Synthesis of 3-methoxycarbonylmethyl derivatives of dihydroquinolone and dihydrochromenone

Full text of DOI:10.1021/jo005703d

J . Org. Chem. 2001, 66, 2175-2177
2175
Sch em e 1a
Syn th esis of 3-Meth oxyca r bon ylm eth yl
Der iva tives of Dih yd r oqu in olon e a n d
Dih yd r och r om en on e
J ames A. Nieman and Michael D. Ennis*
Structural, Analytical & Medicinal Chemistry,
Pharmacia Corp., Kalamazoo, Michigan 49001
a
Conditions: (a) NaOH(aq), ZCl; (b) NaH, allyl bromide, THF.
Ta ble 1. Con d ition s for th e F or m a tion of 1a fr om 3 via a
P a lla d iu m -Ca ta lyzed Ca r bon yla tive Cycliza tion a
michael.d.ennis@am.pnu.com
Received October 27, 2000
Recently, we required the 3-substituted dihydroqui-
nolone compounds 1a and 1b.1 Unfortunately, a search
relative product distributionb (%)
(isolated yield, %)
pressure
T
equiv of
entry CO (psi) (°C) MeOH
1a
21
50
62
67 (47)
67 (46)
76 (46)
70 (60)
66 (57)
4
5
1
2
3
4
5
6
7
8
600
1200
1200
1200
1200
1600
1600
1600
100
100
80
60
50
60
60
60
4
4
4
4
4
4
20
40
49
42
34
22
16
19
18
18
of the literature revealed no facile method for their
preparation. All previous approaches to 3-carbomethoxy-
methyl-2,3-dihydro-4-quinolones required at least six
steps and proceeded in 7-25% yield.2 These approaches
first involved an annulation to construct a 2,3-dihydro-
4-quinolone ring system3,4 and then relied upon either
Stork enamine2 or Mannich chemistry2a to introduce the
required acetate side-chain. We believed that a more
efficient preparation could be accomplished by the ap-
plication of a palladium-catalyzed carbonylative cycliza-
tion reaction to simultaneously construct the 2,3-dihy-
droquinolone and install the 2-acetate side-chain (e.g.,
3 f 1a , Scheme 1). Although the carbocyclic analogue
1d has previously been synthesized via this methodology
by Negishi,5-7 no analogous heterocyclic examples have
been reported.
To examine the viability of the palladium-mediated
carbonylative cyclization protocol for the synthesis of 1a
(Scheme 1), we prepared 3 in two steps from 2-iodoaniline
(2).8 When the conditions reported by Negishi to form
carbocycle 1d were applied to aniline derivative 3,5 only
a modest amount of the desired compound 1a was
observed (Table 1, entry 1). The dominant product
observed was the indoline 4, where intramolecular car-
4
8
4
8
12
a
All reactions were performed in a high-pressure minireactor
(“bomb”) with 1 mmol of 3, 2 equiv of Et3N, MeOH (4 equiv except
in entries 7 and 8), 5 mol % PdCl2(PPh3)2, 10 mL of PhH and 10
mL of MeCN. b Obtained from integration of 1H NMR of unpurified
reaction products.
bopalladation had occurred faster than the desired CO
insertion.9 We therefore repeated the reaction using a
higher pressure of CO with the hopes of favoring the
formation of 1a . Indeed, doubling the CO pressure more
than doubled the relative amount of desired product 1a
(entry 2).10 Unfortunately, a significant amount of indo-
line 4 was still observed. We found that lowering the
reaction temperature significantly attenuated the rate
(6) For some other related papers by Negishi and co-workers see:
Negishi, E.; Ma, S.; Amanfu, J .; Cope´ret, C.; Miller, J . A.; Tour, J . M.
J . Am. Chem. Soc. 1996, 118, 5919. Cope´ret, C.; Ma, S.; Negishi, E.
Angew Chem Int. Ed. Engl. 1996, 35, 2125. Negishi, E.; Cope´ret, C.;
Sugihara, T.; Shimoyama, I.; Zhang, Y.; Wu, G.; Tour, J . M. Tetrahe-
dron 1994, 50, 425. For some similar reactions not incorporating carbon
monoxide, see: Larock, R. C.; Berrios-Pena, N.; Narayanan, K. J . Org.
Chem. 1990, 55, 3447. Larock, R. C.; Stinn, D. E. Tetrahedron Lett.
1988, 37, 4687. Odle, R.; Blevins, B.; Ratcliff, M.; Hegedus, L. S. J .
Org. Chem. 1980, 45, 2709.
* To whom correspondence should be addressed.
(1) Nieman, J . A.; Ennis, M. D. Org. Lett. 2000, 2, 1395.
(2) (a) Nakao, T.; Kawakami, M.; Morita, K.; Obata, M.; Morimoto,
Y.; Takehara, S.; Tahara, T. Yakugaku Zasshi 1990, 110, 573. (b) Lin,
M.-S.; Snieckus, V. J . Org. Chem. 1971, 36, 645.
(3) For some previous synthesis of various N-protected 2,3-dihydro-
4-quinolones, see: J ohnson, W. S.; DeAcetis, W. J . Am. Chem. Soc.
1953, 75, 2766. J ohnson, W. S.; Woroch, E. L.; Buell, B. G. J . Am.
Chem. Soc. 1949, 71, 1901. Collins, R. F. J . Chem. Soc. 1960, 2053.
Kano, S.; Ebata, T.; Shibuya, S. J . Chem. Soc., Perkin Trans. 1 1980,
2105. Braunholtz, J . T.; Mann, F. G. J . Chem. Soc. 1957, 4166 and
references cited within.
(4) For some alternative, lower-yielding methods, see also: Benin-
cori, T.; Brenna, E.; Sannicolo`, F. J . Chem Soc. Perkin Trans. 1 1991,
2139. Crabb, T. A.; Soilleux, S. L. J . Chem. Soc., Perkin Trans. 1 1985,
1381. Proctor, G. R.; Thonson, R. H. J . Chem. Soc. 1957, 2312.
(5) (a) Tour, J . M.; Negishi, E. J . Am. Chem. Soc. 1985, 107, 8289.
(b) Negishi, E.; Cope´ret, C.; Ma, S.; Mita, T.; Sugihara, T.; Tour, J . M.
J . Am. Chem. Soc. 1996, 118, 5904.
(7) (a) For some recent reviews, see: Grigg, R.; Sridharan, V. J .
Organomet. Chem. 1999, 576, 65; and Negishi, E.; Cope´ret, C.; Ma,
S.; Liou, S.-Y.; Liu, F. Chem. Rev. 1996, 96, 365. (b) For synthesis of
lactams and lactones see: El Ali, B.; Alper, H. Synlett 2000, 161. (c)
For a recent enantioselective example, see: Hayashi, T.; Tang, J .; Kato,
K. Org. Lett. 1999, 1, 1487. (d) For
a multistep enantioselective
synthesis of 1d , see: Imai, M.; Hagihara, A.; Kawasaki, H.; Manabe,
K.; Koga, K. Tetrahedron 2000, 56, 179.
(8) (a) Bose, D. S.; Thurston, D. E. Tetrahedron Lett. 1990, 31, 6903.
(b) Hadida, S.; Super, M. S.; Beckman, E. J .; Curran, D. P. J . Am.
Chem. Soc. 1997, 119, 7406.
(9) Product ratio determined by 1H NMR of unpurified product.
(10) The insertion of CO into a carbon-palladium bond is believed
to be a reversible process. For more information see ref 7a.
10.1021/jo005703d CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/17/2001

2176 J . Org. Chem., Vol. 66, No. 6, 2001
Notes
psi CO pressure, 4 equivalents methanol, 100 °C)17 in a
high-pressure minireactor (“bomb”), the main product
obtained was the naphthol 7. Only a 14% yield of 1d was
isolated after purification. If, however, the CO pressure
was increased to 1200 psi and the methanol concentra-
tion18 was increased (20 equivalents, 0.9 M) product 1d
was obtained in a similar chemical yield (55%) to that
previously reported.
Sch em e 2a
a
Conditions: (a) LDA, allyl bromide, THF, 98%; (b) PdCl2(PPh3)2,
Et3N, MeOH, PhH, MeCN, CO (1450 psi), 60 °C, 68%; (c) K2CO3,
allyl bromide, DMF, 72%; (d) conditions b with CO (1200 psi) and
130 °C, 51%.
In summary, we have successfully developed facile
syntheses of 1a (55% yield, three steps), 1b (67% yield,
two steps), and 1c (37% yield, two steps) by application
of a palladium-catalyzed carbonylative cyclization as the
key transformation. For these reactions, we found that
CO pressure (greater than 1200 psi), temperature, and
methanol concentration are all important factors in
optimizing production of the desired γ-ketoester products.
It is interesting to note that the chromanone 1c and the
tetralone 1d required higher reaction temperatures (100
and 130 °C) to obtain good yields than did the quinolone
substrates 1a and 1b (60 °C).
of undesired carbopalladation leading to 4 (entries 3-5),
but even at 60 °C (entry 4) a disappointing 47% yield of
1a was obtained.11 Performing the reaction at 1600 psi
failed to improve the isolated yield, but did improve the
1
proportion of desired product observed by H NMR. We
felt that the unexpectedly low isolated yield of 1a may
be due to polymerization of a late-stage intermediate.12
To diminish this potential polymerization, we studied the
effect of increasing methanol concentration on the ob-
served product ratios and isolated yields (entries 7 and
8). Although higher concentrations of methanol increased
the quantity of benzoate 5 observed, we also realized an
improved yield of 1a . The best chemical yield obtained
utilized 20 equiv of methanol (0.9 M final concentration)
and produced a 60% isolated yield of desired compound
1a (entry 7).13,14
With a good procedure for the formation of 1a in hand,
we turned our attention to the formation of the analogous
heterocycles 1b and 1c (Scheme 2). Subjection of the
N-allyl derivative of 2-iodoaniline15 to the palladium-
catalyzed carbonylative cyclization conditions generated
an impressive yield of 67% for the two-step formation of
1b. Although allylation of 2-iodophenol proceeded as
previously reported,16 attempts to form 1c at low tem-
perature (60 °C) or lower pressure (600 psi) resulted in
predominantly formation of methyl salicylate. Performing
the palladium-catalyzed carbonylative cyclization at 130
°C with a CO pressure of 1200 psi resulted in a 51%
isolation yield of the desired annulated product 1c.
Exp er im en ta l Section
Gen er a l Meth od s. Proton and carbon magnetic resonance
spectra were recorded in CDCl3 at 300 and 75.5 MHz, respec-
tively, and are reported in ppm on the δ scale. Infrared spectra,
mass spectra, and combustion analysis were determined by
Structural and Analytical Chemistry, Pharmacia Corp. Anhy-
drous THF was distilled prior to use from sodium metal/
benzophenone ketyl. Dry benzene, DMF, and acetonitrile were
purchased from Aldrich in Sure-Seal bottles. For the high-
pressure carbon monoxide reactions, a stainless steel 100 mL
high-pressure minireactor or “bomb” (Parr Instrument Company,
Series 4560) equipped with a thermocouple, gas inlet, gas outlet,
pressure gauge (to 2000 psi), and mechanical stirrer was used.
Unless otherwise noted, all nonaqueous reactions were carried
out under a nitrogen atmosphere using oven-dried glassware.
N-Ben zyloxyca r b on yl-2-iod oa n ilin e.8a To 2-iodoaniline
(20.0 g, 91.3 mmol) was added a 1.0 N aqueous sodium hydroxide
solution (91.3 mL, 91.3 mmol). The resulting suspension was
stirred vigorously as benzyl chloroformate (19.6 mL, 137 mmol)
was added slowly from an addition funnel. The temperature was
maintained close to room temperature by cooling as needed. The
progress of the reaction was followed by loss of starting material
by TLC. When the 2-iodoaniline was completely consumed (∼0.5
h), the reaction mixture was poured into ethyl acetate. The ethyl
acetate layer was separated and the aqueous layer was extracted
three times with ethyl acetate. The organic layers were com-
bined, dried over MgSO4, filtered, and concentrated in vacuo.
The resulting crude product was purified on a Waters Prep 500
(1:20 ethyl acetate-n-heptane) to give N-benzyloxycarbonyl-2-
iodoaniline (31.9 g, 90.3 mmol, 99% yield) as a white solid: mp
Considering that optimum formation of 1a -c required
higher CO pressures and greater equivalents of methanol
than the carbocyclic example (1d ) reported by Negishi
and co-workers,5b we decided to investigate the conver-
sion of 6 to 1d (reaction 1). When 6 was subjected to the
reaction conditions previously reported by Negishi (600
(11) Attempts to use DMF or benzene as the solvent under identical
conditions to entry 5 (Table 1) failed to improve the isolated yield.
(12) Drent, E.; Budzelaar, P. H. M. Chem. Rev. 1996, 96, 663.
(13) Different palladium sources and phosphine ligands were also
investigated using identical conditions to entry 7 (Table 1), but none
provided a better isolated yield for 1a . Other sources (5 mol %) and
ligands tried included the following: PdCl2(Po-tol3)2, 29% yield; PdCl2-
BINAP, 31%; Pd(PPh3)4, 51%; Pd(dba)2, 28%; Pd(OAc)2, 32%; Pd(OAc)2
with 5 mol % dppp, 20%; and Pd(OAc)2 with 10 mol % P(t-Bu)3, 36%.
(14) Benzene can be replaced by toluene in the benzene: acetonitrile
solvent mixture. This chemistry has been performed on a 15 g scale
with the toluene/acetonitrile mixture resulting in a 54% isolated yield
of 1a .
1
61.1-61.7 °C; IR (drift) 3380, 1739, 1587, 1526, 1432 cm-1; H
NMR δ 8.09 (d, J ) 8 Hz, 1 H), 7.77 (dd, J ) 1, 8 Hz, 1 H),
7.46-7.32 (m, 6 H), 7.04 (bs, 1H), 6.81 (dt, J ) 1, 8 Hz, 1H),
5.24 (s, 2H); 13C NMR δ 153.1, 138.8, 138.2, 135.7, 129.2, 128.6,
128.3, 128.3, 125.1, 120.3, 88.8, 67.2; MS (EI) m/z 353 (M+). Anal.
Calcd for C14H12INO2: C, 47.61; H, 3.42; N, 3.97. Found: C,
47.96; H, 3.46; N, 3.89.
(17) Negishi and co-workers used a different apparatus (i.e., an
autoclave). See ref 5b for more details.
(15) Molander, G. A.; Harring, L. S. J . Org. Chem. 1990, 55, 6171.
(16) Curran, D. P.; Totleben, M. J . J . Am. Chem. Soc. 1992, 114,
6050.
(18) In scaling up the reaction of 3a to 1a , we have observed that
the concentration of methanol appears to be more important for
obtaining high yields than the number of equivalents.

Notes
N-Allyl-N-ben zyloxyca r bon yl-2-iod oa n ilin e (3). N-Ben-
J . Org. Chem., Vol. 66, No. 6, 2001 2177
(dd, J ) 2, 8 Hz, 1 H), 7.86 (d, J ) 8 Hz, 1 H), 7.52 (dt, J ) 2,
7 Hz, 1 H), 7.44-7.34 (m, 5 H), 7.19 (dt, J ) 1, 8 Hz, 1 H), 5.33
(d, J ) 12 Hz, 1 H), 5.27 (d, J ) 12 Hz, 1 H), 4.64 (dd, J ) 5, 13
Hz, 1 H), 3.79 (dd, J ) 12, 13 Hz, 1 H), 3.69 (s, 3 H), 3.27-3.17
(m, 1 H), 2.88 (dd, J ) 5, 17 Hz, 1 H), 2.57 (dd, J ) 8, 17 Hz, 1
H); 13C NMR δ 194.3, 171.6, 153.5, 143.3, 135.5, 134.1, 128.5,
128.3, 128.0, 127.5, 124.2, 124.1, 123.1, 68.1, 51.8, 48.3, 44.0,
31.7; MS (EI) m/z 353 (M+); HRMS (FAB) calcd for C20H19NO5
+Na1 376.1161, found 376.1177. Anal. Calcd for C20H19NO5: C,
67.98; H, 5.42; N, 3.96. Found: C, 67.76; H, 5.53; N, 3.98.
Meth yl 2-(4-Oxo-1,2,3,4-tetr a h yd r o-3-qu in olin yl)a ceta te
(1b). Compound 1b was synthesized using the general procedure
described above. The reaction was run at a temperature of 65
°C and a CO pressure of 1400 psi with the following quantities:
N-allyl-2-iodoaniline,15 250 mg (0.965 mmol); benzene, 10 mL;
acetonitrile, 10 mL; triethylamine, 0.269 mL (1.93 mmol);
methanol, 0.782 mL (0.93 M final concentration, 20 equiv); Pd-
(PPh3)2Cl2, 33.9 mg (0.0482 mmol). The crude product was
purified by radial column chromatography (2 mm plate, 1:2 ethyl
acetate-n-heptane, the sample was loaded onto the column as
a solution in chloroform) producing 1b (144 mg, 0.657 mmol,
68% yield) as a light brown solid: mp 146.6-147.2 °C; IR (drift)
zyloxycarbonyl-2-iodoaniline (15.3 g, 43.2 mmol) was dissolved
in 100 mL anhydrous THF and the solution was cooled to 0 °C.
Sodium hydride (60% dispersion, 1.90 g, 47.5 mmol) was added
portionwise. Ca u tion : h yd r ogen ga s evolved . Upon cessation
of gas evolution, the ice bath was removed and the suspension
was stirred at room temperature for 15 min. and then recooled
to 0 °C. Allyl bromide (4.49 mL, 51.8 mmol) was added and the
reaction mixture was slowly warmed to room-temperature
overnight (∼19 h). The reaction was quenched by the addition
of water (Ca u tion : h yd r ogen ga s evolved ) followed by ethyl
acetate. The ethyl acetate layer was separated and the aqueous
layer was extracted three times with ethyl acetate. The organic
layers were combined, dried over MgSO4, filtered, and concen-
trated in vacuo. The resulting cloudy oil was subjected to silica
gel column chromatography (1:20 ethyl acetate-n-heptane; the
sample was loaded as a solution in chloroform) resulting in the
isolation of 3 (15.8 g, 40.1 mmol, 93% yield) as a clear, colorless
oil: IR (liquid) 1710, 1472, 1440 cm-1; 1H NMR δ 7.89 (d, J ) 8
Hz, 1 H), 7.44-7.16 (m, 7 H), 7.02 (t, J ) 8 Hz, 1 H), 5.97-5.90
(m, 1 H), 5.28-5.08 (m, 4 H), 4.60 (dd, J ) 7, 15 Hz, 1 H), 3.81
(dd, J ) 7, 15 Hz, 1 H); 13C NMR δ 154.6, 143.3, 139.4, 136.3,
132.9, 129.9, 129.1, 128.8, 128.1, 127.6, 127.4, 118.3, 100.3, 67.2,
52.7; MS (EI) m/z 393 (M+). Anal. Calcd for C17H16INO2: C,
51.93; H, 4.10; N, 3.56. Found: C, 51.84; H, 4.04; N, 3.54.
Gen er a l P r oced u r e for P a lla d iu m -Ca t a lyzed Ca r b on -
yla tive Cycliza tion . The aryl iodide (1.00 mmol), benzene (10
mL), acetonitrile (10 mL), triethylamine (2 equiv), methanol (4-
40 equiv), and the palladium catalyst (0.05 equiv.) were placed
in a 100 mL bomb. The apparatus was assembled, stirring was
commenced, and the bomb was purged thoroughly with CO
before charging to the required pressure. Ca u tion : ca r bon
m on oxid e is h igh ly toxic. The bomb was warmed to the
reaction temperature (50-130 °C) using a Parr temperature
controller (Model 4841) and bomb support and stirrer drive
system. As the reaction temperature increased, small quantities
of gas were released to maintain the desired pressure (600-
1600 psi). After the reaction had been maintained at the desired
pressure and temperature for 18 h it was cooled, depressurized,
and poured into water. The resulting mixture was extracted
three times with ethyl acetate. The ethyl acetate layers were
combined, dried over MgSO4, filtered, and concentrated in vacuo.
1
3386, 1727, 1671, 1611, 1512 cm-1; H NMR δ 7.78 (dd, J ) 1,
8 Hz, 1 H), 7.25 (dt, J ) 2, 7 Hz, 1 H), 6.67 (t, J ) 8 Hz, 1 H),
6.66 (dd, J ) 1, 8 Hz, 1 H), 4.67 (bs, 1 H), 3.68 (s, 3 H), 3.58 (dd,
J ) 5, 12 Hz, 1 H), 3.34 (t, J ) 13 Hz, 1 H), 3.17-3.08 (m, 1 H),
2.91 (dd, J ) 5, 17 Hz, 1 H), 2.36 (dd, J ) 8, 17 Hz, 1 H); 13C
NMR δ 193.9, 172.4, 151.7, 135.0, 127.5, 118.1, 117.6, 115.7, 51.7,
46.3, 42.7, 31.5; MS (EI) m/z 219 (M+); HRMS (FAB) calcd for
C12H13NO3 + H1 220.0974, found 220.0971. Anal. Calcd for
C
12H13NO3: C, 65.74; H, 5.98; N, 6.39. Found: C, 65.61; H, 5.94;
N, 6.38.
Met h yl 2-(4-Oxo-3,4-d ih yd r o-2H -ch r om en -3-yl)a cet a t e
(1c). Compound 1c was synthesized using the general procedure
described above. The reaction was run at a temperature of 130
°C and a CO pressure of 1200 psi with the following quantities:
2-iodophenyl allyl ether,16 247 mg (0.950 mmol); benzene, 10 mL;
acetonitrile, 10 mL; triethylamine, 0.265 mL (1.90 mmol);
methanol, 0.769 mL (0.91 M final concentration, 20 equiv.); Pd-
(PPh3)2Cl2, 33.3 mg (0.0475 mmol). The only modification to the
general procedure was acidification of the water layer during
the aqueous/organic partitioning. The crude product was purified
by radial column chromatography (2 mm plate, 1:5 ethyl
acetate-n-heptane, the sample was loaded as a solution in
chloroform) producing 1c (107 mg, 0.487 mmol, 51% yield) as a
light orange oil. The characterization data obtained for 1c
matched that previously reported.19
1
The H NMR of this crude product gave the product ratios. The
desired γ-ketoester was purified by silica gel column chroma-
tography.
Ben zyl 3-(2-Meth oxy-2-oxoeth yl)-4-oxo-3,4-dih ydr o-1(2H)-
qu in olin eca r boxyla te (1a ). Compound 1a was synthesized
using the general procedure described above. The reaction was
run at a temperature of 65 °C and a CO pressure of 1600 psi
with the following quantities: 3, 356 mg (0.905 mmol); benzene,
10 mL; acetonitrile, 10 mL; triethylamine, 0.252 mL (1.81 mmol);
methanol, 0.733 mL (0.87 M final concetration, 20 equiv.); Pd-
(PPh3)2Cl2, 30.8 mg (0.0439 mmol). The crude product was
purified by silica gel column chromatography (1:5 ethyl acetate-
n-heptane, the sample was loaded as a solution in chloroform)
producing 1a (192 mg, 0.543 mmol, 60% yield) as a light orange
viscous oil which solidified upon standing: mp 70.6-74.6 °C;
Ack n ow led gm en t. We thank Pharmacia Corpora-
tion for supporting J ames A. Nieman as a Postdoctoral
Research Scientist. We also thank Brian Conway for his
assistance in the scale-up of the palladium-catalyzed
carbonylative cyclization for the formation of 1a .
J O005703D
(19) For the synthesis of 1c via a different route, see: Ciganek, E.
Synthesis 1995, 1311.
IR (mull) 1737, 1709, 1690, 1483, 1403 cm-1 1H NMR δ 8.01
;