6.33 (s, 2H), 4.67
(d, J = 6.9 Hz, 2H), 3.73 (s, 2H), 2.95 (s, 3H),
2.45 (s, 3H), 2.30 (s, 6H); 13C{1H} NMR (176
MHz, CDCl3): Î´ 170.6, 149.2, 145.5, 139.2, 133.9,
130.0, 128.8, 121.2, 111.4, 59.9, 58.6, 40.1, 21.8, 21.7. HRMS (ESI) m/z: calcd [M + H]+ for C19H25N2O3S+, 361.1580;
found, [M + H]+ 361.1579.</p><!><p>The crude
material (reaction time: 72 h) was purified by column chromatography
(n-hexane/ethyl acetate 75:25) to give the product
as a brownish sticky solid (6.8 mg, 23% yield). 1H NMR
(700 MHz, CDCl3): Î´ 7.72 (d, J =
8.1 Hz, 2H), 7.53 (br t, −NH), 7.33 (d, J = 8.1 Hz, 2H), 6.85 (d, J = 9.0 Hz, 2H),
6.67 (d, J = 9.0 Hz, 2H), 4.70 (d, J = 6.9 Hz, 2H), 3.78 (s, 3H), 3.65 (s, 2H), 2.91 (s, 3H), 2.45 (s,
3H); 13C{1H} NMR (176 MHz, CDCl3):
Î´ 170.5, 153.6, 145.6, 143.7, 133.8, 130.0, 128.8, 115.7, 114.8,
59.9, 59.6, 55.7, 41.1, 21.8; HRMS (ESI) m/z: calcd [M + H]+ for C18H23N2O4S+, 363.1373; found, [M + H]+ 363.1375.</p><!><p>The crude material (reaction time: 72 h)
was purified by column chromatography (n-hexane/ethyl
acetate 75:25) to give the product as a white solid (9.0 mg, 30% yield). 1H NMR (700 MHz, CDCl3): Î´ 7.59 (d, J = 8.1 Hz, 2H), 7.33 (t, J = 7.8 Hz, 2H),
7.27 (d, J = 8.0 Hz, 2H), 7.02–6.99 (m, 2H),
6.91 (d, J = 8.3 Hz, 2H), 4.73–4.69 (m, 1H),
4.47–4.44 (m, 1H), 3.96–3.94 (m, 1H), 3.90–3.88
(m, 2H), 3.82–3.78 (m, 2H), 3.43–3.40 (m, 1H), 3.24–3.
21 (m, 1H), 2.43 (s, 3H); 13C{1H} NMR (176 MHz,
CDCl3): Î´ 170.1, 149.2, 145.4, 133.9, 129.9, 129.8,
128.7, 121.9, 117.1, 67.7, 66.5, 60.6, 59.9, 48.1, 21.8; HRMS (ESI) m/z: calcd [M + H]+ for C19H23N2O4S+, 375.1373;
found, [M + H]+ 375.1375.</p><!><p>The crude
material (reaction time: 72 h) was purified by column chromatography
(n-hexane/ethyl acetate 85:15) to give the product
as a beige amorphous solid (8.3 mg, 30% yield). 1H NMR
(700 MHz, CDCl3): δ 7.68–7.67 (m, 2H), 7.32–7.26
(m, 4 H), 6.87–6.85 (m, 1H), 6.65 (d, J =
6.3 Hz, 2H), 4.66–4.65 (m, 2H), 3.73 (s, 2H), 3.43–3.39
(m, 2H), 2.45 (s, 3H), 1.18–1.16 (m, 3H); 13C{1H} NMR (176 MHz, CDCl3): δ 170.4, 147.3,
145.5, 133.8, 129.9, 129.6, 128.8, 119.0, 113.7, 59.8, 55.4, 46.5,
21.8, 11.5; HRMS (ESI) m/z: calcd
[M + H]+ for C18H23N2O3S+, 347.1424; found, [M + H]+ 347.1426.</p><!><p>To a 4 mL colorless
screw-cap glass vial equipped with a magnetic stir bar were added
the pro-nucleophile (0.08 mmol), N-phenyl-1,2,3,4-tetrahydroisoquinoline
(33.4 mg, 0.16 mmol, 2 equiv.), and 800 Î¼L of dry MeCN (0.1
M). Then, 4-isocyanobiphenyl 1 (2.9 mg, 0.016 mmol, 20%
mol) was added to the resulting mixture, which was stirred open flask
in a Photoredox box (EvoluChem), under 30 W blue LED irradiation,
at room temperature, for 20 h. After the completion of the reaction,
as monitored by TLC, the solvent was removed under vacuum and the
crude mixture was purified by silica gel chromatography.</p><!><p>The crude
material was purified by column chromatography (n-hexane + triethylamine 0.1% v/v) to give the product as a yellowish
sticky solid (11.7 mg, 40% isolated yield; NMR yield: 94%). 1H NMR (400 MHz, CDCl3): δ 7.30–7.08 (m, 6H),
6.98 (d, J = 8.1 Hz, 2H), 6.75 (t, J = 7.3 Hz, 1H), 5.72 (d, J = 9.1 Hz, 1H), 4.16–3.95
(m, 4H), 3.89 (d, J = 9.2 Hz, 1H), 3.71–3.62
(m, 2H), 3.11–3.03 (m, 1H), 2.91–2.85 (m, 1H), 1.17
(t, J = 7.1 Hz, 3H), 1.09 (t, J =
7.1 Hz, 3H); 13C{1H} NMR (176 MHz, CDCl3): Î´ 168.0, 167.2, 148.9, 136.0, 134.83, 129.1, 128.9,
127.5, 127.2, 126.0, 118.5, 115.1, 61.6, 59.6, 57.9, 42.3, 26.1, 13.9,
13.9; HRMS (ESI) m/z: calcd [M +
H]+ for C22H26NO4+, 368.1856; found, [M + H]+ 368.1856.</p><!><p>The crude
material
was purified by column chromatography (n-hexane +
triethylamine 0.05% v/v) to give the product as a yellowish solid
(14.0 mg, 75% isolated yield; NMR yield: 98%). 1H NMR (700
MHz, CDCl3): δ 7.39–7.36 (m, 2H), 7.34–7.27
(m, 3H), 7.25 (d, J = 7.5 Hz, 1H), 7.10 (d, J = 8.0 Hz, 2H), 7.03 (t, J = 7.3 Hz, 1H),
5.53 (s, 1H), 3.80–3.77 (m, 1H), 3.52–3.48 (m, 1H),
3.20–3.15 (m, 1H), 3.00–2.97 (m, 1H); 13C{1H} NMR (176 MHz, CDCl3): δ 148.4, 134.6,
129.6, 129.4, 128.8, 127.1, 126.9, 121.9, 117.8, 117.6, 53.3, 44.2,
28.6. HRMS (ESI) m/z: calcd [M +
H]+ for C16H15N2+, 235.1230; found, [M + H]+ 235.1232.</p><!><p>The crude
material was purified by column chromatography (n-hexane/ethyl acetate 85:15) to give the product as a yellow sticky
solid (16.1 mg, 63% yield). 1H NMR (700 MHz, CDCl3): δ 7.39–7.37 (m, 2H), 7.30–7.28 (m, 2H), 7.24–7.18
(m, 2H), 7.00 (d, J = 7.7 Hz, 2H), 6.84 (t, J = 7.0 Hz, 1H), 5.23 (d, J = 20.3 Hz,
1H), 4.06–4.02 (m, 1H), 3.69 (d, J = 10.5
Hz, 3H), 3.67 (d, J = 10.5 Hz, 3H), 3.67–3.65
(m, 1H), 3.11–3.01 (m, 2H); 13C{1H} NMR
(176 MHz, CDCl3): δ 149.2 (d, JC–P = 6.3 Hz), 136.4 (d, JC–P = 6.0 Hz), 130.4, 129.3, 128.8 (d, JC–P = 2.5 Hz), 127.9 (d, JC–P = 4.9
Hz), 127.5 (d, JC–P = 3.7 Hz),
126.0 (d, JC–P = 2.5 Hz), 118.7,
114.8, 58.8 (d, JC–P = 160.0 Hz),
53.9 (d, JC–P = 6.9 Hz), 52.9 (d, JC–P = 7.6 Hz), 43.6, 26.7; HRMS (ESI) m/z: calcd [M + K]+ for C17H20KNO3P+, 356.0812; found,
[M + K]+ 356.0813.</p><!><p>To a 4 mL
colorless
screw-cap glass vial equipped with a magnetic stir bar were added N-phenyl-1,2,3,4-tetrahydroisoquinoline (16.7 mg, 0.08 mmol),
nitromethane (130 Î¼L, 2.4 mmol, 30 equiv.), and 800 Î¼L
of dry MeCN (0.1 M). Then, 4-isocyanobiphenyl 1 (2.9
mg, 0.016 mmol, 20% mol) was added to the resulting mixture, which
was stirred open flask in a Photoredox box (EvoluChem), under 30 W
blue LED irradiation, at room temperature, for 20 h. After the completion
of the reaction, as monitored by TLC, the solvent and the excess of
nitromethane were removed under vacuum and the crude mixture was purified
by preparative TLC (n-hexane/tetrahydrofuran 8:2)
to give the product as a yellow amorphous solid (12,2 mg, 57% isolated
yield; NMR yield: 69%). 1H NMR (700 MHz, CDCl3): δ 7.29–7.25 (m, 3H), 7.22–7.19 (m, 2H), 7.14
(d, J = 7.5 Hz, 1H), 6.98 (d, J =
8.3 Hz, 2H), 6.85 (t, J = 7.3 Hz, 1H), 5.55 (t, J = 7.2 Hz, 1H), 4.88 (dd, Ja = 11.9, Jb = 7.8 Hz, 1H), 4.57 (dd, Ja = 11.9, Jb =
6.7 Hz, 1H), 3.69–3.61 (m, 2H), 3.11–3.07 (m, 1H), 2.82–2.78
(m, 1H); 13C{1H} NMR (176 MHz, CDCl3): Î´ 148.4, 135.3, 132.9, 129.5, 129.2, 128.1, 127.0, 126.7,
119.4, 115.1, 78.8, 58.2, 42.1, 26.5; HRMS (ESI) m/z: calcd [M + H]+ for C16H17N2O2+, 269.1285; found,
[M + H]+ 269.1285.</p><!><p>To a 4 mL
colorless screw-cap glass vial equipped with a magnetic stir bar were
added N-phenyl-1,2,3,4-tetrahydroisoquinoline (16.7
mg, 0.08 mmol), malononitrile (26.6 Î¼L, 0.48 mmol, 6 equiv.),
and 800 Î¼L of dry MeCN (0.1 M). Then, 4-isocyanobiphenyl 1 (2.9
mg, 0.016 mmol, 20% mol) was added to the resulting mixture, which
was stirred open flask in a Photoredox box (EvoluChem), under 30 W
blue LED irradiation, at room temperature, for 20 h. After the completion
of the reaction, as monitored by TLC, the solvent and the excess of
malononitrile were removed under vacuum and the crude 1H NMR spectrum in the presence of 1,3,5-trimethoxybenzene as the
internal standard was registered (NMR yield: 27%).</p><!><p>Absorption/fluorescence
spectra, complete experimental
procedures, characterization data, 1H- and 13C NMR, HRMS, and absorption/fluorescence spectra (PDF)</p><p>jo1c02378_si_001.pdf</p><p>The authors declare no
competing financial interest.</p>