Base-catalyzed intramolecular hydroamination of conjugated enynes

Article abstract of DOI:10.1021/ol800334m

A de novo intramolecular hydroamination of conjugated enynes was developed using commercially available n-BuLi as a precatalyst. This hydroamination reaction successfully afforded allenyl-substituted pyrrolidines with up to 95% yield. One of the resulting allenyl pyrrolidines was converted to the natural products irniine and irnidine in three steps.

Full text of DOI:10.1021/ol800334m

ORGANIC
LETTERS
2008
Vol. 10, No. 10
2023-2026
Base-Catalyzed Intramolecular
Hydroamination of Conjugated Enynes
Wen Zhang,† Jenny B. Werness,‡ and Weiping Tang*,†
The School of Pharmacy and Department of Chemistry, UniVersity of Wisconsin,
777 Highland AVenue, Madison, Wisconsin 53705-2222
wtang@pharmacy.wisc.edu
Received February 19, 2008
ABSTRACT
A de novo intramolecular hydroamination of conjugated enynes was developed using commercially available n-BuLi as a precatalyst. This
hydroamination reaction successfully afforded allenyl-substituted pyrrolidines with up to 95% yield. One of the resulting allenyl pyrrolidines
was converted to the natural products irniine and irnidine in three steps.
New methods for producing nitrogen heterocycles in a
catalytic manner are of fundamental importance in organic
chemistry and pharmaceutical sciences. Intramolecular hy-
droamination of alkenes1 would be, in terms of an optimum
material balance, a superior atom-economical process.2
Impressive progress has been made recently for transition
metal catalyzed intramolecular additions of amides and
sulfonamides to alkenes, allenes, and dienes.3 The addition
of unprotected amines to alkenes, arguably the most impor-
tant donors and acceptors,4 has been studied in very limited
systems. The intramolecular addition of unprotected amines
to monosubstituted alkenes has been tested in a number of
catalytic systems based on rare earth metals,5 titanium and
zirconium,6,7 zinc,8 alkali metals,9,10 and late transition
metals.11 A few catalysts were developed for the intramo-
lecular addition of unprotected amines to 1,1-disubstituted
alkenes12,13 and 1,2-disubstituted alkenes.14 To extend the
scope of olefin substrates for the preparation of nitrogen
(5) Gagne, M. R.; Marks, T. J. J. Am. Chem. Soc. 1989, 111, 4108.
Kim, Y. K.; Livinghouse, T.; Bercaw, J. E. Tetrahedron Lett. 2001, 42,
2933. Kim, Y. K.; Livinghouse, T. Angew. Chem., Int. Ed. 2002, 41, 3645.
Gribkov, D. V.; Hultzsch, K. C.; Hampell, F. Chem. Eur. J. 2003, 9, 4796.
O’Shaughnessy, P. N.; Knight, P. D.; Morton, C.; Gillespie, K. M.; Scott,
P. Chem. Commun. 2003, 1770. Hong, S.; Marks, T. J. Acc. Chem. Res.
2004, 37, 673. Lauterwasser, F.; Hayes, P. G.; Brase, S.; Piers, W. E.;
Schafer, L. L. Organometallics 2004, 23, 2234. Kim, J. Y.; Livinghouse,
T. Org. Lett. 2005, 7, 1737. Gribkov, D. V.; Hultzsch, K. C.; Hampel, F.
J. Am. Chem. Soc. 2006, 128, 3748
.
(6) Knight, P. D.; Munslow, I.; O’Shaughnessy, P. N.; Scott, P. Chem.
Commun. 2004, 894. Gribkov, D. V.; Hultzsch, K. C. Angew. Chem., Int.
Ed. 2004, 43, 5542. Muller, C.; Loos, C.; Schulenberg, N.; Doye, S. Eur.
J. Org. Chem. 2006, 2499. Marcsekova, K.; Loos, C.; Rominger, F.; Doye,
S. Synlett 2007, 2564. Wood, M. C.; Leitch, D. C.; Yeung, C. S.; Kozak,
J. A.; Schafer, L. L. Angew. Chem., Int. Ed. 2007, 46, 354. Ackermann, L.;
† The School of Pharmacy.
‡ Department of Chemistry.
(1) Hultzsch, K. C. AdV. Synth. Catal. 2005, 347, 367. Beller, M.;
Breindl, C.; Eichberger, M.; Hartung, C. G.; Seayad, J.; Thiel, O. R.; Tillack,
A.; Trauthwein, H. Synlett 2002, 1579. Mueller, T. E.; Beller, M. Chem.
ReV. 1998, 98, 675.
Kaspar, L. T.; Althammer, A. Org. Biomol. Chem. 2007, 5, 1975
(7) Bexrud, J. A.; Beard, J. D.; Leitch, D. C.; Schafer, L. L. Org. Lett.
2005, 7, 1959
.
(2) Trost, B. M. Science 1991, 254, 1471. Trost, B. M. Angew. Chem.,
Int. Ed. 1995, 34, 259.
.
(3) Qin, H.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem.
Soc. 2006, 128, 1611. Komeyama, K.; Morimoto, T.; Takaki, K. Angew.
Chem., Int. Ed. 2006, 45, 2938. Zhang, Z. B.; Bender, C. F.; Widenhoefer,
R. A. J. Am. Chem. Soc. 2007, 129, 14148. Han, X. Q.; Widenhoefer, R. A.
Angew. Chem., Int. Ed. 2006, 45, 1747. Bender, C. F.; Widenhoefer, R. A.
Chem. Commun. 2006, 4143. Zhang, J. L.; Yang, C. G.; He, C. J. Am.
Chem. Soc. 2006, 128, 1798. Liu, X. Y.; LiC. H.; Che, C. M. Org. Lett.
2006, 8, 2707. LaLonde, R. L.; Sherry, B. D.; Kang, E. J.; Toste, F. D.
J. Am. Chem. Soc. 2007, 129, 2452. Zhang, Z. B.; Bender, C. F.;
Widenhoefer, R. A. Org. Lett. 2007, 9, 2887.
(8) Zulys, A.; Dochnahl, M.; Hollmann, D.; Lohnwitz, K.; Herrmann,
J. S.; Roesky, P. W.; Blechert, S. Angew. Chem., Int. Ed. 2005, 44, 7794.
Dochnahl, M.; Lohnwitz, K.; Pissarek, J. W.; Biyikal, M.; Schulz, S. R.;
Schon, S.; Meyer, N.; Roesky, P. W.; Blechert, S. Chem. Eur. J. 2007, 13,
6654.
(9) Fujita, H.; Tokuda, M.; Nitta, M.; Suginome, H. Tetrahedron Lett.
1992, 33, 6359
(10) Ates, A.; Quinet, C. Eur. J. Org. Chem. 2003, 1623. Martinez, P. H.;
Hultzsch, K. C.; Hampel, F. Chem. Commun. 2006, 2221
(11) Bender, C. F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2005, 127,
1070.
.
.
(4) Ritter, S. Chem. Eng. News 2008, 86, 12.
10.1021/ol800334m CCC: $40.75
Published on Web 04/25/2008
2008 American Chemical Society

heterocycles bearing key substituents present in naturally
occurring compounds, conjugated amino dienes,15,16 vinyl
arenes,7,9,17 and highly reactive aminoallenes18 have been
used to prepare substituted nitrogen heterocycles via in-
tramolecular hydroamination.
Despite impressive progress on the hydroamination of
carbon-carbon multiple bonds, the intramolecular hydroami-
nation of conjugated enynes has never been explored
(Scheme 1).19 An interesting question arises because two
1. Herein, we report the first intramolecular hydroamination
of conjugated enyne 1, which selectively affords allenyl
amine 2.
Alkali metals have been used to catalyze the addition of
amines to monosubstituted alkenes,9,10 1,1-disubstituted
alkenes,12 1,3-butadienes,16,20 and conjugated vinyl arenes9,21
including electron-rich vinylarenes22 via deprotonation of the
amine followed by addition to the double bonds.23 In an
effort to develop a catalyst that is cost-effective and readily
accessible, we decided to explore the potential of alkali
metals for the intramolecular hydroamination of conjugated
enynes.
When we first treated aminoenyne 1a24 with 120 mol %
of n-BuLi at -78 °C in THF, compound 1a was completely
cycloisomerized to allenyl pyrrolidine 2a with a 1.8:1
diastereomeric ratio after 1 h. We then reduced the amount
of n-BuLi to 20 mol % and increased the concentration of
the aminoenyne to 0.4 M in THF. A 100% conversion was
achieved at -78 °C with a 1.6:1 diastereomeric ratio after
1 h. No homopropargyl amine 3 was observed under these
conditions.
Scheme 1. Intramolecular Hydroamination of Alkenes
We then investigated the scope of the hydroamination of
conjugated aminoenynes using 20 mol % of n-BuLi as a
precatalyst (Table 1). Amino enynes with different substit-
uents on the amino group all worked well under optimal
conditions with no significant changes of the yields and
diastereomeric ratios. Surprisingly, increasing the steric bulk
of the alkyne improved the diastereomeric ratio from 2:1 to
5:1 (Table 1, entries 3 and 7). It is worth mentioning that
amines with a removable benzyl group worked well (Table
1, entries 6 and 8). A phenyl substituted enyne also provided
a high yield of the hydroamination product (Table 1, entry
9). Substituted pyrroldine 2j was obtained as a mixture of
two diastereomers, which yielded only the cis-1,2-disubsti-
tuted pyrrolidine upon hydrogenation (Table 1, entry 10).
Efforts toward the formation of six-membered-ring hetero-
cycles via hydroamination of enynes were not successful
(Table 1, entry 11).
potential hydroamination products can be formedsallenyl
amine 2 and homopropargyl amine 3 as shown in Scheme
(12) Evans, B. E.; Anderson, P. S.; Christy, M. E.; Colton, C. D.; Remy,
D. C.; Rittle, K. E.; Engelhardt, E. L. J. Org. Chem. 1979, 44, 3127
.
(13) Molander, G. A.; Dowdy, E. D. J. Org. Chem. 1998, 63, 8983.
Molander, G. A.; Dowdy, E. D. J. Org. Chem. 1999, 64, 6515. Molander,
G. A.; Pack, S. K. J. Org. Chem. 2003, 68, 9214. Kim, H.; Lee, P. H.;
Livinghouse, T. Chem. Commun. 2005, 5205. Dochnahl, M.; Pissarek, J. W.;
Blechert, S.; Lohnwitz, K.; Roesky, P. W. Chem. Commun. 2006, 3405
.
(14) Ryu, J.-S.; Marks, T. J.; McDonald, F. E. Org. Lett. 2001, 3, 3091.
Kim, Y. K.; Livinghouse, T.; Horino, Y. J. Am. Chem. Soc. 2003, 125,
9560. Ryu, J.-S.; Marks, T. J.; McDonald, F. E. J. Org. Chem. 2004, 69,
1038. Stubbert, B. D.; Marks, T. J. J. Am. Chem. Soc. 2007, 129, 4253.
The proposed mechanism for the base catalyzed hy-
droamination of XXenynes is shown in Scheme 2.23 The
Liu, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 1570
.
(15) Hong, S.; Marks, T. J. J. Am. Chem. Soc. 2002, 124, 7886. Hong,
S.; Kawaoka, A. M.; Marks, T. J. J. Am. Chem. Soc. 2003, 125, 15878.
Sakai, N.; Ridder, A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 8134.
(19) A Pd-catalyzed intermolecular hydroamination of conjugated enynes
yielded 1,4-diaminoalkenes via π-allyl palladium complexes: Radhakrishnan,
U.; Al-Masum, M.; Yamamoto, Y. Tetrahedron Lett. 1998, 39, 1037.
(20) Takabe, K.; Katagiri, T.; Tanaka, J.; Fujita, T.; Watanabe, S.; Suga,
K. Org. Synth. 1989, 67, 44. Inoue, S.; Takaya, H.; Tani, K.; Otsuka, S.;
Sato, T.; Noyori, R. J. Am. Chem. Soc. 1990, 112, 4897. Lebeuf, R.; Robert,
F.; Landals, Y. Org. Lett. 2005, 7, 4557.
Tobisch, S. Chem. Eur. J. 2007, 13, 9127
.
(16) Lebeuf, R.; Robert, F.; Schenk, K.; Landais, Y. Org. Lett. 2006, 8,
4755
.
(17) Thomson, R. K.; Bexrud, J. A.; Schafer, L. L. Organometallics
2006, 25, 4069. Takemiya, A.; Hartwig, J. F. J. Am. Chem. Soc. 2006,
128, 6042. Kaspar, L. T.; Fingerhut, B.; Ackermann, L. Angew. Chem.,
(21) Beller, M.; Breindl, C.; Riermeier, T. H.; Eichberger, M.; Trauth-
wein, H. Angew. Chem., Int. Ed. 1998, 37, 3389. Beller, M.; Thiel, O. R.;
Trauthwein, H.; Hartung, C. G. Chem. Eur. J. 2000, 6, 2513. Barry, C. S.;
Simpkins, N. S. Tetrahedron Lett. 2007, 48, 8192. Kumar, K.; Michalik,
D.; Castro, I. G.; Tillack, A.; Zapf, A.; Arlt, M.; Heinrich, T.; Bottcher,
H.; Beller, M. Chem. Eur. J. 2004, 10, 746. Ogata, T.; Ujihara, A.; Tsuchida,
S.; Shimizu, T.; Kaneshige, A.; Tomioka, K. Tetrahedron Lett. 2007, 48,
6648.
Int. Ed. 2005, 44, 5972
.
(18) Arredondo, V. M.; McDonald, F. E.; Marks, T. J. J. Am. Chem.
Soc. 1998, 120, 4871. Arredondo, V. M.; McDonald, F. E.; Marks, T. J.
Organometallics 1999, 18, 1949. Arredondo, V. M.; Tian, S.; McDonald,
F. E.; Marks, T. J. J. Am. Chem. Soc. 1999, 121, 3633. Sweeney, Z. K.;
Salsman, J. L.; Andersen, R. A.; Bergman, R. G. Angew. Chem., Int. Ed.
2000, 39, 2339. Straub, B. F.; Bergman, R. G. Angew. Chem., Int. Ed. 2001,
40, 4632. Shi, Y.; Ciszewski, J. T.; Odom, A. L. Organometallics 2001,
20, 3967. Ackermann, L.; Bergman, R. G. Org. Lett. 2002, 4, 1475.
Ackermann, L.; Bergman, R. G.; Loy, R. N. J. Am. Chem. Soc. 2003, 125,
11956. Ackermann, L. Organometallics 2003, 22, 4367. Michael, F. E.;
Duncan, A. P.; Sweeney, Z. K.; Bergman, R. G. J. Am. Chem. Soc. 2003,
125, 7184. Hoover, J. M.; Petersen, J. R.; Pikul, J. H.; Johnson, A. R.
Organometallics 2004, 23, 4614. Meguro, M.; Yamamoto, Y. Tetrahedron
Lett. 1998, 39, 5421. Patil, N. T.; Lutete, L. M.; Nishina, N.; Yamamoto,
Y. Tetrahedron Lett. 2006, 47, 4749.
(22) Trost, B. M.; Tang, W. J. Am. Chem. Soc. 2003, 125, 8744. Pathak,
R.; Naicker, P.; Thompson, W. A.; Fernandes, M. A.; de Koning, C. B.;
van Otterlo, W. A. L. Eur. J. Org. Chem. 2007, 5337. van Otterlo, W. A. L.;
Pathak, R.; de Koning, C. B.; Fernandes, M. A. Tetrahedron Lett. 2004,
45, 9561.
(23) Seayad, J.; Tillack, A.; Hartung, C. G.; Beller, M. AdV. Synth. Catal.
2002, 344, 795.
(24) The aminoenynes can be prepared in two to four steps from
commerically available materials. See the Supporting Informationfor
details.
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Org. Lett., Vol. 10, No. 10, 2008

Table 1. Hydroamination of Conjugated Enynesa
Scheme 2. A Proposed Mechanism
antimycotic activity29 and a strong binding affinity for
DNA.30 From the same natural source, derivatives of irniine
such as irnidine 13 have also been isolated.31 We envisioned
Scheme 3. Short Syntheses of Irniine and Irnidine
that an alkyne-zipper reaction32 could convert the allene
functional group next to the pyrrolidine ring in 2a-f to a
terminal alkyne, which can then be further transformed to a
desired functionality. Indeed, treatment of hydroamination
product 2d with excess potassium hydride in a solution of
1,3-diaminopropane completely isomerized allene 2d to
terminal alkyne 7. Sonogashira cross-coupling reactions33
between alkyne 7 and iodobenzene 8 or 1-iodo-2-methoxy-
benzene 9 provided penultimate intermediates 10 and 11.
Palladium catalyzed hydrogenation of alkyne 10 and 11 then
cleanly afforded natural products irniine 12 and its congener
irnidine 13.
a All reactions were performed at -78 °C with n-BuLi (20 mol %) in
THF (0.4 M). b Ratios were determined using NMR in CD3COCD3.
amine N-H was first deprotonated by n-BuLi to form lithium
amide 4 which presumably served as the catalytic species.
A 5-exo-trig cyclization could generate propargyllithium 5
and/or allenyllithium 6,25 which could then be protonated
by amino enyne 1 to give allenylamine 2 and catalyst 4.
Substituted pyrrolidines exist in numerous natural products
and pharmaceutical agents and display a broad spectrum of
biological activities.26 For example, irniine 12 (Scheme 3)
was isolated from the tubers of Arisarum Vulgare, a toxic
amceae responsible for human and animal poisonings in
Morocco.27 Irniine28 displayed significant antibacterial and
(28) Takahata, H.; Ihara, K.; Kubota, M.; Momose, T. Heterocycles 1997,
46, 349. Jossang, A.; Melhaoui, A.; Bodo, B. Heterocycles 1996, 43, 755.
(29) Rakba, N.; Melhaoui, A.; Rissel, M.; Morel, I.; Loyer, P.; Lescoat,
G. Toxicon 2000, 38, 1389.
(30) Melhaoui, A.; Belouali, H. J. Ethnopharmacol. 1998, 62, 67.
(31) Melhaoui, A. Planta Med. 1998, 64, 476.
(25) Reich, H. J.; Holladay, J. E.; Mason, J. D.; Sikorski, W. H. J. Am.
Chem. Soc. 1995, 117, 12137.
(32) Brown, C. A.; Yamashita, A. J. Am. Chem. Soc. 1975, 97, 891.
(33) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467.
(26) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435.
(27) Melhaoui, A.; Jossang, A.; Bodo, B. J. Nat. Prod. 1992, 55, 950.
Org. Lett., Vol. 10, No. 10, 2008
2025

In summary, we report the first intramolecular hydroami-
nation of conjugated enynes. The reaction was catalyzed by
lithium amide to yield allenylpyrrolidines in up to 95% yield.
A stereogenic center and an axial chiral allene were generated
in this cycloisomerization reaction, and a diastereomeric ratio
of up to 5:1 was achieved. The resulting allene could be
further functionalized34 as demonstrated in the divergent
synthesis of the natural products irniine and irnidine. The
sequential enyne-hydroamination followed by alkyne-zipper
reaction should be applicable to the synthesis of other
pyrrolidines with remote functional groups, such as the
family of broussonetine iminosugars.26 The low cost of
commercially available n-BuLi precatalyst and the mild
conditions make this hydroamination feasible for industrial
production of substituted pyrrolidines. The current results
also encourage further development of a catalytic, diastereo-,
and enantioselective hydroamination method for conjugated
enynes.
Acknowledgment. We thank Professor Richard Hsung
(UWsMadison) for helpful discussions, the University of
Wisconsin Graduate School and the School of Pharmacy for
generous startup funding, and the School of Pharmacy
Analytical Instrument Center (AIC) for mass spectrometry
services and NMR support.
(34) Krause, N.; Hashmi, A. S. K. Modern Allene Chemistry; Wiley-
VCH Verlag GmbH & Co. KGaA: Weinheim, 2004; Vols. 1 and 2.
Brandsma, L. Acetylenes, allenes and cumulenes; Elsevier: Amsterdam,
2005. Tracey, M. R.; Hsung, R. P.; Antoline, J. A.; Kurtz, K. C. M.; Shen,
L.; Slafer, B. W.; Zhang, Y. Houben-Weyl Methods of Molecular
Transformations. In Science of Synthesis; Weinreb, S. M., Ed.; Georg
Thieme Verlag KG: Stuttgart, 2005; Chapter 21.4. MaS., Chem. ReV. 2005,
105, 2829.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL800334M
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Org. Lett., Vol. 10, No. 10, 2008