Malononitrile as acylanion equivalent

Article abstract of DOI:10.1055/s-0028-1083540

The oxidation of derivatives of malononitrile with peracid in methanol proceeds with loss of the cyano groups to yield methyl esters in high yield. The method was applied to a variety of malononitrile derivatives, some of which were prepared by Pd- or Ir-catalyzed asymmetric allylic substitution. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083540

LETTER
2803
Malononitrile as Acylanion Equivalent
Malononitrile
e
as
A
cylanio
b
n Equivalen
a
t
stian Förster, Olena Tverskoy, Günter Helmchen*
Organisch-Chemisches Institut der Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Fax +49(6221)544205; E-mail: g.helmchen@oci.uni-heidelberg.de
Received 15 July 2008
O
R
OMe
NC
R
CN
OH
[O], MeOH
– 2 HCN
Abstract: The oxidation of derivatives of malononitrile with perac-
id in methanol proceeds with loss of the cyano groups to yield
methyl esters in high yield. The method was applied to a variety of
malononitrile derivatives, some of which were prepared by Pd- or
Ir-catalyzed asymmetric allylic substitution.
2
4
– HCN
O
Key words: oxidations, cyanohydrins, allylations, iridium, asym-
metric catalyses, Michael additions
NC
NC
R
CN
– HCN
R
Over the last few years, the Ir-catalyzed asymmetric allyl-
ic alkylation with stabilized carbanions has become a
highly developed, reliable method. However, the range of
C-nucleophiles is limited to malonic acid derivatives and
b-ketoesters.1 For further development it was desirable to
implement C1-nucleophiles, in particular acylanion equiv-
alents,2 in order to make vinyl-substituted a-stereogenic
carboxylic acid derivatives accessible. Attempts with cy-
anide and nitromethane were not successful in our hands.
Scheme 1 Oxidative degradation of malononitrile derivatives
boxylic acid; the yield was not stated.7 De et al. oxidized
a heterocyclic malononitrile derivative with aqueous
KMnO4 under basic conditions to give a carboxylic acid
in moderate yield.8 Both procedures were unsuited for our
purpose.
We prepared a series of the requisite malononitrile deriv-
atives by Ir-catalyzed allylic alkylation with malononitrile
under salt-free conditions (Scheme 2, Table 1).6
For Pd-catalyzed allylic substitutions several acylanion
equivalents have been used successfully: phenylsulfonyl-
methylennitronate,3 a-acetoxymalonate,4 a-acetoxy- and
silyloxymalononitrile (MAC reagents),5 which gave
methyl esters after methanolysis (Figure 1). Unfortunate-
ly, the requisite reagents are poorly available or the subse-
quent transformations are cumbersome.
Malononitrile derivative 2c (R = CH2OSiPh2t-Bu) was
used as a test compound for the development of the oxida-
tive degradation method. Initially, autoxidation of 2c was
attempted, using CeCl3 or Mn(OAc)2 as catalysts, which
are successful with b-keto esters.10 The product was iso-
lated in only 16% yield (Table 2, entries 1 and 2). Then
the combination H2O2 and Cs2CO3 was tested. The reac-
tion was fast, however, the yield was low (entry 3). With
t-BuO2H as oxidant, side products were formed and the
yield of the desired product was only 13% (entry 4).
MeO2C
CO2Me
OCOR2
NC
CN
OR1
O2N
SO2Ph
Figure 1 Important acylanion equivalents (R1 = Ac, SiMe2t-Bu)
Inspired by Nemoto’s MAC reagents, we have now devel-
oped a new method, which solely requires readily avail-
able reagents (Scheme 1). The broadly applicable
malononitrile is used as pronucleophile, which has proven
useful, for example in allylic substitutions.6 It was essen-
tial to find a method for oxidation of the malononitrile de-
rivative yielding the corresponding cyanohydrin, which
would decompose to the acyl cyanide to be transformed
into a carboxylic acid derivative. Furthermore, epoxida-
tion and migration of the double bond as well as racemiza-
tion had to be avoided.
NC
CN
∗
R
2
CH2(CN)2
+
R
OCO2Me
[Ir(COD)Cl]2, L*
TBD, THF, r.t.
CN
1
R
3
CN
S
S
Ar
Ar
O
P
N
aS
1a–3a R = Ph
1b–3b R = n-Pr
1c–3c R = CH2OSiPh2t-Bu
1d–3d R = CH2OCPh3
O
Oxidation of malononitrile derivatives has been reported
twice. Patai and Dayagi oxidized a-tritylmalononitrile
with aqueous H2O2–NaOH to give the corresponding car-
L1 Ar = Ph
L2 Ar = 2-MeOC6H4
Scheme 2 Iridium-catalyzed allylic alkylation with malononitrile as
pronucleophile {TBD = 1,5,7-triazabicyclo[4.4.0]dec-5-ene}
SYNLETT 2008, No. 18, pp 2803–2806
Advanced online publication: 15.10.2008
1
4
.1
1
.2
0
0
8
DOI: 10.1055/s-0028-1083540; Art ID: G23608ST
© Georg Thieme Verlag Stuttgart · New York

2804
S. Förster et al.
LETTER
O
Table 1 Iridium-Catalyzed Allylic Alkylation with Malononitrile
According to Scheme 2
Mg
O
CO3H
Entry
Substrate
L*
Time Yield
Ratio 2/3b
ee
2
(h)
(%)a
80
87
73
89
77
70
68
78
(%)c
NC
R
CN
O
R
OMe
(0.75 equiv)
1d,e
2e
3
1a
1a
1b
1b
1c
1c
1d
1d
L1
L2
L1
L2
L1
L2
L1
L2
4
96:4
96
98
96
96
98
96
97
94
M2CO3, MeOH
∗
∗
2
4
3
97:3
2a, 4a R = Ph
2b, 4b R = n-Pr
2c, 4c R = CH2OSiPh2t-Bu
2d, 4d R = CH2OCPh3
10
2
87:13
90:10
84:16
73:27
89:11
89:11
4
Scheme 3 Oxidative degradation of chiral malononitrile derivatives
5f
6f
7
15
5
was tested (Table 2, entry 6). With 2c complete conver-
sion was obtained at 0 °C after three hours, but the isolat-
ed yield was lower (62%) than that obtained with
MCPBA.
24
8
5
a Isolated yield of 2a, 3a and 2b, 3b and isolated yield of 2c and 2d.
b Determined by 1H NMR or GC of the crude products.
c Determined by HPLC or GC with chiral columns.9
d Reaction at 40 °C.
Finally, the best results were achieved with magnesium
monoperoxyphthalate as oxidant (Table 2, entry 7,
Scheme 3). This oxidation agent is commercially avail-
able, and workup was very easy. Under the optimized
conditions,11 tests with other malononitrile derivatives
(2a,b,d) also gave excellent results (Table 3).
e Traces of the diallylation product were detected.
f These results were already reported and are given here for compari-
son.6
Further malononitrile derivatives were probed in order to
assess the scope of the new procedure. The simple com-
pounds 5 and 7 were prepared via alkylation of malononi-
trile. The oxidative degradation gave the methyl esters 6
and 8 in high yield. Furthermore, the malononitrile deriv-
ative 9, which was prepared via Pd-catalyzed asymmetric
allylic alkylation, was transformed into the methyl car-
boxylate 10. Again, neither racemization nor double-bond
migration were observed.
Despite of the possibility of epoxidation of the double
bond of 2c, percarboxylates were tested as oxidation
agents. Complete conversion was obtained with MCPBA
and Cs2CO3 at –20 °C in MeOH after three hours, and the
methyl ester 4c was isolated in 87% yield (Table 2, entry
5). Epoxidation products were not detected, but at temper-
atures higher than 0 °C isomerization of the double bond
occurred yielding a,b-unsaturated methyl esters. This was
not the case with Li2CO3 as base, although the reaction
rate was only sufficient above 0 °C. Decrease of the enan-
tiomeric excess, another problem, was negligable (0–2%).
However, purification of the product was difficult because
of the formation of methyl m-chlorobenzoate as side prod-
uct. Therefore, peracetic acid, which was prepared in situ,
Another possibility to generate malononitrile derivatives
is the 1,4-addition of enolates to 1,1-dicyanoethylenes,
which are strong Michael acceptors. We have prepared ra-
cemic 11 by reaction of acetophenone with 2-benzylidene-
malononitrile. The transformation into the g-oxomethyl
carboxylate 12 proceeded in 75% yield.
Table 2 Oxidation of 2c under Various Conditions
Entry Conditions
Time (h) Temp (°C) Comment
Yield (%)a
16
1
CeCl3 (10 mol%), NaOMe (2 equiv), O2 (1 atm), MeOH
240
r.t.
Slow reaction; removal of the
protecting group
2
Mn(OAc)2 (20 mol%), NaOMe (2 equiv),
O2 (1 atm), MeOH
0.1
r.t.
Decomposition
0
3
4
5
6
7
Cs2CO3 (1 equiv), H2O2 (1.2 equiv), MeOH
Cs2CO3 (1 equiv), t-BuO2H (1.3 equiv), MeOH
Cs2CO3 (1.05 equiv), MCPBA (1.5 equiv), MeOH
Li2CO3 (1.5 equiv), MeCO3H (1.5 equiv), MeOH
2.5
3
–20
–20
–20
0
Side products (not isolated)
Side products (not isolated)
39
13
3
Formation of 3-ClC6H4CO2Meb 87
3
Side products (not isolated)
–
62
81
Cs2CO3 (1.1 equiv), Mg[o-(CO2)C6H4CO3H]2 (0.75 equiv),
MeOH
3
–20
a Isolated yield.
b Removal of methyl m-chlorobenzoate required extensive column chromatography.
Synlett 2008, No. 18, 2803–2806 © Thieme Stuttgart · New York

LETTER
Malononitrile as Acylanion Equivalent
2805
Table 3 Results of the Oxidative Degradation of Malononitrile Derivatives According to Scheme 3
Entry
Educt
2a
Product
4a
Ma
Cs
Li
Time (h) Temp (°C)
Yield (%)b
ee (%)c
1
2
3
4
5
1.5
2
–20
0
80
76
81
50
81
98
94.5
96
97
–
2b
4b
2c
4c
Cs
Li
3
–20
0
2d
4d
3
Li
3.5
0
n-HeptCO2Me
n-HeptCH(CN)2
5
6
6
7
8
Csd
Li
2
3
3
–20
0
84
86
75
–
CH(CN)2
CO2Me
Br
Br
7
8
78
0
CH(CN)2
CO2Me
9
10
Li
0
Ph
O
Ph
CO2Me
O
Ph
CH(CN)2
Ph
11
12
a Cs2CO3 (1.1 equiv), Li2CO3 (1.5 equiv).
b Isolated yield.
c Determined by HPLC or GC with chiral columns.
The ∆ee-value [ee(substrate) – ee(product)] was also determined: entry 2 ∆ee = 1.5%; entry 3 ∆ee = 2%; in all the other cases ∆ee = 0.12
d Cs2CO3 (1.5 equiv).
(5) (a) Nemoto, H.; Kubota, Y.; Yamamoto, Y. J. Org. Chem.
1990, 55, 4515. (b) Nemoto, H.; Ibaragi, T.; Bando, M.;
Kido, M.; Shibuya, M. Tetrahedron Lett. 1999, 40, 1319.
(c) Shibuya, M.; Suzuki, I.; Ma, R.; Li, X.; Nemoto, H.
Tetrahedron Lett. 2003, 44, 73. (d) Nemoto, H.; Ma, R.;
Kawamura, T.; Kamiya, M.; Shibuya, M. J. Org. Chem.
2006, 71, 6038.
In conclusion, we have developed a versatile and conve-
nient method for oxidation of malononitrile derivatives to
give esters as degradation products under very mild con-
ditions. Thus, we have established malononitrile as an
acylanion equivalent.
(6) Gnamm, C.; Förster, S.; Miller, N.; Brödner, K.; Helmchen,
Acknowledgment
G. Synlett 2007, 790.
(7) Patai, S.; Dayagi, S. J. Chem. Soc. 1962, 716.
(8) (a) Datta, S.; De, A.; Brunskill, J. S. A. Sulfur Lett. 1986, 4,
37. (b) Datta, S.; Bhattacharya, S.; De, A.; Chakravarty,
A. K. J. Chem. Res., Miniprint 1988, 667.
This work was supported by the Deutsche Forschungsgemeinschaft
(GK 850). We thank Prof. Dr. Klaus Ditrich (BASF SE) for enan-
tiomerically pure 1-arylethylamines.
(9) GC: Chiraldex g-Trifluoracetyl (G-TA), 30 m × 0.25 mm ×
References and Notes
0.125 mm; injector temperature: 200 °C, detector
temperature: 250 °C; 2a (column temperature: 140 °C,
isothermal): tR (–)-(S)-2a = 27 min, tR (+)-(R)-2a = 28 min;
2b (column temperature: 100 °C, isothermal), tR (+)-(S)-2b
= 25 min, tR (–)-(R)-2b = 26 min.
(1) Helmchen, G.; Dahnz, A.; Dübon, P.; Schelwies, M.;
Weihofen, R. Chem. Commun. 2007, 675.
(2) (a) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239;
Angew. Chem. 1979, 91, 259. (b) Enders, D.; Breuer, K. In
Comprehensive Asymmetric Catalysis, Vol. 3; Jacobsen,
E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer: New York,
1999, 1093; and literature cited therein.
(3) Trost, B. M.; Kuo, G. H.; Benneche, T. J. Am. Chem. Soc.
1988, 110, 621.
(4) (a) Seemann, M.; Schöler, M.; Kudis, S.; Helmchen, G. Eur.
J. Org. Chem. 2003, 2122. (b) Bergner, E. J.; Helmchen, G.
J. Org. Chem. 2000, 65, 5072. (c) Schleich, S.; Helmchen,
G. Eur. J. Org. Chem. 1999, 2515.
HPLC: Daicel Chiralcel OD-H, 250 × 4.6 mm, 5 mm, with
precolumn 10 × 4 mm, 5 mm; 2c [n-hexane–i-PrOH (99:1),
flow = 0.5 mL min–1, 20 °C, 210 nm], tR (–)-(S)-2c = 18 min,
tR (+)-(R)-2c = 22 min; 2d (n-hexane–i-PrOH (95:5), 20 °C,
220 nm, tR (–)-(S)-2d = 20 min, tR (+)-(R)-2d = 28 min.
(10) (a) Christoffers, J. J. Org. Chem. 1999, 64, 7668.
(b) Werner, T.; Christoffers, J. Synlett 2002, 119.
(11) General Procedure for the Oxidative Degradation
Magnesium monoperoxyphthalate hexahydrate (0.75 equiv,
80% technical grade from Sigma Aldrich, used as received)
was added in small portions to a suspension of the substrate
and M2CO3 (1.1 equiv/1.5 equiv) in MeOH (c 0.15 M) at the
given temperature. The mixture was stirred for the given
time and was then filtered through a short column of SiO2,
which was washed with PE–EtOAc. The solvent was
Synlett 2008, No. 18, 2803–2806 © Thieme Stuttgart · New York

2806
S. Förster et al.
LETTER
evaporated in vacuo, and the crude product was purified by
bulb-to-bulb distillation or recrystallization.
HPLC: Daicel Chiralcel OD-H, 250 × 4.6 mm, 5 mm, with
precolumn 10 × 4 mm, 5 mm; 4b¢ [n-hexane–i-PrOH (99:1),
flow = 0.5 mL min–1, 20 °C, 210 nm], tR (–)-(S)-4b¢ = 15
min, tR (+)-(R)-4b¢ = 16 min); 4c [n-hexane–i-PrOH
(12) (a) The ester 4b was treated with PhMgBr to give 1,1-di-
phenyl-2-propylbut-3-en-1-ol (4b¢). Similarly, 10 was
reacted with PhMgBr to produce cyclohex-2-en-1-yl-
(diphenyl)methanol (10¢), a known compound, see ref. 12b.
GC: Chiraldex g-Trifluoracetyl (G-TA), 30 m × 0.25 mm ×
0.125 mm; injector temperature: 200 °C, detector
temperature: 250 °C; 4a (column temperature: 100 °C,
isothermal), tR (+)-(S)-4a = 24 min, tR (–)-(R)-4a = 25 min;
9 (column temperature: 140 °C, isothermal), tR (–)-9 = 12
min, tR (+)-9 = 13 min.
(99.7:0.3), flow = 0.5 mL min–1, 20 °C, 210 nm], tR (+)-(S)-
4c = 12 min, tR (–)-(R)-4c = 14 min; Daicel Chiralcel AD-H,
250 × 4.6 mm, 5 mm, with precolumn 10 × 4 mm, 5 mm; 4d
[n-hexane–i-PrOH (99.4:0.6), flow = 0.5 mL min–1, 20 °C,
210 nm), tR (–)-(R)-4d = 22 min, tR (+)-(S)-4d = 29 min; 10¢
[n-hexane–i-PrOH (98:2), flow = 0.5 mL min–1, 20 °C, 210
nm), tR (+)-10¢ = 20 min, tR (–)-10¢ = 22 min. (b) Eisch,
J. J.; Merkley, J. H.; Galle, J. E. J. Org. Chem. 1979, 44, 587.
Synlett 2008, No. 18, 2803–2806 © Thieme Stuttgart · New York

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