An expedient phosphine-catalyzed [4 + 2] annulation: Synthesis of highly functionalized tetrahydropyridines

Article abstract of DOI:10.1021/ja0344009

Ethyl 2-methyl-2,3-butadienoate acts as a 1,4-dipole synthon and undergoes [4 + 2] annulation with N-tosylimines in the presence of an organic phosphine catalyst. The resulting adducts, ethyl 6-substituted-1-(4-tosyl)-1,2,5,6-tetrahydro-pyridine-3-carboxylates, are formed in excellent yields with complete regioselectivity. Mechanistic reasoning for this new annulation has led to an expansion of the reaction scope by employing ethyl 2-(substituted-methyl)-2,3-butadienoates to give ethyl 2,6-cis-disubstituted-1-(4-tosyl)-1,2,5,6-tetrahydro-pyridine-3-carboxylates with high diastereoselectivities. Copyright

Full text of DOI:10.1021/ja0344009

Published on Web 03/28/2003
An Expedient Phosphine-Catalyzed [4 + 2] Annulation: Synthesis of Highly
Functionalized Tetrahydropyridines
Xue-Feng Zhu, Jie Lan, and Ohyun Kwon*
Department of Chemistry and Biochemistry, UniVersity of California, Los Angeles, California 90095-1569
Received January 29, 2003; E-mail: ohyun@chem.ucla.edu
Table 1. Synthesis of Tetrahydropyridines 3 from Ethyl
Functionalized tetrahydropyridines and piperidines are common
substructures found in biologically active natural products and
synthetic pharmaceuticals.1 One of the most versatile methods to
prepare six-membered heterocycles is the [4 + 2] cycloaddition
reaction. Among the [4 + 2] cycloadditions, examples of 1,4-dipolar
cycloadditions providing six-membered heterocycles are scarce.2
For the most part, this is due to the fact that Diels-Alder reactions
rather than 1,4-dipolar cycloadditions have provided the means to
construct heterocyclic six-membered rings.3 The reactivity and
regioselectivity of Diels-Alder reactions, however, are predeter-
mined by the molecular orbital coefficients of dienes and dieno-
philes and limit the scope of accessible heterocycles. For example,
while Diels-Alder reaction of 2-methylene-but-3-enoates4 with
imines could potentially provide tetrahydropyridine derivatives, this
diene only dimerizes in the presence of N-tosylbenzaldimine.5 As
part of a program focused on the development of organic phosphine-
catalyzed annulation reactions6 to form heterocycles, and inspired
by recent accounts of phosphine-catalyzed reactions of 2,3-
butadienoates or 2-butynoates, we herein report the discovery of a
2-methylene-but-3-enoate synthon and its phosphine-catalyzed
[4 + 2] annulation with aldimines to provide highly substituted
tetrahydropyridine derivatives.
2-Methyl-2,3-butadienoate and N-Tosylaldiminesa
entry
R
product
yield (%)b
1
2
3
4
5
6
Ph (2a)
3ac
3b
3c
3d
3e
3f
98
99
95
96
93
95
98
98
96
97
92d
86
0
4-OMeC6H4 (2b)
4-MeC6H4 (2c)
3-ClC6H4 (2d)
2-ClC6H4 (2e)
4-FC6H4 (2f)
7
8
9
4-CNC6H4 (2g)
2-CF3C6H4 (2h)
1-naphthyl (2i)
2-furyl (2j)
4-pyridyl (2k)
4-NO2C6H4 (2l)
2-OHC6H4 (2m)
2-OTBSC6H4 (2n)
2-pyrrolyl (2o)
N-Boc-2-pyrroyl (2p)
trans-styrenyl (2q)
t-butyl (2r)
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
10
11
12
13
14
15
16
17
18
19
93
0
99
tracee
86f
0g
n-propyl (2s)
The formation of pyrroline derivatives upon mixing imines with
2,3-butadienoates in the presence of a phosphine catalyst is triggered
by R-addition of the zwitterionic intermediate to the imine.7 We
envisioned that substitution of the hydrogen at the 2-position of
2,3-butadienoates with a methyl group might block the R-attack of
the zwitterionic intermediate and lead to an unprecedented reaction
mode initiated by γ-addition of the zwitterionic intermediate to
imines (see discussion on mechanism below). To our delight, mixing
2-methyl-2,3-butadienoate 1 with N-tosylbenzaldimine in the pres-
ence of a catalytic amount of PBu3 resulted in the formation of
tetrahydropyridine 3a (eq 1). In the present reaction, ethyl 2-methyl-
2,3-butadienoate acts as a 1,4-dipole synthon A.
a See Supporting Information for a detailed experimental procedure.
b Isolated yields. c The structure was confirmed by X-ray crystallographic
analysis. d 30 mol % PBu3 was used. e The product was inseparable from
the starting imine. f 3 equiv of Na2CO3 was added. g The imine was
decomposed to aldehyde and p-toulenesulfonamide.
Scheme 1. Mechanistic Rationale for the Formation of 3
Using conditions optimized for the formation of 3a, we prepared
various tetrahydropyridine derivatives (Table 1). Several charac-
teristics of this annulation reaction are noteworthy. Tetrahydropyr-
idines (Table 1, 3a-3k) were obtained in over 90% yield when 1
was allowed to react with various aryl N-tosylimines8 2 in the
presence of 20 mol % PBu3, with the exception of an aryl group
bearing a nitro-substituent (Table 1, 3l). Interestingly, salicyl and
2-pyrrolyl N-tosylmines provided none of the desired product (Table
1, 3m and 3o) while their O-TBS and N-Boc protected counterparts
underwent the annulation uneventfully (Table 1, 3n and 3p). The
presence of acidic protons is believed to be detrimental to the
reaction. For alkyl and vinyl N-tosylimines, none or trace amounts
of cycloadducts were isolated. Only N-tosylpivalaldimine afforded
the desired product (Table 1, 3r) in 86% yield in the presence of
Na2CO3.
The mechanism of this unprecedented cyclization reaction has
not been unequivocally established, but one reasonable possibility
is outlined in Scheme 1. Tri-n-butylphosphine acts as a nucleophilic
trigger and forms intermediate 4, which exists as a resonance-
stabilized zwitterionic intermediate 4 T 5. Allylic carbanion 5 adds
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J. AM. CHEM. SOC. 2003, 125, 4716-4717
10.1021/ja0344009 CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Synthesis of Tetrahydropyridines 13 from Ethyl
reaction with N-tosylaldimines to form tetrahydropyridine deriva-
tives in excellent yields with complete regioselectivity and high
diastereoselectivities. Future effort will focus on expanding the
versatility of these new 1,4-dipole synthons as well as on performing
the annulation in an enantioselective manner.
2-Benzyl-2,3-butadienoates and N-Tosylaldiminesa
entry
R
R′
product yield (%)b
drc
Acknowledgment. We are grateful to UCLA for startup research
funding and to the NSF under Equipment Number CHE-9974928
and CHE-0092036. We thank Dr. Saeed Khan for performing X-ray
crystallographic analysis. O.K. thanks Professors Christopher S.
Foote, Miguel A. Garcia-Garibay, Kendall N. Houk, Mike E. Jung,
Mark Mascal (also for editorial assistance), Craig A. Merlic, and
Fred Wudl for helpful discussions.
1
2
3
4
5
6
7
8
9
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
4-CNC6H4 (12a)
2-FC6H4 (12b)
3-OMeC6H4 (12c) 13c
2-MeC6H4 (12d)
Ph (12e)
13a
13b
99
99
99
82
99
99
90
99
80
96
99
98:2
97:3
98:2
88:12
98:2
97:3
95:5
98:2
90:10
83:17
98:2
13d
13ed
13f
4-OMeC6H4 (2b) Ph (12e)
4-NO2C6H4 (2l)
3-ClC6H4 (2d)
2-CF3C6H4 (2h)
Ph (12e)
4-CNC6H4 (12a)
4-CNC6H4 (12a)
3-OMeC6H4 (12c) 13j
3-OMeC6H4 (12c) 13k
13g
13h
13i
Supporting Information Available: Representative experimental
procedures and spectral data for all new compounds (PDF). Crystal-
lographic data for compounds 3a and 13e (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
10 2-ClC6H4 (2e)
11 4-MeC6H4 (2c)
a See Supporting Information for a detailed experimental procedure.
b Isolated yields. c Diastereomer ratio determined by 1H NMR (500 MHz).
d The structure was confirmed by X-ray crystallographic analysis.
References
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transfer steps shuffle the proton on the â′-carbon to the â-carbon
of intermediate 6. Thus formed intermediate 9 undergoes 6-endo
cyclization followed by expulsion of PBu3 to generate tetrahydro-
pyridine 3.
The proton-transfer process is believed to be the rate-determining
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enoate 10 undergoes the annulation reaction with N-tosylbenzaldi-
mine (2a) much more sluggishly than 1 and provides 11 (R ) Ph)
only in 31% yield. This observation prompted us to test the reaction
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obtained in 99% yield in 30 min with high diastreoselectivity (dr,
98:2) favoring the formation of 2,6-cis-adduct. Syntheses of
tetrahydropyridines 13 employing 2-benzyl-2,3-butadienoates10 12
are summarized in Table 2.
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The [4 + 2] annulation reactions of 2-benzyl-2,3-butadienoates
12 with N-tosylbenzaldimine (2a) in the presence of PBu3 incor-
porated various aryl groups into the 2-position of tetrahydropyri-
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diastereoselectivities. An exception was noted for ethyl 2-(2-
methylbenzyl)-2,3-butadienoate (Table 2, 12d). Upon investigation
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groups providing poorer results. Thus, the presence of an ortho-
substituent of significant steric bulk (Table 2, entries 4, 9, and 10)
on the aryl rings diminishes the reaction yield as well as
compromising the reaction diastereoselectivity. On the contrary,
the presence of an ortho-fluoro group afforded the desired 2,6-cis-
tetrahydropyridine 13b in nearly quantitative yield (99%) with high
diastereoselectivity (dr, 97:3). It was again apparent that the reaction
yield diminished when a nitro-substituted aryl N-tosylimine (2l)
was employed (Table 2, entry 7).
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step.
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In conclusion, our effort to expand the scope of phosphine-
catalyzed annulations has led us to the discovery of a new class of
1,4-dipole synthons, 2-alkyl-2,3-butadienoates. The importance of
this finding was exemplified by their expedient [4 + 2] annulation
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