Synthesis of isoquinuclidines from highly substituted dihydropyridines via the Diels-Alder reaction

Article abstract of DOI:10.1021/ol303040r

A stereo- and regioselective Diels-Alder reaction for the synthesis of highly substituted isoquinuclidines from dihydropyridines and electron-deficient alkenes has been developed. While reactions with activated dienophiles proceed readily under thermal conditions, the use of Lewis acid additives is necessary to facilitate cycloadditions for less reactive alkenes. This procedure affords the target compounds in high yields and diastereoselectivities.

Full text of DOI:10.1021/ol303040r

ORGANIC
LETTERS
2013
Vol. 15, No. 3
444–447
Synthesis of Isoquinuclidines from
Highly Substituted Dihydropyridines
via the DielsÀAlder Reaction
Rhia M. Martin,† Robert G. Bergman,*,‡ and Jonathan A. Ellman*,†
Department of Chemistry, Yale University, New Haven, Connecticut, 06520,
United States, and Division of Chemical Sciences, Lawrence Berkeley National
Laboratory, and Department of Chemistry, University of California;Berkeley,
Berkeley, California 94720, United States
rbergman@berkeley.edu; jonathan.ellman@yale.edu
Received November 5, 2012
ABSTRACT
A stereo- and regioselective DielsÀAlder reaction for the synthesis of highly substituted isoquinuclidines from dihydropyridines and electron-
deficient alkenes has been developed. While reactions with activated dienophiles proceed readily under thermal conditions, the use of Lewis acid
additives is necessary to facilitate cycloadditions for less reactive alkenes. This procedure affords the target compounds in high yields and
diastereoselectivities.
The synthesis of nitrogen heterocycles is an important
area of research due to their prevalence in natural products
and drugs.1,2 Recently, we reported Rh(I)-catalyzed
β-CÀH bond alkenylation of R,β-unsaturated imines
followed by in situ electrocylization to give N-alkyl and
-aryl 1,2-dihydropyridines (Scheme 1A).3 These highly sub-
stituted dihydropyridines would be difficult to prepare by
alternative methods and have proven to be versatile inter-
mediates to other classes of heterocycles.4 For example,
aromatization to the corresponding pyridines can be accom-
plished in an overall one-pot procedure (Scheme 1A).3a,5
Alternatively, 1,2,3,6-tetrahydropyridines can be obtained
with high diastereoselectivities via protonation of the en-
amine followed by in situ reduction of the resulting iminium.3b
In our efforts to further harness the 1,2-dihydropyridine
intermediates generated through Rh-catalyzed CÀH ac-
tivation, we became interested in the potential of gen-
erating isoquinuclidines utilizing a DielsÀAlder reaction
(Scheme 1B). Isoquinuclidines have been used as inter-
mediates in the preparation of tetrahydroisoquinoline
† Yale University.
‡ University of California, Berkeley.
(1) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org.
Biomol. Chem. 2006, 4, 2337.
(4) (a) For a recent review on the synthesis of dihydropyridines from
pyridines, see: Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B.
Chem. Rev. 2012, 112, 2642. For leading references on alternative methods
for accessing substituted 1,2-dihydropyridines, see: (b) Harrison, D. P.;
Sabat, M.; Myers, W. H.; Harman, W. D. J. Am. Chem. Soc. 2010, 132,
17282. (c) Harschneck, T.; Kirsch, S. F. J. Org. Chem. 2011, 76, 2145.
(2) For recent reviews on heterocycle synthesis via CÀH activation,
see: (a) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem., Int.
Ed. 2012, 51, 2. (b) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc.
Chem. Res. 2012, 45, 788. (d) Yeung, C. S.; Dong, V. M. Chem. Rev.
€
2011, 111, 1215. (e) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F.
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M. J. Chem. Soc. Rev. 2011, 40, 1885. (g) Lyons, T. W.; Sanford, M. S.
Chem. Rev. 2010, 110, 1147. (h) Colby, D. A.; Bergman, R. G.; Ellman,
J. A. Chem. Rev. 2010, 110, 624. (i) Xu, L.-M.; Li, B.-J.; Yang, Z.; Shi,
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r
10.1021/ol303040r
Published on Web 01/15/2013
2013 American Chemical Society

generated by N-acylation followed by nucleophilic addi-
tion to pyridines.10À13 However, the incorporation of
an acyl protecting group attenuates the nucleophilicity
of the dihydropyridine substrates.11 Moreover, reliance
on pyridine inputs generally results in dihydropyridine
productslacking a high degree of substitution.4 Herein, we
report that isoquinuclidines with unprecedented substitu-
tion levels are obtained in good yield and with high regio-
and stereoselectivities by DielsÀAlder reaction between
highly substituted N-alkyl and aryl-1,2-dihydropyridines
and electron-deficient alkenes.
Scheme 1. Rh-Catalyzed CÀH Functionalization Provides
Versatile 1,2-Dihydropyridine Intermediates
DielsÀAlder reactions for a range of dienophiles with
differential relative reactivity were first investigated
(products 3aÀd, Scheme 2). The most reactive dienophile,
N-phenyl maleimide, underwent efficient cycloaddition to
give isoquinuclidine 3a at room temperature within 16 h
with only the endo isomer detected by 1H and 13C NMR
analysis of the unpurified reaction mixture. Methyl acry-
late and acrylonitrile required more forcing conditions
but provided the desired products 3b and 3c, respectively,
in high yield when run neat with heating to 105 °C.
Isoquinuclidines 3b and 3c were each produced as a single
regioisomer, and for 3b only the endo product was ob-
served while for 3c a 93:7 endo/exo ratio was obtained.
Identifying effective conditions for coupling the less
reactive crotonaldehyde required significant optimization
(Table 1). Performing the reaction at 0.1 or 0.5 M in
CH2Cl2 with heating to 50 °C provided little if any con-
version (entries 1 and 2). Even when the reaction was
performed neat with excess crotonaldehyde with heating
at 105 °C only a trace amount of product was detected
(entry 3). Lewis acid additives have proven to be effective
for increasing the rate of DielsÀAlder reactions for dienes
alkaloids,6 piperidines,7 Iboga alkaloids,8 and the related
Cantharanthus alkaloids,9 which have been developed as
cancer therapeutics. Isoquinuclidines are most often pre-
pared by a DielsÀAlder reaction of 1,2-dihydropyridines
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Tetrahedron Lett. 2010, 51, 1994. (e) Hodgson, D. M.; Galano, J.-M. Org.
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1990, 55, 6028. (g) Krow, G. R.; Shaw, D. A.; Lynch, B.; Lester, W.;
Szczepanski, S. W.; Raghavachari, R.; Derome, A. E. J. Org. Chem. 1988,
53, 2258. (h) Sundberg, R. J.; Amat, M.; Fernando, A. M. J. Org. Chem.
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(11) For select examples of the preparation of isoquinuclidines from
N-alkyl 1,2-dihydropyridines and alkenes, see: (a) Taylor, S. J.; Taylor,
A. M.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 1681. (b) Reine,
I.; Muceniece, V. L.; Kemme, A. Heterocycl. Commun. 2002, 8, 173. (c)
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Gulini, U.; Cantalamessa, F.; Venturi, F. Eur. J. Med. Chem. 1987, 22, 1.
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Org. Lett., Vol. 15, No. 3, 2013
445

Scheme 2. Substrate Scope of DielsÀAlder Reactionsa
Table 1. Optimization of DielsÀAlder Reaction with
Crotonaldehydea
Lewis
acid
concn
(M)
temp
yieldb
(%)
entry
(°C)
1
2
3
4
5
6
À
0.1
0.5
À
50
50
105
0
trace
trace
trace
10c
À
À
AlEtCl2
AlCl3
ZnCl2
0.5
0.5
0.5
0
43
0
59
a All reactions were performed using 0.05 mmol of dihydropyridine
1a and 0.5 mmol of crotonaldehyde. b Yields were determined by NMR
relative to 1,3,5-trimethoxybenzene. c Reaction was performed in 1:1
CH2Cl2/hexanes.
Different substitution patterns at other sites within the
dihydropyridine ring were also acceptable. The tetracyclic
isoquinuclidine 3h was prepared as a single diastereomer
in high yield. Dihydropyridines substituted with the
branched isopropyl group were also effective coupling
partners (3i, j, and o). Even a dihydropyridine bearing
the electronically deactivating methyl ester group reacted
with N-phenyl maleimide to provide 3i in good yield and as a
single isomer. A 4-phenyl substituted dihydropyridine also
underwent a DielsÀAlder reaction to provide isoquinuclidine
3m as a single isomer. Additionally, as should be expected,
isoquinuclidines can be prepared in high yields and excellent
selectivities from 1,2-dihydropyridines with modestly lower
substitution levels (3nÀp).
The relative configuration of isoquinuclidine 3g was
established by X-ray crystallography of the corresponding
ammonium salt (Figure 1). By analogy, we assigned the
endo configuration to the other dihydropyridine products.
a Yields correspond to the yields of isolated products. The diastereos-
electivities were determined by 1H NMR analysis of unpurified material.
b
c
ZnCl2 (1.1 equiv), 0.5 M CH2Cl2, 0 °C, 6 h. N-Phenyl maleimide
(1.05 equiv), 0.1 M CH2Cl2, rt. d Neat, 105 °C. e 24 h. f 72 h. gN-Phenyl
maleimide (1.05 equiv), 0.5 M CH2Cl2, 50 °C. h 48 h.
incorporated within nitrogen heterocycles.6a,e,12,14 We
therefore examined their effect upon our substrate combi-
nation (entries 4À6). The aluminum-based Lewis acids
AlEtCl2 and AlCl3 led to modest yields of the isoquinucli-
dine 3d (entries 4 and 5). Employing ZnCl2 as a Lewis acid
additive at 0 °C provided better results, with 3d obtained as
Figure 1. Relative configuration and ball-and-stick representation
of 3g.
a single diastereomer in 59% yield (entry 6). BF3 OEt2 was
3
also investigated but did not yield the desired isoquinucli-
dine 3d.
In conclusion, the 1,2-dihydropyridines that result from
the rhodium-catalyzed CÀH alkenylation of R,β-unsaturated
imines and subsequent electrocyclization are versatile inter-
mediates for the preparation of highly functionalized
nitrogen heterocycles. The DielsÀAlder reaction with a
variety of dienophiles provides access to isoquinuclidines
As illustrated in Scheme 2, a range of differently sub-
stituted 1,2-dihydropyridines underwent DielsÀAlder re-
actions in high yields. A variety of nitrogen substituents
were well-tolerated, including N-benzyl (3aÀd, hÀp),
branched N-alkyl (3e), and N-phenyl (3fÀg) groups.
446
Org. Lett., Vol. 15, No. 3, 2013

with unprecedented substitution levels in high yields and
with excellent regio- and stereoselectivities.
collecting the high resolution mass spectrometry (HRMS)
data and to Dr. Michael Takase at the Chemical and
Biophysical Instrumentation Center at Yale University
for solving the structure of 3g.
Acknowledgment. This work was supported by the
NIH Grant GM069559 (to J.A.E.). R.G.B. acknowledges
funding from The Director, Office of Energy Research,
Office of Basic Energy Sciences, Chemical Sciences Divi-
sion, DOE, under Contract DE-AC02-05CH11231. R.M.
M. is grateful for a NSF Predoctoral Fellowship and
a UC, Berkeley Chancellor’s Fellowship. The authors
are grateful to the Keck Center of Yale University for
Supporting Information Available. Full experimental
procedures, characterization data, and NMR spectra for
all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 3, 2013
447