Reductive ring-opening of phthalan and isochroman: Application to the stereoselective synthesis of tetrahydroisoquinolines and tetrahydrobenzazepines

Article abstract of DOI:10.1002/ejoc.201000111

The reaction of the dianionic intermediates 2a,b resulting from the lithiation of phthalan (la) and isochroman (lb) with chiral N-tert-butylsulfinyl aldimines 9 in the presence of ZnMe₂ gave, after hydrolysis, N-tert-butylsulfinyl amino alcohol

Full text of DOI:10.1002/ejoc.201000111

FULL PAPER
DOI: 10.1002/ejoc.201000111
Reductive Ring-Opening of Phthalan and Isochroman: Application to the
Stereoselective Synthesis of Tetrahydroisoquinolines and
Tetrahydrobenzazepines
Daniel García,[a] Francisco Foubelo,*[a] and Miguel Yus*[a]
Dedicated to Professor Saverio Florio on the occasion of his 70th birthday
Keywords: Lithium / Lithiation / Zincates / Diastereoselectivity / Hydrolysis / Nitrogen heterocycles / Sulfinylimines
The reaction of the dianionic intermediates 2a,b resulting
from the lithiation of phthalan (1a) and isochroman (1b) with
chiral N-tert-butylsulfinyl aldimines 9 in the presence of
ZnMe2 gave, after hydrolysis, N-tert-butylsulfinyl amino
alcohols 10 and 13, respectively, with high diastereoselectiv-
ity. Successive treatment of compounds 10 and 13 with hy-
drogen chloride in methanol, thionyl chloride in chloroform
and sodium hydroxide led to the formation of tetrahydroiso-
quinolines 19 and tetrahydrobenzazepines 20. Depending on
the structure of the starting chiral imine 9, benzoindolizidine
21, benzoquinolizidine 22 and benzopyrroloazepine 23 are
also accessible through this methodology.
by exchanging lithium by another metal. For instance, con-
jugate addition products 5 are obtained upon reaction of
electrophilic olefins with dianions 2 in the presence of cop-
per(I) salts and dimerisation leading to compounds 6 occurs
with copper(II) chloride.[10] Also, compounds 7[11] have
been prepared by the palladium-catalysed Negishi cross-
coupling reaction of aryl bromides and the in situ generated
organozinc reagents resulting from a lithium–zinc transme-
tallation of intermediates 2 with zinc bromide. Another syn-
thetically useful finding is the reaction of intermediates 2
with an equimolecular amount of zinc bromide and copper
cyanide followed by treatment with different allylic chlo-
rides or bromides to give almost exclusively the correspond-
ing alcohols 8[12] resulting from an SN2Ј displacement in a
highly regioselective manner (Scheme 1).
We considered it of interest to study the reactivity of the
anionic intermediates 2 [resulting from the reductive ring-
opening of phthalan (1a) and isochroman (1b)] with chiral
N-tert-butylsulfinylimines as electrophiles in order to apply
this methodology to the synthesis of substituted nitrogen-
containingheterocyclessuchastetrahydroisoquinolines[13]and
-benzazepines. These electrophilic reagents have found
many applications in synthesis[14] due to the possibility of
preparing both their enantiomers[15] and also because the
chiral auxiliary can be easily removed under acidic condi-
tions.[16] In addition, practical processes for recycling the
tert-butylsulfinyl group upon deprotection of N-tert-butyl-
sulfinylamines have been reported recently, making this chi-
ral auxiliary of interest for large-scale industrial pro-
cesses.[17] Tetrahydroisoquinolines are present in many natu-
ral products[18] that display antitumour and antimicrobial
Introduction
Functionalised organolithium compounds[1] are of inter-
est in organic synthesis because their reactions with electro-
philes yield polyfunctionalised molecules in a single process.
Organolithium compounds can be prepared through a wide
range of methodologies,[2] including by the reductive ring-
opening of some heterocycles[3] such as strained heterocy-
cles (three- and four-membered-ring heterocycles) and those
bearing activated bonds (cyclic compounds with allylic and
benzylic carbon–heteroatom bonds[4] as well as aryl ethers
and thioethers). Lithium metal is the lithiating reagent in
these electron-transfer processes,[5] either alone or in the
presence of an arene in a stoichiometric or catalytic
amount.[6] Phthalan (1a)[7] and isochroman (1b)[8] can be
regarded as special kinds of cyclic benzyl ethers. These
heterocycles are opened reductively with lithium and a cata-
lytic amount of 4,4Ј-di-tert-butylbiphenyl (DTBB) at 0 °C
to afford dianions 2 which have found widespread use in
organic synthesis. Thus, the reactions of these intermediates
with different electrophiles lead after hydrolysis to function-
alised alcohols 3.[9] In the case of phthalan (1a), it is pos-
sible to introduce two different electrophiles at both benz-
ylic positions in a sequential manner by performing a
double lithiation to give compounds of type 4.[7a] The reac-
tivity of organolithium intermediates 2 can be modulated
[a] Departamento de Química Orgánica, Facultad de Ciencias and
Instituto de Síntesis Orgánica (ISO), Universidad de Alicante,
Apdo. 99, 03080 Alicante, Spain
Fax: +34-965-903-549
E-mail: foubelo@ua.es; yus@ua.es
Eur. J. Org. Chem. 2010, 2893–2903
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2893

D. García, F. Foubelo, M. Yus
FULL PAPER
Scheme 1. Synthetic applications of the dianionic species 2 resulting from the reductive ring-opening lithiation of phthalan (1a) and
isochroman (1b).
activities. For this reason the asymmetric synthesis of sub- and 11d in a 78:22 ratio, the major diastereoisomer 10d be-
stituted tetrahydroisoquinolines[19] is of great interest for ing isolated in a yield of 47% (Table 1, entry 1). Different
synthetic organic chemists. With regard to tetrahydrobenza- additives and reaction conditions were applied to improve
zepines, 1- and 4-substituted 2,3,4,5-tetrahydro-1H-benza- both the diastereoselectivity and yield of the reaction. It has
zepines[20] are dopamine receptor agonists and antago- previously been reported that the yields and diastereoselec-
nists[21] and also promising candidates for combating neu- tivities of the reactions of organolithium compounds with
rological disorders such as Parkinson’s[22] and Alzheimer’s ketimines are improved in the presence of AlMe3.[16] For
disease.[23]
this reason, AlMe3 was added to a THF solution of inter-
mediate 2a and the mixture was stirred for 15 min at room
temperature prior to the addition of aldimine (R)-9d at
–65 °C. Under these reaction conditions, amino alcohol de-
rivatives 10d and 11d were obtained with a higher diastereo-
selectivity (95:5 dr) but in a very low yield due to a poor
conversion (Table 1, entry 2). The yield increased to 42%
when the reaction was performed with the same additive at
–55 °C and the organolithium intermediate 2a was added
to a solution of aldimine (R)-3 and AlMe3 (an inverse ad-
dition), however, the diastereomeric ratio was in this case
69:31 (Table 1, entry 3). We recently found that dialkylzincs
do not react with N-tert-butylsulfinylimines, but the reac-
tion with triorganozincates gave the expected α-branched
sulfinamides in good-to-excellent yields with diastereomeric
Results and Discussion
Dianionic intermediate 2a was prepared by the treatment
of phthalan (1a) with an excess of lithium (1:10 molar ratio)
and a catalytic amount of DTBB (5 mol-%) in THF at 0 °C
for 40 min. After removing the excess lithium by filtration
at room temperature, a THF solution of the chiral aldimine
(R)-9d [easily prepared from benzaldehyde and (R)-tert-
butylsulfinamide][24] was added to the resulting solution of
the functionalised organolithium compound 2a at –78 °C
and the reaction mixture was allowed to warm to room
temperature over 12 h. Final hydrolysis led to a mixture of
the diastereomeric N-tert-butylsulfinylamino alcohols 10d
Table 1. Screening and optimisation of the reaction conditions for the reaction of oranolithium 2a and aldimine (R)-9d.[a]
Conditions
T [°C] (time [h])
Product
Entry
Additive (1.1 equiv.)
Hydrolysis temp. [°C]
Yield [%][b]
10d/11d[c]
1
2
3
4
5
6
7
–
–78 to 20 (12)
–65 (12)
–55 (12)
–65 (12)
–30 (12)
–5 (12)
–78 to 20
–65 to 20
–55 to 20
–65 to 20
–30 to 20
–5 to 20
47
25
42
78
69
78:22
95:5
69:31
86:14
83:17
67:33
63:37
AlMe3
AlMe3
ZnMe2
ZnMe2
ZnMe2
ZnEt2
61
–65 (12)
–65 to 20
27[d]
[a] Intermediate 2a was prepared from phthalan (1a; 3 equiv.). [b] Yield of the major reaction product 10d based on the starting aldimine
(R)-9d. [c] The diastereomeric mixture was determined by 1H NMR analysis of the crude reaction mixture. [d] Sulfinamide 12 was
obtained in 37% yield.
2894
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2893–2903

Reductive Ring-Opening of Phthalan and Isochroman
ratios of up to 98:2.[25] Thus, when ZnMe2 was used as an
additive, the reaction of the resulting mixed organozincate
with aldimine (R)-9d at –65 °C for 12 h gave, after hydroly-
sis, the expected mixture of amino alcohols 10d and 11d in
78% yield and 86:14 ratio (Table 1, entry 4). The yields and
stereoselectivities were lower when the process was per-
formed with the same additive at –30 and –5 °C (Table 1,
entries 5 and 6). A mixture of the expected compounds 10d
and 11d and the sulfinamide 12 (Figure 1) was also ob-
tained when ZnEt2 was used instead of ZnMe2. Compound
12 results from the addition of the ethyl group to the imine
(Table 1, entry 7). For the resulting mixed zincate, in this
case there is competition between the benzyl and ethyl
groups to be transferred because both are transferable.
However, in the case of ZnMe2, and due to the slow transfer
rate of the methyl group, it can be used as a non-transfera-
ble group in these processes. The stereochemistry of the
major isomer 10d was unambiguously determined by single-
crystal X-ray analysis and the structure obtained showed
that the configuration of the new stereogenic centre was R
(Figure 1). This result is consistent with an approach of the
nucleophile to the less hindered re face of C=N in a s-cis-
like conformation. Theoretical calculations[26] support the
view that it is the most stable conformation of the two-fold
Figure 1. Structure of compound 12, the most stable conformation
of (R)-9d and X-ray crystal structure of 10d.
Lewis acid (there is a large excess of lithium cations and easily removed from compounds 10 and 13 after treatment
organozinc compounds) coordinated (R)-sulfinyl aldimine with a 4  HCl/dioxane solution in methanol to give amino
(Figure 1).
alcohols of general structure 14 and 15 (Figure 2) in almost
The dianionic intermediate 2a was then treated with dif- quantitative yields for the phthalan (1a) and isochroman
ferent chiral N-sulfinyl aldimines 9 under the optimised (1b) derivatives, respectively. Under these acidic reaction
conditions (Table 1, entry 4). Compounds 10 were obtained conditions, the tetrahydropyranyl group was also removed
in good-to-moderate yields (Scheme 2, Table 2, entries 1– and amino diols 16, 17 and 18 (Figure 2) were obtained
10) and diastereomeric ratios ranging between 71:29 and from compounds 10f, 10g and 13f, respectively (Table 2, en-
87:13 (Table 2, entries 9 and 3, respectively). The major dia- tries 6, 7 and 16, respectively). The successive treatment of
stereomers were easily isolated after column chromatog- amino alcohols 14–18 with thionyl chloride in chloroform
raphy and fully characterised in all cases. Aiming to at 50 °C and then with a 5  aqueous solution of sodium
broaden the scope of this tandem reductive ring-opening hydroxide in THF at room temperature led to nitrogen-con-
lithiation–transmetallation reaction with chiral N-tert- taining heterocycles through an intramolecular dehydration
butylsulfinyl aldimines 9, we studied the process with iso- process (Scheme 2 and Table 2).[27] In this way, tetrahydro-
chroman (1b). Under the same reaction conditions, the ex- isoquinolines 19 were prepared in situ from amino alcohols
pected N-tert-butylsulfinylamino alcohol derivatives 13 14 (Table 2, entries 1–5 and 8–10), whereas the homologous
were generally obtained in fairly good yields (Scheme 2, amino alcohols 15 led to tetrahydrobenzazepines 20
Table 2, entries 11–17). In all cases we assume that the nu- (Table 2, entries 11–15 and 17). Interestingly, amino diols
cleophilic attack occurs predominantly on the re face of the 16–18 underwent a double dehydration reaction leading to
imine unit with RS isomers (Table 2, entries 1–7 and 11–16) benzoindolizidine 21, benzoquinolizidine 22 and benzopyr-
and on the si face in the case of SS derivatives (Table 2, roloazepine 23, respectively (Table 2, entries 6, 7, and 16,
entries 8–10 and 17), which are the less hindered faces of respectively). The ee values of the heterocycles 19–23 were
the imines according to the most stable proposed s-cis con- determined by chiral HPLC analysis and in all cases were
formation (Figure 1). The tert-butylsulfinyl group was obtained with a purity in excess of 95%.
Scheme 2. Reagents and conditions: (i) Li, DTBB (5 mol-%), THF, 0 °C, 40 min; (ii) filtration; (iii) ZnMe2, 20 °C, 15 min; (iv)
RCH=NS(O)tBu (9), –65 °C, 12 h; (v) H2O, –65 to 20 °C; (vi) 4  HCl/dioxane, MeOH, 20 °C; (vii) Cl2SO, CHCl3, 50 °C; (viii) 5 
NaOH/H2O, THF, 20 °C.
Eur. J. Org. Chem. 2010, 2893–2903
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2895

D. García, F. Foubelo, M. Yus
FULL PAPER
Table 2. Preparation of nitrogen-containing heterocycles 19–23.
[a] Products 10, 13 and 19–23 were Ն95% pure (GLC and 300 MHz 1H NMR). [b] ee Ն 95%, as determined by HPLC using a ChiralCel
OJ column. [c] Isolated yield of the major diastereoisomer based on the starting aldimine 9. [d] Diastereomeric ratio was determined by
1H NMR analysis of the crude reaction mixture. [e] Isolated yield from compounds 10 and 13. [f] The reaction was performed in the
absence of ZnMe2 as additive.
2896
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2893–2903

Reductive Ring-Opening of Phthalan and Isochroman
Tdetector = 300 °C, Tcolumn = 60 °C (3 min) and 60–270 °C (15 °C/
min), and P = 40 kPa as routine working conditions. 1H NMR
spectra were recorded with a Bruker AC-300 spectrometer using
CDCl3 as the solvent and TMS as the internal standard. The data
is reported as s = singlet, d = doublet, t = triplet, q = quartet, m
= multiplet or unresolved, br. s = broad signal, coupling con-
stant(s) in Hz, integration. 13C NMR spectra were recorded with
proton-decoupling with
a Bruker 75 MHz spectrometer and
DEPT-135 experiments were performed to assign CH, CH2 and
CH3. Optical rotations were measured with a Perkin–Elmer 341
polarimeter (concentration is given in g/100 mL, solvent). HRMS
(EI) were recorded with a Finnigan MAT 95S spectrometer.
Typical Procedure for the Diastereoselective Synthesis of Compounds
10 and 13: A solution of phthalan (1a, 360 mg, 3.0 mmol) or isoch-
roman (1b, 402 mg, 3.0 mmol) was added dropwise to a blue sus-
pension of lithium powder (140 mg, 20.0 mmol) and a catalytic
amount of DTBB (80.0 mg, 0.3 mmol) in THF (5 mL) under argon
and the mixture was stirred at 0 °C for 45 min. Then the excess
lithium was filtered off (by cannula under argon and used a filter
plate) and a solution of ZnMe2 (3.0 mL, 1.0  in hexane) was
added dropwise. Stirring was continued for 15 min at room tem-
perature. After that, the reaction mixture was cooled to –65 °C and
a solution of the corresponding aldimine 9 (1.0 mmol) in THF
(0.4 mL) was added dropwise. After 12 h at the same temperature,
the reaction mixture was finally hydrolysed with water (5 mL), ex-
tracted with ethyl acetate (3ϫ15 mL) once at room temp., dried
with anhydrous MgSO4 and evaporated (15 Torr). The residue was
purified by column chromatography (silica gel, hexane/ethyl acet-
ate) to yield pure products 10 and 13.
Figure 2. Structures of amino alcohols 14–18.
Conclusions
We have reported herein a straightforward synthesis of
substituted tetrahydroisoquinolines 19, tetrahydrobenz-
azepines 20, benzoindolizidine 21, benzoquinolizidine 22
and benzopyrroloazepine 23 with high enantiomeric purity
starting from phthalan (1a) or isochroman (1b) and chiral
N-tert-butylsulfinyl aldimines 9 by a strategy of two one-
pot processes: 1) reaction of the dianionic intermediate 2
(resulting from reductive ring-opening of the corresponding
heterocycle 1) with chiral aldimines 9 in the presence of
ZnMe2 and 2) cyclisation of the amino alcohol resulting (2S,RS)-N-(tert-Butylsulfinyl)-1-[2-(hydroxymethyl)phenyl]decan-2-
amine (10a): Yellow oil; Rf = 0.21 (hexane/EtOAc, 1:1). [α]2D0 = +14
from the removal of the tert-butylsulfinyl unit. The configu-
(c = 0.84, CH Cl ). IR (film): ν = 3315, 3063, 3014, 2959, 2924,
˜
2
2
rations of the chiral heterocycles were determined from
those of the starting chiral aldimines 9 and thus both enan-
tiomeric heterocycles are accessible through this methodol-
ogy by choosing the appropriate starting chiral aldimine 9.
1
2849 cm–1. H NMR: δ = 0.88 (t, J = 7.0 Hz, 3 H), 0.92 (s, 9 H),
1.23–1.39 (m, 10 H), 1.41–1.49 (m, 2 H), 1.62–1.72 (m, 1 H), 1.77–
1.84 (m, 2 H), 2.85–2.89 (m, 2 H), 3.44 (br. s, 1 H), 4.25–4.46 (br.
s, 2 H), 4.49 (d, J = 11.6 Hz, 1 H), 4.72 (d, J = 11.6 Hz, 1 H), 7.17–
7.34 (m, 4 H) ppm. 13C NMR: δ = 14.2, 22.5 (CH3), 22.7, 26.2,
29.4, 29.7, 29.8, 32.0, 37.8, 37.9 (CH2), 56.3 (C), 59.0 (CH), 63.0
(CH2), 126.5, 128.0, 129.7, 129.9, 138.3, 139.1 (ArC) ppm. MS: m/z
(%) = 311 (2) [M – C4H8]+, 293 (15), 244 (35), 190 (10), 142 (10),
133 (11), 132 (100), 119 (10), 117 (10), 104 (23), 91 (13), 57 (13).
HRMS: calcd. C17H29NSO2 [M – C4H8]+ 311.1919; found
311.1913.
Experimental Section
General: All reactions requiring anhydrous conditions were per-
formed in oven-dried glassware under argon. Unless otherwise indi-
cated, all commercially available chemicals were purchased from
Acros or Aldrich and used without purification. N-tert-Butanesulf-
inamides (SS and RS) were a gift from Medalchemy (Ͼ99% ee by
chiral HPLC on a Chiracel AS column, 90:10 n-hexane/iPrOH,
1.2 mL/min, λ = 222 nm). N-tert-Butanesulfinylimines were pre-
pared from freshly distilled aldehydes and N-tert-butanesulfinam-
ides (SS and RS, Ͼ99% ee) following a previously reported pro-
cedure with CuSO4.[28] TLC was performed on Merck silica gel 60
F254 using aluminium plates and visualised with phosphomolybdic
acid (PMA) stain. Chromatographic purification was performed by
flash chromatography using Merck silica gel 60 (0.040–0.063 mm)
and n-hexane/EtOAc as eluent.
(2R,RS)-N-(tert-Butylsulfinyl)-1-[2-(hydroxymethyl)phenyl]-3-meth-
ylbutan-2-amine (10b): White solid; m.p. 87–88 °C (pentane/dichlo-
romethane); Rf = 0.20 (hexane/EtOAc, 1:2). [α]2D0 = +33 (c = 0.57,
CH2Cl2). IR (KBr): ν˜ = 3258, 3069, 3020, 2955, 2916, 2872 cm–1.
1H NMR: δ = 0.86 (s, 9 H), 1.09 (t, J = 7.0 Hz, 6 H), 2.12–2.16
(m, 1 H), 2.77–2.90 (m, 2 H), 3.34–3.39 (m, 1 H), 4.54 (d, J =
11.3 Hz, 1 H), 4.71 (d, J = 6.8 Hz, 1 H), 4.78 (d, J = 11.3 Hz, 1
H), 7.14–7.22 (m, 3 H), 7.27–7.30 (m, 1 H) ppm. 13C NMR: δ =
17.4, 18.9, 22.5 (CH3), 32.7, 33.3 (CH2), 56.4 (C), 63.1 (CH), 64.1
(CH2), 126.4, 128.1, 2ϫ129.8, 138.7, 139.0 (ArC) ppm. MS: m/z
(%) = 241 (6) [M – C4H8]+, 223 (29), 174 (47), 133 (18), 132 (100),
120 (14), 117 (18), 105 (10), 104 (16), 91 (15), 57 (20). HRMS:
calcd. for C12H19NO2S [M – C4H8]+ 241.1136; found 241.1137.
IR spectra were recorded (film) with a Nicolet Impact 510 P-FT
spectrometer. Melting points were measured with an OptiMelt
(Stanford Research Systems) apparatus using open-glass capillaries.
HPLC analyses were performed on a JASCO 200-series instrument
equipped with a Chiralcel-OJ column. Gas chromatographic analy-
ses (GLC) were determined with a Hewlett–Packard HP-5890 in-
strument equipped with a flame-ionisation detector (FID) and a
12 m capillary column (0.2 mm diameter, 0.33 µm film thickness)
using nitrogen (2 mL/min) as a carrier gas with Tinjector = 275 °C,
(2S,RS)-N-(tert-Butylsulfinyl)-1-[2-(hydroxymethyl)phenyl]-4-phen-
ylbutan-2-amine (10c): White solid; m.p. 85–86 °C (pentane/dichlo-
romethane); Rf = 0.19 (hexane/EtOAc, 1:2). [α]2D0 = –8 (c = 0.61,
CH Cl ). IR (KBr): ν = 3261, 3060, 3025, 2925, 2865 cm–1. 1H
˜
2
2
NMR: δ = 0.97 (s, 9 H), 2.00–2.10 (m, 2 H), 2.12–2.22 (m, 2 H),
2.79–2.96 (m, 3 H), 2.99–3.04 (m, 1 H), 3.50–3.57 (m, 1 H), 3.92
Eur. J. Org. Chem. 2010, 2893–2903
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2897

D. García, F. Foubelo, M. Yus
FULL PAPER
(br. s, 1 H), 4.27 (d, J = 6.1 Hz, 1 H), 4.51 (d, J = 11.6 Hz, 1 H),
4.75 (d, J = 11.6 Hz, 1 H), 7.17–7.32 (m, 9 H) ppm. 13C NMR: δ
= 22.5 (CH3), 32.0, 37.6, 39.1 (CH2), 56.3 (C), 58.4 (CH), 63.0
(CH2), 126.0, 126.4, 128.0, 128.5, 128.6, 129.6, 129.8, 138.1, 139.0,
141.7 (ArC) ppm. MS: m/z (%) = 303 (8) [M – C4H8]+, 286 (10),
285 (51), 238 (12), 237 (25), 236 (74), 164 (10), 133 (20), 132 (100),
131 (10), 117 (35), 105 (14), 104 (13), 91 (79), 77 (12), 57 (22).
HRMS: calcd. for C21H29NO2S 359.1919 [M]+; found 359.1909.
7.33 (m, 1 H) ppm. 13C NMR: δ = 19.7, 19.8 (CH2), 22.5 (CH3),
26.2, 26.3, 30.7, 30.8, 33.6, 33.7 (CH2), 38.2, 38.3 (CH2), 56.2 (C),
58.4, 58.5 (CH), 62.4, 62.5, 63.0, 67.3, 67.4 (CH2), 99.0 (CH), 126.6,
128.0, 129.8, 130.0, 137.8, 139.2 (ArC) ppm. MS: m/z (%) = 341
(1) [M – C4H8]+, 257 (28), 239 (16), 192 (16), 191 (16), 190 (19),
172 (15), 132 (29), 122 (11), 118 (14), 85 (100), 57 (24). HRMS:
calcd. for C17H27NSO4 [M – C4H8]+ 341.1655; found 341.1640.
(2S,RS)-N-(tert-Butylsulfinyl)-1-[2-(hydroxymethyl)phenyl]-6-(tetra-
hydro-2H-pyran-2-yloxy)hexan-2-amine (10g): Colourless oil; Rf =
(1R,RS)-N-(tert-Butylsulfinyl)-2-[2-(hydroxymethyl)phenyl]-1-phen-
ylethanamine (10d): White solid; m.p. 129–130 °C (pentane/dichlo-
romethane); Rf = 0.20 (hexane/EtOAc, 1:2). [α]2D0 = –40 (c = 0.16,
0.14 (hexane/EtOAc, 1:6). [α]2D0 = +10.5 (c = 0.95, CH2Cl2). IR
1
(film): ν = 3400, 3063, 2941, 2866, 1033 cm–1. H NMR: δ = 0.94
˜
CH Cl ). IR (KBr): ν = 3450–3310, 2920 cm–1. 1H NMR: δ = 1.00
˜
(s, 9 H), 1.14–1.86 (m, 12 H), 2.88–2.99 (m, 2 H), 3.41–3.50 (m, 3
H), 3.76–3.88 (m, 2 H), 4.39 (br. s, 1 H), 4.52–4.57 (m, 3 H), 4.78
(d, J = 11.4 Hz, 1 H), 7.16–7.23 (m, 3 H), 7.31 (d, J = 7.3 Hz, 1
H) ppm. 13C NMR: δ = 19.7 (CH2), 22.4 (CH3), 22.8, 25.4, 29.7,
30.7, 37.9, 38.0 (CH2), 56.1 (C), 58.6 (CH), 62.4, 62.9, 67.3 (CH2),
98.9 (CH), 126.4, 127.9, 129.6, 129.8, 137.9, 139.1 (ArC) ppm. MS:
m/z (%) = 271 (27) [M – C4H8 – C5H8O]+, 253 (20), 206 (12), 205
(17), 204 (22), 132 (50), 85 (100), 57 (17). HRMS: calcd. for
C13H21NSO3 [M – C4H8 – C5H8O]+ 271.1242; found 271.1226.
2
2
(s, 9 H), 3.02 (dd, J = 13.6, 6.3 Hz, 1 H), 3.43 (dd, J = 13.6, 8.7 Hz,
1 H), 4.22 (br. s, 1 H), 4.48 (d, J = 11.5 Hz, 1 H), 4.59–4.65 (m, 1
H), 4.72 (d, J = 11.5 Hz, 1 H), 5.11 (br. s, 1 H), 7.10–7.15 (m, 1
H), 7.16–7.24 (m, 2 H), 7.23–7.32 (m, 4 H), 7.41 (d, J = 7.2 Hz, 2
H) ppm. 13C NMR: δ = 22.5 (CH3), 40.2 (CH2), 56.3 (C), 60.9
(CH2), 63.0 (CH), 126.8, 127.2, 127.8, 127.9, 128.5, 129.6, 130.3,
136.7, 139.0, 142.5 (ArC) ppm. MS (MALDI-TOF): m/z = 332 [M
+ H]+. HRMS: calcd. for C19H23NOS [M – H2O]+ 313.1500; found
313.1487.
(2R,SR)-N-(tert-Butylsulfinyl)-1-(2-hydroxymethylphenyl)decan-2-
amine (ent-10a): The physical and spectroscopic data were found
to be same as for 10a. [α]2D0 = –15 (c = 0.79, CH2Cl2).
Crystal Data of 10d: C19H25NO2S, M = 331.46, monoclinic, a =
10.3893(9), b = 18.4104(16), c = 10.3906(9) Å, β = 106.513(2)°, V
= 1905.5(3) Å3, space group P2(1), Z = 4, Dc = 1.155 Mg/m3; λ =
0.71073 Å, µ = 0.179 mm–1, F(000) = 712, T = 23Ϯ1 °C. Data
collection was performed with a Bruker Smart CCD diffractometer
based on three ω scans (starting = –34°) at φ = 0, 120 and 240°
with the detector at 2θ = –32°. For each of these runs, 606 frames
were collected at 0.3° intervals and 30 s per frame. An additional
run at φ = 0° of 100 frames was collected to improve redundancy.
The diffraction frames were integrated by using the program
SAINT[29] and the integrated intensities were corrected for Lorentz/
polarisation effects with SADABS.[30] The structure was solved by
direct methods[31] and refined to all 7474 unique Fo by full-matrix
least-squares.[31] All the hydrogen atoms were placed at idealised
positions and refined as rigid atoms. Final wR2 = 0.1176 for all
data and 429 parameters, R1 = 0.0454 for 6318 FoϾ4σ(Fo).
(2S,SR)-N-(tert-Butylsulfinyl)-1-[2-(hydroxymethyl)phenyl]-3-meth-
ylbutan-2-amine (ent-10b): The physical and spectroscopic data
were found to be same as for 10b. [α]2D0 = –45 (c = 0.57, CH2Cl2).
(1S,SR)-N-(tert-Butylsulfinyl)-2-[2-(hydroxymethyl)phen-
yl]-1-phenylethanamine (ent-10d): Physical and spectroscopic data
were found to be same than for 10d. [α]2D2 = +34 (c = 0.67, CH2Cl2).
(1S,RS)-N-(tert-Butylsulfinyl)-2-[2-(hydroxymethyl)phenyl]-1-phen-
ylethanamine (11d): M.p. 127–128 °C (pentane/dichloromethane);
Rf = 0.14 (hexane/EtOAc, 1:2). [α]2D0 = –38 (c = 0.48, CH2Cl2). IR
(KBr): ν = 3430–3300, 2923 cm–1. 1H NMR: δ = 1.10 (s, 9 H), 3.12
˜
(dd, J = 11.8, 5.3 Hz, 1 H), 3.20 (dd, J = 11.8, 6.3 Hz, 1 H), 3.70
(br. s, 1 H), 4.10–4.16 (m, 1 H), 4.62–4.71 (m, 3 H), 7.11–7.16 (m,
1 H), 7.26–7.34 (m, 8 H) ppm. 13C NMR: δ = 22.7 (CH3), 42.1
(CH2), 56.0 (C), 60.8 (CH2), 63.3 (CH), 127.3, 127.5, 127.8, 128.5,
128.7, 130.2, 130.8, 136.2, 139.6, 142.6 (ArC) ppm. MS (MALDI-
TOF): m/z = 332 [M + H]+.
CCDC-727086 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.
(2S,RS)-N-(tert-Butylsulfinyl)-1-[2-(2-hydroxyethyl)phenyl]decan-2-
amine (13a): Colourless oil; Rf = 0.34 (hexane/EtOAc, 1:2). [α]2D0
=
(1R,RS)-N-(tert-Butylsulfinyl)-2-[2-(hydroxymethyl)phenyl]-1-(4-
methoxyphenyl)ethanamine (10e): Yellow oil; Rf = 0.14 (hexane/
–13 (c = 1.32, CH Cl ). IR (film): ν = 3359, 3069, 3020, 2926,
˜
2
2
1
2854 cm–1. H NMR: δ = 0.87 (t, J = 6.9 Hz, 3 H), 1.04 (s, 9 H),
1.23–1.33 (m, 13 H), 1.41–1.45 (m, 1 H), 1.57–1.68 (m, 1 H), 2.87–
2.93 (m, 4 H), 3.42 (q, J = 6.5 Hz, 1 H), 3.55 (d, J = 6.0 Hz, 1 H),
3.74–3.81 (m, 2 H), 7.16–7.30 (m, 4 H) ppm. 13C NMR: δ = 14.1
(CH3), 21.0 (CH2), 22.5 (CH3), 25.9, 29.3, 29.4, 29.5, 31.8, 35.2,
35.8, 36.0, 39.1 (CH2), 55.8 (C), 58.0 (CH), 63.2 (CH2), 126.3,
126.5, 129.9, 130.6, 138.3, 139.4 (ArC) ppm. HRMS: calcd. for
C22H40NO2S [M + H]+ 382.277; found 382.276.
EtOAc, 1:2). [α]2D0 = –36 (c = 0.90, CH Cl ). IR (film): ν = 3316,
˜
2
2
3057, 2965, 2861, 2834 cm–1. 1H NMR: δ = 1.00 (s, 9 H), 2.99 (dd,
J = 7.3, 6.3 Hz, 1 H), 3.42 (dd, J = 8.6, 5.0 Hz, 1 H), 3.74 (s, 3 H),
4.47 (br. s, 1 H), 4.49 (d, J = 11.4 Hz, 1 H), 4.51–4.58 (m, 1 H),
4.78 (d, J = 11.4 Hz, 1 H), 5.08 (br. s, 1 H), 6.83 (d, J = 8.8 Hz, 1
H), 7.10–7.20 (m, 3 H), 7.26–7.35 (m, 3 H) ppm. 13C NMR: δ =
22.6 (CH3), 40.5 (CH2), 55.3 (CH3), 56.4 (C), 61.0 (CH), 63.1
(CH2), 113.9, 126.8, 128.0, 128.4, 129.8, 130.2, 135.1, 137.3, 139.1,
159.1 (ArC) ppm. MS: m/z (%)= 343 (3) [M – H2O]+, 241 (27), 240
(34), 224 (21), 223 (100), 184 (44), 166 (10), 136 (18), 135 (23), 134
(20), 121 (16), 115 (10), 57 (12). HRMS: calcd. for C16H17O2 [M –
C4H9SONH]+ 241.1223; found 241.1216.
(2R,RS)-N-(tert-Butylsulfinyl)-1-[2-(2-hydroxyethyl)phenyl]-3-meth-
ylbutan-2-amine (13b): Pale-yellow oil; Rf = 0.17 (hexane/EtOAc,
1:2). [α]2D0 = –10 (c = 1.1, CH Cl ). IR (film): ν = 3346, 3057, 3020,
˜
2
2
2957, 2861 cm–1. 1H NMR: δ = 1.00–1.04 (m, 15 H), 2.05–2.07 (m,
1 H), 2.81 (d, J = 7.0 Hz, 2 H), 2.89 (d, J = 7.0 Hz, 2 H), 3.39–
3.42 (m, 1 H), 3.76–3.87 (m, 3 H), 7.13–7.27 (m, 4 H) ppm. 13C
NMR: δ = 17.9, 18.4, 22.5 (CH3), 32.0 (CH), 34.8, 36.0 (CH2), 56.1
(C), 62.9 (CH), 63.4 (CH2), 126.4, 126.7, 127.2, 130.1, 130.8, 137.2,
(2S,RS)-N-(tert-Butylsulfinyl)-1-[2-(hydroxymethyl)phenyl]-5-(tetra-
hydro-2H-pyran-2-yloxy)pentan-2-amine (10f): Colourless oil; Rf =
0.10 (hexane/EtOAc, 1:5). [α]2D0 = –1.5 (c = 1.21, CH2Cl2). IR (film):
1
ν = 3359, 3238, 3039, 2950, 2868, 1034 cm–1. H NMR: δ = 0.97
˜
(s, 9 H), 1.50–1.59 (m, 4 H), 1.70–1.86 (m, 6 H), 2.84–3.03 (m, 2 137.5 (ArC) ppm. MS: m/z (%) = 255 (68) [M – C4H8]+, 176 (17),
H), 3.41–3.57 (m, 3 H), 3.79–3.87 (m, 2 H), 4.26 (br. s, 1 H), 4.54–
147 (16), 173 (100), 166 (12), 151 (14), 135 (37), 133 (54), 131 (16),
4.58 (m, 2 H), 4.78 (d, J = 11.6 Hz, 1 H), 7.17–7.23 (m, 3 H), 7.29– 120 (81), 119 (27), 118 (16), 117 (57), 115 (22), 105 (28), 104 (15),
2898
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2893–2903

Reductive Ring-Opening of Phthalan and Isochroman
104 (15), 103 (12), 91 (26), 77 (11), 72 (43), 57 (37), 56 (13), 41
HCl (1 mL) solution in dioxane was added to a stirred solution of
(13). HRMS: calcd. for C13H21NO2S [M – C4H8]+ 255.1293; found the corresponding N-tert-butylsulfinylamino alcohol derivative 10
255.1287.
or 13 (0.50 mmol) in MeOH (6 mL) at 0 °C. After stirring for 3 h
at this temperature, a saturated NaHCO3 solution was added. The
reaction mixture was extracted with ethyl acetate (3ϫ10 mL), dried
with anhydrous MgSO4 and evaporated (15 Torr) to yield the corre-
sponding amino alcohol 14–18 which was pure enough for the next
step. The residue was taken up in chloroform (5 mL) and thionyl
chloride (0.1 mL, 1.7 mmol) was added at 0 °C. The solution was
stirred at 50 °C for 4 h. After that, the solvents were evaporated
(15 Torr) and the resulting residue was dissolved in THF (5 mL)
and a 5  sodium hydroxide solution (10 mL) was added. The re-
sulting mixture was vigorously stirred for 10 h at 20 °C and then it
was extracted with ethyl acetate (3ϫ15 mL), dried with anhydrous
MgSO4 and evaporated (15 Torr). The residue was purified by col-
umn chromatography (silica gel, chloroform/methanol) to yield
pure heterocycles 19–23.
(2S,RS)-N-(tert-Butylsulfinyl)-1-[2-(2-hydroxyethyl)phenyl]-4-phen-
ylbutan-2-amine (13c): Colourless oil; Rf = 0.11 (hexane/EtOAc,
1:2). [α]2D0 = –33 (c = 0.54, CH Cl ). IR (film): ν = 3345, 3057,
˜
2
2
3010, 2953, 2910, 2855 cm–1. 1H NMR: δ = 1.02 (s, 9 H), 1.95–2.05
(m, 2 H), 2.70–2.85 (m, 5 H), 2.92–2.97 (m, 1 H), 3.44–3.49 (m, 1
H), 3.56 (br. s, 1 H), 3.69–3.81 (m, 2 H), 7.10–7.17 (m, 7 H), 7.23–
7.26 (m, 2 H) ppm. 13C NMR: δ = 22.5 (CH3), 32.0, 36.0, 37.0,
39.2 (CH2), 55.9 (C), 57.5 (CH), 63.2 (CH2), 126.0, 126.3, 126.6,
128.4, 130.0, 130.6, 136.9, 137.2, 141.3 (ArC) ppm. MS: m/z (%) =
317 (57) [M – C4H8]+, 238 (12), 235 (22), 182 (19), 167 (13), 166
(11), 164 (31), 157 (11), 151 (24), 149 (17), 135 (14), 134 (37), 133
(89), 132 (16), 131 (50), 129 (14), 119 (17), 118 (23), 117 (96), 106
(13), 105 (58), 104 (12), 103 (15), 91 (100), 79 (11), 77 (15), 57
(31). HRMS: calcd. for C18H23NO2S [M – C4H8]+ 317.1449; found
317.1444.
(S)-1-(2-Hydroxymethylphenyl)decan-2-amine (14a): Yellow oil; Rf
= 0.41 (chloroform/methanol, 5:1). IR (film): ν = 3413, 3063, 3002,
˜
(1R,RS)-N-(tert-Butylsulfinyl)-2-[2-(2-hydroxyethyl)phenyl]-1-phen-
ylethanamine (13d): White foam; Rf = 0.14 (hexane/EtOAc, 1:2).
2924, 2853 cm–1. 1H NMR: δ = 0.89 (t, J = 6.7 Hz, 3 H), 1.17–1.48
(m, 13 H), 1.52–1.59 (m, 1 H), 2.64 (dd, J = 9.7, 3.5 Hz, 1 H), 2.80
(dd, J = 9.7, 3.5 Hz, 1 H), 2.90–3.18 (br. s, 4 H), 4.39 (d, J =
11.5 Hz, 1 H), 4.76 (d, J = 11.5 Hz, 1 H), 7.17–7.34 (m, 4 H) ppm.
13C NMR: δ = 14.2 (CH3), 22.7, 26.4, 29.3, 29.6, 29.7, 32.0, 38.4,
40.1 (CH2), 52.1 (CH), 68.1 (CH2), 126.6, 128.2, 130.1, 130.3,
138.6, 140.5 (ArC) ppm. MS: m/z (%) = 245 (2) [M – H2O]+, 133
(11), 132 (100), 130 (13), 104 (11). HRMS: calcd. for C17H27N
[M]+ 245.2143; found 245.2135. [α]2D0 = +14.5 (c = 1.00, CH2Cl2).
[α]2D0 = –74 (c = 0.97, CH Cl ). IR (KBr): ν = 3331, 3068, 3015,
˜
2
2
2925, 2872 cm–1. 1H NMR: δ = 1.12 (s, 9 H), 2.82 (dt, J = 7.0,
2.0 Hz, 2 H), 2.91 (dd, J = 8.2, 5.5 Hz, 1 H), 3.46 (dd, J = 7.3,
6.0 Hz, 1 H), 3.52 (br. s, 1 H), 3.70–3.82 (m, 2 H), 3.94 (br. s, 1 H),
4.52–4.57 (m, 1 H), 6.81 (d, J = 7.3 Hz, 1 H), 6.96–6.98 (m, 1 H),
7.10–7.27 (m, 7 H) ppm. 13C NMR: δ = 22.6 (CH3), 35.8, 40.4
(CH2), 56.0 (C), 60.2 (CH), 63.4 (CH2), 126.1, 126.8, 127.3, 127.9,
128.5, 129.8, 130.8, 135.9, 137.4, 141.9 (ArC) ppm. HRMS: calcd.
for C20H25NOS [M – H2O]+ 327.1657; found 327.1660.
(R)-1-[2-(hydroxymethyl)phenyl]-3-methylbutan-2-amine (14b): Yel-
(1R,RS)-N-(tert-Butylsulfinyl)-2-[2-(2-hydroxyethyl)phenyl]-1-(4- low oil; Rf = 0.27 (chloroform/methanol, 7:1). [α]2D0 = +26 (c = 0.54,
methoxyphenyl)ethanamine (13e): Yellow oil; Rf = 0.16 (hexane/
CH Cl ). IR (film): ν = 3372, 3027, 2957, 2930, 2871 cm–1. 1H
˜
2 2
EtOAc, 1:2). [α]2D0 = –60 (c = 0.88, CH Cl ). IR (film): ν = 3354,
NMR: δ = 1.02 (t, J = 6.5 Hz, 6 H), 1.77–1.81 (m, 1 H), 2.63–2.77
(m, 3 H), 2.90 (br. s, 2 H), 3.71–3.77 (m, 1 H), 4.35 (d, J = 11.7 Hz,
1 H), 4.80 (d, J = 11.7 Hz, 1 H), 7.10–7.29 (m, 3 H), 7.32 (d, J =
˜
2
2
3057, 3020, 2957, 2871 cm–1. 1H NMR: δ = 1.12 (s, 9 H), 2.82–2.91
(m, 4 H), 3.45 (dd, J = 7.5, 6.0 Hz, 1 H), 3.78 (br. s, 5 H), 3.88 (br.
s, 1 H), 4.47–4.52 (m, 1 H), 6.77–6.81 (m, 2 H), 6.98 (t, J = 7.3 Hz, 7.6 Hz, 1 H) ppm. 13C NMR: δ = 18.2, 19.0 (CH3), 34.4 (CH2),
1 H), 7.07–7.16 (m, 4 H) ppm. 13C NMR: δ = 22.5 (CH3), 35.8,
40.2 (CH2), 55.2 (CH3), 55.9 (C), 59.6 (CH), 63.3 (CH2), 113.8,
126.0, 126.7, 128.4, 129.8, 130.8, 133.9, 136.0, 137.3, 159.1
37.0, 57.9 (CH), 63.1 (CH2), 126.6, 128.4, 130.0, 130.4, 139.4, 140.5
(ArC) ppm. MS: m/z (%) = 174 (2) [M – H – H2O]+, 133 (11), 132
(100), 131 (10), 130 (38), 104 (11). HRMS: calcd. for C12H16N [M –
(ArC) ppm. MS: m/z (%) = 255 (70) [M – C4H9SONH]+, 240 (64), H2O]+ 174.1288; found 174.1290.
238 (22), 237 (100), 184 (93), 183 (11), 166 (17), 136 (14), 135 (65),
(S)-1-[2-(hydroxymethyl)phenyl]-4-phenylbutan-2-amine (14c): Pale-
134 (33), 133 (23), 129 (27), 121 (43), 119 (12), 115 (10), 105 (11),
91 (14), 57 (15). HRMS: calcd. for C21H29NO3S [M]+ 375.1831;
found 375.1831.
yellow oil; Rf = 0.41 (chloroform/methanol, 5:1). [α]2D0 = –2.5 (c =
0.75, CH Cl ). IR (film): ν = 3354, 3020, 2919, 2861 cm–1. 1H
˜
2
2
NMR: δ = 1.73–1.85 (m, 2 H), 1.89–2.01 (m, 2 H), 2.66–3.02 (m,
7 H), 3.59–3.65, 3.72–3.79 (2 m, 1 H), 4.40 (d, J = 11.7 Hz, 1 H),
4.76 (d, J = 11.7 Hz, 1 H), 7.14–7.34 (m, 9 H) ppm. 13C NMR: δ
= 32.8, 39.9, 40.0 (CH2), 51.6 (CH), 63.2 (CH2), 126.2, 126.8, 128.3,
128.4, 128.6, 130.1, 130.5, 138.3, 140.5, 141.5 (ArC) ppm. MS: m/z
(%) = 237 (3) [M – H2O]+, 133 (10), 132 (100), 130 (18), 104 (15),
91 (10). HRMS: calcd. for C17H19N [M – H2O]+ 237.1517; found
237.1508.
(2S,RS)-N-(tert-Butylsulfinyl)-1-[2-(2-hydroxyethyl)phenyl]-5-(tetra-
hydro-2H-pyran-2-yloxy)pentan-2-amine (13f): Colourless oil; Rf =
0.14 (hexane/EtOAc, 1:5). [α]2D0 = –12.5 (c = 1.89, CH2Cl2). IR
(film): ν = 3355, 3235, 3057, 3020, 2943, 2870, 1037 cm–1. 1H
˜
NMR: δ = 1.08 (s, 9 H), 1.42–1.58 (m, 4 H), 1.68–1.78 (m, 6 H),
2.79–3.05 (m, 5 H), 3.38–3.52 (m, 4 H), 3.74–3.88 (m, 4 H), 4.54
(m, 1 H), 7.14–7.19 (m, 4 H) ppm. 13C NMR: δ = 19.6, 19.7 (CH2),
22.6 (CH3), 25.5, 26.0, 26.1, 30.7, 32.3, 32.4, 36.1, 39.3 (CH2), 55.8
(C), 57.5, 57.6 (CH), 62.4, 62.5, 63.4, 67.1 (CH2), 98.9, 99.1 (CH),
126.4, 126.7, 130.0, 130.9, 137.2 (ArC) ppm. MS: m/z (%) = 355
(1) [M – C4H8]+, 272 (17), 271 (100), 192 (27), 189 (15), 136 (10),
133 (10), 118 (44), 117 (19), 85 (100), 70 (14), 57 (24). HRMS:
calcd. for C18H28NSO4 [M – C4H9]+ 354.1734; found 354.1784.
(R)-2-[2-(hydroxymethyl)phenyl]-1-phenylethanamine (14d): Pale-
yellow oil; Rf = 0.45 (chloroform/methanol, 7:1). [α]2D0 = +21 (c =
0.43, CH Cl ). IR (film): ν = 3400–3100, 3353, 3288, 3061 cm–1.
˜
2
2
1H NMR: δ = 2.92–3.09 (m, 2 H), 3.09 (br. s, 3 H), 4.14 (dd, J =
9.2, 4.6 Hz, 1 H), 4.44 (d, J = 11.7 Hz, 1 H), 4.84 (d, J = 11.7 Hz,
1 H), 7.10–7.41 (m, 9 H) ppm. 13C NMR: δ = 42.2 (CH2), 56.4
(CH), 63.0 (CH2), 126.0, 126.8, 127.4, 128.2, 128.6, 129.8, 130.2,
137.6, 140.4, 145.0 (ArC) ppm. MS: m/z (%) = 209 (39) [M – H2O]
+, 208 (29), 207 (26), 206 (26), 178 (10), 130 (18), 104 (100), 103
(32), 90 (16), 78 (21), 77 (17), 51 (10). HRMS: calcd. for C15H15N
[M – H2O]+ 209.1204; found 209.1215.
(1S,SS)-N-(tert-Butylsulfinyl)-2-[2-(2-hydroxyethyl)phenyl]-1-phenyl-
ethanamine (ent-13d): The physical and spectroscopic data were
found to be same as for 13d. [α]2D0 = +64 (c = 0.64, CH2Cl2).
Typical Procedure for the Stereoselective Synthesis of Heterocyclic
Compounds 19–23 via Intermediate Amino Alcohols 14–18: A 4 
Eur. J. Org. Chem. 2010, 2893–2903
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2899

D. García, F. Foubelo, M. Yus
FULL PAPER
(R)-2-[2-(hydroxymethyl)phenyl]-1-(4-methoxyphenyl)ethanamine (14e):
Orange oil; Rf = 0.45 (chloroform/methanol, 7:1). [α]2D0 = +21.5 (c
105 (18), 104 (22), 103 (15), 79 (15), 78 (10), 77 (16). HRMS: calcd.
for C16H14 [M – H2O – NH3]+ 206.1095; found 206.1078.
= 0.71, CH Cl ). IR (film): ν = 3352, 3063, 2956, 2924, 2855 cm–1.
˜
2
2
(R)-2-[2-(2-Hydroxyethyl)phenyl]-1-(4-methoxyphenyl)ethanamine
(15e): Yellow oil; Rf = 0.16 (chloroform/methanol, 7:1). [α]2D0 = –6.0
1H NMR: δ = 2.92–3.07 (m, 5 H), 3.80 (s, 3 H), 4.12 (dd, J = 9.3,
5.0 Hz, 1 H), 4.44 (d, J = 11.8 Hz, 1 H), 4.85 (d, J = 11.8 Hz, 1
H), 6.89 (d, J = 8.7 Hz, 2 H), 7.19–7.37 (m, 6 H) ppm. 13C NMR:
δ = 42.5 (CH2), 55.3 (CH3), 55.9 (CH), 63.2 (CH2), 114.1, 127.3,
128.4, 130.0, 130.4, 137.4, 137.9, 140.6, 135.1, 159.0 (ArC) ppm.
MS: m/z (%) = 239 (87) [M – H2O]+, 238 (62), 224 (17), 222 (10),
208 (12), 134 (26), 132 (10), 131 (13), 130 (18), 121 (23), 105 (19),
104 (100), 103 (27), 78 (23). HRMS: calcd. for C16H17NO [M –
H2O]+ 239.1310; found 239.1318.
(c = 0.73, CH Cl ). IR (film): ν = 3384, 3051, 2929, 2861 cm–1. 1H
˜
2
2
NMR: δ = 2.78–3.03 (m, 7 H), 3.66–3.74 (m, 1 H), 3.76 (s, 3 H),
3.80–3.85 (m, 1 H), 4.13–4.17 (m, 1 H), 6.84 (d, J = 8.6 Hz, 2 H),
7.11–7.18 (m, 4 H), 7.26 (d, J = 8.6 Hz, 2 H) ppm. 13C NMR: δ =
36.5, 42.1 (CH2), 55.2 (CH3), 56.5 (CH), 63.5 (CH2), 113.9, 126.5,
126.7, 127.5, 129.8, 130.4, 137.1, 137.4, 138.6 (ArC) ppm. MS: m/z
(%) = 165 (1) [M – PhOMe]+, 137 (10), 136 (100), 109 (10), 93 (10).
HRMS: calcd. for C10H13NO [M – PhOMe-H]+ 163.0992; found
163.0961.
(R)-1-(2-Hydroxymethylphenyl)decan-2-amine (ent-14a): The physi-
cal and spectroscopic data were found to be same as for 14a. [α]2D0
= –14 (c = 0.84, CH2Cl2).
(S)-2-[2-(2-Hydroxyethyl)phenyl]-1-phenylethanamine (ent-15d): The
physical and spectroscopic data were found to be same as for 15d.
[α]2D0 = +9 (c = 0.70, CH2Cl2).
(S)-1-[2-(hydroxymethyl)phenyl]-3-methylbutan-2-amine (ent-14b):
The physical and spectroscopic data were found to be same as for
14b. [α]2D0 = –25.5 (c = 1.10, CH2Cl2).
(S)-4-Amino-5-(2-hydroxymethylphenyl)pentan-1-ol (16): Yellow oil;
Rf = 0.18 (chloroform/methanol, 2:1). [α]2D0 = +13.5 (c = 0.52,
CH Cl ). IR (film): ν = 3354, 3045, 3008, 2928, 2855 cm–1. 1H
˜
2
2
(S)-[2-(hydroxymethyl)phenyl]-1-phenylethanamine (ent-14d): The
physical and spectroscopic data were found to be same as for 14d.
[α]2D0 = –20 (c = 0.54, CH2Cl2).
NMR: δ = 1.47–1.53 (m, 1 H), 1.62–1.79 (m, 3 H), 2.65 (dd, J =
9.5, 3.8 Hz, 1 H), 2.84 (dd, J = 9.5, 3.8 Hz, 1 H), 2.98 (m, 1 H),
3.20 (br. s, 4 H), 3.72–3.77 (m, 2 H), 4.45 (d, J = 11.9 Hz, 1 H),
4.72 (d, J = 11.9 Hz, 1 H), 7.16–7.24 (m, 2 H), 7.26 (t, J = 7.3 Hz,
1 H), 7.33 (d, J = 7.9 Hz, 1 H) ppm. 13C NMR: δ = 29.8, 35.2,
40.2 (CH2), 52.1 (CH), 62.4, 63.0 (CH2), 126.8, 128.2, 130.1, 130.2,
138.2, 140.1 (ArC) ppm. MS: m/z (%) = 192 (3) [M – OH]+, 149
(10), 132 (16), 130 (15), 104 (16), 91 (16), 88 (100), 77 (12), 71 (82),
70 (41), 43 (16). HRMS: calcd. for C12H15N [M – 2H2O]+ 173.1204;
found 173.1165.
(S)-1-[2-(2-Hydroxyethyl)phenyl]decan-2-amine (15a): Yellow oil; Rf
= 0.14 (chloroform/methanol, 7:1). [α]2D0 = +5.8 (c = 1.02, CH2Cl2).
IR (film): ν = 3356, 3069, 3020, 2925, 2849 cm–1. 1H NMR: δ =
˜
0.89 (t, J = 6.7 Hz, 3 H), 1.18–1.28 (m, 13 H), 1.47–1.51 (m, 1 H),
2.58–3.10 (m, 7 H), 3.68–3.71 (m, 1 H), 3.72–3.85 (m, 2 H), 7.14–
7.29 (m, 4 H) ppm. 13C NMR: δ = 14.2 (CH3), 22.7, 26.4, 29.4,
29.7, 31.9, 35.3, 36.6, 37.7, 39.9 (CH2), 52.5 (CH), 63.5 (CH2),
126.5, 126.7, 129.8, 130.4, 138.0, 138.6 (ArC) ppm. MS: m/z (%) =
258 (5) [M – H2O – H]+, 257 (30), 145 (12), 144 (100), 143 (10),
115 (10). HRMS: calcd. for C18H27N [M – H2O – 2H]+ 257.2143;
found 257.2143.
(S)-5-Amino-6-[2-(hydroxymethyl)phenyl]hexan-1-ol (17): Yellow
oil; Rf = 0.18 (chloroform/methanol, 10:1). [α]2D0 = +12.5 (c = 0.75,
1
CH Cl ). IR (film): ν = 3344, 3063, 3020, 2933 cm–1. H NMR: δ
˜
2
2
= 1.47–1.62 (m, 6 H), 2.66 (dd, J = 9.6, 3.7 Hz, 1 H), 2.83 (dd, J
= 13.4, 3.7 Hz, 1 H), 3.02 (br. s, 5 H), 3.64 (t, J = 6.0 Hz, 2 H),
4.41 (d, J = 11.8 Hz, 1 H), 4.75 (d, J = 11.8 Hz, 1 H), 7.17–7.31
(m, 3 H), 7.33 (d, J = 7.1 Hz, 1 H) ppm. 13C NMR: δ = 22.6, 32.6,
37.8, 40.0 (CH2), 52.1 (CH), 62.3, 63.1 (CH2), 126.8, 128.3, 130.1,
130.3, 138.4, 140.3 (ArC) ppm. MS: m/z (%) = 206 (2) [M – OH]+,
132 (16), 130 (10), 104 (16), 103 (11), 102 (100), 91 (12), 85 (72),
84 (15), 67 (14), 57 (11), 56 (12), 44 (16). HRMS: calcd. for
C13H17N [M – 2H2O]+ 187.1361; found 187.1363.
(2)-1-[2-(2-Hydroxyethyl)phenyl]-3-methylbutan-2-amine (15b): Yel-
low oil; Rf = 0.11 (chloroform/methanol, 10:1). [α]2D0 = –14.0 (c =
1
0.72, CH Cl ). IR (film): ν = 3357, 2947, 2861 cm–1. H NMR: δ
˜
2
2
= 0.98 (dd, J = 4.6, 2.2 Hz, 6 H), 1.65–1.73 (m, 1 H), 2.76–2.86
(m, 4 H), 3.58–3.79 (m, 2 H), 3.82–3.88 (m, 1 H), 7.13–7.23 (m, 4
H) ppm. 13C NMR: δ = 18.1, 19.2 (CH3), 34.5 (CH), 36.5, 36.6
(CH2), 58.0 (CH), 63.6 (CH2), 126.5, 126.6, 127.2, 129.8, 130.4,
138.4, 138.7 (ArC) ppm. MS: m/z (%) = 164 (8) [M – iPr]+, 119
(10), 118 (10), 91 (10), 72 (100), 55 (23). HRMS: calcd. for C13H21N
[M]+ 164.1070; found 164.1077.
(S)-4-Amino-5-[2-(2-hydroxyethyl)phenyl]pentan-1-ol (18): Yellow
oil; Rf = 0.18 (chloroform/methanol, 2:1). [α]2D0 = +9 (c = 0.61,
CH Cl ). IR (film): ν = 3354, 3057, 3008, 2929, 2867 cm–1. 1H
(S)-1-[2-(2-Hydroxyethyl)phenyl]-4-phenylbutan-2-amine (15c): Yel-
˜
2
2
low oil; Rf = 0.11 (chloroform/methanol, 7:1). [α]2D0 = –13 (c = 0.79,
NMR: δ = 1.47–1.49 (m, 1 H), 1.65–1.76 (m, 3 H), 2.63–3.07 (m,
8 H), 3.59–3.85 (m, 4 H), 7.14–7.20 (m, 4 H) ppm. 13C NMR: δ =
30.2, 35.5, 36.3, 41.0 (CH2), 52.4 (CH), 61.7, 62.7 (CH2), 126.7,
126.8, 130.1, 130.4, 137.7, 137.9 (ArC) ppm. MS: m/z (%) = 192
(3) [M – CH2OH]+, 117 (10), 115 (10), 91 (10), 88 (100), 71 (69),
70 (33), 43 (10). HRMS: calcd. for C13H17N [M – 2H2O]+ 187.1361;
found 187.1339.
1
CH Cl ). IR (film): ν = 3355, 3023, 2926, 2859 cm–1. H NMR: δ
˜
2
2
= 1.66–1.92 (m, 2 H), 2.51 (m, 3 H), 2.61–3.00 (m, 6 H), 3.58–3.86
(m, 3 H), 7.11–7.30 (m, 9 H) ppm. 13C NMR: δ = 21.6, 32.7, 36.6,
39.3, 40.0 (CH2), 52.0 (CH), 63.5 (CH2), 126.0, 126.6, 128.4, 128.5,
129.9, 130.4, 137.7, 138.6, 141.8 (ArC) ppm. MS: m/z (%) = 164
(1) [M – CH2CH2Ph]+, 135 (11), 134 (100), 117 (26), 115 (10), 104
(11), 91 (75). HRMS: calcd. for C10H14NO [M – CH2CH2Ph]+
164.1070; found 164.1076.
(S)-3-Octyl-1,2,3,4-tetrahydroisoquinoline (19a): Brown oil; Rf
=
=
0.21 (hexane/EtOAc, 1:3); HPLC analysis (0.8 mL/min,
λ
(R)-2-[2-(2-Hydroxyethyl)phenyl]-1-phenylethanamine (15d): Yellow
oil; Rf = 0.16 (chloroform/methanol, 10:1). [α]2D0 = –6 (c = 1.0,
215 nm, n-hexane/iPrOH, 99:1): tr = 9.8 min (95% ee). [α]2D0 = +60
(c = 0.96, CH Cl ). IR (film): ν = 3318, 3020, 2953, 2924,
˜
2
2
1
CH Cl ). IR (film): ν = 3351, 3060, 3020, 2929, 2867 cm–1. 1H
2852 cm–1. H NMR: δ = 0.89 (t, J = 6.8 Hz, 3 H), 1.23–1.30 (m,
10 H), 1.42–1.55 (m, 4 H), 2.25 (br. s, 1 H), 2.52 (dd, J = 10.2,
5.8 Hz, 1 H), 2.77–2.88 (m, 2 H), 4.06 (d, J = 15.6 Hz, 2 H), 7.00–
7.14 (m, 4 H) ppm. 13C NMR: δ = 12.2 (CH3), 22.8, 26.1, 29.4,
˜
2
2
NMR: δ = 3.01 (br. s, 3 H), 3.01–3.12 (m, 4 H), 3.77–3.92 (m, 1
H), 4.25 (dd, J = 9.2, 5.2 Hz, 1 H), 7.16–7.42 (m, 9 H) ppm. 13C
NMR: δ = 36.3, 41.9 (CH2), 57.1 (CH), 63.4 (CH2), 126.3, 126.4,
126.6, 127.2, 128.4, 129.8, 130.2, 137.1, 138.5, 144.9 (ArC) ppm. 29.7, 29.9, 32.0, 35.5, 36.9 (CH2), 48.6 (CH), 53.8 (CH2), 125.8,
MS: m/z (%) = 223 (2) [M – H2O]+, 115 (12), 107 (11), 106 (100), 126.1, 126.2, 129.4, 135.0, 135.6 (ArC) ppm. MS: m/z (%) = 245
2900
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2893–2903

Reductive Ring-Opening of Phthalan and Isochroman
(3) [M]+, 133 (10), 132 (100), 130 (18), 104 (10). HRMS: calcd. for analysis (1.0 mL/min, λ = 215 nm, n-hexane/iPrOH, 99:1): tr
=
C17H27N [M]+ 245.2143; found 245.2138.
79.9 min (99% ee). [α]2D2 = –99 (c = 0.41, CH2Cl2).
(S)-2-Octyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (20a): Yellow oil;
Rf = 0.10 (hexane/EtOAc, 1:5); HPLC analysis (0.7 mL/min, λ =
215 nm, n-hexane): tr = 9.2 min (99% ee). [α]2D0 = +4.5 (c = 0.77,
(R)-3-Isopropyl-1,2,3,4-tetrahydroisoquinoline (19b): Pale-brown oil;
Rf = 0.25 (chloroform/methanol, 10:1); HPLC analysis (0.8 mL/
min, λ = 215 nm, n-hexane/iPrOH, 98:2): tr = 6.0 min (99% ee).
CH Cl ). IR (film): ν = 3400–3210, 3069, 3017, 2924, 2852 cm–1.
[α]2D0 = –98 (c = 0.98, CH Cl ). IR (film): ν = 3400, 3057, 3020,
˜
˜
2
2
2
2
1H NMR δ = 0.88 (t, J = 6.9 Hz, 3 H), 1.25–1.39 (m, 11 H), 1.42–
1.50 (m, 2 H), 1.52–1.88 (m, 1 H), 2.77–2.86 (m, 3 H), 2.97–3.09
(m, 1 H), 3.09–3.12 (m, 1 H), 3.74–3.80 (m, 1 H), 3.86–3.91 (m, 1
H), 7.11–7.19 (m, 4 H) ppm. 13C NMR: δ = 14.2 (CH3), 22.8, 26.3,
29.4, 29.7, 29.8, 32.0, 36.6, 37.0, 39.2 (CH2), 52.8 (CH), 63.7 (CH2),
126.7, 126.8, 129.9, 130.5, 137.7, 138.9 (ArC) ppm. MS: m/z (%) =
259 (4) [M]+, 154 (62), 147 (13), 146 (100), 118 (11), 171 (14), 115
(10), 56 (11). HRMS: calcd. for C18H29N [M]+ 259.2300; found
259.2293.
1
2957, 2922, 2867 cm–1. H NMR: δ = 1.01 (dt, J = 6.8, 3.5 Hz, 6
H), 1.70–1.77 (m, 2 H), 2.58–2.65 (m, 2 H), 2.75 (d, J = 12.1 Hz,
1 H), 4.05 (s, 2 H), 7.01 (d, J = 8.4 Hz, 1 H), 7.07–7.12 (m, 3
H) ppm. 13C NMR: δ = 18.6, 19.2 (CH3), 32.2 (CH2), 33.1, 49.2
(CH), 59.6 (CH2), 125.7, 126.0, 126.1, 129.5, 135.3, 136.0
(ArC) ppm. MS: m/z (%) = 174 (2) [M – H]+, 133 (10), 132 (100),
130 (36), 104 (11). HRMS: calcd. for C12H16N [M]+ 174.1288;
found 174.1290.
(S)-3-(2-Phenylethyl)-1,2,3,4-tetrahydroisoquinoline (19c): Orange
oil; Rf = 0.31 (hexane/EtOAc, 1:3); HPLC analysis (0.5 mL/min, λ
(R)-2-Isopropyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (20b): Yellow
oil; Rf = 0.30 (chloroform/methanol, 10:1); HPLC analysis (0.8 mL/
= 215 nm, n-hexane/iPrOH, 99:1): tr = 70.0 min (98% ee). [α]2D0
=
min, λ = 215 nm, n-hexane/iPrOH, 98:2): tr = 6.0 min (96% ee). [α]
+56 (c = 0.64, CH Cl ). IR (film): ν = 3327, 3063, 3023, 2920,
˜
2
2
20
2853 cm–1. 1H NMR: δ = 1.82–1.90 (m, 2 H), 2.27 (br. s, 1 H),
2.52–2.61 (m, 1 H), 2.77–2.91 (m, 4 H), 4.05 (s, 2 H), 6.99–7.31 (m,
9 H) ppm. 13C NMR: δ = 32.4, 35.3, 38.4 (CH2), 48.3 (CH), 53.2
(CH2), 125.9, 126.0, 126.1, 126.3, 2ϫ128.5, 129.3, 134.6, 135.4,
142.1 (ArC) ppm. MS: m/z (%) = 237 (2) [M]+, 133 (11), 132 (100),
130 (19), 104 (15), 91 (10). HRMS: calcd. for C17H19N [M]+
237.1517; found 237.1520.
= +7 (c = 0.38, CH Cl ). IR (film): ν = 3363, 3066, 3020, 2955,
˜
D
2
2
2867 cm–1. 1H NMR: δ = 1.01 (dt, J = 6.8, 3.5 Hz, 6 H), 1.70–1.77
(m, 2 H), 2.58–2.65 (m, 2 H), 2.75 (d, J = 12.1 Hz, 1 H), 4.05 (s, 2
H), 7.01 (d, J = 8.4 Hz, 1 H), 7.07–7.12 (m, 3 H) ppm. 13C NMR:
δ = 18.5, 18.9 (CH3), 33.6 (CH), 38.5, 40.8 (CH2), 57.7 (CH), 61.8
(CH2), 126.3, 126.4, 129.2, 129.5, 141.0, 141.9 (ArC) ppm. MS: m/z
(%) = 189 (2) [M]+, 147 (10), 146 (100), 129 (11), 117 (15), 115
(11), 81 (20). HRMS: calcd. for C13H19N [M]+ 189.1517; found
189.1508.
(R)-3-Phenyl-1,2,3,4-tetrahydroisoquinoline (19d):[32] Yellow oil; Rf
= 0.34 (chloroform/methanol, 10:1); HPLC analysis (1.0 mL/min,
λ = 215 nm, n-hexane/iPrOH, 99:1): tr = 84.2 min (99% ee). [α]2D0
(S)-2-Phenethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine
(20c):
Orange oil; Rf = 0.27 (chloroform/methanol, 10:1); HPLC analysis
(1.0 mL/min, λ = 215 nm, n-hexane/iPrOH, 99:1): tr = 32.3 min
= +125 (c = 0.55, CH Cl ). IR (KBr): ν = 3420–3385, 3063, 3026,
˜
2
2
2923, 2851 cm–1. 1H NMR: δ = 2.02 (br. s, 1 H), 3.02 (d, J = 7.5 Hz,
2 H), 4.05 (t, J = 7.5 Hz, 1 H), 4.17 (d, J = 15.5 Hz, 1 H), 4.28 (d,
J = 15.5 Hz, 1 H), 7.07–7.18 (m, 4 H), 7.29–7.40 (m, 3 H), 7.44 (d,
J = 7.2 Hz, 2 H) ppm. 13C NMR: δ = 37.8 (CH2), 49.3 (CH), 58.7
(CH2), 126.1, 126.4, 126.8, 127.6, 128.6, 128.8, 129.2, 134.7, 134.8,
143.9 (ArC) ppm. MS: m/z (%) = 209 (33) [M]+, 208 (26), 207 (26),
206 (31), 132 (16), 130 (12), 105 (22), 104 (100), 103 (29), 102 (14),
90 (10), 89 (21), 78 (29), 77 (26), 76 (10). HRMS: calcd. for
C15H15N [M]+ 209.1204; found 209.1204.
(94% ee). [α]2D0 = –15.5 (c = 0.85, CH Cl ). IR (film): ν = 3353,
˜
2
2
3057, 3022, 2930 cm–1. 1H NMR: δ = 1.73–1.89 (m, 2 H), 2.66–
2.99 (m, 6 H), 3.01–3.17 (m, 1 H), 3.55 (br. s, 2 H), 3.72–3.84 (m,
1 H), 7.07–7.26 (m, 9 H) ppm. 13C NMR: δ = 21.7, 32.3, 32.5, 36.3,
37.4, 38.6, 39.4, 46.0 (CH2), 52.1 (CH), 63.3 (CH2), 125.9, 126.0,
126.5, 126.6, 126.7, 128.3, 128.4, 129.1, 129.7, 129.9, 130.3, 137.4,
138.5, 141.2, 141.4, 141.6 (ArC) ppm. MS: m/z (%) = 251 (6)
[M]+, 160 (25), 147 (10), 146 (100), 117 (20), 115 (15), 105 (12), 91
(36), 77 (11). HRMS: calcd. for C18H21N [M]+ 251.1674; found
251.1663.
(R)-3-(4-Methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline
(19e):
Brown oil; Rf = 0.21 (EtOAc); HPLC analysis (1.0 mL/min, λ =
215 nm, n-hexane/iPrOH, 95:5): tr = 19.2 min (92% ee). [α]2D0 = +87
(R)-2-Phenyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (20d): Yellow
oil; Rf = 0.12 (chloroform/methanol, 10:1); HPLC analysis (1.0 mL/
(c = 0.85, CH Cl ). IR (film): ν = 3308, 3069, 2953, 2921, 2851,
˜
2
2
1
2833 cm–1. H NMR: δ = 1.95 (br. s, 1 H), 2.95 (d, J = 7.1 Hz, 2
H), 3.80 (s, 3 H), 3.96 (t, J = 7.2 Hz, 1 H), 4.15 (d, J = 15.6 Hz, 1
H), 4.26 (d, J = 15.6 Hz, 1 H), 6.90 (d, J = 8.7 Hz, 2 H), 7.07–7.16
(m, 4 H), 7.35 (d, J = 8.5 Hz, 2 H) ppm. 13C NMR: δ = 37.8 (CH2),
49.4 (CH), 55.4 (CH3), 58.1 (CH2), 114.0, 125.9, 126.2, 126.3,
127.7, 129.2, 135.1, 136.6, 159.0 (ArC) ppm. MS: m/z (%) = 239
(80) [M]+, 238 (47), 224 (15), 208 (11), 134 (20), 132 (10), 131 (10),
130 (17), 121 (24), 105 (16), 104 (100), 103 (25), 78 (23), 77 (16).
HRMS: calcd. for C16H17NO [M]+ 299.1310; found 239.1301.
min, λ = 215 nm, n-hexane/iPrOH, 99:1): tr = 10.8 min (99% ee).
1
[α]2D0 = –29 (c = 1.20, CH Cl ). IR (film): ν = 3323, 3060 cm–1. H
˜
2
2
NMR: δ = 2.41 (br. s, 1 H), 2.75–3.01 (m, 3 H), 3.15–3.24 (m, 1
H), 3.31–3.43 (m, 1 H), 3.37 (d, J = 9.8 Hz, 1 H), 3.72 (d, J =
9.8 Hz, 1 H), 7.05–7.45 (m, 9 H) ppm. 13C NMR: δ = 38.9, 46.9
(CH2), 48.8 (CH), 63.7 (CH2), 126.2, 126.4, 126.5, 127.2, 128.6,
129.2, 129.6, 140.8, 142.3, 146.0 (ArC) ppm. MS: m/z (%) = 223
(48) [M]+, 181 (13), 118 (100), 117 (14), 115 (16), 105 (11), 91 (51),
77 (13). HRMS: calcd. for C16H17N [M]+ 223.1361; found
223.1367.
(R)-3-Octyl-1,2,3,4-tetrahydroisoquinoline (ent-19a): The physical
and spectroscopic data were found to be same as for 19a. HPLC
(R)-2-(4-Methoxyphenyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine
(20e): Brown oil; Rf = 0.36 (chloroform/methanol, 10:1). [α]2D0
=
analysis (0.8 mL/min, λ = 215 nm, n-hexane/iPrOH, 99:1): tr
=
7.7 min (96% ee). [α]2D0 = –58 (c = 0.87, CH2Cl2).
–23 (c = 0.67, CH Cl ). IR (film): ν = 3351, 3069, 3020, 2931,
˜
2
2
2837 cm–1. 1H NMR: δ = 2.75–3.00 (m, 4 H), 3.37 (br. s, 1 H),
3.52–3.64 (m, 2 H), 3.72–3.76 (m, 1 H), 3.78 (d, J = 6.0 Hz, 3 H),
6.84–6.89 (m, 2 H), 7.08–7.18 (m, 4 H), 7.24 (d, J = 8.5 Hz, 1 H),
7.40 (d, J = 8.5 Hz, 1 H) ppm. 13C NMR: δ = 35.9, 36.9, 42.9, 44.5
(CH2), 55.4 (CH3), 56.8 (CH), 61.9 (CH2), 113.9, 114.1, 126.7,
126.8, 126.9, 127.1, 127.6, 128.3, 129.4, 129.9, 130.7 (ArC) ppm.
MS: m/z (%) = 253 (100) [M]+, 252 (16), 238 (11), 209 (10), 149
(S)-3-Isopropyl-1,2,3,4-tetrahydroisoquinoline (ent-19b): The physi-
cal and spectroscopic data were found to be same as for 19b. HPLC
analysis (0.8 mL/min, λ = 215 nm, n-hexane/iPrOH, 98:2): tr
=
7.0 min (94% ee). [α]2D0 = +89 (c = 0.77, CH2Cl2).
(S)-3-Phenyl-1,2,3,4-tetrahydroisoquinoline (ent-19d): The physical
and spectroscopic data were found to be same as for 19d. HPLC
Eur. J. Org. Chem. 2010, 2893–2903
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2901

D. García, F. Foubelo, M. Yus
FULL PAPER
867–926; b) C. Nájera, J. M. Sansano, M. Yus, Tetrahedron
2003, 59, 9255–9303; c) R. Chinchilla, C. Nájera, M. Yus,
Chem. Rev. 2004, 104, 2667–2722; d) R. Chinchilla, C. Nájera,
M. Yus, Tetrahedron 2005, 61, 3139–3176; e) F. Foubelo, M.
Yus, Chem. Soc. Rev. 2008, 37, 2620–2633.
(11), 148 (82), 147 (11), 135 (23), 134 (23), 121 (56), 118 (23), 117
(22), 116 (14), 115 (21), 91 (16), 78 (13), 77 (13). HRMS: calcd. for
C17H19NO [M]+ 253.1467; found 253.1454.
(S)-2-Phenyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (ent-20d): The
physical and spectroscopic data were found to be same as for 20d.
HPLC analysis (1.0 mL/min, λ = 215 nm, n-hexane/iPrOH, 99:1):
tr = 17.1 min (98% ee). [α]2D0 = +25 (c = 0.26, CH2Cl2).
[2] For a monograph, see: J. Clayden, in: Organolithiums: Selectiv-
ity for Synthesis, Pergamon Press, Oxford, 2002.
[3]
For recent reviews, see: a) M. Yus, Pure Appl. Chem. 2003, 75,
1453–1475; b) M. Yus, F. Foubelo, Adv. Heterocycl. Chem.
2006, 91, 135–158.
For the last papers on this topic from our laboratory, see: a) F.
Foubelo, D. García, B. Moreno, M. Yus, Tetrahedron Lett.
2007, 48, 3379–3383; b) D. García, F. Foubelo, M. Yus, Hetero-
cycles 2007, 74, 507–519; c) D. García, F. Foubelo, M. Yus,
Tetrahedron 2008, 64, 4275–4286; d) D. García, F. Foubelo, M.
Yus, Heterocycles 2009, 77, 991–1005.
For recent mechanistic studies, see: a) C. Melero, A. Guijarro,
M. Yus, Tetrahedron Lett. 2006, 47, 6267–6271; b) C. Melero,
H. Pérez, A. Guijarro, M. Yus, Tetrahedron Lett. 2007, 48,
4105–4109; c) C. Melero, A. Guijarro, V. Baumann, A. J. Pérez-
Jiménez, M. Yus, Eur. J. Org. Chem. 2007, 5514–5526; d) C.
Melero, R. P. Herrera, A. Guijarro, M. Yus, Chem. Eur. J. 2007,
13, 10096–10107; e) H. Pérez, C. Melero, A. Guijarro, M. Yus,
Tetrahedron 2009, 65, 10764–10783.
(S)-1,2,3,5,10,10a-Hexahydropyrrolo[1,2-b]isoquinoline (21): Brown
oil; Rf = 0.28 (chloroform/methanol, 10:1); HPLC analysis (1.0 mL/
min, λ = 215 nm, n-hexane/iPrOH, 99:1): tr = 7.0 min (92% ee). [α]
[4]
20 = +46 (c = 0.58, CH Cl ). IR (film): ν = 3063, 3014, 2961, 2904,
˜
D
2
2
2873, 2775, 2718 cm–1. 1H NMR: δ = 1.49–1.62 (m, 1 H), 1.79–
1.96 (m, 2 H), 2.05–2.29 (m, 1 H), 2.32–2.45 (m, 2 H), 2.73 (dd, J
= 15.8, 10.4 Hz, 1 H), 3.00 (dd, J = 15.9, 3.9 Hz, 1 H), 3.26 (dd, J
= 8.6, 2.7 Hz, 1 H), 3.48 (d, J = 14.7 Hz, 1 H), 4.14 (d, J = 14.7 Hz,
1 H), 7.05–7.16 (m, 4 H) ppm. 13C NMR: δ = 21.6, 31.1, 36.1,
54.9, 56.0 (CH2), 60.8 (CH), 125.7, 126.2, 126.7, 129.1, 134.9, 135.1
(ArC) ppm. MS: m/z (%) = 173 (55) [M]+, 172 (100), 170 (10), 144
(10), 130 (13), 117 (13), 115 (16), 105 (13), 104 (51), 103 (18), 78
(18), 77 (14). HRMS: calcd. for C12H15N [M]+ 173.1204; found
173.1192.
[5]
[6]
For a recent review, see: M. Yus in The Chemistry of Organo-
lithium Compounds (Eds.: Z. Rappoport, I. Marek), Wiley,
Chichester, 2004, vol. 1, pp. 647–747.
(S)-2,3,4,6,11,11a-Hexahydro-1H-pyrido[1,2-b]isoquinoline
(22):
Yellow oil; Rf = 0.25 (chloroform/methanol, 10:1); HPLC analysis
(0.5 mL/min, λ = 215 nm, n-hexane/iPrOH, 99:1): tr = 13.0 min
[7] a) J. Almena, F. Foubelo, M. Yus, Tetrahedron 1995, 51, 3351–
3364; b) U. Azzena, S. Demartis, M. G. Fiori, G. Melloni, L.
Pisano, Tetrahedron Lett. 1995, 36, 8213–8216.
(97% ee). [α]2D0 = +26 (c = 0.50, CH Cl ). IR (film): ν = 3063, 3020,
˜
2
2
2930, 2852, 2796, 2756 cm–1. 1H NMR: δ = 1.25–1.40 (m, 2 H),
1.67–1.86 (m, 4 H), 2.08–2.17 (m, 1 H), 2.24–2.27 (m, 1 H), 2.73–
2.77 (m, 2 H), 2.76 (d, J = 4.7 Hz, 1 H), 3.40 (d, J = 15.2 Hz, 1
H), 3.87 (d, J = 15.2 Hz, 1 H), 6.99–7.25 (m, 4 H) ppm. 13C NMR:
δ = 24.3, 25.9, 33.6, 36.8, 56.2, 58.3 (CH2), 58.4 (CH), 125.6, 126.0,
126.3, 128.1, 133.9, 134.2 (ArC) ppm. MS: m/z (%) = 187 (51)
[M]+, 186 (100), 158 (12), 145 (15), 130 (10), 104 (34). HRMS:
calcd. for C13H17N [M]+ 187.1361; found 187.1387.
[8]
J. Almena, F. Foubelo, M. Yus, Tetrahedron 1995, 51, 3365–
3374.
[9] a) T. Soler, A. Bachki, L. R. Falvello, F. Foubelo, M. Yus, Tet-
rahedron: Asymmetry 2000, 11, 493–517; b) L. R. Falvello, F.
Foubelo, T. Soler, M. Yus, Tetrahedron: Asymmetry 2000, 11,
2063–2066; c) F. Foubelo, T. Soler, M. Yus, Tetrahedron: Asym-
metry 2001, 12, 801–810.
[10]
a) I. Pastor, M. Yus, Tetrahedron Lett. 2000, 41, 1589–1592; b)
I. Pastor, M. Yus, Tetrahedron 2001, 57, 2371–2378.
a) M. Yus, J. Gomis, Tetrahedron Lett. 2001, 42, 5721–5724; b)
M. Yus, J. Gomis, Eur. J. Org. Chem. 2002, 1989–1995.
M. Yus, J. Gomis, Eur. J. Org. Chem. 2003, 2043–2048.
For a preliminary report, see: D. García, B. Moreno, T. Soler,
F. Foubelo, M. Yus, Tetrahedron Lett. 2009, 50, 4710–4713.
For reviews, see: a) F. A. Davis, P. Zhou, B.-C. Chen, Chem.
Soc. Rev. 1998, 27, 13–18; b) J. A. Ellman, T. D. Owens, T. P.
Tang, Acc. Chem. Res. 2002, 35, 984–995; c) J. A. Ellman, Pure
Appl. Chem. 2003, 75, 39–46; d) P. Zhou, B.-C. Chen, F. A.
Davis, Tetrahedron 2004, 60, 8003–8030; e) D. Morton, R. A.
Stockman, Tetrahedron 2006, 62, 8869–8905; f) G.-Q. Lin, M.-
H. Xu, Y.-W. Zhong, X.-W. Sun, Acc. Chem. Res. 2008, 41,
831–840; g) F. Ferreira, C. Botuha, F. Chemla, A. Pérez-Luna,
Chem. Soc. Rev. 2009, 38, 1162–1186.
a) D. J. Weix, J. A. Ellman, Org. Lett. 2003, 5, 1317–1320; b)
D. J. Weix, J. A. Ellman, Org. Synth. 2005, 82, 157–165.
D. A. Cogan, G. Liu, J. Ellman, Tetrahedron 1999, 55, 8883–
8904.
a) M. Wakayama, J. A. Ellman, J. Org. Chem. 2009, 74, 2646–
2650; b) V. K. Aggarwal, N. Barbero, E. M. McGarrigle, G.
Mickle, R. Navas, J. R. Suárez, M. G. Unthank, M. Yar, Tetra-
hedron Lett. 2009, 50, 3482–3484.
(S)-1,2,3,4,5,6,11,11a-Octahydro-1H-benzo[d]pyrrolo[1,2-a]azepine
(23): Brown oil; Rf = 0.23 (chloroform/methanol, 10:1); HPLC
analysis (0.7 mL/min, λ = 215 nm, n-hexane): tr = 8.4 min (99%
[11]
[12]
[13]
ee). [α]2D0 = –18.5 (c = 0.71, CH Cl ). IR (film): ν = 3057, 3018,
˜
2
2
2959, 2925, 2792, 2748 cm–1. 1H NMR: δ = 1.67–1.81 (m, 2 H),
1.87–2.10 (m, 2 H), 2.14–2.26 (m, 2 H), 2.34 (q, J = 9.2 Hz, 1 H),
2.78–2.85 (m, 2 H), 3.04–2.10 (m, 1 H), 3.21–3.27 (m, 2 H), 3.34–
3.38 (d, J = 14.7 Hz, 1 H), 7.09–7.16 (m, 4 H) ppm. 13C NMR: δ
= 20.5, 32.5, 36.0, 41.0, 54.0, 56.7 (CH2), 64.9 (CH), 126.7, 129.3,
129.7, 140.1, 141.3 (ArC) ppm. MS: m/z (%) = 187 (91) [M]+, 186
(79), 173 (18), 172 (100), 170 (22), 159 (15), 158 (15), 144 (11), 130
(19), 129 (14), 128 (17), 118 (68), 117 (64), 116 (26), 115 (56), 105
(13), 104 (35), 103 (31), 96 (17), 91 (42), 83 (28), 82 (74), 78 (26),
77 (29), 63 (18), 55 (50), 54 (23). HRMS: calcd. for C13H17N [M]+
187.1361; found 187.1343.
[14]
[15]
[16]
[17]
Acknowledgments
This work was generously supported by the Spanish Ministerio de
Educación y Ciencia (MEC) (Grant no. CTQ2004–01261, the Con-
solider Ingenio 2010-CSD2007-00006), and the Generalitat Valen-
ciana (Grant no. PROMETEO/2009/039). D. G. thanks the Univer-
sity of Alicante for a predoctoral fellowship. We also thank Medal-
chemy S. L. and Chemetall GmbH for a gift of enantiopure tert-
butylsulfinamides (S and R) and lithium, respectively.
[18]
[19]
For a review, see: J. D. Scott, R. M. Williams, Chem. Rev. 2002,
102, 1669–1730.
For reviews, see: a) J. L. Vicario, D. Badia, L. Carrillo, J. Etxeb-
arria, Curr. Org. Chem. 2003, 7, 1775–1792; b) A. B. J. Bracca,
T. S. Kaufman, Tetrahedron 2004, 60, 10575–10610; c) P. Sien-
galewicz, U. Rinner, J. Mulzer, Chem. Soc. Rev. 2008, 37, 2676–
2690.
[20]
[1] For recent reviews on functionalised organolithium com-
For recent syntheses of substituted 2,3,4,5-tetrahydro-1H-
benzazepines, see: a) J. Crecente-Campo, M. P. Vázquez-Tato,
pounds, see: a) C. Nájera, M. Yus, Curr. Org. Chem. 2003, 7,
2902
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2893–2903

Reductive Ring-Opening of Phthalan and Isochroman
J. A. Seijas, Tetrahedron 2009, 65, 2655–2659; b) S. M. Husain,
M. T. Heim, D. Schepmann, B. Wünsch, Tetrahedron: Asym-
metry 2009, 20, 1383–1392.
a) J. Weinstock, J. P. Hieble, J. W. Wilson III, Drug Fut. 1985,
10, 645–697; b) I. Pettersson, T. Liljefors, K. Bogeso, J. Med.
Chem. 1990, 33, 2197–2204; c) W. L. Wu, D. A. Burnett, R.
Spring, J. Med. Chem. 2005, 48, 680–693.
[25] a) R. Almansa, D. Guijarro, M. Yus, Tetrahedron: Asymmetry
2008, 19, 603–606; b) R. Almansa, D. Guijarro, M. Yus, Tetra-
hedron: Asymmetry 2008, 19, 2484–2491.
[26] a) P. V. Bharatam, Amita, D. Kaur, J. Phys. Org. Chem. 2002,
15, 197–203; b) P. V. Bharatam, P. Uppal, Amita, D. Kaur, J.
Chem. Soc. Perkin Trans. 2 2000, 43–50.
[27] F. Foubelo, C. Gómez, A. Gutiérrez, M. Yus, J. Heterocycl.
Chem. 2000, 37, 1061–1064.
[28] G. Liu, D. A. Cogan, T. D. Owens, T. P. Tang, J. A. Ellman, J.
Org. Chem. 1999, 64, 1278–1284.
[29] SAINT, Area-Detector Integration Software, version 6.02A, Sie-
mens Industrial Automation, Inc., Madison, WI, 1995.
[30] G. M. Sheldrick, SADABS: Area-Detector Absorption Correc-
tion, University of Göttingen, Göttingen, 1996
[31] G. M. Sheldrick, SHELX97 [includes SHELXS97, SHELXL97
and CIFTAB], Programs for Crystal Structure Analysis (rel.
97-2), University of Göttingen, Göttingen, 1998.
[32] D. Enders, V. Braig, M. Boudou, G. Raabe, Synthesis 2004,
2980–2990.
[21]
[22]
K. K. Gnanalingham, A. J. Hunter, P. Jenner, C. D. Marsden,
Psychopharmacology (Berlin, Ger.) 1995, 117, 403–412.
[23] A. D. Medhurst, A. R. Atkins, I. J. Beresford, K. Brackenbor-
ough, M. A. Briggs, A. R. Calver, J. Cilia, J. E. Cluderay, B.
Crook, J. B. Davis, R. K. Davis, R. P. Davis, L. A. Dawson,
A. G. Foley, J. Gartlon, M. I. Gonzalez, T. Heslop, W. D. Hirst,
C. Jennings, D. N. C. Jones, L. P. Lacroix, A. Martyn, S. Oc-
iepka, A. Ray, C. M. Regan, J. C. Roberts, J. Schogger, E. Sou-
tham, T. O. Stean, B. K. Trail, N. Upton, G. Wadsworth, J. A.
Wald, T. White, J. Witherington, M. L. Woolley, A. Worby,
D. M. Wilson, J. Pharmacol. Exp. Ther. 2007, 321, 1032–1045.
[24] M. Medjahdi, J. C. González-Gómez, F. Foubelo, M. Yus, Het-
erocycles 2008, 76, 569–581.
Received: January 27, 2010
Published Online: April 8, 2010
Eur. J. Org. Chem. 2010, 2893–2903
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2903