One-pot synthesis of cyanohydrin derivatives from alkyl bromides via incorporation of two one-carbon components by consecutive radical/ionic reactions

Article abstract of DOI:10.3762/bjoc.10.12

The consecutive radical/ionic reaction consisting of radical formylation of alkyl bromides and nucleophilic addition of a cyanide ion was investigated, which gave moderate to good yields of cyanohydrin derivatives in one-pot.

Full text of DOI:10.3762/bjoc.10.12

One-pot synthesis of cyanohydrin derivatives from
alkyl bromides via incorporation of two one-carbon
components by consecutive radical/ionic reactions
Shuhei Sumino, Akira Fusano, Hiroyuki Okai, Takahide Fukuyama
and Ilhyong Ryu*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 150–154.
Department of Chemistry, Graduate School of Science, Osaka
Prefecture University, Sakai, Osaka 599-8531, Japan
doi:10.3762/bjoc.10.12
Received: 30 September 2013
Accepted: 10 December 2013
Published: 14 January 2014
Email:
Ilhyong Ryu* - ryu@c.s.osakafu-u.ac.jp
* Corresponding author
This article is part of the Thematic Series "Multicomponent reactions II".
Guest Editor: T. J. J. Müller
Keywords:
alkyl bromide; carbon monoxide; cyanohydrin; ethyl cyanoformate;
multicomponent; radical reaction
© 2014 Sumino et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The consecutive radical/ionic reaction consisting of radical formylation of alkyl bromides and nucleophilic addition of a cyanide
ion was investigated, which gave moderate to good yields of cyanohydrin derivatives in one-pot.
Introduction
Radical carbonylation reactions have been recognized as a to the radical centre [14], thus we developed a hydroxymethyla-
versatile tool for the synthesis of a wide variety of carbonyl tion method using Bu4NBH4 and a radical initiator [15-17].
compounds [1-4]. In 1990, we demonstrated that aldehydes can Recent work in collaboration with Dennis Curran has revealed
be prepared from alkyl or aromatic halides and CO under that, with the use of NHC-borane [18], hydroxymethylation of
typical radical chain reaction conditions using tributyltin aromatic iodides can be attained [19]. All these reactions consist
hydride and AIBN [5,6]. Under the reaction conditions where a of the combination of radical formylation with CO and ionic
catalytic amount of fluorous tin hydride and an excess amount hydride reduction by hydride reagents (Scheme 1, reaction 1).
of sodium cyanoborohydride were used, initially formed alde- During the course of our study on borohydride-mediated radical
hydes can be converted into hydroxymethylated compounds in hydroxymethylation of alkyl halides with CO, we found that
one-pot [7-9], since borohydride acts not only as the reagent for cyanohydrin was obtained as a byproduct when Bu4NBH3CN
the regeneration of tin hydride [10-13] but also as the reagent was used as a radical mediator [15], which led us to investigate
for aldehyde reduction. Later on we found that borohydride the one-pot synthesis of cyanohydrins based on radical formyla-
reagents can also serve as radical mediator delivering hydrogen tion. Thus, we thought that the two step radical/ionic reactions
150

Beilstein J. Org. Chem. 2014, 10, 150–154.
Scheme 1: Sequential radical formylation and derivatization.
can be extended to the consecutive C–C bond forming reac- cyanoformate (2a) was used together with Et3N [29], the cyano-
tions.
hydrin 3a was obtained in 62% yield. When we used higher CO
pressure such as 120 atm, the yield of 3a increased to 79%.
Cyanohydrins are important subunits frequently found in bio-
logically active compounds and are also versatile building We examined various alkyl bromides 1 in the present radical/
blocks for further synthetic transformations [20,21]. The ionic three-component coupling reaction (Table 1). Primary
common method to obtain cyanohydrins is the reaction of alde- alkyl bromides 1b–e containing a chlorine atom, an ester group,
hydes with a cyanide sources such as TMSCN [22,23], ethyl a cyano group, or a phenyl group worked well to give the
cyanoformate [24-26] or acyl cyanide [27,28]. We provide here corresponding cyanohydrin derivatives 3b–e in good yields
an efficient one-pot method for the synthesis of cyanohydrin (Table 1, entries 2–5). The reaction of secondary and tertiary
derivatives via consecutive radical/ionic C–C bond forming alkyl bromides 1f–i also proceeded well to give the corres-
reaction of alkyl bromides, CO and ethyl cyanoformate ponding cyanohydrins 3f–i in good yields (Table 1, entries
(Scheme 1, reaction 2).
6–9). The reaction using cyclopropylmethyl bromide (1j)
afforded the lowest yield of cyanohydrin 3j, which possessed an
olefin structure arising from the ring-opening of a cyclopropyl-
Results and Discussion
We examined AIBN-induced radical formylation of 1-bromo- carbinyl radical (Table 1, entry 10) [30,31].
octane (1a) with Bu3SnH under 80 atm of CO pressure in the
presence of a cyanide source (Scheme 2). Under the employed Conclusion
conditions, the reaction using TMSCN (2a') was slow, which In summary, we have demonstrated a three-component coupling
gave 16% of 3a' and 51% of nonanal. The use of AcCN (2a'') reaction comprising alkyl bromides 1, CO and ethyl cyanofor-
also gave 3a'' but only in 12% yield. However, when ethyl mate (2a) in the presence of Bu3SnH, AIBN, and Et3N, which
Scheme 2: Examination of cyanide source.
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Beilstein J. Org. Chem. 2014, 10, 150–154.
Table 1: Three-component coupling reaction leading to cyanohydrin derivatives.
entry
1b
alkyl bromide
CO (atm)
120
product
yielda (%)
79
1a
3a
3b
3c
3d
2
3
4
80
80
60
83
76
1b
1c
1d
120
5
6
7
120
120
120
61
61
74
1e
1f
3e
3f
1g
1h
3g
3h
8
120
73
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Beilstein J. Org. Chem. 2014, 10, 150–154.
Table 1: Three-component coupling reaction leading to cyanohydrin derivatives. (continued)
9
110
110
82
45
1i
1j
3i
3j
10
aIsolated yield after flash chromatography on SiO2. b0.03 M.
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carbonylation and ionic cyanation.
Experimental
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Typical procedure for radical/ionic three-component coupling
reaction leading to cyanohydrin derivatives 1-cyanononyl ethyl
carbonate (3a) [34] (Table 1, entry 1): A mixture of 1-bromo-
octane (1a, 96.6 mg, 0.5 mmol), ethyl cyanoformate (2a,
79.3 mg, 0.8 mmol), tributyltin hydride (174.6 mg, 0.6 mmol),
triethylamine (13.2 mg, 0.13 mmol), and AIBN (24.6 mg,
0.15 mmol) in C6H6 (17 mL) were placed in a 100 mL stainless
steel autoclave. The reaction mixture was degassed 3 times with
10 atm of CO and charged with 90 atm of CO at −40 °C
(MeCN–dry ice bath). Then the autoclave was allowed to warm
to room temperature, which caused the pressure gauge to indi-
cate 120 atm. Then the reaction was conducted at 80 °C for 3 h.
After cooling to room temperature, the reaction mixture was
concentrated and purified by silica gel flash chromatography
(hexane/EtOAc 97:3) to afford 3a (95.3 mg, 79%). 1H NMR
(CDCl3, 500 MHz) δ 5.18 (t, J = 6.8 Hz, 1H), 4.4–4.2 (m, 2H),
2.0–1.9 (m, 2H), 1.6–1.5 (m, 2H), 1.4–1.2 (m, 13H), 0.88 (t, J =
6.9 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 153.56, 116.51,
65.27, 64.66, 32.31, 31.68, 29.12, 28.99, 28.71, 24.34, 22.53,
14.05, 13.93.
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Acknowledgements
We acknowledge a Grant-in-Aid for Scientific Research on
Innovative Areas (No. 2105) from the Ministry of Education,
Culture, Sports, and Technology (MEXT), Japan.
See for a review on NHC-borane.
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