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selectivity: Higher order, mixed lithio-sodio cyanocuprates
Tetrahedron Letters,Vol.29,No.8,pp printed in Great Britain
893-896,1988
0040-4039/88 ~JournalsLtd.
$3.00
+ .00
EFPECTS OF GENGENIONS ON ORGANOCUPBATE RRACTIVITY/SELECTIVITY: BIGHRR ORDER, HIXED LITNIO-a
CYANOCUPRATES
Bruce Ii.Lipshutr*l and Edmund L. Ellsworth Department of Chemistry University of California, Santa Barbara, CA
93106
James R. Behling and Arthur L. Campbell G.D. Searle & Co., 4901 Searle Parkway Skokie, Illinois 60076
Summary: Several different types of reactions characteristic of organocuprates have been studied using reagents RTRRCu(CN)LiNa derived from CuCN and on8 equivalent each of an organolithium (RTLI) and organosodium (RRNa) species.
Modern organocuprate chemistry derives, in essence, from early observations in which inorganic copper(I) salts were found to react with organolithium2a or Grignard reagents2b to form new species. These cuprates, R2CuM (M-LI, MgX), effect many types of useful carboncarbon bond forming processes.3
And yet, aside from a historical advantage, one might
wonder why the vast majority of cuprate chemistry is based on lithium or magnesium halide as the gegenion. It has bean known for over a decade that cuprate reactivity is strongly dependent on the presence of a counterion in the cluster.4 Just which type of cation imparts the best spectrum of reactivity, selectivity, efficiency, and reagent stability has yet to be established. The advent of higher order cuprates, however, provides an opportunity to assess the importance of lithium relative to other metals.
In this report we now
describe the facile preparation of the first higher order mixed metal cupratas containing sodium ions, 4, and their coupling reactions with a variety of organic substrates.6
MF R,H
+
n-BuNa
-
R,Na
CuCN -
2
R,Cu(CN)Na
w _
RTR&u(CN)LiNa
d& 4b,%=
893
RR= 2-Th t&o=
894
Generation of mixed cuprates 4 was predicated on the use of readily available R-BuNa, 1, following a modified procedure7 of Lochman.8 Metalation of either thiophene or the methyl ether of commercially available, inexpensive 2-methyl-3-butyn-2-01with 1 occurs readily under conditions described using R-BuL~.~ Addition of 2 to CuCN (1 equiv) produces a lower order sodio cuprate 1 (i.e., a Cu(1) monoanion) to which is then added at -78O 1 equivalent of an organolithium (RTLi) of one's choosing, thereby forming 4.
These new.cuprates (4) are
usually homogeneous up to ~8. 0.3 M in THF, and are slighter darker in color (but still tan) and somewhat less stable at elevated temperatures (> 0' C) than their dilithio analogs. Several different types of couplings were investigated so as to gauge the impact of substituting a sodium ion for a lithium ion in the cuprate cluster. Table I summarizes our results, which include conjugate additions, halide and epoxide displacements, and 1,2-additions, as well as the effects of additives on cuprate reactivity and diastereoselectivity. In general, these lithio-sodio reagents are less prone toward Michael additions requiring higher temperatures and longer reaction times. Yields can also be significantly lower than with the corresponding dilithio cuprates (entries 1 and 9).
Prior addition
of BF3*Et201° to 4 can lead to much improved results (entries 5 vs. 6, 9 vs. 10 ), while the presence of TMS-C1ll unexpectedly reduces product yield (entry 7 vs. 8).
Substitution
reactions of epoxides give good yields of alcohols (entries 13 and 14), while primary halides (e.g., entry 15) give moderate yields. 1,2-Additions to aldehyde 2 afford a mix of S~H to anti products fiand z, respectively. Interestingly, while Bu2Cu(CN)LiNa shows little selectivity, the presence of BF3 improves this ratio to 6.7~1. Better results were realized using Bu2Cu(CN)LiNa together with BF3*Et20 (2 equiv) and 15-Cr-5 (2 equiv vs. cuprate), which gives a similar ratio (6.5:1) but a quantitative yield of 6 plus 1.
TMS-Cl also
affects the stereochemical outcome, as Bu(2-Th)Cu(CN)Li2/2TMS-Cl leads to a 7:l svn:anti mix, while Bu(P-Th)Cu(CN)LiNa/ZTMS-Cl improves the ratio to ll:l, both reagents being of similar efficiency (75-90+%). Two other comparisons with H.O. dilithio cuprates were made.
Treatment of unsaturated
ester 8 with ha, as judged from TLC and GC analyses, leads to little 1,4-adduct (although starting enoate is consumed), while Bu(P-Th)Cu(CN)Li2 gives the expected ester 9 in excellent isolated yield.g Attempts to form cuprates u
"in &&"
tachnology12 utilizing a
n-Bu(2-m)Cu(CNILiNa
n-Bu(2-m)Cu(CN)U,
vinylstannane and &,
RT - Me, a process which works well for Me(P-Th)Cu(CN)Lig, leads to
none of the product of 1,4-addition to an enone. Apparently the presence of Na+ impedes transmetalationbetween copper and tin, since had cuprate n
formed (judging from Table I),
the 1,4-addition would have taken place. s"O"s M.@T~)CU(CN)L~N~
+ R,s”~
+
-(P-m)Cu(CN)LiNa
----
10 (+M&lR3)
1.4-addua
695
Table Entry
of Mlxed Lithio Sodio H. 0. Cyanocuprates, R,R,Cu(CN)LiNa,
I. Reactions
Substrate
Cuprate
COnditlOnS
Pmduct(s)a
Additive
& neld (%)b
0 1
4sJ..R-nau
I
b 0
2 3
I
4
”
6
”
65 [951C
35mbl
Bu&u(CN)LiNa
-78O, 2h
4a,R=wBu
Q, 35 min
68 (93)d
4lJR=n-Bu
40-00 2h
68 wd
SR=vinyl
-78400 2h
2 5
-78--*00
I
68
0
P
-78’, 1 h
0
&
7
6
I
-78=., 2h
9
0
-78-00 2h
10
A+
-7(p, 3h
OD+rl 6h
11 w
-78O, 2h
~R=vW
Phv 0 0
14 ti 15
2-lMs-a
75 23-40
8,
-
26 (70)d [491”
2.2BFg Et@
74 WI”
-
63
Ph OH
0
12
13
96
0
-78doD 2h
I
67 (75)d
3BFa*Ew
20+40[68]c PhYy
-78-v 125h
-
81
-78-p lh
-
73
-78 --too 4h
Bro4~
60 n-Bu
Ph&HO
e
Ph OH
1
(81 wn 16
1
-78-00 2h
17
1
-78O, 2.5h
16
1
I
19
1
4&J.R-kl-BU
-78O, 3h
: anti
1.&l-
(7) quant.’
-3*Et20
6.7
:1
66 I76l=
4BFa’W 2 15-0-5
6.5
:1
quant.’
2TMS-U
11 :1
75’
*All new compounds gave satkfxtoty IR. NMR, MS, and HRMS data. b lwlated yields, unless stated otherwise. cY&ldoMaineduslrgthediliU&cuprate.dY&ld basedon recoveredstarting material. lRatbdetermined by capwaly Qc. ‘ByqlcMwveGC.
896
In conclusion. the nature of H.O. cuprates R$i@_I(CN)LiNa
(4)
which contain a Na+ ion in
place of one Li+, is indeed altered by this change in gegion. Reactivity of 4 towards Michael acceptors and carbons bearing leaving groups is somewhat reduced, while additions to saturated aldehydes occur quite smoothly. Additives do play a role, but not necessarily in a uniformly positive sense. For routine cuprate use, therefore, there seems to be little reason to wander from strictly dilithio (or lithio-magnesio) reagents. However, they may prove useful, e.g., in large scale applications where very low temperature control in reactions of
R$b@(CN)Li2
is necessary
but costly, and lower reagent reactivity (and hence, a
higher reaction temperature) is desirable.
Acknowledeement. Financial support provided by the National Science Foundation (CHE 8703757) and the donors of the Petroleum Research Fund is acknowledged.
&.eferencesand Noteq 1. A.P. Sloan Fellow, 1984-1988; Dreyfus Teacher-Scholar, 1984-1989. 2. (a) Gilman, H., Jones, R.G., Woods, L.A., J. Org. Chem., 1952, u, 1630; (b) Kharasch, M.S., Tawney, P.O., J. Am. Chem. Sot., 1941, 62, 2308. 3. Posner, G.H., Org. React., 1972, m, 1; &j&, 1975. 2, 253. 4. Ouannes,C., Dressaire, G., Langlois, Y., Tet. Lett,, 1977, 815; see also Hallnemo, G., Ullenius, C., ihip., 1986, 2, 395. 5. For a recent review, see Lipshutx, B.H., a., 1987, 325. 6. For a study on the chemistry of lower order sodio cuprates R2CuNa, see Bertx, S.H., et al., Organometallics, in press. 7. To a O°C suspension of 4 g (41.67 mmol) of sodium r-butoxide in 70 mL of dry, olefinfree hexane, 18.5 mL of 2.70 M D-BuLi in hexane was added dropwise with stirring. The resulting white, heterogeneous mixture was stirred for 1 h at O°C and then for 1.5 h at room temperature. The mixture was then transferred u canula to a closed filtration vessel containing a medium glass frit. The R-BuNa precipitate was washed several times with fresh hexane and dried under a stream of argon. The filtration vessel was placed in a dry-box and its contents transferred to a 25 mL round-bottomed flask. Hexane (10 mL) was then added to form a slurry which was cooled to -7S°C and then dry THF (10 mL) was introduced dropwise with stirring to result in a yellow, homogeneous solution resembling p-BuLi. The solution (at -78OC) was titrated in a inverse manner to that described by Watson and Eastham,13 to avoid THF decomposition. The B-BuNa solution can be stored at dry-ice temperatures for 2-3 days without loss of titer. Preferably, D-BuNa is stored as a solid at room temperature in a well-sealed dessicator and may last for weeks under these conditions. 8. Lochman, L., Puspisil, J., Lim, D., Tet. Lett,, 1966, 257. 9. Lipshutz, B.H., Koxlowski, J.A., Parker, D.A., Nguyen, S.L., McCarthy, K.E., J. Organomet. Chem., 1985, 281, 437. 10. Yamamoto, Y., Angew. Chem. Int. Ed. Engl.. 1986, a, 947. 11. See Johnson, C.R., Marren, T.J., Tet. Lett., 1987, 28, 27. and references therein. 12. Behling, J.R., Babiak, K.A., Ng, J.S., Campbell, A.L., Moratti, R., Koarnar, M., Lipshutx, B.H., J. Am. Chem. Sot., in press. 13. Watson, S.C., Eastham, J.F., J. Organomet. Chem., 1967, 2, 165. (Received
in USA 9 December
1987)
893-896,1988
0040-4039/88 ~JournalsLtd.
$3.00
+ .00
EFPECTS OF GENGENIONS ON ORGANOCUPBATE RRACTIVITY/SELECTIVITY: BIGHRR ORDER, HIXED LITNIO-a
CYANOCUPRATES
Bruce Ii.Lipshutr*l and Edmund L. Ellsworth Department of Chemistry University of California, Santa Barbara, CA
93106
James R. Behling and Arthur L. Campbell G.D. Searle & Co., 4901 Searle Parkway Skokie, Illinois 60076
Summary: Several different types of reactions characteristic of organocuprates have been studied using reagents RTRRCu(CN)LiNa derived from CuCN and on8 equivalent each of an organolithium (RTLI) and organosodium (RRNa) species.
Modern organocuprate chemistry derives, in essence, from early observations in which inorganic copper(I) salts were found to react with organolithium2a or Grignard reagents2b to form new species. These cuprates, R2CuM (M-LI, MgX), effect many types of useful carboncarbon bond forming processes.3
And yet, aside from a historical advantage, one might
wonder why the vast majority of cuprate chemistry is based on lithium or magnesium halide as the gegenion. It has bean known for over a decade that cuprate reactivity is strongly dependent on the presence of a counterion in the cluster.4 Just which type of cation imparts the best spectrum of reactivity, selectivity, efficiency, and reagent stability has yet to be established. The advent of higher order cuprates, however, provides an opportunity to assess the importance of lithium relative to other metals.
In this report we now
describe the facile preparation of the first higher order mixed metal cupratas containing sodium ions, 4, and their coupling reactions with a variety of organic substrates.6
MF R,H
+
n-BuNa
-
R,Na
CuCN -
2
R,Cu(CN)Na
w _
RTR&u(CN)LiNa
d& 4b,%=
893
RR= 2-Th t&o=
894
Generation of mixed cuprates 4 was predicated on the use of readily available R-BuNa, 1, following a modified procedure7 of Lochman.8 Metalation of either thiophene or the methyl ether of commercially available, inexpensive 2-methyl-3-butyn-2-01with 1 occurs readily under conditions described using R-BuL~.~ Addition of 2 to CuCN (1 equiv) produces a lower order sodio cuprate 1 (i.e., a Cu(1) monoanion) to which is then added at -78O 1 equivalent of an organolithium (RTLi) of one's choosing, thereby forming 4.
These new.cuprates (4) are
usually homogeneous up to ~8. 0.3 M in THF, and are slighter darker in color (but still tan) and somewhat less stable at elevated temperatures (> 0' C) than their dilithio analogs. Several different types of couplings were investigated so as to gauge the impact of substituting a sodium ion for a lithium ion in the cuprate cluster. Table I summarizes our results, which include conjugate additions, halide and epoxide displacements, and 1,2-additions, as well as the effects of additives on cuprate reactivity and diastereoselectivity. In general, these lithio-sodio reagents are less prone toward Michael additions requiring higher temperatures and longer reaction times. Yields can also be significantly lower than with the corresponding dilithio cuprates (entries 1 and 9).
Prior addition
of BF3*Et201° to 4 can lead to much improved results (entries 5 vs. 6, 9 vs. 10 ), while the presence of TMS-C1ll unexpectedly reduces product yield (entry 7 vs. 8).
Substitution
reactions of epoxides give good yields of alcohols (entries 13 and 14), while primary halides (e.g., entry 15) give moderate yields. 1,2-Additions to aldehyde 2 afford a mix of S~H to anti products fiand z, respectively. Interestingly, while Bu2Cu(CN)LiNa shows little selectivity, the presence of BF3 improves this ratio to 6.7~1. Better results were realized using Bu2Cu(CN)LiNa together with BF3*Et20 (2 equiv) and 15-Cr-5 (2 equiv vs. cuprate), which gives a similar ratio (6.5:1) but a quantitative yield of 6 plus 1.
TMS-Cl also
affects the stereochemical outcome, as Bu(2-Th)Cu(CN)Li2/2TMS-Cl leads to a 7:l svn:anti mix, while Bu(P-Th)Cu(CN)LiNa/ZTMS-Cl improves the ratio to ll:l, both reagents being of similar efficiency (75-90+%). Two other comparisons with H.O. dilithio cuprates were made.
Treatment of unsaturated
ester 8 with ha, as judged from TLC and GC analyses, leads to little 1,4-adduct (although starting enoate is consumed), while Bu(P-Th)Cu(CN)Li2 gives the expected ester 9 in excellent isolated yield.g Attempts to form cuprates u
"in &&"
tachnology12 utilizing a
n-Bu(2-m)Cu(CNILiNa
n-Bu(2-m)Cu(CN)U,
vinylstannane and &,
RT - Me, a process which works well for Me(P-Th)Cu(CN)Lig, leads to
none of the product of 1,4-addition to an enone. Apparently the presence of Na+ impedes transmetalationbetween copper and tin, since had cuprate n
formed (judging from Table I),
the 1,4-addition would have taken place. s"O"s M.@T~)CU(CN)L~N~
+ R,s”~
+
-(P-m)Cu(CN)LiNa
----
10 (+M&lR3)
1.4-addua
695
Table Entry
of Mlxed Lithio Sodio H. 0. Cyanocuprates, R,R,Cu(CN)LiNa,
I. Reactions
Substrate
Cuprate
COnditlOnS
Pmduct(s)a
Additive
& neld (%)b
0 1
4sJ..R-nau
I
b 0
2 3
I
4
”
6
”
65 [951C
35mbl
Bu&u(CN)LiNa
-78O, 2h
4a,R=wBu
Q, 35 min
68 (93)d
4lJR=n-Bu
40-00 2h
68 wd
SR=vinyl
-78400 2h
2 5
-78--*00
I
68
0
P
-78’, 1 h
0
&
7
6
I
-78=., 2h
9
0
-78-00 2h
10
A+
-7(p, 3h
OD+rl 6h
11 w
-78O, 2h
~R=vW
Phv 0 0
14 ti 15
2-lMs-a
75 23-40
8,
-
26 (70)d [491”
2.2BFg Et@
74 WI”
-
63
Ph OH
0
12
13
96
0
-78doD 2h
I
67 (75)d
3BFa*Ew
20+40[68]c PhYy
-78-v 125h
-
81
-78-p lh
-
73
-78 --too 4h
Bro4~
60 n-Bu
Ph&HO
e
Ph OH
1
(81 wn 16
1
-78-00 2h
17
1
-78O, 2.5h
16
1
I
19
1
4&J.R-kl-BU
-78O, 3h
: anti
1.&l-
(7) quant.’
-3*Et20
6.7
:1
66 I76l=
4BFa’W 2 15-0-5
6.5
:1
quant.’
2TMS-U
11 :1
75’
*All new compounds gave satkfxtoty IR. NMR, MS, and HRMS data. b lwlated yields, unless stated otherwise. cY&ldoMaineduslrgthediliU&cuprate.dY&ld basedon recoveredstarting material. lRatbdetermined by capwaly Qc. ‘ByqlcMwveGC.
896
In conclusion. the nature of H.O. cuprates R$i@_I(CN)LiNa
(4)
which contain a Na+ ion in
place of one Li+, is indeed altered by this change in gegion. Reactivity of 4 towards Michael acceptors and carbons bearing leaving groups is somewhat reduced, while additions to saturated aldehydes occur quite smoothly. Additives do play a role, but not necessarily in a uniformly positive sense. For routine cuprate use, therefore, there seems to be little reason to wander from strictly dilithio (or lithio-magnesio) reagents. However, they may prove useful, e.g., in large scale applications where very low temperature control in reactions of
R$b@(CN)Li2
is necessary
but costly, and lower reagent reactivity (and hence, a
higher reaction temperature) is desirable.
Acknowledeement. Financial support provided by the National Science Foundation (CHE 8703757) and the donors of the Petroleum Research Fund is acknowledged.
&.eferencesand Noteq 1. A.P. Sloan Fellow, 1984-1988; Dreyfus Teacher-Scholar, 1984-1989. 2. (a) Gilman, H., Jones, R.G., Woods, L.A., J. Org. Chem., 1952, u, 1630; (b) Kharasch, M.S., Tawney, P.O., J. Am. Chem. Sot., 1941, 62, 2308. 3. Posner, G.H., Org. React., 1972, m, 1; &j&, 1975. 2, 253. 4. Ouannes,C., Dressaire, G., Langlois, Y., Tet. Lett,, 1977, 815; see also Hallnemo, G., Ullenius, C., ihip., 1986, 2, 395. 5. For a recent review, see Lipshutx, B.H., a., 1987, 325. 6. For a study on the chemistry of lower order sodio cuprates R2CuNa, see Bertx, S.H., et al., Organometallics, in press. 7. To a O°C suspension of 4 g (41.67 mmol) of sodium r-butoxide in 70 mL of dry, olefinfree hexane, 18.5 mL of 2.70 M D-BuLi in hexane was added dropwise with stirring. The resulting white, heterogeneous mixture was stirred for 1 h at O°C and then for 1.5 h at room temperature. The mixture was then transferred u canula to a closed filtration vessel containing a medium glass frit. The R-BuNa precipitate was washed several times with fresh hexane and dried under a stream of argon. The filtration vessel was placed in a dry-box and its contents transferred to a 25 mL round-bottomed flask. Hexane (10 mL) was then added to form a slurry which was cooled to -7S°C and then dry THF (10 mL) was introduced dropwise with stirring to result in a yellow, homogeneous solution resembling p-BuLi. The solution (at -78OC) was titrated in a inverse manner to that described by Watson and Eastham,13 to avoid THF decomposition. The B-BuNa solution can be stored at dry-ice temperatures for 2-3 days without loss of titer. Preferably, D-BuNa is stored as a solid at room temperature in a well-sealed dessicator and may last for weeks under these conditions. 8. Lochman, L., Puspisil, J., Lim, D., Tet. Lett,, 1966, 257. 9. Lipshutz, B.H., Koxlowski, J.A., Parker, D.A., Nguyen, S.L., McCarthy, K.E., J. Organomet. Chem., 1985, 281, 437. 10. Yamamoto, Y., Angew. Chem. Int. Ed. Engl.. 1986, a, 947. 11. See Johnson, C.R., Marren, T.J., Tet. Lett., 1987, 28, 27. and references therein. 12. Behling, J.R., Babiak, K.A., Ng, J.S., Campbell, A.L., Moratti, R., Koarnar, M., Lipshutx, B.H., J. Am. Chem. Sot., in press. 13. Watson, S.C., Eastham, J.F., J. Organomet. Chem., 1967, 2, 165. (Received
in USA 9 December
1987)