Hypophosphorous acid-iodine: A novel reducing system. Part 1: Reduction of diaryl ketones to diaryl methylene derivatives

Article abstract of DOI:10.1016/S0040-4039(00)01359-9

A mixture of hypophosphorous acid (H₃PO₂) and iodine in hot acetic acid reduces diaryl ketones quickly and aryl alkyl ketones slowly to the corresponding methylene derivatives. The active reducing agent is hydrogen iodide, generated by reaction between iodine and hypophosphorous acid. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01359-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7817–7820
Hypophosphorous acid–iodine: a novel reducing system.
Part 1: Reduction of diaryl ketones to diaryl methylene
derivatives
Latorya D. Hicks, Ja Kyung Han and Albert J. Fry*
Chemistry Department, Wesleyan University, Middletown, CT 06459, USA
Received 28 June 2000; accepted 1 August 2000
Abstract
A mixture of hypophosphorous acid (H3PO2) and iodine in hot acetic acid reduces diaryl ketones
quickly and aryl alkyl ketones slowly to the corresponding methylene derivatives. The active reducing
agent is hydrogen iodide, generated by reaction between iodine and hypophosphorous acid. © 2000
Elsevier Science Ltd. All rights reserved.
Hypophosphorous acid (H3PO2), although often used for the reductive deazoniation of
aryldiazonium ions (ARN2+“ArH+N2),1 has only rarely been used as a synthetic reagent in
organic chemistry.2–4 We have found that a mixture of hypophosphorous acid and a catalytic
amount of iodine in refluxing acetic acid converts diaryl ketones to the corresponding diaryl-
methylenes (Eq. (1)) in high yield (Table 1). Diaryl ketones are reduced considerably faster than
arylalkyl ketones (compare runs 1 or 2 with runs 11 and 14). The latter are in turn reduced
much faster than dialkyl ketones; in fact, cyclohexanone undergoes self-aldol condensation
under the reaction conditions faster than it can be reduced to cyclohexane (run 13). Benzalde-
hyde undergoes the known adduct formation of H3PO2 with aldehydes (run 12).5 4-Bromo-
benzophenone is readily reduced without hydrogenolysis of the bromine atom (run 3). Reduc-
tion of 4-hydroxybenzophenone proceeds readily, except that the product is partially esterified
under the reaction conditions (run 8). Interestingly, this reagent system also readily reduces the
carbonꢀcarbon bond of a,b-unsaturated ketones: the carbonꢀcarbon double bond of benzalaceto-
phenone (1) is quickly reduced, affording dihydro derivative 2, which then undergoes slow
reduction of its carbonyl group (run 14). Dibenzosuberenone (6), in which the double bond
H PO
ArCOAr% ꢀꢀꢀꢀ3ꢀꢀꢀꢀꢀꢁ ArCH2Ar%
(1)
2
I
(cat.)
2
97ꢀ100%
HOAC, reflux
* Corresponding author. E-mail: afry@wesleyan.edu
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01359-9

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Run
Table 1
Reduction of carbonyl compounds with hypophosphorous acid–iodine in refluxing acetic acid
Ketone
Product(s), yielda
1
2
Fluorenone
Benzophenone
Fluorene, 99%
Diphenylmethane, 100%
3
4
5
4-Bromobenzophenone
3,4-Dimethylbenzophenone
Dibenzosuberone (3)
Dibenzosuberenone (6)
Dibenzosuberenone (6)
4-Hydroxybenzophenone
1,4-Dibenzoylbenzene
1,4-Dibenzoylbenzene
Acetophenone
4-Bromodiphenylmethane, 97%
3,4-Dimethyldiphenylmethane, 100%
Dibenzosuberane (4), 98%
Dibenzosuberane (4), 35%; dibenzosuberene (5), 64%
Dibenzosuberane (4), 100%
6
7b
8
4-Hydroxydiphenylmethane, 81%; 4-acetoxydiphenylmethane, 19%
1,4-Dibenzylbenzene, 99%
9
10c
11
12
13
14
4-Benzylbenzophenone, 30%; 1,4-dibenzylbenzene, 70%
Ethylbenzene, 11%d
Benzaldehyde
Cyclohexanone
Benzalacetophenone (1)
0% Toluenee
0% Cyclohexanef
2,3-Dihydrobenzalacetophenone (2), 97%; 1,3-diphenylpropane, 3%
a Carbonyl cpd (4 mmol), iodine (0.4 mmol), 50% aq. hypophosphorous acid (19.3 mmol) acetic acid (65 mL) 24
h reflux under N2.
b Extended heating (72 h).
c Reaction carried out in air.
d Plus 89% starting material.
e See text.
f Trimer 7 is produced in 95% yield.
is formally conjugated with the carbonyl group, undergoes reduction of the double bond
competitively with the carbonyl group to produce dibenzosuberane (4) in substantial yield in
competition with simple reduction of the carbonyl group (run 6). Longer heating converts 6 to
4 (run 7). Incomplete reduction in run 10 may be a result of consumption of H3PO2 by reaction
with air. Cyclohexanone underwent double aldol condensation to afford known trimer 76 as a
ca 98:2 mixture of stereoisomers in >95% yield under our standard conditions. We are exploring
this surprising reaction further.
Reductions effected by a mixture containing iodine, an oxidizing agent, are of obvious
mechanistic interest. We believe that the active reducing agent in these reactions is hydrogen
iodide, generated through reduction of iodine by hypophosphorous acid (Scheme 1).7 In this
proposed scheme, hydride transfer from HI to a protonated carbonyl group generates the
secondary alcohol and an ‘I+’ equivalent (e.g. IOAc or similar positive iodine species), which
then combines with iodide to regenerate iodine. Hypophosphorous acid then again reduces

7819
iodine to continue the catalytic cycle; H3PO2 is therefore the ultimate source of reducing
equivalents. However, an iodine source is necessary: we found in a control experiment less than
2% conversion of benzophenone into diphenylmethane when iodine was omitted from the
reaction medium. Hydrogen iodide has previously been shown to reduce aryl carbinols to the
corresponding aralkanes in acidic solution.8 Indeed, we have found that our postulated
intermediate benzhydrol is reduced much faster than benzophenone under our standard
conditions.9
Scheme 1.
Summary. An acetic acid solution of hypophosphorous acid containing a catalytic quantity of
iodine reduces diaryl ketones to the corresponding diarylmethylene compounds (ArCOAr%“
ArCH2Ar%) in close to quantitative yield. This reaction is competitive in terms of yield,
convenience, and general synthetic utility with the traditional processes for this conversion, e.g.
the Wolff–Kishner10 and Clemmensen11 reductions, and with more recent processes such as
reduction by silanes.12,13 Arylalkyl ketones are reduced more slowly, and dialkyl ketones slowest
of all. The carbonꢀcarbon double bond of some a,b-unsaturated ketones such as benzal-
acetophenone (1) is reduced much faster than the carbonyl group by H3PO2ꢀI2; we will report
further on this reaction later because we are still exploring several unusual processes we have
observed with activated alkenes.
Aqueous hydrogen iodide, either alone, in refluxing acetic acid, or with added elemental
phosphorus, has previously been found to reduce quinones, hydroquinones, polycyclic aromatic
phenols, and a few aryl ketones to the corresponding arenes.14 The reactions in Table 1 occur
substantially more slowly when aqueous hydrogen iodide is substituted for iodine. This may
possibly be due to the higher water content of the medium. Finally, the present procedure has
an economic advantage, with hydriodic acid and hypophosphorous acid currently selling for ca
$60/mole and $10/mole, respectively.
Reduction of 4-bromobenzophenone (representative experiment): Iodine (1.00 g, 4.0 mmol) and
acetic acid (50 mL) were stirred together under N2 in a flask fitted with a condenser and a
dropping funnel. Hypophosphorous acid, 50% aq. (2 mL, 19.3 mmol) was added and the
mixture was heated to reflux. A solution of 4-bromobenzophenone (3.18 g, 12.0 mmol) in 15 mL
of acetic acid was added over a period of 1–2 h. The mixture was then stirred and refluxed for
an additional 24 h, cooled, diluted with water and extracted with hexane. The hexane was dried
of MgSO4. Analysis by GC-mass spectrometry showed that the hexane contained only a single
constituent, 4-bromodiphenylmethane. The hexane was concentrated and purified by flash
1
chromatography to afford 4-bromodiphenylmethane15 (2.70 g, 84%); H NMR (300 MHz,
CDCl3: l 3.95 (s, 2H), 7.06–7.43 (m, 9H); mass spectrum: 246, 248 (25, p+); 167 (100, p-Br).

7820
Acknowledgements
Financial support by the National Science Foundation (Grant No. CHE-9713306 to A.J.F.)
is gratefully acknowledged. Ja Kyung Han received a Hughes Foundation Summer Research
Grant.
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