MIB: An advantageous alternative to DAIB for the addition of organozinc reagents to aldehydes

Article abstract of DOI:10.1039/a904042k

3-exo-Morpholinoisoborneol (MIB) catalyzes the addition of organozinc reagents to aldehydes in high enantiomeric excess and provides several advantages over the venerable amino alcohol ligand DAIB.

Full text of DOI:10.1039/a904042k

MIB: an advantageous alternative to DAIB for the addition of organozinc
reagents to aldehydes
William A. Nugent
DuPont Company, Central Research and Development, PO Box 80328, Wilmington, DE 19880-0328, USA.
E-mail: william.a.nugent@usa.dupont.com
Received (in Corvallis, OR, USA) 14th May 1999, Accepted 10th June 1999
3
-exo-Morpholinoisoborneol (MIB) catalyzes the addition of
Table 1 Enantioselective addition of Et
+)-MIBa
2
Zn to aldehydes catalyzed by
(
organozinc reagents to aldehydes in high enantiomeric
excess and provides several advantages over the venerable
amino alcohol ligand DAIB.
MIB/
mol% T/°C t/h
Yield Ee
b
(%)b
Entry Aldehyde
(%)
The addition of organozinc reagents to aldehydes catalyzed by
1
2
3
4
5
6
7
8
9
0
Benzaldehyde
m-Tolualdehyde
p-Fluorobenzaldehyde
3-Furaldehyde
Hexanal
Isobutyraldehyde
Cyclohexanecarboxaldehyde
2-Ethylbutyraldehyde
Cyclopropanecarboxaldehyde 5
Trimethylacetaldehyde
2
2
5
5
5
5
5
5
0
0
0
0
0
0
0
25
0
25
3
3
3
6
3
3
3
18
3
24
98
97
98
91
96
94
94
92
91
62
98
98
98
97
91
99
99
99
98
97
1
enantiopure b-amino alcohols represents the enantioselective
2
counterpart of the Grignard addition reaction. The extensive
research on this transformation has been summarized in review
3
articles. The first ligand to provide high enantioselectivities in
such reactions was 3-exo-dimethylaminoisoborneol (DAIB, 1b)
4
which was developed by Noyori and co-workers. Despite the
5
many alternative b-amino alcohol ligands now available,
interest in DAIB has remained remarkably high. Recent studies6
provide detailed insight into the mechanism of DAIB-promoted
additions and new applications of this venerable ligand continue
to appear.7
1
a
5
All reactions contained aldehyde (3.0 mmol) and Et Zn (6.0 mmol) in 2+1
2
hexane–toluene (9 ml); for details see note ‡. b Determined by chiral
capillary column gas chromatography on Cyclodex B stationary phase
While DAIB has enjoyed great success, three factors
somewhat limit further extensions of this technology. (i) The
most efficient synthesis, that developed by White and co-
workers,8 requires three steps for the conversion of parent
amino alcohol 1a to DAIB. (ii) DAIB is somewhat air-sensitive
and slowly decomposes upon storage.4 (iii) While DAIB-
promoted addition of organozinc reagents to aromatic alde-
hydes proceeds in excellent enantiomeric excess, it has not yet
proven possible to obtain similar ees in the case of a-branched
(
J&W Scientific); in all cases (R)-enantiomer formed preferentially.
alkoxides to the corresponding acetate esters and allows direct
analysis of the product mixture by chiral capillary column gas
chromatography. As exemplified by entries 1–4, addition of
Et Zn to aromatic and heteroaromatic aldehydes proceeded
2
cleanly with enantiomeric excesses similar to those reported
using DAIB. Moreover, we were delighted to find that addition
10
4
aliphatic aldehydes. Here we report that a simple structural
of Et
6
2
Zn to several a-branched aliphatic aldehydes (entries
modification circumvents these problems whilst retaining the
desirable features of DAIB.
–10) also proceeded in 97–99% enantiomeric excess. Only in
the case of the straight-chain aliphatic aldehyde hexanal did the
ee begin to erode. In all cases in Table 1 the major enantiomer
of the product had the R absolute configuration, thus the sense
of chirality obtained from (+)-MIB is the same as that obtained
from (+)-DAIB.
(
2R)-(+)-3-exo-Aminoisoborneol (+)-1a was prepared by
LiAlH
4
reduction of anti-(1S)-(2)-camphorquinone 3-oxime
8,9
following the literature procedure. Treatment of (+)-1a with
commercial bis(2-bromoethyl) ether in the presence of excess
Et
).† Extractive work-up followed by crystallization from
hexanes afforded (2R)-(+)-3-exo-morpholinoisoborneol
(+)-MIB] as transparent crystals, mp 65–67 °C. The enantio-
3
N resulted in dialkylation of the amine nitrogen (Scheme
2
The reduced yield observed for addition of Et Zn to the
1
tertiary aliphatic aldehyde trimethylacetaldehyde requires some
comment. The limited yield can be traced to competing
reduction of the the aldehyde to the zinc alkoxide of neopentyl
alcohol which is subsequently acetylated under our reaction
conditions (Scheme 3). The formation of minor amounts of
2
[
mer (2)-MIB was prepared similarly from (2)-1a.
Like DAIB, MIB promotes the enantioselective addition of
organozinc reagents to aldehydes (Scheme 2). The addition of
2
BnOH as a side-product of DAIB-catalyzed addition of Et Zn to
Et
fold excess Et
Table 1. The reactions in Table 1 were quenched by addition of
Ac O which quantitatively converts the intermediate zinc
2
Zn to a series of aldehydes under standard conditions (two-
11
benzaldehyde has been noted by Noyori and co-workers. In
our experience, detectable amounts of primary alcohol are
invariably formed during addition of organozinc reagents to
aldehydes in the presence of b-amino alcohols. This side-
reaction is most severe in the case of sterically bulky aldehydes
bearing tertiary alkyl substituents. In contrast, for the other
aldehydes in Table 1, this reductive pathway occurs to the extent
of 2% or less for aromatic and primary aliphatic aldehydes
2
Zn in 2+1 hexane–toluene)‡ is summarized in
2
(
BrCH2CH2)2O
OH
OH
NR2
DMSO, Et3N
N
(
(
entries 1–5) and 5% or less for secondary aliphatic aldehydes
entries 6–9).
O
1
a R = H
2
b R = Me
Scheme 1
O
OAc
(1) Et2Zn/(+)-MIB
+
OAc
(2) Ac2O
H
O
OAc
(
1) Et2Zn/(+)-MIB
2) Ac2O
H
R
(
62%
38%
R
H
Scheme 2
Scheme 3
Chem. Commun., 1999, 1369–1370
1369

one 13C resonance is too broad to observe at room temperature); [a]25
+4.4,
O
H
OH
D
(
‡
c = 2.03, MeOH).
Typical procedure: A solution of freshly distilled aldehyde (3.00 mmol),
H
(1) Me2Zn/MIB
toluene (3.0 ml), internal standard (chlorobenzene or tert-butybenzene) and
+)-2 (14.4 mg, 0.060 mmol) was cooled to 0 °C. After dropwise addition
of 1.0 M Et Zn in hexane solution (6.0 ml, 6.0 mmol), the mixture was
maintained at 0 °C for 3 h. Ac O (1.2 ml, 13 mmol) was added and the
(
2) H2O
(
CH3
CH3
2
2
Scheme 4
mixture was allowed to stand overnight prior to capillary column GC
analysis on a Cyclodex B stationary phase (J&W Scientific).
2
5
12
§
Optical rotation data: [a]
D
+40.5 (c = 1.48, EtOH), lit. for (R)-
MIB can also be used to effect the addition of Me
aldehydes although longer reaction times are required to
compensate for the lower reactivity of this organozinc reagent.
2
Zn to
21
21
enantiomer, [a]
D
+40.4 (c 0.530, EtOH), lit.12 for (S)-enantiomer, [a]
D
241.9 (c = 0.500, EtOH).
Addition of Me
% (+)-MIB] afforded (R)-(+)-1-(m-tolyl)ethanol§ in 95% ee
and 88% isolated yield after flash chromatography (Scheme
).
It is also noteworthy that the crystalline nature of MIB
imparts greater air-stability as compared with DAIB. A sample
of MIB stored under air at ambient conditions for three months
showed no degradation of spectroscopic properties nor catalytic
performance when compared with freshly prepared material.
Given the several advantages of MIB, we suggest that it should
be considered as an alternative ligand for reactions where DAIB
has previously been utilized.
2
Zn to m-tolualdehyde [18 h, room temperature,
1 N. Oguni and T. Omi, Tetrahedron Lett., 1984, 25, 2823.
2 V. Grignard, C. R. Hebd. Sceances Acad. Sci. , 1900, 130, 1322.
3 K. Soai and S. Niwa, Chem. Rev., 1992, 92, 833; R. Noyori, Asymmetric
Catalysis in Organic Synthesis, Wiley, New York, 1994, ch. 5.
5
4
4
M. Kitamura, S. Suga, K. Kawai and R. Noyori, J. Am. Chem. Soc.,
986, 108, 6071.
1
5
See for example: L. Sola, K. S. Reddy, A. Vidal-Ferran, A. Moyano,
M. A. Pericas, A. Riera, A. Alvarez-Larena and J.-F. Piniella, J. Org.
Chem., 1998, 63, 7078; J. Beliczey, G. Giffels, U. Kragl and C.
Wandrey, Tetrahedron: Asymmetry, 1997, 8, 1529; A. Vidal-Ferran, A.
Moyano, M. A. Pericas and A. Riera, J. Org. Chem., 1997, 62, 4970; K.
Soai, S. Yokoyama and T. Hayasaka, J. Org. Chem., 1991, 56, 4264.
6 M. Kitamura, S. Suga, H. Oka and R. Noyori, J. Am. Chem. Soc., 1998,
2
0, 9800; M. Yamakawa and R. Noyori, Organometallics, 1999, 18,
1
28.
7
P. I. Dosa and G. F. Fu, J. Am. Chem. Soc. 1998, 120, 445; A. H. M. De
Vries, J. F. G. A. Jansen and B. L. Feringa, Tetrahedron, 1994, 50, 4479;
W. Oppolzer and R. N. Radinov, J. Am. Chem. Soc., 1993, 115, 1593;
W. Oppolzer, R. N. Radinov and J. De Brabander, Tetrahedron Lett.,
1995, 36, 2607.
Notes and references
†
Preparation of (+)-2: Amino alcohol (+)-1a (4.53 g, 26.8 mmol) was
dissolved in DMSO (25 ml) and Et N (10 ml). A solution of di(2-
bromoethyl) ether (8.07 g, 90% pure, 31.3 mmol) in DMSO (20 ml) was
added dropwise. After 72 h the mixture was added to 250 ml water and 60
3
8 J. D. White, D. J. Wardup and K. F. Sundermann, Org. Synth., submitted
for publication (procedure no. 2822); J. D. White, personal communica-
tion, March, 1999.
9 R. A. Chittenden and G. H. Cooper, J. Chem. Soc. C, 1970, 49.
10 W. A. Nugent, G. Licini, M. Bonchio, O. Bortolini, M. G. Finn and B.
W. McCleland, Pure Appl. Chem., 1998, 70, 1071.
11 M. Kitamura, S. Okada, S. Suga and R. Noyori, J. Am. Chem. Soc.,
1989, 111, 4028.
ml 1 M NaOH and was extracted into Et
solvent at reduced pressure the product was taken up in Et
M HCl (50 ml), released with NaOH, and again extracted into Et
2
O (3 3 100 ml). After removal of
O, extracted into
O. After
2
1
2
removal of volatiles, the residue was dissolved in hexanes (4 ml per g of
crude product), filtered and cooled to 230 °C to produce 2 (2.95 g, 46%) as
a white crystalline solid, mp 65–67 °C. (C14
H25NO
2
: Calc: C, 70.25; H,
(C ) 0.69 (s, 3
H), 0.73 (m, 1 H), 0.88 (m, 1 H), 1.04 (s, 3 H), 1.15 (s, 3 H), 1.31 (td, 1 H),
10.53; N, 5.85; found: C, 70.18; H, 10.83, N, 5.94%). d
H
6 6
D
12 K. Nakamura, M. Kawasaki and A. Ohno, Bull. Chem. Soc. Jpn., 1996,
69, 1079.
1.52 (m, 1 H), 1.67 (d, 1 H), 1.99 (d, 1 H), 2.13 (br, 2 H), 2.31 (br, 2 H),
3.32–3.42 (m, 5 H total), 3.92 (br d, 1 H); d (C ) 11.88, 21.10, 22.19,
27.99, 32.56, 45.35, 46.64, 49.52, 66.82, 73.37, 79.03 (as in the case of 1b,
c
6 6
D
Communication 9/04042K
1370
Chem. Commun., 1999, 1369–1370