Regioselective Rh-catalyzed Allylic Amination/Ring-closing Metathesis Approach to Monocyclic Azacycles: Diastereospecific Construction of 2,5-disubstituted Pyrrolines

Article abstract of DOI:10.1021/ol991064l

(Matrix presented) Regioselective rhodium-catalyzed allylic amination followed by ring-closing metathesis, using the Grubbs' catalyst, provides an expeditious route to monosubstituted azacycles. The enantiomerically enriched allylamine 1 can also be resub

Full text of DOI:10.1021/ol991064l

ORGANIC
LETTERS
1999
Vol. 1, No. 12
1929-1931
Regioselective Rh-Catalyzed Allylic
Amination/Ring-Closing Metathesis
Approach to Monocyclic Azacycles:
Diastereospecific Construction of
2,5-Disubstituted Pyrrolines
P. Andrew Evans* and John. E. Robinson
Brown Laboratory, Department of Chemistry and Biochemistry,
UniVersity of Delaware, Newark, Delaware 19716
paeVans@udel.edu
Received September 17, 1999
ABSTRACT
Regioselective rhodium-catalyzed allylic amination followed by ring-closing metathesis, using the Grubbs’ catalyst, provides an expeditious
route to monosubstituted azacycles. The enantiomerically enriched allylamine 1 can also be resubjected to the reaction sequence with (R)-
and (S)-2b to facilitate the diastereospecific construction of 2,5-disubstituted pyrrolines 3/4.
The stereoselective construction of nitrogen heterocycles
remains a topic of intense synthetic interest.1,2 This may be
attributed to their ubiquity in biologically interesting natural
and unnatural products, in addition to the challenges associ-
ated with the design of stereochemical and architecturally
flexible approaches to these molecules. Hence, although a
number of interesting and synthetically useful methods have
been developed, they are often specific to a particular ring
size and/or stereochemical motif which imparts limitations
to their utility as general methods.1 In a program directed
toward controlling the regioselectivity in metal-catalyzed
allylic substitution reactions,3 we demonstrated that Wilkin-
son’s catalyst [Rh(PPh3)3Cl)] can be modified in situ with
trimethyl phosphite to furnish a catalyst that facilitates the
regioselective and enantioselective allylic amination of
unsymmetrical acyclic allylic carbonates, to afford the
secondary substituted products in excellent yield and with
almost complete retention of absolute configuration.4,5
Herein, we describe the combination of the regioselective
allylic amination with ring-closing metathesis as a strategy
for the construction of mono- and disubstituted azacycles,
Vide infra.6,7 This strategy requires that the allylic amination
be tolerant of homologated alkenyl substituents in order to
(1) For a recent review of methods for constructing saturated nitrogen
heterocycles, see: Nadin, A. J. Chem. Soc., Perkin Trans. 1 1998, 3493.
(2) For recent examples of general azacycle construction, see: (a)
Barluenga, J.; Toma´s, M.; Ballesteros, A.; Santamar´ıa, J.; Sua´rez-Sobrino,
A. J. Org. Chem. 1997, 62, 9229. (b) Arredondo, V. M.; McDonald, F. E.;
Marks, T. J. J. Am. Chem. Soc. 1998, 120, 4871. (c) Meguro, M.;
Yamamoto, Y. Tetrahedron Lett. 1998, 39, 5421. (d) Larock, R. C.; Ty,
C.; Pace, P. J. Org. Chem. 1998, 63, 6859. (e) Serino, C.; Stehle, N.; Park,
Y. S.; Florio, S,; Beak, P. J. Org. Chem. 1999, 64, 1160. (f) Naito, T.;
Nakagawa, K.; Nakamura, T.; Kasei, A.; Ninomiya, I.; Kiguchi, T. J. Org.
Chem. 1999, 64, 2003 and pertinent references therein.
(3) (a) Evans, P. A.; Nelson, J. D. Tetrahedron Lett. 1998, 39, 1725. (b)
Evans, P. A.; Nelson, J. D. J. Am. Chem. Soc. 1998, 120, 5581.
(4) Evans, P. A.; Robinson, J. E.; Nelson, J. D. J. Am. Chem. Soc. 1999,
121, 6761.
(5) For a recent review on allylic amination, see: Johannsen, M.;
Jørgensen, K. A. Chem. ReV. 1998, 98, 1689 and pertinent references therein.
10.1021/ol991064l CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/16/1999

system to determine whether the enantiospecific rhodium-
catalyzed allylic amination with a chiral non-racemic nu-
cleophile occurs through matched and mismatched transition
states.3b
This strategy required an alternative protecting group, to
facilitate the formation of the N-p-toluenesulfonyl allylamine
1. Scheme 2 summarizes how this was accomplished.
Table 1. Regioselective Allylic Amination/Ring-Closing
Metathesis Approach to Monocyclic Azacycles
allylic
yield
(%)b
yield of 7
(%)b,d
Nua
n ) 1
ratio of 5:6c
entry carbonate 2
1
2
3
4
5
6
7
8
9
Me
a
b
c
a
b
c
a
b
c
89
91
84
85
87
94
87
92
86
a
g99:1
32:1
g99:1
23:1
44:1
35:1
91
86
84
84
89
84
94
93
89
Ph
b
c
d
e
f
BnOCH2
Me
n ) 2
n ) 3
Ph
Scheme 2. Preparation of the Allylamine 1
BnOCH2
Me
g
h
i
g99:1
89:1
84:1
Ph
BnOCH2
a All rhodium-catalyzed allylic amination reactions were carried out on
a 1 mmol reaction scale using 2 equiv of the nucleophile. b Isolated yields.
c Ratios of regioisomers were determined by crude HPLC. d All ring-closing
metathesis reactions were carried out on a 0.5 mmol reaction scale using 5
mol % of Grubbs’ catalyst.
provide the versatility required for a general approach to this
problem.
Table 1 summarizes the results for the rhodium-catalyzed
allylic amination using the lithium anion of the N-p-
toluenesulfonyl alkenylamines as nucleophiles with a variety
of racemic allylic carbonates 2a-c (Scheme 1). The allylic
Treatment of the enantiomerically enriched allylic carbonate
ent-2c (g99% ee)4 with trimethyl phosphite modified
Wilkinson’s catalyst and the lithium anion of N-p-toluene-
sulfonyl p-methoxybenzylamine furnished the allylamines
8a/b in 86% yield as a 70:1 mixture of regioisomers favoring
8a. Treatment of 8a with trifluoroacetic acid at room
temperature furnished the allylamine 1 (g99% ee by HPLC)
in 89% yield.
Scheme 1. General Strategy for Monosubstituted Azacycles
The allylamine 1 was then resubjected to the allylic
amination reaction as outlined in Scheme 3. Diastereospecific
rhodium-catalyzed allylic amination with the enantiomeri-
cally enriched allylic carbonates (R)- and (S)-2b using the
lithium anion of 1 furnished the dienes 9/10 and 11/10 in
87% and 85% yield, as 31:1 and 42:1 mixtures of regioiso-
mers, favoring 9 and 11, respectively. Interestingly, the
matched alkylation with (R)-2b proceeded with excellent
diastereospecificity (ds g 99:1), while the analogous alky-
(7) For recent approaches to nitrogen heterocycles using ring-closing
metathesis, see: (a) Fu, G. C,; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114,
7324. (b) Overleeft, H. S.; Bruggeman, P.; Pandit, U. K. Tetrahedron Lett.
1998, 39, 3869. (c) White, J. D.; Hrnciar, P.; Yokochi, A. F. T. J. Am.
Chem. Soc. 1998, 120, 7359. (d) Veerman, J. J. N.; Maarseveen, J. H.;
Visser, G. M.; Kruse, C. G.; Schoemaker, H. E.; Hiemstra, H.; Rutjes, F.
P. J. T. Eur. J. Org. Chem. 1998, 3. (e) Kozmin, S. A.; Rawal, V. H. J.
Am. Chem. Soc. 1998, 120, 13523. (f) Pernerstorfer, J.; Schuster, M.;
Blechert, S. Synthesis 1999, 138. (g) Tanner, D.; Hagberg, L.; Poulsen, A.
Tetrahedron 1999, 55, 1427. (h) Kingsbury, J. S.; Harrity, J. P. A.;
Bonitatebus, P. J. Jr.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791.
(i) Martin, S. F.; Humphrey, J. M.; Ali, A.; Hillier, M. C. J. Am. Chem.
Soc. 1999, 121, 866. (j) Tarling, C. A.; Holmes, A. B.; Markwell, R. E.;
Pearson, N. D. J. Chem. Soc., Perkin Trans. 1 1999, 1695. (k) Piscopio, A.
D.; Miller, J. F.; Koch, K. Tetrahedron 1999, 55, 8189. (l) Jo, E.; Na, Y.;
Chang, S. Tetrahedron Lett. 1999, 40, 5581. (m) Paquette, L. A.; Leit, S.
M. J. Am. Chem. Soc. 1999, 121, 8126 and pertinent references cited therein.
(8) For recent examples of 2,5-disubstituted pyrrolidine construction,
see: (a) Dhimane, H.; Vanucci-Bacque´, C.; Hamon, L.; Lhommet, G. Eur.
J. Org. Chem. 1998, 1955. (b) Kawanami, Y.; Iizuna, N.; Okano, K. Chem.
Lett. 1998, 1231. (c) Senboku, H.; Hasegawa, H.; Orito, K. Tokuda, M.
Heterocycles 1999, 50, 333. (d) Grigg, R.; Thornton-Pett, M.; Yoganathan,
G. Tetrahedron 1999, 55, 1763. (e) Katritzky, A. R.; Cui, X.-L. Yang, B.
Steel, P. J. J. Org. Chem. 1999, 64, 1979 and pertinent references therein.
amination reaction furnished products 5/6a-i in 84-94%
yield with excellent regioselectivity (g23:1) in favor of 5.
The dienes 5a-i were then subjected to ring-closing me-
tathesis, using Grubbs’ catalyst, to furnish monosubstituted
nitrogen-containing heterocycles 7a-i in 84-94% yield.
The application of this strategy to the diastereospecific
construction of 2,5-disubstituted pyrrolines was anticipated
to provide a stereochemically versatile route to this type of
heterocycle.8 Furthermore, this approach provided the ideal
(6) For recent reviews on ring-closing metathesis, see: (a) Randall, M.
L.; Snapper, M. L. J. Mol. Catal. A: Chem. 1998, 133, 29. (b) Armstrong,
S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371. (c) Grubbs, R. H.
Tetrahedron 1998, 54, 4413. (d) Pandit, U. K.; Overleeft, H. S.; Borer, B.
C.; Bieraugel, H. Eur. J. Org. Chem. 1999, 9.
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Org. Lett., Vol. 1, No. 12, 1999

Scheme 3. Diastereospecific Construction of cis- and trans-2,5-Disubstituted Pyrrolines
lation with the mismatched carbonate (S)-2b proceeded with
support. We also thank Zeneca Pharmaceuticals for an
Excellence in Research Award, Eli Lilly for a Young Faculty
Grantee Award, and Glaxo Wellcome for a Chemistry
Scholar Award. The Camille and Henry Dreyfus Foundation
is thanked for a Camille Dreyfus Teacher-Scholar Award
(P.A.E.). Brian M. Wagner and Thomas H. Bailey are
acknowledged for obtaining high-resolution mass spectral
data.
the expected lower, but synthetically useful diastereospeci-
ficity (ds ) 22:1). Treatment of the dienes 9 and 11 with
Grubbs’ catalyst in refluxing benzene furnished the cis- and
trans-2,5-disubstituted pyrrolines 3 and 4 in 86% and 87%
yield, respectively.
In conclusion, we have demonstrated that the rhodium-
catalyzed allylic amination may be combined with ring-
closing metathesis to provide a general approach to mono-
substituted azacycles. Furthermore, the allylic amination
product may be deprotected and resubjected to the reaction
sequence to facilitate the diastereospecific construction of
cis- and trans-2,5-disubstituted pyrrolines.
Supporting Information Available: Experimental pro-
cedures for the preparation of 3 and spectroscopic data for
all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. We sincerely thank the National
Institutes of Health (GM58877) for generous financial
OL991064L
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