Selective protodeboronation: synthesis of 4-methyl-2-thiopheneboronic anhydride and demonstration of its utility in Suzuki-Miyaura reactions

Article abstract of DOI:10.1016/j.tetlet.2007.09.060

An efficient synthesis of 4-methyl-2-thiopheneboronic anhydride is reported. Regioselective lithiation of 3-methylthiophene followed by reaction with triisopropylborate and hydrolysis provides a 92:8 ratio of 4-methyl-2-thiopheneboronic acid (1) and regio

Full text of DOI:10.1016/j.tetlet.2007.09.060

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8242–8245
Selective protodeboronation: synthesis of 4-methyl-2-
thiopheneboronic anhydride and demonstration of its utility
in Suzuki–Miyaura reactions
Liane M. Klingensmith,* Matthew M. Bio and George A. Moniz*
Chemical Process R&D, Amgen Inc., One Kendall Square, Bldg. 1000, Cambridge, MA 02139, United States
Received 20 August 2007; revised 4 September 2007; accepted 4 September 2007
Available online 14 September 2007
Abstract—An efficient synthesis of 4-methyl-2-thiopheneboronic anhydride is reported. Regioselective lithiation of 3-methylthioph-
ene followed by reaction with triisopropylborate and hydrolysis provides a 92:8 ratio of 4-methyl-2-thiopheneboronic acid (1) and
regioisomeric 2-methyl-3-thiopheneboronic acid (3). The undesired regioisomer is selectively protodeboronated with concentrated
acid to provide only the desired 4-methyl-2-thiopheneboronic acid (1). The title compound is isolated by dehydration/crystallization
and employed in several Suzuki–Miyaura reactions.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
OH
OH
S
S
B
Boronic acids are useful compounds in organic synthesis
due to their reactivity in a wide range of reactions,1
including the carbon–carbon bond forming Suzuki–
Miyaura reaction.2 The corresponding cyclic boronic
anhydrides are similarly reactive and, in many cases,
more easily isolated as a single species.3 As part of a
recent project, we required an efficient and practical
synthesis of 4-methyl-2-thiopheneboronic acid (1)
(Fig. 1).4 Substituted thiophenes are common structural
moieties in pharmaceuticals;5 thus a regioselective syn-
thesis of 1 would be a valuable addition to current
chemistry.
1
2
Figure 1. 4-Methyl-2-thiopheneboronic acid (1).
lithiation been developed for this substrate; however,
the method reported is inefficient and impractical on
scale due to the use of expensive stoichiometric reagents
and cryogenic (i.e., ꢀ78 ꢁC) reaction conditions.6a
Our efforts towards the selective generation of boronic
acid 1 are shown in Table 1. A screen of lithiation pro-
tocols revealed that the use of in situ generated LDA at
0 ꢁC or ꢀ35 ꢁC followed by a boronate quench and
hydrolysis gave the best ratio of 1 to 3 (Table 1). Impor-
tantly, both lithiation and quench could be carried out
at more industrially useful temperatures than reported
previously.
2. Results and discussion
Two challenges associated with designing a synthesis of
1 were the regioselective metallation of 2 and the iso-
lation and purification of the product boronic acid.
Seeking to further upgrade the purity of 1 beyond the
12:1 mixture obtainable via selective lithiation, we con-
sidered the possibility of selectively protodeboronating
3 in the presence of 1. Such a protocol would constitute
a valuable control point for controlling the ultimate
purity of 1. In 1961, Kuivila reported that the rate of
protodeboronation of substituted phenylboronic acids
was impacted by acid strength and substituent effects.
In general, protodeboronation was shown to proceed
via an A-SE2 mechanism, where protonation of the aryl
The lithiation of 2 has been the subject of several litera-
ture reports.6 Only recently has a highly regioselective
Keywords: Regioselective; Lithiation; Protodeboronation; Suzuki.
*
Corresponding authors. Tel.: +1 617 444 5198; fax: +1 617 621 3916
(G.A.M.); e-mail addresses: lianek@amgen.com; gmoniz@amgen.
com
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.060

L. M. Klingensmith et al. / Tetrahedron Letters 48 (2007) 8242–8245
8243
Table 1. Selectivity of lithiation-quench sequence with several lithiat-
ing reagents
this substrate would protodeboronate more rapidly than
its 2-methyl-substituted counterpart. Similar relative
reactivities were expected for the thiophene system
based upon Roques work.9
(HO)2B
B(OH)2
S
S
S
i) RLi (1.05 equiv)
ii) B(O-iPr)3 (1.1 equiv), -40 °Ca
iii) 1 N HCl
3
2
In the event, treatment of a mixture of boronate esters 8
and 9 in a 92:8 ratio with 6 N HCl resulted in hydrolysis
followed by selective protodeboronation of undesired
regioisomer 3 (Scheme 2). The final product mixture
was enriched to greater than a 91:1 ratio of 1 to 3, indi-
cating that the rate of protodeboronation of 3 is approx-
imately eight-fold than that of 1. Using this protocol,
the desired boronic acid (1) could be generated to the
near exclusion of regioisomer 3.
1
Entry RLi
T (ꢁC) 1:3b
1
2
3
4
5
6
n-Butyllithium
n-Butyllithium/TMEDA
n-Butyllithium/diisopropylamine
n-Butyllithium/diisopropylamine
n-Butyllithium/TMP (20%)c
n-Butyllithium/diisopropylamine (20%)c
ꢀ35
ꢀ35
ꢀ35
0
3:1
4:1
12:1
12:1
8:1
0
0
7:1
a Higher temperatures resulted in bis-addition of thiophene to boron.
b Complete lithiation was observed in all cases. The ratio of 1:3 was
measured by HPLC.
With a selective protodeboronation protocol estab-
lished, efforts were focused on developing an efficient
isolation of boronic acid 1. Unfortunately, all attempts
to crystallize the free boronic acid resulted in a mixture
of 1 and the corresponding boronic anhydride 10
(Fig. 2). Even when isolated from methanol/water,
drying of the solid resulted in near complete dehydration
of 1 to 10. Given the apparent ease of dehydration, and
cognizant that boronic anhydrides often display reactiv-
ity similar to boronic acids, we targeted the isolation of
10. Under optimized conditions, boronic anhydride 10
was isolated in 84% yield as a crystalline solid from
toluene/heptane. Residual boronic acid 3 was present
in the product in less than 1%.10
c n-Butyllithium (1.05 equiv), amine (0.20 equiv).
ring was the rate-determining step and was followed by
a rapid ionic cleavage of the boron–carbon bond (4!5,
Scheme 1).7 Stronger acid resulted in more rapid
protodeboronation, as did the use of more electron-rich
substituents (e.g., p-methoxyphenylboronic acid vs
p-fluorophenylboronic acid).
Subsequent to these reports, Roques studied the impact
of substituents on the protodeboronation rates of
furanboronic acids.8 As with phenylboronic acids,
electron-withdrawing substituents retarded the rate of
protodeboronation (Table 2, cf, entries 2 and 3); how-
ever, the rate decrease was greater when such substitu-
ents were located at the 3-position (6c, entry 3)
compared to the 2-position (6b, entry 2). The rate of
protodeboronation was also shown to be proportional
to the pKa of the boronic acid, with the most acidic
furanboronic acids having the slowest rates of protode-
boronation. Extrapolating these results to 3-methyl-2-
furanboronic acid (6d, entry 4), it could be expected that
The utility of boronic anhydride 10 was demonstrated in
several Suzuki–Miyaura reactions (Table 3). These
unoptimized reactions utilizing Pd(OAc)2 and XPhos11
as the precatalyst clearly show that 10 can be used in
place of the free boronic acid.12
In conclusion, we have developed a practical and
efficient synthesis of 4-methyl-2-thiopheneboronic
O
O
S
S
O
O
S
S
1) LDA
H2SO4 (aq)
B
B
X
B(OH)2
X
H
2) B(O-iPr)3
2
8 92%
9 8%
2 < 1%
4
5
Rate: X = OMe > CH3 > F > H
6 N HCl (7 equiv)
0 ˚C - rt
2-4 hours
Scheme 1.
S
(HO)2B
B(OH)2
S
S
1 91%
3 < 1%
2 9%
Table 2. Rates of protodeboronation and acidity constants for several
substituted furanboronic acids
Scheme 2.
O
O
B(OH)2
R2
H3O+
H
R1
6a-d
R1
R2
7a-d
S
Entry
Substrate
R1
R2
pKa
k (sꢀ1
)
B
O
O
B
1
2
3
4
6a
6b
6c
6d
H
CHO
H
H
H
CHO
CH3
7.89
2.15
0.95
8.5
4
S
B
6.0 · 10ꢀ4
1.7 · 10ꢀ4
NRa
O
S
10
Figure 2. 4-Methyl-2-thiopheneboronic anhydride (boroxine) (10).
H
a Not reported.

8244
L. M. Klingensmith et al. / Tetrahedron Letters 48 (2007) 8242–8245
Table 3. Demonstration of the utility of 4-methyl-2-thiopheneboronic
anhydride (10) in Suzuki–Miyaura reactions
5. For several examples: (a) Kochanny, M. J.; Adler, M.;
Ewing, J.; Griedel, B. D.; Ho, E.; Karanjawala, R.; Lee,
W.; Lentz, D.; Liang, A. M.; Morrissey, M. M.; Phillips,
G. B.; Post, J.; Sacchi, K. L.; Sakata, S. T.; Subramanyam,
B.; Vergona, R.; Walters, J.; White, K. A.; Whitlow, M.;
Ye, B.; Zhao, Z.; Shaw, K. J. Bioorg. Med. Chem. 2007,
15, 2127–2146; (b) Poehler, T.; Schadt, O.; Niepel, D.;
Rebernik, P.; Berger, M. L.; Noe, C. R. Eur. J. Med.
Chem. 2007, 42, 175–197; (c) Duplantier, A. J.; Bachert, E.
L.; Cheng, J. B.; Cohan, V. L.; Jenkinson, T. H.; Kraus,
K. G.; McKechney, M. W.; Pillar, J. D.; Watson, J. W. J.
Med. Chem. 2007, 50, 344–349; (d) Denton, T. T.; Zhang,
X.; Cashman, J. R. J. Med. Chem. 2005, 48, 224; (e)
10 (0.5 equiv)
Pd(OAc)2 ( 2%)
S
Br
XPhos ( 4%)
Na2CO3
2-butanol, 100 °C, 16 h
R
R
Entry
ArBr
Product
Isolated yield (%)
Br
1
2
11
12
93
96
MeO
´
´
Conde, S.; Perez, D. I.; Martınez, A.; Perez, C.; Moreno,
F. J. J. Med. Chem. 2003, 46, 4631; (f) Collins, I.; Moyes,
C.; Davey, W. B.; Rowley, M.; Bromidge, F. A.; Quirk,
K.; Atack, J. R.; McKernan, R. M.; Thompson, S.-A.;
Wafford, K.; Dawson, G. R.; Pike, A.; Sohal, B.; Tsou, N.
N.; Ball, R. G.; Castro, J. L. J. Med. Chem. 2002, 45, 1887.
6. The regioselectivity is reported as 99:1 at ꢀ78 ꢁC with a
variety of electrophiles, not including boronates. (a)
Smith, K.; Barratt, M. L. J. Org. Chem. 2007, 72, 1031–
1034; (b) Gronowitz, S.; Cederlund, B.; Hornfeldt, A.-B.
Chem. Scripta 1974, 5, 217–226.
Br
O
3
13
90
Br
7. (a) Kuivila, H. G.; Nahabedian, K. V. J. Am. Chem. Soc.
1961, 83, 2159; (b) Kuivila, H. G.; Nahabedian, K. V. J.
Am. Chem. Soc. 1961, 83, 2164; (c) Nahabedian, K. V.;
Kuivila, H. G. J. Am. Chem. Soc. 1961, 83, 2167.
8. (a) Florentin, D.; Fournie-Zaluski, M. C.; Callanquin, M.;
Roques, B. P. J. Heterocycl. Chem. 1976, 13, 1265–1272;
(b) Brown, R. D.; Buchanan, A. S.; Humffray, A. A. Aust.
J. Chem. 1965, 18, 1521–1525.
anhydride (10) utilizing a selective protodeboronation
protocol to achieve regioisomeric purity. Controlled
dehydration and isolation of the crystalline boronic
anhydride has also been developed to deliver the
product in excellent yield. In addition, the utility of 10
in Suzuki–Miyaura couplings was successfully demon-
strated. We anticipate that this protocol will provide
ready access to a range of pharmaceutically important
thiophene-containing compounds.
9. Roques, B. P.; Florentin, D.; Callanquin, M. J. Hetero-
cycl. Chem. 1975, 12, 195–196.
10. Procedure for the synthesis of 4-methyl-2-thiophenecyclo-
triboroxane (10): 3-Methylthiophene (2, 10.0 g, 0.102 mol,
1.0 equiv), diisopropylamine (15.1 mL, 0.107 mol,
1.05 equiv) and THF (100 mL) were added to a 1 L
three-neck round-bottomed-flask equipped with an over-
head stirrer and internal temperature probe, which had
previously been evacuated/backfilled with N2(g) three
times. The flask was then cooled to 0 ꢁC in an ice bath.
When the internal temperature reached 2.0 ꢁC, the drop-
wise addition of n-BuLi (1.58 M) (67.7 mL, 0.107 mol,
1.05 equiv) was initiated. Addition required 1.5 h, and the
internal temperature did not exceed 3 ꢁC. The mixture was
allowed to stir at 0 ꢁC for 1 h before cooling to ꢀ40 ꢁC in
an acetonitrile/dry ice bath. After 1 h, the internal
temperature was ꢀ38.5 ꢁC and the dropwise addition of
triisopropylborate (25.8 mL, 0.112 mol, 1.1 equiv) was
initiated. Addition required 45 min, and the internal
temperature did not exceed ꢀ38 ꢁC. The mixture was
stirred with warming to rt over a period of 16 h. Analysis
of an aliquot (three drops, via syringe, quenched into 1 N
HCl (three drops), and then diluted with methanol) by
HPLC revealed a product distribution of 92.5:7.2:0.3
(1:3:2). The reaction mixture was cooled to 0 ꢁC in an ice
bath and 6 N HCl (119 mL, 0.714 mol, 7.00 equiv) was
added dropwise over 2 h such that the internal tempera-
ture did not exceed 4 ꢁC. The mixture was again sampled
and analyzed by HPLC, revealing a product ratio of
92.6:6.7:0.5 (1:3:2). The mixture was warmed to rt and
sampled at intervals until the product ratio reached
91.1:0.3:8.6 (1:3:2) (2 h after the end of acid addition).
The mixture was again cooled to 0 ꢁC, and 6 N NaOH
(86 mL, 0.516 mol, 5.1 equiv) was added slowly over 1.5 h
until pH 4. The internal temperature did not exceed 5 ꢁC.
The mixture was warmed to rt, and the phases were
separated. The organic layer consisted of a product ratio
Acknowledgements
Kelly Nadeau, Steve Hollis, Karl Hansen and Kelvin
Billingsly are acknowledged for helpful conversations.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.09.060.
References and notes
1. Hall, D. C. Boronic Acids: Preparation and Applications in
Organic Synthesis and Methods; Wiley: NY, 2005.
2. For two reviews on the Suzuki–Miyaura reaction, see: (a)
Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483;
(b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147–168.
3. (a) Periasamy, M. Sci. Synth. 2004, 6, 301–320; (b)
Gerrard, W. The Organic Chemistry of Boron; Academic
Press: London, 1961, p 67–70; (c) Li, W.; Nelson, D. P.;
Jensen, M. S.; Hoerrner, R. S.; Cai, D.; Larsen, R. D.;
Reider, P. J. J. Org. Chem. 2002, 67, 5394.
4. For the synthesis of similar compounds in the literature:
(a) Ye, X.-S.; Wong, H. N. C. Chem. Commun. 1996, 339–
340; (b) Dickinson, R. P.; Iddon, B. J. Chem. Soc. C 1970,
1926–1928.

L. M. Klingensmith et al. / Tetrahedron Letters 48 (2007) 8242–8245
8245
of 90.5:0.2:9.2 (1:3:2). The organic phase was washed with
10% NaHSO4 (100 mL), and brine (100 mL). The organic
phase was concentrated to 40 mL, toluene (100 mL) was
added, and the solution was concentrated to 40 mL total
volume. This process was repeated four times, or until all
of the THF (0% remaining by NMR) and isopropyl
alcohol (0.6% remaining by NMR) were removed. The
final 40 mL solution of toluene (containing precipitate)
was stirred in a 250 mL round-bottomed-flask, and
heptane (70 mL) was added with stirring. The mixture
was stirred for 30 min at rt before cooling to 0 ꢁC and
stirring for an additional 30 min. The slurry was filtered
through a 60 mL medium porosity fritted funnel and the
wet cake was rinsed with 2 · 10 mL of cold (0 ꢁC) heptane.
The filtrate contained 339 mg (2.2%) of 1. The solids were
dried on the filter frit under vacuum with a sweep of
nitrogen for 16 h to yield 10.64 g (84.2%) of 10 as a white
solid, mp 203–207 ꢁC. This compound cannot be observed
by HPLC due to hydrolysis. 1H NMR (400 MHz, DMSO)
d 7.30 (s, 1H), 7.27 (s, 1H), 2.24 (s, 3H); 13C NMR
(400 MHz, DMSO) d 139.8, 138.0, 136.3, 126.1, 15.0; IR
(neat, cmꢀ1) 2920 (m), 2865 (w), 1541 (s), 1420 (s), 1320
(m), 1255 (s), 1194 (s), 1019 (s), 861 (s), 751 (s), 701 (s);
Anal. Calcd for C15H15B3O3S3: C, 48.44; H, 4.07; S, 25.87.
Found: C, 48.55; H, 4.23; S, 25.78.
11. Huang, X.; Anderson, K. W.; Danilo, Z.; Jiang, L.;
Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
6653.
12. For detailed experimental conditions and spectroscopic
data, see Supplementary data.