Palladium-Catalyzed Ring-Forming Alkene Aminoaroylation of Unsaturated Hydrazones and Sulfonamides

Article abstract of DOI:10.1021/acs.orglett.8b01208

The first example of a Pd(OAc)₂-catalyzed ring-forming alkene aminoaroylation of unsaturated hydrazones and sulfonamides is described. This protocol features the use of diaryliodonium salts as both oxidants and aryl sources, thus enabling mild

Full text of DOI:10.1021/acs.orglett.8b01208

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Ring-Forming Alkene Aminoaroylation of
Unsaturated Hydrazones and Sulfonamides
Jun Chen,†,§ Meng-Nan Yang,†,§ 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 & Chemical Biology Ministry of Education, College of Chemistry, Central China Normal
University, 152 Luoyu Road, Wuhan, Hubei 430079, China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, 345 Lingling Road, Shanghai 200032,
China
S
* Supporting Information
ABSTRACT: The first example of a Pd(OAc)2-catalyzed ring-forming alkene
aminoaroylation of unsaturated hydrazones and sulfonamides is described. This
protocol features the use of diaryliodonium salts as both oxidants and aryl
sources, thus enabling mild reaction conditions, good chemoselectivity, a broad
substrate scope, and high functional group tolerance. A wide range of
synthetically and biologically important functionalized dihydropyrazoles and
isoxazolidines have been obtained in good yields.
ver the past decade, palladium-catalyzed ring-forming
alkene aminofunctionalizations have been established as a
that the overall sequence to be aminopalladation and metal
oxidation, followed by aryl-nitrogen bond formation from the
PdIV intermediate; diaryliodonium salts work as external
oxidants and aryl sources. Notably, the competing β-H
elimination from the initially formed alkyl PdII complex was
overriden by its oxidation to PdIV species. On the basis of this
mechanistic scenario, we are proposing to alter the outcome of
the subsequent reaction profile of the initially formed alkyl PdII
complex by incorporation of CO-based carbonylation using
unsaturated hydrazones and sulfonamides as substrates.8 The
achievement of this reaction mode would enable ring-forming
alkene aminoaroylation of unsaturated hydrazones and
sulfonamides,9 thus providing a useful approach to benzoyl-
substituted dihydropyrazoles and isoxazolidines (Scheme 1c).10
To the best of our knowledge, such a transformation is still
unknown. However, several challenges might be encountered,
such as the direct aminoarylation reaction previously developed
by us and an aza-Heck-type reaction. Herein, we wish to report
a successful introduction of a strategy of PdII/PdIV catalysis for
a ring-forming alkene aminoaroylation reaction.
O
reliable and powerful synthetic tool for construction of a variety
of nitrogen heterocycles.1,2 Most of these reactions involve the
coupling between nucleophilic nitrogen-containg alkenes, and
aryl or alkenyl halides based on Pd0/PdII catalysis. Extensive
mechanistic studies have also revealed that nearly all of these
processes proceed through PdII-promoted C−N bond forming
aminopalladation as the key step. A series of amides,
carbamates, and sulfonamides have proven to be suitable
nucleophilic nitrogen sources. Despite tremendous advances
and their advantages, however, a strong stoichiometric base or
high temperature is typically required to achieve satisfactory
reaction efficiency. Thus, development of more general,
efficient, and mild ring-forming alkene aminofunctionalization
with readily available starting materials to access diversely
substituted nitrogen heterocycles is still highly desirable.
In contrast to Pd0/PdII catalysis, the PdII/PdIV catalysis has
recently emerged as a new potentially powerful activation mode
to develop novel transformations; the unique reactivity of the
PdIV intermediates enables a wide substrate scope, high
functional group tolerance, and mild reaction conditions.3 For
example, the groups of Muniz4 and Sorensen5 independently
disclosed the first Pd-catalyzed oxidative diamination of
sulfonamides and aminoacetoxylation of N-tosyl carbamates,
respectively; in these processes, PhI(OAc)2 serves as an oxidant
or as both an oxidant and a source of acetate (Scheme 1a).
Inspired by these pioneering works and the inherent properties
of diaryliodonium salts,6 we have also recently developed a
general and mild Pd(TFA)2-catalyzed aminoarylation reaction
of β,γ-unsaturated hydrazones using diaryliodonium salts,
leading to a practical access to diversely substituted
dihydropyrazoles (Scheme 1b).7 Mechanistically, we postulate
On the basis of our recently reported Pd-catalyzed
aminoarylation,7 we examined the feasibility of the target
alkene aminoaroylation of β,γ-unsaturated hydrazone 1a with
diphenyliodonium tetrafluoroborate 2a under 1 atm of CO at
room temperature. Gratifyingly, using the combination of
Pd(TFA)2 (10 mol %) and PPh3 (20 mol %) as the catalyst in
i
the presence of PrNEt as a base, the desired reaction indeed
worked to give the aminoaroylation product 3aa in 48% yield
(Table 1, entry 1). The product 3aa was also confirmed by
Received: April 16, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01208
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. PdII/PdIV-Catalyzed Oxidative Cyclization and
New Reaction Design
that use of THF resulted in the reaction being more efficient,
producing 3aa in 75% yield (entry 8). In agreement with our
previous study,7 the bases also have an obvious effect on the
current reaction, when using Pd(OAc)2/PPh3 as the catalyst.
Compared to the bases such as iPr2NEt, Na2CO3, Cs2CO3, and
Et3N, NaHCO3 proved to be the best, increasing the yield of
3aa from 75% to 86% (entry 9 vs entries 8 and 10−12).
Notably, with 2 mol % of catalyst loading, the reaction also
proceeded smoothly with a good NMR yield (entry 13).
With the optimal reaction conditions in hand, we first
explored the substrate scope by reacting a range of β,γ-
unsaturated hydrazones 1 with 2a under 1 atm of CO on a 0.2
mmol scale (Scheme 2a). As for the aryl-substituted
Scheme 2. Substrate Scope of Pd-Catalyzed Ring-Forming
a b
,
Aminoaroylation of Unsaturated Hydrazones
a
Table 1. Condition Optimization
b
entry
[Pd]
Pd(TFA)2
solvent
base
yield (%)
1
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
NaHCO3
Na2CO3
Cs2CO3
Et3N
48
64
46
33
35
38
47
75
86
2
Pd(OAc)2
Pd(acac)2
3
4
Pd(BF4)2(MeCN)4
PdCl2(PhCN)2
PdCl2
a
Reaction conditions: 1 (0.20 mmol), 2 (0.30 mmol), CO (1 atm),
5
Pd(OAc)2 (10 mol %), PPh3 (20 mol %), and NaHCO3 (0.40 mmol)
6
b
in 4.0 mL of THF at rt for 16−24 h. Isolated yields.
7
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
8
hydrazones, it was found that variation of the electronic or
steric properties of the subsituents on the phenyl ring has no
obvious effect on the reaction. Along with 1a, hydrazone
substrates 1b−1h with an electron-donating (e.g., Me, MeO) or
electron-withdrawing (e.g., Cl, Br) group at the para-, meta-, or
ortho-positions of the phenyl ring participated in the reaction
smoothly. The corresponding products 3ba−3ha were isolated
in 70−88% yields. Furthermore, the reaction with 2-furyl-
substituted hydrazone 1i also worked well to give the expected
product 3ia in 75% yield. Once again, cyclic and linear aliphatic
hydrazones, such as 1j and 1k, reacted well to furnish 3ja and
3ka in 83% and 76% yields, respectively. As demonstrated in
the synthesis of 3la, variation of the withdrawing Ts group is
also viable with a good yield.
9
THF
c
10
11
12
THF
76
c
THF
60
c
THF
63
d
c
13
THF
NaHCO3
90
a
Reaction conditions: 1a (0.10 mmol), 2a (0.15 mmol), CO (1 atm),
palladium catalyst (10 mol %), PPh3 (20 mol %), and base (0.20
b
c
mmol) in 2.0 mL of solvent at rt for 18 h. Isolated yields. NMR
yields, determined by 1H NMR analysis using 1,3,5-trimethoxybenzene
d
as an internal standard. With 2 mol % catalyst loading.
single crystal X-ray crystallographic analysis (shown in Scheme
2; CCDC 1837102). Then, we continued to examine a series of
commonly used Pd(II) and Pd(0) salts to further improve the
yield. It was found that all of these palladium salts proved to be
suitable for the reaction, though with variable yields (entries 2−
7), and Pd(OAc)2 was indentified to be optimal, giving a 64%
yield of 3aa (entry 2).11 A brief screening of solvents revealed
Then, we attempted to extend the current catalytic system to
a representative set of readily avaible symmetric diaryliodonium
salts 2b−2e by reacting with 1a (Scheme 2b). Again,
diaryliodonium salts 2b−2d bearing functional groups such as
Br, Cl, and Me at the para- or ortho-positions of the phenyl ring
B
DOI: 10.1021/acs.orglett.8b01208
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
were all well tolerated, affording products 3ab−3ad in good
yields (77−79%). The current catalytic system also proved to
be suitable for 1-naphthyl-substituted substrate 2e, leading to
formation of product 3ae in 72% yield.
Scheme 4. Substrate Scope of Pd-Catalyzed Ring-Forming
Aminoaroylation of Unsaturated Sulfonamides
a b
,
Interestingly, when reacting γ,δ-unsaturated hydrazones such
as 4a and 4b with diphenyliodonium tetrafluoroborate 2a,
synthetically and biologically important tetrahydropyridazines
5aa and 5ba, formed in a 6-endo cyclization/aroylation fashion,
were obtained in 70% and 65% yields, respectively (eq 1). This
result also highlights the synthetic potential of the current
protocol.
As a continuation of our ongoing research for the synthesis
of structurally diverse isoxazolidines,9 we then attempt to
expand the Pd-catalyzed alkene aminoaroylation strategy to
include unsaturated sulfonamides. The reaction would provide
a complementary method for incorporation of a benzoyl group
into the isoxazolidine scaffold. After an extensive condition
optimization,11 we finally established that a combination of
Pd(OAc)2 and tris(4-fluorophenyl)phosphane allowed the
model reaction between N-sulfonyl-O-butenyl hydroxylamine
6a to proceed smoothly under the same conditions (Scheme
3). The desired product 3,5-cis 7aa was obtained exclusively in
Scheme 3. Pd-Catalyzed Ring-Forming Aminoaroylation of
Unsaturated Sulfonamide 6a
a
Reaction conditions: 6 (0.20 mmol), 2 (0.30 mmol), CO (1 atm),
Pd(OAc)2 (10 mol %), P(p-FC6H4)3 (20 mol %), and NaHCO3 (0.40
b
c
mmol) in 4.0 mL of THF at rt for 24 h. Isolated yields. 1.0 mmol
scale.
79% yield (CCDC 1837103). As demonstrated in the reaction
of 6a and 2a′, the diaryliodonium salt with other counteranions
could also be well tolerated, with 7aa being formed in
comparable yield.
6p also proved to be suitable for the reaction, though with only
a moderate yield. Remarkably, switching the tosyl group to its
analogue such as those in substrates 6q−6s, or a methane-
sulfonyl group (e.g., 6t), could also allow formation of the
expected products 7qa−7ta in high yields. Interestingly,
substrate 6u with an easily removable Boc group participated
in the reaction smoothly as well with product 7ua isolated in
80% yield. Finally, it was also found that all of the
diaryliodonium salts 2b−2e reacted well with unsaturated
sulfonamide 6a, and the corresponding products 7ab−7ae were
afforded in 56−68% yields. In accordance with our previously
reported radical alkene hydroamination of unsaturated
sulfonamides,9 all of these 3,5-disubstituted isoxazolidines
were formed as a single diastereomer, probably due to the
steric effect involved in the ring-forming aminopalladation
process.1
To further demonstrate the synthetic potential of the
method, we subjected the enantiopure unsaturated sulfonamide
(R)-6a to the standard conditions (eq 2). The reaction also
proceeded smoothly to give chiral product 7aa in 72% yield
with >99% ee. This result confirms that the labile benzylic
stereocenter in 6a was not affected by the current reaction
conditions.
Next, we continued to investigate the generality and
limitation of the method by applying the standard conditions
to a range of unsaturated sulfonamides. As summarized in
Scheme 4, the catalytic system also demonstrated a broad
substrate scope and high functional group tolerance regarding
the unsaturated sulfonamides. In addition to 6a, the reactions of
substrates 6b−6g bearing an electron-rich, neutral, or electron-
poor phenyl ring all worked well; substituents such as MeO, Cl,
Br, F, and CF3 were all well tolerated, giving products 7ba−7ga
in 63%−76% yields. Moreover, as shown in the cases of 6h−6k,
the substitution pattern of the aryl moiety has no obvious effect
on the reaction, and products 7ha−7ka were obtained in 76−
84% yields. Notably, the present catalytic system could also
maintain its efficiency when applied on a synthetically useful
scale (1.0 mmol), resulting in the formation of 7ha with a
comparable yield. Moreover, 2-thienyl- and 2-naphthyl-
substituted substrates 6l and 6m reacted well to furnish the
corresponding products 7la and 7ma in good yields. Once
again, as shown in the synthesis of isoxazolidines 7na and 7oa,
the current reaction could be extended to those substrates
containing a cyclic or linear aliphatic moiety. Simple substrate
C
DOI: 10.1021/acs.orglett.8b01208
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
differently substituted dihydropyrazoles and isoxazolidines
were obtained in good yields. Further application of this
aminoaroylation strategy to other nucleophilic N−H-containing
alkenes is currently underway.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01208.
■
To gain some insight into the mechanism, we examined the
use of phenylboronic acid or iodobenzene as an aryl source
under the standard conditions; however, no desired product
was detected (eq 3). Moreover, even when adding Cu(OAc)2
as a standard oxidant for mediating Pd0/PdII catalysis, no
expected product 7aa was obtained either.5 Control experi-
ments also confirmed that the ligand is critical to the reaction,
as significant Pd-black was formed without a phosphorus
ligand.11
S
Experimental procedures, full analysis data for new
compounds, and copies of NMR spectra (PDF)
Accession Codes
CCDC 1837102−1837103 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
At the current stage, we could not rule out the possibility of a
Pd0/PdII catalytic cycle.11 On the basis of our recent
mechanistic study on the aminoarylation reaction of β,γ-
unsaturated hydrazones7 and literature reports,3,6,12 we
currently believe that PdII/PdIV catalysis should be the
predominant pathway for the reaction (Scheme 5). An initial
■
Corresponding Author
*E-mail: chenjiarong@mail.ccnu.edu.cn.
ORCID
Jia-Rong Chen: 0000-0001-6054-2547
Wen-Jing Xiao: 0000-0002-9318-6021
Author Contributions
Scheme 5. Mechanistic Proposal
§J.C. and M.-N.Y. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the NNSFC (Nos. 21472057, 21622201,
21472058, and 21772053), the Science and Technology
Department of Hubei Province (Nos. 2016CFA050 and
2017AHB047), and the Program of Introducing Talents of
Discipline to Universities of China (111 Program, B17019) for
support of this research.
REFERENCES
■
(1) For selected reviews, see: (a) Wolfe, J. P. Eur. J. Org. Chem. 2007,
2007, 571. (b) Minatti, A.; Muniz, K. Chem. Soc. Rev. 2007, 36, 1142.
(c) Jensen, K. H.; Sigman, M. S. Org. Biomol. Chem. 2008, 6, 4083.
(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.
(2) For selected recent examples, see: (a) Hopkins, B. A.; Wolfe, J. P.
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.
C−N bond forming nucleophilic amino-palladation results in
the formation of the alkyl palladium intermediate A, which
undergoes a facile CO insertion to give acyl PdII complex B.
Then, Pd-oxidation of B by the diaryliodonium salt 2 gives rise
to PdIV intermediate C that would undergo reductive elimation
more readily than intermediate A to give the final products. The
diaryliodonium salt 2 works as both aryl sources and oxidants.
The insertion of CO and change in the oxidation state of
palladium should be the main elements that suppress the
competing aza-Heck-type reaction and aminoarylation of
intermediate A.8
In conclusion, we have developed a general and efficient
Pd(OAc)2-catalyzed ring-forming alkene aminoaroylation of
unsaturated hydrazones and sulfonamides with diaryliodonium
salts and 1 atm of CO. This protocol characterizes use of
diaryliodonium salts as both oxidants and aryl sources, mild
reaction conditions, good chemoselectivity, a broad substrate
scope, and high functional group tolerance. A range of
(3) For selected reviews on high-valent palladium catalysis, see:
(a) Deprez, N. R.; Sanford, M. S. Inorg. Chem. 2007, 46, 1924.
(b) Muniz, K. Angew. Chem., Int. Ed. 2009, 48, 9412. (c) Sehnal, P.;
̃
Taylor, R. J.; Fairlamb, I. J. Chem. Rev. 2010, 110, 824. (d) McDonald,
R. I.; Liu, G.; Stahl, S. S. Chem. Rev. 2011, 111, 2981. (e) Hickman, A.
J.; Sanford, M. S. Nature 2012, 484, 177.
D
DOI: 10.1021/acs.orglett.8b01208
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(4) (a) Streuff, J.; Hovelmann, C. H.; Nieger, M.; Muniz, K. J. Am.
̈
̃
Chem. Soc. 2005, 127, 14586. (b) Muniz, K. J. Am. Chem. Soc. 2007,
129, 14542.
̃
(5) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc. 2005,
127, 7690.
(6) For selected reviews on the chemistry of diaryliodonium salts,
see: (a) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299.
(b) Merritt, E. A.; Olofsson, B. Angew. Chem., Int. Ed. 2009, 48, 9052.
(c) Duan, Y.; Jiang, S.; Han, Y.; Sun, B.; Zhang, C. Youji Huaxue 2016,
36, 1973. (d) Novak
́
, Z.; Aradi, K.; Tot
́
h, B.; Tolnai, G. Synlett 2016,
27, 1456. (e) Fananas
́
-Mastral, M. Synthesis 2017, 49, 1905. (f) Wang,
̃
X.; Studer, A. Acc. Chem. Res. 2017, 50, 1712.
(7) Yang, M.-N.; Yan, D.-M.; Zhao, Q.-Q.; Chen, J.-R.; Xiao, W.-J.
Org. Lett. 2017, 19, 5208.
(8) For selected reviews on metal-catalyzed carbonylation reactions,
see: (a) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Soc. Rev. 2011, 40,
4986. (b) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Rev. 2013, 113, 1.
(c) Wu, X.-F.; Fang, X.; Wu, L.; Jackstell, R.; Neumann, H.; Beller, M.
Acc. Chem. Res. 2014, 47, 1041. (d) Gadge, S. T.; Bhanage, B. M. RSC
Adv. 2014, 4, 10367. (e) Peng, J.-B.; Wu, X.-F. Angew. Chem., Int. Ed.
2018, 57, 1152.
(9) Chen, J.; Guo, H.-M.; Zhao, Q.-Q.; Chen, J.-R.; Xiao, W.-J. Chem.
Commun. 2018, DOI: 10.1039/c7cc09871e.
(10) For selected reviews on dihydropyrazoles and isoxazolidines,
see: (a) Alex, J. M.; Kumar, R. J. Enzyme Inhib. Med. Chem. 2014, 29,
427. (b) Yusuf, M.; Jain, P. Arabian J. Chem. 2014, 7, 553. (c) Berthet,
M.; Cheviet, T.; Dujardin, G.; Parrot, I.; Martinez, J. Chem. Rev. 2016,
116, 15235. (d) Li, M.; Song, B.; Imerhasan, M. Youji Huaxue 2018,
38, 378.
(11) See the Supporting Information for more details.
(12) Peng, J.; Chen, C.; Xi, C. Chem. Sci. 2016, 7, 1383.
E
DOI: 10.1021/acs.orglett.8b01208
Org. Lett. XXXX, XXX, XXX−XXX