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N-(Trimethylsilyl)amino Acid Trimethylsilyl Esters as Reagents for Directed Self-Condensation of Methyl Ketones under Mild Conditions.

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N-(Trirnethylsi1yl)amino Acid Trimethylsilyl Esters as
Reagents for Directed Self-condensation of Methyl
Ketones under Mild Conditions['*]
By Giinter Schulz and Wolfgang Steglichp]
Self-condensation of methyl ketones to u,P-unsaturated
dimers generally requires strongly alkaline or acid conditions[']. On use of secondary amines several days' boiling
in benzene is necessary even with n-alkyl methyl ketones"!
We have found that the reaction proceeds under extremely
mild conditions with N-(trimethylsilyl)amino acid trimethyl
silyl esters.
On addition of N-(trimethylsi1yl)-P-alanine trimethylsilyl
ester (2)[31 (1.5 equiv.) and a few grains of p-toluenesulfonic
acid monohydrate to methyl levulinate (1 ), f3-alanine (0.5
equiv.) is soon precipitated in an exothermic reaction. According to the 'H-NMR spectrum quantitative formation of the
~ ' takes place [in CCI,: 6=0.26ppm (s,
ketimine ( 3 ~ ) ' also
9H); 1.86 (s, 3H); 2.47 (s, 4H); 2.53 (t, 2H); 3.40 (t, 2H);
3.58 (s, 3H)].
If p-toluenesulfonic acid monohydrate (0.1 equiv.) is now
added and the mixture heated to 80°C for 5 h the signals
of unreacted (3 a ) and hexamethyldisiloxane are accompanied
only by those of the condensation product ( 5 a ) [in ccI4
b= 1.63ppm (s, 3H) and 5.63 (broad s, 1H) are characteristic
for ( 5 a ) I .
After stirring with water the a,P-unsaturated ketone can
be isolated as a 4 : 1 mixture of the stereoisomers ( 6 a ) and
( 6 b ) in 58 % yield [b.p. 14O0C/O.05 torr (bulb-tube distillation); IR (CCl,): 1740 (broad), 1695, 1630 cm-'; 'H-NMR
(CC14) of (a): 6=2.14ppm (d, 3H); 2.78 (s, 4H); 2.81 (dd,
2H); 3.01 (dd, 2H); 3.64 (s, 6H); 6.07 (broad s, 1H); 'H-NMR
(CCl,) of ( 6 b ) : b= 1.91 ppm (d, 3H) instead of 2.14 (d, 3H)
as for ( 6 a ) l .
The reaction proceeds in regioselective manner and with
exclusive participation of the acetyl group. In contrast, the
ester group of ( 1 ) reacts with basic condensation reagents
such as sodium methoxide['].
The above self-condensation is not the result of a simple
acid-catalyzed ketimine dimerization['' since protonation of
the ketimine (3 a ) with anhydrous p-toluenesulfonic acid,
which can be reversed with triethylamine, does not lead to
the condensation product ( 5 a). Apparently, expulsion of the
silyl group from ( 4 a ) to form ( 4 b ) is of importance since
the amine component required for condensation can subsequently be released as a low energy betaine. This concept
finds support in the reaction of (1 ) with N-(trimethylsily1)-Palanine methyl ester to form the ketimine (3 b), which also
shows no tendency to form the dimer ( 5 b ) in the presence
of p-toluenesulfonic acid monohydrate.
Methylglyoxal dimethyl acetal and cyclopropyl methyl
ketone can also be condensed to form the unsaturated ketones
(7) and (8) respectively in 49 and 23% yield with the aid
of (2). The ratios of ( Z ) and ( E ) isomers are 1 :20 and 1 :3.
The condensation can also be accomplished with pertrimethylsilylated cc-amino acidsr6].Thus N-(trimethylsi1yl)glycine trimethylsilyl ester yields exclusively the a,P-unsaturated ketones
(9) to (12) in yields of 30 to 70% (not optimized) with
acetone, methyl ethyl ketone, methyl n-propyl ketone, and
methyl isopropyl ketone; the ( E ) isomer always predominates
in the product.
Procedure
p/"COZR
-[TosOH.
1 3HzO]c 0 2 c ~ 0 2 c H 3
H3CAAC02CH3
R02CwNH
(4a), R = Si(CH3)3
( 3 a ) , R = Si(CH3)3
( 3 b ) , R = CH3
/46), R = H
[TOSOH' HzO]
-8-Alanme
H3C02C
Synthesis of (7): Methylglyoxal dimethyl acetal (2.03g)
is stirred with (2) (6.00g) in anhydrous CHC13 (5 ml). Within
a short time the mixture warms and p-alanine precipitates.
After 5 min, p-toluenesulfonic acid monohydrate (0.14g) is
added and the mixture heated to 85°C (bath temperature)
for 3 h. After partitioning between water and CHzC12 the
dehydrated organic phase is evaporated down and the residue
distilled in a bulb-tube (110°C/0.05 torr). Yield 0.92g (49 %),
colorless oil; IR (CCI,): 1705, 1640cm-'; 'H-NMR (CDC13),
(E)-(7)r 6=2.12ppm (d, J = 2 H z , 3H); 3.31 (s, 6H); 3.43
(s, 6H); 4.52 (s, 1H); 4.64 (broad s, I H ) ; 6.68 (quintuplet,
J = 2 Hz, 1H); (Z)-(7):6 = 1.92ppm (d, J = 2 Hz, 3 H) instead
of 2.12 (d, J = 2 H z , 3H).
TCozcH3
Received: October 28, 1976 [Z 596a IE]
German version: Angew. Chem. 89, 255 (1977)
Publication delayed at Authors' request
cH3
(5u), R = Si(CHd3
(56), R = CH3
0
H c C 0 , C H 3
R'
( 6 a ) , R' =
R2 =
(6b), R' =
R2 =
CHzCHzCOzCH3
CH3
CH3
CHzCHzCOzCH3
CAS Registry numbers:
( l ) , 624-45-3; ( 2 ) . 17891-06-0; ( 3 ~ ) 61010-40-0;
,
( 3 b 1 , 61010-41-1; ( S u ) ,
61010-42-2;( 6 a ) , 61010-43-3;(6b), 61010-44-4; ( 2 ) - ( 7 ) , 61010-45-5;(E)-f 7),
61010-46-6; (2)-(8), 37714-95-7; ( E ) - ( 8 ) , 37715-04-1; ( 9 ) , 141-79-7: ( l o ) ,
20685-44-3; (lZ), 22287-10-1; ( 1 2 1 , 61010-47-7; p-toluenesulfonic acid. 10415-4; N-(trimethylsily1)-p-alanine methyl ester, 61010-48-8; methylglyoxal
dimethyl acetal, 6342-56-9; cyclopropyl methyl ketone, 765-43-5: N-(trimethylsi1yl)glycine trimethylsilyl ester, 7364-42-3; acetone, 67-64-1 ; methyl ethyl
ketone, 78-93-3; methyl n-propyl ketone, 107-87-9; methyl isopropyl ketone,
563-80-4
[*] DipLChem. G. Schulz, Prof. Dr. W. Steglich
Institut fur Organische Chemie und Biochemie der Universitat
Max-Planck-Strasse 1, D-5300 Bonn (Germany)
[**] This work was supported by the Deutsche Forschungsgemeinschaft.
Angew. Chem. l n t . E d . Engl. 16 (1977) No. 4
[I] H . 0.House: Modern Synthetic Reactions. 2nd Edit., Benjamin, Menlo
Park, Calif. 1972, pp. 629ff.; J. Mathieu, J. Weill-Raynal: Formation
of C-C Bonds. Thieme, Stuttgart 1975, Vol. 11, p. 542.
251
121 P. Madsen, S . 4 . Lawesson, Rec. Trav. Chim. Pays-Bas 85, 753 (1966).
[3] H. R. Kricheldorf, M . Fehrle, Synthesis 1974, 420.
[4] R. Corn;, R. W Franck, R. Reitano, S. Weinreb, Tetrahedron Lett. 1973,
3107. The stoichiometry of ketimine formation obeys the equation:
( I ) + 1.5 ( 2 ) + ( 3 ) + 0.5 H3NfCH2CH2CO; + [(CH3)3SiI20.
[ 5 ] R. P. Eosrigneeva, K A. Glybinu, E . 1.: Okart, N. A. Preobrazlimskii,
Zh. Obshch. Khim. 30, 2261 (1960); N . K Zotchik, L. D.Miroshnichenko,
R. P. Eosrigneeua, N. A. Preobrazhenskii, ibid. 32, 2823 (1962).
[6] L . Birkhofer, A. Ritter, Chem. Ber. 93, 424 (1 960).
Condensation of u-Acylaminoalkyl Methyl Ketones to
Give N - A c y l p y r r o l e s [ * * l
By Giinter Schulz and Wolfgang Steglichp]
We have reported N-(trimethylsily1)-p-alaninetrimethylsilyl
ester (2) as a novel reagent for the self-condensation of methyl
ketones"! We have now also established that this reagent
is suitable for preparation of N-acylpyrroles from ct-acylaminoalkyl methyl ketones ( 1 ) which are readily accessible
from a-amino acids with acetic anhydride/4-(dimethylamino)pyridine[*I.
Compound ( I ) is suspended in (2) (1.5 equiv.) and a catalytic amount of p-toluenesulfonic acid monohydrate is added.
After brief warming (1) goes into solution and J3-alanine
is precipitated. Further p-toluenesulfonic acid monohydrate
is added and the mixture heated to 80°C for several hours"].
The resulting N-acylpyrroles ( 5 ) are freed from unreacted
starting material by filtration over silica gel.
S = 1.94 ppm (s, 3 H) ;2.03 (s, 3 H) ;2.51 (s, 3H) ;4.47 (d, J = 6 Hz,
IH); 6.13 (broad s, IH); 6.4-6.9 (broad, IH); 6.79 (broad
s, 1 H).
The acetyl group can be removed from the pyrrole nucleus
by hydrolysis with 2 N NaOH (1 h, room temperature).
Procedure:
Synthesis of ( 5 b ) : 3-Acetylaminobutan-2-one(1.I 1 g) and
(2) (3.00 g) are united in an argon-purged flask and warmed
with stirring to 80 to 90°C (bath temperature), the acetylamino
ketone being dissolved. P-Alanine is precipitated within a
few minutes of adding a catalytic amount of p-toluenesulfonic
acid monohydrate. Further p-toluenesulfonic acid monohydrate (0.1 equiv.) is added and the mixture diluted with anhydrous CHCI3 (1 ml). After 24h, the mixture is stirred with
CH2CI2,p-alanine is filtered off, the filtrate evaporated down,
and the residue recrystallized from ether or sublimed in uucuo.
Yield:O.S7g(60 %)ofcolorlesscrystals; m.p. 139°C;IR (KBr):
3260, 1692, 1639cm-'; 'H-NMR (CDC13): 6=1.39ppm (d,
J=6.5Hz, 3H); 1.93 (s, 6H); 2.29 (broad s, 3H); 2.58 (s,
3 H); 5.43 (broad m, 1 H); 6.07 (broad s, 1 H); 6.67 (very broad
d, J = 9 Hz, 1H).
Received: October 28, 1976 [Z 596b IE]
German version: Angew. Chem. 89,256 (1977)
Publication delayed at Authors' request
CAS Registry numbers:
( 1 a ) , 7737-16-8; ( I b ) , 6628-81-5; ( I c), 18227-62-8; ( I d ) , 40689-12-1; ( 2 ) ,
17891-86-0; ( 5 a ) , 38120-89-7; ( 5 6 ) . 61009-71-0; (Sc), 61009-72.1; ( 5 d ) ,
61009-73-2; p-toluenesulfonic acid, 104-15-4
G. Schulz, W Steglirh. Angew. Chem. 8Y, 255 (1977); Angew. Chem.
Int. Ed. Engl. 16, 251 (1977).
121 W Steglich, G. Hbfle, Angew. Chem. 81, 1001 (1969); Angew. Chem.
Int. Ed. Engl. 8, 981 (1969).
[3] ( 5 d ) in CCL: vc0=1710, 1670cm-', vN,=3415cm-'.
[4] S. I. Zaujalov, N. I. Aronocn, I . F. Mnstufaeoa, Izv. Akad. Nauk SSSR,
Ser. Khim. 1972, 1625.
[I]
Control of the Direction of Addition in the
Nickel-Catalyzed 2: 1-Cooligomerization of Butadiene
with Monoolefins by Perturbation of the M o n o o l e f i n C * * ]
(421, R = S i ( C H &
= H
(4b),R
R'
R2
Yield
["/.I
M.p.
["CI
The constitution of the acylpyrroles ( 5 ) follows from elemental analyses, mass spectra, and the IR and 'H-NMR spectra [IR in KBrr3]: v,=1700-1690
and 1640--163Ocm-',
vNH=3280-3260 an-'; 'H-NMR (CDCI3) of ( 5 a ) :
[*] DipLChem. G. Schulz, Prof. Dr. W. Steglich
Institut fur Organische Chemie und Biochemie der Universitat
Max-Planck-Strasse 1, D-5300 Bonn (Germany)
[**I This work was supported by the Deutsche Forschungsgemeinschaft.
252
By Paul Heimbach, Achim Roloff, and Hartmut Schenkluhnp]
It has often been observed that the formation of different
products in metal-catalyzed reactions depends on the nature
of the ligand on the catalyst (ligandcontrol), e. g . in the cyclooligomerization of butadienel'], in the dimerization of propene
on Ni catalysts121, and in the 0x0 synthesis on Rh
In order to investigate the corresponding substrate control,
systems are required which are not subject to ligand control.
In the cooligomerization of butadiene with propylene on nickel
we found that the direction of addition during
the insertion of the monoolefin into the metal-ally1 bond
~l.
is independent of the nature of additional l i g a n d ~ ~However,
Prof. Dr. P. Heimbach ['I, Dr. A. Roloff, Dr. H. Schenkluhn
Universitat Essen-Gesamthochschule, Fachbereich Chemie
Postfach 6843, D-4300 Essen 1 (Germany)
and
Max-Planck-Institut fur Kohlenforschung
Kaiser-Wilhelm-Platz I, D-4330 Mulheim (Germany)
['I To whom correspondence should be addressed.
['*I Control of Metal-Catalyzed Reactions, Part 2-Part
1 : F. Erille, P.
Heimbuch, H . Srhenkluhn, unpublished.
This work was supported by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie.
Angew. Chem. Int. Ed. Engl. 16 ( 1 9 7 7 ) No. 4
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acid, methyl, trimethylsilyl, condensation, self, mild, reagents, esters, amin, ketone, conditions, directed
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