Lewis acid catalyzed intramolecular ring-opening of triazole-substituted methylenecyclopropanes: An approach to 4 H -[1,2,3]triazolopyrazines and 4 H -[1,2,3]triazolo[1,4]diazepines

Article abstract of DOI:10.1055/s-0034-1378977

A series of novel methylenecyclopropane-triazoles have been successfully prepared. Their intramolecular nucelophilic cyclizations have been explored in the presence of Yb(NTf₂)₃ catalyst, giving the corresponding triazole containing six- and seven-membered heterocycles in good yields upon heating in toluene.

Full text of DOI:10.1055/s-0034-1378977

CLUSTER
▌2293
cLluestewr is Acid Catalyzed Intramolecular Ring Opening of Triazole-Substituted
Methylenecyclopropanes: An Approach to 4H-[1,2,3]Triazolopyrazines and
4H-[1,2,3]Triazolo[1,4]diazepines
4H-[1,2,3]Triazolopyrazines and 4H-[1,2,3]Triazolo[1,4]diazepines
Run Sun,a Di-Han Zhang,b Min Shi*a,b
a
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, School of Chemistry & Molecular Engineering, East China
University of Science and Technology, 130 Mei-Long Road, Shanghai 200237, P. R. of China
b
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin
Road, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: mshi@mail.sioc.ac.cn
Received: 27.05.2014; Accepted after revision: 28.07.2014
tones (mode C, Scheme 1).7 Moreover, gold(I)-catalyzed
Abstract: A series of novel methylenecyclopropane-triazoles have
intramolecular hydroamination and ring opening of MCP
been successfully prepared. Their intramolecular nucelophilic cy-
has been disclosed by our group (mode D, Scheme 1).8 On
clizations have been explored in the presence of Yb(NTf2)3 catalyst,
the basis of above achievements, we attempted to investi-
gate the intramolecular nucleophilic addition of MCP
bearing a nucleophilic group in which the nucleophile and
MCP are tethered with a nitrogen atom in the presence of
Lewis acid such as Yb(OTf)3 or Yb(NTf2)3 (Scheme 1,
this work). Therefore, we designed and synthesized a nov-
el type of triazole-substituted MCP 1, which contain a co-
ordinative double bond, a strained carbocycle, and an
additional triazole group. We envisioned that through an
intramolecular hydroamination along with a C–C bond
cleavage of the cyclopropane in the presence of Lewis ac-
id, 4H-[1,2,3]triazolo[1,5-a]pyrazine derivative 2 and 4H-
[1,2,3]triazolo[1,5-a][1,4]diazepine 3 could be formed.
These products can be biologically interesting because
several compounds bearing substituted triazolopyrazines
have been used to treat type 2 diabetes by inhibiting di-
peptidyl peptidase IV (DPP-4) such as Sitagliptin.9
giving the corresponding triazole containing six- and seven-mem-
bered heterocycles in good yields upon heating in toluene.
Key words: triazole, methylenecyclopropanes, Lewis acid, intra-
molecular cyclization
Methylenecyclopropanes (MCP), as highly strained but
readily accessible molecules, have been important build-
ing blocks in organic synthesis for a long time1 because
they can undergo a variety of ring-opening reactions
through the release of cyclopropyl ring strain (40
kcal/mol).2 The strained energy can provide a thermody-
namic driving force for reactions and the π-character of
the bonds within the cyclopropane can afford the kinetic
opportunity to initiate the ring opening.3 Over the past few
decades, several excellent review articles have been pub-
lished on the transformation of these exo-methylene three-
membered carbocycles.4 Besides transition-metal cata-
lysts, Lewis and Brønsted acids can be also used as cata-
lysts or reagents in the reactions of MCP with a variety of
substrates. It has been disclosed that substituents on the
terminus of the double bond or cyclopropyl ring of MCP
significantly affect the reaction pathways, and some inter-
esting transformations have been found during the past
decade by our group and others.
Using MCP-triazole 1a as substrate, we examined the re-
action outcomes with a variety of Lewis acids in toluene
at 110 °C. The results are summarized in Table 1. Using
BF3·OEt2 (10 mol%) as the catalyst afforded the desired
products 2a and 3a in 38% yield with a 1:1.1 ratio (Table
1, entry 1). In the presence of Ti(Oi-Pr)4, FeCl2, FeCl3, or
Brønsted acid HOTf, complex product mixtures were pro-
duced under the standard conditions (Table 1, entries 2–
5). Many triflated metal salts were more efficient catalysts
in this reaction and we identified that In(OTf)3, In(NTf2)3,
and Yb(NTf2)3 were the most efficient catalysts in this re-
action, affording 2a and 3a in >82% yield (Table 1, entries
6–18). Next, using Yb(NTf2)3 as the catalyst, we exam-
ined the solvent effects in DCE, THF, hexane, and MeCN,
but no better result could be produced (Table 1, entries
19–22). Increasing the catalyst loading to 15 mol%, 2a
and 3a were obtained in 89% yield in toluene within 12
hours, which are the best conditions for this reaction (Ta-
ble 1, entry 23). Upon prolonging the reaction, the decom-
position of the desired products was identified at 80 °C
because complex product mixture was formed (Table 1,
entry 24). The reaction did not give any desired products
Several studies have focused on intramolecular nucleo-
philic addition of MCP bearing a nucleophilic group
(Scheme 1). For example, our group and Huang’s group
reported the efficient stereoselective synthesis of bicy-
clo[3.1.0]hexane from the reaction of 2-substituted MCP
with iodine (mode A, Scheme 1).5 Lautens and co-work-
ers studied the MgI2-mediated ring expansions of second-
ary MCP amides, giving the isomeric five-membered
unsaturated lactams in good yields (mode B, Scheme 1).6
Ma and co-workers reported a regioselective palladium-
catalyzed ring-opening cycloisomerization of MCP ke-
SYNLETT 2014, 25, 2293–2296
Advanced online publication: 08.09.2014
0
9
3
6
-
5
2
1
4
1
4
3
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2
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DOI: 10.1055/s-0034-1378977; Art ID: st-2014-s0461-c
© Georg Thieme Verlag Stuttgart · New York

2294
R. Sun et al.
CLUSTER
E+
Table 1 Optimization of Reaction Conditions
Nu–
E
I2
NTs
TsN
NTs
catalyst
R1
R2
N
mode A
ref. 5
(10 mol%)
N
N
Nu
R1
R2
N
+
Ph
110 °C
TsN
N
Ph
N
N
N
Ph
2a
3a
1a
Nu
Nu
Nu–
[Mg]
Entrya Catalyst
Solvent
Time (h) 2a/3ab Yield (%)c
+
mode B
ref. 6
R1
R2
R1
R2 R1
R2
1
2
BF3·OEt2
Ti(Oi-Pr)4
FeCl2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCE
35
>48
>48
>48
24
1:1.1
–
38
complex
complex
complex
complex
45
Nu
Nu–
3
–
[Pd]
R1
+
R1
R2
+
mode C
4
FeCl3
–
ref. 7
Nu
Nu
R2
R1
R2
R1
R2
5
HOTf
–
6
AgOTf
35
1.2:1
1:1
1:1
1:1.3
1.1:1
1:1
1.3:1
1.3:1
1:1
1:1.3
1:1
1:1
1:1
1.1:1
–
Nu
Nu–
O
O
7
Cu(OTf)3
Yb(OTf)3
Bi(OTf)3
Eu(OTf)3
La(OTf)3
Dy(OTf)3
Tm(OTf)3
Ce(OTf)3
Ce(OTf)4
In(OTf)3
In(NTf2)3
Yb(NTf2)3
Yb(NTf2)3
Yb(NTf2)3
Yb(NTf2)3
Yb(NTf2)3
Yb(NTf2)3
Yb(NTf2)3
Yb(NTf2)3
30
51
H+
[Au]
mode D
ref. 8
8
30
64
R1
R2
R1
R2
9
35
41
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
35
63
Nu
Nu
N
Nu–
NTs
+
[Yb]
H+
35
36
NTs
This work
Ts
30
58
R1
R1
R1
30
58
46
50
Scheme 1 Intramolecular nucleophilic addition of 2-substituted
MCP. Nu = nucleophile. E = electrophile.
46
53
35
82
in a sealed reaction tube under strictly anhydrous condi-
tions (Table 1, entry 25).
22
86
With the optimal reaction conditions in hand, we subse-
quently explored the substrate scope and the results are
shown in Table 2. We found that the substituents on the
aromatic rings of the MCP moiety slightly affected the re-
action outcomes since only in the case of substrate 1f in
which the benzene ring of MCP-triazole has an electron-
donating methoxyl group, the corresponding products 2f
and 3f were obtained in 55% yield and others were all over
60% yield (Table 2, entries 3–11). Furthermore, the olefin
configuration of MCP 1 did not have significant impact on
the reaction outcomes. For example, MCP-triazoles 1a
and 1b as well as 1g and 1h gave the similar results under
the standard conditions (Table 2, entries 1, 2 and 7, 8).
MCP-triazole 1l with a heteroaromatic ring was also suit-
able in this reaction, but affording the corresponding
products 2l and 3l in moderate yields, perhaps due to the
coordination between the heteroatom with Lewis acid cat-
alyst (Table 2, entry 12). All these cyclized products 2 and
3 can be easily separated by preparative thin layer chro-
matography (TLC).
25
88
35
49d
THF
>48
35
complexd
36d
hexane
MeCN
toluene
toluene
toluene
1:1
1:1
1:1
–
12
82d
12
89e
>48
12
complexe,f
n.d.e,g
–
a Reaction conditions: 1a (0.1 mmol), catalyst (0.01 mmol), toluene
(2 mL), 110 °C.
b Compounds 2 and 3 can be separated individually by TLC.
c Isolated yield.
d Reaction was carried within a sealed tube.
e Conditions: 0.015 mmol (15 mol%) catalyst was added.
f Reaction was carried at 80 °C.
g The reaction was carried out under strictly anhydrous conditions;
n.d. = not determined.
It should be noted that using MCP-triazole 1m as the sub-
strate, in which the aromatic ring in the MCP moiety hav-
ing an electron-withdrawing nitro group, none of the
desired product was isolated and we only identified the
formation of hydrolyzed product 4m in 34% yield
(Scheme 2). This result suggests that this reaction might
be initiated from the coordination between the double
Synlett 2014, 25, 2293–2296
© Georg Thieme Verlag Stuttgart · New York

CLUSTER
4H-[1,2,3]Triazolopyrazines and 4H-[1,2,3]Triazolo[1,4]diazepines
2295
To identify whether this reaction proceeds through a SET
process, several control experiments were conducted
(Scheme 3). Addition of the electron-transfer scavenger
1,4-dinitrobenzene (0.2 equiv)11 or the radical inhibitor
hydroquinone (0.2 equiv) to the standard reaction mix-
tures did not impair the reaction outcomes, rendering that
a SET reaction pathway may not be involved in the cata-
lytic cycle.
Table 2 Yb(NTf2)3-Catalyzed Ring-Opening Reaction of Triazole-
Substituted MCP
N
NR2
NR2
N
N
Yb(NTf2)3
(15 mol%)
N
+
NR2
N
R1
toluene, 110 °C
R1
N
TsN
N
N
R1
2
3
1
NTs
TsN
NTs
Entrya Substrate R1
R2
Config.2/3b
Yield (%)c
Yb(NTf2)3
(15 mol%)
N
N
N
N
+
1
2
1a
1b
1c
1d
1e
1f
Ph
Ts
Ts
Ts
Ts
Ts
E
Z
E
E
E
Z
E
Z
E
E
E
Z
1:1
1:1
89
72
Ph
additive
110 °C, 12 h
TsN
N
Ph
N
N
N
Ph
Ph
3a
1a
2a
3
2-MeC6H4
3-MeC6H4
4-MeC6H4
1:1.6 71
1:1.7 79
1:1.9 64
1:1.3 55
1.4:1 76
1.1:1 62
additive
none
yield (%) (2a + 3a)
4
89
86
85
1,4-dinitrobenzene
hydroquinone
5
6
4-MeOC6H4 Ts
Scheme 3 Control experiments
7
1g
1h
1i
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-ClC6H4
1-Np
Ts
Ts
Bs
Ts
Ts
Ts
8
To further verify the reaction pathway, the deuterium-la-
beling experiment was carried out by performing the reac-
tion of 1g in the presence of D2O (5.0 equiv) under the
standard conditions (Scheme 4). The deuterium-incorpo-
rated products 2g and 3g were formed in 42% and 36%
yields along with 67% deuterium incorporation, respec-
tively. This result suggests that ambient water is involved
in the reaction. In addition, the deuterium-labeled sub-
strate 4a-d did not furnish any deuterium-incorporated
products 2a and 3a under the standard conditions, indicat-
ing that an intramolecular hydrogen-transfer pathway is
not involved in the reaction and the proton is derived from
the ambient water source (Scheme 4).
9
1:1
82
10
11
12
1k
1k
1l
1:1.5 58
1:1.2 74
1.2:1 33
2-thienyl
a Reaction conditions: 1a (0.1 mmol), catalyst (0.01 mmol), toluene (2
mL), 110 °C.
b Compounds 2 and 3 can be separated individually by TLC.
c Isolated yield.
bond in the MCP moiety and the Lewis acid (π-activa-
tion).10 The lower electron density in the double bond of
substrate 1m did not facilitate the intramolecular cycliza-
tion to take place. To verify this hypothesis, we synthe-
sized relatively electron-rich substrate 4a and examined
its reactivity under the standard conditions. To our de-
light, the corresponding products 2a and 3a were obtained
in 31% and 20% yields, respectively, indicating that com-
pound 4 might be the reaction intermediate (Scheme 2).
TsN
N
N
N
NTs
N
H (67% D)
2g-d, 42%
Br
Yb(NTf2)3
(15 mol%)
N
TsN
+
N
N
toluene
D2O (5 equiv)
110 °C
N
NTs
NTs
Br
1g
Yb(NTf2)3
(15 mol%)
NTs
TsN
N
N
NH
O2N
H (67% D)
3g-d, 36%
O2N
N
MeCN
110 °C
N
Br
4m, 34%
TsN
1m
NTs
NTs
Yb(NTf2)3
(15 mol%)
N
N
TsN
NTs
Yb(NTf2)3
(15 mol%)
NTs
ND
N
N
+
N
N
N
N
Ph
+
toluene
110 °C
N
Ph
N
NH
toluene
110 °C
N
N
Ph
Ph
N
N
N
N
Ph
2a, 31%
3a, 20%
4a
(71% D)
3a, 36%
2a, 38%
4a-d
Scheme 2 Mechanistic studies and control experiment
Scheme 4 Isotopic labeling experiments
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2293–2296

2296
R. Sun et al.
CLUSTER
A proposed mechanism for this reaction is outlined in
Scheme 5 on the basis of the above deuterium-labeling
and control experiments. The Lewis acid first coordinates
to the Ts-triazole moiety through a σ-activation12 and the
alkene moiety in the MCP part via a π-activation to give
intermediate A, which may then undergo an intramolecu-
lar cyclization via two possible reaction pathways along
with the hydrolysis of the sulfonyl group by ambient wa-
ter to give the intermediates B (path a) and B′ (path b).
Protonation of the intermediates B and B′ furnishes the
corresponding 4H-[1,2,3]triazolo[1,5-a]pyrazine deriva-
tive 2 and 4H-[1,2,3]triazolo[1,5-a][1,4]diazepine 3 and
regenerates the Yb3+ catalyst.
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000083.SunogIpimrfiantoSuIpg
n
fonirtat
ori
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– TsOH
Scheme 5 A proposed reaction mechanism
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Acknowledgment
We are grateful for the financial support from Shanghai Municipal
Committee of Science and Technology (11JC1402600), the Natio-
nal Basic Research Program of China (973)-2010CB833302, and
the National Natural Science Foundation of China (20472096,
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21302203 and 20732008).
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