Regio- and stereoselective methoxyselenenylation of chiral 2-vinyl perhydro-1,3-benzoxazines promoted by selenium-heteroatom nonbonded interactions

Article abstract of DOI:10.1021/jo052582e

Regio- and diastereoselective methoxyselenenylations of double bonds attached to the N,O-ketalic carbon of chiral perhydrobenzoxazines occur in high yields by reaction with benzeneselenenyl chloride in dichloromethane-methanol. The diastereoselection is d

Full text of DOI:10.1021/jo052582e

Regio- and Stereoselective Methoxyselenenylation of Chiral 2-Vinyl
Perhydro-1,3-benzoxazines Promoted by Selenium-Heteroatom
Nonbonded Interactions
Rafael Pedrosa,* Celia Andre´s,* Raquel Arias, Pilar Mendiguch´ıa, and Javier Nieto
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, UniVersidad de Valladolid, Dr. Mergelina s/n,
47011-Valladolid, Spain
pedrosa@qo.uVa.es
ReceiVed December 15, 2005
Regio- and diastereoselective methoxyselenenylations of double bonds attached to the N,O-ketalic carbon
of chiral perhydrobenzoxazines occur in high yields by reaction with benzeneselenenyl chloride in
dichloromethane-methanol. The diastereoselection is dependent on the reaction conditions and the structure
of the starting compounds and can be rationalized by accepting the coordination of the selenium to the
oxygen atom of the heterocycle.
Introduction
of a seleniranium ion intermediate followed by attack of a
nucleophile. The reaction exhibits anti stereoselectivity and
predominantly Markownikoff regioselectivity.
Functionalization of double bonds promoted by an electro-
phile is versatile and one of the most utilized reactions.1 In this
context, the electrophilic selenenylation of alkenes2 and cy-
closeleno functionalization3 reactions gained increased popular-
ity because the selenium derivatives obtained are useful
intermediates in organic synthesis and have interesting biological
applications.4 Transformations of selenoderivatives into car-
banions, reductive deselenylation, oxidation to the corresponding
selenoxide or selenone and subsequent substitution or elimina-
tion, and participation in radical coupling processes make the
organoselenium derivatives versatile building blocks in organic
synthesis.5
Different strategies can be used for the control of the absolute
stereochemistry. The selenylation reaction of alkenes in the
presence of enantiomerically pure nucleophiles has been em-
ployed in the preparation of 1,4-dioxanes,6 carbohydrate deriva-
tives,7 cyclitols,8 and morpholines9 but with modest diastereo-
facial discrimination. Recently chiral organoselenium reagents
have been used to effect asymmetric synthesis.10,11 Several types
of chiral selenium electrophiles have been investigated for this
purpose, but diastereoselectivity tends to be highly dependent
(5) (a) Krief, A. In ComprehensiVe Organometallic Chemistry; Abel, E.
W., Stone, G. A. F., Wilkinson, G., Eds; Pergamon: Oxford, 1995; Vol.
11, p 515. (b) Reich, H. J.; Wollowitz, S. Org. React. 1993, 44, 1. (c)
Organoselenium Chemistry; Liotta, D., Ed.; Wiley: New York, 1987. (d)
Paulmier, C. Selenium Reagents and Intermediates in Organic Synthesis;
Pergamon: Oxford, 1986. (e) The Chemistry of Organic Selenium and
Tellurium Compounds; Patai, S., Rappoport, Z., Eds.; Wiley: New York,
1986. (f) Nicolau, K. C.; Petasis, N. A. Selenium in Natural Products
Synthesis; CIS: Philadelphia, 1984. (g) Liotta, D. Acc. Chem. Res. 1984,
17, 28. (h) Clive, D. L. J. Tetrahedron 1978, 34, 1049.
(6) Tiecco, M.; Testaferri, L.; Marini, F.; Sternativo, S.; Santi, C.;
Bagnoli, L.; Temperini, A. Tetrahedron: Asymmetry 2003, 14, 1095.
(7) Kim, S. K.; Moon, C. W.; Park, J. I.; Han, S. H. J. Chem. Soc.,
Perkin Trans. 1 2000, 1341.
(8) Kim, S. K.; Park, J. I.; Moon, H. K.; Yi, H. Chem. Commun. 1998,
1945.
(9) Tiecco, M.; Testaferri, L.; Marini, F.; Sternativo, S.; Santi, C.;
Bagnoli, L.; Temperini, A. Tetrahedron: Asymmetry 2003, 14, 2651.
(10) For general reviews on chiral selenium compounds, see: (a) Wirth,
T. Tetrahedron 1999, 55, 1. (b) Wirth, T. Angew. Chem., Int. Ed. 2000, 39,
3740.
The electrophilic selenenylation reaction of alkenes is known
to occur by a two-step mechanism that involves the formation
(1) Block, E.; Schwan, A. L. In ComprehensiVe Organic Synthesis, Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 4, p 329.
(2) (a) Beaulien, P. L.; Deziel, R. In Organoselenium Chemistry: A
Practical Approach; Back, T. G., Ed.; Oxford University: Oxford, 1999;
p 35. (b) Mikolajczyk, M.; Drabowicz, J.; Kielbasinski, P. StereoselectiVe
Synthesis, Houben-Weyl; Georg Thieme Verlag: Stuttgart, 1996; Vol. E21D,
p 5083.
(3) (a) Ranganathan, S.; Muraleedharan, K. M.;. Vaish, N. K.; Jayaraman,
N. Tetrahedron 2004, 60, 5273. (b) Petragnani, N.; Stefani, H. A.; Valduga,
C. J. Tetrahedron 2001, 57, 1411. (c) Tiecco, M. Top. Curr. Chem. 2000,
208, 7.
(4) (a) Selenium Its Molecular Biology and Role in Human Health;
Hatfield, D. L., Ed.; Kluwer Academic Publishers: Boston, 2001. (b)
Selenium in Biology and Human Health; Burk, R. F., Ed.; Springer-
Verlag: New York, 1994.
10.1021/jo052582e CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/14/2006
2424
J. Org. Chem. 2006, 71, 2424-2428

Regio- and StereoselectiVe Methoxyselenenylation
TABLE 1. Methoxyselenenylation of Alkenes 3a-h
time yield
upon the reaction conditions and substitution patterns of the
alkene. In addition, the mixture of diastereoisomers formed are
unseparable,11c,d limiting the scope and general effectiveness
of this method. However, the use of a chiral auxiliary covalently
attached to the alkene has been less studied.
Recently, it has been shown12-14 that perhydro-1,3-benzox-
azines derived from (-)-8-aminomenthol are useful chiral
templates in asymmetric synthesis, and we now focus our
attention on the preparation of selenenyl perhydro-1,3-benzox-
azine derivatives by regio- and stereoselective methoxyselene-
nylation of 2-vinylperhydro-1,3-benzoxazines.15
T
products
(ratio)b
entry compd R1
R2
(°C) (h) (%)a
1
2
3
4
5
6
7
8
3a
3a
3b
3c
3d
3d
3d
3e
3e
3f
H
H
H
H
H
H
H
H
H
H
C6H5
C6H5
2-NO2-C6H4
4-NO2-C6H4
2-CH3O-C6H4
2-CH3O-C6H4
-15
24
48 93
22
4a (>96)
22 168 70c 4b (>96)
22 168 71d 4c (>96)
22
22
24 95
72 93
24 98
24 96
48 96
72 89
4d (58) 5d (42)
4d (35) 5d (65)
4d (>96)
4e (50) 5e (50)
4e (>96)
4f (>96)
2-CH3O-C6H4 -15
4-CH3O-C6H4 22
4-CH3O-C6H4 -15
9
10
11
12
13
14
CH3
22
22
4
3g
3g
3h
3h
Bn C6H5
Bn C6H5
96 76e 4g (81) 5g (19)
168 42f 4g (88) 5g (12)
Results and Discussion
Bn 2-CH3O-C6H4
22 108 75g 4h (50) 5h (50)
Bn 2-CH3O-C6H4 -15 168 60h 4h (>96)
The starting chiral compounds 3a-f were prepared in nearly
a Yield refers to pure compounds after column chromatography. b De-
termined by 1H NMR of the reaction mixtures. c 22% of 3b was recovered.
d 0% of 3c was recovered. e 16% of 3g was recovered. f 51% of 3g was
recovered. g 20% of 3h was recovered. h 31% of 3h was recovered.
quantitative yield by condensation of (-)-8-amino menthol16
1
with R,â-unsaturated aldehydes in toluene at room temperature,
whereas the N-benzyl perhydro-1,3-benzoxazines 3g and 3h
were prepared by condensation of (-)-8-benzylamino menthol13b
2 with cinnamaldehyde and 2-methoxycinnamaldeyde in re-
fluxing toluene.
SCHEME 1. Synthesis of Compounds 3a-h and Their
Methoxyselenenylation
In a typical experiment, PhSeCl (1.1 equiv) was dissolved in
methanol, and a solution of the corresponding perhydroben-
zoxazine in CH2Cl2 was added at the temperature indicated in
Table 1. The reaction was quenched with 10% aqueous NaOH,
the products were isolated by flash chromatography, and the
results are summarized in Scheme 1 and Table 1.
The methoxyselenenylation of alkene 3a did not take place
at -15 °C (entry 1 in the table) but gave a very clean conversion
at room temperature for 48 h with excellent yield and total regio-
and stereoselectivity (entry 2). Only the formation of diastereo-
isomer 4a, of the four possible, resulting from an anti addition
with attack of methanol at the benzylic position was observed
in the reaction mixture.
As expected, the methoxyselenenylation of alkenes 3b and
3c with an electron-withdrawing nitro group was much slower
and the chemical yield decreased, although the excellent levels
of regio- and stereoselectivity were maintained (entries 3 and
4).
The effect of temperature has been shown to be very critical
in methoxyselenylation of activated alkenes 3d and 3e. At room
temperature the reaction was completed after 24 h with excellent
chemical yield and total regioselectivity (entries 5 and 8), but
the reaction showed a very low degree of stereoselection and
almost equimolar mixtures of the two possible stereoisomers
4d/5d and 4e/5e were obtained. By contrast, the methoxy-
selenenylation of 3d and 3e at -15 °C produces excellent yields
and total stereoselection (entries 7 and 9).
The diastereoselectivity of the addition to 3d was also
dependent on the reaction time. Thus, the ratio of diastereo-
isomers 4d: 5d varied when the reaction time increased
(compare entry 5 vs 6), changing from 58:42 after 24 h to
35:65 after 72 h at room temperature. These results are a
consequence of the reversivility of this reaction,17 diastereo-
isomer 4d was favored under kinetic conditions, whereas 5d is
the major diastereoisomer formed under thermodynamic control.
Interestingly, although it is known that disubstituted alkenes
without aryl groups yield mixtures of regioisomers with low
diastereoselectivity,18 methoxyselenenylation of 3f, with a
(11) For some recent examples, see: (a) Tiecco, M.; Testaferri, L.; Santi,
C.; Tomassini, C.; Bonini, R.; Marini, F.; Bagnoli, L.; Temperini, A. Org.
Lett. 2004, 6, 4751. (b) Khokhar, S. S.; Wirth, T. Eur. J. Org. Chem. 2004,
4567. (c) Tiecco, M.; Testaferri, L.; Santi, C.; Tomassini, F.; Marini, F.;
Bagnoli, L.; Temperini, A. Angew. Chem., Int. Ed. 2003, 42, 3131. (d) Back,
T. G.; Moussa, Z.; Parvez, M. J. Org. Chem. 2002, 67, 499. (e) Tiecco,
M.; Testaferri, L.; Santi, C.; Tomassini, C.; Marini, F.; Bagnoli, L.;
Temperini, A. Chem. Eur. J. 2002, 8, 1118. (f) Tiecco, M.; Testaferri, L.;
Santi, C.; Tomassini, C.; Marini, F.; Bagnoli, L.; Temperini, A. Tetrahe-
dron: Asymmetry 2002, 13, 429. (g) Uehlin, L.; Fragale, G.; Wirth, T. Chem.
Eur. J. 2002, 8, 1125. (h) Tiecco, M.; Testaferri, L.; Bagnoli, L.; Purgatori,
V.; Temperini, A.; Marini, F.; Santi, C. Tetrahedron: Asymmetry 2001,
12, 3297. (i) Tiecco, M.; Testaferri, L.; Marini, F.; Sternativo, S.; Bagnoli,
L.; Santi, C.; Temperini, A. Tetrahedron: Asymmetry 2001, 12, 1493.
(12) (a) Pedrosa, R.; Andre´s, C.; Mart´ın, L.; Nieto, J.; Roso´n, C. J. Org.
Chem. 2005, 70, 4332. (b) Pedrosa, R.; Andre´s, C.; Nieto, J.; del Pozo, S.
J. Org. Chem. 2005, 70, 1408. (c) Pedrosa, R.; Andre´s, C.; Roso´n, C. D.;
Vicente, M. J. Org. Chem. 2003, 68, 1852.
(13) (a) Eliel, E. L.; He, X. C. J. Org. Chem. 1990, 55, 2114. (b) He, X.
C.; Eliel, E. L. Tetrahedron 1987, 43, 4979.
(14) (a) Saucy, C.; Lacoste, J. E.; Breau, L. Tetrahedron Lett. 1998, 39,
9117. (b) Lacoste, J. E.; Saucy, C.: Rochon, F. D.; Breau, L. Tetrahedron
Lett. 1998, 39, 9121.
(15) (a) Pedrosa, R.; Andre´s, C.; Duque-Soladana, J. P.; Roso´n, C. D.
Tetrahedron: Asymmetry 2000, 11, 2809 (b) Andre´s, C.; Duque-Soladana,
J. P.; Pedrosa, R. J. Org. Chem. 1999, 64, 4273. (c) Andre´s, C.; Duque-
Soladana, J. P.; Pedrosa, R. J. Org. Chem. 1999, 64, 4282.
(17) (a) Wirth, T.; Fragale, G.; Spichty, M. J. Am. Chem. Soc. 1998,
120, 3376. (b) Gruttadauria, M.; Aprile, C.; Riela, R.; Noto, R. Tetrahedron
Lett. 2001, 42, 2213. (c) Gruttadauria, M.; Lo Meo, P.; Noto, R. Tetrahedron
2001, 57, 1819.
(18) (a) Wirth, T. Angew. Chem., Int. Ed. Eng. 1995, 34, 1726. (b)
Cooper, M. A.; Ward, D. Tetrahedron Lett. 1995, 36, 2327.
(16) Rassat, A.; Rey, P. Tetrahedron 1974, 30, 3315.
J. Org. Chem, Vol. 71, No. 6, 2006 2425

Pedrosa et al.
possible seleniranium ions intermediates.21 Because the reaction
is a reversible process and the electrophilic attack is the rate-
determining step, the diastereomeric ratio of the products reflects
the stability of the preceding seleniranium intermediates.
Alternatively, coordination of the selenium to the heteroatom
of the perhydrobenzoxazine could occur prior to the formation
of the seleniranium ion intermediate, followed by intramolecular
delivery of the electrophilic selenium species to the double
bond.22
SCHEME 2. Deselenylation of Compounds 4d, 4f, and 5d
On the other hand, it is well-known that PhSeCl reacts
instantaneously with dialkylamines to form selenamides (PhSe-
NR1R2), which can act as efficient PhSe+ donors to the olefinic
double bond.
To determine if a selenium-nitrogen coordination intermedi-
ate was responsible for the high stereoselectivity, we envisaged
that the transformation of perhydrobenzoxazines into their
ammonium salts would prevent the further coordination of the
nitrogen atom. To this end, we tested the transformation of 3d
into the corresponding methiodide by reaction with excess of
methyl iodide, but no ammonium derivative was isolated. On
the contrary, 3d was transformed into its hydrochloride by
bubbling dry hydrogen chloride through a solution of 3d in ether
and filtration of the precipitate. Otherwise, this salt could be
formed prior to the methoxyselenenylation by quaternization
of the starting perhydrobenzoxazines with hydrogen chloride
formed by reaction of PhSeCl with methanol used as solvent.
The nitrogen atom of 3d-HCl is unable to coordinate the
selenium reagents, but the reaction of the hydrochloride with
PhSeCl at -15 °C yielded 4b with total regio- and stereo-
selectivity. This result suggests that chelation with oxygen is
preferred over coordination with nitrogen. Moreover, this fact
is supported by the observation of intramolecular Se‚‚‚O
nonbonding interactions23 in 4g and 4h. The shorter atomic
distances between Se and the O atom of the oxazine ring (rSe-O
) 2.765 Å for 4g and rSe-O ) 2.773 Å for 4h) relative to the
sum of van der Waals radii (3.42 Å) and the almost linear O(1)-
Se(1)-C(13) angle show the presence of a hypervalent Se-O
interaction for these compounds. The coordination geometry
around the selenium atom is a distorted T-shape as described
for other selenium compounds with nonbonding Se-heteroatom
interaction.24
SCHEME 3. Stereochemical Correlation of Compound 4d
methyl group at the terminus of the double bond, proceeded
with total regio- and stereoselectivity (entry 10).
The influence of a substituent at the nitrogen atom of the
perhydro-1,3-benzoxazine was investigated in N-benzyl deriva-
tives 3g and 3h (entries 11-14). These alkenes were less
reactive to electrophilic attack and the addition products are
formed with lower yields and diastereoselectivities, but a very
good level of diastereoselectivity is retained for methoxy-
selenenylation of alkene 3h when the reaction was carried out
at -15 °C. This fact demonstrates that the size of the substituent
at the nitrogen atom has no influence on the stereochemical
outcome of the selenenylation of the double bond.
The structure of compounds 4a-h and 5d-h was determined
on the basis of the 1H and 13C NMR data after chromatographic
purification and confirmed by reductive deselenenylation of 4d,
4f, and 5d to 6d, 6f, and 7d, respectively, with triphenyltin
hydride in the presence of catalytic amounts of AIBN in
refluxing toluene (Scheme 2).19
The absolute configuration of the N-benzyl derivatives 4g
and 4h was established by X-ray diffraction analysis,20 whereas
the absolute configuration of the minor diastereoisomers 5g and
5h was assigned by assuming an anti addition on the basis of
the literature precedents.
The absolute configuration of the newly created stereocenters
in 4d was determined by its conversion into perhydrobenzox-
azine 8d by nucleophilic ring opening of the N,O-acetal moiety
by aluminum hydride and condensation of the resulting 1,3-
amino alcohol derivative with acetaldehyde (Scheme 3). X-ray
diffraction analysis allowed for the determination of the
stereochemistry of 8d.20
The reason for the preferential coordination to the oxygen
rather than to the nitrogen atom might be a consequence of the
axial position of the substituents at the nitrogen atom in the
perhydrobenzoxazine and the assumption that the selenium-
heteroatom nonbonded interaction would involve the axial rather
than the equatorial lone pair of the heteroatom.
Two possible seleniranium intermediates A and B with
nonbonded Se‚‚‚O interactions can be envisaged (Figure 1). The
intermediate A is more stable and responsible for the formation
of the single or major diastereoisomers 4a-h. Intermediate B
is clearly sterically less favorable due to the steric hindrance
The high regio- and stereoselectivity observed in the meth-
oxyselenylation of alkenes 3a-h could be readily understood
by accepting the complexation of the selenium to the nitrogen
or oxygen atoms of the perhydro-1,3-benzoxazine ring, so that
this nonbonded interaction stabilizes preferably one of the two
(21) (a) Kim, K. S.; Park, H. B.; Kim, J. Y.; Ahn, Y. H.; Jeong, I. H.
Tetrahedron Lett. 1996, 37, 1249. (b) Cooper, M. A.; Ward, A. D.
Tetrahedron 2004, 60, 7963.
(22) Liotta, D.; Zima, G.; Saindane, M. J. Org. Chem. 1982, 47, 1258.
(23) For some examples of intramolecular Se‚‚‚O nonbonded interaction,
see: (a) Komatsu, H.; Iwaoka, M.; Tomoda, S. Chem. Commun. 1999, 205.
(b) Iwaoka, M.; Komatsu, H.; Katsuda, T.; Tomoda, S. J. Am. Chem. Soc.
2004, 126, 5309 and references therein.
(24) (a) Iwaoka, M.; Komatsu, H.; Tomoda, S. J. Organomet. Chem.
2000, 611, 164. (b) Klapo¨tke, T. M.; Krumm, B.; Polborn, K. J. Am. Chem.
Soc. 2004, 126, 710. (c) Mugesh, G.; Singh, H. B.; Butcher, R. J.
Tetrahedron: Asymmetry 1999, 10, 237.
(19) Clive, D. L. J.; Chittattu, G. J.; Farina, V.; Kiel, W. A.; Menchen,
S. M.; Russell, C. G.; Singh, A.; Wong, C. K.; Curtis, N. J. J. Am. Chem.
Soc. 1980, 102, 4438.
(20) Crystallographic data can be obtained from the Cambridge Crystal-
lographic Data Center, 12, union Road, Cambridge CB2 1EZ, UK. E-mail:
deposit@ccdc.cam.ac.uk.
2426 J. Org. Chem., Vol. 71, No. 6, 2006

Regio- and StereoselectiVe Methoxyselenenylation
2H); 7.19 (dd, 1H, J1 ) 7.4 Hz, J2 ) 1.2 Hz); 7.60 (dd, 1H, J1 )
7.8 Hz, J2 ) 1.2 Hz). 13C NMR (δ): 20.0; 22.2; 25.5; 29.8; 31.3;
34.9; 41.4; 51.3; 51.6; 57.5; 59.9; 74.7; 78.1; 79.6; 123.3; 126.6;
128.0; 128.2 (2C); 129.1; 129.9; 131.7; 133.5 (2C); 135.3; 150.7.
IR (film): 3285, 3060, 1730, 1690, 785, 740, 695, 670, 620 cm-1
.
Anal. Calcd for C26H34N2O4Se: C, 60.34; H, 6.62; N, 5.41.
Found: C, 60.49; H, 6.78; N, 5.29.
(2S,4aS,7R,8aR)-2-[(1R,2R)-2-Methoxy-2-(4-nitro-phenyl)-1-
phenylselenyl-ethyl]-4,4,7-trimethyl-octahydro-benzo[e][1,3]-
oxazine (4c). Colorless solid. Mp 139-140 °C (from EtOH). [R]25
D
1
) -93.3 (c 1.1, CHCl3). H NMR (δ): 0.93-1.20 (m, 4H); 0.95
FIGURE 1. Plausible structures for the seleniranium intermediates.
(d, 3H, J ) 6.5 Hz); 1.16 (s, 3H); 1.20 (s, 3H); 1.47 (m, 1H);
1.69-1.72 (m, 2H); 1.95 (m, 1H); 2.55 (s, broad, 1H); 3.16 (s,
3H); 3.29 (d, 1H, J ) 10.6 Hz); 3.50 (td, 1H, J1 ) 10.3 Hz, J2 )
4.1 Hz); 4.54 (d, 1H, J ) 10.6 Hz); 4.97 (s, 1H); 6.85-6.92 (m,
4H); 7.03 (m, 1H); 7.27 (d, 2H, J ) 8.6 Hz); 7.85 (d, 2H, J ) 8.6
Hz). 13C NMR (δ): 20.0; 22.2; 25.5; 29.8; 31.3; 34.9; 41.6; 51.3;
51.7; 57.1; 59.0; 74.8; 79.6; 83.8; 122.5 (2C); 126.8; 128.3 (2C);
129.1 (2C); 129.5; 133.6 (2C); 147.3; 147.5. IR (Nujol): 3275,
3050, 1685, 1605, 740, 695 cm-1. Anal. Calcd for C26H34N2O4Se:
C, 60.34; H, 6.62; N, 5.41. Found: C, 60.21; H, 6.79; N, 5.53.
(2S,4aS,7R,8aR)-2-[(1R,2R)-2-Methoxy-2-(2-methoxy-phenyl)-
between the olefinic hydrogen and the perhydrobenzoxazine
framework; 5d, 5e, 5g, and 5h are formed as minor diastere-
omers, or no products were formed from this conformation.
The described regio- and stereochemical results can also be
interpreted in terms of simple electrostatic arguments, so that
the electrophilic attack occurs preferentially at the R carbon and
syn to the oxygen, as described for related reactions in acyclic
chiral allylic systems with oxygen substituents.25
In summary, we have shown that chiral perhydrobenzoxazines
serve as excellent templates to promote methoxyselenenylation
with total regio- and diastereoselectivity. Depending on the
reaction conditions, this methodology yields better face dis-
crimination than when chiral selenyl derivatives are used and
offer the advantage of an easier purification of the mixtures of
stereoisomers.
1-phenylselenyl-ethyl]-4,4,7-trimethyl-octahydro-benzo[e][1,3]-
1
oxazine (4d). Colorless oil. [R]25 ) -42.6 (c 0.9, CHCl3). H
D
NMR (333 K) (δ): 0.79-1.09 (m, 4H); 0.84 (d, 3H, J ) 6.5 Hz);
1.03 (s, 3H); 1.05 (s, 3H); 1.38 (m, 1H); 1.57-1.60 (m, 2H); 1.84
(m, 1H); 2.60 (s, broad, 1H); 3.10 (s, 3H); 3.34 (td, 1H, J1 ) 10.2
Hz, J2 ) 4.1 Hz), 3.44 (s, 3H); 3.59 (dd, 1H, J1 ) 10.0 Hz, J2 )
1.5 Hz); 4.72 (d, 1H, J ) 10.0 Hz); 4.80 (d, 1H, J ) 1.5 Hz); 6.53
(dd, 1H, J1 ) 8.1 Hz, J2 ) 1.1 Hz); 6.63 (td, 1H, J1 ) 7.6 Hz, J2
) 1.1 Hz); 6.84-6.89 (m, 2H); 6.93-7.14 (m, 5H). 13C NMR (333
K) (δ): 20.0; 22.2; 25.6; 29.9; 39.4; 35.2; 41.8; 51.3; 52.0; 55.1;
57.1; 57.6; 74.8; 80.3; 80.6; 110.7; 119.9; 126.5; 128.1 (3C); 128.5;
130.0, 130.6; 134.6 (2C); 158.3. IR (film): 3280, 1600, 1580, 750,
695, 620 cm-1. Anal. Calcd for C27H37NO3Se: C, 64.53; H, 7.42;
N, 2.79. Found: C, 64.70; H, 7.56; N, 2.92.
Experimental Section
Methoxyselenenylation of Alkenes 3a-h. General Method.
To a stirred mixture of benzeneselenenyl chloride (1.1 g, 5.7 mmol)
in methanol (20 mL was added a solution of the oxazine 3a-h
(5.2 mmol) in CH2Cl2 (5 mL). The solution was stirred at the
temperature and for the time shown in Table 1 and then diluted
with a 10% aqueous solution of NaOH. The CH2Cl2 and the
methanol were removed under reduced pressure, and the aqueous
phase was extracted with chloroform (3 × 30 mL). The combined
organic extracts were washed with H2O and dried over MgSO4,
the solvent was removed under reduced pressure, and the residue
was chromatographed on silica gel using mixtures of hexane/EtOAc
as eluent.
(2S,4aS,7R,8aR)-[(1S,2S)-2-Methoxy-2-(2-methoxy-phenyl)-1-
phenylselenyl-ethyl]-4,4,7-trimethyl-octahydro-benzo[e][1,3]-
oxazine (5d). Colorless oil. 1H NMR (δ): 0.8-1.15 (m, 4H); 0.90
(d, 3H, J ) 6.5 Hz); 1.06 (s, 3H); 1.10 (s, 3H); 1.38 (m, 1H);
1.62-1.66 (m, 2H); 1.84 (m, 1H); 2.51 (s, broad, 1H); 3.21 (s,
3H); 3.35 (td, 1H, J1 ) 10.5 Hz, J2 ) 4.3 Hz); 3.65 (s, 3H); 3.75
(dd, 1H, J1 ) 8.4 Hz, J2 ) 1.8 Hz) 4.75 (d, 1H, J ) 1.8 Hz); 4.83
(d, 1H, J ) 8.4 Hz); 6.75 (dd, 1H, J1 ) 8.1 Hz, J2 ) 0.9 Hz); 6.86
(td, 1H, J1 ) 7.4 Hz, J2 ) 0.9 Hz); 7.06-7.38 (m, 5H); 7.39-7.40
(m, 2H). 13C NMR (CDCl3) δ: 19.6 (CH3); 22.3 (CH3); 25.3 (CH2);
30.0 (CH3); 31.3 (CH); 35.0 (CH2); 41.4 (CH2); 51.3 (CH + C);
54.5 (CH); 55.0 (CH3); 57.3 (CH3); 75.0 (CH); 78.9 (CH); 82.8
(CH); 110.3 (CH); 120.1 (CH); 126.7 (CH); 128.0 (C); 128.3 (2CH);
128.5 (CH); 130.8 (C); 134.0 (CH); 134.5 (2CH); 157.7 (CH). Anal.
Calcd for C27H37NO3Se: C, 64.53; H, 7.42; N, 2.79. Found: C,
64.39; H, 7,47; N, 2.64
(2S,4aS,7R,8aR)-2-[(1R,2R)-2-Methoxy-2-(4-methoxy-phenyl)-
1-phenylselenyl-ethyl]- 4,4,7-trimethyl-octahydro-benzo[e][1,3]-
oxazine (4e). Colorless oil. [R]25D ) -58.3 (c 1.1, CHCl3). 1H NMR
(δ): 0.86-1.18 (m, 4H); 0.94 (d, 3H, J ) 6.5 Hz); 1.15 (s, 3H);
1.18 (s, 3H); 1.46 (m, 1H); 1.68-1.71 (m, 2H); 1.95 (m, 1H); 2.52
(s, broad, 1H); 3.13 (s, 3H); 3.29 (d, 1H, J ) 10.6 Hz); 3.48 (td,
1H, J1 ) 10.3 Hz, J2 ) 4.1 Hz); 3.73 (s, 3H); 4.36 (d, 1H, J )
10.6 Hz); 4.95 (s, 1H); 6.59 (d, 2H, J ) 8.6 Hz); 6.89-6.96 (m,
4H); 7.03 (m, 1H); 7.04 (d, 2H, J ) 8.6 Hz). 13C NMR (δ): 20.1;
22.3; 25.5; 29.9; 31.4; 35.0; 41.7; 51.3; 51.7; 55.2; 56.6; 60.2; 74.7;
79.9; 84.0; 112.9 (2C); 126.6; 128.1 (2C); 129.5 (2C); 130.0; 132.0;
134.4 (2C); 159.0. IR (film): 3325, 1610, 1510, 830, 745, 735,
690 cm-1. Anal. Calcd for C27H37NO3Se: C, 64.53; H, 7.42; N,
2.79. Found: C, 64.63; H, 7.56; N, 2.68.
(2S,4aS,7R,8aR)-2-[(1R,2R)-2-Methoxy-2-phenyl-1-phenylse-
lenyl-ethyl]-4,4,7-trimethyl-octahydro-benzo[e][1,3]oxazine (4a).
Colorless solid. Mp 98-99 °C (from EtOH). [R]25 ) -62.1 (c
D
1.3, CH2Cl2). 1H NMR (δ): 0.88-1.18 (m, 4H); 0.93 (d, 3H, J )
6.4 Hz); 1.13 (s, 3H); 1.17 (s, 3H); 1.46 (m, 1H); 1.53-1.73 (m,
2H); 1.95 (m, 1H); 2.61 (s, broad, 1H); 3.12 (s, 3H); 3.29 (d, 1H,
J ) 10.7 Hz); 3.46 (td, 1H, J1 ) 10.1 Hz, J2 ) 3.9 Hz); 4.41 (d,
1H, J ) 10.7 Hz); 4.97 (s, 1H); 6.86-6.88 (m, 4H); 6.96-7.14
(m, 6H). 13C NMR (δ): 19.9; 22.1; 25.3; 29.7; 31.1; 34.8; 41.4;
50.9; 51.5; 56.5; 59.8; 74.4; 79.6; 84.3; 126.4; 127.3 (3C); 127.9
(2C); 128.3 (2C); 129.7; 134.1 (2C); 139.6. IR (Nujol): 3270, 3050,
1580, 740, 700, 620 cm-1. Anal. Calcd for C26H35NO2Se: C, 66.09;
H, 7.47; N, 2.96. Found: C, 66.22; H, 7.59; N, 3.08.
(2S,4aS,7R,8aR)-2-[(1R,2R)-2-Methoxy-2-(2-nitro-phenyl)-1-
phenylselenyl-ethyl]-4,4,7-trimethyl-octahydro-benzo[e][1,3]-
1
oxazine (4b). Yellow oil. [R]25 ) -213.9 (c 1.0, CH2Cl2). H
D
NMR (δ): 0.80-1.12 (m, 4H); 0.86 (d, 3H, J ) 6.4 Hz); 1.06 (s,
3H); 1.10 (s, 3H); 1.41 (m, 1H); 1.59-1.61 (m, 2H); 1.85 (m, 1H);
2.45 (s, broad, 1H); 3.21 (s, 3H), 3.22 (d, 1H, J ) 10.4 Hz); 3.37
(td, 1H, J1 ) 10.5 Hz, J2 ) 4.2 Hz); 4.82 (s, 1H); 5.25 (d, 1H, J )
10.4 Hz); 6.81-6.85 (m, 2H); 6.86-6.96 (m, 3H); 7.00-7.11 (m,
(25) (a) Kahn, S. D.; Hehre, W. J. J. Am. Chem. Soc. 1987, 109, 666.
(b) Kahn, S. D.; Pau, C. F.; Chamberlin, A. R.; Hehre, W. J. J. Am. Chem.
Soc. 1987, 109, 650. Chamberlin, A. R.; Mulholland, R. L., Jr.; Kahn, S.
D.; Hehre, W. J. J. Am. Chem. Soc. 1987, 109, 672.
(2S,4aS,7R,8aR)-2-[(1S,2S)-2-Methoxy-2-(4-methoxy-phenyl)-
1-phenylselenyl-ethyl]- 4,4,7-trimethyl-octahydro-benzo[e][1,3]-
oxazine (5e). Colorless oil. [R]25D ) +34.5 (c 1.0, CHCl3). 1H NMR
J. Org. Chem, Vol. 71, No. 6, 2006 2427

Pedrosa et al.
(δ): 0.81-1.12 (m, 4H); 0.93 (d, 3H, J ) 6.5 Hz); 1.03 (s, 3H);
1.09 (s, 3H); 1.45 (m, 1H); 1.63-1.67 (m, 2H); 1.93 (m, 1H); 2.51
(s, broad, 1H); 3.15 (s, 3H); 3.38 (td, 1H, J1 ) 10.5 Hz, J2 ) 4.1
Hz); 3.47 (dd, 1H, J1 ) 9.7 Hz, J2 ) 2.2 Hz); 3.77 (s, 3H); 4.47 (d,
1H, J ) 9.7 Hz); 4.79 (d, 1H, J ) 2.2 Hz); 6.73 (d, 2H, J ) 8.6
Hz); 7.02-7.27 (m, 7H). 13C NMR (δ): 19.4; 22.3; 25.4; 30.0;
31.3; 35.0; 41.6; 51.2; 51.7; 55.1; 55.8; 56.3; 75.1; 83.3; 83.8; 113.1
(2C); 126.9; 128.3 (2C); 129.2 (2C); 130.3; 132.0; 134.5 (2C);
159.1. IR (film): 3325, 3060, 1610, 1580, 830, 740, 690, 670, 640
cm-1. Anal. Calcd for C27H37NO3Se: C, 64.53; H, 7.42; N, 2.79.
Found: C, 64.61; H, 7.50; N, 2.89.
(2S,4aS,7R,8aR)-2-[(1R,2R)-2-Methoxy-1-phenylselenyl-pro-
pyl]- 4,4,7-trimethyl-octahydro-benzo[e][1,3]oxazine (4f). Color-
less oil. [R]25D ) +16.5 (c 1.0, CHCl3). 1H NMR (δ): 0.83-1.11
(m, 4H); 0.91 (d, 3H, J ) 6.5 Hz); 1.12 (s, 3H); 1.13 (s, 3H); 1.24
(d, 3H, J ) 6.2 Hz); 1.42 (m, 1H); 1.66-1.68 (m, 2H); 1.86 (m,
1H); 2.43 (s, broad, 1H); 3.13 (d, 1H, J ) 9.0 Hz); 3.29 (s, 3H);
3.41 (td, 1H, J1 ) 10.4 Hz, J2 ) 4.2 Hz); 3.63 (dq, 1H, J1 ) 9.0
Hz, J2 ) 6.2 Hz); 4.71 (s, 1H); 7.18-7.27 (m, 3H); 7.59-7.62 (m,
2H). 13C NMR (δ): 18.2; 19.8; 22.1; 25.3; 29.6; 31.1; 34.7; 41.3;
50.9; 51.4; 56.6; 58.9; 74.3; 78.4; 80.1; 126.7; 128.6 (2C); 130.6;
133.4 (2C). IR (film): 3280, 3060, 1580, 785, 740, 690 cm-1. Anal.
Calcd for C21H33NO2Se: C, 61.45; H, 8.10; N, 3.41. Found: C,
61.54; H, 8.22; N, 3.56.
133.8 (2C); 139.8; 143.0. IR (film): 3060, 3030, 1600, 1580, 740,
760, 670, 650, 615 cm-1. Anal. Calcd for C33H41NO2Se: C, 70.44;
H, 7.34; N, 2.49. Found: C, 70,56; H, 7.21; N, 2.61.
(2S,4aS,7R,8aR)-3-Benzyl-2-[(1R,2R)-2-methoxy-2-(2-methoxy-
phenyl)-1-phenylselenyl-ethyl]-4,4,7-trimethyl-octahydro-benzo-
[e][1,3]oxazine (4h). Colorless solid. Mp 159-160 °C (from
EtOH). [R]25D ) +37.7 (c 1.0, CHCl3). 1H NMR (CDCl3) δ: 0.87
(s, 3H); 0.901.11 (m, 2H); 0.99 (d, 3H, J ) 6.4 Hz); 1.03 (s, 3H);
1.19 (m, 1H); 1.45-1.59 (m, 3H); 1.73 (m, 1H); 2.13 (m, 1H);
3.20 (s, 3H); 3.39 (s, 3H); 3.53 (t, 1H, J ) 1.9 Hz); 3.65 (td, 1H,
J1 ) 10.5 Hz, J2 ) 3.9 Hz); 3.72 (d, 1H, J ) 18.6 Hz); 4.50 (d,
1H, J ) 1.9 Hz); 4,57 (d, 1H, J ) 18.6 Hz); 5.09 (d, 1H, J ) 1.9
Hz); 6.74 (d, 1H, J ) 8.1 Hz); 6.97-7.32 (m, 12H); 7.50 (d, 1H,
J ) 7.2 Hz). 13C NMR (δ): 20.3; 22.1; 24.7; 26.3; 31,1; 34.9; 40.8;
45.4; 46.0; 51.5; 53.7; 57.2; 58.0; 76.3; 78.7; 82.8; 109.4; 119.5:
125.2; 126.3; 126.5; 126.8; 127.0; 127.5 (2C); 127.9 (2C); 128.0;
130.0; 135.0 (2C); 144.0; 156.3. IR (Nujol): 3060, 3040, 1600,
1590, 740, 720, 690, 635 cm-1. Anal. Calcd for C34H43NO3Se: C,
68.90; H, 7.31; N, 2.36. Found: C, 69.01; H, 7.22; N, 2.50.
(2S,4aS,7R,8aR)-3-Benzyl-2-[(1S,2S)-2-methoxy-2-(2-methoxy-
phenyl)-1-phenylselenyl-ethyl]-4,4,7-trimethyl-octahydro-benzo-
[e][1,3]oxazine (5h). Colorless oil. [R]25D ) -37.7 (c 0.5, CHCl3).
1H NMR (δ): 0.71-1.05 (m, 3H); 0.84 (s, 3H); 0.85 (d, 3H, J )
6.3 Hz); 1.25-1.67 (m, 5H); 1.32 (s, 3H); 3,24 (s, 3H); 3.31 (td,
1H, J1 ) 10.4 Hz, J2 ) 4.0 Hz); 3.56 (s, 3H); 3.86 (d, 1H, J )
17.4 Hz); 3.90 (dd, 1H, J1 ) 8.7 Hz, J2 ) 3.0 Hz); 4.10 (d, 1H, J
) 17.4 Hz); 4.55 (d, 1H, J ) 3.0 Hz); 5,17 (d, 1H, J ) 8.7 Hz);
6.71 (d, 1H, J ) 8.2 Hz); 6.86 (t, 1H, J ) 7.0 Hz); 7.11-7.34 (m,
8H); 7.41 (dd, 2H, J1 ) 7.4 Hz, J2 ) 1.5 Hz); 7.52 (d, 2H, J ) 7.2
Hz). 13C NMR (δ): 22.3; 22.9; 24.8; 27.8; 31.4; 35.2; 40.4; 43.5;
47.4; 50.9; 54.6; 58.0; 58.5; 77.0; 78.1; 86.4; 109.7; 119.5; 125.4;
127.0; 127.3 (2C); 127.4; 127.5; 127.7 (2C); 128.2 (2C); 128.8;
130.5; 135.2 (2C); 143.7; 156.5. IR (film): 3065, 3040, 1600, 1585,
750, 740, 720, 690 cm-1. Anal. Calcd for C34H43NO3Se: C, 68.90;
H, 7.31; N, 2.36. Found: C, 68.79; H, 7.38; N, 2.49.
(2S,4aS,7R,8aR)-3-Benzyl-2-[(1R,2R)-2-methoxy-2-phenyl-1-
phenylselenyl-ethyl]-4,4,7-trimethyl-octahydro-benzo[e][1,3]-
oxazine (4g). Colorless solid. Mp 124-125 °C (from EtOH). [R]25
D
1
) +39.4 (c 1.0, CHCl3). H NMR (δ): 0.82-1.18 (m, 3H); 0.92
(d, 3H, J ) 6.5 Hz);; 1.00 (s, 3H); 1.09 (s, 3H); 1.40-1.49 (m,
2H); 1.56 (m, 1H); 1.64 (m, 1H); 1.97 (m, 1H); 3.13 (s, 3H); 3.42
(dd, 1H, J1 ) 4.1 Hz, J2 ) 3.8 Hz); 3.47 (td, 1H, J1 ) 10.4 Hz, J2
) 3.9 Hz); 3.68 (d, 1H, J ) 18.3 Hz); 4.18 (d, 1H, J ) 4.1 Hz);
4.35 (d, 1H, J ) 18.3 Hz); 4.92 (d, 1H, J ) 3.8 Hz); 6.76-6.84
(m, 2H); 6.88-6.95 (m, 2H); 7.02-7.07 (m, 3H); 7.17-7.28 (m,
8H). 13C NMR (δ): 19.4; 22.2; 24.9; 26.9; 31.2; 34.9; 40.9; 46.3;
46.7; 54.7; 57.4; 57.8; 76.1; 83.0; 84.8; 125.9; 126.5; 126.9 (2C);
127.3 (3C); 127.7 (2C); 128.0 (2C); 128.3 (2C); 130.6; 134.2 (2C);
139.3; 143.4. IR (Nujol): 3060, 3040, 1600, 1580, 770, 745, 710,
700, 640 cm-1. Anal. Calcd for C33H41NO2Se: C, 70.44; H, 7.34;
N, 2.49. Found: C, 70.60; H, 7.45; N, 2.58.
Acknowledgment. The authors gratefully acknowledge the
financial support provided by the Spanish Ministerio de Edu-
cacio´n y Ciencia (DGICYT, Projects BQU 2002-01046 and
CTQ2005-01191/BQU) and Dr. Alfonso Pe´rez for X-ray
determinations. P.M. is also grateful for a predoctoral fellowship
(FPU).
(2S,4aS,7R,8aR)-3-Benzyl-2-[(1S,2S)-2-methoxy-2-phenyl-1-
phenylselenyl-ethyl]-4,4,7-trimethyl-octahydro-benzo[e][1,3]-
1
oxazine (5g). Colorless oil. [R]25 ) -17.5 (c 1.2, CHCl3). H
D
Supporting Information Available: General experimental
methods and physical and spectral characteristics for compounds
3g,h, 6d, 6f, 7d, and 8d. Copies of 1H NMR and 13C NMR spectra
for all of the described compounds. ORTEP representations of X-ray
structures for compounds 4g, 4h, and 8d including CIF files. Table
of selected bond lengths and bond angles for 4g and 4h. This
material is available free of charge via the Internet at http://
pubs.acs.org.
NMR (δ): 0.88-1.03 (m, 3H); 0.93 (d, 3H, J ) 6.5 Hz); 0.94 (s,
3H); 1.06 (s, 3H); 1.31 (m, 1H); 1.48-1.56 (m, 2H); 1.67 (m, 1H);
1.79 (m, 1H); 3.07 (s, 3H); 3.37 (td, 1H, J1 ) 10.4 Hz, J2 ) 4.0
Hz); 3.72 (dd, 1H, J1 ) 8.3 Hz, J2 ) 3.7 Hz); 3.80 (d, 1H, J )
17.9 Hz); 4.11 (d, 1H, J ) 17.9 Hz); 4.56 (d, 1H, J ) 3.7 Hz);
4,69 (d, 1H, J ) 8.3 Hz); 7.06-7.13 (m, 4H); 7.18-7.33 (m, 9H);
7.43-7.51 (m, 2H). 13C NMR (δ): 21.0; 22.3; 24.9; 27.5; 31.3;
35.1; 40.9; 44.8; 47.5; 54.1; 56.7; 58.1; 76.5; 81.9; 87.6; 125.7;
126.6; 127.2; 127.3 (2C); 127.5 (4C); 128.1 (2C); 128.4 (2C); 131.3;
JO052582E
2428 J. Org. Chem., Vol. 71, No. 6, 2006