3,3-Sigmatropic rearrangements involving N-O bond-cleavage of enehydroxylamine derivatives

FULL PAPER

3,3-Sigmatropic Rearrangements Involving N؊O Bond-Cleavage of

Enehydroxylamine Derivatives

Lucinda V. Reis,^[a][‡]Ana M. Lobo,*^[a]Sundaresan Prabhakar,*^[a]and Mariana P. Duarte^[a]

Keywords: Amines / Cleavage reactions / Sigmatropic rearrangement

Enehydroxylamines, derived from carbocyclic and heterocyc- ment by use of deuterium-labelled compounds showed that

lic 1,3-dioxo compounds, react with a variety of unsaturated

electrophiles to give, in good to excellent yields, substances

that in general undergo 3,3-sigmatropic rearrangements

either spontaneously or upon heating. In those cases in

which such reactions failed, addition of sodium hydride was

no crossover occurs, indicating the intramolecular nature of

the process. The method provides 2,3- or 3,4-disubstituted

cyclohexenones, 5,6-disubstituted barbiturates and the cor-

responding fused pyrrole and imidazolinone derivatives.

( Wiley-VCH Verlag GmbH & Co KGaA, 69451 Weinheim,

found to induce the transformation. A study of the rearrange- Germany, 2003)

Introduction

The seminal disclosure of the generation of such rearran-

ging O-acyl-N-alkenylhydroxylamine systems in situ by

quaternisation of O-acyl oximes containing one α-hydrogen

atom, followed by base treatment, was made by House^[4]

more than 30 years ago. Other workers have applied the

same methodology for the preparation of α-acyloxy-

imines,^[5]α-amido ketones,^[6]α-amino acids,^[7]oxazolin-

ones,^[8]imidazoles,^[9]furans,^[10]and pyrroles.^[11]

Since it was thought that the full synthetic potential of

the cyclic enehydroxylamines had been left largely underex-

ploited, we examined their chemistry from the standpoint

of their 3,3-sigmatropic rearrangements. In this paper we

give a full account of our work involving rearrangement of

derivatives of N-alkylenehydroxylamine 2, and extending it

to amidic N-hydroxy-1,3-dicarbonyl compounds derived

from barbituric acid, and show the usefulness of the process

for the production of 2,3- and 3,4-heterodisubstituted

cyclohexen-1-ones, fused pyrrolocyclohexenones, and 5,6-

uracil derivatives. A brief preliminary communication of

part of this work has already appeared.^[12]

Enehydroxylamines 1, which are tautomers of nitrones,

are compounds with interesting chemical and biological

properties, acting as 5-lipoxygenase and IL-1 inhibitors,^[1]

due to the presence of two adjacent functional groups: a

weak NϪO bond and an enamine nitrogen atom.^[2]Of spe-

cial relevance is the possible involvement of derivatives 2 in

3,3-sigmatropic rearrangements,^[3]in which the NϪO bond

is cleaved, and the departing group is introduced at the ad-

jacent α-carbon atom to give 3 in a thermodynamically

driven process (Scheme 1).

Results and Discussion

Scheme 1

Compounds of types 4, 5, and 6 were readily obtainable

in reasonable to good yields from the corresponding cyclo-

hexane-1,3-diones

or

6-chloro-1,3-dimethylbarbituric

[a]

´

acid^[13]and the appropriate N-substituted hydroxylamines,

essentially by published methods^[14](see Exp. Sect.)

(Table 1). A slight modification of the reported procedure,

involving the prior liberation of the free hydroxylamines

from their salts, was found to facilitate the isolation of the

products, and hence improve the yields. However, only poor

yields were obtained with N-isopropyl- and N-cyclohexylhy-

droxylamines.

Departamento de Quımica, CQFB/REQUIMTE, Faculdade de

ˆ

Ciencias e Tecnologia, Universidade Nova de Lisboa, and

SINTOR-UNINOVA,

2829 Monte da Caparica, Portugal

Fax: (internat.) ϩ 351-212948550

E-mail: aml@fct.unl.pt

[‡]

´

Present address: Departamento de Quımica, Universidade de

Tras-os-Montes e Alto Douro,

Apartado 202, 5001-911 Vila Real Codex, Portugal

Fax: (internat.) ϩ 351-259350480

E-mail: lvrfisco@utad.pt

´

190

 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0101Ϫ0190 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 190Ϫ208

3,3-Sigmatropic Rearrangements of Enehydroxylamines

FULL PAPER

structures, deuterium exchange at C-2 occurred readily on

shaking a CDCl₃solution of the compounds with D₂O.

Reactions of Enehydroxylamines with Electrophiles

Reactions with Methanesulfonyl Chloride, N,N-Dimethyl-

thiocarbamoyl Chloride and 1-Fluoro-2,4-dinitrobenzene

With a satisfactory method for the preparation of 4Ϫ6 at

hand, their reactions with a variety of electrophiles were

studied. Table 2 lists reactions with MeSO₂Cl,

Me₂NC(S)Cl, 1-fluoro-2,4-dinitrobenzene, methyl propiol-

ate, and dimethyl acetylenedicarboxylate, which directly

provided products 3 of a 3,3-sigmatropic rearrangement,

according to the general Scheme 1.

Table 1. Enehydroxylamines 4Ϫ6: yields and diagnostic spectro-

scopic data

R¹

Yield^[a][%]

ν˜^[b][cm^Ϫ1

]

δ_Hα[ppm]

[c]

When, for example, enehydroxylamines 4a, 4b, and 5a

were treated with equimolar amounts of the powerful elec-

trophile methanesulfonyl chloride in the presence of

Hünig’s base at 0 °C to room temp., the corresponding re-

arranged products 8a, 8b, and 8c were obtained in yields

ranging from 84 to 93% (Table 2, Entries 1, 2, and 3, and

Scheme 2, a). For compound 6a, however, the yield of the

rearranged product 10a dropped to 41% and a product

identified as 10aЈ was isolated in 48% yield. While 10a was

the expected product of a 3,3-sigmatropic rearrangement,

compound 10aЈ may have arisen from attack of the anion,

4a Me

4b CH₂Ph

4c iPr

70

87

24

1550

1555

1550

1540

1590

1538

1650

1613

5.46

5.69

5.78

5.16

5.52

5.68

5.70

5.76

4d C₆H₁₁(cyclohexyl) 23

5a Me^[d]

5b CH₂Ph

6a Me

80

68

80

55

6b CH₂Ph

[a]

[b]

[d]

Isolated yields. KBr phase. ^[c]CDCl₃solution. Ref.^[14]

The infrared spectra of the enehydroxylamines reported liberated from the electrophile, at the adjacent carbon atom

here indicated extensive electronic delocalisation (Table 1), C-2 prior to the rearrangement (Scheme 2, b), or through

as is observed for N-alkylenaminones of similar struc- the decomposition of an earlier intermediate (represented

1

tures.^[15,16]The H NMR spectra of these compounds con- in Scheme 2, c). This difference in behaviour of compounds

tained, inter alia, the characteristic one-proton singlet in of type 6 was to be a constant theme with most of the reac-

the olefinic region (the α-proton in 4, 5, and 6) at δ ഠ tions studied involving electrophiles bearing an halogen an-

5.8Ϫ5.2 ppm (Table 1). Consistent with the delocalised ion as the initially departing group.

Table 2. Treatment of 4Ϫ6 with electrophiles

Entry

Starting material

(SM)

Electrophile

(E)

Ratio

SM/E

Conditions

Time t

[h]

Products (yield^[a][%])

[3,3]-Rearrang.

Others

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

4a

4b

5a

6a

4a

5a

6a

4a

5a

6a

5a

6a

4a

5a

6a

4a

5a

6a

MeSO₂Cl

1:1

1:3

1:1.3

1:1

A^[b]

A

1.5

0.7

3

8a (87)

8b (84)

8c (93)

10a (41)

8d (53)

8e (63)

N.R.

8dЈ (63)

8eЈ (84)

10b (30)

11 (89)

12 (73)

13a (82)

13b (76)

N.R.

Ϫ

A

1

10aЈ (48)

Ϫ

10bЈ (55)

Ϫ

14a (77)

14b (74)

Ϫ

14c (90)

14d (88)

Ϫ

Me₂NC(S)Cl

1-F-2,4-(O₂N)₂C₆H₃

HCCCO₂Me

MeO₂CCCCO₂Me

B^[c]

B

24

4.5

72

3.5

4

4.5

2

2.5

48

96

144

40

144

B

C^[d]

C

D^[e]

D

E^[f]

E

13c (69)

13d (70)

N.R.

[a]

[b]

[c]

Isolated yields. EtiPr₂N (1 equiv.), THF, 0 °C Ǟ room temp. Et₃N (3 equiv.), THF, 0 °C Ǟ room temp. ^[d]NaH (2 equiv.), THF,

[e]

[f]

0 °C Ǟ room temp. NaH (1.2 equiv.), THF, 0 °C Ǟ room temp. EtiPr₂N (1 equiv.), THF, 0 °C Ǟ room temp.; for 14a/b: reflux

13a/b in toluene; for 14c/d: reflux 13c/d in toluene/cat. p-TSA.

Eur. J. Org. Chem. 2003, 190Ϫ208

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L. V. Reis, A. M. Lobo, S. Prabhakar, M. P. Duarte

FULL PAPER

For treatment with N,N-dimethylthiocarbamoyl chloride

(1 equiv.) Ϫ a softer electrophile Ϫ in the presence of trie-

thylamine, compounds 4a and 4b gave the corresponding 8d

(53%) and 8e (63%), while 6a failed to react. A threefold

increase in the ratio of the electrophile to the enehydroxyl-

amines, coupled with substitution of the Et₃N by NaH, im-

proved the yields of the products 8dЈ (63%) and 8eЈ (84%)

and resulted in the rearrangement of a product derived

from 6a to yield 10b (30%). In this last reaction, however,

the major compound was the N-deoxy compound 10bЈ

(55%) (Table 2, Entry 10).

A C-2ϪC-Ar bond, produced by a 3,3-shift, could also

be established with a remarkable ease, as demonstrated by

treatment of 5a with 1-fluoro-2,4-dinitrobenzene in the

presence of NaH (1.3 equiv.). The product, phenol 11, pre-

sumably formed via the diethyl ether 11A, was obtained in

high yield (89%, Scheme 3). Similarly, 6a yielded the barbit-

urate derivative 12 (73%), a type of compound otherwise

difficult to obtain.

Scheme 3

Scheme 2

192

Eur. J. Org. Chem. 2003, 190Ϫ208

3,3-Sigmatropic Rearrangements of Enehydroxylamines

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4-Oxo-4,5,6,7-tetrahydroindoles

a view to achieve a short synthesis of N-monosubstituted

imidazolones fused to a carboxylic ring. Indeed, 4a, on

treatment with BrCN in the presence of Et₃N, furnished the

desired product 15a, albeit in a modest yield (36%, Table 3,

Entry 1, Scheme 5). With DABCO as the base, however,

a vastly improved yield of the same compound (81%) was

obtained (Entry 2). Other enehydroxylamines with bulky al-

kyl substituents at the nitrogen atom, such as isopropyl (4c)

or cyclohexyl (4d), were found to give poorer yields or no

reaction (Entries 4, 32%; Entry 5, no reaction).

When applied to 6a, the procedure also did not provide

the analogous imidazolinone. Instead, the spectral and ana-

lytical data of the only compound isolated (in 7.5% yield)

from a very complex mixture pointed to 5-bromo-1,3-di-

methyl-6-(methylamino)uracil (10aЈЈ). Clearly, the mixture

of DABCO and BrCN was acting as a brominating agent

in this instance. It is known that the species formed from

BrCN and 4-(dimethylamino)pyridine exists essentially as

N-cyano-4-(dimethylamino)pyridinium bromide (CAP).^[18]

Use of this reagent for treatment of 6a in stoichiometric

quantities provided a mixture of the N-cyanated and the

non-cyanated imidazolinones. With an excess of this re-

agent, however, the cyanamide 16a could be obtained in

high yield (79%, Table 3, Entry 11, Scheme 6). Reactions

with other enehydroxylamines took a similar course.

Of relevance in this context is the unique ability of this

reagent to convert the sulfo nitrone 17 into the N-cyanoimi-

dazolone 18 in high yield. Alternative combinations of

BrCN^[19]with other bases exclusively afforded the α-bromo

nitrone 19 (Scheme 7).

4-Oxo-4,5,6,7-tetrahydroindoles derivatives have often

served as key intermediates^[17]for the preparation of im-

portant 4-substituted indoles. Treatment of 4a, 5a, and 6a

with methyl propiolate and dimethyl acetylenedicarboxylate

was therefore examined as a means to achieve such an end.

Accordingly, when equimolar amounts of 4a, Hünig’s base

and methyl propiolate were allowed to stand at room temp.,

a smooth reaction ensued (Table 2, Entry 13, Scheme 4).

The carbinol amine 13a, isolated in 82% yield, was readily

dehydrated in toluene under reflux to afford the synthetic-

ally useful pyrrolecarboxylate 14a (77%). In an analogous

manner, 5a gave Ϫ via the intermediate 13b (76%) Ϫ 14b

(74%). For the more reluctant 13c and 13d a catalytic

amount of p-toluenesulfonic acid proved essential for high

yields in the dehydration to the corresponding 14c and 14d.

Reactions with Benzoyl Chloride and Diethyl

Chlorophospate

While the reactions between enehydroxylamines and the

electrophiles discussed so far had given the rearranged

products directly, treatment of 4a with benzoyl chloride, on

the other hand, enabled the unrearranged 7f to be isolated

in 92% yield. This compound was then induced to proceed

to 8f (90%) by heating it in toluene at reflux (Table 4, Entry

1). Similarly 4b, 5a, and 5b gave 8g, 8h, and 8i in excellent

yields. Compound 6a similarly gave 9c, but the rearranged

product 10c spontaneously cyclised upon heating to give

the bicyclic 20 (Entry 5, Scheme 8). This structure was as-

signed on the basis of the following facts: the product was

found by mass spectrometry to be isomeric with 10c, it

lacked the IR absorption due to the carbonyl group of the

enolic benzoate, the diagnostic NHϪCH₃doublet of 10c, at

δ ϭ 2.98 ppm, now appeared as a singlet, and the low-field

resonances (δ ϭ 8.15Ϫ8.18 ppm) for the two aromatic H

atoms ortho to the carbonyl group of the benzoate were also

absent. The labile NϪH resonance of 10c at δ ϭ 4.56 ppm

was replaced in 20 by a signal, also exchangeable with D₂O,

at δ ϭ 6.17 ppm. Moreover, the compound’s ¹³C NMR

spectrum in CD₂Cl₂showed a quaternary carbon signal at

δ ϭ 126.9 ppm, which could be attributed to a tetrahedral

carbon atom. Similar values of tetrahedral carbon atoms

attached to two oxygen atoms, one nitrogen atom, and a

phenyl group have been reported.^[20]

Scheme 4

Imidazolinones

A system incorporating a cyano group linked to the N-

hydroxy group of the hydroxylamines was examined with

Eur. J. Org. Chem. 2003, 190Ϫ208

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L. V. Reis, A. M. Lobo, S. Prabhakar, M. P. Duarte

FULL PAPER

Table 3. Treatment of 4Ϫ6 with bromocyanogen and CAP

Entry

Starting material

(SM)

Electrophile

(E)

Ratio

SM/E

Conditions

Time t

[h]

Products

(yield^[a][%])

1

2

3

4

5

6

7

8

9

4a

4b

4c

4d

5a

6a

4a

4b

5a

6a

BrCN

CAP

1:1

A^[b]

B^[c]

B

A

0.5

2

1.0

0.5

30

1

15a (36)

15a (81)

15b (94)

15c (32)

N.R.

15d (83)

N.R.

15aЈ (80)

15bЈ (83)

15dЈ (89)

16a (79)

1:1.3

1:1.5

1:1

1:1.3

1:1

1:3

B

2

C^[d]

C

28

24

48

CAP

10

11

C

[a]

[b]

[c]

[d]

Isolated yields. Et₃N (1 equiv.), THF, 0 °C Ǟ room temp. DABCO (1.3 equiv.), THF, 0 °C Ǟ room temp. EtiPr₂N (1 equiv.),

THF, 50 °C.

Scheme 7

Scheme 5

Reactions with Phenyl Isocyanate

Unexpectedly, a class of closely related compounds failed

to behave chemically in a similar manner on thermolysis

(Scheme 9, Table 5). For instance, of the three structurally

similar carbamate derivatives 7k, 7l, and 9e, only the last

underwent rearrangement in toluene at reflux, to provide

the product, the vic-diamine 10e (55%) and the derivative

10bЈ (36%, Scheme 10, a).

However, the reluctance of 7k to participate usefully in

the rearrangement could be overcome if its anion was gen-

erated with NaH in THF and the resulting mixture was

heated under reflux (Scheme 11). Acidic workup, followed

Scheme 6

With diethyl chlorophosphate (Table 4, Entries 6 and 7), by purification gave

high-yield rearrangements converted 7j and 9d into 8j and C₂₀H₂₁N₃O₂. Its H NMR spectrum contained signals due

a

product (49%) analysing as

1

10d, respectively.

to 10 aromatic protons, two NH resonances at δ ϭ 7.53 and

Eur. J. Org. Chem. 2003, 190Ϫ208

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3,3-Sigmatropic Rearrangements of Enehydroxylamines

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Table 4. Reactions of 4Ϫ6 with benzoyl chloride and diethyl chlorophosphate

Entry

Starting material

(SM)

Electrophile

(E)

Ratio

SM/E

Conditions

Time t

[h]

Products (yield^[a][%])

Before rearrang.

After rearrang.

1

2

3

4

5

6

7

4a

4b

5a

5b

6a

5a

6a

PhC(O)Cl

(EtO)₂P(O)Cl

1:1

A^[b]

A

1.5

2

1

4

1.5

7f (92)

7g (88)

7h (97)

7i (97)

9c (79)

7j (86)

9d (86)

8f (90)

8g (90)

8h (94)

8i (85)

10c (22), 20 (58)

8j (77)

10d (78)

A

B^[c]

B

[a]

[b]

[c]

Isolated yields.

EtiPr₂N (1 equiv.), THF, 0 °C Ǟ room temp.; for 8, 10: reflux 7, 9 in toluene. NaH (1.2 equiv.), THF, 0 °C Ǟ

room temp.; for 8, 10: reflux 7, 9 intoluene.

Scheme 8

Scheme 10

6.70 ppm (each 1 H), and a singlet at δ ϭ 3.10 (3 H) ppm.

The absence of a signal due to the olefinic C-2 proton, in

conjunction with the presence of IR absorptions at ν˜ ϭ

3210, 1670, and 1595 cm^Ϫ1, uniquely defined it as 8k. It is

a general feature of all compounds of type 8 (R¹ϭ Me;

R²ϭ H) in this study that they exhibit the NϪCH₃¹H

NMR signal either as a broad singlet or as a doublet (J ഠ

Scheme 9

Table 5. Treatment of 4Ϫ6 with phenyl isocyanate and rearrangement

Entry

Starting material

(SM)

Electrophile

(E)

Ratio

SM/E

Conditions

Time t

[h]

Products (yield^[a][%])

Before rearrang. After rearrang.

1

2

3

4

5

6

4a

5a

6a

PhCNO

1:1

1:2.5

1:1

1:2.5

1:1

1:2.5

A^[b]

B^[c]

A

B

A

2

3

4

1.25

2

7k (90)

Ϫ

8k (84)

Ϫ

7l (85)

Ϫ^[d]

Ϫ

9e (95)

Ϫ

10e (55), 10bЈ (36)

10eЈ (47), 16b (51)

B

7

[a]

[b]

[c]

[d]

Isolated yields. EtiPr₂N (1 equiv.), THF, 0 °C Ǟ room temp. NaH (1.3 equiv.), THF, 0 °C Ǟ room temp. Complex mixture.

Eur. J. Org. Chem. 2003, 190Ϫ208

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L. V. Reis, A. M. Lobo, S. Prabhakar, M. P. Duarte

FULL PAPER

Scheme 11

5 Hz), sharpening or collapsing to a singlet on addition of referred to resonated as a triplet at δ ϭ 5.44 (1 H) ppm

D₂O. (collapsing to a singlet on irradiation at δ ഠ 2.2 ppm), while

It is proposed that the sodium salt 7kA undergoes two in 22 it appeared as a multiplet centred at higher field (δ ϭ

concurrent reactions on thermolysis, a rearrangement to 4.27 ppm). This information, coupled with their exact [M^ϩ],

7kC and a dissociation into PhNCO and the anion 7kAЈ. permitted unequivocal attribution of the structures shown.

It is the electrophile generated in this manner that reacts

with the intermediate 7kC to provide 7kD, which sub- presupposes that the starting material is wholly converted

sequently undergoes decarboxylation to afford 8k. into a mixture of N,O-disilylated derivatives 23A and 23B.

A mechanism that can be proposed for the above changes

The fact that product 8k was obtained in 84% yield when Both of these would, on rearrangement, give rise to the cor-

the above reaction was performed in the presence of an ex- responding silyl ethers of 24A and 24B, from which 21 and

cess of electrophile (Table 5, Entry 2) is consistent with the 22 are obtained on workup.

above argument. For reasons not clearly understood, no

An analogous change in the site of attack (C-4 vs. C-2)

useful products could be isolated from the dimedone deriv- was observed for the benzoate 7f, which, when subjected to

ative 7l, although the heterocycle 6a participated readily similar conditions (TBDMSCl instead of TMSCl), fur-

enough in a similar reaction to provide the rearranged 10eЈ, nished the benzoate 25 in 29% yield (Scheme 13). Interest-

which readily cyclised to the imidazolone 16b (Entry 6 in ingly, however, when a mixture containing 7f, prepared in

Scheme 10, b, above).

situ from 4a, PhC(O)Cl (1 equiv.) and a slight excess of

The ready availability and the relative stability of the en- NaH (1.3 equiv.) at 0 °C in THF, was heated to reflux (4 h)

ehydroxylamine derivative 7k prompted us to assess the the two isomeric benzoates 8f and 25 were isolated in al-

possibility of generating a new enamine system, also cap- most equal proportions (46% and 47% yields, respectively).

able of participating in a sigmatropic reaction. Accordingly,

A cursory examination of the reactions between 5a and

7k in THF was treated with KHMDS (3.3 equiv.) in the bromonitrile oxide and between 5a and (diethylamino)sul-

presence of excess TMSCl at Ϫ80 °C and the mixture was fur trifluoride (DAST) identified only the 5-bromo and the

allowed to warm to room temp. Acidic workup, followed 5-fluoro cyclic derivatives 26a and 26b, respectively, from

by purification of the resulting products furnished two com- the complex mixtures (Scheme 14).

pounds 21 and 22 in 54% and 14% yields, respectively

The Intramolecularity of the Rearrangement

(Scheme 12). The IR spectra of both compounds contained

absorptions characteristic of the enamino system. Whilst

The clean thermal reactions of the deuterium-labelled de-

1

the H NMR spectra of both compounds exhibited the C- rivative 7g-d₅and 7i were selected for mechanistic study

2 olefinic hydrogen atoms as singlets (1 H) with their ex- (Scheme 15). The rearrangement of 7g-d₅was conducted in

pected δ values, significant differences in chemical shift toluene at 100 °C in the presence of an equimolar amount

were observed for the C-4 protons. In 21 the hydrogen atom of compound 7i. This experiment gave only the two prod-

196

Eur. J. Org. Chem. 2003, 190Ϫ208

3,3-Sigmatropic Rearrangements of Enehydroxylamines

FULL PAPER

Scheme 12

ucts A and B. Their mass spectra were compared with those observed, indicating an intramolecular rearrangement. The

of authentic 8g, 8g-d₅, 8i, and 8i-d₅(Table 6). relative independence of the kinetic rate constant of the

The rearrangement could in principle take place either solvents employed while conducting the rearrangement of

intramolecularly (synchronously, or via a diradical or an 7g in toluene (ε ϭ 2.4) and DMSO (ε ϭ 48.8) at 373 K,

intimate ion-pair)^[21]or intermolecularly, in which case the (k_obsd.ϭ 3.7Ϯ0.4·10^Ϫ4s^Ϫ1and 1.5Ϯ0.2·10^{Ϫ4 Ϫ1}, respect-

s

appearance of crossover products would be expected. As ively), is consistent with a non-ionic transition state.^[22]

can easily be deduced from the results, the mass spectra of However, our data do not allow us to conclude whether the

compounds A and B correspond to those of authentic 8i rearrangement proceeds through a concerted mechanism or

and 8g-d₅, respectively; that is, no crossover products were a non-concerted one.^[23]

Eur. J. Org. Chem. 2003, 190Ϫ208

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L. V. Reis, A. M. Lobo, S. Prabhakar, M. P. Duarte

FULL PAPER

Scheme 13

Scheme 14

Scheme 15

Table 6. Mass spectrometric data for 8g, 8g-d₅, 8i, 8i-d₅, A, and B (Scheme 15)

8g

8g-d₅

8i

8i-d₅

A

B

m/z

(%)

m/z

(%)

m/z

(%)

m/z

(%)

m/z

(%)

m/z

(%)

321

216

188

105

91

(18.4)

(28.6)

(9.6)

(100.0)

(55.6)

(20.6)

326

216

188

110

91

(16.2)

(26.1)

(8.5)

(100.0)

(53.0)

(23.1)

349 (24.8)

244 (52.8)

216 (16.6)

105 (100.0)

91 (85.1)

77 (20.0)

354

244

216

110

91

(19.3)

(46.6)

(13.3)

(100.0)

(76.1)

(23.0)

349

244

216

105

91

(19.6)

(43.9)

(13.7)

(100.0)

(78.2)

(21.5)

326

216

188

110

91

(16.4)

(26.5)

(9.7)

(100.0)

(60.0)

(23.1)

77

82

77

82

198

Eur. J. Org. Chem. 2003, 190Ϫ208

3,3-Sigmatropic Rearrangements of Enehydroxylamines

FULL PAPER

125 (25.6), 113 (100.0). HR-MS: C₇H₁₁NO₂: calcd. 141.078979;

found 141.079164. Treatment of N-methylhydroxylamine hydro-

chloride (746 mg, 8.93 mmol) with cyclohexane-1,3-dione (1.00 g,

8.93 mmol) in toluene (15 mL) as described in General Procedure

A (30 min) gave 4a (201 mg) in only 16%.

Conclusions

O-Acyl and related derivatives of enehydroxylamines, of-

ten postulated as reactive intermediates, have been isolated

and their chemistry studied. It has been shown that com-

pounds with this functionality serve as starting materials

for the facile preparation not only of polyfunctional cyclo-

hexanes, namely 2,3- or 3,4-disubstituted cyclohexenones,

but also of heterocycles such as hydroindoles, 5,6-disubsti-

tuted uracils, and uric acid derivatives. Evidence for the in-

tramolecular nature of the rearrangement of O-benzoyl de-

rivatives of carbocyclic enehydroxylamines is provided.

Compound 4b: Treatment of N-benzylhydroxylamine hydrochloride

(1.00 g, 6.3 mmol) with cyclohexane-1,3-dione (471 mg, 4.2 mmol)

in toluene (50 mL) as described in General Procedure B (6 h) gave

4b as colourless crystals (93 mg, 87%). M.p. 113Ϫ115 °C (EtOAc/

petroleum ether). IR (KBr): ν˜ ϭ 3100Ϫ3200, 1555 cm^Ϫ1. ¹H NMR:

δ ϭ 1.86Ϫ1.93 (m, 2 H, 5-CH₂), 2.21 (t, J ϭ 6.3 Hz, 2 H, 4- or 6-

CH₂), 2.48 (t, J ϭ 6.3 Hz, 2 H, 6- or 4-CH₂), 4.76 (s, 2 H, CH₂Ph),

5.69 (s, 1 H, 2-H, D₂O exchange), 7.26Ϫ7.36 (m, 5 H, ArH), 9.53

(br. s, 1 H, OH, D₂O exchange) ppm. ¹³C NMR: δ ϭ 21.6, 25.6,

34.3, 56.8 (NCH₂Ph), 95.4 (C-2), 127.1, 127.1, 127.7, 128.6, 128.6,

135.3, 165.4 (C-3), 196.0 (C-1) ppm. EI-MS: m/z (%) ϭ 217 (3.1)

[M^ϩ], 201 (24.6), 173 (18.7), 144 (27.2), 91 (100.0). HR-MS:

C₁₃H₁₅NO₂: calcd. 217.110279; found 217.111588. Treatment of N-

benzylhydroxylamine hydrochloride (286 mg, 1.79 mmol) with

cyclohexane-1,3-dione (201 mg, 1.79 mmol) in toluene (5 mL) as

described in General Procedure A (7 h) gave 4b (54.4 mg) in only

14% yield.

Experimental Section

General: Melting points were determined with a Reichert Thermo-

var apparatus and are uncorrected. IR spectra were measured with

PerkinϪElmer 598 or 298 spectrophotometers. H and ¹³C NMR

1

spectra were recorded with a Varian Unity 300, unless stated other-

wise (Bruker ARX 400 spectrometer) with TMS as internal stand-

ard and solutions in CDCl₃. EI-MS spectra were recorded with

AEI MS-9, Kratos MS 25 RF, or Fisons TRIO 2000 spectrometers

at 70 eV, and HR-MS data were determined with an AutoSpecQ

spectrometer at Imperial College of Science, Technology and Medi-

cine, London. Elemental analyses were performed at the National

Institute of Industrial Engineering and Technology, Lisbon, and at

the Imperial College of Science, Technology and Medicine, Lon-

don. Thin layer chromatography (TLC) was performed on Merck

GF₂₅₄silica gel plates. Column chromatography was carried out on

Merck 60 silica gel (230Ϫ400 mesh). All solvents were purified by

standard procedures and anhydrous solvents were dried and

freshly distilled.

Compound 4c: Treatment of N-isopropylhydroxylamine hydro-

chloride (200 mg, 1.8 mmol) with cyclohexane-1,3-dione (200 mg,

1.8 mmol) in toluene (3 mL) as described in General Procedure A

(7 h) afforded 4c as a colourless oil (73 mg, 24%). IR (neat): ν˜ ϭ

1

3200Ϫ2500, 1550 cm^Ϫ1. H NMR: δ ϭ 1.30 (d, J ϭ 6.3 Hz, 6 H,

CH₃), 1.94Ϫ1.99 (m, 2 H, 5-CH₂), 2.27 (t, J ϭ 6.3 Hz, 2 H, 4- or

6-CH₂), 2.46 (t, J ϭ 6.3 Hz, 2 H, 6- or 4-CH₂), 4.07Ϫ4.14 [m, 1

H, NCH(CH₃)₂], 5.33 (br. s, 1 H, OH, D₂O exchange), 5.78 (s, 1

H, s, 2-H, D₂O exchange) ppm. EI-MS: m/z (%) ϭ 169 (60.1) [M^ϩ],

127 (40.6), 126 (47.4), 99 (87.7), 96 (100.0). HR-MS: C₉H₁₅NO₂:

calcd. 169.110279; found 169.110400.

Compound 4d: Treatment of N-cyclohexylhydroxylamine hydro-

chloride (290 mg, 1.91 mmol) with cyclohexane-1,3-dione (214 mg,

1.91 mmol) in toluene (5 mL) as described in General Procedure A

(47 h) yielded 4d as colourless crystals (91.8 mg, 23%). M.p.

Synthesis of Enehydroxylamines

General Procedure A: The N-alkylhydroxylamine hydrochloride (1

equiv.) and triethylamine (2 equiv.) were added at room temp. un-

der N₂to a vigorously stirred suspension of 1,3-dione (1 equiv.) in

toluene. The progress of the reaction was monitored by TLC (silica;

EtOAc/MeOH, 95:5). The toluene solution was then decanted and

the resulting residue was purified by PTLC (silica; EtOAc/MeOH,

95:5). General Procedure B: The N-alkylhydroxylamine hydro-

chloride (1.5 equiv.) was slowly added to a solution of triethylamine

(1.5 equiv.) in toluene, and the resulting dispersion was vigorously

stirred overnight under N₂at room temperature. Triethylammon-

ium chloride was then removed by filtration and washed several

times with toluene. A solution of the 1,3-dione (1 equiv.) in the

same solvent was slowly added to the filtrate solutions, and the

mixture was stirred at room temp. The toluene solution was then

decanted and the resulting solid was recrystallised from an appro-

priate solvent.

156Ϫ157 °C (Et₂O/CHCl₃). IR (KBr): ν˜ ϭ3245, 1540 cm^Ϫ^{1 1}H

.

NMR: δ ϭ 1.10Ϫ1.40 (m, 5 H), 1.61Ϫ1.78 (m, 3 H), 1.92Ϫ2.02

(m, 4 H), 2.30Ϫ2.34 (m, 4 H), 3.20Ϫ3.30 (m, 1 H), 4.69 (br. s, 1

H, OH, D₂O exchange), 5.16 (s, 1 H, 2-H) ppm. EI-MS: m/z (%) ϭ

193 (32.4), 112 (100.0). FAB-MS (glycerol): m/z (%) ϭ 210 (7.3)

[M^ϩϩ H], 194 (100.0) [M^ϩϩ H Ϫ O]. HR-MS: C₁₂H₁₉NO₂: calcd.

209.141549; found 209.144118.

Compound 5a: Treatment of N-methylhydroxylamine hydrochloride

(448 mg, 5.36 mmol) with 5,5-dimethylcyclohexane-1,3-dione

(500 mg, 3.57 mmol) in toluene (40 mL) as described in General

Procedure B (2 h) afforded 5a as colourless crystals (483 mg, 80%).

M.p. 158Ϫ160 °C (CHCl₃/n-hexane) (158Ϫ160 °C)^[14]. IR (KBr):

1

ν˜ ϭ 3100Ϫ2500, 1590, 1500 cm^Ϫ1. H NMR: δ ϭ 1.06 (s, 6 H, 5-

CH₃), 2.12 (s, 2 H, 4- or 6-CH₂), 2.30 (s, 2 H, 6- or 4-CH₂), 3.35

(s, 3 H, NCH₃), 4.77 (br. s, 1 H, OH, D₂O exchange), 5.52 (s, 1 H,

2-H, D₂O exchange) ppm. FAB-MS (glycerol): m/z (%) ϭ 170

(100.0) [M^ϩϩ H].

Compound 4a: Treatment of N-methylhydroxylamine hydrochloride

(1.67 g, 20.0 mmol) with cyclohexane-1,3-dione (1.50 g, 13.4 mmol)

in toluene (120 mL) as described in General Procedure B (6 h) gave

4a as colourless crystals (1.32 g, 70%). M.p. 126Ϫ128 °C (EtOAc/

Compound 5b: Treatment of N-benzylhydroxylamine hydrochloride

MeOH). IR (KBr): ν˜ ϭ 3000Ϫ2200, 1550 cm^Ϫ^{1 1}H NMR: δ ϭ (1000 mg, 6.27 mmol) with 5,5-dimethylcyclohexane-1,3-dione

.

1.91Ϫ1.99 (m, 2 H, 5-CH₂), 2.26 (t, J ϭ 6.4 Hz, 2 H, 4- or 6-CH₂),

(585 mg, 4.17 mmol) in toluene (80 mL) as described in General

2.50 (t, J ϭ 6.3 Hz, 2 H, 6- or 4-CH₂), 3.35 (s, 3 H, NCH₃), 5.46 Procedure B (6 h) afforded 5b as colourless crystals (686 mg, 68%).

(s, 1 H, 2-H, D₂O exchange), 7.62 (br. s,1 H, OH, D₂O exchange)

M.p. 142Ϫ143 °C (CHCl₃/n-hexane). IR (KBr): ν˜ ϭ 3433, 1538,

1

ppm. ¹³C NMR: δ ϭ 21.6, 25.8, 34.4, 40.7 (NCH₃), 94.6 (C-2),

1494 cm^Ϫ1. H NMR (400 MHz): δ ϭ 1.00 (s, 6 H, 5-CH₃), 2.08

165.1 (C-3), 195.3 (C-1) ppm. EI-MS: m/z (%) ϭ 141 (84.6) [M^ϩ], (s, 2 H, 4- or 6-CH₂), 2.31 (s, 2 H, 6- or 4-CH₂), 4.77 (s, 2 H,

Eur. J. Org. Chem. 2003, 190Ϫ208

199

L. V. Reis, A. M. Lobo, S. Prabhakar, M. P. Duarte

FULL PAPER

NCH₂Ph), 5.68 (s, 1 H, 2-H), 7.25Ϫ7.38 (m, 5 H, ArH) ppm. EI-

Compound 8a: Treatment of 4a (200 mg, 1.42 mmol) with meth-

MS: m/z (%) ϭ 245 (8) [M^ϩ], 144 (10), 91 (100.0). HR-MS: anesulfonyl chloride (163 mg, 1.42 mmol) in anhydrous THF

C₁₅H₁₉NO₂: calcd. 245.141579; found 245.141380.

(10 mL), as described above (1 h 30 min), gave 8a (270 mg, 87%)

as colourless crystals. M.p. 147Ϫ148 °C (Et₂O/CH₂Cl₂). IR (KBr):

1

ν˜ ϭ 3375, 1580, 1355, 1180 cm^Ϫ1. H NMR: δ ϭ 1.98Ϫ2.06 (m, 2

Compounds 6a and 10bЈ: NaHCO₃(4.20 g, 50 mmol) was added to

a

solution of N-methylhydroxylamine hydrochloride (2.99 g,

H, 5-CH₂), 2.42 (t, J ϭ 6.6 Hz, 2 H, 4- or 6-CH₂), 2.61 (t, J ϭ 6.3

Hz, 2 H, 6- or 4-CH₂), 2.98 (d, J ϭ 4.8 Hz, 3 H, NHCH₃, collapses

to s on irradiation at 5.61), 3.41 (s, 3 H, SCH₃), 5.61 (br. s, 1 H,

NH, D₂O exchange) ppm. EI-MS: m/z (%) ϭ 219 (10.4) [M^ϩ], 140

(52.3), 112 (100.0). HR-MS: C₈H₁₃NO₄S: calcd. 219.056530;

found 219.057511.

35.8 mmol) in ethanol (51 mL), and the resulting mixture was vig-

orously stirred at room temp. After 30 min, a solution of 6-chloro-

1,3-dimethyluracil^[13](2.50 g, 14.3 mmol) in the same solvent

(50 mL) was added, and the mixture was heated under reflux for

3 h. The mixture was then cooled and filtered, and the resulting

solid was washed several times with ethanol. The combined filtrates

were concentrated to dryness under reduced pressure and the resid-

ual oil was purified by CC (silica; EtOAc with gradual addition of

MeOH) to give 10bЈ (266 mg, 11%) followed by 6a (2.12 g, 80%),

both as colourless needles. Physical data for 6a: M.p. 152Ϫ154 °C

Compound 8b: Treatment of 4b (100 mg, 0.46 mmol) with meth-

anesulfonyl chloride (52.7 mg, 0.46 mmol) in anhydrous THF

(3 mL), as described above (40 min), gave 8b (114 mg, 84%) as col-

ourless prisms. M.p. 127Ϫ128 °C (Et₂O/CH₂Cl₂). IR (KBr): ν˜ ϭ

1

3380, 1635, 1575, 1330, 1165 cm^Ϫ1. H NMR: δ ϭ 1.90Ϫ1.98 (m,

(dec.) (EtOH). IR (KBr): ν˜ ϭ 3120, 1700, 1650 cm^Ϫ^{1 1}H NMR:

.

2 H, 5-CH₂), 2.36 (t, J ϭ 6.4 Hz, 2 H, 4- or 6-CH₂), 2.57 (t, J ϭ

6.0 Hz, 2 H, 6- or 4-CH₂), 3.35 (s, 3 H, SCH₃), 4.49 (d, J ϭ 6.3

Hz, 2 H, NHCH₂Ph, collapses to s on irradiation at 5.97), 5.97 (br.

s, 1 H, NH), 7.27Ϫ7.41 (m, 5 H, ArH) ppm. EI-MS: m/z (%) ϭ

295 (2.1) [M^ϩ], 216 (25.2), 188 (11.9), 91 (100.0). HR-MS:

C₁₄H₁₇NO₄S: calcd. 295.087830; found 295.087588.

δ ϭ 3.01 (s, 3 H, NCH₃), 3.33 (s, 3 H, NCH₃), 3.42 (s, 3 H, NCH₃),

5.70 (s, 1 H, 5-H, D₂O exchange), 5.98 (br. s, 1 H, OH, D₂O ex-

change) ppm. ¹³C NMR: δ ϭ 28.0, 32.8, 44.5, 86.6, 152.4, 160.7

(CϭO), 163.9 (CϭO) ppm. EI-MS: m/z (%) ϭ 169 (100.0) [M^ϩ

Ϫ

O]. FAB-MS (4-NBA): m/z ϭ 186 (100.0) [M^ϩϩ H]. C₇H₁₁N₃O₃:

calcd. C 45.40, H 5.99, N 22.69; found C 45.62, H 5.87, N 22.41.

Physical data for 10bЈ: M.p. 248Ϫ249 °C (EtOH) [244Ϫ245 °C^[13]

(H₂O)]. IR (KBr): ν˜ ϭ 3300, 1710, 1650 cm^Ϫ1. ¹H NMR: δ ϭ 2.86

(d, J ϭ 4.8 Hz, 3 H, NHCH₃, collapses to s on irradiation at 4.57),

3.22 (s, 3 H, NCH₃), 3.40 (s, 3 H, NCH₃), 4.57 (br. s, 1 H, NH),

4.86 (s, 1 H, 5-H) ppm. EI-MS: m/z (%) ϭ 169 (64.1) [M^ϩ], 82

(100.0).

Compound 8c: Treatment of 5a (100 mg, 0.59 mmol) with meth-

anesulfonyl chloride (67.6 mg, 0.59 mmol) in anhydrous THF

(5 mL), as described above (3 h), afforded 8c (135 mg, 93%) as col-

ourless prisms. M.p. 141Ϫ142 °C (CH₂Cl₂/Et₂O). IR (KBr): ν˜ ϭ

1

3385, 1590, 1355, 1180 cm^Ϫ1. H NMR: δ ϭ 1.14 (s, 6 H, 5-CH₃),

2.30 (s, 2 H, 4- or 6-CH₂), 2.45 (s, 2 H, 6- or 4-CH₂), 2.97 (d, J ϭ

5.4 Hz, 3 H, NHCH₃, collapses to s on irradiation at 5.55), 3.43

(s, 3 H, SCH₃), 5.55 (br. s, 1 H, NH, D₂O exchange) ppm. EI-MS

m/z (%) ϭ 247 (53.0), 168 (62.5), 140 (27.0), 139 (53.0), 56 (100.0).

C₁₀H₁₇NO₄S (247.3): calcd. C 48.56, H 6.93, N 5.56; found C

48.44, H 6.99, N 5.54.

Compound 6b and 6-(Benzylamino)-1,3-dimethyluracil: By a proced-

ure similar to the previous one, compounds 6b (55%) and 6-

(benzylamino)-1,3-dimethyluracil (12%) were obtained when N-

benzylhydroxylamine hydrochloride was used. Physical data for 6b:

M.p. 175Ϫ177 °C (CHCl₃/n-hexane). IR (KBr): ν˜ ϭ 3185, 1709,

1613 cm^{Ϫ1 1}H NMR: δ ϭ 3.28 (s, 3 H, NCH₃), 3.44 (s, 3 H,

.

Compound 10a and Compound 10aЈ: Treatment of 6a (163 mg,

0.88 mmol) with methanesulfonyl chloride (101 mg, 0.88 mmol) in

anhydrous THF (8 mL), as described above (1 h), and separation

of the resulting residue by PTLC (silica; EtOAc/petroleum ether,

1:1) gave 10a (94.8 mg, 41%) followed by 10aЈ (85.8 mg, 48%), both

as colourless crystals. Physical data for 10a: M.p. 148Ϫ149 °C

(CHCl₃/Et₂O). IR (KBr): ν˜ ϭ 3425, 1700, 1640, 1615, 1550, 1335,

NCH₃), 4.18 (s, 2 H, NCH₂Ph), 5.76 (s, 1 H, 5-H, D₂O exchange),

6.98 (br. s, 1 H, OH, D₂O exchange), 7.34Ϫ7.39 (m, 5 H, ArH)

ppm. ¹³C NMR: δ ϭ 28.0, 32.2, 61.0, 88.8, 128.2, 128.7, 128.8,

134.7, 152.4, 159.6 (CϭO), 163.4 (CϭO) ppm. EI-MS: m/z (%) ϭ

261 (1.5) [M^ϩ], 245 (13.4), 91 (100.0). HR-MS: C₁₃H₁₅N₃O₃: calcd.

261.110487; found 261.111342. Physical data for 6-(benzylamino)-

1,3-dimethyluracil: M.p. 158Ϫ159 °C (MeOH/petroleum ether). IR

1170 cm^{Ϫ1 1}H NMR: δ ϭ 3.16 (d, J ϭ 5.4 Hz, 3 H, NHCH₃,

.

(KBr): ν˜ ϭ 3241, 1698, 1626 cm^Ϫ^{1 1}H NMR: δ ϭ 3.28 (s, 3 H,

.

collapses to s on irradiation at 4.40), 3.17 (s, 3 H, NCH₃), 3.46 (s,

3 H, SCH₃), 3.48 (s, 3 H, NCH₃), 4.40 (br. s, 1 H, NH, D₂O ex-

change) ppm. EI-MS: m/z (%) ϭ 263 (5.9) [M^ϩ], 184 (53.5), 183

(36.7), 156 (36.7), 55 (100.0). C₁₈H₁₃N₃O₅S: calcd. C 36.50, H 4.89,

N 15.91; found C 36.70, H 4.89, N 15.92. Physical data for 10aЈ:

M.p. 192Ϫ193 °C (EtOAc/CHCl₃) (190Ϫ192 °C)^[24]. IR (KBr): ν˜ ϭ

NCH₃), 3.41 (s, 3 H, NCH₃), 4.24 (d, J ϭ 4.8 Hz, 2 H, NCH₂Ph),

4.86 (s, 1 H, 5-H, D₂O exchange), 5.16 (br. s, 1 H, NH, D₂O ex-

change), 7.28Ϫ7.38 (m, 5 H, ArH) ppm. EI-MS: m/z (%) ϭ 245

(29.1) [M^ϩ], 91 (100.0). HR-MS: C₁₃H₁₅N₃O₂: calcd. 245.116083;

found 245.116427.

1

3370, 1700, 1635 cm^Ϫ1. H NMR: δ ϭ 3.00 (d, J ϭ 5.7 Hz, 3 H,

Treatment of Enehydroxylamines with Methanesulfonyl Chloride.

General Procedure: N,N-Diisopropylethylamine (1 equiv.) and

methanesulfonyl chloride (1 equiv.) were added under N₂to a

stirred, ice-cooled suspension of enehydroxylamine (1 equiv.) in an-

hydrous THF. After 40 min, the mixture was allowed to stand at

room temp. until the reaction was complete. The organic salt was

removed by filtration and washed with anhydrous THF. The com-

bined organic filtrates were concentrated under reduced pressure,

and the resulting residue was dissolved in a mixture of diethyl ether

and dichloromethane (1:1) and washed with water. The aqueous

layer, after separation by decantation, was extracted several times

with diethyl ether and the combined organic layers were dried with

anhydrous sodium sulfate. Solvent removal under reduced pressure

furnished a residue, which was recrystallised.

NHCH₃, collapses to s on irradiation at 4.50), 3.38 (s, 3 H, NCH₃),

3.50 (s, 3 H, NCH₃), 4.50 (br. s, 1 H, NH, D₂O exchange) ppm.

EI-MS: m/z (%) ϭ 203/205 (100.0/32.6) [M^ϩ/M^ϩϩ 2], 168 (6.6),

167 (13.2).

Treatment of Enehydroxylamines with N,N-Dimethylthiocarbamoyl

Chloride. General Procedure A: Triethylamine (3 equiv.) and a solu-

tion of N,N-dimethylthiocarbamoyl chloride (3 equiv.) in anhyd-

rous THF were added under N₂to a stirred, ice-cooled suspension

of enehydroxylamine (1 equiv.) in the same solvent. After the reac-

tion was complete, the organic salt was removed by filtration and

washed several times with anhydrous THF. The combined filtrates

were concentrated at reduced pressure and the residue was purified

by PTLC (silica; EtOAc/MeOH, 95:5). General Procedure B: A 60%

200

Eur. J. Org. Chem. 2003, 190Ϫ208

3,3-Sigmatropic Rearrangements of Enehydroxylamines

FULL PAPER

dispersion of sodium hydride in mineral oil (2 equiv.) was added

under N₂to a stirred, ice-cooled suspension of enehydroxylamine

(1 equiv.) in anhydrous THF. After 1 h, a solution of N,N-dimethyl-

thiocarbamoyl chloride (3 equiv.) in the same solvent was added.

NMR: δ ϭ 2.77 (s, 6 H, CH₃), 3.02 (s, 3 H, CH₃), 3.43 (s, 3 H,

CH₃), 3.47 (s, 3 H, CH₃), 3.49 (s, 3 H, CH₃), 3.53 (s, 3 H, CH₃)

ppm. FAB-MS (glycerol): m/z (%) ϭ 360 (100.0) [M^ϩϩ H].

C₁₃H₂₁N₅O₃S₂(359.5): calcd. C 43.44, H 5.89, N 19.48; found C

When the reaction was complete, the solvent was removed under 43.74, H 6.12, N 19.57.

reduced pressure and a mixture of water and diethyl ether was ad-

Treatment of Enehydroxylamines with 1-Fluoro-2,4-dinitrobenzene.

ded to the residue. The aqueous layer was separated by decantation

and extracted several times with diethyl ether, and the combined

organic layers were dried with anhydrous sodium sulfate. Solvent

removal at reduced pressure left a yellow solid, which was purified

by PTLC (silica; EtOAc/MeOH, 95:5).

Compound 11: A 60% dispersion of sodium hydride in mineral oil

(40.6 mg, 1.69 mmol) was added under N₂and protected from light

to a stirred, ice-cooled suspension of 5a (220 mg, 1.3 mmol) in an-

hydrous THF (6 mL), followed 1 h later by 1-fluoro-2,4-dinitroben-

zene (315 mg, 1.69 mmol). After 1 h, the solvent was removed un-

der reduced pressure and the remaining residue was dissolved in

Compound 8d: Treatment of 4a (100 mg, 0.71 mmol) with N,N-di-

methyl-thiocarbamoyl chloride (263 mg, 2.13 mmol) in anhydrous water and extracted with ethyl acetate. The aqueous layer, after

THF (3 mL) as described in General Procedure A (24 h) afforded

separation by decantation, was neutralised with aqueous HCl (5%)

and extracted several times with ethyl acetate. The combined or-

8d (86.0 mg, 53%) as a colourless oil. IR (KBr): ν˜ ϭ 3300, 1660,

1560 cm^Ϫ1. ¹H NMR: δ ϭ 2.02Ϫ2.10 (m, 2 H, 5-CH₂), 2.50 (t, J ϭ ganic layers were dried with anhydrous sodium sulfate, the solvent

6.4 Hz, 2 H, 4- or 6-CH₂), 2.64 (t, J ϭ 6.3 Hz, 2 H, 6- or 4-CH₂),

2.96 (s, 3 H, NCH₃), 3.00 (d, J ϭ 5.1 Hz, 3 H, NHCH₃, collapses recrystallised to give 11 (388 mg, 89%) as yellow crystals. M.p. Ͼ

to s on irradiation at 6.26), 3.15 (s, 3 H, NCH₃), 6.26 (br. s, 1 H, 308 °C (EtOH/Et₂O). IR (KBr): ν˜ ϭ 3300, 1600, 1540, 1395,

NH) ppm. EI-MS: m/z (%) ϭ 228 (8.8) [M^ϩ], 183 (15.7), 156 (7.8), 1345 cm^Ϫ1. H NMR: δ ϭ 1.20 (s, 6 H, 5-CH₃), 2.33 (s, 2 H, 4- or

was removed under reduced pressure, and the resulting residue was

1

72 (100.0). HR-MS: C₁₀H₁₆N₂O₂S: calcd. 228.093250; found

228.093492.

6-CH₂), 2.49 (s, 2 H, 6- or 4-CH₂), 2.91 (d, J ϭ 4.8 Hz, 3 H,

NHCH₃, collapses to s on irradiation at 5.09), 3.46 (s, 1 H, OH,

D₂O exchange), 5.09 (br. s, 1 H, NH, D₂O exchange), 8.24 (d, J ϭ

3.0 Hz, 1 H, ArH), 8.93 (d, J ϭ 3.0 Hz, 1 H, ArH) ppm. FAB-

MS (glycerol): m/z (%) ϭ 336 (100.0) [M^ϩϩ H]. HR-MS (FAB):

C₁₅H₁₈N₃O₆: calcd. 336.119561; found 336.119026 [M^ϩϩ H].

Compound 8e: Treatment of 5a (100 mg, 0.59 mmol) with N,N-di-

methylthiocarbamoyl chloride (220 mg, 1.78 mmol) in anhydrous

THF (3 mL) as described in General Procedure A (4 h 30 min) gave

8e (95.2 mg, 63%) as colourless crystals. M.p. 116Ϫ117 °C (Et₂O/

1

CH₂Cl₂). IR (KBr): ν˜ ϭ 3380, 1670, 1630, 1570 cm^Ϫ1. H NMR:

Compound 12: Treatment of 6a (215 mg, 1.16 mmol) with 1-fluoro-

δ ϭ 1.17 (s, 6 H, 5-CH₃), 2.38 (s, 2 H, 4- or 6-CH₂), 2.46 (s, 2 H, 2,4-dinitrobenzene (280 mg, 1.50 mmol) in anhydrous THF (6 mL)

6- or 4-CH₂), 2.96 (s, 3 H, NCH₃), 2.99 (d, J ϭ 5.4 Hz, 3 H, as described above (2 h 40 min) gave, after recrystallisation of the

NHCH₃, collapses to s on irradiation at 6.24), 3.15 (s, 3 H, NCH₃), resulting residue, 12 (297 mg, 73%) as yellow crystals. M.p.

6.24 (br. s, 1 H, NH) ppm. EI-MS: m/z (%) ϭ 211 (100.0) [M^ϩ

Ϫ

208Ϫ210 °C (dec.) (CH₂Cl₂/EtOH). IR (KBr): ν˜ ϭ 3360, 1700,

1

HN(CH₃)₂], 196 (27.3), 182 (26.6), 155 (78.1). C₁₂H₂₀N₂O₂S 1600, 1550, 1340 cm^Ϫ1. H NMR: δ ϭ 2.60 (d, J ϭ 4.8 Hz, 3 H,

(256.4): calcd. C 56.22, H 7.86, N 10.93; found C 56.25, H 7.93,

N 10.74.

NHCH₃, collapses to s on irradiation at 4.30), 3.38 (s, 3 H, NCH₃),

3.56 (s, 3 H, NCH₃), 4.30 (br. s, 1 H, NH, D₂O exchange), 8.45 (d,

J ϭ 2.4 Hz, 1 H, ArH), 9.05 (d, J ϭ 2.4 Hz, 1 H, ArH), 11.46 (br.

s, 1 H, OH, D₂O exchange) ppm. FAB-MS (glycerol): m/z (%) ϭ

352 (100.0) [M^ϩϩ H]. C₁₃H₁₃N₅O₇(351.3): calcd. C 44.46, H 3.73,

N 19.94; found C 44.73, H 3.57, N 19.94.

Compound 8dЈ: Treatment of 4a (100 mg, 0.71 mmol) with N,N-

dimethylthiocarbamoyl chloride (263 mg, 2.13 mmol) in anhydrous

THF (4 mL) as described in General Procedure B (3 h 30 min) af-

forded 8dЈ (141 mg, 63%) as colourless crystals. M.p. 133Ϫ134 °C

(Et₂O/CH₂Cl₂). IR (KBr): ν˜ ϭ 1670, 1570 cm^Ϫ1

2.10Ϫ2.18 (m, 2 H, 5-CH₂), 2.62 (t, J ϭ 6.6 Hz, 2 H, 4- or 6-CH₂),

.

¹H NMR: δ ϭ Treatment of Enehydroxylamines with Methyl Propiolate or Di-

methyl Acetylenedicarboxylate. General Procedure: N,N-Diisoprop-

2.74 (t, J ϭ 6.3 Hz, 2 H, 6- or 4-CH₂), 2.86 [s, 6 H, N(CH₃)₂], 3.19 ylethylamine (1 equiv.) was added under N₂to a stirred, ice-cooled

(s, 3 H, NCH₃), 3.48 [s, 6 H, N(CH₃)₂] ppm. EI-MS: m/z (%) ϭ suspension of enehydroxylamine (1 equiv.) in anhydrous THF, fol-

315 (50.0) [M^ϩ], 271 (27.5), 270 (24.0), 243 (100.0), 211 (94.0).

C₁₃H₂₁N₃O₂S₂(315.5): calcd. C 49.50, H 6.71, N 13.32; found C

49.52, H 6.73, N 13.23.

lowed 30 min later by dropwise addition of methyl propiolate or

dimethyl acetylenedicarboxylate (1 equiv.). When the reaction was

complete, the solvent was removed under reduced pressure and the

resulting residue was washed with diethyl ether and purified by

PTLC or recrystallisation.

Compound 8eЈ: Treatment of 5a (100 mg, 0.59 mmol) with N,N-

dimethylthiocarbamoyl chloride (219 mg, 1.77 mmol) in anhydrous

THF (5 mL) as described in General Procedure B (4 h) afforded

Compound 13a: Treatment of 4a (150 mg, 1.06 mmol) with methyl

8eЈ (170 mg, 84%) as colourless crystals. M.p. 125Ϫ126 °C (Et₂O/ propiolate (89.0 mg, 1.06 mmol) in anhydrous THF (4 mL) as de-

1

CH₂Cl₂). IR (KBr): ν˜ ϭ 1690, 1650 cm^Ϫ1. H NMR: δ ϭ 1.18 (s,

6 H, 5-CH₃), 2.51 (s, 2 H, 4- or 6-CH₂), 2.56 (s, 2 H, 6- or 4-CH₂), sulting residue by PTLC (silica; EtOAc/MeOH, 98:2) gave 13a

2.87 [s, 6 H, N(CH₃)₂], 3.19 (s, 3 H, NCH₃), 3.48 [s, 6 H, N(CH₃)₂] (196 mg, 82%) as a colourless oil. IR (KBr): ν˜ ϭ 3400Ϫ2700, 1740,

ppm. EI-MS: m/z (%) ϭ 343 (80.5) [M^ϩ], 299 (21.7), 271 (75.2), 1600, 1550, 1520 cm^Ϫ1. ¹H NMR: δ ϭ 1.99Ϫ2.06 (m, 2 H, 6-CH₂),

scribed in the General Procedure (48 h) and purification of the re-

239 (78.9), 72 (100.0). C₁₅H₂₅N₃O₂S₂(343.5): calcd. C 52.45, H

7.34, N 12.23; found C 52.49, H 7.41, N 12.13.

2.14Ϫ2.50 (m, 4 H, 5- and 7-CH₂), 3.03 (s, 3 H, NCH₃), 3.70 (s, 3

H, OCH₃), 3.74 (br. s, 1 H, 3-H), 5.28 (d, J ϭ 2.7 Hz, 1 H, 2-H),

6.40 (br. s, 1 H, OH, D₂O exchange) ppm. FAB-MS (4-NBA): m/z

(%) ϭ 226 (100.0) [M^ϩϩ H], 208 (18.2) [M^ϩϩ H Ϫ H₂O], 166

(55.6). HR-MS (CI, ammonia): C₁₁H₁₆NO₄: calcd. 226.107933;

found 226.109193 [M^ϩϩ H].

Compounds 10b and 10bЈ: Treatment of 6a (100 mg, 0.54 mmol)

with N,N-dimethylthiocarbamoyl chloride (200 mg, 1.62 mmol) in

anhydrous THF (3 mL) as described in General Procedure B (4 h

30 min) gave 10b (58.2 mg, 30%) and 10bЈ (50.2 mg, 55%), both as

colourless crystals. Physical data for 10b: M.p. 215Ϫ216 °C (Et₂O/

Compound 14a: A solution of 13a (95.0 mg, 0.42 mmol) in toluene

CH₂Cl₂). IR (KBr): ν˜ ϭ 1710, 1660, 1580, 1440, 1380 cm^Ϫ1

.

¹H was heated under reflux (5 h 30 min) and the reaction mixture was

Eur. J. Org. Chem. 2003, 190Ϫ208

201

L. V. Reis, A. M. Lobo, S. Prabhakar, M. P. Duarte

FULL PAPER

worked up as described above to afford 14a (66.9 mg, 77%) as col-

OCH₃), 4.19 (s, 1 H, 3-H), 4.72 (s, 1 H, OH, D₂O exchange) ppm.

ourless crystals. M.p. 167Ϫ168 °C (CH₂Cl₂/Et₂O). IR (KBr): ν˜ ϭ

FAB-MS (glycerol): m/z (%) ϭ 312 (100.0) [M^ϩϩ H]. HR-MS (CI,

1

1720, 1660 cm^Ϫ1. H NMR: δ ϭ 2.08Ϫ2.17 (m, 2 H, 6-CH₂), 2.43 ammonia): C₁₅H₂₂NO₆: calcd. 312.144713; found 312.145444 [M^ϩ

(d, J ϭ 6.9 Hz, 1 H, 7-HЈ), 2.44 (d, J ϭ 7.5 Hz, 1 H, 7-H), 2.72 ϩ H].

(m, 2 H, 5-CH₂₎3.55 (s, 3 H, NCH₃or OCH₃), 3.76 (s, 3 H, OCH₃

Compound 14d: A solution of 13d (146 mg, 0.47 mmol) and p-tolu-

or NCH₃), 7.19 (s, 1 H, 2-H) ppm. EI-MS: m/z (%) ϭ 207 (43.9)

enesulfonic acid (8.94 mg, 0.047 mmol) in toluene was heated under

[M^ϩ], 179 (48.5), 176 (19.7), 121 (100.0). C₁₁H₁₃NO₃(207.2): calcd.

reflux for 1 h. Solvent removal at reduced pressure and purification

C 63.76, H 6.32, N 6.76; found C 63.72, H 6.19, N 6.71.

of the resulting residue by PTLC (silica; EtOAc) afforded 14d

Compound 13b: Treatment of 5a (100 mg, 0.59 mmol) with methyl

propiolate (50.0 mg, 0.59 mmol) in anhydrous THF (4 mL) as de-

(121 mg, 88%) as colourless crystals. M.p. 146Ϫ147 °C (Et₂O/

1

CH₂Cl₂). IR (KBr): ν˜ ϭ 1730, 1715, 1675, 1490 cm^Ϫ1. H NMR:

scribed above (96 h) afforded, after recrystallisation from EtOAc, δ ϭ 1.14 (s, 6 H, 6-CH₃), 2.37 (s, 2 H, 7-CH₂), 2.64 (s, 2 H, 5-

13b (113 mg, 76%) as colourless crystals. M.p. 147Ϫ149 °C (dec.) CH₂), 3.82 (s, 3 H, OCH₃or NCH₃), 3.83 (s, 3 H, OCH₃or NCH₃),

(CH₂Cl₂/Et₂O). IR (KBr): ν˜ ϭ 3300Ϫ2600, 1740, 1590, 1550,

3.94 (s, 3 H, NCH₃or OCH₃) ppm. FAB-MS (glycerol): m/z (%) ϭ

1510 cm^Ϫ^{1 1}H NMR: δ ϭ 1.09 (s, 3 H, 6-CH₃), 1.12 (s, 3 H, 6- 294 (33.3) [M^ϩϩ H]. C₁₅H₁₉NO₅(293.3): calcd. C 61.42, H 6.53,

.

CH₃), 2.16 (s, 2 H, CH₂), 2.26 (s, 2 H, CH₂), 3.01 (s, 3 H, NCH₃),

3.70 (s, 3 H, OCH₃), 3.76 (br. s, 1 H, 3-H), 4.84 (br. s, 1 H, OH,

D₂O exchange), 5.26 (d, J ϭ 1.8 Hz, 1 H, 2-H) ppm. EI-MS: m/z

(%) ϭ 253 (10.4) [M^ϩ], 235 (40.7) [M^ϩϪ H₂O], 221 (21.2), 194

(46.7), 179 (100.0). C₁₃H₁₉NO₄(253.3): calcd. C 61.64, H 7.56, N

5.53; found C 61.48, H 7.41, N 5.46.

N 4.78; found C 61.45, H 6.40, N 4.76.

Treatment of Enehydroxylamines with Bromocyanogen. General Pro-

cedure A: Bromocyanogen (1 equiv.) was added under N₂to a

stirred suspension of enehydroxylamine (1 equiv.) and triethylamine

(1 equiv.) in anhydrous THF. After the reaction was complete, the

solvent was removed under reduced pressure and the remainder

solid was dissolved in dichloromethane. This solution was washed

with water and dried with anhydrous sodium sulfate, and the solv-

ent was removed under reduced pressure. The dark residues ob-

tained were purified by PTLC (silica, EtOAc). General Procedure

Compound 14b: A solution of 13b (100 mg, 0.4 mmol) in toluene

was heated under reflux for 7 h 30 min. Solvent removal at reduced

pressure and purification of the resulting residue by PTLC (silica,

EtOAc/MeOH, 95:5) gave 14b (69.6 mg, 74%), as colourless crys-

tals. M.p. 142Ϫ143 °C (CH₂Cl₂/Et₂O). IR (KBr): ν˜ ϭ 1730, B: Bromocyanogen (1.3Ϫ1.5 equiv.) was added under N₂to a

1

1660 cm^Ϫ1. H NMR, [D₆]acetone: δ ϭ 1.09 (s, 6 H, 6-CH₃), 2.27

(s, 2 H, CH₂), 2.72 (s, 2 H, CH₂), 3.67 (s, 3 H, NCH₃or OCH₃), DABCO (1.3Ϫ1.5 equiv.) in anhydrous THF. After the reaction

3.69 (s, 3 H, OCH₃or NCH₃), 7.33 (s, 1 H, 2-H) ppm. EI-MS: was complete, the solvent was removed under reduced pressure, and

m/z (%) ϭ 235 (41.2) [M^ϩ], 220 (3.2), 204 (17.7), 179 (100.0). dichloromethane and water were added to the residual solid. The

stirred, ice-cooled suspension of enehydroxylamine (1 equiv.) and

C₁₃H₁₇NO₃(235.2): calcd. C 66.36, H 7.28, N 5.95; found C 66.34,

H 7.29, N 5.98.

aqueous layer, after separation by decantation, was extracted with

dichloromethane and/or ethyl acetate. The combined organic layers

were dried with anhydrous sodium sulfate, the solvent was removed

under reduced pressure, and the resulting residue was recrystallised

from an appropriate solvent.

Compound 13c: Treatment of 4a (300 mg, 2.1 mmol) with dimethyl

acetylenedicarboxylate (300 mg, 2.1 mmol) in anhydrous THF

(10 mL) as described in the General Procedure (40 h) afforded 13c

(410 mg, 69%) as colourless crystals. M.p. 163Ϫ165 °C (dec.) Compound 15a: Treatment of 4a (63.5 mg, 0.45 mmol) with BrCN

(Et₂O/MeOH). IR (KBr): ν˜ ϭ 3260Ϫ2600, 1750, 1550, 1500 cm^Ϫ1

.

(47.7 mg, 0.45 mmol) in anhydrous THF (3 mL) as described in

¹H NMR: δ ϭ 2.07Ϫ2.16 (m, 2 H, 6-CH₂), 2.25Ϫ2.58 (m, 4 H, 5 General Procedure A (30 min) gave 15a (26.9 mg, 36%) as colour-

and 7-CH₂), 2.82 (s, 3 H, NCH₃), 3.68 (s, 3 H, OCH₃), 3.83 (s, 3 less crystals. M.p. 241Ϫ242 °C (dec.) (Et₂O/CH₂Cl₂). IR (KBr):

1

H, OCH₃), 4.10 (s, 1 H, 3-H), 4.81 (br. s, 1 H, OH, D₂O exchange)

ν˜ ϭ 3230, 1725, 1690, 1625 cm^Ϫ1. H NMR: δ ϭ 2.15Ϫ2.24 (m, 2

ppm. EI-MS: m/z (%) ϭ 283 (81.0) [M^ϩ], 265 (38.0) [M^ϩϪ H₂O], H, CH₂), 2.50 (t, J ϭ 6.6 Hz, 2 H, CH₂), 2.67 (t, J ϭ 6.0 Hz, 2 H,

251 (18.6), 224 (61.2), 164 (100.0). HR-MS (CI, ammonia): CH₂), 3.28 (s, 3 H, NCH₃), 8.72 (br. s, 1 H, NH, D₂O exchange)

C₁₃H₁₈NO₆: calcd. 284.113413; found 284.112759 [M^ϩϩ H].

ppm. EI-MS: m/z (%) ϭ 166 (100.0) [M^ϩ], 137 (61.0), 110 (26.3) .

HR-MS: C₈H₁₀N₂O₂: calcd. 166.074228; found 166.073808. Treat-

ment of 4a (353 mg, 2.5 mmol) with BrCN (344 mg, 3.25 mmol) in

anhydrous THF (15 mL) as described in General Procedure B (2 h)

afforded 15a (336 mg, 81%).

Compound 14c: A solution of 13c (127 mg, 0.45 mmol) and p-tolu-

enesulfonic acid (8.56 mg, 0.045 mmol) in toluene was heated at

reflux for 1 h 30 min. Solvent removal under reduced pressure and

recrystallisation from Et₂O/CH₂Cl₂, afforded 14c (107 mg, 90%) as

colourless crystals. M.p. 127Ϫ128 °C. IR (KBr): ν˜ ϭ 1740, 1710,

Compound 15b: Treatment of 4b (1.00 g, 4.61 mmol) with BrCN

1

1670 cm^Ϫ1. H NMR: δ ϭ 2.14Ϫ2.23 (m, 2 H, CH₂), 2.49 (d, J ϭ (732 mg, 6.91 mmol) in THF (25 mL) as described in General Pro-

6.9 Hz, 1 H, 7-HЈ), 2.51 (d, J ϭ 6.9 Hz, 1 H, 7-H), 2.79 (m, 2 H,

CH₂), 3.82 (s, 3 H, OCH₃or NCH₃), 3.84 (s, 3 H, OCH₃or NCH₃), 184Ϫ185 °C (CH₂Cl₂/Et₂O). IR (KBr): ν˜ ϭ 3100, 1715, 1655 cm^Ϫ1

3.95 (s, 3 H, NCH₃or OCH₃) ppm. EI-MS: m/z (%) ϭ 265 (86.4)

¹H NMR: δ ϭ 2.04Ϫ2.13 (m, 2 H, CH₂), 2.43 (t, J ϭ 6.0 Hz, 2 H,

cedure B (1 h) afforded 15b (1.05 g, 94%) as white needles. M.p.

.

[M^ϩ], 237 (100.0), 234 (72.7), 179 (31.8). HR-MS (CI, ammonia): CH₂), 2.53 (t, J ϭ 6.9 Hz, 2 H, CH₂), 4.90 (s, 2 H, NCH₂Ph),

C₁₆H₁₄NO₅: calcd. 266.105528; found 266.104713 [M^ϩϩ H].

7.25Ϫ7.40 (m, 5 H, ArH), 10.20 (br. s, 1 H, NH, D₂O exchange)

ppm. ¹³C NMR: δ ϭ 21.1, 22.9, 36.7, 45.2 (NCH₂Ph), 128.3, 127.6,

128.2, 129.2, 136.7, 141.2, 154.2 (CϭO), 185.8 (CϭO) ppm. EI-

MS: m/z (%) ϭ 242 (100.0) [M^ϩ], 151 (2.37), 91 (43.6). HR-MS:

C₁₄H₁₄N₂O₂: calcd. 242.105528; found 242.103999.

Compound 13d: Treatment of 5a (372 mg, 2.2 mmol) with dimethyl

acetylenedicarboxylate (313 mg, 2.2 mmol) in anhydrous THF

(10 mL) as described in the General Procedure (40 h) afforded 13d

(479 mg, 70%) as colourless crystals. M.p. 160Ϫ162 °C (dec.)

(Et₂O/CH₂Cl₂). IR (KBr): ν˜ ϭ 3000Ϫ2500, 1750, 1590, 1550, Compound 15c: Treatment of 4c (65.9 mg, 0.39 mmol) with BrCN

1500 cm^{Ϫ1 1}H NMR: δ ϭ 1.11 (s, 3 H, 6-CH₃), 1.16 (s, 3 H, 6- (41.3 mg, 0.39 mmol) in THF (3 mL) as described in General Pro-

.

CH₃), 2.23 (d, J ϭ 4.2 Hz, 2 H, CH₂), 2.29 (d, J ϭ 8.4 Hz, 2 H, cedure A (30 min) afforded 15c (24.2 mg, 32%) as colourless crys-

CH₂), 2.82 (s, 3 H, NCH₃), 3.76 (s, 3 H, OCH₃), 3.89 (s, 3 H, tals. M.p. 246Ϫ247 °C (dec.) (EtOAc/petroleum ether). IR (KBr):

202

Eur. J. Org. Chem. 2003, 190Ϫ208

3,3-Sigmatropic Rearrangements of Enehydroxylamines

FULL PAPER

ν˜ ϭ 3200, 1730, 1695, 1650 cm^Ϫ1. ¹H NMR: δ ϭ 1.47 [d, 6 H, J ϭ

Compound 16a: CAP (370 mg, 1.62 mmol) in anhydrous THF

6.9 Hz, CH(CH₃)₂, collapses to s on irradiation at the frequency of (7.0 mL) was treated with 6a (100 mg, 0.54 mmol), as described in

CH(CH₃)₂], 2.14Ϫ2.23 (m, 2 H, CH₂), 2.48 (t, J ϭ 6.6 Hz, 2 H, the General Procedure (48 h). The reaction mixture was filtered,

CH₂), 2.77 (t, J ϭ 6.3 Hz, 2 H, CH₂), 4.47 [m, 1 H, CH(CH₃)₂, and water and chloroform were added to the remaining residue.

collapses to s on irradiation at the frequency of CH(CH₃)₂], 8.57

After separation of the resulting solid by filtration, washing with

(br. s, 1 H, NH, D₂O exchange) ppm. EI-MS: m/z (%) ϭ 194 (50.5) cool water and recrystallisation yielded 16a (100 mg, 79%), as col-

[M^ϩ], 152 (100.0). HR-MS: C₁₀H₁₄N₂O₂: calcd. 194.105528;

found 194.106569.

ourless crystals. M.p. 307Ϫ308 °C (dec.) (CH₃CN). IR (KBr): ν˜ ϭ

2260, 1775, 1765, 1710, 1700, 1670 cm^Ϫ^{1 1}H NMR [D₃]aceto-

nitrile: δ ϭ 3.27 (s, 3 H, NCH₃), 3.55 (s, 3 H, NCH₃); 3.62 (s, 3 H,

NCH₃) ppm. FAB-MS (4-NBA): m/z (%) ϭ 236 (100.0) [M^ϩ

.

Compound 15d: Treatment of 5a (514 mg, 3.04 mmol) with BrCN

(418 mg, 3.95 mmol) in THF (20 mL) as described in General Pro-

cedure B (1 h) yielded 15d (489 mg, 83%) as white needles. M.p.

236Ϫ238 °C (dec.) (Et₂O/CH₂Cl₂). IR (KBr): ν˜ ϭ 3100, 1695,

ϩ

H]. HR-MS (CI, ammonia): C₉H₁₀N₅O₃: calcd. 236.078364; found

236.078536 [M^ϩϩ H].

Compound 17: N-Methylhydroxylamine hydrochloride (1077 mg,

12.9 mmol) and sodium acetate (1058 mg, 12.9 mmol) were added

to a solution of 1-phenyl-2-(phenylsulfonyl)ethanone^[25](560 mg,

2.15 mmol) in ethanol (2 mL), and the resulting mixture was heated

at 40 °C for 8 d. The reaction mixture was then diluted with water

and neutralised with NaHCO₃. The aqueous layer, after separation

by decantation, was extracted several times with dichloromethane.

The combined organic layers were dried with anhydrous magnes-

ium sulfate and the solvent was removed at reduced pressure to give

17 (510 mg, 82%) as colourless crystals. M.p. 139Ϫ140 °C (CH₂Cl₂/

MeOH). IR (KBr): ν˜ ϭ 1550, 1320, 1145 cm^Ϫ1. ¹H NMR: δ ϭ 3.61

(s, 3 H, NCH₃), 4.83 (s, 2 H, 2-CH₂), 7.35Ϫ7.56 (m, 7 H, Ar-H),

7.62Ϫ7.67 (m, 1 H, Ar-H), 7.98Ϫ8.01 (m, 2 H, Ar-H) ppm. EI-

MS: m/z (%) ϭ 289 (1.6) [M^ϩ], 273 (7.6) [M^ϩϪ O], 149 (61.0) [M^ϩ

Ϫ SO₂Ph ϩ H], 148 (38.5) [M^ϩϪ SO₂Ph], 103 (100.0) [PhCN^ϩ].

C₁₅H₁₅NO₃S (289.4): calcd. C 62.27, H 5.23, N 4.84; found C

62.32, H 5.34, N 4.89.

1

1655 cm^Ϫ1. H NMR: δ ϭ 1.17 (s, 6 H, CH₃), 2.37 (s, 2 H, CH₂),

2.53 (s, 2 H, CH₂), 3.26 (s, 3 H, NCH₃), 9.05 (br. s, 1 H, NH, D₂O

exchange) ppm. EI-MS: m/z (%) ϭ 194 (100.0) [M^ϩ], 179 (17.9),

138 (24.2), 110 (44.7). C₁₀H₁₄N₂O₂(194.2): calcd. C 61.84, H 7.27,

N 14.42; found C 61.90, H 7.10, N 14.40.

Treatment of Enehydroxylamines with N-Cyano-4-(dimethylamino)-

pyridinium Bromide (CAP). General Procedure: Cyanogen bromide

(1 equiv.) was added under N₂to a stirred, ice-cooled solution of

4-DMAP (1 equiv.) in anhydrous THF. After 30 min, a solution of

enehydroxylamine (0.3 equiv.) and N,N-diisopropylethylamine (0.3

equiv.) in the same solvent was added to the freshly prepared CAP,

and the mixture was heated at 50 °C until the reaction was com-

plete. The solvent was then removed under reduced pressure, and

water and dichloromethane were added to the remaining residue.

The aqueous layer, after separation by decantation, was extracted

several times with dichloromethane, and the combined organic

layers were dried with anhydrous sodium sulfate. Solvent removal

under reduced pressure furnished a residue, which was recrys-

tallised.

Compound 18: CAP (192.4 mg, 1.04 mmol) in anhydrous THF

(1.0 mL) was treated with a solution of 17 (40.5 mg, 0.35 mmol)

and N,N-diisopropylethylamine (0.35 mmol) in the same solvent

(1.5 mL), as described in the General Procedure (24 h). The reac-

tion mixture was filtered and the residual solid was washed several

times with diethyl ether. Removal of solvent from the combined

diethyl ether solutions at reduced pressure afforded 18 (95 mg,

80%) as colourless crystals. M.p. 177Ϫ178 °C (EtOH). IR (KBr):

Compound 15aЈ: Treatment of CAP (486 mg, 2.13 mmol) in anhyd-

rous THF (5.0 mL) with a solution of 4a (100 mg, 0.71 mmol) in

the same solvent, as described in the General Procedure (28 h) gave

15aЈ (108 mg, 80%) as colourless prisms. M.p. 204Ϫ205 °C

(EtOAc). IR (KBr): ν˜ ϭ 2230, 1760, 1670 cm^Ϫ^{1 1}H NMR: δ ϭ

.

ν˜ ϭ 2270, 1750, 1370, 1160 cm^Ϫ^{1 1}H NMR: δ ϭ 3.03 (s, 3 H,

.

2.20 (m, 2 H, CH₂), 2.54 (t, J ϭ 6.6 Hz, 2 H, CH₂), 2.75 (t, J ϭ

6.0 Hz, 2 H, CH₂), 3.32 (s, 3 H, NCH₃) ppm. EI-MS: m/z (%) ϭ

191 (100.0) [M^ϩ], 176 (16.4), 163 (86.8), 135 (63.8). C₉H₉N₃O₂

(191.2): calcd. C 56.54, H 4.74, N 21.98; found C 56.45, H 4.72,

N 22.06.

NCH₃), 7.34Ϫ7.37 (m, 2 H, Ar-H), 7.54Ϫ7.67 (m, 6 H, Ar-H),

7.75Ϫ7.78 (m, 2 H, Ar-H) ppm. ¹³C NMR: δ ϭ 29.6, 102.5, 116.0,

124.2, 127.8, 128.9, 129.6, 129.9, 131.4, 134.5, 135.9, 140.0, 150.1

ppm. FAB-MS (4-NBA): m/z (%) ϭ 340 (100.0) [M^ϩϩ H], 339

(66.1) [M^ϩ], 314 (6.5) [M^ϩϩ H Ϫ CN], 173 (28.3) [M^ϩϩ H Ϫ

CN Ϫ SO₂Ph]. C₁₇H₁₃N₃O₃S (339.4): calcd. C 60.55, H 3.79, N

12.27; found C 60.37, H 3.83, N 12.28.

Compound 15bЈ: Treatment of CAP (315 mg, 1.38 mmol) in anhyd-

rous THF (7.0 mL) with 4b (100 mg, 0.46 mmol), as described in

the General Procedure (24 h), yielded 15bЈ (102 mg, 83%) as col-

ourless prisms. M.p. 160Ϫ161 °C (CH₂Cl₂/Et₂O). IR (KBr): ν˜ ϭ

Compound 19: N,N-Diisopropylethylamine (0.28 mmol) and BrCN

(14.8 mg, 0.14 mmol) were added under N₂to a stirred, ice-cooled

solution of 17 (40.5 mg, 0.14 mmol) in anhydrous THF (5 mL).

After 1 h, the solvent was removed at reduced pressure and the

remaining residue was extracted several times with diethyl ether.

The combined ethereal solutions were concentrated to dryness to

yield 19 (42.8 mg, 83%) as white crystals. M.p. 130Ϫ131 °C (Et₂O/

1

2240, 1750, 1655 cm^Ϫ1. H NMR: δ ϭ 2.08Ϫ2.16 (m, 2 H, CH₂),

2.48 (t, J ϭ 6.6 Hz, 2 H, CH₂), 2.57 (t, J ϭ 6.0 Hz, 2 H, CH₂),

4.87 (s, 2 H, NCH₂Ph), 7.26Ϫ7.29 (m, 2 H, ArH), 7.36Ϫ7.43 (m,

3 H, ArH) ppm. EI-MS: m/z (%) ϭ 267 (12.1) [M^ϩ], 242 (5.4), 91

(100.0). HR-MS: C₁₅H₁₃N₃O₂: calcd. 267.100777; found

267.099921.

CHCl₃). IR (KBr): ν˜ ϭ 1585, 1530, 1335, 1160 cm^{Ϫ1 1}H NMR:

.

δ ϭ 3.59 (s, 3 H, NCH₃), 7.00 (s, 1 H, 2-H), 7.50Ϫ7.60 (m, 7 H,

Ar-H), 7.70 (br. t, J ϭ 7.2 Hz, 1 H, Ar-H), 7.97 (d, J ϭ 7.8 Hz, 2

H, Ar-H) ppm. EI-MS: m/z (%) ϭ 367/369 (0.1/0.1) [M^ϩ/M^ϩϩ 2],

351/353 (0.2/0.2) [(M^ϩϪ O)/(M^ϩϩ 2 Ϫ O)], 141 (21.8) [PhSO₂^ϩ],

118 (19.5) [M^ϩϪ CHBrSO₂Ph], 77 (100.0) [Ph^ϩ]. HR-MS:

C₁₅H₁₄⁸¹BrNO₃S: calcd. 368.985730; found 368.987268.

C₁₅H₁₄⁷⁹BrNO₃S: calcd. 366.987776; found 366.987639.

Compound 15dЈ: Treatment of CAP (406 mg, 1.78 mmol) in anhyd-

rous THF (8.0 mL) with 5a (100 mg, 0.59 mmol), as described

above (24 h), afforded 15dЈ (115 mg, 89%) as colourless crystals.

M.p. 184Ϫ185 °C (CH₂Cl₂/EtOAc). IR (KBr): ν˜ ϭ 2250, 1750,

1

1670 cm^Ϫ1. H NMR: δ ϭ 1.20 (s, 6 H, CH₃), 2.43 (s, 2 H, CH₂),

2.57 (s, 2 H, CH₂), 3.30 (s, 3 H, NCH₃) ppm. EI-MS: m/z (%) ϭ

219 (100.0) [M^ϩ], 204 (57.7), 191 (23.8), 163 (64.0), 135 (55.0).

C₁₁H₁₃N₃O₂(219.2): calcd. C 60.26, H 5.95, N 19.17; found C

59.94, H 5.97, N 19.05.

Treatment of Enehydroxylamines with Benzoyl Chloride. General

Procedure: N,N-Diisopropylethylamine (1 equiv.) and benzoyl

Eur. J. Org. Chem. 2003, 190Ϫ208

203

L. V. Reis, A. M. Lobo, S. Prabhakar, M. P. Duarte

chloride (1 equiv.) were added under N₂to a stirred, ice-cooled Compound 7i-d₅: Treatment of 5b (46 mg, 0.19 mmol) and [D₅]ben-

FULL PAPER

suspension of enehydroxylamine (1 equiv.) in anhydrous THF.

After the reaction was complete, the organic salt was removed by

filtration and washed with anhydrous THF. The filtrate was con-

centrated to dryness, and the resulting residue was dissolved in a

mixture of diethyl ether and dichloromethane (1:2) and washed

with water. The aqueous layer, after separation by decantation, was

extracted several times with diethyl ether, and the combined organic

layers were dried with anhydrous sodium sulfate. Solvent removal

under reduced pressure gave a residue, which was recrystallised.

zoyl chloride (27.6 mg, 0.19 mmol) in anhydrous THF (1.5 mL) as

described in the General Procedure (1 h) gave 7i-d₅(68 mg, 99%)

as a colourless oil. ¹H NMR (400 MHz): δ ϭ 1.08 (s, 6 H, 5-CH₃),

2.21 (s, 2 H, 4- or 6-CH₂), 2.39 (s, 2 H, 6- or 4-CH₂), 4.84 (s, 2 H,

NCH₂Ph), 5.49 (s, 1 H, 2-H), 7.30Ϫ7.37 (m, 5 H, ArH) ppm.

Compound 9c: Treatment of 6a (100 mg, 0.54 mmol) and benzoyl

chloride (75.9 mg, 0.54 mmol) in anhydrous THF (3 mL) as de-

scribed in the General Procedure (1 h) yielded 9c (123 mg, 79%) as

colourless crystals. M.p. 138Ϫ140 °C (dec.) (Et₂O/CH₂Cl₂). IR

(KBr): ν˜ ϭ 1755, 1705, 1650, 1475, 1450 cm^Ϫ1. ¹H NMR: δ ϭ 3.22

(s, 3 H, NCH₃), 3.36 (s, 3 H, NCH₃), 3.42 (s, 3 H, NCH₃), 5.76 (s,

1 H, 5-H), 7.47Ϫ7.52 (m, 2 H, ArH), 7.63Ϫ7.68 (m, 1 H, ArH),

7.99Ϫ8.02 (m, 2 H, ArH) ppm. ¹³C NMR: δ ϭ 28.1, 31.7, 42.8,

89.7, 127.0, 128.8, 129.6, 134.3, 152.1, 157.3 (CϭO), 162.6 (CϭO),

163.5 (CϭO) ppm. FAB-MS (glycerol): m/z (%) ϭ 290 (100.0) [M^ϩ

ϩ H]. C₁₄H₁₅N₃O₄(289.3): calcd. C 58.13, H 5.23, N 14.53; found

C 57.95, H 5.27, N 14.46.

Compound 7f: Treatment of 4a (700 mg, 4.96 mmol) and benzoyl

chloride (697 mg, 4.96 mmol) in anhydrous THF (10 mL) as de-

scribed in the General Procedure (1 h 30 min) afforded 7f (1.12 g,

92%) as colourless crystals. M.p. 71Ϫ73 °C (CHCl₃/Et₂O). IR

1

(KBr): ν˜ ϭ 1755, 1640, 1570 cm^Ϫ1. H NMR: δ ϭ 2.00Ϫ2.09 (m,

2 H, 5-CH₂), 2.34 (t, J ϭ 6.6 Hz, 2 H, 4- or 6-CH₂), 2.50 (t, J ϭ

6.2 Hz, 2 H, 6- or 4-CH₂), 3.34 (s, 3 H, NCH₃), 5.42 (s, 1 H, 2-H),

7.51 (t, J ϭ 7.6 Hz, 2 H, ArH), 7.64Ϫ7.69 (m, 1 H, ArH),

8.06Ϫ8.09 (m, 2 H, ArH) ppm. EI-MS: m/z (%) ϭ 245 (2.7) [M^ϩ],

125 (26.9), 122 (31.2), 105 (100.0). C₁₄H₁₅NO₃(245.3): calcd. C

68.56, H 6.16, N 5.71; found C 68.65, H 6.18, N 5.65.

Rearrangement of O-Benzoylenehydroxylamines

Compound 8f: A solution of 7f (100 mg, 0.41 mmol) in toluene was

heated under reflux until all starting material was consumed (5 h).

Solvent removal under reduced pressure and purification of the

resulting residue by PTLC (silica; EtOAc/n-hexane, 1:1) gave 8f

(90.0 mg, 90%) as a colourless oil. IR (KBr): ν˜ ϭ 3300, 1730,

1570 cm^Ϫ1. ¹H NMR: δ ϭ 1.98Ϫ2.07 (m, 2 H, 5-CH₂), 2.41 (t, J ϭ

6.6 Hz, 2 H, 4- or 6-CH₂), 2.55 (t, J ϭ 6.0 Hz, 2 H, 6- or 4-CH₂),

2.88 (d, J ϭ 5.4 Hz, 3 H, NHCH₃, collapses to s on irradiation at

5.15), 5.15 (br. s, 1 H, NH, D₂O exchange), 7.46Ϫ7.48 (m, 2 H,

ArH), 7.56Ϫ7.62 (m, 1 H, ArH), 8.15Ϫ8.18 (m, 2 H, ArH) ppm.

EI-MS: m/z (%) ϭ 245 (20.5) [M^ϩ], 140 (7.1), 112 (12.0), 105

(100.0). HR-MS: C₁₄H₁₅NO₃: calcd. 245.105194; found

245.105726.

Compound 7g: Treatment of 4b (100 mg, 0.46 mmol) and benzoyl

chloride (65.0 mg, 0.46 mmol) in anhydrous THF (3 mL) as de-

scribed in the General Procedure (2 h) afforded 7g (130 mg, 88%)

Ϫ1

as a colourless oil. IR (neat): ν˜ ϭ 1760, 1640, 1580 cm

.

¹H

NMR: δ ϭ 2.01Ϫ2.10 (m, 2 H, 5-CH₂), 2.34 (t, J ϭ 6.3 Hz, 2 H,

4- or 6-CH₂), 2.57 (t, J ϭ 6.7 Hz, 2 H, 6- or 4-CH₂), 4.84 (s, 2 H,

NCH₂Ph), 5.49 (s, 1 H, 2-H), 7.27Ϫ7.35 (m, 5 H, ArH), 7.45 (t,

J ϭ 7.7 Hz, 2 H, ArH), 7.60Ϫ7.65 (m, 1 H, ArH), 7.95Ϫ7.98 (m,

2 H, ArH) ppm. EI-MS: m/z (%) ϭ 321 (100.0) [M^ϩ], 199 (47.5),

122 (35.6), 105 (68.8), 91 (46.3). HR-MS: C₂₀H₁₉NO₃: calcd.

321.136494; found 321.137472.

Compound 7g-d₅: Treatment of 4b (400 mg, 1.84 mmol) and

[D₅]benzoyl chloride (268 mg, 1.84 mmol) in anhydrous THF

(8 mL) as described above (2 h) afforded 7g-d₅(545 mg, 91%) as a

Compound 8g: A solution of 7g (38.5 mg, 0.12 mmol) in toluene

was heated under reflux for 2 h. Reaction workup as described

above gave 8g (35.0 mg, 90%) as colourless crystals. M.p. 114Ϫ115

°C (Et₂O/CH₂Cl₂). IR (KBr): ν˜ ϭ 3220, 1730, 1590, 1540 cm^Ϫ1. ¹H

NMR: δ ϭ 2.03Ϫ2.08 (m, 2 H, 5-CH₂), 2.49 (t, J ϭ 6.4 Hz, 2 H,

4- or 6-CH₂), 2.62 (t, J ϭ 6.0 Hz, 2 H, 6- or 4-CH₂), 4.45 (d, J ϭ

6.0 Hz, 2 H, NHCH₂Ph, collapses to s on irradiation at 5.43), 5.43

(br. s, 1 H, NH, D₂O exchange), 7.23Ϫ7.38 (m, 5 H, ArH),

7.44Ϫ7.49 (m, 2 H, ArH), 7.57Ϫ7.60 (m, 1 H, ArH), 8.16Ϫ8.17

(m, 2 H, ArH) ppm. EI-MS: See Table 6. HR-MS: C₂₀H₁₉NO₃:

calcd. 321.136494; found 321.139207.

colourless oil. IR (neat): ν˜ ϭ 1762, 1708, 1566 cm^Ϫ^{1 1}H NMR

.

(400 MHz, CDCl₃): δ ϭ 1.99Ϫ2.05 (m, 2 H, 5-CH₂), 2.32 (t, J ϭ

6.4 Hz, 2 H, 4- or 6-CH₂), 2.54 (t, J ϭ 6.4 Hz, 2 H, 6- or 4-CH₂),

4.83 (s, 2 H, NCH₂Ph), 5.49 (s, 1 H, 2-H), 7.27Ϫ7.33 (m, 5 H,

ArH) ppm.

Compound 7h: Treatment of 5a (100 mg, 0.59 mmol) and benzoyl

chloride (83.0 mg, 0.59 mmol) in anhydrous THF (3 mL) as de-

scribed in the General Procedure (1 h) gave 7h (156 mg, 97%) as

colourless needles. M.p. 111Ϫ112 °C (CH₂Cl₂/Et₂O). IR (KBr):

1

ν˜ ϭ 1750, 1640, 1590 cm^Ϫ1. H NMR: δ ϭ 1.10 (s, 6 H, 5-CH₃),

Compound 8g-d₅: A solution of 7g-d₅gave, as above, 8g-d₅, as col-

ourless crystals. M.p. 114Ϫ115.5 °C (Et₂O/CH₂Cl₂). IR (KBr): ν˜ ϭ

3455, 1733, 1588, 1543 cm^Ϫ1. ¹H NMR (400 MHz): δ ϭ 2.01Ϫ2.07

(m, 2 H, 5-CH₂), 2.47 (t, J ϭ 6.4 Hz, 2 H, 4- or 6-CH₂), 2.60 (t,

J ϭ 6.0 Hz, 2 H, 6- or 4-CH₂), 4.44 (d, J ϭ 6.0 Hz, 2 H,

NHCH₂Ph, collapses to s on irradiation at 5.24), 5.24 (br. s, 1 H,

NH, D₂O exchange), 7.23Ϫ7.31 (m, 3 H, ArH), 7.36 (d, J ϭ 7.2

Hz, 2 H, ArH) ppm. EI-MS: See Table 6.

2.21 (s, 2 H, 4- or 6-CH₂), 2.33 (s, 2 H, 6- or 4-CH₂), 3.33 (s, 3 H,

NCH₃), 5.42 (s, 1 H, 2-H), 7.49Ϫ7.54 (m, 2 H, ArH), 7.64Ϫ7.69

(m, 1 H, ArH), 8.06Ϫ8.09 (m, 2 H, ArH) ppm. EI-MS: m/z (%) ϭ

273 (4.1) [M^ϩ], 153 (20.0), 138 (20.0), 122 (10.3), 105 (100.0). HR-

MS: C₁₆H₁₉NO₃: calcd. 273.136494; found 273.135677.

Compound 7i: Treatment of 5b (500 mg, 2.06 mmol) and benzoyl

chloride (290 mg, 2.09 mmol) in anhydrous THF (8 mL) as de-

scribed in the General Procedure (1 h) gave 7i (700 mg, 97%) as a

Compound 8h: A solution of 7h (112 mg, 0.41 mmol) in toluene was

heated under reflux for 5 h 15 min. Reaction workup as described

colourless oil. IR (neat): ν˜ ϭ 1760, 1639, 1579 cm^Ϫ1

.

¹H NMR

(CDCl₃, 400 MHz): δ ϭ 1.08 (s, 6 H, 5-CH₃), 2.20 (s, 2 H, 4- or 6-

above furnished 8h (105 mg, 94%) as a colourless oil. IR (KBr):

1

CH₂), 2.39 (s, 2 H, 6- or 4-CH₂), 4.83 (s, 2 H, NCH₂Ph), 5.47 (s, 1 ν˜ ϭ 3300, 1740, 1590 cm^Ϫ1. H NMR: δ ϭ 1.17 (s, 6 H, 5-CH₃),

H, 2-H), 7.28Ϫ7.37 (m, 5 H, ArH), 7.45 (t, J ϭ 7.8 Hz, 2 H, ArH), 2.29 (s, 2 H, 4- or 6-CH₂), 2.39 (s, 2 H, 6- or 4-CH₂), 2.87 (d, J ϭ

7.61 (t, J ϭ 7.6 Hz, 1 H, ArH), 7.96 (d, J ϭ 7.8 Hz, 2 H, ArH)

ppm. EI-MS: m/z (%) ϭ 349 (6) [M^ϩ], 144 (14), 122 (10.3), 105

5.4 Hz, 3 H, NHCH₃, collapses to s on irradiation at 5.10), 5.10

(br. s, 1 H, NH, exchangeable D₂O), 7.46 (t, J ϭ 7.8 Hz, 2 H,

(100.0). HR-MS: C₂₂H₂₃NO₃: calcd. 349.167794; found ArH), 7.59 (t, J ϭ 7.7 Hz, 1 H, ArH), 8.17 (d, J ϭ 6.9 Hz, 2 H,

349.167624.

ArH) ppm. EI-MS: m/z (%) ϭ 273 (62.3) [M^ϩ], 258 (42.0), 168

204

Eur. J. Org. Chem. 2003, 190Ϫ208

3,3-Sigmatropic Rearrangements of Enehydroxylamines

FULL PAPER

(40.6), 140 (46.4), 105 (100.0). HR-MS: C₁₆H₁₉NO₃: calcd.

273.136494; found 273.136657.

at 5.41 and with D₂O), 5.14 (s, 1 H, 2-H), 5.41 (br. s, 1 H, NH,

D₂O exchange), 5.73 (m, 1 H, 4-H), 7.46Ϫ7.51 (m, 2 H, Ar-H),

7.60Ϫ7.66 (m, 1 H, Ar-H), 8.04Ϫ8.07 (m, 2 H, Ar-H) ppm. EI-

MS: m/z (%) ϭ 245 (18.1) [M^ϩ], 140 (12.2) [M^ϩϪ COPh], 105

(100.0) [COPh^ϩ]. HR-MS (EI): C₁₄H₁₅NO₃(245.3): calcd.

245.105194; found 245.105395.

Compound 8i: A solution of 7i (40.0 mg, 0.11 mmol) in toluene was

heated under reflux for 6 h. Reaction workup as described above

gave 8i (32.8 mg, 85%) as colourless crystals. M.p. 195Ϫ196 °C (n-

1

hexane/CH₂Cl₂). IR (KBr): ν˜ ϭ 3314, 1737, 1592, 1544 cm^Ϫ1. H

Treatment of Enehydroxylamines with Diethyl Chlorophosphate

NMR (400 MHz): δ ϭ 1.14 (s, 6 H, 5-CH₃), 2.34 (s, 2 H, 4- or 6-

CH₂), 2.44 (s, 2 H, 6- or 4-CH₂), 4.43 (d, J ϭ 6.0 Hz, 2 H,

NCH₂Ph), 5.24 (br. s, 1 H, NH, D₂O exchange), 7.22Ϫ7.38 (m, 5

H, Ar), 7.45 (t, J ϭ 7.6 Hz, 2 H, ArH), 7.58 (t, J ϭ 7.4 Hz, 1 H,

ArH), 8.17 (d, J ϭ 7.6 Hz, 2 H, ArH) ppm. EI-MS: See Table 6.

HR-MS: C₂₀H₁₉NO₃: calcd. 349.167794; found 349.168242.

Compound 7j: A 60% dispersion of sodium hydride in mineral oil

(134.1 mg, 1.42 mmol) was added under N₂to a stirred, ice-cooled

suspension of 5a (200 mg, 1.18 mmol) in anhydrous THF (4 mL),

protected from light, followed 30 min later by diethyl chloro-

phosphate (204 mg, 1.18 mmol). After 4 h, the solvent was removed

under reduced pressure and a mixture of dichloromethane and

water was added to the residue. The aqueous layer, after separation

by decantation, was extracted with dichloromethane and ethyl acet-

ate and the combined organic layers were dried with anhydrous

sodium sulfate. Solvent removal under reduced pressure and puri-

fication of the resulting residue by PTLC (silica; EtOAc/MeOH,

99:1) yielded 7j (310 mg, 86%) as a yellow oil. IR (neat): ν˜ ϭ 1650,

Compound 8i-d₅: A solution of 7i-d₅gave, as above, 8i-d₅, as colour-

less crystals. M.p. 196Ϫ198 °C (n-hexane/CHCl₃). IR (KBr): ν˜ ϭ

1

3314, 1736, 1592, 1543 cm^Ϫ1. H NMR (400 MHz): δ ϭ 1.14 (s, 6

H, 5-CH₃), 2.34 (s, 2 H, 4- or 6-CH₂), 2.44 (s, 2 H, 6- or 4-CH₂),

4.43 (d, J ϭ 6.0 Hz, 2 H, NCH₂Ph), 5.23 (br. s, 1 H, NH, D₂O

exchange), 7.23Ϫ7.38 (m, 5 H, ArH) ppm. EI-MS: See Table 6.

1

1600, 1370, 1280, 1170, 1040 cm^Ϫ1. H NMR: δ ϭ 1.16 (s, 6 H, 5-

Compounds 10c and 20: A solution of 9c (49.0 mg, 0.17 mmol) in

toluene was heated under reflux for 7 h. Reaction workup as de-

scribed above gave 10c (10.8 mg, 22%) as colourless crystals, fol-

lowed by 20 (28.5 mg, 58%) as white needles. Physical data for 10c:

M.p. 191Ϫ192 °C (CH₂Cl₂/Et₂O). IR (KBr): ν˜ ϭ 3330, 1750, 1700,

1620, 1540 cm^Ϫ1. ¹H NMR: δ ϭ 2.98 (d, J ϭ 5.1 Hz, 3 H, NHCH₃,

collapses to s on irradiation at 4.56), 3.33 (s, 3 H, NCH₃), 3.42 (s,

3 H, NCH₃), 4.56 (br. s, 1 H, NHCH₃), 7.49 (t, J ϭ 8.0 Hz, 2 H,

ArH), 7.62 (t, J ϭ 7.2 Hz, 1 H, ArH), 8.15Ϫ8.18 (m, 2 H, ArH)

ppm. FAB-MS (glycerol): m/z (%) ϭ 290 (100.0) [M^ϩϩ H]. HR

MS (CI, ammonia): C₁₄H₁₅N₃O₄: calcd. 290.114081; found

290.114446 [M^ϩϩ H]. Physical data for 20: M.p. 158Ϫ160 °C

CH₃), 1.36 (t, J ϭ 7.0 Hz, 6 H, OCH₂CH₃), 2.22 (s, 2 H, 4- or 6-

CH₂), 2.30 (s, 2 H, 6- or 4-CH₂), 3.24 (s, 3 H, NCH₃), 4.17Ϫ4.29

(m, 4 H, OCH₂CH₃), 5.67 (s, 1 H, 2-H) ppm. FAB-MS (glycerol):

m/z (%) ϭ 306 (100.0) [M^ϩϩ H]. HR-MS (CI, ammonia):

C₁₃H₂₅NO₅P: calcd. 306.147037; found 306.148643 [M^ϩϩ H].

Compound 9d: Treatment of 6a (200 mg, 1.08 mmol) with diethyl

chlorophosphate (186 mg, 1.08 mmol) in anhydrous THF (4 mL)

as described above (1 h 30 min) afforded 9d (298 mg, 86%) as a

colourless oil. IR (neat): ν˜ ϭ 1710, 1660, 1485, 1450, 1275, 1160,

1030 cm^{Ϫ1 1}H NMR: δ ϭ 1.36 (t, J ϭ 7.2 Hz, 6 H, OCH₂CH₃,

.

(dec.) (CH₂Cl₂Et₂O). IR (KBr): ν˜ ϭ 3340, 1710, 1650 cm^{Ϫ1 1}H

.

collapses to s on irradiation at 4.2), 3.11 (s, 3 H, NCH₃), 3.34 (s, 3

H, NCH₃), 3.42 (s, 3 H, NCH₃), 4.14Ϫ4.25 (m, 4 H, OCH₂CH₃),

5.88 (s, 1 H, 5-H) ppm. FAB-MS (glycerol): m/z (%) ϭ 322 (100.0)

NMR: δ ϭ 3.29 (s, 3 H, NCH₃), 3.33 (s, 3 H, NCH₃), 3.39 (s, 3 H,

NCH₃), 6.17 (br. s, 1 H, OH, D₂O exchange), 7.27Ϫ7.33 (m, 2 H,

ArH), 7.34Ϫ7.45 (m, 3 H, ArH) ppm. ¹³C NMR (CD₂Cl₂) (qua-

ternary carbon atoms): δ ϭ 126.9, 131.8, 134.3, 149.0, 159.9 (Cϭ

O), 170.4 (CϭO) ppm. FAB-MS (glycerol): m/z (%) ϭ 290 (100.0)

[M^ϩϩ H]. C₁₄H₁₅N₃O₄(289.3): calcd. C 58.13, H 5.23, N 14.53;

found C 58.10, H 5.24, N 14.80. When a solution of 9c (70.0 mg,

0.24 mmol) in toluene was heated under reflux for 15 h 30 min and

worked up as described above, 10c and 20 were obtained in 15 and

81% yields, respectively.

[M^ϩ

ϩ H]. HR-MS (CI, ammonia): C₁₁H₂₁N₃O₆P: calcd.

322.116799; found 322.116061 [M^ϩϩ H].

Rearrangement of O-(Diethoxyphosphoryl)enehydroxylamines

Compound 8j: A solution of 7j (104 mg, 0.34 mmol) in toluene was

heated under reflux for 15 min. Solvent removal under reduced

pressure and purification of the remaining residue by PTLC (silica;

EtOAc/MeOH, 95:5) yielded 8j (80.1 mg, 77%) as a colourless oil.

1

IR (KBr): ν˜ ϭ 3400, 1580, 1270, 1155, 1040 cm^Ϫ1. H NMR: δ ϭ

Compound

25:

1,1,1,3,3,3-Hexamethyldisilazane

(HMDS,

1.12 (s, 6 H, 5-CH₃), 1.35 (t, J ϭ 7.2 Hz, 6 H, OCH₂CH₃, collapses

to s on irradiation at 4.3), 2.27 (s, 2 H, 4- or 6-CH₂), 2.41 (d, J ϭ

1.8 Hz, 2 H, 6- or 4-CH₂), 2.94 (d, J ϭ 5.1 Hz, 3 H, NHCH₃,

collapses to s on irradiation at 5.94), 4.24Ϫ4.34 (m, 4 H,

OCH₂CH₃), 5.94 (br. s, 1 H, NH) ppm. FAB-MS (glycerol): m/z

1.22 mmol) was added under N₂to a stirred 35% dispersion of

potassium hydride in mineral oil (1.22 mmol, washed free of oil

with anhydrous THF) in THF (2 mL), and the mixture was kept

at room temp., protected from light, for 4 h. The resulting suspen-

sion was added slowly under N₂to a vigorously stirred solution of

7f (100.6 mg, 0.41 mmol) and tert-butyldimethylsilyl chloride

(TBDMSCl, 2.04 mmol) in anhydrous THF (2 mL), cooled to Ϫ80

°C and protected from light. When the addition was complete, the

temperature was slowly raised to room temp. and, after 2 h, the

solvent was removed at reduced pressure. The resulting residue was

redissolved in a mixture of ethyl acetate and water and the aqueous

(%)

ϭ ϩ H]. HR-MS (CI, ammonia):

306 (100.0) [M^ϩ

C₁₃H₂₅NO₅P: calcd. 306.147037; found 306.147492 [M^ϩϩ H].

Compound 10d: A solution of 9d (57.8 mg, 0.18 mmol) in toluene

was heated under reflux for 1 h. Solvent removal at reduced pres-

sure and recrystallisation of the resulting residue afforded 10d

(45.1 mg, 78%) as colourless crystals. M.p. 119Ϫ120 °C (CH₂Cl₂/

layer, after separation by decantation, was extracted several times Et₂O). IR (KBr): ν˜ ϭ 3300, 1710, 1620, 1610, 1250, 1160,

with ethyl acetate. The combined organic layers were dried with

anhydrous sodium sulfate and the solvent was removed at reduced

pressure to leave a residue, which was separated by PTLC (silica;

1030 cm^Ϫ^{1 1}H NMR: δ ϭ 1.37 (t, J ϭ 7.2 Hz, 6 H, OCH₂CH₃,

.

collapses to s on irradiation at 4.32), 2.98 (d, J ϭ 5.1 Hz, 3 H,

NHCH₃collapses to s on irradiation at 5.08), 3.34 (s, 3 H, NCH₃),

EtOAc) to give 25 (29.2 mg, 29%) as colourless crystals. M.p. 3.43 (s, 3 H, NCH₃), 4.27Ϫ4.37 (m, 4 H, OCH₂CH₃), 5.08 (m, 1

121Ϫ122 °C (Et₂O). IR (KBr): ν˜ ϭ 3240, 1720, 1615, 1580,

H, NH). FAB-MS (glycerol): m/z (%) ϭ 322 (100.0) [M^ϩϩ H].

C₁₁H₂₀N₃O₆P (321.3): calcd. C 41.12, H 6.27, N 13.08; found C

41.32, H 6.09, N 13.02.

1530 cm^{Ϫ1 1}H NMR: δ ϭ 2.17Ϫ2.51 (m, 3 H), 2.61Ϫ2.75 (m, 1

.

H), 2.79 (d, J ϭ 5.1 Hz, 3 H, NHCH₃, collapses to s on irradiation

Eur. J. Org. Chem. 2003, 190Ϫ208

205

L. V. Reis, A. M. Lobo, S. Prabhakar, M. P. Duarte

FULL PAPER

Treatment of Enehydroxylamines with Phenyl Isocyanate. General (m, 2 H, ArH), 7.42Ϫ7.44 (m, 2 H, Ar-H), 7.55 (br. s, 1 H, NH,

Procedure A: N,N-Diisopropylethylamine (1 equiv.) was added un-

der N₂to a stirred, ice-cooled suspension of enehydroxylamine (1

equiv.) in anhydrous THF, followed by the slow addition of phenyl

D₂O exchange) ppm. EI-MS: m/z (%) ϭ 169 (1.9) [M^ϩϪ CONPh],

151 (20.6), 119 (100.0), 91 (47.9). FAB-MS (glycerol): m/z (%) ϭ

289 (100.0) [M^ϩϩ H]. C₁₆H₂₀N₂O₃(288.3): calcd. C 66.65, H 6.99,

isocyanate (1 equiv.). After the reaction was complete, the solvent N 9.72; found C 66.72, H 7.08, N 9.70.

was removed under reduced pressure and the residue was recrys-

Compound 9e: Treatment of 6a (100 mg, 0.54 mmol) with phenyl

tallised. General Procedure B: A 60% dispersion of sodium hydride

in mineral oil (1.3 equiv.) was added under N₂to a stirred, ice-

cooled suspension of enehydroxylamine (1 equiv.) in anhydrous

THF. After hydrogen evolution had ceased, phenyl isocyanate (2.5

equiv.) was added, and the mixture was kept at room temperature

for 1 h and then heated at reflux until the reaction was completed.

Solvent was removed under reduced pressure and the resulting res-

idue was redissolved in water, acidified to pH ഠ 5 with a 5% aque-

ous solution of HCl and extracted several times with ethyl acetate

and diethyl ether. After drying of the combined organic layers with

anhydrous sodium sulfate and solvent removal under reduced pres-

sure, a residue was obtained and purified by recrystallisation or

PTLC.

isocyanate (64.3 mg, 0.54 mmol) in anhydrous THF (3 mL) as de-

scribed in General Procedure A (2 h) yielded 9e (156 mg, 95%) as

colourless crystals. M.p. 150Ϫ151 °C (dec.) (Et₂O/CH₂Cl₂). IR

(KBr): ν˜ ϭ 3340, 1770, 1700, 1650, 1650 cm^Ϫ1. ¹H NMR: δ ϭ 3.14

(s, 3 H, NCH₃), 3.35 (s, 3 H, NCH₃), 3.44 (s, 3 H, NCH₃), 5.65 (s,

1 H, 5-H), 7.11Ϫ7.16 (m, 1 H, ArH), 7.32Ϫ7.37 (m, 2 H, ArH),

7.45Ϫ7.48 (m, 2 H, ArH), 7.83 (br. s, 1 H, NH, D₂O exchange)

ppm. FAB-MS (4-NBA): m/z (%) ϭ 305 (100.0) [M^ϩϩ H], 186

(24.0), 185 (45.0), 169 (78.0). C₁₄H₁₆N₄O₄(304.3): calcd. C 55.26,

H 5.30, N 18.41; found C 55.16, H 5.35, N 18.45.

Compounds 10e and 10bЈ: A solution of 9e (30.4 mg, 0.1 mmol)

in toluene was heated under reflux until all starting material was

consumed (1 h). Solvent removal at reduced pressure and purifica-

tion of the resulting residue by PTLC (silica; EtOAc/MeOH, 95:5)

gave 10e (14.3 mg, 55%), followed by 10bЈ (6.1 mg, 36%) (as above),

both as colourless crystals. Physical data for 10e: M.p. 197Ϫ198 °C

(dec.) (CHCl₃/MeOH). IR (KBr): ν˜ ϭ 3360, 3300, 1685, 1625,

1600, 1550 cm^Ϫ1. ¹H NMR: δ ϭ 2.93 (br. s, 3 H, NHCH₃, collapses

to a sharp s on irradiation at the frequency of NHCH₃), 3.34 (s, 3

H, NCH₃), 3.52 (s, 3 H, NCH₃), 4.79 (br. s, 1 H, NHCH₃),

6.63Ϫ6.66 (m, 2 H, ArH), 6.78Ϫ6.83 (m, 1 H, ArH), 7.16Ϫ7.21

(m, 3 H, ArH ϩ NH) ppm. FAB-MS (4-NBA): m/z (%) ϭ 261

(88.2) [M^ϩϩ H], 260 (100.0) [M^ϩ]. HR-MS (CI, ammonia):

C₁₃H₁₇N₄O₂: calcd. 261.135151; found 261.136036 [M^ϩϩ H].

Compound 7k: Treatment of 4a (300 mg, 2.13 mmol) with phenyl

isocyanate (254 mg, 2.13 mmol) in anhydrous THF (7 mL) as de-

scribed in General Procedure A (2 h) gave 7k (498 mg, 90%) as

colourless crystals. M.p. 126Ϫ129 °C (dec.) (EtOAc). IR (KBr):

1

ν˜ ϭ 3245, 1765, 1610, 1580 cm^Ϫ1. H NMR: δ ϭ 2.01Ϫ2.09 (m, 2

H, 5-CH₂), 2.35 (t, J ϭ 6.6 Hz, 2 H, 4- or 6-CH₂), 2.49 (t, J ϭ 6.3

Hz, 2 H, 6- or 4-CH₂), 3.30 (s, 3 H, NCH₃), 5.42 (s, 1 H, 2-H),

7.10Ϫ7.16 (m, 1 H, ArH), 7.31Ϫ7.36 (m, 2 H, ArH), 7.40Ϫ7.43

(m, 3 H, ArH ϩ NH) ppm. FAB-MS (4-NBA): m/z (%) ϭ 261

(74.4) [M^ϩϩ H], 142 (100.0) ppm. C₁₄H₁₆N₂O₃(260.3): calcd. C

64.60, H 6.20, N 10.76; found C 64.85, H 6.15, N 10.84.

Compound 8k: Treatment of 4a (180 mg, 1.28 mmol) with phenyl

isocyanate (379 mg, 3.18 mmol) in anhydrous THF (6 mL) as de-

scribed in General Procedure B (3 h) afforded 8k (360 mg, 84%) as

colourless crystals. M.p. 217Ϫ218 °C (EtOAc/MeOH). IR (KBr):

Compounds 10eЈ and 16b: Treatment of 6a (100 mg, 0.54 mmol)

with phenyl isocyanate (161 mg, 1.35 mmol) in anhydrous THF

(4 mL) as described in General Procedure B (7 h) and purification

of the resulting residue by PTLC (silica; EtOAc/petroleum ether,

1:1) afforded 10eЈ (94.9 mg, 47%) and 16b (78.8 mg, 51%), both as

colourless crystals. Physical data for 10eЈ: M.p. 212Ϫ217 °C (dec.)

1

ν˜ ϭ 3210, 1670, 1595, 1565 cm^Ϫ1. H NMR: δ ϭ 1.99Ϫ2.05 (m, 2

H, 5-CH₂), 2.50Ϫ2.53 (m, 2 H, 4- or 6-CH₂), 2.66 (t, J ϭ 6.3 Hz,

2 H, 6- or 4-CH₂), 3.10 (s, 3 H, NCH₃), 6.70 (br. s, 1 H, NH, D₂O

exchange), 6.97Ϫ7.03 (m, 1 H, ArH), 7.10Ϫ7.14 (m, 2 H, ArH),

7.21Ϫ7.43 (m, 7 H, ArH), 7.53 (br. s, 1 H, NH, D₂O exchange)

ppm. FAB-MS (4-NBA): m/z (%) ϭ 336 (24.3) [M^ϩϩ H], 243

(100.0). C₂₀H₂₁N₃O₂(335.4): calcd. C 71.66, H 6.26, N 12.53;

found C 71.57, H 6.30, N 12.56. Alternatively, a 60% dispersion of

sodium hydride in mineral oil (4.56 mg, 0.19 mmol) was added un-

der N₂to a stirred solution of 7k (50.0 mg, 0.19 mmol) in anhyd-

rous THF (4 mL), protected from light. After hydrogen evolution

had ceased, the reaction mixture was heated under reflux until all

starting material was consumed. The solvent was then removed un-

der reduced pressure and a mixture of diethyl ether and water (1:1)

was added to the resulting residue. The aqueous layer, after separa-

tion by decantation, was acidified to pH ഠ 5 with aqueous HCl

(5%) and extracted several times with dichloromethane and ethyl

acetate. After drying of the combined organic layers with anhyd-

rous sodium sulfate, solvent removal under reduced pressure and

recrystallisation of the resulting residue from EtOAc/MeOH, 8k

(31.2 mg, 49%) was obtained.

(Et₂O/CH₂Cl₂). IR (KBr): ν˜ ϭ 3340, 3230, 1710, 1670, 1640 cm^Ϫ1

.

¹H NMR [D₆]acetone: δ ϭ 2.95 (s, 3 H, NCH₃), 3.20 (s, 3 H,

NCH₃), 3.25 (s, 3 H, NCH₃), 6.87Ϫ6.93 (m, 1 H, ArH), 7.07Ϫ7.21

(m, 5 H, ArH), 7.30Ϫ7.36 (m, 2 H, ArH), 7.40Ϫ7.43 (m, 2 H,

ArH), 7.92 (br. s, 1 H, NH, D₂O exchange), 8.23 (br. s, 1 H, NH,

D₂O exchange) ppm. FAB-MS (glycerol): m/z (%) ϭ 380 (100.0)

[M^ϩϩ H]. C₂₀H₂₁N₅O₃: calcd. C 63.31, H 5.58, N 18.46; found C

63.37, H 5.67, N 18.47. Physical data for 16b: M.p. 270 °C (Et₂O/

CH₂Cl₂). IR (KBr): ν˜ ϭ 1740, 1730, 1690, 1670, 1540 cm^Ϫ^{1 1}H

.

NMR: δ ϭ 2.99 (s, 3 H, NCH₃), 3.41 (s, 3 H, NCH₃), 3.65 (s, 3 H,

NCH₃), 7.35Ϫ7.38 (m, 2 H, ArH), 7.54Ϫ7.57 (m, 3 H, ArH) ppm.

FAB-MS (glycerol): m/z (%) ϭ 287 (100.0) [M^ϩϩ H]. HR-MS (CI,

ammonia): C₁₄H₁₅N₄O₃: calcd. 287.114416; found 287.114306 [M^ϩ

ϩ H].

Compounds 21 and 22: 1,1,1,3,3,3-Hexamethyldisilazane (HMDS,

1025 mg, 6.35 mmol) was added to a 35% dispersion of potassium

hydride in mineral oil (255 mg, 6.35 mmol, washed free of oil with

anhydrous THF) in anhydrous THF (20 mL) and vigorously stirred

under N₂. When hydrogen evolution had ceased (3 h), the mixture

was cooled to Ϫ80 °C and a solution of 7k (500 mg, 1.92 mmol)

in the same solvent (25 mL) and TMSCl (1.04 g, 9.6 mmol) were

Compound 7l: Treatment of 5a (380 mg, 2.25 mmol) with phenyl

isocyanate (268 mg, 2.25 mmol) in anhydrous THF (5 mL) as de-

scribed in General Procedure A (4 h) afforded 7l (551 mg, 85%) as

colourless crystals. M.p. 130Ϫ132 °C (dec.) (Et₂O). IR (KBr): ν˜ ϭ slowly added. When the addition was complete, the temperature of

1

3240, 1770, 1615, 1585 cm^Ϫ1. H NMR: δ ϭ 1.11 (s, 6 H, 5-CH₃),

the reaction mixture was slowly raised to room temp. After 3 h, the

2.22 (s, 2 H, 4- or 6-CH₂), 2.32 (s, 2 H, 6- or 4-CH₂), 3.30 (s, 3 H, solvent was removed under reduced pressure and the residue was

NCH₃), 5.43 (s, 1 H, 2-H), 7.08Ϫ7.12 (m, 1 H, ArH), 7.28Ϫ7.33 dissolved in a mixture of diethyl ether and aqueous NaHCO₃. The

206

Eur. J. Org. Chem. 2003, 190Ϫ208

3,3-Sigmatropic Rearrangements of Enehydroxylamines

FULL PAPER

aqueous layer, after separation by decantation, was extracted with

diethyl ether and ethyl acetate and the combined organic layers

were dried with anhydrous sodium sulfate. Solvent removal at re-

duced pressure and recrystallisation of the remaining residue

yielded 21 (270 mg, 54%) as colourless crystals. M.p. 195Ϫ196 °C

Kinetic Method: A solution (0.5Ϫ1.5 mL) of the enehydroxylamine

derivative (0.08Ϫ0.1 ) in [D₈]toluene or [D₆]DMSO was heated in

the H NMR probe at the required temperature (80Ϫ100 Ϯ 0.1 °C

1

range) and the first-order reaction corresponding to the disappear-

ance of the starting material was monitored by integration of relev-

.

¹H ant signals: for 7g at δ ϭ 4.43 (CH₂Ph) or δ ϭ 5.60 (2-H); for 7i

(Et₂O/MeOH). IR (KBr): ν˜ ϭ 3390, 1715, 1595, 1565 cm^Ϫ1

NMR: δ ϭ 2.11Ϫ2.41 (m, 3 H, 5-CH₂and 6-H), 2.56Ϫ2.65 (m, 1 at δ ϭ 4.42 (CH₂Ph) or δ ϭ 5.60 (2-H) ppm.

H, 6-HЈ), 2.78 (d, J ϭ 5.1 Hz, 3 H, NHCH₃collapses to s on

Rearrangements of 7i and 7g-d₅: A toluene solution (2 mL) con-

irradiation at 5.71), 5.10 (s, 1 H, 2-H), 5.44 (t, 1 H, J_ax,eqϭ J_eq,eqϭ

4.2 Hz, 4-H, collapses to s on irradiation at ca. 2.2), 5.71 (br. s, 1

H, NHCH₃, D₂O exchange), 7.07Ϫ7.13 (m, 1 H, ArH), 7.27Ϫ7.36

(m, 2 H, ArH), 7.46Ϫ7.49 (m, 2 H, ArH), 8.06 (br. s, 1 H, NH,

D₂O exchange) ppm. EI-MS: m/z (%) ϭ 260 (2.5) [M^ϩ], 141 (29.2),

119 (100.0), 91 (50.8). HR-MS: C₁₄H₁₆N₂O₃: calcd. 260.116093;

found 260.115026. Purification of the mother liquors from recrys-

tallisation of 21 by PTLC (silica; EtOAc) afforded 22 (14%), as

colourless crystals. M.p. 170Ϫ172 °C (EtOAc/MeOH). IR (KBr):

taining compounds 7i (101.0 mg, 0.29 mmol) and 7g-d₅(167.6 mg,

0.33 mmol) was heated at 100 °C until total disappearance of the

starting materials (7 h 30 min; TLC monitoring: silica; EtOAc).

The solvent was removed under reduced pressure and the only two

products formed Ϫ A and B Ϫ were isolated by PTLC. Their mass

spectra were then taken and, by comparison with the mass spectra

of authentic 8g, 8g-d₅, 8i and 8i-d₅(see Table 6), A was found to

be identical with 8i and B with 8g-d₅.

1

ν˜ ϭ 3370, 3300, 1610, 1560, 1510 cm^Ϫ1. H NMR: δ ϭ 1.93Ϫ2.10

(m, 1 H), 2.21Ϫ2.29 (m, 1 H), 2.42Ϫ2.49 (m, 2 H), 2.81 (d, J ϭ

4.8 Hz, 3 H, NHCH₃, collapses to s on irradiation at 5.87), 3.49

Acknowledgments

This research was partially financed by the Fundaca˜o para a Cien-

cia e a Tecnologia (FC&T, Lisbon, Portugal). We thank Dr. S. N.

Swami (Pfizer, UK) for his interest. Two of us (L. V. R. and M. P.

D.) thank FC&T for the award of research grants.

(m, 1 H, NH, D₂O exchange), 4.23Ϫ4.30 (m, 1 H, 4-H, J_ax,ax

ϭ

ˆ

¸

12.0, J_ax,eqϭ 4.0 Hz, 4-H collapses to dd with D₂O), 5.14 (s, 1 H,

2-H), 5.87 (br. s, 1 H, NHCH₃, D₂O exchange), 6.71Ϫ6.74 (m, 2

H, ArH), 6.83Ϫ6.88 (m, 1 H, ArH), 7.21Ϫ7.27 (m, 2 H, ArH) ppm.

EI-MS: m/z (%) ϭ 216 (100.0) [M^ϩ], 188 (23.2), 187 (24.1), 97

(43.0), 93 (58.9). HR-MS: C₁₃H₁₆N₂O: calcd. 216.126263; found

216.126923.

[1]

S. W. Wright, D. J. Pinto, S. R. Sherk, A. M. Green, R. L.

Treatment of Enehydroxylamine with Bromonitrile Oxide

Magolda, Bioorg. Med. Chem. Lett. 1992, 2, 1079Ϫ1084.

[2]

A. M. Lobo, S. Prabhakar, Pure Appl. Chem. 1997, 35,

Compound 26a: K₂CO₃(300 mg, 3.0 mmol) was added with vigor-

ous stirring to an ice-cooled mixture of 5a (101 mg, 0.6 mmol),

THF (6 mL) and H₂O (0.6 mL), followed by a solution of dibromo-

formaldoxime^[26,27](365 mg, 1.8 mmol) in THF (1.5 mL). After 2 h,

the inorganic solid was removed by filtration and washed with di-

ethyl ether and ethyl acetate. The combined filtrates were dried with

anhydrous sodium sulfate, the solvent was removed under reduced

pressure, and the resulting residue was purified by PTLC (silica;

EtOAc/MeOH, 9:1) to give 26a (50.1 mg, 36%), as colourless crys-

tals. M.p. 177Ϫ179 °C (MeOH/C₆H₆). IR (KBr): ν˜ ϭ 3300,

2747Ϫ2750.

S. Blechert, Synthesis 1989, 71Ϫ82.

Rev. 1984, 84, 205Ϫ247.

[3] [3a]

[3b]

R. P. Lutz, Chem.

[4]

H. O. House, F. A. Richey, J. Org. Chem. 1969, 34, 1430Ϫ1439.

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R. M. Coates, C. H. Coates, J. Org. Chem. 1983, 48,

[5b]

2070Ϫ2076.

R. M. Coates, C. H. Cummins, J. Org. Chem.

1986, 51, 1383Ϫ1389.

[6]

I. Lantos, W.-Y. Zhang, Tetrahedron Lett. 1994, 35,

5977Ϫ5980.

[7] [7a]

Y. Endo, S. Hizatate, K. Shudo, Synlett 1991, 649Ϫ650. ^[7b]

Y. Endo, T. Uchida, S. Hizatate, K. Shudo, Synthesis 1994,

1096Ϫ1105.

1

1580 cm^Ϫ1. H NMR: δ ϭ 1.11 (s, 6 H, 5-CH₃), 2.40 (s, 2 H, 4- or

[8]

C. A. Marques, M. Selva, P. Tundo, F. Montanari, J. Org.

Chem. 1993, 58, 5765Ϫ5770.

6-CH₂), 2.44 (s, 2 H, 6- or 4-CH₂), 3.02 (d, J ϭ 5.4 Hz, 3 H,

NHCH₃, collapses to s on irradiation at 5.71), 5.71 (br. s, 1 H,

NHCH₃, D₂O exchange) ppm. FAB-MS (glycerol): m/z (%) ϭ 234/

232 (100.0/100.0) [M^ϩϩ H/MЈ^ϩϩ H]. HR-MS (CI, ammonia):

C₉H₁₅⁸¹BrNO: calcd. 234.031654; found 234.029234 [M^ϩϩ H].

C₉H₁₅⁷⁹BrNO: calcd. 232.033700; found 232.031193 [MЈ^ϩϩ H].

[9] [9a]

I. Lantos, W.-Y. Zhang, X. Shui, D. S. Eggleston, J. Org.

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Chem. 1993, 58, 7092Ϫ7095.

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A. J. Castelino, H. Rapoport, J. Org. Chem. 1984, 49,

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4399Ϫ4404.

T. Sheradsky, G. Salemnick, J. Org. Chem.

1971, 36, 1061Ϫ1063.

Treatment of Enehydroxylamine with (Diethylamino)sulfur Trifluor-

ide (DAST)

[11]

[12]

T. Sheradsky, Tetrahedron Lett. 1970, 25Ϫ26.

L. V. Reis, A. M. Lobo, S. Prabhakar, Tetrahedron Lett. 1994,

35, 2747Ϫ2750.

Compound 26b: N,N-Diisopropylethylamine (76.3 mg, 0.59 mmol)

was added under N₂to a stirred, ice-cooled suspension of 5a

(100 mg, 0.59 mmol), protected from light, followed by careful ad-

dition of DAST (95.1 mg, 0.59 mmol). After 2 h, the solvent was

removed under reduced pressure and the resulting residue was puri-

fied by PTLC (silica; EtOAc/MeOH, 97:3) to give 26b (32.3 mg,

32%), as colourless crystals. M.p. 124Ϫ125 °C (CH₂Cl₂/Et₂O). IR

(KBr): ν˜ ϭ 3220, 1610, 1540, 1385, 1370 cm^Ϫ1. ¹H NMR: δ ϭ 1.23

(s, 6 H, 5-CH₃), 2.28 (d, J ϭ 2.7 Hz, 2 H, 4- or 6-CH₂), 2.39 (d,

J ϭ 4.2 Hz, 2 H, 6- or 4-CH₂), 2.97 (d, J ϭ 4.8 Hz, 3 H, NHCH₃,

collapses to s on irradiation at the frequency of NH), 5.02 (br. s, 1

H, NH) ppm. EI-MS: m/z (%) ϭ 171 (100.0) [M^ϩ], 156 (43.5), 128

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Article Doi

3,3-Sigmatropic rearrangements involving N-O bond-cleavage of enehydroxylamine derivatives

DOI: 10.1002/1099-0690(200301)2003:1<190::AID-EJOC190>3.0.CO;2-W

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