Asymmetric conjugate hydrocyanation of α,β-unsaturated n -acylpyrroles with the ru(phgly)2(binap)-CH3OLi catalyst system

Article abstract of DOI:10.1021/ol403545b

Asymmetric conjugate hydrocyanation of α,β-unsaturated carboxylic acid derivatives catalyzed by a Ru[(S)-phgly]₂[(S)-binap]- CH₃OLi system was examined. The N-acylpyrrole gave the best result in terms of reactivity and enantioselectivity. A series of substrates with alkyl or heterosubstituted alkyl groups at the β-position reacted with a substrate-to-catalyst molar ratio of 200-2000 to afford the β-cyano products in the range of 88%->99% ee. The mode of enantioselection in the hydrocyanation was proposed.

Full text of DOI:10.1021/ol403545b

Letter
pubs.acs.org/OrgLett
Asymmetric Conjugate Hydrocyanation of α,β-Unsaturated
N‑Acylpyrroles with the Ru(phgly)2(binap)−CH3OLi Catalyst System
Yusuke Sakaguchi, Nobuhito Kurono, Kohei Yamauchi, and Takeshi Ohkuma*
Division of Chemical Process Engineering and Frontier Chemistry Center, Faculty of Engineering, Hokkaido University, Sapporo,
Hokkaido 060-8628, Japan
S
* Supporting Information
ABSTRACT: Asymmetric conjugate hydrocyanation of α,β-
unsaturated carboxylic acid derivatives catalyzed by a Ru[(S)-
phgly]2[(S)-binap]−CH3OLi system was examined. The N-
acylpyrrole gave the best result in terms of reactivity and
enantioselectivity. A series of substrates with alkyl or
heterosubstituted alkyl groups at the β-position reacted with
a substrate-to-catalyst molar ratio of 200−2000 to afford the β-
cyano products in the range of 88%−>99% ee. The mode of
enantioselection in the hydrocyanation was proposed.
unsaturated carboxylic acid derivatives with our original chiral
nantioselective conjugate cyanation of α,β-unsaturated
Ecarboxylic acid derivatives is a reliable procedure for the Ru−Li combined catalyst.12
The reaction of N-acylpyrrole derived from crotonic acid 1a
production of optically active β-cyano compounds that can be
readily converted to the biologically important β-substituted-γ-
amino carboxylic acids.1,2 A variety of chiral catalysts have been
developed for this reaction based on the diverse array of
potential unsaturated substrates and cyanide sources. The
conjugate reaction of α,β-unsaturated imides and the
(CH3)3SiCN/2-propanol system with chiral salen−Al or
cooperative bimetallic catalysts afforded the β-cyano adducts
in up to 98% enantiomeric excess (ee).3,4 The turnover number
(TON) of the catalyst was as high as 50. The chiral polymetallic
Gd or Sr species catalyzed the reaction of α,β-unsaturated N-
acylpyrroles with the trialkylsilyl cyanide/protic compound
system (TON: up to 200; ee: up to 99%).5 The use of
trialkylsilyl cyanide is crucial to achieve high yield of products
in both cases.3,5 Chiral phase-transfer catalysts with the
quinuclidine backbone promoted the conjugate addition of
acetone cyanohydrin to α,β-unsaturated N-acylpyrroles (TON:
up to 10; ee: up to 98%).6 Alkylidenemalonates are cyanated in
a conjugate manner with the ethyl cyanoformate/2-propanol
system in the presence of chiral modular Ti catalysts (TON: up
to 10; ee: up to 94%).7 Chiral phase-transfer catalysts with the
binaphthyl backbone promoted the reaction of alkylidenemal-
onates and KCN (TON: up to 320; ee: up to 95%).8 All of the
above reactions achieved high enantioselectivity, but there is
room for improvement in the catalytic activity. Furthermore, no
successful examples have been reported using HCN, the
simplest cyanide source.
(1.0 mmol, 0.15 M)13 and HCN prepared in situ by mixing
(CH3)3SiCN (1.5 mmol) and CH3OH (1.5 mmol) in
t‑C4H9OCH3 at 25 °C proceeded smoothly in the presence
of Ru[(S)-phgly]2[(S)-binap]14 ((SA,SP)-3: 2.0 μmol; substrate-
to-catalyst molar ratio (S/C) = 500) and CH3OLi (0.10 M in
CH3OH, 2.0 μmol) to afford the β-cyano compound (S)-2a as
a sole observable product in 98% yield and 88% ee in 2 h
(Table 1, entry 1). The higher concentration of 1a (0.30 M)
resulted in the lower ee value of 2a (83%). The
enantioselectivity decreased when the reaction was conducted
in cyclo-C5H9OCH3 or (C2H5)2O (entries 2 and 3). No
conversion was observed in less polar toluene solution (entry
4). A higher enantioselectivity was achieved under the lower
temperature conditions, although the reaction rate slowed
down (entries 5 and 7). Thus, the ee value reached 96% at −20
°C. The reaction using isolated HCN15 instead of HCN formed
in situ proceeded smoothly to give 2a in the same ee (entry 6 vs
entry 5), suggesting that this reaction is the hydrocyanation
without substantial influence from the existing silicone
compounds.
The conjugate cyanation of the N-acyl-3,5-dimethylpyrazole
analogue 1b afforded the β-cyano adduct 2b in high ee, but the
moderate yield of 44% with an S/C of 200 at 0 °C for 15 h was
not satisfactory (Table 1, entry 8). The unsaturated amide 1c
was feebly reactive (entry 9). The cyanation of the
pyrrolidinone-derived imide 1d with an S/C of 200 at 0 °C
was completed in 24 h to give 2d with a moderate ee of 61%
(entry 10). The reaction of the oxazolidinone 1e, the structure
of which is similar to that of the imide 1d, also proceeded
Recently, we reported asymmetric conjugate addition of
HCN to α,β-unsaturated ketones catalyzed by the combined
system of Ru(phgly)2(binap) and C6H5OLi.9−11 A series of
aromatic, heteroaromatic, and aliphatic β-cyano ketones was
obtained in high enantioselectivity. This observation prompted
us to investigate asymmetric conjugate hydrocyanation of α,β-
Received: December 7, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol403545b | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Enantioselective Conjugate Cyanation of
α,β‑Unsaturated Carboxylic Acid Derivatives 1
Table 2. Enantioselective Conjugate Hydrocyanation of
a
a
α,β‑Unsaturated N-Acylpyrroles 4
b
c
d
entry
4
S/C
temp, °C time, h
% yield
% ee
1
4a
4b
4c
4d
4d
4d
4e
4f
500
−20
−20
−20
−20
−20
−40
25
27
24
34
22
72
72
48
24
13
24
18
16
>99 (91)
91 (88)
97 (S)
96 (S)
88
2
500
500
500
2000
500
50
3
>99 (97)
>99 (99)
>99 (95)
>99 (94)
61 (55)
4
91
5
88
6
>99
7
41
98
93
92
88
88
8
500
250
500
250
200
0
66 (40)
9
4g
4h
4i
0
>99 (86)
>99 (99)
>99 (90)
94 (93)
10
11
12
−20
0
temp,
°C
b
c
d
e
entry
1
S/C
solvent
time, h % yield
% ee
4j
−20
1
2
3
4
5
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1e
1f
500
500
500
500
500
500
500
200
200
200
200
200
200
TBME
CPME
Et2O
25
2
2
98
98
98
<1
97
88
88 (S)
82 (S)
55 (S)
a
25
25
25
0
Unless otherwise stated, the reactions were carried out using
substrates (0.5−1.0 mmol) and HCN (1.5 equiv) in t-C4H9OCH3
with (SA,SP)-3 and CH3OLi (3/CH3OLi = 1:1). HCN was prepared in
2
f
toluene
TBME
TBME
TBME
TBME
TBME
TBME
TBME
TBME
TBME
2
nd
b
situ from (CH3)3SiCN and CH3OH in a 1:1 ratio. Substrate/catalyst
12
12
25
15
12
24
24
48
24
91 (S)
91 (S)
96 (S)
93
c
g
(3) molar ratio. Determined by GC or 1H NMR analysis. The
6
0
d
isolated yield is stated in parentheses. Determined by chiral GC or
HPLC analysis. The absolute configuration is given in parentheses.
7
−20
0
96 (94)
44 (43)
<1
8
f
9
0
nd
and 4d, gave the products at around 90% ee (entries 3 and 4).
The high reactivity of 4d achieved complete conversion in this
reaction with an S/C of 2000 at −20 °C in 72 h (entry 5). The
ee value of 5d reached >99% in the cyanation at −40 °C (entry
6). The β-aryl substrate 4e reacted slowly with moderate
enantioselectivity (entry 7).
The reactivity of the heterosubstituted unsaturated N-
acylpyrroles seems to be highly dependent on the features of
the functional groups. The N-acylpyrrole with an ester group 4f
exhibited excellent enantioselectivity of 98% at 0 °C with a
modest reaction rate (Table 2, entry 8). The cyanation of 4g
bearing a carbamate functional group with an S/C of 250 at
0 °C completed in 13 h to afford the β-adduct in 93% ee (entry
9). The benzyl ether 4h showed high reactivity and
enantioselectivity comparable to those of the β-alkyl substrates
(entry 10). The dimethoxy or chloro substituent led to a
decrease in the reaction rate, but the desired products 5i and 5j
were both obtained in ≥94% yield and in 88% ee under the
appropriate conditions (entries 11 and 12).
We previously reported that the ruthenium complex 3
couples with a lithium alkoxide or lithium halide to form the
Ru−Li combined species [Li{Ru(phgly)2(binap)}]+ ([Li(3)]+)
in the solution phase.14,16 This species appears to act as a Lewis
acidic catalyst for the hydrocyanation. A single-crystal X-ray
analysis of [Li{(SA,SP)-3}]Br revealed that the lithium cation
interacts with the carbonyl oxygen of PhGly, and the bromide
locates between two nitrogens of PhGlys, probably due to
hydrogen bonds with the amino protons of the coordinated
amino groups (see the Supporting Information).17
10
11
12
13
0
>99 (92)
99
61
0
81
−20
0
98 (94)
43
92 (S)
53
a
Unless otherwise stated, the reactions were carried out using 1 (1.0
mmol) and HCN (1.5 mmol) in solvent (6 mL) with (SA,SP)-3 and
CH3OLi (3/CH3OLi = 1:1). HCN was prepared in situ from
b
(CH3)3SiCN and CH3OH in a 1:1 ratio. Substrate/catalyst (3) molar
c
d
ratio. TBME: t-C4H9OCH3. CPME: cyclo-C5H9OCH3. Determined
by GC or 1H NMR analysis. The isolated yield is stated in parentheses.
e
Determined by chiral GC or HPLC analysis. The absolute
configuration is given in parentheses. Not determined. Isolated
HCN was used.
f
g
smoothly with better enantioselectivity (entry 11). The ee value
of 2e reached 92% in the reaction at −20 °C (entry 12). The
linear analogue, N-acylcarbamate 1f, showed moderate
reactivity and enantioselectivity (entry 13).
Thus, we selected the α,β-unsaturated N-acylpyrroles 4 to
examine the substrate scope for the asymmetric conjugate
hydrocyanation catalyzed by the Ru[(S)-phgly]2[(S)-binap]
[(SA,SP)-3]−CH3OLi combined system in t-C4H9OCH3. The
results are summarized in Table 2. The hydrocyanation of the
N-acylpyrrole derived from (E)-2-hexenoic acid 4a (R = n-
C3H7) with an S/C of 500 at −20 °C completed in 27 h to
afford the β-cyano product (S)-5a in 97% ee (entry 1). The
degree of enantioselectivity was comparable to that in the
reaction of 1a (R = CH3; see Table 1, entry 7). The phenylethyl
analogue 4b reacted somewhat slowly, but it maintained the
high enantioselectivity (entry 2). The cyanation of substrates
with a secondary or tertiary alkyl group at the β-position, 4c
A plausible reaction pathway incorporating these observa-
tions is shown in Scheme 1. CH3OLi reacts with HCN to give
B
dx.doi.org/10.1021/ol403545b | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 1. Molecular models for enantioselection in the conjugate cyanation of 1a with the chiral Ru−Li combined catalyst (SA,SP)-6.
In summary, we have examined asymmetric conjugate
hydrocyanation of α,β-unsaturated carboxylic acid derivatives
catalyzed by the Ru(phgly)2(binap)−CH3OLi system. Among
them, the N-acylpyrrole gave the best result in terms of
reactivity and enantioselectivity. A series of substrates with alkyl
or heterosubstituted alkyl groups at the β-position reacted with
an S/C of 200−2000 to yield the β-cyano products in the range
of 88%−>99% ee. The reaction pathway and the mode of
enantioselection in this conjugate addition were also proposed.
Scheme 1. Plausible Reaction Pathway of the Asymmetric
Conjugate Hydrocyanation of α,β-Unsaturated
N‑Acylpyrroles
ASSOCIATED CONTENT
* Supporting Information
■
S
Procedures for asymmetric conjugate hydrocyanation of α,β-
unsaturated carboxylic acid derivatives, NMR, GC, and HPLC
behavior of products, together with [α]D values (PDF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: ohkuma@eng.hokudai.ac.jp.
Notes
The authors declare no competing financial interest.
LiCN and CH3OH. Complexation of (SA,SP)-3 with LiCN
forms the bimetallic cyanide species [Li{(SA,SP)-3}]CN
((SA,SP)-6), which catalyzes the conjugate hydrocyanation.
(SA,SP)-6 reacts smoothly with the α,β-unsaturated N-
acylpyrrole to afford the enolate of the β-cyano ketone with
the bimetallic countercation 7. Spontaneous protonation of 7
with HCN results in the desired β-adduct and regenerates the
catalyst (SA,SP)-6.
ACKNOWLEDGMENTS
■
This work was supported by Grants-in-Aid from the Japan
Society for the Promotion of Science (JSPS) (No. 24350042
and No. 25410031) and the MEXT (Japan) program “Strategic
Molecular and Materials Chemistry through Innovative
Coupling Reactions” of Hokkaido University.
We propose the mode of enantioselection in the cyanation of
the N-acylpyrrole 1a catalyzed by (SA,SP)-6 resulting in (S)-2a
as shown in Figure 1. The structure of 6 is drawn based on the
X-ray-determined structure of [Li{(SA,SP)-3}]Br,17 in which the
Li cation interacts with the carbonyl oxygen of PhGly and the
cyanide is located between two amino protons interacting with
the hydrogen bonds. The unsaturated N-acylpyrrole 1a is
activated by the Lewis acidic lithium cation moiety of the
catalyst 6. Thus, addition of cyanide at the β-position of 1a
proceeds through Path A or Path B to afford enantiomers of 2a
in opposite configurations.18 The reaction through path A
proceeds smoothly because the cyanide and the β-position of
1a are in close proximity. On the other hand, the β-position of
1a is located too far from the cyanide to perform the smooth
reaction through Path B. Therefore, (S)-2a is predominantly
produced via the si-face selective Path A.
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Organic Letters
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D
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