Dearomatizing anionic cyclization of N-alkyl-N-benzyl(dinaphthyl) phosphinamides. A facile route to γ-(amino)dihydronaphthalenylphosphinic acids

Article abstract of DOI:10.1021/jo701607s

(Chemical Equation Presented) The dearomatizing anionic cyclization of N-alkyl-N-benzyldi(n-naphthyl)phosphinamides (n = 1, 2) and subsequent trapping with a series of electrophiles (MeOH, MeI, CF₃SO₃Me, Me₃O⁺BF₄^-, AllylBr, and PhCH ₂Br) have been accomplished. Optimized reaction conditions (base, temperature, reaction time) allow for synthesizing tetrahydro-1H-naphtho[1,2-c] [1,2]-azaphosphole 1-oxides 13 and 18 and tetrahydro1H-naphtho[2,1-c][1,2] azaphosphole 3-oxides 16 and 27-29 in high yield and diastereoselectivity. Appropriate selection of the base proved to be critical for promoting anionic cyclization of 2-naphthyl derivatives. The dearomatized heterocycles are transformed quantitatively into γ-(N-alkylamino)phosphinic acids by acid hydrolysis of the P-N linkage. Bioactivity assays on five human tumor cell lines for one of these amino acids revealed growth inhibition factors (GI ₅₀) at a micromolar scale. Additionally, evidence for the feasibility of intermolecular nucleophilic dearomatization and sequential nucleophilic attack to both aromatic rings of dinaphthylphosphinamides have been obtained.

Full text of DOI:10.1021/jo701607s

Dearomatizing Anionic Cyclization of
N-Alkyl-N-benzyl(dinaphthyl)phosphinamides. A Facile Route to
γ-(Amino)dihydronaphthalenylphosphinic Acids
Gloria Ruiz-Go´mez,† Mar´ıa Jose´ Iglesias,† Manuel Serrano-Ruiz,‡ and
Fernando Lo´pez-Ortiz*,†
AÄ rea de Qu´ımica Orga´nica and AÄ rea de Qu´ımica Inorga´nica, UniVersidad de Almer´ıa, Carretera de
Sacramento, 04120 Almer´ıa, Spain
flortiz@ual.es
ReceiVed August 9, 2007
The dearomatizing anionic cyclization of N-alkyl-N-benzyldi(n-naphthyl)phosphinamides (n ) 1, 2) and
subsequent trapping with a series of electrophiles (MeOH, MeI, CF3SO3Me, Me3O+BF4 , AllylBr, and
-
PhCH2Br) have been accomplished. Optimized reaction conditions (base, temperature, reaction time)
allow for synthesizing tetrahydro-1H-naphtho[1,2-c][1,2]-azaphosphole 1-oxides 13 and 18 and tetrahydro-
1H-naphtho[2,1-c][1,2]azaphosphole 3-oxides 16 and 27-29 in high yield and diastereoselectivity.
Appropriate selection of the base proved to be critical for promoting anionic cyclization of 2-naphthyl
derivatives. The dearomatized heterocycles are transformed quantitatively into γ-(N-alkylamino)phosphinic
acids by acid hydrolysis of the P-N linkage. Bioactivity assays on five human tumor cell lines for one
of these amino acids revealed growth inhibition factors (GI50) at a micromolar scale. Additionally, evidence
for the feasibility of intermolecular nucleophilic dearomatization and sequential nucleophilic attack to
both aromatic rings of dinaphthylphosphinamides have been obtained.
Introduction
constitute an attractive approach for the regio- and stereo-
controlled formation of hydroaromatic compounds incor-
porating different degrees of functionalization.3 The nucleophilic
attack can occur either inter- or intramolecularly, the
latter process being called dearomatizing anionic cyclization
(DAC).2,4 Drozd and co-workers discovered the feasibility
of DAC reactions almost 40 years ago when investigating the
lithiation of aryl mesityl sulfones.5 However, the synthetic scope
of these transformations was rather limited.6 The boost of DAC
methodology as a useful synthetic tool in organic chemistry
started in the late 1990s with the work of Clayden’s group on
tertiary arylcarboxamides.7 The anionic cyclization of N-benzylic
Many natural products and compounds of pharmaceutical
importance consist of a partially saturated carbocyclic or
heterocyclic system which imparts some rigidity to the molecule
and acts as a scaffold to which a variety of functional groups
are connected. This architecture provides the harmonious
combination of conformational preferences and spatial arrange-
ment of substituents appropriated for eliciting a biological
response.1 Nucleophilic dearomatizing reactions (NDAr),2 i.e.,
the conjugate addition of a nucleophile to an aromatic ring,
* Corresponding author. Fax: +34 950 015481. Tel.: +34 950 015478.
† AÄ rea de Qu´ımica Orga´nica.
‡ AÄ rea de Qu´ımica Inorga´nica.
(3) For reviews on NDAr reactions based on complexation of aromatic
π-systems to transition metals, see: (a) Brooks, B. C.; Gunnoe, T. B.;
Harman, W. D. Coord. Chem. ReV. 2000, 206-207, 3. (b) Pape, A. R.;
Kaliappan, K. P.; Ku¨ndig, E. P. Chem. ReV. 2000, 100, 2917. (c) Smith, P.
L.; Chordia, M. D.; Harman, W. D. Tetrahedron 2001, 57, 8203. (d) Keane,
J. M.; Harman, W. D. Organometallics 2005, 24, 1786. For some recent
contributions, see: (e) Pigge, F. C.; Coniglio, J. J.; Dalvi, R. J. Am. Chem.
Soc. 2006, 128, 3498. (f) Pigge, F. C.; Dhanya, R.; Hoefgen, R. E. Angew.
Chem., Int. Ed. 2007, 46, 2887.
(1) (a) Harborne, J. B., Baxter, H., Eds. Phytochemical Dictionary. A
Handbook of BioactiVe Compounds from Plants; Taylor & Francis: London,
1993. (b) Pettit, G. R.; Pierson, F. H.; Herald, C. L. Anticancer Drugs from
Animals, Plants, and Microorganisms; John Wiley: New York, 1994. (c)
Dewick, P. M. Medicinal Natural Products. A Biosynthetic Approach, 2nd
Ed.; John Wiley: Chichester, England, 2001.
(2) Lo´pez-Ortiz, F.; Iglesias, M. J.; Ferna´ndez, I.; Andu´jar-Sa´nchez, C.;
Ruiz-Go´mez, G. Chem. ReV. 2007, 107, 1580.
10.1021/jo701607s CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/03/2007
9704
J. Org. Chem. 2007, 72, 9704-9712

DAC of N-Alkyl-N-benzyl(dinaphthyl)phosphinamides
SCHEME 1a
a Conditions: (i) sBuLi (1.5-2.5 equiv), HMPA or DMPU (6 equiv), THF, -90 °C, 0.5-12 h; for 1d tBuLi, HMPA or DMPU (6 equiv), THF, -90 °C,
1 min to 12 h; (ii) MeOH (5.0 equiv), -90 °C, 0.5 h; (iii) E+ ) DTBMP, RX, or RCHO, -90 °C, 0.5-2 h; (iv) 2 N HCl (aq), Me2CO or 0.6 N HCl (g),
MeOH, rt; (v) tBuLi, THF, -90 °C, 2 h; (vi) E+ ) MeI, PhCHO, Me3SnCl, (nBu)3SnCl, Ph3SnCl.
phenyl and naphthyl carboxamides furnished dihydroaromatic
products containing a pyrrolid-2-one fragment that proved to
be valuable starting materials for the synthesis of natural
products of the kainic acid family8 and some non-natural
analogues.9
benzazaphospholes 3 and 4 with high regio- and stereocontrol
(Scheme 1).11 DAC reactions of chiral phosphinamides (e.g.,
1d) and subsequent alkylation proceed with very high enanti-
oselectivity.12 The dearomatized products 3 and 4 were readily
transformed into the corresponding γ-aminophosphinic acids 6
and 7 by solvolysis of the P-N linkage. This family of
compounds showed interesting antitumor properties.13
Mechanistic studies14 have shown that the PO linkage of
phosphinamides 1 direct the lithiation in THF at both the ortho
and benzylic positions. The coordinating cosolvent (HMPA or
DMPU) seems to catalyze the conversion of the ortho anion
into the corresponding benzylic species that cyclize to the
phosphorus-stabilized lithium intermediate 2. Interestingly, in
the absence of HMPA or DMPU tertiary diphenylphosphina-
mides can be deprotonated at the ortho position almost
quantitatively and trapped very efficiently with a variety of
electrophiles to give ortho functionalized phosphinamides 7 and
8 with low to moderate regioselectivity (Scheme 1).15
The essentials of DAC methodology are the existence of
acidic protons, generally of benzylic type, in the proximity of
an electron-withdrawing group linked to an aromatic ring. This
group directs the approach of the base to the deprotonation site
without suffering nucleophilic addition and, at the same time,
activates the aromatic ring toward the subsequent intramolecular
attack of the carbanion formed. N-Benzylphosphinamides fulfill
nicely these criteria. We have shown that N-alkyl-N-benzyl-
diphenylphosphinamides 1a-c can be lithiated at the benzylic
position upon treatment with sBuLi in THF in the presence of
HMPA or DMPU. The NCR anions formed undergo anionic
cyclization by Michael addition to the ortho position of the
P-phenyl ring leading to dearomatized species,10 which were
trapped with a series of electrophiles affording tetrahydro-2,1-
Naphthalenes are known to be less reluctant to nucleophilic
addition than benzenes.2 Furthermore, the introduction of a
dihydronaphthalene fragment would be very interesting taking
into account that dihydronaphthalenes are useful skeletons for
the synthesis of biological active molecules.1,2,16 In a preliminary
communication we have reported that the nucleophilic dearo-
matization of N-alkyl-N-benzyldi(1-naphthyl)phosphinamides
affords new benzo[e]-1-phosphisoindoles in high yield and
(4) For reviews, see: (a) Clayden, J. Organolithiums: SelectiVity for
Synthesis; Pergamon: Amsterdam, The Netherlands, 2002. (b) Mealy, M.
J.; Bailey, W. F. J. Organomet. Chem. 2002, 646, 59. (c) Clayden, J.;
Kenworthy, M. N. Synthesis 2004, 1721. For some recent examples, see:
(d) Monje, P.; Gran˜a, P.; Paleo, M. R.; Sardina, F. J. Org. Lett. 2006, 8,
951. (e) Wang, Z.; Xi, Z. Synlett 2006, 1275. (f) Nishiwaki, K.; Ogawa,
T.; Tagami, K.-I.; Tanabe, G.; Muraoka, O.; Matsuo, K. Tetrahedron 2006,
62, 10854. (g) Liu, L.; Wang, Z.; Zhao, F.; Xi, Z. J. Org. Chem. 2007, 72,
3484.
(5) (a) Drozd, V. N. Int. J. Sulfur Chem. 1973, 8, 443. (b) Truce, W. E.;
Madaj, E. J., Jr. Sulfur Rep. 1983, 3, 259.
(6) (a) Crandall, J. K.; Ayers, T. A. J. Org. Chem. 1992, 57, 2993. (b)
Padwa, A.; Filipkowski, M. A.; Kline, D. N.; Murphree, S.; Yeske, P. E. J.
Org. Chem. 1993, 58, 2061. (c) Clayden, J.; Kenworthy, M. N.; Heliwell,
M. Org. Lett. 2003, 5, 831.
(7) (a) Ahmed, A.; Clayden, J.; Rowley, M. Chem. Commun. 1998, 297.
(b) Ahmed, A.; Clayden, J.; Yasin, S. A. Chem. Commun. 1999, 231. (c)
Clayden, J.; Knowles, F. E.; Menet, C. J. J. Am. Chem. Soc. 2003, 125,
9278.
(8) (a) Clayden, J. In Strategies and Tactics in Organic Synthesis;
Harmata, M., Ed.; Elsevier: Amsterdam, The Netherlands, 2004; Vol. 4,
Chapter 4, pp 71-96. (b) Clayden, J.; Tchabanenko, K. Chem. Commun.
2000, 317. (c) Clayden, J.; Menet, C. J.; Tchabanenko, K. Tetrahedron
2002, 58, 4727. (d) Clayden, J.; Knowles, F. E.; Baldwin, I. R. J. Am. Chem.
Soc. 2005, 127, 2412.
(10) Mora´n-Ramallal, A.; Lo´pez-Ortiz, F.; Gonza´lez, J. Org. Lett. 2004,
6, 2141.
(11) (a) Ferna´ndez, I.; Lo´pez-Ortiz, F.; Tejerina, B.; Garc´ıa-Granda, S.
Org. Lett. 2001, 3, 1339. (b) Ferna´ndez, I.; Lo´pez-Ortiz, F.; Mene´ndez-
Vela´zquez, A.; Garc´ıa-Granda, S. J. Org. Chem. 2002, 67, 3852. (c)
Ferna´ndez, I.; Force´n-Acebal, A.; Garc´ıa-Granda, S.; Lo´pez-Ortiz, F. J. Org.
Chem. 2003, 68, 4472. (d) Ferna´ndez, I.; Ruiz Go´mez, G.; Iglesias, M. J.;
Lo´pez-Ortiz, F.; AÄ lvarez-Manzaneda, R. ArkiVoc 2005, 375.
(12) Ferna´ndez, I.; Ruiz Go´mez, G.; Alfonso, I.; Iglesias, M. J.; Lo´pez-
Ortiz, F. Chem. Commun. 2005, 5408.
(13) (a) Ruiz-Go´mez, G.; Ferna´ndez, I.; Lo´pez-Ortiz, F. Patent to
PharmaMar S.A., P200601793. Es 2006. (b) Ruiz-Go´mez, G.; Iglesias, M.
J.; Serrano-Ruiz, M.; Garc´ıa-Granda, S.; Francesch, A.; Lo´pez-Ortiz, F.;
Cuevas, C. J. Org. Chem. 2007, 72, 3790.
(14) (a) Ferna´ndez, I.; Gonza´lez, J.; Lo´pez-Ortiz, F. J. Am. Chem. Soc.
2004, 126, 12551. (b) Mora´n-Ramallal, A.; Ferna´ndez, I.; Lo´pez-Ortiz, F.;
Gonza´lez, J. Chem. Eur. J. 2005, 11, 3022.
(15) Ferna´ndez, I.; On˜a-Burgos, P.; Ruiz-Go´mez, G.; Bled, C.; Garc´ıa-
Granda, S.; Lo´pez-Ortiz, F. Synlett 2007, 611.
(9) (a) Ahmed, A.; Bragg, R. A.; Clayden, J.; Tchabanenko, K.
Tetrahedron Lett. 2001, 42, 3407. (b) Bragg, R. A.; Clayden, J.; Blandon,
M.; Ichihara, O. Tetrahedron Lett. 2001, 42, 3411. (c) Clayden, J.;
Kenworthy, M. N.; Heliwell, M. Org. Lett. 2003, 5, 831.
J. Org. Chem, Vol. 72, No. 25, 2007 9705

Ruiz-Go´mez et al.
SCHEME 2 a
a Conditions: (i) nBuLi, THF, -30 °C, 30 min; (ii) PCl3 (2 equiv), THF, -30 °C, 45 min; (iii) ArMgBr (Ar ) 1- or 2-naphthyl) (2.15 equiv), THF-Et2O,
rt, 1 h; (iv) mCPBA, CH2Cl2, 0 °C, 30 min.
TABLE 1. Isolated Yields and 31P NMR Data of Compounds
diastereoselectivity.17 In contrast to diphenylphosphinamides,
the process can be performed very efficiently in the absence of
10-12
yield
(%)
δ31P
(ppm)
coordinating additives without observing products derived from
ortho lithiation. We describe here the detailed study of the
dearomatizing anionic cyclization-electrophilic quench se-
quence of 1-naphthyl- and 2-naphthylphosphinamides. The
dearomatized anions generated in the DAC reaction were
trapped with methanol as protonating agent and with a series
of alkylating agents. The reaction conditions were optimized
for each electrophile, and the results are compared with those
obtained for diphenylphosphinamides. The elaboration of the
new azaphosphol derivatives formed into the corresponding
γ-aminophosphinic acids is examined. In addition, preliminary
anticancer assays on one of the new dihydronaphthyl γ-ami-
nophosphinic acids obtained are also shown.
product
R
Ar
10a
10b
11a
11b
11c
12a
12b
12c
Me
Bn
Me
Bn
Me
Me
Bn
Me
>97
77
94
88
80
>97
>97
96
164.08
161.07
56.03
54.71
68.55
39.66
40.38
32.97
1-Np
1-Np
2-Np
1-Np
1-Np
2-Np
SCHEME 3 a
Results and Discussion
The starting phosphinamides 12a-c were synthesized through
the three step process shown in Scheme 2:17 (i) preparation of
dichloroaminophosphines 10 through reaction of the appropriate
lithiated amine with PCl3; (ii) condensation of 10 with 1-naph-
thyl or 2-naphthylmagnesium bromide to give diarylamino-
phosphines 11; and (iii) oxidation of 11 by treatment with meta-
chloroperbenzoic acid (mCPBA). Compounds 10a,b have been
previously synthesized through reaction of PCl3 with the
corresponding benzylamine. However, neither yields nor the full
characterization of these compounds were given.18 In our hands,
the use of this methodology19 afforded a mixture of mono- and
di-addition products after a tedious workup. We found that
dichloroaminophosphines 10 can be prepared in almost quantita-
tive yields by allowing the reaction of 2 equiv of phosphorus
trichloride with a solution of the lithium benzylamine resulting
from the deprotonation of the corresponding benzylamine 9 with
a Conditions: (i) sBuLi (2.5 equiv), THF, -90 °C, 30 min; (ii) MeOH
(2 mL), -90 °C, 20 min.
formed into phosphinamides 12 upon oxidation with m-
chloroperbenzoic acid21 at 0 °C (Scheme 2). Yields and 31P
NMR data of compounds 10-12 are given in Table 1.
Dearomatization-Protonation Studies. First, we investi-
gated the DAC reactions of 1-naphthylphosphinamides. Lithia-
tion of compounds 12a,b by reaction with 2.5 equiv of sBuLi
in THF at -90 °C for 30 min, followed by quenching with
methanol at the same temperature, led to the formation of the
phosphorus-containing tricyclic systems 13 showing a trans 6,5-
ring junction in very high yield, together with small amounts
(2 - 6%) of the epimer at the NCR carbon, 14 (Scheme 3). The
diastereoselectivity of the process improves with increasing the
bulkiness of the R substituent linked to the nitrogen. Thus, the
ratio 13a:14a of 94:6 for R ) Me increases to 98:2 for 13b:
14b, where R ) PhCH2. The dearomatized products 13a,b were
purified by precipitation from diethyl ether. Crystals of 13a
suitable for X-ray analysis were grown by recrystallization from
a mixture of dichloromethane, acetonitrile, and tetrahydrofurane
at room temperature (see Supporting Information for structural
data). Compound 14a could be isolated through column chro-
1
nBuLi in THF at -30 °C for 30 min. The H and 31P NMR
spectra of the crude products indicated purities higher than 97%.
Therefore, the compounds were used without additional puri-
fication. The condensation of dichlorophosphines 10 with an
excess of 1-naphthyl- or 2-naphthylmagnesium bromide20 at
room temperature was monitored through 31P NMR. The
conversion of 10 into 11 is evidenced by an upfield shift of ca.
100 ppm. The dinaphthylphosphinamines 11 thus formed were
isolated as syrups stable to air and were quantitatively trans-
(16) (a) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297. (b)
Hulme, A. N.; Henry, S. S.; Meyers, A. I. J. Org. Chem. 1995, 60, 1265.
(c) Reynolds, A. J.; Scott, A. J.; Turner, C. I.; Sherburn, M. S. J. Am. Chem.
Soc. 2003, 125, 12108. (d) Engelhardt, U.; Sarkar, A.; Linker, T. Angew.
Chem., Int. Ed. 2003, 42, 2487.
(19) PCl3 was added to a toluene solution of N-methylbenzylamine and
triethylamine (2.5 equiv) at -78 °C, and the mixture was stirred for 30
min at this temperature.
(17) Ruiz-Go´mez, G.; Lo´pez-Ortiz, F. Synlett 2002, 781.
(18) (a) For 10a (bp 165 °C/0.15 Torr), see: Imbery, D.; Friebolin, H.
Z. Naturforsch. B 1968, 23, 759. (b) For 10b (δ (31P, 30% CHCl3) ) 138.1
ppm), see: Gouesnard, J. P.; Dorie, J.; Martin, G. J. Can. J. Chem. 1980,
58, 1295.
(20) For other examples of Grignard addition to aminodichlorophos-
phines, see: (a) Burg.; A. B.; Slota, P. J., Jr. J. Am. Chem. Soc. 1958, 80,
1107. (b) Strecker, R. A.; Snead, J. L.; Sollot, G. P. J. Am. Chem. Soc.
1973, 95, 210.
(21) Alternatively, the oxidation can be also performed with H2O2.
9706 J. Org. Chem., Vol. 72, No. 25, 2007

DAC of N-Alkyl-N-benzyl(dinaphthyl)phosphinamides
TABLE 2. Distribution of Products Obtained in the Dearomatization-Alkylation of Dinaphthylphosphinamides 12a,b
T
t
SM
EX
(°C)
(h)
18
19
20
21
22
23
1
2
3
4
5
6
7
8
9
12aa
12ab
12ac
12ad
12a
MeI
MeI
MeI
MeI
CF3SO3Me
Me3OBF4
Me3OBF4
MeI
-90
-90
-90
-90
-90
-90
-30
-90
-30
-30
-30
-30
2
2
2
8
8
14
8
8
8
8
42 (a)
43 (a)
64 (a)
76 (a)
89 (a)
51 (a)
64 (a)
11 (b)
78 (b)
30 (b)
41 (b)
41 (c)
6 (a)
6 (a)
9 (a)
7 (a)
4 (a)
1 (a)
2 (a)
4 (a)
3 (a)
24
6
-
-
-
1
-
-
-
-
-
28
-
-
3
-
-
-
-
-
1
-
9 (a)e
12af
12ag
12bh
12b
2 (a)
4 (a)
16 (a)
-
-
13 (a)
3 (b)
10 (b)
20 (b)
15 (b)
5 (c)
-
-
MeI
4 (b)
-
27 (b)
-
-
10
11
12
12bi
12bk
12a
CF3SO3Me
Me3OBF4
CH2dCHCH2Br
29 (b)j
-
8
23
11 (c)
a HMPA (6 equiv) was used as cosolvent. A total of 6% and 3% of dearomatized compounds 13a and 13b were also obtained. b A total of 19% of 13a
was isolated. c TMEDA (6 equiv) was used as cosolvent. A total of 13% and 1% of dearomatized compounds 13a and 13b were also detected. d Only 2%
of 13a was formed. e Not isolated. f A total of 15% of dearomatized protonation products was also formed. g Small amounts of 13a (5%) and 13b (2%) were
isolated. h The major product formed was 13b (73%). i The NMR spectra for the reaction crude showed the presence of two other diastereomers in percentages
of 8% and 2%. j A total of 9% of 13b. k Minor amounts (∼5%) of the products corresponding to the 1,4-conjugated addition of the organolithium to the
phosphinamide were also detected.
SCHEME 4 a
SCHEME 5 a
a Conditions: (i) sBuLi (2.5 equiv), THF, HMPA (6 equiv), -90 °C, 30
min; (ii) MeOH, -90 °C, 20 min; (iii) LDA (2.5 equiv), THF, -85 °C to
-30 °C, 1.5 h; (iv) -30 °C, 1 h; (v) MeOH, -30 °C, 20 min.
matography (eluent: ethyl acetate/hexane 1:1). The very small
amount of benzo-1-phosphaisoindol 14b formed did not allow
its isolation. It was identified from the crude reaction mixture.22
Compared with the DAC reactions of diphenylphosphina-
mides 1,11 and arylcarboxamides,7a,8a the nucleophilic dearo-
matization-protonation of naphthylphosphinamides 12a,b shows
two notable differences. First, the anionic cyclization of lithiated
12a,b occurs almost quantitatively without the requirement of
a coordinating cosolvent. Moreover, addition of HMPA during
the metalation step proved to be detrimental for the process.
After protonation with methanol, a mixture of seven products
is obtained and the yield of 13a decreases until 73%. Second,
the annelation of the five-membered ring to the desaromatized
naphthalene system takes place with a trans stereochemistry
exclusively. The preference for the trans junction may be
explained by assuming that the methanol approach to the
carbanionic center is under the control of the P-O linkage
through hydrogen-bonding formation.
a Conditions: (i) sBuLi (2.5 equiv), THF, T (°C), 30 min; (ii) EX (2.5
equiv), T (°C), t (h).
1
products, as evidenced by the H and 31P NMR spectra of the
crude reaction mixture. When the lithiation with sBuLi is
realized in the presence of HMPA, the conversion reaches 91%.
Careful column chromatography of the crude reaction mixture
allowed the isolation of dihydronaphthalenes 15 in a yield of
46% as a mixture of diastereoisomers in a ratio of 59:41,
coeluting with phosphinamide 12c (Scheme 4). Compounds 15
are the [1,4] conjugated addition products resulting from the
attack of the organolithium base to the R position of phosphi-
namide 12c.22 The relative configuration of the sterogenic
centers of 15 could not be established unequivocally. Attempts
of promoting the anionic cyclization of 12c by using alternative
protonating agents23 and increasing the temperature of the
reaction to -30 °C, were unsuccessful.
Next, as a logical extension, we decided to apply the DAC-
protonation methodology developed for 1-naphthylphosphina-
mides to the 2-naphthyl derivative 12c. Unfortunately, under
the reaction conditions shown in Scheme 3 for phosphinamides
12a,b, the isomer 12c furnishes a very complex mixture of
Dihydronaphthalenes 15 represent the first examples of an
intermolecular nucleophilic dearomatizing reaction of an arylphos-
phinamide.2 However, the performance of this NDAr reaction
is very modest both in terms of yield and degree of structural
diversity that may be achieved. To avoid the direct attack of
(22) The structures of all new compounds were assigned based on their
spectroscopic data: APCI-MS and 1D (1H, 13C, 31P, DEPT, selective
gTOCSY) and 2D (gCOSY45, gHMQC, gHMBC, and gNOESY) NMR
experiments. See Supporting Information for structural characterization.
(23) 2,6-di-tert-Butil-4-methylphenol, tert-butanol, p-toluensulphonic
t
acid, and BuCONHCHMe2 were also used as the proton source.
J. Org. Chem, Vol. 72, No. 25, 2007 9707

Ruiz-Go´mez et al.
SCHEME 6 a
a Conditions: (i) sBuLi (2.5 equiv), THF -90 °C, 30 min; (ii) PhCH2Br (2.5 equiv), -90 °C, 8 h; (iii) H2O.
SCHEME 7 a
a Conditions: (i) LDA (2.5 equiv), THF, -85 °C to -30 °C, 1.5 h; (ii) -30 °C, 1 h; (iii) MeI (2.5 equiv), -30 °C, 12 h.
the alkyl-lithium base to the 2-naphthyl ring of 12c we explored
the feasibility of using the non-nucleophilic and bulky base LDA
as deprotonating agent. Clayden and co-workers showed that
lithium amides metalate tertiary N-benzyl-arylcarboxamides at
the NCR position and that the anions undergo dearomatizing
anionic cyclization very efficiently.24 We were pleased to see
that the deprotonation of 12c with LDA in THF in the
temperature range of -85 to -30 °C, followed by quenching
with methanol at -30 °C, provided the anticipated dearomatized
heterocycle 16 in high yield and selectivity (Scheme 4). Similar
to the analogous DAC reaction of naphthylcarboxamides, the
product with a cis 6,5-ring junction is exclusively formed.24a
Purification of benzophosphaisoindol 16 was achieved by flash
chromatography.22
However, at this temperature the analogous reaction of dearo-
matized 17b (R ) Bn) furnishes 18b in very low yield (11%,
entry 8). Fortunately, at -30 °C anions 17b undergo addition
to MeI very efficiently to give 18b in 78% yield. Methylations
with harder electrophiles produced a beneficial effect only for
the reaction of 17a with CF3SO3Me. The dearomatization is
quantitative, and the amount of 18a obtained increases to 89%
(entry 5). The 31P NMR spectrum of the crude mixture showed
the presence of a new stereoisomer in 7% yield, tentatively
assigned to product 21 (Scheme 5) based on the magnitude of
the 31P chemical shift (δP 61.82 ppm, see Chart S1, Supporting
Information). Under the reaction conditions optimized for
quenching with MeI, the methylations of 17b with CF3SO3Me
-
and of 17a,b with Me3O+BF4 proceed with low yield and/or
Dearomatization-Alkylation Studies. In order to expand
the scope of the dearomatizing anionic cyclization reactions of
dinaphthylphosphinamides 12a-c, the electrophilic quenching
with several alkylating agents was also investigated. The results
obtained in the DAC-alkylation process using MeI, CF3SO3-
Me, Me3O+BF4-, AllylBr, and BnBr are shown in Schemes
5-8 and Table 2.
stereocontrol. Increasing the temperature or the reaction time
(entries 6, 7) does not produce significant improvements. These
results indicate that Me3O+BF4- reacts in a more indiscriminate
manner25 as compared with the other methylating reagents and
that bulky R substituents linked to the nitrogen hinder the
approach of the electrophile to the carbanionic center.
Alkylation of 17a by reaction with allylbromide revealed the
existence of two competing pathways, electrophilic trapping of
the dearomatized anion and oxidation of the anion restoring the
aromaticity of the naphtlyl ring. High conversions are observed
when the process is accomplished at -30 °C for 23 h. In this
way, dearomatized allylheterocycle 18c is obtained in moderate
yield (41%) together with isomers 19 (5%) and 21 (11%) and
significant amounts of the rearomatized derivative 22 (28%)
(Scheme 5, Table 2, entry 12).22 Additionally, compound 23
epimer of 22 at the NCR carbon was barely detectable in the
31P NMR spectrum of the crude mixture. Rearomatization
becomes the dominant process when anion 17a is allowed to
react with benzyl bromide. Under the reaction conditions
optimized for the methylation with MeI (THF, -90 °C, 8 h),
Three reagents, MeI, CF3SO3Me, and Me3O+BF4-, were
evaluated for installing a methyl group adjacent to the phos-
phorus atom of the dearomatized anions 17a,b formed in the
benzylic deprotonation of 12a and 12b. In all cases, heterocycles
18a,b are the major products formed. They were isolated by
precipitation from diethyl ether.22 Compound 18b could be
recrystallized from a mixture of ethanol, dichloromethane, and
hexane at room temperature. The crystal structure obtained
through X-ray diffraction is given as Supporting Information.
After some optimization, we find out that methylation of 17a
(R ) Me) with MeI at -90 °C for 8 h affords 18a in high yield
and with high stereoselectivity (Table 2, cf. entries 1-4).
(24) (a) Clayden, J.; Menet, C. J.; Mansfield, D. Org. Lett. 2000, 2, 4229.
(b) Clayden, J.; Tchabanenko, K.; Yasin, S. A.; Turnbull, M. D. Synlett
2001, 302. (c) Clayden, J.; Menet, C. J.; Mansfield, D. J. Chem. Commun.
2002, 38. (d) Clayden, J.; Menet, C. J. Tetrahedron Lett. 2003, 44, 3059.
(25) In the reaction of 17a with Me3O+BF4-, small amounts of
rearomatized byproducts 22 and 23 are also formed (Table 2, entry 6).
9708 J. Org. Chem., Vol. 72, No. 25, 2007

DAC of N-Alkyl-N-benzyl(dinaphthyl)phosphinamides
SCHEME 8 a
a Conditions: (i) 4.5 N H2SO4, dioxane (1:1), reflux, 8 h; (ii) 1 N NaOH; (iii) 2 N HCl, acetone, rt, then 1 N NaOH.
the treatment of 17a with BnBr provides a mixture of 2,3-
dihydro-1H-naphtho[1,2-c]1,2azaphosphole 1-oxides 22 (66%),
23 (5%), 24 (15%), and 25 (4%) (Scheme 6). The benzylation
of 17a at -30 °C affords similar results. Isolation of these
compounds was achieved by flash chromatography (ethyl
acetate:hexane, 1:1).22 Compounds 22 and 23 represent the two
possible diastereoisomers generated in the rearomatization of
17a. The stereogenic centers of the major isomer 22 show the
same relative configuration observed for the major dearomatized
products 13 and 18.
under the reaction conditions used.11d,27 For brominated elec-
trophiles, oxidation promoted by a small release of bromine
could also be operative.
The DAC-alkylation process was extended to N-benzyl-N-
methyl-(2-naphthyl)phosphinamide 12c. The lithiation with LDA
and subsequent addition of MeI at -30 °C provides a mixture
of tetrahydro-1H-naphtho[2,1-c][1,2]azaphosphole 3-oxides 27,
28, and 29 in a yield of 89% and in a ratio of 30:42:28 (Scheme
7).22 Compounds 27 and 28 arise from MeI attack to both faces
of anion 26 at the R-position with respect to the phosphorus.
The regioisomer 29 represents the product of methylation
through the γ-position of the allylic anion 26. Heterocycles 27-
29 were purified through flash column chromatography.
Synthesis of Naphthalenyl γ-Aminophosphinic Acids. We
have previously shown that intramolecular anionic dearoma-
tizing processes of N-alkyl-N-benzyldiphenylphosphinamides
constitute a useful strategy for synthesizing conformationally
constrained functionalized γ-aminophosphinic acids.11,12 These
are compounds of a great interest due to the relevance of their
biological properties.13,28 To ascertain the utility of the present
metholodology for the synthesis of γ-(N-alkylamino)(dihy-
dronaphthalenyl)phosphinic acids, the dearomatized compounds
13a, 16, 18a, and 27 were submitted to acid hydrolysis. In
contrast to benzazaphospholes 3 and 4 (Scheme 1), which are
readily hydrolyzed upon treatment with dilute hydrochloric acid
The formation of heterocycles 24 and 25 can be explained
by the action of the excess of reagents used on 22 or 23.
Successive NCR deprotonation-benzylation of 22 (alkylation
with inversion of configuration) or 23 (alkylation with retention
of configuration) leads to 24, whereas compound 25 results from
the NDAr process consisting of the addition of sBuLi to the
ortho position of the naphthyl ring of 22, activated by the
phosphinamide moiety, followed by protonation. As far as we
know, heterocycle 25 constitutes the first example of a tandem
process on a diaryl system in which one aromatic ring undergoes
anionic cyclization while the other is dearomatized by nucleo-
philic addition.2 Although only small amounts of heterocycles
24 and 25 are generated, their presence may help to shed light
on the rearomatization process. The synthesis of these two
compounds implies that rearomatization occurs prior to workup.
Aromatization byproducts have been previously detected in the
DAC reaction and subsequent alkylation of diphenylphosphin-
amides.11a,c In this case, the presence of HMPA may contribute
to accelerate the departure of a hydride anion necessary for
rearomatization.26 However no additives intervene in the forma-
tion of 24 and 25. We suggest that the distribution of alkylated
dearomatized products and rearomatized compounds result from
a balance between competing C- vs O-alkylation of the
intermediate phosphorus-stabilized anions formed in the DAC
step. C-Alkylation leads to stable dihydroaromatic systems,
whereas the O-alkylated derivatives evolve via rearomatization
(26) (a) Andu´jar-Sa´nchez, C. M.; Iglesias, M. J.; Pe´rez-AÄ lvarez, I. J.;
Lo´pez-Ortiz, F. Tetrahedron Lett. 2003, 44, 8441. (b) Andu´jar-Sa´nchez,
C. M.; Iglesias, M. J.; Garc´ıa-Lo´pez, J.; Pe´rez-AÄ lvarez, I. J.; Lo´pez-Ortiz,
F. Tetrahedron 2006, 62, 3468.
(27) Imamoto, T.; Kikuchi, S.-I.; Miura, T.; Wada, Y. Org. Lett. 2001,
3, 87.
(28) (a) Logusch, E. W.; Walker, D. M.; McDonald, J. F.; Franz, J. E.;
Villafranca, J. J.; Dilanni, C. L.; Colanduoni, J. I.; Li, B.; Schineller, J. B.
Biochemistry 1990, 29, 366. (b) Kukhar, V. P.; Hudson, H. R., Eds.
Aminophosphonic and Aminophosphinic Acids. Chemistry and Biological
ActiVity; John Wiley: New York, 2000. (c) Kafarski, P.; Lejczak, B. Curr.
Med. Chem.-Anti-Cancer Agents 2001, 1, 301.
J. Org. Chem, Vol. 72, No. 25, 2007 9709

Ruiz-Go´mez et al.
at ambient temperature,11a,b, rupture of the P-N bond of
compounds 13a and 18a required heating under reflux a solution
of the heterocycles in a mixture of dioxane and 4.5 N aqueous
H2SO4 (1:1) during 8 h.29 In this way, γ-aminophosphinic acids
30 and 31 (δP (DMSO-d6) 26.25 and 36.60 ppm, respectively)
are quantitatively obtained as the corresponding sulfates.17
Neutralization of 31 by treatment with 1 N NaOH allows the
isolation of the free amino acid as zwitterion 32 (Scheme 8).
Hydrolysis of 16 and 27, however, could be smoothly achieved
by reaction with 2 N aqueous HCl in acetone at room
temperature.30 After neutralization with 1 N NaOH the respec-
tive γ-aminophosphinic acids 33 and 34 are isolated in quantita-
tive yield (Scheme 8).22
Preliminary antitumor studies reveled that naphthalenyl
γ-aminophosphinic acid 32 showed promising growth cell
inhibition levels against five human tumor cell lines. The in
vitro GI50 (µM) values obtained are as follows: prostate (LN-
caP) 0.85, breast (SK-BR3) 8.7, leukemia (K-562) 8.32, pancreas
(PANC1) 9.39, and cervix (HELA) 2.76.
Experimental Section
For general experimental and X-ray data, see Supporting
Information.
Synthesis of Dichlorophosphinamines 10a,b. To a solution of
N-methyl-N-benzylamine (13.5 mmol) or N,N-dibenzylamine (10.1
mmol) in THF (50 mL) was added a solution of nBuLi (8.44 mL/
6.30 mL of a 1.6 M solution in hexane, 13.5 mmol/10.1 mmol) at
-30 °C. After 30 min of stirring at this temperature, a solution of
phosphorus trichloride (2.70 mmol/20.2 mmol) in THF (5 mL) was
added. This reaction mixture was stirred at -30 °C for 45 min.
Then, the generated LiCl was filtered under inert atmosphere, and
the THF and the excess of PCl3 were distilled under vacuum. The
reaction crude thus obtained is dried, and 50-70 mL of dry toluene
or diethyl ether was added. Once the amine chlorhidrate was
eliminated by filtration, solvent evaporation in vacuum afforded
the phosphinamines 10a,b with purity higher than 97% (NMR).
This allowed their use in the next synthetic step without further
purification.
Dichloro-N-benzyl-N-methyphosphinamine (10a): isolated
1
3
yield >97% (3.00 g); H NMR δ 2.80 (d, 3H, JPH 9.5 Hz), 4.41
3
(d, 2H, JPH 12.5 Hz), 7.32-7.36 (m, 2H), 7.36-7.47 (m, 3H);
13C NMR δ 33.67 (d, 2JPC 10.2 Hz), 55.67 (d, 2JPC 34.2 Hz), 127.97,
128.04, 128.77, 136.04 (d, 3JPC 6.6 Hz); 31P NMR δ 164.08. Anal.
Calcd (%) for C8H10NPCl2 (222.05): C, 43.27; H, 4.54; N, 6.31.
Found: C, 43.24; H, 6.30; N, 6.35.
Conclusions
Optimized conditions have been found for the dearoma-
tization anionic cyclization of N-alkyl-N-benzyldinaphthylphos-
phinamides. DAC reactions of 1-naphthyl derivatives can be
achieved expeditiously by metalation with sBuLi at low
temperatures. 2-Naphthylphosphinamides undergo anionic cy-
clization when the deprotonation is carried out with LDA. In
contrast to diphenylphosphinamides, the cyclization reactions
do not require the use of additives such as HMPA or DMPU.
Quenching the dearomatized anions with methanol, MeI, or
CF3SO3Me affords tetrahydronaphthoazaphosphole oxides in
high yields and diastereoselectivities. Slight differences in the
performance of these transformations are assigned to the
influence of the bulkiness of the substituent linked to the
nitrogen. Electrophilic trapping with allylBr leads to a mix-
ture of dearomatized allylated products and rearomatized
naphthalenyl derivatives. The latter are exclusively obtained
when benzyl bromide is used as electrophile. The evolution
of the dearomatized anions through these two pathways is
explained by the participation of competing C- and O-alkylation
processes. Although naphthylphosphinamides are lithiated
in the absence of coordinating cosolvents, products of ortho
metalation are not detected. This is a significant difference
with the DAC reactions of diphenylphosphinamides. Addi-
tionaly, the formation of some minor byproducts suggests that
intermolecular DNAr reactions and sequential double de-
aromatization of both aromatic rings bonded to a phosphin-
amide moiety may be feasible. The new dearomatized pro-
ducts obtained are quantitatively converted into γ-(N-alkylami-
no)phosphinic acids by hydrolysis of the P-N linkage
present in the azaphosphole system. The connection of the
amino and phosphinic acid groups to a dihydronaphthalene
ring may contribute to reduce the conformational mobility
of the system. These motional constraints are important
features for applications in peptidomimetic chemistry.
The evaluation of γ-aminophosphinic acid 32 as an
antitumor agent shows promising results, with GI50 values
in the range of 0.85-9.39 µM for five human tumor cell lines.
Synthesis of Dinaphthylphosphinamines 11a-c. To a solution
of naphthylmagnesium bromide in ether-toluene (1 equiv) was
added the dichlorophosphinamines 10a,b (0.48 equiv) in THF (5
mL) at room temperature for 1-naphthylmagnesium bromide or
0 °C for 2-naphthylmagnesium bromide. The reaction mixture was
stirred at room temperature for 1 h, and then the magnesium salts
were eliminated by filtration. The liquid was then poured into 0.08
M HCl, extracted with ethyl acetate (3 × 15 mL), and washed with
1 N NaOH (1 × 15 mL) and water (1 × 15 mL). The organic
layers were dried over Na2SO4 and concentrated in vacuum
affording compounds 11a-c in the presence of small amounts of
naphthalene, as syrups stable to air. These mixtures can be used
without further purification in the next oxidation step, or in addition,
naphthalene in excess can be eliminated by sublimation before the
next synthetic step.
N-Benzyl-N-methyl-P,P-di-1-naphthylphosphinamine (11a):
isolated yield 94% (5.14 g); 1H NMR δ 2.43 (d, 3H, 3JPH 5.2 Hz),
4.48 (d, 2H, 3JPH 8.5 Hz), 7.28-7.94 (m, 17H), 8.35 (dd, 2H, 3JHH
8.7 Hz,4JPH 3.4 Hz); 31P NMR δ 56.03. Anal. Calcd (%) for C28H24-
NP (405.48): C, 82.94; H, 5.97; N, 3.45. Found: C, 83.01; H,
5.95; N, 3.47.
Oxidation of Dinaphthylphosphinamines to 12a-c. To a
solution of dinaphthylphosphinamines 11a-c (8.23-4.05 mmol)
in THF or dichloromethane was added 30% v/v (0.63 mL, 6.17
mmol) hydrogen peroxide or 77% m-chloroperbenzoic acid (mCP-
BA) (6.17 mmol) at 0 °C. Once the oxidation was complete (30
min), the reaction was poured into ice water and extracted with
ethyl acetate (3 × 15 mL) and washed with 1 N NaOH (2 × 15
mL) and water (1 × 15 mL). The organic layers were dried over
Na2SO4 and concentrated in vacuo. Precipitation from Et2O afforded
12a,b as solids with a purity higher than 97%. Compound 12c was
obtained as white foam with a purity of 90% (NMR).
N-Benzyl-N-methyl-P,P-di-1-naphthylphosphinamide (12a):
yield after precipitation from Et2O > 97% (3.47 g); mp 140-
142 °C; 1H NMR δ 2.62 (d, 3H, 3JPH 9.6 Hz), 4.47 (d, 2H, 3JPH 7.8
3
Hz), 7.26-7.46 (m, 7H), 7.52-7.53 (m, 4H), 7.54 (ddd, 2H, JHH
6.8 Hz, 4JHH 1.5 Hz, 3JPH 16.4 Hz), 7.91 (m, 2H), 8.03 (d, 2H, 3JHH
2
8.2 Hz), 8.98 (m, 2H); 13C NMR δ 34.76 (d, JPC 4.5 Hz), 53.06
(d, 2JPC 3.5 Hz), 124.60 (d, 3JPC 15.0 Hz), 126.74, 127.61, 127.63,
128.01 (d, 4JPC 4.4 Hz), 128.57, 128.92, 129.24 (d, 1JPC 123.0 Hz),
(29) Myers, A. G.; Gleason, J. L.; Yoon, T.; Kung, D. J. Am. Chem.
Soc. 1997, 119, 656.
(30) (a) Harger, M. J. P. J. Chem. Soc., Chem. Commun. 1976, 520. (b)
Harger, M. J. P. J. Chem. Soc., Perkin Trans. 1 1979, 1294.
2
4
129.43, 133.22 (d, JPC 13.3 Hz), 133.29 (d, JPC 3.5 Hz), 134.22
(d, 3JPC 9.7 Hz), 134.31 (d, 2JPC 8.8 Hz,), 137.84 (d, 3JPC 3.5 Hz);
31P NMR δ 39.66; IR (KBr) 1196 cm-1; MS (API-ES) m/z 422 (M
9710 J. Org. Chem., Vol. 72, No. 25, 2007

DAC of N-Alkyl-N-benzyl(dinaphthyl)phosphinamides
2
2
+ 1). Anal. Calcd (%) for C28H24NOP (421.48): C, 79.79; H, 5.74;
N, 3.32. Found: C, 79.73; H, 5.76; N, 3.30.
Hz), 70.08 (d, JPC 17.0 Hz), 120.47 (d, JPC 8.0 Hz), 126.28 (d,
2JPC 10.9 Hz), 126.78-128.63, 128.76 (d, JPC 4.8 Hz), 128.94,
128.99, 129.14 (d, JPC 1.3 Hz), 130.52 (d, JPC 11.6 Hz), 130.63
(d, JPC 127.5 Hz), 131.90 (d, JPC 2.6 Hz), 132.63 (d, JPC 13.8
Hz), 133.88 (d, JPC 9.4 Hz), 134.83 (d, JPC 2.3 Hz), 138.72 (d,
3JPC 10.3 Hz); 31P NMR δ 49.50; IR (KBr) 1259, 1180 cm-1; MS
(API-ES) m/z 422 (M + 1). Anal. Calcd (%) for C28H24NOP
(421.47): C, 79.79; H, 5.74; N, 3.32. Found: C, 79.76; H, 5.76;
N, 3.27.
General Procedure for the Preparation of N-Methyl-γ-
aminophosphinic Acids 28-29 (Procedure A) and 30-31
(Procedure B). Procedure A: A solution of the appropriate
benzazaphosphole (13a, 18a) (1.64 × 10-4 mol) in a mixture of
dioxane (0.60 mL), water (0.53 mL), and concentrated sulfuric acid
(0.07 mL) was heated to reflux for 8 h. Then, the solution was
cooled and optional pH was set to neutral by adding 1 N NaOH.
The resulting solution was extracted with ethyl acetate (3 × 15
mL). The organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo to afford aminophosphinic acids 30 and 32.
Procedure B: To a solution of the appropriated benzazaphosphole
(16, 27) (2.37 × 10-4 mol) in acetone (10 mL), 2 N HCl (1 mL)
was added at room temperature. The mixture reaction was stirred
2 h for 16 and 6 h for 27 precursors. Then, the reaction mixture
was treated with 1 N NaOH until neutral pH and extracted with
ethyl acetate (3 × 15 mL). The organic layers were dried over Na2-
SO4, filtered, and concentrated in vacuo to afford aminophosphinic
acids 33 and 34.
3
4
3
General Procedure for the Dearomatizing Reactions on
Dinaphthylphosphinamides 12a,b. To a solution of the appropriate
phosphinamide (4.75 × 10-4 mol) in THF (25 mL) was added a
solution of sBuLi (0.91 mL of a 1.3 M solution in cyclohexane,
1.19 × 10-3 mol) at -90 or -30 °C. After 30 min of metalation,
the corresponding electrophile (2.37 × 10-3 mol for protonation
and 1.19 × 10-3 for the other electrophiles) dissolved in THF (4
mL) was added. The reaction mixture was stirred at -90 or -30
°C for t min (specified for each reaction in the main text). Then,
the reaction mixture was poured into ice water and extracted with
ethyl acetate (3 × 15 mL). The organic layers were dried over Na2-
SO4 and concentrated in vacuum. 1H, 1H{31P}, and 31P NMR spectra
of the crude reaction were measured in order to determine the
stereoselectivity of the process. The reaction crude was then purified
by precipitation from Et2O or flash column chromatography using
different mixtures of ethyl acetate/hexane as eluent.
General Procedure for the Dearomatizing Reactions on
Dinaphthylphosphinamides 12c. To a solution of LDA in THF
(1.19 × 10-3 mol) was added a solution of 12c (4.75 × 10-4 mol)
in THF (15 mL) at -85 °C. The mixture reaction was stirred for
1.5 h and allowed to reach -30 °C. After 1 h at -30 °C, MeOH
(2.37 × 10-3 mol) for protonation or MeI (1.19 × 10-3) as
electrophiles dissolved in THF (4 mL) was added at the same
temperature. The reaction mixture was stirred at -30 °C for t min
(specified for each reaction in the main text). 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 vacuum. The reaction crude was then purified by
flash column chromatography using different mixtures of ethyl
acetate/hexane as eluent.
1
4
3
2
4
1-Naphthyl-{(1R*,2R*)-2-[(1R*)-1-(methylamino)(phenyl)-
methyl]-1,2-dihydronaphthalen-1-yl}phosphinic acid sulfate
1
(30): yield crude reaction >97% (88 mg). H NMR (DMSO-d6,
2
75 °C) δ 2.10 (s, 3H), 3.16 (d, 1H, JPH 20.8 Hz), 3.67 (d, 1H,
3JHH 8.8 Hz), 4.15 (m, 1H), 6.04 (bm, 1H, ArH), 6.21(bs, 2H),
6.68-6.76 (m, 2H), 6.91 (m, 1H), 7.16-7.43 (m, 8H), 7.64 (dd,
1H, 3JHH 7.1 Hz, 3JPH 13.2 Hz), 7.83 (d, 1H, 3JHH 8.2 Hz),7.90 (d,
1H 3JHH 8.2 Hz), 8.37 (d, 1H, 3JHH 8.8 Hz); 13C NMR (DMSO-d6,
75 °C) δ 32.43, 37.33, 44.46 (d, 1JPC 85.3 Hz), 67.59 (d, 3JPC 18.0
(1RP*,3S*,3aS*,9bS*)-2-Methyl-1-(1-naphthyl)-3-phenyl-2,3,-
3a,9b-tetrahydro-1H-naphtho[1,2-c][1,2]azaphosphole 1-oxide
(13a): 88% yield after precipitation from Et2O (176 mg); mp 201-
203 °C; 1H NMR δ 2.69 (d, 3H, 3JPH 7.8 Hz), 3.78 (dddt, 1H, 3JHH
18.3 Hz, 3JHH 7.1 Hz, 3JHH 2.5 Hz, 3JPH 4.6 Hz), 3.94 (dd, 1H, 3JHH
3
Hz), 124.36 (d, JPC 13.2 Hz), 125.40, 125.94-126.77, 126.85,
127.81, 128.32, 128.52-129.04, 129.43 (d, JPC 7.2 Hz), 131.37,
3
2
3
3
18.3 Hz, JPH 22.1 Hz), 4.77 (dd, 1H JHH 7.1 Hz, JPH 13.3 Hz),
5.83 (dt, 1H, 3JHH 9.7 Hz, 3JHH 2.5 Hz, 4JPH 2.5 Hz), 6.24 (dd, 1H,
3JHH 9.7 Hz, 4JHH 2.5 Hz), 6.72 (dt, 1H, 3JHH 7.5 Hz, 4JHH 1.7 Hz),
131.65 (bm), 133.39 (d, JPC 9.6 Hz), 133.90 (d, JPC 9.6 Hz), 134.14
(d, 2JPC 7.2 Hz), 135.60 (d, 4JPC 3.6 Hz), 208.47; 31P NMR (DMSO-
d6, 75 °C) δ 26.80; MS (API-ES) m/z 440 (M + 1 for γ-amino-
phosphinic acid). Anal. Calcd (%) for C28H26NO2P‚H2SO4
(537.56): C, 62.56; H, 5.25; N, 2.61. Found: C, 62.52; H, 5.28;
N, 2.67.
3
4
5
6.89 (dt, 1H, JHH 7.5 Hz, JHH 1.7 Hz, JPH 1.7 Hz), 6.96 (t, 1H,
3JHH 7.5 Hz), 7.35 (d, 1H, 3JHH 7.5 Hz), 7.40 (dt, 1H, 3JHH 7.1 Hz,
4JHH 1.7 Hz), 7.47 (ddd, 1H, JHH 7.9 Hz, JHH 7.1 Hz, JPH 2.7
3
3
4
3
3
3
Hz), 7.50 (t, 2H, JHH 7.1 Hz), 7.61 (ddd, 1H, JHH 8.2 Hz, JHH
6.9 Hz, 4JHH 1.2 Hz), 7.66 (dd, 2H 3JHH 7.1 Hz, 4JHH 1.7 Hz), 7.78
1-Naphthyl-{(1R*,2S*)-1-methyl-2-[(1S*)-1-(methylamino)-
(phenyl)methyl]-1,2-dihydronaphthalen-1-yl}phosphinic acid
(32): yield crude reaction >97% (74 mg). 1H NMR (65 °C) δ 1.81
3
3
4
(ddd, 1H, JHH 8.6 Hz, JHH 6.9 Hz, JHH 1.7 Hz), 7.87 (ddd, 1H,
3JHH 7.1 Hz, 4JHH 1.4 Hz, 3JPH 15.7 Hz), 7.91 (dd, 1H, 3JHH 8.2 Hz,
4JHH 1.7 Hz), 8.01 (d, 1H, 3JHH 7.9 Hz), 9.79 (d, 1H, 3JHH 8.6 Hz);
3
3
(d, 3H, JPH 12.8 Hz), 2.66 (s, 3H), 3.23 (ddd, 1H, JHH 4.4 Hz,
13C NMR δ 29.54 (d, JPC 3.9 Hz), 42.39 (d, JPC 4.8 Hz), 43.31
(d, 1JPC 92.8 Hz), 66.60 (d, 2JPC 8.7 Hz), 124.38 (d, 3JPC 14.1 Hz),
126.41, 126.57 (d, 3JPC 21.3 Hz), 126.68, 126.80 (d, 1JPC 99.1 Hz),
3JHH 2.8 Hz, JPH 33.4 Hz), 4.77 (s, 1H), 6.11 (dd, 1H, JHH 7.5
2
2
3
3
Hz, 4JPH 1.9 Hz), 6.39 (t, 1H, 3JHH 7.5 Hz), 6.80 (dd, 1H, 3JHH 10.6
4
3
Hz, JHH 1.7 Hz), 6.93-7.16 (m, 7H), 7.35 (t, 1H, JHH 7.2 Hz),
7.51 (dt, 1H, 3JHH 8.3 Hz, 4JHH 1.9 Hz), 7.63 (d, 2H, 3JHH 7.8 Hz),
7.79 (d, 1H, 3JHH 8.3 Hz), 7.96 (d, 1H, 3JHH 8.3 Hz), 8.17 (bs, 1H),
7.37 (bs, 1H), 11.56 (bs, 1H, OH), 13.12 (bs, 1H, NH); 13C NMR
(60 °C) δ 21.99 (d, JPC 1.8 Hz), 32.00, 46.27 (d, JPC 82.9 Hz),
53.07 (d, 2JPC 3.0 Hz), 62.31 (d, 3JPC 2.4 Hz), 123.94 (d, 3JPC 12.6
Hz), 124.18-125.26, 126.06 (d, JPC 2.4 Hz), 126.29 (d, JPC 3.0
Hz), 126.46 (d, JPC 3.0 Hz), 126.59 (d, JPC 3.6 Hz), 127.43, 127.73,
3
126.84 (d, JPC 6.0 Hz), 127.04, 127.16, 127.33, 127.56, 127.80,
127.98, 128.13, 128.84, 129.15, 130.22, 133.67 (d, JPC 3.3 Hz),
4
3
2
2
134.01 (d, JPC 9.0 Hz), 134.18 (d, JPC 10.5 Hz), 135.62 (d, JPC
11.1 Hz), 137.54; 31P NMR δ 45.74; IR (KBr) 1151 cm-1; MS
(API-ES) m/z 422 (M + 1). Anal. Calcd (%) for C28H24NOP
(421.48): C, 79.79; H, 5.74; N, 3.32. Found: C, 79.75; H, 5.73;
N, 3.30.
2
1
4
128.48, 128.76, 130.51, 131.63 (d, JPC 3.0 Hz), 133.04 (d, JPC
(1R*,3RP*,3aS*,9bS*)-2-Methyl-3-(2-naphthyl)-1-phenyl-2,3,-
3a,9b-tetrahydro-1H-naphtho[2,1-c][1,2]azaphosphole 3-oxide
(16): yield after chromatography (ethyl acetate/hexane 1:1) was
10.2 Hz), 135.14-135.58, 133.59 (d, JPC 7.2 Hz), 136.27, 137.91
(d, JPC 3.0 Hz); 31P NMR (65 °C) δ 34.34; IR (KBr) 3438, 1261
2
cm-1; MS (API-ES) m/z 454 (M+1). Anal. Calcd (%) for C29H28-
NO2P (453.51): C, 76.80; H, 6.22; N, 3.09. Found: C, 76.82; H,
6.24; N, 3.08.
1
3
72% (144 mg). Oil. H NMR δ 2.48 (d, 3H, JPH 8.8 Hz), 3.39
3
4
2
(ddt, 1H, JHH 8.5 Hz, JHH 2.7 Hz, JPH 11.3 Hz), 3.56 (ddd, 1H,
3JHH 9.8 Hz, 3JHH 8.5 Hz, 4JHH 1.0 Hz), 4.34 (d, 1H, 3JHH 9.8 Hz),
3
3
3
6.13 (d, 1H, JHH 7.4 Hz), 6.35 (dddt, 1H, JHH 12.2 Hz, JHH 9.8
Hz, 4JHH 2.7 Hz, 4JHH 1.0 Hz, 3JPH 9.8 Hz), 6.77 (ddt, 1H, 3JHH 9.8
2-Naphthyl-{(1R*,2R*)-1-[(1S*)-1-(methylamino)(phenyl)-
methyl]-1,2-dihydronaphthalen-2-yl}phosphinic acid (33): yield
crude reaction >97% (72 mg); mp 292-294 °C (decomposed); 1H
4
4
3
4
Hz, JHH 2.7 Hz, JPH 2.7 Hz), 6.89 (dt, 1H, JHH 7.4 Hz, JHH 1.8
Hz), 7.13-8.04 (m, 13H), 8.67 (d, 1H, 3JPH 14.2 Hz); 13C NMR δ
NMR NMR δ 2.42 (s, 3H), 3.50 (m, 1H, JPH 20.3 Hz), 4.35 (s,
2
2
1
2
3
3
28.91 (d, JPC 2.4 Hz), 38.63 (d, JPC 84.1 Hz), 48.41 (d, JPC 1.2
2H), 6.00 (dt, 1H, JHH 9.2 Hz, JHH 2.3 Hz,3JPH 9.2 Hz), 6.45 (d,
J. Org. Chem, Vol. 72, No. 25, 2007 9711

Ruiz-Go´mez et al.
3
1H, JHH 7.3 Hz), 6.57-6.66 (m, 2H), 6.91-8.06 (m, 13H), 8.61
01792), is gratefully acknowledged. G.R.G. thanks Ministerio
de Ciencia y Tecnolog´ıa for a doctoral fellowship. We thank
PharmaMar S.A. for the biological assays carried out.
(d, 1H, 3JPH 12.3 Hz), 11.47 (bs, 1H), 12.62 (bs, 1H); 13C NMR δ
31.42, 42.08 (d, JPC 95.2 Hz), 43.06 (d, JPC 3.5 Hz), 61.47,
125.53-129.49, 132.59, 132.78 (d, JPC 3.5 Hz), 133.32 (d, JPC
8.5 Hz), 134.42 (d, 4JPC 1.8 Hz), 135.19 (d, 3JPC 14.0 Hz), 135.35;
31P NMR δ 33.77; IR (KBr) 3410, 1182 cm-1; MS (API-ES) m/z
440 (M + 1). Anal. Calcd (%) for C28H26NO2P (439.49): C, 76.52;
H, 5.96; N, 3.19. Found: C, 76.54; H, 5.94; N, 3.18.
1
2
3
2
Supporting Information Available: Structural analysis, ex-
perimental procedures, and characterization data for all compounds,
1
1D H, 13C, and DEPT135 of all new compounds, 2D gNOESY
spectra of 13a,b, 14a, 18a-c, 22-25, 27, 33, and 34, 1D
experiments of 30 and 32 at different temperatures, and X-ray data
of 13a and 18b. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. Dedicated to Prof. Vicente Gotor on the
occasion of his 60th birthday. Financial support through
Ministerio de Educacio´n, Cultura y Deporte (project CTQ2005-
JO701607S
9712 J. Org. Chem., Vol. 72, No. 25, 2007