Effect of ligand structure on the asymmetric cyclization of achiral olefinic organolithiums

Article abstract of DOI:10.1021/jo049477+

The ability of a large and chemically diverse set of 30 chiral ligands to effect asymmetric cyclization of 2-(N,N-diallylamino)phenyllithium (1), derived from N,N-diallyl-2-bromoaniline (2) by low-temperature lithium-bromine exchange, has been investigated in an attempt to elucidate the structural motifs required to provide high enantiofacial selectivity in the ring closure. Although none of the ligands examined in this study afforded 1-allyl-3-methylindoline in significantly higher ee than previously observed for the cyclization of 1 in the presence of the benchmark ligand (-)-sparteine, several ligands, structurally unrelated to sparteine and available in either enantiomeric form, were found to match the utility of (-)-sparteine in this chemistry.

Full text of DOI:10.1021/jo049477+

Effect of Liga n d Str u ctu r e on th e Asym m etr ic Cycliza tion of
Ach ir a l Olefin ic Or ga n olith iu m s
Michael J . Mealy,†,§ Matthew R. Luderer,† William F. Bailey,*,† and Michael Bech Sommer‡
Department of Chemistry, The University of Connecticut, Storrs, Connecticut 06269-3060, and
H. Lundbeck A/ S, Process Chemistry, DK-2500 Copenhagen, Denmark
bailey@uconn.edu
Received March 31, 2004
The ability of a large and chemically diverse set of 30 chiral ligands to effect asymmetric cyclization
of 2-(N,N-diallylamino)phenyllithium (1), derived from N,N-diallyl-2-bromoaniline (2) by low-
temperature lithium-bromine exchange, has been investigated in an attempt to elucidate the
structural motifs required to provide high enantiofacial selectivity in the ring closure. Although
none of the ligands examined in this study afforded 1-allyl-3-methylindoline in significantly higher
ee than previously observed for the cyclization of 1 in the presence of the benchmark ligand (-)-
sparteine, several ligands, structurally unrelated to sparteine and available in either enantiomeric
form, were found to match the utility of (-)-sparteine in this chemistry.
The conversion of achiral materials into chiral, non-
racemic compounds is one of the most intensely studied
areas of modern organic chemistry. Although a substan-
tial portion of such study has focused on transition-metal-
mediated methods,1 significant progress has been made
in the exploitation of main group metals for this purpose.
Thus, for example, the chiral organolithium complexes
generated by the enantioselective deprotonation of Boc-
protected amines or carbamoyl-protected alcohols with
s-BuLi/(-)-sparteine provide a powerful method for the
installation of a stereogenic center adjacent to a nitrogen2
or oxygen3 atom in both cyclic and alicyclic systems. The
asymmetric intermolecular carbometalation of olefins
with either organolithium4 or other organometallic4a,5
reagents has also been a productive area of research.
Recently, the intramolecular carbolithiation of an olefinic
organolithium has been found to proceed in a highly
enantioselective fashion in the presence of (-)-sparteine,6
and the two techniques of enantioselective deprotonation
and anionic cyclization have been combined7 to provide
highly functionalized systems with good enantioselectiv-
ity.
A vexing problem with all sparteine-mediated chem-
istry arises from the fact that only the (-)-enantiomer
of the compound is commercially available. The (+)-
enantiomer has been prepared by resolution of the
racemate, obtained from rac-lupanine,8 and recently by
asymmetric total synthesis;9 however, at this time neither
approach is a particularly attractive solution to the
“missing enantiomer” quandary. A clever technique,
involving invertive metal-metal exchange,2a was intro-
duced by Beak to circumvent this problem in the asym-
metric deprotonation chemistry; unfortunately, no such
technique is available for the anionic cyclization meth-
odology, as the stereogenic center is introduced in an
irreversible carbon-carbon bond-forming step.10 For this
reason, we have explored the ability of a variety of
chemically diverse chiral ligands, available in most cases
in either enantiomeric form from the chiral pool, to act
as surrogates for sparteine in effecting the asymmetric
cyclization of an achiral olefinic organolithium. Where
possible, we have attempted to draw conclusions about
the effect of the ligand structure on the enantioselectivity
of the cyclization.
† University of Connecticut.
‡ H. Lundbeck A/S, Copenhagen, Denmark.
§ Current address: H. Lundbeck A/S, Process Development, Lumsås,
Denmark.
(1) For recent reviews of asymmetric processes see: (a) O’Brien, P.
J . Chem. Soc., Perkin Trans. 1 2001, 95. (b) Tye, H.; Comina, P. J . J .
Chem. Soc., Perkin Trans. 1 2001, 1729. (c) Christoffers, J .; Mann, A.
Angew. Chem., Int. Ed. Engl. 2001, 40, 4591.
(2) (a) Beak, P.; Basu, A.; Gallagher, D. J .; Park, Y. S.; Thayumana-
van, S. Acc. Chem. Res. 1996, 29, 552. (b) Gallagher, D. J .; Wu, S.;
Nikolic, N. A.; Beak, P. J . Org. Chem. 1995, 60, 8148. (c) Wiberg, K.
B.; Bailey, W. F. J . Am. Chem. Soc. 2001, 123, 8231 and references
therein.
The well-studied 5-exo cyclization of 2-(N,N-diallylami-
no)phenyllithium (1) to (1-allyl-3-indolinyl)methyllithium
(4), which proceeds in an enantioselective fashion when
(6) (a) Bailey, W. F.; Mealy, M. J . J . Am. Chem. Soc. 2000, 122, 6787.
(b) Gil, G. S.; Groth, U. M. J . Am. Chem. Soc. 2000, 122, 6787. (c)
Barluenga, J .; Fan˜ana´s, F. J .; Sanz, R.; Marcos, C. Org. Lett. 2002, 4,
2225.
(3) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. Engl. 1997, 36,
2282.
(4) (a) Marek, I. J . Chem. Soc., Perkin Trans. 1 1999, 535. (b)
Norsikian, S.; Baudry, M.; Normant, J . F. Tetrahedron Lett. 2000, 41,
6575. (c) Norsikian, S.; Marek, I.; Klein, S.; Poisson, J . F.; Normant,
J . F. Chem. Eur. J . 1999, 5, 2055. (d) Norsikian, S.; Marek, I.; Poisson,
J .-F.; Normant, J . F. J . Org. Chem. 1997, 62, 4898.
(5) Nakamura, M.; Hirai, A.; Nakamura, E. J . Am. Chem. Soc. 2000,
122, 978.
(7) (a) Woltering, M. J .; Fro¨hlich, R.; Wibbeling, B.; Hoppe, D. Synlett
1998, 797. (b) Deiters, A.; Wibbeling, B.; Hoppe, D. Adv. Synth. Catal.
2001, 343, 181.
(8) Clemo, G. R.; Raper, R.; Short, W. S. J . Chem. Soc. 1949, 663.
(9) Smith, B. T.; Wendt, J . A.; Aube´, J . Org. Lett. 2002, 4, 2577.
(10) Bailey, W. F.; Khanolkar, A. D.; Gavaskar, Ovaska, T. V.; Rossi,
K.; Thiel, Y.; Wiberg, K. B. J . Am. Chem. Soc. 1991, 113, 5720.
10.1021/jo049477+ CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/06/2004
6042
J . Org. Chem. 2004, 69, 6042-6049

Cyclization of Achiral Olefinic Organolithiums
TABLE 1. Yield s a n d P r od u ct Distr ibu tion fr om Liga n d
Scr een in g Stu d ies
products, yielda (% d1)b
entry
ligand/solventc
6
5
% eed
1
2
3
4
5
6
7
3/A
7/A
8/B
9/B
11(L)
39(M)
e
89(L)
61(M)
16(L)
23(L)
79(H)
73(L)
0
80
-16
0
60
62
77(L)
21(L)
27(L)
100(L)
41(M)
55
100(H)
95(H)
78(H)
83(M)
14(L)
100(L)
22(L)
37(L)
46(L)
25(L)
41(L)
53(H)
45
10/A
11/A
12/A
13/A
14/A
15/A
16/A
17g/B
18/A
19/B
20/B
21/A
22/A
23/A
24/A
25/A
26/B
27/B
28/B
29/A
30/A
31/A
32/B
33/B
34/B
35h/B
-44
8
59(H)
45
-78
-52
9f
10
11
12
13
14
15
16
17
18
19
20
21
22f
23
24
25
26
27
28
29
30
0
5(L)e
22(H)
17(M)
86(H)
0
27
-12
-18
30
78(H)
63(H)
54(H)
75(H)
59(L)
47(H)
55
29(M)
24(H)
15(H)
27(H)
10(H)
9(H)
8(H)
0
80
78
76
68
68
76
-52
-32
6
0
2
12
10
2
F IGURE 1. Enantioselectivity in the cyclization of 1 imparted
by diamine ligands.
71
76(M)
85(H)
73(H)
90(H)
91(H)
92(H)
100(H)
Resu lts a n d Discu ssion
Following a convenient convention introduced by Beak
in another context,2b the effectiveness of a ligand in
promoting enantiofacially selective cyclization is ex-
pressed as positive when it leads to preferential formation
of (R)-5, the predominant enantiomer obtained using (-)-
sparteine; a negative ee indicates preferential formation
of (S)-5. Using this convention, the results from experi-
ments involving a diverse set of ligands are summarized,
from highest (R)-selectivity to highest (S)-selectivity, in
Figures 1-4. Chemical yield, product distribution, and
enantioselectivities for all experiments are reported in
Table 1.
a
Yields determined by GC analysis of reaction mixtures as-
suming identical detector response for the isomeric products. b Due
to the large M+ - 1 fragment, % d1 is listed as a range: L )
0-29%; M ) 30-59%; H ) 60-100%. c Solvent system A:
d
n-C5H12-Et2O (9:1 v/v); solvent system B: Et2O. A positive ee
indicates the major enantiomer posesses the (R)-configuration, a
negative ee indicates that the major enantiomer has the (S)-
configuration. e The product coelutes with the ligand. f The reac-
g
tion was quenched with MeOH. The ligand is only partially
soluble in pure diethyl ether. The ligand was added as
suspension in pentane.
h
a
Ch ir a l Dia m in e Liga n d s. Cursory inspection of the
data displayed in Figure 1 reveals that none of the
diamine ligands studied surpasses the enantioselectivity
imparted by (-)-sparteine (3). However, several of the
diamines are reasonably effective ligands. The pyrrolidine
ligands, such as 7 and (S)-(-)-nicotine (8), are poorly
suited to this process. Indeed, in the presence of nicotine,
the conversion to 5 was quite poor (Table 1, entry 3), and
numerous byproducts were formed, most likely as a result
of well-known reactions of an organolithium with the
pyridine ring.14 The reaction mediated by the amino acid
derived i-Pr-Box ligand (9) proceeded with reasonable
enantioselectivity; however, the unnatural amino acid
would be required to complement the (-)-sparteine-
mediated chemistry. The trans-diaminocyclohexane ligands
(10 and 11) lead to moderate enantioselectivity, but the
more sterically demanding ligand 11 appears to be less
effective than 10. The rigid, bicyclic diamine 12 led to
no cyclization, presumably because of competitive con-
sumption of the organolithium species via a metalation-
elimination sequence. The cis-1,5-diazadecalin ligand
(13), which has been used by Kozlowski’s group as an
adjuvant in asymmetric lithiation-substitution chemis-
try,15 is nearly as effective as is (-)-sparteine in the
conducted in the presence of (-)-sparteine (3),6 was
selected as the model system for our investigation. As
noted previously, the rate of cyclization of an olefinic
organolithium is strongly temperature-dependent;11 how-
ever, the addition of a lithiophilic ligand, such as
N,N,N′,N′-tetramethylethylenediamine (TMEDA), accel-
erates the cyclization reaction.12,13 Thus, in the presence
of (-)-sparteine, the rearrangement of 1 to 4 occurs at
-40 °C in 1.5 h to furnish, after quench with CH3OD,
(R)-1-allyl-3-deuteriomethylindoline [(R)-5] in ca. 80%
yield with 86% ee.6a It should be noted that in the absence
of a ligand the cyclization is very slow at -40 °C and
only trace amounts of 1-allyl-3-methylindoline (5) are
produced after a reaction time of 1.5 h. It is also
important to note that the exploratory reactions described
below were conducted under identical conditions to assess
the enantioselectivity imparted by each ligand; conse-
quently, with one exception (vide infra), no attempt was
made to optimize product yield for reaction involving a
particular ligand.
(11) Bailey, W. F.; Patricia, J . J .; DelGobbo, V. C.; J arret, R. M.;
Okarma, P. J . J . Org. Chem. 1985, 50, 1999.
(12) Bailey, W. F.; Nurmi, T. T.; Patricia, J . J .; Wang, W. J . Am.
Chem. Soc. 1987, 109, 2442.
(13) Chamberlin, A. R.; Bloom, S. H.; Cervini, L. A.; Fotsch, C. H.
J . Am. Chem. Soc. 1988, 110, 4788.
(14) Wakefield, B. J . The Chemistry of Organolithium Compounds;
Pergamon Press: Oxford, 1974.
(15) Li, X.; Schenkel, L. B.; Kozlowski, M. C. Org. Lett. 2000, 2, 875.
J . Org. Chem, Vol. 69, No. 18, 2004 6043

Mealy et al.
F IGURE 3. Systematic structural variation of the (1S,2S)-
(+)-pseudoephedrine substitution pattern.
of >4 equiv of ligand decreases the rate of the cyclization
(Table 2, cf. entries 1 and 2).
The aminoethers that incorporate a pyrrolidine unit
(17 and 18) are poor ligands for use in this chemistry
(Table 1, entries 12 and 13). Not only is the cyclization
of 1 slow in the presence of 17 or 18, but the enantiose-
lectivity is low as well (Figure 2). The tetrahydrofur-
furalamine ligand 19 also gives product in low ee, while
the use of aminoindanol-derived ligand 20 results in
quench of organolithium 1 (Table 1, entry 15).
F IGURE 2. Enantioselectivity in the cyclization of 1 imparted
by aminoether ligands.
TABLE 2. Effect of Tem p er a tu r e a n d Liga n d
Stoich iom etr y on th e Cycliza tion of 1 in th e P r esen ce of
Oxa zolid in e 16
A more successful result with ligands derived from
(1S,2S)-(+)-N-methylpseudoephedrine led us to conduct
a systematic investigation into the influence of nitrogen
and oxygen substituents on that core structure. The
results of these experiments are summarized in Figure
3; the ligands are arranged in the order of decreasing
enantioselectivity. Remarkably, the most effective ligand,
21, matches the enantioselectivity observed in the pres-
ence of (-)-sparteine and is the simplest in relation to
the substitution pattern. Increasing the size of the oxygen
substituent appears to have little influence on the enan-
tioselectivity, as evidenced by the result observed in the
presence of ligands 22 and 23. In general, it appears that
substitution on nitrogen is better tolerated if the alkyl
chain on oxygen is also lengthened (cf. ligand 23 and
ligands 24 and 25). Be that as it may, none of the
“functionalized” pseudoephedrine derivatives participated
more effectively in the asymmetric cyclization of 1 than
the simple permethylated ligand, 21.
Given the reasonably high enantioselectivity observed
for the cyclization of a n-pentane-diethyl ether solution
of 1 at -40 °C in the presence of (1S,2S)-N,O-dimeth-
ylpseudoephedrine (21), the effect of several experimental
variables on the yield and selectivity of this ring closure
was explored. The results are summarized in Table 3.
Not surprisingly, the yield of cyclized product may be
increased by simply allowing the reaction mixture to
stand for a longer time at -40 °C (Table 3, cf. entries 4
and 5); after standing for 3 h at this temperature a yield
of 86% is obtained. At temperatures lower than ca. -40
°C, the cyclization is rather slow but the enantioselec-
tivity is somewhat increased (Table 3, entries 9 and 10).
At temperatures higher than -40 °C, a more rapid
cyclization is purchased at the expense of enantioselec-
tivity (Table 3, entries 1-3). Nonetheless, even at room
temperature, cyclization of 1 in the presence of 21 is fairly
selective. Significantly, as was the case for cyclization of
1 conducted in the presence of (-)-sparteine,6a solvent
has a profound effect on the enantioselectivity of the
products, relative yield
entry conda ligand, equiv
6b
(R)-5
% ee
1
2
3
4
A
A
B
B
2.5
4.5
2.0
4.7
42
58
41
∼5
7
12
20
27
59
∼95
93
a
Reaction conditions: A ) +22 °C, 1.0 h; B ) -40 °C, 1.5 h.
b
X ) H.6a
asymmetric cyclization of 1 (Table 1, entry 8). Unfortu-
nately, 13 is not commercially available, and its synthesis
requires a resolution.15
Am in oeth er Liga n d s. The results of a screening of a
series of aminoethers, derived primarily from com-
mercially available (1R,2S)-(-)-norephedrine, are sum-
marized in Figure 2. It might be noted that the enantio-
mer, (1S,2R)-(+)-norephedrine, is also commercially avail-
able. Evidently, the cyclization of 1 is sensitive to even
slight changes in the norephedrine structure. Cyclization
of 1 in the presence of ligand 14 is modestly enantiose-
lective; however, in the presence of 15, which differs only
in chain length of the alkyl group on nitrogen, cyclization
was completely suppressed (Table 1, entry 10). Somewhat
unexpectedly, connecting the nitrogen and oxygen atoms
of the (1R,2S)-ephedrine skeleton by a methylene tether
to give 16 led to a reversal of the enantioselectivity of
the cyclization. It is possible that oxazolidine 16 binds
to the lithium of 1 in an η1 fashion; the cyclization of 1
in the presence of 16 is sluggish at -40 °C, and as
illustrated in Table 2 (entries 3 and 4), less than 10% of
cyclized product is formed. The cyclization is more rapid
at room temperature, but it appears that the presence
6044 J . Org. Chem., Vol. 69, No. 18, 2004

Cyclization of Achiral Olefinic Organolithiums
TABLE 3. Effect of Tem p er a tu r e a n d Solven t on th e
En a n tioselective Cycliza tion of 1 in th e P r esen ce of
Liga n d 21
entry temp, °C time, h
solventa
yield, % (R)-5 % ee
1
2
3
4
5
6
7
8
9
+25
0
1.0
1.0
2.0
1.5
3.0
3.0
3.0
3.0
6.0
8.0
n-C5H12-Et2O
n-C5H12-Et2O
n-C5H12-Et2O
n-C5H12-Et2O
n-C5H12-Et2O
Et2O
n-C5H12
THF
n-C5H12-Et2O
n-C5H12-Et2O
89
87
89
78
86
87
61
48
52
10
64
68
74
80
78
80
72
8
-20
-40
-40
-40
-40
-40
-60
-78
82
86
10
a
The relative proportion of n-C5H12-Et2O mixtures was 9:1 by
vol.
process: pentane-diethyl ether mixtures (Table 3, entries
4 and 5), diethyl ether (Table 3, entry 6), and to a lesser
extent, pure pentane (Table 3, entry 7) are effective
media for the reaction, but THF should be avoided
because it leads to essentially racemic product (Table 3,
entry 8).
F IGURE 4. Enantioselectivity in the cyclization of 1 imparted
by ether ligands.
Eth er Liga n d s. The results of a more extensive
survey of chiral ethers as ligands are summarized in
Figure 4. The C2-symmetric dimethyl ether of hydroben-
zoin (26) is nearly as effective as is (-)-sparteine in
promoting the asymmetric cyclization of 1. Several
carbohydrate derivatives were explored as potential
ligands because they were either commercially available
or could be readily prepared.
SCHEME 1
The carbohydrate-derived ligands (27, 28, 32-34) were
insoluble in pentane-diethyl ether (9:1 v/v) solvent at
low temperature. For this reason, these ligands were used
in pure diethyl ether solvent (Table 1, entries 22, 23, 27-
29). Commercially available isosorbide dimethyl ether
(27) afforded product in reasonable ee and is as effective
as is aminoether 14; however, isomannide dimethyl ether
(28), the diastereomer of 27 having a cis-orientation of
the ether moieties, is considerably less effective as a
ligand for the cyclization of 1. Other carbohydrate-derived
ethers, such as 32-34, are essentially ineffective in
promoting the asymmetric cyclization of 1. Moreover,
ligands 29-31, which are subunits of 32-34, do not
impart enantiofacial selectivity in the cyclization of 1. The
chiral BINOL derivative 35 also proved ineffective at
facilitating the cyclization, most likely as a result of the
poor solubility of the ligand-substrate complex.
provided by the behavior of the organolithium derived
from N,N-diallyl-2-bromo-3-methylaniline (36).
An approximately 0.1 M solution of [2-(N,N-diallyl-
amino)-6-methyl]phenyllithium (37) in n-pentane-dieth-
yl ether (9:1 v/v) was prepared, as illustrated in Scheme
2, by treatment of 36 with 2.2 molar equiv of t-BuLi at
-78 °C. When 2.2 molar equiv of TMEDA was added and
the resulting mixture was then allowed to stand at -40
°C for 1.5 h, 1-allyl-3,4-dimethylindoline (38) was isolated
in 87% yield following quench of the reaction mixture
with MeOH. In striking contrast to this result, an
analogous experiment conducted in the presence of 2.2
molar equiv of (-)-sparteine and quenched with MeOD
led exclusively to the formation of N,N-diallyl-2-deuterio-
3-methylaniline (39). Given the rapid cyclization of 37
in the presence of TMEDA, the failure to observe any
cyclic product when the reaction is conducted in the
presence of (-)-sparteine was a surprise. One possibility,
of course, is that sparteine does not form a complex with
37. This does not appear to be the case.
Com p lica tion s: Liga n d -Su bstr a te In ter a ction s.
We have noted elsewhere that the ability of a chiral
ligand to facilitate the cyclization of an achiral, unsatur-
ated organolithium is not sufficient to render the cycliza-
tion enantioselective.6a More recently it has become
apparent that complexation of a ligand with the lithium
atom of a substrate may, in fact, hinder the cyclization.
A particularly striking example of this phenomenon is
J . Org. Chem, Vol. 69, No. 18, 2004 6045

Mealy et al.
SCHEME 2
SCHEME 3
of the parent [2-(N,N-diallylamino)phenyl]lithium (1) in
the presence of either (-)-sparteine or (1R,2R)-(-)-
N,N,N′,N′-tetramethyl-1,2-cyclohexanediamine (10) af-
forded the same product, viz., (R)-(-)-1-allyl-3-methylin-
doline (Figure 1 and Table 1, entries 1 and 5). On the
assumption that cyclization of 37 in the presence of the
cyclohexanediamine ligand (10) proceeds with the same
facial selectivity as does the cyclization of 1 in the
presence of this ligand, the absolute configurations of (+)-
and (-)-1-allyl-3,4-dimethylindoline (38) are tenatively
assigned as shown in Scheme 3.
Con clu sion s
The ability of a diverse set of chiral ligands to effect
enantiofacially selective cyclization of 2-(N,N-diallylami-
no)phenyllithium (1) has been investigated. Although (-)-
sparteine remains the best ligand for enantioselective
cyclization of 1, three structurally unrelated ligands, cis-
1,5-diazadecalin (13), (1S,2S)-1,2-dimethoxy-1,2-diphen-
ylethane (26), and (1S,2S)-N,O-dimethylpseudoephedrine
(21), which are available in either enantiomeric form,
approach the efficiency of sparteine in this reaction. The
N,O-dimethylpseudoephedrine ligand (21) is a particu-
larly effective surrogate for sparteine, affording 1-allyl-
3-methylindoline in good yield and high ee. The fact that
seemingly minor variation in substrate structure (viz., 1
and 37) may have a pronounced effect on the ability of a
given ligand to facilitate the cyclization suggests that
caution should be exercised in generalizing the results
of this study to other substrates.
As illustrated in Scheme 2, [2-(N,N-diallylamino)-6-
methyl]phenyllithium (37) readily cyclizes in the absence
of diamine ligand upon standing at room temperature
for 1.5 h to give, after quench with MeOH, a 94% yield
of 1-allyl-3,4-dimethylindoline (38). However, when 2
molar equiv of (-)-sparteine was added to 37 and the
mixture was allowed to stand for an extended period (7
h) at room temperature, only 16% of the indoline was
obtained; the major product (81%) was secondary amine
40. The formation of 40 is likely the result of a [2,3]-
sigmatropic rearrangement of the allylic anion initiated
by removal of an allylic proton when the reaction mixture
is warmed for an extended period.16
The cyclization of 37 does proceed in reasonable yield
and with modest enantioselectivity when conducted in
the presence of (1R,2R)-(-)-N,N,N′,N′-tetramethyl-1,2-
cyclohexanediamine (10). As illustrated in Scheme 3, (-)-
1-allyl-3,4-dimethylindoline (38) is the major product of
the reaction when 37 is allowed to stand for 1.5 h at -40
°C in the presence of 2 molar equiv of 10. Moreover, the
enantioselectivity of the cyclization (er ) 85:15) is
comparable to that observed for the cyclization of [2-(N,N-
diallylamino)phenyl]lithium (1) in the presence of this
ligand (Figure 1).
Exp er im en ta l Section
P r oced u r e for Liga n d Scr een in g in th e Asym m etr ic
Cycliza tion of [2-(N,N-Dia llyla m in o)p h en yl]lith iu m (1).
A one-necked round-bottomed flask, fitted with a rubber
septum and a magnetic spinbar was flame-dried under a
stream of argon. The cooled, dry flask was charged with N,N-
diallyl-2-bromoaniline (2) (typically 1.7-3.0 mmol) and suf-
ficient solvent (Table 1) to give a 0.1 M solution of the aniline.
The resulting solution was cooled to -78 °C in a dry ice-
acetone bath, 2.2 molar equiv of t-BuLi in heptane was added
dropwise over 5 min, and the solution was allowed to stir for
approximately 10 min during which time a white precipitate
was observed to form. The ligand (2.1-2.5 molar equiv) was
An unexpected feature of the cyclization of 37 is the
fact that, whereas ring closure in the presence of (-)-
sparteine produces (+)-38, the cyclization mediated by
10 affords the (-)-enantiomer. As noted above, cyclization
(16) Bailey, W. F.; Carson, M. W. Tetrahedron Lett. 1997, 38, 1329.
6046 J . Org. Chem., Vol. 69, No. 18, 2004

Cyclization of Achiral Olefinic Organolithiums
then added dropwise, and the cloudy, white-to-yellow mixture
was stirred for an additional 7 min. The reaction vessel was
then transferred to a constant-temperature bath maintained
at -40 °C and stirred for 90 min prior to quench with 1.0 mL
of dry, deoxygenated MeOD. The reaction mixture was poured
onto 25 mL of water, residual material was transferred with
25 mL of diethyl ether, and the layers were separated. The
aqueous layer was discarded, and the organic phase was
washed with saturated aqueous sodium chloride and dried over
magnesium sulfate. Relative yields and the extent of deute-
rium incorporation, summarized in Table 1, were determined
by GC and GC-MS analysis of an aliquot that was concen-
trated under a stream of nitrogen. Concentration of the
remaining solution by rotary evaporation and medium-pres-
sure chromatography of the residue on silica gel (9:1 hexanes-
dichloromethane, Rf ) 0.21) gave 1-allyl-3-methylindoline (5)6a
as a clear, colorless oil: 1H NMR (CDCl3) δ 7.09-7.04 (m, 2H),
6.71-6.66 (m, 1H), 6.51 (d, J ) 7.64 Hz, 1H), 5.98-5.84 (m,
1H), 5.32-5.16 (m, 2H), 3.82-3.52 (m, 3H), 3.30-3.27 (m, 1H),
2.84 (apparent t, J ) 8.54 Hz, 1H), 1.28 (app d, J ) 7.73 Hz,
2H). The enantiomeric excess was determined by CSP-GC as
described in Supporting Information: the (S)-enantiomer
eluted after 27.1 min, followed by the (R)-enantiomer at 28.2
min.
P r oced u r e A: E sch w eiler -Cla r k e Met h yla t ion of
Am in es. Tertiary amines were prepared following the proce-
dure of Clarke17 and worked up by the method of Cope.18 Thus,
5.0 molar equiv of 96% aqueous formic acid was cooled to ∼0
°C in an ice-water bath, and 1.0 equiv of the amine was added
slowly. A 37% aqueous formaldehyde solution (2.2 molar equiv)
was then added in one portion, and the solution was heated
until carbon dioxide evolution began at which time heating
was discontinued. Once the formation of gas was no longer
apparent, heating was resumed for 14-22 h. The cooled
reaction mixture was then poured onto 1.1 molar equiv of ice-
cold 10% aqueous hydrochloric acid and washed with four
portions of diethyl ether. The pH of the aqueous phase was
adjusted to 10 by the addition of solid NaOH pellets, and the
solution was extracted with two portions of diethyl ether. The
+23.1 (c 1.71, CH2Cl2). Anal. Calcd for C20H42N2: C, 77.35; H,
13.63; N, 9.02. Found: C, 77.07; H, 13.28; N, 9.09.
(1S ,4S )-(+)-2,5-D im e t h y l-2,5-d ia z a b ic y c lo [2.2.1]-
h ep ta n e (12). A solution of 10.8 g (39.3 mmol) of (1S,4S)-(+)-
2-methyl-2,5-diazabicyclo[2.2.1]heptane dihydrobromide19 in
5.0 mL of water was cooled to 0 °C and the pH was adjusted
to ∼8 by addition of 6 M aqueous sodium hydroxide. To this
solution was slowly added 16.9 mL (393 mmol) of 96% aqueous
formic acid, followed by 6.44 mL (86.5 mmol) of 37% aqueous
formaldehyde solution, and the solution was heated until
carbon dioxide evolution began at which time heating was
discontinued. Once the formation of gas was no longer appar-
ent, heating was resumed for 12 h, and the cooled reaction
mixture was poured onto 30.0 mL (87.0 mmol) of ice-cold 10%
aqueous hydrochloric acid and washed with four 30-mL
portions of diethyl ether. The pH of the aqueous phase was
adjusted to 10 by the addition of solid NaOH pellets, and this
solution was continuously extracted with diethyl ether for 18
h. The organic portion was dried over a potassium hydroxide-
sodium sulfate mixture and concentrated by rotary evapora-
tion. Rigorous drying of the product by heating with sodium
metal and subsequent Kugelrohr distillation from fresh sodium
gave 2.24 g (45%) of a clear, colorless oil: bp 55-60 °C (13
mm); 1H NMR (CDCl3) δ 3.18 (m, 2H), 2.78-2.76 (m, 2H),
2.64-2.61 (m, 2H), 2.37 (s, 6H), 1.71 (app s, 2H); 13C NMR
(CDCl3) δ 63.8, 57.0, 40.9, 33.2; [R]28 ) +65.8 (c 2.97, CH2-
D
Cl2); HRMS calcd for C7H14N2 126.1157, found 126.1170.
(1R,2S)-(-)-N,N-Dib u t yl-O-m et h yln or ep h ed r in e (15).
Following General Procedure B, 4.74 g (20.1 mmol) of (1R,2S)-
(+)-N,N-dibutylnorephedrine19 afforded 4.01 g (72%) of the title
compound as a yellow oil that was used without further
purification. An analytical sample was prepared by preparative
GC (10 ft, 10% SE-30, 190 °C): 1H NMR (CDCl3) δ 7.33-7.29
(m, 2H), 7.26-7.21 (m, 3H), 4.12 (d, J ) 5.60 Hz, 1H), 3.20 (s,
3H), 2.85 (5-line pattern, J ) 6.54 Hz, 1H), 2.41-2.37 (m, 4H),
1.28-1.12 (m, 8H), 1.03 (d, J ) 6.71 Hz, 3H), 0.83 (t, J ) 7.15
Hz, 6H); 13C NMR (CDCl3) δ 142.0, 127.8, 127.2, 126.9, 86.3,
60.7, 56.8, 50.4, 30.2, 20.5, 14.2, 9.3; [R]23 ) -12.7 (c 1.61,
D
CH2Cl2). Anal. Calcd for C18H31NO: C, 77.92; H, 11.26; N, 5.05.
Found: C, 78.01; H, 11.03; N, 5.20.
combined organic portions were dried over
a potassium
(1R ,2S )-(-)-1-Me t h oxy-1-p h e n yl-2-p yr r olid in ylp r o-
p a n e (18). Following General Procedure B, 5.10 g (24.8 mmol)
of (1R,2S)-(+)-1-phenyl-2-pyrrolidinyl-1-propanol20 gave 4.30
g (79%) of the title compound as a clear, slightly yellow oil
contaminated with ca. 5% of the starting alcohol (δ 0.79 (d, J
) 6.64 Hz, 3H)). An analytically pure sample was prepared
by preparative GC on a 10 ft, 10% SE-30 on Anakrom A (40
mesh) column: 1H NMR (CDCl3) δ 7.36-7.23 (m, 5H), 4.52
(d, J ) 2.60 Hz, 1H), 3.32 (s, 3H), 2.71-2.65 (m, 4H), 2.42-
2.40 (m, 1H), 1.86-1.78 (m, 4H), 0.97 (d, J ) 6.68 Hz, 3H);
13C NMR (CDCl3) δ 140.5, 128.0, 126.9, 126.8, 84.4, 65.1, 57.2,
hydroxide-sodium sulfate mixture and concentrated by rotary
evaporation. Rigorous drying of the product by heating with
sodium metal and subsequent Kugelrohr distillation from fresh
sodium provided the tertiary amines.
P r oced u r e B: O-Meth yla tion of N,N-Dia lk yln or ep h ed -
r in es. A mixture of N,N-dialkylnorephedrine (1.0 equiv) and
potassium tert-butoxide (1.2 equiv) was diluted at room
temperature with enough THF to give a 0.1-0.5 M solution.
After 15 min, iodomethane (1.3 equiv) was added dropwise and
a white precipitate was observed to form after a few seconds.
On a scale greater than 10 mmol, iodomethane should be
added at 0 °C as precipitate formation is accompanied by a
mild exotherm. The mixture was stirred for 1 h at room
temperature and then concentrated by rotary evaporation. The
residue was partitioned between water and ether, the phases
were separated, and the organic portion was washed with
brine, dried over sodium sulfate, and concentrated by rotary
evaporation. In some cases the residue was purified by
Kugelrohr distillation from sodium metal; however, in several
instances, decomposition was evident upon addition of sodium.
51.6, 23.4, 11.0; [R]22 ) -59.6 (c 2.22, CH2Cl2). Anal. Calcd
D
for C14H21NO: C, 76.67; H, 9.65; N, 6.39. Found: C, 76.32; H,
9.47; N, 6.42.
(R)-(+)-N,N-Dim eth yltetr ah ydr ofu r fu r ylam in e (19). Fol-
lowing General Procedure A, 2.01 g (19.9 mmol) of (R)-(-)-
tetrahydrofurfurylamine19 afforded 1.85 g (72%) of the title
compound as a clear, colorless oil: bp 60-65 °C (18 mm) [lit.21
1
(racemate) bp 50 °C (13 mm)]; H NMR (CDCl3) δ 4.01-3.95
(m, 1H), 3.90-3.84 (m, 1H), 3.77-3.71 (m, 1H), 2.45-2.40 (m,
1H), [overlapping patterns, 2.32-2.27 (m, 1H), 2.28 (s, 6H)],
2.03-1.95 (m, 1H), 1.91-1.84 (m, 2H), 1.54-1.45 (m, 1H); 13
C
(1S,2S)-(+)-N,N′-Bis(3,3-d im eth ylbu tyl)-N,N′-d im eth yl-
1,2-d ia m in ocycloh exa n e (11). Following Procedure A, 0.99
g (3.5 mmol) of (1S,2S)-(+)-N,N′-bis(3,3-dimethylbutyl)-1,2-
cyclohexanediamine19 gave 0.75 g (68%) of the title compound
as a clear, colorless oil: bp 140-145 °C (5 mm); 13C NMR
NMR (CDCl3) δ 76.9, 67.8, 64.2, 46.0, 30.1, 25.4; [R]24D ) +4.21
(c 1.76, CH2Cl2).
(1S,2R)-(-)-1-Dim eth ylam in o-2-m eth oxyin dan (20). The
amino-ether was prepared according to General Procedure B.
Thus, 2.84 g (16.0 mmol) of (1S,2R)-(+)-1-(dimethylamino)-2-
indanol22 and 2.20 g (19.6 mmol) of potassium tert-butoxide
(CDCl3) δ 62.7, 50.1, 42.2, 37.0, 29.8, 29.6, 25.9, 25.2; [R]28
)
D
(17) Clarke, H. T.; Gillespie, H. B.; Weisshaus, S. Z. J . Am. Chem.
Soc. 1933, 55, 4571.
(18) Cope, A. C.; Ciganek, E.; Fleckenstein, L. J .; Meisinger, M. A.
P. J . Am. Chem. Soc. 1960, 82, 4651.
(20) Zhao, D.; Chen, C.-Y.; Xu, F.; Tan, L.; Tillyer, R.; Pierce, M. E.;
Moore, J . R. Organic Syntheses; Wiley: New York, 2004; Collect. Vol.
X, p 556.
(19) Commercially available.
(21) Schultz, O. E.; Ziegler, A. Pharmazie 1970, 25, 472.
J . Org. Chem, Vol. 69, No. 18, 2004 6047

Mealy et al.
were combined under an atmosphere of argon and diluted with
32 mL of THF. After 15 min of stirring, the reaction vessel
was cooled to 0 °C, and 1.30 mL (20.8 mmol) of iodomethane
was added via syringe. The cooling bath was then removed,
and stirring was continued for 1 h. After concentration and
standard workup, 3.09 g (>100%) of 93% pure material was
obtained (remainder starting alcohol). Preparative GC (10 ft,
10% SE-30, 200 °C) afforded an analytically pure sample of
the title compound: 1H NMR (CDCl3) δ 7.32-7.31 (m, 1H),
7.26-7.21 (m, 3H), 4.24-4.16 (m, 2H), 3.47 (s, 3H), 3.09-2.96
(m, 2H), 2.39 (s, 6H); 13C NMR (CDCl3) δ 140.5, 139.5, 127.9,
1H), 3.16 (s, 3H), 3.14-3.06 (m, 1H), 2.97 (app sep, J ) 6.47
Hz, 1H), 2.24 (s, 3H), 1.07 (d, J ) 6.47 Hz, 3H), 1.02 (d, J )
6.47 Hz, 3H), 0.75 (d, J ) 6.87 Hz, 3H); 13C NMR (CDCl3) δ
141.6, 128.2, 128.1, 127.6, 87.2, 59.4, 56.9, 52.4, 32.6, 21.0, 20.0,
13.5; [R]27 ) +90.6 (c 4.40, CH2Cl2). Anal. Calcd for C14H23
-
D
NO: C, 75.97; H, 10.47; N, 6.33. Found: C, 75.59; H, 10.10;
N, 6.31.
N,N-Dia llyl-2-br om o-3-m eth yla n ilin e (36). Following the
general procedure of Tidwell and Buchwald,24 1.79 g (9.63
mmol) of 2-bromo-3-methylaniline,25 4.08 g (38.5 mmol) of
sodium carbonate, and 3.33 mL (38.5 mmol) of allyl bromide
were added to 40 mL of dry DMF, and the resulting mixture
was heated at reflux under an atmosphere of argon for 8 h.
Upon cooling, the salts were removed by filtration, and the
mother liquor was partitioned between diethyl ether and
water. The layers were separated, and the aqueous phase was
extracted twice with diethyl ether. The combined organic
layers were washed with water and brine, dried over magne-
sium sulfate, and concentrated. The crude yellow oil was
purified by Kugelrohr distillation to give 2.29 g (89%) of the
clear, slightly yellow oil: bp 82-86 °C (0.2 mm); 1H NMR
(CDCl3) δ 7.09 (apparent t, J ) 7.76 Hz, 1H), 6.94-6.86 (m,
2H), 5.89-5.76 (m, 2H), 5.21-5.07 (m, 4H), 3.66-3.64 (m, 4H),
2.41 (s, 3H); 13C NMR (CDCl3) δ 149.3, 139.6, 135.0, 126.5,
126.3, 126.2, 125.0, 82.9, 69.1, 57.6, 42.2, 37.0; [R]23 ) -96.7
D
(c 1.47, CH2Cl2). Anal. Calcd for C12H17NO: C, 75.35; H, 8.96;
N, 7.32. Found: C, 75.04; H, 8.83; N, 7.39.
(1S,2S)-(+)-N-Meth yl-O-eth ylpseu doeph edr in e (22). Fol-
lowing a modification of General Procedure B, a solution of
3.34 g (18.6 mmol) of (1S,2S)-(+)-N-methylpseudoephedrine19
in 37 mL of THF was treated with 5.22 g (46.6 mmol) of
potassium tert-butoxide for 15 min at 0 °C. A 3.48 mL (46.6
mmol) portion of ethyl bromide was added dropwise via
syringe, and the reaction mixture was allowed to stir at room
temperature for 1 h. After concentration and workup in the
usual way, 3.22 g (83%) of a clear, pale yellow oil was
obtained: bp 150 °C (6 mm); 1H NMR (CDCl3) δ 7.34-7.24
(m, 5H), 4.16 (d, J ) 8.60 Hz, 1H), 3.35-3.23 (m, 2H), 2.94-
2.87 (m, 1H), 2.39 (s, 6H), 1.14 (t, J ) 7.01 Hz, 3H), 0.66 (d, J
) 6.79 Hz, 3H); 13C NMR (CDCl3) δ 141.6, 128.1, 127.8, 127.5,
125.7, 124.4, 121.6, 117.4, 55.6, 24.2. Anal. Calcd for C13H16
-
NBr: C, 58.66; H, 6.06; N, 5.26. Found: C, 58.50; H, 6.08; N,
5.36.
84.1, 63.7, 63.5, 41.0, 15.3, 11.2; [R]27 ) +82.7 (c 7.35, CH2-
(()-1-Allyl-3,4-d im eth ylin d olin e (38). A solution of 323
mg (1.21 mmol) of N,N-diallyl-2-bromo-3-methylaniline (36)
in 10.9 mL of n-pentane and 1.2 mL of diethyl ether was cooled
to -78 °C under an atmosphere of argon, and 1.34 mL of a
1.99 M solution of t-BuLi in heptane (2.67 mmol) was added
dropwise over a 5 min period. The resulting mixture was
stirred at -78 °C for 10 min before addition of 0.40 mL (2.67
mmol) of TMEDA. After 10 min at -78 °C, the mixture was
transferred to a thermostated bath at -40 °C and stirred for
1.5 h before addition of 1.2 mL of dry, deoxygenated MeOH.
The reaction mixture was partitioned between 15 mL of water
and 15 mL of diethyl ether, and the organic portion was
washed with water, saturated aqueous ammonium chloride,
and brine. After drying over magnesium sulfate, concentration
by rotary evaporation gave 0.201 g (89%) of 85% pure indoline.
Preparative GC (10 ft, 10% FFAP, 200 °C) afforded analytically
pure clear and colorless oil: 1H NMR (CDCl3) δ 6.98 (apparent
t, J ) 7.70 Hz, 1H), 6.48 (d, J ) 7.56 Hz, 1H), 6.35 (d, J )
7.80 Hz, 1H), 5.94-5.84 (m, 1H), 5.29-5.23 (m, 1H), 5.18-
5.15 (m, 1H), 3.79 (m, 1H), 3.58 (m, 1H), 3.35 (apparent t, J )
8.49 Hz, 1H), 3.31-3.23 (m, 1H), 3.09 (dd, J ) 8.49, 2.61 Hz,
1H), 2.25 (s, 3H), 1.23 (d, J ) 6.84 Hz, 3H); 13C NMR (CDCl3)
δ 151.2, 134.3, 133.6, 133.4, 127.5, 119.5, 117.0, 105.0, 60.8,
51.8, 34.2, 19.0, 18.1. Anal. Calcd for C13H17N: C, 83.37; H,
9.15; N, 7.48. Found: C, 83.13; H, 9.51; N, 7.39.
P r epar ation of (S)-(+)-1-Allyl-3,4-dim eth ylin dolin e [(S)-
38]: An Un exp ected [2,3]-Sigm a tr op ic Rea r r a n gem en t
in th e P r esen ce of (-)-Sp a r tein e. A solution of 385 mg (1.45
mmol) of N,N-diallyl-2-bromo-3-methylaniline (36) in 13.1 mL
of n-pentane and 1.4 mL of diethyl ether was cooled to -78
°C under an atmosphere of argon, and 1.60 mL of a 1.99 M
solution of t-BuLi in heptane (3.18 mmol) was added dropwise
over a 5 min period. A white precipitate formed, and after 10
min at -78 °C 0.800 g (3.41 mmol) of (-)-sparteine was added
dropwise (the solution was noted to turn a cloudy yellow color).
The mixture was stirred for an additional 10 min at -78 °C,
the cooling bath was removed, and the solution was allowed
to stir for 7 h at room temperature before quench with 1.4 mL
of dry, deoxygenated MeOH. The mixture was partitioned
between water and pentane, and the organic portion was
washed with saturated aqueous ammonium chloride, and brine
D
Cl2); HRMS-FAB [M + 1]+ calcd for C13H22NO 208.1701, found
208.1707.
(1S,2S)-(+)-N-Eth yl-O-eth ylp seu d oep h ed r in e (23). The
amino ether was prepared by modification of General Proce-
dure B. Thus, a solution of 5.96 g (30.8 mmol) of (1S,2S)-(+)-
N-ethylpseudoephedrine23 in 123 mL of THF was treated with
8.63 g (77.0 mmol) of potassium tert-butoxide for 15 min at 0
°C. A 5.75 mL (77.0 mmol) portion of ethyl bromide was added
dropwise via syringe, and the reaction mixture was allowed
to warm to room temperature and stir for 1 h. After standard
workup and concentration, the crude product was found to be
a ∼7:3 mixture of product and starting material, as determined
by GC-MS analysis. This material was resubjected to the
conditions described above and purified in the usual way to
afford 4.64 g (68%) of a clear, pale yellow oil: bp 155 °C (3
mm); 1H NMR (CDCl3) δ 7.37-7.22 (m, 5H), 4.18 (d, J ) 8.43
Hz, 1H), 3.34-3.21 (m, 2H), 3.03-2.96 (m, 1H), 2.72-2.53 (m,
2H), 2.37 (s, 3H), 1.13 (t, J ) 7.01 Hz, 3H), 1.08 (t, J ) 7.14
Hz, 3H), 0.70 (d, J ) 6.84 Hz, 3H); 13C NMR (CDCl3) δ 142.0,
128.3, 128.0, 127.6, 84.7, 64.0, 62.7, 48.0, 37.7, 15.6, 14.1, 12.7;
[R]23 ) +92.4 (c 3.95, CH2Cl2). Anal. Calcd for C14H23NO: C,
D
75.97; H, 10.47; N, 6.33. Found: C, 75.71; H, 10.65; N, 6.51.
(1S,2S)-(+)-N-Eth yl-O-m eth ylpseu doeph edr in e (24). Fol-
lowing General Procedure B, 4.82 g (24.9 mmol) of (1S,2S)-
(+)-N-ethylpseudoephedrine23 afforded 3.95 g (77%) of the title
1
compound as a clear, pale yellow oil: bp 150 °C (3 mm); H
NMR (CDCl3) δ 7.37-7.24 (m, 5H), 4.03 (d, J ) 8.83 Hz, 1H),
3.14 (s, 3H), 3.05-2.98 (m, 1H), 2.70-2.61 (m, 1H), 2.54-2.46
(m, 1H), 2.33 (s, 3H), 1.10 (t, J ) 7.15 Hz, 3H), 0.64 (d, J )
6.80 Hz, 3H); 13C NMR (CDCl3) δ 141.2, 128.3, 127.9, 127.7,
86.4, 62.2, 56.5, 47.6, 37.3, 13.9, 10.7; [R]22 ) +103 (c 4.50,
D
CH2Cl2); HRMS-FAB [M + 1]+ calcd for C13H22NO 208.1701,
found 208.1711.
(1S,2S)-(+)-N-Isopr opyl-O-m eth ylpseu doeph edr in e (25).
Following General Procedure B, 4.11 g (19.8 mmol) of (1S,2S)-
(+)-N-isopropylpseudoephedrine23 afforded 2.16 g (49%) of the
title compound as a clear, pale yellow oil: bp 150 °C (2 mm);
1H NMR (CDCl3) δ 7.37-7.24 (m, 5H), 4.02 (d, J ) 7.60 Hz,
(22) For a description of the (1R,2S)-enantiomer, see: Senanayake,
C. H.; Bakale, R. P.; Fang, Q. K.; Grover, P. T.; Heefner, D. L.; Rossi,
R. F.; Wald, S. A. Preparation of Cycloalkylphenylglycolate Enantio-
mers by Asymmetric Synthesis. PCT Int. Appl. 9950205, 1999.
(23) For a description of the (1R,2R)-enantiomer, see: Enders, D.;
Zhu, J .; Kramps, L. Liebigs Ann./ Recueil. 1997, 6, 1101.
(24) Tidwell, J . H.; Buchwald, S. L. J . Am. Chem. Soc. 1994, 116,
11797.
(25) Krolski, M. E.; Renaldo, A. F.; Rudisill, D. E.; Stille, J . K. J .
Org. Chem. 1988, 53, 1170.
6048 J . Org. Chem., Vol. 69, No. 18, 2004

Cyclization of Achiral Olefinic Organolithiums
and dried over magnesium sulfate. Concentration afforded
0.180 g (66%) of an oil consisting of three isomeric com-
pounds: N,N-diallyl-3-methylaniline (3%), (+)-1-allyl-3,4-di-
methylindoline (16%), and N-(1-vinylbut-3-enyl)-3-methyla-
niline (81%). The minor products proved to be spectroscopically
identical to independently prepared samples of N,N-diallyl-3-
methylaniline (39)26 and (()-1-allyl-3,4-dimethylindoline (38).
Isolation of the indoline by preparative GC (10 ft, 15% FFAP,
200 °C) and subsequent analysis by CSP-GC (30 m, G-TA, 110
°C) indicated an enantiomeric excess of 29.6%. A 22% ee
sample of the indoline prepared under conditions differing from
Ack n ow led gm en t. We thank the following indi-
viduals for generous gifts of chiral, nonracemic materi-
als: Prof. Mukund Sibi (University of North Dakota)
for compound 9; Prof. Marisa C. Kozlowski (University
of Pennsylvania) for (R,R)-(+)-cis-decahydro-1,5-naph-
thyridine (R,R)-tartrate; Dr. Richard Tillyer (Depart-
ment of Process Research, Merck Research Laborato-
ries) for (1S,2R)-(-)-cis-1-amino-2-indanol and compounds
17 and 26; and Mr. Nabyl Merbouh (University of
Connecticut) for diacetone-D-galactose. We are grateful
to Dr. J ames Schwindeman of FMC, Lithium Division,
for a generous gift of t-BuLi in heptane. This work was
supported by a grant from the Process Chemistry
Division, H. Lundbeck A/S, Copenhagen, Denmark.
those described above had the following specific rotation: [R]29
D
) +33 (c 0.33, CH2Cl2). The major product was identified as
N-(1-vinylbut-3-enyl)-3-methylaniline (40) based upon the
following spectroscopic data: 1H NMR (CDCl3) δ 7.04 (dd, J
) 7.64, 7.64 Hz, 1H), 6.52-6.50 (m, 1H), 6.43 (m, 2H), 5.82-
5.78 (m, 2H), 5.26-5.12 (m, 4H), 3.91-3.89 (m, 1H), 2.41-
2.35 (m, 2H), 2.26 (s, 3H); 13C NMR (CDCl3) δ 147.5, 139.6,
138.9, 134.5, 129.0, 118.4, 118.0, 115.1, 114.3, 110.6, 54.9, 40.1,
21.6; HRMS calcd for C13H17N 187.1361, found 187.1379.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal methods and copies of the 1H and 13C NMR spectra of
compounds 11, 12, 15, 18-20, 22-25, 36, 38, and 40. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(26) (a) Menschutkin, N.; Simanowsky, L. Zh. Russ. Fiz.-Khim.
O-va. 1903, 35, 205. (b) Menschutkin, N.; Simanowsky, L. Chem.
Zentralbl. 1903, 74, 28.
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