A sydnone cycloaddition route to pyrazole boronic esters

Article abstract of DOI:10.1002/anie.200703767

(Chemical Equation Presented) From dipole to diazole! A direct and regioselective route to functionalized pyrazole boronic esters is developed that employs the cycloaddition of alkynylboronates with sydnones. Functionalization of these products by Suzuki coupling and N-deprotection processes highlight the potential synthetic utility of these species.

Full text of DOI:10.1002/anie.200703767

Communications
DOI: 10.1002/anie.200703767
Cycloaddition Reactions
A Sydnone Cycloaddition Route to Pyrazole Boronic Esters**
Duncan L. Browne, Matthew D. Helm, Andrew Plant, and Joseph P. A. Harrity*
Aromatic and heteroaromatic boronic esters are among the
most valuable synthetic intermediates in modern organic
chemistry.[1] They are used throughout both industry and
academia, largely because of their ability to form carbon–
carbon bonds to various aromatic substrates through a Pd-
catalyzed cross-coupling reaction.[2] However, they also
participate in carbon–heteroatom bond formation to provide
amines and ethers as well as undergoing nucleophilic addition
reactions to imines, aldehydes, and enones.[3] Despite their
popularity, their synthesis generally requires a functional
group transformation from a starting organohalide or tri-
flate.[4] The requirement for these precursors can become
problematic if one wishes to generate highly functionalized
aromatic boronates because the starting halide/triflate may be
difficult to access or the substrateꢀs functionality may be
incompatible with conditions required to transform the
substrate into the boronic ester product. An alternative and
Scheme 1. Cycloaddition approaches to pyrazoles.
increasingly popular approach to these compounds is through
cycloaddition reactions of alkynylboronates.[5] To date, metal-
mediated[6] and metal-catalyzed[7] processes have been devel-
oped, as well as techniques based on pericyclic[8] reactions.
In an effort to expand the scope of hetereoaromatic
compounds available by this strategy, we were attracted to the
preparation of pyrazole boronic esters. Pyrazoles are com-
monly employed in the pharmaceutical and agrochemical
industries;[9] therefore, a direct and flexible route for the
synthesis of pyrazole boronic esters would allow a broad
range of analogues to be made available by exploiting the rich
chemistry available to these organoboron reagents.[10] We
contemplated three approaches towards this goal:
1) [3+2] cycloadditions of diazoalkanes; 2) [3+2] cycloaddi-
tions of nitrile imines; and 3) cycloaddition/retrocycloaddi-
tion of sydnones. We set out to establish the potential of each
approach, and our preliminary results are highlighted in
Scheme 1. Attempts to prepare nitrile imines and perform the
cycloaddition in situ[11] were unsuccessful, and a complex
mixture of unidentifiable products was obtained
(Scheme 1a). The [3+2] cycloaddition of diazoalkane deriv-
atives appeared to be a more promising alternative as
Matteson had demonstrated the feasibility of this reaction
through the cycloaddition of a terminal alkyne boronic ester
with ethyl diazoacetate.[12] Although we were able to repeat
these findings, the reaction was extremely slow and limited
only to the terminal alkyne substrate (Scheme 1b). We next
turned our attention to the cycloaddition of alkynylboronates
with sydnones.[13] Although there was no precedent for the
reaction of alkynylboronates with this class of reagent,
successful cycloadditions of these mesoionic compounds
were reported during the course of this work with alkynyl-
stannanes and -silanes.[14] To our delight, heating a mixture of
the alkynylboronate derived from phenylacetylene and N-
methylsydnone in refluxing mesitylenes provided the corre-
sponding pyrazole in good yield (Scheme 1c). Moreover, only
a single regioisomer could be identified from the reaction
mixture.[15] We therefore decided to carry out further inves-
tigations into the scope of this promising transformation.
We performed the cycloaddition of a series of alkynylbor-
onates with N-aryl sydnones to establish the reaction scope
and regioselectivity; our results are summarized in Table 1.
We were pleased to find that N-phenylsydnone 1a reacted
smoothly with a range of alkynylboronates to provide the
corresponding pyrazoles in good to high yield (entries 1–4).
We were surprised to find significant variation in reaction
regioselectivity. Whereas phenyl alkynylboronate 2a pro-
vided a single regioisomer, more modest regiocontrol was
observed with alkynes 2b and 2c, and a switch in regiochem-
istry was found when terminal alkyne 2d was employed. We
were intrigued by the possibility of modulating reaction rate
and regiochemistry by changing the electronic nature of the
sydnone and therefore opted to investigate the cycloaddition
of substrates bearing electron-rich/-deficient aryl groups. We
found that electron-rich sydnone 1b was rather sluggish in the
[*] D. L. Browne, M. D. Helm, Dr. 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
Dr. A. Plant
Research Chemistry
Syngenta
Jealott’s Hill International Research Centre
Bracknell, Berkshire, RG42 6EY (UK)
[**] The authors are grateful to the EPSRC and Syngenta for financial
support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
8656
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 8656 –8658
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
&
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
Take advantage of blue reference links
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&

Angewandte
Chemie
Table 1: Cycloaddition reactions of alkynyl boronic esters with N-phenyl
sydnone.
Entry R1
R2[b]
t [h] Product Yield [%] (a:b)[c]
1
2
3
4
5
6
7
8
9
Ph (1a)
Ph (2a)
16
16
3
4
5
6
7
8
9
10
11
12
58 (>98:2)
64 (5:2)
76 (2:1)
Ph (1a)
Ph (1a)
Ph (1a)
p-MeOC6H4 (1b) Ph (2a)
p-NO2C6H4 (1c) Ph (2a)
p-MeOC6H4 (1b) Bu (2b)[b]
p-NO2C6H4 (1c) Bu (2b)[a]
Bu (2b)[a]
Me3Si (2c) 16
H (2d)[a]
16
24
4
24
8
54 (1:7)
58 (>98:2)
70 (>98:2)
55 (5:1)
62 (5:1)
61 (2:1)
Scheme 2. Cycloaddition with C-substituted sydnones. DCB: o-dichlor-
obenzene.
p-MeOC6H4 (1b) Me3Si (2c) 22
p-NO2C6H4 (1c) Me3Si (2c)
10
4
83 (3:2)
[a] Reactions run in refluxing mesitylenes. [b] Reaction run in refluxing
o-dichlorobenzene.
cycloaddition reaction (entries 5, 7, 9) whereas significantly
faster reaction rates were observed when more-electron-
deficient sydnone 1c was employed (entries 6, 8, 10). This
observation is in line with recent kinetics and computational
studies from our labs that suggest that alkynylboronates
participate as electron-rich components in cycloadditions.[16]
Nonetheless, although the reaction rate was found to depend
on the electronic nature of the mesoionic reagent, reaction
regioselectivity was largely unaffected. Notably, the
regioisomers generated in entries 2, 3, 4, and 9 were readily
separable by chromatography; hence, essentially single iso-
mers of pyrazole boronic esters could easily be obtained in
seven of the ten reactions studied.
We next decided to explore the cycloaddition chemistry of
more heavily substituted sydnones with a view to generating
more-complex pyrazoles. We also anticipated that the
increased steric bulk present in these substrates could lead
to more generally regioselective cycloadditions. Accordingly,
we prepared sydnones 13 and 14; our cycloaddition studies
are highlighted in Scheme 2. We were delighted to find that
sydnone 13 underwent efficient cycloaddition to provide
direct access to the fully substituted pyrazoles 15 and 16 and
that these compounds were isolated as single regioisomers.
Moreover, changing the sydnone to include an N-aryl
substituent (14) did not have a deleterious effect on yield or
regioselectivity.
Having demonstrated that the cycloaddition chemistry
could provide tri- and tetrasubstituted pyrazole boronic
esters, we wished to confirm that these intermediates could
be further elaborated through Suzuki coupling reactions.
Additionally, our reaction scope studies had provided func-
tionalized N-arylpyrazoles (Table 1, entries 5–10) and we
hoped to show that these provided a means for deprotection
of the cross-coupled pyrazole products. In the event
(Scheme 3), cross-coupling reactions of pyrazoles 3, 7, and 8
proceeded without incident to give the corresponding prod-
Scheme 3. Functionalization of pyrazole boronic esters. a) 20: CAN
(5 equiv), MeCN, H2O (3:2) (63%); b) 21: i) NH2NH2.H2O, 10% Pd/C,
EtOH, 508C, 3 h; ii) CAN (5 equiv), MeCN, H2O (3:2) (48% over two
steps). DPPF=bis(diphenylphosphanyl)ferrocene.
ucts in good to excellent yield. Moreover, we were able to
demonstrate the utility of these intermediates by removing
the N-aryl moiety in compounds 20 and 21; specifically,
oxidation of 20 with ceric ammonium nitrate (CAN) pro-
ceeded in 63% yield to provide pyrazole 22. Moreover,
reduction of the nitro group in 21 to the corresponding aniline
allowed 22 also to be accessed by CAN oxidation.
In conclusion, we report the first example of alkynylbor-
onate cycloadditions with sydnones as a means to the direct
preparation of functionalized pyrazole boronic esters. More-
over, we have demonstrated that these compounds can be
further functionalized by Pd-catalyzed cross-coupling reac-
tions and N-deprotection processes.
Angew. Chem. Int. Ed. 2007, 46, 8656 –8658
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8657
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
&
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
Take advantage of blue reference links
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&

Communications
[5] For recent overviews, see: a) G. Hilt, P. Bolze, Synthesis 2005,
2091; b) V. Gandon, C. Aubert, M. Malacria, Chem. Commun.
2006, 2209.
Experimental Section
Typical cycloaddition procedure, as exemplified by the formation of
3:
4,4,5,5-Tetramethyl-2-phenethynyl[1,3,2]dioxaborolane
(2a;
[6] a) C. Ester, A. Maderna, H. Pritzkow, W. Siebert, Eur. J. Inorg.
Chem. 2000, 1177; b) M. W. Davies, C. N. Johnson, J. P. A.
Harrity, J. Org. Chem. 2001, 66, 3525; c) V. Gandon, D. Leca,
T. Aechtner, K. P. C. Vollhardt, M. Malacria, C. Aubert, Org.
Lett. 2004, 6, 3405; d) V. Gandon, D. Leboeuf, S. Amslinger,
K. P. C. Vollhardt, M. Malacria, C. Aubert, Angew. Chem. 2005,
117, 7276; Angew. Chem. Int. Ed. 2005, 44, 7114.
[7] a) G. Hilt, K. I. Smolko, Angew. Chem. 2003, 115, 2901; Angew.
Chem. Int. Ed. 2003, 42, 2795; b) G. Hilt, S. Luers, K. I. Smolko,
Org. Lett. 2005, 7, 251; c) G. Hilt, W. Hess, F. Schmidt, Eur. J.
Org. Chem. 2005, 2526; d) Y. Yamamoto, J.-i. Ishii, H. Nish-
iyama, K. Itoh, J. Am. Chem. Soc. 2004, 126, 3712; e) Y.
Yamamoto, J.-i. Ishii, H. Nishiyama, K. Itoh, Tetrahedron 2005,
61, 11501; f) Y. Yamamoto, K. Hattori, J.-i. Ishii, H. Nishiyama,
Tetrahedron 2006, 62, 4294.
228 mg, 1 mmol) and N-phenyl sydnone (1a; 81 mg, 0.5 mmol) were
dissolved in xylenes (0.5 mL), heated at reflux for 16 h, and then
rapidly cooled in an ice bath. The reaction mixture was purified by
flash chromatography on silica gel (100% petrol to 30% ethyl acetate
in petrol). Product 3 was isolated as a colorless solid (100 mg, 58%).
Further purification could be carried out by trituration with diethyl
ether. M.p. 158–1608C; 1H NMR (250 MHz, CDCl3): d = 8.30 (s, 1H),
8.02–8.10 (m, 2H), 7.75–7.83 (m, 2H), 7.25–7.50 (m, 6H), 1.34 ppm (s,
12H); 13C NMR (62.9 MHz, CDCl3): d = 157.9, 139.8, 136.3, 133.9,
129.4, 128.44, 128.0, 126.6, 119.3 (2C), 83.6, 24.8 ppm; FTIR: 2978
(m), 1600 (m), 1532(s), 1446 (m), 1356 (m), 1307 (m), 1217 (m), 1146
(m), 1126 (m), 1062 (m), 993 (m), 958 cmÀ1 (m). HRMS calcd for
C21H23BN2O2: m/z 346.1853, found: 346.1866.
Received: August 16, 2007
[8] a) J. E. Moore, M. W. Davies, K. M. Goodenough, R. A. J.
Wybrow, M. York, C. N. Johnson, J. P. A. Harrity, Tetrahedron
2005, 61, 6707; b) M. D. Helm, J. E. Moore, A. Plant, J. P. A.
Harrity, Angew. Chem. 2005, 117, 3957; Angew. Chem. Int. Ed.
2005, 44, 3889; c) J. E. Moore, M. York, J. P. A. Harrity, Synlett
2005, 860; d) P. M. Delaney, J. E. Moore, J. P. A. Harrity, Chem.
Commun. 2006, 3323.
Published online: October 4, 2007
Keywords: boronic esters · cycloaddition · heterocycles ·
.
regioselectivity
[9] J. Elguero in Comprehensive Heterocyclic Chemistry II, Vol. 3
(Eds.: A. R. Katritzky, C. W. Rees, E. F. V. Scriven), Pergamon,
Oxford, 1996, p. 1; C. Lamberth, Heterocycles 2007, 71, 1467.
[10] For organolithium-based approaches, see: a) A.V. Ivachtchenko,
D. V. Kravchenko, V. I. Zheludeva, D. G. Pershin, J. Heterocycl.
Chem. 2004, 41, 931; b) A.-L. Gꢁrard, C. Mahatsekake, V. Collot,
S. Rault, Tetrahedron Lett. 2007, 48, 4123.
[11] A. Ponti, G. Molteni, J. Org. Chem. 2001, 66, 5252.
[12] D. S. Matteson, J. Org. Chem. 1962, 27, 4293.
[13] F. H. C. Stewart, Chem. Rev. 1964, 64, 129.
[1] Boronic Acids (Ed.: D. G. Hall), Wiley-VCH, Weinheim, 2005.
[2] a) M. Miura, Angew. Chem. 2004, 116, 2251; Angew. Chem. Int.
Ed. 2004, 43, 2201; b) J. Hassan, M. Sevignon, C. Gozzi, E.
Schulz, M. Lemaire, Chem. Rev. 2002, 102, 1359; c) A. Suzuki,
Pure Appl. Chem. 1994, 66, 213.
[3] a) J. C. Antilla, S. L. Buchwald, Org. Lett. 2001, 3, 2 077; b) D. A.
Evans, J. L. Katz, T. R. West, Tetrahedron Lett. 1998, 39, 2937;
c) N. A. Petasis, I. A. Zavialov, J. Am. Chem. Soc. 1997, 119, 445;
d) M. Ueda, N. Miyaura, J. Org. Chem. 2000, 65, 4450; e) Y.
Takaya, M. Ogasawara, T. Hayashi, M. Sakai, N. Miyaura, J. Am.
Chem. Soc. 1998, 120, 5579.
[14] A. M. Gonzalez-Nogal, M. Calle, P. Cuadrado, R. Valero,
Tetrahedron 2007, 63, 224.
[4] a) M. Vaultier, B. Carboni in Comprehensive Organometallic
Chemistry II, Vol. 11 (Eds.: E. W. Abel, F. G. A. Stone, G.
Wilkinson), Pergamon, Oxford, 1995, p. 191; b) M. Murata, T.
Oyama, S. Watanabe, Y. Masuda, J. Org. Chem. 2000, 65, 164.
[15] Details of pyrazole regiochemical assignments are included in
the Supporting Information.
[16] E. Gomez-Bengoa, M. D. Helm, A. Plant, J. P. A. Harrity, J. Am.
Chem. Soc. 2007, 129, 2691.
8658
www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 8656 –8658
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
&
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
Take advantage of blue reference links
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&