Novel Kumada coupling reaction to access cyclic (2-azaallyl)stannanes. Cycloadditions of cyclic nonstabilized 2-azaallyllithium species derived from cyclic (2-azaallyl)stannanes

Article abstract of DOI:10.1021/jo049429p

A Kumada cross-coupling reaction involving organomagnesium reagents and (3-methylthio-2-azaallyl)stannanes with a Ni(O) catalyst provided cyclic nonstabilized (2-azaallyl)stannanes in moderate to good yields. Primary alkyl, aryl, and allylic organomagnesi

Full text of DOI:10.1021/jo049429p

Novel Ku m a d a Cou p lin g Rea ction to Access Cyclic
(
2-Aza a llyl)sta n n a n es. Cycloa d d ition s of Cyclic Non sta bilized
2
-Aza a llyllith iu m Sp ecies Der ived fr om Cyclic
2-Aza a llyl)sta n n a n es
(
Douglas M. Mans and William H. Pearson*,†
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055
wpearson@berryassoc.com
Received April 6, 2004
A Kumada cross-coupling reaction involving organomagnesium reagents and (3-methylthio-2-
azaallyl)stannanes with a Ni(0) catalyst provided cyclic nonstabilized (2-azaallyl)stannanes in
moderate to good yields. Primary alkyl, aryl, and allylic organomagnesium reagents can be used
2
as the cross-coupling partner. In general, NiCl dppp in toluene at room temperature provided the
shortest reaction times and most consistent yields. The azomethine ylides and 2-azaallyllithium
species derived from these stannanes were shown to undergo efficient [3 + 2] cycloaddition reactions
to provide azabicyclo[n.2.1]alkanes as the endo cycloadducts. These cycloadducts were found to be
useful as starting materials for further elaboration into aza-bridged bicyclic natural and unnatural
products of biological interest. Although cyclic 2-azaallyllithium species have been generated
previously, this work reports the first generation and cycloaddition of entirely nonstabilized
2
-azaallyllithium species. In addition a novel extension of the Kumada coupling was developed to
allow for the preparation of the cyclic (2-azaallyl)stannanes, which are precursors to the
nonstabilized 2-azaallyllithium species.
In tr od u ction
the synthesis of the heteroatom-substituted cyclic (2-
azaallyl)stannanes 2a and 2b and their use as cycload-
The generation of highly substituted pyrrolidines via
cycloaddition reactions with acyclic nonstabilized 2-azaal-
lyllithium species, produced from the corresponding (2-
azaallyl)stannanes, has proven to be useful. The (2-
azaallyl)stannanes are readily prepared by the conden-
1b,5
dition precursors (Scheme 1).
Whereas the cyclic (3-
methoxy-2-azaallyl)stannane 2a and the (3-methylthio-
-azaallyl)stannane 2b could be made, all attempts to
2
1
synthesize an amidine version met with failure. In
addition, only the (3-methoxy-2-azaallyl)stannane 2a was
found to undergo cycloaddition reactions with alkenes.
The (3-methylthio-2-azaallyl)stannane 2b instead gave
only decomposition under the cycloaddition reaction
sation of the desired aldehydes or ketones with R-ami-
2
nostannanes. Work done in our laboratories has shown
that (2-azaallyl)stannanes are excellent latent 2-azaal-
lyllithium sources upon a tin-lithium exchange. These
reactive 2-azaallyllithium species have been used in
numerous total syntheses of pyrrolidine-containing natu-
ral products.1
1b
conditions. Another unforeseen obstacle was the fact
that the cycloadduct 3 arising from a 3-methoxy-2-
azaallyllithium invariably possessed a bridgehead meth-
oxy group, which proved resistant to removal or conver-
sion to another functional group under numerous con-
a,3,4
Attempts to extend the scope of this methodology to
include cyclic nonstabilized (2-azaallyl)stannanes have
met with limited success. Previous reports have disclosed
1b
ditions. Thus it was not possible to generate simple
alkyl-substituted cycloadducts 4. A possible solution to
this problem would be to synthesize the unsubstituted
cyclic nonstabilized (2-azaallyl)stannanes, which upon
conversion to the cyclic nonstabilized 2-azaallyllithiums
should participate in [3 + 2] cycloadditions to give the
simple alkyl-substituted cycloadducts 4 directly.
We now report the synthesis of cyclic nonstabilized (2-
azaallyl)stannanes from the corresponding cyclic (3-
methylthio-2-azaallyl)stannane 2b via a Kumada cou-
pling of organomagnesium reagents using a Ni(0) catalyst.
In addition, the generation of the corresponding cyclic
†
Current address: Berry and Associates, Inc., 2434 Bishop Circle
East, Dexter, MI 48103.
(
1) Leading references: (a) Pearson, W. H.; Stoy, P. Synlett 2003,
9
9
03-921. (b) Pearson, W. H.; Stevens, E. P. J . Org. Chem. 1998, 63,
812-9827.
(
222. (b) Pearson, W. H.; Postich, M. J . J . Org. Chem. 1992, 57, 6354-
357.
2) (a) Chong, J . M.; Park, S. B. J . Org. Chem. 1992, 57, 2220-
2
6
(
3) (a) Pearson, W. H.; Ren, Y. J . Org. Chem. 1999, 64, 688-689.
(
b) Pearson, W. H.; Lian, B. W. Angew. Chem., Int. Ed. 1998, 37, 1724-
1
3
1
726. (c) Pearson, W. H.; Lovering, F. E. J . Org. Chem. 1998, 63, 3607-
617. (d) Pearson, W. H.; Barta, N. S.; Kampf, J . W. Tetrahedron Lett.
997, 38, 3369-3372. (e) Pearson, W. H.; Lovering, F. E. J . Am. Chem.
2
-azaallyllithium and azomethine ylide species and their
Soc. 1995, 117, 12336-12337. (f) Pearson, W. H.; Lovering, F. E.
Tetrahedron Lett. 1994, 35, 9173-9176.
(
4) Pearson, W. H.; Mi, Y.; Lee, I. Y.; Stoy, P. J . Am. Chem. Soc.
(5) Pearson, W. H.; Stevens, E. P. Tetrahedron Lett. 1994, 35, 2641-
2644.
2
001, 123, 6724-6725.
1
0.1021/jo049429p CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/21/2004
J . Org. Chem. 2004, 69, 6419-6426
6419

Mans and Pearson
SCHEME 1. P r eviou s Wor k w ith
Heter oa tom -Su bstitu ted Cyclic
(
SCHEME 3. Syn th esis of (2-Aza a llyl)sta n n a n es 2a
a n d 2b
a
2-Aza a llyl)sta n n a n es1b
a
Conditions: (a) NaBH4, 2% aq HCl, EtOH; (b) benzotriazole,
AcOH, (79% from 8); (c) Bu3SnH, LDA, THF, 0 °C (90%); (d)
Me2SO4, (71%); (e) (i) Lawesson’s reagent, (60%), (ii) Me2SO4,
(92%).
SCHEME 4. F a iled Ad d ition -Elim in a tion
Rea ction w ith 2a
SCHEME 2. P ossible Bon d Discon n ection s
even when the particularly reactive allylmagnesium
bromide was used. Suspecting that deprotonation to form
the metalloenamine was the problem, 2a was treated
with methylmagnesium bromide and quenched with
methyl iodide (Scheme 4). However, none of the methy-
lated product 13 was observed. The poor reactivity of
cyclic stannyl imidate 2a with various organomagnesium
reagents is unclear at this point. The presence of the
cycloaddition with alkenes gave azabicyclo[n.2.1]alkanes
in good yields with high endo selectivity.
Resu lts a n d Discu ssion
(
tributyl)tin moiety may decrease the electrophilicity of
On the basis of previous work done in our labora-
two possible routes to the cyclic nonstabilized
2-azaallyl)stannanes 6 were envisioned (Scheme 2).
the imidate carbon by virtue of inductive electron dona-
tion, thus causing nucleophilic addition to be more
difficult. Another explanation could be the formation of
a pentacoordinate stannate complex such as 12, which
may be stable under the reaction conditions and hydro-
lyzed upon aqueous workup (Scheme 4).8 Unfortunately,
the more reactive alkyllithium species were not viable
alternatives as a result of the extremely facile tin-
lithium transmetalation reaction, which would form an
undesired 2-azaallyllithium species. Other organometal-
lic reagents, such as alkylzincs and organocopper re-
agents, were either less reactive than organomagnesium
reagents10 or were also incompatible with the tin moiety.
Thus an alternative approach was sought in which
stannyl lactam 11 was converted into a more reactive
tories,1
(
b,2b
Formation of bond a might arise from reaction of an
organometallic reagent with either the methylimidate 2a
or methylthioimidate 2b by an addition-elimination
process. Alternatively, bond b may arise from an in-
tramolecular condensation reaction of an amino ketone
such as 7. Formation of bond b was deemed less suitable
because of difficulties encountered in preparing the
condensation precursors. Therefore formation of bond a
was pursued.
,9
As described previously,1b partial reduction of succin-
imide 8 and in situ conversion to the known ethoxy N,O-
acetal 9 was performed using the conditions reported by
6
Speckamp (Scheme 3). Conversion of 9 to the benzo-
triazole 10 followed by displacement with (tributyl)-
tinlithium1 gave the stannyl lactam 11. Methylation
with dimethyl sulfate provided (3-methoxy-2-azaallyl)-
stannane 2a . Additionally, treatment of 11 with Lawes-
son’s reagent and methylation with dimethyl sulfate
generated (3-methylthio-2-azaallyl)stannane 2b.
With tin precursors 2a and 2b in hand, the addition-
elimination reaction was examined. Unfortunately, treat-
ment of 2a and 2b with organomagnesium reagents
under a variety of conditions failed to produce the desired
stannanes 6. Starting material was returned in all cases,
(
8) The formation of a pentacoordinate stannate complex has been
b,7
verified experimentally and is proposed to be an intermediate in tin-
lithium exchange in THF (see ref 9). See: (a) Reich, H. J .; Bevan, M.
J .; Gudmundsson, B. O.; Puckett, C. L. Angew. Chem., Int. Ed. 2002,
41, 3436-3439. (b) Ashe, A. J ., III; Lohr, L. L.; Al-Taweel, S. M.
Organometallics 1991, 10, 2424-2431. (c) Maercker, A.; Bodenstedt,
H.; Brandsma, L. Angew. Chem., Int. Ed. Engl. 1992, 31, 1339-1341.
(
9) (a) Seyferth, D.; Weiner, M. A. J . Org. Chem. 1959, 24, 1395-
1396. (b) Reich, H. J .; Phillips, N. H. Pure Appl. Chem. 1987, 59, 1021-
1
2
026. (c) Reich, H. J .; Phillips, N. H. J . Am. Chem. Soc. 1986, 108,
102-2103. (d) Reich, H. J .; Borst, J . P.; Coplien, M. B.; Phillips, N.
H. J . Am. Chem. Soc. 1992, 114, 6577-6579. (e) Reich, H. J .; Borst, J .
P.; Dykstra, R. R. Organometallics 1994, 13, 1-3.
(10) The presence of the nitrogen in the O-methyl imidate leads to
a much less electrophilic carbon at the imidate center compared to an
ester. Thus rather reactive organometallic reagents would be required.
For example, Smith showed that alkyllithium reagents are needed in
order to add to simple cyclic O-methyl imidates: Zezza, C. A.; Smith,
M. B.; Ross, B. A.; Arhin, A.; Cronin, P. L. E. J . Org. Chem. 1984, 49,
4397-4399.
(
6) Hubert, J . C.; Wijnberg, J . B. P. A.; Speckamp, W. N. Tetrahedron
975, 31, 1437-1441.
7) (a) Pearson, W. H.; Stevens, E. P. Synthesis, 1994, 904-906. (b)
Katritzky, A. R.; Chang, H.-X.; Wu, J . Synthesis 1994, 907-908.
1
(
6
420 J . Org. Chem., Vol. 69, No. 19, 2004

Cyclic (2-Azaallyl)stannanes
appeared in the literature.15 However, all of these
involved aromatic S-methyl thioimidates, indicating that
the C-S bond of 2b may not be suitably activated for
the oxidative addition/transmetalation sequence to occur.
However, a report of a copper-mediated Pd(0)-catalyzed
SCHEME 5. Attem p ts a t Im id oyl Ch lor id e a n d
Im id oyl Tr ifla te F or m a tion
1
6
thioester cross-coupling reaction by Liebeskind prompted
us to explore a similar coupling with 2b.
Initial examination of the cross-coupling reaction of
thioimidate 2b with phenylboronic acid using 1 mol % of
Pd
2 3
dba , 1.6 equiv of copper(I) thiophene carboxylate
(CuTC), and 3 mol % of trifurylphosphine (TFP) in
deoxygenated THF at 50 °C led only to decomposition of
the starting stannane in which the (tributyl)tin moiety
was removed (Table 1, entry 1). This result was not
wholly unexpected since Falck and co-workers have
shown that Cu(I) salts efficiently transmetalate with
stannanes to generate the corresponding organocopper
reagents.17 Performing the reaction without CuTC led
only to recovered starting material (entry 2). At this point
it became apparent that thioimidate 2b was not reactive
enough to participate in these relatively mild coupling
conditions.
intermediate (Scheme 5). Initial efforts focused on form-
ing an imidoyl chloride similar to those formed in the
Vilsmeier-Haack reaction.11 However, treatment of 11
with a variety of chlorinating reagents and acid scaven-
gers all led to decomposition of the starting material
Previously, Casalnouvo and co-workers reported the
successful Pd(0)-catalyzed coupling of the more reactive
benzylzinc bromide with 2-(methylthio)benzothiazole in
good yields.1 It was thought that the use of the more
reactive alkylzinc reagents would help facilitate the
transmetalation sequence enabling the coupling reaction
to proceed. Thus treatment of thioimidate 2b with
benzylzinc bromide and palladium tetrakis(triphenyl)-
phosphine in THF at 60 °C gave a 45% yield of 5-benzyl-
(Scheme 5). A second option was to form an imidoyl
triflate 16 from lactam 11. A report by Charette disclosed
the mild conversion of acyclic amides into imidoyl tri-
5l
flates and trapping with an amine to produce the desired
amidine.12 Unfortunately, using the conditions reported,
only the formation of N-triflated product 18 was observed.
The similar imidoyl benzotriazole was not investigated
because of the relatively harsh conditions for its forma-
2
-(tributylstannyl)-3,4-dihydro-2H-pyrrole 20 (entry 3).
tion and the tendency of organometallic reagents to
attack the benzotriazole moiety.13
Unfortunately, 20 was also accompanied with a 45% yield
of benzyl(tributyl)tin. All attempts to minimize this side
The strategy of using imidoyl chloride 14 and/or triflate
1
4
1
6 in transition metal catalyzed cross-coupling reactions
(15) (a) Tamao, K. In Comprehensive Organic Synthesis; Trost, B.
was also apparent to us. Our inability to generate these
species (14 and 16) led us to consider other intermediates
that could serve as cross-coupling partners. Numerous
examples of S-methyl thioimidates participating in cross-
coupling reactions with Pd(0) or Ni(0) catalysts have
M., Fleming, I., Pattenden, G., Eds.; Pergamon: New York, 1991; Vol.
3, pp 435-480. (b) Farina, V. In Comprehensive Organometallic
Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Hegedus, L.
S., Eds.; Pergamon: New York, 1995; Vol. 2, pp 161-240. (c) Alphonse,
F.-A.; Suzenet, F.; Keromnes, A.; Lebret, B.; Guillaumet, G. Org. Lett.
2003, 5, 803-805. (d) Egi, M.; Liebeskind, L. S. Org. Lett. 2003, 5,
8
01-802. (e) Kusturin, C. L.; Liebeskind, L. S.; Neumann, W. L. Org.
Lett. 2002, 4, 983-985. (f) Liebeskind, L. S.; Srogel, J . Org. Lett. 2002,
4, 979-981. (g) Ghosh, I.; J acobi, P. A. J . Org. Chem. 2002, 67, 9304-
9309. (h) Takei, H.; Miura, M.; Sugimura, H.; Okamura, H. Chem. Lett.
1979, 1447-1450. (i) Tiecco, M.; Testaferri, L.; Tingoli, M. Tetrahedron
1983, 39, 2289-2294. (j) Okamura, H.; Miura, M.; Takei, H. Tetrahe-
dron Lett. 1979, 20, 43-46. (k) Okamura, H.; Takei, H. Tetrahedron
Lett. 1979, 20, 3425-3428. (l) Angiolelli, M. E.; Casalnuovo, A. L.;
Selby, T. P. Synlett 2000, 6, 905-907.
(16) (a) Liebeskind, L. S.; Srogl, J . J . Am. Chem. Soc. 2000, 122,
11260-11261. (b) Savarin, C.; Srogl, J .; Liebeskind, L. S. Org. Lett.
2000, 2, 3229-3231. For additional examples, see also: (c) Shimizu,
T.; Seki, M. Tetrahedron Lett. 2001, 42, 429-432. (d) Tokuyama, H.;
Yokoshima, S.; Yamashita, T.; Fukuyama, T. Tetrahedron Lett. 1998,
39, 3189-3192.
(17) The transmetalation was shown to be extremely facile when a
coordinating heteroatom was present in the substrate allowing for
coordination of the Cu(I) to help direct and stabilize the incoming Cu-
(I) salt; for leading references, see: Falck, J . R.; Bhatt, R. K.; Ye, J . J .
Am. Chem. Soc. 1995, 117, 5973-5982. For further examples of Cu-
Sn transmetalation, see: (a) Bhatt, R. K.; Ye, J .; Falck, J . R.
Tetrahedron Lett. 1996, 37, 3811-3814. (b) Behling, J . R.; Babiak, K.
A.; Ng, J . S.; Campbell, A. L. J . Am. Chem. Soc. 1988, 110, 2641-
2643. (c) Lipshutz, B. H.; Ellsworth, E. L.; Dimock, S. H.; Reuter, D.
C. Tetrahedron Lett. 1989, 30, 2065-2068. (d) Farina, V.; Kapadia,
S.; Krishnan, B.; Wang, C.; Liebeskind, L. S. J . Org. Chem. 1994, 59,
5905-5911. (e) Allred, G. D.; Liebeskind, L. S. J . Am. Chem. Soc. 1996,
118, 2748-2749. (f) Piers, E.; McEachern, E. J .; Burns, P. A. Tetra-
hedron 2000, 56, 2753-2765. (g) Piers, E.; Wong, T. J . Org. Chem.
1993, 58, 3609-3610. (h) Piers, E.; Gladstone, P. L.; Yee, J . G. K.;
McEachern, E. L. Tetrahedron 1998, 54, 10609-10626. (i) Kang, S.-
K.; Kim, J .-S.; Choi, S.-C. J . Org. Chem. 1997, 62, 4208-4209.
(
11) For reviews, see: (a) Meth-Cohn, O.; Stanforth, S. P In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 2, pp 777-794. (b) Kantlehner, W. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 6, pp 485-599. (c) Marson, C. M.
Tetrahedron 1992, 48, 3659-3726. (d) Bonnett, R. in The Chemistry
of the Carbon-Nitrogen Double Bond; Patai, S., Ed.; Wiley-Inter-
science: New York, 1970; pp 597-662.
(
12) (a) Charette, A. B.; Chua, P. Tetrahedron Lett. 1998, 39, 245-
2
8
48. (b) Charette, A. B.; Chua, P. Tetrahedron Lett. 1997, 38, 8499-
502. (c) Sforza, S.; Dossena, A.; Corradini, R.; Virgili, E.; Marchelli,
R. Tetrahedron Lett. 1998, 39, 711-714.
13) For the synthesis of imidoylbenzotriazoles, see: Katritzky, A.
R.; Stevens, C. V.; Zhang, G.-F.; J iang, J . Heterocycles 1995, 40, 231-
38. For a review of benzotriazoles as an auxiliary, see: Katritzky, A.
R.; Rachwal, S.; Hitchings, G. J . Tetrahedron 1991, 47, 2683-2732.
14) For cross-coupling reactions involving imidoyl chlorides: (a) Lin,
(
2
(
S.-Y.; Sheng, H.-Y.; Huang, Y.-Z. Synthesis 1991, 235-236. (b) Kosugi,
M.; Koshiba, M.; Atoh, A.; Sano, H.; Migita, T. Bull. Chem. Soc. J pn.
1
986, 59, 677-679. (c) Kobayashi, T.; Sakakura, T.; Tanaka, M.
Tetrahedron Lett. 1985, 26, 3463-3466. (d) Rouden, J .; Bernard, A.;
Lasne, M.-C. Tetrahedron Lett. 1999, 40, 8109-8112. (e) Ito, Y.; Inouye,
M.; Murakami, M. Chem. Lett. 1989, 1261-1264. For cross-coupling
2
reactions involving sp -bound triflates, see: (f) Farina, V.; Krishna-
murthy, V.; Scott, W. In Organic Reactions; Paquette, L. A., Ed.; J ohn
Wiley & Sons: New York, 1997; Vol. 50, pp 1-633. (g) Farina, V.;
Krishnan, B.; Marshall, D. R.; Roth, G. R. J . Org. Chem. 1993, 58,
434-5444. (h) Scott, W. J .; Stille, J . K. J . Am. Chem. Soc. 1986, 108,
033-3040. (i) Echavarren, A. M.; Stille, J . K. J . Am. Chem. Soc. 1987,
09, 5478-5486.
5
3
1
J . Org. Chem, Vol. 69, No. 19, 2004 6421

Mans and Pearson
TABLE 1. Scr een in g of Cr oss-Cou p lin g Rea ction s w ith Th ioim id a te 2ba
entry
R-Met
cat./ligand
solvent
temp (°C)
time (h)
yield (%)
product
1
2
3
4
5
6
7
8
PhB(OH)2
PhB(OH)2
BnZnBr
BnZnBr
PhZnBr
PhZnBr
PhZnBr
PhZnBr
Pd2dba3 CuTC/TFP
Pd2dba3 TFP
Pd(PPh3)4
Pd2dba3 TFP
PdCl2(PPh3)2
PdCl2dppf
THF
THF
THF
THF
PhCH3
PhCH3
PhCH3
PhCH38
50
50
60
60
22
50
50
22
0.25
18
22
40
18
24
18
18
dec
nr
45
nr
nr
nr
19
19
20
20
19
19
19
19
NiCl2dppe
NiCl2dppp
dec
nr
a
THF deoxygenated prior to use using freeze-pump-thaw method (3×). TFP ) trifurylphosphine, CuTC ) copper(I) thiophene
carboxylate, dba ) dibenzylidene acetone, dppf ) 1,1′-bis(diphenylphosphino)ferrocene, dppe ) 1,2-bis(diphenylphosphino)ethane, dppp
1,3-bis(diphenylphosphino)propane.
)
reaction, such as varying the catalyst loading, substrate
concentration, and temperature, failed. Presumably trans-
metalation with benzylzinc bromide occurs under the
reaction conditions. This was supported by treating 2b
with benzylzinc bromide in THF at 60 °C, leading to the
slow disappearance of starting material and concomitant
formation of benzyl(tributyl)tin by GC-MS. Attempts to
trap the resultant 2-azaallylzinc species with either
trans-stilbene in a [3 + 2] cycloaddition or methyl iodide
in a substitution reaction both failed. Switching to the
ether was used as solvent on the basis of reports that a
less coordinating solvent (Et O vs THF) helped facilitate
oxidative addition because of the lowered tendency of the
2
1
8
catalyst to be deactivated by solvent coordination.
Although these results seemed to be borne out in our
experiments, a small (∼10%) amount of destannylated
material was consistently observed in these reactions.
This was thought to be due to tin-metal transmetalation
that is greatly facilitated in polar solvents.19 Switching
to the noncoordinating and less polar solvents toluene
and methylene chloride provided much improved results.
2 3
more stable Pd dba failed to give any reaction (entry 4).
Attempts to utilize the less reactive phenylzinc bromide
were unsuccessful with a variety of catalysts including
the more reactive Ni(0) catalysts (entries 5-8). From the
2 2
With NiCl dppp or NiCl dppe a dramatic improvement
is observed using toluene, providing 21 in 80% yield
(entries 5 and 6) compared to a 67% yield when ether is
used (entry 3). However, other catalyst systems with
toluene as solvent provided only inferior yields or no
reaction (entries 7-11). In addition virtually no destan-
nylated material could be observed by GC-MS when
3 4
results with BnZnBr and Pd(PPh ) it appeared that
oxidative addition was occurring; however, the trans-
metalation step appeared to still be sluggish. The litera-
ture contains numerous examples of the use of additives
to speed up stubborn transmetalation steps, such as the
so-called “copper-effect”.1 However, on the basis of
previous studies (vida supra) it appeared that the use of
such additives often increases the destannylation of 2b
whether by transmetalation or some other process.
Instead, use of more reactive catalysts and organome-
tallic reagents was pursued.
toluene was used as the solvent along with NiCl
2
dppp
7d
or NiCl dppe. Use of methylene chloride as the solvent
2
failed to give any reaction at all (entry 12). As a control,
no reaction was observed when either the organomag-
nesium reagent or nickel catalyst was absent.
Using the optimized conditions (0.2 M in 2b, 5 mol %
catalyst, 1.1 equiv of RMgX in toluene) for the Kumada
coupling various other organomagnesium reagents were
also examined. Similar results were obtained with me-
thylmagnesium chloride providing product 22 in 75%
yield (Table 2, entry 13). Unfortunately, attempts to use
secondary organomagnesium reagents such as isopropyl-
magnesium chloride led only to decomposition (Table 2,
entries 15-19). The reason for the failure is uncertain,
Having come full circle, we were once again faced with
using organomagnesium reagents, this time to effect the
transmetalation step. Work in the late 1970s by Kumada
2
and co-workers had shown that sp C-S and C-X bonds
underwent smooth insertion of a Ni(0) catalyst and
coupling with organomagnesium reagents.18 Fortunately,
our earlier work showed that organomagnesium reagents
should not destannylate the stannyl thioimidate 2b (vide
supra). Treatment of stannyl thioimidate 2b with 1.1
equiv of n-butylmagnesium chloride and 5 mol % of 1,3-
3
but it is known that compounds possessing sp -hybridized
centers undergo â-elimination to generate metal hydride
species. Apparently â-elimination is faster than reductive
elimination with isopropylmagnesium chloride, whereas
reductive elimination is as fast or faster than â-elimina-
tion for butylmagnesium chloride with the Ni(0) cata-
lysts. Trost and others have utilized nickel hydride
species, generated in situ from the reaction of isopropyl-
2
bis(diphenylphosphino)propane nickel(II) chloride (NiCl -
dppp) in diethyl ether (0.2 M) at 45 °C in a sealed tube
led to a 12% yield of 5-butyl-2-(tributylstannyl)-3,4-
dihydro-2H-pyrrole 21 (Table 2, entry 1). Lowering the
temperature to 25 °C gave a 51% yield (entry 2), and a
6
7% yield was obtained when the reaction was performed
2 3 2
magnesium bromide and NiCl (PPh ) catalyst, for the
2
20
at 0 °C (entry 3). Reaction temperatures lower than 0 °C
gave lower yields (Table 2, entry 4). Initially, diethyl
reductive cleavage of sp carbon-sulfur bonds. Thus it
is conceivable that a nickel hydride species is generated
from â-hydride elimination, which reacts with 2b leading
(
18) For leading reference, see: Tamao, K.; Sumitani, K.; Kiso, Y.;
Zembayashi, M.; Fujioka, A.; Kodama, S.; Nakajima, I.; Minato, A.;
Kumada, M. Bull. Chem. Soc. J pn. 1976, 49, 1958-1969.
(19) See ref 9e and also Grana, P.; Paleo, M. R.; Sardina, F. J . J .
Am. Chem. Soc. 2002, 124, 12511-12514.
6
422 J . Org. Chem., Vol. 69, No. 19, 2004

Cyclic (2-Azaallyl)stannanes
TABLE 2. Ku m a d a Cou p lin g of Th ioim id a te 2b a
success. Various experimental conditions were explored
with allylmagnesium bromide (Table 2, entries 21-26).
The best results were obtained by addition of 1.1 equiv
of allylmagnesium bromide to a suspension of 5 mol %
NiCl
2
dppp and thioimidate 2b in toluene (0.2 M) at 25
°
C for 15 min (entry 21). Using these conditions a 31%
yield of the allylated product 24 was obtained in which
the alkene had migrated into conjugation with the imine.
A survey of different ligands did not improve the yield
or reaction rate. For example, using 1,3-bis(2,6-di-iso-
propylphenyl) imidazolium chloride 27 as the ligand
(
entries 23 and 24) led to complete decomposition of the
temp time yield pro-
cat./ligand solvent (°C) (h) (%) duct
entry
R-Met
starting material. In previous reports the 1,2-bis(di-
methylphosphino)ethane (dmpe)21 ligand has been shown
to be the most effective ligand for coupling with allyl and
vinyl organomagnesium reagents.18 The proposed ration-
ale being that more basic phosphine ligands such as dmpe
help favor a conversion from a π-allylnickel complex 29
to the more reactive σ-bound allyl-nickel complex 28 (eq
1) through stabilization of the electron-deficient Ni(II)
center by σ-donation from the phosphorus ligands; whereas
less basic ligands such as 1,3-bis(diphenylphosphino)-
propane (dppp) form a more stable five-coordinate π-al-
lylnickel complex 31 (eq 2).18 Unfortunately, in this
instance the dmpe ligand failed to give any product (entry
25).
1
2
3
4
5
6
7
8
9
BuMgCl
BuMgCl
BuMgCl
BuMgCl
BuMgCl
BuMgCl
BuMgCl
BuMgCl
BuMgCl
BuMgCl
BuMgCl
BuMgCl
MeMgCl
MeMgCl
i-PrMgCl
i-PrMgCl
i-PrMgCl
PrMgCl
PrMgCl
BnMgCl
NiCl2dppp
NiC2dppp
NiCl2dppp
NiCldppp
NiCldppp
NiCldppe
NiCl,
Et2O
Et2O
Et2O
Et2O
PhCH3
PhCH3
PhCH3
45 24
22 18
0 18
12 21
51 21
67 21
40 21
80 21
75 21
nr 21
nr 21
nr 21
22 21
nr 21
nr 21
75 22
nr 22
dec 23
dec 23
dec 23
dec 23
dec 23
dec 20
31 24
-10 24
22 0.25
22 0.75
22 18
22 18
22 18
22 18
22 18
22 18
22 0.25
22 18
22 18
22 18
22 18
22 18
22 18
22 18
22 0.25
22 0.25
NiCl2(PPh3)2 PhCH3
NiCl2dppt
PdCl2dppt
Pd(Ph3)4
NiCl2dppp
NuCl2dppp
NiCl2dppp
NiCl2dppp
NiCl2dppp
NiCl2
PhCH3
PhCH3
PhCH3
CH2Cl2
PhCH3
CH2Cl2
PhCH3
CH2Cl2
PhCH3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
NiCl2(PPh3) PhCH3
NiClzdppt
PdCldppf
PhCH,
PhCH,
PhCH,
CHCl2
c
allylMgBr NiCl2dppp
allylMgBr NiCl2dppp
allylMgBr Ni(acac)2, 27 PhCH3
allylMgBr Ni(acac)2, 27 THF
allylMgBr NiCl2drnpe PhCH3
20 24c
c
22 0.33 dec 24
22 0.5
22 18
dec 24c
c
7
24
c
allylMgCl PdCl2dppt
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
0
22
1
1
dec 24
35 19
nr 19
36 19
55 19
nr 25
PhMgBr
PhMgBr
PhMgBr
PhMgBr
NiCl2dppp
NiCl2dppp
NiCl2dppe
PdCl2dppt
b
22 18
22 0.25
22
4
1-propenyl- NiCl2dppp
MgBr
22 18
Likewise, under the conditions just mentioned, phen-
ylmagnesium bromide gave a 35% yield of 5-phenyl-2-
3
3
2
3
vinylMgBr NiCl2dppp
vinylMgBr PdCl2dppt
PhCH3
PhCH3
22 18
nr 26
dec 26
22
1
(tributylstannyl)-3,4-dihydro-2H-pyrrole 19 (Table 2, en-
a
try 27). However, the reaction was much slower, taking
an hour rather than minutes to reach completion. It is
well-known that an increase in the “bite-angle” created
by the phosphine ligands, and the shorter Ni-C bonds
can result in increased steric interactions at the coupling
centers, which can dramatically increase the reaction
rate.22 The larger P-Ni-P angle created by the dppe
ligand and hence smaller R-Ni-R′ angle may increase
the steric interactions experienced by the pyrroline and
the alkyl group helping facilitate reductive elimination.
This observation appears to be borne out as a screen of
various ligands revealed that the 1,3-bis(diphenylphos-
phino)ethane (dppe) ligand gave a much faster reaction
time and comparable yields to the 1,3-bis(diphenylphos-
phino)propane (dppp) ligand (entry 27 vs 29). Surpris-
Conditions: 0.2 M in stannane, 5 mol % catalyst, 1.1 equiv of
b
R-Met. Catalysts were preactivated with 10 mol % BuMgCl.
Migration of the alkene into conjugation occurred with all allyl
Grignard reactions. dmpe ) 1,2- bis(dimethylphosphino)ethane,
acac ) acetylacetonate, 27 ) 1,3- bis(2,6-di- isopropylphenyl)imi-
dazolium chloride.
c
to decomposition or cleavage of the C-S bond. Appar-
ently, the product of reductive cleavage, if formed at all,
is not stable to the reaction conditions. 2-(Tributylstan-
nyl)-3,4-dihydro-2H-pyrrole (the proposed product of
reductive C-S cleavage) was eventually synthesized but
via the amine condensation method (bond disconnection
b, Scheme 2) instead (vide infra).
Aryl and allyl organomagnesium reagents were also
examined for reaction with thioimidate 2b with limited
2
ingly, use of PdCl dppf instead provided a 55% yield of
(
20) (a) Trost, B. M.; Ornstein, P. L Tetrahedron Lett. 1981, 22,
19 (entry 30).
3
7
5
4
463-3466. (b) Trost, B. M.; Ornstein, P. L. J . Org. Chem. 1982, 47,
48-751. (c) Trost, B. M.; Lavoie, A. C. J . Am. Chem. Soc. 1983, 105,
075-5090. (d) Fabre, J .-L.; J ulia, M. Tetrahedron Lett. 1983, 24,
311-4314. (e) Cuvigny, T.; Fabre, J . L.; du Penhoat, C.; J ulia, M.
Tetrahedron Lett. 1983, 24, 4319-4322. (f) Capet, M.; Cuvigny, T.;
Penhoat, H.; J ulia, M.; Loomis, G. Tetrahedron Lett. 1987, 28(50),
2
(21) For preparation of NiCl dmpe, see: Booth, G.; Chatt, J . J .
Chem. Soc. 1965, 3238-3241.
(22) (a) Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi,
T.; Hirotsu, K. J . Am. Chem. Soc. 1984, 106, 158-163. (b) Saito, S.;
Oh-Tani, S.; Miyaura, N. J . Org. Chem. 1997, 62, 8024-8030.
6
273-6276.
J . Org. Chem, Vol. 69, No. 19, 2004 6423

Mans and Pearson
SCHEME 6. Th ioim id a te Ku m a d a Cr oss-Cou p lin g
lithium species and azomethine ylides participate in
cycloaddition reactions with a variety of alkenes to give
substituted pyrrolidines.1
,2b,3-5
In addition, recent work
has demonstrated that conjugated polyenes can also
serve as efficient anionophiles.26 The goal was then to
examine if similar reactivity is observed with nonstabi-
lized cyclic 2-azaallyllithiums derived from stannanes 19,
2
1, 22, and 49.
Stannane 21 was chosen as a representative 2-azaal-
The reason for the relatively low yields observed with
the allyl and aryl organomagnesium reagents as well as
the complete absence of reaction with vinyl organomag-
nesium reagents (Table 2, entries 31-33) remains un-
certain. However, the lower reactivity of the aryl and
vinyl organomagnesium reagents compared to the alkyl
organomagnesium reagents most likely means decompo-
sition pathways may be able to compete with the desired
reaction to drain off the starting materials. As mentioned
earlier the allylmagnesium bromide may be forming a
stable π-allylnickel complex that does not undergo cross-
coupling with 2b. In addition the presence of the induc-
tively electron-donating (tributyl)tin group may slow the
oxidative addition/transmetalation steps for the same
reasons as discussed earlier for the addition-elimination
reaction (Scheme 4).
lyllithium precursor to probe the reactivity profile with
various dipolarophiles (Table 3). trans-Stilbene 36 pro-
vided 2,3-diphenyl-7-azabicyclo[2.2.1]heptanes 43a /b as
a 1:1 mix of diastereomers in 87% yield. Structural
assignment was made using the coupling constants
observed with the lone bridgehead proton.26 In a similar
manner, reaction with phenyl vinyl sulfide 37 and phenyl
vinyl selenide 38 gave the corresponding endo cycload-
ducts 44a /b and 45a /b in 43% and 74% yields, respec-
tively, both as a 1:1 mix of diastereomers. An endo/exo
assignment could not be made with the trans-stilbene
adducts 43a /b as a result of the nature of the dipolaro-
phile, which masks the approach of the alkene in the
transition state. Unfortunately, only decomposition prod-
ucts were observed when vinyltrimethylsilane 39 was
used as the dipolarophile. The failure with vinyltrimeth-
ylsilane is somewhat surprising since the analogous
reaction with acyclic 2-azaallyllithiums has been shown
to proceed with moderate yields.27 Rather surprising is
the result observed when trimethyl(phenylethynyl)silane
During the early stages of development of the cross-
coupling conditions, the known nonstannyl thioimidate
2
3
3
3
was also investigated to examine the generality of
the reaction for forming imines (Scheme 6). The opti-
mized conditions for the cross-coupling of thioimidate 33
with organomagnesium reagents were found to be 5 mol
4
0 was employed as the anionophile. No cycloadduct was
%
catalyst, 1.1 equiv of RMgX, and 0.2 M 33 in toluene.
observed; however, (2-azaallyl)silane 46 was recovered
in 55% yield most likely as a result of desilylation by the
2
1
0
The known 5-butyl-3,4-dihydro-2H-pyrrole 34 and
5
7
-phenyl-3,4-dihydro-2H-pyrrole 3510 were obtained in
5% and 80% isolated yields, respectively. None of the
-azaallyllithium intermediate.
The cyclic (2-azaallyl)stannanes were also shown to
pyrrolidine resulting from a second organomagnesium
addition was seen in any of the cases examined. In
comparison, the well-known alkyllithium addition to
cyclic imidates is often plagued by bis-addition to give
the pyrrolidine instead.24 The nickel catalyst is required
as no reaction is observed in its absence, leading to
recovery of starting thioimidate 33. The method devel-
oped provides an alternative to the current methods25 for
the generation of cyclic and acyclic imines.
With a series of novel cyclic (2-azaallyl)stannanes now
in hand, the reactivity profile in 2-azaallyllithium and
azomethine ylide cycloaddition reactions were investi-
gated. Previous work has shown that acyclic 2-azaallyl-
undergo [π6s + π4s] cycloaddition reactions with conju-
gated polyenes. Addition of n-butyllithium to a solution
of cycloheptatriene 41 and stannane 21 yielded the [π6s
+
π4s] cycloadduct 47a and the cyclic imine 47b (1:1) in
7% combined yield (Table 3). The tricyclic amine 47a
6
was formed exclusively as the endo-adduct with the
structural assignment being based on comparison of the
coupling constants observed with similar compounds
previously reported.2 In addition, reaction of stannane
6a
2
1 with cyclohexadiene 42 provided the endo-cycload-
ducts 48a /b as a 1.5:1 mix of double bond regioisomers
in 68% combined yield. Both results are in accord with
previous findings using conjugated polyenes in the
6b
2
-azaallyllithum cycloaddition reactions.2
(
23) Anbazhagan, M.; Dixit, A. N.; Rajappa, S. J . Chem. Soc., Perkin
Trans. 1 1997, 16, 2421-2424.
24) See ref 10 and (a) Neilson, D. G. In The Chemistry of Amidines
It should also be mentioned that, unlike the butyl- and
methyl-substituted stannyl imines 21 and 22, the phenyl-
substituted imine 19 produced 1,2,3-triphenyl-7-azabicyclo-
(
and Imidates; Patai, S., Rappoport, Z., Eds.; J ohn Wiley & Sons, Ltd.:
New York, 1991; Vol. 2, pp 425-483. (b) Bielawski, J .; Brandange, S.;
Lindblo, L. J . Heterocycl. Chem. 1978, 15, 97-99. (c) Dudek, V.; Kvan,
L. Collect. Czech. Chem. Commun. 1965, 30, 2472-2474. (d) Lukes,
R.; Cerny, M. Collect. Czech. Chem. Commun. 1961, 26, 2886-2890.
[2.2.1]heptane 50 as the sole product in 40% yield when
reacted with trans-stilbene 36 (Table 4). The reason for
the diastereoselectivity with imine 19 may be attributed
to a steric clash between the bridgehead phenyl and one
of the phenyls on trans-stilbene in the transition state.
All attempts with 24 (Table 2, entry 21) in these
cycloaddition reactions led only to decomposition. The
reason for the failure is unclear at this point since
(
e) Cervinka, O. Collect. Czech. Chem. Commun. 1959, 24, 1146-1150.
25) Some examples include (a) Hua, D. H.; Miao, S. W.; Bharathi,
S. N.; Katsuhira, T.; Bravo, A. A. J . Org. Chem. 1990, 55, 3682-3684.
b) Ahn, Y.; Cardenas, G. I.; Yang, J .; Romo, D. Org. Lett. 2001, 3,
51-754. (c) Padwa, A.; Gasdaska, J . R.; Haffmanns, G.; Rebello, H.
(
(
7
J . Org. Chem. 1987, 52, 1027-1035. (d) Hoffman, R. V.; Buntain, G.
A. J . Org. Chem. 1988, 53, 3316-3321. (e) Tsuge, O.; Kanemasa, S.;
Yamada, T.; Matsuda, K. J . Org. Chem. 1987, 52, 2523-2530. (f)
Kondo, T.; Okada, T.; Mitsudo, T. J Am. Chem. Soc. 2002, 124, 186-
1
87. (g) Giovannini, A.; Savoia, D.; Umani-Ronchi, A. J . Org. Chem.
989, 54, 228-234. (h) Keppens, M.; deKimpe, N.; Stevens, C.
(26) (a) Pearson, W. H.; Mans, D. M.; Kampf, J . W. Org. Lett. 2002,
4, 3099-3102. (b) Pearson, W. H.; Mans, D. M.; Kampf, J . W. J . Org.
Chem. 2004, 69, 1235-1247.
(27) See refs 1b and 2b and Pearson, W. H.; Szura, D. P.; Postich,
M. J . J . Am. Chem. Soc. 1992, 114, 1329-1345.
1
Tetrahedron Lett. 1993, 34, 4693-4696. (i) Keppens, M.; deKimpe, N.;
Fonck, G. Synth. Commun. 1996, 26, 3097-3102 and references
therein.
6
424 J . Org. Chem., Vol. 69, No. 19, 2004

Cyclic (2-Azaallyl)stannanes
TABLE 3. Cycloa d d ition Rea ction of Alk en es w ith Cyclic Sta n n a n e 21
a
Isolated as the picrate salt.
tions32 followed by Swern oxidation33 provided the con-
TABLE 4. Cycloa d d ition of tr a n s-Stilben e w ith
Sta n n a n es 19, 22, a n d 49
densation precursor 56. Hydrazinolysis of 56 with
hydrazine monohydrate under reflux in ethanol resulted
in deprotection of the phthalimide followed by amine
condensation to generate the cyclic imine 49. Apparently
concomitant hydrazone formation with the aldehyde
under the hydrazinolysis conditions has a favorable
enough equilibrium to allow formation of the cyclic imine.
Unfortunately, attempts to prepare the homologous
2
-(tributylstannyl)-2,3,4,5-tetrahydropyridine through the
same route failed when attempting the hydrazinolysis/
condensation sequence.
SCHEME 7. Syn th esis of Sta n n yl Im in e 49a
Treatment of stannane 49 with trans-stilbene 36 and
n-butyllithium gave a 36% yield of the endo bicyclic
amine 52 as a single diastereomer (Table 4). The lower
yields obtained with imine 49 may be due to a greater
inherent instability of the corresponding 2-azaallyl-
lithium species enabling a greater proportion of the
reactive anion to access alternate decomposition path-
ways compared to the 2-azaallyllithium species derived
from stannanes 19, 21, and 22. A valuable route to the
tropane ring system could also be accessible via a higher-
order cycloaddition reaction with a 6π-addend such as
a
Conditions: (a) TBSCl, NaH, THF, 99%; (b) (COCl)2, Et3N,
DMSO, CH2Cl2, -78 °C, 99%; (c) LDA, Bu3SnH, THF, -78 °C; (d)
phthalimide, DEAD, PPh3, THF, 55% over 2 steps.; (e) AcOH/THF/
H2O (3:1:1), 75%; (f) (COCl)2, Et3N, DMSO, CH2Cl2, -78 °C, 91%;
34
cycloheptatriene. The resulting tricyclic amine could
(
g) H2NNH2, EtOH, reflux, 49%.
3
5
then be further transformed into cocaine analogues.
However, attempts to react stannane 49 with cyclohep-
tatriene 41 were unsuccessful.
conjugated 2-azaallyllithium species have been shown to
participate in the [3 + 2] cycloaddition reaction.28
In addition to using the cyclic alkyl-substituted (2-
In addition to the 2-azaallyllithium cycloaddition reac-
tions discussed above, the complimentary azomethine
ylide cycloaddition manifold36 was briefly investigated
using electron-poor dipolarophiles. Heating a solution of
imine 21 with methyl iodide and N-methylmaleimide at
reflux in toluene for 18 h provided a 40% yield of the endo
cycloadduct 57 as the sole product (Scheme 8). Similarly,
use of the phenyl-substituted imine 19 gave only the endo
2
9
azaallyl)stannanes, 5-(tributylstannyl)-2-pyrroline 49
was prepared to provide further insight into the chem-
istry of the cyclic stannanes. The synthesis of stannane
9 began with a McDougal protection30 of 1,4-butanediol
4
5
5
3 followed by Swern oxidation to give known aldehyde
3
1
4
(Scheme 7). Addition of aldehyde 54 to a solution of
(tributyl)tinlithium, prepared from LDA and (tributyl)-
tin hydride, produced a R-hydroxy stannane, which was
immediately converted to the phthalimide 55 via Mit-
sunobu reaction.2 Silyl-deprotection under Corey condi-
(32) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,
6190-6191.
a
(
33) Mancuso, A. J .; Huang, S. L.; Swern, D. J . Org. Chem. 1978,
4
3, 2480-2482.
(
28) See ref 3a,d and Pearson, W. H.; J acobs, V. A. Tetrahedron Lett.
994, 35, 7001-7004.
29) Stevens, E. P. Ph.D. Thesis, University of Michigan at Ann
Arbor, 1997.
(34) See ref 26a for initial work in this area.
(35) For leading references on cocaine analogues and the rationale
1
(
for making them, see: (a) Kozikowski, A. P.; Saiah, M. K. E.; J ohnson,
K. M.; Bergmann, J . S. J . Med. Chem. 1995, 38, 3086-3093. (b)
Kozikowski, A. P.; Araldi, G. L.; Ball, R. G. J . Org. Chem. 1997, 62,
503-509. (c) Lounasmaa, M.; Tamminen, T. In The Alkaloids; Cordell,
G. A., Ed.; Academic Press: New York, 1993; Vol. 44, pp 1-114. (d)
Singh, S. Chem. Rev. 2000, 100, 925-1024.
(
30) McDougal, P. G.; Rico, J . G.; Oh, Y.-I.; Condon, B. D. J . Org.
Chem. 1986, 51, 3388-3390.
(
13.
31) Tori, M.; Toyoda, N.; Sono, M. J . Org. Chem. 1998, 63, 306-
3
J . Org. Chem, Vol. 69, No. 19, 2004 6425

Mans and Pearson
SCHEME 8. Azom eth in e Ylid e Cycloa d d ition w ith
Alk yl-Su bstitu ted (2-Aza a llyl)sta n n a n es
bilized cyclic azomethine ylides used in [3 + 2] cycload-
3
7
ditions to produce (M+3)-azabicyclo[m.2.1]alkanes.
In summary, we have developed an efficient and novel
transition-metal-catalyzed cross-coupling reaction be-
tween organomagnesium reagents and thioimidate 2b.
The reaction works well with primary alkyl organomag-
nesium reagents. In addition aryl and allyl organomag-
nesium reagents also participate in the cross-coupling
reaction albeit in only moderate yields. The resultant
cyclic alkyl-substituted (2-azaallyl)stannanes have also
been shown to be viable precursors to the reactive
2
-azaallyllithium species and azomethine ylides, which
undergo [3 + 2] cycloaddition reactions with dipolaro-
philes to give exclusively the endo cycloadducts. These
cycloadducts can serve as suitable starting points for
further elaboration into biologically important bicyclic
alkaloids.
cycloadduct 58 in 19% yield. Unsubstituted imine 49
failed to give any products under the same conditions.
To our knowledge these results are only the second
reported use of completely nonstabilized endocyclic azo-
methine ylides in [3 + 2] cycloadditions. The other report
comes from work by Pandey and co-workers in which a
AgF-induced sequential double desilylation of N-alkyl-
R,R′-bis(trimethylsilyl) cyclic amines generates nonsta-
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM-52491) for funding and Abbott
Laboratories for a graduate fellowship for D.M.M. (2002-
2
003).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and 1H and/or C spectra for all new compounds
described herein. This material is available free of charge via
the Internet at http://pubs.acs.org.
13
(36) For leading references concerning work done in our laboratories,
see ref 1a and (a) Pearson, W. H.; Stoy, P.; Mi, Y. J . Org. Chem. 2004,
J O049429P
6
9, 1919-1939. (b) Clark, R. B.; Pearson, W. H. Org. Lett. 1999, 1,
49-351. For further examples of azomethine ylides, see: (c) Lown,
3
J . W. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley-
Interscience: New York, 1984; Vol. 1, pp 653-732. (d) Vedejs, E. In
Advances in Cycloaddition; J AI Press: Tokyo, 1988; Vol. 1, pp 33-51.
(37) For leading reference on forming nonstabilized endocyclic
azomethine ylides, see: Pandey, G.; Laha, J . K.; Lakshmaiah, G.
Tetrahedron 2002, 58, 3525-3534. For general references concerning
nonstabilized exocyclic azomethine ylides, see: (a) Castulik, J .; Marek,
J .; Mazal, C. Tetrahedron 2001, 57, 8339-847. (b) Grigg, R.; Savic,
V.; Thornton-Pett, M. Tetrahedron 1997, 53, 10633-10642. (c) Novello,
F.; Prato, M.; Da Ros, T.; De Amici, M.; Bianco, A.; Toniolo, C.; Maggini,
M. Chem. Commun. 1996, 903-904. (d) Pandey, G.; Lakshmaiah, G.
Tetrahedron Lett. 1993, 34, 4861-4864. (e) Roussi, G.; Zhang, J . D.
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