Addition of α-halo-substituted carbonitriles to and aldehydesketones in the presence of iron pentacarbonyl

Article abstract of DOI:10.1023/B:RUJO.0000034937.39138.2a

Halo-substituted carbonitriles in the presence of iron pentacarbonyl react with aldehydes and ketones by Reformatsky reaction type. In contract to halo-substituted esters the nitriles are considerably more reactive toward ketones than aldehydes. At the same time the structure and yield of products obtained from both nitriles and esters are strongly and similarly affected by the character of the para-substituents in the benzaldehyde.

Full text of DOI:10.1023/B:RUJO.0000034937.39138.2a

Russian Journal of Organic Chemistry, Vol. 40, No. 2, 2004, pp. 174-177. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 2, 2004,
pp. 199-203.
Original Russian Text Copyright Ó 2004 by Vasil’eva, Kuz’mina, Chakhovskaya, Mysova, Terent’ev .
Addition of a-Halo-substituted Carbonitriles to
and AldehydesKetones in the Presence of Iron Pentacarbonyl
T. T. Vasil’eva, N. A. Kuz’mina, O. V. Chakhovskaya, N. E. Mysova, and A. B. Terent’ev
Nesmeyanov Institute of Organoelemental Compounds, Russian Academy of Sciences, Moscow, 119991 Russia
e-mail: terent@ineos.ac.ru
Received October 2, 2002
Abstract—Halo-substituted carbonitriles in the presence of iron pentacarbonyl react with aldehydes and ketones
by Reformatsky reaction type. In contract to halo-substituted esters the nitriles are considerably more reactive
toward ketones than aldehydes. At the same time the structure and yield of products obtained from both nitriles
and esters are strongly and similarly affected by the character of the para-substituents in the benzaldehyde.
p-chlorobenzaldehyde IIe, p-methoxybenzaldehyde IIf,
and pivalaldehyde IIg.
We showed formerly [1], that the addition of a-halo-
substituted carboxylic acids esters to aldehydes and ke-
tones by Reformatsky reaction type can be performed in
good yields in homogeneous medium in the presence of
iron pebtacarbonyl (heating at reflux of the reagents mix-
ture in benzene for 2–3 h). This procedure furnished
b-hydroxyacids esters or the corresponding derivatives
of acrylic acids esters. Therewith the reaction with alde-
hydes was found to occur very efficiently, and with ke-
tones more difficultly. It was shown besides that reac-
tions with para-substituted benzaldehydes were notably
affected by the polar character of the substituents: the
process with p-chlorobenzaldehyde proceeded like that
with benzaldehyde or even better to give hydroxyacids
esters whereas anisaldehyde either could not be involved
into the reaction or affords only unsaturated products [2]
(formally arising from hydroxyesters dehydration ).
Nitriles Ia, b with ketone IIa afforded hydroxynitrile
III. Therewith at the use instead of the highly reactive
iodide Ia less active bromide Ib the yield of product III
decreased from 70 to 23%. The reaction proceeds along
the scheme:
)Hꢁ&2ꢂ
;&+ &1ꢀꢀꢀ
&1
2
2+
,DꢁꢂE
,,
,,,
I, X = I (a), Br (b).
These reactions proceeded in the same manner with
acetophenone IIb although the yield was low even with
the active iodide Ia.As a result were obtained 3-hydroxy-
3-phenylbutyronitrile IV and a product of acetophenone
aldol condensation. The addition of benzaldehyde IId
occurred unexpectedly inefficiently affording the
corresponding hydroxynitrile Va in a low yield (5–8%).
In this study we used for the first time an iron
pentacarbonyl to effect reactions of a-halo-substituted
nitriles with aldehydes and ketones by Reformatcky re-
action type planning to obtain b-hydroxynitriles and fur-
ther aminoalkohols, synthons for preparation of a number
of biologically active substances [3]. It turned out unex-
pectedly that behavior of nitriles in reactions involving
Fe(CO)5 was essentially unlike that of esters, in contrast
to reactions of Reformatsky type carried out in the pres-
ence of cromium(II) salts [4].
The process involving aldehyde IIe occurred
selectively and gave adduct Vb in a high yield whereas
with anisaldehyde (IIf, Y = OMe) under the same
conditions only the product of a formal dehydration,
3-(p-methoxyphenyl)acrylonitrile VI, was obtained in a
yield as low as 12%.
We brought into the reaction of halonitriles I with
carbonyl compounds substrates of dissimilar reactivity:
acetonitriles substituted by iodine Ia and bromine Ib,
dibromoacetonitrile Ic, and 2-bromopropionitrile Id. As
carbonyl compounds II were applied 2-hexanone IIa,
acetophenone IIb, cyclopentanone IIc, benzaldehyde IId,
&1
)Hꢂ&2ꢃ
;&+ &1ꢀꢀꢁꢀꢀ<& + &+2
<& +
2+
9 ꢀꢁE
, ꢀꢁE ,,GꢀꢁH
II, Y = H (d), Cl (e); V, Y = H (a), Cl (b).
1070-4280/04/4002-0174Ó2004 MAIK “Nauka/Interperiodica”

175
ADDITION OF a-HALO-SUBSTITUTED CARBONITRILES
The most reactive of the nitriles studied, dibromo-
acetonitrile Ic, afforded the target products in good yield
both with benzaldehyde IId and methyl butyl ketone IIa,
XIV, but in the former case the hydroxynitrile yield is
twice as large as in the latter.
The situation in analogous reactions of methyl
bromopropionate [1] is quite the opposite: the yield with
benzaldehyde is considerably higher than with methyl
butyl ketone.
in somewhat lesser yield with cyclopentanone IIc
.
However the reactoins carried out at 60°C resulted only
in unsaturated compounds (due to elimination of Br and
OH). In particular, from benzaldehyde cynnamonitrle VII,
and from ketone IIa 3-methyl-2-heptenylcyanide VIII
were obtained. Only at room temperature we succeeded
to prepare in plausible yield benzaldehyde adduct IX.
ꢄꢅꢀ&
& + &+ &+&1
9,,
)Hꢂ&2ꢃ
&+%U &1ꢀꢁꢀ& + &+2
,F
,,G
ꢆꢅꢀ&
& + &+&+%U&1
With the sterically hindered carbonyl compounds,
acetophenone IIb and pivalaldehyde IIg, both bromo-
propionitrile Id and methyl bromopropionate [1] are
approximately equally reactive furnishing adducts XV and
XVI in about 30% yield.Asimilar behavior of esters and
nitriles is also observed in reactions with the para-sub-
stituted benzaldehydes. In reactions of haloacetonitriles
Ia, b and of bromopropionitrile Id with p-chloro-
benzaldehyde IId the yield of hydroxynitriles Vb and XVII
attained about 60–90%, whereas with p-methoxy-
benzaldehyde IIe formed only the corresponding
derivatives of acrylonitrile VI or of adduct XVIII in 12–
30% yield.
2+
,;
Reactions with p-chloro- and p-methoxybenz-
aldehyde gave rise to p-chloro VIIa and p-methoxy VIIb
derivatives of nitrile VII.
We believe that in reaction with cyclopentanone the
intermediately formed adduct X loses BrOH and the
arising cyclopentylideneacetonitrile XI rearranges with
a double bond migration into the ring to afford unsaturated
adduct XII whose structure is proved by the spectral
data.
The probable reason of the different behavior
demonstrated by nitriles and esters in the reactions under
study lies in the analogy with a mechanism we suggested
previously [2] that involves the reaction between
halonitrile and iron pentacarbonyl to form a radical
followed by its reduction to carbanion; the latter in the
transition state of A type attacks the C=O group of the
electrophile.
ꢀ
&+%U &1
2
,,F
,F
)Hꢀ&2ꢁ
+2
&+%U&1
%U
&+&1
;,
2
5
5
;
&
)H
B
&+
&1
+ &
$
&+ &1
Inasmuch as the cyano group is considerably stronger
electron-acceptor than alkoxycarbonyl group the reaction
site of nitrile is more electron-deficient and naturally
should react better with the electrophile possessing higher
relative electron density on its reaction site, namely, with
ketone.
;,,
The difference and similarity in the behavior of
haloesters [1] and the corresponding halonitriles studied
here is the most clearly seen by an example of reactions
between 2-bromopropionitrile Id with aldehydes and
ketones. Nitrile Id reacts both with ketone IIa providing
hydroxynitrile XIII and with aldehyde IId giving adduct
To the same result should lead the probable change in
the reaction mechanism towards prevalence of the radical
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176
VASIL’EVA et al.
character in the intermediate species due to stabilization
of radicals with a neighboring nitrile group arising in the
first stage [reaction of Fe(CO)5 with halogenated
substrate]. In this case the side reaction involving
hydrogen abstraction by radicals from the carbonyl
compound that competes with radical reduction into a
carbanion should occur more readily just with aldehydes.
8:1:1). The yields were determined by GLC with respect
to a reference compound.
Reaction of iodoacetonitrile with carbonyl com-
pounds. 3-Hydroxy-3-methylenanthonitrile III (isolated
by preparative GLC), yield 70%, nD20 1.4450, d420 0.9349.
1H NMR spectrum, d, ppm (J, Hz): 2.56 s (1H, OH),
2.44 s (2H, CH2CN), 1.50, 1.25 both m (3CH2), 1.27 s
(3H, CH3C), 0.84 t (3H, CH3, J 3). 13C NMR spectrum,
d, ppm: 118.6 (CN), 71.7 (COH), 41.9 (CH2CN), 31.8,
27.2, 26.6 (3CH2), 23.6 (CH3C), 14.6 (CH3CH2). Mass
spectrum, m/z (Irel,%): 126 [M–CH3]+. (6), 101 [M–
CH2CN]+ (23), 84 [M–C4H9]+. (100), 57 [C4H9]+ (20),
43 [C3H7]+ (87). Found, %: C 68.20; H 10.73; N 9.91.
C8H15NO.
Hence the application of the iron pentacarbonyl permits
a successful performance under relatively simple
homogeneous conditions (boiling of the reagents mixture
in benzene for 3–4 h), without anhydrous solvents or inert
gas atmosphere, of Reformatsky type reaction involving
halo-substituted nitriles and furnishing in good or plausible
yields the corresponding hydroxynitriles that can be easily
converted into aminoalcohols [3]. Taking into account that
nitriles and esters can easily be interconverted the
reactions described affording hydroxy derivatives of
nitriles and esters well supplement each other. The
syntheses with aldehydes are more favorable with
haloesters, with aliphatic ketones the reactions with
halonitriles are more feasible.
Calculated, %: C 68.04; H 10.70; N 9.92.
3-Hydroxy-3-phenylpropionitrile Va [5], yield 8%.
Mass spectrum, m/z (Irel , %): 147 [M]+ (19.0), 129 [M –
O]+ (65.0), 107 [M – CH2CN]+ (100.0), 77 [C6H5]+
(85.0); cinnamonitrile (mixture of cis-trans-isomers).
Mass spectrum, m/z (Irel, %): 129 [M]+ (100), 102 [M –
HCN]+.
3-Hydroxy-3-(p-chloroðphenyl)propionitrile Vb (cf.
[5]), yield 55%. Mass spectrum, m/z (Irel, %): 181 [M]+
(8.0), 163 [M – H2O]+ (32.0), 141 [M–CH2CN]+ (100.0),
113 [C6H4Cl]+ (36.0).
EXPERIMENTAL
1H and 13C NMR spectra were registered on spectro-
meter Bruker WP-200 (200 MHz) from solutions in
CDCl3. Chemical shifts are presented in d scale with
respect to Me4Si. Mass spectra were measured on GC-
MS instrument FINNIGAN MAT MAGNUM, column
25 long (Ultra-2), temperature programmed in the range
30–220°C at a rate 2.5 deg min-1. GLC analysis was
carried out on chromatograph LKhM-80 equipped with
a steel column (1300´3 mm), stationary phase 15%
SKTFT-50X on Chromaton-N-AW, carrier gas helium,
flow rate 60 cm3 min-1), detector katharometer,
temperature programmed in the range 50–250°C at a
3-(p-Methoxyphenyl)acrylonitrile VI, yield 12%. Mass
spectrum, m/z (Irel, %): 159 [M]+ (100.0), 144 [M – CH3]+.
(35.0), 129 [C6H5CH=CHCN]+ (10.0).
3-Hydroxy-3-phenylbutyronitrile IV, yield 10%. Mass
spectrum, m/z (Irel,%): 161 [M]+ (IV), yield 10%. Mass
spectrum, m/z (Irel, %): 161 [M]+ (1), 143 [M–H2O]+ (23),
121 [M–CH2CN]+, 105 [C6H5CO]+ (30), 77 [C6H5]+ (35),
43 [CH3CO]+ (100).
1-Oxo-1,3-diphenyl-2-butene, yield 5%. Mass
spectrum, m/z (Irel, %): 222 [M]+. (100), 207 [M – CH3]+
(12), 145 [M – C6H5]+(15), 117 [C6H5C3H4]+ (17), 105
[C6H5CO]+ (20), 77 [C6H5]+ (15).
rate 6 deg min-1
. All organic reagents were purified by
distillation, Fe(CO)5 from FLUKA (97%) was used
without additional purification.
Reaction of bromoacetonitrile with carbonyl com-
pounds. 3-Hydroxy-3-methylenanthonitrile III, yield
23%. 3-Hydroxy-3-phenylpropionitrile Va, yield 5%.
3-Hydroxy-3-(p-chlorophenyl)propionitrile Vb, yield 48%.
3-(p-methoxyphenyl)acrylonitrile VI, yield 12%.
Experimental procedure. A solution of a mixture
of a halide (1 mmol), a carbonyl compound (1 mmol),
Fe(CO)5 (2 mmol), CCl3Br (1–2 drops in reactions of
monobromides) in benzene (2ml) was heated for 3–4 h
at 80°C (in reactions with monohalides) or was left
standing at room temperature for 24 h (in case of
dibromoacetonitrile). Then the reaction mixture was
diluted with benzene (2 ml), treated with 1 N hydrochloric
acid, washed with water, and dried on MgSO4. The
products were isolated by preparative GLC or TLC
(eluent petroleum ether–chloroform–ethyl acetate,
Reaction of dibromoacetonitrile with carbonyl
compounds. 3-Methyl-2-heptenenitrile VIII (mixture
of cis- and trans-isomers 1:2.5), yield 78% (run at 60°C,
3 h), nD20 1.4519, d420 0.8408. 1H NMR spectrum, d , ppm
(J, Hz): 0.87, 0.90 both t (3H, CH3CH2, J 6, 4), 1.25–
1.48 m (4H, CH2CH2), 1.85, 2.00 both s (3H, CH3C),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 2 2004

177
ADDITION OF a-HALO-SUBSTITUTED CARBONITRILES
14.5, 14.6 (CH3CH), 13.2, 13.6 (CH3CH2). Mass spec-
trum, m/z (Irel, %): 155 [M]+ (0), 140 [M –CH3]+. (7), 101
[C4H9C(OH)CH3]+ (88), 98 [M – C4H9]+. (99), 85
[C4H9CO]+ (28), 83 [M – C4H9–CH3]+ (36), 56 [C4H8]+.
(100), 43 [CH3CO]+ (92). Found, %: C 70.04; H 10.96;
N 9.18. C9H17NO. Calculated, %: C 69.68; H 10.97;
N 9.03.
2.13, 2.36 both t [2H, CH2C, J 8 (both)], 5.05 s (1H,
CH=). 13C NMR spectrum, d, ppm: 166.4, 166.2 (CN),
117.7, 117.9 (C=), 96.1, 95.6 (CH=), 36.6, 39.0 (CH2C),
30.3, 29.8 (CH2), 21.6, 22.8 (CH2CH3), 22.9, 23.4 (CH3C),
14.4 (CH3CH2). Mass spectrum, m/z (Irel, %): 123 [M]+
(12), 95 [M–C2H4]+ (10), 81 [M–C3H6]+ (100), 56
[C4H8]+. (42). Found, %: C 77.95; H 10.43; N 11.45.
C8H13N. Calculated, %: C 78.00; H 10.69; N 11.37. The
same nitrile formed in the experiment carried out at room
temperature for 24 h
3-Hydroxy-3-phenyl-2-methylpropionitrile XIV, yield
38% (isolated by preparative GLC). 1H NMR spectrum,
d, ppm (J, Hz): 1.12, 1.13, 1.15, 1.16 d.d (3H, CH3CH,
both J 2), 2.87 m (CHCN), 3.31 br.s (1H, OH), 4.58,
4.62, 4.66, 4.70 d.d (1H, CHOH, both J 8), 7.2–7.4
(C6H5). 13C NMR spectrum, d, ppm: 127.1, 127.2 (CN),
74.8, 75.5 (CO), 34.7, 35.3 (CH), 15.4, 15.8 (CH3). Mass
spectrum, m/z (Irel, %): 161 [M]+ (1), 143 [M – H2O]+
(4), 107 [C6H5CHOH]+ (100), 77 [C6H5]+ (28). Found,
%: C 73.50; H 6.65; N 8.23. C10H11NO. Calculated, %:
C 74.50; H 6.88; N 8.69.
Cinnamonitrile VII (run at 60°C, 3 h), yield 70%, mix-
1
ture of cis- and trans-isomers (1:2.5). H NMR spec-
trum, d, ppm (J, Hz): (one of isomers): 5.77, 5.85 d (1H,
CH=, J 16), 7.04, 7.10 d (1H, CH=, J 12). Mass spec-
trum, m/z(Irel, %): 129 [M]+ (100), 102 [M – HCN]+. (37),
51 [CHCCN]+ (15).
3-Hydroxy-3-phenyl-2-bromopropionitrile IX (room
temperature, 24 h), yield 46% (isolated by TLC). Mixture
of diastereomers, 1:1. 1H NMR spectrum, d, ppm (J, Hz):
3.45 br.s (1H, OH), 4.40, 4.42 d (1H, CHBr, J 4), 4.91,
3-Hydroxy-3-(p-chlorophenyl)-2-methylpropionitrile
1
XVII, yield 90%. H NMR spectrum d, ppm (J, Hz):
13
2.65, 2.68 d (2H, CH2, J 6), 3.15 br.s (1H, OH), 4.93 t
(1H, CH, J 6), 7.23–7.33 m (Ar). Mass spectrum, m/z
(Irel, %): 195 [M]+ (0), 177 [M–H2O]+ (8), 141, 143 [M–
CH3CHCN]+ (100), 111, 113 [ClC6H4]+ (17), 77 [C6H5]+
(69), 55 [CH3CH2CN]+. (10).
4.94; 4.97, 4.99 both d (1H, CHOH, J 6, 4). C NMR
spectrum, d, ppm: 15.9, 116.2 (CN), 75.3, 75.5 (CHO),
35.0, 35.5 (CHBr). Mass spectrum, m/z (Irel, %): 129 [M–
BrOH]+ (95), 107 [C6H5CHOH]+ (100), 77 [C6H5]+ (70).
p-Chlorocinnamonitrile VIIa (run at 60°C, 3 h), yield
50%, mixture of cis- and trans-isomers (1:3). 1H NMR
spectrum, d, ppm (J, Hz): (one of isomers) 5.17, 5.23;
6.78, 6.85 both d (1H each, CH=, J 12 and 14), 7.71 m
(4H,Ar). 13C NMR spectrum, d, ppm: 149.8, 97.6 (2CH=),
118.5 (CN). Mass spectrum, m/z (Irel, %): 163, 165 [M]+
(100.0, 36.6), 136 [M–HCN]+. (12.8), 128 [M–Cl]+.
(64.4).
3-Hydroxy-3-(p-methoxyphenyl)-2-methylbutyroni-
trile XVIII, yield 30%. Mass spectrum, m/z (Irel, %): 191
[M]+ (5), 173 [M–H2O]+ (45), 137 [M–CH3CHCN]+
(100).
3-Hydroxy-3-phenyl-2-methylbutyronitrile XV, yield
34%. Mass spectrum, m/z (Irel, %): 157 [M – H2O]+ (8),
121 [C6H5C(CH3)OH]+ (99), 105 [C6H5CO]+ (31), 77
[C6H5]+ (30), 43 [CH3CO]+ (100).
p-Methoxycinnamonitrile VIIb (run at 60°C, 3 h), yield
10%, mixture of cis- and trans-isomers (1:1.5). Mass
spectrum, m/z (Irel, %): 159 [M]+ (100.0), 144 [M– CH3]+.
(18.1), 116 [M –H3OC]+. (30.7), 102 [M– OCH3]+. (2.6),
89.
3-Hydroxy-2,4,4-trimethylvaleronitrile XVI, yield 35%
Mass spectrum, m/z (Irel, %): 141 [M]+ (0), 108 [M –
CH3–H2O]+. (1), 87 [(CH3)3–CHOH]+ (23), 58 [C4H10]+.
(49), 57 [C4H9]+ (100), 41 [C3H5]+ (35).
1-Cyclopentenylacetonitrile XII, yield 30%. 1H NMR
spectrum, d, ppm (J, Hz): 1.21 s (CH2CN, 2H), 1.74 t
(2H, CH2, J 2), 2.41, 2.55 both mCH2), 5.18 t (1H, CH=,
J 2.3). Mass spectrum, m/z (Irel, %): 107 [M]+ (28), 80
[M – HCN]+. (15), 41 [C3H5 , CH3CN]+ (100).
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1.26 both s (6H, CH3C, CH3CH), 1.27–1.65 m (6H, 3
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37.7 (CH2C), 26.1, 26.2, 23.6 (2 CH2), 24.4, 24.7 (CH3C),
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