Lithium trihydroxy/triisopropoxy-2-pyridylborate salts (LTBS): Synthesis, isolation, and use in modified Suzuki-Miyaura cross-coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2012.06.145

We describe herein shelf-stable, isolable, and characterizable pyridyl lithium trihydroxy and triisopropoxy 2-borate salts (LTBS) for use in modified Suzuki-Miyaura cross-coupling reactions that can be produced in quantities greater than one hundred grams. Pyridyl LTBS provide a viable cross-coupling alternative to unstable 2-pyridylboronic acids, boronates, and trifluoroborate salt derivatives. We also demonstrate the synthesis and cross-coupling of shelf-stable LTBS reagents of other sp²-hybridized nitrogen-containing heterocycles including thiazole, pyrazine, quinoline, and isoquinoline heterocycles.

Full text of DOI:10.1016/j.tetlet.2012.06.145

Tetrahedron Letters 53 (2012) 4873–4876
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Lithium trihydroxy/triisopropoxy-2-pyridylborate salts (LTBS): synthesis,
isolation, and use in modified Suzuki–Miyaura cross-coupling reactions
⇑
Kuanchiang Chen , Richard Peterson, Shivanand K. Math, James B. LaMunyon, Charles A. Testa,
Dustin R. Cefalo
Frontier Scientific Inc., 195 South 700 West, Logan, Utah 84323, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe herein shelf-stable, isolable, and characterizable pyridyl lithium trihydroxy and triisoprop-
oxy 2-borate salts (LTBS) for use in modified Suzuki–Miyaura cross-coupling reactions that can be pro-
duced in quantities greater than one hundred grams. Pyridyl LTBS provide a viable cross-coupling
alternative to unstable 2-pyridylboronic acids, boronates, and trifluoroborate salt derivatives. We also
demonstrate the synthesis and cross-coupling of shelf-stable LTBS reagents of other sp2-hybridized nitro-
gen-containing heterocycles including thiazole, pyrazine, quinoline, and isoquinoline heterocycles.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 31 May 2012
Revised 28 June 2012
Accepted 29 June 2012
Available online 6 July 2012
Keywords:
2-Pyridyl lithium trihydroxy borate salts
2-Pyridyl lithium triisopropoxy borate salts
LTBS
Suzuki–Miyaura cross-coupling reactions
sp2-Hybridized nitrogen-containing
heterocycles
Introduction
can be found in which lithium triisopropoxyborate salts were gen-
erated in situ and immediately used for coupling10,18 or for conver-
Palladium-catalyzed Suzuki–Miyaura cross-coupling reactions
have become invaluable methods for constructing carbon-carbon
bonds due to their efficiency, environmentally benign byproducts,
and the wide range of functional groups compatible with the reac-
tion conditions.1,2 Highlighting the significance of the approach is
the awarding of the 2010 Nobel Prize in Chemistry to Heck, Negi-
shi, and Suzuki ‘for palladium-catalyzed cross couplings in organic
synthesis’. Many boronic acids, boronates, and potassium trifluo-
roborate salts have been developed to accommodate the fast grow-
ing demand for the construction of C–C, C–N, and C–O bonds.
Pyridines and other sp2-hybridized nitrogen-containing heterocy-
cles are unique in that the substitution of boronic acids on carbons
at positions adjacent to the nitrogen is inherently unstable. There-
fore, the incorporation of a boronic acid functionality at this posi-
tion is not trivial. Two recent reviews have addressed this issue and
surveyed a broad range of alternatives.3,4 There are numerous re-
ports of boronic acid substituents at positions 3, 4, and 5 of the pyr-
idine ring. However, few reports of the isolation, purification, and
characterization of boronic acids at the pyridyl 2-position exist.
Exceptions include halo-2-pyridinylboronic acids and their esters,5
azaheteroarylboronic acids,6 and N-methyliminodiacetic acid
(MIDA)-protected boronate esters.7,8 A limited number of reports
sions into pinacol5 and MIDA8 boronates. A single report by
Billingsley and Buchwald details the coupling of a limited number
of triisopropoxyborates in high yields using sealed Schlenk tubes
equipped with Teflon screw valves.9 There is a single report for
the synthesis of unsubstituted 2-pyridylborate,11 while in 1957,
Mikhailov and Kozminskaya reported the synthesis of lithium tri-
isobutoxy-2-pyridylborate and its subsequent conversion into lith-
ium trihydroxy-2-pyridylborate.12 The synthesis of aryl
trihydroxyborates has been previously published, but no hetero-
aryl analogs were included.13 Herein, we expand upon the earlier
work of Billingsley and Buchwald by elaborating on the scaffolds.
We report the large-scale synthesis (grams to >100 g) of pyridyl
LTBS and additional LTBS heterocycles that were demonstrated as
coupling partners for aryl bromides under ambient pressure. The
work presented represents an approach that is more broadly appli-
cable, albeit at a modest decrease in yield. Further optimization of
these preliminary coupling conditions is expected to provide high-
er yielding procedures.
Results and discussion
To address the unmet need for the availability of stable 2-pyr-
idylborates, we report the scalable synthesis of LTBS versions of
pyridine and other sp2-hybridized nitrogen heterocycles and de-
scribe broadly the applicable coupling conditions for performing
⇑
Corresponding author. Tel.: +1 435 753 1901; fax: +1 435 753 6731.
E-mail address: kcchen@frontiersci.com (K. Chen).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.145

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K. Chen et al. / Tetrahedron Letters 53 (2012) 4873–4876
Synthesis of lithium 2-pyridyl trihydroxyborate salts
1).n-BuLi
2).(i-PrO)3B
R
R
N
BF3K
Trihydroxyborates were generated from the corresponding tri-
isopropoxyborate by treating with water (Table 2). For some 2-pyr-
idyl borates, protodeboronation occurs during the hydrolysis,
requiring they remain in the triisopropoxy form. In particular, this
N
Br(I)
3).KHF2, Acetone/H2O
Scheme 1. Synthesis of potassium 2-pyridyltrifluoroborates.
Table 2
Synthesis of trihydroxy LTBS from the corresponding halides
n-BuLi
R
R
(i-PrO)3B
N
B(Oi-Pr)3Li
N
Br(I)
1). n-BuLi/(i-PrO)3B
Ether or THF/Toluene
R
R
-78 °C
Acetone/H2O
R
N
B(OH)3Li
N
Br(I)
N
B(OH)3Li
2). Acetone/H2O
r.t.
Scheme 2. General scheme for LTBS synthesis.
Entry
Starting halide
LTBS
Yield (%)
CF3
CF3
Suzuki–Miyaura cross-coupling reactions under N2 at ambient
pressure.
6
47
N
Br
N
B(OH)3Li
6
Initial efforts on multi-gram scales (17–285 g) to produce 2-pyr-
idyltrifluoroborate salts using the method outlined in Scheme 1
were unsuccessful. The desired products were obtained in ꢀ15%
yields and were not reproducible in several experiments.
Using the general conditions outlined in Scheme 2, 24 LTBS
were produced in moderate to high yields with high purity (>95
% by 1H, 13C, 11B, and 19F NMR (where applicable); see Experimen-
tal Section).
F3C
F3C
7
8
9
46
N
N
B(OH)3Li
B(OH)3Li
N
N
Br
7
8
35a
64
F3C
F
F3C
F
Synthesis of lithium 2-pyridyl triisopropoxyborate salts
The triisopropoxyborates that were synthesized are shown in
Table 1 along with yields from the corresponding halides.
N
I
N
B(OH)3Li
9
Cl
Br
NC
O
Cl
Br
NC
O
10
11
12
13
37
53
42
75
N
I
N
B(OH)3Li
10
Table 1
Synthesis of triisopropoxy LTBS from the corresponding halides
N
N
N
I
N
N
B(OH)3Li
11
n-BuLi, (i-PrO)3B
R
R
N
B(Oi-Pr)3Li
N
Br(I)
Ether or THF/Toluene,
-78 °C
I
I
B(OH)3Li
12
Entry
1
Starting halide
LTBS
Yield (%)
Cl
Cl
N
N
B(OH)3Li
13
53
55
N
Br
N
B(Oi-Pr)3Li
1
F
F
14
15
16
17
89
45
95
76
O
N
N
Br
O
N
B(OH)3Li
2
N
N
N
Br
N
N
N
B(Oi-Pr)3Li
2
14
Br
B(OH)3Li
15
3
4
74
81
Br
B(Oi-Pr)3Li
3
N
I
N
B(OH)3Li
16
Br
B(Oi-Pr)3Li
4
CF3
CF3
Br
N
Br
N
B(OH)3Li
17
5
33
N
N
B(Oi-Pr)3Li
5

K. Chen et al. / Tetrahedron Letters 53 (2012) 4873–4876
4875
Table 4
Table 2 (continued)
Cross-coupling reactions for LTBS with 5-bromo-2-(1,3-dioxolan-2-yl)pyridine (25)a
Entry
Starting halide
LTBS
Yield (%)
100
Entry
1
LTBS
HerAry
Yield (%)
F
F
Cl
18
N
O
Br
N
O
B(OH)3Li
18
10
32 (12)b
N
26
O
O
N
2
3
17
4
27
37
N
27
19
20
54
85
N
Br
B(OH)3Li
19
N
28
O
O
N
Br
N
B(OH)3Li
Cl
O
O
4
5
6
1
52
56
17
N
20
29
a
Lithiation was accomplished by de-protonation with LTMP.
S
N
30
N
23
21
Table 3
Other heterocyclic LTBS synthesized
Entry
Starting halide
LTBS
Yield (%)
54
N
31
N
N
a
21
Standard conditions: LTBS (2.0 equiv), 25 (1.0 equiv), PdCl2(dppf) (0.05 equiv),
N
I
N
B(OH)3Li
21
CuCl (0.1 equiv), ZnCl2 (1.0 equiv), Cs2CO3 (2 equiv), in DMF (100 mL), the mixture
was heated to specified temperature and time.
b
Yield shown in parenthesis represents the conditions without applying ZnCl2.
22
23
48
71
N
I
N
B(OH)3Li
22
Suzuki–Miyaura cross-coupling reactions of LTBS
N
N
The LTBS in Tables 1–3 are stable at room temperature or at
refrigerator temperature under inert atmosphere for extended per-
iod of time,19 and are suitable coupling partners with aryl halides.
These 2-pyridylborates may also be useful intermediates for
preparing other boronic acid surrogates, including, boronic acids,5
glycol esters,5 organotrifluoroborates, phenyldiethanolamine
boronates,5,15,16 cyclic-N-triolboronates,14 and MIDA-boronate
esters.8
B(Oi-Pr)3Li
23
S
S
N
N
24
52
I
B(OH)3Li
24
Ultimately, in order for these reagents to serve as key building
blocks for Suzuki–Miyaura cross-coupling reactions, successful
use needs to be demonstrated. Typical conditions for Suzuki–Miya-
ura cross-coupling reactions include a palladium catalyst such as,
PdCl2(dppf), Pd(PPh3)4, Pd(OAc)2 etc and bases such as, Cs2CO3,
K2CO3, KOAc etc to facilitate coupling to an aryl halide. Previous
work reports utilizing four different 2-pyridyl triisopropoxyb-
orates, with additional substitutions at only the 5- or 6- positions,
for Suzuki–Miyaura cross-coupling reactions.9 However, couplings
required elevated pressure, which may limit the application to
scale-up and commercialization. To address this concern, we have
developed a novel coupling process that is compatible with the iso-
lated LTBS reagents described in this paper using an ambient pres-
sure reaction vessel. The process involves incorporation of ZnCl2 as
well as a catalytic amount of CuCl as shown in Scheme 3.
The coupling reactions of selected LTBS reagents and the corre-
sponding heteroarylbromide are shown in Table 4. Most notably,
adding zinc chloride and replacing the role of copper as main trans-
metallating reagent increased the yield by more than threefold
when compared to standard Suzuki–Miyaura coupling conditions.
Yield enhancement can be seen in the example of lithium 5-
chloro-2-pyridylborate 10 (entry 1) coupling with the heteroarylbr-
omide. Here it was clearly demonstrated that using the co-catalyst
CuCl with ZnCl2 enhanced cross-coupling when compared to reac-
tion conditions lacking ZnCl2. The specific role of ZnCl2 is currently
under investigation.
Br
HetAry-LTBS
+
O
N
O
25
HetAry
PdCl2(dppf), CuCl, ZnCl2
Cs2CO3, DMF, 100 °C
O
N
O
Scheme 3. Reaction conditions for enhanced coupling reactions.
was commonly observed for pyridyl LTBS that have a functional
group at the 3-position, with exceptions being lithium (3-methyl-
pyridin-2-yl)triisopropoxyborate, 4, as well as the unsubstituted
lithium (pyridin-2-yl)triisopropoxyborate, 3 (Table 1).
Synthesis of non-pyridine sp2-hybridized nitrogen containing
heterocyclic LTBS
In addition to 2-pyridylborates, LTBS of other heterocycles with
borates on carbons alpha to sp2-nitrogens were prepared: pyra-
zine, quinoline, thiazole, and isoquinoline (Table 3). This should
be also applicable to other remaining heterocycles containing
sp2-hybridized nitrogen atoms, such as oxazoles, imidazoles, pyra-
zoles, isoxazoles, triazoles, pyridazines, pyrimidines, triazines etc.

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K. Chen et al. / Tetrahedron Letters 53 (2012) 4873–4876
In summary, the LTBS compounds reported in this work
References and notes
represent unique reagents that overcome the limitations of typical
pyridylboronic acids, namely the instability of substituted pyridine
2-boronic acids. Furthermore, we report the isolation of stable
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substituted and unsubstituted borates at the
a-position of
sp2-hybridized nitrogen heterocycles besides pyridine. In addition
to developing new reagents for Suzuki–Miyaura cross-coupling
reactions, we have identified conditions for enhancing their reac-
tivity in Pd-catalyzed cross-coupling. Through incorporation of
CuCl (catalytic quantity) and ZnCl2 (stoichiometric quantity) we
were able to significantly enhance the cross-coupling of LTBS in
an ambient pressure reaction vessel. This finding is expected to
have broad utility in a variety of additional reaction mechanisms
as mentioned in a recent publication.17 Although further optimiza-
tion of the coupling conditions is still necessary,20 this report pre-
sents the first example of successful coupling reactions using
substituted 2-pyridylborates and N-heterocycles as starting mate-
rials in conjunction with the use of zinc chloride and copper chlo-
ride to enhance the reactivity under the irradiation of microwave.
14. Yamamoto, Y.; Takizawa, M.; Yu, X.-Q.; Miyaura, N. Angew. Chem., Int. Ed. 2008,
47, 928–9310.
15. Hodgson, P. B.; Salingue, F. H. Tetrahedron Lett. 2004, 45, 685–687.
16. Gros, P.; Doudouh, A.; Fort, Y. Tetrahedron Lett. 2004, 45, 6239–6241.
17. Li, Y.; Wheeler, K. A.; Dembinski, R. Eur. J. Org. Chem. 2011, 2767–2771.
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Acknowledgments
19. Stability seems to be general under inert atmosphere except LTBS 5 that
decomposed in less than 48 h at room temperature. For example: LTBS 3 is
stable up to a month.9 LTBS 17 underwent 10% of protodeboronation after
21 months in a refrigerator (4 °C), while LTBS 4, 10, 13, and 21 remain pure in
the refrigerator after 22 months.
20. Since cesium carbonate (Cs2CO3) and zinc chloride (ZnCl2) are extremely
hygroscopic, the use of these flame-dried reagents may enhance the yield
greatly as kindly suggested by a reviewer.
We greatly thank Professor Glenn Prestwich for guidance on
this project and Dr. Tony Tang for helpful scientific discussions.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.06.
145.