Base-Induced Transformation of 2-Acyl-3-alkyl-2H-azirines to Oxazoles: Involvement of Deprotonation-Initiated Pathways

Article abstract of DOI:10.1021/acs.joc.7b00904

An experimental study of base-induced transformation reaction of 2-acyl-3-alkyl-2H-azirines to oxazoles indicated that a deprotonation-initiated mechanism is involved, in addition to nucleophilic addition to the imine functionality. Calculations suggested

Full text of DOI:10.1021/acs.joc.7b00904

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Article
Base-Induced Transformation of 2-Acyl-3-Alkyl-2H-Azirines
to Oxazoles: Involvement of Deprotonation-Initiated Pathway
Yingtang Ning, Yuko Otani, and Tomohiko Ohwada
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 23 May 2017
Downloaded from http://pubs.acs.org on May 25, 2017
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The Journal of Organic Chemistry
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Base-Induced Transformation of 2-Acyl-3-Alkyl-2H-Azirines to Oxazoles: Involvement of
Deprotonation-Initiated Pathway
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Yingtang Ning, Yuko Otani, Tomohiko Ohwada*
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Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo
113-0033, Japan
Supporting Information Placeholder
O
O
K
N
N
Ph
·
2
tert-BuOK
O
N
N
O
Ph
– H+
3
pseudo π*
carbanion
H
Ph
Ph
ABSTRACT: An experimental study of base-induced transformation reaction of
2-acyl-3-alkyl-2H-azirines to oxazoles indicated that a deprotonation-initiated mechanism is involved,
in addition to nucleophilic addition to the imine functionality. Calculations suggested the participation
of a ketenimine (ethenimine) intermediate generated by azirine ring opening of the carbanion
intermediate formed by α-deprotonation of 2H-azirine. The ketenimine intermediate possessing methyl
substituents at C(3) appears to be more stable than the tautomeric nitrile ylide which was proposed to be
involved in photo-induced and pyrolysis reactions of 2-acyl-3-alkyl-2H-azirines to afford oxazoles.
Thus, intermediacy of ketenimine is consistent with both experimental and computational results, at
least under strongly basic reaction conditions.
Introduction
2H-Azirines are strained unsaturated heterocyclic compounds possessing a C=N double bond within a
three-membered ring. The chemistry of 2H-azirines has thrived over the past few decades, and these
compounds have been utilized for the construction of various heterocyclic compounds.1, 2 In particular,
2-acyl-3-alkyl-2H-azirines are key intermediates in the transformation of isoxazoles to oxazoles,3-5 and
they can be directly transformed into oxazoles under photoirradiation (Figure 1 (a)).3 As shown in
Figure 1 (b), the intermediacy of a nitrile ylide, formed through C-C bond cleavage, in this
transformation was proposed on the basis of observation of the infrared (IR) spectra in an argon matrix
at 15K.6 On the other hand, a similar transformation of 2H-azirines has been reported to occur under
basic conditions (Na2CO3 in MeOH).3b The mechanism of the latter transformation is shown in Figure 1
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(c), involving nucleophilic addition of methanol to the azirine. However, this kind of transformation has
been little studied, in marked contrast to the corresponding photochemical reactions, and the reaction is
seldom utilized.3b, 7
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9
O
a)
N
N
O
O
hv
or
N
hv
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Na2CO3
MeOH
heat
3a
2a
2H-azirine
intermediate
1a
O
N
O
N
b)
c)
3a
4a
nitrile ylide
2a
MeO
N
O
NH
O
base
2a
3a
OMe
MeOH
5a
6a
•
d)
N
HO
O
O
N
N
ring
opening
base
-Ha
Hb
Ha
Hb
2a
Hb
+H
9a
8a
ketenimine
(ethenimine)
Figure 1. Transformations of Azirins. a) Previously reported transformation from isoxazole 1a and
azirine 2a to oxazole 3a. b). Mechanism of photoirradiation-initiated transformation via nitrile ylide
intermediate. c) Mechanism of base-initiated transformation from 2a to 3a proposed by Singh et al. (ref.
1). d) Plausible deprotonation reaction of 2a under basic conditions. Two acidic protons (Ha and Hb) are
shown.
We are interested in the reactivity of 2-acyl-3-alkyl-2H-azirines under basic conditions, in view of the
similarity of the (pseudo)-π-isolobal properties of 2H-azirine and nitrile functionalities (Figure 2 and
Figure S1).8 Although there is limited experimental support, the previously proposed reaction
mechanism for the base-induced transformation from 2a to 3a seems plausible, being consistent with the
high reactivity of azirines towards nucleophiles (e.g., Neber rearrangement).2a, 9 However, the feasibility
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of deprotonation of 2H-azirines to afford ketenimines (ethenimines) (Figure 1 (d), 8a) remains
unclear, though it is a commonly observed transformation for nitrile compounds.10 In the present study,
we examined whether or not deprotonation-initiated reaction of 2-acyl-3-alkyl-2H-azirines can lead to
the formation of oxazoles. DFT calculations were consistent with the formation of ketenimine
intermediates after deprotonation of the azirines. These results throw new light on the reactivities of
2-acyl-3-alkyl-2H-azirines.
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N C
b
a
N C
N
N
C
C
N
C
N
C
Figure 2. Similarity of the (pseudo)-π-isolobal properties of 2H-azirine and nitrile functionalities.
Valence bond (VB) models of nitrile (a) and 2H-azirine (b). See also Figure S1, to view similarity of
vacant orbitals.
Results and Discussion
Influence of Bases and Nucleophiles on the Reaction
To distinguish between the addition-initiated reaction mechanism (Figure 1 (c)) and the
deprotonation-initiated reaction mechanism (Figure 1 (d)), we first examined the influence of
nucleophiles on the reaction (Table 1).
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Table 1. Study of reaction conditions for the transformation from azirine 2b-c to oxazole 3b-c. a, b
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9
R
O
O
O
N
N
Conditions
NH
O
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R
2b, R=Me
2c, R=Ph
3b, R=Me
3c, R=Ph
7c
oxazole 3c recovered 2c
Entry Substrate
Base
time
solvent
1d
2d
3
2b
2c
2b
76% (82%)e
–
K2CO3
K2CO3
MeOH
MeOH
30 min
30 min
1 min
67% (71%)e
–
85% (89%)e
–
Toluene
Toluene
tert-BuOK
10% (17%)e
19% (22%)e
4f
5
2c
2b
2c
tert-BuOK
KH
1 hr
THF
THF
64% (72%)e
–
–
30 min
1 hr
77% (80%)e
KH
6
(7 %)e
–
69% (76%)e
tert-BuONa Toluene
7
8
2b
2b
1 min
2 hr
25% (42%)e
(22%)e
–
THF
NaH
a All reactions were performed on 0.3 mmol scale in 3.0 ml of solvent at 20 ºC. b Quenching: acetic acid
before aqueous work up.. c Isolated yields. d Quenching: filtration through a pad of Celite with MeOH.
e Yields determined by 1H NMR with 1, 2-dichloroethane as internal standard is shown in parentheses.
f 7c was isolated in 41% yield.
Compounds 2b and 2c were chosen for the study to avoid possible side reactions caused by
deprotonation of another acidic proton(s) (Hb at the α position of the ketone, Figure 1 (d) and Figure
S2). It was found that the reaction of 2b readily occurred at 20 ºC in the presence of K2CO3 in MeOH,
giving the oxazole 3b in good yield (76%) (Table 1, entry 1) (see also Table S1). A similar reaction
proceeded smoothly for 2c (entry 2). Because the deprotonation mechanism (Figure 1, (d)) is not
available for 2c, these results (entries 1 and 2) suggest that the previously proposed addition mechanism
(Figure 1, (c)) may be reasonable. When tert-BuOK was employed as a base in a nonpolar solvent,
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toluene (entry 3), it was found that the reaction of 2b still proceeded in good yield (85 %). In the
quenching process, acetic acid was added before aqueous work up to avoid hydrolysis of any unreacted
starting materials, which also improved the yield (see footnotes of Table 1 and Table S1). This
quenching procedure was also applied to the KH conditions (vide infra). The half-life (t1/2) of the
reaction with tert-BuOK (entry 3), based on the consumption of 2b, was less than 30 sec, even though
tert-BuOK is poorly nucleophilic. In contrast, the reaction of 2c with tert-BuOK was much slower, and
afforded 3c in only 10 % yield, together with 2c (recovery, 19%) and open-chain 7c (41 %), even after 1
hr (entry 4). The generation of 7c is attributable to the nucleophilic addition reaction of tert-BuOK11 to
the C=N double bond (Scheme S1). This clear difference in the reactivities of 2b and 2c is indicative of
the involvement of a different mechanism in the tert-BuOK-induced transformation of 2b to 3b.
Furthermore, in the reaction using KH as a base in THF,12 3b was obtained as a major product (64%
yield) from 2b (entry 5), while only recovered 2H-azirine was obtained in the case of 2c (entry 6).
Therefore, these results suggest that the presence of a nucleophile is not necessary for the transformation
of 2b to 3b, which possesses an acidic H, whereas the nucleophile seems essential for the transformation
from 2c to 3c. Thus, we propose that an alternative mechanism, probably involving deprotonation,
operates in the transformation of 2b, especially in the presence of non-nucleophilic bases, tert-BuOK
(entry 3) and KH (entry 5). A less efficient reaction was also observed when 2b was treated with a
sodium base (tert-BuONa and NaH, entries 7 and 8) compared to the reactions using a potassium base
(tert-BuOK and KH, entries 3 and 5).
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Isotope labeling experiments suggested that deprotonation of Ha of 2b occurs in the tert-BuOK-initiated
reactions with tert-BuOK/tert-BuOD (Scheme 1a (1)), because deuterium was incorporated at the
2-methyl group, but not at the 5-methyl group, in the product 3b (Scheme 1a). In the
tert-BuOK-initiated reactions, H-D exchange does not occur upon quenching the reaction with AcOD.
Furthermore, treatment of the isolated product 3b with tert-BuOK/tert-BuOD did not afford deuterated
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3b. The H-D exchange behaviors of 2b and 3b in the presence of K2CO3/MeOD were similar to those in
tert-BuOK/tert-BuOD. Multiple deuteration of the 2-methyl protons of 3b was also observed in
K2CO3/MeOD (Scheme 1a, (2)), which may suggest a deprotonation-protonation equilibrium during the
reaction.
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Scheme 1. Isotope labeling study of base-induced transformation from 2b to 3b.
a. isotope experiment on the transformation of 2b to 3b
2
tert-BuOK (2.0 eq.)
tert-BuOD (4.0 eq.)
Toluene, 20 ºC;
2.17 H
O
O
0.95 H
O
N
N
(1)
(2)
K2CO3
N
H
H
5
2b
MeOD
20 ºC
73%
then AcOH
(work-up)
69%
CH3
2b
3b
H
H
3.05 H
3b
3.04 H
2.00H (meta,assumed)
2.00H (meta, assumed)
b. Deprotonation initiated mechanism for the transformation of 2b to 3b
O
O
K
·
ring-
opening
K
N
N
O
Base
CH3
N
cyclization
3b
CH2
2b
9b
8b-K
c. isotope experiment on the transformation of 10b to 11b
CD2H
O
O
K2CO3
0.92 H
N
N
H
KIE= 1.94 (0 ºC)
2.18 (-5.5 ºC)
MeOH
20 ºC
78%
CD3
10b
3.05 H
11b
2.00H (meta, assumed)
H
These experimental results inspired us to consider an alternative deprotonation-initiated mechanism, as
shown in Scheme 1(b). After deprotonation to afford anion 9b,13 cleavage of the C-C bond of the
azirine ring could occur through a Grob-type fragmentation (9b → 8b-K), in a similar manner to
heterolytic cleavage of donor-acceptor cyclopropanes.14 The cleavage can be explained by the high
8, 9
strain in the azirine ring
and the electron-withdrawing nature of the neighboring carbonyl group.15
Cyclization of the resulting ketenimine intermediate (8b) would occur to give 3b after protonation.
When 10b (D-labeled 2b) was treated with K2CO3 in MeOH solution, the reaction also afforded the
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deuterium-to-proton-exchanged H-labeled product 11b (Scheme 1c). We measured the kinetic isotope
effect (KIE) in MeOH solution, and found that the KIEs of 2b and 10b in K2CO3/MeOH are 1.94 at 0 ºC
and 2.18 at -5.5 ºC, based on the concentration changes of 2b and 10b. These KIEs are much larger than
a steric KIE, or a secondary KIE caused by the difference of bending frequency, and therefore these
results are consistent with the idea that deprotonation reaction of 2b can occur under the K2CO3/MeOH
conditions. Therefore, both the addition-initiated mechanism (Figure 1(c)) and the
deprotonation-initiated mechanism (Figure 1(d)) probably take part in the transformation of 2b to 3b in
K2CO3/MeOH.
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Computational Studies
To further explore the reaction mechanism, we embarked on a computational study of the reaction
pathway from 2b to 3b,16 using the reaction of 2b with tert-BuOK (Table 1, entry 3) as a model. As
shown in Figure 3 (a), the ring-opening reaction of 2b occurs stepwise, and 2b was found to be
deprotonated without a significant activation barrier to give deprotonated 9b (R1→TS1→P1).
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O
TS2
6.2
1
2
3
K
H
N
O
Ph
a)
N(2)
4
5
6
7
8
9
C(3)
0.22
0.0
C(1)
C(4)
TS3
-7.2
R1
TS1
( 2b + tertBuOK)
-9.8
2b
K
N
O
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K
O
TS4
O
H
Ph
Ph
-18.6
O
-28.8
CH3
-30.8
N
P1
K
O
O
-35.1
H
N
K
Ph
O
·
Ph
P4
( 3b + tertBuOK)
H
O
P2
N
H
H
C(4)
C(1)
b)
P3
N(2)
N(2)
N(2)
N(2)
C(1)
C(1)
C(4)
C(1)
C(4)
C(4)
TS3
P1
TS2
P2
Bond
Length (Å)
C(1)-C(4)C(1)-N(2)
1.364 1.310
C(1)-C(4) C(1)-N(2)
1.343 1.243
C(1)-C(4) C(1)-N(2)
1.327 1.226
C(1)-C(4) C(1)-N(2)
1.350 1.253
Figure 3. Energy Diagram of Deprotonation-Initiated Pathway. a) Free energy profile [ΔG in
kcal·mol−1 at 298 K, M06-2X-D3/def2-TZVPP/CPCM// M06-2X/6-31+G(d,p)/CPCM] for
tert-BuOK-induced transformation of 2b in toluene. b) Geometry of the reactant (P1), transition state
(TS2) and product (P2) for the ring-opening step and transition state (TS3) for the cyclization step;
tert-BuOH and K+ are removed for clarity.
The CH2 group containing the C(4) atom in the resulting carbanion 9b is planar, with a shorter
C(4)-C(1) distance (1.364 Å, Figure 3 (b), P1) than the corresponding covalent radius (1.524 Å).17 The
Mayer bond orders18 of the C(4)-C(1) bond and C(1)-N(2) bond are 1.39 and 1.38, respectively,
suggesting delocalization of negative charge and therefore stabilization of 9b. This is also in agreement
with the results of nature population analysis (NPA),19 which indicated that negative charge is
distributed on both the C(4) and N(2) atoms in P1 (C(4): -0.764, N(2): -0.634)). Computational study
also confirmed the formation of ketenimine intermediate 8b from deprotonated 9b (P1→TS2→P2).
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This ring-opening step is the most energy-demanding step (16.0 kcal/mol) in the putative transformation.
The C(1)-C(4) bond and C(1)-N(2) bonds both become shorter and the reaction gives a slightly NCC
angle-bent ketenimine (∠NCC=172.9º). This angle and the bond length in the resulting ketenimine
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3
4
5
6
7
8
9
moiety are similar to reported values.10 The ketenimines are good electrophiles,10 and the intramolecular
cyclization reaction proceeds with an energy barrier of 11.4 kcal/mol (P2→TS3→P3) to give the
oxazolyl anion (P3), which is converted into oxazole after protonation (P3→TS4→P4).
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1
2
3
4
K
K
2.660 Å
O
5
6
7
8
(a)
2.532 Å
2.843 Å
2.843 Å
O
9
N
10
11
12
13
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N
P2
rX
(Å)
P1
rX
rK
ΔrX-K
rK
ΔrX-K
(Å)
(Å)
(Å)
(Å)
(Å)
1.822
1.909
1.056
0.887
1.767
1.898
0.879
0.958
O---K
N---K
O---K
N---K
1.766
1.772
Na
2.286 Å
(b)
Na
2.178 Å
2.337 Å
N
O
2.446 Å
O
N
P1-Na
P2-Na
rX
rNa
ΔrX-Na
rNa
ΔrX-Na
rX
(Å)
(Å)
(Å)
(Å)
(Å)
(Å)
1.809
1.907
0.977
0.807
1.763
1.894
0.825
0.956
O---Na
N---Na
O---Na
N---Na
1.346
1.347
Figure 4. Roles of Metal Cations. The mutual penetration distance (ΔrX-Μ) of a) K+ coordinated
intermediates and b) Na+ coordinated intermediates.
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2b exhibited greater reactivity in terms of yield and reaction rate when using a potassium base,
tert-BuOK or KH, compared to the corresponding sodium base, tert-BuONa or NaH (Table 1 and also
see Table S1). To evaluate the role of potassium ion (K+) in addition to the difference in basicity, the
properties of the corresponding Na-coordinated azirine anion (P1-Na) and ketenimine intermediate
(P2-Na) were calculated (Figure 4). For the X – M interactions (X = O, N and M = K, Na), we
calculated the mutual penetration distance (ΔrX-Μ) between atoms X and M.20 The mutual penetration
distance is defined as the difference between the summation of the non-bonded radii of two atoms, X
(rX) and M (rM), and the corresponding bonded distance between atoms X and M (rX-M), i.e., ΔrX-M = rX
+ rM - rX-M. The non-bonded radius is defined as the closest distance of a nucleus to the charge density
contour of 0.001 a.u.. The larger the mutual penetration distance (ΔrX-Μ) is, the more in contact the
two atoms are. For potassium ketenimine P2 in which O and N interact with K+, the mutual penetration
ΔrX-K values are 1.056 Å (X = O) and 0.887 Å (X = N), respectively. These values are larger than the
corresponding values for Na+ coordinated species P2-Na (0.977 Å for O–Na and 0.808 Å for N-Na).
Similar trends are also observed in the product azirine anions P1(K+) and P1-Na. Therefore, the K+ ion
can stabilize the azirine anion and ketenimine intermediates to a greater extent than the Na+ ion, which
is related to the efficiency of the reaction of 2b under tert-BuOK and KH conditions.
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Me
O
1
2
3
4
5
6
7
8
OMe
O
K
(18.3)
(16.4)
O
addition-initiated pathway
K
OMe
N
N
[-21.6]
Ph
K
K
Ph
O
O
N
N
A3
OMe
A4 [+3.8]
(9.9)
[-5.7]
Ph
Ph
(5.4)
[-24.9]
A2 [-6.9]
A1
KOMe
9
Ph
O
(5.8)
KOMe
O
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N
Ph
( 2b + KOMe)
[-37.9]
N1
N
P
(3b + KOMe)
K
OMe
H
[-13.6]
K
N
(0.8)
O
N
(1.2)
[-4.8]
K
OMe
O
Me
O
H
Ph
Ph
H
OMe
H
Ph
K
(16.3)
[-11.5]
(13.2)
O
O
D2 [-8.7]
D1
N
H
H
•
Ph
N
[+2.4]
D3
D4 [-11.1]
deprotonation -initiated pathway
Figure 5. Compatibility of the two reaction pathways. All numbers next to arrows are ΔG in
kcal·mol−1 at 298 K, calculated at the M06-2X-D3/def2-TZVPP/CPCM//M06-2X/6-31+G(d,p)/CPCM
level in methanol. (numbers in blue): relative energies of the corresponding transition state; [numbers in
black]: relative energies of the product compared to corresponding precursors.
The deprotonation-initiated mechanism (D1→ D2→ D3→ D4 → P) and addition-initiated mechanism
(A1→ A2→ A3→ A4 → P) were also studied in the MeOK-MeOH system (Figure 5). MeOK serves as
a base and a nucleophile at the same time, which simplifies our experimental system of K2CO3/ MeOH.
While this simplification may lead to underestimation of the energy barriers for the addition step
(A1→A2, 5.4 kcal/mol) and deprotonation step (D1→D2, 0.8 kcal/mol), these model calculations
provide invaluable insight into the following ring-opening steps and cyclization step. The ring-opening
steps in both reaction pathways possess similar energy barriers (16.4 kcal/mol for A2→A3; 16.3
kcal/mol for D2→D3), affording methyl acetimidate A3 and ketenimine D3, respectively.
Further cyclization of A3 and D3 can afford oxazoline A4 and oxazolyl anion D4, respectively, and
finally A4 and D4 will be transformed into the common oxazole product P. Notably, the energy barrier
for the transformation from acetimidate A3 to oxazoline A4 (18.3 kcal/mol) is more energy-demanding,
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The Journal of Organic Chemistry
compared to the preceding step (16.4 kcal/mol, A2→A3) in the addition-initiated mechanism as well as
the ring-opening step (D2→D3) in the deprotonation-initiated mechanism. However, considering that
the transformation from A2 to A3 is highly exothermic (-21.6 kcal/mol), both the addition-initiated
mechanism and deprotonation-initiated mechanism seem feasible.
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a.
OH
O
•
N
N
•
Ketenimine 8b
(ΔG = 0 kcal/mol)
Nitrile Ylide 4b
(ΔG = 14.7 kcal/mol)
b.
O
Me
Me
O
•
•
N
Me
N
Me
Me
O
λ = 222 nm
H
H
N
syn-14
anti-14
O
N
Ar matrix 15 K
Me
Me
Me
O
N
13
12
Me
Me
15
Figure 6. a. Comparisons of Ketenimine and Nitrile Ylide. Calculated relative Gibbs free energy of
ketenimine form 8b and nitrile ylide form 4b in gas phase. [ΔG in kcal·mol−1 at 298 K,
M06-2X-D3/def2-TZVPP//M06-2X/6-31+G(d,p)]; b. Internal ketenimines (14) observed in
isoxazole-oxazole phototransformation (see reference [6b]).
The nitrile ylide N1, which has been proposed6, 21 and directly observed6b to be the intermediate in the
photolysis and pyrolysis reactions from 2H-azirines to oxazoles, is unstable under these basic conditions
(Figure 5) and N1 can readily collapse into methanol-adduct A3 and ketenimine D3,22 respectively. N1
can also undergo cyclization reaction to afford oxazole product P.23 The computational results also
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indicate that the ketenimine form (8b) is thermodynamically more stable than the tautomeric nitrile
ylide form (4b) (by 14.7 kcal/mol, Figure 6, a). Thus, we propose that ketenimines are also likely to be
a common intermediate in various transformations of azirines, especially those possessing methyl
substituents at C(3). Interestingly, previously reported studies on the photo-induced transformation of
isoxazole (Figure 1) suggest the generation of a different kind of internal keteneimine species from a
vinyl nitrene intermediate 13 (Figure 6, b), together with the formation of 2H-azirine 15.6b
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Reaction Generality
Finally, we studied the generality of the deprotonation-initiated rearrangement reaction from related
azirines to oxazoles (Table 2). With the optimal conditions using tert-BuOK as a base in toluene, the
azirines with multiple acidic protons (2a, 2n), as well as those bearing different substituents (ester: 3i;
olefin: 3l) react smoothly under our conditions. For 2a in which R2 is an H atom, oxazole 3a was only
obtained in 32% yield. The reaction of 2k bearing a cyclopropyl group (R2) also gave oxazole 3k in a
good yield (76%), which excludes the possibility of radical generation.6 Substrate 2l, possessing an allyl
group, is prone to generate thermodynamically more stable oxazoles (E)-3l and (Z)-3l. Substrates 2n
and 2o, possessing an aliphatic ketone functionality, also underwent smooth reaction to afford oxazoles
3n and 3o, respectively. When the substituent R3 was changed to an ethyl group (2p), the corresponding
oxazole (3p) was formed in 88 % yield.
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The Journal of Organic Chemistry
1
2
3
Table 2. Generality of base-induced isomerization from 2 to 3.a-c
4
5
6
7
8
R3
tert-BuOK (2.0 equiv.)
O
O
Toluene (0.1 M)
20 ºC, 5 min
O
N
N
N
R1
R1
9
R2
R2
3a, 3d-3o
R3
Then AcOH
MeOOC
N
2l
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2a, 2d-2p
O
O
N
N
O
3i 75%
3m 87%
N
O
O
N
H
N
3a 32%
3j 74%
3n 72%d
O
O
O
R
N
N
3d R = OMe, 88%
3e R = Me, 84%
3o 71%
3k 76%
O
N
O
O
X
N
N
3f X = F, 72%
3g X = Cl, 79%
3h X = Br, 70%
(E)-3l 61% + (Z)-3l 9.4%c
3p 88%
a
b
c
Isolated yield. All reactions were carried out at 0.3 mmol scale. Oxazoles 3l were obtained from
2l(R2= allyl). d THF was used as solvent.
Conclusion
In conclusion, we found effective reaction conditions for base-induced transformation of
2-acyl-3-alkyl-2H-azirines 2 to oxazoles 3, and we obtained evidence of the involvement of multiple
reaction pathways in this base-induced isomerization reaction. Computational studies indicated that the
deprotonation-initiated mechanism and addition-initiated mechanism are both energetically reasonable,
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and in the reaction with less nucleophilic bases, including tert-BuOK and KH, the
deprotonation-initiated mechanism may be the major reaction pathway. The computational results are
consistent with the idea that deprotonation of 2 yields ketenimines, which is an unprecedented
transformation of 2H-azirines. Since ketenimine (8b) is thermodynamically favored over nitrile ylide
(4b), we anticipate that ketenimines would be involved in various transformations of 2H-azirines.
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Experimental Section
General Methods:
All reactions were carried out under argon atmosphere in oven-dried glassware. Toluene was purified by
distillation over sodium and stored with molecular sieves 4A. All other commercially available
compounds and solvents were used as received unless otherwise mentioned.
Open column chromatography was carried out using Kanto chemical silica gel (silica gel 60 N (100-210
μm)). Melting points were determined with a Yanaco micro melting point apparatus without
correction. 1H- (400 MHz) and 13C- (100 MHz) NMR spectra were recorded on a Bruker Avance 400.
Chemical shifts were calibrated with tetramethylsilane and solvent as an internal standard or with the
solvent peak, and are shown in ppm (δ) values, and coupling constants are shown in hertz (Hz). The
following abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, dt
= double triplet, dq = double quartet, h = hextet, m = multiplet, brs = broad singlet, br = broad signal.
Temperature in the NMR experiments was calibrated using signals of methanol according to the
reported method.24 Electron spray ionization time-of-flight mass spectra (ESI-TOF MS) were recorded
on a Bruker micrOTOF-05 to give high-resolution mass spectra (HRMS). The combustion analyses
were carried out in the microanalytical laboratory of this department.
Synthesis of 2H-azirines
N
O
2a
2H-azirine 2a. 2a was synthesized according to the literature procedure.6a Red oil. 1H NMR (CDCl3): δ
8.04 (2H, dd, J=8.4, 1.2 Hz), 7.06-7.58 (1H, m), 7.52-7.48 (2H, m), 3.47 (1H, s), 2.55 (3H, s). 13C NMR
(CDCl3): δ 198.1, 157.1, 137.7, 133.3, 128.7, 128.2, 32.5, 12.7. HRMS (ESI-TOF, [M+Na]+): Calcd. for
C10H9NNaO+, 182.0576. Found: 182.0584.
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The Journal of Organic Chemistry
O
1
N
2
3
Ph
Ph
4
5
2c
6
7
8
9
2H-azirine 2c. 2c was synthesized according to the literature procedure.25 Yellow solid. Mp.: 67-69 ºC
1H NMR (CDCl3): δ 7.89 (2H, d, J= 8.0 Hz), 7.66 (2H, d, J=8.4 Hz), 7.62-7.58 (2H, m), 7.45-7.41 (1H,
m), 7.35-7.32 (2H, m), 1.75 (3H, s). C NMR (CDCl3): δ 201.9, 166.0, 137.0, 133.8, 131.6, 130.0,
13
129.5, 128.4, 128.1, 123.3, 43.3, 19.1. HRMS (ESI-TOF, [M+Na]+): Calcd. for C16H13NNaO+, 258.0889.
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11
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Found: 258.0892. Anal. Calcd. for C16H13NO: C, 81.68; H, 5.57; N, 5.95. Found: C, 81.36; H, 5.79; N,
5.67.
N
O
Ph
2n
1
2H-azirine 2n. 2n was synthesized according to the literature procedure.4c Colorless oil. H NMR
(CDCl3): δ 7.36-7.29 (5H, m), 2.59 (3H, s), 2.04 (3H, s). C NMR (CDCl3): δ 206.1, 163.1, 136.5,
13
128.5, 128.2, 127.9, 47.5, 27.9, 12.7. HRMS (ESI-TOF, [M+Na]+): Calcd. for C11H11NNaO+, 196.0733.
Found: 196.0727. Anal. Calcd. for C11H11NO: C, 76.28; H, 6.40; N, 8.09. Found: C, 76.11; H, 6.49; N,
7.91.
O
N
2b
2H-azirine 2b. To a solution of 2-methyl-1-phenylbutane-1,3-dione (1.75 g, 10.0 mmol) and pyridine
(2.5 mL) in ethanol (20.0 mL) was added hydroxylamine hydrochloride (700.0 mg, 10.07 mmol) at 0 ºC.
The mixture was stirred at 0 ºC for 1 hr and diluted with EtOAc (40 mL). The whole was washed with
2M aqueous HCl, water and brine and dried over MgSO4. The solvent was evaporated and the residue
was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford
3-(hydroxyimino)-2-methyl-1-phenylbutan-1-one (white solid, 1.02 g, 5.34 mmol, 53%). Due to the
unstable nature of the oxime compound, the oxime compound was immediately used in the next step.
To a solution of the oxime 3-(hydroxyimino)-2-methyl-1-phenylbutan-1-one in 20.0 mL of CH2Cl2 was
added 1,4-diazabicyclo[2.2.2]octane (DABCO, 1.50 g, 13.4 mmol) at 0 ºC followed by addition of a
solution of MsCl (0.67 g, 5.8 mmol) in 10 mL of CH2Cl2. The whole was stirred at room temperature for
1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent
was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 4: 1) to
afford (2,3-dimethyl-2H-azirin-2-yl) (phenyl)methanone 2b (colorless oil, 808.6 mg, 88%, 47% for 2
steps).
1H NMR (CDCl3): δ 7.62 (2H, dd, J=2.0, 8.0 Hz), 7.48-7.44 (1H, m), 7.40-7.36 (2H, m), 2.47 (3H, s),
1.55 (3H, s). C NMR (CDCl3): δ 202.2, 166.7, 137.3, 131.5, 128.2, 128.2, 42.0, 19.0, 12.9. HRMS
13
(ESI-TOF, [M+Na]+): Calcd. for C11H11NNaO+, 196.0733. Found: 196.0746. Anal. Calcd. for
C11H11NO: C, 76.28; H, 6.40; N, 8.13. Found: C, 76.48; H, 6.55; N, 8.13.
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N
O
1
2
3
4
1b
5
6
7
8
Note: the oxime compound was unstable over silica gel and transformed into isoxazole 1b. Same
transformation was observed by elevating the reaction temperature.
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N
O
MeO
2d
2H-azirine 2d. To a solution of 1-(4-methoxyphenyl)-2-methylbutane-1, 3-dione (513.7 mg, 2.491
mmol) and pyridine (1.0 mL) in ethanol (10.0 mL) was added hydroxylamine hydrochloride (175.0 mg,
2.518 mmol) at 0 ºC. The mixture was stirred at 0 ºC for 1 hr and diluted with EtOAc (40 mL). The
whole was washed with 2M aqueous HCl, water and brine and dried over MgSO4. The solvent was
evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 4: 1) to
3-(hydroxyimino)-1-(4-methoxyphenyl)-2-methylbutan-1-one (sticky oil, 406.2 mg, 1.838 mmol, 74%).
To a solution of the oxime 3-(hydroxyimino)-1-(4-methoxyphenyl)-2-methylbutan-1-one in 5.0 mL of
CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 550.0 mg, 4.903 mmol) at 0 ºC followed by
addition of a solution of MsCl (230.0 mg, 2.008 mmol) in 5 mL of CH2Cl2. The whole was stirred at
room temperature for 1 hr. The reaction was quenched with water and the mixture was extracted with
CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography
(Hexane: EtOAc= 4: 1) to afford 2d (colorless oil, 315.4 mg, 84%, 62% for 2 steps).
1H NMR (CDCl3): δ 7.74-7.72 (2H, m), 6.87 (2H, d, J=8.8 Hz), 3.83 (3H, s), 2.46 (3H, s), 1.53 (3H, s).
13C NMR (CDCl3): δ 199.8, 167.4, 162.6, 131.0, 129.5, 113.5, 55.4, 41.6, 19.6, 12.9. HRMS (ESI-TOF,
[M+Na]+): Calcd. for C12H13NNaO2+, 226.0839. Found: 226.0829.
N
O
Me
2e
2H-azirine 2e. To a solution of 2-methyl-1-(p-tolyl)butane-1,3-dione (497.8 mg, 2.618 mmol) and
pyridine (1.0 mL) in ethanol (10.0 mL) was added hydroxylamine hydrochloride (200.0 mg 2.878
mmol) at 0 ºC. The mixture was stirred at 0 ºC for 1 hr and diluted with EtOAc (40 mL). The whole was
washed with 2M aqueous HCl, water and brine and dried over MgSO4. The solvent was evaporated and
the residue was purified with column chromatography (Hexane: EtOAc= 6: 1) to afford
3-(hydroxyimino)-2-methyl-1-(p-tolyl)butan-1-one (sticky oil, 238.3 mg, 1.161 mmol, 44%).
To a solution of the oxime 3-(hydroxyimino)-2-methyl-1-(p-tolyl)butan-1-one in 3.0 mL of CH2Cl2 was
added 1,4-diazabicyclo[2.2.2]octane (DABCO, 350.0 mg, 3.120 mmol) at 0 ºC followed by addition of
a solution of MsCl (150.0 mg, 1.309 mmol) in 2 mL of CH2Cl2. The whole was stirred at room
temperature for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2.
The solvent was evaporated and the residue was purified with column chromatography (Hexane:
EtOAc= 4: 1) to afford 2e (colorless oil, 187.0 mg, 86%, 38% for 2 steps).
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1H NMR (CDCl3): δ 7.57 (2H, d, J=8.4 Hz), 7.19 (2H, d, J=8.0 Hz), 2.47 (3H, s), 2.37 (3H, s), 1.54 (3H,
s). C NMR (CDCl3): δ 201.6, 166.9, 142.3, 134.5, 128.9, 128.5, 41.8, 21.6, 19.2, 12.9. HRMS
1
2
3
4
13
(ESI-TOF, [M+Na]+): Calcd. for C12H13NNaO+, 210.0889. Found: 210.0897. Anal. Calcd. for
C12H13NO: C, 76.98; H, 7.00; N, 7.48. Found: C, 77.06; H, 7.16; N, 7.34.
5
6
7
8
N
O
9
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F
2f
2H-azirine 2f. To a solution of 1-(4-fluorophenyl)-2-methylbutane-1,3-dione (362.0 mg, 1.864 mmol)
and pyridine (1.0 mL) in ethanol (10.0 mL) was added hydroxylamine hydrochloride (140.0 mg, 2.014
mmol) at 0 ºC. The mixture was stirred at 0 ºC for 1 hr and diluted with EtOAc (40 mL). The whole was
washed with 2M aqueous HCl, water and brine and dried over MgSO4. The solvent was evaporated and
the residue was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford
1-(4-fluorophenyl)-3-(hydroxyimino)-2-methylbutan-1-one (white solid, 190.1 mg, 0.909 mmol, 49%).
To a solution of the oxime 1-(4-fluorophenyl)-3-(hydroxyimino)-2-methylbutan-1-one in 3.0 mL of
CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 250.0 g, 2.229 mmol) at 0 ºC followed by
addition of a solution of MsCl (110.0 mg, 0.960 mmol) in 2 mL of CH2Cl2. The whole was stirred at
room temperature for 1 hr. The reaction was quenched with water and the mixture was extracted with
CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography
(Hexane: EtOAc= 4: 1) to afford 2f (colorless oil, 156.4 mg, 90%, 45% for 2 steps).
1H NMR (CDCl3): δ 7.72-7.69 (2H, m), 7.08-7.04 (2H, m), 2.47 (3H, s), 1.54 (3H, s). C NMR
13
(CDCl3): δ 200.3, 167.1, 164.7 (d, JC, F=251.7 Hz), 133.2 (d, JC, F=3.4 Hz), 131.1 (d, JC, F=8.9 Hz), 115.3
(d, JC, F=21.7 Hz), 41.9, 19.0, 12.9. HRMS (ESI-TOF, [M+Na]+): Calcd. for C11H10FNNaO+, 214.0639.
Found: 214.0631.
N
O
Cl
2g
2H-azirine 2g. To a solution of 1-(4-chlorophenyl)-2-methylbutane-1,3-dione (496.2 mg, 2.355 mmol)
and pyridine (1.0 mL) in ethanol (10.0 mL) was added hydroxylamine hydrochloride (180.0 mg, 2.590
mmol) at 0 ºC. The mixture was stirred at 0 ºC for 1 hr and diluted with EtOAc (40 mL). The whole was
washed with 2M aqueous HCl, water and brine and dried over MgSO4. The solvent was evaporated and
the residue was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford
1-(4-chlorophenyl)-3-(hydroxyimino)-2-methylbutan-1-one (white solid, 394.5 mg, 1.748 mmol, 74%).
To a solution of the oxime 1-(4-chlorophenyl)-3-(hydroxyimino)-2-methylbutan-1-one in 3.0 mL of
CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 500.0 mg, 4.45 mmol) at 0 ºC followed by
addition of a solution of MsCl (220.0 mg, 1.92 mmol) in 3 mL of CH2Cl2. The whole was stirred at
room temperature for 1 hr. The reaction was quenched with water and the mixture was extracted with
CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography
(Hexane: EtOAc= 6: 1) to afford 2g (light yellow oil, 300.4 mg, 82%, 61% for 2 steps).
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1H NMR (CDCl3): δ 7.58 (2H, d, J=8.8 Hz), 7.35 (2H, d, J=8.8 Hz), 2.45 (3H, s), 1.58 (3H, s). C
NMR (CDCl3): δ 200.8, 166.9, 138.0, 135.4, 129.9, 128.5, 42.1, 18.8, 12.8. HRMS (ESI-TOF,
[M+Na]+): Calcd. for C11H10ClNNaO+, 230.0343, Found: 230.0335. Anal. Calcd. for C11H10ClNO: C,
63.62; H, 4.85; N, 6.75. Found: C, 63.49; H, 4.99; N, 6.58.
13
1
2
3
4
5
6
N
O
7
8
9
Br
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2h
2H-azirine 2h. To a solution of 1-(4-bromophenyl)-2-methylbutane-1,3-dione (539.9 mg, 2.116 mmol)
and pyridine (1.0 mL) in ethanol (10.0 mL) was added hydroxylamine hydrochloride (160.0 mg, 2.30
mmol) at 0 ºC. The mixture was stirred at 0 ºC for 1 hr and diluted with EtOAc (40 mL). The whole was
washed with 2M aqueous HCl, water and brine and dried over MgSO4. The solvent was evaporated and
the
residue
was
purified
by
recrystallization
from
isopropanol
to
afford
1-(4-bromophenyl)-3-(hydroxyimino)-2-methylbutan-1-one (white solid, 355.3 mg, 1.315 mmol, 62%).
To a solution of the oxime 1-(4-bromophenyl)-3-(hydroxyimino)-2-methylbutan-1-one in 5.0 mL of
CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 400.0 mg, 3.566 mmol) at 0 ºC followed by
addition of a solution of MsCl (160.0 mg, 1.397 mmol) in 2.5 mL of CH2Cl2. The whole was stirred at
room temperature for 1 hr. The reaction was quenched with water and the mixture was extracted with
CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography
(Hexane: EtOAc= 6: 1) to afford 2h (colorless oil, 272.4 mg, 82%, 51% for 2 steps).
1H NMR (CDCl3): δ 7.56-7.51 (4H, m), 2.48 (3H, s), 1.55 (3H, s). C NMR (CDCl3): δ 201.0, 166.9,
13
135.9, 131.5, 123.0, 126.5, 42.1, 18.8, 12.9. HRMS (ESI-TOF, [M+Na]+): Calcd. for C11H10BrNNaO+,
273.9838. Found: 273.9841.
N
O
MeOOC
2i
2H-azirine 2i. To a solution of methyl 4-(2-methyl-3-oxobutanoyl) benzoate (303.7 mg, 1.296 mmol)
and pyridine (1.0 mL) in ethanol (5.0 mL) was added hydroxylamine hydrochloride (100.0 mg, 1.439
mmol) at 0 ºC. The mixture was stirred at 0 ºC for 1 hr and diluted with EtOAc (20 mL). The whole was
washed with 2M aqueous HCl, water and brine and dried over MgSO4. The solvent was evaporated and
the residue was purified with column chromatography (Hexane: EtOAc= 3: 2) to methyl
4-(3-(hydroxyimino)-2-methylbutanoyl)benzoate (white solid, 138.2 mg, 0.554 mmol, 43%).
To a solution of the oxime methyl 4-(3-(hydroxyimino)-2-methylbutanoyl)benzoate in 2.0 mL of
CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 160.0 mg, 1.426 mmol) at 0 ºC followed by
addition of a solution of MsCl (70.0 mg, 0.611 mmol) in 2.0 mL of CH2Cl2. The whole was stirred at
room temperature for 1 hr. The reaction was quenched with water and the mixture was extracted with
CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography
(Hexane: EtOAc= 7: 3) to afford 2i (colorless oil, 121.2 mg, 94%, 40% for 2 steps).
1H NMR (CDCl3): δ 8.03 (2H, d, J=8.4 Hz), 7.60 (2H, d, J=8.8 Hz), 3.92 (3H, s), 2.45 (3H, s), 1.53
(3H, s). C NMR (CDCl3): δ 202.1, 166.4, 166.3, 141.4, 132.3, 129.4, 127.9, 52.4, 42.4, 18.4, 12.9.
13
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The Journal of Organic Chemistry
HRMS (ESI-TOF, [M+Na]+): Calcd. for C13H13NNaO3+, 254.0788. Found: 254.0797. Anal. Calcd. for
C13H13NO3: C, 67.52; H, 5.67; N, 6.06. Found: C, 67.51; H, 5.73; N, 5.91.
1
2
3
4
N
O
5
6
7
8
2j
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2H-azirine 2j. To a solution 1-(naphthalen-2-yl)butane-1,3-dione (592.5 mg, 2.618 mmol) and pyridine
(1.0 mL) in ethanol (10.0 mL) was added hydroxylamine hydrochloride (200.0 mg, 2.878 mmol) at 0 ºC.
The mixture was stirred at 0 ºC for 1 hr and diluted with EtOAc (40 mL). The whole was washed with
2M aqueous HCl, water and brine and dried over MgSO4. The solvent was evaporated and the residue
was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford
3-(hydroxyimino)-2-methyl-1-(naphthalen-2-yl)butan-1-one (white solid, 377.7 mg, 1.565 mmol, 60%).
To a solution of the oxime 3-(hydroxyimino)-2-methyl-1-(naphthalen-2-yl)butan-1-one in 5.0 mL of
CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 400.0 mg, 3.566 mmol) at 0 ºC followed by
addition of a solution of MsCl (180.0 mg, 1.572 mmol) in 2 mL of CH2Cl2. The whole was stirred at
room temperature for 1 hr. The reaction was quenched with water and the mixture was extracted with
CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography
(Hexane: EtOAc= 4: 1) to afford 2j (yellow oil, 263.4 mg, 75%, 45% for 2 steps).
1H NMR (CDCl3): δ 8.18 (1H, s), 7.91 (1H, d, J=7.6 Hz), 7.85-7.83 (2H, m), 7.72 (1H, dd, J=1.6, 8.8
Hz), 7.59-7.51 (2H, m), 2.48 (3H, s), 1.61 (3H, s). C NMR (CDCl3): δ 201.9, 167.0, 134.7, 134.5,
13
132.3, 129.4, 129.3, 128.1, 128.0, 127.7, 126.7, 124.6, 42.1, 19.2, 12.9. HRMS (ESI-TOF, [M+Na]+):
Calcd. for C15H13NNaO+, 246.0889. Found: 246.0890.
N
O
2k
2H-azirine 2k. To a solution of 2-(cyclopropylmethyl)-1-phenylbutane-1,3-dione (727.7 mg, 3.365
mmol) and pyridine (1.0 mL) in ethanol (15.0 mL) was added hydroxylamine hydrochloride (240.0 mg,
3.453 mmol) at 0 ºC. The mixture was stirred at 0 ºC for 1 hr and diluted with EtOAc (20 mL). The
whole was washed with 2M aqueous HCl, water and brine and dried over MgSO4. The solvent was
evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 6: 1) to afford
2-(cyclopropylmethyl)-3-(hydroxyimino)-1-phenylbutan-1-one (colorless oil, 427.2 mg, 1.847 mmol,
55%).
To a solution of the oxime 2-(cyclopropylmethyl)-3-(hydroxyimino)-1-phenylbutan-1-one in 2.5 mL of
CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 520 mg, 4.635 mmol) at 0 ºC followed by
addition of a solution of MsCl (230.0 mg, 2.008 mmol) in 2.5 mL of CH2Cl2. The whole was stirred at
room temperature for 1 hr. The reaction was quenched with water and the mixture was extracted with
CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography
(Hexane: EtOAc= 4: 1) to afford 2k (colorless oil, 299.0 mg, 76%, 42% for 2 steps).
1H NMR (CDCl3): δ 7.65 (2H, dd, J=1.6, 8.4 Hz), 7.48-7.45 (1H, m), 7.40-7.36 (2H, m), 2.52 (3H, s),
2.05 (1H, dd, J=7.6, 15.2 Hz), 1.96 (1H, dd, J=6.8, 15.2 Hz) 0.59-0.55 (1H, m), 0.55-0.52 (2H, m),
0.26-0.22 (2H, m). 13C NMR (CDCl3): δ 202.1, 166.4, 137.4, 131.6, 128.2, 128.2, 46.2, 36.4, 14.0, 7.7,
4.8, 4.6. HRMS (ESI-TOF, [M+Na]+): Calcd. for C14H15NNaO+, 236.1046. Found: 236.1035.
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1
2
3
N
O
4
5
6
7
2l
8
9
2H-azirine 2l. To a solution of 2-allyl-1-phenylbutane-1,3-dione (458.9 mg, 2.269 mmol) and pyridine
(1.0 mL) in ethanol (10.0 mL) was added hydroxylamine hydrochloride (160.0 mg, 2.302 mmol) at 0 ºC.
The mixture was stirred at 0 ºC for 1 hr and diluted with EtOAc (40 mL). The whole was washed with
2M aqueous HCl, water and brine and dried over MgSO4. The solvent was evaporated and the residue
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60
was
purified
with
column
chromatography
(Hexane:
EtOAc=
7:
2-(1-(hydroxyimino)ethyl)-1-phenylpent-4-en-1-one (colorless oil, 262.0 mg, 1.206 mmol, 53%).
3)
to
To a solution of the oxime 2-(1-(hydroxyimino)ethyl)-1-phenylpent-4-en-1-one in 3.0 mL of CH2Cl2
was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 340.0 mg, 3.031 mmol) at 0 ºC followed by
addition of a solution of MsCl (150.0 mg, 1.310 mmol) in 3.0 mL of CH2Cl2. The whole was stirred at
room temperature for 1 hr. The reaction was quenched with water and the mixture was extracted with
CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography
(Hexane: EtOAc= 2: 1) to afford 2l (light yellow oil, 210.8 mg, 88%, 47% for 2 steps).
1H NMR (CDCl3): δ 7.63-7.61 (2H, m), 7.47-7.43 (1H, m), 7.40-7.36 (2H, m), 5.74-5.64 (1H, m),
5.09-5.04 (2H, m), 2.89-2.83 (1H, m), 2.745-2.683 (1H, m), 2.46 (3H, s). C NMR (CDCl3): δ 201.4,
13
166.4, 137.2, 133.4, 131.6, 128.2, 128.2, 118.0, 45.2, 36.3, 13.7. HRMS (ESI-TOF, [M+Na]+): Calcd.
for C13H13NNaO+, 222.0889. Found: 222.0877.
N
O
2m
Azirine 2m. To a solution of 2-acetyl-3,4-dihydronaphthalen-1(2H)-one (501.7 mg, 2.665 mmol) and
pyridine (1.0 mL) in ethanol (10.0 mL) was added hydroxylamine hydrochloride (190.0 mg, 2.734
mmol) at 0 ºC. The mixture was stirred at 0 ºC for 1 hr and diluted with EtOAc (20 mL). The whole was
washed with 2M aqueous HCl, water and brine and dried over MgSO4. The solvent was evaporated and
the residue was purified with column chromatography (Hexane: EtOAc= 7: 3) to afford
2-(1-(hydroxyimino)ethyl)-3,4-dihydronaphthalen-1(2H)-one (colorless oil, 373.6 mg, 1.838 mmol,
69%).
To a solution of the oxime 2-(1-(hydroxyimino)ethyl)-3,4-dihydronaphthalen-1(2H)-one in 5 mL of
CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 520 mg, 4.636 mmol) at 0 ºC followed by
addition of a solution of MsCl (230.0 mg, 2.008 mmol) in 5 mL of CH2Cl2. The whole was stirred at
room temperature for 1 hr. The reaction was quenched with water and the mixture was extracted with
CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography
(Hexane: EtOAc= 4: 1) to afford 2m (colorless oil, 259.2 mg, 76%, 52% for 2 steps).
1H NMR (CDCl3): δ 8.00 (1H, dd, J=7.6, 0.8 Hz), 7.53-7.49 (1H, m), 7.36-7.30 (1H, m), 3.28-3.03 (2H,
m), 2.52 (3H, s), 2.20-2.07 (2H, m). C NMR (CDCl3): δ 197.1, 162.3, 143.8, 133.8, 133.6, 128.6,
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The Journal of Organic Chemistry
127.2, 126.8, 41.3, 30.2, 28.6, 12.3. HRMS (ESI-TOF, [M+Na]+): Calcd. for C12H11NNaO+, 208.0733.
Found: 208.0717. Anal. Calcd. for C12H11NO: C, 77.81; H, 5.99; N, 7.56. Found: C, 77.69; H, 6.28; N,
7.20.
1
2
3
4
5
6
7
O
N
8
9
tBu
Bn
10
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2o
Azirine 2o. To a solution of 3-benzyl-5,5-dimethylhexane-2,4-dione (250.2 mg, 1.077 mmol) and
pyridine (0.5 mL) in ethanol (1.0 mL) was added hydroxylamine hydrochloride (80.0 mg, 1.151 mmol)
at 0 ºC. The mixture was stirred at 0 ºC for 1 hr and diluted with EtOAc (20 mL). The whole was
washed with 2M aqueous HCl, water and brine and dried over MgSO4. The solvent was evaporated and
the residue was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford
4-benzyl-5-(hydroxyimino)-2,2-dimethylhexan-3-one (colorless oil, 139.0 mg, 0.606 mmol, 53%).
To a solution of the oxime 4-benzyl-5-(hydroxyimino)-2,2-dimethylhexan-3-one in 2 mL of CH2Cl2 was
added 1,4-diazabicyclo[2.2.2]octane (DABCO, 75.0 mg, 0.668 mmol) at 0 ºC followed by addition of a
solution of MsCl (76.5 mg, 0.668 mmol) in 2 mL of CH2Cl2. The whole was stirred at room temperature
for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent
was evaporated to give mesylated oxime as a colorless oil.
The crude mesylated oxime was dissolved in 2.0 ml of CH2Cl2 and added 0.5 ml of
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The whole was stirred at room temperature for 2 hr. The
reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was
evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 8: 1) to afford
2o (colorless oil, 95.7mg, 0.417 mmol, 39% for 3 steps).
1H NMR (CDCl3): δ 7.28-7.24 (2H, m), 7.22-7.17 (1H, m), 7.13-7.11 (2H, m), 3.49 (1H, d, J=14.4 Hz),
2.98 (1H, d, J=14.8 Hz), 2.19 (3H, s), 1.07 (9H, s). C NMR (CDCl3): δ 212.5, 167.0, 137.8, 129.9,
13
128.3, 126.3, 46.3, 43.4, 38.9, 26.6, 13.8. HRMS (ESI-TOF, [M+Na]+): Calcd. for C15H19NNaO+,
252.1359. Found: 252.1357.
O
N
2p
Azirine 2p. To a solution of 2-ethyl-1-phenylpentane-1,3-dione (1.4613 g, 7.154 mmol) and pyridine
(3.0 mL) in ethanol (30.0 mL) was added hydroxylamine hydrochloride (550.0 mg, 7.913 mmol) at 0 ºC.
The mixture was stirred at 0 ºC for 1 hr and diluted with EtOAc (60 mL). The whole was washed with
2M aqueous HCl, water and brine and dried over MgSO4. The solvent was evaporated and the residue
was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford
2-ethyl-3-(hydroxyimino)-1-phenylpentan-1-one (colorless oil, 585.7 mg, 2.671 mmol, 37%).
To a solution of the oxime afford 2-ethyl-3-(hydroxyimino)-1-phenylpentan-1-one in (239.1 mg, 1.090
mmol) in 5 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 500 mg, 4.450 mmol) at
0 ºC followed by addition of TsCl (250.0 mg, 1.311 mmol) in 2.5 mL of CH2Cl2. The whole was stirred
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at room temperature for 1 hr. The reaction was quenched with water and the mixture was extracted with
CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography
(Hexane: EtOAc= 6: 1) to afford 2p (colorless oil, 141.8 mg, 70%, 24% for 2 steps).
1
2
3
4
5
6
1H NMR (CDCl3): δ 7.68-7.66 (2H, m), 7.50-7.46 (1H, m), 7.43-7.38 (2H, m), 2.86-2.74 (2H, m),
2.26-2.16 (1H, m), 2.01-1.92 (1H, m), 1.26 (3H, t, J=7.2 Hz), 0.87 (3H, t, J=7.2 Hz). C NMR
13
7
8
9
(CDCl3): δ 201.9, 170.4, 137.4, 131.5, 128.3, 128.2, 47.8, 24.7, 21.7, 10.1, 8.7. HRMS (ESI-TOF,
[M+Na]+): Calcd. for C13H15NNaO+, 224.1046. Found: 224.1049.
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Transformation of 2H-azirines to oxazoles with tert-BuOK/Toluene
O
N
3b
A suspension of t-BuOK (67.3 mg, 0.600 mmol) in 1.5 mL of toluene was kept at 20 ºC with an external
water bath. A solution of 2b (52.0 mg, 0.300 mmol) in 1.5 mL of toluene was added dropwise at 20 ºC.
The solution was stirred at 20 ºC for 5 min and quenched with 0.3 mL of acetic acid. The reaction
mixture was diluted with EtOAc (10 mL) and washed with water, saturated aqueous NaHCO3 solution
and brine. The solvent was evaporated and the residue was purified with column chromatography
(Hexane: EtOAc= 2: 1) to afford oxazole 3b (white solid, 44.4 mg, 85%).
Mp.: 42-44 ºC. 1H NMR (CDCl3): δ 7.57 (2H, dd, J=2.0, 8.0 Hz), 7.44-7.40 (2H, m), 7.31-7.29 (1H, m),
2.48 (3H, s), 2.38 (3H, s). C NMR (CDCl3): δ 159.4, 145.1, 131.6, 129.3, 128.7, 127.3, 125.1, 13.9,
13
13.2. HRMS (ESI-TOF, [M+Na]+): Calcd. for C11H11NNaO+, 196.0733. Found: 196.0744. Anal. Calcd.
for C11H11NO: C, 76.28; H, 6.40; N, 8.13. Found: C, 76.11; H, 6.39; N, 8.17.
O
N
H
3a
Oxazole 3a. A suspension of t-BuOK (67.3 mg, 0.600 mmol) in 1.5 mL of toluene was kept at 20 ºC
with an external water bath. A solution of 2a (47.8 mg, 0.300 mmol) in 1.5 mL of toluene was added
dropwise at 20 ºC. The solution was stirred at 20 ºC for 5 min and quenched with 0.3 mL of acetic acid.
The reaction mixture was diluted with EtOAc (10 mL) and washed with water, saturated aqueous
NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column
chromatography (Hexane: EtOAc= 4: 1) to afford oxazole 3a (yellow solid, 15.5 mg, 32%).
Mp.: 51-53 ºC. 1H NMR (CDCl3): δ 7.62-7.59 (2H, m), 7.43-7.38 (2H, m), 7.33-7.30 (1H, m), 7.21 (1H,
s), 2.53 (3H, s). C NMR (CDCl3): δ 161.0, 151.1, 128.9, 128.2, 128.1, 123.9, 121.9, 14.1. HRMS
13
(ESI-TOF, [M+H]+): Calcd. for C10H10NO+, 160.0757. Found: 160.0779.
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The Journal of Organic Chemistry
1
2
3
4
O
N
MeO
5
3d
6
7
8
9
Oxazole 3d. A suspension of t-BuOK (67.3 mg, 0.600 mmol) in 1.5 mL of toluene was kept at 20 ºC
with an external water bath. A solution of 2d (61.0 mg, 0.300 mmol) in 1.5 mL of toluene was added
dropwise at 20 ºC. The solution was stirred at 20 ºC for 5 min and quenched with 0.3 mL of acetic acid.
The reaction mixture was diluted with EtOAc (10 mL) and washed with water, saturated aqueous
NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column
chromatography (Hexane: EtOAc= 1: 1) to afford oxazole 3d (colorless oil, 53.6 mg, 88%).
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1H NMR (CDCl3): δ 7.49 (2H, d, J=8.8 Hz), 6.95 (2H, d, J=8.8 Hz), 3.84 (3H, s), 2.46 (3H, s), 2.33 (3H,
s). C NMR (CDCl3): δ 158.9, 158.8, 145.1, 130.0, 126.6, 122.2, 114.2, 55.3, 13.9, 13.0. HRMS
13
(ESI-TOF, [M+Na]+): Calcd. for C12H13NNaO2+, 226.0839. Found: 226.0822.
O
N
Me
3e
Oxazole 3e. A suspension of t-BuOK (67.3 mg, 0.600 mmol) in 1.5 mL of toluene was kept at 20 ºC
with an external water bath. A solution of 2e (56.2 mg, 0.300 mmol) in 1.5 mL of toluene was added
dropwise at 20 ºC. The solution was stirred at 20 ºC for 5 min and quenched with 0.3 mL of acetic acid.
The reaction mixture was diluted with EtOAc (10 mL) and washed with water, saturated aqueous
NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column
chromatography (Hexane: EtOAc= 4: 1) to afford oxazole 3e (light yellow oil, 47.5 mg, 84%).
1H NMR (CDCl3): δ 7.46 (2H, d, J=8.4 Hz), 7.23 (2H, d, J=8.0 Hz), 2.47 (3H, s), 2.38 (3H, s), 2.36 (3H,
s). C NMR (CDCl3): δ 159.1, 145.3, 137.2, 130.9, 129.4, 126.3, 125.1, 21.3, 13.9, 13.2. . HRMS
13
(ESI-TOF, [M+H]+): Calcd. for C12H14NO+, 188.1070. Found: 188.1071. Anal. Calcd. for C12H13NO:
C, 76.98; H, 7.00; N, 7.48. Found: C, 76.63; H, 7.17; N, 7.29.
O
N
F
3f
Oxazole 3f. A suspension of t-BuOK (67.3 mg, 0.600 mmol) in 1.5 mL of toluene was kept at 20 ºC
with an external water bath. A solution of 2f (57.4 mg, 0.300 mmol) in 1.5 mL of toluene was added
dropwise at 20 ºC. The solution was stirred at 20 ºC for 5 min and quenched with 0.3 mL of acetic acid.
The reaction mixture was diluted with EtOAc (10 mL) and washed with water, saturated aqueous
NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column
chromatography (Hexane: EtOAc= 4: 1) to afford oxazole 3a (yellow oil, 41.2 mg, 72%).
1H NMR (CDCl3): δ 7.54-7.51 (2H, m), 7.13-7.09 (2H, m), 2.46 (3H, s), 2.34 (3H, s). C NMR
13
(CDCl3): δ 161.9 (d, JC, F=246.0 Hz), 159.3, 144.4, 131.2, 126.9 (d, JC, F=9.0 Hz), 125.6 (d, JC, F=3.5 Hz),
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115.8 (d, JC, F=21.7 Hz), 13.9, 13.1. HRMS (ESI-TOF, [M+H]+): Calcd. for C11H11FNO +, 192.0819.
Found: 192.0822.
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Cl
3g
Oxazole 3g. A suspension of t-BuOK (67.3 mg, 0.600 mmol) in 1.5 mL of toluene was kept at 20 ºC
with an external water bath. A solution of 2g (62.5 mg, 0.301 mmol) in 1.5 mL of toluene was added
dropwise at 20 ºC. The solution was stirred at 20 ºC for 5 min and quenched with 0.3 mL of acetic acid.
The reaction mixture was diluted with EtOAc (10 mL) and washed with water, saturated aqueous
NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column
chromatography (Hexane: EtOAc= 4: 1) to afford oxazole 3g (yellow solid, 49.2 mg, 79%).
Mp.: 41-42 ºC. 1H NMR (CDCl3): δ 7.48 (2H, d, J=8.8 Hz), 7.37 (2H, d, J=8.8 Hz), 2.46 (3H, s), 2.35
(3H, s). C NMR (CDCl3): δ 159.6, 144.2, 133.0, 132.1, 128.9, 127.8, 126.2, 13.9, 13.3. HRMS
13
(ESI-TOF, [M+H]+): Calcd. for C11H11ClNO , 208.0524. Found: 208.0518. Anal. Calcd. for
C11H10ClNO: C, 63.62; H, 4.85; N, 6.75. Found: C, 63.52; H, 5.00; N, 6.65.
+
O
N
Br
3h
Oxazole 3h. A suspension of t-BuOK (67.3 mg, 0.600 mmol) in 1.5 mL of toluene was kept at 20 ºC
with an external water bath. A solution of 2h (75.6 mg, 0.300 mmol) in 1.5 mL of toluene was added
dropwise at 20 ºC. The solution was stirred at 20 ºC for 5 min and quenched with 0.3 mL of acetic acid.
The reaction mixture was diluted with EtOAc (10 mL) and washed with water, saturated aqueous
NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column
chromatography (Hexane: EtOAc= 4: 1) to afford oxazole 3h (light yellow solid, 52.6 mg, 70%).
Mp.: 47-50 ºC. 1H NMR (CDCl3): δ 7.53 (2H, d, J=8.8 Hz), 7.42 (2H, d, J=8.4 Hz), 2.46 (3H, s), 2.35
(3H, s). C NMR (CDCl3): δ 159.6, 144.2, 132.2, 131.9, 128.2, 126.5, 121.1, 13.9, 13.3. HRMS
13
(ESI-TOF, [M+H]+): Calcd. for C11H11BrNO , 252.0019. Found: 252.0008. Anal. Calcd. for
C11H10BrNO: C, 52.41, H, 4.00, N, 5.56; Found: C, 52.48, H, 4.32, N, 5.20.
+
O
N
MeOOC
3i
Oxazole 3i. A suspension of t-BuOK (67.3 mg, 0.600 mmol) in 1.5 mL of toluene was kept at 20 ºC
with an external water bath. A solution of 2i (69.4 mg, 0.300 mmol) in 1.5 mL of toluene was added
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The Journal of Organic Chemistry
dropwise at 20 ºC. The solution was stirred at 20 ºC for 5 min and quenched with 0.3 mL of acetic acid.
The reaction mixture was diluted with EtOAc (10 mL) and washed with water, saturated aqueous
NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column
chromatography (Hexane: EtOAc= 1: 1) to afford oxazole 3i (white solid, 52.1 mg, 75%).
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8
Mp.: 76-77 ºC. 1H NMR (CDCl3): δ 8.08 (2H, d, J=8.8 Hz), 7.63 (2H, d, J=8.8 Hz), 3.93 (3H, s), 2.49
(3H, s), 2.42 (3H, s). C NMR (CDCl3): δ 166.7, 160.2, 144.3, 134.0, 133.4, 130.1 128.5, 124.5, 52.2,
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14.0, 13.6. HRMS (ESI-TOF, [M+H]+): Calcd. for C13H14NO3 , 232.0968, Found: 232.0969. Anal.
Calcd. for C13H13NO3: C, 67.52; H, 5.67; N, 6.06. Found: C, 67.42; H, 6.03; N, 5.72.
+
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O
N
3j
Oxazole 3j. A suspension of t-BuOK (67.3 mg, 0.600 mmol) in 1.5 mL of toluene was kept at 20 ºC
with an external water bath. A solution of 2j (67.1 mg, 0.301 mmol) in 1.5 mL of toluene was added
dropwise at 20 ºC. The solution was stirred at 20 ºC for 5 min and quenched with 0.3 mL of acetic acid.
The reaction mixture was diluted with EtOAc (10 mL) and washed with water, saturated aqueous
NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column
chromatography (Hexane: EtOAc= 4: 1) to afford oxazole 3j (white solid, 49.8 mg, 74%).
1
Mp.: 74-77 ºC. H NMR (CDCl3): δ 8.03 (1H, s), 7.92-7.84 (3H, m), 7.74 (1H, dd, J=2.0, 8.4 Hz),
13
7.55-7.48 (2H, m), 2.55 (3H, s), 2.50 (3H, s). C NMR (CDCl3): δ 159.5, 145.3, 133.4, 132.4, 132.1,
128.5, 128.1, 127.7, 126.7, 126.6, 126.2, 123.8, 123.1, 14.0, 13.5. HRMS (ESI-TOF, [M+H]+): Calcd.
for C15H14NO+, 224.1070. Found: 224.1054.
O
N
3k
Oxazole 3k. A suspension of t-BuOK (67.3 mg, 0.600 mmol) in 1.5 mL of toluene was kept at 20 ºC
with an external water bath. A solution of 2k (64.0 mg, 0.300 mmol) in 1.5 mL of toluene was added
dropwise at 20 ºC. The solution was stirred at 20 ºC for 5 min and quenched with 0.3 mL of acetic acid.
The reaction mixture was diluted with EtOAc (10 mL) and washed with water, saturated aqueous
NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column
chromatography (Hexane: EtOAc= 4: 1) to afford oxazole 3k (colorless oil, 48.8 mg, 76%).
1H NMR (CDCl3): δ 7.57 (2H, dd, J=1.2, 8.4 Hz), 7.42-7.39 (2H, m), 7.31-7.29 (1H, m), 2.68 (2H, d,
J=6.4 Hz), 2.49 (3H, s), 1.16-1.09 (1H, m), 0.53-0.50 (2H, m), 0.26-0.22 (2H, m). 13C NMR (CDCl3): δ
159.6, 145.2, 135.4, 129.2, 128.7, 127.5, 125.4, 31.2, 14.0, 10.1, 4.3. HRMS (ESI-TOF, [M+H]+): Calcd.
for C14H16NO+, 214.1226. Found: 214.1231.
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1
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3l-E
3l-Z
7
8
9
Oxazole 3l. A suspension of t-BuOK (67.3 mg, 0.600 mmol) in 1.5 mL of toluene was kept at 20 ºC
with an external water bath. A solution of 2l (59.8 mg, 0.300 mmol) in 1.5 mL of toluene was added
dropwise at 20 ºC. The solution was stirred at 20 ºC for 5 min and quenched with 0.3 mL of acetic acid.
The reaction mixture was diluted with EtOAc (10 mL) and washed with water, saturated aqueous
NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column
chromatography (Hexane: EtOAc= 6: 1) to afford oxazole (E)-3l (colorless oil, 36.3 mg, 61%) and
(Z)-3l (yellow oil, 5.6 mg, 9.4%).
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Oxazole (E)-3l. 1H NMR (CDCl3): δ 7.1 (2H, dd, J=1.2, 8.4 Hz), 7.43-7.39 (2H, m), 7.33-7.28 (1H, m),
6.37 (1H, dd, J=2.0, 15.7), 5.92-5.84 (1H, m), 2.52 (3H, s), 2.02 (3H, dd, J=2.0, 6.8 Hz). C NMR
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(CDCl3): δ 159.4, 146.3, 133.2, 130.5, 129.1, 128.6, 127.7, 125.9, 119.0, 15.3, 14.1. HRMS (ESI-TOF,
[M+H]+): Calcd. for C13H14NO+, 200.1070. Found: 200.1065. Anal. Calcd. for C13H13NO: C, 78.36; H,
6.58; N, 7.03. Found: C, 78.06; H, 6.76; N, 6.65.
1
Oxazole (Z)-3l. H NMR (CDCl3): δ 7.59 (2H, dd, J=1.2, 7.6 Hz), 7.44-7.40 (2H, m), 7.33-7.28 (1H,
m), 6.56-6.54 (2H, m), 2.49 (3H, m), 1.91 (3H, d, J=5.2 Hz). 13C NMR (CDCl3): δ 160.1, 144.3, 133.8,
129.3, 129.1, 128.8, 127.8, 125.9, 120.0, 18.6, 14.0. HRMS (ESI-TOF, [M+H]+): Calcd. for C13H14NO+,
200.1070. Found: 200.1089.
O
N
3m
Oxazole 3m. A suspension of t-BuOK (67.3 mg, 0.600 mmol) in 1.5 mL of toluene was kept at 20 ºC
with an external water bath. A solution of 2m (55.6 mg, 0.300 mmol) in 1.5 mL of toluene was added
dropwise at 20 ºC. The solution was stirred at 20 ºC for 5 min and quenched with 0.3 mL of acetic acid.
The reaction mixture was diluted with EtOAc (10 mL) and washed with water, saturated aqueous
NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column
chromatography (Hexane: EtOAc= 7: 3) to afford oxazole 3m (colorless oil, 48.6 mg, 87%).
1H NMR (CDCl3): δ 7.32 (1H, d, J=7.2 Hz), 7.22-7.10 (3H, m), 3.04 (2H, t, J=8.0 Hz), 2.82 (2H, t,
J=8.0 Hz), 2.51 (3H, s). C NMR (CDCl3): δ 160.8, 146.0, 135.4, 134.1, 128.1, 127.0, 126.8, 126.4,
13
119.1, 29.0, 21.5, 14.2. HRMS (ESI-TOF, [M+H]+): Calcd. for C12H12NO+, 186.0913. Found: 186.0898.
Anal. Calcd. for C12H11NO: C, 77.81; H, 5.99; N, 7.56. Found: C, 77.54; H, 6.33; N, 7.19.
O
N
3n
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The Journal of Organic Chemistry
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Oxazole 3n. A suspension of t-BuOK (67.3 mg, 0.600 mmol) in 1.5 mL of THF was kept at 20 ºC with
an external water bath. A solution of 2n (52.0 mg, 0.300 mmol) in 1.5 mL of THF was added dropwise
at 20 ºC. The solution was stirred at 20 ºC for 5 min and quenched with 0.3 mL of acetic acid. The
reaction mixture was diluted with EtOAc (10 mL) and washed with water, saturated aqueous NaHCO3
solution and brine. The solvent was evaporated and the residue was purified with column
chromatography (Hexane: EtOAc= 6: 1) to afford oxazole 3n (yellow oil, 36.5 mg, 72%).
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1H NMR (CDCl3): δ 7.63 (2H, dd, J=8.0, 1.2 Hz), 7.41 (2H, t, J=7.6 Hz), 7.19 (1H, d, J=7.2 Hz), 2.49
(3H, s), 2.46 (3H, s). C NMR (CDCl3): δ 159.1, 145.4, 134.3, 132.5, 128.6, 127.1, 126.5, 13.8, 11.8.
13
HRMS (ESI-TOF, [M+Na]+): Calcd. for C11H11NNaO+, 196.0733. Found: 196.0732. Anal. Calcd. for
C11H11NO: C, 76.28; H, 6.40; N, 8.09. Found: C, 76.29; H, 6.44; N, 7.97.
O
N
3o
Oxazole 3o. A suspension of t-BuOK (67.3 mg, 0.600 mmol) in 1.5 mL of toluene was kept at 20 ºC
with an external water bath. A solution of 2o (68.8 mg, 0.300 mmol) in 1.5 mL of toluene was added
dropwise at 20 ºC. The solution was stirred at 20 ºC for 5 min and quenched with 0.3 mL of acetic acid.
The reaction mixture was diluted with EtOAc (10 mL) and washed with water, saturated aqueous
NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column
chromatography (Hexane: EtOAc= 4: 1) to afford oxazole 3o (colorless oil, 48.6 mg, 71%).
1H NMR (CDCl3): δ 7.31-7.18 (5H, m), 3.95 (2H, s), 2.39 (3H, s), 1.34 (9H, s). C NMR (CDCl3): δ
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158.3, 153.8, 140.1, 130.7, 128.4, 128.3, 126.0, 32.9, 32.4, 29.6, 13.9. HRMS (ESI-TOF, [M+Na]+):
Calcd. for C15H19NNaO+, 252.1359. Found: 252.1354.
O
N
3p
Oxazole 3p. A suspension of t-BuOK (67.3 mg, 0.600 mmol) in 1.5 mL of toluene was kept at 20 ºC
with an external water bath. A solution of 2o (60.4 mg, 0.300 mmol) in 1.5 mL of toluene was added
dropwise at 20 ºC. The solution was stirred at 20 ºC for 5 min and quenched with 0.3 mL of acetic acid.
The reaction mixture was diluted with EtOAc (10 mL) and washed with water, saturated aqueous
NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column
chromatography (Hexane: EtOAc= 6: 1) to afford oxazole 3o (colorless oil, 52.9 mg, 88%).
1H NMR (CDCl3): δ 7.57 (2H, dd, J=1.2, 7.2 Hz), 7.44-7.40 (2H, m), 7.32-7.29 (1H, m), 2.82 (2H, q,
J=7.6 Hz), 2.76 (2H, q, J=7.6 Hz), 1.38 (3H, t, J=7.6 Hz), 1.31 (3H, t, J=7.6 Hz). 13C NMR (CDCl3): δ
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