Photoinduced direct 4-pyridination of C(sp3)-H Bonds

Article abstract of DOI:10.1039/c3sc51080h

Direct substitution of hydrogen in C(sp³)-H bonds by 4-pyridine was achieved by employing benzophenone and 4-cyanopyridine in aqueous acetonitrile under photo-irradiating conditions. This simple and mild 4-pyridination proceeds in a highly chemoselective manner especially at benzylic C(sp³)-H bonds without affecting polar functional groups, and enables intermolecular formation of sterically hindered bonds between alkylaromatics and 4-pyridine. The present methodology thus serves as a powerful tool for construction of biologically active and functional molecules with 4-pyridine substructures.

Full text of DOI:10.1039/c3sc51080h

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Photoinduced direct 4-pyridination of C(sp3)–H Bonds†
*
Tamaki Hoshikawa and Masayuki Inoue
Cite this: DOI: 10.1039/c3sc51080h
Direct substitution of hydrogen in C(sp3)–H bonds by 4-pyridine was achieved by employing
benzophenone and 4-cyanopyridine in aqueous acetonitrile under photo-irradiating conditions. This
simple and mild 4-pyridination proceeds in a highly chemoselective manner especially at benzylic
C(sp3)–H bonds without affecting polar functional groups, and enables intermolecular formation of
sterically hindered bonds between alkylaromatics and 4-pyridine. The present methodology thus serves
as a powerful tool for construction of biologically active and functional molecules with 4-pyridine
substructures.
Received 23rd April 2013
Accepted 15th May 2013
DOI: 10.1039/c3sc51080h
www.rsc.org/chemicalscience
Introduction
Pyridines have a range of applications in many areas of chem-
istry. They are not only found in the structural cores of
numerous agrochemicals, pharmaceuticals and natural prod-
ucts, but are also widely used as building blocks in the prepa-
ration of chiral ligands and functional materials with new
photo- or electrochemical properties.1,2 Consequently, chemists
have been developing methodologies for pyridine synthesis for
over a century and it is unlikely that interest in the eld will
decrease due to the continued importance of the pyridine
substructure in both biological and chemical elds. Among the
many methods to generate pyridines,3 the substitution of
hydrogen in C–H bonds by a pyridine fragment is particularly
valuable, since such a transformation can eliminate extra steps
for the prior activation of substrates and can greatly simplify
synthetic schemes. Although a wealth of transition-metal cata-
lyzed methods has recently been developed for this purpose,4
little work has focused on the pyridination of unreactive C(sp3)–
H bonds of alkanes. Furthermore, the direct introduction of
sterically cumbersome tertiary and quaternary carbon centers
adjacent to the pyridine ring remains challenging largely due to
the general difficulty in activating hindered C(sp3)–H bonds
with transition-metal catalysts.
Scheme 1 Photochemically induced coupling reaction of 4-cyanopyridine and
C(sp3)–H Bonds.
employing benzophenone (Ph2C]O) and 4-cyanopyridine 2
under photo-irradiation conditions (1 / 3).7,8 The present
metal-free reaction proceeds in a highly chemoselective manner
at benzylic C(sp3)–H bonds without affecting polar functional
groups, and realizes intermolecular attachment of congested
tertiary or quaternary carbon centers at C4 of pyridine via ipso-
substitution.9
Radical-based reactions have proven to be suitable for
coupling between pyridines and alkanes as exemplied by the
Minisci reaction in Scheme 1.5,6 Nonetheless, low positional
selectivity, modest yields and narrow substrate scope have
diminished its applicability to architecturally complex
Results and discussion
Recently, we developed photoinduced direct cyanation and
alkynylation of C(sp3)–H bonds by using photo-excited Ph2C]O
(A, Scheme 1) to induce C(sp3)–H cleavage without transition
metal reagents.10,11 Reecting the electrophilic nature of oxyl
radical A, the electron-rich methylene and methine C(sp3)–H
bonds were chemoselectively functionalized to construct tri-
and tetra-substituted carbons, respectively.12 In this context, we
selected Ph2C]O as a hydrogen acceptor and cumene 1a as an
electron-rich hydrogen donor in order to establish the direct 4-
pyridination reaction (Table 1). Aer screening pyridine deriv-
atives,13 it was found that 4-cyanopyridine 2 functioned as an
substrates. Herein, we report
a powerful photochemical
protocol for direct 4-pyridination of alkylaromatics by
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/c3sc51080h
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Table 1 Optimization of reaction conditionsab
Table 2 Transformation of butylbenzene derivativesab
Entry
1
R1
R2
t, h
3
Yieldc, %
1
2
3
4
5
6
7
8
9
10
1b
1c
1d
1e
1f
1g
1h
1i
H
H
H
H
H
H
H
H
12
10
10
12
16
12
12
14
14
14
3b
3c
3d
3e
3f
3g
3h
3i
72
83
71
63
65
68
70
79
83
62
OMe
OAc
NHAc
CO2Me
Br
Cl
H
H
H
1a,
Entry equiv. Solvent
t, h Yield 3a, %c Recovery 2, %d
1
2
3
4
3
3
3
3
2
2
2
2
0
t-BuOH
Benzene
MeCN
MeCN/H2O (2 : 1)
10 69
20 (2)
20 (55)
0
72
22
0
OBz
CO2Me
Br
6
87
1j
1k
3j
3k
5
MeCN/H2O (2 : 1) 10 91
MeCN/H2O (2 : 1) 12 90
MeCN/H2O (2 : 1) 24 (74)
MeCN/H2O (2 : 1) 24 (5)
0
0
16
84
81
6e
7f
8g
9e
a
Reaction conditions: 1 : 2 : Ph2C]O ¼ 2 : 1 : 0.5, MeCN/H2O (2 : 1, 0.04
M), rt, photo-irradiation using a Riko 100 W medium pressure mercury
lamp. b In all entries, the formation of 4 was observed in approximately
15% yield. c Isolated yield.
MeCN/H2O (2 : 1) 12
0
a
Reaction conditions: 1a, 2, Ph2C]O (1 equiv.), solvent (0.04 M), rt,
photo-irradiation using a Riko 100 W medium pressure mercury
b
butylbenzene 1b (2 equiv.) in the presence of Ph2C]O
(0.5 equiv.) cleanly provided the alkylated pyridine 3b (entry 1).
Further pyridination of product 3b was not observed, presum-
ably because the pyridine-substituted benzylic C–H bond of 3b
is more electron decient and thus less reactive than that of 1b
toward the photoactivated Ph2C]O (A, Scheme 1). Para-
substituted electron-donating groups, such as methoxy (1c),
acetoxy (1d) and acetamide (1e), and the electron-withdrawing
methoxy carbonyl group (1f) had little effect on the product
yields of 3c–3f (entries 2–5). The reaction worked well in the
presence of bromine (1g) and chlorine (1h) on the aromatic
ring, and pyridine derivatives 3g and 3h were obtained without
the loss of halogen atoms (entries 6 and 7). The substrates with
benzoyloxy (1i) and methoxy carbonyl (1j) groups on the termini
of the alkyl chain underwent the transformation to provide 3i
and 3j, respectively (entries 8 and 9). Even the weak C(sp3)–Br
bond of 1k was preserved in this radical reaction to produce
adduct 3k (entry 10). Overall, these results demonstrated the
mildness and high functional group tolerance of the C(sp3)–H
pyridination.
The broad scope of the methodology was further demon-
strated using structurally varied alkylbenzenes (Table 3). In
addition to methine (Table 1, entry 6) and methylene C–H
bonds (Table 2, entry 1), the primary C–H bond of toluene 1l was
transformed into the pyridine derivative 3l under the optimized
conditions (Table 3, entry 1). The yields of the pyridine deriva-
tives 3a (90%), 3b (72%) and 3l (51%) correlated to the number
of alkyl substituents at the reacting carbon, conrming that the
hydrogen of the more electron-rich C–H bond was more effi-
ciently abstracted by electron-decient oxyl radical A.12,16
Remarkably, a quaternary carbon center was introduced at the
most hindered C–H bond on the cyclohexane ring of 1m,
leading to 3m (entry 2). The reaction of m-acetoxy (1n) and
o-acetoxy (1o) ethylbenzenes with 4-cyanopyridine provided
lamp.
The formation of 4 was observed in entries 1–7 in
c
approximately 5% yield. Isolated yield. NMR yield is shown in
parentheses. Yield was determined by NMR analysis. Ph2C]O (0.5
equiv.) was employed. Ph2C]O (0.1 equiv.) was employed. The
reaction was carried out without Ph2C]O.
d
e
f
g
effective coupling agent to produce adduct 3a (69% yield,
entry 1) when treated with 1a (3 equiv.) and Ph2C]O (1 equiv.)
in t-BuOH under the photo-irradiation conditions. Importantly,
byproduct 4 was formed only in a trace amount, indicating that
coupling between 2 and Ph2C]O was the minor pathway.8a
Formation of 3a was inhibited when the t-BuOH solvent was
replaced with benzene (entry 2), and decelerated upon use of
MeCN (entry 3). On the other hand, a mixed solvent of MeCN
and H2O signicantly accelerated the reaction and increased
the yield of 3a (87% yield, entry 4). Under these conditions, the
amount of 1a could be reduced from 3 equiv. to 2 equiv. without
affecting the product yield (entry 5).14 Moreover, adduct 3a was
produced in 90% and 74% yields, even when the equivalents of
Ph2C]O were changed from 1 to 0.5 and 0.1, respectively
(entries 6 and 7).15 Only a trace amount of adduct 3a was formed
without the addition of Ph2C]O (entry 8), and even formation
of 4 was inhibited in the absence of hydrogen donor 1a (entry 9).
These two experiments demonstrated the crucial role of both
Ph2C]O and 1a for promotion of the radical reactions (vide
infra). Because high-yielding construction of 3a with the
quaternary carbon from 1a and 2 was successfully achieved
using the optimal conditions in entry 6, the scope of this
transformation was next investigated in detail.
The methylene C–H bonds of the benzylic compounds 1b–
1k, having a variety of functional groups on the aromatic
rings (R1) or the side chains (R2), site-selectively underwent the
4-pyridination (Table 2). The photoirradiation of 2 with
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Table 3 Transformation of various alkylbenzenesab
Table 3 (Contd. )
Yieldc, %
51
Entry Starting material
t, h
Product
Yieldc, %
Entry Starting material
1d
t, h
Product
24
2
18
50
16
10
71f
3
4
14
24
83
68(80)
5
15
75e
17
12
72g
6
7
2
66
87
a
12
Reaction conditions: 1 : 2 : Ph2C]O ¼ 2 : 1 : 0.5, MeCN/H2O (2 : 1, 0.04
M), rt, photo-irradiation using a Riko 100 W medium pressure mercury
lamp. b In all entries, the formation of 4 was observed in approximately
15% yield. c Isolated yield. Yield based on recovered 4-cyanopyridine 2 is
d
shown in parentheses. Starting material 1 (3 equiv.) was employed.
e
f
g
Yield was determined by NMR analysis. 3aa-a : 3aa-b ¼ 2 : 1. 3bb-
a : 3bb-b ¼ 2 : 3.
8
22
74
alkylated pyridines 3n and 3o, respectively (entries 3 and 4),
while the transformation of ibuprofen methyl ester 1p selec-
tively took place at the more electron-rich benzylic position,
affording adduct 3p (entry 5). The oxygen-substituted benzylic
C–H bond of 1q was transformed to 3q within only 2 h (entry 6),
indicating that the butyl ether functionality enhanced the
reactivity of the benzylic position.17 Diphenyl methane 1r was
smoothly converted into its pyridine derivative 3r (entry 7),18
and the hindered quaternary carbon of 3s was constructed from
1,1-diphenyl propane 1s (entry 8).19
9
1t: X ¼ CH2
1u: X ¼ CH2CH2
1v: X ¼ O
8
12
1
3t
89
70
75
77
10
11d
12
3u
3v
3w
1w: X ¼ NBoc
1
Direct couplings between 4-pyridine and multicyclic
compounds were successfully achieved (entries 9–17, Table 3).
High-yielding mono-pyridination of the ve-membered and six-
membered carbocycles 1t and 1u was realized to produce 3t and
3u, respectively (entries 9 and 10), while phthalane 1v and N-Boc
isoindoline 1w were converted to the corresponding products 3v
and 3w, respectively (entries 11 and 12). Shorter reaction times
for 3v and 3w than those for 3t and 3u again conrmed that
13
0.5
82
14
15
1y: X ¼ O
12
24
3y
3z
84
84(91)
1z: X ¼ NH
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oxygen and nitrogen atoms increased the reactivity of the occurred at the isopropyl group. The intrinsically more reactive
proximal C–H bonds. By taking advantage of this feature, the methine C–H bond on the isopropyl substituent of 1bb was
nitrogen-substituted benzylic C–H bond of 1x was chemo- sterically shielded by the Piv group, which explains the site-
selectively functionalized in the presence of its carbon- selective functionalization of the methylene C–H bond to
substituted counterpart, leading to 3x as the sole product (entry generate 3bb. Consequently, syntheses of the seventeen diverse
13). Lactone 1y and lactam 1z were converted to the corre- molecular frameworks in Table 3 veried the robustness and
sponding products 3y and 3z, respectively (entries 14 and 15), reliability of the methodology.
showing that the acidic protons [e.g. C(O)NH or C(O)CH] in the
Even broader applicability of the present protocol was
substrates were inconsequential to the reaction outcomes. proven by successful transformations of heteroaromatics,
Finally, 4-pyridine was directly attached to two architecturally alkenes and alkanes (Table 4). The reaction of 2-butylthiophene
complex tricyclic compounds, both of which were derived from 1cc and 3-butylthiophene 1dd with 4-cyanopyridine resulted in
natural products (entries 16 and 17). Pyridination of podocarpic the selective transformation of the C(sp3)–H bond adjacent to
acid derivative 1aa20 took place smoothly to provide the corre- the thiophene ring, affording 3cc and 3dd, respectively (entries
21
`
¨
sponding adduct 3aa-a as the major product along with its 1 and 2). Even though Paterno-Buchi [2 + 2] cycloaddition
epimer 3aa-b (3aa-a : 3aa-b ¼ 2 : 1). Although the additional between furan 1ee and Ph2C]O competed, pyridine derivative
isopropyl group on the phenyl ring affected the stereochemical 3ee was produced by using an excess amount of the reagents
outcome, O-pivaloyl totarol 1bb was converted to pyridine (entry 3). The allylic C–H bond of cyclohexene 1ff was selectively
derivative 3bb (3bb-a : 3bb-b ¼ 2 : 3), and no pyridination functionalized to give the corresponding product 3ff.8a
Furthermore, the less reactive C(sp3)–H bonds of alkanes
underwent the 4-pyridination when benzylic and allylic C–H
Table 4 Transformation of other alkylarenes, alkene, and alkanesab
bonds were absent. Namely, subjection of cyclooctane 1gg to the
photoirradiating conditions provided 3gg (entry 5), while the
most electron-rich methine C–H bond of linear alkane 1hh
underwent the 4-pyridination, providing product 3hh with a
quaternary carbon (entry 6).
Entry
Starting material
t, h
Product
Yieldc, %
Although the precise reaction mechanism remains to be
claried, a radical-based ipso-substitution pathway from 1 to 3
is proposed (Scheme 2). First, the most reactive C–H bond of 1,
such as the benzylic C–H bond, is abstracted by photochemi-
cally generated oxyl radical A, affording stabilized benzyl radical
B22 and a-hydroxy radical C. Electron-rich radical C and elec-
tron-decient 4-cyanopyridine 2 reorganize through the highly
favored proton-coupled electron transfer,23 resulting in the
formation of stable carbon radical D24 and regeneration of
Ph2C]O through loss of the electron and proton from C. Next, a
1
16
67
2
24
16
47(60)
51(72)
3d
4e
10
22
44(51)
35
5f
6f
20
43
a
Reaction conditions: 1 : 2 : Ph2C]O ¼ 2 : 1 : 0.5, MeCN/H2O (2 : 1, 0.04
M), rt, photo-irradiation using a Riko 100 W medium pressure mercury
lamp. b In all entries, the formation of 4 was observed in approximately
15% yield. c Isolated yield. Yield based on recovered 4-cyanopyridine 2 is
shown in parentheses. d The reaction was carried out using Ph2C]O (2
e
equiv.) and 1ee (8 equiv.). Cyclohexene 1ff (3 equiv.) was employed.
f
Alkane 1gg or 1hh (5 equiv.) was employed.
Scheme 2 Proposed reaction mechanism.
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facile radical–radical coupling reaction between B and D
proceeds to give E, which should be rapidly aromatized by
expulsion of HCN to give pyridine derivative 3a. The side reac-
tion to byproduct 4 occurs when radical D couples with C.
Generation of C as the key intermediate is supported by the
necessity of both hydrogen donor 1 and Ph2C]O to generate
adduct 3 or 4 (Table 1). It is noteworthy that the reactive radical
species A, B, C, D and E appear to properly follow the order of
these multiple reactions, judging from the high yielding
transformations in Tables 1–4.25
R. W. Hartmann, J. Med. Chem., 2008, 51, 5009; (f) Q. Hu,
L. Yin, C. Jagusch, U. E. Hille and R. W. Hartmann, J. Med.
Chem., 2010, 53, 5049.
3 For recent reviews on pyridine synthesis, see: (a) G. D. Henry,
Tetrahedron, 2004, 60, 6043; (b) M. D. Hill, Chem.–Eur. J.,
2010, 16, 12052; (c) J. A. Bull, J. J. Mousseau, G. Pelletier
and A. B. Charette, Chem. Rev., 2012, 112, 2642.
4 For recent reviews on the transition metal-catalyzed direct
arylation of C(sp3)–H bonds, see: (a) F. Bellina and
R.
Rossi,
Chem.
Rev.,
2010,
110,
1082;
(b)
C. C. C. Johansson and T. J. Colacot, Angew. Chem., Int. Ed.,
2010, 49, 676; (c) O. Baudoin, Chem. Soc. Rev., 2011, 40, 4902.
5 For reviews on the Minisci reaction, see: (a) F. Minisci,
Synthesis, 1973, 1; (b) F. Minisci, E. Vismara and
F. Fontana, Heterocycles, 1989, 28, 489; (c) F. Minisci,
F. Fontana and E. Vismare, J. Heterocycl. Chem., 1990, 27,
79; (d) M. A. J. Duncton, Med. Chem. Commun., 2011, 2, 1135.
6 For representative examples of direct syntheses of
alkylpyridine and alkylquinoline derivatives through
Minisci reactions, see: (a) F. Minisci and F. Fontana,
Tetrahedron Lett., 1994, 35, 1427; (b) D. H. R. Barton,
J. Boivin, N. Ozbalik, K. M. Schwartzentruber and
K. Jankowski, Tetrahedron Lett., 1985, 26, 447; (c)
F. Minisci, E. Vismara, G. Morini, F. Fontana, S. Levi and
M. Serravalle, J. Org. Chem., 1986, 51, 476; (d) F. Minisci,
E. Vismara, F. Fontana, G. Morini, M. Serravalle and
C. Giordano, J. Org. Chem., 1986, 51, 4411; (e)
D. H. R. Barton, F. Halley, N. Ozbalik, M. Schmitt,
E. Young and G. Balavoine, J. Am. Chem. Soc., 1989, 111,
7144; (f) F. Fontana, F. Minisci, Y.-M. Yong and Z. Lihua,
Tetrahedron Lett., 1993, 34, 2517; (g) G. Deng and C.-J. Li,
Org. Lett., 2009, 11, 1171; (h) A. P. Antonchick and
L. Burgmann, Angew. Chem., Int. Ed., 2013, 52, 3267.
Conclusions
In summary, a new photochemical metal-free methodology for
the one-step preparation of 4-alkylpyridine derivatives has been
developed by using the reagent combination of 4-cyanopyridine
and Ph2C]O in aqueous MeCN. The C–H pyridination
proceeds at ambient temperature under neutral conditions, and
is applicable to various alkylaromatics and even to alkenes and
alkanes. The obtained 28 compounds in Tables 1–4 possess
characteristic 4-pyridine-attached carboskeletons, which are
not easily accessible by other known methods. The salient
features of the present methodology include the simplicity of
the procedure, predictability in terms of chemoselectivity,
compatibility with various polar and halogen functionalities,
and efficiency in the single-step construction of hindered link-
ages between carboskeletons and pyridine. Because of these
advantages, 4-pyridination of C(sp3)–H bond introduces a novel
and powerful strategy for streamlined synthesis of numerous
pyridine-containing compounds, including natural products,
agrochemicals, pharmaceuticals, and functional materials.
Acknowledgements
7 For recent examples of non-radical approaches for the
synthesis of 4-alkylpyridines, see: (a) M. Ishikura, T. Ohta
and M. Terashima, Heterocycles, 1986, 24, 2793; (b)
P. H. Lee, K. Lee, J. H. Shim, S. G. Lee and S. Kim,
Heterocycles, 2006, 67, 777; (c) G. A. Molander,
O. A. Argintaru, I. Aron and S. D. Dreher, Org. Lett., 2010,
12, 5783; (d) Y. Nakao, Y. Yamada, N. Kashihara and
T. Hiyama, J. Am. Chem. Soc., 2010, 132, 13666; (e)
T. Andou, Y. Saga, H. Komai, S. Matsunaga and M. Kanai,
Angew. Chem., Int. Ed., 2013, 52, 3213; (f) A. D. Thompson
and M. P. Huestis, J. Org. Chem., 2013, 78, 762; (g) Q. Chen,
X. M. du Jourdin and P. Knochel, J. Am. Chem. Soc., 2013,
135, 4958.
This research was nancially supported by the Funding
Program for Next Generation World-Leading Researchers (JSPS)
to M.I.
Notes and references
1 J. A. Joule and K. Mills, Heterocyclic Chemistry, 5th edn,
Wiley, Chichester, 2010.
2 For recent examples of bioacitve molecules that possess 4-
pyridine structures at the benzylic positions, see: (a)
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8 For related examples of radical-based ipso-substitution
reactions
of
cyanopyridine
derivatives,
see:
(a)
B. M. Vittimberga, F. Minisci and S. Morrocchi, J. Am.
Chem. Soc., 1975, 97, 4397; (b) T. Caronna, S. Morrocchi
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R. Bernardi, T. Caronna, G. Poggi and B. M. Vittimberga,
¨
C. Jagusch, U. Muller-Vieira, T. Lauterbach and
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T. Caronna, D. Dal Pio Luogo, S. Morrocchi, G. Poggi and
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B. M. Vittimberga, J. Chem. Soc., Perkin Trans. 1, 1996, 15 We also carried out the present reaction on 1 gram scale by
1593; (i) R. Bernardi, T. Caronna, S. Morrocchi and
M. Ursini, J. Heterocycl. Chem., 1996, 33, 1137; (j)
R. Bernardi, T. Caronna, S. Morrocchi, P. Traldi and
using catalytic amount of Ph2C]O (0.1 equiv.) and
successfully obtained the product 3aa in 78% (87% brsm)
yield. See ESI† for details.
B. M. Vittimberga, J. Chem. Soc., Perkin Trans. 1, 1981, 16 The bond dissociation energy of the C–H bond of toluene
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A. McNally, C. K. Prier and D. W. C. MacMillan, Science,
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decreases upon attachment of Me groups. [e.g. H–CH2Ph
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Chem. Sci.
This journal is ª The Royal Society of Chemistry 2013