A new version of the reverse-Cope elimination initiated by the nucleophilic addition of allylamines to nitrones: A synthesis of vicinal diamines

Article abstract of DOI:10.1039/b003959o

Attempts to utilize the sugar-derived nitrones 1 in enantioselective [1,3]dipolar cycloadditions with protected aliylamines 6 are only partly successful, giving mixtures of the expected adducts 7. However, reactions between nitrones 1 and unprotected ally

Full text of DOI:10.1039/b003959o

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A new version of the reverse-Cope elimination initiated by the
nucleophilic addition of allylamines to nitrones: a synthesis of
vicinal diamines
1
Michael B. Gravestock,a David W. Knight,*b,c K. M. Abdul Malikc and Steven R. Thorntonb
a AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire,
UK, SK10 4TG
b School of Chemistry, Nottingham University, University Park, Nottingham, UK NG7 2RD
c Chemistry Department, Cardiff University, PO Box 912, Cardiff, UK CF10 3TB
Received (in Cambridge, UK) 17th May 2000, Accepted 31st July 2000
First published as an Advance Article on the web 18th September 2000
Attempts to utilize the sugar-derived nitrones 1 in enantioselective [1,3]dipolar cycloadditions with protected
allylamines 6 are only partly successful, giving mixtures of the expected adducts 7. However, reactions between
nitrones 1 and unprotected allylamine 11 follow a different pathway involving sequential nucleophilic addition to the
nitrone by the amine, reverse-Cope cyclization and Meisenheimer rearrangement leading to the 1,2,5-oxadiazinanes
12 and 13. Similar reactions with the benzaldehyde derived nitrone 8 are successful, giving the trans-oxadiazinanes
24, 33 and the stereoisomers 38 and 39 from linalylamine 37, but only when the terminus of the allylamine is
unsubstituted are the reactions efficient. A range of N-alkylallylamines 43, 45, 47 and 49, however, react smoothly
with nitrone 8, as competing imine formation is precluded. Various mechanistic aspects are discussed, along with
the effects of aryl substituents in N-benzylallylamines 57 and at the 4-position (59) of the nitrone 8, none of which
is found to enhance the overall reaction rate. The initial oxadiazinanes are useful as precursors to both amino-
hydroxylamines 69 and vicinal diamine derivatives 70.
Synthetic approaches to polyhydroxylated pyrrolizidines and
indolizidines, along with similarly festooned pyrrolidines and
piperidines, have attracted enormous interest during the past
decade or so, stimulated especially by the prospects of discover-
ing novel antiviral agents.1 Obvious, but by no means exclusive,
starting materials for these syntheses are natural sugars, a
inner carbon of the dipolarophile,4,5 with, hopefully, useful
levels of stereocontrol induced by the sugar residue. Subsequent
unmasking of the latent ketone function, along with N–O bond
cleavage would lead to synthetic equivalents of the polyoxygen-
ated diaminononanone array 3 and thence to a range of both
mono- and bicyclic azasugars, such as the quinolizidine 4. An
attraction of this idea is that the precursor hexulofuranosonic
acid 5a is cheap and readily available, being both an intermedi-
ate in the industrial synthesis of Vitamin C as well as a powerful
systemic plant growth regulator, marketed as its sodium salt
under various names including ‘Dikegulac’, ‘Atrinal’ and ‘Cut-
less’.6 The idea of using carbohydrate-derived nitrones in this
area is not new: for example, Vasella and co-workers7 have used
dipolar cycloadditions of a nitrone prepared from a mannose
oxime to access chiral isoxazolidines which serve as proline
analogues while the Kibayashi group8 have employed a related
nitrone, obtained from -gulono-γ-lactone, in cycloadditions
with protected allylamines as the key starting point in a total
synthesis of (ϩ)-negamycin.
strategy most elegantly exemplified by the Fleet group.2
A
combination of this and our interest in nitrone chemistry3 led
us to speculate that nitrones 1 could be useful as precursors of
a variety of bicyclic azasugars, following [1,3]dipolar cyclo-
addition to an allylamine derivative which we expected would
proceed regioselectively to stereoisomers 2 (Scheme 1), given
the usual propensity for the oxygen of the nitrone to add to the
Results and discussion
The nitrones 1a–c were obtained as summarized in Scheme 2.
Previous methods for obtaining ester 5b include the use of
diazomethane on a small scale and KH–MeI on a larger scale,9
along with a combination of MeI and potassium carbonate in
DMF.10 We found it more convenient to substitute 4-methyl-
pentan-2-one as solvent and were able to secure a 95% isolated
yield of the methyl ester 5b. Direct reduction using diisobutyl-
aluminium hydride (DIBAL) in hexanes at Ϫ78 ЊC provided
convenient access to the required aldehyde 5c, despite a typical
conversion of around 60%, the remainder of the material being
the separable ester 5b. The aldehyde, which was isolated as a
hydrate, was then converted into the nitrones 1a–c, which
turned out to be rather sensitive intermediates and which were
Scheme 1
3292
J. Chem. Soc., Perkin Trans. 1, 2000, 3292–3305
This journal is © The Royal Society of Chemistry 2000
DOI: 10.1039/b003959o

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Fig. 1
Scheme 3
stereoselectivity of the cycloaddition. While we were aware of
the possibility that the free amine could attack the nitrone to
give an aminal, the reversibility of this should still allow the
desired cycloaddition to take place. In the event, however,
the reaction took an entirely different pathway.12 A solution of
the nitrone 1a and two equivalents of allylamine 11 was
refluxed for 10 h until TLC and 1H NMR analysis again
indicated complete disappearance of the former. Two adducts
were separated by column chromatography in 36 and 10%
yield, respectively, which were evidently very different from the
[1,3]dipolar cycloadducts 7 according to preliminary 1H NMR
analysis. Mass spectral data showed clearly that these were 1:1
adducts and NMR data showed that the sugar residue was
1
intact. Spectacular differences in the H NMR spectra of both
products, relative to the dipolar cycloadducts 7, included the
appearance of methyl resonances as doublets [δH 0.88 and 1.17
(both J 6.3 Hz), respectively]. The major isomer also showed an
apparent ABX system as part of a six-membered ring [dH 2.67
(dd, J 13.7 and 10.6 Hz, HAax); 2.89 (dd, J 13.7 and 3.0 Hz,
HBeq); 2.41 (dqd, J 10.6, 6.3 and 3.0 Hz, HXax)], suggestive of a
partial structure -CH2CH(Me)-. The appearance of an addi-
tional sharp singlet at δH 4.66 led us to speculate that the
product was the trans-1,2,5-oxadiazinane 12a, a proposal con-
sistent with these data and 13C NMR and some NOE data, and
that the minor isomer was hence the corresponding cis-isomer
13a. The latter showed much more indistinct resonances at
ambient temperature, consistent with a not unreasonable con-
formational mobility. A third minor product, visible in 1H
NMR spectra of the crude product, was not isolated but was
tentatively identified as the imine 14 on the basis of typical
Scheme 2
therefore prepared as required. The [1,3]dipolar cycloadditions
between the nitrones 1 and both N-Boc-allylamine 6a and
N-benzoylallylamine 6b were carried out in refluxing toluene, as
is typical of many such reactions.3–5 TLC analysis indicated com-
plete reaction after approximately 10 h but only poor returns
of the isoxazolidines 7 were isolated with a dismal level of
stereoselection, although the cycloadditions were highly regio-
selective, as expected.3–5 In the case of the N-tert-butyl nitrone
1c, a single isoxazolidine 7e was isolated in poor yield; another
isomer, presumably cis-7e, was visible in the 1H NMR spectrum
of the crude product. The structures were assigned particularly
on the basis of the relatively high-field shifts of the 4-CH2 pro-
tons in the 1H NMR spectra of the isomeric products 7, as well
as by comparisons with known, related structures3–5 and NOE
data (Fig. 1). In view of the almost complete lack of stere-
oselection, this synthetic method was not pursued further.
In view of the poor yields of the isoxazolidines 7, the
relatively brief reaction time for the reactions to go to ‘comple-
tion’ no doubt reflected the instability of the nitrones 1 in
refluxing toluene, rather than an acceleration of the cyclo-
addition reactions. By contrast, reaction between N-benzoyl-
allylamine 6b and the more robust nitrone 811 had not gone to
completion after 192 h, typical of such reactions (Scheme 3),4,5
to give the trans- and cis-substituted isoxazolidines 9 and 103
in 35 and 11% isolated yield, respectively, again with a relatively
poor level of stereoselection. Returning to the original nitrones
1, we wondered if a cycloaddition with allylamine itself might
prove more successful, because of the smaller size of this
dipolarophile and on the possibility that hydrogen bonding
between the two reactants could enhance both the rate and
N-allyl group resonances and a singlet at δH 8.14 (RCH᎐
᎐
NCH2). Presumably, this was formed by an exchange reaction,
initiated by nucleophilic attack of the allylamine 11 onto the
nitrone 1a, followed by expulsion of N-methylhydroxylamine
(Scheme 4). This novel oxadiazinane synthesis was further
exemplified by a similar reaction between allylamine 11 and
nitrone 1b which led to the related N2-benzyl-1,2,5-oxadiazin-
anes 12b and 13b, in 56 and 19% isolated yield, respectively,
along with traces of the imine 14. In contrast, the N-tert-
butyl nitrone 1c failed to give more than traces of oxadiazinanes
but instead gave only the imine 14. Fortunately, crystallization
of the minor isomer 13a produced material suitable for
X-ray analysis, as it seemed rather dangerous to propose the
oxadiazinane structures 12 and 13 solely on the basis of
spectroscopic analysis. The structure found is shown in Fig. 2
and confirms the foregoing assignments, although there still
exists an uncertainty about which centre in the corresponding
trans-isomers 12 has the opposite configuration with respect to
the cis-isomers 13.
The 1,2,5-oxadiazinane ring system is relatively obscure; the
first examples of such compounds were reported contempor-
aneously by Katritzky13 and Riddell14 and co-workers and were
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Fig. 2 X-ray molecular structure of compound 13a.
Scheme 5
Scheme 6
pyrrolidine 20, presumably via the N-oxide 19 (Scheme 6). It
was only in the 1990s that interest was renewed in this trans-
formation, largely due to the extensive and definitive studies of
Ciganek and his colleagues.18 A further seminal report by the
Oppolzer group19 settled any doubt that the reaction is a
thermal pericyclic process, belonging to the general class of
1,3-azaprotio cyclotransfer reactions, as defined by Grigg,20 as
well as providing elegant applications of the cyclization in
alkaloid synthesis. Subsequent theoretical work21 and further
examples22 strongly indicate that the five participating atoms
must lie in a single plane; hence the depiction of the intermedi-
ate N-oxide 19 with the new methyl group syn to the N–O bond.
In this respect, it seems likely that the intermediate N-oxides 16,
proposed but not observed in the present studies, are also
formed as single diastereoisomers with the hexulose residue, the
methyl group and the N–O bond all on the same face.23 The
reverse-Cope reaction can also be applied to alkynylhydroxyl-
amines and indeed, given a choice, cyclization onto an alkyne
occurs in preference to a similarly suitably positioned alkene.24
In general,16,18,19,23 substituents at the distal end of the partici-
pating alkene slow the cyclization, in some examples sufficiently
to render the process not viable, as substrate or product decom-
position takes preference. Although pyrrolidines are the typical
products, the cyclization can also be used to obtain piper-
idines16,25 but, as yet, there is no case known of a successful
cyclization onto a terminally substituted alkene leading to a
piperidine, i.e. the reaction can only be applied to a-methyl-
piperidine synthesis. One method recently found whereby
reverse-Cope cyclizations can be activated is to position a
hydroxy or derived ether group at an allylic position of the
reacting alkene.26 The second step of the proposed mechanism
(Scheme 5) is a Meisenheimer rearrangement,27 being the
migration of an alkyl group from nitrogen to oxygen. The
Scheme 4
prepared during a general survey of the NMR properties of the
oxadiazinane ring system in general (see also Scheme 7 below).
As for a mechanism for the formation of the 1,2,5-oxadiazin-
anes 12 and 13, a tentative proposal is shown in Scheme 5. The
expected and presumed reversible addition of allylamine 11 to
the nitrones 1 (see above) leads to the unsaturated hydroxyl-
amines 15, which can react in two ways. First, expulsion of
N-methylhydroxylamine gives the imine 14, observed in varying
amounts in each of the reactions of nitrones 1 with allylamine
11. More productively, the intermediates 15 could undergo a
reverse-Cope cyclization to give the N-oxides 16, which are
unstable with respect to ring opening to the iminium ions 17.
Finally, these reclose by a 6-endo process leading to the
observed products 12 and 13. The retro- or reverse-Cope reac-
tion, as the name implies, is the reverse of the well known Cope
elimination of tertiary amine N-oxides leading to a hydroxyl-
amine and an alkene.15 It was first discovered serendipitously
by House and co-workers16 and by Oppolzer’s group17 over
twenty years ago. The latter report features the simplest version
of this type of cyclization whereby N-pent-4-enylhydroxyl-
amine 18 cyclizes at 40 ЊC to give N-hydroxy-2-methyl-
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accepted mechanism for this usually high-temperature process,
which is also largely limited to the migration of allyl or benzyl
groups, involves radical intermediates, to judge from the exten-
sive studies carried out by the Schöllkopf group.28 However, the
present process represents a rather special case and clearly does
not necessitate the evocation of radicals. Indeed, there is litera-
ture precedent for relatively simple Meisenheimer rearrange-
ments involving α-aminoamine N-oxides.29,30 Thus, direct sup-
port for this mechanism comes from the observation that
rearrangement of the N-oxides 21a, derived by peracid oxida-
tion of the corresponding imidazolidines, occurs at ambient
temperature to give the oxadiazinanes 23a, presumably via the
iminium species 22a (Scheme 7).30 Consistent with this is the
during the final 6-endo ring closure involving the proposed anti-
iminium species (see Scheme 5), which would have a chair-like
conformation with the new methyl group positioned equatori-
ally. Two other mechanistic aspects have been investigated.
First, it has been suggested32 that the oxaziridine 27, derived
from rearrangement of the nitrone 8, could be involved. How-
ever, experiments using independently prepared oxaziridine 27
in place of the nitrone clearly established that it was not an
intermediate.33 Secondly, when the deuteriated allylamine 28
was treated with nitrone 8, only the deuteriated oxadiazinane
29 was formed (Scheme 9); hardly proof, but at least evidence
Scheme 9
that a pathway totally different to that shown in Scheme 5 is
probably not involved. Finally, the oxadiazinane structure 24
was further confirmed by conversion into the crystalline 4-
nitrobenzoyl derivative 30. The understandably sensitive nature
Scheme 7
finding that the corresponding oxazolidines 21b undergo a simi-
lar rearrangement via the intermediates 22b, to the 1,5,2-
dioxazinanes 23b but only when heated to 170 ЊC, presumably
because the oxygen lone pair necessary to trigger the reaction is
much more tightly bound.31
Naturally, we wondered if this sequence possessed any degree
of generality. We were therefore delighted to find that when a
solution of equal amounts of the benzaldehyde nitrone 8 and
allylamine 11 in deuteriochloroform was monitored by 1H
NMR, a new set of signals slowly appeared, culminating in
complete conversion to a new, single compound after approxi-
mately 7 days at ambient temperature. In the light of the fore-
going, this was identified as the 1,2,5-oxadiazinane 24, the trans
stereochemistry being evident from coupling constant13,14 and
NOE data, which also indicated that the compound existed in
the not unexpected chair conformation 25, at least in chloro-
form at ambient temperature (Scheme 8). The reaction was
of oxadiazinane 24 meant that Hunig’s base, rather than tri-
ethylamine, had to be used in this derivatization and it was
essential to add this prior to the acid chloride. The amide 30
turned out to be highly rotameric at ambient temperature, pre-
sumably due to rotation about the new amide bond, but usable
NMR data could be obtained at 63 ЊC, which suggested that
3-H was now equatorial (J3,4eq 4.1 Hz), and hence the conform-
ation 31, a known phenomenon in the case of N-acylated
2-substituted piperidines,34 engendered by the avoidance of
A(1,2) strain, present if the 2-substituent is positioned
equatorially.
As mentioned above, substituents at the distal end of partici-
pating alkenes retard the reverse-Cope cyclization.17–19 Hence, it
was not surprising that reaction between nitrone 8 and (E)-
cinnamylamine 3235 was very slow in refluxing chloroform, an
optimum solvent for reverse-Cope cyclization,18 and gave only a
40% isolated yield of the oxadiazinane 33, accompanied by a
similar amount of the exchange product, the imine 34. Even
worse, similar reactions between nitrone 8 and (E)-crotonyl-
amine 35 gave only the corresponding imine and very little
oxadiazinane 36. By contrast, reaction between nitrone 8 and
linalylamine 37,36 although slow, gave good yields of the separ-
able oxadiazinanes 38 and 39, accompanied by only 9% of the
related imine 40 (Scheme 10). The stereochemistry of the two
isomers was confirmed by NOE measurements as being the
expected chair conformations 41 and 42; the stereoselection was
presumably controlled by the larger homoprenyl residue. The
success of this transformation, despite the crowded nature of
the allylamine 37, is not too surprising, as the reverse-Cope
cyclization is known to benefit from the Thorpe–Ingold effect;
the latter is crucial to the success of many examples.18 Attempts
to use other benzaldehyde nitrones were not productive. Reac-
tion between N-benzyl-C-phenylnitrone was some seven times
slower with allylamine in chloroform at ambient temperature
while the corresponding N-tert-butyl nitrone showed very little
reaction.
Scheme 8
similarly efficient but took 36 h to go to completion at 45 ЊC,
while in refluxing toluene conversion was complete in less than
17 h, but the product was accompanied by the benzaldehyde
imine 26, again formed by simple exchange of the amino
groups. Under all conditions, only the trans-isomer 24 was
formed but the proposed intermediate imidazolidine (cf. 16;
Scheme 5) was not observed; small transitory doublets around
δH 1.1 indicated the formation of this and perhaps other species,
but evidence better than this was not secured. The trans-
stereochemistry in the product 24 is presumably established
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Scheme 10
We reasoned that to extend this chemistry, it might be an idea
to use a secondary allylamine, hence preventing the exchange
reaction with the nitrone partner leading to the corresponding
imines; any equilibrium between the reactants and an iminium
salt and a hydroxylamine should lie very much on the side of
the former. However, the evident sensitivity of the reverse-Cope
cyclization to substituent effects made us uncertain if this idea
would be successful. In the event, we were delighted to observe
that N-methylallylamine 43a reacted slowly with the nitrone
8 at ambient temperature to give the 1,2,5-oxadiazinane 44a.
Subsequently, heating in chloroform for 16 h delivered essen-
tially a quantitative yield of the trans-isomer 44a; no evidence
for formation of the corresponding cis-isomer was visible in 1H
NMR spectra of the crude product. Fortunately, the products
of this and other equally efficient cyclizations were generated
with sufficient purity to be used in further transformations as
losses were considerable during chromatographic purification.
Similarly, the N-allyl- and N-benzylallylamine 43b and 43c
were converted into the oxadiazines 44b and 44c, respectively,
but both reactions took considerably longer to reach comple-
tion (Scheme 11), indicating a rate retardation associated with
these substituents in this position. Again, substituents at the
distal end of the alkene function also retarded such reverse-
Cope cyclizations: reactions between the substituted N-methyl-
allylic amines 45 and nitrone 8 gave the oxadiazinanes 46, again
as single trans-isomers, but in lower yields and after consider-
ably increased reactions times. However, incorporation of a
Scheme 11
substituent adjacent to the amine group led to excellent yields
under relatively mild conditions during the formation of trisub-
stituted oxadiazinanes 48, as the single diastereoisomers shown,
from amines 47. Again, the stereochemistry of these is presum-
ably set during the initial reverse-Cope cyclization and is
controlled by the substituent R2 adopting a pseudoequatorial
position.22 The internally substituted allylic amine 49 also
reacted smoothly to provide an excellent yield of the
dimethyl derivative 50, despite the apparent steric crowding. A
limitation of this scheme was reached when two deactivating
groups were present in the allylic amine: reaction between
N-benzylcinnamylamine 51 and nitrone 8 gave a mere 12%
isolated yield of the oxadiazinane 52 and only after prolonged
reaction times. Interestingly, however, the pyrrolidine nitrone
53 reacted smoothly, if slowly, with N-methylallylamine 43a to
provide excellent yields of the 1,4-diazabicyclo[3.3.1]nonane 54,
as a single diastereoisomer of undetermined stereochemistry
(Scheme 12), thus providing more evidence of the validity of
the proposed overall mechanism (Scheme 5). Once again, the
proposed intermediates (Scheme 12) were not observed by
NMR; the delicate nature of the nitrone 53 and especially that
of the product 54 precluded further thermal acceleration and
also successful reactions with distally substituted allylic amines.
3296
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Scheme 14
60b was not isolated from similar reactions of nitrone 59b,
despite the fact that this group should significantly accelerate
the initial nucleophilic attack by allylamine 11. Presumably,
in the latter case, the p-nitro group destabilizes the inter-
mediates involved in the later Meisenheimer rearrangement.
Two features are evident: first, and not surprisingly, more than
one rate-determining step is probably involved in the sequence,
and secondly, and disappointingly, incorporation of these
electronically extreme functions in either reactant did not result
in useful rate increases but rather made no difference or, worse,
reduced the overall rate significantly. Not unexpectedly, the
effect of the phenyl group in nitrone 8 can be transmitted by
an alkene link. Thus, the cinnamylnitrone 61 reacted in a
similar manner to give a good yield of the rather sensitive
6-styryloxadiazinane 62 (Scheme 15). In view of the foregoing
Scheme 12
As a final mechanistic check, the N-deuteriated allylamine
55 was treated with nitrone 8 in hot deuteriochloroform and
provided only the monodeuteriated product 56; the absence
of deuterium elsewhere in the product again precludes many
alternative pathways. Throughout these experiments and
despite the sometimes lengthy reaction times, no products from
[1,3]dipolar cycloadditions were observed.
In an effort to define more reactive components, we briefly
examined some homologues of the two starting materials.
Competition experiments between the para-substituted N-
benzylallylamines 57 leading to the oxadiazinanes 58, carried
out using equimolar amounts of the allylamines 57a,b and 43c
and the nitrone 8 with 1H NMR monitoring, revealed the rela-
tive rates shown in Scheme 13. In a similar fashion, the para-
Scheme 15
together with Ciganek’s results,18 it came as no surprise that
the allylic amines 63 and 64 failed to react with the nitrone 8;
the N-phenyl derivative 65 was similarly recalcitrant, pre-
sumably by reason of reduced nucleophilicity at nitrogen.
Finally, we had a tantalizing insight into a future direction
for this chemistry, which has subsequently been successfully
exploited:33 the C-cyclopropyl nitrone 66 underwent reaction
with N-methylallylamine 43a at ambient temperature to provide
a quantitative return of the trans-oxadiazinane 67 (Scheme 16).
Scheme 13
substituted nitrones 59 gave the oxadiazinanes 60 at the rela-
tive rates shown (Scheme 14). While the effect of the p-methoxy
group in allylamine 57a is almost negligible, it was unexpected
that the reaction would be slower, as one might expect acceler-
ation of the initial nucleophilic attack (Scheme 5); presumably,
this step is much slower in allylamine 57b where the p-nitro
group renders the amine less nucleophilic. Similarly odd was the
finding (Scheme 14) that a p-methoxy group in the nitrone 59a
had very little effect on the overall rate whereas a p-nitro group
slowed the reaction greatly, meaning that the oxadiazinane
Scheme 16
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The same compound 67 was even obtained after storage of
a solution of the two reactants in chloroform at Ϫ20 ЊC for a
few days. Hence, a final conclusion is that the C-phenyl nitrone
8, attractive as a test substrate by reason of its stability and
crystallinity, is not the most reactive system in this chemistry,
for reasons which are, as yet, not entirely clear.
Overall, a main interest in the overall sequence (Scheme 5) is
that a carbon–nitrogen bond is formed, effectively by the
uncatalysed addition of an amine to an alkene, unactivated in a
Michael sense. We have briefly examined some further reactions
of the initial oxadiazinanes in order to emphasize this feature.
First, exposure of four representative oxadiazinanes to dilute
hydrochloric acid led to good yields of the aminohydroxyl-
amines 69 (Scheme 17). These might well find use as ligands and
Scheme 20
nucleophilic addition of the nitrone oxygen. Finally, we have
reported that similar but more limited chemistry can be carried
out using allylthiols in place of allylamines.23
Experimental
General details
Scheme 17
Melting points were determined on a Köfler hot-stage appar-
atus and are uncorrected. Optical rotations were measured
using a JASCO DIP-370 instrument; [α]D-values are given in
units of 10Ϫ1 deg cm2 gϪ1. IR spectra were recorded using a
Perkin-Elmer 1720 series Fourier transform spectrometer using
thin films between sodium chloride plates, unless other-
synthetic intermediates and are not too easy to obtain in other
ways; the ease of preparation of the monoacylated derivative
69d is also of note. Finally, zinc reduction led to similarly good
isolated yields of the diamines 70 (Scheme 18); again, this
1
wise stated. H NMR spectra were determined using a Bruker
WM-250 or a Bruker AM-400 spectrometer. 13C NMR spectra
were determined using a JEOL EX270 spectrometer operating
at 67.8 MHz or the Bruker AM-400 instrument operating at
100 MHz. Unless otherwise stated, all spectra were determined
using dilute solutions in deuteriochloroform and tetramethyl-
silane as internal standard. J-Values are expressed in Hertz.
Relative molecular masses and mass spectra were measured
using a VG 7070E instrument, operating in the electron-impact
mode.
Scheme 18
Unless otherwise stated, all reactions were carried out under
an atmosphere of dry nitrogen in anhydrous solvents which
were obtained by the usual methods.39 All organic solutions
from work-ups were dried by brief exposure to anhydrous mag-
nesium sulfate followed by filtration. Solvents were removed by
rotary evaporation. CC refers to column chromatography over
Sorbsil C60-H (40–60 µm) silica gel using the eluants specified.
Light petroleum (LP) refers to the fraction with distillation
range 40–60 ЊC. Ether refers to diethyl ether. The benzaldehyde-
derived nitrone 8 was prepared by an established method.11,40
provides access to a monoacylated derivative 70b which is also
not easily accessible by alternative routes.
There are three footnotes to this work. First, this is not the
first report of a reaction between a nitrone and allylamine:
Black has reported that the acyl nitrones 71 react with
allylamine 11 in refluxing diethyl ether to give the products 73
of a particularly simple intramolecular [1,3]dipolar cycloaddi-
tion of the intermediate imines 72 (Scheme 19).37 Evidently, the
Methyl 2,3:4,6-di-O-isopropylidene-ꢀ-L-xylo-hex-2-ulofurano-
sonate 5b
Iodomethane (21.3 ml, 48.55 g, 342 mmol) was added to
4-methylpent-2-anone (500 ml), anhydrous potassium carbon-
ate (23.5 g, 171 mmol) and 2,3:4,6-di-O-isopropylidene--xylo-
hex-2-ulosonic acid monohydrate 5a (50 g, 171 mmol; Aldrich)
and the resulting mixture was stirred and refluxed for 4 h,
then cooled and filtered. The solid was washed thoroughly
with acetone and the combined filtrates were evaporated. The
residual viscous oil was dissolved in ether (100 ml) and the
resulting solution was washed successively with saturated aq.
sodium hydrogen carbonate (50 ml) and brine (50 ml), then
dried and evaporated to leave the crude ester as a viscous
yellow oil. CC (EtOAc–hexane, 1:2), collection of the fraction
with Rf 0.24 (visualized using anisaldehyde spray) and crystal-
lization from hexane gave the ester 5b (46.8 g, 95%) as colour-
Scheme 19
amine prefers to react with the carbonyl group in these dis-
torted nitrones rather than with the nitrone function itself; if
the latter had occurred, this would presumably have led to
chemistry related to that described above. Secondly, the
oxadiazinane ring system 76 has been obtained from a nitrone
previously, but by a rather different pathway (Scheme 20).38
Formally, or perhaps in reality, this is a [6π ϩ 4π] process, or
one which features a double Mannich reaction between the
pyrrole iminium salt 74 and the nitrone 75, triggered by
3298
J. Chem. Soc., Perkin Trans. 1, 2000, 3292–3305

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less needles, mp 47 ЊC (lit.9 46–47 ЊC); [α]D20 Ϫ155.6 (c 1, CHCl3)
(Found: C, 54.1; H, 6.8. Calc. for C13H20O7: C, 54.1; H, 7.0%);
νmax/cmϪ1 1750; δH (250) 1.35 (3H, s), 1.43 (6H, s, 2 × Me), 1.53
(3H, s), 3.86 (3H, s, OMe), 4.10 (1H, d, J 2.0, 6-Ha), 4.11 (1H,
d, J 1.0, 4-H), 4.17 (1H, ddd, J 2.0, 2.0 and 1.0, 5-H), 4.31 (1H,
d, J 2.0, 6-Hb) and 4.84 (1H, s, 3-H); δC (67.8) 18.4, 25.3, 26.5,
28.4 (all Me), 52.6 (OMe), 59.3 (CH2), 72.2, 73.5, 87.2 (all CH),
97.1, 109.9, 113.6 (all C) and 167.0 (CO); m/z 273 (Mϩ Ϫ 15,
50%), 229 (8), 215 (14), 187 (11), 171 (25), 158 (17), 143 (27),
59 (32) and 43 (100) (Found: Mϩ Ϫ Me, 273.0973. C12H17O7
requires m/z, 273.0974).
Ph); m/z 243 (28%), 229 (36), 171 (51), 113 (26), 91 (90), 77 (4)
and 48 (100).
The sample showed no carbonyl stretch in the IR spectrum
and was used promptly and not further purified due to its
limited stability.
N-(1-Deoxo-2,3:4,6-di-O-isopropylidene-ꢀ-L-xylo-hex-2-ul-1-
ylidene)-tert-butylamine N-oxide 1c
N-tert-Butylhydroxylamine hydrochloride (0.97 g, 7.75 mmol)
was added to a stirred solution of sodium methoxide (0.42 g,
7.75 mmol) in methanol (50 ml) and the resulting mixture was
stirred for 0.5 h, then cooled to 0 ЊC. The aldehyde 5c (2.00 g,
7.75 mmol) as a solution in toluene (20 ml) was added dropwise
and the resulting solution was stirred at ambient temperature
without further cooling for 16 h, then was dried and evapor-
ated. The residue was dissolved in dry ether, the solution was
filtered and the filtrate evaporated to leave the nitrone 1c (2.42 g,
95%) as a colourless glass, νmax/cmϪ1 1580; δH (250) 1.47 (3H, s),
1.55 (3H, s), 1.66 (9H, s), 1.67 (3H, s), 1.82 (3H, s), 4.18 (1H,
d, J 2.0, 6-Ha), 4.25 (1H, d, J 1.0, 4-H), 4.30 (1H, app. q, J 2.0,
5-H), 4.47 (1H, d, J 2.0, 6-Hb), 5.32 (1H, s, 3-H) and 7.13 (1H, s,
CHN); m/z 329 (4%), 314 (9), 243 (19), 229 (29), 171 (33), 157
(11), 113 (24) and 57 (100).
2,3:4,6-Di-O-isopropylidene-ꢀ-L-xylo-hex-2-ulose monohydrate
5c
A stirred solution of the ester 5b (8.34 g, 28.4 mmol) in hexane
(500 ml) was maintained at Ϫ78 ЊC during the dropwise add-
ition of DIBAL (31.8 ml of a 1 M solution in hexanes, 31.8
mmol). Stirring at this temperature was continued for 5.5 h,
then the reaction was quenched by the addition of aq. methanol
(9:1; 2.5 ml). The resulting suspension was filtered through a
pad of silica gel (20 g) with an upper layer of dried magnesium
sulfate (10 g). The solid was washed with ethyl acetate (200 ml)
and the combined filtrates were evaporated. CC (EtOAc–
hexane–Et3N, 1:1:0.02) of the residue separated the aldehyde
monohydrate 5c (4.36 g, 58%), Rf 0.10, as a colourless solid, mp
46 ЊC; [α]D20 Ϫ147 (c 1, CHCl3); νmax/cmϪ1 3700–3200 and 1768;
δH (250) 1.28 (3H, s), 1.38 (3H, s), 1.43 (3H, s), 1.50 (3H, s), 4.05
(1H, d, J 2.0, 6-Ha), 4.06 (1H, d, J 1.0, 4-H), 4.18 (1H, ddd,
J 2.0, 2.0 and 1.0, 5-H), 4.30 (1H, d, J 2.0, 6-Hb), 4.48 (1H, s,
3-H) and 9.62 (1H, s, CHO); m/z 229 (Mϩ Ϫ CHO, 49%), 185
(12), 171 (63), 157 (7), 113 (33), 59 (34) and 43 (100) (Found:
Mϩ Ϫ CHO, 229.1042. C11H17O5 requires m/z, 229.1076).
Earlier fractions contained the ester 5b (3.25 g, 39%
recovery).
(؉)-(3R,5R)- and (؊)-(3R,5S)-5-(tert-Butoxycarbonylamino-
methyl)-3-(2-deoxy-3,5-O-isopropylidene-1,2-isopropylidene-
dioxy-ꢁ-L-xylo-furanosyl)-2-methylisoxazolidine 7a and 7b
A solution of N-tert-butoxycarbonylprop-2-en-1-amine 6a
(0.272 g, 1.74 mmol) and the N-methyl nitrone 1a (0.50 g, 1.74
mmol) in toluene (20 ml) was refluxed for 10 h then cooled and
evaporated. CC (EtOAc–hexane–Et3N, 1:4:0.01) of the residue
separated (i) the (3R,5R)-isoxazolidine 7a (99 mg, 13%), Rf 0.58
(EtOAc–hexane–Et3N, 1:2:0.1), as a colourless oil, [α]D20 ϩ1.7
(c 0.36, CHCl3); νmax/cmϪ1 3360 and 1705; δH (250) 1.37 (3H, s),
1.43 (3H, s), 1.44 (9H, s, But), 1.45 (3H, s), 1.48 (3H, s), 2.10
(1H, ddd, J 12.7, 10.3 and 10.3, 4-Ha), 2.67 (1H, ddd, J 12.7, 6.4
and 4.0, 4-Hb), 2.85 (3H, s, NMe), 3.31 (1H, dd, J 10.3 and 4.0,
3-H), 3.43 (1H, m, 6-H), 4.04–4.14 (5H, m), 4.27 (1H, d, J 2.5),
4.53 (1H, s) and 4.85 (1H, t, J 4.0, NH); m/z 388 (Mϩ ϩ H Ϫ But,
7%), 159 (100), 141 (19), 115 (13), 98 (15), 84 (9), 68 (9), 59 (28)
and 57 (25) (Found: Mϩ ϩ H Ϫ But, 388.1819. C17H28N2O8
requires m/z, 388.1846) and (ii) the (3R,5S)-isoxazolidine 7b (84
mg, 11%), Rf 0.40 (EtOAc–hexane–Et3N, 1:2:0.1), as a colour-
less oil, [α]D20 Ϫ34.4 (c 0.46, CHCl3); νmax/cmϪ1 3360 and 1708;
δH (250) 1.36 (3H, s), 1.43 (6H, s, 2 × Me), 1.44 (9H, s, But), 1.51
(3H, s), 2.12 (1H, ddd, J 12.5, 9.5 and 9.5, 4-Ha), 2.59 (1H, ddd,
J 12.5, 5.9 and 2.6, 4-Hb), 2.80 (3H, s, NMe), 3.18 (1H, dd, J 9.5
and 2.6, 3-H), 3.25 (1H, m, CHaNH), 3.45 (1H, m, CHbNH),
4.05–4.08 (3H, m), 4.07 (1H, d, J 2.0), 4.27 (1H, d, J 1.9), 4.38
(1H, s) and 4.85 (1H, t, J 5.0, NH); m/z 388 (Mϩ ϩ H Ϫ But,
9%), 159 (100), 141 (17), 115 (15), 98 (11), 84 (7), 68 (10), 59 (18)
and 57 (22) (Found: Mϩ ϩ H Ϫ But, 388.1842).
N-(1-Deoxo-2,3:4,6-di-O-isopropylidene-ꢀ-L-xylo-hex-2-ul-1-
ylidene)methylamine N-oxide 1a
N-Methylhydroxylamine (0.15 g, 3.1 mmol) was added to a
stirred mixture of the aldehyde monohydrate 5c (0.80 g, 3.1
mmol), dried magnesium sulfate (3.0 g) and methanol (0.5 ml)
in ether (30 ml) maintained at 0 ЊC. After 1 h, the mixture was
warmed to ambient temperature and filtered. The solid was
washed with ether and the combined filtrates were evaporated
to leave the nitrone 1a (0.90 g, 95%) as colourless crystals, mp
35 ЊC; νmax/cmϪ1 1605; δH (250) 1.33 (3H, s), 1.43 (3H, s), 1.52
(3H, s), 1.65 (3H, s), 3.76 (3H, s, NMe), 4.04 (1H, d, J 2.0,
6-Ha), 4.07 (1H, d, J 1.0, 4-H), 4.15 (1H, ddd, J 2.0, 2.0 and 1.0,
5-H), 4.36 (1H, d, J 2.0, 6-Hb) 5.21 (1H, s, 3-H) and 6.92 (1H, s,
CHN); m/z 287 (Mϩ, 3%), 272 (12), 243 (15), 229 (21), 171 (31),
142 (14), 126 (9), 113 (18), 101 (20), 85 (21), 69 (23), 59 (48) and
48 (100).
The sample showed no carbonyl stretch in the IR spectrum
and was used promptly and not further purified due to its
limited stability.
(؉)-(3R,5R)- and (؊)-(3R,5S)-5-(Benzoylaminomethyl)-3-(2-
deoxy-3,5-O-isopropylidene-1,2-isopropylidenedioxy-ꢁ-L-xylo-
furanosyl)-2-methylisoxazolidine 7c and 7d
N-(1-Deoxo-2,3:4,6-di-O-isopropylidene-ꢀ-L-xylo-hex-2-ul-1-
ylidene)benzylamine N-oxide 1b
By the foregoing method, reaction between the N-methyl
nitrone 1a (0.727 g, 2.53 mmol) and N-prop-2-enylbenzamide
6b (0.41 g, 2.53 mmol) in toluene (30 ml) followed by CC
(EtOAc–hexane–Et3N, 1:4:0.1) separated (i) the (3R,5R)-
isoxazolidine 7c (204 mg, 18%), Rf 0.39, as a colourless solid,
mp 151 ЊC (Found: C, 61.6; H, 7.3; N, 6.3. C23H32N2O7 requires
C, 61.6; H, 7.2; N, 6.3%) [α]D20 ϩ13.9 (c 0.42, CHCl3); νmax/cmϪ1
3350 and 1640; δH (250) 1.35 (3H, s), 1.43 (3H, s), 1.45 (3H, s),
1.48 (3H, s), 2.17 (1H, ddd, J 12.8, 10.0 and 10.0, 4-Ha), 2.73
(1H, ddd, J 12.8, 6.1 and 3.7, 4-Hb), 2.89 (3H, s, NMe), 3.34
(1H, dd, J 10.0 and 3.7, 3-H), 3.47 (1H, ddd, J 14.0, 7.3 and 5.2,
CHaNH), 3.88 (1H, ddd, J 14.0, 6.1 and 3.1, CHbNH), 4.06
N-Benzylhydroxylamine (0.647 g, 5.26 mmol) was added in one
portion to a stirred solution of the aldehyde monohydrate 5c
(1.35 g, 5.26 mmol) in ether (30 ml) maintained at 0 ЊC. After 1
h, the mixture was warmed to ambient temperature, dried and
evaporated to leave the nitrone 1b (1.88 g, 98%) as a colourless
glass, νmax/cmϪ1 1600; δH (250) 1.27 (3H, s), 1.40 (3H, s), 1.52
(3H, s), 1.64 (3H, s), 4.01 (1H, d, J 2.0, 6-Ha), 4.06 (1H, d, J 1.0,
4-H), 4.14 (1H, ddd, J 2.0, 2.0 and 1.0, 5-H), 4.34 (1H, d, J 2.0,
6-Hb), 4.89 (1H, d, J 10.8, PhCHa), 4.99 (1H, d, J 10.8, PhCHb),
5.16 (1H, s, 3-H), 6.97 (1H, s, CHN) and 7.28–7.44 (5H, m,
J. Chem. Soc., Perkin Trans. 1, 2000, 3292–3305
3299

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(1H, d, J 2.3), 4.11 (1H, d, J 2.3), 4.20–4.25 (2H, m), 4.28 (1H,
d, J 2.0), 4.52 (1H, s), 6.49 (1H, m, NH), 7.45–7.51 (3H, m) and
7.78–7.84 (2H, m); m/z 448 (Mϩ, 12%), 219 (72), 172 (25), 134
(9), 105 (100), 98 (26), 84 (19), 77 (22), 70 (9), 59 (23), 48 (40)
and 43 (29) (Found: Mϩ, 448.2203. C23H32N2O7 requires M,
448.2209) and (ii) the (3R,5S)-isoxazolidine 7d (159 mg, 14%),
Rf 0.31 (EtOAc–hexane–Et3N, 1:2:0.1), as a colourless glass,
νmax/cmϪ1 3550 and 1640; δH (250) 1.35 (3H, s), 1.42 (6H, s,
2 × Me), 1.49 (3H, s), 2.17 (1H, m, 4-Ha), 2.69 (1H, ddd, J 12.5,
6.1 and 2.6, 4-Hb), 2.85 (3H, s, NMe), 3.22 (1H, dd, J 9.4 and
2.6, 3-H), 3.52 (1H, ddd, J 14.0, 5.6 and 3.5, CHaNH), 3.85
(1H, ddd, J 14.0, 6.1 and 3.5, CHbNH), 4.06 (1H, s), 4.18–4.24
(2H, m), 4.27 (1H, d, J 2.0), 4.37 (1H, s), 4.38 (1H, s), 6.47 (1H,
t, J 3.5, NH), 7.43–7.51 (3H, m) and 7.77–7.80 (2H, m); m/z 448
(Mϩ, 20%), 219 (89), 172 (24), 134 (6), 105 (100), 98 (18),
84 (11), 77 (22), 70 (12), 59 (11), 48 (14) and 43 (24) (Found:
Mϩ, 448.2211).
(11), 136 (13), 126 (6), 115 (22), 83 (14), 74 (100), 69 (23), 58
(68), 43 (42) and 30 (20) (Found: Mϩ, 344.1945. C16H28N2O6
requires M, 344.1947) and (ii) the cis-1,2,5-oxadiazinane 13a
(62 mg, 10%), Rf 0.14, as a colourless solid, mp 83 ЊC (Found:
C, 55.6; H, 8.5; N, 7.8%) [α]D20 Ϫ65.5 (c 0.49, CHCl3); νmax/cmϪ1
3320; δH (250) 1.13 and 1.17 (3H, d, J 6.3, 3-Me), 1.38 (3H, s),
1.40 (3H, s), 1.43 (3H, s), 1.45 (3H, s), 2.38 (1H, br s, NH), 2.56
and 2.57 (3H, s, 2-Me), 2.67 (1H, m, 4-Hax), 2.75 (1H, br, 3-H),
2.81 (1H, dd, J 13.7 and 4.8, 4-Heq), 4.05–4.14 (3H, m), 4.26
(1H, m), 4.61 (1H, s) and 4.74 (1H, s, 6-H); m/z 344 (Mϩ, 47%),
329 (8), 256 (10), 155 (16), 136 (17), 115 (32), 74 (100), 69 (29)
and 58 (52) (Found: Mϩ, 344.1924).
(؉)-trans- and (؊)-cis-2-Benzyl-6-(2-deoxy-3,5-O-isopropyl-
idene-1,2-isopropylidenedioxy-ꢁ-L-xylo-furanosyl)-3-methyl-
1,2,5-oxadiazinane 12b and 13b
A solution of allylamine 11 (0.270 g, 5.17 mmol) and the N-
benzyl nitrone 1b (1.88 g, 5.17 mmol) in toluene (30 ml) was
refluxed for 10 h then, was cooled and evaporated. CC (EtOAc–
hexane–Et3N, 1:1:0.1) of the residue separated (i) the trans-
1,2,5-oxadiazinane 12b (1.23 g, 56%), Rf 0.45, as a colourless
solid, mp 98 ЊC (from ether–LP) (Found: C, 62.8; H, 7.7; N, 6.7.
C22H32N2O6 requires C, 62.8; H, 7.7; N, 6.7%), [α]D20 ϩ74 (c 1,
CHCl3); νmax/cmϪ1 3300; δH (250) 1.02 (3H, d, J 5.7, 3-Me), 1.31
(3H, s), 1.40 (3H, s), 1.41 (3H, s), 1.42 (3H, s), 2.82 (1H, ddq,
J 8.7, 8.7 and 5.7, 3-H), 2.83 (1H, dd, J 8.7 and 8.7, 4-Hax), 3.00
(1H, app. d, J 8.7, 4-Heq), 3.69 (1H, d, J 14.7, PhCHa), 3.86 (1H,
d, J 14.7, PhCHb), 4.03 (1H, d, J 2.8), 4.05 (1H, d, J 1.9), 4.14
(1H, d, J 1.9), 4.16-4.19 (1H, m), 4.53 (1H, s), 4.73 (1H, s, 6-H),
7.23–7.32 (3H, m) and 7.38–7.45 (2H, m); δC (67.8) 15.9 (3-Me),
18.6, 26.3, 27.3, 28.8 [all MeC(O)O], 51.0 (4-CH2), 58.8
(5Ј-CH2), 59.5 (3-CH), 59.9 (PhCH2), 72.5, 72.9, 84.9 (all
CHO), 89.0 (6-CH), 97.1, 112.2, 112.6 (all C), 126.4, 127.8,
128.2 (all Ph CH) and 138.0 (Ph C); m/z 420 (Mϩ, 9%), 175 (20),
150 (29), 134 (12), 91 (100) and 59 (15) (Found: Mϩ, 420.2258.
C22H32N2O6 requires M, 420.2260) and (ii) the cis-1,2,5-
oxadiazinane 13b (420 mg, 19%), Rf 0.58, as a colourless glass
(Found: C, 62.4; H, 7.8; N, 6.3%) [α]D20 Ϫ30.8 (c 1.01, CHCl3);
νmax/cmϪ1 3340; δH (250) 1.00 (3H, d, J 6.9, 3-Me), 1.38 (3H, s),
1.42 (9H, s), 2.82 (1H, dqd, J 10.1, 6.9 and 2.6, 3-H), 2.85 (1H,
dd, J 13.1 and 10.1, 4-Hax), 3.01 (1H, dd, J 13.1 and 2.6, 4-Heq),
4.02–4.11 (4H, m), 4.21 (1H, d, J 13.1, PhCHa), 4.23 (1H, d,
J 13.1, PhCHb), 4.50 (1H, s), 4.90 (1H, s, 6-H), 7.25–7.32 (3H,
m) and 7.41–7.45 (2H, m); δC (67.8) 15.9 (3-Me), 18.7, 26.0,
27.4, 28.6 [all MeC(O)O], 50.8 (4-CH2), 59.2 (5Ј-CH2), 59.8
(3-CH), 60.1 (PhCH2), 72.3, 72.9, 84.7 (all CHO), 88.4 (6-CH),
97.3, 112.4, 113.2 (all C), 127.7, 128.1, 128.2 (all Ph CH) and
138.1 (Ph C); m/z 420 (Mϩ, 14%), 175 (9), 150 (90), 134 (10)
and 91 (100) (Found: Mϩ, 420.2246).
(3RS,5RS)- and (3RS,5SR)-5-Benzoylaminomethyl-2-methyl-3-
phenylisoxazolidine 9 and 10
A solution of N-2-propen-1-ylbenzamide 6b (1.20 g, 7.40
mmol) and the benzaldehyde-derived nitrone 8 (1.00 g, 7.40
mmol) in toluene (40 ml) was refluxed for 192 h, then cooled
and evaporated. CC (EtOAc–LP, 1:1] of the residue separated
(i) the (3RS,5RS)-trans-isoxazolidine 9 (770 mg, 35%), Rf 0.27,
as a colourless solid, mp 99–100 ЊC (Found: C, 72.9; H, 7.1;
N, 9.4. C18H20N2O2 requires C, 72.9; H, 6.8; N, 9.5%), νmax/cmϪ1
3330 and 1635; δH (250) 2.15 (1H, ddd, J 12.7, 8.0 and 5.6,
4-Ha), 2.60 (3H, s, 2-Me), 2.83 (1H, ddd, J 12.7, 8.0 and 8.0,
4-Hb), 3.56 (1H, dd, J 8.0 and 8.0, 3-H), 3.69 (1H, ddd, J 13.9,
3.7 and 3.7, CHaNH), 3.74 (1H, ddd, J 13.9, 5.3 and 3.7,
CHbNH), 4.47 (1H, m, 5-H), 7.21–7.29 (5H, m), 7.40–7.45 (3H,
m) and 7.78–7.83 (2H, m); δC (67.8) 42.4 (4-CH2), 43.0 (2-Me),
44.5 (1Ј-CH2), 73.5 (3-CH), 75.0 (5-CH), 127.0, 127.5, 128.0,
128.5, 128.7 (Ph CH), 131.4, 138.4 (Ph C) and 167.6 (CO);
m/z 296 (Mϩ, 33%), 251 (14), 160 (39), 147 (41), 120 (76), 106
(23), 105 (100), 91 (16) and 77 (98) (Found: Mϩ, 296.1512.
C18H20N2O2 requires M, 296.1525) and ii) the (3RS,5SR)-cis-
isoxazolidine 10 (250 mg, 11%), Rf 0.17, as a colourless solid,
mp 83–85 ЊC (Found: C, 72.8; H, 6.8; N, 9.3), νmax/cmϪ1 3307
and 1641; δH (250) 2.38–2.44 (2H, m, 4-CH2), 2.58 (3H, s,
2-Me), 3.44–3.50 (1H, m, 3-H), 3.61 (1H, ddd, J 13.0, 5.9 and
5.9, CHaNH), 3.74 (1H, ddd, J 13.0, 5.9 and 3.6, CHbNH),
4.44–4.49 (1H, m, 5-H), 6.93 (1H, br res, NH), 7.32–7.42 (8H,
m) and 7.78–7.83 (2H, m); δC (67.8) 42.2 (4-CH2), 42.7 (2-Me),
43.1 (1Ј-CH2), 73.1 (3-CH), 75.7 (5-CH), 126.9, 127.5, 127.8,
128.5, 128.7 (Ph CH), 131.3, 138.6 (Ph C) and 167.6 (CO);
m/z 296 (Mϩ, 3%), 147 (11), 120 (12), 106 (9), 105 (100), 91 (8)
and 77 (46) (Found: Mϩ, 296.1526).
(؉)-trans- and (؊)-cis-6-(2-deoxy-3,5,-O-isopropylidene-1,2-
isopropylidenedioxy-ꢁ-L-xylo-furanosyl)-2,3-dimethyl-1,2,5-
oxadiazinane 12a and 13a
trans-2,3-Dimethyl-6-phenyl-1,2,5-oxadiazinane 24
(i) A solution of the nitrone 8 (100 mg, 0.74 mmol) and
allylamine 11 (42 mg, 0.74 mmol) in deuteriochloroform (1 ml)
was stirred at ambient temperature for 7 days (NMR monitor-
ing), then evaporated to leave the oxadiazinane 24 (142 mg,
100%) as a pale yellow oil which exhibited spectral data identi-
cal to the sample described below in (iii) and which was pure
according to NMR analysis (see below).
(ii) A solution of the nitrone 8 (100 mg, 0.74 mmol) and
allylamine 11 (42 mg, 0.74 mmol) in deuteriochloroform (1 ml)
was stirred at 45 ЊC for 36 h (NMR monitoring), then evapor-
ated to leave the oxadiazinane 24 (142 mg, 100%) as a pale
yellow oil which exhibited spectral data identical to the sample
below and which was pure according to NMR analysis (see
below).
A solution of allylamine 11 (0.198 g, 3.48 mmol) and the
N-methyl nitrone 1a (0.318 g, 1.74 mmol) in toluene (30 ml) was
refluxed for 10 h, then was cooled and evaporated. CC (EtOAc–
hexane–Et3N, 1:1:0.1) of the residue separated (i) the trans-
1,2,5-oxadiazinane 12a (213 mg, 36%), Rf 0.20, as a colourless
solid, mp 71 ЊC (from ether–LP) (Found: C, 55.6; H, 8.4; N, 7.8.
C16H28N2O6 requires C, 55.8; H, 8.2; N, 8.1%) [α]D20 ϩ10.4 (c 1.06,
CHCl3); νmax/cmϪ1 3320; δH (250) 0.88 (3H, d, J 6.3, 3-Me), 1.31
(3H, s), 1.33 (3H, s), 1.36 (3H, s), 1.41 (3H, s), 2.41 (1H, dqd,
J 10.6, 6.3 and 3.0, 3-H), 2.60 (3H, s, 2-Me), 2.67 (1H, dd, J 13.7
and 10.6, 4-Hax), 2.89 (1H, dd, J 13.7 and 3.0, 4-Heq), 3.98 (1H,
d, J 2.2), 4.01 (2H, app. d, J 2.5), 4.18 (1H, d, J 2.2), 4.52 (1H, s)
and 4.66 (1H, s, 6-H); δC (67.8) 15.4 (3-Me), 18.4, 26.2, 27.1,
28.6 [all MeC(O)O], 43.5 (2-Me), 50.2 (4-CH2), 59.6 (6Ј-CH2),
61.6 (3-CH), 72.1, 73.1, 85.2 (all CHO), 88.9 (6-CH), 97.1,
112.0 and 112.5 (all C); m/z 344 (Mϩ, 18%), 183 (7), 171 (8), 155
(iii) A solution of the benzaldehyde nitrone 8 (1.0 g, 7.4
mmol) and allylamine 11 (0.55 ml, 7.4 mmol) in toluene (30 ml)
was refluxed for 17 h, then cooled and evaporated. CC (EtOAc–
hexane, 1:2) of the residue gave the oxadiazinane 24 (1.14 g,
3300
J. Chem. Soc., Perkin Trans. 1, 2000, 3292–3305

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80%), Rf 0.48, as a pale yellow oil; νmax/cmϪ1 3301 and 915;
δH (400) 1.00 (3H, d, J 6.3, 3-Me), 2.49 (1H, dqd, J 10.4, 6.3 and
4.1, 3-Hax), 2.71 (3H, s, 2-Me), 2.87 (1H, dd, J 13.8 and 10.4,
4-Hax), 3.05 (1H, dd, J 13.8 and 4.1, 4-Heq), 5.53 (1H, s, 6-Hax),
7.19–7.35 (3H, m) and 7.41–7.50 (2H, m); δC (100) 16.3 (3-Me),
44.3 (2-Me), 51.8 (4-CH2), 62.4 (3-CH), 90.0 (6-CH), 126.3,
128.6, 128.8 (all Ph CH) and 139.1 (Ph C); m/z 192 (Mϩ, 59%),
175 (9), 146 (30), 118 (54), 106 (12), 105 (36), 91 (40), 77 (38)
and 74 (100) (Found: Mϩ, 192.1234. C11H16N2O requires M,
192.1263).
128.3, 129.1, 130.3 (all Ph CH), 130.6 and 131.2 (both Ph C);
m/z 341 (Mϩ, 3%), 224 (33), 223 (100), 175 (51), 118 (11), 106
(14), 105 (20), 91 (16) and 77 (19) (Found: Mϩ, 341.1371.
C18H19N3O4 requires M, 341.1375).
In the crude product, the imine 34 was present to an extent of
ca. 40%; δH (80) 4.15 (2H, d, J 5, NCH2), 6.20 (1H, dd, J 16 and
5, ᎐CH), 6.45 (1H, d, J 16, ᎐CH), 7.60–7.70 (2H, m) and 8.13
᎐
᎐
(1H, s, ᎐CHN).
᎐
(3RS,4RS,6RS)- and (3RS,4SR,6RS)-2,3,4-Trimethyl-4-(4-
methylpent-3-enyl)-6-phenyl-1,2,5-oxadiazinane 38 and 39
A solution of nitrone 8 (0.96 g, 7.12 mmol) and linalylamine36
37 (1.09 g, 7.12 mmol) in toluene (50 ml) was refluxed for
3 days, then was cooled and evaporated. CC (ether–pentane,
1:15) of the residue separated (i) the (3RS,4RS,6RS)-
NOE data: 2-Me ~ 3-Me (1.7%); 3-Me ~ 4-Hax (1.0%); 3-Hax
~
4-Heq (3.5%); 4-Hax ~ 6-Hax (3.0%); all other enhancements
were < 1%.
The crude reaction mixture from the latter experiment in
toluene also contained approximately 20% of the imine 26,
formed from benzaldehyde and allylamine, identified by
oxadiazinane 38 (0.97 g, 47%), Rf 0.12, as a colourless oil; νmax
/
δH (250) 4.20 (2H, d, J 6.1, CH CH᎐), 5.12 (1H, d, J 10.6,
᎐
cmϪ1 3310 and 1607; δH (400) 0.96 (3H, d, J 6.6, 3-Me), 1.28
(3H, s, 4-Me), 1.25–1.35 (1H, m, 1Ј-Ha), 1.54–1.61 (1H, m,
1Ј-Hb), 1.61 (3H, s, MeC᎐), 1.67 (3H, s, MeC᎐), 2.12–2.32 (2H,
2
᎐CHc), 5.23 (1H, d, J 16.0, ᎐CHt), 6.04 (1H, ddt, J 16.0, 10.6
᎐
᎐
and 6.1, ᎐CH) and 8.18 (1H, s, CHN).
᎐
᎐
᎐
m, 2Ј-CH2), 2.41 (1H, q, J 6.6, 3-H), 2.65 (3H, s, 2-Me), 5.11
(1H, tt, J 7.1 and 1.0, 3Ј-H), 5.70 (1H, s, 6-H), 7.25–7.36 (3H,
trans-5-Deuterio-3-deuteriomethyl-2-methyl-6-phenyl-1,2,5-
oxadiazinane 29
m) and 7.46–7.48 (2H, m); δ (100) 13.1 (4-Me), 17.7 (MeC᎐),
᎐
C
Allylamine 11 (2.0 g, 35 mmol) was stirred in deuterium oxide
(25 ml) for 1 h, then the solution was treated with solid sodium
hydroxide (3.0 g) and, after complete dissolution of the solid,
was extracted with chloroform (2 × 20 ml). The combined
extracts were dried and filtered and the filtrate was added to the
benzaldehyde nitrone 8 (1.60 g, 11.7 mmol). NMR analysis
showed approximately 50% deuterium incorporation at the
amino function. The resulting solution was refluxed for 5 h,
then was cooled and evaporated. Last traces of allylamine were
removed under high vacuum to leave the deuteriated oxadiazi-
nane 29 (2.27 g, 99% based on the nitrone). Approximately 50%
deuterium incorporation was evident from δH (250) 0.90–1.05
(2H, m, 3-CH2D) and δC (67.8) 15.1 (t, J 19.5, 3-CH2D); m/z
Mϩ, 194.1379. C11H14D2N2O requires M, 194.1388. There was
no other evidence for deuterium incorporation.
18.0 (1Ј-CH ), 21.2 (3-Me), 25.7 (MeC᎐), 40.4 (2Ј-CH ), 44.2
(2-Me), 54.5 (4-C), 69.2 (3-CH), 85.1 (6-CH), 124.4 (3Ј-CH:),
᎐
2
2
126.0, 128.3 (both Ph CH), 131.8 (4Ј-C᎐) and 139.2 (Ph C); m/z
᎐
288 (Mϩ, 6%), 215 (20), 146 (100), 91 (14) and 77 (9) (Found:
Mϩ, 288.2203. C18H28N2O requires M, 288.2202), (ii) the
(3RS,4SR,6RS)-oxadiazinane 39 (0.46 g, 22%), Rf 0.21, as a
colourless oil; νmax/cmϪ1 3310 and 1607; δH (400) 0.93 (3H, d,
J 6.7, 3-Me), 1.08 (3H, s, 4-Me), 1.20–1.30 (1H, m, 1Ј-Ha), 1.35–
1.44 (1H, m, 1Ј-Hb), 1.63 (3H, s, MeC᎐), 1.69 (3H, s, MeC᎐),
᎐
᎐
1.94–2.01 (1H, m, 2Ј-H), 2.22–2.26 (1H, m, 2Ј-H), 2.37 (1H, q,
J 6.7, 3-H), 2.65 (3H, s, 2-Me), 5.20 (1H, tt, J 7.1 and 1.0, 3Ј-H),
5.61 (1H, s, 6-H), 7.25–7.35 (3H, m) and 7.41–7.47 (2H, m);
δ (100) 13.1 (4-Me), 17.7 (MeC᎐), 21.8 (1Ј-CH ), 25.2 (3-Me),
᎐
C
2
25.8 (MeC᎐), 29.9 (2Ј-CH ), 41.2 (2-Me), 54.2 (4-C), 72.0
᎐
2
(3-CH), 85.0 (6-CH), 124.4 (3Ј-CH᎐), 126.0, 128.2, 128.3 (all Ph
᎐
CH), 131.1 (4Ј-C᎐) and 139.2 (Ph C); m/z 288 (Mϩ, 7%), 215
᎐
(20), 146 (100), 91 (21) and 77 (15) (Found: Mϩ, 288.2207) and
trans-2,3-Dimethyl-5-(4-nitrobenzoyl)-6-phenyl-1,2,5-
oxadiazinane 30
(iii) the imine 40 (0.16 g, 9%), Rf 0.46, as a colourless oil; νmax
/
cmϪ1 1693; δ (250) 1.33 (3H, s, 3-Me), 1.58 (3H, s, MeC᎐), 1.66
᎐
A solution of 4-nitrobenzoyl chloride (0.96 g, 5.2 mmol) in
dichloromethane (20 ml) was slowly added to a stirred solution
of the oxadiazinane 24 (1.00 g, 5.2 mmol) and diisopropylethyl-
amine (0.67 g, 5.2 mmol) in dichloromethane (50 ml) cooled in
an ice bath. After 1 h, the solvent was evaporated. CC (EtOAc–
LP, 2:1) of the residue and collection of the fraction with Rf
0.54 gave the benzoyloxadiazinane 30 (1.61 g, 91%) as yellow
crystals, mp 171–173 ЊC (from ether–LP) (Found: C, 63.1; H,
5.8; N, 12.5. C18H19N3O4 requires C, 63.3; H, 5.6; N, 12.3%);
νmax(KBr)/cmϪ1 1630 and 931; δH (400; 63 ЊC, sealed tube) 1.20
(3H, d, J 6.3, 3-Me), 2.59 (3H, s, 2-Me), 2.92 (1H, br m, 4-Hax),
3.64 (1H, dd, J 12.8 and 4.1, 4-Heq), 4.00 (1H, br m, 3-H), 6.52
(1H, br s, 6-H), 7.32–7.39 (5H, m), 7.59 (2H, d, J 8.6) and 8.20
(2H, d, J 8.6); δC (100; 63 ЊC, sealed tube) 10.5 (br, 3-Me), 42.4
(2-Me), 45.9 (br, 4-CH2), 58.3 (br, 3-CH), 86.8 (br, 6-CH),
123.9, 126.5, 128.2, 128.5, 128.8 (all Ph CH), 137.6, 141.8, 148.9
(all Ph C) and 169.5 (CO); m/z 341 (Mϩ, 3%), 224 (33), 223
(100), 175 (51), 118 (11), 106 (14), 105 (20), 91 (16) and 77 (19)
(Found: Mϩ, 341.1371. C18H19N3O4 requires M, 341.1375).
H
(3H, s, MeC᎐), 1.71–1.75 (2H, m, 4-CH ), 2.04 (2H, q, J 7.5,
᎐
2
5-CH2), 5.16 (1H, dd, J 17.4 and 1.4, 1-Ht), 5.20 (1H, dd, J 10.9
and 1.4, 1-Hc), 5.92 (1H, dd, J 17.4 and 10.9, 2-H), 5.12 (1H, m,
6-H), 7.37–7.42 (3H, m), 7.73–7.79 (2H, m) and 8.24 (1H,
s, NCH); δC (100) 17.6 (MeC᎐), 22.8 (4-CH ), 24.1 (3-Me),
᎐
2
25.6 (MeC᎐), 42.3 (5-CH ), 63.9 (3-C), 113.7 (1-CH ), 124.7
᎐
2
2
(6-CH᎐), 127.9, 128.4, 130.2 (all PhCH), 131.1 (C᎐),137.0 (Ph
᎐
᎐
C), 144.1 (2-CH) and 157.5 (CHN); m/z 241 (Mϩ, 12%), 226
(20), 159 (100), 118 (15), 106 (18), 104 (61), 91 (13), 81 (15) and
77 (10) (Found: Mϩ, 241.1879. C17H23N requires M, 241.1830).
NOE data (3RS,4RS,6RS)-38: 2-Me ~ 3-Hax (2%); 3-Me ~
4-Meax (9%); 4-Meax ~ 3Ј-:CH (16%); 4-Meax ~ 6-Hax (4%); all
other enhancements were <1%. (3RS, 4SR, 6RS)-39: 3-Hax
~
4-Meeq (13%); 6-Hax ~ 1Ј-CH2 (11%); 6-Hax ~ 2Ј-CH2 (10%);
3-Hax ~ Ph (3%); all other enhancements were р1%.
trans-2,3,5-Trimethyl-6-phenyl-1,2,5-oxadiazinane 44a
A solution of the nitrone 8 (1.90 g, 14.1 mmol) and N-methyl-
allylamine 43a (1.00 g, 14.1 mmol) in chloroform (5 ml) was
stirred and heated at 60 ЊC for 20 h, then was cooled and evap-
orated to leave the oxadiazinane 44a (2.76 g, 95%) as a colour-
less oil which was essentially a single compound according to
1H NMR analysis. Attempted CC resulted in considerable loss
of material, although TLC analysis (EtOAc–LP, 1:1) indicated
a single product with Rf 0.27. The product showed νmax/cmϪ1
918; δH (400) 1.00 (3H, d, J 6.2, 3-Me), 1.98 (3H, s, 5-Me), 2.40
(1H, dd, J 11.0 and 10.7, 4-Hax), 2.66 (3H, s, 2-Me), 2.90 (1H,
dqd, J 10.7, 6.2 and 2.8, 3-Hax), 2.94 (1H, dd, J 11.0 and 2.8,
trans-3-Benzyl-2-methyl-6-phenyl-1,2,5-oxadiazinane 33
A solution of the nitrone 8 (0.31 g, 2.3 mmol) and (E)-
cinnamylamine35 32 (0.31 g, 2.3 mmol) in chloroform (50 ml)
was refluxed for 192 h, then was cooled and evaporated. Rapid
CC (EtOAc) separated the oxadiazinane 33 (0.25 g, 40%) as a
pale yellow oil; νmax/cmϪ1 3600–3200, 1958, 1644 and 911;
δH (250) 2.45–2.90 (5H, m), 2.75 (3H, s, 2-Me), 6.50 (1H, s, 6-H)
and 7.10–7.50 (10H, m); δC (67.5) 36.8 (4-CH2), 44.3 (2-Me),
62.7 (PhCH2), 67.2 (3-CH), 89.2 (6-CH), 126.2, 127.2, 128.0,
J. Chem. Soc., Perkin Trans. 1, 2000, 3292–3305
3301

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4-Heq), 4.81 (1H, s, 6-H), 7.29–7.35 (3H, m, Ph) and 7.44–7.47
(2H, m, Ph); δC (100) 16.1 (3-Me), 38.8 (5-Me), 43.2 (2-Me),
59.3 (3-CH), 61.4 (4-CH2), 97.3 (6-CH), 127.8, 128.1, 128.7 (all
Ph CH) and 137.4 (Ph C); m/z 206 (Mϩ, 28%), 132 (100), 118
(73), 91 (12) and 77 (19) (Found: Mϩ, 206.1456. C12H18N2O
requires M, 206.1419).
CC (EtOAc–LP, 1:4) gave the 3-butyloxadiazinane 46b (68 mg,
45%) as a pale yellow oil; νmax/cmϪ1 936; δH (400) 0.92 (3H, t,
J 7.0, 4Ј-Me), 1.25–1.40 (6H, m, 1Ј-, 2Ј- and 3Ј-CH2), 2.00 (3H,
s, 5-Me), 2.40 (1H, dd, J 12.8 and 11.3, 4-Hax), 2.69 (3H, s,
2-Me), 2.84 (1H, m, 3-H), 3.09 (1H, dd, J 11.3 and 2.6, 4-Heq),
4.76 (1H, s, 6-H), 7.32–7.36 (3H, m, Ph) and 7.44–7.47 (2H, m,
Ph); δC (100) 13.9 (4Ј-Me), 23.0, 27.4, 30.1 (all CH2), 39.3
(5-Me), 43.5 (2-Me), 59.4 (4-CH2), 64.4 (3-CH), 97.6 (6-CH),
128.0, 128.2, 128.4 (Ph CH) and 137.5 (Ph C); m/z 248 (Mϩ,
82%), 120 (21), 119 (47), 118 (100), 105 (19), 91 (29), 77 (28)
and 72 (14) (Found: Mϩ, 248.1877. C15H24N2O requires M,
248.1889).
trans-2,3-Dimethyl-6-phenyl-5-(prop-2-enyl)-1,2,5-oxadiazinane
44b
The nitrone 8 (3.00 g, 22.2 mmol) and diallylamine 43b (2.16 g,
22.2 mmol) were refluxed together in chloroform (100 ml)
for 72 h. Evaporation of the cooled solution left the N-
allyloxadiazinane 44b (5.16 g, 100%) as a colourless oil; νmax
/
trans-3-Ethyl-2,5-dimethyl-6-phenyl-1,2,5-oxadiazinane 46c
cmϪ1 1642 and 916; δH (400) 1.00 (3H, d, J 6.4, 3-Me), 2.35 (1H,
dd, J 11.9 and 10.4, 4-Hax), 2.60 (1H, dd, J 13.8 and 6.5, 1Ј-Ha),
2.67 (3H, s, 2-Me), 2.88 (1H, dqd, J 10.4, 6.4 and 2.9, 3-Hax),
3.03 (1H, ddt, J 13.8, 5.5 and 1.6, 1Ј-Hb), 3.05 (1H, dd, J 11.9
and 2.9, 4-Heq), 5.06 (1H, br d, J 10.0, 3Ј-Hc), 5.08 (1H, s, 6-H),
5.09 (1H, ddd, J 17.1, 3.0 and 1.6, 3Ј-Ht), 5.72 (1H, dddd,
J 17.1, 10.0, 6.5 and 5.5, 2Ј-H), 7.27–7.36 (3H, m, Ph) and 7.46–
7.50 (2H, m, Ph); δC (100) 16.3 (3-Me), 43.5 (2-Me), 53.5
(4-CH2), 57.5 (1Ј-CH2), 59.2 (3-CH), 96.1 (6-CH), 117.2
(3Ј-CH2), 128.0, 128.3, 128.8 (all Ph CH), 135.0 (2Ј-CH) and
137.6 (Ph C); m/z 232 (Mϩ, 12%), 186 (27), 159 (51), 158 (66),
144 (54), 118 (100), and 91 (62) (Found: Mϩ, 232.1597.
C14H20N2O requires M, 232.1576).
The nitrone 8 (310 mg, 2.3 mmol) and (E)-N-methylcrotyl-
amine42 45c (195 mg, 2.30 mmol) were refluxed together in
benzene (5 ml) for 120 h. Evaporation of the cooled solution
and CC (ether) gave the 3-ethyloxadiazinane 46c (480 mg, 95%)
as a pale yellow oil, Rf 0.38; νmax/cmϪ1 933; δH (400) 0.96 (3H, t,
J 7.5, 2Ј-Me), 1.29–1.40 (1H, m, 1Ј-H), 1.53–1.63 (1H, m, 1Ј-H),
2.01 (3H, s, 5-Me), 2.40 (1H, dd, J 11.7 and 11.7, 4-Hax), 2.70
(3H, s, 2-Me), 2.75–2.79 (1H, m, 3-H), 3.10 (1H, dd, J 11.7 and
2.6, 4-Heq), 4.76 (1H, s, 6-H), 7.33–7.38 (3H, m, Ph) and 7.45–
7.49 (2H, m, Ph); δC (100) 9.7 (2Ј-Me), 23.4 (1Ј-CH2), 39.4
(5-Me), 43.6 (2-Me), 59.0 (4-CH2), 65.6 (3-CH), 97.7 (6-CH),
128.0, 128.1, 128.5 (Ph CH) and 138.6 (Ph C); m/z 220 (Mϩ,
33%), 133 (40), 132 (100), 120 (10), 119 (20), 118 (48), 105 (16),
91 (13), 77 (17) and 72 (5) (Found: Mϩ, 220.1579. C13H20N2O
requires M, 220.1576).
trans-5-Benzyl-2,3-dimethyl-6-phenyl-1,2,5-oxadiazinane 44c
A solution of the nitrone 8 (100 mg, 0.74 mmol) and
N-benzylallylamine41 43c (108 mg, 0.74 mmol) in chloroform
(2 ml) was kept at 60 ЊC for 48 h, then was cooled and evapor-
(3RS,4RS,6RS)-2,3,4,5-Tetramethyl-6-phenyl-1,2,5-
oxadiazinane 48a
1
ated to leave essentially pure product, according to H NMR
analysis, as a viscous yellow oil in 95% yield. CC (EtOAc–LP,
1:5) and collection of the fraction with Rf 0.29, gave the N-
benzyloxadiazinane 44c (198 mg, 56%) as a colourless solid, mp
63–64 ЊC (Found: C, 76.8; H, 7.9. C18H22N2O requires C, 76.7;
H, 7.9%); νmax/cmϪ1 917; δH (400) 0.95 (3H, d, J 6.3, 3-Me), 2.32
(1H, dd, J 12.0 and 10.4, 4-Hax), 2.69 (3H, s, 2-Me), 2.86 (1H,
dd, J 12.0 and 2.0, 4-Heq), 2.90 (1H, dqd, J 10.4, 6.3 and 2.0,
3-H), 3.06 (1H, d, J 13.5, 1Ј-Ha), 3.61 (1H, d, J 13.5, 1Ј-Hb),
5.20 (1H, s, 6-H), 7.19–7.61 (10H, m, Ph); δC (100) 16.3 (3-Me),
43.6 (2-Me), 54.5 (1Ј-CH2), 57.5 (4-CH2), 59.2 (3-CH), 96.4
(6-CH), 126.9, 128.1, 128.3, 128.6, 128.7, 129.0 (all Ph CH),
137.9 and 138.7 (both Ph C); m/z 282 (Mϩ, 21%), 265 (4), 236
(6), 209 (18), 208 (13), 194 (11), 189 (9), 146 (7), 118 (91), 105
(8), 91 (100) and 77 (9) (Found: Mϩ, 282.1738. C18H22N2O
requires M, 282.1732).
A solution of the nitrone 8 (263 mg, 1.96 mmol) and N-methyl-
but-3-en-2-amine42 47a (166 mg, 1.96 mmol) in benzene (20 ml)
was stirred and refluxed for 20 h, then was cooled and evapor-
ated. CC (ether) separated the tetramethyloxadiazinane 48a
(408 mg, 95%) as an oil, Rf 0.34; νmax/cmϪ1 930; δH (400) 1.06
(3H, d, J 6.3, 3-Me), 1.20 (3H, d, J 6.2, 4-Me), 1.93 (3H, s,
5-Me), 2.53–2.57 (2H, m, 3- and 4-H), 2.68 (3H, s, 2-Me), 5.04
(1H, s, 6-H), 7.32-7.38 (3H, m, Ph) and 7.45–7.49 (2H, m, Ph)
δC (100) 15.3, 16.5 (3- and 4-Me), 34.8 (5-Me), 44.1 (2-Me), 63.0
(4-CH), 65.1 (3-CH), 97.0 (6-CH), 128.4, 128.7, 129.1 (Ph CH)
and 137.7 (Ph C) (Found: Mϩ, 220.1561. C13H20N2O requires
M, 220.1576).
(3RS,4RS,6RS)-5-Butyl-2,3-dimethyl-4,6-diphenyl-1,2,5-
oxadiazinane 48b
A solution of the nitrone 8 (0.30 g, 2.20 mmol) and N-butyl-1-
phenylprop-2-enamine43 47b (0.41 g, 2.20 mmol) in toluene (20
ml) was stirred and refluxed for 17 h, then was cooled and
evaporated. CC (EtOAc–LP, 1:2) separated the 4-phenyl-
oxadiazinane 48b (0.632 g, 89%) as an oil, Rf 0.30; νmax/cmϪ1
917; δH (400) 0.50 (3H, t, J 7.2, 4Ј-Me), 0.70 (2H, m, 3Ј-CH2),
0.81 (3H, d, J 6.4, 3-Me), 0.90–0.95 (1H, m, 2Ј-Ha), 1.00–1.10
(1H, m, 2Ј-Hb), 2.09 (2H, m, 1Ј-CH2), 2.68 (3H, s, 2-Me), 2.84
(1H, dq, J 9.0 and 6.4, 3-H), 3.56 (1H, d, J 9.0, 4-H), 5.38 (1H,
s, 6-H), 7.28–7.40 (6H, m, Ph), 7.43–7.49 (2H, m, Ph) and 7.55–
7.63 (2H, m, Ph); δC (100) 13.6 (4Ј-Me), 14.9 (3-Me), 20.3, 25.3
(2Ј- and 3Ј-CH2), 43.9 (2-Me), 48.3 (1Ј-CH2), 66.7 (3-H), 70.1
(4-H), 95.1 (6-H), 127.5, 128.2, 128.3, 128.6, 129.1, 129.2 (all Ph
CH), 138.3 and 140.7 (Ph C); m/z 324 (Mϩ, 35%), 307 (13), 251
(65), 194 (32), 118 (100), 91 (57) and 77 (34) (Found: Mϩ,
324.2172. C21H28N2O requires M, 324.2202).
trans-3-Benzyl-2,5-dimethyl-6-phenyl-1,2,5-oxadiazinane 46a
The nitrone 8 (208 mg, 1.54 mmol) and (E)-N-methyl-
cinnamylamine41 45a (200 mg, 1.54 mmol) were refluxed in
toluene (20 ml) for 48 h. The cooled solution was evaporated
and the residue separated by CC (ether) to give the 3-benzyl-
oxadiazinane 46a (265 mg, 65%) as an oil, Rf 0.60; νmax/cmϪ1
900; δH (250) 1.91 (3H, s, 5-Me), 2.34 (1H, dd, J 11.7 and 10.3,
4-Hax), 2.79 (3H, s, 2-Me), 2.80 (1H, m, 4-Heq), 3.15 (1H, m,
3-H), 3.16 (1H, m, 1Ј-Ha), 3.24 (1H, m, 1Ј-Hb), 4.76 (1H, s, 6-H)
and 7.20–7.55 (10H, m, Ph); δC (67.8) 37.2 (PhCH2), 39.2
(5-Me), 44.0 (2-Me), 59.2 (4-CH2), 65.4 (3-CH), 97.7 (6-CH),
128.1, 128.3, 128.4, 128.5, 128.9, 129.1 (all Ph CH), 137.6 and
138.4 (both Ph C); m/z 282 (Mϩ, 41%), 265 (7), 191 (25), 175
(100), 132 (99), 118 (63) and 91 (62) (Found: Mϩ, 282.1728.
C18H22N2O requires M, 282.1732).
NOE data: 3-Me ~ 4-Hax (9%); 4-Hax ~ 1Ј-CH2 (5%); 1Ј-
CH2 ~ 6-Hax (5%); 3-Hax ~ Ph (δH 7.43–7.49) (16%).
trans-3-Butyl-2,5-dimethyl-6-phenyl-1,2,5-oxadiazinane 46b
The nitrone 8 (82 mg, 0.61 mmol) and (E)-N-methylhex-2-
enamine42 45b (69 mg, 0.61 mmol) were refluxed together in
toluene (2 ml) for 21 h. Evaporation of the cooled solution and
2,3,3,5-Tetramethyl-6-phenyl-1,2,5-oxadiazinane 50
The nitrone 8 (79 mg, 0.58 mmol) and N,2-dimethylprop-2-
3302
J. Chem. Soc., Perkin Trans. 1, 2000, 3292–3305

View Article Online
enamine42 49 (50 mg, 0.58 mmol) were heated together at 60 ЊC
for 16 h in chloroform (2 ml). The cooled solution was evapor-
ated to leave the 3,3-dimethyloxadiazinane 50 (120 mg, 93%) as
a colourless oil, consisting of a single component according to
1H NMR and TLC analysis [Rf 0.36 (EtOAc–LP, 1:8)], which
showed νmax/cmϪ1 941; δH (270) 1.05 (3H, s, 3-Me), 1.40 (3H, s,
3-Me), 1.91 (3H, s, 5-Me), 2.34 (1H, d, J 10.9, 4-Ha), 2.54 (3H,
s, 2-Me), 2.75 (1H, d, J 10.9, 4-Hb), 4.58 (1H, s, 6-H), 7.26–7.37
(3H, m, Ph) and 7.48–7.52 (2H, m, Ph); δC (100) 15.7, 25.3 (both
3-Me), 37.7 (5-Me), 40.3 (2-Me), 67.4 (4-CH2), 99.3 (6-CH),
128.4, 128.5, 129.3 (Ph CH) and 138.0 (Ph C); m/z 220 (Mϩ,
40%), 174 (6), 133 (57), 119 (48), 118 (100), 91 (16) and 77 (20)
(Found: Mϩ, 220.1600. C13H20N2O requires M, 220.1576).
A solution of the foregoing N-deuterioamine 55 (276 mg,
1.86 mmol) and the nitrone 8 (252 mg, 1.86 mmol) in deuterio-
chloroform (2 ml) was kept at 60 ЊC for 48 h, then was cooled
and evaporated. 1H NMR analysis showed complete and clean
conversion into the expected deuteriated and non-deuteriated
oxadiazinanes 56 and 44c. The signals due to the minor, non-
deuteriated product 44c were identical to those displayed by the
previously characterized material (see above). The major, deute-
riated product 56 showed data which were also identical to those
of the foregoing sample, except νmax/cmϪ1 2196; δH (400) 0.95
(2H, d, J 6.3, 3-CH2D) and 2.87–2.93 (1H, m, 3-H); δD (250;
CDCl3 as solvent and standard) 0.95 (br s, 3-CH2D); δC (100)
15.7 (t, J 19.2, 3-CH2D), 43.3 (2-Me), 54.1 (1Ј-CH2), 57.1
(4-CH2), 58.6 (3-CH), 96.0 (6-CH), 126.7, 127.8, 128.0, 128.2,
128.3, 128.6 (all Ph CH), 137.7 and 138.4 (both Ph C); m/z 283
(Mϩ, 12%), 266 (14), 209 (11), 190 (33), 118 (59), 105 (16), 91
(100) and 77 (15) (Found: Mϩ, 283.1800. C18H21DN2O requires
M, 283.1795).
trans-3,5-Dibenzyl-2-methyl-6-phenyl-1,2,5-oxadiazinane 52
The nitrone 8 (0.84 g, 6.25 mmol) and N-benzyl-(E)-
cinnamylamine41 51 (1.40 g, 6.25 mmol) were heated together in
chloroform (2 ml) in a sealed tube at 110 ЊC for 120 h. Evapor-
ation of the cooled solution followed by CC (ether–LP, 1:8)
separated the dibenzyloxadiazinane 52 (0.27 g, 12%) as a yellow
oil, Rf 0.19; νmax/cmϪ1 910; δH (400) 2.18 (3H, s, 2-Me), 2.46 (1H,
dd, J 9.3 and 8.6, 4-Heq), 2.74 (1H, dd, J 13.1 and 8.6, 4-Hax),
2.87 (1H, m, 3-H), 2.98 (1H, dd, J 9.2 and 4.4, 1Ј-Ha), 3.01 (1H,
dd, J 9.2 and 4.4, 1Ј-Hb), 3.09 (1H, d, J 13.5, NCHa), 3.63 (1H,
s, 6-H), 3.69 (1H, d, J 13.5, NCHb), 7.15–7.25 (9H, m, Ph),
7.30–7.40 (4H, m, Ph) and 7.50–7.60 (2H, m, Ph); δC (100) 38.2
(2-Me), 41.4 (4-CH2), 55.9, 56.4 (both PhCH2), 65.5 (3-CH),
91.6 (6-CH), 125.7, 126.6, 128.0, 128.2, 128.5, 129.2, 129.3
(all Ph CH), 139.2, 139.5 and 140.6 (all Ph C); m/z 341 (Mϩ,
9%), 265 (17), 251 (100) and 91 (98) (Found: Mϩ Ϫ 17,
341.2008. C24H25N2 requires M, 341.2018).
The 1H and 13C NMR data showed no evidence of deuterium
incorporation at any other site in the product.
trans-5-(4-Methoxybenzyl)-2,3-dimethyl-6-phenyl-1,2,5-
oxadiazinane 58a
A solution of the nitrone 8 (1.41 g, 10.5 mmol) and (4-
methoxybenzyl)allylamine41 57a (1.86 g, 10.5 mmol) in toluene
(50 ml) was stirred and refluxed for 53 h, then was cooled and
evaporated. Crystallization of the product from MeOH–
CH2Cl2–LP, (2:1:1) gave the oxadiazinane 58a (2.84 g, 87%) as
a colourless solid, mp 139–141 ЊC (Found: C, 72.9; H, 7.8; N,
8.9. C19H24N2O2 requires 73.0; H, 7.8; N, 9.0%); νmax/cmϪ1 905;
δH (400) 0.95 (3H, d, J 6.2, 3-Me), 2.28 (1H, dd, J 12.2 and 11.0,
4-Hax), 2.69 (3H, s, 2-Me), 2.84 (1H, dd, J 11.0 and 2.7, 4-Heq),
2.86 (1H, dqd, J 12.2, 6.2 and 2.7, 3-H), 2.98 (1H, d, J 13.2,
1Ј-Ha), 3.53 (1H, d, J 13.2, 1Ј-Hb), 3.76 (3H, s, OMe), 5.16 (1H,
s, 6-H), 6.81 (2H, d, J 8.6, 2 × ArH), 7.16 (2H, d, J 8.6,
2 × ArH), 7.30–7.39 (3H, m, Ph) and 7.58–7.60 (2H, m, Ph);
δC (100) 16.4 (3-Me), 43.6 (2-Me), 53.9 (1Ј-CH2), 55.3 (OMe),
57.4 (4-CH2), 59.2 (3-CH), 96.5 (6-CH), 113.7, 128.1, 128.6,
129.0, 129.8 (all Ar CH), 130.6, 137.9 and 158.7 (all Ar C); m/z
312 (Mϩ, 100%), 122 (63), 121 (9), 105 (14) and 91 (35) (Found:
Mϩ, 312.1802. C19H24N2O2 requires M, 312.1838).
1,4-Diaza-9-oxa-2,4,8,8-tetramethylbicyclo[3.3.1]nonane 54
5,5-Dimethyl-∆Ј-pyrroline N-oxide 53 (75 mg, 0.66 mmol) and
N-methylallylamine 43a (47 mg, 0.66 mmol) were heated in deu-
1
teriochloroform (1.5 ml) at 60 ЊC for 72 h. H NMR analysis
showed a 75% yield of the product 54, together with decom-
position products. Attempted purification by CC resulted in
decomposition.
An identical solution was stored in a sealed NMR tube at
1
ambient temperature for approximately 2 months, when H
NMR analysis showed complete conversion into the bicyclo-
nonane 54 (≈ 100%), as an oil which showed νmax/cmϪ1 920;
δH (400) 1.04 (3H, s, 8-Mea), 1.17 (3H, d, J 6.5, 2-Me), 1.23 (1H,
ddd, J 8.4, 8.4 and 1.8, 7-Ha), 1.33 (3H, s, 8-Meb), 1.54 (1H,
ddd, J 8.4, 8.4 and 1.8, 7-Hb), 1.98–2.03 (2H, m, 6-CH2), 2.35
(3H, s, 4-Me), 2.41 (1H, dd, J 10.7 and 9.2, 3-Ha), 2.68 (1H, dd,
J 10.7 and 4.9, 3-Hb), 3.33 (1H, m, 2-H) and 4.05 (1H, d, J 2.3,
5–H); δC (100) 22.3, 24.4, 24.8 (all Me), 26.0, 27.6 (6- and
7-CH2), 43.3 (4-Me), 51.5 (3-CH2), 53.1 (2-CH), 56.1 (8-C) and
85.0 (5-CH); m/z 184 (Mϩ, 18%), 167 (38), 125 (16), 112 (20),
111 (29), 110 (21), 99 (18), 98 (75), 96 (21), 85 (22), 84 (91),
82 (29), 81 (42), 70 (45), 69 (23), 56 (32), 55 (34), 44 (55)
and 42 (100) (Found: Mϩ, 184.1568. C10H20N2O requires M,
184.1575).
trans-2,3-Dimethyl-5-(4-nitrobenzyl)-6-phenyl-1,2,5-
oxadiazinane 58b
A solution of the nitrone 8 (2.00 g, 14.8 mmol) and (4-
nitrobenzyl)allylamine41 57b (2.85 g, 14.8 mmol) in toluene (50
ml) was stirred and refluxed for 230 h, then was cooled and
evaporated to leave the oxadiazinane 58b (4.75 g, 98%) as a
brown oil; νmax/cmϪ1 917; δH (400) 0.96 (3H, d, J 6.2, 3-Me), 2.44
(1H, dd, J 11.9 and 10.5, 4-Hax), 2.71 (3H, s, 2-Me), 2.78 (1H,
dd, J 11.9 and 2.7, 4-Heq), 2.91 (1H, dqd, J 10.5, 6.2 and 2.7,
3-H), 3.23 (1H, d, J 14.9, 1Ј-Ha), 3.66 (1H, d, J 14.9, 1Ј-Hb),
5.29 (1H, s, 6-H), 7.11–7.61 (7H, m, ArH) and 8.10–8.23 (2H,
m, ArH); δC (100) 15.9 (3-Me), 43.3 (2-Me), 53.3 (1Ј-CH2), 57.4
(4-CH2), 58.4 (3-CH), 95.6 (6-CH), 123.2, 127.6, 128.4, 128.7
(all Ar CH), 137.1 and 146.7 (both Ar C); m/z 327 (Mϩ, 100%),
254 (37), 91 (68) and 77 (29) (Found: Mϩ, 327.1587. C18H21-
N3O3 requires M, 327.1583).
trans-5-Benzyl-3-deuteriomethyl-2-methyl-6-phenyl-1,2,5-
oxadiazinane 56
N-Benzylallylamine 43c (2.00 g, 13.6 mmol) was stirred in deu-
terium oxide (50 ml) for 12 h, and then the solution was
extracted with ether (3 × 50 ml). The combined organic extracts
were dried and evaporated and the residue distilled to give the
N-deuterio derivative 55 (1.70 g, 85%); δH (250) 3.16 (2H, dt, J 7
trans-6-(4-Methoxyphenyl)-2,3-dimethyl-1,2,5-oxadiazinane 60a
A solution of the C-4-methoxyphenyl nitrone 59a11,40 (182 mg,
1.10 mmol) and allylamine II (83 µl, 1.10 mmol) in deuterio-
chloroform (1 ml) was sealed in an NMR tube and kept at 60 ЊC
for 12 h. The cooled solution was evaporated to leave the oxadi-
azinane 60a (240 mg, 99%) as a light yellow oil; νmax/cmϪ1 3362
and 952; δH (400) 1.00 (3H, d, J 6.3, 3-Me), 2.49 (1H, dqd,
J 10.3, 6.3 and 3.2, 3-H), 2.70 (3H, s, 2-Me), 2.86 (1H, dd, J 13.7
and 10.3, 4-Hax), 3.04 (1H, dd, J 13.7 and 3.2, 4-Heq), 3.78 (3H,
and 1, CH CH᎐), 3.56 (2H, s, PhCH ), 5.07 (1H, ddd, J 10, 2
᎐
2
2
and 1, ᎐CHc), 5.14 (1H, ddd, J 17, 2 and 1, ᎐CHt), 5.87 (1H,
᎐
᎐
ddd, J 17, 10 and 7, CH᎐CH ) and 7.12–7.28 (5H, m, Ph); m/z
᎐
2
148 (Mϩ, 5%), 91 (100) and 77 (11). The 1H NMR data showed
deuterium incorporation of 83%.
J. Chem. Soc., Perkin Trans. 1, 2000, 3292–3305
3303

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s, OMe), 5.48 (1H, s, 6-H), 6.85–6.95 (2H, m, ArH) and 7.36–
7.44 (2H, m, ArH); δC (67.8) 15.7 (3-Me), 43.8 (2-Me), 51.3
(4-CH2), 55.2 (OMe), 61.8 (3-CH), 89.3 (6-CH), 113.6, 127.1
(both Ar CH), 136.1 and 159.3 (both Ar C); m/z 222 (Mϩ, 26%),
135 (100), 121 (31) and 74 (46) (Found: Mϩ, 222.1393.
C12H18N2O2 requires M, 222.1368).
(0.59 g, 85%) as a colourless oil; νmax/cmϪ1 3500–3200; δH (250)
1.01 (3H, d, J 6.4, 3-Me), 2.54 (3H, s, NMe), 2.59–2.63 (1H, m,
1-H), 2.73–2.77 (1H, m, 1-H), 2.82–2.86 (1H, m, 2-H), 3.75
(1H, d, J 14.2, 1Ј-Ha), 3.79 (1H, d, J 14.2, 1Ј-Hb), 5.55–5.75
(2H, br, NH and OH) and 7.20–7.35 (5H, m, Ph); m/z 133
(15%), 106 (6), 91 (100) and 74 (5).
trans-2,3,5-Trimethyl-6-styryl-1,2,5-oxadiazinane 62
N2-Hydroxy-N1-(4-methoxybenzyl)-N2-methylpropane-1,2-
diamine 69c
(E)-N-Methyl-C-styrylnitrone11,40 61 (3.00 g, 18.6 mmol) and
N-methylallylamine 43a (1.32 g, 18.6 mmol) were refluxed
together in toluene (5 ml) for 24 h, then the solution was cooled
By the foregoing procedure, hydrolysis of the 5-(methoxy-
benzyl)oxadiazinane 58a (0.924 g, 2.96 mmol) gave the
1
and evaporated. H NMR analysis of the residue showed no
N-hydroxydiamine 69c (0.67 g, 99%) as a colourless oil; νmax/
starting materials to be present and the presence of ≈80% of
the oxadiazinane 62, together with unidentified decomposition
and other products. Attempted purification by CC led to
decomposition. The major product was identified as the oxadi-
azinane 62 on the basis of νmax/cmϪ1 1658 and 910; δH (250) 0.97
(3H, d, J 6.1, 3-Me), 2.24 (3H, s, 5-Me), 2.25 (1H, dd, J 10.2
and 10.2, 4-Hax), 2.67 (3H, s, 2-Me), 2.85 (1H, dd, J 10.2 and
2.8, 4-Heq), 2.83–2.87 (1H, m, 3-H), 4.50 (1H, dd, J 7.0 and 0.4,
6-H), 6.11 (1H, dd, J 16.1 and 7.0, 1Ј-H), 6.76 (1H, d, J 16.1,
2Ј-H) and 7.13–7.47 (5H, m, Ph); δC (67.8) 15.6 (3-Me), 37.9
(5-Me), 42.8 (2-Me), 58.2 (3-CH), 60.3 (4-CH2), 95.0 (6-CH),
125.0 (1Ј-CH), 126.1, 127.6, 127.9 (all Ph CH), 134.7 (2Ј-CH)
and 135.5 (Ph C); m/z 232 (Mϩ, 36%), 215 (15), 172 (9), 158
(84), 144 (100), 103 (18), 91 (23) and 77 (27) (Found: Mϩ,
232.1543. C14H20N2O requires M, 232.1576).
cmϪ1 3500–3100; δH (250) 0.99 (3H, d, J 6.3, 3-Me), 2.55 (3H, s,
NMe), 2.57–2.63 (1H, m, 1-H), 2.73–2.77 (1H, m, 1-H), 2.76–
2.83 (1H, m, 2-H), 3.66 (1H, d, J 12.9, 1Ј-Ha), 3.68 (1H, d,
J 12.9, 1Ј-Hb), 3.76 (3H, s, OMe), 5.20–5.40 (2H, br, NH and
OH), 6.82 (2H, d, J 8.6, 2 × ArH) and 7.18 (2H, d, J 8.6,
2 × ArH).
N2-Hydroxy-N2-methyl-N1-(4-methylbenzoyl)propane-1,2-
diamine 69d
By the foregoing procedure, hydrolysis of the 5-(4-methyl-
benzoyl)oxadiazinane 68 (3.80 g, 12.2 mmol), prepared by
N-acylation of the oxadiazinane 24 derived from allylamine
with 4-methylbenzoyl chloride as described above for the prep-
aration of the corresponding 4-nitrobenzoyl derivative 30, gave
the N1-acyl-N2-hydroxydiamine 69d (2.23 g, 82%) as a colour-
less solid, mp 122–124 ЊC (from ether–LP) (Found: C, 64.8; H,
8.2; N, 12.5. C12H18N2O2 requires C, 64.8; H, 8.2; N, 12.6%);
νmax/cmϪ1 (Nujol) 3301, 3300–3100 and 1634; δH (400) 1.04 (3H,
d, J 6.5, 3-Me), 2.33 (3H, s, ArMe), 2.60 (3H, s, NMe), 2.80
(1H, dqd, J 6.8, 6.5 and 3.7, 2-H), 3.42 (1H, ddd, J 14.0, 7.2
and 6.8, 1-Ha), 3.58–3.63 (1H, m, 1-Hb), 7.10 (2H, d, J 8.1,
2 × ArH), 7.34 (1H, br t, J ≈7.2, NH) and 7.65 (2H, d, J 8.1,
2 × ArH); δC (100) 12.0 (3-Me), 21.3 (ArMe), 43.0 (1-CH2), 44.5
(NMe), 62.3 (2-CH), 127.1, 129.0 (both 2 × Ar CH), 131.5,
141.7 (both Ar C) and 168.3 (CO); m/z 222 (Mϩ, 6%), 204 (13),
192 (7), 148 (14), 131 (7), 120 (25), 91 (87) and 74 (100) (Found:
Mϩ, 222.1383. C12H18N2O2 requires M, 222.1368).
trans-6-Cyclopropyl-2,3,5-trimethyl-1,2,5-oxadiazinane 67
C-Cyclopropyl-N-methylnitrone44 66 (0.59 g, 5.90 mmol) and
N-methylallylamine 43a (0.42 g, 5.90 mmol) were stirred
together in chloroform (2 ml) at ambient temperature for 24 h.
Evaporation of the solvent left the cyclopropyloxadiazinane 67
(1.00 g, 99%) as a colourless oil; νmax/cmϪ1 912; δH (250) 0.38–
0.45 (2H, m, 2 × cyclopropyl H), 0.58–0.65 (3H, m, 3 × cyclo-
propyl H), 0.96 (3H, d, J 6.2, 3-Me), 2.31 (1H, dd, J 12.6 and
11.0, 4-Hax), 2.41 (3H, s, 5-Me), 2.66 (3H, s, 2-Me), 2.76 (1H,
dqd, J 11.0, 6.2 and 2.7, 3-H), 2.80 (1H, dd, J 12.6 and 2.7,
4-Heq) and 3.25 (1H, d, J 8.1, 6-H); δC (67.8) 1.8, 3.7 (both
cyclopropyl CH2), 12.4 (cyclopropyl CH), 15.9 (3-Me), 38.0
(5-Me), 43.1 (2-Me), 58.3 (3-CH), 61.1 (4-CH2) and 99.1
(6-CH); m/z 170 (Mϩ, 8%), 131 (6), 124 (9), 122 (9), 113 (33), 96
(18), 84 (100), 82 (25), 70 (11), 68 (15), 58 (15) and 41 (27)
(Found: Mϩ, 170.1420. C9H18N2O requires M, 170.1419).
N1-Benzyl-N2-methylpropane-1,2-diamine 70a
The 5-benzyloxadiazinane 44c (4.82 g, 17.1 mmol) and zinc
(5.60 g, 85.5 mmol) were added to 2 M hydrochloric acid (170
ml) and the resulting mixture was stirred and heated at 80 ЊC for
1 h.45 After cooling of the mixture, dichloromethane (100 ml)
was added and, after mixing, the aqueous layer was separated
and added to 2 M aq. sodium hydroxide (250 ml). The resulting
mixture was extracted with dichloromethane (3 × 100 ml) and
the combined extracts were dried and evaporated. Distillation
of the residue gave the diamine 70a (2.58 g, 85%) as a yellow oil,
bp 140 ЊC at 1.5 mmHg; νmax/cmϪ1 3163; δH (250) 1.01 (3H, d,
J 5.9, 3-Me), 2.58 (3H, s, NMe), 2.72–2.78 (1H, m, 2-H), 2.78
(1H, dd, J 8.6 and 8.6, 1-Ha), 2.76–2.81 (1H, m, 1-Hb), 3.75
(1H, d, J 13.2, 1Ј-Ha), 3.80 (1H, d, J 13.2, 1Ј-Hb) and 7.19–
7.35 (5H, m, Ph); δC (100) 12.0 (br, 3-Me), 44.1 (NMe), 52.6
(1-CH2), 53.6 (1Ј-CH2), 61.6 (2-CH), 126.8, 128.0, 128.1 (all
Ph CH) and 139.4 (Ph C); m/z 119 (12%), 91 (100), 58 (36)
and 42 (24).
N1-Allyl-N2-hydroxy-N2-methylpropane-1,2-diamine 69a
The 5-allyl-1,2,5-oxadiazinane 44b (3.00 g, 12.9 mmol) was
added to 2 M hydrochloric acid (86 ml) and the resulting mix-
ture was stirred vigorously for 5 min at ambient temperature,
then diluted with dichloromethane (80 ml). After mixing, the
aqueous layer was separated, and treated with 2 M aq. sodium
hydroxide (130 ml) followed by dichloromethane (200 ml).
After mixing, the organic layer was separated, dried and evap-
orated to leave the N-hydroxydiamine 69a (1.33 g, 72%) as a
colourless oil; νmax/cmϪ1 3500–3150; δH (400) 1.03 (3H, d, J 6.2,
3-Me), 2.55 (3H, s, NMe), 2.58–2.64 (1H, m, 1-Ha), 2.79–2.85
(2H, m, 1-Hb and 2-H), 3.23–2.27 (2H, m, 1Ј-CH2), 5.10 (1H,
dd, J 10.3 and 1.3, 3Ј-Hc), 5.18 (1H, dd, J 17.1 and 1.6, 3Ј-Ht)
and 5.90 (1H, ddd, J 17.1, 10.3 and 6.1, 2Ј-H); δC (67.8) 12.4
(3-Me), 44.5 (NMe), 52.2 (1Ј-CH2), 53.0 (1-CH2), 61.7 (2-CH),
116.3 (3Ј-CH ᎐) and 136.3 (2Ј-CH᎐); m/z 144 (Mϩ, 5%), 128 (5),
N2-Methyl-N1-(4-methylbenzoyl)propane-1,2-diamine 70b
᎐
᎐
2
By the foregoing procedure, reduction of the 5-(4-methyl-
benzoyl)oxadiazinane 68 (335 mg, 1.50 mmol) using zinc (500
mg, 7.50 mmol) gave the N-acyldiamine 70b as a highly hygro-
scopic oil which showed νmax/cmϪ1 3319 and 1643; δH (250) 1.10
(3H, d, J 6.4, 3-Me), 2.15 (1H, br, NH), 2.37 (3H, s, ArMe),
2.41 (3H, s, NMe), 2.84 (1H, qdd, J 6.4, 6.2 and 4.5, 2-H), 3.32
(1H, ddd, J 13.7, 6.2 and 5.8, 1-Ha), 3.46 (1H, ddd, J 13.7, 4.5
and 4.5, 1-Hb), 7.12 (1H, app. br t, J ≈ 5.8, CONH), 7.19 (2H, d,
109 (6), 96 (5), 91 (4), 86 (9), 83 (28), 74 (88), 70 (67), 58 (85), 56
(45), 42 (100) and 41 (74) (Found: Mϩ, 144.1301. C7H16N2O
requires M, 144.1263).
N1-Benzyl-N2-hydroxy-N2-methylpropane-1,2-diamine 69b
By the foregoing procedure, hydrolysis of the 5-benzyloxadiaz-
inane 44c (1.00 g, 3.60 mmol) gave the N-hydroxydiamine 69b
3304
J. Chem. Soc., Perkin Trans. 1, 2000, 3292–3305

View Article Online
11 B. H. Todder, G. B. Mullen and V. St. Georgiev, Helv. Chim. Acta,
J 8.0, 2 × ArH) and 7.71 (2H, d, J 8.0, 2 × ArH); δC (100) 18.0
(3-Me), 21.4 (ArMe), 33.5 (NMe), 44.0 (1-CH2), 54.1 (2-CH),
127.0, 129.1 (both 2 × Ar CH), 131.3, 141.6 (both Ar C) and
167.7 (CO); m/z 91 (41%), 72 (7) and 58 (100).
1990, 73, 169.
12 For a preliminary communication, see M. B. Gravestock, D. W.
Knight and S. R. Thornton, J. Chem. Soc., Chem. Commun., 1993,
169.
13 A. R. Katritzky and R. C. Patel, J. Chem. Soc., Perkin Trans. 1, 1979,
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14 F. G. Riddell and E. S. Turner, J. Chem. Soc., Perkin Trans. 1, 1979,
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15 A. C. Cope and E. R. Trumble, Org. React., 1960, 11, 317.
16 H. O. House, D. T. Manning, D. G. Melillo, L. F. Lee, O. R. Hayes
and B. E. Wilkes, J. Org. Chem., 1976, 41, 855; H. O. House and
L. F. Lee, J. Org. Chem., 1976, 41, 863.
X-ray crystallography for 13a†
Single crystals of the oxadiazinane 13a were obtained by
recrystallization from ethyl acetate–LP. X-ray data were col-
lected on a CAD4 diffractometer using monochromatized
Mo-Ka radiation (λ = 0.710 73 Å) and ω-scans.
17 W. Oppolzer, S. Siles, R. L. Snowden, B. H. Bakker and M.
Petrzilka, Tetrahedron Lett., 1979, 4391. See also D. St. C. Black
and J. E. Doyle, Aust. J. Chem., 1978, 31, 2317.
18 E. Ciganek, J. Org. Chem., 1995, 60, 5803; E. Ciganek, J. M. Read
and J. C. Calabrese, J. Org. Chem., 1995, 60, 5795.
19 W. Oppolzer, A. C. Spivey and C. G. Bochet, J. Am. Chem. Soc.,
1994, 116, 3139.
20 R. Grigg, J. Markandu, T. Perrior, S. Sukendrakumar and J.
Warnock, Tetrahedron, 1992, 48, 6929.
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3554.
22 D. W. Knight, M. P. Leese and A. R. Wheildon, Tetrahedron Lett.,
1997, 38, 8553; J. R. Hanrahan and D. W. Knight, Chem. Commun.,
1998, 2231.
23 M. P. Coogan, M. B. Gravestock, D. W. Knight and S. R. Thornton,
Tetrahedron Lett., 1997, 38, 8549.
24 A. B. Holmes, A. L. Smith, S. F. Williams, L. R. Hughes, Z. Lidert
and C. Swithenbank, J. Org. Chem., 1991, 56, 1393; E. C. Davison,
A. B. Holmes and I. T. Forbes, Tetrahedron Lett., 1995, 36, 9047;
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Soc., Perkin Trans. 1, 1994, 3379; A. B. Holmes, B. Bourdin,
I. Collins, E. C. Davison, A. J. Rudge, T. C. Stork and J. A. Warner,
Pure Appl. Chem., 1997, 69, 531.
25 I. A. O’Neil and J. M. Southern, Tetrahedron Lett., 1998, 39, 9089.
26 D. W. Knight and R. Salter, Tetrahedron Lett., 1999, 40, 5915.
27 J. Meisenheimer, Ber. Dtsch. Chem. Ges., 1919, 52, 1667.
28 U. Schöllkopf, M. Patsch and H. Schäfer, Tetrahedron Lett., 1964,
2515; U. Schöllkopf and H. Schäfer, Justus Liebigs Ann. Chem.,
1965, 683, 42; U. Schöllkopf, U. Ludwig, M. Patsch and W. Franken,
Justus Leibigs Ann. Chem., 1967, 703. See also W. Carruthers and
R. A. W. Johnstone, J. Chem. Soc., 1965, 1653.
Crystal data. C16H28N2O6, M = 344.40, orthorhombic, a =
9.311(2), b = 11.104(2), c = 17.245(2) Å, V = 1782.9(6) Å3,
T = 293 K, space group P212121 (no. 19), Z = 4, µ(Mo-
Kα) = 0.098 mmϪ1. Total 3676 reflections (3.22 у θ у 25.2Њ)
were measured, of which 3202 were unique (Rint = 0.0552) and
used in the calculations. The structure was solved by direct
methods (SHELXS-86)46 and refined on F2 (SHELXL-96)47 to
final wR2 (on F2) = 0.1329 (all data) and R1 (on F) = 0.0541
(1873 data with F2 > 2σ(F2). The non-hydrogen atoms were
anisotropic, the hydrogen atom on N(2) was located from a
difference map and freely refined; other hydrogen atoms were
included in calculated positions (riding model). The absolute
structure could not be determined reliably from these crystal
data, due to the absence of any significant anomalous scatter in
the molecule.
Acknowledgements
We are very grateful to Professor Charles W. Rees and
Dr Philip Cornwall for helpful discussions and to AstraZeneca
Pharmaceuticals and the EPSRC for financial support under
the CASE Scheme (to S. R. T.). We also thank the EPSRC
Mass Spectrometry service at University College, Swansea for
the provision of some high-resolution mass spectral data, and
the Royal Society for a Leverhulme Senior Research Fellowship
(to D. W. K.).
29 L. D. Quin and G. L. Roof, J. Org. Chem., 1962, 27, 4451; L. D.
Quin and F. A. Sherburne, J. Org. Chem., 1965, 30, 3135; A. R.
Lepley, P. M. Cook and G. F. Willard, J. Am. Chem. Soc., 1970, 92,
1101. For a review of amine oxide chemistry in general, see A.
Albini, Synthesis, 1993, 263.
30 W. Kliegel and G.-H. Franckenstein, Justus Liebigs Ann. Chem.,
1977, 956.
31 S. Saba, P. W. Domkowski and F. Firooznia, Synthesis, 1990, 921.
32 We are grateful to Professor C. W. Rees (Imperial College, London)
for this idea.
33 K. E. Bell, M. P. Coogan, D. W. Knight and M. B. Gravestock,
Tetrahedron Lett., 1997, 38, 8545.
34 See, for example, Y. L. Chow, C. J. Colon and J. N. S. Tam, Can. J.
Chem., 1968, 46, 2821.
35 M. Vaultier, M. Knouzi and R. Carrie, Tetrahedron Lett., 1983, 24,
763.
36 L. A. Clizbe and L. E. Overman, Org. Synth., 1978, 58, 5.
37 D. StC. Black, R. F. Crozier and I. D. Rae, Aust. J. Chem., 1978, 31,
2013.
38 U. Burger and A. O. Bringhen, Tetrahedron Lett., 1988, 29, 4415.
39 W. L. F. Armarego and D. D. Perrin, Purification of Laboratory
Chemicals, Butterworth/Heinemann, Oxford, 1996.
40 For general reviews, see J. Hamer and A. Macaluso, J. Org. Chem.,
1964, 29, 473; G. R. Delpierre and M. Macaluso, Q. Rev., 1965, 329.
41 Prepared by reduction of the corresponding imine: see R. B. Cheikh,
R. Chaabouni, A. Laurent, P. Mison and A. Nafti, Synthesis, 1983,
685; W. Emerson, Org. React., 1948, 4, 174; J. H. Billman and
A. C. Diesing, J. Org. Chem., 1957, 22, 1068.
42 A. W. Weston, A. W. Ruddy and C. M. Suter, J. Am. Chem. Soc.,
1943, 65, 674.
43 Prepared by the addition of vinylmagnesium chloride to the corre-
sponding imine: R. B. Moffett, Org. Synth., 1963, Coll. vol. IV, 605.
44 A. Z. Bimanand and K. N. Houk, Tetrahedron Lett., 1983, 24, 435.
45 cf. S. I. Murahashi, Y. Imada, Y. Tanaguchi and Y. Kodera,
Tetrahedron Lett., 1988, 29, 2973.
† CCDC reference number 207/463. See http://www.rsc.org/suppdata/
p1/b0/b003959o/ for crystallographic files in .cif format.
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