Synthesis of 3,4-Dihydrobenzo[f]phthalazines via Iodine/tert-Butyl Hydroperoxide-Mediated Annulation Cascade of Yne-Allenones

Article abstract of DOI:10.1002/adsc.201900063

An iodine (I₂)/tert-butyl hydroperoxide (TBHP)-mediated annulation cascade between yne-allenones and sulfonyl hydrazides has been established, in which a wide set of dihydrobenzo[f]phthalazines were synthesized through one-pot, two-step strategy under metal-free conditions. The synthetic utility of these transformations leads to subsequent C?C and C?N bond-forming reactions to effectively build up functional aza-heterocycle with potential significance. (Figure presented.).

Full text of DOI:10.1002/adsc.201900063

Title: Synthesis of 3,4-Dihydrobenzo[f]phthalazines via Iodine/tert-Butyl
Hydroperoxide-Mediated Annulation Cascade of Yne-Allenones
Authors: Bo Jiang, Rong Fu, Meng-Fan Li, Peng Zhou, Wen-Juan Hao,
and Shu-Jiang Tu
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900063
Link to VoR: http://dx.doi.org/10.1002/adsc.201900063

Advanced Synthesis & Catalysis
10.1002/adsc.201900063
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis of 3,4-Dihydrobenzo[f]phthalazines via Iodine/tert-
Butyl Hydroperoxide-Mediated Annulation Cascade of Yne-
Allenones
Rong Fu,[a],[1] Meng-Fan Li,[a],[1] Peng Zhou, Wen-Juan Hao,* Shu-Jiang Tu, and Bo Jiang*
[a]
,[a]
[a]
,[a]
[
a]
School of Chemistry & Materials Science, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional
Materials, Jiangsu Normal University, Xuzhou, 211116, P. R. China; E-mail: wjhao@jsnu.edu.cn (W.J.H.);
jiangchem@jsnu.edu.cn (B.J.); Tel./fax: +86 516 83500065; These authors contributed equally.
[
1]
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. An iodine (I
2
)/tert-butyl hydroperoxide
aryldiazonium salts and DABCO bis(sulfur dioxide)
(DABSO) for the synthesis of
(
TBHP)-mediated annulation cascade between yne-
allenones and sulfonyl hydrazides has been established,
in which a wide set of dihydrobenzo[f]phthalazines were
synthesized through one-pot, two-step strategy under
metal-free conditions. The synthetic utility of these
transformations leads to subsequent C−C and C−N bond-
forming reactions to effectively build up functional aza-
heterocycle with potential significance.
Figure 1. Biologically active phthalazines
Keywords: Annulation; Yne-allenones; Oxidation;
[
2+2] Cycloaddition; Benzo[f]phthalazines
cyclobuta[a]naphthalen-4-ols, in which the in situ
generated [2+2] cycloadduct serves as a good radical
[7]
acceptor (Scheme 1a). To continue our efforts in
this project, we made an attempt to adopt this
cycloadduct intermediate to capture sulfonyl radical
and iodo radical, enabling their 1,4-addition to
achieve iodosulfonylation of yne-allenones (Scheme
The efficient construction of fused aza-heterocyclic
skeletons of chemical and biomedical importance
have attracted considerable interest from the organic
community since they have been widely applied in
chemical, medical, and life sciences.[1] Among these
1
b). A survey of literatures revealed that the
skeletons, substituent-diverse phthalazines represent
an important structural motif commonly found in
generation of sulfonyl radicals from sulfonyl
hydrazides under oxidative conditions is well
variety of natural products, pharmaceuticals, and
[8]
other synthetics (Figure 1).[2] Functional phthalazines
established. For these reasons, the reaction of yne-
allenones with sulfonyl hydrazides was conducted by
combining I and tert-butyl hydroperoxide (TBHP) as
have been found to exhibit a broad range of
biological activities, such as anticonvulsant,
2
a catalytic oxidative system. Instead of the expected
cyclobuta[a]naphthalen-4-ol products 3 (Scheme 1c),
the reaction proceeded in another direction to give
antimicrobial, anti-inflammatory, antimycobacterial,
and antitumor, etc.[
3]
With these significant
bioactivities, great efforts have been made to develop
many reliable chemical methods for the construction
of fused and functionalized phthalazines, mainly
3
,4-dihydrobenzo[f]phthalazin-6-ols 4, accompanied
with naphthalen-1-ol intermediates 5. In the presence
of Et N, the intermediates 5 were more efficiently
converted into 3,4-dihydrobenzo[f]phthalazin-6-ols 4
Scheme 1d). Notably, this cascade bicyclization
3
relying
on
conventional
acid/base-mediated
strategies,[ or transition metal catalysis. Despite
4]
[5]
(
much effort, efficient and atom-economic protocols
have not been established to assemble functionalized
fused phthalazines, especially metal-free version.
Meanwhile, yne-allenones bearing both a C–C triple
bond and an allene unit are a class of versatile
precursors for constructing synthetically significant
polycyclic molecules in a convergent manner. Very
recently, we reported [2+2] cycloaddition/1,4-radical
addition cascades of yne-allenones and with
reaction was tolerant to air and completely oriented
the regioselectivity to assemble a wide range of
structurally
diverse
benzo[f]phthalazin-6-ol
framework. Herein, we contribute our efforts to
elaborate this interesting one-pot two-step
transformation. To the best of our knowledge, the
current protocol represents the first combination of [2
[6]
+
2] cycloaddition with ring expansion from yne-
allenones for the direct synthesis of new nitrogen-
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201900063
containing polyheterocycles via TBHP/I
2
-mediated
substrate ratio of 1a and 2a in 1:1.3 led to a
[
9]
phthalazine annulation without any metal catalyst.
remarkably higher yield of 53% (entry 7). Besides,
increasing the amount of H O is beneficial to this
2
reaction, and a slightly higher yield of 57% was
obtained (entry 8), which may be due to a certain
amount of water could promote the dissolution of
salts generated in situ. Exchanging I for TBAI or KI
2
as an iodine source completely suppressed the
generation of 4a (entries 9-10). The very inferior
result was observed when I
2
was replaced by Br
2
(
entry 11). A relatively lower conversion was
observed with the reaction temperature being at 40, or
0 °C (entries 12-13). Next, our endeavors aimed at
6
improving the formation of 4a were contributed by
changing the reaction media. Screening of several
solvents, such as 1,4-dioxane, DCE, DMF, and EtOH
(
entries 14-17), indicated that 1,4-dioxane was
proved to be the best choice in the current
transformation, as 4a was furnished in 72% yield
(
entry 14). The other three have a detrimental impact
on the generation of 4a (entries 15-17). The use of
other oxidants, such as di-tert-butyl peroxide (DTBP)
and tert-butyl peroxybenzoate (TBPB) did not give
the desired product 4a (entries 18-19).
Table 1 Optimization of the reaction conditions[a]
Scheme 1. Profiles of Cycloaddition of Yne-allenones
Our initial investigations focused on optimizing the
reaction conditions by treatment with 1-(2-
(
phenylethynyl)phenyl)buta-2,3-dien-1-one (1a) with
tosylhydrazide (2a). The results are listed in Table 1.
The reaction of 1a with 2a in 1:1.5 mole ratio was
entry variation of the reaction conditions
yield (%)[b]
2
O 30
performed in the presence of 10 equivalents of water
in CH
o
1
I
(
I
I
2
(20 mol %)/TBHP (1.2 equiv)/H
10 equiv)
3
CN at 50 C for 5 hours by using tert-butyl
hydroperoxide (TBHP, 70% in water) and I
mol %). Without observation
2
(20
of
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
(50 mol %)
(70 mol %)
39
40
ND
ND
ND
53
cyclobuta[a]naphthalen-4-ol product 3a, a new
tricyclic 3,4-dihydrobenzo[f]phthalazin-6-ol product
2
without I
without H
without TBHP
(50 mol %) (1a:2a = 1:1.3)d
O (13 equiv)
TBAI (50 mol %) instead of I
KI (50 mol %) instead of I
Br (50 mol %) instead of I
2
O[c]
2
4
a was obtained in 24% yield, accompanied with
naphthalen-1-ol intermediate 5a. Due to the
instability of this intermediate, Et N was added into
I
H
2
3
57
the reaction system to promote the conversion of 5a
into 4a after completion of the first-step reaction, and
the yield of product 4a was increased to 30% (entry
2
2
ND
ND
trace
50
43
72
ND
trace
21
0
1
2
3
4
5
6
7
8
9
2
1
). Its analogue 4b was unambiguously determined
by X-ray diffraction analysis (see Supporting
2
2
o
at 60 C
[10]
o
at 40 C
Information).
Enticed by the potential of these
1,4-dioxane instead of CH
3
CN
results, an improvement on the efficiency of this
transformation was attempted by adjusting the
DCE instead of CH
DMF instead of CH
EtOH instead of CH
3
CN
CN
CN
amount of I
2
. An increase in the amount of I to 50
2
3
mol% facilitated the reaction process, delivering the
3
DTBP (1.2 equiv) instead of TBHP trace
TBPB (1.2 equiv) instead of TBHP trace
product 4a in 39% yield (entry 2). The yield of 4a
levelled off when the I
to 70 mol % (entry 3). Without either I
2
loading was further increased
, H O, or
a
Reaction conditions: i) 1a (0.2 mmol, 1.0 equiv), 2a (0.3 mmol, 1.5
2
2
equiv), solvent (3.0 mL), TBHP (70% in water, 0.24 mmol, 1.2 equiv),
TBHP, the reaction did not work, indicating that
these reagents are necessary for the success of this
transformation (entries 4-6). Decreasing the substrate
ratio could promote the transformation, as the
o
air, 50 C, 5 h; ii) trimethylamine (0.3 mL), 5 min.
b
Isolated yield based on 1a.
c
Dry acetonitrile, TBHP (5.5 M in n-decane), 4 Å MS (100 mg).
d
Adjusting 1a:2a to 1:1.3 mole ratio.
ND = Not detected.
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201900063
amount of the desired product 4j, which failed to
be isolated. Subsequently, we independently
With these established conditions in hand, we
next explored the generality of this one-pot, two- introduced methoxy- (1k and 1l), methyl- (1m
step transformation with an assortment of yne- and 1n), fluoro- (1o) and chloro- (1p) groups into
allenone
the C4 or C5 position of the internal arene ring of
substrates and evaluated the effect of the
1
electronic nature of these substituents on the
transformations. Satisfyingly, all these reactions
worked well with the standard conditions,
providing the corresponding products 4k-4p in
5
0%-73% yields. Next, a brief survey of the
possible variation in the structures of sulfonyl
hydrazides was investigated by adopting yne-
2
allenone 1b as a representative substrate. As
anticipated, the reaction proceeded smoothly
under the standard conditions with various
functional groups, including methyl (2b), tert-
butyl (2c), iso-propyl (2d), methoxy (2e), chloro
(
2g), bromo (2h and 2i), and nitro (2j) residing in
the different positions of the arene ring,
furnishing the corresponding benzo[f]phthalazin-
6
6
-ols 4q-4aa with yields ranging from 45% to
6%. Alternatively, both 2-naphthyl (2-Np) and
benzyl counterparts 2k and 2l were also
compatible with this catalytic oxidative system,
enabling the present bicyclization strategy for
synthesizing
dihydrobenzo[f]phthalazin-6-ols 4z and 4aa in
8% and 40% yields, respectively. Unluckily, o-
the
corresponding
3,4-
6
chlorophenyl analogue 2m did not work in the
reaction. Similarly, the pyridine-linked yne-
allenone 1q was an ineffective candidate as only
a trace amount of the target product 4cc was
observed. Moreover, the target products 4dd and
4ee were not observed when acetyl hydrazine and
phenyl hydrazine were employed to replace
sulfonyl hydrazines, respectively (Scheme 2).
Scheme 2. Substrate Scope for the Synthesis of 4.
Reaction conditions: i) 1 (0.2 mmol, 1.0 equiv), 2 (0.26 mmol, 1.3 equiv),
1
0
,4-dioxane (3.0 mL), I (0.1 mmol, 0.5 equiv), TBHP (70% in water,
.24 mmol, 1.2 equiv), air, 50 C, 5 h; ii) trimethylamine (0.3 mL), 5 min.
2
o
b
Isolated yield based on 1.
and sulfonyl hydrazide components, and the
results are depicted in Scheme 2. Yne-allenones
with diverse electron nature and different
substituent patterns were first examined in
combination with tosyl hydrazide (2a) under the
optimal conditions. Both electron-donating and
electron-withdrawing
groups
at
different
1
positions of the arylalkynyl moiety (R )
completely oriented the regioselectivity to the
formation of the corresponding products 4b-4i in
4
6%-80% yields. Functional groups, such as
methyl (1b), methoxy (PMP = p-methoxyphenyl,
), tert-butyl (1d), ethyl (1e), chloro (1f and 1g),
Scheme 3. Control Experiments
1
c
and bromo (1h), all tolerate this catalytic
oxidative system well. Notably, sterically more
To determine the mechanism of the reaction, we
demanding substituents attached by the alkyne carried out several control experiments. Yne-
moiety, for example, the o-chlorophenyl (1g) and allenone 1a was subjected to the reaction with 2a
1
-naphthyl (1-Np, 1i) groups, were suitable for and
this transformation, delivering
3,4- (TEMPO, 2.0 equiv) under the standard
dihydrobenzo[f]phthalazin-6-ol products 4g and conditions without observation of expected
in acceptable yields. However, substrate 1j dihydrobenzo[f]phthalazine 4a However,
2,2,6,6-tetramethyl-1-piperidinyloxy
4i
.
with a terminal alkyne moiety only gave a trace
increasing the amount of TEMPO led to the
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201900063
desired product 4a in 28% yield. BHT as a radical
inhibitor was used to detect the above
transformation and the desired product8]4a was
allenones and sulfonyl hydrazides. The reaction
mechanism is believed to undergo the in-situ
formation of iodomethyl substituted 1-naphthol
intermediates and the following nucleophilic
[
obtained in 45% yield (Scheme 3a). These
substitution.
This
metal-free
transformation
results suggested that this reaction may not
include a radical mechanism and TBHP could
oxidize the iodine anion to molecular iodine.
Without trimethylamine, the reaction of 1p with
proceeded smoothly, resulting in the construction of
two new rings (including arene and pyridazine) and
three chemical bonds. The current protocol features
mild reaction conditions (under air conditions), good
tolerance of functional group and high atom
utilization as well as simple operation.
2
a
was carried out under standard conditions, the
product 4p was isolated in 30% yield along with
8% yield of iodinated product 5p, determined by
X-ray diffraction analysis (Scheme 3b and see
2
[10]
Supporting Information) , indicating that
iodinated product may be an intermediate for
Experimental Section
forming final product 4.
General Procedure for the Preparation of 4
Example for the synthesis of 4a: 1-Phenyl-3-tosyl-3,4-
On the basis of the above observations and
literature reports,[
forming products
6-8],[11]
a feasible mechanism for
was proposed in Scheme 4.
dihydrobenzo[f]phthalazin-6-ol
4
1
-(2-(Phenylethynyl)phenyl)buta-2,3-dien-1-one 1a (49
mg, 0.2 mmol, 1.0 equiv), tosylhydrazide (2a, 48 mg, 0.26
mmol, 1.3 equiv), I (26 mg, 0.1 mmol, 0.5 equiv), and
,4-dioxane (3.0 mL) were introduced in a 10 mL reaction
tube, water (13.0 equiv) and TBHP (70% in water, 31 mg,
.24 mmol, 1.2 equiv) were then successively added and
Initially, I -promoted intramolecular [2 + 2]
2
cycloaddition of yne-allenones
yield cyclobutene intermediate
1 rapidly occurs to
[
11]
2
A
,
followed by
1
1
,6-addition of sulfonyl hydrazides to gives
intermediate
B
. Subsequent ring-opening of
B in
0
the presence of I
naphthol intermediate
final products
2
gives iodomethyl substituted 1-
o
sealed. The mixture stirred at 50 C (5 hours) until
complete consumption of the starting material 1a. Then,
the reaction system was cooled to room temperature and
trimethylamine (0.3 mL) was added into the reaction
system with a syringe. Next, the reaction system was
5
, which converts into the
through intramolecular
4
nucleophilic substitution. The observation of
ring-opening of cyclobutene ring is different from
our previous reports.[
12]
The reason may be
2
stirred for 5 minutes and H O (5 mL) was poured into the
attributed to the strong nucleophilicity and steric
hindrance of sulfonyl hydrazides, which could
system. The reaction mixture was extracted with ethyl
acetate, concentrated under vacuum and purified by flash
column chromatography (silica gel, mixtures of petroleum
ether / acetic ester, 5:1, v/v) to afford the desired pure
product 4a as yellow solid.
suppress I
from cyclobutene ring of intermediate
inhibit the formation of iodide ion between
. With Et N, intramolecular nucleophilic
substitution is more favourable. The eliminated
2
to activate the double carbon-carbon
and to
and
A
A
I
2
3
Acknowledgements
HI was oxidized by TBHP to regenerate I
2
, which
completes the catalytic cycle.[13]
We are grateful for financial support from the NSFC (Nos.
2
1602087 and 21871112), NSF of Jiangsu Province
(
BK20160212), and the Qing Lan Project of Jiangsu Education
Committee (QL2016006).
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