Electronic halocyclization and radical haloazidation of benzene-linked 1,7-dienes for the synthesis of functionalized 3,1-benzoxazines

Article abstract of DOI:10.1039/c6ob02566h

A novel electronic halocyclization and radical haloazidation of benzene-linked 1,7-dienes for the formation of functionalized 3,1-benzoxazines has been achieved by using TMSN₃ as an azido source and NBS as a halogen source. This methodology is highlighted by its mild conditions and wide substrate scope, which concomitantly introduces one C-N and two C-halogen bonds into one molecule.

Full text of DOI:10.1039/c6ob02566h

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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PAPER
Electronic Halocyclization and Radical Haloazidation of Benzene-
Linked 1,7-Dienes for the Synthesis of Functionalized 3,1-
Benzoxazines
Received 00th January 20xx,
Accepted 00th January 20xx
Yuan-Ming Sun,a Liu-Zhu Yu,a Zi-Zhong Zhu,a Xu-Bo Hu,a Yu-Ning Gao,a and Min Shi*a,b
DOI: 10.1039/x0xx00000x
A
novel electronic halocyclization and radical haloazidation of benzene-linked 1,7-dienes for the formation of
www.rsc.org/
functionalized 3,1-benzoxazines has been achieved by using TMSN3 as an azido source and NBS as a halogen source. This
methodology is highlighted by its mild conditions, wide substrate scope, which concomitantly introduces one C−N and two
C−halogen bonds in one molecule.
Introduction
Compounds containing the benzoxazine scaffold usually
exhibit various biological activities and have been used as an
anticonvulsant drug, fungicide, and progesterone receptor
agonist (Figure 1).1 In the past decades, a series of efficient
methodologies have been developed by many research groups
for their syntheses.2 However, some traditional methodologies
usually require harsh conditions and are limited to narrow
substrate scope.3 Electrophilic cyclization of olefinic amides
represents a simple and convenient strategy to construct
functionalized benzoxazine molecules (Scheme 1a).4 Notably,
our group also reported a palladium-catalyzed cyclization
Figure 1 Bioactive compounds containing a 3,1-benzoxazine core.
reaction
to
synthesize
functionalized
benzoxazine
compounds.5 Despite these achievements, developing other
suitable and efficient protocols for the preparation of
benzoxazine derivatives is still urgent.
The difunctionalization of alkenes is one of the most
attractive research areas in organic chemistry.6 Typically,
organic azide-driven difunctionalization of alkenes has been a
research hotspot in this field in recent years (Scheme 1b).7 Its
major superiority lies in the direct introduction of two new
functional groups in a single operation such as carbon-carbon
bond,8 carbon-oxygen bond,9 carbon-nitrogen bond10 or
carbon-halogen bond11 for the synthesis of organic azides.
Scheme 1 Electronic halocyclization/radical haloazidation of 1,7-dienes.
Recently, our group reported iron- or copper-catalyzed
trifluoromethyl radicals involved 1,7-diene-cyclization to
synthesize benzazepine derivatives.12 Based on this finding, we
envisaged whether an azido radical triggered cyclization was
feasible. Beyond our expectation, a consecutive halocyclization
and haloazidation reaction of 1,7-dienes was found (Scheme
1c). Herein, we wish to present our primary investigation on
this reaction.
a.Key Laboratory for Advanced Materials and Institute of Fine Chemicals, School of
Chemistry and Molecule Engineering, East China University of Science and
Technology, and 130 MeiLong Road, Shanghai 200237, P. R. China.
b.State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, P.
R. China. E-mail: mshi@mail.sioc.ac.cn.
† Electronic Supplementary Information (ESI) available: Experimental procedures,
characterization data of new compounds, and CCDC 1457765. See DOI:
10.1039/b000000x/
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methoxylsubstituted substrate 1i was utilized for this reaction
under the conditions adopted above. When R2 was substituted
by methyl or chlorine atom, the desired products 2j and 2k
were isolated in moderate yields (52% and 47%). The reaction
of two electron-withdrawing groups substituted substrate 1l
was observed to be sluggish and only trace amount of the
respective 2l was isolated. When R1 is a methyl group or a
naphthyl group, the desired products 2m and 2n were
obtained in 82% and 66% yields, respectively. Additionally, the
reaction of substrate 1o bearing a phenyl group as the R3
group proceeded smoothly to give the corresponding product
2o in 73% yield. Notably, the reaction of 1p which has a
thiophenyl group also proceeded efficiently to furnish the
corresponding product 2p in good yield (87%).
Results and discussion
To validate the feasibility of the proposed processes, we
selected acrylamide-tethered alkylidenecyclopropane 1a as
the model substrate for the optimization of reaction
conditions. Initially, the reaction was carried out with
commercially available trimethylsilylazide (TMSN3) as a radical
N3 source without oxidants in 1,2-dichloroethane (DCE) at 60
°C for 30 minutes in absence of any oixdants (Table 1, entry 1).
To our delight, the reaction proceeded to give access to the
desired bromoazidation product 2a, albeit with a moderate
yield and its structure has been unambiguously identified by X-
ray diffraction (see the Supporting Information). Notably,
product 2a was formed as a pair of diastereoisomers with a
1:1.2 ratio. Among the oxidants examined, PhI(OAc)2 was the
best one, PhI(OPiv)2 and PhI(OCOCF3)2 were less effective
(entries 2–4). We next changed other reaction parameters,
including solvent, reaction temperature and loading of TMSN3.
However, the yield of 2a did not increase further (entries 7–
13). The use of 1.0 eq. of PhI(OAc)2 gave the best yield, but if
the amount of PhI(OAc)2 was increased, the yield of 2a did not
increase further (entries 5 and 6).
Table 2 Substrate scope of 1,7-dienes 1a, b with a cyclopropane moiety
Table 1 Optimization of reaction conditions for forming product 2a
a
Reaction conditions: 1,7-dienes 1 (0.2 mmol), PhI(OAc)2 (0.2 mmol), NBS (0.4
mmol), TMSN3 (0.8 mmol), DCE (2.0 mL), 60 oC, 30 minutes. b Isolated yield.
To further extend the substrate scope of this reaction, no
cyclopropane-containing substrates were examined (Table 3).
1,7-Dienes bearing electron-donating (m-Me) or electron-
withdrawing (p-Cl, p-Br) groups on the aromatic moiety R1
were tolerated well to produce the corresponding products in
a Reaction conditions: 1,7-dienes 1a (0.2 mmol), oxidant, NBS (0.4 mmol), TMSN3
(0.8 mmol), solvent (2.0 mL), T, 30 minutes. b Isolated yield. c Product 2a consists
d
e
of a pair of diastereoisomers and the ratio is 1:1.4. 0.6 mmol NBS was used.
moderate yields
(2q-2t) as a pair of diastereoisomers.
0.8 mmol of NBS was used.
Substrates 1u and 1v produced the corresponding products 2u
and 2v in 40% and 41% yields, respectively. Gratifyingly, when
R2 is a hydrogen atom rather than a methyl group, 1w and 1x
were effectively converted to the corresponding products 2w
and 2x in good yields.
Having the optimized the reaction conditions in hand, we
next examined the scope and limitations of this
bromocyclization and bromoazidation reaction. Acrylamide-
tethered alkylidenecyclopropanes were first chosen as
On the basis of our success with bromocyclization and
bromoazidation of 1,7-dienes, we decided to evaluating the
feasibility of chloroazidation of 1a by changing NBS to N-
chlorosuccinimide (NCS). Unfortunately, substrate 1a would be
decomposed when NCS was chosen as a halogen source
(Scheme 3).
substrates (Table 2). Substrates
donating or electron-withdrawing substituents on the benzene
ring all afforded the corresponding products 2b 2h in
1 bearing either electron-
-
moderate to good yields ranging from 53% to 80%. However,
the reaction system became very complex when the o-
2 | J. Name., 2012, 00, 1-3
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A two-steps experiment was carried out to understand the
details of the mechanism (Scheme 4). In the presence of NBS,
1a underwent a bromocyclization process to give 4a in 80%
yield. Under the standard condition as shown in Table 2,
bromoazidation of 4a provided the desired benzoxazine 2a in
70% yield as a pair of diastereoisomers.
Table 3 Substrate scope of 1,7-dienes 1a, b without a cyclopropane moiety
Scheme 5 Control experiments
.
On the basis of the control experiments and related
literature,8c, 13, 14 a plausible reaction mechanism is depicted in
a
Reaction conditions: 1,7-dienes 1 (0.2 mmol), PhI(OAc)2 (0.2 mmol), NBS (0.4
mmol), TMSN3 (0.8 mmol), DCE (2.0 mL), 60 oC, 30 minutes. b Isolated yield.
Scheme 6. A bromonium ionic intermediate
initial stage of the reaction due to electrophilic addition of the
bromide ion. Intermediate undergoes an intramolecular
electrophilic cyclization to provide the product . The azido
A is formed at the
A
In order to gain more insights into the reaction mechanism,
several control experiments were conducted. The reaction of
1,7-diene 1a with TMSN3, PhI(OAc)2, and NBS in the presence
of 4.0 equiv of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO)
or butylhydroxytoluene (BHT) were carried out and the desired
product 2a was formed only in trace or in a lower yield (10%)
(Scheme 5, eq. 1 and eq. 2). However, the inhibition of 2a
could occur either in the bromocyclization of 1a or in the
bromoazidation of 4a. Thus, we then conducted the reaction
of 1a with NBS in the presence of TEMPO or BHT, respectively
and found that the transformation of 1a to 4a was suppressed
by TEMPO nearly (16% yield) and by BHT slightly (61% yield)
(eq. 3 and eq. 4). Moreover, the use of TEMPO and BHT in the
bromoazidation of 4a all produced 2a in lower yields (eq. 5 and
eq. 6), thus indicating that a free radical process would be
4
radical may be generated from the homolysis of BrN3 (path a)
or the interaction between TMSN3 and PhI(OAc)2 (path b). The
azido radical attacks alkene
4, affording radical intermediate B.
In the presence of a bromide radical, intermediate
B
is
transformed to the desired functionalized benzoxazine
radical coupling.
2
by a
involved in the bromoazidation of 4a to 2a
.
The
bromoazidation of 4a in the absence of PhI(OAc)2 also
produced 2a in moderate yield (51 %, eq. 7), thus suggesting
that the combination of NBS with TMSN3 allowed the
generation of BrN3 in situ.11a-c,11g-i Then, bromide radical and
azido radical will be generated from the homolytic cleavage of
BrN3 (Table 1, entry 1 and Scheme 5, eq. 7).
Scheme 6 A plausible reaction mechanism.
Scheme 3 Chloroazidation of 1a.
Conclusion
In
conclusion,
we
have
established
a
novel
halocyclization/haloazidation reaction of 1,7-dienes under mild
conditions, leading to functionalized 3,1-benzoxazines in
moderate to good yields. This reaction enables electronic
halocyclization and radical haloazidation process and
represents a new strategy for the construction of nitrogen
containing heterocycles. Furthermore, in comparison with
other reported methods for electrophilic cyclization of olefinic
Scheme 4 Bromocyclization/bromoazidation of 1a by two steps.
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amides, this approach not only exhibits the simplicity of the 699 cm-1. HRMS (ESI) Calcd. for C20H20NO [M+H]+ requires:
reaction procedure but also concomitantly introduces one C−N 290.1539, Found: 290.1540.
and two C−halogen bonds in one molecule. The process shows
considerable synthetic advantages in terms of the functional General procedure for the synthesis of 1q-1v
group tolerance, substrate scope and mild reaction conditions. The solution of 2-propylmagnesium bromide (20 mmol, 1
mol/L in THF) was added dropwise to a solution of 2-
o
aminobenzophenones (5.0 mmol) in THF (15 mL) at 0 C and
Experimental section
General methods
the mixture was allowed to be warmed to room temperature
overnight. The resulting mixture was quenched by saturated
Melting points were determined on a digital melting point aqueous NH4Cl (30 mL), extracted with EtOAc, and washed by
apparatus and temperatures were uncorrected. NMR spectra brine. The combined extracts were dried over anhydrous
were recorded with a Bruker spectrometer at 400 MHz (1H Na2SO4. Then the solvent was removed under reduced
NMR), 100 MHz (13C NMR) and 376 MHz (19F NMR) in CDCl3, pressure to get the crude product without purification. The
respectively. Chemical shift were reported in ppm down field crude product and MgSO4 (50 mmol) were combined in xylene
from internal TMS. Organic solvents used were dried by (20 mL) and the mixture was heated at 120 oC overnight. Then
standard methods when necessary. Commercially available the reaction mixture was filtered with a Celite and the filtered
reagents were used without further purification. All reactions residue was washed with EtOAc for three times. The filtrate
were monitored by TLC with Huanghai GF254 silica gel coated was combined and solvent was removed under reduce
plates. Flash column chromatography was carried out using pressure. The residue was purified by
a flash column
300-400 mesh silica gel at increased pressure. Infrared spectra chromatography on silica gel to afford olefinic anilines (eluent:
were recorded on a Perkin-Elmer PE-983 spectrometer with petroleum ether / ethyl acetate = 50 / 1). A solution of olefinic
absorption in cm-1. Mass spectra were recorded by ESI and anilines (1.0 mmol) in CH2Cl2 (5.0 mL) was stirred at 0 oC. Then
HRMS was measured on a HP-5989 instrument.
Et3N (2.0 mmol) and methacyloyl chloride (1.2 mmol) were
added dropwise respectively and the resulting mixture was
warmed to room temperature and stirred overnight. Upon
completion, the resulting mixture was quenched by saturated
General procedure for the synthesis of 1a-1p
1a-1p were prepared according to our previous work12.
A solution of 3-bromopropyltriphenylphosphonium bromide aqueous NaHCO3, extracted with DCM. The combined organic
(5.96 g, 13 mmol) and NaH (600 mg, 25 mmol) in THF (20 mL) layers were dried over anhydrous Na2SO4 and concentrated
was stirred at 70 oC under argon for 12 h. Afterwards under reduced pressure. The residue was purified by a flash
compound 2-aminobenzophenones (10 mol) in THF (10 mL) column chromatography on silica gel to afford 1q-1v
o
was added and the reaction solution was stirred at 70 C for N-(2-(2-methyl-1-phenylprop-1-en-
.
another 12 h, the reaction was cooled to room temperature 1yl)phenyl)methacrylamide (1q)
and the mixture was filtered through a celite. The filtrate was A yellow solid, 244 mg, 84% yield, m. p. 80-83 oC. 1H NMR (400
concentrated under reduced pressure and the residue was MHz, CDCl3, TMS) 8.42 (d, J = 8.0 Hz, 1H), 7.94 (br, 1H), 7.30-
purified by silica gel flash chromatography to afford the 7.26 (m, 3H), 7.22-7.05 (m, 5H), 5.61 (s, 1H), 5.37 (s, 1H), 1.98
alkylidenecyclopropanes in moderate yield.
(s, 3H), 1.97 (s, 3H), 1.70 (s, 3H). 13C NMR (100 MHz, CDCl3)
A solution of alkylidenecyclopropanes (1.0 mmol) in CH2Cl2 (5.0 165.8, 140.77, 140.76, 135.3, 135.2, 132.7, 132.5, 130.2, 129.2,
mL) was stirred at 0 oC. Then Et3N (2.0 mmol) and methacyloyl 128.2, 127.9, 126.8, 123.8, 120.1, 120.0, 22.8, 22.0, 18.6. IR
chloride (1.2 mmol) were added dropwise respectively and the (EtOH) 3411, 3050, 2911, 1682, 1512, 1441, 1306, 1161,
resulting mixture was warmed to room temperature and 1040, 923, 754, 700 cm-1. HRMS (ESI) Calcd. for C20H22NO
stirred overnight. Upon completion, the resulting mixture was [M+H]+ requires: 292.1696, Found: 292.1697.
quenched by saturated aqueous NaHCO3, extracted with DCM.
The combined organic layers were dried over anhydrous General Procedure for the Synthesis of 2
Na2SO4 and concentrated under reduced pressure. The residue 1,7-Dienes
1 (0.2 mmol), N-bromosuccinimide (NBS, 2.0 equiv,
was purified by a flash column chromatography on silica gel to 0.4 mmol), and phenyliodine diacetate (PIDA, 1.0 equiv, 0.2
afford 1a-1p
.
mmol) were introduced in a 25 mL Schlenk tube and 1,2-
dichloroethane (2 mL) and azidotrimethylsilane (TMSN3, 4.0
equiv, 0.8 mmol) were then successively added, and the
mixture was stirred at 60 °C for 30 minutes. The reaction
N-(2-
(cyclopropylidene(phenyl)methyl)phenyl)methacrylamide
(1a)
o
1
A yellow solid, 258 mg, 89% yield, m. p. 116-118 C. H NMR mixture was concentrated in vacuum, and the resulting residue
(400 MHz, CDCl3, TMS) 8.41 (dd, J1 = 1.2 Hz, J2 = 8.4 Hz, 1H), was purified by a silica gel column chromatography (eluent:
7.49-7.47 (m, 3H), 7.38-7.25 (m, 5H), 7.17 (td, J1 = 1.2 Hz, J2 = petroleum ether / ethyl acetate = 200 / 1) to afford the desired
7.6 Hz, 1H), 5.16 (s, 1H), 5.141-5.136 (m, 1H), 1.69 (t, J = 1.2 Hz products 2.
, 3H), 1.67-1.64 (m, 2H), 1.26-1.19 (m, 2H). 13C NMR (100 MHz, (anti)-2-(1-azido-2-bromopropan-2-yl)-4-(1-
CDCl3) 165.7, 140.4, 138.5, 135.6 130.7, 130.5, 128.8, 128.3, bromocyclopropyl)-4-phenyl-4H-benzo[d][1,3]oxazine (2a)
127.8, 127.7, 126.6, 126.2, 124.1, 120.7, 119.8, 18.1, 5.7, 1.9. A white solid, 32 mg, 33% yield, m. p. 105-107 oC. 1H NMR (400
IR (EtOH) 3424, 2972, 2900, 1677, 1514, 1315, 1054, 763, MHz, CDCl3, TMS) 7.68-7.66 (m, 2H), 7.45-7.34 (m, 3H), 7.30-
4 | J. Name., 2012, 00, 1-3
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J. F. Zhao, X. H. Duan, H. Yang and L. N. Guo, J. Org. Chem.,
2015, 80, 11149.
Y. C. Yuan, H. B. Yang, X. Y. Tang, Y. Wei, M. Shi, Chem. Eur. J.
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For selected reviews, see: (a) H. Egami and M. Sodeoka,
Angew. Chem. Int. Ed., 2014, 53, 8294; (b) R. M. Romero, T.
7.25 (m, 2H), 7.10-7.06 (m, 1H), 6.84 (d, J = 8.0 Hz, 1H), 4.38 (d,
J = 12.4 Hz, 1H), 3.84 (d, J = 12.4 Hz, 1H), 2.20 (s, 3H), 1.45-1.39
(m, 1H), 1.20-1.14 (m, 1H), 1.12-1.06 (m, 1H), 0.87-0.82 (m,
1H). 13C NMR (100 MHz, CDCl3) 159.3, 141.4, 138.1, 129.7,
128.2, 128.1, 127.7, 127.3, 126.9, 125.7, 123.0, 87.4, 59.8, 59.3,
36.7, 26.8, 14.2, 12.5. IR (EtOH) 2969, 2920, 2115, 1635,
1598, 1448, 1265, 1152, 1074, 1041, 995, 766, 700 cm-1. HRMS
(ESI) Calcd. for C20H19Br2N4O [M+H]+ requires: 488.9920, Found:
488.9918.
5
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H. Woste and K. Muniz, Chem. Asian J., 2014,
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(syn)-2-(1-azido-2-bromopropan-2-yl)-4-(1-
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bromocyclopropyl)-4-phenyl-4H-benzo[d][1,3]oxazine (2a’)
A white solid, 44 mg, 45% yield, m. p. 120-123 oC. 1H NMR (400
MHz, CDCl3, TMS) 7.67-7.64 (m, 2H), 7.45-7.34 (m, 3H), 7.27-
7.25 (m, 2H), 7.09-7.03 (m, 1H), 6.80 (d, J = 7.6 Hz, 1H), 4.45 (d,
J = 12.4 Hz, 1H), 3.91 (d, J = 12.0 Hz, 1H), 2.13 (s, 3H), 1.46-1.40
(m, 1H), 1.24-1.18 (m, 1H), 1.13-1.07 (m, 1H), 0.88-0.82 (m,
1H). 13C NMR (100 MHz, CDCl3) 159.1, 141.8, 138.1, 129.7,
128.1, 127.6, 127.4, 126.9, 125.8, 122.8, 87.4, 59.9, 59.5, 36.7,
25.5, 14.1, 12.6. IR (EtOH) 2967, 2920, 2114, 1636, 1597,
1448, 1250, 1152, 1072, 994, 773, 699 cm-1. HRMS (ESI) Calcd.
for C20H19Br2N4O [M+H]+ requires: 488.9920, Found: 488.9918.
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We are grateful for the financial support from the National
Basic Research Program of China (973)-2015CB856603, and
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C6OB02566H
COMMUNICATION
Journal Name
Electronic halocyclization and radical haloazidation of
benzene-linked 1,7-dienes by using TMSN3 as an azidyl
source and NBS as a halogen source has been disclosed in
this paper, producing a series of functionalized 3,1-
benzoxazines in moderate to good yields.
Electronic Halocyclization and Radical Haloazidation of
Benzene-Linked 1,7-Dienes for the Synthesis of
Functionalized 3,1-Benzoxazines
O
R2
R2
Br
N
R2 R2
HN
R1
O
R4
NBS
R3
R1
+
TMSN3
R3
PhI(OAc)2
N3
R4
Br
♦ electrophilic cyclization and radical haloazidation
♦ one C-N and two C-halogen bonds formation
Yuan-Ming Sun, Liu-Zhu Yu, Zi-Zhong Zhu, Xu-Bo Hu, Yu-Ning Gao
and Min Shi*
♦
24 examples, up to 87% yield
6 | J. Name., 2012, 00, 1-3
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