Preparation of Enamines by the Reaction of Ketones and Secondary Amines with Silylating Agents

Full text of DOI:10.1021/jo9712613

J . Org. Chem. 1998, 63, 377-378
377
Ta ble 1. Rela tion sh ip betw een th e Am ou n t of MeI a n d
P r ep a r a tion of En a m in es by th e Rea ction
of Keton es a n d Secon d a r y Am in es w ith
Silyla tin g Agen ts
th e P r od u ct Ra tio
Yasushi Yamamoto*
Silicone-Electronic Materials Research Center,
Shin-Etsu Chemical Co., Ltd., 1-10 Hitomi, Matsuida,
Gunma 379-02, J apan
Chinami Matui
a
Gunma Complex, Shin-Etsu Chemical Co., Ltd.,
Product ratio was estimated by GC.
2
-13-1 Isobe, Annaka, Gunma 379-01, J apan
Sch em e 1
Received J uly 11, 1997
1
. In tr od u ction
Enamines are useful intermediates in organic synthe-
sis, and many methods for their preparation have been
developed.1 Of these protocols, the azeotropic removal
2
of water in benzene or toluene is the most common,
3
4
4
though methods using molecular sieves, TiCl , and
Sch em e 2
metal amides5 have also been reported. Franck and
Weinreb were the first to report the use of N-silylamines
for the preparation of enamines from aldehydes and
ketones.6 While this method is convenient, it suffers from
requiring 2 equiv of the silylamine to drive the reaction
to completion.
Previously we have reported that an equimolar mixture
of silylamine and methyl iodide reacts with ketones much
like trimethylsilyl iodide to generate silyl enol ethers.7
While studying this reaction in detail, we observed
enamine formation as a competitive process when less
than 1 equiv of methyl iodide was used (see Table 1).
From a mechanistic standpoint, we believe that reaction
of methyl iodide with the silylamine generates an active
silylating adduct that transfers a TMS group to the
ketone. When 1 equiv of MeI is used, the amount of
active adduct is sufficient to consume all of the starting
ketone. However, when less than 1 equiv of MeI is used,
the silyl enol ether is generated first, corresponding to
the amount of used methyl iodide. Then residual silyl-
amine reacts with ketone to give enamine according to
the scheme reported by Franck and Weinreb. The
product distribution is a function of the amount of MeI
employed, and when a catalytic amount is used, enamine
formation is almost exclusive.
In this paper, we disclose a method that uses N,O-bis-
trimethylsilyl)acetamide (BSA) and a catalytic amount
of methyl iodide for the preparation of enamines from
ketones.
(
2
. Resu lts a n d Discu ssion
5
7
On the basis of previous reports and our own results,
we anticipated that an appropriate silylating agent
bearing two transferable silyl groups on a moiety that
would be inert to the ketone substrate should eliminate
the need for N-silylamines as a starting material. N,O-
8
Bis(trimethylsilyl)acetamide fulfills this requirement.
When cyclopentanone was added to a solution of pyrro-
lidine and methyl iodide in benzene followed by the
addition of BSA, enamine formation proceeded unevent-
fully (Table 2, entry 1a). Encouraged by these results,
we further explored the scope of this reaction.
Our results are summarized in Table 2. The yields of
enamine are good to excellent, and the reaction is general
for cyclic and acyclic ketones, though it appears to be
(
1) (a) Cook, A. G. In Enamines, Synthesis Structure and Reactions;
Marcel Dekker: New York, 1969. (b) Otaka C. In Preparation of
Enamines; Rappaport, Z., Ed.; J ohn Wiley and Sons: 1994; Chapter
9
, p 467.
2) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J .;
Terrell, R. J . Am. Chem Soc. 1963, 85, 207.
(
(8) Bis(trimethylsilyl) derivatives of primary amines are not ap-
propriate for this reaction because they react with ketones to yield
imines. Duffault, N.; Dupin, J . Bull. Soc. Chim. Fr. 1966, 3205.
(9) (a) Nagarajan, K.; Rajappa, S. Tetrahedron Lett. 1969, 2293. (b)
Kuehne, M. E.; Garbacik, T. J . Org. Chem. 1970, 35, 1555. (c) Tourwe,
D.; Van Binst, G.; De Graaf, S. A. G.; Pandit, U. K. Org. Magn. Reson.
1971, 7, 433. (d) Blanchard, E. P., J r. J . Org. Chem. 1963, 28, 1397.
(e) Gurowitz, W. D.; J oseph, M. A. Tetrahedron Lett. 1965, 4433. (f)
Gurowitz, W. D.; J oseph, M. A. J . Org. Chem. 1967, 32, 3289. (g)
Kennedy, J .; Lewis, A.; McCorkindale, N. J .; Raphael, R. A. J . Chem.
Soc. 1961, 4945. (h) Huebner, C. H.; Dorfman, L.; Robinson, M. M.;
Donoghue, E.; Pierson, W. G.; Strachan, P. J . Org. Chem. 1963, 28,
3134. (i) Brannock, K. C.; Burpitt, R. D.; Goodlett, V. W.; Thweatt, J .
H. J . Org. Chem. 1963, 28, 1464. (j) Pouchert, C. J . In The Aldrich
Library of Infrared Spectra, Edition III; Aldrich Chemical Co., Inc.:
Milwaukee, 1981. (k) Pouchert, C. J . In The Aldrich Library of NMR
Spectra, Edition II; Aldrich Chemical Co., Inc.: Milwaukee, 1983.
(3) Taguchi, K.; Westheimer, F. H. J . Org. Chem. 1971, 36, 1570.
(4) White, W. A.; Weingarten, H. J . Org. Chem. 1967, 32, 213.
(5) (a) Weingarten, H.; White, W. A. J . Org. Chem. 1966, 31, 4041.
(b) Von Hirsch, H. Chem. Ber. 1967, 100, 1289. (c) Pommier, J . C.;
Roubineau, A. J . Organomet. Chem. 1973, 50, 101. (d) Nelson, P.;
Pelter, A. J . Chem. Soc. 1965, 5142. (e) Koketsu, J .; Ishii, Y. J . Chem.
Soc., C 1971, 511. (f) Ando, F.; Ohashi, K.; Koketsu, J . Bull. Chem.
Soc. J pn. 1976, 49, 727.
(
6) Comi, R.; Franck, R. W.; Reitano, M.; Weinreb, S. M. Tetrahedron
Lett. 1973, 3107.
7) (a) Yamamoto, Y.; Shimizu, H.; Hamada, Y. J . Organomet. Chem.
996, 509, 119. (b) Hamada, Y.; Yamamoto, Y.; Shimizu, H. J .
(
1
Organomet. Chem. 1996, 510, 1. (c) Yamamoto, Y.; Shimizu, H.; Matui,
C.; Chinda, M. Main Group Chem. 1996, 1, 409. (d) Yamamoto, Y.;
Matui, C. Organometallics 1997, 16, 2204.
S0022-3263(97)01261-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/23/1998

3
78 J . Org. Chem., Vol. 63, No. 2, 1998
Ta ble 2. P r ep a r a tion of En a m in es Usin g BSA a s a Deh yd r a tin g Agen t
Notes
a
Reaction time includes the addition time of BSA. b 1-Pyrrolidino-2-methylcyclohexene was not detected by GC-MS and 13C NMR.
sensitive to steric interactions (Table 2, entries 3b,c).
Furthermore, a variety of enamines can be prepared by
this method, though in general pyrrolidine appears to be
the most reactive amine (Table 2, entry 3a vs 3b,c and
note that the pyrrolidine reactions always proceed at 30-
ating agent, affording the morpholine enamine of cyclo-
hexanone in 90% yield (eq 2). Finally, p-toluensulfonic
acid can be used in place of methyl iodide with no
appreciable loss in effectiveness (eq 2).
3
. Exp er im en ta l Section
5
0 °C).
Gen er a l R em a r k s. Commercially available BSA, bis(tri-
methylsilyl)urea, amines, ketones, petroleum ether, benzene,
and methyl iodide were used without purification. The structure
of enamines was confirmed by comparison of the spectral data
with those described in the literature.2
-6,9
Illu st r a t ive P r oced u r e for t h e P r ep a r a t ion of E n -
a m in es. In a four-necked flask, equipped with a mechanical
stirrer, a condenser, a thermometer, and a dropping funnel was
placed 41.8 g (0.48 mol) of morpholine, 1.7 g of methyl iodide
(0.012 mol), and 100 mL of petroleum ether, and the mixture
was heated at 40-50 °C for 0.5 h. To this solution was added
3
8
3.6 g (0.4 mol) of cyclopentanone, followed by the addition of
1.2 g (0.4 mol) of BSA over a period of 0.5 h. The mixture was
stirred at 70-80 °C for 1 h, until the ketone was consumed, as
shown by gas chromatography. After the addition of 100 mL of
petroleum ether, the reaction mixture was cooled in an ice water
bath. After the precipitated acetamide was separated by filtra-
tion, the volatile materials were evaporated.10 The residue was
fractionally distilled to give 54.5 g (89%) of 1-morpholinocyclo-
pentene, bp 80-81 °C/3 Torr. The IR spectrum was identical
with an authentic spectrum:9 IR (KBr) 3070, 1630 cm
j
-1
;
1
H
NMR (C D , 60 MHz) δ 1.47-2.13 (m, 2H), 1.90-2.50 (m, 4H),
6
6
2
.50-2.90 (m, 4H), 3.10-3.83 (m, 4H), 4.47 (t, J ) 3 Hz, 1H).
Not surprisingly, the reaction is not limited to BSA.
Bis(trimethylsilyl)urea was equally effective as the silyl-
Ack n ow led gm en t. We express our gratitude to Mr.
Kunio Itoh, General Manager of Silicone Electronic
Materials Research Center, Shin-Etsu Chemical Co.
Ltd., for his suggestions during this work.
(10) When using benzene as solvent, the reaction mixture was
evaporated under reduced pressure and the residue was mixed with
petroleum ether in order to efficiently separate the precipitated
acetamide.
J O9712613