N-Heterocyclic Carbene Catalysis Exploiting Oxidative Imine Umpolung for the Generation of Imidoyl Azoliums

Article abstract of DOI:10.1021/acs.joc.0c00360

Although NHC-catalyzed umpolung of imines are known, the related reactions under oxidative conditions are limited. Described herein is the two-step process involving the initial formation of aldimines from the corresponding aldehydes and 2-amino benzyl alcohols followed by NHC-catalyzed cyclization proceeding via the imidoyl azoliums under oxidative conditions. The reaction allowed the synthesis of trifluoromethylated 3,1-benzoxazines in good yields and broad scope. The role of NHC in the intramolecular cyclization and preliminary mechanistic experiments are also provided.

Full text of DOI:10.1021/acs.joc.0c00360

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Note
N-Heterocyclic Carbene Catalysis Exploiting Oxidative
Imine Umpolung for the Generation of Imidoyl Azoliums
Tamal Kanti Das, Krishnaprasad Madica, Jagadeesh Krishnan, Udaya Kiran Marelli, and Akkattu T. Biju
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00360 • Publication Date (Web): 12 Mar 2020
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N-Heterocyclic Carbene Catalysis Exploiting Oxidative Imine
Umpolung for the Generation of Imidoyl Azoliums
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Tamal Kanti Das,†,∫ Krishnaprasad Madica,‡ Jagadeesh Krishnan,‡ Udaya Kiran
Marelli,*,†,∫ and Akkattu T. Biju*,‡
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† Organic Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road,
Pune-411008, India
∫ Academy of Scientific and Innovative Research (AcSIR), New Delhi 110020, India
‡ Department of Organic Chemistry, Indian Institute of Science, Bangalore-560012, India
E-mail: m.udayakiran@ncl.res.in; atbiju@iisc.ac.in
CF3
OH
Ph
N
OH
Ar
F3C
N
N
CF3
CF3
OH
Ar
PTSA
4Å MS
Ph
NH2
O
N
N
+
N
toluene,
[O]
N
H
N
Ar
110 °C, 24 h
N
via.
O
Ar
(+) mild conditions
(+) 26 examples
(+) up to 95% yield
Imidoyl azolium
ABSTRACT: Although NHC-catalyzed umpolung of imines are known, the related reactions
under oxidative conditions are limited. Described herein is the two-step process involving the
initial formation of aldimines from the corresponding aldehydes and 2-amino benzyl alcohols
followed by NHC-catalyzed cyclization proceeding via the imidoyl azoliums under oxidative
conditions. The reaction allowed the synthesis of trifluoromethylated 3,1-benzoxazines in good
yields and broad scope. The role of NHC in the intramolecular cyclization, and preliminary
mechanistic experiments are also provided.
A variety of heterocyclic compounds are accessible from readily available substrates by
employing N-heterocyclic carbene (NHC) organocatalysis.1 The key to success for many of these
reactions is the remarkable ability of NHCs to reverse the normal mode of reactivity (umpolung)
of electrophiles.2 For instance, the addition of NHCs to aldehydes could generate the nucleophilic
Breslow intermediate,3 which can add to various carbonyl compounds,4 imines,5 activated and
even unactivated carbon-carbon multiple bonds.6,7 This aldehyde umpolung can be extended to
-unsaturated aldehydes for the generation of homoenolate equivalents followed by interception
with electrophiles for the synthesis of various four- to seven-membered heterocycles.8 Moreover,
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two-electron oxidation of the conjugate umpolung species (NHC-enal adduct) could generate the
-unsaturated acylazoliums, which can be intercepted with various bisnucleophiles for the
synthesis of various heterocycles.9 The umpolung concept using NHCs has been extended to
Michael acceptors by Fu and co-workers (intramolecular)10 and independently by Matsuoka and
Glorius groups (intermolecular),11 and these reactions are envisioned to proceed via the deoxy-
Breslow intermediates.
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In the context of our studies on NHC organocatalysis, in 2017, we demonstrated the NHC-
catalyzed umpolung of aldimines (intramolecular) for the synthesis of 2,3-disubstituted indoles
and the reaction was envisaged to proceed via the aza-Breslow intermediates (Scheme 1, eq 1).12
Subsequently, Lupton and co-workers uncovered the intermolecular imine umpolung for
enantioselective synthesis of imino lactones (eq 2).13,14 Inspired by the oxidation of Breslow
intermediates to acylazoliums demonstrated by Studer and co-workers,15,16 we have recently
reported the synthesis of benzoxazoles (from aldimines obtained from 2-amino phenols and
aromatic aldehydes) by the oxidation of the aza-Breslow intermediates using Kharasch oxidant to
imidoyl azoliums.17,18 Herein, we report the two-step synthesis of trifluoromethylated 3,1-
benzoxazines from aromatic aldehydes and 2-amino benzyl alcohols (eq 3). The initially formed
aldimine undergoes intramolecular cyclization catalyzed by NHCs and the reaction proceeds via
the imidoyl azolium intermediates.
Scheme 1. Umpolung of Aldimines Catalyzed by NHCs
NHC-catalyzed umpolung of aldimines (intramolecular)
COR2
COR2
NHC
R
R
(1)
(2)
R1
R1
ref. 12a
N
N
H
NHC-catalyzed umpolung of aldimines (intermolecular, enantioselective)
R
R
*
Bz
H
NHC
N
Bz
+
N
ref. 13a
Ar
O
O
Ar
H
O
O
NHC-catalyzed generation of imidoyl azoliums for 3,1-benzoxazine synthesis
OH
Ar
F3C
CF3
CF3
OH
H
Ph
PTSA (cat.)
(i)
O
N
N
(3)
Ar
+
O
Ar
N
(ii)
N
N
NH2
NHC
, [O]
via.
imidoyl azolium
(this work)
The present study was initiated by treating (2-aminophenyl)-2,2,2-trifluoroethanol 1a with
4-nitro benzaldehyde 2a in the presence of catalytic amounts of p-toluene sulfonic acid (PTSA)
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thus generating the aldimine 4a followed by the treatment with carbene generated from 5 using
Cs2CO3 under oxidative conditions using the bisquinone 6 (Scheme 2). The two-step procedure
afforded the trifluoromethylated 3,1-benzoxazine 3a in 95% yield. Control experiments confirmed
the role of NHC and oxidant in this annulation and formation of dihydro 3,1-benzoxazine was not
observed under this condition.19
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Scheme 2. Two-step Synthesis of 3,1-Benzoxazines
N
N
BF4
Ph
CF3
OH
NH2
N
CF3
CF3
OH
Ar
PTSA (5 mol %)
4Å MS
5
(10 mol %)
4Å MS
O
t-Bu
t-Bu
toluene, 110 °C
24 h
1a
N
Ar
N
O
O
+
t-Bu
t-Bu
H
4a
Ar = 4-NO2C6H4
6
(1.0 equiv)
3a
(95%)
O
Ar
Cs2CO3 (20 mol %)
toluene, 30 °C, 12 h
2a
With the reaction conditions in hand, we examined the substrate scope of this two-step
reaction (Scheme 3). A series of aromatic aldehydes bearing electron-withdrawing, -neutral and -
releasing groups at the 4-position of the ring underwent smooth aldimine formation and subsequent
NHC-catalyzed reaction via the generation of imidoyl azoliums, and in all the cases, the substituted
3,1-benzoxazines were formed in moderate to high yields (3a-3g). Notably, the benzoxazine 3e
has the core structure of Efavirenz, which is a potential drug for HIV infection.20 Moreover,
aldehydes having substitution at the 3-position, 2-position and disubstitution worked well under
the present conditions to afford the desired products in good yields (3h-3o). In addition, aldimines
obtained from -unsaturated aldehydes and heteroaromatic aldehydes easily afforded the
expected product in moderate to high yields (3p-3w). Special aldehydes such as pyrene
carboxaldehyde afforded the product 3o in 62% yield and ferrocene carboxaldehyde furnished 3x
in 90% yield. Interestingly, phthalaldehyde underwent two-fold aldimine formation and the NHC-
catalyzed cyclization with excess amine 1a resulted in the formation of the desired product 3y in
80% yield. The structure of 3y was confirmed by X-ray analysis.19,21 Besides, substitution at the
aryl ring of 1 did not affect the outcome of the reaction and the corresponding products are formed
in moderate to good yields (3z-3ab). Furthermore, the reaction performed using the -CF3
containing benzylic tertiary alcohols also furnished the desired products in moderate to good yields
thus demonstrating the versatility of the present annulation (3ac-3ad). It may be noted that the
trifluoromethyl group in 1a was required for this annulation and the reactions performed using 2-
amino benzyl alcohol did not afford the desired product under the present conditions.22
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To get insight into the mechanism of the reaction and the role of NHC in the aldimine
cyclization, we performed several experiments. Given the fact that the 2-amino benzyl alcohol can
react with aldehydes followed by oxidation leading to the 3,1-benzoxazines via dihydro 3,1-
benzoxazines,23 we have performed the reaction of alcohol 1a with 2a following analogous
procedure. Interestingly, under these conditions, the expected 1,3-benzoxazine 3a was not formed
(Scheme 4, eq 4). Moreover, 3a was not formed in toluene at 30 °C, and the aldimine 4a
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Scheme 3. Substrate Scope of the Reactiona
CF3
CF3
PTSA (5 mol %)
4Å MS, toluene
(i)
H
OH
O
R
+
R
O
Ar
5
6
(10 mol %)
(1.0 equiv)
(ii)
NH2
N
Ar
1
2
3
Cs2CO3 (20 mol %), toluene
R1 = NO2, , 95%
CF3
CF3
3a
R1 = NMe2, , 71%
b
3b
O
O
N
b
R1 = OMe, , 80%
3c
R1 = Br, , 69 %
N
3d
R1 = Cl, , 58 %
3e
R1
b
R1 = CN, , 89%
3h
R2 = OMe, , 57%
R2 = NO2, , 80%
b
3f
R2
CF3
b
R1 = CF3, , 41%
3i
3g
O
CF3
CF3
N
O
O
O2N
N
N
3j
, 90%
OMe
Br
3l
CF3
OMe
CF3
b
b
3k
, 63%
, 76%
OMe
O
CF3
N
O
O
HO
, 79%
N
N
3m
OMe
CF3
b
b
3n
3o
, 62%
, 59%
CF3
O
CF3
N
O
R3 = NO2, , 80%
R3 = NMe2, , 88%
O
3p
R3
b
N
3q
N
N
3t
X = O, , 89%
N
CF3
3r
3s
, 94%
CF3
O
, 50%
CF3
3u
X = S, , 65%
O
c
3v
X = NH, , 52%
O
N
X
N
N
CF3
O
Fe
b
3x
, 90%
b
O
3w
, 79%
CF3
N
R4O
N
O
O
N
R4 = Me, , 68%
b
3z
b,d,e
CF3
b
NO2
R4 = Bz,
, 45%
3y
, 80%
3aa
Me CF3
O
F3C CF3
CF3
O
N
O
N
MeO2C
N
NO2
b
b,d,f
b
NO2
3ab
3ac
3ad
, 47%
, 53%
, 74%
NO2
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a General reaction conditions: 1 (0.50 mmol), 2 (0.50 mmol), 5 (10 mol %), Cs2CO3 (20 mol %), 6 (1.0
equiv) toluene (4.0 mL). Yields of the isolated products are given. b The reaction run for 18 h. c Run for 32
h. d Reaction performed on 0.25 mmol scale. e Reaction carried out with 5 (20 mol %) and Cs2CO3 (40 mol
%). f Reaction done using 5 (50 mol %) and Cs2CO3 (100 mol %).
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formation was observed at 110 °C. These studies shed light on the role of NHC in the
intramolecular cyclization leading to the formation of 3,1-benzoxazines. To get more information
on the intermediacy of aldimine 4a, this imine was synthesized and subjected to the NHC-
catalyzed oxidative conditions (eq 5). The formation of 3a in 97% yield confirms that the aldimine
4a is the intermediate in this two-step reaction.24 The reaction performed without 5 or 6 did not
afford 3a indicating that the carbene and oxidant are crucial for this cyclization.25,26
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Scheme 4. Control Experiments
CF3
CF3
CHO
OH
(i) MeOH, 30 °C, 5 h
(ii) NaOCl, 30 °C, 24 h
O
(4)
+
NH2
N
NO2
2a
NO2
1a
3a
(not observed)
CF3
CF3
O
5
6
(10 mol %)
(1.0 equiv)
OH
(5)
Cs2CO3 (20 mol %)
4Å MS, toluene
30 °C, 12 h
N
N
NO2
NO2
4a
3a
(97%)
To get further insight into the role of NHC generated from 5 in the intramolecular
cyclization of 4a, five sets of reaction were performed from 0-20 mol % of 5 and 0-40 mol % of
Cs2CO3 and these reactions were quenched after 30 minutes. The reaction carried out using 5 mol
% of 5 afforded 26% of 3a and 80% of 3a was formed with 20 mol % of 5 (Figure 1a). These
experiments clearly indicate the role of NHC generated from 5 in the intramolecular cyclization
(the reaction performed with more carbenes furnished better yield of 3a) leading to the formation
of 3,1-benzoxazines. Moreover, the kinetic studies on the NHC-catalyzed aldimine cyclization
revealed a first order dependency with respect to the aldimine 4a (Figure 1b).19
Figure 1. (a) Reactions performed with variation in catalyst loading. (b) Reaction profile with 0.10
and 0.05 mmol of aldimine 4a.
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To get information on the electrophilic nature of the aldimine 4a and the imidoyl azolium
intermediate A, we performed the natural population analysis (NPA).27 The NPA for the aldimine
4a gives a charge of 0.135 for the carbon C1, and for the imidoyl azolium A the charge on C2 is
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+
0.255. Moreover, the electrophilic Fukui function (fk ) for the aldimine 4a is 0.05 whereas for the
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imidoyl azolium intermediate A is 0.25 (Figure 2). This indicates that the C2 of imidoyl azolium
intermediate A is more electrophilic than C1 of the aldimine 4a. Moreover, the nucleophilic Fukui
-
function (fk ) on O2 is found to be higher for imidoyl azolium intermediate A compared to aldimine
4a, indicating that O2 is more nucleophilic.
N
N
N
N
Ph
C1
N
C2
F3C
O1
NO2
NO2
O2
H
F3C
H
A
4a
Figure 2. Structure of aldimine 4a and imidoyl azolium A.
Based on the above studies, a tentative mechanism of this NHC-catalyzed annulation
reaction is represented in Scheme 5. The free carbene generated from 5 using base adds to the in
situ formed aldimine 4 resulting in the formation of the tetrahedral intermediate I, which undergoes
a proton transfer to generate the nucleophilic aza-Breslow intermediate II.14 Notably, the
intermediate II was detected in the HRMS of a stoichiometric reaction between 1a and 5
(Calculated mass: 510.1748; observed mass: 510.1760). In the presence of bisquinone 5, the aza-
Breslow intermediate II gets oxidized to the key imidoyl azolium intermediate A. The
intramolecular nucleophilic addition of alcohol to imine carbon generates the NHC-bound azolium
intermediate III, which on subsequent elimination of NHC results in the formation of the product
3.
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Scheme 5. Tentative Mechanism of the Reaction
5
6
7
8
Ar
N
Ar
N
O
N
4
nucleophilic
attack
F3C
OH
N
N
Ph
CF3
N
3
9
Cs2CO3
N
N
Ph
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H
N
N
BF4
Ph
Ar
N
N
N
N
N
Ph
I
OH
F3C
Ar
5
O
HN
CF3
proton
transfer
N
N
N
III
N
N
N
Ph
Ph
OH
CF3
Ar
N
Ar
N
H
OH
F3C
A
II
[O]
aza-Breslow
intermediate
imidoyl
azolium
It is important to note that functionalized 3,1-benzoxazines are core structures found in
drug molecules such as Efavirenz (A having anti HIV activity)20 and Etifoxin (B, useful for the
psychiatric illness).28 Moreover, 6-aryl benzoxazines C are potent progesterone receptor (PR)
modulator agonists (Figure 3).29 Due to the biological importance of 3,1-benzoxazines, the
development of one-pot, atom-economic synthetic routes to synthesize this structural motif is
highly desirable.
NC
S
F3C
R
Ph Me
O
Cl
Cl
Me Me
O
O
Et
N
O
N
N
H
H
N
H
Me
A
B
)
progesterone
receptor agonist (
Efavirenz (
anti HIV activity
)
Etifoxin (
psychiatric illness
C
)
Figure 3. Selected biologically important 3,1-benzoxazines.
In conclusion, we have reported the NHC-catalyzed umpolung of aldimines under
oxidative conditions for the synthesis of trifluoromethylated 3,1-benzoxazines.19,30 The key
imidoyl azolium intermediate was generated by the oxidation of catalytically generated aza-
Breslow intermediate using the bisquinone. In a two-step process, a series of aromatic aldehydes
reacted with 2-amino benzyl alcohols under the present conditions to afford the product in
moderate to good yield and broad scope. Detailed mechanistic studies clearly indicate the role of
NHC in the intramolecular cyclization.
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Experimental Section
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General Information:
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Unless otherwise specified, all reactions were carried out under an atmosphere of argon in
flame-dried reaction vessels with Teflon screw cap. 30 °C Corresponds to the room temperature
of the lab when the experiments were carried out. Dry toluene was purchased from commercial
sources and stored under argon over metallic sodium. The aldehydes were purchased from
commercial sources and were used without any further purification. 2-Aminobenzyl alcohols 1
were synthesized following the reported procedure.31 Cs2CO3 was purchased from commercial
sources and was used as received. The triazolium salt 5 was synthesized following the literature
procedure.32 All compounds were fully characterized. 1H and 13C NMR spectra were recorded in
CDCl3 as solvent. Chemical shifts (δ) are given in ppm. The residual solvent signals were used as
references and the chemical shifts converted to the TMS scale. For CDCl3: δH = 7.26 ppm, δC =
77.16 ppm. Infrared (IR) spectra were recorded on an FT-IR spectrometer as thin films using NaCl
plates. HRMS measurements were carried out using ESI method and ion-trap mass analyzer.
General Procedure for the Synthesis of Trifluoromethylated 3,1-Benzoxazines
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In a flame-dried screw-capped test tube, a mixture of (2-aminophenyl)-2,2,2-
trifluoroethanol 1 (0.5 mmol) and aldehyde 2 (0.5 mmol) were dissolved in dry toluene (4.0 mL).
Then, 4 Å MS (200 mg) and PTSA (4.0 mg, 5 mol %) were added to the mixture and heated at
110 °C (using an oil bath) for 24 h. The reaction mixture was cooled to room temperature (30 °C),
filtered and the solvent was evaporated to get the crude imine 4 (~0.5 mmol). This crude imine
was then added to a solution of triazolium salt 5 (13.6 mg, 0.05 mmol) and Cs2CO3 (32.5 mg, 0.10
mmol) in dry toluene (4.0 mL), in a screw-capped test tube equipped with a magnetic stir bar under
argon atmosphere (solid imines were directly added and liquid or sticky solid crude imines were
dissolved in dry toluene (2 mL) and the resulting solution was added to the reaction mixture). To
this mixture was added oxidant 6 (204.0 mg, 0.50 mmol) and 4 Å MS (100 mg) and it was stirred
at 30 °C. When the reaction was complete, the reaction mixture was filtered, and the solvent was
evaporated to get the crude residue, which was purified by flash column chromatography on silica
gel to afford the corresponding trifluoromethylated 3,1-benzoxazine derivative 3.
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Procedure for 1.0 mmol Scale Reaction for the Synthesis of 3a
5
6
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In a flame-dried screw-capped test tube, a mixture of 1-(2-aminophenyl)-2,2,2-
trifluoroethan-1-ol 1a (192.0 mg, 1.0 mmol) and 4-nitrobenzaldehyde 2a (152.0 mg, 1.0 mmol)
were dissolved in dry toluene (8.0 mL). Then, 4 Å MS (400 mg) and PTSA (8.0 mg, 5 mol %)
were added to the mixture and heated at 110 °C (using an oil bath) for 24 h. The reaction mixture
was cooled to room temperature (30 °C), filtered and the solvent was evaporated to get the crude
imine 4a (~1.0 mmol). This crude imine was then added to a solution of triazolium salt 5 (27.2
mg, 0.1 mmol) and Cs2CO3 (65.0 mg, 0.20 mmol) in dry toluene (8.0 mL), in a screw-capped test
tube equipped with a magnetic stir bar under argon atmosphere. To this mixture was added oxidant
6 (408.0 mg, 1.0 mmol) and 4 Å MS (200 mg) and it was stirred at 30 °C for 12 h. Then the reaction
mixture was filtered, and the solvent was evaporated to get the crude residue, which was purified
by flash column chromatography (Pet.ether-EtOAc:95:5) to afford 2-(4-nitrophenyl)-4-
(trifluoromethyl)-4H-benzo[d][1,3]oxazine 3a as a pale yellow solid (303.0 mg, 94% yield).
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Synthesis and Characterization of 3,1-Benzoxazine Derivatives
2-(4-nitrophenyl)-4-(trifluoromethyl)-4H-benzo[d][1,3]oxazine (3a): Pale yellow solid,154.0
mg in 0.5 mmol scale, 95% yield. Rf (Pet. ether /EtOAc = 95/5): 0.35; mp 113-115 °C; 1H NMR
(400 MHz, CDCl3) δ 8.32 – 8.27 (m, 4H), 7.49 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.34
(td, J = 7.5, 1.1 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 5.78 (q, J = 6.7 Hz, 1H). 13C{1H} NMR (100
MHz, CDCl3) δ 152.6, 149.8, 138.3, 137.1, 131.4, 129.1, 128.3, 126.7, 126.5, 123.7, 122.9 (q, J =
285.0 Hz), 115.4, 73.5 (q, J = 33.5 Hz). HRMS (ESI) m/z: [M + H]+ Calcd for C15H10F3N2O3
323.0638; Found 323.0645. FTIR (cm-1) 2924, 2856, 1637, 1597, 1458, 1230, 1184, 1087, 1014.
N,N-dimethyl-4-(4-(trifluoromethyl)-4H-benzo[d][1,3]oxazin-2-yl)aniline (3b): Pale yellow
solid, 114.0 mg in 0.5 mmol scale, 71% yield. Rf (Pet. ether /EtOAc = 95/5): 0.27; mp 150-152
°C; 1H NMR (400 MHz, CDCl3) δ 8.08 – 8.04 (m, 2H), 7.46 – 7.41 (m, 1H), 7.36 (dd, J = 7.9, 1.1
Hz, 1H), 7.22 (td, J = 7.3, 1.3 Hz, 1H), 7.17 (d, J = 7.2 Hz, 1H), 6.73 – 6.69 (m, 2H), 5.68 (q, J =
6.9 Hz, 1H), 3.03 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 155.5, 152.9, 140.0, 130.9, 129.8,
126.5, 125.9, 125.3, 123.4 (q, J = 284.4 Hz), 118.1, 115.5, 111.2, 73.1 (q, J = 33.5 Hz), 40.1.
HRMS (ESI) m/z: [M+H] + Calcd for C17H16F3N2O 321.1215; Found 321.1215. FTIR (cm-1)
2918, 2824, 1619, 1577, 1440, 1281, 1134.
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2-(4-Methoxyphenyl)-4-(trifluoromethyl)-4H-benzo[d][1,3]oxazine (3c): Pale yellow solid,
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123.0 mg in 0.5 mmol scale, 80% yield. Rf (Pet. ether /EtOAc = 95/5): 0.35; mp 84-86 °C; H
NMR (400 MHz, CDCl3) δ 8.13 – 8.10 (m, 2H), 7.44 (td, J = 7.6, 1.5 Hz, 1H), 7.37 (dd, J = 7.6,
0.8 Hz, 1H), 7.27 – 7.23 (m, 1H), 7.18 (d, J = 7.5 Hz, 1H), 6.99 – 6.95 (m, 2H), 5.70 (q, J = 6.9
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Hz, 1H), 3.85 (s, 3H). C{1H} NMR (100 MHz, CDCl3) δ 162.9, 154.7, 139.4, 131.1, 130.1,
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126.7, 126.5, 125.7, 123.8, 123.2 (q, J = 285.1 Hz), 115.5, 113.9, 73.2 (q, J = 33.8 Hz), 55.5.
HRMS (ESI) m/z: [M+H] + Calcd for C16H13F3NO2 308.0898; Found 308.0898. FTIR (cm-1)
3075, 2932, 1632, 1600, 1512, 1257, 1174.
2-(4-Bromophenyl)-4-(trifluoromethyl)-4H-benzo[d][1,3]oxazine (3d): Pale yellow solid,
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123.0 mg in 0.5 mmol scale, 69% yield. Rf(Pet. ether /EtOAc = 95/5): 0.54; mp 93-95 °C; H
NMR (400 MHz, CDCl3) δ 8.03 – 8.00 (m, 2H), 7.61 – 7.58 (m, 2H), 7.46 (td, J = 7.5, 1.2 Hz,
1H), 7.37 (dd, J = 7.9, 1.3 Hz, 1H), 7.29 (td, J = 7.5, 1.3 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 5.72
(q, J = 6.8 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 154.0, 138.9, 131.9, 131.2, 130.4, 129.7,
127.5, 126.9, 126.6, 126.6, 126.1, 121.1 (q, J = 284.6 Hz), 115.5, 73.4 (q, J = 33.7 Hz). HRMS
(ESI) m/z: [M+H] + Calcd for C15H10BrF3NO 355.9898; Found 355.9896. FTIR (cm-1) 3073,
2923, 1634, 1596, 1448, 1181, 1138.
2-(4-Chlorophenyl)-4-(trifluoromethyl)-4H-benzo[d][1,3]oxazine (3e): white solid, 90.0 mg in
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0.5 mmol scale, 58% yield. Rf (Pet. ether /EtOAc = 97/3): 0.6; mp 112-114 °C; H NMR (400
MHz, CDCl3) δ 8.10 – 8.08 (m, 2H), 7.48-7.43 (m, 3H), 7.37 (d, J = 7.8 Hz, 1H), 7.29 (td, J = 7.5,
1.2 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 5.73 (q, J = 6.8 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3)
δ 153.9, 138.9, 138.4, 131.2, 130.0, 129.6, 128.9, 127.4, 126.6, 126.1, 124.7 (q, J = 284.4 Hz),
115.5, 73.4 (q, J = 33.5 Hz). HRMS (ESI) m/z: [M+H]+ Calcd for C15H10F3N2O3 323.0638; Found
323.0645. FTIR (cm-1) 2925, 1633, 1597, 1567, 1456, 1401, 1346, 1016.
4-(4-(Trifluoromethyl)-4H-benzo[d][1,3]oxazin-2-yl)benzonitrile (3f): white solid, 135.0 mg in
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0.5 mmol scale, 89% yield. Rf (Pet. ether /EtOAc = 95/5): 0.4; mp 128-130 °C; H NMR (400
MHz, CDCl3) δ 8.26 – 8.24 (m, 2H), 7.76 – 7.74 (m, 2H), 7.48 (td, J = 7.8, 1.4 Hz, 1H), 7.40 (dd,
J = 7.8, 1.0 Hz, 1H), 7.34 (td, J = 7.5, 1.3 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 5.77 (q, J = 6.7 Hz,
1H). 13C{1H} NMR (100 MHz, CDCl3) δ 152.8, 138.3, 135.5, 132.3, 131.4, 128.6, 128.1, 126.6,
126.4, 123.0 (q, J = 285.5 Hz), 118.4, 115.4, 115.2, 73.4 (q, J = 33.6 Hz). HRMS (ESI) m/z:
[M+H]+ Calcd for C16H10F3N2O 303.0740; Found 303.0746. FTIR (cm-1) 3076, 1633, 1599, 1487,
1408, 1354, 1283, 1018.
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2-(3,4-Dimethoxyphenyl)-4-(trifluoromethyl)-4H-benzo[d][1,3]oxazine (3g): white solid, 73.0
mg in 0.5 mmol scale, 41% yield. Rf (Pet. ether /EtOAc = 95/5): 0.43; mp 92-94 °C; 1H NMR (400
MHz, CDCl3) δ 8.27 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 8.7 Hz, 2H), 7.50 – 7.46 (m, 1H), 7.41 (d, J
= 7.8 Hz, 1H), 7.32 (td, J = 7.4, 1.3 Hz, 1H), 7.22 (d, J = 7.3 Hz, 1H), 5.76 (q, J = 6.5 Hz, 1H).
13C{1H} NMR (100 MHz, CDCl3) δ 153.4, 138.6, 134.8, 133.5 (q, J = 32.2 Hz), 131.3, 128.5,
127.9, 126.6, 126.3, 125.5 (q, J = 4.0 Hz), 124.0 (q, J = 272.5 Hz), 123.1 (q, J = 285.6 Hz), 115.6,
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73.4 (q, J = 33.3 Hz). HRMS (ESI) m/z: [M+H] Calcd for C16H10F6NO 346.0661; Found
346.0665. FTIR (cm-1) 2934, 1637, 1603, 1577, 1458, 1324, 1281, 1177, 1065, 1018.
2-(3-Methoxyphenyl)-4-(trifluoromethyl)-4H-benzo[d][1,3]oxazine (3h): yellow viscous
liquid, 88.0 mg in 0.5 mmol scale, 57% yield. Rf (Pet. ether /EtOAc = 95/5): 0.31; 1H NMR (400
MHz, CDCl3) δ 7.81 – 7.75 (m, 2H), 7.50 - 7.40 (m, 3H), 7.34 – 7.30 (m, 1H), 7.23 (d, J = 7.4 Hz,
1H), 7.14 – 7.11 (m, 1H), 5.76 (q, J = 6.8 Hz, 1H), 3.92 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3)
δ 159.7, 154.6, 139.0, 132.8, 131.1, 129.6, 127.2, 126.5, 126.0, 123.2 (q, J = 284.7 Hz), 120.7,
118.9, 115.6, 112.8, 73.3 (q, J = 33.5 Hz), 55.5. HRMS (ESI) m/z: [M+H]+ Calcd for
C16H13F3NO2 308.0898; Found 308.0898. FTIR (cm-1) 3077, 2960, 1634, 1582, 1488, 1283, 1182,
1136.
2-(3-Nitrophenyl)-4-(trifluoromethyl)-4H-benzo[d][1,3]oxazine (3i): Pale yellow solid, 129.0
mg in 0.5 mmol scale, 80% yield. Rf (Pet. ether /EtOAc = 95/5): 0.35; mp 136-138 °C; 1H NMR
(400 MHz, CDCl3) δ 9.01 (s, 1H), 8.49 (d, J = 8.2 Hz, 1H), 8.40 (d, J = 8.2 Hz, 1H), 7.68 (t, J =
7.7, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.27 (t, J = 7.4 Hz, 1H), 5.82 (q, J =
6.7 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 152.3, 148.4, 138.2, 133.6, 131.3, 129.6, 128.0,
126.6, 126.2, 124.3, 123.0, 122.9 (q, J = 285.0 Hz), 115.4, 73.3 (q, J = 33.5 Hz). HRMS (ESI)
m/z: [M+H] + Calcd for C15H10F3N2O3 323.0644; Found 323.0642. FTIR (cm-1): 3088, 2363,
1638, 1531, 1351, 1184, 1137, 1073, 1019, 882.
2-(2-Nitrophenyl)-4-(trifluoromethyl)-4H-benzo[d][1,3]oxazine (3j): white solid, 145.0 mg in
0.5 mmol scale, 90% yield. Rf (Pet. ether /EtOAc = 95/5): 0.25; mp 104-106 °C; 1H NMR (400
MHz, CDCl3) δ 7.89 (d, J = 7.3 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.67-7.58 (m, 2H), 7.43 (t, J =
7.2 Hz, 1H), 7.32 – 7.30 (m, 2H), 7.20 (d, J = 7.0 Hz, 1H), 5.75 (d, J = 6.0 Hz, 1H). 13C{1H} NMR
(100 MHz, CDCl3) δ 152.4, 149.1, 138.0, 132.5, 131.7, 131.2, 130.8, 128.2, 126.6, 126.3, 126.2,
124.1, 122.8 (q, J = 283.8 Hz), 115.0, 73.8 (q, J = 33.5 Hz). HRMS (ESI) m/z: [M+H] + Calcd for
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C15H10F3N2O3 323.0638; Found 323.0641. FTIR (cm-1) 3077, 2882, 2363, 2327, 1648, 1604,
1538, 1488, 1456, 1355, 1283, 1229, 1184, 1138, 1072, 1005.
2-(3,4-Dimethoxyphenyl)-4-(trifluoromethyl)-4H-benzo[d][1,3]oxazine (3k): yellow solid,
106.0 mg in 0.5 mmol scale, 63% yield. Rf (Pet. ether /EtOAc = 90/110): 0.29; mp 82-84 °C; 1H
NMR (400 MHz, CDCl3) δ 7.73 (dd, J = 8.4, 2.0 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.45 – 7.41
(m, 1H), 7.37 (dd, J = 7.8, 1.1 Hz, 1H), 7.24 (td, J = 7.4, 1.3 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H),
6.90 (d, J = 8.4 Hz, 1H), 5.69 (q, J = 6.9 Hz, 1H), 3.97 (s, 3H), 3.92 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 154.6, 152.5, 148.9, 139.3, 131.0, 126.7, 126.5, 125.7, 123.9, 123.2 (q, J = 285.0
Hz), 121.9, 115.5, 110.6, 110.5, 73.2 (q, J = 33.3 Hz), 56.0. HRMS (ESI) m/z: [M+H] + Calcd for
C17H15F3NO3 338.1004; Found 338.1006. FTIR (cm-1) 3084, 2930, 1630, 1598, 1578, 1514, 1461,
1275, 1137.
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2-(2-Bromo-4-methoxyphenyl)-4-(trifluoromethyl)-4H-benzo[d][1,3]oxazine (3l): pale yellow
liquid, 148.0 mg in 0.5 mmol scale, 76 % yield. Rf (Pet. ether /EtOAc = 95/5): 0.5; 1H NMR (400
MHz, CDCl3) 7.72 (t, J = 8.2 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.38 (d, J = 7.6, 1H), 7.30 (t, J =
8.2 Hz, 1H), 7.21 (m, 2H), 6.92 (dd, J = 8.8 Hz, J = 2.5 Hz, 1H), 5.74 (q, J = 6.7 Hz, 1H), 3.83 (s,
1H). 13C{1H} NMR (100 MHz, CDCl3) δ 161.5, 154.5, 138.6, 132.8, 132.6, 131.1, 127.5, 126.4,
125.3, 123.0 (q, J = 283.0 Hz), 115.1, 113.3, 73.5 (q, J = 33.5 Hz). HRMS (ESI) m/z: [M+H] +
Calcd for C16H11BrF3NO2H 386.0004; Found 386.0003. FTIR (cm-1): 2924, 1643, 1598, 1493,
1279, 1223, 1180, 1137.
2-Methoxy-6-(4-(trifluoromethyl)-4H-benzo[d][1,3]oxazin-2-yl)phenol (3m): pale yellow
solid, 128.0 mg in 0.5 mmol scale, 79% yield. Rf (Pet. ether /EtOAc = 90/10): 0.5; mp 158-160
°C; 1H NMR (400 MHz, CDCl3) δ 13.39 (s, 1H), 7.46 (t, J = 7.8 Hz, 2H), 7.29 (d, J = 7.08 Hz,
2H), 7.21 (d, J = 7.08 Hz, 1H), 7.03 (d, J = 7.72 Hz, 1H), 6.85 (t, J = 8.0 Hz, 1H), 5.76 (q, J = 6.07
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Hz, 1H), 3.92 (s, 3H). C{1H} NMR (100 MHz, CDCl3) δ 157.4, 151.7, 148.7, 136.5, 131.4,
127.6, 126.7, 124.7, 122.8 (q, J = 284.0 Hz), 119.3, 118.2, 115.7, 114.8, 112.9, 73.3 (q, J = 34.5
Hz), 56.3. HRMS (ESI) m/z: [M+H] + Calcd for C16H13F3NO3 324.0842; Found 324.0848. FTIR
(cm-1) 2939, 1628, 1609, 1577, 1456, 1258, 1183, 1072.
2-(Naphthalen-2-yl)-4-(trifluoromethyl)-4H-benzo[d][1,3]oxazine (3n): pale yellow solid,
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99.0 mg in 0.5 mmol scale, 59 % yield. Rf (Pet. ether /EtOAc = 95/5): 0.4; mp 174-176 °C; H
NMR (400 MHz, CDCl3) 8.65 (s, 1H), 8.26 (d, J = 8.2 Hz, 1H), 7.99 (d, J = 8.2, 1H), 7.91 (t, J =
8.2 Hz, 1H), 7.57 (m, 2H), 7.47 (m, 2H), 7.31(t, J = 7.6 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 5.82 (q,
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J = 6.7 Hz, 1H), C{1H} NMR (100 MHz, CDCl3) δ 154.6, 139.1, 135.1, 132.7, 131.1, 129.2,
128.9, 128.6, 127.1, 126.6, 126.5,126.0, 123.1 (q, J = 283 Hz), 115.6, 73.3 (q, J = 33.5 Hz). HRMS
(ESI) m/z: [M+H] + Calcd for C19H13F3NO 328.0949; Found 328.0950. FTIR (cm-1): 2938, 1629,
1596, 1487, 1282, 1185, 1079.
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2-(Pyren-1-yl)-4-(trifluoromethyl)-4H-benzo[d][1,3]oxazine (3o): pale yellow solid, 124.0 mg
in 0.5 mmol scale, 62 % yield. Rf (Pet. ether /EtOAc = 95/5): 0.5; mp 154-156 °C; 1H NMR (400
MHz, CDCl3) 9.34 (d, J = 9.2 Hz, 1H), 8.56 (d, J = 8.4 Hz, 1H), 8.25 (m, 4H), 8.18 (d, J = 8.8 Hz,
1H), 8.08 (m, 2H), 7.55 (m, 2H), 7.38 (td, J = 6.8 Hz, J = 1.8 Hz, 1H), 7.31(d, J = 7.3 Hz, 1H),
5.90 (q, J = 6.7 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ = 155.7, 139.1, 133.6, 131.1, 130.6,
130.4, 129.3, 129.0, 127.4, 127.2, 126.6, 126.3, 126.1, 126.0, 125.1, 125.0, 124.4, 124.3, 123.3 (q,
+
J = 283 Hz), 119.1, 73.6 (q, J = 33.5 Hz). HRMS (ESI) m/z: calculated [M+H] Calcd for
C25H15F3NO 402.1106; Found 402.1106. FTIR (cm-1): 3042, 2921, 2852, 2363, 2328, 1630, 1583,
1487, 1347, 1271, 1223, 1184, 1133, 1082, 846.
(E)-2-(4-Nitrostyryl)-4-(trifluoromethyl)-4H-benzo[d][1,3]oxazine (3p): pale yellow solid,
139.0 mg in 0.5 mmol scale, 80% yield. Rf (Pet. ether /EtOAc = 95/5): 0.18; mp 137-139 °C; 1H
NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 16.1
Hz, 1H), 7.48 – 7.44 (m, 1H), 7.33 – 7.29 (m, 2H), 7.20 (d, J = 7.27 Hz, 1H), 6.79 (d, J = 16.1 Hz,
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1H), 5.68 (q, J = 6.87 Hz, 1H). C{1H} NMR (100 MHz, CDCl3) δ 154.0, 148.2, 141.4, 138.8,
137.1, 131.3, 128.4, 127.9, 126.6, 126.1, 124.9, 124.3, 123.0 (q, J = 283.9 Hz), 115.6, 73.1 (q, J =
32.87 Hz). HRMS (ESI) m/z: [M+H]+ Calcd for C17H12F3N2O3 349.0795; Found 349.0800. FTIR
(cm-1) 3075, 1641, 1598, 1484, 1343, 1183, 1072.
(E)-N,N-Dimethyl-4-(2-(4-(trifluoromethyl)-4H-benzo[d][1,3]oxazin-2-yl)vinyl)aniline (3q):
solid powder, 152.0 mg in 0.5 mmol scale, 88% yield. Rf (Pet. ether /EtOAc = 90/10): 0.5; mp
118-120 °C; 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 16.0 Hz, 1H), 7.45 (d, J = 8.74 Hz, 2H),
7.41 (t, J = 7.7 Hz,1H), 7.27 (d, J = 8.4 Hz, 1H), 7.22 (t, J = 7.65 Hz, 1H), 7.15 (d, J = 7.48 Hz,
1H), 6.69 (d, J = 8.8 Hz, 2H), 6.47 (d, J = 15.9 Hz, 1H), 5.61 (q, J = 6.7 Hz, 1H), 3.02 (s, 6H).
13C{1H} NMR (100 MHz, CDCl3 and MeOH-d4) δ 156.7, 151.7, 141.5, 139.1, 130.9, 129.5, 126.5,
124.6, 123.0 (q, J = 284.5 Hz), 122.7, 115.3, 113.9, 111.9, 72.8 (q, J = 34.03 Hz), 40.0. HRMS
(ESI) m/z: [M+H] + Calcd for C19H18F3N2O 347.1366; Found 347.1371. FTIR (cm-1) 2942, 1620,
1571, 1481, 1344, 1278, 1177, 1076.
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2-(Pyridin-4-yl)-4-(trifluoromethyl)-4H-benzo[d][1,3]oxazine (3r): white solid, 131.0 mg in
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0.5 mmol scale, 94% yield. Rf (Pet. ether /EtOAc = 90/10): 0.16; mp 73-75 °C; H NMR (400
MHz, CDCl3) δ 8.72 (d, J = 5.5 Hz, 2H), 7.92 (d, J = 6.0 Hz, 2H), 7.45 – 7.41 (m, 1H), 7.38 – 7.36
(m, 1H), 7.28 (td, J = 7.3, 1.4 Hz, 1H), 7.17 (d, J = 7.5 Hz, 1H), 5.73 (q, J = 6.7 Hz, 1H). 13C{1H}
NMR (100 MHz, CDCl3) δ 152.6, 150.4, 138.8, 138.1, 131.3, 129.9, 126.6, 126.5, 126.4, 122.9
(q, J = 284.4 Hz), 121.5, 115.5, 73.3 (q, J = 33.9 Hz). HRMS (ESI) m/z: [M+H]+ Calcd for
C14H10F3N2O 279.0745; Found 279.0745. FTIR (cm-1) 3075, 2922, 1638, 1599, 1489, 1182, 1138.
2-(Pyridin-2-yl)-4-(trifluoromethyl)-4H-benzo[d][1,3]oxazine (3s): solid, 70.0 mg in 0.5 mmol
scale, 50% yield. Rf (Pet. ether /EtOAc = 60/40): 0.3; mp 132-134 °C; 1H NMR (400 MHz, CDCl3)
8.78 (d, J = 5.2 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 7.80 (t, J = 8.2 Hz, 1H), 7.44 (m, 1H), 7.39 (m,
1H), 7.29 (m, 1H), 7.19 (m, 1H), 5.80 (q, J = 6.7 Hz, 1H), 13C{1H} NMR (100 MHz, CDCl3) δ =
153.1, 150.0, 149.1, 138.4, 136.8, 131.1, 127.8, 126.6, 126.6, 126.4, 126.9, 124.3, 123.9, 123.7,
122.9 (q, J = 283 Hz), 118.7, 115.5. 73.4 (q, J = 33.5 Hz). HRMS (ESI) m/z: [M+H]+ Calcd for
C14H10F3N2O 279.0745; Found 279.0747. FTIR (cm-1): 2935, 1634, 1573, 1474, 1355, 1284,
1182, 1136, 1096, 924.
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2-(Furan-2-yl)-4-(trifluoromethyl)-4H-benzo[d][1,3]oxazine (3t): pale yellow solid, 119.0 mg
in 0.5 mmol scale, 89% yield. Rf (Pet. ether /EtOAc = 95/5): 0.24; mp 129-131 °C; 1H NMR (400
MHz, CDCl3) δ 7.63 (d, J = 0.8 Hz, 1H), 7.46 – 7.42 (m, 2H), 7.29 – 7.23 (m, 1H), 7.17 - 7.13 (m,
2H), 6.54 (dd, J = 3.4, 1.7 Hz, 1H), 5.66 (q, J = 6.7 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ
147.5, 146.3, 145.3, 138.4, 131.2, 127.2, 126.6, 126.5, 126.0, 123.0 (q, J = 283.9 Hz), 115.9, 115.4,
112.1, 73.0 (q, J = 33.8 Hz). HRMS (ESI) m/z: [M+H]+ Calcd for C13H9F3NO2 268.0585; Found
268.0583. FTIR (cm-1) 3137, 2926, 1649, 1599, 1560, 1455, 1176, 1130.
2-(Thiophen-2-yl)-4-(trifluoromethyl)-4H-benzo[d][1,3]oxazine (3u): pale yellow solid, 92.0
mg in 0.5 mmol scale, 65% yield. Rf (Pet. ether /EtOAc = 95/5): 0.48; mp 67-69 °C; 1H NMR (400
MHz, CDCl3) δ 7.81 (dd, J = 3.7, 1.2 Hz, 1H), 7.56 (dd, J = 5.0, 1.2 Hz, 1H), 7.48 – 7.44 (m, 1H),
7.38 (d, J = 7.9 Hz, 1H), 7.28 (td, J = 7.6, 1.2 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.15 (dd, J = 5.0,
13
3.8 Hz, 1H), 5.70 (q, J = 6.8 Hz, 1H). C{1H} NMR (100 MHz, CDCl3) δ 151.3, 139.0, 135.4,
131.3, 131.2, 130.8, 128.0, 127.0, 126.6, 126.6, 125.7, 123.2 (J = 284.9 Hz), 115.4, 73.4 (q, J =
33.4 Hz). HRMS (ESI) m/z: [M+H] + Calcd for C13H9F3NOS 284.0357; Found 284.0355. FTIR
(cm-1) 2924, 1629, 1596, 1485, 1281, 1181, 1136.
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2-(1H-Pyrrol-2-yl)-4-(trifluoromethyl)-4H-benzo[d][1,3]oxazine (3v): yellow viscous liquid,
69.0 mg in 0.5 mmol scale, 52% yield. Rf (Pet. ether /EtOAc = 90/10): 0.17; 1H NMR (400 MHz,
CDCl3) δ 10.34 (s, 1H), 7.42 (td, J = 7.8, 1.6 Hz, 1H), 7.30 – 7.20 (m, 3H), 7.01 – 6.93 (m, 2H),
6.32 (dt, J = 3.7, 2.5 Hz, 1H), 5.69 (q, J = 6.8 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 150.4,
139.2, 131.2, 126.8, 126.2, 124.7, 123.6, 121.1 (q, J = 284.9 Hz), 114.4, 110.6, 73.1 (q, J = 33.6
Hz). HRMS (ESI) m/z: [M+H]+ Calcd for C13H10F3N2O 267.0745; Found 267.0744. FTIR (cm-
1) 3418, 3075, 2966, 1633,1593, 1486, 1419,1283, 1137.
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2-(Benzofuran-2-yl)-4-(trifluoromethyl)-4H-benzo[d][1,3]oxazine (3w): white solid, 125.0 mg
in 0.5 mmol scale, 79% yield. Rf (Pet. ether /EtOAc = 95/5): 0.2; mp 119-121 °C; 1H NMR (400
MHz, CDCl3) δ 7.68 – 7.64 (m, 2H), 7.53-7.45 (m, 3H), 7.43 (td, J = 7.39, 1.0 Hz, 1H), 7.33 –
7.28 (m, 2H), 7.20 (d, J = 7.5 Hz, 1H), 5.72 (q, J = 6.73 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3)
δ 156.2, 147.9, 146.6, 138.2, 131.4, 127.8, 127.5, 127.3, 126.7, 126.5, 123.9, 123.0 (q, J = 286.0
Hz), 122.5, 115.6, 112.4, 112.2, 73.2 (q, J = 34.6 Hz). HRMS (ESI) m/z: [M+H]+ Calcd for
C17H11F3NO2 318.0736; Found 318.0743. FTIR (cm-1) 2949, 1646, 1599, 1554, 1486, 1286, 1258,
1176, 1137.
2-(Ferrocenyl)-4-(trifluoromethyl)-4H-benzo[d][1,3]oxazine (3x): pale yellow solid, 173.0 mg
in 0.5 mmol scale, 90% yield. Rf (Pet. ether /EtOAc = 95/5): 0.32; mp 121-123 °C; 1H NMR (400
MHz, CDCl3) δ 7.41 (td, J = 7.84, 1.3 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.24 (td, J = 7.6, 1.1 Hz,
1H), 7.15 (d, J = 7.5 Hz, 1H), 5.62 (q, J = 7.0 Hz, 1H), 4.94 – 4.91 (m, 2H), 4.44 (ddt, J = 4.7, 3.8,
2.4 Hz, 2H), 4.26 (s, 5H). 13C{1H} NMR (100 MHz, CDCl3) δ 159.4, 139.4, 131.1, 126.6, 126.2,
125.2, 123.3 (q, J = 285.8 Hz), 115.0, 74.8, 72.9 (q, J = 33.3 Hz), 71.2, 70.9, 69.9, 69.0, 69.0.
HRMS (ESI) m/z: [M+H]+ Calcd for C19H15F3NOFe 385.0450; Found 385.0373. FTIR (cm-1)
3087, 2946, 1634, 1594, 1485, 1351, 1281, 1102.
1,4-Bis(4-(trifluoromethyl)-4H-benzo[d][1,3]oxazin-2-yl)benzene (3y): white solid, 95.0 mg in
0.25 mmol scale, 80% yield. Rf (Pet. ether /EtOAc = 90/10): 0.52; mp 161-163 °C; 1H NMR (400
MHz, CDCl3) δ 8.24 (d, J = 1.6 Hz, 2H), 7.48 (td, J = 7.8, 1.3 Hz, 1H), 7.42 (dd, J = 7.8, 1.0 Hz,
13
1H), 7.31 (td, J = 7.4, 1.3 Hz, 1H), 7.22 (d, J = 7.4 Hz, 1H), 5.77 (q, J = 6.7 Hz, 1H). C{1H}
NMR (100 MHz, CDCl3) δ 154.0, 138.9, 134.4, 131.2, 128.2, 127.6, 126.6, 126.3, 123.1 (q, J =
286.0 Hz), 115.6, 73.4 (q, J = 33.4 Hz). HRMS (ESI) m/z: [M+H]+ Calcd for C24H15F6N2O2
477.1038; Found 477.1032. FTIR (cm-1) 3072, 2956, 1631, 1597, 1562, 1486, 1348, 1277, 1227.
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6-Methoxy-2-(4-nitrophenyl)-4-(trifluoromethyl)-4H-benzo[d][1,3]oxazine (3z): light red
solid, 120.0 mg in 0.5 mmol scale, 68% yield. Rf (Pet. ether /EtOAc = 95/5): 0.2; mp 135-137 °C;
1H NMR (400 MHz, CDCl3) δ 8.28 (s, 4H), 7.36 (d, J = 8.7 Hz, 1H), 7.00 (dd, J = 8.8, 2.8 Hz,
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1H), 6.75 (s, 1H), 5.73 (q, J = 6.7 Hz, 1H), 3.86 (s, 3H). C{1H} NMR (100 MHz, CDCl3) δ
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159.5, 150.7, 149.6, 137.4, 131.7, 128.7, 127.9, 123.7, 123.0 (q, J = 286.2 Hz), 116.5, 116.2, 112.3,
73.5 (q, J = 34.1 Hz), 55.8. HRMS (ESI) m/z: [M+H]+ Calcd for C16H12F3N2O4 353.0744; Found
353.0749. FTIR (cm-1) 2944, 1637, 1597, 1496, 1404, 1350, 1277, 1187.
2-(4-Nitrophenyl)-4-(trifluoromethyl)-4H-benzo[d][1,3]oxazin-6-yl benzoate (3aa): white
solid, 100.0 mg in 0.5 mmol scale, 45% yield. Rf (Pet. ether /EtOAc = 90/10): 0.2; mp 177-179
°C; 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 4H), 8.21 (d, J = 7.6 Hz, 2H), 7.67 (t, J = 7.4 Hz, 1H),
7.54 (t, J = 7.7 Hz, 2H), 7.49 (d, J = 8.5 Hz, 1H), 7.36 (dd, J = 8.5, 2.4 Hz, 1H), 7.17 (s, 1H), 5.81
(q, J = 6.5 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 165.0, 152.5, 150.3, 150.0, 137.0, 136.1,
134.2, 130.4, 129.1, 129.1, 128.9, 127.8, 124.8, 123.8, 122.9 (q, J = 284.7 Hz), 120.2, 116.4, 73.3
(q, J = 34.3 Hz). HRMS (ESI) m/z: [M+H]+ Calcd for C22H14F3N2O5 443.0849; Found 443.0854.
FTIR (cm-1) 1738, 1637, 1597, 1491, 1347, 1219, 1185.
Methyl 2-(4-nitrophenyl)-4-(trifluoromethyl)-4H-benzo[d][1,3]oxazine-7-carboxylate (3ab):
white solid,101 mg in 0.5 mmol scale, 53% yield. Rf (Pet. ether /EtOAc = 95/5): 0.2; mp 174-176
°C; 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 4H), 8.07 (s, 1H), 8.01(d, J = 7.8 Hz, 1H), 7.32 (d, J =
13
7.6 Hz, 1H), 5.83 (q, J = 6.7 Hz, 1H), 3.96 (s, 1H). C{1H} NMR (100 MHz, CDCl3) δ 166.0,
153.2, 150.1, 138.7, 136.7, 133.5, 129.3, 129.1, 127.6, 126.8, 123.8, 123.0 (q, J = 285.0 Hz), 119.8,
73.5 (q, J = 33.5 Hz), 52.7. LCMS m/z: [M]+ Calcd for C17H11F3N2O5 380.0; Found 380.0. FTIR
(cm-1) 3419, 2958, 2847, 2363, 1722, 1633, 1519, 1348, 1281, 1136, 1076, 973.
4-Methyl-2-(4-nitrophenyl)-4-(trifluoromethyl)-4H-benzo[d][1,3]oxazine (3ac): Solid, 62.0
mg in 0.25 mmol scale, 74% yield). Rf (Pet. ether /EtOAc = 95/5): 0.6; mp 130-132 °C; 1H NMR
(400 MHz, CDCl3) δ 8.31 (s, 4H), 7.49 – 7.44 (m, 1H), 7.39 (d, J = 7.5 Hz, 1H), 7.36 – 7.30 (m,
2H), 2.01 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 152.9, 149.9, 138.3, 137.5, 131.1, 129.0,
128.4, 126.6, 125.4, 124.4 (q, J = 286.3 Hz), 123.7, 120.9, 78.9 (q, J = 30.9 Hz), 22.1. HRMS
(ESI) m/z: [M+H]+ Calcd for C16H12F3N2O3 337.0795; Found 337.0800. FTIR (cm-1) 3111, 3076,
2963, 2923, 2863, 1734, 1695, 1638, 1600, 1525, 1487, 1381, 1348, 1315, 1253, 1190, 1165, 1084,
1011, 867.
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2-(4-Nitrophenyl)-4,4-bis(trifluoromethyl)-4H-benzo[d][1,3]oxazine (3ad): pale yellow
viscous liquid, 91 mg in 0.5 mmol scale, 47% yield. Rf (Pet. ether /EtOAc = 97/3): 0.67; 1H NMR
(400 MHz, CDCl3) δ 8.33 (s, 4H), 7.61-7.55 (m, 2H), 7.50 (d, J = 7.8 Hz, 1H), 7.43 (t, J = 8.1 Hz,
1H), 13C{1H} NMR (100 MHz, CDCl3) δ 150.2, 149.9, 137.9, 136.0, 132.7, 129.2, 129.0, 127.9,
126.0, 123.9, 121.5 (q, J = 289.2 Hz), 111.8, 79.6, 79.0. HRMS (ESI) m/z: [M+H]+ Calcd for
C16H8F6N2O3 391.0517; Found 391.0515. FTIR (cm-1) 2959, 2923, 2847, 2363, 1650, 1530, 1460,
1347, 1209, 1098, 969.
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Supporting Information
Details on mechanistic experiments, study towards enantioselective version of the reaction, NMR
spectra of functionalized 3,1-benzoxazines and details on Natural Population Analysis (PDF), and
crystal data of 3y (cif).
The Supporting Information is available free of charge on the ACS Publications website.
ACKNOWLEDGMENT
Generous financial support by Science and Engineering Research Board-DST, Government of
India (File Number: EMR/2016/007021) is gratefully acknowledged. T. K. D thanks CSIR for the
senior research fellowship and K. M. thanks UGC for the D S Kothari post-doctoral fellowship.
We thank Prof. A. K. Das and Mr. Avik Ghosh for natural population analysis.
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yields without NHC in the presence of oxidant and excess base.
19. For details, See the Supporting Information.
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20. Young, S. D.; Britcher, S. F.; Tran, L. O.; Payne, L. S.; Lumma, W. C.; Lyle, T. A.; Huff, J.
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21. CCDC 1941009 (3y) contains the supplementary crystallographic data for this paper. These
data
can
be
obtained
free
of
charge
from
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
22. It may be noted that use of aliphatic aldehydes did not afford the desired annulated product
under the present conditions.
23. (a) Bendorf, H. D.; Vebrosky, E. N.; Eck, B. J. Synthesis and Characterization of 1,4-Dihydro-
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Experiment. J. Chem. Educ. 2016, 93, 1637. (b) Kumar, R. A.; Maheswari, C. U.; Ghantasala,
S.; Jyothi, C.; Reddy, K. R. Synthesis of 3H-Quinazolin-4-ones and 4H-3,1-Benzoxazin-4-
ones via Benzylic Oxidation and Oxidative Dehydrogenation using Potassium Iodide-tert-
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%) in toluene at 30 °C did not result in the formation of the desired product 3a because of the
lack of formation of the aldimine 4a at this condition.
25. Notably, the use of air as an oxidant instead of bisquinone 6 afforded 3a in 70% yield.
26. We also considered the role of NHC as a Brønsted base for the deprotonation of the aldimine
4a followed by intramolecular cyclization. However, this possibility was ruled out by
performing a reaction using a strong base KOt-Bu (instead of 5 and Cs2CO3), where no
cyclization was observed. For a review on the role of NHC as a Brønsted base, see: Wang, N.;
Xu, J.; Lee, J. K. The importance of N-heterocyclic carbene basicity in organocatalysis. Org.
Biomol. Chem. 2018, 16, 8230.
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30. Preliminary studies on the enantioselective version of the reaction using chiral NHC catalyst
afforded the product in 33% yield and 34% ee. Further studies on kinetic resolution of
secondary alcohols using this strategy is ongoing in our laboratory.
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