Conjugate addition reactions of α-aminoalkylcuprates with α,β-enones and enals

Article abstract of DOI:10.1016/S0040-4020(00)00130-7

Deprotonation of Boc-protected amines with sec-BuLi or transmetallation of α-aminostannanes with n-BuLi affords α-aminoalkyllithium reagents which can be converted into α-aminoalkylcuprate reagents with CuCN or THF soluble CuCN·2LiCl. These reagents under

Full text of DOI:10.1016/S0040-4020(00)00130-7

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 2767±2778
Conjugate Addition Reactions of a-Aminoalkylcuprates with
a,b-Enones and Enals
²
R. Karl Dieter, Christopher W. Alexander and Lois E. Nice
*
Howard L. Hunter Laboratory, Department of Chemistry, Clemson University, Clemson, SC 29634-0973, USA
Received 24 November 1999; revised 6 January 2000; accepted 13 January 2000
AbstractÐDeprotonation of Boc-protected amines with sec-BuLi or transmetallation of a-aminostannanes with n-BuLi affords
a-aminoalkyllithium reagents which can be converted into a-aminoalkylcuprate reagents with CuCN or THF soluble CuCN´2LiCl.
These reagents undergo conjugate addition reactions with a,b-enones and enals. Reagents prepared from 2 equiv. of the a-aminoalkyllithium
reagent give higher yields of conjugate adducts than those prepared from RCuCNLi, particularly when insoluble CuCN is employed. When
CuCN´2LiCl is used, the two cuprate reagents give comparable yields of 1,4-adducts and the RCuCNLi reagent, economical in a-aminoalkyl
ligand, is preferred. The Boc protecting group can be removed with PhOH/TMSCl and the amino ketone isolated as the hydrochloride salt.
q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
pivalamides14 have been used in addition to the form-
amidines and tert-butylcarbamates. More recently,
a-aminoalkyl carbanions have been generated from unacti-
vated systems by reductive metallation of N,S-acetals15 or
transmetallations of a-aminoalkylstannanes,16a±d a-halo-
methylimides,6c and a-stannylimines.16e Although several
reports have described the reaction of cuprates derived
from a-nitrogen substituted carbanions with alkyl
halides,8a±c,11a our preliminary reports17 described the ®rst
utilization of a-aminoalkylcuprates in conjugate addition
reactions. Recently, non-racemic a-aminoalkyllithium
reagents derived from anilino benzylic or allylic amines
have been shown to participate in asymmetric conjugate
addition reactions with a,b-enones.9e We have extended
the range of a-aminoalkylmetal chemistry by development
of a-aminoalkylcopper reagents capable of participating in
conjugate addition reactions,17 and substitution reactions
with acyl chlorides,18a vinyl tri¯ates,18b vinyl iodides,18c
epoxides, allylic,18d and propargylic substrates.18e In this
full report, we detail the development of a-aminoalkyl-
cuprates derived from tert-butoxycarbonyl (Boc) carba-
mates and their utility in conjugate addition reactions to a
variety of a,b-enone, and enal acceptors.
For many years, organocopper chemistry1 has been limited
to a narrow range of alkyl ligands compatible with the
organometallic precursors used to generate the copper
reagents. Recently, the development of highly functional-
ized organocopper reagents has been an important focus in
organocopper chemistry. Copper reagents derived from a-
heteroatom stabilized carbanions have been an active area
of investigation centered on oxygen,2,3 sulfur,4 and phos-
phorous5 stabilized anions with much of the work focusing
on the a-alkoxyalkylcuprates. Although sometimes limited
in reactivity, the development of organozinc based copper
reagents has enormously extended the range of functional-
ized ligands amenable to organocopper chemistry.6 Recent
advances in the use of Rieke copper provides additional
opportunities to prepare functionalized organocopper
reagents.7
Pioneering work by Meyers8 on formamidines and Beak9 on
carbamates has provided readily accessible routes to
a-aminoalkyl carbanions.10 The general approach involves
dipole stabilized anions bearing electron withdrawing
groups on nitrogen which facilitate deprotonation adjacent
to the nitrogen atom. Activating groups such as oxazo-
lines,11 dithiocarbamate thiolates,12 phosphoramides,13 and
Results
Meyers' formamidines were initially examined in an effort
to effect conjugate addition of a-aminoalkyl ligands to
a,b-enones.17a N,N-Dimethyl-tert-butylformamidine8b (1)
was deprotonated and treated with a variety of Cu(I) salts
in an effort to prepare ef®cacious cuprate reagents (Eq. (1),
Table 1). In preliminary screening, the homocuprate
Keywords: conjugate addition; a-aminoalkylcuprates; carbamates; enones.
* Corresponding author. Fax: 11-864-656-6613;
e-mail: dieterr@clemson.edu
Present address: Department of Chemistry & Biochemistry, College of
Charleston, Charleston, SC 29424, USA.
²
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00130-7

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R. K. Dieter et al. / Tetrahedron 56 (2000) 2767±2778
Table 1. Reaction of organocopper reagents generated from 1 with cyclo-
hexenone (Eq. (1)) (reaction conditions as depicted in Eq. (1))
for the preparation of a-aminoalkylcuprates.
CuX or CuLXLi
n RLi Solvent/additive (equiv.) % Yield (2a)a
CuSPh
CuSPh
CuSPh
CuI
C4H9CuCcuCNLi
2-thienylCuCNLi
CuCN
1.0 THF
1.0 THF/Et2Ob
86
66
49
89
50
44
85
1.0 THF/TMSCl (2)
1.0 THF/TMEDA/TMSCl (2.5)
1.0 THF/TMSCl (5)
1.0 THF/TMSCl (5)
2.0 THF/TMSCl (5)
ꢀ1†
a Conversion of enone (%) to 2a as determined by 1H NMR.
b Et2O/THF (4:1).
The N-tert-butoxycarbonyl (Boc) protected amines 3a±5a
were prepared in high yields from N,N-dimethylamine,
pyrrolidine, and piperidine [di-tert-butyldicarbonate,
triethylamine (TEA), CH2Cl2, 08C to room temperature]
and were puri®ed by vacuum distillation.22 a-Stannyl carba-
mates 3b±5b were prepared by deprotonation of the carba-
mates with sec-BuLi [TMEDA, Et2O, 2788C, 1 h] followed
by quenching with tri-n-butyltin chloride.9a,c±e The organo-
stannanes were puri®ed by column chromatography (silica
gel) followed by Kugelrohr distillation to give colorless oils
which were stored in refrigeration.
reagent, R2CuLi (Rˆa-aminoalkyl ligand), prepared from
CuI failed to give conjugate addition while the mixed
cuprate reagent, RCuSPhLi,19 effected conjugate addition
to cyclohexenone but failed with other enones. Interest-
ingly, the phenylthio mixed cuprate reagent did not require
the addition of TMSCl. The alkylcopper reagent, RCu/
TMEDA,20 and Lipshutz's reagent21 (2RLi1CuCN) proved
effective in the presence of trimethylsilylchloride (TMSCl),
and the latter reagent was adopted for further studies
examining the effect of substrate structure. The RCu reagent
required the addition of TMEDA which proved dif®cult to
remove from the basic formamidines which underwent
varying degrees of decomposition upon silica gel chroma-
tography. The reagent, (2RLi1CuCN), in the presence of
TMSCl transferred the aminomethyl ligand derived from 1
to 2-cyclopentenone (83%), methyl vinyl ketone (98%), and
mesityl oxide (61%) while the 2-pyrrolidinyl ligand was
transferred to 2-cyclopentenone (83%), and methyl vinyl
ketone (71%). Cuprates prepared by addition of RLi to
RntCuCNLi (Rntˆ1-hexynyl, 2-thienyl) gave only modest
yields of conjugate adducts and required the use of
TMSCl. These yields were estimated from NMR molar
ratios since puri®cation resulted in signi®cant loss of
product. The reagents failed to added to 3-methyl-2-cyclo-
pentenone. Cleavage of the formamidine protecting group to
afford amino ketones proved insurmountable using either
oxidation, reduction, or hydrolytic methods, although 2a
could be deprotected with MeOH/H2O in capricious yields
and then formylated to give a sample of 2b for analysis.
Given these puri®cation and deprotection dif®culties,
attention turned to the utilization of Beak's carbamates9
The development and subsequent optimization of the
reaction resulted in several different procedures for the
preparation of the a-aminoalkylcuprate reagents. The requi-
site a-lithio carbamates were prepared either from the
a-stannyl carbamates via transmetallation or directly from
the carbamates via deprotonation in either diethyl ether or
THF. The cuprates were prepared from various copper(I)
species, but were generally prepared from either CuCN or
the THF soluble CuCN´2LiCl6 (Scheme 1).
Initial studies involved deprotonation of 4a [sec-BuLi,
TMEDA, Et2O, 2788C]9a,c±e and cuprate formation
[CuCN (0.5 equiv.), THF, 278 to 2558C] followed by
addition of cyclohexenone and 5.0 equiv. of TMSCl.
Upon addition of CuCN, the reaction mixtures were
generally warmed to 2558C to insure cuprate formation.
An early experiment afforded the conjugate adduct in 41%
yield, but repeated efforts to reproduce the result were
unsuccessful. Boc protected 2-lithiopyrrolidine, obtained
from stannane 4b via transmetallation, gave a cuprate
reagent (2RLi1CuCN) that transferred one a-aminoalkyl
ligand to 2-cyclohexenone in nearly quantitative yield in
the presence of 2±5 equiv. of TMSCl (Table 2, entry 15).
Scheme 1. (a) 3a±5a: i. sec-BuLi, Et2O, 2788C, 2.5 h, TMEDA or (2)-sparteine. ii. CuCN, 278 to 2508C, 30 min. (b) 3b±5b: i. n-BuLi, THF, 2788C, 15±
20 min. ii. CuCN, 278 to 2508C, 20±30 min. (c) 3a±5a: i. sec-BuLi, Et2O, 2788C, 1±2 h, TMEDA or (2)-sparteine. ii. CuCN´2LiCl, 278 then 2508C,
45 min.

R. K. Dieter et al. / Tetrahedron 56 (2000) 2767±2778
2769
Table 2. Conjugate addition of a-aminoalkylcuprates prepared from carbamates with a,b-enones
Entry
Enone
No.a
Additive
Cu salt
equiv.b
Solvent
TMSCl equiv.
Product
% Yieldc
1
2
3
4
5
6
7
8
3b
3b
3b
3b
3a
3a
3a
3b
3b
3b
3b
3b
3a
3a
±
±
±
CuCN
(0.5)
(0.5)
(0.5)
(1.0)
(0.5)
(0.5)
(0.5)
(1.0)
(1.0)
(1.0)
(1.0)
(0.5)
(0.5)
(1.0)
THF
THF
THF
THF
Et2O/THF
Et2O
Et2O/THF
5
5
2
2
5
5
5
1
2
98d
56e
91
23±36
63
43
73
13
37
23
18
71
90
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
±
TMEDA
TMEDA
Sparteine
±
±
±
±
±
9
10
11
12
13
14
5
(2)f
(2)g
5
CuI
CuCN´2LiCl
CuCN´2LiCl
Sparteine
Sparteine
THF
THF
5
83
15
16
17
18
19
20
21
22
4b
4a
4a
4a
5a
3b
3a
3a
±
CuCN
CuCN
CuCN´2LiCl
CuCN´2LiCl
CuCN´2LiCl
CuCN
(0.5)
(0.5)
(0.5)
(1.0)
(0.5)
(1.0)
(1.0)
(0.5)
THF
5
5
5
5
5
5
5
5
99
71±99
82
Sparteine
Sparteine
Sparteine
Sparteine
±
Et2O/THF
THF
THF
Et2O/THF
THF
90
86
50d
64
Sparteine
Sparteine
CuCN´2LiCl
CuCN´2LiCl
THF
THF
86
23
24
25
3b
3a
3a
±
CuCN
CuCN´2LiCl
CuCN´2LiCl
(0.5)
(0.5)
(1.0)
THF
THF
THF
5
5
5
49d
74
Sparteine
Sparteine
47
26
27
28
3b
3b
3a
±
CuCN
CuCN
CuCN´2LiCl
(0.5)
(1.0)
(0.5)
THF
THF
Et2O/THF
5
2
5
64d
25
±
Sparteine
83
29
30
31
3b
3a
3a
±
CuCN
CuCN´2LiCl
CuCN´2LiCl
(1.0)
(1.0)
(0.5)
THF
THF
THF
5
5
5
62d
62
Sparteine
Sparteine
61
32
33
34
4b
5b
4a
±
CuCN
CuCN
CuCN´2LiCl
(0.5)
(0.5)
(1.0)
THF
THF
THF
5
5
5
86d
100d
±
Sparteine
59 (85)
35
36
3b
3a
±
Sparteine
CuCN
CuCN´2LiCl
(1.0)
(1.0)
THF
THF
5
35d
26
a The a-lithiocarbamates were prepared from the organostannanes via transmetallation [n-BuLi, THF, 2788C] or directly from the carbamate via depro-
tonation [sec-BuLi, diamine, THF or Et2O, 2788C].
b Stoichiometry of 0.5 CuX corresponds to [2RLi1CuX] and 1.0 to [RLi1CuX]. RLi was added to the Cu(I) salt at 2788C and warmed to 2558C, followed
by cooling to 2788C before addition of the enone.
c Isolated yields based upon the enone as limiting reagent. Puri®cation was achieved by preparative TLC or column chromatography unless otherwise noted.
d Yield re¯ects double puri®cation by chromatography (silica gel) followed by Kugelrohr distillation.
1
e This one experiment utilized unpuri®ed stannane which appeared spectroscopically clean by H NMR analysis and homogenous by analytical TLC.
f 2.0 equiv. of BF3´Et2O employed.
g 1.0 equiv. of TMSCN and 1.0 equiv. of TMSCl were used with CuI.

2770
R. K. Dieter et al. / Tetrahedron 56 (2000) 2767±2778
Table 3. Reaction of a-aminoalkylcuprates with a,b-enals
Table 4. Effects of the diamine additive on the conjugate addition reaction
of a-aminoalkylcuprates with 2-cyclohexenone
Entry
RCHO
R
Boca Cuprateb
Product
%c Yield
Entry SMa Diamine
Cu saltb
equiv.
Product
%c Yield
1
2
3
4
5
6
Me
Me
Me
Me
Ph
3a
A
47
95
47
50
13f
75
3a Bd,e
3a Cd,e
3b Ae
1
3a TMEDA CuCN
3a TMEDAd CuCN
3a Sparteine CuCN
3a Sparteine CuCN´2LiCl (1.0)
3a TMEDA CuCN´2LiCl (1.0)
(0.5)
(0.5)
(0.5)
63
2
3
4
5
6
7
8
9
10
11
12
13
14
43
73
83
74±85
65±69
98
86
74
0±41
69±72
71±73
90
3a
A
Ph
3a Bd,e
3a
3b
±
±
CuCN´2LiCl (1.0)
CuCN
(0.5)
(0.5)
(0.5)
(0.5)
3b TMEDAe CuCN
3b TMEDAf CuCN
4a TMEDA CuCN
7
Me
4
Bd,e
81
4a TMEDA CuCN´2LiCl (1.0)
4a Sparteine CuCN (0.5)
4a Sparteine CuCN´2LiCl (1.0)
4b CuCN (0.5)
±
99
8
9
3b
3a Bd,e
A
62
51
a The carbamate starting material (SM) was deprotonated with sec-BuLi
in Et2O (2788C for CuCN) or THF (2788C for CuCN´2LiCl) unless
otherwise noted.
b Reactions were run in Et2O´THF (1.1) for cuprates prepared from
CuCN and in THF for Cuprates prepared from CuCN´2LiCl unless
otherwise noted. Cyclohexenone/TMSCl (5.0 equiv.) were added to
the cuprate solutions at 2788C.
10
4
Bd,e
37
c Based upon isolated yields of products puri®ed by TLC or column
chromatography.
a Carbamates 3a and 4a were deprotonated with sec-BuLi (Et2O,
TMEDA, 2788C, 1.25 h). Carbamate 3b underwent transmetallation
with n-BuLi (THF, 2788C, 0.25 h).
d Reaction run in Et2O.
e Diamine added after transmetallation.
f Diamine added after cuprate formation.
b Aˆ2RLi1CuCN. BˆRLi1CuCN´2LiCl. Cˆ2RLi1CuCN´2LiCl. The
a-lithiocarbamates were added to CuCN or CuCN´2LiCl at 2788C,
warmed to 255 to 2508C, and then cooled to 2788C (enal added at
2508C for entries 2, 3, 6, 7, and 9). Reactions were run in an Et2O:THF
(1:1) solvent mixture unless otherwise noted and enal/5.0 equiv.
TMSCl were added to the cuprate solution at 2788C.
c Based upon products puri®ed and isolated by chromatography and with
the aldehyde as limiting reagent.
entries 23, 26 and 35). The reaction failed in the absence
of TMSCl and low yields were obtained when BF3´Et2O was
substituted for TMSCl (entries 10,11).
Efforts to extend the reactions of a-aminoalkylcuprates
eventually resulted in the use of THF soluble CuCN´2LiCl
for preparation of the cuprate reagents from the a-lithio
carbamates. Under these reaction conditions, the yields of
conjugate adducts utilizing the deprotonation protocol were
often comparable (Table 2, entries 13 vs. 1 and 3, 17 vs. 15)
to the transmetallation procedure and in some instances
superior (Table 2, entries 24 vs. 23, 28 vs. 26) for cuprates
prepared from 2RLi1CuCN´2LiCl. Cyanocuprates
prepared from RLi1CuCN´2LiCl via the deprotonation
procedure generally gave signi®cantly higher yields than
the cuprates prepared from CuCN via the transmetallation
protocol (Table 2, entries 14 vs. 4 and 8, 21 vs. 20), although
comparable yields were sometimes obtained (Table 2, entries
30 vs. 29, 36 vs. 35). Simple enones gave yields only
slightly lower with RCuCNLi prepared from CuCN´2LiCl
via the deprotonation protocol than those obtained by using
2 equiv. of a-lithio carbamates (via transmetallation) and
CuCN (Table 2, entries 14 vs 1 and 3, 18 vs. 15, 34 vs.
32). Yields obtained with the former reagents were,
however, signi®cantly lower than the 2RLi1CuCN´2LiCl
reagents when 3-alkyl substituted substrates were employed
(Table 2, entry 25 vs. 24). Cuprates prepared from 4a failed
to undergo reaction with sterically hindered enones such as
isophorone and 3-methylcyclopentenone and gave trace
amounts of adducts with sterically hindered acyclic enones
such as mesityl oxide.
d Deprotonation was achieved with sec-BuLi and sparteine (THF,
2788C, 1 h).
e The reaction was run in THF.
f The 1,2-addition product was isolated in 44% yield.
Similarly, a dialkylcuprate prepared from stannane 3b
reacted with 2-cyclohexenone to afford good to excellent
yields of the conjugate adduct (Table 2, entries 1±3) and
the yields appeared to be sensitive to impurities in the organo-
stannane. Utilization of unpuri®ed stannane that appeared
homogeneous by TLC and spectroscopically clean gave
lower yields (Table 2, entry 2). Cuprates prepared from
2 equiv. of the a-lithiocarbamate obtained from 3b and
CuCN gave modest yields of the conjugate adduct with
a,b-enones such as 3-methylcyclopentenone (Table 2,
entry 23) and isophorone (Table 2, entry 26). The corre-
sponding a-aminoalkyl(cyano)cuprates generally gave
signi®cantly lower yields (Table 2, entries 4 vs. 1±3, and
27 vs. 26). The cyanocuprate reagent prepared from 3b gave
a good yield with methyl vinyl ketone (Table 2, entry 29)
but a low yield with the more sterically hindered mesityl
oxide (Table 2, entry 35). The cuprate prepared from 4b or
5b (2RLi1CuCN) gave excellent yields of conjugate
adducts upon reaction with methyl vinyl ketone (Table 2,
entries 32, 33) and cyclohexenone (from 4b: Table 2, entry
15). These reaction conditions worked well for cuprates
prepared from carbamates 3b±5b with simple a,b-enones.
Yields of conjugate adducts decreased as the alkyl substi-
tution pattern increased on the enone system (Table 2,
a-Aminoalkylcuprates prepared from CuCN reacted with
a,b-enals, although the regiochemistry of the addition

R. K. Dieter et al. / Tetrahedron 56 (2000) 2767±2778
2771
proved highly sensitive to substrate structure. Reaction of
the cuprates (2RLi1CuCN) prepared from 3a or 3b with
crotonaldehyde gave the conjugate adducts in 47 and 50%
yield (Table 3, entries 1, 4), respectively, showing no
difference between the deprotonation and transmetallation
protocols. However, the cuprate prepared from 3a reacted
with cinnamaldehyde to afford the conjugate adduct in 13%
yield and the 1,2-addition product in 44% yield (Table 3,
entry 5). Preparation of the cyanocuprates, RCuCNLi, from
3a or 4a and CuCN´2LiCl resulted in excellent to good
yields of conjugate adducts while the reagent prepared
from addition of 2RLi gave modest yields (Table 3, entries
2, 6, 7 vs. 3). The yields re¯ected characteristic substrate
reactivity and steric hindrance factors illustrated in the reac-
tions with myrtenal (Table 3, entries 8±10).
ferred both the a-aminoalkyl and methyl ligands in 51 and
41% yields, respectively. Mixed cuprates prepared from
1-hexyne or 3-methyl-3-methoxy-1-butyne gave capricious
results (0±65%), although in single experiments the desired
conjugate adduct could be obtained in yields of 65 and 50%
respectively. Signi®cant yields of the conjugate adducts
were only obtained when excess MeLi or n-BuLi were
used to deprotonate the alkyne or added after the fact. The
mixed alkynyl cuprate prepared from p-methoxyphenyl-
acetylene and stannane 3b transferred the a-aminoalkyl
ligand in 52% yield. These yields were generally lower
than those obtained from RCuCNLi prepared from CuCN.
Subsequent discovery of the generally superior ability of the
RLi1CuCN´2LiCl protocol provided a satisfactory solution
to the problem of ef®cient ligand utilization (Table 2),
although the use of CuCN´2LiCl did not make signi®cant
improvements in the use of other non-transferable ligands
[e.g., 32% for (Me(Boc)NCH2CuNiPr2)Li].
Initial efforts to effect conjugate addition with cuprates
prepared from 4a, via deprotonation, and CuCN were
frequently unsuccessful and the focus changed to the use
of organostannane 4b for generation of the requisite a-lithio
carbamate. During the course of these studies, it was
observed that cuprates prepared via deprotonation of 3a
underwent conjugate addition with cyclohexenone,
although the yields were sensitive to solvent (Table 4,
entries 1,2). Serendipitously, it was discovered that replace-
ment of TMEDA, used to facilitate deprotonation of 3a,
with (2)-sparteine resulted in a 10% increase in yield
(Table 4, entries 1 vs. 3). Deprotonation of 4a with sec-
BuLi in the presence of (2)-sparteine followed by cuprate
formation with CuCN afforded conjugate addition of the
pyrrolidinyl ligand in 71±73% yields (Table 4, entry 12).
Although these results suggested a signi®cant effect of
diamine upon the ef®ciency of the conjugate addition
reaction with 2-pyrrolidinylcuprates, similar yields were
eventually obtained in the presence of TMEDA which was
distilled immediately prior to utilization. Addition of
TMEDA prior to and subsequent to cuprate formation via
stannane 3b resulted in a diminution in yields (Table 4,
entries 7 vs. 8, 9). The chemical yields were signi®cantly
less sensitive to the diamine employed when the cuprate
reagent was prepared from THF soluble CuCN´2LiCl (Table
4, entries 4 vs. 3, 11 vs. 10, and 13 vs. 12), although these
results involve a comparison between RLi1CuCN´2LiCl
and 2RLi1CuCN. Variability in the yields obtained with
CuCN´2LiCl appeared to correlate with a dif®culty in
insuring the dryness of the LiCl and latter experiments
involved ¯ame drying the reaction ¯ask and the addition
of LiCl prior to the addition of CuCN and THF.
The Boc-protecting group can be removed with PhOH/
TMSCl to afford the amino ketones as the hydrochloride
salts (Eq. (2)) or as the free amine. The free amines are
unstable and must be used immediately or frozen in benzene
for storage.
ꢀ2†
Discussion
The development of a-aminoalkylcuprate chemistry has
emerged from extensive experimentation and empirical
observations. Although reliable protocols have been
developed, the underlying basis for the sensitivity of these
reagents to various reaction conditions is not well under-
stood. General trends and patterns have emerged from this
work, although substantial variation from experiment to
experiment precludes a detailed analysis. The principal
development has been the enhanced reliability, reproduc-
ibility, and chemical yields obtained with cuprates generated
from CuCN´2LiCl permitting the use of reagents RCuCNLi
ef®cient in transferable ligand.
Cuprate reagents generated from a-aminostannanes gave
poor to modest yields with the RCuCNLi reagent (Table
2). Efforts to minimize the inef®cient utilization of only
one of the a-aminoalkyl ligands (i.e., in 2RLi1CuCN)
focused on standard non-transferable ligands such as cya-
nide, 2-thienyl, phenylthiomethyl, and substituted alkynyl
groups. The mixed cuprate 2-thienyl(R)CuLi failed to
ef®ciently transfer the a-aminoalkyl ligand when generated
via the deprotonation protocol (17%) or when BF3´Et2O
(2.0 equiv., 14%) was used instead of TMSCl. A modest
yield was obtained when this mixed cuprate was prepared
from the stannane 3b and reacted with cyclohexenone in the
presence of TMSCl (48%). A mixed cuprate prepared from
MeLi and the a-lithio carbamate obtained from 3b trans-
The initial work with insoluble CuCN gave very low yields
of 1,4-adducts with pyrrolidinyl cuprates generated in the
presence of TMEDA, although modest yields could be
achieved with the aminomethylcuprate derived from 3a.
Cuprates generated from 3a±4a gave higher and more
reproducible yields when (2)-sparteine was employed,
although similar yields could be obtained when the
TMEDA was distilled immediately before use. These results
suggest that impurities present in TMEDA have a dele-
terious effect upon cuprate formation, stability, or reactivity.

2772
R. K. Dieter et al. / Tetrahedron 56 (2000) 2767±2778
In addition, the high yields of 1,4-adducts obtained in the
absence of diamines (cuprates prepared via transmetallation
of aminostannanes) and the diminished yields obtained
when diamines were added at various stages in the reaction,
suggests that chelation effects (e.g., lithium ions or copper
species and diamines) may play a signi®cant role. This is
consistent with the improvement in yields achieved with
CuCN´2LiCl where additional lithium ions have been
added to the solution. Although the effectiveness of
TMEDA±Li1 coordination in THF has been called into
question,23 it is clear from synthetic,24 mechanistic,25 and
structural studies26 that Li1 ions play crucial roles in cuprate
structure and in conjugate addition chemistry and enone±
Li1 complexes have been observed27 spectroscopically. In
solid state structures Li1 ions appear to be the `glue' holding
the cluster together, and in solution Li1 ion coordination to
the carbonyl oxygen at some point along the reaction coor-
dinate appears crucial for successful conjugate addition25 as
evidenced by solvent effects24b,28 upon reaction rates. In this
regard, it is interesting that a-aminoalkylcuprates generated
from formamidines appear to be more reactive than those
prepared from carbamates. This is re¯ected in the ability to
achieve conjugate addition in higher yields with mixed
cuprates containing non-transferable ligands generated
from the formamidines than in those generated from the
carbamates. This observation is consistent with the view
that THF is a more effective ligand for Li1 than TMEDA
(i.e., oxygen vs. nitrogen), but contrasts with the observed
rate enhancements for cuprates with heteroatoms in the
ligand29 permitting internal complexation. The relative
steric dimensions of these formamidine and carbamate
ligands arising from internal complexation could also be
expected to play a role.
member ring involving lithium coordination with the nitrile
nitrogen atoms while the 2RLi1CuCN reagent gave a
monomeric R2Cu anion and a triamine complexed LiCNLi
cation. Although this solid state structure need not re¯ect the
solution phase species, it provides a picture consistent with
the empirical results and parallels our reaction con-
ditions which contained diamines in the deprotonation
protocols. Computational studies suggest that dimeric
cuprate and Me2CuLi´Li clusters allow the cooperative
interaction of two lithium and one copper atom with the
substrate during the course of conjugate addition reac-
tions.32
From a synthetic perspective, the CuCN´2LiCl protocol is
the procedure of choice since higher yields, cleaner reac-
tions, and ef®cient use of the aminoalkyl ligand in
RCuCNLi reagents are achieved. Although the yields are
slightly lower than those achieved with (2RLi1CuCN)
obtained via the aminostannane protocol, the need to prepare
and purify the aminostannane renders the CuCN´2LiCl
direct deprotonation protocol more ef®cient. Whether
these yields can be increased by use of TMSCl and
Sc(OTf)3 or other Lewis acids33 remains to be deter-
mined. Although the Boc protecting group can be
removed by use of PhOH/TMSCl in the presence of
the ketone, synthetic application of this methodology
must accommodate the general instability of the free
amino ketones.
Summary
In summary, we have developed procedures for the prepa-
ration of a-aminoalkylcuprates from Boc-protected amines
or from a-aminostannanes that ef®ciently transfer the
a-aminoalkyl ligands to a,b-enones and enals in a 1,4-fash-
ion. The direct deprotonation of Boc-protected amines is
ef®cient and reliable when the cuprate reagents are
generated from CuCN´2LiCl. This protocol allows the utili-
zation of RCuCNLi reagents ef®cient in a-aminoalkyl
ligand.
The presence of additional lithium ions in solution may
account for the differing reactivity of RCuCNLi prepared
from CuCN and CuCN´2LiCl. The latter reagent permits
generation of the cuprate reagents at 2788C which could
have a signi®cant and variable effect upon chemical yields
since the a-lithio carbamates display a greater thermal
instability than the cuprate reagents.22 The use of CuCN´2LiCl
also provides additional lithium ions for complexation to the
carbonyl oxygen, and provides soluble chloride ions that
could, in principle, facilitate the reductive elimination
process that forms the b±C±C bond. In allylic substitutions,
product yields have been correlated with CuX (yields:
XˆCl.Br.I) and attributed to more electronegative
ligands accelerating the rate of reductive elimination.30
The conjugate addition reactions, however, require the
presence of TMSCl suggesting that alone, chloride ions
like HMPA25c may stabilize the copper intermediate25d
undergoing rate-limiting reductive elimination25e thereby
diminishing reactivity. The use of CuCN´2LiCl may also
affect the aggregation state of the cuprate reagent, the extent
of equilibrium between monomeric and dimeric cuprate
species, or the composition of the cuprate reagent. Cryo-
scopic measurements in THF solution indicate that lower
order cuprates prepared from CuCN can exist as either
monomers or dimers while the 2RLi1CuCN reagent was
measured as a monomer.31 In this regard, it is signi®cant that
crystalline cuprate species were obtained upon mixing RLi
or 2RLi1CuCN in the presence of a triamine.26d The result-
ing RCuCNLi crystal consisted of a dimer with a four
Experimental
NMR spectra were recorded at 300 MHz (1H) and 75 MHz
(13c). Solvents and additives were distilled from sodium
benzophenone ketyl [tetrahydrofuran (THF), diethyl ether
(Et2O)], CaH2 [CH2Cl2, N,N,N0N0-tetramethylethylene-
diamine (TMEDA), chlorotrimethylsilane (TMSCl)], and
Ê
4 A molecular sieves (TMSCl), or puri®ed by simple distil-
lation (BF3´Et2O). CuCN was used without puri®cation, but
dried when necessary (<0.005 mmHg, 90±1008C with
stirring) CuI was puri®ed34a and stored in the dark.
CuBr´SMe2 was prepared according to Wuts34b and CuSPh
was purchased from Aldrich or prepared34c by the method of
Adams. Alkyllithium reagents were obtained from Aldrich
or FMC and titrated regularly by the method of Shapiro and
co-workers using 1,3-diphenylacetone p-tosylhydrazone.35
Glassware used in the cuprate experiments was cleaned in
a potassium hydroxide±isopropyl alcohol bath, rinsed with
water, 48% aq. HBr, and then with copious amounts of
water. Oven-dried glassware was ¯ame-dried and cooled

R. K. Dieter et al. / Tetrahedron 56 (2000) 2767±2778
2773
under a dry N2 atmosphere. Cuprate reactions were con-
General procedure A: conjugate addition reactions
employing lithio-N-Boc carbamates generated from
a-aminostannanes and CuCN (2RLi1CuCN)
ducted under a positive, dry nitrogen±argon atmosphere in
round bottomed ¯asks ®tted with new, clean rubber septa
secured with Para®lm. Flask to ¯ask transfer of air and
moisture sensitive intermediates was completed using
double-tipped needles (cannula) under a positive argon pres-
sure maintained by double layered balloons ®lled with argon.
To the a-aminostannane (1.0 mmol) in THF (2 mL) cooled
to 2788C, was added n-BuLi (0.45 mL, 1.0 mmol) and the
resulting mixture was stirred for 15 min (colorless solution).
To CuCN (0.0457 g, 0.5 mmol) suspended in THF (2 mL)
cooled to 2788C was added the carbanion solution by
cannular transfer, plus a 1 mL THF rinse of the carbamate
pot. The mixture was allowed to warm slowly to 2558C
over 32 min and then cooled back to 2788C (homogenous
solution). To this solution was added a cold (2788C)
solution of 2-cyclohexenone (0.04 mL, 0.41 mmol) and
TMSCl (0.32 mL, 2.5 mmol) in THF (2 mL) by cannular
transfer. The reaction mixture was stirred at 2788C for
40 min and monitored by analytical TLC until the reaction
appeared to be complete. The reaction was quenched with
H2O, stirred at room temperature brie¯y, diluted with Et2O,
and vacuum ®ltered through Celite. The organic phase was
separated, the aqueous phase extracted with Et2O
(10 mL£4) and the combined organic phases were washed
with saturated NH4Cl (aq., 1£), 5% NaHCO3 (aq.), brine
and dried over a mixture of anhydrous Na2SO4 and
K2CO3. Evaporation of the solvent in vacuo afforded the
crude 1,4-adduct.
N0-(1,1-Dimethylethyl)-N-methyl-[N-(3-oxocyclohexyl)-
methyl]methanimidamide (2a). (RCuSPhLi19 in THF): To
formamidine 1 (0.1978 g, 1.5 mmol) in THF (2 mL) at
2788C was added tert-BuLi (0.94 mL, 1 mmol) and the
resulting solution was stirred at 2308C for 75 min (faint
yellow solution), then it was transferred by cannula to
CuSPh suspended in THF (3 mL) at 230/2358C (plus a
1 mL THF rinse of the formamidine pot) and the mixture
was stirred for 41 min resulting in a brown±yellow solution.
The reaction mixture was cooled to 2788C and 2-cyclo-
hexen-1-one (0.09 mL, 0.95 mmol) was added dropwise
by syringe. The mixture was allowed to stir for 1 h
(2788C), warmed to rt over 10 h, quenched by the addition
of H2O, and vacuum ®ltered through Celite with an Et2O
rinse. The ®ltered solution was washed with brine and back
extracted with CH2Cl2. The combined organic phases were
dried over a mixture of anhydrous Na2SO4 and MgSO4.
Evaporation of the solvent afforded crude 2a (0.2275 g) in
86% yield as estimated by NMR analysis: IR 2966 (s), 1714
(s), 1644 (s), 1356 (m), 1264 (w) 1222 (m) 1110 (w), 1082
(m); 1H NMR d 1.14 (s, 9H), 1.57±1.74 (m, 1H), 1.84±1.87
(m, 1H), 1.96±2.15 (m, 3H), 2.21±2.24 (m, 3H), 2.81 (s,
3H), 3.10 (m, 2H), 7.30 (s, 1H); 13C NMR d 24.98, 28.60,
31.24 (3 C), 34.66, 37.99, 41.37, 45.54, 52.81, 56.14,
150.63, 210.85; mass spectrum (GC±MS) m/z (intensity)
EI 224 (M1), 209 (M1±CH3), 129 (M1±CHvNtBu).
General procedure B: conjugate addition reactions
employing a-lithio-N-Boc carbamates generated from
a-aminostannanes and CuCN (RLi1CuCN)
To a-aminostannane (0.5 mmol) in THF (1 mL) cooled to
2788C was added n-BuLi (0.5 mmol) and the resulting
mixture stirred (<20 min). To CuCN (0.5 mmol) suspended
in THF (2 mL) cooled to 225/2308C was added the carb-
anion solution by cannular transfer, plus a 1 mL THF rinse
of the carbamate pot. The mixture was allowed to stir for
20±25 min and then cooled to 2788C whereupon a cold
(2788C) solution of a,b-enone (0.4±0.437 mmol) and
TMSCl (1.0±2.5 mmol) in THF (2 mL) was added by
cannular transfer. The mixture was stirred at 2788C for
15±25 min, allowed to warm to room temperature over
3.5±6 h, quenched with saturated NH4Cl (aqueous) and
work-up as described for procedure A.
[N-Methyl-N-[(3-oxocyclohexylmethyl]-N-formyl]amine
(2b). Crude formamidine 2a (0.2945 g) was dissolved in a
1:1 mixture of MeOH±H2O (6 mL) and stirred at rt for
2.5 days. The reaction mixture was extracted 4 times with
CH2Cl2 and the combined extracts were dried over anhy-
drous K2CO3. Evaporation of the solvent in vacuo gave
crude amino ketone (0.281 g) as a mixture of products. To
this crude residue in THF (1 mL) was added ethyl formate
(0.12 mL, 1.48 mmol) and the mixture was stirred at rt over-
night. The solvent and excess ethyl formate were removed
in vacuo. Careful fractionation by Kugelrohr distillation
(40±658C, 0.75 mmHg) afforded 2b (0.1115 g) and the pot
residue was subjected to a second Kugelrohr distillation
(90±1158C, 0.005 mmHg) to give analytically pure 2b as
a colorless oil (0.0966 g, 46%): IR 2938 (s), 2868 (m), 1714
(s), 1672 (s), 1447 (m), 1498 (m), 1257 (w), 1229 (m), 1103
(w), 1068 (m), 955 (w), 871 (w); 1H NMR d 1.25±1.50 (br
m, 1H), 1.56±1.75 (br m, 1H), 1.87 (m, 1H), 1.96±2.18 (br
m, 3H), 2.18±2.49 (br m, 4H), 2.86 and 2.96 (s, 3H, rota-
mer), 3.10±3.40 (br m, 2H), 8.02 and 8.08 (s, 1H, rotamer);
13C NMR d 24.53, 24.75 (rotamer), 28.33, 28.66 (rotamer),
30.02, 35.01 (rotamer), 36.54, 36.80 (rotamer), 41.09,
44.93, 45.32 (rotamer), 49.19, 54.73 (rotamer), 162.53,
162.79 (rotamer), 209.47, 210.20 (rotamer); mass spectrum
m/z (intensity) EI 170 (2.7, M11), 169 (1.5, M1), 97 (27.3,
CH2(CH3)NCHO), 72 (91.7, cyclohexane1); CI 170 (100,
M11). Anal. Calcd for C9H15NO2: C, 63.93; H, 8.87. Found
C, 64.08; H, 8.95.
General procedure C: conjugate addition reactions
employing CuCN and a-lithio-N-Boc carbamates
(2RLi1CuCN) generated by deprotonation
sec-BuLi (0.91 mL, 1.0 mmol) was added by syringe to
(2)-sparteine (0.23 mL, 1.0 mmol) in Et2O (1 mL) at
2788C and the resulting mixture was stirred for 15 min.
The carbamate (1.0 mmol) in Et2O (1 mL) at 2788C was
added to the (2)-sparteine mixture and this solution plus a
0.5 mL Et2O rinse of the pot was stirred for 2 h. [Alterna-
tively, TMEDA (0.15 mL, 1.0 mmol) was added to the
carbamate (1.0 mmol) in Et2O (2 mL) and this solution
was cooled to 2788C whereupon sec-BuLi (0.91 mL,
1.0 mmol) was added by syringe and the resulting mixture
was stirred for approximately 1 h (colorless to faintly
cloudy solution).] To CuCN (0.5 mmol) suspended in
THF (2 mL) and cooled to 2788C was added the lithio-
carbamate solution by cannular transfer, plus a 1 mL THF

2774
R. K. Dieter et al. / Tetrahedron 56 (2000) 2767±2778
rinse of the carbamate pot. The mixture was allowed to
warm slowly to 2568 C over 23 min and then cooled to
2788C (a white suspension resulted when TMEDA was
employed and with the lithiated pyrrolidine sparteine
combination). To this solution was added a cold (2788C)
solution of 2-cyclohexen-1-one (0.04 mL, 0.41 mmol) and
TMSCl (0.32 mL, 2.5 mmol) in THF (2 mL) by cannular
transfer. The reaction mixture was stirred at 2788C for
20±30 min (monitored by TLC). The reaction was
quenched with H2O or saturated NH4Cl and worked up as
described for procedure A. Evaporation of the solvent in
vacuo afforded the crude product as the trimethylsilyl enol
1,1-Dimethylethyl 2-(3-oxocyclohexyl)-1-pyrrolidinecarb-
oxylate (7a). General procedure A was empoyed using
a-aminostannane 4b (0.4578 g, 1.0 mmol), n-BuLi
(0.43 mL, 0.95 mmol), CuCN (0.0454 g, 0.5 mmol),
2-cyclohexenone (0.04 mL, 0.41 mmol), and TMSCl
(0.32 mL. 2.5 mmol). Puri®cation using preparative TLC
[silica gel, 50% Et2O±50% hexane, v/v] gave 7a
(0.1095 g, 100%) which was doubly puri®ed by Kugelrohr
distillation (74±1128C, 0.005 mmHg) to give analytically
pure 7a as a colorless oil (0.1084 g, 99% yield): IR 2973
(m), 1713 (shoulder), 1693 (s), 1391 (s), 1167 (m), 1106
1
(m), 861 (w), 772 (w); H NMR d 1.44 (br s, 11 H, 1.45
1
ether adduct by analytical TLC, and/or H and 13C NMR
rotamer), 1.60±1.69 (m, 1H), 1.78 (br m, 5H), 2.10 (br m,
2H), 2.17±2.40 (m, 3H), 3.23 (m, 1H), 3.34±3.61 (m, 1H),
3.67±3.89 (m, 1H); 13C NMR d (rotameric and diastereo-
meric mixture) 22.45, 23.19, 23.77, 26.24, 26.60, 27.42,
28.22, 32.48, 41.09, 41.64, 78.91, 79.11, 81.31, 154.51,
154.75, 154.84, 155,08, 210.94, 211.28. Anal. Calcd for
C15H25N2O3: C, 67.44; H, 9.35. Found C, 67.51; H, 9.48.
analysis. To the crude residue in THF (3 mL) at room
temperature was added tetra-butyl ammonium ¯uoride
(TBAF) (1.23 mL of 1 M solution in THF, 1.23 mmol)
and the resulting mixture was stirred for 35 min. Evapo-
ration of the solvent in vacuo and puri®cation by silica gel
preparative TLC [20% EtOAc±80% petroleum ether (v/v)]
afforded pure conjugate addition product.
1,1-Dimethylethyl 2-(3-oxocyclohexyl)-1-piperidinecar-
boxylate (7b). General procedure D was employed using
N-tert-butyoxycarbonyl piperidine 5a (0.185 g, 1.0 mmol in
ether), TMEDA (0.15 mL, 1.0 mmol), sec-BuLi (1.0 mmol),
CuCN´2LiCl dissolved in THF, and cyclohexenone
(0.096 g, 1.0 mmol) dissolved in TMSCl (0.63 mL,
5.0 mmol). Puri®cation by ¯ash column chromatography
[silica gel, 5% EtOAc±95% petroleum ether, v/v] gave
General procedure D: conjugate addition employing
CuCN´2LiCl and a-lithio-N-Boc carbamates
(2RLi1CuCN and RLi1CuCN) generated by
deprotonation
To tert-butyl carbamate (2.0 mmol) in THF (4 mL) cooled
to 2788C was added (2)-sparteine (0.46 mL, 2.0 mmol).
sec-BuLi (2.0 mmol) was added by syringe and allowed to
stir for 1 h. A light green solution of THF soluble CuCN´2
LiCl complex, prepared by dissolving CuCN (0.0895 g,
1 mmol) and LiCl (0.0840 g, 2 mmol, ¯amed dried under
vacuum prior to use and purged with argon) in THF (2 mL)
at room temperature, was added via syringe to the 2-lithio-
N-Boc carbamate (clear to pale yellow) at 2508C. The
mixture was allowed to stir at 2508C for 45 min to generate
the cuprate as a clear to light yellow homogeneous solution.
Next a solution of enone (1 mmol) dissolved in TMSCl
(0.63 mL, 5 mmol) was added and the reaction stirred at
2508C for 30 min and then was allowed to stir at room
temperature for 1.5 h. The reaction was quenched with satu-
rated NH4Cl (aq.), worked-up as described for procedure A
and dried over MgSO4. Concentration in vacuo afforded the
crude 1,4-adducts. Puri®cation by column chromatography
[5% EtOAc±95% petroleum ether (v/v)] gave pure
1,4-adducts.
1
pure 7b as an oil (0.2419 g, 86% yield); H NMR d 1.11±
2.44 (m, 16H), 1.40 (s, 9H)(1.37 rotamer and/or diastereo-
mer), 2.45±2.75 (m, 1H), 3.83 (v br s, 1H); 13C NMR d
18.9(19.1), 25.0, 25.3, 27.5(26.0), 28.4(t-Bu), 29.0, 37.0,
39.9(several peaks), 41.2, 45.5(44.3), 54.8(several peaks),
79.3, 155.0, 211.1 (rotamer and/or diastereomers).
1,1-Dimethylethyl [N-methyl-N-[3-oxocyclopentyl)methyl]
carbamate (8): General procedure A was employed using
a-aminostannane 3b (0.2169 g, 0.5 mmol), n-BuLi
(0.21 mL, 0.5 mmol), CuCN (0.0453 g, 0.5 mmol), 2-cyclo-
penten-1-one (0.34 mL, 0.41 mmol), and TMSCl (0.32 mL,
2.5 mmol). Puri®ed by preparative TLC [silica gel, 20%
EtOAc±80% petroleum ether, v/v] gave 8 (0.0556 g,
59%). Kugelrohr distillation (698C, 0.005 mmHg) gave
analytically pure 8 as a colorless oil (0.0469 g, 50%
yield): IR 2973 (m), 1743 (s), 1693 (s), 1482 (m), 1398
1
(s), 1363 (m), 1250 (m), 1166 (s), 878 (w), 772 (w); H
NMR d 1.45 (s, 9H), 1.61±1.68 (m, 1H), 1.89±1.98 (m,
1H), 2.04±2.26 (m, 2H), 2.30±2.38 (m, 2H), 2.45±2.60
(m, 1H), 2.89 (s, 3H), 3.28 (br d, Jˆ5.98 Hz, 2H); 13C
NMR d 26.78, 28.36, 34.57 (34.98, rotamer), 35.93,
37.71, 42.84, 52.69, 79.86, 155.64 (155.90, rotamer),
218.39. Anal. Calcd for C12H21NO3: C, 63.45; H, 9.24.
Found: C, 63.16; H, 9.14.
1,1-Dimethylethyl N-methyl-N-[(3-oxocyclohexyl)methyl]
carbamate (6). General procedure A was employed. Puri®-
cation by preparative TLC [silica gel, 20% EtOAc±80%
petroleum ether, v/v] gave 6 (0.127 g) which was further
puri®ed by Kugelrohr distillation to afford analytically
pure 6 as a colorless oil (0.0971 g, 98% yield): IR 2973
(s), 2931 (s), 1714 (s, shoulder), 1699 (s, shoulder), 1680
(shoulder), 1394 (s), 1365 (s), 1220 (s), 1160 (s), 878 (m),
773 (m); 1H NMR d 1.45 (s, 9H), 1.56±1.75 (m, 2H), 1.81±
1.93 (m, 1H), 2.00±2.18 (m, 3H), 2.21±2.43 (m, 3H), 2.83±
2.85 (m, 3H), 3.09±3.28 (m, 2H); 13C NMR d 25.07, 28.37
(3 C), 28,91, 34.97, 37.92 (38.30, rotamer), 41.36, 45.61,
53.74 (54.28, rotamer), 79.46, 155.67 (155.98, rotamer),
210.73 (211.13, rotamer). Anal. Calcd for C13H23NO3: C,
64.75; H, 9.53. Found: C, 64.81; H, 9.65.
1,1-Dimethylethyl N-methyl-N-[(1-methyl-3-oxocyclo-
pentyl)methyl] carbamate (9). General procedure A was
employed using a-aminostannane 3b (0.4322 g, 1.0 mmol),
n-BuLi (0.42 mL, 1.0 mmol), CuCN (0.0461 g, 0.5 mmol),
3-methyl-2-cyclopenten-1-one (0.04 mL, 0.41 mmol), and
TMSCl (0.32 mL, 2.5 mmol). Puri®cation using gravity
column chromatography [silica gel, 19% EtOAc±81%
petroleum ether afforded 9 (0.050 g, 50%). Kugelrohr distil-
lation (93±988C, 0.005 mmHg) gave analytically pure 9 as a

R. K. Dieter et al. / Tetrahedron 56 (2000) 2767±2778
2775
colorless oil (0.0486 g, 49% yield): IR 2973 (m), 1743 (s),
1693 (s), 1454 (m) 1391 (m), 1363 (m), 1166 (s), 878 (w),
772 (w); H NMR d 1.09 (s, 3H), 1.46 (s, 9H), 1.66±1.77
208.01 (208.41, rotamer). Anal. Calcd for C13H23NO3: C,
64.75; H, 9.53. Found C, 64.76; H, 9.65.
1
(m, 1H), 1.86±2.04 (m, 2H), 2.20±2.34 (m, 3H), 2.92±2.94
(m, 3H), 3.18±3.37 (m, 2H); 13C NMR d 24.18 (24.33,
rotamer), 28.24, 33.29, 36.38, 37.54, 42.13, 50.39, 57.98,
79.41 (79.96, rotamer), 156.06, 218.44. Anal. Calcd for
C13H23NO3: C, 64.75; H, 9.53. Found: C, 64.79; H, 9.64.
1,1-Dimethylethyl 2-(3-oxobutyl)-1-piperidinecarboxy-
late 12b. General procedure A was employed using
a-aminostannane 5b (0.4957 g, 1.0 mmol), n-BuLi
(0.41 mL, 1.0 mmol), CuCN (0.0450 g, 0.5 mmol), methyl
vinyl ketone (0.04 mL, 0.48 mmol), and TMSCl (0.32 mL,
2.5 mmol). Puri®cation by preparative TLC [silica gel, 30%
EtOAc±70% petroleum ether] gave 12b (0.1299 g). Kugel-
rohr distillation (908C, 0.005 mmHg) afforded pure 12b as a
colorless oil (0.1278 g, 100% yield): IR 2983 (s), 2860 (m),
1717 (m), 1685 (s), 1418 (s), 1364 (s), 1264 (s), 1160 (s),
925 (w), 867 (m), 812 (w), 768 (m); 1H NMR d 1.23±1.68
(m, 17H), 1.95±2.09 (m, 1 H), 2.13 (m, 2H), 2.72 (br t,
Jˆ13 Hz, 1H), 3.95 (br d, Jˆ10 Hz, 1H), 4.21 (br t,
Jˆ4.5 Hz, 1H); 13C NMR d 18.96, 23.50, 25.50, 28.39 (3
C), 28.91, 29.96, 38.66, 40.21, 49.71, 79.15, 155.06, 208.24.
Anal. Calcd for C14H25NO3: C, 67.36; H, 10.19. Found C,
66.86; H, 10.31.
1,1-Dimethylethyl N-methyl-N-[(1,3,3-trimethyl-5-oxo-
cyclohexyl)methyl] carbamate (10). General procedure
A was employed using a-aminostannane 3b (0.4380 g,
1.0 mmol), n-BuLi (0.41 mL, 1.0 mmol), CuCN (0.0449,
0.5 mmol), isophorone (0.06 mL, 0.4 mmol), and TMSCl
(0.32 mL, 2.5 mmol). Puri®cation using preparative TLC
[silica gel, 20% EtOAc±80% petroleum ether] afforded 10
(0.079 g, 69% yield). Kugelrohr distillation (1068C,
0.005 mmHg) gave analytically pure 10 as a colorless oil
(0.0733 g, 64%): IR 2959 (m), 1714 (shoulder), 1699 (s),
1391 (m), 1363 (m), 1222 (w), 1166 (m), 878 (w), 772 (w);
1H NMR d 1.03 (s, 3H), 1.04 (s, 3H), 1.08 (s, 3H), 1.46 (s,
9H), 1.64±1.77 (m, 1H), 2.00±2.43 (m, 4H), 2.85±2.96 (m,
3H), 3.06±3.17 (m, 2H); 13C NMR d 25.04, 28.27, 29.09,
34.06, 35.72, 38.37, 41.95, 47.91, 50.57, 53.77, 61.53
(61.93, rotamer), 79.41 (79.91, rotamer), 156.31
(156.72, rotamer), 211.62 (211.88, rotamer). Anal.
Calcd for C16H29NO3: C, 67.86; H, 10.24. Found: C,
67.58; H, 10.17.
1,1-Dimethylethyl N-methyl-N-(2,2-dimethyl-4-oxopen-
tyl) carbamate (13). General procedure B was employed
using a-aminostannane 3b (0.2169 g, 0.5 mmol), n-BuLi
(0.21 mL, 0.5 mmol), CuCN (0.0466 g, 0.5 mmol), mesityl
oxide (0.05 mL, 0.437 mmol), and TMSCl (0.32 mL,
2.5 mmol). Puri®cation by preparative TLC [silica gel,
10% EtOAc±90% petroleum ether, v/v] afforded pure 13
(0.043 g,
40%).
Kugelrohr
distillation
(898C,
1,1-Dimethylethyl N-Methyl-N-(4-oxopentyl) carbamate
(11). General procedure A was employed using a-amino-
stannane 3b (0.2182 g, 0.5 mmol), n-BuLi (0.23 mL,
0.5 mmol), CuCN (0.0438 g, 0.5 mmol), methyl vinyl
ketone (0.034 mL, 0.408 mmol), and TMSCl (0.32 mL,
2.5 mmol). The crude material was puri®ed by preparative
TLC [silica gel, 20% EtOAc±petroleum ether, v/v] afford-
ing 11 (0.0707 g). Kugelrohr distillation (73±808C,
0.005 mmHg) gave analytically pure 11 as a colorless oil
(0.0545 g, 62% yield): IR 2973 (m), 2931 (m), 1715
(shoulder), 1693 (s), 1395 (m), 1367 (m), 1168 (s), 1140
(m), 880 (w), 774 (w); 1H NMR d 1.45 (s, 9H), 1.78 (quintet
Jˆ7.2 Hz, 2H), 2.15 (s, 3H), 2.43 (t, Jˆ7.2 Hz, 2H), 2.82 (s,
3H), 3.21 (t, Jˆ6.9 Hz, 3H); 13C NMR d 21.63, 28.39,
29.93, 33.95, 40.34, 47.59 (47.86, rotamer), 79.29, 155.83,
208.06 (208.21, rotamer). Anal. Calcd for C11H21NO3: C,
61.42; H, 9.76. Found: C, 61.41; H, 9.82.
0.005 mmHg) gave analytically pure 13 as colorless oil
(0.0374 g, 35% yield): IR 2973 (m), 1714 (shoulder),
1693 (s), 1391 (m), 1363 (m), 1166 (m), 878 (w), 772
1
(w); H NMR d 1.02 (s, 6H), 1.45 (s, 9H), 2.12 (s, 3H),
2.38 (s, 2H), 2.90 (s, 3H), 3.19 (s, 2H); 13C NMR d 25.82
(2 C), 28.35 (3 C), 32.21, 36.45, 37.92, 52.12 (53.37,
rotamer), 59.08, 79.15 (79.96, rotamer), 156.61, 208.14.
Anal. Calcd for C13H25NO3: C, 64.21; H,10.28. Found: C,
64.03; H, 10.32.
Non-transferable ligand studies: mixed cuprates
(RLi1RntLi1CuCN1TMSCl)
Several mixed cuprates containing 2-thienyl, methyl,
p-methoxyphenylethynyl, and 1-hexynyl as potential non-
transferable ligands were examined. A general procedure
for these experiments is summarized: To a-aminostannane
3a (0.2166 g, 0.5 mmol) in THF (1.0 mL) cooled to 2788C
was added n-BuLi (0.22 mL, 0.5 mmol) and the resulting
mixture was stirred for 27 min. To RntCu(CN)Li [For
Rntˆ2-thienyl, the reagent 2-thienylCuCNLi was purchased
from Aldrich. For RntˆMe or 1-hexynyl: prepared from
CuCN (0.0457 g, 0.5 mmol in THF (2 mL) at 2788C by
addition of MeLi (0.53 mL, 0.5 mmol) or 1-lithio-1-hexyne
(1-hexyne (0.057 mL, 0.5 mmol) and then stirring at 08C for
2±15 min for MeCuCNLi)] cooled to 2788C was added the
carbanion solution by cannular transfer plus a 0.5 mL THF
rinse and then stirred at 08C for 1 min. The homogenous
light yellow [RLi1(2-thienylCuCNLi), RLi1MeCuCNLi,
and RLi1(p-Methoxyphenylacetylenyl)CuCNLi] or amber
[RLi11-hexynylCuCNLi] colored solution was cooled to
2788C and to this was added a cold (2788C) solution of
2-cyclohexenone (0.02 mL, 0.206 mmol) and TMSCl
(0.32 mL, 0.5 mmol) in THF (2 mL) by cannular transfer
1,1-Dimethylethyl 2-(3-oxobutyl)-1-pyrrolidinecarboxy-
late (12a). General procedure A was employed using
a-aminostannane 4b (0.4612 g, 1.0 mmol), n-BuLi
(0.41 mL, 1.0 mmol), CuCN (0.0442 g, 0.5 mmol), methyl
vinyl ketone (0.033 mL, 0.408 mmol), and TMSCl
(0.32 mL, 2.5 mmol). The crude material was puri®ed by
gravity column chromatography [silica gel, 20% EtOAc±
80% petroleum ether] to give pure 12a (0.0843 g, 86%).
Kugelrohr distillation (85±958C, 0.005 mmHg) afforded
pure 12a as a colorless oil (0.0849 g, 86% yield): IR 2974
(m), 1714 (shoulder), 1693 (s), 1395 (s), 1366 (m), 1152
(w), 1172 (m), 1103 (m), 771 (w); 1H NMR d 1.46 (s, 9H),
1.56±1.70 (m, 2H), 1.75 ±2.00 (m, 4H), 2.15 (s, 3H), 2.45
(br, 2H), 3.21±3.58 (m, 2H), 3.81 (br s, 1H); 13C NMR d
22.84 (23.50, rotamer), 28.35 (3 C), 28.49, 29.66, 30.16
(30.59, rotamer), 40.47, 46.19, 56.35, 78.81, 154.67,

2776
R. K. Dieter et al. / Tetrahedron 56 (2000) 2767±2778
and allowed to stir for 36 min (monitored by TLC). The
reaction was quenched with H2O and was stirred at rt
brie¯y. The mixture was further diluted with Et2O and
vacuum ®ltered through Celite. The organic phase was
separated and the aqueous phase was extracted 3 times
with Et2O. The combined organic phases were washed 1
time with saturated NH4Cl (aq), 5% NaHCO3 (aq), brine
and dried over anhydrous K2CO3. Evaporation of the solvent
in vacuo afforded the crude product 6. Puri®cation by silica
gel column chromatography (gravity) eluting with 50%
Et2O±50% petroleum ether (v/v) mixture afforded pure 6
[RLi12-thienylCuCNLi (48%); RLi1MeCuCNLi (0.051 g
51%)13-methylcyclohexanone isolated as mixture with
7.39 (m, 5H); 13C NMR d 28.28 (3 C), 36.43 (35.77, rota-
mer), 55.31, 72.02, 80.12, 126.38 (2 C), 127.54, 128.44 (2
C), 129.67, 130.77, 136.61, 157.61. Anal. Calcd for
C16H23NO3: C, 69.33; H, 8.29. Found: C, 69.36; H, 8.33.
1,1-Dimethylethyl 2-(1-methyl-2-formyl)ethyl]-1-pyrro-
lidinecarboxylate (15). General procedure D was employed
using N-Boc pyrrolidine (4a) (0.188 g, 1.10 mmol in THF),
(2)-sparteine (0.23 mL, 1.10 mmol), sec-BuLi (0.90 mL,
1.10 mmol), a mixture of CuCN (0.0979 g, 1.10 mmol)
and LiCl (0.0924 g, 2.2 mmol), crotonaldehyde (0.070 g,
1.0 mmol) and TMSCl (0.63 mL, 5.0 mmol). Puri®cation
by ¯ash chromatography [silica gel, 5% EtOAc±95% petro-
leum ether, v/v] gave 15 as an oil (0.195 g, 81% yield): 1H
NMR d 0.95 (d, Jˆ7.0 Hz, 3H) [0.92 (d, Jˆ6.8 Hz, 3H),
diastereomer, 57:43], 1.26 (s, 9H), 1.57±2.00 (m, 4H),
2.05±2.70 (m, 3H), 2.90±3.29 (m, 1H), 3.30±4.00 (m,
2H), 9.73 (s, 1H) (9.59 diastereomer1rotamer); 13C NMR
d 16.0 (15.4), 24.0 (22.6), 27.2 (26.0), 28.4, 31.0 (32.0),
46.8 (46.0), 48.1 (47.3), 61.1 (60.7), 79.3 (79.2), 155.1,
202.7 [203.4, diastereomer (56:44)1rotamers].
1
carbamate 3a (0.0269 g, 38% yield as estimated by H
NMR analysis of this isolated mixture); RLi11-hexynyl-
CuCNLi (0.065 g, 65%)13-butyl-2-cyclohexan-1-one
(0.0228 g, 34% as determined by NMR analysis on an
isolated mixture containing carbamate 3a); RLi1p-methoxy-
phenylacetylenylCuCNLi (0.052 g, 52% yield)].
1,1-Dimethylethyl N-methyl-N-[(2-methyl-3-formyl)pro-
pyl] carbamate (14a). General procedure C was employed
using carbamate 3a (0.1453 g, 1.0 mmol in Et2O), TMEDA
(0.15 mL, 1.0 mmol), sec-BuLi (0.90 mL, 1.0 mmol),
CuCN (0.0458 g, 0.5 mmol in THF), crotonaldehyde
(0.034 mL, 0.41 mmol), and TMSCl (0.32 mL, 2.5 mmol).
Puri®cation by preparative TLC [silica gel, 20% EtOAc±
80% petroleum ether, v/v] afforded 14a (0.0486 g, 48%
yield); Kugelrohr distillation (73±818C, 0.005 mm Hg)
gave pure 14a (0.395 g, 47% yield) as an oil: IR 2973 (s),
2931 (s), 1728 (shoulder), 1699 (s), 1482 (m), 1457 (m),
1396 (s), 1367 (m), 1253 (m), 1171 (s), 1068 (w), 880 (m),
847 (m), 774 (w); 1H NMR d 0.95 (d, Jˆ6.6 Hz, 3H), 1.45
(s, 11H), 2.23±2.53 (m, 2H), 2.84 (br m, 3H), 2.97±3.21 (br
m, 2H), 9.75 (s, 1H); 13C NMR d 17.70, 27.34, 28.34 (3C),
33.79, 48.38, 54.18 (54.27 rotamer), 79.50, 155.94 201.64
(201.91, rotamer).
1,1-Dimethylethyl N-methyl-N-[(bicyclo[3.1.1](4,4-dimethyl-
6-formyl)heptyl)methyl] carbamate (16). To a-amino-
stannane 3b (0.4327 g, 1.0 mmol) in THF (2 mL) cooled
to 2788C was added n-BuLi (0.41 mL, 1.0 mmol) and the
resulting mixture was stirred for 17 min. To CuCN
(0.0455 g, 0.5 mmol) suspended in THF (2 mL) cooled to
2788C was added the carbanion solution by cannular trans-
fer, plus a 0.5 mL THF rinse of the carbamate pot. The
mixture was allowed to warm slowly to 2538C over
25 min and then cooled back to 2788C. To this solution
was added a cold (2788C) solution of (1R)-(2)-myrtenal
(0.06 mL, 0.4 mmol) and TMSCl (0.32 mL, 2.5 mmol) in
THF (2 mL) by cannular transfer. The reaction mixture
was stirred at 2788C for 57 min and then allowed to
warm to 08C over 2.25 h. The reaction was quenched with
saturated NH4Cl (aq.) and was stirred at rt brie¯y. The
mixture was further diluted with Et2O and ®ltered by
vacuum through Celite. The organic phase was separated
and the aqueous phase was extracted 3 times with Et2O.
The combined organic phases were washed 1 time with
saturated NH4Cl (aq.), brine and dried over anhydrous
MgSO4. Evaporation of the solvent in vacuo afforded the
crude material (0.548 g). Puri®cation by MPLC [silica gel,
15% Et2O±85% petroleum ether, v/v] gave 16; Kugelrohr
distillation (1038C, 0.005 mmHg) afforded analytically pure
16 as a white solid (0.074 g, 62% yield): mpˆ75±768C; IR
(solution cell, CDCl3) 2980 (m), 2931 (m), 1721 (s) 1679
1,1-Dimethylethyl N-methyl-N-[(2-phenyl-3-formyl)pro-
pyl] carbamate (14b) and trans-1,1-dimethylethyl
N-methyl-N-[(2-hydroxy-phenyl)-3-butenyl] carbamate.
General procedure C was employed using carbamate 3a
(0.1472 g, 1.0 mmol in Et2O), TMEDA (0.15 mL,
1.0 mmol), sec-BuLi (0.91 mL, 1.0 mmol), CuCN
(0.0487 g, 0.5 mmol in THF), cinnamaldehyde (0.05 mL,
0.396 mmol), and TMSCl (0.32 mL, 2.5 mmol). Puri®-
cation by preparative TLC [silica gel, 20% EtOAc±80%
petroleum ether, v/v] afforded 14b as an oil (0.0143 g,
<13% yield) and 1,2-adduct as an oil (0.0461 g, 44%
yield). 1,4-Adduct 14b: IR 2980 (s), 2931 (s), 1693 (s),
1482 (s), 1398 (s), 1363 (m), 1236 (m), 1159 (s), 920 (m),
1
(s), 1475 (w), 1454 (w), 1398 (m), 1370 (m), 1125 (s); H
NMR d 0.67 (s, 3H), 1.17 (br s, 4H), 1.39 (br s, 12H), 1.94
(br s, 1H), 2.04 (m, 1H), 2.34±2.61 (m, 3H), 2.79 (s, 3H),
2.84±3.50 (m, 1H), 9.01 (s, 1H); 13C NMR d 22.59, 24.65,
26.57, 28.38 (3 C), 29.77, 30.36, 30.69, 34.05, 38.72, 40.98,
42.16, 57.10, 57.88, 79.35, 155.85, 156.03, 156.03, 156.40,
156.59, 203.94, 204.42. Anal. Calcd for C17H29NO3: C,
69.17; H, 9.82. Found: C, 69.06; H, 9.97.
1
878 (m), 765 (m), 730 (m), 702 (m); H NMR d 1.40-1.45
(m, 9H), 2.69±2.79 (m, 3H), 2.88 (br s, 2H), 3.12±3.72 (m,
3H), 7.18±7.33 (m, 5H), 9.68 (s, 1H); 13C NMR d 28.26
(rotamer 28.36, 3 C), 34.47 (rotamers 34.78, 35.00), 38.55
(rotamer 38.78), 46.86 (rotamer 47.10), 54.38 (rotamer
54.83), 79.55, 127.04, 127.63 (2 C), 128.68 (2 C), 141.08
(rotamer 141.27), 155.38 (rotamer, 155.93), 200.63 (rota-
mer 210.10). 1,2-adduct: IR 3416 (br, m), 2973 (m), 2931
(m), 1693 (s), 1672 (s), 1398 (m), 1229 (m), 1152 (s), 969
1,1-Dimethylethyl 2-[bicyclo[3.1.1](4,4-dimethyl-6-formyl)-
heptyl]-1-pyrrolidinecarboxylate (17). General Procedure
D was employed using N-Boc pyrrolidine (2a) (0.180 g,
1.05 mmol in THF), (2)-sparteine (0.23 mL, 1.05 mmol),
sec-BuLi (0.90 mL, 1.05 mmol), a mixture of CuCN
1
(m), 878 (m), 751 (m), 695 (m); H NMR d 1.45 (s, 10H),
2.94 (s, 3H), 3.39 (br s, 2H), 4.52 (br s, 1H), 6.18 (dd,
Jˆ9.9 Hz, Jˆ6 Hz, 1H), 6.68 (d, Jˆ18.6 Hz, 1H), 7.23±

R. K. Dieter et al. / Tetrahedron 56 (2000) 2767±2778
2777
2117. (b) Strekowski, L.; Gulevich, Y.; Van Aken, K.; Wilson,
D. W.; Fox, K. R. Tetrahedron Lett. 1995, 36, 225. (c) Knochel,
P.; Chou, T.-S.; Jubert, C.; Rajagopal, D. J. Org. Chem. 1993, 58,
588.
(0.0939 g, 1.05 mmol) and LiCl (0.0882 g, 2.1 mmol)
dissolved in THF (2.1 mL), and (1R)-(2)-mytrenal
(0.150 g, 1.0 mmol) dissolved in TMSCl (0.63 mL,
5.0 mmol) in the indicated quantities. Puri®cation by ¯ash
chromatography [5% EtOAc±95% petroleum ether, v/v]
gave the 1,4-adduct as an oil (0.0867 g, 37% yield) existing
as a complex mixture of diastereomers.
7. For a review on reactive metals see: Rieke, R. D.; Hanson, M. V.
Tetrahedron 1997, 53, 1925.
8. (a) Edwards, P. D.; Meyers, A. I. Tetrahedron Lett. 1984, 25,
939. (b) Meyers, A. I.; Edwards, P. D.; Rieker, W. F.; Bailey, T. R.
J. Am. Chem. Soc. 1984, 106, 3270. (c) Meyers, A. I.; Edwards,
P. D.; Bailey, T. R.; Jagdmann, Jr. J. Org. Chem. 1985, 50, 1019.
(d) Gonzalez, M. A.; Meyers, A. I. Tetrahedron Lett. 1989, 30, 43.
(e) Shawe, T. T.; Meyers, A. I. J. Org. Chem. 1991, 56, 2751.
9. (a) Beak, P.; Lee, W.-K. J. Org. Chem. 1990, 55, 2578. (b)
Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109. (c) Idem,
Tetrahedron Lett. 1989, 30, 1197. (d) Kerrick, S. T.; Beak, P.
J. Am. Chem. Soc. 1991, 113, 9708. (e) Park, Y. S.; Weisenburger,
G. A.; Beak, P. J. Am. Chem. Soc. 1997, 119, 10537.
[N-Methyl-N-(1-methyl-3,3-dimethyl-5-oxocyclohexyl)-
methyl]amine-hydrochloride (18).36 A solution of 1 M
TMSCl in CH2Cl2 (0.83 mL, 3.32 mmol) and 4 M phenol
in CH2Cl2 (2.5 mL, 10 mmol) was stirred under a nitrogen
atmoshphere at rt for 18 min. This solution was added by
syringe to 1,4-adduct 10 (0.0634 g, 0.224 mmol) in CH2Cl2
(1 mL) at rt and stirred for 0.5 h. The solvent was evapo-
rated in vacuo and then the residue was dissolved in anhy-
drous Et2O. The solution was supercooled in liquid nitrogen
and allowed to slowly warm to rt. A precipitate was isolated
by vacuum ®ltration to give the g-aminoketone hydro-
chloride salt 18 (0.0382 g, 77% yield) which was .95%
pure by 1H NMR analysis: mp 218.9±2208C (decomposed);
IR (solution cell, CHCl3) 2966 (s), 2727 (br), 1714 (s), 1595
(w), 1461 (m), 1285 (m), 1233 (m); 1H NMR (D2O) d 0.80
(s, 3H), 0.85 (s, 3H), 0.92 (s, 3H), 1.51 (app. q, Jˆ8.7 Hz,
2H), 1.99 (app. d, Jˆ13.5 Hz, 2H), 2.23 (app. t, Jˆ14.4 Hz,
2H), 2.50 (s, 3H), 2.77 (app. q, Jˆ7.5 Hz, 2H); 13C NMR
(CDCl3) d 26.33, 29.85, 32.48, 35.02, 35.92, 38.69, 46.63,
49.88, 53.74, 61.54, 209.43.
10. For reviews see: (a) Beak, P.; Reitz, D. B. Chem. Rev. 1978,
78, 275. (b) Beak, P.; Zajdel, W. J.; Reitz, D. B. Chem. Rev. 1984,
84, 471. (c) Meyers, A. I. Aldrichimica Acta 1985, 18, 59. (d)
Gawley, R. E.; Rein, K. In Comprehensive Organic Synthesis;
Trost, B. M., Ed.; Pergamon Press: Oxford, 1990; Vol. 1, Chapter
2.1 and Vol. 3, Chapter 1.2. (e) Beak, P.; Basu, A.; Gallagher, D. J.;
Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552.
11. (a) Gawley, R. E.; Hart, G. C.; Bartolotti, L. J. J. Org. Chem.
1989, 54, 175. (b) Rein, K. S.; Chen, Z.-H.; Perumal, P. T.;
Echegoyen, L.; Gawley, R. E. Tetrahedron Lett. 1991, 32, 1941.
12. Ahlbrecht, H.; Kornetzky, D. Synthesis 1988, 775.
13. Savignac, P.; Leroux, Y.; Normant, H. Tetrahedron 1975, 31,
877.
14. Huber, I. M. P.; Seebach, D. Helv. Chim. Acta 1987, 70, 1944.
Acknowledgements
Ã
15. Tsunoda, T.; Fujiwara, K.; Yamamoto, Y.; Ito, S. Tetrahedron
Lett. 1991, 32, 1975.
This work was generously supported by the National
Science Foundation (CHE-9408912).
16. (a) Chong, J. M.; Park, S. B. J. Org. Chem. 1992, 57, 2220. (b)
Pearson, W. H.; Postich, M. J. J. Org. Chem. 1992, 57, 6354. (c)
Burchat, A. F.; Chong, J. M.; Park, S. B. Tetrahedron Lett. 1993,
34, 51. (d) Pearson, W. H.; Lindbeck, A. C.; Kampf, J. W. J. Am.
Chem. Soc. 1993, 115, 2622. (e) Ahlbrecht, H.; Baumann, V.
Synthesis 1993, 981.
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