Reactions between nitrile oxides and carbenium ions: Synthesis of benzoxazines, oximes, and amides through intramolecular ortho or ipso attack

Article abstract of DOI:10.1002/1099-0690(200207)2002:14<2411::AID-EJOC2411>3.0.CO;2-N

Reactions between nitrile oxides and benzylic carbocations are described. Different results were obtained when the carbocations were generated from the corresponding chlorides with different Lewis acids, with addition products such as benzoxazines, oximes, and amides being produced. Primary, secondary, and tertiary carbocations showed different reactivities. The product ratios strongly depended on the substituents on the aromatic ring of the benzylic carbocations. Evidence for the proposed mechanism is reported. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200207)2002:14<2411::AID-EJOC2411>3.0.CO;2-N

FULL PAPER
Reactions between Nitrile Oxides and Carbenium Ions: Synthesis of
Benzoxazines, Oximes, and Amides through Intramolecular ortho or ipso
Attack
Sergio Auricchio,*[a] Caterina Magnani,[a] and Ada M. Truscello[a]
Keywords: Benzoxazines / Carbocations / Cycloadditions / Nitrile oxides
Reactions between nitrile oxides and benzylic carbocations
ivities. The product ratios strongly depended on the substitu-
are described. Different results were obtained when the car- ents on the aromatic ring of the benzylic carbocations. Evid-
bocations were generated from the corresponding chlorides
with different Lewis acids, with addition products such as
benzoxazines, oximes, and amides being produced. Primary,
ence for the proposed mechanism is reported.
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
secondary, and tertiary carbocations showed different react- 2002)
Introduction
Results
We started our study with a stable nitrile oxide Ϫ 2,6-
Nitrile oxides are widely used as dipoles in cycloaddition
reactions for the synthesis of various heterocyclic rings.[1]
As the carbon atom of the dipole is quite electrophilic,
many 1,3-addition reactions have also been performed.[2,3]
Nitrile oxides can react with various nucleophiles, such as
amines, alkoxides, azides, and alcohols,[2] but as a matter of
fact the attack of the dipole’s carbon atom at another car-
bon atom is less easy, and the few reported examples are
reactions between nitrile oxides and strong nucleophiles
such as carbanions or cyanides.[2] In order to promote reac-
tions between nitrile oxides and less reactive carbon nucleo-
philes, we became involved in the study of the reactivity of
nitrile oxides towards Lewis acids.[4] We had previously
found that, in the presence of gaseous BF3, nitrile oxides
gave complexes in which the electrophilicity of the carbon
atom was so enhanced that it could react with aromatic
systems, stereoselectively yielding aryl oximes, or with tetra-
substituted alkenes to give cycloaddition products.[5] We
therefore decided to examine the reactivity of nitrile oxides
towards particular Lewis acids such as carbocations, and
we now wish to report here that this dipole reacted with
benzylic carbocations to provide addition products via an
intermediate that underwent intramolecular attack. Al-
though reactions between benzhydryl carbocations and al-
kenes have been studied in detail,[6] this is to the best of our
knowledge the first example of reactions between carboca-
tions and dipoles.
dichlorobenzonitrile oxide (1) Ϫ and trityl tetrafluorobor-
ate (2). The reaction between 1 and 2 gave benzoxazine 3
(20%), the cleavage products oxime 4a (40%) and amide 5a
(20%), and also benzophenone (Scheme 1).
Scheme 1. Reaction between 1 and trityl tetrafluoroborate
We then extended this reaction to unstable secondary car-
bocations. Carbenium ions were generated from the corres-
ponding benzhydryl chlorides 6aϪi in the presence of
[7]
HBF4 or of other Lewis acids such as BCl3,[8] SbCl5,[9]
and gaseous BF3. Reactions between 1 and 7aϪi, generated
with tetrafluoroboric acid, gave only oximes 4aϪd, amides
5aϪd, and aldehydes 8aϪd, and not the expected benzoxaz-
ine 3 (Scheme 2). The yields of 4 and 5 are given in Table 1.
Tetrafluoroborate 7a, prepared from benzhydryl chloride
(6a), gave 2,6-dichlorobenzophenone oxime (4a), N-aryl-
benzamide 5a, and benzaldehyde (8a) (Entry 1). Bis(p-
phenyl)-substituted carbocations 7b and 7c (Entries 2 and
3) gave the p-phenyl-substituted oximes 4b and 4c, the p-
phenyl-substituted benzamides 5b and 5c, and the p-phenyl-
substituted aldehydes 8b and 8c, respectively. The bis(m-
methyl)benzhydryl-substituted salt 7d (Entry 4) gave m-
methyl-substituted oxime 4d, amide 5d, and aldehyde 8d.
When the phenyl group of the salt was strongly activated
by a methoxy group in meta position (Entries 5 and 9), the
[a]
Dipartimento di Chimica, Materiali e Ingegneria Chimica
‘‘Giulio Natta’’, Politecnico di Milano,
Via Mancinelli 7, 20131 Milano, Italy
Eur. J. Org. Chem. 2002, 2411Ϫ2416  WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0714Ϫ2411 $ 20.00ϩ.50/0
2411

S. Auricchio, C. Magnani, A. M. Truscello
FULL PAPER
Table 2. Reaction between 7a and 1 in the presence of HBF4
Equiv. of HBF4
Yield of 4a (%)
Yield of 5a (%)
1
5
10
35
15
traces
10
35
50
All these results showed that nitrile oxide reacted with
carbocations in good overall yields, and that the interme-
diate underwent CϪC cleavage under these reaction condi-
tions.
The nature of the Lewis acid used to generate the car-
bocations proved to be very important. BCl3 and SbCl5,
generally used in carbocation reactions, had to be dis-
carded, as the use of their corresponding tetrachlorobor-
ates[8] and hexachloroantimonates[9] was unsuccessful and
gave no reaction with 1.
Scheme 2. Reactions between 1 and benzhydryl chlorides 6aϪi in
the presence of HBF4
Table 1. Reactions between 1 and carbocations 7aϪi
When the carbocation was generated by means of an-
other Lewis acid, such as gaseous boron trifluoride, it was
possible to isolate benzoxazine, the addition product in
which no bond cleavage had occurred.
Carbocations were therefore prepared by bubbling BF3
into a solution of the chlorides at Ϫ78 °C. As in the case
of tetrachloroborate, the salt 9 probably existed in equilib-
rium with the chloride 6[8] and its treatment with nitrile
oxide 1 gave Ϫ besides the oximes 4, amides 5, and alde-
hydes 8 Ϫ the benzoxazines 10 and oximate 11 (Scheme 3);
yields are given in Table 3.
Entry
Carbocation
Yield (%)[a]
Yield (%)[a]
1
2
3
4
5
7a
7b
7c
7d
7e
4a (34)
5a (10)
5b (13)
5c (21)
5d (10)
4b (45)
4c (59)
4d (49)
unchanged 1 and
tar recovered
4a (18) ϩ 4b (23)
4c (54)
6
7
8
9
7f
7g
7h
7i
5a (5) ϩ 5b (11)
5c (18)
5c (15)
4c (56)
unchanged 1 and
tar recovered
[a]
Yields given are those obtained after purification by column
chromatography.
carbocation underwent polymerization under these reaction
conditions, and no reaction with 1 was observed. When the
two aromatic rings of the carbocations were differently sub-
stituted (Entries 6Ϫ8), their reactions would have been ex-
pected to give mixtures of the possible oximes, amides, and
aldehydes as the carbocations underwent carbonϪcarbon
cleavage. Only in one case Ϫ that of p-methylbenzhydryl
cation 7f (Entry 6) Ϫ did the reaction afford both possible
oximes 4a and 4b, amides 5a and 5b, and aldehydes 8a and
8b. In each of the other two cases (Entries 7 and 8), only
one oxime, one amide, and one aldehyde were isolated.
The amides 5 had not been formed through in situ re-
arrangement of oximes 4, as we found that the oximes did
not give the corresponding amides under the same reaction
conditions (and reaction times). We also found that the ra-
tio between oximes and amides was strongly dependent on
the amount of HBF4 used in the reaction. When a large
excess of the acid was used, it was possible essentially to
obtain only amides (Table 2).
Scheme 3. Reactions between 1 and benzhydryl chlorides 6aϪe and
6i in the presence of BF3
It was possible to obtain oximes instead, by Beckmann
Benzhydryl chloride (6a), chlorobis(p-methylphenyl)-
rearrangement, by use of PCl5. Stereoisomerically pure ox- methane (6b), and chlorobis(m-methylphenyl)methane (6d)
imes were found to have been formed in all these reactions, again gave mixture of oximes, amides, and aldehydes (Ent-
the hydroxy group always being on the side opposite to the ries 1, 2, and 4). Under these reaction conditions, however,
nitrile oxide’s aromatic substituent.
polymerization of m-phenyl-substituted carbocations was
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Reactions between Nitrile Oxides and Carbenium Ions
FULL PAPER
Table 3. Reaction between 1 and 6aϪe and 6i in the presence of
BF3
Entry Chloride
T
Yield
Yield
(%)[a]
Yield
(%)[a]
Yield
(%)[a]
[°C] (%)[a]
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6e
6i
Ϫ78 4a (3) 5a (60)
Ϫ78 4b (15) 5b (45)
Ϫ78 4c (10) 5c (10)
Ϫ78 4d (21) 5d (41)
11c (40)
Ϫ78
ϩ25
Ϫ78
ϩ25
5e (traces)
5e (12)
5a (20) ϩ 5e (12) 10i (30)
5a (15) ϩ 5e (15) 10i (40)
10e (33)
10e (40)
6i
Scheme 4. Reaction between 1 and primary benzylic chloride 6j in
the presence of BF3
[a]
Yields given are those obtained after purification by column
chromatography.
occur at the ortho position of the aromatic ring, in which
case the benzoxazine 10 or 3 would be formed (pathway A),
or at the ipso position with formation of the intermediate
13 (pathway B). The intermediate 12 could also undergo
chloride attack to form open-chain products 11 (pathway
C).
reduced. Benzoxazines 10e and 10i were obtained together
with amides 5e and/or 5a on treatment of activated m-me-
thoxy-substituted chlorides 6e and 6i with 1 (Entries 5Ϫ8).
The corresponding oximes were not isolated. The p-me-
thoxyphenyl-substituted chloride 6c gave the open-chain
product 11c, together with oxime 4c, amide 5c, and alde-
hyde 8c (Entry 3). Product 11c could originate from a reac-
tion between 1 and the chloride 6c, as analogous reactions
have been reported.[10] We found, however, that 1 and 6c
did not react in the same reaction time as used above. Reac-
tion did take place in one week, though, affording 11c.
In all these reactions, the yields of amides were almost
always greater than those of oximes; excess BF3 favored
formation of amides more than excess HBF4.
The yields of the benzoxazines 10e and 10i were slightly
influenced by temperature, and increased to 40% in both
cases (Entries 6 and 8) if the reaction was carried out at
room temperature.
Treatment with triphenylmethyl chloride at Ϫ75 °C in the
presence of BF3 gave benzoxazine 3 (30%), oxime 4a (10%),
and amide 5a (31%), together with benzophenone. As re-
ported above, the use of stable tetrafluoroborate 2 gave dif-
ferent results.
Scheme 5. Proposed mechanism for the reaction between 1 and
tertiary and secondary carbocations
Treatment with a primary chloride such as 6j in the pres-
ence of BF3 produced quite different results; a mixture of
oximes 4j and 4k (4:1) was obtained after 6 h at Ϫ75 °C, 4j
undergoing cyclisation to benzoxazine 10j on treatment
with NaOH (Scheme 4). Partial cyclization also occurred
during chromatography on silica gel. When the reaction was
performed at room temperature, the ratio between the two
oximes was almost 1:1.
Formation of oximes, amides, and aldehydes (or ketones)
was clearly due to intermediate 13. On cleavage of the α
bond (Scheme 6) the spiro intermediate 13 would give rise
to intermediate 14, which could in turn hydrolyze to oxime
4 and aldehyde or ketone. All amides obtained were N-(2,6-
dichlorophenyl)-substituted, and so there must have been a
Beckmann-type migration, and so formation of the amides
from open-chain derivative 11 can hence be ruled out. As
amides 5 would not be formed by Beckmann rearrangement
of oximes 4, they may have originated by rearrangement
from either intermediate 13 or 14 and subsequent hydro-
lysis.
Discussion
On the basis of the products obtained from the reactions
For both pathway A and pathway B, if two different sub-
between tertiary and secondary halides and 1, we suggest stituted aromatic rings were present in the carbocation, the
that the mechanism involved the initial attack of the car- ipso or ortho attack should occur only or mainly on the ring
bocation at the oxygen atom of the nitrile oxide, giving in- with the activated positions (see Table 1, Entries 6Ϫ8).
termediate 12 (Scheme 5). Carbocation 12, in turn, would
It therefore seems clear that the formation of oxime,
be able to undergo intramolecular electrophilic substitution amide, and aldehyde was due to preference for the ipso at-
and could give rise to different products. The attack could tack over the ortho one.
Eur. J. Org. Chem. 2002, 2411Ϫ2416
2413

S. Auricchio, C. Magnani, A. M. Truscello
FULL PAPER
In this way, depending on the substituents on the aro-
matic ring of the carbocation, formal [3ϩ3] or [3ϩ2] cyclo-
additions occurred. When the ortho position was activated,
[3ϩ3] cycloaddition took place and benzoxazines were ob-
tained. When, in contrast, the ipso position was activated,
[3ϩ2] cycloaddition took place, and carbocations of 2-oxa-
3-azaspiro[4.5]deca-3,6,9-trienes were produced as unstable
intermediates. These intermediates give oximes and amides
through cleavage of a carbonϪcarbon bond.
As far as we know, this is the first example of a reaction
between 1,3-dipoles and a carbocation, but as it should not
be the only one, this work may open new routes for the
formation of heterocyclic rings from zwitterions.
Scheme 6. Proposed mechanism for the formation of oximes and
amides from intermediate 13
Oximes and/or amides were always obtained in these re-
actions, and so the ipso attack must always have taken
place, even when the position was not activated. The altern-
ative ortho attack occurred only if this position of the aro-
matic ring was strongly activated, as in 6e and 6i.[11] It was
noteworthy that, in the case of tertiary carbocation 2, al-
though the ortho position was not activated, ortho attack
occurred and benzoxazine 3a was formed. The influence of
aromatic substituents, the reversibility of addition, and the
formation of benzylic carbocation 14 all have to be consid-
ered to explain the marked preference for the ipso position
in these intramolecular electrophilic substitutions.
Experimental Section
General: NMR spectra were recorded with a Bruker 250 MHz spec-
trometer with TMS as internal standard. Mass spectra were per-
formed with a Finnigan TSQ 70 instrument. Melting points are
uncorrected. Chromatographic separations were performed on
Merck 60 Kieselgel. The stereochemistries of the oximes were de-
termined by Beckmann rearrangement with PCl5. Alcohols used in
the synthesis of benzydryl chlorides 6 were prepared, when com-
mercially not available, from the corresponding aldehydes and aryl
In the case of primary carbocations, the formation of the bromides by Grignard reactions. Yields given are those obtained
after purification by column chromatography; in almost all these
reactions, small quantities of nitrile oxide and nitrile oxide dimer
(furoxan) were found; yields of aldehydes are not reported as these
were always eluted as mixtures with nitrile oxide or nitrile oxide
dimer. In some reactions, 1H NMR monitoring of the mixture
showed that the quantity of aldehyde formed was, as would be ex-
pected, similar to those of oxime and amide.
two isomeric oximes and the absence of benzoxazine in the
reaction medium, make us believe that the reaction mech-
anism was actually different and that the attack occurred at
the carbon atom of the nitrile oxide complex formed in the
reaction media (Scheme 7).
Preparation of Benzhydryl Chlorides 6b؊i: Benzhydryl chlorides
6bϪi were prepared by bubbling gaseous HCl into a cooled (Ϫ10
°C) solution of the corresponding alcohols (0.0164 mol) in dry
CH2Cl2 (40 mL) in the presence of CaCl2 (4 g). At the end of the
reaction, the solvent was removed and the crude chlorides were
either crystallized or distilled. Yields were quantitative.
Reaction between 2,6-Dichlorobenzonitrile Oxide (1) and Trityl
Fluoroborate (2): Trityl fluoroborate (2) (1.00 g, 3.00 mmol) was
dissolved in CH2Cl2 (100 mL), and compound 1 (0.57 g, 3.0 mmol)
was added to this solution. The mixture was stirred at room tem-
perature overnight. The mixture was washed with H2O, a 10% solu-
tion of NH4Cl, and again with H2O. It was dried, and the solvent
was removed. Column chromatography gave 4-(2,6-dichloro-
phenyl)-1,1-diphenyl-1H-2,3-benzoxazine (3, 0.26 g, 20%), (E)-2,6-
dichlorobenzophenone oxime (4a,[4a] 0.32 g, 40%), and 2,6-dichlo-
robenzanilide (5a, 0.16 g, 20%).
Scheme 7. Proposed mechanism for the reaction between 1 and
primary benzylic chlorides
At low temperatures, reaction took place in 6 h and was
under kinetic control: the main product was 4j. At room
temperature, in contrast (reaction occurred instantan-
eously), the reaction was under thermodynamic control and
the 4j/4k ratio was almost 1.
Compound 3: White solid (cyclohexane), m.p. 109Ϫ110 °C. 1H
NMR (250 MHz, CDCl3, ppm): δ ϭ 7.08Ϫ7.62 (m, 12 H), 7.78
(m, 5 H). EI MS: m/z (%) ϭ 429 (4) [Mϩ], 394 (10), 326 (15), 243
(100), 187 (20). C26H17Cl2NO (430.3): calcd. C 72.57, H 3.98, N
3.25; found C 72.52, H 4.03, N 3.16.
Conclusions
Reactions between a 1,3-dipole, such as a nitrile oxide,
and benzylic carbocations are discussed. The carbocations
reacted with nitrile oxides acting both as reagent and as
Lewis acid promoting the addition. The interaction of the
carbocation, the Lewis acid, with the negative part of the
zwitterion enhanced the dipole electrophilicity and pro-
moted an intramolecular FriedelϪCrafts-type attack, re-
sulting in the formation of cyclic products.
General Procedure for the Treatment of 1 with Chlorides 6a؊i in the
Presence of HBF4: Benzhydryl chlorides 6aϪi were dissolved in a
two-necked flask in dry n-hexane (30 mL) under a stream of nitro-
gen. The solution was cooled to Ϫ50 °C, and a 54% solution of
HBF4 (1 mol-equiv.) in diethyl ether was added. After the precipita-
tion of a red solid, nitrogen was bubbled through the mixture to
2414
Eur. J. Org. Chem. 2002, 2411Ϫ2416

Reactions between Nitrile Oxides and Carbenium Ions
FULL PAPER
remove the solvent, and a solution of 1 in dry CH2Cl2 (30 mL),
cooled to Ϫ50 °C, was added. After a few hours, the mixture was
washed with a 10% solution of NH4Cl and water, and dried. The
solvent was removed. Products were separated by column chroma-
tography [eluent from n-hexane/ethyl acetate (95:5) to pure ethyl
acetate].
Reaction between 6h and 1: Treatment of 6h (0.50 g, 2.0 mmol) and
1 (0.38 g, 2.0 mmol) in the presence of HBF4 (0.28 mL) afforded,
after workup and purification, (E)-2,6-dichloro-4Ј-methoxybenzo-
phenone oxime (4c, 0.33 g, 56%) and 2Ј,6Ј-dichloro-4-methoxyben-
zanilide (5c, 0.09 g, 15%).
Reaction between 6a and 1 in the Presence of BF3: BF3 gas was
bubbled into a solution of 6a (0.44 g, 2.2 mmol) in 50 mL of dry
CH2Cl2 at Ϫ78 °C. A solution of 1 (0.41 g, 2.2 mmol) in dry
CH2Cl2 (20 mL), cooled to Ϫ78 °C, was added under a stream of
nitrogen. After 4 h, the mixture was treated with H2O, a 10% solu-
tion of NH4Cl, and again with H2O, and dried. The solvent was
removed. Column chromatography afforded (E)-2,6-dichloroben-
zophenone oxime (4a, 0.02 g, 3%) and 2Ј,6Ј-dichlorobenzanilide
(5a, 0.35 g, 60%).
Reaction between 6a and 1: Treatment of 6a (0.46 g, 2.3 mmol) with
1 (0.43 g, 2.3 mmol) in the presence of HBF4 (0.32 mL) afforded,
after workup and purification, (E)-2,6-dichlorobenzophenone ox-
ime (4a, 0.21 g, 34%) and 2,6-dichlorobenzanilide (5a, 0.06 g, 10%).
Reaction between 6b and 1: Treatment of 6b (0.50 g, 2.2 mmol) with
1 (0.41 g, 2.2 mmol) in the presence of HBF4 (0.30 mL) afforded,
after workup and purification, (E)-2,6-dichloro-4Ј-methylbenzo-
phenone oxime (4b, 0.28 g, 45%) and 2Ј,6Ј-dichloro-4-methyl-
benzanilide (5b, 0.08 g, 13%).
Reaction between 6b and 1 in the Presence of BF3: BF3 gas was
bubbled into a solution of 6b (0.50 g, 2.2 mmol) in dry CH2Cl2
(50 mL) at Ϫ78 °C. A solution of 1 (0.41 g, 2.2 mmol) in dry
CH2Cl2 (20 mL), cooled to Ϫ78 °C, was added under a stream of
nitrogen. After 4 h, the mixture was treated with H2O, a 10% solu-
tion of NH4Cl, and again with H2O, and dried. The solvent was
removed. Column chromatography afforded (E)-2,6-dichloro-4Ј-
methylbenzophenone oxime (4b, 0.09 g, 15%) and 2Ј,6Ј-dichloro-4-
methylbenzanilide (5b, 0.28 g, 45%).
Compound 4b:[4b] White solid (ethanol/water), m.p. 148Ϫ150 °C.
1H NMR (250 MHz, CDCl3, ppm): δ ϭ 2.35 (s, 3 H), 7.18 (dt, J ϭ
2 and 9 Hz, 2 H), 7.20Ϫ7.30 (m, 3 H), 7.60 (dt, J ϭ 2 and 9 Hz, 2
H), 8.48 (br. s, 1 H). EI MS: m/z (%) ϭ 281 (64) [Mϩ ϩ 2], 280
(21), 279 (100) [Mϩ], 262 (27), 244 (27).
Compound 5b: White solid (ethanol/water), m.p. 170Ϫ171 °C. 1H
NMR (250 MHz, CDCl3, ppm): δ ϭ 2.43 (s, 3 H), 7.18 (dd, J ϭ 8
and 9 Hz, 1 H), 7.29 (d, J ϭ 8 Hz, 2 H), 7.39 (d, J ϭ 8 Hz, 2 H),
7.68 (br. s, 1 H), 7.86 (d, J ϭ 8 Hz, 2 H). EI MS: m/z (%) ϭ 279
(2) [Mϩ], 244 (24), 119 (100). C14H11Cl2NO (280.2): calcd. C 60.02,
H 3.96, N 5.00; found C 59.97, H 4.05, N 4.82.
Reaction between 6c and 1 in the Presence of BF3: BF3 gas was
bubbled into a solution of 6c (0.60 g, 2.3 mmol) in dry CH2Cl2
(50 mL) at Ϫ78 °C. A solution of 1 (0.43 g, 2.3 mmol) of dry
CH2Cl2 (20 mL), cooled to Ϫ78 °C, was added under a stream of
nitrogen. After 4 h, the mixture was treated with H2O, a 10% solu-
tion of NH4Cl, and again with H2O, and dried. The solvent was
removed. Column chromatography afforded N-[bis(4-methoxy-
Reaction between 6c and 1: Treatment of 6c (0.50 g, 1.9 mmol) with
1 (0.36 g, 1.9 mmol) in the presence of HBF4 (0.26 mL) afforded,
after workup and purification, (E)-2,6-dichloro-4Ј-methoxybenzo-
phenone oxime (4c,[4a] 0.33 g, 59%) and 2Ј,6Ј-dichloro-4-methoxyb- phenyl)methoxy]-2,6-dichlorobenzenecarboximidoyl chloride (11c,
enzanilide (5c,[4a] 0.12 g, 21%).
0.41 g, 40%), (E)-2,6-dichloro-4Ј-methoxybenzophenone oxime (4c,
0.07 g, 10%), and 2Ј,6Ј-dichloro-4-methoxybenzanilide (5c, 0.07 g,
10%).
Reaction between 3d and 1: Treatment of 6d (0.50 g, 2.2 mmol) with
1 (0.41 g, 2.2 mmol) in the presence of HBF4 (0.30 mL) afforded,
after workup and purification, (E)-2,6-dichloro-3Ј-methylbenzo-
phenone oxime (4d, 0.30 g, 49%) and 2Ј,6Ј-dichloro-3-methyl-
benzanilide (5d, 0.06 g, 10%).
1
Compound 11c: White solid (n-hexane), m.p. 94Ϫ95 °C. H NMR
(250 MHz, CDCl3, ppm): δ ϭ 3.80 (s, 6 H), 6.34 (s, 1 H), 6.88 (m,
4 H), 7.30 (m, 7 H). 13C NMR (CDCl3, ppm): δ ϭ 55.2, 87.4,
113.7, 128.0, 128.7, 131.4, 132.3, 132.4, 132.7, 135.4, 159.2. MS: m/
z (%) ϭ 449 (1) [Mϩ], 228 (48), 227 (100). C22H18Cl3NO3 (450.7):
calcd. C 58.62, H 4.03, N 3.11; found C 58.51, H 3.91, N 2.97.
Compound 4d: White solid (ethanol/water), m.p. 142Ϫ144 °C. 1H
NMR (250 MHz, CDCl3, ppm): δ ϭ 2.34 (s, 3 H), 7.10Ϫ7.50 (m,
7 H), 8.35 (br. s, 1 H). EI MS: m/z (%) ϭ 279 (16) [Mϩ], 262 (25),
244 (57), 91 (100). C14H11Cl2NO (280.2): calcd. C 60.02, H 3.96,
N 5.00; found C 59.95, H 4.09, N 4.87.
Reaction between 6d and 1 in the Presence of BF3: BF3 gas was
bubbled into a solution of 6d (0.50 g, 2.2 mmol) in dry CH2Cl2
(50 mL) at Ϫ78 °C. A solution of 1 (0.41 g, 2.2 mmol) in dry
CH2Cl2 (20 mL), cooled to Ϫ78 °C, was added under a stream of
nitrogen. After 4 h, the mixture was treated with H2O, a 10% solu-
tion of NH4Cl, and again with H2O, and dried. The solvent was
removed. Column chromatography afforded (E)-2,6-dichloro-3Ј-
methylbenzophenone oxime (4d, 0.13 g, 21%) and 2Ј,6Ј-dichloro-3-
methyl-benzanilide (5d, 0.25 g, 41%).
Compound 5d: White solid (ethanol/water), m.p. 168Ϫ169 °C. 1H
NMR (250 MHz, CDCl3, ppm): δ ϭ 2.45 (s, 3 H), 7.20 (dd, J ϭ 8
and 9 Hz, 1 H), 7.36Ϫ7.46 (m, 4 H), 7.66 (br. s, 1 H), 7.70Ϫ7.82
(m, 2 H). EI MS: m/z (%) ϭ 279 (2) [Mϩ], 244 (37), 119 (100).
C14H11Cl2NO (280.2): calcd. C 60.02, H 3.96, N 5.00; found C
60.01, H 3.99, N 4.94.
Reaction between 6f and 1: Treatment of 6f (0.50 g, 2.3 mmol) with
1 (0.44 g, 2.3 mmol) in the presence of HBF4 (0.32 mL) afforded,
after workup and purification, 0.11 g (18%) of (E)-2,6-dichloroben-
zophenone oxime (4a), (E)-2,6-dichloro-4Ј-methylbenzophenone
oxime (4b, 0.15 g, 23%), 2,6-dichlorobenzanilide (5a, 0.03 g, 5%),
and 2Ј,6Ј-dichloro-4-methylbenzanilide (5b, 0.07 g, 11%).
Reaction between 6e and 1 in the Presence of BF3. Procedure a: BF3
gas was bubbled into a solution of 6e (0.53 g, 2.0 mmol) in dry
CH2Cl2 (100 mL) at Ϫ78 °C. A solution of 1 (0.38 g, 2.0 mmol) in
dry CH2Cl2 (20 mL), cooled to Ϫ78 °C, was added under a stream
of nitrogen. After 6 h the mixture was washed with water, a 10%
solution of NH4Cl, and again with H2O, and dried. The solvent
was removed. Column chromatography afforded 4-(2,6-dichloro-
phenyl)-7-methoxy-1-(3-methoxyphenyl)-1H-2,3-benzoxazine (10e,
0.27 g, 33%) and traces of 2Ј,6Ј-dichloro-3-methoxybenzanilide
Reaction between 6g and 1: Treatment of 6g (0.50 g, 2.2 mmol) with
1 (0.41 g, 2.2 mmol) in the presence of HBF4 (0.30 mL) afforded,
after workup and purification, (E)-2,6-dichloro-4Ј-methoxybenzo-
phenone oxime (4c, 0.35 g, 54%) and 2Ј,6Ј-dichloro-4-methoxyben- (5e). Procedure b: BF3 gas was bubbled into a solution of 6e (0.53 g,
zanilide (5c, 0.12 g, 18%).
2.0 mmol) and 1 (0.38 g, 2.0 mmol) in dry CH2Cl2 (100 mL) at
Eur. J. Org. Chem. 2002, 2411Ϫ2416
2415

S. Auricchio, C. Magnani, A. M. Truscello
FULL PAPER
room temperature. Reaction was instantaneous and afforded, after
reaction was instantaneous, and 1H NMR examination of the mix-
ture showed that oximes 4j and 4k were present in a ratio of 45:55.
The mixture was treated with NaOH and gave a mixture of 4-(2,6-
dichlorophenyl)-7-methoxy-1H-2,3-benzoxazine (10j, 0.35 g, 35%)
and oxime 4k (0.44 g, 40%).
purification,
4-(2,6-dichlorophenyl)-7-methoxy-1-(3-methoxy-
phenyl)-2,3-benzoxazine (10e, 0.33 g, 40%) and 2Ј,6Ј-dichloro-3-
methoxybenzanilide (5e, 0.07 g, 12%).
1
Compound 10e: Oil. H NMR (250 MHz, CDCl3, ppm): δ ϭ 3.76
1
(s, 3 H), 3.82 (s, 3 H), 6.12 (s, 1 H), 6.49 (s, 1 H), 6.81 (m, 2 H), Compound 4j: White solid (n-hexane), m.p. 143Ϫ146 °C. H NMR
6.94 (m, 1 H), 7.05 (m, 2 H), 7.20Ϫ7.50 (m, 4 H). EI MS: m/
z (%) ϭ 415 (70) [M ϩ 2], 413 (100) [Mϩ], 379 (65), 347 (60),
227 (84).
(250 MHz, CDCl3, ppm): δ ϭ 3.85 (s, 3 H), 4.78 (s, 2 H), 6.80 (dd,
J ϭ 3 and 9 Hz, 1 H), 7.03 (d, J ϭ 9 Hz, 1 H), 7.20Ϫ7.40 (m, 4
H), 7.88 (br. s, 1 H). EI MS: m/z (%) ϭ 343 (3) [Mϩ], 326 (30), 307
(100), 272 (60). C12H12Cl3NO2 (344.6): calcd. C 52.28, H 3.51, N
4.06; found C 52.45, H 3.73, N 3.82.
Compound 5e: White solid (ethanol/water), m.p. 188Ϫ189 °C. 1H
NMR (250 MHz, CDCl3, ppm): δ ϭ 3.88 (s, 3 H), 7.06Ϫ7.30 (m,
2 H), 7.35Ϫ7.56 (m, 5 H), 7.63 (br. s, 1 H). EI MS: m/z (%) ϭ 295
(10) [Mϩ], 260 (100), 135 (100). C14H11Cl2NO2 (296.2): calcd. C
56.78, H 3.74, N 4.73, Cl 23.94; found C 56.96, H 3.95, N 4.51.
Compound 4k: White solid (n-hexane), m.p. 184Ϫ185 °C. 1H NMR
(250 MHz, CDCl3, ppm): δ ϭ 3.78 (s, 3 H), 4.57 (s, 2 H), 6.98 (m,
2 H), 7.17Ϫ7.35 (m, 3 H), 7.49 (d, J ϭ 8 Hz, 1 H), 8.50 (br. s, 1
H). EI MS: m/z (%) ϭ 343 (2) [Mϩ], 326 (50), 308 (80), 252 (35),
91 (100). C12H12Cl3NO2 (344.6): calcd. C 52.28, H 3.51, N 4.06;
found C 52.28, H 3.88, N 4.37.
Reaction between 6i and 1 in the Presence of BF3. Procedure a: BF3
gas was bubbled into a solution of 3i (0.47 g, 2.0 mmol) in dry
CH2Cl2 (100 mL) at Ϫ78 °C. A solution of 1 (0.38 g, 2.0 mmol) in
dry CH2Cl2 (20 mL), cooled to Ϫ78 °C, was added under a stream
of nitrogen. After 4 h and the usual workup, the reaction afforded
4-(2,6-dichlorophenyl)-7-methoxy-1-phenyl-1H-2,3-benzoxazine
(10i, 0.23 g, 30%), 2Ј,6Ј-dichloro-3-methoxybenzanilide (5e, 0.07 g,
12%), and 2Ј,6Ј-dichlorobenzanilide (5a, 0.12 g, 20%). Procedure b:
BF3 gas was bubbled at room temperature into a solution of 6i
Compound 10j: White-purple solid (ethyl acetate), m.p. 108Ϫ110
1
°C. H NMR (250 MHz, CDCl3, ppm): δ ϭ 3.84 (s, 3 H), 5.12 (s,
2 H), 6.78 (m, 3 H), 7.30Ϫ7.48 (m, 3 H). EI MS: m/z (%) ϭ 309
(60) [M ϩ 2], 307 (100) [Mϩ], 276 (70), 272 (65). C15H11Cl2NO2
(308.2): calcd. C 58.46, H 3.60, N 4.55, Cl 23.01; found C 58.57,
H 3.88, N 4.37.
(0.47 g, 2.0 mmol) and
1 (0.38 g, 2.0 mmol) in dry CH2Cl2
Reaction between 6c and 1: Chloride 6c (0.25 g, 9.5 mmol) and 1
(0.18 g, 9.5 mmol) were dissolved in 30 mL of dry CH2Cl2. After a
week, column chromatography afforded 11c (0.17 g, 40%).
(100 mL). Reaction was instantaneous and afforded, after workup
and purification, 4-(2,6-dichlorophenyl)-7-methoxy-1-phenyl-2,3-
benzoxazine (10i, 0.31 g, 40%), 2Ј,6Ј-dichloro-3-methoxybenzanil-
ide (5e, 0.09 g, 15%), and 2Ј,6-dichlorobenzanilide (5a, 0.09 g,
15%).
[1]
P. Caramella, P. Grünanger, ‘‘Nitrile Oxides and Imines’’, in:
Compound 10i: White solid (ethyl acetate), m.p. 108Ϫ110 °C. 1H
NMR (250 MHz, CDCl3, ppm): δ ϭ 3.77 (s, 3 H), 6.15 (s, 1 H),
6.47 (s, 1 H), 6.81 (m, 2 H), 7.25Ϫ7.55 (m, 8 H). 13C NMR (CDCl3,
ppm): δ ϭ 55.4, 78.5, 111.2, 113.3, 115.2, 126.0, 128.0, 128.1, 128.3,
128.5, 128.7, 130.8, 131.5, 135.6, 135.7, 136.2, 137.2, 156.4, 162.8.
EI MS: m/z (%) ϭ 385 (48) [M ϩ 2], 383 (69) [Mϩ], 348 (100), 317
(28), 239 (59), 197 (85). C21H15Cl2NO2 (384.3): calcd. C 65.64, H
3.93, N 3.65; found C 65.40, H 3.84, N 3.29.
A. Padwa (Ed.), 1,3-Dipolar Cycloaddition, vol. 1 (General Het-
erocyclic Chemistry) (Ser. Eds.: E. C. Taylor, A. Weisserberger),
Wiley-Interscience, New York, 1984.
[2]
[2a] C. Grundmann, P. Grünanger, The Nitrile Oxides, Springer-
Verlag, Berlin, 1971. [2b] K. B. G. Torssell, Nitrile Oxides, Nitro-
nes, and Nitronates in Organic Synthesis, VCH, New York,
1988.
[3] [3a]
J. N. Kim, E. K. Ryu, J. Org. Chem. 1992, 57, 1088Ϫ1092.
A. Selva, S. Auricchio, A. M. Truscello, Org. Mass Spec-
[3b]
trom. 1994, 29, 232Ϫ237.
[4a] S. Auricchio, A. Bini, E. Pastormerlo, A. Ricca, A. M. Trus-
[4]
Reaction between Triphenylmethyl Chloride and 1 in the Presence of
BF3: BF3 gas was bubbled into a solution of triphenylmethyl chlor-
ide (0.61 g, 2.2 mmol) in dry CH2Cl2 (50 mL) at Ϫ78 °C. A solution
of 1 (0.41 g, 2.2 mmol) in dry CH2Cl2 (20 mL), cooled to Ϫ78 °C,
was added under a stream of nitrogen. After 6 h, the mixture was
treated with H2O, a 10% solution of NH4Cl, and again with H2O,
and dried. The solvent was removed. Column chromatography af-
forded 4-(2,6-dichlorophenyl)-1,1-diphenyl-2,3-benzoxazine (3,
0.28 g, 30%), (E)-2,6-dichlorobenzophenone oxime (4a, 0.06 g,
10%) and 2Ј,6Ј-dichlorobenzanilide (5a, 0.18 g, 31%).
[4b]
cello, Tetrahedron 1994, 50, 7589Ϫ7596.
J. N. Kim, E. K.
[4c]
Ryu, Tetrahedron Lett. 1993, 34, 3567Ϫ3570.
H. Yamam-
oto, S. Watanabe, K. Kadotani, M. Hasegawa, M. Noguchi, S.
Kanemasa, Tetrahedron Lett. 2000, 41, 3131Ϫ33136.
S. Auricchio, F. Costantino, E. Pastormerlo, A. Ricca, A. M.
Truscello, Euchem Conference. Cycloadditions and Related Re-
actions: Theory and Practice, Vulcano, Italy, June 21Ϫ24, 1995,
abstr. p. 77Ϫ78.
[5]
[6]
[6a] H. Mayr, Angew. Chem. Int. Ed. Engl. 1990, 27, 1371Ϫ1384
[6b]
and reference cited therein.
H. Mayr, T. Bug, M. F. Gotta,
N. Hering, B. Irrgang, B. Janker, B. Kempf, R. Loos, A. R.
Ofial, G. Remennikov, H. Schimmel, J. Am. Chem. Soc. 2001,
123, 9500Ϫ9512.
G. A. Olah, J. J. Svoboda, J. A. Olah, Synthesis 1972, 544.
R. Schneider, H. Mayr, P. H. Plesch, Phys. Chem. 1987, 91,
1369Ϫ1374.
Reaction between 3-Methoxybenzyl Chloride (6j) and 1 in the Pres-
ence of BF3. Procedure A: BF3 gas was bubbled into a solution of
6j (0.50 g, 3.2 mmol) in dry CH2Cl2 (50 mL) at Ϫ70 °C. A cooled
solution of 1 (0.60 g, 3.2 mmol) in dry CH2Cl2 (20 mL), cooled to
Ϫ78 °C, was added under a stream of nitrogen. After 8 h, a mixture
of oximes 4j and 4k was obtained. The mixture, after workup and
column chromatography on silica gel, gave a mixture of 4j, 4k, and
10j in variable ratio. When the crude mixture was washed with a
10% solution of NaOH, the mixture gave after column chromato-
graphy 4-(2,6-dichlorophenyl)-7-methoxy-1H-2,3-benzoxazine (10j,
0.60 g, 61%) and the oxime 4k (0.10 g, 9%). Procedure B: BF3 gas
was bubbled at room temperature into a solution of 6j (0.50 g,
3.2 mmol) and 1 (0.60 g, 3.2 mmol) in dry CH2Cl2 (50 mL). The
[7]
[8]
[9]
J. Holmes, R. Pettit, J. Org. Chem. 1963, 28, 1695Ϫ1696.
[10] [10a] H. Wieland, B. Rosenfeld, Justus Liebigs Ann. Chem. 1930,
484, 236Ϫ245. [10b] W. I. Awad, M. Sobhy, Can. J. Chem. 1969,
47, 1473Ϫ1477.
[11]
For competition between ipso and ortho attack in carbocation
cyclisation see, for instance: T. J. Doyle, M. Hendrix, J. Hasel-
tine, Tetrahedron Lett. 1994, 35, 8295Ϫ8298.
Received February 18, 2002
[O02100]
2416
Eur. J. Org. Chem. 2002, 2411Ϫ2416