Preparation and ring-opening reactions of N,O-bis(diphenylphosphinyl) hydroxymethylaziridine ('Di-Dpp')

Article abstract of DOI:10.1016/S0040-4020(03)00551-9

N,O-bis(diphenylphosphinyl)-2-(hydroxymethyl)aziridine ('DiDpp', 1) is efficiently prepared from 2-aminoethane-1,3-diol: this activated aziridine undergoes two sequential reactions with copper(I)-modified Grignard reagents, yielding α-branched N-Dpp amines in good yield.

Full text of DOI:10.1016/S0040-4020(03)00551-9

Tetrahedron 59 (2003) 3677–3690
Preparation and ring-opening reactions of
N,O-bis(diphenylphosphinyl) hydroxymethylaziridine (‘Di-Dpp’)
b
J. B. Sweeneya and Alex A. Cantrill
,
*
aSchool of Chemistry, University of Reading, Whiteknights, Reading RG6 6AD, UK
bSchool of Chemistry, University of Bristol, Bristol BS8 1TS, UK
Received 5 February 2003; revised 14 March 2003; accepted 4 April 2003
Abstract—N,O-bis(diphenylphosphinyl)-2-(hydroxymethyl)aziridine (‘DiDpp’, 1) is efficiently prepared from 2-aminoethane-1,3-diol: this
activated aziridine undergoes two sequential reactions with copper(I)-modified Grignard reagents, yielding a-branched N-Dpp amines in
good yield. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
We have, of late, investigated the use of the diphenyl-
phosphinyl (abbreviated in our previous publications to
‘Dpp’) group as an activating group for ring-opening of
aziridines. Accordingly, we have developed such reactions
using heteroatom-centred, organometallic1 and (in the case
of vinylaziridines2) enolate nucleophiles. We further
2. Results and discussion
reported the fruits of our initial labours into the design
and utility of N,O-bis(diphenylphosphinyl)-2-(hydroxy-
methyl)aziridine (‘DiDpp’, 1) as a convenient synthetic
equivalent for the 2-aminopropane-1,2-dication synthon 2.3
In this paper we describe, in full, the synthesis and some
ring-opening reactions of this moiety.4 We also describe for
the first time the preliminary results we have garnered
concerning the mechanism of the reaction of 1 with
nucleophiles, via the ring-opening reaction of enantiomeri-
cally-pure (2R)-DiDpp.
We have previously described the synthesis of DiDpp and
its reaction with Grignard reagents in the presence of sub-
stoichiometric amounts of Cu(I) salts. Thus, we utilized the
nucleofugacity of the diphenylphosphinate anion in a ‘one-
pot’ preparation of 1 from commercially-available 2-amino-
propane-1,3-diol (Scheme 1) in 60% yield.
The fulcrum of this reaction is the intramolecular
displacement of diphenylphosphinate from the intermediate,
Scheme 1. One-pot preparation of (^)-DiDpp.
Keywords: aziridinemethanol; ring-opening; phosphinate.
*
Corresponding author. Tel.: þ44-118-931-6585; fax: þ44-118-378-6331; e-mail: j.b.sweeney@rdg.ac.uk
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00551-9

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J. B. Sweeney, A. A. Cantrill / Tetrahedron 59 (2003) 3677–3690
Scheme 2. Mechanistic possibilities in ring-opening of DiDpp.
in situ-generated, trisphosphinylated amide anion 3, pre-
pared by the introduction of excess sodium hydride to the
phosphinylation reaction vessel. The cyclization process is
relatively sluggish compared to the phosphinylation,
requiring reaction for up to three days at room temperature
for complete conversion; elevation of the reaction tempera-
ture enhanced the speed of the transformation but at the
expense of yield. As might be expected, 1 is extremely
polar, but may be purified by standard flash chromato-
graphy; using this protocol, gram quantities may be
obtained in a few days.
R-configured sample we would expect to observe opposite
enantiomers depending upon the precise mechanistic course
followed.
We first proposed to investigate the reaction of racemic
DiDpp with at least 2 equiv. of nucleophiles, assuming that
under these conditions double nucleophilic attack would
occur, thus avoiding any complication arising from the
possibility that the first product of nucleophilic attack might
react itself, leading to a range of products. It was, therefore,
gratifying to observe that the reaction of DiDpp with an
excess of lithium thiophenolate gave a single product,
2-(diphenylphosphinyl)amino-1,3-bis(phenylsulfanyl)pro-
pane, 4, in good yield (Scheme 3), demonstrating the
validity of our assumption that DiDpp could function
effectively as a doubly-electrophilic species.
The essence of the proposed reactions of 1 with nucleo-
philes is captured in Scheme 2. Thus, we anticipated that
ring-strain would dominate the synthetic proclivities of
DiDpp and, therefore, that 1 would react with a nucleophile
firstly by ring-cleavage; the intermediate amide anion thus
generated would, we reasoned, react slowly with nucleo-
philes (due to its negative charge) and would preferentially
displace diphenylphosphinate in a manner analogous to that
seen in our preparations of a range of N-Dpp aziridines, to
give a new aziridine (path a). If the diphenylphosphinate
leaving group proved more reactive a nucleofuge, then path
b would furnish the aziridine antipodal to that generated via
path a. There also existed the possibility that the nucleophile
might react at least as rapidly with the newly-formed
aziridines as with DiDpp, thereby leading to a branched
secondary amine as another product of the reaction; such a
product would also be observed if the intermediate anion
proved amenable to nucleophilic attack (path c). If these
reactions were not faster than the initial processes, our
proposed method would give entry (if performed upon an
enantiomerically-pure sample of DiDpp) to ‘non-proteino-
genic’ (i.e. not derived from naturally-occurring 2-amino-
acids) aziridines of high enantiomeric purity, compounds of
considerable synthetic potential.
Scheme 3. Reaction of (^)-DiDpp with phenylthiolate.
Of course, it was of more interest to us to assess the
reactivity of 1 with carbon-centred nucleophiles and so we
proceeded immediately to examine the reaction of DiDpp
with Grignard reagents in the presence of sub-stoichio-
metric amounts of copper(I) bromide, employing the
conditions previously developed.1 When DiDpp reacted in
the presence of CuBr·SMe2 with 5 equiv. of the Grignard
reagent generated from 2-methylbromopropane, a single
product (5a) was obtained, again arising from double
nucleophilic attack, in 78% yield (Scheme 4).
Of course, if ring-cleavage was accompanied by direct
displacement of ODpp by a nucleophile as the first step of
the reaction, the mechanistic situation would lead to
problems in terms of enantiocontrol. Furthermore, con-
vincing data concerning the mechanism would only be
forthcoming if enantiomerically-pure DiDpp were
employed in the reactions: thus, if either path a or path b
were the favoured mechanistic pathways, using an
Scheme 4. Reaction of (^)-DiDpp with isobutyl magnesium bromide/
CuBr.

J. B. Sweeney, A. A. Cantrill / Tetrahedron 59 (2003) 3677–3690
3679
Table 1. Reaction of (^)-DiDpp with excess copper(I)-modified Grignard
reagents
nucleophiles. Thus, DiDpp was reacted with a single
equivalent of ethylmagnesium bromide in THF, again in
the presence of a sub-stoichiometric amount of copper(I),
initially at 2108C and subsequently at reflux. After usual
aqueous work-up and flash chromatography, a single
product, N-Dpp-2-propylaziridine, 8a, was isolated from
the reaction, in good yield (Scheme 6).
This reaction demonstrates that there is a pronounced
difference in the reactivity of the aziridine and phosphinate
electrophilic components, because one might reasonably
expect to see a mixture of aziridine and ring-opened
products if the two electrophilic centres reacted at a similar
rate.
Product
R
Yield (%)
78
5a
5b
5c
75
75
However, since the DiDpp used in the reaction was racemic,
no comment could be made concerning the order of events
(viz., reaction following path a or path b), but the absence of
any other product was, we felt, a very encouraging finding.
Similar yields of non-proteinogenic N-Dpp aziridines 8b–d
were obtained from reaction of (^)-DiDpp with a range of
copper-modified Grignards, as displayed in Table 2. When
secondary bromides were used in the reaction, however, the
yields of aziridines 8e and 8f were significantly lower (by
20–30%) and these products were accompanied by varying
5da
5e
78
70
a
Chloride used in place of bromide.
Scheme 5. Reaction of (^)-DiDpp with cyclohex-2-enyl magnesium bromide/CuBr.
Table 2. Reaction of (^)-DiDpp with 1 equiv. of copper(I)-modified
Grignard reagents
The reactions of DiDpp with a range of Grignard reagents
proceeded in a similar manner to give amides 5b–e,
summarized in Table 1. Only when the Grignard reagent
derived from 3-bromocyclohexene was employed in the
process was the reaction not successful (Scheme 5). In this
case, bromomethyl aziridine 6 and N-Dpp-2-amino-1,3-
dibromoethane 7 were obtained from the reaction after
column chromatography, in 16 and 11% yields, respect-
ively; when DiDpp was reacted with 1,2-dibromoethane,
Aziridine
R
Yield of 8 (%)
Yield of 6 (%)
magnesium and CuBr·SMe2 under identical reaction
conditions to those previously employed, 6 was obtained
in 60% yield.
8a
8b
8c
70
52
63
0
0
0
Having demonstrated that both the aziridine and phos-
phinate moieties of DiDpp could act as electrophilic centres,
we next turned our attention to the question of which species
was more reactive with the cuprates so far employed as
8d
8e
76
42
0
24
8f
37
40
31
25
25
25
8g
8h
Scheme 6. Reaction of (^)-DiDpp with 1 equiv. of ethyl magnesium
bromide in the presence of CuBr.

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J. B. Sweeney, A. A. Cantrill / Tetrahedron 59 (2003) 3677–3690
amounts of bromomethylaziridine 6. A wide variation in
reaction conditions was examined in an attempt to minimize
the bifurcation in reaction pathway, but the yields shown in
Table 2 represent the best attainable in our hands.
to synthesize (R)-DiDpp by the protocol outlined in
Scheme 8.
Our synthetic endeavour commenced with the phosphinyl-
ation of (R)-glycidol; reaction of this commercially-
available epoxide with diphenylphosphinic chloride
proceeded smoothly to give the corresponding phosphinate
(11) in 75% yield. We next attempted to ring-open the
epoxide with trimethylsilyl azide, using a number of
reaction condition reported to effect similar reactions on
structurally-related glycidols, but to no avail. Gratifyingly,
reaction of 11 with sodium azide proved a very efficient
reaction, delivering the desired, ring-opened azide 12 as a
colourless solid in excellent yield. Without further purifi-
cation, this azide was directly converted to (2R)-DiDpp by a
two-step process; thus, 12 was reacted firstly with
triphenylphosphine in refluxing acetonitrile for 2 h and the
crude product of this reaction was obtained simply by
removal of solvent. This yellow oil was then dissolved in
dichloromethane and treated sequentially with triethylamine
and diphenylphosphinic chloride and the reaction mixture
stirred overnight at room temperature. Following usual
work-up and flash chromatography, two highly polar
products were obtained from the reaction: these proved to
be (2S)-N,O,O-tris(diphenylphosphinyl)-1-aminopropane-
2,3-diol, 13 (obtained in 16% yield), and (2R)-DiDpp
(29% yield). Clearly, 13 results from aminodiol 14, which is
itself generated as a by-product of incomplete conversion of
oxazaphospholidine 15 to the corresponding aziridine 16.
Despite extensive variation of reaction conditions, little
could be done to alter the ratio and yield of these two
products.
Having isolated a range of novel N-Dpp aziridines, we next
examined their own reactivity with a range of nucleophiles.
In the first instance, reaction of aziridine 8a with
phenylthiolate gave the expected ring-opening product (9)
in good yield (Scheme 7).
Scheme 7. Reaction of (^)-8a with phenylthiolate.
We next turned our attention to the use of organocuprates;
the results of these reactions are gathered in Table 3. Thus,
aziridines 8a–h smoothly underwent nucleophilic ring-
opening to give a range of secondary amines, 10a–i, in
acceptable yield. In these reactions, no side-reactions were
observed, even when the nucleophilic component of the
reaction was a-branched (entries 2 and 3).
Table 3. Reaction of (^)-DiDpp aziridines 8a–h with copper(I)-modified
Grignard reagents
Armed with our enantiomerically-pure aziridine, we next
reacted it with the cuprate derived from phenyl magnesium
bromide, anticipating that the reaction would furnish
2-benzyl aziridine, whose optical rotation could be
compared to the known enantiomerically-pure compound.
Unfortunately, the reaction gave a complex mixture of
products under a range of conditions; furthermore, this
finding was again encountered with other organometallic
reagents, thus hindering our mechanistic studies consider-
ably. Finally, we were able to execute an efficient reaction
using the cuprate derived from (freshly distilled) 1-bromo-
propane using the protocol followed for reaction of racemic
aziridine; the single product of the reaction was (2R)-N-
Dpp-2-butylaziridine (R)-(8b), which was obtained in 70%
yield after flash chromatography (Scheme 9).
Entry Product
R
R0
Yield of 10 (%)
1
2
10a
10b
52
75
3
4
5
6
7
8
10c
10d
10e
10f
77
65
64
60
66
72
The optical rotation exhibited for this non-aminoacid-
derived aziridine was recorded as þ9.1 (c 5, CH2Cl2),
which compares well in terms of magnitude with other
N-Dpp aziridines which had previously been prepared
unambiguously from enantiomerically-pure 2-aminoacids
(Table 4). The sign of the rotation was, however, the
opposite of the values seen for (2S)-configured aziridines,
suggesting that the product had the opposite absolute
stereochemistry of the aminoacid-derived aziridines, i.e.
that the aziridine possessed (R)-stereochemistry at its single
asymmetric centre. Thus we tentatively assigned this
stereochemical label to (R)-8b.
10g
10h
9
10i
66
We have referred above to the mechanistic possibilities in
the reactions of DiDpp with nucleophiles and have
described how these nuances could most easily be revealed
by using an enantiomerically-pure DiDpp. Thus, we set out
This finding suggests that the mechanistic route followed

J. B. Sweeney, A. A. Cantrill / Tetrahedron 59 (2003) 3677–3690
3681
Scheme 8. Synthesis of (2R)-DiDpp.
(R)-8b and to derivatize the branched primary amine, (2R)-
10e, thus formed in a manner suitable to enable us to
ascertain whether the product was enantiomerically-pure.
We anticipated that preparation of a Mosher’s amide5 would
satisfy our needs, and so we reacted (R)-8b with an excess of
the organocuprate derived from bromocyclopentane: (2R)-
N-Dpp-2-amino-1-(cyclopentyl)hexane, (2R)-10e, was thus
obtained in 74% yield after chromatographic purification.
This amine was dephosphinylated and reacted with (R)-2-
methoxy-2-trifluoromethylphenylacetic acid in the presence
of DMAP and DCC, giving (R, R)-amide 17 (Scheme 10).
Scheme 9. Ring-opening of (2R)-DiDpp.
Table 4. Optical rotation values of optically-active DiDpp aziridines
The 19F NMR spectrum of this species exhibited a single
resonance (dF¼268.41); as expected, the amide derived
from the racemic amine showed two 19F resonances in its
NMR spectrum (dF¼268.37 and 268.41) (Fig. 1). Thus, it
is clear that the reaction of (2R)-DiDpp with the cuprate
derived from 1-bromopropane proceeds to give an enantio-
merically-pure compound, whose optical properties
strongly support an assignment of (2R) to the single
asymmetric centre. From this, in turn, can be inferred the
notion that the reaction of DiDpp with this nucleophile
proceeds via a two-step, ring-opening/ring-closure mech-
anism, indicating that the aziridine is more reactive than the
phosphinate (at least when considering reaction with
Grignard-derived propylcuprates).
R
[a]2D3a
R
[a]2D3a
þ9.1
21.5
215.01
27.11
214.91
24.61
23.71
210.31
1021 deg cm22 g21
.
a
3. Conclusion
during the reaction is path a, in other words, that the reaction
with a single equivalent of Grignard-derived organocuprates
proceeds via aziridine ring-opening as the first step;
subsequent intramolecular displacement of diphenyl-
phosphinate yields (2R)-N-Dpp-butylaziridine. As con-
firmation of this hypothesis (and given that this aziridine
was not aminoacid-derived), we next sought to ring-open
We have investigated the ability of N,O-bis(diphenyl-
phosphinyl)-2-(hydroxymethyl)aziridine (DiDpp) (1) and
showed it to function as a synthetic equivalent for the
2-aminopropane-1,3-dication (2). Preliminary results
obtained from the reaction of (2R)-DiDpp indicate that the
mechanism of the reaction with organocuprates proceed via
a ring-opening/ring-closing pathway. We are currently

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J. B. Sweeney, A. A. Cantrill / Tetrahedron 59 (2003) 3677–3690
Scheme 10. Preparation of Mosher’s amide 17.
Figure 1. 19F NMR spectra of Mosher’s amides (R,R)-17 and (RS,R)-17.
1
engaged in research to strengthen the validity of this
conclusion in our laboratory.
a VG9090 mass spectrometer. H and 13C NMR spectra
were recorded on Jeol GX-270, Jeol GX-400, and Lambda
300 MHz spectrometers. Unless otherwise stated, deutero-
chloroform was used as solvent and tetramethylsilane as the
internal standard. Chemical shifts in 1H and 13C NMR
spectra are expressed as ppm downfield from tetramethyl-
silane. 13C Spectra were referenced to CDCl3 when the TMS
signal could not be observed. Coupling constants are quoted
in Hz. 31P spectra were recorded using a Jeol GX-400 or
Lambda 300 MHz spectrometer with chemical shifts
reported relative to phosphoric acid. 19F spectra were
recorded using a Lambda 300 MHz spectrometer with
chemical shifts reported relative to trichlorofluoromethane.
4. Experimental
4.1. General
All organic solvents were distilled prior to use and all
reagents were purified by standard procedures. Light
petroleum refers to the fraction with the boiling range
40–608C. Diethyl ether and THF were distilled from
sodium benzophenone ketyl; toluene from sodium;
dichloromethane, triethylamine and acetonitrile from
calcium hydride.
Reactions involving chemicals or intermediates sensitive to
air and/or moisture were performed under nitrogen or argon
atmosphere in flame or oven dried apparatus. Grignard
reagents were prepared in situ, or used as commercially-
available solutions in the solvent employed in the reaction.
Flash column chromatography was performed using Merck
or Fluka Kieselgel 60 silica. Analytical thin layer chroma-
tography (tlc) was performed on precoated Merck kieselgel
Melting points were recorded on a Kofler hot-stage
apparatus and are uncorrected. IR spectra were recorded
on a Perkin–Elmer 881 spectrophotometer. Optical
rotations were measured at 208C using the sodium D-line
by means of a Perkin–Elmer 241 MC polarimeter and are
quoted in 1021 deg cm2 g21. Mass spectra were recorded on

J. B. Sweeney, A. A. Cantrill / Tetrahedron 59 (2003) 3677–3690
3683
60 F254 aluminium-backed Plate and visualised under UV
4.2. General method for copper-modified Grignard
reactions using excess of Grignard reagent
light (254 nm) or by staining with an acidic ammonium
molybdate spray and acidic potassium permanganate
spray.
To copper(I) bromide dimethylsulfide complex (5 mol%),
under argon, at ambient temperature was added a solution of
N-diphenylphosphinylaziridine in THF, (typically 1.0 mmol
in 15 mL). The solution was then cooled to 2108C, and a
solution of Grignard reagent (5 equiv.) in THF (5 mL),
added dropwise. The resulting yellow solution was then
warmed to room temperature, before being refluxed for
30 min, during which time the reaction mixture turned
black. Upon cooling to room temperature the reaction was
quenched with saturated ammonium chloride solution
(30 mL), and partitioned with EtOAc, (30 mL, and then
2£10 mL). The combined organic layers were washed with
brine, dried (MgSO4), filtered and the solvent removed
under reduced pressure. The products were purified by flash
chromatography.
4.1.1. N,O-Bis(Diphenylphosphinyl)-2-(hydroxymethyl)-
aziridine (1). To a suspension of 2-amino-1,3-propanediol
(Aldrich Chemical Co.) (0.5 g, 5.5 mmol), in THF
(100 mL), under argon at 08C was added diphenyl-
phosphinic chloride (3.2 mL, 16.5 mmol), and triethylamine
(3.1 mL, 22.0 mmol). A white precipitate of triethylamine
hydrochloride was immediately formed. The suspension
was stirred for 20 h, after which time sodium hydride (1.0 g,
41.7 mmol), was added at 08C. This dense grey suspension
was stirred at room temperature for a further 72 h. After this
time water (1 mL) was added, before filtering through
anhydrous magnesium sulfate. The resulting filter cake was
washed with 150 mL of ethyl acetate. The solvent was
removed under reduced pressure to leave a pale yellow oil.
Purification by flash chromatography (1% methanol, EtOAc
eluent), afforded a colourless oil. Crystallisation from
EtOAc/hexane gave aziridine (1) (1.56 g, 60%) as a
colourless solid. Rf 0.4 (10% methanol, EtOAc); mp 138–
1398C. (Found: C, 68.3; H, 5.4; N, 2.8. C27H25NO3P2
requires C, 68.5; H, 5.3; N, 3.0%); nmax (CHCl3)/cm21 2982
(CH), 1438 (PhP), 1132 (PvO), 1022, 834 (aromatic); dH
(300 MHz, CDCl3), 2.03 (1H, dd, J¼3.0, 12.3 Hz, CH of
CH2N), 2.58 (1H, dd, J¼6.0, 15.8 Hz, CH of CH2N) 3.04–
3.19 (1H, m, CHN), 3.89–3.97 and 4.19–4.23 (2H, 2£m,
CH2ODpp), 7.27–7.95 (20H, m, ArH); dC (67.5 MHz,
CDCl3) 26.85, (CH2N), 34.13, (CHN), 65.69, (CH2ODpp),
128.8 131.5; dP (161.9 MHz), 31.91 and 32.68; m/z (CI),
474 (MHþ, 95%), 419 (9), 274 (M2Ph2P(O), 9), 219 (100),
201 (Ph2P(O), 41). (Found: [MH]þ 474.1376. C27H25NO3P2
requires [MH]þ 474.1387).
4.2.1. 2,8-Dimethyl-5-(diphenylphosphinamido)nonane
(5a). By following the general procedure described above
N,O-bis(diphenylphosphinyl)-2-(hydroxymethyl)aziridine
(1) (0.5 g, 1.06 mmol), copper(I) bromide dimethylsulfide
complex (0.01 g, 0.05 mmol) and 2-methylpropylmag-
nesium bromide (5 equiv.), prepared from magnesium
(0.13 g, 5.4 mmol), and 1-bromo-2-methylpropane
(0.6 mL, 5.3 mmol), were reacted in THF (20 mL), to
produce a yellow oil. Purification by flash chromatography
(gradient 20–60% EtOAc in light petroleum), gave (5a)
(0.31 g, 78%) as a colourless solid. Rf 0.6 (EtOAc); mp
131–1328C. (Found: C, 74.4; H, 9.4; N, 3.6. C23H34NOP
requires C, 74.4; H, 9.2, N, 3.8%); nmax/cm21, 3201 (NH),
2868 (CH), 1435 (PhP), 1187 (PvO), 722 and 694
(aromatics); dH (270 MHz, CDCl3) 0.83 and 0.86 (12H,
2£d, J¼2.2 Hz, CH(CH3)2), 1.10–1.26 (4H, m, 2£CH2-
CH(CH3)2), 1.41 – 1.52 (6H, m, 2£CH2CHN, and
CH(CH3)2), 2.62 (1H, dd, J¼5.9, 10.6 Hz, NH), 3.01–
3.10 (1H, m, CHN), 7.39–7.52 (6H, m, ArH), and 7.87–
7.96 (4H, m, ArH); dC (67.5 MHz, CDCl3); 22.30 and 22.90
(4£CH3), 27.66 and 27.95 (2£CH(CH3)2), 33.98 and 34.17
(4£CH2), 51.51 (CH), 128.1 131.5, 133.13 (d, J¼128.6 Hz);
dP (121.4 MHz, CDCl3) 21.49; m/z (CI) 372 (MHþ, 100%),
300 (57), 294 (26), 201 (12). (Found: [MH]þ 372.2456.
C23H34NOP 2456).
4.1.2. 2-(Diphenylphosphinamido)-1,3-bis(thiophenyl)-
propane (4). To a solution of thiophenol (0.07 g,
0.6 mmol) in THF (8 mL), under argon at 2428C, was
added BuLi (0.26 mL, 2.65 M, 0.6 mmol) dropwise. The
solution was stirred at 2428C for 0.5 h, after which time a
solution of N,O-bis(diphenylphosphinyl)-2-(hydroxymethyl)-
aziridine (0.1 g, 0.2 mmol) in THF (2 mL) was added. The
solution was gradually allowed to warm to ambient
temperature and then stirred overnight. The reaction
mixture was partitioned between H2O (10 mL), and
EtOAc (2£15 mL), the organic layer separated and washed
with brine (15 mL), dried (Na2SO4), filtered, and the solvent
removed under reduced pressure to leave a yellow oil.
Purification by flash chromatography (EtOAc/light
petroleum 1:1), gave (4) (0.07 g, 70%) as a colourless
solid. Rf 0.5 (EtOAc); mp 1428C. (Found: C, 67.9; H, 5.5; N,
2.85. C27H26NOPS2 requires C, 68.2; H, 5.5; N, 2.95%);
4.2.2. 6-(Diphenylphosphinamido)undeca-1,10-diene
(5b). By following the general procedure described above
N,O-bis(diphenylphosphinyl)-2-(hydroxymethyl)aziridine
(1) (0.5 g, 1.06 mmol), copper(I) bromide dimethylsufide
complex (0.01 g, 0.05 mmol) and but-4-enyl magnesium
bromide (5 equiv.), prepared from magnesium (0.13 g,
5.35 mmol), and 4-bromobutene (0.54 mL, 5.3 mmol),
were reacted together in THF (20 mL) to produce a yellow
oil. Purification by flash chromatography (gradient 20–60%
EtOAc in light petroleum), gave (5b) (0.30 g, 76%) as a
colourless solid. Rf 0.5 (EtOAc); mp 89–908C. (Found C,
75.3; H, 8.3; N, 3.7. C23H30NOP requires C, 75.2; H, 8.2; N,
3.8%); nmax/cm21 3191 (NH), 2929 (CH), 1641 (CvC),
1435 (PhP), 1183, 1123 (PvO), 723, 694 (aromatics); dH
(400 MHz, CDCl3), 1.18–1.63 (8H, m, 4£CH2), 1.87–2.15
(4H, m, 2£CH2), 2.69 (1H, dd, J¼4.5, 11.5 Hz, CHNH),
3.02–3.18 (1H, m, CHNH), 4.91–5.03 (4H, m, CHvCH2),
5.64–5.84 (2H, m, CHvCH2), 7.38–7.98 (10H, m, ArH);
n
max/cm21 2980 (CH), 1438 (PhP), 1124 (PvO) 1056, 844,
696 (aromatic); dH (270 MHz, CDCl3), 1.71 (1H, br s, NH),
3.21 (2H, dd, J¼6.6, 13.9 Hz, 2£CH of CH2SPh), 3.47–
3.51 (3H, m, 2£CH of CH2SPh and CHN); dC (67.5 MHz,
CDCl3), 38.32 and 38.34 (2£CH2), 50.18 (CHN), 126.09,
128.50 (d, J¼13.0 Hz), 129.03, 131.9, 135.35; dP
(161.9 MHz) 21.96; m/z (CI), 476.49 (MHþ, 100%),
352.34 (55), 218.21 (66), 201 (Ph2P(O), 50). (Found:
[MH]þ 476.1280. C27H26NOPS2 requires [MH]þ
476.1272).

3684
J. B. Sweeney, A. A. Cantrill / Tetrahedron 59 (2003) 3677–3690
dC (67.5 MHz, CDCl3), 24.25 (CH2vCHCH2CH2CH2),
32.93 and 35.04 (CH2vCHCH2CH2CH2), 51.03 (CHNH),
114.18 (CHvCH2), 128.13 (d, J¼10.7 Hz), 131.8, 132.9,
138.78 (CHvCH2); dP (161.7 MHz, CDCl3), 21.32; m/z
(CI) 368 (MHþ, 43%), 298 (36), 201 (17) 83 (100). (Found:
[MH]þ 368.2140, C23H30NOP requires [MH]þ 368.2143).
5.3 mmol), were reacted together in THF (20 mL) to
produce a yellow oil. Purification by flash chromatography
(gradient 20–60% EtOAc in light petroleum), afforded (5d)
(0.56 g, 70%) as a colourless solid. Rf 0.5 (EtOAc); mp 84–
858C. (Found: C, 80.2; H, 8.0; N, 2.7. C33H38NOP requires
C, 80.0; H, 7.7; N, 2.8%); nmax/cm21 3202 (NH), 2929
(CH), 1434 (PhP), 1188, 1123 (PvO), 748, 697 (aromatic);
dH (400 MHz, CDCl3), 1.26–1.41 and 1.49–1.59 (12H, m,
6£CH2), 2.52–2.64 (5H, m, 2£CH2 and NH), 2.97–3.10
(1H, m, CHNHDpp), 7.10–7.50 (16H, m, ArH), and 7.84–
7.90 (4H, m, ArH); dC (100 MHz, CDCl3), 25.0 (CH2CH2-
Ph), 31.2 (CH(NH)CH2CH2), 35.7 (CH(NH)CH2CH2), 36.6
(CH2Ph), 51.4 (CHNH), 125.56, 128.3, 131.5, 132.12 (d,
J¼9.1 Hz), 133.0 (d, J¼129.0 Hz), 142.44; dP (121.4 MHz,
CDCl3) 21.37; m/z (CI) 496 (MHþ, 100%), 418 (8), 362
(28), 201 (Ph2PO, 9). (Found: [MH]þ 496.2778,
C33H38NOP requires [MH]þ 496.2769).
4.2.3. 1,3-Diphenyl-2-(diphenylphosphinamido)propane
(5c). By following the general procedure described above
N,O-bis(diphenylphosphinyl)-2-(hydroxymethyl)aziridine
(1), (0.5 g, 1.06 mmol), copper(I) bromide dimethylsulfide
complex (0.01 g, 0.05 mmol) and phenyl magnesium
bromide (5 equiv.), prepared from magnesium (0.13 g,
5.35 mmol), and bromobenzene (0.52 mL, 5.3 mmol),
were reacted together in THF (20 mL) to produce a yellow
oil. Purification by flash chromatography (gradient 20–60%
EtOAc in light petroleum), gave (5c) (0.33 g, 75%), as a
colourless solid. Rf 0.4 (EtOAc); mp 138–1398C. (Found C,
78.8; H, 6.6; N, 3.4. C27H26NOP requires C, 78.8; H, 6.4; N,
3.4%); nmax/cm21 3169 (NH), 2924 (CH), 1438 (PhP),
1188, 1123 (PvO), 749, 723 (aromatic); dH (400 MHz,
CDCl3), 2.73 (1H, br dd, J¼5.8, 11.5 Hz, NH), 2.81 (2H, dd,
J¼6.4, 13.4 Hz, CH of CH2Ph), 2.93 (2H, dd, J¼5.6,
13.4 Hz, CH of CH2Ph), 3.46–3.54 (1H, m, CHNH) 7.18–
7.54 (20H, m, ArH); dC (100 MHz, CDCl3), 42.82 and 42.88
(2£CH2), 42.70 (CH), 126.36, 128.29 (d, J¼13.0 Hz),
128.32, 129.93, 131.49 (d, J¼3.0 Hz), 132.0, 138.34; dP
(161.9 MHz, CDCl3), 21.40; m/z (CI) 412 (MHþ, 100%),
334 (12), 320 (24), 201 (Ph2PO). (Found: [MH]þ 412.1817,
C27H26NOP requires [MH]þ 412.1830).
4.2.6. N-Diphenylphosphinyl-2-(bromomethyl)aziridine
(6) and 1,3-dibromo-2-(diphenylphosphinamido)pro-
pane (7). By following the general procedure described
above
N,O-bis(diphenylphosphinyl)-2-(hydroxymethyl)-
aziridine (1) (1.4 g, 3.0 mmol), copper(I) bromide dimethyl-
sulfide complex (0.03 g, 0.15 mmol) and cyclo-
hexenemagnesium bromide (5 equiv.), prepared from
magnesium (0.37 g, 15.3 mmol), and 3-bromocyclohexene
(1.7 mL, 14.8 mmol), were reacted in THF to produce a
yellow oil. Purification by flash chromatography (gradient
20–60% EtOAc in light petroleum), gave 1,3-dibromo-2-
(diphenylphosphinamido)propane (7) (0.16 g, 11%) as a
colourless solid. Rf 0.5 (EtOAc); mp 154–1568C. (Found C,
43.3; H, 4.2; N, 3.2. C15H16NOPBr2 requires C, 43.2 H, 3.9
N, 3.4%); nmax/cm21 3122 (NH), 2872 (CH), 1438 (PhP),
1180, 1125 (PvO), 839, 697 and 691 (aromatic); dH
(400 MHz, CDCl3), 3.52 (2H, d, broad, J¼6.3 Hz, CHNH),
3.61–3.63 (2H, m, CH2Br), 3.83 and 3.85 (2H, 2£br s,
CH2Br), 7.44–7.56 (6H, m, ArH), and 7.79–7.93 (4H, m,
ArH); dH D2O shake, (270 MHz, CDCl3), 3.47–3.57 (1H,
m, CHNH), 3.63 (2H, dd, J¼6.6, 10.3 Hz, CH of CH2Br),
3.84 (2H, dd, J¼3.4, 10.3 Hz, CH of CH2Br), 7.41–7.59
(6H, m, ArH), and 7.79–8.05 (4H, m, ArH); dC (100 MHz,
CDCl3), 36.10 and 36.16 (2£CH2Br), 51.10 (CHNH), 128.5
131.5; dP (161.9 MHz, CDCl3), 22.91; m/z (FAB),
[calcd(obs.)], 421 [5.4 (5.5)], 420 [31.9 (31.5)], 419 [11.1
(11)], 418[64 (64)], 417[5.7 (5.5)], 416[32.6 (32.5)], 247
(65), 201 (100, Ph2PO); m/z (CI) 418 (MHþ, 5%), 338
(M2Br, 8), 201 (7) 83 (100). (Found: [MH]þ 417.9414.
C15H16NOPBr2 requires [MH]þ 417.9394).
4.2.4. 2,6-Dimethyl-4-(diphenylphosphinamido)heptane
(5d). By following the general procedure described above
N,O-bis(diphenylphosphinyl)-2-(hydroxymethyl)aziridine
(1), (0.5 g, 1.06 mmol), copper(I) bromide dimethylsulfide
complex (0.01 g, 0.05 mmol) and 2-(methyl)ethylmagne-
sium chloride, (2.7 mL, 2.0 M, 5.3 mmol) were reacted
together in THF (20 mL) to produce a yellow oil.
Purification by flash chromatography (gradient 20–60%
EtOAc in light petroleum), gave (5d) (0.26 g, 72%). Rf 0.45
(EtOAc); mp 1628C. (Found C, 73.45; H, 9.0; N, 4.1.
C21H30NOP requires C, 73.4; H, 8.8; N, 4.1%); nmax/cm21
3145 (NH), 2957 (CH), 1437 (PhP), 1186, 1123 (PvO),
727, 696 (aromatic); dH (400 MHz, CDCl3), 0.72–0.81
(12H, m, 4£CH3), 1.25–1.42 (4H, m, 2£CH(CH3)2, and one
CH from each CH2CH(NHDpp)), 1.71–1.83 (2H, m, 2£CH,
CH2CH(NHDpp)), 2.53 (1H, dd, J¼5.1, 10.6 Hz, NH),
2.95–3.10 (1H, m, CH), 7.4–7.55 and 7.85–8.00 (10H,
ArH); dC (100 MHz, CDCl3), 22.68 and 24.73 (4£CH3),
24.27 (2£CH(CH3)2), 47.72 and 47.76 (2£CH2), 48.47
(CH(NHDpp)), 128.38 (d, J¼13.6 Hz), 131.70 (d,
J¼2.4 Hz), 132.35 (d, J¼9.3 Hz), 133.13 (d, J¼128.7 Hz);
dP (100 MHz, CDCl3), 20.82; m/z (CI) 344 (MHþ, 100%),
286 (48), 266 (15), 218 (11), 201 (Dpp, 11%). (Found:
[MH]þ 344.2149. C21H30NOP requires [MH]þ 344.2143).
Further elution, (gradient 60–100% EtOAc in light
petroleum), gave N-diphenylphosphinyl-2-(bromomethyl)-
aziridine (6) (0.11 g, 16%), as an unstable pale yellow oil. Rf
0.4 (EtOAc); nmax/cm21 3057 (CH), 1203, 1126 (PvO),
727, 695 (aromatic); dH (400 MHz, CDCl3), 2.10 (1H, dd,
J¼3.2, 12.5 Hz, CH of CH2N), 2.70 (1H, dd, J¼5.9,
16.8 Hz, CH of CH2N), 3.04–3.11 (1H, m, CHN), 3.35 (2H,
d, J¼6.1 Hz, CH2Br), 7.45–7.96 (10H, m, ArH); dC
(67.5 MHz, CDCl3), 30.10 (CH2Br), 32.88 (CH2N), 35.45
(CHN), 128.5 131.7; dP (161.9 MHz, CDCl3), 31.59; m/z
(FAB), 338 and 336 (bromine isotope pattern, 79%), 256
(M2Br, 12%), 201 (Ph2PO, 100%); m/z (CI) 338 and 336
(16%), 258 (40), 201 (9) 79 (100). (Found: [MH]þ
336.0148, C15H15NOPBr requires [MH]þ 336.0153).
4.2.5. 1,9-Diphenyl-5-(diphenylphosphinamido)nonane
(5e). By following the general procedure described above
N,O-bis(diphenylphosphinyl)-2-(hydroxymethyl)aziridine
(1), (0.5 g, 1.06 mmol), copper(I) bromide dimethylsulfide
complex (0.01 g, 0.05 mmol) and 3-phenylpropylmagne-
sium bromide (5 equiv.), prepared from magnesium (0.13 g,
5.4 mmol), and 1-bromophenylpropane (0.8 mL,

J. B. Sweeney, A. A. Cantrill / Tetrahedron 59 (2003) 3677–3690
3685
4.3. General method for copper-modified Grignard
reactions using 1 equiv. of Grignard reagent
CDCl3) 31.78; m/z (CI) 300 (MHþ, 100%), 222 (18), 218
(14), 98 (5), 83 (14). (Found: [MH]þ 300.1509, C18H22NOP
requires [MH]þ 300.1517).
N,O-Bis(diphenylphosphinyl)-2-(hydroxymethyl)aziridine
(typically 1 mmol), and copper(I) bromide dimethylsulfide
complex (5 mol%) were dissolved in THF (10 mL), and
cooled to approximately 2108C. A solution of freshly
prepared Grignard reagent in THF (5 mL), was then added
dropwise (1.1 equiv.). The resulting yellow solution was
warmed to room temperature over 30 min, and then heated
to reflux for 30 min, during which time the reaction mixture
often turned black. Upon cooling to room temperature the
reaction was quenched with saturated ammonium chloride
solution (20 mL), and partitioned with EtOAc (50 mL, and
then 2£15 mL) the combined organic layers were then
washed with brine (20 mL), dried (MgSO4), filtered and the
solvent removed under reduced pressure. The products were
purified by flash chromatography.
4.3.3. N-Diphenylphosphinyl-2-(3-methylbutyl)aziridine
(8c). By following the general procedure described above
N,O-bis(diphenylphosphinyl)-2-(hydroxymethyl)aziridine
(0.5 g, 1.06 mmol), copper(I) bromide dimethylsulfide
complex (0.01 g, 0.05 mmol), and 1.1 equiv. of Grignard
reagent formed from magnesium (0.03 g, 1.27 mmol), and
1-bromo-2-methylpropane (0.13 mL, 1.16 mmol) were
reacted together in THF to produce a yellow oil. Purification
by flash chromatography (gradient 20–50% EtOAc in light
petroleum), gave (8c) (0.21 g, 63%) as a pale yellow oil. Rf
0.5 (EtOAc); nmax/cm21, 2955 (CH), 1438 (PhP), 1203,
1125 (PvO), 727, 696 (aromatics); dH (270 MHz, CDCl3),
0.73–0.75 and 0.77–0.79 (6H, 2£d, J¼6.6 Hz, CH(CH3)2),
1.00–1.12 (2H, m, (CH3)2CHCH2CH2), 1.37–1.62 (3H, m,
(CH3)2CHCH2CH2), 1.92 (1H, ddd, J¼1.1, 3.6, 12.5 Hz,
CH of CH2N), 2.53 (1H, ddd, J¼1.1, 5.9, 17.6 Hz, CH of
CH2N) 2.61–2.73 (1H, m, CHN), 7.40–7.50 (6H, m, ArH),
and 7.89–7.97 (4H, m, ArH); dC (67.5 MHz, CDCl3) 21.88
and 22.14 (2£CH3), 27.03 (CH(CH3)2), 27.60 and 29.13
(2£CH2), 29.22 (CH2N), 35.32 (CHN), 128.1, 131.5; dP
(161.9 MHz, CDCl3), 31.78; m/z (CI) 314 (MHþ, 100%),
298 (5), 236 (27), 201 (7). (Found: [MH]þ 314.1680.
C19H24NOP requires [MH]þ 314.1674).
4.3.1. N-Diphenylphosphinyl-2-propylaziridine (8a). By
following the general procedure described above N,O-
bis(diphenylphosphinyl)-2-(hydroxymethyl)aziridine (0.5 g,
1.06 mmol), copper(I) bromide dimethylsulfide complex
(0.01 g, 0.05 mmol), and 1.1 equiv. of Grignard reagent
formed from magnesium (0.03 g, 1.2 mmol), and bromo-
ethane (0.09 mL, 1.16 mmol) were reacted together in THF
to produce a pale yellow oil, which was purified by flash
chromatography (gradient 20–60% EtOAc in light
petroleum), to give (8a) (0.21 g, 70%) as a colourless oil.
Rf 0.3 (EtOAc); nmax/cm21 2929 (CH), 1437 (PhP), 1202,
1125 (PvO), 727, 696 (aromatic); dH (270 MHz, CDCl3),
0.80 (3H, t, J¼7.5 Hz, CH3), 1.19–1.54 (4H, m, CH3CH2-
CH2), 1.92 (1H, dd, J¼2.2, 12.5 Hz, CH of CH2N), 2.58
(1H, dd, J¼5.9, 16.9 Hz, CH of CH2N), 2.68–2.74 (1H, m,
CHN), 7.37–7.51 (6H, m, ArH), and 7.88–7.96 (4H, m,
ArH); dC (67.5 MHz, CDCl3) 14.13 (CH3), 20.10, 29.56,
(2£CH2), 34.64 (CH2N), 35.37 (CHN), 128.3 131.7, 133.08
and 133.15 (d, J¼122.2 Hz); dP (161.9 MHz) 31.95; m/z
(CI) 286 (MHþ, 100%), 272 (7), 208 (27), 201 (Ph2P(O), 9).
(Found: [MH]þ 286.1355, C17H20NOP requires [MH]þ
286.1360).
4.3.4. N-Diphenylphosphinyl-2-(pent-4-enyl)aziridine
(8d). By following the general procedure described above
N,O-bis(diphenylphosphinyl)-2-(hydroxymethyl)aziridine
(0.5 g, 1.06 mmol), copper(I) bromide dimethylsulfide
complex (0.01 g, 0.05 mmol), and 1.1 equiv. of Grignard
reagent formed from magnesium (0.03 g, 1.27 mmol), and
4-bromobut-1-ene (0.12 mL, 1.16 mmol) were reacted
together in THF to produce a yellow oil. Purification by
flash chromatography (gradient 20–60% EtOAc in light
petroleum), gave (8d) (0.25 g, 76%) as a clear oil. Rf 0.4
(EtOAc); nmax/cm21, 2931 (CH), 1438 (PhP), 1203, 1125
(PvO), 727, 696 (aromatic); dH (400 MHz, CDCl3), 1.22–
1.59 (4H, m, CH2vCHCH2CH2), 1.86–2.04 (3H, m, CH of
CH2N and CH2CHN), 2.55 (1H, ddd, J¼1.4, 6.0, 15.4 Hz,
CH of CH2N), 2.66–2.67 (1H, m, CHN), 4.87–4.93 (2H, m,
CHvCH2), 5.60–5.73 (1H, m, CHvCH2), 7.41–7.52 (6H,
m, ArH), and 7.89–7.95 (4H, m, ArH); dC (100 MHz,
CDCl3), 25.60, 29.24, 31.84, 35.34 (4£CH2), 36.35 (CHN,
d, J¼6 Hz), 114.74 (CHvCH2), 128.30 (d, J¼12.1 Hz),
131.7, 132.7 and 132.8 (2£d, J¼122.9 Hz), 138.30
(CHvCH2); dP (121.4 MHz, CDCl3), 32.00; m/z (CI) 312
(MHþ, 100%), 298 (9), 201 (15) 83 (12). (Found: [MH]þ
312.1512. C19H22NOP requires [MH]þ 312.1517).
4.3.2. N-Diphenylphosphinyl-2-butylaziridine (8b). By
following the general procedure described above N,O-
bis(diphenylphosphinyl)-2-(hydroxymethyl)aziridine(0.75 g,
1.59 mmol), copper(I) bromide dimethylsulfide complex
(0.01 g, 0.05 mmol), and 1.1 equiv. of Grignard reagent
formed from magnesium (0.04 g, 1.9 mmol), and bromo-
propane (0.16 mL, 1.74 mmol) were reacted together in
THF to produce a pale yellow oil, which was purified by
flash chromatography (gradient 20–80% EtOAc in light
petroleum), to give (8b) (0.31 g, 66%) as a colourless oil. Rf
0.4 (EtOAc); nmax/cm21 2956 (CH), 1438 (PhP), 1203,
1125 (PvO), 727, 696 (aromatic); dH (400 MHz, CDCl3),
0.77 (3H, t, J¼7.1 Hz, CH3CH2), 1.17–1.36 (4H, m,
CH3CH2CH2), 1.47–1.52 (2H, m, CH2CHN), 1.91 (1H,
ddd, J¼1.2, 3.4, 12.5 Hz, CH of CH2N), 2.53 (1H, ddd,
J¼1.2, 6.1, 17.4 Hz, CH of CH2N), 2.65–2.74 (1H, m,
CHN), 7.41–7.51 (6H, m, ArH), and 7.90–7.95 (4H, m,
ArH); dC (75 MHz, CDCl3), 13.72 (CH3), 22.25, 28.80
(CH3CH2CH2) 29.44 (CH2CHN), 32.06 (CH2N, d,
J¼4.2 Hz) 35.51 (CHN, d, J¼6.2 Hz), 128.3 131.4,
132.81 and 132.87 (2£d, J¼127.1 Hz); dP (161.9 MHz,
4.3.5. N-Diphenylphosphinyl-2-benzylaziridine (8e).1 By
following the general procedure described above N,O-
bis(diphenylphosphinyl)-2-(hydroxymethyl)aziridine (0.5 g,
1.06 mmol), copper(I) bromide dimethylsulfide complex
(0.01 g, 0.05 mmol), and 1.1 equiv. of Grignard reagent
formed from magnesium (0.03 g, 1.26 mmol), and bromo-
benzene (0.12 mL, 1.16 mmol) were reacted together in
THF to produce a yellow oil. Purification by flash
chromatography (gradient 20–60% EtOAc in light
petroleum), gave (8e) (0.15 g, 42%) as a colourless solid.
Mp 103–1048C (lit.1 103–1058C); Rf 0.5 (EtOAc); dH

3686
J. B. Sweeney, A. A. Cantrill / Tetrahedron 59 (2003) 3677–3690
(270 MHz, CDCl3), 2.03 (1H, ddd, J¼1.2, 3.3, 12.5 Hz, CH
of CH2N), and 2.58 (1H, ddd, J¼1.2, 5.9, 17.3 Hz, CH of
CH2N), 2.82 (2H, d, J¼5.6 Hz, PhCH2), 2.95–3.07 (1H, m,
CHN), and 7.06–7.56 (11H, m, ArH), and 7.72–8.04 (4H,
m, ArH).
(Found: C, 74.1; H, 7.9; N, 3.9. C21H26NOP requires C,
74.3; H, 7.7; N, 4.1%); nmax/cm21 2923 (CH), 1438 (PhP),
1203, 1126 (PvO), 727, 696 (aromatic); dH (270 MHz,
CDCl3) 0.74–1.57 (13H, m, hexyl ring, and CH2CHN), 1.90
(2H, 2£ddd, J¼1.1, 3.3 Hz, 12.5, CH of CH2N), 2.54 (1H,
ddd, J¼1.1, 5.9, 17.5 Hz, CH of CH2N), 2.71–2.80 (1H, m,
CHN), 7.40–7.53 (6H, m, ArH), and 7.88–7.97 (4H, m,
ArH); dC (67.5 MHz, CDCl3) 25.57, 25.85, 25.98, 33.38 and
33.57 (5£CH2 cyclohexyl ring), 29.79 (CH cyclohexyl
ring), 32.14 (CH2), 35.89 (CH2N), 40.10 (CHN, d,
J¼5.0 Hz), 128.1 (d, J¼12.8 Hz), 131.4, 132.73 and
132.82 (2£d, J¼126.4 Hz); dP (161.9 MHz, CDCl3),
31.79; m/z (CI) 340 (MHþ, 100%), 262 (24), 201 (8), 79
(17). (Found: [MH]þ 340.1833. C21H26NOP requires
[MH]þ 340.1830).
4.3.6. N-Diphenylphosphinyl-2-(2-methylpropyl)aziri-
dine (8f). By following the general procedure described
above
N,O-bis(diphenylphosphinyl)-2-(hydroxymethyl)-
aziridine (0.5 g, 1.06 mmol), copper(I) bromide dimethyl-
sulfide complex (0.01 g, 0.05 mmol), and 1.1 equiv. of
Grignard reagent formed from magnesium (0.03 g,
1.27 mmol), and 2-bromopropane (0.11 mL, 1.16 mmol)
were reacted together in THF to produce a yellow oil.
Purification by flash chromatography (gradient 20–70%
EtOAc in light petroleum), gave (8g) (0.12 g, 37%) as a
colourless solid. Rf 0.4 (EtOAc); mp 62–648C. (lit.1 65–
668C); nmax/cm21 2956 (CH), 1438 (PhP), 1203, 1125
(PvO), 727, 696 (aromatic); dH (270 MHz, CDCl3), 0.76
and 0.83 (6H, 2£d, J¼6.2 Hz, CH(CH3)2), 1.22–1.30 (1H,
m, CH(CH3)2), 1.49–1.58 (2H, m, CH2CHN), 1.93 (1H,
ddd, J¼1.1, 3.7, 12.5 Hz, CH of CH2N), 2.72 (1H, ddd,
J¼1.1, 5.9, 17.8 Hz, CH of CH2N), 2.68–2.78 (1H, m,
CHN), 7.40–7.53 (6H, m, ArH), and 7.88–7.97 (4H, m,
ArH).
4.4. Ring-opening of aziridines 8a–h
4.4.1. 2-(Diphenylphosphinamido)-1-(thiophenyl)pen-
tane (9). To a solution of thiophenol (0.15 mL, 2.1 mmol)
in THF (8 mL), under argon at 2428C, was added BuLi
(0.9 mL, 2.5 M, 2.3 mmol) dropwise. The solution was
stirred at 2428C for 0.5 h, after which time a solution of
N-diphenylphosphinyl-2-propylaziridine
(8a)
(0.2 g,
0.7 mmol) in THF (2 mL) was added. The solution was
then gradually warmed to room temperature over 3–4 h,
before being partitioned between H2O (10 mL), and EtOAc
(2£10 mL), the combined organic layers washed with brine
(15 mL), dried (MgSO4), filtered, and the solvent removed
under reduced pressure to leave a yellow oil. Purification by
flash column chromatography, (gradient 0–50% EtOAc in
light petroleum), gave (9) (0.19 g, 69%) as a pale yellow oil.
Rf 0.6 (EtOAc); nmax (CHCl3)/cm21 3361 (NH), 2958 (CH),
1439, 1176, 1124 (PvO), 1025, 875 (aromatics); dH
(400 MHz, CDCl3), 0.82 (3H, t, J¼7.1 Hz, CH3), 1.16–
1.78 (4H, m, CH3CH2CH2), 3.09–3.14, (2H, m, CH of
CH2SPh and CHNH), 3.27–3.38 (2H, m, CH of CH2SPh
and CHNH), 7.13–7.52 (11H, m, ArH), and 7.79–7.88 (4H,
m, ArH); dC (67.5 MHz, CDCl3) 13.84 (CH3), 19.05
(CH2CH3), 38.0 (CH2CHNH), 40.95 (CH2SPh), 50.86
(CHNHDpp), 126.04, 128.48 (d, J¼12.8 Hz), 128.96,
129.37, 132.3, 136.26; m/z (CI) 396 (MHþ, 100%), 272
(86), 218 (32), 201 (40), 111 (44). (Found: [MH]þ:
396.1538, C23H25NOPS requires [MH]þ 396.1551).
4.3.7. N-Diphenylphosphinyl-2-(cyclopentylmethyl)azir-
idine (8g). By following the general procedure described
above
N,O-bis(diphenylphosphinyl)-2-(hydroxymethyl)-
aziridine (0.5 g, 1.06 mmol), copper(I) bromide dimethyl-
sulfide complex (0.01 g, 0.05 mmol), and 1.1 equiv. of
Grignard reagent formed from magnesium (0.03 g,
1.27 mmol), and cyclopentyl bromide (0.12 mL,
1.16 mmol) were reacted together in THF to produce a
yellow solid. Purification by flash chromatography (gradient
20–80% EtOAc in light petroleum), gave (8g) (0.14 g,
40%) as a colourless solid. Rf 0.5 (EtOAc); mp 80–818C.
(Found: C, 73.7; H, 7.4; N, 4.0. C20H24NOP requires C,
73.8; H, 7.4; N, 4.3). nmax/cm21 2949 (CH), 1438 (PhP),
1203, 1125 (PvO), 727, 695 (aromatic); dH (270 MHz,
CDCl3), 0.98–1.64 (11H, m, 4£CH2, CH, ring, and CH2),
1.90 (1H, ddd, J¼1.3, 3.5, 12.5 Hz, CH of CH2N) 2.55 (1H,
ddd, J¼1.3, 5.9, 17.6 Hz, CH of CH2N), 2.64–2.78 (1H, m,
CHN), 7.39–7.52 (6H, m, ArH), and 7.88–7.98 (4H, m,
ArH); dC (67.5 MHz, CDCl3), 24.62, 29.82, 31.95, 32.62
(4£CH2 ring), 34.85 (CH, ring), 38.17 (CH2N), 38.68
(CHN, d, J¼5.2 Hz) 128.21 (d, J¼12.8 Hz), 131.5, 132.86
and 132.96 (2£d, J¼126.4 Hz); dP (121.4 MHz, CDCl3)
31.96; m/z (CI) 326 (MHþ, 100%), 248 (27), 203 (35), 79
(55). (Found: [MH]þ 326.1680. C20H24NOP requires
[MH]þ 326.1674).
4.4.2. 2-(Diphenylphosphinamido)octane (10a). The
general method for copper-modified Grignard reactions
using excess Grignard reagent as above was utilised.
N-Diphenylphosphinyl-2-propylaziridine
(8a)
(0.5 g,
1.8 mmol), copper(I) bromide dimethylsulfide complex
(0.01 g, 0.05 mmol) and propylmagnesium bromide
(5 equiv.), prepared from magnesium (0.22 g, 8.9 mmol),
and 1-bromopropane (0.8 mL, 8.8 mmol), were reacted
together in THF (20 mL) to produce a yellow solid.
Purification by flash chromatography (gradient 20–50%
EtOAc in light petroleum), gave (10a) (0.30 g, 52%) as a
colourless solid. Rf 0.6 (EtOAc); mp 81–828C. (Found: C,
72.7; H, 8.8; N, 4.3. C20H28NOP requires C, 72.9; H, 8.6; N,
4.25%); nmax (CCl4)/cm21 3370 (NH), 2966, 2932 (CH),
1124, 1024 (PO), 624 (aromatic); dH (270 MHz, CDCl3)
0.78–0.89 (6H, m, 2£CH3), 1.25–1.54 (10H, m, 5£CH2),
2.67 (1H, dd, J¼5.5, 16.7 Hz, NH), 3.00–3.10 (1H, m,
CHN), 7.41–7.51 (6H, m, ArH) and 7.88–7.95 (4H, m,
4.3.8. N-Diphenylphosphinyl-2-(cyclohexylmethyl)aziri-
dine (8h). By following the general procedure described
above
N,O-bis(diphenylphosphinyl)-2-(hydroxymethyl)-
aziridine (0.5 g, 1.06 mmol), copper(I) bromide dimethyl-
sulfide complex (0.01 g, 0.05 mmol), and 1.1 equiv. of
Grignard reagent formed from magnesium (0.03 g,
1.27 mmol),
and
cyclohexylbromide
(0.14 mL,
1.16 mmol) were reacted together in THF to produce a
yellow oil. Purification by flash chromatography (gradient
20–60% EtOAc in light petroleum), gave (8h) (0.11 g,
31%) as a colourless solid. Rf 0.5 (EtOAc); mp 101–1038C.

J. B. Sweeney, A. A. Cantrill / Tetrahedron 59 (2003) 3677–3690
3687
ArH); dC (67.5 MHz, CDCl3), 13.82 and 13.91 (2£CH3),
18.49, 22.46, 35.19, 36.40, 45.92 (5£CH2), 128.4, 131.9; dP
(121.4 MHz, CDCl3), 21.40; m/z (CI), 330 (MHþ, 100%),
286 (20), 272 (19), 252 (18), 201 (8), 79 (15). (Found:
[MH]þ 330.1978. C20H28NOP requires [MH]þ 330.1987).
4.4.5. 1-Cyclopentyl-2-(diphenylphosphinamido)-4-
methylpentane (10d). The general method for copper-
modified Grignard reactions using excess Grignard reagent
as above was utilised. N-Diphenylphosphinyl-2-(2-methyl-
propyl)aziridine (8f) (0.33 g, 1.1 mmol), copper(I) bromide
dimethylsulfide complex (0.01 g, 0.05 mmol) and cyclo-
pentylmagnesium bromide (5 equiv.), prepared from
magnesium (0.14 g, 5.6 mmol) and cyclopentyl bromide
(0.6 mL, 5.5 mmol), were reacted together in THF (20 mL)
to produce a yellow oil. Purification by flash chromato-
graphy (gradient 10–40% EtOAc in light petroleum), gave
(10d) (0.26 g, 65%) as colourless solid. Rf 0.5 (EtOAc). Mp
132–1348C (lit.1 133–134.5); nmax/cm21 3179 (NH), 2950
(CH), 1437 (PhP), 1188, 1123 (PvO), 721, 696 (aromatics);
dH (270 MHz, CDCl3), 0.76 and 0.78 (6H, 2£d, J¼6.4 Hz,
CH(CH3)2), 0.82–1.97 (14H, m, (CH3)2CHCH2CHCH2 and
cyclopentyl), 2.58 (1H, dd, J¼5.2, 10.5 Hz, NH), 2.93–3.06
(1H, m, CH), 7.40–7.52 (6H, m, ArH) and 7.88–7.97 (4H,
m, ArH); dC (67.5 MHz, CDCl3) 22.52 and 22.66
((CH3)2CH), 24.62 ((CH3)2CH), 24.97, 32.67, 32.81
(cyclopentyl CH2), 36.54 (CH), 44.49 (d, J¼4.5 Hz, CH2),
47.42 (d, J¼5.5 Hz, CH2), 49.51 ((CH3)2CHCH2CH),
128.18, 128.37, 131.54, 131.97, 132.05, 132.13, 132.257,
133.88, 133.97 (ArC); dP (161.7 MHz, CDCl3) 20.64; m/z
(CI) 398 (Mþ29, 18%), 370 (Mþ1, 91), 312 (M2Me2-
CHCH2, 84), 286 (M2CH2cyclopentyl, 100) and 201
(POPh2, 76); Found: 370.2293. C23H33NPO requires
370.2300.
4.4.3. 1-Cyclopentyl-2-(diphenylphosphinamido)pentane
(10b). The general method for copper-modified Grignard
reactions using excess Grignard reagent as above was
utilised.
N-Diphenylphosphinyl-2-(cyclopentylmethyl)-
aziridine (8g) (0.4 g, 1.2 mmol), copper(I) bromide
dimethylsulfide complex (0.01 g, 0.05 mmol) and ethyl-
magnesium bromide (5 equiv.), prepared from magnesium
(0.15 g, 6.2 mmol), and bromoethane (0.5 mL, 6.1 mmol),
were reacted together in THF (20 mL) to produce a
colourless solid. Purification by flash chromatography
(gradient 20–50% EtOAc in light petroleum), provided
(10b) (0.32 g, 75%) as a colourless solid. Rf 0.4 (EtOAc);
mp 105–1078C. (Found C, 74.6; H, 8.8; N, 3.9. C22H30NOP
requires C, 74.3; H, 8.5; N, 3.9%); nmax/cm21 3208 (NH),
1435 (PhP), 1187, 1123 (PvO), 722, 696 (aromatic); dH
(270 MHz, CDCl3), 0.86 (3H, t, J¼7 Hz, CH3), 0.91–0.96,
1.31–1.63 and 1.86–1.94 (15H, m, 7£CH2 and CH of
cyclopentyl), 2.63 (1H, dd, J¼5.7, 10.9 Hz, NH), 2.98–3.2
(1H, m, CHN), 7.40–7.51 (6H, m, ArH), and 7.88–7.96
(4H, m, ArH); dC (67.5 MHz, CDCl3), 13.94 (CH3), 18.36
(CH2CH3), 24.84, 32.46, and 32.68 (4£CH2 ring), 36.49
(CH cyclopentyl) 39.39 (CH2CH2CH), 43.65 (CHCH2-
pentyl), 50.75 (CHNH), 128.1 (d, J¼12.9 Hz), 132.2; dP
(121.4 MHz, CDCl3), 21.13; m/z (CI) 356 (MHþ, 100%),
312 (21), 272 (27), 218 (8), 203 (15), 79 (52). (Found:
[MH]þ 356.2141. C22H30NOP requires [MH]þ 356.2143).
4.4.6. 1-Cyclopentyl-2-(diphenylphosphinamido)hexane
(10e). The general method for copper-modified Grignard
reactions using excess Grignard reagent as above was
utilised. N-Diphenylphosphinyl-2-(n-butyl)aziridine (8b)
(0.15 g, 0.5 mmol), copper(I) bromide dimethylsulfide
complex (0.01 g, 0.05 mmol) and cyclopentylmagnesium
bromide (5 equiv.), prepared from magnesium (0.06 g,
2.6 mmol), and cyclopentyl bromide (0.3 mL, 2.5 mmol),
were reacted together in THF (15 mL) to produce a yellow
oil. Purification by flash chromatography (gradient 20–50%
EtOAc in light petroleum), provided (10e) (0.12 g, 64%) as
a colourless oil. Rf 0.5 (EtOAc), nmax/cm21 3218 (NH),
2952 (CH), 1436 (PhP), 1187, 1123 (PvO), 722, 695
(aromatic); dH (270 MHz, CDCl3), 0.88 (3H, t, J¼7.0 Hz,
CH3), 0.91–1.00 and 1.21–2.05 (17H, m, cyclopentyl and
4£CH2), 2.63 (1H, dd, J¼5.0, 10.4 Hz, NH), 3.00–3.05
(1H, m, CHN), 7.41–7.53 (6H, m, ArH), and 7.79–7.94
(4H, m, ArH); dC (75 MHz, CDCl3), 14.07 (CH3), 22.67,
24.99, 27.36, 32.66, 32.83 (6£CH2), 36.64 (CH pentyl),
37.01 (CH2CH2CHNH, d, J¼4.5 Hz), 43.74 (pentyl-CH2-
CHNH, d, J¼5.2 Hz), 51.03 (CHN, d, J¼2.5 Hz), 128.3 (d,
J¼12.3 Hz), 132.2; dP (121.4 MHz, CDCl3), 21.22; m/z (CI)
370 (MHþ, 100%), 292 (14), 201 (8), 218 (7). (Found:
[MH]þ 370.2286. C23H32NOP requires [MH]þ 370.2230).
4.4.4. 1-Cyclopentyl-2-(diphenylphosphinamido)-3-
phenylpropane (10c). The general method for copper-
modified Grignard reactions using excess Grignard reagent
as above was utilised. N-Diphenylphosphinyl-2-(cyclo-
pentylmethyl)aziridine (8g) (0.32 g, 1.0 mmol), copper(I)
bromide dimethylsulfide complex (0.01 g, 0.05 mmol) and
phenylmagnesium bromide (5 equiv.), prepared from mag-
nesium (0.17 g, 7.1 mmol), and bromobenzene (0.52 mL,
6.9 mmol), were reacted together in THF (20 mL) to
produce a pale yellow solid. Purification by flash chroma-
tography (gradient 20–60% EtOAc in light petroleum),
provided (10c) as a colourless solid (0.30 g, 77%). Rf 0.4
(EtOAc); mp 125–1268C. (Found: C, 77.3; H, 7.6; N, 3.4.
C26H30NOP requires C, 77.4; H, 7.45; N, 3.5%); nmax/cm21
;
3182 (NH), 2946 (CH), 1437 (PhP), 1188, 1122 (PvO),
724, 698 (aromatic); dH (270 MHz, CDCl3), 0.85–1.03 and
1.25–1.70 (10H, m, 4£CH2 cyclopentyl and cyclopentyl-
CH2CHN), 1.94–2.15 (1H, m, CH cyclopentyl); 2.65 (1H,
dd, J¼5.1, 11.2 Hz, CHNH), 2.76–2.98 (2H, 2£ dd, J¼5.9,
13.4 Hz, benzyl CH2), 3.16–3.31 (1H, m, CHNH), 7.15–
7.90 (15H, m, ArH); dC (125 MHz, CDCl3); 24.98, 25.05,
32.59, 32.69 (4£CH2 cyclopentyl), 36.69 (CH cyclopentyl),
43.34 (CH2cyclopentyl, d, J¼5.1 Hz), 43.44 (benzyl-CH2,
d, J¼5.1 Hz), 52.40 (CHN), 126.3, 128.3, 128.38 (d,
J¼12.4 Hz), 130.1, 131.59, and 131.71 (2£d, J¼2.1 Hz),
132.10 and 132.27 (2£d, J¼9.3 Hz), 132.48 and 132.95
(2£d, J¼129.3 Hz), 138.3; dP (202 MHz, CDCl3) 21.15; m/z
(CI), 404 (MHþ, 100%), 312 (68), 218 (25), 201 (35), 91
(20). (Found: [MH]þ: 404.2132. C26H30NOP requires
[MH]þ 404.2143).
4.4.7. 8-(Diphenylphosphinamido)-2-methyldec-9-ene
(10f). The general method for copper-modified Grignard
reactions using excess Grignard reagent as above was
utilised. N-Diphenylphosphinyl-2-(3-methylbutyl)aziridine
(8c) (0.3 g, 0.9 mmol), copper(I) bromide dimethylsulfide
complex (0.02 g, 0.1 mmol) and 5 equiv. of Grignard
reagent, prepared from magnesium (0.11 g, 4.3 mmol),
and 4-bromobut-1-ene (0.4 mL, 4.1 mmol), were reacted in
THF to produce a yellow oil. Purification by flash

3688
J. B. Sweeney, A. A. Cantrill / Tetrahedron 59 (2003) 3677–3690
chromatography (gradient 20–60% EtOAc in light
petroleum), gave (10f) (0.19 g, 60%), as a colourless
solid. Rf 0.6 (EtOAc); mp 101–1038C; nmax/cm21 3200
(NH), 2929 (CH), 1435 (PhP), 1185, 1123 (PvO), 722, 694
(aromatic); dH (270 MHz, CDCl3), 0.83–0.87 (6H, 2£d,
J¼1.7 Hz, CH(CH3)2), 1.14–1.25, and 1.38–1.56, and
1.96–2.03 (11H, m, CH(CH3)2 and 5£CH2), 2.70 (1H,
dd, J¼6.3, 10.3 Hz, NH), 3.02–3.08 (1H, m, CHNH), 4.91–
5.02 (2H, m, CHvCH2), 5.70–5.83 (1H, m, CHvCH2),
7.39–7.51 (6H, m, ArH), and 7.86–7.95 (4H, m, ArH); dC
(67.5 MHz, CDCl3), 22.01 and 22.33 (2£CH3), 24.52
(CH2CH(CH3)2), 27.72 (CH(CH3)2), 30.01 and 33.41
(PvO), 722, 697 (aromatics); dH (270 MHz, CDCl3),
0.83–0.87 (6H, 2£d, J¼3.2 Hz, (CH3)2CH) 1.08–1.24
and 1.28–1.60 (11H, m, Ph(CH2)3CH(NH)(CH2)2-
CH(CH3)2), 2.57–2.61 (2H, m, PhCH2), 2.65 (1H, dd,
J¼6.1, 10.8 Hz, NHCH), 3.00–3.07 (1H, m, CHNH), 7.15–
7.28 (5H, m, PhCH2), 7.40–7.50 (6H, m, ArH), and 7.87–
7.92 (4H, m, ArH); dC (67.5 MHz, CDCl3), 22.23
((CH3)2CH), 27.51 ((CH3)2CH), 24.58, 30.83, 34.04,
34.14, 35.28, 36.04, ((CH2)6), 51.15 (CHNH), 125.19,
128.4 (d, J¼12.9 Hz), 128.9, 131.9, 142.08; dP (121.4 MHz,
CDCl3), 21.45; m/z (CI) 434 (MHþ, 100%), 362 (20), 201
(17). (Found: [MH]þ 434.2610. C28H36NOP requires
[MH]þ 434.2613).
(CH2CH2CHvCH2),
34.20
and
35.92
(CH2-
CH(NHDpp)CH2), 51.32 (CHNH), 114.37 (CHvCH2),
128.31 (d, J¼12.9 Hz), 132.2, 138.64 (CHvCH2); dP
(161.9 MHz, CDCl3), 21.38; m/z (CI) 370 (MHþ, 100%),
300 (23), 292 (19), 218 (15), 83 (76). (Found: [MH]þ
370.2306. C23H32NOP requires [MH]þ 370.2300).
4.4.10. 2-(Diphenylphosphinamido)-1-phenylhept-6-ene
(10i). The general method for copper-modified Grignard
reactions using excess Grignard reagent as above was
utilised.
4.4.8. 1-Cyclohexyl-2-(diphenylphosphinamido)-5-
methylhexane (10g). The general method for copper-
modified Grignard reactions using excess Grignard reagent
as above was utilised. N-Diphenylphosphinyl-2-(3-methyl-
butyl)aziridine (8c) (0.23 g, 0.72 mmol), copper(I) bromide
dimethylsulfide complex (0.01 g, 0.05 mmol) and cyclo-
hexylmagnesium bromide (5 equiv.), prepared from
magnesium (0.09 g, 3.7 mmol), and bromocyclohexane
(0.4 mL, 3.6 mmol), were reacted together in THF
(20 mL) to produce a yellow oil. Purification by flash
chromatography (gradient 20–40% EtOAc in light
petroleum), gave (10g) (0.19 g, 66%) as a colourless solid.
Rf 0.6 (EtOAc); mp 120–1218C. (Found: C, 75.8; H, 9.4; N,
N-Diphenylphosphinyl-2-(pent-4-enyl)aziridine (8d) (0.2 g,
0.65 mmol), copper(I) bromide dimethylsulfide complex
(0.01 g, 0.05 mmol) and phenylmagnesium bromide
(5 equiv.), prepared from magnesium (0.08 g, 3.28 mmol),
and bromobenzene (0.3 mL, 3.21 mmol), were reacted
together in THF (20 mL) to produce a yellow oil.
Purification by flash chromatography (gradient 20–80%
EtOAc in light petroleum), gave (10i) (0.17 g, 66%) as a
colourless solid. Rf 0.5 (EtOAc); mp 118–1198C. (Found:
C, 77.1; H, 7.2; N, 3.5. C25H38NOP requires C, 77.1; H,
7.25; N, 3.6%); nmax/cm21, 3181 (NH), 2927 (CH), 1437
(PhP), 1186, 1122 (PvO), 723, 698 (aromatics); dH
(270 MHz, CDCl3), 1.44–1.60 and 1.96–2.05 (6H, m,
CH(NH)(CH2)3) 2.68 (1H, dd, J¼4.9, 11.0 Hz, NH), 2.80
(1H, dd, J¼6.1, 13.4 Hz, CH of CH2Ph), 2.91 (1H, dd,
J¼6.1, 13.4 Hz, CH of CH2Ph), 3.25–3.30 (1H, m, CHNH),
4.91–4.97 (2H, m, CHvCH2), 5.71–5.81 (1H, m,
CHvCH2), 7.15–7.89 (15H, m, ArH); dC (67.5 MHz,
CDCl3), 24.87 (CH2CH2CHvCH2), 33.25 (CH2CHvCH2),
35.88 (CH(NH)CH2), 42.81 (PhCH2), 52.77 (CHNH),
114.40 (CHvCH2), 126.08, 128.05 128.2, 129.67, 131.4,
132.83 and 132.91 (2£d, J¼124.3 Hz), 128.19, 138.24
(CHvCH2); dP (161.9 MHz, CDCl3), 21.23; m/z (CI) 390
(MHþ, 100%), 298 (37), 201 (18) 79 (67). (Found: [MH]þ
390.1975, C25H38NOP requires [MH]þ 390.1986).
3.5. C25H36NOP requires C, 75.5; H, 9.1; N, 3.5%); nmax
/
cm21 3210 (NH), 2921 (CH), 1436 (PhP), 1190, 1122
(PvO), 720, 696 (aromatic); dH (270 MHz, CDCl3), 0.84
and 0.86 (6H, 2£d, J¼1.9 Hz, CH(CH3)2), 1.12–1.63 (18H,
m, CH(CH3)2, 3£CH2, and cyclohexyl ring), 2.62 (1H, dd,
J¼5.8, 10.6 Hz, NH), 3.04–3.16 (1H, m, CHNH), 7.40–
7.50 (6H, m, ArH) and 7.86–7.94 (4H, m, ArH); dC
(100 MHz, CDCl3), 22.54 (CH(CH3)2), 26.21, 26.44, 33.50,
34.06 and 34.13, (5£CH2 hexyl), 27.91 (CH(CH3)2), 34.29
(CH hexyl), 34.32 and 45.05 (CH2CH(NH)CH2hexyl),
49.13 (CHNH), 128.3, 132.0, 132.93 and 133.18 (2£d,
J¼129.0 Hz); dP (161.9 MHz, CDCl3), 21.14; m/z (CI) 398
(MHþ, 100%), 326 (24), 300 (24), 218 (10), 201 (9).
(Found: [MH]þ 398.2632, C25H36NOP requires [MH]þ
398.2613).
4.5. Preparation of (2R)-DiDpp
4.5.1. (2R)-(1)-(O-Diphenylphosphinyl)-2-(hydroxy-
methyl)oxirane (11). (R)-(þ)-Glycidol (1 mL, 15.1 mmol)
was dissolved in dichloromethane (100 mL), and cooled to
08C, under an argon atmosphere. Triethylamine (3.1 mL,
22.6 mmol), and diphenylphosphinic chloride (3.2 mL,
16.6 mmol) were then added to the clear solution, which
was stirred overnight. The solution was then quenched with
water (20 mL), and acidified to pH 2 with 1 M hydrochloric
acid, and partitioned. The aqueous layer washed with
dichloromethane (2£10 mL), and the combined organic
layers washed with brine, and dried (MgSO4), filtered and
the solvent removed under reduced pressure. The resulting
pale yellow oil was then purified by flash chromatography
(gradient 40–60% EtOAc in hexane), which afforded
oxirane (11) (3.08 g, 75%) as a colourless oil. Rf 0.5
(EtOAc); [a]¼þ17.9 (c 5, CH2Cl2); nmax/cm21 2934 (CH),
4.4.9. 5-(Diphenylphosphinamido)-8-methyl-1-phenyl-
nonane (10h). The general method for copper-modified
Grignard reactions using excess Grignard reagent as above
was utilised. N-Diphenylphosphinyl-2-(3-methylbutyl)-
aziridine (8c) (0.43 g, 1.31 mmol), copper(I) bromide
dimethylsulfide (0.01 g, 0.05 mmol) and 3-phenylpropyl-
magnesium bromide (5 equiv.), prepared from magnesium
(0.16 g, 6.67 mmol), and 1-bromo-3-phenylpropane
(1.0 mL, 6.5 mmol), were reacted together in THF
(20 mL) to produce a yellow oil. Purification by flash
chromatography (gradient 20–50% EtOAc in light
petroleum), gave (10h) (0.4 g, 72%) as a colourless solid.
Rf 0.6 (EtOAc); mp 99–1018C. (Found C, 77.5; H, 8.25; N,
3.1. C28H36NOP requires C, 77.6; H, 8.4; N, 3.2%); nmax
/
cm21, 3188 (NH), 2932 (CH), 1437 (PhP), 1188, 1122

J. B. Sweeney, A. A. Cantrill / Tetrahedron 59 (2003) 3677–3690
3689
1440 (PvO), 1226 (C–O epoxide), 1162, 1130 (PvO),
732, 698 (aromatic); dH (400 MHz, CDCl3), 2.64 and 2.81
(2H, 2£dd, J¼1.6, 4.4 Hz, CH(O)CH2), 3.25–3.30 (1H, m,
CH), 3.89–3.98 (1H, m, CH of DppOCH2), 4.31 (1H, ddd,
J¼3.2, 8.0, 13.2 Hz, CH of DppOCH2), 7.38–7.59 (6H, m,
ArH), and 7.75–7.97 (4H, m, ArH); dC (100 MHz, CDCl3),
44.61 (CH(O)CH2), 50.40 (CH(O)CH2), 65.33 (DppOCH2),
128.4, 131.9; dP (161.9 MHz, CDCl3), 32.90; m/z (CI) 275
(MHþ, 100%), 219 (25), 141 (9), 79 (9). (Found: [MH]þ
275.0836, C15H15O3P requires [MH]þ 275.0837).
(1.2 g, 29%) as a colourless solid. Rf 0.4 (10% methanol/
EtOAc); mp 1408C (racemic 138–1398C); [a]¼21.5 (c 5,
CH2Cl2). Other physical data was identical to that recorded
for (^)-1.
Further elution furnished (13) (0.95 g, 16%) as a white
foam. Rf 0.1 (5% methanol/95%EtOAc); nmax (CHCl3)/
cm21 3057 (NH) 2966, 1418, 1060, 1167 (PvO) 828, 650
(aromatics); dH (400 MHz, CDCl3), 3.29–3.32 (2H, m,
CH2NHDpp), 4.12–4.22 (2H, m, DppOCH2), 4.58–4.64
(1H, m, CH), 4.96–4.98 (1H, br m, NHDpp), 7.28–7.85
(30H, m, ArH); dC (100 MHz, CDCl3), 41.77 (CH2NHDpp),
64.16 (CH2ODpp), 75.96 (CH), 128.5, 132.4; dP
(161.9 MHz, CDCl3), 24.36 (NP), 33.44, and 33.66 (OP);
m/z (CI) 692 (MHþ, 82%), 474 (M2ODpp, 92), 256 (28),
219 (HODpp,11). (Found: [MH]þ 692.1903. C39H36NO5P3
requires [MH]þ 692.1884).
4.5.2. (2R)-(1)-1-Azido-3-(O-diphenylphosphinyl)-pro-
pane-2,3-diol (12). Oxirane (11), (2.8 g, 10.2 mmol), was
dissolved in methanol (100 mL) under an atmosphere of
nitrogen. Ammonium chloride (1.64 g, 30.7 mmol), and
sodium azide (2.00 g, 30.7 mmol), were then added to the
clear solution. The resulting suspension was then heated to
reflux for 3 h. After cooling the solution was diluted with
EtOAc (100 mL), and water (50 mL). The organic layer was
partitioned and the aqueous layer washed with EtOAc
(2£20 mL). The combined organic layers were then dried
(MgSO4), filtered and the solvent removed under reduced
pressure. Often the colourless solid isolated was found to
still contain water, and so the product was redissolved in
chloroform (40 mL), and partitioned with brine (2£10 mL).
The organic layer dried (MgSO4), filtered and the solvent
removed under reduced pressure. Azide (12) (2.93 g, 90%)
was afforded as a colourless solid. Rf 0.4 (EtOAc); mp 97–
988C; [a]¼þ23.8 (c 5, CH2Cl2), nmax (CHCl3)/cm21 3545
(OH), 2107 (N3), 1437, 1180, 1125 (PvO), 727, 696
(aromatic); dH (400 MHz, CDCl3), 3.42 (2H, dd, J¼2.6,
5.8 Hz, CH(OH)CH2N3), 3.99–4.05 (1H, m, CH), 4.10–
4.14 (2H, ddd, J¼1.0, 4.1, 11.7 Hz, CH(OH)CH2ODpp),
7.26–7.58 and 7.78–7.84 (10H, m, ArH); dC (100 MHz,
CDCl3), 51.45 (CH(OH)CH2N3) 66.68 (CH) 68.34
(DppOCH2CH(OH)) 128.8, 131.5; dP (161.5 MHz,
CDCl3), 36.09; m/z (CI) 318 (MHþ, 100%), 275 (M2N3,
21), 261 (35), 219 (68), 201 (Dpp,10). (Found: [MH]þ
318.0996. C15H16N3O3P requires [MH]þ 318.1008).
4.6. Ring-opening of (2R)-DiDpp
4.6.1. (2S)-(1)-N-(Diphenylphosphinyl)-2-butylaziridine
(8b). By following the general procedure for copper-
modified Grignard reactions using 1 equiv. of Grignard
reagent described earlier (2 S)-(2)-N,O-bis(diphenyl-
phosphinyl)-2-(hydroxymethyl)aziridine (2R)-1 (0.5 g,
1.06 mmol), copper(I) bromide dimethylsulfide complex
(0.01 g, 0.05 mmol), and 1.1 equiv. of Grignard reagent
formed from magnesium (0.03 g, 1.27 mmol), and 1-bromo-
propane (0.11 mL, 1.16 mmol) were reacted together in
THF to produce a pale yellow oil. Purification by flash
chromatography (gradient 20–70% EtOAc in light
petroleum), gave (2R)-8b (0.22 g, 62%) as a clear oil. Rf
0.3 (EtOAc); [a]¼þ9.1 (c 5, CH2Cl2); nmax (CHCl3)/cm21
2968 (CH), 1438 (PhP), 1173, 1130 (PvO), 990, 729, 698
(aromatic); dH (270 MHz, CDCl3), 0.77 (3H, t, J¼7.1 Hz,
CH3CH2), 1.15–1.23 (4H, m, CH3CH2CH2), 1.48–1.52
(2H, m, CH2CHN), 1.92 (1H, ddd, J¼1.2, 3.4, 12.5 Hz, CH
of CH2N), 2.53 (1H, ddd, J¼1.2, 6.1, 17.3 Hz, CH of
CH2N), 2.65–2.74 (1H, m, CH2CHN), 7.41–7.51 (6H, m,
ArH), and 7.89–7.95 (4H, m, ArH); m/z (CI), 300 (MHþ,
100%), 286, (10%), 258, (34%), 201 (Ph2P(O),19%).
(Found: [MH]þ 300.1516 C18H22NOP requires [MH]þ
300.1517). Other data as for (^)-8b.
4.5.3. (2R)-N,O,O-Tris(diphenylphosphinyl)-1-amino-
propane-2,3-diol (13) and (2R)-(2)-N,O-bis(diphenyl-
phosphinyl)-2-(hydroxymethyl)aziridine (1). Azide (12),
(2.73 g, 8.61 mmol) was dissolved in acetonitrile (100 mL),
to which triphenylphosphine (2.48 g, 9.47 mmol) was
added. The resulting suspension was heated to reflux for
2 h, after which time the azide was judged to have been
consumed using infra-red analysis. The solvent was then
removed under reduced pressure, affording a yellow oil.
This oil was then dissolved in dichloromethane (100 mL),
under an atmosphere of argon. Triethylamine (1.8 mL,
12.9 mmol) and diphenylphosphinic chloride (1.8 mL,
9.50 mmol) were then added, and the mixture stirred
overnight. The solution was then quenched with brine
(20 mL), and acidified to pH 2 with 1 M hydrochloric acid.
The organic layer was partitioned and the aqueous layer
washed with dichloromethane (2£10 mL). The combined
organic layers were then dried (MgSO4), filtered and the
solvent removed under reduced pressure. The resulting pale
yellow oil was then purified by flash chromatography
(gradient 0–10% methanol in EtOAc), which afforded (2R)-
1 (5% methanol/95% ethyl acetate eluent), as a pale yellow
oil. Crystallisation from ethyl acetate/hexane afforded (221)
4.7. MTPA amide of (2R)-(2)-2-amino-1-cyclo-
pentylhexane (17)
4.7.1. (2R)-1-Cyclopentyl-2-(diphenylphosphinamido)-
hexane (10e). By following the general procedure for
copper-modified Grignard reactions using excess Grignard
reagent as described earlier, (2R)-(þ)-N-diphenylphos-
phinyl-2-butylaziridine (8b) (0.22 g, 0.7 mmol), copper(I)
bromide dimethylsulfide complex (0.01 g, 0.05 mmol), and
cyclopentylmagnesium bromide (5 equiv.) prepared from
magnesium (0.08 g, 3.4 mmol) and cyclopentyl bromide
(0.4 mL, 3.3 mmol) were reacted in THF (10 mL) to
produce a yellow oil. Purification by flash chromatography
(gradient 20–60% EtOAc in light petroleum), gave (10e)
(0.2 g, 74%), as a colourless oil. Rf 0.45 (EtOAc); nmax
/
cm21 3217 (NH) 2952, 2831 (CH), 1436 (PhP), 1187
(PvO), 1123, 749, 722, 695 (aromatics); dH (400 MHz,
CDCl3), 0.90 (3H, t, J¼7.0 Hz, CH2CH3), 0.92–1.00 and
1.22–1.96 (17H, m, cyclopentyl and 4£CH2), 2.63 (1H, dd,

3690
J. B. Sweeney, A. A. Cantrill / Tetrahedron 59 (2003) 3677–3690
J¼4.9, 10.4 Hz, CHNH), 3.01–3.05 (1H, m, CHNH), 7.41–
7.53 (6H, m, ArH), and 7.79–7.94 (4H, m, ArH); m/z (CI)
370 (MHþ, 100%), 312 (10), 292 (12), 218 (7). (Found:
[MH]þ 370.2289. C23H32NOP requires [MH]þ 370.2230).
Other data as for (^)-10e.
(10), 253 (9), 225 (100), 98 (48), 83 (56). (Found: [MH]þ
386.2313 C21H30NO2F3 requires [MH]þ 386.2307).
4.7.4. MTPA amide of (2RS)-(2)-2-amino-1-cyclo-
pentylhexane (17). By following the procedure directly
above, using racemic amine, (RS,R)-17 (0.029 g, 34%) was
obtained, as a colourless oil. dH (300 MHz, CDCl3), 0.84
(3H, t, J¼7.0 Hz, CH2CH3), 1.07–1.96 (17H, m, cyclo-
pentyl and 4£CH2), 3.01 (3H, s, OCH3), 3.99–4.05 (1H, m,
CHNH), 6.51 (1H, br d, J¼6.0 Hz, NHCO), 7.38–7.54 (5H,
m, ArH); dF (282 MHz, CDCl3), 68.37 and 68.41
(ratio¼1:1); m/z (CI) 386 (MHþ, 74%), 379 (28), 316
(27), 253 (31), 225 (100), 207 (24), 123 (32), 98 (48), 83
(56). (Found: [MH]þ 386.2315 C21H30NO2F3 requires
[MH]þ 386.2307).
4.7.2. (2R)-(2)-2-Amino-1-cyclopentylhexane. To (2R)-1-
cyclopentyl-2-(diphenylphosphinamido)hexane
(10e)
(0.2 g, 0.5 mmol) in CH2Cl2 (2 mL) under argon was
added methanol (2 mL) followed by boron trifluoride
etherate (0.1 mL). The solution was stirred overnight, after
which time H2O (2 mL) was added. The aqueous layer was
then extracted with CH2Cl2 (3£10 mL), basified (NaHCO3),
and extracted with further CH2Cl2 (10 mL). The organic
layers were combined, washed with brine (10 mL), dried
(Na2SO4), filtered and the solvent removed under reduced
pressure to yield the free amine (0.045 g, 49%), as a
colourless oil. [a]¼27.1 (c 4.5, CH2Cl2); nmax/cm21 2953
and 2867 (CH br by NH2), 1604, 1517; dH (400 MHz,
CDCl3), 0.92 (3H, t, J¼7.0 Hz, CH2CH3), 1.03–2.05 (17H,
m, cyclopentyl and 4£CH2), 3.13–3.19 (1H, m, CHNH2),
7.82 (2H, br s, NH2); dC (75 MHz, CDCl3), 13.86 (CH3),
22.35, 25.00, 25.07, 27.31, 32.45, 32.66, 32.78 (7£CH2),
36.10 (CH pentyl), 39.26 (pentyl-CH2CH(NH2), d,
J¼5.2 Hz), 51.95 (CH(NH2)); m/z (CI) 170 (MHþ, 37%),
168 (27), 112 (29), 83 (100), 57 (98). (Found: [MH]þ
170.1905. C11H23N requires [MH]þ 170.1909).
Acknowledgements
We thank the EPSRC and Parke-Davis Neuroscience
Research Centre (CASE award to AAC) and ZENECA
(award to J. B. S. from the Strategic Research Fund) for
financial support for these investigations. We also thank Mr
B. L. Dell for the advice offered over a range of research
issues.
4.7.3. MTPA amide of (2S)-(2)-2-amino-1-cyclopentyl-
hexane (17). DCC (0.035 g, 0.2 mmol), was added to a
solution of (2S)-(-)-2-Amino-1-cyclopentylhexane (0.035 g,
0.2 mmol) and methoxytrifluoromethylphenylacetic acid
(0.049 g, 0.2 mmol) in dichloromethane (5 mL). N,N-4-
(Dimethylamino)pyridine (ca. 1 mg) was then added.
Within 1 h a precipitate had formed. The reaction was
stirred for 10 h after which time dicyclohexylurea was
filtered off and the filtrate concentrated under reduced
pressure. The residual oil was purified by flash chromato-
graphy (ethyl acetate/hexane 1:4) to give (R,R)-17 (0.054 g,
64%) as a colourless oil. Rf 0.35; nmax/cm21 3324 (NH)
2930, 2854 (CH), 1600 (CvO), 1164, 804, 716 (aromatic);
dH (300 MHz, CDCl3), 0.83 (3H, t, J¼7.0 Hz, CH2CH3),
1.07–1.91 (17H, m, cyclopentyl and 4£CH2), 2.98 (3H, s,
OCH3), 3.98–4.03 (1H, m, CHNH), 6.48 (1H, d,
J¼10.0 Hz, NHCO), 7.41–7.57 (5H, m, ArH); dF
(282 MHz, CDCl3), 68.41; m/z (CI) 386 (MHþ, 20%), 306
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