(α-Aminoalkyl)cuprates Prepared from Soluble Copper(I) Salts: Conjugate Additions to α,βUnsaturated Carboxylic Acid Derivatives

Full text of DOI:10.1021/jo970443u

3
798
J . Org. Chem. 1997, 62, 3798-3799
(
r-Am in oa lk yl)cu p r a tes P r ep a r ed fr om
tions of (R-aminoalkyl)cuprates to a variety of carboxylic
acid derivatives (eq 1).
Solu ble Cop p er (I) Sa lts: Con ju ga te
Ad d ition s to r,â-Un sa tu r a ted Ca r boxylic
Acid Der iva tives
R. Karl Dieter* and Sadanandan E. Velu
Hunter Laboratory, Department of Chemistry,
Clemson University, Clemson, South Carolina 29634-1905
Received March 11, 1997
In initial studies, (R-aminoalkyl)cuprates prepared
from tert-butoxycarbonyl (Boc)-protected pyrrolidine (1)
or N,N-dimethylamine (2) and CuCN in either Et
2
O or
The development of (R-aminoalkyl)cuprate chemistry
has been hampered by the limited reactivity of these
reagents. While they undergo conjugate addition to R,â-
THF failed to undergo conjugate addition to either methyl
acrylate or methyl crotonate. Cuprates prepared from
the Boc carbamate of N-methyl-N-[(tri-n-butylstannyl)-
methyl]amine via transmetallation ((i) n-BuLi, -78 °C,
THF, absence of sparteine; (ii) CuCN) also failed to react
with methyl acrylate.11 Low yields of conjugate adducts
could be obtained with the alkylcopper reagent prepared
1
enones, the reaction could not be extended to R,â-enoates
consistent with cuprate-enoate reactivity profiles. Al-
though numerous homo and mixed organocuprates readily
transfer alkyl ligands to the â-carbon atom of R,â-enones,
the conjugate addition reaction is often sluggish with the
less reactive enoate substrates. Cuprates prepared from
2
3
CuCN (2 RLi + CuCN), cuprous thiophenoxides, and
2 2 2
from CuI in Et O (9%) or CH Cl
(28%).11 Subsequent
experimentation revealed that preparation of the cuprate
4
copper(I) (trimethylsilyl)acetylide 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.4
Gilman reagents also effect high-yield conjugate addition
reactions with mono â-alkyl-substituted enoates, en-
amides, and enecarbamates in ether in the presence of
TMSCl.5 Alkylcopper compounds also participate with
enoates in conjugate addition reactions in synthetically
reagent from 1 or 2 [i. sec-BuLi, (-)-sparteine, THF, -78
°
C, 1 h; (ii) CuCN‚2LiCl, THF, -78 to -55 °C, 45 min]
and LiCl-solubilized CuCN 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 (Table 1,
entries 1 and 2). Utilization of ethyl crotonate resulted
in significantly reduced yields of conjugate adducts
accompanied by recovered carbamates (Table 1, entries
useful yields in the presence of additives such as BF
3
2
‚Et O
and chloro- or iodotrimethylsilane.6
3
(
and 8). Deprotonation of 1, aided by either TMEDA or
-)-sparteine, gave similar results for the subsequent
cuprate conjugate additions to ethyl crotonate (52% vs
6-77% yields, respectively), and the use of CuCN‚2LiI
The choice of copper(I) salt often plays a significant
role in the chemistry of the resultant organocopper and
cuprate reagents, and CuCN and CuBr‚SMe have been
2
5
promoted as the best Cu(I) precursors.7 Organocopper
reagents prepared from CuCN and either 1 or 2 equiv of
an alkyllithium reagent often display superior attributes
with regard to chemical yields, suggesting an important
role of the cyanide anion. The structure of the latter
reagent has been the subject of considerable interest
centering around the location of the cyanide ion.8 Al-
though THF-soluble CuCN‚2LiCl has been extensively
used by Knochel in the Cu-promoted reactions of organo-
(
(
53%) or excess LiCl (i.e., CuCN‚4LiCl) had little effect
58% vs 56-77%, Table 1, entry 8).1 Cuprates prepared
a
from 2 failed to react with ethyl tiglate or with methyl
cyclohexene-1-carboxylate, while cuprates prepared from
1
gave low yields with the former (Table 1, entry 17) and
no conjugate adduct with the latter (Table 1, entry 19).
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
9
zinc reagents, this source of Cu(I) has not been widely
used in the generation of cuprates from alkyllithium or
Grignard reagents.10 We have found that the combined
use of LiCl-solubilized CuCN and TMSCl synergistically
improve chemical yields in the conjugate addition reac-
1
2
their reactivity with cuprate reagents.
Anticipating
competitive acylation13 and conjugate addition pathways,
both the n-butyl and tert-butyl thiol esters were exam-
ined. Surprisingly, both derivatives gave good to excel-
lent yields of conjugate adducts with no acylation prod-
ucts being observed (Table 1, entries 4, 6, 10, and 12).
The thiol esters offered little advantage in the reactions
with the acyclic R-alkyl-substituted substrates (Table 1,
entry 18) but facilitated the reaction with the 1-cyclo-
hexene derivative (Table 1, entry 20). In an effort to
probe the greater reactivity of the thiol esters, a series
of organocopper reagents were examined. The cyano-
(1) (a) Dieter, R. K.; Alexander, C. W. Synlett 1993, 407. (b) Dieter,
R. K.; Alexander, C. W. Tetrahedron Lett. 1992, 33, 5693.
(
(
(
(
2) Lipshutz, B. H. Tetrahedron Lett. 1983, 24, 127.
3) Behforousz, M.; Curran, T. T.; Bolan, J . Ibid. 1986, 27, 3107.
4) Sakata, H.; Kuwajima, I. Tetrahedron Lett. 1987, 28, 5719.
5) Alexakis, A.; Berlan, J .; Besace, Y. Tetrahedron Lett. 1986, 27,
1
047.
(
6) (a) Bergdahl, M.; Lindstedt, E.-L.; Nilsson, M. Tetrahedron 1988,
4
4, 2055. (b) Yamamoto, Y.; Yamamoto, S.; Yatagai, H.; Ishihara, Y.;
Maruyama, K. J . Org. Chem. 1982, 47, 119.
7) Bertz, S. H.; Gibson, C. P.; Dabbagh, G. Tetrahedron Lett. 1987
8, 4251.
8) (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,
0, 4312. (c) Barnhart, T. M.; Huang, H.; Penner-Hahn, J . E. J . Org.
Chem. 1995, 60, 4310. (d) Lipshutz, B. H.; J ames, B. Ibid. 1994, 59,
(
2
(11) Alexander, C. W. Ph.D Dissertation, Clemson University, 1993.
(12) 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.
(13) (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. Ibid. 1979, 101, 7131. (c) Collum,
D. B.; McDonald, J . H.; Still, W. C. Ibid. 1980, 102, 2120.
(
6
7
585.
(9) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117.
10) Backvall, J .-E.; Persson, E. S. M.; Bombrun, A. J . Org. Chem.
(
1
6
994, 59, 4126. (b) Schlosser, M.; Bossert, H. Tetrahedron 1991, 47,
287.
S0022-3263(97)00443-X CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 12, 1997 3799
Ta ble 1. Con ju ga te Ad d ition of (r-Am in oa lk yl)cu p r a tes
w ith r,â-Alk en yl a n d Alk yn yl Ca r boxylic Acid
Der iva tives
quantitative yields could be achieved with RCuCNLi
reagents prepared from 1 or 2 under similar conditions
(Table 1, entries 21 and 23). The product enoate obtained
from 1 was isolated as a 65:35 mixture of Z:E geometrical
isomers, which was confirmed by amine deprotection to
quantitatively afford a lactam and (E)-ethyl 3-(2-pyrrol-
idinyl)-2-heptenoate in a 65:35 ratio, respectively.
The cuprate reagents prepared from 1 or 2 and
CuCN‚2LiCl also underwent conjugate addition to an
imide in excellent to modest yields (Table 1, entries 15
and 16 respectively). These yields are intriguing since
the imides have particularly high LUMO energies in
comparison to the esters or thiol esters.12 These results
are suggestive of the crucial role that lithium cation
coordination to the unsaturated carbonyl moiety plays
in these conjugate addition reactions.
The success of these conjugate addition reactions
requires the activating influence of TMSCl and the
utilization of LiCl-solubilized CuCN for the preparation
of the cuprate reagents. The presence of the LiCl
dramatically raises the yields of these reactions from zero
to 39-77% for the ester substrates in THF and is
consistent with added LiCl acting as a Lewis acid via
coordination with the carbonyl oxygen atom. This is in
marked contrast to the report that cuprate reactivity is
greater in conjugate addition reactions in the absence of
LiX.14 The failure of the conjugate addition reactions of
(R-aminoalkyl)cuprates to proceed with esters in the
absence of added LiCl finds analogy in the poor reactivity
of ortho-substituted â-aryl enoates containing three
oxygen atoms in the side chain with lithium dialkyl-
cuprates.15 In cuprates prepared from CuCN alone, it
appears that the dipole-stabilizing carbamate functional-
ity ties up the lithium ions, making them unavailable
for coordination to the enoate carbonyl, which is neces-
sary for the conjugate addition reaction to proceed.
Conjugate addition of cuprates prepared from 1 to ethyl
crotonate are not promoted by BF
TMSCl (5 equivs) while addition of BF
to the CuCN‚2LiCl/TMSCl (5 equivs) system has little
effect (52% vs 56-77% yields, Table 1, entry 8).
3
‚Et
3
2
O (2.0 equivs)/
O (2.0 equiv)
‚Et
2
In summary, reaction conditions have been developed
for the conjugate addition of relatively unreactive hetero-
atom-functionalized cuprate reagents with the less reac-
tive carboxylic acid derivatives. The conjugate addition
reaction of (R-aminoalkyl)cuprates to R,â-unsaturated
carboxylic acid derivatives is a feasible transformation
if the reagents are prepared from LiCl-solubilized CuCN
and TMSCl is used as an additive. Yields can be
improved by utilization of thiol esters. The method
currently fails with cyclic substrates and is limited to
derivatives lacking an R-alkyl substituent. These results
suggest that LiCl-solubilized CuCN may be a particularly
useful source of Cu(I) for the preparation of heteroatom-
functionalized cuprate reagents where intramolecular
lithium ion complexation reduces the reactivity of the
cuprate reagent.
a
A ) 2RLi + CuCN‚2LiCl. B ) RLi + CuCN‚2LiCl. C ) RLi
b
+
CuCl‚2LiCl. Reaction of the organocopper reagent with the
unsaturated substrate and TMSCl (5.0 equivs) in THF at -55 °C
(
30 min) and then at rt (1.5 h) gave the conjuate addition products.
c
Yields are based upon isolated purified products unless otherwise
noted. Yield determined by NMR using tetrachloroethane as
internal standard.
d
cuprate reagents, RCuCNLi, gave good to excellent yields
of conjugate addition products with the thiol esters (Table
, entries 5, 7, 11, and 13) and poor yields with esters
Ack n ow led gm en t. This work was generously sup-
ported by the National Science Foundation (CHE-
1
(
Table 1, entry 9). Utilization of an alkylcopper reagent
9
408912).
prepared from 1 and CuCl‚2LiCl gave a modest yield of
product (Table 1, entry 14). These results suggest the
possibility that the cuprate and copper reagents are
coordinating to the thiol esters and in this manner
facilitating the conjugate addition reactions.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
and a procedure (29 pages).
J O970443U
A cuprate reagent prepared from 2 equiv of 1 and
CuCN‚2LiCl gave a modest yield of conjugate adduct
(Table 1, entry 22) with an R,â-ynoate, while nearly
(
14) Krauss, S. R.; Smith, S. G. J . Am. Chem. Soc. 1981, 103, 141.
(15) Hallnemo, G.; Ullenius, C. Tetrahedron Lett. 1986, 27, 395.