Aqueous enantioselective organocatalytic Diels-Alder reactions employing hydrazide catalysts. A new scaffold for organic acceleration

Article abstract of DOI:10.1021/ol051476w

(Chemical Equation Presented) Cyclic hydrazides function as asymmetric organocatalysts in aqueous Diels-Alder reactions. The hydrazide is employed as the catalytic machinery in a compact camphor-derived framework that imparts facial selectivity to the cyc

Full text of DOI:10.1021/ol051476w

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4141-4144
Aqueous Enantioselective
Organocatalytic Diels Alder Reactions
−
Employing Hydrazide Catalysts. A New
Scaffold for Organic Acceleration
Mathieu Lemay and William W. Ogilvie*
Department of Chemistry, UniVersity of Ottawa, 10 Marie Curie,
Ottawa, Ontario, Canada K1N 6N5
wogilVie@science.uottawa.ca
Received June 23, 2005
ABSTRACT
Cyclic hydrazides function as asymmetric organocatalysts in aqueous Diels−Alder reactions. The hydrazide is employed as the catalytic
machinery in a compact camphor-derived framework that imparts facial selectivity to the cycloadditions. Kinetic evidence suggests the reaction
involves rapid iminium formation.
Recent interest in asymmetric organocatalytic transformations
has been intense.1 Many reactions have been enantioselec-
tively accelerated by organic compounds. Among these,
aldols, alkylations, and Mannich reactions have generally
received the most attention.1 The use of organocatalysis in
cycloaddition reactions has been less extensively explored.2-5
The most general mode of enantioselective organocatalysis
in cycloadditions is the generation of active iminium ions.3
These species act to lower the energy of the dienophile
LUMO, producing acceleration analogous to that of Lewis
acids.3 In this paper, we disclose the design and synthesis
of a new structural class of organic catalysts functioning in
water. A hydrazide is employed as the catalytic machinery
in a compact camphor-derived framework that imparts facial
(3) (a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2000, 122, 4243. (b) Northrup, A. B.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2002, 124, 2458. (c) Selka¨la¨, S. A.; Tois, J.; Pihko, P. M.;
Koskinen, A. M. P. AdV. Synth. Catal. 2002, 344, 941. (d) Juhl, K.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 1498. (e) Selka¨la¨, S.
A.; Koskinen, A. M. P. Eur. J. Org. Chem. 2005, 8, 1620. (f) Jurcik, V.;
Wilhelm, R. Org. Biomol. Chem. 2005, 3, 239. (g) Ishihara, K.; Nakano,
K. J. Am. Chem. Soc. 2005, 127, 10504. (h) Wilson, R. M.; Jen, W. S.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2005, in press.
(4) For Diels-Alder reactions catalyzed by biopolymers, see: (a) Roelfes,
G.; Feringa, B. L. Angew. Chem., Int. Ed. 2005, 45, 3230. (b) Tarasow, T.
M.; Tarasow, S. R.; Eaton, B. E. J. Am. Chem. Soc. 2000, 122, 1015. (c)
Helm, M.; Petermeier, M.; Ge, B.; Fiammengo, R.; Ja¨schke, A. J. Am. Chem.
Soc. 2005, 127, 10492.
(1) (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138-
5175. (b) List, B. AdV. Synth. Catal. 2004, 346, 1021. (c) Houk, K. N.;
List, B. Acc. Chem. Res. 2004, 37, 487. (d) Notz, W.; Tanaka, F.; Barbas,
C. F., III. Acc. Chem. Res. 2004, 37, 580. (e) Dalko, P. I.; Moisan, L. Angew.
Chem., Int. Ed. 2001, 40, 3726. (f) France, S.; Guerin, D. J.; Miller, S. J.;
Lectka, T. Chem. ReV. 2003, 103, 2985.
(2) (a) Riant, O.; Kagan, H. Tethrahedron Lett. 1989, 30, 7403. (b) Riant,
O.; Kagan, H. Tethrahedron 1994, 50, 4543. (c) Koerner, M.; Rickborn,
B. J. Org. Chem. 1990, 55, 2662. (d) Braddock, D. C.; MacGilp, I. D.;
Perry, B. G. Synlett 2003, 1121. (e) Braddock, D. C.; MacGilp, I. D.; Perry,
B. G. AdV. Synth. Catal. 2004, 346, 1117.
(5) For [3 + 2] cycloadditions, see: (a) Jen, W. S.; Wiener, J. J. M.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 9874. (b) Karlsson, S.;
Ho¨gberg, H.-E. Eur. J. Org. Chem. 2003, 2782.
10.1021/ol051476w CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/24/2005

selectivity to Diels-Alder reactions. Evidence of a novel
mechanism of action, involving rapid iminium formation, is
also presented.
Table 1. Hydrazide-Catalyzed Asymmetric Diels-Alder
Reactions
Scheme 1. Iminium Catalysis in Diels-Alder Cycloadditions
yield exo:endo endo ee (6)11
entry catalyst
R
(%)a
(4:6)
(%)
1
2
3
4
5
7
8
9
5
10
Ph
H
Me
Bn
25
25
18
90
1.1:1
0.9:1
1.2:1
2.1:1
1.7:1
60
3
58
82
74
CH2-1-naphthyl 82
a Combined isolated yield.
The design of our organocatalysts was driven by the goal
of increasing catalyst turnover. Catalysis in iminium-based
processes involves three phases: formation of an iminium,
such as 2 from catalyst 1 and aldehyde, cycloaddition to form
3, and finally hydrolysis to release products and regenerate
catalyst 1. It has been suggested6 that the overall efficiency
in iminium-catalyzed reactions is dictated by the rate of
iminium generation. To address this issue, we decided to
enhance the nucleophilicity of our catalyst by means of the
R-heteroatom effect.7 Such a modification would presumably
increase the rate of formation of 2, while maintaining a high
rate of conversion to 3. This hypothesis has led to the
development of a new catalyst system based on cyclic
hydrazides.8 Our catalyst design sought to incorporate a
hydrazide moiety into a chiral framework featuring a five-
membered ring. The hydrazide would provide the necessary
R-heteroatom for nucleophilic acceleration together with an
electron-withdrawing moiety to improve the rate of iminium
hydrolysis (3 f 1). Such architecture would require geminal
substitution R to the carbonyl in order to suppress â-elimina-
tion. A readily available scaffold, which provides such
features, is found in hydrazides such as 5 that are readily
synthesized in four steps from camphorsulfonic acid.
reactivity and enantioselectivity. Removal of the side chain
was deleterious to catalyst activity12 and resulted in almost
no enantioselectivity (entry 2). Small aliphatic groups at this
position gave yields and facial selectivity similar to that of
7 (entry 3). Catalyst 5, however, gave efficient conversion
to product with an enantioselectivity of 82% (entry 4). The
reaction displayed selectivity for exo isomer 4, and both the
exo and endo isomers showed similar enantioselectivities.
Increasing the size of the aromatic function relative to a
benzyl group did not improve enantioselectivity (entry 5).
The use of catalyst 5 in a variety of aqueous solvent
mixtures (9:1 solvent:H2O) was explored. We found that
aqueous mixtures of MeOH (yield 90%, endo ee 82%) and
CH3NO2 (yield 92%, endo ee 75%) gave efficient and
enantioselective conversion to products, whereas the use of
CH3CN (yield 49%, endo ee 73%), THF (yield 23%, endo
ee 83%), or CH2Cl2 (yield 64%, endo ee 75%) resulted in
only moderate yields. Enantioselectivity was less sensitive
to the nature of the solvent. Optimal catalyst performance
was noted in water, in which an enantioselectivity of 85%
and a chemical yield of 82% were achieved. Reactions in
water were biphasic, and enantioselectivity was maintained
with substrate concentrations up to 2 M.
Tuning the acid co-catalyst led to a further performance
enhancement for catalyst 5. A striking correlation was
apparent between the strength of the acid used and the
efficiency of the reaction (Table 2). Steady erosion in both
yield and enantioselectivity was observed as the acidity of
the co-catalyst was decreased. We obtained the best results
using CF3SO3H, which gave not only the best yield and
selectivity but also the cleanest and fastest reactions. To our
knowledge, such a correlation has not been previously
observed in organically catalyzed asymmetric reactions.5a
Such strong acids could have been capable of catalyzing
the Diels-Alder process, resulting in lowered enantioselec-
tivity through a competing achiral process.13 The potential
impact of this background reaction was tested using 0.2 equiv
The efficiency of this system was first evaluated using
hydrazide 79 in a Diels-Alder reaction between cinnamal-
dehyde and cyclopentadiene. This strategy proved successful
as the use of 7 resulted in catalysis of the cycloaddition with
modest enantioselectivity10 and low yield (Table 1, entry 1).11
Changes to the indicated side chain proved crucial for
(6) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
1172.
(7) Fleming, I. Fronteir Orbitals and Organic Chemical Reactions;
Wiley-Interscience: Chichester, U.K., 1976.
(8) For catalysis with acyclic achiral hydrazides, see: Cavill, J. L.; Peters,
J.-U.; Tomkinson, N. C. O. J. Chem. Soc., Chem. Commun. 2003, 728.
(9) Yang, K.-S.; Chen, K. Org. Lett. 2000, 2, 729.
(10) (a) Fujioka, H.; Kotoku, N.; Fujita, T.; Inoguchi, R.; Murai, K.;
Nagatomi, Y.; Sawama, Y.; Kita, Y. Chirality 2003, 15, 60. (b) Ishihara,
K.; Kurihara, H.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 3049.
(11) Enantiomer ratios were determined on the aldehydes by chiral GLC
1
and by H 500 MHz NMR of the corresponding (+)-(R,R)-hydrobenzoin
acetals. The absolute configurations of major products 4 and 6 were
established by comparison to the NMR spectra of the (+)-(R,R)-hydroben-
zoin acetals of (S)-4 and (S)-6 prepared independently (refs 3 and 10).
(12) In contrast, acyclic hydrazides lacking substitution at this position
are effective in an achiral sense. See ref 8.
4142
Org. Lett., Vol. 7, No. 19, 2005

We examined the structure of the iminiums formed in our
reactions using semiempirical calculations (PM3 in Spartan
Pro). These calculations indicated that the iminium illustrated
below (Figure 1) was the lowest energy conformer. This
Table 2. Effect of Acid Co-catalyst on the Asymmetric
Diels-Alder Reactions of Cyclopentadiene and Cinnamaldehyde
Catalyzed by 5a
yield
(%)b
exo:endo
(4:6)
endo ee
(%)11
entry
acid
pKa
1
2
3
4
5
6
CF3SO3H
HClO4
CSA
CH3SO3H
CF3CO2H
CH3CO2H
-14
-10
-3
-2.6
-0.3
4.8
89
82
17
8
13
7
1.9:1
1.7:1
1.6:1
1.2:1
1.7:1
1:1
88
85
57
15
30
2
a With 1 M in water using 20 mol % of 5 and indicated acid. b Combined
isolated yield.
of catalyst 5 with varying amounts of CF3SO3H (0.1, 0.2,
and 0.4 equiv). In all cases, the enantioselectivities were
identical, indicating that strong acid was not detrimental to
selectivity.
Experiments that outline the scope of the present process
are given in Table 3. Substituted cinnamaldehyde dienophiles
Figure 1. Minimum energy iminium ion formed from cinnama-
ldehyde and 5.
geometry was confirmed by spectral analysis of the iminium
formed between 5 and cinnamaldehyde. A NOESY spectrum
of this species showed strong correlations between the
hydrogens, consistent with the calculated structure. Approach
of the diene to the bottom face of this favored iminium as
indicated leads to the major stereoisomers in all cases.
Using 1H NMR, we monitored the rate of iminium
formation and discovered that the process was extremely
rapid, in agreement with our initial hypothesis. This is in
contrast to the case of imidazolidinone catalyst 11,3a which
forms an iminium species considerably more slowly and is
not fully implicated as the reactive form, even after several
hours (Figure 2). This suggests that the rate-limiting step
Table 3. Asymmetric Diels-Alder Reactions between
Cyclopentadiene and Various Dienophiles Catalyzed by 5a
yield
exo ee
entry diene
dienophile
(%)c exo:endo (%)11,14
1
2
CPb
CP
CP
CP
(E)-PhCHdCHCHO
96
1.9:1
2.2:1
2:1
1.7:1
-
1.9:1
1.2:1
2.1:1
1.6:1
2.6:1
90
(E)-4-NO2-PhCHdCHCHO 93
92
3
(E)-4-Cl-PhCHdCHCHO
92
84
90d
90d
85
4
(E)-4-iPr -PhCHdCHCHO
5
PBD (E)-4-NO2-PhCHdCHCHO 86
MPD (E)-4-NO2-PhCHdCHCHO 71
CP
CP
CP
CP
6
69d
87
7
(E)-2-NO2-PhCHdCHCHO 90
(E)-3-NO2-PhCHdCHCHO 88
8
94d
81
9
(E)-PrCHdCHCHO
83
84
10
(E)-iPr CHdCHCHO
85
a Conditions: 3 equiv of diene, 1 equiv of dienophile, 0.2 equiv of 5,
0.2 equiv of CF3SO3H, H2O, 20 °C. b CP: cyclopentadiene; PBD:
2-phenylbutadiene; PMD: 2-methyl-1,3-pentadiene. c Combined isolated
yield. d The endo isomer.
produced excellent selectivity and yields (entries 1-4).15
A
variety of substitutions on the aryl ring, including electron-
withdrawing and -donating groups, were tested and gave
excellent enantioselectivities. Ortho or meta substitution was
tolerated and gave high facial selectivity (entries 7 and 8).
Aliphatic substitution was also possible with increased bulk
of the substituent, producing slight advantages in terms of
facial selectivity (entries 9 and 10).16 Substituted dienes, such
as 2-phenylbutadiene, gave high enantioselectivity when the
addition was catalyzed by 5, as did the use of doubly
substituted dienes (entries 5 and 6).
Figure 2. Extent of iminium formation over time.
(13) An uncatalyzed reaction did not produce any detectable product after
24 h at 23 °C. A reaction catalyzed by 0.2 equiv of acid gave a trace of
product (<5%) after 24 h at 23 °C, showing a slight preference for the
endo product (1.3:1).
(14) Enantiomeric excesses for endo isomers are given in Supporting
Information.
for the present reaction is not iminium formation, as has been
proposed for the case of catalysis by compounds, such as
(15) The absolute configurations of products were established by
correlation of the chemical shifts of the (+)-(R,R)-hydrobenzoin acetals
with those of the corresponding acetals derived from 4 and 6.3,10
(16) The absolute configurations of the major products of entries 9 and
10 were established by GLC comparison to authentic samples.3
Org. Lett., Vol. 7, No. 19, 2005
4143

11,6 but is another transformation in the overall process.
Investigations into the mechanism of the current process are
ongoing.
well as investigations of other chiral transformations using
hydrazides derived from 5 will be described shortly.
We have developed a new class of catalysts for asymmetric
organocatalyzed Diels-Alder reactions. The catalysts func-
tion best in water, providing an environmentally benign
reaction that gives excellent yields and enantioselectivities.
The reactions produce a preference for the exo isomer, and
enantioselectivities for both the exo and endo products were
excellent. Acid co-catalyst strength was important, with
strong acids producing the best selectivity. Preliminary
mechanistic studies indicate that iminium formation is
extremely rapid, suggesting a catalytic process distinct from
other organocatalytic cycloadditions. Further studies to
address the scope and mechanism of this transformation as
Acknowledgment. M.L. is grateful for graduate scholar-
ships from NSERC, OGSST, and from the University of
Ottawa. Thanks to Dr. Glen Facey for technical assistance.
This research has been supported by NSERC, the Canadian
Foundation for Innovation, and by the University of Ottawa.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL051476W
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