Photochemically induced radical transformation of C(sp3)-H bonds to C(sp3)-CN bonds

Article abstract of DOI:10.1021/ol202659e

A general protocol for direct transformation of unreactive C(sp ³)-H bonds to C(sp³)-CN bonds has been developed. The C-H activation was effected by photoexcited benzophenone, and the generated carbon radical was subsequently trapped with tosyl cyanide to afford the corresponding nitrile in a highly efficient manner. The present methodology is widely applicable to versatile starting materials and, thus, serves as a powerful tool for selective one-carbon elongation for construction of architecturally complex molecules.

Full text of DOI:10.1021/ol202659e

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5928–5931
Photochemically Induced Radical
Transformation of C(sp3)ꢀH Bonds
to C(sp3)ꢀCN Bonds
Shin Kamijo, Tamaki Hoshikawa, and Masayuki Inoue*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
inoue@mol.f.u-tokyo.ac.jp
Received October 3, 2011
ABSTRACT
A general protocol for direct transformation of unreactive C(sp3)ꢀH bonds to C(sp3)ꢀCN bonds has been developed. The CꢀH activation was
effected by photoexcited benzophenone, and the generated carbon radical was subsequently trapped with tosyl cyanide to afford the
corresponding nitrile in a highly efficient manner. The present methodology is widely applicable to versatile starting materials and, thus,
serves as a powerful tool for selective one-carbon elongation for construction of architecturally complex molecules.
The formation of new carbonꢀcarbon bonds is one of the
most important transformations in organic chemistry. The
direct transformation of CꢀH bonds to CꢀC bonds has
attracted much interest in recent years, because it avoids
prior functional group manipulations for the synthesis of a
preactivated precursor and thus greatly streamlines syn-
thetic sequences. Among such reactions, functionalization
of unreactive C(sp3)ꢀH bonds is particularly advantage-
ous for the construction of highly complex natural products,
whichgenerallycontainahighratioofsp3-hybridized carbon
centers. However, this extremely useful reaction remains
challenging mainly due to the lack of general strategies
for activating inert C(sp3)ꢀH bonds in comparison to
C(sp2)ꢀH bonds of aromatic compounds.1,2 Here we report
a simple, yet powerful, protocol for direct conversion of
C(sp3)ꢀH bonds to C(sp3)ꢀCN bonds.3 The present cya-
nation has a broad substrate scope. Alkanes, benzylic
compounds, ethers, alcohols, and amine derivatives all react
to generate nitriles 2 under photochemical conditions using
benzophenone (Ph2CdO) as a CꢀH activator and tosyl
cyanide (TsCN) as a radical acceptor (Scheme 1).4,5 Since
the attached nitrile moieties can be utilized as handles for
(3) We recently reported direct photoinduced C(sp3)ꢀH acylation
and carbamoylation. (a) Kamijo, S.; Hoshikawa, T.; Inoue, M. Tetra-
hedron Lett. 2010, 51, 872. (b) Kamijo, S.; Hoshikawa, T.; Inoue, M.
Tetrahedron Lett. 2011, 52, 2885.
(1) For recent reviews on direct CꢀH transformations, see:
(a) Handbook of CꢀH Transformations; Dyker, G., Ed.; Wiley-VCH:
Weinheim, 2005; Vols. 1 and 2. (b) Handbook of Reagents for Organic
Synthesis: Reagents for Direct Functionalization of CꢀH Bonds; Paquette,
L. A., Fuchs, P. L., Eds.; Wiley: Chichester, 2007. (c) Special issue on `CꢀH
Functionalizations in organic synthesis': Chem. Soc. Rev. 2011, 40 (4).
(2) For recent reviews on direct C(sp3)ꢀH transformation to form
CꢀC bonds, see: (a) Ishii, Y.; Sakaguchi, S.; Iwahama, T. Adv. Synth.
Catal. 2001, 343, 393. (b) Fokin, A. A.; Schreiner, P. R. Adv. Synth.
Catal. 2003, 345, 1035. (c) Knorr, R. Chem. Rev. 2004, 104, 3795.
(d) Davies, H. M.; Manning, J. R. Nature 2008, 451, 417. (e) Kakiuchi,
F.; Kochi, T. Synthesis 2008, 3013. (f) Chen, X.; Engle, K. M.; Wang, D.-
H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (g) Li, C.-J. Acc.
Chem. Res. 2009, 42, 335. (h) Akindele, T.; Yamada, K.; Tomioka, K.
Acc. Chem. Res. 2009, 42, 345. (i) Daugulis, O.; Do, H.-Q.; Shabashov,
D. Acc. Chem. Res. 2009, 42, 1074. (j) Shi, W.; Liu, C.; Lei, A. Chem. Soc.
Rev. 2011, 40, 2761. (k) Klussmann, M.; Sureshkumar, D. Synthesis
2011, 353. (l) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293.
(4) Representative examples of direct C(sp3)ꢀH cyanation, which are
mostly limited to amine derivatives, with allylic and benzylic compounds
€
as starting material. (a) Muller, E.; Huber, H. Chem. Ber. 1963, 96, 670.
€
(b) Muller, E.; Huber, H. Chem. Ber. 1963, 96, 2319. (c) Hayashi, Y.;
Mukaiyama, T. Chem. Lett. 1987, 1811. (d) Lemaire, M.; Doussot, J.;
Guy, A. Chem. Lett. 1988, 1581. (e) Zhdankin, V. V.; Kuehl, C. J.;
Krasutsky, A. P.; Bolz, J. T.; Mismash, B.; Woodward, J. K.; Simonsen,
A. J. Tetrahedron Lett. 1995, 36, 7975. (f) Zheng, Z.; Hill, C. L. Chem.
Commun. 1998, 2467. (g) Tajima, T.; Nakajima, A. J. Am. Chem. Soc.
2008, 130, 10496. (h) Murahashi, S.-I.; Nakae, T.; Terai, H.; Komiya, N.
J. Am. Chem. Soc. 2008, 130, 11005. (i) Singhal, S.; Jain, S. L.; Sain, B.
Chem. Commun. 2009, 2371. (j) Han, W.; Ofial, A. R. Chem. Commun.
2009, 5024. (k) Shu, X.-Z.; Xia, X.-F.; Yang, Y.-F.; Ji, K.-G.; Liu, X.-Y.;
Liang, Y.-M. J. Org. Chem. 2009, 74, 7464. (l) Allen, J. M.; Lambert,
€
T. H. J. Am. Chem. Soc. 2011, 133, 1260. (m) Hari, D. P.; Konig, B. Org.
Lett. 2011, 13, 3852.
r
10.1021/ol202659e
Published on Web 10/12/2011
2011 American Chemical Society

syntheses of various carbon-branched skeletons via further
chain extension, this methodology holds promise for appli-
cation to complex molecule synthesis.
accessible radical acceptor, TsCN, in the presence of other
potentially reactive species, leading to nitrile 2a with expul-
sion of sulfinyl radical D.9 When D abstracts the hydrogen
from ketyl radical B, it regenerates Ph2CdO to provide
sulfinic acid and closes the cycle.
Scheme 1. Direct Photochemical Transformation of C(sp3)ꢀH
Bonds to C(sp3)ꢀCN Bonds
Table 1. Optimization of Cyanation Conditionsa
To screen efficient photochemical conditions6 for the
direct CꢀH cyanation, we first selected dioxane 1a as a
substrate, based on the expectation that the symmetry of 1a
would simplify the outcome of the reaction.7 Among a
variety of reactants, it was found that a reagent combination
of TsCN8 (1 equiv) and Ph2CdO (1 equiv) efficiently pro-
moted the conversion of 1a (8 equiv) to nitrile 2a in benzene
(74% yield, entry 1, Table 1). In this reaction, recovery of
Ph2CdO (59%) and formation of its dimer (1,1,2,2-tetra-
phenylethane-1,2-diol) were observed. Whereas the absence
of Ph2CdO resulted in no product formation and recovery
of TsCN (entry 2), using different amounts of Ph2CdO
(0.5 equiv, entry 3) or 1a (2 equiv, entry 4) led to generation
of 2a in reasonable yields. When dioxane 1a was also
employed as the solvent, the cyanation was complete within
1 h to provide 2a in 85% yield (entry 5). The reaction also
proceeded in both MeCN (entry 6) and t-BuOH (entry 7).
Judging from the high yield of 2a and recovered Ph2CdO
even when using a reduced amount (entry 8), use of MeCN
as the solvent appeared to be the most favorable for the
photochemical reaction.
Ph2CdO
yield, %b
Ph2CdO
entry
solvent
equiv
t, h
2a
recovery
1
benzene
benzene
benzene
benzene
dioxane
MeCN
1
6
74c
0d
64c
46
59
ꢀ
2
0
12
12
24
1
3
0.5
1
<4
48
90
87
<5
88
4e
5f
6
1
85
1
6
72 (63)c,g
63
7
t-BuOH
MeCN
1
18
6
8
0.5
74
a Reaction conditions: 1a/TsCN/Ph2CdO = 8:1:1, solvent (0.04 M),
rt, irradiated using a Riko 100 W medium pressure mercury lamp unless
otherwise noted. b Yield was determined by NMR analysis of the crude
mixture. Isolated yield is shown in parentheses. c TsCN was recovered in
ca. 10% yield. d TsCN was recovered in 83% yield. e The reaction was
conducted using 2 equiv of 1a. Recovery of TsCN (21%) was observed
after the reaction. f Dioxane 1a was employed as a solvent; 1a/TsCN/
Ph2CO = ∼300:1:1. g Due to its volatile nature, the isolated yield of 2a
was lower than that indicated by NMR analysis.
Having successfully developed this high-yielding cyana-
tion protocol, we next investigated chemoselective func-
tionalization of a variety of electron-rich CꢀH bonds
adjacent to oxygen- and nitrogen-based functional groups
(Table 2). The photoreactions of THF 1b and phthalan 1c
proceeded smoothly to produce nitriles 2b10 and 2c, respec-
tively, in excellent yields (entries 2 and 3). Monocyanation
took place exclusively for 15-crown-5 ether 1d, despite the
presence of many potentially reactive ethereal CꢀH bonds
(entry 4). While the CꢀH bond adjacent to the primary
hydroxyl group of 1e was selectively functionalized to afford
cyanohydrin 2e (entry 5), treatment of 1-cyclopropylethanol
1f under the same conditions quantitatively furnished 1-cyano-
4-pentanone 2f via radical-promoted ring opening of the
cyclopropane and subsequent CN trapping (entry 6).
Exclusive formation of 2f instead of the corresponding
cyanohydrin confirmed the radical formation at the OH-
substituted carbon during the course of the reaction.
The single-step conversion of the amine derivatives 1gꢀ1i
to the R-amino acid analogues was realized under the same
conditions (entries 7ꢀ9, Table 2). Both the Boc-protected
pyrrolidine 1g and isobutylamine 1h were cyanated selec-
tively at the carbon center adjacent to the nitrogen atom,
affording proline analogue 2g (entry 7) and valine analogue
The direct photoinduced CꢀH cyanation of dioxane 1a to
2a should consist of a series of well-ordered radical reactions
(Scheme 2).3 Electrophilic oxyl radical A, photochemically
generated from Ph2CdO, abstracts the hydrogen of the
electron-rich C(sp3)ꢀH bond of 1a to furnish carbon radicals
Band C. Next, the nucleophilic R-alkoxy radical Cselectively
reacts with the electron-deficient and sterically most
(5) Nitrile-containing pharmaceuticals have recently been high-
lighted. Fleming, F. F.; Yao, L.; Ravikumar, P. C.; Funk, L.; Shook,
B. C. J. Med. Chem. 2010, 53, 7902.
(6) For recent reviews on photochemical reactions, see: (a) Fagnoni,
M.; Dondi, D.; Ravelli, D.; Albini, A. Chem. Rev. 2007, 107, 2725.
(b) Hoffmann, N. Chem. Rev. 2008, 108, 1052. See also references in ref 3a.
(7) Dioxane has less reactive R-oxy CꢀH bonds in comparison to cyclic
ethers such as tetrahydrofuran and tetrahydropynan. (a) Malatesta, V.;
Ingold, K. U. J. Am. Chem. Soc. 1981, 103, 609. (b) Jenkins, I. D. J. Chem.
Soc., Chem. Commun. 1994, 1227. (c) Busfield, W. K.; Grice, D.; Jenkins,
I. D. J. Chem. Soc., Perkin Trans. 2 1994, 1079.
(8) For representative examples of radical reactions using TsCN as a
cyanogen source, see: (a) Barton, D. H. R.; Jaszberenyl, J. C.; Theodorakis,
E. A. Tetrahedron 1992, 48, 2613. (b) Kim, S.; Song, H.-J. Synlett
2002, 2110. (c) Kim, S.; Cho, C. H.; Kim, S.; Uenoyama, Y.; Ryu, I.
Synlett 2005, 3160. (d) Schaffner, A.-P.; Darmency, V.; Renaud, P.
Angew. Chem., Int. Ed. 2006, 45, 5847. (e) Gaspar, B.; Carreira, E. M.
Angew. Chem., Int. Ed. 2007, 46, 4519.
(9) Formation of ArSO2SO2Ar, dimerized sulfinyl radical D, was
observed in some cases. For the reported 1H NMR data of the disulfone,
see: (a) Liu, Y.; Zhang, Y. Tetrahedron Lett. 2003, 44, 4291. (b) Weber,
W. G.; McLeary, J. B.; Sanderson, R. D. Tetrahedron Lett. 2006, 47,
4771.
(10) Bailey, S.; Humphries, P. S.; Skalitzky, D. J.; Su, W.-G.;
Zehnder, L. R. Patent WO 2004/092145 A1, 2004.
Org. Lett., Vol. 13, No. 21, 2011
5929

Scheme 2. Proposed Mechanism for Transformation of C(sp3)ꢀH
Bonds to C(sp3)ꢀCN Bonds
Table 2. CꢀH Cyanation Adjacent to Heteroatom-Based
Functionalitiesa
2h (entry 8), respectively, in high yields. The reaction of cyclic
carbamate 1i in turn generated threonine derivative 2i as a
single isomer through 1,2-stereoinduction (entry 9).
The cyanation protocol developed for the heteroatom-
substituted substrates was successfully applied to functio-
nalization of the less reactive CꢀH bonds of alkanes and
benzylic compounds (Table 3). Cyclooctane 1j was effi-
ciently converted to the corresponding carbon-branched
carbocycle 2j under the optimized conditions (entry 1). The
reactions of adamantane 1k (entry 2) and its hydroxylated
derivative 1l (entry 3) both proceeded exclusively at the
methine positions to install the quaternary carbons of 2k
and 2l, respectively. The cyanation of benzoate 1m gave
rise to compound 2m with a quaternary carbon (entry 4).
The displayed chemoselectivities in entries 2ꢀ4 must ori-
ginate from the higher reactivities of the more alkylated
CꢀH bonds.11 Thus, the electron-rich tertiary CꢀH bond
was selectively converted to a CꢀCN bond in the presence
of primary and secondary CꢀH bonds. Intriguingly, the
contrasting results in entry 5, Table 2 and entry 4, Table 3
demonstrated that the reaction site can be predictably
directed to either the R-alkoxy carbon at C1 or the tertiary
carbon at C4 just by detaching or attaching the electron-
withdrawing Bz group.
a Reaction conditions: 1/TsCN/Ph2CdO = 8:1:1, MeCN (0.04 M),
rt, irradiated using a Riko 100 W medium pressure mercury lamp unless
otherwise noted. b Isolated yield. NMR yield is shown in parentheses.
c Benzene was employed as a solvent instead of MeCN.
and installation of the electron-withdrawing acetoxy
group (1p) decreased the yield (entry 7). The cyanation
of ibuprofen methyl ester 1q occurred on the isobutyl
substituent to give benzyl nitrile 2q as the major
product along with its regioisomer 2q0 (entry 8). The
results in entry 8 showed the higher reactivity of the
benzylic CꢀH bond in comparison to the tertiary CꢀH
bond.2
The reactivity of the benzylic CꢀH bond was next
examined. The reaction of butylbenzene 1n furnished
benzyl cyanide 2n in 41% yield (entry 5, Table 3).
Installation of the electron-donating methoxy group
on the phenyl ring (1o) increased the yield (entry 6),
Direct chemoselective cyanation of more complex struc-
tures demonstrated the general applicability of the present
transformation (Scheme 3). The cyanation of proline
derivative 1r took place chemoselectively at the methy-
lene CꢀH bond adjacent to the nitrogen atom, providing
(11) It was often demonstrated that the more electron-rich CꢀH
bonds are more reactive toward CꢀH bond functionalizations (R3CH
> R2CH2 > RCH3) when using electrophilic reactants. For example,
see: (a) Mello, R.; Fiorentino, M.; Fusco, C.; Curci, R. J. Am. Chem.
Soc. 1989, 111, 6749. (b) Chen, M. S.; White, M. C. Science 2007, 318,
783. (c) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417.
(d) Fiori, K. W.; Espino, C. G.; Brodsky, B. H.; Du Bois, J. Tetrahedron
2009, 65, 3042. (e) Newhouse, T.; Baran, P. S. Angew. Chem., Int. Ed.
2011, 50, 3362. (f) Kamijo, S.; Amaoka, Y.; Inoue, M. Synthesis 2010, 14,
2475. (g) Kamijo, S.; Matsumura, S.; Inoue, M. Org. Lett. 2010, 12,
4195.
(12) The stereochemistry of the ester-attached carbon of 2r was con-
25
firmed to be retained. Optical rotation of 2r: [R]D ꢀ100.0. For compar-
ison, see: (a) Yamamoto, Y.; Hoshino, J.; Fujimoto, Y.; Ohmoto, J.;
Sawada, S. Synthesis 1993, 298. (b) Sunilkumar, G.; Nagamani, D.;
Argade, N. P.; Ganesh, K. N. Synthesis 2003, 2304.
5930
Org. Lett., Vol. 13, No. 21, 2011

Table 3. Cyanation of Alkanes and Benzylic Compoundsa
Scheme 3. Cyanation of Proline Derivative, Protected Cyclo-
hexane-1,2-Diol, and (ꢀ)-Ambroxide
71%) was observed when treating a limited amount of 1t
(1 equiv) with excess amounts of TsCN (4 equiv).
In conclusion, we have developed a photochemical proto-
col for the direct transformation of unreactive C(sp3)ꢀH
bonds to C(sp3)ꢀCN bonds by the action of TsCN and
Ph2CdO. The CꢀH cyanation proceeds at ambient tem-
perature with high applicability to various starting materials
including alkanes, benzylic compounds, ethers, alcohols, and
amine derivatives. Overall, the reaction selectively installs a
one-carbon unit onto a starting molecular framework at the
most electron-rich CꢀH bond. Simplicity in the operation,
predictability in the stereo- and chemoselectivity, and effi-
ciency in the single-step construction of hindered tetrasub-
stituted carbons are particularly of note. Since the branched
CN moiety can be universally used as a reactive functional
group for further carbon elongation, the present CꢀH
transformation should serve as a powerful tool for the
synthesis of complex natural products and molecules of
pharmaceutical interest.
a Reaction conditions: 1/TsCN/Ph2CdO = 8:1:1, MeCN (0.04 M),
rt, irradiated using a Riko 100 W medium pressure mercury lamp unless
otherwise noted. b Isolated yield. c Trace amount of product cyanated at
methylene CꢀH bond was observed. d Benzene was employed as a
solvent instead of MeCN. e Recovery of TsCN was observed.
trans-substituted product 2r in a completely stereoselective
fashion (91% yield).12 When the acetal-protected cis-1,2-
diol 1s was subjected to the reaction in the presence of 2,6-
di(tert-butyl)pyridine,13 cis-fused nitrile 2s was obtained
in 84% yield as the sole isomer. Thus, this single reaction
enabled the introduction of a tetrasubstituted carbon
center stereoselectively via functionalization of a hindered
tertiary ethereal CꢀH bond. Cyanation of (ꢀ)-ambroxide
1t again exhibited high chemoselectivity at the ethereal
CꢀH bond, leading to nitrile 2t in 89% yield without
affecting the other methylene and methine CꢀH bonds.
Importantly, only a slight decrease in yield (89% vs
Acknowledgment. This research was financially sup-
ported by the Funding Program for Next Generation
World-Leading Researchers (JSPS) to M.I.
Supporting Information Available. Experimental pro-
cedures and spectroscopic and analytical data for relevant
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(13) Because of the acid sensitive nature of the acetals of 1s and 2s,
2,6-di(tert-butyl)pyridine was added for neutralization of the generated
sulfinic acid during the reaction (see Scheme 2). The yield of 2s
significantly decreased, when the reaction was performed without addi-
tion of 2,6-di(tert-butyl)pyridine.
Org. Lett., Vol. 13, No. 21, 2011
5931