Dehydroxymethylation: an unusual reverse reaction of nucleophilic addition to formaldehyde

Article abstract of DOI:10.1016/j.tetlet.2006.09.017

An unusual dehydroxymethylation has been observed in an acyclic primary alcoholic system. The relief of steric congestion is considered as the primary driving force in this reaction.

Full text of DOI:10.1016/j.tetlet.2006.09.017

Tetrahedron Letters 47 (2006) 8175–8178
Dehydroxymethylation: an unusual reverse reaction of
nucleophilic addition to formaldehyde
Lingling Peng, Ming Ma, Xiu Zhang, Shiwei Zhang and Jianbo Wang*
Beijing National Laboratory of Molecular Sciences (BNLMS), Green Chemistry Center (GCC) and Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University,
Beijing 100871, PR China
Received 17 June 2006; revised 2 September 2006; accepted 5 September 2006
Available online 25 September 2006
Abstract—An unusual dehydroxymethylation has been observed in an acyclic primary alcoholic system. The relief of steric conges-
tion is considered as the primary driving force in this reaction.
Ó 2006 Elsevier Ltd. All rights reserved.
The nucleophilic additions of carbon nucleophiles to
aldehydes or ketones are highly favourable processes.
Nucleophilic addition of carbon anion to a carbonyl
group is normally exothermic. This is attributed to the
high reactivity of carbon anion. Moreover, thermo-
dynamically stable products are generated in this
reaction. As a result, the reverse process, b-cleavage of
alkoxy anion, is rare. The b-cleavage of alkoxy anion be-
comes a facile process mainly in a ring-fused system, in
which the hydroxyl group is positioned at a bridgehead.
The driving force for this process is obviously the relief
of the fused-ring strain. This type of b-cleavage has been
successfully utilized in the synthesis of medium- to large-
sized rings.1 In this letter, we report an unusual alkoxy
anion b-cleavage in a non-cyclic system.
1a, Ar = 4-BrC6H4, Ar' = 2-ClC6H4
1b, Ar = 3,4-Cl2C6H3, Ar' = 2-ClC6H4
1c, Ar = 4-NO2C6H4, Ar' = 2-ClC6H4
1d, Ar = 3-MeC6H4, Ar' = 2-ClC6H4
1e, Ar = C6H5, Ar' = 2-ClC6H4
1f, Ar = 4-ClC6H4, Ar' = C6H5
1g, Ar = 3-ClC6H4, Ar' = C6H5
1h, Ar = 4-MeOC6H4, Ar' = C6H5
Ar
Ar'
OH
S
, Ar' = C6H5
1j, Ar = C6H5, Ar' = C6H5
1i, Ar =
S
3a, in which the hydroxymethyl group was lost (Scheme
1). The structure of 3a was further confirmed by X-ray
crystallography analysis, as shown in Figure 1.
This dehydroxymethylation was found to be general for
sulfones 2b–j. As shown in Table 1, the oxidation of 1b–j
with mCPBA gave sulfones 2b–j in high yields, subse-
quent treatment of 2b–j with sodium hydride in THF
afforded dehydroxymethylation products in moderate
to good yields. The substituent on the Ar group was
found to have no influence on the reaction. As shown
by entries 2 and 7, both the electron-withdrawing NO2
group and electron-donating OMe group gave dehydr-
oxymethylation products in similar yields.
+
O
HCHO
In connection with our study on stereoselective [2,3] r
rearrangement of sulfur ylides generated from metal car-
bene and allyl sulfides, a series of tertiary sulfides 1a–j
was prepared.2
Oxidation of the sulfides 1a with mCPBA gave sulfone
2a. When sulfone 2a was treated with sodium hydride,
a new product was isolated. Inspection of the spectral
data suggested that the structure of this product was
The extrusion of hydroxymethyl group from 2a is
surprising.4 A mechanism is proposed for this process.
Upon treatment with sodium hydride, the alkoxy anion
A is first generated and then followed by the b-cleavage
of C–C bond to afford 3a after protonation. The carbon
Keywords: Dehydroxymethylation; Retro-aldol reaction; Primary alco-
hol; Formaldehyde.
*
Corresponding author. E-mail: wangjb@pku.edu.cn
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.017

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L. Peng et al. / Tetrahedron Letters 47 (2006) 8175–8178
Br
Br
Br
NaH
m
CPBA
2a
1a
OH
THF, r.t.
O
CH2Cl2
r.t., 20 min
S
S
S
O
O
O
O
O
O
HCHO
H2O
Cl
Cl
Cl
B
2a
A
Br
Br
3a
NaH
S
THF, r.t.
H
O
S
O
Cl
O
O
Cl
C
3a
Scheme 1. Oxidation and reaction of 1a with NaH.
Scheme 2. Proposed reaction mechanism for the dehydroxymethyl-
ation.
PhCH2NH2
OH NaH
THF, r.t.
MgSO4
S
O
3j
r.t., 20 h
O
+
2j
N
N
N
48 %
4
Scheme 3. Formaldehyde-trapping experiments with 2e.
Figure 1. X-ray structure of 3a.
To confirm the extrusion of formaldehyde, the reaction
of 2j with NaH was carried out, and then the reaction
mixture was treated with benzylamine (Scheme 3). The
reaction gave 3j, together with 4, which was derived
from the reaction of formaldehyde with benzylamine.5
The isolation of 4 is a conclusive evidence to support
the extrusion of formaldehyde.
Table 1. Oxidation of 1b–j and subsequent reaction with NaH3
Ar
Ar
Ar'
OH
NaH
Ar'
m
CPBA
S
H
S
O
1b~j
O
O
THF, r.t.
3-5 h
CH2Cl2
O
r.t., 20 min
2b~j
3b~j
In order to gain insights into the effects of the structure
on this reaction, alcohols 1a and 5–11 were subjected to
identical conditions with NaH in THF (Scheme 4). First,
no reaction occurred for 1a under the same conditions.
Compound 5, in which the aryl group on the carbon is
replaced with methyl, was found to give an aromatic
substitution product 11. No dehydroxymethylation
product was identified. If the chloro substituent on the
sulfonyl aromatic ring is removed, no dehydroxymethyl-
ation occurred under the same conditions, as shown by
6. Interestingly, compound 7, in which the methyl group
has been replaced by hydrogen, gave a diene derivative
12 in 71% yield. On the other hand, when phenylsulfonyl
substrate 8 was subjected to NaH/THF, the dehydr-
oxymethylation product 13 was isolated in 81% yield.
However, when the substituent on sulfur is changed to
o-chlorobenzyl group, no dehydroxylation product
could be observed, as shown by the example of 10.
Entry
Sulfide 1 (Ar@, Ar0@)
Product 3
Yielda (%)
1
2
3
4
5
6
7
1b, 3,4-Cl2C6H3, 2-ClC6H4
1c, 4-NO2C6H4, 2-ClC6H4
1d, 3-MeC6H4, 2-ClC6H4
1e, C6H5, 2-ClC6H4
1f, 4-ClC6H4, C6H5
1g, 3-ClC6H4, C6H5
3b
3c
3d
3e
3f
81
83
75
82
65
53
62
3g
3h
1h, 4-MeOC6H4, C6H5
8
9
1i,
, C6H5
3i
3j
79
70
S
1j, C6H5, C6H5
a Isolated yields for the two steps combined.
anion B is stabilized by the strong electron-withdrawing
sulfonyl group and the aromatic substituent, as shown
by its resonance structure of C (Scheme 2).

L. Peng et al. / Tetrahedron Letters 47 (2006) 8175–8178
8177
or allyl bromide. However, only dehydroxymethylation
product 3a could be isolated. The expected product 14
or 15 was not observed (Scheme 5).
Br
NaH
These experiments demonstrate the remarkable influ-
ence of the structure on this unusual dehydroxymethyl-
ation reaction. The results suggest that the reaction is
very sensitive to steric congestion around the reaction
site, as demonstrated by the reactions of 8 and 9. The re-
lief of steric congestion seems to be a major driving force
for the dehydroxylmethylation. On the other hand, elec-
tronic effect is also critical for the reaction. A strong
electron withdrawing group is required to stabilize the
carbon anion. The aromatic substituent is also impor-
tant in stablizing the anion, as shown by the reactions
of 5 and 6.
OH
1a recovered
S
THF, r.t.
CH3
Cl
1a
CH3
O
CH3
O
OH
NaH
S
S
THF, r.t.
O
O
O
O
Cl
5
11
CH3
NaH
OH
OH
S
6 recovered
THF, r.t.
O
In conclusion, we have observed an unusual dehydroxy-
methylation reaction. This unusual reaction suggests
that the steric congestion and electronic effect may work
together to reverse the equilibrium of carbon anion
addition to carbonyl group, although the latter is
usually a highly favourable process.
6
H
NaH
S
S
THF, r.t.
71 %
O
O
Cl
O
O
O
Cl
12
7
Acknowledgements
NaH
OH
This project was generously supported by the Natural
Science Foundation of China (Grant No. 20572002,
20521202, 20225205, 20390050) and the Ministry of
Education of China (Cheung Kong Scholars Program).
THF, r.t.
81 %
S
S
H
CH3
CH3
O
O
O
O
8
13
NaH
OH
References and notes
9 recovered
S
THF, r.t.
H
O
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3. General procedure for oxidation and subsequent reaction
with NaH. Sulfides 1 (0.5 mmol) and mCPBA (1.5 mmol)
were mixed in CH2Cl2 at room temperature. After about
0.5 h, 1 disappeared as judged by TLC. Then saturated
NaHSO3 was added and the mixture was extracted with
CH2Cl2, the organic layers were washed by saturated
NaHCO3 and dried over Na2SO4. Removal of the solvent
in vacuo gave 2. Under a nitrogen atmosphere, 2 and NaH
(0.6 mmol) were mixed in THF at room temperature. When
2 disappeared as judged by TLC, saturated NH4Cl was
added. After removal of THF in vacuo the mixture was
extracted with CH2Cl2. The combined organic layers were
dried over Na2SO4 and evaporated, and the residue was
purified by silica gel column, eluted with petroleum ether/
acetone (30:1) to afford 3.
9
Cl
CH3
OH
NaH
S
10 recovered
O
O
THF, r.t.
10
Scheme 4. Reaction of alcohols 5–10 with NaH in THF.
NaH
MeI
or
2a
3a
THF, r.t.
Br
Br
Br
or
S
O
S
O
Cl
O
O
Cl
14
15
not observed
Scheme 5. Attempted trapping of intermediate anion.
Finally, with alcohol 2a as the substrate we tried to trap
the intermediate anion by the addition of methyl iodide
4. Transition metal-catalyzed dehydroxymethylation of acy-
clic alcohol has been known, see: (a) Ishige, M.; Sakai, K.;

8178
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