A Mild and Regiospecific Synthesis of Pyrazoleboranes

Article abstract of DOI:10.1002/chem.201701019

Alkynylboranes show unprecedented reactivity in their [4+2] cycloaddition of sydnones offering access to fully substituted pyrazoles within a few hours at room temperature. This method delivers synthetically valuable pyrazoleboranes with complete control of regioselectivity, and these intermediates can be further elaborated through functionalization of the C?B bond.

Full text of DOI:10.1002/chem.201701019

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Title: A Mild and Regiospecific Synthesis of Pyrazoleboranes
Authors: Joseph P.A. Harrity, Andrew Brown, and Julia Comas-Barcelo
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Cycloadditions
A Mild and Regiospecific Synthesis of Pyrazoleboranes
Andrew W. Brown, Júlia Comas-Barceló and Joseph P.A. Harrity*
Pyrazoles are commonly employed in the discovery of
pharmaceuticals and as crop protection agents.[1] Therefore, methods
that allow these compounds to be readily prepared and
functionalized are of significant value. However, synthetic
approaches to these diazoles can be non-trivial and often result in
the formation of isomeric mixtures.[2] Dipolar cycloaddition
strategies offer a convenient way to access complex pyrazoles from
simple substrates, and this approach is widely used. In this context,
the [4 + 2] cycloaddition/retro-cycloaddition of alkynes and
sydnones can be particularly effective, as unlike most dipolar
reagents, sydnones are bench stable compounds that can be easily
generated and stored under ambient conditions for long periods.[3]
Despite widespread interest in the utilization of sydnones for
pyrazole synthesis,[4] significant challenges persist with respect to
the reaction conditions. Indeed, the synthesis of fully-substituted
pyrazoles via the reaction of unsymmetrical internal alkynes and 4-
substituted sydnones is currently very limited, with relatively few
examples, all of which require high reaction temperatures, long
reaction times and which often deliver poor reaction regiocontrol.[5]
Studies in our group have focused on the cycloaddition of sydnones
with alkynyl boronic esters to address this limitation.[6] However,
while good regiocontrol can be achieved in some cases, the
reactions require temperatures >140 C over extended reaction times
(>24 h). A representative example that illustrates this point is shown
in Scheme 1. Attempts to prepare bioactive pyridylpyrazoles[7] by
cycloaddition/cross-coupling methods were hampered by low yields
encountered during the key cycloaddition step.
rate.[8] In this regard, we have shown that alkynylboranes[9] promote
the Diels-Alder reaction of electron deficient 6-membered ring
dienes through the formation of a temporary tether. A number of
interesting issues become apparent if one envisages the
implementation of this strategy with sydnones. Specifically, (i)
cycloaddition would require bond formation between two electron
rich centers rather than complementary charges and (ii) the initial
cycloadduct and final products would engender higher ring strain
(Scheme 2). These challenges prompted us to explore the directed
cycloaddition reactions of sydnones, and we report herein that this
strategy does offer access to fully-substituted pyrazoles under
unprecedented mild cycloaddition conditions with complete
regiocontrol.
Scheme 2. Directed cycloaddition strategy and potential challenges.
We began our investigations by studying the cycloaddition
reaction of 4-pyridylsydnone 1 and the alkynyl trifluoroborate
derived from 1-octyne. Preliminary experiments showed that the use
of 3 equivalents each of alkyne and Lewis acid provided the
corresponding pyrazole under ambient conditions and within 3 h in
54% yield (Table 1, Entry 1). A particularly surprising feature of the
reaction was that we only observed dialkynylborane 2 rather than
the expected difluoroborane 3. Reducing the equivalents of Lewis
acid had no noticeable effect on reaction conversion (Entry 2), and
increasing reaction time to 24 h or steadily increasing the number
Scheme 1. Synthesis of fully substituted pyrazoles by sydnone
cycloadditions.
Substrate directed reactions offer an enticing opportunity to
control reaction selectivity whilst significantly enhancing reaction
Table 1. Preliminary cycloaddition studies and optimization.
[]
A.W. Brown, J. Comas-Barceló, Prof. J.P.A. Harrity
Department of Chemistry
University of Sheffield
Sheffield, S3 7HF (UK)
Fax: (+44) 114-222-9346
E-mail: j.harrity@sheffield.ac.uk
Equiv. BF3
Equiv. alkyne
Conversion[a,b]
Entry
65% (54%)
65%
1
2
3
4
3.0
1.1
1.1
2.0
3.0
3.0
5.0
[] This work was supported by Cancer Research UK and
Yorkshire Cancer Research and the FP7 Marie Curie
Actions of the European Commission via the ITN
ECHONET Network (MCITN-2012-316379).
65%
100% (100%)
5.0
1
[a] Conversion estimated by 400 MHz H NMR spectroscopy. [b]
Isolated yields in parenthesis.
equivalents of alkyne also failed to improve conversion to pyrazole
(Entry 3). As the reaction formally requires a 3:1 stoichiometry of
Supporting information for this article is available on the
WWW under http://www.angewandte.org or from the
author.
1
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10.1002/chem.201701019
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alkyne:BF3·OEt2 for complete conversion to 2, it is perhaps
unsurprising that increasing the number of equivalents of alkyne but
not Lewis acid did not affect conversion. However, it is notable that
this variation in stoichiometry did not lead to other borane-
containing pyrazoles (ie mono- or di-fluoroboranes) either. Finally,
increasing the equivalents of Lewis acid in the presence of 5
17-20 in excellent yield. In contrast, the oxazoline substituted
sydnone did not afford the expected cycloadduct 21. In this case, the
borane appeared to be sensitive towards protodeborylation such that
the alkyne moieties were cleaved upon workup and purification to
deliver the corresponding boronic acid 22 which was isolated in low
yield. Finally, we were surprised to find that amide 23 did not
promote cycloadditions as this had previously proven to be a rather
general directing group.[9]
equivalents of trifluoroborate salt provided
a
significant
improvement in conversion, allowing the isolation of pyrazole 2 in
quantitative yield after 2 hours (Entry 4). This study therefore
confirmed that fully-substituted pyrazoles could be accessed from
sydnones within a few hours under ambient conditions for the first
time. This result represents a significant rate acceleration in these
reactions, and offers a mild and regiocontrolled means for accessing
functionalized pyrazoles.
With optimal conditions in hand, we turned our attention to
investigating the reaction scope (Table 2). Beginning with the nature
of the sydnone N-substituent, we were pleased to find that both
aromatic and aliphatic groups were tolerated, providing the
corresponding pyrazoles 4-7 in high yield (entries 1-4). This
methodology is therefore especially well suited to the cycloaddition
of N-alkyl sydnones, which are typically less stable and less reactive
than the N-aryl analogs and often perform poorly in
cycloadditions.[10] To further demonstrate the versatility of the
chemistry, the cycloaddition scope with respect to the alkynyl
trifluoroborate salts was undertaken (entries 5-9). We found the
reaction to be tolerant of a selection of substituent types including
aryl, alkenyl, tert-alkyl, silyl and the corresponding terminal alkyne.
The regiochemistry of formation of 9 is especially noteworthy as the
1,4,5-trisubstituted pyrazole boronate substitution pattern
complements the natural 1,3,5-substitution observed in thermally
promoted reactions of sydnones and terminal alkynylboronates.[4]
Scheme 3. Directing group scope. [a] Reaction conducted over 4 h.
Table 2. Pyrazole synthesis scope.
The regiochemistry of the reaction was unambiguously
confirmed by X-ray crystallography in the case of pyrazole 8,[11] and
other substrates were assigned by analogy. The crystal structure
confirmed the existence of a bonding interaction between the
pyridine nitrogen and boron.
After demonstrating the versatility of the chemistry in
accessing a broad library of pyrazole dialkynylboranes, we sought to
demonstrate that the dialkynylborane motif could be used as handle
for functionalization. To the best of our knowledge, the reactivity of
Entry[a]
Sydnone
R1, R2
Product
Yield
1
2
3
4
4-FC6H4, C6H13
4-MeOC6H4, C6H13
Me, C6H13
4; 85%
5; 99%
6; 76%
7; 70%
Bn, C6H13
5
6
7
8
9
Ph, Ph
8; 100%
9; 78%
Ph, H
Ph, t-Bu
10; 81%
11; 72%
12; 61%
Ph, C(Me)=CH2
Ph, SiMe3
Finally, we explored the effect of the directing group on the reaction
(Scheme 3). Gratifyingly, incorporation of a methyl group at all
positions on the pyridine ring did not have a significant effect on
reactivity and boranes 13-16 were all formed in high yield. Both
electron donating and electron withdrawing groups positioned para
to the pyridine nitrogen were tolerated, and the reaction was
successfully extended to include a quinoline and an oxazine
directing group, all of which afforded the corresponding pyrazoles
Scheme 4. Functionalization of dialkynylboranes.
2
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10.1002/chem.201701019
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this unusual motif has never been investigated. We first sought
conditions for protodeboronation. Pleasingly, heating 2 in THF/H2O
in the presence of sodium carbonate furnished 24 in excellent yield
(Scheme 4). We next turned our attention to oxidation. Gratifyingly,
gentle heating of 2 with hydrogen peroxide afforded phenol 25 in
good yield. We were also pleased to find that heating 2 with pinacol
and caesium carbonate furnished the pinacol ester 26 in excellent
yield, even when carried out on 0.5 g scale. Finally, we found 2 to
be a rather demanding substrate for Suzuki-Miyaura coupling.
However, the use of the 2nd generation XPhos precatalyst
successfully promoted formation of cross-coupled product 27 using
4-bromoanisole.
8.96-9.05 (1H, m); 13C NMR (101 MHz, CDCl3) δ 96.5, 98.8 (b),
117.5, 122.3, 125.0, 125.1, 127.1, 127.3, 127.9, 128.0, 128.6, 128.7,
129.7, 131.9, 133.8, 137.1 (b), 139.8, 142.0, 143.5, 145.9, 146.9,
152.9; 11B NMR (128 MHz, CDCl3) δ -10.0; FTIR: νmax 3216 (s),
2262 (w), 2178 (w), 1623 (m), 1597 (m), 1488 (s), 1441 (s), 1195
(m), 986 (m), 919 (m); HRMS (ESI-TOF) m/z [M+H]+ calculated
for C36H2511BN3: 510.2142. Found: 510.2166.
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
Overall therefore, the experimentally observed directed
cycloaddition reaction of sydnones and alkynylboranes was found to
proceed under mild conditions and in high yields. A number of
unexpected observations were made during the course of these
studies; i) the strategy is successful for a number of pyridine based
directing groups; ii) directing group ring size may be important;
whilst 1,3-oxazines are effective, the corresponding 1,3-oxazolines
and oxazoles are poor directing groups; iii) amides do not promote
the cycloaddition process; iv) the products are generated as
dialkynylboranes with no trace of the corresponding difluoroboranes.
The products are probably formed via disproportionation of the in
situ generated alkynyldifluoroborane followed by cycloaddition,[9d]
although the lack of further disproportionation to difluoroboranes is
unexpected. In order to understand the surprising differences
observed in this study, both theoretical and mechanistic
investigations have been undertaken and these will be reported
elsewhere.
In conclusion, sydnones bearing pyridines and related azines at
C4 undergo rapid cycloaddition with alkynylboranes to generate
pyrazoleboranes with complete control of regioselectivity. These
reactions proceed under ambient conditions, demonstrating
unprecedented reactivity for the [4 + 2] cycloaddition of sydnones
with simple alkynes. The pyrazoleboranes undergo typical
organoboron functionalization reactions such as oxidation and cross-
coupling, confirming the value of these products for organic
synthesis.
Keywords: cycloaddition · sydnone · alkynylborane · regioselective ·
pyrazole
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Typical cycloaddition procedure as exemplified by the formation of
8: to a suspension of 1 (50 mg, 0.21 mmol) and potassium(1-
phenylethyn-2-yl)triflouroborate (218 mg, 1.05 mmol) in
dichloroethane (1 mL, 0.2 M) under an atmosphere of nitrogen at 25
C was added a solution of BF3.OEt2 (60 mg, 0.42 mmol) in
dichloroethane (1 mL, 0.4 M). The reaction was stirred for 2 hours
at 25 C before brine was added. The resulting mixture was
extracted with dichloromethane and the combined organic layers
dried over MgSO4, filtered through a short pad of celite® and
concentrated in vacuo. Flash silica chromatography (gradient
starting with 100% 40-60 petroleum ether and ending with 40%
ethyl acetate in 40-60 petroleum ether) afforded 8 as a tan solid (107
mg, 100%). M.p.: 246-248 C (dec.); 1H NMR (400 MHz, CDCl3) δ
7.15-7.23 (6H, m), 7.29-7.54 (10H, m), 7.59 (2H, t, J = 8.5 Hz),
7.65-7.72 (2H, m), 7.90-7.99 (1H, m), 8.39 (2H, dd, J = 8.0, 1.0 Hz),
3
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Entry for the Table of Contents
Cycloadditions
A.W. Brown, J. Comas-Barceló, J.P.A.
Harrity* __________ Page – Page
A Mild and Regiospecific Synthesis of
Pyrazoleboranes
Go direct! Alkynylboranes show unprecedented reactivity in their [4 + 2]
cycloaddition of sydnones offering access to fully substituted pyrazoles within a few
hours at room temperature. This method delivers synthetically valuable
pyrazoleboranes with complete control of regioselectivity, and these intermediates
can be further elaborated through functionalization of the C-B bond.
4
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Chemistry - A European Journal
S1
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