A novel entry to cyclopenta[b]quinolines via thermal ring-expansion of (2-aminophenyl)-ethynyl-substituted squaric acid derivatives

Article abstract of DOI:10.1016/j.tet.2008.03.025

Substituted cyclopenta[b]quinolin-1-ones were prepared by thermal ring-expansion of substituted N-Boc protected 4-(2-aminophenylethynyl)-4-hydroxy-2-cyclobuten-1-ones forming the corresponding 2-aminophenylmethylidene substituted 4-cyclopentene-1,3-diones. Deprotection of the amine resulted in spontaneous condensation giving cyclopenta[b]quinolin-1-ones. Sodium borohydride reduction of these products produced cyclopenta[b]quinolin-1-ols.

Full text of DOI:10.1016/j.tet.2008.03.025

Tetrahedron 64 (2008) 5336–5344
Contents lists available at ScienceDirect
Tetrahedron
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A novel entry to cyclopenta[b]quinolines via thermal ring-expansion
of (2-aminophenyl)-ethynyl-substituted squaric acid derivatives
Peter S. Zehr a, Reem Kayali a, Eduardo Pen˜a-Cabrera b, Omar Robles-Resendiz b,
,
Alma D. Villanueva-Rendon b, Bjo¨rn C.G. So¨derberg a
*
a C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, WV 26505-6045, USA
b Department of Chemistry, Universidad de Guanajuato, Col. Noria Alta S/N, Guanajuato, GTO 36050, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
Substituted cyclopenta[b]quinolin-1-ones were prepared by thermal ring-expansion of substituted N-Boc
protected 4-(2-aminophenylethynyl)-4-hydroxy-2-cyclobuten-1-ones forming the corresponding 2-
aminophenylmethylidene substituted 4-cyclopentene-1,3-diones. Deprotection of the amine resulted in
spontaneous condensation giving cyclopenta[b]quinolin-1-ones. Sodium borohydride reduction of these
products produced cyclopenta[b]quinolin-1-ols.
Received 17 October 2007
Received in revised form 25 February 2008
Accepted 7 March 2008
Available online 12 March 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
the product did not correspond to the expected hydroxycarbazole
5. A new methine having a carbon resonance at 68.7 ppm and the
Thermally induced ring-expansions of 4-alkynyl-4-hydroxy-
2-cyclobuten-1-ones giving 1,4-benzoquinones and/or 5-alkylide-
necyclopentenediones have been reported in a number of cases.1,2
In general, alkyl-substituted alkynes offer a clean conversion to
quinones.3–9 In contrast, ethynyl trimethylsilane, alkynes with
electron-withdrawing groups or alkenyl-substituted alkynes affords
only five-membered products10 and alkynes with electron-donating
groups, and aryl-substituted alkynes afford mixtures of five- and
six-membered rings. Ring-expansions of 4-alkynyl-4-hydroxy-2-
cyclobuten-1-ones giving 5-alkylidenecyclopentenediones have
also been reported using electrophilic reagents such as palladiu-
m(II),11 NBS,12 and iodine in the presence of an oxidizing reagent.13
Thermal reaction of 2 was examined as part of a project
to prepare complex heterocyclic compounds via ring-expansion of
4-hydroxy-2-cyclobuten-1-ones having heteroatoms tethered to
the cyclobutenone, in the 4-position, via an alkyne or an alkene
(Scheme 1). Compound 2 was obtained via dilithiation of the
corresponding proton resonance at 5.02 ppm was observed. These
resonances cannot be assigned to any of the carbons or protons of
the hydroxycarbazole 5. Subjecting the product obtained from the
reduction of 4 to gHMBC and gHMQC NMR experiments revealed
that the product was in fact the fused quinolinol 8 and not 5. This in
turn meant that the initial ring-expansion did not yield 3 but the
five-membered counterpart 6 (Scheme 2). Subsequent removal of
the Boc-group gave the fused quinoline 7. The ring-expansion was
very selective with regard to ring-size, and only the five-membered
ring was observed by 1H NMR of the crude reaction mixture.
The Friedla¨nder reaction, that is acid- or base-mediated reaction
between 2-aminobenzaldehydes or 2-aminobenzoketones and an
aldehyde or ketone bearing an a-methylene group, is arguably the
most commonly used methodology for the preparation of quino-
lines including 2,3-fused quinolines.14 For example, the Friedla¨nder
quinoline synthesis was used to prepare the indeno[1,2-b]quinolin-
11-one tetracyclic ring system of a new class of DNA-binding agents
(Scheme 3).15 Similar tetracyclic compounds having a fused five-
membered ketone have been examined as antiinfective agents.16
Herein, we report a novel synthesis of a number of related fused
quinolines, cyclopenta[b]quinolines, based on the preliminary
results described in Scheme 2.
N-protected 2-aminophenylalkyne
1 followed by alkylation
with 2,3-bis(1-methylethoxy)-2-cyclobuten-1,4-dione (diisopropyl
squarate). Cyclobutenone 2 was dissolved in toluene and heated at
reflux overnight. Workup and purification by chromatography
on silica gel gave a new compound that was initially thought to
be the 1,4-quinone 3 based on 1H and 13C NMR data. Deprotection
of the putative compound produced a new product seemingly de-
rived from the formation of a quinone-imine 4. However upon
attempted sodium borohydride reduction of 4, the spectral data of
2. Results and discussion
A
number of additional examples of this novel cyclo-
penta[b]quinoline synthesis were examined. The starting materials
were prepared from 2-iodoarylamines via a sequence of steps
consisting of N-Boc protection of the amino group, Sonogashira
* Corresponding author. Tel.: þ1 3042933435; fax: þ1 3042934904.
E-mail address: bjorn.soderberg@mail.wvu.edu (B.C.G. So¨derberg).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.025

P.S. Zehr et al. / Tetrahedron 64 (2008) 5336–5344
5337
O
OiPr
OiPr
OiPr
BOC
O
OiPr
O
OH
BOC
H+
1) nBuLi
heat
BOC
2)
O
OiPr
OiPr
N
H
N
H
N
H
O
3
1
2 (50%)
OiPr
O
OiPr
O
OH
O
NaBH4
OiPr
OiPr
OiPr
N
H
N
NH2
OiPr
4
5
Scheme 1.
O
OiPr
NHBOC
O
O
OiPr
OH
H+
heat
OiPr
OiPr
OiPr
OiPr
BOC
N
N
H
O
2
6 (63%)
7 (62%)
OH
NaBH4
OiPr
OiPr
N
8 (84%)
Scheme 2.
O
O
MeO
MeO
CHO
NH2
AcOH, Δx
+
18%
N
O
N
N
N
N
Scheme 3.
coupling using ethynyl trimethylsilane, desilylation, and alkylation.
The first three steps proceeded smoothly in good to excellent yields
in all the five cases examined (Scheme 4).
followed by addition of benzaldehyde gave the expected alkylation
product 16 (Scheme 6). We have presently no explanation for this. In
addition to the alkylation route described above, Sonogashira cou-
pling of alkyne 13 with a selection of aryl iodides 1, 9b, 9c, 9e, and 9f
was examined. This reaction also proved difficult and a satisfactory
yield of product (12b) was only isolated from 9b. All other substrates
either failed to couple or gave a low yield.
Thermal ring-expansion of 12a–12d gave the expected cyclo-
pentenediones 15a–15d. Removal of the Boc-group gave the cyclo-
penta[b]quinoline-1-ones(16a–16d)and,finally, sodiumborohydride
reduction furnished the cyclopenta[b]quinoline-1-ols (17a–17d).
Although easy to isolate, the cyclopenta[b]quinoline-1-ols (17a–17d)
slowly oxidized to the corresponding cyclopenta[b]quinoline-1-ones
(16a–d) upon standing in air (Scheme 7).
Alkylation of diisopropyl squarate was, however, more prob-
lematic and a significant amount of the alkyne starting material was
often recovered (Scheme 5). For the 5-methoxy-substituted sub-
strate, an inseparable mixture of the expected alkylation product
12b and alkylation of the squarate with excess butyllithium was
isolated. The 4-bromo-substituted substrate 11e was also examined
with the idea that the bromine could be replaced in the final product
using the very rich palladium-catalyzed cross-coupling chemistry.
Unfortunately, no alkylation product was observed for this com-
pound, a result initially thought to be the result of a non-productive
metal–halogen exchange. However, treatment of 11e with n-BuLi

5338
P.S. Zehr et al. / Tetrahedron 64 (2008) 5336–5344
TMS
R
R
R
R
I
I
F- or
OH-
PdCl2(PPh3)2, CuI
1) NaHMDS
2) (BOC)2O
X
X
X
NEt3
X
NHBOC
NH2
NHBOC
NHBOC
H
TMS
a R=4-Cl; X=CH
b R=5-OMe; X=C
c R=5-Me; X=C
d R=H, X=N
9a (81%)
9b (88%)
9ca(92%)
9da
10a (89%)
11a (92%)
11b (70%)
11c (79%)
11d (94%)
11e (99%)
10b (quant.)
10c (80%)
10d (quant.)
10e (88%)
f R=4-Br; X=CH
9e
a) Known compound see experimental section.
Scheme 4.
O
OiPr
OiPr
R
X
R
I
PdCl2(PPh3)2, CuI
NEt3
1) n-BuLi
2)
O
R
OH
NHBOC
X
OiPr
OiPr
NHBOC
NHBOC
X
O
OiPr
13
O
OiPr
OH
11a R=4-Cl; X=CH
11b R=5-OMe; X=C
11c R=5-Me; X=C
11d R=H, X=N
12a (45%)
9a
9b
9c
9d
9e
1
12b (from 11b,b64%)a
12c (21%, not observed from 9c)
12d (57%)
11e R=4-Br; X=CH
12e (not observed from 9/11e)
14 R=H; X=CH
2 (50%,37%)a
a) The yield in italicis is for the Sonogashira coupling. b) Not calculated, an inseparable 4:1 mixture with 4-butyl-4-hydroxy-2,3-
di(1-methylethoxy)-2-cyclobuten-1-one.
Scheme 5.
be explained by a facile E to Z isomerization of the alkene prior to
OH
Ph
cyclization. Isomerization of E-19 to Z-19 was observed by 1H NMR
by allowing the NMR sample to sit for a few hours at ambient
temperature.
H
Br
Br
1) nBuLi
2) PhCHO, 47%
In conclusion, a novel route to cyclopenta[b]quinolin-1-ones
and -ols has been developed. The key step in the sequence is a
thermally induced ring-expansion of 4-(2-aminophenylethynyl)-
4-hydroxy-2-cyclobuten-1-ones.
NHBOC
NHBOC
Scheme 6.
As
a final example, 3-(1-methylethoxy)-4-methyl-3-cyclo-
butene-1,2-dione was allowed to react with the dianion formed
from 1 giving the expected alkylation product 18 as a single
regioisomer in 41% (59% based on recovered 1, Scheme 8). Ring-
expansion of 18 furnished the expected cyclopentenedione 19 as an
8.3:1 E/Z mixture. The E-isomers have previously been shown to be
the kinetic products from ring-expansions of related compounds.1
Although condensation of the carbonyl having a vinylogous alk-
oxide is expected to be much slower, we were somewhat surprised
to observe only one quinoline isomer (20) upon removal of the Boc-
protecting group. The product is derived from cyclization of the
thermodynamically more stable Z-isomer. This observation can
3. Experimental section
3.1. General procedures
All NMR spectra were determined in CDCl3 at 600 MHz (1H
NMR) and 150 MHz (13C NMR) if not otherwise stated. The chemical
shifts are expressed in d values relative to Me4Si (0.0, 1H and 13C)
or CDCl3 (77.0, 13C) internal standards. Results of DEPT-13C NMR
experiments are shown in parentheses where, relative to CDCl3,
(ꢀ) denotes CH3 or CH and (þ) denotes CH2 or C.
O
OiPr
OiPr
NHBOC
O
O
O
OH
R
R
R
R
OH
NHBOC
heat
H+
NaBH4
OiPr
OiPr
OiPr
OiPr
OiPr
OiPr
X
X
X
X
N
N
12a
15a (60%)
16a (54%)
16b (78%)
16c (70%)
16d (84%)
17a (68%)
17b (70%)
17c (70%)
17d (51%)
12b
12c
12d
15b (25%)a
15c (81%)
15d (47%)
a) Yield in two steps from 11b.
Scheme 7.

P.S. Zehr et al. / Tetrahedron 64 (2008) 5336–5344
5339
O
Me
NHBOC
O
O
OiPr
OH
BOC
heat
1) nBuLi
OiPr
BOC
2)
O
Me
N
H
N
H
Me
O
OiPr
1
18 (48%)
19 (41%)
O
OH
H+
NaBH4
Me
Me
OiPr
N
N
OiPr
20 (30%)
21 (55%)
Scheme 8.
Tetrahydrofuran (THF), toluene, dichloromethane, triethylamine,
and diethyl ether were dried by passing through a steel column filled
with activated alumina (8ꢁ14 mesh, Sorbent Technology) using ar-
gonpressure. Hexanes, EtOAc, and 1,2-dichloroethane were distilled
from calcium hydride. Chemicals prepared according to literature
procedures were referenced the first time used; all other reagents
were obtained from commercial sources and used as-received. All
reactions were performed in oven-dried glassware under a nitrogen
atmosphere. Solvents were removed on a rotary evaporator at water
aspirator pressure unless otherwise stated.
3.1.3. (2-Iodo-5-methylphenyl)-carbamic acid 1,1-dimethylethyl
ester (9c)
Reaction of 2-iodo-5-methyl-1-aminobenzene18 (897 mg,
3.84 mmol), sodium bis(trimethylsilyl)amide (1.0 M in THF, 4.2 mL,
8.4 mmol), and Boc2O (846 mg, 3.88 mmol) in THF, as described for
9a (24 h), gave after workup and chromatography (hexanes/EtOAc,
8:2) 9c (1.122 g, 3.38 mmol, 88%) as an off-white solid. Mp 79.5–
82 ꢂC; 1H NMR d 7.91 (s, 1H), 7.59 (d, 1H, J¼8.2 Hz), 6.79 (br s, 1H),
6.60 (dd, 1H, J¼8.1, 1.6 Hz), 2.31 (s, 3H), 1.54 (s, 9H); 13C NMR d 152.5
(þ), 139.4 (þ), 138.4 (þ), 138.3 (ꢀ), 125.7 (ꢀ), 120.6 (ꢀ), 84.6 (þ),
80.9 (þ), 28.3 (ꢀ), 21.3 (ꢀ); IR (CCl4) 3396, 2979, 2360, 1736,
1160 cmꢀ1; HRMS calcd for C12H17NO2I (MþHþ) 334.0300, found
334.0304.
3.1.1. (4-Chloro-2-iodophenyl)-carbamic acid 1,1-dimethylethyl
ester (9a)
To
a solution of 4-chloro-2-iodo-1-aminobenzene (1.44 g,
3.1.4. (4-Chloro-2-(trimethylsilylethynyl)phenyl)-carbamic acid
5.67 mmol)inTHF(5 mL)wasaddedsodiumbis(trimethylsilyl)amide
(1.0 MinTHF,12.5 mL,12.5 mmol)via syringe overa 15 minperiod. To
the reaction mixture was added dropwise a solution of Boc2O (1.24 g,
5.67 mmol) in THF (5 mL). The reaction mixture was stirred at am-
bient temperature (24 h). The solvent was removed under reduced
pressure and the residue was partitioned between HCl (aq, 0.1 M,
50 mL) and EtOAc (20 mL). The layers were separated and the aque-
ous layer was treated with sodium bicarbonate (saturated aq,10 mL).
The resulting aqueous phase was extracted with EtOAc (2ꢁ20 mL).
The organic layers were combined, dried (MgSO4), filtered, and the
solvent was removed under reduced pressure. The crude product was
purified by chromatography (hexanes/EtOAc, 95: 5) to give 9a (1.63 g,
4.60 mmol, 81%) as an off-white solid. Mp 42–45 ꢂC; 1H NMR d 8.00
(d, 1H, J¼8.9 Hz), 7.72 (d, 1H, J¼2.4 Hz), 7.28 (dd, 1H, J¼8.9, 2.4 Hz),
6.79 (br s, 1H), 1.53 (s, 9H); 13C NMR d 152.3 (þ), 137.7 (ꢀ), 137.6 (þ),
129.1 (ꢀ), 128. 4 (þ), 120.4 (ꢀ), 88.2 (þ), 81.4 (þ), 28.2 (ꢀ); IR (CCl4)
3400, 2980, 1738, 1157 cmꢀ1; HRMS calcd for C11H14NO2ClI (MþHþ)
353.9758, found 353.9753.
1,1-dimethylethyl ester (10a)
A
mixture of 9a (681 mg, 1.9 mmol), bis(triphenylphos-
phine)palladium dichloride (13 mg, 0.019 mmol), copper iodide
(7 mg, 0.037 mmol), and ethynyl trimethylsilane (0.29 mL,
1.93 mmol) in triethylamine (20 mL) was stirred at ambient tem-
perature (24 h). The reaction was diluted with water (50 mL) and
the resulting biphasic mixture was extracted with diethyl ether
(3ꢁ50 mL). The combined organic layers were washed with NH4OH
(10% aq, 25 mL), dried (MgSO4), filtered, and the solvent were
removed under reduced pressure. The crude product was purified
by chromatography (hexanes/EtOAc, 95:5) to give 10a (378 mg,
1.50 mmol, 89%) as a yellow solid. Mp 72–76 ꢂC; 1H NMR d 8.08 (d,
1H, J¼9.1 Hz), 7.34 (d, 1H, J¼2.6 Hz), 7.31 (br s, 1H), 7.25 (dd, 1H,
J¼8.9, 2.4 Hz), 1.53 (s, 9H), 0.29 (s, 9H); 13C NMR d 152.1 (þ), 138.8
(þ), 130.7 (ꢀ), 129.8 (ꢀ), 126.6 (þ), 118.3 (ꢀ), 112.3 (þ), 103.4 (þ),
99.0 (þ), 80.9 (þ), 28.2 (ꢀ), ꢀ0.3 (ꢀ); IR (CCl4) 3400, 2977, 2152,
1737, 1157 cmꢀ1; HRMS calcd for C16H23NO2ClSi (MþHþ) 324.1187,
found 324.1187.
3.1.2. (2-Iodo-5-methoxyphenyl)-carbamic acid 1,1-dimethylethyl
ester (9b)
3.1.5. (5-Methoxy-2-trimethylsilylethynylphenyl)-carbamic acid
1,1-dimethylethyl ester (10b)
Reaction of 2-iodo-5-methoxyaniline17 (409 mg, 1.64 mmol),
sodium bis(trimethylsilyl)amide (1.0 M inTHF, 3.60 mL, 3.60 mmol),
and Boc2O (355 mg, 1.63 mmol) in THF, as described above for
9a (24 h), gave after workup and chromatography (hexanes/EtOAc,
8:2) 9b (528 mg, 1.51 mmol, 92%) as an off-white solid. Mp 37–
39 ꢂC; 1H NMR d 7.79 (d, 1H, J¼2.8 Hz), 7.57 (d, 1H, J¼8.9 Hz), 6.83
Reaction of 9b (504 mg, 1.44 mmol), bis(triphenylphos-
phine)palladium dichloride (54 mg, 0.077 mmol), copper iodide
(14 mg, 0.074 mmol), and ethynyl trimethylsilane (230 mL,
1.59 mmol) in triethylamine (30 mL), as described for 10a (ambient
temperature, 24 h), gave after workup and chromatography (hex-
anes/EtOAc, 95:5) 10b (360 mg, 1.16 mmol, 80%) off-white solid. Mp
39–41 ꢂC; 1H NMR d 7.78 (s, 1H), 7.39 (s, 1H), 7.26 (d, 1H, J¼9.0 Hz),
(br s, 1H), 6.40 (dd, 1H, J¼8.9, 2.9 Hz), 3.80 (s, 3H), 1.54 (s, 9H); 13
C
NMR d 160.7 (þ), 152.4 (þ), 139.6 (þ), 138.7 (ꢀ), 111.7 (ꢀ), 105.1 (ꢀ),
81.1 (þ), 55.4 (ꢀ), 28.3 (ꢀ), 0.0 (ꢀ); IR (CCl4) 3396, 2981, 1734,
1158 cmꢀ1; HRMS calcd for C12H17NO3I (MþHþ) 350.0253, found
350.0251.
6.49 (dd, 1H, J¼9.0, 2.4 Hz), 3.82 (s, 3H), 1.53 (s, 9H), 0.28 (s, 9H); 13
C
NMR d 160.9 (þ), 152.3 (þ), 141.9 (þ), 132.2 (ꢀ), 108.9 (ꢀ), 103.0 (þ),
102.1 (ꢀ), 100.8 (þ), 100.5 (þ), 80.6 (þ), 55.4 (ꢀ), 28.3 (ꢀ), ꢀ0.1 (ꢀ);

5340
P.S. Zehr et al. / Tetrahedron 64 (2008) 5336–5344
IR (CCl4) 3395, 2963, 2347, 2144, 1734, 1157 cmꢀ1; HRMS calcd for
C
2980, 2361, 1737, 1156 cmꢀ1; HRMS calcd for C13H15NO2Cl (MþHþ)
17H26NO3Si (MþHþ) 320.1682, found 320.1679.
252.0791, found 252.0790.
3.1.6. (5-Methyl-2-trimethylsilylethynylphenyl)-carbamic acid 1,1-
dimethylethyl ester (10c)
3.1.10. (2-Ethynyl-5-methoxyphenyl)-carbamic acid 1,1-
dimethylethyl ester (11b)
Reaction of 9c (450 mg, 1.36 mmol), bis(triphenylphos-
phine)palladium dichloride (48 mg, 0.068 mmol), copper iodide
(16 mg, 0.084 mmol), and ethynyl trimethylsilane (200 mL,
1.42 mmol) in triethylamine (10 mL), as describe for 10a (ambient
temperature, 24 h), gave after workup and chromatography (hex-
anes/EtOAc, 95:5) 10c (409 mg, 1.35 mmol, 100%) as a colorless oil.
1H NMR d 7.96 (s, 1H), 7.40 (br s, 1H), 7.15 (d, 1H, J¼7.5 Hz), 6.75 (d,
1H, J¼7.7 Hz), 2.34 (s, 3H), 1.53 (s, 9H), 0.28 (s, 9H); 13C NMR
d (150 MHz) 152.4 (þ),140.5 (þ),140.1 (þ),131.0 (ꢀ),122.8 (ꢀ),117.7
(ꢀ), 108.1 (þ), 101.3 (þ), 100.8 (þ), 80.5 (þ), 28.3 (ꢀ), 22.0 (ꢀ), ꢀ0.1
(ꢀ); IR (CCl4) 3396, 2977, 2348, 2148, 1736, 1159 cmꢀ1; HRMS calcd
for C17H26NO2Si (MþHþ) 304.1733, found 304.1742.
To a solution of 10b (603 mg, 1.89 mmol) in methanol/THF/
water (5:5:1, 11 mL) was added anhydrous potassium fluoride
(334 mg, 5.75 mmol) and the resulting mixture was stirred (am-
bient temperature, 1 h). The reaction was diluted with water
(50 mL) and extracted with diethyl ether (3ꢁ50 mL). The combined
organic layers were washed with brine (20 mL), dried (MgSO4),
filtered, and the solvents were removed at reduced pressure. The
crude product was purified by chromatography (hexanes/EtOAc,
95:5) to give 11b (314 mg, 1.3 mmol, 70%) as a colorless solid. Mp
around ambient temperature; 1H NMR d 7.83 (d, 1H, J¼2.4 Hz), 7.32
(d, 1H, J¼8.5 Hz), 7.29 (br s, 1H), 6.51 (dd, 1H, J¼8.7, 2.6 Hz), 3.83 (s,
3H), 3.42 (s, 1H), 1.53 (s, 9H); 13C NMR d 161.1 (þ), 152.3 (þ), 141.8
(þ), 133.1 (ꢀ), 109.1 (ꢀ), 102.4 (ꢀ), 101.8 (þ), 82.8 (þ), 80.9 (þ), 79.5
3.1.7. (4-Trimethylsilylethynyl-3-pyridinyl)-carbamic acid 1,1-
dimethylethyl ester (10d)
(þ), 55.4 (ꢀ), 28.3 (ꢀ); IR 3407, 3309, 2980, 2360, 1734, 1157 cmꢀ1
HRMS calcd for C14H18NO3 (MþHþ) 248.1287, found 248.1280.
;
Reaction of (4-iodo-3-pyridinyl)-carbamic acid 1,1-dimethyl-
ethyl ester19 (1.96 g, 6.14 mmol), bis(triphenylphosphine)palladium
dichloride (65 mg, 0.093 mmol), copper iodide (17 mg, 0.89 mmol),
and ethynyl trimethylsilane (1.33 mL, 6.45 mmol) in triethylamine
(20 mL), as described for 10a (ambient temperature, 24 h), gave
after workup and chromatography (hexanes/EtOAc, 1:1) 10d
(1.78 g, 6.14 mmol, 100%) as a brown solid. Mp 59–61 ꢂC; 1H NMR
d 9.39 (s, 1H), 8.24 (d, 1H, J¼4.9 Hz), 7.21 (d, 1H, J¼4.9 Hz), 7.12 (br s,
1H), 1.55 (s, 9H), 0.31 (s, 9H); 13C NMR 151.8 (þ), 142.9 (ꢀ), 139.9
(ꢀ), 135.8 (þ), 124.2 (ꢀ), 118.2 (þ), 106.9 (þ), 97.6 (þ), 81.4 (þ), 28.1
(ꢀ), ꢀ0.4 (ꢀ); IR (CCl4) 3389, 2978, 2155, 1736, 1155 cmꢀ1; HRMS
calcd for C15H23N2O2Si (MþHþ) 291.1529, found 291.1541.
3.1.11. (2-Ethynyl-5-methylphenyl)-carbamic acid 1,1-
dimethylethyl ester (11c)
Reaction of 10c (400 mg, 1.32 mmol) with NaOH (1 M aq, 4 mL)
in ethanol/THF (1:1, 20 mL), as described for 11a (ambient tem-
perature, 2 h), gave after workup and chromatography (hexanes/
EtOAc, 9:1) 11c (241 mg, 1.05 mmol, 79%) as a yellow solid. Mp 75–
77 ꢂC; 1H NMR d 8.01 (s, 1H), 7.31 (d, 1H, J¼7.9 Hz), 7.24 (br s, 1H),
6.78 (d, 1H, J¼7.9), 3.4 (s, 1H), 2.35 (s, 3H), 1.53 (s, 9H); 13C NMR
d 152.4 (þ), 140.7 (þ), 140.1 (þ), 131.9 (ꢀ), 122.9 (ꢀ), 117.9 (ꢀ), 106.9
(þ), 83.4 (þ), 80.7 (þ), 79.5 (þ), 28.3 (ꢀ), 21.9 (ꢀ); IR (CCl4) 3408,
3309, 2978, 2926, 2347,1735,1157 cmꢀ1; HRMS calcd for C14H18NO2
(MþHþ) 232.1338, found 232.1333.
3.1.8. (4-Bromo-2-(trimethylsilylethynyl)phenyl)-carbamic acid
1,1-dimethylethyl ester (10e)
3.1.12. (4-Ethynyl-3-pyridinyl)-carbamic acid 1,1-dimethylethyl
ester (11d)
A mixture of 9e20 (724 mg, 1.82 mmol), bis(triphenylphos-
phine)palladium dichloride (66 mg, 0.094 mmol), copper iodide
(18 mg, 0.095 mmol), and ethynyl trimethylsilane (243 mg,
2.47 mmol) in triethylamine (20 mL) was stirred at ambient tem-
perature (24 h). The reaction was diluted with water (50 mL) and
the resulting biphasic mixture was extracted with diethyl ether
(3ꢁ50 mL). The solvent was removed and the crude product was
purified by chromatography (hexanes/EtOAc, 95:5) to give 10e
(591 mg, 1.60 mmol, 88%) as a pale yellow solid. Mp 81–84 ꢂC; 1H
NMR d 8.03 (d, 1H, J¼8.9 Hz), 7.49 (d, 1H, J¼2.4 Hz), 7.39 (dd, 1H,
J¼8.9, 2.4 Hz), 7.31 (br s,1H),1.52 (s, 9H); 0.29 (s, 9H); 13C NMR 152.0
(þ), 139.3 (þ), 133.5 (ꢀ), 132.6 (ꢀ), 118.6 (ꢀ), 113.8 (þ), 111.7 (þ),
103.5 (þ), 98.8 (þ), 80.9 (þ), 28.2 (ꢀ), ꢀ0.3 (ꢀ); IR (CCl4) 3395, 2964,
2154, 1739, 1507, 1154 cmꢀ1; HRMS calcd for C16H22BrNNaO2Si
(MþNaþ) 390.0495, found 390.0502.
Reaction of 10d (1.78 g, 6.14 mmol) with potassium fluoride
dihydrate (1.72 g, 18.3 mmol) in methanol/THF (1:1, 15 mL), as de-
scribed for 10b (ambient temperature, 20 min), gave after workup
and chromatography (hexanes/EtOAc, 1:1) 11d (1.25 g, 5.8 mmol,
94%) as a brownish solid. Mp 77–80 ꢂC; 1H NMR d 9.40 (s, 1H), 8.26
(d, 1H J¼4.9 Hz), 7.28 (d, 1H, J¼5.1 Hz), 7.09 (br s, 1H), 3.69 (s, 1H),
1.57 (s, 9H); 13C NMR d 151.9 (þ), 143.0 (ꢀ), 140.4 (ꢀ), 136.0 (þ),
125.2 (ꢀ), 117.3 (þ), 88.1 (þ), 88.0 (þ), 81.7 (þ), 28.2 (ꢀ); IR (CCl4)
3407, 3298, 2982, 2248, 1727, 1160 cmꢀ1
C
; HRMS calcd for
12H15N2O2 (MþHþ) 219.1134, found 219.1135.
3.1.13. (4-Bromo-2-ethynylphenyl)-carbamic acid 1,1-dimethylethyl
ester (11e)
Reaction of 10e (869 mg, 2.36 mmol) with NaOH (1 M aq,
4.4 mL) in ethanol/THF (1:1, 20 mL), as described for 11a (ambient
temperature, 3 h), gave after workup and chromatography (hex-
anes/EtOAc, 95:5) 11e (693 mg, 2.34 mmol, 99%) as a pale yellow
solid. Mp 65–67 ꢂC; 1H NMR d 8.08 (d, 1H, J¼9.1 Hz), 7.53 (d, 1H,
J¼2.4 Hz), 7.42 (dd, 1H, J¼9.1, 2.4 Hz), 7.21 (br s, 1H), 3.52 (s, 1H),
1.53 (s, 9H); 13C NMR d 152.1 (þ), 139.4 (þ), 134.4 (ꢀ), 133.0 (ꢀ),
119.0 (ꢀ), 113.9 (þ), 111.6 (þ), 85.2 (þ), 81.2 (þ), 77.9 (þ), 28.2 (ꢀ);
IR (CCl4) 2985, 2255, 1727, 1509, 1156 cmꢀ1; HRMS calcd for
3.1.9. (4-Chloro-2-ethynylphenyl)-carbamic acid 1,1-dimethylethyl
ester (11a)
To a solution of 10a (924 mg, 2.85 mmol) in absolute ethanol/
THF (1:1, 30 mL) was added a solution of NaOH (1 M, 3 mL) and the
resulting reaction mixture was allowed to stir (ambient tempera-
ture, 2 h). The solvents were removed at reduced pressure and the
residue was suspended in water (10 mL) and extracted with diethyl
ether (3ꢁ50 mL). The organic layers were combined, dried (MgSO4),
filtered, and the solvent was removed under reduced pressure. The
crude product was purified by chromatography (hexanes/EtOAc,
9:1) to give 11a (664 mg, 2.64 mmol, 92%) as an off-white solid. Mp
61–63 ꢂC; 1H NMR d 8.13 (d,1H, J¼9.1 Hz), 7.39 (d,1H, J¼2.4 Hz), 7.29
(dd, 1H, J¼9.1, 2.6 Hz), 7.21 (br s, 1H), 3.52 (s, 1H), 1.53 (s, 9H); 13C
NMR d 152.1 (þ), 138.9 (þ), 131.5 (ꢀ), 130.1 (ꢀ), 126.7 (þ), 118.7 (ꢀ),
111.2 (þ), 85.1 (þ), 81.2 (þ), 77.9 (þ), 28.2 (ꢀ); IR (CCl4) 3411, 3305,
C
13H15BrNO2 (MþHþ) 296.0281, found 296.0286.
3.1.14. [2-(1-Hydroxy-2,3-bis(1-methylethoxy)-4-oxo-cyclobut-2-
enylethynyl)phenyl]-carbamic acid 1,1-dimethylethyl ester (2)
To a ꢀ5 ꢂC cold solution of (2-ethynylphenyl)-carbamic acid 1,1-
dimethylethyl ester (1)21,22 (155 mg, 0.71 mmol) in THF (10 mL)
was slowly added n-BuLi (1.6 M in THF, 1.1 mL, 1.8 mmol) via sy-
ringe. After 15 min, a ꢀ5 ꢂC cold solution 3,4-bis(1-methylethoxy)-

P.S. Zehr et al. / Tetrahedron 64 (2008) 5336–5344
5341
3-cyclobutene-1,2-dione (141 mg, 0.71 mmol) in THF (10 mL)
was added to the dilithiated compound via a cannula. The resulting
reaction mixture was stirred (ambient temperature, 30 min) fol-
lowed by the addition of water (40 mL). The biphasic mixture was
extracted with diethyl ether (3ꢁ50 mL) and the combined organic
layers were dried (MgSO4), filtered, and the solvents were removed
under reduced pressure. The crude product was purified by chro-
matography (hexanes/EtOAc, 8:2) to afford 2 (149 mg, 0.35 mmol,
50%) as a brown oil. 1H NMR d 8.14 (d, 1H, J¼8.3 Hz), 7.40 (dd, 1H,
J¼7.7, 1.4 Hz), 7.32 (dt, 1H, J¼8.7, 1.6 Hz), 7.14 (br s, 1H), 6.95 (dt,
1H, J¼7.5, 1.0 Hz), 5.02 (heptet, 1H, J¼6.1 Hz), 4.92 (heptet, 1H,
J¼6.1 Hz), 3.07 (br s, 1H), 1.53 (s, 9H), 1.48 (d, 3H, J¼6.3 Hz), 1.47 (d,
3H, J¼6.1 Hz), 1.33 (d, 3H, J¼6.1 Hz), 1.32 (d, 3H, J¼6.1 Hz); 13C NMR
d 180.4 (þ), 164.1 (þ), 152.4 (þ), 139.7 (þ), 133.8 (þ), 132.2 (ꢀ), 130.1
(ꢀ), 122.0 (ꢀ), 117.8 (ꢀ), 109.9 (þ), 90.2 (þ), 83.8 (þ), 80.9 (þ), 78.9
(þ), 78.1 (ꢀ), 74.3 (ꢀ), 28.3 (ꢀ), 22.7 (ꢀ), 22.6 (ꢀ), 22.5 (ꢀ); IR (CCl4)
3402, 2980, 2933, 1734, 1158 cmꢀ1; HRMS calcd for C23H30NO6
(MþHþ) 416.2073, found 416.2081.
Alternative procedure: A solution of 9b (912 mg, 2.61 mmol),
bis(triphenylphosphine)palladium dichloride (91 mg, 0.13 mmol),
copper iodide (496 mg, 2.60 mmol), and 13 (581 mg, 2.59 mmol) in
triethylamine (30 mL) was stirred at ambient temperature (20 h).
The reaction was diluted with water (50 mL) and the resulting
biphasic mixture was extracted with diethyl ether (3ꢁ50 mL). The
combined organic phases were washed with NH4OH (10%-aqueous,
20 mL), dried (MgSO4), filtered, and the solvent was removed. The
crude product was purified by chromatography (hexanes/EtOAc,
8:2) giving 12b (747 mg, 1.68 mmol, 64%) as a yellow-orange solid.
Mp 38–42 ꢂC; HRMS calcd for C24H3NNaO7 (MþNaþ) 468.1993,
found 468.1992.
3.1.17. (2-(1-Hydroxy-2,3-di(1-methylethoxy)-4-oxo-cyclobut-2-
enylethynyl)-5-methylphenyl)-carbamic acid 1,1-dimethylethyl
ester (12c)
Reaction of 11c (217 mg, 0.94 mmol), n-BuLi (1.6 M in THF,
1.47 mL, 2.36 mmol), and 3,4-bis(1-methylethoxy)-3-cyclobutene-
1,2-dione (187 mg, 0.94 mmol) in THF (30 mL total), as described
for 2 (30 min), gave after workup and chromatography (hexanes/
EtOAc, 8:2) 12c (89 mg, 0.21 mmol, 21%) as a yellow oil and 11c
(89 mg, 0.39 mmol). 1H NMR d 7.98 (s, 1H), 7.26 (d, 1H, J¼7.9 Hz),
7.12 (br s, 1H), 6.77 (d, 1H, J¼7.9 Hz), 5.02 (heptet, 1H, J¼6.1 Hz),
4.90 (heptet, 1H, J¼6.1 Hz), 3.16 (br s, 1H), 2.34 (s, 3H), 1.53 (s, 9H),
1.48 (d, 3H, J¼6.3 Hz), 1.46 (d, 3H, J¼6.1 Hz), 1.32 (d, 3H, J¼6.1 Hz),
1.31 (d, 3H, J¼6.1 Hz); 13C NMR d 180.3 (þ), 164.1 (þ), 152.4 (þ),
140.9 (þ), 139.6 (þ), 133.9 (þ), 131.9 (ꢀ), 123.0 (ꢀ), 118.3 (ꢀ), 106.9
(þ), 89.6 (þ), 84.1 (þ), 80.8 (þ), 78.9 (þ), 78.0 (ꢀ), 74.3 (ꢀ), 28.3 (ꢀ),
22.7 (ꢀ), 22.6 (ꢀ), 22.5 (ꢀ), 21.9 (ꢀ); IR (CCl4) 3424, 2978, 1731,
1637, 1161 cmꢀ1; HRMS calcd for C24H32NO6 (MþHþ) 430.2230,
found 430.2242.
Alternative procedure: A solution of 1 (394 mg, 1.23 mmol),
bis(triphenylphosphine)palladium dichloride (44 mg, 0.063 mmol),
copper iodide (238 mg, 1.24 mmol), and 4-ethenyl-4-hydroxy-2,3-
di(1-methylethoxy)-2-cyclobuten-1-one23 (272 mg, 1.21 mmol) in
triethylamine (30 mL) was stirred at ambient temperature (20 h).
The reaction was diluted with water (50 mL) and the resulting
biphasic mixture was extracted with diethyl ether (3ꢁ50 mL). The
combined organic phases were washed with NH4OH (10%-aqueous,
20 mL), dried (MgSO4), filtered, and the solvent was removed. The
crude product was purified by chromatography (hexanes/EtOAc,
8:2) giving 12b (189 mg, 0.45 mmol, 37%) as a yellow-orange solid
in addition to 1 (155 mg, 0.49 mmol).
3.1.15. (4-Chloro-2-(1-hydroxy-2,3-di(1-methylethoxy)-4-oxo-
cyclobut-2-enylethynyl)phenyl)-carbamic acid 1,1-dimethylethyl
ester (12a)
3.1.18. (4-(1-Hydroxy-2,3-di(1-methylethoxy)-4-oxo-cyclobut-2-
enylethynyl)-pyridin-3-yl)-carbamic acid 1,1-dimethylethyl
ester (12d)
Reaction of 11a (250 mg, 0.99 mmol), n-BuLi (2.65 M in THF,
0.93 mL, 2.4 mmol), and 3,4-bis(1-methylethoxy)-3-cyclobutene-
1,2-dione (198 mg,1.00 mmol) in THF (20 mL total), as described for
2 (30 min), gave after workup and chromatography (hexanes/EtOAc,
8:2),12a (200 mg, 0.44 mmol, 45%) as a yellow solid and 11a (97 mg,
0.39 mmol). Mp 123–125 ꢂC; 1H NMR d 8.08 (d, 1H, J¼8.9 Hz), 7.34
(d, 1H, J¼2.4 Hz), 7.25 (dd, 1H, J¼8.9, 2.6 Hz), 7.15 (br s, 1H), 5.02
(heptet,1H, J¼6.1 Hz), 4.89 (heptet,1H, J¼6.1 Hz), 3.74 (br s,1H),1.53
(s, 9H), 1.48 (d, 3H, J¼6.1 Hz), 1.47 (d, 3H, J¼6.1 Hz);1.32 (d, 6H,
J¼6.1 Hz); 13C NMR d 180.6 (þ), 164.2 (þ), 152.3 (þ), 138.4 (þ), 133.8
(þ), 131.4 (ꢀ), 130.1 (ꢀ), 126.8 (þ), 119.1 (ꢀ), 111.4 (þ), 91.3 (þ), 82.4
(þ), 81.2 (þ), 78.6 (þ), 78.2 (ꢀ), 74.3 (ꢀ), 28.2 (ꢀ), 22.7 (ꢀ), 22.6 (ꢀ),
22.5 (ꢀ); IR (CCl4) 3424, 2968, 2355, 1734, 1157 cmꢀ1; HRMS calcd
for C23H29NO6Cl (MþHþ) 450.1683, found 450.1687.
Reaction of 11d (1.05 g, 4.81 mmol), n-BuLi (2.89 M in THF,
4.16 mL,12.04 mmol), and 3,4-bis(1-methylethoxy)-3-cyclobutene-
1,2-dione (0.96 g, 4.83 mmol) in THF (40 mL total), as described for
2, gave after workup and chromatography (hexanes/EtOAc, 1:1) to
give 12d (1.14 g, 2.74 mmol, 57%) as a brown oil. 1H NMR d 9.40 (s,
1H), 8.24 (d, 1H, J¼4.9 Hz), 7.24 (d, 1H, J¼4.9 Hz), 6.99 (br s, 1H),
5.02 (heptet, 1H, J¼6.1 Hz), 4.91 (heptet, 1H, J¼6.1 Hz), 4.57 (br s,
1H), 1.53 (s, 9H), 1.47 (d, 3H, J¼6.3 Hz),1.46 (d, 3H, J¼6.1 Hz), 1.32 (d,
3H, J¼6.1 Hz), 1.31 (d, 3H, J¼6.1 Hz); 13C NMR d 180.0 (þ), 164.0 (þ),
151.8 (þ), 142.3 (ꢀ), 139.9 (ꢀ), 139.8 (ꢀ), 135.7 (þ), 133.8 (þ), 125.3
(ꢀ), 118.0 (þ), 95.5 (þ), 81.6 (þ), 80.5 (þ), 78.5 (þ), 78.1 (ꢀ). 78.0
(ꢀ), 74.3 (ꢀ), 74.2 (ꢀ), 28.1 (ꢀ), 22.6 (ꢀ), 22.5 (ꢀ), 22.4 (ꢀ); IR (CCl4)
3405 (br), 2978, 2360, 1737, 1158 cmꢀ1; HRMS calcd for C22H29N2O6
(MþHþ) 417.2026, found 417.2027.
3.1.16. (2-(1-Hydroxy-2,3-di(1-methylethoxy)-4-oxo-cyclobut-2-
enylethynyl)-5-methoxyphenyl)-carbamic acid 1,1-dimethylethyl
ester (12b)
3.1.19. (2-(3-Hydroxy-3-phenyl-1-propynyl)-4-bromophenyl)-
carbamic acid 1,1-dimethylethyl ester
Reaction of 11b (192 mg, 0.80 mmol), n-BuLi (1.4 M in THF,
1.43 mL, 2.01 mmol), and 3,4-bis(1-methylethoxy)-3-cyclobutene-
1,2-dione (106 mg, 0.81 mmol) in THF (25 mL total), as described
for 2 (30 min), gave after workup and chromatography (hexanes/
EtOAc, 8:2) an inseparable mixture of 12b and 4-butyl-4-hydroxy-
2,3-di(1-methylethoxy)-2-cyclobuten-1-one (215 mg, 4:1 ratio). 1H
NMR d 7.80 (d, 1H, J¼2.2 Hz), 7.28 (d, 1H, J¼8.3 Hz), 7.17 (br s, 1H),
6.50 (dd, 1H, J¼8.5, 2.6 Hz), 5.02 (heptet, 1H, J¼6.1 Hz), 4.90 (heptet,
1H, J¼6.3 Hz), 3.82 (s, 3H), 3.21 (br s, 1H), 1.53 (s, 9H), 1.48 (d, 3H,
J¼6.3 Hz), 1.46 (d, 3H, J¼6.1 Hz), 1.32 (d, 3H, J¼6.1 Hz), 1.31 (d, 3H,
J¼6.1 Hz); 13C NMR d 180.7 (þ), 164.3 (þ), 161.1 (þ), 152.3 (þ), 141.3
(þ), 133.7 (þ), 133.1 (ꢀ), 109.1 (ꢀ), 102.5 (ꢀ), 101.9 (þ), 89.1 (ꢀ), 83.9
(þ), 80.9 (þ), 78.9 (þ), 74.2 (ꢀ), 28.3 (ꢀ), 22.7 (ꢀ), 22.6 (ꢀ), 22.5 (ꢀ),
A THF (5 mL) solution of compound 11e (108 mg, 0.44 mmol)
was reacted with n-BuLi (1.8 M in THF, 610 mL, 1.10 mmol) as
described for 2. Benzaldehyde (39 mg, 0.54 mmol) was added via a
syringe at ꢀ78 ꢂC and the resulting mixture was stirred for 30 min.
The solvent was removed under reduced pressure and the crude
product was purified by chromatography (hexanes/EtOAc, 9:1) to
give in order of elution 11e (28 mg, 0.11 mmol) and the title com-
pound (85 mg, 0.21 mmol, 48%) as a red-brown oil. 1H NMR
(270 MHz) d 8.05 (d, 1H, J¼9.1 Hz), 7.60 (dd, 2H, J¼8.1, 1.8 Hz), 7.52
(d, 1H, J¼3.4 Hz), 7.48–7.24 (m, 4H), 7.13 (br s, 1H), 5.75 (d, 1H,
J¼5.9 Hz), 2.39 (d, 1H, J¼6.1 Hz), 1.51 (s, 9H); 13C NMR d 152.1, 140.2,
139.0, 134.2, 132.9, 128.9, 128.8, 126.5, 119.2, 114.1, 112.1, 96.9, 81.3,
80.6, 65.1, 28.3; IR (neat) 3400, 1732, 1710, 1508 cmꢀ1; HRMS calcd
for C20H20BrNNaO3 (MþNaþ) 424.0519, found 424.0525.
22.3 (ꢀ); IR (CCl4) 3565, 2989, 2942, 1731, 1161 cmꢀ1
.

5342
P.S. Zehr et al. / Tetrahedron 64 (2008) 5336–5344
3.1.20. (2-(3,4-Di(1-methylethoxy)-2,5-dioxo-3-cyclopenten-1-
ylmethyl)phenyl)-carbamic acid 1,1-dimethylethyl ester (6)
3.1.24. (4-(3,4-Di(1-methylethoxy)-2,5-dioxo-3-cyclopenten-1-
ylmethyl)-3-pyridinyl)-carbamic acid 1,1-dimethylethyl ester (15d)
Reaction of 12d (107 mg, 0.26 mmol) in 1,2-dichloroethane
(20 mL), as described for 6 (reflux, 18 h), gave after chromatography
(hexanes/EtOAc, 6:4) 13e (50 mg, 0.12 mmol, 47%) as a brown solid.
Mp 117–119 ꢂC; 1H NMR d 8.99 (s,1H), 8.40 (d,1H, J¼5.3 Hz), 7.66 (d,
1H, J¼5.2 Hz), 7.30 (s, 1H), 6.45 (br s, 1H), 5.61 (m, 2H), 1.51 (s, 9H),
1.41 (d, 6H, J¼6.3 Hz), 1.38 (d, 6H, J¼6.3 Hz); 13C NMR d (150 MHz)
184.5 (þ), 183.6 (þ), 153.1 (þ), 152.6 (þ), 150.8 (þ), 144.8 (ꢀ), 144.3
(ꢀ),133.1 (þ),132.3 (þ),130.7 (þ),127.3 (ꢀ),124.2 (ꢀ), 81.6 (þ), 75.5
(ꢀ), 75.4 (ꢀ), 28.1 (ꢀ), 23.0 (ꢀ); IR (CCl4) 3000, 2960, 1740, 1690,
1160 cmꢀ1; HRMS calcd for C22H29N2O6 (MþHþ) 417.2026, found
417.2034.
A solution of 2 (291 mg, 0.70 mmol) in toluene (20 mL) was
heated at reflux overnight. The reaction was cooled to ambient
temperature and the solvent was removed under reduced pressure.
The crude residue was purified by chromatography (hexanes/EtOAc,
95:5) to give 6 (184 mg, 0.44 mmol, 63%) as an orange solid. Mp 93–
96 ꢂC; 1H NMR d 7.91 (dd, 1H, J¼7.9, 1.6 Hz), 7.80 (d, 1H, J¼8.1 Hz),
7.44 (s, 1H), overlapping 7.40 (t, 1H, J¼8.7 Hz), 7.13 (t, 1H, J¼7.5 Hz),
6.54 (br s, 1H), 5.59 (m, 2H), 1.51 (s, 9H), 1.40 (d, 6H, J¼6.3 Hz), 1.37
(d, 6H, J¼6.1 Hz); 13C NMR d 185.9 (þ),184.4 (þ),152.8 (þ),151.9 (þ),
149.4 (þ), 137.8 (þ), 131.7 (ꢀ), 131.5 (ꢀ), 130.8 (ꢀ), 127.3 (þ), 124.2
(þ), 123.4 (ꢀ), 122.2 (ꢀ), 80.9 (þ), 74.9 (ꢀ), 74.8 (ꢀ), 28.2 (ꢀ), 22.9
(ꢀ), 22.6 (ꢀ); IR (CDCl3) 3326 (br), 2980, 2933, 1733, 1156 cmꢀ1
HRMS calcd for C23H30NO6 (MþHþ) 416.2073, found 416.2073.
;
3.1.25. 2,3-Di(1-methylethoxy)cyclopenta[b]quinolin-1-one (7)
A solution of 6 (169 mg, 0.41 mmol) in EtOAc/HCl (1:1, 3 M aq
HCl, 20 mL) was stirred at ambient temperature (6 d). The solvents
were removed under reduced pressure and the resulting residue
was suspended in water (20 mL) and extracted with diethyl ether
(3ꢁ50 mL). The organic layers were washed with NaHCO3 (aq
saturated 25 mL), dried (MgSO4), filtered, and the solvent was re-
moved under reduced pressure. The crude product was purified by
chromatography (hexanes/EtOAc, 8:2) to give 7 (75 mg, 0.25 mmol,
62%) as a yellow-orange solid. Mp 59–61 ꢂC; 1H NMR d 8.05 (d, 1H,
J¼8.3 Hz), 7.79 (s, 1H), 7.71 (dd, 1H, J¼7.9, 1.4 Hz), 7.62 (dt, 1H, J¼7.1,
1.4 Hz), 7.42 (dt, 1H, J¼8.1, 1.2 Hz), 5.68 (heptet, 1H, J¼6.3 Hz), 5.26
(heptet, 1H, J¼6.1 Hz), 1.50 (d, 6H, J¼6.1 Hz), 1.35 (d, 6H, J¼6.1 Hz);
13C NMR d 187.2 (þ), 158.0 (þ), 156.8 (þ), 149.2 (þ), 138.2 (þ), 130.6
(ꢀ), 129.8 (ꢀ), 129.7 (ꢀ), 127.7 (þ), 126.8 (ꢀ), 126.3 (ꢀ), 123.7 (þ),
76.5 (ꢀ), 73.8 (ꢀ), 22.9 (ꢀ), 22.8 (ꢀ); IR (CCl4) 3436, 2978, 1695,
1102 cmꢀ1; HRMS calcd for C18H20NO3 (MþHþ) 298.1443, found
298.1438.
Alternative procedure: Compound 2 (95 mg, 0.23 mmol) was
transferred to an airless flask. The compound was heated neat in an
oil bath at 140 ꢂC for 30 min. The residue was purified by chro-
matography (hexanes/EtOAc, 8:2) to afford 6 (80 mg, 0.19 mmol,
85% yield).
3.1.21. (4-Chloro-2-(3,4-di(1-methylethoxy)-2,5-dioxo-3-
cyclopenten-1-ylmethyl)phenyl)-carbamic acid 1,1-dimethylethyl
ester (15a)
Reaction of 12a (452 mg, 1.00 mmol) in toluene (20 mL), as de-
scribed for 6, gave after workup and chromatography (hexanes/
EtOAc, 8:2) 13a (268 mg, 0.60 mmol, 60%) as a yellow solid. Mp 57–
62 ꢂC; 1H NMR d 7.93 (d, 1H, J¼2.4 Hz), 7.79 (d, 1H, J¼8.5 Hz), 7.34
(dd, 1H, J¼8.7, 2.4 Hz), 7.32 (s, 1H), 6.48 (br s, 1H), 5.59 (m, 2H), 1.51
(s, 9H),1.40 (d, 6H, J¼5.5 Hz),1.38 (d, 6H, J¼5.9 Hz); 13C NMR d 185.4
(þ), 184.0 (þ), 152.7 (þ), 152.6 (þ), 149.8 (þ), 136.3 (þ), 131.2 (ꢀ),
131.0 (ꢀ), 128.9 (þ), 128.7 (ꢀ), 128.5 (þ), 81.3 (þ), 75.2 (ꢀ), 75.1 (ꢀ),
65.8 (þ), 28.2 (ꢀ), 23.0 (ꢀ), 23.0 (ꢀ), 15.2 (ꢀ); IR (CDCl3) 3149, 2982,
2254, 1727, 1160 cmꢀ1; HRMS calcd for C23H29NO6Cl (MþHþ)
450.1683, found 450.1683.
3.1.26. 7-Chloro-2,3-di(1-methylethoxy)cyclopenta[b]quinolin-1-
one (16a)
Reaction of 15a (163 mg, 0.44 mmol) in EtOAc/HCl (1:1, 3 M aq
HCl, 30 mL), as described for 7 (ambient temperature, 3 d), gave
after workup and chromatography (hexanes/EtOAc, 8:2), 14a
(71 mg, 0.24 mmol, 54%) as an orange solid. Mp 104–106 ꢂC; 1H
NMR d 7.99 (d, 1H, J¼8.9 Hz), 7.69 (s, 1H), 7.68 (s, 1H) overlapping
7.61 (d, 1H, J¼2.3 Hz), 7.55 (dd, 1H, J¼8.7,2.3 Hz), 5.66 (heptet, 1H,
J¼6.1 Hz), 5.28 (heptet, 1H, J¼6.1 Hz), 1.51 (d, 6H, J¼6.3 Hz), 1.36 (d,
6H, J¼6.3 Hz); 13C NMR d 186.5 (þ), 158.5 (þ), 156.7 (þ), 147.5 (þ),
138.4 (þ), 132.4 (þ), 131.0 (ꢀ), 128.6 (ꢀ), 128.5 (ꢀ), 125.2 (ꢀ), 124.6
(þ), 75.3 (ꢀ), 73.9 (ꢀ), 22.9 (ꢀ), 22.8 (ꢀ); IR (CCl4) 3410, 2982, 2931,
2360, 1700, 1101 cmꢀ1; HRMS calcd for C18H19NO3Cl (MþHþ)
332.1053, found 332.1054.
3.1.22. (2-(3,4-Di(1-methylethoxy)-2,5-dioxo-3-cyclopenten-1-
ylmethyl)-5-methoxy-phenyl)-carbamic acid 1,1-dimethylethyl
ester (15b)
Reaction of a 4:1 mixture of 12b and 4-butyl-4-hydroxy-
2,3-di(1-methylethoxy)-2-cyclobuten-1-one (215 mg) in toluene
(20 mL), as described for 6 (reflux, overnight), gave after chroma-
tography (hexanes/EtOAc, 8:2) 13b (87 mg, 0.20 mmol, 25% from
11b) as an orange-yellow solid. Mp 99–102 ꢂC; 1H NMR d 8.15 (d, 1H,
J¼9.0 Hz), 7.48 (br s,1H), 7.38 (s,1H), 6.79 (s, 2H), 6.68 (dd,1H, J¼8.4,
2.4 Hz), 5.53 (m, 2H), 3.85 (s, 3H), 1.52 (s, 9H), 1.39 (d, 6H, J¼6.0 Hz),
1.38(d, 6H,J¼6.0 Hz);13CNMRd(150 MHz)186.8(þ),185.0(þ),162.9
(þ),152.5(þ),151.4(þ),148.4(þ),140.3(þ),133.8(ꢀ),130.5(ꢀ),124.5
(þ),116.0 (þ),110.1 (ꢀ),106.3 (þ), 81.1 (þ), 74.8 (ꢀ), 74.7 (ꢀ), 55.4 (ꢀ),
3.1.27. 2,3-Di(1-methylethoxy)-6-methoxycyclopenta[b]quinolin-
1-one (16b)
28.2 (þ), 22.9 (þ); IR (CCl4) 3445, 2980, 2933,1733,1670,1156 cmꢀ1
HRMS calcd for C24H32NO7 (MþHþ) 446.2179, found 446.2180.
;
Reaction of 15b (154 mg, 0.35 mmol) in EtOAc/HCl (4:3, 3 M aq
HCl, 35 mL), as described for 6 (ambient temperature, 2 d), gave
after workup and chromatography (hexanes/EtOAc, 8:2) 14b
(88 mg, 0.27 mmol, 78%) as a yellow oil. 1H NMR d 7.73 (s, 1H), 7.60
(d, 1H, J¼8.7 Hz), 7.48 (d, 1H, J¼2.6 Hz), 7.05 (dd, 1H, J¼8.7, 2.6 Hz),
5.62 (heptet, 1H, J¼6.1 Hz), 5.23 (heptet, 1H, J¼6.1 Hz), 3.92 (s, 3H),
1.49 (d, 6H, J¼6.1 Hz), 1.34 (d, 6H, J¼6.1 Hz); 13C NMR d 187.6 (þ),
161.6 (þ), 159.2 (þ), 156.1 (þ), 151.0 (þ), 137.1 (þ), 130.6 (ꢀ), 126.1
(ꢀ), 121.9 (þ), 121.2 (þ), 117.9 (ꢀ), 109.9 (ꢀ), 74.8 (ꢀ), 73.7 (ꢀ), 55.5
3.1.23. (2-(3,4-Di(1-methylethoxy)-2,5-dioxo-3-cyclopenten-1-
methylidene)-5-methyl-phenyl)-carbamic acid 1,1-dimethylethyl
ester (15c)
Reaction of 12c (59 mg, 0.14 mmol) in toluene (20 mL), as
described for 6 (reflux, overnight), gave after chromatography
(hexanes/EtOAc, 8:2) 13c (48 mg, 0.11 mmol, 81%) as a colorless oil.
1H NMR d 7.89 (d, 1H, J¼8.1 Hz), 7.65 (s, 1H), 7.42 (s, 1H), 6.95 (d, 1H,
J¼7.1 Hz), 6.56 (br s, 1H), 5.57 (m, 2H), 2.37 (s, 3H), 1.51 (s, 9H), 1.40
(d, 6H, J¼6.1 Hz), 1.37 (d, 6H, J¼6.1 Hz); 13C NMR d 186.3 (þ), 184.7
(þ), 152.8 (þ), 151.8 (þ), 149.1 (þ), 142.8 (þ), 137.9 (þ), 131.8 (ꢀ),
130.8 (ꢀ), 126.4 (þ), 124.5 (ꢀ), 122.5 (ꢀ), 121.3 (þ), 80.9 (þ), 74.9
(ꢀ), 74.8 (ꢀ), 29.7 (þ), 28.3 (ꢀ), 23.0 (ꢀ), 21.8 (ꢀ); IR (CCl4) 3437,
2980, 2360, 1734, 1672, 1157 cmꢀ1; HRMS calcd for C24H32NO6
(MþHþ) 430.2230, found 430.2236.
(ꢀ), 22.8 (ꢀ), 22.7 (ꢀ); IR (CCl4) 2980, 2932, 2359, 1701, 1108 cmꢀ1
HRMS calcd for C19H22NO4 (MþHþ) 328.1549, found 328.1537.
;
3.1.28. 2,3-Di(1-methylethoxy)-6-methylcyclopenta[b]quinolin-1-
one (16c)
Reaction of 15c (185 mg, 0.43 mmol) in EtOAc/HCl (3:2, 3 M aq
HCl, 25 mL), as described for 7 (ambient temperature, 2 d), gave

P.S. Zehr et al. / Tetrahedron 64 (2008) 5336–5344
5343
after workup and chromatography (hexanes/EtOAc, 8:2) 14c
3.1.32. 2,3-Di(1-methylethoxy)-6-methoxycyclopenta[b]quinolin-
1-ol (17b)
(94 mg, 0.30 mmol, 70%) as a yellow-orange solid. Mp 78–80 ꢂC; 1H
NMR d 7.85 (s, 1H), 7.75 (s, 1H), 7.60 (d, 1H, J¼8.1 Hz), 7.26 (dd, 1H,
J¼7.5, 1.4 Hz), 5.67 (heptet, 1H, J¼6.1 Hz), 5.22 (heptet, 1H,
J¼6.1 Hz), 2.46 (s, 3H), 1.49 (d, 6H, J¼6.1 Hz), 1.34 (d, 6H, J¼6.1 Hz);
13C NMR d 187.3 (þ), 158.5 (þ), 156.5 (þ), 149.2 (þ), 141.2 (þ), 137.8
(þ), 129.5 (ꢀ), 129.4 (ꢀ), 128.5 (ꢀ), 126.2 (ꢀ), 125.3 (þ), 122.8 (þ),
74.9 (ꢀ), 73.7 (ꢀ), 22.9 (ꢀ), 22.7 (ꢀ), 21.7 (ꢀ); IR (CCl4) 3000, 2950,
Reaction of 16b (61 mg, 0.19 mmol), NaBH4 (80 mg, 2.11 mmol),
and methanol (0.91 mL, 20.95 mmol) in THF (10 mL), as described
for 7 (overnight), gave after workup and chromatography (hexanes/
EtOAc, 8:2) 15b (43 mg, 0.13 mmol, 70%) as a yellow oil. 1H NMR
d 7.78 (s, 1H), 7.56 (d, 1H, J¼8.9 Hz), 7.40 (d, 1H, J¼2.4 Hz), 7.03 (dd,
1H, J¼8.7, 2.6 Hz), 5.34 (heptet, 1H, J¼5.7 Hz), 5.12 (heptet, 1H,
J¼5.9 Hz), 5.06 (d, 1H, J¼6.9 Hz), 3.92 (s, 3H), 1.38 (m, 12H); 13C
NMR d 160.2 (þ), 159.9 (þ), 151.1 (þ), 149.7 (þ), 133.9 (þ), 128.8 (þ),
127.9 (ꢀ), 120.9 (þ), 116.6 (ꢀ), 107.9 (ꢀ), 72.9 (ꢀ), 72.3 (ꢀ), 68.6 (ꢀ),
1715, 1645, 1155 cmꢀ1
312.1600, found 312.1606.
;
HRMS calcd for C19H22NO3 (MþHþ)
3.1.29. 2,3-Di(1-methylethoxy)-6-aza-cyclopenta[b]quinolin-
1-one (16d)
55.4 (ꢀ), 22.9 (ꢀ), 22.6 (ꢀ); IR (CCl4) 3412, 2977, 2931, 1105 cmꢀ1
HRMS calcd for C19H24NO4 (MþHþ) 330.1705, found 330.1707.
;
To a 0 ꢂC cold solution of 15d (273 mg, 0.66 mmol) in CH2Cl2
(15 mL) was slowly added trifluoroacetic acid (1.0 mL, 5.93 mmol).
The reaction mixture was allowed to stir (0 ꢂC, 4 h, then reflux, 1 h).
The solvent was removed under reduced pressure and the residue
was suspended in NaHCO3 (aq saturated, 10 mL). The suspension
was extracted with CH2Cl2 (100 mL) and the combined organic
layers were, dried (MgSO4), filtered, and the solvents were removed
under reduced pressure. The crude product was purified by chro-
matography (hexanes/EtOAc, 1:1) to give 14d (163 mg, 0.55 mmol,
84%) as an orange solid. Mp 73–76 ꢂC; 1H NMR d 9.37 (s,1H), 8.55 (d,
1H, J¼5.3 Hz), 7.74 (s, 1H), 7.55 (d, 1H, J¼5.2 Hz), 5.71 (heptet, 1H,
J¼6.1 Hz), 5.32 (heptet, 1H, J¼6.1 Hz), 1.51 (d, 6H, J¼6.1 Hz), 1.36 (d,
6H, J¼6.1 Hz); 13C NMR d (150 MHz) 185.6 (þ), 159.6 (þ), 156.9 (þ),
152.9 (ꢀ), 145.4 (ꢀ), 143.9 (þ), 139.8 (þ), 131.9 (þ), 127.7 (þ), 124.2
(ꢀ), 121.9 (ꢀ), 75.6 (ꢀ), 74.1 (ꢀ), 22.9 (ꢀ), 22.8 (ꢀ); IR (CHCl3) 2985,
2348, 2254, 1704, 1094 cmꢀ1; HRMS calcd for C17H19N2O3 (MþHþ)
299.1396, found 299.1396.
3.1.33. 2,3-Di(1-methylethoxy)-6-methylcyclopenta[b]quinolin-1-
ol (17c)
Reaction of 16c (94 mg, 0.30 mmol), NaBH4 (118 mg, 2.80 mmol),
and methanol (1.44 mL, 33.2 mmol) in THF (10 mL), as described for
8 (overnight), gave after workup and chromatography (hexanes/
EtOAc, 8:2) 15c (66 mg, 0.21 mmol, 70%) as a faint yellow oil. 1H
NMR d 7.79 (s, 2H), 7.58 (d, 1H, J¼7.9 Hz), 7.21 (d, 1H, J¼9.1 Hz), 5.39
(heptet,1H, J¼6.1 Hz), 5.15, (heptet,1H, J¼6.1 Hz), 5.04 (d, J¼5.1 Hz),
2.51 (s, 3H), 1.38 (m, 12H); 13C NMR d 159.6 (þ), 151.4 (þ), 148.1 (þ),
138.8 (þ), 133.7 (þ), 130.2 (þ), 127.9 (ꢀ), 127.7 (ꢀ), 127.5 (ꢀ), 126.6
(ꢀ),124.1 (þ), 72.8 (ꢀ), 72.2 (ꢀ), 68.5 (ꢀ), 22.9 (ꢀ), 22.6 (ꢀ), 21.6 (ꢀ);
IR (CCl4) 3400, 2978, 2933, 1105 cmꢀ1; HRMS calcd for C19H24NO3
(MþHþ) 314.1756, found 314.1759.
3.1.34. 2,3-Di(1-methylethoxy)-6-azacyclopenta[b]quinolin-
1-ol (17d)
To a 0 ꢂC cold solution of 16d (414 mg, 3.36 mmol) in THF/MeOH
(1:1, 10 mL) was added NaBH4 (110 mg, 2.91 mmol). The reaction
was stirred for 10 min at 0 ꢂC and subsequently quenched with
water. The mixture was quickly extracted with ethyl acetate
(3ꢁ50 mL), and the combined organic layers were dried (Na2SO4),
filtered, and the solvents were removed under reduced pressure.
The residue was purified by chromatography (hexanes/EtOAc, 3:7)
to give 15d (212 mg, 0.71 mmol, 51%) as a white solid that quickly
turned yellow. Tentative NMR assignments from a rapidly decom-
posing compound. 1H NMR d 9.25 (s, 1H), 8.39 (d, 1H, J¼5.3 Hz), 7.77
(s, 1H), 7.46 (d, 1H, J¼5.5 Hz), 5.25 (overlapping heptet, 2H), 5.07 (s,
1H), 1.46–1.32 (m, 12H); 13C NMR d 161.5 (þ), 153.6 (þ), 151.6 (ꢀ),
143.4 (þ), 142.2 (ꢀ), 136.3 (þ), 133.5 (þ), 130.3 (þ), 126.1 (ꢀ), 120.7
(ꢀ), 73.4 (ꢀ), 72.5 (ꢀ), 68.3 (ꢀ), 28.2 (ꢀ), 22.9 (ꢀ), 22.6 (ꢀ).
3.1.30. 2,3-Di(1-methylethoxy)cyclopenta[b]quinolin-1-ol (8)
To a 0 ꢂC cold solution of 7 (96 mg, 0.32 mmol) in THF (10 mL)
was added NaBH4 (130 mg, 3.44 mmol) and the resulting mixture
was allowed to stir (3 h). Methanol (1.55 mL, 35.51 mmol) was
added and the mixture was diluted with water (20 mL) and
extracted with EtOAc (3ꢁ30 mL). The combined organic layers
were dried (MgSO4), filtered, and the solvents were removed under
reduced pressure. The crude product was purified by chromatog-
raphy (hexanes/EtOAc, 8:2) to afford 8 (81 mg, 0.27 mmol, 84%) as
a pale yellow oil. 1H NMR d (600 MHz) 7.93 (d, 1H, J¼7.8), 7.68 (s,
1H), 7.53 (m, 2H), 7.32 (dt, 1H, J¼1.2, 7.8 Hz), 5.29 (heptet, 1H,
J¼5.4 Hz), 5.13 (heptet, 1H, J¼6.0 Hz), 5.02 (br s, 1H), 2.75 (br s, 1H),
1.36 (d, 3H, J¼5.4 Hz), 1.34 (d, 3H, J¼6.0 Hz), 1.33 (d, 3H, J¼6.0 Hz),
1.31 (d, 3H, J¼6.0 Hz); 13C NMR d 159.8 (þ), 151.5 (þ), 148.2 (þ),
133.8 (þ), 131.1 (þ), 128.7 (ꢀ), 128.5 (ꢀ), 128.1 (ꢀ), 127.9 (ꢀ), 126.4
(þ), 124.8 (ꢀ), 72.9 (ꢀ), 72.3 (ꢀ), 68.7 (ꢀ), 22.91 (ꢀ), 22.90 (ꢀ),
22.64 (ꢀ), 22.61 (ꢀ); IR (CCl4) 3277, 3061, 2979, 2935, 2360, 1317,
1104 cmꢀ1; HRMS calcd for C18H22NO3 (MþHþ) 300.1600, found
300.1600.
3.1.35. (2-(1-Hydroxy-2-(1-methylethoxy)-3-methyl-4-oxo-
cyclobut-2-enylethynyl)-phenyl)-carbamic acid 1,1-dimethylethyl
ester (18)
Reaction of 1 (406 mg, 1.87 mmol), n-BuLi (1.6 M in THF, 2.90 mL,
4.67 mmol),
and
3-methyl-4-(1-methylethoxy)-3-cyclobutene-
1,2-dione23 (290 mg,1.88 mmol) inTHF (30 mL total), as described for 2
(30 min), gave after workup and chromatography (hexanes/EtOAc, 8:2)
16 (33 mg, 0.89 mmol, 48%) as a yellow solid and 2 (81 mg, 0.37 mmol).
1HNMRd8.11(d,1H, J¼8.5 Hz), 7.33(dt,1H, J¼1.6, 7.5 Hz), 7.21 (br s,1H),
6.93 (dt,1H, J¼7.5, 1.0 Hz), 5.11 (heptet, 1H, J¼6.3 Hz), 4.24 (brs,1H),1.71
(s, 1H), 1.53 (s, 9H), 1.49 (d, 6H, J¼6.3 Hz); 13C NMR d 187.6 (þ), 180.1
(þ), 152.5 (þ), 139.7 (þ), 132.1 (ꢀ), 130.1 (ꢀ), 124.3 (þ), 122.1 (ꢀ), 118.0
(ꢀ), 110.0 (þ), 90.1 (þ), 84.8 (þ), 83.2 (þ), 80.9 (þ), 78.5 (ꢀ), 28.2 (ꢀ),
3.1.31. 7-Chloro-2,3-di(1-methylethoxy)cyclopenta[b]quinolin-
1-ol (17a)
Reaction of 16a (80 mg, 0.27 mmol) with NaBH4 (106 mg,
2.80 mmol), and methanol (1.30 mL, 29.58 mmol) in THF (10 mL),
as described for 8 (3 h), gave after workup and chromatography
(hexanes/EtOAc, 8:2) 15a (55 mg, 0.18 mmol, 68%) as a light yellow
oil. 1H NMR d (600 MHz) 7.83 (d, 1H, J¼9.0 Hz), 7.58 (s, 1H), 7.51 (d,
1H, J¼1.8 Hz), 7.47 (dd, 1H, J¼8.4, 2.4 Hz), 5.24 (heptet, 1H,
J¼6.0 Hz), 5.15 (heptet, 1H J¼6.0 Hz), 5.01 (br s, 1H), 2.75 (br s, 1H),
1.40 (d, 3H, J¼6.0 Hz), 1.36 (d, 3H, J¼6.0 Hz), 1.35 (d, 3H, J¼6.0 Hz),
1.34 (d, 3H, J¼6.0 Hz); 13C NMR d (150 MHz) 160.3 (þ), 152.2 (þ),
146.8 (þ), 133.8 (þ), 132.2 (þ), 130.4 (ꢀ), 130.1 (ꢀ), 129.6 (þ), 127.3
(ꢀ), 127.2 (ꢀ), 126.9 (þ), 73.4 (ꢀ), 72.7 (ꢀ), 68.8 (ꢀ), 23.17 (ꢀ), 23.15
(ꢀ), 22.87 (ꢀ), 22.83 (ꢀ); IR (CHCl3) 3366 (br.), 2976, 1313, 1104;
HRMS calcd for C18H21NO3Cl (MþHþ) 334.1210, found 334.1205.
22.9 (ꢀ), 22.6 (ꢀ), 6.5 (ꢀ); IR (CCl4) 3410, 2980, 2380, 1735,1157 cmꢀ1
;
HRMS calcd for C21H26NO5 (MþHþ) 372.1811, found 372.1808.
3.1.36. E- and Z-(2-(3-(1-Methylethoxy)-4-methyl-2,5-dioxo-3-
cyclopenten-1-ylmethyl)phenyl)-carbamic acid 1,1-dimethylethyl
ester (19)
Reaction of 16 (310 mg, 0.83 mmol) in 1,2-dichloroethane
(20 mL), as described for 6 (reflux, 18 h), gave after chromatography

5344
P.S. Zehr et al. / Tetrahedron 64 (2008) 5336–5344
(hexanes/EtOAc, 8:2) an inseparable mixture of E- and Z-19
(127 mg, 0.34 mmol, 8.3:1 ratio, 41%) as a yellow solid. Mp 132–
136 ꢂC; 1H NMR d 8.05 (dd, 1H, J¼7.9, 1.6 Hz), 7.76 (d, 1H, J¼8.3 Hz),
7.48 (s, 1H), 7.43 (dt, 1H, J¼7.7, 1.6 Hz), 7.16 (t, 1H), 6.63 (br s, 1H),
5.73 (heptet, 1H, J¼6.1 Hz), 1.99 (s, 3H), 1.51 (s, 9H), 1.41 (d, 6H,
J¼5.9 Hz); 13C NMR d (150 MHz) 189.3 (þ), 188.2 (þ), 164.8 (þ),
152.9 (þ), 138.1 (þ), 137.5 (þ), 132.7 (ꢀ), 132.2 (ꢀ), 131.9 (ꢀ), 131.5
(ꢀ), 127.9 (þ), 123.7 (ꢀ), 122.6 (ꢀ), 80.9 (þ), 74.8 (ꢀ), 74.7 (ꢀ), 28.2
(ꢀ), 23.2 (ꢀ), 7.2 (ꢀ); IR (CCl4) 3400, 2978, 2931, 2359, 1733,
1156 cmꢀ1; HRMS calcd for C21H26NO5 (MþHþ) 372.1811, found
372.1813.
Acknowledgements
This work was supported by research grants from the National
Science Foundation (CHE 0611096), the National Institute of Gen-
eral Medical Sciences, National Institutes of Health (RO1 GM57416),
and the American Chemical Society Petroleum Research Fund
(40665-AC1). NSF-EPSCoR (Grant #1002165R) is gratefully ac-
knowledged for the funding of a 600 MHz Varian Inova NMR and
a Thermo-Finnegan LTQ-FT Mass Spectrometer and the NMR and
MS facilities in the C. Eugene Bennett Department of Chemistry at
West Virginia University.
3.1.37. 2-(1-Methylethoxy)-3-methylcyclopenta[b]quinolin-
1-one (20)
References and notes
Reaction of 19 (107 mg, 0.29 mmol) in EtOAc/HCl (3:2, 3 M aq
HCl, 25 mL), as described for 7 (ambient temperature, 2 d), gave
after workup and chromatography (hexanes/EtOAc, 8:2) 18 (22 mg,
0.087 mmol, 30%) as a yellow-orange solid. Mp 78–80 ꢂC; 1H NMR
d 7.94 (d,1H, J¼8.3 Hz), 7.93 (s,1H), 7.71 (d,1H, J¼8.3 Hz), 7.63 (t,1H,
J¼7.1 Hz), 7.39 (t, 1H, J¼7.5 Hz), 5.28 (heptet, 1H, J¼6.1 Hz), 2.19 (s,
3H), 1.34 (d, 6H, J¼6.1 Hz); 13C NMR d (150 MHz) 189.4 (þ), 163.9
(þ), 156.1 (þ), 150.1 (þ), 139.0 (þ), 131.3 (ꢀ), 130.5 (ꢀ), 129.6 (ꢀ),
128.1 (ꢀ), 127.5 (þ), 126.6 (ꢀ), 123.3 (þ), 73.9 (ꢀ), 23.2 (ꢀ), 8.3 (ꢀ);
IR (CCl4) 2988, 2254, 1707, 1636, 1102 cmꢀ1; HRMS calcd for
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C
16H16NO2 (MþHþ) 254.1181, found 254.1189.
3.1.38. 2-(1-Methylethoxy)-3-methylcyclopenta[b]quinolin-
1-ol (21)
Reaction of 20 (90 mg, 0.36 mmol), NaBH4 (140 mg, 3.70 mmol),
and methanol (1.7 mL, 39.1 mmol) in THF (10 mL), as described for
8 (3 h), gave after workup and chromatography (hexanes/EtOAc) 19
(50 mg, 0.20 mmol, 55%) as a yellow oil. Tentative NMR assign-
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ments from
a
rapidly decomposing compound: 1H NMR
d (600 MHz) 7.76 (d, 1H, J¼8.4 Hz), 7.53 (dt, 1H, J¼7.8, 2.4 Hz), 7.24
(dt, 1H, J¼8.4, 1.8 Hz), 7.15 (dd, 1H, J¼7.8, 1.8 Hz), 6.99 (s, 1H), 5.01
(heptet, 1H, J¼5.4 Hz), 4.97 (t, 1H, J¼1.8 Hz), 1.91 (d, 3H, J¼1.2 Hz),
1.46 (d, 3H, J¼6.6 Hz), 1.30 (d, 3H, J¼6.6 Hz); 13C NMR d 167.3 (þ),
164.7 (þ), 147.7 (þ), 132.1 (þ), 128.8 (ꢀ), 128.3 (ꢀ), 127.5 (ꢀ), 127.4
(þ), 126.3 (þ), 124.1 (ꢀ), 115.8 (þ), 72.7 (ꢀ), 69.6 (ꢀ), 23.3 (ꢀ), 23.1
(ꢀ), 6.9 (ꢀ); HRMS calcd for C16H18NO2 (MþHþ) 256.1338, found
256.1335.
23. Liebeskind, L. S.; Fengl, R. W.; Wirtz, K. R.; Shawe, T. T. J. Org. Chem. 1988, 53,
2482–2488.