A [4 + 3] Annulation Reaction of aza- o-Quinone Methides with Arylcarbohydrazonoyl Chlorides for Synthesis of 2,3-Dihydro-1 H-benzo[ e][1,2,4]triazepines

Article abstract of DOI:10.1021/acs.orglett.8b00990

An unprecedented [4 + 3] annulation reaction of aza-ortho-quinone methides with arylcarbohydrazonoyl chlorides has been achieved under mild conditions. The annulation underwent a sequential conjugate addition/intramolecular annulation/rearrangement, providing a useful method for the synthesis of biologically interesting 2,3-dihydro-1H-benzo[e][1,2,4]triazepine.

Full text of DOI:10.1021/acs.orglett.8b00990

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A [4 + 3] Annulation Reaction of aza‑o‑Quinone Methides with
Arylcarbohydrazonoyl Chlorides for Synthesis of 2,3-
Dihydro‑1H‑benzo[e][1,2,4]triazepines
Zhenyan Guo, Hao Jia, Honglei Liu, Qijun Wang, Jiaxing Huang, and Hongchao Guo*
Department of Applied Chemistry, China Agricultural University, Beijing 100193, P. R. China
S
* Supporting Information
ABSTRACT: An unprecedented [4 + 3] annulation reaction of
aza-ortho-quinone methides with arylcarbohydrazonoyl chlorides
has been achieved under mild conditions. The annulation
underwent a sequential conjugate addition/intramolecular
annulation/rearrangement, providing a useful method for the
synthesis of biologically interesting 2,3-dihydro-1H-benzo[e]-
[1,2,4]triazepine.
Scheme 1. Cycloaddition Reactions Involving aza-ortho-
Quinone Methides (ao-QMs)
itrogen-containing seven-membered heterocycles are
N
widely found in natural products and artificial drugs.1
As one type of the seven-membered heterocyclic compounds,
triazepines display a variety of practical pharmacological
activities and have widely been used as anticancer agents,
antibiotics, antiviral drugs, psychotropic drugs, antisecreta-
gogues, CCK2 antagonists, analgesics, and antiinflammatory
drugs.2 Among various triazepines, 1,2,4-benzotriazepines were
nonpeptide parathyroid hormone-1 receptor (PTH1R) antag-
onists and have been used in the treatment of malignancy-
associated hypercalcaemia (MAHCa).3 It is of great value to
explore practical synthetic methods of 1,2,4-benzotriazepines.
ortho-Quinone methides (o-QMs) and aza-ortho-quinone
methides (ao-QMs) are known to be very reactive
intermediates that have been utilized in both biological
processes and organic synthesis for decades.4 By using
stabilized or in situ generated o-QMs as an oxa-diene,
numerous [4 + 1],5 [4 + 2],6 [4 + 3],7 and [4 + 4]8
cycloadditions have been established to furnish synthesis of
various heterocyclic compounds. In contrast, ao-QMs have
mainly been used in [4 + 2] cycloaddition reactions with
olefins, alkynes, and other reaction substrates bearing a
carbon−nitrogen double bond9 or a carbon−sulfur double
bond (Scheme 1a).10 In comparison with [4 + 2] cyclo-
additions, other types of cycloaddition reactions involving ao-
QMs are quite limited. One of these limited examples was the
[4 + 1]11 annulation reaction of ao-QMs generated in situ with
sulfur ylides, affording indole products.12 Other examples
focused on [4 + 3] cycloaddition reactions. In 2015, the [4 + 3]
cycloaddition between ao-QMs and MBH adducts derived from
isatins was achieved to give a challenging azaspirocycloheptane
oxindole scaffold.13 The [4 + 3] cycloaddition reaction of in
situ generated ao-QMs with C,N-cyclic azomethine imines led
to 1,2,4-triazepine derivatives.14 NHC-catalyzed asymmetric [4
+ 3] annulation of isatin-derived enals with in situ generated
aza-o-quinone methides afforded spirobenzazepinones.15As an
important type of 1,3-dipoles,16 nitrilimines generated in situ
from the hydrazonyl halides have been widely utilized in various
cycloaddition reactions. They often react with olefins or alkynes
to form heterocyclic compounds such as pyrazolines and
pyrazoles through the [3 + 2] cycloaddition.17 Other types of
cycloaddition reactions of nitrilimines have received little
attention. On the basis of the above-mentioned [4 + 3]
cycloadditions involving ao-QMs13−15,18 and our previous work
on cycloaddition reactions,19 we envisioned that when ao-QMs
meet with nitrilimines, a new [4 + 3] annulation for synthesis of
seven-membered heterocyclic compounds might be accom-
plished to furnish 4,5-dihydro-1H-benzo[e][1,2,4]triazepine
(Scheme 1b). However, an unexpected [4 + 3] annulation of
Received: March 28, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00990
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
aza-ortho-quinone methides with arylcarbohydrazonoyl chlor-
ides was observed, leading to 2,3-dihydro-1H-benzo[e][1,2,4]-
triazepine (Scheme 1b). Herein, we report this [4 + 3]
annulation reaction for the synthesis of 2,3-dihydro-1H-
benzo[e][1,2,4]triazepines (Scheme 1b).
In the initial study, the reaction of ao-QMs precursor 1a with
N-phenylbenzohydrazonoyl chloride 2a was chosen as the
model reaction for screening the reaction conditions (Table 1).
aggregation of the ao-QM at lower temperature, the reaction
was carried out at −40 °C, however, the yield was not improved
(entry 11). In contrast, increasing the temperature to −20 °C
slightly improved the yield to 76% (entry 12), but further
increasing the reaction temperature to −10 and 0 °C resulted in
a remarkable side reaction and thus deteriorated the yields
(entries 13−14). According to the observation that the silica
could promote conversion of the intermediate 3 to the product
4aa, the experimental procedure was modified. After the
reaction mixture of ao-QMs precursor 1a and the substrate 2a
was stirred in dichloromethane at −30 °C for 36 h, the silica gel
was added into the flask to promote conversion of the
intermediate to the desired product and the resulting mixture
continued to be stirred for 12 h to give the product in 78%
yield (entry 15).
a
Table 1. Optimization of Reaction Conditions
With the optimal reaction conditions identified, the scope of
the substrates was then investigated. As shown in Table 2,
b
entry
base
solvent
t (°C)
yield (%)
c
1
DIPEA
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
−30
−30
−30
−30
−30
−30
−30
−30
−30
−30
−40
−20
−10
0
NR
2
KOAc
57
10
27
54
72
63
42
40
29
72
76
65
64
78
a
Table 2. Scope of Arylcarbohydrazonoyl Chlorides 2
3
NaOAc
K2CO3
4
5
Cs2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
6
7
8
1,4-dioxane
toluene
THF
b
entry
R1
R2, R3
Ph, Ph (2a)
4
yield (%)
9
10
11
12
13
14
1
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
4-Me (1d)
4-Me (1d)
4aa
4ab
4ac
4ad
4ae
4af
78
52
64
70
59
55
62
54
71
70
74
71
55
53
53
72
53
76
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
2
2-FC6H4, Ph (2b)
3-FC6H4, Ph (2c)
4-FC6H4, Ph (2d)
2-BrC6H4, Ph (2e)
3-BrC6H4, Ph (2f)
4-BrC6H4, Ph (2g)
3-ClC6H4, Ph (2h)
4-MeC6H4, Ph (2i)
4-MeOC6H4, Ph (2j)
1-naphthyl, Ph (2k)
2-naphthyl, Ph (2l)
Ph, 4-BrC6H4 (2m)
Ph, 4-ClC6H4 (2n)
Ph, 3-FC6H4 (2o)
Ph, 4-MeC6H4 (2p)
4-MeC6H4, Ph (2i)
Ph, 4-MeC6H4 (2p)
3
4
5
d
15
−20
6
a
7
4ag
4ah
4ai
Unless otherwise noted, reactions were conducted with 1a (0.1
mmol), 2a (0.12 mmol), and base (0.2 mmol) in solvent (2 mL) for
36 h. Isolated yield. No reaction. After the reaction mixture was
stirred for 36 h, 500 mg of silica gel were added and the resulting
mixture was stirred for 12 h at rt.
8
b
c
d
9
10
11
12
13
14
15
16
17
18
4aj
4ak
4al
Since the base plays a key role in the reaction of ao-QMs, we
first examined two bases such as diisopropylethylamine
(DIPEA) and KOAc. In the presence of organic base DIPEA,
the reaction did not work and no product was observed (Table
1, entry 1). With the use of KOAc as the base, the reaction of
ao-QMs precursor 1a with N-phenylbenzohydrazonoyl chloride
2a was performed in dichloromethane at −30 °C for 36 h.
During the reaction process, two products were observed on
TLC. Moreover, the major product could convert into the
minor one during purification through flash column. It
indicated that the silica gel promoted the conversion of the
intermediate to the final product. Through NMR data and the
X-ray crystallographic analysis, the intermediate was identified
as the benzohydrazonoyl chloride 3 (CCDC 1832290). The
product was determined as a 2,3-dihydro-1H-benzo[e][1,2,4]-
triazepine derivative 4aa (CCDC 1587333), which is an
unexpected [4 + 3] annulation product and was isolated in 57%
yield by flash column chromatography (entry 2). Different
inorganic bases such as acetate and carbonate bases were next
screened to improve the yield (entries 3−6). To our delight,
the yield of the product 4aa was increased to 72% with the use
of Na2CO3 as the base (entry 6). The impact of the solvent was
also examined. Compared with dichloromethane, 1,2-dichloro-
ethane (DCE), 1,4-dioxane, toluene, and tetrahydrofuran
(THF) led to a decrease in yields (entries 7−10). Considering
that the yield might be increased by suppressing the self-
4am
4an
4ao
4ap
4di
4dp
a
Unless otherwise noted, reactions were performed with 1a (0.1
mmol), 2a (0.12 mmol), and Na2CO3 (0.2 mmol) in CH2Cl2 (2.0
mL) at −20 °C for 36 h, then 500 mg of silica gel were added, and the
resulting mixture was stirred at rt for 12−36 h depending on TLC
b
monitoring. Isolated yield.
various arylcarbohydrazonoyl chlorides 2 having diverse
electron-donating or -withdrawing groups at different positions
of the benzene ring performed the reaction well to give the
products 4 in moderate to high yields (52−78%) (entries 1−
10). In general, substrates with electron-donating groups on the
benzene ring exhibited higher reactivity than those with
electron-withdrawing groups (entries 9−10 vs 2−8). The
substrates bearing substituents at the 4-position of the aryl
showed relative higher reactivity than their corresponding
analogues with substituents at the 2- or 3-position of the aryl as
a result of the steric hindrance effect, leading to the
corresponding products in a slightly higher yield (entries 4, 7,
9−10). In addition, arylcarbohydrazonoyl chlorides with
B
DOI: 10.1021/acs.orglett.8b00990
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
different R3 substituents could also be tolerated (entries 13−
16). The reaction of methyl-substituted ao-QMs and methyl-
substituted arylcarbohydrazonoyl chlorides also underwent the
reaction to give the corresponding products in moderate to
high yields (entries 17−18).
Scheme 2. Control Experiments
Next, we carried out an investigation on ao-QM precursors 1
(Table 3). A series of ao-QM bearing different R groups were
a
Table 3. Scope of ao-QM Precursors 1
b
entry
1
R
4
yield (%)
H (1a)
4aa
4ba
4ca
4da
4ea
4fa
78
37
65
70
65
62
54
59
c
2
6-Me (1b)
5-Me (1c)
4-Me (1d)
3-Me (1e)
5-F (1f)
3
4
5
6
7
8
3-F (1g)
3-Cl (1h)
4ga
4ha
a
Unless otherwise noted, reactions were performed with 1a (0.1
Scheme 3. A Plausible Mechanism
mmol), 2a (0.12 mmol), and Na2CO3 (0.2 mmol) in CH2Cl2 (2.0
mL) at −20 °C for 36 h, and then 500 mg of silica gel were added, and
b
c
the mixture was stirred at rt for 12−36 h. Isolated yield. The reaction
temperature was 25 °C.
compatible with the reaction. With the exception of 6-Me-
substituted ao-QM precursor (1b), other substrates carried out
the annulation reaction to give the corresponding products 4 in
moderate to good yields (Table 3, entries 1, 3−8). The
electronic properties or position of the substituent on the
benzene ring seems to have no significant effect on the reaction
(entries 1, 3−8). The 6-Me-susbstitiued ao-QM precursor was
not very reactive and only gave the product 4ba in 37%yield
(entry 2). Delightedly, the reaction could be scaled up. Using 1
mmol of ao-QM precursor 1d as the substrate, the
corresponding product 4da was obtained in 64% yield (see
Supporting Information).
In order to shed light on the reaction mechanism, some
control experiments had been carried out (Scheme 2). The
substrate 2g derived from 4-bromobenzoyl chloride reacted
with ao-QMs to give the products 4ag (CCDC 1587334), in
which 4-bromophenyl sits at the 5-position of the triazepine.
On the other hand, the substrate 2m derived from (4-
bromophenyl)hydrazine reacted with ao-QMs to afford the
corresponding product 4am (CCDC 1587335), in which 4-
bromophenyl sits at the 3-position of the triazepine. On the
basis of the experimental results, as shown in Scheme 3, a
plausible mechanism for the stepwise annulation reaction was
proposed. The ao-QM A generated in situ from ao-QMs
precursor 1a in the presence of Na2CO3 reacts with the
substrate 2a through conjugate addition to produce an
intermediate 3, which has been isolated and confirmed by its
X-ray crystallographic data. In the presence of silica gel, the
intermediate 3 performs deprotonation and isomerization to
afford the intermediate B, which undergoes an intramolecular
annulation to produce the intermediate C. Further rearrange-
ment due to aromatization results in the product 4aa. The role
of the silica gel in the conversion of the intermediate B to the
product 4aa has been explored. In the reaction process, acetic
acid, benzoic acid, and p-toluene sulfonic acid were added
instead of silica gel, respectively, leading to no remarkable
conversion. It indicated that the protonic acid can prevent the
isomerization of the intermediate 3. Furthermore, by replacing
silica gel with anhydrous FeCl3 and MgSO4, the product was
obtained in 57% and 64% yield, respectively (Scheme 2). On
the basis of the above observations, on one hand, the silica gel’s
function probably is increasing the contact surface of the
intermediate 3 with solvent, thus making the further trans-
formation more easy; on the other hand, the silica gel might
activate the intermediates 3 and B.
In conclusion, we have developed a useful method for
synthesis of biologically significant 2,3-dihydro-1H-benzo[e]-
[1,2,4]triazepine through the [4 + 3] annulation reaction
between in situ generated aza-ortho-quinone methides and
arylcarbohydrazonoyl chlorides with the use of Na2CO3 as the
base in the presence of silica gel. The reaction underwent a
sequential conjugate addition, intramolecular annulation, and
rearrangement processes. The ao-QMs functioned as an
C
DOI: 10.1021/acs.orglett.8b00990
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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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.or-
glett.8b00990.
Experimental procedure, characterization data, and NMR
spectra (PDF)
Accession Codes
CCDC 1587333−1587335 and 1832290 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing 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.
(7) (a) Izquierdo, J.; Orue, A.; Scheidt, K. A. J. Am. Chem. Soc. 2013,
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̃
̃
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hchguo@cau.edu.cn.
ORCID
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Hongchao Guo: 0000-0002-7356-4283
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by the NSFC (Nos. 21372256,
21572264) and the Program for Changjiang Scholars and
Innovative Research Team Project IRT1042.
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