Synthesis of ynone trifluoroborates toward functionalized pyrazoles

Article abstract of DOI:10.1021/ol302418b

The synthesis of a range of novel ynone trifluoroborates has been achieved, in a two-pot process from propargylic alcohols. These alkynes have been subsequently used in the formation of a range of pyrazole trifluoroborate salts via cyclization with hydrazines. The products are generated with high levels of regiocontrol and in excellent yields and represent versatile synthetic intermediates.

Full text of DOI:10.1021/ol302418b

ORGANIC
LETTERS
2012
Vol. 14, No. 20
5354–5357
Synthesis of Ynone Trifluoroborates
toward Functionalized Pyrazoles
James D. Kirkham,*,† Steven J. Edeson,† Stephen Stokes,‡ and Joseph P. A. Harrity*,†
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, S3 7HF, United
Kingdom, and Research and Development, AstraZeneca, Alderley Park, Macclesfield,
SK10 4TG, United Kingdom
j.harrity@sheffield.ac.uk
Received September 14, 2012
ABSTRACT
The synthesis of a range of novel ynone trifluoroborates has been achieved, in a two-pot process from propargylic alcohols. These alkynes have
been subsequently used in the formation of a range of pyrazole trifluoroborate salts via cyclization with hydrazines. The products are generated
with high levels of regiocontrol and in excellent yields and represent versatile synthetic intermediates.
Heteroaromatic compounds play a pivotal role in all
aspects of the chemical sciences and are found as core
motifs in a wide range of compounds from ligands in
coordination complexes to biologically active molecules
and building blocks used in smart materials.1 Accordingly,
a range of techniques have been developed for the ring
synthesis of functionalized heteroaromatic compounds.
Among the many methods now available, those that
endow the heteroaromatic products with a readily elabo-
rated functional group are of particular interest, as they
offer the potential to incorporate these motifs into a range
of new chemical frameworks. In this context, previous
studies within our group have demonstrated that a wide
range of aromatic and heteroaromatic boronic acid deri-
vatives can be synthesized via cycloaddition reactions of
alkynylboronates (Scheme 1, eq 1).2 This chemistry ex-
ploits the compatibility of the alkyne with a range of dienes
and 1,3-dipolar intermediates, as well as metal catalyzed
benzannulation techniques. However, a strategically dif-
ferent but equally versatile employment of alkynes in
heterocycle synthesis involves the addition of a nucleophile
across an ynone.3 To the best of our knowledge, such a
transformation has not been reported to date using bory-
lated alkynes. We therefore wanted to develop a robust
route to a range of ynone boronic acid derivatives and to
explore the participation of these compounds in the forma-
tion of functionalized heteroaromatic scaffolds (Scheme 1,
eq 2). We report our results toward this goal herein.
Scheme 1. Proposed Route to Aromatic Boronic Esters
† University of Sheffield.
‡ AstraZeneca.
(1) (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry; Blackwell
Publishing: 2001. (b) Trofimenko, S. Chem. Rev. 1993, 93, 943. (c) Fustero,
S.; Sanchez-Rosello, M.; Barrio, P.; Simon-Fuentes, A. Chem. Rev.
2011, 111, 6984.
(2) (a) Moore, J. E.; Davies, M. W.; Goodenough, K. M.; Wybrow,
R. A. J.; York, M.; Johnson, C. N.; Harrity, J. P. A. Tetrahedron 2005,
61, 6707. (b) Helm, M. D.; Moore, J. E.; Plant, A.; Harrity, J. P. A.
Angew. Chem., Int. Ed. 2005, 44, 3889. (c) Moore, J. E.; York, M.;
Harrity, J. P. A. Synlett 2005, 860. (d) Delaney, P. M.; Moore, J. E.;
Harrity, J. P. A. Chem. Commun. 2006, 3323. (e) Browne, D. L.; Vivat,
J. F.; Plant, A.; Gomez-Bengoa, E.; Harrity, J. P. A. J. Am. Chem. Soc.
2009, 131, 7762. (f) Huang, J.; Macdonald, S. J. F.; Harrity, J. P. A.
Chem. Commun. 2009, 436. (g) Delaney, P. M.; Browne, D. L.; Adams,
H.; Plant, A.; Harrity, J. P. A. Tetrahedron 2008, 64, 866. (h) Vivat, J. F.;
Adams, H.; Harrity, J. P. A. Org. Lett. 2010, 12, 160. (i) Kirkham, J. D.;
Butlin, R. J.; Harrity, J. P. A. Angew. Chem., Int. Ed. 2012, 6402.
Our first task was to devise a practical route toward the
requisite alkynylboronate intermediates. These compounds
have received only scant attention in the literature, and while
r
10.1021/ol302418b
Published on Web 10/01/2012
2012 American Chemical Society

a selection of alkynyl diamidoboranes are known,4 only a
single example of a propiolate derived alkynylboronate
has been reported.5 Indeed, our attempts to prepare anal-
ogous propiolate-based alkynylboronates failed, and de-
spite significant efforts to optimize this procedure we were
unable to isolate any target material using this method
(Scheme 2).
In the event, we were able to employ Evano’s method
successfully to form the trifluoroborate salt of 1-phenyl
propargyl alcohol, albeit in low yield. Further optimiza-
tion of the reaction stoichiometry and boronate ester
source highlighted that this process could be significantly
improved, providing a convenient means for preparing 2a
in high yield (Table 1). Moreover, on turning our attention
to the key oxidation step, we were delighted to find that
manganese dioxide smoothly delivered the desired ynone
3a in high yield (Scheme 3).
Scheme 2. Attempted Syntheses of Propiolate Boronates
Scheme 3. Synthesis of an Ynone Trifluoroborate
Given the difficulties observed in isolating the key
electron-deficient alkynylboronates, we opted to explore
the corresponding trifluoroborates. These compounds are
widely acknowledged to exhibit enhanced stability in com-
parison to the corresponding boronic acid derivatives.6
While ynone trifluoroborates had not been documented in
the literature, we were encouraged by a recent report by
Evano which demonstrated the direct synthesis of a pro-
pargyl alcohol trifluoroborate from the corresponding
propargylic alcohol.7 This offered the intriguing possibility
of carrying out direct conversion of the borate-substituted
propargyl alcohols to the target ketones by taking advan-
tage of the functional group tolerance of trifluoroborates
toward oxidation.8
As stated earlier, alkynylborane derivatives bearing
electron-deficient groups are rather rare, so we opted to ex-
plore the scope of this protocol for the synthesis of a range
of these compounds, and our results are summarized in
Table 2. We were pleased to find that the products can be
formed on multigram scale, although in slightly reduced
yield (Table 2, entry 2). The method was also effective for
electron-rich aryl-substituted propargyl alcohols (Table 2,
entries 3 and 4). Notably, the oxidation is not restricted to
aryl-substituted propargyl alcohols. Oxidation of aliphatic
substituted compounds 2eÀ2g took place smoothly to
provide the corresponding products in acceptable overall
yields (Table 2, entries 6À8).
Table 1. Optimization of a Trifluoroborate Synthesisa
Table 2. Synthesis of Ynone Trifluoroborate Salts
entry
method
B(OR)3
yield 2a/%
yield
overall
yield/%
entry
R
yield (i)À(iii)/%
(iv)/%
1
2
3
4
A
B
B
B
B(OMe)3
B(OMe)3
B(OiPr)3
iPrOBPin
22
56
43
92
1
2a
3
4
5
6
7
8
Ph; 1a
Ph; 1a
2a; 92
2a; 81
2b; 42
2c; 62
2d; 48
2e; 48
2f; 80
2g; 63
3a; 80
3a; 61
3b; 78
3c; 83
3d; 93
3e; 60
3f; 81
3g; 91
74
49
33
51
45
29
65
57
p-MeOC6H4; 1b
o-MeOC6H4; 1c
p-F3CC6H4; 1d
Me; 1e
a Method A: BuLi (1.1 equiv), B(OR)3 (1.5 equiv), KHF2 (6.0 equiv).
Method B: BuLi (2.2 equiv), B(OR)3 (3.0 equiv), KHF2 (12.0 equiv).
n-Pr; 1f
€
t-Bu; 1g
(3) (a) Birkofer, L.; Hansel, E.; Steigel, A. Chem. Ber. 1982, 115, 2574.
(b) Leardini, R.; Pedulli, G. F.; Tundo, A.; Zanardi, G. J. Chem. Soc.,
Chem. Commun. 1984, 1320. (c) Miller, R. D.; Reiser, O. J. Heterocycl.
Chem. 1993, 30, 755. (d) Adlington, R. M.; Baldwin, J. E.; Catterick,
D. E.; Pritchard, G. J. J. Chem. Soc., Perkin Trans. 1 1999, 855. (e)
Bagley, M. C.; Dale, J. W.; Hughes, D. D.; Ohnesorge, M.; Phillips,
N. G.; Bower, J. Synlett 2001, 1523. (f) Bagley, M. C.; Hughes, D. D.;
Taylor, P. H. Synlett 2003, 259.
(4) (a) Lhermitte, F.; Carboni, B. Synlett 1996, 377. (b) Blanchard,
C.; Vaultier, M.; Mortier, J. Tetrahedron Lett. 1997, 51, 8863.
(5) Morita, R.; Shirakawa, E.; Tsuchimoto, T.; Kawakami, Y. Org.
Biomol. Chem. 2005, 3, 1263.
a Reaction performed on 5 g scale.
Having successfully achieved the synthesis of a library of
ynone trifluoroborates, attention was turned to their use as
precursors to heteroaromatic trifluoroborates. We decided
to investigate the addition of highly nucleophilic hydrazines
(6) Molander, G. A.; Canturk, B. Angew. Chem., Int. Ed. 2009, 48,
9240.
(8) Molander, G. A.; Petrillo, D. E. J. Am. Chem. Soc. 2006, 128,
(7) Jouvin, K.; Couty, F.; Evano, G. Org. Lett. 2010, 12, 3272.
9634.
Org. Lett., Vol. 14, No. 20, 2012
5355

Pleasingly, we found that the cross-coupling of both
pyrazoles 4 and 8 could be achieved successfully utilizing
conditions previously reported by Molander, affording
coupled products 13 and 14 in excellent and moderate
yield, respectively (Scheme 5).11
Scheme 4. Synthesis of N-H Pyrazole Trifluoroborates
Table 3. Synthesis of Pyrazole Trifluoroborate Salts
entry
R1
R2
time/h
yield/%
ratio a:b
to our borylated ynones, as this would provide a con-
venient means for preparing pyrazole scaffolds which are
of interest as intermediates within the fine chemicals
sector.1c As outlined in Table 3, simply stirring a mixture
of aromatic ynones 3aÀ3d with methylhydrazine in
ethanol at room temperature delivered the correspond-
ing functionalized pyrazole trifluoroborates in excellent
yields and regioselectivities within 4 h (Table 3, entries
1À4). Moreover, the method could be extended to include
the corresponding alkyl substituted ynones 3eÀ3g (Table 3,
entries 5À7).9 Interestingly, use of phenyl hydrazine reverses
the reaction regioselectivity, providing 3-borylated pyrazole
11b (Table 3, entry 8). This result mirrors the observations
made by Bishop, who proposed that reaction regioselec-
tivity arises from conjugate addition of the most nucleophi-
lic hydrazine nitrogen atom on the enyne.10
The results outlined in Table 3 highlight the flexibility of
this technique for the synthesis of a range of 1,3,5-trisub-
stituted pyrazoles; however, we recognized that perform-
ing the reaction with hydrazine could offer a direct method
for generating these analogues with a free amino group. As
outlined in Scheme 4, we were pleased to find that this
method is very well suited to the synthesis of these parti-
cular compounds, and the appropriate pyrazoles were ob-
tained in acceptable yields in all cases.
1
Ph
Me
Me
Me
Me
Me
Me
Me
Ph
4
4; 96
5; 63
6; 92
7; 98
8; 74
9; 78
10; 92
11; 88
16:1
7:1
2
p-MeOC6H4
o-MeOC6H4
p-F3CC6H4
Me
2
3
3
>98:2
>98:2
9:1
4
0.5
18
18
16
19
5a
6a
7
n-Pr
15:1
>98:2
<2:98
t-Bu
8a
Ph
a Reactions heated at 40 °C.
We were also pleased to find that the azidonation of
pyrazole 4 could be achieved smoothly (Scheme 6). Uti-
lizing conditions previously reported by Aldrich, azido-
nated pyrazole 15 formed in excellent yield.12 A one-pot
azidonationÀclick reaction was also successful, pro-
viding pyrazole-triazole product 16 in excellent yield,
as a single regioisomer. Reduction of azido-pyrazole 15
was also achieved, affording amino-pyrazole 17 in high
yield.13
Scheme 6. CÀN Functionalization of Pyrazole Trifluoroborates
Scheme 5. Cross-Coupling of Pyrazole Trifluoroborates
In conclusion, we have demonstrated a novel route
to substituted pyrazole trifluoroborates via the cyclization
To demonstrate the utility of the pyrazole trifluoroborates,
a number of further functionalizations were performed.
(11) (a) Molander, G. A.; Canturk, B.; Kennedy, L. E. J. Org. Chem.
2009, 74, 973. (b) Molander, G. A.; Argintaru, O. A.; Aron, I.; Dreher,
S. D. Org. Lett. 2010, 12, 5783.
(12) Grimes, K. D.; Gupte, A.; Aldrich, C. C. Synthesis 2010, 1441.
(13) Browne, D. L.; Taylor, J. B.; Plant, A.; Harrity, J. P. A. J. Org.
Chem. 2010, 75, 984.
(9) To determine the reaction regioselectivity, pyrazoles 4, 6, 8, 9, and
11 were subjected to a base-mediated deborylation, affording a pre-
viously reported 1,3- or 1,5-substituted pyrazole as the major product in
each case (see Supporting Information for details).
(10) Bishop, B. C.; Brands, K. M. J.; Gibb, A. D.; Kennedy, D. J.
Synthesis 2004, 43.
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Org. Lett., Vol. 14, No. 20, 2012

reaction of ynone trifluoroborates with hydrazines. Uti-
lizing this method, a range of pyrazole trifluoroborates
has been synthesized under mild conditions, in excellent
yields and regioselectivities. The resulting products
undergo CÀC and CÀN bond forming reactions giving
rise to a series of functionalized pyrazole scaffolds. We
hope that, in the future, we can demonstrate the use of
ynone trifluoroborates as precursors to a range of alter-
native borylated heteroaromatics.
Acknowledgment. We are grateful to the EPSRC and
the University of Sheffield for a Doctoral Prize Fellowship
(J.D.K.) and to AstraZeneca for support.
Supporting Information Available. Full experimental
1
details and characterization data, copies of H and 13C
NMR spectra for all products. This material is available
free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 20, 2012
5357