A robust protocol for Pd(ii)-catalyzed C-3 arylation of (1H) indazoles and pyrazoles: Total synthesis of nigellidine hydrobromide

Article abstract of DOI:10.1039/c3sc50184a

C3-arylated indazole and pyrazoles are privileged structural motifs in agrochemicals and pharmaceuticals. C-3 C-H arylation of (1H) indazole and pyrazole has been a significant challenge due to the poor reactivity of the C-3 position. Herein, we report a practical Pd(ii)/Phen catalyst and conditions for the direct C-3 arylation of indazole and pyrazole with ArI or ArBr without using Ag additives as halide scavengers. The use of toluene, chlorobenzene, trifluoromethylbenzene and mesitylene as the solvent was found to be crucial for the selectivity and reactivity. We further demonstrate the robustness of this protocol through the first total synthesis of nigellidine hydrobromide as well as the expedient preparation of heterocycles structurally related to pesticides and drug molecules.

Full text of DOI:10.1039/c3sc50184a

Chemical Science
View Article Online
View Journal
EDGE ARTICLE
A robust protocol for Pd(II)-catalyzed C-3 arylation of
(1H) indazoles and pyrazoles: total synthesis of
nigellidine hydrobromide†
Cite this: DOI: 10.1039/c3sc50184a
Mengchun Ye,a Andrew J. F. Edmunds,b James A. Morris,c David Sale,c Yejia Zhanga
a
*
and Jin-Quan Yu
C3-arylated indazole and pyrazoles are privileged structural motifs in agrochemicals and pharmaceuticals.
C-3 C–H arylation of (1H) indazole and pyrazole has been a significant challenge due to the poor reactivity
of the C-3 position. Herein, we report a practical Pd(II)/Phen catalyst and conditions for the direct C-3
arylation of indazole and pyrazole with ArI or ArBr without using Ag additives as halide scavengers. The
use of toluene, chlorobenzene, trifluoromethylbenzene and mesitylene as the solvent was found to be
crucial for the selectivity and reactivity. We further demonstrate the robustness of this protocol through
the first total synthesis of nigellidine hydrobromide as well as the expedient preparation of heterocycles
structurally related to pesticides and drug molecules.
Received 21st January 2013
Accepted 18th March 2013
DOI: 10.1039/c3sc50184a
www.rsc.org/chemicalscience
at the C-3 of pyrazole via C–H activation can only be achieved by
using an elegantly devised protecting-group-switch strategy.6a
Introduction
Transition metal-catalyzed arylation of heteroarene C–H
bonds has regained considerable attention over recent years.1
These reactions can potentially provide concise routes for
constructing bi(hetero)aryls, as well as late-stage diversica-
tion of bioactive target molecular scaffolds.2 As an important
class of heteroarenes, indazole and pyrazole motifs are
embedded in numerous pharmaceuticals and agrochemicals
with a broad range of biological activities,3 including anti-
inammatory (Celebrex, Fig. 1),3a antiemetic (Granisol),3b
antipsychotic (CDPPB),3c and anticancer (Pyrazolanthrone)3d
drugs, as well as herbicides (uazolate),3e and insecticides
(chlorantraniliprole).3f
This strategy essentially converts the C-3 position into the more
reactive C-5 position. It has also been shown that an efficient
arylation protocol for the C-3 arylation of (2H) indazole is not
applicable to (1H) indazole substrates.8
Building on our previous success with the C-3 selective ary-
lation and olenation of pyridines using Pd(II)/Phen (phenan-
throline) catalysts,10 we embarked on the development of
related protocols for the C-3 arylation of (1H) indazoles and
pyrazoles. While our manuscript was in preparation, the Itami
and El Kazzouli groups independently reported Pd/Phen (phe-
nanthroline) catalysts for the C-3 arylation of (1H) indazole.11 In
As a result, extensive efforts have been directed towards the
development of practical and efficient catalytic systems for the
direct arylation of indazole and pyrazole in recent years. These
protocols have been applied to the rapid syntheses of indazole
or pyrazole bi(hetero)aryls, or late-stage modication of
complex indazole or pyrazole scaffolds.4–9 Despite the develop-
ment of several efficient protocols for C-4,4,5 or C-5 arylation of
pyrazole,6 and C-3 arylation of (2H) indazole,7,8 C-3 arylations of
pyrazole and (1H) indazole remain a formidable challenge due
to lack of reactivity (Fig. 2).9 Indeed, installation of an aryl group
aDepartment of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd.,
La Jolla, CA, 92037, USA. E-mail: yu200@scripps.edu
bSyngenta Crop Protection AG Schaauserstrasse, CH-4332 Stein, Switzerland
cSyngenta Ltd., Jealott's Hill International Research Centre, Bracknell, Berkshire, UK,
RG42 6EY
† Electronic supplementary information (ESI) available: Data for new compounds
and experimental procedures. See DOI: 10.1039/c3sc50184a
Fig. 1 Biologically active indazoles and pyrazoles.
This journal is ª The Royal Society of Chemistry 2013
Chem. Sci.

View Article Online
Chemical Science
Edge Article
adapted for the C-3 arylation of (1H) indazole and pyrazole. We
were aware of several potential problems that we could
encounter in applying this Pd/Phen system to the C-3 arylation
of pyrazole and indazole. Firstly, the N–N bond is known to be
unstable under previously reported conditions (eqn (2)).13
Secondly, the sp2 nitrogen at the 2-position could direct further
arylation of the newly installed aryl groups (eqn (3)).
(2)
Fig. 2 Reactivity of indazole and pyrazole towards C–H arylation.
(3)
Itami's protocol, the reaction was run with 10 mol% PdCl2,
10 mol% Phen, 2.0 equiv. K3PO4, and 1.5 equiv. Ag2CO3 in
DMA.11a El Kazzouli's conditions required 20 mol% Pd(OAc)2
and 40 mol% Phen in polar DMA.11b While these reactions
represent exciting developments for the C-3 arylation of (1H)
indazole, both yields and substrate scope remain to be
substantially improved. The use of a stoichiometric amount of
Ag additive as a halide scavenger, or high catalyst loading
(20 mol% Pd) are also drawbacks. Herein, we report a highly
efficient Pd/Phen catalytic system for the C-3 arylation of (1H)
indazole and pyrazole without using a Ag additive (eqn (1)).‡ We
demonstrate the utility of this protocol by achieving the rst
total synthesis of nigellidine.
Based on our previous protocol for the C-3 arylation of
pyridines, we began to screen conditions for the arylation of 1-
methyl indazole 1a. We found that the reaction of 1 equiv. 1a
with 1 equiv. iodobenzene in DMF in the presence of 10 mol%
Pd(OAc)2, 30 mol% Phen and 3.0 equiv. Cs2CO3 under air at
ꢀ
140 C gave the desired arylated product 2a in 24% yield aer
48 h (entry 1, Table 1). The undesired by-product 3 from further
directed arylation of product 2a was also isolated in 3% yield.
Increasing the amount of iodobenzene to 2 equiv. improved
the yield of 2a to 51%. Unfortunately, the yield of side product
3 also increased to 14% (entry 2, Table 1). We reasoned that
(1)
Table 1 Investigation of the C-3 C–H arylation of indazolea
Results and discussion
Initial studies and reaction optimization
There exist two major challenges in the development of selective
C–H functionalization methods for heterocycles, namely,
controlling the regioselectivity among C–H bonds with subtle
electronic and steric differences, and preventing the non-
productive coordination of the heteroatom of the substrates
with the metal catalysts. In the search for solutions to these two
problems, we found that the phenanthroline ligand coordinates
strongly with Pd(II) centers and weakens coordination of the
N-atom of pyridine substrates, most likely through sterics.10 The
dissociation of the pyridine enhances the local concentration of
substrate in the vicinity of the Pd(II) catalysts for productive
p-binding which triggers the C-3 C–H functionalizations.
Computational studies suggest that the C-3 selectivity can be
attributed to the recognition of the highest electron density at
this carbon by the catalyst.12 Encouraged by these preliminary
results, we began to test if the Pd(II)/Phen system could be
Entry
Phl (equiv.)
Ligand
Base
2ab (%)
3b (%)
1
2
3
4
5
6
1.0
2.0
2.0
2.0
2.0
2.0
Phen
Phen
Phen-PhMe
Dpya
Phen
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
24
51
21
42
47
3
3
14
0
0
6
Phen
K2HPO4
0
a
Reaction conditions: indazole (0.25 mmol) in solvent (1 mL) at 140 ꢀC
for 48 h. Yield was determined using 1H NMR spectroscopy, using
b
CH2Br2 as an internal standard.
Chem. Sci.
This journal is ª The Royal Society of Chemistry 2013

View Article Online
Edge Article
Chemical Science
a bulkier or tridentate ligand would prevent the nitrogen at the reduced to 10 mol% and 1 equiv., respectively only when
2-position from directing further arylation of product 2a. toluene is used as solvent (entries 13, 14). Control experiments
Indeed, bulkier (Phen-PhMe, entry 3) and tridentate (Dpya, showed that the Pd(OAc)2, Phen and base are essential for the
entry 4) ligands inhibited the formation of 3, with ligand Dpya observed reactivity (entries 15, 16).
affording 2a in 42% yield (entry 4). Although the result obtained
with Dpya was promising, we further optimized conditions
using phenanthroline due to its ready availability, and found
Substrate scope
that the use of K3PO4 as the base in DMF diminished the
formation of 3 (entry 5) while affording 2a in 47% yield.
Disappointingly, the material balance under all these condi-
tions was only around 60%.
With this signicantly improved protocol in hand, we examined
the scope of aryl halide coupling partners for the C-3 arylation of
indazoles. Both aryl iodides and bromides worked well to give
the corresponding 3-arylated indazoles in high to excellent yield
(2a–2p, Table 3). Aryl chlorides also reacted under these
conditions to give the arylated product in 29% yield, albeit
requiring the use of excess phenyl chloride (entry 9, Table 2).
The possibility of using aryl chlorides as coupling partners upon
further development is appealing from a practical perspective. A
wide range of functional groups on the aryl iodides were toler-
ated including electron-donating and -withdrawing groups,
OMe, MeS, F, Cl, CF3, CN and CO2Et (2e–2m). The tolerance of a
strongly chelating MeS group is a valuable feature for making
sulfur containing compounds. Most importantly, arylation with
heteroaryl bromides also proceeded smoothly to afford biolog-
ically important biheteroaryls in good to excellent yields (2n–
2p), which speaks for the robustness of the Pd/Phen catalyst and
conditions.
To improve the material balance, we examined the solvent
effect using K3PO4 as a base (entries 1–4, Table 2). Strikingly, the
use of PhCl as the solvent completely suppressed the formation
of the side product 3 (entry 4). Most importantly, the material
balance in PhCl reached above 90%. The stability of the inda-
zole substrate in thiꢀs solvent prompted us to raise the reaction
temperature to 160 C which improved the yield to 60% (entry
5). This dramatic solvent effect urged us to revisit the use
Cs2CO3 as the base. To our delight, Cs2CO3 in PhCl improved
the yield to 89% with the formation of only 3% of by-product 3
(entry 6). Either reducing the loading of ligand (entry 7) or the
amount of base resulted in a lower yield (entry 8). We also
observed that PhCl reacted with indazole in the absence of PhI
(entry 9) which could be a potential problem in synthetic
applications. In light of these two drawbacks, we further
screened arene-based solvents and found that toluene, PhCF3
and mesitylene also gave comparable results (entries 10–12).
Importantly, the loading of Phen ligand and base can be
Next, we focused our attention on the scope of the indazoles
and pyrazoles. Unprotected indazole and pyrazole gave no
reaction under the optimal conditions. To improve the versa-
tility of this protocol, we tested various synthetically useful
Table 2 Optimization of the C-3 arylation of indazolea
Entry
Pd(OAc)2 (mol%)
Phen (mol%)
Base (equiv.)
Solvent (1 mL)
Temp. (ꢀC)
Yieldb (%) 2a (3)
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
10
10
10
10
10
10
5
30
30
30
30
30
30
10
30
30
30
30
30
10
5
K3PO4 (3.0)
K3PO4 (3.0)
K3PO4 (3.0)
K3PO4 (3.0)
K3PO4 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (1.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Dioxane
DMSO
o-Xylene
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCF3
Mesitylene
Toluene
Toluene
Toluene
Toluene
Toluene
140
140
140
140
160
160
160
160
160
160
160
160
160
160
160
160
0 (0)
45 (0)
19 (0)
45 (0)
60 (0)
89 (3)
72 (1)
64 (0)
29 (0)c
87 (0)
77 (4)
85 (3)
93 (0)
23 (0)
0
9
10
11
12
13
14
15
16
10
0
0
10
0
a
Reaction conditions: indazole (0.25 mmol) and PhI (0.5 mmol) in solvent (1 mL) for 48 h. b Yield was determined using 1H NMR spectroscopy, using
CH2Br2 as an internal standard. c No PhI was added.
This journal is ª The Royal Society of Chemistry 2013
Chem. Sci.

View Article Online
Chemical Science
Edge Article
Table 3 Various aryl halides in C-3 arylationsa
Table 4 Various substituted indazoles and pyrazolesa
a
Reaction conditions: Pd(OAc)2 (10 mol%), Phen (10 mol%), Cs2CO3
(1.0 equiv.), indazole (0.25 mmol), ArI (0.5 mmol) in toluene (1 mL)
b
for 48 h and then isolated yield was obtained. 30 mol% of Phen was
c
used. Reaction was run for 12 h to give the same yield when
chlorobenzene was used.
ring, thus allowing subsequent further cross couplings at this
position. Finally, C-3 arylations of substituted pyrazoles
including a hindered triphenyl pyrazole were also successful
(4a–4c).16 Prior to our work, a single example of tristri-
uoromethylphenylation of N-methylpyrazole in a moderate
yield (52%) using [Pd(Phen)2](PF6)2 as catalyst was reported by
Murai et al.17
As expected, arylation of (2H) indazole under these reaction
conditions gave the desired product in 91% yield (Fig. 3).
Competition experiments using (1H) indazole and (2H) indazole
in the same reaction afforded 75% C3-arylated (2H) indazole
a
Reaction conditions: Pd(OAc)2 (10 mol%), Phen (10 mol%), Cs2CO3
(1.0 equiv.), indazole (0.25 mmol), ArX (0.5 mmol) in toluene (1 mL)
for 48 h and then isolated yield was obtained. 3-Bromopyridine
(1.0 mmol) was used.
b
N-protecting groups. Unfortunately, electron-withdrawing pro-
tecting groups such as Ac, Boc, and Ts inhibit the reaction
severely. To our delight, the practically useful alkyl protecting
groups, such as Bn (2q, 2r), SEM (2s), and THP (2t) were
compatible with this reaction (Table 4).14 It is worth noting that
the undesired directed ortho-arylation of the benzyl groups was
not observed. The synthetic utility of the C-3 arylation of Bn-
protected indazole was demonstrated by a one-step synthesis of
biologically active agent YD-3 (2r) in 89% yield using para-
methoxylcarbonylaryliodide as coupling partner.15 Various
substituents including uoro, chloro and ester on the indazole
phenyl ring were tolerated (2u–2y), although 4-Cl substituted
indazole reacted very slowly due to the sterics, giving 44% yield
in 72 h (2u). We were pleased that azaindazole, a biologically
important structural motif, was also successfully arylated to give
the desired product in 81% yield (2y), without any reaction of
the highly activated chloro group at the 2-position of the pyridyl Fig. 3 Competition reaction between (1H) indazole and (2H) indazole.
Chem. Sci.
This journal is ª The Royal Society of Chemistry 2013

View Article Online
Edge Article
Chemical Science
and 8% C-3 arylated (1H) indazole, conrming that the reac- this catalytic reaction was demonstrated in the rst total
tivity of (2H) indazole is superior to that of (1H) indazole.
synthesis of natural alkaloid nigellidine hydrobromide as well
as the one-step synthesis of drug molecule YD-3.
Synthetic application
Acknowledgements
Developing C–H activation reactions as enabling synthetic
disconnections to allow highly convergent synthesis is one
major impetus for our efforts in this eld.18,19 We therefore
sought to demonstrate the utility of our C-3 indazole arylation
in a total synthesis of the natural alkaloid nigellidine (12).
Nigellidine was isolated in 1995 from the seeds of Nigella sativa,
which are used to treat various diseases.20 While related inda-
zole natural products have been synthesized by Kelly et al.,21 no
total synthesis of nigellidine has yet been reported. We envi-
sioned a convergent synthesis of nigellidine could be rapidly
accomplished using this C-3 arylation reaction as a key step.
Thus, commercially available 4-methoxy-6-methyl-(1H)-indazole
was rst protected using the readily removable THP group to
give 7. C-3 arylation of 7 under the optimized conditions fur-
nished 8 in 54% isolated yield on the gram scale (Fig. 4).
Deprotection of the THP group and stepwise N-alkylations with
1,4-dibromobutane afforded precursor 11. Subsequent deme-
thylation by treating 11 with BBr3 afforded the natural product
nigellidine hydrobromide (12), which was conrmed by X-ray
crystallographic analysis. Thus, the rst total synthesis of
nigellidine hydrobromide was completed in six steps with an
overall yield of 18%.
We gratefully acknowledge The Scripps Research Institute,
Syngenta and the National Institutes of Health (NIGMS 1 R01
GM102265-01) for nancial support.
Notes and references
‡ General procedure for the C-3 arylation of indazoles and pyrazoles: to a 35 mL
sealed tube were added Pd(OAc)2 (5.6 mg, 0.025 mmol), 1,10-phenanthroline (4.5
mg, 0.025 mmol), Cs2CO3 (82 mg, 0.25 mmol), aryl halide (0.25 mmol), indazole
derivative (0.25 mmol), and toluene (1 mL). The tube was capped and stirred at
160 ꢀC for 48–72 h. The reaction mixture was cooled to room temperature and
diluted with EtOAc, ltered through a short pad of Celite, washed with EtOAc, and
concentrated in vacuo. The resulting residue was puried by PTLC using hexanes–
EtOAc (10 : 1 to 6 : 1, depending on different substrates) as the eluent.
1 For recent reviews on the arylation of heteroarenes, see: (a)
J. Roger, A. L. Gottumukkala and H. Doucet,
ChemCatChem, 2010, 2, 20–40; (b) L. Ackermann, R. Vicente
and A. R. Kapdi, Angew. Chem., Int. Ed., 2009, 48, 9792–
9826; (c) F. Bellina and R. Rossi, Tetrahedron, 2009, 65,
10269–10310; (d) G. P. McGlacken and L. M. Bateman,
Chem. Soc. Rev., 2009, 38, 2447–2464; (e) J. C. Lewis,
R. G. Bergman and J. A. Ellman, Acc. Chem. Res., 2008, 41,
1013–1025; (f) I. V. Seregin and V. Gevorgyan, Chem. Soc.
Rev., 2007, 36, 1173–1193; (g) D. Alberico, M. E. Scott and
M. Lautens, Chem. Rev., 2007, 107, 174–238; (h) T. Satoh
and M. Miura, Chem. Lett., 2007, 36, 200–205.
2 (a) C. Meyer, B. Neue, D. Schepmann, S. Yanagisawa,
J. Yamaguchi, E.-U. Wuerthwein, K. Itami and B. Wuensch,
Org. Biomol. Chem., 2011, 9, 8016–8029; (b) H.-X. Dai,
A. F. Stepan, M. S. Plummer, Y.-H. Zhang and J.-Q. Yu,
J. Am. Chem. Soc., 2011, 133, 7222–7228.
Conclusions
In summary, we have developed a practical Pd/Phen catalyst
system for the C-3 arylation of indazole and pyrazole. This
protocol in general gives high yields and accommodates a broad
range of substrates and coupling partners. The robustness of
3 (a) T. D. Penning, J. J. Talley, S. R. Bertenshaw, J. S. Carter,
P. W. Collins, S. Docter, M. J. Graneto, L. F. Lee,
J. W. Malecha, J. M. Miyashiro, R. S. Rogers, D. J. Rogier,
S. S. Yu, G. D. Anderson, E. G. Burton, J. N. Cogburn,
S. A. Gregory, C. M. Koboldt, W. E. Perkins, K. Seibert,
A. W. Veenhuizen, Y. Y. Zhang and P. C. Isakson, J. Med.
Chem., 1997, 40, 1347–1365; (b) G. L. Plosker and
K. L. Goa, Drugs, 1991, 42, 805–824; (c) T. de Paulis,
K. Hemstapat, Y. Chen, Y. Zhang, S. Saleh, D. Alagille,
R. M. Baldwin, G. D. Tamagnan and P. J. Conn, J. Med.
Chem., 2006, 49, 3332–3344; (d) S. Okuno, A. Saito,
T. Hayashi and P. H. Chan, J. Neurosci., 2004, 24, 7879–
7887; (e) B. D. Maxwell, J. Labelled Compd. Radiopharm.,
2000, 43, 645–654; (f) G. P. Lahm, D. Cordova and
J. D. Barry, Bioorg. Med. Chem., 2009, 17, 4127–4133.
4 For intramoleular C-4 direct arylation of pyrazole, see:
S. Kumar, H. Ila and H. Junjappa, J. Org. Chem., 2009, 74,
7046–7051.
5 For intermolecular C-4 direct arylation of pyrazole, see:
Y. Fall, H. Doucet and M. Santelli, Synthesis, 2010, 127–135.
Fig. 4 Total synthesis of nigellidine hydrobromide.
This journal is ª The Royal Society of Chemistry 2013
Chem. Sci.

View Article Online
Chemical Science
Edge Article
6 For intermolecular C-5 direct arylation of pyrazole, see: 15 For previous syntheses of YD-3, see: (a) H.-S. Chen, S.-C. Kuo,
(a) R. Gikhman, T. L. Jacques and D. Sames, J. Am.
Chem. Soc., 2009, 131, 3042–3048; (b) C. Mateos,
J. Mendiola, M. Carpintero and J. M. Minguez, Org.
Lett., 2010, 12, 4924–4927; (c) A. Beladhria, K. Beydoun,
H. Ben Ammar, R. Ben Salem and H. Doucet, Synthesis,
2011, 2553–2560.
C.-M. Teng, F.-Y. Lee, J.-P. Wang, Y.-C. Lee, C.-W. Kuo,
C.-C. Huang, C.-C. Wu and L.-J. Huang, Bioorg. Med.
Chem., 2008, 16, 1262–1278; (b) F.-Y. Lee, J.-C. Lien,
L.-J. Huang, T.-M. Huang, S.-C. Tsai, C.-M. Teng, C.-C. Wu,
F.-C. Cheng and S.-C. Kuo, J. Med. Chem., 2001, 44, 3746–
3749, also see ref. 11a
7 For intramolecular direct arylation of 2H indazole, see: 16 Arylation of THP-protected unsubstituted pyrazole under
B. Laleu and M. Lautens, J. Org. Chem., 2008, 73, 9164–9167.
8 For intermolecular direct arylation of 2H indazole, see:
S. A. Ohnmacht, A. J. Culshaw and M. F. Greaney, Org. 17 F. Shibahara, E. Yamaguchi and T. Murai, J. Org. Chem.,
these conditions occurs at C-5 predominantly (C5 : C4 : C3
¼ 12 : 1.5 : 1), consistent with previous reports.
Lett., 2010, 12, 224–226.
2011, 76, 2680–2693.
9 For intramolecular C-3 arylation of pyrazole, see: 18 (a) D.-H. Wang and J.-Q. Yu, J. Am. Chem. Soc., 2011, 133,
E. J. Brnardic, R. M. Garbaccio, M. E. Fraley, E. S. Tasber,
J. T. Steen, K. L. Arrington, V. Y. Dudkin, G. D. Hartman,
5767–5769; (b) J. Yamaguchi, A. D. Yamaguchi and
K. Itami, Angew. Chem., Int. Ed., 2012, 51, 8960–9009.
S. M. Stirdivant, B. A. Drakas, K. Rickert, E. S. Walsh, 19 Total synthesis using Pd-catalyzed C–H functionalizations of
ˆ
K. Hamilton, C. A. Buser, J. Hardwick, W. Tao, S. C. Beck,
X. Mao, R. B. Lobell, L. Sepp-Lorenzino, Y. Yan, M. Ikuta,
S. K. Munshi, L. C. Kuo and C. Kreatsoulas, Bioorg. Med.
Chem. Lett., 2007, 17, 5989–5994.
heterocycles: (a) B. M. Trost, S. A. Godleski and J. P. Genet,
J. Am. Chem. Soc., 1978, 100, 3930–3931; (b) T. D. Cushing,
J. F. Sanz-Cervera and R. M. Williams, J. Am. Chem. Soc.,
1993, 115, 9323–9324; (c) P. S. Baran and E. J. Corey, J. Am.
Chem. Soc., 2002, 124, 7904–7905; (d) N. K. Garg,
D. D. Caspi and B. M. Stoltz, J. Am. Chem. Soc., 2004, 126,
9552–9553; (e) J. Lu, X. Tan and C. Chen, J. Am. Chem. Soc.,
2007, 129, 7768–7769; (f) E. M. Beck, R. Hatley and
M. J. Gaunt, Angew. Chem., Int. Ed., 2008, 47, 3004–3007;
(g) A. L. Bowie Jr and D. Trauner, J. Org. Chem., 2009, 74,
1581–1586; (h) D. Mandal, A. D. Yamaguchi, J. Yamaguchi
and K. Itami, J. Am. Chem. Soc., 2011, 133, 19660–19663.
10 (a) M. Ye, G.-L. Gao and J.-Q. Yu, J. Am. Chem. Soc., 2011, 133,
6964–6967; (b) M. Ye, G.-L. Gao, A. J. F. Edmunds,
P. A. Worthington, J. A. Morris and J.-Q. Yu, J. Am. Chem.
Soc., 2011, 133, 19090–19093.
11 For the most recent intermolecular C-3 arylation of 1H
indazole, see: (a) K. Hattori, K. Yamaguchi, J. Yamaguchi
and K. Itami, Tetrahedron, 2012, 68, 7605–7612, therein, a
protocol using CuI/Phen/LiOtBu for this arylation has also
been reported; (b) A. Ben-Yahia, M. Nass, S. El Kazzouli, 20 Atta-ur-Rahman, S. Malik, S. S. Hasan, M. I. Choudhary,
E. K. Essassi and G. Guillaumet, Eur. J. Org. Chem., 2012,
7075–7081.
12 A. Petit, J. Flygare, A. T. Miller, G. Winkel and D. H. Ess, Org.
Lett., 2012, 14, 3680–3683.
13 A. Unsinn and P. Knochel, Chem. Commun., 2012, 48, 2680–
2682, also see ref. 11a
14 Arylation of phenyl protected indazole also proceeded to give
the desired product in 50% isolated yield.
C.-Z. Ni and J. Clardy, Tetrahedron Lett., 1995, 36, 1993–1996.
21 For relevant syntheses of the nigellidine family, see: (a)
E. L. Elliott, S. M. Bushell, M. Cavero, B. Tolan and
T. R. Kelly, Org. Lett., 2005, 7, 2449–2451; (b) A. Schmidt,
T. Habeck, M. K. Kindermann and M. Nieger, J. Org.
Chem., 2003, 68, 5977–5982; (c) K. Inamoto, M. Katsuno,
T. Yoshino, Y. Arai, K. Hiroya and T. Sakamoto,
Tetrahedron, 2007, 63, 2695–2711.
Chem. Sci.
This journal is ª The Royal Society of Chemistry 2013