A direct efficient diastereoselective synthesis of enantiopure 3-substituted-isobenzofuranones

Article abstract of DOI:10.1016/j.tet.2006.08.058

Condensation of (-)-8-benzylaminomenthol with o-phthaldehyde lead to the chiral perhydro-1,3-benzoxazine 2 as single diastereoisomer. That compound reacted with different organometallics leading to 3 in excellent de. Hydrolysis of carbinols, followed by oxidation of the intermediates allowed for the synthesis of enantiopure phthalides.

Full text of DOI:10.1016/j.tet.2006.08.058

Tetrahedron 62 (2006) 10400–10407
A direct efficient diastereoselective synthesis of enantiopure
3-substituted-isobenzofuranones
y
*
Rafael Pedrosa, Sonia Sayalero and Martina Vicente
´
Departamento de Quımica Organica, Facultad de Ciencias, Universidad de Valladolid, Dr. Mergelina s/n, 47011 Valladolid, Spain
ꢀ
Received 6 July 2006; revised 7 August 2006; accepted 18 August 2006
Available online 11 September 2006
Abstract—Condensation of (ꢀ)-8-benzylaminomenthol with o-phthaldehyde lead to the chiral perhydro-1,3-benzoxazine 2 as single dia-
stereoisomer. That compound reacted with differentorganometallics leading to 3 in excellent de. Hydrolysis of carbinols, followed by oxidation
of the intermediates allowed for the synthesis of enantiopure phthalides.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
aminoalcohol, after the creation of a novel stereocenter
and further elaboration of the intermediate allowed for the
synthesis of a great variety of enantioenriched 3-substituted
phthalides.
Phthalides (1(3H)-isobenzofuranones) are valuable synthetic
intermediates1 and a class of compounds possessing signifi-
cant biological properties.2 For example, some 3-alkyl
substituted phthalides exhibit pharmacological applications,3
and some others have been used as starting materials for the
synthesis of carbo- and heterocycles.4 These facts led to an
increased interest in the synthesis of these compounds.5 Spe-
cially interesting are the methodologies leading to optically
active 3-alkyl substituted phthalides and, in this way, asym-
metric hydrogenations6 or alkylations,7 enantioselective
additions of alkylzinc,8 asymmetric reductions of ketoesters,9
and the use of chiral templates10 have been successfully
developed.
The versatility of the method is based on the possibility to
introduce different substituents at C-3 in the final phthalides
starting from a single compound by simply changing the
nature of the nucleophile.
2. Results and discussion
The starting perhydro-1,3-benzoxazine 213 was prepared as
previously described by condensation of (ꢀ)-8-benzylamino-
menthol and o-phthaldehyde in excellent yield and total
diastereoselectivity, and transformed into the corresponding
alcohols 3a–k by reaction with different organometallics
(Scheme 1). To this end, a solution of 2 in an ethereal solvent
was reacted with excess of Grignard, organolithium, organo-
zinc, and organocerium reagents14 to afford alcohols 3a–k as
single diastereomers or with good diastereomeric excesses
except for allylmagnesium or allylzinc derivatives (Table 1).
Herein we report on a versatile diastereoselective synthesis
of chiral 3-substituted phthalides in excellent enantiomeric
excess (ee) by using a chiral perhydro-1,3-benzoxazine
derived from (ꢀ)-8-benzylaminomenthol.11 This template
has been successfully used in diastereoselective synthesis
of aza-heterocycles by intramolecular cyclizations,12 and
now we envisaged that it can be used in a different diastereo-
selective approach. In this way, the perhydro-1,3-benz-
oxazine nucleus is now used as a chiral inductor in
diastereoselective additions of different organometallics to
a carbonyl group and a masked formyl substituent. The
hydrolysis of the template, with recovering of the starting
The chemical yields are excellent except for the reactions
with ethyl-, isopropyl-, and n-butylmagnesium bromides. In
these cases significant amount of the reduction derivative 4
was isolated (entries 3–6), but this problem was circumvented
by using organollithium reagents, which lead to alkylation
products, and no reduction derivatives were formed (compare
entries 1 and 6, vs 2 and 7, respectively). The organocerium
derivatives15 also provided better yields than those obtained
with Grignard or lithium reagents maintaining the degree of
diastereoselection (compare entry 11 vs 9). Trifluromethy-
lated alcohol 3i was obtained in very good yield by addition
Keywords: Asymmetric synthesis; (ꢀ)-8-Benzylaminomenthol; Chiral tem-
plates; Isobenzofuranones; Phthalides.
* Corresponding author. Tel.: +34 983 423211; fax: +34 983 423013;
e-mail: pedrosa@qo.uva.es
Present address: Institute of Chemical Research of Catalonia (ICIQ), Av.
y
€
Paısos Catalans 16, 43007 Tarragona, Spain.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.08.058

R. Pedrosa et al. / Tetrahedron 62 (2006) 10400–10407
10401
CHO
in THF, was used instead (entry 16 in Table 1). The reaction
with allylzinc bromide occurred also with moderate dia-
stereoselection.
OHC
Bn
O
OH
NH
Bn
N
PhH, reflux,
16h
The configuration of the formed quaternary stereocenter was
determined as R for compound 3a and S for the difluoroace-
tate derivative 3k by X-ray diffraction analysis,18 extended
for all the alcohols, and later confirmed after elimination
of the chiral auxiliary.
CHO
1
2
RMX
or RM
Bn
Bn
O
N
O
The sense of the excellent 1,4-stereoinduction observed is
coincident with that previously observed for related com-
pounds13 and the described 1,2-stereoinduction for the addi-
tion to carbonyl groups placed at the same chiral inductor.19
It can be explained by accepting that the addition occurs in
the conformation shown in Figure 1, determined by the
strong (9%) NOE observed between the hydrogen atoms
placed at the formyl group and the C-2 of the template.
The major adducts are formed by the preferred nucleophilic
attack from the less hindered Re face of the carbonyl group
according to a Felkin–Anh model. Probably a coordination
of the organometallic to the oxygen atom of the template
occurred prior to the addition of the carbonyl group.19
N
R
H
HO
HO
H
R
3a-k
epi-3a-k
4, R = H
a
b
c
d
e
f
g
Me
Et i-Pr n-Bu Ph Bn CH2=CH-
h
i
j
k
CH2=CHCH2- CF3 -CH2CO2Et -CF2CO2Et
Scheme 1. Synthesis of 2 and reaction with organometallics.
of TMSCF3 catalyzed by anhydrous TBAF.16 Treatment of 2
with 4 equiv of Reformatsky reagents17 gave alcohols 3j and
3k in good to excellent yields, but they highly decreased
when less than 4 equiv of organometallic was used.
Bn
Re face
O
N
H
The nucleophilic addition of organometallics to aldehyde 2
is also stereochemically noteworthy. In most cases only
one diastereoisomer was detected in the 1H NMR of the re-
action mixtures, and the stereochemistry of the novel created
stereocenter is independent on the organometallic used in
the reaction. An exception to this general behavior was the
reactions with allylmagnesium bromide in Et2O (entries 14
and 15 in Table 1), but a significant improvement in the
stereoselection was observed when allylmagnesium chloride,
H
O
9.0 % nOe
Figure 1. Preferred conformation in CDCl3 solution for compound 2.
In order to gain further information concerning 1,4-stereo-
inductionwithperhydro-1,3-benzoxazinesaschiraltemplates
we explore the chiral aryllithium derived from 5 in an alterna-
tive preparation of carbinols 3. Some chirons bearing a chiral
acetal appendage have been previously used in diastereo-
selective additions to carbonyl compounds.7d,20 Compound
5 was prepared in 65% yield, as a single diastereoisomer,
by condensation of 1 with o-bromobenzaldehyde and con-
verting into the organolithium derivative by treatment with
2.2 equiv of t-BuLi at ꢀ90 ꢁC in THF. Addition of the appro-
priate aldehyde (1.5 equiv) at that temperature afforded alco-
hols 3a, 3c, and 3e as major diastereoisomers but in lower
yield and diastereoselectivity than those above described
(Scheme 2).
Table 1. Nucleophilic addition of organometallic reagents to 2
Entry Reagent
Temp Solvent Time Products
(ꢁC)
(h)
(%)a
1
2
3
MeMgI
MeLi
EtMgBr
0
0
0
Et2O
THF
THF
0.5 3a:epi-3a (93:3)
0.5 3a:epi-3a (96:3)
1
3b:epi-3b (85:2)
4 (11)
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
i-PrMgBr
i-PrMgBr
n-BuMgBr
n-BuLi
ꢀ30 Et2O
ꢀ30 Et2O
ꢀ30 Et2O
ꢀ30 THF
ꢀ78 THF
25 Et2O
1.5 3c (47) 4(39)
1.5 3c (52) 4(43)
2.3 3d (70) 4(13)
0.5 3d (98)b
n-BuLi–CeCl3
PhMgBr
PhLi
3
3d (96)b
1.5 3e (82)b
0.75 3e:epi-3 (95:3)
The transformation of the benzylic alcohols into the final
phthalides 7a–k was performed in two steps as depicted in
Scheme 3. Hydrolytic cleavage of the N,O-ketal by reaction
with dilute (2%) aqueous alcoholic HCl solution allows for
the regeneration of the carbonyl group and the formation
of the acetals 6a–k as an equimolar mixture of cis and trans
isomers in good to excellent yield. The mixture of these
isomers was not isolated but used in the next step after puri-
fication. The 3-alkyl derivatives were easily hydrolyzed and
transformed into 6a–d after 12–48 h of reaction (entries 1–4
in Table 2) but in these conditions, the hydrolysis of per-
hydrobenzoxazines 6e–k occurred very slowly, and long
periods of reaction or refluxing conditions were necessary to
obtain the ketals (entries 5–7). The benzyl derivative 3f was
hydrolyzed at rt very slowly (entry 6), but the transformation
ꢀ78 THF
PhMgBr–CeCl3
PhCH2MgBr
CH2]CHMgBr
0
THF
0.5 3e (94)b
ꢀ30 Et2O
0.75 3f (87)b
25 Et2O
3
3g (96)b
CH2]CHCH2MgBr ꢀ30 Et2O
CH2]CHCH2MgBr ꢀ78 Et2O
CH2]CHCH2MgCl ꢀ78 THF
0.5 3h:epi-3h (43:39)
0.5 3h:epi-3h (48:46)
0.5 3h:epi-3h (78:14)
1.5 3h:epi-3h (77:15)
0.75 3i (96)b
CH2]CHCH2ZnBr
CF3TMS
BrZnCH2CO2Et
BrZnCF2CO2Et
25 THF
0
0
0
THF
THF
THF
24
2
3j (72)b,c
3k (95)b,c
a
Yields in parenthesis refer to pure and isolated compounds.
Only one diastereoisomer was observed in the 1H NMR spectra of the
reaction mixtures.
It was necessary to use 4 equiv of the organometallic to achieve complete
conversion.
b
c

10402
R. Pedrosa et al. / Tetrahedron 62 (2006) 10400–10407
Br
Treatment of compounds 6a–k with MCPBA and
OHC
BF3$OEt221 in CH2Cl2 at rt gave the enantiopure isobenzo-
furan-1-ones 7a–k in good to excellent yields (Table 2). All
the phthalides were purified by column chromatography or
recrystallization, except the vinyl derivative 7g, which could
not be isolated from the reaction crude. The optical rotations
of compounds 7a,22 7b,23 7d,24 7e,9 and 7h25 were compared
with those previously described, allowing to confirm the
absolute configuration of the stereocenter formed as R.
This result was consistent with the absolute configuration
determined for the alcohols 3a and 3k, and therefore, essen-
tially no racemization is taking place during the hydrolysis
and oxidation conditions. Enantiomeric excesses for com-
pounds 7a–h were determined as >99% by HPLC analysis
(see Section 3).
Bn
O
OH
NH
Bn
N
CH2Cl2, 120 °C
120h, sealed tube
Br
1
5
1. t-BuLi,
THF, -90 °C
2. RCHO
Bn
O
Bn
O
N
N
R
H
HO
epi-3
HO
H
R
3
R
Yield (%) Products (ratio)
Me
i-Pr
Ph
89
67
80
3a: epi-3a (2.7: 1)
3c: epi-3c (5.7: 1)
3e: epi-3e (2.2: 1)
In summary, our methodology allows for the preparation of
enantiopure 3-substituted phthalides starting from easily
accesible compounds. In addition, a great variety of substit-
uents can be introduced merely by changing the nucleophile
acting on the formyl group of the aryl substituent at C-2 in
the starting chiral perhydro-1,3-benzoxazine.
Scheme 2. Reaction of the aryllithium derived from 5 with aldehydes.
Bn
O
2% HCl, EtOH
N
EtO
O
H
H
HO
3. Experimental
3.1. General
R
R
3a-k
6a-k
mCPBA
BF3.OEt2
CH2Cl2
All reactions were carried out under an argon atmosphere in
an oven-dried glassware. Solvents and bases were dried by
standard methods: CH2Cl2 was distilled from CaH2 and benz-
ene, THF and Et2O from Na. (Trifluoromethyl)trimethyl-
silane was used as 2 M solution in THF. 1H NMR (300 MHz),
13C NMR (75 MHz), and 19F (282.38 MHz) spectra were
registered in CDCl3 as solvent and TMS or CFCl3 as internal
reference, and chemical shifts are given in parts per million.
Specific rotations were determined on a digital polarimeter
using Na lamp, and concentration is given in grams per
100 mL. Melting points were obtained with open capillary
tubes and are uncorrected. TLC was performed on glass-
backed plates coated with silica gel 60 with an F254 indicator.
The chromatograms were visualized under UV light and/or
by staining with I2 or phosphomolybdic acid. Flash chroma-
tography was carried out on silica gel (230–240 mesh).
O
O
H
R
7a-k
Scheme 3. Synthesis of phthalides 7a–k.
Table 2. Hydrolysis of 3a–k and oxidation to 3H-isobenzofuran-1-ones
7a–k
Entry
Hydrolysis time
(h)
Product
(%)a
Oxidation time
(h)
Product
(%)b
1
2
3
4
5
6
7
8
12
12
12
48
6a (96)
6b (91)
6c (97)
6d (84)
6e (97)
6f (95)
6g (70)
6h (95)
6i (85)
6j (65)f
6k (62)f
3
4
4
7a (72)
7b (71)
7c (52)d
7d (76)
7e (90)
7f (83)
7g (—)e
7h (58)
7i (80)
7j (62)
7k (60)
3
720
192
720
14c
12c
7c
0.5
3.5
3
3.1.1. Synthesis of alcohols 3a–k. General method. To a
solution of the aldehyde 2 (5.3 mmol) in the appropriate
ethereal solvent (Table 1, 5 mL) under argon and at the
temperature showed in Table 1 was slowly added a solution
of the appropriate organometallic reagent (5.83 mmol) and
the mixture was stirred at that temperature until disappear-
ance of the starting material (TLC). The reaction mixture
was quenched with saturated ammonium chloride, and the
product was extracted with diethyl ether (3ꢂ5 mL). The
organic extracts were washed with brine and dried over an-
hydrous MgSO4, and the solvent was evaporated in vacuo.
The residue was purified by flash chromatography on silica
gel using hexanes–ethyl acetate as eluent.
3
9
10
11
72
24
48
7c
a
Yields in parenthesis refer to isolated compounds.
b
Yields in parenthesis refer to total yields, and were calculated from
alcohols 3.
Reflux.
Conversion was total in the oxidation step.
Compound 7g could not be purified.
As a mixture of 1-ethoxy- and 1-hydroxy-1,3-dihydroisobenzofurans.
c
d
e
f
of 3h–k was only possible at reflux of ethanol. The hydro-
lysis of alcohols 3e (R¼Ph) and 3g (R¼vinyl) was performed
at rt for 30 days because under refluxing conditions they lead
to a complex mixture of reaction and the desired isobenzo-
furanes could not be isolated.
3.1.1.1. (1R,20S,4a0S,70R,8a0R)-1-(2-(N-Benzyl-40,40,70-
trimethyl-octahydro-2H-benzo[e][1,3] oxazin-20-yl)phenyl)-
ethanol (3a). White solid. Mp: 88–90 ꢁC (from hexane).
[a]2D3 +9.9 (c 1.20, CHCl3); [a]D23 +10.2 (c 1.0, CH2Cl2).

R. Pedrosa et al. / Tetrahedron 62 (2006) 10400–10407
10403
1H NMR (d): 0.93 (d, 3H, J¼6.5 Hz); 0.97–1.24 (m, 3H);
1.21 (s, 3H); 1.28 (d, 3H, J¼6.5 Hz); 1.38 (s, 3H); 1.42–
1.60 (m, 1H); 1.62–1.74 (m, 3H); 1.98 (m, 1H); 3.52 (d,
1H, J¼16.2 Hz); 3.67 (td, 1H, J1¼10.5 Hz, J2¼4.2 Hz);
3.84 (s, 1H); 3.90 (d, 1H, J¼16.2 Hz); 5.33 (q, 1H,
J¼6.5 Hz); 5.84 (s, 1H); 6.73–6.76 (m, 2H); 6.93–6.99 (m,
3H); 7.10–7.21 (m, 3H); 7.56 (d, 1H, J¼7.0 Hz). 13C NMR
(d): 19.0; 20.9; 22.2; 25.0; 28.3; 31.3; 34.9; 41.3; 46.3;
47.1; 58.4; 63.9; 76.2; 86.3; 124.6; 125.7; 126.8; 127.5
(2C); 127.7 (3C); 128.3; 136.8; 142.1; 143.3. IR (Nujol):
3200; 1600; 1590; 820; 780; 750 cmꢀ1. CI/MS (m/z, %):
394 (M+1, 100). Anal. Calcd for C26H35NO2 (393.56): C,
79.33; H, 8.97; N, 3.56. Found: C, 79.51; H, 8.82; N, 3.44.
Calcd for C27H37NO2 (407.59): C, 79.56; H, 9.15; N, 3.44.
Found: C, 79.62; H, 9.02; N, 3.31.
3.1.1.5. (1R,20S,4a0S,70R,8a0R)-1-(2-(N-Benzyl-40,40,70-
trimethyl-octahydro-2H-benzo[e][1,3] oxazin-20-yl)phenyl)-
2-methylpropan-1-ol (3c). Colorless oil. [a]2D3 +1.1 (c 0.50,
1
CHCl3). H NMR (d): 0.67–1.00 (m, 2H); 0.70 (d, 3H,
J¼6.7 Hz); 0.89 (d, 3H, J¼6.2 Hz); 0.91 (d, 3H,
J¼6.4 Hz); 1.10–1.24 (m, 1H); 1.22 (s, 3H); 1.42 (s, 3H);
1.44–1.78 (m, 5H); 1.94 (m, 1H); 2.82 (s, 1H); 3.63 (td,
1H, J1¼10.5 Hz, J2¼4.1 Hz); 3.65 (d, 1H, J¼16.4 Hz);
3.77 (d, 1H, J¼16.4 Hz); 4.79 (d, 1H, J¼7.5 Hz); 5.91 (s,
1H); 6.73–6.77 (m, 2H); 6.90–7.16 (m, 6H); 7.62 (dd, 1H,
J1¼7.7 Hz, J2¼1.1 Hz). 13C NMR (d): 18.4; 19.6; 21.4;
22.3; 25.0; 28.2; 31.4; 34.1; 35.1; 41.4; 45.5; 45.8; 57.8;
73.3; 76.6; 83.8; 125.5; 125.7; 126.4; 126.6; 127.5 (4C);
127.7; 136.7; 142.0; 142.4. IR (Nujol): 3360; 3060; 3020;
1600; 1590; 1450; 780; 750 cmꢀ1. CI/MS (m/z, %): 422
(M+1, 100). EI/MS (m/z, %): 421 (M, 0.1); 148 (72); 91
(100). Anal. Calcd for C28H39NO2 (421.61): C, 79.76; H,
9.32; N, 3.32. Found: C, 79.85; H, 9.43; N, 3.21.
3.1.1.2. (1S,20S,4a0S,70R,8a0R)-1-(2-(N-Benzyl-40,40,70-
trimethyl-octahydro-2H-benzo[e][1,3] oxazin-20-yl)phenyl)-
ethanol (epi-3a). Colorless oil. [a]2D3 +8.5 (c 0.29, CH2Cl2).
1H NMR (d): 0.83–0.92 (m, 1H); 0.95 (d, 3H, J¼6.5 Hz);
0.98–1.16 (m, 3H); 1.25 (s, 3H); 1.31 (s, 3H); 1.32 (d, 3H,
J¼6.8 Hz); 1.33–1.77 (m, 3H); 1.99 (m, 1H); 3.23 (d, 1H,
J¼16.0 Hz); 3.61 (td, 1H, J1¼10.5 Hz, J2¼4.2 Hz); 3.87
(d, 1H, J¼16.0 Hz); 5.51–5.55 (m, 1H); 5.55 (s, 1H);
6.75–6.79 (m, 2H); 6.97–7.18 (m, 6H); 7.39–7.42 (m, 1H).
13C NMR (d): 15.1; 22.2; 24.3; 25.2; 28.2; 31.2; 34.9;
41.3; 48.3; 48.7; 58.0; 66.5; 75.6; 90.7; 125.8; 126.2;
126.3; 127.5 (2C); 127.8 (2C); 128.6; 128.9; 135.9; 142.6;
146.5. IR (Film): 3520; 3400; 3060; 3020; 1600; 1590;
750; 720; 700 cmꢀ1. CI/MS (m/z, %): 394 (M+1, 34);
133(100). Anal. Calcd for C26H35NO2 (393.56): C, 79.33;
H, 8.97; N, 3.56. Found: C, 72.25; H, 9.09; N, 3.68.
3.1.1.6. (1R,20S,4a0S,70R,8a0R)-1-(2-(N-Benzyl-40,40,70-
trimethyl-octahydro-2H-benzo[e][1,3] oxazin-20-yl)phenyl)-
pentan-1-ol (3d). Colorless oil. [a]2D3 +17.6 (c 1.44, CHCl3).
1H NMR (d): 0.95 (t, 3H, J¼7.5 Hz); 0.97–1.10 (m, 1H);
1.02 (d, 3H, J¼6.5 Hz); 1.13–1.49 (m, 5H); 1.30 (s, 3H);
1.50 (s, 3H); 1.50–1.78 (m, 7H); 2.08 (m, 1H); 2.92 (s,
1H); 3.68 (d, 1H, J¼16.2 Hz); 3.76 (td, 1H, J1¼10.5 Hz,
J2¼4.0 Hz); 3.95 (d, 1H, J¼16.2 Hz); 5.25 (m, 1H); 5.97
(s, 1H); 6.81–6.84 (m, 2H); 6.97–7.07 (m, 3H); 7.15–7.28
(m, 3H); 7.68 (d, 1H, J¼8.0 Hz). 13C NMR (d): 14.2; 20.1;
22.3; 22.9; 25.0; 28.3; 28.7; 31.4; 35.0; 36.0; 41.4; 46.0;
46.6; 58.2; 68.2; 76.6; 85.3; 125.0; 125.7; 126.7; 127.2;
127.6 (2C); 127.7 (2C); 128.2; 136.7; 142.7; 143.0. IR
(Film): 3560; 3420; 3210; 3060; 3020; 1600; 1590; 1570;
1450; 820; 750; 730; 710 cmꢀ1. CI/MS (m/z, %): 436
(M+1, 100). Anal. Calcd for C29H41NO2 (435.64): C,
79.95; H, 9.49; N, 3.22. Found: C, 80.07; H, 9.60; N, 3.34.
3.1.1.3. (1R,20S,4a0S,70R,8a0R)-1-(2-(N-Benzyl-40,40,70-
trimethyl-octahydro-2H-benzo[e][1,3] oxazin-20-yl)phenyl)-
propan-1-ol (3b). Colorless oil. [a]2D3 +3.3 (c 1.08, CHCl3).
1H NMR (d): 0.95–1.12 (m, 2H); 0.97 (t, 3H, J¼7.5 Hz);
0.97 (d, 3H, J¼6.5 Hz); 1.18–1.38 (m, 1H); 1.25 (s, 3H);
1.47 (s, 3H); 1.50–1.78 (m, 6H); 2.02 (m, 1H); 2.82 (s,
1H); 3.68 (d, 1H, J¼16.2 Hz); 3.73 (td, 1H, J1¼10.5 Hz,
J2¼4.0 Hz); 3.90 (d, 1H, J¼16.2 Hz); 5.10 (dd, 1H,
J1¼8.1 Hz, J2¼5.0 Hz); 5.93 (s, 1H); 6.77–6.80 (m, 2H);
6.97–7.10 (m, 3H); 7.10–7.24 (m, 3H); 7.65 (d, 1H,
J¼7.5 Hz). 13C NMR (d): 11.0; 20.3; 22.3; 25.0; 28.3;
29.1; 31.4; 35.0; 41.4; 45.9; 46.5; 58.2; 68.2; 76.6; 85.3;
125.0; 125.7; 126.7; 127.2; 127.6 (2C); 127.7 (2C); 128.2;
136.7; 143.0 (2C). IR (Film): 3560; 3420; 3210; 3060;
1600; 1590; 1570; 820; 750; 730; 710 cmꢀ1. CI/MS (m/z,
%): 408 (M+1, 100). Anal. Calcd for C27H37NO2 (407.59):
C, 79.56; H, 9.15; N, 3.44. Found: C, 79.70; H, 9.28; N, 3.32.
3.1.1.7. (1R,20S,4a0S,70R,8a0R)-1-(2-(N-Benzyl-40,40,70-
trimethyl-octahydro-2H-benzo[e][1,3] oxazin-20-yl)phenyl)
phenyl-methanol (3e). Colorless oil. [a]2D3 +14.0 (c 0.80,
1
CHCl3). H NMR (d): 1.07–1.12 (m, 1H); 1.07 (d, 3H,
J¼6.5 Hz); 1.24–1.47 (m, 2H); 1.26 (s, 3H); 1.53 (s, 3H);
1.64–1.81 (m, 4H); 2.06 (m, 1H); 3.76 (d, 1H, J¼
16.2 Hz); 3.78 (td, 1H, J1¼10.5 Hz, J2¼4.1 Hz); 4.00 (d,
1H, J¼16.2 Hz); 5.07 (s, 1H); 6.18 (s, 1H); 6.30 (s, 1H);
6.70 (d, 1H, J¼7.7 Hz); 6.89–6.96 (m, 2H); 7.06–7.18 (m,
3H); 7.20–7.36 (m, 7H); 7.76 (d, 1H, J¼7.4 Hz). 13C
NMR (d): 20.8; 22.3; 24.9; 28.5; 31.4; 35.0; 41.3; 42.5;
46.6; 58.9; 71.2; 76.8; 85.0; 125.9; 127.1 (2C); 127.3 (2C);
127.5; 127.6; 127.7 (2C); 128.1 (3C); 128.2 (2C); 137.5;
142.0; 142.2 (2C). IR (Film): 3580; 3220; 3060; 3020;
1720; 1690; 1600; 1570; 1450; 750; 730; 690 cmꢀ1. CI/
MS (m/z, %): 456 (M+1, 92); 195 (100). Anal. Calcd for
C31H37NO2 (455.63): C, 81.72; H, 8.19; N, 3.07. Found:
C, 81.52; H, 8.30; N, 2.87.
3.1.1.4. (1S,20S,4a0S,70R,8a0R)-1-(2-(N-Benzyl-40,40,70-
trimethyl-octahydro-2H-benzo[e][1,3] oxazin-20-yl)phenyl)-
propan-1-ol (epi-3b). Colorless oil. [a]2D3 +0.9 (c 1.62,
1
CHCl3). H NMR (d): 0.97 (d, 3H, J¼6.9 Hz); 1.00–1.20
(m, 3H); 1.28 (s, 3H); 1.32 (s, 3H); 1.39–1.77 (m, 6H); 2.00
(m, 1H); 3.00 (br s, 1H); 3.38 (d, 1H, J¼16.0 Hz); 3.64 (td,
1H, J1¼10.7 Hz, J2¼4.0 Hz); 3.90 (d, 1H, J¼16.0 Hz);
5.09 (m, 1H); 5.71 (s, 1H); 6.80–6.83 (m, 2H); 7.00–7.10
(m, 4H); 7.12–7.25 (m, 2H); 7.49 (dd, 1H, J1¼7.3 Hz, J2¼
1.2 Hz). 13C NMR (d): 11.1; 16.8; 22.3; 25.1; 28.3; 31.2;
31.4; 34.9; 41.3; 47.8; 47.9; 58.3; 73.2; 75.8; 91.0; 125.8;
126.4; 127.1; 127.5 (2C); 127.8 (2C); 128.3; 128.7; 136.2;
142.4 (2C). IR (Film): 3550; 3400; 3050; 1590; 1450; 750;
720; 690 cmꢀ1. CI/MS (m/z, %): 408 (M+1, 100). Anal.
3.1.1.8. (1S,20S,4a0S,70R,8a0R)-1-(2-(N-Benzyl-40,40,70-
trimethyl-octahydro-2H-benzo[e][1,3] oxazin-20-yl)phenyl)
phenyl-methanol (epi-3e). Colorless oil. [a]2D3 ꢀ1.6 (c
1
0.61, CHCl3). H NMR (d): 0.87–1.08 (m, 1H); 0.90 (d,

10404
R. Pedrosa et al. / Tetrahedron 62 (2006) 10400–10407
3H, J¼6.5 Hz); 1.10–1.37 (m, 2H); 1.13 (s, 3H); 1.18 (s,
3H); 1.39–1.73 (m, 4H); 1.94 (m, 1H); 3.38 (td, 1H,
J1¼10.5 Hz, J2¼4.0 Hz); 3.65 (d, 1H, J¼16.2 Hz); 4.00
(d, 1H, J¼16.2 Hz); 5.62 (s, 1H); 5.90 (s, 1H); 6.89–6.96
(m, 2H); 7.02–7.13 (m, 4H); 7.15–7.33 (m, 8H); 7.76 (d,
1H, J¼7.4 Hz). 13C NMR (d): 20.1; 22.3; 24.7; 28.5; 31.2;
34.9; 41.0; 44.9; 47.2; 59.5; 75.7; 77.5; 85.7; 126.1; 126.4
(2C); 126.6; 127.5; 127.8 (2C); 127.9 (2C); 128.2 (3C);
128.9; 130.2; 137.4; 140.9; 141.2; 144.6. IR (Film): 3253;
3060; 3030; 1603; 1451; 756; 732; 692 cmꢀ1. Anal. Calcd
for C31H37NO2 (455.63): C, 81.72; H, 8.19; N, 3.07. Found:
C, 81.84; H, 8.30; N, 3.19.
J2¼1.0 Hz); 5.18 (dd, 1H, J1¼17.7 Hz, J2¼1.7 Hz); 5.26–
5.40 (m, 1H); 5.60–5.88 (m, 1H); 5.95 (s, 1H); 6.84–6.87
(m, 2H); 7.00–7.09 (m, 3H); 7.10–7.28 (m, 3H); 7.71 (d,
1H, J¼7.3 Hz). 13C NMR (d): 20.3; 22.4; 25.1; 28.3; 31.4;
35.1; 40.9; 41.4; 46.1; 46.7; 58.2; 67.8; 76.6; 85.5; 116.8;
124.5; 125.7; 126.9; 127.4; 127.6 (2C); 127.7 (2C); 128.2;
135.8; 136.6; 142.3; 142.7. IR (Film): 3560; 3420; 3060;
3020; 1640; 1600; 1580; 1450; 760; 740; 710 cmꢀ1. CI/MS
(m/z, %): 420 (M+1, 100); 159 (59). Anal. Calcd for
C28H37NO2 (419.60): C, 80.15; H, 8.89; N, 3.34. Found: C,
79.42; H, 8.32; N, 3.19.
3.1.1.12. (1S,20S,4a0S,70R,8a0R)-1-(2-(N-Benzyl-40,40,70-
trimethyl-octahydro-2H-benzo[e][1,3] oxazin-20-yl)phenyl)-
but-3-en-1-ol (epi-3h). Colorless oil. [a]2D3 ꢀ12.0 (c 1.60,
3.1.1.9. (1R,20S,4a0S,70R,8a0R)-1-(2-(N-Benzyl-40,40,70-
trimethyl-octahydro-2H-benzo[e][1,3] oxazin-20-yl)phenyl)-
2-phenylethanol (3f). Colorless oil. [a]2D3 +9.7 (c 3.10,
1
CHCl3). H NMR (d): 0.98 (d, 3H, J¼6.5 Hz); 1.01–1.21
1
CHCl3). H NMR (d): 0.96 (d, 3H, J¼6.4 Hz); 0.98–1.12
(m, 2H); 1.29 (s, 3H); 1.33 (s, 3H); 1.40–1.68 (m, 2H);
1.76–1.80 (m, 2H); 1.95 (m, 1H); 2.22–2.32 (m, 1H);
2.43–2.49 (m, 1H); 3.27 (d, 1H, J¼16 Hz); 3.64 (td, 1H,
J1¼10.5 Hz, J2¼4.0 Hz); 3.80 (d, 1H, J¼16 Hz); 5.08–
5.18 (m, 2H); 5.39–5.42 (m, 1H); 5.61 (s, 1H); 5.86–5.99
(m, 1H); 6.79–6.81 (m, 2H); 6.99–7.12 (m, 4H); 7.13–7.27
(m, 2H); 7.46 (d, 1H, J¼7.2 Hz). 13C NMR (d): 15.5; 22.3;
25.2; 28.23; 31.2; 34.9; 41.3; 42.9; 43.2; 46.4; 58.1; 70.2;
75.7; 90.1; 116.3; 125.8; 126.7; 126.9; 127.5 (2C); 127.8
(2C); 128.5; 128.9; 136.1; 136.5; 142.4 (2C). IR (Film):
3580; 3410; 3060; 3020; 1640; 1600; 1580; 1450; 760;
720; 700 cmꢀ1. CI/MS (m/z, %): 420 (M+1, 100). Anal.
Calcd for C28H37NO2 (419.60): C, 80.15; H, 8.89; N, 3.34.
Found: C, 79.64; H, 8.27; N, 3.63.
(m, 2H); 1.18–1.26 (m, 1H); 1.21 (s, 3H); 1.37 (s, 3H);
1.40–1.53 (m, 2H); 1.68–1.75 (m, 2H); 1.95 (m, 1H); 2.19
(br s, 1H); 2.78 (dd, 1H, J1¼13.6 Hz, J2¼5.0 Hz); 2.97
(dd, 1H, J1¼13.6 Hz, J2¼8.1 Hz); 3.52 (td, 1H, J1¼
10.4 Hz, J2¼3.8 Hz); 3.62 (d, 1H, J¼16.3 Hz); 3.84 (d,
1H, J¼16.3 Hz); 5.46 (dd, 1H, J1¼8.1 Hz, J2¼5.0 Hz);
5.57 (s, 1H); 6.77–6.80 (m, 2H); 6.96–7.02 (m, 3H); 7.12–
7.24 (m, 8H); 7.62 (d, 1H, J¼7.0 Hz). 13C NMR (d): 20.6;
22.4; 24.9; 25.0; 28.3; 31.4; 35.1; 41.4; 43.9; 46.1; 46.5;
57.9; 69.2; 76.3; 84.9; 125.2; 125.7; 126.2; 126.9; 127.0;
127.5 (4C); 128.2 (3C); 129.4 (2C); 136.6; 138.9; 142.4;
143.2. IR (Film): 3530; 3200; 3060; 3020; 1720; 1600;
1580; 1490; 1450; 760; 730; 700 cmꢀ1. CI/MS (m/z, %):
470 (M+1, 100). Anal. Calcd for C32H39NO2 (469.66): C,
81.83; H, 8.37; N, 2.98. Found: C, 81.70; H, 8.48; N, 3.09.
3.1.1.13. (1S,20S,4a0S,70R,8a0R)-1-(2-(N-Benzyl-40,40,70-
trimethyl-octahydro-2H-benzo[e][1,3] oxazin-20-yl)phenyl)-
2,2,2-trifluoroethanol (3i). White solid. Mp: 103–104 ꢁC
3.1.1.10. (1R,20S,4a0S,70R,8a0R)-1-(2-(N-Benzyl-40,40,70-
trimethyl-octahydro-2H-benzo[e][1,3] oxazin-20-yl)phenyl)-
prop-2-en-1-ol (3g). White solid. Mp: 102–103 ꢁC (from
1
(from methanol). [a]2D3 ꢀ25.5 (c 1.00, CHCl3). H NMR
(d): 0.96–1.14 (m, 2H); 1.03 (d, 3H, J¼6.5 Hz); 1.26 (q,
1H, J¼11.8 Hz); 1.39 (s, 3H); 1.52 (s, 3H); 1.54–1.62 (m,
2H); 1.73–1.83 (m, 2H); 2.08 (m, 1H); 3.77 (td, 1H,
J1¼10.5 Hz, J2¼6.0 Hz); 3.82 (s, 2H); 5.92 (q, 1H,
J1¼17.1 Hz); 5.96 (s, 1H); 6.80–6.83 (m, 2H); 7.04–7.09
(m, 3H); 7.19–7.26 (m, 2H); 7.31–7.42 (m, 1H); 7.82 (d,
1H, J¼7.0 Hz). 19F NMR (d): ꢀ77.1 (br s, 3F). 13C NMR
(d): 20.8; 22.3; 25.1; 28.3; 31.4; 35.2; 41.3; 46.1; 46.48;
1
ethanol). [a]2D3 +29.0 (c 0.80, CHCl3). H NMR (d): 0.88
(d, 3H, J¼6.5 Hz); 0.92–1.00 (m, 1H); 1.10–1.37 (m, 1H);
1.21 (s, 3H); 1.30 (s, 3H); 1.44–1.45 (m, 1H); 1.56–1.68
(m, 4H); 1.94 (m, 1H); 3.38 (d, 1H, J¼16.0 Hz); 3.62 (td,
1H, J1¼10.5 Hz, J2¼4.1 Hz); 3.84 (d, 1H, J¼16.0 Hz);
3.87 (s, 1H); 5.11 (dt, 1H, J1¼10.5 Hz, J2¼1.7 Hz), 5.29
(dt, 1H, J1¼17.2 Hz, J2¼1.7 Hz); 5.40–5.65 (m, 1H); 5.67
(s, 1H); 5.80 (br s, 1H); 6.71–6.88 (m, 2H); 6.90–6.97 (m,
4H); 7.06 (dt, 1H, J1¼7.5 Hz, J2¼1.5 Hz); 7.15 (dt, 1H,
J1¼6.5 Hz, J2¼1.5 Hz); 7.48 (d, 1H, J¼7.3 Hz). 13C NMR
(d): 18.0; 22.2; 25.1; 28.3; 31.3; 34.8; 41.2; 46.7; 46.8;
58.3; 68.9; 76.4; 88.1; 114.4; 125.7; 126.9; 127.1; 127.6
(3C); 127.7 (2C); 128.5; 137.1; 138.6; 141.6; 141.9. IR
(Film): 3560; 3400; 3060; 3020; 1635; 1600; 1570; 1450;
750; 730; 710; 690 cmꢀ1. CI/MS (m/z, %): 406 (M+1, 96);
145 (100). Anal. Calcd for C27H35NO2 (405.57): C, 79.96;
H, 8.70; N, 3.45. Found: C, 79.32; H, 8.70; N, 3.01.
2
57.9; 67.2 (q, JCF¼31.6 Hz); 76.5; 84.1; 126.0; 127.6
(2C); 127.8 (2C); 128.1; 128.2; 128.7; 129.1; 133.4; 137.9;
143.1. IR (KBr): 3554; 3080; 3060; 3030; 1726; 1600;
1493; 1455; 1243; 1154; 1103; 764; 714 cmꢀ1. CI/MS
(m/z, %): 448 (M+1, 100); 447 (M, 11); 428 (23). Anal. Calcd
for C26H32F3NO2 (447.53): C, 69.78; H, 7.21; N, 3.13.
Found: C, 69.70; H, 7.34; N, 3.05.
3.1.1.14. (3R,20S,4a0S,70R,8a0R)-Ethyl 3-(2-(N-benzyl-
40,40,70-trimethyl-octahydro-2H-benzo[e][1,3] oxazin-20-
yl)phenyl)-3-hydroxypropanoate (3j). Yellow solid. Mp:
1
3.1.1.11. (1R,20S,4a0S,70R,8a0R)-1-(2-(N-Benzyl-40,40,70-
trimethyl-octahydro-2H-benzo[e][1,3] oxazin-20-yl)phenyl)-
but-3-en-1-ol (3h). Colorless oil. [a]2D3 +17.0 (c 1.97,
131–132 ꢁC (from hexane). [a]D23 +9.7 (c 0.34, CHCl3). H
NMR (d): 0.97 (d, 3H, J¼6.5 Hz); 1.00–1.09 (m, 2H);
1.21–1.30 (m, 1H); 1.28 (t, 3H, J¼7.1 Hz); 1.28 (s, 3H);
1.44 (s, 3H); 1.48–1.55 (m, 1H); 1.62–1.78 (m, 3H); 2.01
(m, 1H); 2.36 (d, 1H, J¼15.4 Hz); 2.71 (dd, 1H,
J1¼15.4 Hz, J2¼9.9 Hz); 3.45 (br s, 1H); 3.54 (d, 1H,
J¼16.2 Hz); 3.72 (td, 1H, J1¼10.5 Hz, J2¼4.0 Hz); 3.91
(d, 1H, J¼16.2 Hz); 4.14–4.23 (m, 2H); 5.82 (d, 1H,
J¼9.9 Hz); 5.86 (s, 1H); 6.78–6.80 (m, 2H); 6.79–7.00 (m,
1
CHCl3). H NMR (d): 1.03–1.26 (m, 2H); 1.04 (d, 3H,
J¼6.5 Hz); 1.28–1.40 (m, 1H); 1.31 (s, 3H); 1.50 (s, 3H);
1.57–1.69 (m, 2H); 1.74–1.83 (m, 2H); 2.02 (m, 1H); 2.30–
2.35 (m, 1H); 2.41–2.59 (m, 1H); 2.93 (br s, 1H); 3.68 (d,
1H, J¼16.0 Hz); 3.75 (td, 1H, J1¼10.6 Hz, J2¼4.1 Hz);
3.96 (d, 1H, J¼16.0 Hz); 5.13 (dt, 1H, J1¼10.0 Hz,

R. Pedrosa et al. / Tetrahedron 62 (2006) 10400–10407
10405
3H); 7.05 (d, 1H, J¼7.5 Hz); 7.16 (dt, 1H, J1¼7.5 Hz,
J2¼1.3 Hz); 7.23 (dt, 1H, J1¼7.5 Hz, J2¼1.3 Hz); 7.60 (d,
1H, J¼7.5 Hz). 13C NMR (d): 14.2; 22.2; 25.0; 28.2; 31.3;
34.9; 41.4; 41.3; 47.1; 58.2; 60.4; 65.1; 76.5; 86.3; 124.9;
125.7; 127.2; 127.5 (3C); 127.7 (2C); 128.4; 136.7; 141.2;
142.3; 171.7. IR (Nujol): 3460; 3040; 1680; 1600; 1580;
1370; 1320; 770; 730; 700 cmꢀ1. CI/MS (m/z, %): 466
(M+1, 100). Anal. Calcd for C29H39NO4 (465.62): C,
74.81; H, 8.44; N, 3.00. Found: C, 74.12; H, 8.21; N, 3.02.
were washed with brine, dried (MgSO4), and concentrated
in vacuo. The resulting 1,3-dihydroisobenzofurans 6a–k
were redissolved in anhydrous CH2Cl2 (10 mL), MCPBA
(4.07 mmol) and BF3$Et2O (0.74 mmol) were added under
argon and the mixture was stirred at rt until the oxidation
was finished (TLC, Table 2). The reaction mixture was
quenched and made alkaline by addition of a saturated solu-
tion of sodium bicarbonate. The aqueous layer was extracted
with diethyl ether (3ꢂ5 mL). The organic extracts were
washed with brine and dried over anhydrous MgSO4, and
the solvent was evaporated invacuo. The residue was purified
by flash chromatography on silica gel using hexanes–ethyl
acetate as eluent. The enantiomeric excesses for compounds
7a–h were determined as >99% by HPLC (Chiralcel OD col-
umn 0.46ꢂ25 cm; solvent ratio (hexane/IPA) 99:1 except for
7e,f (90/10) and 7d (98/2); flow rate: 1.1 mL/min for 7a,b,e,f;
1.0 mL/min for 7c,d and 1.2 mL/min for 7h; and UV detec-
tion at 225 nm for 7a–d,h and at 208 nm for 7e and 7f).
3.1.1.15. (3S,20S,4a0S,70R,8a0R)-Ethyl 3-(2-(N-benzyl-
40,40,70-trimethyl-octahydro-2H-benzo[e][1,3] oxazin-
20-yl)phenyl)-2,2-difluoro-3-hydroxypropanoate (3k).
White solid. Mp: 140–141 ꢁC (from hexane). [a]2D3 ꢀ30.0
1
(c 0.83, CHCl3). H NMR (d): 0.96–1.12 (m, 2H); 1.01 (d,
3H, J¼6.5 Hz); 1.23–1.30 (m, 1H); 1.36 (s, 3H); 1.37 (t,
3H, J¼7.1 Hz); 1.50–1.70 (m, 2H); 1.59 (s, 3H); 1.72–1.81
(m, 2H); 2.08 (m, 1H); 3.76 (td, 1H, J1¼10.5 Hz,
J2¼4.0 Hz); 3.81 (s, 2H); 4.32–4.42 (m, 2H); 6.05 (s, 1H);
2
2
6.09 (dd, 1H, JHF¼19.6 Hz, JHF¼3.1 Hz); 6.81 (m, 2H);
6.97–7.07 (m, 3H); 7.17–7.27 (m, 2H); 7.32–7.37 (m, 1H);
7.83 (d, 1H, J¼7.7 Hz). 19F NMR (d): ꢀ110.3 (d, 1F,
J¼260.6 Hz); ꢀ124.6 (dd, 1F, J1¼260.6 Hz, 2JHF¼19.6 Hz).
13C NMR (d): 13.9; 21.4; 22.4; 25.1; 28.3; 31.4; 35.19; 41.4;
The (ꢀ)-8-benzylaminomenthol can be recovered in 90–
95% from the aqueous phase of the hydrolysis simply by
adding a solution of sodium carbonate to pH¼8 and extrac-
tion with diethyl ether (4ꢂ50 mL). The ethereal solution was
dried over anhydrous MgSO4, and the solvent was evapo-
rated in vacuo giving a white solid, which was recrystallized
from hexanes.
2
2
45.9; 46.1; 57.7; 62.9; 67.7 (dd, JCF¼32.5 Hz, JCF
¼
21.7 Hz); 76.4; 83.7; 114.0 (dd); 125.9; 126.7; 127.4;
127.5 (2C); 127.6 (2C); 127.7; 128.5; 133.4; 138.3; 143.7;
163.5 (dd). IR (Nujol): 3520; 3060; 1770; 1730; 1600;
1590; 1320; 770; 740; 710; 700 cmꢀ1. CI/MS (m/z, %):
502 (M+1, 100). Anal. Calcd for C29H37F2NO4 (501.61):
C, 69.44; H, 7.43; N, 2.79. Found: C, 68.92; H, 6.97; N, 2.36.
3.1.3.1. (R)-3-Methylisobenzofuran-1(3H)-one (7a).
White solid. Mp: 47–49 ꢁC (from hexane). [a]2D3 +41.4 (c
1
1.39, CH2Cl2). H NMR (d): 1.65 (d, 3H, J¼6.7 Hz); 5.58
(q, 1H, J¼6.7 Hz), 7.45 (dd, 1H, J1¼7.5 Hz, J2¼0.7 Hz);
7.53 (t, 1H, J¼7.5 Hz); 7.69 (dt, 1H, J1¼7.6 Hz, J2¼
1.1 Hz); 7.91 (d, 1H, J¼7.6 Hz). 13C NMR (d): 20.3; 77.7;
121.7; 125.3; 125.5; 129.0; 134.1; 151.1; 170.4. IR (Film):
1780; 1600; 1590; 1450; 770; 740; 700 cmꢀ1. MS (m/z,
%): 149 (M+1, 100). EI/MS (m/z, %): 105 (100); 133 (56).
Anal. Calcd for C9H8O2 (148.16): C, 72.96; H, 5.44. Found:
C, 73.08; H, 5.52. HPLC analysis: 3S isomer 24.59 min, 3R
isomer 25.84 min.
3.1.2. Synthesis of (2S,4aS,7R,8aR)-3-benzyl-2-(2-bromo-
phenyl)-4,4,7-trimethyl-octahydro-2H-benzo[e][1,3]
oxazine (5). A solution of (ꢀ)-8-N-benzylaminomenthol
(11.5 mmol) and 2-bromobenzaldehyde (23 mmol) was
stirred in a sealed tube at 120 ꢁC until disappearance of
the starting aminoalcohol (TLC, 5 days). Then 50 mL of eth-
anol was added and the mixture ethanol–water was evapo-
rated in vacuo. The residue was chromatographed on silica
gel with hexanes–ethyl acetate 1:60 as eluent. Yield 65%.
White solid. Mp: 71 ꢁC (from hexane). [a]2D3 +54.9 (c 1.20,
3.1.3.2. (R)-3-Ethylisobenzofuran-1(3H)-one (7b).
1
Colorless oil. [a]2D3 +78.7 (c 1.37, CHCl3). H NMR (d):
1
CHCl3). H NMR (d): 0.97–1.16 (m, 2H); 0.98 (d, 3H,
1.00 (t, 3H, J¼7.3 Hz); 1.83 (dq, 1H, J1¼14.5 Hz, J2¼
7.2 Hz); 2.14 (ddq, 1H, J1¼14.5 Hz, J2¼7.2 Hz, J3¼
4.3 Hz); 5.47 (dd, 1H, J1¼7.1 Hz, J2¼4.3 Hz); 7.45 (dd,
1H, J1¼7.5 Hz, J2¼1.0 Hz); 7.53 (t, 1H, J¼7.5 Hz); 7.69
(dt, 1H, J1¼7.5 Hz, J2¼1.0 Hz); 7.88 (d, 1H, J¼7.5 Hz).
13C NMR (d): 8.7; 27.5; 82.3; 121.7; 125.4; 126.1; 129.0;
133.9; 149.6; 170.7. IR (Film): 1770; 1600; 1590; 1450;
760; 740; 700; 690 cmꢀ1. EI/MS (m/z, %): 162 (M, 10);
133 (100); 105 (35). Anal. Calcd for C10H10O2 (162.19): C,
74.06; H, 6.21. Found: C, 74.00; H, 6.02. HPLC analysis:
3S isomer 18.74 min, 3R isomer 20.16 min.
J¼6.5 Hz); 1.06 (s, 3H); 1.23 (q, 1H, J¼11.7 Hz); 1.48 (s,
3H); 1.54–1.70 (m, 3H); 1.75–1.78 (m, 1H); 1.99 (m, 1H);
3.67 (d, 1H, J¼17.1 Hz); 3.73 (td, 1H, J1¼10.5 Hz,
J2¼4.1 Hz); 3.95 (d, 1H, J¼17.1 Hz); 5.99 (s, 1H); 6.90–
7.14 (m, 7H); 7.34 (dd, 1H, J1¼7.9 Hz, J2¼1.2 Hz); 7.60
(dd, 1H, J1¼7.8 Hz, J2¼1.7 Hz). 13C NMR (d): 19.8; 22.4;
25.1; 27.8; 31.5; 35.2; 41.6; 46.0; 46.6; 58.2; 76.7; 87.3;
123.3; 125.4; 126.8; 127.0 (2C); 129.1; 130.2; 132.3;
138.8; 143.7. IR (Film): 3060; 3020; 1600; 1590; 1450;
750; 720; 690 cmꢀ1. CI/MS (m/z, %): 428 (M+1, 100),
430 (M+2, 90). Anal. Calcd for C24H30BrNO (428.41): C,
67.29; H, 7.06; N, 3.27. Found: C, 67.20; H, 7.21; N, 3.18.
3.1.3.3. (R)-3-Isopropylisobenzofuran-1(3H)-one (7c).
White solid. Mp: 59–60 ꢁC (from hexane). [a]2D3 +73.0
1
3.1.3. Synthesis of 3H-isobenzofuran-1-ones (7a–k). Gen-
eral method. A solution of the corresponding perhydro-
benzoxazines 3a–k (4 mmol) in ethanol (60 mL) and 2%
aqueous hydrochloric acid (30 mL) was stirred at rt or
refluxing (see experimental conditions in Table 2) until
the hydrolysis was complete (TLC). The aqueous layer
was extracted with hexane (3ꢂ60 mL). The organic extracts
(c 1.03, CHCl3). H NMR (d): 0.80 (d, 3H, J¼6.8 Hz);
1.13 (d, 3H, J¼6.8 Hz); 2.24–2.35 (m, 1H); 5.38 (d, 1H,
J¼3.7 Hz); 7.47 (dd, 1H, J1¼7.4 Hz, J2¼0.9 Hz); 7.54 (t,
1H, J¼7.4 Hz); 7.68 (dt, 1H, J1¼7.4 Hz, J2¼0.9 Hz); 7.88
(d, 1H, J¼7.4 Hz). 13C NMR (d): 15.5; 18.6; 32.2; 85.6;
122.1; 125.5; 126.5; 128.9; 133.8; 149.8; 170.8. IR (Nujol):
1740; 1600; 730; 690 cmꢀ1. CI/MS (m/z, %): 177 (M+1,

10406
R. Pedrosa et al. / Tetrahedron 62 (2006) 10400–10407
100). Anal. Calcd for C11H12O2 (176.21): C, 74.98; H, 6.86.
Found: C, 74.79; H, 6.57. HPLC analysis: 3S isomer
11.37 min, 3R isomer 12.30 min.
168.3; 170.5. IR (Nujol): 1760; 1600; 1590; 1450; 770;
720; 700 cmꢀ1. CI/MS (m/z, %): 203 (M+1, 100). Anal.
Calcd for C9H5F3O2 (202.13): C, 53.48; H, 2.49. Found:
C, 53.08; H, 2.79.
3.1.3.4. (R)-3-Butylisobenzofuran-1(3H)-one (7d).
1
Colorless oil. [a]2D3 +49.1 (c 0.65, CHCl3). H NMR (d):
3.1.3.9. (R)-Ethyl 2-(3-oxo-1,3-dihydroisobenzofuran-
1-yl)acetate (7j). Yellow oil. [a]2D3 +4.8 (c 0.92, CHCl3).
1H NMR (d): 1.27 (t, 3H, J¼7.2 Hz); 2.91 (d, 2H,
J¼6.7 Hz); 4.21 (q, 2H, J¼7.2 Hz); 5.89 (t, 1H, J¼6.7 Hz);
7.50 (d, 1H, J¼7.5 Hz); 7.55 (t, 1H, J¼7.5 Hz); 7.69
(t, 1H, J¼7.5 Hz); 7.90 (d, 1H, J¼7.5 Hz). 13C NMR (d):
14.1; 39.5; 61.2; 77.0; 122.1; 125.7; 125.8; 129.5; 134.3;
148.7; 169.2; 169.9. IR (Film): 1760; 1730; 1600; 1590;
1450; 770; 740; 700 cmꢀ1. CI/MS (m/z, %): 221 (M+1,
100). Anal. Calcd for C12H12O4 (220.22): C, 65.45; H,
5.49. Found: C, 65.56; H, 5.59.
0.88 (t, 3H, J¼7.0 Hz); 1.23–1.48 (m, 4H); 1.71–1.76 (m,
1H); 2.00–2.05 (m, 1H); 5.46 (dd, 1H, J1¼7.8 Hz, J2¼
4.0 Hz); 7.42 (dd, 1H, J1¼7.5 Hz, J2¼1.0 Hz); 7.50 (t, 1H,
J¼7.5 Hz); 7.66 (dt, 1H, J1¼7.5 Hz, J2¼1.0 Hz); 7.88 (d,
1H, J¼7.5 Hz). 13C NMR (d): 13.8; 22.4; 26.8; 34.4; 81.5;
122.7; 125.6; 125.7; 129.0; 134.0; 150.1; 180.7. IR (Film):
1740; 1610; 1590; 1450; 730; 710; 690 cmꢀ1. EI/MS (m/z,
%): 190 (M, 1); 41 (100); 133 (39); 77 (27); 105 (13).
Anal. Calcd for C12H14O2 (190.24): C, 75.76; H, 7.42.
Found: C, 75.90; H, 7.52. HPLC analysis: 3S isomer
11.79 min, 3R isomer 12.43 min.
3.1.3.10. (S)-Ethyl 2,2-difluoro-2-(3-oxo-1,3-dihydro-
isobenzofuran-1-yl)acetate (7k). Yellow oil. [a]2D3 +47.6
(c 0.84, CHCl3). 1H NMR (d): 1.30 (t, 3H, J¼7.1 Hz);
3.1.3.5. (R)-3-Phenylisobenzofuran-1(3H)-one (7e).
White solid. Mp: 152–153 ꢁC (from hexane). [a]2D3 ꢀ45.5
1
2
(c 0.4, CHCl3). H NMR (d): 6.41 (s, 1H); 7.27–7.41 (m,
4.34 (q, 2H, J¼7.1 Hz); 5.87 (dd, 1H, J1HF¼14.0 Hz,
6H); 7.57 (t, 1H, J¼7.5 Hz); 7.65 (dt, 1H, J1¼7.5 Hz,
J2¼1.1 Hz); 7.98 (d, 1H, J¼7.5 Hz). 13C NMR (d): 82.6;
122.8; 125.6; 126.9 (2C); 128.9 (2C); 129.3; 134.3; 136.3;
149.6; 170.5. IR (Nujol): 1760; 1600; 1590; 770; 750;
700 cmꢀ1. CI/MS (m/z, %): 211 (M+1, 100); 133 (16).
Anal. Calcd for C14H10O2 (210.23): C, 79.98; H, 4.79.
Found: C, 79.66; H, 5.07. HPLC analysis: 3S isomer
9.87 min, 3R isomer 12.76 min.
2J2HF¼4.5 Hz); 7.64 (m, 2H); 7.75 (t, 1H, J¼7.5 Hz); 7.95
(d, 1H, J¼7.5 Hz). 19F NMR (d): ꢀ121.4 (dd, 1F, J1¼
2
274.8 Hz, JHF¼14.0 Hz); ꢀ112.4 (dd, 1F, J1¼274.8 Hz,
2JHF¼4.5 Hz). 13C NMR (d): 13.8; 63.8; 76.6 (t,
2JCF¼32.2 Hz); 112.0 (dd); 123.8; 126.1; 126.3; 130.8;
134.7; 141.6; 161.5 (t); 168.6. IR (Film): 1776; 1760;
1602; 1468; 740; 726; 690 cmꢀ1. CI/MS (m/z, %): 257
(M+1, 100). Anal. Calcd for C12H10F2O4 (256.2): C,
56.26; H, 3.93. Found: C, 56.37; H, 4.05.
3.1.3.6. (R)-3-Benzylisobenzofuran-1(3H)-one (7f).
White solid. Mp: 93–94 ꢁC (from hexane). [a]2D3 +56.0 (c
1.12, CHCl3). 1H NMR (d): 3.15 (dd, 1H, J1¼14.0 Hz,
J2¼7.5 Hz); 3.23 (dd, 1H, J1¼14.0 Hz, J2¼7.5 Hz); 5.67
(t, 1H, J¼6.4 Hz); 7.18–7.29 (m, 6H); 7.45 (t, 1H, J¼
7.5 Hz); 7.58 (t, 1H, J¼7.5 Hz); 7.80 (d, 1H, J¼7.5 Hz).
13C NMR (d): 40.8; 81.3; 122.4; 125.6; 126.1; 127.1; 128.5
(2C); 129.2; 129.7 (2C); 133.8; 135.0; 149.1; 170.4. IR
(Nujol): 1730; 1600; 730; 700 cmꢀ1. CI/MS (m/z, %): 225
(M+1, 100); 133 (5). Anal. Calcd for C15H12O2 (224.25):
C, 80.34; H, 5.39. Found: C, 80.02; H, 5.28. HPLC analysis:
3S isomer 16.81 min, 3R isomer 17.38 min.
Acknowledgements
ꢀ
Authors thank the Spanish Ministerio de Educacion y Cien-
cia (DGI, Projects BQU2002-01046 and CTQ2005-01191/
ꢀ
BQU) for financial support. We also thank Dr. A. Perez-
Encabo for the determination of X-ray structures.
References and notes
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2.75 (m, 2H); 5.12–5.16 (m, 1H); 5.20–5.21 (m, 1H); 5.52
(t, 1H, J¼5.9 Hz); 5.75 (ddt, 1H, J1¼11.0 Hz, J2¼9.7 Hz,
J3¼6.7 Hz); 7.27–7.52 (m, 2H); 7.67 (dt, 1H, J1¼7.4 Hz,
J2¼1.0 Hz); 7.90 (d, 1H, J¼7.5 Hz). 13C NMR (d): 38.6;
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133 (31). Anal. Calcd for C11H10O2 (174.20): C, 75.85; H,
5.79. Found: C, 75.67; H, 5.81. HPLC analysis: 3S isomer
22.21 min, 3R isomer 24.93 min.
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one (7i). White solid. Mp: 44–45 ꢁC (from hexane). [a]2D3
1
2
+32.7 (c 1.13, CHCl3). H NMR (d): 5.53 (q, 1H, JHF
5.8 Hz); 7.57 (dt, 2H, J1¼7.5 Hz, J2¼0.7 Hz); 7.68 (dt,
¼
1H, J1¼7.5 Hz, J2¼1.1 Hz); 7.89 (d, 1H, J¼7.5 Hz). 19F
2
NMR (d): ꢀ77.1 (d, 3F, JHF¼5.8 Hz). 13C NMR (d): 76.4
2
(q, JCF¼35.7 Hz); 123.4; 126.3; 131.1; 134.9; 140.6;

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