Regioselective cross-coupling reactions of boronic acids with dihalo heterocycles

Article abstract of DOI:10.1021/jo101223z

The carboxylic acid anion moiety has been used as a tunable directing group in the cross-coupling reaction of 2,6-dichloronicotinic acid and 2,5-dibromo-1,2,4-triazole derivatives producing selectively the 2- or 6-substituted nicotinic acids, while only the 5-substituted triazoles were obtained under a variety of conditions.

Full text of DOI:10.1021/jo101223z

pubs.acs.org/joc
SCHEME 1. Selective Carboxylate-Directed Coupling of 1 and 2
Regioselective Cross-Coupling Reactions of Boronic
Acids with Dihalo Heterocycles
Ioannis N. Houpis,*,† Renmao Liu,‡ Yanfei Wu,‡
Yukuan Yuan,‡ Youchu Wang,‡ and Ulrike Nettekoven§
†Janssen Pharmaceutica, API Development, Turnhoutseweg
30, 2340 Beerse, Belgium, ‡Process Research and
Development, WuXi AppTec Co. LTD, 288 Fute Zhonglu,
Shanghai 200131, China, and §Solvias A.G. Business
Unit Synthesis and Catalysis, Mattenstrasse 22,
4002 Basel, Switzerland
the chemistry of the heterocycles 1 and 2 compared to the
carbocyclic analogues.
In contrast to the amide and carbamate3 functionalities,
the directing effect of the carboxylate anion4 has not been
extensively studied, most likely due to its weaker directing
“power” in reactions such as ortho-metalations or C-H
activations.5 The Yu group recently demonstrated, in an
elegant series of studies, the ability of the sodium carboxylate
group to effect the site-specific ortho-C-H activation of ben-
zoic acid derivatives followed by cross-coupling reactions,
halogenations and other useful elaborations.6 Very recently,
they have also used carboxamide derivatives to affect the
hitherto unprecedented C-H activation of the pyridine ring
followed by cross-coupling with a variety of aryl bromides.7
More closely related to our work, Wen and co-workers
(eq 1)8 have achieved regioselective coupling of arylboronic
acids with 1 in the presence of Pd(PPh3)4 in order to prepare
6-substituted chloronicotinic acid derivatives; however, the
directing effect of the carboxylate, as the reason for the
selectivity observed, was not examined in that work.
yhoupis@its.jnj.com
Received June 22, 2010
The carboxylic acid anion moiety has been used as a
tunable directing group in the cross-coupling reaction of
2,6-dichloronicotinic acid and 2,5-dibromo-1,2,4-triazole
derivatives producing selectively the 2- or 6-substituted
nicotinic acids, while only the 5-substituted triazoles were
obtained under a variety of conditions.
In addition, Yang and co-workers have demonstrated the
directing effect of the easily deprotonated secondary amide
function in effecting selective cross-coupling reactions of
electronically equivalent 2,6-dichloronicotinamide deriva-
tives. Interesting for our work is the demonstration, by the
Selective functionalization of core structures to induce
structural diversity has long been a goal of synthetic chemists
and particularly medicinal chemists.1 In connection with a
Discovery program, we sought to provide such diversifying
methodology using our tunable carboxylate-directed cross-
coupling reactions of electronically equivalent dihalo aro-
matics and applying it to two selected key templates invol-
ving nicotinic acid l and triazoleacetic acid 2 (Scheme 1).2 In
this paper, we describe the successful application of this
methodology and the significant differences observed in
(4) Reviews: (a) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439.
(b) Yu, J.-Q.; Giri, R.; Chen, X. Org. Biomol. Chem. 2006, 4, 4041.
(5) Representative examples of carboxylate-directed processes: Ortho-
metalation reactions: (a) Anctil, E.; Snieckus, V. J. Organomet. Chem. 2002,
653, 150. (b) Anctil, E. J.-G.; Snieckus, V. In Metal-Catalyzed Cross Couping
Reactions, 2nd ed.; Diedrich, F., De Meijere, A., Eds.; Wiley: New York,
2004; pp 761-814. (c) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P.
Angew. Chem., Int. Ed. 2004, 43, 2206. For initial reports of the carboxylate
directing effect see: (d) Maehara, A,; Tsurugi, H,; Satoh, V; Miura, M. Org.
Lett. 2008, 10, 1159. (e) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9,
1407. (f) Tanaka, D.; Stuart, S. P.; Myers, A. G. J. Am. Chem. Soc. 2005, 127,
10323. (g) Chiong, H. A.; Pham, Q.-N.; Daugulis, O. J. Am. Chem. Soc. 2007,
129, 9879. (h) Review: Li, B.-J.; Yang, S.-D.; Shi, Z.-J. Synlett 2008, 15, 949.
(i) For Cu-catalyzed carboxylate-directed aminations, see: Wolf, C.; Liu, S.;
Mei, X.; August, A. T.; Casimir, M. D. J. Org. Chem. 2006, 71, 3270.
(6) (a) Giri, R.; Maugel, N.; Li, J.-J.; Wang, D.-H.; Breazzano, S. P.;
Saunders, L. B.; Yu, J.-Q. J. Am. Chem. Soc. 2007, 129, 3510. (b) Mei, T.-S.;
Giri, R.; Maugel, N.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 5215.
(7) Wasa, M.; Worrell, B. T.; Yu, J.-Q. Angew. Chem., Int. Ed. 2010, 49,
1275.
(1) Several comprehensive reviews for the synthesis of such pharmaco-
phores are available: (a) Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106, 4644.
(b) Henry, G. D. Tetrahedron 2004, 60, 6043.
(2) (a) Houpis, I. N.; Huang, C.; Nettekoven, U.; Chen, J. G.; Liu, R.;
Canters, M. Org. Lett. 2008, 10, 5601. (b) Houpis, I. N.; Van Hoeck, J.-P.;
Tilstam, U. Synlett 2007, 14, 2179.
(3) (a) Review: Li, B.-J.; Yang, S.-D.; Shi, Z.-J. Synlett 2008, 7, 949.
(b) Furuta, T.; Kitamura, Y.; Hashimoto, A.; Fuji, S.; Tanaka, K.; Kan, T.
Org. Lett. 2007, 9, 183. (c) Shibata, Y.; Otake, Y.; Hirano, M.; Tanaka, K.
Org. Lett. 2009, 11, 689. (d) Li, L.; Wang, X.; Zhang, X.; Jiang, Y.; Ma, D.
Org. Lett. 2009, 11, 1309.
(8) Ma, M.; Li, C.; Li, X.; Wen., K.; Liu, Y. A. J. Heterocycl. Chem. 2008,
45, 1847.
DOI: 10.1021/jo101223z
r
Published on Web 09/14/2010
J. Org. Chem. 2010, 75, 6965–6968 6965
2010 American Chemical Society

Houpis et al.
JOCNote
TABLE 1. Initial Screening of Reaction Conditions of 1 with Tolylboronic Acid
entry
catalystb/ligand
solvent, T (°C)
base (equiv)
conc (%)
ratio of 3a:3b:3c HPLC yielda (%)
1
2
3
4
5
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3/CHCl3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
NMP-H2O, 50
NMP-H2O, 50
MeOH, 55
MeOH, 55
MeOH, 55
MeOH, 55
ethylene glycol, 70
EtOH, 70
MeOH, 55
H2O, 100
MeOH, 55
LiOH (2.2)
30
31
51
45
72
83
81
98
99
64
98
17
10
33
27
56
74
69
86
0
ND
ND
<1
3
2.5
2
4
ND
ND
2.7
5
3.7
4
8
6
2.2
11
2.2
Na2CO3 (2.2)
Na2CO3 (2.2)
LiOH (2.2)
Na2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
Na2CO3 (3.0)
Na2CO3 (3.0)
Na2CO3 (4.0)
6
7
8c
9d
10
11
2
86
40
69
11
0
aThe in situ yield was determined at 220 nm against a standard. bCommercial catalyst was used (3 mol %) unless otherwise noted. c1.5 mol % of
catalyst used. The catalyst was recrystallized from CHCl3; d3 mol % of catalyst was used. The Pd/PPh3 ratio was 1:2.
same researchers, that the ester group exerts a predominantly
“para-directing” effect (5:1 in favor of the 6-substitued
nicotinic ester derivative) under reaction conditions similar
to our own (eq 2).9
Again, the role of the carboxylate was not explored in
determining the observed selectivity; however, the results
elegantly corroborate our observations detailed below. Our
work began by examining the cross coupling of 2,6-dichlor-
onicotinic acid (1) with our model tolylboronic acid 4 (eq 3).
Surprisingly, the reaction conditions that were most success-
ful in the dihalobenzoic acid series2a proved totally ineffec-
tive for the nicotinic acid analogue, with only ca. 30% con-
FIGURE 1. Isolated yields of the reaction of 1 with various ArB-
(OH)2 using 1.5 mol % of Pd2(dba)3/CHCl3 as catalyst.
version with both LiOH and Na2CO3 (our most successful
bases) in NMP-H2O (our most successful solvent com-
bination). Increasing the equivalents of base (between 2
and 4) or its nature (LiOH or Na2CO3) had no beneficial
effect (Table 1, entries l and 2). Though the conversion was
low in both cases, we were pleased to see that the selectivity
was high, exclusively generating the 2-substituted product.
After significant investigation, we established that per-
forming the reaction in an alcohol in the presence of 3 equiv
of a carbonate base (Table 1, entries 3-8) gave high yields;
EtOH and K2CO3 gave the highest conversion (98%) and
isolated yield of 3a (72%). A small amount of regioisomeric
product 3b also was formed along with 6% of the bis-
arylation product (3c). Similarly to the observations of Yang
FIGURE 2. Isolated yields of the reaction of 1 with various ArB-
(OH)2 using 3 mol % of Pd(OAc)2/PPh3 (1:2 ratio) as catalyst.
et al., the presence of ca. 1-5% of water was essential for the
success of the reaction. The particle size of the carbonate was
also crucial, and milled K2CO3 must be used for maximum
yield. Interestingly, we have not found any trace of substitu-
tion of the halide moieties by EtOH or water at either the
2- or 6-position of 1 as was observed previously.9
a heteroaromatic boronic acid was not successful (Figure 1, 9a)
due to competitive decomposition of the thiopheneboronic
acid as observed by quantitative HPLC analysis.
As observed in our previous work, employing phosphine
ligands with Pd(OAc)2 gave selectively the regioisomeric
6-substituted product 3b with only traces of the bis-derivative
3c. Surprisingly, PPh3 afforded very high selectivity (Table 1,
entry 9). This is an unexpected result since in the case of the
carbocylic derivative 2,4-dibromobenzoic acid, PPh3 gave a
l:1 mixture of ortho to para products and DPEphos was
required for higher selectivity (ortho to para = 1:9).2a
The mechanistic rationale for this interesting change
in selectivity is not yet understood and is under active
The reaction appears to have a relatively wide scope
(Figure 1), affording good yields and selectivity with phe-
nylboronic acids containing both electron-withdrawing
and -donating substituents. However, our single attempt at using
(9) Yang, W.; Wang, Y.; Corte, J. R. Org. Lett. 2003, 5, 3131.
6966 J. Org. Chem. Vol. 75, No. 20, 2010

Houpis et al.
JOCNote
TABLE 2. Initial Screening of Reaction Conditions of 2 with Tolylboronic Acid 4
entry
catalyst/ligand
solvent T (°C)
base (equiv)
conc (%)
10a:10b:10c yielda (%)
1b
2
Pd2(dba)3/CHCl3
PdCl2/PPh3 1:2
Pd2(dba)3/PPh3 (1:2)
PdCl2/PPh3 1:2
PdCl2/PPh3 1:4
NMP-H2O, 80
NMP-H2O, 80
NMP-H2O, 80
NMP-H2O, 80 °C
NMP-H2O, 80
NMP-H2O, 80
NMP-H2O, 80
NMP-H2O, 80
NMP-H2O, 80
K2CO3 (3.2)
K2CO3 (2.0)
K2CO3 (2.0)
Na2CO3 (2.0)
Na2CO3 (3.0)
NaHCO3 (3.0)
Na2CO3 (3.0)
Na2CO3 (3.0)
Na2CO3 (3.0)
0
96
97
65
95
92
95
95
95
51
63
42
70
64
72
73
72
3
4
2
5
4
6
3
3
4
7
4
9
8
9
6
8
3
4c
5d
6
PdCl2/PPh3 1:2
7
(ACN)2PdCl2/PPh3 1:2
Pd(acac)2/PPh3 1:2
Pd(acac)2/PPh3 1:2
8c
9d
aThe in situ yield % was determined at 220 nm against a standard. bCommercial catalyst was used (2 mol %) unless otherwise noted. c3.0 mol %
catalyst was used. The catalyst was recrystallized from CHCl3. d1 mol % of catalyst was used.
investigation.10 The reaction is general and affords good
yields and excellent selectivity with a variety of electron-rich
or electron-poor boronic acids.
Under the conditions of entry 9 (Table 1), even thiophe-
neboronic acid afforded excellent results (Figure 2). Thus,
we have shown that the carboxylic acid moiety serves as a
tunable directing group for the preparation of either the 2- or
6- substituted nicotinic acids leaving the other site available
for further elaboration.
products were obtained in cross-coupling reactions.12 Whether
this result is due to the intrinsic electron density at C-5 of
triazoles or the result of the coordination of the Pd to
carboxylate is debatable.10
It can be argued that electronic factors predominate,
rendering the C-5 position of the triazole electron deficient
and thus promoting C-5 substitution, as put forth by Mieth-
chen. However additional, albeit preliminary, results from
our laboratory indicate that the carboxylate may have a pro-
found effect on the site-selectivity. For example, the propio-
nic acid derivative, which would have electronic properties
similar to those of 2 but would involve a 7-membered pal-
ladacycle10 transition state, only gives a 2:1 ratio of isomers
favoring the 5-position (eq 5).
A different picture emerged when we attempted to expand
the scope of this reaction and examined the carboxylate
directing effect in the case of the 1,2,4-triazole derivative 2
(eq4). Reactionof the latterwithboronic acid4, usingPd2dba3
(Table 2, entry 1), gave no product 10a-c under a variety of
conditions of solvent, base, or temperature. Intrigued, we
evaluated a number of ligands, using robotic parallel experi-
mentation, and we observed that only in the presence of
phosphines did the reaction proceed at all. Even more remark-
able was the fact that in all these successful “hits” (conversion
>60%) the major product was the C-5-substituted 10a and
not the distal coupling product 10b, which would be expected
in the presence of phosphine ligands based on all our previous
experience. All our efforts to reverse the selectivity of this
reaction have not been successful to date.11 Similar results
have been observed by Miethchen et al. in the case of 2,5-
dihalohalo-4-glycosidyl-1,2,4-triazoles where 5-substituted
Thus, we believe that the coordination of the carboxylate
determines the site of the initial oxidative addition. This
conclusion is also supported by the results of Yang (eq 2),
where substitution of the carboxylate by an ester, thus
diminishing the coordination effects compared to a carbox-
ylate ion, led to substitution at the distal C-6 position due to
the steric effect we propose. Of course, the observed results
can be due to a combination of electronic and coordinative
effects to direct the oxidative addition and subsequent cross-
coupling to C-5.
(10) Our initial observations would tend to support that the selectivity is
determined by the coordinating effect of the CO2 in the absence of
-
phosphine ligands, while in the presence of phosphines the oxidative addition
takes place in the less sterically encumbered position. As shown by us (eq 3)
and Yang et al.,9 under conditions where the formation of the palladacycle is
not advantageous, the selectivity for the proximal reaction site is significantly
reduced.
Being unable to tune the site of the coupling, we set out to
optimize the reaction. From our screens, PPh3 emerged as
the most effective and inexpensive ligand, while NMP-H2O
(1:1) proved to be the best solvent combination. The opti-
mization of the metal precursor, Pd/PPh3 ratio, and base are
shown in Table 2. Thus, Pd(acac)2 (3 mol %) was a margin-
ally superior Pd precursor (Table 2, entry 8), although most
catalyst precursors performed well. Carbonate bases were
somewhat more effective than hydroxide. The counterion
was of little significance, although the equivalents of base are
important (Table 2, entries 4 vs 8). Finally, it was determined
that 80 °C was the best temperature to achieve reasonable
reaction rates (reactions required ca. 18 h for completion).
(11) A number of phosphines such as H(PCy3)BF4, n-BuAd2, BnPAd2,
S-Phos, PPh3, (4-MeO-3,4-Me-Ph)3P, H(P-t-Bu3)BF4, X-Phos, Xantphos,
iPrPh-Im-Cl, and commercially available PEPPSI were investigated. The
metal precursors were Pd2(dba)3, Pd(OAc)2. Bases were chosen from K2CO3,
K3PO4, KF, and Cs2CO3. Solvents included EtOH, MeOH, dioxane/H2O,
DMF/H2O, and DMA/H2O. Some product could be observed in all cases
except in the case of the imidazolinium carbene ligands where no reaction was
observed. In all cases, 10a was formed predominantly in varying ratios with
PPh3 affording the best results.
(12) Wille, S.; Hein, M.; Miethchen, R. Tetrahedron 2006, 62, 3301.
J. Org. Chem. Vol. 75, No. 20, 2010 6967

Houpis et al.
JOCNote
until HPLC analysis indicated complete consumption of nico-
tinic acid (conversion >95%). The reaction mixture was cooled
to 25 °C and filtered to remove the solids, and the filtrate was
concentrated under vacuum and partitioned between a solution
of CH2Cl2 (20 mL) and NaOH (1 M, 30 mL). The aqueous layer
was acidified to pH = 2-3 by using citric acid (1 M) followed by
extraction with EtOAc (2 ꢀ 20 mL). The combined EtOAc
layers were dried over MgSO4, filtered, and concentrated to give
an off-white or yellowish residue which was purified by flash
chromatography on silica gel using CH2Cl2/MeOH (v/v 10/1) as
1
eluent: H NMR (DMSO, 400 MHz) 2.32 (3H, s, CH3), 7.15
(2H, d, J = 8 Hz, Ar), 7.27 (1H, d, J = 8 Hz, Ar), 7.65 (1H, d,
J = 8 Hz, Ar), 7.69 (2H, d, J = 8 Hz, Ar); 13C NMR (DMSO,
400 MHz) 20.8, 121.9, 128.4, 136.5, 137.5, 137.8, 138.7, 146.1,
153.5, 171.1; HRMS calcd for C13H11ClNO2 [M þ H]þ 248.0473,
found 248.0467.
Representative experimental procedures for the preparation
of compounds 3b-9b:
FIGURE 3. Isolated yields of the reaction of 2 with various ArB-
(OH)2 using 3 mol % of Pd(OAc)2/PPh3 (1:2 ratio).
Combining these observations produced the most success-
ful reaction (Table 2, entry 8) that afforded ca. 73% in situ
yield of 10a, while 3% and 6% of 10b and 10c were produced,
respectively. The catalyst load can be decreased to 1 mol %,
but significantly lower reaction rates were observed.
The reaction appears to be general with both electron-
withdrawing and -donating benzeneboronic acids giving
good in situ yields (>70%) of l0a-l5a, although the isola-
tion of each product has not yet been optimized (Figure 3).
In conclusion, we have managed to extend our previously
developed methodology, wherein the carboxylic acid moiety
serves as a tunable directing group for the regioselective
preparation of these pharmaceutically interesting 2- or
6-substituted heteroaromatic systems, with good control of the
regiochemistry in the case of nicotinic acids.
3b. 2,6-Dichloronicotinic acid (1.92 g, 10 mmol), toluene-
boronic acid (11 mmol), Na2CO3 (3.18 g, 30 mmol), and PPh3
(0.157 g, 0.6 mmol) in MeOH (40 mL) were stirred under
nitrogen. Pd(OAc)2 (0.067 g, 0.3 mmol) was added, and the
mixture was heated to 55 °C for 18 h until HPLC indicated
complete consumption of nicotinic acid (conversion >95%).
The reaction mixture was cooled to 25 °C and filtered to remove
the solid, and the filtrate was concentrated under vacuum. The
residue was slurried in CH2Cl2 for 12 h and filtered to give an
off-white or yellowish solid. This solid compound was dissolved
in H2O (200 mL) and then was acidified to pH = 2-3 by using
citric acid (1 M) to form a precipitate. The precipitate was
filtered, washed with 100 mL of water twice, and dried in the
oven for 12 h to give white solid product: 1H NMR (DMSO, 400
MHz) 2.35 (3H, s, CH3), 7.32 (2H, d, J = 8 Hz, Ar), 8.0 (2H, d,
J = 8 Hz, Ar), 8.03 (1H, d, J = 8 Hz, Ar), 8.26 (1H, d, J = 8 Hz,
Ar); 13C NMR (DMSO, 400 MHz) 21.3, 119.0, 125.9, 130.1,
133.7, 140.9, 141.9, 148.5, 158.7, 166.0; HRMS calcd for
C13H11ClNO2 [M þ H]þ 248.0473, found 248.0471.
In addition, we have developed conditions for effective
cross-couplings involving 3,5-dibromo-1H-1,2,4-triazole-1-
acetic acid and a variety of aromatic boronic acids to
produce C-5 substituted 1,2,4-triazoleacetic acid derivatives.
Acknowledgment. We are thankful to Drs. Vittorio Farina
and Kirk Sorgi for their constructive comments during the
preparation of the manuscript.
Experimental Section
Representative experimental procedures for the preparation
of compounds 3a-9a:
3a. 2,6-Dichloronicotinic acid (0.57 g, 3 mmol), tolueneboronic
acid (3.3 mmol), and K2CO3 (1.24 g, 9 mmol) in EtOH (15 mL)
were stirred under nitrogen. Pd2(dba)3 CHCl3 (0.077 g, 0.075
mmol) was added, and the mixture was heated to 70 °C for 18 h
Supporting Information Available: Compound character-
ization data and copies of spectra supporting the structural
assignments. This material is available free of charge via the
Internet at http://pubs.acs.org.
3
6968 J. Org. Chem. Vol. 75, No. 20, 2010