Formation of 1,3-diazocine by palladium catalyzed C-H arylation

Article abstract of DOI:10.1016/j.tetlet.2016.04.050

From multi-substituted 8-aminoimidazo[1,2-a]pyrazines, prepared via modified Groebke-Blackburn-Bienaymé reaction, a Pd-catalyzed cyclization reaction was discovered, leading to a rare (Z)-4,5-dihydro-3H-[1,3]diazocine system. Conditions of this cyclization were screened and DMF solvent was found as one of the key factors for the cyclization.

Full text of DOI:10.1016/j.tetlet.2016.04.050

Tetrahedron Letters 57 (2016) 2311–2314
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Formation of 1,3-diazocine by palladium catalyzed C–H arylation
Le Tang a,b, Jing Ren a,c, Yuchi Ma a,c, Xin Wang a,c, Lin Chen a,c, Jingkang Shen a,c, Yue-Lei Chen a,c,
,
⇑
Bing Xiong a,c,
⇑
a State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China
b College of Pharmacy, Nanchang University, 461 Bayi Road, Nanchang 330006, PR China
c University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
From multi-substituted 8-aminoimidazo[1,2-a]pyrazines, prepared via modified Groebke–Blackburn–
Bienaymé reaction, a Pd-catalyzed cyclization reaction was discovered, leading to a rare (Z)-4,5-dihy-
dro-3H-[1,3]diazocine system. Conditions of this cyclization were screened and DMF solvent was found
as one of the key factors for the cyclization.
Received 21 March 2016
Revised 12 April 2016
Accepted 14 April 2016
Available online 25 April 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
1,3-Diazocine
C–H arylation
8-Aminoimidazo[1,2-a]pyrazines
8-Membered ring
Groebke–Blackburn–Bienaymé reaction
Introduction
Thus, we screened the cyclization condition, and prepared some
useful (Z)-4,5-dihydro-3H-[1,3]diazocine derivatives with different
We have previously reported the synthesis of multi-substituted
8-aminoimidazo[1,2-a]pyrazine by Groebke–Blackburn–Bienaymé
reaction.1 Derivatization from these 8-aminoimidazo[1,2-a]pyrazi-
nes was explored, and one conversion was found highly interest-
ing. When compound 2, prepared from compound 1 by borane
reduction, was treated with Pd(OAc)2 in DMF at elevated tempera-
ture, eight-membered ring product 3 was isolated,2 along with the
expected five-membered ring product 4.3 The structure of com-
pound 3 was further corroborated with single crystal analysis,
8-aminoimidazo[1,2-a]pyrazine substrates. Details of the work will
be disclosed herein.
O
N
O
N
O
N
O
N
N8
N
N
N
O
N
N
N
O
N
a
b
N
N
3
NH
5
O
+
N
NH
N
clearly displaying
a
distorted eight-membered ring system
O
N
(Scheme 1).4
NH
In respect of similar reactions, intermolecular C–H arylation at
C-5 of imidazo[1,2-a]pyrazines have been reported by several
groups.5 Palladium catalysts and phosphine ligands were usually
involved. In our case, phosphine ligands were found detrimental
to the reaction, while DMF solvent was identified necessary for
the conversion. In terms of the product structure, the central motif
of compound 3 can be regarded as (Z)-4,5-dihydro-3H-[1,3]dia-
zocine (Scheme 1), which constitutes the rare eight-membered
ring heterocycles,6 and could serve as a valuable scaffold for
organic synthesis and medicinal chemistry.
Br
Br
O
1
3
2
4
O
N
N
N
N
O
8
5
1
4
7
6
2
3NH
The 8-membered ring core of 3:
(Z)-4,5-dihydro-3H-[1,3]diazocine
cystal structure of 3
Scheme 1. Cyclization of compound 2 led to 3 containing an eight-membered ring
and 4 containing a five-membered ring. Reaction conditions: (a) BH3–THF complex,
THF, 80 °C, 1–2 h; (b) Pd(OAc)2, Cs2CO3, DMF, 70 °C, overnight. Recovered 2: 5%;
Yield of 3: 45%; Yield of 4: 8%.
⇑
Corresponding authors. Tel.: +86 21 50806600x5407.
E-mail addresses: chenyuelei@gmail.com (Y.-L. Chen), bxiong@simm.ac.cn
(B. Xiong).
http://dx.doi.org/10.1016/j.tetlet.2016.04.050
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

2312
L. Tang et al. / Tetrahedron Letters 57 (2016) 2311–2314
Table 1
Products and yields of the reactions described in Scheme 2
No.
R1
Products 6–7
R2
Products 8–10
Products 11–13
R3
Products
Products
and yields
and yields
and yields
1, 14a–14k
and yields
2, 15a–15l
and yields
O
N
O
1
2
1, 88%
2, 76%
6, 92%
Me–
8, 86%
11, 98%
Br
14a, 88%
15a, 77%
Br
O
O
F
3
4
14b, 87%
14c, 84%
15b, 73%
15c, 73%
Br
Br
F3C
5
6
7
8
14d, 79%
14e, 83%
14f, 91%
14g, 61%
15d, 80%
15e, 71%
15f, 82%
15g, 74%
Br
Cl
I
Br
9
14h, 90%
14i, 83%
14j, 86%
14k, 90%
15h, 83%
15i, 87%
15j, 85%
15k, 74%
BnNH-
7, 61%
Me–
9, 84%
12, 96%
Br
F
10
11
12
Br
O
Br
O
O
10, 77%
13, 95%
Br
Br
R1
Results and discussion
N
N
Cl
N
R1
N
a
R2
b
c
N
As described in Scheme 2, to prepare 8-aminoimidazo[1,2-a]
pyrazine substrates, pyrazine 5 was condensed with morpholine
or benzylamine to produce diaminopyrazines 6 and 7, which were
subjected to a variation of Groebke–Blackburn–Bienaymé multi-
component reaction (MCR) previously developed by us.1 With
two types of aldehyde components, the yields of multi-substituted
8-aminoimidazo[1,2-a]pyrazines 8–10 were generally good. Next,
the alkyl protections on 3-NH2 of compounds 8–10 were removed
under acidic condition with excellent yields, releasing the free ami-
nes 11–13, which were subjected to acylation to give compounds
1, and 14a–14k. At last, the amide oxygen of compounds 1, and
14a–14k were reduced by borane to afford compounds 2, and
15a–15k. Thus, in a five-step sequence, substrates for the projected
cyclization study were prepared efficiently. The structures and
yield details are listed in Table 1.
N
5
NH2
N
6-7
NH2
HN
8-10
R1
R1
R1
N
N
N
N
R2
R3
R2
O
N
N
N
N
R2
d
e
N
HN
HN
R3
NH2
11-13
2, 15a-15k
1, 14a-14k
Scheme 2. Preparations of substrates for the cyclization study. Reaction conditions:
(a) morpholine or BnNH2, NMP, DIPEA,120–130 °C, 12 h; (b) Yb(OTf)3, 2-isocyano-
2,4,4-trimethylpentane, R2CHO, MeOH, 65 °C, 2 h; (c) HCl/EtOAc, MeOH, 25 °C, 8 h;
(d) R3COOH, HOBt, EDCI, TEA, DCM, RT, 8 h; (e) BH3–THF complex, THF, 80 °C, 1 h.
See Table 1 and supporting information for structural and experimental details.
absence of palladium catalyst was first inspected and showed no
conversion at all (Table 2, entry 1). As Snieckus et al has suggested
and experimentally validated,5b the C–H arylation on C-5 of
Meanwhile, using compound 2 as a probe, we also screened the
conditions for cyclization. The results are described in Table 2. The

L. Tang et al. / Tetrahedron Letters 57 (2016) 2311–2314
2313
Table 2
Condition screening for the cyclization described in Scheme 1a
No
Catalyst
Base
Solvent
Recovered 2
Yield of 3
Yield of 4
1
—
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
toluene
DMAC
NMP
HCONH2
HCO-NHMe
DMSO
100%
n.d.
41%
86%
n.d.
n.d.b
6%
n.d.
n.d.
39%
12%
82%
74%
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
5%
n.d.
n.d.
n.d.
16%
n.d.
n.d.
n.d.
4%
2c
Pd(OAc)2
Pd(OAc)2
3d
4
5
6
7
10%
n.d.
10%
14%
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
39%
36%
n.d.
n.d.
11%
7%
PdCl2 (MeCN)2
PdCl2(dppf)
Pd(PPh3)4
10% Pd/C
CuBr-DMS
CuOTf-benzene
Ni (II) acetyl-acetonate
RhCl-(PPh3)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
n.d.
100%
100%
100%
100%
100%
100%
n.d.
8
9
10
11
12
13
14
15
16
17
18
19
20e
21f
22g
23h
24
25
n.d.
96%
92%
56%
72%
n.d.
72%
98%
98%
n.d.
HMPA
Sulfolane
THF + DMF
THF + DMF
THF + urea
THF + succin-imide
DMF
n.d.
5%
n.d.
n.d.
n.d.
35%
15%
45%
75%
Pd(OAc)2
Na2CO3
DMF
4%
a
b
c
Unless otherwise mentioned, 0.2 equiv of metal catalyst and 1.4 equiv of base were always reacted under nitrogen at 70 °C overnight. Yields were determined by HPLC.
n.d.: not detected by HPLC.
Reaction was performed with dry air balloon.
Reaction was performed at 110 °C.
With 3 equiv of DMF.
With 200 equiv of DMF.
With 3 equiv of urea.
d
e
f
g
h
With 3 equiv of succinimide.
imidazo[1,2-a]pyrazines proceeds through Heck-type mechanism,
but not C–H oxidative mechanism. Thus, we ran one control
experiment with a dry air balloon, and found that the cyclization
yield was significantly reduced, most probabaly due to the
presence of oxygen (Table 2, entry 2). The reaction temperature
was next examined, and elevated temperature decreased the
yield of compound 3 (Table 2, entry 3). Therefore the reaction
temperature was kept at 70 °C and palladium catalysts with
different ligands were screened. It was found that no other
tested palladium catalysts could compete with Pd(OAc)2 in
producing the 8-membered ring 3, as other palladium catalysts
promoted the formation of amination product 4 (Table 2, entries
4–7). Metal catalysts other than palladium salts, including
copper, nickel, and rhodium salts, were also tested and gave no
conversion to either 3 or 4 (Table 2, entries 8–11). Different
reaction solvents were investigated, too (Table 2, entries 12–19).
Not surprisingly, polar solvents favored the consumption of
starting material 2. Furthermore, for the 8-membered ring
cyclization, certain amide solvents, including DMAc and NMP
performed better than sulfoxide or phosphoramide solvents such
as DMSO, sulfolane, or HMPA. To find if the amide structure
supported the cyclization, stoichiometric amounts of DMF, urea,
and succinimide were tested in THF solvent, and it was found
that only a large excess of DMF could still enable the conversion
(Table 2, entries 20–23). In addition, other alkaline bases,
including Na2CO3 and K2CO3 were examined and found less
efficient than Cs2CO3 (Table 2, entries 24 and 25). Eventually, the
original cyclization condition described in Scheme 1 was found
the best one so far.
R1
N
a
N
N
15a-15k
R2
R3
NH
N
16-22
O
N
O
N
O
N
O
N
N
N
N
N
N
N
N
N
N
N
N
F3C
O
NH
NH
NH
NH
O
F
16
46% from
30% from
17
18
19
15a
15f
53% from 15b
57% from 15c
15d
32% from
NHBn
N
NHBn
N
NHBn
N
N
N
N
N
N
N
F
NH
NH
NH
O
20
27% from
21
22
15h
22% from 15i
15j
25% from
Scheme 3. Cyclization reactions of compounds 15a–15k. Reaction conditions: (a)
Pd(OAc)2, Cs2CO3, DMF, 70 °C, overnight.
The cyclization condition in Scheme 1 was then applied on
substrates 15a–15k (Scheme 3). Compounds 15a–15d with
bromobenzene side chains gave diazocine products 16–19 with
22–57% yields. The iodo-derivative 15f did not show better cycliza-
tion yield, and the chloro-analogue 15e failed to give cyclization.
Compound 15g with a shorter linker between imidazole ring and
phenyl ring did not cyclize to a 7-membered ring, and the starting
Due to the important role of DMF in this cyclization, it might be
proposed that it formed a catalytic intermediate with Pd.7 Since
large excess of DMF was required, and typical Pd ligands inhibited
the cyclization, the contact between DMF and Pd should be weak.

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L. Tang et al. / Tetrahedron Letters 57 (2016) 2311–2314
material could be recovered, indicating the intramolecular cycliza-
tion has a unique geometry demand. Compounds 15h–15j with
benzylamine substitution instead of morpholin gave cyclization
products 21–22 with low yields, indicating the C–H arylation can
be sensitive to the electron density on the pyrazine ring. The last
substrate 15k with a piperonyl substitution on the imidazole ring
failed to give the cyclization product. Additionally, amide 1 could
not react under the same condition. Both cases again revealed
the sterical requirement of the C–H arylation.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.04.
050.
References and notes
1. Ren, J.; Yang, M.; Liu, H.; Cao, D.; Chen, D.; Li, J.; Tang, L.; He, J.; Chen, Y.-L.; Geng,
M.; Xiong, B.; Shen, J. Org. Biomol. Chem. 2015, 13, 1531–1535.
2. See supporting information for details.
3. This is an example of intramolecular Buchwald–Hartwig amination. For several
reviews of this amination: (a) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534–1544;
(b) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27–50.
Conclusion
In summary, some new multi-substituted 8-aminoimidazo
[1,2-a]pyrazine substrates were efficiently prepared in a 5-step
procedure, including a modified Groebke–Blackburn–Bienaymé
reaction. Starting from these substrates, a Pd-catalyzed cyclization
reaction was discovered, leading to the formation of rare
(Z)-4,5-dihydro-3H-[1,3]diazocine system, which could be useful
for further study in the fields of organic chemistry and medicinal
chemistry. Also, conditions of this cyclization were screened and
DMF solvent was found one of the key factors for the conversion.
Much information could be derived from the condition screening
and could be used for further study of mechanism related to this
unusual cyclization reaction.
4. CCDC 1446772 contains the supplementary crystallographic data for compound
3. These data can be obtained free of charge at http://www.ccdc.cam.ac.
uk/conts/retrieving.html [or from the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK; fax: (internat.)+44(1223)336–033,
e-mail: deposit@ccdc.cam.ac.uk]. See supporting information for details.
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Wang, J.-X.; McCubbin, J. A.; Jin, M.; Laufer, R. S.; Mao, Y.; Crew, A. P.; Mulvihill,
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2014, 2014, 5456–5461; (b) Maggio, B.; Raffa, D.; Raimondi, M. V.; Cascioferro,
S.; Plescia, S.; Sabatino, M. A.; Bombieri, G.; Meneghetti, F.; Daidone, G. ARKIVOC
2008, 130–143; For reviews: (c) Rúnarsson, Ö. V.; Artacho, J.; Wärnmark, K. Eur.
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Acknowledgements
This work was supported by the National Natural Science
Foundation of China (81273368) and the National Science &
Technology Major Project
– Key New Drug Creation and
Manufacturing Program – of China (Grant No. 2014ZX09507-002).