Microwave-assisted preparation of fused bicyclic heteroaryl boronates: Application in one-pot suzuki couplings

Article abstract of DOI:10.1021/jo060218p

The rapid and efficient synthesis of various disubstituted 5,6-fused heterocycles using a microwave-assisted one-pot cyclization-Suzuki coupling approach is described. This work highlights the tolerance of the boronic ester functional group to a variety o

Full text of DOI:10.1021/jo060218p

Microwave-Assisted Preparation of Fused
Bicyclic Heteroaryl Boronates: Application in
One-Pot Suzuki Couplings
SCHEME 1. Retrosynthetic Routes to Target Libraries 1-3
Erin F. DiMauro* and Jason R. Vitullo†
Department of Chemistry Research and DiscoVery,
Amgen Inc., One Kendall Square, Building 1000,
Cambridge, Massachusetts 02139
erin.dimauro@amgen.com
ReceiVed February 1, 2006
The rapid and efficient synthesis of various disubstituted 5,6-
fused heterocycles using a microwave-assisted one-pot
cyclization-Suzuki coupling approach is described. This
work highlights the tolerance of the boronic ester functional
group to a variety of reaction conditions and the utility of
functionalized boronates as penultimate intermediates in the
synthesis of diverse compound libraries.
assisted synthetic routes to access a variety of 2,5-disubstituted
5
6
benzo[b]thiophenes, benzo[b]furans, and 2,6-disubstituted imi-
7
dazo[1,2-a]pyridines, exemplified by quinazolines of general
structures 1-3. We sought divergent routes that would allow
1
for easy variation of the aryl group at C5/C6 and the R group
at C2. Thus, we set out to prepare small libraries of 2-substituted
(benzo[b]thiophen-5-yl)boronates (5), (benzo[b]furan-5-yl)bo-
ronates (6), and imidazo[1,2-a]pyridine-6-boronates (7), each
of which could be coupled under Suzuki conditions to a variety
of bromoquinazolines (4) in order to obtain a diverse set of
target libraries 1-3 (Scheme 1). An alternative strategy to
libraries 1-3 would involve reversing the Suzuki coupling
partners. The drawback of this route lies in the requirement for
the preparation, purification and storage of multiple quinazoline
boronates derived from bromides 4. In our hands, such deriva-
tives were difficult to isolate owing to their insolubility in
organic solvents and instability to silica gel chromatography.
The broad utility of Suzuki-Miyaura coupling reactions is
1
widely appreciated in the synthetic community. Consequently,
the establishment of new routes to functionalized boronic acid
and boronic ester precursors is an ongoing effort in several
2
research groups. Substituted 5,6-fused heterocycles can be
found in many types of synthetic and naturally occurring
3
medicinal substances. The exploration of convenient synthetic
routes to these compounds is a priority in drug discovery and
the benefits of microwave-assisted approaches are becoming
increasingly evident.4
To expand the scope of our small molecule drug discovery
programs, we wished to identify practical and general microwave-
2
Also, this approach would require that R be compatible with
the reaction conditions necessary for the formation of the
boronate from 4.
Our initial efforts were focused on identifying convenient
routes to boronates 5 or 6 toward target libraries 1 and 2. The
most obvious synthetic route to compounds such as 6 involves
the conversion of 5-halobenzofurans (9) to boronic esters or
acids using Pd(0) catalysis or lithiation-substitution (Scheme
*
To whom correspondence should be addressed. Tel: 617-444-5189. Fax:
6
17-621-3907.
†
University of Pennsylvania.
(1) (a) For a review, see: Suzuki, A. J. Organomet. Chem. 1999, 576,
1
2
47-168. (b) Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 15, 2419-
440.
1
(
2) (a) Zenk, R.; Partzsch, S.; Chimica Oggi 2003, 21, 70-73. (b) Tyrrell,
E.; Brookes, P. Synthesis 2003, 4, 469-483.
3) (a) Jones, G., Ed. ComprehensiVe Heterocyclic Chemistry. II. Volume
2). A major limitation with this approach is that R must be
compatible with the reaction conditions required for the forma-
tion of the boronate. Furthermore, for library generation or
(
8
: Fused FiVe-and Six-Membered Rings with Ring Junction Heteroatom;
Pergamon: Oxford, 1996. (b) Ramsden, C. A., Ed. ComprehensiVe
Heterocyclic Chemistry. II. Volume 7: Fused FiVe-and Six-Membered Rings
without Ring Junction Heteroatom; Pergamon: Oxford, 1996.
(5) For a review on the synthesis of benzo[b]thiophenes, see: Rayner,
C. M.; Graham, M. A. Sci. Synth. 2001, 10, 155-184.
(
4) (a) Kappe, C. O.; Dallinger, D. Nat. ReV. Drug DiscoVery 2006, 5,
1-63. (b) Besson, T.; Braun, C. T. In MicrowaVe Assisted Organic
Synthesis; Tierney, J. P., Lidstr o¨ m, P., Eds.; CRC Press: Boca Raton, FL,
005; pp 44-74.
(6) For a review on the synthesis of benzo[b]furans, see: Dell, C. P.
Sci. Synth. 2001, 10, 11-86.
5
(7) For a review on the synthesis of azaindolizines (including imida-
zopyridines), see: Hajos, G.; Riedl, Z. Sci. Synth. 2002, 12, 613-678.
2
1
0.1021/jo060218p CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/14/2006
J. Org. Chem. 2006, 71, 3959-3962
3959

SCHEME 2. Common Route to
(
TABLE 1. One-Pot Preparation of 5 and Conversion to 1:
(Step 1)a 11 + HSCH R1 (Step 2)b 5 + 4a
Benzo[b]furan-5-yl)boronatesa
2
entry
1
R1
Tb (°C)
tb (h)
% yield
1
2
1a
1b
1c
1d
1e
CO2Et
CO2i-Pr
CO2H
CONHPh
CONHMe
90
90
95
90
95
0.5
1.0
1.0
1.0
1.5
57
60
24
41
17
c
3
d
4
5
a
1
Step 1: 1.0 equiv of 11, 1.1 equiv of HSCH2R , 1.0 equiv of K2CO3,
a
µW, CH CN, 140 °C, 0.5 h. b Step 2: 0.8 equiv of 4a, 0.13 equiv of
Key: (a) (i) BuLi, (ii) B(OMe)3, (iii) HCl; (b) cat. Pd(0), bis(pinaco-
3
lato)diboron, KOAc, ∆.
Pd(dppf)Cl2, 1.6 equiv of K2CO3, H2O/CH3CN (1:3); µW, T and t as
reported. c Step 1: CH3CN/EtOH (1:1), 1 h. Step 2: 1.0 equiv of K2CO3,
d
SCHEME 3. Route A to Target Libraries 1 and 2
0.3 equiv of Pd(dppf)Cl2, H2O/CH3CN/EtOH (1:2:1). Step 2: 1.5 equiv
of 4a, 0.3 equiv of Pd(dppf)Cl2.
the methylene hydrogens are rendered acidic. Although route
A is an atypical method for the preparation of benzofurans,
similar methodology has been employed in the prepartion of
1
1,12
benzo[b]thiophenes.
Furthermore, 11 has been used as a
9
a
substrate for nucleophilic aromatic substitutions.
The reaction of 11 and ethyl mercaptoacetate was examined
in the microwave using a variety of organic solvents and bases.
Optimal conditions for the preparation of 2-ethylcarboxylate-
(benzo[b]thiphen-5-yl)boronate (5a) in 74% yield were quickly
identified (eq 1).
medicinal chemistry applications, it would be preferable to
1
introduce the diversity element R later in the reaction sequence.
Recently, derivatization of functionalized arylboronic acids has
been accomplished using a solid-phase resin immobilization
8
strategy. Similarly, there have been several reports of deriva-
9
tization of functionalized arylboronic esters. The most recently
We then determined that crude 5a, prepared in this manner,
can be used directly without workup, in a subsequent microwaVe-
assisted Suzuki coupling to bromoquinazoline 4a. Likewise,
developed method for the formation of 2-substituted (benzo[b]-
furan-5-yl)boronate esters 6 from functionalized aryl boronic
esters is lengthy and low yielding.9
c
2-mercaptoacetic acid and derivatives were condensed with 11,
We first examined the reaction of R-activated alcohols or
thiols with 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
and the resulting crude boronates were coupled with 4a to
prepare target compounds 1a-e (Table 1). Attempts to condense
2
-yl)benzaldehyde (11) followed by coupling of the boronate
1
2
benzylmercaptan boronates (R ) Ar) with 11 were unsuccess-
intermediates 5 or 6 with 6-bromoquinazolin-2-amine (4a, R
NH2) (route A, Scheme 3). Although 11 can be obtained by
13
ful. In these cases, the SNAr intermediates, observed by LCMS,
were reluctant to cyclize to the benzothiophenes, presumably
because of the decreased acidity of the R-protons.
)
the reaction of pinacol and 4-fluoro-3-formylphenylboronic acid
as previously demonstrated,9a we prepared 11 in 82% yield
directly from commercially available 10 using the method of
Despite numerous attempts, no conditions were identified to
prepare the analogous 2-ethyl carboxylate-(benzo[b]furan-5-yl)-
boronate intermediate 6a in acceptable yield from 11 and ethyl
Miyaura et al.10 For formation of 5 or 6, the desired transforma-
tion is an SNAr with concomitant condensation and cyclization.
1
4
1
2-hydroxyacetate. As anticipated, the required SNAr reaction
is significantly slower with the alkoxide nucleophile than with
the thiolate. Route A for target library 2 was therefore abandoned.
Next, we investigated the reaction of R-activated halides with
The activating group R on the alcohol/thiol should be aryl,
ester, amide, NO2, CN, etc., such that the basicity and
nucleophilicity of the alcohol/thiol is somewhat attenuated and
2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benz-
(
8) Gravel, M.; Thompson, M. Z.; Berube, C.; Hall, D. G. J. Org. Chem.
002, 67, 3-15.
9) (a) Holland, R.; Spencer, J.; Deadman, J. J. Synthesis 2002, 2379-
382. (b) Spencer, J.; Burd, A.; Goodwin, C. A.; Metrette, S. A. M.; Scully,
2
aldehyde (12) (route B, Scheme 4). While this method is
(
commonly employed in the synthesis of 2-substituted benzo-
2
15
[
b]furans, it has not been demonstrated in the presence of a
M. F.; Adatia, T.; Deadman, J. J. Tetrahedron 2002, 58, 1551-1556. (c)
McKierman, G. J.; Hartley, R. C. Org. Lett. 2003, 5, 4389-4392. (d) Bois-
Choussy, M.; Cristau, P.; Zhu, J. Angew. Chem., Int. Ed. 2003, 42, 4238-
(11) (a) Patel, M.; Rohde, J. J.; Kolasa, T. Tetrahedron Lett. 2003, 44,
4
241. (e) Kaiser, M.; Siciliano, C.; Assfalg-Machleidt, I.; Groll, M.;
6665-6667. (b) Bridges, A. J.; Lee, A.; Schwartz, C. E.; Towle, M. J.;
Littlefield, B. A. Bioorg. Med. Chem. 1993, 1, 403-410. (c) Bridges, A.
J.; Lee, A.; Maduakor, E. C.; Schwartz, C. E. Tetrahedron Lett. 1992, 33,
7499-7502. (d) Osuga, H.; Suzuki, H.; Tanaka, K. Bull. Chem. Soc. Jpn.
1997, 70, 891-897.
(12) To the best of our knowledge, there have been no prior reports of
this cyclization in the presence of boronic ester or acid functionality.
(13) Conditions examined: 4-chloro or 4-methoxybenzylmercaptan,
various bases, µW, ∆.
(14) Best conditions identified: DMA, K2CO3, MS 4Å, 130 °C, 30 min,
µW.; 50% conversion.
Milbradt, A. G.; Moroder, L. Org. Lett. 2003, 5, 3435-3437. (f) Schulz,
M. J.; Coats, S. J.; Hlasta, D. J. Org. Lett. 2004, 6, 3265-3268. (g) Lautens,
M.; Mancuso, J. J. Org. Chem. 2004, 69, 3478-3487. (h) Moore, J. E.;
York, M.; Harrity, J. P. A. Synlett 2005, 860-862. (i) Moore, J. E.; Davies,
M. W.; Goodenough, K. M.; Wybrow, R. A. J.; York, M.; Johnson, C. N.;
Harrity, J. P. A. Tetrahedron 2005, 61, 6706-6714. (j) Zhang, H.; Vogels,
C. M.; Wheaton, S. L.; Baerlocher, F. J.; Decken, A.; Westcott, S. A.
Synthesis 2005, 2739-2743.
(
10) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
7
508-7510.
3
960 J. Org. Chem., Vol. 71, No. 10, 2006

SCHEME 4. Route B to Target Library 2
SCHEME 5. Route C to Target Library 3
TABLE 3. One-Pot Preparation of 7 and Conversion to 3:
a
1
b
TABLE 2. One-Pot Preparation of 6 and Conversion to 2:
(Step 1) 13 + BrCH2COR (Step 2) 7 + 4a
a
1
b
(
Step 1) 12 + XCH2R (Step 2) 6 + 4a
entry
3
R1
% yield
entry
2
R1
X
Ta (°C)
% yield
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
Ph
26
43
42
36
50
27
26
54
1
2
3
4
5
2a
2b
2c
2d
2e
CO2Et
Br
Cl
Cl
Br
Br
150
140
140
150
150
33
40
55
74
72
2-OMe-C H4
3-OMe-C H4
4-OMe-C6H4
3-thiophene
5-benzo[d][1,3]dioxole
Et
t-Bu
6
CONHPh
CO(morpholine)
COPh
6
COt-Bu
a
1
3g
3h
Step 1: 1.0 equiv of 12, 1.1 equiv of XCH2R , 2.0 equiv of K2CO3,
b
CH3CN, µW, T as reported, 1 h. Step 2: 0.8 equiv of 4a, 0.13 equiv of
Pd(dppf)Cl2, 1.6 equiv of K2CO3, H2O/CH3CN (1:3); µW, 90 °C, 0.5 h.
a
1
Step 1: 1.0 equiv of 13, 1.1 equiv of BrCH2COR , EtOH, µW, 130
°
C, 0.5 h. b Step 2: 0.8 equiv of 4a, 0.13 equiv of Pd(dppf)Cl2, 3.0-3.6
equiv of K2CO3, H2O/EtOH (1:3); µW, 90 °C, 0.5 h.
boronic ester functionality. Microwave conditions for the one-
step preparation of 12 from 8 were rapidly developed. Previously
reported conditions for the synthesis of 12 from 8 involve a
three-step protecting group strategy.9
General conditions for the one-pot, two-step cyclization-
Suzuki coupling to access disubstituted imidazopyridines of
target library 3 were developed in short order (Table 3).
Further work is underway to extend target libraries 1-3 and
to employ our microwave-assisted one-pot cyclization-Suzuki
approach in the synthesis of other disubstituted 5,6- and 6,6-
fused heterocycles. This work highlights the tolerance of the
boronic ester functional group to a variety of reaction conditions.
Owing to the wealth of commercially available aryl halides,
these methods should allow for the rapid preparation of other
modular target libraries from a single commercial or readily
available aryl boronate building block.
c
The reaction of 12 and ethyl 2-bromoacetate was examined
in the microwave using a variety of organic solvents and bases.
Optimal conditions for the preparation of 2-ethyl carboxylate-
(benzo[b]furan-5-yl)boronate (6a) in 73% yield were identified
(eq 2).
Experimental Section
As observed for the benzothiophene series, crude 6a, prepared
Ethyl 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzo-
in this manner, can be used directly without workup, in a
subsequent microwaVe-assisted Suzuki coupling to bromo-
quinazoline 4a. A brief substrate scope analysis of this one-pot
cyclization-Suzuki coupling protocol (Table 2) served to
validate route B as a suitable strategy to access target library 2.
Having met with success in the microwave-assisted prepara-
tion of benzothiophenes 1 and benzofurans 2, we set out to
extend the methodology and target compound libraries to include
quinazoline imidazopyridines of general structure 3 via route
C (Scheme 5).
[
b]thiophene-2-carboxylate (5a). To a 10-20 mL microwave
reaction vessel were added 11 (0.500 g, 2.00 mmol), ethyl
-mercaptoacetate (0.241 mL, 2.20 mmol), K CO (0.276 g, 2.00
mmol), and CH CN (5.0 mL). The vessel was sealed, and the system
2
2
3
3
2
was purged with N . The mixture was heated in the microwave for
30 min at 140 °C and then allowed to cool to room temperature,
filtered, and concentrated. The crude product was purified by MPLC
(
g, 1.48 mmol, 74%) as an off-white solid: LCMS (ESI, pos ion)
m/z 333.1 [M + 1]; HRMS calcd for [C17
found 333.13335; H NMR (400 MHz, DMSO-d
2 2 2
SiO , eluent: 100% CH Cl ) to afford the title compound (0.492
+
H22BO
4
S] 333.13264,
) δ 8.44 (s, 1H),
.33 (s, 1H), 8.12 (d, J ) 8.0 Hz, 1H), 7.82 (d, J ) 8.0 Hz, 1H),
.42 (q, J ) 8.0 Hz, 2H), 1.40 (t, J ) 8.0 Hz, 3H), 1.39 (s, 12H);
1
6
Optimal conditions for the microwave preparation of 2-phen-
ylimidazo[1,2-a]pyridine 6-boronate (7a) from 13 and 2-bromo-
8
4
1
-phenylethanone were identified (eq 3).12
13
C NMR (100 MHz, DMSO-d
6
) δ 161.9, 144.1, 138.3, 133.1,
(15) (a) Paizs, C.; Tosa, M.; Majdik, C.; Moldovan, P.; Novak, L.;
Kolonits, P.; Marcovici, A.; Irimie, F.-D.; Poppe, L. Tetrahedron: Asym-
metry 2003, 14, 1495-1501. (b) D′Sa, B. A.; Kisanga, P.; Verkade, J. G.
Synlett 2001, 670-672. (c) Pestellini, V.; Giolitti, A.; Pasqui, F.; Abelli,
L.; Cutrufo, C.; De Salvia, G.; Evangelista, S.; Meli, A. Eur. J. Med. Chem.
1
988, 23, 203-206. (d) Lamotte, G.; Demerseman, P.; Royer, R. Synthesis
1984, 1068-1070.
J. Org. Chem, Vol. 71, No. 10, 2006 3961

1
32.8, 132.0, 131.1, 122.5, 83.9, 61.5, 24.7, 14.1 (C-B signal not
3
to room temperature, transferred to a round-bottom flask with CH -
CN, and concentrated. The initial crude product was first purified
by a MeOH wash. The solid was then further purified by MPLC
obserVed up to 40 mg/mL).
Ethyl 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzo-
furan-2-carboxylate (6a). To a 10-20 mL microwave reaction
vessel were added 12 (0.200 g, 0.806 mmol), ethyl bromoacetate
(SiO
OH) in CH
2
, gradient eluent: 20 to 40% 90:10:1 (CH
Cl ).
2 2 3 4
Cl /CH OH/NH -
2
2
(
0.098 mL, 0.886 mmol), K
CN (2.0 mL). The vessel was sealed, and the system was purged
with N . The mixture was heated in the microwave for 60 min at
50 °C and then allowed to cool to room temperature, transferred
to round-bottom flask with CH CN, and concentrated. The crude
product was purified by MPLC (SiO , eluent: 100% CH Cl ) to
2
CO
3
(0.223 g, 1.61 mmol), and CH
3
-
General Method B: Preparation of Benzofuran Quinazolines
(2). To a 10-20 mL microwave reaction vessel were added 12
2 3
(0.200 g, 0.806 mmol), the halide (0.886 mmol), K CO (0.223 g,
2
1
1.61 mmol), and CH
system was purged with N
3
CN (2.0 mL). The vessel was sealed, and the
. The mixture was heated in the
3
2
2
2
2
microwave for 1 h at 140-150 °C and then cooled to room
temperature and unsealed. To the reaction vessel were added 4a
afford the title compound (0.187 g, 0.590 mmol, 73%) as an off-
white solid: LCMS (ESI, pos ion) m/z 317.0 [M + 1]; HRMS calcd
(0.150 g, 0.670 mmol), Pd(dppf)Cl
CO (0.185 g, 1.34 mmol), CH CN (2.0 mL), and water (1.3 mL).
The vessel was sealed, and the system was purged with N . The
mixture was heated in the microwave for 30 min at 90 °C then
allowed to cool to room temperature, transferred to a round-bottom
2 2
(0.082 g, 0.101 mmol), K -
+
1
for [C17
MHz, DMSO-d
H), 7.78 (d, J ) 8.0 Hz, 1H), 4.43 (q, J ) 8.0 Hz, 2H), 1.38 (t,
H22BO
5
]
317.15548, found 317.15580; H NMR (400
3
3
6
) δ 8.23 (s, 1H), 7.85 (s, 1H), 7.84 (d, J ) 8.0 Hz,
2
1
13
J ) 8.0 Hz, 3H), 1.38 (s, 12H); C NMR (100 MHz, DMSO-d
δ 158.6, 156.9, 145.3, 133.5, 130.5, 126.6, 114.2, 111.7, 83.8, 61.3,
4.7, 14.1.
-Phenyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-H-
6
)
flask with CH
first purified by a CH
by MPLC (SiO , gradient 0 to 40% 90:10:1 (CH
OH) in CH Cl ).
3
CN, and concentrated. The initial crude product was
OH wash. The solid was then further purified
Cl /CH OH/NH
2
3
2
2
2
2
3
4
-
imidazo[1,2-a]pyridine Hydrobromide (7a). To a 10-20 mL
microwave reaction vessel were added 13 (0.200 g, 0.909 mmol),
2
2
General Method C: Preparation of Imidazopyridine Quinazo-
lines (3). To a 10-20 mL microwave reaction vessel were added
13 (0.200 g, 0.909 mmol), the bromo ketone (1.00 mmol), and EtOH
(2.0 mL). The vessel was sealed, and the system was purged with
2-bromoacetophenone (0.199 g, 1.00 mmol), and EtOH (2.0 mL).
The vessel was sealed, and the system was purged with N . The
2
mixture was heated in the microwave for 30 min at 130 °C. After
cooling to room temperature, the precipitate was collected using a
membrane Buchner filtration apparatus and washed with EtOH to
afford the title compound (0.177 g, 0.440 mmol, 48%) as a white
solid: HPLC complete hydrolysis to boronic acid on LC column,
N
2
. The mixture was heated in the microwave for 30 min at 130
°C and then cooled to room temperature and unsealed. To the
reaction vessel were added 4a (0.170 g, 0.758 mmol), Pd(dppf)Cl
(0.093 g, 0.114 mmol), K CO (0.356 g, 2.58 mmol), EtOH (2.0
mL), and water (1.3 mL). The vessel was sealed, and the system
was purged with N . The mixture was heated in the microwave for
2
2
3
99.4%; LCMS (ESI, pos ion) complete hydrolysis to boronic acid
on LC column, m/z 239.1 [M + 1]; HRMS calcd for [C19
H
22
-
2
+
321.17688, found 321.17792; 1H NMR (400 MHz,
) δ 9.20 (s, 1H), 8.88 (s, 1H), 8.06-8.03 (m, 4H), 7.72-
.64 (m, 4H), 1.45 (s, 12H); 13C NMR (100 MHz, DMSO-d
) δ
BN
2
O
2
]
30 min at 90 °C then allowed to cool to room temperature,
transferred to a round-bottom flask with EtOH, and concentrated.
DMSO-d
6
7
1
8
6
The initial crude product was first purified by a CH
solid was then further purified by MPLC (SiO , gradient eluent:
20 to 40% 90:10:1 (CH Cl /CH OH/NH OH) in CH Cl ).
3
OH wash. The
41.2, 136.4, 135.9, 134.9, 130.4, 129.5, 126.6, 126.2, 112.0, 111.2,
4.8, 73.5, 24.7.
2
2
2
3
4
2
2
General Method A: Preparation of Benzothiophene Quinazo-
Acknowledgment. J.R.V. thanks Amgen, Inc., for a summer
internship. We thank Mr. Russell Graceffa and Dr. Jay Larrow
for the synthesis of 4a and 11.
lines (1). To a 10-20 mL microwave reaction vessel were added
1 (0.200 g, 0.800 mmol), the thiol (0.880 mmol), K CO (0.111
g, 0.800 mmol), and CH CN (2.0 mL). The vessel was sealed, and
the system was purged with N . The mixture was heated in the
1
2
3
3
2
Supporting Information Available: General experimental
considerations. New methods for preparing 4a, 11, and 12.
microwave for 30 min at 140 °C then cooled to room temperature
and unsealed. To the reaction vessel were added 4a (0.149 g, 0.667
1
Experimental details and analytical data for libraries 1-3. H and
mmol), Pd(dppf)Cl
mmol), CH CN (2.0 mL), and water (1.3 mL). The vessel was
sealed, and the system was purged with N . The mixture was heated
in the microwave for 0.5-1.5 h at 90 °C and then allowed to cool
2 2 3
(0.082 g, 0.100 mmol), K CO (0.184 g, 1.33
13
C NMR spectral data of boronates 5a, 6a, and 7a. This material
3
is available free of charge via the Internet at http://pubs.acs.org.
2
JO060218P
3
962 J. Org. Chem., Vol. 71, No. 10, 2006