The reductive coupling of tertiary amides to give enediamines using PhMe2SiLi

Article abstract of DOI:10.1039/a800648b

PhMe₂SiLi reacts with tertiary amides to give enediamines, which can be isolated in good yield when the α-carbon is branched; the enediamines can be hydrolysed more or less easily to α-amino ketones, isomerised from Z to E, oxidised to dienedia

Full text of DOI:10.1039/a800648b

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The reductive coupling of tertiary amides to give enediamines using PhMe2SiLi
Ian Fleming,*a† Usha Ghosh,a Stephen R. Macka and Barry P. Clarkb
a Department of Chemistry, Lensfield Road, Cambridge, UK CB2 1EW
b Eli Lilly and Co., Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey, UK GU20 6PH
Me2N
NMe2
PhMe2SiLi reacts with tertiary amides to give enediamines,
which can be isolated in good yield when the a-carbon is
branched; the enediamines can be hydrolysed more or less
easily to a-amino ketones, isomerised from Z to E, oxidised
to dienediamines and isomerised to amino enamines.
NMe2
O
NMe2
O
i
ii
1a
5
83%
6
92%
We have been studying the reactions of PhMe2SiLi1 with a
variety of substrates, including carbon electrophiles at the
oxidation state of a carboxylic acid. One goal in this work had
been to find a synthesis of acylsilanes that might be even easier
than the reaction between an acid chloride and a silyl cuprate.2
We reported almost no success, and several surprises, in the
reaction between the silyllithium reagent and nitriles,3 some
success in the reaction with esters,4 and some success with
tertiary amides 1a?2, provided that the reaction is carried out
and quenched at dri ice–acetone temperatures.4 To avoid this
delicate operation, the standard device when synthesising
aldehydes or ketones from amides is to use a Weinreb amide,5
but we find that this does not work for the synthesis of
acylsilanes, because the Weinreb amide 1b gives N–O cleavage
instead (Scheme 1), presumably by elimination of methoxide
from the tetrahedral intermediate 3 giving the secondary amide
4.6 Among the variety of unexpected reactions of the silyl-
lithium reagent that we have already reported, none has been as
surprising as the reactions with tertiary amides carried out at
higher temperatures, which we report here and in the following
two papers.
When we treated the same N,N-dimethylamide 1a with a little
over 1 equiv. of the silyllithium reagent at 220 °C, and
quenched the mixture with aq. NaHCO3 at that temperature, we
obtained a good yield of the crystalline enediamine 5 (Scheme
2). Although there is one precedent for this type of reaction,
where a 14% yield of an enediamine was obtained from N,N-
diethylbenzamide with Et3SiLi,7 we were at first uneasy about
the structure of this compound, since it had survived dissolution
in dilute hydrochloric acid overnight at room temperature—
conditions that are far more vigorous than those usually needed
for the hydrolysis of an enamine. An X-ray crystal structure
NMe2
Me2N
R
NMe2
NMe2
O
i
iii
R
R
R
R
O
7a R = Pri
b R = But
c R = Prn
8a 80%
9a 79%
b 6%
c 81%
d 72%
e 75%
f 59%
g 52%
h 69%
i 60%
j 46%
k 51%
d R = Me(CH2)8
e R = CH2=CH(CH2)2
f R = CH2=CH(CH2)3
g R = Bn
h R = Ph(CH2)2
i R = PH(CH2)3
j R = Ph(CH2)4
k R = Ph
Scheme 2 Reagents and conditions: i, PhMe2SiLi (1.1 equiv.) THF, 278 ?
220 °C, 1 h; ii, 3 m HCl, 70 °C, 18 h; iii, 3 m HCl, various times and
temperatures
(Fig. 1) confirmed that it was the enediamine and showed also
that it was the Z isomer.8‡
The stability in acid was now convincingly explained—the
lone pairs on both nitrogen atoms are in the plane of the double
bond, and not conjugated to it as they are in a typical enamine.
Hydrolysis of the enediamine 5 required heating to 70 °C in
dilute hydrochloric acid for 18 h in order to obtain the a-amino
ketone 6. Clearly, in contrast to the one precedent, the reductive
coupling of amides can be a high-yielding reaction. We find that
the amides 7a–k undergo reductive coupling followed by
hydrolysis to give the a-amino ketones 9a–k, but the enedia-
mines 8a–k, although detectably intermediates, were only
easily isolated when they carry branched substituents, as with
8a, to confer on them this remarkable hydrolytic stability.
The enediamines 5 and 8a showed a number of unexpected
reactions (Scheme 3). When we treated the enediamine 5 with
methyl acrylate, attempting to induce a cycloaddition charac-
teristic of enamines,9 it isomerised to the E isomer 11a, which
was remarkable for the substantial difference in its properties
from the Z isomer: the Rf value on silica gel eluting with hexane
changed from 0.1 to 0.7 and the mp changed from 89–90 °C to
175–176 °C. The isomerisation from the Z isomers 5 and 8a to
O
O
i, ii
NMeR
SiMe2Ph
R = Me
1a R = Me
b R = OMe
2
69%
i
R = OMe
O
SiMe2Ph
O
Me
N
ii
NHMe
OMe
3
4 67%
Scheme 1 Reagents and conditions: i, PhMe2SiLi (1.2 equiv.) THF,
278 °C, 1.5 h; ii, NH4Cl, H2O, 278 °C ? room temp.
Fig. 1 Stereoview of the enediamine 5
Chem. Commun., 1998
711

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Me2N
NMe2
R
We thank Dr P. R. Raithby, Dr H. R. Powell and C. Wilson
for carrying out the X-ray structure determination, the EPSRC
and Lilly Industries for a CASE studentship for S. R. M., and
Duckhee Lee for the experiment with the Weinreb amide.
R
R
R
5
R–R = (CH2)5
8a R = Me
Notes and References
v
i, ii
† E-mail: if10000@cam.ac.uk
‡ Crystal data for 5: C18H34N2, FM
or iv
iii
= 278.47, monoclinic, P2(1)/n,
a = 6.3930(6), b = 13.3934(11), c = 20.962(2) Å, b = 91.6833(11)°,
T = 293(2) K, Z = 4, m = 0.443 mm21, 5035 reflections collected, of
which 3621 were independent, R1 = 0.0884, wR2 = 0.1811. CCDC
182/765.
Me2N
R
R
Me2N
R
Me2N
R
R
i, ii
v
R
R
R
R
R
R
NMe2
R
NMe2
NMe2
1 M. V. George, D. J. Peterson and H. Gilman, J. Am. Chem. Soc., 1960,
82, 403; A. S. Guram and G. A. Krafft, in Encyclopaedia of Reagents for
Organic Synthesis, ed. L. A. Paquette, Wiley, Chichester, 1995, p. 2113;
I. Fleming, in Synthetic Methods of Organometallic and Inorganic
Chemistry (Hermann/Brauer), ed. N. Auner and U. Klingebiel, Georg
Thieme, Stuttgart, 1996, vol. 2, p. 167.
11a
94% from 11a
78% from 11b
97%
83% from 5
12a
10a
R–R = (CH2)5
42%
77% from 11b
b
b
b R = Me
vi
vi
vi
2 B. F. Bonini, F. Busi, R. C. de Laet, G. Mazzanti, J.-W. J. F. Thuring,
P. Zani and B. Zwanenburg, J. Chem. Soc., Perkin Trans. 1, 1993, 1011;
B. F. Bonini, M. Comes-Franchini, G. Mazzanti, U. Passamonti,
A. Ricci and P. Zani, Synthesis, 1995, 92. For some related reactions see
also: J. Kang, J. H. Lee, K. S. Kim, J. U. Jeong and C. Pyun, Tetrahedron
Lett., 1987, 28, 3261; A. G. Brook, A. Baumegger and A. J. Lough,
Organometallics, 1992, 11, 310; K. Yamamoto, A. Hayashi, S. Suzuki
and J. Tsuji, Organometallics, 1987, 6, 974; A. Ricci, A. Degl’Inno-
centi, S. Chimichi, M. Fiorenza, G. Rossini and H. J. Bestmann, J. Org.
Chem., 1985, 50, 130; F. Jin, B. Jiang and Y. Xu, Tetrahedron Lett.,
1992, 33, 1221; M. Nakada, S. Nakamura, S. Kobayashi and M. Ohno,
Tetrahedron Lett., 1991, 32, 4929; P. Bourgeois, J. Dunogue`s and
N. Duffaut, J. Organomet. Chem., 1974, 80, C25; J.-P. Picard, R. Calas,
J. Dunogue`s, N. Duffaut, J. Gerval and P. Lapouyade, J. Org. Chem.,
1979, 44, 420; P. Bourgeois, J. Organomet. Chem., 1974, 76, C1;
N. Kise, H. Kaneko, N. Uemoto and J. Yoshida, Tetrahedron Lett.,
1995, 36, 8839.
3 I. Fleming, M. Solay and F. Stolwijk, J. Organomet. Chem., 1996, 521,
121.
4 I. Fleming and U. Ghosh, J. Chem. Soc., Perkin Trans. 1, 1994, 257.
5 S. Nahm and S. M. Weinreb, Tetrahedron Lett., 1981, 22, 3815.
6 D. Lee, Ph.D., Thesis, Cambridge, 1997.
7 D. A. Bravozhitivitovsk, S. D. Pigarev, I. D. Kalikhman, O. A.
Vyazankina and N. S. Vyazankin, J. Organomet. Chem., 1983, 114,
51.
8 P. R. Raithby, H. R. Powell and C. Wilson, unpublished work,
Cambridge, 1994.
NMe2
O
R
O
R
R
R
R
R
R
R
O
92% from 11a, 82% from 10a
79% from 8a
6
13a
93%
56%
9a
b
Scheme 3 Reagents and conditions: i, (CO2H)2, recrystallise from EtOAc;
ii, NaOH, H2O; iii, CH2NCHCO2Me, 60 °C, 24 h; iv, PtO2, MeOH, 50 °C,
15 min; v, Pd/C, MeOH, room temp., 4 h; vi, 3 m HCl, 70 °C, 18 h
the E isomers 11a, b, respectively, is actually better carried out
using a short treatment with Adams’ catalyst. The enediamines,
both the Z and E isomers, gave oxalate salts, but simple
recrystallisation of these salts, followed by basification, gave
the isomers 10a and 10b of the enediamines in which the double
bond had moved. All of the enediamines could be hydrolysed to
the a-amino ketones 6 and 9a, but all attempts to reduce any of
them to the saturated vicinal diamine failed. Most remarkable
amongst our attempts was the oxidation of the enediamines 5 or
11a using hydrogen and palladium on charcoal, which gave the
dienediamine 12a. Needless to say, this oxidation was better
performed without the hydrogen, and the first step, when carried
out on the Z isomers, appears to be isomerisation to the E
isomers. Hydrolysis of the dienediamines 12 gave the
a-diketones 13.
9 K. C. Brannock, A. Bell, R. D. Burpitt and C. A. Kelly, J. Org. Chem.,
1964, 29, 801; K. C. Brannock, R. D. Burpitt, V. W. Goodlett and
J. G. Thweatt, J. Org. Chem., 1964, 29, 813; I. Fleming and J. Harley-
Mason, J. Chem. Soc., 1964, 2165.
10 A. Ogawa, N. Takami, M. Sekiguchi, I. Ryu, N. Kambe and N. Sonoda,
J. Am. Chem. Soc., 1992, 114, 8729.
The reductive coupling of the amide carbonyls resembles the
McMurry coupling of aldehydes and ketones, and even more
closely the reductive coupling of amides using samarium and its
iodide,10 and other lanthanides and their salts.11 While an
electron transfer mechanism might be operating in our reaction,
the very different reagent that we have used led us to suspect
otherwise. We describe our investigations into the mechanism
of the coupling in the following paper.
11 A. Ogawa, T. Nanke, N. Takami, M. Sekiguchi, N. Kambe and
N. Sonoda, Appl. Organomet. Chem., 1995, 9, 461.
Received in Liverpool, UK, 12th November 1997; revised manuscript
received, 21st January 1998; 8/00648B
712
Chem. Commun., 1998