Base-dependent regio- and diastereoselective alkylation of chiral perhydro 1,3,2-oxazabenzophosphorinane-2-oxides derived from (-)-8-benzylamino menthol

Article abstract of DOI:10.1055/s-2004-822914

The regioselectivity in the alkylation of chiral perhydro 1,3,2-benzoxazaphosphorinane-2-oxides is dependent on the base used for deprotonation. The ethyl oxazaphosphorinanes are benzylated at the nitrogen substituent after deprotonation with n-BuLi, but

Full text of DOI:10.1055/s-2004-822914

1300
LETTER
Base-Dependent Regio- and Diastereoselective Alkylation of Chiral Perhydro
1,3,2-Oxazabenzophosphorinane-2-oxides Derived from (–)-8-Benzylamino
Menthol
Base-Dependent
R
egio- and
f
D
iastere
a
oselective
A
e
lkylation l Pedrosa,* Alicia Maestro, Alfonso Pérez-Encabo, Rubén Raliegos
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Valladolid, Dr. Mergelina s/n, 47011-Valladolid, Spain
E-mail: pedrosa@qo.uva.es
Received 24 February 2004
by 2) were prepared by Arbuzov reaction, in refluxing
Abstract: The regioselectivity in the alkylation of chiral perhydro
toluene, between benzyl bromide or ethyl iodide and 2-
1,3,2-benzoxazaphosphorinane-2-oxides is dependent on the base
ethoxy-1,3,2-oxazaphosphorinane 3, itself obtained from
(–)-8-benzylamino menthol and ethyl dichlorophos-
used for deprotonation. The ethyl oxazaphosphorinanes are ben-
zylated at the nitrogen substituent after deprotonation with n-BuLi,
but a to the phosphorous atom by deprotonation with LDA. On the phite.10
contrary, the benzyl oxazaphosphorinane is alkylated a to the phos-
phorous atom after deprotonation with both, n-BuLi or LDA.
Key words: alkylation, alkyl phosphonates, asymmetric synthesis,
diastereoselective reactions, 2-oxo-1,3,2-oxazaphosphorinanes
Phosphorous stabilized chiral carbanions have been wide-
ly used in the diastereoselective formation of carbon-car-
bon bonds. Among them, compounds with stereogenic
phosphorous atom and phosphorous derivatives modified
by chiral auxiliaries have been successfully employed.1
Chiral diamines and amino alcohols constitute specially
interesting auxiliaries in the formation of cyclic
phosphonamides2 and oxaphosphonamides,3 which un-
dergo diastereoselective transformations with excellent
Scheme 1 Synthesis of perhydro 2-oxo-1,3,2-oxazabenzophos-
phorinanes 1–4
diastereomeric excess.
It is well known that the diastereoselection of these reac-
tions is dependent on the structure of the electrophile,4 the
stereochemistry of the phosphorous atom,5 the nature of
the substituents at the nitrogen atom,3b the size6 and the
configurational and conformational characteristics of the
heterocyle.7 Thus the search for new stereocontrolling el-
ements constitutes an active area of interest.
The stereochemistry of 1 and 2 was tentatively assigned
on the basis of the 31P NMR signals (d = 34 ppm for com-
pound 1 and d = 30 ppm for 2),11 and confirmed by X-ray
diffraction studies12 (Figures 1– 3).
The geometry around the nitrogen atom of this kind of
compounds varies from planar13 to pyramidal,12 and the
conformations13a of the six-membered ring are dependent
In this way, (–)-8-aminomenthol derivatives have been
shown as excellent auxiliaries in various diastereoselec-
tive cyclizations,8 and now we report on the diastereo-
selective alkylation of chiral perhydro 1,3,2-
oxazabenzophosphorinane-2-oxides derived from this
1,3-amino alcohol.
To this end, perhydro ethyl- (1, 2) and benzyl-1,3,2-ox-
azabenzophosphorinane-2-oxide (4) were prepared as
outlined in Scheme 1. Diastereomers 1 (31%) and 2 (61%)
were obtained by direct cyclization9 of (–)-benzylamino
menthol with ethyl phosphonic dichloride and triethyl-
amine in methylene chloride. Alternatively, compounds 4
(as a single diastereomer) and 1 (accompanied in ca. 3%
Figure 1 Chem 3D representation of X-ray for compound 1. For
clarity, only H atoms of CH2 of the benzyl group attached to the N
atom are shown
SYNLETT 2004, No. 7, pp 1300–1302
Advanced online publication: 27.04.2004
DOI: 10.1055/s-2004-822914; Art ID: D05204ST
© Georg Thieme Verlag Stuttgart · New York
0
3.
0
6.
2
0
0
4

LETTER
Base-Dependent Regio- and Diastereoselective Alkylation
1301
Figure 2 Chem 3D representation of X-ray for compound 2
Scheme 2 Alkylation of compounds 1, 2 and 4 with benzyl bromi-
de.
led to a mixture of 10 and 11 (72:28, entry 5 in Table 1),
whereas 1 yielded the alkylation product at the benzylic
position of the nitrogen 7 in 64%, as a single diastereomer
(entry 2 in Table 1).
Compound 2 also led to alkylated products at the nitrogen
side 8 and 9 (83:17) after deprotonation with n-BuLi and
reaction with benzyl bromide (entry 3 in Table 1). The
stereochemistry of compound 8 was determined by X-ray
crystallography (Figure 4), whereas the configuration of
the benzylic carbon attached to the nitrogen atom in 7 was
determined by conversion of both to (S)-1,2-diphenyleth-
yl amine by heating with 6 N HCl (Scheme 3).
Figure 3 Chem 3D representation of X-ray for compound 4
This constitutes the first observation of alkylation at the
nitrogen substituent in N-benzyl derivatives, although re-
cently similar reaction products have been obtained in
moderate yield, but only for benzhydryl substituted 1,3,2-
oxazaphosphorinane-2-oxides.16 The formation of these
on the nature of the substituents. In our case, the nitrogen
atom is trigonal in compounds 4 and 2 but pyramidal for
compound 1, and the ring adopts a slightly distorted chair
conformation in compounds 1 and 2. However, in com-
pound 4 the conformation for the ring is half chair, with
C(6)-O(1)-P(2)-N(3)-C(4) near planar.
Table 1 Alkylation of 1, 2 and 4 with Benzyl Bromide
Alkylation14 of compound 1, in THF at –78 °C, with LDA
as base and benzyl bromide as electrophile led to a mix-
ture of diastereomers 5 and 6 in 45% yield in a ratio 62:38
(determined by 31P NMR; Scheme 2 and entry 1 in
Table 1).
Entry
Substrate Base
Yielda
45
Products (dr)b
5:6 (62:38)
7 (>99:1)
1
2
3
4
5
1
1
2
4
4
LDA
n-BuLi
n-BuLi
LDA
64
77
8:9 (83:17)
10:11 (71:29)
10:11 (72:28)
Compound 4 also reacts under the same experimental con-
ditions giving a mixture of diastereomers 10 and 11
(71:29) in 71% yield (entry 4 in Table 1). The stereo-
chemistry of the major compounds 5 and 10 was identi-
fied, after chromatographic purification, by hydrolysis to
the known phosphonic acids.15 Under the described exper-
imental conditions, but using n-BuLi (2 equiv) as base, 4
71
n-BuLi
56
a Yields are given after purification by flash chromatography.
b Determined in the reaction mixture by integration of the 31P NMR
signals.
Synlett 2004, No. 7, 1300–1302 © Thieme Stuttgart · New York

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R. Pedrosa et al.
LETTER
Acknowledgment
Authors thank the Spanish Ministerio de Ciencia y Tecnología for
financial support (Project BQU 2002-01046).
References
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Figure 4 Chem 3D representation of X-ray for compound 8
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(12) CCDC contain supplementary crystallographic data for
compounds 1 (CCDC 233645), 2 (CCDC 233647), 4 (CCDC
233644), and 8 (CCDC 233646), respectively. These data
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Scheme 3
compounds has been explained by alkylation of the anion
formed by direct deprotonation at the nitrogen side chain
or by proton transfer from that position to the anion a to
the phosphorous atom, but these and our results can also
be explained as a consequence of the formation of dian-
ionic species that are first alkylated a to the nitrogen atom.
The stereochemistry of the single (7) or major (8) dia-
stereomer formed in these reactions is consistent with the
model proposed for alkylation of amides with retention at
the anionic center.17
Crystallographic Data Centre, 12 Union Road, Cambridge
CB12 1EZ, UK; fax: (internat.) +44(1223)336033; e-mail:
deposit@ccdc.cam.ac.uk.
Taking into account the stereochemistry of the starting
compounds and the structure of the anionic inter-
mediates18 the formation of 5 and 10 as major diastereo-
mers can be explained by accepting that the alkylation
occurs from the less hindered oxygen face of the hetero-
cycle.12
(13) (a) Afarinkia, K.; Angell, R.; Jones, C. L.; Lowman, J.
Tetrahedron Lett. 2001, 42, 743. (b) Bentrude, W. G.;
Setzer, W. N.; Sopchik, A. E.; Bajwa, G. S.; Burright, D. D.;
Hutchinson, J. P. J. Am. Chem. Soc. 1986, 108, 6669.
(14) Typical Experimental Procedure: To a cooled (–78 °C)
solution of the corresponding 1,3,2-oxazaphosphorinane
(0.9 mmol) in dry THF (20 mL) under argon atmosphere was
added the base (1.8 mmol), and the mixture was stirred for
30 min. Then, benzyl bromide (1.8 mmol) was added and the
stirring was continued until the reaction was finished (TLC).
The reaction was quenched with H2O (9 mL) and stirred
until the mixture was reached r.t. THF was removed under
reduced pressure and the aqueous mixture extracted with
CH2Cl2 (3 × 25 mL). The combined organic layers were
dried (MgSO4), filtered and concentrated. The residue was
purified by flash chromatography on silica gel and hexane–
EtOAc (1:2) as eluent.
In summary, both the nature of the substituent at phospho-
rous atom and the base used in the deprotonation step have
a significant influence on alkylation of perhydro 1,3,2-
benzoxaphosphorinane 2-oxides. When the deprotonation
is carried out with n-BuLi both diastereomers (1 and 2) of
the ethyl oxazaphosphorinanes are alkylated at the nitro-
gen atom substituent, whereas deprotonation with LDA
leads to the alkylation product at the phosphorous substit-
uent. On the contrary, deprotonation with LDA or n-BuLi
of the benzylphosphorinane 4, followed by reaction with
benzyl bromide yields the alkylation product at the phos-
phorous substituent.
(15) Bennani, Y. L.; Hanessian, S. Tetrahedron 1996, 52, 13837.
(16) Afarinkia, K.; Jones, C. L.; Yu, H.-W. Synlett 2003, 509.
(17) See for instance: (a) Iula, D. M.; Gawley, R. E. J. Org.
Chem. 2000, 65, 6196. (b) Kopach, M. E.; Meyers, A. I. J.
Org. Chem. 1996, 61, 6764.
Further studies on the generality of the described reactions
are under investigation in our laboratory.
(18) Kranz, M.; Denmark, S. E.; Swiss, K. A.; Wilson, S. R. J.
Org. Chem. 1996, 65, 8551.
Synlett 2004, No. 7, 1300–1302 © Thieme Stuttgart · New York