Palladium-Catalyzed Aminomethylamination and Aromatization of Aminoalkenes with Aminals via C-N Bond Activation

Article abstract of DOI:10.1021/acs.orglett.6b03001

Thanks to the facile imine-enamine tautomerization, the β,γ-unsaturated hydrazones have been successfully utilized as surrogates of aminodienes for realizing the Pd-catalyzed tandem aminomethylamination/aromatization reaction with aminals via C-N bond activation. This direct and operationally simple protocol provides a fundamentally novel strategy to synthesize aromatic heterocycles from alkenes in the absence of external oxidant and base. Mechanistic studies suggested that aminal not only functioned as an aminomethyl source but also acted as formal oxidant and inner base to promote the aromatization.

Full text of DOI:10.1021/acs.orglett.6b03001

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Aminomethylamination and Aromatization of
Aminoalkenes with Aminals via C−N Bond Activation
Lixin Li,†,§ Peipei Liu,† Yijin Su,† and Hanmin Huang*,†,‡
†State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, Lanzhou 730000, P. R. China
‡Department of Chemistry, University of Science and Technology of China, Hefei, 230026, P. R. China
§University of Chinese Academy of Science, Beijing 100049, P. R. China
S
* Supporting Information
ABSTRACT: Thanks to the facile imine-enamine tautomerization,
the β,γ-unsaturated hydrazones have been successfully utilized as
surrogates of aminodienes for realizing the Pd-catalyzed tandem
aminomethylamination/aromatization reaction with aminals via C−
N bond activation. This direct and operationally simple protocol
provides a fundamentally novel strategy to synthesize aromatic heterocycles from alkenes in the absence of external oxidant and
base. Mechanistic studies suggested that aminal not only functioned as an aminomethyl source but also acted as formal oxidant
and inner base to promote the aromatization.
Scheme 1. Aminomethylamination/Aromatization of β,γ-
Unsaturated Hydrazones with Aminals via C−N Bond
Activation
N-Heterocycles hold a vital position in modern organic
chemistry due to their ubiquity in nature and serve as a class of
most important molecules in medical and life sciences.1 As a
result, there has been a long-standing interest in the development
of direct synthetic approaches to N-heterocycles. In this respect,
the palladium-catalyzed cyclization of aminoalkenes established
by combining the selective C−C and C−N bonds formation
reactions has evolved into a powerful strategy for the synthesis of
structurally diverse N-heterocycles.2 However, aromatic halides
or super stoichiometric amounts of oxidants are required to
initiate and sustain the Pd-catalytic cycle, and thus, a large
amount of waste is formed. Moreover, the viability to prepare
aromatic heterocycles via these methods remains a challenge.3
In the palladium catalysis, the reactive organopalladium
species cooperative with efficient bond-formation strategy
plays pivotal roles for establishing catalytic new reactions.4 The
discovery of a new and versatile organopalladium species, such as
an active Pd−C and Pd−N species, often revolutionizes the
catalytic performance in terms of reactivity, selectivity, and
productivity.5 Cognizant of both this goal and the ideal of green
chemistry, we recently have invented a unique electrophilic
cyclopalladated complex I benefited from the newly developed
C−N bond activation of aminals (Scheme 1).6 Unlike the well-
established oxidative addition processes for generation of ArPdX
species from aromatic halides,4 the released R2N− from the
oxidative addition reaction of aminal with Pd(0) not only could
be used as a nitrogen-nucleophile for enabling a C−N bond
formation process, but also might act as strong base to promote
some new reaction processes. Thus, a number of catalytic new
reactions have been established with this Pd-alkyl species as a
leading complex.6 Very recently, we have developed an
asymmetric intermolecular aminomethylamination reaction of
1,3-conjugated dienes with aminals led by this Pd-alkyl species,
where the π-allylic palladium intermediate was facilely formed
and trapped by the amino moiety released from the C−N bond
activation process to furnish the desired 1,3-diamines.6g It would
be therefore of interest to explore a cyclization reaction between
aminodienes and aminals based on this concept in which the π-
allylic palladium intermediate would be alternatively captured by
the tethered nitrogen-nucleophile in intramolecular manner.
Given the facile imine-enamine tautomerization, β,γ-unsaturated
hydrazones could be viewed as the surrogates of 1,3-conjugated
dienes with amine functionality.7 Inspired by this inherent
feature of β,γ-unsaturated hydrazone, we envisaged that it might
act as a suitable substrate to accomplish the above idea. We
anticipated that aminodiene 1′ would be formed and then
reacted with Pd-complex I to give a reactive azaallylic anion
under basic reaction conditions.8 Due to its high reactivity, the
azaallylic anion can be trapped by electrophilic Pd-complex I
again to give the target aromatic β-aminoethylpyrazoles via
nucleophilic substitution and β-hydride elimination (Scheme 1).
Received: October 6, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03001
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Organic Letters
Letter
Herein, we reported a palladium-catalyzed cascade amino-
methylamination/aromatization reaction of β,γ-unsaturated
hydrazones with aminals via C−N bond activation. Such reaction
would be particularly valuable for the synthesis of bioactive
pyrazoles, which would also provide a great opportunity to
accelerate biological and biosynthetic studies of β-amino-
ethylpyrazoles.3,9,10
To explore the scope of this palladium-catalyzed aromatization
process, various β,γ-unsaturated hydrazones were coupled with
aminal 2a under the optimized reaction conditions (Table 2). As
a
Table 2. Substrate Scope of Hydrazone
Our investigations began with the reaction of (E)-4-methyl-
N′-(1-phenylbut-3-en-1-ylidene)benzenesulfonohydrazide (1a)
and N,N,N′,N′-tetrabenzylmethanediamine (2a) in CH3CN at
120 °C with Pd(CH3CN)2Cl2 as a catalyst precursor. After an
extensive screening of the phosphine ligands, DPPP stood out as
the best ligand for delivering desired product 3aa in 65% yield.
The structure of 3aa was unambiguously confirmed by NMR
spectroscopy and X-ray diffraction analysis.11 Inspired by this
promising lead, we next sought to improve the efficiency of the
reaction. Among the solvents tested, CH2Cl2 was the best,
though the reaction was also compatible with common organic
solvents (Table 1, entries 12−16). The yield decreased to 70%
b
entry
1
R1
R2
3
yield (%)
C6H5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
3aa
3ba
3ca
3da
3ea
3fa
84
68
75
81
80
79
79
77
83
77
72
57
81
80
83
80
72
75
60
77
56
36
c
2
2-FC6H4
3
3-FC6H4
4
4-FC6H4
5
4-CF3C6H4
4-ClC6H4
3,4-Cl2C6H3
3-BrC6H4
4-BrC6H4
3-MeC6H4
4-MeC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
3,5-(MeO)2C6H3
2-naphthalene
2-thiophene
3-indole
6
7
3ga
3ha
3ia
8
9
a
Table 1. Screening of Reaction Conditions
10
11
3ja
3ka
3la
c
12
13
14
15
16
17
18
3ma
3na
3oa
3pa
3qa
3ra
3sa
3ta
b
entry
ligand
solvent
t (°C)
yield (%)
1
DPPM
DPPE
DPPP
DPPB
DPPPen
DPPHex
Xantphos
DPEphos
DPPF
PPh3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
toluene
i-PrOH
DMF
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
100
80
8
2
43
65
50
37
22
17
15
39
40
6
3
c
4
19
i-Pr
c
5
20
c
t-Bu
6
21
Cy
3ua
3va
7
22
C6H5
a
8
Reaction conditions: 1 (0.5 mmol), 2a (1.0 mmol), [Pd(DPPP)
(CH3CN)2]OTf2 (5.0 mol %), CH2Cl2 (1.5 mL), 80 °C, 24 h.
9
b
c
10
11
12
13
14
15
16
17
18
Isolated yield. 100 °C.
PCy3
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
78
69
29
12
49
76
70
86
42
shown in Table 2, both electron-rich and electron-withdrawn
hydrazones showed high reactivity to afford the corresponding
desired products in moderate to good yields. The electronic
factor has negligible effect on this transformation, as strongly
electron-withdrawing substituents or donating groups like −CF3
and −OMe gave their corresponding products in good to
excellent yields. However, the steric factor has a negative impact
on the reaction, as aryl hydrazones with electron-withdrawing or
electron-donating substituents at the ortho position of the phenyl
ring showed lower reactivities. To our delight, raising the
temperature to 100 °C, the corresponding functionalized
pyrazoles could be obtained in moderate yields (Table 2, entries
2 and 12). Significantly, both meta- and para-substituted
hydrazones were converted into the desired products in good
yields. Disubstituted hydra-zones underwent the cyclization-
aromatization quite well (Table 2, entries 7 and 15). In addition,
both 2-naphthalene-substituted hydrazone and heteroaromatic
hydrazones, such as 2-thiophenehydrazone and Boc-protected 3-
indolehydrazone, participated in the present reaction well to give
the corresponding pyrazoles in good yields (Table 2, entries 16−
18). Gratifyingly, moderate to good yields (56−77%) were
obtained when the reaction conducted with aliphatic ketone
derived hydrazones (Table 2, entries 19−21). The reaction of 1v
with a methyl group at the α-position was found to yield
cyclization product 2va in 36% yield.
THF
CH2CI2
CH2CI2
CH2Cl2
CH2Cl2
c
19
80
d
20
80
a
Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), [Pd] (3.0 mol
%), ligand (3.6 mol %), AgOTf (6.0 mol %), solvent (1.5 mL) for 12
b
c
h. Isolated yield. [Pd] (5.0 mol %), DPPP (6.0 mol %), AgOTf (10
d
mol %), 24 h. Pd2(dba)3 (2.5 mol %), DPPP (6.0 mol %), HOTf (6.0
mol %), 24 h.
when the reaction was carried out at 80 °C in CH2Cl2, but the
loss of yield could be offset by increasing the catalyst loading and
prolonging the reaction time to 24 h (Table 1, entry 19). The
reaction could proceed with Pd2(dba)3 as the palladium source in
the presence of DPPP, suggesting that Pd(0) was involved in the
present reaction (Table 1, entry 20). As expected, almost the
same yield (84%) of 3aa was gained when the cationic
[Pd(DPPP)(CH3CN)2]OTf2 was utilized as catalyst (the
structure of the catalyst was confirmed by X-ray analysis).11
Finally, no desired product was detected in the absence of
palladium catalyst under otherwise identical reaction conditions.
B
DOI: 10.1021/acs.orglett.6b03001
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Next, we explored the scope and limitation of this cascade
process for various substituted aminals with (E)-4-methyl-N′-(1-
phenylbut-3-en-1-ylidene)benzenesulfonohydrazide (1a) as
shown in Table 3. Irrespective of the electronic nature of the
Scheme 3. Control Experiments
a
Table 3. Substrate Scope of Aminals
b
CDCl3 at 80 °C (see Supporting Information). This result
suggested that one molecule of Bn2NCH2 moiety was converted
into Bn2NCH3, thus indicating reductive elimination of
Bn2NCH2PdH was most likely involved in the catalytic cycle
of the present reaction and aminal might act as a formal oxidant
to promote the aromatization. The substrate bearing two
germinal methyl groups at the α-position was reported to
proceed as a kinetically favorable cyclization due to Thorpe−
Ingold effect.12 Therefore, 8 was tested as a substrate in the
current reaction. To our surprise, no reaction took place, and the
substrate 8 was recovered unchanged, which might indicate that
the process of aminopalladation did not take place under the
present reaction conditions. Furthermore, when (E)-4-methyl-
N′-(1-phenylpent-4-en-1-ylidene)benzenesulfonohydrazide 9,
which could be potentially converted into six-membered
heterocycles via aminopalladation, was also examined under
the standard conditions. As expected, no desired cyclization
reaction occurred, indicating that the aminopalladation/
reductive elimination pathway was ruled out. These results
confirmed our hypothesis that the reactive hydrazones had to be
transferred to the corresponding 1,3-dienes via imine−enamine
tautomerization, and the reaction was most likely initiated via
migratory insertion of diene with the cyclopalladated complex I.
Although the mechanistic details are not clear at this stage, on
the basis of the present results and precedent reports,6 a plausible
reaction pathway was proposed (Figure 1). After formation of
entry
R
3
yield (%)
1
2
3
4
5
6
7
C6H5CH2
3aa
3ab
3ac
3ad
3ae
3af
84
71
75
62
33
43
42
4-FC6H4CH2
4-CF3C6H4CH2
3,5-t-BuC6H3CH2
CH3CH2
CH3CH2CH2
-CH2CH2OCH2CH2−
3ag
a
Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), [Pd(DPPP)
(CH3CN)2]OTf2 (5 mol %), CH2Cl2 (1.5 mL), 80 °C, 24 h. Isolated
b
yield.
substituents in the phenyl-ring of benzylamine derived aminals,
the reactions performed well to give the corresponding products
in good yields. Several aminals derived from simple alkylamines,
such as Et2NH and n-Pr2NH, were also compatible with this
process to afford the desired products 3ae−3af in moderate
yields. Moreover, aminal 2g derived from cyclic amine could also
be used as a coupling partner, giving the corresponding product
3ag in good yield.
The reaction could be performed on a gram scale with good
yield even at a lower catalyst loading (2.5 mol %), providing 1.3 g
of 3aa in 71% yield (Scheme 2). The Ts group of 3aa could be
Scheme 2. Synthetic Utility of the Functionalized Pyrazoles
easily removed under mild conditions to give 4 in excellent yield.
The two benzyl groups in 4 were removed to give 5 via Pd/C-
catalyzed hydrogenolysis with H2. Furthermore, compound 4
was rapidly brominated with Br2 to give 6 in 90% isolated yield.
One benzyl group in 6 was selectively removed to give 7 by
treatment with CAN in CH3CN/H2O at room temperature. The
products 5 and 7 are derivatives of Betazole, a powerful gastric
secretory stimulant in medicinal chemistry,9 suggesting that the
current protocol for synthesis of β-aminoethylpyrazoles might
find broad application in medicinal chemistry.
Figure 1. Plausible reaction mechanism.
To gain insights into the possible mechanism of this process,
several experiments were conducted under the standard
conditions (Scheme 3). First, an in situ NMR experiment for
investigation of the reaction of 1a with 2a was conducted in J-
Young-type NMR tube. The HNMR spectra revealed that
desired product 3aa together with Bn2NCH3 was simultaneously
the active palladium(0) species, oxidative addition of the
protonated aminal takes place to form the cyclopalladated
complex I. Then migratory insertion of double bond of the diene
1a′ (generated in situ from 1a via imine−enamine tautomeriza-
tion) into the C−Pd bond of I affords the key π-allylic palladium
intermediate II. The species II undergoes an intramolecular
nucleophilic addition to give rise to intermediate III together
1
produced in almost 1:1 ratio when the reaction was conducted in
C
DOI: 10.1021/acs.orglett.6b03001
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Organic Letters
Letter
(3) For a review on transition metal-mediated synthesis of aromatic
heterocycles: Gulevich, A. V.; Dudnik, A. S.; Chernyak, N.; Gevorgyan,
V. Chem. Rev. 2013, 113, 3084.
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with regeneration of palladium(0) to furnish the first amino-
methylamination catalytic cycle under the basic conditions.
Deprotonation of III with another molecule of aminal forms the
azaallylic anion IV,8b which is captured by the electrophilic
cationic Pd-complex I again to give the species V. Finally, β-
hydride elimination from V releases the desired product 3aa
together with VI, which undergoes reductive elimination to give
Bn2NCH3 and regenerates Pd(0) species, thus completing the
catalytic cycle.
In summary, we have developed the first palladium-catalyzed
aminomethylamination/aromatization of β,γ-unsaturated hydra-
zones with aminals via C−N bond activation, leading to a variety
of substituted β-aminoethylpyrazoles that are of interest in
medicinal chemistry. The present reaction provides a new
strategy to construct aromatic heterocycles from aminoalkenes in
the absence of external oxidant and base under the palladium
catalysis. Mechanistic studies suggest that the aminal not only
acts as an aminomethyl group source but also functions as an
internal base and formal oxidant to promote the aromatization.
This inherent unique character of aminals and the cyclo-
palladated complex promise a broad perspective in many other
reactions.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03001.
Experimental procedures and compound characterization
(PDF)
Full spectroscopic data for compound 1e (CIF)
Full spectroscopic data for [Pd(dppp)(CH3CN)2](OTf)2
(CIF)
(9) (a) Segal, H. L.; Rumbold, J. C.; Friedman, B. L.; Finigan, M. M. N.
Engl. J. Med. 1959, 261, 544. (b) Jones, R. G.; Mann, M. J. J. Am. Chem.
Soc. 1953, 75, 4048. (c) Ghosh, T.; Lewis, D. I.; Aliment, A. E.
Pharmacol. Ther. 2011, 33, 768.
(10) For reviews on the synthesis of pyrazoles: (a) Janin, Y. L. Chem.
Rev. 2012, 112, 3924. (b) Fustero, S.; Sanchez-Rosello, M.; Barrio, P.;
Simon-Fuentes, A. Chem. Rev. 2011, 111, 6984.
Full spectroscopic data for compound 3aa (CIF)
AUTHOR INFORMATION
■
(11) CCDC 1498309 (3aa), 1498307 (1e), and 1498311
([Pd(DPPP)2(CH3CN)2](OTf)2 contain the supplementary crystallo-
graphic data for this paper. This data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Corresponding Author
*E-mail: hanmin@ustc.edu.cn.
Notes
The authors declare no competing financial interest.
(12) Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105, 1735.
ACKNOWLEDGMENTS
■
This research was supported by the CAS Interdisciplinary
Innovation Team, the National Natural Science Foundation of
China (21133011 and 21672199).
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D
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Org. Lett. XXXX, XXX, XXX−XXX