3-(Triflyloxy)benzynes Enable the Regiocontrolled Cycloaddition of Cyclic Ureas to Synthesize 1,4-Benzodiazepine Derivatives

Article abstract of DOI:10.1055/s-0036-1591924

A versatile synthesis of 1,4-benzodiazepine derivatives through the reaction of various 3-(trifluoromethanesulfonyloxy)benzynes with N -(p -toluenesulfonyl)imidazolidin-2-ones is reported. This reaction system provides a 1,4-benzodiazepine bearing a trifluoromethanesulfonyloxy group as a single regioisomer among the four possible regioisomers.

Full text of DOI:10.1055/s-0036-1591924

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–F
letter
A
en
H. Kaneko et al.
Letter
Synlett
3-(Triflyloxy)benzynes Enable the Regiocontrolled Cycloaddition
of Cyclic Ureas to Synthesize 1,4-Benzodiazepine Derivatives
activation
a variety of imidazolidinones
Hideki Kanekoa
Takashi Ikawa*a
Yuta Yamamotob
Sundaram Arulmozhirajab
Hiroaki Tokiwab
O
TfO
EWG
TfO
EWG
O
N
0
0
0
0
0-
0
0
2
1-
6
4
2
3-
2
7
3
R2
N
Matched
R2
+
N
N
R1
control of
R1
nucleophilic site
regioselective formation
of various derivatives
Shuji Akai*a
R1 = H or OMe
12 examples, 24–77% isolated yield
a Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka,
Suita, Osaka 565-0871, Japan
b Department of Chemistry, Research Center for Smart Molecules, Rikkyo University,
3-34-1 Nishi-Ikebukuro, Toshimaku, Tokyo 171-8501, Japan
ikawa@phs.osaka-u.ac.jp
akai@phs.osaka-u.ac.jp
Received: 06.12.2017
Accepted after revision: 09.01.2018
Published online: 09.02.2018
controlled cycloaddition reaction of 3-(triflyloxy)benzynes
3a or 3b with a range of imidazolidin-2-one derivatives 2
(Scheme 1).
DOI: 10.1055/s-0036-1591924; Art ID: st-2017-u0880-l
Yoshida and co-workers reported a synthesis of 1,4-
benzodiazepines 4a through the cycloaddition reaction of
Abstract A versatile synthesis of 1,4-benzodiazepine derivatives
through the reaction of various 3-(trifluoromethanesulfonyloxy)benzynes
with N-(p-toluenesulfonyl)imidazolidin-2-ones is reported. This reaction
system provides a 1,4-benzodiazepine bearing a trifluoromethanesulfo-
nyloxy group as a single regioisomer among the four possible regioiso-
mers.
benzynes
3 with 1,3-dimethylimidazolidin-2-one (2a;
Scheme 1);9a however, examples were limited to the sym-
metrical imidazolidin-2-one 2a for the preparation of
benzodiazepine 4a, where 2a (23 equiv) also acted as the
reaction solvent. The application of nonsymmetrical imid-
azolidin-2-ones in similar reactions with benzyne remains
largely unexamined. To address this problem, we report the
use of a range of imidazolidin-2-ones 2, each bearing an
electron-withdrawing tosyl group on one of the two nitro-
gen atoms, to achieve regioselective addition to benzynes
through differentiation of the nucleophilicities of the two
nitrogen atoms. Our method is expected to be effective due
to the presence of the strongly electron-withdrawing tri-
flyloxy group at the C-3 position of the benzynes 3a and 3b,
which should render the C-1 position more electrophilic,
thereby permitting control of the reactive site, and promot-
ing nucleophilic addition of the less-reactive N-tosylimid-
azolidin-2-ones 2 to give 4.
Keywords benzodiazepines, benzynes, triflyloxy group, imidazolidi-
nones, regioselectivity, directing group
Benzynes are key reaction intermediates for the synthe-
sis of polysubstituted benzenes and fused aromatic com-
pounds.1,2 However, regiocontrol of the reactions of unsym-
metrically substituted benzynes to afford desired products
with high regioselectivity is particularly challenging. Con-
sequently, several benzyne substituents have thus been de-
veloped to direct the orientation of such reactions, with the
majority of these substituents being introduced at the C-3
position of the benzyne skeleton.3–5 For example, Hosoya
and co-workers6a and our group6b have reported the intro-
duction of a trifluoromethanesulfonyloxy (triflyloxy) group
to impart regioselective control on these cycloaddition
reactions. The effect of this group was superior to that of
the methoxy group, due to the greater electron-withdraw-
ing nature of the triflyloxy group.6b Moreover, the triflyloxy
directing group can be easily converted into a range of
other substituents through palladium-catalyzed coupling
reactions of the benzyne reaction products. Here, we pro-
vide tangible evidence for the efficiency of the triflyloxy
group in a highly versatile synthesis of 1,4-benzodiazepines
4, which are important scaffolds for drug discovery.7–9 We
propose that this conversion takes place through a regio-
Initially, we examined the influence of the R1 substitu-
ent at the C-3 position of benzynes 3, generated from the
corresponding 2-(trimethylsilyl)phenyl triflates 1c–f by
reaction with CsF in 1,4-dioxane at 80 °C. The resulting
benzynes
3 reacted with 1-methyl-3-(p-toluenesulfo-
nyl)imidazolidin-2-one (2b; R3 = Ts), and the results are
outlined in Table 1 (entries 1–4). The reactions of the un-
substituted benzyne 3c (R1 = H) and the 3-methoxybenzyne
3d (R1 = OMe) with 2b did not produce the desired 1,4-ben-
zodiazepines 4b and 4c (Table 1, entries 1 and 2), probably
due to the insufficient electrophilicities of 3c and 3d.
Whereas the reaction of the more electrophilic 3-fluoroben-
zyne 3e (R1 = F) with 2b provided 6-fluoro-1,4-benzo-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

B
H. Kaneko et al.
Letter
Synlett
a variety of
imidazolidinones
This work
O
EWG
activation
TfO
N
N
O
TfO
OTf
EWG
EWG
R3
3
SiMe2tBu
O
N
2
N
2
R3
R3
N
CsF
OTf
R2
1
N
1,4-dioxane
80 °C
R2
R2
control of
nucleophilic site
1a (R2 = H)
1b (R2 = OMe)
3a (R2 = H)
3b (R2 = OMe)
2
4
regioselective formation
of various derivatives
specific symmetric
imidazolidinone
Previous work
O
fixed region
MeN NMe
O
Me
N
O
SiMe3
OTf
NMe
2a (solvent)
N
CsF
Me
N
R1
R1
R1
20 °C
Me
2a
3
1
4a
Scheme 1 Comparison of the previous and current work on the reaction of benzynes 3 with imidazolidin-2-ones 2
diazepine 4d in 34% isolated yield (entry 3), the reaction
with 3-(triflyloxy)benzyne 3a (R1 = OTf), generated from
1f,6c gave 6-(triflyloxy)-1,4-benzodiazepine 4e in a signifi-
cantly higher yield (65%), along with a small amount of the
phenol derivative 4e′ (4%, R1 = OH) (entry 4). However, a
slightly better yield (69%) of 4e was obtained by using 2-
(tert-butyldimethylsilyl)phenyl triflate 1a6b (R2 = t-Bu) as a
precursor for 3a (entry 5). Importantly, the regioselectivity
of this transformation was successfully controlled by the
presence of a triflyloxy group in 3a and a tosyl group in 2b
to produce 4e as a single regioisomer.
The reactions of imidazolidin-2-ones bearing benzyl and al-
lyl groups instead of methyl groups on their nitrogen atoms
(2g and 2h) gave the corresponding benzodiazepines 4k
and 4l (Table 2, entries 1 and 2), albeit in slightly lower
yields (43 and 30%, respectively) than that of 4e (Table 1,
Table 1 Optimization of the R1 and R3 Substituents of Benzyne 3 and
Imidazolidin-2-one 2a
R1
O
R3
R1
R1
3
O
N
SiMe2R2
CsF
2
1
Me
R3
N
N
+
2
+
1,4-dioxane
80 °C
Note that a similar reaction of 3a with 1,3-dimethyl-
imidazolidin-2-one (2a; R3 = Me), which should be more
nucleophilic than 2b, produced a lower yield (48%) of the
desired product 4f (Table 1, entry 6) compared with that of
4e. These contrasting results also indicate the importance
of a suitable combination of the less nucleophilic tosyl-
containing urea 2b and the highly electrophilic 3-(triflyl-
oxy)benzyne 3a (R1 = OTf) to achieve efficient coupling of
these two components. In addition, a similar reaction of 1-
benzyl-3-methylimidazolidin-2-one (2c; R3 = Bn) with 3a
gave a mixture of two regioisomers 4g (43%) and 4g′ (11%)
(entry 7). This result clearly indicates that the steric differ-
ences between the methyl and benzyl groups of 2c have no
significant effect in determining the nucleophilic site of the
urea reagent. Furthermore, the reactions of benzyne 3a
(R1 = OTf) with imidazolidin-2-ones 2d–f bearing other
N
OTf
Me
1
2
3
4
Entry R1
R2
1
R3
2
3
4
Yieldb (%)
1
2
H
Me
1c
Ts
2b
2b
2b
2b
2b
2a
2c
2d
2e
2f
3c
3d
3e
3a
3a
3a
3a
3a
3a
3a
4b
4c
4d
4e
4e
4f
0c
OMe
F
Me
1d
1e
1f
Ts
0c
3
Me
Ts
34
4
OTf
OTf
OTf
OTf
OTf
OTf
OTf
Me
Ts
65 (4)d
69e
48
5
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
1a
1a
1a
1a
1a
1a
Ts
6
Me
Bn
Ms
Ac
Cbz
7f
8
4g
4h
4i
43 (11)g
43
9
42
10
4j
23
electron-withdrawing substituents, such as mesyl (R3
=
a Reaction conditions: 1 (1.0 equiv), 2 (3.0 equiv), CsF (3.0 equiv),
1,4-dioxane, 80 °C, 40–60 min.
Ms), acetyl (R3 = Ac), or carbobenzyloxy (R3 = Cbz) groups
gave lower yields (23–43%) of the corresponding products
4h–j (entries 8–10).
b Isolated yield.
c No benzodiazepines were observed.
d In addition to 4e, the hydrolyzed benzodiazepine 4e′ (R1 = OH) was also
isolated in 4% yield.
After the successful reaction of 3-(triflyloxy)benzyne
(3a) with 1-tosyl-1,3-imidazolidin-2-one (2b), we examined
the scope and limitations of a range of 1-tosylimidazolidin-
2-ones 2g–j in the reaction with 3-(triflyloxy)benzyne (3a).
e The hydrolyzed benzodiazepine 4e′ (R1 = OH) was not observed.
f Reaction at r.t. for 3 h.
g In addition to 4g, 1-benzyl-4-methyl-6-(triflyloxy)-1,4-benzodiazepine
(4g′) was also isolated in 11% yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

C
H. Kaneko et al.
Letter
Synlett
entry 5). This is probably due to steric hindrance; however,
these protecting groups can be easily cleaved when re-
quired. We then examined the reactions of 2i and 2j bear-
ing alkyl substituents (methyl or isopropyl) at the C-5 posi-
tion. In this case, the desired products 4m and 4n were ob-
tained in 44 and 24% isolated yields, respectively.
Furthermore, the chiral integrity of the optically active (R)-
2i (89% ee) was maintained during the cycloaddition reac-
tion to produce (R)-4m (89% ee) (entry 3). Unfortunately, a
similar reaction of 3a with the six-membered urea, 1-tosyl-
tetrahydropyrimidin-2-one, did not provide the desired
1,4-benzodiazocine.
benzodiazepines 4e and 4k–n from the corresponding
monocyclic substrates 2b and 2g–j (Tables 1 and 2). This
improvement can be accounted for by firstly considering
Table 3 Synthesis of Pyrrolo-1,4-benzodiazepines 4 by Using Fused
Cyclic Ureas 2: Scope and Limitationsa
O
O
TfO
TfO
Ts
N
SiMe2tBu
CsF
Ts
N
N
R
+
1,4-dioxane
80 °C
N
OTf
R
1a
2
4
Entry
Fused cyclic urea 2
Product 4
Yieldb (%)
Table 2 Synthesis of 1,4-Benzodiazepines 4 with Various Monocyclic
Ureas 2: Scope and Limitationsa
O
TfO
Ts
O
N
Ts
O
N
N
TfO
O
TfO
Ts
H
1
70
R1
Ts
SiMe2tBu
N
CsF
N
N
N
H
R2
+
1,4-dioxane
80 °C
(R)-2k (88% ee)
R2
OTf
(R)-4o (88% ee)
N
R1
4
2
1a
O
TfO
O
N
Ts
H
N
Entry Cyclic amide 2
Product 4
Yieldb (%)
Ts
N
OAc
2
3
63
73
AcO
O
N
TfO
Ts
Ts
Ts
O
OAc
H
N
Allyl
Ts
2l
N
N
1
2
43 (11)c
4p
OAc
N
O
TfO
2g
Allyl
Ts
N
O
N
4k
Ts
N
O
TfO
H
O
AcO
N
N
H
Bn
Ts
N
N
30
2m
N
OAc
4q
2h
Bn
4l
O
TfO
Ts
N
O
O
TfO
O
Ts
N
O
N
N
H
O
Me
Ts
4
77
N
N
N
Me
3
4
44
24
O
H
N
Me
O
(S)-2n
Me
(S)-4r
(R)-2i (89% ee)
(R)-4m (89% ee)
O
TfO
Ts
N
O
O
TfO
O
Ts
N
Ts
Me
Ts
N
N
N
N
iPr
H
5
75
N
N
iPr
H
(
)-2j
(
)-4n
Me
(
)-2o
a Conditions: 1a (1.0 equiv), 2 (3.0 equiv), CsF (3.0 equiv), 1,4-dioxane,
80 °C, 40–50 min.
( )-4s
b Isolated yield.
O
TfO
O
Ts
N
c In addition to 4k, the hydrolyzed benzodiazepine 4k′ bearing a phenolic
hydroxyl group was also isolated in 11% yield.
Ts
N
N
Ph
Ph
6
49
H
N
H
The reactions of fused bicyclic imidazolidin-2-ones 2k–
p with 3-(triflyloxy)benzyne (3a), generated from 1a,
provided the desired pyrrolo-1,4-benzodiazepines 4o–t
(Table 3). Interestingly, the resulting products were
obtained in greater yields (49–77%) than those of the 1,4-
Ph
(
)-2p
(
)-4t
Ph
a Conditions: 1a (1.0 equiv), 2 (3.0 equiv), CsF (3.0 equiv), 1,4-dioxane, 80
°C, 40–50 min.
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

D
H. Kaneko et al.
Letter
Synlett
that the orbitals for the lone-pair of electrons on the nitrogen
atoms at the ring junctions in 2k–p should have more
s-character, due to the presence of two fused five-
membered rings, thereby producing less conjugation with
the carbonyl group (see calculated data for the s-character
in the Supporting Information). Additionally, it should also
be considered that the 5,5-fused ring systems of 2k–p
should be fixed in the cis-configuration at the ring
junctions, thereby hampering inversion of the nitrogen
center. For these two reasons, the lone pair of electrons on
the nitrogen atom should be more nucleophilic. We also
found that the substituents present on 2 had no significant
effect on the yields of 4o–t (Table 3, entries 2–6).
Additionally, both the acetoxy group (entries 2 and 3) and
the acetal moiety (entry 4) were tolerated under the
reaction conditions that were used.
successful replacement of the triflyloxy group of 4e with an
aromatic substituent under Suzuki coupling conditions to
provide the 6-aryl-1,4-benzodiazepine 6 in quantitative
yield. The tosyl group of 6 was then removed by using
sodium naphthalenide to provide 7. Interestingly, the triflyl
group of 4q was easily hydrolyzed to give phenol 8 with the
acetoxy group intact; this was achieved under the same re-
action conditions employed for benzyne generation using
CsF, but with a longer reaction time. Furthermore, treat-
ment of 4q with Zn4(OCOCF3)6O (ZnTAC)10 resulted in the
selective cleavage of the acetoxy group of 4q, although the
triflyloxy group remained intact to give 9 in 96% isolated
yield. Moreover, the fused benzodiazepine 4q was trans-
formed into the aromatized pyrrolo-1,4-benzodiazepine 10
by a deacetoxylation/oxidation sequence.
O
Ar
We then examined the reaction of 2k with 3-methoxy-
6-(triflyloxy)benzyne (3b), generated from 1,2-bis(triflyl-
oxy)-4-methoxy-3-(trimethylsilyl)benzene (1b), which gave
the 9-methoxy-6-(triflyloxy)-1,4-benzodiazepine 4u in 41%
isolated yield as a single regioisomer (Scheme 2). This result
clearly indicates that the triflyloxy group exerts a signifi-
cantly stronger directing effect than the methoxy group in
the reaction of benzynes. Following the successful prepara-
tion of 4u, the triflyloxy group was effectively removed by a
palladium catalyst in the presence of formic acid to give 9-
methoxy-1,4-benzodiazepine 5 quantitatively. The 1,4-
benzodiazepine 5 bearing an oxygen substituent at the C-9
position is regiocomplementary to 4o synthesized from 1a.
Ts
N
N
O
Ar
O
H
H
(Ar = 4-MeOC6H4)
Me
Ts
N
N
6, quant (from 4e)
N
N
Me
Me
7, 63% (from 4e)
4b, quant (from 4e)
(Ar = 4-MeOC6H4)
4e, 4q
O
O
HO
TfO
Ts
Ts
N
N
O
H
TfO
N
N
Ts
O
N
TfO
TfO
Ts
O
TfO
N
N
OAc
8, 79% (from 4q)
10, 66% (from 4q)
Ts
H
H
OTf
N
N
H
(R)-2k
+ (R)-2k
SiMe3
9, 96% (from 4q)
N
OH
CsF, 1,4-dioxane
80 °C, 30 min
OMe
3b
OMe
1b
MeO
Scheme 3 Transformations of the triflyloxy-containing 1,4-benzo-
diazepines 4e and 4q. Reagents and conditions: a 4e, Pd(OAc), PPh3,
Et3N, HCO2H, DMF, 60 °C, 10 h; b 4e, Pd(PPh3)4, 4-MeOC6H4B(OH)2,
K2CO3, DMF, 80 °C, 15 h; c 4e, Pd(PPh3)4, 4-MeOC6H4B(OH)2, K2CO3,
DMF, 80 °C, 15 h, then Na+C10H8–•, THF, r.t., 10 min; d 4q, CsF, 1,4-diox-
ane, 80 °C, 13 h; e 4q, ZnTAC, MeOH, reflux, 9 h; f 4q, TsOH·H2O, DDQ,
MeCN, r.t., 36 h.
(R)-4u, 41%
single isomer
O
Ts
N
Pd(OAc)2, PPh3
HCO2H, Et3N
H
N
DMF, 60 °C
10 h
MeO
(R)-5, quant
Finally, we proposed two plausible mechanisms (a non-
synchronous concerted mechanism and a stepwise mecha-
nism) for the reaction between 3-(triflyloxy)benzyne (3a)
and imidazolidin-2-one 2b, as outlined in Scheme 4. Densi-
ty functional theory (DFT) calculations were performed to
study these two proposed mechanisms. The B3LYP-D3
functional with 6-31G(d) basis set was utilized for the cal-
culations with Gaussian09 software.11 The structures of re-
actants 3a and 2b, product 4e, intermediate 11, and transi-
tion states TS-I to TS-III were optimized, and the nature of
these structures were confirmed by frequency calculations.
Scheme 2 Regiocontrolled synthesis of 9-methoxy-1,4-benzo-
diazepine 5
The prepared 1,4-benzodiazepines 4e and 4q were then
easily converted into a range of derivatives 4b and 6–10, as
outlined in Scheme 3. For example, reductive cleavage of
the triflyloxy group of 4e gave benzodiazepine 4b, attempts
at the preparation of which from the unsubstituted
benzyne 3c and 2b had previously proved unsuccessful
(Table 1, entry 1). In addition, we also demonstrated the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

E
H. Kaneko et al.
Letter
Synlett
expanding the scope of this reaction. Indeed, it should be
emphasized that the fused imidazolidin-2-ones provided
improved yields of pyrrolo-1,4-benzodiazepines, which are
found in many pharmaceutical products and drug candi-
dates. We therefore believe that our proposed method
might be suitable for application in drug-discovery pro-
grams. Further studies into the potential synthetic applica-
tions of this process, in addition to detailed mechanistic in-
vestigations, are currently underway in our laboratory, and
the results will be presented in due course.
O
Ts
N
TS-IV
OTf
N
Ts
O
Me
–OTf
N
12
N
92.2 kcal/mol
Me
TS-I
OTf
7.92 kcal/mol
OTf
O
Ts
N
N
Me
TS-III
N
N
Me
Ts
2.52 kcal/mol
TS-II
O
Funding Information
3a + 2b
0.95 kcal/mol
0.00 kcal/mol
This work was financially supported by the JSPS KAKENHI (grant
number 16K08164) and a Grant-in-Aid for JSPS (grant number
A16J008680), Life Science Research funded by the Japanese Agency
for Medical Research and Development (AMED) under Grant Number
17am0101084j0001, the Research Foundation for Pharmaceutical Sci-
–2.15 kcal/mol
OTf
ences, and the Kobayashi International Scholarship Foundation.
a
Jp
a
n
S
o
ecity
o
f
r
hte
P
or
m
o
itn of
S
ecince 1(
6
K
0
8
1
6
4) A(
1
6
0
J
0
8
6
8
0aJ)p
a
n
ese
A
g
e
n
c
y
o
f
r
M
e
dcai
l
Research
h
a
n
d
D
e
v
oelp
m
e
nt
A
(
M
E
D) 1(
7
a
m
0
1
0
1
0
8
4
0
j
0
0
1)
N
4e
N
Me
Ts
O
–63.13 kcal/mol
11
Acknowledgment
Scheme 4 Plausible reaction mechanisms for the formation of benzo-
diazepines 4 via benzynes 3a
We thank The Japan Society for the Promotion of Science for the pre-
doctoral fellowship to H.K.
Interestingly, the calculated activation energy for the
concerted mechanism (7.92 kcal/mol) was higher than that
for the stepwise mechanism (4.67 kcal/mol), and the calcu-
lated activation energy for the second step of the stepwise
mechanism (4.67 kcal/mol) was significantly higher than
that of the first step (0.95 kcal/mol). The DFT results, there-
fore, indicate that the reaction probably proceeds by a step-
wise mechanism via intermediate 11, with the rate-limiting
step being the second cyclization step. In this case, the
cyclization step might potentially be accelerated by the
electron-withdrawing p-toluenesulfonyl group present on
the nitrogen atom of 11.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591924.
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References and Notes
(1) For selected recent reviews on benzynes, see: (a) Sanz, R. Org.
Prep. Proced. Int. 2008, 40, 215. (b) Kitamura, T. Aust. J. Chem.
2010, 63, 987. (c) Tadross, P. M.; Stoltz, B. M. Chem. Rev. 2012,
112, 3550. (d) Yoshida, S.; Hosoya, T. Chem. Lett. 2015, 44, 1450.
(e) Shi, J.; Li, Y.; Li, Y. Chem. Soc. Rev. 2017, 46, 1707.
Although the intermediate 11 might possibly be con-
verted into another benzyne 12 through the elimination of
the triflyloxy group, the energy of 12 (92.2 kcal/mol) is too
high to be reached from 11 (–2.15 kcal/mol), and therefore
this conversion can be ruled out under the present reaction
conditions. The stepwise mechanism, therefore, accounts
for the successful preparation of the desired 1,4-benzo-
diazepine 4e without the observed formation of benzyne 12.
In summary, we have successfully developed a novel
modular approach to the synthesis of 1,4-benzodiazepines
through the cycloaddition reactions of 3-(triflyloxy)-
benzynes with 1-(p-toluenesulfonyl)imidazolidin-2-ones.12–14
The combination of highly electrophilic 3-(triflyloxy)ben-
zynes with weakly nucleophilic imidazolidin-2-ones was
the key to the success of this process. DFT calculations indi-
cated that the reactions between 3-(triflyloxy)benzynes
and cyclic ureas proceeded in a stepwise manner. Subse-
quent transformations of the cycloaddition products pro-
vided a range of substituted 1,4-benzodiazepines, thereby
(2) For selected recent papers on syntheses of fused heteroaromat-
ics using benzynes, see: (a) Wang, T.; Hoye, T. R. J. Am. Chem.
Soc. 2016, 138, 13870. (b) Pérez-Gómez, M.; García-López, J.-A.
Angew. Chem. Int. Ed. 2016, 55, 14389. (c) Ikawa T., Sumii Y.,
Masuda S., Wang D., Emi Y., Takagi A., Akai S.; Synlett; DOI:
10.1055/s-0036-1591722.
(3) For selected papers on 3-alkoxybenzynes, see: (a) Matsumoto,
T.; Hosoya, T.; Katsuki, M.; Suzuki, K. Tetrahedron Lett. 1991, 32,
6735. (b) Tadross, P. M.; Gilmore, C. D.; Bugga, P.; Virgil, S. C.;
Stoltz, B. M. Org. Lett. 2010, 12, 1224. (c) Umezu, S.; dos Passos
Gomes, G.; Yoshinaga, T.; Sakae, M.; Matsumoto, K.; Iwata, T.;
Alabugin, I.; Shindo, M. Angew. Chem. Int. Ed. 2017, 56, 1298.
(4) For selected recent papers on silylbenzynes, see: (a) Akai, S.;
Ikawa, T.; Takayanagi, S.-i.; Morikawa, Y.; Mohri, S.;
Tsubakiyama, M.; Egi, M.; Wada, Y.; Kita, Y. Angew. Chem. Int.
Ed. 2008, 47, 7673. (b) Ikawa, T.; Nishiyama, T.; Shigeta, T.;
Mohri, S.; Morita, S.; Takayanagi, S.-i.; Terauchi, Y.; Morikawa,
Y.; Takagi, A.; Ishikawa, Y.; Fujii, S.; Kita, Y.; Akai, S. Angew.
Chem. Int. Ed. 2011, 50, 5674. (c) Bronner, S. M.; Mackey, J. L.;
Houk, K. N.; Garg, N. K. J. Am. Chem. Soc. 2012, 134, 13966.
(d) Ikawa, T.; Takagi, A.; Goto, M.; Aoyama, Y.; Ishikawa, Y.; Itoh,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

F
H. Kaneko et al.
Letter
Synlett
Y.; Fujii, S.; Tokiwa, H.; Akai, S. J. Org. Chem. 2013, 78, 2965.
(e) Yoshida, H.; Yoshida, R.; Takaki, K. Angew. Chem. Int. Ed.
2013, 52, 8629. (f) Ikawa, T.; Masuda, S.; Takagi, A.; Akai, S.
Chem. Sci. 2016, 7, 5206.
with EtOAc (×3), and the organic phases were combined,
washed with sat. brine, and dried (MgSO4). The solvent was
removed under reduced pressure, and the crude product was
purified by flash column chromatography (silica gel, hexane–
EtOAc).
(5) For selected papers on borylbenzynes, see: (a) Ikawa, T.; Takagi,
A.; Kurita, Y.; Saito, K.; Azechi, K.; Egi, M.; Kakiguchi, K.; Kita, Y.;
Akai, S. Angew. Chem. Int. Ed. 2010, 49, 5563. (b) Takagi, A.;
Ikawa, T.; Saito, K.; Masuda, S.; Ito, T.; Akai, S. Org. Biomol. Chem.
2013, 11, 8145. (c) Yoshida, S.; Shimomori, K.; Nonaka, T.;
Hosoya, T. Chem. Lett. 2015, 44, 1324; see also Ref. 4d.
(6) For selected papers on 3- and 4-(triflyloxy)benzynes, see:
(a) Yoshida, S.; Uchida, K.; Igawa, K.; Tomooka, K.; Hosoya, T.
Chem. Commun. 2014, 50, 15059. (b) Ikawa, T.; Kaneko, H.;
Masuda, S.; Ishitsubo, E.; Tokiwa, H.; Akai, S. Org. Biomol. Chem.
2015, 13, 520. (c) Shi, J.; Qiu, D.; Wang, J.; Xu, H.; Li, Y. J. Am.
Chem. Soc. 2015, 137, 5670. (d) Uchida, K.; Yoshida, S.; Hosoya,
T. Org. Lett. 2017, 19, 1184. (e) Uchida, K.; Yoshida, S.; Hosoya, T.
Synthesis 2016, 48, 4099.
(7) For selected papers on biologically active 1,4-benzodiazepines,
see: (a) Baud, M. G. J.; Lin-Shiao, E.; Zengerle, M.; Tallant, C.;
Ciulli, A. J. Med. Chem. 2016, 59, 1492. (b) Siegrist, R.; Pozzi, D.;
Jacob, G.; Torrisi, C.; Colas, K.; Braibant, B.; Mawet, J.; Pfeifer, T.;
de Kanter, R.; Roch, C.; Kessler, M.; Corminboeuf, O.; Bezençon,
O. J. Med. Chem. 2016, 59, 10661.
(8) For selected recent papers on the synthesis of 1,4-benzodiaze-
pine, see: (a) Li, X.; Yang, L.; Zhang, X.; Zhang-Negrerie, D.; Du,
Y.; Zhao, K. J. Org. Chem. 2014, 79, 955. (b) Fier, P. S.; Whittaker,
A. M. Org. Lett. 2017, 19, 1454.
(13) 1-Methyl-5-oxo-4-tosyl-2,3,4,5-tetrahydro-1H-1,4-benzodi-
azepin-6-yl Triflate (4e; Table 1, Entry 5)
By following the general procedure, a mixture of CsF (46 mg,
0.30 mmol), 1-methyl-3-tosyl-2-imidazolidone (2b; 76 mg,
0.30 mmol), and 2-(tert-butyldimethylsilyl)-1,3-bis(trifluoro-
methanesulfonyloxy)benzene (1a; 50 mg, 0.10 mmol) was
stirred in 1,4-dioxane (1.0 mL) for 40 min at 80 °C. The crude
product was purified by column chromatography [silica gel,
EtOAc–hexane (1:2)] to give a colorless solid; yield: 33 mg
(69%); mp 47–50 °C. IR (neat): 1697 cm–1 1H NMR (400 MHz,
.
CDCl3): δ = 2.44 (s, 3 H), 2.87 (s, 3 H), 3.36 (t, J = 5.5 Hz, 2 H),
4.11 (t, J = 5.5 Hz, 2 H), 6.84 (d, J = 8.0 Hz, 1 H), 6.96 (d, J = 8.0 Hz,
1 H), 7.33 (d, J = 8.5 Hz, 2 H), 7.42 (dd, J = 8.0, 8.0 Hz, 1 H), 7.97
(d, J = 8.5 Hz, 2 H). 13C NMR (100 MHz, CDCl3): δ = 21.7, 40.5,
44.1, 58.6, 115.6, 118.4 (q, J = 319 Hz), 118.6, 122.7, 128.8,
129.3, 133.1, 135.3, 145.1, 147.3, 149.4, 164.3. 19F NMR (376
MHz, CDCl3): δ = –73.0. HRMS (MALDI): m/z [M + Na]+ calcd for
C
18H17F3N2NaO6S2: 501.0372; found: 501.0371.
The regiochemistry of 4e was determined by NOE experiments.
(14) (3aR)-6-Oxo-5-tosyl-2,3,3a,4,5,6-hexahydro-1H-benzo[f]pyr-
rolo[1,2-a][1,4]diazepin-7-yl Triflate [(R)-4o; Table 3,
Entry 1]
By following the general procedure, a mixture of CsF (46 mg,
0.30 mmol), (R)-2-tosylhexahydro-3H-pyrrolo[1,2-c]imidazole-
3-one [(R)-2k] (84 mg, 0.30 mmol), and 2-(tert-butyldimethyl-
silyl)-1,3-bis(trifluoromethanesulfonyloxy)benzene (1a; 50 mg,
0.10 mmol) in 1,4-dioxane (1.0 mL) was stirred for 40 min at
80 °C. The crude product was purified by column chromatogra-
phy [silica gel, EtOAc–hexane (2:3)] to give a yellow solid; yield:
35 mg (70%); mp 141–143 °C; [α]D20 +5.5 (c 0.15, CHCl3). IR
(9) For selected papers on the synthesis of 1,4-benzodiazepine via
benzyne or azabenzyne (heteroarynes), see: (a) Yoshida, H.;
Shirakawa, E.; Honda, Y.; Hiyama, T. Angew. Chem. Int. Ed. 2002,
41, 3247. (b) Goetz, A. E.; Garg, N. K. Nat. Chem. 2013, 5, 54.
(10) Iwasaki, T.; Agura, K.; Maegawa, Y.; Hayashi, Y.; Ohshima, T.;
Mashima, K. Chem. Eur. J. 2010, 16, 11567.
(11) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B. et al. Gaussian 09,
Revision D.01; Gaussian, Inc: Wallingford, 2009.
(neat): 1699, 1684 cm–1 1H NMR (400 MHz, CDCl3): δ = 1.86–
.
(12) 1,4-Benzodiazepines 4; General Procedure
1.98 (m, 2 H), 2.05–2.16 (m, 2 H), 2.43 (s, 3 H), 3.24–3.35 (m, 2
H), 3.48–3.52 (m, 1 H), 4.07 (dd, J = 4.5, 16.0 Hz, 1 H), 4.24 (dd,
J = 3.0, 16.0 Hz, 1 H), 6.67 (d, J = 8.0 Hz, 1 H), 6.75 (d, J = 8.5 Hz, 1
H), 7.29–7.34 (m, 3 H), 7.95 (d, J = 8.5 Hz, 2 H). 13C NMR (100
MHz, CDCl3): δ = 21.6, 22.1, 29.5, 45.1, 48.9, 65.8, 112.6, 116.0,
117.3, 118.4 (q, J = 319 Hz), 129.1, 129.2, 132.7, 135.2, 145.0,
146.4, 148.6, 164.9. 19F NMR (376 MHz, CDCl3): δ = –73.1. HRMS
(MALDI): m/z [M + Na]+ calcd for C20H19F3N2NaO6S2: 527.0529;
found: 527.0519.
The enantiomeric excess of the product (R)-4o was determined
to be 88% by HPLC on CHIRALCEL AD-3 [hexane–i-PrOH (90:10),
flowrate: 1.0 mL/min]; tR [(R)-isomer] = 30.0 min, tR [(S)-
isomer] = 33.0 min. The absolute configuration was assigned on
the basis of that of (R)-2k, synthesized from D-proline.
CsF (3.0 equiv) was flame-dried under reduced pressure in a
flask equipped with a three-way stopcock, and the flask was
backfilled with argon. Cyclic urea 2 (3.0 equiv) and a magnetic
stirrer bar were loaded into the flask, which was subject to
three cycles of evacuation and backfilling with argon. 1,4-
Dioxane (one-fifth of the total volume of the solvent) was added
to the flask from a syringe. A solution of the appropriate precur-
sor 1a–f (1.0 equiv) in anhyd 1,4-dioxane (one-fifth of total
volume) was added to the flask through a cannula, which was
washed with 1,4-dioxane (three-fifth of total volume). The
mixture was then stirred at 80 °C for 30–60 min until the
benzyne reaction was complete (TLC). The reaction was then
quenched by addition of H2O. The aqueous phase was extracted
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F