Synthesis of substituted pyridine derivatives via the ruthenium-catalyzed cycloisomerization of 3-azadienynes

Article abstract of DOI:10.1021/ja060626a

We describe a two-step conversion of various N-vinyl and N-aryl amides to the corresponding substituted pyridines and quinolines, respectively. The process involves the direct conversion of amides, including sensitive N-vinyl amides, to the corresponding trimethylsilyl alkynyl imines followed by a ruthenium-catalyzed protodesilylation and cycloisomerization. A wide range of new alkynyl imines are prepared and readily converted to the corresponding azaheterocycles. Copyright

Full text of DOI:10.1021/ja060626a

Published on Web 03/22/2006
Synthesis of Substituted Pyridine Derivatives via the Ruthenium-Catalyzed
Cycloisomerization of 3-Azadienynes
Mohammad Movassaghi* and Matthew D. Hill
Massachusetts Institute of Technology, Department of Chemistry, Cambridge, Massachusetts 02139
Received January 26, 2006; E-mail: movassag@mit.edu
Due to the prominence of azaheterocycles in natural products,
pharmaceuticals, and functional materials, efficient methods for the
synthesis of these compounds are of great value.1 The majority
of synthetic routes to pyridine and quinoline derivatives rely on
condensation reactions of amines and carbonyl compounds.3 The
convergent synthesis of N-vinyl and N-aryl amides readily provides
Scheme 1
,2
,4
valuable precursors for the preparation of azaheterocycles (Scheme
Table 1
5
1). Herein we report a mild and efficient two-step procedure for
the conversion of N-vinyl and N-aryl amides to the corresponding
substituted pyridines.
The metal-catalyzed cycloisomerization of dienynes via catalyti-
cally generated metal-vinylidene intermediates represents a highly
6
effective method for the synthesis of aromatic compounds. We
sought to explore the use of 3-azadienynes as substrates for a metal-
catalyzed cycloisomerization reaction, providing a general approach
to a broad range of substituted pyridine derivatives 1 (Scheme 1).7
To take full advantage of the wide range of N-vinyl amides available
5
by metal-catalyzed C-N bond formation, we required a mild and
efficient procedure for the direct conversion of amides 2 to the
8
corresponding 3-azadienynes 3 (Table 1). Inspired by recent reports
9
on the electrophilic activation of amides we developed a single-
step process for the conversion of N-vinyl/aryl amides 2 to the
corresponding alkynyl imines 3. Under our optimum conditions, a
cold solution of the N-phenyl benzamide (2a, Scheme 2) in
dichloromethane is treated sequentially with 2-chloropyridine (2-
ClPyr, 4.0 equiv) and trifluoromethanesulfonic anhydride (Tf
.2 equiv), followed by copper trimethylsilylacetylide (2.7 equiv),
which affords the desired trimethylsilyl alkynyl imine 3a in 97%
2
O,
1
10
yield (Table 1, entry 1, 2.5-g scale). The use of 2-chloropyridine
11
as the base was found to be critical in obtaining the desired alkynyl
imines.10 Significantly, this single-step and mild procedure provides
access to new alkynyl imines, in particular, those derived from
8
N-vinyl amides. For comparison, the use of existing methods for
the synthesis of N-2-thienyl and N-dihydropyranyl alkynyl imines
3
(Table 1, entries 13 and 15) gave none and <10% yield of the
desired product, respectively.
Early in our studies we identified the readily available chloro-
cyclopentadienyl bis(triphenylphosphine) ruthenium complex (CpRu-
(
PPh
terminal alkynyl imine 4a to product 1a (Scheme 2). While imine
a could be prepared by protodesilylation of the corresponding
3
)
2
Cl, 5)12 as an effective catalyst for cycloisomerization of
a
Isolated yields: all entries are an average of two experiments. Optimum
13
conditions used uniformly. b Gram-scale experiments. Yield of the cor-
c
responding desilylated imine.10 d Kept at -78 °C.
10 e
5 mol % of catalyst
4
system used.
trimethylsilyl derivative 3a (Scheme 2), this required an additional
step and resulted in decreased stability of the substrate and yield
of the cycloisomerization reaction. These considerations prompted
the development of a process for the direct use of trimethylsilyl
alkynyl imine 3a as substrate. The trimethylsilyl alkynyl imine 3a,
was used to survey a series of metal complexes, supporting ligands,
additives, and solvents.10 The combination of ruthenium complex
set of conditions, as illustrated by the clean conversion of imine
3a to quinoline 1a in 90% yield (Table 1, entry 1, 1.0-g scale).
1
0
Interestingly, neither SPhos nor PPh alone were ideal ligands
3
when used independently with chlorocyclopentadienyl cycloocta-
15
1,5-diene ruthenium complex (CpRuCODCl, 6) for cycloisomer-
10
ization of 3-azadienyne 3a. However, the combination of these
5
(10 mol %), 2-dicyclohexyl-phosphino-2′,6′-dimethoxy-1,1′-
ligands in conjunction with ruthenium complex 6 provided a catalyst
14
10
biphenyl (SPhos, 10 mol %), and ammonium hexafluorophosphate
1 equiv) in toluene (0.2 M) at 105 °C was identified as the optimal
system with activity equal to that of the optimal system. While
the exact role of SPhos is unclear at this time,1
6
31
P NMR
(
4592
9
J. AM. CHEM. SOC. 2006, 128, 4592-4593
10.1021/ja060626a CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2 a
their direct Ru-catalyzed protodesilylation and cycloisomerization
to the corresponding azaheterocycles. This Ru-catalyzed conversion
of C6-trimethylsilyl 3-azadienynes to azaheterocycles, not only
reduces a three-step sequence4 to a single-step but also does not
require the isolation of sensitive and/or inaccessible terminal alkynyl
imines as substrates.
c
a
Reagents and conditions: a) Tf2O, 2-ClPyr, CH2Cl2; TMSCtCCu,
THF, -78f0 °C. b) 5, SPhos, NH4PF6, toluene, 105 °C. c) K2CO3, MeOH.
d) 5, toluene, 105 °C.
Acknowledgment. M.M. is a Dale F. and Betty Ann Frey
Damon Runyon Scholar supported by the Damon Runyon Cancer
Research Foundation (DRS-39-04). M.M. is a Firmenich Assistant
Professor of Chemistry. We acknowledge ACS-PRF (40631G1),
NSF (547905), Amgen Inc., and MIT for funding.
Scheme 3
Supporting Information Available: Experimental procedures and
spectroscopic data for all products. This material is available free of
charge via the Internet at http://pubs.acs.org.
3
experiments confirm that PPh outcompetes SPhos in displacement
of COD from 6, providing complex 5 and remaining SPhosssimilar
to the optimal precatalyst mixture. Also, H NMR monitoring of
the cycloisomerization reaction of azadienyne 3a, employing
complex 6 and SPhos alone, revealed the formation of the inactive
complex.17
6 6 5 6
CpRu(η -C H Me)PF
The optimal reaction conditions proved to be compatible with a
variety of C-silyl alkynyl imines (Table 1). In particular, we found
even highly sensitive N-vinyl/heterocyclic imines to be excellent
substrates (Table 1, entries 9-16), providing a convergent and
versatile azaheterocycle synthesis. Importantly, the direct conversion
of C-silyl alkynyl imines 3 to the corresponding azaheterocycles 1
with this Ru-catalyst system avoids the isolation of the more
sensitive terminal alkynyl imines (i.e., Table 1, entry 4). In only
two cases (entries 7 and 16) in situ desilylation was found to be
exceedingly slow, prompting the use of the corresponding terminal
alkyne derivatives as the substrates for cycloisomerization. In the
synthesis of the acid-sensitive N-triisopropylsilylazaindole (entry
References
1
(1) For recent reviews, see: (a) Henry, G. D. Tetrahedron 2004, 60, 6043.
(
b) Michael, J. P. Nat. Prod. Rep. 2005, 22, 627. (c) Abass, M.
Heterocycles 2005, 65, 901.
(
2) (a) Jones, G. In ComprehensiVe Heterocyclic Chemistry II; Katritzky, A.
R., Rees, C. W., Scriven, E. F. V., McKillop, A., Eds; Pergamon: Oxford,
1
996; Vol. 5; p 167. (b) Larock, R. C. ComprehensiVe Organic
Transformations: A Guide to Functional Group Preparations; Wiley-
VCH: New York, 1999.
(
3) For reviews on metal-catalyzed heterocycle synthesis, see: (a) B o¨ nnemann,
H.; Brijoux, W. AdV. Heterocycl. Chem. 1990, 48, 177. (b) Nakamura, I.;
Yamamoto, Y. Chem. ReV. 2004, 104, 2127. (c) Zeni G.; Larock, R. C.
Chem. ReV. 2004, 104, 2285. (d) Varela, J. A.; Sa a´ , C. Chem. ReV. 2004,
104, 3787.
(4) For related recent metal-catalyzed azaheterocycle syntheses, see: (a)
Roesch, K. R.; Larock, R. C. Org. Lett. 1999, 1, 553, (b) Varela, J. A.;
Castedo, L.; Sa a´ , C. J. Org. Chem. 2003, 68, 8595, (c) Sangu, K.; Fuchibe,
K.; Akiyama, T. Org. Lett. 2004, 6, 353, (d) Zhang, X.; Campo, M. A.;
Yao, T.; Larock, R. C. Org. Lett. 2005, 7, 763, (e) McCormick, M. M.;
Duong, H. A.; Zuo, G.; Louie, J. J. Am. Chem. Soc. 2005, 127, 5030 and
references therein.
(
5) (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131. (b)
Hartwig, J. F. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E., Ed.; Wiley-Interscience: New York, 2002; p 1051.
(
c) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004, 248,
16), lowering the catalyst loading (5 mol %) from our standard
2337. (d) Dehli, J. R.; Legros, J.; Bolm, C. Chem. Commun. 2005, 973.
conditions was beneficial.
(
6) For related reviews, see: (a) Bruneau, C.; Dixneuf, P. H. Acc. Chem.
Res. 1999, 32, 311. (b) Trost, B. M.; Toste, F. D.; Pinkerton, A. B. Chem.
ReV. 2001, 101, 2067. (c) Nevado, C.; Echavarren, A. M. Synthesis 2005,
Subjecting the alkynyl imine 3a-d
5
(eq 1) to our standard
conditions gave the quinoline 1a-d
5
(eq 1) with C4-deuterium
167. For related representative reports, see: (d) Trost, B. M.; Dyker, G.;
Kulawiec, R. J. J. Am. Chem. Soc. 1990, 112, 7809. (e) Wang, Y.; Finn,
M. G. J. Am. Chem. Soc. 1995, 117, 8045. (f) Merlic, C. A.; Pauly, M. E.
J. Am. Chem. Soc. 1996, 118, 11319. (g) Ohe, K.; Kojima, M.; Yonehara,
K.; Uemura, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 1823. (h) Maeyama,
K.; Iwasawa, N. J. Am. Chem. Soc. 1998, 120, 1928.
(
7) (a) Boger, D. L. J. Heterocycl. Chem. 1998, 35, 1003. (b) Jayakumar, S.;
Ishar, M. P. S.; Mahajan, M. P. Tetrahedron 2002, 58, 379.
incorporation (68%).10 The use of terminal alkynyl imine 4a-d
, without NH PF ) as substrate provided quinoline 1a-d (eq 1)
with C3-deuterium incorporation (72%). Furthermore, employing
ammonium hexafluorophospate-d in the cycloisomerization of
alkynyl imine 3a (eq 1), provided the quinoline 1a-d (eq 1) with
C3-deuterium incorporation (68%).10 The protodesilylated imine
a (Scheme 2) was not detected as a persistent intermediate by
TLC or H NMR monitoring experiments (Table 1, entry 1), and
the silyl alkynyl imine 3a was recovered unchanged from the
reaction mixture in the absence of Ru-complex 5. Additionally, only
a trace amount of the desired desilylated and cycloisomerized
product was detected when the ammonium hexafluorophosphate
was omitted, returning the starting material as the mass balance.
These observations suggest the direct conversion of the silyl alkynyl
imine 3a to the C-silyl metal vinylidene18 7 (Scheme 3) followed
by protodesilylation and cycloisomerization to give 1a.
(eq
(8) For reports on the synthesis of alkynyl imines via a two-step procedure
1
involving imidoyl chlorides, see: (a) Ried, W.; Erle, H.-E. Chem. Ber.
1
4
6
1
1979, 112, 640. (b) Austin, W. B.; Bilow, N.; Kelleghan, W. J.; Lau, K.
10
S. Y. J. Org. Chem. 1981, 46, 2280. (c) Lin, S.-Y.; Sheng, H.-Y.; Huang,
Y.-Z. Synthesis 1991, 235. For related reports, see: (d) Kel’in, A. V.;
Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074. (e)
Van den Hoven, B. G.; Alper, H. J. Am. Chem. Soc. 2001, 123, 10214.
(9) (a) Baraznenok, I. L.; Nenajdenko, V. G.; Balenkova, E. S. Tetrahedron
4
1
2000, 56, 3077. (b) Charette, A. B.; Grenon, M. Can. J. Chem. 2001, 79,
4
1694.
1
(10) See the Supporting Information for details.
(
11) Myers, A. G.; Tom, N. J.; Fraley, M. E.; Cohen, S. B.; Madar, D. J. J.
Am. Chem. Soc. 1997, 119, 6072.
(
12) (a) Gilbert, J. D.; Wilkinson, G. J. Chem. Soc. (A) 1969, 1749. (b)
Blackmore, T.; Bruce, M. I.; Stone, F. G. A. J. Chem. Soc. (A) 1971,
2376. (c) Bruce, M. I.; Windsor, N. J. Aust. J. Chem. 1977, 30, 1601.
(
13) (a) For a related report on metal-catalyzed isomerization of N-aryl
benzamide derived terminal alkynes (i.e., 4a) using W(CO)
‚THF (20-
00 mol %) to afford 2-arylquinolines after treatment with NMO, see ref
5
1
4c. (b) For a report on Ru-catalyzed C2-vinylation of pyridines, see:
Murakami, M.; Hori, S. J. Am. Chem. Soc. 2003, 125, 4720.
14) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2004, 43, 1871.
(
(
15) Albers, M. O.; Robinson, D. J.; Shaver, A.; Singleton, E. Organometallics
The chemistry described here provides a two-step process for
the synthesis of substituted pyridine derivatives from readily
available N-vinyl/-aryl amides (Scheme 2, steps a and b). Note-
worthy features of this chemistry include the single-step conversion
of a wide range of readily available amides, including sensitive
N-vinyl amides, to the corresponding C-silyl alkynyl imines and
1986, 5, 2199.
(16) For related discussions on the steric and electronic effects of phosphines
used with complex 6 in Ru-vinylidene formation, see: Trost, B. M.;
Rhee, Y. H. J. Am. Chem. Soc. 1999, 121, 11680.
(17) McNair, A. M.; Schrenk, J. L.; Mann, K. R. Inorg. Chem. 1984, 23, 2633.
18) Schneider, D.; Werner, H. Angew. Chem., Int. Ed. Engl. 1991, 30, 700.
(
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