Photochemically induced radical alkynylation of C(sp3)-H bonds

Article abstract of DOI:10.1039/c2ob26785c

A general strategy for photochemical alkynylation of unreactive C(sp ³)-H bonds has been developed. After C-H abstraction by the photo-excited benzophenone, a two-carbon unit was efficiently transferred to the generated radical from 1-tosyl-2-(trimethylsilyl)acetylene to afford the alkynylated product. The present reaction enables construction of various tri- and tetra-substituted carbons from heteroatom-substituted methylenes, methines and alkanes in a highly chemoselective fashion, and would serve as a new synthetic strategy for rapid construction of complex structures. The Royal Society of Chemistry.

Full text of DOI:10.1039/c2ob26785c

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Photochemically induced radical alkynylation of
C(sp3)–H bonds†
Cite this: Org. Biomol. Chem., 2013, 11,
164
Tamaki Hoshikawa, Shin Kamijo‡ and Masayuki Inoue*
A general strategy for photochemical alkynylation of unreactive C(sp3)–H bonds has been developed.
After C–H abstraction by the photo-excited benzophenone, a two-carbon unit was efficiently transferred
to the generated radical from 1-tosyl-2-(trimethylsilyl)acetylene to afford the alkynylated product. The
present reaction enables construction of various tri- and tetra-substituted carbons from heteroatom-sub-
stituted methylenes, methines and alkanes in a highly chemoselective fashion, and would serve as a new
synthetic strategy for rapid construction of complex structures.
Received 11th September 2012,
Accepted 12th October 2012
DOI: 10.1039/c2ob26785c
www.rsc.org/obc
(Scheme 1).6–8 The present reaction enables the construction
of various tri- and tetra-substituted carbons from heteroatom-
Introduction
Carbon–carbon (C–C) bond formation plays a central role in substituted methylenes, methines and alkanes, and provides a
chemical syntheses, and innovations in these types of reac- new synthetic strategy for rapid construction of architecturally
tions profoundly improve the overall synthetic efficiency. complex molecules.
Among the various C–C forming strategies, the direct trans-
formation of C(sp3)–H bonds into C(sp3)–C bonds has
attracted much interest in recent years, since it eliminates
Results and discussion
prior functional group manipulations for substrate activation,
Our plan for the direct C(sp3)–H alkynylation is illustrated in
Scheme 1. We employed benzophenone (Ph2CvO) as an oxyl
radical precursor and 1-tosyl-2-(trimethylsilyl)acetylene 2 as an
alkynylating agent (Scheme 1).9,10 The photochemically
formed A is an electrophilic oxyl radical, and thus would chemo-
selectively abstract the hydrogen of an electron-rich C–H
bond of 1 to furnish carbon radical C.11 Upon reaction with
the electron-deficient alkyne 2, C is expected to preferentially
add at the α-position than the β-position of the sulfonyl group,
due to the unfavorable steric interaction with the bulky
resulting in simpler and shorter synthetic schemes.1,2
Typically, such a direct transformation is a challenge,
because the reagents are required to cleave the requisite strong
C(sp3)–H bond selectively without affecting other C–H bonds
in the organic molecules. Recently, we employed photochemi-
cally-generated highly reactive oxyl radicals to induce C(sp3)–H
functionalizations,3 and developed chemoselective acylation,4a
carbamoylation,4b and cyanation strategies.4c These studies
prompted us to apply the photochemical reaction system for
attachment of an alkyne, a more versatile building block.
The carbon–carbon triple bond is one of the most impor-
tant functional groups in organic chemistry due to its unique
physicochemical properties, as well as the wide range of avail-
able methods for its functionalization.5 Therefore, direct trans-
fer strategies of acetylene to organic molecules are highly
desirable in the syntheses of functional materials, pharmaceu-
ticals and natural products. Here we report direct alkynylation
of C(sp3)–H bonds under photo-irradiation conditions
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan.
E-mail: inoue@mol.f.u-tokyo.ac.jp; Fax: (+81) 3-5841-0568
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c2ob26785c
‡Current address: Graduate School of Science and Engineering, Yamaguchi
University, Yoshida, Yamaguchi 753-8511, Japan.
Scheme 1 Direct alkynylation of C(sp3)–H bonds and proposed reaction
mechanism.
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Table 1 Optimization of alkynylation conditionsa
methylene proximal to the N-Boc group to generate 3i (entry
9), clearly indicating that the C–H bond attached to the nitro-
gen atom is more reactive than that attached to the oxygen
atom. When the substrates with preexisting stereocenters were
used, high diastereoselectivity was observed (entries 10 and
11). C–H alkynylations of the cyclic carbamate 1j and the
proline derivative 1k stereoselectively produced the 1,2-trans-
disubstituted 3j and the 1,3-trans-disubstituted 3k, respect-
ively, in a completely chemo- and stereoselective fashion.
The present protocol realized high-yielding functionaliza-
tions of oxygen-substituted methylenes (Table 2, entries
12–15). Dioxane 1l (entry 12) and 15-crown-5 ether 1m (entry
13) underwent mono-alkynylation to produce the adducts 3l
and 3m, respectively, while (−)-ambroxide 1n was chemoselec-
tively alkynylated at the ethereal C–H bond among other
potentially reactive C–H bonds to provide 3n (entry 14). More-
over, two carbon-elongation of the non-protected primary
alcohol 1o was possible, leading to the propargylic alcohol 3o
(entry 15). The order of the favorable reactive sites is clarified
from Table 2, and determined to be nitrogen- > oxygen- > non-
heteroatom-substituted carbons.
Despite their more sterically hindered nature, tertiary C–H
bonds adjacent to nitrogen- and oxygen-based functional
groups were efficiently transformed (Table 3). Alkynylation of
5-methylpyrrolidin-2-one 1p under the optimized conditions
in Table 1 (conditions A: 1p/2/Ph2CvO = 8 : 1 : 1) resulted in
formation of the alkyne-attached tetrasubstituted carbon of 3p
in quantitative yield within 1 h (entry 1). Because the product
3p does not have a reactive propargylic C–H bond, increasing
the irradiation time did not cause over-reactions of 3p, and
thus reducing the reagent amount was possible without
decreasing the yield. Namely, 3p was obtained in 75% yield
even upon irradiating a limited amount of 1p (1 equiv.) with
1.5 equiv. of 2 and 0.5 equiv. of Ph2CvO (conditions B: 1p/2/
Ph2CvO = 1 : 1.5 : 0.5) for 10 h (entry 2). Significantly, con-
ditions B were applicable for construction of nitrogen- and
oxygen-substituted tetrasubstituted carbons in high yields
(entries 3–6). The bicyclic lactam 1q14 was chemoselectively
alkynylated at the methine position in the presence of the less
hindered oxygen-substituted methylene, providing 3q in 81%
yield (entry 3).15,16 Mono-functionalization of both the cis- and
trans-diaminocyclohexane derivatives 1r and 1s17 took place
stereoselectively, providing the same cis-fused bicyclic com-
pound 3r as a sole product (entries 4 and 5). The configura-
tional change of the bicyclic system between 1s and 3r
supported the intermediacy of an α-amino carbon radical.4,18
Alkynylation of the ethereal tertiary C–H bond in the cyclo-
hexanediol derivative 1t stereoselectively furnished the cis-
fused ring system 3t in 70% yield (entry 6).15,19 Since the sec-
ondary alcohol 1u exhibited lower reactivity, conditions A were
again adopted to generate the propargylic alcohol 3u in 57%
yield (entry 7).
Yieldb Recoveryb
Entry 1, equiv. 2, equiv. Solvent
T (h) (%)
(%)
1
2
3
4
3
3
3
8
1
1
1
1
MeCN
4
4
1
1
53
52
57
83c
31
9
13
0
Benzene
t-BuOH
t-BuOH
a Reaction conditions: 1a, 2, Ph2CvO (1 equiv.), solvent (0.04 M), rt,
photo-irradiation using a Riko 100 W medium pressure mercury lamp.
b Yield was determined by NMR analysis. c Isolated yield.
trimethylsilyl group. Subsequent release of the tosyl radical D
from the produced vinyl radical intermediate would result in
formation of the alkynylated product 3, while D abstracts a
hydrogen from the ketyl radical B to regenerate Ph2CvO.
Importantly, high-yielding transformation from 1 to 3 is rea-
lized only when all the radical species properly follows the
series of reactions depicted in Scheme 1.
We first established the optimum photochemical con-
ditions for an efficient C–H alkynylation (Table 1). Pyrrolidi-
none 1a was selected as a substrate based on the expectation
that the nitrogen functionality would secure the selective func-
tionalization of its electron-rich nitrogen-substituted methyl-
ene. In fact, irradiation of 1a (3 equiv.), 2 (1 equiv.) and
Ph2CvO (1 equiv.) in MeCN with a medium-pressure mercury
lamp successfully provided the adduct 3a in 53% yield (entry
1). While the reaction proceeded in benzene and t-BuOH in
similar yields (entries 2 and 3), conversion in t-BuOH was
apparently faster in comparison to other solvents. The modest
yields in entries 1–3 appeared to originate from the undesired
reaction involving the reactive propargylic tertiary C–H bond of
3a, since disappearance of 3a was observed upon irradiation of
3a just in the presence of Ph2CvO.12 Consequently, a signifi-
cant improvement in the yield of 3a was attained by applying
8 equiv. of 1a in t-BuOH (83%, entry 4).13
The established conditions were next applied to a variety of
electron-rich secondary C–H bonds adjacent to nitrogen-based
functional groups (Table 2). Similar to alkynylation of the five-
membered lactam 1a (entry 1), both the six- and seven-mem-
bered lactams 1b and 1c were chemoselectively functionalized
to afford the corresponding adducts 3b and 3c, respectively, in
high yields (entries 2 and 3). The reactions of the protected
piperidines, bearing Boc 1d, Ac 1e, and Troc 1f, all efficiently
provided the corresponding products 3d–3f (entries 4–6). The
Boc-substituted alkylamine 1g and the Ph-substituted diethyl-
amine 1h were also converted to the non-cyclic products 3g and
3h, respectively (entries 7 and 8). In the case of N-Boc morpho-
line 1i, C–H functionalization chemoselectively occurred at the
The protocol was then utilized for the direct alkynylation of
C–H bonds of alkanes, which are known to be less reactive
than those of heteroatom-substituted compounds (Table 4).
Cyclooctane 1v was converted to the alkyne-branched
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Table 2 Alkynylation of C–H bonds of heteroatom-substituted methylenesa
Entry
Starting material
t (h)
Product
Yieldb (%)
1
2
3
1a: n = 1
1b: n = 2
1c: n = 3
1
1.5
2
3a
3b
3c
83
81
73
4
5
6
1d: R = Boc
1e: R = Ac
1f: R = Troc
1
1.5
1.5
3d
3e
3f
82
89
87
7
2.5
62
8
1.5
78
9
1
3
92
77
10
11
2
94
12c
13
2
1
75
82
14
1
74d
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Table 2 (Contd.)
Entry
15
Starting material
t (h)
Product
Yieldb (%)
73
2
a Reaction conditions: 1/2/Ph2CvO = 8 : 1 : 1, t-BuOH (0.04 M), rt, photo-irradiation. b Isolated yield. c 1l (16 equiv.) was used. d Mixture of
diastereomers (dr = 3 : 4).
Table 3 Alkynylation of C–H bonds of heteroatom-substituted methinesa
Entry
1
Starting material
Cond., t (h)
Product
Yieldb (%)
99
A, 1
2
B, 10
B, 7
75
81
3c
4
5
6c,d
1r: cis
1s: trans
B, 10
B, 20
3r
3r
80
52d
B, 12
70e
7
A, 4
57
a Conditions A: 1/2/Ph2CvO = 8 : 1 : 1, t-BuOH (0.04 M), rt, photo-irradiation; conditions B: 1–2–Ph2CvO = 1 : 1.5 : 0.5, t-BuOH (0.04 M), rt,
photo-irradiation. b Isolated yield. c Reaction was conducted in the presence of 2,6-di(t-butyl)pyridine (1 equiv.). d Recovery of 1 was observed in
10% yield. e Ph2CvO (1 equiv.) was used.
carbocycle 3v in 70% yield (entry 1). When the alcohol was structures (Tables 3 and 4, entries 2–4) demonstrated the
capped with an electron-withdrawing Ac group, alkynylation power and generality of the present methodology.
did not occur at the α-oxy carbon, but the most electron-rich
The synthetic utility of the introduced C–C triple bond was
and hindered tertiary C–H bond was selectively functionalized exemplified by the two functional group transformations
in the presence of less electron-rich primary and secondary from the proline derivative 3k (Scheme 2). Treatment of 3k
C–H bonds, giving rise to 3w in 54% yield (entry 2). In the case with RuO2 and Oxone20 transformed the alkyne moiety to
of the adamantane structures 1x and 1y, the reaction also pro- the carboxylic acid via oxidative C–C bond cleavage,
ceeded exclusively at the methine positions to install the qua- giving rise to the differentially protected C2-symmetric
ternary carbons. Consequently, compound 3x was obtained in pyrrolidine
4
in 88% yield.21 On the other hand, the
86% yield (entry 3), and 3y, which is a two carbon homolog of Sonogashira-type reaction22 using the combination of Pd0
the antiviral drug, amantadine, was isolated in 73% yield after and AgI catalysts directly coupled TMS-protected acetylene
removal of the Boc group (entry 4). In particular, constructions 3k and phenyl iodide to provide phenylacetylene 5 in 89%
of the hindered tetrasubstituted centers from a variety of yield.
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Table 4 Alkynylation of alkanesa
highly suitable for streamlined construction of pharmaceuti-
cals and natural products.
Entry Starting material t (h) Product
Yieldb (%)
70
1
2
2
Acknowledgements
This research was financially supported by the Funding
Program for Next Generation World-Leading Researchers
(JSPS) to M.I.
24
54
86
Notes and references
3
4
4
6
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Scheme 2 Transformations of the TMS-protected acetylene.
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Conclusions
In conclusion, we developed a direct photochemical alkynyla-
tion of unreactive C(sp3)–H bonds using Ph2CvO as the pre-
cursor reagent of the C–H bond abstraction and 1-tosyl-2-
(trimethylsilyl)acetylene as the alkynylating agent. The present
transformation proceeds at ambient temperature with wide
applicability of starting substrates, including amine deriva-
tives, ethers, alcohols, and alkanes, and enables one-step con-
struction of tetrasubstituted carbon centers. The sequence of
the preferred reaction sites was established to be nitrogen- >
oxygen-substituted carbons > non-substituted methines > non-
substituted methylenes. The simple procedure, mild con-
ditions, and predictable chemoselectivity make this protocol a
unique and powerful tool for carbon–carbon bond formation.
Since transformations of the introduced C–C triple bonds
allow further attachments of a variety of carbon units at the
alkyne terminus as well as the conversion to carboxylic acids,
the newly developed C–H alkynylation strategy should be
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responsible for the difference in yields between 1r and 1s.
11 Generally, the more electron rich C–H bonds are more reac-
tive toward C(sp3)–H bond functionalizations when using 19 Alkynylation of 1t under conditions A gave the adduct 3t
electrophilic reactants. See, for examples: (a) R. Mello,
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12 Compound 3a was recovered only in 24% yield after photo-
irradiation of only 3a for 2 h at rt in the presence of
Ph2CvO (1 equiv.) in t-BuOH (0.04 M).
This journal is © The Royal Society of Chemistry 2013
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