Stereoselective synthesis of 3-substituted tetrahydroisoquinolines from phthalan and chiral N-sulfinylimines

Article abstract of DOI:10.1016/j.tetlet.2009.06.010

The reaction of the dianionic intermediate [resulting from the reductive opening of phthalan (1) with lithium] with chiral N-tert-butylsulfinyl aldimines 3 in the presence of ZnMe₂ gives, after hydrolysis, N-tert-butylsulfinyl amino alcohols 4

Full text of DOI:10.1016/j.tetlet.2009.06.010

Tetrahedron Letters 50 (2009) 4710–4713
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of 3-substituted tetrahydroisoquinolines
from phthalan and chiral N-sulfinylimines
*
*
Daniel García, Benjamín Moreno, Tatiana Soler, Francisco Foubelo , Miguel Yus
Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of the dianionic intermediate [resulting from the reductive opening of phthalan (1) with
lithium] with chiral N-tert-butylsulfinyl aldimines 3 in the presence of ZnMe2 gives, after hydrolysis,
N-tert-butylsulfinyl amino alcohols 4 with high diastereoselectivity. Successive treatment of compounds
4 with hydrogen chloride in methanol, thionyl chloride in chloroform and sodium hydroxide yields 3-
substituted tetrahydroisoquinolines 6.
Received 5 May 2009
Revised 2 June 2009
Accepted 2 June 2009
Available online 6 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Reductive ring opening
Phthalan
DTBB-catalysed lithiation
Chiral sulfinylimines
Organozincates
Diastereoselective addition
Isoquinoline alkaloids1 are widespread represented in nature. In
many cases, these natural products are cytotoxic agents that dis-
play antitumor and antimicrobial activities, which are closely re-
lated to the tetrahydroisoquinoline unit. For this reason the
asymmetric synthesis2 of substituted tetrahydroisoquinolines has
been of great interest for synthetic organic chemists in the aim
of discovering new drugs. One of the most direct and reliable
methods for the asymmetric synthesis of amine derivatives is the
addition of an organometallic reagent (mainly organomagnesium,3
organolithium,4 organozinc5 and organoindium6 derivatives) to the
C@N bond of enantiopure sulfinylimines. In this context, N-tert-
butylsulfinyl derivatives have found high applicability in synthe-
sis7 as electrophiles due to the possibility of preparing both enan-
tiomers in large-scale processes8 and also because the chiral
auxiliary can be easily removed under acidic conditions.4b In addi-
tion, practical processes for recycling the tert-butylsulfinyl group
upon deprotection of N-tert-butylsulfinylamines have been re-
ported recently, making this chiral auxiliary even more attractive.9
On the other hand, functionalised organolithium compounds10 are
accessible through different procedures, among them, the reduc-
tive ring opening of heterocycles11 using an arene-catalysed lithia-
tion.12 The benzylic carbon–oxygen bonds are susceptible to
suffering reductive cleavage by means of a lithiating reagent to
generate benzylic organolithium compounds. In the case of phtha-
lan (1), the resulting dianionic intermediate 213 (Table 1) has
shown a wide use in organic synthesis. For instance, the reaction
of 2 with keto derivatives of some protected monosaccharides (glu-
cose and fructose),14 as well as steroids (estrone and cholestan-
one),15 gives the expected selectively functionalised natural
products. Racemic 3-substituted tetrahydroisoquinolines were ob-
tained upon cyclisation of the resulting amino alcohols after reac-
tion of
2
with non-enolisable N-trimethylsilylaldimines.16
Intermediate 2 has also been transformed into the corresponding
functionalised organozinc derivative by a lithium–zinc transmetal-
lation process with zinc bromide and its reactivity towards differ-
ent electrophiles was studied.17 Substituted phthalans at both the
five-membered heterocyclic ring18 and the aromatic ring19 under-
go in most cases a regioselective reductive cleavage leading to the
corresponding functionalised benzylic organolithium compounds.
In addition, García Ruano and co-workers found that benzylic orga-
nolithium derivatives reacted with N-p-tolylsulfinylimines with
high stereoselectivity.20 With these antecedents, we considered
of interest to explore the reactivity of the anionic intermediate 2
resulting from the reductive opening of phthalan (1) with chiral
N-tert-butylsulfinylimines in order to apply this methodology to
the synthesis of substituted tetrahydroisoquinolines in a highly
enantioselective manner.
The lithiation of the phthalan (1) with an excess of lithium (1:10
molar ratio) and a catalytic amount of 4,40-di-tert-butylbiphenyl
(DTBB; 5 mol %) in THF at 0 °C for 40 min led to a solution of the
corresponding intermediate 2. After filtration of the excess of lith-
ium at room temperature, to the resulting solution of the function-
alized organolithium compound 2 was added a THF solution of the
* Corresponding authors. Fax: +34 965 903549 (M.Y.).
E-mail addresses: foubelo@ua.es (F. Foubelo), yus@ua.es (M. Yus).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.010

D. García et al. / Tetrahedron Letters 50 (2009) 4710–4713
4711
Table 1
Screening and optimisation of the reaction conditionsa
O
S
N
t-Bu
OH
HN
O
S
OH
HN
O
S
1. Li, DTBB (5 mol %)
THF, 0 ºC, 40 min
2. Filtration
3a
Reaction
Ph
OLi
Li
+
O
Ph
Ph
conditions
1
2
4a
4a'
Entry
Reaction conditions
Product
Additives (1.1 equiv)
T (time)
Hydrolysis
Yieldb (%)
4a:4a0 ratioc
1
2
3
4
5
6
7
—
ꢀ78 to 20 °C (12 h)
ꢀ65 °C (12 h)
ꢀ55 °C (12 h)
ꢀ65 °C (12 h)
ꢀ30 °C (12 h)
ꢀ5 °C (12 h)
ꢀ78 to 20 °C
ꢀ65 to 20 °C
ꢀ55 to 20 °C
ꢀ65 to 20 °C
ꢀ30 to 20 °C
ꢀ5 to 20 °C
ꢀ65 to 20 °C
47
25
42
78
69
61
27d
78:22
95:5
AlMe3
AlMe3
ZnMe2
ZnMe2
ZnMe2
ZnEt2
69:31
86:14
83:17
67:33
63:37
ꢀ65 °C (12 h)
a
Phthalan (1, 3 equiv) was treated with an excess of lithium in the presence of a catalytic amount of DTBB at 0 °C. After filtration of the excess of lithium, the corresponding
additive was added at room temperature and after 15 min, the reaction mixture was cooled down and aldimine 3a (1 equiv) was added.
b
Yield of the major reaction product 4a based on the starting aldimine 3a.
c
Diastereomeric mixture was determined by 1H NMR analysis of the crude reaction mixture.
d
Sulfinamide 5 was obtained in 37% yield.
chiral aldimine (R)-3a [easily prepared from benzaldehyde and (R)-
tert-butylsulfinamide]21 at ꢀ78 °C and the reaction mixture was al-
M+
O
‡
lowed to reach the room temperature for 12 h. Final hydrolysis led
to a mixture of diastereomeric N-tert-butylsulfinyl amino alcohols
4a and 4a0 in a 78:22 ratio, the major diastereoisomer 4a being iso-
lated in a 47% yield (Table 1, entry 1). In order to improve, both dia-
stereoselectivity and the yield of the reaction, AlMe3 was added to
the THF solution of intermediate 2 and the mixture was stirred for
15 min at room temperature prior to the addition of aldimine (R)-
3a at ꢀ65 °C. Under these reaction conditions, aminoalcohols 4
were obtained with a higher diastereoselectivity (95:5 dr) but in
a very low yield due to a poor conversion (Table 1, entry 2). It
has been reported that yields and diastereoselectivities are im-
proved when the addition of organolithium compounds to keti-
mines is performed in the presence of AlMe3.3b When the
reaction was performed with the same additive at ꢀ55 °C, through
an inverse addition, that means addition of organolithium interme-
diate 2 to a solution of aldimine (R)-3 and AlMe3, the yield in-
creased to 54% but diastereomeric ratio was 69:31 (Table 1, entry
3). In our research group we found out recently that the reaction
of triorganozincates with N-tert-butylsulfinylimines gives the ex-
O
S
H
N
HN
Ph
M+
Ph
Nu
Open TS
X-ray structure of 4a
5
Chart 1.
re-face of C@N through an open transition state in the twofold Le-
wis acid coordinated (Rs)-sulfinylimine, due to the large excess of
lithium cations and organozinc compounds (Chart 1). Theoretical
calculations support that a like s-cis conformation of these sulfi-
nylimines is the most stable conformation.7g,25
The reaction of the dianionic intermediate 2 with different chi-
ral N-sulfinyl aldimines 3 was performed under the previously
optimised conditions (Table 1, entry 4). Compounds 4 were ob-
tained in rather good yields and high diastereoselectivities
(Scheme 1 and Table 2). The major diastereomers were isolated
after column chromatography and fully characterised in all cases.
The nucleophilic attack occurs predominantly to the re-face of
the imine unit for RS-isomers (Table 2, entries 1–4) and to the si-
face in the case of SS-derivatives (Table 2, entries 5-7) according
to the proposed open transition state. The tert-butylsulfinyl group
was easily removed under acidic conditions, yielding the corre-
sponding amino alcohols in quantitative yields. These amino alco-
hols are adequate precursors of tetrahydroisoquinolines 6 after
pected
a-branched sulfinamides in good to excellent yields with
diastereomeric ratios of up to 98:2, however, no reaction was ob-
served with dialkylzincs.22 Thus, when ZnMe2 was used as addi-
tive, the reaction of the resulting mixed organozincate with
aldimine 3a at ꢀ65 °C for 12 h gave, after hydrolysis, the expected
mixture of amino alcohols 4a and 4a0 in 78% yield and 86:14 ratio
(Table 1, entry 4).23 Due to the slow transfer rate of the methyl
group, it can be used as a non-transferable one in these processes.
Yields and stereoselectivities were lower when the process was
performed with the same additive and at ꢀ30 °C and ꢀ5 °C (Table
1, entries 5 and 6). A mixture of the expected compounds 4 and
sulfinamide 5 (Chart 1) was obtained when ZnEt2 was used as an
additive. Compound 5 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 a competition between the benzyl and the ethyl
groups which both are transferable. Regarding the stereochemistry
of the major isomer 4a, it was unambiguously determined by sin-
gle X-ray analysis24 and the obtained structure showed that the
configuration of the new stereogenic centre was R (Chart 1). This
result is consistent with an approach of the nucleophile from the
OH
HN
O
S
i-v
vi-viii
NH
O
R
R
1
4
6
Scheme 1. 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)t-Bu (3), ꢀ65 °C, 12 h; (v) H2O,
ꢀ65 to 20 °C; (vi) HCl/dioxane (4 M), MeOH, 20 °C; (vii) Cl2SO, CHCl3, 50 °C; (viii)
NaOH/H2O (5 M), THF, 20 °C.

4712
D. García et al. / Tetrahedron Letters 50 (2009) 4710–4713
Table 2
Preparation of 3-substituted tetrahydroisoquinolines 6
Entry
Aldimines 3
Compounds 4a
Tetrahydroisoquinolines 6a,b
No.
R
No.
Structure
Yieldc (%)
78
drd
No.
Structure
Yielde (%)
72
OH
HN
O
S
NH
Ph
1
(R)-3a
Ph
4a
86:14
6a
Ph
OH
HN
O
S
NH
2
3
(R)-3b
(R)-3c
i-Pr
4b
4c
69
79
77:23
85:15
6b
6c
74
80
i-Pr
i-Pr
OH
HN
O
S
NH
( )7
CH3(CH2)7
( )7
OHa O
S
NH
HN
4
(R)-3d
Ph(CH2)2
4d
71
87:13
6d
79
Ph
( )2
( )2
Ph
OH
HN
O
S
NH
Ph
5f
(S)-3a
(S)-3b
Ph
4e
4f
54
57
77:23
71:29
6e
6f
67
78
Ph
OH
HN
O
S
NH
6
i-Pr
i-Pr
i-Pr
OH
HN
O
S
NH
( )7
7
(S)-3c
CH3(CH2)7
4g
55
85:15
6g
80
( )7
a
Products 4 and 6 were ꢁ95% pure (GLC and 300 MHz 1H NMR) and were fully characterised by spectroscopic means (IR, 1H and 13C NMR and LRMS/HRMS).
ee ꢁ 97% determined by HPLC using a ChiralCel OJ column.
b
c
d
e
f
Isolated yield of the major diastereoisomer based on the starting aldimine 3.
Diastereomeric mixture was determined by 1H NMR analysis of the crude reaction mixture.
Isolated yield from compounds 4.
The reaction was performed in the absence of ZnMe2 as additive.
intramolecular dehydration when they were successively treated
University of Alicante for a predoctoral fellowship. We also thank
Medalchemy S. L. and Chemetall GmbH for a gift of enantiopure
tert-butylsulfinamides (S and R) and lithium, respectively.
with thionyl chloride in chloroform at 50 °C and then with a 5 M
aqueous solution of sodium hydroxide in THF at room temperature
(Scheme 1 and Table 2).26 The ee values of chiral tetrahydroiso-
quinolines 6 were determined by chiral HPLC analysis, being in
all cases higher than 97%.
References and notes
In conclusion, we describe here a straightforward synthesis of
3-substituted tetrahydroisoquinolines 6 with high enantiomeric
purity starting from phthalan (1) and chiral N-tert-butylsulfinyl
aldimines 3, through a two-pot strategy: (1) Reaction of the dian-
ionic intermediate 2 resulting from the reductive opening lithia-
tion of phthalan (1) with chiral aldimines 3 in the presence of
ZnMe2 and (2) cyclisation of the amino alcohol resulting from
the removal of the tert-butylsulfinyl unit.
1. For a review, see: Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669–1730.
2. For reviews, see: (a) Vicario, J. L.; Badia, D.; Carrillo, L.; Etxebarria, J. Curr. Org.
Chem. 2003, 7, 1775–1792; (b) Bracca, A. B. J.; Kaufman, T. S. Tetrahedron 2004,
60, 10575–10610; (c) Siengalewicz, P.; Rinner, U.; Mulzer, J. Chem. Soc. Rev.
2008, 37, 2676–2690.
3. (a) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119, 9913–9914; (b)
Cogan, D. A.; Liu, G.; Ellman, J. A. Tetrahedron 1999, 55, 8883–8904; (c) Davis, F.
A.; McCoull, W. J. Org. Chem. 1999, 64, 3396–3397; (d) McMahon, J. P.; Ellman, J.
A. Org. Lett. 2004, 6, 1645–1647; (e) Lu, B. Z.; Senanayake, C.; Li, N.; Han, Z.;
Bakale, R. P.; Wald, S. A. Org. Lett. 2005, 7, 2599–2602; (f) Dirscherl, G.;
Rooshenas, P.; Schreiner, P. R.; Lamaty, F.; König, B. Tetrahedron 2008, 64, 3005–
3016.
4. (a) Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 268–269; (b) Cogan, D.
A.; Liu, G.; Ellman, J. Tetrahedron 1999, 55, 8883–8904; (c) Davis, F. A.;
Melamed, J. Y.; Sharik, S. S. J. Org. Chem. 2006, 71, 8761–8766.
5. (a) Chemla, F.; Ferreira, F. J. Org. Chem. 2004, 69, 8244–8250; (b) Chemla, F.;
Ferreira, F. Synlett 2004, 983–986; (c) Ferreira, F.; Audouin, M.; Chemla, F.
Chem. Eur. J. 2005, 11, 5269–5278; (d) Chemla, F.; Ferreira, F. Synlett 2006,
Acknowledgements
This work was generously supported by the Spanish Ministerio
de Educación
y Ciencia (MEC; Grant Nos. CSD2007-00006,
CTQ2004-01261 and Consolider Ingenio 2010). D.G. thanks the

D. García et al. / Tetrahedron Letters 50 (2009) 4710–4713
4713
2613–2616; (e) Sun, X.-W.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2006, 8, 4979–4982;
(f) Kolodney, G.; Sklute, G.; Perrone, S.; Knochel, P.; Marek, I. Angew. Chem., Int.
Ed. 2007, 46, 9291–9294; (g) Chemla, F.; Ferreira, F.; Gaucher, X.; Palais, L.
Synthesis 2007, 1235–1241; (h) Voituriez, A.; Pérez-Luna, A.; Ferreira, F.;
Botuha, C.; Chemla, F. Org. Lett. 2009, 11, 931–934.
23. Typical procedure for the diastereoselective synthesis of compounds 4a and 4a0. To
a blue suspension of lithium powder (140 mg, 20.0 mmol) and a catalytic
amount of DTBB (80.0 mg, 0.3 mmol) in THF (5 mL) was added dropwise a
solution of phthalan (1, 360 mg, 3.0 mmol) under argon and the mixture was
stirred at 0 °C for 45 min. Then, the excess of lithium was filtered off and a
solution of ZnMe2 (3.0 mL, 1.0 M in hexane) was added dropwise and stirring
was continued for 15 min at room temperature. After this, the reaction mixture
6. (a) Foubelo, F.; Yus, M. Tetrahedron: Asymmetry 2004, 15, 3823–3825; (b) Wang,
Z.-Q.; Feng, C.-Q.; Xu, M.-H.; Lin, G.-Q. J. Am. Chem. Soc. 2007, 129, 5336–5337;
(c) Sun, X.-W.; Liu, M.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2008, 10, 1259–1262; (d)
González-Gómez, J. C.; Foubelo, F.; Yus, M. Synlett 2008, 2777–2780; (e)
Medjahdi, M.; González-Gómez, J. C.; Foubelo, F.; Yus, M. Heterocycles 2008, 76,
569–581.
7. For reviews, see: (a) Davis, F. A.; Zhou, P.; Chen, B.-C. Chem. Soc. Rev. 1998, 27,
13–18; (b) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984–
995; (c) Ellman, J. A. Pure Appl. Chem. 2003, 75, 39–46; (d) Zhou, P.; Chen, B.-C.;
Davis, F. A. Tetrahedron 2004, 60, 8003–8030; (e) Morton, D.; Stockman, R. A.
Tetrahedron 2006, 62, 8869–8905; (f) Lin, G.-Q.; Xu, M.-H.; Zhong, Y.-W.; Sun,
X.-W. Acc. Chem. Res. 2008, 41, 831–840; (g) Ferreira, F.; Botuha, C.; Chemla, F.;
Pérez-Luna, A. Chem. Soc. Rev. 2009, 38, 1162–1186.
was cooled down to ꢀ65 °C and
a solution of aldimine (R)-3a (209 mg,
1.0 mmol) in THF (0.4 mL) was added dropwise. After 12 h at the same
temperature, finally the reaction mixture was hydrolysed with water (5 mL),
extracted with ethyl acetate (3 ꢂ 15 mL) once at rt, dried over anhydrous
MgSO4 and evaporated (15 Torr). The residue was purified by column
chromatography (silica gel, hexane/ethyl acetate) to yield pure products 4a
and
phenylethanamine (4a): mp 129–130 °C (pentane/dichloromethane);
ꢀ40 (c 0.16, CH2Cl2); Rf: 0.20 (n-hexane/EtOAc: 1:2); IR (KBr) 3450–3310,
2920 cmꢀ1 1H NMR d 1.00 (s, 9H), 3.02 (dd, J = 13.6, 6.3 Hz, 1H), 3.43 (dd, J = 13.6,
4a0.
(1R,RS)-N-tert-Butylsulfinyl-2-(2-hydroxymethylphenyl)-1-
½ ꢃ
a 2D0
m
;
8.7 Hz, 1H), 4.22 (br s, 1H), 4.48 (d, J = 11.5 Hz, 1H), 4.59–4.65 (m, 1H), 4.72 (d,
J = 11.5 Hz, 1H), 5.11 (br s, 1H), 7.10–7.15 (m, 1H), 7.16–7.24 (m, 2H), 7.23–7.32
(m, 4H), 7.41 (d, J = 7.2 Hz, 2H); 13C NMR d 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); MS (MALDI-TOF): m/z 332 (M+H)+; HRMS: (M-H2O)+ found
313.1487, C19H23NOS requires 313.1500. (1S,RS)-N-tert-Butylsulfinyl-2-(2-
hydroxymethylphenyl)-1-phenylethanamine (4a0): mp 127–128 °C (pentane/
8. (a) Weix, D. J.; Ellman, J. A. Org. Lett. 2003, 5, 1317–1320; (b) Weix, D. J.; Ellman,
J. A. Org. Synth. 2005, 82, 157–165.
9. (a) Wakayama, M.; Ellman, J. A. J. Org. Chem. 2009, 74, 2646–2650; (b)
Aggarwal, V. K.; Barbero, N.; McGarrigle, E. M.; Mickle, G.; Navas, R.; Suárez, J.
R.; Unthank, M. G.; Yar, M. Tetrahedron Lett. 2009, 50, 3482–3484.
10. For reviews on functionalised organolithium compounds, see: (a) Nájera, C.;
Yus, M. Trends Org. Chem. 1991, 2, 155–181; (b) Nájera, C.; Yus, M. Org. Prep.
Proc. Int. 1995, 27, 383–457; (c) Nájera, C.; Yus, M. Recent Res. Dev. Org. Chem.
1997, 1, 67–96; (d) Yus, M.; Foubelo, F. Rev. Heteroatom Chem. 1997, 17, 73–
107; (e) Nájera, C.; Yus, M. Curr. Org. Chem. 2003, 7, 867–926; (f) Nájera, C.;
Sansano, J. M.; Yus, M. Tetrahedron 2003, 59, 9255–9303; (g) Chinchilla, R.;
Nájera, C.; Yus, M. Chem. Rev. 2004, 104, 2667–2722; (h) Chinchilla, R.; Nájera,
C.; Yus, M. Tetrahedron 2005, 61, 3139–3176; (i) See also the special issue of
Tetrahedron Symposium in Print (Eds.: Nájera, C; Yus, M.) devoted to
‘Functionalised Organolithium Compounds’, Tetrahedron 2005, 61, issue no.
13.; (j) Yus, M.; Foubelo, F. In Handbook of Functionalized Organometallics;
Knochel, P., Ed.; Wiley-VCH: Weinheim, 2005. Chapter 2; (k) Foubelo, F.; Yus,
M. Chem. Soc. Rev. 2008, 37, 2620–2633.
dichloromethane); ½a D20
ꢃ
ꢀ38 (c 0.48, CH2Cl2); Rf: 0.14 (n-hexane/EtOAc: 1:2); IR
m
(KBr) 3430–3300, 2923 cmꢀ1
;
1H NMR d 1.10 (s, 9H), 3.12 (dd, J = 11.8, 5.3 Hz,
1H), 3.20 (dd, J = 11.8, 6.3 Hz, 1H), 3.70 (br s, 1H), 4.10–4.16 (m, 1H), 4.62–4.71
(m, 3H), 7.11–7.16 (m, 1H), 7.26–7.34 (m, 8H); 13C NMR d 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); MS (MALDI-TOF): m/z 332 (M+H)+.
24. Crystal data (excluding structure factors deposited at the Cambridge
Crystallographic Data Centre as supplementary publication number CCDC
727086):
b = 18.4104(16) Å, c = 10.3906(9) Å, b = 106.513(2); V = 1905.5(3) Å3; space
group P2(1); Z = 4; Dc = 1.155 Mg mꢀ3 = 0.179 mmꢀ1
k = 0.71073 Å;
F(000) = 712; T = 23 1 °C. Data collection was performed on a Bruker Smart
CCD diffractometer, based on three
C19H25NO2S,
M = 331.46;
monoclinic,
a = 10.3893(9) Å,
;
l
;
11. For reviews, see: (a) Yus, M.; Foubelo, F. Rev. Heteroatom Chem. 1997, 17, 73–
107; (b) Yus, M.; Foubelo, F. In Targets in Heterocyclic Systems; Attanasi, O. A.,
Spinelli, D., Eds.; Italian Society of Chemistry: Rome, 2002; pp 136–171; (c)
Yus, M. Pure Appl. Chem. 2003, 75, 1453–1475; (d) Yus, M.; Foubelo, F. Adv.
Heterocycl. Chem. 2006, 91, 135–158.
x-scan runs (starting = ꢀ34°) at values
u = 0°, 120°, 240° with the detector at 2h = ꢀ32°. For each of these runs, 606
frames were collected at 0.3° intervals and 30 s per frame. An additional run at
u = 0° of 100 frames was collected to improve redundancy. The diffraction
frames were integrated using the program SAINT (SAINT Version 6.02A: Area-
12. For reviews, see: (a) Yus, M. Chem. Soc. Rev. 1996, 25, 155–161; (b) Ramón, D. J.;
Yus, M. Eur. J. Org. Chem. 2000, 225–237; (c) Yus, M. Synlett 2001, 1197–1205;
(d) Yus, M.; Ramón, D. J. Lat. J. Chem. 2002, 79–92; (e) Ramón, D. J.; Yus, M. Rev.
Cubana Quim. 2002, 14, 75–115; (f) Yus, M.. In The Chemistry of Organolithium
Compounds; Rappoport, Z., Marek, I., Eds.; John Wiley & Sons: Chichester, 2004;
Vol. 1,. Part 2, Chapter 11.
13. Almena, J.; Foubelo, F.; Yus, M. Tetrahedron 1995, 51, 3351–3364.
14. (a) Soler, T.; Bachki, A.; Falvello, L. R.; Foubelo, F.; Yus, M. Tetrahedron:
Asymmetry 1998, 9, 3939–3943; (b) Soler, T.; Bachki, A.; Falvello, L. R.; Foubelo,
F.; Yus, M. Tetrahedron: Asymmetry 2000, 11, 493–517.
15. (a) Falvello, L. R.; Foubelo, F.; Soler, T.; Yus, M. Tetrahedron: Asymmetry 2000,
11, 2063–2066; (b) Foubelo, F.; Soler, T.; Yus, M. Tetrahedron: Asymmetry 2001,
12, 801–810.
16. Foubelo, F.; Gómez, C.; Gutiérrez, A.; Yus, M. J. Heterocycl. Chem. 2000, 37,
1061–1064.
Detector Integration Software.; Siemens Industrial Automation, Inc.: Madison,
WI, 1995) and the integrated intensities were corrected for Lorentz-
polarisation effects with SADABS (Sheldrick, G. M. SADABS
: Area-Detector
Absorption Correction; Göttingen University, 1996). The structure was solved
by direct methods27 and was refined to all 7474 unique Fo by full matrix least
squares.27 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 Fo > 4r(Fo).
25. (a) Bharatam, P. V.; Amita; Kaur, D. J. Phys. Org. Chem. 2002, 15, 197–203; (b)
Bharatam, P. V.; Uppal, P.; Amita; Kaur, D. J. Chem. Soc. Perkin Trans. 2 2000, 43–
50.
26. Typical procedure for stereoselective synthesis of compound 6a. To a stirred
solution of 4a (165 mg, 0.50 mmol) in MeOH (6 mL) was added a 4 M HCl
(1 mL) solution in dioxane at 0 °C. After 3 h stirring at this temperature, a
saturated NaHCO3 solution was added. The reaction mixture was extracted
with ethyl acetate (3 ꢂ 10 mL), dried over anhydrous MgSO4 and evaporated
(15 Torr). 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 this, solvents were evaporated (15 Torr) and the resulting residue was
dissolved in THF (5 mL) and a 5 M sodium hydroxide solution (10 mL) was
added. The resulting mixture was vigorously stirred for 10 h at 20 °C and then
it was extracted with ethyl acetate (3 ꢂ 15 mL), dried over anhydrous MgSO4
and evaporated (15 Torr). The residue was purified by column chromatography
(silica gel, chloroform/methanol) to yield pure title product (R)-3-phenyl-
17. (a) Pastor, I. M.; Yus, M. Tetrahedron Lett. 2000, 41, 1589–1592; (b) Pastor, I. M.;
Yus, M. Tetrahedron 2001, 57, 2371–2378; (c) Yus, M.; Gomis, J. Tetrahedron
Lett. 2001, 42, 5721–5724; (d) Yus, M.; Gomis, J. Eur. J. Org. Chem. 2002, 1989–
1995; (e) Yus, M.; Gomis, J. Eur. J. Org. Chem. 2003, 2043–2048.
18. Azzena, U.; Demartis, S.; Melloni, G. J. Org. Chem. 1996, 61, 4913–4919.
19. (a) Foubelo, F.; García, D.; Moreno, B.; Yus, M. Tetrahedron Lett. 2007, 48, 3379–
3383; (b) García, D.; Foubelo, F.; Yus, M. Tetrahedron 2008, 64, 4275–4286.
20. (a) García Ruano, J. L.; Carreño, M. C.; Toledo, M. A.; Aguirre, J. M.; Aranda, M.
T.; Fischer, J. Angew. Chem., Int. Ed. 2000, 39, 2736–2737; (b) García Ruano, J. L.;
Alemán, J.; Soriano, J. F. Org. Lett. 2003, 5, 677–680; (c) García Ruano, J. L.;
Alemán, J. Org. Lett. 2003, 5, 4513–4516; (d) García Ruano, J. L.; Aranda, M. T.;
Aguirre, J. M. Tetrahedron 2004, 60, 5383–5392; (e) Arroyo, Y.; Meana, A.;
Rodríguez, J. F.; Santos, M.; Sanz-Tejedor, M. A.; García Ruano, J. L. J. Org. Chem.
2005, 70, 3914–3920; (f) García Ruano, J. L.; Alemán, J.; Parra, A. J. Am. Chem.
Soc. 2005, 127, 13048–13054; (g) García Ruano, J. L.; Alemán, J.; Cid, M. B.
Synthesis 2006, 687–691; (h) Arroyo, Y.; Rodríguez, J. F.; Santos, M.; Sanz
Tejedor, M. A.; García Ruano, J. L. J. Org. Chem. 2007, 72, 1035–1038; (i) Arroyo,
Y.; Meana, A.; Sanz Tejedor, M. A.; Alonso, I.; García Ruano, J. L. J. Org. Chem.
2009, 74, 764–772.
1,2,3,4-tetrahydroisoquinoline (6a):28 a 2D0
½ ꢃ +125 (c 0.55, CH2Cl2); Rf: 0.34
(chloroform/methanol: 10:1); HPLC analysis (HPLC analyses were performed
on a JASCO 200-series equipped with a CHIRALCEL-OJ column, 1.0 mL/min,
k = 215 nm, 99:1 n-hexane/i-PrOH), tR = 79.7 min; IR
m (KBr) 3420–3385, 3063,
3026, 2923, 2851 cmꢀ1 1H NMR d 2.02 (br s, 1H), 3.02 (d, J = 7.5 Hz, 2H), 4.05
;
(t, J = 7.5 Hz, 1H), 4.17 (d, J = 15.5 Hz, 1H), 4.28 (d, J = 15.5 Hz, 1H), 7.07–7.18
(m, 4H), 7.29–7.40 (m, 3H), 7.44 (d, J = 7.2 Hz, 2H); 13C NMR d 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); MS: m/z 209 (M+, 33%), 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: M+ found 209.1204, C15H15N requires 209.1204.
21. See, for instance: Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J.
Org. Chem. 1999, 64, 1278–1284.
22. (a) Almansa, R.; Guijarro, D.; Yus, M. Tetrahedron: Asymmetry 2008, 19, 603–
606; (b) Almansa, R.; Guijarro, D.; Yus, M. Tetrahedron: Asymmetry 2008, 19,
2484–2491.
27. SHELX97 [includes SHELXS97, SHELXL97 and CIFTAB]—Programs for Crystal Structure
Analysis (Release 97-2). Sheldrick, G. M., Institüt für Anorganische Chemie der
Universität, Tammanstrasse 4, D-3400 Göttingen, Germany, 1998.
28. Enders, D.; Braig, V.; Boudou, M.; Raabe, G. Synthesis 2004, 2980–2990.