Camphor sulfonyl hydrazines (CaSH) as organocatalysts in enantioselective Diels-Alder reactions

Article abstract of DOI:10.1021/ol8005826

(Chemical Equation Presented) Cyclic sulfonyl hydrazine was demonstrated for the first time as a new functionality for organocatalysis. A series of six-membered cyclic hydrazines derived from camphor sulfonic acid were synthesized. With trichloroacetic acid as cocatalyst, they are efficient organocatalysts for enantioselective Diels-Alder reactions with good chemical yields and up to 96% ee. The reactions took place in brine at 0 °C to room temperature.

Full text of DOI:10.1021/ol8005826

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2421-2424
Camphor Sulfonyl Hydrazines (CaSH) as
Organocatalysts in Enantioselective
Diels-Alder Reactions
Hao He, Bao-Jian Pei, Ho-Hsuan Chou,† Tian Tian,‡ Wing-Hong Chan, and
Albert W. M. Lee*
Department of Chemistry, Hong Kong Baptist UniVersity, Kowloon Tong,
Hong Kong SAR, China
alee@hkbu.edu.hk
Received March 13, 2008
ABSTRACT
Cyclic sulfonyl hydrazine was demonstrated for the first time as a new functionality for organocatalysis. A series of six-membered cyclic hydrazines
derived from camphor sulfonic acid were synthesized. With trichloroacetic acid as cocatalyst, they are efficient organocatalysts for enantioselective
Diels-Alder reactions with good chemical yields and up to 96% ee. The reactions took place in brine at 0 °C to room temperature.
Many of the biologically and pharmaceutically important
molecules exist in chiral forms. In many cases, only one of the
two possible chiral forms (enantiomers) of these molecules is
active. Therefore, the challenge faced by synthetic chemists is
how to prepare these useful molecules in pure enantiomeric
forms by means of asymmetric synthesis. Various approaches
such as chiral auxiliary and asymmetric catalysis have been used
to realize asymmetric synthesis. The use of synthetic complexes
of transition metals in asymmetric catalysis has been a very
productive approach in the past decades.1 In recent years, a new
approach emerged. Asymmetric organocatalysis, the use of
small chiral organic molecules to catalyze asymmetric trans-
formations, has captured the attention of chemists around the
world.2,3 In this letter, we would like to report for the first
time that sulfonyl hydrazine is a new functionality for
effective organocatalysis. Moreover, brine is the reaction
medium4 for the hydrophobic effect.5
Camphor and its derivatives such as camphor sulfonic acid
(CSA), which are readily available in optically pure forms
for both of the enantiomers, are widely used synthons in
asymmetric synthesis. The most noticeable example probably
is the Oppolzer’s sultam chiral auxiliary developed from
CSA.6 The preparation of the previously unknown camphor
sulfonyl hydrazines (CaSH) from CSA via camphor sulfonyl
chloride is outlined in Scheme 1.
Optically pure (+)-camphor sulfonyl chloride (1) readily
prepared from CSA was cyclized with hydrazine monohy-
drate in the presence of a catalytic amount of acetic acid.
After being reduced by sodium cyanoborohydride, the
unsubstituted cyclic camphor sulfonyl hydrazine (CaSH) 4
could be obtained in high overall yield.
The concept behind the design of this sulfonyl hydrazine
catalyst is the R-heteroatom effect.7,8 It is well-established that
the nucleophilicity of an amine will be greatly enhanced if a
heteroatom is attached to it. For example, as compared to imine
formation from aldehyde with amine, oxime and hydrazone are
more readily formed from hydroxyamine (O-substituted amine)
and hydrazine (N-substituted amine), respectively. It has been
suggested that enhancing the nucleophilicity of the amine
† Exchange Student from the National Tsing Hua University, Taiwan,
‡ Exchange Student from the Wuhan University, China.
(1) (a) Knowles, W. S. Angew. Chem., Int. Ed. 2002, 41, 1998. (b)
Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008. (c) Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2024.
10.1021/ol8005826 CCC: $40.75
Published on Web 05/16/2008
2008 American Chemical Society

to 7, Scheme 1) took place exclusively at the R-nitrogen,
while alkylation (4 to 6) went after the ꢀ-nitrogen only. These
four NR-acylated (7a-c) and Nꢀ-benzylated (6) CaSHs gave
better chemical yields than unsubstituted CaSH 4 in catalytic
Diels-Alder reactions between cyclopentadiene and cinna-
maldehyde (Table 1, entries 2-5). Moderate endo enanti-
oselectivities were observed for 7b and 6 (entries 3 and 5).
The last variation, the NR-alkylated CaSH, could not be
prepared directly by alkylation of 4, to which alkylation
proceeded after the ꢀ-nitrogen. The NR-alkylated CaSHs were
eventually synthesized by first alkylation of cyclic hydrazone
2 under phase transfer condition then followed by reduction
with sodium cyanoborohydride in the presence of trifluoro-
acetic acid. The first NR-alkylated CaSH, NR-benzyl camphor
sulfonyl hydrazine 5a, prepared by us performed pretty well
as an organocatalyst for the Diels-Alder reaction. In brine
with trifluoromethanesulfonic acid as cocatalyst, a chemical
yield of 90% with 80% endo ee was achieved (entry 6).
By comparing the results between Nꢀ-benzyl CaSH 6
(entry 5) and NR-benzyl CaSH 5a (entry 6), it is obvious
that NR-alkylated CaSH is a better catalytic system than the
Nꢀ-alkylated variant. Before we further fine-tune the structure
of our catalysts, the role of the acid cocatalyst was addressed.
We found that the strongest acid may not necessarily be the
best cocatalyst and the results were summarized in Table 2.
It was found that less acidic trichloroacetic acid is also an
effective cocatalyst (entry 2). In particular, when the loading
was reduced to 0.1 equiv, the yield was good and the percent
ee of the endo isomer was up to 86% (entry 3). Further
reducing the amount of acid used did not afford better results
(entry 4). Meanwhile, the brine was switched to water to
investigate whether the hydrophobic effect5 did exist (entry
5). It took 2 days for the reaction in water to complete as
compared to 8 h in brine. Also, both the chemical yield and
enantioselectivity are higher in brine than in water. p-
Toluenesulfonic acid and 3,5-dinitrobenzoic acid were also
tested but the results were inferior (entries 6 and 7).
Scheme 1
.
Preparation of the Camphor Sulfonyl Hydrazines
(CaSH)
nitrogen will accelerate the formation of the active imine ion
intermediate in the catalytic cycle of an organocatalysis
reaction.9Therefore, by attaching a heteroatom onto the amine
nitrogen, one should be able to design a better organocatalyst.
For example, Ogilvie has recently reported that conformationally
rigid cyclic hydrazide is a new scaffold for organocatalysis.9c,d
We screened the efficiencies of simple hydrazines and
other heteroatom-substituted amines and found that the
effects were minimal. By modifying the hydrazine to
sulfonyl-substituted hydrazine, we observed a satisfactory
catalytic effect. Camphor is selected to provide the chiral
scaffold of the sulfonyl hydrazine organocatalyst.
Unsubstituted CaSH 4 did show some catalytic effect in
the Diels-Alder reaction. However, the yield and percent
ee were poor (Table 1, entry 1). We then move to investigate
the NR- or Nꢀ-substituted CaSH. Interestingly, cyclic sulfonyl
hydrazine 4 exhibits good selectivity between N-acylation
After acid cocatalyst was successfully fine-tuned, we
moved on to investigate the effect of the alkyl group on the
t
and N-alkylation. Acylation (acetyl, BOC, and benzoyl, 4
Table 1. Enantioselective Diels-Alder Reaction Catalyzed by N-Acylated and N-Benzylated Camphor Sulfonyl Hydrazines
entry
catalyst
R1
R2
yield (%)
exo:endoa
endo eeb (%)
1
2
3
4
5
6
4
H
H
H
H
H
18
35
68
30
30
90
1:1.4
1:1.4
1:1
1:1.2
1:1.4
1:1.3
32
18
56
18
53
80
7a
7b
7c
6
CH3CO
t-BOC
C6H5CO
H
C6H5CH2
H
5a
C6H5CH2
a Determined by 1H NMR. b Endo enantiomeric excess was determined by 1H 400 MHz NMR of the corresponding (R,R)-(+)-hydrobenzoin acetal of the
aldehyde.9c
2422
Org. Lett., Vol. 10, No. 12, 2008

Table 2. Effects of Acid Cocatalyst and Reaction Medium on Enantioselective Diels-Alder Reactions Catalyzed by 5a
entry
acid (equiv)
F3CSO3H (0.2)
Cl3CCOOH (0.2)
Cl3CCOOH (0.1)
Cl3CCOOH (0.05)
Cl3CCOOH (0.1)
p-toluenesulfonic acid (0.1)
3,5-dinitrobenzoic acid (0.1)
solvent
time (h)
yield (%)
exo:endo
endo ee (%)
1
2
3
4
5
6
7
brine
brine
brine
brine
H2O
8
8
8
96
48
48
48
90
85
90
73
82
48
32
1:1.3
1:1.2
1:1.2
1:1.1
1:1.2
1:0.9
1:1
80
82
86
65
84
59
31
brine
brine
R-nitrogen. A series of NR-alkylated CaSHs were synthesized
in high yields by the above-mentioned procedures (Scheme
1, 5a-f). Their performance as enantioselective organocata-
lysts in Diels-Alder reactions was tested by using trichlo-
roacetic acid as cocatalyst in brine (Table 3).
The results indicated that the NR-alkylated hydrazines are
good organocatalysts. Almost all of the NR-alkylated CaSHs
gave outstanding performance except 5f (entry 8). Among all
the NR-alkylated catalysts, 5a (NR-benzyl) and 5c (NR-ethyl) gave
the best results. They can catalyze the reaction efficiently even
at 0 °C with good chemical yields and up to 90% and 93%
endo ee respectively (entries 3 and 7). However, as for similar
organocatalytic Diels-Alder reactions reported in the litera-
ture,9,10 the endo/exo diastereoselectivity is also not very good
in our case.
with good to excellent yields and enantioselectivities. In general,
the enantioselectivity of the endo products is slightly better than
that of the exo products. Aromatic dienophiles performed
slightly better than aliphatic dienophiles on enantioselectivity,
while aliphatic dienophiles had faster reaction rates than
aromatic ones. For the p-chloro- and p-bromocinnamaldehyde,
the endo enantiomeric excess was up to 96% in both cases
(entries 7 and 8). Most of the reactions were carried out at 0
°C and these reactions could be completed within 6 to 12 h.
Some cases were carried out at room temperature because these
reactions were relatively slow at 0 °C (entries 4 and 6). The
aromatic dienophiles with an electron withdrawing group had
a faster reaction rate than those with an electron-donating group.
Especially, for the case of p-nitrocinnamaldehyde, the reaction
was completed in 8 h at 0 °C (entry 5). But for the case of
o-nitrocinnamaldehyde, the poor solubility of the dienophile in
the reaction medium slowed down the reaction rate (entry 6).
To address the stereochemistry of our reactions, we
examined a molecular model of the proposed transition state
of the iminium ion formed between NR-ethyl CaSH (5c) and
cinnamaldehyde as depicted in Figure 1.
To extend the scope of our catalytic system, we chose the
best performing catalyst NR-ethyl CaSH 5c to carry out further
studies with various alkyl- and aryl-substituted R,ꢀ-unsaturated
aldehydes. The results are summarized in Table 4.
NR-Ethyl CaSH is a good Diels-Alder organocatalyst for
both the aliphatic and aromatic R,ꢀ-unsaturated aldehydes
Table 3. NR-Alkylated CaSHs-Catalyzed Enantioselective Diels-Alder Reactions
entry
catalyst
R
condition (°C, h)
yield (%)
exo:endo
endo ee (%)
1
2
3
4
5
6
7
8
5b
5c
5c
5d
5e
5a
5a
5f
CH3
CH3CH2
CH3CH2
n-C4H9
rt, 18
rt, 6
0, 12
rt, 40
rt, 24
rt, 8
88
95
92
85
88
90
85
48
1:1
85
90
93
82
88
86
90
29
1:1.1
1:1.1
1:1
1:1.1
1:1.2
1:1.5
1:1.5
n-C8H17
C6H5CH2
C6H5CH2
9-CH2-anthracene
0, 12
rt, 48
Org. Lett., Vol. 10, No. 12, 2008
2423

Table 4. Enantioselective Diels-Alder Reactions between Cyclopentadiene and Various Dienophiles Catalyzed by NR-Ethyl CaSH 5c
entry
R
condition (°C, h)
yield (%)
exo:endo
exo eea (%)
endo eea (%)
1
2
3
4
5
6
7
8
methyl
n-propyl
phenyl
p-methoxyphenyl
p-nitrophenyl
o-nitrophenyl
p-chlorophenyl
p-bromophenyl
0, 6
0, 6
92
71
92
82
99
94
81
81
1:1.5
1:1.3
1:1.1
1:0.9
1:1.1
1:2.5
1:1.1
1:1.1
83
90
93
91
91
90
96
96
66
78
81
81
72
84
86
1
0, 12
rt, 24
0, 8
rt, 24
0, 12
0, 12
a
The ee was determined by chiral HPLC analysis on the benzoylate derivation of the reduced alcohol and/or by H NMR of the corresponding (R,R)-
(+)-hydrobenzoin acetal derivatives of the aldehydes. The absolute configurations were assigned by correlation to literature9c reported NMR spectra of the
(R,R)-(+)-hydrobenzoin acetal of the major cycloadducts.
good to excellent chemical yields and enantioselectivity. The
reactions were carried out at 0 °C or room temperature in brine
without any added organic solvent. The application of our CaSH
catalyst in other asymmetric transformations is in progress.
Acknowledgment. Financial support from the Faculty
Research Grant (FRG/07-08/II04) and the CERG Grant from
the University Grant Committee are acknowledged.
Supporting Information Available: Experimental pro-
cedures, characterization data, and NMR spectra. This
material is available free of charge via the Internet at
Figure 1. Iminium ion intermediate 8.
http://pubs.acs.org.
OL8005826
The top face of 8 is blocked by the dimethyl groups of the
camphor scaffold. Cyclopentadiene approached from the bottom
face leading to the observed products. In the case of NR-CH2-
anthracene-substituted CaSH (5f), the substituent is so bulky
that the bottom face is also blocked. This led to poor chemical
yield and enantioselectivity as observed (Table 3, entry 8).
In summary, a new type of organocatalyst, NR-alkylated
camphor sulfonyl hydrazine (CaSH), was developed. The
CaSH-catalyzed asymmetric Diels-Alder reaction afforded
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