Synthesis of Azolo[1,3,5]triazines via Rhodium(III)-Catalyzed Annulation of N-Azolo Imines and Dioxazolones

Article abstract of DOI:10.1021/acs.joc.8b01249

A wide range of azolo[1,3,5]triazines were obtained by Rh(III)-catalyzed annulation of N-azolo imines and dioxazolones. The reaction proceeds by the first catalytic C-H amidation of an imidoyl C-H bond followed by cyclodehydration. Good yields were obtain

Full text of DOI:10.1021/acs.joc.8b01249

Note
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
pubs.acs.org/joc
Synthesis of Azolo[1,3,5]triazines via Rhodium(III)-Catalyzed
Annulation of N‑Azolo Imines and Dioxazolones
Gia L. Hoang, Kim Søholm Halskov, and Jonathan A. Ellman*
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520, United States
*
S Supporting Information
ABSTRACT: A wide range of azolo[1,3,5]triazines were obtained by
Rh(III)-catalyzed annulation of N-azolo imines and dioxazolones. The
reaction proceeds by the first catalytic C−H amidation of an imidoyl
C−H bond followed by cyclodehydration. Good yields were obtained
for N-azolo imines derived from aminoazoles and aromatic and
heteroaromatic aldehydes. A range of dioxazolone amidating reagents
were employed to introduce aryl, heteroaryl, and alkyl substituents. The
reaction was also performed with a benchtop setup at 1 mmol scale using microwave heating.
ridgehead N-fused [5,6]-bicyclic heterocycles are priv-
ileged pharmacophores in drug discovery and are present
starting materials 1 by simple condensation of readily available
aminoazoles with the enormous range of commercially
available aromatic and heteroaromatic aldehydes is an
important practical aspect of this method. Given that diverse
N-azolo imines 1 can readily be accessed, we are extensively
pursuing different types of transition-metal-catalyzed imidoyl
C−H functionalization of 1 for heterocycle synthesis, including
for the preparation of other subclasses having the privileged N-
fused [5,6]-bicyclic heterocycle framework.
B
in numerous U.S. FDA approved drugs and many clinical
1
,2
candidates. We have recently reported the first examples of
Rh(III)-catalyzed imidoyl C−H activation of N-azolo imines 1
enabling annulations with alkynes, diazoketones, and sulfoxo-
3
,4
nium ylides to give azolopyrimidines 2 (Scheme 1A). The
straightforward one-step preparation of diverse N-azolo imine
The 1,4,2-dioxazol-5-one amidating reagents 4 were initially
identified by Sauer and Mayer in the late 1960s as a safe
alternative to acyl azides for N-acyl nitrene formation. This
Scheme 1. Preparation of Bridgehead N-Fused [5,6]-
Bicyclic Heterocycles via Catalytic C−H Functionalization
5
elegant finding was subsequently applied to direct C−N bond
6
7
formation by Dube and Bolm. Chang and co-workers later
́
on introduced and developed 1,4,2-dioxazol-5-ones as
extremely efficient amidating reagents in C−H functionaliza-
8
tion reactions. These reagents have now been employed by a
9
number of laboratories for C−H amidation. In work relevant
to N-fused [5,6]-bicyclic heterocycle synthesis, we recently
reported that C-alkenyl azoles 3 could be amidated with 1,4,2-
dioxazol-5-ones 4 to afford azolopyrimidines 5 after cyclo-
10
dehydration (Scheme 1B). Cheng and co-workers have also
recently reported that tricyclic or higher order derivatives can
11
be obtained by annulations with 2-arylimidazoles. Herein, we
describe Rh(III)-catalyzed imidoyl C−H amidation followed
by cyclodehydration of readily available N-azolo imines 1 with
1,4,2-dioxazol-5-ones 4 having diverse electronic and steric
properties to give azolo[1,3,5]triazines 6 (Scheme 1C), which
have been recognized as privileged scaffolds in medicinal
12
chemistry.
Annulation of N-azolo imine 1a and dioxazolone 4a
provided azolotriazine 6aa in good yield using the cationic
Rh(III) catalyst [Cp*Rh(MeCN) ](SbF ) with NaOAc and
3
6 2
pivalic acid (PivOH) as additives in dioxane at 120 °C (entry
Received: May 15, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b01249
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
, Table 1). Under these conditions, complete consumption of
Note
1
Using the optimal reaction conditions, we explored the
scope of dioxazolone 4 for annulations with N-imidazo imine
the starting imine 1a was observed and no significant
1
a (Scheme 2). A series of 3-aryl-substituted 1,4,2-dioxazol-5-
Table 1. Reaction Parameters for Annulations to
Azolotriazines 6
a
Scheme 2. Dioxazolone Scope for Rh(III)-Catalyzed
Annulation to Give Azolotriazines 6
a
b
entry
imine
variation
yield (%)
c
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
none
[Cp*RhCl ] , AgSbF
6
75 (73)
60
8
d
2
2
[Cp*RhCl ] (5 mol %)
2
2
no Rh
no PivOH
no NaOAc
NaOAc (1 equiv)
100 °C
0
12
16
79
70
46
11
9
25
10
0
0.2 M
10
11
12
13
14
15
16
17
toluene as solvent
DCE as solvent
MeCN as solvent
[Cp*IrCl ] , AgSbF
6
d
2
2
[Cp*Co(MeCN) ](SbF )
6 2
3
e
none
NaOAc (1 equiv)
100 °C
53 (55)
37
43
a
b
Conditions: 1 (0.10 mmol), 4a (0.15 mmol), 0.1 M, 16 h. Yield
determined by H NMR relative to 1,3,5-trimethoxybenzene as the
external standard. Isolated yield of a 0.30 mmol scale (see Scheme
). [Cp*MCl ] (5 mol %) and AgSbF (20 mol %). Isolated yield
1
a
b
Standard conditions as shown. NaOAc (1 equiv) was used.
c
d
e
2
2 2 6
ones 4a−g with different electronic properties were effective
under the standard conditions, giving bicyclic products 6aa−
of a 0.30 mmol scale (see Scheme 3).
6
ag in moderate to good yields (46−73%). Thiophene-
containing dioxazolone (4h) was also a good coupling partner
affording product 6ah in 58% yield. A variety of alkyl-
substituted dioxazolones including n-alkyl (4i), methyl (4j), α-
branched (4k), and benzyl (4l) served as effective inputs in the
coupling reactions providing 6ai−6al in good to excellent
yields (66−82%).
We next investigated the scope for the N-azolo imines 1
derived from several different aminoazoles and various
aromatic and heteroaromatic aldehydes (Scheme 3). As
indicated in the optimization studies, furfural-derived imine
byproducts were detected. An active cationic catalyst could
also be formed in situ from [Cp*RhCl ] and AgSbF but
2
2
6
provided a slightly lower yield of product (entry 2). When the
halide was not abstracted from [Cp*RhCl ] , only trace
2
2
amounts of product were observed (entry 3). As expected,
product was not obtained when a Rh(III) catalyst was not
added (entry 4). Both PivOH and NaOAc are essential for C−
H amidation and cyclodehydration to azolotriazine 6aa. When
either additive was excluded, only a small amount of 6aa was
13
obtained but with no remaining imine (entries 5 and 6).
When stoichiometric NaOAc was used, a comparable yield of
aa was obtained (entry 7); however, a substoichiometric
1
b coupled with 3-phenyl-substituted 1,4,2-dioxazol-5-one 4a
to generate heterocycle 6ba (55%). The same imine coupled
equally well with alkyl-substituted dioxazolone 4i to afford 6bi
in 58% yield. In addition to 1a, a series of imines derived from
6
quantity of NaOAc was found to be more general (vide infra).
Lowering the temperature to 100 °C led to a slight reduction
in yield (entry 8). Doubling the concentration resulted in a
significantly lower yield (entry 9), as did performing the
reaction in toluene, DCE, or MeCN (entries 10−12). In
comparison to Cp*Rh(III) catalysis, Cp*Ir(III) and Cp*Co-
2-amino-imidazole and benzaldehydes bearing electron-defi-
cient (1c, 1d, and 1f) and electron-rich (1e) substituents at the
para- and meta-positions efficiently coupled with both aryl- and
alkyl-substituted dioxazolones under standard conditions to
give bicyclic heterocycles 6ca−6fi (59−77%). Ortho-substi-
tuted benzaldimine 1g also coupled to give azolotriazine 6gi,
albeit with a slight reduction in yield (46%). Significantly, the
bromo- (1f) and chloro- (1g) substituted imines afforded
products that are amenable to subsequent cross-coupling
chemistry. Annulations of N-azolo imines 1 from enolizable
aldehydes were not investigated because this type of imine was
difficult to prepare.
(
III) catalysts were ineffective and provided little to no product
under the same reaction conditions (entries 13 and 14). The
optimal conditions were also effective for furfural-derived
imine 1b (entry 15). In contrast to imine 1a, furfural-derived
imine 1b is more sensitive to the stoichiometry of the NaOAc
additive. When 1 equiv rather than 0.5 equiv was used, a lower
yield was observed (entry 16). Lowering the temperature to
100 °C also resulted in a lower yield (entry 17).
B
DOI: 10.1021/acs.joc.8b01249
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 3. N-Azolo Imine Scope for Rh(III)-Catalyzed
Annulations to Give Azolotriazines 6
Scheme 5. Proposed Mechanism for Annulation
a
metalation−deprotonation to give rhodacycle A. In our
3
previously published report, a rhodacycle obtained by imidoyl
C−H activation was rigorously characterized by X-ray
crystallography and was shown to be competent in the
catalytic cycle. In accord with Chang’s detailed mechanistic
8a
studies on dioxazolone-mediated C−H amidation, insertion
of the N-acyl nitrene with release of CO then generates the
2
six-membered rhodacycle B. Proto-demetalation affords amide
C to regenerate the active Rh(III) catalyst. Under the reaction
conditions, amide C undergoes cyclodehydration to provide
the bicyclic heterocycle product 6.
In conclusion, Rh(III)-catalyzed imidoyl C−H amidation of
imines 1 followed by cyclodehydration affords azolotriazines 6.
The reaction proceeds in good yields for a range of aryl,
heteroaryl, benzyl, and alkyl dioxazolones 4. N-Azolo imines 1
derived from amino imidazoles and triazoles and a variety of
different aromatic and heteroaromatic aldehydes are also
effective inputs. Moreover, the reaction is applicable to a
straightforward benchtop setup at 1 mmol scale using
microwave heating.
a
b
c
Standard conditions as shown. NaOAc (1 equiv) was used. DCE
(100 °C) was used instead of dioxane (120 °C).
Imine 1h with dimethyl substitution on the imidazole ring
EXPERIMENTAL SECTION
■
was also an effective coupling partner to give imidazotriazine
hi. Although imines derived from 3-aminopyrazoles were not
effective coupling partners (data not shown), N-triazolo imines
i and 1j afforded triazolotriazines 6ii and 6ji in reasonable
General Information. Unless otherwise noted, all commercially
available reagents were purchased and used as received. Solvents
including 1,4-dioxane, toluene, 1,2-dichloroethane (DCE), and
acetonitrile (MeCN) were deoxygenated by sparging with argon
and stored over activated 3 Å molecular sieves in a nitrogen filled
glovebox. The microwave reaction was performed using a microwave
reactor with an external IR sensor and in a closed reaction vessel.
6
1
yields (56−57%). It is notable that imine 1j with multiple
potential sites for directed C−H functionalization was still
selective for imidoyl C−H activation to give 6ji.
1
13
Commercial AgSbF was stored in a nitrogen filled glovebox. H, C,
Lastly, 6ai was prepared on the benchtop at 1 mmol scale
6
1
9
and F NMR spectra were recorded on 400, 500, or 600 MHz
(
Scheme 4). For practical purposes, the reaction was
performed using a microwave reactor with a 2 h reaction
time. Bicyclic product 6ai was isolated in reasonable yield
65%).
A possible mechanism for the annulation is depicted in
Scheme 5. On the basis of our previous study on annulations of
spectrometers. The chemical shift [δ (ppm)], coupling constants [J
Hz)], multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
(
pent = pentet, m = multiplet, br = broad), and integration are
(
1
13
reported. Chemical shifts for H and C NMR are reported relative
1
to residual undeuterated solvent in CDCl (7.24 ppm for H NMR
3
1
3
1
and 76.99 ppm for C NMR) and (CD ) SO (2.47 ppm for H
3
2
1
3
N-azolo imines with alkynes, diazoketones, and sulfoxonium
NMR and 39.94 ppm for C NMR). Flash chromatography was
3
ylides, we propose that imine 1 undergoes concerted
carried out with slica gel with 40−63 μm particle size and with 230−
00 mesh. Partial data are provided for IR spectra. Melting points are
4
reported uncorrected. High-resolution mass spectra (HRMS) were
obtained using electrospray ionization (ESI) on a time-of-flight
Scheme 4. Bench-Top Reaction Setup on a 1 mmol Scale
(
(
TOF) mass spectrometer (Yale University) or electron ionization
EI ) obtained by University of Illinois SCS Mass Spectrometry
+
Laboratory.
Preparation of Catalysts and Reactants. [Cp*Rh-
(
MeCN) (SbF ) ] was synthesized according to literature procedur-
3 6 2
8a
es. N-Azolo imine substrates 1a−g were synthesized according to
3
,14
literature procedures.
Dioxazolones 4a−h and 4j−l were
8a,11,15
synthesized according to literature procedures.
Imine 1h was
C
DOI: 10.1021/acs.joc.8b01249
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1
4
prepared via literature procedures with slight modification. Imines
i and 1j were synthesized as described below. Dioxazolone 4i was
prepared according to a literature procedure with slight modificatio-
adding carbonyldiimidazole (CDI) (6.57 g, 40.5 mmol, 1.50 equiv),
the reaction mixture was stirred under nitrogen at rt for 1 h, and then,
hydroxylamine chloride (3.75 g, 54.0 mmol, 2.00 equiv) was added.
After an overnight stir at rt, the resultant mixture was transferred to a
separatory funnel, diluted with aqueous KHSO4 (300 mL), and
extracted with ethyl acetate (3 × 100 mL). The combined organic
extracts were washed with brine, dried (anhyd. Na SO ), and
concentrated under reduced pressure to afford crude N-hydroxy-4-
phenylbutanamide (4.9 g, quantitative) as a white solid, which was
used in the next step without further purification.
1
8a
n.
(
E)-N-(4,5-Dimethyl-1H-imidazol-2-yl)-1-phenylmethanimine
14
(
1h). Imine 1h was prepared via literature procedures with slight
modification. To a flame-dried 50 mL round-bottom flask was added
-amino-4,5-dimethylimidazole ethyl sulfate (1.9 g, 8.0 mmol, 1.0
equiv). The flask was degassed and filled with nitrogen. To the flask
was added CH Cl (10 mL) and then benzaldehyde (0.81 mL, 8.0
mmol, 1.0 equiv), Ti(OiPr) (3.79 mL, 12.8 mmol, 1.60 equiv), and
Et N (4.46 mL, 32.0 mmol, 4.00 equiv) were sequentially added
2
4
16
2
2
2
4
Dioxazolone 4i was prepared via a literature procedure for a related
8a
3
compound. The above crude N-hydroxy-4-phenylbutanamide (4.85
dropwise. The resultant mixture was stirred overnight at rt, and the
reaction was quenched with water (20 mL). The resulting mixture
was immediately filtered and washed with CH Cl . The filtrate was
g, 27.0 mmol, 1.00 equiv) was redissolved in CH Cl (300 mL). After
2
2
adding CDI (4.38 g, 27.0 mmol, 1.00 equiv), the reaction mixture was
stirred under nitrogen at rt for 30 min and quenched with 1 N HCl
(150 mL). The resulting mixture was transferred to a separatory
funnel, and the organic layer was separated. The aqueous layer was
extracted with CH Cl (×2). The combined organic extracts were
2
2
transferred to a separatory funnel. The organic layer was separated,
and the aqueous layer was washed with CH Cl (×2). The combined
2
2
organic extracts were dried (anhyd. Na SO ) and concentrated under
2
4
2
2
reduced pressure. Purification by silica gel column chromatography
20−40% ethyl acetate/hexanes) afforded 1h (814 mg, 51%) as a
yellow solid. mp 199−201 °C. FTIR (neat) 2918, 1600, 1572, 1450,
dried (anhyd. Na SO ) and concentrated under reduced pressure.
2 4
(
Purification by silica gel column chromatography (10% ethyl acetate/
hexanes) afforded 4i (5.03 g, 91%) as a colorless liquid. FTIR (neat)
−
1
1
−1 1
1
431, 1246, 872, 755, 685, 561, 494 cm . H NMR (600 MHz,
1871, 1824, 1636, 1148, 981, 752, 699 cm . H NMR (500 MHz,
CDCl ) δ 10.07 (s, 1H), 9.22 (s, 1H), 7.85 (d, J = 6.7 Hz, 2H), 7.47−
CDCl ) δ 7.32 (t, J = 7.5 Hz, 2H), 7.23 (t, J = 7.4 Hz, 1H), 7.18 (d, J
3
3
1
3
7
.34 (m, 3H), 2.17 (s, 3H), 2.03 (s, 3H). C NMR (151 MHz,
= 6.9 Hz, 2H), 2.75 (t, J = 7.4 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H), 2.07
1
3
CDCl ) δ 158.6, 148.1, 135.7, 132.9, 131.5, 129.0, 128.8, 121.7, 12.5,
9
1
(p, J = 7.4 Hz, 2H). C NMR (126 MHz, CDCl ) δ 166.4, 154.1,
3
3
+
+
+
+
.5. HRMS (EI ): m/z [M−H] calcd for C H N , 198.1031; found
98.1029.
E)-N-(3-Methyl-1H-1,2,4-triazol-5-yl)-1-phenylmethanimine
139.7, 128.7, 128.4, 126.5, 34.5, 25.9, 24.0. HRMS (EI ): m/z [M]
1
2
12
3
calcd for C H O N, 205.0739; found 205.0742.
1
1
11
3
(
General Procedures for C−H Functionalization of N-Azolo
Imines with 3-Substituted 1,4,2-Dioxazol-5-ones (0.3 mmol
Scale). To a flame-dried 2−5 mL Biotage microwave vial (#351521)
charged with a stir bar in a glovebox was added N-azolo imine (0.300
mmol, 1.00 equiv), 3-substituted 1,4,2-dioxazol-5-one (0.450 mmol,
1.50 equiv), [Cp*Rh(MeCN) ](SbF ) (10 mol %, 0.0300 mmol,
(
1i). Inside a glovebox, to a flame-dried 10−20 mL Biotage microwave
vial (#354833) was added 3-methyl-1H-1,2,4-triazol-5-amine (441
mg, 4.50 mmol, 1.00 equiv), benzaldehyde (0.460 mL, 4.50 mmol,
1
.00 equiv), 3 Å molecular sieves (approximately 7.5 g), and THF
(20.0 mL). The vial was capped with a Teflon-lined cap and removed
3
6 2
from the glovebox, and the mixture was stirred with a preheated stem
block filled with oil at 100 °C overnight. The resulting mixture was
filtered through a pad of Celite, washed with ethyl acetate, and
concentrated under reduced pressure. The crude residue was
recrystallized with hot ethyl acetate to afford 1i (621 mg, 74%) as a
white solid. mp 139−141 °C. FTIR (neat) 1622, 1558, 1450, 1314,
25.0 mg), PivOH (0.600 mmol, 2.00 equiv, 61.2 mg), NaOAc (0.150
mmol, 0.500 equiv, 12.3 mg), and dioxane (0.100 M, 3.00 mL). The
vial was capped with a Teflon-lined cap and removed from the
glovebox, and the mixture was stirred with a preheated stem block
filled with oil at 120 °C for 16 h. The resultant mixture was then
cooled to rt, filtered through a pad of Celite, washed thoroughly with
acetone, and concentrated under reduced pressure. The product was
purified by silica gel column chromatography.
−
1 1
1
220, 1149, 1063, 878, 763, 687, 544, 496 cm . H NMR (600 MHz,
CDCl ) δ 13.49 (s, 1H), 9.30 (s, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.50
3
1
3
(
(
1
1
t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.4 Hz, 2H), 2.59 (s, 3H). C NMR
2,4-Diphenylimidazo[1,2-a][1,3,5]triazine (6aa). The reaction
was performed according to the general procedure employing 51.4
mg of N-imidazo imine 1a and 73.4 mg of 3-phenyl-1,4,2-dioxazol-5-
one 4a. Purification by silica gel column chromatography (5−30%
acetone/hexanes) afforded 6aa (59.9 mg, 73%) as a yellow solid. mp
156−158 °C. FTIR (neat) 1593, 1572, 1477, 1391, 1329, 1257, 1132,
151 MHz, CDCl ) δ 165.0, 164.4, 155.6, 135.3, 132.4, 129.5, 128.9,
3
+
+
3.0. HRMS (EI ): m/z [M−H] calcd for C H N , 185.0827; found
1
0
9
4
85.0824.
E)-1-Phenyl-N-(3-phenyl-1H-1,2,4-triazol-5-yl)methanimine (1j).
Inside a glovebox, to a flame-dried 2−5 mL Biotage microwave vial
#351521) was added 3-phenyl-1H-1,2,4-triazol-5-amine (801 mg,
.00 mmol, 1.00 equiv), benzaldehyde (0.510 mL, 5.00 mmol, 1.00
equiv), 3 Å molecular sieves (approximately 200 mg), and toluene
2.00 mL). The vial was capped with a Teflon-lined cap and removed
(
−
1 1
(
5
759, 737, 687, 607, 479 cm . H NMR (400 MHz, CDCl ) δ 8.72−
3
8.55 (m, 2H), 8.09 (d, J = 6.6 Hz, 2H), 7.84−7.76 (m, 2H), 7.72−
1
3
7.60 (m, 3H), 7.53−7.46 (m, 3H). C NMR (101 MHz, CDCl ) δ
3
(
159.6, 155.1, 150.7, 136.6, 135.8, 132.6, 131.8, 131.6, 129.2, 128.8,
+
from the glovebox, and the mixture was stirred with a preheated stem
block filled with oil at 100 °C overnight (Note: a white solid
precipitated out of the reaction mixture after about 2 h). The solid
was scraped off, transferred to a filtered frit, and washed thoroughly
with ethyl acetate. The resulting solid (mixed with molecular sieves)
was dissolved with hot chloroform and filtered through a pad of
Celite. The filtrate was then concentrated under reduced pressure to
afford 1j (992 mg, 80%) as a white solid. mp 169−172 °C. FTIR
128.7, 128.5, 109.1. HRMS (ESI): m/z [M + H] calcd for
C H N , 273.1135; found 273.1121.
+
1
7
13
4
4-(4-Chlorophenyl)-2-phenylimidazo[1,2-a][1,3,5]triazine (6ab).
The reaction was performed according to the general procedure
employing 51.4 mg of N-imidazo imine 1a and 88.9 mg of 3-(4-
chlorophenyl)-1,4,2-dioxazol-5-one 4b. Purification by silica gel
column chromatography (10−30% acetone/hexanes) afforded 6ab
(55.1 mg, 60%) as a yellow solid. mp >200 °C. FTIR (neat) 3171,
3099, 1605, 1589, 1565, 1471, 1367, 1330, 1254, 1131, 1064, 731,
(
neat) 1618, 1564, 1472, 1381, 1219, 1158, 987, 770, 694, 572, 509
−
1
1
−1 1
cm . H NMR (600 MHz, (CD ) SO) δ 9.30 (s, 1H), 8.07−8.00
(
685, 485 cm . H NMR (400 MHz, CDCl ) δ 8.70−8.53 (m, 2H),
3
2
3
1
3
m, 4H), 7.60−7.42 (m, 6H). C NMR (151 MHz, (CD ) SO) δ
8.06 (d, J = 8.6 Hz, 2H), 7.84−7.74 (m, 2H), 7.63 (d, J = 8.5 Hz,
3
2
1
3
1
64.9, 163.3, 157.7, 135.6, 133.0, 130.1, 129.8, 129.5, 129.3, 126.3.
2H), 7.54−7.44 (m, 3H). C NMR (101 MHz, CDCl ) δ 159.5,
3
+
+
HRMS (EI ): m/z [M−H] calcd for C H N , 247.0984; found
154.0, 150.7, 139.1, 136.9, 135.6, 131.7, 130.1, 130.1, 129.6, 128.7,
1
5
11
4
+
+
2
47.0984.
-(3-Phenylpropyl)-1,4,2-dioxazol-5-one (2i). The starting hy-
droxamic acid (N-hydroxy-4-phenylbutanamide) was prepared
128.6, 108.8. HRMS (ESI): m/z [M + H] calcd for C H ClN ,
17 12 4
3
307.0745; found 307.0736.
2-Phenyl-4-(4-(trifluoromethyl)phenyl)imidazo[1,2-a][1,3,5]-
triazine (6ac). The reaction was performed according to the general
procedure employing 51.4 mg of N-imidazo imine 1a and 104 mg of
3-(4-(trifluoromethyl)phenyl)-1,4,2-dioxazol-5-one 4c. Purification by
17
according to a literature procedure for a related compound. To a
flame-dried 100 mL round-bottom flask was added 4-phenylbutanoic
acid (4.43 g, 27.0 mmol, 1.00 equiv) and THF (45.0 mL). After
D
DOI: 10.1021/acs.joc.8b01249
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
silica gel column chromatography (10−30% acetone/hexanes)
afforded 6ac (47.1 mg, 46%) as a yellow solid. mp 158−161 °C.
FTIR (neat) 1593, 1571, 1479, 1390, 1324, 1254, 1168, 1110, 1064,
1580, 1531, 1468, 1425, 1329, 1254, 1131, 862, 761, 706, 683, 480
−
1 1
cm . H NMR (600 MHz, CDCl ) δ 8.65−8.58 (m, 2H), 8.15 (d, J
3
= 3.8 Hz, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.78
−
1
1
13
1
8
2
014, 848, 768, 716, 687, 440 cm . H NMR (400 MHz, CDCl ) δ
(d, J = 4.9 Hz, 1H), 7.54−7.45 (m, 3H), 7.31 (t, J = 4.4 Hz, 1H).
C
3
.68−8.52 (m, 2H), 8.22 (d, J = 8.1 Hz, 2H), 7.92 (d, J = 8.2 Hz,
NMR (151 MHz, CDCl ) δ 159.0, 151.1, 148.9, 137.3, 135.7, 135.1,
3
H), 7.82 (d, J = 1.7 Hz, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.54−7.44
133.6, 132.0, 131.5, 128.8, 128.7, 128.5, 108.9. HRMS (ESI): m/z [M
m, 3H). 13C NMR (101 MHz, CDCl ) δ 159.5, 153.7, 150.5, 137.1,
+
+
(
+ H] calcd for C H N S , 279.0699; found 279.0698.
3
15 11 4
1
35.5, 135.1, 134.3 (q, J = 33.1 Hz), 131.8, 129.2, 128.8, 128.6, 126.3
2-Phenyl-4-(3-phenylpropyl)imidazo[1,2-a][1,3,5]triazine (6ai).
The reaction was performed according to the general procedure
employing 51.4 mg of N-imidazo imine 1a and 92.3 mg of 3-(3-
phenylpropyl)-1,4,2-dioxazol-5-one 4i. Purification by silica gel
column chromatography (5−35% acetone/hexanes) afforded 6ai
1
9
(
q, J = 3.7 Hz), 123.4 (q, J = 272.9 Hz), 108.7. F NMR (376 MHz,
CDCl ) δ −63.19. HRMS (ESI): m/z [M + H] calcd for
+
3
+
C H F N , 341.1009; found 341.1010.
18
12
3
4
4
-(4-Methoxyphenyl)-2-phenylimidazo[1,2-a][1,3,5]triazine
(
6ad). The reaction was performed according to the general
(
3
75.6 mg, 80%) as an off-white solid. mp 121−123 °C. FTIR (neat)
procedure employing 51.4 mg of N-imidazo imine 1a and 86.9 mg
of 3-(4-methoxyphenyl)-1,4,2-dioxazol-5-one 4d. Purification by silica
gel column chromatography (5−30% acetone/hexanes) afforded 6ad
104, 2930, 1592, 1501, 1400, 1259, 1141, 747, 705, 697, 621, 501
−1
1
cm . H NMR (400 MHz, CDCl ) δ 8.68−8.49 (m, 2H), 7.72
(
7
(
3
apparent s, 1H), 7.53−7.44 (m, 3H), 7.34 (d, J = 1.6 Hz, 1H), 7.33−
(
1
64.6 mg, 71%) as a yellow foam. FTIR (neat) 1574, 1501, 1473,
391, 1329, 1260, 1246, 1132, 1038, 766, 713, 687, 611 cm . H
.18 (m, 5H) 3.07 (t, J = 7.4 Hz, 2H), 2.85 (t, J = 7.4 Hz, 2H), 2.38
−
1 1
13
p, J = 7.4 Hz, 2H). C NMR (101 MHz, CDCl ) δ 159.1, 158.0,
3
NMR (400 MHz, CDCl ) δ 8.65−8.56 (m, 2H), 8.08 (d, J = 8.8 Hz,
3
1
1
49.7, 140.7, 136.3, 135.9, 131.5, 128.74, 128.6, 128.5, 128.5, 126.3,
2
H), 7.81 (d, J = 1.7 Hz, 1H), 7.75 (d, J = 1.7 Hz, 1H), 7.52−7.43
+
07.2, 35.0, 32.3, 26.1. HRMS (ESI): m/z [M + H] calcd for
1
3
(m, 3H), 7.10 (d, J = 8.9 Hz, 2H), 3.91 (s, 3H). C NMR (101 MHz,
+
C H N , 315.1604; found 315.1605.
2
0
19
4
CDCl ) δ 163.1, 159.5, 154.7, 150.9, 136.4, 136.0, 131.4, 130.7, 128.7,
3
4
-Methyl-2-phenylimidazo[1,2-a][1,3,5]triazine (6aj). The reac-
+
1
28.5, 123.9, 114.5, 109.0, 55.6. HRMS (ESI): m/z [M + H] calcd
tion was performed according to the general procedure with slight
modification (1 equiv (24.6 mg) of NaOAc was used) employing 51.4
mg of N-imidazo imine 1a and 45.5 mg of 3-methyl-1,4,2-dioxazol-5-
one 4j. Purification by silica gel column chromatography (10−35%
acetone/hexanes) afforded 6aj (43.1 mg, 68%) as a yellow solid. mp
+
for C H N O , 303.1240; found 303.1242.
18
15
4
4
-(3-Bromophenyl)-2-phenylimidazo[1,2-a][1,3,5]triazine (6ae).
The reaction was performed according to the general procedure
employing 51.4 mg of N-imidazo imine 1a and 109 mg of 3-(3-
bromophenyl)-1,4,2-dioxazol-5-one 4e. Purification by silica gel
column chromatography (10−30% acetone/hexanes) afforded 6ae
>
200 °C. FTIR (neat) 1605, 1592, 1503, 1432, 1261, 1145, 768, 717,
−
1 1
7
2
07, 685, 542 cm . H NMR (400 MHz, CDCl ) δ 8.65−8.47 (m,
3
(
64.2 mg, 61%) as a yellow solid. mp 147−150 °C. FTIR (neat) 3167,
H), 7.75 (d, J = 1.6 Hz, 1H), 7.52−7.45 (m, 3H), 7.44 (d, J = 1.6
3
8
8
7
133, 3104, 3063, 1588, 1562, 1464, 1389, 1327, 1253, 1131, 901,
1
3
−
1
1
Hz, 1H), 2.87 (s, 3H). C NMR (101 MHz, CDCl ) δ 159.3, 155.4,
3
69, 765, 731, 688, 609 cm . H NMR (400 MHz, CDCl ) δ 8.69−
3
1
49.6, 136.3, 135.8, 131.5, 128.7, 128.5, 107.6, 20.8. HRMS (ESI): m/
.55 (m, 2H), 8.22 (t, J = 1.8 Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H),
.84−7.78 (m, 2H), 7.77 (d, J = 1.6 Hz, 1H), 7.56−7.46 (m, 4H).
+
+
1
3
z [M + H] calcd for C12
H N , 211.0978; found 211.0976.
11 4
C
4
-Isopropyl-2-phenylimidazo[1,2-a][1,3,5]triazine (6ak). The re-
NMR (101 MHz, CDCl ) δ 159.5, 153.6, 150.5, 136.9, 135.6, 135.5,
3
action was performed according to the general procedure employing
51.4 mg of N-imidazo imine 1a and 58.1 mg of 3-isopropyl-1,4,2-
dioxazol-5-one 4k. Purification by silica gel column chromatography
1
(
33.6, 131.8, 131.7, 130.7, 128.8, 128.6, 127.1, 123.4, 108.9. HRMS
ESI): m/z [M + H]+ calcd for C H BrN , 351.0240; found
+
1
7
12
4
3
51.0238.
-(3-Methoxyphenyl)-2-phenylimidazo[1,2-a][1,3,5]triazine
3af). The reaction was performed according to the general procedure
(
5−35% acetone/hexanes) afforded 6ak (58.4 mg, 82%) as a white
solid. mp 102−104 °C. FTIR (neat) 3120, 3097, 2971, 2934, 1606,
593, 1501, 1402, 1332, 1252, 1126, 771, 739, 692, 619, 525, 483
4
(
1
employing 51.4 mg of N-imidazo imine 1a and 86.9 mg of 3-(3-
methoxyphenyl)-1,4,2-dioxazol-5-one 4f. Purification by silica gel
column chromatography (10−30% acetone/hexanes) afforded 6af
−
1 1
cm . H NMR (400 MHz, CDCl ) δ 8.69−8.49 (m, 2H), 7.73 (d, J
3
=
(
1.7 Hz, 1H), 7.51 (d, J = 1.7 Hz, 1H), 7.49−7.42 (m, 3H) 3.40
hept, J = 6.8 Hz, 1H), 1.51 (d, J = 6.8 Hz, 6H). 1 C NMR (101
MHz, CDCl ) δ 162.6, 159.3, 149.9, 136.2, 136.0, 131.4, 128.7, 128.5,
3
59.2 mg, 65%) as a yellow foam. FTIR (neat) 1574, 1501, 1473,
391, 1329, 1289, 1260, 1246, 1132, 1038, 766, 713, 687, 611 cm .
−
1
3
+
+
1
07.3, 32.3, 19.1. HRMS (ESI): m/z [M + H] calcd for C H N ,
14 15 4
3
239.1291; found 239.1292.
4-Benzyl-2-phenylimidazo[1,2-a][1,3,5]triazine (6al). The reac-
H), 7.66−7.44 (m, 6H), 7.19 (dd, J = 8.3, 1.9 Hz, 1H), 3.91 (s, 3H).
C NMR (101 MHz, CDCl ) δ 160.1, 159.6, 155.0, 150.6, 136.5,
3
tion was performed according to the general procedure with slight
modification (1 equiv (24.6 mg) of NaOAc was used) employing 51.4
mg of N-imidazo imine 1a and 79.7 mg of 3-benzyl-1,4,2-dioxazol-5-
one 4l. Purification by silica gel column chromatography (5−30%
acetone/hexanes) afforded 6al (56.5 mg, 66%) as a yellow solid. mp
35.8, 132.9, 131.6, 130.3, 128.8, 128.5, 120.7, 118.3, 114.4, 109.2,
+
+
18 15 4
4
-(2-Chlorophenyl)-2-phenylimidazo[1,2-a][1,3,5]triazine (6ag).
1
7
8
7
61−163 °C. FTIR (neat) 1608, 1592, 1498, 1402, 1330, 1133, 909,
−
1 1
32, 703, 686, 623, 563, 537 cm . H NMR (400 MHz, CDCl ) δ
3
.64−8.51 (m, 2H), 7.68 (d, J = 1.7 Hz, 1H), 7.56−7.45 (m, 3H),
1
3
.42 (d, J = 1.7 Hz, 1H), 7.38−7.25 (m, 5H) 4.48 (s, 2H). C NMR
(101 MHz, CDCl ) δ 159.3, 156.5, 149.9, 136.4, 135.8, 132.7, 131.5,
584, 1500, 1462, 1399, 1329, 1251, 1135, 1026, 763, 712, 690, 607,
3
−1 1
1
29.1, 128.9, 128.8, 128.5, 127.9, 107.8, 40.9. HRMS (ESI): m/z [M
38 cm . H NMR (400 MHz, CDCl ) δ 8.67−8.52 (m, 2H), 7.76
3
+
+
+ H] calcd for C18H N , 287.1291; found 287.1293.
15 4
1
3
2-(Furan-2-yl)-4-phenylimidazo[1,2-a][1,3,5]triazine (6ba). The
reaction was performed according to the general procedure employing
48.3 mg of N-imidazo imine 1b and 73.4 mg of 3-phenyl-1,4,2-
dioxazol-5-one 4a. Purification by silica gel column chromatography
(10−35% acetone/hexanes) afforded 6ba (43.2 mg, 55%) as a yellow
solid. mp 130−132 °C. FTIR (neat) 1567, 1503, 1476, 1446, 1325,
3
+
+
17
12
4
2
-Phenyl-4-(thiophen-2-yl)imidazo[1,2-a][1,3,5]triazine (6ah).
−
1 1
1259, 1132, 759, 740, 694, 631, 594, 465 cm . H NMR (400 MHz,
CDCl ) δ 8.06−7.98 (m, 2H), 7.77−7.74 (m, 2H), 7.70−7.56 (m,
4H), 7.49 (d, J = 3.5 Hz, 1H), 6.59 (dd, J = 3.5, 1.7 Hz, 1H).
3
1
3
C
NMR (101 MHz, CDCl ) δ 155.7, 152.3, 150.8, 149.9, 146.1, 136.7,
3
E
DOI: 10.1021/acs.joc.8b01249
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1
+
32.7, 131.4, 129.3, 128.7, 115.9, 112.5, 109.3. HRMS (ESI): m/z [M
132.8 (q, J = 32.5 Hz), 128.9, 128.6, 128.4, 126.4, 125.5 (q, J = 3.7
+
+
19
H] calcd for C H N O , 263.0927; found 263.0929.
Hz), 124.0 (q, J = 272.4 Hz), 107.5, 35.0, 32.4, 26.1. F NMR (376
15
11
4
+
2
-(Furan-2-yl)-4-(3-phenylpropyl)imidazo[1,2-a][1,3,5]triazine
6bi). The reaction was performed according to the general procedure
employing 48.3 mg of N-imidazo imine 1b and 92.3 mg of 3-phenyl-
,4,2-dioxazol-5-one 4i. Purification by silica gel column chromatog-
MHz, CDCl ) δ −62.86. HRMS (ESI): m/z [M + H] calcd for
3
+
(
C H F N , 383.1478; found 383.1480.
2
1
18
3
4
2-(4-Methoxyphenyl)-4-phenylimidazo[1,2-a][1,3,5]triazine
1
(6ea). The reaction was performed according to the general
procedure employing 60.4 mg of N-imidazo imine 1e and 73.4 mg
of 3-phenyl-1,4,2-dioxazol-5-one 4a. Purification by silica gel column
chromatography (5−30% acetone/hexanes) afforded 6ea (55.1 mg,
61%) as a yellow solid. mp 173−176 °C. FTIR (neat) 1591, 1573,
1500, 1471, 1448, 1391, 1310, 1249, 1165, 1138, 1023, 851, 777, 704,
raphy (10−35% acetone/hexanes) afforded 6bi (53.2 mg, 58%) as a
tan solid. mp 117−119 °C. FTIR (neat) 3108, 2925, 2668, 1603,
1
4
7
7
2
583, 1498, 1455, 1414, 1327, 1264, 1166, 1110, 1005, 750, 701, 594,
97 cm . H NMR (400 MHz, CDCl ) δ 7.70 (d, J = 1.7 Hz, 1H),
.65 (dd, J = 1.7, 0.9 Hz, 1H), 7.44 (dd, J = 3.5, 0.9 Hz, 1H), 7.35−
.13 (m, 6H), 6.57 (dd, J = 3.5, 1.8 Hz, 1H), 3.05 (t, J = 7.4 Hz, 2H),
−
1 1
3
−
1 1
691, 577, 516 cm . H NMR (400 MHz, CDCl ) δ 8.57 (d, J = 8.9
3
1
3
.82 (t, J = 7.4 Hz, 2H), 2.31 (p, J = 7.5 Hz, 2H). C NMR (101
Hz, 2H), 8.07 (d, J = 6.8 Hz, 2H), 7.78−7.71 (m, 2H), 7.70−7.59 (m,
1
3
MHz, CDCl ) δ 158.7, 151.9, 150.9, 149.0, 146.1, 140.6, 136.4, 128.6,
3H), 6.98 (d, J = 8.9 Hz, 2H), 3.87 (s, 3H). C NMR (101 MHz,
3
1
28.5, 126.4, 115.8, 112.5, 107.5, 35.0, 32.5, 26.4. HRMS (ESI): m/z
CDCl ) δ 162.6, 159.5, 154.9, 150.8, 136.2, 132.5, 131.9, 130.6, 129.1,
3
+
+
+
[
M + H] calcd for C H N O , 305.1397; found 305.1396.
128.7, 128.4, 113.9, 108.9, 55.4. HRMS (ESI): m/z [M + H] calcd
1
8
17
4
+
Methyl 4-(4-Phenylimidazo[1,2-a][1,3,5]triazin-2-yl)benzoate
for C H N O , 303.1240; found 303.1255.
1
8
15
4
(
6ca). The reaction was performed according to the general
2-(4-Methoxyphenyl)-4-(3-phenylpropyl)imidazo[1,2-a][1,3,5]-
triazine (6ei). The reaction was performed according to the general
procedure employing 60.4 mg of N-imidazo imine 1e and 92.3 mg of
3-phenyl-1,4,2-dioxazol-5-one 4i. Purification by silica gel column
chromatography (10−30% acetone/hexanes) afforded 6ei (64.1 mg,
62%) as a yellow solid. mp 101−104 °C. FTIR (neat) 1593, 1508,
1493, 1399, 1307, 1249, 1165, 1028, 842, 784, 744, 698, 582, 503
procedure employing 68.8 mg of N-imidazo imine 1c and 73.4 mg
of 3-phenyl-1,4,2-dioxazol-5-one 4a. Purification by silica gel column
chromatography (5−30% acetone/hexanes) afforded 6ca (64.3 mg,
6
1
5%) as a yellow solid. mp >200 °C. FTIR (neat) 3160, 3104, 1719,
−
1 1
612, 1576, 1477, 1283, 1254, 1107, 761, 735, 692 cm . H NMR
(400 MHz, CDCl ) δ 8.70 (d, J = 8.6 Hz, 2H), 8.15 (d, J = 8.5 Hz,
3
−
1 1
2
3
1
1
H), 8.10 (d, J = 6.7 Hz, 2H), 7.89−7.81 (m, 2H), 7.76−7.61 (m,
cm . H NMR (400 MHz, CDCl ) δ 8.53 (d, J = 9.0 Hz, 2H), 7.67
3
1
3
H), 3.94 (s, 3H). C NMR (101 MHz, CDCl ) δ 166.7, 158.5,
(d, J = 1.6 Hz, 1H), 7.34−7.18 (m, 6H), 6.98 (d, J = 8.9 Hz, 2H),
3
55.3, 150.4, 139.9, 137.1, 132.8, 132.5, 131.6, 129.7, 129.3, 128.7,
3.87 (s, 3H), 3.05 (t, J = 7.4 Hz, 2H), 2.85 (t, J = 7.4 Hz, 2H), 2.37
+
13
28.6, 109.3, 52.3. HRMS (ESI): m/z [M + H] calcd for
(p, J = 7.4 Hz, 2H). C NMR (101 MHz, CDCl
) δ 162.5, 159.0,
3
+
C H N O , 331.1190; found 331.1191.
157.7, 149.9, 140.8, 135.9, 130.6, 128.6, 128.5, 128.5, 126.3, 113.9,
19
15
4
2
+
Methyl 4-(4-(3-Phenylpropyl)imidazo[1,2-a][1,3,5]triazin-2-yl)-
106.9, 55.4, 35.0, 32.3, 26.1. HRMS (ESI): m/z [M + H] calcd for
+
benzoate (6ci). The reaction was performed according to the general
procedure with slight modification (1 equiv (24.6 mg) of NaOAc was
used) employing 68.8 mg of N-imidazo imine 1c and 92.3 mg of 3-
phenyl-1,4,2-dioxazol-5-one 4i. Purification by silica gel column
chromatography (5−30% acetone/hexanes) afforded 6ci (61.1 mg,
C H N O , 345.1710; found 345.1707.
2
1
21
4
2-(3-Bromophenyl)-4-phenylimidazo[1,2-a][1,3,5]triazine (6fa).
The reaction was performed according to the general procedure
employing 75.0 mg of N-imidazo imine 1f and 73.4 mg of 3-phenyl-
1,4,2-dioxazol-5-one 4a. Purification by silica gel column chromatog-
raphy (10−30% acetone/hexanes) afforded 6fa (62.2 mg, 59%) as a
yellow solid. mp 179−182 °C. FTIR (neat) 1597, 1572, 1504, 1479,
1380, 1324, 1248, 1227, 1131, 1069, 764, 735, 690, 674, 661, 608
5
1
5%) as a white solid. mp 108−110 °C. FTIR (neat) 1721, 1610,
593, 1504, 1495, 1410, 1273, 1252, 1016, 870, 770, 731, 718, 699
−
1 1
cm . H NMR (400 MHz, CDCl ) δ 8.64 (d, J = 8.5 Hz, 2H), 8.14
3
−
1 1
(d, J = 8.5 Hz, 2H), 7.77 (d, J = 1.6 Hz, 1H), 7.38 (d, J = 1.6 Hz, 1H),
cm . H NMR (400 MHz, CDCl ) δ 8.78 (t, J = 1.9 Hz, 1H), 8.56
3
7
7
.34−7.15 (m, 5H), 3.94 (s, 3H), 3.10 (t, J = 7.4 Hz, 2H), 2.86 (t, J =
(d, J = 7.9 Hz, 1H), 8.14−8.05 (m, 2H), 7.87−7.79 (m, 2H), 7.73−
1
3
13
.4 Hz, 2H), 2.40 (p, J = 7.4 Hz, 2H). C NMR (101 MHz, CDCl )
7.59 (m, 4H), 7.36 (t, J = 7.9 Hz, 1H). C NMR (101 MHz, CDCl )
3
3
δ 166.7, 158.3, 158.0, 149.4, 140.6, 139.9, 136.7, 132.4, 129.7, 128.6,
28.5, 126.4, 107.5, 52.3, 35.0, 32.4, 26.1. HRMS (ESI): m/z [M +
δ 158.1, 155.3, 150.3, 137.9, 136.9, 134.4, 132.8, 131.7, 131.5, 130.1,
+
1
129.3, 128.8, 127.3, 122.8, 109.3. HRMS (ESI): m/z [M + H] calcd
+
+
+
H] calcd for C H N O , 373.1659; found 373.1657.
for C H BrN , 351.0240; found 351.0245.
22
21
4
2
17 12
4
4
-Phenyl-2-(4-(trifluoromethyl)phenyl)imidazo[1,2-a][1,3,5]-
2-(3-Bromophenyl)-4-(3-phenylpropyl)imidazo[1,2-a][1,3,5]-
triazine (6fi). The reaction was performed according to the general
procedure employing 75.0 mg of N-imidazo imine 1f and 92.3 mg of
3-phenyl-1,4,2-dioxazol-5-one 4i. Purification by silica gel column
chromatography (10−30% acetone/hexanes) afforded 6fi (72.1 mg,
61%) as a white solid. mp 100−102 °C. FTIR (neat) 1600, 1495,
triazine (6da). The reaction was performed according to the general
procedure employing 71.8 mg of N-imidazo imine 1d and 73.4 mg of
3
-phenyl-1,4,2-dioxazol-5-one 4a. Purification by silica gel column
chromatography (5−30% acetone/hexanes) afforded 6da (59.8 mg,
5
1
4
8
5
1
9%) as a yellow solid. mp 143−146 °C. FTIR (neat) 1619, 1595,
−
1 1
573, 1478, 1318, 1257, 1169, 1104, 1064, 1015, 858, 774, 694, 590,
1455, 1319, 1253, 1131, 807, 779, 739, 719, 696, 673, 436 cm . H
−
1 1
40 cm . H NMR (400 MHz, CDCl ) δ 8.74 (d, J = 8.1 Hz, 2H),
NMR (400 MHz, CDCl ) δ 8.74 (t, J = 1.8 Hz, 1H), 8.50 (d, J = 7.9
3
3
.09 (d, J = 7.4 Hz, 2H), 7.84 (d, J = 8.8 Hz, 2H), 7.79−7.58 (m,
Hz, 1H), 7.74 (d, J = 1.6 Hz, 1H), 7.61 (ddd, J = 7.9, 2.1, 1.1 Hz,
1H), 7.43−7.12 (m, 8H), 3.09 (t, J = 7.4 Hz, 2H), 2.86 (t, J = 7.4 Hz,
H). 13C NMR (101 MHz, CDCl ) δ 158.1, 155.4, 150.3, 139.1,
3
1
3
37.1, 132.9 (q, J = 32.6 Hz), 132.9, 131.5, 129.3, 129.0, 128.7, 125.5
q, J = 3.7 Hz), 124.0 (q, J = 272.4 Hz), 109.4. F NMR (376 MHz,
2H), 2.38 (p, J = 7.4 Hz, 2H). C NMR (101 MHz, CDCl ) δ 158.3,
3
1
9
(
157.6, 149.4, 140.6, 138.0, 136.6, 134.3, 131.7, 130.1, 128.6, 128.5,
+
CDCl ) δ −62.86. HRMS (ESI): m/z [M + H] calcd for
127.2, 126.4, 122.8, 107.4, 35.0, 32.4, 26.1. HRMS (ESI): m/z [M +
3
+
+
+
C H F N , 341.1009; found 341.1013.
H] calcd for C H BrN , 393.0709; found 393.0708.
1
8
12
3
4
20 18 4
4
-(3-Phenylpropyl)-2-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]-
2-(2-Chlorophenyl)-4-(3-phenylpropyl)imidazo[1,2-a][1,3,5]-
triazine (6gi). The reaction was performed according to the general
procedure with slight modification (1 equiv (24.6 mg) of NaOAc was
used) employing 61.7 mg of N-imidazo imine 1g and 92.3 mg of 3-
phenyl-1,4,2-dioxazol-5-one 4i. Purification by silica gel column
chromatography (5−30% acetone/hexanes) afforded 6gi (48.3 mg,
46%) as a clear oil. FTIR (neat) 1587, 1495, 1329, 1261, 1247, 1139,
[
1,3,5]triazine (6di). The reaction was performed according to the
general procedure employing 71.8 mg of N-imidazo imine 1d and
2.3 mg of 3-phenyl-1,4,2-dioxazol-5-one 4i. Purification by silica gel
column chromatography (5−30% acetone/hexanes) afforded 6di
9
(
1
6
87.8 mg, 77%) as a white solid. mp 96−99 °C. FTIR (neat) 1617,
595, 1496, 1415, 1319, 1253, 1164, 1107, 1063, 1015, 857, 784, 739,
−
1
1
−1 1
97, 592, 489 cm . H NMR (400 MHz, CDCl ) δ 8.68 (d, J = 8.2
1107, 1049, 910, 761, 735, 698 cm . H NMR (600 MHz, CDCl ) δ
3
3
Hz, 2H), 7.78 (d, J = 1.6 Hz, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.39 (d, J
1.6 Hz, 1H), 7.34−7.26 (m, 2H), 7.26−7.17 (m, 3H), 3.11 (t, J =
7.97−7.92 (m, 1H), 7.81 (d, J = 1.6 Hz, 1H), 7.53−7.48 (m, 1H),
7.41 (d, J = 1.6 Hz, 1H), 7.41−7.36 (m, 2H), 7.31−7.27 (m, 2H),
7.24−7.17 (m, 3H), 3.11 (t, J = 7.4 Hz, 2H), 2.85 (t, J = 7.4 Hz, 2H),
=
1
3
7.4 Hz, 2H), 2.87 (t, J = 7.4 Hz, 2H), 2.40 (p, J = 7.4 Hz, 2H).
C
1
3
NMR (101 MHz, CDCl ) δ 158.4, 157.6, 149.3, 140.5, 139.2, 136.8,
2.36 (p, J = 7.4 Hz, 2H). C NMR (151 MHz, CDCl ) δ 159.8,
3
3
F
DOI: 10.1021/acs.joc.8b01249
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1
1
58.1, 149.0, 140.7, 136.6, 136.0, 133.3, 132.1, 131.0, 130.9, 128.6,
6ai (205.3 mg, 65%) as an off-white solid. H and 13C NMR spectra
1
28.5, 126.8, 126.3, 107.3, 34.9, 32.5, 26.2. HRMS (ESI): m/z [M +
matched with 6ai obtained from a small scale (0.3 mmol).
+
+
H] calcd for C H ClN , 349.1215; found 349.1214.
20
18
4
6
,7-Dimethyl-2-phenyl-4-(3-phenylpropyl)imidazo[1,2-a][1,3,5]-
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b01249.
■
triazine (6hi). The reaction was performed according to the general
procedure employing 59.8 mg of N-imidazo imine 1h and 92.3 mg of
3
*
S
-phenyl-1,4,2-dioxazol-5-one 4i. Purification by silica gel column
chromatography (10−35% acetone/hexanes) afforded 6hi (53.5 mg,
5
1
2%) as a yellow solid. mp 149−152 °C. FTIR (neat) 1606, 1595,
NMR spectra (PDF)
495, 1487, 1405, 1264, 1229, 1133, 1022, 756, 737, 697, 565, 487
−
1 1
cm . H NMR (400 MHz, CDCl ) δ 8.58−8.45 (m, 2H), 7.52−7.43
3
AUTHOR INFORMATION
Corresponding Author
*E-mail: jonathan.ellman@yale.edu.
ORCID
Gia L. Hoang: 0000-0003-2332-1854
Jonathan A. Ellman: 0000-0001-9320-5512
Notes
(
m, 3H), 7.34−7.17 (m, 5H), 3.26 (t, J = 7.5 Hz, 2H), 2.84 (t, J = 7.4
■
1
3
Hz, 2H), 2.49 (s, 3H), 2.35 (s, 3H), 2.30 (p, J = 7.5 Hz, 2H).
C
NMR (101 MHz, CDCl ) δ 158.1, 157.2, 148.6, 143.5, 141.0, 136.1,
31.0, 128.5, 128.4, 128.4, 126.2, 114.0, 34.9, 33.0, 27.9, 13.6, 11.9.
HRMS (ESI): m/z [M + H] calcd for C H N , 343.1917; found
3
1
+
+
2
2
23
4
3
43.1918.
-Methyl-5-phenyl-7-(3-phenylpropyl)-[1,2,4]triazolo[1,5-a]-
1,3,5]triazine (6ii). The reaction was performed according to the
2
[
general procedure with slight modification (1 equiv (24.6 mg) of
NaOAc was used; DCE was used instead of dioxane; temp = 100 °C)
employing 55.9 mg of N-triazolo imine 1i and 92.3 mg of 3-phenyl-
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
1
,4,2-dioxazol-5-one 4i. Purification by silica gel column chromatog-
■
raphy (10−30% ethyl acetate/hexanes) afforded 6ii (56.4 mg, 57%)
This work was supported by the NIH (R35GM122473 to
J.A.E.). The Villum Foundation (VKR023371) is also
acknowledged for postdoctoral support to K.S.H.
as a white solid. mp 117−120 °C. FTIR (neat) 1610, 1593, 1529,
1
478, 1445, 1407, 1376, 1312, 768, 746, 687, 677, 587, 570, 491
−
1 1
cm . H NMR (400 MHz, CDCl ) δ 8.58 (d, J = 6.8 Hz, 2H), 7.57−
3
7
=
.46 (m, 3H), 7.29−7.15 (m, 5H), 3.35 (t, J = 7.5 Hz, 2H), 2.84 (t, J
REFERENCES
13
■
7.6 Hz, 2H), 2.62 (s, 3H), 2.39 (p, J = 7.6 Hz, 2H). C NMR (101
(
1) For selected approved drugs incorporating a [5,6]-bicyclic
MHz, CDCl ) δ 167.6, 163.3, 160.1, 157.4, 140.8, 135.2, 132.3, 129.3,
28.7, 128.5, 128.4, 126.2, 35.2, 31.4, 26.5, 15.2. HRMS (ESI): m/z
M + H] calcd for C H N , 330.1713; found 330.1721.
2
triazine (6ji). The reaction was performed according to the general
procedure with slight modification (1 equiv (24.6 mg) of NaOAc was
used; DCE was used instead of dioxane; temp = 100 °C) employing
3
heterocycle core with a ring junction nitrogen, see: anagliptin,
olprinone, minodronic acid, vardenafil, zalepton, acalabrutinib,
zolpidem, and ponatinip. The compound structure, bioactivity, list
of literature, and access to ongoing clinical trials, applications, and
usage can be obtained by searching the compound name in
PubChem.
(2) For select phase II and III clinical candidates incorporating a
[5,6]-bicyclic heterocycle core with a ring junction nitrogen, see:
LY2090314, dipraglurant, AMG-337, irbinitinib, dinaciclib, empeser-
tib, fligotinib, entospletinib, and volitinib. The compound structure,
bioactivity, list of literature, and access to ongoing clinical trials,
applications, and usage can be obtained by searching the compound
name in PubChem.
1
[
+
+
20 20 5
,5-Diphenyl-7-(3-phenylpropyl)-[1,2,4]triazolo[1,5-a][1,3,5]-
7
4.5 mg of N-triazolo imine 1j and 92.3 mg of 3-phenyl-1,4,2-
dioxazol-5-one 4i. Purification by silica gel column chromatography
5−10% ethyl acetate/hexanes) afforded 6ji (65.7 mg, 56%) as a
white solid. mp 136−138 °C. FTIR (neat) 1607, 1595, 1527, 1511,
(
−
1 1
1
(
7
2
449, 1410, 1375, 1276, 767, 703, 697, 688, 607, 501 cm . H NMR
400 MHz, CDCl ) δ 8.62 (d, J = 6.7 Hz, 2H), 8.40−8.32 (m, 2H),
3
.60−7.47 (m, 6H), 7.31−7.15 (m, 5H), 3.43 (t, J = 7.4 Hz, 2H),
13
(
3) Halskov, K. S.; Witten, M. R.; Hoang, G. L.; Mercado, B. Q.;
.88 (t, J = 7.5 Hz, 2H), 2.44 (p, J = 7.5 Hz, 2H). C NMR (101
Ellman, J. A. Rhodium(III)-Catalyzed Imidoyl C−H Activation for
MHz, CDCl ) δ 166.8, 163.3, 160.5, 157.7, 140.9, 135.2, 132.4, 131.1,
29.8, 129.3, 128.7, 128.7, 128.5, 128.4, 127.8, 126.2, 35.2, 31.4, 26.5.
HRMS (ESI): m/z [M + H] calcd for C H N , 392.1870; found
3
Annulations to Azolopyrimidines. Org. Lett. 2018, 20, 2464−2467.
1
+
+
(
4) For selected reviews on transition-metal-catalyzed C−H
2
5
22
5
functionalization that include applications to nitrogen heterocycle
synthesis, see: (a) Satoh, T.; Miura, M. Oxidative Coupling of
Aromatic Substrates with Alkynes and Alkenes under Rhodium
Catalysis. Chem. - Eur. J. 2010, 16, 11212−11222. (b) Song, G.;
Wang, F.; Li, X. C−C, C−O and C−N Bond Formation via
Rhodium(III)-Catalyzed Oxidative C−H Activation. Chem. Soc. Rev.
2012, 41, 3651−3678. (c) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K.
C−H Bond Functionalization: Emerging Synthetic Tools for Natural
Products and Pharmaceuticals. Angew. Chem., Int. Ed. 2012, 51,
8960−9009. (d) Mesganaw, T.; Ellman, J. A. Convergent Synthesis of
Diverse Tetrahydropyridines via Rh(I)-Catalyzed C−H Functionali-
zation Sequences. Org. Process Res. Dev. 2014, 18, 1097−1104.
3
92.1875.
Procedure for C−H Functionalization of N-Imidazo Imine
1
a with 3-(3-Phenylpropyl)-1,4,2-dioxazol-5-one 4i Using a
Microwave Reactor (1 mmol Scale). With a benchtop setup, to a
flame-dried 10−20 mL Biotage microwave vial (#354833) charged
with a stir bar was added N-imidazo imine 1a (171 mg, 1.00 mmol,
1
.00 equiv), [Cp*Rh(MeCN) ](SbF ) (10 mol %, 0.100 mmol, 83.3
3 6 2
mg), PivOH (204 mg, 2.00 mmol, 2 equiv), and NaOAc (41.0 mg,
.500 mmol, 0.500 equiv). The vial was capped with a Teflon-lined
cap and flushed with N for ca. 5 min, and then, dioxane (10.0 mL,
0
2
0.100 M) was added. To the resulting mixture was added 3-(3-
phenylpropyl)-1,4,2-dioxazol-5-one 4i (0.260 mL, 306 mg, 0.450
mmol, 1.50 equiv) dropwise via syringe. The reaction vial was flushed
with N for a further ca. 5 min before heating with a Biotage Initiator+
(e) Gulías, M.; Mascarenas, J. L. Metal-Catalyzed Annulations
̃
through Activation and Cleavage of C−H Bond. Angew. Chem., Int.
Ed. 2016, 55, 11000−11019. (f) Newton, C. G.; Wang, S.-G.;
Oliveira, C. C.; Cramer, N. Catalytic Enantioselective Trans-
formations Involving C−H Bond Cleavage by Transition-Metal
Complexes. Chem. Rev. 2017, 117, 8908−8976. (g) Hummel, J. R.;
Boerth, J. A.; Ellman, J. A. Transition-Metal-Catalyzed C−H Bond
Addition to Carbonyls, Imines, and Related Polarized π Bonds. Chem.
Rev. 2017, 117, 9163−9227. (h) Park, Y.; Kim, Y.; Chang, S.
Transition Metal-Catalyzed C−H Amination: Scope, Mechanism, and
Applications. Chem. Rev. 2017, 117, 9247−9301. (i) Dong, Z.; Ren,
2
(#356007), which employs an external IR sensor and a closed
reaction vessel. The resultant mixture was stirred in the microwave
reactor for 2 h at 170 °C using the following settings (absorption
level, low; vial type, 10−20 mL; prestirring, 0; initial power, 0;
dynamic deflector optimization, ON; pressure: OFF; power, OFF;
fixed hold time, ON; stir rate, 600). After cooling to rt, the resultant
mixture was filtered through a pad of Celite, washed thoroughly with
acetone, and concentrated under reduced pressure. Purification by
silica gel column chromatography (5−35% acetone/hexanes) afforded
G
DOI: 10.1021/acs.joc.8b01249
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Z.; Thompson, S. J.; Xu, Y.; Dong, G. Transition-Metal-Catalyzed C−
H Alkylation Using Alkenes. Chem. Rev. 2017, 117, 9333−9403.
(
5) Sauer, J.; Mayer, K. K. Thermolyse und Photolyse von 3.4-
2
2
Diphenyl-Δ -1.2.4-oxdiazolinon-(5) und 2.4-Diphenyl-Δ -1.3.4-oxdia-
zolinon-(5). Tetrahedron Lett. 1968, 9, 319−324.
(
6) Dube, P.; Nathel, N. F. F.; Vetelino, M.; Couturier, M.;
́
Aboussafy, C. L.; Pichette, S.; Jorgensen, M. L.; Hardink, M.
Carbonyldiimidazole-Mediated Lossen Rearrangement. Org. Lett.
2
(
009, 11, 5622−5625.
7) Bizet, V.; Buglioni, L.; Bolm, C. Light-Induced Ruthenium-
Catalyzed Nitrene Transfer Reactions: A Photochemical Approach
towards N-Acyl Sulfimides and Sulfoximines. Angew. Chem., Int. Ed.
2
(
014, 53, 5639−5642.
8) (a) Park, Y.; Park, K. T.; Kim, J. G.; Chang, S. Mechanistic
Studies on the Rh(III)-Mediated Amido Transfer Process Leading to
Robust C−H Amination with a New Type of Amidating Reagent. J.
Am. Chem. Soc. 2015, 137, 4534−4542. (b) Park, Y.; Jee, S.; Kim, J.
G.; Chang, S. Study of Sustainability and Scalability in the
Cp*Rh(III)-Catalyzed Direct C−H Amidation with 1,4,2-Dioxazol-
5
(
-ones. Org. Process Res. Dev. 2015, 19, 1024−1029.
9) For a recent review including 1,4,2-dioxazol-5-one as an efficient
amidating reagent in C−H functionalization, see ref 4h and references
cited therein.
(
10) Halskov, K. S.; Roth, H. S.; Ellman, J. A. Synthesis of [5,6]-
Bicyclic Heterocycles with a Ring-Junction Nitrogen Atom: Rhodium-
III)-Catalyzed C−H Functionalization of Alkenyl Azoles. Angew.
Chem., Int. Ed. 2017, 56, 9183−9187.
11) Wu, X.; Sun, S.; Xu, S.; Cheng, J. Rh-Catalyzed Annulation of
(
(
ortho-C−H Bonds of 2-Arylimidazoles with 1,4,2-Dioxazol-5-ones
toward 5-Arylimidazo[1,2-c]quinazolines. Adv. Synth. Catal. 2018,
3
(
60, 1111−1115.
12) Lim, F. P. L.; Dolzhenko, A. V. 1,3,5-Triazine-Based Analogues
of Purine: From Isosteres to Privileged Scaffolds in Medicinal
Chemistry. Eur. J. Med. Chem. 2014, 85, 371−390.
(
13) Li reported that Zn(OAc) in conjunction with a cobalt catalyst
2
provides an efficient system for annulations to enamides and
pyrimidones. See: Liu, Y.; Xie, F.; Jia, A.-Q.; Li, X. Cp*Co(III)-
Catalyzed Amidation of Olefinic and Aryl C−H Bonds: Highly
Selective Synthesis of Enamides and Pyrimidones. Chem. Commun.
2
018, 54, 4345−4348. Co(III) and Rh(III) catalysts employed with
Zn(OAc)2 instead of NaOAc/PivOH were tried but proved
unsuccessful: no desired bicyclic product was detected by crude H
1
NMR.
(14) Li, H.; Zhao, J.; Zeng, L.; Hu, W. Organocatalytic Asymmetric
Domino Aza-Michael−Mannich Reaction: Synthesis of Tetrahydroi-
midazopyrimidine Derivatives. J. Org. Chem. 2011, 76, 8064−8069.
(15) (a) Mishra, A.; Mukherjee, U.; Vats, T. K.; Deb, I. Ir(III)/
MPAA-Catalyzed Mild and Selective C−H Amidation of N-Sulfonyl
Ketimines: Access to Benzosultam-Fused Quinazolines/ Quinazoli-
nones. J. Org. Chem. 2018, 83, 3756−3767. (b) Chen, Y.; Zhang, R.;
Peng, Q.; Xu, L.; Pan, X. Rhodium(III)-Catalyzed Directed C−H
Amidation of N-Nitrosoanilines and Subsequent Formation of 1,2-
Disubstituted Benzimidazoles. Chem. - Asian J. 2017, 12, 2804−2808.
(
c) Bizet, V.; Bolm, C. Sulfur Imidations by Light-Induced
Ruthenium-Catalyzed Nitrene Transfer Reactions. Eur. J. Org. Chem.
015, 2015, 2854−2860.
16) Little, T. L.; Webber, S. E. A Simple and Practical Synthesis of
-Aminoimidazoles. J. Org. Chem. 1994, 59, 7299−7305.
17) Usachova, N.; Leitis, G.; Jirgensons, A.; Kalvinsh, I. Synthesis of
2
(
2
(
Hydroxamic Acids by Activation of Carboxylic Acids with N,N′-
Carbonyldiimidazole: Exploring the Efficiency of the Method. Synth.
Commun. 2010, 40, 927−935.
H
DOI: 10.1021/acs.joc.8b01249
J. Org. Chem. XXXX, XXX, XXX−XXX