New functional derivatives of 9-phenylquinine

Article abstract of DOI:10.1055/s-0029-1216933

A rapid synthesis of various 9-aryl derivatives of quinine is presented. They are obtained via coupling reactions of functionalized arylmagnesium halides and 9-chloroquinine.

Full text of DOI:10.1055/s-0029-1216933

PAPER
3113
New Functional Derivatives of 9-Phenylquinine
F
unctionalDe
r
rivatives
z
of 9-Pheny
e
lquinine mysław J. Boratyński, Jacek Skarżewski*
Department of Organic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wyspiańskiego 27, Wrocław 50-317, Poland
Fax +48(71)3284064; E-mail: jacek.skarzewski@pwr.wroc.pl
Received 14 March 2009; revised 13 May 2009
iodo- and 4-iodotoluene with (9S)-9-chloroquinine (1).
Abstract: A rapid synthesis of various 9-aryl derivatives of quinine
The respective (9S)-9-tolylquinines 2a and 2b were ob-
tained in fair yields. The higher was achieved for the
is presented. They are obtained via coupling reactions of function-
alized arylmagnesium halides and 9-chloroquinine.
ortho-product, indicating that the presence of a substituent
Key words: cinchona alkaloid, Grignard reaction, chiral pool, cou-
at this position has no unfavorable effect on the reaction
pling reaction, quinine
outcome (Table 1). The stereochemical course of the reac-
tion with phenylmagnesium bromide has previously been
established by X-ray crystallography,6 and this time the
Enantioselective bifunctional organocatalysts have at-
tracted much interest over the last decade.1 Most notably
Table 1 Synthesis of 9-Aryl Derivatives of Quinine
they concern the derivatives of cinchona alkaloids.2 These
compounds, apart from the native basic and nucleophilic
OMe
OMe
center of the quinuclidine moiety, may contain a hydrogen
bond donor such as a phenolic group (cupreines)3 or
thiourea4 (Figure 1). Although new catalytic applications
of these types of compounds continue to evolve rapidly,
the number of possible derivatizations is still very limited.
ArMgX
THF–toluene
80 °C, 18 h
N
N
Ar
Cl
N
N
2a–p
1
Entry
Ar
Product
2a
Yield (%)
OMe
OH
1
2
3
4
5
6
7
8
9
2-MeC6H4
4-MeC6H4
54
38
74
43
456
62
67
61
45
N
CF3
N
OBz
2b
NH
2-MOMOC6H4
3-MOMOC6H4
4-MOMOC6H4
2-(MOMOCH2)C6H4
3-(MOMOCH2)C6H4
3-Bn2NC6H4
2c
N
S
N
CF3
N
H
2d
Figure 1 Selected bifunctional cinchona alkaloid derivatives3,4
2e
2f
There is a single, dated report of a coupling reaction be-
tween 9-chloroquinine 1 and phenylmagnesium bromide
to afford 9-phenylquinine of unspecified configuration.5
In our preliminary study we discovered that this reaction
proceeds with surprisingly high stereoselectivity towards
the 8,9-like isomer.6 This approach seemed to provide a
new way to introduce additional functionalities to the cin-
chona alkaloid framework. So far, however, only one such
substituted compound has been obtained.6 Later we uti-
lized the same approach to obtain a dimeric cinchona al-
kaloid derivative.7
2g
2h
4-Bn2NC6H4
2i
N
N
10
11
2j
31
40
2k
In this paper we present the syntheses of a series of substi-
tuted 9-arylquinine derivatives, bearing various heteroat-
oms. We also further investigate the scope of the coupling
reaction between 9-chloroquinine and various Grignard
reagents.
12
13
14
15
3-IC6H4
2l
23
80
49
70
4-IC6H4
2m
2n
2o
3-BrC6H4
4-BrC6H4
In the initial experiments we separately reacted the Grig-
nard reagents obtained from magnesium turnings and 2-
SYNTHESIS 2009, No. 18, pp 3113–3119
Advanced online publication: 14.08.2009
x
x.
x
x
.
2
0
0
9
16
2p
47
DOI: 10.1055/s-0029-1216933; Art ID: T05809SS
© Georg Thieme Verlag Stuttgart · New York

3114
P. J. Boratyński, J. Skarżewski
PAPER
same configuration of products were confirmed by
NOESY NMR experiments.
OMe
OMe
N
N
The organomagnesium compounds obtained from meth-
oxymethoxy (MOM)-protected 2- and 3-iodophenol were
added to a solution of (9S)-9-chloroquinine (1); the reac-
tion afforded the respective protected phenolic derivatives
of quinine 2c and 2d. These experiments concluded the
series with the known 4-isomer 2e.6 The yields were ex-
ceptionally good for the 2-MOM ether 2c. Similarly 2-
and 3-iodobenzyl alcohols were protected as their MOM
ethers which, unlike THP protection, proved appropriate
for their transformation to Grignard reagents. The reaction
of these compounds with 1 afforded 2f and 2g in good
yields. The deprotection step, uncovering the hydroxy
functionality was carried out by the treatment of the phe-
nol ethers with 95% trifluoroacetic acid for two hours.
While quantitative transformation was observed for 2d
and 2e, 2-MOM-phenyl 2c remained unchanged. An ap-
plication of slightly harsher conditions (4 M HCl in
MeOH, 48 h) allowed for the quantitative removal of the
MOM group from 2c as well. The same conditions were
used to cleave the MOM groups from the primary alco-
hols 2f and 2g (Table 2).
1) BuLi, THF –25 °C
2) DMF
48%
N
N
O
O
MOM
MOM
2c
4
Scheme 1 Reactivity of 2c with butyllithium
with the respective iodoaniline. The reaction of the de-
rived Grignard reagents with 1 produced the coupling
products 2h and 2i in fair to good yields. However, the
corresponding synthesis of the 2-(dibenzylamino)phenyl
isomer was unsuccessful. An attempted cleavage of the
benzyl groups in 2h,i under hydrogenation conditions
failed and only the vinyl group reacted affording 5 from
2h (Scheme 2).
OMe
OMe
N
N
H2, Pd
MeOH
NBn2
NBn2
87%
Table 2 Removal of MOM group from 2c–g
N
N
5
2h
OMe
OMe
Scheme 2 Catalytic hydrogenation of 2h
N
N
n = 0, 1
The Grignard reagents bearing tertiary aliphatic amino
groups were also coupled with 9-chloroquinine 1. The re-
action of either 2-(pyrrolidin-1-ylmethyl)phenylmagne-
sium iodide and 2-(piperidin-1-ylmethyl)phenyl-
magnesium iodide resulted in the respective products 2j
and 2k in 31% and 40% yields.
N
N
OMOM
OH
n
n
2c–g
3c–g
Entry Substrate Conditions
Product Yield (%)
1
2
3
4
5
6
2c
2c
2d
2e
2f
TFA–H2O (20:1), 2 h
3c
3c
3d
3e
3f
0
98
93
99
98
96
The presence of an additional halogen atom at the new
benzene ring makes the product suitable for further cou-
plings. Thus we obtained mono-Grignard reagents from
1,3- and 1,4-isomers of diiodobenzene and dibromoben-
zene. The coupling reaction was very effective, however
the crude products contained also (9S)-9-phenylquinine.
This problem particularly concerned the syntheses of 3-
substituted products 2l and 2n and caused their yields to
be much lower (23% and 49%). On the other hand, 4-sub-
stituted products 2m and 2o were obtained in very good
yields.
The substitution of 1 proceeded well with most of the sp2-
Grignard reagents and even very bulky ones like pyren-1-
ylmagnesium bromide affording coupling product 2p in
modest yields. However, the synthesis was ineffective
with sp3-type Grignard reagents. No coupling product was
isolated with either ethyl,6 cyclohexyl, or allyl reagents.
Yet, when we reacted the sp-organomagnesium com-
pound derived from phenylacetylene with (9S)-9-chloro-
quinine (1), the alkyne-substitution product 2q
spontaneously rearranged to the respective allene 6
(Scheme 3). The diastereoselectivity of the overall pro-
4 M HCl in MeOH, 48 h
TFA–H2O (20:1), 2 h
TFA–H2O (15:1), 2 h
4 M HCl, MeOH, 48 h
TFA–H2O (20:1), 2 h
2g
3g
In order to functionalize the introduced aromatic ring fur-
ther, 2c was treated of with butyllithium at –25 °C, aiming
at a lithiation (hydrogen–metal exchange) at a site adja-
cent to the MOM group. However, this reaction resulted
in butylation at the C2¢ atom only to give 4 (Scheme 1),
analogous to the reaction of native quinine.8 The 1H NMR
spectrum of phenol 3c, in which the hydroxy group is in
the 2-position, showed two sets of signals that exhibited
coalescence at 40 °C (DG‡ ~14.5 kcal/mol).
Having successfully introduced both aromatic and ali-
phatic hydroxy functionalities, we attempted the same
with amino groups. First we obtained and N,N-dibenzyl-
3- and -4-iodoaniline by the reaction of benzyl chloride
Synthesis 2009, No. 18, 3113–3119 © Thieme Stuttgart · New York

PAPER
Functional Derivatives of 9-Phenylquinine
3115
OMe
OMe
OMe
N
N
N
PhC≡CMgCl
THF
Cl
30%
N
N
N
Ph
Ph
6
1
2q
aS/aR ca. 1.5:1
Scheme 3 Reaction of phenylethynylmagnesium chloride with (9S)-9-chloroquinine (1)
HRMS: m/z [M + H]+ calcd for C27H31N2O: 399.2431; found:
399.2434.
cess was poor, which is likely to be associated with a re-
arrangement step lacking stereoselectivity. The final
yellow product 6 was isolated as a mixture of axial iso-
mers. Both infrared (1938 cm–1) and 13C NMR (d = 206.6/
206.2) spectra confirmed their structure.
(8S,9S)-6¢-Methoxy-9-(4-methylphenyl)cinchonan (2b)
Rf = 0.31 (CHCl3–MeOH, 10:1); [a]D28 –112 (c 1, CH2Cl2).
IR (KBr): 2936, 2860, 1620, 1586, 1508, 1471, 1430, 1258, 1230,
1031, 841, 826, 632 cm–1.
In summary, we have demonstrated that various function-
alities can be introduced to the cinchona alkaloid scaffolds
by a coupling reaction of properly substituted arylmagne-
sium iodides with 9-chloroquinine. The products were
formed in fair to very good yields. The syntheses were at
most two steps and the final deprotection usually proceed-
ed quantitatively.
1H NMR (300 MHz, CDCl3): d = 8.67 (d, J = 4.7 Hz, 1 H), 7.91 (d,
J = 9.2 Hz, 1 H), 7.43 (br, 1 H), 7.32 (d, J = 4.7 Hz, 1 H), 7.26 (dd,
J = 9.2, 2.6 Hz, 1 H), 7.18 (d, J = 7.7 Hz, 2 H), 6.97 (d, J = 7.7 Hz,
2 H), 5.87 (ddd, J = 17.4, 9.9, 7.3 Hz, 1 H), 4.95–5.03 (m, 2 H), 4.64
(d, J = 11.2 Hz, 1 H), 3.89 (s, 3 H), 3.63 (m, 1 H), 3.23 (m, 1 H),
3.16 (dd, J = 14.1, 10.1 Hz, 1 H), 2.60–2.73 (m, 2 H), 2.21 (m, 1 H),
2.15 (s, 3 H), 1.84 (m, 1 H), 1.45–1.66 (m, 3 H), 0.75 (m, 1 H).
13C NMR (75.5 MHz, CDCl3): d = 157.7, 147.6, 147.0, 144.7,
142.0, 139.1, 136.2, 131.8, 129.3, 128.7, 127.7, 120.9, 119.5, 114.3,
102.1, 59.6, 56.6, 55.5, 49.3, 40.9, 39.6, 28.9, 28.1, 28.0, 21.0.
HRMS: m/z [M + H]+ calcd for C27H31N2O: 399.2431; found:
399.2428.
The iodoaryls were protected with methoxymethoxy or benzyl
groups according to known procedures9 using commercially avail-
able materials. 1 was most conveniently prepared by treatment of
quinine with SOCl2.10 1H NMR samples in CDCl3 (TMS as internal
standard) were recorded on a Brucker DRX 300 spectrometer (300
MHz). IR spectra were recorded on a Perkin Elmer 1600 FT-IR
spectrophotometer. Observed rotations at 589 nm were measured
using an Optical Activity Ltd. Model AA-5 automatic polarimeter.
HRMS were recorded on a Waters LCT Premier XE (oa-TOF/ESI)
apparatus. Silica gel (60–120 mesh) was used for chromatographic
separation.
Anal. Calcd for C27H30N2O·0.5 H2O: C, 79.57; H, 7.67; N, 6.87.
Found: C, 79.54; H, 7.67; N, 6.98.
(8S,9R)-6¢-Methoxy-9-[2-(methoxymethoxy)phenyl]cinchonan
(2c)
Thiocyanate salt of 2c (NH4SCN and 2c dissolved in boiling
MeOH, precipitated on cooling); mp 204–206 °C (dec.).
9-Substituted 6¢-Methoxycinchonans 2a–p; General Procedure
A clean and dry 25-mL 2-necked flask containing a magnetic stirrer
bar, equipped with a reflux condenser and a septum, kept under ar-
gon was charged with Mg (52 mg, 2.17 mmol), THF (8 mL), aryl
halide (2.1 mmol), and 1,2-dibromoethane (0.01 mL). The mixture
was stirred under reflux until most of the Mg dissolved (1–2 h). A
soln of (9S)-9-chloroquinine (1, 377 mg, 1.1 mmol) in toluene (10
mL)11 was added with a syringe. The mixture was heated in an oil
bath at 80 °C for 18 h. Then it was allowed to attain r.t. and 3.0 M
aq NH4Cl was added (5 mL). The mixture was extracted with CHCl3
(3 × 15 mL), dried (Na2SO4), and purified by column chromatogra-
phy (silica gel, CHCl3–MeOH, 25:1 to 15:1).
Rf = 0.25 (CHCl3–MeOH, 10:1); [a]D18 –34.5 (c 0.99, CH2Cl2).
IR (KBr): 3431 (H2O), 2932, 2859, 1621, 1586, 1508, 1489, 1472,
1454, 1230, 1151, 1078, 1032, 993, 919, 850, 752 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.62 (d, J = 4.6 Hz, 1 H), 7.90 (d,
J = 9.3 Hz, 1 H), 7.71 (d, J = 2.8 Hz, 1 H), 7.35 (dd, J = 7.7, 0.9 Hz,
1 H), 7.28 (dd, J = 9.3, 2.8 Hz, 1 H), 7.26 (d, J = 4.8 Hz, 1 H), 7.04
(td, J = 7.7, 1.8 Hz, 1 H), 6.93 (d, J = 8.2 Hz, 1 H), 6.89 (td, J = 7.3,
1.5 Hz, 1 H), 5.86 (m, 1 H), 5.23 (d, J = 11.5 Hz, 1 H), 5.10 (d,
J = 6.6 Hz, 1 H), 4.95–5.03 (m, 3 H), 3.91 (s, 3 H), 3.60 (m, 1 H),
3.29 (m, 1 H), 3.13 (m, 1 H), 3.12 (s, 3 H), 2.59–2.73 (m, 2 H), 2.20
(m, 1 H), 1.41–1.58 (m, 4 H), 0.81 (dd, J = 13.4, 7.5 Hz, 1 H).
13C NMR (75.5 MHz, CDCl3): d = 157.6, 154.7, 147.7, 147.5,
144.5, 142.1, 131.6, 131.0, 129.4, 128.1, 127.6, 121.9, 120.7, 120.5,
114.2, 113.7, 102.9, 94.5, 59.6, 56.4, 55.9, 55.5, 41.3, 41.2, 39.7,
28.2, 28.1, 27.9.
HRMS: m/z [M + H]+ calcd for C28H33N2O3: 445.2486; found:
445.2491.
(8S,9S)-6¢-Methoxy-9-(2-methylphenyl)cinchonan (2a)
Rf = 0.25 (CHCl3–MeOH, 10:1); [a]D20 –183.5 (c 1.36, CH2Cl2).
1H NMR (300 MHz, CDCl3): d = 8.58 (d, J = 4.7 Hz, 1 H), 7.95 (d,
J = 9.2 Hz, 1 H), 7.59 (d, J = 2.7 Hz, 1 H), 7.54 (d, J = 7.7 Hz, 1 H),
7.32 (dd, J = 9.2, 2.6 Hz, 1 H), 7.18–7.24 (m, 1 H), 7.19 (d, J = 4.7
Hz, 1 H), 7.03 (t, J = 7.5 Hz, 1 H), 6.97 (dd, J = 7.7, 1.1 Hz, 1 H),
5.80 (ddd, J = 17.3, 10.4, 7.5 Hz, 1 H), 4.90–5.00 (m, 3 H), 3.90 (s,
3 H), 3.61 (q, J = 9.5 Hz, 1 H), 3.15 (dd, J = 13.8, 10.1 Hz, 1 H),
3.09 (m, 1 H), 2.63–2.79 (m, 2 H), 2.13–2.23 (m, 1 H), 2.17 (s, 3 H),
1.38–1.64 (m, 4 H), 0.99 (dd, J = 13.6, 7.4 Hz, 1 H).
(8S,9S)-6¢-Methoxy-9-[3-(methoxymethoxy)phenyl]cinchonan
(2d)
Rf = 0.29 (CHCl3–MeOH, 10:1); [a]D20 –72.5 (c 1, CH2Cl2).
13C NMR (75.5 MHz, CDCl3): d = 157.8, 147.7, 147.0, 144.6,
142.0, 140.4, 136.5, 132.1, 130.7, 129.1, 127.3, 126.5, 126.2, 121.8,
121.1, 114.3, 101.9, 59.8, 26.1, 55.5, 43.7, 41.3, 39.7, 28.3, 27.8,
26.9, 20.8.
IR (film): 2938, 2861, 1621, 1585, 1506, 1487, 1471, 1229, 1150,
1079, 1023, 995, 921, 851, 829, 714, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.68 (d, J = 4.8 Hz, 1 H), 7.92 (d,
J = 9.3 Hz, 1 H), 7.43 (br, 1 H), 7.31 (d, J = 4.8 Hz, 1 H), 7.27 (dd,
Synthesis 2009, No. 18, 3113–3119 © Thieme Stuttgart · New York

3116
P. J. Boratyński, J. Skarżewski
PAPER
J = 9.3, 2.8 Hz, 1 H), 7.09 (t, J = 8.1 Hz, 1 H), 6.92–6.97 (m, 2 H),
6.76 (m, 1 H), 5.87 (m, 1 H), 5.02 (s, 1 H), 5.03 (s, 1 H), 4.96–5.05
(m, 2 H), 4.65 (d, J = 10.8 Hz, 1 H), 3.89 (s, 3 H), 3.64 (m, 1 H),
3.35 (s, 3 H), 3.24 (m, 1 H), 3.16 (dd, J = 13.9, 10.1 Hz, 1 H), 2.62–
2.74 (m, 2 H), 2.20 (m, 1 H), 1.82 (m, 1 H), 1.63 (m, 1 H), 1.46–1.59
(m, 2 H), 0.74 (m, 1 H).
13C NMR (75.5 MHz, CDCl3): d = 157.7, 157.3, 147.6, 146.5,
144.7, 143.8, 142.0, 131.9, 129.4, 128.8, 121.4, 121.1, 119.5, 116.3,
114.3, 113.9, 101.9, 94.4, 59.5, 56.5, 55.9, 55.5, 49.5, 40.9, 39.5,
28.8, 28.0 (2 overlapping signals).
1H NMR (300 MHz, CDCl3): d = 8.68 (d, J = 4.7 Hz, 1 H), 7.97 (d,
J = 9.1 Hz, 1 H), 7.50 (br, 1 H), 7.10–7.33 (m, 14 H), 6.59 (d,
J = 8.7 Hz, 2 H), 5.89 (m, 1 H), 4.96–5.06 (m, 2 H), 4.65 (d, J = 10.4
Hz, 1 H), 4.51 (s, 4 H), 3.87 (s, 3 H), 3.65 (m, 1 H), 3.29 (m, 1 H),
3.24 (dd, J = 13.8, 10.2 Hz, 1 H), 2.68–2.80 (m, 2 H), 2.25 (m, 1 H),
1.82 (m, 1 H), 1.63 (m, 1 H), 1.53–1.58 (m, 2 H), 0.77 (dd, J = 12.9,
6.4 Hz, 1 H).
13C NMR (75.5 MHz, CDCl3): d = 157.7, 147.9, 147.7, 147.6,
144.8, 142.0, 138.7, 131.9, 130.0, 128.8, 128.6, 128.6, 126.8, 126.7,
120.9, 119.6, 114.3, 112.6, 102.2, 59.5, 56.5, 55.5, 54.2, 48.4, 40.9,
39.6, 28.9, 28.1, 28.0.
HRMS: m/z [M + H]+ calcd for C28H33N2O3: 445.2486; found:
445.2491.
HRMS: m/z [M + H]+ calcd for C40H42N3O: 580.3322; found:
580.3328.
(8S,9R)-6¢-Methoxy-9-[2-(methoxymethoxymethyl)phenyl]cin-
chonan (2f)
(8S,9S)-6¢-Methoxy-9-[2-(pyrrolidin-1-ylmethyl)phenyl]cin-
chonan (2j)
Rf = 0.10 (CHCl3–MeOH, 10:1).
Rf = 0.26 (CHCl3–MeOH, 10:1); [a]D20 –179.5 (c 1.036, CH2Cl2).
IR (film): 2939, 2884, 1622, 1507, 1472, 1247, 1228, 1148, 1097,
1032, 919, 849, 747 cm–1.
IR (KBr): 2935, 2874, 1673, 1620, 1587, 1508, 1471, 1456, 1431,
1238, 1031, 849, 829 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.59 (d, J = 4.8 Hz, 1 H), 7.98 (d,
J = 9.3 Hz, 1 H), 7.86 (d, J = 2.6 Hz, 1 H), 7.72 (d, J = 7.9 Hz, 1 H),
7.42 (m, 1 H), 7.38 (dd, J = 9.2, 2.6 Hz, 1 H), 7.18 (d, J = 4.7 Hz, 1
H), 7.12–7.17 (m, 2 H), 5.81 (ddd, J = 17.4, 10.3, 7.4 Hz, 1 H), 5.51
(d, J = 11.4 Hz, 1 H), 4.98 (dt, J = 11.4, 1.5 Hz, 1 H), 4.95 (dt,
J = 10.3, 1.4 Hz, 1 H), 4.58 (d, J = 6.6 Hz, 1 H), 4.57 (d, J = 12.5
Hz, 1 H), 4.53 (d, J = 6.6 Hz, 1 H), 4.23 (d, J = 12.5 Hz, 1 H), 4.03
(s, 3 H), 3.64 (m, 1 H), 3.31 (s, 3 H), 3.21 (dd, J = 13.8, 10.0 Hz, 1
H), 3.19 (m, 1 H), 2.77 (ddd, J = 13.8, 4.8, 2.3 Hz, 1 H), 2.66 (m, 1
H), 2.24 (m, 1 H), 1.47–1.71 (m, 3 H), 1.36 (m, 1 H), 0.81 (ddt
J = 13.5, 7.0, 1.8 Hz, 1 H).
1H NMR (300 MHz, CDCl3): d = 8.52 (d, J = 4.7 Hz, 1 H), 7.95 (d,
J = 9.2 Hz, 1 H), 7.81 (d, J = 2.3 Hz, 1 H), 7.65 (d, J = 7.8 Hz, 1 H),
7.29–7.38 (m, 2 H), 6.96–7.12 (m, 3 H), 5.96 (d, J = 11.6 Hz, 1 H),
5.75 (ddd, J = 17.4, 10.3, 7.5 Hz, 1 H), 4.85–4.96 (m, 2 H), 3.96 (s,
3 H), 3.67 (d, J = 12.2 Hz, 1 H), 3.54 (m, 1 H), 3.28 (m, 1 H), 3.17
(dd, J = 13.7, 10.0 Hz, 1 H), 2.72 (d, J = 12.2 Hz, 1 H), 2.51–2.71
(m, 2 H), 2.12–2.44 (m, 5 H), 1.08–1.79 (m, 9 H).
13C NMR (75.5 MHz, CDCl3): d = 157.8, 147.8, 146.7, 141.8,
141.6, 137.8, 131.8, 131.5, 131.1, 129.7, 127.7, 127.6, 126.3, 122.1,
120.5, 114.2, 103.7, 59.7, 55.9, 55.6, 54.2, 41.6, 40.2, 40.6, 39.6,
28.2, 27.9, 25.9, 23.4.
13C NMR (75.5 MHz, CDCl3): d = 158.1, 147.7, 147.5, 144.7,
141.9, 141.7, 135.7, 131.8, 130.9, 129.3, 128.6, 127.7, 126.4, 121.8,
121.6, 114.2, 101.6, 94.3, 66.9, 59.5, 56.1, 55.4, 55.3, 42.2, 40.7,
39.6, 28.2, 27.8, 26.3.
HRMS: m/z [M + H]+ calcd for C31H38N3O: 468.3009; found:
468.3015.
HRMS: m/z [M + H]+ calcd for C29H35N2O3: 459.2642; found:
459.2648.
(8S,9S)-6¢-Methoxy-9-[2-(piperidin-1-ylmethyl)phenyl]cincho-
nan (2k)
Rf = 0.16 (CHCl3–MeOH, 10:1).
(8S,9S)-6¢-Methoxy-9-[3-(methoxymethoxymethyl)phenyl]cin-
chonan (2g)
[a]D18 –193 (c 1, CH2Cl2).
1H NMR (300 MHz, CDCl3): d = 8.51 (d, J = 4.8 Hz, 1 H), 7.95 (d,
J = 9.2 Hz, 1 H), 7.78 (d, J = 2.6 Hz, 1 H), 7.66 (d, J = 7.7 Hz, 1 H),
7.35 (dd, J = 9.2, 2.6 Hz, 1 H), 7.30–7.36 (m, 1 H), 7.09 (d, J = 4.7
Hz, 1 H), 7.06 (td, J = 7.3, 1.1 Hz, 1 H), 6.94 (dd, J = 7.6, 1.5 Hz, 1
H), 5.86 (d, J = 11.6 Hz, 1 H), 5.74 (ddd, J = 17.6, 10.3, 7.6 Hz, 1
H), 4.84–4.96 (m, 2 H), 3.96 (s, 3 H), 3.52 (m, 1 H), 3.43 (d,
J = 12.3 Hz, 1 H), 3.34–3.43 (m, 1 H), 3.18 (dd, J = 13.7, 10.1 Hz,
1 H), 2.71 (ddd, J = 13.7, 5.1, 2.1 Hz, 1 H), 2.62 (d, J = 12.3 Hz, 1
H), 2.52–2.63 (m, 1 H), 2.12–2.34 (m, 4 H), 1.19–1.75 (m, 12 H).
13C NMR (75.5 MHz, CDCl3): d = 157.9, 148.3, 147.9, 144.6,
142.1, 142.0, 136.7, 132.2, 132.0, 129.8, 128.1, 127.7, 126.1, 122.3,
120.5, 114.2, 103.8, 63.0, 59.8, 56.0, 55.7, 55.1, 41.8, 40.9, 39.8,
28.2, 28.0, 26.3, 36.0, 24.7.
[a]D20 –48 (c 1.01, CH2Cl2).
IR (KBr): 3375 (H2O), 2932, 2861, 1621, 1586, 1509, 1471, 1454,
1240, 1230, 1029, 828, 715 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.67 (d, J = 4.5 Hz, 1 H), 7.92 (d,
J = 9.2 Hz, 1 H), 7.43 (br, 1 H), 7.32 (d, J = 4.5 Hz, 1 H), 7.25 (s, 1
H), 7.20–7.30 (m, 2 H), 7.16 (t, J = 7.6 Hz, 1 H), 7.04 (d, J = 7.5 Hz,
1 H), 5.84 (ddd, J = 17.4, 9.7, 7.5 Hz, 1 H), 4.95–5.04 (m, 2 H), 4.69
(d, J = 10.0 Hz, 1 H), 4.56 (s, 2 H), 4.44 (s, 2 H), 3.89 (s, 3 H), 3.64
(m, 1 H), 3.26 (s, 3 H), 3.19–3.30 (m, 1 H), 3.15 (dd, J = 13.9, 10.0
Hz, 1 H), 2.60–2.73 (m, 2 H), 2.22 (m, 1 H), 1.83 (m, 1 H), 1.63 (m,
1 H), 1.44–1.58 (m, 2 H), 0.77 (dd J = 13.5, 6.7 Hz, 1 H).
(8S,9S)-9-[3-(Dibenzylamino)phenyl]-6¢-methoxycinchonan
(2h)
HRMS: m/z [M + H]+ calcd for C32H40N3O: 482.3166; found:
482.3171.
1H NMR (300 MHz, CDCl3): d = 8.52 (d, J = 4.8 Hz, 1 H), 7.90 (d,
J = 9.1 Hz, 1 H), 7.40 (br, 1 H), 7.07–7–32 (m, 12 H), 6.96 (t,
J = 7.7 Hz, 1 H), 6.66 (d, J = 7.5 Hz, 1 H), 6.58 (s, 1 H), 6.46 (dd,
J = 8.4, 2.5 Hz, 1 H), 5.80 (m, 1 H), 4.90–4.99 (m, 2 H), 4.41–4.62
(m, 1 H), 4.50 (s, 4 H), 3.81 (s, 3 H), 3.41 (m, 1 H), 3.01–3.18 (m,
2 H), 2.49–2.66 (m, 2 H), 2.16 (m, 1 H), 1.34–1.77 (m, 4 H), 0.62
(m, 1 H).
(8S,9S)-9-(3-Iodophenyl)-6¢-methoxycinchonan (2l)
Rf = 0.43 (CHCl3–MeOH, 10:1); [a]D20 –27.5 (c 1, CH2Cl2).
IR (KBr): 2932, 2859, 1620, 1585, 1561, 1507, 1452, 1470, 1260,
1228, 1030, 922, 825, 697 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.69 (d, J = 4.7 Hz, 1 H), 7.94 (d,
J = 9.2 Hz, 1 H), 7.61 (s, 1 H), 7.21–7.49 (m, 5 H), 6.91 (t, J = 7.7
Hz, 1 H), 5.87 (m, 1 H), 4.95–5.06 (m, 2 H), 4.59 (d, J = 11.0 Hz, 1
H), 3.90 (s, 3 H), 3.63 (m, 1 H), 3.19 (m, 1 H), 3.16 (dd, J = 13.9,
9.9 Hz, 1 H), 2.62–2.76 (m, 2 H), 2.24 (m, 1 H), 1.42–1.94 (m, 4 H),
0.75 (dd, J = 13.4, 7.0 Hz, 1 H).
(8S,9S)-9-[4-(Dibenzylamino)phenyl]-6¢-methoxycinchonan (2i)
22
Rf = 0.24 (CHCl3–MeOH, 10:1); [a]D –154.1 (c 1.28, CH2Cl2);
[a]D22 –176.5 (c 1.15, EtOH).
Synthesis 2009, No. 18, 3113–3119 © Thieme Stuttgart · New York

PAPER
Functional Derivatives of 9-Phenylquinine
3117
13C NMR (75.5 MHz, CDCl3): d = 157.9, 147.6, 145.7, 144.8,
141.8, 137.0, 135.7, 132.0, 130.2, 128.6, 127.3, 127.1, 121.1, 119.8,
114.4, 101.8, 94.6, 59.3, 56.5, 55.5, 49.2, 40.9, 39.5, 28.7, 28.00,
27.96.
HRMS: m/z [M + H]+ calcd for C26H28IN2O: 511.1241; found:
511.1246.
(8S,9S)-6¢-Methoxy-9-pyren-1-ylcinchonan (2p)
Rf = 0.30 (CHCl3–MeOH, 10:1); [a]D20 +62 (c 1, CH2Cl2).
IR (KBr): 2938, 2917, 2857, 1620, 1579, 1505, 1471, 1429, 1240,
1226, 1220, 1034, 845, 836, 712 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.66 (d, J = 4.7 Hz, 1 H), 8.57 (d,
J = 9.5 Hz, 1 H), 7.86–8.14 (m, 9 H), 7.67 (d, J = 2.6 Hz, 1 H), 7.45
(d, J = 4.5 Hz, 1 H), 7.23 (dd, J = 9.2, 2.6 Hz, 1 H), 5.94 (ddd,
J = 17.2, 9.8, 7.3 Hz, 1 H), 5.77 (d, J = 10.6 Hz, 1 H), 5.00–5.07 (m,
2 H), 3.95 (m, 1 H), 3.78 (s, 3 H), 3.32 (m, 1 H), 3.06 (dd, J = 13.9,
10.1 Hz, 1 H), 2.75 (m, 1 H), 2.59 (ddd, J = 14.4, 10.4, 4.3 Hz, 1 H),
2.23 (m, 1 H), 1.92 (m, 1 H), 1.44–1.78 (m, 3 H), 1.19 (dd, J = 13.7,
7.7 Hz, 1 H).
13C NMR (75.5 MHz, CDCl3): d = 157.9, 147.6, 147.4, 144.7,
142.1, 136.4, 132.0, 131.4, 130.4, 130.0, 129.0, 128.9, 127.7, 127.5,
127.0, 125.8, 125.5, 125.28, 125.25, 125.17, 125.1, 124.7, 122.6,
121.4, 120.9, 114.4, 101.9, 60.9, 56.5, 56.7, 44.3, 41.7, 39.7, 28.3,
28.2, 28.1.
(8S,9S)-9-(4-Iodophenyl)-6¢-methoxycinchonan (2m)
Rf = 0.26 (CHCl3–MeOH, 10:1); [a]D20 –138.5 (c 1.2, CH2Cl2).
IR (KBr): 3435 (H2O), 2926, 2906, 2861, 1620, 1505, 1484, 1470,
1427, 1244, 1225, 1027, 1007, 834, 841, 719, 624 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.68 (d, J = 4.7 Hz, 1 H), 7.94 (d,
J = 9.1 Hz, 1 H), 7.47 (d, J = 8.4 Hz, 2 H), 7.35 (br, 1 H), 7.29 (dd,
J = 9.1, 2.6 Hz, 1 H), 7.27 (d, J = 4.7 Hz, 1 H), 7.03 (d, J = 8.4 Hz,
2 H), 5.86 (ddd, J = 17.4, 10.1, 7.4 Hz, 1 H), 4.95–5.03 (m, 2 H),
4.62 (d, J = 11.0 Hz, 1 H), 3.88 (s, 3 H), 3.57 (m, 1 H), 3.18 (m, 1
H), 3.16 (dd, J = 14.0, 10.0 Hz, 1 H), 2.61–2.73 (m, 2 H), 2.23 (m,
1 H), 1.82 (m, 1 H), 1.63 (m, 1 H, H4), 1.46–1.58 (m, 2 H), 0.75
(ddt, J = 13.5, 7.1, 1.6 Hz, 1 H).
HRMS: m/z [M + H]+ calcd for C36H33N2O: 509.2587; found:
509.2593.
13C NMR (75.5 MHz, CDCl3): d = 157.8, 147.6, 146.1, 144.7,
142.0, 141.9, 139.2, 137.5, 132.0, 129.9, 120.9, 119.7, 114.4, 102.0,
92.2, 59.4, 56.5, 55.5, 48.9, 41.0, 39.4, 28.7, 28.02, 27.96.
9-(Hydroxyphenyl)-6¢-methoxycinchonans 3c–g; General Pro-
cedure
A 25-mL flask was charged with the MOM derivative 2c–g (1
mmol) and either TFA [8 mL, containing H2O (0.4 mL)] or 4 M HCl
in MeOH (8 mL). The mixture was stirred at r.t. for the specified
time (Table 2), then the solvent was removed in vacuo. The residue
was suspended in 5% aq NH3 (10 mL) and extracted with CHCl3.
The extracts were dried (anhyd Na2SO4). Removal of solvents in
vacuo afforded products that did not require further purification.
HRMS: m/z [M + H]+ calcd for C26H28IN2O: 511.1241; found:
511.1246.
(8S,9S)-9-(3-Bromophenyl)-6¢-methoxycinchonan (2n)
Rf = 0.35 (CHCl3–MeOH, 10:1); [a]D20 –72 (c 0.974, CH2Cl2).
IR (film): 3058, 3021, 2947, 2864, 1618, 1587, 1561, 1508, 1428,
1359, 1224, 1132, 1088, 1074, 1033, 907, 845, 828, 771, 754, 436
cm–1.
1H NMR (300 MHz, CDCl3): d = 8.70 (d, J = 4.7 Hz, 1 H), 7.95 (d,
J = 9.1 Hz, 1 H), 7.61 (s, 1 H), 7.01–7.42 (m, 6 H), 5.86 (ddd,
J = 17.6, 10.0, 7.6 Hz, 1 H), 4.96–5.04 (m, 2 H), 4.63 (d, J = 10.9
Hz, 1 H), 3.89 (s, 3 H), 3.85 (m, 1 H), 3.19 (m, 1 H), 3.16 (dd,
J = 13.9, 10.2 Hz, 1 H), 2.62–2.75 (m, 2 H), 2.23 (m, 1 H), 1.83 (m,
1 H), 1.64 (m, 1 H), 1.45–1.58 (m, 2 H), 0.75 (dd, J = 13.5, 7.0 Hz,
1 H).
(8S,9R)-9-(2-Hydroxyphenyl)-6¢-methoxycinchonan (3c)
Mp 181–184 °C (CH2Cl2); Rf = 0.15 (CHCl3–MeOH, 10:1).
Perchlorate salt of 3c (NH4ClO4 and 3c were dissolved in hot EtOH,
precipitated on cooling); mp 259–261 °C (dec.).
[a]D20 –47 (c 0.5, EtOH).
IR (KBr): 3427, 3068, 1932, 1862, 1621, 1586, 1509, 1473, 1454,
1433, 1272, 1241, 1030, 846, 751 cm–1.
13C NMR (75.5 MHz, CDCl3): d = 157.8, 147.6, 145.9, 144.7,
144.5, 141.9, 132.0, 131.0, 130.0, 129.8, 126.6, 123.0, 122.5, 121.1,
119.7, 114.4, 101.8, 59.4, 56.5, 55.5, 49.2, 41.0, 39.5, 28.7, 28.01,
27.96.
HRMS: m/z [M + H]+ calcd for C26H28BrN2O: 463.1379; found:
463.1385.
1H NMR (300 MHz, CDCl3, 313 K): d = 8.66 (d, J = 4.4 Hz, 1 H),
7.94 (d, J = 9.2 Hz, 1 H), 7.29 (d, J = 2.6 Hz, 1 H), 7.24 (dd, J = 9.2,
2.6 Hz, 1 H), 7.20 (d J = 4.4 Hz, 1 H), 6.95 (td, J = 7.6, 1.5 Hz, 1
H), 6.83 (dd, J = 8.0, 1.5 Hz, 1 H), 6.60 (dd, J = 8.0, 1.4 Hz, 1 H),
6.43 (td, J = 7.6, 1.4 Hz, 1 H), 5.72 (ddd, J = 17.8, 10.8, 7.2 Hz, 1
H), 4.98 (d, J = 17.8 Hz, 1 H) 4.97 (d, J = 10.8 Hz, 1 H), 4.74 (br, 1
H), 3.77 (s, 3 H), 3.69 (q, J = 8.5 Hz, 1 H), 3.33 (m, 1 H), 3.21 (dd,
J = 13.8, 10.3 Hz, 1 H), 2.79–2.94 (m, 2 H), 2.33 (m, 1 H), 1.71 (m,
1 H), 1.52–1.67 (m, 3 H), 0.91 (dd, J = 13.6, 7.9 Hz, 1 H).
13C NMR (75.5 MHz, CDCl3, 313 K): d = 157.8, 156.6, 147.1,
146.3, 145.2, 140.5, 131.7, 130.4, 128.5, 128.2, 127.7, 123.0, 121.7,
119.2, 118.9, 115.1, 102.7, 59 (br), 55.5, 54.3, 40.6, 38.7, 28.8,
27.7, 27.2 (1 signal not observed due to coalescence).
(8S,9S)-9-(4-Bromophenyl)-6¢-methoxycinchonan (2o)
Rf = 0.36 (CHCl3–MeOH, 10:1); [a]D25 –79 (c 1, CH2Cl2).
IR (film): 2938, 2861, 1622, 1588, 1507, 1488, 1469, 1260, 1230,
1069, 1032, 1005, 836, 810 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.68 (d, J = 4.6 Hz, 1 H), 7.94 (d,
J = 9.1 Hz, 1 H), 7.35 (br, 1 H), 7.25–7.32 (m, 3 H), 7.08–7.21 (m,
3 H), 5.86 (ddd, J = 17.3, 10.0, 7.4 Hz, 1 H), 4.95–5.05 (m, 2 H),
4.64 (d, J = 11.4 Hz, 1 H), 3.87 (s, 3 H), 3.58 (m, 1 H), 3.13–3.26
(m, 1 H), 3.16 (dd, J = 13.9, 10.0 Hz, 1 H), 2.61–2.76 (m, 2 H), 2.23
(m, 1 H), 1.64 (m, 1 H), 1.83 (m, 1 H), 1.44–1.58 (m, 2 H), 0.75 (dd,
J = 13.7, 6.8 Hz, 1 H).
HRMS: m/z [M + H]+ calcd for C26H29N2O2: 401.2223; found:
401.2229.
Anal. Calcd for C26H28N2O2·0.5 H2O: C, 74.25; H, 7.13; N, 6.84.
Found: C, 76.33; H, 7.13; N, 6.80.
(8S,9S)-9-(3-Hydroxyphenyl)-6¢-methoxycinchonan (3d)
Mp 165–172 °C (CH2Cl2–hexane); Rf = 0.09 (CHCl3–MeOH, 10:1);
[a]D20 –102 (c 0.764, EtOH).
13C NMR (75.5 MHz, CDCl3): d = 157.9, 147.5, 146.1, 144.7,
141.9, 141.2, 132.0, 131.6, 129.6, 128.8, 120.9, 120.5, 119.7, 114.4,
102.0, 59.4, 56.5, 55.5, 48.9, 41.0, 39.5, 28.7, 28.05, 27.96.
IR (KBr): 3634, 3077, 2941, 2862, 1621, 1586, 1507, 1482, 1472,
1455, 1364, 1259, 1243, 1226, 1027, 831, 715 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.66 (d, J = 4.7 Hz, 1 H), 7.91 (d,
J = 9.2 Hz, 1 H), 7.45 (d, J = 2.3 Hz, 1 H), 7.37 (d, J = 4.7 Hz, 1 H),
HRMS: m/z [M + H]+ calcd for C26H28BrN2O: 463.1379; found:
463.1385.
Synthesis 2009, No. 18, 3113–3119 © Thieme Stuttgart · New York

3118
P. J. Boratyński, J. Skarżewski
PAPER
7.24 (dd, J = 9.2, 2.6 Hz, 1 H), 6.95 (t, J = 7.8 Hz, 1 H), 6.81 (d,
J = 7.7 Hz, 1 H), 6.44 (s, 1 H), 6.21 (d, J = 7.8 Hz, 1 H), 5.89 (ddd,
J = 17.3, 10.3, 7.3 Hz, 1 H), 5.08 (d, J = 10.3 Hz, 1 H), 5.00 (d,
J = 17.3 Hz, 1 H), 4.62 (d J = 11.2 Hz, 1 H), 3.85 (s, 3 H), 3.78 (m,
1 H), 3.89 (m, 1 H), 3.09 (dd, J = 13.8, 10.3 Hz, 1 H), 2.72 (m, 1 H),
2.56–2.72 (m, 2 H), 2.02 (t, J = 11.2 Hz, 1 H), 1.71 (m, 1 H), 1.52–
1.69 (m, 2 H), 0.86 (m, 1 H).
13C NMR (75.5 MHz, CDCl3): d = 158.1, 157.9, 147.2, 146.4,
144.5, 141.7, 140.7, 131.6, 129.5, 128.8, 121.3, 119.1, 118.6, 115.2,
115.0, 114.9, 102.1, 59.9, 56.4, 55.5, 50.5, 40.5, 38.6, 28.9, 27.7,
27.3.
extracted with CHCl3, dried (Na2SO4), and concentrated in vacuo.
The residue was purified (silica gel, CHCl3–MeOH, 25:1) to afford
4 (167 mg, 48%) as an oil.
Rf = 0.29 (CHCl3–MeOH, 10:1).
1H NMR (300 MHz, CDCl3): d = 7.86 (d, J = 9.2 Hz, 1 H), 7.69 (d,
J = 2.3 Hz, 1 H), 7.36 (d, J = 7.4 Hz, 1 H), 7.23 (dd, J = 9.2, 2.8 Hz,
1 H), 7.19 (s, 1 H), 6.85–7.05 (m, 3 H), 5.87 (ddd, J = 17.8, 10.6,
7.3 Hz, 1 H), 5.22 (d, J = 11.3 Hz, 1 H), 5.11 (d, J = 6.6 Hz, 1 H),
5.04 (d, J = 6.6 Hz, 1 H), 4.95–5.02 (m, 2 H), 3.87 (s, 3 H), 3.60 (m,
1 H), 3.31 (m, 1 H), 3.16 (s, 3 H), 3.13 (dd, J = 14.3 10.1 Hz, 1 H),
2.86 (t, J = 7.7 Hz, 2 H), 2.69 (m, 1 H), 2.62 (m, 1 H), 2.19 (m, 1
H), 1.40–1.77 (m, 6 H), 1.34 (sext, J = 7.5 Hz, 2 H), 0.88 (t, J = 7.4
Hz, 3 H), 0.82 (dd, J = 13.2, 7.2 Hz, 1 H).
HRMS: m/z [M + H]+ calcd for C26H29N2O2: 401.2223; found:
401.2228.
Anal. Calcd for C26H28N2O2·H2O: C, 74.65; H, 7.22; N, 6.69.
Found: C, 73.52; H, 7.29; N 6.71.
13C NMR (75.5 MHz, CDCl3): d = 159.9, 157.0, 154.8, 147.8,
144.3, 142.2, 131.2, 131.0, 128.1, 127.8, 127.6, 122.0, 120.6, 120.3,
114.2, 113.8, 103.2, 94.6, 59.9, 56.6, 56.0, 55.6, 41.3, 41.2, 39.8,
38.9, 32.3, 28.3, 28.2, 28.0, 22.6, 14.1.
HRMS: m/z [M + H]+ calcd for C32H41N2O3: 501.3112; found:
501.3117.
(8S,9S)-9-[2-(Hydroxymethyl)phenyl]-6¢-methoxycinchonan
(3f)
Rf = 0.21 (CHCl3–MeOH, 10:1); [a]D20 –179.5 (c 0.86, EtOH).
IR (KBr): 3385, 3163, 2936, 2860, 1622, 1587, 1510, 1472, 1432,
1252, 1240, 1229, 1023, 851, 748, 726 cm–1.
(8S,9S)-9-[3-(Dibenzylamino)phenyl]-10,11-dihydro-6¢-meth-
oxycinchonan (5)
A 25-mL flask was charged with 2h (347 mg, 0.6 mmol), MeOH
(10 mL), EtOAc (5 mL), and 10% Pd–C (60 mg). A thin stream of
H2 was passed through the suspension for 90 h. Then, the mixture
was filtered through Cellite and washed with MeOH. The solvents
were removed in vacuo to afford 5 (301 mg, 87%).
1H NMR (300 MHz, CDCl3): d = 8.54 (d, J = 4.7 Hz, 1 H), 7.87 (d,
J = 9.2 Hz, 1 H), 7.45–7.48 (m, 2 H), 7.13–7.26 (m, 4 H), 7.06 (t,
J = 7.3 Hz, 1 H), 5.82 (m, 1 H), 5.32 (d, J = 10.7 Hz, 1 H), 4.93–
5.00 (m, 2 H), 4.81 (d, J = 12.0 Hz, 1 H), 4.53 (br, 1 H), 4.34 (d,
J = 12.0 Hz, 1 H), 3.87 (s, 3 H), 3.50 (m, 1 H), 3.24 (m, 1 H), 3.02
(dd, J = 13.8, 10.1 Hz, 1 H), 2.60–2.71 (m, 2 H), 2.20 (m, 1 H), 1.75
(m, 1 H), 1.67 (m, 1 H), 1.55 (m, 1 H), 1.44 (m, 1 H), 0.92 (dd,
J = 13.5, 8.5 Hz, 1 H).
13C NMR (75.5 MHz, CDCl3): d = 158.1, 147.1, 146.6, 144.6,
141.7, 140.7, 139.7, 131.7, 130.3, 129.0, 128.4, 128.2, 127.0, 121.7,
121.7, 114.7, 101.3, 63.5, 60.9, 55.6, 55.5, 42.8, 41.2, 39.4, 27.9,
27.8, 27.8.
Rf = 0.24 (CHCl3–MeOH, 10:1); [a]D18 –101 (c 0.443, CH2Cl2).
IR (KBr): 2929, 2858, 1620, 1599, 1507, 1495, 1451, 1360, 1230,
1028, 729, 696 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.52 (d, J = 4.6 Hz, 1 H), 7.91 (d,
J = 9.3 Hz, 1 H), 7.39 (br, 1 H), 7.08–7.33 (m, 12 H), 6.98 (t, J = 7.7
Hz, 1 H), 6.66 (d, J = 7.3 Hz, 1 H), 6.54 (s, 1 H), 6.49 (m, 1 H),
4.46–4.63 (m, 5 H), 3.82 (s, 3 H), 3.11–3.65 (m, 3 H), 2.74 (m, 1 H),
2.39 (m, 1 H), 1.48–1.79 (m, 7 H), 0.81 (t, J = 7.2 Hz, 3 H), 0.76–
0.82 (m, 1 H).
HRMS: m/z [M + H]+ calcd for C27H31N2O2: 415.2380; found:
415.2383.
(8S,9R)-9-[3-(Hydroxymethyl)phenyl]-6¢-methoxycinchonan
(3g)
13C NMR (75.5 MHz, CDCl3): d = 157.8, 149.3, 147.4, 145.9,
144.6, 141.9, 138.5, 131.7, 129.5, 128.64, 128.59, 126.8, 126.5,
121.2, 119.1, 116.7, 112.2, 111.6, 101.8, 59.8, 57.7, 55.6, 54.8,
49.4, 40.9, 36.4, 27.9, 27.4, 27.3, 25.5, 11.9.
HRMS: m/z [M + H]+ calcd for C40H44N3O: 582.3479; found:
582.3484.
Rf = 0.08 (CHCl3–MeOH, 10:1); [a]D20 –67.7 (c 1.167, EtOH).
1H NMR (300 MHz, CDCl3): d = 8.55 (d, J = 4.7 Hz, 1 H), 7.85 (d,
J = 9.2 Hz, 1 H), 7.43 (br, 1 H), 7.32 (s, 1 H), 7.28 (d, J = 4.7 Hz, 1
H), 7.21 (dd, J = 9.2, 2.6 Hz, 1 H), 7.20 (m, 1 H), 7.13 (t, J = 7.4 Hz,
1 H), 7.01 (d, J = 7.4 Hz, 1 H), 5.84 (ddd, J = 17.4, 9.9, 7.4 Hz, 1
H), 4.94–5.02 (m, 2 H), 4.67 (d, J = 11.3 Hz, 1 H), 4.47 (s, 2 H),
3.87 (s, 3 H), 3.62 (m, 1 H), 3.21 (m, 1 H), 3.07 (dd, J = 13.8, 10.2
Hz, 1 H), 2.52–2.67 (m, 2 H), 2.20 (m, 1 H), 2.0 (br, 1 H), 1.82 (m,
1 H), 1.62 (m, 1 H), 1.36–1.57 (m, 2 H), 0.74 (dd, J = 13.7, 7.0 Hz,
1 H).
13C NMR (75.5 MHz, CDCl3): d = 157.7, 147.5, 146.6, 144.6,
142.3, 141.8, 141.5, 131.8, 128.7, 128.5, 127.0, 126.5, 125.5, 120.9,
119.6, 114.4, 102.0, 65.0, 59.6, 56.4, 55.5, 49.6, 40.8, 39.4, 28.7,
27.98, 27.91.
(8S)-6¢-Methoxy-9-(phenylvinylidene)cinchonan (6)
A dry 25-mL 2-neck flask containing a magnetic stirrer bar,
equipped with a reflux condenser and a septum, kept under argon
was charged with phenylacetylene (0.22 mL, 2 mmol), THF (4 mL),
and 2 M i-PrMgBr in THF (1 mL). The mixture was stirred at r.t. for
1 h and a soln of (9S)-9-chloroquinine (1, 498 mg, 1.46 mmol) in
toluene (5 mL) was added.11 The mixture was initially stirred at r.t.
for 0.5 h then heated under reflux 2 h. Then it was allowed to attain
r.t. and sat. aq NH4Cl was added (15 mL). The mixture was extract-
ed with CH2Cl2, dried (Na2SO4), and purified by column chroma-
tography (silica gel, CHCl3–MeOH, 20:1) to afford 6 (180 mg,
30%) as an yellow oil as an aS/aR isomer mixture.
HRMS: m/z [M + H]+ calcd for C27H31N2O2: 415.2380; found:
415.2384.
(8S,9R)-2¢-Butyl-6¢-methoxy-9-[2-(methoxymethoxy)phe-
nyl]cinchonan (4)
Rf = 0.26 and 0.23 (CHCl3–MeOH, 10:1).
IR (film): 3064, 2936, 2867, 1938, 1668, 1620, 1580, 1505, 1470,
1454, 1429, 1361, 1225, 1030, 848, 753, 695 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.652/8.648 (2 d, J = 4.6 Hz, 1 H),
7.909/7.903 (2 d, J = 9.3 Hz, 1 H), 7.54 (d, J = 4.6 Hz, 3/5 H), 7.13–
7.41 (m, 7 2/5 H), 6.546/6.539 (2 s, 1 H), 5.79–5.94 (m, 1 H), 4.94–
5.05 (m, 2 H), 3.69–4.00 (m, 1 H) 3.56/3.48 (2 s, 3 H), 3.09–3.28
A dry 10-mL 2 neck flask with an argon atmosphere was charged
with 2c (312 mg, 0.7 mmol), THF (6 mL), TMEDA (0.1 mL, 0.7
mmol), and cooled to –25 °C. 2.5 M BuLi in hexanes (0.3 mL, 0.75
mmol) was added. The mixture was stirred for 0.25 h and DMF (0.1
mL, 1.4 mmol) was added and the stirring continued for an addition-
al 18 h. The reaction was quenched with sat. aq NH4Cl. The product
Synthesis 2009, No. 18, 3113–3119 © Thieme Stuttgart · New York

PAPER
Functional Derivatives of 9-Phenylquinine
3119
(m, 2 H), 2.56–2.77 (m, 2 H), 2.18–2.29 (m, 1 H), 1.96–2.08 (m, 1
H), 1.37–1.80 (m, 4 H).
R. Tetrahedron Lett. 2007, 48, 8456. (d) Guo, G.; Xue, M.-
X.; Zhu, M.-K.; Gong, L.-Z. Angew. Chem. Int. Ed. 2008,
47, 3414.
13C NMR (75.5 MHz, CDCl3): d = 206.6/206.2, 157.8/157.7, 147.5/
147.3, 144.8/144.7, 142.3/142.2, 141.6/141.5, 133.3/133.1, 131.4,
129.5/129.3, 129.00, 129.97, 128.89, 128.4, 127.8, 127.7, 127.6,
127.5, 127.2/127.1, 121.9/121.8, 120.4/120.2, 114.63/114.61,
108.7/108.2, 102.9/102.8, 98.8/98.7, 59.3/58.2, 55.4, 55.33, 55.31,
55.28, 41.5/41.3, 39.4/39.3, 28.0/27.9, 27.7/27.4, 26.5/26.3.
(4) (a) Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006,
128, 6048. (b) Tillman, A. L.; Ye, J.; Dixon, D. J. Chem.
Commun. 2006, 1191. (c) Peschiulli, A.; Quigley, C.;
Tallon, S.; Gun’ko, Y. K.; Connon, S. T. J. Org. Chem.
2008, 73, 6409. (d) Vakulya, B.; Varga, S.; Soós, T. J. Org.
Chem. 2008, 73, 3475. (e) Amere, M.; Lasne, M.-C.;
Rouden, J. Org. Lett. 2007, 9, 2621.
(5) Ochiai, E.; Tsunashima, K.; Kobayashi, Y. J. Pharm. Soc.
Jpn. 1949, 69, 10; Chem. Abstr. 1950, 44, 3508D.
(6) Boratyński, P. J.; Turowska-Tyrk, I.; Skarżewski, J. Org.
Lett. 2008, 10, 385.
HRMS: m/z [M + H]+ calcd for C28H29N2O: 409.2274; found:
409.2284.
Acknowledgment
(7) Boratyński, P. J.; Turowska-Tyrk, I.; Skarżewski, J. J. Org.
Chem. 2008, 73, 7357.
(8) Hintermann, L.; Schmitz, M.; Englert, U. Angew. Chem. Int.
Ed. 2007, 46, 5164.
We are grateful to the Polish Ministry of Science and Higher Edu-
cation for financial support, grant N N204 161036.
(9) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups
in Organic Synthesis, 4th ed.; Wiley: New York, 2007.
(10) Klayman, D. L.; Griffin, T. S.; Bower, J. D.; Page, S. W.
J. Med. Chem. 1973, 16, 1042.
(11) (9S)-9-Chloroquinine (1) is not very soluble in toluene at r.t.;
more concentrated solutions can be obtained by dissolving 1
in toluene at 100 °C then cooling.
References
(1) Enantioselective Organocatalysis; Dalko, P. J., Ed.; Wiley-
VCH: Weinheim, 2007.
(2) Review: Connon, S. J. Chem. Commun. 2008, 2499.
(3) (a) Marcelli, T.; van Maarseveen, J. H.; Hiemstra, H. Angew.
Chem. Int. Ed. 2006, 45, 7496. (b) Li, H.; Wang, B.; Deng,
L. J. Am. Chem. Soc. 2006, 128, 732. (c) Chen, F.-X.; Shao,
C.; Wang, Q.; Gong, P.; Zhang, D.-Y.; Zhang, B.-Z.; Wang,
Synthesis 2009, No. 18, 3113–3119 © Thieme Stuttgart · New York