Liquid-phase synthesis with solid-phase workup: Application to multistep and combinatorial syntheses

Full text of DOI:10.1021/jo9809074

2110
J . Org. Chem. 1999, 64, 2110-2113
Ta ble 1. P r ecip ita tion of 1 w ith Su lfu r ic Acid fr om
Liqu id -P h a se Syn th esis w ith Solid -P h a se
Wor k u p : Ap p lica tion to Mu ltistep a n d
Com bin a tor ia l Syn th eses
Va r iou s Solven ts
solvent (0.2 M
compound 1)
recovered
yield of 1a (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
AcOEt
CH2Cl2
DME
CH3CN
89
91
83
82
oilb
71
81
56
71
65
71
86
88
He´le`ne Perrier* and Marc Labelle
Merck Frosst Centre for Therapeutic Research, P.O. Box
1005, Pointe Claire-Dorval, Que´bec, Canada, H9R 4P8
DMF
DMF/AcOEt/H2Oc
DMF/ CH2Cl2
MeOH
Received May 12, 1998
MeOH/AcOEt/H2Oc
EtOH
Combinatorial chemistry1 is emerging as an important
new tool for medicinal chemistry. In general, combina-
torial chemistry is performed with the substrate attached
to a solid support, and this fact has triggered extensive
work in reaction condition optimization2 for solid phase.
Reaction optimization is doubly important in solid-phase
combinatorial chemistry since the reaction must not only
be applicable to a wide variety of substrates and reac-
tants but also must be as complete as possible since the
intermediates of a multistep synthesis usually remain
admixed with the reaction side products. The method
development lead time, the limitation in reaction con-
centration, and the difficulty in monitoring the reactions
are some of the reasons behind the important thrust for
liquid-phase synthetic methods applicable to combina-
torial chemistry.
EtOH/AcOEt/H2Oc
CHCl3
THF
a
b
Yield after precipitation and neutralization recovery. The
bisulfate salt separated from the mixture as an oil. c The hydro-
philic solvent was first removed by aqueous extraction, followed
by precipitation from ethyl acetate-ether.
The quinoline group is a stable, low molecular weight,
and “neutral” group, with normal solubility properties
in standard reaction solvents. However, protonation
dramatically affects the solubility of the molecule. Using
molecule 1 as a model,7 efficient precipitation conditions
from various solvents were sought. Protonation of 1 with
In liquid-phase methods and strategies, the innovation
lies mostly with the isolation of the product from the
reaction mixture. The method of Boger3 uses the acidic
or basic properties of the desired molecule as a handle
for separating it from the reaction mixture. The method
of Kim,4 on the other hand, assembles many desired
molecules into a supermolecule and uses the size of this
assembly as a means of separation. The methods of
J anda5 and Curran6 both attach the molecule of interest
to a solubility control device and use the special solubility
properties of these devices to isolate the desired material
from reaction mixtures. In the former case, a poly-
(ethylene glycol) unit is used as a precipitation device.
In the latter case, a fluorous phase soluble unit allows
for the liquid-liquid extraction of the desired material
(or reagents) from the reaction mixture.
With the solubility control device concept in mind, we
sought a low molecular weight group that would have
switchable solubility properties to allow separation on
demand and that would allow reaction monitoring and
intermediate characterization by standard methods.
Herein, we describe our work on the use of a quinoline
unit to effect separation of the desired reaction products
from the reaction mixtures by simple precipitation.
mineral acids, in particular phosphoric and sulfuric acid,
showed promise. It appeared from these preliminary
experiments that the presence of ether in the mixture
was helpful to induce effective precipitation. The quino-
line substitution pattern was explored with the 2-, 4-,
and 8-positional isomers of 1. When the quinoline unit
was attached by its 3-position, the protonated form was
more insoluble, and the solid was easier to handle. It was
noted at this point that sulfuric acid provided better
behaved solids than phosphoric acid and was therefore
used throughout the rest of this study.
Table 1 summarizes the results of precipitating 1 from
various commonly used reaction solvents. Using a pro-
cedure which calls for an ether dilution of the mock
reaction mixture, followed by slow addition of 1 mol of
sulfuric acid per mole of 1, most of the common reaction
solvents gave satisfactory results. A recovery problem
arose with DMF and alcoholic solvents. This problem was
solved in two different ways. In a first procedure, an
extraction method was applied (entries 6, 9, and 11)
where the mock reaction mixture was diluted with an
ethyl acetate-water mixture, the organic phase was
separated, and the compound was precipitated from that
(1) Ellman, J . A. Acc. Chem. Res. 1996, 29, 132-143 and references
therein.
(2) For a review of this type of optimization, see: Hermkens, P. H.
H.; Ottenheijm, H. C. J .; Rees, D. Tetrahedron 1996, 13, 4527-4554.
(3) Cheng, S.; Comer, D. D.; Williams, J . P.; Myers, P. L.; Boger, D.
L. J . Am. Chem. Soc., 1996, 118, 2567-2573.
(4) Kim, R. M.; Manna, M.; Hutchins, S. M.; Griffin, P. R.; Yates,
N. A.; Bernick, A. M.; Chapman, K. T. Proc. Natl. Acad. Sci. U.S.A.
1996, 93, 10012-10017.
(7) This work exemplifies the concept with two ester linkers between
the molecule of interest and the quinoline precipitation device. Other
linkers such as silicon-based traceless linkers may also be compatible
with this method and are being investigated. Boehm, T. L.; Showalter,
H. D. H. J . Org. Chem. 1996, 61, 6498-6499. Chenera, B.; Finkelstein,
J . A.; Veber, D. F. J . Am. Chem. Soc. 1995, 117, 11999-12000. Han,
Y.; Walker, S. D.; Young, R. N. Tetrahedron Lett. 1996, 16, 2703-
2706.
(5) Han, H.; Wolfe, M. M.; Brenner, S.; J anda, K. D. Proc. Natl. Acad.
Sci. U.S.A. 1995, 92, 6419-6423. See also: Bayer, E.; Mutter, M.
Nature, 1972, 237, 512-513.
(6) Studer, A.; Hadida, S.; Ferritto, R.; Kim, S.-Y.; J eger, P.; Wipf,
P.; Curran, D. P. Science 1997, 275, 823-826.
10.1021/jo9809074 CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/23/1999

Notes
J . Org. Chem., Vol. 64, No. 6, 1999 2111
Sch em e 1a
phenols were obtained in somewhat less than expected
yields (68%-82%), their recovery being complicated by
their low solubility in the standard bicarbonate/ethyl
acetate resolubilization procedure. The seven compounds
were then mixed and split into seven benzyl bromide
coupling reactions. The progress of the coupling reactions
was monitored on TLC by disappearance of the group of
more polar spots and appearance of a group of less polar
spots. After precipitative workup, the desired products
were freed from their quinoline group by saponification.
The quinoline alcohol moiety was precipitated out with
sulfuric acid, leaving the mixture of seven compounds in
solution. LC-MS analysis of these mixtures showed the
presence of all seven desired compounds in all seven
reaction mixtures, with 0.1 and 2% contamination from
3-quinolinemethanol.
In conclusion, the quinoline precipitation device offers
normal organic compound solubility in the neutral state,
but very high insolubility as the bisulfate salt. This
feature, along with its low molecular weight, makes it
possible to handle quinoline intermediates exactly like
any other organic intermediate (reactions under standard
solution conditions, TLC, NMR, MS, flash chromatogra-
phy, ion exchange isolation9) when necessary, but offers
the advantages of a solid-phase workup upon treatment
with sulfuric acid. Using ester linkers as examples, the
usefulness of the quinoline as a separation device has
been demonstrated in multistep and combinatorial syn-
theses. Further investigation of the scope and limitations
of this method and application of the concept to reagents
are in progress.
a
Key: (a) 3-bromobenzyl alcohol, EDCI, CH2Cl2, 92%; (b)
3-nitrobenzeneboronic acid, Pd(PPh3)4, DME, 83%; (c) Fe, NH4Cl,
EtOH-H2O, 89%; (d) benzoyl chloride, Et3N, CH2Cl2, 91%; (e)
LiOH, THF-H2O, 85%.
phase after dilution with ether. A second procedure (entry
7) simply involved a 4-fold dilution with methylene
chloride of the mock reaction mixture (from 0.5 M in DMF
to 0.12 M), followed by the standard ether dilution to 0.08
M and acid precipitation. Under these conditions, the
compound precipitated in better yield and the solid had
useful mechanical properties.
The second phase of the isolation procedure, after the
isolation the precipitated quinolinium salt from the
reaction mixture, consists in neutralizing the salt to
return the molecule back to the soluble form. We found
that addition of 5% NaHCO3 and AcOEt to the solid
quinolinium salt resulted in a rapid neutralization of the
salt in all cases. Evaporation of the organic layer yielded
the desired free base quinoline.
The usefulness of the quinoline precipitation device
was tested in a multistep synthesis (Scheme 1). Several
features of this synthesis are noteworthy. All of the
purification steps were accomplished by sulfuric acid
precipitation only, which gave high yields and very
expedient workups. The progress of the reactions was
monitored by TLC, and the reaction intermediates were
characterized by NMR and MS. The overall yield of this
sequence was 53%, and the compound was 98% pure (λ
) 260) by HPLC. The quinoline moiety 2 was recovered
in the alkaline aqueous phase, leaving the desired
compound 7 in solution. It was also demonstrated that 2
could be separated from 7 by acid precipitation. The
recovered 2 was of sufficient purity for reuse without
further purification.
Exp er im en ta l Section
P en ta d ecyl 3-Qu in olin eca r boxyla te (1). To a solution of
pentadecanol (7.9 g, 34 mmol), 3-quinolinecarboxylic acid (4.0
g, 23 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (4.9 g, 25 mmol) in methylene chloride (40 mL)
was added DMAP (0.1 g, 2.3 mmol). After 3 h of stirring at
ambient temperature, the reaction mixture was washed with
water (40 mL) and diluted with ether (30 mL). Addition of H2-
SO4 (1.26 mL, 23.0 mmol) under rapid stirring deposited a white
precipitate. After filtration, the solid was taken with AcOEt (40
mL) and 5% NaHCO3 (30 mL). Evaporation of the organic layer
gave 7.1 g (80%) of 1. 1H NMR (500 MHz, acetone-d6): δ 0.85 (t,
J ) 4.1 Hz, 3H), 1.28 (m, 28H), 7.72 (t, J ) 4.8 Hz, 1H), 7.95 (t,
J ) 4.8 Hz, 1H), 8.18 (m, 4H), 8.9 (s, 1H), 9.35 (s, 1H). 13C NMR
(400 MHz, CDCl3): δ 164.6, 149.3, 149.2, 147.3, 138.3, 131.8,
129.3, 128.8, 127.4, 126.4, 122.7, 78.8, 65.1, 60.9, 32.6, 31.4, 29.2,
29.1, 28.8, 28.7, 28.2, 25.6, 25.5, 22.2, 13.9 ppm. MS(EI): 370.1
(M+, 100), 174.1 (33), 197.1 (10). IR (CHCl3): 2900, 2820, 1720,
1290 cm-1. An analytical sample was prepared by flash chro-
matography (AcOEt:hexane 1:4). Anal. Calcd for C25H32NO2: C,
78.28; H, 9.72; N, 3.65. Found: C, 77.96; H, 10.16; N, 3.63.
3-Br om oben zyl-3-qu in olin e Ca r boxyla te (3). To a solution
of 3-bromobenzyl alcohol (3.3 mL, 27 mmol), 4.0 g of 3-quinoli-
necarboxylic acid (4.0 g, 23 mmol), and 1-ethyl-3-(3-dimethy-
laminopropyl)carbodiimide hydrochloride (5.3 g, 27 mmol) in
methylene chloride (50 mL) was added DMAP (0.1 g, 2.3 mmol).
After 3 h of stirring at ambient temperature, the reaction
mixture was washed with water (40 mL) and diluted with ether
(30 mL). Addition of H2SO4 (1.26 mL, 23 mmol) under rapid
stirring deposited a white precipitate. After filtration, the solid
was taken with AcOEt (40 mL) and 5% NaHCO3 (30 mL).
Evaporation of the organic layer gave 7.3 g (92%) of 3. 1H NMR
(500 MHz, acetone-d6): δ 5.32 (s, 2H), 7.48 (t, J ) 4.8 Hz, 1H),
It is interesting that 5, which has an aniline group of
basicity comparable to the quinoline group, and therefore
offers two different sites for protonation, underwent
precipitation under the same 1:1 H2SO4:quinoline ratio
as the other intermediates of the sequence, with no
observable difference.
This method was also applied to the synthesis of
mixtures of compounds (Scheme 2). The first step of this
sequence was the individual coupling of the phenol acids
to the chloromethylquinoline 4.8 The seven quinoline
(8) Acosta, C. K.; Bahr, M. L.; Burdett, J . E.; Cessac, J . W.; Martinez,
R. A.; Rao, P. N.; Kim, H. K. J . Chem. Res. Miniprint 1991, 5, 914-
934.
(9) Siegel, M. G.; Hahn, P. J .; Dressman, B. A.; Fritz, J . A.; Grunwell,
J . R.; Kaldor, S. W. Tetrahedron Lett. 1997, 19, 3357-3360.

2112 J . Org. Chem., Vol. 64, No. 6, 1999
Notes
Sch em e 2
7.58 (t, J ) 4.5 Hz, 2H), 7.77 (t, J ) 5.2 Hz, 1H), 7.8 (s, 1H),
7.95 (t, J ) 5.1 Hz, 1H), 8.16 (m, 2H), 9.0 (s, 1H), 9.4 (s, 1H).
13C NMR (400 MHz, DMSO-d6): δ 164.7, 149.5, 149.3, 138.9,
138.7, 132.5, 131.3, 130.9, 129.8, 128.9, 127.9, 127.3, 126.6, 122.5,
7.62 (m, 5H), 7.68 (m, 2H), 7.9 (m, 3H), 8.05 (d, J ) 2.5 Hz, 1H),
8.16 (d, J ) 4.8 Hz, 1H), 8.21 (d, J ) 4.8 Hz, 1H), 8.28 (s, 1H),
9.05 (s, 1H), 9.4 (s, 1H), 9.59 (bs, 1H). 13C NMR (400 MHz,
DMSO-d6): δ 165.9, 164. 9, 149.5, 149.3, 140.5, 140.4, 139.8,
138.8, 136.8, 134.9, 132.5, 131.9, 129.9, 129.5, 128.9, 128.6, 127.9,
127.8, 127.6, 126.8, 126.7, 126.6, 122.7, 122.3, 119.7, 118.9, 66.9
ppm. An analytical sample was prepared by flash chromatog-
raphy (AcOEt:hexane 1:4). IR (neat): 3300, 1650, 1610, 1550,
1290 cm-1. HRMS(FAB): calcd for C30H22N2O2 459.1709, found
459.1709.
121.9, 65.8 ppm. IR (CHCl3): 1720, 1620, 1370, 1280 cm-1
.
HRMS(FAB): calcd for C17H13NO2Br 342.0011, found 342.0128.
3′-Nitr obip h en yl-3-qu in olin e Ca r boxyla te (4). To a solu-
tion of compound 3 (0.37 g, 1.1 mmol) in DME (4 mL) were added
Pd(PPh3)4 (0.03 g, 0.03 mmol), Na2CO3 ( 1.35 mL of 2 M, 2.71
mmol), and p-nitroboronic acid (0.37 g, 2.1 mmol). After 4 h at
75 °C the reaction mixture was washed with water (10 mL) and
CH2Cl2 (15 mL). The precipitation procedure described for
compound 1 using H2SO4 (58 µL, 1.1 mmol) and ether (5 mL)
N-(3′-(Hyd r oxym eth yl)bip h en yl-3-yl)ben za m id e (7). To
a solution of compound 6 (0.051 g, 0.11 mmol) in THF (1 mL)
was added LiOH (2 M, 0.8 mL, 0.17 mmol). After 1 h at 55 °C,
the reaction mixture was washed with ether (5 mL), extracted,
and evaporated to give 28 mg of 7 (85%). 1H NMR (500 MHz,
acetone-d6): δ 4.29 (t, J ) 5.8 Hz, 1H), 4.71 (d, J ) 6 Hz, 2H),
7.35 (d, J ) 8 Hz, 1H), 7.41 (m, 3H), 7.55 (m, 4H), 7.67 (s, 1H),
7.88 (d, J ) 4.8 Hz, 1H), 8.05 (d, J ) 7.8 MHz, 1H), 8.17 (s, 1H),
9.62 (bs, 1H). 13C NMR (400 MHz, DMSO-d6): δ 166.1, 143.6,
141.1, 140.5, 140.2, 135.2, 132.1, 129.6, 129.2, 128.8(2), 128.0-
(2), 126.1, 125.4, 125.0, 122.4, 119.7, 118.9, 63.2 ppm. MS(EI):
1
gave 0.35 g of 4 (83%). H NMR (500 MHz, acetone-d6): δ 5.58
(s, 2H), 7.6-7.93 (m, 5H), 7.91 (t, J ) 8.5 Hz, 1H), 8.01 (s, 1H),
8.15-8.25 (m, 4H), 8.5 (s, 1H), 9.05 (s, 1H), 9.4 (s, 1H). 13C NMR
(400 MHz, DMSO-d6): δ 154.4, 154.2, 145.4, 145.2, 144.7, 143.7,
141.6, 139.7, 137.4, 136.7, 134.4, 133.7, 132.7, 132.6, 132.5, 131.6,
131.5, 131.4, 127.5, 124.5, 123.7, 71.6 ppm. IR (CHCl3): 1720,
1540, 1350, 1285 cm-1. HRMS(FAB): calcd for C23H17N4O2
385.1188, found 385.1184.
3′-Am in obip h en yl-3-qu in olin e Ca r boxyla te (5). To a solu-
tion of compound 4 (0.11 g, 0.43 mmol) in EtOH (1.5 mL) and
H2O (0.5 mL) were added NH4Cl (0.02 g, 0.55 mmol) and iron
(0.12 g, 0.5 mmol). After 3 h at 60 °C, the reaction mixture was
filtered through Celite and diluted with ether (4 mL). The
precipitation procedure described for compound 1 using H2SO4
304 (M+, 100). IR (neat): 3300, 1640, 1600, 1540, 1305 cm-1
.
An analytical sample was prepared by flash chromatography
(AcOEt:hexane1:4). Anal. Calcd for C20H17NO2: C, 79.19; H, 5.65;
N, 4.62. Found: C, 78.99; H, 5.71; N, 4.47.
Gen er a l P r oced u r e for 9a -g. To a solution of the desired
phenol acid (3.50 mmol) in DMF (2 mL) was added 3-(chlorom-
ethyl)quinoline hydrochloride (1.46 mmol) and Hunig’s base (3.21
mmol). After the reaction was stirred overnight at 80 °C, one of
the two work up procedures was followed (see individual
preparation): (A) to the reaction mixture was added CH2Cl2 (3
mL), H2SO4 (1.46 mmol), and then slowly ether (10 mL), under
rapid stirring; (B) the reaction mixture was diluted with water
(8 mL) and CH2Cl2 (5 mL); after phase separation, addition of
H2SO4 (1.46 mmol) and then slowly, ether (10 mL), under rapid
stirring.
After filtration, the solid was dissolved with 50 mL of AcOEt
and 20 mL of 5% NaHCO3. Evaporation of the organic layer gave
the corresponding compounds 9a -g.
3-{[(6-H y d r o x y -2-n a p h t h y l)c a r b o n y lo x y ]m e t h y l}-
qu in olin e (9a ). Work up procedure: A. Yield: 68%. 1H NMR
(500 MHz, acetone-d6): δ 5.64 (s, 2H), 7.26 (dd, J ) 2.7 Hz, 6.5
Hz, 1H), 7.36 (s, 1H), 7.62 (t, J ) 7.2 Hz, 1H), 7.77 (q, J ) 1.4
Hz, 2.4 Hz, 2H), 7.88 (m, 3H), 8.07 (d, J ) 7.8 Hz, 1H), 8.46 (s,
1H), 8.59 (s, 1H), 9.10 (s, 1H). 13C NMR (400 MHz, DMSO-d6):
1
(21 µL, 0.43 mmol) gave 0.105 g of 5 (95%). H NMR (500 MHz,
acetone-d6): δ 4.7 (bs, 2H), 5.52 (s, 2H), 6.66 (d, J ) 2.5 Hz,
1H), 6.89 (d, J ) 5 Hz, 1H), 6.98 (s, 1H), 7.14 (t, J ) 7.8 Hz,
2H), 7.52 (m, 2H), 7.59 (d, J ) 2.5 Hz, 1H), 7.69 (t, J ) 7.8 Hz,
1H), 7.76 (s, 1H), 7.91 (t, J ) 7.2 Hz, 1H), 8.14 (m, 2H), 8.98 (s,
1H), 9.4 (s, 1H). 13C NMR (400 MHz, DMSO-d6): δ 164.8, 149.5,
149.3, 141.5, 140.7, 138.7, 136.4, 132.4, 129.8, 129.6, 128.8, 127.8,
127.2, 126.6, 122.63, 114.63, 113.5, 112.4, 66.9 ppm. IR (neat):
3460, 3360, 1710, 1600, 1290 cm-1. HRMS(FAB): calcd for
C23H19N2O2 355.1447, found 355.1431.
3′-(Ben zoyla m in o)bip h en yl-3-qu in olin e Ca r boxyla te (6).
To a solution of compound 5 (0.066 g, 0.18 mmol), in CH2Cl2
(0.7 mL) was added NEt3 (26 µL, 0.19 mmol), and benzoyl
chloride (24 µL, 0.19 mmol). After 4 h at 25 °C, the reaction
mixture was washed with CH2Cl2 (0.5 mL) and with ether (0.5
mL). The precipitation procedure described for compound 1 using
1
H2SO4 (9 µL, 0.18 mmol) gave 0.080 g of 6 (92%). H NMR (500
MHz, acetone-d6): δ 5.57 (s, 2H), 7.45 (d, J ) 2.5 Hz, 2H), 7.5-

Notes
J . Org. Chem., Vol. 64, No. 6, 1999 2113
δ 166.2, 158.9, 151.0, 147.4, 137.6, 135.4, 131.3, 130.9, 129.9,
129.6, 128.8, 128.3, 127.5, 127.1, 126.5, 126.4, 125.2, 123.2, 120.3.
108.9, 64.2 ppm. MS(EI): 330.1 (M+, 100), 160 (20). IR (CHCl3):
1695, 1620, 1470, 1270 cm-1. Anal. Calcd for C21H15NO2: C,
76.58; H, 4.59; N, 4.25. Found: C, 76.01; H, 4.51; N, 4.31.
3-{[(3-H y d r o x y -2-n a p h t h y l)c a r b o n y lo x y ]m e t h y l}-
qu in olin e (9b). Work up procedure: B. Yield: 82%. 1H NMR
(500 MHz, acetone-d6): δ 5.76 (s, 2H), 7.33 (t, J ) 3.8 Hz, 2H),
7.55 (t, J ) 7.2 Hz, 1H), 7.62 (t, J ) 7.2 Hz, 1H), 7.80 (m, 2H),
7.93 (d, J ) 8.2 Hz, 1H), 8.01 (d, J ) 7.9 Hz, 1H), 8.05 (d, J )
8.4 Hz, 1H), 8.52 (s, 1H), 8.67 (s, 1H), 9.13 (s, 1H), 10.3 (bs, 1H).
13C NMR (400 MHz, DMSO-d6): δ 165.7, 155.8, 151.1, 148.4,
147.4, 137.7, 135.9, 135.8, 130.4, 130.1, 129.9, 129.0, 128.8,
128.32, 128.1, 127.3, 127.1, 125.9, 123.2, 119.6, 65.4 ppm. MS-
(EI): 330.1 (M+, 80), 160 (100). IR (neat): 3400, 1720, 1590,
1490, 1250 cm-1. Anal. Calcd for C21H15NO3: C, 76.58; H, 4.59;
N, 4.25. Found: C, 76.88; H, 4.49; N, 4.18.
3-{[(4-Hyd r oxy-3-m eth oxyp h en yl)ca r bon yloxy]m eth yl}-
qu in olin e (9f). Work up procedure: A. Yield: 79%. 1H NMR (500
MHz, acetone-d6): δ 3.88 (s, 3H), 5.56 (s, 2H), 6.90 (d, J ) 8.3
Hz, 1H), 7.61 (m, 3H), 7.75 (t, J ) 5.5 Hz, 1H), 7.97 (d, J ) 8.2
Hz, 1H), 8.02 (d, J ) 8.3 Hz, 1H), 8.4 (bd, 2H), 9.04 (s, 1H). 13C
NMR (400 MHz, DMSO-d6): δ 165.6, 151.9, 150.9, 147.6, 147.3,
135.3, 130.1, 129.7, 128.8, 128.4, 127.4, 127.2, 120. 3, 115.4,
112.7, 63.8 ppm. MS(EI): 310 (M+, 100), 160 (15), 142 (12). IR
(CHCl3): 1710, 1290 cm-1. Anal. Calcd for C18H15NO4: C, 69.89;
H, 4.89; N, 4.53. Found: C, 69.4; H, 4.94; N, 4.39.
3-{[(2-Ch lor o-4-h yd r oxyp h en yl)ca r b on yloxy]m et h yl}-
qu in olin e (9g). Work up procedure: A. Yield: 71%. 1H NMR
(500 MHz, acetone-d6): δ 5.56 (s, 2H), 6.87 (d, J ) 8.7 Hz, 1H),
6.97 (s, 1H), 7.61 (t, J ) 7.1 Hz, 1H), 7.76 (t, J ) 7.0 Hz, 1H),
7.90 (d, J ) 8.7 Hz, 1H), 7.98 (d, J ) 8.2 Hz, 1H), 8.05 (d, J )
8.1 Hz, 1H), 8.41 (s, 1H), 9.04 (s, 1H). 13C NMR (400 MHz,
DMSO-d6): δ 164.2, 161.8, 150.9, 147.3, 135.5, 134.7, 133.9,
130.0, 129.4, 128.8, 128.3, 127.4, 127.2, 119.1, 117.8, 114.6, 64.3
ppm. MS(EI): 313.9 (M+, 100), 160 (20). IR (CHCl3): 1715, 1600,
1560, 1290 cm-1. Anal. Calcd for C17H12ClNO3: C, 65.08; H, 3.86;
N, 4.46. Found: C, 65.08; H, 4.05; N, 4.47.
3-{[(4-H yd r oxyp h en yl)ca r b on yloxy]m et h yl}q u in olin e
(9c). Work up procedure: A. Yield: 70%. 1H NMR (500 MHz,
acetone-d6): δ 5.55 (s, 2H), 6.92 (d, J ) 3.0 Hz, 1H), 7.59 (t, J )
7.1 Hz, 1H), 7.76 (t, J ) 7.1 Hz, 1H), 7.96 (d, J ) 3.2 Hz, 1H),
7.98 (d, J ) 8.2 Hz, 1H), 8.05 (d, J ) 8.5 Hz, 1H), 8.40 (s, 1H),
9.03 (s, 1H). 13C NMR (400 MHz, DMSO-d6): δ 165.6, 162.4,
150.9, 147.3, 135.3, 131.9, 130.0, 129.7, 128.8, 128.3, 127.4, 127.2,
120.9, 120.1, 115.6, 63.8 ppm. MS(EI): 280.1 (M+, 100), 160.1
Mixtu r es 10 a n d 11. To an equimolar mixture solution of
compounds 9a -g (0.47 mmol total concentrated) in acetone (2
mL) were added the desired benzyl bromide (0.85 mmol) and
K2CO3 (0.52 mmol). After the reaction was stirred overnight
stirring at 55 °C, CH2Cl2 (3 mL) was added, and the precipitation
procedure described for compound 1 using H2SO4 (0.472 mmol)
gave the corresponding compounds 10a -g. The seven mixtures
were taken separately in 2 mL of THF and 2 M LiOH (0.872
mmol). After 1 h at 55 °C, the precipitation procedure described
for compound 1 was used adding H2SO4 (excess), ether (3 mL),
and H2O (3 mL). The organic layer was evaporated to yield an
average of 50% with a maximum of 77% and a minimum of 48%
from the mixture of 9a -g. The seven mixtures were analyzed
by HPLC and MS (negative ion) to show the presence of the
expected molecular ion for the compounds 11a -g.
(10), 142 (40). IR (neat): 3400, 1705, 1605, 1595, 1290 cm-1
.
Anal. Calcd for C17H13NO3: C, 73.11; H, 4.69; N, 5.02. Found:
C, 73.03; H, 4.89; N, 4.77.
3-{[(3-H yd r oxyp h en yl)ca r b on yloxy]m et h yl}q u in olin e
(9d ). Work up procedure: B. Yield: 76%. 1H NMR (500 MHz,
acetone-d6): δ 5.58 (s, 2H), 7.09 (dd, J ) 1.0 Hz, 1.6 Hz, 1H),
7.33 (t, J ) 7.9 Hz, 1H), 7.52 (m, 2H), 7.62 (t, J ) 5.6 Hz, 1H),
7.76 (t, J ) 5.6 Hz, 1H), 7.98 (d, J ) 8.1 Hz, 1H), 8.05 (d, J )
8.4 Hz, 1H), 8.42 (s, 1H), 8.68 (bs, 1H), 9.05 (s, 1H). 13C NMR
(400 MHz, DMSO-d6): δ 165.8, 157.8, 150.9, 147.4, 135.5, 130.8,
130.1, 129.4, 128.8, 128.3, 127.5, 127.2, 120.8, 120.2, 115.9, 64.3
ppm. MS(EI): 280.1 (M+, 100), 160.1 (30), 142 (8). IR (CHCl3):
3400, 1715, 1590, 1280 cm-1. Anal. Calcd for C17H13NO3: C,
73.11; H, 4.69; N, 5.02. Found: C, 73.051; H, 4.85; N, 4.92.
3 -{[ ( 4 -H y d r o x y b i p h e n y l ) c a r b o n y l o x y ] m e t h y l }-
qu in olin e (9e). Work up procedure: A. Yield: 71%. 1H NMR (500
MHz, acetone-d6): δ 5.62 (s, 2H), 6.94 (d, J ) 4.8 Hz, 1H), 7.58
(m, 3H), 7.75 (m, 3H), 7.99 (d, J ) 8.1 Hz, 1H), 8.07 (d, J ) 8.1
Hz, 1H), 8.11 (d, J ) 4.8 Hz, 1H), 8.45 (s, 1H), 8.57 (bs, 1H),
9.07 (s, 1H). 13C NMR (400 MHz, DMSO-d6): δ 165.7, 158.2,
150.9, 147.3, 145.1, 135.4, 130.2, 130.1, 129.5, 129.4, 128.8, 128.3,
127.4, 127.2,127.1, 126.1, 116.1, 64.3 ppm. MS(EI): 356.1 (M+,
100). IR (CHCl3): 1705, 1490, 1450, 1270 cm-1. Anal. Calcd for
Ack n ow led gm en t. The authors thank Dwight Mac-
donald and Claudio Sturino for useful discussions and
J ames Yergey and Chun Li for help with the mass
spectroscopy.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra for
precipitated compounds 3-7 and 9a -g as well as HPLC and
LC-MS data for the mixture 11a -g. This material is available
free of charge via the Internet at http://pubs.acs.org.
C
23H17NO3: C, 77.73; H,4.82; N,3.94. Found: C, 77.53; H, 4.75;
N, 3.93.
J O9809074