The asymmetric addition of malononitrile to α,β-unsaturated ketones catalyzed by RuCl2[(R,R)-DPEN](PPh3)2 as the precatalyst

Article abstract of DOI:10.1016/j.tetlet.2014.04.045

Non-borohydride ruthenium complex, RuCl₂[(R,R)-DPEN](PPh ₃)₂ (1f), was demonstrated to catalyze asymmetric Michael addition of malononitrile to acyclic enones with weak bases. Michael addition of malononitrile to chalcone

Full text of DOI:10.1016/j.tetlet.2014.04.045

Accepted Manuscript
The Asymmetric Addition of Malononitrile to α,β-Unsaturated Ketones Cata-
lyzed by RuCl [(R,R)-DPEN](PPh ) as the Precatalyst
2
3 2
Xuefeng Li, Yaping Ma, Zhikui Xing, Ning Tang, Jin Zhu, Jingen Deng
PII:
S0040-4039(14)00657-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.045
TETL 44507
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
20 January 2014
9 April 2014
15 April 2014
Please cite this article as: Li, X., Ma, Y., Xing, Z., Tang, N., Zhu, J., Deng, J., The Asymmetric Addition of
Malononitrile to α,β-Unsaturated Ketones Catalyzed by RuCl [(R,R)-DPEN](PPh ) as the Precatalyst, Tetrahedron
2
3 2
Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.04.045
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The Asymmetric Addition of Malononitrile to α,β-Unsaturated
Ketones Catalyzed by RuCl [(R,R)-DPEN](PPh ) as the Precatalyst
2
3 2
b
Xuefeng Li , Yaping Ma , Zhikui Xing , Ning Tang , Jin Zhu and Jingen Deng *
d
c
c
d
a,e
a
Department of Medicinal Chemistry and Key Laboratory of Drug-Targeting of Education
Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
b
College of Chemistry and Environment Protection Engineering, Southwest University for
Nationalities, Chengdu 610041, China
c
College of Chemistry and Chemical Engineer, Lanzhou University, Lanzhou 730000, China
d
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
e
Jiangxi Key Laboratory of Organic Chemistry, Jiangxi Science & Technology Normal University,
Nanchang 330013, China
(* E-mail: jgdeng@scu.edu.cn)
Abstract
2 3 2
Non-borohydride ruthenium complex, RuCl [(R,R)-DPEN](PPh ) (1f), was demonstrated to
catalyze asymmetric Michael addition of malononitrile to acyclic enones with weak bases.
Michael addition of malononitrile to chalcone and analogues was promoted by combining CsOAc
with CsOH in the presence of 1f and gave good yields and up to 82% ee.
Keywords: Asymmetric catalysis; Michael addition; Malononitrile; Acyclic enone; Ruthenium
diamine complex
The stereoselective formation of carbon-carbon bonds is of central importance for modern
organic synthesis, and the conjugate addition of carbanion nucleophiles to α,β-unsaturated
carbonyl compounds represents one of the best-established construction strategies for this purpose.
Thus the development of asymmetric catalytic versions of this type of transformation has been the
1
subject of intensive research over the past several years. Although substantial progress has been
realized in this field, examples employed malononitrile as nucleophiles are relatively less explored
and most of them don’t achieve high enantioselectivity, probably owing to its incapability of
2
two-point binding with catalysts. Malononitrile is an equivalent to a 1,3-dicarbonyl compound

2
n-t,3
and the nitrile group is a versatile functional group for further elaboration.
Therefore, the
development of efficient Michael addition involved malononitrile is still highly desirable.
On the other hand, chiral ruthenium complexes have been successfully applied to promote
4
enantioselective Michael addition by Ikariya and Morris since Suzuki’s initial investigation in
5
6
Michael reaction of α-keto esters and methyl vinyl ketone. The Michael addition of malonates
4
a-c,f
4d
(up to 99% ee) and nitroalkenes (up to 98% ee) to
was achieved with prochiral cyclic enones
afford the desired adducts in excellent enantioselectivities catalyzed by the 16-electron ruthenium
complexes 1a and 1b (Figure 1), respectively. The similar transformation was accomplished by
Morris group using ternary catalyst of the binap, aminophosphine-ruthenium hydride borohydride
Complex 1d (97% ee) and ruthenium hydride borohydride Complex 1e with chiral phosphinite
5
and diamine ligands (90% ee) (Figure 1). All these ruthenium complexes have exhibited excellent
performance in case of cyclic enones, however, unsatisfactory results were observed when linear α,
6
β-unsaturated ketones were adopted. As a result, expanding the scope of the efficient asymmetric
Michael reaction with respect to acyclic α,β-unsaturated enones catalyzed by ruthenium
complexes would represent an important advance. Based on our group continuous work on
7
asymmetric conjugated reduction and understanding of the Ru-diamine complexes, we are
interested in the possibility of employing air- and moisture-stable Ru-diamine complexes to
promote the Michael addition of malononitrile and acyclic enones. Also, as part of our continuous
8
effort to develop the catalytic asymmetric Michael reaction of malononitrile, herein we would
like to report an enantioselective and efficient Michael addition of malononitrile to chalcone and
2 3 2
its analogues catalyzed by non-borohydride complex RuCl [(R,R)-DPEN](PPh ) (1f, DPEN =
1,2-diphenylethylenediamine) in combination with CsOAc and CsOH.

Figure 1. The well-designed Ru-complexes for asymmetric Michael addition.
Our study commenced with the preparation of 18-electron Ru-complex 1f (Figure 1), after
stirring the metal precursor RuCl
2
(PPh
3
)
3
and chiral ligand (R,R)-DPEN in THF under Argon, the
[(R,R)-DPEN](PPh
desired complex 1f was obtained and its structure was confirmed as RuCl
2
3 2
)
9
based on single-crystal X-ray analysis, which is consistent with Ding’s report. We were pleased to
1
find that 1f in combination with t-BuOK exhibited high catalytic activity for the asymmetric
0
2
e,2i,2n,8,11
12
in toluene, the desired adducts 4a
13
Michael addition of malononitrile 2 to chalcone 3a
was cleanly isolated with 40% ee almost in quantitive yield (Table 1, entry 1). Noticeably, Morris
attained racemic adduct in the case of Michael addition of dimethylmalonate to
5
-cyclohexene-1-one catalyzed by complex 1d in combination with t-BuOK. At the same time,
a
2
we examined the enantioselectivity of 16-electron Ru-complex 1c (Figure 1) toward the Michael
o
addition of malononitrile 2 and chalcone 3a in 1 mL of toluene at 15 C and only racemic adduct
was detected regardless of its well-defined performance in the Michael addition of cyclic
4
a-c,f
ketones.
Encouraged by this finding, we subsequently screened the inorganic base additives
1
with 1f. It turned out that the additives had a remarkable influence on the enantioselectivity and
0
1
2
reactivity and this transformation hardly proceeded in the absence of additive. As illustrated in
Table 1, the bases containing inorganic anions displayed a better reactivity than those additives
containing organic anions, however, higher enantioselectivities were achieved with the latter
3 2
additives (entries 5–7 vs entries 2–4). CF CO K was not catalytically active maybe due of too
weak basicity (entry 8). The reaction was also significantly influenced by cationic ions of the

additives (entries 5 and 9–11). The reactivity increased in the order of LiOAc < CsOAc < NaOAc
KOAc. Compared with other additives, KOAc was much more enantioselective and furnished
<
the corresponding adduct with 63% ee (entry 5), however, it remained less reactive and cost 54 h
to completely consume the starting substrates. We hypothesized that mixing KOAc and KOH
1
4
could result in high reactivity and enantioselectivity. The Michael addition was indeed much
more reactive after adding a mixture of KOH and KOAc at different ratio, but the ee decreased in
comparison with KOAc (entries 12-14 vs entry 5). Compared with KOH, higher enantioselectivity
(
55% ee) was obtained by using CsOH as a base (entry 15 vs entry 2). Thus, we further
investigated the effect of a mixture of CsOH and CsOAc, to our delight, it remained the high
reactivity and afforded the desired adduct with comparable ee (entries 16-18). When CsOH and
CsOAc were added at the ratio of 1 : 2, an adduct 4a was obtained in 56% ee and almost
quantitive yield after 4 h (entry 18). The transition metal additive was also used but no desired
adduct was attained even after 96 h in the presence of Ni(OAc)
2
, which could coordinate to the
1
5
carbonyl oxygen and the olefin π-bond in the s-cis conformation (entry 19). While organic bases
were used as an additive, the conjugate addition occurred smoothly with (R,R)-DPEN and TEA
(
TEA = triethylamine), but considerably reduced enantioselectivities were observed (entries 20
and 21).
Table 1
a
Additive screening studies of asymmetric Michael addition of malononitrile 2 to chalcone 3a
b
c
Entry
Additive
t-BuOK
KOH
t (h)
18
48
7.5
15
54
96
80
96
96
Yield (%)
99
Ee (%)
40
1
2
3
4
5
6
7
8
9
97
44
K
2
CO
3
99
30
KHCO
KOAc
3
99
38
99
63
PhCO
HCO
CF CO
LiOAc
2
K
45
55
2
K
99
54
3
2
K
NR
26
/
d
31

1
0
NaOAc
70
72
2
90
81
99
99
99
99
99
99
99
nr
41
50
51
52
51
55
52
55
56
/
11
CsOAc
1
1
1
1
1
1
1
1
2
2
2
3
4
5
6
7
8
9
0
1
KOH/KOAc = 2:1
KOH/KOAc = 1:1
KOH/KOAc = 1:2
2
2
d
CsOH
d
CsOH /CsOAc = 2:1
48
4
d
CsOH /CsOAc = 1:1
d
CsOH /CsOAc = 1: 2
4
4
d
Ni(OAc)2
96
70
96
e
(R,R)-DPEN
99
64
42
8
3
Et N
a
Unless otherwise noted, all of the reactions were performed with 0.1 mmol of 3a, 0.16 mmol of
o
malononitrile, 10 mol% of 1f and 30 mol% of additive in 2 mL of toluene at 24 C.
b
Isolated yield after flash chromatography on silica gel.
c
Determined by HPLC on chiral OD column.
d
The available hydrate was directly used.
e
With (R,R)-DPEN (30 mol%) in the absence of 1f, 4a was obtained only in 10% yield and 6% ee
1
6
after 24 h.
2
Subsequently, we kept the ratio of CsOH·H O and CsOAc constant (CsOH/CsOAc = 1 : 2) and
investigated the effect of the loading of additives on the enantioselectivity and reactivity. As
illustrated in Table 2, the enantioselectivity was somewhat influenced by the quantities of the
additives (entries 1–5). Gratifyingly, the addition product 4a was formed with 61% ee in the
presence of 45 mol% additives (entry 4). We conducted the Michael reaction at lower temperature
to improve the enantioselectivity and pleased to find that a higher ee (73% ee) was obtained at –10
o
o
C (entry 7). Further lowering the temperature to –20 C resulted in marginal increase in
enantioselectivity (entry 8). In the hope of further enhancing the enantioselectivity, the other
ruthenium complexes containing diamine and diphosphine ligands (Figure 2) were employed and
the results were presented in Table 2 (entries 10–15). The reactions were carried out in the
o
presence of 5 mol% catalyst in toluene at –10 C. The complexes 1g and 1h, generated with (R)-
1
7
and (S)-binap respectively, provided the desired adduct in 91% and 90% yield and lower ee
values after 70 h (entries 10 and 11). It was noteworthy that they afforded 4a with same
configuration in spite of the opposite configuration of the phosphine ligand. The results obviously

indicated that the chiral diamine played a crucial role in the asymmetric induction. Enlightened by
this observation, this transformation was then conducted in the presence of the novel ruthenium
complex containing (R,R)-DACH (DACH = 1,2-cyclohexanediamine) (Figure 2, 1i).
Unfortunately, no beneficial effect was observed in terms of enantioselectivity (17% ee) although
it exhibited high reactivity (entry 12). Furthermore, the ruthenium complexes containing modified
9
phosphine ligands (Figure 2, 1j and 1k) had been applied in the conjugate addition. The Michael
addition proceeded smoothly to afford 4a in 50% ee and 96% yield with 1j, but no desired adduct
was attained with 1k, probably due to steric hindrance of the bulky phosphine ligand (entries 13
1
8
and 14). Noticeably, we explored the mixed catalysts consisting of diastereomers of 1l and 4a
was obtained with poorer enantioselectivity in the presence of them (entry 15). As a result, 1f was
the best choice of the catalyst for the present reaction.
Table 2
Asymmetric Michael addition of malononitrile 2 to chalcone 3a with various catalysts under
a
different conditions
o
Entry CsOH/CsOAc (1:2, Catalyst T ( C)
b
Yield (%) Ee (%)
c
t (h)
mol %)
1
2
3
4
5
6
7
8
9
1
20
30
40
45
50
45
45
45
45
45
45
45
45
45
45
1f
1f
1f
1f
1f
1f
1f
1f
1f
1g
1h
1i
24
4
99
99
97
99
99
99
99
96
95
91
90
80
96
NR
70
56
56
60
61
54
66
73
74
72
47
37
17
50
/
24
4
24
4
24
4
24
4
0
12
24
48
30
70
70
24
48
90
48
–10
–20
–10
–10
–10
–10
–10
–10
–10
d
d
0
d
d
1
1
1
1
1
1
2
d
d
d
3
4
5
1j
1k
1l
21
a
Unless otherwise noted, all of the reactions were performed with 0.1 mmol of 3a, 0.16 mmol of
malononitrile, 10 mol% of Ru-complex in 2 mL of toluene.
b
Isolated yield of 4a after flash chromatography on silica gel.
c
Determined by HPLC on chiral OD column.
d
Perform with 5 mol% of catalyst.

Figure 2. The structure of the ruthenium complexes.
1
2
With the optimal reaction condition in hand, we then examined a variety of α,β-unsaturated
ketones to establish the general utility of the catalytical transformation. As illustrated in Table 3,
o
chalcone analogues bearing various substitutes on the aryl ring proceeded smoothly at –10 C in
2
the presence of 1f (10 mol%), CsOAc (30 mol%) and CsOH·2H O (15 mol%), providing the
desired products 4b–g with moderate to good enantioselectivities (entries 1–7). The
enantioselectivities and reactivities were dependent upon the electronic properties of substituted
groups. 3c and 3e with electron-withdrawing substituents on aryl ring proceeded with higher
enantioselectivities and reactivities than 3b and 3d with electron-donating substituents (entries 3
and 5 vs entries 2 and 4). The highest enantioselectivity (82% ee) was obtained in the case of the
nitro-derivative 3c (entry 3). Moreover, the reaction was remarkably influenced by sterical
hindrance, 3g furnished the desired product 4g only in 30% ee and 18% yield even after prolonged
time (entry 7). 3h with 2-naphthyl group on terminal double bond occurred smoothly and
satisfactory enantioselectivity was obtained (71% ee, entry 8). Furthermore, heteroaryl enones 3i
and 3j underwent clean reaction as well, and afforded the corresponding adducts 4i and 4j with
65% and 67% ee, respectively (entries 9 and 10). In addition, chalcone and diethyl malonate (5)

11
occurred smoothly at room temperature and furnished the adduct 6 with 33% ee and 77% yield
after 40 h (Scheme 1). However, when the unsaturated ketone bears an aliphatic group, no reaction
o
occurs for 4-phenylbut-3-en-2-one (3k) at 24 C (entry 11). Moreover, cyclohex-2-enone (3l) gave
72% yield for 100 h but only 6% ee (entry 12).
Table 3
a
Asymmetric Michael addition of malononitrile 2 to α,β-unsaturated ketones 3
Entry
R
1
R
2
6
Substrate Product Time Yield Ee
b
c
(
h)
(%)
99
55
93
73
95
90
18
98
50
97
(%)
d
1
2
3
4
5
6
7
8
9
C
6
C
6
C
6
H
5
C
H
5
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
24
70
24
70
24
70
70
70
70
24
70
100
73
H
5
p-CH
3
OC
6
H
4
70
82
64
68
72
30
71
66
67
H
5
2 6 4
p-NO C H
p-CH OC H
4
3
6
C
6
C
6
C
6
C
6
C
6
C
6
H
5
p-NO C H
2
6
4
H
5
p-FC H
6
4
H
5
1,3,5-(CH
2-naphthyl
2-thienyl
3
)
3
C
6
H
2
H
5
3g
3h
3i
4g
4h
4i
H
5
H
5
10
C
6
6
H
5
2-furanyl
CH
3j
4j
e
11
f
/
f
/
C
H
5
3
3k
3l
4k
4l
e
12
-(CH
2
)
3
-
72
6
a
Unless otherwise noted, all of the reactions were performed with 0.1 mmol of 3a, 0.16 mmol of
malononitrile, 10 mol% of 1f, 30 mol% CsOAc and 15 mol% CsOH·H O in 2 mL of toluene at
2
o
10 C.
–
b
Isolated yield after flash chromatography on silica gel.
c
Determined by HPLC on chiral column.
d
The absolute configuration of 4a was (R)-form determined by comparison of the specific optical
1
rotation with that reported in the literature, and the other adducts were assigned accordingly.
3a
e o
At 24 C.
f
No reaction.

Scheme 1. The Michael addition of chalcone and diethyl malonate.
In summary, we have developed a novel ruthenium-catalyst system for asymmetric Michael
2 3 2
addition of acyclic enones. In combination with CsOAc and CsOH, RuCl [(R,R)-DPEN](PPh )
can effectively promote the Michael addition of malononitrile to chalcone and analogues in high
yields with moderate to good entantioselectivities (up to 82% ee). To the best of our knowledge,
this is the first example that ruthenium complex is used to promote Michael addition of
malononitrile to α,β-unsaturated carbonyl compounds especially acyclic enones. It is also notable
that the reactivity can be greatly improved after adding the mixed bases. At the same time, new
ruthenium complexes are prepared and applied to this asymmetric transformation. Further
investigation into the reaction mechanism is under the way.
Acknowledgements
This work was financially supported by the National Natural Science Foundation of China (No.
2
1172152, 21372161), the National Basic Research Program of China (973 Program, No.
010CB833300), Sichuan University and the Science and Technology Department of Sichuan
2
Province (No. 2013JY0135, 2013FZ0075). We thank Professor Ding Kuiling, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, China for friendly affording 1k.
Supplementary data
Supplementary data associated with this article can be found in the online version, at
http://dx.doi.org/10.1016/j.tetlet.
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8.
9.
Jing, Q.; Zhang, X., Sun, J.; Ding, K. L. Adv. Synth. Catal. 2005, 347, 1193.
1
0. t-BuOK, KOH and K
Ohkuma, T.; Ooka, H.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117,
675. (b) Ohkuma, T.; Koizumi, M.; Doucet, H.; Pham, T.; Kozawa, M.; Murata, K.;
2 3
CO were engaged as additives in hydrogenation originally, see: (a)
2
Katayama, E.; Yokozawa, T.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1998, 120, 13529.
1. (a) Ooi, T.; Ohara, D.; Fukumoto, K.; Maruoka, K. Org. Lett. 2005, 7, 3195. (b) Wang, J.; Li,
H.; Zu, L. S.; Jiang, W.; Xie, H. X.; Duan, W. H.; Wang, W. J. Am. Chem. Soc. 2006, 128,
1
1
2652.
1
2. Other solvents (N,N’-Dimethylformamide, Acetonitrile, Tetrahydrofuran, Dichloromethane,
tert-Butanol, Benzene) displayed inferior enantioselectivities comparing with toluene when
the corresponding Michael addition was performed in the presence of 10 mol % 1f and 30
mol% (R,R)-DPEN. In the absence of base, very low activity was observed with only
complex 1f (9% yield and 14% ee for 137 h).
13. (a) Yasuda, K.; Shindo, M.; Koga, K. Tetrahedron Lett. 1996, 37, 6343. (b) Yue, L.; Du, W.;
Liu, Y. K.; Chen, Y. C. Tetrahedron Lett. 2008, 49, 3881.

1
1
1
4. Yamaguchi, M.; Shiraishi, T.; Hirama, M. J. Org. Chem. 1996, 61, 3520.
5. de Vries, A. H. M.; Imbos, R.; Feringa, B. L. Tetrahedron: Asymmetry 1997, 8, 1467.
2 3 3
6. When 10 mol% RuCl (PPh ) and 30 mol% (R,R)-DPEN were used to prepare the catalyst in
situ, 70% yield and 57% ee of 4a was obtained for 21 h. (R)-1,1'-Binaphthalene-2,2'-diamine,
(
(
S)-pyrrolidin-2-ylmethanamine,
(1R,2R)-1,2-dicyclohexylethane-1,2-diamine,
and
1R,2R)-1,2-bis(4-methoxyphenyl)ethane-1,2-diamine (p-MeODPEN) were also tested in the
conditions and only less than 8% ee of 4a was gained except p-MeODPEN, which gave 59%
ee but lower reactivity (60% yield, 70 h).
1
7. Doucet, H.; Ohkuma, T.; Murata, K.; Yokozawa, T.; Kozawa, M.; Katayama, E.; England, A.
F.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. 1998, 37, 1703.
8. Mikami, K.; Korenaga, T.; Terada, M.; Ohkuma, T.; Pham, T.; Noyori, R. Angew. Chem., Int.
Ed. 1999, 38, 495.
1

Graphical Abstract
The Asymmetric Addition of Malononitrile to α,β-Unsaturated Ketones Catalyzed by
RuCl
2
[(R,R)-DPEN](PPh
3
)
2
as the Precatalyst
b
Xuefeng Li , Yaping Ma , Zhikui Xing , Ning Tang , Jin Zhu and Jingen Deng *
d
c
c
d
a,e