Short and efficient diastereoselective synthesis of enantiopure 1-substituted 1H-2-benzopyrans

Article abstract of DOI:10.1002/ejoc.200600585

The reaction of homophthaldehyde with (-)-8-(benzylamino)-menthol is regio- and diastereo-selective, leading to the chiral perhydro-1,3-benzoxazine 3 as a single diastereoisomer. The addition of different organometallics to 3 yielded alcohols 4 in excelle

Full text of DOI:10.1002/ejoc.200600585

FULL PAPER
DOI: 10.1002/ejoc.200600585
Short and Efficient Diastereoselective Synthesis of Enantiopure 1-Substituted
1H-2-Benzopyrans
Rafael Pedrosa,*[a] Sonia Sayalero,[a][‡] and and Martina Vicente[a]
Keywords: Asymmetric synthesis / 1,3-Amino alcohols / Benzopyrans / Isochromanes / Isochromenes
The reaction of homophthaldehyde with (–)-8-(benzylamino)- 2% HCl in methanol or ethanol, allowed for the synthesis of
menthol is regio- and diastereo-selective, leading to the chi-
ral perhydro-1,3-benzoxazine 3 as a single diastereoisomer.
1,3-disubstituted isochromanes, but hydrolysis in toluene led
to enantiopure 1-substituted isochromenes.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
The addition of different organometallics to
3 yielded
alcohols 4 in excellent yields. Hydrolysis of carbinols, with
zine, derived from (–)-8-(benzylamino)menthol,[15] we now
present a novel diastereoselective synthesis of enantioen-
riched 1H-isochromenes. The method is based on that used
for the perhydrobenzoxazine system as a chiral template to
promote diastereoselective addition to a benzaldehyde de-
rivative, recovery of the masked formyl group by hydrolysis
and cyclization to form the final products. In this way, dif-
ferent chiral 1-substituted 1H-isochromenes are prepared
from a common dialdehyde (homophthaladehyde), ob-
tained by ozonolysis of indene.[16]
Introduction
In contrast to chromanes or chromenes that possess sig-
nificant biological properties,[1] 1H-2-benzopyrans (1H-
isochromenes) are less common natural metabolites.[2] Their
synthesis has been studied less probably because they are
not very stable and show a tendency towards oxidation and
polymerization.[3]
Earlier preparations of 1H-isochromenes consisted of the
dehydration of isochromanols[4] or the heating of 1-acylben-
zocyclobutanes to form the corresponding acyl-o-quinodi-
methanes followed by their cyclization.[5] 3-Alkyl-2-amino-
substituted isochromenes have also been synthesized by
thermolysis of aryl α-diazo ketones,[6] whereas 1-substituted
1H-2-benzopyrans have also been prepared from arylli-
thium derivatives.[7] More recently, 3-vinyl-substituted 1H-
isochromenes have been prepared by the palladium-cata-
lyzed reactions of ketones with o-bromophenyl allyl
ethers,[8] or cycloisomerizations of o-alkynyl benzyl alcohols
catalyzed by palladium iodide.[9] 2-Allyl-3-hydroxyalkyl-1,4-
naphthoquinone also cyclizes to form benzoisochromene-
quinone by reaction with a palladium(II) complex.[10]
Highly substituted 1H-isochromenes are obtained by cycli-
zation of o-(1-alkynyl) aryl ketones or aldehydes promoted
by PdII,[11] bis(pyridine)iodonium tetrafluoroborate,[12] or
iodine, bromine, sulfur, or selenium derivatives,[13] but to
the best of our knowledge, there are no prior reports of the
asymmetric synthesis of 2-substituted 1H-isochromenes.
Based on previous work on the diastereoselective alky-
lation[14] of imines attached to a chiral perhydrobenzoxa-
Results and Discussion
Condensation of 2-(o-formylphenyl)acetaldehyde (1)
with (–)-8-(benzylamino)menthol (2) in refluxing benzene,
under Dean–Stark conditions, for 24 h led to the starting
material perhydrobenzoxazine (3) in 40% yield after col-
umn chromatography. The reaction is totally regio- and ste-
reo-selective. The condensation only occurs with the ali-
phatic formyl group, leading to a single diastereoisomer
with S configuration at C-2 in the perhydrobenzoxazine
ring (Scheme 1).
[a] Departamento de Química Orgánica, Facultad de Ciencias,
Universidad de Valladolid,
Scheme 1. Synthesis of perhydrobenzoxazine 3.
Dr. Mergelina, s/n, 47011 Valladolid, Spain
Fax: +34-983-423013
Aldehyde 3 was transformed into a mixture of dia-
stereomeric secondary alcohols 4a–g and epi-4ag by reac-
tion with different organometallics at –90 °C in diethyl
ether or THF in an argon atmosphere (Scheme 2 and
E-mail: pedrosa@qo.uva.es
[‡] Present address: Institute of Chemical Research of Catalonia
(ICIQ),
Av. Països Catalans 16, 43007 Tarragona, Spain
5110
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 5110–5116

Enantiopure 1-Substituted 1H-2-Benzopyrans
FULL PAPER
Table 1). Diastereoisomeric alcohols were isolated and puri- to 3:1 when methyllithium was used as the nucleophile in
fied by flash chromatography except for compounds 4b and diethyl ether or THF (entries 4, 5).
epi-4b which could not be separated.
The use of bulkier magnesium reagents, such as isopropyl
or butyl derivatives, increased the diastereomeric ratios to
ca. 2:1 and 4:1 (entries 6–8 in Table 1), respectively, but
50% of product 5[17] was formed in the reaction with iso-
propylmagnesium chloride in diethyl ether or 25% with n-
butylmagnesium chloride in THF, as a consequence of a
competitive reduction process.[18] The reduced alcohol 5
was not formed when n-butyllithium was used in either di-
ethyl ether or THF, although by using THF the ratio of
diastereoisomers was better (entries 9 and 10).
Vinylmagnesium bromide also reacted quantitatively
with 3 yielding a mixture (2:1) of diastereoisomers 4e and
epi-4e, and allylmagnesium reagents led to mixtures of 4f
and epi-4f with diastereomeric ratios that varied from ca.
3:1 (entries 15 and 17 in Table 1) to 4:1 for reactions with
allylmagnesium bromide in THF (entry 16), respectively.
The bulkiest tert-butyllithium led to the best dr in the
addition to 3 when the reaction was carried out in THF
(entry 19). However, the process is slow at –90 °C when the
solvent is changed to diethyl ether, and the starting alde-
hydes were recovered even at room temp. In these condi-
tions the dr decreased to 5:3 (entry 18).
Aldehyde 3 was also reacted in THF at –78 °C, with or-
ganocerium compounds[19] but the yields and dr were very
similar to those obtained in the reactions with their precur-
sors magnesium or lithium reagents.
The stereochemistry at the new stereocenter in the major
diastereoisomers was determined as R by X-ray diffraction
analysis for compound 4d[20] and extended to all the
alcohols on the basis of their 1H NMR and 13C NMR spec-
troscopic data. For instance, in the 13C NMR spectra the
hydroxylic carbon for the R diastereoisomer appears 4.6–
6.6 ppm at higher field than for the S epimer, except for
compounds 4g and epi-4g where the difference is only of
0.2 ppm.
Scheme 2. Addition of organometallics to aldehyde 3.
Table 1. Nucleophilic addition of organometallics to aldehyde 3.
Reagent (equiv.)
R
Solvent Time
[min]
Product ratio [%][a]
1
2
3
4
5
6
7
8
MeMgI (2)
Me
Me
Me
Me
Me
iPr
nBu
nBu
nBu
nBu
Ph
Et2O
Et2O
THF
Et2O
THF
Et2O
Et2O
THF
Et2O
THF
Et2O
THF
THF
60
120
90
45
45
60
30
30
30
4a/epi-4a (52:44)
4a/epi-4a (55:41)
4a/epi-4a (66:30)
4a/epi-4a (74:22)
4a/epi-4a (75:21)
4b/epi-4b (33:16)[b]
4c/epi-4c (60:32)[c]
4c/epi-4c (56:15)[c]
4c/epi-4c (68:27)
4c/epi-4c (76:22)
4d/epi-4d (52:44)
4d/epi-4d (53:43)
4d/epi-4d (55:42)
4e/epi-4e (64:32)
4f/epi-4f (74:22)
4f/epi-4a (76:19)
4f/epi-4f (74:21)
4g/epi-4g (51:32)
4g/epi-4g (85:9)
MeMgCl (2)
MeMgCl (2)
MeLi (1.1)
MeLi (1.1)
iPrMgCl (2)
nBuMgI (2)
nBuMgCl (2)
nBuLi (2)
9
10
11
12
13
14
15
16
17
18
19
nBuLi (2)
30
PhMgBr (1.1)
PhMgBr (1.1)
PhMgCl (1.1)
CH2=CHMgBr (2)
CH2=CHCH2MgBr (2) allyl
CH2=CHCH2MgBr (2) allyl
CH2=CHCH2MgCl (2) allyl
120
120
120
30
30
15
15
120[d]
90
Ph
Ph
vinyl Et2O
Et2O
THF
THF
Et2O
THF
The formation of the major diastereoisomer can be ex-
plained as a consequence of a preferred addition to the oxy-
gen face of the heterocycle, probably because it is the less
hindered face or because the coordination of the organome-
tallic to the oxygen of the template, occurs prior to the reac-
tion as described previously.[14,21]
Alcohols 4 were transformed into the final products in
two different ways (Scheme 3 and Table 2). Isochromanes 6
were obtained in good to excellent yields, as a mixture of
cis and trans isomers, by refluxing in methanol with a 2%
tBuLi (2)
tBuLi (2)
tBu
tBu
[a] Yields refer to isolated products after flash chromatography. [b]
Determined by integration of the signals of 1H NMR spectra of
the mixture, 50% of the reduction product 5 was detected. [c] 4%
(entry 5) and 25% (entry 6) of product 5 was isolated, respectively.
[d] The reaction was allowed to reach room temp., but 15% of the
starting compound was recovered.
The feasibility of the reaction was explored using Grig- solution of hydrochloric acid (entries 1–4 in Table 2). The
nard and lithium reagents. The reactions were quantitative hydrolytic cleavage was also carried out using ethanol as
in most cases but the ratio of diastereoisomers is dependent the solvent. The corresponding ethyl ketals 7 were also ob-
on either the nature of the organometallic or the solvent. tained as a cis/trans mixture of isomers (entries 5–9 in
The reactions with methylmagnesium iodide or chloride in Table 2).
diethyl ether (entries 1 and 2 in Table 1) or with phenylmag-
Attempts at further transformations of compounds 6 and
nesium bromide or chloride (entries 11–13 in Table 1) give 7 into the corresponding isochromanones by oxidation with
a near equimolar mixture of diastereoisomers using diethyl m-CPBA,[22] sodium hypochlorite,[21b] or Bismuth(III) ni-
ether or THF as the solvent. The ratio of diastereoisomers trate[23] failed, and unidentifiable mixtures of compounds
increased to ca. 2:1 in the reaction using methylmagnesium were observed. However, compounds 4 were cleanly trans-
chloride in THF (entry 3). The diastereoselection increased formed into enantiopure 2-substituted isochromenes 8 after
Eur. J. Org. Chem. 2006, 5110–5116
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5111

R. Pedrosa, S. Sayalero, M. Vicente
FULL PAPER
dard methods: CH2Cl2 was distilled from CaH2 and benzene, THF
and Et2O from Na. 1H NMR (300 MHz) and 13C NMR (75 MHz)
spectra were recorded using CDCl3 as the solvent and TMS as an
internal reference, and chemical shifts are given in ppm. Specific
rotations were determined using a digital polarimeter using a Na
lamp, and the concentration is given in g per 100 mL. Melting
points were obtained using open capillary tubes and are uncor-
rected. TLC was performed using glass-backed plates coated with
silica gel 60 with an F254 indicator; the chromatograms were visual-
ized under UV light and/or by staining with I2 or phosphomolybdic
acid. Flash chromatography was carried using silica gel (230–
240 mesh).
Synthesis of (2S,4aS,7R,8aR)-2-[(N-Benzyl-4,4,7-trimethyloctahy-
dro-2H-benzo[e][1,3]oxazin-2-yl)methyl]benzaldehyde (3): A solution
of (–)-8-(benzylamino)menthol 2 (1.68 g, 6.5 mmol) and 2-(o-for-
mylphenyl)acetaldehyde (1) (0.64 g, 4.3 mmol) in benzene (100 mL)
was heated at reflux with a Dean–Stark trap for 24 h. The solvent
was removed in vacuo and the residue was purified by flash
chromatography using silica gel and toluene as the eluent. Aldehyde
3 was isolated as a pale yellow oil (0.67 g, 40%). [α]2D3 = –32.8 (c =
0.70, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.84–1.06 (m, 3
H), 0.87 (d, J = 6.4 Hz, 3 H), 1.09 (s, 3 H), 1.18 (s, 3 H), 1.19–1.32
(m, 1 H), 1.43–1.75 (m, 4 H), 2.99 (d, J = 6.8 Hz, 1 H), 3.00 (d, J
= 4.4 Hz, 1 H), 3.25 (td, J1 = 10.5 Hz, J2 = 4.0 Hz, 1 H), 3.92 (d,
J = 17.9 Hz, 1 H), 4.17 (d, J = 17.9 Hz, 1 H), 4.70 (dd, J1 = 6.8 Hz,
J2 = 4.4 Hz, 1 H), 7.13–7.31 (m, 5 H), 7.37–7.47 (m, 3 H), 7.78
(dd, J1 = 7.7 Hz, J2 = 1.3 Hz, 1 H), 10.23 (s, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 19.8, 22.2, 25.0, 27.2, 31.2, 35.0, 41.2, 37.5,
41.0, 46.6, 46.7, 57.4, 75.9, 88.3, 126.0, 126.7, 126.8 (2 C), 128.1 (2
C), 129.7, 132.0, 133.2, 134.6, 141.7, 143.9, 192.5 ppm. IR (film):
Scheme 3. Preparation of isochromanes 6–7 and isochromenes 8.
Table 2. Transformation of alcohols 4 into isochromanes 6–7 and
isochromenes 8.
Solvent
R
Product [%][a] Time [h] cis/trans Ratio [%][b]
1
2
3
4
5
6
7
8
9
MeOH
MeOH
MeOH
MeOH
EtOH
EtOH
EtOH
EtOH
EtOH
Me
nBu
Ph
6a (68)
6c (65)
6d (98)
5
24
5
(67:33)
(66:34)
(68:32)
(54:46)
(60:40)
(65:35)
(62:38)
(85:15)
(74:26)
vinyl 6e (98)
24
72
24
4
23
30
30
20
25
20
Me
nBu
Ph
7a (76)
7c (50)
7d (98)
allyl 7f (81)
tBu
Me
nBu
Ph
7g (50)[c]
8a (43)[c]
8c (85)
10 toluene
11 toluene
12 toluene
13 toluene
ν = 3060, 3020, 1685, 1600, 1570, 1450, 770, 730, 700 cm–1.
˜
C26H33NO2 (391.55): calcd. C 79.76, H 8.50, N 3.58; found C
79.69, H 8.61, N 3.61.
8d (87)
tBu
8g (45)[c]
Synthesis of Alcohols 4a–g. General Method: To a solution of the
aldehyde 3 (5.3 mmol), in the appropriate ethereal solvent (Table 1,
5 mL) at –90 °C in an argon atmosphere, a solution of the organo-
metallic reagent (5.83 mmol) was slowly added and the mixture was
stirred at that temperature until the starting material has disap-
peared (TLC, Table 1). The reaction mixture was quenched with
saturated ammonium chloride, and the product was extracted with
diethyl ether (3×5 mL). The organic extracts were washed with
brine and dried with anhydrous MgSO4, and the solvent was evapo-
rated in vacuo. The residue was purified by flash chromatography
using silica gel and hexanes/ethyl acetate as the eluent.
[a] Yields refer to isolated products after flash chromatography. [b]
Determined by integration of the signals of 1H NMR spectra of
the mixture. [c] Partially decompose during flash chromatography.
boiling in toluene with 2% HCl solution for 20–30 h. The
reaction is nearly quantitative, and the moderate yields of
8a and 8g are due to partial decomposition of these isoch-
romenes during purification by flash chromatography (en-
tries 10–13 in Table 2). The transformation of 4 into 8 can
also be carried out by using THF as the solvent and 5%
solution of sulfuric acid. The reaction is faster (5–7 h of
reflux) but the yields of the isolated isochromenes are lower.
In these cases hydrolytic cleavage of the chiral (–)-8-(ben-
zylamino)menthol, used as chiral template, was recovered
in 90–95% simply by neutralization of the aqueous phase
and extraction with chloroform.
In summary, the described methodology allows for the
preparation of enantiopure 1-substituted isochromenes
starting from easily accessible compounds. In addition, dif-
ferent substituents can be introduced merely by changing
the nucleophile acting on the formyl group of the substitu-
ent at C-2 in the starting chiral perhydro-1,3-benzoxazine.
(1R,2ЈS,4aЈS,7ЈR,8aЈR)-1-{2-[(N-Benzyl-4Ј,4Ј,7Ј-trimethyloctahy-
dro-2H-benzo[e][1,3]oxazin-2Ј-yl)methyl]phenyl}ethanol (4a): 1.08 g,
49.9%. [α]2D3 = –15.9 (c = 0.38, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 0.84 (d, J = 6.5 Hz, 3 H), 0.86–1.02 (m, 2 H), 1.02–
1.10 (m, 1 H),1.12 (s, 3 H), 1.28 (s, 3 H), 1.31–1.35 (m, 2 H), 1.54
(d, J = 6.4 Hz, 3 H), 1.58–1.66 (m, 2 H), 1.75 (m, 1 H), 2.51 (dd,
J1 = 14.0 Hz, J2 = 1.6 Hz, 1 H), 3.04 (dd, J1 = 14.0 Hz, J2 = 9.5 Hz,
1 H), 3.36 (td, J1 = 10.7 Hz, J2 = 4.0 Hz, 1 H), 3.95 (d, J = 18.0 Hz,
1 H), 4.23 (d, J = 18.0 Hz, 1 H), 4.66 (s, 1 H), 4.81 (dd, J1 = 9.5 Hz,
J2 = 1.6 Hz, 1 H), 5.05 (q, J = 6.4 Hz, 1 H), 7.16–7.25 (m, 4 H),
7.30–7.41 (m, 2 H), 7.41–7.50 (m, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 20.4, 21.0, 22.1, 24.9, 27.2, 31.2, 34.9, 37.5, 40.4, 45.9,
46.6, 57.2, 63.7, 76.3, 89.9, 125.0, 126.1, 126.7 (2 C), 126.8, 127.6,
128.3 (2 C), 130.3, 137.2, 142.9, 143.8 ppm. IR (Nujol): ν = 3400,
˜
3060, 3020, 1590, 730, 710 cm–1. C27H37NO2 (407.59): calcd. C
79.56, H 9.15, N 3.44; found C 78.97, H 8.46, N 3.36.
Experimental Section
General: All reactions were carried out in an argon atmosphere
using oven-dried glassware. Solvents and bases were dried by stan-
(1S,2ЈS,4aЈS,7ЈR,8aЈR)-1-{2-[(N-Benzyl-4Ј,4Ј,7Ј-trimethyloctahy-
dro-2H-benzo[e][1,3]oxazin-2Ј-yl)methyl]phenyl}ethanol (epi-4a):
5112
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 5110–5116

Enantiopure 1-Substituted 1H-2-Benzopyrans
FULL PAPER
0.91 g, 42.2%. [α]2D3 = –39.2 (c = 0.94, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 0.79–0.97 (m, 2 H), 0.88 (d, J = 6.5 Hz, 3 H), 1.01–
1.17 (m, 1 H), 1.08 (s, 3 H), 1.28 (s, 3 H), 1.35 (d, J = 6.5 Hz, 3
H), 1.38–1.66 (m, 4 H), 1.80 (m, 1 H), 2.60 (dd, J1 = 14.2 Hz, J2
= 3.2 Hz, 1 H), 3.03 (dd, J1 = 14.2 Hz, J2 = 8.2 Hz, 1 H), 3.15 (br.
s, 1 H), 3.39 (td, J1 = 10.7 Hz, J2 = 4.0 Hz, 1 H), 3.93 (d, J =
18.0 Hz, 1 H), 4.21 (d, J = 18.0 Hz, 1 H), 4.86–4.92 (m, 2 H), 7.11–
7.19 (m, 4 H), 7.21–7.34 (m, 3 H), 7.38–7.40 (m, 2 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 21.2, 22.3, 25.0 (2 C), 27.3, 31.4, 35.1,
37.3, 41.1, 45.9, 46.5, 57.3, 68.8, 76.3, 89.2, 125.9, 126.4, 126.5,
126.9 (2 C), 127.1, 128.1 (2 C), 130.5, 136.0, 144.0, 144.2 ppm. IR
(2 C), 128.2, 130.0, 137.4, 142.5, 143.4, 143.7 ppm. IR (film): ν
˜
= 3300, 3040, 3020, 1600, 1590, 1450, 740, 690 cm–1. C32H39NO2
(469.66): calcd. C 81.83, H 8.37, N 2.98; found C 81.13, H 8.45, N
2.70.
(1S,2ЈS,4aЈS,7ЈR,8aЈR)-1-{2-[(N-Benzyl-4Ј,4Ј,7Ј-trimethyloctahy-
dro-2H-benzo[e][1,3]oxazin-2Ј-yl)methyl]phenyl}(phenyl)methanol
(epi-4d): Colorless oil. 1.01 g, 40.7%. [α]2D3 = +12.5 (c = 0.14,
1
CHCl3). H NMR (300 MHz, CHCl3): δ = 0.92 (d, J = 6.0 Hz, 3
H), 0.96–1.07 (m, 2 H), 1.14 (s, 3 H), 1.19–1.25 (m, 1 H), 1.29 (s,
3 H), 1.40–1.48 (m, 2 H), 1.51–1.72 (m, 2 H), 1.89 (m, 1 H), 2.14
(d, J = 14 Hz, 1 H), 2.66 (dd, J1 = 14.0 Hz, J2 = 9.3 Hz, 1 H), 3.41
(td, J1 = 10.6 Hz, J2 = 4.0 Hz, 1 H), 3.85 (d, J = 16.8 Hz, 1 H),
3.95 (d, J = 16.8 Hz, 1 H), 4.86 (d, J = 9.3 Hz, 1 H), 5.20 (br. s, 1
H), 5.77 (s, 1 H), 7.08–7.37 (m, 14 H) ppm. 13C NMR (75 MHz,
CHCl3): δ = 21.3, 22.1, 24.9, 27.3, 31.2, 34.9, 38.0, 40.5, 45.9, 46.0,
57.1, 76.3, 76.6, 89.5, 125.5 (2 C), 125.7, 126.4 (2 C), 126.8 (2 C),
127.9 (2 C), 128.1 (3 C), 130.8, 131.6, 137.4, 142.3, 143.5, 145.2
(Nujol): ν = 3385, 3060, 3020, 1595, 760, 730 cm–1. C H NO
˜
27 37
2
(407.59): calcd. C 79.56, H 9.15, N 3.44; found C 79.14, H 8.94, N
3.17.
(1R,2ЈS,4aЈS,7ЈR,8aЈR)-1-{2-[(N-Benzyl-4Ј,4Ј,7Ј-trimethyloctahy-
dro-2H-benzo[e][1,3]oxazin-2Ј-yl)methyl]phenyl}pentan-1-ol (4c):
1.64 g, 69%. [α]2D3 = +7.17 (c = 1.00, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 0.84–0.94 (m, 1 H), 0.85 (d, J = 6.5 Hz, 3 H), 0.89 (t,
J = 7.1 Hz, 3 H), 1.07–1.15 (m, 1 H), 1.11 (s, 3 H), 1.24–1.47 (m,
5 H), 1.28 (s, 3 H), 1.51–1.85 (m, 6 H), 1.98 (m, 1 H), 2.50 (dd, J1
= 14.0 Hz, J2 = 1.7 Hz, 1 H), 3.05 (dd, J1 = 14.0 Hz, J2 = 9.6 Hz,
1 H), 3.35 (td, J1 = 10.6 Hz, J2 = 4.0 Hz, 1 H), 3.96 (d, J = 18 Hz,
1 H), 4.23 (d, J = 18 Hz, 1 H), 4.28 (s, 1 H), 4.79 (m, 2 H), 7.17–
7.26 (m, 4 H), 7.33 (t, J = 7.5 Hz, 2 H), 7.41 (m, 1 H), 7.49 (d, J
= 7.2 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.0, 20.9,
22.0, 22.8, 24.9, 27.1, 28.7, 31.2, 34.2, 34.9, 37.3, 40.4, 45.9, 46.6,
57.2, 68.1, 76.4, 89.4, 125.5, 126.0, 126.7 (2 C), 126.8, 127.4, 128.2
ppm. IR (film): ν = 3350, 3060, 3020, 1600, 1590, 1450, 760, 720,
˜
700 cm–1. C32H39NO2 (469.66): calcd. C 81.83, H 8.37, N 2.98;
found C 81.49, H 7.96, N 2.69.
(1R,2ЈS,4aЈS,7ЈR,8aЈR)-1-{2-[(N-Benzyl-4Ј,4Ј,7Ј-trimethyloctahy-
dro-2H-benzo[e][1,3]oxazin-2Ј-yl)methyl]phenyl}(phenyl)prop-2-en-1-
ol (4e): 1.36 g, 61.4%. [α]2D3 = +1.5 (c = 0.92, CHCl3). 1H NMR
(300 MHz, CHCl3): δ = 0.85 (d, J = 6.5 Hz, 3 H), 0.89–0.95 (m, 1
H), 1.08–1.23 (m, 2 H), 1.12 (s, 3 H), 1.25–1.42 (m, 1 H), 1.28 (s,
3 H), 1.46–1.67 (m, 3 H), 1.77 (m, 1 H), 2.53 (d, J = 13.9 Hz, 1
H), 3.04 (dd, J1 = 13.9 Hz, J2 = 9.6 Hz, 1 H), 3.35 (td, J1 = 10.5 Hz,
J2 = 3.9 Hz, 1 H), 3.95 (d, J = 17.9 Hz, 1 H), 4.22 (d, J = 17.9 Hz,
1 H), 4.71 (s, 1 H), 4.81 (d, J = 9.6 Hz, 1 H), 5.32 (dd, J1 = 10.6 Hz,
J2 = 1.7 Hz, 1 H), 5.40–5.41 (m, 1 H), 5.53 (dd, J1 = 17.1 Hz, J2 =
1.7 Hz, 1 H), 6.07 (ddd, J1 = 17.1 Hz, J2 = 10.6 Hz, J3 = 4.4 Hz, 1
H), 7.16–7.24 (m, 4 H), 7.29–7.34 (m, 3 H), 7.48 (d, J = 7.6 Hz, 2
H) ppm. 13C NMR (75 MHz, CHCl3): δ = 21.1, 22.1, 24.9, 27.2,
31.3, 34.9, 37.6, 40.4, 46.0, 46.6, 57.3, 68.9, 77.5, 89.7, 114.9, 126.1,
126.7 (2 C), 126.8, 127.3, 127.9, 128.3 (2 C), 130.3, 137.3, 138.4,
(2 C), 130.2, 137.5, 142.4, 143.9 ppm. IR (film): ν = 3420, 3060,
˜
3020, 1710, 1600, 1590, 1450, 750, 730, 710 cm–1. C30H43NO2
(449.67): calcd. C 80.13, H 9.64, N 3.11; found C 79.64, H 9.11, N
3.08.
(1S,2ЈS,4aЈS,7ЈR,8aЈR)-1-{2-[(N-Benzyl-4Ј,4Ј,7Ј-trimethyloctahy-
dro-2H-benzo[e][1,3]oxazin-2Ј-yl)methyl]phenyl}pentan-1-ol (epi-4c):
0.51 g, 21.5%. [α]2D3 = –34.9 (c = 0.83, CHCl3). 1H NMR (300 MHz,
CHCl3): δ = 0.85 (t, J = 6.9 Hz, 3 H), 0.89 (d, J = 6.4 Hz, 3 H),
0.91–0.97 (m, 2 H), 1.04–1.28 (m, 5 H), 1.10 (s, 3 H), 1.29 (s, 3 H),
141.6, 143.8 ppm. IR (film): ν = 3400, 3060, 3020, 1645, 1600, 1590,
˜
1450, 990, 750, 730, 715, 690 cm–1. C28H37NO2 (419.60): calcd. C
80.15, H 8.89, N 3.34; found C 79.98, H 9.04, N 3.49.
1.31–1.71 (m, 6 H), 1.81 (m, 1 H), 2.57 (dd, J1 = 14.2 Hz, J2
=
3.0 Hz, 1 H), 3.05 (dd, J1 = 14.2 Hz, J2 = 8.4 Hz, 1 H), 3.26 (br. s,
1 H), 3.39 (td, J1 = 10.7 Hz, J2 = 4.1 Hz, 1 H), 3.94 (d, J = 17.8 Hz,
1 H), 4.22 (d, J = 17.8 Hz, 1 H), 4.66 (dd, J1 = 7.9 Hz, J2 = 5.1 Hz,
1 H), 4.91 (dd, J1 = 8.4 Hz, J2 = 3.0 Hz, 1 H), 7.15–7.23 (m, 5 H),
7.25–7.30 (m, 2 H), 7.41 (d, J = 7.1 Hz, 2 H) ppm. 13C NMR (75
MHz, CHCl3): δ = 14.0, 21.1, 22.1, 22.7, 24.9, 27.2, 28.5, 31.2, 35.0,
37.3, 38.7, 40.9, 45.8, 46.3, 57.2, 73.6, 76.3, 89.1, 125.8, 126.2, 126.8
(2 C), 127.0, 127.3, 128.0 (2 C), 130.5, 136.2, 143.2, 144.0 ppm. IR
(1S,2ЈS,4aЈS,7ЈR,8aЈR)-1-{2-[(N-Benzyl-4Ј,4Ј,7Ј-trimethyloctahy-
dro-2H-benzo[e][1,3]oxazin-2Ј-yl)methyl]phenyl}(phenyl)prop-2-en-1-
ol (epi-4e): 0.68 g, 30.7%. [α]2D3 = –13.5 (c = 0.92, CHCl3). 1H NMR
(300 MHz, CHCl3): δ = 0.89–1.27 (m, 3 H), 0.89 (d, J = 6.5 Hz, 3
H), 1.12 (s, 3 H), 1.30 (s, 3 H), 1.38–1.68 (m, 4 H), 1.82 (m, 1 H),
2.45 (dd, J1 = 14.2 Hz, J2 = 2.1 Hz, 1 H), 3.19 (dd, J1 = 14.2 Hz,
J2 = 9.2 Hz, 1 H), 3.39 (td, J1 = 10.6 Hz, J2 = 4.0 Hz, 1 H), 3.95
(d, J = 17.9 Hz, 1 H), 4.17 (d, J = 17.9 Hz, 1 H), 4.53 (d, J =
5.9 Hz, 1 H), 4.87 (dd, J1 = 9.2 Hz, J2 = 2.1 Hz, 1 H), 5.09 (td, J1
(film): ν = 3400, 3060, 3020, 1720, 1600, 1590, 1450, 750, 720, 700,
˜
690 cm–1. C30H43NO2 (449.67): calcd. C 80.13, H 9.64, N 3.11;
found C 79.84, H 9.48, N 2.91.
= 10.5 Hz, J2 = 2.0 Hz, 1 H), 5.16 (m, 1 H), 5.34 (ddd, J1
=
17.2 Hz, J2 = 3.8 Hz, J3 = 2.0 Hz, 1 H), 5.99 (ddd, J1 = 17.2 Hz,
J2 = 10.5 Hz, J3 = 3.8 Hz, 1 H), 7.16–7.33 (m, 7 H), 7.44 (d, J =
7.4 Hz, 2 H) ppm. 13C NMR (75 MHz, CHCl3): δ = 21.2, 22.2,
24.9, 27.3, 31.3, 35.0, 37.8, 40.7, 45.9, 46.4, 57.2, 75.5, 76.4, 89.5,
113.5, 126.0, 126.6, 126.8 (2 C), 127.9, 128.1 (2 C), 129.4, 131.2,
(1R,2ЈS,4aЈS,7ЈR,8aЈR)-1-{2-[(N-Benzyl-4Ј,4Ј,7Ј-trimethyloctahy-
dro-2H-benzo[e][1,3]oxazin-2Ј-yl)methyl]phenyl}(phenyl)methanol
(4d): White solid m.p. 146–147 °C (hexanes). 1.32 g, 53.3%. [α]2D3
=
1
+10.8 (c = 0.20, CHCl3). H NMR (300 MHz, CHCl3): δ = 0.81–
1.10 (m, 2 H), 0.87 (d, J = 6.5 Hz, 3 H), 1.13 (s, 3 H), 1.16–1.25
(m, 2 H), 1.30 (s, 3 H), 1.49–1.68 (m, 3 H), 1.83 (m, 1 H), 2.62 (dd,
J1 = 14.0 Hz, J2 = 1.6 Hz, 1 H), 3.21 (dd, J1 = 14.0 Hz, J2 = 9.5 Hz,
1 H), 3.40 (td, J1 = 10.6 Hz, J2 = 4.0 Hz, 1 H), 3.99 (d, J = 18 Hz,
1 H), 4.26 (d, J = 18 Hz, 1 H), 4.87 (dd, J1 = 9.5 Hz, J2 = 1.6 Hz,
1 H), 4.90 (s, 1 H), 6.09 (s, 1 H), 6.79 (dd, J1 = 7.4 Hz, J2 = 1.2 Hz,
1 H), 7.02–7.08 (m, 1 H), 7.15–7.29 (m, 4 H), 7.30–7.47 (m, 6 H),
137.4 (2 C), 141.3, 143.9 ppm. IR (film): ν = 3400, 3060, 3020,
˜
1720, 1600, 1590, 1450, 995, 740, 700 cm–1. C28H37NO2 (419.60):
calcd. C 80.15, H 8.89, N 3.34; found C 80.28, H 8.72, N 3.47.
(1R,2ЈS,4aЈS,7ЈR,8aЈR)-1-{2-[(N-Benzyl-4Ј,4Ј,7Ј-trimethyloctahy-
dro-2H-benzo[e][1,3]oxazin-2Ј-yl)methyl]phenyl}(phenyl)but-3-en-1-
ol (4f): 1.65 g, 72.2%. [α]2D3 = –3.7 (c = 1.19, CHCl3). 1H NMR
7.50 (d, J = 7.4 Hz, 2 H) ppm. 13C NMR (75 MHz, CHCl3): δ = (300 MHz, CHCl3): δ = 0.86 (d, J = 6.5 Hz, 3 H), 0.90–1.00 (m, 2
21.0, 22.0, 24.8, 27.1, 31.2, 34.8, 37.6, 40.4, 45.8, 46.4, 57.1, 70.3,
76.5, 89.7, 126.0, 126.6 (3 C), 126.7 (3 C), 127.6, 127.8 (2 C), 128.1
H), 1.04–1.16 (m, 1 H), 1.12 (s, 3 H), 1.29 (s, 3 H), 1.33–1.77 (m,
5 H), 2.53 (dd, J1 = 14 Hz, J2 = 2 Hz, 1 H), 2.61 (td, J1 = 14.1 Hz,
Eur. J. Org. Chem. 2006, 5110–5116
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5113

R. Pedrosa, S. Sayalero, M. Vicente
J2 = 7 Hz, 1 H), 2.78 (td, J1 = 14.1 Hz, J2 = 7 Hz, 1 H), 3.04 (dd, (2ЈS,4aЈS,7ЈR,8aЈR)-1-{2-[(N-Benzyl-4Ј,4Ј,7Ј-trimethyloctahydro-
FULL PAPER
J1 = 14 Hz, J2 = 9.6 Hz, 1 H), 3.36 (td, J1 = 10.6 Hz, J2 = 4.1 Hz,
1 H), 3.96 (d, J = 17.9 Hz, 1 H), 4.23 (d, J = 17.9 Hz, 1 H), 4.34
(s, 1 H), 4.80 (dd, J = 8.4 Hz, 1 H), 4.89 (t, J = 7 Hz, 1 H), 5.05
2H-benzo[e][1,3]oxazin-2Ј-yl)methyl]phenyl}methanol (5): 1.04 g,
50%. [α]2D3 = –11.3 (c = 0.17, CHCl3). 1H NMR (300 MHz, CHCl3):
δ = 0.86 (d, J = 6.5 Hz, 3 H),0.90–1.11 (m, 3 H), 1.15 (s, 3 H), 1.32
(s, 3 H), 1.35–1.49 (m, 2 H), 1.52–1.70 (m, 2 H), 1.77 (m, 1 H),
(dd, J1 = 11 Hz, J2 = 1.6 Hz, 1 H), 5.14 (dd, J1 = 17.1 Hz, J2
=
1.6 Hz, 1 H), 5.84 (ddt, J1 = 17.1 Hz, J2 = 11 Hz, J3 = 7 Hz, 1 H), 2.59 (d, J = 13.8 Hz, 1 H), 2.95 (dd, J1 = 13.8 Hz, J2 = 9.1 Hz, 1
7.18–7.27 (m, 4 H), 7.29–7.40 (m, 2 H), 7.43 (m, 1 H), 7.50 (d, J H), 3.40 (td, J1 = 10.6 Hz, J2 = 4.0 Hz, 1 H), 3.99 (d, J = 18 Hz,
= 7.6 Hz, 2 H) ppm. 13C NMR (75 MHz, CHCl3): δ = 21.0, 24.9,
1 H), 4.24 (d, J = 18 Hz, 1 H), 4.31 (d, J = 11.9 Hz, 1 H), 4.60 (br.
s, 1 H), 4.80 (d, J = 11.9 Hz, 1 H), 4.86 (d, J = 9.1 Hz, 1 H), 6.85–
27.2, 31.3, 34.9, 37.3, 39.0, 40.5, 45.9, 46.6, 57.3, 68.0, 76.4, 89.8,
117.0, 125.6, 126.0, 126.7 (2 C), 126.8, 127.6, 128.2 (2 C), 130.3, 7.50 (m, 7 H), 7.52 (d, J = 7.8 Hz, 2 H) ppm. 13C NMR (75 MHz,
135.6, 137.5, 141.6, 143.8 ppm. IR (film): ν = 3400, 3060, 3020, CHCl3): δ = 20.9, 22.0, 24.9, 27.2, 31.2, 34.8, 38.0, 40.3, 45.9, 46.5,
˜
1630, 1600, 1590, 1450, 750, 720, 700 cm–1. C29H39NO2 (433.63):
calcd. C 80.33, H 9.07, N 3.23; found C 79.81, H 8.78, N 3.01.
57.2, 63.6, 76.4, 89.5, 126.1, 126.7 (2 C), 126.8, 128.2 (3 C), 130.3,
130.5, 137.8, 139.5, 143.7 ppm. IR (film): ν = 3350, 3060, 3020,
˜
1600, 1590, 1450, 1020, 740, 690 cm–1. HRMS (CI+, m/z, %): 394
(M + 1, 66), 272 (100) cm–1. C26H35NO2 (393.56): calcd. C 79.35,
H 8.96, N 3.56; found C 79.05, H 9.10, N 3.14.
(1S,2ЈS,4aЈS,7ЈR,8aЈR)-1-{2-[(N-Benzyl-4Ј,4Ј,7Ј-trimethyloctahy-
dro-2H-benzo[e][1,3]oxazin-2Ј-yl)methyl]phenyl}(phenyl)but-3-en-1-
1
ol (epi-4f): 0.41 g, 18%. [α]2D3 = –40.5 (c = 0.19, CHCl3). H NMR
(300 MHz, CHCl3): δ = 0.03–0.99 (m, 2 H), 0.91 (d, J = 6.5 Hz, 3
H), 1.03–1.16 (m, 1 H), 1.12 (s, 3 H), 1.31 (s, 3 H), 1.39–1.54 (m,
2 H), 1.60–1.70 (m, 2 H), 1.82 (m, 1 H), 2.39 (td, J1 = 14.4 Hz, J2
= 7.3 Hz, 2 H), 2.43 (dd, J1 = 14.4 Hz, J2 = 7.3 Hz, 1 H), 2.61 (dd,
J1 = 14.2 Hz, J2 = 2.8 Hz, 1 H), 3.04 (dd, J1 = 14.2 Hz, J2 = 8.4 Hz,
1 H), 3.32 (br. s, 1 H), 3.40 (td, J1 = 7.3 Hz, J2 = 5.4 Hz, 1 H),
4.92 (dd, J1 = 8.4 Hz, J2 = 2.8 Hz, 1 H), 5.07 (d, J = 10.1 Hz, 1 H),
5.08 (d, J = 16.9 Hz, 1 H), 5.79 (ddt, J1 = 16.9 Hz, J2 = 10.1 Hz, J3
= 7.3 Hz, 1 H), 7.16–7.34 (m, 7 H), 7.43 (d, J = 7.6 Hz, 2 H) ppm.
13C NMR (75 MHz, CHCl3): δ = 21.1, 22.2, 24.9, 27.2, 31.3, 34.9,
37.4, 41.0, 43.4, 45.9, 46.3, 57.2, 72.6, 76.3, 89.1, 117.3, 125.9,
126.3, 126.8 (2 C), 127.2 (2 C), 128.1 (2 C), 130.5, 135.3, 136.2,
Synthesis of Isochromanes 6–7. General Method: A solution of the
corresponding perhydrobenzoxazine 4 (1 mmol) in methanol or
ethanol (15 mL) and 2% aqueous hydrochloric acid (7 mL) was
refluxed until the hydrolysis was complete (TLC). The aqueous
layer was extracted with hexane (3×20 mL). The organic extracts
were washed with brine, dried with anhydrous MgSO4, and concen-
trated in vacuo. The residues were purified by flash chromatog-
raphy on silica gel using hexanes/ethyl acetate as the eluent to ob-
tain acetals 6 and 7 as an inseparable mixture of cis and trans
diastereoisomers.
(1R)-3-Methoxy-1-methylisochromane (6a): Colourless oil. 121 mg,
68%. Mixture of cis and trans diastereoisomers. 1H NMR (300
MHz, CHCl3): δ = 1.58 (d, J = 7.1 Hz, 3 H), 1.63 (d, J = 7.1 Hz,
3 H), 2.79 (dd, J1 = 16.0 Hz, J2 = 2.5 Hz, 1 H), 2.92 (m, 2 H), 3.14
(dd, J1 = 11.9 Hz, J2 = 4.6 Hz, 1 H), 3.51 (s, 3 H), 3.59 (s, 3 H),
4.77 (dd, J1 = 8.0 Hz, J2 = 3.5 Hz, 1 H), 4.95 (m, 2 H), 5.08 (dd,
J1 = 4.7 Hz, J2 = 2.3 Hz, 1 H), 7.08–7.16 (m, 4 H), 7.16–7.22 (m,
4 H) ppm.
142.2, 143.9 ppm. IR (film): ν = 3420, 3060, 3020, 1635, 1600, 1590,
˜
1450, 755, 730, 715, 690 cm–1. C29H39NO2 (433.63): calcd. C 80.33,
H 9.07, N 3.23; found C 79.98, H 8.97, N 3.24.
(1R,2ЈS,4aЈS,7ЈR,8aЈR)-1-{2-[(N-Benzyl-4Ј,4Ј,7Ј-trimethyloctahy-
dro-2H-benzo[e][1,3]oxazin-2Ј-yl)methyl]phenyl}-2,2-dimethylpro-
pan-1-ol (4g): 1.98 g, 79.9%. [α]2D3 = –27.0 (c = 0.18, CHCl3). 1H
NMR (300 MHz, CHCl3): δ = 0.98 (s, 9 H), 0.99 (d, J = 4.6 Hz, 3
H), 0.93–1.07 (m, 2 H), 1.14–1.21 (m, 1 H),1.21 (s, 3 H), 1.30 (s, 3
H), 1.39–1.87 (m, 5 H), 2.03 (br. s, 1 H), 2.53 (d, J = 14.4 Hz, 1
H), 1.58–1.66 (m, 2 H), 1.75 (m, 1 H), 2.51 (dd, J1 = 14.0 Hz, J2
= 1.6 Hz, 1 H), 3.05 (dd, J1 = 14.0 Hz, J2 = 9.0 Hz, 1 H), 3.43 (td,
J1 = 10.6 Hz, J2 = 4.0 Hz, 1 H), 4.05 (d, J = 17.8 Hz, 1 H), 4.28
(d, J = 17.8 Hz, 1 H), 4.84 (d, J = 9 Hz, 1 H), 4.88 (s, 1 H), 7.24–
7.33 (m, 4 H), 7.41 (t, J = 7.5 Hz, 2 H), 7.54 (d, J = 7.4 Hz, 3 H)
ppm. 13C NMR (75 MHz, CHCl3): δ = 21.0, 22.3, 25.0, 26.4 (3 C),
27.4, 31.4, 35.1, 36.0, 37.9, 41.3, 46.1, 46.7, 57.3, 76.1, 76.2, 89.3,
125.7, 126.0, 126.8 (3 C), 127.6, 128.2 (2 C), 129.2, 137.3, 141.9,
(1R)-1-Butyl-3-methoxyisochromane (6c): Yellowish oil. 143 mg,
65%. Mixture of cis and trans diastereoisomers. 1H NMR (300
MHz, CHCl3): δ = 0.91 (t, J = 7.1 Hz, 3 H), 0.92 (t, J = 7.1 Hz, 3
H), 1.30–1.50 (m, 8 H), 1.75–1.90 (m, 2 H), 1.90–2.10 (m, 2 H),
2.76 (dd, J1 = 15.8 Hz, J2 = 2.5 Hz, 1 H), 2.92 (m, 2 H), 3.15 (dd,
J1 = 11.7 Hz, J2 = 4.4 Hz, 1 H), 3.49 (s, 3 H), 3.58 (s, 3 H), 4.74
(dd, J1 = 7.9 Hz, J2 = 3.5 Hz, 1 H), 4.85 (m, 2 H), 5.06 (dd, J1 =
4.7 Hz, J2 = 2.4 Hz, 1 H), 7.08–7.16 (m, 4 H), 7.16–7.22 (m, 4 H)
ppm.
(1R)-3-Methoxy-1-phenylisochromane (6d): Yellowish oil. 235 mg,
98%. Mixture of cis and trans diastereoisomers. 1H NMR (300
MHz, CHCl3): δ = 2.90 (d, J = 16.4 Hz, 1 H), 3.08 (m, 2 H), 3.35
(dd, J1 = 10.9 Hz, J2 = 4.6 Hz, 1 H), 3.51 (s, 3 H), 3.54 (s, 3 H),
4.93 (dd, J1 = 7.6 Hz, J2 = 3.1 Hz, 1 H), 5.15 (dd, J1 = 4.5 Hz, J2
= 2.2 Hz, 1 H), 5.80 (s, 2 H), 7.05–7.40 (m, 18 H) ppm.
144.3 ppm. IR (film): ν = 3450, 3060, 3020, 1600, 1590, 1450, 770,
˜
730, 690 cm–1. C30H43NO2 (449.67): calcd. C 80.13, H 9.64, N 3.11,
found C 80.27, H 9.50, N 3.24.
(1S,2ЈS,4aЈS,7ЈR,8aЈR)-1-{2-[(N-Benzyl-4Ј,4Ј,7Ј-trimethyloctahy-
dro-2H-benzo[e][1,3]oxazin-2Ј-yl)methyl]phenyl}-2,2-dimethylpro-
pan-1-ol (epi-4g): 0.20 g, 8.0%. [α]2D3 = –31.9 (c = 0.20, CHCl3). 1H
NMR (300 MHz, CHCl3): δ = 0.85 (s, 9 H), 0.90–1.08 (m, 2 H),
0.97 (d, J = 6.6 Hz, 3 H), 1.13 (s, 3 H), 1.17–1.27 (m, 1 H), 1.36
(s, 3 H), 1.39–1.59 (m, 2 H), 1.64–1.74 (m, 2 H), 1.90 (m, 1 H),
2.71 (d, J = 13.2 Hz, 1 H), 3.13 (br. s, 1 H), 3.48 (td, J1 = 10.5 Hz,
J2 = 4.0 Hz, 1 H), 3.98 (d, J = 18 Hz, 1 H), 4.27 (d, J = 18 Hz, 1
H), 4.54 (s, 1 H), 5.00 (dd, J1 = 7.8 Hz, J2 = 3.3 Hz, 1 H), 7.17–7.34
(m, 7 H), 7.37–7.43 (m, 2 H) ppm. 13C NMR (75 MHz, CHCl3): δ
= 21.3, 22.2, 24.9, 26.3 (3 C), 27.1, 31.3, 35.0, 36.7, 37.8, 41.0, 45.8,
(1R)-3-Methoxy-1-vinylisochromane (6e): Yellowish oil. 186 mg,
98%. Mixture of cis and trans diastereoisomers. 1H NMR (300
MHz, CHCl3): δ = 2.74 (dd, J1 = 16.2 Hz, J2 = 2.4 Hz, 1 H), 3.05
(m, 2 H), 3.20 (dd, J1 = 11.9 Hz, J2 = 4.6 Hz, 1 H), 3.36 (s, 3 H),
3.54 (s, 3 H), 4.12 (m, 2 H), 4.56 (t, J1 = 8.0 Hz, 1 H), 5.12 (m, 1
H), 5.23 (m, 1 H), 5.38–5.50 (m, 1 H), 5.92–6.08 (m, 1 H), 6.14–
6.24 (m, 1 H), 7.12–7.30 (m, 8 H) ppm.
(1R)-3-Ethoxyl-1-methylisochromane (7a): Yellowish oil. 146 mg,
46.0, 57.1, 76.3 (2 C), 89.0, 125.1, 125.7, 126.7 (3 C), 127.9 (2 C), 76%. Mixture of cis and trans diastereoisomers. 1H NMR (300
129.2, 130.1, 137.1, 140.3, 143.9 ppm. IR (film): ν = 3400, 3060,
MHz, CHCl3): δ = 1.23 (t, J = 7.1 Hz, 3 H), 1.29 (t, J = 7.1 Hz, 3
3020, 1600, 1450, 740, 720 cm–1. C30H43NO2 (449.67): calcd. C H), 1.58 (d, J = 6.6 Hz, 3 H), 1.60 (d, J = 6.5 Hz, 3 H), 2.71 (dd,
80.13, H 9.64, N 3.11; found C 80.28, H 9.76, N 3.13. J1 = 16.5 Hz, J2 = 2.3 Hz, 1 H), 2.93 (m, 2 H), 3.17 (dd, J1
˜
=
5114
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 5110–5116

Enantiopure 1-Substituted 1H-2-Benzopyrans
FULL PAPER
11.7 Hz, J2 = 4.7 Hz, 1 H), 3.55–3.66 (m, 2 H), 3.83–3.91 (m, 1 H),
4.0–4.1 (m, 1 H), 4.82 (dd, J1 = 8.0 Hz, J2 = 3.7 Hz, 1 H), 4.93 (m,
(R)-1-Phenyl-1H-isochromene (8d):[7] White solid. M.p. 51–53 °C
(from hexanes). 0.72 g, 87%. [α]2D3 = +9.2 (c = 0.50, CHCl3). 1H
2 H), 5.14 (dd, J1 = 4.7 Hz, J2 = 2.4 Hz, 1 H), 7.09–7.16 (m, 4 H), NMR (300 MHz, CHCl3): δ = 5.84 (d, J = 5.7 Hz, 1 H), 6.10 (s, 1
7.16–7.22 (m, 4 H) ppm.
H), 6.59 (d, J = 5.7 Hz, 1 H), 6.69 (dd, J1 = 7.5 Hz, J2 = 0.7 Hz,
2 H), 7.02 (d, J = 7.5 Hz, 1 H), 7.09 (dt, J1 = 7.5 Hz, J2 = 1.2 Hz,
1 H), 7.22 (dt, J1 = 7.5 Hz, J2 = 1.2 Hz, 1 H), 7.30–7.43 (m, 5 H)
ppm. 13C NMR (75 MHz, CHCl3): δ = 79.5, 105.3, 123.1, 125.5,
126.7, 128.0 (2 C), 128.2, 128.4 (3 C), 130.2 (2 C), 140.0, 145.0
(1R)-1-Butyl-3-ethoxyisochromane (7c): Yellowish oil. 167 mg,
50%. Mixture of cis and trans diastereoisomers. 1H NMR (300
MHz, CHCl3): δ = 0.93 (t, J = 7.1 Hz, 6 H), 1.22 (t, J = 7.1 Hz, 3
H), 1.29 (t, J = 7.1 Hz, 3 H), 1.35–1.60 (m, 8 H), 1.75–1.90 (m, 2
H), 1.90–2.10 (m, 2 H), 2.77 (dd, J1 = 16.4 Hz, J2 = 2.3 Hz, 1 H),
2.93 (m, 1 H), 3.15 (dd, J1 = 11.7 Hz, J2 = 4.7 Hz, 1 H), 3.54–3.66
(m, 2 H), 3.83–3.91 (m, 2 H), 4.82 (m, 2 H), 5.15 (dd, J1 = 4.7 Hz,
J2 = 2.2 Hz, 1 H), 7.09–7.16 (m, 4 H), 7.16–7.22 (m, 4 H) ppm.
ppm. IR (film): ν = 3065, 3032, 1628, 1600, 1486, 1454, 1048, 754,
˜
699 cm–1. C15H12NO (208.26): calcd. C 86.51, H 5.81; found C
86.64, H 5.95.
(R)-1-tert-Butyl-1H-isochromene (8g): Colorless oil. 0.34 g, 45%. [α]
23
1
= +134.1 (c = 1.29, CHCl3). H NMR (300 MHz, CHCl3): δ =
D
(1R)-3-Ethoxy-1-phenylisochromane (7d): Yellowish oil. 249 mg,
98%. Mixture of cis and trans diastereoisomers. 1H NMR (300
MHz, CHCl3): δ = 1.26 (t, J = 6.9 Hz, 3 H), 1.29 (t, J = 7.3 Hz, 3
H), 2.92 (dd, J1 = 16.3 Hz, J2 = 2.1 Hz, 1 H), 3.05–3.25 (m, 2 H),
3.35 (dd, J1 = 11.8 Hz, J2 = 4.5 Hz, 1 H), 3.55–3.65 (m, 2 H), 3.93–
4.01 (m, 2 H), 5.05 (dd, J1 = 7.8 Hz, J2 = 3.2 Hz, 1 H), 5.28 (dd,
J1 = 4.6 Hz, J2 = 2.4 Hz, 1 H), 5.82 (s, 2 H), 7.05–7.46 (m, 18 H)
ppm.
0.90 (d, J = 6.5 Hz, 9 H), 4.78 (s, 1 H), 5.46 (d, J = 5.7 Hz, 1 H),
6.44 (d, J = 5.7 Hz, 1 H), 6.81 (d, J = 7.5 Hz, 2 H), 7.01 (dt, J1 =
7.5 Hz, J2 = 1.5 Hz, 1 H), 7.09 (m, 1 H) ppm. 13C NMR (75 MHz,
CHCl3): δ = 26.0 (3 C), 39.3, 85.0, 103.3, 122.9, 125.5, 127.1, 127.8,
130.6 (2 C), 145.7 ppm. IR (film): ν = 3067, 3025, 1633, 1452, 1394,
˜
1365, 1052, 766 cm–1. C13H16O (188.27): calcd. C 82.94, H 8.57;
found C 83.80, H 8.73.
(1R)-1-Allyl-3-Methoxyisochromane (7f): Yellowish oil. 177 mg,
81%. Mixture of cis and trans diastereoisomers. 1H NMR (300
MHz, CHCl3): δ = 1.26 (t, J = 7.0 Hz, 3 H), 1.27 (t, J = 7.0 Hz, 3
H), 2.60–2.90 (m, 6 H), 2.90–3.20 (m, 2 H), 3.48–3.58 (m, 2 H),
3.82–3.92 (m, 2 H), 4.82 (dd, J1 = 4.7 Hz, J2 = 2.3 Hz, 1 H), 4.90–
5.02 (m, 1 H), 5.10–5.25 (m, 8 H), 7.10–7.35 (m, 8 H) ppm.
Acknowledgments
Authors thank the Spanish Ministerio de Educación y Ciencia
(DGI, Projects BQU2002-01046 and CTQ2005-01191/BQU) for fi-
nancial support.
(1R)-1-tert-Butyl-3-ethoxyisochromane (7g): Yellowish oil. 167 mg,
50%. Mixture of cis and trans diastereoisomers. 1H NMR (300
MHz, CHCl3): δ = 0.95 (s, 9 H), 0.96 (t, J = 7.1 Hz, 3 H), 0.97 (s,
9 H), 1.12 (t, J = 7.1 Hz, 3 H), 2.71 (dd, J1 = 16.7 Hz, J2 = 2.3 Hz,
1 H), 2.89–2.96 (m, 2 H), 3.06 (dd, J1 = 11.8 Hz, J2 = 4.7 Hz, 1
H), 3.54–3.61 (m, 2 H), 3.68–3.77 (m, 2 H), 4.44 (s, 1 H), 4.55–4.72
(m, 1 H) 4.88 (s, 1 H), 5.22 (dd, J1 = 4.6 Hz, J2 = 2.4 Hz, 1 H),7.12–
7.28 (m, 8 H) ppm.
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of the corresponding perhydrobenzoxazine 4 (4 mmol) in toluene
(60 mL) and 2% aqueous hydrochloric acid (30 mL) was refluxed
until the hydrolysis was complete (TLC). The aqueous layer was
extracted with hexane (3×60 mL). The organic extracts were
washed with brine, dried (MgSO4), and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel using
hexanes/ethyl acetate as the eluent.
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(R)-1-Methyl-1H-isochromene (8a): Colorless oil. 0.25 g, 43%. [α]
23
1
= +15.0 (c = 0.50, CHCl3). H NMR (300 MHz, CHCl3): δ =
D
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1.59 (d, J = 6.5 Hz, 3 H), 5.21 (q, J = 6.5 Hz, 1 H), 5.75 (d, J =
7.5 Hz, 1 H), 6.50 (d, J = 5.7 Hz, 1 H), 6.93–7.11 (m, 2 H), 7.12–
7.22 (m, 2 H) ppm. 13C NMR (75 MHz, CHCl3): δ = 19.7, 73.5,
104.7, 123.0, 123.3, 126.6, 127.8, 129.6, 132.4, 144.8 ppm. IR (film):
6457.
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10 10
59, 6251.
(146.19): calcd. C 82.16, H 6.89; found C 82.29, H 7.02.
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(R)-1-Butyl-1H-isochromene (8c): Colorless oil. 0.64 g, 85%. [α]2D3
=
1
+66.1 (c = 0.87, CHCl3). H NMR (300 MHz, CHCl3): δ = 0.91
(t, J = 7.1 Hz, 3 H), 1.30–1.66 (m, 4 H), 1.65–1.76 (m, 1 H), 1.97–
2.09 (m, 1 H), 5.07 (dd, J1 = 8.5 Hz, J2 = 4.7 Hz, 1 H), 5.72 (d, J
= 5.7 Hz, 1 H), 6.48 (d, J = 5.7 Hz, 1 H), 6.86–7.00 (m, 2 H), 7.03–
7.22 (m, 2 H) ppm. 13C NMR (75 MHz, CHCl3): δ = 14.0, 22.5,
27.6, 33.8, 77.4, 104.4, 123.1, 124.0, 126.4, 127.7, 129.6, 131.6,
144.3 ppm. IR (film): ν = 3067, 3020, 1626, 1600, 1453, 1052,
˜
768 cm–1. C13H16O (188.27): calcd. C 82.94, H 8.57; found C 83.10,
H 8.69.
Eur. J. Org. Chem. 2006, 5110–5116
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5115

R. Pedrosa, S. Sayalero, M. Vicente
FULL PAPER
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from The Cambridge Crystallographic Data Centre via
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Received: July 10, 2006
Published Online: September 18, 2006
5116
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 5110–5116