Sequential diastereoselective addition of allylic and homoallylic grignard reagents to 2-Acyl-perhydro-1,3-benzoxazines and ring-closing Metathesis: An asymmetric route to azepin-3-ol and azocin-3-ol derivatives

Article abstract of DOI:10.1002/ejoc.200400836

Chiral 2-acyl-3-allyl-substituted perhydrobenzoxazines derived from (-)-8-aminomenthol react with allyl or homoallyl Grignard reagents to provide the corresponding tertiary alcohols in very good yields and with excellent diastereo-selectivities. The 1,8-

Full text of DOI:10.1002/ejoc.200400836

FULL PAPER
Sequential Diastereoselective Addition of Allylic and Homoallylic Grignard
Reagents to 2-Acyl-perhydro-1,3-benzoxazines and Ring-Closing Metathesis:
an Asymmetric Route to Azepin-3-ol and Azocin-3-ol Derivatives
Rafael Pedrosa,*[a] Celia Andrés,*[a] Agustín Gutiérrez-Loriente,[a] and Javier Nieto[a]
Keywords: Amino alcohols / Asymmetric synthesis / Azaheterocycles / Ring-closing metathesis
Chiral 2-acyl-3-allyl-substituted perhydrobenzoxazines de-
rived from (–)-8-aminomenthol react with allyl or homoallyl
Grignard reagents to provide the corresponding tertiary
RCM reaction increased when the hydrochlorides were used
instead of the neutral azadienes. The removal of the chiral
adjuvant allowed the preparation of enantiopure azepin-3-ol
alcohols in very good yields and with excellent diastereo- and azocin-3-ol derivatives.
selectivities. The 1,8- and 1,9-azadienes prepared in this way
participate in RCM reactions to give good yields of seven-
and eight-membered nitrogen heterocycles. The yields of the
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
this way, the chiral perhydrobenzoxazine furnishes the envi-
ronment necessary for the diastereoselective transforma-
tions and introduces a cyclic conformational constraint that
greatly enhances the ability of dienes to undergo RCM to
afford eight-membered rings.[12,13]
Introduction
Seven- and eight-membered nitrogen heterocycles are an
important class of compounds with applications in natural
products chemistry and pharmaceutical research[1] and so
are popular targets for synthetic chemistry. However, cycli-
zation reactions affording medium-ring heterocycles are
often slow and hampered by unfavorable enthalpies and en-
tropies of reaction, especially in the case of eight-membered
rings.[2] Accordingly, relatively few methods for their prepa-
ration are available.
Results and Discussion
The preparation of the starting 2-benzoyl-perhydro-1,3-
benzoxazines 3a–c was accomplished in two steps from
The tremendous growth in the area of transition metal- (–)-8-aminomenthol (1; Scheme 1). Condensation of 1 with
mediated synthetic methodology in the past decade[3] has phenylglyoxal quantitatively afforded 2, which was alkyl-
allowed the development of new cyclization strategies for ated with allylic bromides in the presence of potassium car-
medium-sized rings.[4] In this context, the ring-closing me- bonate in acetonitrile at reflux[14] to give 3a–c.
tathesis (RCM) reaction catalyzed by metal alkylidene com-
Treatment of 1 with ethyl glyoxylate ethyl hemiacetal
plexes has emerged as a powerful tool for the preparation yielded 4, which was alkylated with allyl bromide to give 5.
of carbo- and heterocycles from acyclic diene precursors,[5,6] This was transformed into a mixture of Weinreb amide 6
including nitrogen heterocycles[7,8] and medium-sized (49%) and isopropyl ketone 3d (36%) by treatment with
rings.[9]
N,O-dimethylhydroxylamine hydrochloride and isopro-
Chiral perhydro-1,3-benzoxazines derived from (–)-8- pylmagnesium chloride in THF at –10 °C.[15] Treatment of
aminomenthol[10] have been shown to be useful in cycliza- isolated 6 with isopropylmagnesium chloride in THF at
tion reactions affording enantiopure nitrogen heterocy- –40 °C yielded further 3d in 88% yield (80% total yield
cles,[11] and we now report on the synthesis of enantiopure from 5).
2,3,4,7-tetrahydro-1H-azepin-3-ols and 1,2,3,4,5,8-hexahy-
As would be expected,[16] treatment of allylic and homo-
droazocin-3-ols with the aid of this template. The method- allylic Grignard reagents with the chiral 2-acyl-perhydro-
ology is based on the sequential diastereoselective addition 1,3-benzoxazines 3a–d provided good chemical yields and
of allylic or homoallylic Grignard reagents to N-allyl-2- excellent diastereoselection. The reactions were carried out
acylperhydro-1,3-benzoxazines and subsequent RCM. In in ether at –10 °C with excesses of Grignard reagent, and
alcohols (7a–i) were obtained as single diastereomers or
with good diastereomeric excesses (de) (Scheme 2 and
Table 1).
The absolute configurations at the newly created ste-
reocenters were assigned as S in agreement with Eliel’s re-
[a] Departamento de Química Orgánica, Facultad de Ciencias,
Universidad de Valladolid,
Doctor Mergelina s/n, 47011 Valladolid, Spain
Fax: +34-983423013
E-mail: pedrosa@qo.uva.es
Eur. J. Org. Chem. 2005, 2449–2458
DOI: 10.1002/ejoc.200400836
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2449

R. Pedrosa, C. Andrés, A. Gutiérrez-Loriente, J. Nieto
FULL PAPER
Table 1. Reagents used to provide 2-acyloxazines 3a–d.
En- R1
try
R2
R3
R4
n
Yield (%)[a] de[b]
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
iPr
iPr
H
H
H
H
CH3
H
CH3
H
H
H
CH3
CH3
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
1
2
1
2
1
1
2
1
2
7a (89)
7b (92)
7c (90)
7d (85)
7e (89)
7f (80)
7g (82)
7h (90)
7i (83)
90
Ͼ95[c]
92
Ͼ95[c]
92
86
Ͼ95[c]
90
H
Ͼ95[c]
[a] Yield refers to isolated major diastereoisomer after column
chromatography. [b] Diastereomeric excesses were determined by
integration of the 1H NMR signals of the reaction mixtures.
[c] Only one diastereoisomer was detected by 1H NMR spec-
troscopy.
crystallization, and were then subjected to ring-closing me-
tathesis. The first-generation ruthenium(ii) complex bis-
(tricyclohexylphosphane)benzylideneruthenium dichloride
was used as the catalyst precursor and the reactions were
carried out under dilute conditions (0.01 m) to avoid com-
petition with dimerization. The results are summarized in
Scheme 3 and Table 2.
Scheme 1. Reagents and conditions: I) HOCCOPh or HO(EtO)
CHCO2Et, CH2Cl2, room temp., quant. ii) allyl bromides, K2CO3,
acetonitrile, reflux, 3a (90 %), 3b (80 %), 3c (88 %), 5 (85 %).
iii) MeNHOMe·HCl, iPrMgCl, THF, –10 °C to room temperature,
6 (49%), 3d (36%). iv) iPrMgCl, THF, –40 °C 3d (88%).
Scheme 2.
Scheme 3.
ports[16] and confirmed on the RCM product for 7e (vide
infra).
Initial experiments were conducted on perhydro-1,3-
All major diastereoisomers formed in each reaction were benzoxacine 7a with monosubstituted olefinic appendages.
isolated and purified by flash chromatography and/or Reactions were carried out in CH2Cl2 at room temperature,
Table 2. Ring-closing metathesis reaction of dienes 7a–i.
Entry
Compound
Solvent
T ( °C)
Catalyst mol-%[a]
Time (h)[a]
Yield (%)[b]
1
2
3
4
5
6
7
8
7a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
C6H6
CH2Cl2
CH2Cl2
C6H6
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
20
20
4
20
8a (40)[d]
8a (80)[d]
8a (90)
7a
4 + 4
4 + 4
20 + 10
10 + 10
10 + 10 + 10
10 + 10 + 10
10 + 10
10 + 18
20 + 10 + 10
15
25 + 20
15
25 + 20
25 + 20
30 + 60 + 60 + 90
30 + 40 + 40
15
7a
reflux
reflux
reflux
20
reflux
reflux
20
20
20
20
20
7b
4 + 4 + 4
4 + 4 + 4
8 + 4[c]
4 + 4
4 + 4 + 4
3
3 + 2
3
3 + 3
3 + 3
8b (56)[d]
8b (68)[d]
8b (15)[d]
8a (90)
7b
7b
7c
7d
8b (48)[d]
8a (95)
9
7a·HCl
7b·HCl
7c·HCl
7d·HCl
7e·HCl
7f·HCl
7g·HCl
7h·HCl
7i·HCl
10
11
12
13
14
15
16
17
8b (80)[d]
8a (93)
8b (70)[d]
8e (92)
reflux
reflux
20
3 + 4 + 4 + 4
3 + 4 + 5
3
8f (67)[d]
–
8h (92)
20
3 + 2
30 + 40
8i (81)[d]
[a] Catalyst was replenished after the time indicated in the Table; see also Experimental Section. [b] Yields refer to pure compounds
after column chromatography. [c] An additional 30 mol-% of Ti(OiPr)4 was added. [d] Different amounts of the starting materials were
recovered.
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An Asymmetric Route to Azepin-3-ol and Azocin-3-ol Derivatives
FULL PAPER
and 4 mol-% of the first-generation Grubbs’ catalyst was of the tertiary allylic amine[25,26] was isolated. The reason
used. Under these conditions azepine 8a was formed after for the difference in reactivity between the hydrochloride
20 h of reaction but only in 40% yield. The yield was in- salts of 7e and 7f is unclear,[27] although the higher reactiv-
creased to 80% if 8 mol-% of catalyst was used, and to 90% ity of 7e may be due to better adoption of a conformation
when the mixture was heated to reflux (Entries 1–3 in more favorable for cyclization.
Table 2). In contrast, the formation of the eight-membered
Nevertheless it was not possible to obtain azocines with
heterocycle was more difficult, and azocine 8b was isolated a trisubstituted double bond under these conditions. The
in only 56% yield from 7b even with 12 mol-% of catalyst in attempted RCM reaction of the hydrochloride salt of 7g
dichloromethane. A change to benzene at reflux as solvent only gave starting material, together with variable amounts
caused a moderate increase in the yield, up to 68% (En- of products identified as dimers resulting from intermo-
tries 4, 5 in Table 2).
lecular cross-metathesis (Entry 15). The second-generation
The moderate yield in the formation of the eight-mem- Grubbs’ catalyst (IMes)(PCy3)(Cl2)Ru=CHPh also failed to
bered ring compound 8b could be due to coordination of give the corresponding azocine. The only cyclized product
the nitrogen atom of the perhydro-1,3-benzoxazine to the obtained in this reaction was the azepine 7e (32%), the re-
ruthenium catalyst, resulting in deactivation of the metal sult of a double bond isomerization[26] prior to the RCM,
complex through heteroatom–metal chelation.[17–19] This and dimeric products.
problem has been solved elsewhere by addition of substo-
Transformation of compounds 8a, 8e, 8f, and 8h into the
ichiometric amounts of Ti(OiPr)4, which competes with the final enantiopure 2,3,4,7-tetrahydro-1H-azepin-3-ols 10a,
nitrogen atom, avoiding the formation of unreactive che- 10e, 10f, and 10h, respectively, and of 8b and 8i into the
lates.[20] In our case, though, addition of 30 mol-% of the enantiopure 1,2,3,4,5,8-hexahydroazocin-3-ols 10b and 10i
titanate to the reaction mixture only cause extensive decom- was performed in two steps,[28] as depicted in Scheme 4. The
position of 7b.
reductive ring-opening of the N,O-acetal moiety by treat-
Because metathesis of monosubstituted olefins is known ment of 8a, 8b, 8e, 8f, 8h, or 8i with aluminium hydride in
to be more rapid than that of disubstituted olefins, we THF at reflux for 10 min gave the amino alcohols 9a, 9b,
tested the metathesis reaction in derivatives 7c and 7d (En- 9e, 9f, 9h, or 9i in very good yields. At this point, the stereo-
tries 7 and 8) with a crotylamine and an allylamine instead, chemistry of compound 9e was determined by X-ray dif-
to ensure that the catalyst would react first with the ter- fraction analysis,[29] corroborating the configurations of the
minal alkene more distant from the nitrogen atom and to quaternary carbinol stereocenters created by addition of the
disfavor formation of the undesired intermediates.[21] In this Grignard reagents to the perhydrobenzoxazines 3a–d. Upon
way, azepine 8a was obtained from 7c in a similar chemical oxidation with PCC in CH2Cl2 at room temperature these
yield to that obtained from 7a (compare Entries 3 and 7), aminomenthol derivatives gave the corresponding amino-
but the eight-membered azocine 8b was formed in lower menthone derivatives, which were treated, without isolation,
yield from 7d than from 7b (compare Entry 5 vs. 8).
with 2.5 m aqueous KOH in THF/methanol to furnish the
Finally we tested the protonation of perhydrobenzoxa- final azepin-3-ol (10a, 10e, 10f, 10h) and azocin-3-ol (10b,
zines to block the basic nitrogen functionality.[22,23] This 10i) derivatives in 44–56% yields from 8a–i.
was easily achieved by bubbling gaseous hydrochloric acid
into ethereal solutions of 7a–i, followed by removal of the
solvent under vacuum. Treatment of the hydrochloride salt
of 7a in CH2Cl2 at room temperature with only 3 mol-% of
Grubbs’ catalyst, followed by a basic workup, gave the de-
sired azepine 8a in an excellent 95% yield (Entry 9). Azoc-
ine 8b was obtained in 80% yield from the hydrochloride
salt of 7b with the use of 5 mol-% of catalyst (Entry 10).
Similar results were obtained for azepine 8h and azocine 8i,
with an isopropyl group instead of a phenyl group (En-
tries 16 and 17). Moreover, when starting from the hydro-
chloride salts of the crotyl derivatives 7c and 7d, azepine 8a
was also isolated in excellent yield (Entry 11) but azocine
8b was isolated only in 70% yield (Entry 12).
Azepines with trisubstituted double bonds were also
formed under these conditions.[24] Azepine 8e was prepared
in 92% yield from the hydrochloride salt of methallyl deriv-
ative 7e by use of 6 mol-% of catalyst (Entry 13), whereas
formation of azepine 8f, also with a trisubstituted double
bond, required up to 15 mol-% of catalyst and heating at
reflux in CH2Cl2 for 240 h to provide a 67% chemical yield
(Entry 14). Under these conditions, moreover, an 18% yield
Scheme 4.
We assume that the epimerization of the newly created
of the N-unsubstituted oxazine resulting from deprotection stereocenters is very difficult in the transformations of 8a–
Eur. J. Org. Chem. 2005, 2449–2458
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R. Pedrosa, C. Andrés, A. Gutiérrez-Loriente, J. Nieto
FULL PAPER
i into the final products 10a–i, and consequently that these
should be enantiopure compounds. To test the stereochemi-
cal purity, ent-10a was prepared as summarized in
Scheme 5. Allyl ketone 3e was obtained (70%) by reaction
of Weinreb amide 6 with allylmagnesium bromide, and was
transformed into the homoallylic alcohol 7j (92%, de Ͼ
96%) by treatment with phenylmagnesium bromide. After
Experimental Section
General Methods: All reactions were carried out under argon in
oven-dried glassware. Solvents were dried by standard methods:
CH2Cl2 was distilled from CaH2, acetonitrile from P2O5, and THF
and benzene from sodium. 1H NMR (300 MHz) and 13C NMR
(75 MHz) spectra were registered in CDCl3 as solvent, and chemi-
cal shifts are reported relative to tetramethylsilane as internal refer-
treatment with anhydrous HCl, compound 7j was trans- ence. Specific rotations were determined on a digital polarimeter
with a Na lamp, and concentration is given in grams per 100 mL.
Melting points were determined in open capillary tubes and are
uncorrected. TLC was performed on glass-backed plates coated
with silica gel 60 with F254 indicator, the chromatograms were
viewed under UV light and/or by staining with I2 or phosphomol-
ybdic acid: Flash chromatography was carried out on silica gel 60
(230–240 mesh).
formed into the azepine derivative 8j in 90% yield under
the general conditions described for the RCM reaction. The
reductive ring-opening to 9j and removal of the menthol
appendage yielded ent-10a in 50% yield from 8j. This com-
pound showed identical physical and spectroscopic proper-
ties and nearly the same optical rotation (with opposite
sign) as 10a. Unfortunately, we were unable to differentiate
the two enantiomers by chiral HPLC under different condi-
tions (Chiralcel OD column 0.46×25 cm and hexane/2-pro-
panol mixtures as eluent)
Compounds 2, 4, 3c, and 3a have been described previously.[14]
Synthesis of Perhydrobenzoxazines 3a–c and 5: A mixture of benz-
oxazine 2 or 4 (20 mmol), potassium carbonate (3.9 g, 28 mmol),
and the appropriate allylic bromide (28 mmol) in acetonitrile
(8 mL) was heated in an oil bath at 80–90 °C until the reaction was
complete (TLC, 60–80 h). The reaction mixture was diluted with
ethyl acetate, and the solid was separated by filtration and washed
with hot ethyl acetate (3×25 mL). The solvents were evaporated
under vacuum and the residue was purified by flash chromatog-
raphy on silica gel with hexanes/ethyl acetate 1:30 as eluent for 3a–
c and 1:50 for 5.
[[2S(2α,4aα,7α,8aβ)]-4,4,7-Trimethyl-3-(2-methylallyl)-octahydro-
benzo[e][1,3]oxazin-2-yl]phenyl-methanone (3b): Colorless solid.
M.p.: 84–85 °C (from EtOH). [α]2D5 = –14.1 (c = 1.0, CH2Cl2). H
1
NMR: δ = 0.92–1.09 (m, 2 H), 0.95 (d, J = 6.5 Hz, 3 H), 1.15 (s,
3 H), 1.26 (m, 1 H), 1.34 (s, 3 H), 1.46 (s, 3 H), 1.48–1.69 (m, 3
H), 1.73 (m, 1 H), 2.03 (m, 1 H), 3.16 (d, J = 17.8 Hz, 1 H), 3.28
(d, J = 17.8 Hz, 1 H), 3.62 (td, J1 = 10.5, J2 = 4.0 Hz, 1 H), 4.40
(d, J = 0.8 Hz, 1 H), 4.63 (d, J = 0.8 Hz, 1 H), 5.89 (s, 1 H), 7.39
(m, 2 H), 7.48 (m, 1 H), 8.10 (m, 2 H) ppm. 13C NMR: δ = 20.1,
20.6, 22.1, 24.8, 26.1, 31.2, 34.8, 41.0, 45.2, 49.2, 57.9, 76.4, 87.4,
111.4, 127.7 (2 C), 129.1 (2 C), 132.7, 135.2, 144.1, 194.6 ppm . IR
(nujol dispersion): ν = 3080, 1700, 1600, 780, 690 cm–1. C H NO
˜
22 31
2
(341.49): C 77.38, H 9.15, N 4.10; found C 77.52, H 9.29, N 4.00.
Ethyl [2S(2α,4aα,7α,8aβ)]-3-Allyl-4,4,7-trimethyl-octahydrobenzo-
[e][1,3]oxazine-2-carboxylate (5): Colorless oil. [α]2D5 = –40.2 (c =
1.1, CH2Cl2). 1H NMR: δ = 0.90–1.04 (m, 2 H), 0.92 (d, J = 6.5 Hz,
3 H), 1.17 (s, 3 H), 1.22 (m, 1 H), 1.23 (s, 3 H), 1.27 (dd, J1 = 7.5,
J2 = 7.0 Hz, 3 H), 1.40–1.53 (m, 2 H), 1.61 (m, 1 H), 1.70 (m, 1
H), 1.97 (m, 1 H), 3.28 (dd, J1 = 17.5, J2 = 5.7 Hz, 1 H), 3.39 (dd,
Scheme 5.
In summary, the synthetic sequence described above con-
stitutes a useful procedure for the preparation of enantio-
pure 2,3,4,7-tetrahydro-1H-azepin-3-ols and 1,2,3,4,5,8-
hexahydroazocin-3-ols. Although 1,9-azadienes are rela- J1 = 17.5, J2 = 5.7 Hz, 1 H), 3.50 (td, J1 = 10.6, J2 = 4.1 Hz, 1 H),
tively poor substrates for RCM,[9] the efficient cyclization
4.06–4.27 (m, 2 H), 4.95 (dd, J1 = 10.3, J2 = 1.7 Hz, 1 H), 5.10 (s,
1 H), 5.11 (dd, J1 = 17.2, J2 = 1.7 Hz, 1 H), 5.83 (m, 1 H) ppm.
in our reagents is probably due to the perhydrobenzoxazine
13C NMR: δ = 13.9, 20.2, 22.0, 24.8, 26.3, 31.2, 34.8, 40.9, 45.7,
moiety to which the reacting alkenes are tethered.[30]
47.0, 57.2, 61.0, 76.0, 85.3, 114.2, 139.0, 169.0 ppm. IR (film): ν =
˜
To this end we also prepared the enantiomer of com-
pound 10a and we studied their separation by HPLC after
coinjection with the described compound. Unfortunately,
we have been unable to find conditions for a good separa-
tion and so cannot determine the enantiopurity in the final
products.
On the other hand, the authors disagree in part with the
comment of one referee, because, once the diastereomeric
purities for compounds 8a–i are established, the conditions
used for their transformation into the final derivatives 10a–
i allow the conservation of their stereochemical integrity.
3080, 1760, 1645, 740 cm–1. C17H29NO3 (295.42): C 69.12, H 9.89,
N 4.74; found C 69.26, H 9.96, N 4.88.
Synthesis of Benzoxazine 3d: A solution of iPrMgCl in diethyl ether
(10.5 mL, 2 m) was slowly added (2 h) to a slurry of the ester 5
(1.5 g, 5.08 mmol) and Me(MeO)NH·HCl (0.74 g, 7.62 mmol) in
THF (25 mL), cooled to –10 °C. The mixture was stirred for 10 min
at –10 °C and then for 15 min at room temperature. The reaction
was quenched with a saturated solution of NH4Cl, and the product
was extracted with diethyl ether (4×20 mL). The organic layer was
dried over MgSO4 and concentrated under vacuum to give an oily
residue, which was purified by flash chromatography on silica gel
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An Asymmetric Route to Azepin-3-ol and Azocin-3-ol Derivatives
FULL PAPER
with hexanes/ethyl acetate as eluent to yield 0.78 g of amide 6 and
0.54 g of ketene 3d.
J1 = 10.1, J2 = 1.3 Hz, 1 H), 4.56 (dq, J1 = 17.5, J2 = 1.3 Hz, 1
H), 4.84 (m, 1 H), 4.90–4.97 (m, 2 H), 4.95 (s, 1 H), 5.56 (m, 1 H),
7.19 (m, 1 H), 7.28 (m, 2 H), 7.35 (m, 2 H) ppm. 13C NMR: δ =
22.3, 22.4, 25.0, 26.9, 31.5, 35.2, 41.6, 44.9, 46.3, 49.6, 57.9, 77.4,
77.1, 89.3, 111.5, 117.6, 126.0, 126.3 (2 C), 127.1 (2 C), 134.0, 142.3
A solution of iPrMgCl (2 mL, 2 m) was slowly added at –40 °C to
a solution of amide 6 in THF (8 mL) . The reaction mixture was
stirred for 30 min and the mixture was treated as above to obtain
0.65 g of ketone 3d.
(2 C) ppm. IR (film): ν = 3530 (broad), 3060, 1630, 1595, 760, 710,
˜
695, 670 cm–1. C24H35NO2 (369.54): C 78.00, H 9.55, N 3.79; found
C 78.16, H 9.71, N 3.67.
[2S(2α,4aα,7α,8aβ)]-3-Allyl-N-methoxy-N,4,4,7-tetramethyl-octahy-
drobenzo[e][1,3]oxazine-2-carboxamide (6): Colorless oil. [α]2D5
=
(1S)-1-[[2S(2α,4aα,7α,8aβ)]-3-Allyl-4,4,7-trimethyl-octahydrobenzo-
[e][1,3]oxazin-2-yl]-1-phenyl-pent-4-en-1-ol (7b): Colorless solid.
–42.7 (c = 0.9, CH2Cl2). 1H NMR: δ = 0.85–1.07 (m, 2 H), 0.92
(d, J = 6.4 Hz, 3 H), 1.17 (s, 3 H), 1.20 (m, 1 H), 1.27 (s, 3 H),
1.38–1.54 (m, 2 H), 1.58 (m, 1 H), 1.70 (m, 1 H), 1.96 (m, 1 H),
3.12 (s, 3 H), 3.17–3.78 (m, 3 H), 3.80 (s, 3 H), 4.89 (d, J = 10.1 Hz,
1 H), 5.02 (d, J = 17.3 Hz, 1 H), 5.63 (s, 1 H), 5.84 (m, 1 H) ppm.
13C NMR: δ = 21.0, 22.0, 24.7, 26.5, 31.1, 32.0, 34.7, 40.9, 45.2,
1
M.p.: 71–72 °C (from EtOH). [α]2D5 = –12.9 (c = 1.0, CH2Cl2). H
NMR: δ = 0.83–1.03 (m, 2 H), 0.92 (s, 3 H), 0.95 (d, J = 6.5 Hz,
3 H), 1.12 (m, 1 H), 1.22 (s, 3 H), 1.45–1.61 (m, 4 H), 1.66–1.76
(m, 2 H), 1.96 (m, 1 H), 2.01–2.16 (m, 2 H), 3.05 (s, 1 H), 3.06 (dd,
J1 = 17.5, J2 = 6.7 Hz, 1 H), 3.62 (td, J1 = 10.5, J2 = 4.0 Hz, 1 H),
3.76 (m, 1 H), 4.45 (d, J1 = 10.1 Hz, 1 H), 4.55 (d, J = 17.2 Hz, 1
H), 4.64 (m, 1 H), 4.82–4.92 (m, 2 H), 4.90 (s, 1 H), 5.70 (m, 1 H),
7.18 (m, 1 H), 7.28 (m, 2 H), 7.34 (m, 2 H) ppm. 13C NMR: δ =
22.3, 22.4, 24.9, 26.9, 27.5, 31.4, 35.1, 41.5, 43.9, 44.7, 46.1, 57.7,
77.2, 77.4, 90.3, 111.3, 113.8, 125.8, 126.2 (2 C), 127.1 (2 C), 139.1,
46.1, 57.4, 61.4, 76.5, 82.0, 113.6, 139.7, 169.5 ppm. IR (film): ν =
˜
3070, 1680, 735, 700 cm–1. C17H30N2O3 (310.43): C 65.77, H 9.74,
N 9.02; found C 65.92, H 9.64, N 9.11.
1-[[2S(2α,4aα,7α,8aβ)]-3-Allyl-4,4,7-trimethyl-octahydrobenzo[e]-
[1,3]oxazin-2-yl]-2-methylpropan-1-one (3d): Colorless oil. [α]2D5
=
–67.4 (c = 1.1, CH2Cl2). 1H NMR: δ = 0.85–1.21 (m, 3 H), 0.92
(d, J = 6.6 Hz, 3 H), 1.03 (d, J = 6.8 Hz, 3 H), 1.11 (d, J = 7.1 Hz,
3 H), 1.15 (s, 3 H), 1.27 (s, 3 H), 1.38–1.43 (m, 2 H), 1.61 (m, 1
H), 1.71 (m, 1 H), 1.96 (m, 1 H), 3.04–3.15 (m, 2 H), 3.32 (dd, J1
= 17.8, J2 = 5.0 Hz, 1 H), 3.48 (td, J1 = 10.6, J2 = 4.0 Hz, 1 H),
142.0, 142.3 ppm. IR (nujol dispersion): ν = 3535 (broad), 3055,
˜
1630, 1595, 758, 695 cm–1. C25H37NO2 (383.57): C 78.28, H 9.72,
N 3.65; found C 78.41, H 9.60, N 3.54.
(1S)-1-[[2S(2α,4aα,7α,8aβ)]-3-(But-2-enyl)-4,4,7-trimethyl-octahy-
drobenzo[e][1,3]oxazin-2-yl]-1-phenylbut-3-en-1-ol (7c): Colorless
4.96 (dd, J1 = 10.3, J2 = 1.7 Hz, 1 H), 5.08 (dd, J1 = 17.2, J2
=
oil. [α]2D5 = +17.3 (c = 1.2, CH2Cl2). H NMR: δ = 0.82–1.04 (m,
1
1.7 Hz, 1 H), 5.19 (s, 1 H), 5.81 (m, 1 H) ppm. 13C NMR: δ = 17.2,
2 H), 0.94 (s, 3 H), 0.95 (d, J = 6.5 Hz, 3 H), 1.12 (m, 1 H), 1.21
(s, 3 H), 1.35 (dd, J1 = 6.1, J2 = 1.0 Hz, 3 H), 1.38–1.68 (m, 3 H),
1.71 (m, 1 H), 1.95 (m, 1 H), 2.49 (dd, J1 = 13.6, J2 = 7.0 Hz, 1
H), 2.68 (dd, J1 = 13.6, J2 = 7.4 Hz, 1 H), 3.02 (dd, J1 = 17.1, J2
= 6.3 Hz, 1 H), 3.15 (s, 1 H), 3.61 (m, 2 H), 4.49 (m, 1 H), 4.87–
4.98 (m, 3 H), 4.94 (s, 1 H), 5.57 (m, 1 H), 7.20 (m, 1 H), 7.28 (m,
2 H), 7.35 (m, 2 H) ppm. 13C NMR: δ = 17.6, 22.3 (2 C), 24.9,
26.6, 31.4, 35.2, 41.6, 44.9, 45.0, 49.4, 57.6, 76.9, 77.3, 89.3, 117.5,
122.0, 125.8, 126.2 (2 C), 126.9 (2 C), 134.0, 134.3, 142.2 ppm. IR
19.3, 21.4, 22.0, 24.8, 26.4, 31.2, 34.8, 36.1, 41.0, 44.8, 47.3, 57.3,
76.3, 88.0, 114.2, 139,5, 210.5 ppm. IR (film): ν = 3060, 1730, 735,
˜
690 cm–1. C18H31NO2 (293.44): C 73.67, H 10.65, N 4.77; found C
73.54, H 10.79, N 4.70.
1-[[2S(2α,4aα,7α,8aβ)]-3-Allyl-4,4,7-trimethyl-octahydrobenzo[e]-
[1,3]oxazin-2-yl]but-3-en-1-one (3e): Colorless oil. [α]2D5 = –62.1 (c =
0.6, CH2Cl2). 1H NMR: δ = 0.84–1.1 (m, 2 H), 0.93 (d, J = 6.5 Hz,
3 H), 1.11 (m, 1 H), 1.15 (s, 3 H), 1.20 (s, 3 H), 1.39–1.50 (m, 2
H), 1.63 (m, 1 H), 1.69 (m, 1 H), 1.96 (m, 1 H), 3.09–3.21 (m, 2
H), 3.37 (dt, J1 = 7.0, J2 = 1.3 Hz, 2 H), 3.46 (td, J1 = 10.6, J2 =
4.1 Hz, 1 H), 4.93 (s, 1 H), 4.94–5.19 (m, 4 H), 5.72–6.0 (m, 2
H) ppm. 13C NMR: δ = 19.8, 22.2, 24.9, 26.5, 31.3, 34.8, 41.1, 43.6,
46.0, 47.1, 57.4, 75.9, 89.6, 115.0, 118.7, 130.6, 138.9, 205.4 ppm.
(film): ν = 3550 (broad), 3070, 1640, 1605, 765, 710, 700, 675 cm–1.
˜
C25H37NO2 (383.57): C 78.28, H 9.72, N 3.65; found C 78.19, H
9.61, N 3.80.
(1S)-1-[[2S(2α,4aα,7α,8aβ)]-3-(But-2-enyl)-4,4,7-trimethyl-octahy-
drobenzo[e][1,3]oxazin-2-yl]-1-phenylpent-4-en-1-ol (7d): Colorless
solid. M.p.: 98–99 °C (from hexane). [α]2D5 = –5.5 (c = 0.9, CH2Cl2).
1H NMR: δ = 0.85–1.02 (m, 2 H), 0.93 (s, 3 H), 0.94 (d, J = 6.6 Hz,
3 H), 1.10 (m, 1 H), 1.20 (s, 3 H), 1.34 (dd, J1 = 6.5, J2 = 1.0 Hz,
3 H), 1.41–1.63 (m, 4 H), 1.65–1.78 (m, 2 H), 1.95 (m, 1 H), 2.03–
2.17 (m, 2 H), 3.00 (dd, J1 = 17.3, J2 = 6.6 Hz, 1 H), 3.06 (s, 1 H),
3.55–3.65 (m, 2 H), 4.43 (m, 1 H), 4.79–4.96 (m, 3 H), 4.89 (s, 1
H), 5.70 (m, 1 H), 7.18 (m, 1 H), 7.27 (m, 2 H), 7.34 (m, 2 H) ppm.
13C NMR: δ = 17.6, 22.3, 22.4, 25.0, 26.7, 27.5, 31.5, 35.2, 41.6,
43.9, 45.0 (2 C), 57.6, 76.6, 77.3, 90.5, 113.8, 122.0, 125.8, 126.3 (2
IR (film): ν = 3078, 1730, 1455, 915 cm–1. C H NO : C 74.18, H
˜
18 29
2
10.03, N 4.81; found C 74.32, H 10.19, N 4.95.
Diastereoselective Addition of Allylic and Homoallylic Grignard
Reagents to 6a–d: A solution of the appropriate freshly prepared
allyl- or homoallylmagnesium bromide derivative[31] (13 mL, 1 m)
in ether was slowly added at –10 °C to a solution of the appropriate
benzoxazine 6a–d (6.0 mmol) in diethyl ether (30 mL). The mixture
was stirred at this temperature until disappearance of the starting
material (TLC, 15–45 min.). The reaction mixture was quenched
with saturated ammonium chloride, and the product was extracted
with diethyl ether (3×25 mL). The organic extracts were washed
with brine and dried over anhydrous MgSO4, and the solvent was
evaporated in vacuo. The residue was chromatographed on silica
gel with hexanes/ethyl acetate 1:70 as eluent.
C), 127.1 (2 C), 134.4, 139.3, 142.3 ppm. IR (nujol dispersion): ν
˜
.
= 3545 (broad), 3075, 3030, 1640, 1600, 765, 700, 650 cm–1
C26H39NO2 (397.59): C 78.54, H 9.89, N 3.52; found C 78.42, H
10.02, N 3.66.
(1S)-1-[[2S(2α,4aα,7α,8aβ)]-4,4,7-Trimethyl-3-(2-methylallyl)-octa-
hydrobenzo[e][1,3]oxazin-2-yl]-1-phenylbut-3-en-1-ol (7e): Colorless
(1S)-1-[[2S(2α,4aα,7α,8aβ)]-3-Allyl-4,4,7-trimethyl-octahydrobenzo-
[e][1,3]oxazin-2-yl]-1-phenylbut-3-en-1-ol (7a): Colorless oil. [α]2D5
oil. [α]2D5 = –21.7 (c = 1.2, CH2Cl2). H NMR: δ = 0.83–1.05 (m, 2
1
1
= –5.6 (c = 0.9, CH2Cl2). H NMR: δ = 0.83–1.00 (m, 2 H), 0.94
H), 0.91 (s, 3 H), 0.95 (d, J = 6.5 Hz, 3 H), 1.12 (m, 1 H), 1.15 (s,
(s, 3 H), 0.95 (d, J = 6.5 Hz, 3 H), 1.12 (m, 1 H), 1.22 (s, 3 H), 3 H), 1.25 (s, 3 H), 1.44–1.63 (m, 3 H), 1.72 (m, 1 H), 1.95 (m, 1
1.46–1.57 (m, 3 H), 1.70 (m, 1 H), 1.95 (m, 1 H), 2.49 (ddt, J1 = H), 2.52 (dd, J1 = 13.7, J2 = 6.9 Hz, 1 H), 2.70 (dd, J1 = 13.7, J2
13.6, J2 = 7.0, J3 = 1.3 Hz, 1 H), 2.68 (ddt, J1 = 13.6, J2 = 7.2, J3
= 1.3 Hz, 1 H), 3.08 (dd, J1 = 17.5, J2 = 6.7 Hz, 1 H), 3.14 (s, 1 J1 = 10.7, J2 = 4.0 Hz, 1 H), 3.76 (d, J = 18.4 Hz, 1 H), 4.20 (s, 2
H), 3.61 (td, J1 = 10.5, J2 = 4.0 Hz, 1 H), 3.75 (m, 1 H), 4.47 (dq, H), 4.90–4.97 (m, 2 H), 4.95 (s, 1 H), 5.54 (m, 1 H), 7.13 (m, 1 H),
= 7.5 Hz, 1 H), 2.90 (d, J = 18.4 Hz, 1 H), 3.10 (s, 1 H), 3.60 (td,
Eur. J. Org. Chem. 2005, 2449–2458
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2453

R. Pedrosa, C. Andrés, A. Gutiérrez-Loriente, J. Nieto
FULL PAPER
7.23 (m, 2 H), 7.30 (m, 2 H) ppm. 13C NMR: δ = 19.8, 22.2 (2 C),
24.9, 25.6, 31.4, 35.1, 41.4, 44.0, 48.3, 48.8, 57.9, 77.2, 77.5, 89.8,
108.5, 117.6, 125.9, 126.1 (2 C), 127.2 (2 C), 134.0, 142.3,
(broad), 3080, 1640 cm–1. C22H39NO2 (349.55): C 75.59, H 11.25,
N 4.01; found C 75.74, H 11.12, N 4.14.
(1R)-1-[[2S(2α,4aα,7α,8aβ)]-3-Allyl-4,4,7-trimethyl-octahydrobenzo-
146.1 ppm. IR (film): ν = 3500 (broad), 3030, 1615, 1585, 745, 690,
˜
[e][1,3]oxazin-2-yl]-1-phenylbut-3-en-1-ol (7j): Colorless oil. [α]2D5
=
680, 670, 620 cm–1. C25H37NO2 (383.57): C 78.28, H 9.72, N 3.65;
found C 78.45, H 9.59, N 3.78.
1
–1.9 (c = 0.8, CHCl3). H NMR: δ = 0.85–1.00 (m, 2 H), 0.92 (d,
J = 6.6 Hz, 3 H), 1.05 (s, 3 H), 1.13 (m, 1 H), 1.27 (s, 3 H), 1.37–
1.52 (m, 2 H), 1.56 (m, 1 H), 1.65 (m, 1 H), 1.92 (m, 1 H), 2.58–
2.72 (m, 2 H), 2.99 (ddt, J1 = 18.8, J2 = 4.5, Hz, J3 = 2.1 Hz, 1 H),
3.19 (ddt, J1 = 18.8, J2 = 4.5, J3 = 2.0 Hz, 1 H), 3,43 (s, 1 H), 3.46
(td, J1 = 10.6, J2 = 3.9 Hz, 1 H), 4.88 (s, 1 H), 4.90–5.10 (m, 4 H),
5,52–5.71 (m, 2 H), 7.18–7.30 (m, 3 H), 7.56 (m, 2 H) ppm. 13C
NMR: δ = 22.2, 23.0, 24.9, 26.3, 31.4, 35.1, 41.1, 44.7, 45.1, 46.4,
53.4, 58.5, 75.6, 78.2, 90.8, 113.4, 117.7, 126.3 (2 C), 127.4 (2 C),
(1S)-1-[[2S(2α,4aα,7α,8aβ)]-3-Allyl-4,4,7-trimethyl-octahydrobenzo-
[e][1,3]oxazin-2-yl]-3-methyl-1-phenylbut-3-en-1-ol (7f): Colorless
1
oil. [α]2D5 = –20.8 (c = 1.2, CH2Cl2). H NMR: δ = 0.83–1.00 (m, 2
H), 0.93 (s, 3 H), 0.95 (d, J = 6.6 Hz, 3 H), 1.11 (m, 1 H), 1.22 (s,
3 H), 1.38 (s, 3 H), 1.42–1.63 (m, 3 H), 1.71 (m, 1 H), 1.95 (m, 1
H), 2.45 (d, J = 13.1 Hz, 1 H), 2.69 (d, J = 13.1 Hz, 1 H), 3.08 (dd,
J1 = 17.5, J2 = 6.7 Hz, 1 H), 3.15 (s, 1 H), 3.60 (td, J1 = 10.4, J2
= 4.0 Hz, 1 H), 3.78 (m, 1 H), 4.47 (dd, J1 = 10.1, J2 = 1.2 Hz, 1
H), 4.52 (d, J = 1.2 Hz, 1 H), 4.54 (dd, J1 = 17.6, J2 = 1.2 Hz, 1
H), 4.72 (d, J = 1.2 Hz, 1 H), 4.84 (m, 1 H), 4.94 (s, 1 H), 7.16 (m,
1 H), 7.25 (m, 2 H), 7.35 (m, 2 H) ppm. 13C NMR: δ = 22.2, 22.4,
24.2, 24.9, 26.8, 31.4, 35.1, 41.5, 44.7, 46.2, 52.8, 57.8, 77.3, 77.4,
89.5, 111.3, 114.7, 125.9, 126.4 (2 C), 126.9 (2 C), 142.2, 142.4,
134.1, 141.0, 144.9 ppm. IR (film): ν = 3490, 3070, 1640, 760,
˜
700 cm–1. C24H35NO2: C 78.00, H 9.55, N 3.79; found C 77.89, H
9.68, N 3.91.
RCM Reaction of Dienes 7a–j: A solution of bis(tricyclohexylphos-
phane)benzylideneruthenium dichloride (0.09 mmol, 74 mg) in
CH2Cl2 (10 mL) was added to a solution of the corresponding 7a–
i·HCl[32] (3 mmol) in CH2Cl2 (290 mL). The resulting mixture was
stirred at room temperature under argon for 15–30 h, and ad-
ditional portions of catalyst were added after the times indicated in
Table 2. Additional heating at reflux was necessary for ring-closing
metathesis of compound 7f. When the reaction was found to be
complete, a saturated aqueous NaHCO3 solution was added. The
solution was extracted with CH2Cl2 (3×25 mL) and the combined
extracts were dried over anhydrous MgSO4 and concentrated under
vacuum. The residue was purified by flash chromatography on sil-
ica gel with mixtures of hexanes/ethyl acetate as eluent.
142.5 ppm. IR (film): ν = 3505 (broad), 3040, 1620, 1585, 700,
˜
680 cm–1. C25H37NO2 (383.57): C 78.28, H 9.72, N 3.65; found C
78.38, H 9.89, N 3.50.
(1S)-1-[[2S(2α,4aα,7α,8aβ)]-4,4,7-Trimethyl-3-(2-methylallyl)-octa-
hydrobenzo[e][1,3]oxazin-2-yl]-1-phenylpent-4-en-1-ol (7g): Colorless
1
oil. [α]2D5 = –26.3 (c = 0.9, CH2Cl2). H NMR: δ = 0.83–1.00 (m, 2
H), 0.90 (s, 3 H), 0.95 (d, J = 6.5 Hz, 3 H), 1.11 (m, 1 H), 1.15 (s,
3 H), 1.24 (s, 3 H), 1.43–1.69 (m, 4 H), 1.63–1.78 (m, 2 H), 1.95
(m, 1 H), 2.02–2.14 (m, 2 H), 2.89 (d, J = 18.5 Hz, 1 H), 3.00 (s, 1
H), 3.62 (td, J1 = 10.5, J2 = 4.0 Hz, 1 H), 3.78 (d, J = 18.5 Hz, 1
H), 4.16 (s, 2 H), 4.81–4.91 (m, 2 H), 4.91 (s, 1 H), 5.71 (m, 1 H),
7.12 (m, 1 H), 7.22 (m, 2 H), 7.28 (m, 2 H) ppm. 13C NMR: δ =
19.8, 22.3 (2 C), 24.9, 25.6, 27.4, 31.4, 35.1, 41.4, 43.3, 43.9, 48.3,
57.7, 77.4, 77.5, 90.6, 108.3, 113.8, 125.8, 126.1 (2 C), 127.3 (2 C),
(3R,4aR,5aS,6S,11aS)-3,11,11-Trimethyl-6-phenyl-2,3,4,4a,5a,6,7,
10,11,11a-decahydro-1H-5-oxa-10a-azacyclohepta[b]naphthalen-6-ol
(8a): Yellow oil. [α]2D5 = –123.6 (c = 0.9, CH2Cl2). H NMR: δ =
1
0.81–0.94 (m, 2 H), 0.86 (d, J = 6.5 Hz, 3 H), 1.05 (m, 1 H), 1.15
(s, 3 H), 1.21 (s, 3 H), 1.24 (m, 1 H), 1.41–1.52 (m, 2 H), 1.63 (m,
1 H), 1.75 (m, 1 H), 2.26 (dd, J1 = 14.8, J2 = 8.0 Hz, 1 H), 3.08
(dd, J1 = 13.8, J2 = 8.3 Hz, 1 H), 3.17 (td, J1 = 10.6, J2 = 4.0 Hz,
1 H), 3.29 (m, 1 H), 3.62 (s, 1 H), 3.84 (dd, J1 = 13.8, J2 = 5.7 Hz,
1 H), 4.52 (s, 1 H), 5.73 (m, 1 H), 6.02 (m, 1 H), 7.19 (m, 1 H),
7.27 (m, 2 H), 7.62 (d, J = 8.7 Hz, 2 H) ppm. 13C NMR: δ = 22.2
(2 C), 25.1, 28.7, 31.3, 34.4, 35.0, 38.0, 40.9, 45.8, 58.2, 71.6, 77.5,
92.0, 126.1 (2 C), 126.5, 127.3 (2 C), 130.3, 131.5, 146.5 ppm. IR
139.2, 142.1, 146.0 ppm. IR (film): ν = 3500 (broad), 3060, 1630,
˜
1590, 750, 725, 690 cm–1. C26H39NO2 (397.59): C 78.54, H 9.89, N
3.52; found C 78.40, H 10.00, N 3.43.
(3S)-3-[[2S(2α,4aα,7α,8aβ)]-3-Allyl-4,4,7-trimethyl-octahydrobenzo-
[e][1,3]oxazin-2-yl]-2-methylhex-5-en-3-ol (7h): Colorless oil. [α]2D5
1
= –18.2 (c = 1.4, CH2Cl2). H NMR: δ = 0.81–1.12 (m, 3 H), 0.92
(d, J = 6.5 Hz, 3 H), 0.94 (d, J = 6.9 Hz, 6 H), 1.06 (s, 3 H), 1.19
(s, 3 H), 1.40–1.58 (m, 3 H), 1.66 (m, 1 H), 1.82 (m, 1 H), 2.14
(sept, J = 6.9 Hz, 1 H), 2.27 (d, J = 7.1 Hz, 2 H), 2.64 (s, 1 H),
(film): ν = 3500 (broad), 3030, 1600, 765, 720, 695, 640 cm–1
.
˜
C22H31NO2 (341.49): C 77.38, H 9.15, N 4.10; found C 77.21, H
9.27, N 3.98.
3.29 (dd, J1 = 18.4, J2 = 5.3 Hz, 1 H), 3.44 (td, J1 = 10.6, J2
=
4.0 Hz, 1 H), 4.12 (m, 1 H), 4.44 (s, 1 H), 4.89–5.04 (m, 3 H), 5.13
(dd, J1 = 17.3, J2 = 1.9 Hz, 1 H), 5.84–6.02 (m, 2 H) ppm. 13C
NMR: δ = 16.7, 17.8, 22.3, 22.5, 24.9, 26.9, 31.4, 32.1, 35.2, 40.4,
41.4, 43.9, 46.2, 58.3, 77.1, 77.3, 88.3, 112.6, 116.0, 135.7,
(3R,4aR,5aS,6S,12aS)-6-Phenyl-3,12,12-trimethyl-2,3,4,4a,6,7,
8,11,12,12a-decahydro-1H,5aH-5-oxa-11a-azacycloocta[b]naphtha-
1
len-6-ol (8b): Yellow oil [α]2D5 = –76.8 (c = 1.2, CH2Cl2). H NMR
142.2 ppm. IR (film): ν = 3560 (broad), 3075, 1635, 680 cm–1
.
˜
(333 K): δ = 0.78–0.97 (m, 2 H), 0.88 (d, J = 6.5 Hz, 3 H), 1.04 (m,
1 H), 1.08 (s, 3 H), 1.21 (s, 3 H), 1.24–1.42 (m, 2 H), 1.55 (m, 1
H), 1.63 (m, 1 H), 1.86 (m, 1 H), 1.95 (m, 1 H), 2.26 (m, 1 H), 2.45
C21H37NO2 (335.52): C 75.17, H 11.12, N 4.17; found C 75.03, H
11.21, N 4.06.
(m, 1 H), 2.80 (m, 1 H), 3.22 (m, 1 H), 3.24 (td, J1 = 10.7, J2
=
(3S)-3-[[2S(2α,4aα,7α,8aβ)]-3-Allyl-4,4,7-trimethyl-octahydrobenzo-
[e][1,3]oxazin-2-yl)-2-methylhept-6-en-3-ol (7i): Colorless oil. [α]2D5
= –28.4 (c = 0.9, CH2Cl2). H NMR: δ = 0.82–1.03 (m, 2 H), 0.91
(d, J = 6.9 Hz, 3 H), 0.92 (d, J = 6.9 Hz, 3 H), 0.93 (d, J = 6.4 Hz,
3 H), 1.05 (s, 3 H), 1.10 (m, 1 H), 1.20 (s, 3 H), 1.42–1.67 (m, 5
H), 1.72 (m, 1 H), 1.84 (m, 1 H), 2.05–2.18 (m, 3 H), 2.69 (s, 1 H),
4.0 Hz, 1 H), 3.40 (s, 1 H), 3.85 (dd, J1 = 15.5, J2 = 8.8 Hz, 1 H),
4.52 (s, 1 H), 5.65 (m, 1 H), 5.78 (m, 1 H), 7.14 (m, 1 H), 7.23 (m,
2 H), 7.69 (d, J = 8.7 Hz, 2 H) ppm. 13C NMR (333 K): δ = 21.4,
22.0, 24.8, 25.2, 27.7, 31.2, 35.0, 36.2, 38.0, 41.2, 47.6, 58.0, 75.2,
76.7, 90.0, 125.5 (2 C), 125.9, 127.2 (2 C), 128.1, 133.4, 150.1 ppm.
1
IR (film): ν = 3490 (broad), 3060, 1600, 760, 735, 700 cm–1
.
˜
3.29 (dd, J1 = 18.4, J2 = 5.3 Hz, 1 H), 3.47 (td, J1 = 10.5, J2
=
C23H33NO2 (355.51): C 77.70, H 9.36, N 3.94; found C 77.59, H
9.23, N 3.82.
4.0 Hz, 1 H), 4.10 (m, 1 H), 4.42 (s, 1 H), 4.88–4.97 (m, 2 H), 5.02
(dd, J1 = 17.1, J2 = 1.8 Hz, 1 H), 5.13 (dd, J1 = 17.3, J2 = 1.8 Hz,
1 H), 5.75–5.98 (m, 2 H) ppm. 13C NMR: δ = 16.6, 17.8, 22.2, 22.5,
24.9, 27.0, 28.6, 31.4, 32.2, 34.6, 35.2, 41.5, 43.8, 46.1, 58.2, 76.9,
(3R,4aR,5aS,6S,11aS)-3,9,11,11-Tetramethyl-6-phenyl-
2,3,4,4a,5a,6,7,10,11,11a-decahydro-1H-5-oxa-10a-azacyclohepta-
77.4, 89.2, 112.7, 113.8, 140.0, 142.1 ppm. IR (film): ν = 3570 [b]naphthalen-6-ol (8e): Colorless solid. M.p.: 122–123 °C (from
˜
2454
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 2449–2458

An Asymmetric Route to Azepin-3-ol and Azocin-3-ol Derivatives
FULL PAPER
hexane). [α]2D5 = –106.5 (c = 1.0, CH2Cl2). 1H NMR: δ = 0.79–0.98
(m, 2 H), 0.86 (d, J = 6.5 Hz, 3 H), 1.06 (m, 1 H), 1.15 (s, 3 H),
(td, J1 = 10.6, J2 = 4.0 Hz, 1 H), 3.66 (s, 1 H), 3.73 (m, 1 H), 5.04
(s, 1 H), 5,54 (m, 1 H), 5,82 (m, 1 H), 7.23 (m, 1 H), 7.33 (m, 2
1.23 (s, 3 H), 1.20–1.48 (m, 2 H), 1.52 (m, 1 H), 1.66 (m, 1 H), 1.74 H), 7.51 (m, 2 H) ppm. 13C NMR: δ = 21.2, 22.1, 25.0, 28.1, 31.1,
(m, 1 H), 1.82 (t, J = 1.7 Hz, 3 H), 2.20 (dd, J1 = 14.7, J2 = 8.0 Hz, 34.9, 38.7, 40.4, 40.9, 46.1, 57.8, 76.1, 77.1, 89.9, 124.6 (2 C), 126.0,
1 H), 2.80 (d, J = 13.6 Hz, 1 H), 3.22 (m, 1 H), 3.19 (td, J1 = 10.7,
J2 = 4.0 Hz, 1 H), 3.47 (s, 1 H), 3.93 (d, J = 13.6 Hz, 1 H), 4.48 (s,
126.4, 127.9 (2 C), 130.6, 149.1 ppm. IR (film): ν = 3530, 3020,
˜
1450, 760, 730, 700 cm–1. C22H31NO2: C 77.38, H 9.15, N 4.10;
1 H), 5.38 (m, 1 H), 7.18–7.33 (m, 3 H), 7.61 (d, J = 8.6 Hz, 2 found C 78.51, H 9.29, N 3.98.
H) ppm. 13C NMR: δ = 21.7, 22.1, 23.3, 25.1, 28.7, 31.2, 34.1, 34.9,
40.8, 43.0, 46.1, 57.8, 71.7, 77.0, 92.0, 122.6, 126.0 (2 C), 126.3,
Synthesis of Amino Alcohols 9a, 9b, 9e, 9f, 9h, and 9i. General
Method: Dry AlCl3 (0.48 g, 3.6 mmol) was added in portions to a
suspension of LiAlH4 (0.41 g, 10.8 mmol) in THF (30 mL) cooled
to –10 °C. The mixture was stirred for an additional 10 min, and a
solution of the corresponding benzoxazine 8a–i (2.16 mmol) in
THF (20 mL) was slowly added. The mixture was stirred for 15 min
at room temperature and was then heated at reflux for 10 min. It
was then allowed to reach room temperature and quenched by ad-
127.1 (2 C), 140.7, 146.3 ppm. IR (nujol dispersion): ν = 3490
˜
(broad), 3040, 1590, 760, 750, 690 cm–1. C23H33NO2 (355.51): C
77.70, H 9.36, N 3.94; found C 77.83, H 9.51, N 4.03.
(3R,4aR,5aS,6S,11aS)-3,8,11,11-Tetramethyl-6-phenyl-
2,3,4,4a,5a,7,7,10,11,11a-decahydro-1H-5-oxa-10a-azacyclohepta-
[b]naphthalen-6-ol (8f): Yellow oil. [α]2D5 = –78.5 (c = 0.8, CH2Cl2).
1H NMR: δ = 0.78–0.94 (m, 2 H), 0.86 (d, J = 6.5 Hz, 3 H), 1.04 dition of 10% aqueous NaOH (2 mL). The mixture was filtered,
(m, 1 H), 1.15 (s, 3 H), 1.21 (s, 3 H), 1.31 (m, 1 H), 1.45 (m, 1 H),
1.52 (m, 1 H), 1.59–1.73 (m, 2 H), 1.69 (s, 3 H), 2.12 (d, J = was dried over MgSO4. The solvent was eliminated under vacuum,
14.2 Hz, 1H), 2.97 (dd, J1 = 13.8, J2 = 8.4 Hz, 1 H), 3.18 (td, J1 = and the residue was chromatographed on silica gel with hexanes/
the solid was washed with hot ethyl acetate, and the organic layer
10.6, J2 = 3.9 Hz, 1 H), 3.44 (d, J = 14.2, 1 H), 3.57 (s, 1 H), 3.78 ethyl acetate 8:1 as eluent.
(dd, J1 = 13.8, J2 = 6.1 Hz, 1 H), 4.49 (s, 1 H), 5.71 (m, 1 H), 7.18–
(3S)-N-(8-Mentholyl)-3-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-ol
7.35 (m, 3 H), 7.63 (d, J = 8.6 Hz, 2 H) ppm. 13C NMR: δ = 21.7,
22.1, 25.0, 26.2, 28.5, 31.2, 34.9, 37.8, 39.6, 40.7, 45.8, 57.9, 71.3,
77.0, 92.1, 124.0, 126.2 (2 C), 126.4, 127.2 (2C), 139.6, 146.5 ppm.
(9a): 719.7 mg, 97% from 8a. Colorless solid. M.p.. 128–129 °C
(from hexane). [α]2D5 = +169.2 (c = 0.9, CH2Cl2). 1H NMR (333 K):
δ = 0.83–1.04 (m, 2 H), 0.87 (s, 3 H,), 0.94 (d, J = 6.5 Hz, 3 H),
1.12 (m, 1 H), 1.20 (s, 3 H), 1.44 (m, 1 H), 1.53–1.73 (m, 2 H),
1.86–2.05 (m, 2 H), 2.47 (dd, J1 = 15.0, J2 = 8.4 Hz, 1 H), 2.78 (m,
1 H), 2.81 (d, J = 14.8 Hz, 1 H), 3.19 (d, J = 14.8 Hz, 1 H), 3.21
(m, 1 H), 3.62–3.76 (m, 2 H), 5.09 (s, broad, 1 H), 5.48 (m, 1 H),
5.70 (m, 1 H), 7.19 (m, 1 H), 7.27 (m, 2 H), 7.59 (d, J = 8.7 Hz, 2
IR (film): ν = 3600, 3040, 1600, 700, 735, 670 cm–1. C H NO
˜
23 33
2
(355.51): C 77.70, H 9.36, N 3.94; found C 77.86, H 9.25, N 4.07.
(3R,4aR,5aS,6S,11aS)-6-Isopropyl-3,11,11-trimethyl-
2,3,4,4a,5a,6,7,10,11,11a-decahydro-1H-5-oxa-10a-azacyclohepta-
[b]naphthalen-6-ol (8h): Yellow oil. [α]2D5 = –88.1 (c = 1.0, CH2Cl2).
1H NMR: δ = 0.84–1.06 (m, 2 H), 0.92 (d, J = 6.5 Hz, 3 H), 0.98 H), 8.45 (s, broad, 1 H) ppm. 13C NMR (333 K): δ = 16.6, 21.0,
(d, J = 6.8 Hz, 3 H), 0.99 (d, J = 6.8 Hz, 3 H), 1.11 (m, 1 H), 1.19
(s, 6 H), 1.34–1.52 (m, 2 H), 1.56 (m, 1 H), 1.70 (m, 1 H), 1.80 124.9 (2 C), 125.0, 126.7, 127.9 (2 C), 128.0, 146.8 ppm. IR (nujol
(sept, J = 6.8 Hz, 1 H), 1.89 (m, 1 H), 2.11 (dd, J1 = 15.0, J2
dispersion): ν = 3360 (broad), 1600, 790, 770, 705, 670 cm–1
8.2 Hz, 1 H), 2.63 (dt, J1 = 15.0, J2 = 3.3 Hz, 1 H), 2.84 (s, 1 H),
3.01 (dd, J1 = 13.9, J2 = 7.8 Hz, 1 H), 3.43 (td, J1 = 10.6, J2
21.8, 25.8, 31.1, 34.9, 39.3, 43.8, 47.9, 51.2, 61.6, 62.2, 73.5, 77.8,
=
.
˜
C22H33NO2 (343.50): C 76.92, H 9.68, N 4.08; found C 77.07, H
9.82, N 4.21.
=
4.0 Hz, 1 H), 3.68 (dd, J1 = 13.9, J2 = 5.7, 1 H), 4.62 (s, 1 H), 5.68
(m, 1 H), 5.96 (m, 1 H) ppm. 13C NMR: δ = 17.3 (2 C), 21.8, 22.1,
25.1, 28.5, 30.8, 31.3, 34.9, 36.5, 37.7, 41.1, 46.1, 58.1, 71.3, 77.1,
(3S)-N-(8-Mentholyl)-3-phenyl-1,2,3,4,5,8-hexahydroazocin-3-ol
(9b): 756.8 mg, 98% from 8b. Colorless oil. [α]2D5 = +76.1 (c = 1.2,
CH2Cl2). H NMR (333 K): δ = 0.78–1.02 (m, 2 H), 0.87 (s, 3 H),
0.92 (d, J = 6.5 Hz, 3 H), 1.09 (m, 1 H), 1.20 (s, 3 H), 1.42 (m, 1
H), 1.53 (m, 1 H), 1.64 (m, 1 H), 1.78 (m, 1 H), 1.89–2.06 (m, 2
H), 2.12–2.40 (m, 2 H), 2.62 (m, 1 H), 2.78 (d, J = 14.4 Hz, 1 H),
3.11 (d, J = 14.4 Hz, 1 H), 3.21 (m, 1 H), 3.58–3.72 (m, 2 H), 5.30
(s, broad, 1 H), 5.66 (m, 1 H), 5.82 (m, 1 H), 7.26 (m, 1 H), 7.38 (m,
2 H), 7.59 (m, 2 H), 8.55 (s, broad, 1 H) ppm. 13C NMR (333 K): δ
= 19.4, 21.6, 21.8, 23.5, 26.1, 31.1, 35.0, 38.7, 43.5, 47.5, 47.8, 61.7,
1
89.9, 130.3, 131.7 ppm. IR (film): ν = 3525, 3040, 700 cm–1
.
˜
C19H33NO2 (307.47): C 74.22, H 10.82, N 4.56; found C 74.38, H
10.87, N 4.43.
(3R,4aR,5aS,6S,12aS)-6-Isopropyl-3,12,12-trimethyl-
2,3,4,4a,6,7,8,11,12,12a-decahydro-1H,5aH-5-oxa-11a-azacyclo-
octa[b]naphthalen-6-ol (8i): Colorless solid, M.p.. 83–84 °C (from
hexane). [α]2D5 = –50.2 (c = 1.2, CH2Cl2). 1H NMR (333 K): δ =
0.85–1.14 (m, 3 H), 0.93 (d, J = 6.5 Hz, 3 H), 0.95 (d, J = 6.8 Hz, 62.0, 73.3, 74.7, 124.7 (2 C), 126.4, 126.8, 127.9 (2 C), 133.5,
3 H), 0.97 (d, J = 6.8 Hz, 3 H), 1.19 (s, 3 H), 1.20 (s, 3 H), 1.31 149.0 ppm. IR (film): ν = 3390 (broad), 3060, 1601, 760, 735,
(m, 1 H), 1.48 (m, 1 H), 1.56–1.76 (m, 3 H), 1.78–1.96 (m, 2 H), 700 cm–1. C23H35NO2 (357.53): C 77.27, H 9.87, N 3.92; found C
˜
2.21–2.49 (m, 3 H), 2.80 (s, 1 H), 3.00 (m, 1 H), 3.45 (td, J1 = 10.6,
J2 = 3.9 Hz, 1 H), 3.76 (m, 1 H), 4.55 (s, 1 H), 5.55 (m, 1 H), 5.72
(m, 1 H) ppm. 13C NMR (333 K): δ = 17.3, 17.5, 21.7, 22.1, 25.3,
25.5, 27.9, 29.4, 31.5, 35.2, 37.8, 39.2, 41.5, 47.3, 58.3, 74.8, 76.7,
77.38, H 9.71, N 4.05.
(3S)-N-(8-Mentholyl)-6-methyl-3-phenyl-2,3,4,7-tetrahydro-1H-
azepin-3-ol (9e): 758.8 mg, 98% from 8e. Colorless solid. M.p.: 165–
1
166 °C (from hexane). [α]2D5 = +143.8 (c = 0.9, CH2Cl2). H NMR
87.9, 127.8, 133.4 ppm. IR (nujol dispersion): ν = 3495, 3040 cm–1.
˜
(333 K): δ = 0.88 (s, 3 H), 0.79–1.05 (m, 2 H), 0.93 (d, J = 6.5 Hz,
3 H), 1.13 (m, 1 H), 1.23 (s, 3 H), 1.44 (m, 1 H), 1.55–1.72 (m, 2
H), 1.68 (s, 3 H), 1.82–2.02 (m, 2 H), 2.41 (dd, J1 = 14.9, J2
C20H35NO2 (321.50): C 74.72, H 10.97, N 4.36; found C 74.59, H
11.11, N 4.23.
=
( 3R, 4 aR, 5 aS, 6R, 1 1 aS) - 3 , 1 1 , 1 1 -Tri methyl-6-phenyl-
2,3,4,4a,5a,6,7,10,11,11a-decahydro-1H-5-oxa-10a-azacyclohepta-
[b]naphthalen-6-ol (8j): Yellow oil. [α]2D5 = –24.8 (c = 0.7, CH2Cl2).
8.5 Hz, 1 H), 2.72 (m, 1 H), 2.73 (d, J = 14.6 Hz, 1 H), 3.06 (d, J
= 16.0 Hz, 1 H), 3.20 (d, J = 14.6 Hz, 1 H), 3.63 (d, J = 16.0 Hz,
1 H), 3.72 (td, J1 = 10.3, J2 = 3.9 Hz, 1 H), 4.96 (s, broad, 1 H),
1H NMR: δ = 0.81–0.92 (m, 2 H), 0.86 (d, J = 6.5 Hz, 3 H), 1.01 5.49 (m, 1 H), 7.21 (m, 1 H), 7.29 (m, 2 H), 7.57 (m, 2 H), 8.42 (s,
(m, 1 H), 1.22 (s, 3 H), 1.28 (s, 3 H), 1.27–1.37 (m, 2 H), 1.56 (m,
1 H), 1.65 (m, 1 H), 1.73 (m, 1 H), 2.32 (dd, J1 = 16.4, J2 = 7.1 Hz,
1 H), 2.99 (m, 1 H), 3.24 (dd, J1 = 16.4, J2 = 7.1 Hz, 1 H), 3.39
broad, 1 H) ppm. 13C NMR (333 K): δ = 16.4, 20.9, 21.8, 23.3,
25.6, 30.9, 34.6, 38.5, 43.5, 47.4, 55.1, 61.5, 61.9, 73.3, 77.9, 120.0,
124.8 (2 C), 126.7, 127.8 (2 C), 134.4, 146.4 ppm. IR (nujol disper-
Eur. J. Org. Chem. 2005, 2449–2458
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2455

R. Pedrosa, C. Andrés, A. Gutiérrez-Loriente, J. Nieto
FULL PAPER
sion): ν = 3370 (broad), 1600, 755, 700 cm–1. C H NO (357.53):
C 77.27, H 9.87, N 3.92; found C 77.43, H 9.75, N 4.08.
under vacuum. The residue was redissolved in a MeOH/THF mix-
ture (1:2, 12 mL) and an aqueous solution of KOH (2.5 m, 4 mL)
was then added. The mixture was stirred at room temperature for
2–3 days. After removal of the solvents under vacuum, H2O
(30 mL) was added and the mixture was extracted with CHCl3
(4×25 mL). The organic layer was washed with H2O and dried
over MgSO4, and the solvent was eliminated under vacuum. The
residue was chromatographed on silica gel with a CHCl3/EtOH
mixture (8:1) as eluent.
˜
23 35
2
(3S)-N-(8-Mentholyl)-5-methyl-3-phenyl-2,3,4,7-tetrahydro-1H-
azepin-3-ol (9f): 679.6 mg, 88% from 8f. Colorless oil. [α]2D5 = +69.0
( c = 1.0, CH2Cl2). 1H NMR (333 K): δ = 0.81–1.02 (m, 2 H), 0.88
(s, 3 H), 0.93 (d, J = 6.6 Hz, 3 H), 1.11 (m, 1 H), 1.20 (s, 3 H),
1.31–1.72 (m, 3 H), 1.65 (s, 3 H), 1.86 (m, 1 H), 2.01 (m, 1 H), 2.23
(d, J = 14.5 Hz, 1 H), 2.89 (d, J = 14.6 Hz, 1 H), 2.98 (d, J =
14.5 Hz, 1 H), 3.19 (d, J = 14.5 Hz, 1 H), 3.21 (m, 1 H), 3.60–3.71
(m, 2 H), 5.02 (s, broad, 1 H), 5.31 (m, 1 H), 7.15–7.33 (m, 3 H),
7.57–7.60 (m, 2 H), 9.20 (s, 1 H) ppm. 13C NMR (333 K): δ = 16.3,
21.0, 21.9, 25.9, 27.1, 31.2, 34.9, 44.0, 45.3, 47.8, 50.5, 61.7, 61.8,
73.5, 76.6, 121.8, 124.9 (2 C), 126.7, 127.9 (2 C), 133.0, 146.9 ppm.
(3S)-3-Phenyl-2,3,4,7-tetrahydro-1H-azepin-3-ol (10a): 137.2 mg,
49% from 9a. Colorless oil. [α]2D5 = –61.2 (c = 0.9, CH2Cl2). 1H
NMR: δ = 2.52 (ddd, J1 = 16.2, J2 = 7.7, J3 = 1.5 Hz, 1 H), 2.75
(dq, J1 = 16.2, J2 = 2.7 Hz, 1 H), 3.04 (dd, J = 13.1, J2 = 1.5 Hz,
1 H), 3.11 (d, J = 13.1 Hz, 1 H), 3.37 (dq, J1 = 15.9, J2 = 2.7 Hz,
1 H), 3.53 (dd, J1 = 15.9, J2 = 7.0 Hz, 1 H), 3.65 (s, broad, 2 H),
5.69 (m, 1 H), 5.91 (m, 1 H), 7.26 (m, 1 H), 7.34 (m, 2 H), 7.49
(m, 2 H) ppm. 13C NMR: δ = 42.9, 48.6, 62.3, 71.7, 124.1 (2 C),
IR (nujol dispersion): ν = 3390, 700, 720, 750 cm–1. C H NO
˜
23 35
2
(357.53): C 77.27, H 9.87, N 3.92; found C 77.40, H 10.03, N 3.79.
(3S)-N-(8-Mentholyl)-3-isopropyl-2,3,4,7-tetrahydro-1H-azepin-3-ol
(9h): 615.0 mg, 92% from 8h. Colorless oil. [α]2D5 = +54.6 (c = 1.1,
1
126.7, 127.3, 128.1 (2 C), 130.7, 147.1 ppm. IR (film): ν = 3330,
˜
CH2Cl2). H NMR (333 K): δ = 0.87–1.14 (m, 3 H), 0.90 (d, J =
3025, 1600, 760, 700 cm–1. C12H15NO (189.25): C 76.16, H 7.99, N
7.40; found C 76.01, H 8.17, N 7.36.
6.4 Hz, 3 H), 0.91 (s, 3 H), 0.95 (d, J = 6.9 Hz, 6 H), 1.19 (s, 3 H),
1.41 (m, 1 H), 1.60–1.77 (m, 3 H), 1.83 (m, 1 H), 1.94 (m, 1 H),
2.22 (dd, J1 = 15.0, J2 = 8.4 Hz, 1 H), 2.41 (m, 1 H), 2.60 (d, J =
14.3 Hz, 1 H), 3.00 (d, J = 14.3 Hz, 1 H), 3.14 (m, 1 H), 3.58–3.71
(m, 2 H), 4.50 (s, broad, 1 H), 5.34 (m, 1 H), 5.51 (m, 1 H), 8.40
(s, broad, 1 H) ppm. 13C NMR (333 K): δ = 16.6, 16.9, 17.7, 21.1,
21.8, 26.0, 31.2, 35.0, 35.1, 35.9, 44.0, 47.9, 51.1, 58.1, 61.8, 73.4,
(3R)-3-Phenyl-2,3,4,7-tetrahydro-1H-azepin-3-ol (ent-10a): Yield:
50%. Colorless oil. [α]2D5 = +60.0 (c = 0.9, CH2Cl2). 1H NMR, 13C
NMR, and IR data are coincident with those reported for 10a.
(3S)-3-Phenyl-1,2,3,4,5,8-hexahydroazocin-3-ol (10b): 175.5 mg,
58% from 9b. Colorless oil. [α]2D5 = +79.2 (c = 1.1, CH2Cl2). 1H
NMR (333 K): δ = 1.78–1.91 (m, 2 H), 2.01 (m, 1 H), 2.80 (s,
broad, 2 H), 2.86 (dd, J1 = 13.7, J2 = 1.5 Hz, 1 H), 2.88 (m, 1 H),
78.1, 125.2, 127.1 ppm. IR (film): ν = 3415, 1615, 800, 670 cm–1.
˜
C19H35NO2 (309.49): C 73.74, H 11.40, N 4.53; found C 73.91, H
11.28, N 4.68.
3.21 (d, J = 13.7 Hz, 1 H), 3.52 (ddt, J1 = 16.2, J2 = 5.6, J3
=
(3S)-N-(8-Mentholyl)-3-isopropyl-1,2,3,4,5,8-hexahydroazocin-3-ol
(9i): 614.9 mg, 88% from 8i. Colorless oil. [α]2D5 = +18.7 (c = 1.3,
1.5 Hz, 1 H), 3.69 (dt, J1 = 16.2, J2 = 2.8 Hz, 1 H), 5.42 (m, 1 H),
5.91 (m, 1 H), 7.22 (m, 1 H), 7.31 (m, 2 H), 7.43 (m, 2 H) ppm.
13C NMR (333 K): δ = 21.4, 42.5, 47.8, 55.4, 72.2, 124.1 (2 C),
1
CH2Cl2). H NMR (333 K): δ = 0.78–1.22 (m, 3 H), 0.83 (d, J =
6.5 Hz, 3 H), 0.87 (s, 3 H), 0.88 (d, J = 6.5 Hz, 3 H), 0.90 (d, J =
6.5 Hz, 3 H), 1.15 (s, 3 H), 1.36 (m, 1 H), 1.50–1.80 (m, 6 H), 1.88
(m, 1 H), 2.04 (m, 1 H), 2.41 (m, 1 H), 2.55 (d, J = 13.7 Hz, 1 H),
2.88 (d, J = 13.7 Hz, 1 H), 3.17 (m, 1 H), 3.51–3.62 (m, 2 H), 5.21
(s, broad, 2 H), 5.42 (m, 1 H), 5.74 (m, 1 H) ppm. 13C NMR
(333 K): δ = 17.0, 17.2, 21.1, 21.7, 21.9, 23.6, 26.3, 31.2, 34.6, 35.3,
38.2, 44.1, 45.2, 48.0, 53.9, 62.3, 73.1, 74.5, 125.8, 134.4 ppm. IR
126.1, 126.3, 128.1 (2 C), 132.5, 148.2 ppm. IR (film): ν = 3500,
˜
3025, 1600, 760, 705 cm–1. C13H17NO (203.28): C 76.81, H 8.43, N
6.89; found C 76.94, H 8.57, N 6.77.
(3S)-6-Methyl-3-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-ol (10e):
162.5 mg, 54% from 9e. Colorless oil. [α]2D5 = –95.7 (c = 0.9,
1
CH2Cl2). H NMR: δ = 1.78 (s, 3 H), 2.41 (ddd, J1 = 15.8, J2 =
(film): ν = 3400, 1600, 730 cm–1. C H NO (323.51): C 74.25, H
8.2, J3 = 1.5 Hz, 1 H), 2.76 (dq, J1 = 15.8, J2 = 1.5 Hz, 1 H), 3.01
(dd, J1 = 13.0, J2 = 1.5 Hz, 1 H), 3.06 (s, broad, 2 H), 3.09 (d, J =
13.0 Hz, 1 H), 3.31 (d, J = 15.4 Hz, 1 H), 3.41 (dt, J1 = 15.4, J2 =
1.5 Hz, 1 H), 5.38 (m, 1 H), 7.21 (m, 1 H), 7.30 (m, 2 H), 7.47 (m,
2 H). NMR: δ = 24.6, 41.6, 53.5, 63.2, 71.8, 120.8, 124.1 (2 C),
˜
20 37
2
11.53, N 4.33; found C 74.11, H 11.46, N 4.49.
(3R)-N-(8-Mentholyl)-3-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-ol
(9j): Yield: 97%. Colorless solid. M.p.: 135–136 °C (from hexane).
[α]2D5 = –68.8 (c = 0.7, CH2Cl2). 1H NMR (333 K): δ = 0.82–1.09
(m, 3 H), 0.91 (s, 3 H), 0.91 (d, J = 6.5 Hz, 3 H), 1.24 (s, 3 H),
1.38–1.69 (m, 5 H), 1.93 (m, 1 H), 2.61 (m, 1 H), 2.77 (m, 1 H),
2.80 (d, J = 13.7 Hz, 1 H), 3.04 (m, 1 H), 3.23 (dd, J1 = 13.7, J2 =
2.2 Hz, 1 H), 3.68 (td, J1 = 10.3, J2 = 3.9 Hz, 1 H), 3.83 (m, 1 H),
4.92 (s, broad, 1 H), 5.70–5.89 (m, 2 H), 7.24 (m, 1 H), 7.33 (m, 2
H), 7.53 (m, 2 H) ppm. 13C NMR (333 K): δ = 19.3, 21.9, 22.1,
26.4, 31.0, 35.2, 39.9, 44.6, 47.8, 50.6, 61.7, 62.6, 72.6, 75.9, 124.6,
126.6, 128.1 (2 C), 140.5, 147.1 ppm. IR (film): ν = 3500, 3065,
˜
3025, 1600, 765, 700 cm–1. C13H17NO (203.28): C 76.81, H 8.43, N
6.89; found C 76.69, H 8.52, N 6.72.
(3S)-5-Methyl-3-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-ol (10f):
135.4 mg, 45% from 9e. Colorless oil. [α]2D5 = –98.6 (c = 1.0,
1
CH2Cl2). H NMR: δ = 1.77 (s, 3 H), 2.31 (d, J = 15.3 Hz, 1 H),
2.96 (d, J = 15.3 Hz, 1 H), 3.05 (d, J = 12.7 Hz, 1 H), 3.07 (s,
broad, 2 H), 3.08 (d, J = 12.7 Hz, 1 H), 3.26 (m, 1 H), 3.39 (dd, J1
= 15.2, J2 = 7.3 Hz, 1 H), 5.73 (m, 1 H), 7.21 (m, 1 H), 7.36 (m, 2
H), 7.48 (m, 2 H) ppm. 13C NMR: δ = 27.6, 47.2, 47.5, 63.5, 70.7,
126.9, 126.9, 128.1 (3C), 130.4, 147.5 ppm. IR (Nujol): ν = 3280
˜
(broad), 760, 725, 700 cm–1. C22H35NO2: C 76.92, H 9.68, N 4.08;
found C 77.16, H 9.54, N 3.96.
124.0 (2C), 124.7, 126.6, 128.0 (2C), 136.9, 147.2 ppm. IR (film): ν
˜
Removal of the Menthol Appendage. General Method: A solution of
the corresponding aminomenthol derivative 9a, 9b, 9e, 9f, 9h, or 9i
(1.48 mmol) and PCC (1.28 g, 5.95 mmol) in CH2Cl2 (35 mL) was
stirred at room temperature with 3-Å molecular sieves (2.5 g) until
the oxidation was complete (TLC, 40–70 h). The solvent was elim-
inated under reduced pressure, the residue was dissolved in a 10%
aqueous solution of NaOH (40 mL), and the resulting solution was
extracted with CHCl3 (5×25 mL). The organic layer was washed
with brine and dried over MgSO4, and the solvents were evaporated
= 3340,3060, 3030, 1600, 760, 700 cm–1. C13H17NO (203.28): C
76.81, H 8.43, N 6.89; found C 76.95, H 8.56, N 6.98.
(3S)-3-Isopropyl-2,3,4,7-tetrahydro-1H-azepin-3-ol (10h): 117.2 mg,
51% from 9h. Colorless oil. [α]2D5 = –42.1 (c = 1.1, CH2Cl2). 1H
NMR: δ = 0.92 (d, J = 6.9 Hz, 3 H), 0.98 (d, J = 6.9 Hz, 3 H),
1.79 (sept, J = 6.9 Hz, 1 H), 2.30 (dq, J1 = 15.4, J2 = 1.6 Hz, 1 H),
2.36 (dd, J1 = 15.4, J2 = 6.7 Hz, 1 H), 2.88 (d, J = 13.0 Hz, 1 H),
3.04 (d, J = 13.0 Hz, 1 H), 3.34 (dq, J1 = 16.1, J2 = 1.6 Hz, 1 H),
2456
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 2449–2458

An Asymmetric Route to Azepin-3-ol and Azocin-3-ol Derivatives
FULL PAPER
[12]
[13]
In general, eight-membered rings can be formed only if confor-
mational restrictions imposed by an existing ring or other func-
tional groups are present in the diene precursor: S. J. Miller, S.-
H. Kim, Z. R. Chen, R. H. Grubbs, J. Am. Chem. Soc. 1995,
117, 2108. See also ref.[9] and references cited therein.
Conformationally flexible acyclic dienes have, with few excep-
tions, not been successfully closed to eight-membered rings by
RCM. For examples, see: a) M. S. Visser, M. N. Heron, M. T.
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RCM of allylic N,O-acetals with good chemical yields has been
described previously, but with the nitrogen functional group
protected as an aryl sulfonamide. S. S. Kinderman, R. Doode-
man, J. W. van Beijma, J. C. Russcher, K. C. M. F. Tjen, T. M.
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stra, H. E. Schoemaker, F. P. J. T. Rutjes, Adv. Synth. Catal.
2002, 344, 736.
Despite the fact that the Grubbs’ ruthenium carbene complexes
show remarkable functional group tolerance, the tolerance is
generally poor for amines: a) G. C. Fu, S.-B. T. Nguyen, R. H.
Grubbs, J. Am. Chem. Soc. 1993, 115, 9856; b) Y.-S. Shon, T. R.
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For some examples of ring-closing metathesis of substrates
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This strategy has been successfully used to avoid the formation
of chelates between the ruthenium carbene and other polar
groups, a) A. Fürstner, K. Langemann, J. Am. Chem. Soc.
1997, 119, 9130; b) P. Wipf, W. S. Weiner, J. Org. Chem. 1999,
64, 5321. See also Ref. 6e and references cited therein.
G. C. Fu, R. H. Grubbs, J. Am. Chem. Soc. 1992, 114, 7324.
It has been demonstrated that ammonium salts are tolerated
by the Grubbs’ ruthenium catalyst: a) D. L. Wright, J. P.
Schulte, II, M. A. Page, Org. Lett. 2000, 2, 1847; b) K. Shimizu,
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ence 18a.
3.58 (dd, J1 = 16.1, J2 = 6.0 Hz, 1 H), 4.68 (s, broad, 2 H), 5.69
(m, 1 H), 5.75 (m, 1 H) ppm. 13C NMR: δ = 16.9 (2 C), 35.9, 37.3,
48.1, 57.8, 72.1, 128.0, 128.3 ppm. IR (film): ν = 3325, 3010, 1700,
˜
730, 660 cm–1. C9H17NO (155.24): C 69.63, H 11.04, N 9.02; found
C 69.48, H 10.89, N 9.21.
(3S)-3-Isopropyl-1,2,3,4,5,8-hexahydroazocin-3-ol (10i): (125.2 mg,
50% from 9i). Colorless oil. [α]2D5 = +44.0 (c = 0.6, CH2Cl2). 1H
NMR (333 K): δ = 0.85 (d, J = 6.9 Hz, 3 H), 0.93 (d, J = 6.9 Hz,
3 H), 1.47 (m, 1 H), 1.60–1.69 (m, 2 H), 1.97 (m, 1 H), 2.68 (m, 1
H), 2.72 (dd, J1 = 13.6, J2 = 1.6 Hz, 1 H), 2.83 (d, J = 13.6 Hz, 1
H), 3.08 (s, broad, 2 H), 3.45 (dd, J1 = 16.1, J2 = 5.8 Hz, 1 H),
3.62 (dt, J1 = 16.1, J2 = 1.6 Hz, 1 H), 5.37 (m, 1 H), 5.87 (m, 1
H) ppm. 13C NMR: δ = 16.7, 17.1, 20.9, 34.0, 38.3, 47.0, 52.1, 71.9,
[14]
[15]
[16]
[17]
125.7, 133.3 ppm. IR (film): ν = 3350, 3010, 1700, 730, 710 cm–1.
˜
C10H19NO (169.26): C 70.96, H 11.31, N 8.28; found C 70.76, H
11.49, N 8.01.
Acknowledgments
The financial support provided by the Spanish DGIC (Project
BQU2002–1046) and the Junta de Castilla y León (Project VA042/
03) is gratefully acknowledged. A.G.-L. also thanks the Spanish
MC y T for a predoctoral grant (FPI program).
[18]
[19]
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[8] For reviews on applications of the RCM in the synthesis of
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[20]
[21]
[22]
[23]
[24]
Protonated pyridines are also compatible with Grubbs’ cata-
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Ed. 2003, 42, 308.
Only in particular cases have seven-membered rings with tri-
substituted double bonds been successfully formed by RCM:
K. Nakashima, K. Inoue, M. Sono, M. Tori, J. Org. Chem.
2002, 67, 6034 and references cited therein.
[25]
[26]
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[27]
Eur. J. Org. Chem. 2005, 2449–2458
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2457

R. Pedrosa, C. Andrés, A. Gutiérrez-Loriente, J. Nieto
FULL PAPER
[28] C. Andrés, J. Nieto, R. Pedrosa, M. Vicente, J. Org. Chem.
1998, 63, 8570.
[29] CCDC-260740 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[31] For the preparation of benzoxazine 7f commercially available
(Aldrich) 2-methylallylmagnesium chloride was used.
[32] The hydrochlorides of 7a–i were obtained by bubbling dry HCl
into ethereal solutions of 7a–i for 5 min and removal of the
solvent.
Received: November 24, 2004
[30] J. D. White, P. Hrnciar, J. Org. Chem. 2000, 65, 9129.
2458
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 2449–2458