Zinc-mediated addition of bromoacetonitrile to carbonyl compounds under solvent-free conditions

Article abstract of DOI:10.3184/174751914X13888556743823

Zinc mediated addition reaction of bromoacetonitrile with aryl aldehydes and ketones produces β-hydroxynitriles under solvent-free conditions. The valuable feature of the methodology are solvent-free and catalyst-free conditions and short reaction times (5 min).

Full text of DOI:10.3184/174751914X13888556743823

JOURNAL OF CHEMICAL RESEARCH 2014
FEBRUARY, 73–75
RESEARCH PAPER 73
Zinc-mediated addition of bromoacetonitrile to carbonyl compounds under
solvent-free conditions
Yumei Zhang*, Xi Du and Bin An
The School of Chemical and Biological Engineering, Lanzhou Jiaotong University, 88 West Anning Road, Lanzhou 730070, P.R. China
Zinc mediated addition reaction of bromoacetonitrile with aryl aldehydes and ketones produces β-hydroxynitriles under
solvent-free conditions. The valuable feature of the methodology are solvent-free and catalyst-free conditions and short
reaction times (5 min).
Keywords: zinc, bromoacetonitrile, carbonyl compounds, β-hydroxynitriles, solvent-free conditions
β-Hydroxynitriles are useful building blocks for the synthesis
of β-hydroxycarboxylic acids and their derivatives, γ-amino
alcohols as well as other important functionalities.1–3 Typically,
β-hydroxynitriles are prepared through the deprotonation of a
nitrile followed by addition to an aldehyde or ketone through
a nucleophilic attack.4 The procedure has the disadvantage of
being harsh on sensitive acidic functional groups present in
the substrate and the facile dehydrations of β-hydroxynitriles
usually give the desired products in unsatisfactory yields.5 To
overcome the above problems, the Reformatsky-type reaction
is recognised as being a good alternative.6–8 Some activated
metals such as nickel,9 antimony,10 tin,11 indium12 and SmI213
are reported to promote Reformatsky-carbonyl addition
reactions of α-halonitriles. However, there are few examples of
satisfactory Reformatsky-type reaction with bromoacetonitriles
mediated by zinc. This is due to the relatively low activity
and the requirement of strict reaction conditions with zinc.
Various methods have been reported to improve the activation
of organozinc, such as ultrasound14,15 and microwave.16 In
our preliminary research, we found that the reactivity of
organozinc could be enhanced dramatically in the absence
of solvent (THF). We have reported the solvent-free addition
reaction of allylzinc bromide and carbonyl compounds.17 Now
we report an efficient addition reaction of bromoacetonitrile
with aryl carbonyl compounds mediated by zinc under solvent-
free conditions. We found that the reactivity with zinc could
be enhanced dramatically in the absence of the solvent THF.
The reaction is very fast in all cases with substrates reacting
completely in less than 5 min at room temperature.
such as a transition-metal catalyst, N2 atmosphere, anhydrous
solvent, and low temperature. However, our solvent-free
reaction is completed in less than 5 min in an open atmosphere
at room temperature and does not need any catalyst. The yields
are good, and the reaction time is very short. The examples are
shown in Scheme 1.
Solvent-free conditions play a major role in the reaction. The
reaction did not proceed at all in the presence of the solvent
THF. The reason is probably that the micro-environment and
the higher concentration of reactants in the absence of solvent
lead to more favourable kinetics than in solution.
The zinc mediated addition reactions of bromoacetonitrile
with a series of aldehydes and ketones under solvent-free
conditions are contained in Table 1. The reaction provides
good yields in reactions utilising aryl aldehydes and ketones.
Aryl aldehydes containing both electron-donating and
electron-withdrawing groups in the aromatic rings and
heteroaryl aldehydes were found to undergo the conversion
smoothly (Table 1, entries 1–5, 8). The corresponding products
β-hydroxynitriles were obtained in yields ranging from 74% to
92%. The approach only gave 1, 2-addition for α, β-unsaturated
aldehydes, and conjugate addition did not occur (Table 1, entries
6 and 7). Aryl ketones also proceed by a similar reaction,
but the yield is lower than with aldehydes. Lower activated
aliphatic aldehydes or ketones, unfortunately, did not undergo
the addition reactions.
In conclusion, zinc-mediated solvent-free nitrile aldol
reaction provides an alternative method for introducing a nitrile
into a carbonyl compound. The method here has the following
advantages: solvent-free, short reaction time (5 min), mediated
by cheap metallic zinc, without another catalyst, adaptability
to a wide variety of aryl aldehydes and ketones, high yield and
environmentally benign.
We now propose that an organozinc compound
(BrZnCH2CN) may be formed through the oxidative addition of
bromoacetonitrile to zinc, and that nucleophilic addition of this
species to carbonyl groups yields the products. The reaction of
organozinc reagents always requires strict reaction conditions
Experimental
IR spectra were measured using an Alpha Centauri FT-IR
O
OH
1
spectrophotometer. H NMR and 13C NMR spectra (400 MHz) were
Zn*
C
BrCH2CN
recorded in CDCl3 using a Bruker AC-E 400 MHz spectrometer.
HRMS was performed on an APEX II FT-ICR. Purification of
products was performed via flash chromatography with 200–400 mesh
silica gel [petroleum ether (bp 60–90°C):ethyl acetate, 10:1]. The
chemicals were obtained from commercial sources.
+
R1
CH2CN
R
C
Solvent-free
R
R1
1
2
3a-i
R = C6H5, p-F-C6H4, p-Cl-C6H4, m-CH3O-C6H4, p-CH3O-C6H4,
C6H5-CH=CH, C6H5-CH=C(CH3), 2-Furyl
R1 = H, CH3
Synthesis of 3a–i; general procedure
In a dried round-bottom flask fitted with magnetic bar and dropping
funnel, zinc powder (0.39 g, 6 mmol) was activated and aromatic
aldehydes or ketones (4 mmol) were added. After this step,
bromoacetonitrile (5 mmol) was added dropwise over 2 minutes and
then the reaction was stirred for 5 minutes at room temperature. After
complete conversion, saturated aqueous ammonium chloride was
poured into the mixture and the mixture was stirred for 5 minutes.
Ethyl ether was added to the reaction mixture and the organic layer was
18
Scheme1
* Correspondent. E-mail: zhangym@mail.lzjtu.cn
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74 JOURNAL OF CHEMICAL RESEARCH 2014
Table 1 Zinc-mediated solvent-free addition reaction of bromoacetonitrile to carbonyl compoundsa
Entry
Substrate
Productb
Yield/%c
85
OH
CHO
3a
3b
3c
1
CH2CN
OH
F
F
CHO
92
88
2
3
CH2CN
OH
Cl
Cl
CHO
CH2CN
H3CO
H3CO
OH
4
3d
74
CHO
CH2CN
OH
H3CO
5
6
H3CO
CHO
3e
3f
83
74
CH2CN
OH
CHO
CH2CN
OH
7
8
3g
3h
76
71
CHO
H3C
H3C
CH2CN
OH
CHO
O
O
CH2CN
O
OH
CH2CN
9
3i
62
CH3
CH3
O
OH
CH2CN
CH3
10
11
3j
0
0
H3C
CH3
H3C
CH3CH2CH2CHCH2CN
OH
CH3CH2CH2CHO
3k
aReaction conditions: activated zinc powder (6 mmoL), aldehydes or ketones (4 mmoL), and bromoacetonitrile (5 mmoL) at
room temperature for 5 min.
bAll products were characterised by IR, 1H NMR and 13C NMR.
cIsolated yield.
separated. The organic extracts were dried over anhydrous MgSO4.
The residue was purified by flash chromatography on silica gel to
obtain an oily product. All the isolated products were characterised
3-(4-Chlorophenyl)-3-hydroxypropanenitrile (3c): Oil,11,12,19 IR (υ/cm–1):
1
3385, 3024, 2241, 1547; H NMR (400 MHz, CDCl3, TMS): 7.39–7.26
(m, 4H), 5.05–5.00 (q, J=6.0 Hz, 1H), 2.79–2.68 (m, 3H); 13C NMR
(100 MHz, CDCl3): 139.4, 134.6, 129.1, 126.9, 117.0, 69.3, 27.9.
3-Hydroxy-3-(3-methoxyphenyl)propanenitrile (3d): Oil,19 IR (υ/cm–1):
3406, 3016, 2233, 1517, 1431; 1H NMR (400 MHz, CDCl3, TMS): 7.32–
7.26 (m, 1H), 6.94 (s, 2H), 6.89–6.86 (t, 1H), 4.99–4.97 (t, J=4.0 Hz,
1H), 3.84–3.79 (t, 3H), 2.80 (br s, 1H, OH), 2.74–2.73(m, 2H); 13C NMR
(100 MHz, CDCl3): 159.9, 142.7, 129.9, 117.7, 117.3, 114.2, 111.1, 69.9,
55.3, 27.9.
1
by IR, H NMR and 13C NMR. The physical and spectra data of the
compounds 3a–i are as follows.
3-Hydroxy-3-phenylpropanenitrile (3a): Oil,11,12 IR (υ/cm–1): 3387,
3012, 2245, 1538; 1H NMR (400 MHz, CDCl3, TMS): 7.40–7.26 (m, 5H),
5.04–5.01 (t, J=6.4 Hz, 1H), 2.76–2.74 (d, 2H), 2.57(br s, 1H, OH) 13
C
NMR (100 MHz, CDCl3): 140.9, 128.9, 128.8, 125.5, 117.3, 69.9, 27.9.
3-(4-Fluorophenyl)-3-hydroxypropanenitrile (3b): Oil,19 IR (υ/cm–1):
3407, 3025, 2243, 1541; 1H NMR (400 MHz, CDCl3, TMS): 7.38–7.05 (m,
3-Hydroxy-3-(4-methoxyphenyl)propanenitrile (3e): Oil,11 IR (υ/cm–1):
3401, 3012, 2243, 1523; 1H NMR (400 MHz, CDCl3, TMS): 7.35–7.26 (m,
2H), 6.94–6.91 (q, 2H), 5.02–4.99 (t, J=6.4 Hz, 1H), 3.82 (s, 3H), 2.82–
4H), 5.00 (t, J=6.0 Hz, 1H), 3.15 (br s, 1H, OH), 2.73–2.71(d, 2H); 13
C
NMR (100 MHz, CDCl3): 163.9, 161.5, 136.8, 136.7, 127.4, 127.3, 117.2,
115.8, 115.6, 69.2, 27.9.
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JOURNAL OF CHEMICAL RESEARCH 2014 75
2.71 (m, 2H), 2.32 (br s, 1H, OH); 13C NMR (100 MHz, CDCl3): 159.9,
133.1, 126.8, 117.3, 114.3, 69.9, 55.3, 27.9.
Received 16 October 2013; accepted 28 November 2013
Paper 1302236 doi: 10.3184/174751914X13888556743823
Published online: 5 February 2014
3-Hydroxy-5-phenylpent-4-enenitrile (3f): Oil,11,12,19 IR (υ/cm–1): 3398,
3019, 2236, 1529; 1H NMR (400 MHz, CDCl3, TMS): 7.57–7.25 (m, 5H),
6.72–6.84 (d, 1H), 6.26–6.20 (t, 1H), 4.64–4.60(q, J=5.6 Hz, 1H), 2.73–
2.61 (m, 2H), 2.51(br s, 1H, OH); 13C NMR (100 MHz, CDCl3): 135.5,
132.9, 128.7, 128.4, 127.9, 126.7, 117.2, 68.6, 26.3.
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