Atroposelectivity in the electrophilic substitution reactions of laterally lithiated and silylated tertiary amides

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Atroposelectivity in the electrophilic substitution reactions of

laterally lithiated and silylated tertiary amides

Jonathan Clayden,*^aJennifer H. Pink,^aNeil Westlund^aand Christopher S. Frampton^b

1

^aDepartment of Chemistry, University of Manchester, Oxford Rd., Manchester, UK M13 9PL

^bRoche Discovery Welwyn, Broadwater Road, Welwyn Garden City, Herts, UK AL7 3AY

Received (in Cambridge, UK) 11th January 2002, Accepted 14th February 2002

First published as an Advance Article on the web 6th March 2002

Lateral lithiation–electrophilic quench of 2-alkyl-1-naphthamides and 2,6-dialkylbenzamides yields products

containing an atropisomeric Ar–CO axis and a new stereogenic centre with high (generally >95 : 5) diastereo-

selectivity. With imines as electrophiles, single diastereoisomers containing an atropisomeric axis and two new

stereogenic centres are formed. 2,6-Dialkylbenzamides may be functionalised stereoselectively at both the

2- and 6-positions, leading (with imines) to symmetrical compounds bearing 1,7-related stereogenic centres.

2-Alkylbenzamides with only one ortho alkyl group are not atropisomeric at ambient temperature but are

functionalised diastereoselectively by lateral lithiation–electrophilic quench at Ϫ78 ЊC. Stabilisation of the

atropisomeric products by further lithiation and alkylation proves their diastereoselective formation. The lack

of stereospeciﬁcity in the ﬂuoride-promoted reaction of a laterally silylated 1-naphthamide with an aldehyde

suggests that reported reactions of laterally silylated benzamides may also be controlled by the rotationally

restricted amide group.

Introduction

Tertiary aromatic amides are among the most reliable directors

of regioselective deprotonation,¹and the ortholithiation of

tertiary amides is a very fruitful source of polycyclic aromatic

compounds.^2–5The amides’ ability to direct ortholithiation is

outclassed only by their ability to direct lateral lithiation—that

is, deprotonation at the more acidic benzylic sites of alkyl

groups located ortho to the amide⁶—and in general a tertiary

amide with acidic hydrogen atoms in both the ortho and lateral

positions is lithiated at the lateral site.^7,8The eﬃciency of both

reactions derives from the complex-induced proximity eﬀect⁹

(initial complexation of the butyllithium to the electron-

rich oxygen atom of the amide^10–15) working in concert with

the acidiﬁcation of ortho and lateral hydrogen atoms by the

electron-withdrawing carbonyl group.

During the last few years, interest in the regioselectivity of

these lithiation reactions has stimulated an interest in their

stereoselectivity.¹⁶For example, lateral lithiation of amide 1

gives organolithium 2 which generates only a single diastereo-

isomer of the amine 3 (an intermediate in a synthesis of

corydalic acid methyl ester) on addition to an imine (Scheme

1).¹⁷Similar reactions lead to enantiomerically enriched prod-

ucts in the presence of sparteine.¹⁸Also in the enantiomerically

pure series, lateral lithiation of 4 gives organolithium 5 which is

conﬁgurationally labile at the lithium-bearing centre but which

reacts enantioselectively in the presence of (Ϫ)-sparteine and

produces laterally functionalised products 6 in up to 92% ee

(Scheme 2).^19,20Chiral lithium amide bases govern the selective

lateral lithiation of one of the pair of enantiotopic methyl

groups of 7, leading to enantiomerically enriched atropisomers

of 8 (Scheme 3).²¹†

Scheme 1 Lateral lithiation and relative stereochemical control.

Ar–CO bond,^24–29‡ and we have previously shown (Scheme 4)

that a rotationally restricted amide can be a stereocontrolling

inﬂuence in the formation of atropisomeric diastereoisomers

(that is, diastereoisomers which arise from restricted rotation)

syn- and anti-10 by the addition of ortholithiated 1-naphth-

amide 9 to aldehydes.^30–32We have now investigated the role

of a rotationally restricted amide group in the construction of

stereogenic centres by lateral lithiation, and in this paper

we report our results in full.^33–35Notably, in nearly every case

we have examined, one atropisomeric diastereoisomer is

formed with >95 : 5 diastereoselectivity: the amide group

imposes not only complete regioselectivity but also complete

stereoselectivity on the reaction.

Amide 8 is chiral because of restricted rotation about the

† In related reactions, Staunton and Regan^22,23obtained high levels of

asymmetric induction when they employed a chiral lithium amide base

in the lithiation–electrophilic quench of 2-methyl substituted aromatic

esters, and asymmetric benzylic lithiation of biaryls with s-BuLi–(Ϫ)-

sparteine aﬀords axially chiral biaryls in moderate ee.

‡ In general, tertiary aromatic amides exhibit atropisomerism about

their Ar–CO bond if they carry a substituent in both the 2- and the

6-positions.

DOI: 10.1039/b200358a

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As far as the stereogenic centre adjacent to the ring was con-

cerned, almost every electrophile (alkylating agents, silylating

agents, an aldehyde, a ketone and an imine) reacted with a high

level of stereoselectivity: the only exceptions were stannylation

(entries 11 and 12) and deuteration (entry 13), which both gave

about 10 : 1 stereoselectivity. The alkylated compounds 16a and

16b are related to one another by epimerisation (atropisomeris-

ation) about the Ar–CO bond, and indeed heating either 16a or

16b to 65 ЊC in toluene for 48 h gave an equilibrated 59 : 41

mixture of 16a : 16b (Scheme 6).^29,36The silylated compounds

17a and 17b could be interconverted by heating to give an equi-

librium mixture of the two atropisomers biased heavily in

favour of 17a, containing only 6% 17b.²⁹Stannanes 25a/b and

26a/b behaved similarly to silanes 17.^29,36

Identiﬁcation of the stereochemistry of the atropisomeric

products turned out to be straightforward with the alkylated

and stannylated pairs of diastereoisomers 16 and 24 and with

the imine 22a because 16a, 24b and 22a were crystalline: X-ray

crystal structures (shown for 22a in Fig. 1¶) conﬁrmed their

Scheme 2 Lateral lithiation and absolute stereochemical control.

Scheme 3 Desymmetrising lateral lithiation.

Fig. 1 X-Ray crystal structure of 22a.

stereochemistry and hence that of their diastereoisomers. The

anti relative stereochemistry of the stereogenic centres of 22a is

in keeping with precedent (see, for example, Scheme 1).¹⁷By

analogy (see also compound 45a below), we therefore assign the

stereochemistry shown to the other imine 23a and the other

stannanes 25. The stereochemistry of the silylated compound

18a was assigned by its stereospeciﬁc Fleming–Tamao oxid-

ation^37,38to the known³¹alcohol 31 (Scheme 7); by analogy we

assign the stereochemistry shown to the pair of silylated

diastereoisomers 17. The stereochemistry of the deuterated

compound 26a has previously been determined by NOE

studies.³⁶

Oxidation of a mixture of the alcohols 20a and 20b gave a

ketone 28a, with only a trace (10%) of its diastereoisomer 28b,

proving that the two diastereoisomers 20 diﬀered in stereo-

chemistry only at the hydroxy-bearing centre (Scheme 8). An

X-ray crystal structure (Fig. 2) of ketone 28a proved its stereo-

chemistry, and therefore the stereochemistry at the benzylic

stereogenic centre of 20a and 20b.

A similar oxidation of 21a and 21b gave the racemic ketone

29. This ketone was enolised stereoselectively by KHMDS: a

single, cis, silyl enol ether 30 was formed with Me₃SiCl. Alkyl-

ation of the same potassium enolate (MeI) gave, with moderate

(3 : 1) stereoselectivity, a mixture of diastereoisomers in which

28a was the minor component, presumably because electro-

philes approach the amide-substituted enolate from the less

Scheme 4 Ortholithiation and stereochemical control.

Results and discussion

Atroposelective lateral lithiation–electrophilic quench of 2-alkyl-

1-naphthamides

The 2-alkylnaphthamides 11,³¹12²⁹and 13,³⁶starting materials

for our lateral lithiation reactions, were made by reacting ortho-

lithiated N,N-diisopropyl-1-naphthamide 9³¹with MeI, EtI and

PrI respectively. Amide 11 was laterally lithiated and treated

with Me₃SiCl to give 14.

These four amides were then laterally lithiated using s-BuLi

in THF at Ϫ78 ЊC, § and the resulting coloured organolithiums

were quenched with electrophiles to give one or both of two

diastereoisomeric atropisomers of general structure 15, as

shown in Scheme 5 and Table 1.

§ Typical procedures for similar lithiations employ TMEDA as a co-

solvent.^5,6We found TMEDA to be unnecessary for high yields in our

reactions.

¶ The X-ray crystal structures of 16a and 24b have been published.³⁶

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Table 1 Atroposelective reactions of 2-alkyl-1-naphthamides

Entry

Starting material

Electrophile

Major product

Minor product

Stereoselectivity

Isolated yield (%)

1^a

2^a

3

4

5

6

7

8

9

10

11^a

12^a

13^a

12

13

12

14

12

11

12

11

12

EtI

MeI

16a

16b

17a

17b

18a

19a

20a

21a

22a

23a

24a

25a

26a

16b

16a

17b

17a

—

97 : 3

99 : 1

98 : 2

98.5 : 1.5

97 : 3

71

84

76

80

85

94

58^c

51

64

71

94

78

Me₃SiCl

MeI

PhMe₂SiCl

Acetone

PhCHO

PhCH᎐NMe

Me₃SnBr

Bu₃SnCl

CD₃OD

—

98 : 2

20b

21b

—

50 : 50^b

56 : 44

>95 : 5

93 : 7

᎐

—

24b

25b

—

89 : 11

91 : 9

100

^aSee ref. 36. ^bSingle stereoisomer with regard to the benzylic stereogenic centre. ^cIsolated as a mixture of diastereoisomers.

Scheme 5 Atroposelective lateral lithiation.

hindered face.³⁹The stereochemistry at the hydroxy-bearing

centres of 20 and 21 has been assigned arbitrarily. We assign the

stereochemistry of 19a on the assumption that aldehydes and

ketones react with the same stereochemical sense.

With all electrophiles except tin halides it therefore appears

that the major products have stereochemistry at the new

benzylic centre as shown in Scheme 9. We recently proved that

the lithiation step in such lateral lithiations is atroposelective

and generates a single conﬁgurationally stable diastereoisomer

of the intermediate organolithium shown in Scheme 9.³⁶The

stereochemical outcome of these reactions must therefore

be a result of stereospeciﬁc electrophilic substitution of this

organolithium. Apparently, all electrophiles react with the

organolithium intermediate with retention except tin halides,

which react with inversion. Such capricious stereospeciﬁcity is

far from unknown in the reactions of benzylic organo-

lithiums,^40–43and it is apparent that soft electrophiles which are

reluctant to coordinate to Li—such as tin halides—have a ten-

dency to react with inversion. When the amide carries a planar,

non-stereogenic nucleophilic centre, as in the enolate derived

from 29, stereoselectivity is much lower—further evidence that

the high levels of stereocontrol in the reactions of laterally lithi-

ated naphthamides arise from stereospeciﬁcity, and not simply

stereoselectivity, in the electrophilic quench step.

Additions to imines potentially display stereoselectivity in

the formation of the new, nitrogen-bearing centre in addition to

any stereospeciﬁcity at the new benzylic centre. A direct

inﬂuence from the atropisomeric amide group is clearly behind

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this stereoselectivity, because even 23a is formed as a single

diastereoisomer. This remarkable (1,5)-stereocontrol is not

matched by additions to aldehydes, maybe as a consequence of

the more permissive stereochemical environment around the

aldehyde oxygen than around the geometrically deﬁned imine

nitrogen. Reversibility is also a feature of the addition to

imines: it is important to quench them at low temperature, since

warming to room temperature causes reversion to lithiated

starting material and imine. Thermodynamic control may

therefore be behind the good stereoselectivity observed in these

reactions.¹⁷

Fig. 2 X-Ray crystal structure of 28a.

Scheme 6 Equilibration of the atropisomers.

Scheme 7 Stereochemistry of 18a.

Scheme 9 Stereoselective lithiation; stereospeciﬁc quench.

Scheme 8 Stereochemistry of 20 and 21.

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Scheme 10 1,5-Stereocontrol by double lateral lithiation.

Atroposelective lateral lithiation–quench of 2,6-dialkybenz-

amides

Evidence that treatment of 39a with s-BuLi led to lateral

lithiation was provided by quenching the lithiated compound

40 with D₂O to give 41. However, 40 would react with N-methyl-

benzaldimine only in the presence of HMPA or DMPU. Warm-

ing the lithioamine product 42 to ambient temperature gave a

low (6%) yield of the isoquinolone 43 as a single diastereo-

isomer. Alternatively, 42 (formed in one pot from 7) could be

benzylated and gave a mixture of compounds in which one

symmetrical diastereoisomer, presumably 45a, predominated.

The crystalline diamine 45a was isolated from a double lateral

lithiation–imine addition to 7 in 74% yield as almost a single

diastereoisomer: >92% was the meso compound shown, whose

stereochemistry was conﬁrmed by an X-ray crystal structure

(Fig. 3).

Tertiary 2,6-dialkylbenzamides may possess a stereogenic

Ar–CO axis like that of the 2-alkyl-1-naphthamides,^29,44but

oﬀer additional possibilities for stereocontrol via double

lateral lithiation–electrophilic quench reactions. In order to

study these reactions, we made the amides 32 and 7²¹from

the respective acyl chlorides. Mesitoyl chloride is commer-

cially available; 32 was made from 1,3,5-triethylbenzene by

bromination (92%),⁴⁵halogen–lithium exchange, and carbon-

ation (60%)–amide coupling (21%) or aminocarbonylation

(24%).

The triethylbenzamide 32 was lithiated and then silylated or

methylated to give, as expected, single diastereoisomers of the

products 33 and 35 (Scheme 10). A second lithiation and silyl-

ation returned 34a with >97 : 3 stereoselectivity (there was no

trace of the diastereoisomer 34b by NMR). The NMR spectral

data of 34a clearly showed it to be meso, and we assign it

syn,syn stereochemistry by analogy with the syn-selective

silylation of the corresponding 1-naphthamide 12. A second

lithiation–methylation of 35 was, surprisingly, not stereo-

selective, and gave a mixture of two diastereoisomers 36a and

36b.||

The trimethylbenzamide 7,²¹in line with the precedent set by

the 1-naphthamide 11, gave excellent stereoselectivity in its

lithiation–quench reaction with the N-methylbenzaldimine but

poor selectivity in its reaction with benzaldehyde (Scheme 11).

Alcohol 37 was formed as a 65 : 35 mixture of diastereoisomers

on addition of PhCHO to lithiated 7,** but amine 38a was

isolated from the reaction of lithiated 7 with N-methylbenz-

aldimine almost stereochemically pure. Amine 38a was resistant

to further lateral lithiation, but could be lithiated successfully

if protected by N-benzylation. Some epimerisation about the

Ar–CO axis was observed on benzylation of 38a, and we found

that the most diastereoselective way to synthesise 39a was to

trap the lithioamine product of the imine addition reaction

directly with benzyl bromide. The best selectivities in subse-

quent reactions of 39a were obtained if it was freshly made and

used in situ for each reaction.

Fig. 3 X-Ray crystal structure of 45a.

Atroposelective lateral lithiation–quench of 2-alkylbenzamides

Tertiary benzamides bearing a single ortho substituent are not

usually⁴⁶conﬁgurationally stable about the Ar–CO bond and

cannot therefore exist as separable atropisomers at ambient

temperature.²⁹The barrier to rotation about Ar–CO in 47 is

59.4 kJ mol^{Ϫ1 47}

making its half-life for enantiomerisation at

,

|| The reason for the lack of stereoselectivity in the second lithiation–

quench step is not clear: maybe the barrier to epimerisation in the

laterally lithiated benzamides is low, and epimerisation in 35 but not 33

is related to the contrasting thermodynamic bias shown in Scheme 6.

** Assignment of stereochemistry to the major and minor products of

this reaction is arbitrary.

room temperature less than 0.01 s. However, assuming con-

stancy of ∆G^‡with temperature, this half-life extends to 10 min

or more at Ϫ78 ЊC. We therefore expect 47, 4, and other

2-substituted tertiary benzamides, to be chiral, racemic atrop-

isomers at temperatures typical of those used for lithiation

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Scheme 11 Stereoselective lithiation–quench of a mesitamide.

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Scheme 12 Trapping low temperature atropisomers.

chemistry.†† For instance, we might expect 4 to be lithiated

diastereoselectively at Ϫ78 ЊC much like 12.

(E = SiMe₃) to products 6 with varying degrees of stereo-

speciﬁcity at the stereogenic centre (Scheme 13).⁴⁹There are two

possible mechanisms by which the silane might communicate its

absolute stereochemistry to the product: an intermediate silicon

ate complex may undergo a stereospeciﬁc electrophilic substitu-

tion, or the rotationally restricted amide axis might provide a

mechanism for conformational “chiral memory” of the starting

material’s conﬁguration. Given the results presented above,

and the probable rapidity of an addition reaction of an in situ

electrophile to a ﬂuoride-generated anion, we feel that the

second explanation is very plausible, even though stereo-

speciﬁcity is maintained even when the reaction is carried out at

ambient temperature.

The problem with testing this hypothesis is the fact that even

if the lithiation–quench of 4 is diastereoselective, giving for

example 48a, rapid epimerisation to a mixture of 48a and 48b is

to be expected on warming the products to room temperature,

destroying all evidence of the stereoselectivity.

We solved this problem in the following way. Compounds 4

and 50 were made from 46 by lithiation and alkylation. Com-

pound 4 was lithiated with s-BuLi at Ϫ78 ЊC and treated with

EtI, presumably giving 48a. This compound was not isolated:

instead, a further equivalent of s-BuLi was added, leading to

ortholithiation.^7,8Reaction with methyl iodide introduces a

second ortho substituent, ﬁxing the conformation of the amide

Ar–CO bond and preventing interconversion of the diastereo-

isomeric atropisomers of 49. Warming and isolation of the

product 49 returned a 91 : 9 mixture of diastereoisomers in

which we assume 49a predominates (Scheme 12).

In order to verify that this diastereoisomeric ratio is under

kinetic and not thermodynamic control,⁴⁴we repeated the

sequence of reactions with 50 as the starting material. Lateral

lithiation, methylation, ortholithiation, and a second methyl-

ation gave again a mixture of 49a and 49b, this time with 49b

predominating in a 93 : 7 ratio, via a compound 48b which

evidently exhibits conformational stability at the temperature

of the reaction. Clearly, at Ϫ78 ЊC, 4 and 50 are chiral and can

undergo diastereoselective reactions. The lower levels of stereo-

selectivity in their reactions when compared with the reactions

of the naphthamide analogues 12 or 13 must be due either to

erosion of kinetic stereoselectivity between the lateral lithiation

and ortholithiation steps, or to a lower level of initial stereo-

selectivity ascribable to the lack of conﬁgurational stabil-

ity^19,20,48in lithiated 4 (= 5) or 50.

To test this hypothesis, we took the two diastereoisomeric

silanes 17a and 17b and treated them with TBAF and benzalde-

hyde under Beak’s conditions (Scheme 14).⁴⁹Each reaction gave

four diastereoisomers of 20 as shown—two of them (20a and

20b) identical with the compounds obtained from reaction of

laterally lithiated 12 with PhCHO. The product mixture from

each of the two reactions was essentially identical, so the reac-

tions are stereoselective and not stereospeciﬁc.⁵⁰Oxidation of

one of the two sets of products gave essentially a single ketone

28a, showing that the major pair of compounds diﬀered in

stereochemistry only at the hydroxy-bearing centre.

Scheme 15 shows the expected outcome from 17a or 17b

under each of the two mechanisms proposed to account for

stereochemical control in Beak’s reaction. If the reaction were a

stereospeciﬁc electrophilic substitution of a silicon ate complex,

the ate complexes from 17a and 17b would be diastereoisomeric

and are therefore expected to give diastereoisomeric products.

The fact that the product mixtures from both 17a and 17b are

essentially identical suggests that this is not the case but that

instead the two diastereoisomeric silanes generate a common

intermediate, represented by the notional anion 54, which

reacts stereoselectively with electrophiles. Stereoselectivity

must presumably arise from the inﬂuence of the rotationally

restricted amide bond of 54, which, as with the organolithiums,

directs formation of 15a rather than 15b.‡‡

The role of atroposelectivity in the ﬂuoride-promoted addition of

benzylsilanes to aldehydes

Beak et al. have reported the stereospeciﬁc transfer of

information from an enantiomerically enriched benzylsilane 6

By analogy, stereospeciﬁcity in Beak’s original reaction is

unlikely therefore to be due to the stereospeciﬁcity of the

electrophilic substitution reaction itself. A more reasonable

†† Amide 4 is expected to be chiral under the conditions used to carry

out its asymmetric functionalisation in the presence of (Ϫ)-sparteine

(ref. 20). However, the consequences of this—such as relative rates of

lithiation of the two enantiomers of 4, or whether complexes of 5 with

(Ϫ)-sparteine can exist as pairs of atropisomeric diastereoisomers—

have not been investigated.

‡‡ The precise nature of 54 is not clear: all that is required of it is that any

stereochemistry associated with the anionic centre has no bearing on

the stereochemistry of its reactions.

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Scheme 13 Stereospeciﬁc ﬂuoride-induced substitution of a silyl benzamide.

Scheme 14 Stereoselective ﬂuoride-induced substitution of a silylnaphthamide.

Scheme 15 Mechanisms of ﬂuoride-induced electrophilic substitution.

explanation is that the reaction is an instance of chiral mem-

Experimental

ory:⁵¹the stereochemistry of the starting silane governs the

conformation of the Ar–CO bond, which retains that conform-

ation for long enough to govern the direction of attack of the

aldehyde on the 2-ethyl amide anion 52. A number of stereo-

speciﬁc reactions are known in which stereochemical control is

mediated by transient lack of conformational mobility in an

otherwise planar intermediate.^52–57

Amides 11,³¹12²⁹and 13³⁶were made by literature methods

from amide 9 in 92, 96 and 82% yield respectively.

N,N-Diisopropyl-2-trimethylsilylmethyl-1-naphthamide 14

sec-Butyllithium (0.94 ml, 1.3 M in cyclohexane, 1.22 mmol)

was added dropwise to a solution of N,N-diisopropyl-2-methyl-

1-naphthamide 11³¹(300 mg, 1.11 mmol) in THF (80 ml) at

Ϫ78 ЊC under nitrogen. The purple solution was stirred for 1 h

and trimethylsilyl chloride (0.21 ml, 1.67 mmol) was added.

After 20 min the mixture was allowed to warm to room tem-

perature. Water (40 ml) was added and the THF was removed

under reduced pressure. The aqueous phase was extracted with

dichloromethane (3 × 20 ml) and the combined extracts were

washed with water (20 ml), dried over magnesium sulfate, ﬁl-

tered and concentrated. Puriﬁcation by ﬂash chromatography⁵⁸

[5% ethyl acetate in light petroleum] gave the silane as a white

In this paper we have proposed mechanisms by which atrop-

isomeric amide groups may direct the stereoselectivity of form-

ation and reaction of adjacent benzylic organolithiums and

anions. Some features of the compound we have described

suggest the ability of a stereogenic centre to control the stereo-

chemistry of the axis (the ability of 52 to “memorise” the

chirality of 6 (E = SiMe₃), and also the relative stabilities of the

diastereoisomers of 16, 17 and 25), a phenomenon we have

discussed before⁴⁴and to which we shall return in more detail in

a future publication.

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crystalline solid (313 mg, 83%), mp 102–103 ЊC; R_f[10%

ethyl acetate in light petroleum] 0.39; ν_max(Nujol mull)/cm^Ϫ1

1626; δ_H(300 MHz; CDCl₃) 7.84–7.67 (3H, m, ArH), 7.51–7.27

(2H, m, ArH), 7.21 (1H, d, J = 8.4 Hz, ArH), 3.68–3.48 (2H, m,

2 × NCH), 2.32–2.16 (2H, AB, J = 13.3, ArCH_AH_B), 1.79 (3H,

d, J = 6.7, NCHCH₃), 1.71 (3H, d, J = 6.9, NCHCH₃), 1.13 (3H,

d, J = 6.7, NCHCH₃), 0.98 (3H, d, J = 6.7, NCHCH₃), 0.10 (9H,

s, Si(CH₃)₃); δ_C(75 MHz; CDCl₃) 169.6 (s, CO), 134.0 (s, Ar),

132.4 (s, Ar), 130.9 (s, Ar), 130.1 (s, Ar), 127.8 (d, Ar), 127.5 (d,

Ar), 127.2 (d, Ar), 126.4 (d, Ar), 124.7 (d, Ar), 124.5 (d,

Ar), 50.8 (d, NCH), 45.8 (d, NCH), 24.4 (t, CH₂), 21.2 (q,

NCHCH₃), 20.9 (q, NCHCH₃), 20.6 (q, NCHCH₃), 20.5 (q,

NCHCH₃), 1.00 (q, Si(CH₃)₃); m/z (CI) 344 (7%), 343 (16), 342

(100), 326 (5), 298 (5), 241 (3), 169 (7) (Found: M^ϩ, 341.2170.

C₂₁H₃₁NOSi requires M, 341.2175).

(2H, m, 2 × NCH), 2.29 (1H, q, J = 7.4, ArCH), 1.82 (3H, d,

J = 6.9, NCHCH₃), 1.71 (3H, d, J = 6.7, NCHCH₃), 1.44 (3H,

d, J = 7.4, SiCHCH₃), 1.16 (3H, d, J = 6.6, NCHCH₃), 1.07 (3H,

d, J = 6.6, NCHCH₃), 0.16 (9H, s, Si(CH₃)₃); δ_C(75 MHz;

CDCl₃) 169.5 (s, CO), 140.3 (s, Ar), 134.2 (s, Ar), 131.4 (s, Ar),

130.1 (s, Ar), 128.0 (d, Ar), 127.8 (d, Ar), 126.7 (d, Ar), 126.1 (d,

Ar), 125.0 (d, Ar), 124.8 (d, Ar), 50.7 (d, NCH), 46.0 (d, NCH),

26.9 (d, ArCH), 21.8 (q, NCHCH₃), 21.0 (q, NCHCH₃), 20.6

(q, NCHCH₃), 20.4 (q, NCHCH₃), 18.9 (q, ArCHCH₃), Ϫ1.7

(q, Si(CH₃)₃); m/z (CI) 357 (22%), 356 (100), 284 (5), 255 (5),

183 (3) (Found: C, 74.50; H, 9.45; N, 4.0%, M^ϩ, 355.2327.

C₂₂H₃₃NOSi requires C, 74.31; H, 9.35; N, 3.94%, M 355.2331).

HPLC analysis of the crude product mixture was carried out

on a phenosphere 100 × 8.00 mm 5 µ silica column, 80 Å,

Perkin Elmer LC-480 Diode Array System, eluant 0.5% ethanol

in hexane, ﬂow rate 2 ml min^Ϫ1, UV at 280 nm, t_R4.34 min (17a,

1.5%), 8.30 (17b, 98.5%).

(R_a*,S*)-N,N-Diisopropyl-2-(1-trimethylsilylethyl)-1-naphth-

amide 17a

The rate of interconversion of the atropisomers has been

published.²⁹

sec-Butyllithium (2.98 ml, 1.3 M solution in cyclohexane, 3.88

mmol) was added dropwise to a solution of N,N-diisopropyl-2-

ethyl-1-naphthamide²⁹12 (1.00 g, 3.53 mmol) in THF (70 ml) at

Ϫ78 ЊC under nitrogen. The resultant dark green solution was

stirred for 1 h and trimethylsilyl chloride (0.67 ml, 5.30 mmol)

was added. After 10 min the mixture was allowed to warm to

0 ЊC. Water (30 ml) was added and the THF was removed under

reduced pressure. The aqueous phase was extracted with

dichloromethane (3 × 25 ml) and the combined extracts were

washed with water (30 ml), dried over magnesium sulfate, ﬁl-

tered and the solvent was evaporated. Puriﬁcation by ﬂash

chromatography⁵⁸[5% ethyl acetate in light petroleum] gave the

silane 17a (0.958 g, 76%) as a white crystalline solid, mp 124–

125 ЊC; R_f[10% EtOAc in petrol] 0.44; ν_max(Nujol mull)/cm^Ϫ1

1623; δ_H(300 MHz; CDCl₃) 7.82–7.74 (3H, m, ArH), 7.51–7.38

(2H, m, ArH), 7.32 (1H, d, J = 8.5, ArH), 3.72–3.54 (2H, m,

2 × NCH), 2.40 (1H, q, J = 7.4, ArCH), 1.81 (3H, d, J = 6.7,

NCHCH₃), 1.70 (3H, d, J = 6.7, NCHCH₃), 1.46 (3H, d, J = 7.4,

SiCHCH₃), 1.13 (3H, d, J = 6.7, NCHCH₃), 0.98 (3H, d, J = 6.7,

NCHCH₃), 0.06 (9H, s, Si(CH₃)₃); δ_C(75 MHz; CDCl₃) 169.5 (s,

CO), 139.4 (s, Ar), 132.3 (s, Ar), 131.1 (s, Ar), 129.9 (s, Ar),

127.7 (d, Ar), 127.5 (d, Ar), 126.3 (d, Ar), 124.8 (d, Ar), 124.7

(d, Ar), 50.6 (d, NCH), 46.0 (d, NCH), 26.3 (d, ArCH), 21.3 (q,

NCHCH₃), 21.0 (q, NCHCH₃), 20.7 (q, NCHCH₃), 20.5 (q,

NCHCH₃), 16.2 (q, ArCHCH₃), Ϫ2.5 (q, Si(CH₃)₃); m/z (CI)

357 (28%), 356 (100), 195 (8), 178 (13), 148 (6) (Found: C, 74.53;

H, 9.39; N, 4.07%, M^ϩ, 355.2325. C₂₂H₃₃NOSi requires C,

74.31; H, 9.35; N, 3.94%, M 355.2331).

(R_a*,S*)-N,N-Diisopropyl-2-(1-dimethylphenylsilylethyl)-1-

naphthamide 18a

sec-Butyllithium (0.90 ml, 1.3 M solution in cyclohexane, 1.16

mmol) was added dropwise to a solution of N,N-diisopropyl-2-

ethyl-1-naphthamide²⁹12 (300 mg, 1.06 mmol) in THF (60 ml)

at Ϫ78 ЊC under nitrogen. The dark green solution was stirred

for 1 h and chlorodimethylphenylsilane (0.356 ml, 2.12 mmol)

was added. After 10 min the mixture was allowed to warm to

0 ЊC. Water (40 ml) was added and the THF was removed under

reduced pressure. The aqueous phase was extracted with

dichloromethane (3 × 20 ml) and the combined extracts were

washed with water (20 ml), dried over magnesium sulfate,

ﬁltered and the solvent was evaporated. Puriﬁcation by ﬂash

chromatography⁵⁸[5% ethyl acetate in light petroleum] gave the

silane 18a (376 mg, 85%) as a white crystalline solid, R_f[10%

EtOAc–petrol] 0.46; δ_H(300 MHz; CDCl₃) 7.84–7.77 (2H, m,

ArH), 7.74 (1H, d, J = 8.6, ArH), 7.66–7.38 (7H, m, ArH), 7.18

(1H, d, J = 8.6, ArH), 3.71–3.53 (2H, m, 2 × NCH), 2.60 (1H, 1,

J = 7.4, ArCH), 1.83 (3H, d, J = 6.9, NCHCH₃), 1.72 (3H, d,

J = 6.9, NCHCH₃), 1.37 (3H, d, J = 7.3, ArCHCH₃), 1.09 (3H,

d, J = 6.6, NCHCH₃), 0.98 (3H, d, J = 6.7, NCHCH₃), 0.39 (3H,

s, SiCH₃), 0.24 (3H, s, SiCH₃); δ_C(75 MHz; CDCl₃); m/z (CI)

419 (21%), 418 (100), 340 (30), 183 (18), 152 (11), 135 (11)

(Found (EI): M^ϩ, 417.2495. C₂₇H₃₅NOSi requires M, 417.2488).

HPLC analysis of the crude product (phenosphere 100 × 8.00

mm 5 µ silica column, 80 Å, Perkin Elmer LC-480 Diode Array

HPLC analysis of the crude product mixture was carried out

on a phenosphere 100 × 8.00 mm 5 µ silica column, 80 Å,

Perkin Elmer LC-480 Diode Array System, eluant 0.5% ethanol

in hexane, ﬂow rate 2 ml min^Ϫ1, UV at 280 nm, t_R4.34 min (17a,

98%), 8.30 (17b, 2%).

System, eluant 0.5% ethanol in hexane, ﬂow rate 2 ml min^Ϫ1

,

UV at 280 nm) showed peaks at t_R4.68 (18a, 97%), 11.16

(tentatively identiﬁed as 18b, 3%).

(R_a*,S*)-N,N-Diisopropyl-2-[(1,2-dimethyl-2-hydroxy)propyl]-

naphthamide 19a

(R_a*,R*)-N,N-Diisopropyl-2-(1-trimethylsilylethyl)-1-naphth-

sec-Butyllithium (0.89 ml, 1.3 M solution in cyclohexane, 1.16

mmol) was added dropwise to a solution of N,N-diisopropyl-2-

ethyl-1-naphthamide²⁹12 (300 mg, 1.059 mmol) in dry THF

(100 ml) at Ϫ78 ЊC under nitrogen. After 1 h, acetone (0.16 ml,

2.12 mmol) was added. The solution was allowed to warm to

0 ЊC, water (30 ml) was added and the THF was removed under

reduced pressure. The aqueous phase was extracted with

dichloromethane (3 × 20 ml) and the combined extracts were

washed with water (25 ml), dried over magnesium sulfate,

ﬁltered and the solvent was evaporated. Puriﬁcation by ﬂash

chromatography⁵⁸[4 : 1 light petroleum–ethyl acetate] gave the

alcohol 19a (339 mg, 94%) as a white crystalline solid, mp 113–

116 ЊC; R_f[EtOAc–petrol, 1 : 4] 0.25; ν_max(ﬁlm)/cm^Ϫ11625;

δ_H(300 MHz; CDCl₃) 7.89–7.74 (2H, m, 2 × ArH), 7.86 (1H, d,

J = 8.7, ArH), 7.57 (1H, d, J = 8.7, ArH), 7.55–7.45 (2H, m,

ArH), 4.38 (1H, s, OH), 3.67 (1H, sept, J = 6.7, NCHCH₃), 3.55

(1H, sept, J = 6.7, NCHCH₃), 3.11 (1H, q, J = 7.1, ArCH ), 1.80

amide 17b

sec-Butyllithium (0.61 ml, 1.3 M solution in cyclohexane, 0.789

mmol) was added dropwise to a solution of naphthamide 14

(245 mg, 0.717 mmol) in THF (60 ml) at Ϫ78 ЊC under nitro-

gen. The dark green solution was stirred at Ϫ78 ЊC for 1 h.

Methyl iodide (67 µl, 1.075 mmol) was added. The solution was

allowed to warm to 0 ЊC, water (30 ml) was added and the THF

was removed under reduced pressure. The aqueous phase was

extracted with dichloromethane (3 × 20 ml), the combined

extracts were washed with water (25 ml), dried over magnesium

sulfate, ﬁltered and the solvent was evaporated. Puriﬁcation by

ﬂash chromatography⁵⁸[7% ethyl acetate in light petroleum]

gave the silane 17b (205 mg, 80%) as a white crystalline solid,

mp 123–124 ЊC; R_f[10% EtOAc–petrol] 0.32; ν_max(Nujol mull)/

cm^Ϫ11617; δ_H(300 MHz; CDCl₃) 7.85–7.73 (3H, m, ArH),

7.50–7.39 (2H, m, ArH), 7.34 (1H, d, J = 8.6, ArH), 3.80–3.55

J. Chem. Soc., Perkin Trans. 1, 2002, 901–917

909

View Article Online

(3H, d, J = 6.7, NCHCH₃), 1.75 (3H, d, J = 6.7, NCHCH₃),

1.44 (3H, d, J = 7.1, ArCHCH₃), 1.38 (3H, s, C(OH)CH₃), 1.26

(3H, s, C(OH)CH₃), 1.09 (3H, d, J = 6.7, NCHCH₃), 1.06 (3H,

d, J = 6.7, NCHCH₃); δ_C(75 MHz; CDCl₃) 171.6 (s, CO), 137.1

(s, Ar), 134.3 (s, Ar), 132.1 (s, Ar), 129.2 (s, Ar), 128.0 (s, Ar),

127.9 (s, Ar), 126.5 (d, Ar), 125.7 (s, Ar), 124.9 (d, Ar), 124.7,

(d. Ar), 72.5 (s, COH), 51.2 (d, NCH), 46.8 (d, CH), 46.3

(d, CH), 31.1 (q, CH₃CH), 23.6 (q, NCHCH₃), 21.0 (q,

NCHCH₃), 20.5 (q, NCHCH₃), 20.5 (q, NCHCH₃), 17.1 (q,

2 × C(OH)CH₃); m/z (CI) 343 (22%), 342 (100), 283 (5), 183 (5)

(Found: C, 77.17; H, 9.19; N, 4.09%, M ϩ H^ϩ, 342.2431.

C₂₂H₃₁NO₂requires C, 77.38; H, 9.15; N, 4.10%).

J = 6.9, NCHCH₃), 1.76 (3H, d, J = 6.7, NCHCH₃), 1.29 (3H, d,

J = 7.1, ArCHCH₃), 1.01 (3H, d, J = 6.7, NCHCH₃), 1.00 (3H,

d, J = 6.7, NCHCH₃); m/z (CI) 391 (29%), 390 (100), (364 (62),

362 (40), 360 (22), 306 (76), 304 (56), 302 (35), 284 (29) (Found:

M ϩ H 390.2427. C₂₆H₃₁NO₂requires 390.2433).

HPLC analysis of the alcohol was carried out [phenosphere

100 × 8.00 mm 5 µ silica column, 80 Å, Perkin Elmer LC-480

Diode Array System, eluant 5% ethanol in hexane, ﬂow rate

2 ml min^Ϫ1, UV at 280 nm, t_R2.88 (20a, 49.3%), 4.20 (20b,

28.6%), 6.36 (20c, 9.10%) and 6.55 min (20d, 12.11%)]; ratio =

1.7 : 1 : 0.32 : 0.42.

HPLC analysis of the crude product was performed on a

phenosphere 100 × 8.00 mm 5 µ silica column, 80 Å, Perkin

Elmer LC-480 Diode Array System, eluant 2% ethanol in

hexane, ﬂow rate 2 ml min^Ϫ1, UV at 280 nm), t_R9.36 (19a, 98%),

14.10 (tentatively identiﬁed as 19b, 2%).

(R_a*,2ЈR*)- and (R_a*,2ЈS*)-N,N-Diisopropyl-2-(2Ј-hydroxy-2Ј-

phenylethyl)-1-naphthamide 21a and 21b

sec-Butyllithium (1.57 ml, 2.04 mmol; 1.3 M solution in

hexanes) was added to a solution of naphthamide³¹11 (457 mg,

1.70 mmol) in THF (25 ml) at Ϫ78 ЊC under nitrogen. After

80 minutes, the purple solution was treated with benz-

aldehyde (0.50 ml, 5.00 mmol), stirred for 45 minutes, warmed

to ambient temperature and quenched with saturated aqueous

ammonium chloride (10 ml). The THF was removed under

reduced pressure and the residue was extracted with dichloro-

methane (4 × 15 ml). The combined organic extracts were dried

(MgSO₄), ﬁltered and concentrated under reduced pressure to

aﬀord the crude product. Puriﬁcation by ﬂash chromato-

graphy⁵⁸[2 : 1 petrol (bp 40–60 ЊC)–EtOAc] aﬀorded a mixture

of the alcohols 21a and 21b (327 mg, 51%).

(R_a*,1ЈR*,2ЈR*)-N,N-Diisopropyl-2-(2Ј-hydroxy-1Ј-methyl-2Ј-

phenylethyl)naphthamide 20a and 20b from 12

sec-Butyllithium (0.88 ml, 1.14 mmol) was added to a solution

of naphthamide²⁹12 (269 mg, 0.95 mmol) in THF (14 ml)

at Ϫ78 ЊC under nitrogen. After 45 minutes, benzaldehyde

(0.18 ml, 1.71 mmol) was added and after a further 30 minutes

saturated aqueous ammonium chloride (10 ml). After work-up

in the manner described for 19a, ¹H NMR of the crude product

showed two diastereoisomers 20a and 20b in a ratio of 1 : 1.

Puriﬁcation by ﬂash chromatography⁵⁸eluting with 2 : 1 petrol

(bp 40–60 ЊC)–EtOAc aﬀorded a 50 : 50 mixture (by ¹H NMR)

of diastereoisomers 20a and 20b as a white solid (215 mg, 58%).

Analytical HPLC (6 : 1 hexane–EtOAc) of the crude product

showed two atropisomers to be present in a ratio of 56 : 44

(t_R6.2 and 6.6 minutes).

N,N-Diisopropyl-2-(2Ј-hydroxy-1Ј-methyl-2Ј-phenylethyl)-

naphthamide 20 from 17a

(R_a*,1ЈR*,2ЈR*)-N,N-Diisopropyl-2-[1Ј-methyl-2Ј-(methyl-

amino)-2Ј-phenylethyl]-1-naphthamide 22a

Tetra-n-butylammonium ﬂuoride (0.422 ml, 1 M solution in

THF, dried over molecular sieves, 0.422 mmol) was added to a

solution of 17a (150 mg, 0.281 mmol) and freshly distilled

benzaldehyde (0.143 ml, 1.405 mmol) in dry THF (5 ml), in an

ice-bath and under nitrogen. The solution was stirred at 0 ЊC for

4 h and saturated aqueous ammonium chloride solution (10 ml)

was added. The aqueous phase was extracted with dichloro-

methane (3 × 10 ml) and the combined extracts were washed

with brine (15 ml), dried over magnesium sulfate, ﬁltered and

the solvent was evaporated. Puriﬁcation by ﬂash chromato-

graphy⁵⁸eluting with 7 : 3 petrol (bp 40–60 ЊC)–EtOAc aﬀorded

a mixture of diastereoisomers of the alcohol 20 as a white solid

(131 mg, 79%) and N,N-diisopropyl-2-ethyl-1-naphthamide

12²⁹(18 mg, 21%). HPLC analysis of the alcohol was carried

out [phenosphere 100 × 8.00 mm 5 µ silica column, 80 Å, Perkin

Elmer LC-480 Diode Array System, eluant 5% ethanol in

hexane, ﬂow rate 2 ml min^Ϫ1, UV at 280 nm, t_R2.79 (20a,

58.0%), 4.18 (20b, 33.7%), 6.14 (20c or 20d, 8.35%)]; ratio =

1.7 : 1 : 0.25.

sec-Butyllithium (0.78 ml, 1.02 mmol; 1.3 M in hexanes) was

added dropwise to a solution of naphthamide²⁹12 (239 mg,

0.85 mmol) in THF (2 ml) at Ϫ78 ЊC under nitrogen. After

30 minutes the dark green–blue solution was treated with

N-benzylidenemethylamine (0.11 ml, 0.93 mmol) and stirred

for 3 hours to give a dark pink–red solution. The reaction

was quenched at Ϫ78 ЊC (raising to ambient temperature

causes reversion to starting material) with saturated aqueous

ammonium chloride (5 ml) and allowed to warmed to ambient

temperature, diluted with water (10 ml) and the THF was

removed under reduced pressure at ambient temperature. The

aqueous residue was extracted with dichloromethane (4 × 7 ml)

and the combined organic extracts were dried (MgSO₄), ﬁltered

and concentrated under reduced pressure to give the crude

1

product as a single atropisomer (by H NMR). Puriﬁcation by

ﬂash chromatography⁵⁸[4 : 1 petrol (bp 40–60 ЊC)–EtOAc ϩ

1% triethylamine] yielded amine 22a (216 mg, 64%) as a white

solid, mp 163–166 ЊC (EtOAc); ν_max(ﬁlm)/cm^Ϫ13330, 1621;

δ_H(300 MHz; CDCl₃) 7.78 (3H, m, ArH), 7.45–7.12 (8H, m,

ArH), 3.54 (2H, m, 2 × NCH), 3.49 (1H, d, J = 9.5, CH-

(CH₃)CHNHCH₃), 3.05 (1H, m, CH(CH₃)CHNHCH₃), 2.02

(1H, br s, NH), 1.93 (3H, s, NHCH₃), 1.74 (3H, d, J = 6.9,

NCHCH₃), 1.70 (3H, d, J = 6.7, NCHCH₃), 0.99–0.90 (9H, m,

2 × NCHCH₃, CH(CH₃)CHNHCH₃); δ_C(75 MHz; CDCl₃)

169.7, 143.6, 138.0, 134.5, 132.2, 129.5, 128.4, 128.2, 128.1,

128.0, 126.9, 126.5, 125.7, 125.1, 123.7, 71.8, 50.9, 46.2,

42.9, 34.7, 21.1, 20.8, 20.7, 20.5 and 19.3; m/z (CI) 403 (71%,

M ϩ H^ϩ) and 120 (100, PhCHNHCH₃); m/z (EI) 402 (1%, M^ϩ),

85 (100), 84 (100), 48 (100) and 35 (100) (Found: M^ϩ, 402.2667.

C₂₇H₃₄N₂O requires M, 402.2671).

N,N-Diisopropyl-2-(2Ј-hydroxy-1Ј-methyl-2Ј-phenylethyl)-

naphthamide 20 from 17b

In the same way, tetra-n-butyl ammonium ﬂuoride (0.21 ml,

0.211 mmol of a 1 M solution in THF, dried over molecular

sieves), 17b (50 mg, 0.141 mmol) and freshly distilled benzalde-

hyde (72 µl, 0.705 mmol) in anhydrous THF (5 ml) aﬀorded a

mixture of diastereoisomers of the alcohol 20 (20 mg, 37%) in

addition to the starting silane 17b (27 mg, 54%) and a small

amount of N,N-diisopropyl-2-ethyl-1-naphthamide 12 (4 mg,

10%), R_f[EtOAc–petrol, 1 : 4] 0.32 and 0.26, δ_H(300 MHz;

CDCl₃) (major diastereoisomer) 7.82–7.75 (2H, m, ArH), 7.63

(1H, d, J = 8.8, ArH), 7.53–7.19 (7H, m, ArH), 6.93 (1H, d,

J = 8.6, ArH), 5.05 (1H, t, J = 3.4, CH(OH)), 3.97 (1H, d,

J = 3.4, OH), 3.64 (1H, sept, J = 6.9, NCH), 3.50 (1H, sept,

J = 6.7, NCH), 3.49–3.37 (1H, m, ArCHCH₃), 1.79 (3H, d,

(R_a*,2ЈR*)-N,N-Diisopropyl-2-[2Ј-(methylamino)-2Ј-phenyl-

ethyl]-1-naphthamide 23a

In the same way, sec-butyllithium (0.77 ml, 1.00 mmol; 1.3 M in

hexanes), naphthamide³¹11 (223 mg, 0.83 mmol) in THF (7 ml)

910

J. Chem. Soc., Perkin Trans. 1, 2002, 901–917

View Article Online

and N-benzylidenemethylamine (0.11 ml, 0.91 mmol) gave

a crude product containing a single atropisomer (by ¹H

NMR). Puriﬁcation by ﬂash chromatography⁵⁸[2 : 1 petrol

(bp 40–60 ЊC)–EtOAc ϩ 1% triethylamine] aﬀorded amine 23a

(226 mg, 71%) as a sticky white oil, ν_max/cm^Ϫ13330, 1621;

δ_H(300 MHz; CDCl₃) 7.70 (2H, m, ArH), 7.56 (1H, d, J = 8.5,

ArH), 7.37 (2H, m, ArH), 7.3–7.1 (5H, m, ArH), 7.03 (1H, d,

J = 8.5, ArH), 3.80 (1H, dd, J = 8.1 and 5.6, CHNCH₃), 3.53

(1H, sept, J = 6.9, NCH), 3.37 (1H, sept, J = 6.6, NCH), 3.01

(1H, dd, J = 13.3 and 8.2, CHHCHNHCH₃), 2.82 (1H, dd,

J = 13.3 and 5.6, CHHCHNHCH₃), 2.12 (3H, s, NCH₃), 1.98

(1H, br m, NH), 1.71 (3H, d, J = 6.9, NCHCH₃), 1.67 (3H, d,

J = 6.7, NCHCH₃), 0.92 (3H, d, J = 6.7, NCHCH₃), 0.88 (3H, d,

J = 6.7, NCHCH₃); δ_C(75 MHz; CDCl₃) 169.6, 144.5, 135.2,

132.1, 132.0, 129.5, 128.3, 127.9, 127.7, 127.6, 127.4, 126.9,

126.5, 125.7, 124.8, 66.8, 51.1, 46.1, 42.5, 34.9, 20.9, 20.9, 20.7

and 20.6; m/z (CI) 389 (100%, M ϩ H^ϩ) and 120 (28, PhCHN-

HCH₃); m/z (EI) 120 (100%, PhCHNHCH₃) (Found: M^ϩ,

388.2518. C₂₆H₃₂N₂O requires M, 388.2515).

reduced pressure to aﬀord the crude product. Puriﬁcation by

ﬂash chromatography⁵⁸[2 : 1 petrol (bp 40–60 ЊC)–EtOAc]

aﬀorded the ketone 29 (268 mg, 82%) as a white solid, mp 162–

163 ЊC; ν_max(ﬁlm)/cm^Ϫ12957, 2932, 2870, 1687, 1624; λ_max/nm

(ε_max) (CH₂Cl₂) 232 (41050), 278 (15110), 324 (10210); δ_H(300

MHz; CDCl₃) 8.11 (2H, m, ArH), 7.87–7.75 (3H, m, ArH), 7.80

(1H, m, ArH), 7.61–7.43 (5H, m, ArH), 7.33 (1H, d, J = 8.5,

ArH), 4.60 (1H, d, J = 16.9, CH_AH_BCOPh), 4.38 (1H, d,

J = 16.9, CH_AH_BCOPh), 3.59 (1H, sept, J = 6.6, NCH), 3.56

(1H, sept, J = 6.9, NCH), 1.77 (3H, d, J = 6.9, CH₃), 1.60 (3H,

d, J = 6.9, CH₃), 0.98 (3H, d, J = 6.6, CH₃), 0.93 (3H, d, J = 6.7,

CH₃); δ_C(75 MHz; CDCl₃) 197.4, 169.3, 136.3, 135.3, 133.3,

132.3, 129.6, 128.7, 128.5, 128.1, 127.9, 127.8, 126.5, 126.0,

124.9, 51.1, 46.2, 42.9, 21.0, 20.9, 20.6 and 20.4; m/z (CI) 374

(100%, M ϩ H^ϩ); m/z (EI) 373 (6%, M^ϩ) and 49 (100) (Found:

M^ϩ, 373.2042. C₂₅H₂₇NO₂requires M, 373.2042).

N,N-Diisopropyl-2-[(Z )-2Ј-phenyl-2Ј-(trimethylsilyloxy)-

ethenyl]naphthalene-1-carboxamide 30

A solution of naphthamide 29 (413 mg, 1.11 mmol) in THF

(9 ml) was added to a solution potassium hexamethyl-

disilazide (2.44 ml, 0.5 M solution in toluene) in THF 4 ml at

Ϫ78 ЊC under nitrogen. After 60 minutes, chlorotrimethylsilane

(0.17 ml, 1.33 ml) was added and after 30 minutes the mixture

was warmed to ambient temperature and concentrated to dry-

(R_a*,R*)-N,N-Diisopropyl-2-(1-benzoylethyl)-1-naphthamide

28a

A solution of oxalyl chloride (0.09 ml, 0.61 mmol) in

dichloromethane (2.4 ml) at Ϫ78 ЊC under a drying tube

(CaSO₄) was treated with a solution of dimethyl sulfoxide

(0.13 ml, 1.11 mmol) in dichloromethane (0.5 ml) and stirred

for 2 minutes. A solution of the alcohols 20 obtained by lithi-

ation of 12 (215 mg, 0.55 mmol) in dichloromethane (1 ml) was

added dropwise over a period of 5 minutes. After 15 minutes,

diisopropylethylamine (0.83 ml, 2.77 mmol) was added. After a

further 5 minutes the mixture was allowed to warm to ambient

temperature (ca. 15 minutes) and saturated aqueous sodium

hydrogen sulfate (2 ml) was added. The solution was extracted

with dichloromethane (4 × 7 ml) and the combined organic

extracts were dried (MgSO₄), ﬁltered and concentrated under

1

ness under reduced pressure. H NMR of the crude product

showed only isomer, which was shown to be the (Z)-isomer by

¹H NOE experiments. Puriﬁcation by ﬂash chromatography⁵⁸

on neutral alumina [25 : 1 petrol (bp 40–60 ЊC)–EtOAc]

aﬀorded the enol ether 30 (483 mg, 98%) as a sticky white solid,

R_f[10 : 1 petrol (bp 40–60 ЊC)–EtOAc] 0.34; ν_max(ﬁlm)/cm^Ϫ1

2964, 2927, 2854, 1621; δ_H(300 MHz; CDCl₃) 8.32 (1H, d,

J = 8.8, ArH), 7.72 (3H, m, ArH), 7.53 (2H, d, J = 8.2 and 1.8,

ortho H on Ph), 7.37 (2H, m, ArH), 7.26 (3H, m, ArH),

6.32 (1H, s, CH᎐CO), 3.55 (2H, m, 2 × NCH), 1.72 (6H, m,

᎐

1

reduced pressure to aﬀord the crude product. H NMR of the

2 × CH₃), 1.01 (3H, d, J = 6.7, CH₃), 0.92 (3H, d, J = 6.7, CH₃),

0.00 (9H, s, SiMe₃); δ_C(75 MHz; CDCl₃) 169.6, 151.8, 139.6,

133.9, 131.9, 129.8, 129.7, 128.1, 127.8, 127.0, 126.5, 126.4,

125.9, 125.6, 124.9, 107.3, 51.1, 46.1, 29.6, 21.0, 21.0, 20.6 and

0.7; m/z (CI) 446 (100%, M ϩ H^ϩ); m/z (EI) 445 (0.5%,

M^ϩ), 345 (M Ϫ NⁱPr₂) and 49 (100) (Found: M^ϩ, 445.2439.

C₂₈H₃₅NO₂Si requires M, 445.2437).

crude product showed a 10 (28a) : 1 (28b) mixture of atrop-

isomers. Puriﬁcation by ﬂash chromatography on silica gel [4 : 1

petrol (bp 40–60 ЊC)–EtOAc] aﬀorded a mixture of naphth-

amides 28a and 28b (201 mg, 94%) as a white solid.

Alternatively, the 1.7 : 1 mixture of amides 20a and 20b

obtained from silane 17a (95 mg, 0.244 mmol) gave amide 28a

as a white solid (94 mg, 100%) requiring no further puriﬁcation.

mp 168–170 ЊC; R_f[3 : 1 petrol (bp 40–60 ЊC)–EtOAc] 0.33; ν_max

(ﬁlm)/cm^Ϫ13056, 2996, 2975, 2934, 1686, 1623; δ_H(300 MHz;

CDCl₃) 8.06 (2H, d, J = 7.3, ArH), 7.94–7.70 (4H, m, ArH),

7.59 (1H, t, J = 7.1, ArH), 7.54–7.43 (4H, m, ArH), 5.13 (1H, q,

J = 7.4, CH(CH₃)COPh), 3.46 (1H, sept, J = 6.6, NCH), 3.39

(1H, sept, J = 6.6, NCH), 1.77 (3H, d, J = 6.9, NCHCH₃), 1.71

(3H, d, J = 7.3, CH(CH₃)COPh), 1.60 (3H, d, J = 6.9,

NCHCH₃), 0.87 (3H, d, J = 6.6, NCHCH₃), 0.55 (3H, d, J = 6.6,

NCHCH₃); δ_C(75 MHz; CDCl₃) 201.1, 169.4, 136.0, 134.5,

133.4, 133.2, 132.4, 129.2, 128.7, 128.6, 128.0, 127.8, 127.1,

126.2, 126.0, 125.1, 51.0, 46.1, 43.8, 20.8, 20.7, 20.6 and 20.3;

m/z (CI) 388 (100%, M ϩ H^ϩ); m/z (EI) 387 (28, M^ϩ), 282 (30,

M Ϫ COPh) and 105 (100, COPh) (Found: C, 80.20; H, 7.70; N,

3.78%; M^ϩ, 387.2203. C₂₆H₂₉NO₂requires C, 80.6; H, 7.5; N,

3.6%; M, 387.2198).

N,N-Diisopropyl-2-(1-benzoylethyl)-1-naphthamide 28b

A solution of naphthamide 29 (122 mg, 0.33 mmol) in THF

(5 ml) was added to a solution of potassium hexamethyl-

disilazide (0.65 ml, 0.33 mmol; 0.5 M solution in toluene) in

THF (1.3 ml) at Ϫ78 ЊC under nitrogen. After 60 minutes the

mixture was added to a solution of methyl iodide (0.10 ml, 1.64

mmol) in THF (1.3 ml) via cannula, stirred for 5 hours, treated

with saturated aqueous ammonium chloride (5 ml) and warmed

to ambient temperature. The solution was extracted with

dichloromethane (4 × 7 ml) and the combined organic extracts

were dried (MgSO₄), ﬁltered and concentrated under reduced

pressure to aﬀord the crude product. Analytical HPLC of the

crude product showed a ratio of 25 (28a) : 75 (28b). Puriﬁcation

by preparative HPLC (10 : 1 hexane–EtOAc) aﬀorded the

ketones 28a and 28b (combined yield 102 mg, 81%) as white

solids. 28b: t_R7.7 min (10 : 1 hexane–EtOAc); mp 159–161 ЊC;

R_f[3 : 1 petrol (bp 40–60 ЊC)–EtOAc] 0.44; ν_max(ﬁlm)/cm^Ϫ1

3062, 2978, 2934, 1679, 1620; δ_H(300 MHz; CDCl₃) 8.27 (2H,

m, ArH), 7.88 (1H, m, ArH), 7.80 (1H, m, ArH), 7.75 (1H, d,

J = 8.7, ArH), 7.55–7.36 (6H, m, ArH), 4.98 (1H, q, J = 6.9,

CH(CH₃)COPh), 3.80–3.55 (2H, m, 2 × NCH), 1.88 (3H, d,

J = 6.9, NCHCH₃), 1.80 (3H, d, J = 6.9, NCHCH₃), 1.65 (3H, d,

J = 6.9, CH(CH₃)COPh), 1.24 (3H, d, J = 6.6, NCHCH₃), 1.06

(3H, d, J = 6.6, NCHCH₃); δ_C(75 MHz; CDCl₃) 200.6, 169.4,

136.2, 134.2, 133.5, 132.8, 132.3, 129.8, 129.3, 128.6, 128.3,

128.0, 126.4, 126.0, 125.3, 124.8, 50.7, 46.4, 44.2, 21.4, 21.0,

N,N-Diisopropyl-2-benzoylmethyl-1-naphthamide 29

Jones reagent [2.72 ml of a solution of CrO₃(2.5 g)–conc.

H₂SO₄(2 ml)–water (8 ml), 6.80 mmol] was added to a solution

of atropisomeric naphthamides 21a and 21b (327 mg, 0.872

mmol) in acetone (18 ml) at 0 ЊC. After 60 minutes, the mixture

was warmed to ambient temperature, stirred for a further

30 minutes and added to saturated aqueous sodium hydrogen

carbonate (52 ml). The solution was extracted with ethyl acetate

(4 × 30 ml), and the combined organic extracts washed with

water (50 ml), dried (MgSO₄), ﬁltered and concentrated under

J. Chem. Soc., Perkin Trans. 1, 2002, 901–917

911

View Article Online

20.9, 20.4 and 19.4; m/z (CI) 388 (100%, M ϩ H^ϩ); m/z (EI) 387

(0.6, M^ϩ) and 49 (100) (Found: M ϩ H^ϩ, 388.2269. C₂₆H₂₉NO₂

requires M ϩ H, 388.2276).

cooled in an ice-bath. Diisopropylamine (5 ml) was added and

the mixture stirred overnight at room temperature. The mixture

was made slightly acidic with 3 M hydrochloric acid and the

aqueous phase was extracted with dichloromethane (3 × 15 ml).

The combined extracts were washed with water (2 × 15 ml) and

saturated aqueous sodium hydrogen carbonate solution (15 ml),

dried over magnesium sulfate, ﬁltered and the solvent was

evaporated. Puriﬁcation by ﬂash chromatography⁵⁸[3% ethyl

acetate in light petroleum] gave the amide 32 (148 mg, 21%) as a

colourless oil. R_f[10% EtOAc in petrol] 0.53; ν_max(ﬁlm)/cm^Ϫ1

1630; δ_H(300 MHz; CDCl₃) 6.93 (2H, s, 2 × ArH), 3.65 (1H,

sept, J = 6.7, NCH), 3.52 (1H, sept, J = 6.7, NCH), 2.74–2.46

(6H, m, 3 × CH₂CH₃), 1.62 (6H, d, J = 6.7, 2 × NCHCH₃), 1.27

(6H, t, J = 7.6, 2 × o-CH₂CH₃), 1.26 (3H, t, J = 7.6, p-CH₂CH₃),

1.11 (6H, d, J = 6.7, 2 × NCHCH₃); δ_C(75 MHz; CDCl₃) 170.1

(s, CO), 143.5 (s, Ar), 139.1 (s, 2 × o-CCH₂), 134.5 (s, Ar), 124.9

(d 2 × CH), 50.4 (d, NCH), 45.5 (d, NCH), 28.7 (t, p-CH₂), 25.7

(t, 2 × o-CH₂), 20.9 (q, NCH(CH₃)₂), 20.4 (q, NCH(CH₃)₂),

15.3 (q, p-CH₂CH₃), 15.1 (q, 2 × o-CH₂CH₃); m/z (CI) 291

(19%), 290 (100), 260 (4), 189 (20), 188 (11) (Found: M^ϩ,

289.2399. C₁₉H₃₁NO requires M, 289.24055).

(R_a*,S*)-N,N-Diisopropyl-2-(1-hydroxyethyl)-1-naphthamide 31

Following the method of Fleming,³⁷silane 18a (100 mg,

0.239 mmol) was dissolved in a solution of peracetic acid

(0.545 g, 1.5 M solution in dilute acetic acid, 7.17 mmol) and

concentrated sulfuric acid (15 µl). Mercuric acetate (114 mg,

0.359 mmol) was added and the mixture kept at room temper-

ature for 5 h. Ether (50 ml) was added and the solution was

washed with sodium thiosulfate solution (30 ml), water (30 ml),

sodium hydrogen carbonate solution (30 ml) and brine (30 ml).

The organic phase was dried over magnesium sulfate, ﬁltered

and concentrated. Puriﬁcation by ﬂash chromatography⁵⁸[3 : 2

ethyl acetate–light petroleum] gave the alcohol 31 (55 mg, 76%)

as a white solid, with ¹H NMR data identical to those quoted in

the literature.³¹

N,N-Diisopropyl-2,4,6-triethylbenzamide 32

By the method of Fuson,⁴⁵1,3,5-triethylbenzene (9.3 ml, 49.30

mmol) was stirred in carbon tetrachloride (5 ml) in a 3-neck

ﬂask ﬁtted with a reﬂux condenser and dropping funnel. Iron

ﬁlings (250 mg, 4.44 mmol) were added and the mixture was

cooled to 0 ЊC. The ﬂask was wrapped in foil to protect the

reaction mixture from light. Bromine (2.54 ml, 49.30 mmol) in

carbon tetrachloride (5 ml) was added dropwise with vigorous

stirring over a period of 2.5 h. The mixture was then left to stir

overnight. Dichloromethane (20 ml) was added and the organic

solution washed with water (2 × 15 ml), 10% sodium hydroxide

solution (20 ml) and again with water until the aqueous layer

was neutral to litmus. The organic layer was dried over mag-

nesium sulfate, ﬁltered and the solvent removed under reduced

pressure to aﬀord 2,4,6-triethylbromobenzene (11.0 g, 92%) as

a colourless oil which was used without further puriﬁcation.

δ_H(300 MHz; CDCl₃) 6.98 (2H, s, 2 × ArH), 2.82 (4H, J = 7.5,

2 × o-ArCH₃), 2.63 (2H, q, J = 7.6, p-ArCH₃), 1.27 (9H, t,

J = 7.5, 3 × CH₂CH₃).

Alternatively, a solution of 2,4,6-triethylbromobenzene

(4.00 g, 16.59 mmol) in dry ether (5 ml) was added dropwise to

dry magnesium turnings (0.403 g, 16.59 mmol) placed in a

3-neck ﬂask equipped with a reﬂux condenser. A few drops of

1,2-dibromoethane were added to initiate the reaction. The

solution was stirred at room temperature for 5 h, then added

dropwise to a solution of diisopropylcarbamyl chloride (2.99 g,

18.27 mmol) in ether (20 ml), cooled in an ice-bath. Stirring was

continued at room temperature overnight, followed by heating

at reﬂux for 2 h. After cooling, water (20 ml) was added and the

aqueous layer was extracted with ether (3 × 15 ml). The com-

bined organic layers were then washed with water (15 ml), dried

over magnesium sulfate, ﬁltered and the solvent was evapor-

ated. Puriﬁcation by ﬂash chromatography⁵⁸[5% ethyl acetate

in light petroleum] gave the amide 32 (1.14 g, 24%) as a colour-

less oil, spectroscopically identical to a sample prepared as

above.

A solution of 2,4,6-triethylbromobenzene (4.00 g, 16.50

mmol) in dry ether (6 ml) was added dropwise to magnesium

turnings (0.403 g, 16.59 mmol) in a 3-neck ﬂask under a

reﬂux condenser. A few drops of 1,2,-dibromoethane were

added to initiate the reaction. The mixture was stirred for 3 h

after the addition was complete by which time all the

magnesium had reacted. The solution was then cooled in

an ice-bath and small pieces of solid carbon dioxide were added

to it. The mixture was allowed to come to room temperature

and stirred overnight, ether (20 ml) was added and then poured

into ice–water (10 ml) containing ammonium chloride (1.5 g)

and concentrated hydrochloric acid (0.7 ml). The ether

layer was separated and washed with dilute hydrochloric acid

(0.25 M, 2 × 10 ml). The aqueous layers were washed with ether

(10 ml) and the combined organic layers were extracted with

aqueous sodium hydroxide solution (10%, 3 × 10 ml). The

combined basic extracts were acidiﬁed, re-extracted with ether

(3 × 10 ml) and the combined organic layers were dried over

magnesium sulfate and ﬁltered. The solvent was evaporated to

aﬀord 2,4,6-triethylbenzoic acid as a white solid (2.0 g, 60%).

δ_H(300 MHz; CDCl₃) 7.00 (2H, s, ArH), 2.80 (4H, q, J = 7.7,

2 × o-CH₂), 2.69 (2H, q, J = 7.7, p-CH₂), 1.31 (6H, t, J = 7.7,

2 × o-CH₂CH₃), 1.29 (3H, t, J = 7.7, p-CH₂CH₃); δ_C(75 MHz;

CDCl₃) 176.0 (s, CO), 146.2, 141.4, 129.1, 125.9 (Ar), 28.7

(t, p-CH₂), 27.0 (t, 2 × o-CH₂), 15.8 (q, 2 × o-CH₂CH₃), 15.3

(q, p-CH₂CH₃).

(R_a*,S*)-N,N-Diisopropyl-2,4-diethyl-6-(1Ј-trimethylsilylethyl)-

benzamide 33

sec-Butyllithium (0.33 ml, 1.3 M solution in cyclohexane,

0.429 mmol) was added dropwise to a solution of the benz-

amide 32 (113 mg, 0.390 mmol) in THF (40 ml) at Ϫ78 ЊC

under nitrogen. After 1 h, trimethylsilyl chloride (74 µl, 0.586

mmol) was added, and after a further 15 min the mixture was

allowed to warm to 0 ЊC. Water (30 ml) was then added and the

THF was removed under reduced pressure. The aqueous phase

was extracted with dichloromethane (3 × 20 ml), the combined

organic extracts were washed with water (30 ml), dried over

magnesium sulfate, ﬁltered and the solvent was evaporated.

Puriﬁcation by ﬂash chromatography⁵⁸[3% ethyl acetate in

light petroleum] gave the silane 33 (101 mg, 72%) as a colourless

oil; R_f[5% EtOAc–petrol] 0.32; ν_max(ﬁlm)/cm^Ϫ11631; δ_H(300

MHz; CDCl₃) 6.84 (1H, s, Ar), 6.79 (1H, s, Ar), 3.71 (1H, sept,

J = 6.7, NCH), 3.51 (1H, sept, J = 6.7, NCH), 2.74–2.43 (4H,

m, o-CH_AH_BCH₃and p-CH₂CH₃), 2.15 (1H, q, J = 7.4,

ArCHCH₃), 1.63 (3H, d, J = 6.7, NCHCH₃), 1.60 (3H, d,

J = 6.7, NCHCH₃), 1.36 (3H, d, J = 7.4, ArCHCH₃), 1.26 (6H,

t, J = 7.6, 2 × ArCH₂CH₃), 1.14 (3H, d, J = 6.6, NCHCH₃), 1.08

(3H, d, J = 6.6, NCHCH₃), 0.00 (9H, s, Si(CH₃)₃); δ_C(75 MHz;

CDCl₃) 170.2 (s, CO), 143.1 (s, Ar), 142.1 (s, Ar), 139.4 (s, Ar),

133.5 (s, Ar), 123.6 (d, Ar), 122.8 (d, Ar), 49.9 (d, NCH), 45.5

(d, NCH), 28.8 (t, ArCH₂), 25.8 (d, ArCH), 25.1 (t, ArCH₂),

20.9 (q, 2 × NCHCH₃), 20.3 (q, NCHCH₃), 20.2 (q,

NCHCH₃), 16.3 (q, ArCHCH₃), 15.4 (q, CH₂CH₃), 15.1 (q,

CH₂CH₃), 2.6 (q, Si(CH₃)₃); m/z (CI) 364 (19%), 362 (100), 361

(18), 332 (19), 189 (33), 90 (17), 73 (65) (Found: M^ϩ, 361.2796.

C₂₂H₃₉NOSi requires M, 361.2801).

2,4,6-Triethylbenzoic acid (500 mg, 2.42 mmol) and thionyl

chloride (0.354 ml, 4.85 mmol) were stirred in dichloromethane

(5 ml) under a drying tube. DMF (0.2 ml) was added and the

solution was stirred for 5.5 h. Volatile materials were removed

under reduced pressure and the residual acid chloride was

912

J. Chem. Soc., Perkin Trans. 1, 2002, 901–917

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(r_a,R*,S*)-N,N-Diisopropyl-4-ethyl-2,6-bis(1-trimethylsilyl-

ethyl)benzamide 34a

(r_a,R*,S*)- and (R*,R*)-N,N-Diisopropyl-2,6-di-sec-butyl-4-

ethylbenzamide 36a and 36b

sec-Butyllithium (0.194 ml, 1.3 M solution in hexanes, 0.252

mmol) was added dropwise to a solution of silane 33 (83 mg,

0.230 mmol) in THF (30 ml) at Ϫ78 ЊC under nitrogen. The

resulting orange solution was stirred for 1 h at Ϫ78 ЊC and

trimethylsilyl chloride (44 µl, 0.345 mmol) was added. After

10 min the solution was allowed to warm to 0 ЊC. Water (20 ml)

was added and the THF was removed under reduced pressure.

The aqueous residue was extracted with dichloromethane and

the combined extracts were washed with water (30 ml), dried

over magnesium sulfate, ﬁltered and the solvent evaporated.

Puriﬁcation by ﬂash chromatography⁵⁸[2–4% ethyl acetate in

light petroleum] gave the bis-silane 34a (60 mg, 60%) as a white

crystalline solid, mp 127.5–128 ЊC; R_f[5% EtOAc in petrol]

0.77; δ_H(300 MHz; CDCl₃) 6.70 (2H, s, 2 × ArH), 3.77 (1H,

sept, J = 6.7, NCH), 3.46 (1H, sept, J = 6.9, NCH), 2.62 (2H, q,

J = 7.6, CH₂CH₃), 2.12 (2H, q, J = 7.4, 2 × ArCH), 1.61 (6H, d,

J = 6.9, NCH(CH₃)₂), 1.35 (6H, d, J = 7.4, 2 × CHCH₃), 1.25

(3H, t, J = 7.6, CH₂CH₃), 1.12 (6H, d, J = 6.7, NCH(CH₃)₂),

0.00 (18H, 2 × Si(CH₃)₃); δ_C(75 MHz; CDCl₃) 170.4 (s,

CO), 143.0 (s, Ar), 142.5 (d, Ar), 132.3 (s, Ar), 121.7 (d, Ar),

49.5 (d, NCH), 45.4 (d, NCH), 28.9 (d, 2 × CH), 25.3 (t, CH₂),

20.9 (q, 2 × NCHCH₃), 20.2 (q, 2 × NCHCH₃), 16.4 (q,

2 × ArCHCH₃), 15.7 (q, p-CH₂CH₃), Ϫ2.7 (q, 2 × Si(CH₃)₃);

m/z (EI) 433 (16), 405 (18), 404 (60), 261 (37), 73 (100) (Found:

M^ϩ, 433.3191. C₂₅H₄₇NOSi₂requires M, 433.3196).

sec-Butyllithium (0.20 ml, 1.3 M solution in cyclohexane, 0.263

mmol) was added dropwise to a solution of amide 35 (76 mg,

0.239 mmol) in THF (30 ml) at Ϫ78 ЊC under nitrogen. The

resultant orange–red solution was stirred at Ϫ78 ЊC for 1 h and

ethyl iodide (29 µl, 0.359 mmol) was added. The solution was

allowed to warm to 0 ЊC, water (30 ml) was added and the THF

was removed under reduced pressure. The aqueous phase was

extracted with dichloromethane (3 × 20 ml), the combined

organic extracts were washed with water (30 ml), dried over

magnesium sulfate, ﬁltered and the solvent was evaporated.

Puriﬁcation by ﬂash chromatography⁵⁸[5% ethyl acetate in

light petroleum] gave the diastereoisomer 36a (36 mg, 44%) as a

solid, mp 25–27 ЊC; R_f[5% EtOAc in petrol] 0.32; ν_max(ﬁlm)/

cm^Ϫ11636; δ_H(300 MHz; CDCl₃) 6.92 (2H, s, ArH), 3.76 (1H,

sept, J = 6.6, NCH), 3.50 (1H, sept, J = 6.9, NCH), 2.70–2.58

(4H, m, 2 × ArCH and ArCH₂), 1.78–1.61 (2H, m, 2 × ArCH-

CH_AH_B), 1.62 (6H, d, J = 6.9, NCH(CH₃)₂), 1.50–1.34 (2H, m,

2 × ArCHCH_AH_B), 1.26 (6H, d, J = 6.9, 2 × ArCHCH₃), 1.25

(3H, t, J = 7.6, ArCH₂CH₃), 1.12 (6H, d, J = 6.6, NCH(CH₃)₂),

0.86 (6H, t, J = 7.4, 2 × CHCH₂CH₃); δ_C(75 MHz; CDCl₃)

170.0 (s, CO), 143.4 (s, 2 × CCH), 134.1 (s, CCH₂), 126.6 (s,

CCO), 122.4 (d, 2 × CH), 50.0 (d, NCH), 45.6 (d, NCH), 37.3

(d, 2 × ArCH), 32.7 (t, 2 × CHCH₂), 28.9 (t, ArCH₂), 20.8 (q,

2 × NCHCH₃), 20.2 (q, 2 × CHCH₃), 20.1 (q, 2 × NCHCH₃),

15.3 (q, ArCH₂CH₃), 12.2 (q, 2 × CHCH₂CH₃); m/z (CI) 347

(23%), 346 (100), 245 (14), 244 (8), 86 (5), 74 (13), 58 (6)

(Found: M^ϩ, 345.3028. C₂₃H₃₉NO requires M, 345.3031).

Also obtained was the diastereoisomer 36b (27 mg, 33%) as

an oil, R_f[5% EtOAc in petrol] 0.29; δ_H(300 MHz; CDCl₃)

6.91 (2H, s, ArH), 3.76 (1H, sept, J = 6.7, NCH), 3.51 (1H, sept,

J = 6.9, NCH), 2.71–2.50 (4H, m, 2 × ArCH and CH₂CH₃),

1.77–1.33 (4H, m, 2 × CHCH₂), 1.61 (6H, d, J = 6.9, NCH-

(CH₃)₂), 1.26 (3H, t, J = 7.6, ArCH₂CH₃), 1.26 (3H, d, J = 6.9,

ArCHCH₃), 1.20 (3H, d, J = 6.7, ArCHCH₃), 1.13 (3H, d,

J = 6.9, NCHCH₃), 1.10 (3H, d, J = 6.7, NCHCH₃), 0.99 (3H, t,

J = 7.4, CHCH₂CH₃), 0.87 (3H, t, J = 7.4, CHCH₂CH₃); δ_C(75

MHz; CDCl₃) 170.0 (s, CO), 144.0 (s, Ar), 143.6 (s, Ar), 143.4 (s,

Ar), 134.0 (s, Ar), 122.6 (d, Ar), 122.4 (d, Ar), 50.1 (d, NCH),

45.6 (d, NCH), 38.1 (d, ArCH), 37.3 (d, ArCH), 32.6 (t,

ArCHCH₂), 29.4 (t, ArCHCH₂), 28.9 (t, ArCH₂), 22.5 (q,

ArCHCH₃), 20.8 (q, 2 × NCHCH₃), 20.4 (q, NCHCH₃), 20.2

(q, NCHCH₃), 19.9 (q, ArCHCH₃), 15.3 (q, ArCH₂CH₃), 12.6

(q, CHCH₂CH₃), 12.2 (q, CHCH₂CH₃); m/z (CI) 347 (26%),

346 (100), 245 (18), 244 (9), 91 (6), 86 (7), 74 (20), 60 (6), 58 (18)

(Found: M^ϩ, 345.3031. C₂₃H₃₉NO requires M, 345.3031.

HPLC analysis of the crude product was carried out on a

phenosphere 5 µ 80 Å column (100 × 8.00 mm), eluant 1%

ethanol in hexane, ﬂow rate 2 ml min^Ϫ1, UV at 255 nm, t_R1.67

(73.8%, disilane). 2.20 min (starting silane, 22.0%). A small

shoulder is on the major peak (<3%) is tentatively assigned to

the diastereoisomer 34b.

(R_a*,S*)-N,N-Diisopropyl-2,4-diethyl-6-sec-butylbenzamide 35

sec-Butyllithium (0.585 ml, 1.3 M solution in cyclohexane,

0.760 mmol) was added dropwise to a solution of benzamide 32

(200 mg, 0.691 mmol) in THF (40 ml) at Ϫ78 ЊC. The red

solution was stirred at Ϫ78 ЊC for 1 h and ethyl iodide (83 µl,

1.04 mmol) was added. The colourless solution was allowed to

warm to 0 ЊC, water (30 ml) was added and the THF was

removed under reduced pressure. The aqueous phase was

extracted with dichloromethane (3 × 30 ml) and the combined

extracts were washed with water (30 ml), dried over magnesium

sulfate, ﬁltered and the solvent was evaporated. Puriﬁcation by

ﬂash chromatography⁵⁸[5% ethyl acetate in light petroleum]

gave the amide 35 (164 mg, 75%) as a colourless oil which crys-

tallised on standing in the freezer; R_f[10% EtOAc in petrol]

0.44; ν_max(ﬁlm)/cm^Ϫ11637; δ_H(300 MHz; CDCl₃) 6.93 (2H, s,

ArH), 3.72 (1H, sept, J = 6.7, NCH), 3.52 (1H, sept, J = 6.7,

NCH), 2.76–2.46 (3H, m, ArCH and o-ArCH_AH_BCH₃), 2.66

(2H, q, J = 7.5, p-ArCH₂CH₃), 1.78–1.36 (2H, m, CHCH₂), 1.63

(3H, d, J = 6.7, NCHCH₃), 1.62 (3H, d, J = 6.7, NCHCH₃),

1.27 (6H, t, J = 7.5, 2 × ArCH₂CH₃), 1.26 (3H, d, J = 7.5,

ArCHCH₃), 1.13 (3H, d, J = 6.7, NCHCH₃), 1.11 (3H, d,

J = 6.7, NCHCH₃), 0.88 (3H, t, J = 7.5, CHCH₂CH₃); δ_C(75

MHz; CDCl₃) 170.0 (s, CO), 143.4 (s, Ar), 143.4 (s, Ar), 139.1 (s,

Ar), 134.3 (s, Ar), 125.0 (d, Ar), 122.3 (d, Ar), 50.2 (d, NCH),

45.6 (d, NCH), 37.2 (d, ArCH), 32.4 (t, CHCH₂), 28.8 (t,

ArCH₂), 25.7 (t, ArCH₂), 20.8 (q, 2 × NCHCH₃), 20.3 (q,

NCHCH₃), 20.3 (q, NCHCH₃), 20.0 (q, ArCHCH₃), 15.3 (q,

ArCH₂CH₃), 15.0 (q, ArCH₂CH₃), 12.1 (q, CHCH₂CH₃); m/z

(CI) 320 (22%), 318 (100), 217 (12), 216 (7), 102 (5) (Found:

M^ϩ, 317.2722. C₂₁H₃₅NO requires M, 317.2719).

HPLC analysis of the crude product mixture was carried out

using a phenosphere 5 µ silica column (100 × 8.00 mm), Merck-

Hitachi system; eluant 0.5% EtOH in hexane; ﬂow 2 ml min^Ϫ1

;

UV at 255 nm; t_R3.12 (36a, 46.6%) and 3.67 min (36b, 32.8%).

(R_a*,2ЈS*)- and (R_a*,2ЈR*)-N,N-Diisopropyl-2,4-dimethyl-6-

(2Ј-hydroxy-2Ј-phenylethyl)benzamide 37a and 37b

By the method used for 21a and 21a, sec-butyllithium (1.7 ml,

2.2 mmol), N,N-diisopropyl-2,4,6-trimethylbenzamide 7²¹

(0.5 g, 2 mmol) and freshly distilled benzaldehyde (0.31 ml,

3 mmol) gave a crude product which was puriﬁed by ﬂash

chromatography [90 : 10 petroleum ether (bp 60–80 ЊC)–ethyl

acetate] to yield a 65 : 35 mixture of the alcohols 37a and 37b

(0.51 g, 72%). δ_H(300 MHz; CDCl₃) [major diastereoisomer]

7.08 (1H, s, ArH), 6.95 (1H, s, ArH), 5.4 (1H, br s, OH), 4.78

(1H, dd, J 8.5, 3.1, ArCHOH), 3.70 (1H, sept, J 6.7, CHMe₂),

3.60 (1H, sept, J 6.7, CHMe), 2.95 (1H, dd, J 12.0, 3.3,

ArCH_AH_B), 2.36 (3H, s, ArMe), 2.30 (3H, s, ArMe), 1.71 (3H,

d, J 6.7, CHMe), 1.65 (1 H, m, ArCH_AH_B), 1.63 (3H, d, J 6.7,

CHMe), 1.21 (3H, d, J 6.7, CHMe), 0.99 (3H, d, J 6.7, CHMe);

[minor diastereoisomer] 6.90 (1H, s, ArH), 6.58 (1H, s, ArH),

5.4 (1H, br s, OH), 5.07 (1H, dd, J 6.5, 3.1, ArCHOH), 3.70

HPLC analysis of the crude product (phenosphere 5 µ, 80 Å

silica column, 100 × 8.00 mm, Merck-Hitachi system, UV at

255 nm, eluant 0.5% ethanol in hexane, ﬂow rate 2 ml min^Ϫ1

,

t_R6.82 (35, 91.9%), 9.37 min (tentatively identiﬁed as the

diastereoisomer, 8.1%).

J. Chem. Soc., Perkin Trans. 1, 2002, 901–917

913

View Article Online

(1H, sept, J 6.7, CHMe), 3.60 (1H, sept, J 6.7, CHMe), 3.05

(1H, dd, J 11.0 and 3.1, ArCH_AH_B), 2.28 (3H, s, ArMe), 2.22

(3H, s, ArMe), 1.67 (1H, m, ArCHH_AH_B), 1.65 (3H, d, J 6.7,

CHMe), 1.62 (3H, d, J 6.7, CHMe), 1.17 (3H, d, J 6.7, CHMe),

1.03 (3H, d, J 6.7, CHMe).

solution in hexanes) and stirred for 25 minutes. The red solution

was quenched with benzyl bromide (0.05 ml, 0.44 mmol),

stirred for a further 3.5 hours, warmed to ambient temperature,

treated with saturated aqueous ammonium chloride (5 ml) and

extracted with dichloromethane (4 × 10 ml). The combined

organic extracts were dried (MgSO₄), ﬁltered and concentrated

1

(R_a*,2ЈS*)- and (R_a*,2ЈR*)-N,N-Diisopropyl-2,4-dimethyl-6-

[2Ј-(methylamino)-2Ј-phenylethyl]benzamide 38a and 38b

under reduced pressure to aﬀord the crude product. H NMR

of the crude product showed an 86 : 14 mixture of atrop-

isomers. Puriﬁcation by ﬂash chromatography⁵⁸[6 : 1 petrol (bp

40–60 ЊC)–EtOAc] aﬀorded amine 39a (132 mg, 73%) as a pale

yellow oil.

In the same way as for compound 23a, benzamide²¹7 (490 mg,

1.98 mmol) in THF (16 ml) at Ϫ78 ЊC was lithiated with sec-

butyllithium (1.53 ml, 1.98 mmol; 1.3 M in hexanes), treated

with N-benzylidenemethylamine (0.27 ml, 2.18 mmol) and

stirred for a further 4 hours. After work-up in the manner of

(R_a*,2ЈS*)-N,N-Diisopropyl-2-{2Ј-[benzyl(methyl)amino]-2Ј-

phenylethyl}-4-methyl-6-[²H]methylbenzamide 41

1

23a, H NMR showed a 96 : 4 ratio of atropisomers 38a and

38b. Puriﬁcation by ﬂash chromatography⁵⁸gave the amines

38a and 38b (626 mg, 86%) as an oil; R_f[10 : 10 : 1 petrol

(bp 40–60 ЊC)–EtOAc–triethylamine] 0.30; ν_max(ﬁlm)/cm^Ϫ1

3336, 3060, 3026, 2967, 2927, 2870, 2890, 1631; δ_H(300 MHz;

CDCl₃) 7.40–7.22 (5H, m, ArH), 7.00 (1H, s, ArH^minor), 6.96

(1H, s, ArH^minor), 6.87 (1H, s, ArH^major), 6.65 (1H, s, ArH^major),

3.98 (1H, dd, J = 9.4 and 2.8, CHNHCH₃^minor), 3.79 (1H, dd,

J = 8.1 and 5.9, CHNHCH₃^major), 3.58 (2H, m, 2 × NCH^major),

2.88 (1H, dd, J = 8.2 and 13.3, ArCHH^major), 2.73 (1H, dd,

J = 13.3 and 5.6, ArCHH^major), 2.31 (3H, s, CH₃^major), 2.25 (3H,

s, CH₃^major), 2.23 (3H, s, CH₃^major), 1.72 (3H, d, J = 6.9, NCH-

CH₃^major), 1.66 (3H, d, J = 6.9, NCHCH₃^major), 1.14 (3H, d,

J = 6.6, NCHCH₃^major), 1.05 (3H, d, J = 6.6, NCHCH₃^major);

δ_C(75 MHz; CDCl₃) (38a only) 170.4, 144.6, 137.0, 135.7,

134.7, 133.0, 128.8, 128.1, 127.7, 127.3, 126.8, 67.2, 50.7,

45.8, 42.1, 34.9, 21.0, 20.9, 20.6, 20.4 and 19.0; m/z (CI) 367

(100%, M ϩ H^ϩ) (Found: M^ϩ, 366.2673. C₂₃H₃₄N₂O requires

M, 366.2671).

sec-Butyllithium (0.17 ml, 1.22 mmol; 1.3 M in hexanes)

was added dropwise to a solution of benzamide 39a (102 mg,

0.22 mmol) in THF (3 ml) at Ϫ78 ЊC under nitrogen. After

55 minutes, deuterium oxide (1 ml, excess) was added to the

orange solution, and the mixture was warmed to ambient

temperature. The solution was extracted with dichloromethane

(4 × 7 ml) and the combined organic extracts were dried

(MgSO₄), ﬁltered and concentrated under reduced pressure at

low temperature to give the deuterobenzamide 41 as a colour-

less oil (99 mg, 97%), δ_H(300 MHz; CDCl₃) 7.20–7.10 (10H,

m, ArH), 6.68 (1H, s, ArH), 6.09 (1H, s, ArH), 3.82 (1H, dd,

J = 8.9 and 5.8, CHNCH₃), 3.53 (1H, m, NCH), 3.52 (1H, d,

J = 13.5, NCHHPh), 3.43 (1H, sept, J = 6.9, NCH), 3.31 (1H,

dd, J = 13.3 and 5.9, ArCHHCH), 3.21 (1H, d, J = 13.5,

NCHHPh), 2.67 (1H, dd, J = 13.3 and 9.1, ArCHHCH), 2.17

(2H, s, CH₂D), 2.11 (3H, s, CH₃), 1.96 (3H, s, CH₃), 1.58 (3H, d,

J = 6.9, NCHCH₃), 1.54 (3H, d, J = 6.7, NCHCH₃), 1.00 (3H, d,

J = 6.6, NCHCH₃), 0.99 (3H, d, J = 6.6, NCHCH₃); m/z (EI)

457.5 (11%, M^ϩ), 366.4 (16, M Ϫ Bn), 210.2 (100, PhCHN-

(Me)Bn) and 91.2 (64, Bn).

(R_a*,2ЈS*)- and (R_a*,2ЈR*)-N,N-Diisopropyl-2-{2Ј-[benzyl-

(methyl)amino]-2Ј-phenylethyl}-4,6-dimethylbenzamide 39a and

39b

(3R*,2ЈS*)-8-{2-[Benzyl(methyl)amino]-2-phenylethyl}-2,6-

dimethyl-3-phenyl-1,2,3,4-tetrahydroisoquinolin-1-one 43

In the same way, benzamide²¹7 (626 mg, 2.53 mmol) in THF

(15 ml) at Ϫ78 ЊC was lithiated with sec-butyllithium (2.14 ml,

2.79 mmol), and treated sequentially with N-benzylidenemethyl-

amine (0.31 ml, 2.53 mmol) and benzyl bromide (0.30 ml,

2.53 mmol) and stirred for a further 3 hours. After work-up in

sec-Butyllithium (0.77 ml, 1.00 mmol; 1.3 M solution in

hexanes) was added to a solution of benzamide 7²¹(199 mg,

0.91 mmol) in THF (6 ml) at Ϫ78 ЊC under nitrogen. After

60 minutes, N-benzylidenemethylamine (0.11 ml, 0.91 mmol)

was added to give a dark pink–red solution. After a further

60 minutes benzyl bromide (0.11 ml, 0.91 mmol) was added.

After a further 60 minutes the pale yellow solution was treated

with sec-butyllithium (0.77 ml, 1.00 mmol; 1.3 M solution in

hexanes) to give a dark red–brown solution and stirred for an

additional 45 minutes. N-Benzylidenemethylamine (0.11 ml,

0.91 mmol) and, after a further 15 minutes, DMPU (0.22 ml,

1.82 mmol) were added. After 4 hours, saturated aqueous

ammonium chloride solution (5 ml) was added and the mixture

was allowed to warm to ambient temperature, diluted with

water (10 ml) and the THF was removed under reduced pres-

sure. Diethyl ether (30 ml) was added and the layers were separ-

ated. The ethereal extract was washed with water (5 × 10 ml),

dried (MgSO₄), ﬁltered and concentrated under reduced pres-

sure to give pale yellow oil. Puriﬁcation by preparative HPLC

(4 : 1 hexane–EtOAc) aﬀorded the isoquinolinone 43 (25 mg,

6%) as a colourless oil, t_R28 min (4 : 1 hexane–EtOAc);

ν_max(ﬁlm)/cm^Ϫ13059, 3025, 3003, 2924, 2873, 2849, 2790, 1642;

δ_H(300 MHz; CDCl₃) 7.25–7.10 (10H, m, ArH), 7.04 (3H, m,

ArH), 6.83 (2H, m, ArH), 6.55 (1H, s, ArH), 6.47 (1H, s, ArH),

4.56 (1H, dd, J = 6.6 and 2.7, PhCH(NMeCO)), 4.03 (1H,

t, J = 7.6, PhCHN(Bn)Me), 3.81 (2H, d, J = 7.4, PhCH-

(NMeCO)CH₂), 3.49 (1H, d, J = 13.5, CHHPh), 3.52 (1H, dd,

J = 15.3 and 6.5, PhCH(N(Bn)Me)CHH), 3.28 (1H, d, J = 13.6,

CHHPh), 3.02 (3H, s, N(CH₃)CO), 2.79 (1H, dd, J = 15.4 and

2.7, PhCH(N(Bn)Me)CHH), 2.15 (3H, s, ArCH₃), 1.98 (3H, s,

CH₃); δ_C(75 MHz; CDCl₃) 140.3, 139.7, 135.8, 132.6, 129.1,

128.6, 128.5, 127.9, 127.6, 127.3, 126.7, 126.4, 126.2, 125.1,

1

the manner of 23a, H NMR showed a 92 : 8 ratio of 39a and

39b. Puriﬁcation by ﬂash chromatography⁵⁸[9 : 1 petrol (bp 40–

60 ЊC)–EtOAc ϩ 1% triethylamine] gave the amines 39a and

39b (860 mg, 74%) as a colourless oil; R_f[6 : 1 petrol (bp 40–

60 ЊC)–EtOAc ϩ 1% triethylamine] 0.34; ν_max(ﬁlm)/cm^Ϫ1

3060, 3027, 2968, 2929, 2872, 2791, 1630; δ_H(300 MHz; CDCl₃)

7.20–7.10 (10H, m, ArH), 6.79 (1H, s, ArH^minor), 6.76 (1H, s,

ArH^minor), 6.68 (1H, s, ArH), 6.09 (1H, s, ArH), 4.13 (1H, dd,

J = 8.2 and 6.2, CHNCH₃^minor), 3.82 (1H, dd, J = 8.9 and 5.8,

CHNCH₃^major), 3.53 (1H, m, NCH^major), 3.52 (1H, d, J = 13.5,

NCHHPh^major), 3.43 (1H, sept, J = 6.9, NCH^major), 3.31 (1H, dd,

J = 13.3 and 5.9, ArCHHCH^major), 3.21 (1H, d, J = 13.5,

NCHHPh^major), 3.10 (1H, dd, J = 14.4 and 8.4, ArCH-

HCH^minor), 2.96 (1H, dd, J = 14.4 and 6.2, ArCHHCH^minor),

2.67 (1H, dd, J = 13.3 and 9.1, ArCHHCH^major), 2.17 (3H, s,

CH₃^major), 2.11 (3H, s, CH₃^major), 1.98 (3H, s, CH₃^minor), 1.96

(3H, s, CH₃^major), 1.58 (3H, d, J = 6.9, NCHCH₃^major), 1.54 (3H,

d, J = 6.7, NCHCH₃^major), 1.48 (3H, d, J = 6.7, NCHCH₃^minor),

1.28 (3H, d, J = 6.7, NCHCH₃^minor), 1.00 (3H, d, J = 6.6, NCH-

CH₃^major), 0.99 (3H, d, J = 6.6, NCHCH₃^major); δ_C(75 MHz;

CDCl₃) (39a only) 170.4, 140.8, 140.2, 136.2, 135.4, 134.4,

132.7, 128.9, 128.7, 128.6, 128.4, 127.9, 127.6, 126.7, 126.5,

69.0, 59.4, 50.6, 45.8, 38.2, 37.2, 21.1, 21.0, 20.8, 20.3 and 18.9;

m/z (CI) 457 (100%, M ϩ H^ϩ) (Found: M ϩ H^ϩ, 457.3222.

C₃₁H₄₀N₂O requires M ϩ H, 457.3219).

Alternatively, a solution of benzamide 38 (96 : 4 38a : 38b;

146 mg, 0.40 mmol) in THF (2 ml) at Ϫ78 ЊC under nitrogen

was treated with n-butyllithium (0.25 ml, 0.40 mmol; 1.6 M

914

J. Chem. Soc., Perkin Trans. 1, 2002, 901–917

View Article Online

70.2, 61.5, 58.5, 38.5, 36.8, 36.5, 34.5 and 20.9; m/z (CI) 475

(17%, M ϩ H^ϩ) and 120 (PhCH₂NMe) (Found: M ϩ H^ϩ,

475.2757. C₃₃H₃₄N₂O requires M ϩ H, 475.2749).

2 × NCH^major), 3.48 (2H, dd, J = 12.6 and 5.5, 2 × CHHCHN-

(CH₃)CH₂Ph^major), 3.37 (2H, d, J = 13.3, 2 × CHHPh^major),

2.73 (2H, dd, J = 12.8 and 9.6, 2 × CHHCHN(CH₃)-

CH₂Ph^major), 2.30 (6H, s, 2 × NCH₃^major), 1.79 (6H, m,

2 × NCHCH₃^major), 1.78 (3H, s, ArCH₃^major), 1.08 (6H, d,

J = 6.6, 2 × NCHCH₃^major); δ_C^major(75 MHz; CDCl₃) 170.6,

141.5, 140.5, 133.9, 129.3, 128.9, 128.7, 128.6, 128.1, 128.0,

127.6, 126.6, 126.5, 69.8, 59.8, 50.5, 45.8, 38.6, 38.1, 21.0, 20.7

and 20.6; m/z (CI) 666 (12%, M ϩ H^ϩ), 210 (77, CH(Ph)-

N(CH₃)Bn) and 120 (100); m/z (EI) 210 (100%, CH(Ph)-

N(CH₃)Bn) and 666 (3, M ϩ H^ϩ) (Found: M ϩ H^ϩ, 666.4436.

C₃₁H₄₀N₂O requires M ϩ H, 666.4423).

(R_a*,2ЈS,2ЉS)-N,N-Diisopropyl-2-{(2S*)-[benzyl(methyl)-

amino]-2-phenylethyl}-4-methyl-6-[(2R*)-2-(methylamino)-2-

phenylethyl]benzamide 44

sec-Butyllithium (0.76 ml, 1.05 mmol; 1.39 M solution in

hexanes) was added to a solution of benzamide²¹36 (217 mg,

0.88 mmol) in THF (5 ml) at Ϫ78 ЊC under nitrogen. After

60 minutes, N-benzylidenemethylamine (0.108 ml, 0.88 mmol)

was added to give a dark pink–red solution. After a further

45 minutes, the reaction mixture was treated with benzyl

bromide (0.104 ml, 0.88 mmol), stirred for a further 70 minutes

to give a pale yellow solution, treated with sec-butyllithium

(0.76 ml, 0.88 mmol; 1.39 M solution in hexanes) to give

a dark red–brown solution and stirred for an additional

45 minutes. N-Benzylidenemethylamine (0.108 ml, 0.88 mmol)

was added and the mixture was stirred for a further 15 minutes.

HMPA (0.31 ml, 1.76 mmol) was added, and after an

additional 60 minutes saturated aqueous ammonium chloride

solution (5 ml) was added and the mixture allowed to warm to

ambient temperature. Water (10 ml) was added and the THF

was removed under reduced pressure. Diethyl ether (30 ml)

was added and the layers were separated. The ethereal extract

was washed with water (5 × 10 ml), dried (MgSO₄), ﬁltered

and concentrated under reduced pressure to give a pale yellow

oil. Puriﬁcation by ﬂash chromatography⁵⁸[1 : 1 petrol (bp

40–60 ЊC)–EtOAc ϩ 1% triethylamine] aﬀorded the diamine 44

(481 mg, 95%) as a yellow oil that crystallised on standing,

ν_max/cm^Ϫ13339, 3083, 3060, 3027, 2966, 2933, 2871, 2847, 2790;

δ_H(300 MHz; CDCl₃) 7.4–7.2 (15H, m, 3 × Ph), 6.38 (1H, s,

ArH), 6.17 (1H, s, ArH), 4.02 (1H, dd, J = 9.2 and 5.9, CH-

NHMe), 3.89 (1H, t, J = 7.1, CHNMeBn), 3.71 (1H, d, J = 13.5,

N(CH₃)CHHPh), 3.59 (2H, m, 2 × NCH), 3.48 (1H, dd,

J = 12.9 and 6.0, CHHCHNMe), 3.35 (1H, d, J = 13.5,

N(CH₃)CHHPh), 2.97 (1H, dd, J = 13.2 and 7.4, CHHCHN-

MeBn), 2.76 (1H, dd, J = 12.6 and 9.3, CHHCHNMe), 2.68

(1H, dd, J = 13.2 and 7.1, CHHCHNMeBn), 2.34 (3H, s, CH₃),

2.27 (3H, s, CH₃), 1.93 (3H, s, CH₃), 1.76 (6H, d, J = 6.7,

2 × NCHCH₃), 1.12 (3H, d, J = 6.6, NCHCH₃), 1.05 (3H, d,

J = 6.6, NCHCH₃); δ_C(75 MHz; CDCl₃) 170.5, 144.3, 141.3,

140.4, 136.1, 135.4, 134.3, 134.1, 129.5, 128.8, 128.7, 128.5,

128.0, 127.9, 127.6, 127.5, 126.7, 126.5, 69.4, 67.1, 59.6, 50.6,

45.8, 42.4, 38.5, 37.8, 35.0, 21.0, 21.0, 20.7 and 20.5; m/z (CI)

576 (5%, M ϩ H^ϩ) and 120 (100) (Found: M ϩ H^ϩ, 576.3955.

C₃₉H₄₉N₃O requires M ϩ H, 576.3954).

N,N-Diisopropylbenzamide 46⁵⁹

Diisopropylamine (12 ml, 85 mmol) was added dropwise

over 10 minutes to benzoyl chloride (5.40 g, 38.4 mmol) in THF

(200 ml) at 0 ЊC and the mixture was stirred for 3 hours. Water

(50 ml) was added and the THF was removed under reduced

pressure. The aqueous residue was extracted with diethyl ether

(4 × 40 ml) and the combined organic extracts were washed

with aqueous 1 M hydrochloric acid (3 × 30 ml) and saturated

aqueous sodium hydrogen carbonate (3 × 20 ml), dried

(MgSO₄), ﬁltered and concentrated under reduced pressure to

aﬀord the crude product as a white solid. Recrystallisation from

petrol (bp 40–60 ЊC) aﬀorded the amide 46⁵⁹as white platelets

(6.766 g, 86%), mp 68–70 ЊC (lit.⁵⁹68–69 ЊC).

N,N-Diisopropyl-2-ethylbenzamide 4¹⁹

sec-Butyllithium (9.48 ml, 1.3 M solution in cyclohexane, 12.32

mmol) was added dropwise to a solution of N,N-diisopropyl-

benzamide (2.30 g, 11.20 mmol) in THF (120 ml) at Ϫ78 ЊC

under nitrogen. After 1 h before ethyl iodide (1.79 ml, 22.40

mmol) was added. The solution was allowed to warm to room

temperature, water (50 ml) was added and the THF was

removed under reduced pressure. The aqueous residue was

extracted with dichloromethane (3 × 30 ml) and the combined

extracts were washed with water (30 ml), dried over magnesium

sulfate, ﬁltered and concentrated under reduced pressure. Puri-

ﬁcation by ﬂash chromatography⁵⁸[5% ethyl acetate in light

petroleum] gave the amide 4¹⁹(2.61 g, 100%) as a white crystal-

line solid, mp 90–92 ЊC (lit.¹⁹91–93 ЊC); R_f[10% EtOAc: petrol]

0.47; δ_H(300 MHz; CDCl₃) 7.34–7.17 (3H, m, ArH), 7.11 (1H,

d, J = 7.3, ArH), 3.71 (1H, sept, J = 7, NCH), 3.54 (1H, sept,

J = 7, NCH), 2.79–2.58 (2H, m, ArCH_ACH_B), 1.61 (6H, d, J = 7,

NCHCH₃), 1.29 (3H, t, J = 7.5, CH₂CH₃), 1.14 (3H, d, J = 7,

NCHCH₃), 1.11 (3H, d, J = 7, NCHCH₃) [lit.¹⁹4.81 (1H, m),

3.84 (4H, m), 2.71 (2H, m), 1.63 (4H, m)]; δ_C(75 MHz; CDCl₃)

170.5 (s, CO), 139.8 (s, Ar), 138.0 (s, Ar), 128.5 (d, Ar), 128.1 (d,

Ar), 125.6 (d, Ar), 124.6 (d, Ar), 50.6 (d, NCH), 45.6 (d, NCH),

25.6 (t, CH₂), 20.6 (q, NCHCH₃), 20.6 (q, NCHCH₃), 20.5

(q, NCHCH₃), 20.4 (q, NCHCH₃), 15.1 (q, CH₂CH₃).

(r_a,R*,S*)- and (R*,R*)-N,N-Diisopropyl-2-{(2R*)-2-[benzyl-

(methyl)amino]-2-phenylethyl}-6-{(2S*)-2-[benzyl(methyl)-

amino]-2-phenylethyl}-4-methylbenzamide 45a and 45b

In the same way, a solution of benzamide²¹7 (1.260 g, 5.10

mmol) in THF (30 ml) at Ϫ78 ЊC was treated sequentially with

sec-butyllithium (4.71 ml, 6.12 mmol; 1.3 M solution in hex-

anes), N-benzylidenemethylamine (0.63 ml, 5.10 mmol), benzyl

bromide (0.61 ml, 5.10 mmol), sec-butyllithium (4.71 ml, 6.12

mmol; 1.3 M solution in hexanes), N-benzylidenemethylamine

(0.63 ml, 5.10 mmol), HMPA (1.77 ml, 10.20 mmol), benzyl

bromide (0.61 ml, 888 mmol) and saturated aqueous ammo-

nium chloride solution (10 ml). After work-up in the manner of

44, puriﬁcation by ﬂash chromatography⁵⁸[7 : 1 petrol (bp 40–

60 ЊC)–EtOAc ϩ 1% triethylamine] aﬀorded diamine 45a (2.503

g, 74%) as a colourless oil which crystallised upon standing. ¹H

NMR showed two atropisomers in a ratio of >92 (45a) : <8

(45b), mp 115–118 ЊC; ν_max/cm^Ϫ13060, 3028, 2967, 2931, 2872,

2846, 2791, 1624; δ_H(300 MHz; CDCl₃) 7.45–7.20 (20H, m,

ArH), 6.00 (2H, s, ArH^major), 6.82 (1H, s, ArH^minor), 6.10 (1H, s,

ArH^minor), 4.00 (2H, dd, J = 9.5 and 5.6, 2 × CHN(CH₃)CH₂-

Ph^major), 3.71 (2H, d, J = 13.5, 2 × CHHPh^major), 3.59 (2H, m,

N,N-Diisopropyl-2-propylbenzamide 50

In the same way, sec-butyllithium (2.47 ml, 1.3 M solution in

cyclohexane, 3.21 mmol), benzamide 46 (0.60 g, 2.92 mmol)

in THF (60 ml) and n-propyl iodide (0.57 ml, 5.84 mmol)

gave, after puriﬁcation by ﬂash chromatography⁵⁸[8 : 2 light

petroleum–ethyl acetate], the amide 50 (0.653 g, 91%) as a

colourless oil; R_f[EtOAc–petrol, 3 : 7] 0.69; ν_max(ﬁlm)/cm^Ϫ1

1632; δ_H(300 MHz; CDCl₃) 7.34–7.10 (4H, m, ArH), 3.71 (1H,

sept, J = 6.7, NCH), 3.54 (1H, sept, J = 6.7, NCH), 2.62 (2H, t,

J = 7.8, ArCH₂), 1.86–1.50 (2H, m, CH₂CH₂CH₃), 1.61 (6H, d,

J = 6.7, 2 × NCHCH₃), 1.15 (3H, d, J = 6.7, NCHCH₃), 1.12

(3H, d, J = 6.7, NCHCH₃), 0.99 (3H, t, J = 7.3, CH₂CH₃); δ_C(75

MHz; CDCl₃) 170.5 (s, CO), 138.5 (s, Ar), 138.1 (s, Ar), 129.2

(d, Ar), 128.0 (d, Ar), 125.6 (d, Ar), 124.8 (d, Ar), 50.6 (d,

NCH), 45.6 (d, NCH), 34.9 (t, ArCH₂), 24.0 (t, CH₂CH₃), 20.7

(q, NCHCH₃), 20.6 (q, NCHCH₃), 20.5 (q, NCHCH₃), 20.4

J. Chem. Soc., Perkin Trans. 1, 2002, 901–917

915

View Article Online

(q, NCHCH₃), 14.1 (q, CH₂CH₃); m/z (EI) 247 (13%), 204 (25),

147 (100), 131 (20), 129 (30), 91 (33) (Found: M^ϩ, 247.1943.

C₁₆H₂₅NO requires M, 247.1936).

Crystal data for 28a§§

C₂₆H₂₉NO₂, M = 387.50, monoclinic, a = 7.4893(18), b =

13.585(4), c = 11.005(4) Å, β = 99.39(2)Њ, U = 1104.7(5) Å³, T =

123(1) K, space group P2₁, 11086 reﬂections measured, 4494

unique (R_int= 0.0218) which were used in all calculations. The

ﬁnal wR(F ²) was 0.0917 (all data).

(R_a*,S*)-N,N-Diisopropyl-2-methyl-6-sec-butylbenzamide 49a

sec-Butyllithium (0.66 ml, 1.3 M solution in cyclohexane, 0.857

mmol) was added dropwise to a solution of N,N-diisopropyl-2-

ethylbenzamide 4 (0.20 g, 0.857 mmol) in THF (60 ml) at

Ϫ78 ЊC under nitrogen. The pink solution was stirred at Ϫ78 ЊC

for 1 h and ethyl iodide (69 µl, 0.857 mmol) was added.

sec-Butyllithium (0.66 ml, 1.3 M solution in cyclohexane,

0.857 mmol) was added. The orange solution was stirred for a

further 1 h and methyl iodide (54 µl, 0.857 mmol) was added.

The solution was allowed to warm to 0 ЊC, water (40 ml) was

added and the THF was removed under reduced pressure. The

aqueous phase was extracted with dichloromethane (3 × 40 ml),

the combined organic extracts were washed with water (40 ml),

dried over magnesium sulfate, ﬁltered and concentrated. Puriﬁ-

cation by ﬂash chromatography⁵⁸[5% ethyl acetate in light

petroleum] gave the amide 49a (147 mg, 62%) as a white crystal-

line solid, mp 49–49.5 ЊC; R_f[10% EtOAc–petrol] 0.47; δ_H(300

MHz; CDCl₃) 7.22 (1H, t, J = 7.5, p-ArH), 7.11 (1H, d, J = 7.5,

m-ArH), 7.04 (1H, d, J = 7.5, m-ArH), 3.70 (1H, sept, J = 6.7,

NCH), 3.54 (1H, sept, J = 6.7, NCH), 2.74–2.58 (1H, m,

ArCH), 2.33 (3H, s, ArCH₃), 1.80–1.39 (2H, m, ArCHCH₂),

1.64 (6H, d, J = 6.7, NCH(CH₃)₂), 1.27 (3H, d, J = 6.9,

ArCHCH₃), 1.14 (6H, d, J = 6.7, NCH(CH₃)₂), 0.87 (3H, t,

J = 7.4, ArCHCH₂CH₃); δ_C(75 MHz; CDCl₃) 169.8 (s, CO),

143.5 (s, Ar), 137.3 (s, Ar), 133.1 (s, Ar), 127.6 (d, Ar), 127.5 (d,

Ar), 122.9 (d, Ar), 50.3 (d, NCH), 45.7 (d, NCH), 37.2 (d,

ArCH), 32.4 (t, CH₂CH₃), 20.9 (q, NCHCH₃), 20.9 (q,

NCHCH₃), 20.3 (q, NCHCH₃), 20.3 (q, NCHCH₃), 20.2

(ArCHCH₃), 19.2 (t, ArCH₃), 12.0 (q, CH₂CH₃); m/z (CI) 277

(22%), 276 (100), 260 (1), 175 (7), 174 (3) (Found: C, 78.74; H,

10.56; N, 5.06%, M^ϩ, 275.2244. C₁₈H₂₉NO requires C, 78.49; H,

10.61; N, 5.09%, M 275.2249).

Crystal data for 45a§§

C₄₆H₅₅N₃O, M = 665.93, triclinic, a = 11.350(2), b = 12.9829(18),

c = 14.928(3) Å, α = 71.775(12)Њ, β = 79.479(16)Њ, γ =

70.577(16)Њ, U = 1962.9(6) Å , T = 123(1) K, space group P1,

18961 reﬂections measured, 7883 unique (R_int= 0.0196) which

were used in all calculations. The ﬁnal wR(F ²) was 0.1144 (all

data).

3

¯

Acknowledgements

We are grateful to the Leverhulme Trust for support (to JHP)

and to Roche Products Ltd. and the EPSRC for a CASE award

(to NW). We thank Dr Francis X. Wilson for many helpful

discussions.

References

1 H. W. Gschwend and H. R. Rodriguez, Org. React., 1979, 26, 1.

2 P. Beak and R. A. Brown, J. Org. Chem., 1977, 42, 1823.

3 P. Beak and V. Snieckus, Acc. Chem. Res., 1982, 15, 306.

4 P. Beak and R. A. Brown, J. Org. Chem., 1982, 47, 34.

5 V. Snieckus, Chem. Rev., 1990, 90, 879.

6 R. D. Clark and A. Jahangir, Org. React., 1995, 47, 1.

7 J. J. Court and D. J. Hlasta, Tetrahedron Lett., 1996, 37, 1335.

8 J. Clayden, J. H. Pink, N. Westlund and F. X. Wilson, Tetrahedron

Lett., 1998, 39, 8377.

9 P. Beak and A. I. Meyers, Acc. Chem. Res., 1986, 19, 356.

10 M. Al-Aseer, P. Beak, D. Hay, D. J. Kempf, S. Mills and S. G. Smith,

J. Am. Chem. Soc., 1983, 105, 2080.

11 P. Beak, J. E. Hunter and Y. M. Jun, J. Am. Chem. Soc., 1983, 105,

6350.

HPLC analysis of the crude product showed a 91 : 9 ratio of

49a : 49b.

12 D. R. Hay, Z. Song, S. G. Smith and P. Beak, J. Am. Chem. Soc.,

1988, 110, 8145.

13 P. Beak, S. T. Kerrick and D. J. Gallagher, J. Am. Chem. Soc., 1993,

115, 10628.

(R_a*,R*)-N,N-Diisopropyl-2-methyl-6-sec-butylbenzamide 49b

14 J. E. Resek and P. Beak, J. Am. Chem. Soc., 1994, 116, 405.

15 D. R. Anderson, N. C. Faibish and P. Beak, J. Am. Chem. Soc., 1999,

121, 7553.

sec-Butyllithium (0.62 ml, 1.3 M solution in cyclohexane, 0.808

mmol) was added dropwise to a solution of N,N-diisopropyl-2-

propylbenzamide (200 mg, 0.808 mmol) in THF (60 ml) cooled

to Ϫ78 ЊC under an atmosphere of nitrogen. The resultant

dark pink solution was stirred at Ϫ78 ЊC for 1 h before the

addition of methyl iodide (50 µl, 0.808 mmol). sec-Butyllithium

(0.62 ml, 1.3 M solution in cyclohexane, 0.808 mmol) was then

added and the yellow solution stirred at Ϫ78 ЊC for a further

1 h, followed by a second addition of methyl iodide (50 µl,

0.808 mmol). The solution was allowed to warm to 0 ЊC, water

(40 ml) was added and the THF was removed under reduced

pressure. The aqueous phase was extracted with dichloro-

methane (3 × 40 ml), the combined organic extracts were

washed with water (40 ml), dried over magnesium sulfate,

ﬁltered and the solvent was evaporated to give the amide 49b.

HPLC analysis of the crude product showed a 93 : 7 ratio of

49b : 49a.

16 J. Clayden, Synlett, 1998, 810.

17 R. D. Clark and Jahangir, J. Org. Chem., 1989, 54, 1174.

18 V. Derdau and V. Snieckus, J. Org. Chem., 2001, 66, 1992.

19 S. Thayumanavan, S. Lee, C. Liu and P. Beak, J. Am. Chem. Soc.,

1994, 116, 9755.

20 S. Thayumanavan, A. Basu and P. Beak, J. Am. Chem. Soc., 1997,

119, 8209.

21 J. Clayden, P. Johnson and J. H. Pink, J. Chem. Soc., Perkin Trans. 1,

2001, 371.

22 A. C. Regan and J. Staunton, J. Chem. Soc., Chem. Commun., 1983,

764.

23 A. C. Regan and J. Staunton, J. Chem. Soc., Chem. Commun., 1987,

520.

24 J. H. Ackerman, G. M. Laidlaw and G. A. Snyder, Tetrahedron Lett.,

1969, 3879.

25 J. H. Ackerman and G. M. Laidlaw, Tetrahedron Lett., 1969, 4487.

26 J. Hauer, E. Treml and H.-D. Lüdemann, J. Chem. Res. (M), 1982,

516.

27 P. M. van Lier, G. H. W. M. Meulendijks and H. M. Buck, Rec. Trav.

Chim. Pays-Bas, 1983, 102, 337.

Crystal data for 22a§§

28 M. A. Cuyegkeng and A. Mannschreck, Chem. Ber., 1987, 120, 803.

29 A. Ahmed, R. A. Bragg, J. Clayden, L. W. Lai, C. McCarthy,

J. H. Pink, N. Westlund and S. A. Yasin, Tetrahedron, 1998, 54,

13277.

30 P. Bowles, J. Clayden and M. Tomkinson, Tetrahedron Lett., 1995,

36, 9219.

31 P. Bowles, J. Clayden, M. Helliwell, C. McCarthy, M. Tomkinson

and N. Westlund, J. Chem. Soc., Perkin Trans. 1, 1997, 2607.

32 M. Anstiss, J. Clayden, A. Grube and L. H. Youssef, Synlett, 2002,

290.

C₂₇H₃₄N₂O, M = 402.56, monoclinic, a = 14.030(3), b =

12.956(4), c = 14.047(3) Å, β = 114.457(13)Њ, U = 2324.3(9) Å³,

T = 123(1) K, space group P2₁/n, 22259 reﬂections measured,

4734 unique (R_int= 0.0200) which were used in all calculations.

The ﬁnal wR(F ²) was 0.0995 (all data).

§§ CCDC reference numbers 177854–177856. See http://ww w .rsc.org/

suppdata/p1/b2/b200358a/ for crystallographic ﬁles in .cif or other

electronic format.

33 J. Clayden and J. H. Pink, Tetrahedron Lett., 1997, 38, 2561.

916

J. Chem. Soc., Perkin Trans. 1, 2002, 901–917

View Article Online

34 J. Clayden and J. H. Pink, Tetrahedron Lett., 1997, 38, 2565.

35 J. Clayden, M. Darbyshire, J. H. Pink, N. Westlund and F. X.

Wilson, Tetrahedron Lett., 1997, 38, 8587.

36 J. Clayden, M. Helliwell, J. H. Pink and N. Westlund, J. Am. Chem.

Soc., 2001, 123, 12449.

37 I. Fleming and P. E. J. Sanderson, Tetrahedron Lett., 1987, 28, 4229.

38 G. Jones and Y. Landais, Tetrahedron, 1996, 52, 7599.

39 J. Clayden, N. Westlund, R. L. Beddoes and M. Helliwell, J. Chem.

Soc., Perkin Trans. 1, 2000, 1351.

48 P. Beak, A. Basu, D. J. Gallagher, Y. S. Park and S. Thayumanavan,

Acc. Chem. Res., 1996, 29, 552.

49 S. Thayumanavan, Y. S. Park, P. Farid and P. Beak, Tetrahedron

Lett., 1997, 38, 5429.

50 H. E. Zimmerman, L. Singer and B. S. Thyagarajan, J. Am. Chem.

Soc., 1959, 81, 108.

51 K. Fuji and T. Kawabata, Chem. Eur. J., 1998, 373.

52 T. Kawabata, K. Yahiro and K. Fuji, J. Am. Chem. Soc., 1991, 113,

9694.

40 R. E. Gawley, Tetrahedron Lett., 1999, 40, 4297.

41 R. E. Gawley, E. Low, Q. Zhang and R. Harris, J. Am. Chem. Soc.,

2000, 122, 3344.

42 A. Carstens and D. Hoppe, Tetrahedron, 1994, 50, 6097.

43 C. Derwing and D. Hoppe, Synthesis, 1996, 149.

44 J. Clayden, P. Johnson, J. H. Pink and M. Helliwell, J. Org. Chem.,

2000, 65, 7033.

45 R. C. Fuson and J. Corse, J. Am. Chem. Soc., 1938, 2063.

46 J. Clayden, C. McCarthy and M. Helliwell, Chem. Commun., 1999,

2059.

47 P. Beak, A. Tse, J. Hawkins, C. W. Chen and S. Mills, Tetrahedron,

1983, 39, 1983.

53 T. Kawabata, T. Wirth, K. Yahiro, H. Suzuki and K. Fuji, J. Am.

Chem. Soc., 1994, 116, 10809.

54 T. Kawabata, H. Suzuki, Y. Nagae and K. Fuji, Angew. Chem.,

Int. Ed., 2000, 39, 2155.

55 B. Beagley, M. J. Betts, R. G. Pritchard, A. Schoﬁeld, R. J. Stoodley

and S. Vohra, J. Chem. Soc., Chem. Commun., 1991, 924.

56 B. Beagley, M. J. Betts, R. G. Pritchard, A. Schoﬁeld, R. J. Stoodley

and S. Vohra, J. Chem. Soc., Perkin Trans. 1, 1993, 1761.

57 M. J. Betts, R. G. Pritchard, A. Schoﬁeld, R. J. Stoodley and

S. Vohra, J. Chem. Soc., Perkin Trans. 1, 1999, 1067.

58 W. C. Still, M. Kahn and A. Mitra, J. Org. Chem., 1978, 43, 2923.

59 N. A. Leister and D. S. Tarbell, J. Org. Chem., 1958, 23, 1152.

J. Chem. Soc., Perkin Trans. 1, 2002, 901–917

917

Article Doi

Atroposelectivity in the electrophilic substitution reactions of laterally lithiated and silylated tertiary amides

DOI: 10.1039/b200358a

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