Synthesis of dihydropyrazoles via ligand-free Pd-catalyzed alkene aminoarylation of unsaturated hydrazones with diaryliodonium salts

Article abstract of DOI:10.1021/acs.orglett.7b02480

A ligand-free, palladium-catalyzed aminoarylation reaction of the unactivated alkenes in β,γ-unsaturated hydrazones is described. This protocol enables efficient and simultaneous formation of C(sp³)-N and C(sp³)-C(sp²) bonds under mild conditions, providing a practical and general approach to various diversely substituted dihydropyrazoles in generally good yields, without the use of any stoichiometric external oxidant.

Full text of DOI:10.1021/acs.orglett.7b02480

Letter
pubs.acs.org/OrgLett
Synthesis of Dihydropyrazoles via Ligand-Free Pd-Catalyzed Alkene
Aminoarylation of Unsaturated Hydrazones with Diaryliodonium
Salts
Meng-Nan Yang, Dong-Mei Yan, Quan-Qing Zhao, Jia-Rong Chen,* and Wen-Jing Xiao*,†,‡
†
†
†
,†
†
CCNU−uOttawa Joint Research Centre, Hubei International Scientific and Technological Cooperation Base of Pesticide and Green
Synthesis, Key Laboratory of Pesticides and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal
University, 152 Luoyu Road, Wuhan 430079, China
‡
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, 345 Lingling Road, Shanghai 200032,
China
*
S Supporting Information
ABSTRACT: A ligand-free, palladium-catalyzed aminoarylation reaction of
the unactivated alkenes in β,γ-unsaturated hydrazones is described. This
3
protocol enables efficient and simultaneous formation of C(sp )−N and
3
2
C(sp )−C(sp ) bonds under mild conditions, providing a practical and general
approach to various diversely substituted dihydropyrazoles in generally good
yields, without the use of any stoichiometric external oxidant.
he synthesis of privileged N−N bond-containing dihy-
dropyrazoles has gained a great deal of research effort
Scheme 1. Exploration of β,γ-Unsaturated Hydrazones for
Nitrogen Heterocycle Synthesis
T
from the synthetic community due to their prevalence in many
natural products and pharmacologically active molecules as well
as versatile utility as building blocks in organic synthesis (Figure
1
1
). Many recent methods for their preparation have mainly
Figure 1. Selected examples of bioactive molecules with dihydropyr-
azole core.
alkene terminus. On the other hand, in recent years, palladium-
catalyzed alkene difunctionalization through C−N bond
formation has been established as a powerful and widely
applied synthetic tool for construction of diverse nitrogen
focused on catalytic cyclization or cycloaddition reactions using
2
organocatalysts or metal catalysts. Given the important effects
5
,6
heterocycles. Among most of these processes, the initial
aminopalladation typically involves amides, carbamates as well
as sulfonamides as nucleophilic nitrogen sources, thus enabling
selective and efficient C−N bond formation. Inspired by such a
type of catalytic activation mode, we envisioned that by
combining palladium-catalyzed aminopalladation of alkene with
appropriate aryl sources, we might realize an intermolecular
aminoarylation of β,γ-unsaturated hydrazones (Scheme 1b).
Unfortunately, our initial attempts to use aryl halides as aryl
sources proved to be unsuccessful probably due to the poor
compatibility of the hydrazone moiety with the relatively harsh
of the substitution patterns and structural diversity on their
biological profile, development of general, efficient and
operationally simple methods for the construction of such a
class of nitrogen heterocycles is still highly desirable.
In this regard, we in 2014 reported a new method for the
synthesis of 4,5-dihydropyrazoles by photoredox-catalyzed
hydrazonyl radical-mediated intramolecular hydroamination of
β,γ-unsaturated hydrazones under visible light irradiation
3
(
Scheme 1a). This strategy also allowed further incorporation
of various functional groups into the terminal alkene by
trapping the related key intermediates with suitable radical
7
4
reaction conditions.
acceptors. However, despite the synthetic utility and broad
substrate scope of these transformations, it has not been
possible to apply the above photocatalytic systems to those β,γ-
unsaturated hydrazones equipped with an aryl group at the
Received: August 10, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02480
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Owing to the highly electron-deficient property of the iodine
center and excellent leaving-group ability of the ArI moiety in
hypervalent iodine(III) reagents, this compound class has also
recently found widespread applications as mild, nontoxic and
selective arylating reagents and oxidants in metal-catalyzed
PhCF and o-xylene, toluene still proved to be the best reaction
3
medium (entries 2 vs 6−10). Further evaluation of several
other organic and inorganic bases did not result in any
improvement of the yield (entries 11−14). Notably, reducing
the amounts of 2a and base loading to 1.2 equiv respectively at
slightly diluted conditions could still afford 3aa in 78% yield
(entry 15). Notably, replacement of 2a with its byproduct PhI
8
cross-coupling reactions and heterocycle synthesis. In
9
particular, the utilization of diaryliodonium salts in copper-
10
7
and palladium-catalyzed difunctionalization of unsaturated
systems has opened new synthetic possibilities for construction
of diverse novel carbocyclic and heterocyclic scaffolds.
Mechanistically, it was postulated that the use of iodine(III)
reagent enabled generation of highly reactive high-valent metal
sepecies that allowed arylation at mild reaction conditions.
Thus, we considered the diaryliodonium salts as the aryl
sources (Scheme 1b, step 2). Herein, we report the first
example of palladium-catalyzed alkene aminoarylation of β,γ-
unsaturated hydrazones.
under standard conditions led to no 3aa.
With the optimized conditions in hand, we then explored the
generality and limitation of this ligand-free palladium-catalyzed
aminoarylation reaction using a range of β,γ-unsaturated
hydrazones (Scheme 2a). It was found that the electronic and
Scheme 2. Substrate Scope of β,γ-Unsaturated Hydrazones
,
a b
and Diaryliodonium Salts
To test our design plan outlined in Scheme 1b, we initially
selected β,γ-unsaturated hydrazone 1a and diphenyliodonium
tetrafluoroborate 2a as the model substrates to optimize the
7
reaction conditions (Table 1). When a mixture of 1a and 2a in
a
Table 1. Condition Optimization
b
entry
[Pd]
Pd(OAc)2
solvent
base
yield (%)
70
i
i
i
i
i
i
i
i
i
i
1
2
3
4
5
6
7
8
9
toluene
toluene
toluene
toluene
toluene
CH Cl
Pr NEt
2
c
Pd(TFA)2
Pr NEt
2
85(79)
Pd(acac)2
Pr NEt
2
50
83
82
49
63
58
73
25
43
57
61
59
Pd(BF ) (MeCN)
Pr NEt
2
4
2
4
PdCl (PhCN)
Pr NEt
2
2
2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pr NEt
2
2
2
CHCl3
Pr NEt
2
PhCl
Pr NEt
2
PhCF3
Pr NEt
2
10
11
12
13
14
15
o-xylene
toluene
toluene
toluene
toluene
toluene
Pr NEt
2
NaHCO3
K CO
d
d
d
d
2
3
NEt3
Cs CO
2
3
,
e
i
c
a
i
Pd(TFA)2
Pr NEt
2
84(78)
1 (0.20 mmol), 2 (0.24 mmol), Pd(TFA) (5 mol %), Pr NEt (1.2
2 2
b c
a
equiv) in toluene (4.0 mL) at rt for 24−36 h. Isolated yield. 1.0
mmol scale.
1
a (0.20 mmol), 2a (0.30 mmol), palladium catalyst (5 mol %), and
b
base (0.40 mmol) in 3.0 mL of solvent at rt for 24 h. Determined by
1
H NMR analysis using 1,3,5-trimethoxybenzene as an internal
c
d
standard. Isolated yield in parentheses. 1.2 equiv of 2a was used.
e
i
positional effects of the substituents on the aryl ring did not
lead to obvious difference in reaction efficiency and reactivity.
In addition to 1a, a range of β,γ-unsaturated hydrazones 1b−g
bearing an electron-donating (e.g., Me, OMe) or electron-
withdrawing (e.g., Cl, Br) subsituent on the para- or meta-
position of the phenyl ring reacted well to give the expected
products 3ba-ga with generally good yields (60−78%).
Moreover, the reaction with a series of linear and cyclic
aliphatic hydrazone substrates 1h−k also proceeded smoothly,
with products 3ha-ka being formed in 52−87% yield. The
heteroarenes, such as 2-thienyl- and 2-furyl-substituted
hydrazones 1l and 1m also proved to be suitable for the
reaction, leading to 3la and 3ma in 39% and 56% yields,
respectively. Notably, this alkene aminoarylation reaction could
be extended by variation of the sulfoamide moiety. For
1
.2 equiv of Pr NEt and 4.0 mL of toluene were used.
2
toluene was treated with 5 mol % of Pd(OAc) without any
2
i
ligand in the presence of 2.0 equiv of Pr NEt as a base at room
2
temperature, the desired reaction proceeded smoothly to give
the aminoarylation product 3aa with 70% NMR yield (entry 1).
The dihydropyrazole 3aa was also unambiguously confirmed by
NMR, HRMS and single crystal X-ray crystallographic
1
1
analysis. Then, we performed a brief screening of commonly
used palladium(II) salts, and identified Pd(TFA) to be the best
2
one with 3aa being isolated in 79% yield (entry 2). With the
catalyst Pd(TFA) , we next examined the effect of the solvents
2
on the reaction, and found that the reaction was highly slovent-
dependent. Compared to the solvents DCM, CHCl , PhCl,
3
B
DOI: 10.1021/acs.orglett.7b02480
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
example, the reactions of substrates 1n and 1o with para-chloro
or 2,4,6-trimethyl groups on the aromatic ring worked well to
afford the corresponding products 3na and 3oa in 56−68%
yield. Then, we continued to examine the substrate scope
briefly by reacting 1a with a representative set of diary-
liodonium salts (Scheme 2b). Once again, the present catalytic
system proved to be suitable for the diaryliodonium salts 2b−d
with electron-withdrawing (e.g., CN, Br) or weakly electron-
donating groups on the aryl ring and 1-naphthyl-substituted
one 2e, furnishing the desired products 3ab−ae in 37−94%
yield. As shown in the synthesis of 3aa, the reaction could also
be performed on 1.0 mmol scale to provide the product in 61%
yield. Product 3aa could also undergo a sequential Ts
deprotection/aromatization to give pyrazole 3aa′ with
analogous to 1 but with a phenyl group at the alkene terminus
were unsuccessful (results not shown).
The present alkene aminoarylation could be extended to γ,δ-
unsaturated hydrazones. For instance, the reactions between
substrates 6a, 6b and 2a proceeded smoothly in a 6-endo
cyclization manner, giving the synthetically and biologically
valuable tetrahydropyridazines 7a and 7b in 60% and 47%
11
yields, respectively (eq 1). Then, we performed the model
7
quantative yield under basic conditions.
Next, we applied the catalytic system to these β,γ-unsaturated
hydrazones equipped with an aryl group at the 2-position of the
alkene (Scheme 3). If successful, the reaction would provide a
Scheme 3. Synthesis of Dihydropyrazoles with a
Tetrasubstituted Carbon Center
,
a b
reaction with deuterated substrate 1a-D to explore syn- vs anti-
addition processes (eq 2). The reaction of 1a-D with 2a gave
3
aa-D with 46% yield and 3:2 dr, indicating that both pathways
7
are operative in the catalytic cycle.
6
,8,10,13
On the basis of the literature reports,
we currently
prefer the Pd(II)/(IV) catalytic cycle for this aminoarylation
reaction as depicted in Scheme 4, though an alternative Pd(0)/
Scheme 4. Proposed Mechanism
a
1
(0.20 mmol), 2 (0.30 mmol), Pd(OAc) (5 mol %), NaHCO (2.0
(II) catalytic cycle cannot be excluded. Taking the syn-addition
pathway as an example with 1a-D and 2a, an initial
2
3
b
7
equiv) in toluene (3.0 mL) at rt for 24 h. Isolated yield.
coordination of the pendant alkene to the catalyst Pd(TFA)2
followed by deprotonation and intramolecular syn-amino-
palladation leads to a alkylpalladium complex B via Pd-amido
practical access to 5-aryl-substituted 4,5-dihydropyrazoles,
which have recently been established as a promising scaffold
12
6
for drug discovery. Again, a wide range of β,γ-unsaturated
hydrazones 4a−f with diverse electron-donating or electron−
withdrawing groups on the aromatic ring and aliphatic
complex A. The diaryliodonium salt 2a serves not only as aryl
source but also as terminal oxidant. Thus, oxidation of
alkylpalladium complex B by 2a forms a transient Pd(IV)
intermediate C. Reductive elimination of C affords the product
3aa and regenerates Pd(II) catalyst.
hydrazone 4g were well tolerated, when using Pd(OAc) as
2
catalyst and NaHCO as the base instead; and the desired
3
products 5aa−ga with a tetrasubstituted carbon center were
formed in 37−93% yield (Scheme 3a). Moreover, as
demonstrated in the synthesis of dihydropyrazoles 5ha−la,
In conclusion, we have developed an efficient ligand-free
Pd(II)-catalyzed aminoarylation reaction of the unactivated
alkenes in β,γ- and γ,δ-unsaturated hydrazones with diary-
liodonium salts as both aryl source and terminal oxidant. This
protocol features great functional group compatibility, uses
convenient materials as well as mild reaction conditions, and
provides a practical access to diversely substituted dihydropyr-
azoles and tetrahydropyridazines.
3
variation in the electronic and steric properties of R substituent
also proved to be possible (Scheme 3b). Notably, an array of
diaryliodonium salts 2b, 2e and 2f reacted well with hydrazone
4
a to furnish the corresponding products in 62−80% yield
(Scheme 3c). However, our attempts to employ hydrazones
C
DOI: 10.1021/acs.orglett.7b02480
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
5) For selected reviews, see: (a) Wolfe, J. P. Eur. J. Org. Chem. 2007,
ASSOCIATED CONTENT
Supporting Information
■
2
007, 571. (b) Minatti, A.; Muniz, K. Chem. Soc. Rev. 2007, 36, 1142.
*
S
(
c) Jensen, K. H.; Sigman, M. S. Org. Biomol. Chem. 2008, 6, 4083.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02480.
(d) McDonald, R. I.; Liu, G.; Stahl, S. S. Chem. Rev. 2011, 111, 2981.
(e) Schultz, D. M.; Wolfe, J. P. Synthesis 2012, 44, 351. (f) Garlets, Z.
J.; White, D. R.; Wolfe, J. P. Asian J. Org. Chem. 2017, 6, 636.
(6) For selected recent examples, see: (a) Hopkins, B. A.; Wolfe, J. P.
Detailed experimental procedures and full spectroscopic
data for all compounds (PDF)
X-ray crystallographic data for 1a (CIF)
X-ray crystallographic data for 3aa (CIF)
X-ray crystallographic data for 7a (CIF)
Angew. Chem., Int. Ed. 2012, 51, 9886. (b) Babij, N. R.; Wolfe, J. P.
Angew. Chem., Int. Ed. 2013, 52, 9247. (c) Garlets, Z. J.; Parenti, K. R.;
Wolfe, J. P. Chem. - Eur. J. 2016, 22, 5919. (d) Orcel, U.; Waser, J.
Angew. Chem., Int. Ed. 2016, 55, 12881. (e) Ye, L.; Lo, K. Y.; Gu, Q.;
Yang, D. Org. Lett. 2017, 19, 308. (f) Du, W.; Gu, Q.; Li, Y.; Lin, Z.;
Yang, D. Org. Lett. 2017, 19, 316. (g) Peterson, L. J.; Luo, J.; Wolfe, J.
P. Org. Lett. 2017, 19, 2817.
AUTHOR INFORMATION
Corresponding Authors
■
(7) See the Supporting Information for more details.
(8) For selected reviews, see: (a) Deprez, N. R.; Sanford, M. S. Inorg.
Chem. 2007, 46, 1924. (b) Zhdankin, V. V.; Stang, P. J. Chem. Rev.
*
E-mail: chenjiarong@mail.ccnu.edu.cn.
E-mail: wxiao@mail.ccnu.edu.cn.
2
2
008, 108, 5299. (c) Merritt, E. A.; Olofsson, B. Angew. Chem., Int. Ed.
009, 48, 9052. (d) Duan, Y.; Jiang, S.; Han, Y.; Sun, B.; Zhang, C.
*
ORCID
Youji Huaxue 2016, 36, 1973. (e) Novak
Tolnai, G. Synlett 2016, 27, 1456. (f) Fan
017, 49, 1905.
9) For selected examples, see: (a) Cahard, E.; Bremeyer, N.; Gaunt,
́
, Z.; Aradi, K.; Tot
́
h, B.;
Jia-Rong Chen: 0000-0001-6054-2547
Wen-Jing Xiao: 0000-0002-9318-6021
Notes
̃
anas-Mastral, M. Synthesis
́
2
(
M. J. Angew. Chem., Int. Ed. 2013, 52, 9284. (b) Zhang, F.; Das, S.;
Walkinshaw, A. J.; Casitas, A.; Taylor, M.; Suero, M. G.; Gaunt, M. J. J.
Am. Chem. Soc. 2014, 136, 8851. (c) Cahard, E.; Male, H. P.; Tissot,
M.; Gaunt, M. J. J. Am. Chem. Soc. 2015, 137, 7986. (d) Sinai, A.;
Vangel, D.; Gati, T.; Bombicz, P.; Novak, Z. Org. Lett. 2015, 17, 4136.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the NNSFC (Nos. 21472058, 21472057, and
1622201), the Distinguished Youth Foundation of Hubei
■
2
(
e) Chen, J.; Chen, C.; Wang, G.; Qu, H. Chem. Commun. 2015, 51,
356.
10) For selected examples, see: (a) Alexanian, E. J.; Lee, C.;
Sorensen, E. J. J. Am. Chem. Soc. 2005, 127, 7690. (b) Streuff, J.;
Hovelmann, C. H.; Nieger, M.; Muniz, K. J. Am. Chem. Soc. 2005, 127,
14586. (c) Muniz, K. J. Am. Chem. Soc. 2007, 129, 14542. (d) Cheng,
J.; Qi, X.; Li, M.; Chen, P.; Liu, G. J. Am. Chem. Soc. 2015, 137, 2480.
e) Wang, Y.; Chen, C.; Peng, J.; Li, M. Angew. Chem., Int. Ed. 2013,
1
(
Province (No. 2016CFA050), and CCNU (No.
CCNU17TS0011 and CCNU16JCZX02) for financial support.
The Program of Introducing Talents of Discipline to
Universities of China (111 Program, B17019) is also
appreciated.
̈
̃
̃
(
5
2, 5323. (f) Chi, Y.; Yan, H.; Zhang, W. X.; Xi, Z. Org. Lett. 2017, 19,
REFERENCES
■
2
694.
(
2
1) For selected reviews, see: (a) Blair, L. M.; Sperry, J. J. Nat. Prod.
013, 76, 794. (b) Marella, A.; Ali, R.; Alam, T.; Saha, R.; Tanwar, O.;
Akhter, M.; Shaquiquzzaman, M.; Mumtaz Alam, M. Mini-Rev. Med.
Chem. 2013, 13, 921. (c) Yusuf, M.; Jain, P. Arabian J. Chem. 2014, 7,
53. (d) Alex, J. M.; Kumar, R. J. J. Enzyme Inhib. Med. Chem. 2014,
9, 427. (e) Maison, W.; Kuchenthal, C.-H. Synthesis 2010, 2010, 719.
2) For selected examples on the synthesis of dihydropyrazoles, see:
a) Chen, J.-R.; Dong, W.-R.; Candy, M.; Pan, F.-F.; Jorres, M.; Bolm,
C. J. Am. Chem. Soc. 2012, 134, 6924. (b) Rueping, M.; Maji, M. S.;
Kucuk, H. B.; Atodiresei, I. Angew. Chem., Int. Ed. 2012, 51, 12864.
(
11) CCDC 1572642 (1a), 1568095 (3aa), and 1568102 (7a)
contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from the Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
5
2
(
(
12) (a) Ali, M. A.; Yar, M. S.; Kumar, M.; Pandian, G. S. Nat. Prod.
̈
Res. 2007, 21, 575. (b) Gembus, V.; Furman, C.; Millet, R.; Mansouri,
R.; Chavatte, P.; Levacher, V.; Briere, J. F. Eur. J. Med. Chem. 2012, 58,
(
3
96. (c) Gawad, N. M.; Georgey, H. H.; Ibrahim, N. A.; Amin, N. H.;
Abdelsalam, R. M. Arch. Pharmacal Res. 2012, 35, 807.
13) Peng, J.; Chen, C.; Xi, C. Chem. Sci. 2016, 7, 1383.
(
(
̈ ̈
c) Hong, X.; Kuc u̧ k, H. B.; Maji, M. S.; Yang, Y.-F.; Rueping, M.;
Houk, K. N. J. Am. Chem. Soc. 2014, 136, 13769. (d) Tripathi, C. B.;
Mukherjee, S. Org. Lett. 2014, 16, 3368. (e) Attanasi, O. A.; De
Crescentini, L.; Favi, G.; Mantellini, F.; Mantenuto, S.; Nicolini, S. J.
Org. Chem. 2014, 79, 8331. (f) Hu, X.-Q.; Chen, J.-R.; Wei, Q.; Liu, F.-
L.; Deng, Q.-H.; Zou, Y.-Q.; Xiao, W.-J. Eur. J. Org. Chem. 2014, 2014,
3082. (g) Wu, X.; Wang, M.; Zhang, G.; Zhao, Y.; Wang, J.; Ge, H.
Chem. Sci. 2015, 6, 5882. (h) Zhang, D.-Y.; Shao, L.; Xu, J.; Hu, X.-P.
ACS Catal. 2015, 5, 5026. (i) Cheng, J.; Xu, P.; Li, W.; Cheng, Y.; Zhu,
C. Chem. Commun. 2016, 52, 11901. (j) Zhang, Q.; Yu, M.; Yuan, J.;
Zhang, R.; Liang, Y.; Tian, J.; Dong, D. J. Org. Chem. 2016, 81, 6036.
(
k) Huang, R.; Tao, H.-Y.; Wang, C.-J. Org. Lett. 2017, 19, 1176.
3) Hu, X.-Q.; Chen, J.-R.; Wei, Q.; Liu, F.-L.; Deng, Q.-H.;
Beauchemin, A. M.; Xiao, W.-J. Angew. Chem., Int. Ed. 2014, 53, 12163.
4) (a) Chen, J.-R.; Hu, X.-Q.; Lu, L.-Q.; Xiao, W.-J. Acc. Chem. Res.
016, 49, 1911. (b) Hu, X.-Q.; Chen, J.; Chen, J.-R.; Yan, D.-M.; Xiao,
(
(
2
W.-J. Chem. - Eur. J. 2016, 22, 14141. (c) Zhao, Q.-Q.; Hu, X. Q.;
Yang, M.-N.; Chen, J.-R.; Xiao, W.-J. Chem. Commun. 2016, 52, 12749.
(
d) Hu, X.-Q.; Qi, X.; Chen, J.-R.; Zhao, Q.-Q.; Wei, Q.; Lan, Y.; Xiao,
W.-J. Nat. Commun. 2016, 7, 11188. (e) Yu, X.-Y.; Zhou, F.; Chen, J.-
R.; Xiao, W.-J. Huaxue Xuebao 2017, 75, 86. (f) Zhao, Q.-Q.; Chen, J.;
Yan, D.-M.; Chen, J.-R.; Xiao, W.-J. Org. Lett. 2017, 19, 3620.
D
DOI: 10.1021/acs.orglett.7b02480
Org. Lett. XXXX, XXX, XXX−XXX