Enantioselective alkylation of aldehydes with chiral organomagnesium amides (COMAs)

Article abstract of DOI:10.1021/ol0258132

(graph presented) Dialkylmagnesiums react with chiral secondary amines to form chiral organomagnesium amides (COMAs). These reagents alkylate aldehydes to form secondary alcohols with enantioselectivities up to 91:9 er.

Full text of DOI:10.1021/ol0258132

ORGANIC
LETTERS
2002
Vol. 4, No. 21
3553-3556
Enantioselective Alkylation of Aldehydes
with Chiral Organomagnesium Amides
(COMAs)
Kelvin H. Yong, Nicholas J. Taylor, and J. Michael Chong*
Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry,
(GWC)2, and Department of Chemistry, UniVersity of Waterloo, Waterloo,
Ontario, Canada N2L 3G1
jmchong@uwaterloo.ca
Received March 4, 2002 (Revised Manuscript Received August 29, 2002)
ABSTRACT
Dialkylmagnesiums react with chiral secondary amines to form chiral organomagnesium amides (COMAs). These reagents alkylate aldehydes
to form secondary alcohols with enantioselectivities up to 91:9 er.
The enantioselective addition of organometallic reagents to
carbonyl compounds to prepare alcohols has been the subject
of intense scrutiny over the past few decades. Significant
advances have been made, particularly with organozinc
reagents,1 to enable such reactions to be carried out with
high degrees of stereoselectivity. However, although con-
siderable attention has been paid to modifying more tradi-
tional organometallics such as organolithiums and magne-
siums with chiral ligands, these metals have enjoyed only
limited success.2 This limited success is due, at least in part,
to the intrinsic high reactivity of these organometallics to
carbonyl compounds coupled with decreased reactivity upon
complexation with chiral ligands. This combination has
meant that modifications with chiral complexing agents have
typically given fairly low selectivities except where very low
temperatures or large excesses of ligand are employed.
Despite these disadvantages, the ready availability of orga-
nomagnesium (Grignard) reagents makes them extremely
attractive targets for enantioselective modification.3 We now
report that by directly linking a chiral ligand to Mg in the
form of organomagnesium amides, good enantioselectivities
in the alkylation of aldehydes may be achieved.4
Achiral organomagnesium amides (RMgNR′2) have been
known for over 20 years,5 but there have been no reports of
chiral versions of these reagents.6-8 This is somewhat
surprising given the tremendous variety of chiral amines that
have been successfully used in other asymmetric transforma-
tions. On the other hand, perhaps the lack of interest in these
reagents for alkylations is to be expected given their known
propensity to enolize5 and reduce (via â-hydride transfer)
(3) Recent examples: (a) Weber, B.; Seebach, D. Tetrahedron 1994,
50, 6117-6128. (b) Nakajima, M.; Tomioka, K.; Koga, K. Tetrahedron
1993, 49, 9751-9758. (c) Knollmu¨ller, M.; Ferencic, M.; Ga¨rtner, P.
Tetrahedron: Asymmetry 1999, 10, 3969-3975.
(4) Disclosed, in part, in: Chong, J. M.; Yong, K. H. Asymmetric
Alkylation of Aldehydes with Chiral Organomagnesium Amides; PacifiChem
2000, Honolulu, HI, 2000.
(5) Ashby, E. C.; Willard, G. F. J. Org. Chem. 1978, 43, 4094-4098.
(6) It was suggested that the use of alkyl(amido)magnesium compounds
as “asymmetric induction reagents” would be studied, but results have not
been reported: Henderson, K. W.; Allan, J. F.; Kennedy, A. R. J. Chem.
Soc., Chem. Commun. 1997, 1149-1150.
(7) Very recently, the enantioselective 1,4-addition of organomagnesium
amides derived from bisoxazolines to enamidomalonates was described:
Sibi, M. P.; Asano, Y. J. Am. Chem. Soc. 2001, 123, 9708-9709.
(8) Related chiral magnesium bisamides have been reported to be
effective for enantioselective deprotonations: (a) Henderson, K. W.; Kerr,
W. J.; Moir, J. H. J. Chem. Soc., Chem. Commun. 2000, 479-480. (b)
Henderson, K. W.; Kerr, W. J.; Moir, J. H. Tetrahedron 2002, 58, 4573-
4587.
(1) Review: Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757-824.
(2) Reviews: (a) Solladie´, G. In Asymmetric Synthesis; Morrison, J. D.,
Ed.; Academic Press: New York, 1983; Vol. 2, pp 157-199. (b) Huryn,
D. M. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds;
Pergamon: Oxford, 1991; Vol. I, part I, pp 49-75.
10.1021/ol0258132 CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/19/2002

ketones.6 Notwithstanding these possible limitations, we
reasoned that direct linkage of an amine ligand as a metal
amide, as in organomagnesium amides, would be more
successful than the use of external coordinating agents. We
therefore prepared some chiral organomagnesium amides and
investigated their reactivity with carbonyl compounds.
Ashby has shown that admixture of Me2Mg with second-
ary amines R2NH in Et2O at room temperature results in a
rapid acid-base reaction to provide MeMgNR2.5 Therefore
we allowed n-Bu2Mg to react with amine 1a, a compound
that has been shown to be an effective chiral ligand in
organocopper chemistry,9 under the same conditions. The
reagent so formed, represented as 2 on the basis of stoichi-
ometry, reacted smoothly with PhCHO (Et2O, -78 °C) to
give a single product, the desired alcohol 3. There was no
evidence of reduction or other competing side reactions. The
selectivity observed (80:20 er) was encouraging enough to
examine this reaction further. Addition of THF or other
Lewis bases (e.g., THP, pyridine, Et3N, PPh3) increased the
selectivity slightly. Best selectivities were observed with THF
at -78 °C (89:11 er, 76% yield). Lowering the reaction
temperature to -90 °C increased the selectivity somewhat
but at the expense of yield (91:9 er, 70% yield). Reactions
in neat THF (-78 °C) gave comparable selectivities (87:13
er) but in much lower yield.
Table 1. Reactions of COMA 2 with Aldehydes
entry
R
product
yielda
erb
1
Ph
Ph
3a
3a
3b
3c
3d
3e
3f
76
70
57
50
71
34d
41e
89:11
91:9
2c
3
4
5
6
4-CH3C6H4
4-ClC6H4
1-naphthyl
MOMO(CH2)8
BnO(CH2)7
88:12
83:17
77:23
82:18
84:16
7
a Percent isolated yields of chromatographed 3. b Determined by HPLC
analysis on a Chiralcel OD column. c Reaction carried out at -90 °C. d The
yield based on recovered starting material was 89%. e The yield based on
recovered starting material was 88%.
(66-80%) and its enantiomeric purity was determined.
Changing the ring size of the tertiary amine (entries 1-3)
showed that a six-membered ring (diamine 1a) gave highest
selectivities and an acyclic analogue (entry 4) decreased the
selectivity.
Variation of the size of R1 (entries 1, 5-7) showed that a
methyl group was best. Finally, changes in R2 (by using
valine, phenylalanine, and tert-leucine in place of phenylg-
lycine in the synthesis of diamine 1, entries 8-10) suggested
that a phenyl group (as in 1a) performs better than alkyl
groups. Somewhat ironically, after probing these simple
structural variations, the first ligand examined, namely, 1a,
has thus far given the highest selectivities.
Scheme 1
The absolute configuration of 3a was determined by
comparison of observed rotations with literature values.10 In
general, for ligands 1a-j, ligands with R configuration gave
Table 2. Effect of Ligand Structure on Stereoselectivity
Thus chiral organomagnesium amide (COMA) 2 was
treated with other aldehydes (Table 1) in Et2O-THF. In
general, reasonable levels of enantioselectivity were obtained,
with highest selectivities observed for various benzaldehydes.
It is noteworthy that even aliphatic aldehydes (Table 1,
entries 6 and 7) gave good induction, albeit with only modest
yields. However, chemical yields based on recovered alde-
hyde were quite high. Quenching experiments with MeOD
suggest that competing enolization may be a problem with
aliphatic aldehydes.
liganda
er of 3b
entry
R1
R2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
R3
no.
R:S
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Et
(CH2)5
(CH2)4
(CH2)6
Et2
1a
1b
1c
1d
1e
1f
1g
1h
1i
89:11
73:27
74:26
67:33
43:57
39:61
46:54
36:64
28:72
25:75
(CH2)5
(CH2)5
(CH2)5
(CH2)5
(CH2)5
(CH2)5
H
To probe the effects of structural variations of the ligand
on the stereoselectivity of alkylation, other diamines were
prepared and evaluated for the butylation of benzaldehyde
(Table 2). In each case, alcohol 3a was isolated in good yield
t-Bu
Me
Me
Me
i-Pr
PhCH2
t-Bu
10
1j
a Ligands 1a-d had R configuration; 1e-j had S configuration.
(9) Rossiter, B. E.; Eguchi, M.; Miao, G.; Swingle, N. M.; Hernandez,
A. E.; Vickers, D.; Medich, J.; Marr, J.; Heinis, D. Tetrahedron 1993, 49,
965-986.
b Determined by HPLC analysis with a Chiralcel OD column.
3554
Org. Lett., Vol. 4, No. 21, 2002

(R)-3a as the major isomer while (S)-ligands produced (S)-
3a preferentially. In addition, for alcohols 3b-e prepared
using ligand 1a (which has R configuration, Table 1), the
absolute configuration of the major enantiomer formed was
always R.11 Thus the absolute configuration of the major
product may be reliably predicted.
Table 3. Alkylation of PhCHO with COMA Reagents
In an effort to better understand this reaction, crystals of
COMA 2 were grown and analyzed by X-ray crystallography
(Figure 1). Structures of a few simple organomagnesium
entry
R
product
yielda
erb
1
2
3
4
5
6
Me
Et
4a
4b
3a
4c
4d
4e
34c
70
76
77
76
44d
86:14
84:16
89:11
89:11
88:12
72:28
n-Bu
n-C7H15
n-C10H21
i-Pr
a Percent isolated yields of chromatographed alcohol. b Determined by
HPLC analysis on a Chiralcel OD column. c Reaction carried out in THF.
Low yield due to incomplete reaction and volatility of product. d Benzyl
alcohol also formed.
Mg with 1a produced COMA reagents, which could alkylate
PhCHO with good levels enantioselectivity (Table 3).
Straight chain alkyl groups of varying lengths all gave similar
selectivities and yields. However, a branched alkyl group
(i-Pr) gave a low yield of the desired secondary alcohol along
with considerable amounts of benzyl alcohol.
This chemistry is not limited to alkyl groups. Ph2Mg could
be used to arylate a substituted benzaldehyde to form a chiral
diaryl carbinol with reasonable selectivity (Scheme 2). Such
Scheme 2
Figure 1. ORTEP drawing of COMA reagent 2.
amides (e.g., Me2Mg/MeHNCH2CH2NMe2) are known12 and
are also dimeric, but this is the first X-ray structure of a
chiral organomagnesium amide. The structure is very similar
to previously reported structures of dialkylzinc-amino
alcohol complexes, materials that are catalyst precursors for
extremely effective enantioselective alkylating agents.13
While mechanistic arguments cannot be made on the basis
of a single X-ray structure, the absolute configurations of
major products in these COMA additions can be rationalized
by invoking arguments of least hindered approach of
aldehydes to a dimeric reagent.
asymmetric arylations have, until recently, been very difficult
to achieve with good selectivities.14
Because the group to be transferred may be more valuable
than n-Bu, we investigated the possibility of preparing
COMAs without sacrificing one of the alkyl groups of the
dialkylmagnesium. When amine 1a was allowed to react with
0.5 equiv of Me2Mg, a clear solution, presumably the
diamidomagnesium was formed. Addition of 0.5 equiv of
Bu2Mg and THF to this solution gave a solution that reacted
with PhCHO in a manner identical to that with the reagent
prepared from the amine and 1 equiv of Bu2Mg (i.e., 73%
yield of 3a, 89:11 er). This method for forming COMAs,
although less convenient, offers the distinct advantage of
sacrificing the readily available Me2Mg as a base rather than
losing a more important alkyl group.
Other alkyl groups could also be transferred using COMA
reagents. Thus reaction of a series of dialkylmagnesiums R2-
(10) (R)-(+)-3a shows [R]25D ) 45.9 (c 6, C6H6): Mukaiyama T.; Soai,
K.; Sato, T.; Shimizu, H.; Suzuki, K. J. Am. Chem. Soc. 1979, 101, 1455-
1460.
(11) See Supporting Information for details.
(12) (a) Henderson, K. W.; Mulvey, R. E.; Clegg, W.; O’Neil, P. A. J.
Organomet. Chem. 1992, 439, 237-250. (b) Magnuson, V. R.; Stucky, G.
D. Inorg. Chem. 1969, 8, 1427-1433. (c) Olmstead, M. M.; Grigsby, W.
J.; Chacon, D. R.; Hascall, T.; Power, P. P. Inorg. Chim Acta 1996, 251,
273-284.
(13) (a) Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem.
Soc. 1989, 111, 4028-4036. (b) Kitamura, M.; Suga, S.; Niwa, M.; Noyori,
R. J. Am. Chem. Soc. 1995, 117, 4832-4842.
In addition, the amine ligand is easily recovered at the
end of the reaction by simple acid-base extraction followed
by distillation. The recovered ligand has been reused in
COMA reactions without affecting the yield or the er.
(14) Huang, W.-S.; Pu, L. J. Org. Chem. 1999, 64, 4222-4223.
Org. Lett., Vol. 4, No. 21, 2002
3555

Overall, we have shown that chiral organomagnesium
amides (COMAs) can be easily prepared from dialkylmag-
nesiums and chiral amines. The first alkylations of aldehydes
using these reagents have been achieved, and good levels of
stereoinduction are observed. The ready accessibility of
dialkylmagnesiums (from Grignard reagents) and the facile
recovery of the amine ligand suggest that this approach to
asymmetrically alkylate aldehydes offers considerable prom-
ise. Studies to develop more selective reagents are underway.
support and the Ontario Ministry of Training, Colleges, and
Universities for a postgraduate scholarship (to K.H.Y.)
Supporting Information Available: Experimental details
for the preparation of and spectral data for compounds 3-5,
procedures for preparation and titration of R2Mg solutions,
details for determinations of enantiomer ratios and absolute
configurations, and X-ray crystallographic data for 2. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada for financial
OL0258132
3556
Org. Lett., Vol. 4, No. 21, 2002