Pd(II)-catalyzed aerobic intermolecular 1,4-diamination of conjugated dienes: A regioselective [4+4] annulation for the construction of medium-ring 1,6-benzodiazocine derivatives

Article abstract of DOI:10.1016/j.tetlet.2017.05.053

The first metal-catalyzed oxidative intermolecular 1,4-diamination of conjugated dienes has been developed. A series of medium ring compounds were constructed via palladium-catalyzed intermolecular [4+4] annulations. Oxygen was successfully used as an oxidant instead of the existing stoichiometric metals or hypervalent iodine reagents. 20 examples are reported, and good yields and regioselectivities could be obtained for the majority of diamines and conjugated diene substrates.

Full text of DOI:10.1016/j.tetlet.2017.05.053

Accepted Manuscript
Pd(II)-catalyzed aerobic intermolecular 1,4-diamination of conjugated dienes:
a regioselective [4+4] annulation for the construction of medium-ring 1,6-ben-
zodiazocine derivatives
Zhengxing Wu, Jingang Zhang, Yunyi Li, Wanbin Zhang
PII:
S0040-4039(17)30631-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.053
TETL 48946
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Tetrahedron Letters
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15 May 2017
Please cite this article as: Wu, Z., Zhang, J., Li, Y., Zhang, W., Pd(II)-catalyzed aerobic intermolecular 1,4-
diamination of conjugated dienes: a regioselective [4+4] annulation for the construction of medium-ring 1,6-
benzodiazocine derivatives, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.05.053
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Tetrahedron Letters
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Pd(II)-catalyzed aerobic intermolecular 1,4-diamination of conjugated dienes:
a regioselective [4+4] annulation for the construction of medium-ring
1,6-benzodiazocine derivatives
Zhengxing Wu, Jingang Zhang, Yunyi Li, and Wanbin Zhang∗
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The first metal-catalyzed oxidative intermolecular 1,4-diamination of conjugated dienes has
been developed. A series of medium ring compounds were constructed via palladium-catalyzed
intermolecular [4+4] annulations. Oxygen was successfully used as an oxidant instead of the
existing stoichiometric metals or hypervalent iodine reagents. 20 examples are reported, and
good yields and regioselectivities could be obtained for the majority of diamines and conjugated
diene substrates.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Palladium
Aerobic
1,4-Diamination
Conjugated diene
Medium-ring
1. Introduction
diamination of conjugated dienes for the preparation of a variety
of functionalized medium-ring 1,6-benzodiazocine derivatives
(Scheme 1, e).
Difunctionalizations of conjugated dienes (1,2- and 1,4-
difunctionalization) are important transformations in the field of
organic synthesis.1 Among the transformations, 1,4-
difunctionalization is an efficient methodology for the
construction of a variety of important molecular structures.1a-c,2
1,4-Diamination, an important 1,4-difunctionalization, has been
well-documented over the past decades (Scheme 1).3-7 With
regards to metal-mediated 1,4-diaminations of conjugated dienes,
the Bäckvall group reported an early Pd(II)-promoted 1,4-
diamination involving a two-step process (Scheme 1, a).3
Recently, the Muñiz group reported a Cu(II)-promoted 1,4-
diamination of conjugated dienes (Scheme 1, b).4 Metal-free 1,4-
diaminations have also been reported.5-7 The Jeffrey group
reported a 1,4-diamination using a pre-oxidized nitrogen source
(Scheme 1, c).5 After then, the Muñiz (Scheme 1, d) and Jeffrey
groups independently reported 1,4-diaminations using PhI(OAc)2
as an oxidant.6,7 Despite these successful examples, the metal-
catalyzed 1,4-diamination of conjugated dienes has not been
reported, even though such a synthetic pathway is worthy of
exploration; the construction of medium ring compounds using
intermolecular annulations are difficult synthetic methodologies
to implement.8 Furthermore, use of molecular oxygen as an
oxidant, instead of presently used stoichiometric quantities of
various metals or hypervalent iodine reagents, is also challenging
in oxidative 1,4-diaminations.9 Therefore in our studies
concerning the Pd(II)-catalyzed functionalization of alkenes,10 we
Scheme 1. 1,4-Diamination methodologies.
developed a Pd(II)-catalyzed aerobic intermolecular 1,4-
———
∗ Wanbin Zhang. Tel.: +86-021-5474-3265; fax: +86-021-5474-3265; e-mail: wanbin@sjtu.edu.cn

2
Tetrahedron
2. Results and discussion
underwent conversion but with a lower yield than 2a (entry 2).
The reaction conditions could also be applied to dienes 2c-2e. For
diene 2c, the reaction activity was poor (entry 3). For diene 2d,
the reaction proceeded well and gave a 93% yield (entry 4). For
diene 2e, the desired product 3ae was obtained in 47% yield
(entry 5).
Table 1. Exploration of reaction conditions.a
Table 2. Scope of conjugated dienes.a
Entry
Pd salts(equiv.)
Oxidant/Additive
(equiv.)
Yield
(%)b
1
Pd(OAc)2 (0.1)
Pd(OCOCF3)2 (0.1)
PdCl2(MeCN)2 (0.1)
PdBr2 (0.1)
-
43
42
-
2
-
3
-
4
-
-
5
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Cu(OAc)2 (0.2)
BQ (1.0)
KCl (0.1)
KBr (0.1)
KI (0.1)
NaOCOCF3 (0.1)
KI (0.05)
KI (0.2)
KI (0.1)
KI (0.1)
KI (0.1)
-
6
55
Trace
-
7
8
9
78
57
43
41
38
45
42
10
11
12
13c
14d
15e
a Unless otherwise noted, the reactions were carried out using 0.1 mmol of
diamine 1a (1.0 equiv.), 4Å molecular sieves (40 mg) and 2,3-dimethyl-1,3-
butadiene 2a (10 equiv.) in MeCN (2 mL) at 70 oC for 48 h under oxygen
atmosphere (10 atm).
b Isolated yields of 3aa.
c Oxygen atmosphere (20 atm).
d Oxygen atmosphere (5 atm).
e Oxygen atmosphere (1 atm, sealed tube).
a Reaction conditions: unless otherwise noted, the reactions were carried out
using diamine 1 (0.1 mmol), Pd(OAc)2 (10 mol%), KI (10 mol%), 4Å
molecular sieves (40 mg), and diene 2 (1.2 equiv.) in MeCN (2 mL) under O2
(10 atm) at 70 oC for 48 h.
We commenced our study by screening the reaction between
toluenesulfonyl protected o-phenylendiamine 1a and 2,3-
dimethyl-1,3-butadiene 2a in the presence of a catalytic amount
of Pd(OAc)2 (10 mol%) under an atmosphere of oxygen (10 atm)
(Table 1, entry 1). The regioselective 1,4-diamination proceeded
smoothly to give the desired product 3aa in 43% yield, with no
1,2-diamination being observed. A series of Pd(II) salts were
then used (entries 2-4) and Pd(OCOCF3)2 proved to be as good as
Pd(OAc)2 (entry 2). However, no reaction occurred when
PdCl2(MeCN)2 or PdBr2 catalysts were used (entries 3, 4).
Addition of a catalytic amount of Cu(OAc)2 restrains the reaction
(entry 5). Addition of benzoquinone led to an increase in yield of
the desired product to 55% (entry 6). Fortunately, using diffenent
salts as additives (entries 7-10), the yield could be improved to
78% when 0.1 equivalent of KI was added (entry 9). NaOCOCF3
also has a positive effect on the diamination (entry 10). The
amount of KI also greatly influences the 1,4-diamination;
increasing or reducing the amount of KI both led to lower yields
(entries 11, 12). Furthermore, increasing the oxygen pressure
increased the number of side products (entry 13). The yield was
also reduced when the oxygen pressure was decreased (entry 14,
15).
b Isolated yields.
c Diene 2 (10 equiv.).
d Diene 2 (3 equiv.).
e Pd(OAc)2 (0.2 equiv.).
A series of nitrogen sources were also surveyed to explore the
scope of the reaction (Table 3). For 2,3-dimethyl-1,3-butadiene
2a, moderate to good yields of the corresponding products were
obtained using different nitrogen sources (3ba-3ga). A o-
phenylenediamine substrate possessing a 4,5-dimethyl group
provided its corresponding product with 75% yield (3ba).
However, a 4,5-dichloro substituted substrate provided poor
reactivity (3ca). A naphthalene substrate gave its corresponding
product (3da) in moderate yield. The reaction proceeded well for
4-mono-substituted diamine substrates bearing either electron-
donating or electron-withdrawing substituent groups, giving the
corresponding products with good yields (3ea-3ga). For 1,2-
dimethylenecyclohexane 2d, a majority of diamine substrates
gave good yields irrespective of whether or not disubstituted or
mono-substituted substrates were used (3bd-3hd). Substrates
possessing a 4,5-dimethyl group or naphthalene ring provided
better reactivities (3bd and 3dd) than a 4,5-dichloro substituted
substrate (3cd). 4-Mono-substituted diamine substrates, such as
those bearing methyl-, fluorine- or chlorine- groups, all provided
With the optimized reaction conditions in hand (Table 1, entry
9), a series of 2,3-disubstituted conjugated dienes were surveyed
to explore the scope of the reaction (Table 2).11 In addition to
diene 2a (Table 2, entry 1), the asymmetrical diene 2b also

good yields (3ed-3gd). For a 3-methyl-substituted compound, a
high yield of the corresponding product was also obtained (3hd).
1,2-Dimethylenecycloheptane 2e generally provided lower
reaction activities compared to other dienes (3be, 3ce). We also
carried out the catalytic reaction of a heteroaromatic diamine,
N,N'-(pyridine-2,3-diyl)bis(4-methyl-benzenesulfonamide), with
2,3-dimethyl-1,3-butadiene 2a, however, the 1,4-diamination did
not occur in our optimized conditions.
Pd(OAc)2 (1.0 equiv.) were reacted, a five-membered palladium-
complex 4a was detected.11 When diamine 1a (1.0 equiv.),
Pd(OAc)2 (1.0 equiv.) and KI (0.5 equiv.) were added in MeCN,
palladium-complex 5a bearing one N-Pd was detected, and Pd(II)
complex 4a and a small amount of other complexes were also
formed.12 When diamine 1a (1.0 equiv.), Pd(OAc)2 (1.0 equiv.)
and KI (1.0 equiv.) were mixed together in MeCN, the
palladium-complex 5a was predominantly formed with some
diamine 1a remaining. When diamine 1a (1.0 equiv.), Pd(OAc)2
(1.0 equiv.) and KI (2.0 equiv.) were added in MeCN, only a
small amount of Pd(II) complex 5a was formed with the rest of
the material being the diamine substrate 1a.12 These results
suggest that the addition of KI prevents the formation of the N-
Pd bond via formation of an I-Pd bond. According to the results
obtained when using different Pd(OAc)2/KI ratios (Table 1,
entries 9, 11 and 12), the best result was obtained when Pd(OAc)2
(0.1 equiv.) and KI (0.1 equiv.) were used, thus suggesting that
the formation of Pd(II) complex 5a bearing one N-Pd bond
accelerates the 1,4-diamination.
Table 3. Scope of nitrogen source.a
Ts
N
NHTs
NHTs
Me
Me
Standard conditions
a)
N
Ts
1a
2a
3aa
with I2 (0.05 equiv.): yield 11%
with I2 (0.05 equiv.), without KI: yield 15%
Ts
NHTs
NHTs
N
N
MeCN
MeCN
Pd(OAc)2 (1.0 equiv.)
MeCN
b)
Pd
Ts
1a (1.0 equiv.)
4a
Ts
N
Pd
MeCN
MeCN
N
Pd(OAc)2 (1.0 equiv.)
KI (0.5 equiv.)
NHTs
Ts
4a
NHTs
MeCN
MeCN
Ts
N
1a (1.0 equiv.)
Pd MeCN
I
a little
other
complexes
NHTs
5a
Pd(OAc)2 (1.0 equiv.)
KI (1.0 equiv.)
MeCN
Ts
NHTs
N
Pd MeCN
I
MeCN
NHTs
NHTs
1a (1.0 equiv.)
5a
Pd(OAc)2 (1.0 equiv.)
KI (2.0 equiv.)
MeCN
Ts
a Reaction conditions: unless otherwise noted, the reactions were carried out
using diamine 1 (0.1 mmol), Pd(OAc)2 (10 mol%), KI (10 mol%), 4Å
molecular sieves (40 mg), and diene 2 (1.2 equiv.) in MeCN (2 mL) under O2
(10 atm) at 70 oC for 24 h. Isolated yields.
NHTs
N
Pd MeCN
I
MeCN
NHTs
1a (1.0 equiv.)
NHTs
5a
Scheme 2. Preliminary mechanism study.
b Diene 2 (10 equiv.) for 48 h.
Based on the preliminary mechanistic studies, a mechanism
for the Pd(II)-catalyzed 1,4-diamination has been proposed
(Scheme 3). Firstly, Pd(II)-complex 5a is formed via reaction of
Pd(OAc)2, diamine 1a and KI. Pd(II)-complex 5a is then
converted to the diene complex 6a via fast ligand exchange.
Diene complex 6a is subsequently converted to π-allyl Pd
intermediate 7a via insertion of the coordinated alkene into the
Pd-N bond.13 Finally, the 1,4-diamination product is formed from
7a via nucleophilic attack.14 The steric effects of the tetrahedral
carbon in the possible 1,2-diamination product restrict the 1,2-
difunctionalization, thereby the competing 1,4-diamination
pathway is favored. Additionally, the formation of the N-Pd bond
pobably be prevented in Pd(II)-complex 7a through the addition
of KI, which may be responsible for the acceleration of the 1,4-
diamination. The resulting Pd(0) is oxidized to Pd(II) by oxygen,
during which MeCN and diene may act as ligands to facilitate the
oxidation process.15
In order to gain further insight into the mechanistic pathway, a
number of control experiments were carried out (Scheme 2).
Considering that KI is capable of accelerating the 1,4-
diamination, we investigated the possibility that iodine may be
formed in the reaction system and thus facilitate the reaction
(Scheme 2, a). Our results showed that when a catalytic amount
of iodine (0.05 equiv.) was added to the standard reaction
conditions, the reaction was restrained. When iodine (0.05
equiv.) was added in place of KI, the reaction was also slower
and the desired product was obtained in only 15% yield. These
results indicate that facilitation of the reaction via formation of
iodine is not possible under our standard conditions. On the basis
of the result that NaOCOCF3 is also able to facilitate 1,4-
diaminations (Table 1, entry 10), we considered the possibility
that the iodide ion may promote the reaction by coordinating with
the palladium metal center. Therefore we investigated the effect
of diffenent Pd(OAc)2/KI ratios on the formation of palladium-
complex (Scheme 2, b). When diamine 1a (1.0 equiv.) and

4
Tetrahedron
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Scheme 3. Proposed reaction mechanism.
Conclusions
In summary, we have developed the first metal-catalyzed
oxidative intermolecular 1,4-diamination of conjugated dienes.
Using a palladium catalyst, a series of diazaheterocycles bearing
medium rings were prepared via intermolecular annulation.
Molecular oxygen was used as the terminal oxidant, in place of
other oxidants such as stoichiometric metals or hypervalent
iodine reagents. Twenty examples were reported, with the
majority of diamines and conjugated diene substrates providing
good yields and regioselectivities.
11. For mono-substituted conjugated dienes (such as 2-substituted
dienes or terminal substituted dienes) or 1,3-butadiene, 1,4-
diamination did not occur under our optimized conditions;
however, 1,2-diamination was successful in other conditions, see:
Wu, Z.; Wen, K.; Zhang, J.; Zhang, W. Org. Lett. 2017, DOI:
10.1021/acs.orglett.7b00919.
Acknowledgments
This work was partially supported by the National Natural
Science Foundation of China (Nos. 21232004, 21672142),
Program of Shanghai Subject Chief Scientists (No.
14XD1402300), the Basic Research Foundation of Shanghai
Science and Technology Committee (No. 15JC1402200). We
thank the Instrumental Analysis Center of Shanghai Jiao Tong
University (SJTU) for analysis and characterization.
12. See the supporting information.
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Supplementary data associated (experimental and
characterization data. Copies of the 1H and 13C NMR spectra of
the products produced in this study) with this article can be
found, in the online version, at http://
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Pd(II)-catalyzed aerobic intermolecular
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1,4-diamination of conjugated dienes: a
regioselective [4+4] annulation for the
construction of medium-ring 1,6-
benzodiazocine derivatives
Zhengxing Wu, Jingang Zhang, Yunyi Li, and Wanbin Zhang∗

6
Tetrahedron
An aerobic intermolecular 1,4-diamination of
conjugated dienes has been developed.
The first metal-catalyzed 1,4-diamination of
conjugated dienes was reported.
A series of medium ring compounds were
constructed via [4+4] annulations.
Oxygen was successfully used as the terminal
oxidant.