Reversal of enantioselectivity by catalyst protonation: Asymmetric hydrocyanation of imines with oxazaborolidines

Article abstract of DOI:10.1055/s-2005-922757

A new application of chiral oxazaborolidines in asymmetric transformation, namely the hydrocyanation of imines, is described. The effect of protonation of these catalysts on the reactivity and enantioselectivity of hydrocyanations is studied. Significant

Full text of DOI:10.1055/s-2005-922757

LETTER
41
Reversal of Enantioselectivity by Catalyst Protonation: Asymmetric
Hydrocyanation of Imines with Oxazaborolidines
Asymmetric
H
ydro
l
cyanat
b
ion of Imine
r
s
echt Berkessel,* Santanu Mukherjee, Johann Lex
Institut für Organische Chemie der Universität zu Köln, Greinstrasse 4, 50939 Köln, Germany
Fax +49(221)4705102; E-mail: berkessel@uni-koeln.de
Received 29 September 2005
N
Ph
HN
Ph
CN
Abstract: A new application of chiral oxazaborolidines in asym-
metric transformation, namely the hydrocyanation of imines, is de-
scribed. The effect of protonation of these catalysts on the reactivity
and enantioselectivity of hydrocyanations is studied. Significant in-
crease in reaction rate is observed upon protonation of the catalysts,
along with the reversal of the sense of stereoinduction.
+
HCN
R
H
R
3
4
Scheme 1 Hydrocyanation of imines
Key words: oxazaborolidine, asymmetric catalysis, hydrocyana-
tion, imine, protonation
reactivity difference between neutral and cationic ox-
azaborolidines, and the effect of protonation on the sense
of stereoinduction.
Initial investigation showed that in the presence of 20
mol% oxazaborolidine 1a (Figure 1), N-benzyl-
benzylidene imine (3a) undergoes facile hydrocyanation
at –25 °C in toluene. After 24 hours, 94% conversion was
obtained with 71% ee in favor of the S-enantiomer
(Table 1, entry 2).7 It is important to note that at this tem-
perature, the imine 3a undergoes significant hydrocyana-
tion without any catalyst (entry 1). Despite this fairly
strong background reaction, 71% ee clearly demonstrate
the catalytic efficiency of oxazaborolidine for this reac-
tion. The background reaction was completely suppressed
at –78 °C, but 20 mol% 1a did not produce any conversion
at this temperature either, even after 24 hours (entry 3). In-
creasing the amount of catalyst to 30 mol% (at –25 °C)
did not improve the enantioselectivity (entry 4), but with
lowering the catalyst loading to 10 mol%, the ee dropped
significantly (entry 5). Similar conversions were obtained
in both the above cases (entries 4 and 5). The solution be-
came turbid and a white solid precipitated upon addition
of HCN to a solution of imine and oxazaborolidines in tol-
uene. This solid (in the case of catalyst 1b)8 was isolated
and crystallized from dichloromethane to obtain crystals
for X-ray diffraction. The X-ray crystal structure revealed
this white solid as the HCN adduct of 1b (Figure 2).9 The
adduct 1b·HCN can be regarded as the result of a non-
productive pathway in which the basic cyanide combines
with the Lewis acidic boron atom. This, in turn disrupts
the activation of imine by the Lewis acidic boron center.
This proposal was supported by the lack of catalytic activ-
ity of the isolated adduct when employed for the hydrocy-
anation reaction. In 1b·HCN, the cyanide occupies an
exo-position on the oxazaborolidine backbone, whereas
the phenyl group on the boron atom is oriented endo
(Figure 2).
Chiral oxazaborolidines 1 (Figure 1) are an important
class of molecules that are mainly known for catalyzing
the enantioselective reduction of prochiral ketones with
BH3·THF or catecholborane as stoichiometric reductants.1
This methodology is widely popular because of its broad
substrate scope and extraordinary predictive power of the
product (alcohol) configuration. This system was initially
introduced by Itsuno et al.2 and later on Corey et al. dis-
closed the concrete structure and conclusive mechanism
for this reduction.1 Corey and co-workers also upgraded
the original stoichiometric reduction process to a catalytic
one.
H
Ar
O
H
Ar
O
Ar
Ar
N
N
B
B
H
OTf
R'
R'
2
1
1a/2a : Ar = Ph, R' = Me
1b/2b : Ar = Ph, R' = Ph
1c/2c : Ar = m-Xyl, R' = o-Tol
Figure 1 Chiral oxazaborolidines 1 and oxazaborolidinium
cations 2
Recently, Corey et al. showed that protonation of ox-
azaborolidines generates a potent cationic Lewis acid.
These oxazaborolidinium cations 2 (Figure 1) can be used
as very active catalysts for the enantioselective Diels–
Alder reaction (both inter- and intramolecular),3 and the
cyanosilylation of aldehydes and ketones.4 The purpose of
this communication is to describe another application of
oxazaborolidines and oxazaborolidinium cations in asym-
metric catalysis, namely the enantioselective hydrocyana-
tion of imines (Scheme 1).5,6 We also investigated the
No such precipitation was observed when the reaction was
conducted in dichloromethane, and the reaction was al-
most complete after 8 hours (entry 6). However, the enan-
tioselectivity obtained in this case was only 39% ee. When
SYNLETT 2006, No. 1, pp 0041–0044
Advanced online publication: 16.12.2005
DOI: 10.1055/s-2005-922757; Art ID: G29605ST
© Georg Thieme Verlag Stuttgart · New York
0
5.
0
1.
2
0
0
6

42
A. Berkessel et al.
LETTER
Table 1 Optimization of Reaction Conditions with Catalysts 1
N
Ph
HN
S CN
4a
Ph
catalyst
toluene
+
HCN
H
3a
Entry
Catalyst
[mol%]
–
Temp (°C)
–25
Time (h)
Conversion (%)a ee (%)a
1
2
3
4
5
6b
7
–
24
24
24
24
24
8
28
94
–
1a
1a
1a
1a
1a
1c
20
–25
71
n.d.c
72
62
39
73
20
–78
<2
99
30
–25
10
–25
95
20
–25
95
20
–25
24
>99
a Conversion and ee were determined by chiral HPLC analysis using a Chiralcel OJ column.
b The reaction was carried out in CH2Cl2.
c Not determined.
hours at –78 °C (Table 2, entry 1). The reaction time
could be shortened to 2 hours (cf. 24 h with 1a, see
Table 1), but the enantioselectivity obtained in this case
was only 38% ee. Surprisingly, the sense of stereoinduc-
tion obtained with catalyst 2a was opposite to the one ob-
tained with neutral oxazaborolidines 1. Using the
protonated catalyst 2a, the R-enantiomer was formed in
excess.7 Enantioselectivity could be increased slightly by
adding HCN slowly over a period of 40 minutes without
affecting the conversion very much (entry 2). Independent
experiments revealed that triflic acid (CF3SO3H) is more
effective in protonating the catalyst than bis-triflimide
(Tf2NH), providing better reactivity and enantioselectivi-
ty. Lowering the catalyst loading to 10 mol% affects nei-
ther the conversion nor the enantioselectivity (entry 3).
However, further lowering of loading (to 5 mol%) dimin-
ishes both the conversion and enantioselectivity signifi-
cantly (entry 4).
Figure 2 X-ray crystal structure of 1b·HCN
1c8 was used as catalyst (20 mol%), complete conversion
was obtained after 24 hours, but not much enhancement in
enantioselectivity was observed (Table 1, entry 7). Very
low conversions as well as low enantioselectivities were
observed using TMSCN or a mixture of TMSCN and
Ph3PO as the cyanide source. Optimization of the N-sub-
stituent of the imine showed that N-benzyl imines are su-
perior substrates compared to N-allyl- or N-benzhydryl
imines, provided better conversions (than in case of N-
benzhydryl imines) and selectivities (than both N-allyl-
and N-benzhydryl imines).
Table 2 Optimization of Reaction Conditions with Catalysts 2
N
Ph
HN
Ph
CN
catalyst
+
HCN
R
H
toluene
–70 °C
3a
4a
Entry
Catalyst [mol%]
Time (h) Conversion ee (%)a
(%)a
1
2a
2a
2a
2a
20
20
10
5
2
2
2
2
>99
97
38
42
42
30
2b
3b
4b
Having optimized the conditions for the reaction cata-
lyzed by the neutral oxazaborolidines 1, we studied the
behavior of the protonated (cationic) oxazaborolidines 2
as catalyst in this reaction (Scheme 1). In the presence of
20 mol% of the protonated oxazaborolidine 2a, the imine
3a was completely converted to the aminonitrile within 2
95
26
a Conversion and ee were determined by chiral HPLC analysis using
Chiralcel-OJ column.
b Slow syringe addition of HCN over a period of 40 min.
Synlett 2006, No. 1, 41–44 © Thieme Stuttgart · New York

LETTER
Asymmetric Hydrocyanation of Imines
43
In order to demonstrate the rather general applicability of amino nitriles upon protonation of the catalysts. Experi-
this protonation-induced switch of the sense of induc- ments are underway in our laboratory to optimize the cat-
tion,10 we prepared several N-benzyl imines and applied alyst structure and to reveal the precise mechanism for
them as substrates for the hydrocyanation reaction this enantioreversal.
(Scheme 1) under the established reaction conditions. The
results are summarized in Table 3. Reversal of the sense
of stereoinduction was observed upon catalyst protona-
tion in all cases (A and B, see Table 3). For example, N-
benzyl-benzylidene imine (3a) furnished 71% ee in favor
of the S-enantiomer with free oxazaborolidine 1a (condi-
tion A), whereas 38% ee in favor of R-enantiomer was ob-
tained with protonated oxazaborolidine 2a (condition B;
entry 1, Table 3). In case of the imine derived from 2-
naphthaldehyde (3b), the S-enantiomer was obtained in
68% ee under condition A with 93% conversion after 24
hours. Changing the reaction condition from A to B pro-
duced 33% ee in favor of the R-enantiomer for the same
substrate (entry 2). p-Methoxybenzaldehyde-derived
imine 3c produced significantly lower enantiomeric ex-
cesses with both neutral and cationic catalyst, 40% and
10%, respectively (entry 3). A similar trend was observed
in the case of the pivalaldehyde-derived imine 3d
(entry 4).
General Procedure for the Asymmetric Hydrocyanation of
Imines
Condition A
In a flame-dried Schlenk flask, a solution of the imine (0.51 mmol)
in 1.25 mL of abs. toluene was cooled to –25 °C under positive ar-
gon pressure. To this cold solution was added 0.1 mL of a 1 M so-
lution of catalyst 1a in toluene (102 mmol, 0.2 equiv) and stirred for
5 min at –25 °C. In a separate flask, 1 mL abs. toluene along with
96 mL TMSCN (765 mmol, 1.5 equiv) was cooled to 0 °C under ar-
gon, and 31 mL MeOH (765 mmol, 1.5 equiv) was added. This solu-
tion was stirred at 0 °C for 1 h and added in one portion to the
reaction flask by means of a syringe. The resulting mixture was
stirred at –25 °C under argon. After 24 h, 0.1 mL of sample was
withdrawn, diluted with 0.9 mL CH2Cl2 and conversion and ee were
determined immediately by HPLC (Daicel Chiralcel OJ, n-hexane–
2-PrOH) or GC (after converting the product to the trifluoroacet-
amide; GC-method: g-TA column, 120 °C isothermal).
Condition B
In a flame-dried Schlenk flask, a mixture of 50 mL of 1 M solution
of catalyst 1a in toluene (51 mmol, 0.1 equiv) and 0.3 mL abs. tolu-
ene was cooled to –70 °C under positive pressure of argon. To this
cold solution was then added a 0.2 M solution of triflic acid in tolu-
ene (0.25 mL, 51 mmol, 0.1 equiv) and stirred for 5 min. A solution
of the imine (0.51 mmol) in 0.75 mL abs. toluene was added and
stirred for another 5 min. An HCN solution (765 mmol, 1.5 equiv)
in 1 mL toluene was then added by slow syringe addition of over a
period of 40 min. The resulting mixture was then stirred at –70 °C
under argon. After 2 or 3 h, the reaction mixture was analyzed in the
same way as described for Condition A.
In conclusion, we have described a new application of the
chiral oxazaborolidines 1 in enantioselective catalysis,
namely the asymmetric hydrocyanation of imines. We
also applied oxazaborolidinium cations 2 as the catalyst
for the same reaction. Like in other reactions reported by
Corey et al.,3,4 oxazaborolidinium cations are found to be
much more active catalysts in this reaction compared to
their neutral counterparts. We furthermore observed a re-
versal of stereoinduction in the formation of the product
Table 3 Asymmetric Hydrocyanation of Imines 3
Condition
A or B
N
Ph
HN
Ph
+
HCN
R
H
R
CN
4a–d
3a–d
Entry
1
Compd
Substrate
Conditiona
Time (h)
24
Conversion (%)b
94
ee (%)b
3a
A
B
71 (S)
N
Ph
N
H
2
95
42 (R)
2
3
3b
3c
A
B
24
2
93
95
68 (S)
33 (R)
Ph
H
A
B
24
3
95
75
40 (S)
10 (R)
N
Ph
H
MeO
4
3d
A
B
24
3
82
76
39 (S)
N
H
Ph
rac
a Condition A: 1.5 equiv HCN, 20 mol% 1a, –25 °C. Condition B: 1.5 equiv HCN, 10 mol% 2a, –70 °C.
b Conversion and ee were determined by Chiral GC or HPLC analysis.
Synlett 2006, No. 1, 41–44 © Thieme Stuttgart · New York

44
A. Berkessel et al.
LETTER
S.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2001, 123, 11594. (i) Vachal, P.; Jacobsen, E.
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(l) Huang, J.; Corey, E. J. Org. Lett. 2004, 6, 5027.
(6) For an excellent review about asymmetric hydocyanation of
imines see: (a) Gröger, H. Chem. Rev. 2003, 103, 2795. See
also: (b) Yet, L. Angew. Chem. Int. Ed. 2001, 40, 875.
(c) Spino, C. Angew. Chem. Int. Ed. 2004, 43, 1764.
(d) Berkessel, A.; Gröger, H. Asymmetric Organocatalysis;
Wiley-VCH: Weinheim, 2005.
Acknowledgment
This work was supported by the Fonds der Chemischen Industrie.
References and Notes
(1) Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37,
1986.
(2) Hirao, A.; Itsuno, S.; Nakahama, S.; Yamazaki, N. J. Chem.
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(7) The absolute configurations of the product a-amino nitriles
4 were determined by comparing the sense of optical rotation
with literature data: (a) Hassan, N. A.; Bayer, E.; Jochims, J.
C. J. Chem. Soc., Perkin Trans. 1 1998, 3747. (b) See ref.
5f.
(8) Oxazaborolidines 1b and 1c were synthesized according to
the literature procedure (see ref. 3).
(9) Crystal data of 1b·HCN has been deposited at the
Cambridge Crystallographic Data Centre with the allocated
deposition number CCDC-281060: C24H23BN2O,
M = 366.25, colorless needles, 0.18 × 0.12 × 0.08 mm,
monoclinic, a = 10.588 (1), b = 6.950 (1), c = 14.249 (2) Å,
b = 105.07°(1), V = 1012.5 (2) Å3, T = 293 (2) K, space
group P21, Z = 2, rcalcd = 1.201 g/cm3, m = 0.073 mm–1.
(10) For examples of additive or temperature-induced reversal of
stereoinduction, see: (a) Trost, B. M.; Fettes, A.; Shireman,
B. T. J. Am. Chem. Soc. 2004, 126, 2660. (b) Casey, C. P.;
Martins, S. C.; Fagan, M. A. J. Am. Chem. Soc. 2004, 126,
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C. J. Am. Chem. Soc. 2005, 127, 6138.
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8106. (b) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2005,
127, 5384.
(5) For previous reports on asymmetric hydrocyanation of
imines, see: (a) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem.
Soc. 1998, 120, 4901. (b) Sigman, M. S.; Jacobsen, E. N. J.
Am. Chem. Soc. 1998, 120, 5315. (c) Corey, E. J.; Grogan,
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Synlett 2006, No. 1, 41–44 © Thieme Stuttgart · New York