Ethyl 2-(diisopropoxyphosphoryl)-2h-azirine-3-carboxylate: Reactions with nucleophilic 1,3-dienes

Article abstract of DOI:10.1055/s-0029-1216945

Ethyl 2-(diisopropoxyphosphoryl)-2H-azirine-3-carboxylate, the first example of an azirine bearing simultaneously ester and phosphonate groups was generated in situ and reacted with a number of 1,3-dienes. Cycloadducts or their ensuing rearranged products

Full text of DOI:10.1055/s-0029-1216945

PAPER
3263
Ethyl 2-(Diisopropoxyphosphoryl)-2H-azirine-3-carboxylate: Reactions with
Nucleophilic 1,3-Dienes
E
thyl 2-(Diisopropoxy
.
phosphoryl)
-
J
2
H
-azirine
o
-3-carboxyl
s
ate: React
é
ions
w
ithNucleo
A
a
Departamento de Química, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
Fax +351(253)678983; E-mail: mja@quimica.uminho.pt
b
Departamento de Química, Bioquímica e Farmácia, Universidade do Algarve, Campus de Gambelas, 8005-137 Faro, Portugal
Fax +351(289)819403; E-mail: alemos@ualg.pt
CIQ, Departamento de Química, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre, 687, 4169-007 Porto, Portugal
Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela,
Spain
c
d
Received 24 March 2009; revised 18 May 2009
3-phosphonopropanoic acid [(S)-AP-3, 1, Figure 1] is
known to be a modulator for the N-methyl-D-aspartate
(NMDA) receptor site.
Abstract: Ethyl 2-(diisopropoxyphosphoryl)-2H-azirine-3-carbox-
ylate, the first example of an azirine bearing simultaneously ester
and phosphonate groups was generated in situ and reacted with a
number of 1,3-dienes. Cycloadducts or their ensuing rearranged
products were isolated in moderate yields.
O
P
NH2
OH
Key words: 2H-azirines, aza-Diels–Alder cycloaddition, dieno-
philes, phosphonates
HO
HO
O
1
Figure 1 (S)-2-Amino-3-phosphonopropanoic acid
2H-Azirines have generated a great deal of interest due to
their versatility as building blocks in the synthesis of im-
portant classes of heterocyclic compounds,1,2 and amino
acids.3 2H-Azirines carrying ester groups are especially
important not only due to their structural similarity to nat-
urally occurring azirines with biological activity, like
azirinomycin4 and (–)-(R)-dysidazirine antibiotics,5 but
also for being excellent precursors in the synthesis of a-6
and b-amino acid7 derivatives. Azirines with C=O, P=O
or heteroaromatic groups conjugated with the C=N bond,
are effective dienophile partners8–10 in Diels–Alder cy-
cloadditions, producing bicyclic and tricyclic compounds.
2H-Azirines devoid of electron-withdrawing groups only
react with specially activated dienes such as 1,3-diphenyl-
isobenzofuran in refluxing toluene11a,b or under Lewis
acid catalysis.11c,d
In connection with our work on 2H-azirines, we envis-
aged that 2-(dialkoxyphosphoryl)-2H-azirine-3-carboxy-
lates would be excellent dienophiles for Diels–Alder
cycloadditions, introducing simultaneously the biologi-
cally important phosphonate group13 into cycloadducts.
This class of compounds has not been previously synthe-
sized, despite of being closely related to (S)-AP-3 1.
This paper reports the unprecedented generation of ethyl
2-(diisopropoxyphosphoryl)-2H-azirine-3-carboxylate (5)
and its interception by a number of electron-rich buta-1,3-
dienes producing mono-, di-, and tricyclic aziridines, car-
rying the a-amino-b-phosphonate carboxylate moiety.
The oxime 3 was obtained from ethyl bromopyruvate
oxime (2)14 and triisopropyl phosphite. Its treatment with
tosyl chloride in the presence of sodium carbonate led to
b-phosphonic tosyloxime ester 4 (Scheme 1). The corre-
sponding 2H-azirine 5 was obtained under Neber condi-
tions, but could not be isolated from the reaction medium.
Although monofunctional 2H-azirine-2-phosphonates15
Excitatory amino acids are the most common neurotrans-
mitters in the mammalian central nervous system thus
their receptors have been exploited in the treatment of
several pathological conditions affecting the brain, such
as Parkinson’s and Alzheimer’s diseases.12 (S)-2-Amino-
OH
OTs
TsCl
CH2Cl2
OH
N
N
N
P(Oi-Pr)3
CH2Cl2
Na2CO3
EtO2C
EtO2C
EtO2C
79%
62%
P
Oi-Pr
Oi-Pr
Br
O
P
O
Oi-Pr
Oi-Pr
2
3
4
Scheme 1 Preparation of b-phosphonic tosyloxime ester
SYNTHESIS 2009, No. 19, pp 3263–3266
x
x.
x
x
.
2
0
0
9
Advanced online publication: 21.08.2009
DOI: 10.1055/s-0029-1216945; Art ID: T06709SS
© Georg Thieme Verlag Stuttgart · New York

3264
M. J. Alves et al.
PAPER
have been produced and isolated before under similar re- were obtained as single isomers, presumably formed by
action conditions, manipulation of the reaction mixture in endo-selective processes, as generally observed in reac-
the present case, however, led to decomposition, accord- tions of 2H-azirines with 1,3-dienes.8 Furan and their de-
ing to 1H NMR analysis.
rivatives are exceptions due to retro-Diels–Alder
cycloadditions of the initially formed endo-cycloadduct
that isomerize to the exo-products.11b The low-field reso-
nance of H3 in the tricyclic products obtained by reaction
of 2H-azirines with cyclopentadiene is a clear feature of
the endo selectivity.8 This can be ascribed to the anisotro-
py of the backside double bond over H3, due to con-
straints of the tricyclic structure. The chemical shift value
of H3 in compound 6d correspond to such an effect ap-
pearing at dH = 1.62.
In a typical procedure tosyloxime 4 was solubilized in
benzene mixed with potassium carbonate (10 equiv), tri-
ethylamine (0.3 equiv), and a 1,3-diene and stirred for
four days at room temperature. The primary cycloadducts
6a,b,d,e were obtained in 9–59% yield. Derivative 7 was
obtained in the case of reaction with the Danishefsky di-
ene in 39% yield, by rearrangement of the primary cy-
cloadduct 6c (Scheme 2). In case 6f, the silyl group
cleaved during chromatography giving 8.
Features of pyridinone 7, obtained by rearrangement of
6c, are the two hydrogens of the CH2 group, coupling to
the phosphorus nucleus with J = 12.0 Hz; the signal at
dH = 6.45, assigned to H5, shows a doublet of doublets
The moderate yields are certainly the reflection of the
two-step sequence in the one-pot procedure together with
the instability of the azirine because of the presence of the
two electron-withdrawing substituents in the ring.
2
(3J = 3.0 Hz to H3 and J = 7.6 Hz to H6) and two dou-
Cycloadduct 6a, obtained from reaction of azirine 5 with
2,3-dimethylbuta-1,3-diene, was isolated in very low
yield, even in the presence of a large excess of diene (5
equiv). Difficulties of the same type had been reported by
Davis in reaction of a 2H-azirine-3-phosphonate with 2,3-
dimethylbuta-1,3-diene, where 100 equivalents of the di-
ene were required.9
blets at dH = 7.35, corresponding to H6, and at dH = 7.03,
corresponding to H3, show matching couplings to H5. Re-
arrangements of this type have been noticed before in bi-
cyclic adducts obtained from the Danishefsky diene and
2H-azirines bearing electrophilic groups.16
In summary, cycloaddition reactions of ethyl 2-(diisopro-
poxyphosphoryl)-2H-azirine-3-carboxylate to nucleo-
philic dienes produced, in moderate yields, a number of
functionalized six-membered-ring fused aziridines. These
may eventually be valuable intermediates at the synthesis
of interesting biological compounds related to (S)-AP3.
Studies to improve the reaction efficiency as well as the
Reaction of the azirine 5 with 1-methoxybuta-1,3-diene
evidenced that the regioselectivity of the cycloaddition is
governed by electronic effects. 1H and 13C NMR data of
product 6b are in accordance with the electron-withdraw-
ing effect of the two heteroatoms attached to C2; H2 is at
dH = 4.80 and C2 at dC = 85.6. The cycloaddition products
CO2Et
TMSO
Oi-Pr
CO2Et
CO2Et
Oi-Pr
O
Oi-Pr
N
N
N
P
P
Oi-Pr
P
Oi-Pr
Oi-Pr
O
O
O
6f
6e 20%
8
19%
TMSO
R3
R2
R3
R2
CO2Et
Oi-Pr
O
N
P
Oi-Pr
Oi-Pr
R1
N
Et3N, K2CO3
R1
P
4
Oi-Pr
EtO2C
O
5
6a R1 = H, R2 = R3 = Me, 9%
TMSO
6b R1 = OMe, R2 = R3 = H, 51%
OMe
CO2Et
Oi-Pr
CO2Et
Oi-Pr
CO2Et
Oi-Pr
TMSO
O
N
P
N
N
P
P
Oi-Pr
MeO
Oi-Pr
O
Oi-Pr
O
O
6d 59%
7
39%
6c
Scheme 2 Generation of azirine 5 and its cycloaddition reactions with 1,3-dienes
Synthesis 2009, No. 19, 3263–3266 © Thieme Stuttgart · New York

PAPER
Ethyl 2-(Diisopropoxyphosphoryl)-2H-azirine-3-carboxylate
3265
Ethyl 7-(Diisopropoxyphosphoryl)-3,4-dimethyl-1-azabicyc-
lo[4.1.0]hept-3-ene-6-carboxylate (6a)
(i) 2,3-Dimethybuta-1,3-diene (1.5 equiv); yield: 0.020 g (8%).
development of an asymmetric synthesis or generation of
the azirine are ongoing.
(ii) 2,3-Dimethybuta-1,3-diene (5.0 equiv); yield: 0.025 g (9%).
IR (neat): 3458, 2981, 2933, 1753 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.29–1.33 (m, 15 H, 5 Me), 1.52
(br s, 3 H, Me), 1.63 (br s, 3 H, Me), 2.16 (d, J = 17.3 Hz, 1 H, H7),
2.38 (br d, J = 17.3 Hz, 1 H, H5), 2.70 (d, J = 17.6 Hz, 1 H, H5),
3.23 (d, J = 17.0 Hz, 1 H, H2), 3.73 (d, J = 17.0 Hz, 1 H, H2), 4.16–
4.26 (m, 2 H, OCH2), 4.68–4.80 (m, 2 H, 2 OCH).
1H and 13C NMR spectra (100.6 or 75.5 MHz) were recorded on a
Bruker Avance III 400 (400 MHz) spectrometer or on a Bruker WM
AMX (300 MHz), using TMS as internal standard. IR spectra were
recorded on a Perkin-Elmer 1640-FT spectrophotometer. Samples
were run as thin films. Mass spectra were recorded on a VG Au-
tospec M. Purification of crude samples was performed by dry flash
chromatography, using silica gel purchased from Carlo Erba (35–70
mm).
13C NMR (75.5 MHz, CDCl3): d = 13.1 (Me), 15.4 (Me), 17.5 (Me),
22.6 (Me), 22.9 (Me), 23.95 (Me), 23.05 (Me), 23.1 (Me), 28.4 (d,
Ethyl 3-(Diisopropoxyphosphoryl)-2-(hydroxyimino)pro-
panoate (3)
1
3JPC = 19 Hz, CH2, C5), 33.1 (d, JPC = 216 Hz, C7), 45.0 (d,
2JPC = 5.0 Hz, C6), 51.6 (d, 3JPC = 6.6 Hz, CH2, C2), 60.3 (CH2O),
69.8 (d, 3JPC = 6.0 Hz, COH), 69.9 (d, 3JPC = 6.3 Hz, COH), 118.7
(C3 or C4), 119.1 (C4 or C3), 168.7 (CO).
To ethyl bromopyruvate oxime (4.7 g, 22 mmol) dissolved in
CH2Cl2 (30 mL) was added P(Oi-Pr)3 (6 mL, 24 mmol) and the mix-
ture stirred at 35 °C for 16 h. H2O (30 mL) was added and the mix-
ture stirred at r.t. for a further 30 min and the organic phase was
dried (MgSO4) and evaporated under vacuum. The oily residue was
subjected to dry-flash chromatography (silica gel, CH2Cl2–EtOAc,
10:1), affording 3 (5.13 g, 79%) as a as colorless oil.
HRMS (FAB): m/z [M + H]+ calcd for C17H31NO5P: 360.1940;
found: 360.1927.
Ethyl 7-(Diisopropoxyphosphoryl)-2-methoxy-1-azabicyc-
lo[4.1.0]hept-3-ene-6-carboxylate (6b)
Yield: 0.125 g (51%).
IR (neat): 3467, 2980, 2931, 1754, 1731 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.23–1.28 (m, 15 H, 5 Me), 2.30
(d, J = 16.6 Hz, 2 H, H5, H7), 2.78 (dd, J = 6.1, 18.5 Hz, 1 H, H5),
3.61 (s, 3 H, OMe), 4.16–4.18 (m, 2 H, OCH2), 4.68 (br s, 2 H,
2 OCH), 4.80 (s, 1 H, H2), 5.39 (d, J = 10.0 Hz, 1 H, H3), 5.62–5.63
(m, 1 H, H4).
IR(neat): 3167, 2982, 2936, 1720, 1252, 995 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.22–1.30 (m, 15 H, 5 Me), 3.29
(d, 1JPH = 24.0 Hz, 2 H), 4.19–4.29 (m, 2 H, OCH2), 4.66–4.74 (m,
2 H, 2 OCH).
13C NMR (75.47 MHz, CDCl3): d = 14.1 (Me), 23.6 (Me), 23.7
1
(Me), 24.6 (Me), 24.6 (d, JPC = 83.8 Hz), 61.5 (OCH2), ~71.1 (d,
2JPC = 13.6 Hz, OCH), 143.6 (C=N), 163.9 (CO).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C11H23NO6P: 296.1263;
found: 296.1258.
13C NMR (75.5 MHz, CDCl3): d = 14.4 (Me), 24.1 (Me), 24.2 (CH2,
C5), 24.4 (Me), 24.42 (Me), 24.6 (Me), 33.2 (d, 1JPC = 217 Hz, C7),
2
45.6 (d, JPC = 4.5 Hz, C6), 57.3 (OMe), 61.8 (OCH2), 71.3 (d,
Ethyl 3-(Diisopropoxyphosphoryl)-2-[(tosyloxy)imino]pro-
panoate (4)
2
2JPC = 6.8 Hz) 71.5 (d, JPC = 6.8 Hz, OCH), 85.6 (C2), 123.1 (C3
or C4), 124.5 (C4 or C3), 168.0 (CO).
HRMS (FAB): m/z [M + H]+ calcd for C16H29NO6P: 362.1732;
found: 362.1731.
To a soln of 3 (4.5 g, 15 mmol) in CH2Cl2 (40 mL) was added
Na2CO3 (4.8 g, 45 mmol) followed by TsCl (3.24 g, 17 mmol) and
the mixture stirred until the disappearance of the starting oxime (~4
h). The insolubles were removed by filtration and the solvent was
evaporated to afford a residue that was subjected to dry-flash chro-
matography (silica gel, hexanes–CH2Cl2–EtOAc, increasing polar-
ity) to product 4 (4.2 g, 62%) as a pale yellow thick oil.
Ethyl 3-(Diisopropoxyphosphoryl)-2-azatricyclo[3.2.1.02,4]oct-
6-ene-4-carboxylate (6d)
Yield: 0.140 g (59%).
IR(neat): 2983, 1737, 1386, 1267, 1194, 993 cm–1.
IR (neat): 3467, 2981, 2937, 1741 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.19–1.30 (m, 15 H, 5 Me), 2.38
(s, 3 H, PhMe), 3.25 (d, 1JPH = 24.0 Hz, 2 H), 4.23 (q, J = 6.0 Hz, 2
H, OCH2), 4.57–4.64 (m, 2 H, 2 OCH), 7.28 (d, J = 6.0 Hz, 2 H),
7.83 (d, J = 6.0 Hz, 2 H).
13C NMR (75.5 MHz, CDCl3): d = 13.8 (Me), 21.6 (Me), 23.4 (Me),
23.5 (Me), 23.6 (Me), 23.7 (Me), 26.5 (d, 1JPC = 135.8 Hz, PCH2),
62.8 (OCH), ~72.0 (d, 2JPC = 12.1 Hz, OCH), 131.7 (C, Ar), 145.7
(C, Ar), 152.1 (C=N), 161.1 (CO).
1H NMR (300 MHz, CDCl3): d = 1.27–1.34 (m, 15 H, 5 Me), 1.62
(d, J = 12.5 Hz, 1 H, H3), 1.71 (t, J = 8.6 Hz, 1 H, H8), 2.43 (d,
J = 8.6 Hz, 1 H, H8), 3.29 (br s, 1 H, H5), 4.24–4.29 (m, 3 H, OCH2,
H1), 4.67–4.78 (m, 2 H, 2 OCH), 5.71–5.73 (m, 1 H, H6 or H7),
6.18–6.22 (m, 1 H, H7 or H6).
13C NMR (75.5 MHz, CDCl3): d = 14.5 (Me), 24.3 (Me), 24.4 (Me),
24.43 (Me), 24.5 (Me), 45.8 (d, 1JPC = 205 Hz, C3), ~48 (C6), 49.6
(C5), 59.4 (d, J = 3.0 Hz, C8), 62.0 (OCH2), 67.6 (d, 3JPC = 7.5 Hz,
2
2
C1), 71.3 (d, JPC = 6.8 Hz, OCH), 71.5 (d, JPC = 6.8 Hz, OCH),
HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H29NO8PS:
450.1351; found: 450.1346.
128.8 (C5 or C6), 133.3 (C6 or C5), 172.0 (CO).
HRMS (FAB): m/z [M + H]+ calcd for C16H27NO5P: 344.1627;
Cycloaddition Reactions; General Procedure
found: 344.1615.
To a soln of tosyloxime 4 (0.3 g, 0.69 mmol) in benzene (5 mL) was
added Et3N (30 mL, 0.33 equiv), K2CO3 (0.96 g, 6.9 mmol, 10
equiv), and the diene (1.0 equiv to large excess). [Cyclopentadiene
was used in large excess (1 mL), other dienes were used in excess:
the Danishefsky diene (1.5 equiv), 1-methoxybuta-1,3-diene (2
equiv), 2,3-dimethylbuta-1,3-diene (1.5 equiv or 5 equiv).] The
mixture was stirred at r.t. for 4 d. Evaporation of the solvent gave
the crude product, which was subjected to dry-flash chromatogra-
phy (silica gel, petroleum ether–Et2O, polarity gradient or EtOAc–
MeOH, 3:1 for 7) affording products 6–8 as oils.
Ethyl 3-(Diisopropoxyphosphoryl)-2-azatricyclo[3.2.2.02,4]non-
6-ene-4-carboxylate (6e)
Yield: 0.088 g (20%).
IR (neat): 2933, 1749, 1653, 1281 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.10 (m, 1 H, H8 or H9), 1.24–
1.34 (m, 16 H, 5 Me, 1 H, H9 or H8), 1.52 (d, J = 13.2 Hz, 1 H, H3),
1.69 (m, 1 H, H8 or H9), 2.1 (m, 1 H, H9 or H8), 3.12 (m, 1 H, H5),
3.99 (m, 1 H, H1), 4.26 (m, 2 H, CO2CH2CH3), 4.66–4.81 (m, 2 H,
2 OCH), 5.68 (m, 1 H, H6 or H7), 6.22 (m, 1 H, H7 or H6).
Synthesis 2009, No. 19, 3263–3266 © Thieme Stuttgart · New York

3266
M. J. Alves et al.
PAPER
13C NMR (100.6 MHz, CDCl3): d = 14.1 (CO2CH2CH3), 19.8 (C8
(2) (a) Pinho e Melo, T. M. V. D.; Lopes, C. S. J.; Gonçalves, A.
M. d’ A. R.; Beja, J. A.; Paixão, A. M.; Silva, M. R.;
Alte da Veiga, L. J. Org. Chem. 2002, 67, 66. (b) Davis, F.
A.; Liang, C.; Liu, H. J. Org. Chem. 1997, 62, 3796.
(c) Banert, K.; Kohler, F. Angew. Chem. Int. Ed. 2001, 40,
174.
or C9), 23.6 (C9 or C8), 23.82, 23.9, 24.0, 24.0 (4 Me), 31.0 (d,
3
1JPC = 212.5 Hz, C3), 32.9 (d, J = 2.6 Hz, C5), 52.3 (d, JPC = 9.2
Hz, C1), 61.4 (CO2CH2CH3), 70.7 (d, 2JPC = 6.3 Hz, OCH), 71.0 (d,
2JPC = 6.3 Hz, OCH), 125.1 (C6 or C7), 130.1 (C7 or C6), 125.5 (q,
C2), 169.2 (C=O).
(3) Heimgartner, H. Angew. Chem., Int. Ed. Engl. 1991, 30, 238.
(4) Miller, T. W.; Tristram, E. W.; Wolf, F. J. J. Antibiot. 1971,
24, 48.
HRMS (FAB): m/z [M + H]+ calcd for C17H29NO5P: 358.1783;
found: 358.1784.
(5) Molinski, T. F.; Ireland, C. M. J. Org. Chem. 1988, 53, 2103.
(6) (a) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599.
(b) Filigheddu, S. N.; Taddei, M. Tetrahedron Lett. 1998, 39,
3857. (c) Zwanenburg, B.; Thi, L. J. Pure Appl. Chem. 1996,
68, 735. (d) Davis, F. A.; Liu, H.; Reddy, C. V. Tetrahedron
Lett. 1996, 37, 5473.
(7) (a) Righi, G.; D’Achielle, R. Tetrahedron Lett. 1996, 37,
6893. (b) Lim, Y.; Lee, W. K. Tetrahedron Lett. 1995, 36,
8431. (c) Tanner, D.; Bergsson, C.; Dhaliwal, H. K.
Tetrahedron Lett. 1990, 31, 1903.
(8) Alves, M. J.; Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1
1998, 299.
(9) (a) Davis, F. A.; Wu, Y.; Yan, H.; Prasad, K. R.; McCoull,
W. Org. Lett. 2002, 4, 655. (b) Bickley, J. F.; Gilchrist, T.
L.; Mendonça, R. ARKIVOC 2002, (vi), 192.
Ethyl 1-[(Diisopropoxyphosphoryl)methyl]-4-oxo-1,4-dihydro-
pyridine-2-carboxylate (7)
Yield: 0.092 g (39%).
IR (neat): 3440, 2983, 2938, 1733, 1633, 1573 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.21–1.27 (m, 12 H, 4 Me), 1.36
(t, J = 7.2 Hz, 3 H, Me), 3.73 (q, J = 7.2 Hz, 2 H, OCH2), 4.63–4.71
(m, 2 H, 2 OCH), 4.71 (d, J = 12.0 Hz, 2 H, H1¢), 6.45 (dd, J = 3.0,
7.6 Hz, 1 H, H5), 7.03 (d, J = 3.0 Hz, 1 H, H3), 7.35 (d, J = 7.6 Hz,
1 H, H6).
13C NMR (75.5 MHz, CDCl3): d = 14.3 (Me), 24.21 (Me), 24.27
(Me), 24.32 (Me), 49.7 (d, 1JPC = 156 Hz, C1¢, CH2), 63.3 (CH2O),
73.0 (d, 2JPC = 7.5 Hz, OCH), 119.7 (C5), 123.3 (C3), 140.2 (C2),
162.9 (CO), 179.5 (CO).
HRMS (FAB): m/z [M + H]+ calcd for C15H25NO6P: 346.1419;
(10) Alves, M. J.; Gil Fortes, A.; Lemos, A.; Martins, C.
found: 346.1419.
Synthesis 2005, 555.
(11) (a) Nair, V. J. J. Org. Chem. 1972, 37, 2508. (b) Hassner,
A.; Anderson, D. J. J. Org. Chem. 1974, 39, 2031. (c) Ray,
C. A.; Risberg, E.; Somfai, P. Tetrahedron Lett. 2001, 42,
9289. (d) Ray, C. A.; Risberg, E.; Somfai, P. Tetrahedron
2002, 58, 5983.
(12) (a) Young, A. B.; Greenamyre, J. T.; Hollingsworth, Z.;
Albin, R.; D’Amato, C.; Shoulson, I.; Penny, J. B. Science
1988, 241, 981. (b) Reyes-Rangel, G.; Marañón, V.; Avila-
Ortiz, C. G.; Parrodi, C. A.; Quintero, L.; Juaristi, E.
Tetrahedron 2006, 62, 8404.
Ethyl 3-(Diisopropoxyphosphoryl)-6-oxo-2-azatricyc-
lo[3.2.2.02,4]nonane-4-carboxylate (8)
Yield: 0.077 g (19%).
IR (neat): 3459, 3274, 3054, 1734, 1602 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.29–1.30 (m, 15 H, 5 Me), 1.73–
1.80 (m, 2 H), 1.88 (d, J = 9.3 Hz, 1 H, H3), 2.07–2.32 (m, 4 H),
3.07 (br s, 1 H, H1), 3.79 (br s, 1 H, H5), 4.26 (m, 2 H, CH2CH3),
4.75 (m, 2 H, 2 OCH).
13C NMR (100.6 MHz, CDCl3): d = 14.0 (Me), 18.5 (C8 or C9),
23.8 (Me), 23.92 (Me), 23.96 (Me), 24.0 (Me), 24.6 (CH2), 33.5 (d,
1JPC = 213.3 Hz, C3), 39.6 (C8 or C9), 43.7 (d, 3JPC = 2.0 Hz, C5),
45.8 (d, 2JPC = 4.0 Hz, C4), 49.7 (d, 3JPC = 8.0 Hz, C1), 61.8 (OCH),
71.4 (d, 2JPC = 6.0 Hz, OCH), 167.0 (C=O), 207.6 (C=O).
HRMS (FAB): m/z [M + H]+ calcd for C17H29NO6P: 374.1732;
found: 374.1729.
(13) (a) Engel, R. In Handbook of Organophosphorus Chemistry;
Dekker Inc.: New York, 1992. (b) Kafarski, P.; Lejczak, B.
Phosphorus, Sulfur Silicon Relat. Elem. 1991, 63, 193.
(14) (a) Gilchrist, T. L.; Roberts, T. G. J. Chem. Soc., Perkin
Trans. 1 1983, 1283. (b) Ottenheijm, H. C. J.; Plate, R.;
Noordik, J. H.; Herscheid, J. D. M. J. Org. Chem. 1982, 47,
2147.
(15) (a) Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I.; Ezpeleta,
J. M. J. Org. Chem. 2000, 65, 3213. (b) Palacios, F.;
Ochoa de Retana, A. M.; Gil, J. I. Tetrahedron Lett. 2000,
41, 5363. (c) Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I.;
López de Munain, R. Org. Lett. 2002, 4, 2405. (d) Palacios,
F.; Ochoa de Retana, A. M.; Gil, J. I.; Alonso, J. M.
Tetrahedron: Asymmetry 2002, 13, 2525. (e) Palacios, F.;
Aparicio, D.; Ochoa de Retana, A. M.; de los Santos, J. M.;
Gil, J. I.; López de Munain, R. Tetrahedron: Asymmetry
2003, 14, 689. (f) Palacios, F.; Ochoa de Retana, A. M.; Gil,
J. I.; Alonso, J. M. Tetrahedron 2004, 60, 8937.
(16) Alves, M. J.; Gil Fortes, A.; Costa, F. T.; Duarte, V. C. M.
Tetrahedron 2007, 63, 11167.
Acknowledgment
Thanks are due to Fundação para a Ciência e Tecnologia and Xunta
de Galicia under project 07CSA008203PR, for financial support.
NMR spectrometer Bruker Avance II 400, acquired with funds from
FCT and FEDER (part of the National NMR Network).
References
(1) For reviews, see: (a) Palacios, F.; Ochoa de Retana, A. M.;
Marigorta, E. M.; de los Santos, J. M. Org. Prep. Proced.
Int. 2002, 34, 219. (b) Gilchrist, T. L. Aldrichimica Acta
2001, 34, 51. (c) Palacios, F.; Ochoa de Retana, A. M.;
Marigorta, E. M.; de los Santos, J. M. Eur. J. Org. Chem.
2001, 2401.
Synthesis 2009, No. 19, 3263–3266 © Thieme Stuttgart · New York