Synthesis of dimethylphosphorylamino diazo esters by a selective tandem Staudinger/Arbuzov rearrangement sequence of azido diazo esters with trimethylphosphite

Article abstract of DOI:10.1016/S0040-4020(03)00856-1

γ-Azido-α-diazo-β-keto esters react selectively with trimethylphosphite by a tandem Staudinger/Arbuzov rearrangement sequence, furnishing γ-(dimethylphosphorylamino)-α-diazo-β-keto esters in good yield under mild conditions. Collected X-ray data for the novel diazo phosphoramides confirm the proposed chemoselectivity.

Full text of DOI:10.1016/S0040-4020(03)00856-1

Tetrahedron 59 (2003) 5441–5447
Synthesis of dimethylphosphorylamino diazo esters by a selective
tandem Staudinger/Arbuzov rearrangement sequence of azido
diazo esters with trimethylphosphite
a
Marcus M. Sa, Gustavo P. Silveira, Adailton J. Bortoluzzi and Albert Padwa
a
a
b
,
*
´
a
´ ´
Departamento de Quımica, Universidade Federal de Santa Catarina, Campus-Trindade, Florianopolis, SC 88040-900, Brazil
bDepartment of Chemistry, Emory University, Atlanta, GA 30322, USA
Received 5 December 2002; revised 29 May 2003; accepted 29 May 2003
Abstract—g-Azido-a-diazo-b-keto esters react selectively with trimethylphosphite by a tandem Staudinger/Arbuzov rearrangement
sequence, furnishing g-(dimethylphosphorylamino)-a-diazo-b-keto esters in good yield under mild conditions. Collected X-ray data for the
novel diazo phosphoramides confirm the proposed chemoselectivity. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
the azido diazo ester 3 with aldehydes mediated by
DABCO. This condensation reaction proceeded under
mild conditions and in high yield (Scheme 1).32 g-Azido-
a-diazo-d-hydroxy-b-keto esters 1 and 2 were subsequently
converted to 2-azido-3-furanones 4 and 5, respectively,
through a rhodium(II) catalyzed intramolecular OH-inser-
tion followed by a [3,3] sigmatropic rearrangement of the
transient allylic azide.33 Chemoselective transformations of
the multiple functional groups present in azido diazo esters
1–3 and their further application to the synthesis of more
elaborated structures not only has the potential of being
synthetically useful, but also represents a challenge since
various selectivity issues need to be addressed. Herein, we
describe the chemical behavior of azido diazo esters towards
phosphorus(III) reagents and the first chemoselective
synthesis of diazo phosphoramides using a Staudinger
reaction with trimethylphosphite.
Organic azides are extremely valuable intermediates for the
synthesis of many nitrogen-containing molecules,1 – 3
including heterocycles and natural products.4–9 The reac-
tivity of azido compounds has received increasing interest
over the past two decades, particularly their reactions with
tertiary phosphorus reagents which afford phosphorus–
nitrogen ylides (the Staudinger reaction).10 These versatile
intermediates11,12 can be further converted to important
nitrogenated compounds such as amines, carboxamides,
phosphoramides, imines and azadienes, among others,13–16
usually in high yield and with pronounced chemoselectivity.
a-Diazo carbonyl compounds are also widely used in
organic synthesis for the preparation of heterocyclic and
carbocyclic rings17–21 commonly related to natural pro-
ducts as well as for the preparation of pharmacologically
active compounds.22–27 The chemistry of the isoelectronic
azido and diazo functionalities are somewhat related, given
that azides can be considered as a diazo group bonded to a
nitrogen atom.18 Surprisingly, the chemical behavior of
compounds that contain both a diazo and azido group in the
same molecule has seldom been explored.28–31 Moreover,
the chemoselective transformation of an azido group in the
presence of a diazo functionality, as far as we can tell, has
not been described in the literature.
2. Results and discussion
Azido diazo esters 3, 6 and 7 (Scheme 1)32 as well as vinyl
azide 8 (Scheme 2) were chosen as model substrates for
representative reactions with triphenylphosphine, tributyl-
phosphine and trimethylphosphite. Compound 8 was
obtained in 68% yield from a Hemetsberger–Knittel
reaction34 of diazo azide 3 with benzaldehyde mediated
by piperidinium acetate in ethanol for 60 h at rt. The
presence of both diazo and azido groups in structure 8 was
confirmed by characteristic IR bands at 2140 and
2110 cm21, respectively. The presence of a large band at
1720 cm21 and a medium one at 1620 cm21 indicate the
existence of carbonyl groups as well a conjugated olefin.
Conclusive assignment for 8 came from its 13C NMR
We recently reported the synthesis of g-azido-a-diazo-d-
hydroxy-b-keto esters 1 and 2 by an aldol-type reaction of
Keywords: azido diazo esters; Staudinger reaction; diazo phosphoramide.
*
Corresponding author. Tel.: þ55-48-3319967; fax: þ55-48-3319711;
e-mail: msa@qmc.ufsc.br
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00856-1

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M. M. Sa et al. / Tetrahedron 59 (2003) 5441–5447
5442
Scheme 1.
spectrum, which showed two carbonyl peaks at d 160–180
and two unsaturated carbon atoms at d 126–133. Also, a
singlet at d 6.42 in the 1H NMR spectrum, characteristic of a
b-olefinic proton cis to the carbonyl group, favors the
proposed double bond geometry as being Z.35–37 Further-
more, the mass spectrum of the protonated compound
confirmed the expected molecular weight (MHþ¼287).
material, only trace amounts of vinyl azide 8 and the
N-piperidinyl derivative 10, together with decomposition
products. When vinyl azide 8 was treated with benzal-
dehyde/piperidinium acetate, it was slowly converted to
azido-cinnamate 9 and also produced unknown decompo-
sition products. These observations suggest that hydroxy
ester 2 is being formed by an aldol reaction of diazo azido
ester 3 with benzaldehyde in the basic media,37,39 while
N-piperidinyl ester 10 is produced either by a condensation
between 3 and the piperidinium ion of the aldehyde34 or by a
Michael addition of piperidine to vinyl azide 8. Vinyl azide
8 could come about by a dehydration of hydroxy ester 2 or
by piperidine elimination from 10.34 Finally, azido-
cinnamate 9 is most likely derived by a slow solvolysis of
the pre-formed vinyl azide 8 in ethanolic media,32 or
possibly from a nucleophilic acyl cleavage reaction which is
characteristic of diazo ketones.40 The above results clearly
depict a complex equilibrium among the involved species,
hence only a tentative explanation for the product
distribution can be made at this moment.
In addition to vinyl azide 8, four by-products were also
isolated in minor (5–10%) quantities after column chroma-
tography, in the following order of elution: the known ethyl
(Z)-2-azidocinnamate 9 (5% yield),37 g-azido-a-diazo-b-
keto-d-N-piperidinyl ester 10 as a single diastereoisomer
(8% yield), and the aldol product 232 as a 1:1 diastereomeric
mixture (8% yield). N-Piperidinyl derivative 10 was
characterized by its spectroscopic data, which shows a
similar NMR pattern to the structurally related aldol 2 and
acetylated derivative 7.32 The relative configuration of the
two stereogenic centers in 10 was suggested by its 1H NMR
spectrum, which shows two methine protons as doublets
(4.16 and 5.60 ppm) with a large coupling constant
(J¼11 Hz) characteristic of the anti configuration.32,38,39
Interestingly, when diazo azide 3 was treated with
benzaldehyde/piperidinium acetate in ethanol for shorter
periods of time (48 h), only the vinyl azide 8 and hydroxy
ester 2 were formed (58 and 30% yield, respectively).
N-Piperidinyl derivative 10 was formed in trace amounts
(less than 5%), but none of the azido-cinnamate 9 could be
detected in the crude reaction nor isolated by column
chromatography. In a control experiment, aldol 2 (1:1
diastereomeric mixture) was submitted to the same reaction
conditions, affording, aside from unreacted starting
In order to evaluate the chemical reactivity of azido diazo
esters 3, 6, 7 and 8 towards phosphorus(III) reagents, each
compound was initially treated with triphenylphosphine at
rt. All the reactions were monitored by IR spectroscopy,
whereby the disappearance (or shifting) of the azido and
diazo bands (2100–2110 and 2135–2145 cm21, respect-
ively) were monitored. Reactions were rapid in all cases;
after 1–2 h at rt or at 08C all the starting materials were
consumed. The IR of the crude reaction mixture showed a
strong band that had been shifted to 2125 cm21, indicating
that both the azido and diazo groups are reactive under these
Scheme 2.

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M. M. Sa et al. / Tetrahedron 59 (2003) 5441–5447
5443
Scheme 3.
Scheme 4.
conditions. However, product purification by column
chromatography led to extensive decomposition of pre-
formed adducts. Trapping any elusive iminophosphorane
intermediates with acetaldehyde11 was also unsuccessful as
a complex mixture of products was observed. It is
interesting to note that when azido diazo 3 was treated
with the more reactive tributylphosphine reagent, the
reaction followed another course. After stirring for 15 min
at 08C, the diazo band at 2140 cm21 had totally disappeared,
suggesting the formation of a phosphazine from the diazo
group, with retention of the azido functionality.30,31
However, isolation of this product was not possible due to
its low thermal stability.
amides, no epimerization being involved. The relative
stereochemistry that was assigned to phosphoramides 12
and 13 was again based on a H NMR analysis, which
showed characteristic coupling constants for the anti-
(8.0 Hz) and syn- (2.0 Hz) isomers of ethyl 5-acetoxy-2-
diazo-4-(dimethylphosphorylamino)-5-phenyl-3-oxo-
pentanoate (13).38
1
The syn and anti isomers of phosphoramide 12 and the syn-
phosphoramide 13 were purified by silica gel column
chromatography, and were submitted to careful crystal-
lization in ethyl ether, furnishing triclinic monocrystals
whose structures were then resolved by X-ray crystal-
lography (Figs. 1–3). The ORTEP structures for anti-12,
syn-12 and syn-13 unambiguously confirms the stereo-
While the outcome of the reaction of phosphines with the
selected azido diazo compounds was disappointing, much
more consistent results were obtained by using trimethyl-
phosphite. The reaction of P(OMe)3 with 3 gave rise to a
slow but very selective disappearance of the band located at
2105 cm21, and cleanly produced the diazo phosphoramide
11 after stirring for 24 h at rt (Scheme 3). Compound 11 was
stable to chromatography, allowing its purification and
complete characterization. The presence of a NH-P moiety
was evident by IR bands at 3340 and 3230 cm21, a D2O-
1
chemistry that had previously been assigned by H NMR
spectroscopy. The obvious presence of the diazo and the
phosphoramide groups in these structures by IR spec-
troscopy, clearly demonstrates the chemoselectivity of the
reaction of azido diazo compounds with trimethylphosphite.
The uncommon occurrence of compounds that contain both
diazo and phosphoramide groups within the same molecule
is also worthy of mention, as only one related report in the
literature has appeared to date.43 Prior to our work, no
1
exchangeable H NMR signal at 3.40 ppm (coupling with
phosphorus) and a singlet at 11.2 ppm in the 31P NMR, a
chemical shift characteristic for the R–NH–P(O)(OR0)2
group.41,42 Phosphoramide 11 is most likely formed by
an initially generated phosphorimide intermediate
[R–NvP(OMe)3], followed by an Arbuzov rearrangement
with subsequent elimination of methanol.11,41
Although vinyl azide 8 underwent decomposition in the
presence of trimethylphosphite, diazo azido esters 6 and 7
reacted smoothly with P(OMe)3, affording phosphoramides
12 and 13, respectively, in good yield after flash
chromatography (Scheme 4). The stereogenic centres in
azido esters 6 and 7 are not directly involved in the
transformation, therefore, the diastereomeric ratios
observed for substrates and products are always identical.
For instance, diastereomerically-enriched azido diazo esters
generated diastereomerically-enriched diazo phosphor-
Figure 1. View of the structure of syn-12 with labeling scheme and the
ellipsoids with 50% of the probability level. Hydrogen atoms were omitted
for clarity.

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M. M. Sa et al. / Tetrahedron 59 (2003) 5441–5447
5444
4. Experimental
4.1. General considerations
All chemicals were of reagent grade and were used as
received. Melting points are uncorrected. 1H NMR
(300 MHz), 13C NMR (75 MHz) and 31P NMR
(162 MHz) spectra were recorded in CDCl3 solution,
1
using tetramethylsilane as internal standard for H and 13C
NMR, and triphenylphosphate as external standard for 31P
NMR. Infrared spectra were acquired using KBr for solids
and film for liquid samples. Mass spectra were determined
at an ionizing voltage of 70 eV. X-Ray were collected with
an automatic X-Ray Diffractometer for monocrystals
ENRAF NONIUS CAD-4. Column chromatography
utilized silica gel (Aldrich, 100–200 mesh particle size).
Azido diazo compounds 3, 6 and 7 were prepared according
to the described method.32
Figure 2. View of the structure of anti-12 with labeling scheme and the
ellipsoids with 50% of the probability level. Hydrogen atoms were omitted
for clarity.
4.1.1. Ethyl (Z)-4-azido-2-diazo-3-oxo-4-phenylpenteno-
ate (8). To a solution containing 0.72 g (3.6 mmol) of
4-azido-2-diazo-3-oxo-butanoate
(3)
and
0.75 mL
(7.4 mmol) of benzaldehyde in 10 mL of absolute ethanol
under argon at 258C was added 0.52 g (3.6 mmol) of
piperidinium acetate. After stirring for 60 h in the dark, the
reaction mixture was diluted with CH2Cl2, washed with
H2O, 10% HCl and H2O again, dried over MgSO4, filtered
and concentrated under reduced pressure. The yellow oil
obtained was submitted to chromatography (hexane/ethyl
eter 3:1) to give five compounds, in order of elution:
4.1.2. Ethyl (Z)-2-azidocinnamate (9).37 Clear oil (5%
1
yield); IR (neat) 2120, 1712 and 1618 cm21; H NMR: d
1.38 (t, 3H, J¼7.0 Hz), 4.35 (q, 2H, J¼7.0 Hz), 6.88 (s, 1H),
7.36 (m, 3H) and 7.81 (m, 2H); 13C NMR: d 14.2, 62.3,
125.3, 125.8, 128.5 (2C), 129.4, 130.6 (2C), 133.2 and
163.5; MS for C11H11N3O2: 218 (MHþ).
4.1.3. Ethyl 4-azido-2-diazo-3-oxo-5-phenyl-5-(N-piper-
idinyl)-pentanoate (10). Colorless solid (8% yield); mp
81–838C; IR (neat) 2142, 2100, 1716 and 1657 cm21; H
1
Figure 3. View of the structure of syn-13 with labeling scheme and the
ellipsoids with 50% of the probability level. Hydrogen atoms were omitted
for clarity.
NMR: d 1.20 (m, 2H), 1.36 (t, 3H, J¼7.0 Hz), 1.42 (m, 4H),
2.10 (m, 2H), 2.51 (m, 2H), 4.19 (d, 1H, J¼11.0 Hz), 4.32
(q, 2H, J¼7.0 Hz), 5.60 (d, 1H, J¼11.0 Hz) and 7.20–7.45
(m, 5H); 13C NMR: d 14.4, 24.1, 26.6 (2C), 51.5 (2C), 58.8,
61.8, 71.2, 127.9, 128.1 (2C), 129.2 (2C), 133.4, 161.2 and
190.5; MS for C18H22N6O3: 371 (MHþ).
general method had previously been available to access
these compounds, and no X-ray data had been reported for
them.
4.1.4. Ethyl (Z)-4-azido-2-diazo-3-oxo-4-phenylpenteno-
ate (8). Clear oil (69% yield); IR (neat) 2140, 2110, 1720
and 1620 cm21; 1H NMR: d 1.28 (t, 3H, J¼7.0 Hz), 4.29 (q,
2H, J¼7.0 Hz), 6.42 (s, 1H), 7.34 (m, 3H) and 7.77 (m, 2H);
13C NMR: d 14.3, 62.0, 75.9, 126.4, 128.5 (2C), 129.5,
130.5 (2C), 130.8, 132.9, 160.5 and 180.8; MS for
C13H11N5O3: 287 (MHþ).
3. Conclusion
The easily available g-azido-a-diazo-b-keto esters 3, 6 and
8 were found to undergo selective reaction with trimethyl-
phosphite to give diazo phosphoramides in good yield under
mild conditions. The overall process involves a novel
tandem Staudinger/Arbuzov rearrangement sequence. The
structures of the resulting products were fully confirmed by
X-ray crystal data, which establishes the relative stereo-
chemistry present in compounds 12 and 13. These diazo
phosphoramides represent new stable multifunctional com-
pounds, and studies dealing with their reactivity and other
chemical properties are currently being investigated.
4.1.5. Ethyl 4-azido-2-diazo-5-hydroxy-3-oxo-5-phenyl-
pentanoate (2). Clear oil, mixture of syn, anti diastereo-
isomers (1:1 ratio, 8% combined yield; spectral data
identical to Ref. 32).
4.1.6. Ethyl 2-diazo-4-(dimethylphosphorylamino)-3-
oxobutanoate (11). To a solution containing 50 mg

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M. M. Sa et al. / Tetrahedron 59 (2003) 5441–5447
5445
(0.25 mmol) of ethyl 4-azido-2-diazo-3-oxobutanoate (3) in
1.5 mL of dry CH2Cl2 under argon at 258C was added
0.03 mL (0.25 mmol) of trimethylphosphite. After stirring
for 24 h the reaction mixture was diluted with CH2Cl2,
washed with H2O, dried over MgSO4, filtered and
concentrated under reduced pressure. The resulting residue
was filtered through a Celite-silica gel plug using ethyl
acetate as the eluent and the filtrate was concentrated under
reduced pressure to give 56 mg (81%) of ethyl 2-diazo-4-
(dimethylphosphorylamino)-3-oxo-butanoate (11) as a clear
yellow oil; IR (neat) 3340, 3230, 2140, 1715 and
phosphorylamino derivative 13 (syn/anti,3:1; 66%
combined yield).
The isolated syn isomer was recrystallized from ethyl ether
to give pale yellow crystals; mp 127–1288C; IR (neat) 3340,
3210, 2142, 1746, 1708 and 1664 cm21; 1H NMR: d 1.36 (t,
3H, J¼7.0 Hz), 2.10 (s, 3H), 3.02 (d, 3H, J¼11.0 Hz), 3.37
(d, 3H, J¼11.0 Hz), 3.72 (dd, 1H, J¼9.5, 10.5 Hz), 4.37 (q,
2H, J¼7.0 Hz), 5.05 (ddd, 1H, J¼1.5, 2.0, 10.5 Hz), 6.31 (d,
1H, J¼1.5 Hz) and 7.25–7.55 (m, 5H); 13C NMR: d 14.3,
20.8, 52.6 (d, J¼5.5 Hz), 53.0 (d, J¼5.5 Hz), 61.7, 62.0,
73.2 (d, J¼7.5 Hz), 126.3 (2C), 128.0, 128.3 (2C), 137.0,
161.1, 169.6 and 189.3; 31P NMR: d 27.36. Anal. calcd for
C17H22N3O8P: C, 47.78; H, 5.19; N, 9.83. Found: C, 47.93;
H, 5.19; N, 9.81.
1
1662 cm21; H NMR: d 1.33 (t, 3H, J¼7.0 Hz), 3.40 (br,
1H, D2O exchange), 3.72 (d, 6H, J¼11.0 Hz), 4.20 (dd, 2H,
J¼9.0, 6.0 Hz), and 4.31 (q, 2H, J¼7.0 Hz); 13C NMR: d
14.2, 49.1, 53.2 (d, J¼5.5 Hz), 61.8, 160.8, and 188.3 (d,
J¼7.5 Hz); 31P NMR: d 11.2; HRMS calcd for C8H15N3O6P
(MHþ): 280.0698. Found: 280.0694.
The anti isomer was obtained impure, even after many
1
recrystallizations: H NMR: d 1.35 (m, 3H), 2.02 (s, 3H),
4.1.7. Ethyl 5-acetoxy-2-diazo-4-(dimethylphosphoryl-
amino)-3-oxohexanoate (12). To a solution containing
3.0 g (10.5 mmol) of ethyl 5-acetoxy-4-azido-2-diazo-3-
oxohexanoate (6; syn/anti,2:1) in 50 mL of dry CH2Cl2
under argon at 258C was added 1.25 mL (10.6 mmol) of
trimethylphosphite. After stirring for 22 h the reaction
mixture was concentrated under reduced pressure and the
resulting residue was purified by chromatography (ethyl
eter/ethyl acetate 9:1) to give phosphorylamino derivative
12 (syn/anti,2:1; 78% combined yield).
3.31 (d, 3H, J¼11.0 Hz), 3.51 (d, 3H, J¼11.0 Hz), 4.35 (m,
2H), 5.21 (m, 1H), 5.81 (d, 1H, J¼8.0 Hz) and 7.20–7.60
(m, 5H).
4.2. X-Ray crystallography
The intensities for all compounds were collected on a CAD4
diffractometer, at rt, with graphite-monochromated Mo Ka
˚
radiation (l¼0.71073 A). The unit cell parameters were
defined on the setting angles of 25 centered reflections in the
˚
Table 1. Selected bond lengths (A) and angles (8) for syn-12 isomer
The isolated syn isomer was recrystallized from ethyl
ether to give pale yellow crystals; mp 79–808C; IR (neat)
3340, 3220, 2140, 1742, 1710 and 1664 cm21; 1H NMR: d
1.32 (t, 3H, J¼7.0 Hz), 1.37 (d, 3H, J¼6.0 Hz), 1.96 (s, 3H),
3.62 (m, 1H), 3.69 (m, 6H), 4.29 (q, 2H, J¼7.0 Hz), 4.79
(t, 1H, J¼10.0 Hz) and 5.27 (q, 1H, J¼6.0 Hz); 13C NMR:
d 14.2, 17.4, 20.9, 53.3–53.4 (m, 2C), 60.2, 61.9, 69.6
(d, J¼6.5 Hz), 161.0, 170.1 and 189.5; 31P NMR: d
27.98; HRMS calcd for C12H20N3O8P (MHþ): 366.1067.
Found: 366.1066. Anal. calcd for C12H20N3O8P: C,
39.46; H, 5.52; N, 11.50. Found: C, 39.53; H, 5.52; N,
11.46.
P1–O5
P1–O4
1.448(3)
1.559(2)
1.600(3)
1.613(2)
1.445(3)
1.110(4)
1.338(4)
1.344(4)
1.453(3)
1.334(4)
1.469(4)
1.538(4)
1.533(4)
1.455(4)
116.88(15)
115.87(19)
98.03(14)
113.20(14)
107.43(13)
103.64(14)
124.16(19)
175.2(3)
118.2(2)
116.3(3)
107.1(2)
108.2(2)
112.5(2)
109.6(2)
112.1(2)
110.8(2)
120.6(3)
121.4(3)
117.9(3)
112.4(3)
116.5(3)
130.9(3)
124.5(3)
124.2(3)
111.3(3)
P1–O3
P1–N1
N1–C3
N2–N3
N2–C5
O1–C9
O1–C2
O8–C6
O8–C7
C2–C3
C3–C4
C4–C5
O5–P1–O4
O5–P1–O3
O4–P1–O3
O5–P1–N1
O4–P1–N1
O3–P1–N1
C3–N1–P1
N3–N2–C5
C9–O1–C2
C6–O8–C7
O1–C2–C1
O1–C2–C3
C1–C2–C3
N1–C3–C4
N1–C3–C2
C4–C3–C2
O6–C4–C5
O6–C4–C3
C5–C4–C3
N2–C5–C4
N2–C5–C6
C4–C5–C6
O7–C6–O8
O7–C6–C5
O8–C6–C5
The isolated anti isomer was recrystallized from ethyl ether
to give pale yellow crystals; mp 74–758C; IR (neat) 3330,
3210, 2140, 1742, 1715 and 1655 cm21; 1H NMR: d 1.17 (d,
3H, J¼6.0 Hz), 1.32 (t, 3H, J¼7.0 Hz), 2.03 (s, 3H), 3.67 (d,
3H, J¼11.0 Hz), 3.72 (d, 3H, J¼11.0 Hz), 3.80 (dd, 1H,
J¼9.5, 10 Hz), 4.31 (q, 2H, J¼7.0 Hz), 4.98 (ddd, 1H,
J¼5.0, 6.0, 9.5 Hz) and 5.05 (m, 1H); 13C NMR: d 14.2,
14.8, 21.1, 53.3–53.4 (m, 2C), 59.7, 62.1, 70.0 (d,
J¼6.5 Hz), 160.4, 169.7 and 189.2 (d, J¼3.5 Hz); 31P
NMR: d 27.46. Anal. calcd for C12H20N3O8P: C, 39.46; H,
5.52; N, 11.50. Found: C, 39.59; H, 5.46; N, 11.57.
4.1.8. Ethyl 5-acetoxy-2-diazo-4-(dimethylphosphoryl-
amino)-5-phenyl-3-oxopentanoate (13). To a solution
containing 2.55 g (7.4 mmol) of ethyl 5-acetoxy-4-azido-
2-diazo-3-oxo-5-phenylpentanoate (7; syn/anti,3:1) in
45 mL of dry CH2Cl2 under argon at 258C was added
1.0 mL (8.5 mmol) of trimethylphosphite. After stirring for
18 h the reaction mixture was concentrated under reduced
pressure and the resulting residue was purified by
chromatography (ethyl eter/ethyl acetate 9:1) to give

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M. M. Sa et al. / Tetrahedron 59 (2003) 5441–5447
5446
˚
Table 2. Selected bond lengths (A) and angles (8) for anti-12 isomer
˚
Table 3. Selected bond lengths (A) and angles (8) for syn-13 isomer
P1–O5
P1–O4
P1–O3
P1–N1
N1–C3
N2–N3
N2–C5
O1–C9
O1–C2
O7–C6
C2–C3
C3–C4
C4–C5
C5–C6
O5–P1–O4
O5–P1–O3
O4–P1–O3
O5–P1–N1
O4–P1–N1
O3–P1–N1
C3–N1–P1
N3–N2–C5
C9–O1–C2
O1–C2–C1
O1–C2–C3
C1–C2–C3
N1–C3–C4
N1–C3–C2
C4–C3–C2
O6–C4–C5
O6–C4–C3
C5–C4–C3
N2–C5–C4
N2–C5–C6
C4–C5–C6
1.462(1)
P1–O5
P1–O4
P1–O3
P1–N1
O1–C8
O1–C1
N1–C2
N2–N3
N2–C4
C1–C12
C1–C2
C2–C3
C3–C4
C4–C5
O5–P1–O4
O5–P1–O3
O4–P1–O3
O5–P1–N1
O4–P1–N1
O3–P1–N1
C8–O1–C1
C2–N1–P1
N3–N2–C4
O1–C1–C12
O1–C1–C2
C12–C1–C2
N1–C2–C3
N1–C2–C1
C3–C2–C1
O6–C3–C4
O6–C3–C2
C4–C3–C2
N2–C4–C5
N2–C4–C3
C5–C4–C3
O7–C5–O8
O7–C5–C4
O8–C5–C4
1.460(2)
1.573(1)
1.583(1)
1.623(1)
1.450(2)
1.106(2)
1.352(2)
1.325(2)
1.451(2)
1.205(2)
1.539(3)
1.527(2)
1.453(2)
1.465(3)
115.73(8)
114.78(8)
99.49(7)
113.58(8)
106.18(7)
105.63(7)
123.88(12)
175.29(19)
119.71(16)
109.57(16)
103.85(14)
114.19(16)
108.42(14)
112.99(15)
108.84(14)
119.47(16)
120.62(15)
119.87(15)
111.59(15)
112.88(15)
135.39(16)
1.551(3)
1.562(3)
1.611(2)
1.326(4)
1.445(3)
1.447(3)
1.106(4)
1.333(4)
1.504(4)
1.537(4)
1.532(4)
1.468(4)
1.444(5)
114.53(17)
115.34(18)
98.7(2)
112.50(14)
108.11(14)
106.53(17)
119.7(3)
125.50(19)
175.9(3)
109.0(2)
107.5(2)
111.8(2)
111.6(2)
110.6(2)
109.4(2)
120.2(3)
122.0(3)
117.7(2)
117.0(3)
112.5(3)
130.5(3)
124.6(3)
124.1(3)
111.3(3)
u range from 9.60 to 14.008. The intensities data were
collected using v/2u scan technique. Intensity control was
carried out using three standards reflections, which were
measured at regular intervals and no significant loss of
intensity was observed during the data collection. The
collected reflections were corrected for Lorentz and
polarization effects.44 No absorption correction was applied.
The structures were solved by direct methods with
SHELXS9745 and refined by full-matrix least-squares
procedure based on F 2 with SHELXL97.46 H atoms
attached to C atoms were placed at idealized positions,
with C–H distances and Ueq values taken from the default
settings of the refinement program. H atoms of the amine
groups were found from difference Fourier maps and treated
as riding atoms. Non-hydrogen atoms were refined with
anisotropic displacement parameters. Selected bond lengths
and angles are listed in Tables 1–3.
0.46£0.26 mm, 3345 reflections collected, unique 3060
[Rint¼0.0184], 219 refined parameters, extinction coef.¼
0.018(3), GOOF¼1.036, final indices R[I.2s(I)]¼0.038 and
wR2¼0.1113 (all data).
4.2.3. syn-13 Isomer. C17H22N3O8P, FW¼427.35, Triclinic,
˚
˚
˚
P-1, a¼8.422(5) A, b¼10.407(2) A, c¼12.859(2) A, a¼
3
˚
88.35(1)8, b¼87.08(2)8, g¼73.50(3)8, V¼1079.1(7) A ,
Z¼2, Dcalc¼1.315 g/cm3, m¼0.174 mm21, crystal 0.50£
0.50£0.33 mm, 4111 reflections collected, unique 3826
[Rint¼0.0119], 302 refined parameters, extinction coef.¼
0.034(4), GOOF¼1.073, final indices R[I.2s(I)]¼0.0594 and
wR2¼0.1754 (all data). Two disorders were observed in this
structure. The oxygen atom of the carboxylic moiety (O2 in
Fig. 3) was found disordered over three positions, where the
site occupancies for the disordered atom were refined and
fixed at 0.56 for one position and 0.22 for two positions. One
terminal carbon atom of the dimethylphosphorylamino group
(C11 in Fig. 3) also occupies three alternative positions, for
which the occupancies factors were also refined and they were
fixed at 0.40, 0.30 and 0.30.
4.2.1. syn-12 Isomer. C12H20N3O8P, FW¼365.28, Triclinic,
˚
˚
˚
3
P-1, a¼8.908(2) A, b¼10.649(2) A, c¼10.877(3) A,
˚
a¼72.26(2)8, b¼70.72(2)8, g¼72.90(2)8, V¼905.9(4) A ,
Z¼2, Dcalc¼1.339 g/cm3, m¼0.194 mm21, crystal 0.50£
0.43£0.26 mm, 3403 reflections collected, unique 3218
[Rint¼0.0096], 218 refined parameters, GOOF¼1.047, final
indices R[I.2s(I)]¼0.057 and wR2¼0.187 (all data).
4.2.2. anti-12 Isomer. C12H20N3O8P, FW¼365.28, Tri-
Acknowledgements
˚
˚
˚
clinic, P-1, a¼6.727(1) A, b¼10.681(1) A, c¼12.382(2) A,
3
˚
a¼78.15(1)8, b¼83.61(1)8, g¼86.48(1)8, V¼864.6(2) A ,
´
The authors are grateful to Central de Analises (Departa-
mento de Quımica, UFSC) for X-ray analysis and to
Z¼2, Dcalc¼1.403 g/cm3, m¼0.203 mm21, crystal 0.50£
´

´
M. M. Sa et al. / Tetrahedron 59 (2003) 5441–5447
5447
25. Clapham, B.; Spanka, C.; Janda, K. D. Org. Lett. 2001, 3,
2173–2176.
National Institutes of Health (GM59384 and GM60003) for
generous support of this work. GPS is grateful to CNPq for a
Predoctoral fellowship.
26. Taber, D. F.; Malcolm, S. C. J. Org. Chem. 2001, 66,
944–953.
27. Padwa, A.; Beall, S.; Eidell, C. K.; Worsencroft, K. J. J. Org.
Chem. 2001, 66, 2414–2421.
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