Divergent synthesis of 2,3,5-substituted thiophenes by C-H activation/borylation/suzuki coupling

Article abstract of DOI:10.3987/COM-09-S(S)135

C-H activation/borylation has been married with Suzuki coupling to prepare DuP 697 (1) and analogs that would be otherwise difficult to obtain via the traditional synthetic route to 1.

Full text of DOI:10.3987/COM-09-S(S)135

HETEROCYCLES, Vol. 80, No. 2, 2010
1429
HETEROCYCLES, Vol. 80, No. 2, 2010, pp. 1429 - 1448. © The Japan Institute of Heterocyclic Chemistry
Received, 20th November, 2009, Accepted, 21st December, 2009, Published online, 21st December, 2009
DOI: 10.3987/COM-09-S(S)135
DIVERGENT SYNTHESIS OF 2,3,5-SUBSTITUTED THIOPHENES BY
C–H ACTIVATION/BORYLATION/SUZUKI COUPLINGa
Venkata A. Kallepalli, Luis Sanchez, Hao Li, Nathan J. Gesmundo, Clarissa
L. Turton, Robert E. Maleczka, Jr.,* and Milton R. Smith, III*
Department of Chemistry, Michigan State University, East Lansing, MI 48824-
1322, USA E-mail: maleczka@chemistry.msu.edu, smithmil@msu.edu
Abstract – C–H activation/borylation has been married with Suzuki coupling to
prepare DuP 697 (1) and analogs that would be otherwise difficult to obtain via
the traditional synthetic route to 1.
INTRODUCTION
Iridium-catalyzed C-H activation/borylation is emerging as a versatile synthetic methodology for organic
chemistry. Our group and others have demonstrated how C-H activation/borylation coupled with other
transformations can be exploited in the synthesis of some previously inaccessible or hard to access
compounds,1-9 and we have recently described its application for the elaboration of thiophenes.2
Thiophenes are an important class of heterocyclic compounds with applications in the design of advanced
materials to the treatment of various diseases. In particular, 2,3-diarylthiophenes have been shown to
selectively inhibit the cycloxygenase-2 (COX-2) enzyme,10-13 which is induced during inflammatory
conditions. DuP 697 (1) is one of the earliest members of this tricyclic class of inhibitors and it is
moderately selective for COX-2. Although its unacceptably long half-life led to its withdrawal during
phase I clinical trials, it was a forbearer to successful selective COX-2 inhibitors like Celebrex™. Thus,
DuP 697 provides an intriguing backdrop for honing synthetic strategies for drug development.
O
O
O
O
S
S
Me
H N
2
N
N
Br
DuP 697 (1)
CF
3
S
Me
F
Celebrex™
ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
aWe dedicate this paper to Professor Suzuki on the occasion of his 80th birthday.

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HETEROCYCLES, Vol. 80, No. 2, 2010
The first published synthesis of DuP 697 (Scheme 1)11 was linear and involved construction of the
thiophene ring from appropriate starting materials. It is interesting that a literature search of 2-
bromothiophenes that bear cyclic substituents at the 4 and 5-positions yields only 56 compounds, 28 of
which have been the subject of biological studies. The route in Scheme 1 likely contributes to this dearth
of structural diversity for the following reasons. First, a linear sequence where the critical 4- and 5-
substituents of the thiophene nucleus are installed in the first steps is not attractive for QSAR studies.
Second, Friedel-Crafts acylation and oxidation steps employed in the synthesis are relatively harsh and
limit the scope of substituents that can be accommodated.
MeS
MeS
H
PhF,
AlCl
MeS
POCl
DMF
O
3
3
O
X
CS ,
2
31%
O
Cl
SOCl ,
2
X = OH
EtOAc,
100%
F
X = Cl
F
3
HSCH CO H,
2
2
pyridine, TEA
MeO S
2
MeO S
2
MeS
Br
mCPBA
CH Cl ,
80%
2
CH Cl /
2
AcOH
< 50%
2
2
2
Br
S
S
S
F
F
F
1, DuP 697
Scheme 1. Original synthesis of DuP 697
To overcome some of these limitations, a second approach to diarylthiophenes related to 1 was devised,
which entailed a series of alternating brominations and Suzuki couplings.13 This route was an
improvement, but an even more attractive strategy would utilize a building block possessing all of
functionality required for the couplings that introduce the 4 and 5-subsitutents. Herein, we show how the
combination of the Suzuki cross-coupling14,15 and C-H activation/borylation makes such an approach to 1
and its analogs possible.
RESULTS AND DISCUSSION
Aryl boronate esters are versatile synthetic intermediates that are widely used in the construction of
carbon–carbon and carbon heteroatom bonds, and Ir-catalyzed borylation of C-H bonds provides a
convenient way to access them. The key player in our approach to 1 and its analogs (Scheme 2) is
compound 2, which is obtained from Ir-catalyzed C–H borylation of 2-chloro-5-trimethylsilylthiophene.
Because C–H borylations are sensitive to steric effects, the selectivity for the C–H at the 3-position is
excellent. The BPin and Cl groups serve as Suzuki coupling sites for elaborating the thiophene core, and
the trimethylsilyl substituent is transformed to Br in the final step.

HETEROCYCLES, Vol. 80, No. 2, 2010
1431
1
1
1
Ar
2
Ar
Ar
Suzuki
coupling
bromination
2
Ar
Ar
Cl
Br
TMS
TMS
2
S
S
S
Ar –B(OH)
2
or
Ar –BPin
2
1
Suzuki
coupling
Ar –X
(X = Br, I, OTf)
H
PinB
iridium C–H
borylation
metalation
Cl
Cl
Cl
TMS
H
TMS
S
S
S
2
Scheme 2. Retrosynthesis of DuP 697and its analogs
Synthesis of 1 provided the first test for this route. As illustrated in Scheme 3, deprotonation at 5-position
of 2-chlorothiophene, followed by trapping with TMSCl generated 3.16 Isolated 3 was then subjected to Ir
C–H borylation conditions to afford compound 2 in excellent yield. Compound 4 was obtained from the
Suzuki cross-coupling of 2 with 1-bromo-4-(methylsulfonyl)benzene. There was no evidence for Suzuki
coupling polymerization, indicating that the chloride position in 2 does not compete with the aryl bromide
partner. Using a catalyst and conditions developed by Buchwald,17 the second aryl ring was introduced by
cross-coupling between chloride 4 and 4-fluorophenylboronic acid. Finally, the trimethylsilyl group is
transformed to bromide with NBS to yield DuP 697 in five steps and 42% overall yield.
1.2 equiv
Br
SO2Me
1.5 equiv HBPin,
1.5 mol % [Ir(OMe)(COD)]2
3.0 mol % dtbpy
PinB
Cl
1.2 equiv LDA
3.0 equiv TMSCl
2.0 mol % PdCl2•dppf•CH2Cl2
1.5 equiv K3PO4•nH2O
TMS
Cl
Cl
TMS
S
S
S
heptane, rt, 42 h
93%
THF, -78 °C to rt
73%
DME, 80 °C, 1 h
87%
3
2
(HO) B
F
1.5 equiv
MeO2S
MeO2S
MeO2S
2
1.0 mol % Pd2dba3
4.0 mol % X-phos
2.0 equiv anhyd K3PO4
1.0 equiv NBS
MeCN, rt, 12 h
87%
t-AmOH, 80 °C, 6 h
Cl
TMS
S
TMS
Br
S
S
85%
F
F
4a
5a
1
Scheme 3. Synthesis of DuP 697 (1) via C–H activation/borylation
Having validated the strategy in Scheme 2, we next assessed its utility for preparing analogs of DuP 697.
Table 1 shows the results obtained for the trimethylsilyl compounds (5b-j) that are potential precursors to
corresponding DuP 697 analogs upon desilylative bromination. The choices for Ar1 and Ar2 were not
based on particular pharmaceutical relevance, even though many of the substituents appear in bioactive
molecules. Rather, Ar1 and Ar2 were chosen to illustrate how the strategy in Scheme 2 enables synthesis
of analogs that would be difficult to obtain via the linear (Scheme 1) or bromination/Suzuki coupling

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HETEROCYCLES, Vol. 80, No. 2, 2010
routes. Suzuki cross-couplings of compound 2 were straightforward, and gave good yields of compounds
4a-f after reaction times of ~ 3 h.
For the second set of Suzuki cross-couplings, three different conditions were used. Entries 2 and 3 were
carried out in toluene/H2O at 100 °C with S-phos. Reactions under these conditions were typically faster,
although Ar2–BPin was prone to deborylation. The remaining couplings were carried in tertiary alcohol
solvents (usually t-BuOH) at 80 °C, using a Pd2dba3/X-phos precatalyst/ligand combination. Both
anhydrous and hydrated K3PO4 were used. Variation in base had little effect on the reactions. With the
exception of entries 6 and 8, the isolation of compounds 5a-j was uneventful. Product 5f could not be
separated from 4-(N,N-dimethylamino)benzonitrile, which arose from deborylation of Ar2–BPin. While
analytically pure 5h could be obtained, a similar quantity of unreacted 4d was also recovered. While it
was not confirmed, a similar deborylation of Ar2–BPin would be consistent with the diminished yield.
The primary advantage of the approach in Scheme 3 over that in Scheme 1 pertains to the Ar2 group. In
Scheme 1, Ar2 is installed via Friedel-Crafts acylation. This imposes several problems. First, the arene,
Ar2H, must be sufficiently electron rich to be a viable substrate. Consequently, introduction of the
bis(trifluoromethyl)phenyl group (entries 2, 3, and 9) would be virtually impossible using the original
synthetic route. Second, the regiochemistry present in the Ar2 rings of 5 must be consistent with the
established regioselectivities for Friedel-Crafts reactions. This clearly is not the case for entry 5, where
substitution would be expected at the 3-position of benzothiophene, or entries 6 and 10, where acylation
would occur ortho to NMe2. The route in Scheme 2 also offers advantages over an iterative
bromination/Suzuki coupling approach, where installation of Ar1 requires the availability of Ar1B(OH)2
or Ar1B(OR)2 coupling partners. Since the BPin group is present in compound 2, the roles of the
electrophile and nucleophile are swapped. Consequently, Ar1 can be introduced using Ar1–X (X = Br,
OTf), which expands the structural diversity that can be accessed for Ar1 substituents. This is highlighted
by entry 10. The thiazole bromide is commercially available, whereas corresponding boron compounds
are unknown.
With compounds 5a–j in hand, the desilylative bromination that successfully affords 1 could be examined.
As shown in Scheme 4, compounds 5b–d were smoothly converted into compounds 6a–c, providing
three new analogs of 1. Under similar conditions compounds 5e, 5f, and 5j gave products 7a–c, where
bromination occurred at the Ar2 ring, leaving the TMS group in place (Scheme 5). Since we envisioned
similar outcomes for substrates 5h and 5i, bromination of these substrates was not examined.

HETEROCYCLES, Vol. 80, No. 2, 2010
1433
Table 1. Trimethylsilyl precursors to Dup 697 analogs.a
Ar1
Ar2
BPin
Ar1
1.2 equiv Ar1–X
1.5 equiv Ar2–BX2
TMS
Cl
TMS
Cl
TMS
2 mol % PdCl2•dppf•CH2Cl2,
1.5 equiv K3PO4•nH2O,
DME (0.5 M), 80 ºC
1-2 mol % Pd precatalyst,
2-4 mol % ligand,
2.0 equiv base, 80-100 ºC
S
S
S
4a-f
5a-j
2
Entry
Ar1 (% yield)
Ar2 (% yield)
1b
4a
(87%)
5a
(85%)
SO2Me
F
2c-e
5b
(77%)
4a
(87%)
F3C
CF3
SO2Me
3c-e
5c
(82%)
CF3
4b
(78%)
F
F3C
CN
4c,f,g
5d
(82%)
4c
(73%)
N
N
F
CN
S
5d,h,i
5e
(83%)
4d
(84%)
F3C
CN
CN
6 d,h-j
7d,h,i
5f
4d
(84%)
F3C
Me2N
CN
CN
4d
(84%)
5g
(78%)
F3C
Me
CN
8d,h,k
5h
(39%)
O
4d
(84%)
F3C
CO2Et
CN
9d,h,i
5i
(63%)
4e
(57%)
Me2N
F3C
CF3
CN
10c,d,g
S
N
4f
(84%)
5j
(78%)
Me2N
EtO2C
b
c
d
aYields are for isolated compounds. See Scheme 3 for conditions. Ar1–X = Ar1–Br. BX2 = BPin.
ePrecatalyst = Pd(OAc)2 (1 mol %), ligand = S-phos (2 mol %), base = K3PO4•nH2O, toluene/H2O
f
g
(10:1), 100 °C. BX2 = B(OH)2. Precatalyst = Pd2dba3 (1 mol %), ligand =X-phos (4 mol %), base =
K3PO4, DME, 80 °C. hAr1–X = Ar1–OTf. iPrecatalyst = Pd2dba3 (5 mol %), ligand =X-phos (20 mol %),
base = K3PO4•nH2O, t-BuOH, 80 °C. Contaminated with ~30% Ar2–H. Precatalyst = Pd2dba3 (2
j
k
mol %), ligand =X-phos (8 mol %), base = K3PO4•nH2O, t-BuOH, 70 °C, 40% recovery of 4d.

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HETEROCYCLES, Vol. 80, No. 2, 2010
1
1
Ar
Ar
1 equiv NBS
2
2
Ar
TMS
MeCN (0.05 M), rt
Ar
Br
S
S
F
MeO S
2
MeO S
2
NC
N
N
F C
3
F C
3
Br
Br
Br
Br
S
S
S
S
F
F
F C
3
F C
3
1
6a
6b
66%
6c
76%
87%
77%
Scheme 4. Synthesis of DuP 697 analogs via desilylative bromination
Ar1
Ar2
Ar1
1-2 equiv NBS
TMS
Ar2
Br
TMS
S
S
CO2Et
S
CN
CN
F3C
F3C
N
Br
Me2N
Br
Me2N
S
TMS
TMS
TMS
S
S
S
CN
CN
Br
7a
91% crude yield
7b
46% crude yield
7c
83%
Scheme 5. Alternate outcomes from attempted desilylative bromination
Because derivatives of 1 where Br is substituted by H are known to be COX-2 selective,12,13 it was of
interest to determine whether the TMS groups in compounds 5 could be deprotected. As shown in
Scheme 6, this indeed proved to be the case as compounds 8a–f were obtained in excellent yield. Rather
than exhaustively surveying all compounds in Table 1, we chose examples where desilylative
brominations were either demonstrated, or likely, to be complicated. It is noteworthy that even though we
could not isolate compound 5f, pure 8a could be obtained by desilylating reaction mixtures that contained
5f. In addition, bromination products 7a and 7c could be deprotected without incident. In two cases, we
showed that desilylated products 8e and 8g (generated in situ from 7b) could be brominated at the 5-
position of the thiophene ring to afford compounds 9 and 11 (Scheme 7). While the yield for 9 was quite
good, NMe2 demethylation and nearly exhaustive arene bromination accompanied formation of 11.

HETEROCYCLES, Vol. 80, No. 2, 2010
1435
Ar1
Ar2
Ar1
2 equiv TBAF
THF or THF/H2O (4:1)
(0.05 M), rt
TMS
Ar2
S
S
CO2Et
S
CN
CN
F3C
F3C
Me2N
N
Me2N
S
S
S
O
CN
CN
EtO2C
8a
58 % from 4d
8b
95 %
8c
81 %
CO2Et
CN
CN
S
F3C
F3C
N
Br
Br
Me2N
S
S
S
S
S
CN
8d
83 %
8e
80 % crude yield
8f
83%
Scheme 6. 2,3-Disubstituted thiophenes from TMS deprotection
CN
CN
F3C
F3C
Br
Br
3 equiv Br2
Br
S
S
benzene,
rt, 6h
S
S
8e
9
87%
CN
CN
CN
F3C
N
F3C
F3C
3 equiv Br2
Br
Br
H
N
H
N
+
benzene,
rt, 6h
R
Br
S
S
S
Br
Br
Br
CN
CN
CN
2 equiv TBAF,
THF/H2O 4:1,
rt, 3h
7b, R = TMS
8g, R = H
10
28%
11
32%
Scheme 7. Bromination of 2,3-disubstituted thiophenes after TMS deprotection
CONCLUSIONS
In conclusion, the DuP 697 family of COX-2 inhibitors serves as a backdrop for demonstrating the
synthetic flexibility that can result when Ir-catalyzed C–H borylation is married to Suzuki cross-couplings.
The halogen tolerance that is a hallmark of Ir C–H borylation1 makes it trivial to construct compound 2, a
building block possessing halogen and boronate ester functionality. This plays directly to one of the
strengths of the Suzuki cross–coupling—its exquisite chemoselectivity for halogen functional groups.14,15
This feature makes 2 a versatile core for efficiently preparing a range 2,3-diaryl thiophenes.

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HETEROCYCLES, Vol. 80, No. 2, 2010
EXPERIMENTALS
Unless otherwise stated, starting materials were subjected to purification before use, yields refer to
chromatographically and spectroscopically pure compounds, and reactions were carried out in oven- or
flame-dried glassware under a nitrogen atmosphere. All solvents were reagent grade. 1,2-
Dimethoxyethane (DME) and tetrahydrofuran (THF) were distilled from sodium/benzophenone and
acetonitrile and toluene were distilled from calcium hydride under nitrogen atmosphere before use.
Freeze-pump-thaw method was preferred for solvent degassing. Pd2(dba)3 (dba = dibenzylideneacetone),
PdCl2•dppf•CH2Cl2 (dppf
=
1,1'-bis(diphenylphosphino) ferrocene), Pd(OAc)2, S-phos (2-
dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl), and X-phos (2-dicyclohexylphosphino-2',4',6'-
triisopropylbiphenyl) were purchased and used as received. Bromide coupling partners: 1-bromo-4-
(methylsulfonyl)benzene, 4-bromo-2-fluorobenzonitrile, 4-bromo-1-methyl-1H-pyrazole, and 2-bromo-4-
methylthiazole-5-carboxylate were purchased and used as received. Triflate partners were prepared from
the
corresponding
precursors
2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-
(trifluoromethyl)benzonitrile and 4-(dimethylamino)-2-hydroxybenzonitrile; these compounds were
purchased and used without purification. Borylated partners: 4-fluorophenylboronic acid, 2-(3,5-
bis(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 2-(benzo[b]thiophen-2-yl)-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane,
4-(dimethylamino)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)benzonitrile, 4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile, and 5-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)furan-2-carboxylate were purchased and used as received. N-
bromosuccinimide was crystallized from water and dried in vacuo. Reactions were monitored by thin
layer chromatography using pre-coated silica gel plates. Column chromatography was performed on 60 Å
1
13
silica gel (230–400 Mesh). H and C NMR spectra were recorded on a Varian Inova-300 (300.11 and
75.47 MHz respectively), Varian VXR-500 or Varian Unity-500-Plus spectrometer (499.74 and 125.67
1
13
MHz respectively) and referenced to residual solvent (CDCl3) signals (ꢀ 7.24 for H and 77.0 for C).
Elemental analyses were performed at Michigan State University using a Perkin Elmer Series II 2400
CHNS/O Analyzer. Melting points were measured on a MEL-TEMP® capillary melting point apparatus
and are uncorrected. High-resolution mass spectra were acquired at the Michigan State University Mass
Spectrometry facility using a Waters QTOF Ultima mass spectrometer equipped with an electrospray
ionization (ESI) source.
Preparation of (5-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)trimethyl-
silane (2):2 To a solution of n-butyllithium (69 mL, 124 mmol, 1.8 M in hexanes) in THF (100 mL) was
added dropwise at –78 °C diisopropylamine (14.9 g, 20.5 mL, 147 mmol, 1.4 equiv). The mixture was
warmed to 0 °C for 10 min and then recooled to –78 °C. This solution was cannula transferred to a

HETEROCYCLES, Vol. 80, No. 2, 2010
1437
mixture of 2-chlorothiophene (12.5 g, 9.7 mL, 105 mmol, 1.0 equiv) and chlorotrimethylsilane (34.2 g,
40.3 mL, 315 mmol, 3.0 equiv) at –78 °C. The solution was allowed to warm to room temperature and
stir at room temperature for 1 h. The reaction mixture was then poured into 600 mL of water containing
10 mL 3 N HCl. The aqueous layer was extracted twice with 550 mL of diethylether. The combined
organic layers were washed with saturated sodium bicarbonate and then brine. After drying over
anhydrous sodium sulfate the solvent was removed by rotary evaporation. Vacuum distillation (70 °C at
1
25 mm Hg) afforded 2-chloro-5-trimethylsilylthiophene (3) as a colorless oil (14.7 g, 73% yield). H
NMR (CDCl3, 500 MHz) ꢀ 6.98 (d, J = 3.5 Hz, 1 H), 6.93 (d, J = 3.5 Hz, 1 H), 0.27 (s, 9 H, CH3 of
TMS); 13C NMR {1H} (CDCl3, 125 MHz) ꢀ 140.2 (C), 134.5 (C), 133.3 (CH), 127.4 (CH), -0.3 (3 CH3 of
TMS); IR (neat) ꢀmax = 2959, 1415, 1251, 1205, 1072, 964, 841 cm–1; GC-MS (EI) m/z (% relative
˜
intensity): M+ 190 (34), 192 (13), 175 (100); Anal. Calcd for C7H11ClSSi: C, 44.07; H, 5.81. Found: C,
43.59; H, 5.90; HRMS (EI): m/z 190.0036 [M+; Calcd for C7H11ClSSi: 190.0039].
In a glove box, a 250 mL round-bottom flask, equipped with a magnetic stirring bar, was charged with
[Ir(OMe)(COD)]2 (424 mg, 0.64 mmol, 3 mol % Ir) and 20 mL heptane. HBPin (9.3 mL, 8.2 g, 64 mmol
1.5 equiv) was then added and the resulting mixture was stirred for 5 min. The dtbpy (343 mg, 1.3 mmol,
3 mol %) dissolved in 20 mL of heptane was then added and this mixture was stirred for 10 min. 2-
Chloro-5-trimethylsilylthiophene (3) (8.1 g, 43 mmol, 1 equiv) was added along with an additional 60 mL
of heptane. The reaction was left to stir in the glove box for 42 h. The solvent was removed under
vacuum and the concentrated reaction mixture was passed through a plug of silica gel eluting with
CH2Cl2. Evaporation of the CH2Cl2 afforded the product as a white solid (12.5 g, 93% yield, mp 68–
69 °C). 1H NMR (CDCl3, 500 MHz) ꢀ 7.26 (s, 1 H), 1.32 (br s, 12 H, 4 CH3 of BPin), 0.26 (s, 9 H, 3 CH3
of TMS); 13C NMR {1H} (CDCl3, 125 MHz) ꢀ 144.7 (C), 139.42 (CH), 139.37 (C), 83.7 (2 C), 24.8 (4
11
˜
CH3 of BPin), –0.24 (3 CH3 of TMS); B NMR (CDCl3, 96 MHz) ꢀ 29.1; IR (neat) ꢀmax = 2980, 1525,
1415, 1363, 1307, 1253, 1238, 1143, 993, 841, 758, 696 cm–1; GC-MS (EI) m/z (% relative intensity) 316
(33), 301 (100), 281 (6), 201 (15); Anal. Calcd for C13H22BClO2SSi: C, 49.30; H, 7.00; Found: C, 49.16;
H, 7.16.
General Procedures
Procedure A: Suzuki coupling of 2 with bromide and triflate partners. In an air-free flask equipped
with a magnetic stir bar were mixed 2 (158 mg, 0.5 mmol), the coupling partner (0.6 mmol),
K3PO4•nH2O (186 mg, 0.75 mmol), and PdCl2•dppf•CH2Cl2 (8.2 mg, 10 ꢀmol). The flask with the solid
mixture was purged and refilled with nitrogen several times. Degassed DME (1 mL) was added under a
nitrogen atmosphere and the reaction mixture was heated to 80 °C. The progress of the reaction was
monitored by TLC. Once finished, usually after 2.5 h for bromide partners and 6 h for triflates, the

1438
HETEROCYCLES, Vol. 80, No. 2, 2010
reaction mixture was filtered through a short plug of silica gel eluting with acetone. The filtrate was
concentrated in vacuo and the crude product was purified by column chromatography.
Procedure B: Suzuki coupling using Pd2dba3 and X-phos. To an air-free flask equipped with a
magnetic stir bar were added the chloride substrate (0.5 mmol), borylated partner (0.75 mmol), anhydrous
potassium phosphate (212 mg, 1.0 mmol), Pd2dba3 (5 mg, 5 ꢀmol), and X-phos (10 mg, 20 ꢀmol), and
the flask with the solid mixture was purged and refilled with nitrogen multiple times. To the flask was
added degassed t-BuOH (1.0 mL), and the resulting suspension was heated to 80 °C. The progress of the
reaction was monitored by TLC. After completion, usually after more than 6 h, the reaction mixture was
filtered through a short plug of silica gel eluting with acetone. The filtrate was concentrated in vacuo and
the crude product was purified by column chromatography.
Procedure C: Suzuki coupling using Pd(OAc)2 and S-phos. To an air-free flask provided with a stir bar
was added chloride substrate (0.50 mmol), borylated partner (0.75 mmol), K3PO4•nH2O (248 mg, 1.0
mmol), palladium(II) acetate (1 mg, 5 ꢀmol), and S-phos (4 mg, 10 ꢀmol), and the flask with the solid
mixture was purged and refilled with nitrogen several times. Under nitrogen atmosphere, degassed
toluene and water (9:1) (1 mL) were added to the flask, and the resulting suspension was heated up to
100 °C. The progress of the reaction was monitored by TLC. After completion, usually after 30 min to 1
h, the reaction mixture was filtered through a short plug of silica gel eluting with acetone. The filtrate was
concentrated in vacuo and the crude product was purified by column chromatography.
Procedure D: Desilylative bromination. N-bromosuccinimide (18 mg, 0.10 mmol) was added to a
solution of silylated substrate (0.1 mmol) in acetonitrile (2 mL), and the mixture was stirred at room
temperature until TLC confirmed completion, usually after 12 h. The reaction mixture was filtered
through a short plug of silica gel eluting with dichloromethane. The filtrate was concentrated in vacuo
and purified by column chromatography.
Procedure E: Desilylation. At room temperature, tetrabutylammonium fluoride (1 M in THF, 0.2 mL,
0.2 mmol) was added dropwise to a solution of silylated substrate (0.1 mmol) in THF (2 mL) or
THF/water (4:1) (2 mL). Completion of the reaction, usually after 2.5–3 h, was confirmed by TLC. When
THF/water (4:1) was used as solvent, the reaction mixture was passed through a short plug of silica gel
eluting with DCM, and the filtrate was concentrated. When THF was used as solvent, the reaction
mixture was quenched with aqueous saturated sodium bicarbonate (5 mL) and extracted with ethyl acetate
(3 x 5 mL); combined organic layers were dried over magnesium sulfate, filtered and concentrated in
vacuo. The desilylation product was purified by column chromatography.
Preparation of DuP 697 (1): Using procedure A, 2 (1.58 g, 5.0 mmol) was coupled with 1-bromo-4-

HETEROCYCLES, Vol. 80, No. 2, 2010
1439
(methylsulfonyl)benzene (1.41 g, 6.0 mmol, 1.2 equiv). After 1 h, the reaction mixture was passed
through a short plug of silica gel eluting with ethyl acetate. Concentration of the filtrate followed by
column chromatography eluting with ethyl acetate/hexanes 2:3 furnished 4a (1.51 g, 87% yield) as a
1
white solid. Rf (4a) = 0.6 (2:3 ethyl acetate/hexanes); mp 110–112 °C; H NMR (300 MHz, CDCl3) ꢀ
7.98 (d, J = 8.5 Hz, 2 H), 7.75 (d, J = 8.8 Hz, 2 H), 7.14 (s, 1 H), 3.08 (s, 3 H, SO2CH3), 0.32 (s, 9 H, 3
13
CH3 of TMS); C NMR (75 MHz, CDCl3) ꢀ 139.8 (C), 139.6 (C), 139.2 (C), 137.5 (C), 134.4 (CH),
˜
131.1(C), 129.3 (CH), 127.5 (CH), 44.5 (CH3), –0.3 (3 CH3 of TMS); IR (neat) ꢀmax = 3019, 2957, 1599,
1533, 1397, 1312, 1252, 1153, 1088, 991, 957, 839, 770 cm–1; Anal. Calcd for C14H17ClO2S2Si: C, 48.75;
H, 4.97; Found: C, 48.34; H, 5.36. 4a (690 mg, 2.0 mmol) was then coupled with 4-fluorophenylboronic
acid (420 mg, 3.0 mmol, 1.5 equiv) using procedure B with t-AmOH as a solvent. Column
chromatography eluting with hexanes/ether 3:7 furnished 5a as a light cream colored solid (689 mg, 85%
yield); Rf (5a) = 0.5 (3:7 hexanes/ether); mp 141–143 °C; 1H-NMR (300 MHz, CDCl3) ꢀ 7.83 (d, J = 8.3
Hz, 2 H), 7.44 (d, J = 8.2 Hz, 2 H), 7.24 (s, 1 H), 7.21 (m, 2 H), 6.97 (m, 2 H), 3.05 (s, 3 H, SO2CH3),
13
1
0.36 (s, 9 H, 3 CH3 of TMS); C-NMR (75 MHz, CDCl3) ꢀ (163.44, 161.47) (d, JC–F = 248.5 Hz, C),
3
144.7 (C), 142.2 (C), 140.4 (C), 138.6 (C), 137.4 (C), 136.5 (CH), (130.92, 130.86) (d, JC–F = 8.3 Hz,
4
2
CH), 129.8 (CH), (129.75, 129.72) (d, JC–F = 3.6 Hz, C), 127.5 (CH), (115.88, 115.70) (d, JC–F = 21.7
˜
Hz, CH), 44.5 (CH3), –0.2 (3 CH3 of TMS); IR (neat) ꢀmax = 3065, 2957, 2930, 2897, 1599, 1537, 1506,
1314, 1252, 1235, 1154, 1094, 1001, 957, 833, 772 cm–1; Anal. Calcd for C20H21FO2S2Si: C, 59.37; H,
5.23; Found: C, 58.47; H, 5.64. HRMS (ESI+): m/z calculated for [C20H22FO2S2Si]+ 405.0815, found
405.0816. 5a (404 mg, 1.0 mmol) was finally subjected to bromination following procedure D. The crude
material was passed through a short plug of silica gel, the filtrate was concentrated and the resulting solid
was washed with hexanes and dried to afford DuP 697 (1) as a white solid (358 mg, 87% yield). mp 129–
131 °C; 1H-NMR (300 MHz, CDCl3) ꢀ 7.82 (d, J = 8.7 Hz, 2 H), 7.37 (d, J = 8.7 Hz, 2 H), 7.16 (m, 2 H),
13
7.11 (s, 1 H), 6.98 (m, 2 H), 3.05 (s, 3 H, SO2CH3); C-NMR (75 MHz, CDCl3) ꢀ (164.38, 161.07) (d,
3
1JC–F = 249.5 Hz, C), 140.8 (C), 140.7 (C), 139.2 (C), 136.5 (C), 132.2 (C), (131.10, 130.99) (d, JC–F
=
=
8.2 Hz, CH), 129.7 (CH), (128.54, 128.49) (d, 4JC–F = 3.6 Hz, C), 127.6 (CH), (116.22, 115.93) (d, 2JC–F
˜
21.9 Hz, CH), 111.9 (CH), 44.4 (CH3); IR (neat) ꢀmax = 3069, 2926, 1597, 1506, 1489, 1439, 1312, 1282,
1235, 1152, 1094, 983, 957, 860, 830, 772, 735, 681, 558, 544 cm–1; Anal. Calcd for C17H21BrFO2S2: C,
49.64; H, 2.94; Found: C, 49.50; H, 3.06.
Preparation of analog 6a: Using procedure C, 4a (173 mg, 0.5 mmol) (see preparation of 1) was
coupled with 2-(3,5-bis(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (255 mg, 0.75
mmol). Column chromatography eluting with hexanes/ethyl acetate 5:1 afforded 5a (201 mg, 0.39 mmol,
77% yield) as an off-white solid. Rf (5a) = 0.3 (hexanes/ethyl acetate 5:1); mp 118–119 ºC; 1H NMR (500
MHz, CDCl3) ꢀ 7.85 (d, J = 8.75 Hz, 2 H), 7.69 (s, 1 H), 7.57 (s, 2 H), 7.38 (d, J = 8.75 Hz, 2 H), 7.20 (s,

1440
HETEROCYCLES, Vol. 80, No. 2, 2010
1 H), 2.98 (s, 3 H), 0.34 (s, 9 H); 13C NMR (75 MHz, CDCl3) ꢀ 142.9, 141.5, 141.4, 139.6, 139.5, 136.8,
2
136.0, (132.4, 132.1, 131.9, 131.6) (q, JC–F = 33.7 Hz), 129.9, 129.0 (m), 127.9, (126.2, 124.0, 121.9,
119.7) (q, 1JC–F = 274.2 Hz), 121.1 (septet, 3JC–F = 3.7 Hz), 44.6, –0.2; IR (neat) ꢀmax = 3091, 2963, 2933,
˜
1599, 1368, 1319, 1281, 1254, 1237, 1181, 1138, 1099, 1087, 1024, 999, 957, 897, 841, 791, 772, 713
cm–1; HRMS (ESI+): m/z calculated for [C22H21F6O2S2Si]+ 523.0651, found 523.0653. 5b (31 mg, 0.063
mmol) was then brominated using procedure D to afford 6a (26 mg, 0.049 mmol, 77% yield) as a white
solid after purification by column chromatography eluting with hexanes/ethyl acetate 5:1. Rf (6a) = 0.21
(hexanes/ethyl acetate 5:1); mp 53–54 ºC; 1H NMR (500 MHz, CDCl3) ꢀ 7.90 (d, J = 8.75 Hz, 2 H), 7.76
(s, 1 H), 7.55 (s, 2 H), 7.38 (d, J = 8.75 Hz, 2 H), 7.18 (s, 1 H), 3.02 (s, 3 H); 13C NMR (75 MHz, CDCl3)
ꢀ 140.1, 139.9, 138.7, 137.6, 134.7, (132.9, 132.5, 132.0, 131.6) (q, 2JC–F = 34.1 Hz), 132.7, 129.9, 129.0
(m), (128.2, 124.6, 121.0, 117.3) (q, 1JC–F = 273.3 Hz), 128.0, 121.7 (septet, 3JC–F = 3.6 Hz), 114.2, 44.5;
˜
IR (neat) ꢀmax = 3087, 2930, 1599, 1469, 1432, 1375, 1279, 1155, 1023, 957, 898, 866, 841, 790, 771,
738 cm–1; HRMS (ESI+): m/z calculated for [C19H12BrF6O2S2]+ 528.9366, found 528.9366.
Preparation of analog 6b: Using procedure A, 2 (986 mg, 3.1 mmol) was coupled with 4-bromo-2-
fluorobenzonitrile (745 mg, 3.7 mmol). Column chromatography eluting with hexanes/ethyl acetate 19:1
afforded 4b (752 mg, 2.4 mmol, 78% yield) as a white solid. Rf (4b) = 0.62 (hexanes/ethyl acetate 5:1);
mp 74–76 ºC; 1H NMR (500 MHz, CDCl3) ꢀ 7.65 (dd, J = 8.0, 7.0 Hz, 1 H), 7.46 (dd, J = 8.0, 1.5 Hz, 1
H), 7.44 (dd, J = 10.25, 1.5 Hz, 1 H), 7.11 (s, 1 H), 0.32 (s, 9 H); 13C NMR (125 MHz, CDCl3) ꢀ (164.1,
162.0) (d, 1JC–F = 256.6 Hz), (141.5, 141.4) (d, 3JC–F = 8.5 Hz), 140.0, 136.3, 134.0, 133.4, 131.7, (124.7,
124.7) (d, 3JC–F = 3.5 Hz), (116.2, 116.1) (d, 2JC–F = 21.3 Hz), 113.9, (100.0, 99.9) (d, 2JC–F = 17.0 Hz), –
0.4; IR (neat) ꢀmax = 2963, 2917, 2856, 2239, 1618, 835 cm–1; HRMS (ESI+): m/z calculated for
˜
[C14H14ClFNSSi]+ 310.0283, found 310.0280. Using procedure C, 4b (124 mg, 0.4 mmol) was coupled
with 2-(3,5-bis(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (204 mg, 0.6 mmol).
Column chromatography eluting with hexanes/ethyl acetate 19:1 afforded 5c (160 mg, 0.33 mmol, 82%
yield) as an off-white solid. Rf (5c) = 0.62 (5:1 hexanes/ethyl acetate); mp 98–100 ºC; 1H NMR (500 MHz,
CDCl3) ꢀ 7.78 (s, 1H), 7.65 (s, 1 H), 7.53 (dd, J = 8.0, 7.0 Hz, 1H), 7.24 (s, 1 H), 7.12 (dd, J = 9.5, 1.5 Hz,
1H), 7.07 (dd, J = 8.0, 1.5 Hz, 1H), 0.37(s, 9 H); 13C NMR (125 MHz, CDCl3) ꢀ (164.2, 162.1) (d, 1JC–F
=
3
261.2 Hz), (143.4, 143.4) (d, JC–F = 8.5 Hz), 143.0, 142.1, 138.2, 136.4, 135.6, 133.6, (132.7, 132.4,
132.1, 131.9) (q, 2JC–F = 33.6 Hz), 129.0, (126.1, 124.0, 121.8, 119.6) (q, 1JC–F = 273.8 Hz), (125.4, 125.4)
3
2
3
(d, JC–F = 3.5 Hz), 121.6 (m), (116.8, 116.6) (d, JC–F = 20.3 Hz), 113.7, (100.3, 100.2) (d, JC–F = 16.5
˜
Hz), –0.3; IR (neat) ꢀmax = 2961, 2237, 1618, 1564, 1497, 1370, 1346, 1311, 1279, 1254, 1181, 1138,
1026, 1001, 949, 897, 841, 758 cm–1; HRMS (ESI+): m/z calculated for [C22H17F7NSSi]+ 488.0734, found
488.0729. Finally 5c (50 mg, 0.10 mmol) was brominated according to procedure D to give 6b (34 mg,
0.068 mmol, 66% yield) as a white solid after purification by column chromatography eluting with

HETEROCYCLES, Vol. 80, No. 2, 2010
1441
hexanes/ethyl acetate (19:1 to 5:1). Rf (6b) = 0.57 (hexanes/ethyl acetate 5:1); mp 148–150 ºC; 1H NMR
(500 MHz, CDCl3) ꢀ 7.81 (s, 1H), 7.60 (s, 1 H), 7.55 (dd, J = 8.0, 6.5 Hz, 1H), 7.15 (s, 1 H), 7.07 (dd, J =
8.5, 1.5 Hz, 1H), 7.04 (dd, J = 8.0, 1.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) ꢀ (164.2, 162.1) (d, 1JC–F
=
3
4
260.2 Hz), (141.4, 141.4) (d, JC–F = 8.4 Hz), 138.3, (137.3, 137.3) (d, JC–F = 2.3 Hz), 134.4, 133.9,
(133.0, 132.7, 132.4, 132.2) (q, 2JC–F = 33.8 Hz), 132.4, 129.0 (m), (126.0, 123.8, 121.6, 119.5) (q, 1JC–F
=
273.4 Hz), (125.3, 125.2) (d, 3JC–F = 3.6 Hz), 122.1 (septet, 3JC–F = 3.4 Hz), (116.8, 116.6) (d, 2JC–F = 20.7
2
˜
Hz), 114.6, 113.4, (101.0, 100.9) (d, JC–F = 15.4 Hz); IR (neat) ꢀmax = 2923, 2853, 2237, 1727, 1620,
1354, 1205, 1179, 1129 cm–1; HRMS (ESI+): m/z calculated for [C19H8BrF7NS]+ 493.9444, found
493.9448.
Preparation of analog 6c: Using procedure A, 2 (200 mg, 0.63 mmol) was coupled with 4-bromo-1-
methyl-1H-pyrazole (122 mg, 0.76 mmol). Column chromatography eluting with hexanes/ethyl acetate
9:1 to 3:1 afforded 4c (125 mg, 0.46 mmol, 73% yield) as a white solid. Rf (4c) = 0.3 (hexanes/ethyl
acetate 5:1); mp 82–83 ºC; 1H NMR (500 MHz, CDCl3) ꢀ 7.80 (s, 1 H), 7.79 (s, 1 H), 7.13 (s, 1 H), 3.93
13
(s, 3 H), 0.29 (s, 9 H); C NMR (125 MHz, CDCl3) ꢀ 138.8, 137.8, 133.2, 133.2, 131.0, 128.0, 115.9,
˜
39.1, –0.4; IR (neat) ꢀmax = 3139, 3091, 3052, 2957, 2898, 1420, 1385, 1312, 1277, 1120, 984, 839, 804,
756 cm–1; HRMS (ESI+): m/z calculated for [C11H16N2SiSCl]+ 271.0492, found 271.0493. 4c (32 mg,
0.12 mmol) was then coupled with 4-fluorophenylboronic acid (25 mg, 0.18 mmol) following procedure
B. Column chromatography eluting with hexanes/ethyl acetate 3:1 to 2:1 afforded 5d (32 mg, 0.096
mmol, 82% yield) as a very thick colorless oil. Rf (5d) = 0 .21 (hexanes/ethyl acetate 3:1); 1H NMR (500
MHz, CDCl3) ꢀ 7.37 (m, 3 H), 7.19 (s, 1 H), 7.15 (s, 1 H), 7.02 (m, 1 H), 3.82 (s, 3 H), 0.33 (s, 9 H) ; 13C
1
NMR (125 MHz, CDCl3) ꢀ (163.4, 161.4) (d, JC–F = 247.7 Hz), 141.1, 138.2, 135.9, (131.0, 131.0) (d,
3JC–F = 8.7 Hz), (130.8, 130.8) (d, 4JC–F = 3.5 Hz), 130.6, 128.0, 117.5, (115.6, 115.5) (d, 2JC–F = 22.0 Hz),
˜
38.9, –0.1; IR (neat) ꢀmax = 3029, 2955, 2897, 2855, 1601, 1527, 1502, 1448, 1265, 1250, 1222, 1157,
1018, 983, 843, 821 cm–1; HRMS (ESI+): m/z calculated for [C17H20N2SiSF]+ 331.1101, found 331.1101.
Using procedure D, 5d (23 mg, 0.069 mmol) was brominated to afford 6c (18 mg, 0.053, 76% yield) as a
very thick colorless oil after purification by column chromatography eluting with hexanes/ethyl acetate
(5:1 to 2:1). Rf (6c) = 0.17 (hexanes/ethyl acetate 3:1); 1H NMR (500 MHz, CDCl3) ꢀ 7.32 (m, 2 H), 7.29
(d, J = 0.5 Hz, 1 H), 7.09 (d, J = 0.5 Hz, 1 H), 7.05 (s, 1 H), 7.03 (m, 2 H), 3.81 (s, 3 H); 13C NMR (125
1
3
MHz, CDCl3) ꢀ (163.7, 161.7) (d, JC–F = 247.9 Hz), 138.1, 136.8, 131.4, (131.3, 131.2) (d, JC–F = 8.4
4
2
Hz), 129.8, (129.6, 129.6) (d, JC–F = 3.2 Hz), 128.0, 116.5, (115.9, 115.7) (d, JC–F = 22.0 Hz), 111.1,
˜
39.0; IR (neat) ꢀmax = 3100, 3071, 2932, 2855, 1603, 1586, 1533, 1504, 1448, 1417, 1288, 1234, 1157,
1100, 1093, 985, 972, 841, 810 cm–1; HRMS (ESI+): m/z calculated for [C14H11N2FSBr]+ 336.9810,
found 336.9810.

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HETEROCYCLES, Vol. 80, No. 2, 2010
Preparation
of
intermediate
4d:
2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-4-
(trifluoromethyl)benzonitrile (600 mg, 2.0 mmol) was weighed into a 20 mL vial and 2 mL of MeOH was
added followed by aqueous H2O2 (0.5 mL, 5 mmol). The mixture was stirred for 4 h at room temperature.
The progress of the reaction was monitored by TLC eluting with hexanes/EtOAc (3:1). Once finished, the
volatiles were removed by rotatory evaporation, and the resulting white solid was stirred with water (10
mL) for 2 h. The resulting fine powder was separated by filtration, washed with cold water, and dried in
vacuo to give 2-hydroxy-4-(trifluoromethyl)benzonitrile (337 mg, 90% yield), mp 118–119 °C, and this
phenol was used without further purification. The phenol and K3PO4•nH2O (1.34 g, 5.4 mmol) were
weighed into a 20 mL vial and there dissolved in water (3 mL) and toluene (3 mL), and cooled to 0 °C.
Trifluoromethanesulfonic anhydride (0.47 mL) was added and the resulting mixture was stirred at 0 °C
for 10 min, and then allowed to warm to room temperature and stirred for 4 h. The progress of the
reaction was monitored by TLC (hexanes/EtOAc 5:1). The reaction mixture was then extracted with
diethyl ether, the combined organic layers were passed through a short plug with silica gel and then dried
over MgSO4. Concentration in vacuo gave 2-cyano-5-(trifluoromethyl)phenyl trifluoromethanesulfonate
(479 mg, 75% yield for two steps) as a slightly yellow clear thick liquid and this triflate was used in
following Suzuki couplings without further purification. 1H NMR (500 MHz, CDCl3) ꢀ 7.95–7.90 (d, J =
8.3 Hz, 1 H), 7.81–7.76 (dd, J = 8.3 Hz, 1.0 Hz, 1 H), 7.73 (d, J = 1.0 Hz, 1 H). Following procedure A, 2
(408 mg, 1.3 mmol) was coupled with the crude triflate (493 mg, 1.5 mmol) using PdCl2•dppf•CH2Cl2
(25 mg, 0.027 mmol) and K3PO4•nH2O (479 mg, 1.9 mmol). Column chromatography eluting with
hexane/EtOAc 9:1 afforded 4d (388 mg, 84% yield) as a white wax. mp 85.5–87.5 °C; 1H NMR (500
MHz, CDCl3) ꢀ 7.90–7.85 (d, J = 8.3 Hz, 1 H), 7.80–7.77 (d, J = 1.2 Hz, 1 H), 7.72–7.68 (dd, J = 8.3, 1.2
13
Hz, 1 H), 0.34–0.30 (s, 9 H); C NMR (125 MHz, CDCl3) ꢀ 140.1, 139.2, 135.0, (134.8, 134.4, 134.1
2
3
133.7) (q, JC–F = 33.4 Hz), 134.2, 134.0, 133.2, (127.80, 127.77, 127.73, 127.70) (q, JF–C = 3.8 Hz),
3
1
(124.89, 124.86, 124.83, 124.80) (q, JF–C = 3.7 Hz), (126.3, 124.1, 121.9, 119.7) (q, JF–C = 273.3 Hz),
116.867, 115.984, –0.382; IR (neat)
= 2232 cm–1; HRMS (ESI+): m/z calculated for
˜
ꢀ
max
[C15H14ClF3NSSi]+ 360.0257, found 360.0255.
Preparation of intermediate 4e: 4-(dimethylamino)-2-hydroxybenzonitrile (81 mg, 0.5 mmol) and
K3PO4•nH2O (372 mg, 1.5 mmol) were weighted in a 20 mL vial, dissolved in 1.5 mL water and 1.5 mL
toluene, and cooled to 0 °C. Trifluoromethanesulfonic anhydride (100 ꢀL, 0.6 mmol) was added and the
resulting mixture was stirred at 0 °C for 10 min and then allowed to warm to room temperature.
Completion of the reaction after 4 h was confirmed by TLC eluting with 5:1 hexanes/EtOAc. The
reaction mixture was then extracted with diethyl ether; combined organic layers were passed through a
short plug of silica gel and then dried over MgSO4. Concentration gave 2-cyano-5-
(dimethylamino)phenyl trifluoromethanesulfonate (77 mg, 52% yield) as a slightly yellow gel and this

HETEROCYCLES, Vol. 80, No. 2, 2010
1443
triflate was used in following Suzuki coupling without further purification. 1H NMR (500 MHz, CDCl3) ꢀ
7.44–7.42 (d, J = 8.9 Hz, 1 H), 6.61–6.59 (dd, J = 8.9, 2.6 Hz, 1 H), 6.58–6.57 (d, J = 2.6 Hz, 1 H).
Following procedure A, 2 (32 mg, 0.099 mmol) was coupled with the crude triflate (38 mg, 0.13 mmol).
Column chromatography eluting with hexane/EtOAc (3:1) afforded 4e (19 mg, 57% yield) as a yellow
gel. 1H NMR (500 MHz, CDCl3) ꢀ 7.55–7.52 (d, J = 8.9 Hz, 1 H), 7.18–7.16 (s, 1 H), 6.67–6.65 (d, J =
2.6 Hz, 1 H), 6.65–6.62 (dd, J = 2.6, 8.9 Hz, 1 H).
Preparation of 5e: Following procedure B, 4d (180 mg, 0.5 mmol) was coupled with 2-
(benzo[b]thiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (195 mg, 0.75 mmol), using Pd2(dba)3
(23 mg, 0.025 mmol) and X-phos (48 mg, 0.1 mmol), and K3PO4•nH2O (248 mg, 1 mmol). Column
chromatography (3:1 hexane/DCM) afforded 5e (191 mg, 83%) as a white wax. mp 192 °C (decomposed).
1H NMR (500 MHz, CDCl3) ꢀ 7.85–7.81 (d, J = 8.2 Hz, 1 H), 7.81–7.78 (d, J = 1.0 Hz, 1 H), 7.75–7.71
(dd, J = 8.2, 1.0 Hz, 1 H), 7.32–7.23 (m, 2 H), 7.23–7.19 (2br s, 2 H), 0.41–0.39 (s, 9 H); 13C NMR (125
2
MHz, CDCl3) ꢀ 142.1, 141.5, 140.5, 140.2, 139.6, 136.4, 135.1, (134.8, 134.5, 134.2, 133.9, q JF–C
=
1
33.4 Hz), 134.7, 133.8, 128.3, (126.3, 124.1, 122.0, 119.8, q, JF–C = 272.1 Hz), 124.9, 124.8, 124.7,
123.7, 123.2, 122.0, 117.0, 116.6, –0.2; IR (neat) ꢀmax = 2232 cm–1; HRMS (ESI+) calculated for
˜
[C23H19F3NS2Si]+ 450.0680, found 450.0682.
Preparation of 5g: Following procedure B, 4d (70 mg, 0.19 mmol) was coupled with 4-methyl-2-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (71 mg, 0.29 mmol), using Pd2(dba)3 (9 mg,
0.01 mmol), X-phos (19 mg, 0.039 mmol), and K3PO4•nH2O (97 mg, 0.39 mmol). Column
chromatography eluting with hexanes/diethyl ether 9:1 afforded 5g (65 mg, 78% yield) as a white solid.
mp 116.5–117.2 °C. 1H NMR (500 MHz, CDCl3) ꢀ 7.75–7.70 (d, J = 8.1 Hz, 1 H), 7.60–7.55 (d, J = 8.1
Hz, 1 H), 7.54–7.51 (s, 1 H), 7.44–7.40 (d, J = 8.0 Hz, 1 H), 7.38–7.36 (s, 1 H), 7.36–7.33 (s, 1 H), 7.22–
13
7.16 (d, J = 8.0 Hz, 2 H), 2.42–2.35 (s, 3 H), 0.42–0.34 (s, 9 H); C NMR (125 MHz, CDCl3) ꢀ 143.8,
143.3, 143.0, 140.8, 137.1, 136.6, (134.5, 134.3, 134.0, 133.7) (q, 2JF–C = 33.0 Hz), 133.9, 133.3, 133.0,
3
129.5, (128.44, 128.42, 128.39, 128.36) (q, JF–C = 3.4 Hz), (124.28, 124.25, 124.22, 124.19) (q, 3JF–C
=
3.7 Hz), (126.2, 124.0, 121.8, 119.7) (q, 1JF–C = 273.6 Hz), 117.7, 117.0, 116.1, 110.0, 21.6, –0.2; IR
(neat) ꢀmax = 2233 cm–1.
˜
Preparation of 5i: Following procedure B, 4e (18 mg, 0.054 mmol) was coupled with 2-(3,5-
bis(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (28 mg, 0.083 mmol), using
Pd2(dba)3 (3 mg, 0.003 mmol), X-phos (6 mg, 0.01 mmol), and K3PO4•nH2O (27 mg, 0.11 mmol).
Column chromatography eluting with hexane/EtOAc 9:1 gave 5i (17 mg, 63% yield) as a yellow gel. 1H
NMR (500 MHz, CDCl3) ꢀ 7.69–7.67 (s, 1 H), 7.66–7.64 (s, 1 H), 7.46–7.43 (d, J = 9.0 Hz, 1 H), 7.73–
7.29 (s, 1 H), 6.63–6.59 (dd, J = 9.0, 2.6 Hz, 1 H), 6.48–6.46 (d, J = 2.6 Hz, 1 H), 2.98–2.95 (s, 6 H,),

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HETEROCYCLES, Vol. 80, No. 2, 2010
0.40–0.35 (s, 9 H); IR (neat) ꢀmax = 2210 cm–1; HRMS (ESI+) calculated for [C24H23N2F6SSi] + 513.1255,
˜
found 513.1250.
Preparation of 8a: Following procedure B, 4d (90 mg, 0.25 mmol) was coupled with 4-
(dimethylamino)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (102 mg, 0.38 mmol), using
Pd2(dba)3 (12 mg, 0.013 mmol), X-phos (24 mg, 0.050 mmol), and K3PO4•nH2O (124 mg, 0.50 mmol).
Purification by column chromatography eluting with 3:1 hexane/EtOAc afforded 89 mg of a mixture
2.5:1 of 5f (corresponding to 67% yield) and 4-(N,N-dimethylamino)benzonitrile, which arose from
deborylation of the coupling partner. HRMS (5f, ESI+) calculated for [C24H23F3N3SSi]+ 470.1334, found
470.1331. Impure 5f was subjected to desilylation according to procedure E without further purification.
The mixture was dissolved in THF (0.67 mL) and water (0.17 mL), TBAF (1M solution in THF, 340 ꢀL,
0.34 mmol) was added and the resulting solution was stirred at room temperature for 3 h. The reaction
mixture was passed through a short plug of silica gel eluting with DCM. After concentration, the crude
material was purified by column chromatography eluting with DCM to give 8a (57 mg, 58% yield for
two steps) as a white gel. 1H NMR (500 MHz, CDCl3) ꢀ 7.77–7.71 (d, J = 8.0 Hz, 1 H), 7.61–7.55 (2 H,
signals overlapping), 7.53–7.49 (d, 1 H, J = 5.1 Hz), 7.36–7.31 (d, J = 8.8 Hz, 1 H), 7.31–7.28 (d, J = 5.1
Hz, 1 H), 6.65–6.62 (d, J = 2.7 Hz, 1 H), 6.59–6.55 (dd, J = 8.8, 2.7 Hz, 1 H), 2.98–2.95 (s, 6 H);
13CNMR (125 MHz, CDCl3) ꢀ 152.1, 140.9, 139.2, 137.1, 135.3, 134.5, (134.3, 134.0, 133.8, 133.5, q,
2JF–C = 33.3 Hz), 133.7, 129.1, (128.35, 128.32, 128.29, 128.26, q, 3JF–C = 3.8 Hz), 126.6, (126.1, 124.0,
121.8. 119.6, q, 1JF–C = 273.1 Hz), (124.28, 124.26, 124.23, 124.20, q, 3JF–C = 3.8 Hz), 119.1, 117.1, 116.0,
114.6, 111.3, 98.5, 39.8; IR (neat) ꢀmax = 2211 cm–1; HRMS (ESI+) calculated for [C21H15N3F3S] +
˜
398.0939, found 398.0936.
Preparation of 8b: Using procedure B, 4d (189 mg, 0.53 mmol) was coupled with ethyl 5-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)furan-2-carboxylate (210 mg, 0.79 mmol), using Pd2(dba)3 (10 mg,
0.011 mmol), X-phos (20 mg, 0.042 mmol), and K3PO4•nH2O (261 mg, 1.1 mmol). Purification by
column chromatography eluting with 3:1 hexane/EtOAc gave 5h (95 mg, 39% yield) as a yellow gel. 1H
NMR (500 MHz, CDCl3) ꢀ 7.90–7.85 (d, 1 H, J = 8.2 Hz), 7.77–7.75 (d, J = 1.3 Hz, 1 H), 7.75–7.70 (dd,
J = 8.2, 1.3 Hz, 1 H), 7.18–7.14 (s, 1 H), 7.09–7.04 (d, J = 3.7 Hz, 1 H), 6.21–6.17 (d, J = 3.7 Hz, 1 H),
13
4.38–4.29 (q, J = 7.1 Hz, 2 H), 1.28–1.22 (t, J = 7.1 Hz, 3 H), 0.38–0.35 (s, 9 H); C NMR (125 MHz,
CDCl3) ꢀ 158.2, 150.9, 143.9, 142.7, 141.3, 136.3, 135.2, 134.8, (134.7, 134.4, 134.1, 133.9, q, 2JF–C
=
3
33.3 Hz), 133.7, (127.76, 127.73, 127.71, 127.68, q, JF–C = 3.7 Hz), (124.79, 124.76, 124.73, 124.70, q,
3JF–C = 3.7 Hz), (126.3, 124.1, 121.9, 119.7, q, 1JF–C = 273.0 Hz), 119.4, 116.6, 116.4, 108.9, 60.8, 14.2, –
0.3; IR (neat) ꢀmax = 2232, 1714 cm–1; HRMS (ESI+) calculated for [C22H21NO3SiF3S]+ 464.0964, found
˜
464.0959. 5h (46 mg, 0.10 mmol) was then dissolved in THF (0.40 mL) and water (0.10 mL). TBAF (1M

HETEROCYCLES, Vol. 80, No. 2, 2010
1445
solution in THF, 200 ꢀL, 0.20 mmol) was added and the reaction mixture was stirred at room temperature.
After 3 h, the reaction mixture was passed through a short plug of silica gel eluting with DCM to afford
8b (37 mg, 95%) as a white gel. 1H NMR (500 MHz, CDCl3) ꢀ 7.89–7.85 (d, J = 8.4 Hz, 1 H), 7.75–7.71
(overlapping s and d, 2 H), 7.47–7.43 (d, J = 5.2 Hz, 1 H), 7.13–7.10 (d, J = 5.1 Hz, 1 H), 7.08–7.05 (d, J
= 3.7 Hz, 1 H), 6.18–6.16 (d, J = 3.7 Hz, 1 H), 4.28–4.20 (q, J = 7.1 Hz, 2 H), 1.30–1.25 (t, J = 7.2 Hz, 3
13
H); CNMR (125 MHz, CDCl3) ꢀ 158.2, 150.6, 144.1, 141.1, 134.8–134.0 (q, 2JF–C = 33.3 Hz), 134.1,
133.7, 130.3, 130.0, 127.9–127.8 (q, 3JF–C = 3.8 Hz), 126.7, 126.2–129.7 (q, 1JF–C = 273.2 Hz), 125.0–
124.9 (q, 3JF–C = 3.7 Hz), 119.3, 116.6, 116.4, 109.1, 60.9, 14.2; IR (neat) ꢀmax = 2233 cm–1; HRMS
˜
(ESI+) calculated for [C19H13NO3F3S]+ 392.0568, found 352.0569.
Preparation of 8c: Using procedure A, 2 (200 mg, 0.63 mmol) was coupled with ethyl 2-bromo-4-
methylthiazole-5-carboxylate (190 mg, 0.76 mmol). Column chromatography eluting with hexanes/ethyl
acetate (19:1 to 5:1) afforded 4f (191 mg, 0.53 mmol, 84% yield) as a pale yellow solid. Rf (4f) = 0.54
(hexanes/ethyl acetate 5:1); mp 63–65 ºC; 1H NMR (500 MHz, CDCl3) ꢀ 7.75 (s, 1 H), 4.34 (q, J = 7.25
13
Hz, 2 H), 2.76 (s, 3 H), 1.38 (t, J = 7.25 Hz, 3 H), 0.32 (s, 9 H); C NMR (125 MHz, CDCl3) ꢀ 162.5,
˜
161.6, 159.7, 139.4, 133.6, 133.6, 133.0, 121.7, 61.2, 17.3, 14.4, –0.4; IR (neat) ꢀmax = 2988, 2959, 2927,
1715, 1539, 1522, 1371, 1321, 1259, 1093, 991, 843, 760 cm–1; HRMS (ESI+): m/z calculated for
[C14H19NO2SiS2Cl]+ 360.0315, found 360.0315. Using procedure C, 4f (37 mg, 0.10 mmol) was coupled
with 4-(dimethylamino)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (22 mg, 0.15 mmol).
Column chromatography eluting with hexanes/ethyl acetate (5:1 to 2:1) afforded 5j (37 mg, 0.080 mmol,
1
78% yield) as a pale yellow solid. Rf (5j) = 0.26 (hexanes/ethyl acetate 3:1); mp 177–178 ºC; H NMR
(500 MHz, CDCl3) ꢀ 7.78 (s, 1 H), 7.54 (d, J = 9.0 Hz, 1 H), 6.70 (dd, J = 9.0, 3.0 Hz, 1 H), 6.66 (d, J =
3.0 Hz, 1 H), 4.25 (q, J = 7.0 Hz , 2 H), 3.03 (s, 6 H), 2.67 (s, 3 H), 1.30 (t, J = 7.0 Hz, 3 H), 0.36 (s, 9 H);
13C NMR (125 MHz, CDCl3) ꢀ 163.7, 162.5, 159.6, 152.4, 144.5, 141.5, 137.8, 134.8, 134.6, 134.3,
˜
122.2, 119.0, 113.9, 111.9, 99.1, 61.1, 40.0, 17.5, 14.3, –0.2; IR (neat) ꢀmax = 2957, 2926, 2857, 2820,
2214, 1711, 1599, 1554, 1516, 1442, 1372, 1323, 1264, 1124, 1093, 1003, 843 cm–1; HRMS (ESI+): m/z
calculated for [C23H28N3O2SiS2]+ 470.1392, found 470.1390. Following procedure E using THF as
solvent, 5j (51 mg, 0.11 mmol) was desilylated to afford 8c (35 mg, 0.088 mmol, 81% yield) as a white
solid after purification by column chromatography eluting with hexanes/ethyl acetate (3:1). Rf (8c) = 0.25
(hexanes/ethyl acetate 3:1); mp 185 ºC; 1H NMR (500 MHz, CDCl3) ꢀ 7.70 (d, J = 5.0 Hz, 1 H), 7.55 (d,
J = 9.0 Hz, 1 H), 7.39 (d, J = 5.0 Hz, 1 H), 6.72 (dd, J = 9.0, 3.0 Hz, 1 H), 6.68 (d, J = 3.0 Hz, 1 H), 4.26
(q, J = 7.5, 2 H), 3.04 (s, 6 H), 2.66 (s, 3 H), 1.30 (t, J = 7.5, 3 H); 13C NMR (75 MHz, CDCl3) ꢀ 163.4,
162.5, 159.6, 152.4, 139.5, 137.4, 134.6, 133.1, 128.3, 125.8, 122.3, 118.9, 114.1, 112.0, 99.5, 61.1, 40.0,
˜
17.5, 14.3; IR (neat) ꢀmax = 3108, 2964, 2928, 2859, 2213, 1716, 1701, 1684, 1653, 1601, 1558, 1522,

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HETEROCYCLES, Vol. 80, No. 2, 2010
1506, 1437, 1373, 1263 cm–1; HRMS (ESI+): m/z calculated for [C20H20N3O2S2]+ 398.0997, found
398.0997.
Preparation of 8d: Using procedure D, 5j (50 mg, 0.11 mmol) (see preparation of 8c) was brominated to
afford 7c (49 mg, 0.089, 83% yield) as white solid after purification by column chromatography eluting
1
with hexanes/EtOAc (7:1 to 5:1). Rf (7c) = 0.22 (hexanes/EtOAc 5:1); mp 134–136 ºC; H NMR (500
MHz, CDCl3) ꢀ 7.86 (s, 1 H), 7.65 (d, J = 8.5 Hz, 1 H), 7.14 (d, J = 8.5 Hz, 1 H), 4.23 (q, J = 7.3 Hz , 2
13
H), 2.92 (s, 6 H), 2.64 (s, 3 H), 1.28 (t, J = 7.3 Hz, 3 H), 0.38 (s, 9 H); C NMR (125 MHz, CDCl3) ꢀ
162.9, 162.3, 159.7, 156.8, 143.4, 142.7, 139.8, 134.9, 134.0, 132.9, 122.0, 121.5, 120.4, 116.9, 108.1,
˜
61.0, 43.7, 17.4, 14.2, –0.2; IR (neat) ꢀmax = 2954, 2924, 2853, 2224, 1717, 1653, 1578, 1523, 1501,
1456, 1437, 1261 cm–1; HRMS (ESI+): m/z calculated for [C23H27N3O2SiS2Br]+ 548.0497, found
548.0498. Following procedure E with THF as solvent, 7c (54 mg, 0.099 mmol) was desilylated to afford
8d (39 mg, 0.082 mmol, 83% yield) as a wax after purification by column chromatography eluting with
hexanes/ethyl acetate (1:1 to 3:1). Rf (8d) = 0.4 (hexanes/ethyl acetate 3:1); mp 53–54 ºC; 1H NMR (500
MHz, CDCl3) ꢀ 7.77 (d, J = 5.25 Hz, 1 H), 7.66 (d, J = 8.5 Hz, 1 H), 7.50 (d, J = 5.25 Hz, 1 H), 7.15 (d, J
= 8.5 Hz, 1 H), 4.24 (q, J = 7 Hz, 2 H), 2.93 (s, 1 H), 2.62 (s, 1 H), 1.28 (t, J = 7 Hz, 3 H); 13C NMR (75
MHz, CDCl3) ꢀ 162.6, 162.3, 159.8, 156.8, 139.4, 138.5, 133.7, 132.9, 127.7, 126.9, 122.1, 121.7, 120.6,
˜
116.9, 108.3, 61.1, 43.7, 17.4, 14.3; IR (neat) ꢀmax = 3110, 2926, 2795, 2224, 1714, 1579, 1522, 1485,
1437, 1373, 1327, 1263, 1128, 1093 cm–1; HRMS (ESI+): m/z calculated for [C20H19N3O2S2Br]+
476.0102, found 476.0105.
Preparation of 8f: Following procedure E, 5e (63 mg, 0.14 mmol) was desilylated using THF/water
(4:1) as solvent. The reaction mixture was passed through a shot plug of silica gel eluting with DCM. Due
to the poor solubility of 8f in DCM, the eluent was monitored under UV light on a TLC plate until no
positive detection was observed. The solvent was evaporated and the resulting solid was washed with
hexanes to give 8f (44 mg, 83%) as a white powder. mp 220–223°C (decomposed). 1H NMR (500 MHz,
THF-CDCl3) ꢀ 7.95–7.90 (d, 1 H, J = 8.3 Hz), 7.85–7.82 (d, J = 1.1 Hz, 1 H), 7.82–7.78 (dd, J = 1.1, 8.3
Hz, 1 H), 7.65–7.60 (2 H, signals overlapping), 7.55–7.51 (d, J = 5.2 Hz, 1 H), 7.26–7.16 (m, 1 H), 7.16–
7.12 (d, J = 5.2 Hz, 1 H); 13C NMR (125 MHz, THF-CDCl3) ꢀ 141.2, 140.1, 139.5, 135.7, (134.8, 134.5,
2
134.3, 134.0, q, JF–C = 33.0 Hz), 134.4, 133.8, 133.7, 129.9, (128.44, 128.41, 128.38, 128.35, q, 3JF–C
=
3.8 Hz), (126.2, 124.0, 121.9, 119.7, q, 1JF–C = 272.9 Hz), 126.1, (125.15, 125.12, 125.09, 125.06, q, 3JF–C
= 3.8 Hz), 124.9, 124.7, 123.7, 123.5, 122.0, 116.9, 116.6; IR (neat) ꢀmax = 2233 cm–1; HRMS (ESI+)
˜
calculated for [C20H11NF3S2]+ 386.285 found 386.292.
Preparation of 9: Compound 5e (28 mg, 0.062 mmol) and NBS (22 mg, 0.12 mmol) were mixed in a 20
mL vial with 0.5 mL CCl4 and stirred for 5 h at room temperature. The resulting mixture is washed

HETEROCYCLES, Vol. 80, No. 2, 2010
1447
through a short plug with silica gel. Concentration in vacuo afforded 7a (35 mg, 0.056 mmol, 91% yield),
which was directly used in the following step. Crude 7a was dissolved in 224 ꢀL of THF and 56 ꢀL of
water, TBAF (1M solution in THF, 112 ꢀL, 0.11 mmol) was added, and the resulting solution was stirred
at room temperature for 3 h. The reaction mixture was passed through a short plug of silica gel and the
filtrate was concentrated to give 8e (21 mg, 0.045 mmol, 80% yield). Finally, crude 8e was mixed with
Br2 (0.5 M stock solution in benzene, 270 ꢀL, 0.14 mmol). The resulting crude material was passed
through a short plug with silica gel and purified by column chromatography to afford 9 (23 mg, 87%
yield or 64% yield for 3 steps). 1H NMR (500 MHz, CDCl3) ꢀ 7.80–7.76 (d, J = 8.1 Hz, 1 H), 7.75–7.71
(d, J = 7.7 Hz, 1 H), 7.70–7.66 (d, J = 7.7 Hz, 1 H), 7.64–7.61 (d, J = 8.1 Hz, 1 H), 7.61–7.59 (s, 1 H),
7.44–7.36 (m, 2 H), 7.27–7.25 (s, 1 H); 13CNMR (125 MHz, CDCl3) ꢀ 139.7, 138.6, 137.9, 137.2, (134.8,
2
3
134.5, 134.3, 134.0, q, JF–C = 32.7 Hz,) 134.0, 131.6, 128.1 (128.00, 127.98, 127.94, 127.92, q JF–C
=
3
3.7 Hz), 126.5, 125.6, (125.15, 125.12, 125.09, 125.06, q JF–C = 3.7 Hz), (126.0, 123.8, 121.6, 119.4, q
1
JF–C = 273.2 Hz), 124.0, 122.2, 116.5, 116.1, 115.7, 110.2; IR (neat) ꢀmax = 2233 cm–1; HRMS (ESI+)
˜
calculated for [C20H9NF3S2Br2] + 541.8495, found 541.8501.
Preparation of 10 and 11: Compound 5f (0.12 mmol from 65 mg of a mixture 2.5:1 of 5f and 4-(N,N-
dimethylamino)benzonitrile, see preparation of 8a) was dissolved in CCl4 (0.5 mL) and NBS (44 mg,
0.24 mmol) was added. The resulting solution was stirred for 5 h in an 80 °C oil bath. The reaction
mixture was passed through a plug of silica gel eluting with dichloromethane. Concentration and
purification by column chromatography (3:1 hexanes/EtOAc) gave 7b (30 mg, 46% yield) as a white gel
that was used in the following reaction without further purification. 1H NMR (500 MHz, CDCl3) ꢀ 7.74–
7.70 (d, J = 8.4 Hz, 2 H), 7.67–7,64 (two overlapping s, 2 H), 7.63–7.59 (dd, J = 8.4, 1.4 Hz, 1 H), 7.31–
7.29 (s, 1H), 6.99–6.97 (s, 1H), 2.83–2.80 (s, 6H), 0.40–0.37 (s, 9H). Compound 7b (30 mg, 0.055 mmol)
was desilylated according to procedure E using THF/water (4:1) as solvent to give 8g. Crude 8g was
mixed with Br2 (0.5M stock solution, 0.33 mL, 0.17 mmol) and stirred at room temperature of 6 h. The
reaction mixture was passed through a plug of silica gel eluting with DCM and the filtrate was
concentrated and purified by column chromatography eluting with 1:1 hexanes/DCM to give 10 (26 mg,
28% yield over 2 steps) 1H NMR (500 MHz, CDCl3) ꢀ 7.83–7.79 (d, J = 8.1 Hz, 1 H), 7.71–7.69 (s, 1 H),
7.65–7.62 (d, J = 5.3 Hz, 1 H), 7.61–7.57 (dd, J =8.1, 1.7 Hz, 1 H), 7.46–7.44 (d, J = 1.7 Hz, 1 H), 4.82–
4.74 (q, J = 5.5 Hz, 1 H), 3.14–3.08 (d, J = 5.6 Hz, 3H); IR (neat) ꢀmax = 2211 cm–1; HRMS (ESI+)
˜
calculated for [C20H11N2F3SBr2] + 539.8988, found 539.8993 and 11 (34 mg, 32% yield over 2 steps) 1H
NMR (500 MHz, CDCl3) ꢀ 7.83–7.79 (d, J = 8.2 Hz, 1 H), 7.79–7.68 (s, 1H), 7.63–6.59 (dd, J = 8.2, 1.0
Hz, 1 H), 7.47–7.45 (d, J = 1.0 Hz, 1 H) 7.35–7.34 (s, 1 H), 4.85–4.76 (br s, 1 H), 3.15–3.10 (s, 3 H); IR
(neat) ꢀmax = 2210 cm–1.
˜

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HETEROCYCLES, Vol. 80, No. 2, 2010
ACKNOWLEDGEMENTS
We thank BASF, Inc. for gifts of HBPin and B2Pin2, and the Michigan Economic Development Corp., the
NIH (GM63188 to M.R.S.), the Astellas USA Foundation (to R.E.M.) the ACS Green Chemistry
Institute’s Pharmaceutical Roundtable, and Pfizer for kind financial support.
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