Double allylation reactions of (2-azaallyl)stannanes: synthesis of N,N-bis(3-butenyl)amines and their conversion to 2,3,6,7-tetrahydroazepines via ring-closing metathesis.

Article abstract of DOI:10.1021/ol015711w

[reaction in text] Treatment of (2-azaallyl)stannanes (i) with 2.2 equiv of allylmagnesium bromide afforded good yields of N,N-bis(3-butenyl)amines derivatives (ii), which were subjected to ring-closing metathesis to afford 2,3,6,7-tetrahydroazepines (iii

Full text of DOI:10.1021/ol015711w

ORGANIC
LETTERS
2001
Vol. 3, No. 9
1327-1330
Double Allylation Reactions of
(2-Azaallyl)stannanes: Synthesis of
N,N-Bis(3-butenyl)amines and Their
Conversion to
2,3,6,7-Tetrahydroazepines via
Ring-Closing Metathesis
William H. Pearson* and Aaron Aponick†
Department of Chemistry, The UniVersity of Michigan,
Ann Arbor, Michigan 48109-1055
wpearson@umich.edu
Received February 14, 2001
ABSTRACT
Treatment of (2-azaallyl)stannanes (i) with 2.2 equiv of allylmagnesium bromide afforded good yields of N,N-bis(3-butenyl)amines derivatives
(ii), which were subjected to ring-closing metathesis to afford 2,3,6,7-tetrahydroazepines (iii). Thus, (2-azaallyl)stannanes are the synthetic
equivalents of amine r,r′-dications.
We have shown that (2-azaallyl)stannanes 1 are precursors
of nonstabilized 2-azaallyllithiums 2 and azomethine ylides
3 (Scheme 1), both of which undergo [3 + 2] cycloadditions
examined the reactions of these compounds with nucleophiles
(1 f 4, Scheme 1). The fate of the intermediate anion 4
was of particular interest.
One impetus for the current study was the unexpected
result summarized in Scheme 2.2 Transmetalation of stannane
5 to 2-azaallyllithium 6 using a single equivalent of n-
butyllithium was attempted for the purpose of a [3 + 2]
cycloaddition with 1-hexene. Rather than the expected
pyrrolidine 7, we obtained the acyclic material 8 in 40%
yield.2 Since nonactivated alkenes are reluctant partners in
2-azaallyl anion cycloadditions, we used 1-hexene as the
solvent. However, it is known that tin-lithium exchange is
slower in noncoordinating solvents;3 thus we propose that
Scheme 1. Reactions of (2-Azaallyl)stannanes
(1) See the following recent papers and the earlier work cited therein:
(a) Pearson, W. H.; Lovering, F. E. J. Org. Chem. 1998, 63, 3607-3617.
(b) Pearson, W. H.; Ren, Y. J. Org. Chem. 1999, 64, 688-689.
(2) Pearson, W. H.; Szura, D. P.; Postich, M. J. J. Am. Chem. Soc. 1992,
114, 1329-1345.
(3) Sawyer, J. S.; Kucerovy, A.; Macdonald, T. L.; McGarvey, G. J. J.
Am. Chem. Soc. 1988, 110, 842-853.
with alkenes to produce pyrrolidines.1 As part of a program
to explore additional uses of (2-azaallyl)stannanes, we have
† Kodak Fellow.
10.1021/ol015711w CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/03/2001

results similar to those shown in Scheme 2, resulting instead
in the formation of tetrabutyltin and decomposition products.
To avoid tin-lithium exchange, we examined other orga-
nometallic reagents as nucleophiles.4 However, n-hexyl-
magnesium bromide, allylzinc bromide, and allyltributyl-
stannane (with or without a Lewis acid)5 were found to react
sluggishly with the (2-azaallyl)stannane.6 Since allylic or-
ganomagnesium reagents are of sufficient reactivity to add
efficiently to imines,4,7 we then examined the reactions of
(2-azaallyl)stannanes with allylmagnesium bromide (vide
infra).
Scheme 2. An Initial Result
First, a variety of (2-azaallyl)stannanes 16 were prepared
as shown in Table 1, where hydrazinolysis of the phthalim-
Table 1. Preparation of (2-Azaallyl)stannanes 16a-f
addition of the n-butyllithium to the imine is competitive
with transmetalation, generating adduct 9 (cf. 4 in Scheme
1). Elimination of tributylstannyllithium from 9 generates
the intermediate imine 10, a substrate for further addition of
n-butyllithium, resulting in the double alkylated intermediate
11 and ultimately the final product 8. Tri-n-butyltin hydride
was observed as a byproduct in the reaction, consistent with
the loss of tributylstannyllithium as shown.
a Yield of pure, Kugelrohr-distilled material.
The result shown in Scheme 2 led us to examine the scope
of (2-azaallyl)stannanes 1 as synthetic equivalents of amine
R,R′-dications 12, which could also be named 2-azaallyl
dications from the alternative resonance form 13 (Figure 1).
ides 148 and 159 was followed by condensation of the
resultant R-aminostannanes with aldehydes and ketones,
respectively.8,10 Kugelrohr distillation provided pure samples
of the stannanes 16a-f.11
Combination of the (2-azaallyl)stannanes 16a-f with 2.2
equiv of allylmagnesium bromide in THF produced the
diallylated materials 17a-l following quenching with various
electrophiles (Table 2).12 The free amines 17a, 17d, 17f, and
17h (entries 1, 4, 6, and 8) were best purified by acid/base
extraction, producing material of sufficient purity to obviate
further purification, which otherwise leads to loss of material
due to volatility. The amine 17k could be purified by
chromatography in 91% yield (entry 11). Direct quenching
of the N-magnesio intermediates with chloroformates was
Figure 1. (2-Azaallyl)stannanes 1 are synthetic equivalents of the
dication 12/13.
The addition of nucleophiles to imines is an important route
to amines and has been investigated in depth.4 The reactions
of stannanes 1 with nucleophiles may provide a new variation
of this venerable chemistry. Initial studies on the combination
of a simple (2-azaallyl)stannane (i.e., 1, R1 ) R2 ) H, R3 )
iPr) with n-butyllithium in hexane or toluene failed to produce
(5) Keck, G. E.; Enholm, E. J. J. Org. Chem. 1985, 50, 146-147.
(6) Wright and co-workers have reported related methodology, where
N-allyl imines were combined with allylmagnesium bromide to afford 4-aza-
1,7-octadienes, which were subjected to ring-closing metathesis to afford
1,2,5,6-tetrahydropyridines. Difficulty adding other organometallics was
encountered. See: Wright, D. L.; Schulte, J. P.; Page, M. A. Org. Lett.
2000, 2, 1847-1850.
(7) Roush, W. R. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, p 1.
(8) Pearson, W. H.; Postich, M. J. J. Org. Chem. 1992, 57, 6354-6357.
(9) Pearson, W. H.; Clark, R. B. Tetrahedron Lett. 1999, 40, 4467-
4471.
(10) Chong, J. M.; Park, S. B. J. Org. Chem. 1992, 57, 2220-2222.
(11) All are new compounds with the exception of imine 16a, which
was prepared previously in lower yield by a more difficult method,2 and
16d, which had been made9 but not isolated prior to the current work.
(4) Selected reviews: (a) Volkmann, R. A. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 1, pp 355-396. (b) Kleinman, E. F.; Volkmann, R. A. In Compre-
hensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 2, pp 975-1006. (c) Enders, D.; Reinhold: U.
Tetrahedron: Asymmetry 1997, 8, 1895-1946. (d) Bloch, R. Chem. ReV.
1998, 98, 8, 1407-1438. (e) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999,
99, 1069-1094.
1328
Org. Lett., Vol. 3, No. 9, 2001

Table 2. Double Allylation of (2-Azaallyl)stannanes 16a-f
Table 3. Tetrahydroazepines via Ring-Closing Metathesis
a Yield of chromatographically purified material unless otherwise noted.
b Acid-base extraction gave pure material that was not purified further.
c Quenched first with water. d Ratio of (R*,R*):(R*,S*) diastereomers )
2.5:1. The relative configuration was assigned after ring-closing metathesis
and reduction (see Table 3). e Ratio of diastereomers ) 1.3:1. The relative
configurations were not assigned.
possible in unhindered systems, leading to the carbamates
17b, 17c, 17e, and 17j (entries 2, 3, 5, and 10). Quenching
with water followed by a separate acylation reaction was
found to produce 17l (entry 12) in higher yield than the direct
acylation method, although the yield of 17l was still only
moderate. Comparison of entry 12 with entry 11 shows that
the allylation reaction was highly efficient in both cases, but
the acylation step in entry 12 is the difficult one, presumably
due to steric hindrance. N-Formylation was also best ac-
complished by quenching with water first (entries 7 and 9).1b
Entries 8-10 involve allylations that produce mixtures of
diastereomers in modest (2.5:1 in entries 8 and 9) to low
stereoselectivity (entry 10).
a All yields are of purified material. b The relative configurations were
assigned after reduction of 18e with LiAlH4 and analysis of the N-methyl
Recently, there has been much interest in the use of ring-
closing methathesis13 for the construction of nitrogen het-
erocycles.6,14,15 The dienes 17 were found to be well-suited
for such cyclizations, producing 2,3,6,7-tetrahydroazepines
18 in an efficient manner (Table 3). The assembly of the
1
derivatives by H NMR/NOE spectroscopy.
relatively crowded tetrahydroazepine 18g is successful. The
relative configurations of the two diastereomers of 18e were
(12) Representative Procedure: Preparation of Diene 17b. Allyl-
magnesium bromide (2.2 mL of a 1.0 M solution in ether, 2.2 mmol) was
added in a dropwise fashion to a solution of the imine 16a (0.374 g, 1.00
mmol) in THF (5 mL) at -78 °C. After 30 min, phenyl chloroformate (0.344
g, 2.20 mmol) was added and the mixture was allowed to warm slowly to
room temperature, then diluted with water and ether. The organic layer
was separated, and the aqueous layer was extracted 3× with ether. The
combined organic phases were dried (MgSO4) and concentrated. Flash
chromatography (0-3% ethyl acetate/hexanes gradient) gave 0.230 g (80%)
of diene 17b as a clear colorless oil. 1H NMR (CDCl3, 400 MHz, room
temperature, rotomers present) δ 7.44-7.07 [m, 5 H containing 7.36 (app t,
J ) 6.6 Hz), 7.18 (app t, J ) 7.2 Hz), 7.09 (app t, J ) 7.2 Hz)], 5.89-5.73
(m, 2 H), 5.16-5.01 (m, 4 H), 3.69 (app br s, 1 H), 3.27-3.17 (m, 2 H),
2.53-2.33 (m, 4 H), 1.90 (app br s, 1 H), 1.02 (app t, J ) 6.4 Hz), 1.00
(app d, J ) 3.2 Hz), 0.98 (app d, J ) 3.2 Hz), 1.04-0.98 (total 6 H). 13C
NMR (CDCl3, 100 MHz) δ 155.22, 151.59, 151.47, 135.94, 135.57, 135.41,
129.56, 129.20, 125.11, 125.02, 121.75, 121.70, 117.15, 116.78, 116.55,
116.41, 64.48 (br), 45.02 (br), 35.31, 34.95, 34.34, 32.98, 31.49, 31.00,
20.49, 20.41, 20.34.
(13) Recent reviews: (a) Schuster, M.; Blechert, S. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2037-2056. (b) Grubbs, R. H.; Chang, S. Tetrahedron
1998, 54, 4413-4450. (c) Armstrong, S. K. J. Chem. Soc., Perkin
Trans. 1 1998, 371-388. (d) Alkene Metathesis in Organic Synthesis;
Fu¨rstner, A., Ed.; Springer-Verlag: Heidelberg, 1998. (e) Schrock, R. R.
Tetrahedron 1999, 55, 8141-8153. (f) Fu¨rstner, A. Angew. Chem., Int.
Ed. 2000, 39, 3012-3043. (g) Roy, R.; Das, S. K. Chem. Commun. 2000,
519-529.
(14) For a review focusing on ring-closing metathesis of nitrogen-
containing compounds, see: (a) Phillips, A. J.; Abell, A. D. Aldrichimica
Acta 1999, 32, 75-89. For recent references in this general area, see: (b)
Taniguchi, T.; Ogasawara, K. Org. Lett. 2000, 2, 3193-3195. (c) Varray,
S.; Gauzy, C.; Lamaty, F.; Lazaro, R.; Martinez, J. J. Org. Chem. 2000,
65, 6787-6790. (d) Cossy, J.; Willis, C.; Bellosta, V.; Bouzbouz, S. Synlett
2000, 1461-1463. (e) Felpin, F.-X.; Vo-Thanh, G.; Robins, R. J.; Villie´ras,
J.; Lebreton, J. Synlett 2000, 1646-1648. (f) Groaning, M. D.; Meyers, A.
I. Chem. Commun. 2000, 1027-1028.
Org. Lett., Vol. 3, No. 9, 2001
1329

assigned by NOE/NMR spectroscopy and thus allowed
assignment of the precursor diene 17i.
The double allylation of (2-azaallyl)stannanes illustrates
a new use of these imines and provides a useful route to
N,N-bis(3-butenyl)amines (or 5-aza-1,8-nonadienes), which
in turn are precursors of 2,3,6,7-tetrahydroazepines via ring-
closing metathesis. We are currently examining the addition
of other organometallics to these stannanes and are especially
interested in adding two different organometallics in a
sequential fashion.
(15) Osipov 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-
1033. For other imine allylation/RCM work, see: (b) Kumareswaran, R.;
Balasubramanian, T.; Hassner, A. Tetrahedron Lett. 2000, 41, 8157-8162.
For iminium ion allylation/RCM to produce tetrahydropiperidines and
2,3,6,7-tetrahydroazepines, see: (c) 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, 3716-3721. For RCMs of N,N-
bis(3-butenyl)amine derivatives to 2,3,6,7-tetrahydroazepines, see the fol-
lowing: (d) Paquette, L. A.; Leit, S. M. J. Am. Chem. Soc. 1999, 121,
8126-8127. (e) Pernerstorfer, J.; Schuster, M.; Blechert, S. Synthesis 1999,
138-144. (f) Schu¨rer, S. C.; Gessler, S.; Buschmann, N.; Blechert, S.
Angew. Chem., Int. Ed. 2000, 39, 3898-3901. For another RCM approach
to tetrahydroazepines, see: (g) Vo-Thanh, G.; Boucard, V.; Sauriat-Dorizon,
H.; Guibe´, F. Synlett 2001, 37-40.
Acknowledgment. We thank the National Institutes of
Health (GM-52491), the Petroleum Research Fund, admin-
istered by the American Chemical Society, and the Eastman
Kodak Company for financial support of this research.
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