Facile preparation and Suzuki-Miyaura cross-coupling of N-2-alkylated 2H-1,2,3-triazole 4-boronates

Article abstract of DOI:10.1016/j.tetlet.2012.10.034

The preparation of N-2 substituted 2H-1,2,3-triazoles substituted at C-4 with an organometallic moiety has no recognised precedent. Herein, we report their efficient preparation via CH borylation and demonstrate their successful application to aryl-aryl S

Full text of DOI:10.1016/j.tetlet.2012.10.034

Tetrahedron Letters 53 (2012) 6849–6852
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile preparation and Suzuki–Miyaura cross-coupling of N-2-alkylated
2H-1,2,3-triazole 4-boronates
Paul R. J. Davey b, Bénédicte Delouvrié a, Delphine Dorison-Duval a, Hervé Germain a, Craig S. Harris a,
,
⇑
Françoise Magnien a, Gilles Ouvry a, Thomas Tricotet a,
⇑
a AstraZeneca Oncology iMed, Centre de Recherches, Z.I. la Pompelle, BP1050, 51689 Reims Cedex 2, France
b AstraZeneca Oncology iMed, Alderley Park, Cheshire SK10 4TG, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation of N-2 substituted 2H-1,2,3-triazoles substituted at C-4 with an organometallic moiety
has no recognised precedent. Herein, we report their efficient preparation via CH borylation and demon-
strate their successful application to aryl–aryl Suzuki cross-coupling.
Received 11 July 2012
Revised 6 October 2012
Accepted 9 October 2012
Available online 16 October 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
2H-1,2,3-Triazole 4-boronates
Direct CH borylation
Suzuki–Miyaura cross-coupling
The 4-piperidine substituted pyrazole fragment (1) has become
an important fragment for recent pharmaceutical programmes. In-
deed, a literature search reveals that this fragment is present in
over 1902 Cas Numbers, 198 references and been cited in over
150 patent documents to date.1 Moreover, it is becoming more
and more cited in recent patent documents with a peak of 46 indi-
vidual citations in 2009 since its first citation in 1999 by workers at
then Parke-Davis (Fig. 1).2 The majority of final compounds cited
having substructure 1 are derived from the key building block 2
whose synthesis is well described.3 In fact, 2 has been reported
for the preparation of Pfizer’s mixed ALK1-ROS1 inhibitor, Crizoti-
nib, that has recently been approved for the treatment of non-small
cell lung cancer.3
During a recent programme, we became interested in preparing
the 2H-1,2,3-triazole analogue of 2. However, the preparation of 2-
substituted 2H-1,2,3-triazole motifs with an organometallic spe-
cies at C-4 (2) and its demonstration as an efficient cross-coupling
partner is not known.4 In fact, inspection of the literature reveals
just one reference with a C-4-ZnCl moiety used in the Negishi reac-
tion with no reported yield.5 Although inversing the electronics,
thus, having the halide at C-4 or the triazole ring and demonstrat-
ing its application to cross-coupling reactions has been reported
recently by Wang et al. in the Boehringer-Ingelheim laboratories,6
this strategy was not appropriate to our exploration as the prepa-
ration of an organometallic precursor on our heavily functionalised
therapeutic (Het)Ar cores failed. In addition, we preferred having
the triazole side chain as the organometallic coupling partner as
there are many more (hetero)aryl halides commercially-available
than their corresponding boronic acid derivatives (Scheme 1).
With this knowledge in hand, we initially focused our efforts on
preparing the C-4-Bu3Sn derivative (9) as we postulated it would
be more stable and less susceptible to proto-demetallation than
its boronate counterpart (10).7 Alkylation of 1H-1,2,3-triazole with
tert-butyl
4-(methylsulfonyloxy)piperidine-1-carboxylate
(6)
afforded a 1:2 mixture of 7 and 8, respectively, easily separated
by silica gel chromatography. Deproto-stannylation of 8 under
standard conditions afforded 9 in good isolated yield but in low
purity, contaminated with co-eluting tributyltin residues. Applica-
tion of 9 to the Stille cross-coupling reaction using an adapted effi-
cient microwave-assisted organic synthesis (MAOS) protocol
reported by Diaz-Ortiz and co-workers,8 afforded just 10% isolated
yield of 11 (Scheme 2).
In parallel with our Stille approach, we were also investigating
the preparation of the C-4-Bpin under classical deproto-borylation
conditions and more recent direct CH borylation conditions opti-
mised by the Hartwig group.9 To our delight, direct CH borylation
using the now standard catalytic system afforded a 70% isolated
yield of our desired building block (10). Furthermore, application
of our standard MAOS Suzuki coupling conditions employed by
the team,10 afforded 11 in very good yield (Scheme 2).
Encouraged by the good isolated yield of 11, we decided to test
the scope of 10 using a small but challenging library of (hetero)aryl
bromides retaining the MAOS Suzuki coupling protocol. To our sat-
isfaction 10 proved to be an excellent substrate for Suzuki cross-
coupling using a basic catalytic system. Aryl bromides having
⇑
Corresponding authors. Tel.: +33 (0)3 26 61 5912; fax: +33 (0)3 26 61 6842.
E-mail address: craig.harris2@astrazeneca.com (C.S. Harris).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.034

6850
P. R. J. Davey et al. / Tetrahedron Letters 53 (2012) 6849–6852
Patents
O
B
50
40
30
20
10
0
H
O
*
N
N
O
H
N
N
N
N
*
1
O
2
1902 CAS No
198 references
150 patents
Key building block
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Figure 1. Importance of this fragment in recent research. ⁄ = Any substitution including H.
(Het)Ar
H
M
H
N
N
N
Deprotometallation /
CH borylation?
O
O
H
Cross-coupling?
(Het)Ar-Br
N
N
N
N
N
N
Alkylation
S
N
N
N
N
N
N
O
N
PG
3
PG
PG
PG
6
4
5
Where M = ZnX / SnR3 / B(OR)2
PG = Z / Boc
Scheme 1. Our preferred retro-analysis of targets 1.
O
H2N
d
Bu3Sn
O
N
N
O
N
N
O
N
N
N
N
b
O
O
N
O
O
9
11
S
N
N
O
N
O
O
O
N
N
O
B
H2N
a
O
O
N
N
N
N
N
N
H
c
N
N
O
N
N
O
N
e
O
N
O
O
O
6
7
8
N
N
O
O
10
11
Scheme 2. Preparation of tert-butyl 4-(2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate substituted at C-4-SnBu3 (9) and C-4-Bpin (10). Reagents and conditions: (a) NaH,
DMF, 0–60 °C, 20 h, 23% (7), 46% (8); (b) n-Bu-Li, Bu3SnCl, THF, ꢀ78 °C to rt, 70% (50% w/w); (c) 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, bis-(1,5-cyclooctadiene)di-mu-
methoxydiiridium(I), 4,40-di-tert-butyl-2,20-bipyridine, pentane, 70%; (d) 5-bromofuran-2-carboxamide, Pd(PPh3)2Cl2, 3 equiv LiCl, 1,2-DME, 150 °C, 30 min., 10%; (e) 5-
bromofuran-2-carboxamide, Pd(PPh3)2Cl2, CsF, MeOH, 120 °C, 20 min, 74%.
acidic and potentially nucleophilic functionality under these condi-
tions (entries 1–4), 2-bromoaniline (entry 5) and relatively hin-
dered bromides (entry 7) gave the desired cross-coupled
products in acceptable to excellent isolated yields (Table 1).
We were also curious to see if we could synthesise a N-pro-
tected analogue of 10 and study its application to the Suzuki
cross-coupling reaction. We chose the base-stable THP protecting
group rather than carbonyl-based protecting groups (i.e., Boc, Ac)

P. R. J. Davey et al. / Tetrahedron Letters 53 (2012) 6849–6852
6851
Table 1
Table 2
Selected results obtained using our MAOS Suzuki cross-coupling protocol of 10 with a
Selected results obtained using our MAOS Suzuki cross-coupling protocol of 21 with a
variety of (Het)Aryl bromides
variety of (Het)Aryl bromides
Entry
1
Compound
(Het)Ar–Br
% Yield
81
O
*
O
B
(Het)Ar
O
22
O
N
N
O
N
N
O
(Het)Ar-Br
NH2
N
N
N
*
5% Pd(PPh3)2Cl2,
3 eq. CsF, MeOH,
120 °C, 20 min
2
3
23
24
80
90
H2NO2S
*
N
O
O
10
Entry
1
Compound
(Het)Ar–Br
% Yield
74
*
N
S
4
5
25
26
94
89
*
O
*
11
O
NH2
*
6
27
94
*
N
2
3
12
13
65
76
HO
*
H2NO2S
O
protection of 1H-1,2,3-triazole afforded a separable mixture of 19
and 20 in acceptable yields. We chose to separate at this stage
rather than proceed with a mixture as we were curious to see if
we could directly borylate isomer 19. Unfortunately, attempts to
prepare the C-4-Bpin of 19 via CH activation failed but in light of
the efficient cycloaddition protocol developed namely by Harrity
and co-workers at Sheffield, UK11 and more recently a MIDA ester
adaptation by Grob et al. at Novartis, US,12 we chose not to invest
any further effort in investigating the process. Borylation of 20
using the protocol used for 10 afforded a 66% isolated yield of 21
(Scheme 3). Finally, we were satisfied to observe that the exact
same Suzuki MAOS protocol was applicable to the synthesis of
our small library of THP protected analogues showing good func-
tional group tolerance (Table 2).
4
5
14
15
57
88
*
HO
NH2
*
*
N
6
7
16
17
65
70
*
In conclusion and to our knowledge, we have developed a novel
and high yielding protocol to prepare the first C-4 Bpin substituted
2-alkylated 2H-[1,2,3]triazole derivatives and demonstrated their
successful application to the Suzuki aryl–aryl cross-coupling reac-
tion with a diverse substrate panel.
O
8
18
61
*
O
Acknowledgments
or sulfonyl protecting groups (i.e., Ts) as we feared both de-activat-
ing the triazole ring towards CH borylation and methanolysis of the
protecting group during the final MAOS Suzuki reaction. THP
The authors would like to acknowledge Mr. Patrice Koza and Dr.
Vanessa Gonnot for their analytical support.
O
B
O
(Het)Aryl
N
N
N
a
N
N
N
N
c
N
b
N
N
N
N
N
N
N
H
O
O
O
O
4
19
20
21
Scheme 3. Preparation of 2-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3-triazole (21). Reagents and conditions: (a) DHP, cat. TsOH,
CH2Cl2, 15 h, 38% (19), 29% (20); (b) 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, bis-(1,5-cyclooctadiene)di-mu-methoxydiiridium(I), 4,40-di-tert-butyl-2,20-bipyridine, pentane,
66%; (c) (Het)Aryl–Br, Pd(PPh3)2Cl2, CsF, MeOH, 120 °C, 20 min, 80–94%.

6852
P. R. J. Davey et al. / Tetrahedron Letters 53 (2012) 6849–6852
2H-1,2,3-triazole, with no preparation details or application as a reactant in
Supplementary data
any type of reaction.
5. Blackaby, W. P.; Atack, J. R.; Bromidge, F.; Lewis, R.; Russell, M. G. N.; Smith, A.;
Wafford, K.; McKernan, R. M.; Street, L. J.; Castro, J. L. Bioorg. Med. Chem. Lett.
2005, 15, 4998–5002.
6. Wang, X-j.; Zhang, L.; Krishnamurthy, D.; Senanayake, C. H.; Wipf, P. Org. Lett.
2010, 12, 4632–4635.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.10.
034.
7. Tsuji, J. Palladium Reagents and Catalysis; John Wiley & Sons, 2004. p. 313.
8. (a) Cebrian, C.; de Cozar, A.; Prieto, P.; Diaz-Ortiz, A.; de la Hoz, A.; Carrillo, J. R.;
Rodriguez, A. M.; Montilla, F. Synlett 2010, 55–60; (b) Germain, H.; Harris, C. S.;
Lebraud, H. Tetrahedron Lett. 2011, 52, 6376–6378.
References and notes
9. For an excellent review see: Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.;
Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010, 110, 890–931. and references cited
therein.
10. Wright, S. W.; Hageman, D. L.; McClure, L. D. J. Org. Chem. 1994, 59, 6095–6097.
11. (a) Huang, J.; MacDonald, S. J. F.; Cooper, A. W. J.; Fisher, G.; Harrity, J. P. A.
Tetrahedron Lett. 2009, 50, 5539–5541; (b) Huang, J.; Macdonald, S. J. F.;
Harrity, J. P. A. Chem. Commun. 2009, 4, 436–438.
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H.; Toogood, P.; Trumpp-Kallmeyer, S. A. PCT Int. Appl. WO9961444, 1999, p
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4. According to a search carried on 28th June 2012, there are just 16 substances
containing the substructure N-2-substituted or non-substituted 4-borylated
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