Trifluoroacetic acid catalyzed dibenzodiazocine synthesis: Optimization and mechanism study

Article abstract of DOI:10.1016/j.tet.2012.09.050

Dibenzo[b,f][1,5]diazocines, a class of potential building blocks for novel electrochemical actuators, were synthesized via a novel, efficient acid-catalyzed reaction of 2-acylbenzoisocyanate at room temperature. Real-time NMR analysis and the captured intermediate showed the mechanism was an unprecedented cyclization of the isocyanate with the neighboring acyl group, followed by the dimerization.

Full text of DOI:10.1016/j.tet.2012.09.050

Tetrahedron 68 (2012) 9665e9671
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Trifluoroacetic acid catalyzed dibenzodiazocine synthesis: optimization
and mechanism study
*
Na Zhao, Li Qiu, Xiao Wang, Jianzhong Li, Yi Jiang, Xiaobo Wan
Qingdao Institute of Bioenergy & Bioprocess Technology, Chinese Academy of Sciences, 189 Songling Road, Qingdao, Shandong Province 266101, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 June 2012
Received in revised form 29 August 2012
Accepted 11 September 2012
Available online 20 September 2012
Dibenzo[b,f][1,5]diazocines, a class of potential building blocks for novel electrochemical actuators, were
synthesized via a novel, efficient acid-catalyzed reaction of 2-acylbenzoisocyanate at room temperature.
Real-time NMR analysis and the captured intermediate showed the mechanism was an unprecedented
cyclization of the isocyanate with the neighboring acyl group, followed by the dimerization.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
together with benzo[b,f][1,5]diazocines in moderate yield.14,15 Ex-
cess of AlCl3 was needed for this reaction. Recently, Jung et al.
[4n
p
]Annulenes, such as cyclooctatetraenes, are anti-aromatic
improved the condensation method. Dibenzo[b,f][1,5]diazocines
were synthesized in the presence of 0.5 equiv of diphenyl phos-
phate (DPP) under microwave irradiation in a high yield and this
method could afford the desired product within a short time.16
There are also some other methods for the synthesis of dibenzo
[b,f][1,5]diazocines, but the yields are fairly low.17,18 Thus, the po-
tential applications and the limitations of the current synthetic
methods to prepare [1,5]diazocines make the development of new
synthetic methodology attractive.
macrocycles, which adopt a non-planar conformation. Such mole-
cules and their hetero-derivatives have gained much attention
since the beginning of this century because these compounds
theoretically can undergo a reversible conformational change to
a planar conformation upon a two-electron reduction or oxidation.
Therefore, they might be used as a hinge in new electroactive
materials for actuation.1 In the past decade, many syntheses of
these compounds, such as cyclooctatetrathiophene,2,3 thiepin,4 and
azepine5 and their applications in electrochemical active polymeric
materials have been reported. [1,5]Diazocine also falls into such
a compound category since it has 8
p electrons in its macrocycle and
could be reduced to a 10
p
electrons anion6 (Scheme 1). Indeed,
dibenzo[b,f][1,5]diazocine has found its niche in polysulfones7,8 as
a co-monomer, which enhanced the thermal stability and me-
chanical properties of the resulting polymer. The preliminary result
of its reversible conformation change during electrochemical redox
process was also reported.7 Furthermore, the derivatives of [1,5]
diazocines are a class of useful synthetic building blocks for bio-
mimetic molecular recognition and supramolecular structures.9
However, most of the synthetic strategies toward dibenzo[b,f][1,5]
diazocines were limited to the condensation reactions of 2-
aminobenzophenone derivatives,10e12 which required water re-
moval techniques, needed long reflux time, and suffered
from the tedious preparation steps of the corresponding pre-
cursors.13 It was reported that the FriedeleCrafts intermediate of
2-isocyanatobenzoyl chlorides could be trapped by 2-
aminobenzophenone, which further reacted to afford anils,
Scheme 1. Anti-aromatic compounds that could undergo reversible conformational
changes upon reduction or oxidation.
Recently, we developed a new method for the synthesis of
dibenzo[b,f][1,5]diazocine, in which the water removal technique
was replaced by the release of CO2 to construct the imine bond in
the diazocine ring. Therefore, the diazocine synthesis was much
faster and more efficient.19 However, this reaction was conducted
using an organic acid as the solvent, which is relatively harsh.
Moreover, although we postulated, at that time, that the mecha-
nism involved an acid promoted intermolecular [2þ2] cyclization
* Corresponding author. Tel./fax: þ86 532 80662740; e-mail address: wanxb@
qibebt.ac.cn (X. Wan).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.050

9666
N. Zhao et al. / Tetrahedron 68 (2012) 9665e9671
between an isocyanate and a ketone moiety, we did not have a solid
proof for it. We wish to report here the optimization of the reaction,
in which we use milder conditions by employing a catalytic amount
of acid, and in addition the clarification of the mechanism of this
reaction.
toluene at 80 ꢀC for 4 h. This intermediate was relatively stable
under neutral conditions, but we noticed that it was so sensitive to
acids that it was partially converted to diazocine even when we
tried to purify it by silica gel chromatography, although in very low
yield (Table 1, entry 1).
2. Results and discussion
Table 1
Optimization of the diazocine synthesis
2.1. Attempts to validate the [2D2] cyclization hypothesis
The previously reported diazocine synthesis by our group was
a tandem reaction of 2-benzoylbenzoyl azide 1 at 80 ꢀC in anhy-
drous acids, such as acetic acid (AcOH) or trifluoroacetic acid (TFA).
The first step in no doubt involved a Curtius rearrangement, but the
mechanism of the following transformation remained unclear. It
showed some similarity with the [2þ2] cyclization reactions be-
tween isocyanates and ketones reported in the literature, in that
the release of CO2 was observed in both cases.20e22 A mechanism
was proposed accordingly, as shown in Scheme 2a.19 The temper-
ature for the diazocine synthesis was, however, much lower than
that reported in the literature (generally above 150 ꢀC) for the [2þ2]
cyclization. If the proposed mechanism was correct, this method
would have the potential to become a more general strategy for
imine bond construction.
We then examined whether this reaction could be expanded to
simple ketones and isocyanates. Unfortunately, when the same
conditions were applied to the reaction between benzoyl azide 4
and benzophenone, no imine bond formation was observed, as
shown in Scheme 2b. 1,3-Diphenylurea was obtained instead,
which was the product of isocyanatobenzene generated in situ.
Other substrates, such as benzaldehyde and DMF, which were the
more reactive and known to react with isocyanatobenzene at
higher temperature,20,22 also failed to form the imine bond with
compound 4. These results casted a heavy doubt on the mechanism
we proposed before: either the diazocine was obtained via a dif-
ferent intermediate rather than the four-membered 1,3-oxazetidin-
2-one, or there was a specific spatial arrangement requirement of
ketone and isocyanate moieties for the [2þ2] cyclization to occur.
Further investigation was needed to clarify the mechanism.
Entry
Acid/solvent
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
Silica gel
AcOH
TFA
d
2
2
12
2
2
12
12
12
12
12
12
12
3
79
70
5
AcOH (1 equiv)/Tol.
TFA (1 equiv)/Tol.
TFA (0.1 equiv)/Tol.
MeSO3H (0.1 equiv)/Tol.
H2SO4 (0.1 equiv)/Tol.
TiCl4 (0.2 equiv)/Tol.
BF3$OEt2 (0.2 equiv)/Tol.
TFA (0.1 equiv)/THF
TFA (0.1 equiv)/MeCN
TFA (0.1 equiv)/CHCl3
75
77
50
75
d
10
90
90
75
9
10
11
12
13
a
Isolated yield.
The formation of diazocine on silica gel implied that this re-
action could occur under much milder conditions. The reaction
temperature was then decreased to room temperature, and the
isocyanate still afforded the diazocine both in dry AcOH and in TFA
in good yields (Table 1, entries 2 and 3). We then tested whether the
reaction could occur in the presence of a catalytic amount of acid.
Although using 1.0 equiv of AcOH was almost ineffective to pro-
mote this reaction (Table 1, entry 4), strong acids, such as TFA and
H2SO4 showed good catalysis capability in this reaction (Table 1,
entries 5e6 and 8). Methanesulfonic acid could also catalyze this
reaction, but resulted in lower yield (Table 1, entry 7). Lewis acids,
such as TiCl4 and BF3$OEt2 were not able to catalyze this reaction
efficiently (Table 1, entries 9e10). TFA was then chosen as the best
catalyst for this reaction. Switching the solvent to THF or MeCN
gave the best yield of diazocine, but longer reaction time was
necessary.
2.2. Optimization of the reaction conditions
Since the first step of the tandem diazocine synthesis was the
Curtius rearrangement, we tried to conduct the reaction stepwise
to see whether any other intermediate could be isolated. Hence, the
corresponding isocyanate 2 was obtained in almost quantitative
yield when 2-benzoylbenzoyl azide 1 was stirred in anhydrous
a) Previously Proposed Mechanism
O
O
N3
C
O
[2+2]
cyclization
O
Curtius
O
N
N
O
- CO2
Rearragement
- N2
N
N
O
N
O
2
1
3
b) Attempts to Verify the [2+2] Mechanism
O
H
N
H
N
O
N
R1
R1 = Ph,
R1 = Ph,
R
2 = Ph
TFA,80 °C
TFA,80 °C
N3
+
R
2 = H
R1
R2
R2
R1 = NMe2, R2 = H
O
4
5
Scheme 2. Previously proposed mechanism and the attempts for validation.

N. Zhao et al. / Tetrahedron 68 (2012) 9665e9671
9667
2.3. A deeper insight into the mechanism
O
C
N
Ph
EtO
O
O
O
Ph
0.1equiv,TFA/CHCl3
rt, 45 min.
EtOH
40%
NH
Given that all the reported [2þ2] cyclizations between iso-
cyanate and ketone require much higher temperature, the cycli-
zation of 2-benzoylphenyl isocyanate at room temperature is
highly unlikely to go through the four-membered intermediate (or
transition state), which is a highly-strained, high-energy species.
There must be another pathway toward the diazocine. Fortunately,
the milder conditions and longer reaction time now made tracking
the intermediate possible. The reaction was then monitored via the
real-time 13C NMR analysis, and the results were shown in Fig. 1
(Full spectra are available in Supplementary data).
2
6
Scheme 3. Capture of the possible intermediate.
[d][1,3]oxazin-2-one 8a, as shown in Scheme 4. TFA might either act
just as a Bronsted acid to catalyze the sigmatropic rearrangement of
2 to afford 8a (Path A), or add to the isocyanate to form the corre-
sponding carbamic anhydride 7,23 which, upon the neighboring
group participation of the carbonyl group, cyclizes to give the same
intermediate (Path B). Although Path A sounded more plausible, we
could not fully rule out the possibility of Path B. Although the aro-
maticity of the benzene ring is lost during this process, the newly
formed 2H-1,3-oxazin-2-one is heteroaromatic hence might com-
pensate this loss and make this reaction occur smoothly at room
temperature. This step is the fast step. In the presence of acid,
compound 8a might also exist in its protonated form 8b. This might
account for that no explicit signal of this intermediate could be
Fig. 1a shows the 13C NMR spectrum of 2-benzoylphenyl iso-
cyanate 2 before the addition of TFA, with trace amount of impu-
rities (labeled in ,) in it. Peaks at 195.5 ppm and 125.2 ppm stand
for C(C]O) and C(NCO), respectively. Five min after the addition of
a catalytic amount of TFA, the intensity of these two characteristic
peaks decreased dramatically to the same intensity level as the
impurities, which acted as an ‘internal standard’, as shown in
Fig. 1b. This observation suggested that most of the starting ma-
terial was consumed at the very early stage of the reaction, but the
characteristic peaks of the corresponding diazocine were barely
seen. Instead, a distinct peak at 124.9 ppm and broad bumps in the
aromatic region appeared, which suggested the presence of a new
intermediate. After 1 h, the characteristic peaks of the starting
material were totally gone, as shown in Fig. 1c, while the in-
termediate peaks remained, with the clear appearance of diazocine
peaks (for example, peak at 169.7 ppm for C(C]N)). Further moni-
toring showed that the intensity of the diazocine peaks increased
with prolonged reaction time, while the intensity of the in-
termediate peaks decreased accordingly (see the Supplementary
data for details). After 24 h, the intermediate was fully converted
to diazocine (Fig. 1d). The broad bumps in the 13C NMR spectra also
implied that the intermediate might exist in a very complicated
form. Luckily, we were able to trap this intermediate, by
adding EtOH to the reaction mixture at the early stage, as shown in
Scheme 3, and compound 6 was obtained in 40% yield. The same
product was isolated by Acharya et al., in their attempts to trap the
FriedeleCrafts intermediate of 2-isocyanatobenzoyl chlorides.15
The isolation of the trapped intermediate 6 strongly suggested
a completely different mechanism from the previously reported
one. It was reasonable to postulate that compound 6 was obtained
via the nucleophilic attack of EtOH at an electron-deficient in-
termediate. The intermediate is very possibly 4-phenyl-2H-benzo
observed in the in situ 13C NMR study. The
a,b-unsaturated imine-
like 2H-[1,3]oxazin-2-one ring is sensitive to nucleophilic attack,
and that is the reason that compound 8a could be trapped by EtOH to
give compound 6. Intermediate 8a might form aggregates in the
solution via
pep interaction, very possibly in an anti-parallel
manner to minimize the dipolar moment, which also favors the
dimerization. In the dimerization, the lone-pair on nitrogen attacks
the electron-poor double bond on the 2H-1,3-oxazin-2-one ring.
The restoration of the aromaticity of the benzene ring is also the
driving force for this step. This is the rate-determining step. The
resulting dimer 9 is much less strained than the previously proposed
four-membered intermediate, hence a more plausible intermediate.
It loses two CO2 to afford diazocine 3.
2.4. Scope and limitations of this reaction
With the clarified mechanism and optimized conditions in
hand, we then investigated the scope of this reaction. A series of
dibenzo[b,f][1,5]diazocines with different substituents were syn-
thesized, as shown in Table 2. In all the cases, the reaction in tol-
uene is faster than the reaction in THF. This may be attributed to the
non-polar nature of toluene, which favors the anti-parallel
Fig. 1. 13C NMR spectra evolution of diazocine synthesis in CDCl3: spectra of 2-benzoylphenyl isocyanate (a) before adding TFA; (b) 5 min after adding TFA; (c) 1 h after adding TFA
and (d) 24 h after adding TFA. (b) and (c) was enlarged for a better view. , stands for the impurities in the reaction, B stands for the distinct new peak of the intermediate.

9668
N. Zhao et al. / Tetrahedron 68 (2012) 9665e9671
Scheme 4. Revised mechanism for acid-catalyzed diazocine synthesis.
Table 2
Scope of the reaction
moiety at adjacent positions also afforded the corresponding
diazocines, but harsher conditions are needed. For example,
dithieno[1,5]diazocines were synthesized from the corresponding
precursors, as shown in Scheme 5. Reflux in pure TFA is needed to
drive such reactions, since side reactions (generation of 3-amino-2-
benzoylthiophene together with some corresponding tri-
fluoroacetamide) would be overwhelming if only a catalytic
amount of acid was used. We are not exactly sure why thiophene
ring behaves quite differently from benzene ring. One of the pos-
sible reason is the lower nucleophilicity of nitrogen atom at 3-po-
sition on the thiophene ring, probably due to the electron-
withdrawing effect of the sulfur atom on thiophene ring, which
makes the dimerization of the intermediate more difficult.
Entry
R
Solvent
Time (h)
Yieldc (%)
1
2
3
4
5
6
7
8
Ph
THF/Tol.
THFb/Tol.
THFb/Tol.
THFb/Tol.
THFb/Tol.
THF/Tol.
Tol.
12/2
90/77
92/88
75/77
65/93
82/76
88/76
80
p-BrPh
p-ClPh
m-NO2Ph
p-MePh
p-MeOPh
Thienyl
t-Bu
24/12
24/12
72/12
24/12
24/12
12
THF/Tol.
36/12
85/84
3. Conclusion
a
TFA (0.1 equiv) was used as the catalyst unless otherwise stated.
TFA (0.2 equiv) was used.
Isolated yield calculated using the corresponding azide as the starting material.
b
c
In summary, we revisited the novel synthetic methodology to
prepare diazocines, potential building blocks for conformational
change-governed electrochemical actuators. The reaction condi-
tions were further optimized and we found the reaction could oc-
cur at room temperature using a catalytic amount of acid. More
importantly, we revised the previously proposed mechanism. The
diazocine is not formed via an intermolecular [2þ2] cyclization
between a ketone and an isocyanate moiety, but by a neighboring
ketone group participated rearrangement of the isocyanate, fol-
lowed by an unprecedented dimerization. The new mechanism is
strongly supported by experimental evidences.
aggregation of the intermediate. The substituent on the ketone
moiety was not limited to phenyl rings bearing electron-donating
or electron-withdrawing groups, heterocyclic substituent, such as
thiophene ring also gave a high yield of the diazocine (Table 2, entry
7). Even the sterically hindered tert-butyl substituted diazocine was
obtained in high yield (Table 2, entry 8).
This methodology is not limited to the synthesis of dibenzo[b,f]
[1,5]diazocines. Heterocycles bearing a ketone and an isocyanate
Ph
O
O
N
O
Et3N
O
O
ClCO2Et
0oC
AlCl3
rt
NaN3
0oC
TFA
80 °C
S
S
O
+
S
S
OH
N
N3
O
S
S
Ph
Ph
40%
10 a
11 a
12 a
Ph
OH
Et3N
1)LDA, PhCHO,
THF, 0oC~rt
2)KMnO4, H2O,
60oC
N
O
O
S
ClCO2Et
NaN3
0oC
TFA
80 °C
O
O
O
0oC
S
S
S
N
N3
OH
38%
10 b
11 b
12 b
Scheme 5. Synthesis of dithieno[1,5]diazocine.

N. Zhao et al. / Tetrahedron 68 (2012) 9665e9671
9669
4. Experimental section
4.1. General methods
obtained as yellow oil-like solid. IR (KBr, cmꢂ1): 3063, 2385, 2259,
1656, 1598, 1579, 1511, 1448, 1427, 1317, 1294, 1265, 1153, 1087,
1001, 928, 806, 763, 748, 696, 638, 566; 1H NMR (600 MHz, CDCl3)
d
7.22 (d, J¼8.4 Hz, 1H), 7.29 (t, J¼7.8 Hz, 1H), 7.48 (d, J¼7.8 Hz, 1H),
7.50 (t, J¼7.8 Hz, 3H), 7.63 (t, J¼7.2 Hz, 1H), 7.83 (d, J¼7.2 Hz, 2H);
13C NMR (150 MHz, CDCl3)
125.1, 125.2, 126.4, 128.6, 130.2, 130.9,
All glassware was thoroughly oven-dried before use. Chemicals
and solvents were either purchased from commercial suppliers or
purified by standards techniques. Thin-layer chromatography
plates were visualized by exposure to ultraviolet light and/or im-
mersion in a staining solution (phosphomolybdic acid) followed by
heating on a hot plate. Flash chromatography was carried out uti-
d
132.3, 132.4, 132.5, 133.5, 137.0, 195.8.
4.3.2. 6,12-Bisphenyldibenzo[b,f][1,5]diazocine (3). Compound 3
was synthesized by the one-step manner in THF. Yield: 90%.
Yellow solid. Mp: 226e227 ꢀC. IR (KBr, cmꢂ1): 3063, 3023, 1622,
1592, 1574, 1477, 1448, 1318, 1304, 1222, 1213, 1148, 1096, 961, 909,
lizing silica gel 200e300 mesh. Chemical shifts are given in
d rela-
tive to tetramethylsilane (TMS), the coupling constants J are given
in hertz. The spectra were recorded in CDCl3 as the solvent at room
835, 777, 671, 649, 605, 574, 522; 1H NMR (600 MHz, CDCl3)
d
7.00
(m, 6H), 7.31 (m, 6H), 7.40 (t, J¼7.8 Hz, 2H), 7.76 (d, J¼8.4 Hz, 4H);
13C NMR (150 MHz, CDCl3)
120.9, 123.4, 126.9, 127.5, 128.2,
temperature. TMS served as the internal standard (
d
¼0 ppm) for 1H
NMR and CDCl3 was used as the internal standard (
d
¼77.00 ppm)
d
for 13C NMR.
129.4, 129.6, 131.0, 137.9, 151.8, 169.5. HRMS (EI): calcd for
[C26H18N2]: 358.1470, found: 358.1469.
4.2. General methods for the synthesis of diazocines
4.3.3. 6,12-Bis(4-bromophenyl)dibenzo[b,f][1,5]diazocine (Table 2,
entry 2). This compound was synthesized by the one-step man-
ner in THF. Yield: 92%. Yellow solid. Mp 236e237 ꢀC. IR (KBr,
cmꢂ1): 3059, 3018, 1618, 1583, 1560, 1475, 1395, 1308, 1069, 1009,
Diazocines were synthesized from the corresponding benzoyl
azide either in a two-steps manner or in a one-step manner. In the
two-steps manner, the benzoyl azide was heated in a toluene under
N2 protection to generate the corresponding isocyanate. Toluene
was then removed and resulting crude product was characterized
and then dissolved a suitable solvent. Catalytic amount of acid was
added to facilitate the cyclization. In the one-step manner, benzoyl
azide was heated in a suitable solvent to generate the corre-
sponding isocyanate. The reaction mixture was then cooled to room
temperature and catalytic amount of acid was added to facilitate
the cyclization.
959, 907, 841, 769, 728, 656, 471; 1H NMR (600 MHz, CDCl3)
d 6.93
(d, J¼7.8 Hz, 2H), 7.02 (t, J¼7.8 Hz, 4H), 7.32 (t, J¼7.8 Hz, 2H), 7.47
(d, J¼8.4 Hz, 4H), 7.61 (d, J¼8.4 Hz, 4H); 13C NMR (150 MHz, CDCl3)
d
120.9, 123.6, 126.0, 126.2, 127.3, 129.9, 130.9, 131.4, 136.8, 151.7,
168.6. HRMS (EI): calcd for [C26H16Br2N2]: 515.9660, found:
515.9653.
4.3.4. 6,12-Bis(4-chlorophenyl)dibenzo[b,f][1,5]diazocine (Table 2,
entry 3). This compound was synthesized by the one-step man-
ner in THF. Yield: 75%. Yellow solid. Mp 217e218 ꢀC. IR (KBr, cmꢂ1):
3064, 3018, 1618, 1587, 1566, 1476, 1400, 1308, 1090, 1013, 960,
4.2.1. Example for one-step synthesis. 2-Benzoylbenzoyl azide
(1.26 g, 5.0 mmol) was dissolved in 5 mL of anhydrous THF and
refluxed for 4 h to afford (2-isocyanatophenyl)(phenyl)methanone
without further purification. After cooling down to room temper-
907, 842, 759, 731, 659, 531; 1H NMR (600 MHz, CDCl3)
d
6.94 (d,
J¼7.8 Hz, 2H), 7.03 (t, J¼7.8 Hz, 4H), 7.32 (m, 6H), 7.69 (d, J¼8.4 Hz,
4H); 13C NMR (150 MHz, CDCl3)
120.9, 123.6, 126.3, 127.4, 128.4,
ature, anhydrous TFA (37.0
mL, 0.5 mmol) was added into the so-
d
lution and stirred for 12 h. The reaction mixture was then
neutralized with saturated Na2CO3 solution and extracted with
dichloromethane (DCM) (3ꢁ20 mL). The combined organic layer
was dried over anhydrous MgSO4. The solvent was evaporated and
the residue was purified by column chromatography on silica gel,
using a 3:2 mixture of petroleum ether/dichloromethane as the
eluent to give the corresponding product 6,12-diphenyldibenzo[b,f]
[1,5]diazocine (3) (0.82 g, 2.3 mmol, 90% yield).
129.9, 130.7, 136.3, 137.4, 151.7, 168.5. HRMS (EI): calcd for
[C26H16Cl2N2]: 428.0661, found: 428.0640.
4.3.5. 6,12-Bis(3-nitrophenyl)dibenzo[b,f][1,5]diazocine (Table 2, en-
try 4). This compound was synthesized by the one-step manner
in THF. Yield: 65%. Yellow solid. Mp 190 ꢀC. IR (KBr, cmꢂ1): 3082,
1625, 1611, 1530, 1478, 1400, 1349, 1313, 1088, 988, 909, 831, 773,
733, 695, 679; 1H NMR (600 MHz, CDCl3)
d 6.99 (m, 2H), 7.10 (m,
4H), 7.40 (m, 2H), 7.53 (t, J¼7.8 Hz, 2H), 8.02 (d, J¼8.4 Hz, 2H),
4.2.2. Example for two-steps synthesis. 2-Benzoylbenzoyl azide
(1.26 g, 5.0 mmol) was dissolved in 5 mL of anhydrous toluene and
refluxed for 4 h. After removing the solvent, the yellow oil-like solid
8.27 (m, 2H), 8.69 (t, J¼1.8 Hz, 2H); 13C NMR (150 MHz, CDCl3)
d
121.2, 123.9, 124.4, 125.2, 127.2, 125.6, 129.4, 130.5, 135.1, 139.4,
148.4, 151.1, 167.4. HRMS (EI): calcd for [C26H16N4O4]: 448.1172,
found: 448.1174.
was dissolved in 5 mL of chloroform. Anhydrous TFA (37.0 mL,
0.5 mmol) was added into the solution and stirred for 12 h. The
reaction mixture was then neutralized with saturated Na2CO3 so-
lution and extracted with dichloromethane (DCM) (3ꢁ20 mL). The
combined organic layer was dried over anhydrous MgSO4. The
solvent was evaporated and the residue was purified by column
chromatography on silica gel, using a 3:2 mixture of petroleum
ether/dichloromethane as the eluent to give the corresponding
product 6,12-diphenyldibenzo[b,f][1,5]diazocine (3) (0.67 g,
1.8 mmol, 75% yield).
4.3.6. 6,12-Bis(4-methylphenyl)dibenzo[b,f][1,5]diazocine (Table 2,
entry 5). This compound was synthesized by the one-step
manner in THF. Yield: 82%. Yellow solid. Mp 190e191 ꢀC. IR
(KBr, cmꢂ1): 3059, 3024, 2913, 1622, 1604, 1589, 1567, 1477,
1314, 960, 840, 827, 769, 728, 667; 1H NMR (600 MHz, CDCl3)
d
2.36 (s, 6H), 7.00 (m, 6H), 7.15 (d, J¼8.4 Hz, 4H), 7.31 (t,
J¼7.8 Hz, 2H), 7.66 (d, J¼8.4 Hz, 4H); 13C NMR (150 MHz, CDCl3)
d
21.4, 120.9, 123.1, 127.2, 127.5, 128.9, 129.4, 129.5, 131.4, 135.4,
152.0, 169.4. HRMS (EI): calcd for [C28H22N2]: 386.1783, found:
386.1778.
4.3. Preparation and characterization of the involved
compounds
4.3.7. 6,12-Bis(4-methoxyphenyl)dibenzo[b,f][1,5]diazocine (Table 2,
entry 6). This compound was synthesized by the one-step manner
in THF. Yield: 88%. Yellow solid. Mp 204e205 ꢀC. IR (KBr, cmꢂ1):
3062, 3009, 2958, 2930, 2835, 1618, 1597, 1570, 1510, 1476, 1310,
1254, 1174, 1147, 1032, 961, 909, 843, 769, 733, 618, 596, 555; 1H
4.3.1. (2-Isocyanatophenyl)(phenyl)methanone (2). 2-Benzoylben
zoyl azide (1.26 g, 5.0 mmol) was dissolved in 5 mL of anhydrous
toluene and refluxed for 4 h. After removing the solvent, almost
quantitative
(2-isocyanatophenyl)(phenyl)methanone
was

9670
N. Zhao et al. / Tetrahedron 68 (2012) 9665e9671
NMR (600 MHz, CDCl3)
d
3.80 (s, 6H), 6.84 (d, J¼9 Hz, 4H), 6.98 (m,
CH2Cl2 (3ꢁ30 mL). The organic layers were combined, washed with
brine, and dried over anhydrous MgSO4. The solvent was evapo-
rated at reduced pressure and the resulting mixture was directly
purified by column chromatography on silica gel, using a 5:1 mix-
ture of petroleum ether/ethyl acetate as the eluent to give 4-
benzoylthiophene-3-carbonyl azide (0.8 g, 3.1 mmol, 80% yield).
IR (KBr, cmꢂ1): 3103, 3059, 2261, 2163, 2136, 1686, 1596, 1578, 1449,
1437, 1386, 1312, 1262, 1216, 1175, 1025, 976, 897, 832, 791, 774, 702,
6H), 7.28 (m, 2H), 7.71 (d, J¼9 Hz, 4H); 13C NMR (150 MHz, CDCl3)
d
55.4, 113.5, 121.0, 123.0, 127.2, 127.5, 129.4, 130.7, 131.1, 152.1, 162.0,
168.8. HRMS (EI): calcd for [C28H22N2O2]: 418.1681, found:
418.1680.
4.3.8. 6,12-Bis(thiophen-2-yl)dibenzo[b,f][1,5]diazocine (Table 2, en-
try 7). This compound was synthesized by the one-step manner in
toluene. Yield: 80%. Yellow solid. Mp 213e214 ꢀC. IR (KBr, cmꢂ1):
3068, 2970, 1738, 1713, 1604, 1477, 1422, 1356, 1309, 1206, 1048,
636, 563; 1H NMR (600 MHz, CDCl3)
d
7.47 (d, J¼7.2 Hz, 2H), 7.53 (d,
J¼3 Hz, 1H), 7.59 (t, J¼7.2 Hz, 1H), 7.8 (d, J¼7.2 Hz, 2H), 8.21 (d,
923, 894, 846, 770, 713; 1H NMR (600 MHz, CDCl3)
d
6.99 (t,
J¼3 Hz, 1H); 13C NMR (150 MHz, CDCl3)
d 128.6, 128.8, 129.5, 133.6,
J¼3.6 Hz, 2H), 7.04 (m, 6H), 7.28 (d, J¼7.8 Hz, 2H), 7.32 (t, J¼7.8 Hz,
135.4, 137.2, 141.4, 166.7, 191.7.
2H), 7.48 (d, J¼5.1 Hz, 2H); 13C NMR (150 MHz, CDCl3)
d 121.8,123.5,
126.2, 127.6, 127.8, 129.9, 131.1, 133.1, 144.7,150.6,163.9. HRMS (ESI):
4.3.13. 5,10-Diphenyldithieno[3,4-b:30,40-f][1,5]diazocine (12a). This
compound was synthesized by heating the corresponding pre-
cursor in TFA at 80 ꢀC for 12 h. Yield: 40%. Yellow solid. Mp
85e86 ꢀC. IR (KBr, cmꢂ1): 3099, 3062, 2242, 2220, 1723, 1615, 1594,
1577, 1525, 1488, 1428, 1365, 1270, 1185, 1144, 1071, 1027, 948, 908,
calcd for [C22H14N2S2þH]þ: 371.0677, found: 371.0682.
4.3.9. 6,12-Bis-tert-butyldibenzo[b,f][1,5]diazocine (Table 2, entry
8). This compound was synthesized using the one-step manner.
Yield: 85%. Yellow solid. Mp 130e131 ꢀC. IR (KBr, cmꢂ1): 3063, 2967,
2928, 2868, 1631, 1594, 1474, 1444, 1391, 1362, 1278, 1237, 1198,
1156, 1114, 1030, 991, 937, 840, 810, 765, 753, 731, 698, 676, 598,
861, 766, 699, 641, 592, 446; 1H NMR (600 MHz, CDCl3)
d 6.83 (d,
J¼3.6 Hz, 2H), 7.06 (d, J¼3.6 Hz, 2H), 7.39 (t, J¼7.2 Hz, 4H), 7.47 (t,
J¼7.2 Hz, 2H), 7.87 (d, J¼7.2 Hz, 4H); 13C NMR (150 MHz, CDCl3)
523, 486; 1H NMR (600 MHz, CDCl3)
d
1.29 (s, 18H), 6.78 (d,
d 116.9, 125.0, 128.7, 129.3, 130.7, 131.3, 138.4, 149.9, 166.9.
J¼7.2 Hz, 2H), 6.87 (t, J¼7.2 Hz, 2H), 6.90 (d, J¼7.2 Hz, 2H), 7.12 (t,
J¼7.2 Hz, 2H); 13C NMR (150 MHz, CDCl3)
d
28.5, 40.5, 119.4, 122.4,
4.3.14. 2-Benzoylthiophene-3-carboxylic acid (10b). To a solution of
125.3, 127.5, 128.4, 151.1, 181.0.
thiophene-3-carboxylic acid (5.0 g, 39 mmol) in THF (200 mL) at
0
ꢀC, was added dropwise 50 mL of THF solution containing
4.3.10. 4-Ethoxy-4-phenyl-1H-benzo[d][1,3]oxazin-2(4H)-one
(6). 2-Benzoylbenzoyl azide (1.26 g, 5.0 mmol) was dissolved in
5 mL of anhydrous toluene and refluxed for 4 h. After removing the
solvent, the yellow oil-like solid was dissolved in 5 mL of chloro-
86 mmol fresh-prepared LDA. Benzaldehyde (4.4 mL, 43 mmol)
was then added to the mixture, and the mixture was warmed up to
room temperature and stirred for 2 h. The reaction was quenched
by the addition of ice-water (100 mL), and the mixture was con-
centrated under reduced pressure and washed with AcOEt
(2ꢁ30 mL). To the residual aqueous layer, was added KMnO4 (12 g,
78 mmol) in portions, and the mixture was stirred for 2 h at 60 ꢀC. It
was then filtrated and washed with hot water, and the resulting
filtrate was acidified to pH¼3 using 3 M aqueous HCl, and extracted
with dichloromethane (3ꢁ100 mL). The organic layers were com-
bined, washed with brine, and dried over anhydrous MgSO4. The
solvent was evaporated at reduced pressure to give 2-
benzoylthiophene-3-carboxylic acid (8.2 g crude), which was
used directly in next step without purification.
form. Anhydrous TFA (37.0 mL, 0.5 mmol) was added into the solu-
tion and stirred for 45 min. Then 5 mL of anhydrous ethanol was
added into the mixture to quench the reaction. The solvent was
evaporated and the residue was purified by column chromatogra-
phy on silica gel, using dichloromethane and a 1:1 mixture of ethyl
acetate/dichloromethane successively as the eluent to afford 6 as
a yellow solid (0.57 g, 2.1 mmol, 42% yield). Yellow solid. Mp
156e157 ꢀC. IR (KBr, cmꢂ1): 3249, 2980, 2927, 1713, 1603, 1497,
1449, 1353, 1276, 1254, 1207, 1132, 1094, 1072, 1001, 971, 913, 749,
699, 653, 458; 1H NMR (600 MHz, CDCl3)
d
1.27 (t, J¼6.6 Hz, 3H),
3.70 (m, 2H), 6.95 (d, J¼7.8 Hz, 1H), 7.04 (m, 2H), 7.30 (t, J¼7.8 Hz,
1H), 7.40 (m, 3H), 7.53 (d, J¼6.6 Hz, 2H), 9.27 (s, 1H); 13C NMR
4.3.15. 2-Benzoylthiophene-3-carbonyl azide (11b). To a 50 mL of
THF solution containing crude 2-benzoylthiophene-3-carboxylic
acid (2.3 g, 10 mmol) at 0 ꢀC, was dropwise added triethyl-
amine (1.6 mL, 11 mmol), followed by the dropwise addition of
ethyl chloroformate (1.1 mL, 11 mmol). After 2 h, a solution of
sodium azide (0.72 g, 11 mmol) in water (30.0 mL) was added
dropwise, and the mixture was stirred for 1 h. THF was then
removed by evaporation, and the remaining aqueous phase was
extracted with CH2Cl2 (3ꢁ30 mL). The organic layers were
combined, washed with brine, and dried over anhydrous MgSO4.
The solvent was evaporated at reduced pressure and the
resulting mixture was directly purified by column chromatog-
raphy on silica gel, using a 5:1 mixture of petroleum ether/ethyl
acetate as the eluent to give 2-benzoylthiophene-3-carbonyl
azide (1.7 g, 6.6 mmol, 66% yield). IR (KBr, cmꢂ1): 3110, 2340,
2245, 2143, 1685, 1580, 1519, 1449, 1382, 1369, 1265, 1234, 1176,
1137, 1070, 1040, 899, 845, 802, 710, 689, 658, 561; 1H NMR
(150 MHz, CDCl3)
d 15.2, 60.4, 107.3, 114.7, 121.1, 123.5, 126.6, 126.7,
128.4, 129.1, 130.2, 134.8, 139.0, 152.0. MS (EI): calcd for
[C16H15NO3þH]þ: 270.1125, found: 270.1123.
4.3.11. 4-Benzoylthiophene-3-carboxylic acid (10a). A mixture of
thieno[3,4-c]furan-1,3-dione24 (1.0 g, 6.4 mmol), benzene (10.0 mL,
110 mmol), and anhydrous AlCl3 (1.7 g, 12.8 mmol) was stirred at
room temperature for 5 h. The reaction mixture was then quenched
with 100 mL of saturated Na2CO3 solution and extracted with
CH2Cl2 (3ꢁ100 mL). The water layer was separated, acidified to
pH¼1 by 3 M HCl solution, and extracted with CH2Cl2 (3ꢁ100 mL).
The organic layers were combined, dried over anhydrous MgSO4,
and filtered to remove the solids thereafter. The filtrate was evap-
orated at reduced pressure to afford the corresponding product in
70% yield.
4.3.12. 4-Benzoylthiophene-3-carbonyl azide (11a). To a 10 mL of
THF solution containing 4-benzoylthiophene-3-carboxylic acid
(0.9 g, 3.9 mmol) at 0 ꢀC, was added dropwise triethylamine
(0.6 mL, 4.3 mmol), followed by the dropwise addition of ethyl
chloroformate (0.4 mL, 4.3 mmol). After 30 min, a solution of so-
dium azide (0.28 g, 4.3 mmol) in water (7 mL) was added dropwise,
and the mixture was stirred for 30 min. THF was then removed by
evaporation, and the remaining aqueous phase was extracted with
(600 MHz, CDCl3)
d
7.51 (m, 4H), 7.63 (t, J¼7.2 Hz, 1H), 7.85 (d,
J¼7.2 Hz, 2H); 13C NMR (150 MHz, CDCl3)
d 127.6, 128.4, 128.8,
129.5, 133.5, 133.9, 137.2, 147.4, 167.3, 189.6.
4.3.16. 5,10-Diphenyldithieno[3,2-b:30,20-f][1,5]diazocine (12b). This
compound was synthesized by heating the corresponding pre-
cursor in TFA at 80 ꢀC for 12 h. Yield: 38%. Yellow solid. Mp
160e161 ꢀC. IR (KBr, cmꢂ1): 3063, 2917, 2227, 1724, 1606, 1593,

N. Zhao et al. / Tetrahedron 68 (2012) 9665e9671
9671
1523, 1488, 1447, 1361, 1278, 1200, 1176, 1027, 998, 933, 909, 834,
756, 690, 659, 606, 455; 1H NMR (600 MHz, CDCl3)
6.88 (d,
(150 MHz, CDCl3)
172.0, 214.2.
d
27.3, 45.0, 125.7, 127.6, 128.6, 130.3, 133.9, 144.2,
d
J¼7.2 Hz, 2H), 7.4 (t, J¼7.2 Hz, 4H), 7.49 (d, J¼4.8 Hz, 2H), 7.48 (d,
J¼7.2 Hz, 2H), 7.84 (d, J¼4.8 Hz, 4H); 13C NMR (150 MHz, CDCl3)
4.4. Real-time 13C NMR analysis of the reaction
d
119.3, 124.4, 128.1, 128.3, 129.7, 131.4, 138.8, 153.8, 165.6.
Preparation of the precursor toward tert-butyl substituted
diazocine was shown in Scheme 6.
(2-Isocyanatophenyl)(phenyl) methanone 2 (50 mg) was dis-
solved in 0.5 mL of CDCl3 in an NMR tube and characterized by 13
C
NMR. Then 0.1 equiv TFA was added into the tube and mixed well.
The 13C NMR spectra of the mixture were collected every 5 min for
the first hour and every 10 min for the next hour. The 13C NMR
spectra of the mixture at 8 h and 24 h after adding TFA were also
collected.
O
O
OH
O
O
THF
0oC
MgCl
O
+
O
13
Acknowledgements
N3
O
Cl
Et3N
ClCO2Et
O
O
NaN3
ice-salt bath
We appreciate the financial support from NSFC (21174157) and
‘100 Talents’ program from Chinese Academy of Sciences and
Shandong Natural Sciences Foundation (Y2008B03 and
BS2009CL026). We also thank Ms. Ying Yang and Dr. Shaohua
Huang for NMR technique supports.
ice-salt bath
14
Scheme 6. Preparation of the precursor toward tert-butyl substituted diazocine.
Supplementary data
4.3.17. 2-Pivaloylbenzoic acid (13). To a 20.0 mL of anhydrous THF
solution containing phthalic anhydride (3.0 g, 20 mmol) at 0 ꢀC,
was added dropwise the fresh-prepared tert-butylmagnesium
chloride/THF (40 mmol) solution. The mixture was then gradually
warmed up to room temperature and stirred overnight. Then
5.0 mL of saturated NH4Cl solution was added slowly into the
mixture at 0 ꢀC and the pH value of the mixture was adjusted to two
using 1 M HCl solution. After extraction with Et2O and removal of
the solvent, 3.7 g of yellow solid was obtained without further
purification.
Supplementary data related to this article is available online at
http://dx.doi.org/10.1016/j.tet.2012.09.050.
References and notes
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containing crude 2-pivaloylbenzoic acid (2.1 g, 10 mmol) immersed
in an ice-salt bath, was added dropwise triethylamine (1.6 mL,
11 mmol), followed by the dropwise addition of ethyl chlor-
oformate (1.1 mL, 11 mmol). After 30 min, a solution of sodium
azide (0.72 g, 11 mmol) in water (30.0 mL) was added dropwise,
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ꢀ
NMR (600 MHz, CDCl3)
d
1.28 (s, 9H), 7.24 (d, J¼7.2 Hz, 1H), 7.47 (t,
J¼7.8 Hz, 1H), 7.64 (t, J¼7.8 Hz, 1H), 7.99 (d, J¼8.4 Hz, 1H); 13C NMR