Communication
Radical Addition of Alkyl Halides to Formaldehyde in the Presence of
Cyanoborohydride as a Radical Mediator. A New Protocol for
Hydroxymethylation Reaction
Takuji Kawamoto, Takahide Fukuyama, and Ilhyong Ryu*
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan
*
S Supporting Information
Table 1. Hydroxymethylation of 1-Haloadamantane with
HCHO) and n-Bu NBH CN
ABSTRACT: Hydroxymethylation of alkyl halides was
achieved using paraformaldehyde as a radical C1 synthon
in the presence of tetrabutylammonium cyanoborohydride
as a hydrogen source. The reaction proceeds via a radical
chain mechanism involving an alkyl radical addition to
formaldehyde to form an alkoxy radical, which abstracts
hydrogen from a hydroborate anion.
(
n
4
3
yield,
a
entry
X (1)
initiator
temp, °C
%
1
2
3
4
5
I (1a)
black light (15 W, Pyrex)
AIBN (20 mol %)
none
25
90
90
25
25
85
87
0
b
I (1a)
hereas the use of formaldehyde as a C1 synthon is quite
I (1a)
1
W
common in carbanion reactions, the synthetic use of
c
c
Br (1a′)
Br (1a′)
black light (15 W, Pyrex)
0
2
−4
formaldehyde in radical reactions is rarely reported. In 1958,
Fuller and Rust reported di-tert-butylperoxide-mediated reaction
of cyclohexane with formaldehyde, leading to cyclohexaneme-
low-pressure Hg lamp
(6 W, quartz)
85
a
b
Isolated yield by flash column chromatography on SiO . (HCHO) ,
7.5 equiv; n- Bu NBH CN, 2.0 equiv. Reaction time, 12 h.
4 3
2
n
2
c
thanol in 38% yield. In 1965, a similar type of reaction with
ethanol and formaldehyde to give ethylene glycol was reported
3
a
by Oyama. Later, the work was followed independently
2
,2′-azobisisobutyronitrile (AIBN) as a radical initiator also
3
b−e
3f,g
by Kollar
and Sanderson. In 1972, Brown and co-workers
worked well (entry 2), whereas the reaction with heating
without AIBN did not proceed (entry 3). This suggests that the
present reaction would proceed via a radical chain process.
When 1-bromoadamantane (1a′) was irradiated with a 15 W
black light, no hydroxymethylation product was obtained.
However, irradiation using a 6 W low-pressure Hg lamp (peak
wavelength at 254 nm) through a quartz tube effected a smooth
hydroxymethylation reaction, which gave 85% yield of 2a
reported the reaction of trialkylborane with formaldehyde under
air to give one-carbon homologated alcohols, which is thought
to involve alkyl radical addition to formaldehyde to form alkyl
borate as the precursor to alcohols. While these reactions were
noteworthy as pioneering efforts to use formaldehyde in radical
reactions, in order to establish the usefulness of formaldehyde as
a radical C1 acceptor, a novel efficient reaction system had to
be explored.
Recently we reported that the radical hydroxymethylation of
alkyl iodides can be carried out under atmospheric pressure of
CO in the presence of borohydride reagents. We became
interested in whether a system in which CO is simply replaced
by formaldehyde would work for the hydroxymethylation of
alkyl halides. In this Communication, we demonstrate that alkyl
iodides and bromides undergo radical-mediated hydroxyme-
thylation with paraformaldehyde in the presence of tetrabuty-
lammonium cyanoborohydride (n-Bu NBH CN) as a radical
4
5,6
(
entry 5).
Encouraged by the results shown in Table 1, we then applied
these reaction conditions to the hydroxymethylation of various
alkyl halides (Table 2). Substituted 1-iodoadamantanes 1b and
7
1
(
c gave the corresponding alcohols 2b and 2c in good yields
entries 3 and 4). Similarly, 1,3-diiodoadamantane (1d)
underwent dihydroxymethylation to give diol 2d in 77% yield
entry 5). Secondary alkyl halides 1e, 1f, and 1g also reacted
(
smoothly with formaldehyde to form the corresponding
alcohols 2e, 2f, and 2g in good yields (entries 6−8). However,
in the reaction of primary alkyl halides such as 1-iododecane
4
3
8
mediator.
1
-Iodoadamantane (1a) was chosen as a model substrate
for the initial study (Table 1). When a mixture of 1a, para-
formaldehyde, and n-Bu NBH CN in acetonitrile was
irradiated with a 15 W black light (peak wavelength at
52 nm) in a Pyrex flask for 4 h under nitrogen, the desired
-hydroxymethyladamantane (2a) was obtained in 85% yield
entry 1). The reaction using NaBH CN also gave 2a in
(
1h) and (2-bromoethyl)benzene (1i), the yields of the hydro-
xymethylated products were low (entries 9 and 10). This is due
to the competitive direct S 2 reduction of the alkyl halides by
the hydride anion. 2-Methoxyiodocyclohexane (1j) underwent
hydroxymethylation to give alcohol 2j in 50% yield (entry 11).
In the case of 2-allyloxyiodocyclohexane (1k), a bicyclic alcohol
4
3
N
3
1
(
9
3
7
0% yield; however, n-Bu NBH , NaBH , BH ·NMe , and
4 4 4 3 3
BH ·NH t-Bu did not work, presumably due to rapid reduction
of formaldehyde. The reaction using thermal conditions with
Received: November 10, 2011
Published: December 20, 2011
3
2
©
2011 American Chemical Society
875
dx.doi.org/10.1021/ja210585n | J. Am. Chem.Soc. 2012, 134, 875−877