Allyl and benzyl iodides by the anomalous action of iodotrimethylsilane

Article abstract of DOI:10.1016/j.bmcl.2006.09.087

Iodotrimethylsilane (TMSI), routinely used for the dealkylation of ethers and esters, has been found to efficiently convert allyl and benzyl phosphotriesters into the corresponding iodides under mild, Bronsted-neutral conditions. In contrast, alkyl and aryl phosphotriesters were dealkylated to the corresponding phosphates under identical conditions.

Full text of DOI:10.1016/j.bmcl.2006.09.087

Bioorganic & Medicinal Chemistry Letters 16 (2006) 6170–6172
Allyl and benzyl iodides by the anomalous
action of iodotrimethylsilane
Qing Zhua,* and Matthew S. Tremblayb
aInstitute of Bioengineering, Zhejiang University of Technology, Hangzhou, Zhejiang Province 310014, PR China
bDepartment of Chemistry, Columbia University, New York, NY 10027, USA
Received 31 July 2006; revised 11 September 2006; accepted 14 September 2006
Available online 1 October 2006
Abstract—Iodotrimethylsilane (TMSI), routinely used for the dealkylation of ethers and esters, has been found to efficiently convert
allyl and benzyl phosphotriesters into the corresponding iodides under mild, Brønsted-neutral conditions. In contrast, alkyl and aryl
phosphotriesters were dealkylated to the corresponding phosphates under identical conditions.
Ó 2006 Elsevier Ltd. All rights reserved.
Phosphate esters are ubiquitous in many classes of bio-
molecules1 and natural products.2 Accordingly, methods
for the preparation and synthetic manipulation of phos-
phate esters are necessary for us to study and control
the important biological processes in which they partici-
pate.3 Typical synthetic routes to phosphate esters pro-
ceed through the unsymmmetrical phosphotriester,
which can be selectively dealkylated to give the desired
phosphate ester. Organosilicon reagents, such as iodotri-
methylsilane (TMSI)4, are often the reagent of choice,
since they usually dealkylate phosphotriesters efficiently
under mild, Brønsted-neutral conditions (Scheme 1A).
The relatively high Lewis acidity of the silicon and the
strong nucleophilicity of iodide make TMSI a competent
reagent for cleaving oxygen containing groups, such as es-
ters, lactones, ethers, ketals, and carbamates, as well as for
the conversion of alcohols and sulfoxides to iodides and
sulfides, respectively.5 During the course of our research
related to the synthesis of biologically relevant phosphate
esters,6 we observed the unexpected conversion of allyl
and benzyl diethylphosphotriesters to the corresponding
iodide in high yield and purity when exposed to standard
cleavage conditions with TMSI (Scheme 1B).
A
B
Scheme 1. The anomalous action of iodotrimethylsilane.
iodination under a variety of conditions (Table 1). A
typical procedure involved addition of TMSI (1–4
equiv) to a room temperature solution of the phospho-
triester in CH3CN. After 20 min, aqueous workup gave
the corresponding iodide in 78–95% yield as assessed by
GC, with isolated yields ranging from 45% to 89%
(Table 1, entries 1–4). Four equivalents of TMSI gave
the best yield. The reaction also proceeded in other sol-
vents, although none proved to be better than CH3CN
(Table 1, entries 5–8).
Given the importance of phosphate esters and the seem-
ing prevalence of TMSI as a key reagent in their synthe-
sis, we thought it prudent to examine this anomalous
Keywords: Phosphates; Protecting groups; Iodotrimethylsilane; Allyl
iodides; Benzyl iodides.
*
The substrate scope of this anomalous iodination was
explored with a variety of allyl diethylphosphates under
Corresponding author. Tel.: +86 571 88320781; fax: +86 579 8832
0781; e-mail: chmzhuq@hotmail.com
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.09.087

Q. Zhu, M. S. Tremblay / Bioorg. Med. Chem. Lett. 16 (2006) 6170–6172
Table 3. Iodination of benzylic phosphate estersa
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Table 1. Optimization of the reaction conditions
Entry
R
R0
Yield Ab
(yield B)c
Entry
Solvent
TMSI (eqs)
Yield Aa (Yield B)b
1
2
3
4
5
6
7
8
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
DMSO
Hexane
Benzene
1
2
3
4
4
4
4
4
45(78)
79(90)
87(95)
89(95)
86(95)
46(70)
20(40)
60(75)
1
2
3
4
5
6
H
H
83(90)
64(90)
82(95)
95(95)
93(95)
81(90)
4-NO2
4-Br
3-CH3
4-Cl
H
H
H
H
H
CH3
a All reactions were performed at room temperature with four equa-
tions TMSI for 20 min.
b Isolated yield.
c GC purity without purification.
a isolated yield.
b GC yield.
Table 2. Iodination of allylic phosphate estersa
Entry
R
R0
Yield Ab (yield B)c
1
2
Ph
OP(O)(OEt)2 89(95)
OP(O)(OEt)2 78(95)
OP(O)(OEt)2 82(90)
OP(O)(OEt)2 94(95)
OP(O)(OEt)2 92(95)
OP(O)(OEt)2 90(95)
OP(O)(OEt)2 94(95)
2-NO2C6H4
4-CH3OC6H4
4-CH3C6H4
2-CH3C6H4
4-ClC6H4
4-CNC6H4
3
4
5
6
7
8
2,4-di-MEOC6H3 OP(O)(OEt)2 n.p.d
9
10
CH3
Ph
OP(O)(OEt)2 68(95)
OMs
n.r.e
Scheme 2. The proposed mechanism for the iodination.
a All reactions were performed at room temperature with four equa-
tions TMSI for 20 min.
b Isolated yield.
c GC purity without purification.
d No desired product.
A proposed mechanism for the iodination is shown in
Scheme 2. Formation of a trimethylsiloxy species acti-
vates the phosphorus center for dealkylation. Iodide
ion reacts with this intermediate at the allylic/benzylic
carbon, resulting in dealkylation of the phosphotriester
and formation of the allyl/benzyl iodide.
e No reaction.
the optimized conditions. Several cinnamyl diethylphos-
phates substituted with both electron-releasing and elec-
tron-withdrawing were efficiently converted to the
iodide (Table 2, entries 1–7). A notable exception was
2,4-dimethoxycinnamyl diethylphosphate (Table 2, en-
try 8): no product was formed and decomposition of
the substrate was observed, most likely due to instability
of the electron-rich arene to TMSI.7 Crotyl diethylphos-
phate also served as a competent substrate for the iodin-
ation, although in lower isolated yield (Table 2, entry 9).
It should be noted that cinnamyl mesylate did not form
the corresponding iodide, with no conversion of the
starting material being observed after exposure to the
reaction conditions (Table 2, entry 10).
In conclusion, we found that the action of TMSI
upon allyl/benzyl diethylphosphates was efficient iodin-
ation of the allyl/benzyl moiety, rather than dealkyla-
tive formation of the allyl/benzyl phosphates. Aside
from being a notably high yielding ‘side reaction,’ this
procedure may actually be useful for the preparation
of allyl/benzyl iodides in certain contexts, since the
conditions reported herein are milder than other
known methods.9
Acknowledgments
A number of substituted benzyl diethylphosphates were
also converted to the corresponding iodides upon
exposure to TMSI at room temperature in CH3CN
(Table 3)8. Electron-rich and electron-deficient benzyl
diethyl phosphates were all converted to the iodides in
excellent yield (Table 3, entries 1–5), and a methyl substi-
tuent in the D-position was tolerated (Table 3, entry 6).
This work was financially supported by the project
sponsored by the Scientific Research Foundation for
the Returned Overseas Chinese Scholars Fund, Zhejiang
Province (No. Z01105002), and Scientific Research
Foundation from Zhejiang University of Technology
(No. 105002329).

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Q. Zhu, M. S. Tremblay / Bioorg. Med. Chem. Lett. 16 (2006) 6170–6172
6. Tremblay, M. S.; Zhu, Q.; Marti, A. A.; Dyer, J.; Halim,
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