Utility of Nitrogen Extrusion of Azido Complexes for the Synthesis of Nitriles, Benzoxazoles, and Benzisoxazoles

Article abstract of DOI:10.1021/acs.joc.5b01305

The utility of the nitrogen extrusion reaction of azido complexes, generated in situ from the corresponding aldehydes or ketones with TMSN₃ in the presence of ZrCl₄ or TfOH, has been described. These azido complexes could undergo three different pathways, depending on the substrates. First, azido methanolate complexes or imine diazonium ions could lead to benzisoxazole products via an intramolecular nucleophilic substitution. Second, imine diazonium ions could also undergo either the elimination of proton to provide nitrile products in good to excellent yields or an aryl migration, followed by an intramolecular nucleophilic addition, to give benzoxazole products in good yields.

Full text of DOI:10.1021/acs.joc.5b01305

Page 1 of 34
The Journal of Organic Chemistry
The Utilities of Nitrogen Extrusion of Azido Complexes for the Synthesis of Nitriles,
Benzoxazoles and Benzisoxazoles
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Phongprapan Nimnual,a Jumreang Tummatorn,*’a,b Charnsak Thongsornkleeba,b
and Somsak Ruchirawata,b
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aProgram on Chemical Biology, Chulabhorn Graduate Institute, Center of Excellence on Environmental
Health and Toxicology (EHT), Ministry of Education, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210,
Thailand
bLaboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6, Laksi,
Bangkok 10210, Thailand
ABSTRACT
The utilities of the nitrogen extrusion reaction of azido complexes, generated in situ from the
corresponding aldehydes or ketones with TMSN3 under the presence of ZrCl4 or TfOH, have been
described. These azido complexes could undergo three different pathways, depending on the substrates.
First, azido methanolate complexs or imine diazonium ions could lead to benzisoxazole products via an
intramolecular nucleophilic substitution. Second, imine diazonium ions could also undergo either the
elimination of proton to provide nitrile products in good to excellent yields or an aryl migration,
followed by an intramolecular nucleophilic addition, to give benzoxazole products in good yields.
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■ INTRODUCTION
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Nitriles,1 benzisoxazoles,2 and benzoxazoles3 are the important precursors for the synthesis of more
complex chemical structures,4 including natural products and pharmaceutical agents.5 Currently, several
synthetic approaches for the synthesis of such compounds use different nitrogen sources. One of the
powerful nitrogen sources for the preparation of several classes of N–containing compounds is azide.6
The N2ꢀextrusion of azides can be induced by both Lewis and Brønsted acids7 which could lead to one
remaining nitrogen atom attached to the desired products. Schmidt reaction and Curtius rearrangement
are the wellꢀknown classical reactions which also involve with the N2ꢀextrusion chemistry.8 Therefore
several synthetic methods pertaining to this chemistry have been developed for the synthesis of Nꢀ
containing molecules. Recently, the conversion of aldehydes to nitriles by HN3 generated from NaN3
and TfOH has been reported.9 However, the reaction between HN3 and strongly electrophilic aldehyde
under these conditions is highly exothermic, presenting a great explosion risk.10 Due to the explosion
hazard of sodium azide and Brønsted acids, we envision to replace this hazardous combination with the
safer alternative of Lewis acid and TMSN3.11 In this work, we aim to develop the new synthetic methods
for the synthesis of nitriles, benzoxazoles and benzisoxazoles using arylaldehyde and arylketone
substrates as proposed in Scheme 1. In our proposed strategy, the aldehyde or ketone will be activated
by Lewis acid and will then undergo the nucleophilic addition with azide to provide the azido
methanolate complex (A), followed by an elimination to generate the imine diazonium ion intermediate
(B). We proposed that this imine diazonium ion could undergo the nitrogen extrusion by three different
pathways, depending on the substrates. First, it could undergo the elimination of proton to provide the
benzonitrile product as shown in pathway A. Alternatively, the OꢀN bond formation may take place
through the nucleophilic substitution in case of substrates containing oꢀhydroxyl group (pathway B).
Lastly, when R1 ≠ H, we anticipated the elimination could not occur, and the aryl migration will ensue to
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generate the nitrilium ion (C) which could cyclize via nucleophilic addition of the oꢀhydroxyl group to
provide the benzoxazole product as shown in pathway C.
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Scheme 1. Our proposed synthetic methodology.
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LA
R1
LA
R1
O
O
R1
N
N3
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N
N
N
N
N
R
R
R
R = H, OH
azido methanolate complex (A)
imine diazonium ion (B)
Pathway B: Nucleophilic substitution
Pathway A: Elimination of proton
H
H
N
R
H
N
N
N
N
N
N
N
O
R
R
OH
Pathway C: Aryl migration
R1
R1
N
O
N
R1
N
N
N
OH
OH
nitrilium ion (C)
■ RESULTS AND DISCUSSION
To demonstrate the plausibility of our proposed methodology, we chose pꢀmethoxybenzaldehyde (1c) as
the initial substrate for our screening of conditions. Treatment of compound 1c with either Sc(OTf)3 or
Bi(OTf)3 in DCM resulted in trace amount of the desired product (2c) (entries 1ꢀ2), whereas no product
was obtained when the reaction was performed using BF3ꢁOEt2 (entry 3). We have previously reported
that ZrCl4 was effective activator for the nitrogen extrusion of azides,12 therefore, we directed our
attention to this reagent for our experiments. The results showed that 1.0 eq of ZrCl4 in DCM could
provide the desired product in 81% yield (entry 4). Next, the effects of solvents were examined,
employing ZrCl4 in several solvents such as DCE, THF, PhCH3, EtOH and CH3CN, and found the
highest yield was obtained when the reaction was carried out in CH3CN (entry 9). Increasing the
equivalent of ZrCl4 could not significantly improve the yield of the product (entry 10), whereas reducing
ZrCl4 to 0.5 equiv. lowered the yield of the product (entry 11). The results showed that the combination
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of ZrCl4 and TMSN3 in CH3CN could be used to convert aldehydes to nitriles, while providing
advantages of safer handling of reagents, room temperature reaction and short reaction time.13
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Table 1. Optimization for the synthesis of benzonitrile 2c.a
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Entry
1 (eq)
1.0
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1.0
1.0
1.0
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1.0
1.0
1.0
1.0
1.0
TMSN3 (eq)
Lewis acids (eq)
Sc(OTf)3 (10 % mol)b
Bi(OTf)3 (10 % mol)b
BF3ꢁOEt2 (10 % mol)b
ZrCl4 (1.0 eq)
Solvent
DCM
Yield (%)
trace
trace
NR
81
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2
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.5
DCM
3
DCM
4
DCM
5
ZrCl4 (1.0 eq)
DCE
89
6
ZrCl4 (1.0 eq)
THF
84
7
ZrCl4 (1.0 eq)
PhCH3
EtOH
CH3CN
CH3CN
CH3CN
43
8
ZrCl4 (1.0 eq)
NR
94
9
ZrCl4 (1.0 eq)
10
11
ZrCl4 (1.5 eq)
95
ZrCl4 (0.5 eq)
81
aIsolated yields. bThe reaction was stirred for overnight.
To explore the scope of substrates, a variety of aldehydes were studied using the optimal conditions
established above (Table 1, entry 9). Most of the benzaldehyde derivatives were converted to the
corresponding products in good to excellent yields. However, it was found that the inductive effect of
metaꢀmethoxy substituent of benzaldehyde derivatives decreased the yields of the desired products (2b,
74% and 2f, 69%). Similarly, benzaldehydes substituted with metaꢀbromine provided the corresponding
product in lower yield (2j, 67%), as compared to the ortho- and para-positions (2i, 72% and 2k, 77%,
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respectively). In addition, benzaldehyde possessing a strong electronꢀwithdrawing paraꢀNO2 group also
afforded the benzonitrile 2n in moderate yield. The results also showed that several functional groups
such as methoxy, hydroxyl, alkyl, aryl, halogen, and nitro groups could tolerate well under these optimal
conditions. Conversely, benzyl group could be partially deprotected to give the corresponding product in
lower yield such as 3,4ꢀdibenzyloxybenzonitrile (2g, 76%), as compared to 3,4ꢀdimethoxybenzonitrile
(2e, 93%). However, 4ꢀformylquinoline (2t) did not react under these conditions. The current procedure
could also be applied to synthesize the cinnamonitrile derivatives in excellent yields (2uꢀ2w). It is
important to note that the reaction provided benzisoxazoles as the side products when benzaldehyde
substrates contained an oꢀmethoxy group, such as 2,4ꢀdimethoxybenzaldehyde (1d) and 2,3,4ꢀ
trimethoxybenzaldehyde (1o). These results provided a strong support that our proposed reaction for the
synthesis of benzisoxazole would occur through pathway B. Therefore, we decided to use oꢀ
hydroxybenzaldehyde derivatives to investigate the proposed methodology as shown in Table 2.
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Scheme 2. The synthesis of nitriles from aldehydes.a
b
aIsolated yields. The reaction was carried out using 1.5 eq of TMSN3 and ZrCl4 and stirred at room
temperature for overnight.
We attempted to optimize the reaction conditions to maximize yields of benzisoxazoles 6.14 However,
we were not able to selectively control the formation of the desired products. We rationalized that the
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electronic property of the aryl ring may impose effects on the product distribution and therefore the
titled conditions were applied to several salicylaldehyde derivatives to evaluate our hypothesis. The
reaction of salicylaldehyde (4a) provided the oꢀhydroxybenzonitrile (5a, 43%) and benzisoxazole (6a,
29%) in almost 1.5:1 ratio and a similar result could be observed in case of compound 4b. Using
electronꢀrich substrates, aldehydes 4c and 4d, benzonitriles (5c and 5d) could be obtained as major
products and benzisoxazoles (6c and 6d) as minor products in 3.5:1 and 2:1 ratios, respectively. The
ratio of two products was reversed when using the substrates containing electronꢀdeficient substituents.
For examples, 5ꢀbromosalicylaldehyde (4e) and 5ꢀchlorosalicylaldehyde (4f) provided benzonitriles as
minor products (5e, 35% and 5f, 32%) whereas the major products (6e and 6f) were obtained in 52%
and 49%, respectively. The effect of a strong electronꢀwithdrawing substituent was even more
pronounced in 5ꢀnitrosalicylaldehyde (4g), which dramatically increased the yield of benzisoxazole (6g)
to 62% together with only 11% of benzonitrile 5g. 2ꢀHydroxynaphthaldehyde (4h) also followed the
same trend as 4g, furnishing benzisoxazole 6h in 65% and benzonitrile 5h in 15%. In the case of 3ꢀ
methoxyꢀ6ꢀbromosalicylaldehyde (4i), the corresponding nitrile (5i) was obtained as the major product
(49%) together with the minor product (6i) in 35% yield. The results from all cases revealed that the
substituents on aryl ring have a substantial influence on the reaction mechanism and products
distribution. The electronꢀdonating group on the aryl aldehyde substrates could accelerate the C–O bond
cleavage to give the imine diazonium intermediate which readily eliminates the proton to form
benzonitriles as the major products (pathway A, Scheme 1). In contrast, the ability of C–O bond
cleavage was diminished when the electronꢀwithdrawing group was present on the aryl ring making the
competing nucleophilic substitution of azido methanolate complex A prevail (pathway D, Scheme 3).
Our current method for the synthesis of benzisoxazoles is comparable to the previously reported
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+
methods2 in that the NꢀO bond formation occurred by the displacement of the leaving group (N2 in our
case) on the imine nitrogen. However, the current method still differs significantly from those in the
literature in which the formation of the imine functional group and the installation of a leaving group
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occurred in sequential steps while the entire process took place directly from the corresponding
aldehyde in a single step using our method. According to our proposed mechanisms, the elimination
pathway may be inhibited when using the oꢀhydroxyarylalkylketone substrates and only benzoxazoles
and benzisoxazoles might be formed as shown in pathways B and C. We therefore used 5ꢀbromoꢀ2ꢀ
hydroxyacetophenone (7d) to investigate the reaction under the current optimal conditions. The result
showed that substrate 7d could only be slightly converted even with the increased equivalents of both
TMSN3 and ZrCl4 (1.5 eq) to afford benzoxazole 8d in only 20% yield along with 55% of recovered
starting material (7d). This result revealed that the reaction mechanism of aryl ketone substrates (7)
favored the aryl migration (pathway C) to form the nitrilium ion intermediate (C, Scheme 1) which
could further react with the intramolecular nucleophile (orthoꢀOH) to provide the desired benzoxazole
8.
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Table 2. The synthesis of benzisoxazoles.a
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aIsolated yields. The reaction was carried out using 1.5 eq of TMSN3 and ZrCl4 and stirred at room
temperature for overnight.
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1
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Scheme 3. Proposed mechanism for the formation of benzisoxazoles.
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9
LA
LA
R1
O
R1
N
O
R1
-H+
pathway D
N
R2
R2
R2
NH
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6
N
N
N
N
O
OH
imine diazonium ion (B)
OH
azido methanolate complex (A)
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In order to achieve a complete conversion, we decided to screen for new optimal conditions using
compound 7d as the substrate. We found that the desired product (8d) was obtained in highest yield
(85%) when using 1.5 eq each of TfOH and TMSN3 in DCM after stirring the reaction overnight
(Scheme 4) along with side product 2ꢀNꢀmethylaminobenzoxazole 9d, which was obtained in 11%
yield. Unfortunately, we could not avoid the formation of 9d under these optimal conditions. To
understand the formation of the side product, compound 8d was subjected to the identical reaction
conditions which resulted in no reaction. This experiment indicated that the side product 9d did not
form from the decomposition of benzoxazole 8d. Therefore, we proposed that the competing reaction
proceeded through the double migration mechanism. Initially, the imine diazonium ion intermediate
underwent an alkyl migration, which is a less favored pathway compared to an aryl migration, providing
oꢀhydroxyarylnitrilium ion. This intermediate could not react intramolecularly with the adjacent OH but
could further react with HN3 via an intermolecular nucleophilic addition, followed by an aryl migration
to give the carbodiimide intermediate which cyclized intramolecularly to furnish byꢀproduct 9 as
demonstrated in Scheme 5. In fact, the rate of the aryl is much faster than the alkyl migration, resulting
in benzoxazole 8d as the major product. In the current strategy for the synthesis of benzoxazoles from
arylketones, we could not avoid the use of TMSN3 and TfOH, which generated HN3 in situ, under the
optimal conditions. It is important to note that the reaction of arylketones under these conditions was not
as exothermic as the reaction of arylaldehydes. Additonally, benzoxazole products could be
conveniently generated directly from the corresponding ketones.
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Scheme 4. Synthesis of benzoxazole.
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Scheme 5. Proposed mechanism for the formation of 9.
To evaluate the generality of the current procedure, we examined a variety of oꢀhydroxyacetophenone
derivatives (7) as shown in Table 3. Substrates containing electronꢀdonating groups or electronꢀ
withdrawing groups such as H, F, Cl, Br, NO2, OMe, and OH at position 5 of oꢀhydroxyacetophenone
were smoothly converted to benzoxazole products in good yields (8aꢀ8g) with only small amounts of
byꢀproducts (9aꢀ9f) obtained. Similarly, the reaction of oꢀhydroxyacetophenones 7h and 7i also
proceeded well under these conditions, providing the corresponding products in excellent yields (8h and
8i). Surprisingly, the proportions of byꢀproducts 9 increased when the substituent was located at position
6 (7j and 7k). These results might be possibly caused by the steric hindrance of the 2,6ꢀdisubstituted
arylimine diazonium ion making the coplanarity of the aromatic ring difficult to attain. Thus the
optimal overlap for aryl migration process could not be achieved and the competing methyl migration
became more viable, resulting in the increase of byꢀproduct. Further investigations were attempted with
oꢀhydroxyacetophenones 7l and 7m to furnish the corresponding products in good yields. For less
electrophilic ketone (7n), the substrate was not completely consumed under these conditions, providing
37% of the recovered starting material along with 49% of the desired product 8n and 7% of minor
product 9n. To see the substituent effects on the migrationꢀnitrogen extrusion step, other oꢀ
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hydroxyarylketones were examined. Therefore, oꢀhydroxyphenylbutylketone (7o) was chosen as the
substrate which furnished benzoxazole 8o in good yield (79 %) together with compound 9o in 16%
yield. Moreover, oꢀhydroxybenzophenone 7p was subjected to the same conditions. In this case, the
results indicated that the rates of migration of both the electron rich oꢀhydroxyphenyl (ring A) and the
phenyl ring (ring B) were comparable, resulting in the formation of the nitrilium intermediates 7pꢀA and
7pꢀB, respectively as shown in Scheme 6. The subsequent reaction of the nitrilium ion 7pꢀA led to the
desired product 8p in 42% yield whereas the reactions of the nitrilium ion 7pꢀB yielded products 9p and
10p in 45% combined yields.
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Table 3. The scope of benzoxazole synthesis.a
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2
O
3
4
5
R1
N
O
N
O
TMSN3 (1.5 eq), TfOH (1.5 eq)
DCM, rt, O/N
R1
R
R
NH
R1
R
OH
8
9
7
6
7
8
9
Entry
1
Product (8)
Product (9)
Yield of 5a
Yield of 6a
Entry
Product (8)
Product (9)
Yield of 5a
Yield of 6a
OH
N
N
O
N
OH
N
77%
8%
Me
Me
NH
11
O
Me
9a
8a
NH
Me
Me
8k
50%
25%
7%
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O
O
9k
F
F
N
O
N
O
2
3
Br
NH
Me
Br
83%
87%
13%
12%
N
O
N
O
12
88%
Me
8l
NH
Me
8b
9b
MeO
MeO
9l
Cl
Cl
N
O
N
O
Me
8c
NH
Me
Cl
9c
N
O
Cl
N
O
13
14
7%
7%
NH
Me
89%
Me
Br
Br
N
O
N
O
9m
8m
Cl
4
5
Me
8d
NH
Me
Cl
85%
83%
78%
11%
12%
10%
9d
OMe
OMe
O2N
O2N
N
O
N
O
N
O
N
O
49%
79%
Me
NH
Me
Me
8e
NH
MeO
MeO
Me
8n
9n
9e
MeO
HO
MeO
HO
N
O
N
O
6
N
O
N
O
Me
8f
NH
Me
16%
O
15
Bu
NH
Bu
9f
8o
9o
N
O
N
O
b
7
8
-
Me
8g
NH
Me
77%
90%
O
N
Ph
NH
N
O
Ph
9g
9h
9i
TMSN3 (1.5 eq)
N
H
Ph
OH
Ph
O
TfOH (1.5 eq)
DCM, rt, O/N
OH
N
O
N
O
8p, 42%
9p, 40%
7p
10p, 5%
NH
Me
8h
8%
Me
MeO
HO
MeO
HO
N
O
N
N
O
O
N
N
OH
OR
O
OH
OR
N
b
NH
9
Me
Me
89%
49%
-
TMSN3 (1.5 eq)
N
Me
+
8i
8j
TfOH (1.5 eq)
DCM, rt, O/N
OEt
OR
R = H, 6q, 32%
R= Me, 6r, 44%
OEt
R = H, 7q
R = Me, 7r
N
O
R = H, 11q, 14%
R = Me, 11r, 23%
N
O
10
NH
48%
Me
9j
aIsolated yields. bByꢀproduct could not be detected.
Scheme 6. The nitrilium ion formation from compound 7p
The results of all cases revealed that the migration of an aryl group is more favorable than an alkyl
group of acyclic ketone substrates to afford the desired benzoxazole products. Furthermore, cyclic
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ketones were next explored. The reactions of tetralone derivatives (7q and 7r) were performed under the
current optimal conditions. Surprisingly in both entries, the intramolecular nucleophilic substitution
(pathway B) was preferred to the aryl migration (pathway C), providing benzisoxazoles 6q and 6r as the
major products in 32% and 44% yields, respectively. Additionally, the alkyl migration was also more
favored than the aryl migration to form the cyclic nitrilium ion intermediate (D) which was
subsequently added by HN3, following an intramolecular cyclization, compounds 11q and 11r were
obtained as minor products.15 The proposed mechanism is illustrated in Scheme 7.
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8
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Scheme 7. The proposed formation of products 11q and 11r.
■ CONCLUSIONS
We have demonstrated the utilities of nitrogenꢀextrusion of azido complexes, generated from aldehydes
or ketones with appropriate substituents in presence of TMSN3 and ZrCl4 or TfOH, to deliver a variety
of Nꢀcontaining compounds. With aldehydes, the products obtained are nitriles whereas when they
contain oꢀhydroxyl group, both nitriles and benzisoxazoles are obtained with varying ratios, depending
on the nature of other substituents. When oꢀhydroxyarylketones are employed, the rearrangement of the
initial azido intermediates leads to an aryl migration to form the nitrilium ion which could cyclize to
form benzoxazoles in good yields.
■ EXPERIMENTAL SECTION
General Procedure. The commercial grade chemicals were used without further purification, unless
otherwise specified. All solvents used were purified by the solvent purification system. The ovenꢀdried
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glassware (110 ºC at least for two hours) was used for all reactions. Crude reaction mixtures were
concentrated under reduced pressure by removing organic solvent with the rotary evaporator. Column
chromatography was performed using silica gel 60 (particle size 0.06ꢀ0.2 mm; 70ꢀ230 mesh ASTM).
Analytical thin layer chromatography (TLC) was performed with silica gel 60 F254 aluminum sheets.
The nuclear magnetic resonance (NMR) spectra were recorded in deuterochloroform (CDCl3) or
dimethyl sulfoxideꢀd6 (DMSOꢀd6) with 300 and 600 MHz spectrometers. Chemical shifts for 1H NMR
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
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58
59
60
and 13C NMR spectra were reported in part per million (ppm,
δ), relative to tetramethylsilane (TMS) as
the internal reference. Coupling constants (J) were reported in Hertz (Hz). Infrared spectra were
measured using FTꢀIR spectrometer and were reported in cmꢀ1. High resolution mass spectra (HRMS)
were obtained using timeꢀofꢀflight (TOF).
General procedure for the synthesis of benzonitriles (2aꢀ2w, Scheme 2): A solution of aldehyde 1c
(134.6 mg, 0.9886 mmol, 1.0 equiv) in CH3CN (2.0 mL/mmol) was added TMSN3 (131ꢀL, 0.9886
mmol, 1.0 equiv) and ZrCl4 (130.4 mg, 0.9886 mmol, 1.0 equiv) at room temperature. The reaction
mixture was stirred for 20 min and then quenched with saturated sodium bicarbonate (NaHCO3). The
resulting solution was extracted with EtOAc, and the combined organic layers were washed with brine,
dried over Na2SO4, filtered and concentrated under reduced pressure to provide the crude product which
was purified on silica gel (1:4 EtOAc/Hexane) to yield the corresponding nitrile product 2c (123.6 mg,
94%). (The reactions of substrates 1j and 1n were stirred at room temperature for overnight and the
reactions of substrates 1h and 1w were quenched with water).
4-tert-Butylbenzonitrile (2a):1f Yield 127.0 mg (78%, yellow oil); (1:4 EtOAc/Hexane); IR (neat): υ max
1
2965, 2228, 1606, 1505, 1465, 1365, 1270, 1106, 1018, 837 cmꢀ1; H NMR (300 MHz, CDCl3) δ 7.59
(d, 2H, J = 8.4 Hz), 7.48 (d, 2H, J = 8.4 Hz), 1.33 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 156.6, 131.9,
126.1, 119.2, 109.2, 35.2, 30.9; LRMS (EI) m/z (rel intensity) 159 (M+, 20), 144 (100), 116 (54), 57
(10).
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3-Methoxybenzonitrile (2b): Yield 96.5 mg (74%, brown oil); (1:9 EtOAc/Hexane); IR (neat): υ
max
1
2
3
1
3078, 2943, 2230, 1595, 1578, 1483, 1289, 1263, 1035, 784, 680 cmꢀ1; H NMR (300 MHz, CDCl3) δ
4
5
6
13
7.40ꢀ7.34 (m, 1H), 7.27ꢀ7.22 (m, 1H), 7.14ꢀ7.13 (m, 2H), 3.83 (s, 3H); C NMR (75 MHz, CDCl3) δ
159.6, 130.2, 124.4, 119.2, 118.6, 116.8, 113.1, 55.4; HRMS (ESIꢀTOF) calcd for C8H7NNaO (M+Na)+
156.0420 found 156.0413.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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35
36
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-Methoxybenzonitrile (2c): Yield 123.6 mg (94%, brown solid); mp 58ꢀ59 °C. (1:4 EtOAc/Hexane); IR
1
(neat): υ
3010, 2925, 2224, 1604, 1507, 1464, 1255, 1022, 833, 682 cmꢀ1; H NMR (300 MHz,
max
13
CDCl3) δ 7.62ꢀ7.57 (m, 2H), 6.98ꢀ6.93 (m, 2H), 3.86 (s, 3H); C NMR (75 MHz, CDCl3) δ 162.8,
133.8, 119.1, 114.6, 103.8, 55.4; HRMS (ESIꢀTOF) calcd for C8H7NNaO (M+Na)+ 156.0420 found
156.0414.
2,4-Dimethoxybenzonitrile (2d): Yield 146.7 mg (91%, yellow solid); mp 91ꢀ92 °C. (1:4
1
EtOAc/Hexane); IR (neat): υ max 3097, 2919, 2229, 1598, 1455, 1211, 1163, 1051, 827, 670 cmꢀ1; H
NMR (300 MHz, CDCl3) δ 7.45 (dd, 1H, J = 8.7, 0.9 Hz), 6.52 (dd, 1H, J = 8.7, 2.1 Hz), 6.46 (d, 1H, J
13
= 2.1 Hz), 3.90 (s, 3H), 3.86 (s, 3H); C NMR (75 MHz, CDCl3) δ 164.5, 162.6, 134.7, 116.9, 105.7,
98.2, 93.6, 55.8, 55.6; HRMS (ESIꢀTOF) calcd for C9H9NNaO2 (M+Na)+ 186.0526 found 186.0533.
3,4-Dimethoxybenzonitrile (2e):9 Yield 159.5 mg (93%, white solid); mp 50ꢀ51 °C. (1:4
EtOAc/Hexane); IR (neat): υ
3086, 2939, 2224, 1598, 1512, 1461, 1266, 1244, 1136, 1018, 927,
max
1
852, 812, 765 cmꢀ1; H NMR (300 MHz, CDCl3) δ 7.29 (dd, 1H, J = 8.4, 1.8 Hz), 7.08 (d, 1H, J = 1.8
Hz), 6.91 (d, 1H, J = 8.4 Hz), 3.94 (s, 3H), 3.90 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 152.4, 148.7,
126.0, 118.8, 113.5, 110.9, 103.3, 55.7, 55.67; LRMS (EI) m/z (rel intensity) 163 (M+, 100), 148 (34),
120 (20), 92 (27), 77 (20).
3,5-Dimethoxybenzonitrile (2f): Yield 116.3 mg (69%, light yellow solid); mp 85ꢀ86 °C. (1:19 to 1:9
1
EtOAc/Hexane); IR (neat): υ max 3097, 2919, 2229, 1598, 1455, 1211, 1163, 1051, 827, 670 cmꢀ1; H
13
NMR (300 MHz, CDCl3) δ 6.76ꢀ6.75 (m, 2H), 6.66ꢀ6.64 (m, 1H), 3.81 (s, 6H); C NMR (75 MHz,
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CDCl3) δ 160.9, 118.7, 113.3, 109.8, 105.6, 55.6; HRMS (ESIꢀTOF) calcd for C9H9NNaO2 (M+Na)+
186.0526 found 186.0526.
1
2
3
4
5
6
7
8
3,4-Bis(benzyloxy)benzonitrile (2g): Yield 237.1 mg (76%, white solid); mp 61ꢀ62 °C. (1:4
EtOAc/Hexane); IR (neat): υ max 3033, 2871, 2224, 1597, 1509, 1454, 1266, 1135, 1003, 851, 809, 734
9
1
cmꢀ1; H NMR (300 MHz, CDCl3) δ 7.42ꢀ7.28 (m, 10H), 7.22ꢀ7.17 (m, 1H), 7.11 (d, 1H, J = 1.5 Hz),
10
11
12
13
14
15
16
17
18
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20
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23
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25
26
27
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29
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46
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53
54
55
56
57
58
59
60
13
6.91 (d, 1H, J = 8.4 Hz), 5.18 (s, 2H), 5.12 (s, 2H); C NMR (75 MHz, CDCl3) δ 152.6, 148.6, 136.0,
135.8, 128.6, 128.1, 127.1, 127.0, 126.7, 119.0, 117.2, 113.8, 104.0, 71.2, 70.7; HRMS (ESIꢀTOF) calcd
for C21H17NNaO2 (M+Na)+ 338.1152 found 338.1155.
4-Hydroxybenzonitrile (2h): Yield 108.7 mg (93%, yellow solid); mp 108ꢀ109 °C. (1:1 EtOAc/Hexane);
IR (neat): υ max 3274, 2230, 1608, 1510, 1438, 1282, 1168, 836, 735, 699 cmꢀ1; H NMR (300 MHz,
1
CDCl3) δ 7.56 (d, 2H, J = 8.7 Hz), 6.95 (d, 2H, J = 8.4 Hz); 13C NMR (75 MHz, CDCl3) δ 160.3, 134.3,
119.4, 116.4, 102.8; HRMS (ESIꢀTOF) calcd for C7H5NNaO (M+Na)+ 142.0263 found 142.0269.
2-Bromobenzonitrile (2i): Yield 126.6 mg (72%, white solid); mp 50ꢀ51 °C. (1:19 EtOAc/Hexane); IR
1
(neat): υ
3748, 3088, 2922, 2225, 1821, 1701, 1584, 1466, 1435, 1264, 1044, 755, 658 cmꢀ1; H
max
13
NMR (300 MHz, CDCl3) δ 7.71ꢀ7.65 (m, 2H), 7.51ꢀ7.41 (m, 2H); C NMR (75 MHz, CDCl3) δ 134.2,
133.8, 133.1, 127.6, 125.2, 117.0, 115.8; HRMS (ESIꢀTOF) calcd for C7H4BrNNa (Brꢀ79) (M+Na)+
203.9419 found 203.9410.
3-Bromobenzonitrile (2j): Yield 120.2 mg (67%, white solid); mp 38ꢀ39 °C. (1:9 EtOAc/Hexane); IR
(neat): υ max 3069, 2233, 1759, 1561, 1472, 1409, 1191, 1076, 882, 786, 675 cmꢀ1; 1H NMR (300 MHz,
CDCl3) δ 7.80 (s, 1H), 7.75 (d, 1H, J = 8.1 Hz), 7.61 (d, 1H, J = 7.8 Hz), 7.37 (t, 1H, J = 7.8); 13C NMR
(75 MHz, CDCl3) δ 136.0, 134.7, 130.64, 130.55, 122.8, 117.2, 114.1; HRMS (ESIꢀTOF) calcd for
C7H5BrN (Brꢀ79) (M+H)+ 181.9600 found 181.9608.
4-Bromobenzonitrile (2k): Yield 140.6 mg (77%, light yellow solid); mp 109ꢀ110 °C. (1:9
EtOAc/Hexane); IR (neat): υ max 3559, 2925, 2369, 2154, 1961, 1678, 1489, 1249, 1071, 1011, 822 cmꢀ
1; H NMR (300 MHz, CDCl3) δ 7.66ꢀ7.62 (m, 2H), 7.55ꢀ7.51 (m, 2H); C NMR (75 MHz, CDCl3) δ
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133.4, 132.6, 128.0, 118.0, 111.2; HRMS (ESIꢀTOF) calcd for C7H5BrN (Brꢀ79) (M+H)+ 181.9600
found 181.9603.
1
2
3
4
5
6
7
3-Fluoro-4-methylbenzonitrile (2l):16 Yield 109.1 mg (74%, white solid); mp 41ꢀ42 °C. (1:9
EtOAc/Hexane); IR (neat): υ max 2925, 2854, 2368, 2110, 1971, 1725, 1509, 1460, 1379, 1262, 1118,
8
9
1
13
803 cmꢀ1; H NMR (300 MHz, CDCl3) δ 7.37ꢀ7.28 (m, 3H), 2.35 (d, 3H, J = 1.5 Hz); C NMR (75
MHz, CDCl3) δ 160.5 (d, JCF = 247 Hz), 132.3 (d, JCF = 6 Hz), 131.3 (d, JCF = 17 Hz), 127.8 (d, JCF = 4
Hz), 118.4 (d, JCF = 26 Hz), 17.7 (d, JCF = 3 Hz), 110.7 (d, JCF = 9 Hz), 14.7 (d, JCF = 3 Hz),; LRMS
(EI) m/z (rel intensity) 135 (M+, 23), 123 (29), 111 (52), 97 (63), 57 (100).
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56
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58
59
60
Biphenyl-4-carbonitrile (2m): Yield 148.9 mg (83%, white solid); mp 83ꢀ84 °C. (1:19 EtOAc/Hexane);
IR (neat): υ max 3404, 3061, 2226, 1931, 1605, 1484, 1396, 769, 697 cmꢀ1; 1H NMR (300 MHz, CDCl3)
δ 7.74ꢀ7.66 (m, 4H), 7.61ꢀ7.57 (m, 2H), 7.52ꢀ7.39 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 145.6, 139.1,
132.6, 129.1, 128.6, 127.7, 127.2, 118.9, 110.8; HRMS (ESIꢀTOF) calcd for C13H10N (M+H)+ 180.0808
found 180.0802.
4-Nitrobenzonitrile (2n):9 Yield 95.2 mg (64%, white solid); mp 145ꢀ146 °C. (1:4 EtOAc/Hexane); IR
1
(neat): υ
3107, 3053, 2233, 1601, 1524, 1489, 1347, 1294, 859, 682 cmꢀ1; H NMR (300 MHz,
max
13
CDCl3) δ 8.40ꢀ8.36 (m, 2H), 7.94ꢀ7.89 (m, 2H); C NMR (75 MHz, CDCl3) δ 150.0, 133.4, 124.2,
118.3, 116.8; LRMS (EI) m/z (rel intensity) 148 (M+, 54), 118 (12), 102 (100), 90 (27).
2,3,4-Trimethoxybenzonitrile (2o): Yield 131.1 mg (68%, white solid); mp 51ꢀ52 °C. (1:49 to 1:9
EtOAc/Hexane); IR (neat): υ max 2945, 2226, 1592, 1491, 1471, 1415, 1298, 1095, 1033, 803, 708 cmꢀ1;
1H NMR (300 MHz, CDCl3) δ 7.29 (d, 1H, J = 9.0 Hz), 6.69 (d, 1H, J = 8.7 Hz), 4.06 (s. 3H), 3.92 (s,
13
3H), 3.87 (s, 3H); C NMR (75 MHz, CDCl3) δ 157.8, 155.6, 141.6, 128.5, 116.3, 107.4, 98.8, 61.5,
60.9, 56.1; HRMS (ESIꢀTOF) calcd for C10H12NO3 (M+H)+ 194.0812 found 194.0814.
3,4,5-Trimethoxybenzonitrile (2p): Yield 171.2 mg (90%, white solid); mp 90ꢀ91 °C. (1:4
EtOAc/Hexane); IR (neat): υ max 3071, 2940, 2225, 1716, 1581, 1501, 1335, 1239, 1128, 996, 736 cmꢀ1;
1H NMR (300 MHz, CDCl3) δ 6.79 (s, 2H), 3.82 (s, 3H), 3.80 (s, 6H); C NMR (75 MHz, CDCl3) δ
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153.4, 142.2, 118.8, 109.3, 106.5, 60.8, 56.2; HRMS (ESIꢀTOF) calcd for C10H11NNaO3 (M+Na)+
216.0631 found 216.0636.
1
2
3
4
5
6
7
8
4-Hydroxy-3,5-dimethoxybenzonitrile (2q): Yield 151.1 mg (85%, orange solid); mp 118ꢀ119 °C. (1:1
EtOAc/Hexane);IR (neat): υ max 3361, 2941, 2224, 1606, 1512, 1455, 1334, 1207, 1109, 852, 736 cmꢀ1;
1H NMR (300 MHz, CDCl3) δ 6.88 (s, 2H), 6.12 (br s, 1H), 3.92 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
147.1, 139.2, 119.2, 109.0, 102.1, 56.5; HRMS (ESIꢀTOF) calcd for C9H10NO3 (M+H)+ 180.0655 found
180.0660.
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10
11
12
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14
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17
18
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20
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23
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59
60
2-Chloro-3,4-dimethoxybenzonitrile (2r): Yield 168.9 mg (85%, white solid); mp 93ꢀ94 °C. (1:4
EtOAc/Hexane); IR (neat): υ max 3015, 2943, 2580, 2227, 1872, 1585, 1484, 1301, 1272, 1039, 1026,
1
927, 807, 696 cmꢀ1; H NMR (300 MHz, CDCl3) δ 7.41 (d, 1H, J = 8.7 Hz), 6.93 (d, 1H, J = 8.7 Hz),
3.97 (s, 3H), 3.89 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 157.5, 146.0, 130.7, 129.6, 116.0, 110.8, 105.3,
60.6, 56.2; HRMS (ESIꢀTOF) calcd for C9H8ClNNaO2 (Clꢀ35) (M+Na)+ 220.0136 found 220.0142.
2-Naphthonitrile (2s): Yield 120.4 mg (81%, yellow solid); mp 60ꢀ61 °C. (1:9 EtOAc/Hexane); IR
(neat): υ max 3059, 2226, 1694, 1627, 1597, 1502, 1366, 1271, 1160, 899, 861, 814, 746 cmꢀ1; 1H NMR
(300 MHz, CDCl3) δ 8.24 (s, 1H), 7.94ꢀ7.88 (m, 3H), 7.68ꢀ7.88 (m, 3H); 13C NMR (75 MHz, CDCl3) δ
134.4, 133.9, 132.0, 129.0, 128.9, 128.2, 127.9, 127.5, 126.1, 119.1, 109.1; HRMS (ESIꢀTOF) calcd for
C11H8N (M+H)+ 154.0651 found 154.0658.
Cinnamonitrile (2u): Yield 122.6 mg (92%, yellow oil); (1:9 EtOAc/Hexane); IR (neat): υ
3054,
max
2217, 1617, 1448, 964, 746, 688 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.44ꢀ7.34 (m, 6H), 5.85 (d, 1H, J
= 16.5 Hz); 13C NMR (75 MHz, CDCl3) δ 150.4, 133.3, 131.0, 128.9, 127.2, 118.0, 96.2; HRMS (ESIꢀ
TOF) calcd for C9H7NNa (M+Na)+ 152.0471 found 152.0475.
(E)-3-(4-Methoxyphenyl)acrylonitrile (2v): Yield 156.7 mg (93%, white solid); mp 58ꢀ59 °C. (1:9
EtOAc/Hexane); IR (neat): υ max 3057, 2936, 2214, 1782, 1615, 1599, 1508, 1250, 1174, 1022, 985, 806
1
cmꢀ1; H NMR (300 MHz, CDCl3) δ 7.40ꢀ7.35 (m, 2H), 7.29 (d, 1H, J = 16.5 Hz), 6.93ꢀ6.88 (m, 2H),
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5.69 (d, 1H, J = 16.5 Hz), 3.83 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.8, 149.8 128.9, 126.1, 118.5,
114.3, 93.1, 55.2; HRMS (ESIꢀTOF) calcd for C10H9NNaO (M+Na)+ 182.0576 found 182.0583.
(E)-3-(4-Hydroxy-3-methoxyphenyl)acrylonitrile (2w): Yield 172.1 mg (97%, yellow solid); mp 107ꢀ
108 °C. (3:7 EtOAc/Hexane); IR (neat): υ max 3386, 3017, 2212, 1775, 1598, 1508, 1457, 1272, 1185,
970, 807 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.29 (d, 1H, J = 16.5 Hz), 7.01ꢀ6.90 (m, 3H), 5.70 (d, 1H,
1
2
3
4
5
6
7
8
9
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32
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35
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
J = 16.5 Hz), 3.92 (s, 3H); C NMR (75 MHz, CDCl3) δ 150.4, 148.6, 146.8, 126.0, 122.3, 118.6,
114.8, 108.6, 93.0, 55.9; HRMS (ESIꢀTOF) calcd for C10H10NO2 (M+H)+ 176.0706 found 176.0707.
6,7-Dimethoxybenzo[d]isoxazole (3o): Yield 7.2 mg (4%, yellow solid); mp 52ꢀ53 °C. (1:49 to 1:9
1
EtOAc/Hexane); IR (neat): υ max 2942, 1619, 1489, 1311, 1281, 1240, 1098, 979, 796 cmꢀ1; H NMR
(300 MHz, CDCl3) δ 8.60 (s, 1H), 7.32 (d, 1H, J = 8.4 Hz), 7.01 (d, 1H, J = 8.7 Hz), 4.24 (s, 3H), 3.97
13
(s, 3H); C NMR (75 MHz, CDCl3) δ 154.4, 151.9, 146.0, 132.9, 117.8, 114.8, 111.2, 60.7, 57.2;
HRMS (ESIꢀTOF) calcd for C9H10NO3 (M+H)+ 180.0655 found 180.0660.
General procedure for the synthesis of benzisoxazoles (Table 2): A solution of aldehyde 4f (152.6
mg, 0.9746, 1.0 equiv) in CH3CN (2.0 mL/mmol) was added TMSN3 (130 ꢀL, 0.9746 mmol, 1.0 equiv)
and ZrCl4 (227.1 mg, 0.9746 mmol, 1.0 equiv) at room temperature. The reaction mixture was stirred
for 20 min and then quenched with saturated sodium bicarbonate (NaHCO3). The resulting solution was
extracted with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4,
filtered and concentrated under reduced pressure to provide the crude product which was purified on
silica gel (3:7 EtOAc/Hexane) to yield the corresponding nitrile product 5f (49.9 mg, 33%) and
benzisoxazole 6f (72.8 mg, 49%) (The reactions of substrates 4bꢀ4d, 4gꢀ4i, and 7d were stirred at room
temperature for overnight and the reactions of substrates 4aꢀ4i, and 7d were quenched with water).
2-Hydroxybenzonitrile (5a):1g Yield 59.3 mg (43%, light yellow solid); mp 90ꢀ91 °C. (1:4
EtOAc/Hexane); IR (neat): υ max 3282, 2953, 2230, 1604, 1455, 1352, 1305, 1233, 1099, 846, 748 cmꢀ
1; 1H NMR (300 MHz, CDCl3) δ 7.51ꢀ7.39 (m, 2H), 7.05 (d, 1H, J = 8.4 Hz), 6.96 (t, 1H, J = 7.5 Hz);
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13C NMR (75 MHz, CDCl3) δ 159.2, 134.9, 133.0, 120.5, 116.6, 116.5, 98.9; LRMS (EI) m/z (rel
intensity) 119 (M+, 92), 97 (33), 91 (100), 81 (43), 69 (58), 57 (46).
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Benzo[d]isoxazole (6a):2c Yield 39.7 mg (29%, light yellow oil); (1:4 EtOAc/Hexane); IR (neat): υ max
3098, 1611, 1512, 1430, 1228, 1175, 934, 839, 744 cmꢀ1; H NMR (300 MHz, CDCl3) δ 8.71 (s, 1H),
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7.73 (d, 1H, J = 7.8 Hz), 7.63ꢀ7.53 (m, 2H), 7.32 (t, 1H, J = 6.9 Hz); C NMR (75 MHz, CDCl3) δ
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162.1, 146.1, 130.0, 123.6, 121.9, 121.2, 109.6.
3,5-Di-tert-Butyl-2-hydroxybenzonitrile (5b): Yield 66.0 mg (28%, light yellow solid); mp 113ꢀ114 °C.
(1:49 to 1:19 EtOAc/Hexane); IR (neat): υ max 3300, 2961, 2232, 1603, 1479, 1363, 1218, 1201, 878 cmꢀ
1; 1H NMR (300 MHz, CDCl3) δ 7.45 (d, 1H, J = 2.4 Hz), 7.23 (d, 1H, J = 2.4 Hz), 5.94 (br s, 3H), 1.34
(s, 9H), 1.21 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 154.8, 143.6, 137.1, 129.8, 126.0, 117.3, 99.5, 35.1,
34.4, 31.2, 29.4; HRMS (ESIꢀTOF) calcd for C15H22NO (M+H)+ 232.1696 found 232.1693.
5,7-Di-tert-butylbenzo[d]isoxazole (6b): Yield 48.7 mg (21%, yellow oil); (1:49 to 1:19
EtOAc/Hexane); IR (neat): υ max 2959, 2871, 1616, 1465, 1364, 1168, 883, 854, 765 cmꢀ1; 1H NMR (300
MHz, CDCl3) δ 8.56 (s, 1H), 7.45 (d, 1H, J = 1.8 Hz), 7.42 (d, 1H, J = 1.5 Hz), 1.45 (s, 9H), 1.30 (s.
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9H); C NMR (75 MHz, CDCl3) δ 159.5, 147.0, 146.3, 133.5, 124.5, 121.8, 115.0, 34.9, 34.6, 31.6,
29.7; HRMS (ESIꢀTOF) calcd for C15H22NO (M+H)+ 232.1696 found 232.1696.
2-Hydroxy-4-methoxybenzonitrile (5c):1d Yield 123.4 mg (77%, white solid); mp 171ꢀ172 °C. (1:4
EtOAc/Hexane); IR (neat): υ max 3218, 2227, 1595, 1435, 1276, 1212, 1104, 830, 673 cmꢀ1; H NMR
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(300 MHz, DMSOꢀd6) δ 7.49 (d, 1H, J = 9.0 Hz), 6.53ꢀ6.50 (m, 2H), 3.76 (s, 3H); C NMR (75 MHz,
DMSOꢀd6) δ 164.0, 161.8, 134.3, 117.4, 106.6, 101.1, 91.3, 55.5. LRMS (EI) m/z (rel intensity) 149
(M+, 100), 119 (12), 106 (38), 91 (30).
6-Methoxybenzo[d]isoxazole (6c):2d Yield 36.0 mg (22%, colorless oil); (1:4 EtOAc/Hexane); IR (neat):
υ max 3091, 2942, 1615, 1491, 1300, 1273, 1114, 946, 822 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 8.58 (s,
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1H), 7.56 (d, 1H, J = 8.7 Hz), 7.04 (s, 1H), 6.93 (dd, 1H, J = 8.7, 2.1 Hz), 3.89 (s, 3H); C NMR (75
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MHz, CDCl3) δ 164.1, 162.2, 145.8, 122.0, 114.7, 114.6, 92.3, 55.7. LRMS (EI) m/z (rel intensity) 149
(M+, 100), 134 (17), 111 (14), 106 (36), 91 (20).
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2d
2-Hydroxy-5-methoxybenzonitrile (5d): Yield 68.0 mg (65%, orange solid); mp 129ꢀ130 °C. (3:7
EtOAc/Hexane); IR (neat): υ max 3292, 2965, 2232, 1599, 1508, 1424, 1202, 1156, 1032, 820 cmꢀ1; H
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NMR (300 MHz, DMSOꢀd6) δ 10.53 (s, 1H), 7.16ꢀ7.09 (m, 2H), 6.94 (d, 1H, J = 9.0 Hz), 3.71 (s, 3H);
13C NMR (75 MHz, DMSOꢀd6) δ 154.4, 151.8, 122.2, 117.3, 116.9, 115.9, 98.5, 55.8. LRMS (EI) m/z
(rel intensity) 149 (M+, 100), 134 (93), 106 (33).
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5-Methoxybenzo[d]isoxazole (6d): Yield 29.1 mg (28%, yellow oil); (3:7 EtOAc/Hexane); IR (neat): υ
1
3100, 2939, 1621, 1515, 1448, 1290, 1209, 1145, 1026, 850, 801, 749 cmꢀ1; H NMR (300 MHz,
max
CDCl3) δ 8.63 (s, 1H), 7.52 (d, 1H, J = 9.3 Hz), 7.19 (dd, 1H, J = 9.0, 2.1 Hz), 7.08 (d, 1H, J = 1.9 Hz),
3.86 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 157.9, 156.4, 146.1, 121.6, 120.7, 110.4, 101.8, 55.8; HRMS
(ESIꢀTOF) calcd for C8H7NO2 (M+H)+ 150.0550 found 150.0554
5-Bromo-2-hydroxybenzonitrile (5e): Yield 70.1 mg (35%, yellow solid); mp 156ꢀ157 °C. (1:4
1
EtOAc/Hexane); IR (neat): υ max 3276, 2926, 2236, 1602, 1491, 1409, 1299, 1121, 822, 760 cmꢀ1; H
NMR (300 MHz, CDCl3) δ 11.42 (br s, 1H), 7.84 (d, 1H, J = 2.7 Hz), 7.64 (dd, 1H, J = 8.7, 2.4 Hz),
6.96 (d, 1H, J = 9.0 Hz); 13C NMR (75 MHz, CDCl3) δ 159.6, 137.5, 135.0, 118.3, 115.6, 109.7, 100.9;
HRMS (ESIꢀTOF) calcd for C7H3BrNO (Brꢀ79) (MꢀH)ꢀ 195.9404 found 195.9404.
5-Bromobenzo[d]isoxazole (6e):2g Yield 106.4 mg (52%, white solid); mp 76ꢀ77 °C. (1:4
EtOAc/Hexane); IR (neat): υ max 3095, 2238, 1901, 1604, 1507, 1420, 1226, 1170, 892, 808, 778, 679
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cmꢀ1; H NMR (300 MHz, CDCl3) δ 8.67 (s, 1H), 7.89 (d, 1H, J = 1.2 Hz), 7.67 (dd, 1H, J = 8.7, 1.8
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Hz), 7.52 (d, 1H, J = 9.0); C NMR (75 MHz, CDCl3) δ 161.1, 145.4, 133.1, 124.4, 123.2, 116.6,
111.2; LRMS (EI) m/z (rel intensity) 198 (M+, 96), 196 (100), 171 (61), 169 (64), 69 (62), 57 (45).
5-Chloro-2-hydroxybenzonitrile (5f): Yield 49.2 mg (33%, brown solid); mp 162ꢀ163 °C. (3:7
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EtOAc/Hexane); IR (neat): υ max 3240, 2240, 1606, 1498, 1412, 1303, 824 cmꢀ1; H NMR (300 MHz,
CDCl3) δ 11.42 (br s, 1H), 7.76 (d, 1H, J = 2.7 Hz), 7.54 (dd, 1H, J = 9.0, 2.7 Hz), 7.02 (d, 1H, J = 9.0
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Hz); C NMR (75 MHz, CDCl3) δ 159.3, 134.7, 132.2, 122.7, 117.9, 115.7, 100.3; HRMS (ESIꢀTOF)
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calcd for C7H3ClNO (Clꢀ35) (MꢀH)ꢀ 151.9909 found 151.9907.
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5-Chlorobenzo[d]isoxazole (6f): Yield 72.3 mg (49%, light yellow solid); mp 59ꢀ60 °C. (3:7
EtOAc/Hexane); IR (neat): υ max 3097, 1739, 1614, 1502, 1423, 1228, 1173, 1116, 807, 700 cmꢀ1; H
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NMR (300 MHz, CDCl3) δ 8.68 (s, 1H), 7.71 (d, 1H, J = 0.9 Hz), 7.58ꢀ7.50 (m, 2H); C NMR (75
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MHz, CDCl3) δ 160.7, 145.6, 130.5, 129.3, 122.5, 121.2, 110.8; HRMS (ESIꢀTOF) calcd for C7H5ClNO
(Clꢀ35) (M+H)+ 154.0054 found 154.0048.
2-Hydroxy-5-nitrobenzonitrile (5g):1d Yield 18.2 mg (11%, yellow solid); mp 171ꢀ172 °C. (3:7
EtOAc/Hexane); IR (neat): υ max 3084, 2235, 1591, 1532, 1489, 1341, 1299, 1134, 1079, 910, 834, 748
1
cmꢀ1; H NMR (300 MHz, CDCl3) δ 8.50 (d, 1H, J = 3.0 Hz), 8.25 (dd, 1H, J = 9.6, 3.0 Hz), 6.96 (d,
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1H, J = 9.3 Hz); C NMR (75 MHz, CDCl3) δ 168.3, 137.1, 130.6, 130.0, 117.7, 116.0, 99.8; LRMS
(EI) m/z (rel intensity) 164 (M+, 24), 149 (100), 111 (34), 85 (48), 69 (57) 57 (76).
5-Nitrobenzo[d]isoxazole (6g):17 Yield 99.7 mg (62%, light yellow solid); mp 122ꢀ123 °C. (3:7
EtOAc/Hexane); IR (neat): υ max 3108, 1619, 1520, 1350, 1267, 1073, 912, 827, 688 cmꢀ1; 1H NMR (300
MHz, CDCl3) δ 8.87 (s, 1H), 8.66 (d, 1H, J = 2.1 Hz), 8.42 (dd, 1H, J = 9.3, 2.4 Hz), 7.68 (d, 1H, J =
9.3 Hz); 13C NMR (75 MHz, CDCl3) δ 164.2, 147.0, 144.6, 125.5, 121.8, 119.2, 110.4; LRMS (EI) m/z
(rel intensity) 164 (M+, 32), 149 (100), 134 (24), 71 (47).
2-Hydroxy-1-naphthonitrile (5h): Yield 28.3 mg (15%, light yellow solid); mp 148ꢀ149 °C. (1:9 to 1:4
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EtOAc/Hexane); IR (neat): υ max 3245, 2925, 2224, 1626, 1515, 1438, 1286, 817, 748 cmꢀ1; H NMR
(300 MHz, CDCl3) δ 8.03 (d, 1H, J = 8.4 Hz), 7.95 (d, 1H, J = 9.0 Hz), 7.82 (d, 1H, J = 8.1 Hz), 7.64
(ddd, 1H, J = 8.4, 7.2, 1.2 Hz), 7.46 (ddd, 1H, J = 8.1, 7.2, 1.2 Hz), 7.18 (d, 1H, J = 9.3 Hz); 13C NMR
(75 MHz, CDCl3) δ 159.4, 135.3, 132.8, 129.1, 128.6, 128.1, 125.2, 124.0, 117.3, 115.6, 92.8; HRMS
(ESIꢀTOF) calcd for C11H7NNaO (M+Na)+ 192.0420 found 192.0415
Naphtho[1,2-d]isoxazole (6h): Yield 119.3 mg (65%, light yellow solid); mp 74ꢀ75 °C. (1:9 to 1:4
EtOAc/Hexane); IR (neat): υ max 3098, 3068, 1632, 1581, 1532, 1486, 1254, 1170, 930, 812, 753 cmꢀ1;
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1H NMR (300 MHz, CDCl3) δ 9.11 (s, 1H), 8.16 (d, 1H, J = 8.4 Hz), 8.01ꢀ7.96 (m, 2H), 7.75ꢀ7.67 (m,
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2H), 7.60ꢀ7.55 (m, 1H); C NMR (75 MHz, CDCl3) δ 162.1, 144.8, 131.6, 130.3, 128.9, 128.1, 126.6,
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125.5, 123.1, 116.3, 110.1; HRMS (ESIꢀTOF) calcd for C11H8NO (M+H)+ 170.0600 found 170.0605.
6-Bromo-2-hydroxy-3-methoxybenzonitrile (5i): Yield 116.1 mg (49%, brown solid); mp 123ꢀ124 °C.
(1:19 EtOAc/Hexane); IR (neat): υ max 3276, 2938, 2240, 1595, 1488, 1438, 1279, 1257, 1068, 881, 804
cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.12 (d, 1H, J = 8.7 Hz), 6.90 (d, 1H, J = 8.7 Hz), 3.94 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 150.6, 145.9, 123.7, 115.2, 114.6, 114.2, 102.4, 56.5; HRMS (ESIꢀTOF)
calcd for C8H6BrNNaO2 (Brꢀ79) (M+Na)+ 249.9474 found 249.9482.
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4-Bromo-7-methoxybenzo[d]isoxazole (6i): Yield 82.5 mg (35%, brown solid); mp 123ꢀ124 °C. (1:19
EtOAc/Hexane); IR (neat): υ
3094, 3004, 2848, 2324, 1860, 1719, 1606, 1460, 1260, 1177, 981,
max
816. 690 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 8.61 (s, 1H), 7.28ꢀ7.26 (d, 1H, J = 8.4 Hz), 6.79 (d, 1H, J
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= 8.1 Hz), 3.96 (s, 3H); C NMR (75 MHz, CDCl3) δ 153.1, 146.3, 143.9, 127.2, 124.2, 112.2, 103.7,
56.5; HRMS (ESIꢀTOF) calcd for C8H7BrNO2 (Brꢀ79) (M+H)+ 227.9655 found 227.9661.
General procedure for the synthesis of benzoxazoles (8aꢀ8p) and benzisoxazoles (6qꢀ6r, Table 3):
A solution of ketones 7d (133.4 mg, 0.6203 mmol, 1.0 equiv) in dry DCM (2 mL, 3.0 mL/mmol) was
added TMSN3 (130 ꢀL, 0.9305 mmol, 1.5 equiv) and TfOH (80 ꢀL, 0.9305 mmol, 1.5 equiv) at room
temperature and stirred for overnight. Then, the reaction mixture was quenched with saturated sodium
bicarbonate (NaHCO3). The resulting solution was extracted with EtOAc, and the combined organic
layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to
provide the crude product which was purified on silica gel (1:9 to 1:1 EtOAc/hexane) to yield the
corresponding product 8d (111.6 mg, 85%) and 9d (14.9 mg, 11%). (The reactions of substrates 7g, 7i,
7k, and 7q were quenched with water).
2-Methylbenzo[d]oxazole (8a): Yield 102.0 mg (77%%, colorless oil); (1:9 to 1:1 EtOAc/hexane); IR
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(neat): νmax 2919, 1241, 1059 cmꢀ1. H NMR (300 MHz, CDCl3) δ 7.68ꢀ7.62 (m, 1H), 7.48ꢀ7.43 (m,
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1H), 7.30ꢀ7.24 (m, 2H), 2.63 (s, 3H); C NMR (75 MHz, CDCl3) δ 163.7, 150.9, 141.3, 124.4, 124.0,
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119.3, 110.1, 14.4. ESIꢀHRMS calcd for C8H8NO (M+H)+ 136.0600, found 134.0605.
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N-Methylbenzo[d]oxazol-2-amine (9a): Yield 11.1 mg (8%, colorless crystal); mp 96ꢀ97 ºC. (1:9 to 1:1
EtOAc/hexane); IR (neat): νmax 3223, 1646, 1584, 1459, 1241, 740 cmꢀ1. 1H NMR (300 MHz, CDCl3) δ
7.37 (dd, 1H, J = 7.8, 0.6 Hz), 7.24 (d, 1H, J = 7.8 Hz), 7.16 (td, 1H, J = 7.8, 1.2 Hz), 7.03 (td, 1H, J =
7.8, 1.2 Hz), 3.12 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.8, 148.5, 142.8, 123.9, 120.8, 116.2, 108.7,
29.4. ESIꢀHRMS calcd for C8H9N2O (M+H)+ 149.0709, found 149.0712.
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5-Fluoro-2-methylbenzo[d]oxazole (8b): Yield 120.8 mg (83%, colorless oil); (1:9 to 1:1
EtOAc/hexane); IR (neat): νmax 2920, 1457, 1261, 1028, 801 cmꢀ1. 1H NMR (300 MHz, CDCl3) δ 7.39ꢀ
7.30 (m, 2H), 7.00 (td, 1H, J = 9.3, 2.7 Hz), 2.62 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.6, 159.7 (d,
JCF = 238 Hz), 147.1 (d, JCF = 1.0 Hz), 142.1 (d, JCF = 13 Hz), 111.8 (d, JCF = 26 Hz), 110.3 (d, JCF = 10
Hz), 105.8 (d, JCF = 26 Hz), 14.5. ESIꢀHRMS calcd for C8H7FNO (M+H)+ 152.0506, found 152.0508.
5-Fluoro-N-methylbenzo[d]oxazol-2-amine (9b): Yield 20.4 mg (13%, white solid); mp 117ꢀ118 ºC.
(1:9 to 1:1 EtOAc/hexane); IR (neat): νmax 3174, 2924, 1682, 1587, 1416, 1130, 833 cmꢀ1. 1H NMR (300
MHz, CDCl3) δ 7.15 (dd, 1H, J = 8.7, 4.5 Hz), 7.05 (dd, 1H, J = 8.7, 2.4 Hz), 6.73 (td, 1H, J = 9.6, 2.7
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Hz), 3.12 (s, 3H); C NMR (75 MHz, CDCl3) δ 163.9, 160.1 (d, JCF = 237 Hz), 144.7, 143.5 (d, JCF =
13.0 Hz), 108.7 (d, JCF = 10 Hz), 107.4 (d, JCF = 26 Hz), 103.4 (d, JCF = 27 Hz), 29.4. ESIꢀHRMS calcd
for C8H8FN2O (M+H)+ 167.0615, found 167.0622.
5-Chloro-2-methylbenzo[d]oxazole (8c): Yield 129.5 mg (87%, white solid); mp 51ꢀ52 ºC. (1:9 to 1:1
EtOAc/hexane); IR (neat): νmax 2925, 1658, 1457, 1260, 1029 cmꢀ1. 1H NMR (300 MHz, CDCl3) δ 7.62
(d, 1H, J = 2.1 Hz), 7.38 (d, 1H, J = 8.7 Hz), 7.26 (dd, 1H, J = 8.7, 2.1 Hz), 2.64 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 165.3, 149.5, 142.5, 129.6, 124.7, 119.4, 110.9, 14.5. ESIꢀHRMS calcd for C8H7ClNO
(Clꢀ35) (M+H)+ 168.0211, found 168.0208.
5-Chloro-N-methylbenzo[d]oxazol-2-amine (9c): Yield 20.0 mg (12%, white solid); mp 132ꢀ133 ºC.
(1:9 to 1:1 EtOAc/hexane); IR (neat): νmax 3062, 2923, 1686, 1578, 1463, 1255, 799 cmꢀ1. 1H NMR (300
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MHz, CDCl3) δ 7.31 (d, 1H, J = 1.8 Hz), 7.14 (d, 1H, J = 8.4 Hz), 6.99 (dd, 1H, J = 8.4, 1.8 Hz), 3.12
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(s, 3H); C NMR (75 MHz, CDCl3) δ 163.5, 147.1, 143.8, 129.4, 120.8, 116.2, 109.3, 29.4. ESIꢀ
HRMS calcd for C8H8ClN2O (Clꢀ35) (M+H)+ 183.0320, found 183.0321.
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5-Bromo-2-methylbenzo[d]oxazole (8d): Yield 111.6 mg (85%, white solid); mp 57ꢀ58 ºC. (1:9 to 1:1
EtOAc/hexane); IR (neat): νmax 2921, 1567, 1449, 1258, 900, 800 cmꢀ1. 1H NMR (300 MHz, CDCl3) δ
7.77 (d, 1H, J = 1.8 Hz), 7.39 (dd, 1H, J = 8.7, 2.1 Hz), 7.32 (d, 1H, J = 8.7 Hz), 2.63 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 165.0, 149.8, 143.0, 127.4, 122.3, 116.7, 111.3, 14.4. ESIꢀHRMS calcd for
C8H7BrNO (Brꢀ79) (M+H)+ 211.9706, found 211.9700.
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5-Bromo-N-methylbenzo[d]oxazol-2-amine (9d): Yield 14.9 mg (11%, yellow solid); mp 139ꢀ140 ºC.
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(1:9 to 1:1 EtOAc/hexane); IR (neat): νmax 3149, 2948, 1684, 1651, 1581, 1299, 1246, 799 cmꢀ1. H
NMR (300 MHz, CDCl3) δ 7.46 (d, 1H, J = 1.8 Hz), 7.14 (dd, 1H, J = 8.7, 1.8 Hz), 7.10 (d, 1H, J = 8.4
13
Hz), 5.71 (br s, 1H), 3.12 (s, 3H); C NMR (75 MHz, CDCl3) δ 163.3, 147.5, 144.3, 123.5, 119.1,
116.7, 109.9, 29.4. ESIꢀHRMS calcd for C8H8BrN2O (M+H)+ 226.9815, found 226.9819.
2-Methyl-5-nitrobenzo[d]oxazole (8e): Yield 129.7 mg (83%, bright yellow solid); mp 154ꢀ155 ºC. (1:4
to 7:3 EtOAc/hexane); IR (neat): νmax 1616, 1518, 1347, 829 cmꢀ1. 1H NMR (300 MHz, CDCl3) δ 8.51
(d, 1H, J = 2.1 Hz), 8.26 (dd, 1H, J = 9.0, 2.4 Hz), 7.59 (d, 1H, J = 9.0 Hz), 2.73 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 167.0, 154.4, 144.9, 141.8, 120.5, 115.6, 110.3, 14.5. ESIꢀHRMS calcd for C8H7N2O3
(M+H)+ 179.0451, found 179.0455.
N-Methyl-5-nitrobenzo[d]oxazol-2-amine (9e): Yield 18.9 mg (12%, yellow solid); mp 232ꢀ233 ºC.
(1:4 to 7:3 EtOAc/hexane); IR (neat): νmax 3086, 2921, 1700, 1517, 1343, 1261, 736 cmꢀ1. 1H NMR (300
MHz, DMSOꢀd6) δ 8.32 (br q, 1H, J = 4.5 Hz), 8.00 (s, 1H), 7.93 (dd, 1H, J = 8.7, 0.6 Hz), 7.55 (d, 1H,
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J = 8.7 Hz), 2.93 (d, 3H, J = 4.8 Hz); C NMR (75 MHz, DMSOꢀd6) δ 164.8, 152.5, 144.38, 144.35,
116.7, 110.1, 108.7, 28.8. ESIꢀHRMS calcd for C8H8N3O3 (M+H)+ 194.0560, found 194.0561.
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5-Methoxy-2-methylbenzo[d]oxazole (8f): Yield 112.0 mg (78%, brown oil); (1:4 to 1:1
EtOAc/hexane); IR (neat): νmax 2932, 1577, 1482, 1172, 1151, 846 cmꢀ1. 1H NMR (300 MHz, CDCl3) δ
7.32 (d, 1H, J = 8.7 Hz), 7.14 (d, 1H, J = 2.4 Hz), 7.87 (dd, 1H, J = 9.0, 2.7 Hz), 3.82 (s, 3H), 2.59 (s,
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3H); C NMR (75 MHz, CDCl3) δ 164.5, 156.9, 145.4, 142.1, 112.5, 110.1, 102.5, 55.7, 14.4. ESIꢀ
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HRMS calcd for C9H10NO2 (M+H)+ 164.0706, found 164.0711.
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5-Methoxy-N-methylbenzo[d]oxazol-2-amine (9f): Yield 15.0 mg (10%, brown solid); mp 87ꢀ88 ºC. (1:4
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to 1:1 EtOAc/hexane); IR (neat): νmax 3227, 2942, 1652, 1587, 1196, 1162, 1062 cmꢀ1. H NMR (300
MHz, CDCl3) δ 7.11 (d, 1H, J = 8.7 Hz), 6.93 (d, 1H, J = 2.4 Hz), 6.59 (dd, 1H, J = 8.7, 2.7 Hz), 3.81
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(s, 3H), 3.11 (s, 3H); C NMR (75 MHz, CDCl3) δ 163.4, 157.0, 143.5, 143.0, 108.6, 107.2, 101.4,
55.9, 29.4. ESIꢀHRMS calcd for C9H11N2O2 (M+H)+ 179.0815, found 179.0814.
2-Methylbenzo[d]oxazol-5-ol (8g): Yield 117.0 mg (77%, brown solid); mp 162ꢀ163 °C. (1:4 to 7:3
EtOAc/hexane); IR (neat): υ max 3136, 2926, 2344, 1612, 1577, 1474, 1282, 1153, 941, 844, 733 cmꢀ1;
1H NMR (300 MHz, CDCl3) δ 7.30 (d, 1H, J = 8.7 Hz), 7.18 (d, 1H, J = 2.4 Hz), 6.86 (dd, 1H, J = 8.7,
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2.4 Hz), 4.18 (br s, 1H), 2.63 (s, 3H); C NMR (75 MHz, CDCl3) δ 165.1, 153.6, 145.3, 141.2, 113.4,
110.5, 104.9, 14.5; HRMS (ESIꢀTOF) calcd for C8H8NO2 (M+H)+ 150.0550 found 150.0547.
6-Methoxy-2-methylbenzo[d]oxazole (8h): Yield 141.4 mg (90%, brown oil); (1:4 to 1:1
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EtOAc/hexane); IR (neat): νmax 2932, 1618, 1488, 1297, 1139, 822 cmꢀ1. H NMR (300 MHz, CDCl3)
δ 7.50 (d, 1H, J = 8.7 Hz), 6.99 (d, 1H, J = 2.4 Hz), 6.88 (dd, 1H, J = 8.7, 2.4 Hz), 3.83 (s, 3H), 2.59 (s,
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3H); C NMR (75 MHz, CDCl3) δ 162.7, 157.6, 151.6, 135.0, 119.1, 111.9, 95.2, 55.8, 14.3. ESIꢀ
HRMS calcd for C9H10NO2 (M+H)+ 164.0706, found 164.0707.
6-Methoxy-N-methylbenzo[d]oxazol-2-amine (9h): Yield 14.5 mg (8%, reddish solid); mp 87ꢀ88 ºC.
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(1:4 to 1:1 EtOAc/hexane); IR (neat): νmax 3178, 1689, 1486, 1135, 1027, 815 cmꢀ1. H NMR (300
MHz, CDCl3) δ 7.25 (d, 1H, J = 8.7 Hz), 6.87 (d, 1H, J = 2.4 Hz), 6.76 (dd, 1H, J = 8.4, 2.4 Hz), 5.14
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(br s, 1H), 3.81 (s, 3H), 3.10 (s, 3H); C NMR (75 MHz, CDCl3) δ 162.3, 155.1, 149.1, 136.4, 115.9,
110.0, 95.9, 56.0, 29.5. ESIꢀHRMS calcd for C9H11N2O2 (M+H)+ 179.0815, found 179.0815.
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2-Methylbenzo[d]oxazol-6-ol (8i): Yield 164.2 mg (89%, brown solid); mp 192ꢀ193 ºC. (1:4 to 7:3
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EtOAc/hexane); IR (neat): νmax 3092, 1625, 1486, 1299, 1232, 1138, 828 cmꢀ1. H NMR (300 MHz,
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CDCl3) δ 7.39 (d, 1H, J = 8.7 Hz), 6.96 (d, 1H, J = 2.1 Hz), 6.77 (dd, 1H, J = 8.4, 2.1 Hz), 3.53 (br s,
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1H), 2.50 (s, 3H); C NMR (75 MHz, CDCl3) δ 162.3, 155.7, 151.7, 134.0, 119.3, 112.9, 97.4, 14.3.
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ESIꢀHRMS calcd for C8H8NO2 (M+H)+ 150.0550, found 150.0547.
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4-Ethoxy-2-methylbenzo[d]oxazole (8j): Yield 58.9 mg (49%, white solid); mp 160ꢀ161 ºC. (1:4 to 1:1
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EtOAc/hexane); IR (neat): νmax 2931, 1683, 1442, 1279, 1090 cmꢀ1. H NMR (300 MHz, CDCl3) δ 7.18
(t, 1H, J = 8.1 Hz), 7.06 (d, 1H, J = 8.1 Hz), 7.74 (d, 1H, J = 8.1 Hz), 4.27 (q, 2H, J = 7.2 Hz), 2.62 (s,
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3H), 1.51 (t, 3H, J = 6.9 Hz); C NMR (75 MHz, CDCl3) δ 162.2, 152.3, 150.3, 130.8, 124.9, 106.6,
102.7, 64.4, 14.7. ESIꢀHRMS calcd for C10H12NO2 (M+H)+ 178.0863, found 178.0869.
4-Ethoxy-N-methylbenzo[d]oxazol-2-amine (9j): Yield 61.7 mg (48%, colorless crystal); mp 161ꢀ163
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ºC. (1:4 to 1:1 EtOAc/hexane); IR (neat): νmax 3043, 2967, 1679, 1070, 718 cmꢀ1. H NMR (300 MHz,
CDCl3) δ 6.96ꢀ6.88 (m, 2H), 6.70 (dd, 1H, J = 7.2, 1.8 Hz), 6.40 (br s, 1H), 4.22 (q, 2H, J = 6.9 Hz),
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3.13 (s, 3H), 1.47 (t, 3H, J = 7.2 Hz); C NMR (75 MHz, CDCl3) δ 162.2, 149.6, 148.1, 131.8, 120.7,
107.2, 102.0, 64.2, 29.3, 14.8, 14.2. ESIꢀHRMS calcd for C10H13N2O2 (M+H)+ 193.0972, found
193.0967.
1H NMR (300 MHz, DMSOꢀd6) δ 7.62 (q, 1H, J = 4.8 Hz), 6.95 (dd, 1H, J = 7.8, 0.9 Hz), 6.88 (t, 1H, J
= 7.8 Hz), 6.72 (dd, 1H, J = 8.1, 1.2 Hz), 4.19 (q, 2H, J = 6.9 Hz), 2.88 (d, 3H, J = 4.8 Hz), 1.35 (t, 3H,
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J = 6.9 Hz); C NMR (75 MHz, DMSOꢀd6) δ 162.3, 149.8, 147.9, 132.4, 120.9, 108.8, 102.3, 64.4,
29.3, 15.3.
2-Methylbenzo[d]oxazol-4-ol (8k): Yield 77.5 mg (50%, white solid); mp 140ꢀ141 ºC. (1:4 to 7:3
EtOAc/hexane); IR (neat): νmax 3104, 1610, 1243, 1186, 732 cmꢀ1. 1H NMR (300 MHz, CDCl3) δ 7.21
(t, 1H, J = 8.1 Hz), 7.02 (dd, 1H, J = 8.1, 0.6 Hz), 6.89 (dd, 1H, J = 8.1, 0.9 Hz), 2.70 (s, 3H); 13C NMR
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(75 MHz, CDCl3) δ 163.5, 152.0, 148.2, 128.8, 125.8, 111.2, 101.7, 14.0. ESIꢀHRMS calcd for
C8H8NO2 (M+H)+ 150.0550, found 150.0547.
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2-(Methylamino)benzo[d]oxazol-4-ol (9k): Yield 41.7 mg (25%, brown solid); mp 117ꢀ118 ºC. (1:4 to
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7:3 EtOAc/hexane); IR (neat): νmax 3387, 2945, 1644, 1247, 1034, 736 cmꢀ1. H NMR (300 MHz,
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CDCl3) δ 6.93 (app t, 1H, J = 8.1 Hz), 6.83 (dd, 1H, J = 7.8, 0.9 Hz), 6.77 (dd, 1H, J = 8.1, 0.9 Hz),
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3.06 (s, 3H); C NMR (75 MHz, CDCl3) δ 161.8, 149.3, 145.7, 129.4, 121.8, 111.6, 101.1, 29.2. ESIꢀ
HRMS calcd for C8H9N2O2 (M+H)+ 165.0659, found 165.0659.
5ꢀBromoꢀ6ꢀmethoxyꢀ2ꢀmethylbenzo[d]oxazole (8l): Yield 174.2 mg (88%, colorless crystal); mp 147ꢀ
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148 ºC. (1:4 to 7:3 EtOAc/hexane); IR (neat): νmax 2951, 1610, 1469, 1297, 1037, 877 cmꢀ1. H NMR
(300 MHz, CDCl3) δ 7.79 (s, 1H), 7.00 (s, 1H), 3.91 (s, 1H), 2.59 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
163.4, 153.4, 150.7, 135.5, 122.9, 107.5, 94.4, 56.6, 14.3. ESIꢀHRMS calcd for C9H9BrNO2 (Brꢀ79)
(M+H)+ 241.9811, found 241.9810.
5-Bromo-6-methoxy-N-methylbenzo[d]oxazol-2-amine (9l): Yield 15.7 mg (7%, reddish solid); mp 157ꢀ
1
158 ºC. (1:4 to 7:3 EtOAc/hexane); IR (neat): νmax 3151, 2961, 1646, 1469, 1297, 1130, 816 cmꢀ1. H
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NMR (300 MHz, CDCl3) δ 7.55 (m, 1H), 6.94 (s, 1H), 5.19 (br s, 1H), 3.90 (s, 3H), 3.12 (s, 3H); C
NMR (75 MHz, CDCl3) δ 162.6, 151.1, 148.2, 136.9, 120.0, 106.8, 95.1, 57.1, 29.6. ESIꢀHRMS calcd
for C9H10BrN2O2 (M+H)+ 256.9920, found 256.9925.
5,7-Dichloro-2-methylbenzo[d]oxazole (8m): Yield 131.1 mg (89%, white solid); mp 110ꢀ111 ºC. (1:4
to 1:1 EtOAc/hexane); IR (neat): νmax 1609, 1574, 1399, 1162, 789 cmꢀ1. 1H NMR (300 MHz, CDCl3)
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δ 7.52 (d, 1H, J = 1.8 Hz), 7.29 (d, 1H, J = 1.8 Hz), 2.67 (s, 3H); C NMR (75 MHz, CDCl3) δ 165.6,
146.3, 143.2, 129.9, 124.9, 118.1, 115.9, 14.5. ESIꢀHRMS calcd for C8H6Cl2NO (M+H)+ 201.9821,
found 201.9816.
5,7-Dichloro-N-methylbenzo[d]oxazol-2-amine (9m): Yield 10.4 mg (7%, colorless crystal); mp 207ꢀ
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208 ºC. (1:4 to 1:1 EtOAc/hexane); IR (neat): νmax 3140, 2949, 1693, 1651, 1577, 1410, 998 cmꢀ1. H
NMR (300 MHz, CDCl3) δ 7.25 (d, 1H, J = 1.8 Hz), 7.07 (d, 1H, J = 1.8 Hz), 5.86 (br s, 1H), 3.17 (s,
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3H); C NMR (75 MHz, CDCl3) δ 162.8, 143.5, 143.4, 130.1, 121.6, 114.8, 114.6, 29.6. ESIꢀHRMS
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calcd for C8H7Cl2N2O (M+H)+ 216.9930, found 216.9936.
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4,6-Dimethoxy-2-methylbenzo[d]oxazole (8n): Yield 73.1 mg (49%, colorless crystal); mp 72ꢀ73 ºC.
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(1:4 to 7:3 EtOAc/hexane); IR (neat): νmax 1619, 1500, 1143, 1103, 848 cmꢀ1. H NMR (300 MHz,
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CDCl3) δ 6.59 (d, 1H, J = 2.1 Hz), 6.37 (d, 1H, J = 2.1 Hz), 3.96 (s, 3H), 3.81 (s, 3H), 2.56 (s, 3H); 13C
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NMR (75 MHz, CDCl3) δ 161.0, 158.4, 152.6, 150.7, 124.8, 95.5, 87.1, 55.9, 55.6, 14.0. ESIꢀHRMS
calcd for C10H12NO3 (M+H)+ 194.0812, found 194.0814.
4,6-Dimethoxy-N-methylbenzo[d]oxazol-2-amine (9n): Yield 11.5 mg (7%, white solid); mp 162ꢀ163
ºC. (1:4 to 7:3 EtOAc/hexane); IR (neat): νmax 3170, 2923, 1683, 1101, 823 cmꢀ1. 1H NMR (300 MHz,
DMSOꢀd6) δ 7.44 (br q, 1H, J = 4.5 Hz), 6.66 (d, 1H, J = 2.1 Hz), 6.35 (d, 1H, J = 2.1 Hz), 3.86 (s,
3H), 3.72 (s, 3H), 2.84 (d, 3H, J = 4.8 Hz); 13C NMR (75 MHz, DMSOꢀd6) δ 161.7, 155.4, 149.9, 148.6,
125.8, 95.9, 88.5, 56.3, 56.1, 29.3. ESIꢀHRMS calcd for C10H13N2O3 (M+H)+ 209.0921, found
209.0914.
2-Butylbenzo[d]oxazole (8o): Yield 122.8 mg (79%, brown oil); (1:4 to 1:1 EtOAc/hexane); IR (neat): υ
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max 3749, 2960, 1615, 1572, 1456, 1242 1153, 762, 744 cmꢀ1; H NMR (300 MHz, CDCl3) δ 7.70ꢀ7.64
(m, 1H), 7.50ꢀ7.44 (m, 1H), 7.32ꢀ7.25 (m, 2H), 2.93 (t, 2H, J = 7.8 Hz), 1.87 (quin, 2H, J = 7.5 Hz),
1.46 (sex, 2H, J = 7.5 Hz), 0.97 (t, 3H, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 167.3, 150.7, 141.3,
124.3, 124.0, 119.4, 110.2, 28.8, 28.3, 22.2, 13.6; HRMS (ESIꢀTOF) calcd for C11H14NO (M+H)+
176.1070 found 176.1077.
3-Butyl-4H-benzo[e][1,2,4]oxadiazine (9o): Yield 27.2 mg (16%, light yellow solid); mp 86ꢀ87 °C. (1:4
to 1:1 EtOAc/hexane); IR (neat): υ max 3407, 3315, 3158, 3050, 2952, 2869, 1910, 1671, 1651, 1585,
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1462, 1245, 1186, 1007, 943, 733 cmꢀ1; H NMR (300 MHz, CDCl3) δ 7.34 (dd, 1H, J = 7.8, 0.6 Hz),
7.24 (d, 1H, J = 7.8 Hz), 7.15 (td, 1H, J = 7.5, 1.2 Hz), 7.01 (td, 1H, J = 7.5, 1.2 Hz), 5.65 (br s, 1H),
3.48 (t, 2H, J = 7.2 Hz), 1.67 (sep, 2H, J = 7.2 Hz), 1.42 (sep, 2H, J = 7.5 Hz), 0.96 (t, 3H, J = 7.5 Hz);
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13C NMR (75 MHz, CDCl3) δ 162.3, 148.4, 142.9, 123.8, 120.6, 116.0, 108.6, 42.8, 31.8, 19.9, 13.7;
HRMS (ESIꢀTOF) calcd for C11H15N2O (M+H)+ 191.1179 found 191.1181.
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2-Phenylbenzo[d]oxazole (8p): Yield 64.3 mg (42%, white solid); mp 95ꢀ96 °C. (1:4 to 1:1
EtOAc/hexane); IR (neat): υ max 3061, 1618, 1552, 1448, 1373, 1024, 924, 759, 744, 688 cmꢀ1; 1H NMR
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(300 MHz, CDCl3) δ 8.29ꢀ8.24 (m, 2H), 7.81ꢀ7.75 (m,1H), 7.59ꢀ7.50 (m, 4H), 7.38ꢀ7.32 (m, 2H); C
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NMR (75 MHz, CDCl3) δ 163.0, 150.7, 142.0, 131.5, 128.9, 127.6, 127.1, 125.1, 124.6, 120.0, 110.6;
HRMS (ESIꢀTOF) calcd for C13H10NO (M+H)+ 196.0757 found 196.0753.
3-Phenyl-4H-benzo[e][1,2,4]oxadiazine (9p): Yield 66.0 mg (40%, white solid); mp 170ꢀ171 °C. (1:4
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to 1:1 EtOAc/hexane); IR (neat): υ max 3049, 1666, 1645, 1576, 1497, 1232, 751, 738 cmꢀ1; H NMR
(300 MHz, CDCl3) δ 7.61 (d, 2H, J = 7.8 Hz), 7.49 (d, 1H, J = 7.8 Hz), 7.43ꢀ7.35 (m, 3H), 7.27ꢀ7.22
(m, 1H), 7.16ꢀ7.10 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 158.8, 147.9, 141.8, 137.9, 129.3, 124.4,
123.4, 121.8, 118.7, 116.8, 109.2; HRMS (ESIꢀTOF) calcd for C13H11N2O (M+H)+ 211.0866 found
211.0868.
2-Hydroxy-N-phenylbenzamide (10p): Yield 8.8 mg (5%, light yellow solid); mp 118ꢀ119 °C. (1:4 to
1:1 EtOAc/hexane); IR (neat): υ max 2984, 2935, 1738, 1652 1446, 1373, 1235, 1044, 847, 757 cmꢀ1; 1H
NMR (600 MHz, CDCl3) δ 11.96 (s, 1H), 7.92 (br s, 1H), 7.59ꢀ7.58 (m. 2H), 7.53 (dd, 1H, J = 8.0, 1.4
Hz), 7.46 (ddd, 1H, J = 8.5, 7.3, 1.4 Hz), 7.42ꢀ7.40 (m, 2H), 7.21 (t, 1H, J = 7.4 Hz), 7.04 (dd, 1H, J =
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8.4, 0.9 Hz), 6.94ꢀ6.92 (m, 1H); C NMR (125 MHz, CDCl3) δ 168.4, 162.0, 136.7, 134.6, 129.2,
125.4, 125.3, 121.2, 119.0, 118.9, 114.6; HRMS (ESIꢀTOF) calcd for C13H12NO2 (M+H)+ 214.0862
found 214.0853.
4,5-Dihydro-3H-naphtho[1,8-cd]isoxazol-6-ol (6q): Yield 45.8 mg (32%, yellow crystal); mp 155ꢀ
1
156°C. (1:4 to 7:3 EtOAc/hexane); IR (neat): υ
3219, 2956, 1622, 1535, 1282, 985, 788 cmꢀ1; H
max
NMR (300 MHz, DMSOꢀd6) δ 9.36 (s, 1H), 7.22 (d, 1H, J = 8.4 Hz), 7.05 (d, 1H, J = 8.7 Hz), 2.94 (t,
2H, J = 6.3 Hz), 2.74 (t, 2H, J = 5.7 Hz), 2.01 (quin, 2H, J = 6.3 Hz); 13C NMR (75 MHz, DMSOꢀd6) δ
30
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