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Reactions of 1-aza-pentadienyl anions with michael acceptors: regiochemistry
Tetrahedron Letters, Vo1.32,No.36.pp 46834686.1991
oo4o4039/91$3.00+ .oa Pergamcm Pressplc
Printedin GreatBritain
RJUL!TIONS
OF
l-AZA-PENTADIENYL
ANIONS
WI!CIi
NICHAEL
ACCKPTORS:
REGI~sTRY
Florian Baumann and Ernst-Ulrich Wiirthwein* Organisch-Chemisches Institut der Westfllischen Wilhelms-Universitat Miinster, Orleansring 23, D-4400 Miinster
-tract: The addition of Michael acceptors 3_6 to 1-aza-pentadienyl metal compounds u provides access to two main regioisomers (Type & and B, BI_); the relative yields may effectively be influenced by the choice of the metal ion of &,_8. 1-Aza-pentadienyl anions are useful ambident nucleophiles in organic synthesis. Depending on the nature of the attacking electrophile they may serve as do, d2 and d4 reactive intermediates lm7).Besides these imine type anions, the corresponding deprotonated hydrazones have also been used successfully in organic synthesis 5). In this communication we report our recent results of a study on the regiochemistry of the reaction of l-azapentadienyl metal compounds u with
simple Michael acceptors 3_6. Michael acceptors themselves are ambident electrophiles; therefore, an addition reaction should principally produce 6 diastereomers.
Examples for attacks of electrophiles
at
nitrogen are rare: although the nitrogen atom in I-azapentadienyl anions carries the highest negative charge in this system and the HOMO shows a big orbital coefficient at nitrogen a), they are only found for acylating agents
as electrophiles,
yielding
the
thermodynamically
very
stable
dienamides 6), and in silylations of sterically hindered anions '). Hydrolysis of the four remaining diastereomeric imines provides access to the corresponding
aldehydes
(type Ad),
which are all interesting
synthetic building blocks. A regioselective pathway to each of these compounds would be highly desirable. N-tert.Butyl-1-aza-pentadienyl-lithium &E was generated by deprotonation of N-tert.butyl-crotonaldimine
using a solution of lithium diisoprop-
ylamide in THF as base at -15°C; the deprotonation reaction was completed by stirring at room temperature for 5h. NMR investigations have shown, that only the all-trans configuration of the I-aza-pentadienyl moiety is formed with the tert.butyl group in exo position '). The methyl substituted systems J& and &
were generated analogously from senecioaldehyde
imine or tiglinaldehyde imine.
4683
4684
C+O
03
R+
O;$
R* t.Bu
,.,,+ Type
1.2
+
A
R’
0
R’
0
Type
B
Type
B’
(Hydrolysis)
R%H=CH-CO-R’ 3-6 1:
M-Li
a:
R1=R2=H
b:
R’*H,
c:
R’=CHJ,
Various
2:
M=l/2CuLi R2-CHJ Type
R2=H
electrophiles
3_6
were
C
Type
D
added to these deeply colored solutions
of la_c at -78'C. In a first series of experiments N-tert.butyl-l-azapentadienyl
lithium
a
was
treated
with
the
cyclic
a,&unsaturated
ketones 3 and 6 and with benzalacetone 5; after addition, the reaction mixture was allowed to warm to room temperature. Then, protonation followed using methanol. The corresponding aldehydes were obtained using several hydrolytic methods depending on the stability of the imines. In most cases, filtration of the reaction mixture over a short silica gel column gave best results; sometimes, an acetate buffer solution was used instead. Yields of pure isolated products lo) are given in the tables. They were obtained after purification via flash chromatography on silica gel (diethyl ether/petrolether mixtures). Depending on the stability of the aldehyde formed, the yields were moderate to good. In all cases, 1,4-attack at r-carbon atom 5 of the lithium compound @ was observed compound u
(type 9, see table). The senecioaldehyde derived lithium gave similar results.
In contrast to the ketones 3-5, from benzylideneacetophenone 6 and u Michael type x products were obtained (after proton shift). The tiglinaldehyde derived lithium compound &,
having an extra methyl
group in 3 position, behaves differently: here, from the reaction of 3 and 4 mixtures of Q- (type B) and s-attack (type a) of the Michael type addition were found, which could be separated via flash chromatography. Benzalacetone 5 gave mainly g-product, together with a small amount of type c product.
4685
In a second series of experiments, the 1-aza-pentadienyl-lithium pounds w
were converted into the corresponding cuprates m
com-
using a
dimethyl sulfide/THF (1:l) solution of the dimethyl sulfide complex of copper(I)brom
11) at -5O'C. The electrophiles 3_6 were added to the
reaction mixture at -78'C; after 4h, protonation with glacial acetic acid took place, followed by silica gel filtration and purification by flash chromatography. Table 1: Isolated yields of aldehydes type 8, B (x) tion reaction of 1-aza-pentadienyl-lithium
and c from the addi-
compounds m
and electro-
philes 3-6 (after flash chromatography). I la I
R3, R4
A
3
-(CH2)3-
51
4
-(CH2)2CH3, Ph
42
5
21
6
Ph, Ph
lc
lb B'
A
B
C
58
10
-
29
44
24
60
57
3
56
-
A
B'
41
36
33
Table 2: Isolated yields of aldehydes type A, B (z) and C from the addition reaction of l-aza-pentadienyl-copper compounds 2a_c and electrophiles 3-6 (after flash chromatography) 2a R3, R4
A
2c
2b
B'
A
B'
A
0
C
-(CH2)3'
30
50
76
-
50
52
-
5
-(CH2)2CH3, Ph
65 51
47
21
-
15
6
Ph, Ph
49
40
10
60
-
3 4
With 1-aza-pentadienyl system a,
in all cases a-attack of the Michael
acceptor was found (Type z product). Hence, as anticipated, the regiochemistry of the addition reaction is highly dependent on the nature of the counter ion of the nucleophile. Likewise, system 2p1gave exclusively products resulting from attack in 3 position (Type E). Similarly, with the tiglinaldehyde derived system &
a-attack (type 8)
was observed. Very unexpected for a copper species, a product of type C was formed in the reaction with benzalacetone 5, together with type A product; as with &,
no type B product was found.
Attempts to control the regioselectivity of the addition reaction of compounds ;La and J& by addition of HMPA (hexamethylphosphoric triamide) as
complexing
cosolvens
had only
little success: we got either no well
defined products or the regiochemistry was practically unchanged compared to the reactions
of B
and u
without cosolvens.
In the case of x
however, in the presence of HMPA mixtures with increased amounts of type B product were obtained with the electrophiles 3 and 4; with electrophile 5, more type A product was formed compared to the reaction of pure &
in
THF. 6 gave the same reaction mixture of regioisomers with and without HMPA. In conclusion, we have shown in this study, that the a,r-regioselectivity of Michael additions for multifunctional nucleophiles like l-aza-pentadienyl metal compounds can be effectively influenced by the choice of the metal ion: regarding the electrophiles, Michael type l,l-addition was predominant in all experiments studied. We thank the Fonds der Chemischen Industrie for financial support and the BASF AG, Ludwigshafen, for chemicals. References
2)
G.Stork, J.Benaim, J.Am.Chem.Soc. 93 (1971) 5938. G.R.Kieczykowski, R.H.Schlessinger, R.B.Sulsky, Tetrahedron Lett.
3)
1976, 597. K.Takabe, N.Nagaoka, T.Endo, T.Katagiri, Chem.Ind.
1)
(London) Q_&&,
540; K.Takabe, H.Fujiwara, T.Katagiri, J-Tanaka, Tetrahedron Lett.
4) 5)
1975 1237. -I K.Vedejs, D.M.Gapinski, Tetrahedron Lett. 22 (1981) 4913. E.J.Corey, D.Enders, Chem.Ber. u (1978) 1337, 1362.
7)
W.Oppolzer, W.Frdstl, Helv.Chim.Acta x - (1975) 587. H.Ahlbrecht, D.Liesching, Svnthesis 1976, 746.
8)
MNDO and ab initio (6-31G*) calculations.
6)
9)
G.Wolf, E.-U.Wiirthwein, Chem.Ber. &?& (1991) 889.
10)
All compounds were completely characterized by spectroscopic methods and gave satisfactory C,H,N analyses. Low,.field 13C-NMR signals of products type A-D: Type A: 151.1-161.l(d,B LCH-), 190.5-195.2(d,,i c, 01.7(d,-CHO), 202.9CHO), 197.9-218.8(s,C=O); Type B: 197.9217.2(s,CO);
Type
Bit" 151.5-158.2(s,&+-),
189.9-195.3(d,-CHO),
199.1-219_O(siC=O); Type C: 195.2(d,-CH'&). 11)
S.H.Bertz, C.P.Gibson, G.Dabbagh, Tetrahedron Lett. z
(ReceivedinGennany 29 May
1991)
(1987) 4251.
oo4o4039/91$3.00+ .oa Pergamcm Pressplc
Printedin GreatBritain
RJUL!TIONS
OF
l-AZA-PENTADIENYL
ANIONS
WI!CIi
NICHAEL
ACCKPTORS:
REGI~sTRY
Florian Baumann and Ernst-Ulrich Wiirthwein* Organisch-Chemisches Institut der Westfllischen Wilhelms-Universitat Miinster, Orleansring 23, D-4400 Miinster
-tract: The addition of Michael acceptors 3_6 to 1-aza-pentadienyl metal compounds u provides access to two main regioisomers (Type & and B, BI_); the relative yields may effectively be influenced by the choice of the metal ion of &,_8. 1-Aza-pentadienyl anions are useful ambident nucleophiles in organic synthesis. Depending on the nature of the attacking electrophile they may serve as do, d2 and d4 reactive intermediates lm7).Besides these imine type anions, the corresponding deprotonated hydrazones have also been used successfully in organic synthesis 5). In this communication we report our recent results of a study on the regiochemistry of the reaction of l-azapentadienyl metal compounds u with
simple Michael acceptors 3_6. Michael acceptors themselves are ambident electrophiles; therefore, an addition reaction should principally produce 6 diastereomers.
Examples for attacks of electrophiles
at
nitrogen are rare: although the nitrogen atom in I-azapentadienyl anions carries the highest negative charge in this system and the HOMO shows a big orbital coefficient at nitrogen a), they are only found for acylating agents
as electrophiles,
yielding
the
thermodynamically
very
stable
dienamides 6), and in silylations of sterically hindered anions '). Hydrolysis of the four remaining diastereomeric imines provides access to the corresponding
aldehydes
(type Ad),
which are all interesting
synthetic building blocks. A regioselective pathway to each of these compounds would be highly desirable. N-tert.Butyl-1-aza-pentadienyl-lithium &E was generated by deprotonation of N-tert.butyl-crotonaldimine
using a solution of lithium diisoprop-
ylamide in THF as base at -15°C; the deprotonation reaction was completed by stirring at room temperature for 5h. NMR investigations have shown, that only the all-trans configuration of the I-aza-pentadienyl moiety is formed with the tert.butyl group in exo position '). The methyl substituted systems J& and &
were generated analogously from senecioaldehyde
imine or tiglinaldehyde imine.
4683
4684
C+O
03
R+
O;$
R* t.Bu
,.,,+ Type
1.2
+
A
R’
0
R’
0
Type
B
Type
B’
(Hydrolysis)
R%H=CH-CO-R’ 3-6 1:
M-Li
a:
R1=R2=H
b:
R’*H,
c:
R’=CHJ,
Various
2:
M=l/2CuLi R2-CHJ Type
R2=H
electrophiles
3_6
were
C
Type
D
added to these deeply colored solutions
of la_c at -78'C. In a first series of experiments N-tert.butyl-l-azapentadienyl
lithium
a
was
treated
with
the
cyclic
a,&unsaturated
ketones 3 and 6 and with benzalacetone 5; after addition, the reaction mixture was allowed to warm to room temperature. Then, protonation followed using methanol. The corresponding aldehydes were obtained using several hydrolytic methods depending on the stability of the imines. In most cases, filtration of the reaction mixture over a short silica gel column gave best results; sometimes, an acetate buffer solution was used instead. Yields of pure isolated products lo) are given in the tables. They were obtained after purification via flash chromatography on silica gel (diethyl ether/petrolether mixtures). Depending on the stability of the aldehyde formed, the yields were moderate to good. In all cases, 1,4-attack at r-carbon atom 5 of the lithium compound @ was observed compound u
(type 9, see table). The senecioaldehyde derived lithium gave similar results.
In contrast to the ketones 3-5, from benzylideneacetophenone 6 and u Michael type x products were obtained (after proton shift). The tiglinaldehyde derived lithium compound &,
having an extra methyl
group in 3 position, behaves differently: here, from the reaction of 3 and 4 mixtures of Q- (type B) and s-attack (type a) of the Michael type addition were found, which could be separated via flash chromatography. Benzalacetone 5 gave mainly g-product, together with a small amount of type c product.
4685
In a second series of experiments, the 1-aza-pentadienyl-lithium pounds w
were converted into the corresponding cuprates m
com-
using a
dimethyl sulfide/THF (1:l) solution of the dimethyl sulfide complex of copper(I)brom
11) at -5O'C. The electrophiles 3_6 were added to the
reaction mixture at -78'C; after 4h, protonation with glacial acetic acid took place, followed by silica gel filtration and purification by flash chromatography. Table 1: Isolated yields of aldehydes type 8, B (x) tion reaction of 1-aza-pentadienyl-lithium
and c from the addi-
compounds m
and electro-
philes 3-6 (after flash chromatography). I la I
R3, R4
A
3
-(CH2)3-
51
4
-(CH2)2CH3, Ph
42
5
21
6
Ph, Ph
lc
lb B'
A
B
C
58
10
-
29
44
24
60
57
3
56
-
A
B'
41
36
33
Table 2: Isolated yields of aldehydes type A, B (z) and C from the addition reaction of l-aza-pentadienyl-copper compounds 2a_c and electrophiles 3-6 (after flash chromatography) 2a R3, R4
A
2c
2b
B'
A
B'
A
0
C
-(CH2)3'
30
50
76
-
50
52
-
5
-(CH2)2CH3, Ph
65 51
47
21
-
15
6
Ph, Ph
49
40
10
60
-
3 4
With 1-aza-pentadienyl system a,
in all cases a-attack of the Michael
acceptor was found (Type z product). Hence, as anticipated, the regiochemistry of the addition reaction is highly dependent on the nature of the counter ion of the nucleophile. Likewise, system 2p1gave exclusively products resulting from attack in 3 position (Type E). Similarly, with the tiglinaldehyde derived system &
a-attack (type 8)
was observed. Very unexpected for a copper species, a product of type C was formed in the reaction with benzalacetone 5, together with type A product; as with &,
no type B product was found.
Attempts to control the regioselectivity of the addition reaction of compounds ;La and J& by addition of HMPA (hexamethylphosphoric triamide) as
complexing
cosolvens
had only
little success: we got either no well
defined products or the regiochemistry was practically unchanged compared to the reactions
of B
and u
without cosolvens.
In the case of x
however, in the presence of HMPA mixtures with increased amounts of type B product were obtained with the electrophiles 3 and 4; with electrophile 5, more type A product was formed compared to the reaction of pure &
in
THF. 6 gave the same reaction mixture of regioisomers with and without HMPA. In conclusion, we have shown in this study, that the a,r-regioselectivity of Michael additions for multifunctional nucleophiles like l-aza-pentadienyl metal compounds can be effectively influenced by the choice of the metal ion: regarding the electrophiles, Michael type l,l-addition was predominant in all experiments studied. We thank the Fonds der Chemischen Industrie for financial support and the BASF AG, Ludwigshafen, for chemicals. References
2)
G.Stork, J.Benaim, J.Am.Chem.Soc. 93 (1971) 5938. G.R.Kieczykowski, R.H.Schlessinger, R.B.Sulsky, Tetrahedron Lett.
3)
1976, 597. K.Takabe, N.Nagaoka, T.Endo, T.Katagiri, Chem.Ind.
1)
(London) Q_&&,
540; K.Takabe, H.Fujiwara, T.Katagiri, J-Tanaka, Tetrahedron Lett.
4) 5)
1975 1237. -I K.Vedejs, D.M.Gapinski, Tetrahedron Lett. 22 (1981) 4913. E.J.Corey, D.Enders, Chem.Ber. u (1978) 1337, 1362.
7)
W.Oppolzer, W.Frdstl, Helv.Chim.Acta x - (1975) 587. H.Ahlbrecht, D.Liesching, Svnthesis 1976, 746.
8)
MNDO and ab initio (6-31G*) calculations.
6)
9)
G.Wolf, E.-U.Wiirthwein, Chem.Ber. &?& (1991) 889.
10)
All compounds were completely characterized by spectroscopic methods and gave satisfactory C,H,N analyses. Low,.field 13C-NMR signals of products type A-D: Type A: 151.1-161.l(d,B LCH-), 190.5-195.2(d,,i c, 01.7(d,-CHO), 202.9CHO), 197.9-218.8(s,C=O); Type B: 197.9217.2(s,CO);
Type
Bit" 151.5-158.2(s,&+-),
189.9-195.3(d,-CHO),
199.1-219_O(siC=O); Type C: 195.2(d,-CH'&). 11)
S.H.Bertz, C.P.Gibson, G.Dabbagh, Tetrahedron Lett. z
(ReceivedinGennany 29 May
1991)
(1987) 4251.