Efficient hydroxymethylation reactions of iodoarenes using CO and 1,3-dimethylimidazol-2-ylidene borane

Article abstract of DOI:10.1021/ol4006294

A hydroxymethylation reaction of a variety of iodoarenes proceeded effectively in the presence of CO, NHC-borane, diMeImd-BH₃ (2) as a radical mediator, and a catalytic amount of AIBN. The reaction took place chemoselectively at the aryl-iodine bond but not at the aryl-bromine and aryl-chlorine bonds. A three-component coupling reaction comprising aryl iodides, CO, and electron-deficient alkenes also proceeded well to give unsymmetrical ketones in good yields. Control experiments show that 2 would act as a hydrogen donor to acyl radicals and iodinated NHC-borane as a reducing agent of aldehydes.

Full text of DOI:10.1021/ol4006294

ORGANIC
LETTERS
2013
Vol. 15, No. 9
2144–2147
Efficient Hydroxymethylation Reactions
of Iodoarenes Using CO and
1,3-Dimethylimidazol-2-ylidene Borane
Takuji Kawamoto,† Takuma Okada,† Dennis P. Curran,‡ and Ilhyong Ryu*,†
Department of Chemistry, Graduate School of Science, Osaka Prefecture University,
Sakai, Osaka 599-8531, Japan, and Department of Chemistry, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260, United States
ryu@c.s.oskakafu-u.ac.jp
Received March 9, 2013
ABSTRACT
A hydroxymethylation reaction of a variety of iodoarenes proceeded effectively in the presence of CO, NHC-borane, diMeImd-BH3 (2) as a radical
mediator, and a catalytic amount of AIBN. The reaction took place chemoselectively at the aryl-iodine bond but not at the aryl-bromine and aryl-
chlorine bonds. A three-component coupling reaction comprising aryl iodides, CO, and electron-deficient alkenes also proceeded well to give
unsymmetrical ketones in good yields. Control experiments show that 2 would act as a hydrogen donor to acyl radicals and iodinated NHC-borane
as a reducing agent of aldehydes.
Organo halides are among the most useful precursors to
access carbon radical species, and they have consequently
found numerous applications in chemical synthesis.1 In the
past two decades, the potential of CO as a radical C1
synthonhas been establishedwithexamples yielding a wide
range of carbonyl compounds.2 Recently, we have re-
ported radical hydroxymethylation3 of alkyl iodides using
CO and tetrabutylammonium borohydride(1a) (Figure1).
We also reported radical hydroxymethylation using HCHO
and tetrabutylammonium cyanoborohydride (1b).4 Due to
a slower H donation ability of the borohydride reagents5
compared with that of tributyltin hydride, the carbonyla-
tion could proceed efficiently, even under an atmospheric
pressure of CO, without premature quenching of the key
radicals by the borohydride reagents. While secondary and
tertiary alkyl iodides worked well in these reactions, primary
alkyl iodides faced competing hydride reduction to the
corresponding alkanes. The other drawback of borohydride-
mediated hydroxymethylation is that it is not compatible
with iodoarenes, as the major product is the directly
reduced arene.
† Osaka Prefecture University.
‡ University of Pittsburgh.
(1) For reviews on radicals in organic synthesis using organic halides,
see: (a) Renaud, P.; Sibi, M. P., Ed. Radicals in Organic Synthesis; Wiley-
VCH: Weinheim, 2001. (b) Togo, H., Ed. Advanced Free Radical Reactions
€
Organic Synthesis; Elsevier: 2004. (c) Heinrich, M. R.; Gansauer, A., Ed.
Topics Current Chemistry; Radicals in Synthesis III; Springer: Berlin,
2012; Vols. 320. (d) Rowlands, G. J. Tetrahedron 2009, 65, 8603.
(2) For reviews on radical carbonylations, see: (a) Ryu, I.; Sonoda,
N. Angew. Chem., Int. Ed. Engl. 1996, 35, 1050. (b) Ryu, I.; Sonoda, N.;
Curran, D. P. Chem. Rev. 1996, 96, 177. (c) Ryu, I. Chem. Soc. Rev. 2001,
30, 16. (d) Also see a review on acyl radicals: Chatgilialoglu, C.; Crich,
D.; Komatsu, M.; Ryu, I. Chem. Rev. 1999, 99, 1991.
Figure 1. Borane reagents available for radical reactions.
(3) Kobayashi, S.; Kawamoto, T.; Uehara, S.; Fukuyama, T.; Ryu, I.
Org. Lett. 2010, 12, 1548.
(4) (a) Kawamoto, T.; Fukuyama, T.; Ryu, I. J. Am. Chem. Soc.
2012, 134, 875. (b) Kawamoto, T.; Ryu, I. Chimia 2012, 66, 372.
(5) Ryu, I.; Uehara, S.; Hirao, H.; Fukuyama, T. Org. Lett. 2008,
10, 1005.
^
Recently, Curran, Lacote, and co-workers showed that
N-heterocyclic carbene boranes (NHC-boranes) can be
used for radical chain reactions as viable hydrogen transfer
r
10.1021/ol4006294
Published on Web 04/16/2013
2013 American Chemical Society

reagents.6 In particular, the second-generation reagent
1,3-dimethylimidazol-2-ylidene borane (diMeImd-BH3, 2),
a stable and easily handled solid, can smoothly reduce
xanthates and related functional groups.7 On the other
hand, radical reduction of organo halides have been
limited to compounds possessing electron-withdrawing
groups at the R-position and this necessitates the use of a
polarity reversal catalyst such as thiols when ordinary
organohalides are employed as substrates.8,9 Indeed, sec-
ondary alkyl radicals react with NHC-boranes with a rate
constant on the order of 104 Mꢀ1 sꢀ1, which is 2 orders of
magnitude slower than that of tributyltin hydride.10 In the
hope of expanding the substrate scope for hydroxymethy-
lation reactions, we decided toexamine the hydroxymethy-
lation reaction of RX with CO using NHC-boranes as the
reducing agent. Herein we report that NHC-borane 2 is an
excellent reagent for radical hydroxymethylation of a wide
variety of organoiodides including iodoarenes.
Having identified NHC-borane 2 as a suitable reagent
for the hydroxymethylation of iodoalkanes, we then
studied hydroxymethylation of iodoarenes.11 We chose
4-iodoanisole (3d) asa model substrate for the initial study,
and the results are summarized in Table 1. Disappoint-
ingly, photoirradiation of an acetonitrile solution contain-
ing 3d (0.1 M) and 2 (1.5 equiv) with atmospheric pressure
of CO for 4 h gave exclusively reduced anisole 5d in 68%
yield (entry 1). However, under 80 atm of CO, the reaction
gave the desired 4-methoxybenzyl alcohol 4d in 71% yield
along with a 10% yield of anisole 5d (entry 2). By decreas-
ing the reaction concentration ([3d] = 0.05 M) 4d was
obtained as the sole product (entry 3).
Table 1. Hydroxymethylation of 4-Iodoanisole (3d)
Scheme 1. Hydroxymethylation of Alkyl Iodides Using 2 and
Atmospheric CO (balloon)
3d
CO
entry
[M]
[atm]
conva
4db
5dc
1d
2
0.1
1
80
80
100%
100%
100%
0%
68%
10%
trace
0.1
71%
78%
3
0.05
1
a Detemined by H NMR. b Isolated yield after flash column chro-
matography on silica gel. c GC yield. d Black light (15 W, Pyrex) was used
instead of AIBN at rt.
Table 2 shows the results of hydroxymethylation of a
variety of aryl iodides, which was conducted at 80 atm of
CO using 2 as a radical mediator and AIBN as a radical
initiator. Iodobenzene (3e), 4-iodotoluene (3f), 1-iodo-
naphthalene (3g), and 2-iodonaphtalene (3h) gave the
corresponding alcohols 4e, 4f, 4g, and 4h in 63, 66, 67,
and 59% yields, respectively (entries 2ꢀ5). The reaction of
ethyl-4-iodobenzoate (3i) was also successful, giving 4i in
66% yield (entry 6). Given the poor result of 4-bromoani-
sole (3d0) (entry 8), we expected that the reaction was
chemoselective with respect to iodoarenes. To confirm this
we found that the reaction of 1-bromo-4-iodobenzene (3j),
1-chloro-4-iodobenzene (3k), and 1-fluoro-4-iodobenzene
(3l) proceeded chemoselectively at the aryl-iodine bond to
give the corresponding bromine-, chlorine-, and fluorine-
containing products 4j, 4k, and 4l, respectively (entries 9ꢀ11).
The tandem intramolecular cyclizationꢀhydroxymethylation
sequence of substrate 3m also proceeded, albeit in 29% yield.
We believe that, in the present hydroxymethylation
reactions using 2, similar to the borohydride reagents
Initially we examined the potential of 2 as a mediator for
radical hydroxymethylation of alkyl iodides using CO.
Under an atmosphere of CO (balloon), a benzene solution
of1-iododecane (3a) and diMeImd-BH3 (2) (1.2 equiv) was
irradiated with a 15 W black light through a Pyrex flask for
6 h at rt, which gave the desired homologated alcohol 4a in
60% isolated yield after flash chromatography on silica gel
(Scheme 1). Secondary and tertiary alkyl iodides, such as
2-iodoocatane (3b) and 1-iodoadamantane (3c), were also
converted to the corresponding alcohols 4b and 4c in good
yields.
(6) For a review on NHC-borane, see: Curran, D. P.; Solovyev, A.;
^
Makhlouf Brahmi, M.; Fensterbank, L.; Malacria, M.; Lacote, E.
Angew. Chem., Int. Ed. 2011, 50, 10294.
(7) For radical deoxygenation of xanthates, see: Ueng, S.-H.;
^
Fensterbank, L.; Lacote, E.; Malacria, M.; Curran, D. P. Org. Lett.
2010, 12, 3002.
(8) For radical dehalogenation of alkyl halides bearing electron-
^
withdrawing groups, see: Ueng, S.-H.; Fensterbank, L.; Lacote, E.;
(11) For radical alkoxycarbonylation of aryl iodides, see: Zhang, H.; Shi,
R.; Ding, A.; Lu, L.; Chen, B.; Lei, A. Angew. Chem., Int. Ed. 2012,51, 12542.
^
Malacria, M.; Curran, D. P. Org. Biomol. Chem. 2011, 9, 3415.
(9) For thiol catalyzed radical dehaloganation reaction, see: Pan, X.;
(12) (a) Horn, M.; Mayr, H.; Lacote, E.; Merling, E.; Deaner, J.;
Wells, S.; McFadden, T.; Curran, D. P. Org. Lett. 2012, 14, 82. (b)
Taniguchi, T.; Curran, D. P. Org. Lett. 2012, 14, 4540.
(13) Lindsay, D. M.; McArthur, D. Chem. Commun. 2010, 46, 2474.
ꢀ
(14) Monot, J.; Solovyev, A.; Bonin-Dubarle, H.; Derat, E.; Curran,
^
ꢀ
Lacote, E.; Lalevee, J.; Curran, D. P. J. Am. Chem. Soc. 2012, 134, 5669.
(10) For estimated rate constants for hydrogen abstraction from N-
heterocyclic carbene borane complexes by an alkyl radical, see: Solo-
vyev, A.; Ueng, S.-H.; Monot, J.; Fensterbank, L.; Malacria, M.;
^
D. P.; Robert, M.; Fensterbank, L.; Malacria, M.; Lacote, E. Angew.
^
Lacote, E.; Curran, D. P. Org. Lett. 2010, 12, 2998.
Chem., Int. Ed. 2010, 49, 9166.
Org. Lett., Vol. 15, No. 9, 2013
2145

discussed earlier,3 the precursors of 4 are the correspond-
ing aldehydes formed by H-abstraction from 2 by acyl
radicals. According to Curran’s12 and Lindsay’s13 work,
however, NHC-boranes are able to reduce aldehydes and
ketones in the presence of SiO2 or Lewis acids. As a control
reaction we took 4-anisaldehyde (6d) and reacted it with 2
at 80 °C. After 1 h, no reduction was observed (Scheme 2).
In a separate experiment, an acetonitrile solution of 0.75
equiv of I2 and 1.5 equiv of 2 was treated with 6d. This
caused the rapid disappearance of 6d over 1 h, and 4d was
isolated in 97% yield after flash column chromatography
on silica gel. This leads us to suggest that the iodinated
NHC-borane 714 may act as an effective aldehyde reducing
agent, but not the NHC-borane itself.
Table 2. Hydroxymethylation of a Variety of Aryl Iodidesa
Scheme 2. Reduction of 4-Anisaldehyde (6d)
The proposed mechanism is shown in Scheme 3. Radical
initiation of aryl iodide leads to generation of the aryl
radical A. A could then add to CO to form the correspond-
ing acyl radical B, which could further abstract hydrogen
from diMeImd-BH3 (2) to give an aldehyde 6 and the
borane radical anion C. Subsequent iodine abstraction
from 3 returns A and iodinated NHC 7, thus completing
the radical chain. Alcohol 4 is formed by hydride reduction
of aldehyde 6 by 7.
Scheme 3. Possible Reaction Mechanism
a Conditions: ArI (0.5 mmol), 2 (0.75 mmol), AIBN (0.1 mmol), CO
(80 atm), 80 °C, 4 h. b Isolated yield after flash column chromatography
on silica gel. c Reaction performed for 8 h. d CO (150 atm). e 3m was
recovered in 31% yield.
We then examined a three-component reaction leading
to unsymmetrical ketones using 2. When a mixture of
2146
Org. Lett., Vol. 15, No. 9, 2013

carried out using CO as a C1 source and diMeImd-BH3 (2)
as a radical mediator. Control experiments suggest that 2
serves as a hydrogen donor to acyl radicals and iodinated
NHC 7, formed by the radical generation process from
iodoarene 3, and serves as the in situ generated hydride
donor to the aldehydes, giving the corresponding alcohol
4. The NHC-borane mediated reaction system can also be
applied to one-pot three-component coupling reactions
leading to unsymmetrical ketones.
Scheme 4. NHC-Borane Mediated Three Component Reaction of
4-Iodoanisole (3d), CO, and Ethyl Acrylate or Ethyl Vinyl Ketone
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, and Technology (MEXT),
Japan. T.K. acknowledges the Research Fellowship of the
Japan Society for the Promotion of Science for Young
Scientists (No. 249927). D.P.C. thanks the US NSF for
funding and OPU for the visiting professorship.
4-iodoanisole (3d), CO, and ethyl acrylate (2 equiv) with
diMeImd-BH3 (2) was subjected to the radical reaction
conditions, unsymmetrical ketone 8d was obtained in 58%
yield along with small amounts of the direct addition
product and hydroxymethylation product 4d (Scheme 4).
Similarly, the reaction of 3d, CO, and ethyl vinyl ketone
gave 1,4-diketone 9d in 67% yield.
Supporting Information Available. Detailed experimen-
tal procedures and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.
org.
In summary, we have demonstrated that hydroxymethy-
lation reactions of alkyl and aryl iodides are successfully
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 9, 2013
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