Imide-amide rearrangement of oxazaphosphorimidates: Studies towards the application to the synthesis of chiral Lewis bases

Tetrahedron 60 (2004) 11933–11949

Imide–amide rearrangement of oxazaphosphorimidates: studies

towards the application to the synthesis of chiral Lewis bases

b

a

Eurico J. Cabrita,^a,Carlos A. M. Afonso and A. Gil Santos

*

a

´ ˆ

REQUIMTE/CQFB, Dep. de Quımica, Faculdade de Ciencias e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal

b

´

CQFM, Dep. Engenharia Quımica, Instituto Superior Tecnico, 1049-001 Lisboa, Portugal

Received 23 April 2004; revised 2 August 2004; accepted 20 September 2004

Available online 19 October 2004

Abstract—The Lewis acid catalysed imide–amide rearrangement of oxazaphosphorimides to diazaphoshoramides is reported for the ﬁrst

time. In spite of the similarity to the previously reported Lewis acid catalysed imide–amide rearrangement of dioxaphosphorimides to

oxazaphosphoramides we show that this rearrangement proceeds by a different mechanism, not involving the formation of an oligomeric

intermediate. The oxazaphosphorimides are prepared in situ by the Staudinger reaction of the appropriate trivalent phosphorus compound

with an azide and after the addition of BF₃$OEt₂, undergo rearrangement to the corresponding diazaphosphoramides. We have found that the

rearrangement occurs with retention of conﬁguration at the phosphorus atom and inversion of conﬁguration at the rearranged carbon atom.

When starting from chiral 1,2-aminoalcohol, substituted at the carbon atom that undergoes rearrangement, a mixture of diastereomers is

obtained, but the diastereomeric ratio, initially obtained in the formation of the trivalent phosphorus compounds is maintained during the

whole transformation. This implies that if the rearrangement is to be used for the preparation of chiral phosphoramides with deﬁned

stereochemistry at the phosphorus atom, a high diastereoselectivity during the preparation of the trivalent phosphorus precursors should be

obtained.

1. Introduction

rearrangement of cyclic phosphorimidates. As a result, we

have reported a detailed mechanistic study of this reaction

when applied to the rearrangement of dioxa 1 to oxaza 2

cyclic compounds. An intermolecular mechanism was

found for this system and an oligomeric material 3, resulting

from a 1,4-addition-type ring-opening polymerisation

(ROP) of the cyclic phosphorimidate 1, was identiﬁed as

being a stable intermediate of the rearrangement reaction,

which occurs with retention of conﬁguration at the carbon

atom (Scheme 1).^8,9

Catalytic processes involving Lewis base activation have

been a topic of increasing interest.¹Among the Lewis bases

reported, phosphoramides have assumed a leading position.

Chiral phosphoric triamides have been successfully

employed as catalysts in a variety of transformations

leading from moderately to good enantioselectivities.^1–7In

spite of the interest that these compounds have attracted,

little or no effort has been devoted to the development of

new synthetic methodologies for their preparation. The

traditional coupling procedure between a reactive phos-

phorus reagent and a diamine ligand is still the best known

synthetic choice when it comes to the preparation of the

chiral catalysts employed in the majority of the transform-

ations reported.³However, most of these are prepared from

chiral C₂-symmetric diamines and therefore the phosphorus

atom is not chiral. Due to our interest in the development of

alternative synthetic pathways for the preparation of

interesting chiral phosphoramides, we initiated a detailed

study on the Lewis acid catalysed imide–amide

We have also established that the most probable mechanism

for the ‘oligomer–monomer’ conversion involves an

Keywords: Imide–amide rearrangement; Phosphoramides; Lewis bases;

Diazaphosphoramides.

* Corresponding author. Tel.: C351 212948300; fax: C351 212948550;

e-mail: ejc@dq.fct.unl.pt

Scheme 1.

doi:10.1016/j.tet.2004.09.079

11934

E. J. Cabrita et al. / Tetrahedron 60 (2004) 11933–11949

Scheme 2.

intramolecular nucleophilic attack of the chain oxygen to

the phosphorus atom in a SNi chain reaction with P–O bond

cleavage and formation of the cyclic product 2.⁹The aim of

the work now reported was to further explore the synthetic

possibilities of the imide–amide rearrangement as a key step

to the preparation of interesting cyclic chiral

diazaphosphoramides.

Scheme 3.

independent experiment where the thermal stability of

compound 8a was tested. Even after prolonged heating no

rearranged product could be detected by ³¹P NMR. This

result is in accordance with the mechanism proposed for the

oligomer–monomer conversion of the parent oligomer 3 and

evidences that a phosphorous bonded oxygen is needed in

the oligomeric chain for the reaction to occur.⁹As we have

shown before for dioxaphosphorimidate substracts, the

steric hindrance introduced by a methyl substituent at the

carbon atom in the ring is sufﬁcient to prevent the ROP to

occur; the same seems to be valid for oxazaphosphorimi-

dates. However, the most striking difference in the

behaviour of these two classes of compounds is that for

the oxazaphosphorimidates the conversion to a diazapho-

sphoramide can only be achieved by blocking the

polymerization mechanism. This conﬁrms the existence of

an alternate mechanism for the imide–amide rearrangement

of these compounds.

We have found that chiral diazaphosphoramides 5 can be

obtained from the imide–amide rearrangement of the

corresponding oxazaphosphorimidate precursors

4

(Scheme 2), but also that the rearrangement reaction of

this class of phosphorimides presents signiﬁcant mechan-

istic differences from the parent dioxaphosphorimidates 1,

reported previously. The scope and limitations of the

application of the imide–amide rearrangement reaction to

the preparation of chiral phosphoramides are discussed in

detail.

2. Results and discussion

The introduction of a substituent (R²) in the ring position 5

of compound 6 (Scheme 3) generates an extra asymmetric

center, therefore a mixture of diastereoisomers is obtained

(also called cis/trans when considering the relative position

of the ring substituent R²to the phosphorous exocyclic

substituent –NEt₂). In addition, the observation of the

rearrangement of compound 7b raises questions about the

enantioselectivity of the rearrangement at the substituted

carbon atom. With the aim of developing a synthetic route to

enantiopure phosphoramides, a detailed study of this

transformation was performed.

As we have mentioned before, the Lewis acid catalysed

imide–amide rearrangement of cyclic dioxaphosphorimi-

dates 1 proceeds via a two step process, involving an

oligomeric intermediate 3, with the reaction being initiated

by a ring opening polymerization (ROP) followed by the

formation of a oxazaphospholidinone in a cyclisation step

(Scheme 1). The formation of the stable phosphoryl bond

plays an important role as a driving force for this ROP and

we have shown that the presence or absence of substituents

at the carbon atoms of the dioxaphospholane ring has a

profound effect on the polymerisation. In the case of

monosubstituted compounds, the polymerisation proceeds

through the non-substituted carbon atom and, when a

di-substituted compound is used, there is no reaction even

under prolonged heating.⁹To probe the behaviour of

structurally related oxazaphosphorimidates towards the

imide–amide rearrangement, compounds 7a and 7b were

prepared and subjected to Lewis acid catalysis (Scheme 3,

Table 1). The formation of oligomer 8 was only detected for

oxazaphosphorimidate 7a, while for compound 7b the

cyclic rearranged product 9b was directly obtained. This

unexpected direct conversion of the more sterically

hindered compound 7b, to the rearranged cyclic phosphor-

amide 9b with a good yield (approx. 60%), points to a

different mechanism for the rearrangement of this class of

compounds, when compared to the parent dioxaphosphor-

imidates 1. In fact, this observation was conﬁrmed in an

2.1. Study of the enantioselectivity of the imide–amide

rearrangement of oxazaphosphorimidates

As a ﬁrst approach, the reaction of racemic 6b with

benzylazide (formation of 7b) and the subsequent evolution

Table 1. Outcome of the imide–amide rearrangement of compounds 7a,b

via Scheme 3

R

R¹

R²

Imide 7

Oligomer 8

O90%^a

Diazaphosphoramide 9

Bn

H

Me

a

b

Not detected

Not detected 59%^b

^aDetermined from the integration of the ³¹P NMR signal in the reaction

mixture.

^bGlobal yield of isolated compounds after column chromatography (40%

cis, 19% trans).

E. J. Cabrita et al. / Tetrahedron 60 (2004) 11933–11949

Table 2. ³¹P NMR chemical shifts of the species involved in the imide–

11935

amide rearrangement and diastereomeric ratios as determined from the

integration of the ³¹P NMR signals

Compound

d

³¹P (ppm)

Diastereomers (%)

cis-6b

trans-6b

140.2

137.1

26

74

cis-7b

trans-7b

26.4

26.8

27

73

cis-9b

trans-9b

27.7

28.3

68

32

Scheme 5.

of the rearrangement reaction after the addition of

BF₃$OEt₂, was followed by NMR; ³¹P NMR was used to

determine the diastereomeric ratio (dr) at every step of the

reaction. The dr initially observed for the mixture of the

trivalent phosphorus diastereomers 6b (74:26) is not altered

by the addition of the benzylazide and the formation of the

imides 7b (73:27). This result is in agreement with the fact

that the Staudinger reaction proceeds with retention of

conﬁguration at the phosphorus centre and is also an

indication of the conﬁgurational stability towards inversion,

of the initial trivalent phosphorus compounds in the reaction

conditions. The determined dr (Table 2) after the rearrange-

ment reaction is complete (68:32, after 8 h under heating at

100 8C) is almost identical to the one from the initial

trivalent phosphorus compounds.

1

conﬁguration (cis/trans) was determined by H NMR as

described before for the racemic compounds. The absolute

conﬁguration was determined by chiral HPLC, comparing

the retention times of the rearrangement products 9, starting

from racemic 6b and chiral 5R-6b, with the ones from

reference chiral compounds cis-(2R,4R)-9b and trans-

(2S,4R)-9b, prepared from a chiral diamine by an indepen-

dent reaction (Scheme 5) (Table 3).

These results are a clear indication that the rearrangement

proceeds with inversion of conﬁguration at the rearranged

carbon atom and, when analysed together with the values of

the dr’s shown before (Table 2), indicate that the reaction

occurs with retention of conﬁguration at the phosphorous

atom. Due to the fact that the dr is maintained through all the

reaction steps, starting from the trivalent phosphorus

compounds until after the imide–amide rearrangement, the

control of the stereochemistry at the phosphorous centre can

be achieved by controlling the diastereomeric ratio during

the synthesis of the trivalent phosphorus compounds.

Since there is no appreciable erosion of the dr, these results

are a strong indication of a highly enantioselective

transformation, occurring with retention or inversion of

conﬁguration at the rearranged centres (carbon and

phosphorus). The determination of the relative conﬁgur-

ation of the ﬁnal products cis-9b and trans-9b was done

1

As we have shown, the use of oxazaphosphorimidates 6a

derived from simple 1,2-aminoalcohols as substracts for the

preparation of diazaphosphoramides, is limited by the fact

that in these cases the favoured pathway for the reaction is

the formation of oligomers. Therefore, the use of chiral 1-

substituted-1,2-aminoalcohols (easily available from the

reduction of natural aminoacids) as precursors should also

be limited, since the favoured reaction pathway for the

oxazaphosphorimidates derived from these compounds

should be the oligomerization. However, in our previous

studies about the imide–amide rearrangement of dioxaphos-

phorimidates we have determined that the polymerization

reaction is very sensible to structural variations that

inﬂuence the electronic nature of the phosphorus atom or

the imidic nitrogen atom. Since the necessary condition to

obtain diazaphosphoramides via the imide–amide

rearrangement of ozaxaphosphorimidates seems to be the

blocking of the polymerization mechanism, we decided to

study the inﬂuence of the substituent nature at the

based on the comparison of the H NMR spectra of the

isolated compounds after column chromatography. Due to

the inﬂuence of the phosphoryl bond, the proton in position

4 in the cis conﬁguration is more deshielded than the one in

the trans conﬁguration and its chemical shift can be used for

the assignment of the relative conﬁguration.^10–13

In order to determine the enantioselectivity of the

rearrangement, the reaction was repeated starting with the

chiral phosphorimidates cis- and trans-(5R)-7b, derived

from the chiral (R)-aminoalcohol ((R)-N-1-benzylamino-

propan-2-ol) (Scheme 4). After rearrangement, the dia-

stereomers were isolated and separated, and their relative

Table 3. Determination of the absolute conﬁguration of the rearrangement

product cis-9b by comparison of retention times as determined by HPLC

using a chiral column for the separation of the enantiomers

Substract

t_R

ee (%)

Absolute

conﬁguration

Racemic 9b (Scheme 3)

28.54

30.53

0

(2R,4R)

(2S,4S)

Authenthic chiral cis-(2R,4R)-9b

Chiral 9b (Scheme 4)

28.80

30.87

O99

(2R,4R)

(2S,4S)

Scheme 4.

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E. J. Cabrita et al. / Tetrahedron 60 (2004) 11933–11949

endocyclic and imidic nitrogen atoms in the polymerization

of some selected oxazaphosphorimidates.

Based on these results, and in order to test the possibility

of employing ozaxaphospholidines derived from chiral

1-substituted-1,2-aminoalcohols as precursors for the prep-

aration of chiral diazaphosphoramides, compounds 11a–b

were prepared. The N-monoalkylated-1,2-aminoalcohols,

were obtained via the reductive monoalkylation of ^L-valine

and ^L-alanine with acetone.¹⁴Compounds 11a and 11b were

obtained as a mixture of diastereomers and were employed

as such for the rearrangement (Table 5). The formation of

the imides 12a and 12b was achieved, as before, via the

Staudinger reaction, in this case with phenylazide. As was

observed previously, the conversion of 11a–b to 12a–b was

complete and without appreciable erosion of the dr (at the

working temperature the oxazaphospholidines inversion

rate must be very slow when compared to the rate of the

Staudinger reaction for both isomers). After the addition of

BF₃$OEt₂the mixtures were heated to 100 8C, to promote

the imide–amide rearrangement and the reactions were

followed by ³¹P NMR in order to monitor their progress. In

both cases, as can be seen in Table 5, products 13 could be

identiﬁed and isolated, with dr’s very similar to the ones of

the initial trivalent phosphorus compounds 11. The relative

conﬁguration of the products was done as before for the

diastereomeric pair 9b.

2.2. Imide–amide rearrangement of selected

oxazaphosphorimidates

For this study the reaction of compounds 6a,c–g with

benzylazide and phenylazide, for the formation of the

corresponding imides 7, and their subsequent rearrangement

under Lewis acid catalysis, were followed by NMR at

100 8C in toluene during 8 h. Table 4 summarizes the results

obtained.

In all cases a complete conversion of the initial oxazaphos-

pholidine 6 in the corresponding oxazaphosphorimidate 7

was observed. Independently of the formation of oligomer

or diazaphosphoramide, in all cases the occurrence of

rearrangement was conﬁrmed by the inspection of the ¹³C

NMR spectra of the reaction mixtures. All the ¹³C NMR

spectra of the oxazaphosphorimidates 7a,c–g showed a

resonance around 60–63 ppm characteristic of oxygen

bonded carbon. This resonance was absent in the ¹³C

NMR spectra obtained 8 h after the addition of BF₃$OEt₂

and was replaced by a new resonance in the region of

40–50 ppm, characteristic of a nitrogen bonded carbon.

The reaction of 11a gave a much lower yield of

rearrangement but, in this case, compound 14a was also

isolated and as the major product of the reaction (64% total

yield as a mixture of diastereomers 58:42). Its formation

was detected by ³¹P NMR in the reaction mixture before

work-up. These results indicate that the imides 12a are less

prone to undergo rearrangement than 12b.

The observation of the ¹H, ¹³C and ³¹P NMR spectra of the

ﬁnal reaction mixtures allowed a ﬁrst identiﬁcation of the

products of the reactions either as diazaphosphoramides 9 or

olygomers 8, since these last show very characteristic and

broad NMR spectra. The isolation and characterization of

diazaphosphoramides 9c–e by column chromatography and

the characterization of oligomers 9a and 9e by MALDI,

conﬁrmed the assignments made in the reaction mixtures.

The results obtained with this study indicate that an alkyl

substituent at the endocyclic nitrogen atom favours the

formation of the diazaphosphoramide over the polymeriz-

ation and, as was also observed for the dioxaphosphor-

imidates, a benzyl group at the imidic nitrogen accelerates

the reaction but seems to favour the formation of olygomers.

The importance of the substituent R at the ring, for the

outcome of the reaction is also clear from the results

Table 4. Inﬂuence of the substituents at the endocyclic and imidic nitrogen atoms in the polymerization of some selected oxazaphosphorimides

Entry

R

R¹

7

8

9

Conv. time

d

³¹P

d

³¹P (%)^a

d

³¹P (%)^a

d

³¹P (%)^b

c

d

Me

Ph

Bn

18.4

17.7

20.4 (O80)

25.7 (O40)

21.5 (36)

27.3 (19)

4 h^d

40 min^d

e

f

Ph

Bn

8.8

18.0

16.1 (O90)

20.7 (O90)

12.6 (!5)

—

14.4 (3)

—

8 h

4 h^d

g

a

Bn

Ph

Bn

19.6

28.2

20.5 (O70)

25.4 (O90)

—

7 h^d

40 min^d

^{a 31}P NMR chemical shift (ppm) and conversion percentage (in brackets) determined by integration of the signals in the reaction mixture.

^{b 31}P NMR chemical shift (in ppm in CDCl₃) and yield (in brackets) after separation by column chromatography.

^cThe formation of oligomer was not detected.

^dAfter 8 h at 100 8C no signiﬁcant variation was detected by NMR.

E. J. Cabrita et al. / Tetrahedron 60 (2004) 11933–11949

11937

Table 5. Imide-amide rearrangement of selected 4-substituted oxazaphosphorimidates derived from chiral 1,2-aminoalcohols

Entry

R

11

³¹P (%)^a

12

³¹P (%)^a

13

Time (h)

d

Reaction^a, %, d ³¹P

20.7

Isolated^b, %, d ³¹P

139.0

(65)

127.9

(35)

19.9

(65)

16.1

(35)

12

cis

18

22.1

(40)

17.9

(60)

(40)

16.6

(60)

a

Me

Prⁱ

35^c

72

48

trans

142.7

(37)

126.4

(63)

19.9

(39)

16.0

(61)

21.5

(62)

17.6

(38)

32

cis

18

trans

22.9

(64)

18.6

(36)

b

81^c

^{a 31}P NMR chemical shift (ppm) and, in brackets, relative percentage of diastereomers as determined by integration of the ³¹P NMR signals in the reaction

mixture.

^bYield and relative stereochemistry of isolated products after column chromatography and ³¹P NMR chemical shift (ppm, in CDCl₃), in brackets, calculated

relative percentage of the isolated diastereomers.

^cPercentage of 13 determined by ³¹P NMR integration in the reaction mixture.

presented. In spite of the fact that the best results are

achieved with the more bulky isopropyl group, it would be

premature to withdraw more conclusions about the

structural factors that inﬂuence the rearrangement without

a more systematic study. However, the good conversion

obtained for compound 11b together with the fact that, as

was already mentioned, the dr’s of the ﬁnal products are

similar to the ones from the initial trivalent phosphorus,

indicate that this reaction may constitute an alternative way

to the preparation of chiral diazaphosphoramides with

deﬁned stereochemistry at the phosphorus atom. The factors

that control the diastereoselectivity during the formation of

these compounds are being studied.

compounds the reactivity towards polymerization could be

explained in terms of differences in the nucleophilic

character of the imidic nitrogen atom and by the steric

hindrance of the ring alkoxide carbon atom.⁹The same

should be true for the oxazaphosphorimidates when

concerning the polymerization reaction only. Nevertheless

these effects do not explain the observed direct conversion

to diazaphosphoramide and suggest that a different type of

reaction might be involved. When a nitrogen atom

substitutes an oxygen atom on the dioxophosphorimidate

ring, to obtain an oxazaphosphorimidate, there are serious

repercussions in the observed reactivity (Tables 4 and 5).

The introduction of the nitrogen atom in the cycle has a

direct inﬂuence over the electronic density at the phos-

phorus atom. This will indirectly affect both the nucleo-

philicity of the uncomplexed oxazaphosphorimidate imidic

nitrogen atom and the electrophilicity of the ring carbon

atom on the BF₃adduct. For the oxazaphosphorimides the

electrophilicity of the carbon atom might be an important

factor to consider since it will be more directly affected by

different substituents in the ring nitrogen atom. However, it

seems clear that for compound 7b the direct conversion to

9b is depending on the blocking of the polymerization

mechanism due to the steric hindrance of the ring methyl

substituent. According to this the equivalent non-substituted

compound 7a is converted almost quantitatively to oligomer

8a (Table 4, entry a).

2.3. Mechanistic considerations

As was already mentioned, the most striking difference in

the behaviour of the oxazaphosphorimidates 7 when

compared to the parent dioxaphosphorimidates 1 is that, in

contrary to these last, the imide–amide rearrangement of the

oxazaphosphorimidates 7 does not involve a ROP and an

oligomeric intermediate. For compounds of type 7 the

conversion to a diazaphosphoramide can only be achieved

by blocking the polymerization mechanism, either by

increasing the steric hindrance at the electrophilic carbon

atom, as in 7b, or by introducing suitable substituents at the

endocyclic and imidic nitrogen atoms, as in 7c,d and 12.

2.3.1. Polymerization versus diazaphosphoramide for-

mation. The formation of oligomers 8 suggests that the

reactivity of oxazaphosphorimidates 7 depends, at least to a

certain extent, on the same activation requisites as those

found for dioxophosphorimidates 1, namely a ﬁne balance

between the nucleophilicity of the imidic nitrogen atom and

the electrophilicity of the ring carbon atom, for the free and

Lewis acid complexed imides, respectively. We have shown

before that, for dioxophosphorimidates 1, the BF₃mediated

electrophilic activation of the ring carbon atom is almost

independent on the imidic nitrogen substituent. For these

In order to get some indication of the reaction pathway for

the formation of the diazaphosphoramides we started by

carefully studying the conversion of the methyl substituted

compound 7b.

2.3.2. Direct conversion. The SNi mechanism hypothesis.

The hypothesis of an intramolecular substitution was

examined and two possibilities for the intramolecular

reaction mechanism were considered (via carbocation or

via aziridinium) (Scheme 6). Nevertheless, both had to be

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E. J. Cabrita et al. / Tetrahedron 60 (2004) 11933–11949

thus excluding this path.

2.3.3. Mechanism proposal for the imide–amide

Scheme 6.

rearrangement of oxazaphosphorimidates. Once

excluded the intramolecular pathway, we turned our

attention to a bimolecular mechanism. For the construction

of a plausible proposal for a bimolecular mechanism, a

crucial experimental observation drew our attention to a

very important aspect of oxazaphosphorimides reactivity.

When attempting to perform the imide–amide rearrange-

ment of 19 we obtained, in addition to the corresponding

rearranged product 21, the dimeric diazadiphosphitidine

20.¹⁸

disregarded because, as we will show, neither of them could

explain all the experimental data.

Both mechanisms have as driving force the formation of the

stable phosphoryl bond and are analogous to the well known

dealkylation reaction of phosphate esters that proceeds

usually by a nucleophilic attack to the alkoxide carbon

atom.¹⁵Also, the intramolecular dealkylation of phosphate

esters, driven by nitrogen, sulfur or oxygen nucleophiles, is

a very well known process that may lead to the degradation

of the initial phosphate ester or to its rearrangement

product.¹⁵After a close examination of the stereochemical

outcome of the reaction for each one of the considered

mechanisms a few directed experiments allowed us to test

their validity. The mechanism involving a carbocation

intermediate was the ﬁrst to be disregarded based on two

experimental observations: (1) the high enantioselective

reaction of (5R)-7b proceeds with inversion of conﬁguration

at the carbon atom. If a carbocation was involved we would

expect to observe at least some racemization; (2) we tried to

perform the reaction with the ephedrine derived compounds

15a and 15b, that would stabilize the formation of a

benzylic carbocation intermediate. No product was

detected in these cases.¹⁶The mechanism involving an

aziridinium intermediate was also disregarded based on the

stereochemical analysis of the products and on some more

additional experimental results. In fact the preferential

attack for the aziridinium ring opening (attack to the less

hindered carbon atom path (b) in Scheme 6) leads to

retention of conﬁguration at the carbon atom. This is the

opposite to the experimentally observed result. However,

and since the attack to the more hindered carbon atom (path

(a) in Scheme 6) could explain the observed stereo-

chemistry, we performed an additional experiment to test

this hypothesis. As can be seen in Scheme 6, if the reaction

is performed with an azide with a group R²different from

the group R¹at the ring nitrogen, then the products from the

two ring opening possibilities differ not only in the

stereochemistry at the carbon atom but also in the ﬁnal

localization of R¹and R². When the reaction was performed

with compound 16, product 17 was obtained as a mixture of

diastereoisomers and no traces of 18 could be detected,¹⁷

The dimerization of imino derivatives of ﬁve-member ring

phosphorous heterocycles has been reported previously.^19–21

According to the literature, the dimerization is highly

dependent on the phosphorus substituents nature, being

favoured by electronegative substituents such as ﬂuorine or

chlorine, that lead to a higher contribution of the betain

(P^C–N^K) structure, thus activating the molecule for the

dimerization. The reduction of the ring strain when going

from 19 to 20, due to the different geometry of the

phosphorus atom in the dimeric form, was also pointed out

as a factor contributing to this process. The dependency of

the dimeric form stabilization on the substituents in the

phosphorus atom, can originate equilibrium mixtures of the

two forms, as was also described. However, it has also been

reported that for compounds 7c and 7e the formation of

dimers was not detected.²⁰This information together with

all the observed experimental facts lead us to propose a

bimolecular mechanism, based on an initial nucleophilic

attack of the imidic nitrogen atom of a free oxazaphos-

phorimidate to the phosphorus atom of a BF₃–oxazaphos-

phorimidate adduct (Scheme 7).

The formation of the BF₃–oxazaphosphorimidate adduct

should increase the electrophilicity both of the phosphorus

atom as well as the ring alkoxide carbon atom. According to

the results in Table 4, there is a strong change in the reactivity

E. J. Cabrita et al. / Tetrahedron 60 (2004) 11933–11949

11939

phosphorimide 12 during work-up. This compound can be

obtained by decomposition of the initial dimer in an

alternative path to B in Scheme 7. If the oxygen atom is not

in a suitable position for the nucleophilic attack to the

phosphorus atom, an attack from the bridged nitrogen atom to

the alkoxide carbon may occur, leading to the decomposition

of the dimer and the formation of 14a.

3. Conclusions

We have shown that the Lewis acid catalysed imide–amide

rearrangement of oxazaphosphorimidates to diazaphosphor-

amides is possible but, also, that the rearrangement reaction

of this class of phosphorimidates presents signiﬁcant

mechanistic differences from the parent dioxaphosphorimi-

dates, previously reported. In contrast to the mechanism

proposed for these last compounds, the imide–amide

rearrangement of oxazaphosphorimidates to diazaphosphor-

amides proceeds without the involvement of an oligomeric

intermediate. We have also determined that the reaction

occurs with retention of conﬁguration at the phosphorus

atom and inversion of conﬁguration at the rearranged carbon

atom, therefore, when applied to 4 or 5-substituted

oxazaphosphorimidates, for the formation of 4 or

5-substituted diazaphosphoramides can constitute a possible

route to the preparation of chiral diazaphosphoramides with

deﬁned stereochemistry at the phosphorus atom. Based in a

number of experimental observations, we have proposed a

mechanism for the imide–amide rearrangement of

oxazaphosphorimidates that involves the formation of a

dimer, through the nucleophilic attack of the imidic nitrogen

of a free phosphorimidate to the phosphorus atom of a Lewis

acid activated molecule. This dimer, upon internal

rearrangement followed by two SNi reactions at the carbon

atoms bearing oxygen, leads to the formation of the

phosphoryl rearranged cyclic products with the correct

stereochemistry. Overall, the possibility of an effective

stereocontrol at the phosphorus atom is depending on the

degree of stereocontrol during the preparation of the

trivalent phosphorus precursors.

Scheme 7.

when the benzyl or the phenyl substituent at the ring nitrogen

(R¹in Scheme 7) is replaced with an alkyl group. The

difference in reactivity can be explained if we consider that it

depends on the relative activation of the phosphorus and the

carbon atoms for a nucleophilic attack. The presence of a

benzyl or a phenyl substituent at the ring nitrogen results in a

stronger activation of the ring carbon atom, thus favoring the

polymerization mechanism, while the presence of an alkyl

group results in a greater electrophilic activation of the

phosphorus atom. The ﬁrst nucleophilic attack of the imidic

nitrogen atom of a free oxazaphosphorimidate molecule to

the phosphorus atom of a BF₃–oxazaphosphorimidate adduct

(A, Scheme 7) is a process analogous to the dimerization

referred previously.^19–21In this case, and in contrast to the

dimerization of 19, we predict the migration of the oxygen

atom of the attacked molecule instead of the imidic nitrogen,

since this last is blocked by the BF₃. This can explain why the

addition of BF₃to a partially dimerized mixture of 19 and 20

leads to the formation of 21 stopping the formation of more

20. The following two steps (B, C) can be considered as a

substitution at the phosphorus atom, in which a bridged

intermediate may be involved. The last two steps (D, E) lead

to the ﬁnal products, being the driving force the formation of

the phosphoryl bond. Our proposal explains the observed

inversion at the rearranged carbon center and is also

consistent with other experimental observations, as is the

partial formation of compound 14a in the reaction mixture,

by an alternative mechanism to the hydrolysis of the initial

4. Experimental

4.1. General

All dried solvents were puriﬁed/dried before use, according

to literature procedures.²²Thin layer chromatography

(TLC) was performed on aluminium sheets coated with

silica gel 60 F₂₅₄(Merck 5554). Column chromatography

was carried out on silica gel 60 (MN 815381, 230–400

Mesh). Melting points were determined on an Eletrothermal

Mod. IA 6304 capillary melting point apparatus and are

uncorrected. Observed rotations at the Na-D line were

measured at 25 8C using an Optical Activity polarimeter

Mod. AA-1000. Low- and high-resolution mass spectra

(MS, HRMS) were obtained on a Fisons Autospec or Kratos

apparatus. ¹H, ¹³C and ³¹P NMR spectra were recorded on a

Bruker ARX400 spectrometer. HPLC analyses were

performed using Merck and Hitachi components L-600A,

L-4250, T-6300, D-6000 using Chiralcel OD column

(0.46 cm, 25 cm) at 25 8C. The IR spectra were recorded

11940

E. J. Cabrita et al. / Tetrahedron 60 (2004) 11933–11949

on a Unicam ATI Mattson Genesis Series FTIR as a ﬁlm,

obtained by evaporation of dichloromethane solutions on

NaCl plates.

–N(CH₂CH₃)₂), 2.76–2.70 (m, 1H, –OCH₂CH₂N–), 2.54–

2.46 (m, 1H, –OCH₂CH₂N), 0.95 (t, J(H,H)Z7.0 Hz, 6H,

–N(CH₂CH₃)₂); ¹³C NMR (100 MHz, tol-d₈, 25 8C, tol-d₈):

dZ140.6 (d, ³J(P,C)Z6.9 Hz, –C–, Ar), 128.5 (–CH–, Ar),

128.3 (d, ⁴J(P,C)Z1.6 Hz, –CH–, o-Ar,), 127.1 (–CH–, Ar),

67.0 (d, ²J(P,C)Z12.2 Hz, –OCH₂CH₂N–), 50.7

(d, ²J(P,C)Z26.5 Hz, –NCH₂Ph), 47.9 (–OCH₂CH₂N–),

38.7 (d, ²J(P,C)Z19.7 Hz, –N(CH₂CH₃)₂), 15.4

The following compounds were prepared, according to

general reported procedures: dichloro diethylphos-

phoramidite,²³diethylphosphoroamidous dichloride,²⁴

benzylazide,²⁵phenylazide.^26,27

3

(d, J(P,C)Z3.5 Hz, –N(CH₂CH₃)₂); ³¹P NMR (160 MHz,

4.2. Preparation of aminoalcohols

tol-d₈, 25 8C, H₃PO₄external): dZ135.4.

4.2.1. 1-N-Benzylamino-2-propanol and (R)-1-N-benzyl-

amino-2-propanol. The title compounds were prepared

from the corresponding aminoalcohol according to the

general procedure for the monobenzylation of primary

amines.²⁸

4.3.2. 3-N-Benzyl-2-diethylamino-5-methyl-1,3,2-oxaza-

phospholidine 6b. The general procedure was followed

using

dichlorodiethylphosphoramidite

(10.0 ml,

68.7 mmol), 1-N-benzylamino-2-propanol (11.36 g,

68.7 mmol) and dry triethylamine (19.2 ml, 137.4 mmol).

Compound 6b was obtained as a slightly viscous colourless

liquid (13.34 g, 73%) as a mixture of cis and trans

4.2.2. (1R)-1-N,-2-N⁰-Dibenzylpropanodiamine 10. The

title compound was prepared from the corresponding

aminoalcohol according to the general procedure for the

monobenzylation of primary amines.²⁸

1

diastereomers (cis/trans, 26:74, as determined by H and

1

³¹P NMR). Bp 110 8C (0.1 mmHg); H NMR (400 MHz,

CDCl₃, 25 8C, TMS): dZ7.27–7.24 (m, 3H, –CH–, Ar, cis

and trans), 7.19–7.18 (m, 2H, –CH–, Ar, cis and trans), 4.45

(m, J(H,H)Z8.5, 6.0, 5.4 Hz, J(P,H)Z1.1 Hz, 1H, –NCH₂-

CH(CH₃)O–, trans), 4.23 (m, J(H,H)Z8.7, 6.7, 6.0 Hz,

J(P,H)Z2.7 Hz, 1H –NCH₂CH(CH₃)O–, cis), 4.125 (dd,

J(H,H)Z14.8 Hz, J(P,H)Z8.3 Hz, 1H, –CH₂Ph, cis), 4.02

(dd, J(H,H)Z14.6 Hz, J(P,H)Z8.5 Hz, 1H, –CH₂Ph,

trans), 3.92 (dd, J(H,H)Z14.6 Hz, J(P,H)Z8.5 Hz, 1H,

–CH₂Ph, trans), 3.687 (dd, J(H,H)Z14.8 Hz, J(P,H)Z

3.8 Hz, 1H, –CH₂Ph, cis), 3.17–3.06 (m, 1H, –NCH₂

CH(CH₃)O trans and 2H, –NCH₂CH₃, trans and cis),

3.04–2.91 (m, 2H, –NCH₂CH₃, trans e cis), 2.82 (m,

J(H,H)Z6.7, 8.7 Hz, J(P,H)Z15.1 Hz, 1H, –NCH₂

CH(CH₃)O–, cis), 2.67 (td, J(H,H)Z8.7, 8.7 Hz, J(P,H)Z

1.0 Hz, 1H, –NCH₂CH(CH₃)O–, cis), 2.36 (td, J(H,H)Z

8.5, 8.5 Hz, J(P,H)Z3.1 Hz, 1H, –NCH₂CH(CH₃)O–,

trans), 1.17 (d, J(H,H)Z6.0 Hz, 3H, –NCH₂CH(CH₃)O–,

trans), 1.00 (t, J(H,H)Z6.7 Hz, 6H, 2!–NCH₂CH₃, cis and

trans); ¹³C NMR (100 MHz, CDCl₃, 25 8C, CDCl₃): dZ

4.2.3. (S)-N-Isopropylalaninol. The title compound was

prepared from (S)-alanine following general reported

procedure.¹⁴Mp 28–29 8C (Et₂O), lit.¹⁴viscous oil;

[a]²_D⁵ZC31.3 (c 1.04, MeOH), lit.¹⁴C34.6 (c 1, MeOH).

4.2.4. (S)-N-Isopropylvalinol. (S)-N-isopropylvalinol was

prepared from (S)-valine following general reported

procedure.¹⁴[a]_D²⁵ZK3.5 (c 1.04, EtOH), lit.¹⁴K3.3

(c 1, EtOH).

4.3. Preparation of 1,3,2-oxazaphospholidines

General procedure for the coupling of dichloro diethylphos-

phoramidite with aminoalcohols. To a stirred, ice-cold

solution of dichloro diethylphosphoramidite in dry diethyl

ether, under argon atmosphere, a solution of the appropriate

dry aminoalcohol (1.0 equiv) and dry triethylamine

(2.0 equiv) in dry diethyl ether was added dropwise. The

addition was controlled in order to avoid that the

temperature of the reaction would raise beyond 10 8C.

After the addition was complete, the mixture was allowed to

stir during 4 h at room temperature. The amine salts were

then separated by ﬁltration under argon atmosphere and

washed repeatedly with dry ethylic ether. The liquid

fractions were combined and the solvent removed by

distillation under argon atmosphere. The residue obtained

was puriﬁed by low pressure distillation.

2

140.0 (d, J(P,C)Z5.0 Hz, –C–, Ar), 128.19 (–CH–, Ar),

127.96 (–CH–, Ar), 127.7 (–CH–, Ar), 126.7 (–CH–, Ar),

2

74.9 (d, J(P,C)Z11.4 Hz, –NCH₂CH(CH₃)O–, cis), 74.1

(d, ²J(P,C)Z11.2 Hz, –NCH₂CH(CH₃)O–, trans), 54.8

(–NCH₂CH(CH₃)O–, trans), 53.25 (d, ²J(P,C)Z2.6 Hz,

–NCH₂CH(CH₃)O–, cis), 50.5 (d, ²J(P,C)Z26.6 Hz,

2

–CH₂Ph, trans), 49.2 (d, J(P,C)Z19.5 Hz, –CH₂Ph, cis),

38.7 (d, ²J(P,C)Z19.8 Hz, –NCH₂CH₃, cis), 38.3 (d,

3

²J(P,C)Z19.4 Hz, –NCH₂CH₃, trans), 21.0 (d, J(P,C)Z

4.0 Hz, –NCH₂CH(CH₃)O–, trans), 20.0 (–NCH₂CH(CH₃)

3

O–, cis), 15.3 (d, J(P,C)Z2.6 Hz, –NCH₂CH₃, cis), 15.2

4.3.1. 3-N-Benzyl-2-diethylamino-1,3,2-oxazaphospholi-

dine 6a. The general procedure was followed using

dichlorodiethylphosphoramidite (1.04 ml, 6.9 mmol),

2-N-benzylaminoethanol (1.03 g, 6.9 mmol) and dry

triethylamine (1.92 ml, 13.8 mmol). Compound 6a was

obtained as slightly yellow viscous liquid (893 mg, 54%).

(d, ³J(P,C)Z2.6 Hz, –NCH₂CH₃, trans); ³¹P NMR

(160 MHz, CDCl₃, 25 8C, H₃PO₄external): dZ141.6

(cis), 136.2 (trans).

4.3.3. (2RS,5R)-3-N-Benzyl-2-diethylamino-5-methyl-

1,3,2-oxazaphospholidine (5R)-6b. The general procedure

was followed using dichlorodiethylphosphoramidite

(903.0 ml, 6.21 mmol), (R)-1-N-benzylamino-2-propanol

(1.026 g, 6.21 mmol) and dry triethylamine (1.73 ml,

12.42 mmol). Compound (5R)-6b was obtained as a slightly

viscous colourless liquid (900 mg, 55%) as a mixture of cis

and trans diastereomers (cis/trans, 26:74, as determined by

1

Bp 150 8C (0.1 mmHg, KughelRohr); H NMR (400 MHz,

tol-d₈, 25 8C, tol): dZ7.19 (t, J(H,H)Z7.2 Hz, 2H, –CH–,

m-Ar), 7.15 (d, J(H,H)Z7.7 Hz, 2H, –CH–, o-Ar), 7.07

(t, J(H,H)Z7.1 Hz, 1H, –CH–, p-Ar), 3.94 (q, JZ8.0 Hz,

1H, –OCH₂CH₂N–), 3.91 (d, J(H,H)Z7.3 Hz, 2H,

–NCH₂Ph), 3.74 (qd, JZ8.7, 4.0 Hz, 1H, –OCH₂CH₂N–),

3.09–2.98 (m, 2H, –N(CH₂CH₃)₂), 2.93 (sxt, JZ7.1 Hz, 2H,

E. J. Cabrita et al. / Tetrahedron 60 (2004) 11933–11949

11941

¹H and ³¹P NMR). Spectroscopic data identical to

compound 6b.

3.21–3.10 (m, 1H, –OCH₂CH(R)NCH(CH₃)₂, cis and 2H,

–N(CH₂CH₃)₂, cis), 3.08–2.95 (m, 2H, –N(CH₂CH₃)₂, cis

and 1H, –OCH₂CH(R)NCH(CH₃)₂, cis), 2.91–2.76 (m, 4H,

–N(CH₂CH₃)₂, trans), 1.26 (d, J(H,H)Z6.7 Hz, 3H,

–NCH(CH₃)₂, trans), 1.15 (d, J(H,H)Z7.0 Hz, 3H, –NCH

(CH₃)₂, cis), 1.12 (d, J(H,H)Z6.4 Hz, 3H, –NCH(CH₃)₂,

cis), 1.04 (d, J(H,H)Z6.5 Hz, 3H, –NCH(CH₃)₂, trans),

0.97 (t, J(H,H)Z6.4 Hz, 6H, –N(CH₂CH₃)₂, cis), 0.90

(t, J(H,H)Z7.2 Hz, 6H, –N(CH₂CH₃)₂, trans), 0.88 (t,

J(H,H)Z5.8 Hz, 3H, –CH₃, cis), 0.83 (d, J(H,H)Z6.1 Hz,

3H, –CH₃, trans); ¹³C NMR (100 MHz, tol-d₈, 25 8C, tol-

4.3.4. 2-Diethylamino-3-N-methyl-1,3,2-oxazaphospholi-

dine 6c. The general procedure was followed using

dichlorodiethylphosphoramidite (3.87 ml, 26.6 mmol),

2-N-methylaminoethanol (2.00 g, 26.6 mmol) and dry

triethylamine (7.42 ml, 53.2 mmol). Compound 6c was

obtained as a slightly viscous colourless liquid (2.35 g,

50%). Bp 150 8C (5 mmHg, KughelRohr); ¹H NMR

(400 MHz, CDCl₃, 25 8C, TMS): dZ4.20–4.13 (m, 1H,

one of –OCH₂CH₂N–), 4.00–3.94 (m, 1H, one of –OCH₂

CH₂N–), 3.15–3.11 (m, 1H, one of –OCH₂CH₂N–), 3.02–

2.90 (m, 4H, –N(CH₂CH₃)₂), 2.88–2.83 (m, 1H, one of

–OCH₂CH₂N–), 2.56 (d, J(P,H)Z11.2 Hz, 1.5H, –NCH₃),

2.54 (d, J(P,H)Z11.2 Hz, 1.5H, –NCH₃), 0.97 (t, J(H,H)Z

6.9 Hz, 3H, –N(CH₂CH₃)₂), 0.96 ((t, J(H,H)Z6.9 Hz, 3H,

–N(CH₂CH₃)₂); ¹³C NMR (100 MHz, CDCl₃, 25 8C,

CDCl₃): dZ66.8 (d, ²J(P,C)Z11.1 Hz, –OCH₂CH₂N–),

50.4 (–OCH₂CH₂N–), 38.3 (d, ²J(P,C)Z19.4 Hz,

2

d₈): d Z74.0 (d, J(P,C)Z9.8 Hz, –OCH₂CH(R)N–, cis),

2

72.8 (d, J(P,C)Z10.0 Hz, –OCH₂CH(R)N–, trans), 52.3

2

(–OCH₂CH(R)N–, cis), 51.7 (d, J(P,C)Z3.6 Hz, –OCH₂

CH(R)N–, trans), 45.8 (d, ²J(P,C)Z25.0 Hz, –OCH₂CH(R)

NCH(CH₃)₂, cis), 44.7 (d, J(P,C)Z15.5 Hz, –OCH₂CH(R)

NCH(CH₃)₂, trans), 38.5 (d, ²J(P,C)Z20.5 Hz,

–N(CH₂CH₃)₂, cis), 38.0 (d, ²J(P,C)Z6.5 Hz, –N(CH₂C

H₃)₂, trans), 23.6 (d, ³J(P,C)Z11.0 Hz, –NCH(CH₃)₂, cis),

23.5 (d, ³J(P,C)Z2.7 Hz, –NCH(CH₃)₂, trans), 23.2

(d, ³J(P,C)Z13.9 Hz, –NCH(CH₃)₂, trans), 20.8 (d,

³J(P,C)Z6.9 Hz, –NCH(CH₃)₂, cis) 19.5 (d, ³J(P,C)Z

2.6 Hz, –OCH₂CH(CH₃)N–, trans), 16.6 (d, ³J(P,C)Z

2

–N(CH₂CH₃)₂), 32.1 (d, J(P,C)Z25.0 Hz, –NCH₃), 15.2

(–N(CH₂CH₃)₂); ³¹P NMR (160 MHz, CDCl₃, 25 8C,

H₃PO₄external): dZ133.6.

3

3.0 Hz, –OCH₂CH(CH₃)N–, cis) 15.2 (d, J(P,C)Z3.7 Hz,

–N(CH₂CH₃)₂, cis), 15.0 (d, ³J(P,C)Z2.8 Hz,

–N(CH₂CH₃)₂, cis), 14.6 (–NCH₂CH₃, trans), 14.4

(d, ³J(P,C)Z2.0 Hz, –NCH₂CH₃, trans); ³¹P NMR

(160 MHz, tol-d₈, 25 8C, H₃PO₄external): dZ139.0 (cis),

127.9 (trans).

4.3.5. 2-Diethylamino-3-N-phenyl-1,3,2-oxazaphospholi-

dine 6e. The general procedure was followed using

dichlorodiethylphosphoramidite (1.1 ml, 7.3 mmol), 2-phe-

nylaminoethanol (1.03 g, 7.3 mmol) and dry triethylamine

(2.9 ml, 14.6 mmol). Compound 6e was obtained as a

slightly yellow viscous liquid (971 mg, 56%). Bp 150 8C

(0.1 mmHg, KughelRohr); ¹H NMR (400 MHz, tol-d₈,

25 8C, tol): dZ7.14 (t, J(H,H)Z7.7 Hz, 2H, –CH–, Ar,

meta), 6.86 (d, J(H,H)Z8.1 Hz, 2H, –C-H–, o-Ar), 6.76

(t, J(H,H)Z7.3 Hz, 1H, –CH–, p-Ar,), 3.99 (q, J(H,H)Z9.2,

9.2, 6.8 Hz, ³J(P,H)Z1.5 Hz, 1H, –OCH₂CH₂N–), 3.82 (qd,

J(H,H)Z9.2, 7.8, 3.3 Hz, ³J(P,H)Z9.1 Hz, 1H, –OCH₂

CH₂N–), 3.05–2.99 (m, J(H,H)Z9.0, 6.8, 3.3 Hz, ³J(P,H)Z

3.2 Hz, 1H, –OCH₂CH₂N–), 2.95–2.84 (m, 4H,

–N(CH₂CH₃)₂), 2.82 (qd, J(H,H)Z9.2, 9.0, 7.8 Hz,

³J(P,H)Z3.4 Hz, 1H, –OCH₂CH₂N–), 0.85 (t, J(H,H)Z

7.1 Hz, 6H, –N(CH₂CH₃)₂); ¹³C NMR (100 MHz, tol-d₈,

4.3.7. (2RS,4S)-2-Diethylamino-3-N-, 4-di-isopropyl-

1,3,2-oxazaphospholidine 11b. The general procedure

was followed using dichlorodiethylphosphoramidite

(2.0 ml, 13.8 mmol), (S)-N-isopropylvalinol (2.0 g,

13.8 mmol) and dry triethylamine (3.84 ml, 27.6 mmol).

Compound 11b was obtained as a slightly viscous colour-

less liquid (1.91 mg, 56%) as a mixture of cis and trans

diastereomers (cis/trans, 37:63, as determined by ¹H and ³¹

P

NMR). Bp 140 8C (0.1 mmHg, KughelRohr); ¹H NMR

(400 MHz, tol-d₈, 25 8C, tol): dZ3.86 (dd, J(H,H)Z8.8,

6.9 Hz, 1H, –OCH₂CH(R)N–, trans), 3.83–3.77 (m, 2H,

–OCH₂CH(R)N–, cis), 3.76–3.70 (m, 1H, –OCH₂CH(R)N–,

trans), 3.29–3.15 (m, 1H, –OCH₂CH(R)N–, trans and 1H,

–NCH(CH₃)₂, trans and 2H, –N(CH₂CH₃)₂, cis), 3.08–2.96

(m, 1H, –OCH₂CH(R)N–, cis and 1H, –NCH(CH₃)₂, cisC

2H, –N(CH₂CH₃)₂, trans), 2.88–2.80 (m, J(H,H)Z7.0 Hz,

2H, –N(CH₂CH₃)₂, trans), 1.82–1.71 (m, 1H, –CH(CH₃)₂,

cis and 1H, –CH(CH₃)₂, trans), 1.30 (d, J(H,H)Z6.7 Hz,

3H, –NCH(CH₃)₂, trans), 1.21 (d, J(H,H)Z7.0 Hz, 3H,

–NCH(CH₃)₂, cis), 1.13 (d, J(H,H)Z6.3 Hz, 3H, –NCH

(CH₃)₂, cis), 1.05 (d, J(H,H)Z6.4 Hz, 3H, –NCH(CH₃)₂,

trans), 0.98 (t, J(H,H)Z7.2 Hz, 6H, –N(CH₂CH₃)₂, cis),

0.96 (t, J(H,H)Z7.1 Hz, 6H, –N(CH₂CH₃)₂, trans), 0.82 (d,

J(H,H)Z7.0 Hz, 3H, –CH(CH₃)₂, cis), 0.85 (d, J(H,H)Z

7.0 Hz, 3H, –CH(CH₃)₂, trans), 0. 72 (d, J(H,H)Z7.0 Hz,

3H, –CH(CH₃)₂, cis), 0.64 (d, J(H,H)Z7.0 Hz, 3H, –CH

(CH₃)₂, trans); ¹³C NMR (100 MHz, tol-d₈, 25 8C, tol-d₈):

2

25 8C, tol-d₈): dZ145.8 (d, J(P,C)Z13.8 Hz, –C–, Ar),

129.2 (–CH–, m-Ar,), 118.8 (–CH–, p-Ar,), 115.2

(d, ³J(P,C)Z11.0 Hz, –CH–, o-Ar,), 66.6 (d, ²J(P,C)Z

11.3 Hz, –OCH₂CH₂N–), 45.3 (d, ²J(P,C)Z2.7 Hz, –OCH₂

2

CH₂N–), 39.1 (d, J(P,C)Z19.5 Hz, –N(CH₂CH₃)₂), 18.9

3

(d, J(P,C)Z3.4 Hz, –N(CH₂CH₃)₂); ³¹P NMR (160 MHz,

tol-d₈, 25 8C, H₃PO₄external): dZ121.3.

4.3.6. (2RS,4S)-2-Diethylamino-3-N-isopropyl-4-methyl-

1,3,2-oxazaphospholidine 11a. The general procedure was

followed using dichloro diethylphosphoramidite (534.0 ml,

3.67 mmol),

(S)-N-isopropylalaninol

(430.0 mg,

3.67 mmol) and dry triethylamine (1.02 ml, 7.34 mmol).

Compound 11a was obtained as a slightly viscous colourless

liquid (346 mg, 43%) as a mixture of cis and trans

1

diastereomers (cis/trans, 65:35, as determined by H and

³¹P NMR). Bp 120 8C (0.05 mmHg, KughelRohr); ¹H NMR

(400 MHz, tol-d₈, 25 8C, tol): dZ4.02 (dd, JZ6.4, 7.8 Hz,

1H, –OCH₂CH(R)N–, trans), 3.89–3.83 (m, 1H, –OCH₂

CH(R)N–, cis), 3.54 (dd, JZ9.0, 9.8 Hz, 1H, –OCH₂

CH(R)N–, cis), 3.78–3.38 (m, 1H, –OCH₂CH(R)N–, trans),

3.33–3.24 (m, 2H, –OCH₂CH(R)NCH(CH₃)₂, trans),

dZ67.5 (d, J(P,C)Z9.7 Hz, –OCH₂CH(R)N–, cis), 65.7

2

(d, ²J(P,C)Z11.1 Hz, –OCH₂CH(R)N–, trans), 61.6 (d,

²J(P,C)Z4.8 Hz, –OCH₂CH(R)N–, trans), 61.3 (–OCH2

2

CH(R)N–, cis), 46.1 (d, J(P,C)Z24.2 Hz, –NCH(CH₃)₂,

cis), 44.5 (d, ²J(P,C)Z13.7 Hz, –NCH(CH₃)₂, trans),

38.6 (–N(CH₂CH₃)₂, cis), 38.3 (d, ²J(P,C)Z20.5 Hz,

11942

E. J. Cabrita et al. / Tetrahedron 60 (2004) 11933–11949

–N(CH₂CH₃)₂, trans), 28.7 (d, ³J(P,C)Z2.6 Hz,

–N(1)CH₂Ph), 3.85 (dd, ³J(P,H)Z8.5 Hz, J(H,H)Z

15.8 Hz, 1H, one of –N(1)CH₂Ph), 3.35–3.26 (m, JZ8.4,

5.1 Hz, J(H,H)Z6.2, 5.9, 1H, –NCH(CH₃)CH₂N–), 3.14–

2.98 (m, 5H, one of –NCH(CH₃)CH₂N– and

–N(CH₂CH₃)₂), 2.55 (ddd, 1H, J(P,H)Z5.9 Hz, J(H,H)Z

8.6, 5.9 Hz, one of –NCH(CH₃)CH₂N), 1.04 (t, J(H,H)Z

7.0 Hz, 6H, –N(CH₂CH₃)₂), 0.93 (d, J(H,H)Z6.2 Hz, 3H,

–NCH(CH₃)CH₂N); ¹³C NMR (100 MHz, CDCl₃, 25 8C,

CDCl₃): dZ128.6 (–CH–, Ar), 128.4 (–CH–, Ar), 128.3

(–CH, Ar), 127.8 (–CH–, Ar), 127.1 (–CH–, Ar), 126.9

(–CH–, Ar), 51.9 (d, ²J(P,C)Z11.7 Hz, –NCH(CH₃)

3

–CH(CH₃)₂, trans), 27.9 (d, J(P,C)Z1.5 Hz, –CH(CH₃)₂,

cis), 24.0 (d, ³J(P,C)Z13.2 Hz, –NCH(CH₃)₂, cis), 23.1 (d,

3

³J(P,C)Z2.0 Hz, –NCH(CH₃)₂, trans), 23.0 (d, J(P,C)Z

14.0 Hz, –NCH(CH₃)₂, trans), 19.7 (–CH(CH₃)₂, cis), 19.3

3

(d, J(P,C)Z8.3 Hz, –NCH(CH₃)₂, cis), 18.7 (–CH(CH₃)₂,

3

trans), 15.55 (–CH(CH₃)₂, cis), 15.2 (d, J(P,C)Z3.6 Hz,

–N(CH₂CH₃)₂, trans), 15.1 (d, ³J(P,C)Z2.7 Hz,

–NCH(CH₃)₂, trans), 15.00 (d, ³J(P,C)Z2.8 Hz,

–N(CH₂CH₃)₂, cis); ³¹P NMR (160 MHz, tol-d₈, 25 8C,

H₃PO₄external): dZ142.7 (cis), 126.4 (trans).

2

CH₂N–), 51.6 (d, J(P,C)Z12.1 Hz, –NCH(CH₃₂)CH₂N–),

2

48.8 (d, J(P,C)Z5.2 Hz, –NCH₂Ph), 46.3 (d, J(P,C)Z

4.4. Preparation of diazaphosphoramides used as chiral

standards cis-(2R,4R)-9b and trans-(2S,4R)-9b

5.7 Hz, –NCH₂Ph), 39.1 (d, ²J(P,C)Z4.3 Hz, –N(CH₂

CH₃)₂), 19.3. (d, ³J(P,C)Z2.4 Hz, –NCH(CH₃)CH₂N–),

14.8 (–N(CH₂CH₃)₂); ³¹P NMR (160 MHz, CDCl₃, 25 8C,

H₃PO₄external): dZ27.7; IR (ﬁlm): n_max(cm^K1)Z2969.5

(CH), 1207.0 (P]O), 1153.1 (P–N–C), 1032.9, 732.2,

699.1; MS (70 eV, EI): m/z (%): 371 (39) [M^C], 356 (30)

[M^CKCH3], 299 (34) [M^CKNEt₂], 224 (27), 91

(100)[^CCH₂Ph], 72 (27), 57 (47), 41 (27); HRMS (EI):

obtained 371.21270; M^CC₂₁H₃₀N₃OP requires 371.21265.

4.4.1. cis-(2R,4R)- and trans-(2S,4R)-1-N-,3-N⁰-Dibenzyl-

2-diethylamino-4-methyl-1,3,2-l⁵-diazaphospholidin-2-

one 9b. The general method for the coupling of aminoalco-

hols with diethylphosphoramidous dichloride described

previously was followed,⁹using (1R)-1-N-,2-N⁰-dibenzyl-

propanodiamine (103.0 mg, 0.405 mmol), diethylphosphor-

amidous dichloride (77.0 mg, 0.405 mmol) and dry

triethylamine (113.0 ml, 0.810 mmol). The residue obtained

was puriﬁed by column chromatography (n-Hex/AcOEt,

4:6), and two fractions corresponding to the two diastereo-

mers cis-(2R,4R)-9b and trans-(2S,4R)-9b were obtained.

4.5. Imide–amide rearrangement of

oxazaphosphorimides of type 7 and 12 obtained in situ

from the oxazaphospholanes of type 6 and 11

General method. Benzylazide or phenylazide was added

dropwise to a toluene solution of oxazaphospholidine

(approx. 1.0 M) in a dry, argon pre-ﬁlled, ﬂask or NMR

tube, stopped with a rubber septum (when using phenylazide

the reaction was cooled in an ice-bath during the addition).

Once the addition was completed, the mixture was heated to

40–60 8C until no more evolution of N₂could be observed

or until the total conversion of the oxazaphospholidine 6 or

11 in oxazaphosphorimide 7 or 12 was conﬁrmed by

³¹P NMR. BF₃$OEt₂(10 mol %) was then added and the

reaction was heated to 100 8C and followed by NMR until

the complete disappearance of the ³¹P NMR signal of the

oxazaphosphorimide 7 or 12. At this point and after cooling

down to room temperature dichloromethane was added, the

resulting solution was washed with satd aq solution of

NaHCO₃and the aqueous layer was extracted twice with

dichloromethane. The combined organic layers were dried

with anhyd MgSO₄and the solvent removed under vacuum.

trans-(2S,4R)-9b. Colourless viscous oil (28.0 mg, 19%);

R_fZ0.45 (n-Hex/AcOEt, 1:1); [a]²_D⁰ZC1.9 (c 0.9, CHCl₃);

¹H NMR (400 MHz, CDCl₃, 25 8C, TMS): dZ7.41

(d, J(H,H)Z7.3 Hz, 2H, –CH–, Ar), 7.30–7.25 (m, 8H,

–CH–, Ar), 4.13–4.00 (m, 2H, one of –N(1)CH₂Ph and one

of –N(3)CH₂Ph), 3.94–3.79 (m, 2H, one of –N(1)CH₂Ph

and one of –N(3)CH₂Ph), 3.27–3.18 (m, JZ7.3, 3.1 Hz,

J(H,H)Z6.2, 5.8, 1H, –NCH(CH₃)CH₂N–), 3.11–2.93 (m,

5H, one of –NCH(CH₃)CH₂N– and –N(CH₂C H₃)₂), 2.53

(ddd, 1H, J(P,H)Z8.3 Hz, J(H,H)Z10.9, 5.8 Hz, one of

–NCH(CH₃)CH₂N), 1.02 (t, J(H,H)Z7.1 Hz, 6H,

–N(CH₂CH₃)₂), 0.96 (d, J(H,H)Z6.1 Hz, 3H, –NCH(CH₃)

CH₂N); ¹³C NMR (100 MHz, CDCl₃, 25 8C, CDCl₃): d Z

132.7 (d, J(P,C)Z18.0 Hz, –C–, Ar), 128.1 (d, J(P,C)Z

3.6 Hz, –C–, Ar), 128.5 (–CH–, Ar), 128.4 (–CH–, Ar),

128.3 (–CH–, Ar), 128.1 (–CH–, Ar), 127.1 (–CH–, Ar),

127.0 (–CH–,Ar), 51.9 (d, J(P,C)Z12.1 Hz, –NCH(CH₃)

CH₂N–), 48.6 (d, J(P,C)Z11.5 Hz, –NCH(CH₃)CH₂N–),

48.6 (d, J(P,C)Z5.5 Hz, –NCH₂Ph), 46.2 (d, J(P,C)Z

5.5 Hz,

–NCH₂Ph),

39.4

(d,

J(P,C)Z5.1 Hz,

4.5.1. Reactions using 6a. With benzylazide. The general

procedure was followed in a NMR tube using the oxazaphos-

pholane 6a (110 mg, 0.44 mmol) and benzylazide (54.5 ml,

0.44 mmol) in dry deuterated toluene (0.4 ml). The total

conversion of 6a (³¹P NMR signal at 135.4 ppm) to the

imide 7a (³¹P NMR signals at 28.2 ppm, ¹³C NMR –OCH₂–

at 62.7 ppm) was conﬁrmed by NMR after 30 min at 40 8C.

After the addition of BF₃$OEt₂(5.6 ml, 10 mol%) the total

conversion of 7b was observed by ³¹P NMR after 40 min at

100 8C (³¹P NMR signals at 25.9–25.4 and 21.4 and broad

¹H NMR and ¹³C NMR signals, total disappearance of

signal –OCH₂– at 62.7 ppm). After 8 h at 100 8C no

variation was detected by NMR. The residue obtained

after work-up was characterized without further puriﬁcation

and identiﬁed as poly-N-benzylamino-N⁰,N⁰-benzylethyl-

amino-N⁰⁰,N⁰⁰-diethylaminophosphorotriamide 8a; ¹H NMR

(400 MHz, tol-d₈, 25 8C, tol): dZ7.42–7.22 (br, 4H, –CH–,

–N(CH₂CH₃)₂), 18.9. (d, J(P,C)Z4.5 Hz, –NCH(CH₃)

CH₂N–), 14.8 (–N(CH₂CH₃)₂); ³¹P NMR (160 MHz,

CDCl₃, 25 8C, H₃PO₄external): d Z28.3; IR (ﬁlm): n_max

(cm^K1)Z2975.1 (CH), 1265.4 (P]O), 739.8 MS (70 eV,

EI): m/z (%): 371 (25) [M^C], 356 (10) [M^CKCH₃], 299

(23) [M^CKNEt₂], 91 (100) [^CCH₂Ph], 72 (27), 57 (21), 41

(25), 28 (50); HRMS (EI): obtained 371.21270; M^C

C₂₁H₃₀N₃OP requires 371.21265.

cis-(2S,4R)-9b. Colourless viscous oil (35.0 mg, 23%); R_fZ

0.35 (n-Hex/AcOEt,1:1); [a]²_D⁰ZC11.8 (c 0.4, CHCl₃); ¹H

NMR (400 MHz, CDCl₃, 25 8C, TMS): dZ7.34–7.15 (m,

10H, –CH–, Ar), 4.127 (dd, ³J(P,H)Z8.5 Hz, J(H,H)Z

15.8 Hz, 1H, one of –N(1)CH₂Ph), 3.99 (dd, ³J(P,H)Z

6.9 Hz, J(H,H)Z15.1 Hz, 1H, one of –N(3)CH₂Ph), 3.95

(dd, ³J(P,H)Z7.3 Hz, J(H,H)Z15.1 Hz, 1H, one of

E. J. Cabrita et al. / Tetrahedron 60 (2004) 11933–11949

11943

Ar), 7.15–7.06 (br, 6H, –CH–, Ar), 4.24–3.60 (br, 3H),

3.14–2.90 (br, 5H), 1.07–0.93 (m, 6H, N(CH₂CH₃)₂); ¹³C

NMR (100 MHz, tol-d₈, 25 8C, tol-d₈): dZ139.4 (br),

128.6–126.3 (br), 52.2 (br), 50.9 (br), 46.1 (br), 45.1 (br),

39.8 (br), 14.3 (br), 14.1 (br); ³¹P NMR (160 MHz, tol-d₈,

25 8C, H₃PO₄external): dZ25.9–25.4 (80%), 21.4 (20%);

IR (ﬁlm): n_max(cm^K1)Z3379.1 (br, NH), 3228.8 (br),

2972.4 (C–H), 2931.6, 2871.1, 1454.2, 1214.6 (P]O),

1059.3, 1028.4 (P–N–C), 943.8, 732.8, 700.2; MS

(MALDI): repeating unit: 357G1 Da; M_nZ3080, M_wZ

3480, polydispersion indexZ1.028.

trans-(2R,4S)-9b. Colourless viscous oil (10.2 mg, 9%);

R_fZ0.13 (Et₂O); [a]²_D⁰ZK0.9 (c 0.2, CHCl₃); other data

identical to the already described trans-(2S,4R)-9b.

cis-(2S,4S)-9b. Colourless viscous oil (26.4 mg, 23%); R_fZ

0.10 (Et₂O); [a]²_D⁰ZK10.4 (c 1.1, CHCl₃); ee O99%

determined by HPLC (n-Hex/i-PrOH; 98:2, 1 ml/min, l_max

254 nm). The determination of the absolute conﬁguration of

cis-(2S,4S)-9b was performed by comparison of its retention

time (30.87 min) with the ones from the chiral authentic cis-

(2S,4R)-9b (28.80 min) and the racemic cis-9b (28.54 and

30.53 min). The retention times are the average values

obtained in three HPLC runs; other data identical to the

already described cis-(2S,4R)-9b.

With phenylazide. The general procedure was followed in a

NMR tube using the oxazaphospholane 6a (110 mg,

0.44 mmol) and phenylazide (52 mg, 0.44 mmol) in dry

deuterated toluene (0.4 ml). The total conversion of 6a (³¹P

NMR signal at 135.4 ppm) to the imide 7g (³¹P NMR

signals at 19.6 ppm, ¹³C NMR –OCH₂– at 63.1 ppm) was

conﬁrmed by NMR after 30 min at 40 8C. After the addition

of BF₃$OEt₂(5.6 ml, 10 mol%) the total conversion of 7g

was observed by ³¹P NMR after 7 h at 100 8C (³¹P NMR

signals at 21.6, 20.5 (70%) and 15.3 and broad ¹H NMR and

¹³C NMR signals, total disappearance of signal –OCH₂– at

62.7 ppm). The residue partly decomposed during work-up

but, due to its spectral characteristics in the reactio₀n

mixture, was identiﬁed as poly-N-benzylethylamino-N⁰,N -

diethylamino-N⁰⁰,N⁰⁰-phenylaminophosphorotriamide 8g.

4.5.4. Reactions using 6c. With phenzylazide. The general

procedure was followed in a NMR tube using the oxazaphos-

pholane 6c (77.5 mg, 0.45 mmol) and phenzylazide (53 mg,

0.44 mmol) in dry deuterated toluene (0.4 ml). The total

conversion of 6c (³¹P NMR signal at 135.0 ppm) to the

imide 7c (³¹P NMR signals at 28.2 ppm, ¹³C NMR –OCH₂–

at 62.7 ppm) was conﬁrmed by NMR after 30 min at 40 8C.

After the addition of BF₃$OEt₂(5.6 ml, 10 mol%) the total

conversion of 7c was observed by ³¹P NMR after 4 h at

100 8C (conversion to ³¹P NMR signal at 20.4 (approx.

85%), 18.0, 15.0 and 14.0 ppm). After 8 h at 100 8C no

variation was detected by NMR. The residue obtained after

work-up was puriﬁed by column chromatography (n-Hex/

AcOEt, 1:9) and 2-diethylamino-3-N⁰-methyl-1-N-phenyl-

1,3,2-l⁵-diazaphospholidin-2-one 8c was obtained as a

yellow solid (42.9 mg, 36%). Mp 35–37 8C; ¹H NMR

(400 MHz, CDCl₃, 25 8C, TMS): dZ7.18 (t, J(H,H)Z

7.4 Hz, 2H, –CH–, Ar), 6.96 (d, J(H,H)Z7.4 Hz, 2H, –CH–,

Ar), 6.83 (t, J(H,H)Z7.4 Hz, 1H, –CH–, Ar), 3.87–3.52 (m,

1H, one of NCH₂–), 3.43 (q, JZ8.4 Hz, 1H, one of –NCH₂–),

3.37–3.27 (m, 1H, one of –NCH₂–), 3.19–3.08 (m, 1H, one

of –NCH₂–), 3.08–2.98 (m, 2H, two of –N(CH₂CH₃)₂),

2.92–2.82 (m, 2H, two of –N(CH₂CH₃)₂), 2.54 (d, J(H,H)Z

10.5 Hz, 3H, –NCH₃), 0.87 (t, J(H,H)Z7.0 Hz, 6H;

–N(CH₂CH₃)₂); ¹³C NMR (100 MHz, CDCl₃, 25 8C,

4.5.2. Reaction using 6b. The general procedure was

followed using the racemic oxazaphospholane 6b (260 mg,

0.976 mmol) and benzylazide (122 ml, 0.976 mmol) in dry

toluene (1.0 ml). The total conversion of 6b (³¹P NMR

signals at 140.2 and 137.1 ppm, in a 26:74 ratio) to the imide

7b (³¹P NMR signals at 26.8 and 26.4 ppm, in a 73:27 ratio)

was conﬁrmed by NMR after 12 h at room temperature.

After the addition of BF₃$OEt₂(12 ml, 10 mol%), the total

conversion of 7b was observed by ³¹P NMR after 8 h at

100 8C. The residue obtained after work-up was puriﬁed by

column chromatography (Et₂O) and two fractions corre-

sponding to the two diastereomers cis-9b and trans-9b were

obtained.

2

CDCl₃): dZ142.2 (d, J(P,C)Z6.7 Hz, –C–), 128.8 (CH–,

2

Ar), 120.4 (–CH–, Ar), 115.4 (d, J(P,C)Z5.4 Hz, –CH–,

2

Ar), 45.7 (d, J(P,C)Z10.9 Hz, one of –NCH₂–), 43.7 (d,

trans-9b. Colourless viscous oil (70.1 mg, 19%); R_fZ0.13

(Et₂O); other spectroscopic data identical to the already

described trans-(2S,4R)-9b.

²J(P,C)Z12.3 Hz, one of –NCH₂–), 39.3(d, ²J(P,C)Z5.4 Hz,

2

one of –N(CH₂CH₃)₂), 30.9 (d, J(P,C)Z5.4 Hz, –NCH₃),

14.0 (–N(CH₂CH₃)₂); ³¹P NMR (160 MHz, CDCl₃, 25 8C,

H₃PO₄external): dZ21.54; IR (KBr): n_max(cm^K1)Z2978.2

(C–H, Ar), 1603.9, 1499.3, 1312.4, 1216.6 (P]O), 1183.3,

1033.3 (P–N–C), 761.7; MS (FAB): m/z (%): 268 (100)

[MH^C], 195 (54) [M^CKHNEt₂], 106 (10) [CH₂]NHPh^C],

72 (12) [NEt^C₂]; HMRS (EI): obtained 267.150765; M^C

C₁₃H₂₂N₃OP requires 267.150051.

cis-9b. Colourless viscous oil (144.0 mg, 40%); R_fZ0.10

(Et₂O); other spectroscopic data identical to the already

described cis-(2S,4R)-9b.

4.5.3. Reaction using (5R)-6b. The general procedure was

followed using the chiral oxazaphospholane (5R)-6b

(81.5 mg, 0.306 mmol) and benzylazide (38.2 ml,

0.306 mmol) in dry toluene (0.4 ml). The total conversion

of 6b (³¹P NMR signals at 140.2 and 137.1 ppm, in a 26:74

ratio) to the imide 7b (³¹P NMR signals at 26.8 and

26.4 ppm, in a 73:27 ratio) was conﬁrmed by NMR after

12 h at room temperature. The total conversion of 7b was

observed by ³¹P NMR after 8 h at 100 8C. The residue

obtained after work-up was puriﬁed by column chromato-

graphy (Et₂O) and two fractions corresponding to the two

diastereomers cis-9b and trans-9b were obtained.

With benzylazide. The general procedure was followed in a

NMR tube using the oxazaphospholane 6c (84.2 mg,

0.48 mmol) and benzylazide (60.0 ml, 0.48 mmol) in dry

deuterated toluene (0.4 ml). The total conversion of 6c

(³¹P NMR signal at 135.0 ppm) to the imide 7d (³¹P NMR

signal at 17.7 ppm, ¹³C NMR –OCH₂– at 62.6 ppm) was

conﬁrmed by NMR after 30 min at 40 8C. After the addition

of BF₃$OEt₂(5.6 ml, 10 mol%) the total conversion of 7c

was observed by ³¹P NMR after 40 min at 100 8C

(conversion to ³¹P NMR signals at 25.7 (approx. 40%),

11944

E. J. Cabrita et al. / Tetrahedron 60 (2004) 11933–11949

23.1 and 18 ppm, ¹³C NMR –NCH₂– duplet at 43.9 ppm).

After 8 h at 100 8C no variation was detected by NMR. The

residue obtained after work-up was puriﬁed by column

chromatography (n-Hex/AcOEt, 1:9) and 2-diethylamino-1-

N-benzyl-3-N⁰-methyl-1,3,2-l⁵-diazaphospholidin-2-one

8d was obtained as a slightly yellow viscous oil (24.9 mg,

19%); ¹H NMR (400 MHz, CDCl₃, 25 8C, TMS): dZ7.31–

7.26 (m, 4H, –CH–, Ar), 7.195 (t, J(H,H)Z7.0 Hz,. –CH–,

Ar), 3.98 (dd, J(H,H)Z14.9 Hz, J(P,H)Z6.1 Hz, 1H, one of

–NCH₂Ph), 3.89 (dd, J(H,H)Z14.9 Hz, J(P,H)Z7.6 Hz,

1H, one of –NCH₂Ph), 3.11–2.91 (m, 8H, NCH₂CH₂N– and

–N(CH₂CH₃)₂), 2.52 (d, J(H,H)Z9.7 Hz, 3H, –NCH₃), 1.06

(t, J(H,H)Z7.1 Hz, 6H, –N(CH₂CH₃)₂); ¹³C NMR

Ar), 6.78 (br, approx. 3H, –CH–, Ar), 3.01–2.37 (br, approx.

8H, –NCH₂CH₂N– and –N(CH₂C H₃)₂), 0.53–0.44 (br,

approx. 6H, –N(CH₂CH₃)₂); ¹³C NMR (100 MHz, CDCl₃,

25 8C, CDCl₃): dZ142.7 (br), 128.8 (br), 125.3 (br), 48.5

(br), 40.4 (br), 13.3 (br); IR (KBr): n_max(cm_K1)Z3400.2

(br, NH), 2972.3, (C–H), 1595.9, 1492.5, 1216.8 (P]O),

1097.2, 1028.1 (P–N–C), 950.1, 698.3; ³¹P NMR

(160 MHz, CDCl₃, 25 8C, H₃PO₄external): dZ15.79

(broad, 87%), 11.17 (broad, 7%), 10.80 (broad, 3%); MS

(MALDI): repeating unit: 329G1 Da; M_nZ5990, M_wZ

6156, polydispersion indexZ1.028.

With benzylazide. The general procedure was followed in a

NMR tube using the oxazaphospholane 6e (104.0 mg,

0.44 mmol) and benzylazide (54.0 ml, 0.44 mmol) in dry

deuterated toluene (0.4 ml). The total conversion of 6e (³¹P

NMR signal at 121.3 ppm) to the imide 7f (³¹P NMR signal

at 18.0 ppm, ¹³C NMR –OCH₂– at 61.6 ppm) was

conﬁrmed by NMR after 30 min at 40 8C. After the addition

of BF₃$OEt₂(5.6 ml, 10 mol%) the total conversion of 7 was

observed by ³¹P NMR after 40 min at 100 8C (conversion to

³¹P NMR signals at 20.7 (approx. 90%) broad ¹H NMR and

¹³C NMR signals, total disappearance of signal –OCH₂– at

61.6 ppm). After 8 h at 100 8C no variation was detected

by NMR. The residue obtained after work-up was

characterized without fur₀ther puriﬁcation and identiﬁed as

poly-N-benzylamino-N ,N⁰-diethylamino-N⁰⁰,N⁰⁰-benzyl-

phenylaminophosphorotriamide 8f; ¹H NMR (400 MHz,

CDCl₃, 25 8C, TMS): dZ7.36–7.07 (br, 9H, –CH–, Ar),

6.76 (br, 1H, –CH–, Ar), 3.95 (br, 2H), 3.76–3.40 (br, 2H),

2.98–2.66 (6H, br, –N(CH₂CH₃)₂), 0.68 (br, 6H,

–N(CH₂CH₃)₂); ¹³C NMR (100 MHz, CDCl₃, 25 8C,

CDCl₃): dZ143.0 (–C–, Ar), 139.6 (–C–, Ar), 128.8

(–CH–, Ar), 128.5–127.9 (br, –CH–, Ar), 127.0 (br, –CH–,

Ar), 51.8, 48.5 e 46.1 (very broad signals), 40.0 (br,

–N(CH₂CH₃)₂), 14.7 (br, –N(CH₂CH₃)₂); ³¹P NMR

(160 MHz, CD₃C₆D₅, 25 8C, H₃PO₄external): dZ20.5 (br,

90%), 17.3 (br, 10%); IR (ﬁlm): n_max(cm^K1)Z3393.8 (br,

NH), 2974.2 (C–H), 1598.6, 1493.6, 1217.3 (P]O), 1193.9,

1068.9, 1029.3 (P–N–C), 949.9, 736.4, 700.4.

2

(100 MHz, CDCl₃, 25 8C, CDCl₃): dZ138.1 (d, J(P,C)Z

5.9 Hz, –C–), 128.3 (–CH–, Ar), 128.0, (–CH–, Ar) 127.0

2

(–CH–, Ar), 48.8 (d, J(P,C)Z5.3 Hz, –NCH₂Ph), 47.0 (d,

²J(P,C)Z12.5 Hz, one of –NCH₂–), 44.1 (d, ²J(P,C)Z12.4,

one of –NCH₂–), 39.0 (d, ²J(P,C)Z4.6 Hz, –N(CH₂CH3)₂),

2

31.0 (d, J(P,C)Z5.6 Hz, –NCH₃), 14.6 (–N(CH₂CH₃)₂);

³¹P NMR (160 MHz, CDCl₃, 25 8C, H₃PO₄external): dZ

27.3; IR (KBr): n_max(cm^K1)Z2934.0 (C–H), 1229.8

(P]O), 1209.4, 1188.4, 1019.72 (P–N–C), 998.5, 701.0.

4.5.5. Reactions using 6e. With phenzylazide. The general

procedure was followed in a NMR tube using the oxazaphos-

pholane 6e (110.0 mg, 0.46 mmol) and phenzylazide

(55 mg, 0.46 mmol) in dry deuterated toluene (0.4 ml).

The total conversion of 6e (³¹P NMR signal at 121.3 ppm)

to the imide 7e (³¹P NMR signals at 8.8 ppm, ¹³C NMR

–OCH₂– at 62.2 ppm) was conﬁrmed by NMR after 30 min

at 40 8C. After the addition of BF₃$OEt₂(5.6 ml, 10 mol%)

the total conversion of 7e was observed by ³¹P NMR after

8 h at 100 8C (conversion to ³¹P NMR signal at 16.1

(approx. 90%), 18.0, 15.0 and 14.0 ppm). The residue

obtained after work-up was puriﬁed by thin layer chromato-

graphy (n-Hex/AcOEt, 1:1) and two fractions were isolated.

2-Diethylamino-1-N-,-3-N⁰-diphenyl-1,3,2-l⁵-diazaphos-

pholidin-2-one 8e. White needles (4.0 mg, 3%); R_fZ0.5

(n-Hex/AcOEt, 1:1). Mp 190–192 8C; ¹H NMR (400 MHz,

CDCl₃, 25 8C, TMS): dZ7.16 (t, J(H,H)Z7.2 Hz, 2H,

–CH–, m-Ar), 7.01 (d, J(H,H)Z7.2 Hz, 2H, –CH–, o-Ar),

6.84 (t, J(H,H)Z7.2 Hz, 1H, –CH–, p-Ar), 3.74–3.65 (m,

4H, –NCH₂CH₂N–), 3.01–2.96 (m, J(H,H)Z7.0 Hz,

J(P,H)Z11.6 Hz, 4H, –N(CH₂CH₃)₂), 0.83 (t, J(H,H)Z

7.0 Hz, 6H, –N(CH₂CH₃)₂); ¹³C NMR (100 MHz, CDCl₃,

25 8C, CDCl₃): dZ141.8 (d, J(P,C)Z7.1 Hz, –C–, Ar),

129.1 (–CH–, Ar), 121.5 (–CH–, Ar), 116.5 (d, J(P,C)Z

5.5 Hz, –CH–, o-Ar), 42.7 (d, J(P,C)Z11.4 Hz, –NCH₂–),

39.3 (d, J(P,C)Z4.8 Hz, –N(CH₂CH₃)₂), 13.3 (–N(CH₂

CH₃)₂); IR (KBr): n_max(cm^K1)Z2964.0 (C–H), 1599.9,

1499.8, 1279.9, 1262.2, 1227.3 (P]O), 1103.8, 1028.7

(P–N–C), 749.4 ³¹P NMR (160 MHz, CDCl₃, 25 8C, H₃PO₄

external): dZ14.43; MS (EI): m/z (%): 329 (83) [M^C], 314

(52) [M^CCH₃], 257 (100) [M^CKNEt₂], 152 (38), 119 (23)

[C₂H₄NPh^C], 106 (50), 72 (25) [NEt₂^C]; HMRS (EI):

obtained 329.165660; M^CC₁₈H₂₄N₃OP requires

329.165701.

4.5.6. Reaction using 11a. The general procedure was

followed in a NMR tube using the oxazaphospholane 11a

(38.0 mg, 0.174 mmol) and phenylazide (20.7 mg,

0.174 mmol) in dry deuterated toluene (0.4 ml). The total

conversion of 11a to the imide 12a (³¹P NMR signals at

19.86 and 16.09 ppm, in a 65:35 ratio) was conﬁrmed by

NMR after 30 min at 40 8C. After the addition of BF₃$OEt₂

(3.6 ml, 10 mol %), the total conversion of 11b was observed

by ³¹P NMR after 72 h at 100 8C. The residue obtained after

work-up was puriﬁed by column chromatography (n-Hex/

AcOEt, 6:4). Three fractions were obtained, the ﬁrst two

corresponding to the two diastereomers cis-13a and trans-

13a and the third fraction corresponding to a mixture of cis

and trans-14a.

cis-13a. Colourless viscous oil (6.3 mg, 12%); R_fZ0.21

(n-Hex:AcOEt, 6:4); [a]²_D⁰ZC43.8 (c 0.32, CHCl₃); H

1

NMR (400 MHz, CDCl₃, 25 8C, TMS): dZ7.17

(t, J(H,H)Z7.5 Hz, 1H, –CH–, m-Ar), 6.99 (d, J(H,H)Z

7.5 Hz, 1H, –CH–, o-Ar), 6.83 (t, J(H,H)Z7.5 Hz, 1H,

–CH–, p-Ar), 3.79–3.71 (m, J(H,H)Z9.2, 6.0 Hz, 1H,

–NCH(CH₃)CH₂N–), 3.52–3.37 (m, 2H, one of –NCH

Poly-diethylamino-N⁰,N⁰-ethylphenylamino-N⁰⁰,N⁰⁰-phenyl-

aminophosphorotriamide 9e. White solid (109.0 mg, 72%);

recovered from the application point; H NMR (400 MHz,

1

CDCl₃, 25 8C, TMS): dZ7.18–6.91 (br, approx. 7H, –CH–,

E. J. Cabrita et al. / Tetrahedron 60 (2004) 11933–11949

11945

(CH₃)CH₂N– and –NCH(CH₃)₂), 3.09–2.96 (m, 3H, one of

–NCH(CH₃)CH₂N– and two of –N(CH₂CH₃)₂), 2.94–2.84

(m, 2H, two of –N(CH₂CH₃)₂), 1.31 (d, J(H,H)Z6.9 Hz,

3H, –NCH(CH₃)CH₂N–), 1.22 (d, J(H,H)Z6.0 Hz, 3H, one

–CH₃of –NCH(CH₃)₂), 1.20 (d, J(H,H)Z6.0 Hz, 3H, one

–CH₃of –NCH(CH₃)₂), 0.82 (t, J(H,H)Z7.0 Hz, 6H,

–N(CH₂CH₃)₂); ¹³C NMR (100 MHz, CDCl₃, 25 8C,

CDCl₃): dZ128.8 (–CH–, m-Ar), 120.5 (–CH–, p-Ar),

115.8 (d, ³J(P,C)Z4.7 Hz, –CH–, o-Ar), 51.6 (d, ₂J(P,C)Z

12.3 Hz, –NCH(CH₃)CH₂N–),45.5 (d, ²J(P,C)Z11.1 Hz,

(d, ²J(P,C)Z4.3 Hz, –NCH(CH₃)CH₂N–), 44.7 (–NCH

(CH₃)₂), 39.3 (d, ²J(P,C)Z5.3 Hz, –N(CH₂CH₃)₂), 21.9

(d ³J(P,C)Z3.5 Hz, one CH₃of NCH(CH₃)₂), 20.6

(d, ³J(P,C)Z8.8 Hz, one CH₃of –NCH(CH₃)₂), 20.1

(–NCH(CH₃)CH₂N–), 13.6 (N(CH₂CH₃)₂); ³¹P NMR

(160 MHz, CDCl₃, 25 8C, H₃PO₄externo): dZ22.13; IR

(ﬁlm): n_max(cm^K1)Z2974.0 (C–H), 1600.8, 1499.7,

1304.8, 1218.1 (P]O), 1193.5, 1031.6 (P–N–C); MS

(70 eV, EI): m/z (%): 309 (92) [M^C], 294 (100)

[M^CKCH₃], 237 (84) [M^CKNEt₂], 223 (66)

[HCNPhP(O)NEt^C₂], 195 (34), 133 (40) [C₃H₆NPh^C], 72

(56) [NEt^C₂].

(m, 1H, one of –NCH(CH₃)CH₂O–, cis and 1H, one of

–NCH(CH₃)CH₂O–, trans), 3.12–2.30 (m, 4H, –N(CH₂

CH₃)₂, trans and 4H, –N(CH₂CH₃)₂, cis), 1.26–1.25 (m, 3H,

–NCH(CH₃)CH₂N–, cis and 3H, one –CH₃of –NCH(CH₃)₂,

trans), 1.22 (d, J(H,H)Z5.5 Hz, 3H, one –CH₃of –NCH

(CH₃)₂, trans), 1.17 (d, J(H,H)Z6.4 Hz, 3H, one –CH₃of

–NCH(CH₃)₂, cis), 1.14 (d, J(H,H)Z7.2 Hz, 3H, –NCH

(CH₃)CH₂N–, trans), 1.11 (d, J(H,H)Z6.4 Hz, 3H, one

–CH₃of –NCH(CH₃)₂, cis), 1.04 (t, J(H,H)Z7.0 Hz, 6H,

N(CH₂CH₃)₂, trans and 6H, –N(CH₂CH₃)₂, cis); d H4 (from

HMQC) d H4Z3.68 ppm (major diastereoisomer—cis) d

H4Z3.62 ppm (minor diastereoisomer—trans); ¹³C NMR

(100 MHz, CDCl₃, 25 8C, CDCl₃): dZ70.2 (–NCH(CH₃)

CH₂O–, trans), 69.9 (NCH(CH₃)CH₂O–, cis), 51.2 (d,

2

²J(P,C)Z16.3 Hz, –NCH(CH₃)₂, trans), 49.5 (d, J(P,C)Z

15.2 Hz, –NCH(CH₃)₂, cis), 45.0 (d, ²J(P,C)Z4.4 Hz,

–NCH(CH₃)CH₂N–, cis), 44.1 (d, ²J(P,C)Z5.7, –NCH

(CH₃)CH₂N–, trans), 39.6 (d, ²J(P,C)Z5.4 Hz, –N(CH₂

CH₃)₂, cis), 39.4 (d, ²J(P,C)Z4.6 Hz, –N(CH₂CH₃)₂,

trans), 22.8 (–NCH(CH₃)CH₂N–, trans), 21.9 (d,

³J(P,C)Z3.0 Hz, one CH₃of –NCH(CH₃)₂, cis), 20.8 (d,

³J(P,C)Z4.0 Hz, one CH₃of –NCH(CH₃)₂, trans), 20.6

(–NCH(CH₃)CH₂N–, cis), 19.8 (d, ³J(P,C)Z7.0 Hz, one

3

CH₃of NCH(CH₃)₂, cis), 19.7 (d, J(P,C)Z2.2 Hz, one

trans-13a. Colourless viscous oil (9.3 mg, 18%); R_fZ0.17

CH₃of –NCH(CH₃)₂, trans), 14.2 (d, ³J(P,C)Z2.0 Hz,

–N(CH₂CH₃)₂, cis), 14.1 (–N(CH₂CH₃)₂, trans); ³¹P NMR

(160 MHz, CDCl₃, 25 8C, H₃PO₄external): dZ28.54 (cis),

25.12 (trans);IR (ﬁlm): n_max(cm_K1)Z2972.9 (C–H),

1381.0, 1245.1 (P]O), 1210.3, 1024.3 (P–N–C), 808.9,

720.8.

1

(n-Hex/AcOEt, 6:4); [a]²_D⁰ZK18.5 (c 0.47, CHCl₃); H

NMR (400 MHz, CDCl₃, 25 8C, TMS): dZ7.17

(t, J(H,H)Z7.8 Hz, 1H, –CH–, m-Ar), 6.99 (d, J(H,H)Z

7.8 Hz, 1H, –CH–, o-Ar), 6.82 (t, J(H,H)Z7.8 Hz, 1H,

–CH–, p-Ar), 3.69–3.60 (m, 2H, one of –NCH(CH₃)CH₂N–

and –NCH(CH₃)CH₂N–), 3.50–3.40 (m, J(H,H)Z6.6 Hz,

1H, –NCH(CH₃)₂), 3.14–2.97 (m, 3H, one of –NCH(CH₃)

CH₂N– and two of –N(CH₂CH₃)₂), 2.94–2.92 (m, 2H, two

of –N(CH₂CH₃)₂), 1.33 (d, J(H,H)Z6.1 Hz, 3H, –NCH

(CH₃)CH₂N–), 1.25 (d, J(H,H)Z6.6 Hz, 3H, one –CH₃of

–NCH(CH₃)₂), 1.21 (d, J(H,H)Z6.6 Hz, 3H, one –CH₃of

–NCH(CH₃)₂), 0.82 (t, J(H,H)Z7.1 Hz, 6H, –N(CH₂

CH₃)₂); dH4Z3.63 ppm (from HMQC); ¹³C NMR

(100 MHz, CDCl₃, 25 8C, CDCl₃): dZ142.8 (d, J(P,C)Z

7.0 Hz, –C–, Ar), 128.9 (–CH–, m-Ar), 120.2 (–CH–, p-Ar),

115.6 (d, ³J(P,C)Z4.7 Hz, –CH–, o-Ar), 51.8 (d, ²J(P,C)Z

12.4 Hz, –NCH(CH₃)CH₂N–), 47.0 (d, ²J(P,C)Z6.3 Hz,

–NCH(CH₃)CH₂N–), 44.3 (d, ²J(P,C)Z12.0 Hz, –NCH

(CH₃)₂), 39.3 (d, ²J(P,C)Z5.1 Hz, –N(CH₂CH₃)₂), 23.8

(d ³J(P,C)Z2.4 Hz, one CH₃of –NCH(CH₃)₂), 21.7 (–NCH

(CH₃)CH₂N–), 21.1 (d, ³J(P,C)Z4.5 Hz, one CH₃of –NCH

(CH₃)₂), 13.6 (–N(CH₂CH₃)₂); ³¹P NMR (160 MHz,

CDCl₃, 25 8C, H₃PO₄external): dZ17.95; IR (ﬁlm): n_max

(cm^K1)Z2968.6 (C–H), 1602.5, 1500.9, 1304.9, 1203.7

(P]O), 1029.7 (P–N–C); MS (70 eV, EI): m/z (%): 309 (89)

[M^C], 294 (100) [M^CKCH₃], 237 (55) [M^CKNEt₂], 223

(71) [HCNPhP(O)NEt₂^C], 195 (35), 133 (39) [C₃H₆NPh^C],

72 (44) [NEt^C₂]. HMRS (EI): obtained 309.196851; M^C

C₁₆H₂₈N₃OP requires 309.197001.

4.5.7. Reaction using 11b. The general procedure was

followed in a NMR tube using the oxazaphospholane 11b

(72.0 mg, 0.292 mmol) and phenylazide (35.0 mg,

0.292 mmol) in dry deuterated toluene (0.4 ml). After the

addition of BF₃$OEt₂(3.6 ml, 10 mol%), the total conver-

sion of 11b to the imide 12b (³¹P NMR signals at 19.92 and

15.99 ppm, in a 39:61 ratio) was conﬁrmed by NMR after

40 min at 40 8C. The total conversion of 11b was observed

by ³¹P NMR after 48 h at 100 8C. The residue obtained after

work-up was puriﬁed by column chromatography (n-Hex/

AcOEt, 7:3 until 1:1) and two fractions corresponding to the

two diastereomers cis-13b and trans-13b were obtained.

trans-13b. White crystals (18.0 mg, 18%); higher R_f

diastereomer; mp 115–117 8C; [a]²_D⁰ZC7.2 (c 0.31,

1

CHCl₃); H NMR (400 MHz, CDCl₃, 25 8C, TMS): dZ

7.18 (t, J(H,H)Z7.6 Hz, 1H, –CH–, m-Ar), 7.03 (d,

J(H,H)Z7.6 Hz, 1H, –CH–, o-Ar), 6.81 (t, J(H,H)Z

7.6 Hz, 1H, –CH–, p-Ar), 3.50–3.40 (m, 3H, –NCH(R)CH₂

N–, –NCH(CH₃)₂and one of –NCH(R)CH₂N–), 3.23 (t, JZ

9.5 Hz, 1H, one of –NCH(R)CH₂N–), 3.09–2.97 (m, 2H,

two of –N(CH₂CH₃)₂), 2.94–2.83 (m, 2H, two of

–N(CH₂CH₃)₂), 2.08–2.00 (m, J(H,H)Z6.9, 6.8, 3.2 Hz,

1H, –CHCH(CH₃)₂), 1.28 (d, J(H,H)Z6.9 Hz, 3H, one

–CH₃of –NCH(CH₃)₂), 1.22 (d, J(H,H)Z6.7 Hz, 3H, one

–CH₃of –NCH(CH₃)₂), 0.96 (d, J(H,H)Z6.8 Hz, 3H, one

–CH₃of –CHCH(CH₃)₂), 0.86 (d, J(H,H)Z6.9 Hz, 3H, one

–CH₃of –CHCH(CH₃)₂), 0.82 (t, J(H,H)Z7.2 Hz, 6H,

–N(CH₂CH₃)₂); dH₄Z3.48 ppm (from HMQC); ¹³C NMR

(100 MHz, CDCl₃, 25 8C, CDCl₃): dZ128.9 (–CH–, m-Ar),

120.0 (–CH–, p-Ar), 115.4 (d, ³J(P,C)Z4.1 Hz, –CH–,

cis-14a and trans-14a (mixture of diastereoisomers 58:42,

1

respectively, as determined by ³¹P and H NMR). Colour-

less viscous oil (26 mg, 64%); R_fZ0.1 (n-Hex/AcOEt, 6:4);

¹H NMR (400 MHz, CDCl₃, 25 8C, TMS): dZ4.21 (q, JZ

8.8 Hz, 1H, one of –NCH(CH₃)CH₂O–, cis), 4.08 (q, JZ

8.8 Hz, 1H, one of –NCH(CH₃)CH₂O–, trans), 3.78–3.59

(m, 1H, one of –NCH(CH₃)CH₂O–, trans, 1H, –NCH

(CH₃)₂, trans and 1H, –NCH(CH₃)₂, cis), 3.50 (q,

JZ8.8 Hz, 1H, one of –NCH(CH₃)CH₂O–, cis), 3.42–3.27

2

o-Ar), 56.1 (d, J(P,C)Z11.1 Hz, –NCH(R)CH₂N–), 44.3

11946

E. J. Cabrita et al. / Tetrahedron 60 (2004) 11933–11949

(d, ²J(P,C)Z7.9 Hz, –NCH(CH₃)₂), 43.7 (d, ²J(P,C)Z

13.4 Hz, –NCH(R)CH₂N–), 39.4 (d, ²J(P,C)Z5.2 Hz,

–N(CH₂CH₃)₂), 30.5 (–CHCH(CH₃)₂), 23.7 (one –CH₃

of –NCH(CH₃)₂), 20.7 (d, ³J(P,C)Z5.5 one –CH₃of

–NCH(CH₃)₂), 19.05 (one –CH₃of –CHCH(CH₃)₂), 14.5

(one –CH₃of –CHCH(CH₃)₂), 13.7 (–N(CH₂CH₃)₂); ³¹P

NMR (160 MHz, CDCl₃, 25 8C, H₃PO₄external): dZ18.62;

IR (KBr): n_max(cm^K1)Z2970.2 (C–H), 1603.4, 1502.2,

1312.9, 1220.3 (P]O), 1187.8, 1033.7 (P–N–C),755.4;

MS (70 eV, EI): m/z (%): 337 (16) [M^C], 308 (10)

[M^CKC₂H₅], 294 (100) [M^C-i-Pr], 265 (10)

[M^CKNEt₂],252 (31) [M^CKi-Pr–CH₂]CHCH₃], 223

(45) [HCNPhP(O)NEt^C₂].

cis and trans-17. Colourless viscous oil (168.8 mg, 56%);

¹H NMR (400 MHz, CDCl₃, 25 8C, TMS): dZ7.31–7.25

(m, 4H minor and 4H major, –CH–, Ar), 7.22–7.16 (m, 4H

minor and 4H major, –CH–, Ar), 7.08 (d, J(H,H)Z8.0 Hz,

2H minor, –CH–, Ar), 6.92 (d, J(H,H)Z8.0 Hz, 2H major,

–CH–, Ar), 6.89 (t, J(H,H)Z8.0 Hz, 1H minor, –CH–, Ar),

6.824 (t, J(H,H)Z8.0 Hz, 1H minor, –CH–, Ar), 4.10–3.97

(m, 2H major, one of –N(CH₃)CHCH₂N– and –N(CH₃)

CHCH₂N– and 2H minor, one of –N(CH₃)CHCH₂N– and

–N(CH₃)CHCH₂N–), 3.97–3.87 (m, 1H major, one of

–N(CH₃)CHCH₂N– and 1H minor, one of –N(CH₃)CHCH₂-

N–), 3.15–3.32 (m, 2H major, two of –N(CH₂CH₃)₂),

3.29–3.24 (m, 1H major, one of –NCH₂Ph and 1H minor,

one of –NCH₂Ph), 3.09–2.97 (m, 2H major, two of

–N(CH₂CH₃)₂), 2.97–2.83 (m, 4H minor, –N(CH₂CH₃)₂),

2.72 (t, J(H,H)Z8.4 Hz, J(P,H)Z8.4 Hz, 1H minor, one

of –NCH₂Ph), 2.61 (dd, JZ21.8, 8.7 Hz, 1H major, one of

–NCH₂Ph), 1.25 (d, J(H,H)Z6.1 Hz, 3H major, –N(CH₃)

HCH₂N–), 1.15 (d, J(H,H)Z6.0 Hz, 3H minor, –N(CH₃)

HCH₂N–), 1.01 (t, J(H,H)Z7.0 Hz, 6H major, –N(CH₂

CH₃)₂), 0.74 (t, J(H,H)Z7.1 Hz, 6H minor, –N(CH₂CH₃)₂);

¹³C NMR (100 MHz, CDCl₃, 25 8C, CDCl₃): dZ140.9 (d,

J(P,H)Z7.2 Hz, –C–, Ar, major), 140.7 (d, J(P,H)Z5.7 Hz,

–C–, Ar, minor), 137.6 (d, J(P,H)Z7.0 Hz, –C–, Ar,

minor.), 137.4 (d, J(P,H)Z8.3 Hz, –C–, Ar, major), 129.0

(–CH–, Ar), 128.7 (–CH–, Ar), 128.5 (–CH–, Ar), 128.4

(–CH–, Ar), 128.2 (–CH–, Ar), 127.3 (–CH–, Ar), 127.2

(–CH–, p-Ar), 121.7 (–CH–, Ar), 120.4 (–CH–, p-Ar,

minor), 119.2 (–CH–, Ar, major), (d, J(P,C)Z4.2 Hz, –CH–,

o-Ar, minor), 116.8 (d, J(P,C)Z5.1 Hz, –CH–, o-Ar, major),

50.6 (d, J(P,C)Z11.1 Hz, –NCH₂Ph, minor), 49.9 (d,

J(P,C)Z11.4 Hz, –NCH₂Ph, major), 49.6 (d, J(P,C)Z

11.4 Hz, –N(CH₃)CHCH₂N–, minor), 49.1 (d, J(P,C)Z

11.6 Hz, –N(CH₃)CHCH₂N–, major), 48.5 (d, J(P,C)Z5.0

Hz, –N(CH₃)CHCH₂N–, minor), 48.1 (d, J(P,C)Z5.3 Hz,

–N(CH₃)CHCH₂N–, major), 39.2 (d, J(P,C)Z5.4 Hz,

–N(CH₂CH₃)₂, major), 39.8 (d, J(P,C)Z5.1 Hz, –N(CH₂

CH₃)₂, minor), 18.9 (–N(CH₃)CHCH₂N–, major), 18.8

(–N(CH₃)CHCH₂N–, minor), 14.1 (–N(CH₂CH₃)₂, major),

13.8 (–N(CH₂CH₃)₂, minor); ³¹P NMR (160 MHz, CDCl₃,

25 8C,H₃PO₄external):dZ24.08(minor, 37%), 22.33(major,

63%); IR (KBr): n_max(cm^K1)Z2965.0 (C–H), 1602.3, 1497,

1305.8, 1299.6 (Ph–N–R), 1225.0 (P]O), 1203.5, 1034.7

(P–O–C), 753.9, 756.5.

cis-13b. Colourless viscous oil (31.0 mg, 32%); [a]²_D⁰ZC

19.8 (c 0.94, CHCl₃); H NMR (400 MHz, CDCl₃, 25 8C,

1

TMS): dZ7.17 (t, J(H,H)Z7.6 Hz, 1H, –CH–, m-Ar), 7.02

(d, J(H,H)Z7.6 Hz, 1H, –CH–, o-Ar), 6.84 (t, J(H,H)Z

7.6 Hz, 1H, –CH–, p-Ar), 3.67–3.61 (m, 1H, –NCH(R)CH₂

N–), 3.35–3.14 (m, 3H, –NCH(CH₃)₂and –NCH(R)CH₂N),

3.03–2.86 (m, 4H, –N(CH₂CH₃)₂), 2.17–2.03 (m, J(H,H)Z

6.9, 6.8, 2.0 Hz, 1H, –CHCH(CH₃)₂), 1.35 (d, J(H,H)Z6.9

Hz, 3H, one –CH₃of –NCH(CH₃)₂), 1.23 (d, J(H,H)Z

6.6 Hz, 3H, one –CH₃of –NCH(CH₃)₂), 0.91 (d,

J(H,H)Z6.9 Hz, 3H, one –CH₃of –CHCH(CH₃)₂), 0.87

(d, J(H,H)Z6.8 Hz, 3H, one –CH₃of –CHCH(CH₃)₂), 0.89

(t, J(H,H)Z7.0 Hz, 6H, N(CH₂CH₃)₂); ¹³C NMR

(100 MHz, CDCl₃, 25 8C, CDCl₃): dZ142.27

2

(d, J(P,C)Z7.2 Hz, –C–, Ar), 128.7 (–CH–, m-Ar), 120.5

(–CH–, p-Ar), 116.0 (d, ³J(P,C)Z4.1 Hz, –CH–, o-Ar), 56.8

2

(d, J(P,C)Z8.6 Hz, –NCH(R)CH₂N–), 45.1 (d, J(P,C)Z

2.2 Hz, –NCH(CH₃)₂), 43.5 (d, ²J(P,C)Z11.1 Hz,

–NCH(R)CH₂N–), 39.1 (d, ²J(P,C)Z4.6 Hz, –N(CH₂

CH₃)₂), 27.1 (d, ²J(P,C)Z8.1 Hz, CHCH(CH₃)₂), 20.4

(one –CH₃of –NCH(CH₃)₂), 20.0 (one –CH₃of –NCH

(CH₃)₂), 18.2 (one CH₃of –CHCH(CH₃)₂), 14.04 (one

–CH₃of –CHCH(CH₃)₂), 13.35 (–N(CH₂CH₃)₂); ³¹P NMR

(160 MHz, CDCl₃, 25 8C, H₃PO₄external): dZ22.91; IR

(ﬁlm): n_max(cm^K1)Z2968.9 (C–H), 1603.6, 1502.8, 1223.3

(P]O), 1203.8, 1184.3, 1033.5 (P–N–C); MS (70 eV, EI):

m/z (%): 337 (31) [M^C], 294 (100) [M^CKi-Pr], 265 (8)

[M^CKNEt₂], 252 (30) [M^CKi-Pr–CH₂]CHCH₃], 223

(39) [HCNPhP(O)NEt^C₂]; HMRS (EI): obtained

337.227622; M^CC₁₈H₃₂N₃OP requires 337.228301.

4.6.2. Preparation of cis- and trans-3-N⁰-benzyl-2-

diethylamine-1-N-phenyl-4-methyl-1,3,2-l⁵-diazaphos-

pholidin-2-one 18. The general method for the coupling of

aminoalcohols with diethylphosphoramidous dichloride

described previously was followed,⁹using 2-N-benzyl-1-

N⁰-phenylpropanodiamine (202.0 mg, 0.84 mmol), diethyl-

phosphoramidous dichloride (160.0 mg, 0.84 mmol) and

dry trietilamine (235.0 ml, 1.68 mmol). The residue obtained

was puriﬁed by column chromathography (n-Hex/AcOEt,

8:2), and two fractions corresponding to the two diastereo-

mers cis-18 and trans-18 were obtained.

4.6. Reactions towards the elucidation of the mechanism

of the imide–amide rearrangement of

oxazaphosphorimidates

4.6.1. Imide–amide rearrangement of 16. The general

procedure (Section 4.5) was followed using the racemic

oxazaphospholane 6b (226 mg, 0.85 mmol) and phenyl-

azide (101 mg, 0.85 mmol) in dry toluene (1.0 ml). After

12 h at room temperature BF₃$OEt₂(10.4 ml, 10 mol%) was

added and the mixture heated to 100 8C. The total

conversion of 16 was observed by ³¹P NMR after 12 h at

100 8C. The residue obtained after work-up was puriﬁed by

column chromatography (CHCl₃/Et₂O, 5:95 until 1:1)

affording an inseparable mixture of the two diastereomers

(minor/major, 37:63) cis- and trans-1-N-benzyl-2-diethyl-

amino-3-N⁰-phenyl-4-methyl-1,3,2-l⁵-diazaphospholidine-

2-one 17.

cis-18. Colourless crystals (60.6 mg, 20%); R_fZ0.32

(n-Hex/AcOEt, 1:1). Mp 123–125 8C (isolated from chro-

matography); H NMR (400 MHz, CDCl₃, 25 8C, TMS):

1

dZ7.47 (d, J(H,H)Z7.4 Hz, 2H, –CH–, o-Ar), 7.25

(t, J(H,H)Z7.4 Hz, 2H, –CH–, m-Ar), 7.18 (t, J(H,H)Z

7.4 Hz, 3H, two –CH–, m-Ar and one –CH–, p-Ar), 7.01

E. J. Cabrita et al. / Tetrahedron 60 (2004) 11933–11949

11947

(d, J(H,H)Z7.4 Hz, 2H, –CH–, o-Ar), 6.83 (t, J(H,H)Z

7.4 Hz, 1H, –CH–, p-Ar), 4.15 (dd, ³J(P,H)Z10.2 Hz,

J(H,H)Z15.3 Hz, 1H, one of –NCH₂Ph), 4.00 (t, ³J(P,H)Z

15.3 Hz, J(H,H)Z15.3 Hz, 1H, one of –NCH₂Ph), 3.55–

3.43 (m, 2H, –NCH(CH₃)CH₂N– and one of –NCH(CH₃)

CH₂N–), 3.11–3.00 (m, 3H, one of –NCH(CH₃)CH₂N– and

one –CH₂– of –N(CH₂CH₃)₂), 2.92–2.80 (m, 2H, one

–CH₂– of –N(CH₂CH₃)₂), 1.08 (d, J(H,H)Z5.6 Hz, 3H,

–NCH(CH₃)CH₂N–), 0.80 (t, J(H,H)Z7.1 Hz, 6H,

–N(CH₂CH₃)₂); ¹³C NMR (100 MHz, CDCl₃, 25 8C,

CDCl₃): dZ142.0 (d, ²J(P,C)Z6.8 Hz, –C–, Ar), 137.4

(–C–, Ar), 128.8 (–CH–, m-Ar), 128.7 (–CH–, o-Ar), 128.3

(–CH–, m-Ar), 127.1 (–CH–, p-Ar), 120.5 (–CH–, p-Ar),

115.6 (d, ³J(P,C)Z5.1 Hz, –CH–, o-Ar), 51.6 (d, ²J(P,C)Z

11.3 Hz, –NCH(CH₃)CH₂N–), 47.7 (d, J(P,C)Z11.9 Hz,

–NCH(CH₃)CH₂N–), 45.8 (d, ²J(P,C)Z5.5 Hz, –NCH₂Ph),

39.5 (d, ²J(P,C)Z4.8 Hz, –N(CH₂CH₃)₂), 18.8

(d, ³J(P,C)Z7.5 Hz, –NCH(CH₃)CH₂N–), 14.0 (–N(CH₂

CH₃)₂); ³¹P NMR (160 MHz, CDCl₃, 25 8C, H₃PO₄

external): dZ22.7; IR (KBr): n_max(cm^K1)Z2967.0 (C–H,

Ar), 1602.9, 1496.9, 1330.1 (Ph–N–R), 1305.8, 1225.1

(P]O), 1203.1, 1030.3 (P–O–C), 756.5; MS (70 eV, EI):

m/z (%): 357 (46) [M^C], 342 (56) [M^CKCH₃], 285 (76)

[M^CKNEt₂], 181 (36), 134 (55) [CH₃CH₂CH₂NHPh^C],

106 (34), 91 (100) [PhCH^C₂], 72 (49); HMRS (EI): obtained

357.197240; M^CC₂₀H₂₈N₃OP requires 357.1970011.

13.8 mmol) and dry triethylamine (3.84 ml, 24.6 mmol) in

dry diethyl ether (30 ml), under argon atmosphere, (S)-N-

isopropylvalinol (2.0 g, 13.8 mmol) was added dropwise.

The addition was controlled in order to avoid that the

temperature of the reaction would rise beyond 10 8C. After

the addition was complete, the mixture was allowed to stir

during 3 h at room temperature. The amine salts were then

separated by ﬁltration under argon atmosphere and wash

repeatedly with dry ethylic ether. The liquid fractions were

combined and the solvent removed by distillation under

argon atmosphere. The residue obtained was puriﬁed by low

pressure distillation affording a colourless slightly viscous

liquid, corresponding to the 2-chloro-oxazaphospholidine

(1.23 g, 43%) as a mixture of cis and trans diastereomers

(cis/trans; 10:90, as determined by ³¹P NMR). Bp 140 8C

(0.05 mmHg, KughelRohr); ¹H NMR (400 MHz, tol-d₈,

25 8C, tol): dZ4.25 (br, ¹H, –OCH₂CH(R)N–), 3.92 (br, ¹H,

–OCH₂CH(R)N–), 3.10 (bl, 1H, –OCH₂CH(R)N–), 3.03 (bl,

–NCH(CH₃)₂), 1.53 (br, 1H, –CH(CH₃)₂), 1.26 (dd,

J(H,H)Z6.7 Hz, J(P,H)Z2.0 Hz, 3H, –NCH(CH₃)₂), 1.06

(br, 3H, NCH(CH₃)₂), 0.52 (br, 6H, –CH(CH₃)₂); ¹³C NMR

(100 MHz, tol-d₈, 25 8C, tol-d₈): dZ70.6 (br, –OCH₂

CH(R)N–), 59.9 (br, –OCH₂CH(R)N–), 45.71 (d,

²J(P,C)Z9.0 Hz, –NCH(CH₃)₂), 27.0 (br, –CH(CH₃)₂),

23.3 (d, ³J(P,C)Z19.7 Hz, –NCH(CH₃)₂), 20.6 (br,

–CH(CH₃)₂), 19.2 (–NCH(CH₃)₂), 14.4 (bl, –CH(CH₃)₂);

³¹P NMR (160 MHz, tol-d₈, 25 8C, H₃PO₄external): dZ

180.7 (cis), 171.2 (trans).

trans-18. Colourless crystals (30.9 mg, 10%); R_fZ0.21

(n-Hex/AcOEt, 1:1). Mp 64–66 8C (isolated from chroma-

1

tography); H NMR (400 MHz, CDCl₃, 25 8C, TMS): dZ

4.7.2. Imide–amide rearrangement of 19. The general

procedure (Section 4.5) was followed in a NMR tube using

the previous described (4S)-2-chloro-3-N-,4-di-isopropil-

1,3,2-oxazaphospholidine (89.0 mg, 0.424 mmol) and

phenylazide (50.5 mg, 0.424 mmmol) in dry toluene-d₈

(0.5 ml). After heating the NMR tube for 30 min at 40 8C,

no N₂evolution could be seen (indicating that the

Staudinger product 19 was not being formed) and therefore

the temperature was slowly raised until N₂evolution started

(80 8C). After 40 min N₂evolution ceased and ³¹P NMR

spectrum was acquired (³¹P NMR: dZK2.31 and

K3.23 ppm, in 86:14 ratio) conﬁrming the formation of

19. BF₃$OEt₂was then added (5.2 ml, 10 mol%) and the

mixture was allowed to react for 18 h. The ³¹P NMR

spectrum acquired at this point revealed that all 19 had been

consumed and three new signals could be seen, two signals

corresponding to cis- and trans-21 the products of the

rearrangement (³¹P NMR: dZ21.38 and 17.63 ppm, in

72:28 ratio) and one broad signal at K0.7 ppm, that was

afterwards identiﬁed as the dimeric compound 20. The

residue obtained after work-up was puriﬁed by column

chromatography (n-Hex/AcOEt, 8:2) and three fractions

corresponding to the two diastereomers cis-(2S,4S)- and

trans-(2R,4S)-2-chloro-1-N-phenyl-3-N⁰-4,4-diisopropyl-1,

3,2-l⁵-diazaphospholidine-2-one 21 and the dispiro[(3-N-,

4-diisopropyl-1,3,2-l⁵-oxazaphospholidine)-2,2⁰-(2⁰,4⁰-

dichloro-1⁰,3⁰-diphenyl-1⁰,3⁰,2⁰-l⁵-diazadiphosphitidine)-4⁰,

2⁰⁰-(3⁰⁰-N-,4⁰⁰-diisopropyl-1⁰⁰,3⁰⁰,2⁰⁰-l⁵-oxazaphospholidine)]

20 were obtained.

7.31–7.18 (m, 7H, –CH–, Ar), 7.00 (d, J(H,H)Z8.0 Hz, 2H,

–CH–, o-Ar), 6.85 (t, J(H,H)Z7.3 Hz, 1H, –CH–, p-Ar),

4.09 (dd, J(P,H)Z7.7 Hz, J(H,H)Z15.2 Hz, 1H, one of

3

–NCH₂Ph), 4.03 (t, ³J(P,H)Z4.8 Hz, J(H,H)Z15.2 Hz, 1H,

one of –NCH₂Ph), 3.66 (td, J(P,H)Z8.5 Hz, J(H,H)Z6.8,

2.3 Hz, 1H, one of –NCH(CH₃)CH₂N–), 3.46–3.36 (m, 1H,

J(P,H)Z18.0 Hz, J(H,H)Z7.4, 6.8, 6.0 Hz, –NCH(CH₃)

CH₂N–), 3.20–3.09 (m, 3H, one of –NCH(CH₃)CH₂N– and

one –CH₂– of –N(CH₂CH₃)₂), 2.97–2.85 (m, 2H, one

–CH₂– of –N(CH₂CH₃)₂), 1.21 (d, J(H,H)Z6.3 Hz, 3H,

–NCH(CH₃)CH₂N–), 0.84 (t, J(H,H)Z7.1 Hz, 6H,

–N(CH₂CH₃)₂); ¹³C NMR (100 MHz, CDCl₃, 25 8C,

CDCl₃): dZ142.5 (d, ²J(P,C)Z6.7 Hz, –C–, Ar), 138.0

2

(d, J(P,C)Z7.9 Hz, –C–, Ar), 128.9 (–CH–, m-Ar), 128.5

(–CH–, o-Ar), 128.2 (–CH–, m-Ar), 127.3 (–CH–, p-Ar),

120.4 (–CH–, p-Ar), 115.5 (d, ³J(P,C)Z4.0 Hz, –CH–,

o-Ar), 51.2 (d, ²J(P,C)Z12.2 Hz, –NCH(CH₃)CH₂N–),

48.3 (d, ²J(P,C)Z10.5 Hz, –NCH(CH₃)CH₂N–), 45.2

2

(d, J(P,C)Z5.6 Hz, –NCH₂Ph), 39.2 (d, J(P,C)Z3.5 Hz,

–N(CH₂CH₃)₂), 18.55 (–NCH(CH₃)CH₂N–), 14.0

(–N(CH₂CH₃)₂); ³¹P NMR (160 MHz, CDCl₃, 25 8C,

H₃PO₄external): dZ20.09; IR (KBr): n_max(cm^K1)Z

2970.0 (C–H, Ar), 1602.3, 1497.1, 1299.6 (Ph–N–R),

1224.2 (P]O), 1203.7, 1034.7 (P–O–C), 753.9, 726.9;

MS (70 eV, EI): m/z (%): 357 (76) [M^C], 342 (57)

[M^CKCH₃], 285 (66) [M^CKNEt₂], 271 (23), 171 (28),

134 (33) [CH₃CH₂CH₂NHPh^C], 91 (100) [PhCH₂^C].

4.7. Imide–amide rearrangement of 19

Compound 20. Colourless crystals (19.4 mg, 15%); R_fZ

0.63 (n-Hex/AcOEt, 8:2). Mp 164–166 8C (AcOEt/n-Hex);

¹H NMR (400 MHz, CDCl₃, 25 8C, TMS): dZ7.36–7.23

(br, 7H, –CH–, Ar), 713–7.06 (br, 3H, –CH–, Ar), 4.14

4.7.1. Preparation of (4S)-2-chloro-3-N-,4-di-isopropil-

1,3,2-oxazaphospholidine—precursor of 19. To a stirred,

ice-cold solution of phosphorus trichloride (1.20 ml,

11948

E. J. Cabrita et al. / Tetrahedron 60 (2004) 11933–11949

3

(br, 1H, one of –OCH₂–), 4.38 (br, 1H, one of –OCH₂–),

3.60–3.50 (br, 4H, –OCH₂– and 2!–N(R)CH), 2.99 (br,

1H, –N(R)CH–), 266–2.59 (br, 1H, –N(R)CH–), 2.33–2.26

(br, 1H, –CH(CH₃)₂), 1.91 (br, 1H, –CH(CH₃)₂), 1.40

(br, 6H, 2!–CH₃), 1.04–0.99 (br, 3H, 1!–CH₃), 0.80–0.68

(m, 9H, 3!–CH₃), 0.53 (br, 3H, 1!CH₃), 0.40 (br, 3H,

1!–CH₃); ¹³C –NMR (100 MHz, CDCl₃, K40 8C, CDCl₃):

dZ136.9, 135.9, 135.6, 130.2, 129.7, 125.3, 125.1, 124.8,

124.1, 122.6, 120.8, 120.3, 118.9, 62.3 (–N(R)CH–), 61.8

(–N(R)CH–), 49.0 (–OCH₂–), 48.5 (–OCH₂–), 47.3

(–CH(CH₃)₂), 33.3 (–CH(CH₃)₂), 23.3, 25.1, 24.2, 22.7,

22.2, 21.6, 21.3, 20.8, 20.1, 19.8; ³¹P NMR (160 MHz,

CDCl₃, 25 8C, H₃PO₄external): dZK0.72 (bl), K1.72 (bl);

IR (KBr): n_max(cm^K1)Z2976.9 (C–H), 1596.2, 1490.3,

1270.8, 1244.7, 1159.1, 1042.5 (P–N–C), 971.1, 948.4,

757.5, 698.1; MS (70 eV, EI): m/z (%): 604 (5), [M^CC4],

602 (25) [M^CC2], 600 (30) [M^C], 557 (100) [M^CKi-Pr],

515 (25) [M^CKi-Pr–CH]CH₂CH₃], 473 (15) [M^CKCH₂

CH(i-Pr)N-i-Pr], 122 (30).

(–CH–, m-Ar), 123.0 (–CH–, p-Ar), 117.5 (d, J(P,C)Z

4.8 Hz, –CH–, o-Ar), 55.7 (d, ²J(P,C)Z10.5 Hz,

–NCH(R)CH₂N–), 46.4 (d, ²J(P,C)Z5.5 Hz, –NCH

(CH₃)₂), 42.8 (d, ²J(P,C)Z15.8 Hz, –NCH(R)CH₂N–),

29.9 (d, ³J(P,C)Z3.2 Hz, –CHCH(CH₃)₂), 21.7 (–NCH

(CH₃)₂), 20.6 (–NCH(CH₃)₂), 18.7 (–CHCH(CH₃)₂), 14.4

(–CHCH(CH₃)₂); ³¹P NMR (160 MHz, CDCl₃, 25 8C,

H₃PO₄external): dZ18.81; IR (KBr): n_max(cm^K1)Z

2974.2 (C–H), 1598.6, 1501.5, 1269.0 (P]O), 1197.9,

1043.1 (P–N–C), 759.6; MS (70 eV, EI): m/z (%): 302 (9)

[M^CC2], 300 (22) [MC], 257 (68) [M^CKi-Pr], 215 (100)

[M^CKi-Pr–CH]CH₂CH₃], 179 (15) [M^CK2!i-Pr–Cl],

104 (16), 77 (27) [C₆H^C₅]; HRMS (EI): obtained

300.115979; M^CC₁₄H₂₂N₂OPCl requires 300.115830.

Acknowledgements

ˆ

We would like to thank Fundac¸a˜o para a Ciencia

e Tecnologia (FCT, project PRAXIS XXI PCEX/C/

QUI/70/96 and grant PRAXIS XXI BD/4508/94).

cis-(2S,4S)-21. 73.2 mg, 57%, R_fZ0.37 (n-Hex/AcOEt,

8:2); white crystals; Mp 128–130 8C (from chromatography;

[a]²_D⁰ZK28.4 (c 0.5, CHCl₃); ¹H NMR (400 MHz, CDCl₃,

25 8C, TMS): dZ7.29–7.22 (m, 4H, –CH–, o-Ar and m-Ar),

7.01 (t, J(H,H)Z7.0 Hz, 1H, –CH–, p-Ar), 3.69.3.63

(m, ³J(P,H)Z9.6 Hz, J(H,H)Z7.0, 6.5, 4.4 Hz, 1H,

–NCH(R)CH₂N–), 3.56–3.42 (m, 2H, –NCH(CH₃)₂and

one of –NCH(R)CH₂N–), 3.23 (td, J(P,H)Z8.9 Hz,

J(H,H)Z8.9, 1.9 Hz, 1H, one of –NCH(R)CH₂N–), 2.19–

2.08 (m, J(H,H)Z7.7, 6.9, 4.4 Hz, 1H, –CHCH(CH₃)₂),

1.52 (d, J(H,H)Z7.0 Hz, 3H, one –CH₃of –NCH(CH₃)₂),

1.29 (d, J(H,H)Z6.5 Hz, 3H, one –CH₃of –NCH(CH₃)₂),

0.91 (d, J(H,H)Z7.7 Hz, 3H, one –CH₃of –CHCH(CH₃)₂),

0.891 (d, J(H,H)Z6.9 Hz, 3H, one –CH₃of –CHCH

(CH₃)₂); ¹³C NMR (100 MHz, CDCl₃, 25 8C, CDCl₃): dZ

References and notes

1. Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2003, 125,

2208–2216.

2. Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000,

432–440.

3. Denmark, S. E.; Su, X.; Nishigaichi, Y.; Coe, D. M.; Wong,

K.-T.; Winter, S. B. D.; Choi, J. Y. J. Org. Chem. 1999,

1958–1967 and references therein.

4. Legrand, O.; Brunel, J. M.; Buono, G. Tetrahedron Lett. 1998,

39, 9419–9422.

2

139.9 (d, J(P,C)Z4.7 Hz, –C–, Ar), 129.3 (–CH–, m-Ar),

123.1 (–CH–, p-Ar), 117.5 (d, ³J(P,C)Z5.4 Hz, –CH–,

5. Brunel, J. M.; Constantieux, T.; Legrand, O.; Buono, A.

Tetrahedron Lett. 1998, 39, 2961–2964.

2

o-Ar), 56.9 (d, J(P,C)Z10.9 Hz, –NCH(R)CH₂N–), 48.8

(d, ²J(P,C)Z5.1 Hz, –NCH(CH₃)₂), 42.5 (d, ²J(P,C)Z

6. Hulst, R.; Heres, H.; Fitzpatrick, K.; Peper, N. C. M. W.;

Kellogg, R. M. Tetrahedron: Asymmetry 1996, 7, 2755–2760.

7. Iseki, T.; Kuroki, Y.; Takahashi, M.; Kobayashi, Y. Tetra-

hedron Lett. 1996, 29, 5149–5150.

14.5 Hz, –NCH(R)CH₂N–), 28.1 (d, ³J(P,C)Z3.6 Hz,

3

–CHCH(CH₃)₂–), 21.2 (–NCH(CH₃)₂), 20.6 (d, J(P,C)Z

2.3 Hz, –NCH(CH₃)₂), 17.7 (–CHCH(CH₃)₂), 14.8

(–CHCH(CH₃)₂); ³¹P NMR (160 MHz, CDCl₃, 25 8C,

H₃PO₄externo): dZ22.25; IR (KBr): n_max(cm^K1)Z

2967.6 8 (C–H), 1602.8, 1502.5, 1267.1 (P]O), 1184.2,

754.6; MS (70 eV, EI): m/z (%): 302 (13) [M^CC2], 300

(27) [M^C], 257 (58) [M^CKi-Pr], 215 (97) [M^CKi-Pr–

CH]CH₂CH₃], 179 (15) [M^CK2!i-Pr–Cl], 104 (31), 83

(100) [HPClNPh^C].

8. Cabrita, E. J.; Candeias, S. X.; Ramos, A. M.; Afonso,

C. A. M.; Santos, A. G. S. Tetrahedron Lett. 1999, 40,

137–140.

9. Cabrita, E. J.; Afonso, C. A. M.; Santos, A. G. S. Chem. Eur. J.

2001, 7, 1455–1467.

10. Setzer, W.; Black, B. G.; Hovanes, B. A. J. Org. Chem. 1989,

54, 1709–1713.

11. Boulet, C. A.; Tregear, S. J.; Hansen, A. S. Heterocycles 1991,

32, 2105–2110.

trans-(2R,4S)-21. 16.2 mg, 13%, R_fZ0.29 (n-Hex/AcOEt,

8:2); colourless viscous oil; [a]²_D⁰ZC68.4 (c 1.41, CHCl₃);

¹H NMR (400 MHz, CDCl₃, 25 8C, TMS): dZ7.29–7.22

(m, 4H, –CH–, o-Ar and m-Ar), 7.01 (t, J(H,H)Z7.0 Hz,

1H, –CH–, p-Ar), 3.67–3.55 (m, ³J(P,H)Z19.5 Hz,

J(H,H)Z6.8, 6.7 Hz, 1H, –NCH(CH₃)₂), 3.51–3.32

(m, 3H, –NCH(R)CH₂N– and –NCH(R)CH₂N–), 2.10–

2.02 (m, J(H,H)Z7.9, 7.7, 4.0 Hz, 1H, –CHCH(CH₃)₂),

1.43 (d, J(H,H)Z6.8 Hz, 3H, one –CH₃of –NCH(CH₃)₂),

1.32 (d, J(H,H)Z6.7 Hz, 3H, one –CH₃of –NCH(CH₃)₂),

0.93 (d, J(H,H)Z7.7 Hz, 3H, one –CH₃of –CHCH(CH₃)₂),

0.91 (d, J(H,H)Z7.9 Hz, 3H, one –CH₃of –CHCH(CH₃)₂);

¹³C NMR (100 MHz, CDCl₃, 25 8C, CDCl₃): dZ129.32

12. Cooper, D. B.; Hall, C. R.; Harrison, J. M.; Inch, T. D.

J. Chem. Soc., Perkin Trans. 1 1977, 1969–1980.

13. Verkade, J. G.; Quin, L. D. Phosphorus-31 NMR Spectroscopy

in Stereochemical Analysis. In Methods in Stereochemical

Analysis; VCH: Deerﬁeld Beach, FL, 1987; Vol. 8,

pp 297–330.

14. Ando, A.; Shiori, T. Tetrahedron 1989, 45, 4969–4988.

15. Nitrogen Compounds, Carboxylic acids, Phosphorus Com-

pounds; Sutherland, I. O., Ed.; Comprehensive Organic

Chemistry.TheSynthesisandReactionsofOrganicCompounds;

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11949

16. The imide–amide rearrangement was performed starting from

the corresponding ephedrine derived oxazaphospholidine and

generating in situ the phosphorimide with benzylazide or

phenylazide, following the general procedure described in

Section 4.5 of Section 4. Compounds 15a and 15b were

allowed to react for 12 h. The ³¹P NMR of the crude showed a

complex mixture with multiple signals. After work-up and

column chromatography the only products isolated were the

phosphorus oxides (30–70% yield) corresponding to the

several possibilities of hydrolysis of 15a and 15b, namely

hydrolysis by loss of NPh or NBn, by loss of NEt₂, and even

loss of the ephedrine moiety.

19. Kukhar, V. P.; Kasheva, T. N.; Kasukhin, L. F.; Ponomarchuk,

M. P. J. Gen. Chem. USSR (Engl. Transl.) 1984, 54,

1360–1364.

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891–904.

21. Gilyarov, V. A.; Tikhonina, N. A.; Andrianov, V. G.;

Struchkov, Yu. T.; Kabachnik, M. I. J. Gen. Chem. USSR

(Engl. Transl.) 1978, 48, 671–677.

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Laboratory Chemicals, 2nd ed.; Pergamon: London, 1980.

23. Perich, J. W.; Johns, R. B. Synthesis 1988, 142.

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Heteroatom Attached by a Single Bond. In Ley, S. V., Ed.;

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Elsevier: Oxford, 1995; Vol. 2.

17. Since compounds 17 and 18 are very similar, compound 18

was also prepared by an independent way, by the coupling of

diethylphosphoramidous dichloride with 2-N⁰-benzyl-1-N-

phenylpropanodiamine. The comparison of the spectral data

conﬁrmed structure 17 as the product of the rearrangement.

18. By warming-up 19 in the absence of BF₃$OEt₂the conversion

to 20 is almost quantitative. An experiment was also made in

order to determine if 20 could be involved in the mechanism of

the rearrangement; 19 was allowed to react until approxi-

mately 50% conversion to 20 was observed, at this point

BF₃$OEt₂was added and the reaction followed by ³¹P NMR.

After the addition of the Lewis acid, the concentration of 20

remain practically unaltered and the remaining 19 was

converted to product 21.

25. Koziara, A.; Osowaka-Pacewicka, K.; Zawadzki, S.; Zwier-

zac, A. Synthesis 1985, 202.

´

26. Alajarin, M.; Molina, P.; Sanchez-Andrada, P. J. Org. Chem.

1999, 64, 1121–1130.

27. Smith, P. A. S.; Brown, B. B. J. Am. Chem. Soc. 1951, 73,

2438–2441.

28. White, E. H.; Field, K. W.; Hendrickson, W. H.; Dzadzic, P.;

Roswell, D. F.; Paik, S.; Mullen, P. W. J. Am. Chem. Soc.

1992, 114, 8008.

Article Doi

Imide-amide rearrangement of oxazaphosphorimidates: Studies towards the application to the synthesis of chiral Lewis bases

DOI: 10.1016/j.tet.2004.09.079

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Full text of DOI:10.1016/j.tet.2004.09.079

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