Synthesis of camphorsulfonamide-based quinoline ligands and their N-oxides: first use in the enantioselective addition of organozinc reagents to aldehydes

Article abstract of DOI:10.1016/j.tetasy.2008.10.020

The preparation of several camphorsulfonamide-based quinoline derivatives and their N-oxides was accomplished via an indirect Friedlaender synthesis using aminobenzylic alcohols and RuCl₂(DMSO)₄ as a catalyst. These ligands were tested in the enantioselective addition of dialkylzinc reagents to aldehydes, with enantiomeric excesses up to 96%. A similar protocol using triphenylborane and diethylzinc gave the corresponding phenylation process.

Full text of DOI:10.1016/j.tetasy.2008.10.020

Tetrahedron: Asymmetry 19 (2008) 2600–2607
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of camphorsulfonamide-based quinoline ligands and their
N-oxides: first use in the enantioselective addition of organozinc
reagents to aldehydes
a,
a,
Ricardo Martínez a, Luca Zoli a,b, Pier Giorgio Cozzi b, , Diego J. Ramón , Miguel Yus
*
*
*
a Instituto de Síntesis Orgánica (ISO) and Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, E-03080-Alicante, Spain
b Dipartimento di Chimica ‘G. Ciamician’, Via Selmi 2, 4012-Bologna, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation of several camphorsulfonamide-based quinoline derivatives and their N-oxides was
accomplished via an indirect Friedländer synthesis using aminobenzylic alcohols and RuCl2(DMSO)4 as
a catalyst. These ligands were tested in the enantioselective addition of dialkylzinc reagents to aldehydes,
with enantiomeric excesses up to 96%. A similar protocol using triphenylborane and diethylzinc gave the
corresponding phenylation process.
Received 15 October 2008
Accepted 22 October 2008
Available online 20 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
hand, we have recently described an easy entry to the indirect
Friedländer synthesis of quinoline derivatives, starting from 2-
Chiral ligands bearing nitrogen chelating donor atoms are of
great interest nowadays1 due to their easy preparation and avail-
ability. Furthermore, they are easily recovered from the reaction
media generally by an acidic–basic extraction. In this context, the
most used chiral nitrogen-donor ligands are those that involve
the pyridine ring.2 The related quinoline derivatives are less devel-
oped and only a few examples with the monoterpene camphor
skeleton have been recently described.3 The synthesis of ligands
1,4 2,5 and 36 always involves an important number of synthetic
steps under very challenging reaction conditions, which hamper
down their possible applications.
aminobenzylic alcohol derivatives and ketones or alcohols, cata-
lyzed by ruthenium.9,10
Herein, we would like to introduce a new and straightforward
pathway to the synthesis of a new class of camphorsulfonamide-
based quinoline ligands, as well as of their corresponding N-oxides,
and their use in the enantioselective addition of organozinc
reagents to aldehydes11 in the presence of titanium tetraiso-
propoxide.12
2. Results and discussion
The previous success in the use of camphorsulfonamide-based
ligands in the enantioselective alkylation of aldehydes13 prompted
us to modify this structure. The addition of a chelating group, such
as a nitrogen atom, might modulate the activity of catalysts and
therefore its reactivity.
PPh2
N
N
N
X
Ph2P
2.1. Synthesis of chiral ligands
2
1
3a:
3b:
X = PPh2
X = SPh
Our previous experience with isoborneolsulfonamide ligands
has taught us that the reactivity of the ligands was strongly depen-
dent on the presence of one or two units of the isoborneol moiety,
even in the presence of an extra-sulfonamide unit (first,14 sec-
ond,15 and third generation16 isoborneolsulfonamide ligands).
With this fact in mind, we synthesized the three related types of
ligands. The first class of ligands 7 (C1-symmetry) was prepared
by reaction of chiral camphorsulfonyl chloride 4 with the ketones
corresponding amine 5, and without a further purification the ob-
tained produces were annulated by reaction with the aminobenzyl
On one hand, we have described different isoborneolsulfona-
mide ligands,7 which have proven to be very useful as promoters
of the addition of organozinc reagents to ketones.8 On the other
* Corresponding authors. Tel.: +35 965 90 35 48; fax: +35 965 90 35 49.
E-mail addresses: piergiorgio.cozzi@unibo.it (P. G. Cozzi), djramon@ua.es (D. J.
Ramón), yus@au.es (M. Yus).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.10.020

R. Martínez et al. / Tetrahedron: Asymmetry 19 (2008) 2600–2607
2601
Table 1
Synthesis of monoquinoline camphorsulfonamide ligands 7
R4
N
1
2
R3
5
i, R R NH , DMAP (45 mol%),
Et3N, CH3CN, 0 ºC, 24 h
R2
O
ii, RuCl2(DMSO)4 (2mol%),
KOH, Ph2CO,1,4-dioxane,
100 ºC, 72 h
O2S
N
R1
SO2Cl
HO
4
7
H2N
R3
R4
6
Entry
R1
R2
R3
R4
No
Yielda (%)
1
2
3
4
H
H
H
Me
Bn
Bn
H
H
7a
7b
7c
7d
71
54
77
74
CH@CHCH@CH
(CH2)2NMe2
(CH2)2NMe2
H
H
H
H
a
Isolated yield after column chromatography.
alcohol 6 (see Table 1). The yields obtained were homogeneous
independently of the initial amine.
catalyzed by ruthenium gave the expected compounds 13, with
moderated overall yields (Scheme 1).
The second type of ligands 8–10 (C2-symmetry) were prepared
in a similar way, but using 1,2-cyclohexanodiamine derivatives
and a double amount of all reagents. It should be noted that the
yields obtained in these cases were slightly higher than those pre-
sented in Table 1.
The related N-dioxides, which appear in Scheme 2, were easily
prepared from the corresponding C2-ligands by oxidation with
m-CPBA in methylenechloride at 0 °C according to the previously
described protocol.17 The resulting derivatives 14–16 were stable
enough to be purified by column chromatography.
N
N
N
N
O
SO2
NH
N
SO2
NH
SO2
NH
SO2
NH
SO2
NH
m-CPBA (208 mol%)
NH
SO2
NH
SO2
NH
SO2
CH2Cl2, 0 ºC, 3 h
NH
NH
SO2
O
N
SO2
N
N
N
N
8
9
10
(84%)
(95%)
(85%)
8
14
(48%)
The third class of quinoline ligands 13 was prepared starting
from chiral diamine 11 by reaction with the corresponding arene-
sulfonyl chloride (12) in two phases media, followed by a standard
reaction with the chiral camphorsulfonyl chloride (4). The final
indirect Friedländer annulation using 2-aminobenzyl alcohol (6a)
N
O
SO2
N
O
O2S
HN
NH
HN
NH
N
O2S
SO2
O
N
O
N
i, 4-XC6H4SO2Cl 12, CH2Cl2,
NaOH (2 M), 0 ºC, 6 h
SO2
NH
NH2
NH2
NH
SO2
ii,
4
16
15
(62%)
(51%)
O
11
Scheme 2. Synthesis of N-oxide derivatives 14–16.
SO2Cl
X
DMAP, Et3N, CH3CN, 0 ºC, 24 h
2.2. Enantioselective addition of orgnaozinc reagents to
aldehydes
13a
13b
X = Me (28%)
X = CF3 (21%)
ii, 2-H2NC6H4CH2OH 6a,
RuCl2(DMSO)4 (2mol%),
KOH, Ph2CO,1,4-dioxane,
100 ºC, 72 h
Once the different types of ligands were synthesized, they were
tested in the enantioselective addition of diethylzinc 18a to benz-
aldehyde 17a as shown in Table 2.
Scheme 1. Synthesis of compounds 13.

2602
R. Martínez et al. / Tetrahedron: Asymmetry 19 (2008) 2600–2607
Table 2
Table 3
Optimization of the enantioselective addition of diethylzinc to benzaldehyde
Enantioselective addition of dialkylzinc reagents to aldehydes
O
OH
O
OH
R2
Ti(OPri)4 (110 mol%)
Ligand
R1
H
+
R22Zn
R1
+ Et Zn
2
H
PhMe, -30 ºC, 24 h
Additive, PhMe
17
18
19
19a
17a
Liganda
18a
N
(240 mol%)
Entry
T (°C)
T (h)
Additiveb
Yieldc (%)
eed (%)
SO2
NH
1
2
7a (10)
7b (10)
7c (10)
7d (10)
8 (10)
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
25
16
16
16
16
16
16
16
16
16
16
16
16
16
16
48
16
16
6
Ti(OPri)4 (110)
Ti(OPri)4 (110)
Ti(OPri)4 (110)
Ti(OPri)4 (110)
Ti(OPri)4 (110)
Ti(OPri)4 (110)
Ti(OPri)4 (110)
Ti(OPri)4 (110)
Ti(OPri)4 (110)
Ti(OPri)4 (110)
Ti(OPri)4 (110)
Ti(OPri)4 (110)
—
95
>95
>95
>95
89
24 (R)
15 (S)
0 (—)
0 (—)
31 (S)
17 (S)
9 (R)
89 (S)
65 (S)
2 (R)
3b
4
NH
SO2
5
6
7
8
9 (10)
10 (10)
95
13a (10 mol%)
>95
>95
>95
93
90
94
38
50
24
14
13a (10)
13b (10)
14 (10)
15 (10)
16 (10)
8 (10)
Entry
R1
R2
No
Yielda (%)
eeb (%)
9
1
2
3
4
5
6
7
8
9
Ph
Ph
4-ClC6H4
Et
Me
Et
Et
Et
Et
Et
Et
Et
Et
19a
19b
19c
19d
19e
19f
19g
19h
19i
>95
94c
89
92 (S)
80 (S)
90 (S)
75 (S)
87 (S)
89 (S)
96 (S)
63 (S)
50 (S)
93 (S)
10
11
12
13
14
15
16
17
18
19
20
21e
22
9 (S)
14 (R)
6 (S)
4-NCC6H4
56c
>95
>95
>95
65
8 (10)
Ti(OPri)4 (10)
—
21 (S)
30 (S)
0 (—)
50 (S)
31 (S)
92 (S)
85 (S)
95 (S)
91 (S)
4-CF3C6H4
4-MeOC6H4
1-Naphthyl
(E)-PhCH@CH
PhC„C
13a (10)
13a (10)
13a (10)
13a (10)
13a (10)
13a (5)
13a (10)
13b (10)
Ti(OPri)4 (10)
Cu(OTf)2 (10)
Ti(OPri)4 (110)
Ti(OPri)4 (110)
Ti(OPri)4 (110)
Ti(OPri)4 (110)
Ti(OPri)4 (110)
21
82
>95
>95
67
86
>95
10
PhCH2CH2
19j
86c
ꢀ30
ꢀ30
ꢀ30
ꢀ30
24
40
24
24
a
Isolated yield after column chromatography.
Enantiomeric excess obtained by HPLC (see Section 4). The absolute configu-
ration is reported in parentheses.
b
c
a
Values after 48 h reaction time.
The amount of ligand is reported in parentheses.
The amount of additive is reported in parentheses.
Yield of isolated alcohol 19a after bulb to bulb distillation.
b
c
d
Enantiomeric excess obtained by HPLC (chiracel OD-H). The absolute configu-
ration is reported in parentheses.
While a decrease in the amount of catalyst 13a at ꢀ30 °C
seemed to have a negative impact on the results, the same
was not true for the amount of diethylzinc (compare entries
19–21).
e
The amount of diethylzinc 18a was reduced to 180 mol %.
The initial reaction conditions, as well as reagent ratios, were
chosen from our standard protocols (a large excess of diethylzinc,
nearly stoichiometric amount of titanium tetraisopropoxide,
10 mol % of ligand in toluene at low temperature).18 The ethylation
took place in 16 h under these conditions using simple quinoline
derivative 7a, giving the expected secondary alcohol 19a in nearly
quantitative yield but in low enantiomeric excess (Table 2, entry
1). The same reaction using the most hindered benzo[h]quinoline
ligand 7b also gave a modest enantioselectivity, with the absolute
configuration of the secondary alcohol 19a surprisingly being the
opposite one (entry 2). The presence of an extra chelating nitrogen
atom different from the quinoline one had an important negative
effect on the enantiomeric excess of the secondary alcohol (entries
3 and 4). The use of the C2-symmetric ligands did not improve the
previous results, although they showed that the absolute configu-
ration of the secondary alcohol 19a was dictated by the diamine
unit and not by the camphor moiety with these ligands (entries
8–10). The reaction using the C1-ligand 13a, bearing only one cam-
phor–quinoline unit, gave a good result not only in terms of yield
but also in enantioselectivity (entry 8). The related more acidic li-
gand 13b gave, however, a lower enantiomeric excess (entry 9).
It should be noted that the N-dioxide derivatives 14–16 gave
even worse results than the initial C2-symmetric ligands (compare
entries 5–7 and 10–12).
Finally, it should be noted that, whereas at ꢀ10 °C the behavior
of both ligands 13 was different (entries 8 and 9), the reaction at
ꢀ30 °C gave similar results independent of the ligand used (entries
19 and 22).
Once the best conditions were found (Table 2, entry 19), the
scope of the reaction was studied, with the results shown in Table
3. The results were similar using different sources of nucleophiles,
such as diethylzinc and dimethylzinc (compare entries 1 and 2).
The electronic character of the arenecarbaldehyde derivative
seemed not to have any important impact on the results, since
para-substituted benzaldehyde derivatives with either electron-
withdrawing or electron-donating groups gave results similar to
those found with benzaldehyde (compare entries 1 and 3–6). The
possible differences might be due to the presence of a new chelat-
ing group, with the cyano derivative giving the lowest results in
this series by competing with the oxygen atom of the carbonyl
group for complexation with the Lewis acid center. The best result
was obtained when the highly hindered naphtha-1-ylcarbaldedyde
was used as the electrophile (entry 7). Surprisingly, when the reac-
tion was carried out using
a,b-unsaturated aldehydes the results
were lower. However, the reaction using the related saturated
OH
When the reaction was performed in the absence of titanium
tetraisopropoxide, or using substoichiometric amounts of either
this Lewis acid or copper(II) triflate, the results were clearly infe-
rior (entries 13–17).
The effect of temperature was the classical one, a lower temper-
ature gave a higher enantioselectivity and reaction time (compare
entries 8, 18, and 19).
i, PhMe, 70 ºC,16 h
Ph
BPh3 + Et2Zn
20 18a
ii, Ti(OPri)4 (110 mol%), PhMe,
13a (5 mol%), 4-ClC6H4CHO,
-30 ºC, 24 h
Cl
21
(68%, 53% e.e.)
Scheme 3. Phenylation of 4-chlorobenzaldehyde.

R. Martínez et al. / Tetrahedron: Asymmetry 19 (2008) 2600–2607
2603
aliphatic aldehyde gave high levels of enantioselectivity (compare
entries 8–10).
4.1. General procedure for the preparation of compounds 7a–d
and 8–10
The final process studied was the phenylation of aldehydes as
shown in Scheme 3. It has been established that the transmetalla-
tion of triphenylborane 20 with diethylzinc 18a gave a new
organozinc reagent bearing both ethyl and phenyl groups. This
new organozinc reagent has been used as an efficient phenylating
agent.19,20 In fact, after the transmetallation process at 70 °C, the
standard reaction with 4-chlorobenzaldehyde 17b in the presence
of titanium tetraisopropoxide and chiral ligand 13a gave, after
hydrolysis, alcohol 21 as the only secondary alcohol isolated. In
fact, we were unable detect the corresponding alcohol 19c by
GC-analysis of the crude mixture. This result showed that the
change of the source of the nucleophilic zinc reagent has an impor-
tant effect on the level of enantioselectivity previously reached,
with this lower enantioselectivity seemingly due to the higher vol-
ume of nucleophile.
To
a solution of the corresponding amine 5 (15 mmol,
7.5 mmol for compounds 8–10), triethylamine (15.6 mmol) and
dimethylaminopyridine (6.75 mmol) in acetonitrile (30 mL) at
0 °C was added dropwise
a solution of (1S)-(+)-10-camp-
horsulfonylchloride 4 (15.6 mmol) in acetonitrile (30 mL). The
solution was stirred for 24 h allowing the temperature to reach
25 °C. Then, the mixture was quenched by the addition of a 3 M
solution of NaOH (30 mL) and the resulting mixture was ex-
tracted with EtOAc (3 ꢂ 30 mL). The combined organic layers
were washed with a 2 M solution of HCl (60 mL), dried over
anhydrous Na2SO4, and filtered. Finally, the solvent was re-
moved under reduced pressure to afford the corresponding cam-
phorsulfonamides. Then, to
a
solution of RuCl2(DMSO)4
(0.3 mmol) and KOH (45 mmol) in 1,4-dioxane (50 mL) was
added the corresponding camphorsulfonamide (ca. 15 mmol) fol-
lowed by the corresponding alcohol 6 (22.5 mmol) and benzo-
phenone (22.5 mmol). The mixture was stirred and heated at
100 °C for a period of 72 h. After this period of time, the mix-
ture was filtered through Celite and the solvent was removed
under reduced pressure. The resulting residue was purified by
flash chromatography on silica gel using suitable mixtures of
either hexane/EtOAc (for compounds 7a,b, 8–10) or EtOAc/
MeOH (for compounds 7c,d) to afford the corresponding quino-
line derivatives 7–10. Yields are reported in Table 1 and text.
Spectroscopic and analytical data follow.
3. Conclusions
In conclusion, we have described the synthesis of a new class of
chiral quinoline ligands, which were prepared by the reaction of
camphorsulfonyl chloride with different amines and final indirect
Firedländer annulation catalyzed by ruthenium. These compounds
have been used as ligands in the enantioselective addition of
organozinc reagents to aldehydes, giving good enantioselectivities
in the case of using either aromatic or aliphatic ones.
4.1.1. N-Benzyl-(1S,12S)-15,15-dimethyl-3-azatetra-
cyclo[10.2.1.02,11.04,9]pentadeca-2(11),3,5,7,9-pentaen-1-
ylmethanesulfonamide 7a
4. Experimental
Melting points were obtained with a Reichert Thermovar appa-
ratus. [a]D were recorded at room temperature (ca. 25 °C) in a DIP-
Rf 0.54 (hexane/EtOAc: 3/2); ½a D20
ꢃ
¼ þ76:9 (c 8.5, CHCl3);
m
(film) 3068, 1634, 1581 cmꢀ1 (C@CH); dH 0.50 and 1.01 (3
and 3H, respectively, 2s, 2 ꢂ CH3), 1.20–1.30, 2.00–2.05, 2.15–
1000 JASCO polarimeter. FT-IR spectra were obtained on a Nicolet
Impact 400D spectrophotometer. NMR spectra were recorded on a
Bruker AC-300 (300 MHz for 1H and 75 MHz for 13C) using CDCl3 as
solvent and TMS as internal standard; chemical sifts are given in d
(ppm) and coupling constants (J) in Hz. Mass spectra (EI) were ob-
tained at 70 eV on a Shimazdu QP-5000 spectrometer, giving frag-
ment ions in m/z with relative intensities (%) that are given in
parentheses. The high resolution mass spectroscopy was per-
formed by the corresponding Mass Spectrometry Service at the
University of Alicante. The purity of volatile products and the chro-
matographic analyses (GLC) were determined with a Hewlett Pack-
ard HP-5890 instrument equipped with a flame ionization detector
and 12 m HP-1 capillary column (0.2 mm diam, 0.33 mm film
thickness, OV-1 stationary phase), using nitrogen (2 mL/min) as
carrier gas, Tinjector = 275 °C, Tdetectror = 300 °C, Tcolumn = 60 °C
(3 min) and 60–270 °C (15 °C/min), P = 40 kPa; tr values are given
in min under these conditions. The enantiomeric ratios (e.r.) for
the calculation of enantiomeric excess of tertiary alcohols were
determined by HPLC analysis in a HP-1100 or a Jasco P-1030 appa-
ratus by using hexane/2-propanol mixtures as solvents, and Chiral-
cel OD-H (ODH) and Chiralcel OJ (OJ) as chiral columns, indicating
in each case the column and solvent ratio used. The tr (R) and tr (S)
values are given in min under these conditions. Thin layer chroma-
tography (TLC) was carried out on Schleicher & Schuell F1400/LS
254 plates coated with a 0.2 mm layer of silica gel; detection by
UV254 light, staining with phosphomolybdic acid (25 g phospho-
molybdic acid, 10 g Ce(SO4)2 ꢁ 4H2O, 60 mL concentrated H2SO4
and 940 mL H2O); Rf values are given under these conditions. Col-
umn chromatography was performed using silica gel 60 of 35–
70 mesh. All reagents were commercially available (Acros, Aldrich,
Strem) and were used as received. Solvents were dried by standard
procedures.
2.25 (1,
1 and 2H, respectively, 3m, CH2CH2), 2.97 (1H, d,
J = 3.3 Hz, CHCH2), 3.22 and 3.55 (1 and 1H, respectively, 2d,
J = 15.2 Hz, CH2SO2), 4.35–4.45 and 4.55–4.60 (1 and 1H, 2m,
CH2N), 7.25–7.45 and 7.70–7.75 (8 and 2H, respectively, 2m,
ArH), 9.51 (1H, t, J = 6.3 Hz, NH); dC 19.0, 20.4, 26.5, 30.25,
48.25, 50.55, 51.75, 55.45, 57.6, 126.15, 127.6, 127.65, 127.7,
127.75, 128.35, 128.7 (2C), 128.75 (2C), 128.8, 137.4, 139.4,
145.15, 168.45; m/z 238 (M+ꢀ168, 10%), 237 (70), 236 (100),
220 (11), 209 (18), 208 (14), 195 (19), 194 (50), 193 (14),
192 (14), 180 (21); HRMS: M+ found 406.1722. C24H26SN2O2 re-
quires 406.1715.
4.1.2. N-Benzyl-(1S,16S)-19,19-dimethyl-3-azapenta-
cyclo[14.2.1.04,13.05,10]nonadeca-2(15),3,5(10),6,8,11,13-
heptaen-1-ylmethanesulfonamide 7b
Rf 0.52 (hexane/EtOAc: 6/4); ½a D2:
ꢃ
¼ þ28:0 (c 13.5, CHCl3);
m
(film) 3295 (NH), 3060, 1613, 1563 (SO2) cmꢀ1 (C@CH); dH
0.48 and 1.04 (3 and 3H, respectively, 2s, 2 ꢂ CH3), 1.22–1.32,
1.95–2.00 and 2.20–2.40 (1,
1 and 2H, respectively, 3m,
CH2CH2), 3.00 (1H, d, J = 3.7 Hz, CHCH2), 3.30 and 3.67 (2H,
2d, J = 15.1 Hz, CH2SO2), 4.48–4.63 (2H, m, CH2N), 7.15–7.40,
7.50–7.65, 7.75–7.85 and 8.78 (6, 2, 3 and 1H, respectively,
3m and d, respectively, J = 8.3 Hz, ArH), 8.82 (1H, t, J = 6.6 Hz,
NH); dC 19.3, 20.15, 26.25, 29.0, 47.5, 50.5, 52.35, 55.75, 58.05,
123.35, 125.4, 125.6, 126.8, 127.05, 127.3, 127.4, 128.0 (2C),
128.2, 128.3 (2C), 128.45, 130.75, 133.25, 137.35, 139.95,
143.3, 166.85; m/z 288 (M+ꢀ168, 11%), 287 (68), 286 (100),
285 (14), 258 (14), 245 (17), 244 (45), 243 (18), 242 (25), 230
(21), 106 (11), 91 (10); HRMS: M+ꢀC7H8NO2S found 286.1593.
C21H20N requires 286.1596.

2604
R. Martínez et al. / Tetrahedron: Asymmetry 19 (2008) 2600–2607
4.1.3. N-(2-Dimethylaminoethyl)-(1S,12S)-15,15-dimethyl-3-
azatetracyclo[10.2.1.02,11.04,9]pentadeca-2(11),3,5,7,9-pentaen-
1-ylmethanesulfonamide 7c
1.20–1.30, 1.40–1.50, 1.60–1.65, 1.80–1.90, 2.15–2.25, 2.35–2.45
and 2.90 [2, 2, 2, 4, 2, 4 and 2H, respectively, 6m and d, respec-
tively, J = 3.9 Hz, (CH2)4 and 2 ꢂ CH2CH2CH)], 3.33 and 4.13 (2H
each one, 2d, J = 15.2 Hz, 2 ꢂ CH2SO2), 3.65–3.70 (2H, m, 2 ꢂ CHN),
7.45–7.50, 7.55–7.60, 7.70–7.75, 7.94 and 8.44 (2, 2, 4, 2 and 2H,
respectively, 3m and 2d, respectively, J = 3.8 and 8.1 Hz, ArH and
2 ꢂ NH); dC 19.20 (2C), 20.25 (2C), 24.20 (2C), 26.30 (2C), 28.75
(2C), 33.75 (2C), 50.60 (2C), 53.35 (2C), 55.00 (2C), 56.15 (2C),
57.40 (2C), 125.90 (2C), 127.15 (2C), 127.55 (2C), 127.75 (2C),
127.95 (2C), 128.25 (2C), 139.30 (2C), 145.40 (2C), 168.75 (2C);
m/z 413 (M++1, 29%), 412 (100), 317 (31), 301 (14), 300 (76), 238
(11), 237 (58), 236 (51), 220 (10), 209 (11), 208 (13), 206 (11),
195 (14), 194 (49), 193 (13), 192 (10), 180 (25); M+ꢀC23H30N3O4S2
found 236.1445. C17H18N requires 236.1439.
Rf 0.55 (MeOH); ½a D20
ꢃ
¼ þ76:2 (c 1.0, CHCl3);
m (film) 3063, 1644,
1578 (C@CH), 1325, 1145 (SO2) cmꢀ1; dH 0.64 and 1.08 (3H each
one, 2s, 2 ꢂ CH3), 1.30–1.35, 2.00–2.10 and 2.20–2.30 (1, 1 and
2H, respectively, 3m, CH2CH2), 2.17 (6H, s, NMe2), 2.45–2.55 and
2.70–2.75 (1 and 1H, respectively, 2m, CH2NMe2), 3.00 (1H, d,
J = 3.3 Hz, CHCH2), 3.35–3.45 (2H, m, CH2NH), 3.26 and 3.92 (1H
each one, 2d, J = 14.9 Hz, CH2SO2), 7.45–7.50, 7.55–7.65, 7.75,
7.80 and 8.10 (1H each one, 2m, d, s and d, respectively, J = 7.8
and 8.3 Hz, respectively, ArH), 8.71 (1H, s, NH); dC 19.05, 20.25,
26.30, 29.85, 41.45, 45.00 (2C), 50.45, 50.70, 55.30, 57.25, 58.75,
125.80, 127.20, 127.25, 127.50, 127.85, 128.20, 139.10, 145.40,
168.25; m/z 330 (M+ꢀ57, 22%), 329 (78), 279 (10), 237 (15), 236
(25), 194 (24), 193 (12), 192 (14), 180 (13), 58 (100); HRMS:
C21H29N3O2S found 387.1978. C21H29N3O2S requires 387.1980.
4.1.7. N-{(1R,2S)-2-[(1S,12S)-15,15-Dimethyl-3-azatetra-
cyclo[10.2.1.02,11.04,9]pentadeca-2(11),3,5,7,9-pentaen-1-
ylmethylsulfonamido]cyclohexyl}-(1S,12S)-15,15-dimethyl-3-
azatetracyclo[10.2.1.02,11.04,9]pentadeca-2(11),3,5,7,9-pentaen-
1-ylmethanesulfonamide 10
4.1.4. N-(2-Dimethylaminoethyl)-N-methyl-(1S,12S)-15,15-
dimethyl-3-azatetracyclo[10.2.1.02,11.04,9]pentadeca-
2(11),3,5,7,9-pentaen-1-ylmethanesulfonamide 7d
Mp 248–250 °C; Rf 0.55 (hexane/EtOAc: 1/1); ½a D20
¼ þ142:0 (c
ꢃ
Rf 0.36 (MeOH); ½a D20
ꢃ
¼ þ17:0 (c 1.2, CHCl3);
m
(film) 3043, 1638,
1.0, CHCl3); m (KBr) 3138, 3065, 2949, 1640, 1574, 1507, (C@CH),
1582 (C@CH), 1346, 1147 (SO2) cmꢀ1; dH 0.60 and 1.27 (3H each
one, 2s, 2 ꢂ CH3), 1.20–1.35, 1.45–1.55, 2.25–2.30, 2.75–2.90 and
2.95 (1H each one, 4m and d, J = 3.7 Hz, CH2CH2CH), 2.30 (6H, s,
NMe2), 2.50–2.65 (2H, m, CH2NMe2), 3.11 (3H, s, NMe), 3.35–
3.45, 3.50–3.60 (1H each one, 2m, CH2NMe), 3.38 and 4.19 (1H
each one, 2d, J = 14.9 Hz, CH2SO2), 7.45–7.50, 7.55–7.65, 7.70–
7.75 and 8.10 (1, 1, 2 and 1H, respectively, 3m and d, respectively,
J = 8.3 Hz, ArH); dC 19.95, 20.00, 26.20, 27.40, 35.05, 45.20 (2C),
47.05, 48.05, 50.95, 54.40, 56.80, 57.55, 125.50, 126.30, 127.40,
127.70, 127.80, 128.55, 138.05, 146.25, 169.45; m/z 279
(M+ꢀ122, 17%), 237 (19), 236 (23), 194 (15), 58 (100); HRMS:
M+ꢀC5H13N2O2S found 236.1441. C17H18N requires 236.1439.
1407, 1140 (SO2) cmꢀ1; dH 0.55, 0.60, 1.01 and 1.04 (3H each
one, 4s, 4 ꢂ CH3), 1.15–1.40, 1.60–2.00, 2.00–2.35, 2.90–2.95 [3,
7,
6
and 2H, respectively, 4m, (CH2)4 and 2 ꢂ CH2CH2CH)],
3.20, 3.43, 3.65 and 4.73 (1H each one, 4d, J = 15.1 Hz,
2 ꢂ CH2SO2), 3.65–3.70 and 4.40–4.45 (1H each one, 2m,
2 ꢂ CHN), 6.65–6.70 and 6.85–6.90 (1H each one, 2m, 2 ꢂ NH),
7.25–7.30, 7.50–7.55, 7.60–7.70, 7.80–7.85, 8.05–8.10 and 8.50–
8.55 (1, 2, 2, 2, 1 and 2H, respectively, 6m, ArH); dC 19.10,
19.20, 20.25, 20.30, 20.70, 23.70, 26.25, 26.50, 27.95, 30.00,
30.40, 31.80, 50.45, 50.75, 51.70, 54.10, 55.05, 55.40, 55.90,
56.00, 57.25, 57.55, 125.75, 125.80, 126.95, 127.25, 127.40,
127.45, 127.50, 127.70, 127.80, 128.00, 128.05, 128.10, 139.20,
140.10, 144.75, 145.60, 168.35, 169.45; m/z 413 (M+ꢀ299,
33%), 412 (100), 317 (27), 302 (12), 301 (16), 300 (85), 237
(40), 236 (56), 220 (12), 209 (11), 208 (14), 195 (15), 194 (57),
193 (16), 192 (12), 180 (29); M+ꢀC23H30N3O4S2 found
236.1434. C17H18N requires 236.1439.
4.1.5. N-{(1R,2R)-2-[(1S,12S)-15,15-Dimethyl-3-azatetra-
cyclo[10.2.1.02,11.04,9]pentadeca-2(11),3,5,7,9-pentaen-1-
ylmethylsulfonamido]cyclohexyl}-(1S,12S)-15,15-dimethyl-3-
azatetracyclo[10.2.1.02,11.04,9]pentadeca-2(11),3,5,7,9-pentaen-
1-ylmethanesulfonamide 8
Mp 163–165 °C; Rf 0.61 (hexane/EtOAc: 1/1); ½a D20
ꢃ
¼ þ60:8 (c
4.2. General procedure for the preparation of compounds 13
1.1, CHCl3);
m (KBr) 3048, 1632, 1588 (C@CH), 1340, 1147 (SO2)
cmꢀ1; dH 0.59 and 1.10 (6H each one, 2s, 4 ꢂ CH3), 1.20–1.35,
1.45–1.50, 1.60–1.65, 1.75–1.80, 1.95–2.00, 2.20–2.40 and 2.97
[2, 2, 2, 2, 2, 6 and 2H, respectively, 6m and d, respectively,
J = 3.7 Hz, (CH2)4 and 2 ꢂ CH2CH2CH)], 3.41 and 4.08 (2H each
one, 2d, J = 14.9 Hz, 2 ꢂ CH2SO2), 3.65–3.75 (2H, m, 2 ꢂ CHN),
7.35–7.45, 7.70–7.75, 7.93 and 8.07 (4, 4, 2 and 2H, respectively,
2m and 2d, respectively, J = 3.8 and 8.1 Hz, ArH and 2 ꢂ NH); dC
14.15 (2C), 19.30 (2C), 20.25 (2C), 24.20 (2C), 26.40 (2C), 29.35
(2C), 50.60 (2C), 52.60 (2C), 55.15 (2C), 57.40 (2C), 57.45 (2C),
125.80 (2C), 127.05 (2C), 127.50 (2C), 127.75 (2C), 128.10 (2C),
128.15 (2C), 139.50 (2C), 145.60 (2C), 168.65 (2C); m/z 413
(M+ꢀ299, 29%), 412 (100), 317 (30), 301 (17), 300 (88), 237 (47),
236 (68), 220 (16), 209 (14), 208 (16), 206 (11), 195 (20), 194
(74), 193 (20), 192 (15), 181 (10), 180 (40); HRMS:
M+ꢀC23H30N3O4S2 found 236.1430. C17H18N requires 236.1439.
To a mixture of (1R,2R)-1,2-diaminocyclohexane 11 (12 mmol)
in a biphasic system of a 2 M solution of NaOH (15 mL) and CH2Cl2
(15 mL) at 0 °C, a solution of the corresponding arenesulfonyl chlo-
ride 12 (12 mmol) in CH2Cl2 (15 mL) was added dropwise over a
period of 20 min. The resulting mixture was stirred and left to
reach room temperature for a period of 6 h. Then, to this solution
was added a 2 M solution of HCl until the pH was acid. The organic
layer was rejected and the aqueous phase was basified using a 6 M
solution of NaOH until basic pH and extracted with CH2Cl2
(4 ꢂ 60 mL). The combined organic layers were dried over anhy-
drous Na2SO4 and filtered. Finally, the solvent was removed under
reduced pressure and the residue was obtained. Then, to a solution
of the above residue, triethylamine (54 mmol) and dimethylami-
nopyridine (6 mmol) in acetonitrile (25 mL) at 0 °C was added
dropwise
a solution of (1S)-(+)-10-camphorsulfonylchloride 4
(18 mmol) in acetonitrile (25 mL). The resulting solution was stir-
red for 24 h allowing the temperature to reach to 25 °C. Then, the
mixture was quenched by the addition of a 3 M solution NaOH
(50 mL) and it was extracted with EtOAc (4 ꢂ 40 mL). The com-
bined organic layers were washed with a 2M solution of HCl
(60 mL), dried over anhydrous Na2SO4, and filtered. Finally, the sol-
vent was removed under reduced pressure to give a new residue.
Finally, to a solution of RuCl2(DMSO)4 (0.2 mmol) and KOH
(40 mmol) in 1,4-dioxane (50 mL) was added the above residue
4.1.6. N-{(1R,2R)-2-[(1R,12R)-15,15-Dimethyl-3-azatetra-
cyclo[10.2.1.02,11.04,9]pentadeca-2(11),3,5,7,9-pentaen-1-
ylmethylsulfonamido]cyclohexyl}-(1R,12R)-15,15-dimethyl-3-
azatetracyclo[10.2.1.02,11.04,9]pentadeca-2(11),3,5,7,9-pentaen-
1-ylmethanesulfonamide 9
Mp 125–127 °C; Rf 0.52 (hexane/EtOAc: 1/1); ½a D20
¼ ꢀ67:2 (c
ꢃ
1.0, CHCl3);
m (KBr) 3056, 2962, 1638, 1570, 1513, (C@CH), 1399,
1149 (SO2) cmꢀ1; dH 0.38 and 1.02 (6H each one, 2s, 4 ꢂ CH3),

R. Martínez et al. / Tetrahedron: Asymmetry 19 (2008) 2600–2607
2605
(ca. 10 mmol) followed by 2-aminobenzyl alcohol (30 mmol) and
benzophenone (30 mmol). The resulting mixture was stirred and
heated at 100 °C for a period of 72 h. After this period, the mixture
was filtered through Celite and the solvent was removed under re-
duced pressure. The resulting residue was purified by flash chro-
matography on silica gel using suitable mixtures of hexane/
EtOAc to afford the corresponding quinolines 13. Yields are re-
ported in Scheme 1. Spectroscopic and analytical data follow.
Yields are reported in Scheme 2. Spectroscopic and analytical data
follow.
4.3.1. 1-{(1R,2R)-2-[(1S,12S)-15,15-Dimethyl-3-olato-3-azonia-
tetracyclo[10.2.1.02,11.04,9]pentadeca-2(11),3,5,7,9-pentaen-1-
ylmethylsulfonamido]cyclohexylsulfamoylmethyl}-(1S,12S)-
15,15-dimethyl-3-azoniatetracyclo[10.2.1.02,11.04,9]pentadeca-
2(11),3,5,7,9-pentaen-3-olate 14
Mp 150–152 °C; Rf 0.79 (EtOAc/MeOH: 9/1); ½a D20
¼ ꢀ4:5 (c 1.1,
ꢃ
4.2.1. N-[(1R,2R)-2-(4-Methylphenylsulfonamido)cyclo-hexyl]-
(1S,12S)-15,15-dimethyl-3-azatetracyclo[10.2.1.02,11.04,9]penta-
deca-2(11),3,5,7,9-pentaen-1-ylmethanesulfonamide 13a
CHCl3); m (KBr) 3077, 2971, 2920, 2859, 1635, 1584, 1501 (C@CH),
1273, 1156 (SO2) cmꢀ1; dH 0.75 and 1.15 (6H each one, 2s,
4 ꢂ CH3), 1.20–1.55, 1.70–1.80, 1.90–2.00, 2.15–2.30, 2.60–2.70
and 2.93 [6, 2, 2, 4, 2 and 2H, respectively, 5m and d, J = 3.7 Hz,
(CH2)4 and 2 ꢂ CH2CH2CH)], 3.50–3.55 (2H, m, 2 ꢂ CHN), 3.73
and 4.14 (2H each one, 2d, J = 15.0 Hz, 2 ꢂ CH2SO2), 7.15 (2H, s,
2 ꢂ NH), 7.47, 7.55–7.65, 7.75 and 8.68 (2, 4, 2 and 2H, respec-
tively, s, m and 2d, respectively, J = 7.6 and 8.4 Hz, ArH); dC 19.05
(2C), 20.70 (2C), 24.05 (2C), 26.05 (2C), 28.25 (2C), 51.65 (2C),
52.05 (2C), 55.50 (2C), 55.75 (2C), 57.80 (4C), 119.25 (2C), 119.35
(2C), 127.50 (2C), 128.05 (2C), 129.05 (2C), 129.60 (2C), 140.95
(2C), 141.85 (2C), 151.20 (2C); m/z 412 (M+ꢀ332, 19%), 238 (15),
237 (87), 236 (100), 235 (14), 234 (13), 222 (20), 220 (19), 209
(22), 208 (23), 206 (12), 204 (11), 195 (24), 194 (72), 193 (22),
192 (21), 181 (10), 180 (34); HRMS: M+ꢀC23H30N3O3S found
316.1053. C17H18NO3S requires 316.1007.
Mp 105–107 °C; Rf 0.53 (hexane/EtOAc: 1/1); ½a D20
¼ ꢀ0:7 (c 1.6,
ꢃ
CHCl3);
m ;
(KBr) 2942, 1648, 1613 (C@CH), 1332, 1159 (SO2) cmꢀ1
dH 0.60, 1.07 and 2.19 (3H each one, 3s, 3 ꢂ CH3), 1.20–1.40, 1.60–
1.70, 1.90–2.10, 2.15–2.30, 2.40–2.45 and 3.02 [5, 2, 2, 2, 1 and 1H,
respectively, 5m and d, respectively, J = 3.7 Hz, (CH2)4 and
CH2CH2CH)], 2.80–2.90 and 3.20–3.30 (1H each one, 2m, 2 ꢂ CHN),
3.35 and 3.52 (1H each one, 2d, J = 15.1 Hz, CH2SO2), 5.75 (1H, d,
J = 3.4 Hz, NH), 7.20 and 7.89 (2H each one, 2d, J = 8.1 Hz,
C6H4CH3), 7.40–7.60 and 7.75–7.80 (3 and 2H, respectively, 2m,
ArH), 8.80 (1H, d, J = 7.2 Hz, NH); dC 18.95, 20.15, 21.20, 23.80,
24.70, 26.30, 30.20, 32.45, 33.75, 50.30, 53.35, 55.35, 56.75,
57.30, 58.20, 126.05, 126.85, 127.55 (2C), 127.65 (2C), 128.30,
136.50 (2C), 139.40, 142.80 (2C), 144.60 (2C), 167.85; m/z 413
(M+ꢀ154, 19%), 412 (70), 317 (32), 301 (19), 300 (100), 237 (42),
236 (69), 220 (12), 208 (13), 195 (14), 194 (54), 193 (17), 192
(13), 180 (29), 96 (26), 91 (23); HRMS: M+ꢀC13H19N2O4S2 found
236.1468. C17H18N requires 236.1439.
4.3.2. 1-{(1R,2R)-2-[(1R,12R)-15,15-Dimethyl-3-olato-3-
azoniatetracyclo[10.2.1.02,11.04,9]pentadeca-2(11),3,5,7,9-
pentaen-1-ylmethylsulfonamido]cyclohexylsulfamoylmethyl}-
(1R,12R)-15,15-dimethyl-3-azoniatetracyclo[10.2.1.02,11.04,9]-
pentadeca-2(11),3,5,7,9-pentaen-3-olate 15
4.2.2. N-[(1R,2R)-2-(4-Trifluoromethylphenylsulfonamido)-
cyclohexyl]-(1S,12S)-15,15-dimethyl-3-azatetracyclo-
[10.2.1.02,11.04,9]pentadeca-2(11),3,5,7,9-pentaen-1-
ylmethanesulfonamide 13b
Mp 152–154 °C; Rf 0.71 (EtOAc/MeOH: 9/1); ½a D20
¼ þ44:0 (c
ꢃ
1.0, CHCl3);
m (KBr) 3067, 2958, 2926, 2853, 1633, 1579, 1501
(C@CH), 1274, 1146 (SO2) cmꢀ1; dH 0.65 and 0.95 (6H each one,
2s, 4 ꢂ CH3), 1.10–1.30, 1.40–1.55, 1.75–1.80, 1.90–2.00, 2.10–
2.20, 2.45–2.50, 2.65–2.75 and 2.90 [2, 4, 2, 2, 2, 2, 2 and 2H,
respectively, 7m and d, J = 3.9 Hz, (CH2)4 and 2 ꢂ CH2CH2CH)],
3.45–3.55 (2H, m, 2 ꢂ CHN), 3.55 and 5.34 (2H each one, 2d,
J = 15.2 Hz, 2 ꢂ CH2SO2), 6.90 (2H, s, 2 ꢂ NH), 7.48, 7.50–7.55,
7.60–7.65, 7.75–7.80 and 8.73 (2H each one, 3m and d, respec-
tively, J = 8.4 Hz, ArH); dC 18.70 (2C), 20.50 (2C), 24.50 (2C), 26.10
(2C), 27.05 (2C), 34.75 (2C), 50.45 (2C), 51.30 (2C), 55.45 (2C),
56.40 (2C), 57.25 (2C), 118.95 (2C), 119.10 (2C), 127.55 (2C),
127.85 (2C), 128.95 (2C), 129.55 (2C), 140.95 (2C), 141.85 (2C),
151.00 (2C); m/z 412 (M+ꢀ332, 7%), 333 (12), 253 (23), 252 (10),
238 (15), 237 (89), 222 (21), 220 (16), 209 (23), 208 (27), 206
(12), 204 (10), 195 (24), 194 (71), 193 (22), 192 (20), 181 (10),
180 (35), 167 (12); HRMS: M+ꢀC23H30N3O5S2 found 252.1351.
C17H18NO requires 252.1388.
Mp 113–115 °C; Rf 0.56 (hexane/EtOAc: 1/1); ½a D20
¼ ꢀ1:1 (c 1.0,
ꢃ
CHCl3);
m ;
(KBr) 2944, 1619, 1583 (C@CH), 1323, 1173 (SO2) cmꢀ1
dH 0.60 and 1.06 (3H each one, 2s, 2 ꢂ CH3), 1.30–1.40, 1.60–1.70,
1.90–2.00, 2.15–2.30, 2.35–2.40 and 3.01 [5, 2, 2, 2, 1 and 1H,
respectively, 5m and d, respectively, J = 3.7 Hz, (CH2)4 and
CH2CH2CH)], 2.90–2.95 and 3.20–3.30 (1H each one, 2m, 2 ꢂ CHN),
3.37 and 3.50 (1H each one, 2d, J = 15.1 Hz, CH2SO2), 6.17 (1H, d,
J = 4.4 Hz, NH), 7.45–7.60 and 7.75–7.80 (3 and 2H, respectively,
2m, ArH), 7.66 and 8.16 (2H each one, 2d, J = 8.3 Hz, C6H4CF3),
8.98 (1H, d, J = 6.8 Hz, NH); dC 19.00, 20.20, 23.95, 24.80, 26.30,
30.35, 32.45, 34.25, 50.40, 53.45, 55.45, 56.95, 57.35, 58.80,
120.45 (q, J1,2 = 272.9 Hz, CF3), 125.75, 125.80, 125.85, 126.15,
126.80, 127.60, 127.70, 127.75, 128.30, 128.45, 133.60 (q,
J1,3 = 33.7 Hz, CCF3), 139.35, 143.40, 144.60, 167.80; m/z 413
(M+ꢀ208, 19%), 412 (70), 317 (32), 301 (20), 300 (100), 237 (26),
236 (66), 222 (11), 220 (11), 208 (12), 195 (12), 194 (51), 193
(16), 192 (12), 180 (27), 145 (15), 138 (42), 96 (18), 83 (10), 55
(12) 43 (12); HRMS: M+ꢀC7H4F3O2S found 412.2083. C23H30N3O2S
requires 412.2059.
4.3.3. 1-{(1R,2S)-2-[(1S,12S)-15,15-Dimethyl-3-olato-3-
azoniatetracyclo[10.2.1.02,11.04,9]pentadeca-2(11),3,5,7,9-
pentaen-1-ylmethylsulfonamido]cyclohexylsulfamoylmethyl}-
(1S,12S)-15,15-dimethyl-3-azoniatetracyclo[10.2.1.02,11.04,9]-
pentadeca-2(11),3,5,7,9-pentaen-3-olate 16
4.3. General procedure for the preparation of N-oxides 14–16
Mp 145–147 °C; Rf 0.65 (EtOAc/MeOH: 9/1); ½a D20
¼ ꢀ32:5 (c
ꢃ
To a solution of the corresponding quinolines 8–10 (5 mmol) in
CH2Cl2 (35 mL s) was added m-chloroperbenzoic acid
(10.85 mmol) at 0 °C. The resulting mixture was allowed to rise
to room temperature. After 3 h, the mixture was quenched by
addition of a saturated solution of NaCl (30 mL) and extracted
with CH2Cl2 (3 ꢂ 25 mL). The combined organic layers were dried
over anhydrous Na2SO4 and filtered. Finally, the solvent was re-
moved under reduced pressure and the resulting residue was
purified by flash chromatography on silica gel using suitable mix-
tures of EtOAc/MeOH to afford the corresponding N-oxides 14–16.
1.1, CHCl3); m (KBr) 3060, 2965, 2932, 2859, 1629, 1579, 1507
(C@CH), 1268, 1150 (SO2) cmꢀ1; dH 0.75, 0.79, 1.09 and 1.11 (3H
each one, 4s, 4 ꢂ CH3), 1.20–1.50, 1.65–2.00, 2.10–2.25, 2.60–2.70
and 2.95 [7, 5, 2, 2 and 2H, respectively, 4m and d, respectively,
J = 4.0 Hz, (CH2)4 and 2 ꢂ CH2CH2CH)], 3.55 and 4.74 (1H each
one, 2d, J = 15.3 Hz, CH2SO2), 3.70 and 4.85 (1H each one, 2d,
J = 15.1 Hz, CH2SO2), 4.03 (2H, s, 2 ꢂ CHN), 7.50–7.70, 7.80 and
8.10–8.80 (6, 2 and 2H, respectively, m, d and m, respectively,
J = 7.5 Hz, ArH); dC 18.75 (2C), 20.65, 20,70, 23.55, 25.90, 26.05,
28.00, 30.45, 30.50, 38.50, 50.95, 51.05, 51.30, 52.55, 53.35,

2606
R. Martínez et al. / Tetrahedron: Asymmetry 19 (2008) 2600–2607
55.25, 55.35, 57.70, 57.85, 67.95, 119.05 (2C), 119.10, 127.55 (2C),
127.90, 128.00, 128.85, 129.00, 129.50, 129.55 (2C), 140.60, 140.70,
141.65, 141.75 (2C), 150.85; m/z 412 (M+ꢀ332, 30%), 317 (11), 300
(25), 238 (15), 237 (84), 236 (100), 235 (13), 234 (12), 222 (21), 220
(20), 209 (23), 208 (24), 206 (13), 204 (11), 195 (26), 194 (80), 193
(25), 192 (23), 181 (11), 180 (37), 167 (14); HRMS:
M+ꢀC23H30N3O5S2 found 252.1316. C17H18NO requires 252.1388.
(CO); dH 2.37 (d, J = 3.3 Hz, 1H, OH), 5.78 (d, J = 3.1 Hz, 1H, CHO),
7.25–7.35 (m, 9H, ArH); dC 75.55, 126.50 (2C), 127.30, 127.85
(2C), 128.50, 128.55 (2C), 128.60 (2C), 142.15, 143.35; m/z 218
(M+, 24%), 217 (13), 216 (41), 181 (12), 167 (16), 166 (10), 165
(23), 152 (11), 141 (26), 139 (67), 113 (12), 111 (24), 106 (11),
105 (100), 78 (10), 77 (50), 76 (10), 75 (19), 51 (19).
Acknowledgments
4.4. General procedure for the enantioselective addition of
dialkylzinc reagents to aldehydes
This work was generously supported by the Dirección General
de Universidades of the Spanish Ministerio de Ciencia e Innovación
(Consolider Ingenio 2010/CSD2007-00006 and CTQ2007-65218/
BQU). We want to thank also the Spanish Ministerio de Ciencia e
Innovación and the Italian Ministero dell’Istruzione, dell’Università
e della Ricerca for an integrated project (HI2007-0219). R. M.
thanks the Generalitat Valenciana for a predoctoral grant. We also
thank MEDALCHEMY SL for the gift of some chemicals.
To a solution of corresponding ligand 13 (0.057 g, 0.1 mmol) in
toluene (2 mL) under a nitrogen atmosphere was added the corre-
sponding solution of dialkylzinc reagent (9 mmol, 4.5 mL, ca. 2M)
at ꢀ30 °C. After 10 min, Ti(OPri)4 (1.1 mmol, 0.33 mL) was added
to the above solution and after 10 additional min, the correspond-
ing aldehyde (1 mmol) was successively added. The resulting mix-
ture was stirred at the same temperature for 24 h. Then, methanol
(ca. 1 mL) and saturated NH4Cl solution (ca. 20 mL) were succes-
sively added, the mixture was filtered through Celite and extracted
with ethyl acetate (3 ꢂ 50 mL), and the organic layer was dried
over Na2SO4. The solvents were removed under reduced pressure
(15 Torr) and the residue was distilled bulb to bulb to yield the ex-
pected alcohols. Yields and enantiomeric excesses are shown in Ta-
bles 2 and 3. Compounds 19a–d and 19f,13a as well as 19e18 and
19h–j13b were already described by us and were characterized by
comparison of their physical and spectroscopic data with those re-
ported in the literature. Spectroscopic and physical data, as well as
literature reference for compound 19g follow.
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min) tr (S) 10.1, tr (R) 16.7; ½a D
ꢃ ¼ ꢀ38:0 (c 3.8, CHCl3) e.r. (S/R):
98/2;
m
(film) 3477 (OH), 1088 cmꢀ1 (CO); dH 0.94 (t, J = 7.3 Hz,
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In a pressure tube charged with triphenylborane 20 (0.387 g,
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mixture was cooled down to 0 °C, and ligand 13a (0.029 g,
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rise to 25 °C, 4-chlorobenzaldedhyde 17b (1 mmol) was added.
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24 h, quenched by the successive addition of methanol (1 mL)
and a saturated solution of NH4Cl (15 mL). The mixture was filtered
through Celite and the resulting solution was extracted with EtOAc
(3 ꢂ 15 mL). The organic layers were dried over anhydrous Na2SO4,
filtered, and concentrated. The residue was purified by flash chro-
matography (hexane/EtOAc) to give the title compound. Yield and
enantiomeric excesses are included in Scheme 3. Physical and
spectroscopic data follow: Colorless oil. Rf 0.41 (hexane/EtOAc: 8/
2); tr (GC) = 14.3 min; HPLC (AD-H, UV 210 nm, hexane/2-propa-
nol: 95/5, flow 0.8 mL/min) tr (R) 17.5, tr (S) 19.2; [
a]D = +6.5 (c
2.4, CHCl3) e.r.(S/R): 76.5/23.5;
m
(film) 3427 (OH), 1089 cmꢀ1

R. Martínez et al. / Tetrahedron: Asymmetry 19 (2008) 2600–2607
2607
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