Rhodium-catalyzed gram-scale synthesis of highly substituted pyridine derivatives

Article abstract of DOI:10.1055/s-0028-1088009

Rhodium-catalyzed chelation-assisted activation of the β-C-H bond of α,β-unsaturated ketoximes and subsequent reaction with alkynes affords highly substituted pyridine derivatives. This new method provides an opportunity for the one-pot synthesis of pyrid

Full text of DOI:10.1055/s-0028-1088009

1400
PRACTICAL SYNTHETIC PROCEDURES
Rhodium-Catalyzed Gram-Scale Synthesis of Highly Substituted Pyridine
Derivatives
R
hodium-Catalyze
a
d
Synthesis
n
of
P
yridine
n
D
erivatives iyappan Parthasarathy, Chien-Hong Cheng*
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan
Fax +886(3)5724698; E-mail: chcheng@mx.nthu.edu.tw
PSP
Received 15 November 2008; revised 5 December 2008
No155
Abstract: Rhodium-catalyzed chelation-assisted activation of the b-C–H bond of a,b-unsaturated ketoximes and subsequent reaction with
alkynes affords highly substituted pyridine derivatives. This new method provides an opportunity for the one-pot synthesis of pyridines with
all five positions (C2–C6) substituted.
Key words: pyridine, ketoxime, rhodium, C–H activation
OH
N
N
Ph
Ph
RhCl(PPh3)3 (3 mol%)
toluene, 130 °C, 5 h
+
Ph
Ph
H
1a
2a
3a 84%
Scheme 1 Synthesis of 2,3,4-trimethyl-5,6-diphenylpyridine (3a)
to provide a 1-azatriene intermediate, followed by 6p-cy-
clization and dehydration (vide infra).
Introduction
Substituted pyridines are an important class of heterocy-
clic compounds.1 The pyridine core is one of the most
prevalent heterocycles found in pharmaceuticals, agro-
chemicals, and natural products.2 The majority of synthet-
ic routes to pyridine rings are based on condensation
reactions of amines with carbonyl compounds,3 Diels–
Alder reactions with 1-azadienes,4 and metal-catalyzed
cycloaddition reactions.5 Herein, we wish to describe a
very convenient and gram-scale synthesis of highly sub-
stituted pyridines from a,b-unsaturated ketoximes and
alkynes via rhodium-catalyzed activation of the b-C–H
bond of the a,b-unsaturated ketoxime. Preliminary results
of this catalytic reaction have appeared.6 The starting ma-
terials, the a,b-unsaturated ketoximes, are easily prepared
by condensation of a,b-unsaturated ketones and hydroxyl-
amine hydrochloride in the presence of sodium acetate
using methanol as the solvent.7
Table 1 Results of the Reaction of a,b-Unsaturated Ketoximes with
Alkynes
OH
N
R3
N
R5
R4
R2
R1
RhCl(PPh3)3
R3
R4
R5
+
toluene, 130 °C
R2
R1
1a–d
2a–d
3a–e
Entry Oxime
R1
1a Me Me Me
Alkyne
Product Yielda
(%)
R2
R3
R4
R5
1
2
3
4
5
2a Ph Ph
2a Ph Ph
3a
3b
3c
84
61
73
77
69
1b
H
H
H
Me
Me
Me
1c Ph
2b Et
Et
1d (CH2)3
2c Ph TMS 3db
2d Me Me 3e
Treatment of a,b-unsaturated ketoxime 1a, with methyl
substituents at the a- and b-carbons, with diphenylacety-
lene (2a) in the presence of 3 mol% of chlorotris(triphe-
nylphosphine)rhodium in toluene at 130 °C for five hours
gave the highly substituted pyridine derivative 3a in 84%
isolated yield (Scheme 1, Table 1). The formation of
product 3a can be viewed as b-alkenylation of oxime 1a
1a Me Me Me
a Isolated yield.
b R5 = H.
The scope of this method was extended with various a,b-
unsaturated ketoximes 1b–d and symmetrical and unsym-
metrical alkynes (Table 1). Thus, methyl vinyl ketoxime
1b reacted with 2a to give the corresponding substituted
pyridine 3b in 61% yield. It is interesting to note that
oxime 1c with a phenyl group at the b-carbon reacted
SYNTHESIS 2009, No. 8, pp 1400–1402
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x
.
x
x
.2
0
0
9
Advanced online publication: 06.03.2009
DOI: 10.1055/s-0028-1088009; Art ID: Z24908SS
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Rhodium-Catalyzed Synthesis of Pyridine Derivatives
1401
2,3,4-Trimethyl-5,6-diphenylpyridine (3a); Typical Procedure
for Gram-Scale Synthesis
nicely with hex-3-yne (2b) to give the expected pyridine
derivative 3c in 73% yield, but failed to react with diphe-
nylacetylene (2a). The steric repulsion between the phe-
nyl groups in 1c and 2a likely accounts for the failure of
this reaction. To understand the regioselectivity of the
present reaction, the reaction of unsymmetrical alkyne, 1-
phenyl-2-(trimethylsilyl)acetylene (2c), with 1d in a high
regioselective manner provided desilylated pyridine de-
rivative 3d in 77% yield in which the phenyl group was at-
tached to C4 of 3d. The regiochemistry of 3d was
confirmed by NOE experiments. Similarly 1a reacted
with but-2-yne (2d) to give the corresponding 2,3,4,5,6-
pentamethylpyridine (3e) in 69% yield. In this reaction,
A screw cap sealed tube (100 mL) initially fitted with a septum con-
taining 3-methylpent-3-en-2-one oxime (1a, 2.00 g, 0.0176 mmol),
diphenylacetylene (2a, 3.78 g 0.021 mmol), and RhCl(PPh3)3 (3.0
mol%) was evacuated and purged with N2 (3 ×). Freshly distilled
toluene (20 mL) was added to the system and the mixture was
stirred at 130 °C for 5 h. Initially the mixture was pale yellow in col-
or, after 10 to 15 min it gradually became red and finally it became
dark brown after 5 h. When the reaction was complete, the mixture
was cooled and diluted with CH2Cl2 (100 mL). The mixture was fil-
tered through a Celite pad and the Celite pad was washed with ad-
ditional CH2Cl2 (50 mL). The filtrate was concentrated and the
residue was purified by column chromatography (silica gel, hex-
ane–EtOAc) to give pure substituted pyridine derivative 3a (84%
three equivalents of alkyne 2d were required to achieve a isolated yield).
good yield of 3e.
Similar procedures were employed for the preparation of com-
pounds 3b–e. For the reactions with unsymmetrical and aliphatic
alkynes, 2 equivalents of alkynes relative to 1 and a reaction time of
12 h were employed.
A possible mechanism for the rhodium-catalyzed cycliza-
tion of a,b-unsaturated ketoximes with alkynes is shown
in Scheme 2.6,8 Coordination of the nitrogen atom in ke-
toxime 1 to the rhodium(I) center followed by C–H bond
activation gives a five-membered hydridoazametalacycle
4. Insertion of alkyne 2 into the Rh–H bond of 4 affords
Mp 59–61 °C.
IR (KBr): 3054, 2923, 1453, 1550 cm–1 (C=N).
1H NMR (400 MHz, CDCl3): d = 7.71–7.23 (m, 5 H), 7.11–7.09 (m,
an alkenyl–Rh intermediate 5. Reductive elimination of 5 3 H), 7.02–7.00 (m, 2 H), 2.62 (s, 3 H), 2.29 (s, 3 H), 2.07 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 159.4, 154.0, 144.2, 141.2, 139.3,
133.8, 130.6, 129.7, 128.8, 127.9, 127.4, 126.7, 126.6, 23.5, 17.5,
15.4.
gives 1-azatriene 6. A 6p-cyclization of 6 followed by de-
hydration provides the final pyridine product 3.
HRMS (EI): m/z [M]+ calcd for C20H19N: 273.1517; found:
273.1521.
OH
N
R2
R3
R3
R3
R4
R5
2,3,4,5,6-Pentamethylpyridine (3e)
R2
R1
OH
R2
R1
OH
1
R1
Mp 49–51 °C.
IR (KBr): 2992, 2926, 2730, 1587 cm–1 (C=N).
2
N
N
Rh(I)
Rh(III)
Rh(III)
1H NMR (400 MHz, CDCl3): d = 2.42 (s, 6 H), 2.15 (s, 6 H), 2.14
5
4
H
R4
(s, 3 H).
R5
13C NMR (100 MHz, CDCl3): d = 152.2, 143.6, 127.0, 23.2, 15.7,
15.1.
HRMS (EI): m/z [M]+ calcd for C10H15N: 149.1204; found:
R3
R3
R2
R3
R2
R1
OH
R2
R1
OH
– H2O
N
149.1205.
N
R1
N
R5
R5
R4
R5
R4
R4
Acknowledgment
6
3
We thank the National Science Council of the Republic of China
(NSC-96-2113M-007-020-MY3) for support of this research.
Scheme 2 Proposed mechanism
In conclusion, we have developed a rhodium-catalyzed
gram-scale synthesis of highly substituted pyridine deriv-
atives. This method is technically simple and can readily
provide pyridines substituted in all five positions (C2–C6)
in one pot.
References
(1) For recent syntheses of highly substituted pyridines, see:
(a) Colby, D. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem.
Soc. 2008, 130, 3645. (b) Barluenga, J.; Fernandez-
Rodriguez, M. A.; Garcia-Garcia, P.; Aguilar, E. J. Am.
Chem. Soc. 2008, 130, 2764. (c) Movassaghi, M.; Hill, M.
D.; Ahmad, O. K. J. Am. Chem. Soc. 2007, 129, 10096.
(2) (a) Rama Rao, A. V.; Ravindra Reddy, G.;
Venkateswara Rao, B. J. Org. Chem. 1991, 56, 4545.
(b) Henry, G. D. Tetrahedron 2004, 60, 6043. (c) Michael,
J. P. Nat. Prod. Rep. 2005, 22, 627.
All reactions were conducted under an N2 atmosphere on a dual-
manifold Schlenk line unless otherwise mentioned and in oven-
dried glassware. All solvents were dried according to known meth-
ods and distilled prior to use.9 RhCl(PPh3)3 was prepared by a pre-
viously published method.10 For all products, physical and
spectroscopic data are given in ref. 6.
(3) For reviews, see: (a) Boger, D. L. J. Heterocycl. Chem.
1998, 35, 1003. (b) Zeni, G.; Larock, R. C. Chem. Rev.
2004, 104, 2285. (c) Varela, J. A.; Saa, C. Chem. Rev. 2003,
103, 3787.
Synthesis 2009, No. 8, 1400–1402 © Thieme Stuttgart · New York

1402
K. Parthasarathy, C.-H. Cheng
PRACTICAL SYNTHETIC PROCEDURES
(4) (a) Schiess, P.; Chia, H.; Ringele, P. Tetrahedron Lett. 1972,
13, 313. (b) Tanaka, K.; Mori, H.; Yamamoto, M.;
Katsumura, S. J. Org. Chem. 2001, 66, 3099. (c) Trost, B.
M.; Gutierrez, A. C. Org. Lett. 2007, 9, 1473.
(5) (a) Varela, J. A.; Castedo, L.; Saá, C. J. Org. Chem. 2003,
68, 8595. (b) Sangu, K.; Fuchibe, K.; Akiyama, T. Org. Lett.
2004, 6, 353. (c) Zhang, X.; Campo, M. A.; Yao, T.; Larock,
R. C. Org. Lett. 2005, 7, 763. (d) McCormick, M. M.;
Duong, H. A.; Zuo, G.; Louie, J. J. Am. Chem. Soc. 2005,
127, 5030; and references cited therein.
(8) (a) Kakiuchi, F.; Yamamoto, Y.; Chatani, N.; Murai, S.
Chem. Lett. 1995, 681. (b) Jun, C.-H.; Moon, C. W.; Lee,
D.-Y. Chem. Eur. J. 2002, 8, 2422. (c) Jun, C.-H.; Moon, C.
W.; Kim, Y. M.; Lee, J.; Lee, H. Tetrahedron Lett. 2002, 43,
4233. (d) Kuninobu, Y.; Tokunaga, Y.; Kawata, A.; Takai,
K. J. Am. Chem. Soc. 2006, 128, 202.
(9) Perrin, D. D.; Armarego, W. L. F. Purification of
Laboratory Chemicals, 3rd ed.; Pergamon Press: New York,
1988.
(10) Osborn, J. A.; Wilkinson, G. In Reagents for Transition
Metal Complex and Organometallic Syntheses, Vol. 28;
Angelici, R., Ed.; Wiley: New York, 1989, 77–79.
(6) Parthasarathy, K.; Jeganmohan, M.; Cheng, C.-H. Org. Lett.
2008, 10, 325.
(7) (a) Shinada, T.; Yoshihara, K. Tetrahedron Lett. 1995, 36,
6701. (b) Booth, S. E.; Jenkins, P. R.; Swain, C. J.; Sweeney,
J. B. J. Chem. Soc., Perkin Trans. 1 1994, 3499.
Synthesis 2009, No. 8, 1400–1402 © Thieme Stuttgart · New York