Visible-light-mediated nucleophilic addition of an α-aminoalkyl radical to isocyanate or isothiocyanate

Article abstract of DOI:10.1021/ol402573j

A visible-light photoredox synthesis of α-amino amide or α-amino thioamide from N,N-dimethylaniline derivatives and aryl isocyanate or aryl isothiocyanate was developed. Bis[2-(4,6-difluorophenyl)pyridinato- C²,N](picolinato)iridium(III) (FIrpic) was found to be the effective catalyst among six catalysts screened. The reaction involves generation of α-aminoalkyl radicals from tertiary amines, followed by radical addition to the electron-deficient carbon of isocyanate and isothiocyanate.

Full text of DOI:10.1021/ol402573j

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Visible-Light-Mediated Nucleophilic
Addition of an r‑Aminoalkyl Radical
to Isocyanate or Isothiocyanate
Hongxia Zhou, Ping Lu, Xiangyong Gu, and Pixu Li*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering, and Materials Science, Soochow University, 199 RenAi Road,
Suzhou, Jiangsu, 215123, China
lipixu@suda.edu.cn
Received September 5, 2013
ABSTRACT
A visible-light photoredox synthesis of R-amino amide or R-amino thioamide from N,N-dimethylaniline derivatives and aryl isocyanate or aryl
isothiocyanate was developed. Bis[2-(4,6-difluorophenyl)pyridinato-C2,N](picolinato)iridium(III) (FIrpic) was found to be the effective catalyst
among six catalysts screened. The reaction involves generation of R-aminoalkyl radicals from tertiary amines, followed by radical addition to the
electron-deficient carbon of isocyanate and isothiocyanate.
Direct sp3 CꢀH functionalization adjacent to a nitrogen
atom has become an important synthetic method of nitro-
gen containing compounds.1 Two pathways are generally
proposed for the N-R-sp3 CꢀH functionalization (Figure 1).
Pathway a involves iminium ion intermediates; pathway b
goes through R-aminoalkyl radicals. In the presence of a
suitable oxidant, the R-aminoalkyl radical could be oxi-
dized to give an iminium ion. Compared to the extensively
studied reactions involving an iminium ion pathway, the
chemistry of R-aminoalkyl radicals is underdeveloped.
Figure 1. General pathways of N-R-sp3 CꢀH activation.
Photochemical N-R-sp3 CꢀH activation under UV-
light irradiation was sysmetically investigated.2 Although
visible-light activated Ru/Ir polybipyridyl complexes were
(1) (a) Campos, K. R. Chem. Soc. Rev. 2007, 36, 1069. (b) Mitchell,
E. A.; Peschiulli, A.; Lefevre, N.; Meerpoel, L.; Maes, B. U. W. Chem.;
Eur. J. 2012, 18, 10092. (c) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (d) Li,
Y. M.; Ma, L. N.; Li, Z. P. Chin. J. Org. Chem. 2013, 33, 704.
(2) For reviews: (a) Hoffmann, N. J. Photochem. Photobiol. C 2008,
9, 43. (b) Hoffmann, N. Chem. Rev. 2008, 108, 1052. (c) Hoffmann, N.
Pure Appl. Chem. 2007, 79, 1949. (d) Hoffmann, N.; Bertrand, S.;
Marinkovic, S.; Pesch, J. Pure Appl. Chem. 2006, 78, 2227.
(3) (a) Bock, C. R.; Connor, J. A.; Gutierrez, A. R.; Meyer, T. J.;
Whitten, D. G.; Sullivan, B. P.; Nagle, J. K. J. Am. Chem. Soc. 1979, 101,
long known to oxidize tertiary amine through single elec-
tron transfer (SET),3 activaton of a N-R-sp3 CꢀH bond by
visible-light attracted attention only very recently.4 Many
elegant photoredox reactions involving activation of an
R-sp3 CꢀH bond of tertiary amine were reported in the
past several years.5 Most of the reported works utilized the
iminium ion pathway, involving tetrahydroisoquinolines,6
4815. (b) Maestri, M.; Gratzel, M. Ber. Bunsen-Ges. Phys. Chem. 1977,
81, 504.
benzylamines,6s,x,7 dimethylanilines,6s,t,7a,8 and other sub-
strates.9 Reactions of an R-aminoalkyl radical were much
less explored. Moreover, the majority of the visible-light
photoredox R-aminoalky radical reactions were conjugate
addition to electron-deficient CdC double bonds since
the first report by Reiser, Paney, and co-workers in 2012.10
(4) For reviews: (a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C.
Chem. Rev. 2013, 113, 5322. (b) Xuan, J.; Xiao, W.-J. Angew. Chem., Int.
Ed. 2012, 51, 6828. (c) Teply, F. Collect. Czech. Chem. Commun. 2011,
76, 859. (d) Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev.
2011, 40, 102. (e) Yoon, T. P.; Ischay, M. A.; Du, J. N. Nat. Chem. 2010,
2, 527. (f) Zeitler, K. Angew. Chem., Int. Ed. 2009, 48, 9785.
r
10.1021/ol402573j
XXXX American Chemical Society

In principle, the addition of an R-aminoalky radical to
other eletrophilic carbon centers is mechanistically viable.
However, very rarely have other electrophiles been re-
ported to react with an R-aminoalky radical under visible-
light photoredox conditions.11 Herein, we would like to
reportavisible-light-mediatedradicaladdition of aromatic
tertiary amine to isocyanate and isothiocyanate catalyzed
by bis[2-(4,6-difluorophenyl)pyridinato-C2,N](picolinato)-
iridium(III) (FIrpic), an Ir-based visible-light sensitizer
that has never been reported in photoredox organic
synthesis.
Table 1. Optimization of the Reaction of N,N-Dimethylaniline
and Phenyl Isocyanatea
entry
catalyst
solvent
yield (%)b
1
Ru(bpy)3(PF6)2
NMP
NMP
NMP
NMP
NMP
NMP
DCM
CH3CN
DMF
DCM
DCM
trace
NR
NR
NR
trace
10
Yoshimitsu, Tanaka, and co-workers reported R-sp3
CꢀH carbamoylation of tertiary amines with aryl isocya-
nates using a combination of Et3B/O2 as the radical ini-
tiator or under UV-light irradiation.12 They are rare
2
Ru(bpy)3Cl2 6H2O
3
3
Ir(ppy)3
4
Ir(ppy)2acac
Ir(ppy)2(dtbbpy)PF6
FIrpic
5
6
7
FIrpic
84
(5) For review: Shi, L.; Xia, W. J. Chem. Soc. Rev. 2012, 41, 7687.
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Chem. Sci. 2013, 4, 1281. (c) To, W.-P.; Liu, Y.; Lau, T.-C.; Che, C.-M.
Chem.;Eur. J. 2013, 19, 5654. (d) Mathis, C. L.; Gist, B. M.; Frederickson,
C. K.; Midkiff, K. M.; Marvin, C. C. Tetrahedron Lett. 2013, 54, 2101. (e)
Zhao, G.; Yang, C.; Guo, L.; Sun, H.; Chen, C.; Xia, W. Chem. Commun.
2012, 48, 2337. (f) Xuan, J.; Feng, Z.-J.; Duan, S.-W.; Xiao, W.-J. RSC Adv.
2012, 2, 4065. (g) Tucker, J. W.; Zhang, Y.; Jamison, T. F.; Stephenson,
C. R. J. Angew. Chem., Int. Ed. 2012, 51, 4144. (h) Rueping, M.; Zoller, J.;
Fabry, D. C.; Poscharny, K.; Koenigs, R. M.; Weirich, T. E.; Mayer, J.
Chem.;Eur. J. 2012, 18, 3478. (i) Rueping, M.; Koenigs, R. M.; Poscharny,
K.; Fabry, D. C.; Leonori, D.; Vila, C. Chem.;Eur. J. 2012, 18, 5170. (j)
Mitkina, T.; Stanglmair, C.; Setzer, W.; Gruber, M.; Kisch, H.; Konig, B.
Org. Biomol. Chem. 2012, 10, 3556. (k) Liu, Q.; Li, Y.-N.; Zhang, H.-H.;
Chen, B.; Tung, C.-H.; Wu, L.-Z. Chem.;Eur. J. 2012, 18, 620. (l) Fu, W.;
Guo, W.; Zou, G.; Xu, C. J. Fluorine Chem. 2012, 140, 88. (m) DiRocco,
D. A.; Rovis, T. J. Am. Chem. Soc. 2012, 134, 8094. (n) Zou, Y.-Q.; Lu,
L.-Q.; Fu, L.; Chang, N.-J.; Rong, J.; Chen, J.-R.; Xiao, W.-J. Angew.
Chem., Int. Ed. 2011, 50, 7171. (o) Rueping, M.; Zhu, S.; Koenigs, R. M.
Chem. Commun. 2011, 47, 12709. (p) Rueping, M.; Zhu, S.; Koenigs, R. M.
Chem. Commun. 2011, 47, 8679. (q) Rueping, M.; Vila, C.; Koenigs, R. M.;
Poscharny, K.; Fabry, D. C. Chem. Commun. 2011, 47, 2360. (r) Rueping,
M.; Leonori, D.; Poisson, T. Chem. Commun. 2011, 47, 9615. (s) Pan, Y.;
Wang, S.; Kee, C. W.; Dubuisson, E.; Yang, Y.; Loh, K. P.; Tan, C.-H.
Green Chem. 2011, 13, 3341. (t) Pan, Y.; Kee, C. W.; Chen, L.; Tan,
8
FIrpic
83
9
FIrpic
8
10
11
FIrpic (no light)
no cat.
NR
NR
a Reaction conditions: N,N-dimethylaniline 1a (3 mmol), phenyl
isocyanate 2a (0.3 mmol), and catalyst (1 mol %) in solvent (2 mL),
irradiated under 14 W CFL at rt for 24 h. b GC yield.
examplesofradical addition toisocyanate. Incontinuation
of our interest in utilizing visible-light photoredox radical
chemistry as a good alternative to traditional radical
initiators, including Et3B/O2,13 we started the study of
screening photocatalysts for the reaction of N,N-dimethy-
laniline with phenyl isocyanate under visible-light irradia-
tion. Typical Ru- or Ir-based catalysts failed to promote
the reaction (Table 1, entries 1ꢀ5), though these catalysts
had been applied to the functionalization of a N-R-sp3
CꢀH bond of dimethylaniline. To our delight, the desired
product 3a was observed when FIrpic was employed as the
photosensitizer, albeit at only 10% GC yield (entry 6).
Compared to Ir(ppy)3, a phenylpyridine ligand was re-
placed by a more electron-withdrawing piconate ligand
in FIrpic. The maximum emission wavelength of photo-
activiated FIrpic (471 nm) is significantly blue-shifted
compared to that of Ir(ppy)3 (516 nm) in acetonitrile.14
Therefore, the E0,0 of FIrpic (2.63 eV) is greater than those
€
C.-H. Green Chem. 2011, 13, 2682. (u) Hari, D. P.; Konig, B. Org. Lett. 2011,
13, 3852. (v) Freeman, D. B.; Furst, L.; Condie, A. G.; Stephenson, C. R. J.
ꢀ
ꢀ
Org. Lett. 2011, 14, 94. (w) Condie, A. G.; Gonzalez-Gomez, J. C.;
Stephenson, C. R. J. J. Am. Chem. Soc. 2010, 132, 1464. (x) Jiang, G.;
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Fronert, J. ACS Catal. 2012, 2, 2810. (b) Miyake, Y.; Nakajima, K.;
Nishibayashi, Y. Chem.;Eur. J. 2012, 18, 16473. (c) Xuan, J.; Cheng,
Y.; An, J.; Lu, L.-Q.; Zhang, X.-X.; Xiao, W.-J. Chem. Commun. 2011,
47, 8337.
(8) (a) Vila, C.; Rueping, M. Green Chem. 2013, 15, 2056. (b)
Rueping, M.; Vila, C. Org. Lett. 2013, 15, 2092.
(9) (a) Zhu, S.; Rueping, M. Chem. Commun. 2012, 48, 11960. (b)
Wang, Z.-Q.; Hu, M.; Huang, X.-C.; Gong, L.-B.; Xie, Y.-X.; Li, J.-H.
J. Org. Chem. 2012, 77, 8705. (c) Maity, S.; Zhu, M.; Shinabery, R. S.;
Zheng, N. Angew. Chem., Int. Ed. 2012, 51, 222. (d) Dai, C.; Meschini,
F.; Narayanam, J. M. R.; Stephenson, C. R. J. J. Org. Chem. 2012, 77,
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Chem., Int. Ed. 2012, 51, 8050.
(10) (a) Kohls, P.; Jadhav, D.; Pandey, G.; Reiser, O. Org. Lett. 2012,
14, 672. (b) Miyake, Y.; Nakajima, K.; Nishibayashi, Y. J. Am. Chem.
Soc. 2012, 134, 3338. (c) Miyake, Y.; Ashida, Y.; Nakajima, K.;
Nishibayashi, Y. Chem. Commun. 2012, 48, 6966. (d) Ju, X.; Li, D.;
Li, W.; Yu, W.; Bian, F. Adv. Synth. Catal. 2012, 354, 3561. (e) Zhu, S.;
Das, A.; Bui, L.; Zhou, H.; Curran, D. P.; Rueping, M. J. Am. Chem.
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J. Org. Chem. 2013, 78, 4107.
2þ
of Ir(ppy)3 (2.40 eV) and Ru(bpy)3 (2.02 eV). As a re-
sult, the Eox Ir(III)*/Ir(II) and Ered Ir(II)/Ir(III) of FIrpic
are higher than typical Ir- or Ru-based catalysts, which
presumably is the key to the success of the reaction.
(11) McNally, A.; Prier, C. K.; MacMillan, D. W. C. Science 2011,
334, 1114.
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Trans. 2012, 41, 9373.
B
Org. Lett., Vol. XX, No. XX, XXXX

The reaction was then carried out in several different
solvents (entries 6ꢀ9). It turned out that methylene chlo-
ride and acetonitrile gave the best results, 84% and 83%
GC yields respectively (entries 7 and 8). Methylene chlo-
ride was selected as the reaction solvent because it gave a
relatively cleaner reaction. Control reactions showed that
no reaction occurred in the absence of either photocatalyst
or visible light, confirming the reaction is a visible light
promoted reaction (entries 10ꢀ11).
Table 2. Scope Survey of Visible Light-Mediated Reaction of
Dimethylaniline Derivatives and Aryl Isocyanatea
We next examined the substrate scope of this transfor-
mation with the optimized reaction conditions. The results
showed that it was fairly general and applicable to a broad
scope of substrates (Table 2). For the reaction of N,N-
dimethylanilineand phenylisocyanate, the isolatedyield of
the product 3a was 77% (entry 1). Various substituted
N,N-dimethylanilines were investigated. The steric effect
seemed to be significant to the reaction. While the para-
and meta-methyl N,N-dimethylanilines gave good results
(75% and 88% for 3b and 3c, respectively, entries 2 and 3),
the ortho-methyl N,N-dimethylaniline only afforded the
corresponding product 3d in 28% yield (entry 4). 3,5-
Dimethyl-N,N-dimethylaniline afforded the correspond-
ingR-amino amide3ein88%isolatedyield (entry5). Weak
electron-withdrawing groups, such as Br and Cl, gave
lower yields (54% and 59% for 3f and 3g, respectively,
entries 6 and 7). A strong electron-withdrawing group
totally shut down the reaction. For example, 4-dimethyla-
minopryidine did not react under the optimized reac-
tion conditions. N,N-Dimethylaniline with an electron-
donating group on the benzene ring, meta-methoxyl
N,N-dimethylamine, afforded 3h in 64% yield (entry 8).
Cyclic aniline derivative N-phenylpyroridine worked ni-
cely to give the corresponding product 3i in 80% yield
(entry 9). Different isocyanates were examined as well.
Methyl, trifluoro methoxy, chloro, and dichloro substi-
tuted phenyl isocyanate, when reacted with N,N-dimethy-
laniline, successfully afforded the desired products 3jꢀ3m
in 64%, 66%, 69%, and 59% isolated yield, respectively
(entry 10ꢀ13). However, alkyl isocyanate did not give
the desired R-amino amide under the current reaction
conditions.
Tofurther extend the scope of thisreaction, wetestedthe
reaction with isothiocyanates. To our delight, the reaction
of N,N-dimethylaniline and phenyl isothiocyanate af-
forded the corresponding R-amino thioamide 5a in 79%
isolated yield (Table 3, entry 1). Substituted phenyl iso-
thiocyanates 4bꢀ4e with methyl, methoxyl, bromo, and
chloro groups afforded the desired products 5bꢀ5e in 62%,
46%, 68%, and 48% yields, respectively (entries 2ꢀ5). The
results showed that it is a practical protocol for R-amino
thioamide synthesis.
a Reaction conditions: N,N-dimethylaniline derivative 1 (3 mmol),
aryl isocyanate 2 (0.3 mmol), and FIrpic (1 mol %) in CH2Cl2 (2 mL),
irradiated under 14 W CFL at rt for 24 h. b Isolated yield.
A proposed mechanism is illustrated in Figure 2. N,N-
Dimethylaniline (1a, Eox = 0.7 V vs SCE) was oxidized by
visible light excited FIrpic*(Eox = 0.72V vs SCE)14 togive
amino radical cation 6 and the [FIrpic]ꢀ anion. Because
no species in the system could abstract a hydrogen atom
from the amino radical cation, the amino radical cation
6 gives up a proton to afford R-aminoalkyl radical 7. The
R-aminoalkyl radical 7 could not form an iminium ion
through another SET because there is no other strong
oxidant in the system. As a consequence, the R-aminoalkyl
radical 7 undergoes nucleophilic radical addition to iso-
cyanate to form a new CꢀC bond and afford R-amino
amido radical 8. The reductive potential of the amido
(15) O’Reilly, R. J.; Karton, A.; Radom, L. J. Phy. Chem. A 2013,
117, 460.
Org. Lett., Vol. XX, No. XX, XXXX
C

pathway.8 The reaction progress was monitored by in situ
IR. Almost no reaction occurred during the “dark” peri-
ods, while the reaction proceeded smoothly with the
reintroduction of light (see Supporting Information). It
was good evidence that the reaction went through the
photoinduced pathway. However, a short-lived chain pro-
pagation mechanism could not be ruled out.
Table 3. Scope Survey of Visible Light-Mediated Reaction of
N,N-Dimethylaniline and Aryl Isothiocyanatea
Figure 2. Proposed mechanism.
In summary, a visible-light-promoted sp3 CꢀH bond
functionalization/CꢀC bond formation reaction of ter-
tiary amine with aryl isocyanate or aryl isothiocyanate
through an R-aminoalkyl radical intermediate was devel-
oped. R-Amino amides and R-amino thioamides were
successfully obtained in the process. FIrpic was discovered
a Reactions conditions: N,N-dimethylaniline 1a (3 mmol), aryl iso-
thiocyanate 4 (0.3 mmol), and FIrpic (1 mol %) in CH2Cl2 (2 mL),
irradiated under 14 W CFL at rt for 24 h. b Isolated yield.
radical is much higher than the typical amino radical
because the single electron is more located on nitrogen in
the amido radical while the negative charge is mostly
located on oxygen in the amide anion. However, there
is no experimental reductive potential data available for
the R-amino amido radical. According to a theoretical
calculation, the Ered of R-amino amido radicals is between
0.94 and 1.48 V.15 The reductive potentials of typical
Ru/Ir-based photoredox catalysts might not be high en-
ough to reduce R-amino amido radical 8. In contrast,
[FIrpic]ꢀ anion (Ered = 1.91 V vs SCE)14 is able to reduce
the R-amino amido radical 8. Therefore, a single electron
transfer from the [FIrpic]ꢀ anion to the R-amino amido
radical 8 completes the photoredox cycle and generates
R-amino amide anion 9, which affords the final R-amino
amide product 3a by abstracting a proton. The R-amino
amido radical pathway is complementary to the recently
reported visible-light protoredox multicomponent reac-
tion of tertiary amine, isonitrile, and alcohol, which gives
a similar R-amino amide product through an iminium ion
to be the effective catalyst presumably due to the high E0,0
.
Investigations of the radical addition reactions of the
R-aminoalkyl radical generated from photooxidation of
a tertiary amine with other electrophiles are currently on-
going in our laboratory. The results will be reported in due
course.
Acknowledgment. Financial support is provided by
NSFC (21102097), the Specialized Research Fund for the
Doctoral Programof HigherEducation(20103201120006),
and Beijing National Laboratory for Molecular Sciences
(BNLMS).
Supporting Information Available. Experimental pro-
1
cedures and H and 13C NMR spectra for all products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX