Second generation CaSH (Camphor Sulfonyl Hydrazine) organocatalysis. asymmetric diels-alder reactions and isolation of the catalytic intermediate

Article abstract of DOI:10.1002/adsc.201000438

In one step, the well known chiral auxiliary, Oppolzer's camphor sultam, is turned into the new generation camphor sulfonyl hydrazine (CaSH II) organocatalyst. With the primary hydrazine functionality external to the tricyclic structure, CaSH II is active

Full text of DOI:10.1002/adsc.201000438

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DOI: 10.1002/adsc.201000438
Second Generation CaSH (Camphor Sulfonyl Hydrazine)
Organocatalysis. Asymmetric Diels–Alder Reactions and
Isolation of the Catalytic Intermediate
Qinghua Li,a Wai-Yeung Wong,a Wing-Hong Chan,a and Albert W. M. Leea,*
a
Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, Peopleꢀs Republic of China
Fax : (+852)-3411-7348; e-mail: alee@hkbu.edu.hk
Received: June 6, 2010; Published online: September 2, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000438.
Abstract: In one step, the well known chiral auxili-
ary, Oppolzerꢀs camphor sultam, is turned into the
new generation camphor sulfonyl hydrazine (CaSH
II) organocatalyst. With the primary hydrazine
functionality external to the tricyclic structure,
CaSH II is active towards ketone substrates in
asymmetric Diels–Alder reactions. The iminium in-
termediate of the catalytic cycle was isolated. When
Scheme 1. Camphor sulfonyl hydrazines.
it was put back into the solution reaction system,
the same level of yield and stereoselectivity was ob-
served. Based on these observations, we argue that
organocatlyst is actually an in situ chiral auxiliary.
asymmetric Diels–Alder,[5] indole alkylation,[6] and
aza-Michael additon reactions.[7]
Keywords: asymmetric Diels–Alder reaction; cam-
phor sulfonyl hydrazine; CaSH; hydrazines; orga-
nocatalysis
CaSH I is quite active towards aldehyde substrates.
However, its reactivity towards ketones is rather lim-
ited. Actually, it is rather common in secondary
amine organocatalysis that they are less reactive to-
wards ketones than aldehydes. Steric hindrance may
be one of reasons for this difference in reactivity.
In CaSH I, the active b-nitrogen is a secondary hy-
Enantioselective organocatalysis, the use of small or- drazine. In this communication we would like to in-
ganic molecules to catalyze asymmetric transforma- troduce a new generation CaSH organocatalyst.
tions, is unarguably one of the most exciting research CaSH II (2), which is an isomer of CaSH I and shows
areas in synthetic organic chemistry in recent years.[1] excellent reactivity towards both aldehyde and ketone
Various catalytic systems have been developed and substrates. The active nitrogen of CaSH II is a pri-
put into practice for the synthesis of chiral molecules. mary hydrazine and is external to the tricyclic struc-
Among different types of organocatalysts,[2] Lewis ture.
base catalysts were first developed and have been
widely applied to various types of asymmetric trans- Scheme 2. Originally, we planned to prepare CaSH II
formations. via a similar route as for the synthesis of CaSH I by
The synthetic approach to CaSH II is outlined in
Among the Lewis base organocatalysts reported in reacting camphor sulfonyl chloride 3 with bis-TMS-
the literature, almost all of them are either secondary protected hydrazine followed by hydride reduction.
or primary amines,[3] and many of them are derived CaSH II could then be prepared by de-protection of 4
from naturally occurring amino acids. Recently, based with fluoride. However, this approach did not work as
on the concept of a-heteroatom effect,[4] we reported planned. Although bis-TMS-protected hydrazine is a
the first example of using hydrazine as a new func- known compound,[8] its preparation was found to be
tionality for Lewis base organocatalysis. CaSH I, cam- troublesome. We then moved to a more direct ap-
phor sulfonyl hydrazine (1, Scheme 1), was prepared proach by amination of camphor sultam (Oppolzerꢀs
and demonstrated as an effective organocatalyst for sultam).[9] Sultam 5 is a well known chiral auxiliary
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Adv. Synth. Catal. 2010, 352, 2142 – 2146

Second Generation CaSH (Camphor Sulfonyl Hydrazine) Organocatalysis
Scheme 2. Synthesis of CaSH II.
that is commercially available or can be easily pre- ment of efficient catalytic systems to effect enantiose-
pared from camphor sulfonyl chloride. After trying lective variants has been the focus in asymmetric cat-
several electrophilic amination agents such as hydrox- alysis.[14]
ylamine-O-sulfonic acid.[10] (HOSA) and 1-oxa-2-
azaspiroACHTUNGTRENNUNG
We are indeed pleased to find that CaSH II, as a
[2.5]octane,[11] we found that O-(diphenyl- primary hydrazine, is much more reactive than CaSH
phosphinyl)-hydroxylamine[12] (DppONH2, 6) gave I towards ketone substrates. In the presence of HCl
the most satisfactory result. Treatment of camphor (added as 1M ether solution) as the acid additive, the
sultam 5 with NaH in THF followed by DppONH2 af- Diels–Alder reaction between a,b-unsaturated ketone
forded CaSH II in over 90% yield. The structure of 7a and cyclopentadiene took place smoothly in
CaSH II is confirmed by X-ray analysis (Figure 1).[13] CHCl3, THF, and toluene at room temperature with
CaSH I is very reactive towards a,b-unsaturated al- good isolated yields, endo/exo selectivities and enan-
dehydes in Diels–Alder reactions, but its reactivity to- tioselectivities (entries 1 to 3, Table 1). However, in
wards a,b-unsaturated ketones is very slow. There- MeOH/H2O or tert-butyl methyl ether (TBME), only
fore, we picked Diels–Alder reactions with a,b-unsa- trace amounts of the product could be detected (en-
turated ketones to probe the reactivity and selectivity tries 4 and 5). Nonetheless, to our surprise and de-
of CaSH II. Being one of the most useful reactions light, a white precipitate was formed when the HCl
for carbon-carbon bond formation and construction salt of CaSH II was mixed with ketone 7a in TBME.
of carbocyclic systems, the Diels–Alder reaction is
The HR-MS data of the white precipitate con-
still one of the most studied and most utilized reac- firmed that it is the iminium ion 11 (Figure 2) formed
tions in organic synthesis. In particular, the develop- between the ketone and CaSH II (HR-MS: m/z=
359.1789; calcd. for C20H27N2O2S: 359.1793). When
the iminium salt suspended in CHCl3 was briefly
treated with solid NaHCO3, two isomeric imine com-
pounds could be isolated by column chromatography.
1H and 13C NMR (d=176.5 and 174.6 for the imine
carbons) also confirmed the structure of 11 with a
Z/E ratio of 1:1. When the white precipitate 11 was
re-dissolved in CHCl3 at room temperature in the
presence of cyclopentadiene and some more added
HCl, the Diels–Alder reaction took place readily and
resulted in the same level of yield (94%) and enantio-
selectivity (88% ee) as compared to the normal cata-
lytic reaction in the same solvent ( compare entry 1 of
Table 1). This provides concrete evidence that imini-
um salt 11 is the reactive intermediate of this CaSH
II-catalyzed Diels–Alder reaction.[15] The reactive in-
termediate in a Lewis base-catalyzed reaction could
be isolated and then put back into solution to com-
plete the reaction. With the isolation of intermediate
Figure 1. X-ray structure of CaSH II.
11, we propose that the Lewis base organocatalyst is
Adv. Synth. Catal. 2010, 352, 2142 – 2146
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Qinghua Li et al.
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Table 1. Optimization of reaction conditions.
Entry
Solvent
Acid additive
T/t [8C/h]
Yield [%]
endo/exo[a,b]
ee[b] of endo [%]
1
2
3
4
5
6
7
8
9
CHCl3
THF
toluene
MeOH/H2O [4/1]
TBME
toluene
toluene
toluene
toluene/THF [4/1]
HCl/ether
HCl/ether
HCl/ether
HCl/ether
HCl/ether
benzoic acid
TCA
0/48
94
90
82
trace
trace
trace
91
90
70
98:2
96:4
97:3
–
–
–
96:4
96:4
98:2
80
82
84
–
–
–
78
74
88
r.t./24
r.t./12
r.t./24
r.t./24
r.t./24
r.t./24
r.t./12
À20/48
TFA
TfOH
[a]
1
The exo/endo ratios were determined by H NMR.
Determined by chiral HPLC using a Chiralcel OD-H or AD-H column.
[b]
marized in Table 2. For b-aryl-substituted a,b-unsatu-
rated ketones (7a–l, entries 1 to 12, Table 2), the
product yields, endo/exo ratios and enantioselectivities
are consistently high with the exception of an ortho-
substituted aryl ketone (entry 6). Electron-withdraw-
ing substituents on the aryl rings did not affect the
enantioselectivities that much. However, an electron-
donating group at the para-position such as 4-me-
thoxy (entry 2) afforded 96% ee. As compared with
methyl ketones, bigger ketones such as ethyl, n-propyl
Figure 2. Isolated iminium ion 11
actually equivalent to an in situ chiral auxiliary. The and phenyl in general afforded slightly poorer ee
organocatalyst forms a covalent iminium intermediate values (entries 8, 9, 10). Reactions with other dienes
in situ with the ketone substrate, which is more reac- such as cyclohexa-1,3-diene and 2,3-dimethylbuta-1,3-
tive than the ketone itself[1d,16,17] and provides the ste- diene also afforded reasonable enantioselectivities,
reochemical control of the enantioselective process. but the reactions were much slower (entries 11 and
Of course, as different from the chiral auxiliary ap- 12). For the aliphatic a,b-unsaturated ketone (7m),
proach, the covalent intermediate in organocatalysis the reaction could be carried at lower temperatures
is not isolated but forms in situ in the catalytic cycle. with moderate ee (entry 13). Assignments of the abso-
After the reaction, the organocatalyst departs from lute configurations of the cycloadducts were based on
the product and re-enters back to the catalytic cycle. optical rotations and literature precedents.
We also studied the effect of an acid additive on
Once again, we have demonstrated that hydrazine
these CaSH II-catalyzed Diels–Alder processes. A is an effective functionality for organocatalysis. This
weaker acid such as benzoic acid was not suitable supplements the uses of primary and secondary
while trichloroacetic acid (TCA, the best acid co-cata- amines in this important research area. CaSH II has
lyst for the CaSH I system) and trifluoroacetic acid been synthesized by simply amination of camphor
afforded comparable results as HCl (entries 6, 7, 8, sultam. In one step, we have turned a well known
Table 1.). Eventually, we found that triflic acid gave chiral auxiliary, Oppolzerꢀs sultam, into an organoca-
the best result in a toluene/THF (7:1) solvent system talyst. In contrasted to CaSH I, CaSH II exhibits ex-
with 90% yield and 88% enantioselectivity (entry 9).
cellent reactivity and selectivity towards ketone sub-
With these optimized conditions, we further ex- strates in asymmetric Diels–Alder reactions with up
plored the scope of the reaction. The results are sum- to 96% ee. In principle, other secondary amine orga-
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Second Generation CaSH (Camphor Sulfonyl Hydrazine) Organocatalysis
Table 2. Scope of CaSH II catalyzed Diels–Alder reactions.
Entry [10]
R1/R2/Diene 8
T/t [8C/h]
Yield[c] [%]
endo/exo[a,b]
ee[b] of endo [%]
1 [10a]
2 [10b]
3 [10c]
4 [10d]
5 [10e]
6 [10f]
7 [10g]
8 [10h]
9 [10i]
10 [10j]
11 [10k]
12 [10l]
13 [10m]
4-MeC6H4/Me/8a
4-MeOC6H4/Me/8a
3-MeOC6H4/Me/8a
4-BrMeC6H4/Me/8a
3-BrMeC6H4/Me/8a
2-BrMeC6H4/Me/8a
4-NO2MeC6H4/Me/8a
4-MeOC6H4/Et/8a
4-MeOC6H4/n-Pr/8a
4-MeOC6H4/Ph/8a
4-NO2MeC6H4/Me/8b
4-NO2MeC6H4/Me/8c
Me/Et/8a
r.t./24
r.t./24
r.t./24
0/12
0/12
0/12
À20/48
r.t./24
r.t./16
r.t./72
r.t./96
r.t/48
À20/48
87
89
88
96
82
85
93
92
96
70
40
82
91
96:4
96:4
96:4
96:4
96:4
85:15
96:4
96:4
96:4
96:4
96:4
96:4
96:4
86
96
72
92
84
11
84
90
86
84
82
70
82
[a]
1
Determined by H NMR.
Determined by chiral HPLC using a Chiralcel OD-H or AD-H column.
Yield refers to isolated materials after purification by flash chromatography on silica gel.
[b]
[c]
400 MHz): d=3.50 (br, 2H) 3.18 (dd, 2H, J=14 Hz), 2.88
(q, 1H, J=4 Hz), 2.12 (m, 1H), 1.93–1.70 (m, 4H), 1.41 (m,
1H), 1.28 (m, 1H), 1.15 (s, 3H), 0.93 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=69.1, 47.7, 47.5, 47.1, 44.4, 35.3, 32.6,
27.1, 20.5, 19.8. HR-MS: m/z=231.1179, calcd. for [M+H]+
(C10H19N2O2S): 231.1162.
nocatalysts could also be transformed to the corre-
sponding hydrazine organocatalysts via a similar elec-
trophilic amination approach.
In addition, the key iminium intermediate of the
Lewis base catalytic process was also isolated. When
it was put back to the solution reaction system, the
same level of yield and selectivity was observed. This
unambiguously proves the intermediacy of the Lewis
base organocatalysis. Based on this observation, we
argue that the organocatalyst is actually an in situ
chiral auxiliary.
General Procedure for CaSH II-Catalyzed Diels–
Alder Reactions
To a mixture of Cash II (2, 0.04 mmol, 9.12 mg) and the a,b-
unsaturated ketone (0.2 mmol) in 1 mL of dried toluene/
THF (7/1) were added dropwise 1.5 mL of trifloromethane-
sulfonic acid solution (4.8 mg, 320 mgmLÀ1, toluene/THF=
4/1). After stirring at À20 or 08C for 15 min, freshly distilled
cyclopentadiene (4 mmol) was added. The reaction mixture
was kept at À20, 08C or room temperature until consump-
tion of the starting ketone (tracked by TLC). The reaction
mixture was directly purified by column chromatography,
first with pure PE then PE/EtOAc from 15/1 to 10/1 to give
the pure Diels–Alder adducts.
Experimental Section
Preparation (À)-2,10-N-Aminocamphorsultam (CaSH
II, 2)
Sodium hydride (60% dispersion in mineral oil, 100 mg,
2.5 mmol) was added to a stirred solution of (À)-2,10-cam-
phorsultam (430 mg, 2 mmol) in THF (20 mL) at 08C. After
[12b]
10 min, DppONH2
(700 mg, 3 mmol) was added in one
portion and the slurry was stirred for 4 h at room tempera-
ture. The solid was removed by filtration and the filtrate
was concentrated to get a white solid. The white solid was
purified by recrystallization using CH2Cl2 and hexane
(1 mL: 10 mL) to afford 2; yield: 415 mg (90%); mp 119–
1218C; [a]2D3: À72 cm3 gÀ1 dmÀ1 (c 1.03 gcmÀ3 in, CH2Cl2); IR
(neat): n=3351, 3000, 2957, 2869, 1616, 1479, 1454, 1427,
Acknowledgements
Finical support from the Faculty Research Grants (FRG1/08-
09/058 and FRG2/09-10/039) and the Hong Kong Research
Grant Council is gratefully acknowledged. A. W. M. Lee
thanks the Nagoya University for the award of the RCMS
Visiting Professorship.
1278, 1261, 1061, 811, 567, 555 cmÀ1 1H NMR (CDCl3,
;
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Qinghua Li et al.
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