B-Alkyl Suzuki-Miyaura cross-coupling of tri-n-alkylboranes with arylbromides bearing acidic functions under mild non-aqueous conditions

Article abstract of DOI:10.1016/j.tetlet.2009.01.090

An efficient and chemoselective Pd-catalyzed B-alkyl Suzuki-Miyaura cross-coupling of tri-n-alkylboranes with arylbromides possessing acidic functions is described. This protocol features the relatively weak base Cs₂CO₃ and mild non-

Full text of DOI:10.1016/j.tetlet.2009.01.090

Tetrahedron Letters 50 (2009) 1596–1599
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Tetrahedron Letters
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B-Alkyl Suzuki–Miyaura cross-coupling of tri-n-alkylboranes
with arylbromides bearing acidic functions under mild non-aqueous conditions
a,
Hui-Xia Sun a, Zhi-Hua Sun b, , Bing Wang
*
*
a Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
b Shanghai Saijia Chemicals Co. Ltd, Suite 402, No. 54, Lane 33, Shilong Road, Shanghai 200232, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2008
Revised 9 January 2009
Accepted 19 January 2009
Available online 23 January 2009
An efficient and chemoselective Pd-catalyzed B-alkyl Suzuki–Miyaura cross-coupling of tri-n-alkylbor-
anes with arylbromides possessing acidic functions is described. This protocol features the relatively
weak base Cs2CO3 and mild non-aqueous conditions. Aldehydes, ketones, nitriles, and chloro substitution
are all tolerated.
Ó 2009 Elsevier Ltd. All rights reserved.
Alkylarenes are omnipresent in all fields of organic chemistry.
Classical methods of preparation for alkylarenes include the Fri-
edel–Crafts alkylation1 and Friedel–Crafts acylation2-reduction3
sequence. Since the 1980s, the Suzuki–Miyaura,4 Negishi5, and
Stille–Migita–Kosugi6 cross-couplings of alkyl-metal species with
aryl halides or sulfonates have emerged as excellent alternatives,
due to their site-specificity, selectivity, and the mildness of pal-
ladium catalysis. Among them, the Suzuki coupling is particu-
larly popular, thanks to the environmental friendliness as well
as the ease of preparation and workup of organoboron com-
pounds. The alkyl-metal reagents in the Suzuki coupling were
normally B-alkyl-9-BBNs, which were usually prepared via hyd-
roboration and used in situ necessitating prior protection for
many sensitive functions. It should also be noted that hydrobo-
ration of lower alkenes is inconvenient. The groups of Molander
and Falck have widened the scope of the reaction by using alkyl-
trifluoroborates7 and alkylboronic acids8 as stable coupling part-
ners. On the other hand, Suzuki coupling using tri-n-
alkylboranes9 has only been documented sporadically in which
the electrophiles were the most reactive aryl iodides or activated
triflates.4b,10 Thus, the advantage of using tri-n-alkylboranes for
the introduction of lower alkyls has not been fully explored
and recognized. Nonetheless, systematic study on the direct cou-
pling in the presence of acidic functions (e.g., carboxylic acids
and phenols) is lacking. Indeed, considering the protolysis of tri-
alkylboranes by carboxylic acids and phenols,11 this type of di-
rect coupling is non-trivial. For example, reaction of 4-
bromobenzoic acid with methylboronic acid was unsatisfac-
tory.12 4-Bromophenol failed to couple with alkyltrifluorobo-
rates.7b Unprotected indole NH was often detrimental.13 In this
respect, Blum and co-workers achieved cross-methylation using
aluminum and indium reagents.14 Excess Grignard reagents did
couple with halobenzoic acids, but apparently aldehydes and ke-
tones cannot survive.15 Herein, we report our results for direct
cross-alkylation of arylbromides bearing unmasked acidic func-
tions as well as common polar groups.
4-Bromobenzoic acid (1a) was chosen as a reference substrate
to explore the reaction conditions (Table 1). Commercial Pd(0)
catalyst with added mono- and bi-dentate phosphane ligands
was inactive (entries 1–4). Pd(0) prepared in situ showed prom-
ising results at
a high catalyst loading (10 mol %), while
Pd(PPh3)2Cl2 improved the conversion marginally. Gratifyingly,
with 2 mol % Pd(dppf)Cl2, the reaction was complete within 2–
3 h in excellent yield (99%). Triethylborane (3 equiv) was used
to drive the reaction to completion, similar to results reported
for alkyl-aluminum and indium reagents14 (entries 7–9). Next,
several bases were screened, among them Cs2CO3 (2 equiv) was
the most effective, while K2CO3 and K3PO4 (in DMF–THF) both
gave inferior results in terms of conversion and yield. It is also
interesting to note that the protocol in Suzuki’s seminal paper4b
(3 M aq KOH) resulted in somewhat lower yields. In this connec-
tion, the anhydrous condition seems to be superior for aryl bro-
mides, probably with some obscure mechanistic causes.8a This
was contrary to the general observation that water was benefi-
cial or even indispensable for the Suzuki coupling in various cat-
alytic systems.
A similar rare exception was also noted by
Molander’s group in the coupling of aryltriflates with potassium
* Corresponding authors. Tel./fax: +86 21 54237570 (B.W.); tel.: +86 21
54361799 (Z.-H.S.).
E-mail addresses: sungaris@gmail.com (Z.-H. Sun), wangbing@fudan.edu.cn (B.
Wang).
alkynyltrifluoroborates.16
Next, the scope and limitation of the reaction were examined
with a series of bromo-substituted aromatic acids (Table 2). For
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.090

H.-X. Sun et al. / Tetrahedron Letters 50 (2009) 1596–1599
1597
Table 1
Table 2
Optimization of reaction conditionsa
Direct Suzuki cross-coupling of bromo aromatic acids
Br
Br
R
Et
Et3B, Pd cat., base
THF, reflux
3 eq. R3B, 2mol% Pd(dppf)Cl 2
2 eq. Cs2CO3, THF, reflux
Y
Y
HOOC
HOOC
COOH
COOH
1a
2a
2
1
Entry
Catalyst (mol %)
Base (equiv)
Conv. (%)
Yieldb (%)
1
2
3
4
5
6
7
Pd2(dba)3-4 PPh3 (5)
Pd2(dba)3-2 dppf (5)
Pd2(dba)3-2 dppp (5)
Pd(PPh3)4 (5)
Pd(OAc)2-4 PPh3 (10)
Pd(PPh3)2Cl2 (3)
Pd(dppf)Cl2 (2)
Pd(dppf)Cl2 (2)
Pd(dppf)Cl2 (2)
Pd(dppf)Cl2 (2)
Pd(dppf)Cl2 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
K2CO3 (3)
K3PO4 (3)
Trace
Trace
Trace
Trace
40
58
100
56
70
<5
90
100
nd
nd
nd
nd
38
54
99
52
66
nd
76
82
Entry
1
2
Yielda (%)
COOH
99
8c
9d
10
11e
12
Et
2a
COOH
Pd(dppf)Cl2 (2)
3 M KOH (3)
a
2
3
4
5
6
7
88
80
91
81
73
94
92
All reactions run on 1.0 mmol scale with 3.0 equiv Et3B in 5.0 mL THF under
reflux for 2–3 h, unless otherwise noted.
Et
b
2b
Isolated yield.
With 1.2 equiv Et3B.
With 2.0 equiv Et3B.
In DMF–THF (1:1), no reaction in THF.
c
d
e
COOH
Bu
these compounds with diverse substitution patterns, including sal-
icylic acid derivatives (entries 4 and 5), good to excellent yields
were obtained. On the other hand, chloro substitution was not af-
fected under the present conditions (entry 5). Variation of the
nucleophiles was also carried out, using tri-n-butylborane, which
gave the desired products in comparable yields (entries 3, 4, and
2c
OH
COOH
7). However, attempts to extend the reaction to a-branched nucle-
Bu
2d
ophiles (e.g., tri-2-propylborane) were unsuccessful, probably due
to very high steric hindrance around boron that impeded the key
process of transmetalation.
OH
Et
Results for substrates bearing other acidic OH and NH func-
tions are summarized in Table 3. We focused on unactivated
bromoarenes, as the coupling of these substrates is more chal-
lenging than those activated by electron-withdrawing groups in
the para-position. In these cases, the amount of boranes can be
reduced to 1.5–2.0 equiv to obtain full conversion. Free phenolic
and benzylic hydroxyls did not interfere with the coupling.
Moreover, aldehydes and enolizable methyl ketones were both
intact (entries 4 and 5). The electronic effects of ring substitu-
tions were not significant, although the electron-donating free
hydroxyl ortho- to bromo substitution caused lower yields and
the formation of minor amounts of reductive de-bromination
byproducts (entries 2 and 5). Excellent yield was obtained for ni-
trile 2k, which also possessed phenolic proton. Acidic NH groups
in sulfonamide and sulfanilide posed no difficulty for the cou-
pling either (entries 6 and 7). As expected, use of tri-n-butylbo-
rane gave coupling products in excellent yields (entries 3, 4, and
8). However, nitro group cannot survive and resulted in a com-
plex mixture, similar to the reaction of B-alkyl-9-BBN.17 Further-
more, our protocol also worked well with heterocyclic
substrates, such as 3-bromopyridine (entry 8).
In summary, an efficient and chemoselective direct Suzuki–
Miyaura cross-coupling of tri-n-alkylboranes with bromoarenes
in the presence of unmasked acidic functions is described, fea-
turing the weak base Cs2CO3 under mild non-aqueous condi-
tions.18 Aldehydes, ketones, nitriles, chloro substitution were all
tolerated. Thus, it is especially useful for the incorporation of
lower n-alkyls to complex aromatics. The reasonable catalyst
loading, the non-aqueous environment and the short reaction
time required (2–6 h) are additional advantages. Application of
Cl
COOH
2e
2f
COOH
MeO
HO
Et
COOH
Bu
2g
2h
COOH
8
Et
a
Isolated yield.
this protocol to the total synthesis of biologically active poly-
substituted aromatics such as dibenzodioxocinone analogs19 will
be pursued. Mechanistic studies are in progress.

1598
H.-X. Sun et al. / Tetrahedron Letters 50 (2009) 1596–1599
5. For reviews, see: (a) Negishi, E. Acc. Chem. Res. 1982, 15, 340; (b) Erdik, E.
Table 3
Tetrahedron 1992, 48, 9577; (c) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93,
2117; (d) Negishi, E. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E., Ed.; John Wiley & Sons: New York, 2002; (e) Negishi, E.;
Zeng, X.; Tan, Z.; Qian, M.; Hu, Q.; Huang, Z. In Metal-Catalyzed Cross-Coupling
Reactions; de Meijere, A., Diederich, F., Eds., 2nd ed.; Wiley-VCH: Weinheim,
2004.
Direct Suzuki coupling of bromoarenes with trialkylboranes
Br
R
2 eq. R3B, 2mol% Pd(dppf)Cl 2
Y
Y
2 eq. Cs2CO3, THF, reflux
XH
XH
2
1
6. For reviews, see: (a) Stille, J. K. Angew. Chem. 1986, 98, 504; (b) Farina, V.;
Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1; (c) Kosugi, M.; Fugami, K.
In Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.;
John Wiley & Sons: New York, 2002; (d) Espinet, P.; Echavarren, A. M. Angew.
Chem., Int. Ed. 2004, 43, 4704.
7. (a) Molander, G. A.; Ito, T. Org. Lett. 2001, 3, 393; (b) Molander, G. A.; Yun, C.-S.;
Ribagorda, M.; Biolatto, B. J. Org. Chem. 2003, 68, 5534; (c) Molander, G. A.;
Ribagorda, M. J. Am. Chem. Soc. 2003, 125, 11148; For a comprehensive review
of potassium organotrifluoroborates, see: (d) Darses, S.; Genet, J.-P. Chem. Rev.
2008, 108, 288.
8. (a) Zou, G.; Reddy, Y. K.; Falck, J. R. Tetrahedron Lett. 2001, 42, 7213; (b)
Molander, G. A.; Yun, C.-S. Tetrahedron 2002, 58, 1465; (c) Kataoka, N.; Shelby,
Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002, 67, 5553; For the first
example of Suzuki coupling using alkylboronic acid, see: (d) Mu, Y. Q.; Gibbs, R.
A. Tetrahedron Lett. 1995, 36, 5669; Suzuki coupling using alkylboronates: (e)
Sato, M.; Miyaura, N.; Suzuki, A. Chem. Lett. 1989, 1405; (f) Andrus, M. B.; Song,
C. Org. Lett. 2001, 3, 3761; Ate-complex of boronate: (g) Zou, G.; Falck, J. R.
Tetrahedron Lett. 2001, 42, 5817.
9. Trialkylboranes were conveniently prepared from Grignard reagents: (a)
Brown, H. C.; Racherla, U. S. J. Org. Chem. 1986, 51, 427; Selected applications
of trialkylboranes: (b) Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am.
Chem. Soc. 1981, 103, 3099; (c) Oppolzer, W.; Rodriguez, I.; Starkemann, C.;
Walther, E. Tetrahedron Lett. 1990, 31, 5019.
10. (a) Harada, T.; Yoshida, T.; Inoue, A.; Takeuchi, M.; Oku, A. Synlett 1995, 283; (b)
O’Connor, S. J.; Barr, K. J.; Wang, L.; Sorensen, B. K.; Tasker, A. S.; Sham, H.; Ng,
S.-C.; Cohen, J.; Devine, E.; Cherian, S.; Saeed, B.; Zhang, H.; Lee, J. Y.; Warner,
R.; Tahir, S.; Kovar, P.; Ewing, P.; Alder, J.; Mitten, M.; Leal, J.; Marsh, K.; Bauch,
J.; Hoffman, D. J.; Sebti, S. M.; Rosenberg, S. H. J. Med. Chem. 1999, 42, 3701; (c)
Güngör, T.; Chen, Y.; Golla, R.; Ma, Z.; Corte, J. R.; Northrop, J. P.; Bin, B.;
Dickson, J. K.; Stouch, T.; Zhou, R.; Johnson, S. E.; Seethala, R.; Feyen, J. H. M. J.
Med. Chem. 2006, 49, 2440.
11. (a) Toporcer, L. H.; Dessy, R. E.; Green, S. I. E. J. Am. Chem. Soc. 1965, 87, 1236;
(b) Morohashi, N.; Kitahara, T.; Arima, T.; Tanaka, S.; Ohba, Y.; Hattori, T. Org.
Lett. 2008, 10, 2845.
12. Herbert, J. M. Tetrahedron Lett. 2004, 45, 817.
13. Prieto, M.; Zurita, E.; Rosa, E.; Munoz, L.; Lloyd-Williams, P.; Giralt, E. J. Org.
Chem. 2004, 69, 6812.
14. (a) Jaber, N.; Gelman, D.; Schumann, H.; Dechert, S.; Blum, J. Eur. J. Org. Chem.
2002, 1628; Triethylaluminum was also shown to couple with aryl bromides
under the assistance of stoichiometric amount of lanthanide, however, the
tolerance of acidic functions in this system was not revealed: (b) Shenglof, M.;
Gelman, D.; Molander, G. A.; Blum, J. Tetrahedron Lett. 2003, 44, 8593.
15. Bumagin, N. A.; Luzikova, E. V. J. Organomet. Chem. 1997, 532, 271.
16. Molander, G. A.; Katona, B. W.; Machrouhi, F. J. Org. Chem. 2002, 67, 8416.
17. Oh-e, T.; Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201.
18. Representative experimental procedure: To a mixture of bromoarene (1.0 mmol),
Cs2CO3 (977 mg, 3.0 mmol), and Pd(dppf)Cl2 (15 mg, 2 mol %) in a Schlenk tube
under Ar atmosphere was added freshly distilled THF (2.0 mL). To the stirred
suspension was added trialkylborane (3.0 mL, 1 M solution in THF, 3.0 mmol)
in one portion, and the mixture was refluxed for 2–6 h. The reaction was cooled
to 0 °C and quenched by 10% aq NaOH and 30% aq H2O2. After stirring for
30 min at rt, the mixture was acidified by dilute aq HCl, and extracted with
ether (3 Â 10 mL). The combined organic layer was washed successively with
aq FeSO4 and brine, dried (Na2SO4), filtered, and concentrated under reduced
pressure. The residue was purified by silica gel flash column chromatography.
Alternative acidic workup: To the cooled reaction mixture was added 50% aq
HOAc (2 mL) and the whole was refluxed for 30 min. The cooled solution was
extracted with ether (3 Â 10 mL). The combined organic layer was washed
successively with water and brine, dried (Na2SO4), filtered, and concentrated
under reduced pressure. The residue was purified by silica gel flash column
chromatography. 5-Butyl-2-hydroxybenzoic acid (2d): Mp 85 °C; 1H NMR
Entry
1
2
Yielda (%)
73
OH
OH
Et
2i
OH
Et
2
3
4
5
6
7
72
95
93
70
88
84
88
MeO
Bu
Bu
Ac
Et
2j
OH
CN
OH
2k
2l
CHO
OH
Et
2m
2n
2o
2p
SO2NH2
NHMs
Et
Bu
8
N
a
Isolated yield.
Acknowledgments
Financial support from the National Natural Science Foundation
of China (20602008, 20832005) and Fudan University is gratefully
acknowledged.
References and notes
1. For reviews, see: (a) Price, C. C. Org. React. 1946, 3, 1; (b) Olah, G. A.;
Krishnamurthi, R.; Surya, G. K.. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Pattenden, G., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, p 293; (c)
Roberts, R. M.; Khalaf, A. A. Friedel–Crafts Alkylation Chemistry; Marcel Dekker:
New York, 1984.
2. For reviews, see: (a) Gore, P. H. Chem. Rev. 1955, 55, 229; (b) Metivier, P. In
Friedel–Crafts Acylation; Sheldon, R. A., Bekkum, H., Eds.; Wiley-VCH:
Weinheim, 2001.
3. Clemmensen reduction: (a) Vedejs, E. Org. React. 1975, 22, 401;
Hydrogenation–hydrogenolysis: (b) Hartung, W. H.; Simonoff, R. Org. React.
1953, 7, 263; (c) Augustine, R. L. Catalytic Hydrogenation; Marcel Dekker: New
York, 1965; Wolff-Kishner reduction: (d) Todd, D. Org. React. 1948, 4, 378;
Silane reduction: (e) Kursanov, D. N.; Parnes, Z. N.; Loim, N. M. Synthesis 1974,
633.
4. (a) Miyaura, N.; Ishiyama, T.; Ishikawa, M.; Suzuki, A. Tetrahedron Lett. 1986, 27,
6369; (b) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.; Suzuki,
A. J. Am. Chem. Soc. 1989, 111, 314; For reviews, see: (c) Miyaura, N.; Suzuki, A.
Chem. Rev. 1995, 95, 2457; (d) Chemler, S. R.; Trauner, D.; Danishefsky, S. J.
Angew. Chem., Int. Ed. 2001, 40, 4544; (e) Miyaura, N. In Metal-Catalyzed Cross-
Coupling Reactions; de Meijere, A., Diederich, F., Eds., 2nd ed.; Wiley-VCH:
Weinheim, 2004.
(CDCl3)
d 10.26 (br s, 1H), 7.70 (d, 1H, J = 2.4 Hz), 7.35 (dd, 1H, J = 8.4,
2.1 Hz), 6.93 (d, 1H, J = 8.7 Hz), 2.57 (t, 2H, J = 7.5 Hz), 1.57 (m, 2H), 1.35 (m,
2H), 0.93 (t, 3H, J = 7.5 Hz). 13C NMR (CDCl3) d 175.0, 160.3, 137.5, 134.0, 129.9,
117.6, 110.8, 34.5, 33.6, 22.2, 13.9. 3-Chloro-5-ethyl-2-hydroxybenzoic acid (2e):
Mp 138 °C; 1H NMR (CDCl3) d 7.68 (s, 1H), 7.48 (s, 1H), 2.60 (q, 2H, J = 7.5 Hz),
1.23 (t, 3H, J = 7.5 Hz). 13C NMR (CDCl3) d 155.8, 136.9, 135.8, 128.2, 122.1,
112.1, 27.7, 15.4. 5-Butyl-2-hydroxybenzonitrile (2k): Mp 58 °C; 1H NMR (CDCl3)
d 7.33–7.25 (m, 2H), 6.89 (d, 1H, J = 8.7 Hz), 5.83 (br s, 1H), 2.55 (t, 2H,
J = 7.5 Hz), 1.55 (m, 2H), 1.35 (m, 2H), 0.92 (t, 3H, J = 7.5 Hz). 13C NMR (CDCl3) d
156.4, 135.7, 135.0, 131.9, 116.6, 116.4, 99.1, 34.2, 33.3, 22.1, 13.8. 5-Butyl-2-
hydroxybenzaldehyde (2l): 1H NMR (CDCl3) d 10.86 (s, 1H), 9.87 (s, 1H), 7.38–
7.32 (m, 2H), 6.91 (d, 1H, J = 9.1 Hz), 2.60 (t, 2H, J = 7.5 Hz), 1.59 (m, 2H), 1.35
(m, 2H), 0.93 (t, 3H, J = 7.5 Hz). 13C NMR (CDCl3) d 196.6, 159.7, 137.4, 134.3,
132.8, 120.3, 117.4, 34.4, 33.5, 22.1, 13.9. 1-(2-Ethyl-4-hydroxyphenyl)ethanone
(2m): Mp 90–92 °C; 1H NMR (CDCl3) d 7.81 (d, 1H, J = 2.1 Hz), 7.74 (dd, 1H,
J = 8.1, 1.8 Hz), 6.82 (d, 1H, J = 8.1 Hz), 5.72 (s, 1H), 2.68 (q, 2H, J = 7.8 Hz), 2.56
(s, 3H), 1.26 (t, 3H, J = 7.5 Hz). 13C NMR (CDCl3) d 198.2, 158.7, 130.4, 130.3,
130.0, 128.6, 114.9, 112.3, 26.3, 23.0, 13.8. 4-Ethyl-benzenesulfonamide (2n):

H.-X. Sun et al. / Tetrahedron Letters 50 (2009) 1596–1599
1599
Mp 109–111 °C; 1H NMR (CDCl3)
d
7.85 (d, 2H, J = 8.7 Hz), 7.34 (d, 2H,
J = 6.9 Hz), 0.93 (t, 3H, J = 7.2 Hz). 13C NMR (CDCl3) d 149.8, 147.0, 137.9, 135.7,
123.2, 33.2, 32.6, 22.1, 13.8.
19. (a) Sassa, T.; Niwa, G.; Unno, H.; Ikeda, M.; Miura, Y. Tetrahedron Lett. 1974, 15,
3941; (b) Brückner, D.; Hafner, F.-T.; Li, V.; Schmeck, C.; Telser, J.;
Vokalopoulos, A.; Wirtz, G. Bioorg. Med. Chem. Lett. 2005, 15, 3611.
J = 8.7 Hz), 4.84 (br s, 2H), 2.73 (q, 2H, J = 7.5 Hz), 1.26 (t, 3H, J = 7.5 Hz). 13C
NMR (CDCl3) d 149.7, 139.2, 128.6, 126.5, 28.8, 15.2. 3-Butylpyridine (2p): 1H
NMR (CDCl3) d 8.44 (br s, 2H), 7.48 (d, 1H, J = 7.8 Hz), 7.20 (dd, 1H, J = 7.5,
5.1 Hz), 2.61 (q, 2H, J = 7.5 Hz), 1.60 (quintet, 2H, J = 7.8 Hz), 1.36 (sextet, 2H,