Conjugate addition reactions of α-aminoalkylcuprates with α,β-alkenyl-, α,β-alkynyl-, α,β-allenyl-, and α,β-γ,δ-dienyl carboxylic acid derivatives, nitriles, and sulfoxides

Article abstract of DOI:10.1021/jo0056038

α-Aminoalkylcuprates prepared from α-lithio carbamates and CuCN·2LiCl participate in 1,4-addition reactions with α,β-unsaturated esters, thiol esters, imides, and nitriles in poor to excellent yields depending upon the electron-withdrawing substituent and the substitution pattern of the unsaturated substrate. These reagents also undergo conjugate addition reactions with α,β-alkynyl esters, sulfoxides, and nitriles and with α,β-β,γ-unsaturated allenyl esters. Excellent stereocontrol is achieved in the conjugate additions of α-aminoalkylcuprates to the allenyl esters, while poor stereoselectivity results in the conjugate additions to the alkynyl derivatives. Deprotection and cyclization of the alkynyl adducts affords pyrrolin-2-ones, while similar treatment of the allenyl adducts affords 4-alkylidine- pyrrolidin-2-ones and pyrrolizidinones.

Full text of DOI:10.1021/jo0056038

J . Org. Chem. 2000, 65, 8715-8724
8715
Con ju ga te Ad d ition Rea ction s of r-Am in oa lk ylcu p r a tes w ith
r,â-Alk en yl-, r,â-Alk yn yl-, r,â-â,γ-Allen yl-, a n d r,â-γ,δ-Dien yl
Ca r boxylic Acid Der iva tives, Nitr iles, a n d Su lfoxid es
R. Karl Dieter,* Kai Lu, and Sadanandan E. Velu
Hunter Laboratory, Department of Chemistry, Clemson University, Clemson, South Carolina 29634-0973
dieterr@clemson.edu.
Received August 10, 2000
R-Aminoalkylcuprates prepared from R-lithio carbamates and CuCN‚2LiCl participate in 1,4-
addition reactions with R,â-unsaturated esters, thiol esters, imides, and nitriles in poor to excellent
yields depending upon the electron-withdrawing substituent and the substitution pattern of the
unsaturated substrate. These reagents also undergo conjugate addition reactions with R,â-alkynyl
esters, sulfoxides, and nitriles and with R,â-â,γ-unsaturated allenyl esters. Excellent stereocontrol
is achieved in the conjugate additions of R-aminoalkylcuprates to the allenyl esters, while poor
stereoselectivity results in the conjugate additions to the alkynyl derivatives. Deprotection and
cyclization of the alkynyl adducts affords pyrrolin-2-ones, while similar treatment of the allenyl
adducts affords 4-alkylidine- pyrrolidin-2-ones and pyrrolizidinones.
In tr od u ction
often sluggish with the less reactive enoate substrates.
Cuprates prepared from CuCN (2RLi + CuCN),6 cuprous
thiophenoxides,7 and copper(I) trimethylsilylacetylide8
have provided partial solutions to this problem. The
reactivity of the latter reagent was enhanced by solvent
composition (4:1 ether/THF) and by the addition of
chlorotrimethylsilane.8 Gilman reagents also effect high
yield conjugate addition reactions with mono â-alkyl-
substituted enoates, enamides, and enecarbamates in
ether in the presence of TMSCl.9 Alkyl copper compounds
also participate with enoates in conjugate addition reac-
tions in synthetically useful yields in the presence of
additives such as BF3‚Et2O10 and chloro- or iodotrimeth-
ylsilane.11 These tactics proved ineffective for R-ami-
noalkylcuprates and their conjugate addition to R,â-
enoates was eventually achieved by use of the THF
soluble complex CuCN‚2LiCl and TMSCl.5 In this full
report we describe the reactions of R-aminoalkylcuprates
with R,â-alkenyl-, R,â-alkynyl- carboxylic acid deriva-
tives5 and nitriles and with R,â-γ,δ-dienoates (Scheme.
1). R-Aminoalkylcuprates also participated effectively in
conjugate addition reactions with an R,â-alkynyl sulfox-
ide and with R,â-allenyl esters (Scheme 1).
Organocopper1 and palladium reagents represent the
two most widely used transition organometallic reagents
in organic synthesis. Although organocopper reagents
effect a wide range of transformations often complemen-
tary to organolithium and Grignard reagents, their
preparation from the latter species limits the compatible
functional groups that can be present in the organic
ligand. The copper-mediated reactions of organozinc
reagents have enormously extended the range of func-
tionalized organocopper reagents, but reactivity problems
have plagued the application of this chemistry to R-ami-
noalkylcuprates.2 Successful development of dipole sta-
bilized R-lithio amine chemistry3 encouraged the explo-
ration of R-aminoalkylcuprate reagents. The first reported
examples of R-aminoalkylcuprate conjugate addition
reactions4 were limited to R,â-enones and enals and early
efforts to effect conjugate addition to R,â-enoates were
unsuccessful consistent with cuprate-enoate reactivity
profiles.5 Although numerous homo and mixed organo-
cuprates readily transfer alkyl ligands to the â-carbon
atom of R,â-enones, the conjugate addition reaction is
(1) For a review on organocopper chemistry see: (a) Lipshutz, B.
H.; Sengupta, S. Org. React. 1992, 41, 135. (b) Lipshutz, B. H. In
Organometallics in Synthesis: A Manual; Schlosser, M., Ed.; J ohn
Wiley & Sons: England, 1994; Chapter 4, p 283. (c) Organocopper
Reagents: A Practical Approach; Taylor, R. J . K., Ed.; Oxford Univer-
sity Press: Oxford, 1994.
(2) For the use of CuCN‚2LiCl catalyzed reactions of alkylzinc
halides see: (a) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 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.; J ubert,
C.; Rajagopal, D. J . Org. Chem. 1993, 58, 588.
(3) 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.
(4) (a) Dieter, R. K.; Alexander, C. W. Synlett 1993, 407. (b) Dieter,
R. K.; Alexander, C. W. Tetrahedron Lett. 1992, 33, 5693. (c) Dieter,
R. K.; Alexander, C. W.; Nice, L. E. Tetrahedron 2000, 56, 2767.
(5) Dieter, R. K.; Velu, S. E. J . Org. Chem. 1997, 62, 3798.
Resu lts
Initial efforts to effect reaction of R-aminoalkylcuprates
with methyl or ethyl acrylate employing procedures that
(6) Lipshutz, B. H. Tetrahedron Lett. 1983, 24, 127.
(7) Behforousz, M.; Curran, T. T.; Bolan, J . Tetrahedron Lett. 1986,
27, 3107.
(8) Sakata, H.; Kuwajima, I. Tetranhedron Lett. 1987, 28, 5719.
(9) Alexakis, A.; Berlan, J .; Besace, Y. Tetrahedron Lett. 1986, 27,
1047.
(10) Yamamoto, Y.; Yamamoto, S.; Yatagai, H.; Ishihara, Y.; Maruya-
ma, K. J . Org. Chem. 1982, 47, 119.
(11) (a) Bergdahl, M.; Lindstedt, E.-L.; Nilsson, M. Tetrahedron
1988, 44, 2055. (b) Bergdahl, M.; Eriksson, M.; Nilsson, M.; Olsson, T.
J . Org. Chem. 1993, 58, 7238. (c) Bergdahl, M.; Iliefski, T.; Nilsson,
M.; Olsson, T. Tetrahedron Lett. 1995, 36, 3227. (d) Eriksson, M.;
Hjelmencrantz, A.; Nilsson, M.; Olsson, T. Tetrahedron 1995, 51,
12631. (e) Eriksson, M.; Nilsson, M.; Olsson, T. Synlett 1994, 271. (f)
Bergdahl M.; Eriksson, M.; Nilsson, M.; Olsson, T. J . Org. Chem. 1993,
58, 7238.
10.1021/jo0056038 CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/17/2000

8716 J . Org. Chem., Vol. 65, No. 25, 2000
Dieter et al.
Ta ble 1. Con ju ga te Ad d ition of r-Am in oa lk ylcu p r a tes
w ith r,â-Alk en yl Nitr iles a n d Ca r boxylic Acid
Der iva tives
Sch em e 1
were successful with R,â-enones either failed or gave low
yields of conjugate adducts. Dialkylcuprates prepared via
organostannanes failed completely, while the J ohnson
alkyl copper12 reagent gave low to modest yields depend-
ing upon solvent (eq 1). Subsequent experimentation
revealed that preparation of the cuprate reagent from 1a ,
2a , or 3a via Beak’s deprotonation protocol13 and LiCl-
solubilized CuCN [i. s-BuLi, (-)-sparteine, THF, -78 °C,
1 h; ii. CuCN‚2LiCl, THF, -78 to -55 °C, 45 min]
generated efficacious reagents that underwent conjugate
addition to methyl acrylate [THF, TMSCl, -55 °C, 0.5 h
to room temperature (1.5 h)] in the presence of TMSCl
in high yields (eq 1 and Table 1, entries 1, 7, and 8).
Utilization of ethyl crotonate resulted in significantly
reduced yields of conjugate adducts accompanied by
recovered carbamates (entries 2 and 9-11). Deprotona-
tion of 2a , aided by either TMEDA or (-)-sparteine, gave
cuprates that reacted with ethyl crotonate, giving similar
yields for additives [i.e., TMEDA or (-)-sparteine, 52%
vs 56-77% yields, respectively]4a and CuCN‚2LiX com-
binations [CuCN‚2LiI (53%), CuCN‚2LiCl (58%), CuCN‚
4LiCl (56-77%)].4c Cuprates prepared from 1a failed to
react with ethyl tiglate or with methyl cyclohexene-1-
carboxylate, while cuprates prepared from 2a gave low
yields with the former (entry 19) and no conjugate adduct
with the latter (entry 21). The lower order cuprate,
a
The carbamate was deprotonated [s-BuLi, (-)-sparteine or
TMEDA (1.0 equiv), -78 °C, 1 h] and added to the Cu(I) salt for
b
cuprate formation. A ) 2RLi + CuCN‚2LiCl. B ) RLi
+
CuCN‚2LiCl. C ) RLi + CuCl‚2LiCl. c Reaction of the organocop-
per reagent with the unsaturated substrate and TMSCl (5.0 equiv)
in THF at -55 °C (30 min) and then at room temperature (1.5 h)
d
gave the conjuate addition products. Yields are based upon
isolated purified products unless otherwise noted. e Yield deter-
mined by NMR using tetrachloroethane as internal standard. f 2.5
(12) J ohnson, C. R.; Marren, T. J . Tetrahedron Lett. 1987, 28, 27.
(13) (a) Beak, P.; Lee, W. K. Tetrahedron Lett. 1989, 30, 1197. (b)
Beak, P.; Lee, W. K. J . Org. Chem. 1993, 58, 1109.
g
equiv of TMSCl was employed. Trace amounts of the R-silylated
nitrile were obtained.

Addition Reactions of R-Aminoalkylcuprates
J . Org. Chem., Vol. 65, No. 25, 2000 8717
Sch em e 2
RCuCNLi prepared from 2a gave significantly lower
yields than the 2RLi + CuCN reagent (entry 10 vs 9).
In an effort to increase the yields of conjugate adducts
with alkyl-substituted alkenyl esters, the corresponding
thiol esters were examined. Anticipating competitive
acylation14 and conjugate addition pathways, both the
n-butyl and tert-butyl thiol esters were studied. Surpris-
ingly, both butylthio derivatives gave good to excellent
yields of conjugate adducts with the cuprates derived
from 1a and 2a with no acylation products being observed
(entries 3-6, and 12-16). The thiol esters offered little
advantage in the reactions with the acyclic R-alkyl-
substituted substrate (entry 20 vs 19) but facilitated the
reaction with the 1-cyclohexene derivative (entry 22 vs
21). In an effort to probe the greater reactivity of the thiol
esters, a series of organocopper reagents were examined.
The cyanocuprate reagents, RCuCNLi, gave good to
excellent yields of conjugate addition products with the
thiol esters (entries 4, 6, 13, and 15) and poor yields with
esters (entry 10). Utilization of an alkyl copper reagent
prepared from 2a and CuCl‚2LiCl gave a modest yield
of product (entry 16). Although both cuprate reagents,
RCuCNLi and R2CuLi‚LiX, gave comparable yields (5-
12% lower for RCuCNLi) with the thiol esters, the
RCuCNLi reagent is more efficient in R-aminoalkyl
ligand and therefore preferred.
Sch em e 3
The R2CuLi‚LiCN cuprate reagents prepared from 1a
or 2a and CuCN‚2LiCl also underwent conjugate addition
to an imide in excellent to modest yields (Table 1, entries
18 and 17, respectively). These cuprates also gave excel-
lent to good yields of conjugate adducts with acrylonitrile
(entries 23 and 26) but the yields diminished greatly with
crotononitrile (entry 28). The RCuCNLi reagents pre-
pared from 1a (entry 24), 2a (entries 27 and 29), and 3a
(entry 25) gave modest yields of conjugate adducts with
either acrylonitrile or crotononitrile. In one instance, the
RCuCNLi reagent gave a higher yield than the R2CuLi‚
LiCN reagent (entry 28 vs 29). In these reactions, the
conjugate adducts were isolated as R-silylnitriles result-
ing from C-silylation of the nitrile enolate anion with the
exception of the piperidine (3a )-derived cuprate, which
gave the R-silylated nitrile as the minor product (entry
25). These yields could not be improved by the use of
Lewis acids such as BF3‚Et2O or Sc(OTf)3.15
R-Aminoalkylcuprates prepared from carbamates 1a -
3a gave good to excellent yields of conjugate adducts with
R,â-alkynyl esters, nitriles, and a sulfoxide and trace
amounts of adduct with a sulfone (Scheme 2, Table 2),
the latter result being consistent with the low yields
generally observed with cuprates and unsaturated sul-
fones.16 In initial studies, a cuprate reagent prepared
from 2 equiv of the lithio derivative of 2a and CuCN‚
2LiCl gave a good yield of conjugate adduct with ynoate
15b, while nearly quantitative yields could be achieved
with RCuCNLi reagents prepared from 1a or 2a under
similar conditions (Table 2, entries 13 vs 12, and 3 and
4). Given this generally superior performance of RCuCN-
Li with 15b and its efficient use of R-aminoalkyl ligand,
this reagent was used to explore a range of R,â-alkynyl
substrates. The reaction proved tolerant of â-aryl (entries
5, 9, and 18), â-carboalkoxy (entry 7), and â-(ω-chloro-
alkyl) (entries 6 and 15-17) substituents. In one experi-
ment, deprotonation of 2a was performed in the absence
of TMEDA and conjugate addition of the resulting
cuprate gave a yield comparable to that obtained with
1a deprotonated in the presence of TMEDA (entry 18 vs
5).
The product enoate obtained from the 2a -derived
cuprate and 15b was isolated as a 65:35 mixture of Z:E
geometrical isomers, which was confirmed by amine
deprotection [PhOH (30 equiv), TMSCl (10 equiv), CH2-
Cl2]17 to quantitatively afford a lactam and (E)-ethyl 3-(2-
pyrrolidinyl)-2-heptenoate in a 65:35 ratio respectively
(Scheme 3). Similarly, the configuration of Z-31a was
confirmed by NOE measurements and by Boc deprotec-
tion and cyclization to the pyrrolizinone, while 31b was
cyclized to the quinolizidine (Scheme 3). The E:Z dia-
stereomeric conjugate adducts from 3a and 17 (E, δ 5.58,
Z δ 5.69), and 1a and 19 (E δ 5.08, Z δ 5.25) were isolated
by chromatography. The Z diastereomers in the series
(Table 2) displayed olefin absorptions downfield (δ 5.25-
(14) (a) Anderson, R. J .; Henrick, C. A.; Rosenblum, L. D. J . Am.
Chem. Soc. 1974, 96, 3654. (b) Corey, E. J .; Hopkins, P. B.; Kim, S.;
Yoo, S.; Nambiar, K. P.; Falck, J . R. J . Am. Chem. Soc. 1979, 101,
7131. (c) Collum, D. B.; McDonald, J . H.; Still, W. C. J . Am. Chem.
Soc. 1980, 102, 2120.
(15) Lipshutz, B. H.; Sclafani, J . A.; Takanami, T. J . Am. Chem.
Soc. 1998, 120, 4021.
(16) Fuchs, P. L.; Braish, T. F. Chem. Rev. 1986, 86, 903 and
references therein.
(17) Kaiser, E., Sr.; Picart, F.; Kubiak, T.; Tam, J . P.; Merrifield, R.
B. J . Org. Chem. 1993, 58, 5167.

8718 J . Org. Chem., Vol. 65, No. 25, 2000
Dieter et al.
Ta ble 2. Rea ction of r-Am in oa lk ylcu p r a tes w ith
r,â-Alk yn yl Ester s, Nitr iles, Su lfoxid es, a n d Su lfon es
Ta ble 3. Rea ction of r-Am in oa lk ylcu p r a tes w ith
r-Allen yl Ester s, RCHdCdCHCO2Et
a
The carbamates were deprotonated [s-BuLi, THF, TMEDA or
(-)-sparteine, -78 °C, 1.25 h (3.5-4 h in Et2O for Boc-piperidine]
b
and reacted with a Cu(I) salt to form the cuprate reagent. A )
a
A ) Carbamate deprotonation (s-BuLi, sparteine or TMEDA,
RLi + CuCN‚2LiCl. B ) 2 RLi + CuCN‚2LiCl. The alkynoates
and TMSCl [neat, 2.5 equiv for B and 5.0 equiv for A] were added
to the R-aminoalkylcuprate at -55 to -60 °C and slowly warmed
to room temperature. Reactions were run in THF or THF/Et2O
(Boc-piperidine). c Based upon products purified and isolated by
THF, -78 °C) followed by sequential addition of 0.5 equiv of
CuCN‚2LiCl (-55 °C, 45 min) and allenyl ester [TMSCl (2.5 equiv),
-55 °C to rt]. B ) Same conditions as in A, except 1.0 equiv
b
CuCN‚2LiCl per RLi was employed [TMSCl (5.0 equiv)]. Isolated
yields based upon products purified by chromatography. c Dia-
stereomeric ratio determined by 1H NMR analysis; >95:5 unless
noted.
d
chromatography unless otherwise noted. The E:Z ratios were
determined from 1H NMR integration ratios of the olefinic proton
absorptions. e The reaction was run in the presence of t-BuOH (1.0
equiv). f Yield determined by NMR using tetrachloroethane as
g
which displayed dramatic differences. The methylene
group syn to the carbonyl absorbed significantly further
downfield.18b Quenching of the reaction at -78 °C with
methanol or running the reaction in the presence of 1.0
equiv of tert-BuOH did not provide any better stereocon-
trol in the protonation of the vinyl cuprate.19 Ratios of
E:Z diastereomers varied as a function of temperature,
concentration, and solvent mixtures. Only the piperidine
(3a )-derived cuprate gave a single geometrical isomer
(Table 2, entry 14). In contrast to the γ-amino-R,â-enones,
PhOH/TMSCl did not effect isomerization and subse-
internal standard. A single diastereomer was obtained and
assigned the E configuration on the basis of the olefinic proton
h
absorption. Deprotonation was achieved without addition of
TMEDA.
6.76) relative to those of the E diastereomers (δ 5.08-
6.66).18 In those instances when both geometric isomers
gave nearly identical chemical shifts for the olefinic
protons, the assignment of stereochemistry was made
from the amino-substituted methylene chemical shifts,
(18) (a) Dieter, R. K.; Silks, L. A., III; Fishpaugh, J . R.; Kastner, M.
E. J . Am. Chem. Soc. 1985, 107, 4679. (b) Piers, E.; Chong, J . M.;
Morton, H. E. Tetrahedron 1989, 45, 363. (c) Dieter, R. K.; Yu, H. Org.
Lett. 2000, 2, 2283.
(19) (a) Klein, J .; Levene, R. J . Chem. Soc., Perkin Trans. 2 1973,
1971. (b) Piers, E.; Wong, T.; Ellis, K. A. Can. J . Chem. 1992, 70, 2058.

Addition Reactions of R-Aminoalkylcuprates
J . Org. Chem., Vol. 65, No. 25, 2000 8719
Ta ble 4. Con ju ga te Ad d ition of r-Am in oa lk ylcu p r a tes
w ith r,â-γ,δ-Dien oa tes
Sch em e 4
a
The carbamates were deprotonated [s-BuLi, THF, TMEDA
quent cyclization18c of the E diastereomer and experi-
mental conditions for the conversion of the E isomer to
the lactam derivatives were not found.20
(entries 2, 3, 5) or (-)-sparteine (entries 1, 4), -78 °C, 1.25 h] and
b
reacted with a Cu(I) salt to form the cuprate reagent. A ) 2RLi
+ CuCN‚2LiCl. B ) RLi + CuCN‚2LiCl. C ) RLi + CuCl‚2LiCl.
The dienoates and TMSCl [neat, 5.0 equiv] were added to the
R-aminoalkylcuprate at -55 to -60 °C, and slowly warmed to room
temperature. Reactions were run in THF. c Based upon products
purified and isolated by chromatography unless otherwise noted.
R-Aminoalkylcuprates also reacted with allenyl esters
to give conjugate adducts in good overall yields (eq 2,
Table 3). Although slightly lower yields were obtained
with RCuCNLi than with the reagent prepared from
2RLi + CuCN‚2LiCl (entries 1 and 7 vs 2 and 8,
respectively) the former reagent is more efficient in the
R-aminoalkyl ligand. Modest yields of conjugate adducts
were obtained with allenyl esters containing a γ-phenyl
substituent (entries 3 and 9) or a γ,γ-disubstitution
pattern (entry 5), although the increased reactivity of the
pyrrolidinylcuprate derived from 2a gave good yields with
a γ,γ-disubstitution pattern (entry 12).
The conjugate addition reactions to the allenyl esters
proceeded stereoselectively to afford the E olefins. The
stereoselectivity of these additions was confirmed by
NOE experiments on 37 and by reduction of 37 to the
homo allylic alcohol, which permitted analysis of the E:Z
diastereomer ratio that was obscured in the NMR spectra
of 37 by the presence of rotomers arising from hindered
rotation about the carbamate N-C bond (Scheme 4).
Treatment of these allylic carbamates with PhOH/TMSCl
or catechol boron bromide effected carbamate deprotec-
tion and cyclization to 4-alkylidine pyrrolidinones and
pyrrolizidinones with regio- and stereocontrol of the olefin
position and geometry (Scheme 4).21
The addition of R-aminoalkylcuprates to ethyl or n-
propylthiol sorbate was examined to explore the competi-
tion between 1,4- and 1,6-additions for these cuprate
reagents.22 Like cuprate reagents in general, the R-ami-
noalkylcuprate preferred to add in a 1,6-fashion and this
pattern was not altered for the thiol esters (Table 4). The
resultant nonconjugated alkenyl esters were obtained as
a mixture of E and Z diastereomers. Attempted addition
of the cuprate derived from 1 to a benzothiazole deriva-
tive gave little conjugate addition.23 Upon quenching with
either methanol or NH4Cl a yellow precipitate was
obtained, suggesting decomposition of the benzothioazole
derivative.
d
The diastereomeric ratios (dr) were determined from GC-mass
selector spectrometry via ion currents. Assignment of E and Z
isomers could not be established from 1H NMR spectroscopy.
reagent. Salts such as CuCN and CuBr‚SMe2 have been
promoted as particularly effective reagent precursors.24
Cuprate reagents prepared from CuCN and either 1 or 2
equiv of an alkyllithium reagent (i.e., RCuCNLi or R2-
CuLi‚LiCN) often display superior attributes with regard
to chemical yields, suggesting an important role of the
cyanide anion in the composition, reactivity, or stability
of the cuprate complex. A higher order cuprate (i.e., R2-
CuCNLi2) was invoked to explain the superior qualities
of the latter reagent and the structure of this reagent
prepared from 2RLi + CuCN has been the subject of
considerable interest centering around the location of the
cyanide ion.26 Nevertheless, in organocopper (i.e., RCu/
TMSI) conjugate additions to lactones and enoates, CuI
affords yields comparable to or better than CuCN-derived
cuprate reagents.11f Similarly, in the CuI/TMSI-promoted
1,4-additions of copper acetylides to R,â-enones and enals
(68-89% yields), replacement of CuI with CuBr, CuCN,
or CuOTf results in greatly diminished yields (1-25%).25
Although THF soluble CuCN‚2LiCl has been extensively
used by Knochel in the copper-promoted reactions of
organozinc reagents,2 this source of Cu(I) has not been
widely used in the generation of cuprates from alkyl-
lithium or Grignard reagents.27 In initial studies, the
conjugate addition reactions of R-aminoalkylcuprates to
R,â-enoates failed when solid CuCN was employed. We
subsequently discovered that use of THF-soluble CuCN‚
2LiCl resulted in the first successful examples of this
reaction reliably forming the 1,4-addition products in
modest to excellent yields.
The success of these conjugate addition reactions
required the activating influence of TMSCl28 and initially
appeared to also require the use of LiCl-solubilized CuCN
Discu ssion
The copper(I) salt often plays a significant role in the
chemistry of the resultant organocopper or cuprate
(24) Bertz, S. H.; Gibson, C. P.; Dabbagh, G. Tetrahedron Lett. 1987
28, 4251.
(25) Eriksson, M.; Iliefski, T.; Nilsson, M.; Olsson, T. J . Org. Chem.
1997, 62, 182.
(26) (a) Bertz, S. H.; Miao, G.; Eriksson, M. J . Chem. Soc., Chem.
Commun. 1996, 815. (b) Snyder, J . P.; Bertz, S. H. J . Org. Chem. 1995,
60, 4312. (c) Barnhart, T. M.; Huang, H.; Penner-Hahn, J . E. J . Org.
Chem. 1995, 60, 4310. (d) Lipshutz, B. H.; J ames, B. J . Org. Chem.
1994, 59, 7585. (e) Krause, N. Angew. Chem., Int. Ed. Engl. 1999, 38,
79.
(27) Backvall, J .-E.; Persson, E. S. M.; Bombrun, A. J . Org. Chem.
1994, 59, 4126. (b) Schlosser, M.; Bossert, H. Tetrahedron 1991, 47,
6287.
(20) Miyata, O.; Shinada, T.; Ninomiya, I.; Naito, T. Synthesis 1990,
1123.
(21) For a preliminary account of this work see: Dieter, R. K.; Lu,
K. Tetrahderon Lett. 1999, 40, 4011.
(22) For a review see: Krause, N.; Gerold, A. Angew. Chem., Int.
Ed. Engl. 1997, 36, 187.
(23) For use of benzothiazole-2-thiol derivatives for control of allylic
substitution see: (a) Calo´, V.; Fiandanese, V.; Nacci, A.; Scilimati, A.
Tetrahedron 1994, 50, 7283. (b) Dieter, R. K.; Velu, S. E.; Nice, L. E.
Synlett 1997, 1114.

8720 J . Org. Chem., Vol. 65, No. 25, 2000
Dieter et al.
for the preparation of the cuprate reagents. Recently, a
cuprate thermal stability study indicated that good yields
of enoate conjugate adducts can also be obtained with
the use of solid CuCN.29a The yields ranged from 59%
(cuprate formation at -50 °C) to >98% (cuprate forma-
tion at 0 °C) for both the R2CuLi and RCuCNLi (R )
N-Boc pyrrolidinyl, ester ) methyl crotonate) reagents
and were dependent upon the temperature at which the
cuprate was allowed to form. The reliable use of THF-
soluble CuCN‚2LiCl, initial failure of solid CuCN, and
successful use of solid CuCN with a strict temperature
protocol in these enoate conjugate addition reactions
arises from a complex interplay of several competing
reactions. From our own observations4,29 and indications
in the literature,30 the lithio carbamates are more
thermally unstable than the corresponding cuprate re-
agents. Significant decomposition of the N-Boc R-lithio-
pyrrolidine occurs at -50 °C.29c The interplay between
the rate of lithio carbamate decomposition and cuprate
formation will have a direct bearing on the observed yield
of conjugate adducts. The apparent rise in yields for the
conjugate addition reactions of R-aminoalkylcuprates
prepared from CuCN‚2LiCl with carboxylic acid deriva-
tives appears to reflect a subtle balance between the
temperature of cuprate formation and the rate of R-lithio
carbamate decomposition. The use of CuCN‚2LiCl per-
mits the formation of the cuprate reagent at -78 °C,
while the use of solid CuCN requires warming of the
solution for complete cuprate formation subjecting the
reaction mixture to all the vagaries of temperature
fluctuation. This would account for the variation in
chemical yields from experiment to experiment. The
successful use of insoluble CuCN for cuprate preparation
suggests that the excess LiCl is not playing a significant
role as an external source of lithium ions accelerating
the conjugate addition reaction by Lewis acid complex-
ation with the carbonyl oxygen.28,31 This is consistent with
the report that cuprate reactivity is greater in conjugate
addition reactions in the absence of LiX.31c
in experiments using CuCN and CuCN‚2LiCl and we
offer the observation as a cautionary note.
We have no rate data on the conjugate addition of
R-aminoalkylcuprates with a variety of R,â-unsaturated
carbonyl compounds, and the complexity of the influence
of additives and reaction conditions makes it difficult to
estimate the intrinsic reactivity of these reagents. A
mixed homocuprate, RCuMeLi [R ) N-Boc-N-methyl-
(aminomethyl)], derived from 1a transfers the R-amino-
alkyl and methyl ligands in comparable yields.4c,32 Ad-
ditionally, the higher yields of conjugate adducts obtained
with the N-Boc pyrrolidinylcuprates [vs N-Boc-N-methyl-
(aminomethyl)cuprates] suggests that the R-aminoalkyl
ligand is comparable in reactivity to the corresponding
alkyl ligands. Nevertheless, our experience and the
failure of these cuprates to transfer the R-aminoalkyl
ligand to lactones, indicates a somewhat lower reactivity
with certain substrates than the simple dialkylcuprates.
It is possible that the carbamate moiety can play the
same role as the ortho-substituted â-aryl enoates con-
taining three oxygen atoms in the side chain which retard
the rate of reaction with lithium dialkylcuprates.33 Either
steric hindrance or coordination of the lithium ion to the
carbamate moiety of the R-aminoalkylcuprate could ac-
count for the diminished reactivity observed with less
reactive substrates such as lactones.
In an effort to circumvent the deleterious effects of
R-alkyl substitution, the corresponding thiol ester func-
tionality was examined with the expectation that the
lower LUMO energies of these substrates might enhance
their reactivity with cuprate reagents.34 Although the
increased yields obtained with the thiol ester derivatives
could arise from coordination of the cuprate and copper
reagents to the sulfur atom thereby facilitating the
conjugate addition reactions, it is more likely that
electronic factors inherent in the thiol ester functionality
are involved. The carbonyl group in thiol esters is more
“ketone-like” and hence more reactive with cuprate
reagents.18b,35 Calculated resonance energies for thiol
esters are significantly smaller than those for esters (i.e.,
5.5 vs 13.5 kcal/mol, respectively), although the carbonyl
oxygen is slightly more negatively charged (e.g., -0.250
vs -0.231, respectively).35a In addition, the lower elec-
tronegativity of S vs O should give rise to a weaker
CdO bond in thiol esters than in esters.35b These yields
involving esters, thiol esters, and imides are intriguing,
since the imides have particularly high LUMO energies
in comparison to the esters or thiol esters.34 These results
are suggestive of the crucial role that lithium cation
coordination to the unsaturated carbonyl moiety plays
in these conjugate addition reactions. The increased
reactivity of the thiol esters is also consistent with this
interpretation (i.e., greater negative charge on the car-
bonyl oxygen), although the thiol esters are also more
akin to a ketonic carbonyl than an ester carbonyl.35 This
We have also observed in our studies with R,â-enones
that use of freshly distilled TMEDA gives generally
higher yields of the conjugate adducts than reactions
using distilled TMEDA that has been stored for some
time. These variations were significantly less dramatic
with the use of (-)-sparteine or when TMEDA was used
in conjunction with CuCN‚2LiCl.4c Although the addition
of TMEDA to cuprate solutions prepared from R-amino-
alkylstannanes reduced the yields of conjugate adducts
with R,â-enones,4c this diamine effect is irreproducible
(28) For discussions on the role of TMSCl in accelerating cuprate
conjugate addition reactions see: (a) Frantz, D. E.; Singleton, D. A. J .
Am. Chem. Soc. 2000, 122, 3288 and references therein. (b) Bertz, S.
H.; Miao, G.; Rossiter, B. E.; Snyder, J . P. J . Am. Chem. Soc. 1995,
117, 11023.
(29) (a) Dieter, R. K.; Topping, C., unpublished results. (b) Dieter,
R. K.; Li, S. J . Org. Chem. 1997, 62, 7726. (c) Chlorotrimethylsilane
quenching of N-Boc R-lithiopyrrolidine after aging at a given temper-
ature for 30 min gave N-Boc 2-trimethylsilylpyrrolidine [-78 °C (94%),
-50 °C (71%), 0 °C (1-2%)]. Li, S. M.S. Thesis, Clemson University,
Clemson, SC, 1996.
(32) Dieter, R. K.; Dieter, J . W.; Alexander, C. W.; Bhinderwala, N.
S. J . Am. Chem. Soc. 1996, 61, 2930.
(33) Hallnemo, G.; Ullenius, C. Tetrahedron Lett. 1986, 27, 395.
(34) AM1 calculations obtained from the MacSpartan program
(Wavefunction, Inc., 18401 Von Karman Ave., #370, Irvine, CA 92715)
gave the following relative ordering of LUMO energies: thiol esters <
esters < imides. The calculated magnitude of the LUMO energies
displayed no clear correlation with the observed chemical yields.
(35) (a) J anssen, M. J . In The Chemistry of Carboxylic Acids and
Esters; Patai, S., Ed.; Wiley: Hungary, 1969; Chapter 15, p 705. (b)
For CdO bond strengths in RCOX as a function of the electronegativity
of X see: Wiberg, K. B. J . Chem. Educ. 1996, 73, 1089 and references
therein.
(30) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J . J . Am. Chem. Soc. 1994,
116, 3231.
(31) For the importance of lithium ion carbonyl oxygen coordination
in cuprate conjugate addition reactions see: (a) Ouannes, C.; Dressaire,
G.; Langlois, Y. Tetrahedron Lett. 1977, 815. (b) House, H. O.; Wilkins,
J . M. J . Org. Chem. 1978, 43, 2443. (c) Krauss, S. R.; Smith, S. G. J .
Am. Chem. Soc. 1981, 103, 141. (d) Vellekoop, A. S.; Smith, R. A. J . J .
Am. Chem. Soc. 1994, 116, 2902. For a review see: (e) Smith, R. A. J .;
Vellekoop, A. S. Advances in Detailed Reaction Mechanisms; Coxon,
J . M., Ed.; J AI Press: Grenwich, CT, 1994; Vol. 3, p 79.

Addition Reactions of R-Aminoalkylcuprates
J . Org. Chem., Vol. 65, No. 25, 2000 8721
Sch em e 5
tion. Simple lithium dialkylcuprates add stereoselectively
syn to alkynoates in THF and the cyano cuprates,
RCuCNLi, also display a greater degree of syn selectivity
than the corresponding Gilman reagents.37 Although the
RCuCNLi (R ) R-aminoalkyl ligand) reagent was used
in THF, the reaction conditions employed for the conju-
gate addition of these reagents to alkynyl esters used
excess lithium chloride (i.e., from CuCN‚2LiCl) which
should favor isomerization of the initially formed Z
alkenylcuprate (i.e., syn addition) while use of TMSCl
should lead to formation of the O-silyl ketene acetal.
Protonation of the latter intermediate upon quenching
will occur in a nonstereoselective manner affording a
mixture of E and Z olefinic diastereomers.37
The allenyl esters gave better yields with the R2CuLi‚
LiCN reagent than with the RCuCNLi, although the
differences were small. While good yields of conjugate
adducts are obtained with allenyl esters containing a
single γ-substituent, the yields diminished for a γ,γ-
disubstituted derivative 36 with the cuprate derived from
1a but remained high for the cuprate derived from the
pyrrolidinyl cuprate 2a . These results reflect a sensitivity
to steric factors in these conjugate addition reactions as
well as the importance of cuprate reactivity. This steric
effect is also seen in the diastereoselectivity of the
reaction. Preferential approach of the cuprate reagent
away from the γ-substituent affords the E diastereomer
with a selectivity generally greater than 90:10 (Scheme
4). The origin of the modest yields obtained with allenyl
ester 34 containing a single γ-phenyl substituent is
unclear, since steric effects should not play a significant
role if the cuprates approach from the side opposite the
phenyl substituent and electronically the phenyl ring is
not in conjugation with the double bond undergoing
attack by the cuprate reagent.
A brief examination of R,â-γ,δ-dienoates reveal that
these substrates afford products arising from 1,6-
conjugate addition. This reflects the inherent tendency
of carbonyl conjugated diene systems.39 Initial cuprate
attack occurs at the C2-C3 double bond to afford a âC-
Cu adduct, which can either undergo reductive elimina-
tion to give the 1,4-addition product or allylic rearrange-
ment and subsequent reductive elimination to give the
1,6-addition product. For most R,â-γ,δ-dienones and
dienoates allylic rearrangement is faster than reductive
elimination and the 1,6-addition product predominates.
This is consistent with the emerging view that the
reductive elimination step in conjugate addition reactions
is the rate determining step.40 Efforts to direct the
reaction toward 1,4-conjugate addition by use of a thiol
ester which could potentially retard allylic rearrange-
ment via intramolecular chelation proved unsuccessful.
would not explain the diminished reactivity of the R,â-
unsaturated nitriles which give poor yields when carrying
a â-alkyl substituent. Silylation of the nitrile enolate on
carbon reflects the relative weakness of the N-Si bond
strength in comparison to the O-Si bond strength. The
absence of a silylated product in the piperidine reaction
(Table 1, entry 25) may reflect steric hindrance to
C-silylation and hydrolysis of the resultant N-silyl keten-
imine during the workup procedure.
The R,â-ynoates gave slightly higher yields of conjugate
adducts with the RCuCNLi reagent than with the R2-
CuLi‚LiCN reagent, in contrast to the R-alkoxyalkyl-
cuprates.36 Currently, these additions are viewed as
involving a carbocupration reaction affording an R-cuprio
ester in equilibrium with an allenyl enolate (Scheme 5).37
It is this temperature and lithium salt (i.e., LiX) depend-
ent isomerization that accounts for the E:Z mixture of
diastereomers obtained in the reactions of cuprates with
R,â-ynoates. The initial syn carbocupration affords the
Z R-cuprio ester and quenching of this intermediate at
low temperature stereoselectively affords the E diaste-
reomer in the reactions of simple lithium dialkylcuprates
with ynoates.37 Upon warming, the Z R-cuprio ester
isomerizes to the E R-cuprio ester via an intermediate
allenyl enolate. Protonation of the E R-cuprio ester
stereoselectively affords the Z enoate diastereomer and
the ratio of E:Z diastereomers reflects the equilibrium
E:Z mixture of alkenyl cuprate intermediates (i.e., R-cup-
rio esters). Trapping of these alkenylcuprates with tri-
methylsilylchoride affords ketene acetals arising from
O-silylation of the allenolate. Formation of this product
reflects the HSAB principle37c or the outcome of a charge
controlled reaction38 rather than the equilibrium mixture
of alkenylcuprates and allenolate intermediates in solu-
Su m m a r y
In summary, reaction conditions have been developed
for the conjugate addition of R-nitrogen heteroatom
functionalized cuprate reagents with the less reactive
carboxylic acid derivatives. The conjugate addition reac-
tions of R-aminoalkylcuprates to R,â-unsaturated car-
boxylic acid derivatives proceeds uneventfully when
CuCN‚2LiCl is used, although higher yields might be
(36) For a comparison of R-alkoxyalkylcopper and cuprate reagents
in conjugate additions to ethyl propiolate see: Linderman, R. J .;
Griedel, B. D. J . Org. Chem. 1991, 56, 5491.
(37) (a) Nilsson, K.; Ullenius, C.; Krause, N. J . Am. Chem. Soc. 1996,
118, 4194. (b) Nilsson, K.; Andersson, T.; Ullenius, C. J . Organomet.
Chem. 1997, 591. (c) Nilsson, K.; Andersson, T.; Ullenius, C.; Gerold,
A.; Krause, N. Chem. Eur. J . 1998, 4, 2051. (d) Nakamura, E.; Mori,
S.; Nakamura, M.; Morokuma, K. J . Am. Chem. Soc. 1997, 119, 4887.
(38) Fleming, I. Frontier Orbitals and Organic Reactions; J ohn Wiley
& Sons: England, 1976; pp 27-32 and 43-47.
(39) Uerdingen, M.; Krause, N. Tetrahedron 2000, 56, 2799.
(40) (a) Frantz, D.; Singleton, D. A.; Snyder, J . P. J . Am. Chem. Soc.
1997, 119, 3383. (b) Nakamura, E.; Mori, S.; Morokuma, K. J . Am.
Chem. Soc. 1997, 119, 4900.

8722 J . Org. Chem., Vol. 65, No. 25, 2000
Dieter et al.
(cannula) under a positive argon pressure maintained by
double layered balloons filled with argon.
achieved with solid CuCN under more stringently con-
trolled reaction conditions. Yields of conjugate adducts
from R-aminoalkylcuprates and conjugated alkenes can
be improved by utilization of unsaturated thiol esters.
These R-aminoalkylcuprates also undergo conjugate ad-
ditions to R,â-alkynyl and allenyl derivatives, with the
latter reaction being highly stereoselective. The alkynyl
substrates may actually involve a carbocupration rather
than a conjugate addition reaction. Although the current
reaction conditions do not afford high stereoselectivities
with the R,â-alkynyl substrates, the evidence for a
carbocupration pathway encourages a continued search
for more effective cuprate reagents and reaction condi-
tions for stereocontrol of the addition event and subse-
quent protonation. The method currently fails with
lactones and is limited to derivatives lacking an R-alkyl
substituent. These conjugate addition reactions of R-ami-
noalkylcuprates provide flexible routes for the prepara-
tion of various N-heterocycles and these applications are
currently under investigation.
P r ep a r a tion of r,â-Yn oa tes 15-17. n-BuLi in hexane (1.6
N, 6.5 mL) was added dropwise via syringe to a solution of
the 1-alkyne (10 mmol) in 30 mL of Et2O at -30 °C. The
reaction mixture was stirred at -30 °C for 30 min, whereupon
a solution of methyl chloroformate (10 mmol) in 5 mL of ether
was added dropwise via syringe. As the addition proceeded a
white solid was formed. The reaction mixture was stirred at
-30 °C for 20 min, warmed to room temperature, filtered, and
concentrated in vacuo to afford crude alkynyl ester. Kugelrohr
distillation gave the pure alkynyl esters in 79-97% yield.
P r ep a r a tion of r,â-Alk yn yl Su lfoxid e 21 a n d Su lfon e
22. n-BuLi in cyclohexane (1.6 N, 5.0 mL, 0.8 equiv) was added
dropwise via syringe to a solution of the 1-alkyne (10 mmol)
in 25 mL of Et2O at -30 °C. The reaction mixture was stirred
at -30 °C for 30 min, whereupon a solution of diphenyl
disulfide (10 mmol) in 5 mL of THF was added dropwise via
syringe. The reaction mixture was stirred at -30 °C for 30
min and then warmed to room temperature. The organic phase
was washed with water (3 × 5 mL), dried over MgSO4, filtered,
and concentrated in vacuo to afford crude alkynyl sulfide (95-
100%), which was used without further purification.
The crude alkynyl sulfide was oxidized to the sulfoxide 21
or sulfone 22 according to an established procedure.43
P r ep a r a tion of S-P r op yl 2,4-h exa d ien oa te. Thionyl
chloride (10 mL) was added dropwise to sorbic acid (10 g) in
50 mL of ether at room temperature whereupon the mixture
was stirred for 5 min and then heated to reflux for 60 min.
Concentration in vacuo and Kugelrohr distillation gave the
acid chloride (10.5 g, 90%).
Propanethiol (2.0 mmol) was added dropwise via syringe to
a suspension of NaH (3.0 mmol) in ether (10 mL) cooled to 0
°C and stirred at this temperature for 20 min. A solution of
2,4-hexadienoyl chloride (2 mmol in 5 mL of Et2O) was added
dropwise via syringe and the reaction mixture was then
allowed to warm to room temperature over a 1 h period. The
solution was quenched and washed with H2O, dried over
MgSO4, and concentrated in vacuo to afford pure thiol ester
upon Kugelrohr distillation (0.28 g, 82%).
Gen er a l P r oced u r e A for Cu p r a tes P r ep a r ed fr om
2RLi + Cu CN‚2LiCl. A solution of N-Boc protected amine (1
mmol) and (-)-sparteine (1 mmol) in THF (4 mL) under an
Ar or N2 atmosphere was cooled to -78 °C. s-BuLi (in
cyclohexane, 1 mmol) was added and this mixture was stirred
at -78 °C for 1 h. A solution of the complex, CuCN‚2LiCl, in
THF (prepared by dissolving 0.5 mmol of CuCN and 1 mmol
of LiCl in 3 mL THF) was added via syringe to the 2-lithio-
N-Boc carbamate and the solution was warmed from -78 to
-55 °C over a period of 45 min to generate the cuprate reagent.
A solution of the electrophile (0.5 mmol) and TMSCl (2.5 mmol)
in THF (1 mL) was added to the cuprate reagent and the
reaction mixture was stirred at -55 °C for 0.5 h and at room
temperature for 1.5 h. The reaction mixture was quenched
with saturated NH4Cl (5 mL), filtered through Celite, extracted
with ether (3 × 10 mL), and washed with saturated NH4Cl (2
× 10 mL) and brine (10 mL). The extract was dried (MgSO4),
filtered, and concentrated in vacuo to afford the crude product,
which was purified by radial chromatography [silica gel, ether/
petroleum ether, 10:90 to 50:50, v/v] to afford the pure product.
Gen er a l P r oced u r e B for Cu p r a tes P r ep a r ed fr om RLi
+ Cu CN‚2LiCl. The procedure was identical to that described
in General Procedure A, except that 1 equiv of RLi was used
per equiv of CuCN‚2LiCl.
Exp er im en ta l Section
Ma ter ia ls. Tetrahydrofuran (THF) and diethyl ether (Et2O)
were distilled from sodium benzophenone ketyl. Dichloro-
methane (CH2Cl2), N,N,N′,N′-tetramethylethylenediamine
(TMEDA) and chlorotrimethylsilane were distilled from CaH2
under a N2 atmosphere. BF3‚Et2O was purified by distillation.
(-)-Sparteine was distilled via Kugelrohr distillation at 150
°C, 0.05 mmHg. CuCN, and CuCl were used without further
purification. s-BuLi (1.5 M in pentane) was purchased from
FMC Corp. and titrated using s-BuOH and 1,10-phenanthro-
line monohydrate in THF.
The R,â-unsaturated esters were either commerically avail-
able or readily prepared via esterification of the commercially
available carboxylic acids. Acrylonitrile and crotononitrile were
commercially available. Alkynyl nitriles41 19 and 20 and
allenyl esters42 33-36 were prepared by established literature
procedures. Ethyl sorbate and sorbic acid were commerically
available and the thiol ester was prepared from the acid
chloride as described below. The alkynyl sufoxide 21 and
sulfone 22 were prepared by oxone oxidation43 of the corre-
sponding sulfide, which in turn was prepared by quenching
the lithium acetylide with diphenyl disulfide as described
below.
All round-bottom flasks used for the preparation of the
organocopper and cuprate reagents were first cleaned with
48% hydrobromic acid, followed by placement into a potassium
hydroxide/isopropyl alcohol bath, rinsed with 10% hydrochloric
acid and copious amounts of water, followed by rinsing with
acetone, and then oven dried (100 °C). All glassware was
flamed-dried under house vacuum pressure, purged with
argon, and then cooled under a dry nitrogen atmosphere. The
LiCl was first dried under high vacuum (0.005 mmHg) with
heat (100-110 °C) and stirring for 3 h. Then after it was
weighed into a flame-dried flask, it was flamed-dried under
vacuum (0.05 mmHg), purged with argon, and then cooled
under a dry nitrogen atmosphere.
All copper reactions were conducted under a positive, dry
nitrogen atmosphere in anhydrous solvents in flasks fitted
with rubber septa. The nitrogen gas was passed through
concentrated sulfuric acid, potassium hydroxide, and indicat-
ing and nonindicating drierite before being introduced into the
reaction flask. Low-temperature baths (-78 °C or warmer)
were prepared using shallow thermoflasks with a Neslab CC-
60 II cyrocool machine or dry ice/2-propanol slush bath
mixtures. Flask to flask transfer of air- and moisture-sensitive
intermediates was completed using double-tipped needles
Gen er a l P r oced u r e C for Cu p r a tes P r ep a r ed fr om RLi
+ Cu Cl‚2LiCl (Alk yl Cop p er ). The procedure was identical
to that describe in General Procedure A, except that CuCl‚
2LiCl was used in place of CuCN‚2LiCl. The CuCl‚2LiCl
solution in THF was prepared and transferred in the same
manner as CuCN‚2LiCl.
Meth yl 1-[(1,1-Dim eth yleth oxy)car bon yl]-2-piper idin e-
p r op a n oa te (6b). General Procedure B was employed (1
mmol). Purification by flash colunm chromatography gave 6b
as a colorless oil (192 mg, 71%): IR (neat) 1742 (s), 1695 (s)
(41) Murray, R. E.; Zweifel, G. Synthesis 1980, 150.
(42) Lang, R. W.; Hansen, H.-J Org. Synth. 1984, 62, 202.
(43) Trost, B. M.; Curran, D. P. Tetrahedron Lett. 1981, 22, 1287.
1
cm-1; H NMR δ 1.42 (s, 9H), 1.20-1.75 (m, 7H), 1.95-2.20

Addition Reactions of R-Aminoalkylcuprates
J . Org. Chem., Vol. 65, No. 25, 2000 8723
(m, 1H), 2.20-2.35 (m, 2H), 2.72 (app. t, J ) 12.9 Hz, 1H),
3.64 (s, 3H), 3.85-4.05 (br m, 1H), 4.15-4.35 (br s, 1H); 13C
NMR δ 19.0, 25.0, 25.5, 28.4, 28.8, 30.9, 38.6, 49.9, 51.5, 79.2,
155.0, 173.9; MS m/z (relative intensity) EI 271 (M+, 02), 215
(M+ - C4H8, 06), 198 (M+ - C4H8 - OH, 07), 184 (M+- CH2-
chromatography gave 23 as a colorless oil (199 mg, 70%) as a
66:34 E:Z mixture of stereoisomers: IR (neat) 1726 (s), 1702
(s) cm-1 1H NMR δ 0.85-0.95 (m, 3H), 1.25-1.45 (m, 4H),
;
1.43 (s, 9H), 2.09 [2.51] (t, J ) 7.5 Hz, 2H), 2.76 (2.74, rotomer)
[2.84] (s, 3H), 3.69 (s, 3H), [3.90] 4.54 (4.55, rotomer) (s, 2H),
[5.60] 5.78 (s, 1H) [E diastereomer]; 13C NMR δ 13.8, 22.5, 28.3,
29.9 (30.5), 33.7, 34.1, 47.4 (46.2), 51.0, 79.1, (113.3) 117.6,
156.0, 160.1, 166.6 (E isomer); MS m/z (relative intensity) EI
229 (M+ - C4H8, 03), 226 (M+ - CO2Me, 02), 212 (M+ - C4H9O,
09), 185 (229 - CO2, 51).
CH2CO2Me, 07), 170 (M+ - C4H9CO2, 28), 128 (M+- C4H8
-
CH2CH2CO2Me, 100), 57 (C4H9, 45). Anal. Calcd for C14H25
-
NO4: C, 61.97; H, 9.40; N, 5.16. Found: C, 61.92; H, 9.40; N,
5.23.
S-Bu tyl 1-[(1,1-Dim eth yleth oxy)ca r bon yl]-â-m eth yl-2-
p yr r olid in ep r op a n eth iola te (7b). 1H NMR (CDCl3) δ 0.75-
0.89 (m, 6H), 1.16-1.34 (m, 2H), 1.40 (s, 9H), 1.43-1.52, (m,
2H), 1.52-1.88 (m, 4H), 2.00-2.26 (m, 1H), 2.26-2.42 (m, 1H),
2.42-2.67 (m, 1H), 2.78 (t, 2H, J ) 7.1 Hz), 3.04-3.22 (m, 1H),
3.21-3.56 (m, 1H), 3.56-3.74 (m, 1H); 13C NMR (CDCl3) δ
13.3, 16.2, 21.7, 23.4, 27.0, 28.3, 29.5, 31.4, 33.7 (33.9), 46.5
Met h yl
3-[[[(1,1-Dim et h ylet h oxy)ca r b on yl]m et h yl-
a m in o]m eth yl]-6-ch lor o-2-h exen oa te (25). General Proce-
dure B was employed (1 mmol). Purification by flash column
chromatography gave 25 as a colorless oil (248 mg, 81%)
existing as a 57:43 E:Z mixture of diastereomers: IR (neat)
1
1725 (s), 1702 (s) cm-1; H NMR δ [1.41] 1.43 (s, 9H), 1.85-
(47.0), 48.3, 61.1, 79.2, 154.8, 198.6. Anal. Calcd for C17H31
-
2.05 (m, 2H) [2.20-2.30 (m, 2H)], 2.61 (t, J ) 7.8 Hz, 2H),
[2.75 (2.73 rotomer)] 2.81 (2.77, rotomer) (s, 3H), [3.49] 3.54
(t, J ) 6.6 Hz, 2H), 3.66 (s, 3H), 3.80 (3.90, rotomer) [4.52] (s,
2H), 5.63 [5.82] (s, 1H) [Z isomer]; 13C NMR δ 28.3, 30.3, 31.3,
34.3, 44.7, 51.1, 55.2, 80.0, 116.0, 118.5, 157.3, 162.2; MS m/z
(relative intensity) EI 249 (M+ - C4H8, 02), 205 (249 - CO2,
67), 57 (100, C4H9). Anal. Calcd for C14H24ClNO4: C, 59.11;
H, 9.92; N, 9.85. Found: C, 59.87; H, 7.78; N, 4.57.
NO3S: C, 62.0; H, 9.5; N, 4.3. Found: C, 61.89; H, 9.48; N,
4.22.
Meth yl 1-[(1,1-Dim eth yleth oxy)ca r bon yl]-â-m eth yl-2-
p ip er id in ep r op a n oa te (8). Employing General Procedure A,
8 was obtained as a 68:32 mixture of diastereomers (45%): IR
1
(neat) 1742 (s), 1692 (s) cm-1; H NMR δ 0.94 [0.86] (d, J )
6.6 Hz, 3H), 1.43 (s, 9H), 1.20-1.80 (m, 6H), 1.90-2.15 (m,
1H), 2.30-2.55 (m, 2H), 2.55-2.80 (m, 1H), 3.64 [3.67] (s, 3H),
3.70-4.10 (br m, 2H) [minor diastereomer]; 13C NMR δ 16.5,
17.5, 18.9 (19.1), 25.4, 25.9, 28.4, 28.8, 38.4, 39.1, 51.4, 79.3,
155.0, (173.0) 174.5 (minor diastereomer); MS m/z (relative
Diet h yl 2-[[[(1,1-Dim et h ylet h oxy)ca r b on yl]m et h yl-
a m in o]m eth yl]-1,4-d ibu ten oic Acid (26). General Proce-
dure B was employed (1 mmol). Purification by flash column
chromatography gave 24 as a colorless oil (201 mg, 64%)
existing as a 65:35 mixture of E:Z diatereomers: IR (neat)
intensity) EI 285 (M+, 01), 229 (M+ - C4H9, 01), 184 (M+
-
C4H9 - CO2, 16), 128 (M+- CHMeCH2CO2Me, 08), 57 (C4H9,
29).
1
1727 (s), 1702 (s) cm-1; H NMR δ 1.29 (t, J ) 7.2 Hz, 6H),
1.43 (s, 9H), [2.85] 2.86 (br s, 3H), 4.10-4.35 (m, 4H), 4.56 (s,
2H), 6.66 [6.76] (br s, 1H) [Z isomer]; 13C NMR δ 14.0, 14.1,
28.2, (33.5) 35.0, (43.3) 45.2, 60.9, 61.5, 79.7, 127.3 (129.0),
145.0, 155.2, 166.2 (165.3) (rotomer or diastereomer); MS m/z
(relative intensity) EI 315 (M+, 01), 259 (M+ - C4H8, 13), 214
(M+ - C4H9CO2, 68), 57 (C4H9, 87).
4-[[(1,1-Dim e t h yle t h oxy)ca r b on yl]m e t h yla m in o]-3-
m eth yl-2-(tr im eth ylsilyl)bu ta n en itr ile (12b). General Pro-
cedure B was employed (1 mmol). Purification by chromatog-
raphy gave 12b as a colorless oil (108 mg, 38%) present as a
85:15 mixture of diastereomers: IR (neat) 2225 (m), 1702 (s)
cm-1; 1H NMR δ 0.19 [0.23] (s, 9H), 1.01 [1.03] (d, J ) 6.9 Hz,
3H), 1.44 (s, 9H), 1.85-1.95 (br s, 1H), 1.95-2.25 (m, 1H), 2.86
[2.85] (s, 3H), 2.95-3.15 (br s, 1H), 3.15-3.39 (br s, 1H)
[diastereomer]; 13C NMR δ -2.2 [-1.78], 15.6, 22.0, 28.3, 30.3,
35.1, 55.4, 79.9, 120.5, 155.8 [diastereomer]; MS m/z (relative
intensity) EI 284 (M+, 02), 228 (M+ - C4H8), 211 (M+ - Si-
(CH3)3, 08), 184 (228 - CO2, 14). Anal. Calcd for C14H28N2O2-
Si: C, 67.22; H, 9.80; N, 4.13. Found: C, 66.92; H, 9.72: N,
4.25.
2-[[[(1,1-Dim e t h yle t h oxy)ca r b on yl]m e t h yla m in o]-
m eth yl]-1-h exen ylsu lfin ylben zen e (29a ). General Proce-
dure B was employed (1 mmol). Purification by flash column
chromatography gave 29a as a colorless oil (245 mg, 70%)
existing as a 47:53 E:Z mixture of diastereomers: IR (neat)
3085 (w), 1702 (s), 1387 (s) cm-1 1H NMR δ 0.80-0.95 (m,
;
3H), 1.26 [1.39] (s, 9H), 1.20-1.50 (m, 4H), 2.40-2.60 (m, 2H),
2.77 (s, 3H), 3.80 [3.87] (s, 2H), 6.02 [6.07] (s, 1H), 7.40-7.95
(m, 5H) [Z isomer]; 13C NMR δ 13.7, 22.8, 28.0, 28.9, 30.6
(30.3), 34.6, 54.3, 80.1, 124.5, 124.8, 127.0, 129.1, 133.1, 142.2,
156.2 (156.9) [155.0 (155.5)] (rotomer) [E isomer]; MS m/z
(relative intensity) EI 294 (M+ - 57, 03), 77 (C6H5, 11).
1,1-[(Dim eth yleth oxy)car bon yl]-2-piper idin epr opan en -
itr ile (13). General Procedure B was employed (1 mmol).
Purification by chromatography gave 13 as a colorless oil (129
1
mg, 54%): IR (neat) 2260 (w), 1693 (s) cm-1; H NMR δ 1.40
Eth yl 3-[(1,1-Dim eth yleth oxy)car bon yl]-2-piper idin yl]-
2-h ep ten oa te (30b). General Procedure B was employed (1
mmol). Purification by flash column chromatography gave 30b
as a colorless oil (250 mg, 74%) existing as a single diastere-
(s, 9H), 1.30-1.75 (m, 7H), 2.09-2.20 (m, 1H), 2.29 (t, J ) 7.2
Hz, 2H), 2.67 (app. t, J ) 12.3 Hz, 1H), 3.90-4.15 (br m, 1H),
4.25-4.45 (m, 1H); 13C NMR δ 14.3, 19.0, 25.3, 26.1, 28.3, 28.6,
38.7, 49.5, 79.9, 119.6, 155.0; MS m/z (relative intensity) EI
238 (M+, 02), 184 (M+ - CH2CH2CN, 20), 137 (M+ - C4H9-
CO2, 41), 128 (M+ - C4H8 - CH2CH2CN, 88), 57 (C4H9, 100).
1,1-[(Dim et h ylet h oxy)ca r b on yl]-r-(t r im et h ylsilyl)-2-
p yr r olid in ep r op a n en itr ile (14a ). General Procedure A was
employed (0.5 mmol). Purification by chromatography gave
14a as a colorless oil (115 mg, 78%) existing as a separable
mixture of diastereomers. Diastereomer 1 (57 mg): IR (neat)
1
omer: IR (neat) 1712 (s), 1702 (s) cm-1; H NMR δ 0.90 (t, J
) 7.2 Hz, 3H), 1.25 (t, J ) 7.2 Hz, 3H), 1.36 (s, 9H), 1.20-
1.90 (m, 10H), 2.05-2.15 (m, 2H), 3.00-3.15 (m, 1H), 3.90-
4.02 (m, 1H), 4.12 (q, J ) 6.6 Hz, 2H), 5.58 (s, 1H), 5.52-5.62
(m, 1H); 13C NMR δ 13.9, 14.3, 19.2, 22.7, 22.8, 27.7, 28.2, 29.9,
31.9, 39.8, 54.0, 59.5, 79.2, 113.7, 155.8, 166.0, 167.0; MS m/z
(relative intensity) EI 282 (M+ - C4H9, 17), 238 (282 - CO2,
32), 57 (C4H9, 100). Anal. Calcd for C19H33NO4: C, 67.22; H,
9.80; N, 4.13. Found: C, 66.96; H, 9.88; N, 4.11.
1
2215 (m), 1702 (s) cm-1; H NMR δ 0.15 (s, 9H), 1.42 (s, 9H),
1.40-1.70 (br m, 1H), 1.70-1.95 (m, 5H), 1.95-2.05 (m, 1H),
3.25-3.40 (br m, 2H), 3.70-3.90 (m, 1H); 13C NMR δ -3.39,
16.4, 22.9, 28.5, 31.2, 32.0, 45.8, 58.4, 79.0, 122.5, 154.5; MS
m/z (relative intensity) EI 296 (M+, 02), 223 (M+ - SiMe3, 09).
(E)-E t h yl 3-(2-p yr r olid in yl)-2-h ep t en oa t e: 1H NMR
(CDCl3) δ 0.92 (t, 3H, J ) 7.2 Hz), 1.28 (t, 3H, J ) 7.2 Hz),
1.33-1.56 (m, 5H), 1.63-1.91 (m, 3H), 1.91-2.14 (m, 1H),
2.14-2.36 (m, 1H), 2.76-2.90 (m, 1H), 2.90-3.02 (m, 1H),
3.02-3.17 (m, 1H), 3.56-3.78 (m, 1H), 4.11 (q, 2H, J ) 7.2
Hz), 5.96 (s, 1H); 13C NMR (CDCl3) δ 13.8, 14.2, 23.2, 25.3,
30.8, 31.5, 40.7, 46.0, 59.4, 63.7, 113.2, 166.1, 166.9.
1-Bu t yl-5,6,7,7a -t et r a h yd r o-3H -p yr r olizin -3-on e: 1H
NMR (CDCl3) δ 0.93 (t, 3H, J ) 7.2 Hz), 1.08-1.30 (m, H),
1.30-1.46 (m, 2H), 1.46-1.62 (m, 2H), 1.98-2.13 (m, 1H),
2.13-2.24 (m, 1H), 2.24-2.41 (m, 3H), 3.17-3.31 (m, 1H),
3.38-3.52 (m, 1H), 4.05-4.17 (m, 1H), 5.68 (s, 1H); 13C NMR
(CDCl3) δ 13.7, 22.4, 28.9, 29.2, 29.3, 29.5, 42.1, 69.0, 121.7,
Diastereomer 2 (58 mg): IR (neat) 2230 (m), 1702 (s) cm-1
;
1H NMR δ 0.18 (s, 9H), 1.20-1.35 (m, 1H), 1.46 (s, 9H), 1.55-
2.15 (m, 6H), 3.20-3.50 (m, 2H), 3.80-4.10 (m, 1H); 13C NMR
δ -3.4, 15.6, 23.0, 28.5, 29.8, 30.6, 46.3, 56.6, 79.6, 121.5, 154.4;
MS m/z (relative intensity) EI (M+ - Si(CH3)3, 09). Anal. Calcd
for C15H28N2O2Si: C, 60.77; H, 9.52; N, 9.45. Found: C, 60.71;
H, 9.59; N, 9.44.
Met h yl
3-[[(1,1-Dim et h ylet h oxy)ca r b on yl]m et h yl-
a m in om eth yl]-2-h ep ten oa te (23b, R1 ) Me). General Pro-
cedure B was employed (1 mmol). Purification by flash column

8724 J . Org. Chem., Vol. 65, No. 25, 2000
Dieter et al.
166.5, 176.7; MS m/z (relative intensity) EI 179 (M+, 39), 136
(100), 122 (19), 109 (39), 94 (39), 67 (20.7), 53 (26).
2H), 5.21 (d, J ) 9.6 Hz, 1H); 13C NMR δ 14.1, 22.7, 27.4, 28.3,
33.1, 33.8 (br), 54.9 (br), 60.5, 79.3, 125.5, 138.8, 155.8, 171.1;
MS m/z (relative intensity) EI 299 (M+, 01), 243 (02, M+
-
Met h yl 3-[[(1,1-Dim et h ylet h oxy)ca r b on yl]-2-p yr r oli-
d in yl]-6-ch lor o-2-h exen oa te 31a . General Procedure B was
employed (1 mmol). Purification by flash column chromatog-
raphy gave a colorless oil (251 mg, 70%) existing as a 35:65
mixture of the E and Z isomers, which could be separated and
C4H8), 226 (05, M+ - CO2Et), 199 (08, 243 - CO2), 156 (100,
199 - C3H7), 57 (33, C4H9). Anal. Calcd for C16H29NO4: C,
64.19; H, 9.76; N, 4.68. Found: C, 64.38; H, 9.66; N, 4.62.
Eth yl 1-[(1,1-Dim eth yleth oxy)ca r bon yl]-â-eth ylid en e-
2-p yr r olid in ep r op a n oa te (41a ). General Procedure A was
employed (0.5 mmol). Purification by flash column chroma-
tography gave 41a as a colorless oil (126 mg, 85%): IR (neat)
isolated. E isomer: IR (neat) 1725 (s), 1702 (s), 1659 (s) cm-1
;
1H NMR δ 1.38 (1.44) (s, 9H), 1.15-1.85 (m, 3H), 1.85-2.35
(m, 4H), 2.90-3.20 (m, 1H), 3.25-3.55 (m, 2H), 3.50-3.65 (m,
2H) 3.67 (s, 3H), 4.20-4.45 (m, 1H), 5.65 (s, 1H) (rotomer);
13C NMR δ 23.3, 28.0, 28.4, 31.4, 31.8, 45.0, 46.9, 51.0, 62.1,
79.9, 113.5, 154.1, 162.7, 166.7; MS m/z (relative intensity) EI
331 (M+, 01), 275 (M+ - C4H8, 06), 231 (275 - CO2, 24), 57
1
1739 (s), 1700 (s) cm-1; H NMR δ 1.23 (t, J ) 7.2 Hz, 3H),
1.40 (s, 9H), 1.63 (d, J ) 6.9 Hz, 3H), 1.70-2.05 (m, 4H), 2.94
(v br s, 2H), 3.05-3.45 (m, 2H), 4.10 (q, J ) 7.2 Hz, 2 H), 4.20-
4.40 (br s, 1H), 5.38 (q, J ) 6.9 Hz,1H); 13C NMR δ 13.5, 14.1,
22.8 (br), 28.4, 31.2 (br), 33.9, 46.7 (br), 60.5, 62.7, 79.0, 122.4,
133.2, 154.5, 171.4; MS m/z (relative intensity) EI 297 (M+,
02), 240 (M+ - C4H9, 06), 224 (10), 196 (240 - CO2, 39), 57
(C4H9, 43). Anal. Calcd for C16H27NO4: C, 64.62; H, 9.15; N,
4.71. Found: C, 64.51; H, 9.30; N, 4.84.
1
(C4H9, 88). Z isomer: IR 1720 (s), 1692 (s), 1460 (s) cm-1; H
NMR δ 1.35 (1.42) (s, 9H), 1.45-1.65 (m, 1H), 1.65-2.05 (m,
4H), 2.05-2.50 (m, 3H), 3.20-3.40 (m, 1H), 3.54 (t, J ) 6.3
Hz, 2H), 3.67 [3.65] (s, 3H), 3.50-3.80 (m, 1H), 5.54 (t, J )
7.8 Hz, 1H), 5.64 (s, 1H); 13C NMR δ 24.3 (24.7), 28.2, 28.4,
(30.4) 30.7, 32.4, 44.2 (44.3), 47.6 (47.8), 51.0, 58.1 (58.3), 79.6,
114.5 (117.7), 154.6, 163.9, 166.3 (rotomer); MS m/z (relative
intensity) EI 331 (M+, 01), 274 (M+ - C4H9, 05), 230 (274 -
CO2, 83).
1-(3-Ch lor op r op yl)-5,6,7,7a -tetr a h yd r o-3H-p yr r olizin -
3-on e. To a CH2Cl2 solution of 31b (Z isomer) were added
PhOH (10 equiv) and TMSCl (3.0 equiv) and the mixture was
stirred at room temperature for 30 min. The reaction mixtue
was diluted with 40 mL of ether, washed with 10% aqueous
sodium hydroxide (3 × 10 mL) and brine, dried over MgSO4,
and concentrated in vacuo to give crude product. Purification
by column chromatography (silica gel, ether/petroleum ether,
1:1 v/v) gave pure material: 1H NMR δ 1.90-2.35 (m, 6H),
2.40-2.55 (m, 2H), 3.20-3.40 (m, 1H), 3.40-3.50 (m, 1 H),
3.55 (t, J ) 7.5 Hz, 2H), 4.05-4.20 (m, 1H), 5.90 (s, 1H); 13C
26.4, 28.6, 29.4, 29.9, 42.1, 43.9, 69.6, 121.9, 165.6, 176.7; MS
m/z (relative intensity) EI 199 (M+, 14), 164 (M+ - Cl, 09),
136 (M+ - CH2CH2Cl, 100), 122 (136 - CH2, 16).
Eth yl 1-[(1,1-Dim eth yleth oxy)ca r bon yl]-â-eth ylid en e-
2-p ip er id in ep r op a n oa te (41b). General Procedure A was
employed (0.5 mmol). Purification by flash column chroma-
tography gave 41b as a colorless oil (135 mg, 87%): IR (neat)
1
1740 (s), 1695 (s) cm-1; H NMR δ 1.24 (t, J ) 7.2 Hz, 3H),
1.44 (s, 9H), 1.35-1.65 (m, 5H), 1.68 (dd, J ) 6.6 Hz, J ) 2.1
Hz, 3H), 1.90-2.05 (m, 1H), 2.65 (dt, J ) 2.4 Hz, J ) 12.8 Hz,
1H), 3.00 (center AB quartet, J AB ) 16.2 Hz, ∆υAB ) 12.8 Hz,
δA ) 2.98, δB ) 3.02, 2H), 3.80-3.95 (m, 1H), 4.10 (q, J ) 7.2
Hz, 2H), 4.71 (br s, 1H), 5.50-5.60 (m, 1H); 13C NMR δ 13.8,
14.2, 19.7, 25.5, 26.0, 28.4, 33.9, 39.9, 54.6, 60.4, 79.2, 124.3,
130.9, 155.3, 171.1; MS m/z (relative intensity) EI 255 (M+
C4H8, 05), 211 (255 - CO2, 19). Anal. Calcd for C17H29NO4: C,
65.57; H, 9.39; N, 4.50. Found: C, 65.46; H, 9.39; N, 4.38.
-
Eth yl 1-[(1,1-Dim eth yleth oxy)ca r bon yl]-â-[(1-m eth yl)-
eth ylid en e]-2-p yr r olid in ep r op a n oa te (44). General Pro-
cedure A was employed (1 mmol). Purification by flash column
chromatography gave 44 as a colorless oil (124 mg, 80%): IR
Gen er a l P r oced u r e D. Con ju ga te Ad d ition of r-Am in o-
a lk ylcu p r a tes to r,â-Allen yl Ester s. To a stirred solution
of the carbamate (1.0 mmol) in THF (3-4 mL) under nitrogen
at room temperature was added TMEDA or sparteine (1.0
mmol). The mixture was cooled to -78 °C and 1.0 mL s-BuLi
(1.1 M in cyclohexane) was added by syringe. The solution was
stirred at -78 °C (1 h) and then warmed to -55 °C, whereupon
a solution of CuCN‚2LiCl (1.0 mmol in 2 mL THF) was added
dropwise and the reaction mixture was stirred for 45 min at
-55 °C. A solution of R,â-allenyl ester (1 mmol) in TMSCl (5.0
mmol, 0.64 mL) was added by syringe, and the reaction
mixture was stirred for an additional 30 min and then warmed
to room temperature over 2 or 3 h. The reaction was quenched
with saturated NH4Cl (3 mL) and extracted with ether. The
extracts were washed with brine, dried over MgSO4, and
concentrated in vacuo. Crude products were purified by
chromatography (silica gel, 10% or 15% ether/petroleum ether).
Eth yl 3-[[[(1,1-Dim eth yleth oxy)car bon yl]m eth ylam in o]-
m eth yl]-3-p en ten oa te (37). General Procedure A was em-
ployed (0.5 mmol). Purification by flash column chromatogra-
phy gave 37 as a colorless oil (111 mg, 82%) existing as a 91:9
1
(neat) 1730 (s), 1697 (s) cm-1; H NMR δ 1.22 (t, J ) 7.2 Hz,
3H), 1.37 (s, 9H), 1.68-1.94 (m, 3H), 1.65 (s, 3H), 1.78 (s, 3H),
1.95-2.15 (m, 1H), 2.83-3.10 (m, 2H), 3.17-3.31 (m, 1H),
3.50-3.70 (br, 1H), 4.08 (q, J ) 6.9 Hz, 2H), 4.50-4.70 (br,
1H); 13C NMR δ 14.2, 20.0, 21.7, 24.0, 28.3, 31.3, 33.1, 48.0,
58.7, 60.3, 78.8, 127.1, 130.0, 154.7, 172.4; MS m/z (relative
intensity) EI 311 (02, M+), 254 (05, M+ - C4H9), 238 (06, M+
- CO2Et), 210 (26, 254 - CO2), 57 (100, C4H9).
Ack n ow led gm en t. This work was generously sup-
ported by the National Science Foundation (CHE-
9408912) and the National Institutes of Health (GM-
60300-01). Support of the NSF Chemical Instrumentation
Program for purchase of a J EOL 500 MHz NMR
instrument is gratefully acknowledged (CHE-9700278).
We thank FMC Corporation Lithium Division for samples
of high quality s-BuLi.
E:Z mixture of diastereomers: IR (neat) 1736 (s), 1702 (s) cm-1
;
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 4, 5b, 5c, 6a , 7a -d , 9, 23a , 30a , (E)-
ethyl 3-(2-pyrrolidinyl)-2-heptenoate, and 1-butyl-5,6,7,7a-
tetrahydro-3H-pyrrolizin-3-one are available in the Supporting
Information for the preliminary communication [Dieter, R. K.;
Velu, S. E. J . Org. Chem. 1997, 62, 3798]. 1H and 13C NMR
spectra for 13, 23b, 26, 27 (trans), 27 (cis), 28, 29a , 30a , 31a
(trans), 31a (cis), 31b (trans), 31b (cis), 32, 38, 40, 42, 44, 45a ,
and 1-(3-chloropropyl)-5,6,7,7a-tetrahydro-3H-pyrrolizin-3-one.
Data reduction (IR, 1H and 13C NMR, mass spectrum) for
compounds 4, 5b, 5c, 6a , 7a , 7c, 7d , 9, 12a , 23a , 24, 27, 28,
30a , 31b, 32, 38, 40, 42, 43a , 43b, 45a , 45b, 46b. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1H NMR δ 1.21 (t, J ) 6.9 Hz, 3H), 1.40 (s, 9H), 1.62 [1.67] (d,
J ) 6.6 Hz, 3H), 2.69 [2.81] (s, 3H), [2.90] 2.98 (s, 2H), 3.79
[3.94] (s, 2H), 4.08 (q, J ) 7.2 Hz, 2H), 5.49 (q, J ) 6.6 Hz,
1H) [Z-isomer]; 13C NMR δ 13.4, 14.1, 28.3, 33.2 (br), 54.4, 54.9,
60.5, 79.3, 125.6, 129.1, 155.6, 170.9; MS m/z (relative inten-
sity) EI 215 (06, M+ - C4H8), 198 (07, M+ - CO2Et), 171 (30,
215 - CO2), 156 (22, 171 - CH3), 57 (100, C4H9). Anal. Calcd
for C14H25NO4: C, 61.97; H, 9.23; N, 5.16. Found: C, 62.19;
H, 9.23; N, 5.10.
Eth yl 3-[[[(1,1-Dim eth yleth oxy)car bon yl]m eth ylam in o]-
m eth yl]-5-m eth yl-3-h exen oa te (39). General Procedure A
was employed (0.5 mmol). Purification by flash column chro-
matography gave 39 as a colorless oil (97 mg, 65%): IR (neat)
1
1736 (s), 1694 (s) cm-1; H NMR δ 0.94 (d, J ) 6.6 Hz, 6H),
1.23 (t, J ) 7.2 Hz, 3H), 1.42 (s, 9H), 2.45-2.60 (m, 1H), 2.72
(br s, 3H), 2.99 (s, 2H), 3.78 (br s, 2H), 4.10 (q, J ) 7.2 Hz,
J O0056038