Sequential amination/annulation/aromatization reaction of carbonyl compounds and propargylamine: A new one-pot approach to functionalized pyridines

Article abstract of DOI:10.1021/jo0347260

A general one-pot synthesis of pyridines 4a-t from the reaction of dialkyl acyclic/cyclic ketones 1a-i, methyl, aryl/heteroaryl ketones 1m-r, and aldehydes bearing α-hydrogens 1s,t with propargylamine 2 is described. Gold and copper salts are efficient catalysts for the reaction of ketones with 2. The formation of the pyridines 4 is suggested to proceed through the sequential amination of carbonyl compounds followed by regioselective 6-endo-dig cyclization of the N-propargylenamine (N-propargyldienamine) intermediate 3(5) and aromatization reaction. Whereas the preparation of linear polycyclic pyridine 4i can be carried out by reacting cholestan-3-one 1i with 2, the angular polycyclic pyridine 4j has been obtained starting from cholest-5-en-3-one 1j. Selectivity of the reaction of polycyclic dicarbonyls 1k,1 with 2 has also been investigated.

Full text of DOI:10.1021/jo0347260

Sequ en tia l Am in a tion /An n u la tion /Ar om a tiza tion Rea ction of
Ca r bon yl Com p ou n d s a n d P r op a r gyla m in e: A New On e-P ot
Ap p r oa ch to F u n ction a lized P yr id in es
†
,‡
‡
‡
Giorgio Abbiati, Antonio Arcadi,* Gabriele Bianchi, Sabrina Di Giuseppe,
‡
†
Fabio Marinelli, and Elisabetta Rossi
Istituto di Chimica Organica “Alessandro Marchesini”, Facolt a` di Farmacia, Universit a` degli Studi di
Milano, Via Venezian, 21, 20133 Milano, Italy, and Dipartimento di Chimica, Ingegneria Chimica e
Materiali, Facolt a` di Scienze, Universit a` di L’Aquila, Via Vetoio, 67010 Coppito(AQ), Italy
arcadi@univaq.it
Received May 29, 2003
A general one-pot synthesis of pyridines 4a -t from the reaction of dialkyl acyclic/cyclic ketones
1
a -i, methyl, aryl/heteroaryl ketones 1m -r , and aldehydes bearing R-hydrogens 1s,t with
propargylamine 2 is described. Gold and copper salts are efficient catalysts for the reaction of ketones
with 2. The formation of the pyridines 4 is suggested to proceed through the sequential amination
of carbonyl compounds followed by regioselective 6-endo-dig cyclization of the N-propargylenamine
(N-propargyldienamine) intermediate 3(5) and aromatization reaction. Whereas the preparation
of linear polycyclic pyridine 4i can be carried out by reacting cholestan-3-one 1i with 2, the angular
polycyclic pyridine 4j has been obtained starting from cholest-5-en-3-one 1j. Selectivity of the
reaction of polycyclic dicarbonyls 1k ,l with 2 has also been investigated.
In tr od u ction
compounds which exactly fit a single receptor subtype.7
In this context, highly substituted pyridines have recently
found applications as antiarteriosclerotics since they
efficiently inhibit HMG-CoA reductase and cholesterol
transport proteins.8
Although many synthetic routes to pyridines already
exist, most methods are scarcely used by the lack of
generality or selectivity, the harsh reactions conditions
Pyridine derivatives have gained considerable atten-
tion due to their central role as versatile building bocks
in the synthesis of natural products and new materials
1
with novel photo- or electrochemical or catalytic proper-
2
3
ties and in the design of therapeutic agents. In nature,
the pyridine nucleus is found in the coenzyme vitamin
4
B
6
family and in numerous alkaloids. Practical synthesis
of alkaloids depends on the existence of available meth-
ods to synthesize the functionalized pyridine nucleus.5
In addition, low molecular weight heterocyclic molecules
(3) (a) Sutherland, A.; Gallagher, T.; Sharples, C. G. V.; Wonnacott,
S. J . Org. Chem. 2003, 68, 2475-2478. (b) Cosford, N. D. P.; Tehrani,
L.; Roppe, J .; Schweiger, E.; Smith, N. D.; Anderson, J .; Bristow, L.;
Brodkin, J .; J iang, X.; McDonald, I.; Rao, S.; Washburn, M.; Varney,
M. A. J . Med. Chem. 2003, 46, 204-206. (c) Enyedy, I. J .; Sakamury,
S.; Zaman, W. A.; J ohnson, K. M.; Wang, S. Biorg. Med. Chem. Lett.
are ideal scaffolds for the high throughput synthesis of
libraries of druglike compounds.6 In particular, the
efficient synthesis of libraries of highly substituted
pyridines is important in the search for biologically active
compounds for the pharmaceutical and agrochemical
sectors. Selective activation or inhibition of a specific
subclass of receptors is an important challenge in me-
dicinal chemistry to design conformationally constrained
2
003, 13, 513-517. (d) Burgey, C. S.; Robinson, K. A.; Lyle, T. A.;
Sanderson, P. E. J .; Lewis, S. D.; Lucas, B. J .; Krueger, J . A.; Singh,
R.; Miller-Stein, C.; White, R. B.; Wong, B.; Lyle, E. A.; Williams, P.
D.; Coburn, C. A.; Dorsey, B. D.; Barrow, J . C.; Stranieri, M. T.;
Holahan, M. A.; Sitko, G. R.; Cook, J . J .; McMasters, D. R.; McDonough,
C. M.; Sanders, W. M., Wallace, A. A.; Clayton, F. C.; Bohn, D.;
Leonard, Y. M.; Detwiler, T. J .; Lynch, J . J .; Yan, Y. M.; Chen, Z. G.;
Kuo, L.; Gardell, S. J .; Shafer, J . A.; Vacca, J . P. J . Med. Chem. 2003,
4
6, 461-463. (e) Narendar, P.; Parthiban, J .; Anbalagan, N.; Gu-
*
To whom correspondence should be addressed. Tel: +39 0862
nasekaran, V.; Leonard, J . T. Biol. Pharm. Bull. 2003, 26, 182-187.
(f) Ravlee, I.; Sivakumar, R.; Muruganantham, N.; Anbalagan, N.;
Gunasekaran, V.; Leonard, J . T. Chem. Pharm. Bull. 2003, 51, 162-
170. (g) Faul, M. M.; Ratz, A. M.; Sullivan, K. A.; Trankle, W. G.;
Winnerroski, L. L. J . Org. Chem. 2001, 66, 5772-5782. Bouras, A.;
Boggetto, N.; Benatalah, Z.; de Rosny, E.; Sicsic, S.; Reboud-Ravaux,
M. J . Med. Chem. 1999, 42, 957-962. (h) Phillips, G.; Davey, D. D.;
Eagen, K. A.; Koovakkat, S. K.; Liang, A.; Ng, H. P.; Pinkerton, M.;
Trinh, L.; Whiltow, M.; Beatty, A. M.; Morrissey, M. M. J . Med. Chem.
1999, 42, 1749-1756.
(4) For reviews, see: Plunkett, A. O. Nat. Prod. Rep. 1994, 11, 581-
590; Daly, J . W.; Pinder, A. R. Nat. Proc. Rep. 1992, 9, 491-504.
Spande, T. F. In The Alkaloids; Brossi, A., Ed.; Academic Press: New
York, 1987; Vol. 31.
(5) Ciufolini, M. A. In Advances in Heterocyclic Natural Product
Synthesis; Pearson, W. H., Ed.; J AI Press Inc.: London, 1996; Vol. 3,
pp 1-55.
4
33774. Fax: + 39 0862 433753.
†
Universit a` degli Studi di Milano.
Universit a` di L’Aquila.
‡
(
1) Wang, Y.; Dong, X.; Larock, R. C. J . Org. Chem. 2003, 68, 3090-
3
098. Moody, C. J .; Hughes, R. A.; Thompson, S. P.; Alcaraz, L. Chem.
Commun. 2002, 1760-1761. Bach, T.; Heuser, S. Synlett 2002, 2089-
2
091.
(2) Puglisi, A.; Benaglia, M.; Roncan, G. Eur. J . Org. Chem. 2003,
1
9
552-1558. Heller, M.; Schubert, U. S. Eur. J . Org. Chem. 2003, 947-
61. Skaff, H.; Emrick, T. Chem. Commun. 2003, 52-53. Tanaka, R.;
Yano, T.; Nishioka, T.; Nakajo, K.; Breedlove, B. K.; Kimura, K.;
Kinoshita, I.; Isobe, K. Chem. Commun. 2002, 1686-1687. Kelly, T.
R.; Lebedev, R. J . Org. Chem. 2002, 67, 2197-2205. Vedernikov, A.
N.; Huffmann, J . C.; Caulton, K. G. Inorg. Chem. 2002, 41, 6867-
6
874. Malkov, A. V.; Bella, M.; Star a´ , G. I.; Ko cˇ ovsky’, P. Tetrahedron
Lett. 2001, 42, 3045-3048.
1
0.1021/jo0347260 CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/02/2003
J . Org. Chem. 2003, 68, 6959-6966
6959

Abbiati et al.
SCHEME 1. Retr osyn th etic Ap p r oa ch to th e
P yr id in e Sca ffold
Resu lts a n d Discu ssion
We selected 1,3-diphenyl acetone 1a for initial studies.
Reaction of 1a with an excess of 2 (1a /2 ) 1:2) in ethanol
at reflux for 12 h led to the isolation of 2-benzyl-3-
phenylpyridine 4a as the sole reaction product, but only
in 32% yield (1a was recovered in 64% yield). Carbonyl
compounds are known to undergo condensation reaction
with primary amines to produce imines. Imines with
R-hydrogens would be expected to be capable of imine-
enamine isomerization. Such an isomerization has been
shown in many cases in reactions involving the R-hydro-
gen atom of imines.15 Then the formation of 4a can occur
through annulation/aromatization reaction of the N-
involved, or the poor yields. More selective methods
9
10
including one-pot approaches, radical reactions, cy-
cloaddition,11 and microwave-assisted procedures have
been developed.12 Nevertheless, the development of a
straightforward one-pot approach to functionalized py-
ridines is still a synthetic challenge. We have developed
a novel one-pot procedure for the synthesis of pyridines
from commercially available ketones (or aldehydes) 1 and
propargylamine 2. From all possible retrosynthetic
schemes of six-membered heterocycles, the best of them
require one C-C bond and one C-heteroatom disconnec-
tion. It was plausible to suppose that condensation
reaction of 2 with carbonyl derivatives could give the title
targets if after the formation of a C-N linkage giving
N-propargylenamine derivatives 3 the required C-C
bond could be formed by a sequential regioselective
1
2
propargylenamine derivative (R ) Ph; R ) PhCH -)
2
generated in situ from the condensation of 1a and 2.
Usually, aliphatic ketones react slowly with amines and
aromatic ketones react even slower than aliphatic ones.
Fair yields of amination derivatives can be obtained by
the use of high temperature, long reaction time, acidic
catalysts, and water removal. We have developed efficient
protocols for condensation reactions of 1,3-dicarbonyl
derivatives with amines.16 In particular, gold salts per-
mitted the synthesis of â-enaminones from 1,3-dicarbonyl
compounds and ammonia/amines at rt providing a milder
1
7
alternative to previous methodologies. Kobayashi et al.
reported that several transition-metal salts exhibit higher
catalytic activity compared to conventional Lewis acids
in aza-Michael reactions of enones. So we first studied
the catalytic activity of various transition-metal salts
(mostly chlorides) in the reaction of 1a and 2 (Table 1).
According to our previous results, gold(III) catalysts
were very effective.16 From all the catalysts screened,
6
-endo-dig annulation/aromatization reaction (Scheme 1).
The endo mode of annulation remains relatively un-
explored compared to the exo cyclizations.13 A variety of
methods of selective endo-5-dig cyclization of 5-en-1-ynes
have been developed, but selective 6-endo-dig cyclizations
are scarcely known.14 We have found that reaction of
carbonyl compounds with 2 gives rise to pyridines 4
through sequential amination/6-endo-dig annulation/
aromatization reaction. Herein, we describe the scope and
limitations of this new entry to functionalized pyridines.
NaAuCl
4
2
‚2H O was the most efficient (Table 1, entry 1)
for the preparation of 4a (98% yield). Copper salts were
also effective catalysts (Table 1, entries 5-10). Ir(I) and
Rh(I) complexes18 are known to catalyze the addition of
amines to acrylic acid derivatives, but in our case these
complexes were not active (Table 1, entries 21 and 22).
2 3 4
ZnCl , AlCl , TiCl
, and other Lewis acids19 have been
reported to be efficient catalysts and water scavengers
in the condensation of ketones with amines, but in our
hands they showed low activity (Table 1, entries 11 and
(
6) Sutherland, A.; Gallagher, T. J . Org. Chem. 2003, 68, 3352-
3
355. Bashford, K. E.; Burton, M. B.; Cameron, S.; Cooper, A. L.; Hogg,
R. D.; Kane, P. D.; MacManus, D. A.; Matrunola, C. A.; Moody, C. J .;
Robertson, A. A. B.; Warne, M. R. Tetrahedron Lett. 2003, 44, 1627-
1
629.
(7) Turner, S. C.; Zhai, H.; Rapoport, H. J . Org. Chem. 2000, 65,
2
0).
8
61-870.
(
8) Schmidt, G.; Stoltefuss, J .; L o¨ gers, M.; Brandes, A.; Schmeck,
We next investigated the reactions of various ketones
C.; Bremm, K.-D.; Bischoff, H.; Schmidt, D. Ger. Offen. 1999, 42, DE
9741399. Stoltefuss, J.; L o¨ gers, M.; Schmidt, G.; Brandes, A.; Schmeck,
with 2 in ethanol by using the most effective catalysts
found for 4a and studied the best reactions conditions
that could be used with a wide variety of carbonyl
derivatives 1b-t by varying the 1/2 molar ratio and the
reaction temperature for both catalysts. The results are
shown in Table 2.
Copper salts were as effective as gold salts when the
most reactive ketones were used. In some cases, a slight
excess of 2 (2/1 ) 1.5) gave satisfactory results, but in
1
C.; Bremm, K.-D.; Bischoff, H.; Schmidt, D. PCT Int. Appl. 1999, 107,
WO 9914215. Smith, H. W. Eur. Pat. Appl. 1985, 35, EP 161867.
(9) Bagley, M. C.; Dale, J . W.; Ohnesorge, M.; Xiong, X.; Bower, J .
J . Combinat. Chem. 2003, 5, 41-44. Yehia, N. A. M.; Polborn, K.;
M u¨ ller, T. J . J . Tetrahedron Lett. 2002, 43, 6907-6910. Bagley, M. C.;
Dale, J . W.; Bower, Chem. Commun. 2002, 1682-1683. Veronese, A.
C.; Morelli, C. F.; Basato, M. Tetrahedron 2002, 58, 9709-9712.
(
10) Baker, S. R.; Cases, M.; Keenan, M.; Lewis, R. A.; Tan, P.
Tetrahedron Lett. 2003, 44, 2995-2999. Navarro-V a´ zquez, A.; Garc ´ı a,
A.; Dom ´ı nguez, D. J . Org. Chem. 2002, 67, 3213-3220.
(11) Coffey, S. C.; Kolis, S. P. May S. A. In Progress in Heterocyclic
Chemistry; Gribble, G. W., Gilchrist, T. L., Eds.; Pergamon: Amster-
dam, 2002; Vol. 14, pp 257-259 and references therein.
(15) Parcell, R. F.; Hauck, F. P., J r. J . Org. Chem. 1963, 28, 3468-
3473.
(
12) Bagley, M. C.; Lunn, R.; Xiong, X. Tetrahedron Lett. 2002, 43,
8
331-8334. Cherng, Y.-J . Tetrahedron 2002, 58, 4931-4935.
(16) Arcadi, A.; Bianchi, G.; Di Giuseppe, S.; Marinelli, F. Green
Chem. 2003, 5, 64-67.
(
13) For recent examples of 5-endo-dig cyclization of 5-en-1-ynes,
see: Iwasawa, N.; Miura, T., Kiyota, K.; Kusama, H.; Lee, K.; Lee, P.
H. Org. Lett. 2002, 4, 4463-4466 and references therein. For recent
examples of 5-exo-dig cyclization of 5-en-ynes, see: Rossi, E.; Arcadi,
A.; Abbiati, G.; Attanasi, O. A.; De Crescentini, L. Angew. Chem., Int.
Ed. 2002, 41, 1400-1402.
(17) Kobayashi, S.; Kakumoto, K.; Sugiura, M. Org. Lett. 2002, 4,
1319-1322.
(18) Kawatsura, M.; Hartwig, J . F. Organometallics 2001, 20, 1960-
1964
(19) Borg, G.; Cogan, D. A.; Elmann, J . A. Tetrahedron Lett. 1999,
40, 6709-6712. Taguchi, K.; Westheimer, F. H. J . Org. Chem. 1971,
36, 1570-1572. Moretti, I.; Torre, G. Synthesis 1970, 141. Billman, J .
H.; Tai, K. M. J . Org. Chem. 1958, 23, 535-539.
(
14) Pastine, S. J .; Youn, S. W.; Sames, D. Org. Lett. 2003, 5, 1055-
058. Berg-Nielsen, K.; Skatebøl, L. Acta Chem. Scand. B: Org. Chem.
Biochem. 1978, 32, 553-556.
1
6
960 J . Org. Chem., Vol. 68, No. 18, 2003

One-Pot Approach to Functionalized Pyridines
TABLE 1. Effect of Ca ta lyst Ch oice on Rea ction a of 1,3-Dip h en yla ceton e 1a w ith P r op a r gyla m in e 2
b
b
entry
catalyst
yield (%)
entry
catalyst
yield (%)
1
2
3
4
5
6
7
8
9
NaAuCl4‚2H2Oc
NaAuCl4‚2H2O
KAuCl4
AuCl
CuI
98
56
85 (13)
51 (46)
62 (31)
79
62 (37)
95
12
13
14
15
16
17
18
19
20
21
22
Cu(NO3)2‚3H2O
NaPdCl4
PtCl4
82 (9)d
40 (54)
53 (43)
43 (53)
37 (63)
52 (45)
44 (51)
65 (22)
e
d
d
d
d
d
K2PtCl4
d
d
NiCl2‚2H2O
d
CuCl
AgNO3
d
(III)
d
CuSO4‚5H2O
Ru Cl3
c
d
CuCl2‚2H2O
FeCl3‚6H2O
ZnCl2
[IrCl(C8H12)]2
Rh(C2H4)(C5H7O2)
d
d
Cu(OAc)2
Cu(CF3SO3)2
TiCl4
80 (7)
35 (61)
21 (77)
19 (78)
d
d
1
1
0
1
74 (16)
6 (92)f
a
b
All reactions were carried out with 1 equiv of 1a , 2 equiv of 2, and 0.025 equiv of the catalyst in ethanol at reflux for 12 h. GC yield.
c
Reaction time 5 h. Figures in parentheses refer to recovered yield of 1a . e 1a /2 ) 1:1.5. f The reaction was carried out with 1 equiv of
a , 2 equiv of 2, and 0.5 equiv of the TiCl4 in toluene (2 mL) at rt for 5 h and at reflux for 19 h.
d
1
4
other cases the best results were obtained when we used
.0 or 3.0 equiv of 2. Increasing the reaction temperature
∆ -polycyclic derivatives. Selectivity of the reaction of
polycyclic dicarbonyls 1k ,l and propargylamine 2 has also
2
2
5
usually resulted an increase of the yield of the pyridine
derivative (i.e., 4c was isolated in 46% yield at 40 °C and
been investigated. The reported procedures for an-
drostanopyridine derivatives involved several steps, two
of which occurred at temperatures over 200 °C. The linear
6
9% yield at 78 °C; Table 2, entries 3 and4). With the
2
6
less reactive aryl alkyl ketones, a temperature of 100 °C
was required (i.e., 4m was isolated in 50% yield at 78 °C
and 65% yield at 100 °C; Table 2, entries 17 and 18). By
this method, a series of mono- and polyannelated py-
ridines in which a five-, six-, seven-, or eight-membered
ring is fused at the 2,3-position of the pyridine ring were
prepared. The new analogue of the nicotinic acetylcholine
cholestanopyridine 4i was previously synthesized
through a three-step pyridoannelation of the 5R-cholestan-
3-one 1i by regiospecific alkylation of its N,N-dimethyl-
hydrazones with bromoethyl-1,3-dioxolane. The angular
polycyclic pyridines 4j,l have not been previously re-
ported. According to the results obtained in the prepara-
tion on enamine derivatives of steroidal carbonyl com-
7
27
receptor agonist 4d was prepared from tropinone 1d
pounds, polycyclic dicarbonyl derivatives having conju-
(Table 2, entry 5). In contrast to our method, the
3
gated carbonyl groups in the C -position undergo selective
traditional preparation of annelated pyridines through
the Friedl a¨ nder condensation20 of cyclic ketones with
â-aminoacrolein provided 2,3-fused pyridines in very poor
yields (i.e., 2,3-trimethylenepyridine 4e was obtained in
amination in the 3-position. Then, the target angular
pyridines 4j,l could derive from the sequential annula-
tion/aromatization reaction of 3,5-dienyl-3-(N-propargyl)-
amino intermediates 5. These results suggest that the
regioselective pyridine fusion to the cyclic skeleton could
be directed by the presence of a saturated or conjugated
carbonyl group in the substrate (Scheme 2).
1
6% yield), and the alternative traditional procedures
involving thermal rearrangements of O-allyl ethers of
ketoxymes21 or intramolecular Diels-Alder reactions of
2
2
2
-(alkynyl)pyrimidines required heating at tempera-
The preparation of 2-aryl(heteroaryl)-substituted py-
ridines (Table 2, entries 19-23) through the reaction of
methyl aryl(heteroaryl) ketones with 2 represents an
tures over 200 °C. Steroids bearing fused heterocyclic
rings23 are interesting as modulators of androgen bio-
synthesis24 and pituitary gonadotropin inhibitors. Our
new approach permitted the synthesis of steroidal de-
28
alternative to the Suzuki cross-coupling procedure.
Aliphatic aldehydes give in general polymeric materials
in their reactions with amines because the initially
formed imines undergo subsequent aldol condensation.
Nevertheless, by adding a slight excess (1.2 equiv) of 2
at rt to a stirred solution of aldehydes 1s,t, we observed
by GC/MS the quantitative formation of the amination
derivative after 1 h; then, the temperature was raised to
120 °C for 12 h and the 3-alkyl-substituted pyridines 4s,t
were isolated after usual workup in good yield (Table 2,
entries 24 and 26). In the presence of the gold catalyst
2
5
rivatives with fused pyridine rings. The gold-catalyzed
condensation of 5-androsten-3â-ol-17-one 1h with 2 at
1
00 °C gave the 5-androsten[17,16-b]pyridin-3â-ol de-
rivative 4h in 56% yield. Linear or angular cholestan-
opyridine derivatives 4i,j were obtained, respectively, by
the gold-catalyzed condensation of the 5R-cholestan-3-
one 1i or the 4-cholesten-3-one 1j with 2. Different
angular polycyclic pyridines were obtained from 3-keto-
(
Table 2, entry 25), the pyridine 4s was obtained in
(
20) Thummel, R. P.; Kohli, D. K. J . Org. Chem. 1977, 42, 2742-
2
2
747.
(
23.
milder conditions and in higher yield. A plausible mech-
21) Kusumi, T.; Yoneda, K.; Kakisawa, H. Synthesis 1979, 221-
(
22) Frissen, A. E.; Marcelis, A. T. M.; Geurtsen, G.; de Bie, D. A.;
(26) Chelucci, G.; Gladiali, S. J . Heterocycl. Chem. 1988, 25, 1761-
van der Plas, H. C. Tetrahedron 1989, 45, 5151-5162.
1765.
(
(
(
23) Arcadi, A.; Rossi, E. Synlett 1997, 667-668.
24) Zhang, X.; Sui, Z. Tetrahedron Lett. 2003, 44, 3071-3073.
25) Miller, T. C. J . Heterocycl. Chem. 1966, 3, 338-342. Sterling
(27) Heyl, F. W.; Herr, M. E. J . Am. Chem. Soc. 1953, 75, 1918-
1920.
(28) Feuerstein, M.; Doucet, H.; Santelli, M. Tetrahedron Lett. 2001,
42, 5659-5662.
Drug Inc. U.S. Patent 3409609; Chem. Abstr. 1969, 70, 47710s.
J . Org. Chem, Vol. 68, No. 18, 2003 6961

Abbiati et al.
TABLE 2. Syn th esis of P yr id in esa 4 fr om th e Rea ction of Ca r bon yls w ith P r op a r gyla m in e 2
6
962 J . Org. Chem., Vol. 68, No. 18, 2003

One-Pot Approach to Functionalized Pyridines
TABLE 2 (Con tin u ed )
J . Org. Chem, Vol. 68, No. 18, 2003 6963

Abbiati et al.
TABLE 2 (Con tin u ed )
a
Unless otherwise stated, reactions were carried out in ethanol (2 mL) using 1 equiv of 1, 1.5 equiv of 2, and 0.025 equiv of catalyst.
Yields are given for isolated products. 3.0 equiv of 2 was used. d 2.0 equiv of 2 was used. e To a solution of 1 equiv of 1 in ethanol (2
b
c
mL) was added 1.2 equiv of 2, and the mixture was stirred for 1 h at rt. Then, the mixture was heated at 120 °C for 24 h.
anism consists of (1) formation of the imino intermediate
through the metal salt catalyzed condensation reaction
to the carbonyl carbon through the formation of a complex
with the CdO group. MX should act as transition-metal
6
n
of the ketone 1 with 2, (2) imine-enamine isomerization
to give 7, (3) regioselective 6-endo-dig intramolecular
nucleophilic attack of the carbon of the enamino moiety
to the activated carbon-carbon triple bond to give an
organometallic intermediate 8, (5) protonolysis of the
catalyst by forming a complex with the alkyne groups
that facilitates the nucleophilic attack of the enamine to
the electron-deficient carbon. In previous studies, we
observed the high efficiency of gold(III) catalysis as Lewis
acid in the condensation reaction of o-amino aromatic
carbonyl compounds with ketones containing active me-
thylene groups30 and both as Lewis acid/transition metal
in sequential amination/annulation reactions of R-pro-
pargyl dicarbonyls with amines, amino alcohols and
C
sp2-M bond to give the dehydropyridine 9, and (6)
31
dehydrogenation reaction to afford the pyridine deriva-
tive 4 (Scheme 3). An effective catalyst of this sequential
amination/cyclization reaction should act simultaneously
2
9
as a Lewis acid and as a transition metal. MX
n
should
catalyze the nucleophilic attack of the amino group of 2
(30) Arcadi, A.; Chiarini, M.; Di Giuseppe, S.; Marinelli, F. Synlett
2
003, 203-206.
(31) Arcadi, A.; Di Giuseppe, S.; Marinelli, F.; Rossi, E. Tetrahedron:
(
29) Asao, N.; Nogami, T.; Takahashi, K.; Yamamoto, Y. J . Am.
Asymmetry 2001, 12, 2715-2720. Arcadi, A.; Di Giuseppe, S.; Marinelli,
F.; Rossi, E. Adv. Synth. Catal. 2001, 343, 443-446.
Chem. Soc. 2002, 124, 764-765.
6
964 J . Org. Chem., Vol. 68, No. 18, 2003

One-Pot Approach to Functionalized Pyridines
SCHEME 2. Lin ea r vs An gu la r P olycyclic P yr id in es
SCHEME 3. Tr a n sition -Meta l-Ca ta lyzed
Sequ en tia l Am in a tion /Cycliza tion /Ar om a tiza tion
Rea ction : P r op osed Mech a n ism
catalyzed condensation reaction of cyclic ketones led to
fused pyridines in which a five-, six-, seven-, or eight--
membered ring is fused at the 2,3-position of the pyridine
ring. This new synthetic approach was successfully
extended to the synthesis of steroidal derivatives with
fused pyridine rings and polyannelated pyridines. Whereas
linear polycyclic pyridines are regioselectively obtained
by the gold-catalyzed condensation reaction of polycyclic
carbonyl compound, the angular polycyclic pyridines are
obtained starting from the corresponding R,â-unsaturated
derivatives. Selective amination of the unsaturated car-
bonyl groups was observed in polycyclic dicarbonyl
compounds.
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r e for th e Sequ en tia l
Am in a tion /An n u la tion /Ar om a tiza tion Rea ction s of Ke-
ton es 1 w ith P r op a r gyla m in e 2. To a 50 mL stainless steel
autoclave charged with a solution of the ketone 1 (1.26 mmol)
in absolute ethanol (5 mL) were added propargylamine 2 (2.52
mmol) and the catalyst (0.03 mmol). The resulting mixture
was heated at reflux under stirring or at 100 or 140 °C.The
reaction was monitored by TLC and GC-MS. After cooling,
the mixture was filtered to remove the catalyst, and the solvent
was concentrated under reduced pressure. The residue was
purified by flash chromatography (silica gel, n-hexanes-ethyl
acetate mixtures) to give pyridine 4. Alternatively, the residue
was dissolved in ethyl acetate and extracted three times with
a 6 M solution of aqueous hydrochloric acid. The combined
aqueous extracts were washed with ethyl acetate, solid NaOH
was added until pH ) 8, and the mixture was extracted three
times with ethyl acetate. The combined organic extracts were
R-aminoesters. The acetylenic bond has been proved to
have a regio-/chemoselective interaction with copper
salts.32
2 4
dried (Na SO ) and evaporated under reduced pressure. The
desired product was distilled under vacuum.
Con clu sion s
The following products were identified by comparison of
their physical and spectral data with those given in the cited
The condensation reaction of carbonyl compounds with
propargylamine represents a new general one-pot entry
into fuctionalized pyridines. The formation of the py-
ridines is suggested to proceed through the sequential
amination of carbonyl compounds followed by regiose-
lective 6-endo-dig cyclization of the N-propargylenamine
1
5
references: 2-benzyl-3-phenylpyridine 4a, 6-tert-butyl-5,6,7,8-
3
3
tetrahydroquinoline 4c, 6-benzyl-5,6,7,8-tetrahydro[1,6]-
naphthyridine34 4e, 6,7-dihydro-5H-1-pyrindine 4f and 5,6,7,8,9,-
2
2
1
0-hexahydrocycloocta[b]pyridine 4g, 5R-cholest-2-eno[3,2-
26
b]pyridine 4i, 2-(4-bromophenyl)pyridine 4n and 2-phenyl-
pyridine 4p , 2-(4-fluorophenyl)pyridine 4o, [2,3′]bipyridine
35
36
(N-propargyldienamine) intermediate and aromatization
reaction. The reaction requires a catalyst. Gold(III) salts
are the most efficient and selective catalysts and their
application is general, but copper salts are also efficient
catalysts when reactive ketones are used. The gold-
(
33) H o¨ nel, M.; Vierhapper, W. J . Chem. Soc., Perkin Trans. 1 1980,
1
933-1939.
(34) Shiozawa, A.; Ichikawa, Y.; Komuro, C.; Kurashige, S.; Miyaza-
ki, H. Chem. Pharm. Bull. 1984, 32, 2522-2529.
(
35) Gutierrez, M. A.; Newkome, G. R.; Selbin, J . J . Organomet.
Chem. 1980, 202, 341-350.
(36) Chkurko, O. P.; Baram, S. G.; Mamajeev, V. P. Khim. Geterotsikl
Soedin. 1983, 1, 66-72.
(
32) Arcadi, A.; Cerichelli, G.; Chiarini, M.; Di Giuseppe, S.;
Marinelli, F. Tetrahedron Lett. 2000, 41, 9195-9198.
J . Org. Chem, Vol. 68, No. 18, 2003 6965

Abbiati et al.
q and [2,4′]bipyridine 4r , 3-phenypyridine28 4s, and 3-ben-
3
7
4
dell’Istruzione, dell’Universit a` e della Ricerca (MIUR)
for financial support.
3
8
zylpyridine 4t.
Ack n ow led gm en t. We gratefully acknowledge the
Universit a` degli Studi di L’Aquila and the Ministero
Su p p or tin g In for m a tion Ava ila ble: Experimental in-
formation including characterization data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(
37) De Koning, A. J .; Budzelaar, J .; Boersma, J .; Van der Kerk, G.
J . M. J . Organomet. Chem. 1980, 199, 153-169.
38) Fraser, R. R.; Mansour, T. S.; Savard, S. J . Org. Chem. 1985,
0, 3232-3234.
(
5
J O0347260
6
966 J . Org. Chem., Vol. 68, No. 18, 2003