Reductive iodonio-Claisen rearrangement of iodothiophene diacetates with allylsilanes: Formal synthesis of Plavix

Article abstract of DOI:10.1016/j.tetlet.2013.07.138

Iodothiophene diacetates react with allyltrimethylsilanes in the presence of boron trifluoride diethyl etherate to afford corresponding ortho-allyliodothiophenes via reductive iodonio-Claisen rearrangement. This method has been successfully applied to the synthesis of Plavix, a blood clot inhibitor used to reduce the risk of heart attack and stroke.

Full text of DOI:10.1016/j.tetlet.2013.07.138

Tetrahedron Letters 54 (2013) 5464–5466
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reductive iodonio-Claisen rearrangement of iodothiophene
diacetates with allylsilanes: formal synthesis of PlavixÒ
⇑
Hai Nguyen, Hem Raj Khatri, Jianglong Zhu
Department of Chemistry and School of Green Chemistry and Engineering, The University of Toledo, 2801 West Bancroft Street, Toledo, OH 43606, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Iodothiophene diacetates react with allyltrimethylsilanes in the presence of boron trifluoride diethyl
etherate to afford corresponding ortho-allyliodothiophenes via reductive iodonio-Claisen rearrangement.
This method has been successfully applied to the synthesis of PlavixÒ, a blood clot inhibitor used to
reduce the risk of heart attack and stroke.
Received 11 July 2013
Revised 22 July 2013
Accepted 25 July 2013
Available online 2 August 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Hypervalent iodine
Allylation
Claisen rearrangement
Pericyclic reaction
Heterocycles
Hypervalent iodine compounds, including both k3-iodanes1 and
k5-iodanes,2,3 have been extensively employed as oxidants for oxi-
dative transformations due to their unique chemical reactivity and
environmentally benign character.4 In addition to serving as gen-
eral oxidants in organic synthesis, hypervalent iodine(III) com-
pounds (k3-iodanes) were also investigated in reductive iodonio-
Claisen rearrangement (RICR) for preparation of various syntheti-
cally useful building blocks bearing versatile aryliodide functional-
ity. Studies of RICR were pioneered by Ochiai et al., and they found
ortho-propargyliodoarenes can be obtained via RICR from k3-iod-
anes and propargyl silanes, germanes, or stannanes in the presence
of boron trifluoride diethyl etherate (BF3ÁEt2O).5 Their observations
were later reaffirmed by Norton and co-workers.6 Additional evi-
dences were also previously reported on the occurrence of RICR
involving reactions between k3-iodanes and allyltrimethylsilane7
or resorcinol derivatives.8,9
Recently, our laboratory has reported efficient synthesis of com-
plex ortho-allyliodoarenes (2) via reductive iodonio-Claisen rear-
rangement from allylsilane and hypervalent iodine(III)
compounds bearing electron-donating groups in the meta-position
(1) (a, Scheme 1).10 The desired products, ortho-allyliodoarenes (2),
are likely formed via re-aromatization of intermediate 4 which
were in turn obtained by RICR of hypervalent allyl(aryl)iodinanes
3. An electron-donating group at the meta-position was found to
be indispensable in order to favor the [3,3]-sigmatropic rearrange-
ment over reductive elimination.10 Based on this success, we spec-
ulated that heteroaromatic hypervalent iodine(III) compounds
(5),11 especially those electron-rich heteroaromatic k3-iodanes,
may be suitable substrates for this type of pericyclic reaction to
give rise to synthetically useful o-allyl iodoheteroarenes (6) (b,
Scheme 1). Herein, we report the synthesis of o-allyl iodoheteroa-
renes via RICR and their application in the synthesis of a therapeu-
tic agent.
Initially, 2-iodothiophene diacetate (7) was prepared11 and
studied in this type of pericyclic transformation. To our delight,
2-iodothiophene diacetate (7) reacted with allyltrimethylsilane in
IX2
I
(a)
(b)
BF3 Et2O
SiMe3
+
EDG
EDG
R
R
2
1
X
X
I
- HX
I
H
[3,3]
EDG
EDG
R
R
3
4
EDG = electron donating group
I
IX2
Lewis acid
SiMe3
Het
Het
+
this work
5
6
⇑
Corresponding author. Tel.: +1 419 530 1501; fax: +1 419 530 4033.
E-mail address: Jianglong.Zhu@Utoledo.edu (J. Zhu).
Scheme 1. Reductive iodonio-Claisen rearrangement.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.138

H. Nguyen et al. / Tetrahedron Letters 54 (2013) 5464–5466
5465
the presence of BF3ÁEt2O at À50 °C to afford the desired 3-allyl-2-
Me3Si
17
iodothiophene (8) in 93% yield (Scheme 2). Given this encouraging
result, we prepared several heteroaromatic hypervalent iodine(III)
compounds, such as 3-iodothiophene diacetate (9), N-methyl-4-
iodopyrazole diacetate (10), N-benzyl-4-iodopyrazole diacetate
(11), and N-tosyl-4-iodopyrazole diacetate (12).11,12 Subsequent
studies revealed that 3-iodothiophene diacetate (9) reacted with
allyltrimethylsilane in the presence of BF3ÁEt2O at À50 °C to afford
the desired 2-allyl-3-iodothiophene 13 in 97% yield, while its reg-
ioisomeric product, 3-allyl-4-iodothiophene 14, was not observed
in the reaction mixture. This is probably because C2 position of 9
is more electron-rich and nucleophilic than C4, which results in
the selective allylation at C2.10 However, less electron-rich pyra-
zole-derived hypervalent iodine(III) compounds (10–12) only
afforded a trace amount of corresponding desired o-allyliodohete-
roarenes. Major side products including corresponding 4-iodopy-
razoles 15 and 4-allylpyrazoles 16 were formed presumably via
reductive elimination10 and ipso-substitution,5 respectively.
Next, we carried out the reductive iodonio-Claisen rearrange-
ment of 2- and 3-iodothiophene diacetates (7 and 9) with substi-
tuted allylsilanes, such as 2-methallylsilane 17 and prenylsilane
20. As shown in Scheme 3, 2-iodothiophene diacetate (7) reacted
with 2-methallyltrimethylsilane 17 to afford desired product 2-
iodo-3-methallylthiophene 18 in 43% isolated yield, while 3-iodo-
thiophene diacetate (9) reacted with 2-methallyltrimethylsilane
17 to afford desired product 3-iodo-2-methallylthiophene 19 in
38% isolated yield. In addition, 2-iodothiophene diacetate (7) re-
acted with prenyltrimethylsilane 20 to afford desired product 2-
iodo-3-prenylthiophene 21 in 25% isolated yield, while 3-iodothio-
phene diacetate (9) reacted with prenyltrimethylsilane 20 to afford
desired product 3-iodo-2-prenylthiophene 22 in 21% isolated yield.
In all these cases, major side products generated via reductive
elimination or ipso-substitution were observed. These experimen-
tal results indicated that the [3,3] rearrangement pathway may
be suppressed by the sterically hindered allylsilanes due to the ste-
ric effect.10
Me
I(OAc)2
Me
S
BF3 Et2O, CH2Cl2, -50° C, 1 h
S
S
I
I
7
18
19
43% yield
17
Me3Si
I(OAc)2
Me
Me
BF3 Et2O, CH2Cl2, -50° C, 1 h
S
S
9
38% yield
Me
Me
Me
Me
Me3Si
20
I(OAc)2
BF3 Et2O, CH2Cl2, -50° C, 1 h
S
I
7
21
25% yield
Me
I
I(OAc)2
Me3Si
Me
20
BF3 Et2O, CH2Cl2, -50° C, 1 h
S
Me
Me
S
9
22
21% yield
Scheme 3. Reductive iodonio-Claisen rearrangement involving substituted
allylsilanes.
I
OHC
EtMgCl, THF;
BocNH2, Et3SiH
S
then DMF, 0 to 12 oC, 2h
66 %
S
TFA, CH3CN, RT
74 %
13
23
Boc
BocHN
HN
Et3SiH, BF3 Et2O, CH2Cl2
N
2.5 % OsO4, NaIO4
S
S
HO
THF, H2O, RT, 1h
62%
-78° C, 2h, then RT, 0.5 h
60 %
24
25
CO2Me
N
To demonstrate the potential utility of these o-allyl iodothioph-
enes, we carried out a concise formal synthesis of PlavixÒ (clopido-
grel),13 a blood clot inhibitor used to reduce the risk of heart attack
and stroke. As depicted in Scheme 4, 2-allyl-3-iodothiophene 13
underwent magnesium–halogen exchange14 to provide corre-
sponding heteroaryl magnesium which was subsequently formy-
lated to afford aldehyde 23 (66%). Aldehyde 23 was then
subjected to reductive amination with tert-butyl carbamate in
the presence of triethylsilane and trifluoroacetic acid to afford
Boc-protected amine 24 (74%). Next, a one-pot dihydroxylation–
ref 14
S
S
Cl
26
plavix
Scheme 4. Synthesis of PlavixÒ
.
oxidative cleavage of the terminal olefin of 24 generated the corre-
sponding aldehyde which spontaneously cyclized to afford hemia-
minal 25 (62%). Finally, reductive amination of hemiaminal 25
using triethylsilane and BF3ÁEt2O followed by in situ deprotection
of the Boc-carbamate functionality provided the key intermediate
26 (60%). This thiophene-containing bicycle 26 has been previously
utilized to prepare PlavixÒ.15 Therefore, our preparation of bicycle
26 constitutes a formal synthesis of PlavixÒ.
Me3Si
I(OAc)2
S
BF3 Et2O, CH2Cl2, -50° C, 1 h
S
I
7
8
93% yield
In summary, our studies on the reductive iodonio-Claisen rear-
rangement using heterocyclic iodine(III) compounds led to the syn-
thesis of various o-allyliodothiophenes. It was found that this
pericyclic reaction was dramatically influenced by steric and elec-
tronic factors, as substituted allylsilanes or electron-poor heteroar-
omatic hypervalent iodine(III) compounds gave lower yields of the
products. In addition, application of one of o-allyliodothiophenes in
the concise synthesis of blood clot inhibitor PlavixÒ has been
achieved.
I(OAc)2
I
Me3Si
I
S
BF3 Et2O, CH2Cl2, -50°C, 1 h
S
N
S
9
14
13
97% yield
I
not observed
I(OAc)2
I(OAc)2
I(OAc)2
N
N
N
N
N
N
N
N
Bn
N
Ts
R
R
Me
16
15
Acknowledgment
10
11
12
R = Me, Bn, Ts
Start-up funding from The University of Toledo is gratefully
acknowledged.
Scheme 2. Reductive iodonio-Claisen rearrangement involving heteroaromatic
iodine(III) compounds.

5466
H. Nguyen et al. / Tetrahedron Letters 54 (2013) 5464–5466
6. Gately, D. A.; Luther, T. A.; Norton, J. R.; Miller, M. M.; Anderson, O. P. J. Org.
Supplementary data
Chem. 1992, 57, 6496–6502.
7. Lee, K.; Kim, D. Y.; Oh, D. Y. Tetrahedron Lett. 1988, 29, 667–668.
8. Van De Water, R. W.; Hoarau, C.; Pettus, T. R. R. Tetrahedron Lett. 2003, 44,
5109–5113.
9. Zhu, J.; Germain, A. R.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2004, 43, 1239–
1243.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
07.138.
10. Khatri, H. R.; Zhu, J. Chem. Eur. J. 2012, 18, 12232–12236.
11. Togo, H.; Nabana, T.; Yamaguchi, K. J. Org. Chem. 2000, 65, 8391–8394.
12. It should be noted that our extensive attempts in the synthesis of
heteroaromatic hypervalent iodine(III) compounds containing furan,
benzofuran, protected pyrrole, and indole moiety were unfruitful, probably
due to the instability of these electron-rich heterocycles towards oxidation.
13. For selected previously reported formal synthesis of PlavixÒ, see: (a) Rogers, E.;
Araki, H.; Batory, L. A.; McInnis, C. E.; Njardarson, J. T. J. Am. Chem. Soc. 2007,
129, 2768–2769; (b) Grainger, R. S.; Patel, B.; Kariuki, B. M.; Male, L.; Spencer,
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