Regio- and diastereoselective preparation of tetrahydrobenzo[c]-1-aza-2lambda(5)-phospholes through dearomatization cyclization of lithiated N-benzyl-N-alkyl(diphenyl)phosphinamides. Synthesis of gamma-(N-alkylamino)phosphinic acids.

Article abstract of DOI:10.1021/jo025587+

A study of the protonation of the cycloadducts derived from the dearomatization reaction of lithiated N-alkyl-N-benzyldiphenylphosphinamides has been carried out. The regio- and stereoselectivity of the process has been analyzed in terms of the size of the N-alkyl substituent, the acidity and size of the protonating reagent, and the cosolvent used. The optimization of these variables allowed the preparation of tetrahydrobenzo[c]-1-aza-2lambda(5)-phospholes containing a 1,3-cyclohexadiene or 1,4-cyclohexadiene system with moderate to excellent regio- and stereocontrol. The heterocycles were readily hydrolyzed, affording gamma-(N-alkylamino)diphenylphosphinic acids with the functionalities linked to a cyclohexadiene substructure.

Full text of DOI:10.1021/jo025587+

3852
J . Org. Chem. 2002, 67, 3852-3860
Regio- a n d Dia ster eoselective P r ep a r a tion of
Tetr a h yd r oben zo[c]-1-a za -2λ5-p h osp h oles th r ou gh Dea r om a tiza tion
Cycliza tion of Lith ia ted
N-Ben zyl-N-a lk yl(d ip h en yl)p h osp h in a m id es. Syn th esis of
γ-(N-Alk yla m in o)p h osp h in ic Acid s
Ignacio Ferna´ndez,† Fernando Lo´pez Ortiz,*,† Amador Mene´ndez Vela´zquez,‡ and
Santiago Garc´ıa Granda‡
AÄ rea de Qu´ımica Orga´nica, Universidad de Almerı´a, Carretera de Sacramento, 04120, Almer´ıa, Spain,
and Departamento de Quı´mica Fı´sica y Analı´tica, Universidad de Oviedo, Avda. J ulia´n Claverı´a 8,
33071 Oviedo, Spain
flortiz@ual.es
Received February 4, 2002
A study of the protonation of the cycloadducts derived from the dearomatization reaction of lithiated
N-alkyl-N-benzyldiphenylphosphinamides has been carried out. The regio- and stereoselectivity of
the process has been analyzed in terms of the size of the N-alkyl substituent, the acidity and size
of the protonating reagent, and the cosolvent used. The optimization of these variables allowed
the preparation of tetrahydrobenzo[c]-1-aza-2λ5-phospholes containing a 1,3-cyclohexadiene or 1,4-
cyclohexadiene system with moderate to excellent regio- and stereocontrol. The heterocycles were
readily hydrolyzed, affording γ-(N-alkylamino)diphenylphosphinic acids with the functionalities
linked to a cyclohexadiene substructure.
1. In tr od u ction
respectively. However, the syntheses of functionalized
derivatives is scarce.9
γ-Aminophosphinic acids and their derivatives are
compounds of great interest, due to the relevance of their
biological properties.1 Phosphinothricin 1a is an impor-
tant member of this family of compounds. It is a γ-ami-
nophosphinic acid contained in the natural tripeptide
bialaphos, currently used as nonselective herbicide.2
Phosphinothricin analogues 1b,c and cyclic derivatives
2 have been found to be inhibitors of glutamine synthe-
tase3 and showed herbicidal activity.4 The inhibitory ac-
tivity is assigned to the tetrahedral phosphinic moiety,
which is a good transition state mimic in amide forma-
tion.5 γ-Aminophosphinic acids 3a ,b are also effective as
GABAB receptors agonists,6 while 4a ,b7 and the cyclic
derivative 58 are potent GABAC receptors antagonists,
* Corresponding author. Tel +34 950 015478; fax: +34 950 0154781.
† Universidad de Almer´ıa.
‡ Universidad de Oviedo.
(1) Kukhar, V. P.; Hudson, H. R., Eds. Aminophosphonic and
Aminophosphinic Acids. Chemistry and Biological Activity; J ohn
Wiley: New York, 2000.
An attractive approach to the preparation of function-
alized alicyclic compounds is based on the dearomatiza-
tion of arenes. This chemistry makes use of stable
materials that are widely available and can be readily
derivatized. The conjugated π system can be broken up
by a number of methods: oxidation,10 reduction,11 pho-
tocycloaddition,12 and electrophilic13 and nucleophilic
addition to activated arenes. The activation for the
(2) Bayer, E.; Gugel, K. H.; Haegele, K.; Hagenmaier, H.; J essipow,
S.; Koenig, W. A.; Zaehner, J . Helv. Chim. Acta 1972, 55, 224.
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1999, 55, 771. (c) Hanrahan, J . R.; Mewett, K. N.; Shebib, M.; Burden,
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10.1021/jo025587+ CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/08/2002

Synthesis of γ-(N-Alkylamino)phosphinic Acids
J . Org. Chem., Vol. 67, No. 11, 2002 3853
Sch em e 1a
a
Conditions: (i) BusLi (1.5 equiv), THF, -90 °C, HMPA (6 equiv), 30 min. (ii) MeOH, 30 min. (iii) Chromatography, AcOEt. (iv) 2 N
HCl(H2O), Me2CO. (v) 0.5 N HCl(g), MeOH.
conjugate addition of nucleophiles to arenes may be
induced by complexation to transition metals14,15 or
through bonding to electron-withdrawing groups. Nu-
cleophilic dearomatization of activated benzenes16 is more
difficult than that of naphthalenes17 or other fused
carbocyclic aromatic systems18 due to the higher reso-
nance stabilization of the benzene ring. Generally, this
dearomatization methodology delivers high degrees of
chemo-, regio-, and stereocontrol, characteristics that are
essential for its application to the synthesis of natural
products19 and nonnatural analogues.20
dearomatized compound was obtained in the anionic
cyclization of N-benzyl-N-methyldiphenylphosphinamide
6a , followed by quenching with methanol, as a mixture
of 7a :8:9a :10 in a 72:5:20:3 ratio in 90% total yield.
Column chromatography using ethyl acetate as eluent
afforded pure 1-aza-2λ5-phosphol 7a (Scheme 1).21
The dearomatized compounds 7a and 9a , the major
components of the reaction mixture, are interesting
products. The dihydrobenzene ring of 7a is stabilized as
a 1,3-butadiene system appropriated for Diels-Alder
reactions.22 In 9a one of the carbon-carbon double bonds
of the cyclohexadiene moiety is nucleophilic, while the
second one has an electrophilic character, due to the
conjugation with the PO linkage. Therefore, these com-
pounds can be considered as scaffolds for the preparation
of families of functionalized γ-aminophosphinic acids of
wide structural diversity. Moreover, the cyclohexane ring
of 7a and 9a may be regarded as a constrained element
restricting the conformational dynamic of the molecule,23
an important factor in molecular recognition events.24
Compounds 7a and 9a are the result of moderate regio-
control in the protonation of the intermediate lithiated
species I formed in the dearomatizing step (Scheme 1).
Considering that this methodology represents a very
facile access to conformationally restrained γ-aminophos-
We have recently described the synthesis of γ-(N-
methylamino)phosphinic acid 11a and ester 12a through
the stereospecific solvolysis of azaphosphol 7a . This
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Pouse´gu, L. Org. Lett. 1999, 10, 1651. (e) Mandal, S.; Macikenas, D.;
Protasiewicz, Sayre, M. L. J . Org. Chem. 2000, 65, 4804. (f) Pierlot,
C.; Poprawski, J .; Marko, J .; Aubry, J . Tetrahedron Lett. 2000, 41, 5063.
(g) Quideau, S.; Pouyse´gu, L.; Oxoby, M.; Looney, M. A. Tetrahedron
2001, 57, 319. For microbial oxidation see: (h) Boyd, D. R.; Sharma,
N. D.; Barr, S. A.; Dalton, H.; Chima, J . J . Am. Chem. Soc. 1994, 116,
1147. (i) Boyd, D. R.; Sharma, N. D.; Bowers, N. I.; Duffy, J .; Harrison,
J . S.; Dalton, H. J . Chem. Soc., Perkin Trans 1 2000, 1345. (j) Bui, V.;
Hansen, T. V.; Stenstrom, Y.; Ribbons, D. W.; Hudlicky, T. J . Chem.
Soc., Perkin Trans. 1 2000, 1669.
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Donohoe, T. J .; Garg, R.; Stevenson, C. A. Tetrahedron: Asymmetry
1996, 7, 317. (c) Schultz, A. Chem. Commun. 1999, 1263.
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T.; Kim, D.; Kim, Y. J . J . Org. Chem. 1998, 63, 1212. (c) Kohmoto, S.;
Masu, H.; Tatsuno, C.; Kishikawa, K.; Yamamoto, M.; Yamaguchi, K.
J . Chem. Soc., Perkin Trans. 1 2000, 4464. (d) Yokoyama, A.; Mizuno,
K. Org. Lett. 2000, 2, 3457.
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(b) Brooks, B. C.; Gunnoe, T. B.; Harman, W. D. Coord. Chem. Rev.
2000, 206-207, 3-61. (c) Smith, P. L.; Chordia, M. D.; Harman, W.
D. Tetrahedron 2001, 57, 8203. See also: (d) Chordia, M. D.; Harman,
W. D. J . Am. Chem. Soc. 2000, 122, 2725. (e) Fujita, M.; Matsushima,
H.; Sugimura, T.; Tai, A.; Okuyama, T. J . Am. Chem. Soc. 2001, 123,
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Coord. Chem. Rev. 2000, 206-207, 3. (c) Smith, P. L.; Chordia, M. D.;
Harman, W. D. Tetrahedron 2001, 57, 8203.
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Imhof, W. Tetrahedron 2000, 56, 2015. (b) Bao, M.; Nakamura, H.;
Yamamoto, Y. J . Am. Chem. Soc. 2001, 123, 759.
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3854 J . Org. Chem., Vol. 67, No. 11, 2002
Ferna´ndez et al.
effects. The structures of the 1-aza-2λ5-phospholes ob-
Sch em e 2a
tained in this study are shown in Scheme 3.
a
Conditions: (i) HN(Bn)R (R ) Me, Bn), Et3N (2.5 equiv),
toluene, 30 min, -78 °C. (i) 30% H2O2/THF, 30 min. (iii) ButNH2,
Et3N (2.5 equiv), toluene, 30 min, -78 °C. (iv) NaH, THF, 30 min,
0 °C, then PhCH2Br, 60 min, rt.
phinic acids,25 we addressed the goal of optimizing the
conditions to achieve the highest regio- and stereoselec-
tivity of the protonation reaction. We focused on two main
aspects: the source of the protons and the substituents
on the nitrogen atom of the phosphinamide. The results
reported in this paper show that it is possible to obtain
different tetrahydrobenzo[c]-1,aza-2λ5-phospholes with
excellent regio- and stereocontrol by an adequate selec-
tion of the protonating agent and the starting phosphi-
namide. Moreover, preliminary anticancer assays on one
of the new azaphospholes obtained showed promising
results.
Str u ctu r a l Ch a r a cter iza tion . Compounds 7a -10a
have been characterized previously.21 The new deriva-
tives 14-16 were isolated by column chromatography
and identified through their NMR data.30 As a rule,
protonation of intermediate species I at the R or γ
position to the phosphorus can be easily established by
1
inspection of the H, 1H{31P}, and 13C NMR spectra. 1,4-
Cyclohexadiene derivatives were characterized by the
signal of the Câ-H to the phosphorus. This proton is
deshielded due to the conjugation of the carbon-carbon
double bond with the PO linkage and appeared as a
multiplet at δ > 6.6 ppm showing a large coupling with
the phosphorus, 3J PH> 16 Hz. The olefinic protons of the
1,3-cyclohexadiene moiety absorbed at δ < 6.5 ppm and
2. Resu lts a n d Discu ssion
1
the 13C spectra showed a doublet of J PC> 75 Hz for the
The phosphinamides 6 were prepared by two methods.
For 6a ,b, the appropriated commercial amine was added
to a toluene solution of chlorodiphenylphosphine and
triethylamine (4 equiv) and the mixture was stirred for
30 min. In situ oxidation with H2O2 afforded 6a ,b in 90%
yield (Scheme 2).26 The synthesis of 6c was carried out
through in situ benzylation of N-(tert-butyl)diphenylphos-
phinamide 13,27 previously obtained following the same
procedure used for the preparation of 6a ,b, by treatment
with sodium hydride and subsequent addition of benzyl
bromide (Scheme 2).28
methine carbon linked to the phosphorus (δ < 45 ppm),
a
31P,13C coupling remarkably large for a sp3 carbon. On
the other hand, compared to 7a and 9a , the inversion of
the configuration of the methine carbon linked to the
nitrogen of 15 and 16 was accompanied by the appear-
3
ance of a J PH in the proton spectrum. The trans junction
of the bicyclic system of 14 and 15 was identified by the
large vicinal coupling between the bridgehead protons,
3J HH
> 20 Hz.31 In all cases, the configurations
trans
assigned were confirmed through the respective NOESY
spectra.
The standard conditions for the dearomatization reac-
tion consisted of the metalation of 6 with 2.5 equiv of
s-BuLi at -90 °C during 30 min in the presence of HMPA
(6 equiv).29 The protonation was carried out also at -90
°C by addition to the reaction mixture of a solution of
the reagent in THF via cannula. After stirring for 30 min,
the reactions were processed through conventional aque-
ous workup. First, the reaction with 6a was used as
reference to identify the quenching reagent giving the
best regio- and diastereoselectivity ratios. Then, these
reagents were applied to the remaining phosphinamides
to analyze the effect of the substitution at the nitrogen.
The acids A1-A8 used for the protonation reaction are
represented above. The reaction time with A8 was
increased to 12 h, due to its insolubility under the con-
ditions essayed. They were selected on the basis of two
criteria: (i) a broad range of pKa values should be covered
(∆pKa ) ∼25), and (ii) they should reveal possible steric
(29) For related intramolecular dearomatization of activated ben-
zenes see: (a) Hauser, C. R.; Eenam, D. N. V. J . Am. Chem. Soc. 1957,
79, 5512. (b) Hayashi, Y.; Oda, R. Tetrahedron Lett. 1968, 5381. (c)
Negishi, E.; Merrill, R. E. J . Chem. Soc., Chem. Commun. 1974, 860.
(d) Shirai, N.; Sumiya, F.; Sato, Y.; Hori, M. J . Org. Chem. 1989, 54,
836. (e) Bolton, R. E.; Moody, C. J .; Rees, C. W. J . Chem. Soc. Perkin
Trans. 1 1989, 2136. (f) Crandall, J . K.; Ayers, T. A. J . Org. Chem.
1992, 57, 2993. (g) Padwa, A.; Filipkowski, M. A.; Kline, D. N.;
Murphree, S.; Yeske, P. E. J . Org. Chem. 1993, 58, 2061. (h) Citterio,
A.; Sebastiano, R.; Maronati, R. S.; Bergamini, F. J . Chem. Soc., Perkin
Trans 1 1994, 1517. (i) Brown, D. W.; Lindquist, M.; Mahon, M. F.;
Malm, B.; Nilsson, G. N.; Ninan, A.; Sainsbury, M.; Westerlund, C. J .
Chem. Soc., Perkin Trans. 1 1997, 2337. (j) Berger, R.; Ziller, J . W.;
van Vranken, D. L. J . Am. Chem. Soc. 1998, 120, 841. (k) Aggarwal,
V. K.; Ferrara, M. Org. Lett. 2000, 2, 4107. (l) Clayden, J .; Menet, C.
J .; Mansfield, D. J . Org. Lett. 2000, 2, 4229 and references therein.
(m) Clayden, J .; Tchabanenko, K.; Yasin, S. A.; Turnbell, M. D. Synlett
2001, 302.
(30) The structural assignment was based on the analysis of the
1D (1H, 13C, 31P, DEPT, selective TOCSY) and 2D (gHMQC, gHMBC
and gNOESY) spectra. Key correlations observed in the (a) HMBC and
(b) NOESY spectrum of 14a are shown below. The HMBC spectrum
afforded the connectivity of the molecule, while the configuration was
obtained from the NOESY spectrum.
(25) Chebib, M.; J ohnston, G. A. R. Clin. Exp. Pharmacol. Physiol.
1999, 26, 937.
(26) This is a slight modification of the method described for the
synthesis of 6b by Edmunson, R. S.; Moran, T. A. J . Chem. Soc. 1970,
1009.
(27) (a) Smith, N. L.; Sisler, H. H. J . Org. Chem. 1961, 26, 5145. (b)
Modro, T. A.; Lawry, M. A.; Murphy, E. J . Org. Chem. 1978, 43, 5000.
(28) An analogous method has been described for the preparation
of 5a , Coulton, S.; Moore, G. A.; Ramaje, R. Tetrahedron Lett. 1976,
4005.
(31) Measured in the 1H{31P} spectrum from the proton R to the
phosphorus atom, which appears at δ 3.0 ppm.

Synthesis of γ-(N-Alkylamino)phosphinic Acids
J . Org. Chem., Vol. 67, No. 11, 2002 3855
Sch em e 3a
a
Conditions: (i) BusLi (1.5 equiv), THF -90 °C, HMPA (6 equiv), 30 min. (ii) A1-A8, -90 °C, THF, 30 min (for A8, 12 h).
Ta ble 1. Distr ibu tion of Dea r om a tized P r od u cts (in %)
us to obtain the azaphosphole 14a in reasonable yield
(42%, entry 7). Considering that the protonation reaction
is irreversible, the products obtained would correspond
to a kinetically controlled reaction. From the data col-
lected in Table 1, one can conclude that the acids A1,
A6, and A8 are the best choice for the synthesis of the
azaphospholes 7a , 9a , and 14a , respectively, in the
anionic dearomatization of 6a . Therefore, these acids
were used as protonating reagents in the analogous
reaction with phosphinamides 6b,c. The results obtained
are shown in Table 2, including those of 6a for compari-
son. A glimpse of the performance of the protonation with
A1 and A6 can be obtained from Figures 1 and 2,
respectively. A graphical representation of the reactions
with A8 is given in Figure S1 (Supporting Information).
Der ived fr om 6a a n d A1-A8 Acid s
acid
7a
8a
9a
10a
14a
% yield
A1
A2
A3
A4
A5
A6
A7
A8
72
53
40
24
40
5
2
20
25
56
70
56
>97
49
3
3
4
90
83
74
82
77
>97
89
84
3
3
4
16
16
3
8
32
50
24
2
Additionally, crystals of 9a suitable for X-ray analysis
were grown by recrystallization from hexane/dichlo-
romethane.32 The molecular structure is shown in Figure
S4 (see Supporting Information) and confirms the as-
signment of the configuration of the stereogenic centers
of the molecule made from the NMR data.
The reactions of dibenzylphosphinamide 6b followed
the same trends outlined for 6a , although with improved
regio- and stereoselectivity: protonation ꢀ to the phos-
phorus did not occur and the 1,3-cyclohexadiene deriva-
tives 8b and 14b were not observed. Yields were slightly
lower due to the formation of a second33 byproduct 17 in
less than 10%.34,35 Under standard conditions, i.e., an
excess of base and HMPA, an additional decrease of the
reaction yield was caused by the formation of 19 and 20
(Table S1, Supporting Information). These products were
derived from the metalation of the benzyl substituent of
7b and 9b and subsequent addition of the new anions to
the N-methylmethyleneimine 18 arising from the depro-
tonation of the HMPA (Scheme 4).36
P r oton a tion Stu d ies. The distribution of products for
a given combination of phosphinamide 5a and quenching
reagent is collected in Table 1.33 Methanol showed the
lowest regioselectivity of all alcohols assayed, affording
a reaction mixture composed by the regioisomers corre-
sponding to the protonation in all possible positions
derived from the delocalization of the negative charge.
However, protonation at the R position to the phosphorus
was the preferred site. In fact, methanol proved to be the
best acid for obtaining 7a in good yield. As shown by the
series of alcohols A1-A3 and A4-A6, the increase of the
size of the carrier of the OH favored the formation of the
nonconjugated cyclohexadiene compound 9a through
γ-attack to the phosphorus (entries 1-6). Even though,
the ratio 9a :7a do not increase linearly with increasing
hindrance around the OH group (see entries 3-5). The
reaction with 2,6-di-tert-butyl-4-methylphenol A6 is re-
ally outstanding, because 9a containing three stereogenic
centers was obtained quantitatively with total regio- and
stereoselectivity.
In the protonation reactions with phenol (A4) and
2-tert-butyl-4-methylphenol (A5), a new product, 14a ,
was formed, although in very low yield. Interestingly, the
yield of 14a increased notably when stronger organic
acids were used as quenching reagents. Thus, trifluoro-
acetic acid (A7) gave a mixture of 7a :8a :9a :14a in a ratio
16:3:49:32 in 89% total yield (entry 6), i.e., 28% of 14a ,
and this compound was the major component of the
reaction with p-toluensulfonic acid (A8), which allowed
(33) In all assays small amounts (<7%) of Ph2P(O)Bus, formed by
nucleophilic attack of the base to the starting phosphinamide, were
observed.
(34) The byproduct 17 was isolated and identified as Ph2P(O)NHCH-
(Ph)CH2Ph. Formation of 17 may be explained through
a [1, 2]
rearrangement of the benzylic anion generated in the metalation of
6b, a process competing with the dearomatization reaction: (a) Eisch,
J . J .; Dua, S. K.; Kovacs, C. A. J . Org. Chem. 1987, 52, 4437. (b) Broka,
C. A.; Shen, T. J . Am. Chem. Soc. 1989, 111, 2981. (c) Coldham, I. J .
Chem. Soc., Perkin Trans. 1 1993, 1275. (d) Gawley, R. E.; Zhang, Q.;
Campagna, S. J . Am. Chem. Soc. 1995, 117, 11817. The participation
of an imine intermediate through
a â-elimination process of the
benzylic anion is not probable because the diphenylphosphinoyl
moiety would be more prone to the elimination than the benzyl group,
see ref 23.
(32) Crystallographic data (excluding structure factors) for the
structure in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication numbers
CCDC 172030. Copies of the data can be obtained free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1 EZ, UK [Fax:
+44(0)-1223-336033. E-mail: deposit@ccdc.cam.ac.uk].
(35) Savignac, P.; Leroux, Y. J . Organomet. Chem. 1973, 57, C47.

3856 J . Org. Chem., Vol. 67, No. 11, 2002
Ta ble 2. P r od u ct Distr ibu tion in th e Dea r om a tiza tion -P r oton a tion Rea ction s of 6a -ca
Ferna´ndez et al.
acid
7a
7b
7c
9a
20c
>97 (97)
9b
9c
14a
14b
14c
16a
16b
16c
A1
A6
72 (90)
62 (80)b
46 (62)
22
19
27d
21
>97 (97)b
79 (77)
88 (78)b
23
12
A8
16 (84)
18 (79)b
28 (74)
24f
82
50
29
16e
Numbers in parentheses indicate reaction total yields. Using DMPU as cosolvent. c Also obtained 8 (5%) and 10 (3%). A 7% of 15
a
b
d
was also formed. e A 4% of 15 was also formed. f A 8% of 8 was also formed. a : R) Me; b: R) Bn; c: R) tBu.
Sch em e 4
F igu r e 1. Distribution of products for the protonation with
methanol. Data correspond to the use of DMPU as cosolvent
for R ) PhCH2.
obtaining 14b; the crude reaction was composed exclu-
sively of a mixture of 7b:9b in a ratio 18:82.
In the series of phosphorus compounds studied, phos-
phinamide 6c has the bulkiest substituent linked to the
nitrogen. A positive consequence of this bulkiness was
prevention of the attack of the base to the PO linkage,
avoiding the formation of phosphine oxide byproducts.33
Similar to 6b, neither compound 8c nor compound 10c
was formed. With regard to 6a , the large size of the But
produced a decrease in both the stereoselectivity of the
process and the reaction yield. Doubling the time of the
metalation step modifies neither the yield nor the dis-
tribution of products appreciably. The general trends
previously mentioned for 6a were maintained: azaphos-
pholes 7c, 9c, and 14c were preferentially formed by
quenching with acids A1, A6, and A8, respectively, even
though 7c was obtained in low yield (29%) and 14c was
a component of a mixture of five compounds 7c:9c:14c:
15c:16c (ratio, 28:23:29:4:16). The stereoselectivity of the
reaction with A6 was much higher, affording a mixture
of 9c:16c in a ratio 79:21 that increased to 88:12 when
DMPU was used as cosolvent. The change in the cosol-
vent did not affect the reaction yield.
F igu r e 2. Distribution of products for the protonation with
2,4-di-tert-butyl-4-methylphenol. Data correspond to the use
of DMPU as cosolvent for R ) PhCH2 and t-Bu.
It is worth mentioning that in all cases significant
amounts of a new stereoisomer of the 1,4-cyclohexadiene
series, 16c, were present. This compound is an epimer
of 9c in the carbon linked to the nitrogen. It can be
assumed that the stereocontrol of that position will be
sensitive to steric hindrance derived from the bulkiness
of the N-R group of the phosphinamide. Accordingly, the
largest effect was observed for R ) But. The fact that the
yield of 16c tends to increase in the series Me , PhCH2
< But indicates that the transition state energy differ-
ences of the dearomatizing steps leading to lithiated 9
and 16 decrease along that series. Another consequence
of increasing the size of R is the increase of the ratio 9:7,
i.e., protonation γ vs R to the phosphorus, which also
follows the series Me < PhCH2 < But. In principle, these
Fortunately, this side reaction was completely sup-
pressed by using DMPU instead of HMPA as cosolvent.
As expected, methanol was the best proton source for
obtaining 7b. The ratio 7b:9b was lower than that of the
N-methyl series, although 7b could be still isolated in
fairly good yield (50%). The protonation with phenol A6
was again exceptionally efficient, affording compound 9b
with total regio- and stereocontrol in quantitative yield;
i.e., no rearranged byproduct was formed. On the con-
trary, p-toluenesulfonic acid (A8) proved to be useless for
(36) Similar transformations of HMPA under strong basic conditions
have been previously reported: (b) Abatjoglou, A. G.; Eliel, E. L. J .
Org. Chem. 1974, 39, 3042. (c) Magnus, P.; Roy, G. Synthesis 1980,
575.

Synthesis of γ-(N-Alkylamino)phosphinic Acids
J . Org. Chem., Vol. 67, No. 11, 2002 3857
Sch em e 5
the anionic dearomatized cycloadducts of N-alkyl-N-
benzyldiphenylphosphinamides. Kinetic acidity and steric
interactions are the two major factors controlling the
outcome of the process. Protonation R to the phosphorus
occurs preferably with methanol, affording azaphospholes
fused to a 1,3-cyclohexadiene system in isolated yields
ranging 29% to 65%. 2,6-Di-tert-butyl-4-methylphenol is
the acid of choice for protonation at the γ position to the
phosphorus, giving rise to 1,4-cyclohexadiene derivatives
with excellent regio- and stereoselectivities and yields.
For 6b,c, the best results were obtained when DMPU was
used as cosolvent, instead of HMPA. On the other hand,
a moderate yield of 14a could be obtained when p-tol-
uensulfonic acid was used as quenching reagent in the
anionic cyclization of phosphinamide 6a . It is interesting
to mention that azaphosphole 9b showed promising
growth cell inhibition (factors higher than 50%, concen-
tration of 1.1 × 10-4 M) against three human tumor cell
lines (lung, breast, central nervous system).38 The het-
erocycles were easily hydrolyzed by treatment with dilute
acid.
Ta ble 3.
21a
δ
31P (p p m ) of Com p ou n d s 21 a n d 22
acid
21b
21c
22a
22b
22c
δ
28
26.4
24.6
34
29.4
28.7
purely steric effects cannot be assigned to possible
interactions between the R group and the incoming acid,
because they are each too far away from the protonation
sites (see Figure S4). A reasonable explanation would be
to assume that the approach of the quenching reagent
to an intermediate I (Scheme 1) is directed by coordina-
tion to the lithium cation, which is also coordinated to
the PO group of the molecule.37 The increase in the
bulkiness of R would force the phenyl ring bonded to the
phosphorus to move away from R to alleviate steric
repulsions. This conformational change would increase
the PO‚‚‚Li distance in the contact ion pair I, thus eroding
the directing power of the PO linkage and, as a conse-
quence, favoring the protonation at the γ site.
To show the utility of the present methodology for the
synthesis of γ-aminophosphinic acids, the dearomatized
compounds 7 and 9 were treated with 2 N HCl in acetone.
As anticipated, the hydrolysis of the P-N bond was
almost instantaneous. The corresponding γ-(N-alkylami-
no)phosphinic acids 21 and 22 were obtained in quantita-
tive yields without affecting the cyclohexadiene system
(Scheme 5, Table 3).
The overall synthetic sequence represents an efficient
methodology for the preparation of γ-(N-alkylamino)-
phosphinic acid containing a 1,3- or 1,4-cyclohexadiene
substructure using very simple reagents. This moiety can
be envisioned as an element of conformational constraint
and further functionalization, two important character-
istic for their application in peptidomimetic chemistry.39
Further work in this field is in progress.
Exp er im en ta l Section 40
X-r a y. A colorless crystal approximately 0.30 × 0.23 × 0.13
mm was used for the measurements at 293(2) K. The unit-
cell dimensions were determined from the angular settings of
25 reflections in the range 15 e θ e 18°. The space group was
inferred to be P21/n from systematic absences. Unit-cell data:
a ) 9.637(3) Å, b ) 15.372(5) Å, c )11.719(2) Å, â ) 101.85-
(4)°, V ) 1699.0(8)(7) Å3, Z ) 4, Dx ) 1.256 Mg/m3, λ )
0.071073 Å, µ ) 0.166 mm-1, F(000) ) 680.
The intensities of 3541 reflections in the range 0°-26° and
in the range -11 e h e 0, -18e k e 0, -14 e l e 14 were
measured using the ω 2θ scan technique with a scan angle
of 1.5° and a variable scan rate with a maximum scan time of
60 s per reflection. Mo KR radiation was used with a graphite-
1
The H NMR spectra revealed the leakage of the P-N
bond through the loss of the phosphorus coupling with
the protons and/or carbons of the R substituent. The
presence of one amino functional group and one acid
produced a broadening of all signals of the spectrum.
Interestingly, the increase of the size of the N-alkyl
substituent produced an upfield shift of δ 31P of the
aminophosphinic acids. Considering the four-bond sepa-
ration of the NHR moiety of 21 and 22 from the
phosphorus atom, the effect of the N-substituent on the
31P chemical shift suggest that 21 and 22 are stabilized
in the form of zwitterions with a close contact between
the polar phosphinate and ammonium groups. For amino
acids 21, the small vicinal coupling between the protons
linked to the sp3 carbons of the cyclohexadiene moiety
and the correlations observed in the NOESY spectra
indicated that no epimerization at the CR to the phos-
phorus occurred during the hydrolysis step.
crystal monochromator on
a Nonius CAD4 single-crystal
diffractometer. The intensity of the primary beam was checked
throughout the collection by monitoring three standard reflec-
tions every 60 min. On all reflections, profile analysis was
performed,41 and 2279 were observed with I > 2σ(Ι). Lorentz
and polarization corrections were applied.
The structure was solved by direct methods using
SHELXS97.42 An empirical absorption correction was applied
at this stage, using XABS2.43 The relative maximum and
minimum transmission factors were 0.953 and 0.975, respec-
tively. The H-atoms were geometrically placed and refined,
(38) Assays for potential chemotherapeutic agents were carried out
at the National Cancer Institute, Bethesda, MD.
(39) (a) Verbruggen, C.; De Craecker, S.; Rajan, P.; J iao, X.-Y.; Boloo,
M.; Smith, K.; Fairlamb, A. H.; Haemers, A. Bioorg. Med. Chem. Lett.
1996, 6, 253. (b) Schiodt, C. B.; Buchardt, J .; Terp, G. E.; Christensen,
U.; Brink, M.; Larsen, Y. B.; Meldal, M.; Foged, N. T. Curr. Med. Chem.
2001, 8, 967. (c) Woll, M. G.; Lai, J . R.; Guzei, I. A.; Taylor, S. J . C.;
Smith, M. E. B.; Gellman, S. H. J . Am. Chem. Soc. 2001, 123, 11077.
(40) For general experimentals, see the Supporting Information in
ref 21.
(41) (a) Grant, D. F.; Gabe, E. J . J . Appl. Crystallogr. 1978, 11, 114.
(b) Lehman, M. S.; Larsen, F. K. Acta Crystallogr. A 1974, 30, 580.
(42) Sheldrick, G. M. SHELXS-97, Program for the Solution of
Crystal Structures; University of Go¨ttingen: Germany, 1997.
(43) Parkin, S.; Moezzi, B.; Hope, H. J . Appl. Crystallogr. 1995, 28,
53. (b) Nardelli, M. Comput. Chem. 1983, 7, 95.
Con clu sion s. Optimized conditions have been found
for the regio- and stereoselective protonation reaction of
(37) (a) Reich, H. J .; Barst, J . P.; Dykstra, R. R.; Green, D. P. J .
Am. Chem. Soc. 1993, 115, 8728. (b) Mohrig, J . R.; Lee, P. K.; Stein,
K. A.; Mitton, M. J .; Rosenberg, R. E. J . Org. Chem. 1995, 60, 3529.
(c) Yadav, V. K.; J eyaraj, D. A. J . Org. Chem. 1998, 63, 3474.

3858 J . Org. Chem., Vol. 67, No. 11, 2002
Ferna´ndez et al.
riding with common isotropic thermal parameters. During the
final stages of the refinements, all positional parameters and
the anisotropic temperature factors of all the non-H atoms
were refined using SHELXL97.44 The final agreement factors
are R ) 0.056 and wR ) 0.162, S ) 1.006 for the 2279
“observed” reflections and 212 variables. The function mini-
sponding proton source (3.12 × 10-3 mol). The reaction mixture
was stirred at -90 °C for 30 min, except for p-toluenesulfonic
acid, where the time increased to 12 h due to insolubility
problems. Then the reaction mixture was poured into ice water
and extracted with ethyl acetate (3 × 15 mL). The organic
layers were dried over Na2SO4 and concentrated in vacuo. 1H,
1H{31P}, and 31P NMR spectra of the crude reaction were
measured in order to determine the stereoselectivity of the
process. The reaction mixture was then purified by flash
column chromatography using different mixtures of ethyl
acetate:hexane as eluent.
mized was ([∑wFo - Fc2)/∑w(Fo2)]1/2,where w ) 1/[σ2(Fo2) +
2
(0.1363P)2] with σ(Fo2) from counting statistics and P ) (Max-
(Fo2,0) + 2Fc2)/3. The maximum shift-to-error ratio in the final
full-matrix least-squares cycle was 0.000, while the highest
and lowest peaks in the final difference Fourier calculated were
0.43 and -0.52 e Å-3.
Atomic scattering factors were taken from International
Tables for X-ray Crystallography.45 Plots were made with the
EUCLID package.46 Geometrical calculations were made with
PARST.47 All calculations were made at the Scientific Com-
puter Centre of the University of Oviedo and on the X-ray
group DEC/AXP- computers.
The same procedure was applied when the reaction was
carried out in the presence of DMPU (3.72 × 10-3 mol) as
cosolvent. Azaphospholes 7a -10a have been characterized
previously.21
(2SP R P ,3RS,8RS,9SR)-2,3,4,9-Tet r a h yd r o-N-b en zyl-3-
p h en ylben zo[c]-1-a za -2λ5-p h osp h ole 2-oxid e (7b): yield
after chromatography (ethyl acetate) 52% (0.104 g, protonation
1
with A1); mp 135-137 °C; H NMR δ 3.01 (m, 1H, J PH 3.7, J
Gen er a l P r oced u r e for th e P r ep a r a tion of P h osp h i-
n a m id es 6a ,b. To a solution of chlorodiphenylphosphine (2.69
mL, 15.03 mmol) and triethylamine (5.21 mL, 37.6 mmol) in
toluene (100 mL) at -30 °C was added the appropiate amine
(2.00 mL). The mixture was stirred during 4 h and then 30%
v/v H2O2 (1.7 mL, 15.03 mmol) was added. Once the oxidation
was completed (1 h), the reaction was poured into ice water
and extracted with ethyl acetate (3 × 15 mL) and washed with
1 N NaOH (2 × 15 mL). The organic layers were dried over
Na2SO4 and concentrated in vacuo, affording 6a ,b as white
solids. The purity of the phosphinamides was higher than 97%
(NMR), and the compounds were used without further puri-
fication in the next synthetic steps. Alternatively, they can be
precipitated from Et2O. Phosphinamides 6a and 6b have been
previously described: 6a , mp 82-83 °C, lit.28 mp 82-83 °C;
6b, mp 125-126 °C, lit.26 mp 126-127 °C.26
N-Ben zyl-N-ter t-bu tyld ip h en ylp h osp h in a m id e (6c). To
a solution of chlorodiphenylphosphine (3.6 mL, 19.03 mmol)
and triethylamine (6.6 mL, 47.57 mmol) in toluene (100 mL)
at -30 °C was added the appropiate amine (2.00 mL). The
mixture was stirred during 4 h and then 30% v/v H2O2 (2.2
mL, 19.03 mmol) was added. Once the oxidation was completed
(1 h), the reaction was poured into ice water and extracted
with ethyl acetate (3 × 15 mL) and washed with 1 N NaOH
(2 × 15 mL). The organic layers were dried over Na2SO4 and
concentrated in vacuo, affording 13 as a white solid (yield 97%).
Then, 13 (5.0 g, 18.31 mmol) was treated at room temperature
with HNa (1.3 g, 36.62 mmol) in THF during 30 min, and then
benzyl bromide (2.2 mL, 18.31 mmol) was added at the same
temperature (1 h), affording, after an identical workup as done
before, 6c as a white solid. The purity of the phosphinamide
was higher than 97% (NMR) and the compound was used
without further purification in the next synthetic steps.
Alternatively, it can be precipitated from Et2O:
9.9, J 10.6 Hz), 3.21 (m, 1H, J PH 11.9, J 10.6 Hz), 3.69 (dd,
1H, J PH 12.6, J 14.7 Hz), 4.14 (d, 1H, J 9.2 Hz), 4.30 (dd, 1H,
J PH 8.9, J 14.7 Hz), 5.41 (m, 1H, J 9.5, J 5.5, J 0.8 Hz), 5.99
(dd, 1H, J 9.5, J 5.1 Hz), 6.19-6.07 (m, 2H), 7.56-7.13 (m,
13H, ArH), 7.97 (m, 2H, ArH); 13C NMR δ 37.62 (d, CH, J PC
84.7 Hz), 43.01 (CH), 45.94 (d, CH, J PC 3.0 Hz), 66.84 (d, CH,
J PC 21.6 Hz), 119.44 (d, HCd, J PC 8.4 Hz), 123.65 (d, HCd,
J PC 11.4 Hz), 124.57 (d, HCd, J PC 3.0 Hz), 124.73 (d, HCd,
J
PC 10.2 Hz), 131.75-126.99 (12CAr), 131.57 (d, CAr, J PC 10.2
Hz), 131.74 (d, CAr, J PC 2.4 Hz), 134.17 (d, Cipso, J PC 126.2 Hz),
136.18 (Cipso), 139.30 (d, Cipso, J PC 9.0 Hz); 31P NMR δ 50.38;
MS (API-ES) m/e 398 (M + 1, 100), 230 (12), 196 (20), 91 (10).
Anal. Calcd (%) for C26H24NOP: C, 78.57; H, 6.08; N, 3.52.
Found: C, 78.51; H, 6.12; N, 3.32.
(2SP RP ,3RS,8RS,9SR)-2,3,4,9-Tetr a h yd r o-N-ter t-bu tyl-
3-p h en ylben zo[c]-1-a za -2λ5-p h osp h ole 2-oxid e (7c): yield
after chromatography (ethyl acetate:hexane 1:1) 28% (0.056
g, protonation with A1); identified from a mixture 7a :7c (66:
1
34); mp 135-136 °C. H NMR δ 1.21 (s, 9H), 3.02 (dddd, 1H,
J PH 11.6, J 10.3, J 4.8, J 1.8 Hz), 3.19 (m, 1H, J PH 24.4 Hz),
4.74 (dd, 1H, J PH 4.1, J 4.8 Hz), 5.61 (dd, 1H, J 9.5, J 4.0 Hz),
5.75 (m, 1H), 6.03 (dd, 1H, J 10.3, J 5.5 Hz), 6.12 (m, 1H),
7.77-7.01 (m, 8H, ArH), 8.02 (m, 2H, ArH); 13C NMR δ 30.46
(d, CH3, J PC 3.0 Hz), 37.61 (d, CH, J PC 78.7 Hz), 44.24 (d, CH,
J PC 1.2 Hz), 57.01 (C), 68.05 (d, CH, J PC 20.4 Hz), 119.54 (d,
HCd, J PC 8.4 Hz), 125.62 (d, HCd, J PC 4.8 Hz), 125.88 (d, HCd
, J PC 10.2 Hz), 126.54 (d, HCd, J PC 5.4 Hz), 132.45-125.98
(10CAr), 134.85 (d, Cipso, J PC 126.8 Hz), 145.60 (d, Cipso, J PC
6.6 Hz); 31P NMR δ 47.79; MS (API-ES) m/e 365 (M + 2, 75),
364 (M + 1, 100). Anal. Calcd (%) for C23H26NOP: C, 76.01;
H, 7.21; N, 3.85. Found: C, 76.11; H, 7.22; N, 3.62.
(2SP RP ,8RS,9SR)-2,3,4,7-Tetr a h yd r o-N-ben zyl-3-p h en -
ylben zo[c]-1-a za -2λ5-p h osp h ole 2-oxid e (9b): yield after
chromatography (ethyl acetate) 94% (0.188 g, protonation with
yield 90-95%; mp 151-153 °C; 1H NMR δ 1.40 (s, 9H), 4.30
(d, CH2, J PH 15.4 Hz), 7.39-7.10 (m, 6H, ArH), 7.76 (m, 4H,
ArH);13C NMR δ 30.87 (d, CH3, J PC 3.3 Hz), 49.62 (d, CH2, J PC
4.5 Hz), 58.65 (d, C, J PC 1.2 Hz), 126.16-130.95 (6CAr), 132.08
(d, CAr, J PC 9.5 Hz), 134.85 (d, Cipso, J PC 126.5 Hz), 141.35 (d,
1
A5); mp 172-175 °C; H NMR δ 2.77 (m, 1H, J 23.1, J 5.1, J
2.6 Hz), 2.92 (m, 1H, J 23.1 Hz), 3.30 (m, 1H), 3.65 (dd, 1H,
J PH 13.9, J 14.7 Hz), 3.95 (d, 1H, J 9.5 Hz), 4.29 (dd, 1H, J PH
8.8, J 14.7 Hz), 5.51 (m, 1H, J 9.9 Hz), 5.73 (m, 1H, J 9.9 Hz,
J 1.5 Hz), 6.78 (d, 1H, J PH 16.9 Hz), 7.57-7.13 (m, 13H, ArH),
8.01 (m, 2H, ArH);13C NMR δ 27.67 (d, CH2, J PC 12.8 Hz), 45.95
(d, CH2, J PC 3.1 Hz), 46.38 (d, CH, J PC 13.9 Hz), 66.18 (d, CH,
J PC 12.6 Hz), 122.78 (d, HCd, J PC 6.4 Hz), 125.02 (d, HCd,
J PC 1.7 Hz), 131.80-127.94 (15CAr), 132.79 (d, Cd, J PC 121.8
Hz), 133.87 (d, Cipso, J PC 133.6 Hz), 135.63 (d, HCd, J PC 9.7
Hz), 136.12 (Cipso), 138.51 (d, Cipso, J PC 8.3 Hz); 31P NMR δ
29.76; MS (API-ES) m/e 398 (M + 1, 100), 91 (6). Anal. Calcd
(%) for C26H24NOP: C, 78.57; H, 6.08; N, 3.52. Found: C, 78.71;
H, 6.10; N, 3.42.
C
ipso, J PC 1.7 Hz); 31P NMR δ 32.14; MS (API-ES) m/e 364 (M
+ 1, 100), 308 (10). Anal. Calcd (%) for C23H26NOP: C, 76.01;
H, 7.21; N, 3.85. Found: C, 76.06; H, 7.12; N, 3.82.
Gen er a l P r oced u r e for th e P r ep a r a tion of Tetr a h y-
d r oben zo[c]-1-a za -2λ5-p h osp h oles. To a solution of the
appropriate phosphinamide (6.23 × 10-4 mol) and HMPA (3.72
× 10-3 mol) in THF (30 mL) was added a solution of s-BuLi
(1.2 mL of a 1.3 M solution in cyclohexane, 1.56 × 10-3 mol)
at -90 °C. After 30 min of metalation was added the corre-
(2SP RP ,8RS,9SR)-2,3,4,7-Tetr ah ydr o-N-ter t-bu tyl-3-ph en -
ylben zo[c]-1-a za -2λ5-p h osp h ole 2-oxid e (9c): yield after
chromatography (ethyl acetate:hexane 1:1) 69% (0.137 g,
protonation with A5); oil; 1H NMR δ 1.17 (s, 9H), 2.71 (ddddd,
1H, J PH 4.8, J 22.7, J 12.5, J 4.8, J 2.6 Hz), 2.88 (m, 1H), 3.22
(m, 1H), 4.33 (d, 1H, J 9.6 Hz), 5.45 (m, 1H, J 9.6 Hz), 5.74
(m, 1H), 6.63 (m, 1H, J PH 16.2 Hz), 7.61-7.19 (m, 8H, ArH),
8.08 (m, 2H, ArH); 13C NMR δ 27.51 (d, CH2, J PC 12.5 Hz),
(44) Sheldrick, G. M. SHELXL-97, Program for the Refinement of
Crystal Structures; University of Go¨ttingen: Germany, 1997.
(45) International Tables for X-ray Crystallography; Kynoch Press:
Birmingham (Present distributor, Kluwer Academic Publishers: Dor-
drecht), 1974; Vol.IV.
(46) Spek, A. L. In Computational Crystallography; Sayre, D., Ed.;
Clerendon Press: Oxford, 1982; p 528.
(47) Nardelli, M. Comput. Chem. 1983, 7, 95.

Synthesis of γ-(N-Alkylamino)phosphinic Acids
J . Org. Chem., Vol. 67, No. 11, 2002 3859
30.84 (d, CH3, J PC 3.2 Hz), 45.63 (d, CH, J PC 14.8 Hz), 57.14
(d, C, J PC 1.4 Hz), 67.03 (d, CH, J PC 12.0 Hz), 122.47 (d, HCd,
J PC 6.9 Hz), 125.11 (d, HCd, J PC 1.4 Hz), 131.17-126.11 (8
CAr), 131.40 (d, CAr, J PC 10.2 Hz), 133.34 (d, HCd, J PC 9.7
Hz), 133.70 (d, Cd, J PC 120.7 Hz), 137.38 (d, Cipso, J PC 132.7
Hz), 143.91 (d, Cipso, J PC 9.7 Hz); 31P NMR δ 32.17; MS (API-
ES) m/e 364 (M + 1, 43), 363 (M+, 25), 362 (M - 1, 100), 306
(24). Anal. Calcd (%) for C23H26NOP: C, 76.01; H, 7.21; N, 3.85.
Found: C, 76.31; H, 7.19; N, 3.81.
mixture was stirred for 30 min. Then, the pH was set to
neutral by adding 1 N NaOH and the reaction was extracted
with ethyl acetate (3 × 15 mL). The organic layers were dried
over Na2SO4 and concentrated in vacuo, affording a white solid
that was washed with diethyl ether. Aminophosphinic acid 21a
has been characterized previously.21
(1SR,6RS,7SR)-1-[6-(Ben zyla m in o)b en zyl)-2,4-cyclo-
h exa d ien yl]p h en ylp h osp h in ic a cid (21b ): yield 96%
(0.192 g); mp 218-219 °C; 1H NMR δ 2.26 (d, 1H, J 22.8
Hz), 2.47 (dddd, 1H, J PH 2.7, J 22.8, J 7.9 Hz), 3.53 (d, 1H, J
13.9 Hz), 3.54 (m, 1H), 4.33 (d, 1H, J 13.9), 4.38 (m, 1H),
5.22 (m, 1H), 5.55 (dd, 1H, J 9.7, J 4.0 Hz), 5.93 (dd, 1H,
J PH 19.7, J 4.0 Hz), 7.60-7.11 (m, 13H, ArH), 7.97 (m, 2H,
ArH), 12.13 (bs, OH + NH); 13C NMR δ 26.94 (d, CH2, J PC
13.6 Hz), 38.61 (d, CH, J PC 9.1 Hz), 48.21 (CH2), 65.62 (CH),
125.75 (HCd), 127.19 (HC), 130.70-127.74 (13CAr), 131.64
(Cipso), 132.71 (d, CAr, J PC 9.1 Hz), 134.17 (Cipso), 134.92 (d,
(2SP R P ,3SR,8RS,9SR)-2,3,4,9-Tet r a h yd r o-N-m et h yl-3-
p h en ylben zo[c]-1-a za -2λ5-p h osp h ole 2-oxid e (14a ): yield
after chromatography (ethyl acetate:hexane 4:1) 42% (0.084
g, protonation with A8); oil; 1H NMR δ 2.46 (d, 3H, J PH 8.8
Hz), 2.79 (m, 1H), 3.00 (m, 1H), 4.28 (d, 1H, J 9.9 Hz), 5.82
(m, 1H), 6.04-5.88 (m, 3H), 7.61-7.31 (m, 8H, ArH), 8.01 (m,
2H, ArH); 13C NMR δ 28.86 (d, CH3, J PC 2.3 Hz), 42.88 (d, CH,
J PC 92.5 Hz), 46.19 (d, CH, J PC 2.3 Hz), 67.34 (d, CH, J PC 8.3
Hz), 122.51 (HCd), 126.31 (d, HCd, J PC 10.6 Hz), 127.31 (d,
HCd, J PC 6.5 Hz), 127.76 (HCd), 132.36-128.19 (10CAr),
C
ipso, J PC 137.3 Hz), 136.92 (HCd), 138.21 (d, Cd, J PC 128.6
Hz); 31P NMR δ 26.40; MS (API-ES) m/e 417 (M + 2, 30), 416
131.95 (d, Cipso, J PC 125.8 Hz), 138.07 (d, Cipso, J PC 7.9 Hz); 31
NMR δ 43.10; MS (API-ES) m/e 321 (M+, 54), 243 (41), 149
(100), 84 (45), 49 (51), 40 (71). Anal. Calcd (%) for C20H20
P
(M + 1, 100), 309 (15), 241 (10). Anal. Calcd (%) for C26H26-
NO2P: C, 75.16; H, 6.31; N, 3.37. Found: C, 75.15; H, 6.24;
N, 3.33.
-
NOP: C, 74.75; H, 6.27; N, 4.36. Found: C, 74.82; H, 6.31; N,
4.12.
(1SR,6RS,7SR)-1-[6-(t er t -Bu t yla m in o)b en zyl)-2,4-cy-
cloh exa d ien yl]p h en ylp h osp h in ic a cid (21c): yield 97%
(0.194 g); mp 220-221 °C; 1H NMR δ 1.26 (s, 9H), 2.57 (s, 1H),
3.72 (d, 1H, J 9.1 Hz), 4.57 (m, 1H), 5.09 (m, 1H), 5.54 (d, 1H,
J 9.1 Hz), 5.86 (d, 1H, J PH 19.8 Hz), 7.58-6.99 (m, 8H, ArH),
8.00 (m, 2H, ArH), 10.59 (bs, OH), 13.00 (bs, NH); 13C NMR δ
27.04 (CH), 27.26 (CH3), 39.15 (d, CH, J PC 9.3 Hz), 56.65 (C),
65.04 (CH), 125.18 (HCd), 130.11-127.52 (8CAr), 128.56 (d,
HCd, J PC 6.5 Hz), 132.92 (d, CAr, J PC 8.6 Hz), 133.98 (d,
HCd, J PC 12.4 Hz), 136.56 (d, Cipso, J PC 133.3 Hz), 137.90 (Cipso),
141.55 (d, Cd, J PC 122.3 Hz); 31P NMR δ 24.57; MS (API-ES)
m/e 383 (M + 2, 25), 382 (M + 1, 100). Anal. Calcd (%) for
(2SP RP ,3SR,8RS,9SR)-2,3,4,9-Tetr a h yd r o-N-ter t-bu tyl-
3-ph en ylben zo[c]-1-aza-2λ5-ph osph ole 2-oxide (14c): yield
after chromatography (ethyl acetate:hexane 1:1) 21% (0.043
g, protonation with A8); oil; 1H NMR δ 1.21 (9H), 2.66 (m, 1H,
J 21.3, J 10.3 Hz), 2.86 (ddt, 1H, J 21.3, J PH 22.7, J 2.2 Hz),
4.51 (d, 1H, J 9.5 Hz), 5.61 (m, 1H,, J 10.3 Hz), 5.98-5.82 (m,
3H), 7.77-7.04 (m, 8H, ArH), 8.12 (m, 2H, ArH); 13C NMR δ
30.96 (d, CH3, J PC 3.2 Hz), 43.28 (d, CH, J PC 92.5 Hz), 44.88
(d, CH, J PC 3.2 Hz), 57.03 (d, C, J PC 0.9 Hz), 64.77 (d, CH, J PC
8.3 Hz), 122.64 (HCd), 126.06 (d, HCd, J PC 13.8 Hz), 126.26
(d, HCd, J PC 8.8 Hz), 127.53 (d, HCd, J PC 11.6 Hz), 132.93-
C
23H28NO2P: C, 72.42; H, 7.40; N, 3.67. Found: C, 72.32; H,
127.80 (8CAr), 132.24 (d, CAr, J PC 9.7 Hz), 135.08 (d, Cipso
,
7.45; N, 3.67.
J PC 124.8 Hz), 142.90 (d, Cipso, J PC 8.8 Hz); 31P NMR δ 45.15;
MS (API-ES) m/e 363 (M+, 26), 362 (M-1, 100), 308 (22). Anal.
Calcd (%) for C23H26NOP: C, 76.01; H, 7.21; N, 3.85. Found:
C, 76.14; H, 7.17; N, 3.72.
(6RS,7SR)-1-[6-(Meth yla m in o)ben zyl)-1,4-cycloh exa d i-
en yl]p h en ylp h osp h in ic a cid (22a ): yield 97% (0.194 g);
mp 129-130 °C dec; 1H NMR δ 2.39 (s, 3H), 2.53 (m, 2H), 3.63
(d, 1H, J 8.3 Hz), 4.30 (m, 1H, J 8.2, J 4.7 Hz), 5.26 (m, 1H),
5.62 (m, 1H), 6.04 (d, 1H, J PH 19.5 Hz), 7.61-7.16 (m, 8H,
ArH), 7.67 (m, 2H, ArH), 10.88 (bs, OH), 12.78 (bs, NH); 13C
NMR δ 27.02 (d, CH2, J PC 13.2 Hz), 31.28 (CH3), 38.86 (d, CH,
J PC 9.1 Hz), 70.21 (CH), 125.94 (HCd), 126.67 (d, HCd, J PC
(2SP RP ,3SR,8RS,9RS)-2,3,4,9-Tetr a h yd r o-N-ter t-bu tyl-
3-ph en ylben zo[c]-1-aza-2λ5-ph osph ole 2-oxide (15c): yield
after chromatography (ethyl acetate:hexane 1:1) 4% (0.009 g,
1
protonation with A1); oil; H NMR δ 1.16 (9H), 3.24 (m, 1H,
J PH 21.5, J 21.6 Hz), 3.46 (m, 1H), 4.86 (dd, 1H, J PH 16.3, J
6.7 Hz), 5.56 (m, 2H), 5.72 (m, 2H), 7.58-7.04 (m, 8H, ArH),
7.98 (m, 2H, ArH); 13C NMR δ 30.42 (d, CH3, J PC 2.9 Hz), 37.76
(d, CH, J PC 98.4 Hz), 43.97 (d, CH, J PC 4.1 Hz), 55.38 (d, C,
J PC 2.9 Hz), 62.37 (d, CH, J PC 9.5 Hz), 122.99 (HCd), 125.67
(d, HCd, J PC 1.6 Hz), 126.34 (d, HCd, J PC 12.0 Hz), 127.02 (d,
HCd, J PC 1.4 Hz), 132.42-127.57 (8CAr), 132.86 (d, CAr, J PC
9.5 Hz), 134.78 (d, Cipso, J PC 119.3 Hz), 141.47 (Cipso); 31P NMR
δ 40.07; MS (API-ES) m/e 364 (M + 1, 20), 256 (100). Anal.
Calcd (%) for C23H26NOP: C, 76.01; H, 7.21; N, 3.85. Found:
C, 76.00; H, 7.25; N, 3.68.
6.6 Hz), 130.64-127.75 (8CAr), 134.20 (Cipso), 135.31 (d, Cipso,
J PC 136.0 Hz), 136.69 (d, HCd, J PC 11.6 Hz), 138.25 (d, Cd,
J PC 124.5 Hz); 31P NMR δ 28.03. MS (API-ES) m/e 341 (M +
2, 22), 340 (M + 1, 100), 309 (8). Anal. Calcd (%) for C20H22
-
NO2P: C, 70.78; H, 6.53; N, 4.13. Found: C, 70.73; H, 6.46;
N, 4.12.
(6RS,7SR)-1-[6-(Ben zyla m in o)ben zyl)-1,4-cycloh exa d i-
en yl]p h en ylp h osp h in ic a cid (22b): yield 91% (0.182 g); mp
228-229 °C; 1H NMR δ 2.73 (d, 1H, J PH 19.8 Hz), 3.52 (m,
1H), 3.60 (d, 1H, J 13.0 Hz), 3.91 (d, 1H, J 13.0 Hz), 4.17 (d,
1H, J 10.2 Hz), 4.98 (m, 1H, J 15.2, J 6.8 Hz), 5.63 (dd, 1H, J
9.6, J 4.5 Hz), 5.69 (ddd, 1H, J PH 11.9, J 8.8, J 2.8 Hz), 5.88
(m, J 8.8, J 3.9 Hz), 7.56-7.13 (m, 13H, ArH), 7.90 (m, 2H,
ArH), 11.72 (bs, OH), 12.71 (bs, NH); 13C NMR δ 35.13 (CH),
41.45 (d, CH, J PC 95.4 Hz), 48.88 (CH2), 57.63 (CH), 123.85
(HCd), 125.03 (HCd), 125.63 (d, HCd, J PC 11.1 Hz), 129.47-
127.65 (13CAr), 128.82 (d, HCd, J PC 12.5 Hz), 132.22 (Cipso),
132.28 (d, CAr, J PC 8.7 Hz), 135.32 (Cipso), 136.13 (d, Cipso, J PC
127.3 Hz); 31P NMR δ 29.38; MS (API-ES) m/e 417 (M + 2,
(2SP RP ,8RS,9RS)-2,3,4,7-Tetr ah ydr o-N-ter t-bu tyl-3-ph en -
ylben zo[c]-1-a za -2λ5-p h osp h ole 2-oxid e (16c): yield after
chromatography (ethyl acetate:hexane 1:1) 17% (0.033 g,
protonation with A1); mp 208-209 °C;1H NMR δ 1.13 (s, 9H),
2.59 (m, 2H), 3.87 (m, 1H), 4.88 (dd, 1H, J PH 7.7, J 18.0 Hz),
5.31 (m, 1H, J 10.3 Hz), 5.43 (m, 1H), 6.58 (m, 1H, J PH 16.1
Hz), 7.56-7.11 (m, 8H, ArH), 7.97 (m, 2H, ArH); 13C NMR δ
26.85 (d, CH2, J PC 12.4 Hz), 30.56 (d, CH3, J PC 2.5 Hz), 42.49
(d, CH, J PC 16.1 Hz), 55.38 (d, C, J PC 2.9 Hz), 64.04 (d, CH,
J PC 12.0 Hz), 123.47 (d, HCd, J PC 6.6 Hz), 124.30 (HCd),
132.19-126.34 (8CAr), 131.57 (d, CAr, J PC 10.8 Hz), 133.03
(d, Cd, J PC 126.5 Hz), 134.61 (d, HCd, J PC 9.9 Hz), 137.15 (d,
30), 416 (M + 1, 100), 398 (10). Anal. Calcd (%) for C26H26
-
NO2P: C, 75.16; H, 6.31; N, 3.37. Found: C, 75.13; H, 6.39;
N, 3.27.
(6RS,7SR)-1-[6-(ter t-Bu tylam in o)ben zyl)-1,4-cycloh exa-
d ien yl]p h en ylp h osp h in ic a cid (22c): yield 94% (0.188 g);
C
ipso, J PC 128.6 Hz), 142.20 (Cipso); 31P NMR δ 26.20. MS (API-
1
ES) m/e 365 (M + 2, 20), 364 (M + 1, 100), 308 (15). Anal.
Calcd (%) for C23H26NOP: C, 76.01; H, 7.21; N, 3.85. Found:
C, 76.08; H, 7.15; N, 3.88.
mp 219-224 °C dec; H NMR δ 1.28 (s, 9H), 3.62 (ddd, 1H,
J PH 23.9, J 7.5, J 6.4 Hz), 3.84 (ddd, 1H, J PH 34.4, J 11.5, J
7.5 Hz), 4.47 (t, 1H, J 10.0 Hz), 4.61 (dd, 1H, J 9.5, J 2.5 Hz),
5.28 (m, 1H), 5.93 (m, 1H, J 9.3, J 4.9 Hz), 6.24 (m, 1H), 7.55-
7.28 (m, 8H, ArH), 7.90 (m, 2H, ArH), 10.10 (bs, OH), 11.31
(bs, NH); 13C NMR δ 27.14 (CH3), 40.25 (CH), 41.02 (d, CH,
J PC 82.2 Hz), 58.67 (C), 60.46 (CH), 123.59 (HCd), 124.62 (d,
Gen er a l P r oced u r e for th e P r ep a r a tion of λ-N-Meth -
yla m in op h osp h in ic Acid s 21 a n d 22. To a solution of the
appropriate phosphole (7, 9) (0.45 × 10-3 mol) in acetone (10
mL) was added 2 N HCl (1 mL) at room temperature, and the

3860 J . Org. Chem., Vol. 67, No. 11, 2002
Ferna´ndez et al.
HCd, J PC 4.0 Hz), 125.37 (d, HCd, J PC 10.6 Hz), 125.53 (d,
HCd, J PC 8.1 Hz), 131.30-127.47 (8CAr), 132.29 (d, CAr, J PC
9.5 Hz), 133.23 (d, Cd, J PC 130.2 Hz), 135.44 (Cipso); 31P NMR
δ 28.66; MS (API-ES) m/e 383 (M + 2, 25), 381 (M + 1, 100).
Anal. Calcd (%) for C23H28NO2P: C, 72.42; H, 7.40; N, 3.67.
Found: C, 72.43; H, 7.39; N, 3.63.
daluc´ıa for a doctoral fellowship. We thank NCI for the
biological essays carried out.
Su p p or tin g In for m a tion Ava ila ble: Figure S1, distribu-
tion of products for the protonation with p-toluensulfonic acid;
Figures S2 and S3, 1D gNOESY spectra of 7b and 9b,
respectively; Table S1, distribution of products in the dearo-
matization-protonation reactions of 6b using HMPA as co-
solvent, characterization of 19 and 20, and X-ray data of 9a .
This material is available free of charge via the Internet at
http://pubs.acs.org.
Ack n ow led gm en t. Financial support through Min-
isterio de Ciencia y Tecnolog´ıa (projects PPQ2001-3266
and BQU2000-0219), European Community (FEDER
Project 1FD97-1651), and FICYT (project PR-01-GE-4)
is gratefully acknowledged. I.F. thank J unta de An-
J O025587+