SnCl2/KI-mediated allylation reactions of formaldehyde in water

Article abstract of DOI:10.1055/s-0030-1260757

An efficient procedure for SnCl₂/KI-mediated allylation reactions of formaldehyde with a variety of allylic bromides in aqueous solution is reported. Under conditions developed in this effort, various homoallylic alcohols and 2-halohomoallylic alcohols are produced in good to excellent yields. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1260757

LETTER
1871
SnCl2/KI-Mediated Allylation Reactions of Formaldehyde in Water
Allylation Reactions
o
e
Formaldeh
i
yde in
-
W
ater Huey Lin,* Long-Zhi Lin, Tsung-Hsun Chuang
Department of Chemistry, National Changhua University of Education, Changhua, Taiwan
Fax +886(4)7211190; E-mail: mhlin@cc.ncue.edu.tw
Received 11 April 2011
Dedicated to Professor Jim-Min Fang on the occasion of his 60th birthday
used in Lewis acid catalyzed allylation reactions in organ-
ic media. Furthermore, typical thermal cracking of
paraformaldehyde to generate formaldehyde monomer is
a tedious procedure. Since one could employ commercial
aqueous solutions of formaldehyde, metal-mediated Bar-
bier-type allylation reactions of formaldehyde would
serve as a facile method to prepare functionalized homoal-
lylic alcohols 1.
Abstract: An efficient procedure for SnCl2/KI-mediated allylation
reactions of formaldehyde with a variety of allylic bromides in
aqueous solution is reported. Under conditions developed in this ef-
fort, various homoallylic alcohols and 2-halohomoallylic alcohols
are produced in good to excellent yields.
Key words: SnCl2/KI-mediated allylation reactions, aqueous solu-
tion, formaldehyde, homoallylic alcohols, 2-halohomoallylic alco-
hols
O
1) TBDPSCl, imidazole
2) DIBAL-H
Formaldehyde is an excellent electrophile for one-carbon
elongation of organic substances. However, the intrinsic
propensity of formaldehyde monomer to undergo poly-
merization dramatically limits its synthetic utility. As a re-
sult, novel procedures have been developed to suppress
polymerization either by using a stable formaldehyde–
organoaluminum complex or by generating this substance
in situ through the conversion of methanol to formalde-
hyde or hydrolysis of the Eschenmoser’s salt.1 However,
carbon–carbon bond-forming reactions with formalde-
hyde remain a great challenge.
(1)
RO
Br
HO
OMe
3) Me(CO)CHN2P(O)(OMe)2,
NaOMe
Me
Me
4) 9-Br-9-BBN, HOAc
R = TBDPS
I
ref. 2a
1) TMSCl, NaI
2) ArCO2H, NaHCO3
HO
(2)
3) ClPO(OEt)2
4) AlMe3, cat. CuBr
Ar
O
OH
O
ref. 2b
Scheme 1 Multistep synthesis of 2-halohomoallylic alcohols
Halohomoallylic alcohols 1a,b, which are comprised of
C5 units with isoprene-type skeletons, have been em-
ployed as useful building blocks in organic syntheses.2 In
addition, these substances could find additional applica-
tions in organic synthesis owing to their possible partici-
pation in transition-metal-catalyzed cross-coupling
reactions that serve as powerful methods for C–C bond
formation.3 However, the preparation of halohomoallylic
alcohols 1a and 1b typically employs multistep routes
starting with methyl 3-hydroxy-2-methylpropanoate or
other equally complicated pathways (Scheme 1, equations
1 and 2).
X
X
O
+
Br
OH
H
H
1a, X = Br
1b, X = I
2
Scheme 2 Straightforward synthesis of 2-halohomoallylic alcohols
To the best of our knowledge, only scattered reports de-
scribe the metal-mediated allylation reactions of formal-
dehyde in aqueous media using Sn or Zn,7 Sn/Al,8 Sn/
InCl3,9 and In.10 However, in these processes only simple
allylic halides were used. Our investigations aimed at the
development of metal-mediated allylation and 2-haloally-
lation reactions of formaldehyde using water as the sol-
vent.11
We envisioned that a straightforward procedure for the
synthesis of halohomoallylic alcohols 1 would involve the
addition of an appropriate allylic organometallic reagent
to formaldehyde (Scheme 2). Although metal-mediated 2-
haloallylation of aldehydes can be promoted by using B/
Sn,4 Sn/HBr,5 and Fe/Cr,6 2-haloallylation of formalde-
hyde has not been reported to date. The conditions em-
ployed for B/Sn- and Fe/Cr-mediated 2-haloallylation of
aldehydes involve the use of nonaqueous solvents and an
inert atmosphere. Thus, the intrinsic polymerization reac-
tivity of monomeric formaldehyde prevents it from being
Tin and tin-containing Lewis acids have been extensively
used in organic chemistry owing to their low cost, com-
mercial availability, and modestly low toxicities.12 Our ef-
fort began with an investigation of tin-mediated 2-
iodoallylation reactions of formaldehyde (commercial
aqueous solution) with allylic bromide 2b in aqueous so-
lution employing a variety of in situ generated allylstan-
nane sources.13 The results of this preliminary exploratory
effort showed that SnCl2 and KI are the optimal combina-
tion for promoting metal-mediated 2-haloallylation of
SYNLETT 2011, No. 13, pp 1871–1874
x
x
.x
x
.2
0
1
1
Advanced online publication: 21.06.2011
DOI: 10.1055/s-0030-1260757; Art ID: W09111ST
© Georg Thieme Verlag Stuttgart · New York

1872
M.-H. Lin et al.
LETTER
Table 1 SnCl2/KI-Mediated Allylation Reactions of Formaldehyde in Water16
R3
R3
O
OMe
OMe
SnCl2, KI
H2O, r.t.
Br
R1
+
or
OH
H
H
R1 R2
H
H
R2
2
1
Entry
1
Allylic bromide
Product
Yield (%) from HCHO (aq) Yield (%) from CH2(OMe)2
Br
Br
Br
92a
89
OH
2a
1a
1b
I
I
2c
3
88
86
Br
OH
OH
2b
Br
64b
56b
1c
O
2c
O
CO2Me
Br
4
94
71
2d
1d
HO
Ph
Br
5d
96
67
82
55
Ph
2e
1e
Br
OH
6
1f
2f
Br
Br
I
7
8
86b
85b
87b
87b
Br
Br
OH
OH
OH
2g
2h
1g
1h
I
I
I
9e
99
83
Br
BzO
OBz
2i
1i
I
I
10e
11
91
96
43
83
OH
OPh
Br
PhO
2j
1j
Ph
Ph
Br
OH
2k
1k
a The product was isolated as the corresponding OBz derivative.
b The product was isolated as the corresponding OTHP derivative.
c Compound 1b (61%) was obtained when paraformaldehyde was used.
d Compound 1e (72%) was obtained when paraformaldehyde was used.
e The reaction was carried in THF–H2O (1 mL each) for 43 h.
Synlett 2011, No. 13, 1871–1874 © Thieme Stuttgart · New York

LETTER
Allylation Reactions of Formaldehyde in Water
1873
formaldehyde in water. Several examples that use stannic zoate derivative. Importantly, impurities arising from side
chloride to promote allylation reactions of aldehydes, ac- reactions were only produced when sluggishly reacting
etals, and enol ethers in aqueous media have been de- substrates were employed (Table 1, entries 1 and 2).
scribed.14
These observations prompted an examination of other
Other processes showed that either none of the desired formaldehyde sources. As mentioned earlier, stannic
product 1b was formed or the yields were low, and signif- chloride has been successively used to promote allylation
icant amounts of unidentified products were produced. reactions of acetals in aqueous media.14b,c Therefore,
The results of allylation reactions of formaldehyde medi- paraformaldehyde and dimethoxymethane were em-
ated by SnCl2 and KI in water are presented in Table 1. In ployed as formaldehyde equivalents in the processes ex-
the cases where volatile homoallylic alcohol products plored in the current effort. As the results given in Table 2
were generated, the yields were determined by transfor- show, the best yield was obtained using an aqueous solu-
mation of these substances to less volatile derivatives (see tion of formaldehyde. The yields were significantly lower
Table 1). As can be seen by viewing the results, the 2-ha- when paraformaldehyde was employed. Importantly,
loallylation reactions of formaldehyde proceeded smooth- however, was the observation that pure iodohomoallylic
ly in good to excellent yields (Table 1, entries 1, 2, 7–10). alcohol 1b was produced after chromatography of the
The yields were lower when sterically hindered (e.g., 3,3- product mixture arising from the reaction in which
dimethylallyl bromide, Table 1, entry 3) and rigid (e.g., 3- dimethoxymethane was employed as the formaldehyde
bromocyclohexene, Table 1, entry 6) substrates were em- equivalent (Table 2, entry 6).
ployed.
Table 2 Screening of Formaldehyde Sources
In contrast to the reactions described above, allylation of
formaldehyde with an allylic gallium reagent derived
from 2c was observed to occur in a relatively poor yield
(21%).15 Interestingly, lactone 1d was formed exclusively
and in excellent yield when ester 2d was employed as the
substrate (Table 1, entry 4). This finding is in contrast to
other examples reported previously.8,10 Lactone formation
also occurred when a long-chain aliphatic aldehyde was
utilized in this process (Scheme 3, equation 3). Also note-
worthy were observations which showed that cinnamyl
bromide reacted to give the formaldehyde adduct 1e
(Table 1, entry 5) and that a high chemoselectivity favor-
ing formaldehyde was observed when the reaction mix-
ture contained an excess amount of acetone (Scheme 3,
equation 4).
Entry
1
Allyl bromide
HCHO equivalent
formalin
Yield (%)
96
Ph
Br
2e
2e
2
3
paraformaldehyde
MeOCH2OMe
72
82
2e
I
4
formalin
88a
Br
2b
2b
5
6
paraformaldehyde
MeOCH2OMe
61a
86
2b
a The product was mixed with an impurity which is difficult to sepa-
rate.
O
O
CO2Me
Br
SnCl2, KI
H2O
C8H17
The results of a study exploring the scope of SnCl2/KI-
mediated allylation and 2-haloallylation reactions of
dimethoxymethane in water are summarized in Table 1.
In general, the same trends are followed in the processes
in which dimethoxymethane and an aqueous solution of
formaldehyde was used. However, the yields of the reac-
tion employing g-substituted allylic bromides and
dimethoxymethane were significantly lower than when
aqueous solutions of formaldehyde were used (Table 1,
entries 4, 5, 9, and 10).
(3)
+
83%
O
OH CO2Me
C8H17CHO
O
SnCl2
H2O
C8H17
+
C8H17
39%
42%
OH
O
H
SnCl2, KI
acetone (2 mL)
+
(4)
Ph
Br
H
Ph
97%
In summary, we report here the first examples of 2-haloal-
lylation reactions of formaldehyde taking place in aque-
ous solution. The process serves as a new, simple,
inexpensive, and environmentally friendly methodology
for the preparation of homoallylic alcohols 1.
Scheme 3
It was important to note that halohomoallylic alcohol
products 1a,b, prepared by using commercial aqueous so-
lution of formaldehyde, were contaminated with minor
impurities that were difficult to separate by chromatogra-
phy. However, in the case of 1a, the impurity could be
removed by transformation of the alcohol group to its ben-
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2011, No. 13, 1871–1874 © Thieme Stuttgart · New York

1874
M.-H. Lin et al.
LETTER
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Acknowledgment
Financial support from the National Science Council of the Repu-
blic of China, Taiwan (NSC98-2119-M-018-001 and NSC99-2119-
M-018-001) and National Changhua University of Education is gra-
tefully acknowledged.
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Synlett 2011, No. 13, 1871–1874 © Thieme Stuttgart · New York