1,4-Asymmetric induction in methoxyselenenylation of double bonds at the nitrogen side of chiral perhydro-1,3-benzoxazines promoted by nonbonded Se...N interactions

Article abstract of DOI:10.1021/jo060566r

Regio- and diastereoselective methoxyselenenylation of cinnamylamines attached to a chiral perhydrobenzoxazine occurs in high yields by reaction with benzeneselenenyl chloride in dichloromethane-methanol. The diastereoselection is dependent on the tempera

Full text of DOI:10.1021/jo060566r

lectivity in asymmetric synthesis using chiral selenium com-
pounds4 and the design of new chiral reagents.5 Furthermore,
these nonbonded interactions, which are derived from the
hypervalent nature of the selenium, can dramatically influence
the regio- and stereochemical outcome of selenenylation and
selenocyclization reactions due to the interaction of the selenium
electrophiles with nearby heteroatoms or external additives.6
Consequently, systematic structural investigations on the origin,
magnitude, and theoretical interpretation of such interactions
that involve Se‚‚‚N,7 Se‚‚‚O,8 and Se‚‚‚X9 (X ) halogen) atoms
have been carried out.
We have previously described the regio- and diastereoselec-
tive methoxyselenenylation of 2-vinylperhydro-1,3-benzox-
azines,10 and the high diastereoselectivities observed were
imputed to nonbonded interactions between the selenium and
the oxygen atom of the oxazine ring. Nevertheless, since Se‚‚
‚N interactions are also possible,7 we envisioned that the
stereoselection of the methoxyselenenylation of an allyl sub-
stituent placed at the nitrogen side of a chiral perhydrobenzox-
azine can be greatly improved due to nonbonded interactions
between the selenium of an incoming electrophile and the
nitrogen atom of the N-allyl substituent. Stereoselective elec-
trophilic selenenylation of allylic alcohol derivatives has been
previously described,11 but to our knowledge, this is the first
example of stereoselective methoxyselenenylation of allylic
amines.12
1,4-Asymmetric Induction in
Methoxyselenenylation of Double Bonds at the
Nitrogen Side of Chiral
Perhydro-1,3-benzoxazines Promoted by
Nonbonded Se‚‚‚N Interactions
Rafael Pedrosa,* Celia Andre´s,* 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 March 14, 2006
With this purpose, perhydro-1,3-benzoxazines 4a-i, which
essentially differ in the nature and size of the substituent at the
N,O-ketalic carbon of the heterocycle, were prepared as sum-
marized in Scheme 1.
Regio- and diastereoselective methoxyselenenylation of
cinnamylamines attached to a chiral perhydrobenzoxazine
occurs in high yields by reaction with benzeneselenenyl
chloride in dichloromethane-methanol. The diastereoselec-
tion is dependent on the temperature of the reaction and the
structure of the substituent at C-2 and can be rationalized
by accepting a 1,4-asymmetric induction process after
coordination of the selenium to the nitrogen atom of the
allylamine system.
(4) (a) Spichty, M.; Fragale, G.; Wirth, T. J. Am. Chem. Soc. 2000, 122,
10914. (b) Wang, X.; Houk, K. N.; Spichty, M.; Wirth, T. J. Am. Chem.
Soc. 1999, 121, 8567. (c) Wirth, T.; Fragale, G.; Spichty, M. J. Am. Chem.
Soc. 1998, 120, 3376.
(5) (a) Back, T. G.; Moussa, Z.; Parvez, M. J. Org. Chem. 2002, 67,
499. (b) Uehlin, L.; Fragale, G.; Wirth, T. Chem.sEur. J. 2002, 8, 1125.
(c) Tiecco, M.; Testaferri, L.; Bagnoli, L.; Marini, F.; Temperini, A.;
Tomassini, C.; Santi, C. Tetrahedron Lett. 2000, 41, 3241. (d) Fragale, G.;
Neuburger, M.; Wirth, T. Chem. Commun. 1998, 1867. (e) Fujita, K.;
Murata, K.; Iwaoka, M.; Shuji, T. Tetrahedron 1997, 53, 2029.
(6) (a) Khokhar, S. S.; Wirth, T. Angew. Chem., Int. Ed. 2004, 43, 631.
(b) Khokhar, S. S.; Wirth, T. Eur. J. Org. Chem. 2004, 4567.
(7) (a) Mugesh, G.; Panda, A.; Singh, H. B.; Butcher, R. J. Chem.sEur.
J. 1999, 5, 1411. (b) Iwaoka, M.; Tomoda, S. J. Am. Chem. Soc. 1996,
118, 8077. See also ref 3b.
(8) (a) Komatsu, T.; Iwaoka, M.; Tomoda, S. Chem. Commun. 1999,
205. (b) Iwaoka, M.; Komatsu, H.; Katsuda, T.; Tomoda, S. J. Am. Chem.
Soc. 2004, 126, 5309. (c) Barton, D. H. R.; Hall, H. B.; Lin, Z.; Parekh, S.
I.; Reibenspies, J. J. Am. Chem. Soc. 1993, 115, 5056.
(9) (a) Iwaoka, M.; Komatsu, H.; Katsuda, T.; Tomoda, S. J. Am. Chem.
Soc. 2002, 124, 1902. (b) Iwaoka, M.; Komatsu, H.; Katsuda, T.; Tomoda,
S. J. Org. Chem. 2005, 70, 321.
Nonbonded interactions between a divalent selenium atom
and an electron donor heteroatom play a significant role in
different fields, such as the activity of therapeutic agents,1 the
catalytic mechanism of glutathione peroxidase mimics,2 and the
stabilization of unstable organoselenium compounds.3 These
interactions are also responsible for the origin of the stereose-
* To whom correspondence should be addressed. Fax: Int. + 983 423 013.
(1) (a) Burling, F. T.; Goldstein, M. B. J. Am. Chem. Soc. 1992, 114,
2313. (b) Goldstein, M. B.; Kennedy, S. D.; Hennen, W. J. J. Am. Chem.
Soc. 1990, 112, 8265. (c) Goldstein, F.; Takusagawa, Y.; Berman, H. M.;
Srivastava, P. C.; Robins, R. K. J. Am. Chem. Soc. 1985, 107, 1394.
(2) (a) Back, T. G.; Moussa, Z. J. Am. Chem. Soc. 2002, 124, 12104.
(b) Mugesh, G.; Panda, A.; Singh, H. B.; Punekar, N. S.; Butcher, R. J.
Am. Chem. Soc. 2001, 123, 839. (c) Mugesh, G.; du Mont, W. W.; Sies, H.
Chem. ReV. 2001, 101, 2125. (d) Mugesh, G.; Singh, H. B. Chem. Soc.
ReV. 2000, 29, 347. (e) Iwaoka, M.; Tomoda, S. J. Chem. Soc., Chem.
Commun. 1992, 1165. (f) Iwaoka, M.; Tomoda, S. J. Am. Chem. Soc. 1994,
116, 2557.
(10) Pedrosa, R.; Andre´s, C.; Arias, R.; Mendiguch´ıa, P.; Nieto, J. J.
Org. Chem. 2006, 71, 2424.
(11) (a) Cooper, M. A.; Ward, D. Tetrahedron 2004, 60, 7963. (b) Aprile,
C.; Gruttadauria, M.; Amato, M.- E.; D’Anna, F.; Lo Meo, P.; Riela, S.;
Noto, R. Tetrahedron 2003, 59, 2241. (c) Kim, K. S.; Ahn, K. O.; Park, J.,
II. Bull. Korean Chem. Soc. 1997, 18, 800. (d) Kim, K. S.; Park, H. B.;
Kim, J. Y.; Ahn, Y. H.; Jeong, H. I. Tetrahedron Lett. 1996, 37, 1249. (e)
Cooper, M. A.; Ward, D. Tetrahedron Lett. 1995, 36, 2327. (f) Haughan,
A. F.; Knight, J. R.; Sweeney, J. B. Tetrahedron Lett. 1994, 35, 1781. (g)
Liotta, D.; Zima, G.; Saindane, M. J. Org. Chem. 1982, 47, 1258.
(12) For different examples of regio- and diastereoselective addition
reactions to chiral allylic amines, see: (a) Aggarwal, V. K.; Fang, G. Y.;
Meek, G. Org. Lett. 2003, 5, 4417. (b) Lai, J.-Y.; Shi, X.-X.; Gong, Y.-S.;
Dai, L.-X. J. Org. Chem. 1993, 58, 4775. (c) Lai, J.-Y.; Wang, F.-S.; Guo,
G.-Z.; Dai, L.-X. J. Org. Chem. 1993, 58, 6944.
(3) (a) Kandasamy, K.; Kumar, S.; Singh, H. B.; Butcher, R. J.; Holman,
K. T. Eur. J. Inorg. Chem. 2004, 1014 and references therein. (b) Mugesh,
G.; Singh, H. B.; Butcher, R. Tetrahedron: Asymmetry 1999, 10, 237. (c)
Iwaoka, M.; Tomoda, S. J. Org. Chem. 1995, 60, 5299.
10.1021/jo060566r CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/15/2006
5388
J. Org. Chem. 2006, 71, 5388-5391

TABLE 1. Methoxyselenenylation of Cinnamylamines 4a-i
SCHEME 1. Synthesis of Chiral N-Allyl
Perhydrobenzoxazines 4a-i
T
yield
product
entry compound
R1
R2
(°C) (%)a
ratios (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
4a
4a
4b
4b
4c
4d
4d
4e
4e
4f
CH3
CH3
iPr
iPr
Bn
Ph
Ph
Ph
Ph
OCH3
22 93 5a (57), 6a (43)
OCH3 -15 92 5a (68), 6a (32)
OCH3
22 90 5b (78), 6b (22)
OCH3 -15 91 5b (>96)c
OCH3 -15 93 5c (56), 6c (44)
OCH3
22 85 5d (86), 6d (14)
OCH3 -15 91 5d (94), 6d (6)
H
H
H
H
H
H
22 92 5e (85), 6e (15)
-15 90 5e (92), 6e (8)
-15 87 5f (95), 6f (5)
-15 88 5g (74), 6g (26)
-15 90 5h (>96)c
3,4-(OCH3)-C6H3
1-naphthyl
2-naphthyl
4-NO2-C6H4
4g
4h
4i
-15 78 5i (80), 6i (20)
a Chemical yield refers to pure compounds after column chromatography.
1
b Determined by H NMR of the reaction mixtures. c Only one diastereo-
1
isomer was detected by H NMR.
methoxyselenenylation of allylamine 4c with a benzylic group
at C-2 of the benzoxazine ring showed a very low degree of
stereoselection, and 5c and 6c were obtained as an almost
equimolar mixture of diastereoisomers (entry 5). In contrast,
4b with a bulkier isopropyl group at C-2 reacted at -15 °C
with total diastereoselectivity, leading a single diastereoisomer
5b in excellent yield (entry 4), although at room temperature
the diastereomeric excess decreased significantly (entry 3).
The behavior of 4d and 4e with a phenyl group at C-2 of the
heterocycle is very similar, and methoxyselenenylation at -15°
C turned out also with high yield and stereoselectivity (entries
7 and 9), although the latter decreases at room temperature
(entries 6 and 8).
SCHEME 2. Methoxyselenenylation of Compounds 4a-i
The good level of stereoselection was maintained for meth-
oxyselenenylation of benzoxazines 4f and 4h with a 3,4-
dimethoxyphenyl and 2-naphthyl group, respectively (entries
10 and 12), but surprisingly, the diastereomeric ratio decreased
for benzoxazines 4g and 4i with similar bulky 1-naphthyl or
4-nitrophenyl substituents at C-2 (entries 11 and 13).
The o-methoxy cinnamyl derivatives 4a-d were prepared
in three steps by condensation of o-methoxycinnamaldehyde
with (-)-8-aminomenthol to the corresponding oxazine13 and
were transformed into the amino alcohol 2 (92%) by reduction
with sodium cyanoborohydride in methanol under slightly acidic
conditions. This amino alcohol was converted into the final
perhydro-1,3-benzoxazines 4a-d (80-86%) by heating with
acetaldehyde or isobutyraldehyde at 80 °C in a sealed tube for
4a and 4b, or by heating with phenylacetaldehyde or benzal-
dehyde in refluxing toluene for 4c and 4d. The N-cinnamyl
derivatives 4e-i were prepared in two steps by condensation
of (-)-8-aminomenthol 1 with the corresponding aldehyde in
refluxing toluene, leading nearly quantitatively to oxazines 3e-
i, which were alkylated with cinnamyl bromide and K2CO3 in
acetonitrile to 4e-i (80-88%).
The diastereoisomers formed in each reaction were separated
by flash chromatography (except the mixture of 5c and 6c, and
the minor products 6b and 6f that were not obtained pure), and
1
the regiochemistry was determined on the basis of the H and
13C NMR data, whereas the absolute stereochemistry of 5a, 5d,15
and the minor product 6a10 was established by X-ray diffraction
analysis.
The interatomic distances between the Se and the N atoms
in the oxazine rings for 5a, 5d, and 6a are 3.008, 3.205, and
2.850 Å, respectively. These distances are shorter than the sum
of van der Waal’s radii (3.5 Å), and they might indicate a weak
secondary interaction between both selenium and nitrogen
atoms. The coordination geometry around the selenium atom
is distorted T-shaped, and the substituent at the nitrogen atom
is equatorially oriented in compounds 5a and 5d but in axial
arrangement in product 6a.
Methoxyselenenylation of 4a-i was carried out employing
benzeneselenenyl chloride as electrophilic reagent,14 in a 4/1
mixture of MeOH/CH2Cl2 at room temperature or at -15 °C.
The results are summarized in Scheme 2 and Table 1.
Both the presence of a nonbonded Se‚‚‚N interaction and the
stereocenter at C-2 in the perhydrobenzoxazines is essential for
good diastereoselectivities. In this way, we observed that the
reaction of the open (-)-8-amino menthol derivative 2 with
phenylselenyl chloride in any of the reaction conditions
described yielded an equimolar mixture of diastereoisomers. In
Methoxyselenenylation of cinnamylamine 4a at room tem-
perature led to 5a and 6a with excellent yield, but with modest
stereoselectivity (entry 1 in Table 1). When the reaction
temperature was lowered to -15 °C, the reaction time increased
but the chemical yield remained excellent, and the diastereo-
selectivity improved to 68:32 (entry 2). In the same conditions,
(13) Pedrosa, R.; Andre´s, C.; Nieto, J. J. Org. Chem. 2002, 67, 782.
(14) The use of different electrophilic reagents, such as PhSeBr or
PhSeOTf, did not improve the results obtained with PhSeCl.
(15) 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.
J. Org. Chem, Vol. 71, No. 14, 2006 5389

by reaction with benzeneselenenyl chloride and methanol. When
a mixture of diastereoisomers was formed, they were easily
separated by column chromatography. This unprecedented
transformation is a novel example of 1,4-asymmetric induction
promoted by the stereocenter placed at C-2 in the perhydroben-
zoxazine system.
Experimental Section
Methoxyselenenylation of Allylamines 4a-i. 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 oxazines 4a-i
(5.2 mmol) in CH2Cl2 (5 mL). The solution was stirred at the
temperature shown in Table 1 until the reaction was completed
(TLC) and then diluted with a 10% aqueous solution of NaOH.
The solvents were removed under reduced pressure, and the aqueous
phase was extracted with chloroform (3 × 30 mL). The combined
organic extracts were washed with H2O, 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.
FIGURE 1. Proposed plausible seleniranium intermediates.
addition, when 4d hydrochloride was subjected to methoxyse-
lenenylation at room temperature, an almost equimolar mixture
of diastereoisomers 5d (54%) and 6d (46%) was obtained in
80%. In this case, the protonated nitrogen is unable to interact
with the selenium atom, and the reaction occurred without
stereoselection. An additional experiment to test the change in
the diastereoselection was made in the presence of an amine
which is able to coordinate to the reagent, but 4e was unable to
react at room temperature with the complex formed from
trithylamine and benzeneselenenyl chloride.
The excellent 1,4-asymmetric induction observed is note-
worthy and can be explained as a consequence of the nonbonded
Se‚‚‚N interaction that forces the substituent of the chiral center
at C-2 of the benzoxazine to come close to the seleniranium
ion intermediate. After coordination of the selenium reagent,
the nitrogen atom became a chiral center, and four possible
intermediates can be envisaged (Figure 1): two intermediates,
A and B, with the nitrogen substituent oriented in equatorial
disposition and two intermediates, C and D, with the same
substituent oriented in axial disposition. When R1 is a methyl
or a benzyl group, intermediates A or B and C or D are similarly
hindered, and the facial discrimination is poor. However, when
R1 is a bulkier substituent, such as isopropyl or aryl groups,
intermediates B and C are sterically less favorable due to the
steric hindrance between the olefinic hydrogen and the sub-
stituent R1, and no products were formed from these conforma-
tions. On the other hand, the substituent attached to the nitrogen
atom is in axial conformation in the most stable conformation
of perhydrobenzoxazines due to the generalized anomeric
effect.16 Nevertheless, the coordination of the selenium atom
to the unshared electron pair of the nitrogen will destroy these
effects, and the substituent attached to the nitrogen atom will
prefer a less hindered equatorial arrangement, so that intermedi-
ate A is clearly favored.
(2S,4aS,7R,8aR)-3-[(2R,3S)-3-Methoxy-3-(2-methoxyphenyl)-
2-phenylselenylpropyl]-2,4,4,7-tetramethyloctahydrobenzo[e]-
[1,3]oxazine (5a). Colorless solid. Mp: 165-166 °C (from EtOH).
1
[R]25 ) -12.0 (c ) 1.0, CH2Cl2). H NMR (300 MHz, CDCl3,
D
333 K): δ 0.72-0.99 (m, 3H), 0.74 (s, 3H), 0.79 (d, 3H, J ) 6.5
Hz), 0.91 (s, 3H), 1.07 (m, 1H), 1.15 (d, 3H, J ) 5.8 Hz), 1.21-
1.40 (m, 2H), 1.52 (m, 1H), 1.75 (m, 1H), 2.54 (dd, 1H, J1 ) 16.1
Hz, J2 ) 3.3 Hz), 3.07 (dd, 1H, J1 ) 16.1 Hz, J2 ) 11.6 Hz), 3.18
(s, 3H), 3.23 (td, 1H, J1 ) 10.5 Hz, J2 ) 4.0 Hz), 3.55 (s, 3H),
3.70 (ddd, 1H, J1 ) 11.6 Hz, J2 ) 3.3 Hz, J3 ) 2.8 Hz), 4.47 (q,
1H, J ) 5.8 Hz), 4.69 (d, 1H, J ) 2.8 Hz), 6.68 (d, 1H, J ) 8.2
Hz), 6.86 (t, 1H, J ) 7.5 Hz), 7.08-7.16 (m, 4H), 7.29 (d, 1H, J
) 7.5 Hz), 7.60-7.65 (m, 2H). 13C NMR (75 MHz, CDCl3, 333
K): δ 19.4, 21.0, 22.1, 25.0, 26.2, 31.4, 35.1, 41.5, 41.6, 45.8,
53.9, 54.9, 57.4, 58.0, 75.9, 80.2, 84.1, 110.5, 120.3, 126.5, 127.1,
128.2, 128.3 (3C), 132.5, 134.8 (2C), 157.1. IR (Nujol): ν 3060,
3040, 1595, 1585, 760, 745, 650 cm-1. Anal. Calcd for C29H41-
NO3Se: C, 65.64; H, 7.79; N, 2.64. Found: C, 65.46; H, 7.64; N,
2.79.
(2S,4aS,7R,8aR)-2-Isopropyl-3-[(2R,3S)-3-methoxy-3-(2-meth-
oxyphenyl)-2-phenylselenylpropyl]-4,4,7-trimethyloctahydrobenzo-
[e][1,3]oxazine (5b). Colorless solid. Mp: 130-131 °C (from
EtOH). [R]25D ) -25.6 (c ) 1.0, CH2Cl2). 1H NMR (CDCl3, 333
K): δ 0.70-1.02 (m, 3H), 0.80 (d, 3H, J ) 6.5 Hz), 0.85 (d, 3H,
J ) 6.5 Hz), 0.87 (d, 3H, J ) 6.5 Hz), 0.93 (s, 3H), 0.97 (s, 3H),
1.21 (m, 1H), 1.28-1.54 (m, 3H), 1.61 (m, 1H), 1.80 (m, 1H),
2.57 (m, 1H), 3.02 (dd, 1H, J1 ) 16.2 Hz, J2 ) 11.4 Hz), 3.20 (td,
1H, J1 ) 10.5 Hz, J2 ) 4.0 Hz), 3.27 (s, 3H), 3.61 (s, 3H), 3.73-
3.79 (m, 2H), 4.71 (d, 1H, J ) 2.5 Hz), 6.75 (d, 1H, J ) 8.2 Hz),
6.93 (t, 1H, J ) 7.5 Hz), 7.15-7.27 (m, 4H), 7.36 (dd, 1H, J1 )
7.5 Hz, J2 ) 1.6 Hz), 7.71-7.74 (m, 2H). 13C NMR (CDCl3, 333
K): δ 17.5, 18.4, 20.8, 22.1, 25.1, 27.0, 29.5, 31.3, 35.1, 41.4,
43.1, 46.8, 52.3, 54.7, 57.6, 58.1, 76.0, 80.4, 93.7, 110.2, 120.2,
126.5, 127.2, 128.0, 128.2, 128.3 (2C), 132.1, 134.7 (2C), 157.0.
IR (Nujol): ν 3060, 1600, 1580, 780, 760, 710, 680 cm-1. Anal.
Calcd for C31H45NO3Se: C, 66.65; H, 8.12; N, 2.51. Found: C,
66.72; H, 8.26; N, 2.62.
The presence of a nonbonded Se‚‚‚N interaction is essential
to achieve good diastereoselectivities because methoxyselene-
nylation of 4d hydrochloride leads to an almost equimolar
mixture of diastereoisomers 5d (54%) and 6d (46%). The
quaternary nitrogen in the salt cannot interact with the selenium
atom, and the reaction showed a very low degree of stereose-
lection.
(2S,4aS,7R,8aR)-3-[(2R,3S)-3-Methoxy-3-(2-methoxyphenyl)-
2-phenylselenylpropyl]-4,4,7-trimethyl-2-phenyloctahydrobenzo-
[e][1,3]oxazine (5d). Colorless solid. Mp: 198-199 °C (from
1
EtOH). [R]25 ) +32.5 (c ) 1.0, CH2Cl2). H NMR (CDCl3): δ
D
0.87-1.18 (m, 3H), 0.89 (d, 3H, J ) 6.5 Hz), 1.03 (s, 3H), 1.23
(s, 3H), 1.46 (m, 1H), 1.51 (m, 1H), 1.61-1.73 (m, 2H), 1.88 (m,
1H), 2.17-2.33 (m, 2H), 3.07 (s, 3H), 3.09 (m, 1H), 3.41 (s, 3H),
3.46 (m, 1H), 4.18 (d, 1H, J ) 1.7 Hz), 4.83 (s, 1H), 6.63 (dd, 1H,
J1 ) 8.3 Hz, J2 ) 1.1 Hz), 6.90 (t, 1H, J ) 7.6 Hz), 7.02-7.28 (m,
10H), 7.43-7.47 (m, 2H). 13C NMR (CDCl3): δ 22.1, 22.2, 25.1,
In summary, cinnamylamines taking part in a chiral perhy-
drobenzoxazine are regio- and stereoselectively functionalized
(16) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley-Interscience: New York, 1994; p 753.
5390 J. Org. Chem., Vol. 71, No. 14, 2006

27.4, 31.0, 34.6, 41.2, 42.1, 49.0, 49.8, 53.9, 57.8 (2C), 74.8, 77.4,
90.8, 109.7, 119.4, 126.5 (2C), 127.1, 127.5 (3C), 128.1 (4C), 131.1,
134.8 (3C), 140.6, 156.4. IR (Nujol): ν 3050, 1600, 1590, 760,
740, 695 cm-1. Anal. Calcd for C34H43NO3Se: C, 68.90; H, 7.31;
N, 2.36. Found: C, 68.79; H, 7.17; N, 2.52.
131.9, 134.0, 134.2 (2C), 135.9, 139.8. IR (Nujol): ν 3040, 1600,
1580, 780, 750, 735, 705, 690 cm-1. Anal. Calcd for C37H43NO2-
Se: C, 72.53; H, 7.07; N, 2.29. Found: C, 72.67; H, 6.96; N, 2.42.
(2S,4aS,7R,8aR)-3-[(2R,3S)-3-Methoxy-3-phenyl-2-phenylse-
lenylpropyl]-4,4,7-trimethyl-2-naphthalen-2-yl-octahydrobenzo-
[e][1,3]oxazine (5h). Colorless oil. [R]25 ) +11.9 (c ) 1.1,
D
(2S,4aS,7R,8aR)-3-[(2R,3S)-3-Methoxy-3-phenyl-2-phenylse-
lenylpropyl]-4,4,7-trimethyl-2-phenyloctahydrobenzo[e][1,3]-
oxazine (5e). Colorless oil. [R]25D ) +33.1 (c ) 1.0, CH2Cl2). 1H
NMR (CDCl3): δ 0.79-1.01 (m, 2H), 0.89 (d, 3H, J ) 6.4 Hz),
1.03 (s, 3H), 1.08 (m, 1H), 1.24 (s, 3H), 1.33 (m, 1H), 1.51 (m,
1H), 1.59-1.72 (m, 2H), 1.89 (m, 1H), 2.19-2.35 (m, 2H), 3.03
(m, 1H), 3.04 (s, 3H), 3.45 (td, 1H, J1 ) 10.5 Hz, J2 ) 4.1 Hz),
3.70 (d, 1H, J ) 2.2 Hz), 4.90 (s, 1H), 6.71-6.77 (m, 2H), 7.05-
7.32 (m, 11H), 7.33-7.42 (m, 2H). 13C NMR (CDCl3): δ 14.0,
22.1, 25.0, 27.4, 31.0, 34.6, 41.2, 42.0, 48.8, 52.9, 57.7, 57.8, 74.9,
82.6, 90.5, 126.4 (3C), 126.7, 126.8, 127.7 (4C), 128.3, 128.5 (3C),
131.2, 134.5 (2C), 139.5, 140.4. IR (film): ν 3060, 3030, 2920,
1600, 1580, 1450, 910, 730, 700, 650 cm-1. Anal. Calcd for C33H41-
NO2Se: C, 70.44; H, 7.34; N, 2.49. Found: C, 70.39; H, 7.51; N,
2.32.
(2S,4aS,7R,8aR)-2-(3,4-Dimethoxyphenyl)-3-[(2R,3S)-3-meth-
oxy-3-phenyl-2-phenylselenylpropyl]-4,4,7-trimethyloctahydro-
benzo[e][1,3]oxazine (5f). Colorless solid. Mp: 138-139 °C (from
EtOH). [R]25D ) +14.7 (c ) 1.0, CH2Cl2). 1H NMR (CDCl3, 333
K): δ 0.79-0.96 (m, 2H), 0.83 (d, 3H, J ) 6.5 Hz), 0.97 (s, 3H),
1.03 (m, 1H), 1.18 (s, 3H), 1.35 (m, 1H), 1.46 (m, 1H), 1.58-1.69
(m, 2H), 1.84 (m, 1H), 2.25 (dd, 1H, J1 ) 14.9 Hz, J2 ) 4.4 Hz),
2.35 (ddd, 1H, J1 ) 11.5 Hz, J2 ) 4.4 Hz, J3 ) 3.1 Hz), 2.97 (s,
3H), 3.01 (dd, 1H, J1 ) 14.9 Hz, J2 ) 11.5 Hz), 3.40 (td, 1H, J1 )
10.5 Hz, J2 ) 4.2 Hz), 3.66 (s, 3H), 3.67 (d, 1H, J ) 3.1 Hz), 3.80
(s, 3H), 4.80 (s, 1H), 6.46 (d, 1H, J ) 8.1 Hz), 6.54 (d, 1H, J )
8.1 Hz), 6.71-6.75 (m, 2H), 6.94 (s, 1H), 7.02-7.13 (m, 6H),
7.28-7.31 (m, 2H). 13C NMR (CDCl3): δ 13.2, 22.1, 25.0, 27.5,
30.9, 34.5, 41.2, 41.9, 49.1, 52.3, 55.3, 55.8, 57.7, 57.8, 74.8, 82.0,
90.6, 110.2, 111.0, 120.2, 126.1 (2C), 126.6 (2C), 127.7 (2C), 128.7
(2C), 131.2, 133.1, 134.0 (2C), 139.7, 148.1, 148.6. IR (Nujol): ν
3040, 1595, 750, 740, 705, 695 cm-1. Anal. Calcd for C35H45NO4-
Se: C, 67.51; H, 7.28; N, 2.25. Found: C, 67.38; H, 7.40; N, 2.10.
1
CH2Cl2). H NMR (CDCl3, 333 K): δ 0.77-0.98 (m, 2H), 0.83
(d, 3H, J ) 6.5 Hz), 1.02 (s, 3H), 1.07 (m, 1H), 1.19 (s, 3H), 1.38
(m, 1H), 1.49 (m, 1H), 1.58-1.68 (m, 2H), 1.85 (m, 1H), 2.34
(ddd, 1H, J1 ) 11.5 Hz, J2 ) 4.4 Hz, J3 ) 3.1 Hz), 2.37 (dd, 1H,
J1 ) 15.3 Hz, J2 ) 4.4 Hz), 2.85 (s, 3H), 3.00 (dd, 1H, J1 ) 15.3
Hz, J2 ) 11.5 Hz), 3.42 (td, 1H, J1 ) 10.5 Hz, J2 ) 4.2 Hz), 3.54
(d, 1H, J ) 3.1 Hz), 5.07 (s, 1H), 6.35 (d, 1H, J ) 7.3 Hz), 6.37
(d, 1H, J ) 7.3 Hz), 6.41-7.07 (m, 5H), 7.10 (d, 1H, J ) 8.1 Hz),
7.12 (d, 1H, J ) 7.8 Hz), 7.29-7.38 (m, 3H), 7.42-7.57 (m, 4H),
7.68 (d, 1H, J ) 7.3 Hz). 13C NMR (CDCl3): δ 13.9, 22.2, 25.9,
27.4, 31.0, 34.7, 41.2, 42.1, 49.0, 53.0, 57.7, 57.9, 75.0, 82.4, 90.8,
125.3, 125.8 (3C), 126.6 (3C), 127.2, 127.3 (2C), 127.7 (2C), 128.5
(2C), 128.7, 131.2, 132.7, 133.4, 134.3 (2C), 137.9, 139.4. IR
(film): ν 3060, 2980, 2920, 2870, 1600, 1580, 740, 705, 695 cm-1
.
Anal. Calcd for C37H43NO2Se: C, 72.53; H, 7.07; N, 2.29. Found:
C, 72.39; H, 7.19; N, 2.37.
(2S,4aS,7R,8aR)-3-[(2R,3S)-3-Methoxy-3-phenyl-2-phenylse-
lenylpropyl]-4,4,7-trimethyl-2-(4-nitrophenyl)octahydrobenzo-
[e][1,3]oxazine (5i). Colorless oil. [R]25 ) +26.1 (c ) 1.0,
D
1
CH2Cl2). H NMR (CDCl3, 333 K): δ 0.87-1.04 (m, 2H), 0.92
(d, 3H, J ) 6.5 Hz), 1.10 (m, 1H), 1.15 (s, 3H), 1.19 (s, 3H), 1.39-
1.53 (m, 2H), 1.63-1.75 (m, 2H), 1.89 (m, 1H), 2.43 (ddd, 1H, J1
) 11.6 Hz, J2 ) 4.2 Hz, J3 ) 3.0 Hz), 2.58 (dd, 1H, J1 ) 15.7 Hz,
J2 ) 4.2 Hz), 3.01 (dd, 1H, J1 ) 15.7 Hz, J2 )11.6 Hz), 3.06 (s,
3H), 3.48 (td, 1H, J1 ) 10.5 Hz, J2 ) 4.2 Hz), 3.93 (d, 1H, J ) 3.0
Hz), 5.20 (s, 1H), 6.76-6.81 (m, 2H), 7.16-7.23 (m, 6H), 7.35-
7.39 (m, 4H), 7.89 (d, 2H, J ) 8.8 Hz). 13C NMR (CDCl3, 333 K):
δ 16.6, 22.1, 25.1, 27.1, 31.2, 34.9, 41.4, 42.2, 47.8, 54.0, 57.7,
58.2, 75.8, 84.3, 89.1, 122.7 (2C), 126.6 (2C), 127.1, 127.2, 128.0
(2C), 128.8 (2C), 129.3 (2C), 131.4, 134.7 (2C), 140.0, 147.4, 147.5.
IR (film): ν 3040, 3020, 1605, 1580, 1530, 740, 700 cm-1. Anal.
Calcd for C33H40N2O4Se: C, 65.23; H, 6.64; N, 4.61. Found: C,
65.40; H, 6.53; N, 4.50.
(2S,4aS,7R,8aR)-3-[(2R,3S)-3-Methoxy-3-phenyl-2-phenylse-
lenylpropyl]-4,4,7-trimethyl-2-naphthalen-1-yl-octahydrobenzo-
Acknowledgment. We thank the Spanish Ministerio de
Educacio´n y Ciencia (DGI, Projects BQU2002-01046 and
CTQ2005-01191/BQU) for financial support. We also thank Dr.
A. Pe´rez-Encabo for the determination of X-ray structures.
[e][1,3]oxazine (5g). Colorless solid. Mp: 164-165 °C (from
1
EtOH). [R]25 ) +7.6 (c ) 1.0, CH2Cl2). H NMR (CDCl3, 333
D
K): δ 0.80-1.07 (m, 2H), 0.83 (d, 3H, J ) 6.5 Hz), 1.13 (m, 1H),
1.15 (s, 3H), 1.16 (s, 3H), 1.34 (m, 1H), 1.52-1.75 (m, 3H), 1.86
(m, 1H), 2.27 (m, 1H), 2.50 (m, 1H), 2.83 (s, 3H), 3.05 (dd, 1H, J1
) 15.6 Hz, J2 ) 11.2 Hz), 3.46 (d, 1H, J ) 2.7 Hz), 3.50 (td, 1H,
J1 ) 10.5 Hz, J2 ) 4.1 Hz), 5.59 (s br, 1H), 6.52-6.55 (m, 2H),
6.69-6.74 (m, 2H), 6.88-7.05 (m, 8H), 7.24-7.33 (m, 2H), 7.60
(d, 1H, J ) 8.3 Hz), 7.69 (m, 1H), 8.63 (m, 1H). 13C NMR (CDCl3,
333 K): δ 17.3, 22.1, 25.3, 27.5, 31.3, 35.0, 41.5, 43.1, 48.6, 53.1,
57.5, 58.5, 75.9, 83.5 (2C), 125.1, 125.2, 125.3, 125.4, 126.4, 126.5,
126.6 (2C), 126.7, 127.7, 127.8 (2C), 128.3 (2C), 128.4, 131.5,
Supporting Information Available: General experimental
methods and physical and spectral characteristics for compounds
2, 3e-i, 4a-i, and 6a-i. Copies of Ortep representation of X-ray
structure for compounds 5a and 5d, and table of selected bond
lengths (Å) and bond angles (deg) for 5a, 5d, and 6a. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO060566R
J. Org. Chem, Vol. 71, No. 14, 2006 5391