Asymmetric Strecker reaction of ketoimines catalyzed by a novel chiral bifunctional N,N′-dioxide

Article abstract of DOI:10.1002/adsc.200600238

A novel bifunctional N,N′-dioxide derived from L-prolinamide was employed to catalyze the enantioselective Strecker reaction of a range of N-tosyl ketoimines, and an effective additive was used to improve the reactivity (up to 99% yield) as well as the en

Full text of DOI:10.1002/adsc.200600238

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DOI: 10.1002/adsc.200600238
Asymmetric Strecker Reaction of Ketoimines Catalyzed by a
NovelChiralBifunctional N,N’-Dioxide
Xiao Huang,a Jinglun Huang,a Yuehong Wen,a and Xiaoming Fenga,b,*
a
Key Laboratory of Green Chemistry & Technology (Sichuan University), Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, Peopleꢀs Republic of China
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Peopleꢀs Republic of
b
China
Fax : (+86)-28-8541-8249; e-mail: xmfeng@scu.edu.cn
Received: May 23, 2006; Accepted: October 18, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A novel bifunctional N,N’-dioxide derived
from l-prolinamide was employed to catalyze the
enantioselective Strecker reaction of a range of N-
tosyl ketoimines, and an effective additive was used
to improve the reactivity (up to 99% yield) as well
as the enantioselectivity (up to 91% ee). In addi-
tion, a rational transition state was proposed to elu-
cidate the origin of chiral induction in which an S-
adduct was produced.
ketoimines to the catalytic Strecker reaction using N-
oxides as promoters. As a result, we have found that,
without any catalyst, N-tosyl ketoimine remained un-
changed after treatment with TMSCN at ambient
temperature even in the presence of a large amount
of methanol (5 equivs.). Consequently, a catalytic
amount of a certain N-oxide (such as trimethylamine
oxide and triethylamine oxide) uniquely promotes
this reaction to produce the N-protected amino nitrile
in quantitive yield.[6] This finding encouraged us to
seek a simple chiral N-oxide for the catalytic asym-
metricStrecker reaction of ketoimines.
Keywords: asymmetricactalysis; ketoimines; orga-
nocatalyst; Strecker reaction
Ketoimine 1a has been selected as the model sub-
strate. Initial catalyst screening started from the pro-
linamide-derived
alkyl-linked
N,N’-dioxides[4]
(Scheme 1). Unfortunately, this alkyl-linked series ex-
The catalytic asymmetric Strecker reaction is of great hibited low enantioselectivities (<35% ee) despite
importance to modern organic chemistry as it offers their high activities (>95% yield).
one of the most direct and viable methods for the
Considering that the conformational flexibility of
asymmetricsynthesis of a-amino acids and their de- the alkylated linkage of catalyst series A may not be
rivatives. Efforts have recently reached a peak of per-
fection in the efficient catalyzed cyanation of aldi-
mines to afford a-amino nitriles in high optical
purity.[1,2] In principle, the same strategy could be ap-
plied to ketoimines to afford a,a-dialkylated amino
nitriles. In practice, however, the catalytic enantiose-
lective Strecker reactions of ketomines are not as
easily performed as those of aldimines. There are only
four catalysts reported to date: Jacobsenꢀs urea cata-
lyst,[3a,d] Shibasakiꢀs Gd-complex catalyst,[3e–g] and
VallØeꢀs Ti-complex[3b] as well as their heterobimetal-
lic[3c] analogues. There is still room for developing
new catalysts for the cyanation of ketoimines. Herein
we report a new bifunctional organocatalyst for the
enantioselective cyanation of ketoimines.
In our previous studies, we have disclosed that an
N-oxide was an excellent promoter for the addition of
TMSCN to aldimines,[2i] aldehydes[4] and ketones.[5] So
Scheme 1. Catalyticasymmetricycanation of ketoimine
1a
we have applied many different kinds of N-protected using the catalyst series A.
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Table 1. Catalyticasymmetriccyanation of ketoimine 1a.[a]
beneficial to construct an effective fixed chiral
pocket, another series of catalysts with more rigidity
has been synthesized (Figure 1). As the results in
Table 1 show, all these catalysts displayed high reac-
Entry
Catalyst
t [h]
Yield[b] [%]
ee[c] [%]
1
2
3
4
B1
B2
B3
B4
B5
B1
B1
B1
B1
B1
36
36
36
36
36
24
30
40
30
140
99
92
85
85
82
99
99
90
99
95
70
44
33
15
11
70
70
61
57
75
5
6[d]
7[e]
8[f]
9[g]
10[h]
[a]
All the reactions were carried out in a 0.2 mmol scale of
1a using 1.5 equivs. of TMSCN in 1 mL toluene with 5
mol% catalyst at 08C in a closed system under air unless
otherwise specified.
Figure 1. Structures of catalyst series B.
tivities, while catalyst B1 achieved superior enantiose-
lectivity (Table 1, entry 1). Substituents on the phenyl
ring of B1 including an electron-donating group
(Table 1, entry 4), an electron-withdrawing group
(Table 1, entry 5), a bulky alkyl group (Table 1,
entry 3) and a methyl group (Table 1, entry 2), all re-
sulted in inferior asymmetricindutcion (Table 1, en-
tries 2–5). Higher catalyst loading has no effect on
enantioselectivity, but the reaction has been speeded
[b]
[c]
[d]
[e]
[f]
Isolated yield (for all tables).
Determined by HPLC on Chiralcel OJ column.
10 mol% catalyst was used under an N2 atmosphere.
2.0 equivs. of TMSCN were used.
1.2 equivs. of TMSCN were used.
2.5 equivs. of TMSCN were used.
[g]
[h]
The reaction was performed at À208C.
up (Table 1, entry 1 vs. 6). A slight increase of enan- catalyst has failed, but the absolute configuration of
tioselectivity at lower temperature was accompanied B1 can be estimated according to the literature.[7,8]
by an intense decrease of reactivity whereby a pro- Other B series catalysts can be obtained in simliar
longed reaction time was needed for complete conver- procedures using substituted isophthalaldehydes.
sion of the substrate (Table 1, entry 10).
In view of the hypersubstituent sensitivity effect on
Catalyst B1, which is a hydrophilic compound with the phenyl ring of B1 and low reactivity at low tem-
quite strong polarity (Scheme 2), is readily prepared perature, further improvement of enantioselectivity
via a simple condensation of commercially available and reactivity was mainly focused on additives.
l-prolinamide and isophthalaldehyde followed by oxi-
As displayed in Table 2, a hydroxy group in the ad-
dation with m-CPBA. Furthermore, any attempt to ditives is essential to accelerate the reaction, while
produce a single crystal from any one of the B series the substituent at the ortho position to the hydroxy
Scheme 2. Preparation of catalyst B1.
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Asymmetric Strecker Reaction of Ketoimines
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Table 2. Additives screening.[a]
(Table 2, entry 15), the reactivity clearly deteriorated.
This may indicate that a trace amount of moisture
was important to accelerate the transformation of the
substrate; meanwhile, it has also suggested that this
catalytic system presents an air-tolerant property.
Substrate generality has been surveyed thereafter.
As shown in Table 3 aromaticsubstrates have general-
ly achieved excellent yield and good enantioselectivity
with 1f (Table 3, entry 6) manifesting the best results
under the present protocol (91% ee). Aliphaticsub-
strates as well as heterocyclic substrates have provid-
ed results comparable with those for aromatic ones
(Table 3, entries 9–11) whereas an a,b-unsaturated
substrate (Table 3, entry 12) furnished a moderate ee
value. It should be noticed that the highly enantiose-
lective cyanation of ketoimine bearing a cyclohexyl
moiety has not been realized yet. To our delight, in
our catalytic system, N-tosyl cyclohexylmethylketo-
imine 1j could be smoothly transformed to the corre-
sponding N-tosylamino nitrile in high yield with good
Entry
Additive
t [h]
Yield [%]
ee[b] [%]
1
phenol
20
20
20
20
20
20
40
20
20
20
20
20
20
68
120
20
20
60
90
95
99
90
90
93
85
90
95
99
99
99
99
99
95
99
99
95
19
60
53
29
44
42
40
61
74
78
80
77
45
85
85
53
5
2
3
4
1-adamantanol
o-tert-butylphenol
biphenol
5
6
7
8
S-binaphthol
R-binaphthol
pyrocatechol
resorcinol
hydroquinone
DBHQ[c]
9
10
11
12[e]
13[f]
14[g]
15[h]
16[i]
17[j]
18[k]
DAHQ[d]
DAHQ
DAHQ
DAHQ
DAHQ
DAHQ
DAHQ
DAHQ
70
[a]
All the reactions were carried out in a 0.2 mmol scale of enantiomericpurity (Table 3, entry 10).
1a using 1.5 equivs. of TMSCN in 1 mL toluene with 5
mol% catalyst and 20 mol% additive at 08C in a closed
system under air unless otherwise specified.
Determined by HPLC on Chiralcel OJ column.
DBHQ: 2,5-di-tert-butylhydroquinone.
DAHQ: 2,5-di-(1-adamantyl)hydroquinone.
10 mol% DAHQ was used.
As to the mechanism, there are extensive literature
precedents that TMSCN reacts rapidly with alcohols
and phenols to produce HCN and this has been dem-
onstrated to be the actual cyanating agent in a
number of previous Strecker reactions involving
TMSCN. In our present system, however, the sub-
strates have proved to be inert to HCN, and in this
manner we speculated that hypervalent silicate and
hydrogen bonds should be crucial for the asymmetric
induction in spite of the HCN produced upon addi-
tion of phenol.[10] Therefore, a possible transition state
was propounded as illustrated in Figure 2. Trimethyl-
silyl cyanide was activated by the twin N,N’-dioxides
at the same time to produce a hypervalent silicate
species whereby a fixed chiral pocket was created, re-
[b]
[c]
[d]
[e]
[f]
40 mol% DAHQ was used.
[g]
[h]
The reaction was performed at À208C.
The reaction was performed at À208C under N2 atmos-
phere.
CH2Cl2 was used as solvent.
THF was used as solvent.
[i]
[j]
[k]
Et2O was used as solvent.
unit plays an important role in enhancement of enan- sulting in the cyanide group being polarized to ac-
tioselectivity. R- or S-binaphthol obtained similar re- quire more reactivity; meanwhile, imine 1a was recog-
sults (Table 2, entry 5 vs. 6); this may indicate that no nized by B1 through hydrogen bonding and inserted
visible chiral recognition occurred between B1 and bi- into the catalytic system via a more suitable pathway.
naphthol, thus the improved asymmetricindutcivity
In TS-2, the phenyl group of 1a and the phenyl ring
probably could be due to a steric effect of the addi- of B1 were repulsing on each other while the carbonyl
tives. A more bulky group at the ortho position of the unit of each one encountered a similar situation,
hydroxy unit performs basically better than smaller hence the attempt to generate the R-product was dis-
ones as expected (Table 2, entry 1 vs. 3 and entry 10 favoured to some extent. On the other hand, howev-
vs. 11). A superior additive (Table 2, entry 11) proved er, the S-product was smoothly produced according to
to be DAHQ[9] which is an extremely sterically hin- TS-1 which was a minimal sterically blocked pathway.
dered species.
Besides, through hydrogen bonding, DAHQ assisted
Other optimizations have also been investigated: B1 to magnify the steric effect of the activated inter-
the best amount of additive proved to be 20 mol% mediate formed in the transition state, leading to an
(Table 2, entry 11); decreasing the reaction tempera- improvement of the stereoselectivity.
ture to À208C led to a slight increase of enantioselec-
In summary, we have developed a new bifunctional
tivity (Table 2, entry 14) whereas further lowering it organocatalyst for the general asymmetric Strecker
to À458C or more rendered the system nearly unreac- reaction of ketoimines in high yields with moderate
tive; other solvents have been found to be inferior to to excellent enantioselectivities. This method possess-
toluene (Table 2, entries 16–18). Notably, when the re- es the agreeable features of air-tolerance and easy
action was performed under an N2 atmosphere manipulation as well as a facile and low cost access to
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Table 3. Substrates scope.[a]
Entry
Substrate
t [h]
Yield [%]
ee[b] [%]
1
2
3
4
5
6
7
1a R=phenyl, R’=Me
68
80
80
80
80
70
80
99
94
91
90
92
95
98
85 (S)[c]
61 (S)[d]
71 (S)[d]
71 (S)[d]
76 (S)[d]
91 (S)[d]
71 (S)[d]
1b R=4-methylphenyl, R’=Me
1c R=4-chlorophenyl, R’=Me
1d R=4-bromophenyl, R’=Me
1e R=4-methoxyphenyl, R’=Me
1f R=3,4-dimethoxyphenyl, R’=Me
1g R=2-naphthyl, R’=Me
8
80
96
65 (S)[d]
9
10
11
1i R=2-thiophyl, R’=Me
1j R=cyclohexyl, R’=Me
1k R=t-butyl, R’=Me
80
68
70
92
99
95
81
85
77
12
80
99
61
[a]
All the reactions were carried out on a 0.2 mmol scale of 1 using 1.5 equivs. of TMSCN in 1 mL toluene with 5 mol% B1
and 20 mol% DAHQ at À208C in a closed system.
[b]
[c]
[d]
Determined by HPLC analysis on OJ or AS-H column.
The absolute configuration was assigned after transformation to the corresponding amino acid.
The absolute configuration was determined by comparing the Cotton effect of the CD spectra with that of 2a.
GeneralProcedures for the Preparation of N-
catalyst and reactants. Further investigations are un-
derway in our laboratory including exploration of a
relative catayst library, detailed mechanism, extended
substrate scope and enhancement of enantioselectivi-
ty.
Tosylimines[11]
To
a
stirred solution of ketone (20 mmol), Ts-NH2
(O-i-
(30 mmol) and ZnCl2 (4 mmol) in toluene (100 mL), TiACHTREUNG
Pr)4 (24 mmol) was added dropwise then the mixture was
heated to reflux for 12 h. 2 N NaOH (4 mL) was added to
the reaction mixture after cooling down to quench the reac-
tion, then the solid formed was filtered off and washed with
200 mL ether. The combined filtrate was washed successive-
ly by 2 N NaOH (2”100 mL), brine (1”100 mL) and dried
over MgSO4. Sovlents were removed under reduced pres-
sure, and the residue was purified by either recrystallization
or silica gel chromatograph to afford the corresponding
imine in 15–80% yield.
ExperimentalSection
GeneralRemarks
All the catalytic manipulations were carried out under air in
a closed system. NMR spectra were recorded on a Bruker
300 MHz or 600 MHz spectrometer. Chemical shifts are re-
ported downfield from TMS (d=0) for 1H NMR. For
13C NMR, chemical shifts are reported on the scale relative
to the solvent used as an internal reference. Data for
1H NMR are reported as follows: chemical shift (d ppm),
multiplicity (s=singlet, d=doublet, t=triplet, q=quartet,
m=multiplet, br=broad), coupling constant (Hz), integra-
tion and assignment. Data for 13C NMR are reported in
terms of chemical shift (d ppm). Melting points are uncor-
rected. Solvents used were purified by usual methods. Other
commercially available reagents were used as received. Op-
tical purity was determined by HPLC analysis on Daicel
Chiralcel OJ or Chiralpak ASH column at 254 nm. Optical
rotations were measured on a Rudolph-Autopl V polarime-
ter.
Preparation of B1
A solution of l-prolinamide (10.5 mmol) and isophthalalde-
hyde (5 mmol) in 10 mL anhydrous ethanol was heated to
reflux for 5 h, then after solvent had been removed under
reduced pressure, the residue was purified by silica gel chro-
matography using ethyl acetate/methanol as eluent to afford
trans B1a as white solid (and a trace amount of cis product
as a later eluting fraction can be collected together with un-
reacted l-prolinamide).
To a stirred solution of 800 mg B1a in 40 mL CH2Cl2 at
À208C, 940 mg (2.2 equivs.) of m-CPBA were added in one
portion and the mixture allowed to stir for 20 min (TLC
analysis to ensure the complete consumption of B1a; and a
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Asymmetric Strecker Reaction of Ketoimines
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Figure 2. A simplified model of proposed transition state.
single product was detected by TLC), then the solvent was
removed under vacuum with the temperature not exceeding
408C. The residue was purified on silica gel using methanol
then NH3 in methanol as eluent to obtain B1 in 95% yield.
Acknowledgements
We thank the National Natural Science Foundation of China
(Nos. 20225206, 20390055 and 20372050), and the Ministry
of Education, P. R. China (No. 104209) for financial support.
We also thank Sichuan University Analytic and Testing
Center for CD spectral analysis.
TypicalProcedure for Racemic Reaction
To a stirred solution of 1a (54.7 mg, 0.2 mmol) and trime-
thylamine oxide (3 mg, 0.04 mmol) in toluene (1 mL),
TMSCN (42 mL, 1.5 equivs.) was added in one portion at
ambient temperature. After complete conversion (moni-
tored by TLC), the residue was purified by flash chromatog-
raphy on silica gel using EtOAc/petroleum ether (1:3, v/v)
as eluent to afford 2a in 99% yield.
References
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TypicalProcedure for Catayl tic Cyanation of
Ketoimine
To a stirred solution of 1a (54.7 mg, 0.2 mmol), DAHQ
(15.2 mg, 0.04 mmol, 20 mol%) and B1 (3.6 mg, 0.01 mmol,
5 mol%) in toluene (1 mL), TMSCN (42 mL, 1.5 equivs.)
was added in one portion at À208C. After complete conver-
sion (monitored by TLC, 68 h), the residue was purified by
flash chromatography on silica gel using EtOAc/petroleum
ether (1:3, v/v) as eluent to afford 2a in 99% yield.
Adv. Synth. Catal. 2006, 348, 2579 – 2584
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2583

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Method I: To
a stirred solution of 1a (27.3 mg,
0.1 mmol) and B1 (3.6 mg, 0.01 mmol, 10 mol%) in
0.5 mL toluene, ethyl cyanoformate (20 mL, 2 equivs.)
was added in one portion at ambient temperature, fol-
lowed by addition of acetic acid (12 mL, 2 equivs.).
Method II: To a stirred solution of 1a (27.3 mg,
0.1 mmol) and B1 (3.6 mg, 0.01 mmol, 10 mol%) in
0.5 mL water-saturated toluene, ethyl cyanoformate
(20 mL, 2 equivs.) was added in one portion at ambient
temperature. These two methods are alternative ways
instead of using TMSCN and phenol that could pro-
duce HCN which could serve as cyanating agent. As
predicted, after 30 h stirring at ambient temperature,
no product was detected (by TLC) for both methods.
This could demonstrate that the silicon reagent plays
an important role in the present catalytic system and
TMSCN is very likely to be the real cyanating agent.
Or we may suggest that a highly reactive intermediate
might be generated by combination of TMSCN and
N,N-dioxide. Comparably, there is no such interaction
between HCN and N,N-dioxide with the result that no
addition occurred.
[4] Y.-H. Wen, X. Huang, J.-L. Huang, Y. Xiong, B. Qin;
X.-M. Feng, Synlett 2005, 16, 2445.
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[6] For racemic preparation see experimental section (see
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Adv. Synth. Catal. 2006, 348, 2579 – 2584