Alkyne [3 + 2] cycloadditions of iodosydnones toward functionalized 1,3,5-trisubstituted pyrazoles

Article abstract of DOI:10.1021/jo902514v

(Chemical Equation Presented) The cycloaddition of 4-iodosydnones with terminal alkynes proceeds with excellent regiocontrol to provide 5-iodo pyrazoles. These products participate smoothly in subsequent C-C and C-heteroatom bond forming processes.

Full text of DOI:10.1021/jo902514v

pubs.acs.org/joc
SCHEME 1
Alkyne [3 þ 2] Cycloadditions of Iodosydnones
Toward Functionalized 1,3,5-Trisubstituted
Pyrazoles
Duncan L. Browne,† John B. Taylor,‡ Andrew Plant,‡,§ and
Joseph P. A. Harrity*,†
quench (Scheme 1).4 While there are no direct methods of
functionalization at C-3, McLaughlin and Sames have em-
ployed an elegant protecting group transposition concept that
provides a regiocontrolled method for achieving this goal.5
Recent studies in our laboratories have also been aimed at
developing regiocontrolled methods for the synthesis of
highly functionalized pyrazoles.6 We have largely opted to
target pyrazole boronic acid derivatives because of the
associated versatility of the boronate motif.7 Accordingly,
we have conducted several studies on the cycloaddition of
sydnones with alkynylboronates for the synthesis of pyrazole
boronic esters (Figure 1). The regiochemical outcome of
these cycloadditions has been delineated and interrogated
by both practical and theoretical examination.6a,c We have
also extended this to a flexible divergent approach through
the discovery of a cross-coupling strategy from an inter-
mediate 4-bromosydnone.6b A potentially powerful exten-
sion of the pyrazole forming strategy outlined in Figure 1
would be the direct cycloaddition of alkynes with 4-halosyd-
nones to provide the corresponding halopyrazoles. In con-
nection with this concept, we report herein the regioselective
synthesis of 5-iodo pyrazoles with specific emphasis on the
flexible introduction of substituents at the C-3 position.
A literature survey suggested that bromosydnones are
unstable at elevated temperatures in nonpolar solvents8
although their participation in cycloaddition processes with
activated alkynes (e.g., dimethylacetylene dicarboxylate and
†Department of Chemistry, University of Sheffield, Sheffield
S3 7HF, U.K., ‡Research Chemistry Syngenta, Jealott’s Hill
International Research Centre, Berkshire RG42 6EY, U.K.,
§
and Syngenta, Mu€nchwilen AG, WST-810.3.38, CH-4332
Stein, Switzerland
j.harrity@sheffield.ac.uk
Received November 26, 2009
The cycloaddition of 4-iodosydnones with terminal
alkynes proceeds with excellent regiocontrol to provide
5-iodo pyrazoles. These products participate smoothly in
subsequent C-C and C-heteroatom bond forming pro-
cesses.
The synthesis and reactions of pyrazoles continues to gain
growing interest within both academic and industrial labora-
tories. This diazole core is finding increasing importance as a
biologically active agent and can be found in a number of
pharmaceutical and agrochemical products.1 Pyrazoles are
also gaining interest as ligands for transition metals and
within materials chemistry.2 The search for new bioactivity
and pyrazole reactivity will be aided by the development of
new and complementary synthetic approaches to such mo-
lecules. In this context, pyrazoles are generally accessed
either via ring synthesis or by ring functionalization.3 With
regard to the latter approach, typical methods of pyrazole
functionalization involve the regioselective halogenation at
the C-4 position followed by metalation or cross-coupling, or
by selective ring lithiation at C-5 with a subsequent electrophilic
FIGURE 1. A sydnone cycloaddition stratgey to pyrazoles.
(4) (a) Li, H.; Wang, Y.; McMillen, W. T.; Chatterjee, A.; Toth, J. E.;
Mundla, S. R.; Voss, M.; Boyer, R. D.; Sawyer, J. S. Tetrahedron 2007, 63,
11763. (b) Grimmett, M. R.; Iddon, B. Heterocycles 1994, 37, 2087.
(5) (a) McLaughlin, M.; Marcantonio, K.; Chen, C.-y.; Davies, I. W.
J. Org. Chem. 2008, 73, 4309. (b) Goikhman, R.; Jacques, T. L.; Sames, D.
J. Am. Chem. Soc. 2009, 131, 3042.
(6) (a) Browne, D. L.; Helm, M. D.; Plant, A.; Harrity, J. P. A. Angew.
Chem., Int. Ed. 2007, 46, 8656. (b) Browne, D. L.; Taylor, J. B.; Plant, A.;
Harrity, J. P. A. J. Org. Chem. 2009, 74, 396. (c) Browne, D. L.; Vivat, J. F.;
Plant, A.; Gomez-Bengoa, E.; Harrity, J. P. A. J. Am. Chem. Soc. 2009, 131,
7762.
(1) (a) Elguero, J. In Comprehensive Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; vol. 3, p 1.
(b) Lamberth, C. Heterocycles 2007, 71, 1467. (c) Singh, P.; Paul, K.; Holzer, W.
Bioorg. Med. Chem. 2006, 14, 5061 and references cited therein.
(2) (a) Trofimenko, S. Prog. Inorg. Chem. 1986, 34, 115. (b) Danel, A.;
He, Z.; Milburn, G. H. W.; Tomasik, P. J. Mat. Chem. 1999, 9, 339.
(3) Heterocyclic Chemistry; Joule, J.A., Mills, K., Eds.; Blackwell
Science: Oxford, 2000.
(7) Boronic Acids; Hall, D.G., Ed.; Wiley-VCH: Weinheim, 2005.
(8) Dickopp, H. Chem. Ber. 1974, 107, 3036.
984 J. Org. Chem. 2010, 75, 984–987
Published on Web 12/23/2009
DOI: 10.1021/jo902514v
r
2009 American Chemical Society

Browne et al.
JOCNote
TABLE 1. 4-Iodo Sydnone Cycloaddition Reactivity and Regioselectivity
Studies
TABLE 2. Scope of the Alkyne Cycloaddition Partner
reaction time
(h)
entry
R
R1
yield % (a:b)
1
2
3
4
5
6
PNPa
PNP
Ph
Ph
PMPb
PMP
H; 1
I; 2
H; 3
I; 4
H; 5
I; 6
8
8
16
16
24
24
60 (19:1); 7
84 (10:1); 8
35 (>19:1); 9
73 (>19:1); 10
30 (10:1); 11
72 (10:1); 12
aPNP: p-nitrophenyl. bPMP: p-methoxyphenyl.
ethyl propiolate) has been documented.9 There were no
reports of thermal instability in the analogous 4-iodosyd-
nones, although again reports of their cycloaddition chem-
istry were similarly limited to activated alkynes.9 In addition,
the outcome of the cycloadditions of 4-iodosydnones and
propiolates suggested little scope for regiocontrol.10 None-
theless, we decided to explore the cycloaddition efficiency
and regioselectivity of a series of nonactivated terminal
alkynes with sydnones bearing an I-atom at C-4. Moreover,
we conducted the cycloaddition reactions of the appro-
priate C-4 unsubstituted sydnones to highlight any advanta-
geous/deleterious effects of the iodide substituent on the
cycloaddition process.11 We chose to begin our studies by
using phenylacetylene as the dipolarophile, and our results are
summarized in Table 1. N-p-Nitrophenyl substituted sydnone 1
underwent efficient cycloaddition to provide the corresponding
1,3-disubstituted pyrazole 7 with excellent regiocontrol (entry
1). The corresponding iodide 2 reacted similarly but gave
an improved overall yield of 1,3,5-trisubstituted pyrazole 8
(entry 2). Changing the N-substituent to more electron rich
aromatic groups resulted in reduced reaction rates but had little
effect on the cycloaddition regiocontrol (entries 3-6). Overall
however, the C-4 iodo substituted sydnones appeared to give a
consistently improved yield of pyrazole products over their C-4
unsubstituted counterparts.
The high selectivities observed in this preliminary study
were extremely encouraging as this strategy represented a
potentially powerful and effective method for installing
substituents at the pyrazole C-3 position, while providing
scope for elaboration at C-5. Moreover, given that this
substituent ultimately emanates from a terminal alkyne, this
approach promised to show significant generality. To con-
firm this, we next turned our attention to assessing the scope
of the pyrazole forming chemistry with respect to the term-
inal alkyne, and our results are highlighted in Table 2.
Surprisingly, the cycloaddition of trimethylsilylacetylene
and PNP-protected sydnones 1 and 2 proceeded in modest
yield when conducted under refluxing xylenes. We envisaged
that this relatively low yield was due to the volatility of this
alkyne, and so we opted to perform the reaction in a sealed
entry
R
R1
yield %a
A:B
1
2
3
4
5
6
7
8
9
TMS
TMS
nBu
H
I
H
I
I
I
I
I
I
75 (45); 13
99 (65); 14
47; 15
82 (64); 16
64; 17
77; 18
62; 19
70; 20
65; 21
8:1
>19:1
10:1
10:1
10:1
nBu
Bn
cyclopropyl
CH2OBn
C(OH)Ph2
17:1
>19:1
>19:1
>19:1
p-MeO2CC6H4
aYields in parentheses represent that when the reaction was con-
ducted under reflux.
tube. Pleasingly, the desired pyrazoles 13 and 14 were
delivered in greatly increased yields (entries 1, 2). Primary
alkyl substituted alkynes (1-hexyne and 3-phenyl-1-propyne)
displayed good selectivity in the cycloaddition reaction,
giving rise to a 10:1 ratio of pyrazole isomers (entries 3-5).
Cycloaddition with cyclopropylacetylene provided an inter-
esting pyrazolyl-3-cyclopropane scaffold 18 in good yield
(entry 6). The latter secondary alkyl substituted alkyne
displayed improved regioselectivity over the primary con-
geners (compare entries 4-6), suggesting an element of steric
control in these cycloadditions. Finally, propargyl alcohol
derivatives and functionalized arylacetylenes were also
found to participate smoothly in the cycloaddition with 2
to provide the pyrazoles 19-21 in good yields and with
excellent regiocontrol (entries 7-9).
From the perspective of library synthesis, we felt that it
was important to demonstrate that the chemistry is amenable
to being performed in a microwave reactor and on gram
scale. We found this to be the case and an illustrative example
of each is provided in Scheme 2.
We concluded from these cycloaddition studies that the
iodosydnone generally undergoes cycloaddition in high yield
(and typically in higher yield than the C-4 unsubstituted
sydnone) and with excellent levels of regiocontrol. To high-
light the potential value of these synthetic intermediates, we
next explored a selection of transformations of the iodide.
Unsurprisingly, these compounds participated smoothly in
the Suzuki-Miyaura cross-coupling reaction.12 However,
ꢀ
(9) Dumitras-cu, F.; Mitan, C. I.; Dumitrescu, D.; Draghici, C.; Caproiu,
ꢀ
M. T. ARKIVOC 2002, 2, 80.
(10) Jiang, Q.; Ryan, M.; Zhichkin, P. J. Org. Chem. 2007, 72, 6618.
(11) Terminal alkynes were reported to undergo cycloaddition with
excellent regiocontrol by Huisgen in his seminal report of this chemistry:
Huisgen, R.; Grashey, R. Angew. Chem., Int. Ed. Engl. 1962, 1, 48.
(12) Pyrazoles 8, 14, 18, underwent cross-coupling with a selection of
boronic acids in yields of >79%. Details of these reactions can be found in
the Supporting Information.
J. Org. Chem. Vol. 75, No. 3, 2010 985

Browne et al.
JOCNote
SCHEME 2. Gram Scale Cycloadditions
SCHEME 3. Functionalization Reactions
we opted to focus our attention on replacing the iodide
substituent with other heteroatoms. We were particularly
keen to introduce a nitrogen atom at the 5-position. Initial
efforts toward this end consisted of a host of unsuccessful
palladium and copper mediated amination reactions. Nota-
bly, in the case of the copper mediated couplings, the oxidative
insertion appeared facile (even at room temperature), as
evidenced by the near quantitative recovery of protodeiodo-
nated pyrazoles following a number of protocols.13 While the
exact reasons for the failure of this chemistry are to date
unclear, to the best of our knowledge there are no reports of
the coupling of 5-halopyrazoles mediated by copper. Moving
to a different tact, we assessed the lithium-halogen exchange
reaction toward the introduction of heteroatoms. To our de-
light, treatment of 5-iodo pyrazole 10 with n-butyllithium at
-78 °C for 2 h followed by quenching with diphenyldisulfide
gave the 5-pyrazolylsulfide 23 in excellent yield (Scheme 3).14
Pyrazolyl ester 24 and aldehyde 25 could be isolated by
treatment of the lithiated intermediate with methylchlorofor-
mate (74%) and DMF (65%), respectively. Moreover, pyr-
azolyl-5-boronic ester 22 was synthesized in 60% yield by the
in situ treatment of the lithiated intermediate with isopropox-
ypinacol boronate. Thisproduct was particularly intriguing as
it represented an alternative means to introduce an amine.
Specifically, a recent report from Liu, Guo, and co-workers
described the transformation of boronic acids to azides at
room temperature in the presence of a copper sulfate cata-
lyst.15 Indeed, treatment of the pyrazole boronic ester 22
under these conditions for 48 h at room temperature delivered
the azide 26 in 99% yield. Furthermore, the pyrazolyl-azide
was successfully reduced to its amino analogue 27 in 88%
yield on the employment of palladium catalyzed hydrogena-
tion. Lastly, a one-pot azidation/click reaction delivered the
corresponding biheteroaryl product 28 in excellent yield
(Scheme 3, 91%).
offers access to a plethora of pyrazole scaffolds where diversity
at the 3 position is seemingly only limited by the availability of
the alkyne. Moreover, we have shown that the iodo pyrazole
intermediates can be further functionalized by a selection of
C-C and C-heteroatom bond forming processes.
Experimental Section
Representative Procedure for the Cycloaddition of Sydnones
with Alkynes. 5-Iodo-1-(4-nitrophenyl)-3-phenyl-1H-pyrazole
(8). To iodosydnone 26c (167 mg, 0.5 mmol) and phenylacetylene
(0.11 mL, 1 mmol) was added xylenes (0.5 mL). The reaction was
heated at reflux for 8 h before cooling and purifying by flash
column chromatography (solvent gradient starting with petro-
leum ether, ending with 20% ethyl acetate in petroleum ether).
Product 8 was isolated as a yellow oil (as a mixture of isomers
10:1, 165 mg, 84%). Further purification allowed 12 to be iso-
lated as a single regioisomer, as a yellow solid, mp 115-118 °C.
1H NMR (400 MHz, CDCl3): δ 7.03 (1H, s), 7.40-7.50 (3H, m),
7.83-7.87 (2H, m), 7.92 (2H, d, J = 9.0 Hz), 8.39 (2H, d, J = 9.0
Hz). 13C NMR (100.6 MHz, CDCl3): δ 80.8, 116.8, 124.4, 125.8,
126.1, 128.9 (2C), 131.6, 144.9, 146.9, 155.6. FTIR: 1595 (m),
1522 (s), 1500 (m), 1456 (m), 1342 (s), 1111 (m), 971 (m), 854 (m)
cm-1. HRMS (ES): m/z [MH]þ calcd for C15H11IN3O2
391.9896, found 391.9899.
Representative Procedure for Lithiation of 4-Iodopyrazoles:
Synthesis of 1,3-Diphenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxabor-
olan-2-yl)-1H-pyrazole (22). 5-Iodopyrazole 10 (100 mg, 0.29
mmol) was dissolved in THF (1 mL) and the reaction mixture
cooled to -78 °C before the addition of n-butyllithium (2.2 M in
hexanes, 290 μL, 0.638 mmol). The resulting reaction mixture
was stirred at -78 °C for 2 h before the addition of iso-pro-
poxypinacolboronate (237 μL, 1.16 mmol). The reaction mix-
ture was stirred for a further 2 h before removal of the cold bath
and allowing to warm to room temperature. After 30 min, the
reaction was quenched with aqueous saturated ammonium
chloride solution and extracted with ethyl acetate. The organic
extracts were dried over MgSO4, filtered, and concentrated to
dryness before purification by flash column chromatography
(solvent gradient starting with petroleum ether, ending with
10% ethyl acetate in petroleum ether). Product 22 was isolated
In summary, iodo sydnones represent useful substrates
for the regioselective synthesis of functionalized pyrazoles
via [3 þ 2] cycloadditions of terminal alkynes. This chemistry
(13) Palladium mediated amination reactions: (a) Yang, B. H.; Buchwald,
S. L. J. Organomet. Chem. 1999, 576, 125. (b) For a discussion of the
challenges associated with Pd-catalyzed amination of iodoarenes, see: Fors,
B. P.; Davis, N. R.; Buchwald, S. L. J. Org. Chem. 2009, 131, 5766. Copper
mediated amination reactions: (c) Xia, N.; Taillefer, M. Angew. Chem., Int.
Ed. 2009, 48, 337. (d) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128,
8742.
(14) Lithiation of pyrazole 12 followed by quenching with PhSSPh
provided the corresponding sulfide in low yield as an impure product. We
speculate that lithiation of this pyrazole is complicated by side reactions at
the N-p-nitrophenyl group.
(15) Tao, C.-Z.; Cui, X.; Li, J.; Liu, A.-X.; Liu, L.; Guo, Q.-X. Tetra-
hedron Lett. 2007, 48, 3525.
1
as a colorless solid (60 mg, 60%), mp 114-117 °C. H NMR
986 J. Org. Chem. Vol. 75, No. 3, 2010

Browne et al.
JOCNote
Acknowledgment. We are grateful to the EPSRC and
Syngenta for financial support.
(400 MHz, CDCl3): δ 1.32 (12H, s), 7.25 (1H, s), 7.32-7.50
(6H, m), 7.62-7.68 (2H, m), 7.90-7.96 (2H, m). 13C NMR
(100.6 MHz, CDCl3): δ 24.6, 84.4, 114.9, 124.8, 125.9, 127.5,
127.8, 128.4, 128.6, 133.1, 141.5, 152.3. FTIR: 3063 (w), 2978
(m), 2931 (w), 1600 (m), 1544 (m), 1510 (m), 1439 (s), 1329 (s),
1240 (m), 1143 (s), 1009 (m), 854 (m) cm-1. HRMS (ES): m/z
[MH]þ calcd for C21H24BN2O2 347.1931, found 347.1935.
Supporting Information Available: Full experimental details
and characterization data, copies of 1H and 13C NMR spectra
for all products. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 3, 2010 987