On the power of super acid - Iodination of aromatic ring in the presence of imidazole moiety of the potent gamma secretase modulators (GSM) en route to tritium labeling

Article abstract of DOI:10.1016/j.tetlet.2012.01.085

Two advanced leads from the GSM program were iodinated selectively on the aromatic ring in the presence of an imidazole fragment using Olah's reagent - the combination of NIS and trifluoromethanesulfonic acid. These iodinated compounds were tritium labele

Full text of DOI:10.1016/j.tetlet.2012.01.085

Tetrahedron Letters 53 (2012) 1725–1727
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Tetrahedron Letters
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On the power of super acid—iodination of aromatic ring in the presence
of imidazole moiety of the potent gamma secretase modulators (GSM) en
route to tritium labeling
Mihirbaran Mandal a, , Carolee Lavey b, Alexei V. Buevich c, Zhaoning Zhu a, Andrew W. Stamford a,
⇑
Xiaoxiang Liu a
a Department of Medicinal Chemistry, Merck Research Laboratory, Kenilworth, NJ 07033, United States
b Department of Radiochemistry, Merck Research Laboratory, Kenilworth, NJ 07033, United States
c Department of Analytical Chemistry, Merck Research Laboratory, Kenilworth, NJ 07033, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Two advanced leads from the GSM program were iodinated selectively on the aromatic ring in the pres-
ence of an imidazole fragment using Olah’s reagent—the combination of NIS and trifluoromethanesulfo-
nic acid. These iodinated compounds were tritium labeled via a transition metal catalyzed sodium
borotritide reduction for the purpose of metabolite studies.
Received 6 January 2012
Revised 18 January 2012
Accepted 20 January 2012
Available online 1 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Electrophile
Iodination
Olah’s reagent
Superacid
Superelectrophile
O
O
N
Undoubtedly, one of the greatest contributions to the field of
chemical science in the last century was the realization of the
power of super acids for mechanistic elucidations, and subsequent
applications for the development of new modes for organic
synthesis. In many of their elegant letters, Olah et al harness the
capabilities of super acid to enhance the electrophilicity of the
electrophile, thereby generating a superelectrophile, to expand
the scope of many organic transformations, such as halogenation,
nitration, Friedel–Crafts alkylation, and acylation.1 Facile synthesis
of many pharmaceutically relevant nitrogen and fluorine contain-
ing compounds mediated by super acids has further broadened
their scope in organic synthesis.2 One such example, described
by Olah et al in the early nineties is the iodination of an unactivat-
OEt
F
variety of
MeO
N
N
no deuterated
product
conditions
N
3
Scheme 1. (a) n-BuLi, THF, À78 °C, then D2O; (b) t-BuLi, THF, À78 °C, then D2O; (c)
n-BuLi, KO-tBu, À78 °C, then D2O.
O
O
O
N
O
N
OEt
F
MeO
N
OEt
F
N
MeO
N
NIS
N
N
AcOH, rt
80%
N
4
3
I
O
Scheme 2. Selective iodination at imidazole ring of 1 using NIS and AcOH.
N
O
N
OH
F
MeO
N
F
F
MeO
N
N
N
N
O
N
O
N
F
O
N
OH
F
MeO
N
OEt
F
MeO
N
2
b
N
1
a
N
3
T
6
I
N
N
Figure 1. GSM lead candidates.
5
⇑
Scheme 3. Reagent and conditions: (a) NIS, CF3SO3H, 0 °C, 70%; (b) (1) NaBT4,
Pd(OAc)2, MeOH; (2) LiAlH4, THF, 59%.
Corresponding author. Tel.: +1 732 4563369; fax: +1 908 740 7152.
E-mail address: mihirbaran.mandal@merck.com (M. Mandal).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.085

1726
M. Mandal et al. / Tetrahedron Letters 53 (2012) 1725–1727
O
N
O
N
N
MeO
N
F
F
MeO
N
F
F
a
b
N
2
T
I
N
N
F
F
7
8
Scheme 4. Reagent and conditions: (a) NIS, CF3SO3H, 0 °C, 80%; (b) NaBT4, Pd(OAc)2, MeOH.
ed aryl group using N-iodosuccinimide (NIS) in the presence of
triflic acid.3 This simple, but powerful, method has found many
practical applications in the pharmaceutical industry as evidenced
by its citation in a large number of patents and publications. In an
effort to further extend this concept Olah et al also discovered a
new system, a combination of NIS and BF3–OEt2 that demonstrates
a wide range of utilities.4 Herein we would like to disclose the
application of such a novel reagent for the selective iodination of
aromatic rings embedded with multiple functionalities en route
to tritium labeling for metabolite studies.
yield.10 Compound
5 was tritiodehalogenated using sodium
borotritide and palladium acetate, followed by careful lithium
aluminum hydride reduction of the ester to give compound 6 in
a 59% yield.11 Starting from 500 mCi of sodium borotritide with a
specific activity of 80 Ci/mmol, 31.8 mCi of 6 was generated with
a specific activity of 13.5 Ci/mmol. Similarly, we converted our
second GSM lead 2 to the iodinated compound 7 in an 80% yield
using NIS and triflic acid combination, which was converted to 8
using the combination of sodium borotritide/palladium acetate in
methanol (Scheme 4).
Our gamma secretase modulator (GSM) program for the
treatment of Alzheimer disease generated two advanced leads—
molecule 1, followed by the second-generation more effective
compound 2 (Fig. 1).5 Before we could progress these molecules
for further studies, it was very important that we studied the
metabolic pathways of these molecules by the identification of
circulating and excreted metabolites.
In conclusion, we have shown that we can selectively iodinate
an aryl or imidazole moiety using NIS and the judicious choice of
acid. Using the NIS/triflic acid combination, we have iodinated
the aryl group in the presence of the electron rich imidazole moiety
by suppressing its inherent reactivity. These findings would serve
as the guideline for the predictable incorporation of iodine into
molecules embedded with both aryl and imidazole moieties.
To aid this process, we undertook to radiolabel these molecules
with minimum perturbation on their potencies. We chose tritium
labeling, a very widely used technique in this endeavor. Selection
of sites for tritiation is vital as labeling at the metabolically labile
position would provide little useful information. After careful
consideration, we selected the aromatic ring embedded between
the imidazole and vinylic moieties as the primary site for position-
ing the radiolabel. For convenience, we chose to survey the reaction
conditions using a deuterium source, and hoped to use the
optimized reaction conditions for tritium labeling. With that in
mind, we started our efforts with the traditional deprotonation—
quenching sequence (Scheme 1). Use of n-BuLi or t-BuLi alone or
the combination of K-OtBu and n-BuLi as the base followed by treat-
ment with D2O led to no deuterium incorporation.
Acknowledgments
The authors like to thank Drs. T. M. Chan, Mary Senior for their
help with the NMR, and to Drs. James Tata and Ann Weber for their
strong support for this work.
References and notes
1. (a) Olah, G. A.; Prakash, G. K. S.; Molnar, A.; Sommer, J. Superacid Chemistry, 2nd
ed.; Wiley
& Sons: New York, 2009; (b) Olah, G. A.; Klumpp, D. A.
Superelectrophiles and their chemistry; Wiley-Interscience: Hoboken, NJ, 2008;
(c) Olah, G. A. Angew. Chem., Int. Ed. Engl 1993, 32, 767–788.
2. (a) Raja, E. K.; Klumpp, D. A. Tetrahedron 2011, 52, 5170–5172; (b) Zhang, Y.;
Sheets, M. R.; Raja, E. K.; Boblak, K. N.; Klumpp, D. A. J. Am. Chem. Soc 2011, 133,
8467–8469; (c) Sheets, M. R.; Li, A.; Bower, E. A.; Weigel, A. R.; Abbott, M. P.;
Gallo, R. M.; Mitton, A. A.; Klumpp, D. A. J. Org. Chem 2009, 74, 2502–2507; (d)
Zhang, Y.; Briski, J.; Zhang, Y.; Rendy, R.; Klumpp, D. A. Org. Lett 2005, 7, 2505–
2508; (e) Klumpp, D. A.; Aguirre, S. L.; Sanchez, G. V., Jr.; de Leon, S. J. Org. Lett
2001, 3, 2781–2784.
3. Olah, G. A.; Wang, Q.; Sandford, G.; Prakash, G. K. S. J. Org. Chem. 1993, 58,
3194–3195.
4. Prakash, G. K. S.; Mathew, T.; Hoole, D.; Esteves, P. M.; Wang, Q.; Rasul, G.; Olah,
G. A. J. Am. Chem. Soc. 2004, 126, 15770–15776.
5. (a) Sun, Z; Asberom, T.; Bara, T.; Bennett, C.; Burnett, D.; Chu, I.; Clader, J.;
Cohen-Williams, M.; Cole, D.; Czarniecki, M.; Durkin, J.; Gallo, G.; Greenlee, W.;
Josien, H.; Huang, X.; Hyde, L.; Jones, N.; Kazakevich, I.; Li, H.; Liu, X.; Lee J.;
MacCoss, M.; McCracken, T.; Nomeir, A.; Mazzola, R.; Palani, A.; Parker, E. M.;
Pissarnitski, D.; Qin, J.; Song, L.; Terracina, G.; Vicarel, M.; Voigt, J.; Xu, R.;
Zhang, L.; Zhang, Q.; Zhao, Z.; Zhu, X.; Zhu, Z. J. Med. Chem, 2012, ASAP.; (b) Qin,
J.; Zhou, W.; Huang, X.; Dhondi, P.; Palani, A.; Aslanian, R.; Zhu, Z.; Greenlee,
W.; Cohen-Williams, M.; Jones, N.; Hyde, L.; Zhang, L. Med. Chem. Lett. 2011, 2,
471–476; (c) Qin, J.; Dhondi, P.; Huang, X.; Mandal, M.; Zhao, Z.; Pissarnitski,
D.; Zhou, W.; Aslanian, R.; Zhu, Z.; Greenlee, W.; Clader, J.; Zhang, L.;
Cohen-Williams, M.; Jones, N.; Hyde, L.; Palani, A. Bioorg. Med. Chem. Lett.
2011, 21, 664–669; (d) Caldwell, J. P.; Bennett, C. E.; McCracken, T. M.; Mazzola,
R. D.; Bara, T.; Buevich, A.; Burnett, D. A.; Chu, I.; Cohen-Williams, M.; Josein,
H.; Hyde, L.; Lee, J.; McKittrick, B.; Song, L.; Terracina, G.; Voigt, J.; Zhang, L.;
Zhu, Z. Bioorg. Med. Chem. Lett. 2010, 20, 5380–5384; (e) Huang, X.; Aslanian, R.;
Zhou, W.; Zhu, X.; Qin, J.; Greenlee, W.; Zhu, Z.; Zhang, L.; Hyde, L.; Chu, I.;
Cohen-Williams, Mary.; Palani, A. ACS Med. Chem. Lett. 2010, 1, 184–187.
6. Tang, Y. S.; Liu, W.; Chaudhary, A.; Melillo, D. G.; Dean, D. C. In Synthesis and
Applications of Isotopically Labelled Compounds; John Wiley & Sons, Ltd, 2004;
vol. 8, p. 71–74.
Detection of several unidentified products in LC–MS suggested
the incompatibility of the starting material toward these strong
bases, and therefore, we resorted to alternative strategies that
avoided the use of a strong base.
The transition metal catalyzed sodium borotritide reduction of
aryl halides is a powerful method to introduce tritium into a mol-
ecule because other potentially reducible groups, such as esters
and alkenes, remain intact.6 In the case in hand, this approach re-
quires the installment of halogen on an aromatic ring in the pres-
ence of an electron rich imidazole (cf. 1). Traditional iodinating
conditions, such as use of NIS alone in acetonitrile under refluxing
conditions or in combination with acetic acid7 at room tempera-
ture resulted in iodination exclusively on the imidazole moiety
(cf. 4 in Scheme 2).8 Use of trifluoroacetic acid instead of acetic acid
led to the complete decomposition of the starting material. Conse-
quently, the iodination using NIS/triflic acid developed by Olah
et al3 became the last resort for the incorporation of a halogen onto
the phenyl ring with the hope that the strong acid would deacti-
vate the imidazole ring through complete protonation.9 In our first
attempt, a stoichiometric amount of NIS/triflic acid in dichloro-
methane led to the formation of 5 as the major product along with
some bis-iodinated product (Scheme 3). Increasing the amount of
triflic acid in the reaction led to the improvement of the yield of
the desired product, and finally using triflic acid as the reaction
medium we were able to obtain the desired product 5 in a 70%
7. Iodination of imidazole using NIS (a) Enguehard-Gueiffier, C.; Croix, C.; Hervet,
M.; Kazock, J-Y.; Gueiffier, A.; Abarbri, M. Helv. Chim. Acta 2007, 90, 2349–2367;
(b) Du, X.; Chen, X.; Mihalic, J. T.; Deignan, J.; Duquette, J.; Li, A-R.; Lemon, B.;
Ma, J.; Miao, S.; Ebsworth, K.; Sullivan, T. J.; Tonn, G.; Collins, T. L.; Medina, J. C.

M. Mandal et al. / Tetrahedron Letters 53 (2012) 1725–1727
1727
Bioorg. Med. Chem. Lett 2008, 18, 608–613; (c) Gudmundsson, K. S.; Johns, B. A.
Org. Lett 2003, 5, 1369–1372.
TFA in water/0.05% TFA in acetonitrile to provide 5 in 70% yield. NMR (CDCl3) d
7.71 (s, 1H), 7.69 (m, 1H), 7.51 (m, 2H), 7.38 (s, 1H), 7.11 (m, 2H), 6.86 (m, 2H),
4.33 (m, 2H), 3.80 (s, 3H), 3.58 (m, 1H), 2.83 (m, 1H), 2.50 (m, 2H), 2.27 (s, 3H),
1.94 (m, 1H), 1.74 (m, 1H), 1.33 (t, J = 7.1 Hz, 3H). Exact mass cacld for
8. Procedure for the iodination at the imidazole ring: To a solution of 3 (50 mg,
0.102 mmol) in 1 mL acetic acid was added N-iodosuccinimide (22.93 mg,
1.0 equiv, 0.102 mmol) and the resulting mixture was stirred at room
temperature for 2 h, whereupon LC–MS indicated the completion of the
reaction. The reaction mixture was diluted with ethyl acetate, washed with
saturated NaHCO3, and then with brine. The organic layer was dried with
MgSO4, filtered, concentrated, and purified by reverse phase C18 column using
0.05% TFA in water/0.05% TFA in acetonitrile to provide 4 in 80% yield. NMR
(CD3OD) d 9.2 (s, 1H), 7.55–7.44 (m, 4H), 7.29 (s, 1H), 7.24–7.20 (m, 3H), 4.35
(q, J = 7.0 Hz, 2H), 3.88 (s, 3H), 3.55 (m, 1H), 2.93 (m, 1H), 2.78 (m, 2H), 1.98 (m,
1H), 1.80 (m, 1H), 1.32 (t, J = 7.0 Hz, 3H). Exact mass cacld for C27H27FIN4O4
(M+H+) 617.1; found 617.2.
C
27H27FIN4O4 (M+H+) 617.1; found 617.3.
11. Procedure for the synthesis of compound 6: To
12.3 mol) in MeOH (0.1 mL) was added palladium (II) acetate (0.27 mg,
1.2 mol). The mixture was stirred for 10 min. An ampoule containing sodium
a solution of 5 (7.6 mg,
l
l
borotritide (500 mCi, 80 Ci/mmol, purchased from ARC) was scored and
cracked open, and the methanol mixture was added, followed by two MeOH
washes (0.1 mL each). The resulting dark brown mixture was stirred for
45 min, then filtered through a small plug of celite using MeOH. The filtrate
was concentrated by passing nitrogen over the solution, and the residue was
immediately purified by RP-HPLC to give 52.2 mCi of the tritiated ester at a
radiochemical purity (RCP) of 97.8%. The LAH reduction to give compound 6
9. With the large access of triflic acid it is highly likely that both imidazole and
oxadiazole moieties are protonated.
was carried out in a stepwise manner. A total of 7.5 lL of LAH (1 M in THF) was
10. Procedure for the iodination at the phenyl ring: The mixture of 3 (144 mg,
0.302 mmol) and NIS (2 equiv, 135 mg, 0.605 mmol) was cooled to 0 °C and
2 mL triflic acid was added. The resulting solution was stirred for 15 min, and
then poured into the solution of saturated sodium thiosulfite while cooling at
0 °C. The resulting mixture was stirred for 15 min, then extracted with ethyl
acetate (3 Â 50 mL), the organic layers were combined and dried with MgSO4,
filtered, concentrated, and purified by reverse phase C18 column using 0.05%
added in two portions over 45 min to a solution of the tritiated ester in THF
(0.1 mL). After an additional 45 min of stirring, the RCP of 6 was 67%. The
reaction was quenched by the addition of water and CH2Cl2. The organic layer
was dried with Na2SO4 and concentrated to give a thin film that was purified
by RP-HPLC (Gemini C18 250 Â 10 mm ID, 254 nm, acetonitrile:0.05 M pH 10
aqueous triethylammonium acetate (40:60)) to give 31.8 mCi of compound 6
with a specific activity of 13.5 Ci/mmol.