A Three-Component, One-Pot Synthesis of Indolizidines and Related Heterocycles Via the [3+2] Cycloaddition of Nonstabilized Azomethine Ylides

A Th r ee-Com p on en t, On e-P ot Syn th esis of In d olizid in es a n d

Rela ted Heter ocycles via th e [3+2] Cycloa d d ition of Non sta bilized

Azom eth in e Ylid es

William H. Pearson,*^,†Patrick Stoy, and Yuan Mi^‡

Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055

wpearson@berryassoc.com

Received October 29, 2003

Nonstabilized azomethine ylides (i.e. those bearing only hydrogens or alkyl groups) can be generated

from (2-azaallyl)stannanes and (2-azaallyl)silanes through an intramolecular N-alkylation/demeta-

lation cascade. The resulting ylides undergo [3+2] cycloaddition with electron-poor or electron-

rich dipolarophiles yielding indolizidines and related 1-aza[m.3.0]bicycloalkane systems in good

yield. An in situ protocol allows for a one-pot, three-component synthesis of indolizidines. The (2-

azaallyl)stannanes tolerate enolizable hydrogens in these cycloadditions, while (2-azaallyl)silanes

do not. The mechanism of the cycloaddition cascade is clarified by a series of control experiments.

The same (2-azaallyl)stannanes may be transmetalated by n-butyllithium to generate 2-azaallyl-

lithiums, which also may undergo a [3+2] cycloaddition/N-alkylation cascade to form indolizidines.

In tr od u ction

Vedejs,²Padwa,³and Achiwa⁴allowed the formation of

such nonstabilized azomethine ylides by the fluoride-

assisted desilylation of (trimethylsilyl)methyl iminium

salts. Variations on this theme, as well as a number of

other methods for the generation of nonstabilized azo-

methine ylides, have been successfully applied to the

synthesis of a variety of nitrogen-containing heterocycles.^1a

Among the heterocycles targeted by such azomethine

ylide cycloaddition methods are the pyrrolizidines⁵(1-

aza[3.3.0]bicyclooctane) and indolizidines⁶(1-aza[4.3.0]-

bicyclononane), which are present in a wide variety of

natural products. Most commonly, these methods use

azomethine ylides stabilized by ester or aryl groups.⁷

However, azomethine ylides not substituted by such

stabilizing groups are often most relevant to many

synthetic targets in these families of natural products.

For instance, Vedejs and co-workers⁸employed a non-

stabilized azomethine ylide generated by desilylation of

an iminium ion in their synthesis of (()-retronecine.

Starting from a chiral pool synthon, Pandey and co-

workers⁹used their double-desilylation methodology to

synthesize nonracemic (+)-retronecine via a nonstabilized

azomethine ylide. Recently, Epperson and Gin¹⁰have

The 1,3-dipolar cycloaddition of azomethine ylides has

emerged as a popular way of constructing heterocycles

containing the pyrrolidine substructure, owing to its high

synthetic efficiency and often high stereoselectivity (eq

1).¹Azomethine ylides have traditionally been generated

bearing various stabilizing substituents such as aryl

groups, esters, and cyano groups. However, the formation

of azomethine ylides without such stabilizing groups has

proven far more difficult. The ground-breaking efforts of

^†Current address: Berry & Associates, Inc., 2434 Bishop Circle

East, Dexter, MI 48130.

^‡Current address: Genomics Institute of Novartis Research Foun-

dation, 10675 J ohn J . Hopkins Dr., San Diego, CA 92121.

(1) (a) Harwood, L. M.; Vickers, R. J . In Synthetic Applications of

1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural

Products; Padwa, A., Pearson, W. H., Eds.; J ohn Wiley & Sons: New

York, 2002; pp 169-252. (b) Kanemasa, S.; Tsuge, O. In Advances in

Cycloaddition; Curran, D. P., Ed.; J AI Press: Greenwich CT, 1993;

Vol. 3, pp 99-159. (c) Grigg, R.; Sridharan, V. In Advances in

Cycloaddition; Curran, D. P., Ed.; J AI Press: Greenwich CT, 1993;

Vol. 3, pp 161-204. (d) Padwa, A. In Comprehensive Organic Synthesis;

Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 4,

pp 1069-1109. (e) Wade, P. A. In Comprehensive Organic Synthesis;

Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 4,

pp 1111-1168. (f) Pearson, W. H. In Studies in Natural Products

Chemistry; Rahman, A., Ed.; Elsevier: Amsterdam, The Netherlands,

1988; Vol. 1, pp 323-358. (g) Vedejs, E. In Advances in Cycloaddition;

Curran, D. P., Ed.; J AI Press: Greenwich, CT, 1988; Vol. 1, pp 33-

51. (h) Lown, W. J . In 1,3-Dipolar Cycloaddition Chemistry; Padwa,

A., Ed.; J ohn Wiley & Sons: New York, 1984; Vol. 1, pp 653-733. (i)

Padwa, A. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.;

J ohn Wiley & Sons: New York, 1984; Vol. 2, pp 227-387.

(2) (a) Vedejs, E.; West, F. G. Chem. Rev. 1986, 86, 941-955. (b)

Vedejs, E.; Martinez, G. R. J . Am. Chem. Soc. 1979, 101, 6452-6454.

(3) Padwa, A.; Chen, Y.-Y. Tetrahedron Lett. 1983, 24, 3447-3450.

(4) (a) Terao, Y.; Aono, M.; Achiwa, K. Heterocycles 1988, 27, 981-

1008. (b) Achiwa, K.; Motoyama, T.; Sekiya, M. Chem. Pharm. Bull.

1983, 31, 3939-3945. (c) Achiwa, K.; Sekiya, M. Chem. Lett. 1981,

1213-1216.

(5) Liddell, J . R. Nat. Prod. Rep. 2002, 19, 773-781.

(6) Michael, J . P. Nat. Prod. Rep. 2002, 19, 719-741.

(7) Obst, U.; Betschmann, P.; Lerner, C.; Seiler, P.; Diederich, F.;

Gramlich, V.; Weber, L.; Banner, D. W.; Schonholzer, P. Helv. Chim.

Acta 2000, 83, 855-909. For a brief review see: Broggini, G.; Gaetano,

Z. Synthesis 1999, 6, 905-917.

(8) Vedejs, E.; Larsen, S.; West, F. G. J . Org. Chem. 1985, 50, 2170-

2174.

(9) Pandey, G.; Lakshmaiah, G. Synlett 1994, 277-278.

Published on Web 02/18/2004

J . Org. Chem. 2004, 69, 1919-1939

1919

Pearson et al.

SCHEME 1. Over a ll Str a tegy To Obta in

In d olizid in es fr om (2-Aza a llyl)sta n n a n es

SCHEME 2. In itia l Attem p ts To Obta in

In d olizid in es via 2-Aza a llyllith iu m

Cycloa d d ition s¹³

adapted a more-stabilized vinylogous version of iminium

desilylation in their elegant approach toward asparaga-

mine A. Several other groups have also reported the

synthesis of pyrrolizidines and indolizidines using non-

stabilized azomethine ylides with methods of varying

generality.¹¹

Although these methods of forming pyrrolizidines and

indolizidines through azomethine ylide cycloadditions

have proven useful, a number of significant limitations

exist in this attractive approach. Most importantly, all

of the methods reported thus far generate azomethine

ylides from preexisting ring structures, which often limits

the accessibility of azomethine ylide precursors and the

convergency of this approach. Furthermore, azomethine

ylide cycloadditions have not yet been applied to the

formation of the 1-aza[5.3.0]bicyclodecane ring system,

despite its prevalence in a growing number of natural

products.¹²Hence, a general method for the rapid as-

sembly of both rings of the 1-aza[m.3.0]bicycloalkane ring

system addressing these limitations would be of great use

in the synthesis of this biologically important class of

structures.

We have previously reported that nonstabilized azo-

methine ylides can be generated from 2-(azaallyl)stan-

nanes and 2-(azaallyl)silanes through a tandem intramo-

lecular N-alkylation/demetalation cascade (Scheme 1).¹³

The resulting azomethine ylides undergo [3+2] cycload-

dition with certain alkenes and alkynes to yield indoliz-

idines and other heterocycles. The 2-(azaallyl)stannanes

and 2-(azaallyl)silanes can also be formed in situ from

the condensation of aldehydes with aminomethylstan-

nanes and aminomethylsilanes, leading to a highly

convergent, multicomponent, one-pot synthesis of 1-aza-

[m.3.0]bicycloalkanes. We now present a full account of

our studies of the efficient construction of indolizidines

and related heterocycles from 2-(azaallyl)stannanes and

2-(azaallyl)silanes via the generation of nonstabilized

azomethine ylides. The geometry and cycloaddition chem-

istry of 1,3-substituted versions of the azomethine ylides

described herein will be discussed in a subsequent report.

Ba ck gr ou n d a n d In itia l Stu d ies

The use of (2-azaallyl)stannanes as azomethine ylide

precursors arose from our investigations into the genera-

tion and [3+2] cycloaddition of nonstabilized 2-azaallyl-

lithiums (i.e. 2-azaallyl anions). We have previously

demonstrated that (2-azaallyl)stannanes undergo tin-

lithium exchange to form 2-azaallyllithiums, which can

cycloadd to certain alkenes to form N-lithiopyrrolidines

and thus N-substituted pyrrolidines upon treatment with

an electrophile.¹⁴We reasoned that by employing a

tethered electrophile, a tandem 2-azaallyllithium cy-

cloaddition/N-alkylation sequence would generate in-

dolizidine structures in one cascade (Scheme 2). Thus,

treatment of (2-azaallyl)stannane 1 with n-BuLi at -78

°C in the presence of typical anionophile traps such as

E-stilbene and phenyl vinyl sulfide yielded indolizidines

3 and 4 via 2-azaallyllithium 2.¹³

The modest yield of these transformations prompted

us to explore an alternative strategy wherein intra-

molecular N-alkylation of 1 was allowed to occur first in

refluxing toluene followed by destannylation of the

resultant iminium intermediate 5 to generate a nonsta-

bilized azomethine ylide 6 (Scheme 3). Cycloaddition of

6 with N-phenylmaleimide yielded the indolizidine 7 in

good yield as a 1:1 mixture of exo and endo diastereo-

mers.¹³

(10) Epperson, M. T.; Gin, D. Y. Angew. Chem., Int. Ed. 2002, 41,

1778-1780.

(11) For pyrrolizidines or indolizidines made from nonstabilized

azomethine ylides (i.e. bearing only hydrogens or alkyl groups) see:

(a) Castulik, J .; Marek, J .; Mazal, C. Tetrahedron 2001, 57, 8339-

8347. (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) Chastanet, J .; Roussi, G. J . Org. Chem. 1988, 53, 653-659.

(f) Chastanet, J .; Roussi, G. J . Org. Chem. 1988, 53, 3808-3812. (g)

Tsuge, O.; Kanemasa, S.; Ohe, M.; Takenaka, S. Bull. Chem. Soc. J pn.

1987, 60, 4079-4089. (h) Vedejs, E.; West, F. G. J . Org. Chem. 1983,

48, 4773-4774. (i) Terao, Y.; Imai, N.; Achiwa, K.; Sekiya, M. Chem.

Pharm. Bull. 1982, 30, 3167-3171. (j) Eschenmoser, A. Chem. Soc.

Rev. 1976, 5, 377.

Ample precedence existed for the initial intramolecular

N-alkylation of an imine by a tethered alkyl halide.¹⁵The

subsequent destannylation of iminium salts to form

azomethine ylides had not been previously reported.

(12) (a) Pilli, R. A.; Ferreira de Oliveira, M. C. Nat. Prod. Rep. 2000,

17, 117-127. (b) Morita, H.; Arisaka, M.; Yoshida, N.; Kobayashi, J .

Tetrahedron 2000, 56, 2929-2934. (c) Garraffo, H. M.; J ain, P.; Spande,

T. F.; Daly, J . W.; J ones, T. H.; Smith, L. J .; Zottig, V. E. J . Nat. Prod.

2001, 64, 421-427.

(14) (a) Pearson, W. H.; Stoy, P. Synlett 2003, 903-921. (b) Pearson,

W. H.; Szura, D. P.; Postich, M. J . J . Am. Chem. Soc. 1992, 114, 1329-

1345.

(15) (a) Pearson, W. H.; Lin, K.-C. Tetrahedron Lett. 1990, 31, 7571-

7574. (b) Evans, D. A. J . Am. Chem. Soc. 1970, 92, 7593-7595.

(13) Pearson, W. H.; Mi, Y. Tetrahedron Lett. 1997, 38, 5441-5444.

1920 J . Org. Chem., Vol. 69, No. 6, 2004

Synthesis of Indolizidines and Related Heterocycles

TABLE 1. Exp lor a tion of Rea ction Con d ition s

SCHEME 3. N-Alk yla tion /Desta n n yla tion Ca sca d e

to In d olizid in es¹³

solvent

(0.1 M)

temp

(°C)

time

(h)

yield^a

(%)

entry

sm

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

1

11

toluene

110

100

65

25

40

60

6

18

6

2

6

14

6

24

6

14

6

77

67

78

58

78

84

0

74

71

62

13

57

52

75

68

0

However, the desilylation of N-(trimethylsilyl)methyl

iminium salts with reactive fluoride reagents has become

the most general method for the generation of nonstabi-

lized azomethine ylides.^1a,d-g,2-4These N-(trimethylsilyl)-

methyl iminium ions are generated through the inter-

molecular N-alkylation or N-acylation of imines, imidates,

or thioimidates.^1a,d-g,2,4A related method investigated by

Padwa generates silyl-substituted iminium ions from the

silver(I) fluoride-promoted decyanation of N-cyanom-

ethyl-N-(trimethylsilyl)methylamines^3,16or from Lewis

acid-induced ionization of N-methoxymethyl-N-(trimeth-

ylsilyl)methylamines.¹⁷Similarly, the oxidative double-

desilylation of bis-N-(trimethylsilyl)methylamines with

silver(II) fluoride developed by Pandey also presumably

proceeds through an N-(trimethylsilyl)methyl iminium

intermediate.¹⁸Since our initial communication of this

work, we have also described the generation and cycload-

dition of nonstabilized N-unsubstituted azomethine ylides

through an N-protonation/demetalation sequence of

2-(azaallyl)stannanes and 2-(azaallyl)silanes by treat-

ment with HF-pyridine or pyridinium p-toluenesulfonate.¹⁹

The most relevant observation to the present study is

the finding of Achiwa and co-workers that aryl-substi-

tuted (2-azaallyl)silanes can undergo intermolecular N-

alkylation/desilylation with alkyl halides and tosylates

to generate aryl-stabilized azomethine ylides.²⁰However,

nonstabilized (i.e. bearing only alkyl groups) or intramo-

lecular variants have not been described, nor have

examples been reported that bear enolizable hydrogens.

Achiwa’s method obviates the need for an external

fluoride source for desilylation, although it appears that

the reaction proceeds only in highly donating solvents

such as HMPA, DMPU, or DMF.

toluene

toluene (0.5 M)

toluene^b

1,4-dioxane

THF

8 + 9

8 + 10

8 + 9

8 + 10

8 + 9

THF

CH₂Cl₂

DMF

pyridine

ethanol

none

115

25

78

110

0

a

Isolated yields of 1:1 ratio of exo/endo diastereomers (sepa-

rable). With KF-Celite present during the reaction.

b

an intramolecular N-alkylation/ring-opening sequence of

2-(4-bromobutyl)-5-ethoxy-1,3-oxazoles and formed 5,6,7,8-

tetrahydroindolizines after trapping with dipolarophiles.

Additionally, Bora and co-workers recently reported a

three-component, one-pot synthesis of indolizines through

pyridinium-derived stabilized azomethine ylides.²²

A

novel three-component synthesis of pyrrolidines featuring

ester-stabilized azomethine ylides derived from the ru-

thenium and copper-catalyzed reaction of R-diazoesters

and N-benzylideneimines has recently been indepen-

dently disclosed by Li and co-workers²³and Galliford and

co-workers.²⁴The studies of Bora,²²Li,²³and Galliford²⁴

are illustrative of the growing impact of multicomponent

reactions²⁵(MCR) on the synthesis of heterocyclic struc-

tures.

Also of note are the studies of Hassner and Fischer,²¹

who generated ester-stabilized azomethine ylides through

Resu lts a n d Discu ssion

Before the [3+2] cycloaddition cascade in Scheme 1

could be realized, a convenient synthesis of the necessary

(2-azaallyl)stannanes bearing a tethered leaving group

had to be established. The preparation of various (2-

azaallyl)stannanes had previously been developed in our

(16) (a) Padwa, A.; Fryxell, A.; Gasdaska, J . R.; Venkatramanan,

M. K. J . Org. Chem. 1989, 54, 644-653. (b) Padwa, A.; Eisenbarth,

P.; Venkatramanan, M. K.; Wong, G. S. K. J . Org. Chem. 1987, 52,

2427-2432. (c) Padwa, A.; Chen, Y.-Y.; Dent, W.; Nimmesgern, H. J .

Org. Chem. 1985, 50, 4006-4014. (d) Padwa, A.; Chen, Y.-Y.; Chiacchio,

U.; Dent, W. Tetrahedron 1985, 41, 3529-3535.

(17) Padwa, A.; Dent, W. J . Org. Chem. 1987, 52, 235-244.

(18) Pandey, G.; Laha, J . K.; Lakshmaiah, G. Tetrahedron 2002, 58,

3525-3534 and references therein.

(19) (a) Pearson, W. H.; Clark, R. B. Tetrahedron Lett. 1999, 40,

4467-4471. (b) Clark, R. B.; Pearson, W. H. Org. Lett. 1999, 1, 349-

352.

(22) Bora, U.; Saikia, A.; Boruah, R. C. Org. Lett. 2003, 5, 435-

438.

(23) Li, G.-Y.; Chen, J .; Yu, W.-Y.; Hong, W.; Che, C.-M. Org. Lett.

2003, 5, 2153-2156.

(24) Galliford, C. V.; Beenen, M. A.; Nguyen, S. T.; Scheidt, K. A.

Org. Lett. 2003, 5, 3487-3490.

(25) For reviews see: (a) Domling, A.; Ugi, I. Angew. Chem., Int.

Ed. 2000, 39, 3168-3210. (b) Armstrong, R. W.; Combs, A. P.; Tempest,

P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123-

131. (c) Weber, L.; Illgen, K.; Almstetter, M. Synlett 1999, 366-374.

(20) (a) Imai, N.; Achiwa, K. Chem. Pharm. Bull. 1987, 35, 593-

601. (b) Achiwa, K.; Imai, N.; Inaoka, T.; Sekiya, M. Chem. Pharm.

Bull. 1984, 32, 2878-2881.

(21) Hassner, A.; Fischer, B. J . Org. Chem. 1992, 57, 3070-3075.

J . Org. Chem, Vol. 69, No. 6, 2004 1921

Pearson et al.

TABLE 2. Com p a r ison of Lea vin g Gr ou p a n d Rin g Size for Non en oliza ble Im in es

a

b

d

All reactions performed at 0.1 M. 1:1 endo/exo ratio of diastereomers in all cases. ^cIsolated yields. Ts ) p-toluenesulfonate. ^e5

mol % of Bu₄NI. ^fDiastereomers not separated. 1.0 equiv of KI. 0.05 M.

g

h

laboratories through the condensation of aldehydes and

(tri-n-butylstannyl)methylamines using 4 Å molecular

sieves in ether.^14a,26We found that this method could be

applied to the synthesis of (2-azaallyl)stannanes 1 by

using 5-chloro-2,2-dimethylpentanal²⁷8 and (tri-n-butyl-

stannyl)methylamine^26b,289 (Table 1). The (2-azaallyl)-

stannanes produced in this way were used immediately

after preparation without further purification. For a

comparison of tin and silicon in the cycloaddition cascade,

we also formed (2-azaallyl)silane 11 from the condensa-

tion of 8 and commercially available (trimethylsilyl)-

methylamine 10. To simplify our initial studies into the

cascade process, enolizable hydrogens on the imines were

purposefully replaced by methyl groups to prevent pos-

sible enamine formation (vida infra).

7 was isolated in a 1:1 ratio of exo and endo diastereo-

mers (entry 1, Table 1). The cycloaddition with (2-

azaallyl)silane 11 proceeded under identical conditions

in 67% yield, demonstrating that N-(trimethylsilyl)-

methyl iminium species can be desilylated by chloride

at elevated temperatures in nonpolar solvents without

the necessity of aryl stabilizing groups (entry 2). Although

most previous work has employed anhydrous sources of

fluoride anion to desilylate N-(trimethylsilyl)methyl imi-

nium species, desilylation by chloride^4b,c,17and water^29,30

has also been observed in several instances.

Conveniently, the aldehyde, amine, and dipolarophile

could be mixed together in a 3-component, one-pot

procedure (entries 3 and 4). The good yields obtained in

these one-pot reactions showed that at least 1 equiv of

water could be tolerated. Although the tolerance of some

When 1 was heated in toluene at reflux with N-

phenylmaleimide a 77% yield of indolizidine cycloadduct

(29) (a) Tsuge, O.; Kanemasa, S.; Yamada, T.; Matsuda, K. J . Org.

Chem. 1987, 52, 2523-2530. (b) Tsuge, O.; Kanemasa, S.; Hatada, A.;

Matsuda. K. Bull. Chem. Soc. J pn. 1986, 59, 2537-2545. (c) Tsuge,

O.; Kanemasa, S.; Yamada, T.; Matsuda, K. Heterocycles 1985, 23,

2489-2492. (d) Tsuge, O.; Kanemasa, S.; Hatada, A.; Matsuda, K.

Chem. Lett. 1984, 801-804.

(26) (a) Pearson, W. H.; Aponick, A. Org. Lett. 2001, 3, 1327-1330.

(b) Pearson, W. H.; Postich, M. J . J . Org. Chem. 1992, 57, 6354-6357.

(27) Le Borgne, J .-F. J . Organomet. Chem. 1976, 122, 123-128.

(28) See the Supporting Information for an improved procedure for

the preparation of 9.

(30) Torii, S.; Okumoto, H.; Genba, A. Chem. Lett. 1996, 747-748.

1922 J . Org. Chem., Vol. 69, No. 6, 2004

Synthesis of Indolizidines and Related Heterocycles

water in azomethine ylide cycloadditions is known^29,30as

in the case of the condensation of secondary R-amino

acids and aldehydes,^11b,31it is more rare for nonstabilized

azomethine ylides.³²Addition of activated 4 Å molecular

sieves did not effect the outcome of the one-pot cycload-

dition cascade.

SCHEME 4. Syn th esis of Ald eh yd es Used in Ta ble 2

Increasing the reaction time or the concentration did

not greatly affect the yield of the reaction (entries 5 and

6). Other solvents, such as 1,4-dioxane, THF, and pyri-

dine, proved suitable for the reaction at elevated tem-

peratures (entries 8, 9, and 14). In the case of (tri-n-

butylstannyl)methylamine 9, the solvents THF, pyridine,

dimethylformamide, and methylene chloride gave good

yields of cycloadduct at or near room temperature,

although longer reaction times were necessary (entries

10, 12, 13, and 15). When (trimethylsilyl)methylamine

10 was used at ambient temperature (entry 11), a very

low yield of cycloadduct 7 was obtained. This result may

indicate desilylation is not as efficient as destannylation

at ambient temperatures.

No cycloadduct was detected when the reaction was

performed in ethanol or in the absence of solvent (entries

16 and 17). Although stannane byproducts made chro-

matographic purification of cycloadducts troublesome in

certain cases, treatment of the crude reaction mixture

with KF-Celite³³or KF(aq)/ether often made purification

easier. No cycloadduct was isolated when KF-Celite was

present during the course of the reaction (entry 7).

The effects of varying leaving group and ring size were

also studied by using the one-pot method with noneno-

lizable aldehydes (Table 2). The synthesis of the requisite

aldehyde partners is outlined in Scheme 4. For the

formation of indolizidine 7, it was found that chloride was

the most effective leaving group (entry 1), although the

tosylate gave a moderate yield of cycloadduct 7 in the

case of both tin and silicon (entries 2 and 3). Reactions

with iodide as the leaving group gave poor yields in the

formation of indolizidine 7 accompanied by rapid decom-

position of the starting materials at room temperature

(entry 4).

The homologous 1-aza[5.3.0]bicyclodecane (also known

as pyrrolo[1,2-a]azepine) system is found in an increasing

number of natural products, including those from the

Stemona,^12aCephalotaxus,^12band Dendrobates^12cgenera.

Initial efforts to form this system from 6-chloro-2,2-

dimethylhexanal²⁷14, (tri-n-butylstannyl)methylamine

9, and N-phenylmaleimide were not successful (entries

5-7). This failure is despite several literature reports of

the successful intramolecular alkylation of imines with

primary chlorides to form seven-membered rings.³⁴Heat-

ing 14 and 9 in toluene or pyridine with catalytic iodide

sources gave the desired cycloadduct 15, albeit in poor

yield (entries 8 and 9). It was discovered that heating

6-iodo-2,2-dimethylhexanal 16 with 9 in refluxing pyri-

dine gave cycloadduct 15 in 34% yield (entry 10). Exami-

1

nation of the crude H NMR revealed unwanted elimi-

nation of the iodide as a competing process. Ultimately,

an excellent yield of 15 was obtained when the reaction

was performed in refluxing xylenes (entry 11). To the best

of our knowledge, this constitutes the first synthesis of

this ring system with an azomethine ylide cycloaddition.

The 1-aza[6.3.0]bicyclounadecane structure presents

itself in a number of complex marine alkaloids.³⁵By

heating 7-iodo-2,2-dimethylheptanal 17 with (tri-n-bu-

tylstannyl)methylamine 9 and N-phenylmaleimide in

refluxing xylenes, a modest yield of 18 was obtained

(entry 12). The poor yield is probably due to a difficult

intramolecular N-alkylation step. This ring system has

not previously been made through azomethine ylide

cycloaddition, although Coldham and co-workers³⁶have

recently proposed constructing the 1-aza[6.3.0]bicyclo-

unadecane core of manzamine A through a stabilized

azomethine ylide.

Our efforts next turned to the use of aldehydes with

enolizable hydrogens in the cycloaddition cascade. In

general, methods which generate azomethine ylides

through the initial formation of N-(trimethylsilyl)methyl

iminium salts followed by desilylation by an external

fluoride source often tolerate the presence of enolizable

hydrogens. Examples exist, however, where fluoride

desilylation methods fail due to the presence of enolizable

(31) (a) Grigg, R.; Surendrakumar, S.; Thianpatanagul, S.; Vipond,

D. J . Chem. Soc., Chem. Commun. 1987, 47-49. (b) Grigg, R.; Idle, J .;

McMeekin, P.; Vipond, D. J . Chem. Soc., Chem. Commun. 1987, 49-

51. (c) Tsuge, O.; Kanemasa, S.; Masayuki, O.; Takenaka, S. Bull.

Chem. Soc. J pn. 1987, 60, 4079-4089.

(32) In the generation of nonstabilized azomethine ylides by fluoride-

induced desilylation of N-(trimethylsilyl)methyl iminium salts, the

added fluoride source typically must be anhydrous. See refs 1d and 2.

(33) Savall, B.; Powell, N. A.; Roush, W. R. Org. Lett. 2001, 3, 3057-

3060.

(34) (a) J ansen, A.; Pitter, S. Monatsh. Chem. 1999, 130, 783-794.

(b) Clemens, M.; Meise, W.; Himmel, K.; J ansen, M. Liebigs Ann. Org.

Bioorg. Chem. 1997, 2, 447-457. (c) Meise, W.; Arth, C.; Zlotos, D.;

J ansen, M.; Feldmann, C. Liebigs Ann. Org. Bioorg. Chem. 1994,

1135-1142. (d) Osbond, J . M. J . Chem. Soc. 1951, 3464-3469.

(35) Magnier, E.; Langlois, Y. Tetrahedron 1998, 54, 6201-6258.

(36) Coldham, I.; Crapnell, K. M.; Fernandez, J .-C.; Moseley, J . D.;

Rabot, R. J . Org. Chem. 2002, 67, 6181-6187.

J . Org. Chem, Vol. 69, No. 6, 2004 1923

Pearson et al.

TABLE 3. Com p a r ison of Rin g Size a n d Lea vin g Gr ou p for En oliza ble Im in es

a

b

All reactions run at 0.1 M. 1:1 ratio of exo/endo diastereomers in all cases (separated). ^cIsolated yields.

hydrogens.³⁷When other species induce desilylation, such

as chloride, bromide, iodide, water, and p-toluene-

sulfonate, enolizable hydrogens are typically not toler-

ated. Two interesting exceptions should be noted. Padwa

and Dent have reported one example of azomethine ylide

formation through zinc chloride mediated ionization/

desilylation of N-methoxymethyl-N-(trimethylsilyl)-

methylamine bearing enolizable hydrogens.¹⁷Also, Torii

and co-workers have shown that azomethine ylides can

be formed by simply heating trimethylsilylmethyl sec-

ondary amines and aldehydes in THF.³⁰In Torii’s work,

three examples with enolizable hydrogens are noted. In

general, however, the generation of azomethine ylides by

desilylation of N-(trimethylsilyl)methyl iminium salts

bearing enolizable hydrogens with nonfluoride nucleo-

philes has proved problematic.³⁸

In this context, we were delighted to find that N-(tri-

n-butylstannyl)methyl iminium salts bearing enolizable

hydrogens readily form azomethine ylides without the

need for an external fluoride source (Table 3). The

pyrrolizidine cycloadduct 21 was made in excellent yield

by condensation of 4-chlorobutanal³⁹20 with (tri-n-

butylstannyl)methylamine 9 in refluxing toluene with

N-phenylmaleimide as the dipolarophile (entry 1). When

the same reaction was conducted with (trimethylsilyl)-

methylamine 10, only a trace of cycloadduct 21 was

detected (entry 2). The reaction of 5-bromopentanal⁴⁰22,

9, and N-phenylmaleimide gave a good yield of indolizi-

dine cycloadduct 23 (entry 3). This example demonstrates

the viability of bromide as a leaving group in the

cycloaddition cascade. Finally, the 1-aza[5.3.0]bicyclo-

decane cycloadduct 25 can be made in excellent yield by

reaction of 6-iodohexanal 24,⁴¹9, and N-phenylmaleimide

in refluxing xylenes (entry 4). The analogous silane

version yielded only decomposition (entry 5). Entries 2

and 5 underscore an important difference between the

N-alkylation/destannylation and N-alkylation/desilyla-

tion cycloaddition cascades: the tin version tolerates

enolizable hydrogens but the silicon version does not.

The azomethine ylide generated from the reaction of

1 or 11 also underwent cycloaddition with a variety of

electron-poor dipolarophiles besides N-phenylmaleimide.

Methyl acrylate, methyl maleate, and trans-methyl cin-

nimate all gave good yields of indolizidine cycloadducts

26, 27, and 30 (entries 1, 2, and 6, Table 4). Cycloadducts

30a -c were taken on separately and reduced with

LiAlH₄to hydroxymethylderivatives 32a -c to elucidate

their stereostructure (Scheme 5). When 1 was heated in

toluene with benzaldehyde or benzophenone good yields

of bicyclic oxazolidines 28 and 29 were obtained (entries

3 and 4). A somewhat higher yield of 29 was observed

when silane 11 was used in place of stannane 1 (entry

5).

(37) (a) Fishwick, C. W. G.; J ones, A. D.; Mitchell, M. B. Tetrahedron

Lett. 1989, 30, 4447-4448. (b) Smith, R.; Livinghouse, T. Tetrahedron

1985, 41, 3559-3568. (c) Livinghouse, T.; Smith, R. J . Chem. Soc.,

Chem. Commun. 1983, 210-211.

(38) Smith, R.; Livinghouse, T. J . Org. Chem. 1983, 48, 1554-1555

and refs 29a, 29c, and 37c. Many other reports of water or halide as

desilylating agents for N-(trimethylsilyl)methyl iminiums conspicu-

ously lack enolizable hydrogens. For example see refs 4b, 4c, 20a, 20b,

29b, and 29d.

(39) Hoffmann, H. M. R.; Henning, R. Helv. Chim. Acta 1983, 66,

828-841.

(40) Kulkarni, S. U.; Patil, V. D. Heterocycles 1982, 18, 163-167.

(41) Hon, Y.-S.; Chang, F.-J .; Lu, L.; Lin, W.-C. Tetrahedron 1998,

54, 5233-5246.

1924 J . Org. Chem., Vol. 69, No. 6, 2004

Synthesis of Indolizidines and Related Heterocycles

TABLE 4. Cycloa d d ition s of Electr on -P oor Alk en e a n d Ca r bon yl Dip ola r op h iles^a

a

b

Reaction conditions: toluene, 110 °C, 1-2 equiv of dipolarophile. Isolated yields.

SCHEME 5. Hyd r oxym eth yl Der iva tives of 30a -c

acetylene dicarboxylate (DMAD) and methyl propiolate

proved viable dipolarophiles, generating tetrahydro-

indolizines 33 and 34 after in situ DDQ oxidation (entries

1 and 2, Table 5). Diphenylacetylene and 2-(trimethyl-

silyl)phenylacetylene⁴²gave no detectable cycloadduct

under typical reaction conditions (refluxing toluene).

Phenylacetylene (10 equiv) also yielded no cycloadduct,

although curiously the piperidine 35 was isolated in

moderate yield (entry 3). A similar reaction with aldehyde

22 using the one-pot method gave the analogous known

piperidine 36⁴³as the only identifiable product (entry 4).

The mechanism of these transformations is unclear,

although no deuterium incorporation into piperidine 35

1

was seen by H NMR or GCMS when 2-deuteriophenyl-

Cycloaddition with naphthoquinone under standard reac-

tion conditions with the one-pot protocol, however, gave

only a low yield of oxidized dione 31 (entry 7).

Electron-poor alkynes have been popular dipolaro-

philes in azomethine ylide cycloadditions,^1a,22-24forming

2,5-dihydropyrroles or pyrroles after oxidation. Dimethyl-

acetylene was used or when the reaction was performed

in toluene-d₈. When n-hexylamine was heated with

aldehyde 8 and phenylacetylene, piperidine 37 was

(42) Kurita, J .; Ishii, M.; Yasuike, S.; Tsuchiya, T. J . Chem. Soc.,

Chem. Commun. 1993, 17, 1309-1310.

J . Org. Chem, Vol. 69, No. 6, 2004 1925

Pearson et al.

TABLE 5. Cycloa d d ition s of Alk yn es

a

b

Reaction conditions: refluxing toluene, 0.1-0.3 M. Isolated yield. ^cAfter DDQ oxidation.

formed in 61% yield (entry 5). The formation of piperidine

37 shows that this transformation does not proceed

through the azomethine ylide, but rather probably in-

volves the addition of phenylacetylene or phenylacetylide

to an iminium salt. In the case of entries 3 and 4, the

final piperidines 35 and 36 are likely formed after

protodestannylation of an intermediate (tri-n-butylstan-

nyl)methylamine. The closest precedent to the formation

of 37 may be the recent work of J iang and Si,⁴⁴who

reported the addition of phenylacetylene to imines in

toluene using chlorotrimethylsilane, zinc chloride, and

triethylamine as promoters.

While the azomethine ylides generated from (2-aza-

allyl)stannanes and silanes cycloadd to typical electron-

poor dipolarophiles such as maleimides and acrylates, a

number of electron-rich dipolarophiles were observed to

cycloadd as well, including phenyl vinyl sulfide, styrene,

and triethyl vinyl silane (Table 6). This is an atypical

result for azomethine ylide cycloadditions, although

examples of electron-rich dipolarophiles undergoing in-

verse-electron demand cycloaddition with highly stabi-

lized azomethine ylides exist.⁴⁵Other electron-rich dipo-

larophiles such as ethyl vinyl ether (sealed tube), vinylene

carbonate, and N-vinylpyrrolidinone failed to cycloadd in

refluxing toluene. As is typical for most intermolecular

azomethine ylide cycloadditions, unactivated dipolaro-

philes such as 1-hexene and norbornylene also failed to

cycloadd. In contrast to styrene, no cycloaddition was

detected with E-stilbene as dipolarophile in refluxing

toluene.

Several structural variations on the aldehyde partner

were explored (Scheme 6 and Table 7). The use of

ketimine 40 (not isolated) in place of the usual aldimine

allowed access to the bridgehead-substituted indolizidine

41 in moderate yield (entry 1). The synthesis of such

bridgehead-substituted indolizidines through azomethine

ylide cycloaddition is not very common, but has recently

been accomplished by Epperson and Gin.¹⁰A secondary

bromide leaving group on imine 42 (not isolated), derived

from aldehyde 43, allows access to 5-substituted indolizi-

dine 44, although with a stereorandom outcome (entry

2). A one-pot version of this reaction with 43 and 9

provided 44 in comparible yield and stereoselectivity

(entry 3). The successful formation of the 1-aza[5.3.0]-

bicyclodecane cycloadduct 46 with chloroaldehyde 45

(entry 4) contrasts with the failure of 6-chloro-2,2-

dimethylhexanal 14 to yield any cycloadduct 15 (recall

Table 2, entry 7). This is likely due to the additional cyclic

constraint of the benzo group, as well as the benzylic

nature of the chloride leaving group.

Mech a n ism

What is the mechanism of this cycloaddition cascade?

One can envision two likely reaction pathways: Path 1

(Scheme 7), in which the piperidine ring is formed first,

followed by ylide generation and cycloaddition, or Path

2 (Scheme 7), which begins with ylide formation followed

by cycloaddition, then finally closure of the piperidine

(43) Takahata, H.; Takahashi, K.; Wang, E. C.; Yamazaki, T. J .

Chem. Soc., Perkin Trans. 1 1989, 1211-1214.

(44) J iang, B.; Si, Y.-G. Tetrahedron Lett. 2003, 44, 6767-6768.

(45) For a recent example see: Kusama, H.; Takaya, J .; Iwasawa,

N. J . Am. Chem. Soc. 2002, 124, 11592-11593.

1926 J . Org. Chem., Vol. 69, No. 6, 2004

Synthesis of Indolizidines and Related Heterocycles

TABLE 6. Cycloa d d ition s of Electr on -Rich Alk en es^a

a

b

Reaction conditions: refluxing toluene, 0.1-0.3 M. Isolated yield.

SCHEME 6. Syn th esis of Som e Ald eh yd e P a r tn er s

In mechanism B, a proton source may activate the (2-

azaallyl)stannane or silane to generate the azomethine

ylide (Scheme 9). Tsuge²⁹has shown that water can

initiate a protonation/desilylation sequence of aryl-

stabilized (2-azaallyl)silanes. The work of Torii³⁰has also

suggested that water may be a viable desilylating agent

under certain conditions. The possibility exists therefore

that the water generated from the imine condensation

in the one-pot protocol can initiate Path 2. Thus, (2-

azaallyl)stannane 47 and (2-azaallyl)silane 48 were

formed in situ and heated to reflux in the presence of

N-phenylmaleimide. Only a trace of cycloadduct 49 was

detected in the stannane case (<5% by ¹H NMR) and

none at all in the case of the silyl version, showing that

water cannot effectively initiate Path 2.

We have previously demonstrated that azomethine

ylides can be formed from (2-azaallyl)stannanes and

silanes by protonation/demetalation with HF‚pyridine in

THF or pyridinium p-toluenesulfonate in toluene.¹⁹Since

both R₃MCl and H₂O are present together in the one-pot

protocol, catalytic amounts of HCl may initiate azo-

methine ylide generation. This possibility was explored

by forming the imine in situ, followed by addition of a

substoichiometric amount of R₃MCl (20 mol %). A low

yield (12%) of cycloadduct 49 was obtained in the stan-

nane case, suggesting this may be a contributing, though

probably minor, pathway. In the case of the silane, no

cycloadduct was detected.

ring to form an indolizidine. The initial ylide formation

shown in Path 2 can be postulated by several possible

mechanisms (A, B, and C). To clarify the cascade mech-

anism, we undertook a number of control experiments

using (2-azaallyl)stannanes and silanes without a teth-

ered electrophile.

In mechanism A, the ylide is generated via a 1,2-metal

shift (Scheme 8). Komatsu and co-workers⁴⁶have re-

ported that 1,3-diaryl-substituted (2-azaallyl)silanes can

undergo a 1,2-silyl shift at elevated temperatures (180

°C) to generate stabilized azomethine ylides. We found

that both (2-azaallyl)stannane 47^14band (2-azaallyl)silane

48 did not undergo such a process in refluxing toluene

as evidenced by Scheme 8. In both cases, only starting

material was observed at the end of the reaction.

In mechanism C, chlorotri-n-butylstannane may act as

the electrophile, forming an N-stannyl azomethine ylide

and regenerating the chlorotri-n-butylstannane (Scheme

10). The feasibility of such a catalytic cycle has been

demonstrated by Achiwa and co-workers in the case of

the alkylation of aryl-substituted (2-azaallyl)silanes with

alkyl halides and tosylates,²⁰and in the generation of

(46) (a) Okada, H.; Akaki, T.; Oderaotoshi, Y.; Minakata, S.;

Komatsu, M. Tetrahedron 2003, 59, 197-205. (b) Komatsu, M.; Okada,

H.; Akaki, T.; Oderaotoshi, Y.; Minakata, S. Org. Lett. 2002, 4, 3505-

3508. (c) Komatsu, M.; Ohno, M.; Tsuno, S.; Ohshiro, Y. Chem. Lett.

1990, 575-576.

J . Org. Chem, Vol. 69, No. 6, 2004 1927

Pearson et al.

TABLE 7. Som e Va r ia tion s on th e Ca r bon yl-Con ta in in g P a r tn er ^a

a

b

Reaction conditions: toluene, 110 °C, 0.1-0.3 M, 1.2 equiv of dipolarophile. Isolated yields. ^cDiastereomers not separated.

SCHEME 7. Tw o P ossible Ca sca d e P a th w a ys

SCHEME 8. Mech a n ism A: 1,2-Meta l Sh ift

azomethine ylides with use of catalytic amounts of

chlorotrimethylsilane and trimethylsilyltriflate from aryl-

and amide-substituted (2-azaallyl)silanes.⁴⁷However,

these reactions proceeded only in polar aprotic solvents

such as HMPA and not in nonpolar solvents such as

benzene, which would be more relevent to our present

studies. Komatsu and co-workers have recently investi-

gated the generation of N-silylated azomethine ylides

from the reaction of fluorosilanes with aryl-substituted

R-silylimines (i.e. (2-azaallyl)silanes) in benzene and

THF, also apparently through a catalytic cycle.⁴⁸To

examine the possibility of such a pathway, we treated

(2-azaallyl)stannane 47 with a substoichiometric amount

of Bu₃SnCl (20 mol %) in refluxing toluene with N-

phenylmaleimide present as the dipolarophile trap

(47) Imai, N.; Achiwa, K. Chem. Pharm. Bull. 1987, 35, 12646-

12655.

(48) Komatsu, M.; Okada, H.; Yokoi, S.; Minakata, S. Tetrahedron

Lett. 2003, 44, 1603-1606. Also see ref 46a.

1928 J . Org. Chem., Vol. 69, No. 6, 2004

Synthesis of Indolizidines and Related Heterocycles

SCHEME 9. Mech a n ism B:

SCHEME 11. N-Alk yla tion /Dem eta la tion

P r oton a tion -Dem eta la tion

Exp er im en ts

SCHEME 10. Mech a n ism C: R₃MCl Activa tion

SCHEME 12. En oliza ble Hyd r ogen s in Azom eth in e

Ylid e F or m a tion

enolizable hydrogens, and constitutes a key difference

between the behavior of (2-azaallyl)stannanes and (2-

azaallyl)silanes.

Why do (2-azaallyl)stannanes tolerate enolizable hy-

drogens in the cycloaddition cascade but (2-azaallyl)-

silanes do not? Although we have not yet studied this

aspect in great depth, we hypothesize that in the case of

(2-azaallyl)silanes, deprotonation (k₂) of iminium 51

outpaces desilylation (k₃), leading to enamine 52 rather

than azomethine ylide 53 (Scheme 12). For (2-azaallyl)-

stannanes, the rate of destannylation (k₃) is greater than

that of deprotonation (k₂), presumably because the Sn-C

bond in 54 is much weaker than the Si-C bond in 51.

Although studies comparing the lability of carbon-metal

(Scheme 10). The cycloadduct 49 was isolated in 32%

yield, indicating that the pathway is catalytic and may

be operative in the cycloaddition cascade. In the case of

(2-azaallyl)silane 48, no cycloadduct was detected.

To check the viability of the proposed Path 1, (2-

azaallyl)stannane 47 was treated with benzyl bromide

in refluxing toluene in the presence of N-phenylmaleim-

ide (Scheme 11). A good yield (77%) of the N-benzylated

cycloadduct 50 was obtained, indicating Path 1 is most

likely the predominant mechanism. The (2-azaallyl)silane

48 was similarly treated with benzyl bromide and benzyl

chloride, but no cycloadduct was detected.⁴⁹This result

is in keeping with the complete failure of the cycloaddi-

tion cascade in the case of (2-azaallyl)silanes bearing

(49) Interestingly, Torii (ref 30) reports a successful azomethine ylide

cycloaddition involving the condensation of isobutyraldehyde with

N-(trimethylsilylmethyl)benzylamine in THF, which presumably pro-

ceeds through iminium 51 in Scheme 12. In Torii’s case, water or

hydroxide are the likely desilylating agents, as opposed to chloride or

bromide in our case.

J . Org. Chem, Vol. 69, No. 6, 2004 1929

Pearson et al.

SCHEME 13. N-Ben zylp yr r olid in es via

In ter m olecu la r N-Alk yla tion of

(2-Aza a llyl)sta n n a n es

tuted pyrrolidine ring.^19bIntermolecular N-alkylation of

(2-azaallyl)stannane 57^14bwith benzyl bromide in the

presence of N-phenylmaleimide affords a moderate yield

of spiropyrrolidine 56, demonstrating that ketimines may

be used in the intermolecular N-alkylation mode as well

as aldimines.

F IGURE 1. Hyperconjugation by carbon-metal bonds in

oxonia and iminium cations.

bonds in metal-substituted iminiums have not been

reported, observations regarding metal-substituted oxo-

nia cations have been made by Linderman.⁵⁰In these

studies, a hyperconjugative interaction between an oxo-

nia cation and a Sn-C, Ge-C, or Si-C bond, akin to the

â-element effect, is inferred from product distribution

studies of the diastereoselective addition of nucleophiles

to oxonia cations (Figure 1). In our case, such a hyper-

conjugative interaction in 54 between the Sn-C bond and

neighboring electron-deficient iminium π-system neces-

sarily weakens the Sn-C bond, leading to facile destan-

nylation. This is plausible because the â-element effect

of tin has been found to be at least 10⁴times stronger

than that of silicon and 10³times stronger than that of

germanium.⁵¹On this basis, the reactivity profile of (2-

azaallyl)germanes is more likely to mirror (2-azaallyl)-

silanes than (2-azaallyl)stannanes, although this has not

yet been experimentally investigated. Note, however, that

both nonstabilized (2-azaallyl)stannanes and (2-azaallyl)-

silanes bearing enolizable hydrogens can generate azo-

methine ylides when N-protonated with HF‚pyridine or

p-toluenesulfonic acid.¹⁹It is not clear whether this is

because enamine formation is reversible in the presence

of acid (i.e. k₂∼ k_-2) or for some other reason. A finer

examination of these mechanistic points will require

additional experimentation.

Con clu sion

We have developed a concise synthesis of indolizidines

and related 1-aza[m.3.0]bicycloalkanes from (2-azaallyl)-

stannanes and (2-azaallyl)silanes through an intra-

molecular N-alkylation/demetalation/cycloaddition se-

quence featuring nonstabilized azomethine ylides. The

(2-azaallyl)stannanes and (2-azaallyl)silanes can be made

in situ, leading to a three-component, one-pot cycloaddi-

tion cascade. The method tolerates at least 1 equiv of

water, and can utilize a range of electron-poor and

electron-rich dipolarophiles. When (2-azaallyl)stannanes

are used, enolizable hydrogens on the imine are tolerated.

This convergent approach allows for the rapid assembly

of the 1-aza[m.3.0]bicycloalkane ring system so prevalent

among alkaloidal natural products. In an upcoming

report we will extend these investigations to the confor-

mations and cycloadditions of 1,3-disubstituted azo-

methine ylides.

Exp er im en ta l Section

For general experimental procedures, see the Supporting

Information.

As Scheme 11 demonstrated, the cycloaddition cascade

can be extended to intermolecular N-alkylation of (2-

azaallyl)stannanes to form N-benzylpyrrolidines. Two

additional examples of N-benzylpyrrolidine formation are

provided in Scheme 13. Treatment of the (2-azaallyl)-

stannane 47 with benzyl bromide in refluxing toluene in

the presence of phenyl vinyl sulfone gave pyrrolidine 55

in excellent yield as a mixture of three diastereomers

(5:3:1). Phenyl vinyl sulfone has proven to be a syntheti-

cally useful dipolarophile^19bsince the phenylsulfonyl

group can be reductively removed to give an unsubsti-

5-Ch lor o-2,2-d im et h ylp en t ylid en e[(t r i-n -b u t yl)st a n -

n ylm eth yl]a m in e (1). (Tri-n-butylstannyl)methylamine 9^26b,28

(450 mg, 1.41 mmol) was dissolved in ether (5 mL), then 4 Å

molecular sieves (2 g) and 5-chloro-2,2-dimethylpentanal 8²⁷

(210 mg, 1.41 mmol) were added at room temperature. After

3 h, the mixture was filtered through a pad of Celite and

concentrated at 0 °C. The crude imine 1 was produced as a

light yellow oil (560 mg, 94%) and used immediately in the

cycloaddition reactions without further purification. IR

(neat) 1645 (m) cm^-^{1 1}H NMR (400 MHz, CDCl₃) δ 7.35 [s,

;

4J (^117/119Sn-¹H) ) 8.4 Hz, 1 H], 3.54 (s, 2J (^117/119Sn-¹H) ) 22.1

Hz, 2 H), 3.50 (t, J ) 6.8 Hz, 2 H), 1.78-1.66 (m, 3 H), 1.54-

1.40 (m, 6 H), 1.40-1.24 (m, 7 H), 1.02 (s, 6 H), 0.98-0.80 (m,

15 H); ¹³C NMR (100 MHz, CDCl₃) δ 165.4, 46.7, 45.6, 38.5,

37.7, 29.0, 28.0, 27.8, 27.4, 25.1, 13.7, 9.1.

(50) (a) Linderman, R. J .; Chen, K. J . Org. Chem. 1996, 61, 2441-

2453. (b) Linderman, R. J .; Anklekar, T. V. J . Org. Chem. 1992, 57,

5078-5080. Also see: (c) Cossrow, J .; Rychnovsky, S. D. Org. Lett.

2002, 4, 147-150. (d) Rychnovsky, S. D.; Cossrow, J . Org. Lett. 2003,

5, 2367-2370.

(51) (a) Hagan, G.; Mayr, H. J . Am. Chem. Soc. 1991, 113, 4954-

4961. (b) Lambert, J . B.; Wang, G.-T.; Teramura, D. H. J . Org. Chem.

1988, 53, 5422-5428. (c) Traylor, T. G.; Koermer, G. S. J . Org. Chem.

1981, 46, 3651-3657.

(1R*,2R*,8a R*)- or (1R*,2R*,8a S*)-Oct a h yd r o-8,8-d i-

m eth yl-1,2-d ip h en ylin d olizin e (3). Imine 1 (300 mg, 0.67

mmol) and trans-stilbene (183 mg, 1.05 mmol) were dissolved

in THF (2 mL) and cooled to -78 °C. The mixture was treated

with n-butyllithium (0.80 mL of a 2.1 M solution in hexane,

1.68 mmol) over 5 min. After 1 h, the reaction was warmed to

1930 J . Org. Chem., Vol. 69, No. 6, 2004

Synthesis of Indolizidines and Related Heterocycles

room temperature, diluted with water, and extracted with CH₂-

Cl₂(3×). The combined organic layers were washed with brine

(1×), dried (MgSO₄), and concentrated. The residue was

chromatographed (20% ethyl acetate/hexanes) to provide 75

mg (31%) of the title compound as a yellow oil. R_f) 0.30 (20%

ethyl acetate/hexanes); ¹H NMR (360 MHz, CDCl₃) δ 7.30-

7.15 (m, 10 H), 3.72 (t, J ) 7.8 Hz, 1 H), 3.55-3.45 (m, 1 H),

3.85-3.75 (m, 2 H), 2.28 (t, J ) 7.8 Hz, 1 H), 2.21 (d, J ) 7.0

Hz, 1 H), 1.90 (m, 1 H), 1.70 (m, 1 H), 1.50-1.40 (m, 1 H),

1.25-1.18 (m, 1 H), 1.15-1.10 (m, 1 H), 0.85 (s, 3 H), 0.24 (s,

3 H); ¹³C NMR (90 MHz, CDCl₃) δ 130.6, 128.4, 127.4, 126.2,

126.1, 77.8, 64.6, 56.6, 55.9, 52.1, 43.3, 28.1, 22.0, 21.5; MS

(EI, 70 eV) m/z (rel intensity) 305 (M⁺, 1.0), 178 (PhCCPh⁺,

22), 125 ([M - PhCHdCHPh]⁺, 14); HRMS (CI, CH₄, and NH₃)

calcd for C₂₂H₂₈N ([M + H]⁺) 306.2222, found 306.2209. The

stereochemistry at C(8a) could not be determined, and it is

assumed the two phenyl groups retain the trans geometry of

the alkene.

Octa h yd r o-8,8-d im eth yl-1-(p h en ylth io)in d olizin e a n d

Octa h yd r o-8,8-d im eth yl-2-(p h en ylth io)in d olizin e (4). A

solution of the imine 1 (210 mg, 0.47 mmol) and phenyl vinyl

sulfide (129 mg, 0.95 mmol) in THF (2 mL) was added to a

solution of n-butyllithium (0.58 mL of a 2.1 M solution in

hexane, 1.22 mmol) in THF (6.2 mL) over 10 min at -78 °C.

After 1.5 h, the reaction was warmed to room temperature,

diluted with water, and extracted with CH₂Cl₂(3×). The

combined organic layers were washed with brine (1×), dried

(MgSO₄), and concentrated. The residue was chromatographed

(20% ethyl acetate/hexanes) to afford 50 mg (41%) of the title

compound as a yellow oil containing two inseparable isomers

(1:1.1 by NMR integration). The regio- and stereochemistry

could not be determined. R_f) 0.25 (20% ethyl acetate/

hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.35-7.20 (m), 7.20-

7.10 (m), 3.75-3.65 (m), 3.50-3.40 (m), 3.10-3.00 (m), 3.00-

2.90 (m), 2.30-2.10 (m), 2.10-1.95 (m), 1.95-1.85 (m), 1.80-

1.60 (m), 1.50-1.35 (m), 1.25-1.10 (m), 1.05 (s), 1.00 (s), 0.90

(s), 0.82 (s); ¹³C NMR (90 MHz, CDCl₃) δ 129.2, 129.0, 128.9,

128.8, 125.9, 125.6, 77.5, 71.5, 62.2, 53.6, 53.5, 53.3, 44.0, 40.1,

40.0, 39.4, 33.9, 33.5, 29.5, 28.8, 22.3, 22.2, 19.8, 19.2; MS (EI,

70 eV) m/z (rel intensity) 261 (M⁺, 26), 246 ([M - CH₃]⁺, 4),

192 ([M - C₅H₉]⁺, 38), 177 ([M - C₆H₁₁]⁺, 34), 152 ([M - SPh]⁺,

100), 125 ([M - CH₂CHSPh]⁺, 21), 77 (Ph⁺, 6); HRMS (EI, 70

eV) calcd for C₁₆H₂₃NS (M⁺) 261.1551, found 261.1551.

The title compound was also prepared by heating imine 1

(330 mg, 0.73 mmol) and phenyl vinyl sulfide (150 mg, 1.1

mmol) in toluene (3 mL) at reflux for 14 h. The reaction was

concentrated and chromatographed (25% ethyl acetate/hex-

anes) to gave 117 mg (61%) of the title compound as a yellow

oil that contained three inseparable isomers (1:1:1 by NMR

integration). The regio- and stereochemistry could not be

determined. Partial data: ¹H NMR (400 MHz, CDCl₃) δ 7.35-

7.10 (m, 5 H), 3.75-3.60 (m, 2 H × 0.33), 3.55-3.40 (m, 2 H ×

0.33), 3.12-2.90 (m, 5 H × 0.33), 2.48 (t, J ) 9.5 Hz, 1 H ×

0.33), 2.30-2.12 (m, 3 H × 0.33), 2.12-1.60 (m, 15 H × 0.33),

1.58-1.40 (m, 6 H × 0.33), 1.20-1.10 (m, 2 H × 0.33), 1.05 (s,

3 H × 0.33), 1.00 (s, 3 H × 0.33), 0.96 (s, 3 H × 0.33), 0.92 (s,

3 H × 0.33), 0.85 (s, 6 H × 0.33); ¹³C NMR (100 MHz, CDCl₃)

δ 129.3, 129.0, 128.9, 128.8, 128.7, 126.0, 125.6, 77.5, 73.1, 71.5,

62.5, 62.2, 53.6, 53.5, 53.3, 44.0, 40.2, 40.1, 39.9, 39.4, 39.3,

33.8, 33.5, 33.3, 33.0, 32.3, 32.1, 29.5, 28.9, 28.8, 22.3, 22.1,

22.0, 19.8, 19.3, 19.2.

(3a S*,9a R*,9bR*)- (7a ) a n d (3a R*,9a R*,9bS*)-Octa h y-

d r o-9,9-d im et h yl-2-p h en yl-1H -p yr r olo[3,4-a ]in d olizin e-

1,3(2H)-d ion e (7b). Imine 1 (100 mg, 0.22 mmol) and N-phen-

ylmaleimide (40 mg, 0.23 mmol) were heated in toluene (1 mL)

at reflux for 3 h. The reaction was concentrated and the residue

chromatographed (30% to 40% ethyl acetate/hexanes, gradient)

to afford 25 mg (38%) of 7a as a clear oil, followed by 27 mg

(40%) of 7b as a yellow oil.

Hz, 1 H, H-9b), 3.22 (dd, J ) 8.2, 6.6 Hz, 1 H, H-3a), 3.16-

3.13 (m, 1 H), 2.25 (dd, J ) 9.3, 6.6 Hz, 1 H), 2.02 (d, J ) 8.8

Hz, 1 H, H-9a), 1.86-1.79 (m, 1 H), 1.76-1.65 (m, 1 H), 1.46-

1.39 (m, 2 H), 1.24 (s, 3 H), 1.10 (dt, 1 H), 1.00 (s, 3 H); ¹³C

NMR (90 MHz, CDCl₃, J MOD) δ 178.2 (-), 177.6 (-), 129.1

(+), 128.5 (+), 126.5 (+), 76.6 (+), 57.2 (-), 54.2 (-), 46.4 (+),

44.3 (+), 42.6 (-), 33.4 (-), 27.2 (+), 21.3 (-), 19.6 (+); MS

(EI, 70 eV) m/z (rel intensity) 298 (M⁺, 49), 283 ([M - CH₃]⁺,

14), 269 ([M - C₂H₅]⁺, 36), 229 ([M - C₅H₉]⁺, 100), 214 (M -

C₆H₁₂]⁺, 14), 173 ([N-phenylmaleimide]⁺, 16); HRMS (EI, 70

eV) calcd for C₁₈H₂₂N₂O₂(M⁺) 298.1681, found 298.1689.

7b (exo): R_f) 0.21 (30% ethyl acetate/hexanes, stained with

I₂); IR (CHCl₃) 1713 (s) cm^-^{1 1}H NMR (360 MHz, CDCl₃) δ

;

7.50-7.24 (m, 5 H), 3.56 (dd, J ) 9.0, 8.9 Hz, 1 H), 3.44 (q, J

) 8.9 Hz, 1 H, H-3a), 3.23 (dd, J ) 8.9, 8.4 Hz, 1 H, H-9b),

3.10-3.02 (m, 1 H), 2.30 (t, J ) 8.9 Hz, 1 H), 2.01 (td, J )

13.1, 3.0 Hz, 1 H), 1.95 (d, J ) 8.1 Hz, 1 H, H-9a), 1.76-1.62

(m, 1 H), 1.55-1.45 (m, 2 H), 1.22-1.14 (m, 1 H), 1.12 (s, 3

H), 1.03 (s, 3 H); ¹³C NMR (90 MHz, CDCl₃, J MOD) δ 176.7

(-), 176.5 (-), 129.1, 128.5 (+), 126.54 (+), 126.49 (+), 75.1

(+), 56.7 (-), 52.8 (-), 46.9 (+), 43.6 (+), 39.6 (-), 33.0 (+),

29.0 (-), 21.8 (+), 19.7 (-); MS (EI, 70 eV) m/z (rel intensity)

298 (M⁺, 43), 283 ([M - CH₃]⁺, 14), 229 ([M - C₅H₉]⁺, 100);

HRMS (EI, 70 eV) calcd for C₁₈H₂₂N₂O₂(M⁺) 298.1681, found

298.1685. The stereochemical assignment of 7a and 7b was

based on two-dimensional (2D) COSY and NOESY experi-

ments. For 7a , there were NOE cross-peaks between the

resonances corresponding to H-9a and H-9b, H-9b and H-3a.

For 7b, there was an NOE cross-peak between the H-9b and

H-3a resonance. However, no NOE cross-peak was observed

between H-9a and H-9b.

5-Ch lor o-2,2-d im eth ylp en ta n a l (8). According to a modi-

fication of the procedure described by Le Borgne,²⁷diisopro-

pylamine (3.97 g, 39.2 mmol) and anhydrous THF (40 mL)

were cooled to 0 °C and treated with n-butyllithium (13.0 mL

of a 2.5 M solution in hexanes, 32.5 mmol). After 30 min at 0

°C, N-cyclohexyl(2-methylpropylidene)amine²⁷(5.00 g, 32.6

mmol) was added at 0 °C with an additional amount of THF

(5 mL). After 30 min at 0 °C, 1-bromo-3-chloropropane (5.13

g, 32.6 mmol) was added dropwise over 1 min at 0 °C. After

10 min at 0 °C, the solution was quenched with saturated

aqueous NH₄Cl and concentrated. Ether and water were added

and the pH was adjusted to 5 with H₃PO₄. The biphasic

mixture was stirred at room temperature for 4 h with H₃PO₄

being added as needed to readjust the pH to 5. The aqueous

phase was extracted with ether (3×), washed with 2% H₃PO₄

(2×) and brine (1×), dried (Na₂SO₄), and concentrated at room

temperature. The residue was chromatographed (pentane to

5% ether/pentane, gradient) to yield 2.97 g (61%) of aldehyde

8 as a clear, colorless oil. R_f) 0.20 (5% ether/pentane, stains

black in phosphomolybdic acid); alternatively, aldehyde 8 could

be purified by distillation (bp 70-76 °C/10 mmHg, lit.²⁷bp 4

1

°C/15 mmHg); IR (CHCl₃) 1723 (s) cm^-1; H NMR (300 MHz,

CDCl₃) δ 9.46 (s, 1 H), 3.54 (t, J ) 6.8 Hz, 2 H), 1.78-1.56 (m,

4 H), 0.19 (s, 6 H); ¹³C NMR (75 MHz, CDCl₃) δ 206.5, 45.1,

34.5, 27.8, 21.8; MS (CI, CH₄) m/z (rel intensity) 149 ([M +

H]⁺, 64), 133 ([M - CH₃]⁺, 10), 113 ([M - Cl]⁺, 100); HRMS

(CI, CH₄) calcd for C₇H₁₄³⁵ClO ([M + H]⁺) 149.0733, found

149.0736.

5-C h lo r o -2,2-d im e t h y lp e n t y lid e n e (t r im e t h y ls ily l-

m eth yl)a m in e (11). 5-Chloro-2,2-dimethylpentanal 8²⁷(122

mg, 0.82 mmol) was added to a solution of (trimethylsilyl)-

methylamine 10 (85 mg, 0.82 mmol) in ether (3 mL), followed

by 4 Å molecular sieves (1 g) and allowed to stir at room

temperature. After 18 h, the mixture was filtered through a

pad of Celite and concentrated at 0 °C to provide 178 mg (93%)

of the title compound as a light yellow oil: IR (neat) 1654 (m)

1

cm^-1; H NMR (400 MHz, CDCl₃) δ 7.32 (t, J ) 1.4 Hz, 1 H),

3.50 (t, J ) 6.7 Hz, 2 H), 3.11 (d, J ) 1.4 Hz, 2 H), 1.78-1.68

(m, 2 H), 1.52-1.46 (m, 2 H), 1.03 (s, 6 H), 0.005 (s, 9 H); ¹³C

NMR (100 MHz, CDCl₃) δ 167.9, 53.3, 45.5, 38.6, 37.4, 27.9,

26.3, 25.0, -2.9.

7a (endo): R_f) 0.29 (30% ethyl acetate/hexanes, stained

with I₂); IR (CHCl₃) 1709 (s) cm^-1; ¹H NMR (360 MHz, CDCl₃)

δ 7.48-7.25 (m, 5 H), 3.59 (d, J ) 9.3 Hz, 1 H), 3.35 (t, J ) 8.6

J . Org. Chem, Vol. 69, No. 6, 2004 1931

Pearson et al.

Tolu en e-4-su lfon ic Acid 4,4-Dim eth yl-5-oxop en tyl es-

ter (12). Diisopropylamine (393 mg, 7.84 mmol) and anhy-

drous THF (10 mL) were cooled to 0 °C and treated with

n-butyllithium (2.87 mL of a 2.5 M solution in hexanes, 7.18

mmol). After 30 min at 0 °C, N-cyclohexyl(2-methylpropylide-

ne)amine²⁷(1.00 g, 6.53 mmol) was added at 0 °C with an

additional amount of THF (5 mL). After 30 min at 0 °C, this

solution was added to a solution of 1,3-propanediol-1,3-di-p-

toluenesulfonate (2.51 g, 6.53 mmol) in THF (10 mL) via

cannula over 1 min at 0 °C. After 30 min at 0 °C, the solution

was quenched with saturated aqueous NH₄Cl and concen-

trated. Ether and water were added and the pH was adjusted

to 5 with H₃PO₄. The biphasic mixture was stirred at room

temperature for 4 h with H₃PO₄being added as needed to

readjust the pH to 5. The aqueous phase was extracted with

ether (3×), washed with 2% H₃PO₄(2×) and brine (1×), dried

(Na₂SO₄), and concentrated at room temperature. The residue

was chromatographed (pentane to 5% ether/pentane, gradient)

to yield 443 mg (24%) of aldehyde 12 as a clear, colorless oil.

R_f) 0.25 (30% ether/pentane, stained black with phosphomo-

lybdic acid); IR (CH₂Cl₂) 2701 (m), 1724 (s), 1356 (s), 1175 (s)

intensity) 313 ([M + H]⁺, 100); HRMS (CI-NH₃) calcd for

C

₁₉H₂₄N₂O₂Na ([M + H]⁺) 313.1916, found 313.1920.

6-Iod o-2,2-d im eth ylh exa n a l (16). Sodium iodide (1.19 g,

7.96 mmol) was added to a solution of 6-chloro-2,2-dimethyl-

hexanal 14²⁷(259 mg, 1.59 mmol) in anhydrous acetone (5 mL)

and heated to reflux in the dark. After 10 h, the reaction was

diluted with ether, washed with 5% Na₂SSO₃(1×) and brine

(1×), dried (MgSO₄), and concentrated at room temperature

to yield 374 mg (93%) of iodoaldehyde 16 as a colorless oil that

was sufficiently pure to be used without further purification.

An analytical sample was purified by chromatography (pen-

tane to 5% ether/pentane, gradient). R_f) 0.40 (5% ether/

pentane, stained black in phosphomolybdic acid); IR (CH₂Cl₂)

2693 (m), 1724 (s) cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 9.46 (s,

1 H), 3.19 (t, J ) 7.0 Hz, 2 H), 1.82 (quint, J ) 7.3 Hz, 2 H),

1.51-1.46 (m, 2 H), 1.38-1.29 (m, 2 H), 1.07 (s, 6 H); ¹³C NMR

(100 MHz, CDCl₃) δ 206.0, 45.7, 35.8, 33.7, 25.2, 21.3, 6.4; MS

(EI, 70 eV) m/z (rel intensity) 254 (M⁺, 2), 225 ([M - CHO]⁺,

20), 183 (C₄H₈I⁺, 33), 169 (C₃H₆I⁺, 30), 155 (C₂H₄I⁺, 34), 127

(I⁺, 66), 97 (C₇H₁₄⁺, 54), 55 (C₄H₇⁺, 100); HRMS (ESI) calcd

for C₈H₁₆OI ([M + H]⁺) 255.0246, found 255.0251.

1

cm^-1; H NMR (500 MHz, CDCl₃) δ 9.39 (s, 1 H), 7.78 (d, J )

7-Iod o-2,2-d im eth ylh ep ta n a l (17). Sodium iodide (2.38 g,

15.8 mmol) was added to a solution of 7-chloro-2,2-dimethyl-

heptanal 19 (700 mg, 3.96 mmol) in anhydrous acetone (10

mL) and heated to reflux in the dark. After 12 h, the reaction

was diluted with ether, washed with 5% Na₂SSO₃(1×), water

(1×), and brine (1×), dried (Na₂SO₄), and concentrated at room

temperature. The residue was chromatographed (pentane to

5% ether/pentane, gradient) to yield 704 mg (66%) of iodo-

aldehyde 17 as a colorless oil. Attempts at Ku¨gelrohr distil-

lation (100 °C, 1.0 mmHg) led to partial decomposition. R_f)

0.40 (5% ether/pentane, stained black in phosphomolybdic

acid); IR (CH₂Cl₂) 2694 (m), 1725 (s) cm^-1; ¹H NMR (400 MHz,

CDCl₃) δ 9.45 (s, 1 H), 3.18 (t, J ) 7.0 Hz, 2 H), 1.82 (quint, J

) 7.3 Hz, 2 H), 1.50-1.45 (m, 2 H), 1.39 (quint, J ) 7.3 Hz, 2

H), 1.27-1.19 (m, 2 H), 1.05 (s, 6 H); ¹³C NMR (100 MHz,

CDCl₃) δ 206.21, 45.74, 36.96, 33.20, 31.00, 23.25, 21.29, 6.81;

MS (EI, 70 eV) m/z (rel intensity) 239 ([M - CHO]⁺, 11), 197

(ICH₂CH₂CH₂CH₂CH₂⁺, 11), 183 (ICH₂CH₂CH₂CH₂⁺, 16), 169

(ICH₂CH₂CH₂⁺, 11), 155 (ICH₂CH₂⁺, 16), 141 (ICH₂⁺, 20), 49

(100); HRMS (ESI) calcd for C₉H₁₇OINa ([M + Na]⁺) 291.0222,

found 291.0222.

(3a S*,3bR*,10a R*)- (18a ) a n d (3a S*,3bS*,10a R*)-4,4-

Dim et h yl-2-p h en yld eca h yd r o-2,9a -d ia za cyclooct a [a ]-

p en ta len e-1,3-d ion e (18b). Iodoaldehyde 17 (101 mg, 0.378

mmol) and (tri-n-butylstannyl)methylamine 9^26b,28(136 mg,

0.425 mmol) were dissolved in xylenes (7.6 mL) and allowed

to stir at room temperature. After 10 min, N-phenylmaleimide

(132 mg, 0.763 mmol) was added in one portion and the

solution was heated to reflux for 14 h. The reaction was

concentrated and the residue was chromatographed (5% to

30% ethyl acetate/hexanes, gradient) to afford 5.9 mg (6%) of

18a and 12.5 mg (11%) of 18b both as colorless oils.

8.5 Hz, 2 H), 7.35 (d, J ) 8.5 Hz, 2 H), 4.01 (t, J ) 5.9 Hz, 2

H), 2.46 (s, 3 H), 1.60-1.52 (m, 2 H), 1.52-1.44 (m, 2 H); ¹³C

NMR (125 MHz, CDCl₃) δ 205.49, 144.83, 132.97, 129.86,

127.88, 70.51, 45.30, 32.62, 23.94, 21.64, 21.25; MS (EI, 70 eV)

m/z (rel intensity) 285 (M⁺, 1), 213 (TsOCH₂CH₂CH₂⁺, 11), 173

(CH₃C₆H₄SO₃H₂⁺, 79), 155 (CH₃C₆H₄SO₂⁺, 27); HRMS (EI, 70

eV) calcd for C₁₄H₂₁O₄S (M⁺) 285.1161, found 285.1162.

5-Iod o-2,2-d im eth ylp en ta n a l (13). Sodium iodide (2.00 g,

13.3 mmol) was added to a solution of chloroaldehyde 8²⁷(395

mg, 2.66 mmol) in anhydrous acetone (5.0 mL) and heated to

reflux in the dark. After 12 h, the reaction was diluted with

ether, washed with 5% Na₂SSO₃(1×), water (1×), and brine

(1×), dried (Na₂SO₄), and concentrated at room temperature.

The residue was chromatographed (pentane to 5% ether/

pentane gradient) to yield 366 mg (58%) iodoaldehyde 13 as a

colorless oil. R_f) 0.23 (5% ether/pentane, stained black with

phosphomolybdic acid); IR (CH₂Cl₂) 2700 (m), 1725 (s) cm^-1

;

¹H NMR (400 MHz, CDCl₃) δ 9.43 (s, 1 H), 3.15 (t, J ) 7.0 Hz,

2 H), 1.77-1.69 (m, 2 H), 1.59-1.53 (m, 2 H), 1.06 (s, 6 H);

¹³C NMR (100 MHz, CDCl₃) δ 205.60, 45.38, 37.80, 28.36,

21.37; MS (EI, 70 eV) m/z (rel intensity) 241 (M⁺, 1), 211 ([M

- CHO]⁺, 12), 169 (ICH₂CH₂CH₂⁺, 22), 155 (ICH₂CH₂⁺, 36),

127 (I⁺, 4), 113 ([M - I]⁺, 100); HRMS (EI, 70 eV) calcd for

C₇H₁₄OI (M⁺) 241.0089, found 241.0092.

(3a S*,3bR*,9a R*)- a n d (3a S*,3bS*,9a R*)-4,4-Dim eth yl-

2-p h en ylocta h yd r o-2,8a -d ia za cyclop en ta [a ]a zu len e-1,3-

d ion e (15). Iodoaldehyde 16 (112 mg, 0.44 mmol) and (tri-n-

butylstannyl)methylamine 9^26b,28(142 mg, 0.44 mmol) were

dissolved in xylenes (4.4 mL) and allowed to stir at room

temperature. After 10 min, N-phenylmaleimide (76 mg, 0.44

mmol) was added in one portion and the solution was heated

to reflux for 14 h. The reaction was diluted in CH₂Cl₂, washed

with 10% Na₂CO₃(1×) and brine (1×), dried (Na₂SO₄), and

concentrated. The residue was chromatographed (5% to 30%

ethyl acetate/hexanes, gradient) to afford 121 mg (88%) 15 as

a colorless oil as an inseparable 53:47 ratio of diastereomers.

R_f) 0.18 (30% ethyl acetate/hexanes, stained with I₂); IR (CH₂-

18a (exo): R_f) 0.29 (30% ethyl acetate/hexanes, stained in

1

I₂); IR (CH₂Cl₂) 1711 (s) cm^-1; H NMR (500 MHz, CDCl₃) δ

7.45-7.50 (m, 2 H), 7.39 (tt, J ) 7.6, 1.5 Hz, 1 H), 7.23-7.27

(m, 5 H), 3.63 (dd, J ) 8.3, 12.3 Hz, 1 H), 3.43 (d, J ) 2.7 Hz,

1 H, H-3b), 3.38 (dt, J ) 2.4, 8.3 Hz, 1 H, H-3a), 3.30 (dd, J )

2.4, 6.8 Hz, 1 H), 3.28 (t, J ) 2.7 Hz, 1 H), 2.71-2.81 (m, 2 H),

1.54-1.86 (m, 6 H), 1.35-1.48 (m, 2 H), 1.00 (s, 3 H), 0.84 (s,

3 H); ¹³C NMR (125 MHz, CDCl₃) δ 179.3, 179.1, 132.1, 129.2,

128.5, 126.1, 72.3, 59.4, 57.9, 48.3, 48.0, 41.4, 38.1, 28.4, 27.9,

25.8, 23.7, 23.4; MS (EI, 70 eV) m/z (rel intensity) 326 (M⁺,

43), 311 ([M - CH₃]⁺, 6), 269 ([M - C₄H₈]⁺, 31), 255 ([M -

C₅H₁₀]⁺, 100); HRMS (EI, 70 eV) calcd for C₂₀H₂₆N₂O₂(M⁺)

326.1994, found 326.1991.

Cl₂) 1712 (s) cm^-^{1 1}H NMR (400 MHz, CDCl₃) δ 7.49-7.43

;

(m, 2 H), 7.40-7.35 (m, 1 H), 7.30-7.25 (m, 2 H), 3.60 (t, J )

8.4 Hz, 1 H × 0.53), 3.47 (d, J ) 9.5 Hz, 1 H × 0.53), 3.40 (q,

J ) 8.8 Hz, 1 H × 0.53), 3.34-3.28 (m, 1 H), 3.15 (t, J ) 7.7

Hz, 1 H × 0.47), 2.99-2.92 (m, 1 H × 0.53), 2.92-2.86 (m, 1

H), 2.62 (t, J ) 9.5 Hz, 1 H × 0.50), 2.58 (dd, J ) 7.3, 9.5 Hz,

1 H × 0.50), 2.50-2.42 (m, 1 H), 2.34-2.25 (m, 1 H), 1.78-

1.42 (m, 6 H + 1 H × 0.50), 1.32 (s, 3 H × 0.53), 1.04 (s, 6 H

× 0.47), 0.94 (s, 3 H × 0.53); ¹³C NMR (100 MHz, CDCl₃) δ

178.31, 178.13, 177.94, 176.56, 132.28, 131.84, 129.04, 128.44,

126.50, 126.32, 81.17, 74.70, 59.69, 58.83, 55.36, 52.13, 49.44,

47.74, 44.57, 43.72, 42.95, 42.61, 36.71, 35.69, 29.53, 29.05,

28.84, 24.64, 22.47, 22.14, 21.48, 18.39; MS (CI-NH₃) m/z (rel

18b (endo): R_f) 0.19 (30% ethyl acetate/hexanes, stained

1

in I₂); IR (CH₂Cl₂) 1709 (s) cm^-1; H NMR (400 MHz, CDCl₃)

δ 7.46 (t, J ) 7.7 Hz, 2 H), 7.38 (tt, J ) 1.5, 7.3 Hz, 1 H),

7.26-7.30 (m, 2 H), 3.33 (t, J ) 8.3 Hz, 1 H, H-3a), 3.29 (d, J

) 9.8 Hz, 1 H), 3.19 (t, J ) 8.1 Hz, 1 H), 3.12 (dd, J ) 15.4,

1.2 Hz, 1 H), 3.03 (dd, J ) 8.3, 14.9 Hz, 1 H), 2.95 (d, J ) 8.3

1932 J . Org. Chem., Vol. 69, No. 6, 2004

Synthesis of Indolizidines and Related Heterocycles

Hz, 1 H, H-3b), 2.89 (dd, J ) 9.8, 7.3 Hz, 1 H), 1.58-1.77 (m,

6 H), 1.24-1.38 (m, 2 H), 1.32 (s, 3 H), 0.98 (s, 3 H); ¹³C NMR

(125 MHz, CDCl₃) δ 178.7, 178.3, 132.33, 129.10, 128.5, 126.6,

68.3, 55.7, 48.8, 47.6, 45.4, 43.7, 35.9, 30.1, 27.3, 22.8, 22.0,

20.0; MS (EI, 70 eV) m/z (rel intensity) 326 (M⁺, 31), 311 ([M

- CH₃]⁺, 6), 269 ([M - C₄H₈]⁺, 60), 255 ([M - C₅H₁₀]⁺, 100);

HRMS (ESI, 70 eV) C₂₀H₂₆N₂O₂([M + H]⁺) 327.2073, found

327.2071. Stereochemical assignments were based on 2D

COSY and 1D NOESY experiments, which showed a strong

NOE between the H-3a and H-3b hydrogens (J _3a-3b) 8.3 Hz)

in 18b, but no similar NOE in 18a (J _3a-3b) 2.4 Hz).

48.48, 48.34, 25.23, 24.91; MS (EI, 70 eV) m/z (rel intensity)

256 (M⁺, 15), 228 ([M - C₂H₅]⁺, 3), 119 (PhNCO⁺, 6), 83 ([M

- N-phenylmaleimide]⁺, 100); HRMS (EI, 70 eV) calcd for

C

₁₅H₁₆N₂O₂(M⁺) 256.1212, found 256.1217. The stereochem-

istry of 21a and 21b is based on correlation with close

literature precident,^11gas well as COSY and one-dimensional

NOESY experiments.

(3a S*,9a R*,9bR*)- (23a ) a n d (3a R*,9a R*,9bS*)-Octa h y-

d r o-2-p h en yl-1H -p yr r olo[3,4-a ]in d olizid in e-1,3(2H )-d i-

on e (23b). 5-Bromopentanal 22⁴⁰(190 mg, 1.15 mmol) was

added to a solution of (tri-n-butylstanyl)methylamine 9^26b,28

(410 mg, 1.28 mmol) in toluene (2.5 mL), immediately followed

by the addition of N-phenylmaleimide (220 mg, 1.27 mmol).

The mixture was heated at reflux for 8 h. The reaction was

concentrated and the residue was chromatographed (30% ethyl

acetate/hexanes) to provide 130 mg (42%) of 23a as a yellow

oil. Further elution (ether) gave 136 mg (44%) of 23b as a

yellow oil.

7-Ch lor o-2,2-d im et h ylh ep t a n a l (19). Diisopropylamine

(3.97 g, 39.2 mmol) and anhydrous THF (40 mL) were cooled

to 0 °C and treated with n-butyllithium (13.0 mL of a 2.5 M

solution in hexanes, 32.5 mmol). After 30 min at 0 °C,

N-cyclohexyl-(2-methylpropylidene)amine²⁷(5.00 g, 32.6 mmol)

was added at 0 °C with an additional amount of THF (5 mL).

After 30 min at 0 °C, 1-bromo-5-chloropentane (5.52 g, 32.6

mmol) was added dropwise over 1 min at 0 °C. After 10 min

at 0 °C, the solution was quenched with saturated aqueous

NH₄Cl and concentrated. Ether and water were added and the

pH was adjusted to 5 with H₃PO₄. The biphasic mixture was

stirred at room temperature for 4 h with H₃PO₄added as

needed to readjust the pH to 5. The aqueous phase was

extracted with ether (3×), washed with 2% H₃PO₄(2×) and

brine (1×), dried (Na₂SO₄), and concentrated at room temper-

ature. The residue was chromatographed (pentane to 5% ether/

pentane, gradient) to yield 3.86 g (67%) of chloroaldehyde 19

as a clear, colorless oil. R_f) 0.21 (5% ether/pentane, stained

black with phosphomolybdic acid); IR (CH₂Cl₂) 2696 (m), 1725

(s) cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 9.45 (s, 1 H), 3.53 (t, J

) 6.6 Hz, 2 H), 1.81-1.73 (m, 2 H), 1.50-1.39 (m, 4 H), 1.27-

1.19 (m, 2 H), 1.05 (s, 6 H); ¹³C NMR (100 MHz, CDCl₃) δ 206.1,

45.7, 44.8, 37.1, 32.4; MS (EI, 70 eV) m/z (rel intensity) 177

23a (endo): R_f) 0.29 (30% ethyl acetate/hexanes, stained

in I₂); IR (CHCl₃) 1708 (s) cm^-1; ¹H NMR (300 MHz, CDCl₃) δ

7.45-7.15 (m, 5 H), 3.46 (d, J ) 9.5 Hz, 1 H), 3.30-3.20 (dd,

J ) 5.3, 1.8 Hz, 2 H), 3.13-3.04 (m, 1 H), 2.45-2.35 (m, 1 H),

2.12-2.01 (m, 1 H), 2.01-1.91 (td, J ) 11.4, 3.0 Hz, 1 H), 1.91-

1.80 (m, 1 H), 1.70-1.57 (m, 1 H), 1.57-1.10 (m, 3 H), 0.98-

0.85 (m, 1 H); ¹³C NMR (90 MHz, CDCl₃, J MOD) δ 178.7 (-),

175.9 (-), 132.1 (-), 129.0 (+), 128.4 (+), 126.5 (+), 65.9 (+),

57.5 (-), 52.7 (-), 47.6 (+), 43.4 (+), 27.9 (-), 24.9 (-), 24.2

(-); MS (EI, 70 eV) m/z (rel intensity) 270 (M⁺, 33), 269 ([M -

H]⁺, 21), 97 ([M - N-phenylmaleimide]⁺, 100); HRMS (EI, 70

eV) calcd for C₁₆H₁₈N₂O₂(M⁺) 270.1368, found 270.1371.

23b (exo): R_f) 0.35 (ether, stained in I₂); IR (CHCl₃) 1777

(m), 1712 (s) cm^-^{1 1}H NMR (300 MHz, CDCl₃) δ 7.60-7.20

;

(m, 5 H), 3.60-3.45 (m, 2 H), 3.15-2.98 (m, 2 H), 2.55-2.40

(m, 1 H), 2.30-2.05 (m, 3 H), 1.86 (m, 1 H), 1.70-1.15 (m, 4

H); ¹³C NMR (90 MHz, CDCl₃, J MOD) δ 177.2 (-), 176.2 (-),

131.7 (-), 129.2 (+), 129.1 (+), 128.6 (+), 126.5 (+), 126.4 (+),

66.7(+), 55.4 (-), 51.7 (-), 50.9 (+), 43.5 (+), 29.4 (-), 23.9

(-), 23.8 (-); MS (EI, 70 eV) m/z (rel intensity) 270 (M⁺, 56),

97 ([M - N-phenylmaleimide]⁺, 100); HRMS (EI, 70 eV) calcd

for C₁₆H₁₈N₂O₂(M⁺) 270.1368, found 270.1360.

(M⁺, 2), 147 ([M - CHO]⁺, 34), 149 ([M - CHO + 2]⁺, 14), 111

([M - ClCH₂CH₂]⁺, 54), 105 (³⁵Cl(CH₂)₅⁺, 26), 107 (³⁷Cl(CH₂)₅

,

+

10), 91 (³⁵Cl(CH₂)₄⁺, 11), 93 (³⁷Cl(CH₂)₄⁺, 4), 72 ([M - Cl-

(CH₂)₅]⁺, 67); HRMS (EI, 70 eV) calcd for C₉H₁₈O³⁵Cl (M⁺)

177.1046, found 177.1049.

(3a S*,3bS*,8a R*)- (21a ) a n d (3a S*,3bR*,8a R*)-2-P h en -

ylh exa h yd r op yr r olo[3,4-a ]p yr r olizin e-1,3-d ion e (21b ).

4-Chloropentanal 20³⁹(56.6 mg, 0.531 mmol) and (tri-n-

butylstannyl)methylamine 9^26b,28(170 mg, 0.531 mmol) were

dissolved in toluene (5.3 mL) and allowed to stir for 5 min.

N-Phenylmaleimide (110 mg, 0.637 mmol) was added in one

portion and the reaction was heated to reflux for 6 h. The

reaction was concentrated and chromatographed (5% ethyl

acetate/hexanes to ethyl acetate to 5% MeOH/ethyl acetate,

gradient) to yield 51.0 mg (37.5%) of 21a and 64.5 mg (47.4%)

of 21b.

The stereochemistry was tentatively assigned based on the

assumption that the geometry of the alkene was retained, and

by analogy to 7a and 7b. NOESY experiments failed to confirm

the stereochemical assignments for 23a and 23b.

(4a S*,4bS*,9a R*)- (25a ) a n d (4a S*,4bR*,9a R*)-2-p h en -

yloct a h yd r o-2,8a -d ia za cyclop en t a [a ]a zu len e-1,3-d ion e

(25b). 6-Iodohexanal 24⁴¹(82.6 mg, 0.366 mmol) and (tri-n-

butylstannyl)methylamine 9^26b,28(117 mg, 0.366 mmol) were

dissolved in xylenes (3.7 mL) and allowed to stir for 5 min at

room temperature. N-Phenylmaleimide (76 mg, 0.44 mmol)

was added in one portion and the reaction was heated to reflux

for 14 h. The reaction was concentrated and chromatographed

(10% to 100% ethyl acetate/hexanes, gradient) to yield 47.0

mg (45%) of 25a and 46.2 mg (45%) of 25b, both as colorless

oils.

21a (exo): R_f) 0.41 (50% ethyl acetate/hexanes, neutral

alumina, stained with I₂); IR (CH₂Cl₂) 1775 (w), 1709 (s) cm^-1

;

¹H NMR (400 MHz, CDCl₃) δ 7.49-7.44 (m, 2 H), 7.38 (tt, J )

7.3, 1.1 Hz, 1 H), 7.34-7.30 (m, 2 H), 3.66 (td, J ) 8.1, 2.2 Hz,

1 H), 3.51 (td, J ) 8.4, 2.6 Hz, 1 H), 3.40 (dd, J ) 10.6, 2.2 Hz,

1 H), 3.34 (dd, J ) 8.4, 2.2 Hz, 1 H), 3.00-2.92 (m, 2 H), 2.83

(ddd, J ) 12.8, 8.1, 4.8 Hz, 1 H), 2.19-2.10 (m, 1 H), 2.09-

1.99 (m, 1 H), 1.85-1.74 (m, 1 H), 1.71-1.61 (m, 1 H); ¹³C NMR

(100 MHz, CDCl₃) δ 178.00, 177.50, 131.88, 129.06, 128.54,

126.45, 69.19, 55.08, 52.00, 50.11, 45.94, 29.72, 23.61; MS (EI,

70 eV) m/z (rel intensity) 256 (M⁺, 26), 228 ([M - C₂H₅]⁺, 4),

119 (PhNCO⁺, 5), 83 ([M - N-phenylmaleimide]⁺, 100); HRMS

(EI, 70 eV) calcd for C₁₅H₁₆N₂O₂(M⁺) 256.1212, found 256.1213.

25a (endo): R_f) 0.49 (ethyl acetate, stained with I₂); IR

1

(CH₂Cl₂) 1773 (w), 1708 (s) cm^-1; H NMR (400 MHz, CDCl₃)

δ 7.45-7.40 (m, 2 H), 7.34 (tt, J ) 7.8, 1.1 Hz, 1 H), 7.27-

7.22 (m, 2 H), 3.42 (d, J ) 9.5 Hz, 1 H), 3.19-3.13 (m, 2 H),

2.94 (dt, J ) 13.2, 4.0 Hz, 1 H), 2.59-2.54 (m, 1 H), 2.50 (td,

J ) 7.7, 2.6 Hz, 1 H), 2.18-2.08 (m, 2 H), 1.75-1.44 (m, 7 H);

¹³C NMR (100 MHz, CDCl₃) δ 178.78, 176.37, 132.15, 129.03,

128.43, 126.49, 68.98, 58.84, 53.21, 48.69, 44.07, 29.21, 26.70,

26.62, 24.09; MS (EI, 70 eV) m/z (rel intensity) 284 (M⁺, 6),

119 (PhNCO⁺, 10), 57 (100); HRMS (EI, 70 eV) calcd for

21b (endo): R_f) 0.29 (50% ethyl acetate/hexanes, neutral

alumina, stained with I₂); IR (CH₂Cl₂) 1774 (w), 1706 (s) cm^-1

;

C

₁₇H₂₀N₂O₂(M⁺) 284.1525, found 284.1528.

¹H NMR (400 MHz, CDCl₃) δ 7.50-7.43 (m, 2 H), 7.39 (tt, J )

7.4, 1.1 Hz, 1 H), 7.30-7.20 (m, 2 H), 3.76 (ddd, J ) 4.0, 8.8,

7.7 Hz, 1 H), 3.58-3.52 (m, 1 H), 3.49 (dd, J ) 8.4, 2.2 Hz, 1

H), 3.43-3.33 (m, 2 H), 3.07 (ddd, J ) 4.7, 9.9, 8.4 Hz, 1 H),

2.52 (q, J ) 8.4 Hz, 1 H), 2.28-2.18 (m, 1 H), 2.16-2.06 (m, 1

H), 1.98-1.78 (m, 2 H); ¹³C NMR (100 MHz, CDCl₃) δ 178.73,

176.85, 131.93, 129.19, 128.59, 125.98, 68.63, 54.84, 53.00,

25b (exo): R_f) 0.19 (ethyl acetate, stained with I₂); IR (CH₂-

Cl₂) 1710 (s) cm^-^{1 1}H NMR (400 MHz, CDCl₃) δ 7.49-7.44

;

(m, 2 H), 7.38 (tt, J ) 7.3, 1.2 Hz, 1 H), 7.30-7.27 (m, 2 H),

3.49 (td, J ) 8.8, 6.1 Hz, 1 H), 3.42 (t, J ) 9.0 Hz, 1 H), 3.07

(dd, J ) 8.8, 6.1 Hz, 1 H), 2.90-2.83 (m, 2 H), 2.77 (dd, J )

9.8, 5.9 Hz, 1 H), 2.56 (ddd, J ) 12.2, 9.8, 2.2 Hz, 1 H), 2.10-

J . Org. Chem, Vol. 69, No. 6, 2004 1933

Pearson et al.

2.03 (m, 1 H), 1.83-1.50 (m, 7 H); ¹³C NMR (100 MHz, CDCl₃)

δ 177.44, 177.09, 131.75, 129.07, 128.53, 126.43, 68.84, 57.26,

53.52, 52.83, 43.82, 33.22, 27.05, 26.22, 25.33; MS (EI, 70 eV)

m/z (rel intensity) 284 (M⁺, 100), 269 ([M - CH₃]⁺, 10), 255

([M - C₂H₅]⁺, 58), 242 ([M - C₃H₇]⁺, 94), 111 ([M - N-

phenylmaleimide]⁺, 78); HRMS (EI, 70 eV) calcd for C₁₇H₂₀N₂O₂

(M⁺) 284.1525, found 284.1518.

were heated in toluene (1.5 mL) at reflux for 1.5 h. The reaction

was concentrated and the residue chromatographed (20% ethyl

acetate/hexanes) to afford 32 mg (63%) of the title compounds

as an inseparable mixture of two diastereomers (3:2), both as

clear oils. Data for the mixture: R_f) 0.51 (30% ethyl acetate/

1

hexanes); H NMR (300 MHz, CDCl₃) δ 7.45-7.20 (m, 5 H),

5.05 (dd, J ) 9.2, 6.2 Hz, 1 H × 0.60, H-2), 4.94 (dd, J ) 8.8,

2.4 Hz, 1 H × 0.40, H-2), 3.70 (s, 1 H × 0.60, H-8a), 3.50 (dd,

J ) 9.7, 3.5 Hz, 1 H × 0.60), 3.36 (s, 1 H × 0.40, H-8a), 3.08

(dd, J ) 8.7, 6.3 Hz, 1 H × 0.40), 3.02-2.88 (m, 1 H), 2.78 (t,

J ) 8.8 Hz, 1 H × 0.40), 2.48 (t, J ) 9.5 Hz, 1 H × 0.60), 2.32

(td, J ) 9.9, 3.3 Hz, 1 H × 0.60), 2.08 (td, J ) 11.1, 3.1 Hz, 1

H × 0.40), 1.84-1.62 (m, 2 H × 0.60), 1.62-1.42 (m, 2 H),

1.30-1.18 (m, 2 H × 0.40), 1.17 (s, 3 H × 0.40), 1.07 (s, 3 H ×

0.60), 1.06 (s, 3 H × 0.60), 1.03 (s, 3 H × 0.40); ¹³C NMR (90

MHz, CDCl₃) δ 128.4, 128.2, 127.3, 126.5, 125.7, 101.4, 101.3,

76.6, 76.3, 62.2, 60.3, 50.8, 50.0, 37.1, 35.7, 34.0, 33.4, 27.3,

27.1, 21.9, 21.7, 20.9, 19.7; MS (EI, 70 eV) m/z (rel intensity)

231 (M⁺, 16), 230 ([M - H]⁺, 14), 216 ([M - CH₃]⁺, 3), 125 ([M

- PhCHO]⁺, 100), 104 (PhCHO⁺, 69), 91 (PhCH₂⁺, 11); HRMS

(EI, 70 eV) calcd for C₁₅H₂₁NO (M⁺) 231.1623, found 231.1615.

Octa h yd r o-8,8-d im eth yl-1-in d olizid in eca r boxylic Acid

Meth yl Ester a n d Octa h yd r o-8,8-d im eth yl-2-in d olizid i-

n eca r boxylic Acid Meth yl Ester (26). Imine 1 (130 mg, 0.29

mmol) and methyl acrylate (47 mg, 0.54 mmol) were heated

at reflux in toluene (0.5 mL) for 3 h. The reaction was

concentrated and the residue chromatographed (40% ethyl

acetate/hexanes) to give 48 mg (79%) of the title compound as

a clear oil containing three inseparable isomers (1:1:1.8 by GC).

Both the regio- and stereochemistry could not be determined.

Data for the mixture: R_f) 0.23 (40% ethyl acetate/hexanes);

IR (CHCl₃) 1738 (s) cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 3.692

(s, 3 H), 3.688 (s, 3 H), 3.678 (s, 3 H), 3.38-3.26 (m, 2 H), 3.10-

2.90 (m, 4 H), 2.90-2.64 (m, 2 H), 2.30-2.16 (m, 3 H), 2.10-

1.56 (m, 15 H), 1.56-1.35 (m, 6 H), 1.20-1.10 (m, 3 H), 0.97

(s, 3 H), 0.94 (s, 3 H), 0.92 (s, 3 H), 0.87 (s, 3 H), 0.86 (s, 3 H),

0.81 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 177.0, 175.75,

175.72, 76.0, 72.9, 72.1, 58.3, 57.5, 54.4, 53.54, 53.47, 53.43,

51.8, 51.7, 51.6, 43.2, 39.6, 39.33, 39.26, 39.23, 39.1, 32.65,

32.24, 32.17, 29.0, 28.9, 28.8, 28.7, 28.3, 27.7, 22.2, 22.1, 22.0,

19.3, 19.1, 18.9; MS (EI, 70 eV) m/z (rel intensity) 211 (M⁺,

30), 210 ([M - H]⁺, 17), 196 ([M - CH₃]⁺, 40), 180 ([M -

OCH₃]⁺, 26), 152 ([M - CO₂CH₃]⁺, 34), 142 (100), 125 ([M -

CH₂CHCO₂CH₃]⁺, 19); HRMS (EI, 70 eV) calcd for C₁₂H₂₁NO₂

(M⁺) 211.1572, found 211.1565.

The regiochemistry was determined based on the splitting

pattern of the bridgehead hydrogen H-8a. The stereochemistry

of the major isomer could not be determined.

Hexa h yd r o-8,8-d im eth yl-2,2-d ip h en yl-5H-oxa zolo[3,2-

a ]p yr id in e (29). Imine 1 (100 mg, 0.43 mmol) and benzophe-

none (75 mg, 0.43 mmol) were heated to reflux in toluene (2

mL) for 1.5 h. The reaction was concentrated and the residue

chromatographed (10% ethyl acetate/hexanes) to afford 87 mg

(66%) of the title compound as a colorless oil: R_f) 0.20 (10%

ethyl acetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.50-

7.10 (m, 10 H), 3.89 (d, J ) 9.1 Hz, 1 H), 3.53 (s, 1 H), 3.02 (d,

J ) 9.1 Hz, 1 H), 2.95-2.87 (m, 1 H), 2.12 (td, J ) 10.6, 3.1

Hz, 1 H), 1.75-1.60 (m, 1 H), 1.54-1.40 (m, 1 H), 1.23-1.14

(m, 1 H), 1.10 (s, 3 H), 1.08 (s, 3 H); ¹³C NMR (90 MHz, CDCl₃)

δ 128.2, 127.9, 126.7, 126.6, 126.3, 125.9, 100.7, 83.7, 67.2, 50.4,

36.5, 33.6, 27.1, 21.7, 20.4; MS (EI, 70 eV) m/z (rel intensity)

307 (M⁺, 9), 180 (Ph₂CO⁺, 51), 125 ([M - Ph₂CO]⁺, 100), 77

(Ph⁺, 22); HRMS (EI, 70 eV) calcd for C₂₁H₂₅NO (M⁺) 307.1936,

found 307.1924.

(1S*,2R*,8a R*)-Octa h yd r o-8,8-d im eth yl-2-p h en yl-1-in -

d olizin eca r boxylic Acid Meth yl Ester (30a ), (1S*,2R*,

8a R*)-Octa h yd r o-8,8-d im eth yl-1-p h en yl-2-in d olizin eca r -

boxylic Acid Meth yl Ester (30b), a n d (1R*,2S*,8a R*)-

Octa h yd r o-8,8-d im eth yl-1-p h en yl-2-in d olizin eca r boxyl-

ic Acid Meth yl Ester (30c). Imine 1 (300 mg, 0.66 mmol)

and trans-methyl cinnamate (161 mg, 1.0 mmol) were heated

to reflux in toluene (4 mL) for 6 h. The reaction was

concentrated and the residue chromatographed (15% to 25%

ethyl acetate/hexanes, gradient) to afford 81 mg (42%) of 30a ,

8 mg (4%) of 30b, and 40 mg (22%) of 30c, all as light yellow

oils.

(1S*,2R*,8a R*)- (27a ) a n d (1R*,2S*,8a R*)-Octa h yd r o-

8,8-d im eth yl-1,2-in d olizin ed ica r boxylic Acid Dim eth yl

Ester (27b). Imine 11 (490 mg, 1.09 mmol) and dimethyl

maleate (160 mg, 1.11 mmol) were heated to reflux in toluene

(2 mL) for 5 h. The reaction was concentrated and the residue

chromatographed (20% to 40% ethyl acetate/hexanes, gradient)

to provide 119 mg (41%) of 27a and 92 mg (31%) of 27b, both

as yellow oils.

27a (exo): R_f) 0.23 (20% ethyl acetate/hexanes); IR (CHCl₃)

1736 (s) cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 3.66 (s, 3 H), 3.64

(s, 3 H), 3.21-3.01 (m, 4 H, H-1, H-2, H-3, and H-5), 2.70-

2.62 (m, 1 H), 2.17 (d, J ) 8.4 Hz, 1 H, H-8a), 2.04 (dt, J )

10.0, 3.0 Hz, 1 H), 1.72-1.61 (m, 1 H), 1.50-1.40 (m, 2 H),

1.14 (dt, J ) 11.1, 4.7 Hz, 1 H), 0.95 (s, 3 H), 0.81 (s, 3 H); ¹³

C

NMR (75 MHz, CDCl₃) δ 174.6, 172.1, 76.4, 56.4, 53.1, 51.8,

46.5, 44.8, 39.5, 32.9, 28.1, 22.0, 19.3; MS (EI, 70 eV) m/z (rel

int) 269 (M⁺, 49), 254 ([M - CH₃]⁺, 47), 238 ([M - OCH₃]⁺,

35), 210 ([M - CO₂CH₃]⁺, 42), 200 (100), 125 ([M - MeO₂-

CCHdCHCO₂Me]⁺, 31); HRMS (EI, 70 eV) calcd for C₁₄H₂₃

-

NO₄(M⁺) 269.1627, found 269.1640.

27b (endo): R_f) 0.19 (30% ethyl acetate/hexanes); IR

(CHCl₃) 1733 (s) cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 3.81 (dd,

J ) 9.8, 6.3 Hz, 1 H), 3.65 (s, 3 H), 3.64 (s, 3 H), 3.33 (dd, J )

8.0, 5.4 Hz, 1 H, H-1), 3.20-3.08 (m, 2 H, H-2 and H-5), 2.47

(dd, J ) 11.1, 9.8 Hz, 1 H), 2.15 (d, J ) 5.4 Hz, 1 H, H-8a),

1.94 (td, J ) 11.5, 3.0 Hz, 1 H), 1.79-1.69 (m, 1 H), 1.44-1.32

(m, 1 H), 1.09-0.99 (m, 1 H), 1.02 (s, 3 H), 0.86 (s, 3 H); ¹³C

NMR (90 MHz, CDCl₃) δ 173.1, 172.2, 76.5, 55.0, 51.9, 47.5,

44.0, 41.7, 33.0, 27.9, 21.9, 18.9; MS (EI, 70 eV) m/z (rel

intensity) 269 (M⁺, 34), 268 ([M - H]⁺, 55), 254 ([M - CH₃]⁺,

38), 238 ([M - OCH₃]⁺, 35), 210 ([M - CO₂CH₃]⁺, 48), 200

(100), 125 ([M - MeO₂CCHdCHCO₂Me]⁺, 35); HRMS (CI,

NH₃) calcd for C₁₄H₂₄NO₄([M + H]⁺) 270.1705, found 270.1695.

30a : R_f) 0.36 (15% ethyl acetate/hexanes); IR (CHCl₃) 1729

(s) cm^-^{1 1}H NMR (300 MHz, CDCl₃) δ 7.24-7.15 (m, 5 H),

;

3.90-3.78 (m, 1 H, H-2), 3.69 (s, 3 H), 3.59 (t, J ) 8.5 Hz, 1

H), 3.30-3.22 (m, 1 H), 3.08 (dd, J ) 8.6, 5.4 Hz, 1 H, H-1),

2.19 (d, J ) 8.6 Hz, 1 H, H-8a), 2.14 (t, J ) 9.6 Hz, 1 H), 1.90-

1.70 (m, 2 H), 1.50-1.35 (m, 2 H), 1.20-1.00 (m, 1 H), 1.08 (s,

3 H), 0.90 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 175.4, 143.3,

128.5, 128.3, 127.5, 126.7, 64.1, 55.0, 53.5, 51.8, 45.7, 42.7, 33.1,

29.1, 28.0, 21.6, 19.8; MS (CI, NH₃) m/z (rel intensity) 288 ([M

+ H]⁺, 100), 287 (M⁺, 4); HRMS (CI, NH₃) calcd for C₁₈H₂₆

-

NO₂([M + H]⁺) 288.1963, found 288.1965. The stereochemical

assignment was based on 2D NOESY experiments, which

showed a cross-peak between H-1 and H-8a, but none between

H-1 and H-2. Assignment of proton resonances was confirmed

by COSY experiments on derivative 32a .

The stereochemical assignment of 27a and 27b was made

by 2D COSY and NOESY experiments. For 27a , there was an

NOE cross-peak between the H-1 and H-2 resonances and no

cross-peak between H-8a and H-1. For 27b, there were NOE

cross-peaks between H-8a and H-1, and H-1 and H-2.

30b: R_f) 0.26 (15% ethyl acetae/hexanes); IR (CHCl₃) 1728

(s) cm^-^{1 1}H NMR (360 MHz, CDCl₃) δ 7.50-7.05 (m, 5 H),

;

(2S*,8a R*)- (28a ) a n d (2R*,8a R*)-Hexa h yd r o-8,8-d i-

m eth yl-2-p h en yl-5H-oxa zolo[3,2-a ]p yr id in e (28b). Imine

1 (100 mg, 0.22 mmol) and benzaldehyde (49 mg, 0.46 mmol)

3.67 (s, 3 H), 3.65-3.55 (m, 2 H, H-1 and H-3), 3.25-3.18 (m,

1 H), 3.10 (td, J ) 8.4, 3.0 Hz, 1 H, H-2), 2.32 (dd, J ) 9.6, 7.9

Hz, 1 H), 2.06 (d, J ) 6.6 Hz, 1 H, H-8a), 1.92-1.85 (m, 1 H),

1934 J . Org. Chem., Vol. 69, No. 6, 2004

Synthesis of Indolizidines and Related Heterocycles

1.68-1.58 (m, 1 H), 1.45-1.35 (m, 1 H), 1.28-1.12 (m, 1 H),

1.10-0.98 (m, 1 H), 0.90 (s, 3 H), 0.14 (s, 3 H); ¹³C NMR (90

MHz, CDCl₃) δ 175.7, 144.0, 130.1, 127.6, 126.5, 76.3, 58.6,

55.5, 52.0, 50.4, 50.1, 42.7, 33.4, 28.1, 21.9, 21.2; MS (EI, 70

eV) m/z (rel intensity) 287 (M⁺, 48), 272 ([M - CH₃]⁺, 31), 256

([M - OCH₃]⁺, 19), 228 ([M - CO₂CH₃], 49), 218 (100), 125

([M - PhCHdCHCO₂Me]⁺, 96), 91 (PhCH₂⁺, 24); HRMS (EI,

70 eV) calcd for C₁₈H₂₅NO₂(M⁺) 287.1885, found 287.1888. The

stereochemical assignment was based on 2D NOESY experi-

ments, which showed a cross-peak between H-1 and H-8a, but

none between H-1 and H-2. Assignment of proton resonances

was confirmed by COSY experiments on derivative 32b.

(1S*,2R*,8a R*)-2-Hyd r oxym eth yl-8,8-d im eth yl-1-p h en -

ylin d olizid in e (32b). 32b was prepared from the ester 30b

(10 mg, 0.035 mmol) and lithium aluminum hydride (3 mg,

0.08 mmol) according to the procedure for the formation of 32a .

Chromatography (40% ethyl acetate/hexanes) afforded 7 mg

(78%) of the title compound as a yellow oil. R_f) 0.12 (30%

ethyl acetate/hexanes); IR (CHCl₃) 3615 (m) cm^-^{1 1}H NMR

;

(400 MHz, CDCl₃) δ 7.50-7.10 (m, 5 H), 3.61 (dABq, J ) 7.0

Hz, Du ) 20.6 Hz, J _AB) 10.7 Hz, 2 H), 3.59-3.51 (m, 1 H,

H-3), 3.27-3.20 (m, 1 H, H-5), 3.07 (dd, J ) 6.6, 2.6 Hz, 1 H,

H-1), 2.50-2.38 (m, 1 H, H-2), 1.95-1.75 (m, 3 H, H-8a, H-3

and H-5), 1.75-1.45 (m, 2 H), 1.45-1.30 (m, 1 H), 1.20-1.10

(m, 1 H), 1.03 (dt, J ) 13.2, 4.0 Hz, 1 H), 0.88 (s, 3 H), 0.15 (s,

3 H); ¹³C NMR (100 MHz, CDCl₃) δ 145.2, 130.5, 129.9, 128.1,

127.3, 126.1, 66.4, 59.4, 56.0, 50.1, 48.6, 42.9, 33.3, 29.7, 28.2,

21.9, 21.2; MS (EI, 70 eV) m/z (rel intensity) 259 (M⁺, 22), 228

([M - CH₂OH]⁺, 19), 125 ([M - PhCHdCHCH₂OH]⁺, 100),

91 (PhCH₂⁺, 11); HRMS (EI, 70 eV) calcd for C₁₇H₂₅NO (M⁺)

259.1936, found 259.1932.

30c: R_f) 0.15 (15% ethyl acetate/hexanes); IR (neat) 1728

(s) cm^-^{1 1}H NMR (400 MHz, CDCl₃) δ 7.38-7.15 (m, 5 H),

;

3.66 (s, 3 H), 3.28-3.20 (m, 1 H, H-2), 3.08-2.98 (m, 2 H),

2.74-2.66 (m, 2 H, H-1 and H-3), 2.19 (d, J ) 9.5 Hz, 1 H,

H-8a), 1.93 (td, J ) 8.6, 3.0 Hz, 1 H), 1.80-1.66 (m, 1 H), 1.50-

1.38 (m, 2 H), 1.14 (td, J ) 13.3, 4.0 Hz, 1 H), 1.04 (s, 3 H),

0.80 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃, APT) δ 176.2 (-),

146.4 (-), 128.5 (+), 127.2 (+), 126.3 (+), 76.5 (+), 62.4 (-),

54.5 (+), 53.6 (-), 51.7 (+), 47.0 (+), 39.7 (-), 33.0 (-), 28.2

(+), 22.1 (-), 19.6 (+); MS (EI, 70 eV) m/z (rel intensity) 287

(M⁺, 21), 272 ([M - CH₃]⁺, 13), 256 ([M - OCH₃]⁺, 12), 228

([M - CO₂CH₃], 23), 125 ([M - PhCHdCHCO₂Me]⁺, 100), 91

(PhCH₂⁺, 12); HRMS (EI, 70 eV) calcd for C₁₈H₂₅NO₂(M⁺)

287.1885, found 287.1886. The stereochemical assignment was

based on 2D NOESY experiments, which showed no cross-

peaks between H-1, H-2, and H-8a. Assignment of proton

resonances was confirmed by COSY experiments on derivative

32c.

(1R*,2S*,8a R*)-2-Hyd r oxym eth yl-8,8-d im eth yl-1-p h en -

ylin d olizid in e (32c). 32c was prepared from the ester 30c

(48 mg, 0.17 mmol) and lithium aluminum hydride (13 mg,

0.34 mmol) according to the procedure for the formation of 32a .

Chromatography (25% ethyl acetate/hexanes) produced 40 mg

(91%) of the title compound as a colorless oil: R_f) 0.38 (40%

ethyl acetate/hexanes); IR (CHCl₃) 3316 (m) cm^-^{1 1}H NMR

;

(360 MHz, CDCl₃) δ 7.40-7.10 (m, 5 H), 3.75-3.60 (m, 2 H),

3.26 (br s, 1 H), 3.15-3.08 (m, 1 H, H-5), 3.07 (d, J ) 9.2 Hz,

1 H, H-3), 2.98 (dd, J ) 9.3, 4.3 Hz, 1 H, H-1), 2.62 (dd, J )

8.9, 7.7 Hz, 1 H, H-3), 2.12-2.05 (m, 1 H, H-2), 2.05 (d, J )

9.3 Hz, 1 H, H-8a), 2.00-1.90 (m, 1 H, H-5), 1.80-1.60 (m, 2

H, H-6ax and H-6eq), 1.52-1.42 (m, 1 H, H-7), 1.40-1.30 (m,

1 H, H-7), 1.08 (s, 3 H), 0.48 (s, 3 H); ¹³C NMR (90 MHz, CDCl₃)

δ 146.5, 128.5, 128.1, 126.1, 80.5, 67.2, 59.2, 53.9, 49.4, 48.2,

40.3, 33.7, 29.2, 22.1, 19.8; MS (EI, 70 eV) m/z (rel intensity)

259 (M⁺, 6), 228 ([M - CH₂OH]⁺, 85), 125 ([M - PhCHd

CHCH₂OH]⁺, 91), 91 (PhCH₂⁺, 37); HRMS (EI, 70 eV) calcd

for C₁₇H₂₅NO (M⁺) 259.1936, found 259.1933.

1,1-Dim eth yl-1,2,3,4-tetr a h yd r oben zo[f]p yr id o[2,1-a ]-

isoin d ole-7,12-d ion e (31). Chloroaldehyde 8²⁷(54 mg, 0.36

mmol) and (tri-n-butylstannyl)methylamine 9^26b,28were ex-

tracted with CH₂Cl₂(3×). The combined organic layers were

washed with brine (1×), dried (Na₂SO₄), and concentrated and

the residue chromatographed (5% ethyl acetate/hexanes to

ethyl acetate, gradient) to yield 7.2 mg (7%) of dione 31 as a

white crystalline solid. R_f) 0.50 (30% ethyl acetate/hexanes);

IR (CH₂Cl₂) 1657 (s), 1641 (s) cm^-1; ¹H NMR (400 MHz, CDCl₃)

δ 8.26 (dd, J ) 7.3, 1.8 Hz, 1 H), 8.20 (dd, J ) 7.3, 1.8 Hz, 1

H), 7.69 (td, J ) 7.0, 2.0 Hz, 1 H), 7.65 (td, J ) 7.3, 1.5 Hz, 1

H), 7.28 (s, 1 H), 4.03 (t, J ) 5.9 Hz, 2 H), 1.97-2.05 (m, 2 H),

1.79-1.82 (m, 2 H), 1.58 (s, 6 H); ¹³C NMR (100 MHz, CDCl₃)

δ 181.0, 179.3, 146.0, 136.7, 134.7, 133.1, 132.4, 127.3, 126.29,

123.2, 122.9, 117.0, 53.4, 47.6, 37.8, 33.3, 26.7, 19.9; MS (EI,

70 eV) m/z (rel intensity) 279 (M⁺, 47), 264 ([M - CH₃]⁺, 100);

HRMS (EI, 70 eV) calcd for C₁₈H₁₇NO₂(M⁺) 279.12593, found

279.1264.

5,6,7,8-Tet r a h yd r o-8,8-d im et h yl-1,2-in d olizin ed ica r -

boxylic Acid Dim eth yl Ester (33). Dimethylacetylene di-

carboxylate (53 mg, 0.37 mmol) was added to a solution of

imine 1 (160 mg, 0.36 mmol) in toluene (1.5 mL) and heated

at reflux for 48 h. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone

(38 mg, 0.17 mmol) was then added and the reaction was

heated at reflux for an additional 24 h. The reaction was

concentrated and the residue was chromatographed (30% ethyl

acetate/hexanes) to afford 73 mg (78%) of the title compound

as a yellow oil: R_f) 0.23 (30% ethyl acetate/hexanes); IR (neat)

1713 (s) cm^-1; ¹H NMR (360 MHz, CDCl₃) δ 7.02 (s, 1 H), 3.89

(t, J ) 6.2 Hz, 3 H), 3.86 (s, 3 H), 3.75 (s, 3 H), 2.02-1.94 (m,

2 H), 1.70-1.64 (m, 2 H), 1.36 (s, 6 H); ¹³C NMR (90 MHz,

CDCl₃) δ 168.0, 164.2, 138.6, 123.8, 114.0, 112.7, 52.0, 51.2,

46.4, 37.4, 32.5, 29.1, 27.8, 19.7; MS (EI, 70 eV) m/z (rel

intensity) 265 (M⁺, 24), 250 ([M - CH₃]⁺, 11), 234 ([M -

(1S*,2R*,8a R*)-1-Hyd r oxym eth yl-8,8-d im eth yl-2-p h en -

ylin d olizid in e (32a ). Ester 30a (66 mg, 0.23 mmol) was

dissolved in THF (1 mL) and cooled to -78 °C. Lithium

aluminum hydride (17 mg, 0.46 mmol) was added in one

portion and the reaction was allowed to warm to room

temperature. The reaction was quenched by addition of water

(50 µL), 20% NaOH (50 µL), and water (150 µL) in sequence.

The mixture was diluted with ether, filtered through a pad of

Celite, and concentrated and the residue chromatographed

(50% ethyl acetate/hexanes) to yield 58 mg (98%) of the title

compound as a colorless oil: R_f) 0.12 (40% ethyl acetate/

OCH₃]⁺, 23), 218 (100); HRMS (EI, 70 eV) calcd for C₁₄H₁₉

NO₄(M⁺) 265.1314, found 265.1305.

-

5,6,7,8-Tetr a h yd r o-8,8-d im eth yl-1-in d olizin eca r boxy-

lic Acid Meth yl Ester (34a ) a n d 5,6,7,8-Tetr a h yd r o-8,8-

dim eth yl-2-in dolizin ecar boxylic Acid Meth yl Ester (34b).

Methyl propiolate (72 mg, 0.85 mmol) and imine 1 (192 mg,

0.43 mmol) were heated to reflux in toluene (2.5 mL) for 10 h.

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (290 mg, 1.28 mmol)

was then added and the mixture was kept at reflux for an

additional 1 h. The reaction was concentrated and the residue

chromatographed (5% ethyl acetate/hexanes) to afford 37 mg

(21%) of 34a and 53 mg (30%) of 34b, both as orange oils. The

regiochemistry was assigned according to similar literature

precedents.

hexanes); IR (CHCl₃) 3316 (br) cm^-^{1 1}H NMR (360 MHz,

;

CDCl₃) δ 7.36-7.10 (m, 5 H), 3.90-3.75 (m, 2 H), 3.55 (t, J )

9.0 Hz, 1 H, H-3), 3.30 (td, J ) 8.8, 3.7 Hz, 1 H, H-2), 3.24-

3.15 (m, 1 H, H-5), 2.50 (br s, 1 H, -OH), 2.42-2.34 (m, 1 H,

H-1), 2.12 (d, J ) 8.9 Hz, 1 H, H-8a), 2.08 (d, J ) 9.4 Hz, 1 H,

H-3), 1.85-1.70 (m, 2 H, H-5 and H-6), 1.50-1.35 (m, 2 H,

H-6 and H-7), 1.25-1.10 (m, 1 H, H-7), 1.15 (s, 3 H), 1.04 (s,

3 H); ¹³C NMR (90 MHz, CDCl₃) δ 145.7, 128.5, 127.6, 126.2,

75.6, 65.2, 64.9, 55.7, 51.4, 46.4, 43.0, 33.3, 28.4, 21.8, 21.6;

MS (CI, NH₃) m/z (rel intensity) 260 ([M + H]⁺, 80), 259 (M⁺,

25), 242 ([M - OH]⁺, 9), 228 ([M - CH₂OH]⁺, 21), 125 ([M -

PhCHdCHCH₂OH]⁺, 100), 91 (PhCH₂⁺, 13); HRMS (CI, NH₃)

calcd for C₁₇H₂₆NO ([M + H]⁺) 260.2014, found 260.2005.

34a : R_f) 0.45 (10% ethyl acetate/hexanes); IR (CHCl₃) 1701

1

(s) cm^-1; H NMR (300 MHz, CDCl₃) δ 6.58 (d, J ) 2.9 Hz, 1

H), 6.38 (d, J ) 2.9 Hz, 1 H), 3.90 (t, J ) 5.9 Hz, 2 H), 3.77 (s,

3 H), 1.96-1.90 (m, 2 H), 1.74-1.68 (m, 2 H), 1.50 (s, 6 H);

J . Org. Chem, Vol. 69, No. 6, 2004 1935

Pearson et al.

¹³C NMR (90 MHz, CDCl₃, J MOD) δ 118.6 (+), 111.6 (+), 50.7

(+), 46.8 (-), 38.9 (-), 32.9 (-), 29.7 (-), 27.6 (+), 20.1 (-);

MS (EI, 70 eV) m/z (rel intensity) 207 (M⁺, 39), 192 ([M -

CH₃]⁺, 72), 176 ([M - OCH₃]⁺, 13), 160 (100); HRMS (EI, 70

eV) calcd for C₁₂H₁₇NO₂(M⁺) 207.1259, found 207.1269.

34b: R_f) 0.27 (10% ethyl acetate/hexanes); IR (neat) 1697

12.8, 4.0 Hz, 1 H), 1.52-1.40 (m, 3 H), 1.37-1.26 (m, 7 H),

1.22 (dt, J ) 12.5, 3.3 Hz, 1 H), 1.15 (s, 3 H), 1.10 (s, 3 H),

0.90 (t, J ) 7.0 Hz, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 131.65,

128.17, 127.59, 123.84, 87.29, 86.48, 62.25, 55.83, 48.76, 34.06,

33.95 (br), 31.80, 27.11, 27.02, 25.66, 22.67, 22.11, 14.09; MS

(EI, 70 eV) m/z (rel intensity) 297 (M⁺, 19), 282 ([M - CH₃]⁺,

9), 268 ([M - C₂H₅]⁺, 5), 254 ([M - C₃H₇]⁺, 27), 240 ([M -

C₄H₉]⁺, 18), 226 ([M - C₆H₁₁]⁺, 100), 212 ([M - C₆H₁₃]⁺, 38);

HRMS (EI, 70 eV) calcd for C₂₁H₃₁N (M⁺) 297.24565, found

297.2450.

1

(s) cm^-1; H NMR (300 MHz, CDCl₃) δ 7.08 (d, J ) 1.9 Hz, 1

H), 6.32 (d, J ) 1.9 Hz, 1 H), 3.90 (t, J ) 6.1 Hz, 2 H), 3.78 (s,

3 H), 2.02-1.95 (m, 2 H), 1.69-1.64 (m, 2 H), 1.28 (s, 6 H);

¹³C NMR (75 MHz, CDCl₃) δ 165.4, 140.1, 123.6, 114.8, 104.0,

50.8, 45.9, 36.1, 31.6, 21.2, 20.2; MS (EI, 70 eV) m/z (rel

intensity) 207 (M⁺, 21), 192 ([M - CH₃]⁺, 100); HRMS (EI, 70

eV) calcd for C₁₂H₁₇NO₂(M⁺) 207.1259, found 207.1261.

1-Meth yl-3,3-d im eth yl-2-p h en yleth yn ylp ip er id in e (35).

Imine 1 (178 mg, 0.76 mmol) and phenylacetylene (755 mg,

7.60 mmol) were dissolved in toluene (7.6 mL) and heated to

reflux overnight. The reaction was concentrated and chro-

matographed (15% ethyl acetate/hexanes) to afford 85 mg

(49%) of the title compound as a colorless oil. R_f) 0.25 (10%

ethyl acetate/hexanes, stained with I₂); IR (CHCl₃) 2200 (m)

cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 7.50-7.40 (m, 2 H), 7.35-

7.25 (m, 3 H), 3.05 (br s, 1 H), 2.62 (m, 1 H), 2.38 (s, 3 H), 2.30

(m, 1 H), 1.70-1.45 (m, 3 H), 1.25-1.15 (m, 1 H), 1.12 (s, 3

H), 1.10 (s, 3 H); ¹³C NMR (75 MHz, CDCl₃, J MOD) δ 131.6

(+), 128.1 (+), 127.6 (+), 123.8 (-), 87.2 (-), 86.8 (-), 65.9

(+), 52.2 (-), 44.9 (+), 34.7 (-), 34.4 (-), 26.9 (+), 26.7 (+),

22.1 (-); MS (EI, 70 eV) m/z (rel intensity) 227 (M⁺, 46), 212

([M - CH₃]⁺, 33), 115 (100), 91 (PhCH₂⁺, 13), 77 (Ph⁺, 18);

HRMS (EI, 70 eV) calcd for C₁₆H₂₁N (M⁺) 227.1674, found

227.1666.

Oct a h yd r o-8,8-Dim et h yl-1-p h en ylin d olizin e or Oc-

ta h yd r o-8,8-d im eth yl-2-p h en ylin d olizin e (38). Imine 1

(160 mg, 0.35 mmol) and styrene (75 mg, 0.72 mmol) were

heated to reflux in toluene (1.0 mL) for 14 h. The reaction was

concentrated and the residue chromatographed (25% ethyl

acetate/hexanes) to afford 25 mg (31%) of the title compound

as a colorless oil. The regio- and stereochemistry could not be

1

determined. R_f) 0.37 (30% ethyl acetate/hexanes); H NMR

(300 MHz, CDCl₃) δ 7.35-7.15 (m, 5 H), 3.39 (dd, J ) 8.3, 7.9

Hz, 1 H), 3.34-3.20 (m, 1 H), 3.15-3.05 (m, 1 H), 2.16 (dd, J

) 9.3, 9.2 Hz, 1 H), 2.08 (dd, J ) 12.0, 10.9 Hz, 1 H), 2.01-

1.88 (m, 2 H), 1.85-1.70 (m, 2 H), 1.54-1.42 (m, 2 H), 1.14

(td, J ) 13.1, 4.5 Hz, 1 H), 0.97 (s, 3 H), 0.88 (s, 3 H); ¹³C

NMR (90 MHz, CDCl₃, J MOD) δ 145.5 (-), 128.3 (+), 127.5

(+), 126.0 (+), 73.8 (+), 64.5 (-), 53.8 (-), 41.0 (+), 39.6 (-),

34.0 (-), 32.5 (-), 28.9 (+), 22.4 (-), 19.0 (+); MS (EI, 70 eV)

m/z (rel intensity) 229 (M⁺, 100), 228 ([M - H]⁺, 51), 214 ([M

- CH₃]⁺, 15), 125 ([M - PhCHCH₂]⁺, 65), 91 (PhCH₂⁺, 18), 77

(Ph⁺, 8); HRMS (EI, 70 eV) calcd for C₁₆H₂₃N (M⁺) 229.1830,

found 229.1829.

1-Meth yl-2-p h en yleth yn ylp ip er id in e (36). By an alter-

nate procedure for this known compound,⁴³phenylacetylene

(1.03 g, 10.0 mmol) was added to a solution of (tri-n-butyl-

stannyl)methylamine 9^26b,28(330 mg, 1.03 mmol) and 5-bro-

mopentanal⁴⁰(170 mg, 1.03 mmol) in toluene (6 mL) and

heated at reflux overnight. The reaction was concentrated and

the residue chromatographed (80% ether/hexane) to yield 90

mg (44%) piperidine 36 as a yellow oil: R_f) 0.35 (80% ether/

Octa h yd r o-8,8-d im eth yl-1-(tr ieth ylsilyl)in d olizin e or

octa h yd r o-8,8-d im eth yl-2-(tr ieth ylsilyl)in d olizin e (39).

Vinyl triethylsilane (120 mg, 0.85 mmol) was added to a

solution of imine 1 (188 mg, 0.42 mmol) in toluene (3.0 mL)

and heated at reflux for 6 h. The reaction was concentrated

and the residue chromatographed (25% ethyl acetate/hexanes)

to give 61 mg (54%) of the title compound as a yellow oil, whose

regio- and stereochemistry could not be determined: R_f) 0.38

(30% ethyl acetate/hexanes, stained with I₂); ¹H NMR (300

MHz, CDCl₃) δ 3.12-3.01 (m, 2 H), 1.92-1.20 (m, 10 H), 1.10-

1.05 (m, 1 H), 0.95 (t, J ) 7.5 Hz, 9 H), 0.90 (s, 3 H), 0.84 (s,

3 H), 0.55 (q, J ) 7.5 Hz, 6 H); ¹³C NMR (90 MHz, CDCl₃) δ

73.8, 58.1, 54.1, 39.7, 32.5, 28.9, 26.7, 22.4, 19.0, 18.2, 7.7, 2.7;

MS (CI, NH₃) m/z (rel intensity) 268 ([M + H]⁺, 100), 267 (M⁺,

8), 238 ([M - CH₂CH₃]⁺, 2), 152 ([M - SiEt₃]⁺, 7); HRMS (CI,

NH₃) calcd for C₁₆H₃₄NSi ([M + H]⁺) 268.2461, found 268.2470.

The regio- and stereochemistry could not be determined.

1

hexanes, stained with I₂); IR (CHCl₃) 2253 (s) cm^-1; H NMR

(300 MHz, CDCl₃) δ 7.48-7.40 (m, 2 H), 7.34-7.26 (m, 3 H),

3.55 (br s, 1 H), 2.70-2.60 (m, 1 H), 2.42 (s, 3 H), 2.40-2.32

(m, 1 H), 1.98-1.42 (m, 6 H); ¹³C NMR (75 MHz, CDCl₃) δ

131.6, 128.1, 127.7, 123.5, 87.7, 86.0, 54.9, 52.1, 44.5, 32.0, 25.9,

21.0; MS (EI, 70 eV) m/z (rel intensity) 199 (M⁺, 48), 198 ([M

- H]⁺, 69), 170 ([M - C₂H₅]⁺, 100), 157 ([M - C₃H₆]⁺, 29),

142 ([M - C₄H₇]⁺, 43), 115 (PhCCCH₂⁺, 44); HRMS (EI, 70

eV) calcd for C₁₄H₁₆N ([M - H]⁺) 198.1283, found 198.1276.

The ¹H NMR resonances do not match the literature data

exactly.⁴³The authors do not specify the field strength (60 or

270 MHz) of their spectrometer.

(1S*,2R*,8a R*)- (41a ) a n d (1R*,2S*,8a R*)-Octa h yd r o-

8a -m eth yl-1,2-in d olizin ed ica r boxylic Acid Dim eth yl Es-

ter (41b). 6-Chlorohexan-2-one (150 mg, 1.11 mmol) and (tri-

n-butylstannylmethyl)amine 9^26b,28(355 mg, 1.11 mmol) were

mixed neat at room temperature, immediately followed by the

addition of toluene (3 mL) and 4 Å molecular sieves (0.5 g) to

form ketimine 40 in situ. After being stirred for 6 h, the

reaction mixture was filtered through a cotton pipet plug.

Dimethyl maleate (400 mg, 2.78 mmol) was added to the

filtrate and the mixture was heated at reflux for 5 h. The

reaction mixture was concentrated and the residue chromato-

graphed (80% ether/petroleum ether to ether, gradient) to give

70 mg (25%) of 41a and 73 mg (26%) of 41b.

lit.⁴³

36

¹H (60 or 270 MHz)

¹H (300 MHz)

7.20-7.10 (m, 5 H)

7.48-7.30 (m, 2 H), 7.34-7.26 (m, 3 H)

3.54 (t, J ) 4 Hz, 1 H) 3.55 (br s, 1 H)

2.90-2.10 (m, 2 H)

2.24 (s, 3 H)

2.70-2.58 (m, 1 H)

2.42 (s, 3 H)

2.10-1.13 (m, 6 H)

2.40-2.32 (m, 1 H), 1.98-1.42 (m, 6 H)

1-Hexyl-3,3-d im eth yl-2-p h en yleth yn ylp ip er id in e (37).

Aldehyde 8²⁷(44.4 mg, 0.30 mmol), n-hexylamine (30.3 mg,

0.30 mmol, and phenylacetylene (306 mg, 3.0 mmol) were

dissolved in toluene (3.0 mL) and heated to reflux for 6 h. The

reaction was diluted with 10% Na₂CO₃and extracted with CH₂-

Cl₂(3×). The combined organic layers were washed with brine

(1×), dried (Na₂SO₄), and concentrated. The residue was

chromatographed (5% to 20% ethyl acetate/hexanes gradient)

to yield 54.2 mg (61%) of piperidine 37 as a colorless oil. R_f)

0.60 (20% ethyl acetate/hexanes, stained with I₂); ¹H NMR (400

MHz, CDCl₃) δ 7.47-7.42 (m, 2 H), 7.33-7.27 (m, 3 H), 3.32

(s, 1 H), 2.55-2.42 (m, 4 H), 1.78-1.65 (m, 1 H), 1.58 (td, J )

1

41a : R_f) 0.45 (ether); IR (CHCl₃) 1729 (s) cm^-1; H NMR

(400 MHz, CDCl₃) δ 3.72 (s, 3 H), 3.69 (s, 3 H), 3.58 (ddd, J )

10.3, 7.7, 5.1 Hz, 1 H), 3.42 (t, J ) 10.3 Hz, 1 H), 3.16 (d, J )

7.7 Hz, 1 H), 3.07 (dd, J ) 9.5, 5.1 Hz, 1 H), 2.94-2.74 (m, 2

H), 1.70-1.46 (m, 3 H), 1.44-1.34 (m, 1 H), 1.32 (s, 3 H), 1.28-

1.20 (m, 1 H), 1.14-1.06 (m, 1 H); ¹³C NMR (400 MHz, CDCl₃)

δ 174.5, 172.5, 61.8, 58.0, 52.2, 51.9, 50.8, 43.8, 42.1, 26.9, 20.9,

20.3, 18.9; MS (EI, 70 eV) m/z (rel intensity) 255 (M⁺, 22), 240

([M - CH₃]⁺, 100), 224 ([M - OCH₃]⁺, 55), 196 ([M - CO₂-

CH₃]⁺, 62), 137 ([M - 2 × CO₂CH₃]⁺, 17); HRMS (EI, 70 eV)

calcd for C₁₃H₂₁NO₄(M⁺) 255.1471, found 255.1460.

1936 J . Org. Chem., Vol. 69, No. 6, 2004

Synthesis of Indolizidines and Related Heterocycles

1

41b: R_f) 0.20 (ether); IR (CHCl₃) 1731 (s) cm^-1; H NMR

44.5, 43.3, 37.0, 34.1, 33.6, 32.9, 29.0, 27.3, 27.0, 26.9, 20.2,

20.0, 9.2; MS (EI, 70 eV) m/z (rel intensity) 312 (M⁺, 17), 297

([M - CH₃]⁺, 100), 243 ([M - C₅H₉]⁺, 70); HRMS (EI, 70 eV)

calcd for C₁₉H₂₄N₂O₂(M⁺) 312.1838, found 312.1838.

(400 MHz, CDCl₃) δ 3.72 (s, 3 H), 3.69 (s, 3 H), 3.50 (ddd, J )

10.3, 8.8, 4.0 Hz, 1 H), 3.14 (dd, J ) 10.2, 4.0 Hz, 1 H), 3.08

(d, J ) 8.8 Hz, 1 H), 2.94 (t, J ) 10.3 Hz, 1 H), 2.68-2.60 (m,

1 H), 2.52-2.42 (m, 1 H), 1.90-1.80 (m, 1 H), 1.64-1.40 (m, 5

H), 0.82 (s, 3 H); ¹³C NMR (400 MHz, CDCl₃) δ 174.7, 172.5,

62.1, 57.0, 52.3, 52.2, 51.8, 45.6, 42.6, 36.3, 24.6, 19.9, 11.3;

MS (EI, 70 eV) m/z (rel intensity) 255 (M⁺, 27), 240 ([M -

CH₃]⁺, 100), 224 ([M - OCH₃]⁺, 53), 196 ([M - CO₂CH₃]⁺, 62);

HRMS (EI, 70 eV) calcd for C₁₃H₂₁NO₄(M⁺) 255.1471, found

255.1463. The stereochemical assignments are arbitrary since

NOESY experiments failed to elucidate the stereostructure of

41a and 41b. However, it is assumed the geometry of the

alkene was retained, as in the case of compounds 27a and 27b.

5-Br om o-2,2-d im et h ylh exa n a l (43). Diisopropylamine

(7.61 g, 75.24 mmol) and anhydrous THF (40 mL) were cooled

to 0 °C and treated with n-butyllithium (27.6 mL of a 2.5 M

solution in hexanes, 69.0 mmol). After 30 min at 0 °C,

N-cyclohexyl-(2-methylpropylidene)amine²⁷(9.61 g, 62.7 mmol)

was added at 0 °C, using an additional amount of THF (5 mL).

After 30 min at 0 °C, 1,3-dibromobutane (13.54 g, 62.7 mmol)

was added and allowed to stir for an additional 30 min at 0

°C. The solution was quenched with saturated aqueous NH₄-

Cl and concentrated. Ether and water were added and the pH

was adjusted to 5 with H₃PO₄. The biphasic mixture was

stirred at room temperature for 4 h with H₃PO₄being added

as needed to readjust the pH to 5. The aqueous phase was

extracted with ether (3×), washed with 2% H₃PO₄(2×) and

brine (1×), dried (Na₂SO₄), and concentrated at room temper-

ature. Ku¨gelrohr distillation (bp 110-113 °C, 1 mmHg)

afforded 6.59 g (51%) of aldehyde 43 as a colorless oil. IR (neat)

1726 (s) cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 9.45 (s, 1 H), 4.16-

4.00 (m, 1 H), 1.80-1.60 (m, 6 H), 1.60-1.45 (m, 1 H), 1.10 (s,

6 H); ¹³C NMR (400 MHz, CDCl₃, APT) δ 205.6 (-), 51.4 (-),

45.3 (+), 35.7 (+), 34.9 (+), 26.3 (-), 21.5 (-), 21.1 (-); MS

(CI, NH₃) m/z (rel intensity) 226 ([M + NH₄+ 2]⁺, 99), 224

([M + NH₄]⁺, 99), 179 ([M + 2]⁺, 19), 177 (M⁺, 19), 127 (100),

97 ([M - Br]⁺, 84); HRMS (CI, NH₃) calcd for C₈H₁₉NO⁷⁹Br

([M + NH₄]⁺) 224.0650, found 224.0662.

3-(2-Ch lor om et h ylp h en yl)-2,2-d im et h ylp r op ion a ld e-

h yd e (45). Diisopropylamine (793 mg, 7.84 mmol) and anhy-

drous THF (12 mL) were cooled to 0 °C and treated with

n-butyllithium (2.87 mL of a 2.5 M solution in hexanes, 7.18

mmol). After 30 min at 0 °C, N-cyclohexyl-(2-methylpro-

pylidene)amine²⁷(1.00 g, 6.53 mmol) was added at 0 °C, using

an additional amount of THF (3 mL). After 30 min at 0 °C,

1,2-bis(chloromethyl)benzene (1.14 g, 6.53 mmol) was added

dropwise over 1 min at 0 °C. After 10 min at 0 °C, the solution

was quenched with saturated aqueous NH₄Cl and concen-

trated. Ether and water were added and the pH was adjusted

to 5 with H₃PO₄. The biphasic mixture was stirred at room

temperature for 4 h with H₃PO₄added as needed to readjust

the pH to 5. The aqueous phase was extracted with ether (3×),

washed with 2% H₃PO₄(2×) and brine (1×), dried (Na₂SO₄),

and concentrated at room temperature. The residue was

chromatographed (pentane to 5% ether/pentane, gradient) to

yield 171 mg (12%) of aldehyde 45 as a clear, colorless oil. R_f

) 0.26 (5% ether/pentane, stained black with phosphomolybdic

acid); IR (CH₂Cl₂) 1722 (s) cm^-1; ¹H NMR (400 MHz, CDCl₃) δ

9.61 (s, 1 H), 7.35-7.39 (m, 1 H), 7.21-7.28 (m, 2 H), 7.07-

7.11 (m, 1 H), 4.63 (s, 2 H), 2.98 (s, 2 H), 1.11 (s, 6 H); ¹³C

NMR (125 MHz, CDCl₃) δ 205.6, 136.3, 135.8, 131.5, 130.8,

128.7, 127.3, 47.3, 44.4, 38.2, 21.8; MS (EI, 70 eV) m/z (rel

intensity) 139 (H₂C(C₆H₄)CH₂³⁵Cl⁺, 100), 141 (H₂C(C₆H₄)CH₂

-

37

Cl⁺, 41); HRMS (CI, NH₄) calcd for C₁₂H₁₉NO³⁵Cl ([M + NH₄]⁺)

228.1155, found 228.1150.

(3a S*,3bR*,11a R*)- (46a ) a n d (3a S*,3bS*,11a R*)-4,4-

Dim et h yl-2-p h en yl-3b ,4,5,10,11,11a -h exa h yd r o-3a H -2,-

10a -d ia za ben zo[f]cyclop en ta [a ]a zu len e-1,3-d ion e (46b).

Chloroaldehyde 45 (79.6 mg, 0.378 mmol) and (tri-n-butyl-

stannyl)methylamine 9^26b,28(121 mg, 0.378 mmol) were dis-

solved in toluene (3.8 mL) and allowed to stir at room

temperature. After 5 min, N-phenylmaleimide (78.5 mg, 0.454

mmol) was added in one portion and the solution was heated

to reflux for 2 h. The reaction was allowed to cool to room

temperature, diluted with 5% Na₂CO₃, and extracted with CH₂-

Cl₂(3×). The combined organic layers were washed with brine

(1×), dried (Na₂SO₄), and concentrated. The residue was

chromatographed (5% to 30% ethyl acetate/hexanes, gradient)

to afford 66.0 mg (49%) of 46a as a colorless oil and 38.4 mg

(28%) of 46b as a colorless crystalline solid.

Octa h yd r o-6,9,9-tr im eth yl-2-p h en yl-1H-p yr r olo[3,4-a ]-

in d olizin e-1,3(2H)-d ion e (44). 5-Bromo-2,2-dimethylhexanal

43 (269 mg, 1.30 mmol) was added to a solution of (tri-n-

butylstannyl)methylamine 9^26b,28(416 mg, 1.30 mmol) in

toluene (4.3 mL) at room temperature, followed by N-phenyl-

maleimide (338 mg, 1.95 mmol) in one portion. The mixture

was heated at reflux for 10 h. Analysis by GC-MS showed four

isomeric products (a :b:c:d ) 1:1.2:1.2:1.3) in the reaction

mixture. After concentration, the residue was chromato-

graphed (20% to 30% ethyl acetate/hexanes) to afford 72 mg

(18%) of a mixture of 44a and 44d , 54 mg (18%) of a mixture

of 44b and 44c, and 134 mg (33%) of a mixture of all isomers,

all as yellow oils. The regio- and stereochemistry of the

diastereomers could not be determined.

46a (exo): R_f) 0.15 (20% ethyl acetate/hexanes, stained with

1

I₂); IR (CH₂Cl₂) 1713 (s) cm^-1; H NMR (400 MHz, CDCl₃) δ

7.47 (t, J ) 7.7 Hz, 2 H), 7.39 (t, J ) 7.0 Hz, 1 H), 7.30 (d, J

) 7.3 Hz, 2 H), 7.09-7.21 (m, 4 H), 4.01 (d, J ) 14.7 Hz, 1 H),

3.74 (d, J ) 14.3, 1 H), 3.43 (t, J ) 8.4 Hz, 1 H), 3.34 (dt, J )

6.2 Hz, 1 H), 3.27 (dd, J ) 4.4, 8.8 Hz, 1 H, H-3a), 3.12 (s, 1 H,

H-3b), 3.10 (d, J ) 9.9 Hz, 1 H), 2.89 (dd, J ) 5.9, 9.2 Hz, 1

H), 2.51 (d, J ) 14.3 Hz, 1 H), 1.21 (s, 3 H), 0.68 (s, 3 H); ¹³C

NMR (100 MHz, CDCl₃) δ 177.68, 177.28, 139.6, 137.7, 132.0,

130.5, 129.1, 128.51, 128.48, 127.3, 126.43, 126.37, 78.1, 56.53,

56.31, 48.95, 48.68, 44.2, 36.1, 30.5, 21.1; MS (EI, 70 eV) m/z

44a and 44d : R_f) 0.56 (40% ethyl acetate/hexanes, stained

with I₂); IR (CHCl₃) 1778 (m), 1706 (s) cm^-^{1 1}H NMR (360

;

MHz, CDCl₃) δ 7.50-7.20 (m, 5 H), 3.76-3.65 (m, 1 H), 3.40-

3.30 (m, 1 H), 3.22-3.14 (m, 1 H), 2.25-2.00 (m, 2 H), 1.95-

1.85 (m, 1 H), 1.55-1.25 (m, 4 H), 1.50-1.15 (m, 3 H), 1.15-

1.05 (m, 3 H), 1.05-0.90 (m, 3 H); ¹³C NMR (90 MHz, CDCl₃)

δ 178.3, 177.6, 132.3, 129.1, 128.5, 128.4, 126.5, 126.4, 76.8,

75.2, 60.1, 58.7, 54.9, 54.1, 46.9, 46.4, 44.1, 43.4, 42.9, 40.0,

33.2, 32.9, 30.8, 30.3, 29.0, 27.1, 21.2, 20.9, 19.7, 19.6; MS (EI,

70 eV) m/z (rel intensity) 312 (M⁺, 19), 297 ([M - CH₃]⁺, 100),

243 ([M - C₅H₉]⁺, 81), 173 (N-phenylmaleimide, 35); HRMS

(EI, 70 eV) calcd for C₁₉H₂₄N₂O₂(M⁺) 312.1838, found 312.1833.

(rel intensity) 360 (M⁺, 41), 345 ([M - CH₃]⁺, 39), 215 ([M -

H₂C(C₆H₄)CH₂C(CH₃)₂]⁺, 94), 145 (H₂C(C₆H₄)CH₂C(CH₃)₂

,

+

59), 131 (H₂C(C₆H₄)CH₂C(CH₃)⁺, 88), 91 (PhCH₂⁺,100); HRMS

(ESI) calcd for

361.1912.

C

₂₃H₂₅N₂O₂([M + H]⁺) 361.1916, found

46b (endo): R_f) 0.08 (20% ethyl acetate/hexanes, stained

with I₂); mp 206-207 °C; IR (CH₂Cl₂) 1709 (s) cm^-1; ¹H NMR

(400 MHz, CDCl₃) δ 7.31-7.41 (m, 3 H), 7.10-7.19 (m, 5 H),

7.02-7.05 (m, 1 H), 3.82 (d, J ) 13.6 Hz, 1 H), 3.72 (d, J ) 9.5

Hz, 1 H), 3.48 (t, J ) 8.4 Hz, 1 H, H-3a), 3.38 (d, J ) 13.6 Hz,

1 H), 3.22 (dd, J ) 7.0, 8.4 Hz, 1 H), 2.95 (d, J ) 14.3 Hz, 1

H), 2.65 (dd, J ) 7.0, 9.5 Hz, 1 H), 2.56 (d, J ) 8.4, 1 H, H-3b),

2.42 (d, J ) 14.3 Hz, 1 H), 1.47 (s, 3 H), 0.64 (s, 3 H); ¹³C NMR

(100 MHz, CDCl₃) δ 177.78, 177.71, 139.9, 136.7, 132.1, 130.1,

129.08, 128.99, 128.6, 127.3, 126.51, 126.45, 83.3, 60.2, 59.1,

44b and 44c: R_f) 0.41 (40% ethyl acetate/hexanes, stained

with I₂); IR (CHCl₃) 1777 (m), 1708 (s) cm^-^{1 1}H NMR (360

;

MHz, CDCl₃) δ 7.50-7.20 (m, 5 H), 3.45-3.10 (m, 4 H), 2.80-

2.60 (m, 2 H), 2.00-1.60 (m, 1 H), 1.55-1.25 (m, 3 H), 1.25-

0.80 (m, 9 H); ¹³C NMR (90 MHz, CDCl₃) δ 178.4, 177.8, 177.2,

177.1, 132.3, 131.9, 129.0, 128.8, 128.4, 127.4, 126.7, 126.5,

126.3, 126.1, 125.1, 67.8, 66.0, 52.7, 51.4, 50.2, 50.0, 46.6, 46.3,

J . Org. Chem, Vol. 69, No. 6, 2004 1937

Pearson et al.

51.3, 48.4, 43.6, 35.6, 28.5, 19.5; MS (EI, 70 eV) m/z (rel

intensity) 360 (2, M⁺), 215 ([M - H₂C(C₆H₄)CH₂C(CH₃)₂]⁺,

100); HRMS (ESI) calcd for C₂₃H₂₅N₂O₂(M + H⁺) 361.1916,

found 361.1917. Stereochemistry was assigned on the basis of

2D COSY and 1D NOESY experiments. No NOE was seen

between the H-3a and H-3b hydrogens (J _3a-3b) 0 Hz) in 46a ,

but a strong NOE was observed between the H-3a and H-3b

hydrogens (J _3a-3b) 8.4 Hz) in 46b.

2-Meth ylpr opyliden e(tr im eth ylsilyl)m eth yla m in e (48).

Isobutyraldehyde (181 mg, 2.51 mmol) and (trimethylsilyl)-

methylamine 10 (259 mg, 2.51 mmol) were dissolved in ether

(7 mL) at room temperature. After 10 min, 4 Å molecular

sieves (1 g) were added. After 18 h, the reaction mixture was

filtered through Celite and concentrated at room temperature.

The residue was purified by Ku¨gelrohr distillation (35 mmHg,

65 °C) to give 285 mg of 48 (72%) as a colorless oil. IR (CH₂-

Cl₂) 1660 (m) cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 7.34 (td, J )

5.5, 1.1 Hz, 1 H), 3.10 (s, 2 H), 2.46-2.34 (m, 1 H), 1.05 (s, 3

H), 1.03 (s, 3 H), 0.01 (s, 9 H); ¹³C NMR (100 MHz, CDCl₃) δ

167.06, 53.38, 34.08, 19.68, -2.82; MS (EI, 70 eV) m/z (rel

intensity) 156 ([M - H]⁺, 30), 142 ([M - CH₃]⁺, 19), 87 ((CH₃)₃-

SiCH₂⁺, 32), 73 ((CH₃)₃Si⁺, 100); HRMS (EI, 70 eV) calcd for

C₈H₁₈NSi ([M - H]⁺) 156.12085, found 156.1208.

(3a R*,4S*,6a S*)- (49a ) a n d (3a R*,4R*,6a S*)-4-Isop r o-

p yl-2-p h en ylt et r a h yd r op yr r olo[3,4-c]p yr r ole-1,3-d ion e

(49b). Chloro(tri-n-butyl)stannane (14 mg, 0.043 mmol) was

added to a solution of imine 47^14b(80 mg, 0.21 mmol) and

N-phenylmaleimide (44 mg, 0.257 mmol) in toluene (2.1 mL)

at room temperature. The reaction was heated to reflux for 6

h, then diluted with 10% Na₂CO₃. The reaction was extracted

with CH₂Cl₂(4×) and the combined organic layers were

washed with brine (1×), dried, and concentrated. The residue

was chromatographed (20% to 100% ethyl acetate/hexanes,

gradient) to yield 17.5 mg (32%) of a 1:1 mixture of 49a and

49b as a colorless oil.

H), 1.02 (d, J ) 6.7 Hz, 3 H); ¹³C NMR (90 MHz, CDCl₃) δ

177.8, 177.3, 138.5, 129.1, 128.5, 128.4, 127.2, 126.3, 72.1, 57.8,

55.6, 46.7, 44.6, 28.7, 20.0, 16.9; MS (CI, NH₃) m/z (rel int)

349 ([M + H]⁺, 100), 212 (75), 108 (19); HRMS (CI, NH₃) calcd

for C₂₂H₂₅N₂O₂([M + H]⁺) 349.1916, found 349.1905.

50b (endo): R_f) 0.23 (20% ethyl acetate/hexanes, stained

in I₂); IR (CHCl₃) 1712 (s) cm^-1; ¹H NMR (360 MHz, CDCl₃) δ

7.50-7.20 (m, 10 H), 4.12 (d, J ) 13.1 Hz, 1 H), 3.43 (d, J )

9.8 Hz, 1 H), 3.33 (t, J ) 8.3 Hz, 1 H, H-3a), 3.20 (dd, J ) 8.0,

7.0 Hz, 1 H), 2.98 (d, J ) 13.1 Hz, 1 H), 2.66 (dd, J ) 8.3, 4.0

Hz, 1 H, H-4a), 2.50-2.40 (m, 1 H), 2.26 (dd, J ) 9.8, 7.0 Hz,

1 H), 1.29 (d, J ) 7.0 Hz, 3 H), 1.07 (d, J ) 7.2 Hz, 3 H); ¹³C

NMR (90 MHz, CDCl₃) δ 178.1, 177.5, 138.2, 132.3, 129.2,

128.5, 128.2, 127.2, 126.4, 72.8, 56.8, 55.5, 46.3, 43.8, 26.6, 17.9,

17.0; MS (CI, NH₃) m/z (rel intensity) 349 ([M + H]⁺, 100),

305 ([M - CH(CH₃)₂]⁺, 10), 257 ([M - PhCH₂]⁺, 13), 215 ([M

- PhCH₂- CH(CH₃)₂]⁺, 6); HRMS (CI, NH₃) calcd for

C

₂₂H₂₅N₂O₂([M + H]⁺) 349.1916, found 349.1900. The stereo-

chemistry at C(4) was determined by examination of the

coupling constant between H-4 and H-3a (50a , J _3a-4) 4.6 Hz;

50b, J _3a-4) 8.3 Hz) with the aid of molecular models.

1-Ben zyl-3-ben zen esu lfon yl-2-isopr opylpyr r olidin e an d

1-Ben zyl-4-ben zen esu lfon yl-2-isop r op ylp yr r olid in e (55).

Benzyl bromide (244 mg, 1.43 mmol) was added to a solution

of imine 47^14b(535 mg, 1.43 mmol) in toluene (7.5 mL), followed

by the addition of phenyl vinyl sulfone (241 mg, 1.43 mmol).

The mixture was heated at reflux for 10 h. After being cooled

to room temperature, the reaction was treated with concen-

trated NH₄OH and stirred for 15 min.⁵²The reaction mixture

was extracted with ether (3×), then the combined organic

layers were washed with brine, dried (MgSO₄), and concen-

trated. The residue was chromatographed (15% to 20% ethyl

acetate/hexanes, gradient) to afford 416 mg (85%) of the title

compound as a colorless oil. The product mixture contained

1

three inseparable isomers (5:3:1 by H NMR integration): R_f

) 0.28 (20% ethyl acetate/hexanes, stained in I₂); IR (CHCl₃)

49a (exo): R_f) 0.24 (ethyl acetate, stained in I₂); IR (CH₂-

1

1305 (s), 1148 (s) cm^-1; H NMR (400 MHz, CDCl₃) δ 7.96-

Cl₂) 3340 (w), 1773 (m), 1712 (s) cm^-^{1 1}H NMR (400 MHz,

;

7.90 (m, 2 H × 0.56), 7.88-7.84 (m, 2 H × 0.33), 7.82-7.76

(m, 2 H × 0.11), 7.70-7.50 (m, 3 H), 7.40-7.10 (m, 5 H), 4.01

(d, J ) 13.2 Hz, 1 H × 0.33), 4.00 (d, J ) 13.5 Hz, 1 H × 0.56),

3.91 (d, J ) 13.2 Hz, 1 H × 0.11), 3.64-3.45 (m, 1 H), 3.36-

3.30 (m, 1 H × 0.56), 3.23 (t, J ) 4.0 Hz, 1 H × 0.56), 3.12 (d,

J ) 13.2 Hz, 1 H × 0.33), 3.02 (dd, J ) 9.7, 7.5 Hz, 1 H ×

0.33), 2.88-2.80 (m, 1 H × 0.56), 3.70-3.50 (m, 1 H × 1.66),

2.44-2.32 (m, 1 H × 0.11), 2.28-2.14 (m, 1 H × 0.89), 2.10-

1.72 (m, 2 H), 0.94-0.83 (m, 3 H × 1.56), 0.80 (d, J ) 7.1 Hz,

3 H × 0.33), 0.66 (d, J ) 6.9 Hz, 3 H × 0.11); ¹³C NMR (90

MHz, CDCl₃) δ 140.2, 138.8, 138.5, 137.8, 133.6, 133.5, 129.3,

129.2, 129.1, 128.9, 128.8, 128.4, 128.3, 128.2, 128.1, 128.0,

127.0, 126.8, 68.8, 68.6, 68.1, 67.9, 65.9, 61.1, 60.8, 59.6, 57.5,

56.9, 54.3, 53.9, 52.5, 31.4, 27.6, 27.2, 27.1, 26.5, 25.7, 19.9,

19.0, 17.3, 14.5, 14.1. Anal. Calcd for C₂₀H₂₅NO₂S: C, 69.94;

H, 7.34; N, 4.08. Found: C, 69.60; H, 7.30; N, 4.02.

CDCl₃) δ 7.50-7.42 (m, 2 H), 7.41-7.36 (m, 1 H), 7.31-7.25

(m, 2 H), 3.46-3.31 (m, 3 H), 3.23 (app. t, J ) 7.3 Hz, 2 H),

1.90 (br s, 1 H), 1.80-1.70 (m, 1 H), 1.08 (d, J ) 6.6 Hz, 3 H),

1.01 (d, J ) 6.6 Hz, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 178.0,

177.7, 131.9, 129.1, 128.5, 126.3, 69.6, 49.6, 49.3, 46.8, 31.3,

19.9, 19.2; MS (CI-NH₃) m/z (rel intensity) 259 ([M + H]⁺, 100),

215 ([M - CH(CH₃)₂]⁺, 56); HRMS (CI-NH₃) calcd for

C

₁₅H₁₉N₂O₂([M + H]⁺) 259.1447, found 259.1441.

49b (endo): R_f) 0.17 (ethyl acetate, stained in I₂); IR (neat)

3349 (m), 1771 (s), 1722 (s) cm^-1; ¹H NMR (400 MHz, CDCl₃)

δ 7.47-7.44 (m, 2 H), 7.41-7.35 (m, 1 H), 7.31-7.25 (m, 2 H),

3.62 (d, J ) 10.6 Hz, 1 H), 3.36 (m, 2 H), 3.08 (dd, J ) 6.8,

10.6 Hz, 1 H), 2.83 (dd, J ) 6.0, 9.7 Hz, 1 H), 1.98-1.86 (m, 1

H), 1.76 (br s, 1 H), 1.22 (d, J ) 6.6 Hz, 3 H), 1.03 (d, J ) 6.6

Hz, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 178.4, 175.7, 132.0,

129.0, 128.5, 126.5, 70.8, 50.0, 46.6, 46.3, 29.6, 21.1, 20.8; MS

(CI-NH₃) m/z (rel intensity) 259 ([M + H]⁺, 100), ([M - CH-

(CH₃)₂]⁺, 71); HRMS (CI-NH₃) calcd for C₁₅H₁₉N₂O₂(M + H⁺)

259.1447, found 259.1435. Stereochemistry was assigned by

NOESY experiments and similarity to compounds 50a and

50b.

(6′a R *,3′a S *)-Dih yd r o-5′-p h e n yl-2′-(p h e n ylm e t h yl)-

s p ir o [c y c lo p e n t a n e -1,1′(2′H )-p y r r o lo [3,4-c]p y r r o l]-

4′,6′(3′H,5′H)-d ion e (56). Cyclopentylidene[(tri-n-butyl)stan-

nylmethyl]amine 57^14b(200 mg, 0.52 mmol) and N-phenyl-

maleimide (99 mg, 0.57 mmol) were dissolved in toluene (1.1

mL) and treated with benzyl bromide (97 mg, 0.57 mmol) at

room temperature. The reaction was heated to reflux over-

night. The reaction was concentrated and the residue chro-

matographed (25% ethyl acetate/hexanes) to afford 97 mg

(52%) of the title compound as a colorless oil. R_f) 0.24 (30%

ethyl acetate/hexanes, stained in I₂); IR (CHCl₃) 1777 (m), 1708

(3a R*,4R*,6a S*)- (50b) a n d (3a S*,4R*,6a R*)-5-Ben zyl-

4-isop r op yl-2-p h en ylocta h yd r op yr r olo[3,4-c]p yr r ole-1,3-

d ion e (50a ). Benzyl bromide (110 mg, 0.64 mmol) was added

to a solution of imine 47^14b(220 mg, 0.59 mmol) and N-

phenylmaleimide (112 mg, 0.65 mmol) in toluene (1.2 mL) at

room temperature and heated to reflux overnight. The reaction

was concentrated and chromatographed (20% ethyl acetate/

hexanes) to afford 43 mg (21%) of 50a and 75 mg (36%) of 50b,

both as colorless oils.

1

(s) cm^-1; H NMR (300 MHz, CDCl₃) δ 7.52-7.20 (m, 10 H),

3.93 (d, J ) 13.7 Hz, 1 H), 3.32-3.24 (m, 3 H), 3.07 (d, J ) 8.0

Hz, 1 H), 2.71 (dd, J ) 9.9, 7.9 Hz, 1 H), 2.35-2.25 (m, 1 H),

1.9-1.4 (m, 7 H); ¹³C NMR (90 MHz, CDCl₃) δ 178.5, 176.5,

139.4, 129.1, 128.5, 128.4, 127.7, 127.0, 126.5, 75.5, 53.9, 53.5,

50a (exo): R_f) 0.35 (20% ethyl acetate/hexanes, stained in

I₂); IR (CHCl₃) 1713 (s) cm^-^{1 1}H NMR (360 MHz, CDCl₃) δ

;

7.50-7.20 (m, 10 H), 3.98 (d, J ) 13.1 Hz, 1 H), 3.40-3.28 (m,

4 H, -NCH₂Ph, H-3a, H-6), 2.94, (t, J ) 4.6 Hz, 1 H, H-4),

2.64-2.56 (m, 1 H), 2.16-2.06 (m, 1 H), 1.10 (d, J ) 6.9 Hz, 3

(52) Seyferth, D.; Vaughan, L. G. J . Organomet. Chem. 1963, 138-

152.

1938 J . Org. Chem., Vol. 69, No. 6, 2004

Synthesis of Indolizidines and Related Heterocycles

51.1, 43.1, 30.5, 29.7, 26.8, 23.8; MS (EI, 70 eV) m/z (rel

discussions, and the National Institutes of Health for

funding (GM-52491).

intensity) 360 (M⁺, 5), 269 ([M - PhCH₂]⁺, 30), 91 (PhCH₂

,

+

100); HRMS (EI, 70 eV) calcd for C₂₃H₂₄N₂O₂(M⁺) 360.1838,

found 360.1847.

Su p p or tin g In for m a tion Ava ila ble: General experimen-

tal methods, ¹H NMR or ¹³C NMR spectra of stable new

compounds without elemental analysis, and an improved

synthesis of (tri-n-butylstannyl)methylamine. This material is

available free of charge via the Internet at http://pubs.acs.org.

Ack n ow led gm en t . We thank Dr. R. B. Clark for

characterization of pyrrolidine 49, Bristol-Myers Squibb

for a fellowship to P. Stoy, Professor D. Y. Gin for helpful

J O030334H

J . Org. Chem, Vol. 69, No. 6, 2004 1939

Article Doi

A Three-Component, One-Pot Synthesis of Indolizidines and Related Heterocycles Via the [3+2] Cycloaddition of Nonstabilized Azomethine Ylides

DOI: 10.1021/jo030334h

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