Dearomatizing anionic cyclizations of N-benzyl-N-methyldiphenylphosphinamides. Synthesis of γ-(N-methylamino)phosphinic acids

Article abstract of DOI:10.1021/ol015716t

(equation presented) The first dearomatizing anionic reaction of a phenyl ring promoted by an N-benzyl-N-methylphosphinamide group is described. The intermediate lithium species can be trapped with different electrophiles, affording tetrahydrobenzo[c]-1-a

Full text of DOI:10.1021/ol015716t

ORGANIC
LETTERS
2
001
Vol. 3, No. 9
339-1342
Dearomatizing Anionic Cyclizations of
N-Benzyl-N-methyldiphenylphosphinamides.
Synthesis of
1
γ-(N-Methylamino)phosphinic Acids
†
,†
†
Ignacio Fern a´ ndez, Fernando L o´ pez Ortiz,* Baudilio Tejerina, and
‡
Santiago Garc ´ı a Granda
AÄ rea de Qu ´ı mica Org a´ nica, UniVersidad de Almer ´ı a, Carretera de Sacramento s/n,
04120 Almer ´ı a, Spain, and Departamento de Qu ´ı mica F ´ı sica y Anal ´ı tica,
UniVersidad de OViedo, AVda. Juli a´ n ClaVer ´ı a 8, 33071 OViedo, Spain
flortiz@ual.es
Received February 16, 2001
ABSTRACT
The first dearomatizing anionic reaction of a phenyl ring promoted by an N-benzyl-N-methylphosphinamide group is described. The intermediate
5
lithium species can be trapped with different electrophiles, affording tetrahydrobenzo[c]-1-aza-2λ -phospholes with excellent diastereoselectivity.
The new process is a simple and very efficient entry to the stereoselective synthesis of functionalized γ-(N-methylamino)phosphinic acids and
esters.
Dearomatizing reactions through sequential addition of a
nucleophile and an electrophile to activated benzenes is a
very useful methodology for the synthesis of regio- and
stereoselectively substituted cyclohexadiene derivatives. The
activation may be achieved by transition metal coordination
nucleophilic dearomatization can be carried out intramo-
lecularly. Very recently, Clayden et al. have extended this
anionic cyclization to the dearomatization of lithium tertiary
7
N-benzylbenzamides. The intermediate dearomatized enolate
1
to the π system or through classical electron-withdrawing
(4) For some leading references on the analogous dearomatization of
2
groups: aldehydes, ketones, esters of carboxylic acids, and
naphthalenes, see: (a) Meyers, A. I.; Barner, B. A. J. Org. Chem. 1986,
51, 120. (b) Meyers, A. I.; Roth, G. P.; Hoyer, D.; Barner, B. A.; Laucher,
D. J. Am. Chem. Soc. 1988, 110, 4611. (c) Tomioka, K.; Shindo, M.; Koga,
K. Tetrahedron Lett. 1990, 31, 1739. (d) Shimano, M.; Meyers, A. I. J.
Am. Chem. Soc. 1994, 116, 6437. (e) Plunian, B.; Mortier, J.; Vaultier, M.;
Toupet, L. J. Org. Chem. 1996, 61, 5206. (f) Ahmed, A.; Clayden, J.;
Rowley, M. Chem. Commun. 1998, 297. (g) Bragg, R. A.; Clayden, J.
Tetrahedron Lett. 1999, 40, 8323. (h) Ahmed, A.; Clayden, J.; Rowley, M.
Synlett 1999, 1954. (i) Clayden, J.; Frampton, C. S.; McCarthy, C.; Weslund,
N. Tetrahedron 1999, 55, 14161. (j) Kolotuchin, S. V.; Meyers, A. I. J.
Org. Chem. 2000, 65, 3018.
imines.3 For phenyl sulfones5 and sulfonamides, the
,4
6
†
Universidad de Almer ´ı a.
Universidad de Oviedo.
‡
(1) (a) Pike, R. D.; Sweigart, D. A. Synlett 1990, 565. (b) Semmelhack,
M. F. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 4, p 517. (c) K u¨ ndig, E. P.; Ripa, A.;
Bernardinelli, G. Angew. Chem., Int. Ed. Engl. 1992, 31, 1071. (d) Harman,
W. D. Chem. ReV. 1997, 97, 1953. (e) Pape, A. R.; Kaliappan, K. P.; K u¨ ndig,
E. P. Chem. ReV. 2000, 100, 2917.
(5) (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.
(
2) (a) Maruoka, K.; Ito, M.; Yamamoto, H. J. Am. Chem. Soc. 1995,
1
17, 9091. (b) Saito, S.; Shimada, K.; Yamamoto, H.; Marigorta, E. M.;
Fleming, I. Chem. Commun. 1997, 1299. (c) Saito, S.; Sone, T.; Shimada,
K.; Yamamoto, H. Synlett 1999, 81.
(6) (a) Breternitz, H. J.; Schaumann, E.; Adiwidjaja, G. Tetrahedron Lett.
1991, 32, 1299. (b) Aggarwal, V. K.; Ferrara, M. Org. Lett. 2000, 2, 4107.
(7) (a) Ahmed, A.; Clayden, J.; Yasin, S. A. Chem. Commun. 1999, 231.
(b) Clayden, J.; Tschabanenko, K. Chem. Commun. 2000, 317. (c) Clayden,
J.; Menet, C. J.; Mansfield, D. J. Org. Lett. 2000, 2, 4229.
(
3) Brown, D. W.; Lindquist, M.; Mahon, M. F.; Malm, B.; Nilsson, G.
N.; Ninan, A.; Sainsbury, M.; Westerlund, C. J. Chem. Soc., Perkin Trans.
1997, 2337.
1
1
0.1021/ol015716t CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/03/2001

has been quenched with several electrophiles with high
stereocontrol.
Scheme 2a
Tertiary phosphonamides are good activating groups for
8
the ortho-lithiation of aromatic rings. Furthermore, the
reaction of N-benzyl-N-methyldiphenylthiophosphinamide
s
with Bu Li in THF/TMEDA also affords the ortho-lithiated
9
derivative. We report here the first anionic highly stereo-
selective cyclization of tertiary N-benzyl-N-methyldiphen-
ylphosphinamides which results in the dearomatization of
one of the phenyl rings bonded to the phosphorus. The
5
tetrahydrobenzo[c]-1-aza-2λ phospholes obtained are readily
transformed in functionalized N-methylaminophosphinic
acids and esters.
10
N-Benzyl-N-methyldiphenylphosphinamide 1 was treated
s
with Bu Li (1.5 equiv) at -90 °C in THF during 30 min in
the presence of HMPA (6 equiv). Quenching the dark red
solution obtained with MeOH (20 equiv) at -90 °C gave
5
11
1
-aza-2λ -phospholes cis-3a:4a:5a:6a in a 72:20:3:5 ratio
12
a
s
in 90% total yield (Scheme 1).
i. Bu Li (1.5 equiv), THF -90 °C, HMPA (6 equiv), 30 min;
ii. E+ (a, E ) H; b, E ) D; c, E ) Me; d, E ) PhCHOH), 30-
20 min.
1
Scheme 1a
to 43% and the stereoselectivity of the reaction was also less
Scheme S1, Supporting Information).
The addition of D O, a harder electrophile, afforded the
(
2
mixture of compounds cis-3b:trans-3b:4b:5b:6b in a ratio
of 22:27:40:8:3 in 88% total yield (Scheme 2, E ) D).
Significantly, no deuterated phosphinamide was detected,
implying that once benzylic deprotonation occurred the
resulting anion attacks intramolecularly to a P-phenyl ring
yielding a new dearomatized phosphorus-stabilized anion of
the type 2 and/or 2HMPA (Scheme 2).
Intermediates 2-2HMPA have been characterized by NMR
a
s
i. Bu Li (1.5 equiv), THF -90 °C, HMPA (6 equiv), 30 min;
31
monitoring of the metalation step. At -80 °C the
P
ii. MeOH, 30 min.
2
31
7
spectrum showed a quartet at δ 35.03 [ J( P, Li) 6.4 Hz]
for monomer 2 and a broad singlet at δ 39.8 assigned to
2
HMPA. On the basis of the deaggregation power of HMPA,
Flash chromatography (eluent: ethyl acetate) allowed for
16
one can assume that 2HMPA is also a monomer. The
structural analysis of 2-2HMPA indicated that both species
have the same bicyclic structure and relative stereochemis-
try. Hence, 2 can be represented as a contact ion pair with
an intramolecular PO‚‚‚Li coordination, in equilibrium with
a solvent-separated ion pair 2HMPA where the lithium cation
13
the isolation of the major components of the mixture. Thus,
high yields of diene cis-3a (65%, isolated) with four
stereogenic centers were obtained. This is the first time that
an anionic cyclization with loss of aromaticity is observed
in phosphinamides.1 Without HMPA, the yield decreased
13
4,15
1
7
is fully coordinated to HMPA molecules.
(
8) (a) Snieckus, V. Chem. ReV. 1990, 90, 879. (b) Dashan, L.; Trippett,
S. Tetrahedron Lett. 1983, 24, 2039.
9) Yoshifuji, M.; Ishizuka, T.; Choi, Y. J.; Inamoto, N. Tetrahedron
Lett. 1984, 25, 553.
10) Phosphinamide 1 was easily prepared in multigram scale by addition
The reaction with IMe was more complex. Besides the
(
dearomatized products cis-3c:trans-3c:4c (53% yield, ratio
(
of N-methylbenzylamine to a toluene solution of chlorodiphenylphosphine
and triethylamine (4 equiv) and then in situ oxidation with H2O2. Yield
Table 1. Product Distribution in the Cyclization-Addition
Reactions
9
0% (Supporting Information).
(
11) Measured from the inverse-gated proton-decoupled 31P NMR
spectrum of the crude reaction using a pulse width of 15°, a relaxation
E+
yield, %a
90b
88b
85c
>98
cis-3
trans-3
4
5
6
delay of 10 s, and an accumulation of 128 scans.
s
(
12) Other products: 1 (4%) and Ph2P(O)Bu (6%).
a
b
c
d
MeOH
D2O
MeI
65
19
6
18
35
39
3
7
4
3
1
(
13) Structural determinations were based on the analysis of 1D ( H,
24
8
1
3
31
C, P, DEPT, selective TOCSY) and 2D (gHMQC, gHMBC, gNOESY,
ROESY) NMR experiments. Full details will be published elsewhere.
14) For benzylic metalation of phosphorus triamides, see: M u¨ ller, J. F.
K.; Spingler, B.; Zehnder, M. Synlett 1997, 1059.
15) For an analogous dearomatization of phenylsulphonamides see refs
a,b.
16) Reich, H. J.; Barst, J. P.; Dykstra, R. R.; Green, D. P. J. Am. Chem.
Soc. 1993, 115, 8728, and references therein.
(
PhCHO
80:20d
a
Crude yield. b Recovered 1 (5%), byproduct Ph2P(O)CH(Me)Et. c Com-
pounds 7 (10%), 7b (15%), and 8 (7%) were also isolated (see ref 18).
(
6
d
31
(
P NMR ratio of epimers in the C-OH carbon.
1340
Org. Lett., Vol. 3, No. 9, 2001

6
:8:39, Table 1, Scheme 2, E ) Me), three additional
compounds were identified: the rearomatized derivatives 7a
10%) and 7b (15%) and the ortho-methylated phosphina-
all other stereocenters being the same. The X-ray structure
of the mixture (R*)-4d:(S*)-4d confirmed this point and
allowed for assignment of the configuration of the hydroxylic
(
18
20
mide 8 (7%) (Figure 1). The rearomatization observed may
carbon of both epimers (Figure 2).
Figure 1.
be a consequence of the workup procedure. However, the
reasons for this particular behavior are not clear at present.
The use of benzaldehyde as electrophile is remarkable.
With HMPA in the medium, epimers (S*)-4d (δ
R*)-4d (δ
31.22) were obtained19 quantitatively in an
0:20 ratio. Interestingly, the use of DMPU as cosolvent
P
31.13) and
(
P
8
afforded similar results (Scheme 3). This implies that when
Figure 2. ORTEP type plot of the molecular structure of the
mixture of epimers (R*)-4d:(S*)-4d, 38:62. Two alternative posi-
tions for the disordered oxygen linked to the benzylic carbon are
shown. The dashed CsO bond corresponds to the major isomer
Scheme 3a
(S*)-4d.
In the absence of HMPA, the yield decreased to 72% and
small amounts of compounds 9 (mixture of epimers in the
COH carbon) and 10 (Scheme 3) were observed. They arise,
respectively, from the addition of PhCHO to the ortho
position of a P-phenyl ring and to the benzylic carbon of
2
1
1
.
The dearomatized compounds 3-4 can be viewed as
masked γ-N-methylaminophosphinic acids. The solvolysis
of the P-N bond is practically instantaneous with aqueous
a
s
°
i. Bu Li (1.5 equiv), THF -90 C, HMPA or DMPU (6 equiv),
s
°
3
3
0 min; ii. PhCHO, 120 min; iii. Bu Li (1.5 equiv), THF -90 C,
0 min.
2
N HCl in acetone and dry 0.6 N HCl in MeOH at room
temperature, affording stereospecifically and quantitatively
the corresponding γ-(N-methylamino)phosphinic acids 11-
12 and methyl esters 13-14, respectively, with inversion at
starting with achiral reagents two new compounds are formed
containing five stereogenic centers i.e., only 2 out of 16
possible diastereoisomers! To our delight they could be
separated by flash chromatography (ethyl acetate:hexane 2:1).
According to NMR data the two isomers resulted from
the nucleophilic attack to the two faces of the carbonyl group,
2
2
the phosphorus center (Scheme 4).
(21) The formation of compounds 8 and 10 suggests that the anionic
cyclization may proceed, at least in part, from an initial ortho lithiation of
a P-phenyl ring which would then intramolecularly deprotonate the benzylic
carbon necessary for the cyclodearomatization, as elegantly demonstrated
by Clayden et al. for the dearomatization of N-benzylnaphthamides. Ahmed,
A.; Clayden, J.; Rowley, M. Tetrahedron Lett. 1998, 39, 6103. We are
currently studying the mechanism of this reaction.
(22) (a) Tyssee, D. A.; Bausher, L. P.; Haake, P. J. Am. Chem. Soc.
1973, 95, 8066. (b) Harger, M. J. P. J. Chem. Soc., Chem. Commun. 1976,
520. (b) Harger, M. J. P. J. Chem. Soc., Perkin Trans. 1 1979, 1294. The
solvolysis of derivative cis-3a furnished the corresponding acid 11 and
methyl ester 13 (Supporting Information).
(23) (a) For a review, see: Hiratake, J.; Oda, J. Biosci. Biotech. Biochem.
1997, 61, 211. (b) Froestl, W.; Mickel, J. S.; Hall, R. G.; von Sprecher, G.;
Strub, D.; Baumann, P. A.; Brugger, F.; Gentsch, C.; Jaekel, J.; Olpe, H.
R.; Rihs, G.; Vassout, A.; Waldmeier, P. C.; Bittiger, H. J. Med. Chem.
1995, 38, 3297. (c) Nyitrai, G.; Emri, Z.; Crunelli, V.; K e´ kesi, K. A.;
Dobolyi, A.; Juha a´ sz, G. Eur. J. Pharmacol. 1996, 318, 295.
(
(
17) The 31P signal of HMPA in 2HMPA and free HMPA are overlapped.
18) The compounds were separated by careful flash chromatography
using ethyl 2:1 acetate:hexane as eluent. Other byproducts: cis-3a (1%),
a (9%), and Ph2P(O)C(Me)2CH2CH3 (8%) (formed by nucleophilic attack
4
s
of Bu Li to 1 followed by metalation and subsequent addition of IMe).
19) Only the configuration of the stereogenic center labeled in Scheme
is given.
20) (R*)-4d:(S*)-4d crystallized as a mixture with the same ratio (38:
2) of isomers found in solution through NMR. The major isomer exhibits
(
3
6
(
an S configuration at the starred carbon and is characterized by a δP 31.13
ppm and a melting point of 201-202 °C. The corresponding values for
(R*)-4d are δP 31.22 ppm, mp 189-190 °C.
Org. Lett., Vol. 3, No. 9, 2001
1341

However, there are very few syntheses of this type of
2
5
26
Scheme 4a
compounds, and these are generally nonstereoselective.
The new dearomatization reaction reported here is a highly
stereoselective and high-yield procedure which allows for
the conversion of readily available aromatic compounds to
functionalized cyclohexadiene derivatives. Furthermore, it
represents an easy entry to the preparation of γ-(N-methyl-
amino)phosphinic acids and esters using low cost commercial
reagents in a very simple one-pot process. Further applica-
tions of the new methodology are in progress.
Acknowledgment. Financial support by CICYT (PB97-
0
587-C02-01 and BQU2000-0219) is gratefully acknowl-
edged. I. F. thanks Junta de Andaluc ´ı a for a predoctoral
fellowship.
a
i. 2 N HCl(H
2
O), Me
2
CO; ii. 0.6 N HCl(g), MeOH.
Supporting Information Available: Scheme S1, syn-
thetic procedures and characterization of 1 and 3-14, X-ray
1
figure and structural information on (R*)-4d/(S*)-4d, H and
γ-Aminophosphinic acids and their derivatives are im-
portant target molecules as inhibitors, analogues of 4-ami-
nobutiric acid (GABA) and glutamic acid. The natural
tripeptide bialaphos is an antibiotic and commercial herbicide
containing the γ-aminophosphinic acid phosphinothricin.
31
31
P NMR spectra of 12 and 14, and P NMR spectrum of
2-2HMPA measured at -80 °C. This material is available free
23
of charge via the Internet at http://pubs.acs.org.
2
4
OL015716T
(
25) For a review, see: Fields, S. C. Tetrahedron 1999, 55, 12237.
(
24) Bayer, E.; Gugel, K. H.; Haegele, K.; Hagenmaier, H.; Jessipow,
(26) Kehler, J.; Ebert, B.; Dahl, O.; Krogsgaard-Larsen, P. J. Chem. Soc.,
Perkin Trans. 1 1998, 3241 and references therein.
S.; Koenig, W. A.; Zaehner, J. HelV. Chim. Acta 1972, 55, 224.
1342
Org. Lett., Vol. 3, No. 9, 2001