The synthesis of homoallylic amines utilizing a cuprate-based 1,2-metalate rearrangement

Article abstract of DOI:10.1021/jo001386z

Lithiation of the N-2,4,6-triisopropylbenzenesulfonyl-2-pyrroline (16) and treatment of the resulting cyclic vinyllithium reagent with R₂CuCNLi₂ produced an acyclic vinyl organometallic species that, when treated with an electrophile (H₂O or RX), gave the homoallylic sulfonamides 18a - k in 37 - 93% yields and in >95% diastereoselectivity. The deprotection of a representative homoallylic sulfonamide 18d was achieved in 83% yield by sonication in the presence of lithium wire and catalytic 4,4′-di-tert-butylbiphenyl (DBB). The efficacy of this general procedure for the production of homoallylic amine derivatives is demonstrated by the preparation of the diene amine 25, a key intermediate in the synthesis of a squalene synthetase inhibitor.

Full text of DOI:10.1021/jo001386z

J . Org. Chem. 2001, 66, 531-537
531
Th e Syn th esis of Hom oa llylic Am in es Utilizin g a Cu p r a te-Ba sed
1,2-Meta la te Rea r r a n gem en t
Christopher E. Neipp, J ohn M. Humphrey, and Stephen F. Martin*
Department of Chemistry and Biochemistry, The University of Texas, Austin, Texas 78712
sfmartin@mail.utexas.edu
Received September 18, 2000
Lithiation of the N-2,4,6-triisopropylbenzenesulfonyl-2-pyrroline (16) and treatment of the resulting
cyclic vinyllithium reagent with R2CuCNLi2 produced an acyclic vinyl organometallic species that,
when treated with an electrophile (H2O or RX), gave the homoallylic sulfonamides 18a -k in 37-
93% yields and in >95% diastereoselectivity. The deprotection of a representative homoallylic
sulfonamide 18d was achieved in 83% yield by sonication in the presence of lithium wire and
catalytic 4,4′-di-tert-butylbiphenyl (DBB). The efficacy of this general procedure for the production
of homoallylic amine derivatives is demonstrated by the preparation of the diene amine 25, a key
intermediate in the synthesis of a squalene synthetase inhibitor.
In tr od u ction
amines have been reported,4-6 but the most commonly
used reactions leading to their preparation involve ad-
ditions of allylic organometallics or allyl silanes to imines
or nitriles.7,8 Unfortunately, none of these methods allow
for a significant degree of stereochemical control in
forming homoallylic amines having either a di- or trisub-
stituted olefin. Indeed, none of the methods that have
been reported for the synthesis of trisubstituted olefins
have been adapted to the direct formation of homoallylic
amines.9,10 Thus, the challenge before us was to develop
a general and stereoselective entry to homoallylic amines
having di- and trisubstituted carbon-carbon double
bonds. From the standpoint of flexibility, a method that
employed a common starting material as a precursor
would have obvious advantages.
The homoallylic amine functional array is an important
structural subunit found in biologically active compounds
as well as in key intermediates in the synthesis of
alkaloid natural products and nitrogen heterocycles. For
example, the homoallylic amines 1 and 2 have been
shown to inhibit squalene synthetase.1 We have used
homoallylic amines and homoallylic diene amines, re-
spectively, as dienophiles and dienes in intramolecular
Diels-Alder reactions that led to the formation of
nitrogen heterocycles found in different families of alka-
loids.2 Indeed, the amine 3 was an intermediate in the
total, enantioselective synthesis of manzamine A.3 Owing
to their obvious importance, the development of general
and efficient methods for the synthesis of homoallylic
amines and their derivatives has been a topic of consid-
erable interest.
(4) Anderson, J .; Dupau, P.; Siddons, D.; Smith, S.; Swarbrick, M.
Tetrahedron Lett. 1998, 39, 2649-2650.
(5) Vankar, Y. D.; Kumaravel, G.; Rao, C. T. Synth. Commun. 1989,
19, 2181-2198.
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1983, 39, 3337-3344. (b) DeShong, P.; Leginus, J . M.; Lander, S. W.,
J r. J . Org. Chem. 1986, 51, 574-576. (c) Armstrong, S. K.; Warren,
S.; Collington, E. W.; Naylor, A. Tetrahedron Lett. 1991, 32, 4171-
4174. (d) Berry, M. B.; Craig, D.; J ones, P. S. Synlett 1993, 513-514.
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Commun. 1984, 1004-1005. (b) Yamamoto, Y.; Komatsu, T.; Maruya-
ma, K. J . Am. Chem. Soc. 1984, 106, 5031-5033. (c) Keck, G. E.;
Enholm, E. J . J . Org. Chem. 1985, 50, 146-147. (d) Tanaka, H.; Inoue,
K.; Pokorski, U.; Taniguchi, M.; Torii, S. Tetrahedron Lett. 1990, 31,
3023-3026. (e) Hua, D. H.; Miao, S. W.; Chen, J . S.; Iguchi, S. J . Org.
Chem. 1991, 56, 4-6. (f) Veenstra, S. J .; Schmid, P. Tetrahedron Lett.
1997, 38, 997-1000. (g) Loh, T.-P.; Ho, D. S.-C.; Xu, K.-C.; Sim, K.-Y.
Tetrahedron Lett. 1997, 38, 865-868. (h) Nakamura, H.; Nakamura,
K.; Yamamoto, Y. J . Am. Chem. Soc. 1998, 120, 4242-4243. (i) Meester,
W. J . N.; Rutjes, F. P. J . T.; Hermkens, P. H. H.; Hiemstra, H.
Tetrahedron Lett. 1999, 40, 1601-1604.
(8) Yu, M.; Zhang, Y.; Guo, H. Synth. Commun. 1997, 27, 1495-
A number of methods for the synthesis of homoallylic
1500.
(9) For reviews on the synthesis of substituted olefins, see: (a)
Faulkner, D. J . Synthesis 1971, 175-189. (b) Reucroft, J .; Sammes,
P. G. Quart. Rev. Chem. Soc. 1971, 25, 135-169.
(1) (a) Steiger, A.; Pyun, H.-J .; Coates, R. M. J . Org. Chem. 1992,
57, 3444-3449. (b) Prashad, M. J . Med. Chem. 1993, 36, 631-632.
(2) (a) Martin, S. F.; Williamson, S. A.; Gist, R. P.; Smith, K. M. J .
Org. Chem. 1983, 47, 5170-5180. (b) Martin, S. F.; Ru¨eger, H.;
Williamson, S. A.; Grzejszczak, S. J . Am. Chem. Soc. 1987, 109, 6124-
6134. (c) Martin, S. F.; Geraci, L. S. Tetrahedron Lett. 1988, 29, 6725-
6728. (d) Martin, S. F.; Liao, Y.; Rein, T.; Wong, Y. Tetrahedron Lett.
1994, 35, 691-694.
(10) (a) Martin, S. F.; Daniel, D.; Cherney, R. J .; Liras, S. J . Org.
Chem. 1992, 57, 2523-2525 (and references therein). (b) Quayle, P.;
Wang, J .; Xu, J ie; Urch, C. J . Tetrahedron Lett. 1998, 39, 485-488.
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7525-7528. (d) Beller, M.; Riermeier, T. H. Eur. J . Inorg. Chem. 1998,
29-35. (e) Cristau, H. J .; Taillefer, M. Tetrahedron 1998, 54, 1507-
1522. (f) Breit, B.; Zahn, S. K. Angew. Chem., Int. Ed. Engl. 1999, 38,
8, 969-971. (g) de Meijere, A.; Brase, S. J . Organomet. Chem. 1999,
576(1-2), 88-110.
(3) Martin, S. F.; Humphrey, J . H.; Ali, A.; Hillier, M. C. J . Am.
Chem. Soc. 1999, 121, 866-867.
10.1021/jo001386z CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/28/2000

532 J . Org. Chem., Vol. 66, No. 2, 2001
Neipp et al.
Sch em e 1
N-substituted pyrrolines 4 as potential starting materials
for the stereoselective synthesis of homoallylic amines
and report herein the results of these studies.
Resu lts a n d Discu ssion
We initially examined whether the N-protected pyr-
rolines 12 and 13 could be used as substrates for the
synthesis of protected homoallylic amines. The initial
deprotonation of 12 seemed well precedented by the work
of Beak and Meyers, who reported that N-Boc and
N-formamidino piperidines and pyrrolidines undergo
facile deprotonation with t-BuLi to give the corresponding
R-amino carbanions.15 However, we found in preliminary
experiments that the N-substituted pyrroline 12 did not
cleanly undergo R-metalation with s-BuLi or t-BuLi
under several conditions, and a number of unidentified
products were produced in these experiments. Although
we found that the N-tosyl pyrroline 13 could be meta-
lated, the reaction of the resulting R-lithio enesulfon-
amide with Me3CuLi2‚LiBr followed by aqueous workup
gave 14, albeit in only about 10% yield. Because 14 was
accompanied with a number of other unidentified prod-
ucts including unreacted 13, we queried whether a
modified sulfonamide derivative might provide superior
results. In this context, it is relevant that 2,4,6-triiso-
propylbenzenesulfonyl (trisyl) hydrazones are superior
to p-toluenesulfonyl hydrazones in the Shapiro olefin
synthesis.16
A search of the literature led us to consider the
possibility that R-lithiation of a suitably protected pyr-
roline such as 4 followed by reaction with an organocu-
prate reagent would generate an intermediate of the
general type 10 (M ) CuR2Li). We anticipated that 10
(M ) CuR2Li) would undergo a 1,2-metalate rearrange-
ment to deliver a vinyl organometallic intermediate 6
that could be trapped in situ with an electrophile to
furnish the homoallylic amine 8 (Scheme 1). This novel
strategy was inspired by Fujisawa’s intriguing discovery
that ortho lithiation of 2,3-dihydrofuran (5) to give 11
(M ) Li), followed by an organocuprate-induced 1,2-
metalate rearrangement via an intermediate of the
general form 7, afforded disubstituted, (E)-homoallylic
alcohols 9 (E ) H).11 This methodology was subsequently
developed extensively by Kocienski, who found that the
reaction could be applied to the stereoselective synthesis
of homoallylic alcohols 9 with di- and trisubstituted
olefins;12 bis-homoallylic alcohols were also accessible by
a variant of this protocol.
In the event, the N-trisyl pyrroline 16 was first
prepared in 64% yield and three steps from 2-pyrrolidi-
none (15) (Scheme 2). Metalation of 16 with t-BuLi at
Despite the obvious appeal of a nitrogen variant of the
Fujisawa-Kocienski reaction for the synthesis of homo-
allylic amines 8, a survey of the literature revealed no
precedent for the ring opening of an R-metalated dihy-
dropyrrole 10 to give an intermediate such as 6. On the
contrary, a recent review by Braun suggests that R-ni-
trogen-substituted alkenyllithium compounds such as 10
(M ) Li) exhibit exclusive carbanion-like activity,13 not
the electrophilic carbenoid behavior of the analogous
oxygen-substituted alkenyllithiums 11 that is ostensibly
necessary for the metalate rearrangement to form 6.
Inasmuch as the poor leaving group ability of R2N-M is
at least partly responsible for the noncarbenoid nature
of R-lithiated amines,14 it occurred to us that placement
of more strongly electron-withdrawing groups on nitrogen
might give metalated derivatives of 10 that would rear-
range to give 6, thereby leading to homoallylic amines
8. Toward this end, we examined the candidacy of several
Sch em e 2
(11) Fujisawa, T.; Kurita, Y.; Kawashima, M.; Sato, T. Chem. Lett.
1982, 1641-1642.
(12) (a) Kocienski, P.; Wadman, S.; Cooper, K. J . Am. Chem. Soc.
1989, 111, 2363-2365. (b) Kocienski, P.; Barber, C. Pure Appl. Chem.
1990, 62, 1933-1940.
(13) Braun, M. Angew. Chem., Int. Ed. Engl. 1998, 37, 430-451.
(14) Boche, G.; Marsch, M.; Harback, J .; Harms, K.; Ledig, B.;
Schubert, F.; Lohrenz, J .; Ahlbrecht, H. Chem. Ber. 1993, 126, 1887-
1894.
(15) (a) Beak, P.; Lee, W. K. J . Org. Chem. 1993, 58, 1109-1117.
(b) Meyers, A. I.; Edwards, P. D.; Bailey, T. R.; J agdmann, G. E., J r.
J . Org. Chem. 1985, 50, 1019-1026.
(16) Chamberlin, A. R.; Stemke, J . E.; Bond, F. T. J . Org. Chem.
1978, 43, 147-154.

Synthesis of Homoallylic Amines
J . Org. Chem., Vol. 66, No. 2, 2001 533
product (18)
Ta ble 1.
entry
cuprate
electrophile
R
E
% yielda,b
a
b
c
d
e
f
g
h
i
Me2CuCNLi2
(CH2)CH)2CuCNLi2
Ph2CuCNLi2
H2O
H2O
H2O
H2O
H2O
H2O
MeI
MeI
allyl bromide
I2
Me3SnCl
Me3SnCl
Me
H2C)CH-
Ph
n-Bu
s-Bu
t-Bu
Me3Sn
t-Bu
t-Bu
t-Bu
t-Bu
Me
H
H
H
H
H
H
71
66
75
77
68
93
37
92
88
92
80
75
n-Bu2CuCNLi2
sec-Bu2CuCNLi2
tert-Bu2CuCNLi2
(Me)3Sn2CuCNLi2
tert-Bu2CuCNLi2
tert-Bu2CuCNLi2
tert-Bu2CuCNLi2
tert-Bu2CuCNLi2
Me2CuCNLi2
Me
Me
allyl
I
Me3Sn
Me3Sn
j
k
l
a
b
Yields are based upon products isolated by column chromatography on silica gel. Isomeric purity was established as >95:5 on the
basis of 1H NMR spectroscopy on a 300 MHz instrument.
Sch em e 3
-78 °C in Et2O proceeded cleanly as evidenced by a
preliminary experiment in which the anion was quenched
with CD3OD to provide 17 with >95% deuterium incor-
poration. After some experimentation, we discovered that
16 could be converted to homoallylic amines 18a -k in
good overall yields and stereoselectivity by sequential
metalation with t-BuLi (-78 °C), reaction with a higher
order cyanocuprate (R2CuCNLi2) (0 °C f rt), followed by
the addition of an electrophile, E+ (see Table 1). The best
results were obtained when a slight excess of R2CuCNLi2
was used; lower yields of homoallylic amines were
obtained when a catalytic quantity (10%) of CuCN was
employed. Those cuprates generated by treatment of
CuBr‚SMe2 with 3 equiv of RLi could also be used
successfully, but the yields of homoallylic amine were not
reproducible. In several control experiments, we found
that simply treating lithiated 16 with another organo-
lithium reagent in the absence of CuCN failed to yield
any homoallylic amine; lithiation of 16 prior to treatment
with a cuprate was necessary for the reaction to proceed.
The ring-opening reaction did not occur when THF was
used as the solvent, and the reaction proceeded slowly
and incompletely when Et2O/THF mixtures were used.
The observation of this solvent effect is consistent with
observations of Fujisawa who screened diethyl ether,
dimethoxyethane, THF, and dioxane as solvents for the
transformation 5 f 9 and found that using diethyl ether
led to higher yields of ring-opened products.11 THF
presumably inhibits metal-assisted ionization of the
intermediate vinyl organometallic agents 10 and 11 to
give the putative electrophilic carbenoid that then un-
dergoes 1,2-metalate rearrangement.17 In this context,
it may also be relevant that such carbenoids are more
stable in THF than in diethyl ether.18
stereochemically pure homoallylic amines are normally
in the range of 70-90%. With respect to entry g there
are several observations that are noteworthy: When a
solution of Me3SnLi that was prepared in THF was used,
none of the homoallylic amine 18g (R ) Me3Sn, E ) Me)
was obtained upon quenching with MeI. This is perhaps
not surprising, because the presence of THF had already
been shown to impede the metalate rearrangement.
Consequently, it was necessary to prepare Me3SnLi from
(Me3Sn)2 in Et2O.19 Because the distannylated product
19 was isolated in 30% yield in addition to the desired
product 18g (Scheme 3), it is conceivable that the
formation of Me3SnLi, which is normally generated in
THF,20 was incomplete in Et2O, and that the (Me3Sn)2
remaining may have reacted with some of the vinyl
organometallic intermediate to produce 19 as a byprod-
uct. No effort was made to optimize this reaction as the
primary purpose for preparing 18g was for NOE studies.
The number of equivalents of the electrophile (other
than H2O) that was used to react with the intermediate
vinyl anion (Table 1, entries g-l) also deserves comment.
In general, we found that optimal yields were obtained
(17) (a) Duraisamy, M.; Walborsky, H. M. J . Am. Chem. Soc. 1984,
106, 5035-5037. (b) Topolski, M.; Duraisamy, M.; Rachon, J .; Gawron-
ski, J .; Gawronska, K.; Goedken, V.; Walborsky, H. M. J . Org. Chem.
1993, 58, 546-555.
(18) (a) Ko¨brich, G.; Akhtar, A.; Ansari, F.; Breckoff, W. E.; Bu¨ttner,
H.; Drischel, W.; Fischer, R. H.; Flory, K.; Fro¨hlich, H.; Goyert, W.;
Heinemann, H.; Hornke, I.; Merkle, H. R.; Trapp, H.; Zu¨ndorf, W.
Angew. Chem., Int. Ed. Engl. 1967, 6, 41-52. (b) Boche, G.; Marsch,
M.; Mu¨ller, A.; Harms, K. Angew. Chem., Int. Ed. Engl. 1993, 32,
1032-1033.
(19) The Me3SnLi used to prepared 11f was made according to the
procedure in ref 18b, except diethyl ether was used as a solvent.
(20) (a) Still, W. C. J . Am. Chem. Soc. 1977, 99, 4836-4838. (b) Still,
W. C. J . Am. Chem. Soc. 1978, 100, 1481-1486. (c) Kitching, W.;
Olszowy, H. A.; Drew, G. M. Organometallics 1982, 1, 1244-1246. (d)
Reimann, W.; Kuivila, H. G.; Farah, D.; Apoussidis, T. Organometallics
1987, 6, 557-565.
Examination of the results summarized in Table 1
reveals that with the exception of entry g, the yields of

534 J . Org. Chem., Vol. 66, No. 2, 2001
Neipp et al.
when 3 equiv of electrophile and 2 equiv of HMPA were
used, as when lesser quantities were employed, the
desired product was obtained in reduced yields. However,
use of a larger excess of electrophile and/or HMPA led
to the formation of C-, N-dialkylated products as il-
lustrated by the formation of 20 (Scheme 3). Of course,
it is recognized that, in some situations, it may be
desirable to alkylate the nitrogen (vide infra).
The stereochemistry assigned to the homoallylic sul-
fonamides was supported by NOE studies performed with
18g and 18l. Specifically, irradiation of the allylic meth-
ylene group in 18g gave a small enhancement to the vinyl
methyl group and none to the trimethylstannyl group,
whereas irradiation of the vinyl hydrogen significantly
enhanced the signal from the trimethylstannyl group and
none to the vinyl methyl group. Similarly, irradiation of
the allylic methylene group in 18l gave a small enhance-
ment to the trimethylstannyl group and none to the vinyl
methyl group, whereas irradiation of the vinyl hydrogen
significantly enhanced the signal from the vinyl methyl
group and none to the trimethylstannyl group.
N-trisyl group remained. Sulfonamide deprotections are
traditionally performed under dissolving metal condi-
tions,23 and there are also several recent reports which
address this issue.24,25 We have found that sonication of
18d with lithium wire (10 equiv) and catalytic 4,4′-di-
tert-butylbiphenyl (DBB) in anhydrous THF at room
temperature led to the rapid removal of the trisyl group,
and the desired homoallylic amine 23 was readily isolated
in good yield as its HCl salt.
The practical utility of this methodology for the syn-
thesis of homoallylic amines is illustrated by the prepa-
ration of the homoallylic diene amine 25, which is a
precursor of the squalene synthetase inhibitor 1. Thus,
reaction of the R-lithio derivative of 16 with the cuprate
derived from 5-lithio-2-methyl-2-pentene and CuCN gave
an intermediate ring-opened vinyl cuprate reagent that
was methylated with excess methyl iodide and HMPA
to give 24 in 73% yield. Deprotection of 24 by the action
of lithium wire and catalytic DBB then furnished 25 in
85% yield. Because of the convergent nature of this
approach to 25, it should be possible to rapidly prepare
a variety of squalene synthetase inhibitors related to 1
simply by varying the cuprate and the electrophile
(Scheme 4).
Sch em e 4
Inasmuch as 2-lithiated 3,4-dihydro-2H-pyran and
benzofuran were known to undergo 1,2-metalate rear-
rangements of the general type shown in Scheme 1,12,21
we were intrigued by the possibility that the analogous
trisyl-protected 1,2,3,4-tetrahydro-pyridine 21 and indole
22 might also undergo metalation with tert-BuLi followed
by ring opening upon treatment with higher order
cyanocuprates. However, while 21 and 22 each under-
went clean R-deprotonation, reaction of the intermediate
R-lithio enamides with tert-Bu2CuCNLi2 did not furnish
the expected ring opened products under the usual
reaction conditions, and multiple products were obtained
when the reactions were conducted at higher tempera-
tures. The increased stability of R-metalated 21 relative
to 10 is consistent with Kocienski’s observation that the
R-cuprate derived from dihydropyran is more stable than
that of dihydrofuran.12 We did not subject the cuprates
derived from 21 and 22 to extensive scrutiny, so it
remains possible that they might be induced to undergo
ring opening reactions under specifically defined condi-
tions.22
Con clu sion
We have invented and developed a convergent and
stereoselective route to homoallylic sulfonamides based
upon a 1,2-metalate rearrangement. Owing to the avail-
ability of a variety of organocuprates and the versatility
offered by the ability to prepare vinyl stannanes and
iodides, it is now possible to rapidly assemble protected
homoallylic amines having a broad range of substitution
(23) (a) Kovacs, J .; Ghatak, U. R. J . Org. Chem. 1966, 31, 119-
121. (b) J i, S.; Gortler, L. B.; Waring, A.; Battisti, A.; Bank, S.; Closson,
W. D.; Wriede, P. J . Am. Chem. Soc. 1967, 89, 5311-5312. (c) D’Souza,
L.; Day, R. A. Science 1968, 160, 882-883. (d) Cottrell, P. T.; Mann,
C. K. J . Am. Chem. Soc. 1971, 93, 3579-3583. (e) Gold, E. H.; Babad,
E. J . Org. Chem. 1972, 37, 2208-2210. (f) Quaal, K. S.; J i, S.; Kim, Y.
M.; Closson, W. D.; Zubieta, J . A. J . Org. Chem. 1978, 43, 1311-1316.
(g) Art, J . F.; Kestemont J . P.; Soumillion, J . Ph. Tetrahedron Lett.
1991, 32, 1425-1428. (h) Fleming, I.; Frackenpohl, J .; Ila, H. J . Chem.
Soc., Perkin Trans. 1 1998, 1229-1235. (i) Dalko, P. I.; Brun, V.;
Langlois, Y. Tetrahedron Lett. 1998, 39, 8979-8982.
Having established the efficacy of this novel approach
to protected homoallylic amines, the task of removing the
(21) Nguyen, T.; Negishi, E. Tetrahedron Lett. 1991, 32, 5903-5906.
(22) 1,2-Metalate rearrangements of various cyclic enol ethers must
be executed under specifically defined reaction conditions. See: Ash-
worth, P.; Broadbelt, B.; J ankowski, P.; Kocienski, P.; Pimm, A.; Bell,
R. Synthesis 1995, 199-206.
(24) Sabitha, G.; Reddy, B. V. S.; Abraham, S.; Yadav, J . S.
Tetrahedron Lett. 1999, 40, 1569-1570.
(25) Nyasse, B.; Grehn, L.; Ragnarsson, U. Chem. Commun. 1997,
1017-1018.

Synthesis of Homoallylic Amines
J . Org. Chem., Vol. 66, No. 2, 2001 535
precipitate was rinsed with EtOAc (4 × 5 mL). The filtrate
was concentrated under reduced pressure, and the resulting
white solid was purified by flash chromatography eluting with
hexanes/EtOAc (4:1) to give 3.13 g (74%) of N-2′,4′,6′-triiso-
propylbenzenesulfonyl-2-pyrrolidinol as a white solid: mp 95-
97 °C; 1H NMR δ 7.15 (s, 2 H), 5.53-5.55 (m, 1 H), 4.19 (hep,
J ) 6.7 Hz, 2 H), 3.46-3.52 (m, 1 H), 3.13-3.22 (m, 1 H), 3.01-
3.07 (br s, 1 H), 2.88 (hep, J ) 6.9 Hz, 1 H), 1.81-2.19 (comp,
4 H), 1.23-1.26 (comp, 18 H); 13C NMR δ 153.2, 151.1, 131.6,
123.9, 83.1, 46.2, 34.1, 34.06, 29.3, 24.8, 23.5, 22.6; IR (CHCl3)
3448, 2962, 2930, 2870, 1600 cm-1; mass spectrum (CI) m/z
354.2103 [C19H31NO3S (M + 1) requires 354.2103], 354, 336
(base), 267.
patterns from a common intermediate. As such this
methodology could find application in combinatorial
synthesis. The removal of the trisyl group may be readily
achieved under mild conditions to give the parent homo-
allylic amines. The practical utility of this method has
been illustrated by the facile synthesis of 25, a key
intermediate in the synthesis of a known inhibitor of
squalene synthetase. Applications of this methodology to
the synthesis of a diverse array of homoallylic amines
by combinatorial and related tactics are the subjects of
current investigations, the results of which will be
reported in due course.
N-2′,4′,6′-Tr iisop r op ylben zen esu lfon yl-2-p yr r olin e (16).
A mixture of citric acid monohydrate (460 mg, 2.2 mmol) and
N-2′,4′,6′-triisopropylbenzenesulfonyl-2-pyrrolidinol (3.13 g, 8.9
mmol) in toluene (30 mL) was heated under reflux with
constant removal of H2O (Dean Stark) for 3 h, whereupon
saturated NaHCO3 (30 mL) was added. The layers were
separated, and the aqueous layer was extracted with EtOAc
(4 × 10 mL). The combined organic layers were washed with
saturated NaCl (30 mL), dried (Na2SO4), and concentrated
under reduced pressure. The resulting white solid was purified
by flash chromatography eluting with hexanes/EtOAc (9:1) to
give 2.7 g (90%) of 16 as a white solid: mp 76-78 °C; 1H NMR
(CD3OD) δ 7.27 (s, 2 H), 6.36-6.38 (m, 1 H), 5.18-5.21 (m 1
H), 4.16 (hep, J ) 6.8 Hz, 2 H), 3.52 (t, J ) 9.1 Hz, 2 H), 2.93
(hep, J ) 7.1 Hz, 1 H), 2.59-2.67 (m, 2 H), 1.22-1.28 (comp,
18 H); 13C NMR (CD3OD) δ 155.0, 152.7, 131.8, 130.5, 125.2,
110.3, 47.5, 35.4, 30.7, 25.1, 24.0; IR (CHCl3) 3019, 2963, 2930,
1600 cm-1; mass spectrum (CI) m/z 336.1989 [C19H29NO2S (M
+ 1) requires 336.1997], 336 (base), 294.
Gen er a l P r oced u r e for Con ver tin g 16 to Hom oa llylic
Su lfon a m id es 18a -l. A solution of RLi (3.6 mmol; 1.5 M
MeLi in Et2O; 0.4 M CH2dCHLi in Et2O/pentane;27 1.4 M PhLi
in cyclohexane/Et2O; 1.2 M n-BuLi in hexanes; 1.1 M sec-BuLi
in cyclohexane; 1.3 M t-BuLi in pentane) was added dropwise
to a slurry of CuCN (160 mg, 1.8 mmol) in dry, degassed
(freeze/pump/thaw, 3×) Et2O (5 mL) at -78 °C under argon.
The resulting slurry was then stirred at 0 °C, whereupon it
became homogeneous. Into a separate flask containing a slurry
of 16 (0.5 g, 1.5 mmol) in dry, degassed (freeze/pump/thaw,
3×) Et2O (2.5 mL) at -78 °C (bath temp) under argon was
added a solution of 1.3 M t-BuLi in pentane (1.2 mL, 1.5 mmol).
The resulting yellow slurry of lithiated 16 was stirred at -78
°C and then at 0 °C for an additional 20 min. To this solution
of 16 was added R2CuCNLi2 in one portion via cannula. The
reaction mixture was then stirred at room temperature until
the ring opening was complete as judged by TLC. (The time
depended upon the cuprate as follows: tert-butyl, sec-butyl,
and trimethylstannyl cuprate required 1 h; butyl cuprate
required 3 h; methyl and phenyl cuprate required 6 h; vinyl
cuprate required 12 h). The resulting mixture was then either
subjected directly to an aqueous work up to give 18a -f
(procedure A) or treated with a suitable electrophile prior to
aqueous work up to give 18g-l (procedure B).
Exp er im en ta l Section
Gen er a l Meth od s. Unless otherwise indicated, all starting
materials were obtained from commercial suppliers and used
without further purification. Tetrahydrofuran (THF) was
distilled from potassium/benzophenone ketyl, and diethyl ether
(Et2O) was distilled from sodium/benzophenone ketyl im-
mediately prior to use. HMPA was distilled from CaH2 and
stored under argon in a flame dried round-bottom flask. Flash
chromatography was conducted according to the Still protocol26
using ICN Biomedicals ICN-SILITech 32-63d silica gel with
the indicated solvents. Melting points are uncorrected. All
NMR spectra were taken on
a 300 MHz instrument in
deuterated chloroform (CDCl3) unless otherwise indicated; 13
C
spectra were taken at 75 MHz. Chemical shifts (δ) are
expressed as ppm relative to tetramethylsilane (δ ) 0.00 ppm)
referenced to the residual protic solvent. Splitting patterns are
designated as: s, singlet; d, doublet; t, triplet; q, quartet; p,
pentet; hep, heptet; m, multiplet; comp, complex multiplet; br,
broad; app, apparent. High-resolution mass spectra were taken
on VG Analytical ZAB2-E instrument. IR spectra were re-
corded as films on sodium chloride plates on a Perkin-Elmer
1600 series FTIR.
N-2′,4′,6′-Tr iisop r op ylb en zen esu lfon yl-2-p yr r olid in -
on e (15). A mixture of a 60% dispersion of NaH in mineral
oil (1.98 g, 24.0 mmol) and 2-pyrrolidinone (2.5 mL, 32.9 mmol)
in THF/Et2O (350 mL, 2.5:1) was stirred for 2 h under argon
at 0 °C (bath temperature). 2,4,6-Triisopropylbenzenesulfonyl
chloride (1.24 g, 4.11 mmol) was then added in one portion,
and the reaction was stirred at 0 °C for 2 h and then at room
temperature for 4 h. Water (200 mL) and saturated NaCl (50
mL) were slowly added. The layers were separated, and the
aqueous layer was extracted with EtOAc (3 × 50 mL). The
combined organic layers were washed with saturated NaCl
(100 mL), dried (Na2SO4), and concentrated under reduced
pressure. Hexanes (300 mL) were added to the residue, and
this resulting mixture was stored at room temperature over-
night. The resulting white precipitate was collected by filtra-
tion and washed with hexanes (20 mL). The filtrate was
concentrated under reduced pressure, and hexane (100 mL)
was added. The resulting second crop of white precipitate was
filtered and triturated with hexanes (5 mL). The combined
precipitates were dried under vacuum to give 11.1 g (96%) of
N-2′,4′,6′-triisopropylbenzenesulfonyl-2-pyrrolidinone as a white
solid: mp 111-112 °C; 1H NMR δ 7.15 (s, 2 H), 4.06 (hep, J )
6.8 Hz, 2 H), 3.93 (t, J ) 6.9 Hz, 2 H), 2.88 (hep, J ) 6.9 Hz,
1 H), 2.45 (t, J ) 8.0, 2 H), 2.11 (app p, J ) 7.6 Hz, 2 H),
1.21-1.26 (comp, 18 H); 13C NMR δ 173.6, 153.9, 151.6, 131.3,
123.9, 46.1, 34.2, 32.2, 29.3, 24.5, 23.5, 18.7; IR (CHCl3) 1732
cm-1; mass spectrum (CI) m/z 352.1942 [C19H29NO3S (M + 1)
requires 352.1946], 352 (base), 310, 244, 203.
P r oced u r e A. The reaction mixture was then cooled to 0
°C (bath temperature), and a solution of saturated NH4Cl/NH4-
OH (10 mL, 9:1) was added in one portion. The resulting gray/
pale blue mixture was transferred to a separatory funnel, and
the organic layer was separated. The aqueous layer was
extracted with EtOAc (3 × 10 mL), and the combined organic
layers were dried (Na2SO4) and concentrated under reduced
pressure at 35 °C. The crude product was purified by flash
chromatography on silica gel eluting with hexanes/EtOAc (9:
1) to give the homoallylic sulfonamides 18a -f.
N-2′,4′,6′-Tr iisop r op ylb en zen esu lfon yl-2-p yr r olid in -
ol. A solution of 1 M DIBAL-H in CH2Cl2 (24 mL, 24 mmol)
was added dropwise with stirring over 30 min to a solution of
N-2′,4′,6′-triisopropylbenzenesulfonyl-2-pyrrolidinone (4.2 g, 12
mmol) in THF (100 mL) at 0 °C (bath temperature) under
argon. Stirring was continued for 10 min, whereupon saturated
aqueous NH4Cl (25 mL) was added dropwise. The ice bath was
removed, and the resulting white slurry was stirred for 1.5 h.
This slurry was filtered through a plug of cotton, and the
P r oced u r e B. The reaction mixture was cooled to -78 °C
(bath temperature), and the appropriate electrophile (3 equiv)
was added in one portion; HMPA (0.52 mL, 3 mmol) was then
added. The cooling bath was removed, and the resulting
(26) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.
(27) Reich, H. J .; Holtan, R. C.; Bolm, C. J . Am. Chem. Soc. 1990,
112, 5609-5617.

536 J . Org. Chem., Vol. 66, No. 2, 2001
Neipp et al.
suspension was stirred at room temperature until the reaction
was complete as judged by TLC. (Typical reaction times varied
with the electrophile as follows: MeI, 2 h; allyl bromide, 30
min; I2, 30 min; Me3SnCl, 30 min.) The reaction was then
subjected to an aqueous workup as described in procedure A
to give the homoallylic sulfonamides 18g-l.
150.3, 143.3, 134.9, 132.1, 123.8, 42.2, 34.1, 29.6, 28.2, 24.9,
23.5, 18.5, -10.2; IR (CHCl3) 2018, 2961, 2869, 1462, 1321
cm-1; mass spectrum (CI) m/z 516.1950 [C23H41NO2SSn (M +
1) requires 516.1958], 516 (base), 500, 352.
N-2′,4′,6′-Tr iisop r op ylben zen esu lfon yl-4,5,5-tr im eth yl-
3(E)-h exen a m in e (18h ): mp 100-102 °C; 1H NMR δ 7.14 (s,
2 H), 5.03 (br t, J ) 7.1 Hz, 1 H), 4.34 (br s, 1 H) 4.15 (hep, J
) 6.7 Hz, 2 H), 2.83-2.97 (comp, 3 H), 2.19 (app q, J ) 7.1
Hz, 2 H), 1.55 (s, 3 H), 1.17-1.26 (comp, 18 H), 0.97 (s, 9 H);
13C NMR δ 152.6, 150.2, 147.2, 132.2, 123.7, 116.1, 42.6, 36.2,
34.1, 29.6, 28.9, 28.4, 24.9, 23.6, 12.9; IR (CHCl3) 3019, 2963,
1221 cm-1; mass spectrum (CI) m/z 408.2930 [C24H41NO2S (M
+ 1) requires 408.2936], 408 (base), 296, 267, 205.
4-ter t-Bu t yl-N-2′,4′,6′-t r iisop r op r ylb en zen esu lfon yl-
3(E),6-h ep ta d ien a m in e (18i): mp 81-83 °C; 1H NMR δ 7.14
(s, 2 H), 5.71-5.58 (m, 1 H), 5.16 (t, J ) 6.9 Hz, 1 H), 4.85-
4.92 (m, 2 H), 4.34 (br t, J ) 6.7 Hz, 1 H), 4.15 (hep, J ) 6.7
Hz, 2 H), 2.83-3.01 (comp, 3 H), 2.77 (dt, J ) 5.9, 1.6 Hz, 2
H), 2.17 (app q, J ) 6.7 Hz, 2 H), 1.18-1.26 (comp, 18 H),
0.97 (s, 9 H); 13C NMR δ 152.6, 150.2, 148.0, 137.0, 132.2,
123.7, 119.0, 114.8, 42.6, 36.7, 34.1, 32.1, 29.6, 29.1, 28.4, 24.9,
23.6; IR (CHCl3) 3019, 2965, 1213, 1151 cm-1, mass spectrum
(CI) m/z 434.3084 [C26H43NO2S (M + 1) requires 434.3093],
434 (base), 269, 205, 186.
4-Iod o-N-2′,4′,6′-t r iisop r op ylb en zen esu lfon yl-5,5-d i-
m eth yl-3(Z)-h exen a m in e (18j): mp 106-108 °C; 1H NMR δ
7.15 (s, 2 H), 5.45 (t, J ) 6.7 Hz, 1 H), 4.44 (br t, J ) 6.3 Hz,
1 H), 4.15 (hep, J ) 6.7 Hz, 2 H), 3.05 (q, J ) 6.7 Hz, 2 H),
2.88 (hep, J ) 6.9 Hz, 1 H), 2.34 (q, J ) 6.7 Hz, 2 H), 1.14-
1.27 (comp, 18 H), 1.11 (s, 9 H); 13C NMR δ 152.7, 150.2, 132.2,
129.9, 126.9, 123.8, 41.4, 40.5, 37.7, 34.1, 30.5, 29.6, 24.9, 23.6;
IR (CHCl3) 3019, 2968, 1425 cm-1; mass spectrum (CI) m/z
520.1741 [C23H38INO2S (M + 1) requires 520.1746], 520 (base),
462, 394.
N-2′,4′,6′-Tr iisop r op ylb en zen esu lfon yl-3(E)-p en t en -
1
a m in e (18a ): mp 49-51 °C; H NMR δ 7.14 (s, 2 H), 5.43-
5.52 (m, 1 H), 5.18-5.28 (m, 1 H), 4.32 (br t, J ) 5.9 Hz, 1 H),
4.12 (hep, J ) 6.6 Hz, 2 H), 2.83-2.99 (comp, 3 H), 2.17 (dt, J
) 6.6, 6.6 Hz, 2 H), 1.56-1.65 (m, 3 H), 1.21-1.28 (comp, 18
H); 13C NMR δ 152.6, 150.2, 132.1, 129.2, 126.8, 123.7, 42.0,
34.1, 32.4, 29.6, 24.8, 23.6, 17.9; IR (CHCl3) 3023, 2962, 2871
cm-1; mass spectrum (CI) m/z 352.2315 [C20H33NSO2 (M + 1)
requires 352.2310], 352 (base), 336, 283, 254.
N-2′,4′,6′-Tr iisop r op ylben zen esu lfon yl-3(E)-3,5-h exa d i-
1
en a m in e (18b): mp 83-85 °C; H NMR δ 7.14 (s, 2 H), 6.22
(dt, J ) 16.7, 10.1 Hz, 1 H), 6.06 (dd, J ) 15.0, 10.1 Hz, 1 H),
5.49 (dt, J ) 15.0, 6.8 Hz, 1 H), 5.11 (d, J ) 16.7 Hz, 1 H),
5.01 (d, J ) 10.1 Hz, 1 H), 4.30 (br t, J ) 6.8 Hz, 1 H), 4.12
(hep, J ) 6.7 Hz, 2 H), 3.02 (app q, J ) 6.8 Hz, 2 H), 2.88
(hep, J ) 7 Hz, 1 H), 2.29 (app q, J ) 6.8 Hz, 2 H), 1.23-1.25
(comp, 18 H); 13C NMR δ 152.7, 150.2, 136.3, 134.2, 132.1,
129.8, 123.8, 116.8, 41.9, 34.1, 32.5, 29.6, 24.8, 23.6; IR (CHCl3)
3327, 2961, 2929, 2870, 1150 cm-1; mass spectrum (CI) m/z
364.2307 [C20H33NSO2 (M + 1) requires 364.2310], 364 (base),
296.
N-2′,4′,6′-Tr iisop r op ylben zen esu lfon yl-4-p h en yl-3(E)-
bu ten a m in e (18c): mp 134-136 °C; 1H NMR δ 7.20-7.28
(comp, 5 H), 7.14 (s, 2 H), 6.41 (d, J ) 15.7 Hz, 1 H), 6.03 (dt,
J ) 15.7, 6.6 Hz, 1 H), 4.43 (br t, J ) 6.6 Hz, 1 H), 4.14 (hep,
J ) 6.8 Hz, 2 H), 3.10 (app q, J ) 6.6 Hz, 2 H), 2.89 (hep, J )
6.9 Hz, 1 H), 2.43 (app q, J ) 6.6 Hz, 2 H), 1.22-1.25 (comp,
18 H); 13C NMR δ 152.7, 150.3, 136.7, 133.3, 132.2, 128.6,
127.5, 126.1, 125.6, 123.8, 42.1, 34.1, 33.1, 29.7, 29.6, 24.8, 23.6;
IR (CHCl3) 3019, 2964, 1213 cm-1; mass spectrum (CI) m/z
414.2466 [C25H35NO2S (M + 1) requires 414.2467], 414 (base),
372.
N-2′,4′,6′-Tr iisop r op ylben zen esu lfon yl-5,5-d im eth yl-4-
tr im eth ylsta n n yl-3(Z)-h exen a m in e (18k ): mp 103-104 °C;
1H NMR δ 7.14 (s, 2H), 5.76 (t, J ) 7.1 Hz, 1 H), 4.25-4.37
(m, 1 H), 4.15 (hep, J ) 6.7 Hz, 2 H), 2.99 (app q, J ) 6.8 Hz,
2 H), 2.88 (hep, J ) 7 Hz, 1 H), 2.19-2.28 (m, 2 H), 1.22-1.26
(comp, 18 H), 0.98 (s, 9 H), 0.25-0.07 (m, 9 H); 13C NMR δ
160.0, 152.6, 150.2, 132.1, 129.7, 123.8, 42.8, 38.7, 34.1, 33.8,
N -2′,4′,6′-Tr iisop r op ylb e n ze n e su lfon yl-3(E )-oct e n -
a m in e (18d ): mp 54-55 °C; 1H NMR δ 7.14 (s, 2 H), 5.48 (dt,
J ) 15.3, 6.7 Hz, 1 H), 5.21 (dt, J ) 15.3, 6.7 Hz, 1 H), 4.31 (br
t, J ) 6.7 Hz, 1 H), 4.13 (hep, J ) 6.8 Hz, 2 H), 2.83-3.00
(comp, 3 H), 2.18 (app q, J ) 6.7 Hz, 2 H), 1.95 (app q, J ) 6.7
Hz, 2 H), 1.22-1.30 (comp, 22 H), 0.86 (t, J ) 7.1 Hz, 3 H);
13C NMR δ 152.6, 150.3, 134.8, 132.1, 125.4, 123.7, 42.1, 34.1,
32.5, 32.2, 31.4, 29.6, 24.8, 23.6, 22.2, 13.9; IR (CHCl3) 3019,
30.4, 29.6, 24.9, 23.6, -5.2; IR (CHCl3) 3018, 2965, 1522 cm-1
;
mass spectrum (CI) m/z 558.2429 [C26H48NO2SSn (M + 1)
requires 558.2428], 556 (base), 542, 394. (Z)-N-2′,4′,6′-Tr iiso-
p r op ylb e n ze n e su lfon yl-4-t r im e t h ylst a n n yl-3-p e n t e n -
a m in e (18l). mp 84-86 °C; 1H NMR δ 7.14 (s, 2 H), 5.76-
5.84 (m, 2 H), 4.29 (br t, J ) 6.2 Hz, 1 H), 4.12 (hep, J ) 6.8
Hz, 2 H), 2.80-3.02 (comp, 3 H), 2.15-2.26 (m, 2 H), 1.76-
1.92 (m, 3 H), 1.22-1.25 (comp, 18 H), 0.035-0.22 (m, 9 H);
13C NMR δ 152.6, 150.3, 143.7, 135.7, 131.9, 123.7, 42.5, 34.1,
34.0, 29.6, 26.5, 24.9, 23.6, -8.8; IR (CHCl3) 3018, 1522, 1424,
1211 cm-1; mass spectrum (CI) m/z 516.1966 [C23H41NO2SSn
(M + 1) requires 516.1958], 516 (base), 514, 500, 394, 352.
3(E)-Octen a m in e Hyd r och lor id e (23). Li (0) wire (∼45
mg, 6.5 mmol) that had been freshly cut into several small
pieces was added to a solution of 4,4′-di-tert-butylbiphenyl (34
mg, 0.13 mmol) and 18d (500 mg, 1.3 mmol) in THF (12 mL)
under argon at room temperature. The reaction flask was
placed in a sonication bath and sonicated for 20 min. The
excess Li metal was removed, and EtOH (0.5 mL) was added.
The mixture was concentrated under vacuum, and the residue
was dissolved in 10% aqueous HCl (5 mL). The aqueous
solution was extracted with Et2O (2 × 2 mL). A 3 M solution
of NaOH saturated with NaCl (5 mL) was carefully added to
the aqueous layer, and the resulting mixture was extracted
with Et2O (3 × 5 mL). The combined organic layers were dried
(Na2SO4) and acidified with 4 M HCl in dioxane (1 mL). This
solution was then concentrated under vacuum, and the solid
residue was dried overnight under high vacuum to give 173
mg (83%) of 23: 1H NMR δ 5.53-5.63 (m, 1 H), 5.26-5.36 (m,
1H), 2.98 (br s, 2 H), 2.40-2.45 (m, 2 H), 1.95-2.02 (m, 2 H),
1.20-1.35 (comp, 4 H), 0.85 (t, J ) 7.1 Hz, 3 H); 13C NMR δ
135.3, 123.5, 39.8, 32.2, 31.3, 30.6, 22.2, 13.9; IR (CHCl3) 3409,
3048, 2974, 1606 cm-1; mass spectrum (CI) m/z 128.1438
[C8H17N (M + 1) requires 128.1439], 128 (base).
2962, 1213 cm-1; mass spectrum (CI) m/z 394.2775 [C23H39
NO2S (M + 1) requires 394.2780], 394 (base), 338.
-
(()-N-2′,4′,6′-Tr iisop r op ylb en zen esu lfon yl-5-m et h yl-
3(E)-h ep ten a m in e (18e): mp 76-78 °C; 1H NMR δ 7.14 (s, 2
H), 5.37 (dd, J ) 15.4, 6.8 Hz, 1 H), 5.18 (dt, J ) 15.4, 6.8 Hz,
1 H), 4.30 (br t, J ) 6.8 Hz, 1 H), 4.13 (hep, J ) 6.7 Hz, 2 H),
2.83-3.00 (comp, 3 H), 2.18 (app q, J ) 6.8 Hz, 2 H), 1.94 (app
hep, J ) 6.8 Hz, 1 H), 1.22-1.26 (comp, 20 H), 0.90 (d, J ) 6.8
Hz, 3 H), 0.80 (t, J ) 7.4 Hz, 2 H); 13C NMR δ 152.6, 150.3,
140.5, 132.2, 123.8, 123.7, 42.2, 38.3, 34.1, 32.6, 29.6, 29.6, 24.9,
23.6, 20.0, 11.7; IR (CHCl3) 3019, 2965, 1213 cm-1; mass
spectrum (CI) m/z 394.2782 [C23H39NO2S (M + 1) requires
394.2780], 394 (base), 283, 267.
N-2′,4′,6′-Tr iisop r op ylb en zen esu lfon yl-5,5-d im et h yl-
3(E)-h exen a m in e (18f): mp 133-134 °C; 1H NMR δ 7.14 (s,
2 H), 5.52 (dt, J ) 15.7, 1.0 Hz, 1 H), 5.14 (dt, J ) 15.7, 6.5
Hz, 1 H), 4.29 (t, J ) 6.5 Hz, 1 H), 4.13 (hep, J ) 6.8 Hz, 2 H),
2.83-3.00 (comp, 3 H), 2.18 (dddd, J ) 6.5, 6.5, 6.5, 1.0 Hz, 2
H), 1.22-1.25 (comp, 18 H), 0.94 (s, 9 H); 13C NMR δ 152.6,
150.2, 145.6, 132.2, 123.7, 120.0, 42.3, 34.1, 33.0, 32.7, 29.58,
29.55, 24.9, 23.6; IR (CHCl3) 3018, 2965, 1211 cm-1; mass
spectrum (CI) m/z 394.2788 [C23H39NO2S (M + 1) requires
394.2780], 394 (base), 352, 296.
N-2′,4′,6′-Tr iisopr opylben zen esu lfon yl-4-tr im eth ylstan -
n yl-3(E)-p en ten a m in e (18g): mp 83-86 °C; 1H NMR δ 7.14
(s, 2 H), 5.38-5.41 (m, 1 H), 4.26-4.30 (m, 1 H), 4.09-4.18
(m, 2 H), 3.00 (app q, J ) 6.6 Hz, 3 H), 2.88 (hep, J ) 7 Hz, 1
H), 2.32 (app q, J ) 6.6 Hz, 2 H), 1.69-1.86 (m, 3 H), 1.22-
1.25 (comp, 18 H), -0.032-0.19 (m, 9 H); 13C NMR δ 152.7,

Synthesis of Homoallylic Amines
J . Org. Chem., Vol. 66, No. 2, 2001 537
N-2′,4′,6′-Tr iisop r op ylben zen esu lfon yl-N,4,9-tr im eth yl-
3(E),7-n on a d ien a m in e (24). Li(0) wire (90 mg, 13 mmol) was
cut up into several small pieces and added to a solution of
5-bromo-2-methyl-2-pentene (0.48 mL, 3.6 mmol) in dry,
degassed (freeze/pump/thaw, 3×) Et2O (4 mL) under argon at
0 °C. This mixture was stirred (using a glass coated stirring
bar) for 1 h at 0 °C. A solution of 1.4 M t-BuLi in pentane
(0.91 mL, 1.3 mmoL) was added to a separate flask containing
a solution of 16 (430 mg, 1.3 mmol) in dry, degassed (freeze/
pump/thaw, 3×) Et2O (2 mL) at -78 °C under argon. The
resulting yellow slurry was stirred at -78 °C for 30 min and
then at 0 °C for 20 min. The solution of 5-lithio-2-methyl-2-
pentene was then added in one portion via cannula to a slurry
of CuCN (140 mg, 1.5 mmol) in dry, degassed (freeze/pump/
thaw, 3×) Et2O (4 mL) at -78 °C under argon. The organo-
cuprate was then stirred at 0 °C for 20 min. The cuprate (a
green solution) was then added in one portion via cannula to
the slurry of lithiated 16 at 0 °C. The reaction was then stirred
at room temperature for 3 h. The reaction was cooled to -78
°C, whereupon HMPA (2.2 mL, 13 mmol) and MeI (0.46 mL,
7.7 mmol) were added. The resulting slurry was stirred for 1
h at room temperature. A solution of saturated NH4Cl/NH4-
OH (10 mL, 9:1) was added and the mixture transferred to a
separatory funnel. The layers were separated, and the aqueous
layer was extracted with EtOAc (4 × 5 mL). The combined
organic layers were dried (Na2SO4) and concentrated under
vacuum. The crude was then purified by flash chromatography
eluting with hexanes/EtOAc (9:1) to give 420 mg (73%) of 21
as a white solid: mp 46-48 °C; 1H NMR δ 7.13 (s, 2 H), 4.98-
5.07 (comp, 2 H), 4.15 (hep, J ) 6.8 Hz, 2 H), 3.08-3.13 (m, 2
H), 2.87 (hep, J ) 6.9 Hz, 1 H), 2.73 (s, 3 H), 2.26 (app q, J )
7.7 Hz, 2 H), 1.92-2.03 (comp, 4 H), 1.64 (s, 3 H), 1.56 (s, 3
H), 1.54 (s, 3 H), 1.21-1.24 (comp, 18 H); 13C NMR δ 152.9,
151.4, 137.8, 131.5, 130.9, 124.1, 123.8, 120.0, 48.1, 39.6, 34.1,
33.2, 29.2, 26.5, 26.3, 25.6, 24.8, 23.6, 17.7, 16.0; IR (CHCl3)
3019, 2962, 2928, 1215, 1149 cm-1; mass spectrum (CI) m/z
448.3244 [C27H43NO2S (M + 1) requires 448.3249], 448 (base),
310.
N,4,9-Tr im eth yl-3(E),7-n on a d ien a m in e Tr iflu or oa ce-
ta te (25). Li(0) wire (∼20 mg, 2.9 mmol) that had been freshly
cut into several small pieces was added to a solution of DBB
(3 mg, 0.011 mmol) and 18d (50 mg, 0.11 mmol) in THF (1
mL) under argon at room temperature. The reaction flask was
placed in a sonication bath and sonicated for 10 min. The
excess Li metal was removed, and 1 M HCl (0.5 mL) and Et2O
(1 mL) were added. The layers were separated, and the organic
layer was extracted with 1 M HCl (3 × 0.5 mL). The aqueous
layers were combined, and 6 M NaOH (0.5 mL) was added.
This mixture was then saturated with NaCl and extracted with
Et2O (5 × 1 mL). The organic layers were combined, dried (Na2-
SO4), and acidified with trifluoroacetic acid (0.5 mL). This
solution was then concentrated under vacuum, and the oily
residue was dried overnight under high vacuum to give 28 mg
(85%) of 25: 1H NMR δ 9.30 (br s, 2H), 4.98-5.06 (br m, 2 H),
2.82-2.96 (br m, 2 H), 2.65 (br s, 3 H), 2.34-2.46 (br m, 2 H),
1.94-2.03 (comp, 4 H), 1.64 (s, 3 H), 1.58 (s, 3 H), 1.56 (s, 3
H); 13C NMR δ 140.2, 131.7, 123.8, 117.3, 49.0, 39.5, 32.8, 26.4,
25.6, 24.7, 17.6, 15.9; IR (CHCl3) 3563, 3015, 2974, 1678, 1431,
1214 cm-1 mass spectrum (CI) m/z 296.1833 [C14H24FNO2 (M
+ 1) requires 296.1837], 296, 182 (base), 115.
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM 25439), the Robert A. Welch
Foundation, Pfizer, Inc., and Merck Research Labora-
tories for their generous support of this research.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O001386Z