Alkylation of magnesium enamide with alkyl chlorides and fluorides

Article abstract of DOI:10.1021/ja055306q

A magnesium enamide derived from N-2-(N′,N′-diethylamino)ethyl imine reacts with a primary and secondary alkyl chloride or a primary alkyl fluoride to give an α-alkylated ketone in good to excellent yield after hydrolysis. The reaction takes place with a high level of inversion of stereochemistry at the electrophilic carbon center and will be useful for production of optically active compounds. Copyright

Full text of DOI:10.1021/ja055306q

Published on Web 09/27/2005
Alkylation of Magnesium Enamide with Alkyl Chlorides and Fluorides
Takuji Hatakeyama, Shingo Ito, Masaharu Nakamura,*,† and Eiichi Nakamura*
Department of Chemistry, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received August 4, 2005; E-mail: masaharu@chem.s.u-tokyo.ac.jp; nakamura@chem.s.u-tokyo.ac.jp
Chart 1. Examined Metal Enamides
Regioselective alkylation of an enolate anion with an alkyl halide
is the fundamental reaction in organic synthesis.1 Major progress
was made in the 1960s and 1970s through development of the
chemistry of metalloenamine,2 lithium enolate,3 and enol silyl ether,4
yet problems remained. The metal enolate or enamide derived from
a ketone being moderately reactive, the alkylating reagents that give
synthetically useful yield and selectivity, have been limited largely
to alkyl iodides and bromides, and benzylic and allylic halides.
Herein we report that a magnesium enamide bearing an internal
nitrogen coordination site, such as 1a, substantially expands the
scope of the Stork metalloenamine chemistry, allowing alkyl
chlorides and fluorides to serve as effective alkylating electrophiles.
The reaction takes place with inversion of stereochemistry at the
electrophilic carbon center.
In our recent studies on R-tertiary alkylation5 of a zinc enamide
with an olefin,6 we learned that the nitrogen substituent on the
enamine exerts a strong impact on the reactivity and the thermal
stability of metal enamides, and decided to investigate a variety of
combinations of the nitrogen substituent (R) and the metal cation
in the SN2 alkylation reaction (eq 1 and Chart 1). The reaction
between a 3-pentanone imine and chlorocycloheptane was used as
a benchmark under the conditions shown in eq 1.7 Mesityl-
magnesium bromide (MesMgBr) was eventually found to be the
most suitable base for deprotonation of the imine.
Table 1. Effect of Alkyl Substitution (R) and Metal Countercation
product yield (%)b
metal
recovery of
entrya
enamide
2
cycloheptene
c-C7H13Cl (mmol)
1
2c
3
1a
1a
1b
1c
1d
1d
1e
1f
88
69
79
4
51
47
1
23
21
3
11
10
17
7
9
8
4
44
4
0.25
0.34
0.29
0.85
0.60
0.66
1.07
0.41
0.95
1.03
4
5
6c
7
8
9
10
1g
1h
3
a The reaction was carried on a 1.0 mmol scale under the conditions
described in eq 1 (at 45 °C for 24 h, and then 60 °C for 12 h) and otherwise
noted. b Yields of 2 and cycloheptene and recovery of the starting
chlorocycloheptane were determined by GC analysis with octane as an
internal standard. c The reaction was carried out at 45 °C for 24 h.
and gave 2 in only 1% yield. A lithium variant 1f was found to be
reactive but far less selective to give a 1:2 mixture of 2 and
cycloheptene (entry 8). Zinc variants 1g and 1h are inactive under
the reaction conditions, reacting very slowly (entries 9 and 10).
The synthetic potential of the new method is illustrated by the
data in Table 2. The reactions were performed using essentially
equimolar amounts of reactants. Examples with alkyl fluorides and
chlorides are reported, while bromide and iodides not reported here
uneventfully took part in the reaction. Primary alkyl fluoride was
found to be an excellent alkylating reagent. An acyclic enamide 3
reacted with 1-fluorodecane to give 9 in 97% isolated yield (entry
1). The reaction of a cyclic enamide 4 and 1-fluorodecane gave 10
in 75% yield (entry 2).
An unsymmetrical enamide 5 prepared from 2-methylpentan-3-
one imine reacted with 1-fluorodecane at the less substituted carbon
center to give 11 with 91% selectivity (90% yield, entry 3). Either
the lack of regioselectivity of the imine deprotonation or in situ
enamide regioisomerization may result in the formation of the minor
regioisomer. The reaction with 1-chlorodecane gave the product
The data in Table 1 indicate that the alkylation reaction shows
a reactivity profile very different from the one found in a related
carbometalation reaction, where the “soft” zinc countercation plays
a key role.6 A magnesium enamide bearing R ) 2-(N,N-diethyl-
amino)ethyl (entry 1; 1a) is, thus, the best reagent in alkylation,8
giving the desired secondary alkylated ketone 2 in 88% yield after
acidic workup of the reaction mixture. The reaction also produced
cycloheptene in 11% yield. The reaction was incomplete after 24
h at 45 °C (69%, entry 2). A 3-(N,N-dimethylamino)propyl
compound 1b is less reactive and less selective than 1a, giving
79% of 2 and 17% of cycloheptene (entry 3). A 2-methoxyethyl
compound 1c produced much lower yield (entry 4). An enamide
without the heteroatom addend behaves very differently. Stork’s
original N-cyclohexyl compound 1d (entry 5) gave 2 in 47% yield
after 24 h at 45 °C, and heating at 60 °C did not improve the yield
much (51%, entry 6), which we ascribe to decomposition of reactive
species. An N-phenyl compound 1e (entry 7) reacted very slowly
† PRESTO, Japan Science and Technology Agency (JST).
9
14192
J. AM. CHEM. SOC. 2005, 127, 14192-14193
10.1021/ja055306q CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. R-Alkylation with Primary and Secondary Alkyl Halides
decane and 1-chlorodecane to give 13 in 93 and 92% yield,
respectively (cis:trans ) 72:28 and 50:50, respectively, entries 5
and 6).
Entries 7-9 describe the use of secondary alkyl chlorides. The
reaction of 2-chloroheptane with 1a took place in 71% yield to
give 14, where we observed 58:42 syn:anti selectivity (entry 8).
(1-Chloroethyl)benzene reacted much faster to give 15 in 85% with
70:30 syn:anti selectivity (entry 9). The origin of this small syn
preference is uncertain at this time.
Entries 10-12 show functional group tolerance. A remote siloxy
group does not interfere at all with the alkylation reaction (entry
10). Entry 11 indicates that the reaction is feasible even in the
presence of a nearby electron-withdrawing siloxy group to give
the product in acceptable yield. The neighboring amino function
in the chloride does not affect much the reaction as shown for N-(2-
chloroethyl)dimethylamine in entry 12.
The substitution reaction takes place with inversion of stereo-
chemistry at the electrophilic carbon atom (eq 2). For instance, (S)-
(1-chloroethyl)benzene 19 (94.0% ee) reacted with enamide 8 at
30-50 °C to give (S)-1,3-diphenylbutan-1-one 20 in 65% yield
with 88.5% ee. We consider that the substitution itself occurred
with a very high level of inversion of stereochemistry along with
partial racemization of the benzylic chloride substrate.9 Availability
of a variety of chiral alkyl halides and enamides10 suggests that
the reaction offers a new opportunity for asymmetric synthesis.
Supporting Information Available: Details of the experimental
procedure, characterization, and physical data of products (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Yamamoto, Y.; Sasaki, N. Stereochemistry of Organometallic and
Inorganic Compounds; Elsevier Science: New York, 1990; Vol. 4, pp
3-92. (b) Caine, D. ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.: Pergamon Press: New York, 1991; Vol. 3, pp 1-64.
(2) (a) Stork, G.; Brizzolarra, A.; Laudesman, H.; Szmuszkovicz, J.; Terrell,
R. J. Am. Chem. Soc. 1963, 85, 207-222. (b) Stork, G.; Dowd, S. R. J.
Am. Chem. Soc. 1963, 85, 2178-2180. (c) Stork, G.; Benaim, J. J. Am.
Chem. Soc. 1971, 93, 5938-5639. (d) Corey, E. J.; Enders, D. Tetrahedron
Lett. 1976, 17, 3-6.
(3) (a) Stork, G.; Rosen, P.; Goldman, N. L. J. Am. Chem. Soc. 1961, 83,
2965-2966. (b) Spencer, T. A.; Britton, R. W.; Watt, D. S. J. Am. Chem.
Soc. 1967, 89, 5727-5729. (c) House, H. O.; Gall, M.; Olmstead, H. D.
J. Org. Chem. 1971, 36, 2361-2371.
(4) (a) Stork, G.; Hudrlik, P. F. J. Am. Chem. Soc. 1968, 90, 4464-4465. (b)
Kuwajima, I.; Nakamura, E. J. Am. Chem. Soc. 1975, 97, 3257-3258.
(c) Kuwajima, I.; Nakamura, E.; Shimizu, M. J. Am. Chem. Soc. 1982,
104, 1025-1030.
a The reaction was carried out in THF (ca. 0.8 M for enamide) on 1.0-
2.2 mmol scale unless otherwise noted. b Metal enamide was prepared from
the corresponding imine and 1.1 equiv of MesMgBr unless otherwise noted.
c Alkyl halide (1.2 equiv) was used unless otherwise noted. d Isolated yield
based on imine used. e cis:trans ) 72:28. f cis:trans ) 50:50. g The reaction
was carried out after THF was mostly removed in vacuo (ca. 2.0 M for
enamide). h The use of 1.5 equiv of alkyl halide. i Alkyl chloride was
prepared in situ by treatment of the corresponding hydrochloric acid salt
with t-BuMgCl. Enamide 7 (1.4 equiv for alkyl chloride) was prepared by
using t-BuMgCl. Yield was determined by GC analysis on the basis of the
alkyl chloride.
(5) (a) Paterson, I. Tetrahedron Lett. 1979, 1519-1520. (b) Reetz, M. T.;
Hu¨ttenhain, S. H.; Walz, P.; Lo¨we, U. Tetrahedron Lett. 1979, 4971-
4974. (c) Reetz, M. T.; Walz, P.; Hu¨bner, F.; Hu¨ttenhain, S. H.; Heimbach,
H.; Schwellnus, K. Chem. Ber. 1984, 117, 322-335.
(6) Nakamura, M.; Hatakeyama, T.; Nakamura, E. J. Am. Chem. Soc. 2004,
126, 11820-11825.
(7) See Supporting Information for details of the deprotonation and the
alkylation procedure.
(8) Some other dialkyl amino derivatives gave comparable results: dimethyl-
amino (87%), piperidyl (88%), pyrrolidyl (72%), and morpholyl (82%).
(9) Heald, K.; Williams, G. J. Chem. Soc. 1954, 362-366.
(10) Nakamura, M.; Hatakeyama, T.; Hara, K.; Nakamura, E. J. Am. Chem.
Soc. 2003, 125, 6362-6363.
in higher yield but with slightly lower regioselectivity (entry 4). In
contrast, an enamide 6 prepared from 2-methylcyclohexanone imine
showed 100% regioselectivity in the reactions with 1-fluoro-
JA055306Q
9
J. AM. CHEM. SOC. VOL. 127, NO. 41, 2005 14193