Synthesis of Six- and Seven-Membered Chloromethyl-Substituted Heterocycles via Palladium-Catalyzed Amino- and Oxychlorination

Article abstract of DOI:10.1055/s-0035-1561671

The synthesis of six- and seven-membered chloromethyl-substituted heterocycles, such as piperazinone, tetrahydroquinoxaline, benzodiazepinone, and benzoxazepinone, is reported using palladium-catalyzed vicinal diheterofunctionalization of nonactivated alkenes. The reaction conditions for this domino process are soft and mild, and the chloromethyl appendage allows various post-functionalizations via simple nucleophilic substitutions.

Full text of DOI:10.1055/s-0035-1561671

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–K
paper
A
A.-D. Manick et al.
Paper
Synthesis
Synthesis of Six- and Seven-Membered Chloromethyl-Substituted
Heterocycles via Palladium-Catalyzed Amino- and Oxychlorination
Ts
N
Anne-Doriane Manick
Farouk Berhal*
R
O
Cl
62–90%
4 examples
R = H, Me, s-Bu, Bn
Guillaume Prestat*
N
PdCl2(PhCN)2 (10 mol%)
NCS (1.2 equiv)
Bn
XH
Université Paris Descartes, Laboratoire de Chimie et Biochimie
Pharmacologiques et Toxicologiques, UMR CNRS 8601, 45 rue des
Saints-Pères, 75006 Paris, France
guillaume.prestat@parisdescartes.fr
farouk.berhal@parisdescartes.fr
or
X
CH2Cl2, r.t.
X = NTs, O
Cl
23–97%
R
13 examples
R = Me, OMe, NO2, Hal
N
Dedicated to our friend and former boss Professor Giovanni Poli
on the occasion of his 60th birthday
Bn
O
Received: 15.04.2016
Accepted after revision: 04.05.2016
Published online: 21.06.2016
Palladium-catalyzed
diheterofunctionalization
of
alkenes is mechanistically based on three elementary steps:
(1) electrophilic activation of the alkene by a Pd(II) complex
followed by (2) nucleopalladation, and finally (3) oxidative
cleavage of the resulting C–Pd bond.2 This versatile process,
mostly based on PdII/PdIV redox cycles,3 tolerates the use of
various nucleophiles in the second elementary step and
various oxidants in the last step allowing thereby the devel-
opment of oxyamination,2,4 dioxygenation,5 diamination,6
as well as aminohalogenation7 of alkenes.8 Surprisingly, ap-
plication of this methodology is limited to the synthesis of
five- and six-membered rings and to moderately function-
alized molecules. Pursuing our research program dedicated
to transition-metal-catalyzed domino reactions,9 we re-
cently reported the synthesis of 1,4-benzodiazepinones and
1,4-benzoxazepinones via palladium-catalyzed amino and
oxyacetoxylation (Scheme 2 a).10 We next envisioned to de-
velop the synthesis of chloromethyl-substituted benzodi-
azepinones and piperazinones via aminochlorination
(Scheme 2 b).
These heterocyclic scaffolds are both well-known privi-
leged structures in medicinal chemistry and are important
synthetic intermediates.11 The introduction of the chloro-
methyl appendage should facilitate their post-functional-
izations towards more complex molecules. We report here-
in our full study.
Our study was initiated by targeting the synthesis of ha-
lomethyl-substituted piperazinones. According to the ret-
rosynthetic analysis depicted in Scheme 1, compound 1a,
chosen as the model substrate, was submitted to the ami-
nochlorination reaction conditions reported by Michael for
the synthesis of pyrrolidine scaffold (Table 1).7e The use of
PdCl2(MeCN)2 (10 mol%) and NCS (1.2 equiv) in dichloro-
methane at room temperature smoothly afforded the de-
sired chloropiperazinone 2a in an excellent 87% yield (Table
DOI: 10.1055/s-0035-1561671; Art ID: ss-2016-t0253-op
Abstract The synthesis of six- and seven-membered chloromethyl-
substituted heterocycles, such as piperazinone, tetrahydroquinoxaline,
benzodiazepinone, and benzoxazepinone, is reported using palladium-
catalyzed vicinal diheterofunctionalization of nonactivated alkenes. The
reaction conditions for this domino process are soft and mild, and the
chloromethyl appendage allows various post-functionalizations via sim-
ple nucleophilic substitutions.
Key words palladium, domino reaction, heterocycles, amination, ha-
logenation
The tremendous development of transition-metal-cata-
lyzed domino reactions allows to reconsider and to shorten
retrosynthetic analyses. Palladium-catalyzed vicinal dihet-
erofunctionalization of alkenes, a recently reported domino
reaction, illustrates plainly this concept.1 Indeed, this pro-
cess, in its intra-intermolecular variant, allows to generate
in a single step an heterocycle and to introduce a functional
group in the vicinity of the cyclizing position starting with
easily accessible alkenes. This methodology leads to analy-
sis of the retrosynthesis of exo-functionalized heterocycles
A as a direct 1,2-diX disconnection giving the alkenyl syn-
thon B and thus avoiding the classical two-step route
through the epoxide (Scheme 1).
FG
X
XH
1,2-diX
[Pd]
A
B
Scheme 1 Pd-catalyzed 1,2-diX disconnection
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

B
A.-D. Manick et al.
Paper
Synthesis
Table 1 Optimization of the Oxidant for the Haloamination of 1aa
a) Our previous work[10]
Ts
Ts
N
Pd(OAc)2 (10 mol%)
PdCl2(MeCN)2 (10 mol%)
oxidant (1.2 equiv)
PhI(OAc)2 (2.5 equiv)
X = O: Bu4NOAc (1 equiv)
X = NTs: DiPEA (1 equiv)
NH
OAc
XH
N
X
X
CH2Cl2, r.t.
O
N
O
N
N
R
R
Bn
Bn
Bn
Bn
O
O
1a
2a
Ts
N
Entry
Oxidant
X
Reaction Yield
time (h) (%)b
R
b) This work:
XH
Cl
O
[Pd(II)] (cat.)
N
1
2
3
4
5
6
7
8
NCS
Cl
2
24
24
24
24
24
24
24
87
0
Bn
oxidant
Trichloroisocyanuric acidc
Cl
Br
I
or
NBS
0
Cl
X
X = NTs, O
NIS
0
Selectfluord
F
0
N
R
Bn
O
e
DAST/PhI(OAc)2
F
0
Scheme 2 Amino- and oxyacetoxylation versus amino- and oxychlori-
NFSI
F
0
nation
f
I2
I
0
a Reaction conditions: 1a (0.2 mmol), PdCl2(MeCN)2 (0.02 mmol), oxidant
(0.24 mmol), CH2Cl2 (1 mL), r.t.
b Yields refer to isolated products.
c Oxidant used: 0.8 equiv.
1, entry 1). A complete degradation of the substrate was ob-
served when NCS was replaced by trichloroisocyanuric acid
(entry 2). As opposed to the use of NCS, NBS and NIS did not
promote the haloamination reaction (entries 3 and 4). Ami-
nofluorination was also tested using Selectfluor and
DAST/NFSI as potential fluorine sources but these trials re-
mained unsuccessful (entries 5–7). Finally, I2 alone did not
promote the cyclization, which excludes a classical iodocy-
clization process (entry 8).
The optimization of the chloroamination reaction con-
ditions was next studied keeping 1a as substrate (Table 2).
In a first set of experiments, the influence of the palladium
source was evaluated. Replacing PdCl2(MeCN)2 with
PdCl2(PhCN)2 allowed to increase the yield up to 90% (Table
2, entry 2 vs 1). It is noteworthy that the conditions report-
ed herein represent a great improvement over the ones re-
ported by Broggini in the course of our study [PdCl2(MeCN)2
(5 mol%), CuCl2 (3 equiv), THF, 70 °C] that afforded 2a in 65%
yield.7j
d Oxidant used: 2.2 equiv.
e Oxidant used: 3 equiv.
f Without Pd.
on the nitrogen atom was next evaluated using our opti-
mized conditions (Table 3). Conveniently, the reaction was
proven to be compatible with a N-Boc protective group. The
desired piperazinone 2b was indeed isolated in a good 73%
yield (Table 3, entry 2). Acetamide derivative 1c was com-
pletely recovered whereas the free amine 1d was degraded
during the course of the reaction (entries 3 and 4).
Table 2 Optimization of the Palladium Source for the Aminochlorina-
tion of 1aa
Ts
Ts
N
[Pd] (10 mol%)
NCS (1.2 equiv)
NH
Cl
Next the use of Pd(OAc)2 was tested with a longer reac-
tion time to reach full conversion; however, this led to a sig-
nificant drop of the yield (72%, Table 2, entry 3). Starting
with a Pd0 source such as Pd2(dba)3 led to the desired prod-
uct in an excellent 89% yield similar to the one obtained by
the use of PdCl2(PhCN)2 (entry 4). A control experiment,
run in the absence of a Pd source, led to the complete recov-
ery of 1a, which unambiguously demonstrated the require-
ment of palladium for this transformation (entry 5). The
influence of the solvent was next examined using
PdCl2(PhCN)2 and NCS. Polar solvents such as MeCN and
DMF were found to completely inhibit the reaction while
Et2O led to a limited 50% conversion. The use of toluene
gave a similar yield to the one previously obtained with di-
chloromethane (90%). The influence of a protective group
CH2Cl2, r.t.
O
N
O
N
Bn
Bn
1a
2a
Entry
[Pd]
Reaction time (h)
Yield (%)b
1
2
3
4
5
PdCl2(MeCN)2
PdCl2(PhCN)2
Pd(OAc)2
Pd2(dba)3
–
2
2
87
90
72
89
0
72
2
4
a Reaction conditions: 1a (0.2 mmol), [Pd] (0.02 mmol), NCS (0.24 mmol),
CH2Cl2 (1 mL), r.t.
b Yields refer to isolated products.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

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A.-D. Manick et al.
Paper
Synthesis
Table 3 Study of the Nitrogen Protecting Group for the Chloroamina-
tion of 1a
Table 4 Scope of the Pd-Catalyzed Aminochlorination To Afford Piper-
azinonesa
R
R
N
Ts
Ts
N
PdCl2(PhCN)2 (10 mol%)
NCS (1.2 equiv)
PdCl2(PhCN)2 (10 mol%)
NCS (1.2 equiv)
NH
NH
Cl
Cl
CH2Cl2, r.t., 2 h
CH2Cl2, r.t.
O
N
O
N
O
N
O
N
Bn
Bn
Bn
Bn
1
2
1
2
Entry
R
Substrate
Product
Yield (%)b
Entry
Substrate Product
Reaction cis/trans Yield
time (h)
(%)b
1
2
3
4
Ts
1a
1b
1c
1d
2a
2b
2c
2d
90
73
0
Ts
Boc
Ac
H
N
Cl
1
1a
1e
1f
2
–
90
O
N
0
2a
2e
Bn
a Reaction conditions: 1a (0.2 mmol), [Pd] (0.02 mmol), NCS (0.24 mmol),
CH2Cl2 (1 mL), r.t., 2 h.
Ts
N
b Yields refer to isolated products.
Cl
2
3
4
5
6
24
24
24
22
18
7:3
8:2
9:1
–
72
71
62
0
The substrate scope and limitations of the aminochlori-
nation reaction was next examined. In a first set of experi-
ments, the synthesis of 3,5-disubstituted piperazinones
was tackled starting with enantiopure substrates derived
from L-alanine 1e, L-phenylalanine 1f, and L-isoleucine 1g
(Table 4). The desired piperazinones 2e–g were obtained as
epimeric mixtures of cis/trans isomers in satisfactory yields
(72%, 71%, and 62%, respectively, Table 4, entries 2–4). For
these compounds, the cyclization process required longer
reaction time than the one observed for the glycine deriva-
tive 2a (24 h vs 2 h, entry 1). Diastereomeric ratios were
correlated to the steric demand of the amino acid residue
ranging from 7:3 to 9:1 in favor of the cis-isomer (entries 2–
4). The relative configurations were elucidated by analysis
of the 1H-1H NOESY spectra (Figure 1).
O
N
Bn
Ts
N
Ph
Cl
O
N
2f
Bn
Ts
N
Cl
1g
1h
1i
O
N
2g
Bn
Ts
N
Cl
Cl
O
O
N
2h
Bn
Ts
N
Ph
H
O
Ts
N
H
O
Ts
N
H
H
H
R
H
R
H
H
H
H
R'
Cl
R'
Cl
–
0
N
N
N
2i
Bn
Bn
Bn
a Reaction conditions: 1 (0.2 mmol), [Pd] (0.02 mmol), NCS (0.24 mmol),
CH2Cl2 (1 mL), r.t.
2e–g major
2e–g minor
trans
cis
b Yields refer to isolated products.
Figure 1 Relative configuration attribution by NOESY correlation
1,2-Disubstituted alkenes are known to be challenging
substrates for palladium-catalyzed vicinal diheterofunc-
tionalization and a limited number of successful examples
have been reported.2,6c,e Nevertheless, crotyl and styryl de-
rivatives 1h,i were tested, and the desired piperazinones
could not be detected (Table 4, entries 5 and 6). The amino-
chlorination reaction was also found to allow the access to
the tetrahydroquinoxaline 4 starting form 3, albeit in mod-
erate yield (60%, Scheme 3).
Ts
Ts
N
[Pd] (10 mol%)
NCS (1.2 equiv)
NH
Cl
CH2Cl2, r.t., 24 h
N
N
Bn
Bn
4
PdCl2(PhCN)2 50%
PdCl2(MeCN)2 60%
3
Scheme 3 Aminochlorination of 3 to afford tetrahydroquinoxaline 4
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

D
A.-D. Manick et al.
Paper
Synthesis
Next our aminochlorination reaction conditions were
applied for the synthesis of seven-membered ring com-
pounds. We initially targeted the synthesis of chloro-
substituted benzodiazepinones starting from anthranilic
acid derivatives (Scheme 4).
rination reaction conditions (Scheme 5). The process ap-
peared less efficient and required longer reaction time
compared to the aminochlorination reaction (60 h vs 24 h).
Nevertheless, the desired benzoxazepinones 8a–f arising
from the one-pot difunctionalization of nonactivated
alkenes were isolated in yields ranging from 42 to 55%. Giv-
en the homogeneity of the yields observed, this process ap-
peared almost insensitive to the electronic properties of the
aromatic substituent.
R2
NH
R2
N
PdCl2(PhCN)2 (10 mol%)
NCS (1.2 equiv)
Cl
R1
R1
CH2Cl2, r.t., 24 h
N
N
Bn
Bn
O
O
PdCl2(PhCN)2 (10 mol%)
NCS (1.2 equiv)
Cl
OH
O
5
6
R
R
CH2Cl2, r.t., 60 h
N
N
Bn
Bn
Cl
Ts
Ts
Ts
O
O
Cl
Cl
Cl
N
N
N
MeO
7
8
Cl
O
N
N
N
MeO
Cl
O
O
Bn
Bn
Bn
O
O
O
6a, 78%
6b, 80%
6c, 97%
N
N
Me
MeO
N
Bn
Bn
Bn
O
O
O
Ts
Ts
N
Ts
N
8c, 42%
8a, 50%
8b, 55%
Cl
Cl
Cl
N
MeO
Cl
Cl
O
Cl
Cl
O
O
F
N
N
N
Bn
Bn
Bn
O
O
O
N
N
Br
N
Cl
Bn
Bn
Bn
6d, 58%
6e, 73%
6f, 62%
O
O
O
8d, 55%
8e, 50%
8f, 52%
Ts
Boc
Cl
Cl
Scheme 5 Scope of the Pd-catalyzed aminochlorination to afford ben-
zoxazepinones. Reaction conditions: 7 (0.2 mmol), [Pd] (0.02 mmol),
NCS (0.24 mmol), CH2Cl2 (1 mL), r.t. Yields refer to isolated products.
N
N
N
N
O2N
Bn
Bn
O
O
6g, 23%, 72 h
6h, 64%
Finally, to illustrate the synthetic potential of the syn-
thesized chloromethyl-substituted scaffolds, model nucleo-
philic substitutions of the chlorine atom were performed.
In DMF, piperazinone 2a was easily converted to azido and
iodo derivatives 9 and 10 (70% and 80% yield, respectively,
Scheme 6). The latter, upon treatment with AgBF4 in water/
acetone, allowed the access to the hydroxyl derivative 11 in
65% yield.
Scheme 4 Scope of the Pd-catalyzed aminochlorination to afford ben-
zodiazepinones. Reaction conditions: 5 (0.2 mmol), [Pd] (0.02 mmol),
NCS (0.24 mmol), CH2Cl2 (1 mL), r.t. Yields refer to isolated products.
The model N-Ts cyclization precursor 5a submitted to
our optimized conditions led to the desired chlorobenzodi-
azepinone 6a in 78% yield after 24 hours (Scheme 4). The
substitution of the aryl ring was next varied keeping the N-
Ts group on the cyclizing nitrogen atom. Compound 6b and
6c bearing electron-donating groups were isolated in good
yields (80% and 97%, respectively). On the other hand, 6d
bearing a meta-substituted methoxy group was obtained in
a moderate yield (58%). Naphthyl derivative 6e was isolated
in 73% yield and the meta-chloro compound 6f in 62% yield.
Introduction of a para-nitro group dramatically lowered
the yield (6g, 23%) of the process, which indicates the im-
portance of the nucleophilicity of the cyclizing nitrogen
atom on the outcome of the reaction. Satisfyingly, the N-
Boc derivative also reacted smoothly to give 6h (64%) albeit
in slightly reduced yield compared to the tosyl derivative 6a
(78%).
Ts
Ts
N
N
N3
Cl
NaN3
O
N
DMF, 80 °C
O
N
Bn
Bn
2a
9, 70%
KI
DMF, 80°C
Ts
N
Ts
N
AgBF4
I
OH
H2O/acetone, r.t.
O
N
O
N
Bn
Bn
Encouraged by these results, we next decided to change
from aminochlorination to oxychlorination. To this extent,
salicylic acid derivatives were submitted to the aminochlo-
10, 80%
11, 65%
Scheme 6 Nucleophilic substitutions with 2a
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

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A.-D. Manick et al.
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Synthesis
Benzodiazepinone 6a was similarly submitted to nucleo-
philic substitution reactions in DMF to afford the azido, io-
do, and acetyl derivatives 12–14 (96%, 72% and 59% yield,
respectively, Scheme 7). Of note, the cleavage of the tosyl
group can be easily performed. Indeed, submitting 14 to
magnesium turnings in methanol led to the removal of both
the tosyl and acetyl group in 75% yield as already reported
by us.10
the MeOH residual peak (δ = 3.31) or the C6H6 residual peak (δ = 7.16)
for 1H NMR. Chemical shifts of 13C NMR are reported relative to CDCl3
(δ = 77.16) or C6D6 (δ = 128.06) or CD3OD (δ = 49.00). Coupling con-
stant (J) are reported in hertz (Hz). Multiplicities are described with
standard abbreviations. Low-resolution mass spectra (LRMS) were re-
corded with an ion trap mass analyzer under electrospray ionization
(ESI) in positive or negative ionization mode detection or atmospher-
ic pressure chemical ionization (APCI). High-resolution mass spectra
(HRMS) were recorded with a TOF mass analyzer under electrospray
ionization (ESI) in positive or negative ionization mode detection, at-
mospheric pressure chemical ionization or atmospheric pressure
photoionization (APPI). Melting points were measured on a Köfler
bench. IR spectra were recorded on a FT-IR spectrophotometer, and
Ts
Ts
Cl
N3
N
N
NaN3
the wavelengths are reported in cm–1
.
DMF, 80 °C
N
N
Bn
Bn
O
O
Amino- and Oxychlorination Reactions; General Procedure
6a
12, 96%
In a dry Schlenk tube were placed alkenyl amide 1, 3, 5, or 7 (0.2
mmol), followed by N-chlorosuccinimide (32 mg, 0.24 mmol) and Pd-
Cl2(PhCN)2 (7.7 mg, 0.02 mmol). The Schlenk tube was flushed with
argon, then CH2Cl2 (1 mL) was introduced. The solution was stirred at
r.t. until total consumption of the starting material (monitored by
TLC). The reaction was then quenched with sat. aq NH4Cl, and the or-
ganic layer was washed with aq 3 M NaOH and brine. The aqueous
layer was extracted with CH2Cl2. The combined organic phases were
dried (MgSO4), filtered, and the solvent was removed under vacuum.
The crude residue was purified by silica gel flash chromatography us-
ing cyclohexane/EtOAc as eluent (9:1 to 7:3).
Ts
N
I
KI
DMF, 80 °C
N
KOAc
DMF, 80 °C
Bn
O
13, 72%
Ts
H
N
OAc
OH
N
Mg
MeOH, r.t.
(ref. 10)
N
N
Bn
Bn
1-Benzyl-5-(chloromethyl)-4-tosylpiperazin-2-one (2a)
O
O
14, 59%
75%
White solid; yield: 79 mg (90%); mp 112–116 °C; Rf = 0.5 (cyclohex-
ane/EtOAc, 1:1); known compound.7j
Scheme 7 Nucleophilic substitutions with 6a
IR (neat): 3059, 3026, 2987, 2920, 1649, 1347, 1163, 684 cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 7.71 (d, J = 8.0 Hz, 2 H), 7.34 (d, J = 8.0
Hz, 2 H), 7.29–7.27 (m, 3 H), 7.07–7.05 (m, 2 H), 4.55 (d, J = 14.5 Hz, 1
H), 4.39 (d, J = 14.5 Hz, 1 H), 4.15 (d, J = 17.0 Hz, 1 H), 4.08–4.02 (m, 1
H), 3.87 (d, J = 17.0 Hz, 1 H), 3.57 (dd, J = 4.0, 11.0 Hz, 1 H), 3.45–3.40
(m, 2 H), 3.27 (dd, J = 4.5, 13.5 Hz, 1 H), 2.45 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 165.0, 144.7, 135.7, 135.1, 130.3,
128.9, 128.5, 128.2, 127.6, 53.3, 49.9, 46.4, 45.4, 42.4, 21.8.
In summary, we have developed mild and efficient con-
ditions for the synthesis of chloromethyl-substituted piper-
azinones, tetrahydroquinoxalines, and benzodiazepinones
via a palladium-catalyzed aminochlorination. This method
allowed in a single step the diheterofunctionalization of
simple and easily accessible alkenes. The reaction was prov-
en to be compatible with the use of N-Ts or N-Boc cycliza-
tion precursors. Moreover, the versatility of the reaction
conditions also allowed the synthesis of chloromethyl-sub-
stituted benzoxazepinone via a palladium-catalyzed oxy-
chlorination. Heterocyclic scaffolds synthesized during this
work can be regarded as versatile synthetic intermediates.
Indeed, taking advantage of the chloromethyl appendage,
we demonstrated that simple nucleophilic substitution al-
lowed an easy post-functionalization of these compounds.
MS (ESI): m/z = 393.1 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C19H22ClN2O3S: 393.1034; found:
393.1037.
tert-Butyl 4-Benzyl-2-(chloromethyl)-5-oxopiperazine-1-carbox-
ylate (2b)
Yellow foam; yield: 81 mg (73%); Rf = 0.21 (cyclohexane/EtOAc, 7:3).
IR (neat): 3063, 3015, 2975, 2927, 1694, 1653, 1426, 1348, 1234,
1177, 724 cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 7.27–7.19 (m, 5 H), 4.59 (d, J = 14.0 Hz,
1 H), 4.50 (d, J = 14.5 Hz, 1 H), 4.38–4.22 (br m, 1 H), 4.18 (d, J = 18.0
Hz, 1 H), 3.85 (d, J = 18.5 Hz, 1 H), 3.49–3.32 (m, 3 H), 3.26 (t, J = 10.0
Hz, 1 H), 1.39 (s, 9 H).
13C NMR (CDCl3, 125 MHz): δ = 165.6, 153.6, 135.9, 128.9, 128.6,
128.1, 81.5, 51.5, 50.1, 46.0, 45.4, 41.1, 28.3.
All reagents were purchased from chemical suppliers and used with-
out further purification. Reactions were performed using freshly dis-
tilled solvents under an argon atmosphere. CH2Cl2 was dried on CaH2.
Anhydrous DMF, toluene, Et2O, and MeCN were purchased from
chemical suppliers. Analytical TLC was performed on commercial sili-
ca gel plates 60F254. Flash column chromatography was performed on
silica gel 60 (40–63 μm). NMR spectra were recorded on a 250 or 500
MHz spectrometer as specified. Chemical shifts (δ) are reported in
ppm relative to TMS (δ = 0.00) or the CHCl3 residual peak (δ = 7.26) or
MS (ESI): m/z = 339.2 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C17H24ClN2O3: 339.1470; found:
339.1468.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

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Paper
Synthesis
(3S)-1-Benzyl-5-(chloromethyl)-3-methyl-4-tosylpiperazin-2-one
(2e)
1H NMR (CDCl3, 500 MHz): δ = 7.65 (d, J = 8.0 Hz, 2 H), 7.32–7.16 (m,
10 H), 6.90–6.84 (m, 2 H), 4.66 (t, J = 5.5 Hz, 1 H), 4.37 (d, J = 14.5 Hz, 1
H), 4.33 (d, J = 14.5 Hz, 1 H), 3.72–3.64 (m, 1 H), 3.45 (dd, J = 5.5, 14.0
Hz, 1 H), 3.28 (dd, J = 3.5, 11.0 Hz, 1 H), 3.22 (dd, J = 6.0, 13.5 Hz, 1 H),
3.10 (dd, J = 6.0, 13.5 Hz, 1 H), 2.97 (dd, J = 5.5, 13.5 Hz, 1 H), 2.67 (t,
J = 11.0 Hz, 1 H), 2.41 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 166.9, 144.6, 136.5, 135.7, 134.9,
130.6, 130.3, 128.8, 128.6, 128.2, 128.0, 127.6, 127.4, 60.1, 53.6, 50.1,
44.4, 43.6, 40.1, 21.7.
Colorless oil; yield: 50 mg (72%); 7/3 dr (cis/trans), Rf (trans) = 0.37
(cyclohexane/EtOAc, 1:1), Rf (cis) = 0.27 (cyclohexane/EtOAc, 1:1).
(3S,5R)-1-Benzyl-5-(chloromethyl)-3-methyl-4-tosylpiperazin-2-
one (trans)
[α]D20 +29 (c 2.05, CHCl3).
1H NMR (CDCl3, 500 MHz): δ = 7.71 (d, J = 8.0 Hz, 2 H), 7.35–7.27 (m, 5
H), 7.24–7.20 (m, 2 H), 4.86 (d, J = 14.5 Hz, 1 H), 4.40 (q, J = 7.0 Hz, 1
H), 4.28 (d, J = 14.5 Hz, 1 H), 4.13–4.07 (m, 1 H), 3.82 (ddd, J = 1.0, 4.0,
10.5 Hz, 1 H), 3.62 (dd, J = 3.0, 13.5 Hz, 1 H), 3.43 (dd, J = 3.5, 13.5 Hz,
1 H), 3.28 (t, J = 11.0 Hz, 1 H), 2.43 (s, 3 H), 1.48 (d, J = 7.0 Hz, 3 H).
MS (ESI): m/z = 483.5 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C26H28ClN2O3S: 483.1504; found:
483.1515.
13C NMR (CDCl3, 125 MHz): δ = 168.7, 144.4, 137.9, 135.9, 130.2,
(3S)-1-Benzyl-3-[(R)-sec-butyl]-5-(chloromethyl)-4-tosylpiperaz-
in-2-one (2g)
129.1, 128.6, 128.2, 127.3, 55.2, 54.8, 50.7, 44.8, 41.8, 21.7, 20.2.
MS (ESI): m/z = 407.7 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C20H24ClN2O3S: 407.1191; found:
Colorless oil; yield: 48 mg (62%); 9:1 dr (cis/trans); Rf = 0.3 (cyclohex-
ane/EtOAc, 1:1).
IR (neat): 2967, 2925, 2873, 1669, 1349, 1164, 749, 656 cm–1
.
407.1194.
1H NMR (C6D6, 500 MHz): δ = 7.75 (d, J = 8.5 Hz, 2 H), 7.03–6.93 (m, 3
H), 6.77 (d, J = 8.0 Hz, 2 H), 6.54 (d, J = 7.0 Hz, 2 H), 4.48 (d, J = 10.5 Hz,
1 H), 4.27 (d, J = 15.0 Hz, 1 H), 3.90 (dd, J = 3.0, 11.0 Hz, 1 H), 3.74 (d,
J = 14.5 Hz, 1 H), 3.64–3.55 (m, 1 H), 3.25 (dd, J = 9.0, 10.5 Hz, 1 H),
2.99 (dd, J = 7.5, 14.0 Hz, 1 H), 2.82 (dd, J = 11.5, 14.0 Hz, 1 H), 2.13–
2.03 (m, 1 H), 1.85 (s, 3 H), 1.42–1.31 (m, 2 H), 0.96 (d, J = 6.5 Hz, 3 H),
0.88 (t, J = 7.5 Hz, 3 H), 0.75 (d, J = 6.5 Hz, 0.3 H), 0.68 (t, J = 7.5 Hz, 0.3
H).
13C NMR (CDCl3, 125 MHz): δ = 168.4, 144.4, 135.9, 134.3, 130.1,
128.8, 128.2, 127.9, 65.6, 55.1, 48.9, 46.5, 44.6, 37.1, 25.8, 21.8, 15.3,
10.9.
MS (ESI): m/z = 449.4 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C23H30ClN2O3S: 449.1660; found:
(3S,5S)-1-Benzyl-5-(chloromethyl)-3-methyl-4-tosylpiperazin-2-
one (cis)
[α]D20 –55 (c 2.1, CHCl3).
IR (neat): 3063, 3031, 2988, 2918, 1656, 1339, 1164, 707, 681 cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 7.70 (d, J = 8.5 Hz, 2 H), 7.33 (d, J = 8.0
Hz, 2 H), 7.28–7.20 (m, 3 H), 6.90–6.86 (m, 2 H), 4.63–4.53 (m, 2 H),
4.22 (d, J = 15.0 Hz, 1 H), 3.93–3.86 (m, 1 H), 3.75 (dd, J = 4.0, 11.0 Hz,
1 H), 3.52 (dd, J = 10.0, 11.5 Hz, 1 H), 3.34 (dd, J = 6.0, 13.5 Hz, 1 H),
3.18 (dd, J = 5.5, 13.0 Hz, 1 H), 2.45 (s, 3 H), 1.59 (d, J = 7.0 Hz, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 168.3, 144.5, 135.7, 135.5, 130.3,
128.9, 128.1, 128.0, 127.5, 54.2, 53.4, 49.9, 45.1, 44.4, 21.8, 21.5.
MS (ESI): m/z = 407.8 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C20H24ClN2O3S: 407.1191; found:
449.1679.
407.1192.
4-Benzyl-2-(chloromethyl)-1-tosyl-1,2,3,4-tetrahydroquinoxaline
(4)
(3S)-1,3-Dibenzyl-5-(chloromethyl)-4-tosylpiperazin-2-one (2f)
Grey foam; yield: 43 mg (50%); Rf = 0.43 (cyclohexane/EtOAc, 7:3).
White foam; yield: 53 mg (71%); 8:2 dr (cis/trans); Rf (trans) = 0.32
(cyclohexane/EtOAc, 7:3), Rf (cis) = 0.24 (cyclohexane/EtOAc, 7:3).
IR (neat): 3088, 2969, 2975, 2901, 1603, 1504, 1340, 1164, 1068, 750,
730, 686 cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 7.76 (dd, J = 1.5, 8.5 Hz, 1 H), 7.41 (d, J =
8.0 Hz, 2 H), 7.25–7.14 (m, 5 H), 7.05–6.98 (m, 1 H), 6.86–6.77 (m, 2
H), 6.77–6.70 (m, 1 H), 6.56 (d, J = 8.5 Hz, 1 H), 4.59–4.52 (m, 1 H),
4.53 (d, J = 17.0 Hz, 1 H), 4.12 (d, J = 17.0 Hz, 1 H), 3.60 (dd, J = 5.5, 11.0
Hz, 1 H), 3.34 (t, J = 10.0 Hz, 1 H), 3.27 (dd, J = 2.5, 12.0 Hz, 1 H), 2.84
(dd, J = 4.5, 12.5 Hz, 1 H), 2.42 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 144.0, 138.4, 137.4, 135.7, 129.8,
128.7, 127.7, 127.5, 127.3, 127.2, 126.5, 119.8, 117.4, 111.9, 54.8, 53.3,
45.9, 43.1, 21.8.
(3S,5R)-1,3-Dibenzyl-5-(chloromethyl)-4-tosylpiperazin-2-one
(trans)
[α]D20 –27 (c 0.5, CHCl3).
1H NMR (CDCl3, 500 MHz): δ = 7.67 (d, J = 8.0 Hz, 2 H), 7.35–7.27 (m, 5
H), 7.23–7.12 (m, 5 H), 7.06 (d, J = 7.0 Hz, 2 H), 4.52–4.42 (m, 2 H),
4.34 (d, J = 14.0 Hz, 1 H), 4.03–3.95 (m, 1 H), 3.71 (dd, J = 4.0, 10.5 Hz,
1 H), 3.46 (dd, J = 5.5, 13.5 Hz, 1 H), 3.26 (dd, J = 4.5, 13.5 Hz, 1 H), 3.19
(dd, J = 4.5, 14.0 Hz, 1 H), 3.14 (t, J = 10.5 Hz, 1 H), 2.49–2.41 (m, 4 H).
13C NMR (CDCl3, 125 MHz): δ = 166.8, 144.6, 136.9, 135.9, 135.6,
130.2, 129.1, 128.9, 128.4, 128.1, 127.6, 127.2, 60.7, 54.9, 50.7, 44.6,
41.5, 39.0, 21.7.
MS (ESI): m/z = 427.1 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C23H24ClN2O2S: 427.1242; found:
427.1234.
(3S,5S)-1,3-Dibenzyl-5-(chloromethyl)-4-tosylpiperazin-2-one
(cis)
[α]D20 –42 (c 2.8, CHCl3).
4-Benzyl-2-(chloromethyl)-1-tosyl-1,2,3,4-tetrahydro-5H-ben-
zo[e][1,4]diazepin-5-one (6a)
White solid; yield: 93 mg (78%); mp 193 °C; Rf = 0.6 (cyclohexane/
EtOAc, 1:1).
IR (neat): 3069, 2967, 2920, 2851, 1645, 1354, 1160, 1098, 717 cm–1
IR (neat): 3065, 3032, 2987, 2923, 2853, 1654, 1337, 1163, 1149, 707,
697 cm–1
.
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

G
A.-D. Manick et al.
Paper
Synthesis
1H NMR (CDCl3, 500 MHz): δ = 7.72 (dd, J = 1.5, 7.5 Hz, 1 H), 7.58–7.43
(m, 5 H), 7.33–7.24 (m, 5 H), 7.14 (d, J = 7.0 Hz, 2 H), 4.67 (d, J = 14.5
Hz, 1 H), 4.59–4.51 (m, 1 H), 3.83 (dd, J = 4.0, 11.0 Hz, 1 H), 3.52 (d, J =
15.0 Hz, 1 H), 3.51 (dd, J = 2.5, 8.5 Hz, 1 H), 3.39 (dd, J = 4.5, 15.5 Hz, 1
H), 3.10 (dd, J = 12.0, 16.0 Hz, 1 H), 2.43 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 167.7, 144.4, 136.5, 135.5, 134.5,
133.4, 132.9, 132.1, 130.5, 130.0, 129.6, 128.9, 128.3, 127.9, 127.4,
61.9, 49.5, 47.6, 44.7, 21.8.
1H NMR (CDCl3, 500 MHz): δ = 7.64 (d, J = 8.5 Hz, 1 H), 7.46 (d, J = 8.5
Hz, 2 H), 7.33–7.26 (m, 5 H), 7.12 (d, J = 7.0 Hz, 2 H), 7.03 (d, J = 2.5 Hz,
1 H), 6.99 (dd, J = 2.5, 8.5 Hz, 1 H), 4.61 (d, J = 15.0 Hz, 1 H), 4.56–4.47
(m, 1 H), 3.88 (s, 3 H), 3.82 (dd, J = 3.5, 11.0 Hz, 1 H), 3.53 (dd, J = 9.0,
11.0 Hz, 1 H), 3.48 (d, J = 15.0 Hz, 1 H), 3.37 (dd, J = 4.5, 15.5 Hz, 1 H),
3.11 (dd, J = 12.0, 15.5 Hz, 1 H), 2.43 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 167.8, 162.4, 144.4, 136.7, 135.4,
134.5, 131.8, 130.1, 128.9, 128.4, 127.9, 127.5, 126.6, 118.4, 115.6,
61.9, 55.9, 49.4, 47.6, 44.8, 21.8.
MS (ESI): m/z = 455.3 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C24H24ClN2O3S: 455.1191; found:
MS (ESI): m/z = 485.4 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C25H26ClN2O4S: 485.1296; found:
455.1184.
485.1298.
4-Benzyl-2-(chloromethyl)-8-methyl-1-tosyl-1,2,3,4-tetrahydro-
5H-benzo[e][1,4]diazepin-5-one (6b)
4-Benzyl-2-(chloromethyl)-1-tosyl-1,2,3,4-tetrahydro-5H-naph-
tho[2,3-e][1,4]diazepin-5-one (6e)
White solid; yield: 73 mg (80%); mp 180–182 °C; Rf = 0.41 (cyclohex-
ane/EtOAc, 1:1).
Pale yellow foam; yield: 74 mg (73%); Rf = 0.4 (cyclohexane/EtOAc,
1:1).
IR (neat): 3007, 2919, 2850, 2927, 1647, 1354, 1221, 1159, 1099, 719
cm–1
.
IR (neat): 3067, 3031, 2958, 2923, 1651, 1629, 1353, 1164, 1093, 730,
706 cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 7.52 (d, J = 2.0 Hz, 1 H), 7.46 (td, J = 2.5,
8.0 Hz, 2 H), 7.40 (d, J = 8.0 Hz, 1 H), 7.35 (dd, J = 2.5, 8.0 Hz, 1 H),
7.32–7.24 (m, 5 H), 7.15–7.11 (m, 2 H), 4.66 (d, J = 14.5 Hz, 1 H), 4.57–
4.48 (m, 1 H), 3.82 (dd, J = 4.0, 11.0 Hz, 1 H), 3.50 (dd, J = 8.5, 11.0 Hz,
1 H), 3.49 (d, J = 15.0 Hz, 1 H), 3.37 (dd, J = 4.5, 15.5 Hz, 1 H), 3.08 (dd,
J = 12.0, 15.5 Hz, 1 H), 2.43 (s, 3 H), 2.41 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 167.9, 144.3, 139.9, 136.6, 135.6,
134.1, 133.2, 132.9, 130.9, 130.2, 130.1, 128.9, 128.3, 127.9, 127.4,
61.8, 49.4, 47.7, 44.7, 21.8, 21.2.
1H NMR (CDCl3, 500 MHz): δ = 8.27 (s, 1 H), 8.01 (s, 1 H), 7.96–7.90
(m, 2 H), 7.64–7.57 (m, 2 H), 7.45 (dt, J = 2.0, 8.5 Hz, 2 H), 7.35–7.26
(m, 5 H), 7.20–7.16 (m, 2 H), 4.75 (d, J = 14.5 Hz, 1 H), 4.65–4.57 (m, 1
H), 3.91 (dd, J = 4.0, 11.0 Hz, 1 H), 3.62 (d, J = 15.0 Hz, 1 H), 3.54 (dd, J =
8.5, 11.0 Hz, 1 H), 3.47 (dd, J = 4.5, 15.5 Hz, 1 H), 3.11 (dd, J = 12.0, 16.0
Hz, 1 H), 2.43 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 167.8, 144.3, 136.6, 135.7, 134.7,
132.8, 132.8, 131.9, 131.7, 130.1, 128.9, 128.8, 128.4, 128.3, 127.9,
127.4, 61.3, 49.7, 47.5, 44.4, 21.8.
MS (ESI): m/z = 469.3 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C25H26ClN2O3S: 469.1347; found:
MS (ESI): m/z = 505.3 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C28H26ClN2O3S: 505.1347; found:
469.1342.
505.1323.
4-Benzyl-2-(chloromethyl)-7,8-dimethoxy-1-tosyl-1,2,3,4-tetrahy-
dro-5H-benzo[e][1,4]diazepin-5-one (6c)
4-Benzyl-8-chloro-2-(chloromethyl)-1-tosyl-1,2,3,4-tetrahydro-
5H-benzo[e][1,4]diazepin-5-one (6f)
Pale yellow solid; yield: 100 mg (97%); mp 141–143 °C; Rf = 0.17 (cy-
clohexane/EtOAc, 7:3).
Yellow solid; yield: 45 mg (62%); mp 138 °C; Rf = 0.27 (cyclohex-
ane/EtOAc, 7:3).
IR (neat): 3067, 2990, 2901, 1652, 1425, 1338, 1220, 1161, 712, 694
cm–1
.
IR (neat): 3069, 3032, 2922, 2854, 1644, 1591, 1344, 1162, 1089, 675
cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 7.47 (d, J = 8.5 Hz, 2 H), 7.35–7.26 (m, 5
H), 7.16 (s, 1 H), 7.15 (d, J = 6.5 Hz, 2 H), 6.98 (s, 1 H), 4.61 (d, J = 15.0
Hz, 1 H), 4.60–4.52 (m, 1 H), 3.96 (s, 3 H), 3.95 (s, 3 H), 3.82 (dd, J =
4.0, 11.5 Hz, 1 H), 3.57 (dd, J = 8.0, 11.0 Hz, 1 H), 3.48 (d, J = 14.5 Hz, 1
H), 3.36 (dd, J = 4.5, 15.5 Hz, 1 H), 3.15 (dd, J = 12.0, 15.5 Hz, 1 H), 2.44
(s, 3 H).
1H NMR (CDCl3, 500 MHz): δ = 7.65 (d, J = 8.5 Hz, 1 H), 7.56 (d, J = 2.0
Hz, 1 H), 7.48–7.43 (m, 3 H), 7.34–7.27 (m, 5 H), 7.15–7.10 (m, 2 H),
4.64 (d, J = 14.5 Hz, 1 H), 4.57–4.47 (m, 1 H), 3.81 (dd, J = 4.0, 11.0 Hz,
1 H), 3.56 (dd, J = 8.5, 11.0 Hz, 1 H), 3.53 (d, J = 15.0 Hz, 1 H), 3.39 (dd,
J = 4.5, 15.5 Hz, 1 H), 3.11 (dd, J = 12.0, 15.5 Hz, 1 H), 2.44 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 167.8, 151.4, 149.7, 144.3, 136.6,
135.3, 130.0, 128.9, 128.3, 127.9, 127.5, 126.6, 126.5, 115.9, 111.9,
62.1, 56.5, 56.3, 49.5, 47.7, 44.9, 21.7.
13C NMR (CDCl3, 125 MHz): δ = 166.8, 144.7, 137.8, 136.2, 135.2,
134.3, 133.4, 132.9, 131.5, 130.2, 129.9, 128.9, 128.4, 128.1, 127.4,
61.9, 49.6, 47.5, 44.8, 21.8.
MS (ESI): m/z = 515.4 [M + H+].
MS (ESI): m/z = 489.2 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C26H28ClN2O5S: 515.1402; found:
HRMS (ESI): m/z [M + H+] calcd for C24H23Cl2N2O3S: 489.0801; found:
515.1404.
489.0800.
4-Benzyl-2-(chloromethyl)-8-methoxy-1-tosyl-1,2,3,4-tetrahydro-
5H-benzo[e][1,4]diazepin-5-one (6d)
4-Benzyl-2-(chloromethyl)-7-nitro-1-tosyl-1,2,3,4-tetrahydro-5H-
benzo[e][1,4]diazepin-5-one (6g)
White solid; yield: 44 mg (58%); mp 147 °C; Rf = 0.12 (cyclohex-
Yellow foam; yield: 22 mg (23%); Rf = 0.29 (cyclohexane/EtOAc, 7:3).
ane/EtOAc, 7:3).
IR (neat): 2988, 2901, 1638, 1604, 1437, 1161, 724, 674 cm–1
IR (neat): 3080, 2925, 2853, 1661, 1524, 1353, 1165, 710 cm–1
.
.
1H NMR (CDCl3, 500 MHz): δ = 8.56 (d, J = 3.0 Hz, 1 H), 8.36 (dd, J = 3.0,
9.0 Hz, 1 H), 7.78 (d, J = 9.0 Hz, 1 H), 7.44 (dt, J = 2.0, 8.0 Hz, 2 H), 7.35–
7.27 (m, 5 H), 7.16–7.11 (m, 2 H), 4.69 (d, J = 14.5 Hz, 1 H), 4.62–4.52
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

H
A.-D. Manick et al.
Paper
Synthesis
(m, 1 H), 3.77 (dd, J = 3.0, 11.5 Hz, 1 H), 3.71 (dd, J = 7.5, 11.5 Hz, 1 H),
3.57 (d, J = 14.5 Hz, 1 H), 3.37 (dd, J = 4.5, 16.0 Hz, 1 H), 3.22 (dd, J =
11.5, 16.0 Hz, 1 H), 2.45 (s, 3 H).
4-Benzyl-2-(chloromethyl)-7-methoxy-3,4-dihydroben-
zo[f][1,4]oxazepin-5(2H)-one (8c)
Pale yellow oil; yield: 28 mg (42%); Rf = 0.26 (cyclohexane/EtOAc, 7:3).
13C NMR (CDCl3, 125 MHz): δ = 165.5, 147.9, 145.2, 139.1, 135.7,
135.6, 134.9, 130.4, 129.1, 128.4, 127.4, 126.4, 125.9, 62.0, 49.7, 47.3,
45.7, 21.8.
MS (ESI): m/z = 500.3 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C24H23ClN3O5S: 500.1041; found:
IR (neat): 3006, 2924, 2856, 1645, 1486, 1431, 1273, 1201, 1042, 701
cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 7.41–7.27 (m, 6 H), 6.96 (dd, J = 3.0, 9.0
Hz, 1 H), 6.93 (d, J = 8.5 Hz, 1 H), 5.10 (d, J = 15.0 Hz, 1 H), 4.59 (d, J =
14.5 Hz, 1 H), 4.39–4.29 (m, 1 H), 3.83 (s, 3 H), 3.60 (dd, J = 5.0, 11.0
Hz, 1 H), 3.50–3.44 (m, 2 H), 3.41 (dd, J = 8.0, 11.5 Hz, 1 H).
500.1056.
13C NMR (CDCl3, 125 MHz): δ = 168.8, 156.6, 146.0, 137.0, 129.0,
tert-Butyl 4-Benzyl-2-(chloromethyl)-5-oxo-2,3,4,5-tetrahydro-
1H-benzo[e][1,4]diazepine-1-carboxylate (6h)
128.9, 128.4, 128.0, 123.4, 119.8, 113.9, 82.7, 55.9, 51.2, 47.3, 42.6.
MS (ESI): m/z = 332.3 [M + H+].
Beige foam; yield: 60 mg (64%); Rf = 0.27 (cyclohexane/EtOAc, 7:3).
HRMS (ESI): m/z [M + H+] calcd for C18H19ClNO3S: 332.1048; found:
IR (neat): 3064, 2973, 2919, 2852, 1687, 1642, 1471, 1164, 1046, 763,
332.1048.
715, 697 cm–1
.
1H NMR (C6D6, 500 MHz): δ = 7.87 (d, J = 7.5 Hz, 1 H), 7.25–7.17 (m, 3
H), 7.14–6.89 (m, 5 H), 4.87–4.27 (br m, 3 H), 3.07 (dd, J = 5.0, 11.0 Hz,
1 H), 3.00–2.82 (br m, 2 H), 2.69 (dd, J = 12.5, 15.5 Hz, 1 H), 1.24 (s, 9
H).
13C NMR (C6D6, 125 MHz): δ = 168.4, 154.6, 138.0, 136.2, 134.3, 130.8,
130.6, 130.1, 129.0, 128.6, 128.4, 80.9, 59.4, 50.3, 48.0, 43.3, 28.0.
4-Benzyl-7-chloro-2-(chloromethyl)-3,4-dihydrobenzo[f][1,4]ox-
azepin-5(2H)-one (8d)
Colorless oil; yield: 37 mg (55%); Rf = 0.3 (cyclohexane/EtOAc, 7:3).
IR (neat): 3065, 3030, 2922, 2851, 1646, 1468, 1428, 1258, 1213,
1046, 700 cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 7.82 (dd, J = 1.0, 2.5 Hz, 1 H), 7.39–7.29
(m, 6 H), 6.96 (d, J = 8.5 Hz, 1 H), 5.08 (d, J = 14.5 Hz, 1 H), 4.59 (d, J =
15.0 Hz, 1 H), 4.43–4.35 (m, 1 H), 3.60 (dd, J = 4.5, 11.5 Hz, 1 H), 3.54
(dd, J = 7.0, 15.5 Hz, 1 H) 3.47 (dd, J = 3.5, 15.0 Hz, 1 H), 3.46 (dd, J =
8.0, 11.5 Hz, 1 H).
MS (ESI): m/z = 401.1 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C22H26ClN2O3: 401.1626; found:
401.1623.
4-Benzyl-2-(chloromethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-
5(2H)-one (8a)
13C NMR (CDCl3, 125 MHz): δ = 167.4, 151.2, 136.6, 132.9, 130.8,
129.9, 129.1, 128.5, 128.2, 123.8, 82.9, 51.3, 46.9, 42.8.
MS (ESI): m/z = 336.3 [M + H+].
Colorless oil; yield: 30 mg (50%); Rf = 0.26 (cyclohexane/EtOAc, 7:3).
IR (neat): 3064, 3030, 2984, 1643, 1603, 1488, 1210, 758, 701 cm–1
.
HRMS (ESI): m/z [M + H+] calcd for C17H16Cl2NO2S: 336.0553, found
1H NMR (CDCl3, 500 MHz): δ = 7.84 (dd, J = 2.0, 8.0 Hz, 1 H), 7.42 (td,
J = 2.0, 8.0 Hz, 1 H), 7.39–7.28 (m, 5 H), 7.22 (td, J = 1.5, 7.5 Hz, 1 H),
7.01 (dd, J = 1.0, 8.0 Hz, 1 H), 5.11 (d, J = 14.5 Hz, 1 H), 4.60 (d, J = 14.5
Hz, 1 H), 4.44–4.35 (m, 1 H), 3.62 (dd, J = 5.0, 11.5 Hz, 1 H), 3.56–3.46
(m, 2 H), 3.44 (dd, J = 8.0, 11.5 Hz, 1 H).
13C NMR (CDCl3, 125 MHz): δ = 168.7, 152.5, 136.9, 133.0, 131.0,
128.9, 128.5, 128.0, 127.9, 124.6, 122.3, 82.8, 51.2, 47.2, 42.7.
336.0552.
4-Benzyl-7-bromo-2-(chloromethyl)-3,4-dihydrobenzo[f][1,4]ox-
azepin-5(2H)-one (8e)
Pale yellow oil; yield: 38 mg (50%); Rf = 0.31 (cyclohexane/EtOAc, 7:3).
IR (neat): 3068, 2923, 2854, 1646, 1467, 1428, 1259, 1212, 1117, 700
cm–1
.
MS (ESI): m/z = 302.2 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C17H17ClNO2: 302.0942; found:
1H NMR (CDCl3, 500 MHz): δ = 7.96 (d, J = 2.5 Hz, 1 H), 7.51 (dd, J = 2.5,
9.0 Hz, 1 H), 7.41–7.28 (m, 5 H), 6.90 (d, J = 8.5 Hz, 1 H), 5.07 (d, J =
15.0 Hz, 1 H), 4.59 (d, J = 15.0 Hz, 1 H), 4.44–4.35 (m, 1 H), 3.60 (dd, J =
5.0, 11.5 Hz, 1 H), 3.54 (dd, J = 7.0, 16.0 Hz, 1 H), 3.50–3.42 (m, 2 H).
302.0938.
4-Benzyl-2-(chloromethyl)-7-methyl-3,4-dihydrobenzo[f][1,4]ox-
azepin-5(2H)-one (8b)
13C NMR (CDCl3, 125 MHz): δ = 167.3, 151.7, 136.6, 135.9, 133.8,
129.3, 129.1, 128.5, 128.2, 124.2, 117.3, 82.9, 51.3, 46.9, 42.8.
MS (ESI): m/z = 380.3 [M + H+].
Colorless oil; yield: 35 mg (55%); Rf = 0.31 (cyclohexane/EtOAc, 7:3).
IR (neat): 3030, 2924, 2854, 1645, 1610, 1487, 1220, 1049, 749 cm–1
.
HRMS (ESI): m/z [M + H+] calcd for C17H16BrClNO2: 380.0047; found:
1H NMR (CDCl3, 500 MHz): δ = 7.62 (d, J = 2.0 Hz, 1 H), 7.38–7.27 (m, 5
H), 7.21 (dd, J = 2.5, 8.5 Hz, 1 H), 6.90 (d, J = 8.5 Hz, 1 H), 5.09 (d, J =
14.5 Hz, 1 H), 4.60 (d, J = 14.5 Hz, 1 H), 4.41–4.31 (m, 1 H), 3.61 (dd, J =
5.0, 11.0 Hz, 1 H), 3.53–3.44 (m, 2 H), 3.43 (dd, J = 8.5, 11.0 Hz, 1 H),
2.36 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 169.0, 150.3, 137.1, 134.4, 133.7,
131.1, 128.9, 128.5, 127.9, 127.8, 122.1, 82.7, 51.2, 47.2, 42.7, 20.8.
380.0048.
4-Benzyl-2-(chloromethyl)-8-fluoro-3,4-dihydrobenzo[f][1,4]ox-
azepin-5(2H)-one (8f)
Colorless oil; yield: 33 mg (52%); Rf = 0.28 (cyclohexane/EtOAc, 7:3).
IR (neat): 3064, 2923, 1644, 1609, 1467, 1430, 1258, 1142, 1103, 745,
701 cm–1
.
MS (ESI): m/z = 316.3 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C18H19ClNO2: 316.1099; found:
1H NMR (CDCl3, 500 MHz): δ = 7.87 (dd, J = 6.5, 8.5 Hz, 1 H), 7.39–7.27
(m, 5 H), 6.92 (td, J = 2.5, 8.5 Hz, 1 H), 6.73 (dd, J = 2.5, 9.5 Hz, 1 H),
5.09 (d, J = 14.5 Hz, 1 H), 4.58 (d, J = 14.5 Hz, 1 H), 4.47–4.35 (m, 1 H),
3.61 (dd, J = 5.0, 11.5 Hz, 1 H), 3.57 (dd, J = 7.0, 16.0 Hz, 1 H), 3.49 (dd,
J = 3.0, 16.5 Hz, 1 H), 3.48 (dd, J = 8.5, 11.0 Hz, 1 H).
316.1095.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

I
A.-D. Manick et al.
Paper
Synthesis
13C NMR (CDCl3, 125 MHz): δ = 167.8, 165.4 (d, J = 251.5 Hz), 154.3 (d,
J = 11.7 Hz), 136.8, 133.2 (d, J = 10.4 Hz), 129.1, 128.5 , 128.1, 123.5 (d,
J = 3.1 Hz), 111.9 (d, J = 21.1 Hz), 109.4 (d, J = 23.0 Hz), 83.0, 51.3, 47.2,
42.9.
MS (ESI): m/z = 320.3 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C17H16ClFNO2S: 320.0848; found:
1-Benzyl-5-(hydroxymethyl)-4-tosylpiperazin-2-one (11)
In a round-bottom flask, 1-benzyl-5-(iodomethyl)-4-tosylpiperazin-
2-one (10; 0.11 mmol, 52 mg) was placed in 10% aq acetone (1 mL).
Then AgBF4 (0.24 mmol, 46 mg) was added. The solution was stirred
at r.t. After 48 h, AgBF4 0.214 mmol, 42 mg) was added followed by an
additional amount of AgBF4 (0.322 mmol, 63 mg) after 48 h. The reac-
tion mixture was washed with brine and the aqueous layer was ex-
tracted with CH2Cl2. The combined organic phases were dried
(MgSO4), filtered, and the solvent was removed under vacuum. The
crude residue was purified by silica gel flash chromatography using
EtOAc as eluent; colorless foam; yield: 26 mg (65%); Rf = 0.2 (cyclo-
hexane/EtOAc, 1:1).
320.0845.
5-(Azidomethyl)-1-benzyl-4-tosylpiperazin-2-one (9)
In a round-bottom flask, 1-benzyl-5-(chloromethyl)-4-tosylpiperaz-
in-2-one (2a; 0.13 mmol, 52 mg) was placed in DMF (1.5 mL) under
argon. Then NaN3 (1.45 mmol, 94 mg) was added. The solution was
stirred at 80 °C. After 12 h, NaN3 (2.65 mmol, 0.172 mg) was added.
After more than 24 h, the reaction mixture was washed with brine
and the aqueous layer was extracted with EtOAc. The combined or-
ganic phases were dried (MgSO4), filtered, and the solvent was re-
moved under vacuum. The crude residue was purified by silica gel
flash chromatography using pentane/EtOAc as eluent (9:1 to 1:1);
yellow foam; yield: 37 mg (70%); Rf = 0.54 (cyclohexane/EtOAc, 1:1).
IR (neat): 2961, 2920, 2851, 2999, 1742, 1651, 1496, 1463, 1378,
1348, 1261, 1162, 1114, 1031, 974, 815, 711, 694, 654 cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 7.71 (d, J = 8.5 Hz, 2 H), 7.32 (d, J = 8.0
Hz, 2 H), 7.30–7.24 (m, 3 H), 7.08–6.99 (m, 2 H), 4.49 (d, J = 14.5 Hz, 1
H), 4.39 (d, J = 14.5 Hz, 1 H), 4.22 (d, J = 17.5 Hz, 1 H), 3.95–3.88 (m, 1
H), 3.91 (d, J = 17.5 Hz, 1 H), 3.68–3.59 (m, 1 H), 3.58–3.48 (m, 1 H),
3.24 (dd, J = 4.0, 13.0 Hz, 1 H), 3.16 (dd, J = 5.5, 13.5 Hz, 1 H), 2.44 (s, 3
H).
13C NMR (CDCl3, 125 MHz): δ = 165.2, 144.4, 135.9, 135.5, 130.2,
128.9, 128.4, 128.1, 127.6, 61.4, 53.4, 49.7, 46.5, 45.0, 21.7.
MS (ESI): m/z = 375.3 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C19H23N2O4S: 375.1373; found:
IR (neat): 3018, 2926, 2853, 2107, 1651, 1597, 1496, 1452, 1426,
1343, 1306, 1158, 1116, 1089, 1032, 937, 817, 723, 694 cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 7.70 (d, J = 8.5 Hz, 2 H), 7.33 (d, J = 8.0
Hz, 2 H), 7.30–7.26 (m, 3 H), 7.08–7.01 (m, 2 H), 4.48 (d, J = 15.0 Hz, 1
H), 4.41 (d, J = 14.5 Hz, 1 H), 4.21 (d, J = 17.0 Hz, 1 H), 3.97–3.89 (m, 1
H), 3.86 (d, J = 17.0 Hz, 1 H), 3.41 (dd, J = 5.0, 12.0 Hz, 1 H), 3.32 (dd, J =
8.5, 12.5 Hz, 1 H), 3.24–3.15 (m, 2 H), 2.44 (s, 3 H).
375.1374.
13C NMR (CDCl3, 125 MHz): δ = 164.9, 144.6, 135.7, 135.2, 130.2,
128.9, 128.4, 128.2, 127.5, 51.3, 50.9, 49.7, 46.2, 45.7, 21.7.
2-(Azidomethyl)-4-benzyl-1-tosyl-1,2,3,4-tetrahydro-5H-ben-
zo[e][1,4]diazepin-5-one (12)
MS (ESI): m/z = 400.2 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C19H22N5O3S: 400.1438; found:
In a round-bottom flask, 4-benzyl-2-(chloromethyl)-1-tosyl-1,2,3,4-
tetrahydro-5H-benzo[e][1,4]diazepin-5-one (6a; 0.088 mmol, 40 mg)
was placed in DMF (1 mL) under argon. Then NaN3 (0.88 mmol, 57
mg) was added. The solution was stirred at 80 °C for 48 h. The reac-
tion mixture was washed with brine and the aqueous layer was ex-
tracted with EtOAc. The combined organic phases were dried
(MgSO4), filtered, and the solvent was removed under vacuum. The
crude residue was purified by silica gel flash chromatography using
pentane/EtOAc as eluent (9:1 to 6:4); white solid; yield: 39 mg (96%);
mp 157 °C; Rf = 0.15 (cyclohexane/EtOAc, 7:3).
400.1432.
1-Benzyl-5-(iodomethyl)-4-tosylpiperazin-2-one (10)
In a round-bottom flask, 2a (0.17 mmol, 68 mg) was placed in DMF
(2.3 mL) under argon. Then KI (5.2 mmol, 862 mg) was added. The
solution was stirred at 80 °C until the starting material was totally
consumed (monitored by TLC, 3 days). The reaction mixture was
washed with brine and the aqueous layer was extracted with EtOAc.
The combined organic phases were dried (MgSO4), filtered, and the
solvent was removed under vacuum. The crude residue was purified
by silica gel flash chromatography using pentane/EtOAc as eluent (8:2
to 6:4); pale yellow solid; yield: 67 mg (80%); mp 118–120 °C, Rf =
0.15 (cyclohexane/EtOAc, 7:3).
IR (neat): 3669, 2988, 2899, 2294, 2105, 1655, 1597, 1449, 1411,
1352, 1259, 1222, 1162, 1065, 881, 763, 745, 712, 663, 613 cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 7.71 (dd, J = 2.0, 8.0 Hz, 1 H), 7.61–7.52
(m, 2 H), 7.50 (td, J = 2.0, 7.5 Hz, 1 H), 7.45 (td, J = 2.0, 8.5 Hz, 2 H),
7.33–7.23 (m, 5 H), 7.14–7.09 (m, 2 H), 4.66 (d, J = 15.0 Hz, 1 H), 4.50–
4.41 (m, 1 H), 3.61 (dd, J = 4.5, 12.5 Hz, 1 H), 3.48 (d, J = 15.0 Hz, 1 H),
3.45 (dd, J = 7.0, 12.5 Hz, 1 H), 3.12 (dd, J = 5.0, 15.5 Hz, 1 H), 3.06 (dd,
J = 11.5, 15.5 Hz, 1 H), 2.42 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 167.7, 144.3, 136.4, 135.5, 134.5,
133.1, 132.9, 132.2, 130.6, 130.1, 129.6, 128.9, 128.2, 127.9, 127.4,
60.7, 53.6, 49.4, 47.5, 21.8.
IR (neat): 3075, 2971, 2923, 2847, 2345, 1656, 1491, 1348, 1164,
1119, 1056, 1008, 811, 688, 663 cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 7.71 (d, J = 8.0 Hz, 2 H), 7.34 (d, J = 8.0
Hz, 2 H), 7.31–7.26 (m, 3 H), 7.11–7.02 (m, 2 H), 4.48 (s, 2 H), 4.14 (d,
J = 17.0 Hz, 1 H), 4.08–4.01 (m, 1 H), 3.85 (d, J = 17.5 Hz, 1 H), 3.46 (dd,
J = 3.5, 13.0 Hz, 1 H), 3.34 (dd, J = 5.0, 13.5 Hz, 1 H), 3.20–3.09 (m, 2 H),
2.44 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 164.7, 144.7, 135.8, 135.1, 130.3,
129.1, 128.5, 128.2, 127.6, 53.5, 49.9, 47.4, 45.9, 21.8, 3.1.
MS (ESI): m/z = 462.3 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C24H24N5O3S: 462.1594; found:
462.1587.
MS (ESI): m/z = 485.2 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C19H22IN2O3S: 485.0390; found:
4-Benzyl-2-(iodomethyl)-1-tosyl-1,2,3,4-tetrahydro-5H-ben-
zo[e][1,4]diazepin-5-one (13)
485.0374.
In a round-bottom flask, 6a (0.44 mmol, 200 mg) was placed in DMF
(4.4 mL) under argon. Then KI (13.2 mmol, 2.2 mg) was added. The
solution was stirred at 80 °C until the starting material was totally
consumed (monitored by TLC, 5 days). The reaction mixture was
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

J
A.-D. Manick et al.
Paper
Synthesis
washed with brine and the aqueous layer was extracted with EtOAc.
The combined organic phases were dried (MgSO4), filtered, and the
solvent was removed under vacuum. The crude residue was purified
by silica gel flash chromatography using pentane/EtOAc as eluent (8:2
to 6:4); white solid; yield: 173 mg (72%); mp 180–182 °C; Rf = 0.3 (cy-
clohexane/EtOAc, 1:1).
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1276, 1261, 1161, 1057, 764, 749, 664 cm–1
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1H NMR (CDCl3, 500 MHz): δ = 7.73–7.68 (m, 1 H), 7.57–7.52 (m, 2 H),
7.50–7.42 (m, 3 H), 7.34–7.25 (m, 5 H), 7.17–7.12 (m, 2 H), 4.63 (d, J =
14.5 Hz, 1 H), 4.48–4.36 (m, 1 H), 3.58–3.52 (m, 2 H), 3.51 (dd, J = 4.0,
10.0 Hz, 1 H), 3.08 (t, J = 10.0 Hz, 1 H), 2.94 (dd, J = 12.0, 16.0 Hz, 1 H),
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13C NMR (CDCl3, 125 MHz): δ = 167.6, 144.3, 136.4, 135.5, 134.5,
133.7, 132.5, 132.0, 130.5, 130.0, 129.6, 128.9, 128.5, 127.9, 127.4,
61.7, 49.6, 49.5, 21.7, 4.5.
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Zibreg, G. H.; Huang, G.; Matthew, J. P.; Ferreira, M. M. M.;
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MS (ESI): m/z = 547.2 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C24H24IN2O3S: 547.0547; found:
547.0529.
(4-Benzyl-5-oxo-1-tosyl-2,3,4,5–tetrahydro-1H-benzo[e][1,4]di-
azepin-2-yl)methyl Acetate (14)
In a round-bottom flask, 6a (0.081 mmol, 37 mg) was placed in DMF
(1 mL) under argon. Then KOAc (2.44 mmol, 240 mg) was added. The
solution was stirred at 80 °C for 5 days. The reaction mixture was
washed with brine and the aqueous layer was extracted with EtOAc.
The combined organic phases were dried (MgSO4), filtered, and the
solvent was removed under vacuum. The crude residue was purified
by silica gel flash chromatography using pentane/EtOAc as eluent (9:1
to 6:4); pale yellow solid; yield: 23 mg (59%); mp 122–126 °C; Rf =
0.45 (cyclohexane/EtOAc, 7:3); known compound.10
IR (neat): 3033, 2926, 2854, 1742, 1646, 1467, 1337, 1226, 1156 cm–1
.
1H NMR (CDCl3, 250 MHz): δ = 7.73 (dd, J = 8.0, 1.5 Hz, 1 H), 7.60–7.42
(m, 5 H), 7.30–7.25 (m, 5 H), 7.18–7.12 (m, 2 H), 4.74–4.66 (m, 2 H),
4.15 (dd, J = 11.5, 5.5 Hz, 1 H), 4.06 (dd, J = 11.5, 5.7 Hz, 1 H), 3.52 (d,
J = 14.7 Hz, 1 H), 3.13 (dd, J = 15.2, 5.2 Hz, 1 H), 3.00 (dd, J = 15.0, 11.5
Hz, 1 H), 2.43 (s, 3 H), 2.01 (s, 3 H).
13C NMR (CDCl3, 62.5 MHz): δ = 170.5, 167.8, 143.9, 136.5, 135.8,
134.7, 133.3, 132.9, 131.9, 130.3, 129.9, 129.4, 128.8, 128.1, 127.8,
127.3, 63.8, 59.9, 49.3, 46.8, 21.6, 20.7.
(8) For vicinal aminoheterofunctionalization of alkenes catalyzed
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Yoon, T. P. J. Am. Chem. Soc. 2012, 134, 12370. (j) Lu, D.-F.; Liu,
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(k) Zhu, C.-L.; Tian, J.-S.; Gu, Z.-Y.; Xing, G.-W.; Xu, H. Chem. Sci.
2015, 6, 3044. (l) Daniel, M.; Blanchard, F.; Nocquet-Thibaut, S.;
Cariou, K.; Dodd, R. H. J. Org. Chem. 2015, 80, 10624. (m) Li, W.;
Liu, G.-Q.; Cui, B.; Zhang, L.; Li, T. T.; Li, L.; Duan, L.; Li, Y.-M. RSC
Adv. 2014, 4, 13509.
MS (ESI): m/z = 479.2 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C16H27N2O5S: 479.1635; found:
479.1626.
Acknowledgment
This work was supported by the CNRS, the Université Paris Descartes,
and the Ministère de l’Education Nationale de l’Enseignement
Supérieur et de la Recherche (Ph.D. grant for A.-D. M.).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561671.
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