2-Azaallyl Dication EquiValents
TABLE 7. Tetrahydroazepines via Ring-Closing Metathesis
SCHEME 5
entry
diene
X
R1
R2
R3
product
% yielda
1
2
3
4
5
6
7
17b
17c
17e
17g
17ib
17jc
17l
CO2Ph
CO2Bn
CO2Bn
CHO
CHO
CO2Me
CO2Me
H
H
H
H
Me
Me
Me
i-Pr
i-Pr
Me
-(CH2)5-
i-Pr
Me
H
H
Me
32a
32b
32c
32d
32e
32f
98
87
65
95
75b
96c
89
H
H
SCHEME 6
-(CH2)5-
32g
a All yields are of purified material. b Ratio of (R*,R*):(R*,S*) diaster-
eomers ) 2.5:1. The relative configurations were assigned after reduction
of 32e with LiAlH4 and analysis of the N-methyl derivatives by 1H NMR/
NOE spectroscopy. c Ratio of diastereomers ) 1.3:1. The relative configura-
tions were not assigned.
nucleophilic addition of allylmagnesium bromide to imine 24
to generate N-magnesio aminonitrile 25. Quenching with water
at this point yields the aminonitrile 26, while cyanide elimination
provides the intermediate imine 27, which can undergo a second
nucleophilic attack by allylmagnesium bromide to provide the
N-magnesio intermediate 28 and the bisallylated product 29 upon
aqueous quench.
As mentioned above, the amine 23, which is derived by
protonation of 25, had been isolated. In an effort to further
elucidate the mechanism, we hoped to establish whether the
imines 27 could form the double addition products 29. The
proposed intermediate 31 was prepared from phthalimide 30
and subjected to the standard reaction conditions (Scheme 6).
The reaction proceeded to give 17m with nearly the same yield
and diastereoselectivity observed in the double allylation of the
corresponding (2-azaallyl)nitrile, making it reasonable to propose
the formation of 27 by elimination of cyanide from 25 during
the double allylation reaction.
Since the more hindered amines were resistant to acylation,
we needed to find conditions to perform the ring-closing
metathesis (RCM) without first acylating the amine. Olefin
metathesis, however, is known to be incompatible with free
amines due to catalyst inhibition by the basic nitrogen, although
the ammonium salts have been shown to undergo metathesis.22
Furthermore, there have been reports of ring-closing metathesis
of secondary and tertiary free amines protonated in situ to form
six-membered heterocycles,23a-c as well as a report of RCM of
a tertiary free amine to form a seven-membered ring under acidic
(19) Recent reviews: (a) Schuster, M.; Blechert, S. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2037. (b) Grubbs, R. H.; Chang, S. Tetrahedron 1998,
54, 4413. (c) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371.
(d) Alkene Metathesis in Organic Synthesis; Fu¨rstner, A., Ed.; Springer-
Verlag: Heidelberg, Germany, 1998. (e) Schrock, R. R. Tetrahedron 1999,
55, 8141. (f) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012. (g) Roy,
R.; Das, S. K. Chem. Commun. 2000, 519. (h) Deiters, A.; Martin, S. F.
Chem. ReV. 2004, 104, 2199.
(20) Recent reviews focusing on ring-closing metathesis of nitrogen-
containing compounds: (a) Phillips, A. J.; Abell, A. D. Aldrichim. Acta
1999, 32, 75. (b) Felpin, F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693.
(21) Dixneuf and co-workers have reported related methodology, where
N-Cbz imines were combined with allylmagnesium bromide or 3-butenyl-
magnesium bromide followed by N-allylation to afford 4-aza-1,7-octadienes
or 4-aza-1,8-nonadienes, respectively, which were subjected to RCM to
afford 1,2,5,6-tetrahydropiperidines or 2,5,6,7-tetrahydroazepines, isomers
of the tetrahydroazepines reported herein. See: (a) Osipov, S. N.; Artyushin,
O. I.; Kolomiets, A. F.; Bruneau, C.; Dixneuf, P. H. Synlett 2000, 1031.
For other imine allylation/RCM work, see: (b) Kumareswaran, R.;
Balasubramanian, T.; Hassner, A. Tetrahedron Lett. 2000, 41, 8157. (c)
Felpin, F.-X.; Lebreton, J. Tetrahedron Lett. 2003, 44, 527. For iminium
ion allylation/RCM to produce tetrahydropiperidines and 2,3,6,7-tetrahy-
droazepines, see: (d) Barrett, A. G. M.; Ahmed, M.; Baker, S. P.; Baugh,
S. P. D.; Braddock, D. C.; Procopiou, P. A.; White, A. J. P.; Williams, D.
J. J. Org. Chem. 2000, 65, 3716. (e) Chevallier, F.; Beaudet, I.; Le Grognec,
E.; Toupet, L.; Quintard, J.-P. Tetrahedron Lett. 2004, 45, 761. For RCMs
of N,N-bis(3-butenyl)amine derivatives to 2,3,6,7-tetrahydroazepines, see
the following: (f) Paquette, L. A.; Leit, S. M. J. Am. Chem. Soc. 1999,
121, 8126. (g) Pernerstorfer, J.; Schuster, M.; Blechert, S. Synthesis 1999,
138. (h) Schu¨rer, S. C.; Gessler, S.; Buschman, N.; Blechert, S. Angew.
Chem., Int. Ed. 2000, 39, 3898. For another RCM approach to tetrahy-
droazepines, see: (i) Vo-Thanh, G.; Boucard, V.; Sauriat-Dorizon, H.;
Guibe´, F. Synlett, 2001, 37.
Grignard reagents can react by either a polar mechanism or
a single electron-transfer mechanism.18 To evaluate the pos-
sibility that radical intermediates were involved in the double
allylation reaction, we prepared the cyclopropylimine 22e and
subjected it to the standard reaction conditions (entry 5, Table
5). If radical intermediates were formed, we expected to observe
rapid ring opening of the cyclopropane ring. Instead, the amine
17n resulting from simple double allylation was isolated with
the cyclopropyl ring intact and no ring-opened product could
be detected. This result suggests that the mechanism of the
reaction involves nucleophilic attack to generate anionic, not
radical, intermediates.
The double allylation products obtained from the reactions
of both (2-azaallyl)nitriles and (2-azaallyl)stannanes were found
to be well suited substrates for ring-closing metathesis reac-
tions.19 Recently, there has been tremendous interest in the use
of ring-closing metathesis for the construction of nitrogen
heterocycles.20,21 In our initial communication,5 we reported the
results summarized in Table 7, in which the dienes 17 were
converted in an efficient manner to 2,3,6,7-tetrahydroazepines
32.
(22) Fu, G. C.; Nguyen, S. B. T.; Grubbs, R. B. J. Am. Chem. Soc. 1993,
115, 9856.
(23) (a) Wright, D.; Schulte, J.; Page, M. Org. Lett. 2000, 2, 1847. (b)
Edwards, A. S.; Wybrow, R. A. J.; Johnstone, C.; Adams, H.; Harrity, J. P.
A. Chem. Commun. 2002, 1542. (c) Verhelst, S. H. L.; Martinez, B. P.;
Timmer, M. S. M.; Lodder, G.; van der Marel, G. A.; Overkleeft, H. S.;
van Boom, J. H. J. Org. Chem. 2003, 68, 9598. (d) Wipf, P.; Rector, S. R.;
Takahashi, H. J. Am. Chem. Soc. 2002, 124, 14848.
(18) (a) Handbook of Grignard Reagents; Silverman, G. S., Rakita, P.
E., Eds.; Marcel Dekker: New York, 1996. (b) Hoffmann, R. W. Chem.
Soc. ReV. 2003, 32, 225 and references therein.
J. Org. Chem, Vol. 71, No. 9, 2006 3537