Bronsted acid catalysis of achiral enamine for regio- and enantioselective nitroso aldol synthesis

Article abstract of DOI:10.1021/ja0444637

Two types of chiral Bronsted acid catalysts have been shown to catalyze regio- and enantioselective nitroso aldol synthesis between nitrosobenzene and achiral enamine. The combination of Bronsted acidity and amine moiety of enamine realizes complete regioselectivity with high enantioselectivity. After a survey of Bronsted acid catalysts, 1-naphthyl glycolic acid is found to be optimal in the O-nitroso aldol pathway, while 1-naphthyl TADDOL is the best catalyst for the N-nitroso aldol pathway. This is based on our finding on the control of regioselectivity by changing the amine moiety of enamine and the choice of Bronsted acidity. Copyright

Full text of DOI:10.1021/ja0444637

Published on Web 01/06/2005
Brønsted Acid Catalysis of Achiral Enamine for Regio- and Enantioselective
Nitroso Aldol Synthesis
Norie Momiyama and Hisashi Yamamoto*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue, Chicago, Illinois 60637
Received September 13, 2004; E-mail: yamamoto@uchicago.edu
Table 1. O-Nitroso Aldol Synthesis Catalyzed by Glycolic Acida
There has been considerable interest in the development of
catalytic enantioselective enolate-electrophile bond constructions,
which typically have employed metal enolates.1 While enamines
have been well-known as useful enol synthons since the pioneering
work by Stork,2 success in such endeavors for asymmetric induction
has proven elusive. The diastereoselective reaction using chiral
enamine3 and asymmetric reaction via a chiral proline enamine and
its analogues4 are recent strategies in this context. However, the
corresponding enantioselective process has not been fully realized
with achiral enamines as nucleophiles.5 We report herein the first
enantioselective Brønsted acid catalysis6 of achiral enamine in
nitroso aldol synthesis, which proceeds in a completely regio- and
highly enantioselective manner (Scheme 1).7
entry
enamine
n
R, R
yield, %b
ee, %c
1d
2
3
4
5
6
7
8
1a
1b
1b
1b
1b
1b
1e
1f
1
0
1
1
1
2
1
1
H, H
H, H
H, H
Me, Me
-(OCH2CH2O)-
H, H
69
63
77
91
83
<1
89
64
70
70
92
90
93
Scheme 1. Brønsted Acid Catalysis of Achiral Enamine
H, H
H, H
91
83
a Reactions were conducted with 30 mol % of 1-nap glycolic acid, 1.0
equiv of nitrosobenzene, and 1.0 equiv of enamine in diethyl ether at -88
to -78 °C for 12 h. b Isolated yield. c Determined by HPLC (see the
Supporting Information). d Reactions were conducted in THF for 2 h.
The first nitroso aldol synthesis using enamine was reported in
1972 by Lewis et al.8 They described that the reaction of morpholine
enamine of cyclohexanone provided the N-nitroso aldol product in
30% yield. Surprisingly, we found that a similar reaction using the
pyrrolidine enamine of cyclohexanone gave rise to the O-nitroso
aldol product exclusively in benzene at 0 °C.9 Furthermore, these
reactions could be accelerated significantly by the addition of
Brønsted acids. Although the reaction of morpholine enamine was
very slow in toluene at -78 °C, rapid access to N-nitroso aldol
synthesis was realized in the presence of methanol.10 Meanwhile,
the pyrrolidine enamine gave no nitroso aldol product at -78 °C
in toluene but significant acceleration for the O-nitroso aldol
pathway took place in the presence of acetic acid.10
Table 2. N-Nitroso Aldol Synthesis Catalyzed by TADDOLa
entry
enamine
n
R, R
yield, %b
ee, %c
With these observations in hand, a variety of chiral carboxylic
acids were examined using the pyrrolidine enamine 1a to produce
the O-nitroso aldol product.11 1-Aryl glycolic acids were identified
as the most successful promoters. It was also quite interesting to
find a significant effect of solvent on this transformation. The best
result was obtained using (S)-1-naphthyl glycolic acid and piperidine
enamine 1b in diethyl ether, giving 92% ee and 77% isolated yield.
For N-nitroso aldol synthesis, we also screened various alcohols
and phenols.11 We immediately found TADDOL to be a promising
Brønsted acid catalyst for our purpose. The best result was obtained
when the reaction was conducted with 30 mol % of 1-naphthyl
TADDOL in toluene using piperidine cyclohexene enamine (1b);
only the N-adduct was produced in 83% ee and 81% isolated yield.
Under these optimized conditions, the scope of the reaction was
explored (Tables 1 and 2).12 In general, high enantiomeric excesses
are observed for cyclohexene enamines bearing a piperidine-based
1
2
3
4
5
6
7
8
1b
1b
1b
1b
1b
1c
1d
1e
0
1
1
1
2
1
1
1
H, H
H, H
Me, Me
-(OCH2CH2O)-
H, H
H, H
H, H
H, H
<1
81
78
63
67
91
88
81
83
82
91
65
79
77
80
a Reactions were conducted with 30 mol % of 1-nap TADDOL, 1.0 equiv
of nitrosobenzene, and 1.0 equiv of enamine in toluene at -88 to -78 °C
for 2 h. b Isolated yield. c Determined by HPLC (see the Supporting
Information).
amine moiety (1b). The most gratifying aspect of this study was
the exclusive formation of a single regioisomer (O vs N) with proper
choice of Brønsted acid and enamine combinations. Thus, enamines
derived from pyrrolidine (1a) and homopiperidine (1f) are generally
9
1080
J. AM. CHEM. SOC. 2005, 127, 1080-1081
10.1021/ja0444637 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
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(a) Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2003, 125, 6038-
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acceptable for O-nitroso aldol synthesis, affording the O-adduct in
good yields and with high enantioselectivities. Morpholino (1c) and
thiomorpholino (1d) enamine are competent substrates in N-nitroso
aldol synthesis.
1H and 13C NMR confirmed that neither the cis nor the trans
azodioxy dimer was observed in the presence of Brønsted acid.13
Thus, initial formation of the azodioxy dimer may be excluded.
The proposed reaction pathway is outlined as follows. The Brønsted
acid coordinates with the nitrogen atom of the NdO bond, followed
by nucleophilic attack at the oxygen atom to give the O-adduct,14
while the oxygen-activated nitrosobenzene is attacked by the
â-carbon to provide a hydroxyamino iminium compound. The sense
of each Brønsted acid catalysis of achiral enamine can be understood
by the fact that the nucleophilicity of enamine is known to be
heavily dependent on the structure of the amine moiety.15 Under
acidic conditions, the rate of the hydrolysis16 of the pyrrolidine
enamine was much slower than that of morpholine enamine. On
the other hand, the hydrolysis of the morpholine enamine proceeds
in highly acidic media. Thus, it is presumed that the less acidic
TADDOL facilitates the reaction of morpholine enamine, while the
more acidic glycolic acid is required for the reaction of pyrrolidine
enamine. Since the hydrolyses of piperidine enamine are not
dramatically different over the whole pH range and maintains a
value between those of pyrrolidine and morpholine, the piperidine
enamines can be used for both N- and O-adduct syntheses.
It should be noted that both catalysts have a possible intramo-
lecular hydrogen bond between two alcoholic and/or carboxylic
acid oxygen lone pairs. We attribute this feature to generating
reactive and stereochemically rigid Brønsted acid assisted Brønsted
acid (BBA) systems which may result in the good selectivities found
for the present reactions.17
In summary, although the scope of the present regio- and
enantioselective nitroso aldol synthesis described herein is still under
investigation, the general pattern of results obtained thus far
encourages optimism. We believe that the process has advanced to
a new level of applicability and generality in nitroso aldol synthesis
on the basis of our findings. Further extension of these concepts
into a general catalytic enantioselective approach to other enolate-
electrophile bond construction is also the subject of ongoing studies.
(8) Lewis, J. W.; Myers, P. L.; Ormerod, J. A. J. Chem. Soc., Perkin Trans.
1 1972, 20, 2521-2524.
(9) See ref 7d.
(10) Detailed results are described in the Supporting Information.
(11) The results are summarized in the Supporting Information.
(12) Unfortunately, this system did not afford enough enantioselectivity for
enamines of aldehydes and acyclic ketones.
(13) (a) Orrell, K. G.; Sik, V.; Stephenson, D. Magn. Reson. Chem. 1987, 25,
1007-1011. (b) Orrell, K. G.; Stephenson, D. Magn. Reson. Chem. 1989,
27, 368-376.
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K. N. Acc. Chem. Res. 2004, 37, 558-569. (b) Cheong, P. H.-Y.; Houk,
K. N. J. Am. Chem. Soc. 2004, 126, 13912-13913.
Acknowledgment. We gratefully acknowledge Prof. Viresh H.
Rawal for helpful discussions. We also thank Dr. Ian M. Steele for
X-ray crystallographic analysis and acknowledge Yamakawa
Chemical Co. for the gift of (S)-2-naphthyl glycolic acid. Support
for this research has been provided by National Institutes of Health
(NIH) Grant No. GM068433-01 and a grant from the University
of Chicago.
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R. J. Am. Chem. Soc. 1963, 85, 207-222. (b) Stamhuis, E. J.; Maas, W.
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Supporting Information Available: Text, tables, and figures giving
experimental procedures, spectral data for all new compounds, and
crystallographic data and an X-ray crystallographic file in CIF format.
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) For a general review of enantioselective reactions of metal enolates, see:
(a) ComprehensiVe Asymmetric Catalysis III; Jacobsen, E. N., Pfalts, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999. (b) Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; Wiley-VCH: New York, 2000; pp 465-697.
(c) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim,
Germany, 2004; Vols. 1 and 2.
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