Ortho-allylation of 1-arylpyrazoles with allyl phenyl ether via iron-catalyzed C-H bond activation under mild conditions

Article abstract of DOI:10.1002/adsc.201400063

An iron salt and a bipyridine-type ligand catalyze the ortho-allylation of 1-arylpyrazoles and congeners with allyl phenyl ether under mild conditions (0 °C). The ligand, an organozinc base, and the nature of the allylating reagent are crucial for the success of this reaction. Under these conditions, a competitive phenylation reaction is largely retarded, and cross-coupling of the organozinc with the allyl electrophile is minimized. The reaction may proceed via iron-catalyzed ortho C-H activation to form a metallic intermediate, which then reacts with the allyl ether in a γ selective fashion.

Full text of DOI:10.1002/adsc.201400063

COMMUNICATIONS
DOI: 10.1002/adsc.201400063
ortho-Allylation of 1-Arylpyrazoles with Allyl Phenyl Ether via
À
Iron-Catalyzed C H Bond Activation under Mild Conditions
Sobi Asako,a Jakob Norinder,a Laurean Ilies,a,* Naohiko Yoshikai,b
and Eiichi Nakamuraa,*
a
Department of Chemistry, School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax : (+81)-3-5800-6889; phone: (+81)-3-5800-6889; e-mail: laur@chem.s.u-tokyo.ac.jp or nakamura@chem.s.u-tokyo.ac.jp
Present Address: Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences,
b
Nanyang Technological University, Singapore 637371, Singapore
Received: January 17, 2014; Revised: February 19, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400063.
À
Abstract: An iron salt and a bipyridine-type ligand
catalyze the ortho-allylation of 1-arylpyrazoles and
congeners with allyl phenyl ether under mild condi-
tions (08C). The ligand, an organozinc base, and the
nature of the allylating reagent are crucial for the
success of this reaction. Under these conditions,
a competitive phenylation reaction is largely retard-
ed, and cross-coupling of the organozinc with the
allyl electrophile is minimized. The reaction may
the cleavage of the C H bond and to control site se-
lectivity.[3] There has been much interest in diversify-
ing the repertoire of directing groups, especially with
the purpose of adding intrinsic value to the reaction
products. The pyrazole group is a privileged structure
of drug molecules and biologically active com-
pounds;[4] therefore, it has been an attractive choice
À
as a directing group for C H functionalization, typi-
cally via the use of precious metal catalysts or harsh
reaction conditions.[5] Herein, we report that an iron
catalyst[6] mediates the ortho-allylation of 1-arylpyra-
zole derivatives with allyl phenyl ether[7] under re-
markably mild conditions.[8] Allylation of arenes
À
proceed via iron-catalyzed ortho C H activation to
form a metallic intermediate, which then reacts
with the allyl ether in a g selective fashion.
[9,10,11,12]
À
À
Keywords: allylation; arenes; C H activation; iron;
pyrazoles
through C H activation
is an attractive alter-
native to the Friedel–Crafts-type reaction,[13] which is
often limited to electron-rich arenes and suffers from
selectivity issues.
The difficulties associated with the utilization of
pyrazole as a directing group became apparent when
The formation of a carbon-carbon bond via transition we attempted to allylate 1-phenylpyrazole using the
[1]
À
metal-catalyzed C H bond activation allows the conditions developed previously in our laboratory for
straightforward creation of molecular complexity the allylation of aromatic carboxamides,[14] which re-
from simple hydrocarbons.[2] A directing group that sulted in complete recovery of the starting material
coordinates with the metal active species is usually [Eq. (1)].
appended to the hydrocarbon substrate, to facilitate
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
Sobi Asako et al.
We ascribed this lack of reactivity to the poor com-
patibility of the pyrazole substrate with the ligand
and organometallic base,[15] resulting in the difficult
formation of the putative metallacycle intermediate,
such as A, that was proposed in our previous stud-
ACHTUNGTRENNUNG
ies.[14,16e,g] Therefore, we commenced an extensive
study of these parameters (see the Supporting Infor-
mation), which led to the finding that the use of a bi-
pyridine-type ligand and diphenylzinc base is the key
to the success of the allylation reaction, possibly by
favoring the formation of an intermediate, such as B
in Eq. (2). Thus, 1 reacted with allyl phenyl ether in
Figure 1. Investigation of several allylating reagents (yields
are based on 1). The reaction time was 15 h, except for the
yields in parentheses, for which the reaction time was 48 h.
the presence of 10 mol% of FeACTHNUTRGNEN(UG acac)3/4,4’-di-tert- uct was observed in a trace amount (<2%). This se-
butyl-2,2’-bipyridyl (dtbpy) and 3 equiv. of a diphenyl- lectivity was in agreement with the poor reactivity of
zinc reagent (prepared from ZnCl2·TMEDA and an ortho-substituted substrate (entry 7), which we as-
PhMgBr) to give the ortho-allylated product 2 with cribed to the steric interactions that disturb the for-
a yield of 80% after isolation. We noted that the pres- mation of a planar metallacycle.[16g] Isomerization of
À
ent catalytic system allowed the C H activation reac- the allylated product to the more thermodynamically
tion to proceed at 08C compared with the reaction in- stable styrene derivative, which is sometimes an issue
dicated in Eq. (1), which required heating. Notably, in the allylation reaction, was largely retarded (<
under these conditions, only a trace amount of com- 5%). We observed though that a prolonged reaction
pound 3, which was obtained via iron-catalyzed oxida- time led to an increase in the amount of the styrene
tive arylation[16] with allyl ether as the oxidant, and derivative.[18] The phenylated product (such as 3) was
46% of 4 (based on 1, 23% based on the initial allyl obtained in a trace amount, with the exception of
ether), which was obtained via iron-catalyzed allylic electron-deficient substrates and 2-naphthylpyrazole
cross-coupling,[17] were generated. As described in the (entries 5, 8, and 10), where it was obtained with
Supporting Information, other ligands and bases re- a yield of 5–7%. The reaction did not reach complete
sulted mainly in the recovery of the starting material. conversion and the starting material was recovered,
Sterically hindered MesMgBr or electron-deficient probably due to catalyst deactivation by the phenox-
C6F5MgBr completely stopped the reaction.
ide anion that is generated as the reaction progresses.
The reaction of substrates bearing an electron-do-
An important factor for the success of this reaction
was the choice of the allylating reagent (Figure 1). nating group at the para-position proceeded smoothly
Thus, allylic electrophiles bearing a poor leaving (entries 2–4), whereas a para-substituted substrate
group, such as thiolate, amide, and siloxy were mostly bearing an electron-withdrawing group was less reac-
recovered, whereas those bearing a better leaving tive (entry 5). The allylation of meta-substituted sub-
group, such as acetate, benzoate, carbonate, or chlo- strates took place selectively at the less hindered posi-
ride, reacted mostly with diphenylzinc to give 4.
tion with good yields (entries 6 and 8). A substrate in
Various 1-arylpyrazoles and congeners could be al- which the pyrazole bears a methyl group reacted
lylated with allyl phenyl ether under the optimized more efficiently than did a substrate in which the pyr-
conditions (Table 1). All the reactions gave the mono- azole bears an ester group (entries 9 and 10). We note
allylated product selectively, and the diallylated prod- that the ester group was untouched under the reaction
2
asc.wiley-vch.de
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

COMMUNICATIONS
ortho-Allylation of 1-Arylpyrazoles with Allyl Phenyl Ether
Table 1. Iron-catalyzed reaction of various 1-arylpyrazoles
of an arene possessing a commonly used directing
group such as pyridine, imine, N-methylamide, or tri-
and congeners with allyl phenyl ether.[a]
AHCTUNGTREGUNaNN zole, which gave mainly the phenylated product
(congener of 3) and recovery of the starting material
(see the Supporting Information).
Substituted allyl ethers reacted sluggishly under
these reaction conditions and the arylpyrazole sub-
strate was partially phenylated.
To gain a mechanistic insight into the allylation
step, 1 was reacted with 1,1-dideuterioallyl phenyl
ether [Eq. (3)]. The two deuterium atoms were found
selectively at the terminal vinylic positions, suggesting
that the allylation took place with high g selectivity.
Benzyl phenyl ether and homoallyl phenyl ether did
not react at all, suggesting that the reaction proceeds
through the insertion of the alkene with the necessary
presence of a b leaving group. Involvement of an
À
iron-catalyzed C H activation step is supported by
the following experimental facts: (i) the reaction in
the absence of an iron catalyst gave no allylated prod-
uct; (ii) the reaction in the presence of one equiv. of
iron and without the allyl ether, followed by quench-
ing with deuterium oxide resulted in deuterium incor-
poration at the ortho-position (see the Supporting In-
formation); (iii) the same reaction performed in the
absence of iron resulted in 0% deuterium incorpora-
tion.
In conclusion, we have developed an iron-catalyzed
allylation of 1-arylpyrazole and congeners with allyl
À
ethers under mild reaction conditions. This C H acti-
vation reaction exploits the medicinally relevant pyra-
zole moiety as a directing group to create a new class
of allylated pyrazole derivatives. Iron catalysis has
been a topic of great interest because of the economic
and environmental merits of iron;[19] the present work
[a]
The reaction was performed under the conditions de-
scribed in Eq. (2) on a 0.4-mmol scale. See the Support-
ing Information for details.
Yield for the isolated product.
On a 0.8-mmol scale.
À
represents a rare example of iron-catalyzed C H acti-
[b]
vation followed by reaction with an electrophile.[14,20]
Further investigation of this reactivity of iron, as well
as the expansion of the scope of the allylic substrate,
will be the subject of our future studies.
[c]
[d]
Containing a trace amount of phenylated product.
[e]
ZnBr2·TMEDA was used instead of ZnCl2·TMEDA.
[f]
1
Determined by H NMR.
conditions and that the unreacted substrate was re-
covered (entry 10). An indazolyl group, found in the
structure of alkaloids such as nigellicine, nigeglanine,
and nigellidine, also acted as an excellent directing
group (entry 11). A further example of the peculiar
nature of pyrazole as a directing group is the reaction
Experimental Section
Typical Procedure
1-Phenyl-1H-pyrazole
(1,
116 mg,
0.8 mmol)
and
ZnCl2·TMEDA (606 mg, 2.4 mmol) were placed in an oven-
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
Sobi Asako et al.
dried Schlenk flask under argon. A solution of PhMgBr in
THF (1.09M, 4.40 mL, 4.8 mmol) was added dropwise to
this mixture at 08C. After stirring for 3 min, allyl phenyl
g) C.-L. Sun, B.-J. Li, Z.-J. Shi, Chem. Rev. 2011, 111,
1293–1314.
[7] a) F. Sasaya, N. Miyaura, A. Suzuki, Bull. Korean
Chem. Soc. 1987, 8, 329–332; b) T. Nishikata, B. H. Lip-
shutz, J. Am. Chem. Soc. 2009, 131, 12103–12105.
[8] J. Wencel-Delord, T. Drçge, F. Liu, F. Glorius, Chem.
Soc. Rev. 2011, 40, 4740–4761.
[9] a) S. Oi, Y. Tanaka, Y. Inoue, Organometallics 2006, 25,
4773–4778; b) K. Cheng, B. Yao, J. Zhao, Y. Zhang,
Org. Lett. 2008, 10, 5309–5312; c) Y. Kuninobu, P. Yu,
K. Takai, Chem. Commun. 2011, 47, 10791–10793;
d) H. Wang, N. Schrçder, F. Glorius, Angew. Chem. Int.
Ed. 2013, 52, 5386–5389; e) Y. Aihara, N. Chatani, J.
Am. Chem. Soc. 2013, 135, 5308–5311.
ether (220 mL, 1.6 mmol) and a solution of FeACTHNURTGNENG(U acac)3/4,4’-di-
tert-butyl-2,2’-bipyridyl in THF (1.0 mL, 0.08M, 80 mmol)
were added sequentially. The reaction mixture was stirred at
08C for 48 h, followed by dilution with Et2O and addition of
a saturated aqueous solution of Rochelleꢁs salt. After extrac-
tion with ethyl acetate, the combined organic layers were
passed through a pad of Florisil and concentrated under re-
duced pressure. The crude product was purified by column
chromatography on silica gel (hexane/AcOEt/NEt3 =99/0.5/
0.5), followed by gel-permeation chromatography (eluent=
toluene) to remove 1, to afford 1-(2-allylphenyl)-1H-pyra-
zole (2) as a colorless oil; yield: 118 mg (80%). The spectro-
scopic data were in agreement with those reported in the lit-
erature.[9d]
[10] a) Y. J. Zhang, E. Skucas, M. J. Krische, Org. Lett. 2009,
11, 4248–4250; b) R. Zeng, C. Fu, S. Ma, J. Am. Chem.
Soc. 2012, 134, 9597–9600; c) B. Ye, N. Cramer, J. Am.
Chem. Soc. 2013, 135, 636–639.
[11] a) T. Yao, K. Hirano, T. Satoh, M. Miura, Angew.
Chem. 2011, 123, 3046–3050; Angew. Chem. Int. Ed.
2011, 50, 2990–2994; b) Y. Makida, H. Ohmiya, M. Sa-
wamura, Angew. Chem. 2012, 124, 4198–4203; Angew.
Chem. Int. Ed. 2012, 51, 4122–4127; c) S. Fan, F. Chen,
X. Zhang, Angew. Chem. 2011, 123, 6040–6045; Angew.
Chem. Int. Ed. 2011, 50, 5918–5923.
[12] S. Usui, Y. Hashimoto, J. V. Morey, A. E. H. Wheatley,
M. Uchiyama, J. Am. Chem. Soc. 2007, 129, 15102–
15103.
Acknowledgements
We thank MEXT (KAKENHI Specially Promoted Research
22000008 to E.N.) and a Grant-in-Aid for Scientific Research
on Innovative Areas (No. 25105711 to L.I.) and the Global
COE Program for Chemistry Innovation. S.A. thanks the
Japan Society for the Promotion of Science for Young Scien-
tists for a Research Fellowship (No. 23-8207).
[13] a) M. Rueping, B. J. Nachtsheim, Beilstein J. Org.
Chem. 2010, 6, No. 6, DOI: 10.3762/bjoc.6.6; b) T. B.
Poulsen, K. A. Jørgensen, Chem. Rev. 2008, 108, 2903–
2915; c) M. Kodomari, S. Nawa, T. Miyoshi, J. Chem.
Soc. Chem. Commun. 1995, 1895–1896.
References
À
[1] Handbook of C H Transformations, (Ed: G. Dyker),
[14] S. Asako, L. Ilies, E. Nakamura, J. Am. Chem. Soc.
Wiley-VCH, Weinheim, 2005.
2013, 135, 17755–17757.
[2] a) K. Godula, D. Sames, Science 2006, 312, 67–72;
b) W. R. Gutekunst, P. S. Baran, Chem. Soc. Rev. 2011,
40, 1976–1991; c) J. Wencel-Delord, F. Glorius, Nat.
Chem. 2013, 5, 369–375.
[3] a) G. B. Shul’pin, Org. Biomol. Chem. 2010, 8, 4217–
4228; b) S. R. Neufeldt, M. S. Sanford, Acc. Chem. Res.
2012, 45, 936–946.
[4] a) S. Fustero, M. Sanchez-Rosellꢂ, P. Barrio, A. Simꢂn-
Fuentes, Chem. Rev. 2011, 111, 6984–7034; b) Y. L.
Janin, Chem. Rev. 2012, 112, 3924–3958.
[5] a) T. Asaumi, N. Chatani, T. Matsuo, F. Kakiuchi, S.
Murai, J. Org. Chem. 2003, 68, 7538–7540; b) T.
Asaumi, T. Matsuo, T. Fukuyama, Y. Ie, F. Kakiuchi, N.
Chatani, J. Org. Chem. 2004, 69, 4433–4440; c) N.
Umeda, K. Hirano, T. Satoh, M. Miura, J. Org. Chem.
2009, 74, 7094–7099; d) P. M. Liu, C. G. Frost, Org.
Lett. 2013, 15, 5862–5865, and references cited therein.
[6] Selected reviews: a) C. Bolm, J. Legros, J. Le Paih, L.
Zani, Chem. Rev. 2004, 104, 6217–6254; b) S. Enthaler,
K. Junge, M. Beller, Angew. Chem. 2008, 120, 3363–
3367; Angew. Chem. Int. Ed. 2008, 47, 3317–3321;
c) Iron Catalysis in Organic Chemistry, (Ed.: B. Plietk-
er), Wiley-VCH, Weinheim, 2008; d) B. D. Sherry, A.
Fꢃrstner, Acc. Chem. Res. 2008, 41, 1500–1511;
e) W. M. Czaplik, M. Mayer, J. Cvengros, A. Jacobi von
Wangelin, ChemSusChem 2009, 2, 396–417; f) E. Naka-
mura, N, Yoshikai, J. Org. Chem. 2010, 75, 6061–6067;
[15] a) K. Gao, N. Yoshikai, J. Am. Chem. Soc. 2011, 133,
400–402; b) L. Ilies, Q. Chen, X. Zeng, E. Nakamura, J.
Am. Chem. Soc. 2011, 133, 5221–5223; c) K. Gao, N.
Yoshikai, Angew. Chem. 2011, 123, 7020–7024; Angew.
Chem. Int. Ed. 2011, 50, 6888–6892; d) P.-S. Lee, N.
Yoshikai, Angew. Chem. 2013, 125, 1278–1282; Angew.
Chem. Int. Ed. 2013, 52, 1240–1244.
[16] a) J. Norinder, A. Matsumoto, N. Yoshikai, E. Naka-
mura, J. Am. Chem. Soc. 2008, 130, 5858–5859; b) N.
Yoshikai, A. Matsumoto, J. Norinder, E. Nakamura,
Angew. Chem. 2009, 121, 2969–2972; Angew. Chem.
Int. Ed. 2009, 48, 2925–2928; c) N. Yoshikai, A. Matsu-
moto, J. Norinder, E. Nakamura, Synlett 2010, 313–316;
d) S. Asako, L. Ilies, E. Nakamura, J. Am. Chem. Soc.
2011, 133, 7672–7675; e) N. Yoshikai, S. Asako, T.
Yamakawa, L. Ilies, E. Nakamura, Chem. Asian J.
2011, 6, 3059–3065; f) L. Ilies, M. Kobayashi, A. Matsu-
moto, N. Yoshikai, E. Nakamura, Adv. Synth. Catal.
2012, 354, 593–596; g) L. Ilies, E. Konno, Q. Chen, E.
Nakamura, Asian J. Org. Chem. 2012, 1, 142–145.
[17] a) A. Yanagisawa, N. Nomura, H. Yamamoto, Synlett
1991, 513–514; b) A. Stephen, K. Hashmi, G. Szeimies,
Chem. Ber. 1994, 127, 1075–1089; c) M. Nakamura, K.
Matsuo, T. Inoue, E. Nakamura, Org. Lett. 2003, 5,
1373–1375; d) R. Martin, A. Fꢃrstner, Angew. Chem.
2004, 116, 4045–4047; Angew. Chem. Int. Ed. 2004, 43,
4
asc.wiley-vch.de
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

COMMUNICATIONS
ortho-Allylation of 1-Arylpyrazoles with Allyl Phenyl Ether
´
3955–3957; e) C. M. R. Volla, D. Markovic, S. R. Dub-
baka, P. Vogel, Eur. J. Org. Chem. 2009, 6281–6288.
[18] M. Mayer, A. Welther, A. Jacobi von Wangelin, Chem-
CatChem 2011, 3, 1567–1571.
[19] a) C. Bolm, Nat. Chem. 2009, 1, 420; b) E. Nakamura,
K. Sato, Nat. Mater. 2011, 10, 158–161.
[20] T. Matsubara, S. Asako, L. Ilies, E. Nakamura, J. Am.
Chem. Soc. 2014, 136, 646–649.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
5
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
6 ortho-Allylation of 1-Arylpyrazoles with Allyl Phenyl Ether
À
via Iron-Catalyzed C H Bond Activation under Mild
Conditions
Adv. Synth. Catal. 2014, 356, 1 – 6
Sobi Asako, Jakob Norinder, Laurean Ilies,*
Naohiko Yoshikai, Eiichi Nakamura*
6
asc.wiley-vch.de
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!