Rearrangement of ammonium ylides produced by intramolecular reaction of catalytically generated metal carbenoids. Part 1. Synthesis of cyclic amines

DOI: 10.1039/b108179a

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Journal of the Chemical Society. Perkin Transactions 1 (2001) p. 3312 - 3324 (2001)

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Authors:

Clark Clark

Hodgson Hodgson

Goldsmith

Street Street

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Article abstract of DOI:10.1039/b108179a

Cyclic amines have been prepared in good yield by [2,3]-rearrangement of ammonium ylides produced by intramolecular reaction of copper carbenoids tethered to allylic amines. Copper(II) acetylacetonate is the optimum catalyst for carbenoid/ylide generation from the diazo ketone precursor, and reactions must be performed at elevated temperatures in order to obtain reasonable reaction rates and high yields. The reaction has been used to prepare five- to eight-membered cyclic amines. In cases where the substrate possesses a substituent on the tether connecting the diazo group to the allylic amine, tandem ylide formation and rearrangement delivers a high yield of the expected 2,5-dialkylpyrrolidinone or 2,6-dialkylpiperidinone, but low levels of diastereocontrol are obtained. Two new methods have been developed for the synthesis of diazo ketones containing a nucleophilic allylic amine substituent. The first method involves conjugate addition of allylic amines to unsaturated diazo ketones and is high yielding but of limited scope. The alternative general sequence involving nitrogen protection, α-diazo ketone formation, deprotection and allylation can be used to prepare the substrates required for intramolecular tandem ylide formation and rearrangement.

Full text of DOI:10.1039/b108179a

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Rearrangement of ammonium ylides produced by intramolecular

reaction of catalytically generated metal carbenoids. Part 1.

Synthesis of cyclic amines

J. Stephen Clark,*^aPaul B. Hodgson,^aMichael D. Goldsmith^aand Leslie J. Street^b

^aSchool of Chemistry, University of Nottingham, University Park, Nottingham, UK NG7 2RD

^bMerck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park,

Harlow, Essex, UK CM20 2QR

Received (in Cambridge, UK) 10th September 2001, Accepted 1st November 2001

First published as an Advance Article on the web 26th November 2001

Cyclic amines have been prepared in good yield by [2,3]-rearrangement of ammonium ylides produced by

intramolecular reaction of copper carbenoids tethered to allylic amines. Copper() acetylacetonate is the optimum

catalyst for carbenoid/ylide generation from the diazo ketone precursor, and reactions must be performed at elevated

temperatures in order to obtain reasonable reaction rates and high yields. The reaction has been used to prepare

ﬁve- to eight-membered cyclic amines. In cases where the substrate possesses a substituent on the tether connecting

the diazo group to the allylic amine, tandem ylide formation and rearrangement delivers a high yield of the expected

2,5-dialkylpyrrolidinone or 2,6-dialkylpiperidinone, but low levels of diastereocontrol are obtained.

Two new methods have been developed for the synthesis of diazo ketones containing a nucleophilic allylic amine

substituent. The ﬁrst method involves conjugate addition of allylic amines to unsaturated diazo ketones and is high

yielding but of limited scope. The alternative general sequence involving nitrogen protection, α-diazo ketone

formation, deprotection and allylation can be used to prepare the substrates required for intramolecular tandem

ylide formation and rearrangement.

Introduction

The formation of ylides by the reaction of catalytically gener-

ated metal carbenoids with amines, ethers and sulﬁdes is a very

attractive alternative to traditional methods of ylide gener-

ation,¹which generally involve deprotonation or desilylation of

the corresponding onium salts.²In general, the generation of

ylides from carbenoids involves mild reaction conditions and

requires only a small amount of an appropriate copper or

rhodium catalyst.¹In recent years, several groups, including our

own, have investigated the synthesis of reduced cyclic amines,

ethers and sulﬁdes from metal carbenoids by intramolecular

generation and subsequent rearrangement of ammonium,^1,3–5

oxonium^1,6–9and sulfonium ylides.^1,10

Natural products containing cyclic amine units are ubiqui-

tous, and these alkaloids frequently possess potent biological

Scheme 1

activity. Consequently, the development of new and more eﬃ-

cient methods for the stereoselective synthesis of cyclic amines

continues to be a burgeoning area of research. In principle, the

intramolecular generation of cyclic ammonium ylides from

metal carbenoids and their subsequent rearrangement could

provide a wide range of cyclic amines of the type found in

natural products. In recent seminal studies, West has thor-

oughly investigated the synthesis of pyrrolidines, piperidines

and morpholines by [1,2] Stevens rearrangement of catalytically

generated cyclic ammonium ylides.³In this paper, we disclose

the results of a systematic study concerning the [2,3] rearrange-

ment of ammonium ylides generated from copper carbenoids in

an intramolecular fashion (Scheme 1), and deﬁne the scope and

limitations of this tandem process for the synthesis of cyclic

amines.⁴

amines by tandem catalytic ammonium ylide generation and

rearrangement (Scheme 1). In order to investigate the reaction

in detail, an eﬃcient route was required for the preparation of

the α-diazo ketones containing allylic amines required to serve

as cyclisation precursors. At the outset, substrate preparation

posed a signiﬁcant problem because nucleophilic amines are

generally incompatible with most of the conventional methods

employed for α-diazo ketone formation. Consequently, it was

necessary either to protect the amino group prior to diazo

ketone formation or to introduce the amine functionality after

preparation of the diazo ketone.

The α-diazo ketone precursors required for the synthesis of

pyrrolidines, were prepared using a route in which the allylic

amine group was introduced after preparation of the diazo

ketone (Scheme 2). The diazo ketone required for this approach,

4-bromo-1-diazobutan-2-one (1),¹¹was prepared in 82% yield

by treatment of 3-bromopropanoic acid with oxalyl chloride in

Results and discussion

Initial studies focused on the construction of simple cyclic

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This journal is © The Royal Society of Chemistry 2001

DOI: 10.1039/b108179a

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Scheme 2 Reagents and conditions: (i), (COCl)₂, DMF (cat.), CH₂Cl₂,

ЊC; (ii), CH₂N₂, Et₂O, ЊC rt (82%, steps); (iii),

MeNHCH₂CHCH₂, Et₃N, EtOAc, 0 ЊC rt (2a, 77%); (iv), DBN,

hydroquinone, Et₂O, Ϫ10 ЊC then NH(CH₂CHCH₂)₂, Et₂O, 0 ЊC

(2b, 73%).

the presence of a sub-stoichiometric amount of N,N-dimethyl-

formamide, and reaction of the resulting acid chloride with a

large excess of diazomethane. Treatment of the α-diazo ketone

1 with 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) at Ϫ10 ЊC

resulted in elimination of HBr and produced a solution of

α-diazo methyl vinyl ketone.¹¹The solution of the α,β-unsatur-

ated diazo ketone was ﬁltered and immediately added to a sol-

ution of diallylamine at 0 ЊC to give the cyclisation precursor 2b

in 73% yield. The cyclisation precursor 2a was prepared in 77%

yield by addition of N-methylallylamine to the α-diazo ketone 1

at room temperature.

Scheme 3 Reagents and conditions: (i), CF₃CO₂Et, Et₃N, MeOH, rt

(3a, 89%; 4a, 90%; 4b, 63%; 5a, 76%); (ii), (COCl)₂, DMF (cat.),

CH₂Cl₂, 0 ЊC; (iii), CH₂N₂, Et₂O, 0 ЊC rt (6a, 80%; 7a, 83%; 7b, 79%;

8a, 82%, steps); (iv), Ba(OH)₂aq. or NaOH aq., rt; (v),

CH₂CHCH₂Br, K₂CO₃, THF, rt (9, 48%; 11, 37%; 12, 54%, 2 steps).

The conjugate addition approach was only applicable to the

synthesis of the precursors required for pyrrolidine synthesis,

and so a general method for the preparation of longer-chain

cyclisation precursors was still required. The most obvious

solution to the problem was to employ a strategy in which the

amino functionality of an amino acid was protected during

conversion of the carboxylic acid group into the corresponding

α-diazo ketone. Subsequent deprotection and allylation at

nitrogen would then provide the required cyclisation precursor.

The number of candidate N-protecting groups was limited

because α-diazo ketones are incompatible with many of the

methods commonly used for N-deprotection e.g. treatment with

acid or hydrogenolysis. Of the commonly used protecting

groups, the triﬂuoroacetyl group was deemed to have the

appropriate reactivity proﬁle because it is compatible with

many of the methods used for diazo ketone synthesis and can

be removed under relatively mild alkaline conditions.¹²Another

candidate protecting group would have been the Fmoc group,

which has been used by Coutts and Saint for N-protection

during the synthesis of diazo ketones from amino acids.¹³

Protection of 4-aminobutanoic acid using triﬂuoroacetic

anhydride gave low yields of the amide 3a, and so alternative

protection conditions were investigated (Scheme 3). Reaction of

the amino acid with ethyl triﬂuoroacetate in the presence of

triethylamine gave the triﬂuoroacetamide 3a in 89% yield,¹²and

this was then converted into the α-diazo ketone 6a in 80% yield

using standard conditions. Subsequent treatment of the amide

6a with potassium carbonate in aqueous ethanol resulted in

extremely slow deprotection and aﬀorded none of the free

amine. In contrast, exposure of the amide 6a to a saturated

aqueous solution of barium hydroxide at room temperature

resulted in complete consumption of the starting material in

less than 20 minutes.¹⁴The resulting free amino α-diazo ketone

product was not isolated, but was treated with allyl bromide to

give the desired cyclisation precursor 9 in 48% yield over two

steps.

the protecting group was eﬀected by treatment of the amide

7b with aqueous sodium hydroxide at room temperature, and

the resulting amine was immediately alkylated to provide the

cyclisation precursor 11. The cyclisation precursor 12 was pre-

pared from 6-aminohexanoic acid by the analogous sequence

of triﬂuoroacetamide protection, diazo ketone formation,

N-deprotection and dialkylation with allyl bromide.

The attempted synthesis of the cyclisation precursor 10 was

unsuccessful. Although the amide 7a was prepared from 5-

aminopentanoic acid in good yield by triﬂuoroacetylation and

subsequent diazo ketone formation using the standard proto-

col, deprotection under basic aqueous conditions delivered the

triazole 14 rather than the required amino-substituted diazo

ketone (Scheme 4). The outcome of the reaction was unantici-

Scheme 4

pated, but it is probable that the triazole 14 was formed by

cyclisation of the intermediate diazo imine 13 produced by

intramolecular condensation. It is well known that related

diazo imines undergo cyclisation to give triazoles.¹⁶When

allylation was performed without puriﬁcation of the intermedi-

ate amine after deprotection, a small amount of the desired

product was obtained but the major product was the triazole

14.

The problem of competitive triazole formation during depro-

tection was also observed when the triﬂuoroacetyl group was

removed from the α-diazo ketone 18 prepared from the lactam

15 (Scheme 5). Reaction of the lactam 15 with concentrated

hydrochloric acid at high temperature in a sealed tube aﬀorded

the amino acid hydrochloride salt 16 in 59% yield, and the

amino functionality was protected by triﬂuoroacetylation. The

acid 17 was then converted into the α-diazo ketone 18 in 82%

yield using the standard protocol, and subsequent hydrolysis of

the triﬂuoroacetyl group with aqueous barium hydroxide

delivered a 57% yield of the triazole 19 instead of the required

amine.

Two longer chain analogues (11 and 12) of the precursor 9

were prepared in a similar manner (Scheme 3). The synthesis of

the diazo ketone 11 commenced with conversion of the hydro-

chloride salt of 5-(N-methylamino)pentanoic acid into the tri-

ﬂuoroacetamide 4b by treatment with ethyl triﬂuoroacetate and

excess triethylamine in methanol at room temperature. The

starting material was prepared in 47% yield by heating com-

mercially available N-methylpiperidin-2-one with concentrated

hydrochloric acid in a sealed tube.¹⁵Conversion of the acid 4b

into the α-diazo ketone 7b via the acid chloride was accom-

plished in 79% yield using the standard protocol. Removal of

It is signiﬁcant that competitive triazole formation was only

encountered when deprotection of the substrates (7a and 18)

aﬀorded a free primary amino group which could condense

J. Chem. Soc., Perkin Trans. 1, 2001, 3312–3324

3313

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After considerable experimentation, it was found that

copper- and rhodium-catalysed reactions proceeded at a satis-

factory rate when performed in benzene at reﬂux. Under these

conditions, the copper() acetylacetonate catalysed reactions

of the precursors 2a and 2b proved to be highly eﬀective, and

the pyrrolidinones 20 and 21 were obtained in yields of 73%

and 76% respectively. Lower yields of the pyrrolidinones were

obtained when rhodium() acetate was employed as the catalyst

under identical conditions (58% and 70% respectively). It is

noteworthy that yields of the pyrrolidinone 21 obtained from

the reactions of the diallyl substrate 2b were generally higher

than the yields of the pyrrolidinone 20 obtained from reactions

of the diazo ketone 2a.

The cyclisation reactions of diazo ketones 9, 11 and 12 were

also performed in benzene at reﬂux. Cyclisation of the substrate

9 proceeded to give the piperidinone 22 in 79% yield when

copper() acetylacetonate was used as the catalyst. When

copper() hexaﬂuoroacetylacetonate and rhodium() acetate

were employed as the catalysts, yields of 73% and 74% were

obtained. Treatment of the α-diazo ketone 11 with copper()

acetylacetonate in benzene at reﬂux gave the azepinone 23 in

84% yield. The use of copper() hexaﬂuoroacetylacetonate or

rhodium() acetate as the catalyst gave lower yields (58% and

56%) of the azepinone 23. Finally, the copper() acetylaceto-

nate catalysed reaction of the substrate 12 aﬀorded the azo-

cinone 24 in 39% yield. Copper() hexaﬂuoroacetylacetonate

was then employed as a catalyst in an attempt to improve the

yield of the azocinone 24. Although this complex is an excellent

catalyst for the synthesis of cyclic ethers from diazo ketones

and has been used to prepare an 8-membered cyclic ether,^4bthe

azocinone 24 was formed in only 13% yield when this complex

was used to cyclise substrate 12. Rhodium() acetate also

proved to be an inferior catalyst, and the azocinone 24 was

obtained in only 5% yield when this complex was used.

Scheme 5 Reagents and conditions: (i), HCl conc., 165 ЊC (59%); (ii),

CF₃CO₂Et, Et₃N, MeOH, rt (69%); (iii), (COCl)₂, DMF (cat.), CH₂Cl₂,

0 ЊC; (iv), CH₂N₂, CH₂Cl₂–Et₂O, 0 ЊC

rt (82%, 2 steps); (v), Ba(OH)₂

aq., rt; (v), CH₂CHCH₂Br, K₂CO₃, THF, rt (57%).

with the ketone carbonyl group to produce a six-membered

cyclic imine. Triazole formation was not observed during the

deprotection of substrates possessing either a longer or shorter

chain between the amide and diazo ketone, or during the depro-

tection of amides in which an N-alkyl substituent prevented

imine formation by the resulting secondary amine.

The metal-catalysed tandem ammonium ylide generation

and [2,3]-rearrangement reactions of the α-diazo ketone sub-

strates were explored (Scheme 6). Cyclisation reactions were

The results described above are consistent with those

obtained by West and co-workers during the synthesis of cyclic

amines by [1,2]-rearrangement of ammonium ylides generated

by copper-catalysed reaction of α-diazo ketones.^3eThey have

shown that higher yields of medium-ring cyclic amines are

obtained when ammonium ylides are generated from copper

carbenoids rather than rhodium carbenoids, and have used the

tandem catalytic ylide generation and [1,2]-Stevens rearrange-

ment reaction to synthesise the alkaloid (Ϫ)-epilupinine.^3c,3f

At this stage in our study, the tandem carbenoid insertion

and ylide rearrangement reaction had been used to prepare

relatively unsubstituted cyclic amines from achiral substrates,

and the issue of diastereocontrol had not been investigated.

Cyclisation of diazo ketones bearing a substituent on the tether

joining the diazo group to the allylic amine would result in two

possible diastereoisomeric products, and the origin of the

stereocontrol should depend on the nature of the substituents

on the nitrogen atom (Scheme 7). In the case where the nitrogen

atom possesses two non-equivalent substituents, ammonium

ylide formation results in the creation of an additional stereo-

genic centre (*) at nitrogen. Provided that ylide formation is not

reversible, the stereochemical outcome of the reaction is deter-

mined at this stage because each diastereoisomeric ylide under-

goes stereospeciﬁc rearrangement.¹⁸In contrast, a substrate

possessing two identical substituents reacts to give an ammo-

nium ylide without the creation of an additional stereogenic

centre (Scheme 7). In this case, a single ammonium ylide is

generated and the level of diastereocontrol is dictated by the

relative propensity of the diastereotopic allyl groups to undergo

subsequent [2,3]-rearrangement.

Scheme 6

performed by slow addition of a dilute solution of the α-diazo

ketone to a solution of the catalyst (2 mol%) at room tempera-

ture or reﬂux. In preliminary studies, the cyclisation reactions

of substrates 2a and 2b were performed in a variety of solvents

at room temperature or reﬂux and copper() acetylacetonate

and rhodium() acetate were employed as the catalysts.

Copper-catalysed reactions required temperatures of >35 ЊC to

initiate carbenoid generation, and reactions performed at reﬂux

in low boiling solvents (e.g. dichloromethane) required

extended reaction times and delivered poor yields of the pyr-

rolidinones. The poor performance of copper catalysts at lower

reaction temperatures is attributable to competitive coordin-

ation of the amine to the metal centre, which blocks the vacant

coordination site(s) required for carbenoid formation. Com-

petitive coordination has been proposed by Doyle et al. to

explain similar results obtained from intermolecular reactions

of rhodium carbenoids with amines.¹⁷

A series of substituted precursors was prepared in order to

explore the stereochemical outcome during the formation of

pyrrolidines and piperidines. The α-diazo ketone precursors

required for pyrrolidine synthesis were prepared by conjugate

addition of either diallylamine or N-methylallylamine to an

unsaturated diazo ketone (Scheme 8). The unsaturated diazo

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J. Chem. Soc., Perkin Trans. 1, 2001, 3312–3324

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Scheme 9 Reagents and conditions: (i), 6 M HCl, reﬂux (76%); (ii),

CF₃CO₂Et, Et₃N, MeOH, rt (89%); (iii), (COCl)₂, DMF (cat.), CH₂Cl₂,

0 ЊC; (iv), CH₂N₂, Et₂O, 0 ЊC rt (68%, 2 steps); (v), Ba(OH)₂aq., rt;

(vi), CH₂CHCH₂Br, K₂CO₃, THF, rt (31%, 2 steps).

ated aqueous solution of barium hydroxide, and immediate

alkylation then delivered the desired cyclisation precursor 33 in

modest yield over two steps.

The cyclisation reactions of the α-diazo ketones 27, 28 and

33, were then investigated (Scheme 10). Reactions were per-

Scheme 7

Scheme 10

formed by slow addition of a dilute solution of the α-diazo

ketone to a solution of the catalyst (2 mol%) in benzene at

reﬂux. The reaction of diazo ketone 28 proceeded to deliver a

mixture of the pyrrolidinones 35a–b in excellent yield but with

little diastereocontrol (≤2 : 1), and the choice of catalyst had

little inﬂuence on either the yield or stereochemical outcome of

the reaction. However, puriﬁcation of the mixture of pyrrol-

idinones 35a–b on silica gel resulted in epimerisation and led to

a dramatic change in the diastereoisomeric ratio. Prolonged

exposure of the mixture to silica gel returned an 8 : 1 mixture of

isomers, as judged by NMR, but it was not possible to deter-

mine the relative conﬁguration of each isomer using NOE

diﬀerence spectroscopy because there was signiﬁcant overlap

Scheme 8 Reagents and conditions: (i), LiHMDS, Ϫ78 ЊC then

CF₃CO₂CH₂CF₃, Ϫ78 ЊC; (ii), MsN₃, Et₃N, MeCN, rt (77%, 2 steps);

(iii), MeNHCH₂CHCH₂, Et₂O, rt (27, 85%); (iv), NH(CH₂CHCH₂)₂,

Et₂O, rt (28, 64%).

ketone 26 was prepared using Danheiser’s two step diazo trans-

fer sequence.¹⁹Thus, deprotonation of pent-3-en-2-one with

lithium hexamethyldisilazane and reaction of the resulting

enolate with 2,2,2-triﬂuoroethyl triﬂuoroacetate aﬀorded the

1,3-dicarbonyl compound 25. The β-diketone was immediately

treated with methanesulfonyl azide and triethylamine to deliver

the α-diazo ketone 26 in 77% yield over two steps.¹⁹Subsequent

conjugate addition with either N-methylallylamine or diallyl-

amine at room temperature then aﬀorded the precursors 27 and

28 in yields of 85% and 64% respectively. The conjugate add-

ition reaction of diallylamine proved to be capricious and often

failed to proceed to completion, resulting in a diﬃcult separ-

ation of the required product 28 from the starting materials.

The ﬁnal substrate to be investigated, α-diazo ketone 33, was

prepared from the lactam 29 by a route in which nitrogen was

protected using the triﬂuoroacetyl group (Scheme 9). The

lactam 29 was ﬁrst heated at reﬂux in 6 M HCl to aﬀord the

amino acid 30 in 76% yield.¹⁵N-Protection then gave the

required triﬂuoroacetamide 31 in high yield and this was con-

verted into the corresponding α-diazo ketone 32 via the acid

chloride using the standard method (Scheme 9). Deprotection

was accomplished by treatment of the amide 32 with a satur-

of signals in the H NMR spectrum. However, based on our

results from related cyclic ethers, the cis-isomer 35b is likely to

be the thermodynamically favoured product arising from

epimerisation.^4a

When one of the allyl groups was replaced by a methyl sub-

stituent, there was no diastereocontrol; the copper() acetyl-

acetonate mediated cyclisation of the diazo ketone 27 aﬀorded

a 1 : 1 mixture of the isomers 34a–b in a combined yield of 70%

(Scheme 10). Increasing the size of the alkyl substituent

resulted in a diminished yield without a signiﬁcant improve-

ment in the level of diastereocontrol. When the crude mixture

of the isomers 34a–b was puriﬁed by column chromatography,

epimerisation occurred and a single isomer was isolated. As in

the case above, overlapping signals in the H NMR spectrum

J. Chem. Soc., Perkin Trans. 1, 2001, 3312–3324

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precluded conﬁrmation of the relative stereochemistry using

NOE diﬀerence spectroscopy. As a result, the relative stereo-

chemistry of the major isomer isolated after epimerisation was

not determined unambiguously, but it is likely that the isomer

34b was the major product for the reasons outlined above.

The cyclisation of the α-diazo ketone 33 proceeded in good

yield but a 1 : 1 mixture of 36a–b was obtained (Scheme 10).

Epimerisation was encountered when the mixture was exposed

to silica gel, and this resulted in a moderate preference (2 : 1 as

judged by NMR) for one of the diastereoisomers. However, it

was not possible to separate the diastereoisomers by column

chromatography and once again NOE diﬀerence spectroscopy

could not be used to determine the relative stereochemistry

ﬁlms on sodium chloride plates, or as solutions in chloroform,

using either a Perkin–Elmer 1720X or 1600 series FTIR spec-

trometer. ¹H NMR spectra were recorded using a Bruker

DRX500 (500 MHz), AM400 (400 MHz) or WM250 (250 MHz)

spectrometer. ¹H NMR data are expressed as chemical shifts in

ppm from an internal standard of tetramethylsilane followed by

the number of protons, multiplicity (s, singlet; d, doublet; t,

triplet; q, quartet; m, multiplet; and br, broad), coupling con-

stant(s) J (Hz), and assignment. ¹³C NMR spectra were

recorded using a JEOL EX270 (67.5 MHz), Bruker AM400

(100 MHz) or Bruker DRX500 (125 MHz) instrument and

multiplicities were obtained using a DEPT sequence. ¹³C NMR

chemical shifts are expressed in parts per million downﬁeld

from tetramethylsilane or the sodium salt of 3-(trimethylsilyl)-

propanesulfonic acid. High resolution mass spectra (HRMS)

were obtained using an AEI MS902 or VG Micromass 70E

mass spectrometer, using electron impact (EI), chemical ionis-

ation (CI) or fast-atom bombardment (FAB). Microanalysis

was performed by the microanalysis section of the School of

Chemistry, University of Nottingham, UK.

because there was insuﬃcient separation of signals in the H

NMR spectrum.

The low levels of diastereocontrol obtained upon cyclisation

of diazo ketones 27, 28 and 33 contrast with results obtained

from the copper-mediated cyclisation reactions of related

oxygen-containing diazo ketones to give ﬁve- and six-

membered cyclic ethers.^8a,8cIt is surprising that the levels of

diastereocontrol are so low irrespective of whether the nitrogen

centre possesses one or two allyl groups which can participate

in the [2,3]-rearrangement of the putative ammonium ylide

intermediate.

In summary, we have developed two new methods for the

synthesis of diazo ketone precursors containing a nucleophilic

allylic amine substituent. Although the preparation of cyclis-

ation precursors by conjugate addition of allylic amines to

unsaturated diazo ketones is of limited scope, the alternative

sequence of nitrogen protection, α-diazo ketone formation,

deprotection and allylation, is general and can be used to pre-

pare a wide range of cyclisation precursors in reasonable yield.

We have also demonstrated that copper() acetylacetonate is

the best catalyst for carbenoid/ylide generation and that reac-

tions must be performed at elevated temperatures in order to

obtain reasonable reaction rates and high yields. The reaction

has been used to prepare ﬁve- to seven-membered cyclic amines

in good yield and eight-membered cyclic amines in modest

yield. However, when the tandem intramolecular ammonium

ylide formation and rearrangement reaction is used to prepare

dialkyl- pyrrolidines or piperidines, it is not possible to achieve

high levels of diastereocontrol directly from the cyclisation

reaction. In addition, we have found that the propensity of

the cyclic amine products to undergo epimerisation upon puri-

ﬁcation would complicate matters even if high levels of

diastereocontrol were achievable during the reaction.

General procedure for the preparation of ꢀ-diazo ketones

Oxalyl chloride was added dropwise to a solution of the carb-

oxylic acid in dry dichloromethane at room temperature or

0 ЊC. A small amount of dry dimethylformamide was added,

and the resulting mixture was stirred at room temperature or

0 ЊC for the time indicated. The solvent was removed in vacuo

and the residue dissolved in dry diethyl ether. The ethereal

solution was added slowly to a solution of diazomethane in

diethyl ether at 0 ЊC, and the resulting solution was stirred at

0 ЊC and then at room temperature. The remaining diazo-

methane was consumed by dropwise addition of glacial acetic

acid and the solution was neutralised with a saturated aqueous

solution of sodium bicarbonate. The organic phase was separ-

ated, the aqueous phase extracted with diethyl ether and the

combined organic extracts were dried before removal of the

solvent in vacuo. The residue was puriﬁed by ﬂash column

chromatography on silica gel to give the α-diazo ketone.

4-Bromo-1-diazobutan-2-one 1¹¹. Following the general pro-

cedure, the acid chloride was prepared by the reaction of 3-

bromopropanoic acid (1.14 g, 7.45 mmol) with oxalyl chloride

(3.00 cm³, 34.4 mmol) and dry dimethylformamide (one drop)

in dry dichloromethane (45 cm³) at room temperature for 2 h.

The acid chloride was dissolved in dry diethyl ether (30 cm³)

and added to a solution of diazomethane (∼33 mmol) in diethyl

ether (120 cm³) at 0 ЊC. The mixture was stirred at 0 ЊC for

30 min and then at room temperature for a further 45 min. The

remaining diazomethane was consumed with glacial acetic acid

(3.50 cm³, 61.1 mmol). Puriﬁcation by ﬂash column chrom-

atography on silica gel (diethyl ether–hexane, 1 : 1) aﬀorded the

α-diazo ketone 1 (1.08 g, 82%) as a yellow liquid; ν_max(ﬁlm)/cm^Ϫ1

3096, 2108, 1634; δ_H(250 MHz, CDCl₃) 5.31 (1H, br s, CHN₂),

3.62 (2H, t, J 6.7, CH₂Br), 2.90 (2H, t, J 6.7, CH₂CO); δ_C

(67.8 MHz, CDCl₃) 191.5 (CO), 55.8 (CH), 43.3 (BrCH₂),

26.5 (CH₂CO); m/z (EI) 175.9579 (M^ϩ. C₄H₅BrN₂O requires

175.9585).

Experimental

General

Air and/or moisture sensitive reactions were performed under

an atmosphere of nitrogen in oven or ﬂame dried apparatus.

Organic solvents and reagents were dried and distilled using

standard methods: tetrahydrofuran (potassium–benzophenone

ketyl), diethyl ether (sodium metal–benzophenone ketyl),

methanol (magnesium methoxide), ethyl triﬂuoroacetate

(anhydrous calcium chloride), allyl bromide (anhydrous mag-

nesium sulfate), benzene, dichloromethane and triethylamine

(calcium hydride). All other solvents and reagents were used

as received from commercial suppliers. All reactions were

monitored by thin layer chromatography using plastic- or

aluminium-backed silica gel 60 F₂₅₄plates. Thin layer chrom-

atography plates were viewed under UV light or were visualised

using either basic potassium permanganate solution or acidic

ethanolic anisaldehyde solution. Flash column chromatography

was performed using Merck 7734 grade silica gel or Fluka silica

gel 60 (220–440 mesh). Melting points were determined using

either Büchi 510 or Reichert hot-stage melting point apparatus.

IR spectra were recorded as potassium bromide disks, as liquid

4-(N-Methyl-N-allylamino)-1-diazobutan-2-one 2a. N-Methyl-

allylamine (0.50 g, 7.0 mmol) and triethylamine (1.13 cm³,

8.11 mmol) were dissolved in dry ethyl acetate (15 cm³). The

mixture was cooled to 0 ЊC and a solution of 4-bromo-1-

diazobutan-2-one (1) (1.36 g, 7.68 mmol) in dry ethyl acetate

(15 cm³) was added over 30 s. The resulting solution was stirred

at 0 ЊC for 25 min and at room temperature for 15 h. The

mixture was then diluted with a saturated aqueous solution

of sodium bicarbonate (40 cm³) and extracted with diethyl

ether (3 × 40 cm³). The combined organic extracts were dried

over anhydrous potassium carbonate and the solvent removed

3316

J. Chem. Soc., Perkin Trans. 1, 2001, 3312–3324

View Article Online

in vacuo. The residue was puriﬁed by ﬂash column chrom-

atography on silica gel (1% triethylamine in diethyl ether) to

give the α-diazo ketone 2a (0.91 g, 77%) as a green liquid;

ν_max(ﬁlm)/cm^Ϫ13080, 2977, 2793, 2104, 1641, 998, 920; δ_H(250

methanol (10 cm³), and the resulting solution was stirred at

room temperature for 18 h. The crude product was diluted with

2 M hydrochloric acid (50 cm³) and extracted with diethyl ether

(3 × 60 cm³). After addition of sodium chloride, the aqueous

layer was extracted with diethyl ether (60 cm³). The product was

puriﬁed by recrystallisation (diethyl ether–hexane) to give the

protected amino acid 4a (3.84 g, 90%) as a white solid; mp 96–98

ЊC [lit.,²⁰94–96 ЊC]; ν_max(CHCl₃)/cm^Ϫ13437, 2955, 1723; δ_H

(250 MHz, CDCl₃) 6.51 (1H, br s, NH), 3.44–3.36 (2H, m,

NCH₂), 2.43 (2H, t, J 6.7, CH₂CO), 1.74–1.63 (4H, m,

NCH₂CH₂and CH₂CH₂CO); δ_C(67.8 MHz, CD₃OD) 177.2

(CO₂H), 159.0 (CON, q, ²J_FC37), 117.5 (CF₃, q, ¹J_FC287), 40.3

(CH₂), 34.2 (CH₂), 29.2 (CH₂), 23.1 (CH₂) (Found C, 39.5; H,

4.8; N, 6.5. C₇H₁₀F₃NO₃requires C, 39.4; H, 4.7; N, 6.6%).

MHz, CDCl ) 5.84 (1H, ddt, J 17.1, 10.2 and 6.5, CH᎐CH ),

᎐

5.39 (1H, br s, CHN ), 5.18 (1H, dtd, J 17.1, 1.1, 0.7, trans CH᎐

᎐

CH ), 5.15 (1H, dtd, J 10.2, 1.1, 0.7, cis CH᎐CH ), 3.01 (2H,

᎐

ddd, J 6.5, 1.1, 1.1, CH CH᎐CH ), 2.70 (2H, t, J 7.0,

᎐

NCH₂CH₂), 2.53–2.45 (2H, m, CH₂CO), 2.23 (3H, s, CH₃); δ_C

(67.8 MHz, CDCl₃) 193.7 (CO), 135.2 (CH), 117.6 (CH₂), 60.6

(CH₂), 54.6 (CH₂), 52.2 (CH₂), 41.8 (CH₃), 38.7 (CH₂); m/z (EI)

139.0998 (M^ϩϪ N₂. C₈H₁₃NO requires 139.0997).

4-(N,N-Diallylamino)-1-diazobutan-2-one 2b. Diazabicyclo-

[4.3.0]non-5-ene (0.74 cm³, 6.0 mmol) was added dropwise to a

vigorously stirred solution of 4-bromo-1-diazobutan-2-one (1)

(1.06 g, 5.99 mmol) and hydroquinone (50 mg, 0.45 mmol) in

dry diethyl ether (50 cm³) at Ϫ10 ЊC. The resulting mixture was

stirred at Ϫ10 ЊC for a further 7 min and then ﬁltered through a

sinter into a solution of diallylamine (2.33 g, 24.0 mmol) in dry

diethyl ether (10 cm³) at 0 ЊC. The mixture was stirred at room

temperature for a further 2 h and the solvent removed in vacuo.

The residue was puriﬁed by ﬂash column chromatography on

silica gel (1% triethylamine in diethyl ether–hexane, 4 : 1) to give

the α-diazo ketone 2b (0.85 g, 73%) as a green liquid; ν_max(ﬁlm)/

cm^Ϫ13080, 2978, 2925, 2809, 2105, 1641, 998, 922; δ_H(250

5-[N-Methyl-N-(triﬂuoroacetyl)amino]pentanoic acid 4b. Fol-

lowing the general protection procedure, 5-(N-methylamino)-

pentanoic acid hydrochloride salt (0.35 g, 2.1 mmol) was

treated with ethyl triﬂuoroacetate (0.31 cm³, 2.6 mmol) and tri-

ethylamine (0.63 cm³, 4.5 mmol) in dry methanol (5 cm³), and

the resulting solution was stirred at room temperature for 29 h.

The crude product was diluted with 1 M hydrochloric acid

(10 cm³) and extracted with diethyl ether (4 × 10 cm³). The

product was puriﬁed by ﬂash column chromatography on silica

gel (diethyl ether–hexane, 3 : 2) to give the protected amino acid

4b (0.30 g, 63%) as a colourless liquid; ν_max(CHCl₃)/cm^Ϫ13179,

2948, 2828, 1694; δ_H(400 MHz, [CD₃]₂SO, 393 K) 2.86 (2H, t,

J 7.3, NCH₂), 2.50 (3H, s, NCH₃), 2.26 (2H, t, J 7.1, CH₂CO),

1.75–1.68 (2H, m, NCH₂CH₂), 1.66–1.58 (2H, m, CH₂CH₂CO);

δ_C(100 MHz, [CD₃]₂SO, 393 K) 173.9 (CO₂H), 156.4 (CON,

MHz, CDCl ) 5.83 (2H, ddt, J 17.1, 10.3, 6.5, 2 × CH᎐CH ),

᎐

5.39 (1H, br s, CHN ), 5.22–5.18 (2H, m, 2 × trans CH᎐CH ),

᎐

5.18–5.11 (2H, m, 2 × cis CH᎐CH ), 3.09 (4H, d, J 6.5, 2 ×

᎐

CH CH᎐CH ), 2.79 (2H, t, J 7.2, NCH CH ), 2.47 (2H, t, J 7.2,

᎐

q, J_FC35), 116.8 (CF₃, q, J_FC289), 48.8 (CH₂), 34.1 (CH₃),

33.3 (CH₂), 25.8 (CH₂), 21.8 (CH₂); m/z (EI) 227.0768 (M^ϩ.

C₈H₁₂F₃NO₃requires 227.0769).

CH₂CO); δ_C(67.8 MHz, CDCl₃) 193.8 (CO), 135.1 (CH), 117.5

(CH₂), 56.6 (CH₂), 54.5 (CH), 48.6 (CH₂), 38.5 (CH₂); m/z (EI)

165.1147 (M^ϩϪ N₂. C₁₀H₁₅NO requires 165.1154).

6-[N-(Triﬂuoroacetyl)amino]hexanoic acid 5a. Following the

general protection procedure, 6-aminohexanoic acid (5.25 g,

40.0 mmol) was treated with ethyl triﬂuoroacetate (6.00 cm³,

50.4 mmol) and triethylamine (5.60 cm³, 40.2 mmol) in dry

methanol (20 cm³), and the resulting solution was stirred at

room temperature for 17 h. The crude product was diluted with

a 2 M hydrochloric acid (100 cm³) and the resulting precipitate

collected by ﬁltration and dissolved in diethyl ether (100 cm³).

The aqueous layer was extracted with diethyl ether (2 × 80 cm³)

and sodium chloride added. The aqueous layer was extracted

with diethyl ether (2 × 80 cm³). The product was puriﬁed by

recrystallisation (diethyl ether–hexane) to give the protected

amino acid 5a (6.90 g, 76%) as a white solid; mp 88–90 ЊC [lit.,²⁰

89–91 ЊC]; ν_max(CHCl₃)/cm^Ϫ13436, 2925, 2848, 1722, 1602;

δ_H(250 MHz, CD₃OD) 3.29 (2H, t, J 7.1, NCH₂), 2.31 (2H,

t, J 7.3, CH₂CO), 1.69–1.53 (4H, m, NCH₂CH₂and CH₂-

CH₂CO), 1.43–1.31 (2H, m, NCH₂CH₂CH₂); δ_C(67.8 MHz,

CD₃OD) 177.5 (CO₂H), 158.9 (CON, q, ²J_FC37), 117.5 (CF₃, q,

¹J_FC287), 40.5 (CH₂), 34.7 (CH₂), 29.5 (CH₂), 27.2 (CH₂), 25.5

(CH₂) (Found C, 42.4; H, 5.5; N, 6.4. C₈H₁₂F₃NO₃requires C,

42.3; H, 5.3; N, 6.2%).

General procedure for triﬂuoroacetyl protection of amino acids

Ethyl triﬂuoroacetate was added dropwise to a solution of the

amino acid and triethylamine in dry methanol. The resulting

solution was stirred at room temperature and the solvent was

then removed in vacuo. The residue was diluted with 2 M hydro-

chloric acid and extracted with diethyl ether, and the aqueous

layer was then saturated with solid sodium chloride and

extracted with further diethyl ether. The combined organic

extracts were dried over anhydrous magnesium sulfate and the

solvent removed in vacuo. The product was puriﬁed by ﬂash

column chromatography on silica gel or by recrystallisation.

4-[N-(Triﬂuoroacetyl)amino]butanoic acid 3a. Following the

general protection procedure, 4-aminobutanoic acid (4.12 g,

40.0 mmol) was treated with ethyl triﬂuoroacetate (6.00 cm³,

50.4 mmol) and triethylamine (5.60 cm³, 40.2 mmol) in dry

methanol (20 cm³), and the resulting solution was stirred at

room temperature for 19 h. The crude product was diluted with

2 M hydrochloric acid (100 cm³) and extracted with diethyl

ether (2 × 100 cm³). After addition of sodium chloride, the

aqueous layer was extracted with diethyl ether (2 × 100 cm³).

The product was puriﬁed by recrystallisation (diethyl ether–

hexane) to give the protected amino acid 3a (7.06 g, 89%) as a

white solid; mp 81–83 ЊC [lit.,²⁰81–82 ЊC]; ν_max(CHCl₃)/cm^Ϫ1

3517, 3438, 3268, 2991, 2947, 1716; δ_H(250 MHz, CDCl₃) 6.78

(1H, br s, NH), 3.46 (2H, t, J 6.4, NCH₂), 2.36 (2H, t, J 6.8,

CH₂CO), 1.86 (2H, tt, J 6.8, 6.4, NCH₂CH₂); δ_C(67.8 MHz,

CD₃OD) 177.1 (CO₂H), 159.6 (CON, q, ²J_FC37), 118.0 (CF₃, q,

¹J_FC287), 40.6 (CH₂), 32.4 (CH₂), 25.6 (CH₂) (Found C, 36.25;

H, 4.2; N, 7.1. C₆H₈F₃NO₃requires C, 36.2; H, 4.0; N, 7.0%).

1-Diazo-5-[N-(triﬂuoroacetyl)amino]pentan-2-one 6a. Follow-

ing the general procedure, the acid chloride was prepared by the

reaction of the N-protected amino acid 3a (4.98 g, 25.0 mmol)

with oxalyl chloride (10.9 cm³, 125 mmol) and dry dimethyl-

formamide (ﬁve drops) in dry dichloromethane (125 cm³) at

0 ЊC for 1 h and then at room temperature for 5 h. The acid

chloride was dissolved in dry dichloromethane (30 cm³) and

added to a solution of diazomethane (∼150 mmol) in diethyl

ether (350 cm³) at 0 ЊC, and the mixture was stirred at 0 ЊC for

2 h. The remaining diazomethane was consumed with glacial

acetic acid (12.9 cm³, 225 mmol). Puriﬁcation by ﬂash column

chromatography on silica gel (diethyl ether–hexane, 1 : 1)

aﬀorded the α-diazo ketone 6a (4.46 g, 80%) as a yellow solid;

mp 39–41 ЊC; ν_max(CHCl₃)/cm^Ϫ13436, 3274, 2940, 2112, 1723,

5-[N-(Triﬂuoroacetyl)amino]pentanoic acid 4a. Following the

general protection procedure, 5-aminopentanoic acid (2.34 g,

20.0 mmol) was treated with ethyl triﬂuoroacetate (3.00 cm³,

25.2 mmol) and triethylamine (2.80 cm³, 20.1 mmol) in dry

J. Chem. Soc., Perkin Trans. 1, 2001, 3312–3324

3317

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1634; δ_H(250 MHz, CDCl₃) 7.68 (1H, br s, NH), 5.36 (1H, br s,

CHN₂), 3.40 (2H, q, J 6.3, NCH₂), 2.46 (2H, t, J 6.3, CH₂CO),

1.94 (2H, tt, J 6.3 and 6.3, NCH₂CH₂); δ_C(67.8 MHz, CDCl₃)

194.9 (CO), 157.4 (CON, q, J_FC36), 115.8 (CF₃, q, J_FC288),

55.1 (CH), 39.5 (CH₂), 37.6 (CH₂), 23.3 (CH₂); m/z (EI)

182.0397 (M^ϩϪ CHN₂. C₆H₇F₃NO₂requires 182.0429).

CHN₂), 3.36 (2H, t, J 6.7, NCH₂), 2.50–2.23 (2H, m, CH₂CO),

1.71–1.55 (4H, m, NCH₂CH₂and CH₂CH₂CO), 1.43–1.30 (2H,

m, NCH₂CH₂CH₂); δ_C(67.8 MHz, CDCl₃) 195.1 (CO), 157.3

(CON, q, J_FC37), 115.8 (CF₃, q, J_FC287), 54.6 (CH), 40.3

(CH₂), 39.5 (CH₂), 28.3 (CH₂), 25.9 (CH₂), 24.2 (CH₂); m/z (EI)

210.0743 (M^ϩϪ CHN₂. C₈H₁₁F₃NO₂requires 210.0742).

1-Diazo-6-[N-(triﬂuoroacetyl)amino]hexan-2-one 7a. Follow-

ing the general procedure, the acid chloride was prepared by the

reaction of the N-protected amino acid 4a (2.13 g, 10.0 mmol)

with oxalyl chloride (4.40 cm³, 50.4 mmol) and dry dimethyl-

formamide (one drop) in dry dichloromethane (50 cm³) at 0 ЊC

for 1 h and then at room temperature for 2 h. The acid chloride

was dissolved in dry dichloromethane (40 cm³) and added to a

solution of diazomethane (∼60 mmol) in diethyl ether (180 cm³)

at 0 ЊC, and the mixture was stirred at 0 ЊC for 2 h and at room

temperature for 1 h. The remaining diazomethane was con-

sumed with glacial acetic acid (6.80 cm³, 119 mmol). Puriﬁca-

tion by ﬂash column chromatography on silica gel (diethyl

ether–hexane, 2 : 1) aﬀorded the α-diazo ketone 7a (1.96 g, 83%)

as a yellow liquid; ν_max(CHCl₃)/cm^Ϫ13440, 3272, 3118, 2947,

2864, 2111, 1722, 1636; δ_H(400 MHz, CDCl₃) 7.03 (1H, br s,

NH), 5.29 (1H, br s, CHN₂), 3.36 (2H, q, J 6.4, NCH₂), 2.39

(2H, br, CH₂CO), 1.73–1.59 (4H, m, NCH₂CH₂and

CH₂CH₂CO); δ_C(67.8 MHz, CDCl₃) 195.1 (CO), 157.3 (CON,

q, ²J_FC37), 115.8 (CF₃, q, ¹J_FC288), 54.6 (CH), 39.6 (CH₂), 39.2

(CH₂), 27.8 (CH₂), 21.6 (CH₂).

1-Diazo-5-(N,N-diallylamino)pentan-2-one 9. The α-diazo

ketone 6a (1.00 g, 4.48 mmol) was dissolved in a saturated

aqueous solution of barium hydroxide (30.0 cm³) and the sol-

ution stirred at room temperature for 18 min. The solution was

then extracted with ethyl acetate (3 × 30 cm³). The aqueous

phase was evaporated to dryness in vacuo and the solid residue

washed with ethyl acetate (2 × 30 cm³). The combined organic

phases were then dried over anhydrous potassium carbonate the

solvent removed in vacuo. Allyl bromide (1.16 cm³, 13.4 mmol)

was then added to a suspension of the residue and potassium

carbonate (1.86 g, 13.5 mmol) in dry tetrahydrofuran (30 cm³).

The resulting suspension was stirred at room temperature for

24 h and the solvent was removed in vacuo. The residue was

diluted with water (45 cm³) and extracted with diethyl ether

(5 × 30 cm³), and the combined organic extracts were dried

over anhydrous potassium carbonate. The solvent was removed

in vacuo and the residue was puriﬁed by ﬂash column chrom-

atography on silica gel (1% triethylamine in diethyl ether) to

give the α-diazo ketone 9 (0.45 g, 48%) as a green liquid;

ν_max(ﬁlm)/cm^Ϫ13078, 3007, 2977, 2930, 2806, 2104, 1641, 997,

920; δ_H(250 MHz, CDCl₃) 5.82 (2H, ddt, J 17.1, 10.2, 6.5, 2 ×

1-Diazo-6-[N-methyl-N-(triﬂuoroacetyl)amino]hexan-2-one

7b. Following the general procedure, the acid chloride was

prepared by the reaction of the N-protected amino acid 4b

(1.93 g, 8.50 mmol) with oxalyl chloride (3.70 cm³, 42.4 mmol)

and dry dimethylformamide (seven drops) in dry dichlo-

romethane (50 cm³) at 0 ЊC for 1 h and then at room tempera-

ture for 2 h 40 min. The acid chloride was dissolved in dry

dichloromethane (50 cm³) and added to a solution of diazo-

methane (∼60 mmol) in diethyl ether (350 cm³) at 0 ЊC, and

the mixture was stirred at 0 ЊC for 1 h 50 min and then at room

temperature for 1 h. The remaining diazomethane was con-

sumed with glacial acetic acid (5.20 cm³, 90.8 mmol). Puriﬁca-

tion by ﬂash column chromatography on silica gel (diethyl

ether–hexane, 2 : 1) aﬀorded the α-diazo ketone 7b (1.69 g,

CH᎐CH ), 5.25 (1H, br s, CHN ), 5.18 (2H, dtd, J 17.1, 1.2, 0.5,

᎐

2 2

2 × trans CH᎐CH ), 5.13 (2H, dtd, J 10.2, 1.2 and 0.5, 2 × cis

᎐

CH᎐CH ), 3.07 (4H, dt, J 6.5, 1.2, 2 × CH CH᎐CH ), 2.47–2.40

᎐

(2H, m, NCH₂CH₂), 2.34 (2H, t, J 6.8, CH₂CO), 1.84–1.72 (2H,

m, NCH₂CH₂); δ_C(67.8 MHz, CDCl₃) 194.8 (CO), 135.5 (CH),

117.2 (CH₂), 56.5 (CH₂), 54.1 (CH), 52.0 (CH₂), 38.4 (CH₂),

22.3 (CH₂); m/z (EI) 171.1313 (M^ϩϪ N₂. C₁₁H₁₇NO requires

171.1310).

6-(N-Allyl-N-methylamino)-1-diazohexan-2-one 11. The α-

diazo ketone 7b (136 mg, 0.573 mmol) was dissolved in a

0.05 M aqueous solution of sodium hydroxide (5.40 cm³) and

the resulting solution stirred at room temperature for 2 h

10 min. After this time, the aqueous phase was extracted with

ethyl acetate (3 × 15 cm³). The aqueous extracts were evapor-

ated in vacuo and the resulting residue dissolved in dry tetra-

hydrofuran (8 cm³). Potassium carbonate (180 mg, 1.30 mmol)

and allyl bromide (0.10 cm³, 1.2 mmol) were added and the

mixture stirred at room temperature for 6 h 30 min. The solvent

was then removed in vacuo and the residue was puriﬁed by ﬂash

column chromatography on silica gel (1% triethylamine in ethyl

acetate) to give the α-diazo ketone 11 (17.9 mg, 17%) as a green

liquid.

The combined organic extracts were dried over anhydrous

potassium carbonate and concentrated in vacuo. The residue

and potassium carbonate (150 mg, 1.09 mmol) were suspended

in dry tetrahydrofuran (5 cm³) and allyl bromide (0.10 cm³,

1.2 mmol) was added. The resulting suspension was stirred at

room temperature for 3 h and the solvent was then removed

in vacuo. The residue was puriﬁed by column chromatography

(1% triethylamine in ethyl acetate) to give the α-diazo ketone 11

(21.1 mg, 20%) as a green liquid (combined yield 38.9 mg, 37%);

ν_max(CHCl₃)/cm^Ϫ12937, 2855, 2109, 1643; δ_H(250 MHz,

79%) as

a yellow liquid (mixture of amide rotamers);

ν_max(ﬁlm)/cm^Ϫ13092, 2948, 2104, 1695, 1642; δ_H(250 MHz,

CDCl₃) 5.32 (1H, br s, CHN₂), 3.47–3.38 (2H, m, NCH₂), 3.12

(2.1H, q, J 1.5, 0.7 × CH₃), 3.02 (0.9H, m, 0.3 × CH₃), 2.38

(2H, s, CH₂CO), 1.72–1.62 (4H, m, NCH₂CH₂and

CH₂CH₂CO); δ_C(100 MHz, CDCl₃) 194.2 (CO), 193.8 (CO),

156.7 (CON, q, J_FC36), 156.6 (CON, q, J_FC36), 116.4 (CF₃,

q, J_FC288), 116.3 (CF₃, q, J_FC288), 54.3 (CH), 49.0 (CH₂),

48.7 (CH₂), 39.7 (CH₂), 34.5 (CH₃), 34.1 (CH₃), 27.5 (CH₂),

25.6 (CH₂), 21.6 (CH₂), 21.4 (CH₂); m/z (EI) 223.0824 (M^ϩ

N₂. C₉H₁₂F₃NO₂requires 223.0820).

1-Diazo-7-[N-(triﬂuoroacetyl)amino]heptan-2-one 8a. Follow-

ing the general procedure, the acid chloride was prepared by the

reaction of the N-protected amino acid 5a (5.86 g, 25.8 mmol)

with oxalyl chloride (10.9 cm³, 125 mmol) and dry dimethyl-

formamide (seven drops) in dry dichloromethane (125 cm³) at

0 ЊC for 2 h and then at room temperature for 2 h 15 min. The

acid chloride was dissolved in dry dichloromethane (70 cm³)

and added to a solution of diazomethane (∼150 mmol) in

diethyl ether (350 cm³) at 0 ЊC, and the mixture was allowed to

warm to room temperature for 16 h. The remaining diazo-

methane was consumed with glacial acetic acid (12.9 cm³,

225 mmol). Puriﬁcation by ﬂash column chromatography on

silica gel (diethyl ether–hexane, 2 : 1) aﬀorded the α-diazo

ketone 8a (5.34 g, 82%) as a yellow solid; mp 48–50 ЊC;

ν_max(CHCl₃)/cm^Ϫ13439, 3297, 3116, 2945, 2862, 2109, 1722,

1634; δ_H(250 MHz, CDCl₃) 7.35 (1H, br s, NH), 5.33 (1H, br s,

CDCl ) 5.82 (1H, m, dddd, J 17.0, 10.2, 6.5, 6.5, CH᎐CH ),

᎐

5.24 (1H, br s, CHN ), 5.18–5.10 (1H, m, trans CH᎐CH ), 5.13–

᎐

5.07 (1H, m, cis CH᎐CH ), 2.96 (2H, d, J 6.5, CH CH᎐CH ),

᎐

2.34–2.28 (4H, m, NCH₂and CH₂CO), 2.17 (3H, s, NCH₃),

1.68–1.42 (4H, m, NCH₂CH₂and CH₂CH₂CO); δ_C(67.8 MHz,

CDCl₃) 194.8 (CO), 135.6 (CH), 117.2 (CH₂), 60.8 (CH₂), 56.6

(CH₂), 54.1 (CH), 41.8 (CH₃), 40.6 (CH₂), 26.7 (CH₂), 22.9

(CH₂); m/z (EI) 167.1323 (M^ϩϪ N₂. C₁₀H₁₇NO requires

167.1310).

3318

J. Chem. Soc., Perkin Trans. 1, 2001, 3312–3324

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7-(N,N-Diallylamino)-1-diazoheptan-2-one 12. The α-diazo

ketone 8a (1.45 g, 5.77 mmol) was dissolved in a saturated

aqueous solution of barium hydroxide (40 cm³) and stirred at

room temperature for 20 min. After this time, further saturated

aqueous barium hydroxide solution (10 cm³) was added. The

reaction was then stirred for 10 min and the solution was

extracted with ethyl acetate (3 × 50 cm³). The aqueous phase

was evaporated to dryness in vacuo and the solid residue washed

with ethyl acetate (2 × 50 cm³). The combined organic phases

were dried over anhydrous potassium carbonate and the solvent

was removed in vacuo. The residue and potassium carbonate

(2.48 g, 17.9 mmol) were suspended in dry tetrahydrofuran

(40 cm³) and allyl bromide (1.55 cm³, 17.9 mmol) was added

in one portion. The resulting suspension was stirred at room

temperature for 20 h and the solvent was then removed in vacuo.

The residue was diluted with water (80 cm³) and extracted with

diethyl ether (4 × 80 cm³). The combined organic extracts were

dried over anhydrous potassium carbonate and the solvent

removed in vacuo. The residue was puriﬁed by ﬂash column

chromatography on silica gel (1% triethylamine in diethyl ether)

to give the α-diazo ketone 12 (0.73 g, 54%) as a green liquid;

ν_max(ﬁlm)/cm^Ϫ13078, 3007, 2977, 2934, 2861, 2801, 2104, 1641,

996, 919; δ_H(250 MHz, CDCl₃) 5.84 (2H, ddt, J 16.9, 10.3, 6.5,

ution was stirred at room temperature for 15 min and then ethyl

triﬂuoroacetate (40 µl, 0.34 mmol) was added dropwise over

15 s. The reaction mixture was stirred at room temperature for

17 h and further portions of triethylamine (80 µl, 0.57 mmol)

and ethyl triﬂuoroacetate (40 µl, 0.34 mmol) were then added.

The resulting solution was stirred at room temperature for a

further 3.5 h and the solvent was then removed in vacuo. The

residue was diluted with a 2 M hydrochloric acid (7.0 cm³) and

extracted with diethyl ether (3 × 10 cm³). The combined organic

extracts were dried over anhydrous magnesium sulfate and

the solvent removed in vacuo. The residue was recrystallised

(diethyl ether–hexane) to give the protected amino acid 17

(49.4 mg, 69%) as a white solid; mp 178–179 ЊC; ν_max(CHCl₃)/

cm^Ϫ13699, 3273, 2927, 2853, 1716, 1602; δ_H(250 MHz,

CD₃OD) 7.95 (1H, dd, J 7.6, 1.2, ArH), 7.47 (1H, td, J 7.5, 1.4,

ArH), 7.35–7.26 (2H, m, 2 × ArH), 3.57 (2H, t, J 6.9,

NCH₂CH₂), 3.23 (2H, t, J 6.9, NCH₂CH₂); δ_C(67.8 MHz,

CD₃OD) 171.1 (CO₂H), 159.2 (CON, q, J 37), 141.8 (C), 133.5

(CH), 133.1 (CH), 132.5 (CH), 131.8 (s), 128.1 (CH), 117.8

(CF₃, q, J 287), 42.5 (CH₂), 34.5 (CH₂); m/z (EI) 261.0590 (M^ϩ.

C₁₁H₁₀F₃NO₃requires 261.0612) (Found C, 50.6; H, 3.85;

N, 5.35. C₁₁H₁₀F₃NO₃requires C, 50.6; H, 3.9; N, 5.4%).

2 × CH᎐CH ), 5.25 (1H, br s, CHN ), 5.16 (2H, dddd, J 16.9,

[2-(N-Triﬂuoroacetylamino)ethyl]diazoacetophenone 18. Fol-

lowing the general procedure, the acid chloride was prepared

by the reaction of the N-protected amino acid 17 (0.39 g,

1.5 mmol) with oxalyl chloride (0.65 cm³, 7.5 mmol) and dry

dimethylformamide (ﬁve drops) in dry dichloromethane

(20 cm³) at 0 ЊC for 35 min and then at room temperature for 2 h

10 min. The acid chloride was dissolved in dry dichloromethane

(10 cm³) and added to a solution of diazomethane (∼9 mmol) in

diethyl ether (30 cm³) at 0 ЊC, and the mixture was stirred at 0 ЊC

for 1 h 30 min and at room temperature for 2 h. The remaining

diazomethane was consumed with glacial acetic acid (1.00 cm³,

17.5 mmol). Puriﬁcation by ﬂash column chromatography on

silica gel (diethyl ether–hexane, 2 : 1) aﬀorded the α-diazo

ketone 18 (0.35 g, 82%) as a yellow solid; mp 85–87 ЊC;

ν_max(CHCl₃)/cm^Ϫ13242, 2108, 1714, 1614, 1558; δ_H(250 MHz,

CDC1₃) 9.02 (1H, br s, NH), 7.39–7.16 (4H, m, 4 × ArH), 5.66

(1H, br s, CHN₂), 3.55–3.47 (2H, m, NCH₂CH₂), 2.95–2.89

(2H, m, NCH₂CH₂); δ_C(67.8 MHz, CDCl₃) 191.0 (CO), 157.4

(CON, q, ²J_FC37), 137.3 (C), 137.2 (C), 131.7 (CH), 131.1 (CH),

127.3 (CH), 126.8 (d), 115.8 (CF₃, q, ¹J_FC288), 57.6 (CH), 42.1

(CH₂), 30.5 (CH₂); m/z (EI) 257.0664 (M^ϩϪ N₂. C₁₂H₁₀F₃NO₂

requires 257.0664).

᎐

1.3, 1.3, 0.6, 2 × trans CH᎐CH ), 5.12 (2H, dddd, J 10.3, 1.3,

᎐

1.3, 0.6, 2 × cis CH᎐CH ), 3.07 (4H, dt, J 6.5, 1.3, 2 × CH CH᎐

᎐

CH₂), 2.43–2.35 (2H, m, NCH₂CH₂), 2.31 (2H, t, J 7.4,

CH₂CO), 1.63 (2H, tt, J 7.4, 7.4, CH₂CH₂CO), 1.53–1.26

(4H, m, NCH₂CH₂and NCH₂CH₂CH₂); δ_C(67.8 MHz, CDCl₃)

195.0 (CO), 135.6 (CH), 117.1 (CH₂), 56.7 (CH₂), 54.1 (CH),

52.9 (CH₂), 40.8 (CH₂), 26.9 (CH₂), 26.5 (CH₂), 24.9 (CH₂);

m/z (EI) 194.1302 (M^ϩϪ C₃H₅. C₁₀H₁₆N₃O requires 194.1293).

4,5,6,7-Tetrahydro-[1,2,3]triazolo[1,5-a]pyridine 14. The α-

diazo ketone 7a (46.0 mg, 0.19 mmol) was dissolved in a 0.18 M

aqueous solution of sodium hydroxide (4.6 cm³) and the mix-

ture was stirred at room temperature for 96 h. The mixture was

extracted with diethyl ether (3 × 10 cm³) and the combined

organic extracts were dried over anhydrous magnesium sulfate.

The solvent was removed in vacuo and the residue was puriﬁed

by ﬂash column chromatography on silica gel (diethyl ether) to

give the triazole 14 (16.0 mg, 67%) as a colourless liquid;

ν_max(CHCl₃)/cm^Ϫ12992, 2948, 2853, 1629; δ_H(250 MHz,

CDCl ) 7.43 (1H, s, CH᎐C), 4.36 (2H, t, J 6.1, NCH ), 2.84

᎐

(2H, t, J 6.3, CH CH᎐C), 2.13–2.00 (2H, m, NCH CH ), 1.99–

᎐

1.86 (2H, m, CH CH C᎐C); δ (67.8 MHz, CDCl₃) 133.1 (C),

᎐

130.4 (CH), 45.8 (CH₂), 22.6 (CH₂), 19.9 (CH₂), 19.9 (CH₂);

5,6-Dihydro-[1,2,3]triazolo[5,1-a]isoquinoline 19. The α-diazo

ketone 18 (100 mg, 0.351 mmol) was dissolved in a saturated

aqueous solution of barium hydroxide (3.70 cm³). The solution

was stirred at room temperature for 18 min and then extracted

with ethyl acetate (3 × 7 cm³). The combined organic extracts

were dried over anhydrous potassium carbonate and the solvent

removed in vacuo. The residue and potassium carbonate

(145 mg, 1.05 mmol) were suspended in dry tetrahydrofuran

(5 ml) and allyl bromide (0.11 cm³, 1.3 mmol) was added in one

portion. The resulting suspension was stirred at room temper-

ature for 18 h and the solvent was then removed in vacuo. The

residue was diluted with water (10 cm³) and extracted with

diethyl ether (3 × 10 cm³), and the combined organic extracts

were then dried over anhydrous sodium sulfate. The solvent was

removed in vacuo and the residue was puriﬁed by ﬂash column

chromatography on silica gel (diethyl ether–hexane, 3 : 1) to

give the triazole 19 (34.1 mg, 57%) as a colourless solid; mp

102–104 ЊC; ν_max(CHCl₃)/cm^Ϫ12993, 2952, 2841, 1651, 985, 908,

m/z (EI) 123.0801 (M^ϩ. C₆H₉N₃requires 123.0797).

2-(2-Aminoethyl)benzoic acid hydrochloride salt 16. The

lactam 15 (1.03 g, 7.00 mmol) and concentrated hydrochloric

acid (13.0 cm³) were heated in a sealed tube at 165 ЊC for 42 h.

The reaction mixture was cooled to room temperature and the

contents of the tube were diluted with water (50 cm³) and

extracted with diethyl ether (3 × 50 cm³). The aqueous phase

was concentrated in vacuo and the residue recrystallised

(methanol–diethyl ether) to give the amino acid hydrochloride

salt 16 (0.83 g, 59%) as a white solid; mp 191–194 ЊC [lit.,²¹199–

200 ЊC]; ν_max(KBr)/cm^Ϫ13028, 1708, 1603, 770, 759, 749; δ_H

(250 MHz, D₂O) 7.93 (1H, dd, J 7.2, 1.4, ArH), 7.62 (1H, dt,

J 7.6 and 1.4, ArH), 7.48–7.41 (2H, m, 2 × ArH), 3.29 (4H, s,

NCH₂CH₂and NCH₂CH₂); δ_C(67.8 MHz, D₂O) 171.6 (CO),

138.7 (C), 134.0 (CH), 132.6 (CH), 132.0 (CH), 130.3 (C), 128.5

(CH), 41.5 (CH₂), 32.5 (CH₂) (Found C, 53.5; H, 6.2; N, 7.1.

C₉H₁₂ClNO₂requires C, 53.6; H, 6.0; N, 6.9%).

830; δ_H(250 MHz, CDCl ) 7.96 (1H, s, NCH᎐C), 7.61–7.55

᎐

(1H, m, ArH), 7.40–7.32 (3H, m, 3 × ArH), 4.61 (2H, t, J 7.0,

NCH₂CH₂), 3.25 (2H, t, J 7.0, NCH₂CH₂); δ_C(67.8 MHz,

CDCl₃) 133.6 (C), 131.8 (C), 129.1 (CH), 128.3 (CH), 128.3

(CH), 127.7 (CH), 124.4 (CH), 124.1 (C), 44.4 (CH₂), 28.5

(CH₂); m/z (EI) 171.0790 (M^ϩ. C₁₀H₉N₃requires 171.0797).

2-[2-(N-(Triﬂuoroacetyl)amino)ethyl]benzoic acid 17. The

amino acid hydrochloride salt 16 (55.2 mg, 0.274 mmol) was

dissolved in dry methanol (5 cm³) and triethylamine (84 µl,

0.60 mmol) was added dropwise over 30 s. The resulting sol-

J. Chem. Soc., Perkin Trans. 1, 2001, 3312–3324

3319

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General procedure for carbenoid generation, ylide formation and

rearrangement

According to the general procedure, a solution of the α-diazo

ketone 2b (196 mg, 1.02 mmol) in dry tetrahydrofuran (80 cm³)

was added to a solution of Rh₂(OAc)₄(8.8 mg, 0.020 mmol) in

dry tetrahydrofuran (40 cm³) at room temperature, over a

period of 2 h 15 min. The resulting solution was stirred at room

temperature for a further 30 min. Puriﬁcation by ﬂash column

chromatography on silica gel (hexane–diethyl ether, 2 : 1) gave

the pyrrolidinone 21 (105 mg, 63%) as a colourless liquid.

According to the general procedure, a solution of the α-diazo

ketone 2b (197 mg, 1.02 mmol) in dry benzene (80 cm³) was

added to a solution of Rh₂(OAc)₄(8.8 mg, 0.020 mmol) in dry

benzene (40 cm³) at room temperature, over a period of 2 h. The

resulting solution was stirred at room temperature for a further

30 min. Puriﬁcation by ﬂash column chromatography on silica

gel (hexane–diethyl ether, 2 : 1) gave the pyrrolidinone 21

(118 mg, 70%) as a colourless liquid.

A solution of the α-diazo ketone in dry solvent was added

dropwise from a pressure-equalising addition funnel through

the condenser to a solution of the appropriate copper() or

rhodium() complex in the same solvent at reﬂux. The resulting

solution was stirred at reﬂux and the solvent was then removed

in vacuo. The residue was puriﬁed by ﬂash column chrom-

atography on silica gel to give the rearrangement product.

2-Allyl-1-methylpyrrolidin-3-one 20. According to the gen-

eral procedure, a solution of the α-diazo ketone 2a (177 mg,

1.06 mmol) in dry benzene (80 cm³) was added to a solution

of Cu(acac)₂(5.2 mg, 0.020 mmol) in dry benzene (20 cm³) at

reﬂux, over a period of 2 h 55 min. The resulting solution was

stirred at reﬂux for a further 15 min. Puriﬁcation by ﬂash

column chromatography on silica gel (diethyl ether) gave the

pyrrolidin-3-one 20 (107 mg, 73%) as a colourless liquid.

According to the general procedure, a solution of the α-diazo

ketone 2a (83.8 mg, 0.501 mmol) in dry benzene (40 cm³)

was added to a solution of Rh₂(OAc)₄(4.5 mg, 0.010 mmol)

in dry benzene (20 cm³) at reﬂux, over a period of 52 min.

The resulting solution was stirred at reﬂux for a further 8 min.

Puriﬁcation by ﬂash column chromatography on silica gel

(hexane–diethyl ether, 2 : 1) gave the pyrrolidinone 20 (40.3 mg,

58%) as a colourless liquid; ν_max(ﬁlm)/cm^Ϫ1(liquid ﬁlm) 3077,

2944, 2844, 2785, 1757, 1642, 996, 916; δ_H(250 MHz, CDCl₃)

According to the general procedure, a solution of the α-diazo

ketone 2b (98.0 mg, 0.507 mmol) in dry dichloromethane

(20 cm³) was added to a solution of Rh₂(OAc)₄(4.4 mg,

0.010 mmol) in dry dichloromethane (20 cm³) at reﬂux, over a

period of 2 h. The resulting solution was stirred at reﬂux for

a further 5 min. Puriﬁcation by ﬂash column chromatography

on silica gel (hexane–diethyl ether, 1 : 1) gave the pyrrolidinone

21 (39.8 mg, 47%) as a colourless liquid.

According to the general procedure, a solution of the α-diazo

ketone 2b (191 mg, 0.988 mmol) in dry tetrahydrofuran (80 cm³)

was added to a solution of Rh₂(OAc)₄(8.8 mg, 0.020 mmol)

in dry tetrahydrofuran (40 cm³) at reﬂux, over a period of

2 h 45 min. The resulting solution was stirred at reﬂux for a

further 15 min. Puriﬁcation by ﬂash column chromatography

on silica gel (hexane–diethyl ether, 2 : 1) gave the pyrrolidinone

21 (111 mg, 68%) as a colourless liquid.

5.75 (1H, dddd, J 17.1, 10.1, 7.0, 7.0, trans CH᎐CH ), 5.16–5.05

᎐

(1H, m, cis CH᎐CH ), 5.09–5.02 (1H, m, CH᎐CH ), 3.38–3.31

᎐

(1H, m, 1 × NCH₂), 2.54–2.31 (6H, m, 1 × NCH₂, NCHCO,

CH CO and CH CH᎐CH ), 2.45 (3H, s, CH ); δ (67.8 MHz,

᎐

According to the general procedure, a solution of the α-diazo

ketone 2b (195 mg, 1.01 mmol) in dry benzene (80 cm³) was

added to a solution of Rh₂(OAc)₄(8.8 mg, 0.020 mmol) in dry

benzene (40 cm³) at reﬂux, over a period of 1 h 55 min. The

resulting solution was stirred at reﬂux for a further 45 min.

Puriﬁcation by ﬂash column chromatography on silica gel

(hexane–diethyl ether, 2 : 1) gave the pyrrolidinone 21 (117 mg,

70%) as a colourless liquid; ν_max(ﬁlm)/cm^Ϫ13078, 2979, 2917,

2799, 1757, 1642, 996, 919; δ_H(250 MHz, CDCl₃) 5.91 (1H,

CDCl₃) 214.9 (CO), 134.1 (CH), 117.1 (CH₂), 71.2 (CH), 51.9

(CH₂), 41.4 (CH₃), 37.1 (CH₂), 32.7 (CH₂); m/z (EI) 139.1004

(M^ϩ. C₈H₁₃NO requires 139.0997).

1,2-Diallylpyrrolidin-3-one 21. According to the general pro-

cedure, a solution of the α-diazo ketone 2b (70.0 mg, 0.362

mmol) in dry dichloromethane (20 cm³) was added to a solution

of Cu(acac)₂(5.2 mg, 0.020 mmol) in dry dichloromethane

(20 cm³) at reﬂux, over a period of 30 min. The resulting sol-

ution was stirred at reﬂux for a further 14 h. Puriﬁcation by

ﬂash column chromatography on silica gel (hexane–diethyl

ether, 2 : 1) gave the pyrrolidinone 21 (18.0 mg, 30%) as a colour-

less liquid.

dddd, J 17.1, 10.1, 7.8, 5.4, NCH CH᎐CH ), 5.77 (1H, dddd,

᎐

J 17.1, 10.1, 7.0, 7.0, CHCH CH᎐CH ), 5.31–5.02 (4H, m,

᎐

NCH CH᎐CH and CHCH CH᎐CH ), 3.57 (1H, ddt, J 13.5,

᎐

5.4, 1.5, 1 × NCH CH᎐CH ), 3.39–3.32 (1H, m, 1 ×

᎐

NCH₂CH₂), 2.95 (1H, ddd, J 13.5, 7.8, 0.7, 1 × NCH₂-

According to the general procedure, a solution of the α-diazo

ketone 2b (194 mg, 1.00 mmol) in dry tetrahydrofuran (80 cm³)

was added to a solution of Cu(acac)₂(5.2 mg, 0.020 mmol)

in dry tetrahydrofuran (40 cm³) at reﬂux, over a period of 2 h

15 min. The resulting solution was stirred at reﬂux for a further

12 min. Puriﬁcation by ﬂash column chromatography on silica

gel (hexane–diethyl ether, 2 : 1) gave the pyrrolidin-3-one 21

(115 mg, 70%) as a colourless liquid.

According to the general procedure, a solution of the α-diazo

ketone 2b (186 mg, 0.960 mmol) in dry benzene (80 cm³) was

added to a solution of Cu(acac)₂(5.2 mg, 0.020 mmol) in dry

benzene (40 cm³) at reﬂux, over a period of 2 h 15 min. The

resulting solution was stirred at reﬂux for a further 20 min.

Puriﬁcation by ﬂash column chromatography on silica gel

(hexane–diethyl ether, 1 : 1) gave the pyrrolidinone 21 (120 mg,

76%) as a colourless liquid.

CH᎐CH ), 2.60 (1H, t, J 4.7, NCHCO), 2.51–2.28 (5H, m,

᎐

1 × NCH₂CH₂, CH₂CO and NCHCH₂); δ_C(100 MHz, CD-

Cl₃) 215.1 (CO), 134.3 (CH), 134.1 (CH), 118.2 (CH₂), 117.2

(CH₂), 69.0 (CH), 57.2 (CH₂), 48.8 (CH₂), 36.9 (CH₂), 33.1

(CH₂); m/z (FAB) 166.1236 (M^ϩϩ H. C₁₀H₁₆NO requires

166.1232).

1,2-Diallylpiperidin-3-one 22. According to the general

procedure, a solution of the α-diazo ketone 9 (73.0 mg,

0.352 mmol) in dry benzene (35 cm³) was added to a solution of

Cu(acac)₂(2.0 mg, 0.0076 mmol) in dry benzene (5 cm³) at

reﬂux, over a period of 40 min. The resulting solution was

stirred at reﬂux for a further 20 min. Puriﬁcation by ﬂash

column chromatography on silica gel (hexane–diethyl ether,

2 : 1) gave the piperidinone 22 (49.7 mg, 79%) as a colourless

liquid.

According to the general procedure, a solution of the α-diazo

ketone 2b (194 mg, 1.00 mmol) in dry dichloromethane (80 cm³)

was added to a solution of Rh₂(OAc)₄(8.5 mg, 0.019 mmol) in

dry dichloromethane (40 cm³) at room temperature, over a

period of 1 h 55 min. The resulting solution was stirred at room

temperature for a further 1 h 30 min. Puriﬁcation by ﬂash col-

umn chromatography on silica gel (hexane–diethyl ether, 2 : 1)

gave the pyrrolidinone 21 (86.0 mg, 52%) as a colourless liquid.

According to the general procedure, a solution of the α-diazo

ketone 9 (99.6 mg, 0.481 mmol) in dry benzene (48 cm³) was

added to a solution of Cu(hfacac)₂(4.8 mg, 0.097 mmol) in dry

benzene (5 cm³) at reﬂux, over a period of 50 min. The resulting

solution was stirred at reﬂux for a further 10 min. Puriﬁcation

by ﬂash column chromatography on silica gel (hexane–diethyl

ether, 2 : 1) gave the piperidinone 22 (63.3 mg, 73%) as a colour-

less liquid.

3320

J. Chem. Soc., Perkin Trans. 1, 2001, 3312–3324

View Article Online

According to the general procedure, a solution of the α-diazo

ketone 9 (104 mg, 0.500 mmol) in dry benzene (45 cm³) was

added to a solution of Rh₂(OAc)₄(4.3 mg, 0.0097 mmol) in dry

benzene (5 cm³) at reﬂux, over a period of 42 min. The resulting

solution was stirred at reﬂux for a further 18 min. Puriﬁcation

by ﬂash column chromatography on silica gel (hexane–diethyl

ether, 2 : 1) gave the piperidinone 22 (66.0 mg, 74%) as a colour-

less liquid; ν_max(ﬁlm)/cm^Ϫ13077, 3007, 2946, 2868, 2811, 1718,

1642, 996, 919; δ_H(250 MHz, CDCl₃) 5.90–5.65 (2H, m,

According to the general procedure, a solution of the α-diazo

ketone 12 (160 mg, 0.678 mmol) in dry benzene (60 cm³) was

added to a solution of Rh₂(OAc)₄(6.8 mg, 0.015 mmol) in dry

benzene (9 cm³) at reﬂux, over a period of 58 min. The resulting

solution was stirred at reﬂux for a further 10 min. Puriﬁcation

by ﬂash column chromatography on silica gel (hexane–diethyl

ether, 1 : 1) gave the azocinone 24 (7.7 mg, 5%) as a colourless

liquid; ν_max(ﬁlm)/cm^Ϫ13076, 3025, 2927, 2859, 2820, 1708, 1640,

996, 915; δ_H(250 MHz, CDCl ) 6.03–5.83 (2H, m, NCH CH᎐

᎐

NCH CH᎐CH and CHCH CH᎐CH ), 5.26–5.14 (2H, m,

CH and CHCH CH᎐CH ), 5.24–4.95 (4H, m, NCH CH᎐CH

᎐ ᎐

2 2 2 2 2

᎐

NCH CH᎐CH ), 5.13–5.01 (2H, m, CHCH CH᎐CH ), 3.29

and CHCH CH᎐CH ), 3.40–3.12 (4H, m, NCHCO, NCH CH᎐

᎐ ᎐

2 2 2

᎐

(1H, ddt, J 13.9, 6.2, 1.3, 1 × NCH CH᎐CH ), 3.21–2.99 (3H,

CH₂and 1 × CH₂CO), 2.75 (1H, ddd, J 12.6, 4.1, 2.9, 1 ×

NCH₂CH₂), 2.63–2.37 (2H, m, 1 × NCH₂CH₂and 1 ×

᎐

m, 1 × NCH CH᎐CH , NCHCO and 1 × NCH CH ), 2.73–

᎐

2.27 (5H, m, 1 × NCH CH , CH CO, CHCH CH᎐CH ), 2.04–

CHCH CH᎐CH ), 2.33–2.20 (1H, m, 1 × CHCH CH᎐CH ),

᎐ ᎐

2 2 2 2

᎐

1.25 (2H, m, NCH₂CH₂); δ_C(67.8 MHz, CDCl₃) 209.6 (CO),

134.6 (CH), 134.3 (CH), 117.9 (CH₂), 116.8 (CH₂), 69.8 (CH),

56.1 (CH₂), 47.0 (CH₂), 38.0 (CH₂), 31.1 (CH₂), 24.0 (CH₂);

m/z (EI) 179.1329 (M^ϩ. C₁₁H₁₇NO requires 179.1310).

2.12–2.03 (1H, m, 1 × CH₂CO), 1.98–1.89 (1H, m, 1 ×

CH₂CH₂CO), 1.85–1.38 (4H, m, 1 × CH₂CH₂CO, NCH₂CH₂

and 1 × NCH₂CH₂CH₂), 1.02–0.86 (1H, m, 1 × NCH₂-

CH₂CH₂); δ_C(67.8 MHz, CDCl₃) 218.7 (CO), 137.4 (CH),

136.6 (CH), 117.6 (CH₂), 115.8 (CH₂), 70.2 (CH), 60.2 (CH₂),

51.9 (CH₂), 38.9 (CH₂), 30.9 (CH₂), 27.6 (CH₂), 26.6 (CH₂),

26.1 (CH₂); m/z (EI) 207.1623 (M^ϩ. C₁₃H₂₁NO requires

207.1623).

2-Allyl-1-methylhexahydroazepin-3-one 23. According to the

general procedure, a solution of the α-diazo ketone 11 (196 mg,

1.00 mmol) in dry benzene (50 cm³) was added to a solution of

Cu(acac)₂(5.7 mg, 0.022 mmol) in dry benzene (5 cm³) at reﬂux,

over a period of 48 min. The resulting solution was stirred at

reﬂux for a further 15 min. Puriﬁcation by ﬂash column

chromatography on silica gel (hexane–diethyl ether, 3 : 1) gave

the azepinone 23 (140 mg, 84%) as a colourless liquid.

According to the general procedure, a solution of the α-diazo

ketone 11 (93.0 mg, 0.476 mmol) in dry benzene (43 cm³) was

added to a solution of Cu(hfacac)₂(4.8 mg, 0.0097 mmol) in

dry benzene (5 cm³) at reﬂux, over a period of 41 min. The

resulting solution was stirred at reﬂux for a further 15 min.

Puriﬁcation by ﬂash column chromatography on silica gel

(hexane–diethyl ether, 1 : 1) gave the azepinone 23 (46.5 mg,

58%) as a colourless liquid.

According to the general procedure, a solution of the α-diazo

ketone 11 (45.9 mg, 0.235 mmol) in dry benzene (20 cm³) was

added to a solution of Rh₂(OAc)₄(2.1 mg, 0.0048 mmol) in dry

benzene (4 cm³) at reﬂux, over a period of 20 min. The resulting

solution was stirred at reﬂux for a further 10 min. Puriﬁcation

by ﬂash column chromatography on silica gel (hexane–diethyl

ether, 2 : 1) gave the azepinone 23 (22.2 mg, 56%) as a colourless

liquid; ν_max(ﬁlm)/cm^Ϫ13075, 2931, 2849, 2799, 1698, 1640, 997,

913; δ_H(250 MHz, CDCl₃) 5.79 (1H, m, dddd, J 17.1, 10.1, 6.9,

1-Diazopent-3-en-2-one 26. n-Butyllithium (7.25 cm³of

1.60 M solution in hexane, 11.6 mmol) was rapidly added to a

solution of hexamethyldisilylamine (1.87 g, 11.6 mmol) at 0 ЊC.

The mixture was stirred at 0 ЊC for 30 min and then cooled to

Ϫ78 ЊC. A solution of pent-3-en-2-one (0.88 g, 10 mmol) was

added dropwise over a period of 30 min and the mixture was

stirred for 1 h. 2,2,2-Triﬂuoroethyl triﬂuoroacetate (2.47 g,

12.7 mmol) was added in one portion and the mixture was

stirred for 30 min then poured into a separatory funnel contain-

ing a mixture of 5% hydrochloric acid (100 cm³) and diethyl

ether (75 cm³). The aqueous phase was extracted with diethyl

ether (2 × 75 cm³) and the combined organic extracts were dried

over anhydrous sodium sulfate and concentrated in vacuo.

The residue was dissolved in acetonitrile (30 cm³), and water

(1.8 cm³) and triethylamine (2.0 cm³, 14.3 mmol) were added.

This was followed by the addition of a solution of methane-

sulfonyl azide (1.85 g, 15.3 mmol) in acetonitrile (30 cm³) over a

period of 30 min. The mixture was stirred at room temperature

for 4 h and then concentrated (∼30 cm³), and diluted with

diethyl ether (75 cm³), then washed with a 10% aqueous sol-

ution of sodium hydroxide (2 × 100 cm³) and brine (100 cm³).

The organic phase was dried over anhydrous magnesium sulfate

and then concentrated in vacuo. The residue was puriﬁed by

ﬂash column chromatography on silica gel (diethyl ether–

hexane, 2 : 1) to give the α-diazo ketone 26 (0.89 g, 77%) as a

yellow liquid; ν_max(ﬁlm)/cm^Ϫ13081, 2970, 2941, 2914, 2850,

2105, 1657, 1604, 966, 917; δ_H(250 MHz, CDCl₃) 6.82 (1H, dq,

J 15.3, 6.9, CHCH₃), 6.03 (1H, dd, J 15.3, 1.6, CHCO), 5.43

(1H, s, CHN₂), 1.88 (3H, dd, J 6.9, 1.6, CH₃CH); δ_C(67.8 MHz,

CDCl₃) 184.4 (CO), 139.7 (CH), 128.5 (CH), 54.5 (CH), 17.5

(CH₃).

6.9, CH᎐CH ), 5.07–5.04 (1H, m, trans CH᎐CH ),5.01–4.94 (1H,

᎐

m, cis CH᎐CH ), 3.30 (1H, t, J 7.0, NCHCO), 3.08–2.96 (1H,

᎐

m, 1 × NCH₂), 2.83–2.71 (1H, m, 1 × NCH₂), 2.56–2.20 (4H, m,

NCHCH₂and CH₂CO), 2.29 (3H, s, NCH₃), 1.83–1.56 (4H, m,

NCH₂CH₂and CH₂CH₂CO); δ_C(67.8 MHz, CDCl₃) 212.9

(CO), 135.5 (CH), 116.3 (CH₂), 71.5 (CH), 57.4 (CH₂), 43.0

(CH₂), 37.6 (CH₃), 33.1 (CH₂), 26.7 (CH₂), 23.5 (CH₂); m/z (EI)

167.1293 (M^ϩ. C₁₀H₁₇NO requires 167.1310) (Found C, 72.1; H,

10.6; N, 8.4. C₁₀H₁₇NO requires C, 71.8; H, 10.2; N, 8.4%).

1,2-Diallyloctahydroazocin-3-one 24. According to the gen-

eral procedure, a solution of the α-diazo ketone 12 (158 mg,

0.673 mmol) in dry benzene (60 cm³) was added to a solution of

Cu(acac)₂(3.5 mg, 0.013 mmol) in dry benzene (7 cm³) at reﬂux,

over a period of 52 min. The resulting solution was stirred at

reﬂux for a further 10 min. Puriﬁcation by ﬂash column chrom-

atography on silica gel (hexane–diethyl ether, 3 : 1) gave the

azocinone 24 (54.4 mg, 39%) as a colourless liquid.

According to the general procedure, a solution of the α-diazo

ketone 12 (159 mg, 0.676 mmol) in dry benzene (60 cm³) was

added to a solution of Cu(hfacac)₂(6.6 mg, 0.013 mmol) in dry

benzene (7 cm³) at reﬂux, over a period of 50 min. The resulting

solution was stirred at reﬂux for a further 10 min. Puriﬁcation

by ﬂash column chromatography on silica gel (hexane–diethyl

ether, 1 : 1) gave the azocinone 24 (18.5 mg, 13%) as a colourless

liquid.

1-Diazo-4-(N-allyl-N-methylamino)pentan-2-one 27. N-Meth-

ylallylamine (1.32 g, 18.6 mmol) was added to a solution of the

α-diazo ketone 26 (1.0 g, 9.1 mmol) in dry diethyl ether (30 cm³)

and the mixture stirred at room temperature for 48 h. The sol-

vent was removed in vacuo and the residue puriﬁed by ﬂash

column chromatography on silica gel (diethyl ether) to give the

amine 27 (1.4 g, 85%) as a yellow liquid; ν_max(ﬁlm)/cm^Ϫ13078,

2969, 2876, 2846, 2791, 2104, 1637, 997, 965, 919; δ_H(250 MHz,

CDCl ) δ 5.77 (1H, dddd, J 16.9, 10.4, 6.3, 6.3, CH᎐CH ), 5.32

᎐

(1H, br s, CHN ), 5.17–5.03 (2H, m, CH᎐CH ), 3.25–3.17 (1H,

᎐

m, CH CH), 2.97 (2H, d, J 6.3, CH CH᎐CH ), 2.56–2.48 (1H,

᎐

m, 1 × CH₂CO), 2.20–2.13 (1H, m, 1 × CH₂CO), 2.13 (3H, s,

CH₃N), 0.98 (3H, d, J 6.6, CH₃CH); δ_C(67.8 MHz, CDCl₃)

194.0 (CO), 136.3 (CH), 116.8 (CH₂), 56.7 (CH₂), 54.8 (CH),

54.8 (CH), 44.2 (CH₂), 36.2 (CH₃), 14.4 (CH₃); m/z (CI, CH₄)

J. Chem. Soc., Perkin Trans. 1, 2001, 3312–3324

3321

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182.1297 (M^ϩϩ H. C₉H₁₆N₃O requires 182.1293), 182 (M^ϩ

methane was consumed with glacial acetic acid (2.80 cm³,

H, 85%), 181 (M^ϩ, 5%), 153 (14), 140 (5), 111 (19), 70 (38).

48.9 mmol). Puriﬁcation by ﬂash column chromatography on

silica gel (diethyl ether–hexane, 2 : 1) aﬀorded the α-diazo

ketone 32 (1.6 g, 68%) as a yellow solid; mp 80–81 ЊC;

ν_max(CHCl₃)/cm^Ϫ12934, 2111, 1716, 1633; δ_H(250 MHz,

CDCl₃) 7.53 (1H, br s, NH), 5.37 (1H, br s, CHN₂), 4.06–3.92

(1H, m, CH₃CH), 2.52–2.32 (2H, m, CH₂CO), 2.00–1.78 (2H,

m, CH₂CH₂CO), 1.25 (3H, d, J 6.6, CH₃CH); δ_C(67.8 MHz,

CDCl₃) 194.8 (CO), 156.8 (CON, q, ²J_FC37), 115.8 (CF₃, q, ¹J_FC

288), 55.1 (CH), 46.4 (CH), 36.8 (CH₂), 30.2 (CH₂), 20.1 (CH₃);

4-Diallylamino-1-diazopentan-2-one 28. Diallylamine (3.6 g,

37 mmol) was added to a solution of the α-diazo ketone 26

(1.0 g, 9.1 mmol) in dry diethyl ether (30 cm³) and the mixture

stirred at room temperature for 48 h. The solvent was removed

in vacuo and the residue puriﬁed by ﬂash column chrom-

atography on silica gel (diethyl ether–petroleum ether 40–60,

2 : 1) to give the amine 28 (1.2 g, 64%) as a yellow liquid;

ν_max(ﬁlm)/cm^Ϫ13078, 3006, 2968, 2930, 2809, 2101, 1640, 993,

965, 919; δ_H(250 MHz, CDCl₃) 5.80 (2H, dddd, J 17.1, 10.3,

m/z (FAB) 238.0804 (M^ϩ

ϩ H. C₈H₁₁F₃N₃O₂requires

238.0803), 238 (M^ϩϩ H, 100%), 210 (12), 154 (36).

6.7, 5.6, 2 × CH᎐CH ), 5.30 (1H, br s, CHN ), 5.18 (2H, dd,

᎐

J 17.1, 1.6, 2 × trans CH᎐CH ), 5.13–5.08 (2H, m, 2 × cis CH᎐

5-(N,N-Diallylamino)-1-diazohexan-2-one 33. The α-diazo

ketone 32 (1.2 g, 5.1 mmol) was dissolved in a saturated

aqueous solution of barium hydroxide (20 cm³) and the mixture

stirred at room temperature for 1 h. The solution was then

extracted with ethyl acetate (2 × 50 cm³) and the aqueous phase

was evaporated to dryness in vacuo. The residue washed with

ethyl acetate (2 × 30 cm³) and the combined organic extracts

were dried over anhydrous potassium carbonate then concen-

trated in vacuo. The residue was dissolved in dry tetrahydro-

furan (30 cm³), potassium carbonate (1.8 g, 13 mmol) and allyl

bromide (1.57 g, 13.0 mmol) were added, and the mixture was

stirred at room temperature for 24 h. The solvent was removed

in vacuo and the residue diluted with a saturated aqueous

solution of sodium bicarbonate (30 cm³) and extracted with

ethyl acetate (3 × 30 cm³). The combined organic extracts were

dried over anhydrous potassium carbonate and concentrated

in vacuo. The residue was puriﬁed by ﬂash column chrom-

atography on silica gel (diethyl ether–hexane, 2 : 1) to give the

amine 33 (0.35 g, 31%) as a yellow liquid; ν_max(ﬁlm)/cm^Ϫ13077,

3005, 2962, 2930, 2809, 2101, 1641, 993, 965, 916; δ_H(250 MHz,

᎐

CH₂), 3.37 (1H, m, CH₃CH), 3.10 (2H, dd, J 14.3, 5.6, 2 ×

CH H CH᎐CH ), 2.98 (2H, dd, J 14.3, 6.7, 2 × CH H CH᎐

᎐

CH₂), 2.56 (1H, dd, J 13.8, 6.6, 1 × CH₂CO), 2.2 (1H, dd,

J 13.8, 7.5, 1 × CH₂CO), 1.0 (3H, d, J 6.7, CH₃); δ_C(67.8 MHz,

CDCl₃) 194.0 (CO), 136.8 (CH), 116.6 (CH₂), 54.8 (CH), 52.4

(CH₂), 51.8 (CH), 44.9 (CH₂), 14.6 (CH₃); m/z (EI) 179.1318

(M^ϩϪ N₂. C₁₁H₁₇NO requires 179.1310).

4-Aminopentanoic acid 30. 5-Methylpyrrolidin-2-one 29

(5.0 g, 50 mmol) was dissolved in 6 M hydrochloric acid and the

mixture heated at reﬂux for 8 h. The mixture was then concen-

trated in vacuo and the residue was puriﬁed by ﬂash column

chromatography on Amberlite^®IR 120B (120 mL), which was

washed with water and eluted with 2 M ammonium hydroxide.

The ninhydrin-positive fractions were collected and concen-

trated in vacuo to give a colourless solid, which was puriﬁed by

recrystallisation (methanol) to give the amino acid 30 (4.5 g,

76%) as colourless prisms; mp 216–218 ЊC [lit.,¹⁵212 ЊC].

ν_max(KBr)/cm^Ϫ13048, 2975, 1642; δ_H(250 MHz, CD₃OD) 3.37–

3.24 (1H, m, CH₃CH), 2.28–2.21 (2H, m, CH₂CO), 1.95–1.66

(2H, m, CH₂CH₂CO), 1.24 (3H, d, J 6.7, CH₃); δ_C(67.8,

CD₃OD) 182.5 (CO₂H), 48.6 (CH), 34.4 (CH₂), 31.5 (CH₂), 18.4

(CH₃); m/z (EI) 117.0790 (M^ϩ. C₅H₁₁NO₂requires 117.0785),

117 (M^ϩ, 2%), 102 (14), 101 (0.3), 73 (0.8), 44 (100).

CDCl ) 5.76 (2H, dddd, J 17.2, 10.0, 7.4, 4.8, CH᎐CH ), 5.30

᎐

(1H, br s, CHN ), 5.23–5.04 (4H, m, CH᎐CH ), 3.21–3.12 (2H,

᎐

m, CH H CH᎐CH ), 2.88–2.72 (3H, m, CH CH and 2 ×

᎐

CH H CH᎐CH ), 2.46–2.39 (2H, m, CH CO), 1.83–1.55 (2H,

᎐

m, CH₂CH₂CO), 0.91 (3H, d, J 6.5, CH₃CH); δ_C(67.8 MHz,

CDCl₃) 196.0 (CO), 137.9 (C), 116.7 (CH₂), 54.0 (CH), 53.6

(CH), 52.6 (CH₂), 38.8 (CH₂), 29.8 (CH₂), 13.7 (CH₃); m/z

(FAB) 222.1604 (M^ϩϩ H. C₁₂H₂₀N₃O requires 222.1606), 222

(M^ϩϩ H, 23%), 193 (2), 180 (5), 152 (8).

4-(Triﬂuoroacetylamino)pentanoic acid 31. Following the

general protection procedure, 4-aminopentanoic acid 30 (4.0 g,

34 mmol) was treated with ethyl triﬂuoroacetate (9.7 g,

68 mmol) and triethylamine (3.5 g, 35 mmol) in dry methanol

(20 cm³), and the resulting solution was stirred at room

temperature for 18 h. The crude product was diluted with 2 M

hydrochloric acid (100 cm³) and extracted with diethyl ether

(3 × 100 cm³). After the addition of sodium chloride, the

aqueous layer was extracted with diethyl ether (100 cm³). The

product was puriﬁed by recrystallisation (diethyl ether–hexane)

to give the protected amino acid 31 (6.5 g, 89%) as a white solid;

mp 101–103 ЊC; ν_max(KBr)/cm^Ϫ13301, 1692; δ_H(250 MHz,

CD₃OD) 4.05–3.95 (1H, m, CH₃CH), 2.33 (2H, t, J 7.5,

CH₂CO₂H), 1.92–1.74 (2H, m, CH₂CH₂CO₂H), 1.21 (3H, d,

J 6.7, CH₃CH); δ_C(67.8 MHz, CD₃OD), 177.8 (CO₂H), 159.6

2-Allyl-1,5-dimethylpyrrolidin-3-one 34a–b. According to the

general procedure, a solution of the α-diazo ketone 27 (0.18 g,

0.99 mmol) in dry benzene (70 cm³) was added to a solution of

Cu(acac)₂(5.2 mg, 0.020 mmol) in dry benzene (30 cm³)

at reﬂux, over a period of 30 min. The resulting solution

was stirred at reﬂux for a further 15 min. Analysis of the

crude reaction mixture by H NMR indicated a 1 : 1 mixture

of diastereoisomers. Puriﬁcation by ﬂash column chroma-

tography on silica gel (hexane–diethyl ether, 5 : 1) gave a mix-

ture of the pyrrolidinones 34a–b (106 mg, 70%) as a colourless

liquid.

(CON, q, J_FC37), 118.6 (CF₃, q, J_FC287), 48.1 (CH), 32.9

(CH₂), 32.6 (CH₂), 21.3 (CH₃); m/z (EI) 213.0610 (M^ϩ.

C₇H₁₀NO₃F₃requires 213.0613), 213 (M^ϩ, 3%), 195 (13), 180

(4), 154 (10), 140 (100) (Found C, 39.4; H, 4.7; N, 6.4.

C₇H₁₀F₃NO₃requires C, 39.4; H, 4.7; N, 6.6%).

According to the general procedure, a solution of the α-diazo

ketone 27 (0.18 g, 0.99 mmol) in dry benzene (70 cm³) was

added to a solution of Rh₂(OAc)₄(8.8 mg, 0.020 mmol) in dry

benzene (30 cm³) at reﬂux, over a period of 30 min. The result-

ing solution was stirred at reﬂux for a further 15 min. Analysis

of the crude reaction mixture by H NMR indicated a 1 : 1

1-Diazo-5-[N-(triﬂuoroacetyl)amino]hexan-2-one 32. Follow-

ing the general procedure, the acid chloride was prepared by the

reaction of the N-protected amino acid 31 (2.1 g, 9.9 mmol)

with oxalyl chloride (6.0 g, 47 mmol) and dry dimethylform-

amide (two drops) in dry dichloromethane (50 cm³) at 0 ЊC.

The mixture was warmed to room temperature and stirred for

3 h. The acid chloride was dissolved in dry dichloromethane

(20 cm³) and added to a solution of diazomethane (∼33 mmol)

in diethyl ether (100 cm³) at 0 ЊC, and the mixture was allowed

to warm to room temperature over 2 h. The remaining diazo-

mixture of diastereoisomers. Puriﬁcation by ﬂash column

chromatography on silica gel (hexane–diethyl ether, 5 : 1) an

inseparable mixture (1 : 1) of the pyrrolidinones 34a–b (95 mg,

62%) as a colourless liquid.

According to the general procedure, a solution of the α-diazo

ketone 27 (0.18 g, 0.99 mmol) in dry benzene (70 cm³) was

added to a solution of Cu(hfacac)₂(9.9 mg, 0.020 mmol) in

dry benzene (30 cm³) at reﬂux, over a period of 30 min. The

resulting solution was stirred at reﬂux for a further 15 min.

Puriﬁcation by ﬂash column chromatography on silica gel

3322

J. Chem. Soc., Perkin Trans. 1, 2001, 3312–3324

View Article Online

(hexane–diethyl ether, 5 : 1) gave a mixture (1 : 1) of the

pyrrolidinones 34a–b (38 mg, 25%) as a colourless liquid.

reﬂux, over a period of 30 min. The resulting solution was

stirred at reﬂux for a further 15 min. Puriﬁcation by ﬂash

column chromatography on silica gel (hexane–diethyl ether,

5 : 1) gave an inseparable mixture (1 : 1) of the piperidinones

36a–b (0.12 g, 72%) as a colourless liquid.

According to the general procedure, a solution of the α-diazo

ketone 27 (0.18 g, 0.99 mmol) in dry benzene (70 cm³) was

added to a solution of copper() triﬂuoroacetylacetonate

[Cu(tfacac)₂] (5.7 mg, 0.015 mmol) in dry benzene (30 cm³)

at reﬂux, over a period of 30 min. The resulting solution was

stirred at reﬂux for a further 15 min. Analysis of the crude

According to the general procedure, a solution of the α-diazo

ketone 31 (0.18 g, 0.81 mmol) in dry benzene (70 cm³)

was added to a solution of Rh₂(OAc)₄(8.8 mg, 0.020 mmol) in

dry benzene (30 cm³) at reﬂux, over a period of 30 min. The

resulting solution was stirred at reﬂux for a further 15 min.

Puriﬁcation by ﬂash column chromatography on silica gel

(hexane–diethyl ether, 5 : 1) gave an inseparable mixture (1 : 1)

of the piperidinones 36a–b (0.11 g, 70%) as a colourless liquid.

According to the general procedure, a solution of the α-diazo

ketone 33 (0.12 g, 0.54 mmol) in dry benzene (50 cm³)

was added to a solution of Cu(hfacac)₂(5.4 mg, 0.011 mmol) in

dry benzene (50 cm³) at reﬂux, over a period of 30 min. The

resulting solution was stirred at reﬂux for a further 15 min.

Puriﬁcation by ﬂash column chromatography on silica gel

(hexane–diethyl ether, 5 : 1) gave an inseparable mixture (1 : 1)

of the piperidinones 36a–b (70 mg, 67%) as a colourless liquid.

A solution of the piperidinones 36a–b (0.1 g, 0.5 mmol) and

silica gel (1 g) in diethyl ether (20 cm³) was stirred at room

temperature for 24 h. The mixture was then ﬁltered and the

solution concentrated in vacuo. The residue was puriﬁed by

ﬂash column chromatography on silica gel to give an insepar-

able mixture (2 : 1) of the piperidinones 36a–b (80 mg, 80%) as a

colourless liquid; ν_max(ﬁlm)/cm^Ϫ13076, 2968, 1716, 1641, 996,

reaction mixture by H NMR indicated a 1 : 1.7 mixture of

diastereoisomers. Puriﬁcation by ﬂash column chromatography

on silica gel (hexane–diethyl ether, 5 : 1) gave a mixture (1 : 1) of

the pyrrolidinones 34a–b (53 mg, 35%) as a colourless liquid.

The mixture of isomers was converted into a single isomer by

dissolution in diethyl ether (25 mL per mmol) and addition of

silica gel (1 g per mmol) followed by stirring at room temper-

ature for 24–48 h. Data for product obtained after epimeris-

ation: ν_max(ﬁlm)/cm^Ϫ13077, 2971, 1756, 1641, 998, 915; δ_H

(250 MHz, CDCl ) δ 5.81 (1H, dddd, J 17.1, 10.3, 6.9, 6.9, CH᎐

᎐

CH ), 5.14–5.00 (2H, m, CH᎐CH ), 2.61–2.41 (5H, m, 1 ×

᎐

CH CO, CH CH, NCHCO, CH CH᎐CH ), 1.95 (1H, dd,

᎐

J 17.8, 10.6, 1 × CH₂CO), 1.26 (3H, d, J 5.8, CH₃CH); δ_C

(67.8 MHz, CDCl₃) δ 214.4 (CO), 134.5 (CH), 116.8 (CH₂), 72.8

(CH), 57.6 (CH), 45.0 (CH₂), 38.5 (CH₃), 33.4 (CH₂), 18.5

(CH₃); m/z (EI) 153.1152 (M^ϩ. C₉H₁₅NO requires 153.1154),

153 (M^ϩ, 1%), 112 (100).

1,2-Diallyl-5-methylpyrrolidin-3-one 35a–b. According to the

general procedure, a solution of the α-diazo ketone 28 (0.10 g,

0.48 mmol) in dry benzene (50 cm³) was added to a solution of

Cu(acac)₂(2.6 mg, 0.010 mmol) in dry benzene (10 cm³) at

reﬂux, over a period of 30 min. The resulting solution was

stirred at reﬂux for a further 15 min. Puriﬁcation by ﬂash

column chromatography on silica gel (hexane–diethyl ether,

5 : 1) gave a mixture (1.7 : 1) of the pyrrolidinones 35a–b (73 mg,

84%) as a colourless liquid.

917; δ_H(250 MHz, CDCl ) 5.93–5.64 (2H, m, NCHCH᎐CH

᎐

and CHCH CH᎐CH ), 5.23–5.00 (4H, m, NCH CH᎐CH and

᎐

CHCH CH᎐CH ), 3.38–2.94 (4H, m, CH CH, NCHCO and

᎐

NCH CH᎐CH ), 2.55–2.32 (4H, m, CH CO and CHCH CH᎐

᎐

CH₂), 2.19–1.71 (2H, m, NCHCH₂), 1.18 (3H, d, J 6.4, CH₃CH

minor isomer), 1.15 (3H, d, J 6.6, CH₃CH major isomer);

δ_C(67.8 MHz, CDCl₃) 211.6 (CO), 210.3 (CO), 136.1 (CH),

135.1 (CH), 134.5 (CH), 134.4 (CH), 117.3 (CH₂), 116.9 (CH₂),

116.6 (CH₂), 116.5 (CH₂), 68.8 (CH), 66.5 (CH), 53.5 (CH),

51.7 (CH₂), 50.9 (CH₂), 48.4 (CH), 38.1 (CH₂), 36.4 (CH₂), 34.4

(CH₂), 31.8 (CH₂), 31.2 (CH₂), 30.7 (CH₂), 20.5 (CH₃), 17.9

(CH₃); m/z (EI) 192.1387 (M^ϩ. C₁₂H₁₈NO requires 192.1388),

192 (M^ϩ, 1%), 152 (100).

According to the general procedure, a solution of the α-diazo

ketone 28 (0.10 g, 0.48 mmol) in dry benzene (50 cm³)

was added to a solution of Rh₂(OAc)₄(4.4 mg, 0.010 mmol) in

dry benzene (10 cm³) at reﬂux, over a period of 30 min. The

resulting solution was stirred at reﬂux for a further 15 min.

Puriﬁcation by ﬂash column chromatography on silica gel

(hexane–diethyl ether, 5 : 1) gave a mixture (2 : 1) of the

pyrrolidinones 35a–b (72 mg, 83%) as a colourless liquid.

According to the general procedure, a solution of the α-diazo

ketone 28 (0.10 g, 0.48 mmol) in dry benzene (50 cm³)

was added to a solution of Cu(hfacac)₂(5 mg, 0.01 mmol) in

dry benzene (10 cm³) at reﬂux, over a period of 30 min. The

resulting solution was stirred at reﬂux for a further 15 min.

Puriﬁcation by ﬂash column chromatography on silica gel

(hexane–diethyl ether, 5 : 1) gave a mixture (1.5 : 1) of the

pyrrolidinones 35a–b (63 mg, 73%) as a colourless liquid.

A solution of the pyrrolidinones 35a–b (0.20 g, 1.1 mmol)

and silica gel (1 g) in diethyl ether (25 cm³) was stirred at room

temperature for 24 h. The mixture was then ﬁltered and the

solution concentrated in vacuo. The residue was puriﬁed by

ﬂash column chromatography on silica gel to give a mixture

(8 : 1) of the pyrrolidinones 35a–b (0.18 g, 90%) as a colourless

liquid. Data for major isomer after epimerisation: ν_max(ﬁlm)/

cm^Ϫ13075, 2972, 2929, 2812, 1755, 1640, 997, 918; δ_H

Acknowledgements

We thank the EPSRC for providing studentship support (to

P. B. H. and M. G. D.). We thank Professor F. G. West

(University of Utah) for helpful discussions.

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