Synthesis of amino-substituted indanes and tetralins via consecutive multibond-forming tandem processes

Article abstract of DOI:10.1021/jo401182r

A rapid and general approach for the synthesis of amino-substituted indanes and tetralins from readily available alkyne-derived allylic alcohols via consecutive multibond-forming tandem processes has been developed. In the first one-pot tandem process, a series of cyclic dienes were prepared using an Overman rearrangement under thermal conditions, followed by a ruthenium(II)-catalyzed ring closing enyne metathesis reaction. The resulting exo-dienes were then subjected to a second one-pot tandem process involving a highly regioselective Diels-Alder reaction with alkynes, quinones or nitriles and a subsequent oxidation step to give a diverse library of C-1 amino-substituted indanes and tetralins in good overall yields.

Full text of DOI:10.1021/jo401182r

Article
pubs.acs.org/joc
Synthesis of Amino-Substituted Indanes and Tetralins via
Consecutive Multibond-Forming Tandem Processes
Mark W. Grafton, Louis J. Farrugia, and Andrew Sutherland*
WestCHEM, School of Chemistry, The Joseph Black Building, University of Glasgow, Glasgow G12 8QQ, United Kingdom
S
* Supporting Information
ABSTRACT: A rapid and general approach for the synthesis
of amino-substituted indanes and tetralins from readily available
alkyne-derived allylic alcohols via consecutive multibond-
forming tandem processes has been developed. In the first
one-pot tandem process, a series of cyclic dienes were prepared
using an Overman rearrangement under thermal conditions,
followed by a ruthenium(II)-catalyzed ring closing enyne
metathesis reaction. The resulting exo-dienes were then
subjected to a second one-pot tandem process involving a highly regioselective Diels−Alder reaction with alkynes, quinones
or nitriles and a subsequent oxidation step to give a diverse library of C-1 amino-substituted indanes and tetralins in good overall
yields.
on construction of the partially saturated ring system and
include the intramolecular cyclization of lithium anions with
imines,9 a CAN-mediated Ritter-type cyclodimerization10 and
an aryne Diels−Alder reaction with acyclic dienes.11 While
many of these methods involve the use of elegant chemistry,
they are generally limited to the preparation of a particular
bicyclic ring system and restricted in scope by the available
substituents on the aryl ring. We were interested in developing
a flexible approach for the generation of either bicyclic motif
that would also allow the late stage introduction of various aryl
ring substituents. Herein, we now report a rapid and general
approach for the synthesis of C-1 amino-substituted indanes
and tetralins from readily available alkyne-derived allylic
alcohols, using consecutive multibond-forming tandem pro-
cesses.12 The use of each tandem process to construct first the
amino-substituted partially saturated ring and then the aryl ring
allows the preparation of a diverse set of compounds
incorporating a range of functional groups.
INTRODUCTION
■
Indane and tetralin scaffolds with C-1 amino functionality have
generated significant interest due to their wide-ranging
pharmacological properties. For example, (+)-sertaline 1
(Zoloft) is prescribed for the treatment of depression,1
(+)-indatraline 2 is a nonselective monoamine transporter,2
while rasagiline 3 (Azilect) is used to treat Parkinson’s disease
(Figure 1).3 Other examples include indinavir, a component of
Figure 1. Biologically active amino-substituted indanes and tetralins.
RESULTS AND DISCUSSION
■
Our approach involved the conversion of alkyne-derived allylic
alcohols 4 to the corresponding allylic amine derivatives 5 using
a [3,3]-sigmatropic rearrangement (Scheme 1). Ring-closing
enyne metathesis (RCEYM) to form dienes 6 would then be
followed by a Diels−Alder reaction with a suitable dienophile
to generate a bicyclic dihydrobenzene. Oxidation would then
give C-1 amino-substituted indanes and tetralins 7.
The study began with the development of a general and
efficient approach for the preparation of alkyne-derived allylic
alcohols (Table 1). Analogues with an all-carbon backbone
were prepared from commercially available 4-pentyn-1-ol (8a)
HIV therapy, and irindalone, which selectively blocks the 5-
HT2 receptor.4,5 Heteroatom analogues are also potent
medicinal agents and have been used as inhibitors of
aldosterone synthase for the treatment of hypertension and
heart failure.6
As a result of these wide-ranging pharmacological activities,
various synthetic approaches have been developed for the
preparation of C-1 amino-substituted indanes and tetralins. A
common approach involves stepwise construction of aryl
substituted carbonyl derivatives that are subjected to an
intramolecular Friedel−Crafts acylation.2,7,8 The amine moiety
can then be introduced via reductive amination of the resulting
bicyclic aryl ketones. Other more specific methods also focus
Received: May 30, 2013
Published: June 18, 2013
© 2013 American Chemical Society
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Scheme 1. Proposed Approach to C-1 Amino-Substituted
Indanes and Tetralins
Table 2. Tandem Synthesis of Dienes 11a−d
entry
4
yield (%)
1
2
3
4
4a X = CH2, n = 0
4b X = CH2, n = 1
4c X = O, n = 1
11a (71)
11b (86)
a
11c (46)
11d (40)
ab
,
4d X = NTs, n = 1
a
b
RCEYM was done at 90 °C using 1,7-octadiene. RCEYM was done
using Hoveyda−Grubbs 2nd generation catalyst (5 mol %).
Table 1. Synthesis of Alkyne-Derived Allylic Alcohols
entry 3). For the synthesis of tetrahydropyridine 11d, an
effective tandem process was realized using Hoveyda−Grubbs
second generation catalyst in combination with 1,7-octadiene
during the RCEYM step. At a catalyst loading of 5 mol %, 11d
was isolated in 40% yield over the three steps (entry 4).22
The next stage of the study investigated the preparation of a
diverse library of C-1 amino-substituted indanes and tetralins
using a second, one-pot, multibond-forming tandem process
involving a Diels−Alder reaction with electron-deficient alkynes
or 1,4-benzoquinones, followed by an oxidation step (Scheme
2).23 It was found that Lewis acid mediated Diels−Alder
reaction of dienes 11a−d with diethyl acetylenedicarboxylate
followed by oxidation of dihydrobenzenes 12 with DDQ could
be performed using microwave heating, resulting in the rapid
preparation of indanes and tetralins 13a−d in good yields over
the two steps. Standard thermal conditions were found to be
more efficient during the highly regioselective Diels−Alder
reaction of dienes 11a,b with methyl propiolate. Oxidation with
DDQ then generated 13e and 13f in 52 and 66% overall yields,
respectively.24 The Diels−Alder reactions of dienes 11a−d with
1,4-benzoquinone, 2-tert-butyl-1,4-benzoquinone and 1,4-naph-
thoquinone for the synthesis of tri- and tetracyclic indanes and
tetralins 14a−h were again found to be more efficient using
standard thermal conditions, while microwave heating was used
for the rapid oxidation step of the one-pot process. In general,
manganese dioxide was established as the best oxidizing agent
for this series of compounds. For analogues 14c, 14f and 14g,
the use of manganese dioxide to perform the oxidation step also
led to trace amounts of products formed from benzylic
oxidation. In these cases, DDQ provided the tetralins in higher
yields. It should be noted that Diels−Alder reaction of dienes
11a−11d with 2-tert-butyl-1,4-benzoquinone followed by
oxidation gave the corresponding indanes or tetralins (14d−
g) solely as a single regioisomer. The regiochemical outcome of
these reactions was determined by X-ray analysis of 14e.25 This
showed that the 8-tert-butyl regioisomer was the product
generated, suggesting these reactions are sterically controlled.
The scope of this process was extended to include
heteroaromatic derivatives (Scheme 3). Hetero Diels−Alder
reaction of dienes 11a or 11b with electron-deficient nitriles
such as p-toluenesulfonyl cyanide, ethyl cyanoformate or
trichloroacetonitrile at 160 °C gave the corresponding pyridines
directly as single regioisomers, without the need of an
oxidant.24,26 During the reaction of 11b with trichloroacetoni-
trile, aromatization of the resulting dihydropyridine was
facilitated by loss of a chlorine atom to give dichloromethyl
entry
8
yield (%)
yield (%)
1
2
3
4
8a X = CH2, n = 0
8b X = CH2, n = 1
8c X = O, n = 1
9a (95)
9b (99)
9c (75)
9d (83)
4a (93)
4b (97)
4c (83)
4d (99)
8d X = NTs, n = 1
and 5-hexyn-1-ol (8b) using a one-pot Swern oxidation and
Horner−Wadsworth−Emmons reaction, performed under
Masumune−Roush conditions.13,14 This gave the correspond-
ing (E)-α,β-unsaturated esters, 9a and 9b in 95 and 99% yield,
respectively (entries 1 and 2). Subsequent reduction of the (E)-
α,β-unsaturated esters with DIBAL-H gave the alkyne-derived
(E)-allylic alcohols, 4a and 4b in excellent overall yields.15 Two
further substrates incorporating an oxygen atom 4c or a N-tosyl
group 4d were also prepared in high yields using a similar
approach from known alcohols, 2-(2′-propynloxy)ethanol
(8c)16 and 2-(N-p-toluenesulfonyl-2′-propynlamino)ethanol
(8d) (entries 3 and 4).17
It was envisaged that the C-1 amino substituent of the
indanes and tetralins could be installed using an Overman
rearrangement18 and that the transformation could be
performed as a one-pot tandem process in combination with
a RCEYM reaction leading directly to the cyclic exo-dienes.19,20
Reaction of (E)-allylic alcohols 4a−d with trichloroacetonitrile
and a catalytic amount of DBU gave the corresponding allylic
trichloroacetimidates, and these were subjected to an Overman
rearrangement under thermal conditions (Table 2). In the case
of analogues with an all-carbon side-chain (entries 1 and 2),
subsequent addition of Grubbs first generation catalyst (10 mol
%) resulted in the efficient preparation of the target dienes 11a
and 11b in 71 and 86% yields, respectively, over the three steps.
The RCEYM reactions of enynes 10c and 10d were
significantly slower (4−6 days), requiring higher catalyst
loading (20 mol %) to generate dihydropyran 11c and
tetrahydropyridine 11d in only modest overall yields (30−
34%). Methods for improving the RCEYM step were
investigated, and the use of 1,7-octadiene as an in situ source
of ethylene was found to be beneficial during the preparation of
dihydropyran 11c,21 allowing a more efficient tandem synthesis
(46% overall yield) at much lower catalyst loading (10 mol %,
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Scheme 2. One-Pot Tandem Synthesis of Amino-Substituted
Indanes and Tetralins 13 and 14
Scheme 3. One-Pot Tandem Synthesis of Heteroaromatic
Analogues 15 and 16
a
Reaction was performed at 125 °C.
with chiral catalysts,28 for the preparation of natural products
and medicinally important compounds, is currently under
investigation.29
EXPERIMENTAL SECTION
■
All reagents and starting materials were obtained from commercial
sources and used as received. All dry solvents were purified using a
solvent purification system. All reactions were performed under an
atmosphere of argon unless otherwise mentioned. Brine refers to a
saturated solution of sodium chloride. Flash column chromatography
was performed using silica gel 60 (35−70 μm). Aluminum-backed
plates precoated with silica gel 60F254 were used for thin layer
chromatography and were visualized with a UV lamp or by staining
1
with potassium permanganate. H NMR spectra were recorded on a
NMR spectrometer at either 400 or 500 MHz, and data are reported as
follows: chemical shift in ppm relative to tetramethylsilane as the
internal standard, multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet or overlap of nonequivalent resonances,
integration). 13C NMR spectra were recorded on a NMR spectrometer
at either 101 or 126 MHz, and data are reported as follows: chemical
shift in ppm relative to tetramethylsilane or the solvent as internal
standard (CDCl3, δ 77.0 ppm or CD3OD, δ 44.0 ppm), multiplicity
with respect to proton (deduced from DEPT experiments, C, CH,
CH2 or CH3). Infrared spectra were recorded on a FTIR
spectrometer; wavenumbers are indicated in cm−1. Mass spectra
were recorded using electron impact, chemical ionization, electrospray
or fast atom bombardment techniques. HRMS spectra were recorded
using a dual-focusing magnetic analyzer mass spectrometer. Melting
points are uncorrected. Microwave reactions were conducted using a
CEM Discover Explorer Synthesis Unit and performed in glass tubes
(capacity 10 mL) sealed with a septum. Temperatures of the reaction
mixtures were monitored by an internal infrared temperature control
probe.
a
Both steps were performed under standard thermal conditions in a
b
Schlenk tube. Oxidation done using MnO2.
derivative 15d. Pyridazines were also generated, via the hetero-
Diels−Alder reaction of 11a or 11b with di-tert-butyl
azodicarboxylate. Treatment of the resulting adducts with
bromine promoted the known sequence of bromination, N-Boc
deprotection and aromatization giving pyridazines 16a and 16b
in good overall yields.27
CONCLUSIONS
■
Ethyl (2E)-hept-2-en-6-ynoate (9a).30 Dimethyl sulfoxide (3.60
mL, 50.8 mmol) was added to a stirred solution of oxalyl chloride
(2.49 mL, 28.4 mmol) in dichloromethane (100 mL) at −78 °C. The
mixture was stirred for 0.3 h before 4-pentyn-1-ol (8a) (1.70 g, 20.3
mmol) in dichloromethane (25 mL) was slowly added. The mixture
was stirred for a further 0.3 h before triethylamine (14.1 mL, 102
mmol) was added. This reaction mixture was stirred for 0.5 h at −78
°C and then allowed to warm to room temperature and stirred for a
further 3 h. A solution of lithium chloride (1.55 g, 36.5 mmol), triethyl
phosphonoacetate (7.24 mL, 36.5 mmol) and 1,8-diazabicyclo[5,4,0]-
In summary, a novel approach for the synthesis of a diverse
library of compounds containing C-1 amino-substituted
indanes and tetralins, privileged structures found within a
range of pharmaceutically important agents, has been
developed. The use of consecutive multibond-forming tandem
processes allowed rapid access to structures with varying ring
sizes, incorporating heteroatoms and substituents in a
regioselective fashion. An asymmetric version of this approach
involving a palladium(II)-catalyzed Overman rearrangement
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undec-7-ene (5.14 mL, 36.5 mmol) in acetonitrile (70 mL) was then
prepared and stirred for 1 h. The Swern solution was concentrated in
vacuo, and then the Horner Wadsworth Emmons solution was added,
and the reaction mixture was stirred at room temperature overnight.
The reaction was quenched with a saturated solution of ammonium
chloride (50 mL) and concentrated to give an orange residue, which
was then extracted with diethyl ether (4 × 75 mL). The organic layers
were combined, dried (MgSO4) and concentrated to give an orange
oil. Purification by flash column chromatography (diethyl ether/
petroleum ether, 1:9) gave ethyl (2E)-hept-2-en-6-ynoate (9a) (2.93 g,
95%) as a yellow oil. Spectroscopic data consistent with literature:30 Rf
(25% diethyl ether/petroleum ether) 0.63; IR (neat) 3302, 2984,
was added dropwise, and the reaction mixture was stirred at −78 °C
for 3 h, before warming to room temperature overnight. The solution
was cooled to 0 °C and quenched by the addition of a saturated
solution of ammonium chloride (10 mL) and warmed to room
temperature with vigorous stirring over 1 h, producing a white
precipitate. The precipitate was filtered through a pad of Celite and
washed with diethyl ether (3 × 50 mL). The filtrate was then dried
(MgSO4) and concentrated in vacuo. Purification by flash column
chromatography (diethyl ether/petroleum ether, 1:1) gave (2E)-hept-
2-en-6-yn-1-ol (4a) (1.01 g, 93%) as a yellow oil. Spectroscopic data
consistent with literature:33 Rf (50% diethyl ether/petroleum ether)
0.33; IR (neat) 3360, 3295, 2915, 1670, 1433, 1084, 997, 968 cm−1;
1H NMR (500 MHz, CDCl3) δ 1.42 (br s, 1H), 1.99 (t, 1H, J 2.5 Hz),
2.28−2.33 (m, 4H), 4.14 (d, 2H, J 4.0 Hz), 5.70−5.81 (m, 2H) ppm;
13C NMR (126 MHz, CDCl3) δ 18.5 (CH2), 31.1 (CH2), 63.5 (CH2),
68.8 (CH), 83.7 (C), 130.5 (CH), 130.6 (CH) ppm; MS (CI) m/z
111 (MH+, 3%), 107 (15), 93 (100), 81 (10), 69 (10).
1
1715, 1657, 1445, 1368, 1267, 1155, 1038, 756 cm−1; H NMR (400
MHz, CDCl3) δ 1.30 (t, 3H, J 7.1 Hz), 2.01 (t, 1H, J 2.5 Hz), 2.34−
2.39 (m, 2H), 2.41−2.48 (m, 2H), 4.20 (q, 2H, J 7.1 Hz), 5.90 (dt,
1H, J 15.7, 1.5 Hz), 6.97 (dt, 1H, J 15.7, 6.7 Hz) ppm; 13C NMR (126
MHz, CDCl3) δ 14.3 (CH3), 17.4 (CH2), 31.0 (CH2), 60.3 (CH2),
69.4 (CH), 82.7 (C), 122.6 (CH), 146.3 (CH), 166.4 (C) ppm; MS
(CI) m/z 153 (MH+, 100%), 139 (5), 113 (10), 97 (5), 81 (15), 69
(15).
(2E)-Octa-2-en-7-yn-1-ol (4b).34 The reaction was carried out as
described for the synthesis of (2E)-hept-2-en-6-yn-1-ol (4a) using
ethyl (2E)-octa-2-en-7-ynoate (9b) (4.10 g, 24.7 mmol). Purification
by flash column chromatography (diethyl ether/petroleum ether, 1:1)
gave (2E)-octa-2-en-7-yn-1-ol (4b) (2.95 g, 97% yield) as a yellow oil.
Spectroscopic data consistent with literature:34 Rf (50% petroleum
ether/diethyl ether) 0.29; IR (neat) 3361, 3302, 2932, 1674, 1435,
1219, 1088, 972 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.29 (br s, 1H),
1.63 (quin, 2H, J 6.9 Hz), 1.96 (t, 1H, J 2.6 Hz), 2.15−2.25 (m, 4H),
4.09−4.15 (m, 2H), 5.63−5.74 (m, 2H) ppm; 13C NMR (101 MHz,
CDCl3) δ 17.8 (CH2), 27.8 (CH2), 31.1 (CH2), 63.7 (CH2), 68.5
(CH), 84.2 (C), 129.9 (CH), 131.9 (CH) ppm; MS (CI) m/z 125
(MH+, 20%), 107 (95), 97 (40), 81 (80), 71 (100).
Ethyl (2E)-octa-2-en-7-ynoate (9b).31 The reaction was carried
out as described for the synthesis of (2E)-hept-2-en-6-ynoate (9a)
using 5-hexyn-1-ol (8b) (3.00 g, 30.6 mmol). Purification by flash
column chromatography (diethyl ether/petroleum ether, 1:9) gave
ethyl (2E)-octa-2-en-7-ynoate (9b) (4.99 g, 99%) as a yellow oil.
Spectroscopic data consistent with literature:31 Rf (50% diethyl ether/
petroleum ether) 0.74; IR (neat) 3295, 2940, 1713, 1651, 1265, 1188,
1150, 1042, 979, 756, 633 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.29
(t, 3H, J 7.1 Hz), 1.70 (quin, 2H, J 6.9 Hz), 1.98 (s, 1H), 2.23 (t, 2H, J
6.9 Hz), 2.33 (q, 2H, J 6.9 Hz), 4.18 (q, 2H, J 7.1 Hz), 5.86 (d, 1H, J
15.6 Hz), 6.94 (dt, 1H, J 15.6, 6.9 Hz) ppm; 13C NMR (101 MHz,
CDCl3) δ 14.3 (CH3), 17.9 (CH2), 26.7 (CH2), 30.9 (CH2), 60.2
(CH2), 69.0 (CH), 83.5 (C), 122.1 (CH), 147.8 (CH), 166.6 (C)
ppm; MS (CI) m/z 167 (MH+, 100%), 139 (42), 113 (10), 97 (12),
81 (25), 71 (30).
(2E)-4-(2′-Propynloxy)but-2-en-1-ol (4c). The reaction was
carried out as described for the synthesis of (2E)-hept-2-en-6-yn-1-ol
(4a) using ethyl (2E)-4-(2′-propynloxy)but-2-enoate (9c) (1.46 g,
8.70 mmol). Purification by flash column chromatography (ethyl
acetate/petroleum ether, 1:1) gave (2E)-4-(2′-propynloxy)but-2-en-1-
ol (4c) (0.91 g, 83%) as a colorless oil: Rf (50% ethyl acetate/
petroleum ether) 0.36; IR (neat) 3385, 3289, 2920, 2855, 1356, 1090,
Ethyl (2E)-4-(2′-propynloxy)but-2-enoate (9c).32 The reaction
was carried out as described for the synthesis of (2E)-hept-2-en-6-
ynoate (9a) using 2-(2′-propynloxy)ethan-1-ol (8c) (1.20 g, 12.0
mmol). Purification by flash column chromatography (diethyl ether/
petroleum ether, 1:3) gave ethyl (2E)-4-(2′-propynloxy)but-2-enoate
(9c) (1.50 g, 75%) as a yellow oil. Spectroscopic data consistent with
literature:32 Rf (25% diethyl ether/petroleum ether) 0.61; IR (neat)
3291, 2982, 1715, 1663, 1368, 1304, 1265, 1177, 1119, 1036, 966
1
999, 970 cm−1; H NMR (500 MHz, CDCl3) δ 1.58 (br s, 1H), 1.99
(t, 1H, J 2.4 Hz), 4.08 (dd, 2H, J 5.8, 1.1 Hz), 4.13−4.18 (m, 4H), 5.80
(dtt, 1H, J 15.6, 5.8, 1.4 Hz), 5.93 (dtt, 1H, J 15.6, 5.3, 1.1 Hz) ppm;
13C NMR (126 MHz, CDCl3) δ 57.3 (CH2), 63.0 (CH2), 69.7 (CH2),
74.5 (CH), 79.8 (C), 127.1 (CH), 133.2 (CH) ppm; MS m/z 127
(MH+, 11), 109 (56), 71 (100); HRMS (CI) calcd for C7H11O2
(MH+), 127.0759, found 127.0762.
1
cm−1; H NMR (500 MHz, CDCl3) δ 1.28 (t, 3H, J 7.1 Hz), 2.44 (t,
1H, J 2.4 Hz), 4.17−4.24 (m, 6H), 6.08 (dt, 1H, J 15.8, 2.0 Hz), 6.93
(dt, 1H, J 15.8, 4.6 Hz) ppm; 13C NMR (126 MHz, CDCl3) δ 14.3
(CH3), 58.1 (CH2), 60.5 (CH2), 68.3 (CH2), 75.0 (CH), 79.3 (C),
122.3 (CH), 143.3 (CH), 166.2 (C) ppm; MS (CI) m/z 169 (MH+,
19%), 155 (5), 145 (87), 131 (7), 127 (7).
(2E)-4-(N-p-Toluenesulfonyl-2′-propynlamino)but-2-en-1-ol
(4d). The reaction was carried out as described for the synthesis of
(2E)-hept-2-en-6-yn-1-ol (4a) using ethyl (2E)-4-(N-p-toluenesulfon-
yl-2′-propynlaminobut-2-enoate (9d) (0.241 g, 0.75 mmol). Purifica-
tion by flash column chromatography (ethyl acetate/petroleum ether,
11:9) gave (2E)-4-(N-p-toluenesulfonyl-2′-propynlamino)but-2-en-1-
ol (4d) (0.21 g, 99%) as a colorless oil: Rf (50% ethyl acetate/
petroleum ether) 0.33; IR (neat) 3538, 3273, 2922, 2864, 1597, 1447,
1344, 1327, 1155, 1090, 893, 735 cm−1; 1H NMR (500 MHz, CDCl3)
δ 1.44 (br s, 1H), 2.03 (t, 1H, J 2.5 Hz), 2.42 (s, 3H), 3.84 (dd, 4H, J
6.5, 1.2 Hz), 4.09 (d, 2H, J 2.5 Hz), 4.13 (br m, 2H), 5.64 (dtt, 1H, J
15.5, 6.5, 1.6 Hz), 5.88 (dtt, 2H, J 15.5, 4.0, 1.2 Hz), 7.29 (d, 2H, J 8.2
Hz), 7.73 (d, 2H, J 8.2 Hz) ppm; 13C NMR (126 MHz, CDCl3) δ 21.5
(CH3), 36.0 (CH2), 48.0 (CH2), 62.7 (CH2), 73.7 (CH), 125.0 (CH),
127.8 (2 × CH), 129.5 (2 × CH), 134.7 (CH), 136.4 (C), 143.6 (C)
ppm; MS m/z 280 (MH+, 22), 263 (100), 210 (6), 157 (2), 113 (4),
85 (5), 69 (6); HRMS (CI) calcd for C14H18NO3S (MH+), 280.1007,
found 280.1012.
1-(2′,2′,2′-Trichloromethylcarbonylamino)-4-ethyl-1″-ene-
cyclopent-4-ene (11a). (2E)-Hept-2-en-6-yn-1-ol (4a) (0.40 g, 3.64
mmol) was dissolved in dichloromethane (30 mL) and cooled to 0 °C.
To the solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.10 mL, 0.728
mmol) and trichloroacetonitrile (0.55 mL, 5.45 mmol) were added.
The reaction mixture was allowed to warm to room temperature
before stirring for 3 h. The reaction mixture was filtered through a
short pad of silica gel, and the filtrate was concentrated in vacuo to
Ethyl (2E)-4-(N-p-toluenesulfonyl-2′-propynlamino)but-2-
enoate (9d). The reaction was carried out as described for the
synthesis of (2E)-hept-2-en-6-ynoate (9a) using 2-(N-p-toluenesul-
fonyl-2′-propynlamino)ethan-1-ol (8d) (1.24 g, 4.90 mmol). Purifica-
tion by flash column chromatography (diethyl ether/petroleum ether,
11:9) gave ethyl (2E)-4-(N-p-toluenesulfonyl-2′-propynlamino)but-2-
enoate (9d) (1.31 g, 83%) as a yellow solid: Rf (50% diethyl ether/
petroleum ether) 0.30; mp 69−71 °C; IR (neat) 3273, 2982, 1717,
1
1661, 1348, 1275, 1157, 1094 cm−1; H NMR (500 MHz, CDCl3) δ
1.28 (t, 3H, J 7.2 Hz), 2.08 (t, 1H, J 2.5 Hz), 2.42 (s, 3H), 3.98 (dd,
2H, J 6.0 1.6 Hz), 4.09 (d, 2H, J 2.5 Hz), 4.19 (q, 2H, J 7.2 Hz), 6.01
(dt, 1H, J 15.7, 1.6 Hz), 6.78 (dt, 1H, J 15.7, 6.0 Hz), 7.30 (d, 1H, J 8.3
Hz), 7.72 (d, 1H, J 8.3 Hz) ppm; 13C NMR (126 MHz, CDCl3) δ 14.1
(CH3), 21.4 (CH3), 36.7 (CH2), 47.1 (CH2), 60.5 (CH2), 74.2 (CH),
76.3 (C), 124.7 (CH), 127.7 (2 × CH), 129.6 (2 × CH), 136.0 (C),
141.1 (CH), 143.8 (C), 165.4 (C) ppm; MS m/z 321 (M+, 18), 276
(40), 248 (16), 166 (100), 155 (50), 120 (35), 91 (50), 65 (10);
HRMS (EI) calcd for C16H19NO4S (M+), 321.1035, found 321.1031.
(2E)-Hept-2-en-6-yn-1-ol (4a).33 Ethyl (2E)-hept-2-en-6-ynoate
(9a) (1.50 g, 9.87 mmol) was dissolved in diethyl ether (50 mL) and
cooled to −78 °C. DIBAL-H (1 M in hexane) (21.7 mL, 21.7 mmol)
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give the allylic trichloroacetimidate, which was used without further
purification. The allylic trichloroacetimidate was dissolved in toluene
(10 mL) containing potassium carbonate (0.05 g) and purged with
argon. The reaction mixture was then heated to 140 °C in a sealed
tube for 24 h. The reaction mixture was then cooled to room
temperature, and toluene (68 mL) was added to achieve a
concentration of 0.048 M of starting material. Grubbs first generation
catalyst (0.225 g, 0.273 mmol) was added, and the reaction mixture
was heated for 18 h at 75 °C. A further portion of Grubbs first
generation catalyst (0.070 g, 0.085 mmol) was added, and the reaction
mixture was stirred at 75 °C for 24 h. The reaction mixture was then
cooled to room temperature, and the solvent was evaporated.
Purification by flash column chromatography (petroleum ether/diethyl
ether 7:1) gave 1-(2′,2′,2′-trichloromethylcarbonylamino)-4-ethyl-1″-
enecyclopent-4-ene (11a) (0.66 g, 71%) as a yellow oil: Rf (50%
diethyl ether/petroleum ether) 0.81; IR (neat) 3320, 2930, 2855,
1690, 1508, 1236, 1065, 908, 818 cm−1; 1H NMR (500 MHz, CDCl3)
δ 1.66−1.74 (m, 1H), 2.35−2.52 (m, 2H), 2.54−2.62 (m, 1H), 4.92−
4.99 (m, 1H), 5.18 (d, 1H, J 10.5 Hz), 5.19 (d, 1H, J 17.6 Hz), 5.61 (d,
1H, J 1.7 Hz), 6.51 (dd, 1H, J 17.6, 10.5 Hz), 6.54 (br s, 1H) ppm; 13C
NMR (126 MHz, CDCl3) δ 29.4 (CH2), 31.0 (CH2), 57.8 (CH), 92.7
(C), 117.6 (CH2), 127.7 (CH), 132.4 (CH), 147.3 (C), 161.1 (C)
ppm; MS m/z 254 (MH+, 100), 220 (58), 184 (17), 132 (5), 85 (23),
69 (37); HRMS (CI) calcd for C9H1135Cl3NO (MH+), 253.9906,
found 253.9906.
(CH2), 122.0 (CH), 134.7 (CH), 139.6 (C), 161.3 (C) ppm; MS m/z
270 (MH+, 38), 236 (29), 200 (11), 146 (24), 113 (15), 73 (100);
HRMS (CI) calcd for C9H1135Cl3NO2 (MH+), 269.9855, found
269.9855.
3-(2′,2′,2′-Trichloromethylcarbonylamino)-1,2,3,6-tetrahy-
dro-1-(p-toluenesulfonyl)-5-ethyl-1″-enepyridine (11d). 3-
(2′,2′,2′-Trichloromethylcarbonylamino)-1,2,3,6-tetrahydro-1-(p-tol-
uenesulfonyl)-5-ethyl-1″-enepyridine (11d) was synthesized as
described for 11a using (2E)-4-(N-p-toluenesulfonyl-2′-
propynlamino)but-2-en-1-ol (4d) (0.074 g, 0.26 mmol). The allylic
trichloroacetimidate was dissolved in toluene (6 mL) containing
potassium carbonate (0.030 g) and purged with argon. The reaction
mixture was then heated to 140 °C and stirred for 5 days. The reaction
mixture was stirred with Hoveyda−Grubbs second generation catalyst
(0.011 g, 0.013 mmol) and 1,7-octadiene (0.15 mL, 1.0 mmol) at 90
°C for 24 h. Purification by flash column chromatography (petroleum
ether/diethyl ether, 1:1) gave 3-(2′,2′,2′-trichloromethylcarbonylami-
no)-1,2,3,6-tetrahydro-1-(p-toluenesulfonyl)-5-ethyl-1″-enepyridine
(11d) (0.044 g, 40%) as a colorless oil: Rf (50% diethyl ether/
petroleum ether) 0.55; IR (neat) 3335, 2922, 1705, 1597, 1499, 1454,
1
1346, 1240, 1161, 1090, 1022, 991, 815 cm−1; H NMR (500 MHz,
CDCl3) δ 2.45 (s, 1H), 2.82 (dd, 1H, J 12.4, 3.4 Hz), 3.33 (d, 1H, J
15.9 Hz), 3.72 (br d, 1H, J 12.4 Hz), 4.27 (d, 1H, J 15.9 Hz), 4.57−
4.64 (m, 1H), 5.20 (d, 1H, J 11.1 Hz), 5.25 (d, 1H, J 17.8 Hz), 5.82
(br d, 1H, J 5.7 Hz), 6.30 (dd, 1H, J 17.8, 11.1 Hz), 7.00 (br d, 1H, J
8.2 Hz), 7.37 (d, 2H, J 8.2 Hz), 7.72 (d, 2H, J 8.2 Hz) ppm; 13C NMR
(126 MHz, CDCl3) δ 21.6 (CH3), 44.3 (CH2), 45.6 (CH), 47.8
(CH2), 92.2 (C), 115.3 (CH2), 123.1 (CH), 127.7 (2 × CH), 130.0 (2
× CH), 132.9 (C), 135.1 (CH), 137.1 (C), 144.3 (C), 161.5 (C) ppm;
HRMS (ESI) calcd for C16H1735Cl3N2NaO3S (MNa+), 444.9918,
found 444.9905.
1-(2′,2′,2′-Trichloromethylcarbonylamino)-5-ethyl-1″-ene-
cyclohex-5-ene (11b). 1-(2′,2′,2′-Trichloromethylcarbonylamino)-
5-ethyl-1″-enecyclohex-5-ene (11b) was synthesized as described for
11a using (2E)-octa-2-en-7-yn-1-ol (4b) (0.050 g, 0.40 mmol). The
reaction mixture was stirred with Grubbs first generation catalyst
(0.024 g, 0.030 mmol) at 75 °C for 18 h. A further portion of Grubbs
first generation catalyst (0.010 g, 0.010 mmol) was added, and the
reaction mixture was stirred at 75 °C for 4 h. Purification by flash
column chromatography (petroleum ether/diethyl ether, 7:1) afforded
1-(2′,2′,2′-trichloromethylcarbonylamino)-5-ethyl-1′-enecyclohex-5-
ene (11b) (0.092 g, 86%) as a white solid: Rf (50% diethyl ether/
petroleum ether) 0.86; mp 77−79 °C; IR (neat) 3258, 2942, 1703,
Diethyl 1-(2′,2′,2′-trichloromethylcarbonylamino)-2,3-dihy-
droindene-6,7-dicarboxylate (13a). 1-(2′,2′,2′-Trichloromethyl-
carbonylamino)-4-ethyl-1″-enecyclopent-4-ene (11a) (0.084 g, 0.33
mmol) was dissolved in toluene (5 mL) and transferred to a
microwave vial containing anhydrous zinc chloride (0.041 g, 0.33
mmol) and hydroquinone (0.011 g, 0.010 mmol). To this, diethyl
acetylenedicarboxylate (0.16 mL, 0.99 mmol) was added with a silicon
carbide bar, and the tube was purged with argon and sealed. The
reaction mixture was stirred at 140 °C in a microwave reactor for 3 h.
The solution was then cooled to room temperature, and 2,3-dichloro-
5,6-dicyanobenzoquinone (0.17 g, 0.73 mmol) was added. The tube
was sealed and stirred at 115 °C in a microwave reactor for 2 h. The
solution was then cooled to room temperature, and the solvent was
evaporated. Purification by flash column chromatography (petroleum
ether/diethyl ether, 1:1) gave diethyl 1-(2′,2′,2′-trichloromethylcarbo-
nylamino)-2,3-dihydroindene-6,7-dicarboxylate (13a) (0.099 g, 71%)
as a yellow solid: Rf (50% diethyl ether/petroleum ether) 0.32; mp
108−110 °C; IR (neat) 3337, 2983, 2361, 1714, 1507, 1368, 1282,
1021 cm−1; 1H NMR (500 MHz, CDCl3) δ 1.37 (t, 6H, J 7.2 Hz), 2.17
(dtd, 1H, J 13.4, 8.9, 4.7 Hz), 2.62−2.72 (m, 1H), 2.99 (ddd, 1H, J
17.0, 8.9, 5.0 Hz), 3.13−3.22 (m, 1H, m), 4.32−4.45 (m, 4H), 5.52
(td, 1H, J 7.5, 4.7 Hz), 6.98 (br d, 1H, J 6.8 Hz), 7.42 (d, 1H, J 7.9
Hz), 7.94 (d, 1H, J 7.9 Hz) ppm; 13C NMR (126 MHz, CDCl3) δ 13.9
(CH3), 14.1 (CH3), 30.5 (CH2), 32.7 (CH2), 56.0 (CH), 61.6 (CH2),
62.2 (CH2), 92.4 (C), 126.2 (CH), 128.2 (C), 131.0 (CH), 132.5 (C),
138.4 (C), 149.9 (C), 161.2 (C), 165.7 (C), 167.7 (C) ppm; MS m/z
422 (MH+, 30), 376 (100), 342 (6), 261 (18), 214 (6), 187 (5);
HRMS (CI) calcd for C17H1935Cl237ClNO5 (MH+), 424.0302, found
424.0300.
1
1684, 1535, 1310, 1273, 1248, 1157, 1073, 993, 907, 824 cm−1; H
NMR (400 MHz, CDCl3) δ 1.57−1.68 (m, 1H), 1.70−1.83 (m, 2H),
1.96−2.07 (m, 1H), 2.16−2.26 (m, 2H), 4.53−4.63 (m, 1H), 5.10 (d,
1H, J 10.6 Hz), 5.26 (d, 1H, J 17.7 Hz), 5.65 (br s, 1H), 6.36 (dd, 1H,
J 17.7, 10.6 Hz), 6.60 (br s, 1H) ppm; 13C NMR (126 MHz, CDCl3) δ
19.4 (CH2), 23.5 (CH2), 28.7 (CH2), 47.7 (CH), 92.7 (C), 113.7
(CH2), 126.4 (CH), 138.6 (CH), 140.5 (C), 161.1 (C) ppm; MS m/z
268 (MH+, 68), 234 (38), 200 (9), 164 (3), 107 (100), 87 (22), 69
(33); HRMS (CI) calcd for C10H1335Cl3NO (MH+), 268.0063, found
268.0059.
1-(2′,2′,2′-Trichloromethylcarbonylamino)-5-ethyl-1″-ene-
1,4-dihydro-1H-pyran (11c). 1-(2′,2′,2′-Trichloromethylcarbonyla-
mino)-5-ethyl-1″-ene-1,4-dihydro-1H-pyran (11c) was synthesized as
described for 11a using (2E)-4-(2′-propynloxy)but-2-en-1-ol (4c)
(0.079 g, 0.62 mmol). The allylic trichloroacetimidate was dissolved in
toluene (15 mL) containing potassium carbonate (0.075 g) and
purged with argon. The reaction mixture was then heated to 140 °C in
a sealed tube for 5 days. The reaction mixture was then stirred with
Grubbs first generation catalyst (0.025 g, 0.030 mmol) and 1,7-
octadiene (0.37 mL, 2.49 mmol) at 90 °C for 18 h. A further portion
of Grubbs first generation catalyst (0.025 g, 0.030 mmol) and 1,7-
octadiene (0.37 mL, 2.49 mmol) was added, and the reaction mixture
was stirred at 90 °C for 24 h. Purification by flash column
chromatography (petroleum ether/diethyl ether, 4:1) gave 1-
(2′,2′,2′-trichloromethylcarbonylamino)-5-ethyl-1″-ene-1,4-dihydro-
1H-pyran (11c) (0.077 g, 46%) as a colorless oil: Rf (50% diethyl
ether/petroleum ether) 0.43; IR (neat) 3318, 2942, 2857, 1697, 1499,
Diethyl 1-(2′,2′,2′-trichloromethylcarbonylamino)-1,2,3,4-
tetrahydronaphthalene-7,8-dicarboxylate (13b). Diethyl 1-
(2′,2′,2′-trichloromethylcarbonylamino)-1,2,3,4-tetrahydronaphtha-
lene-7,8-dicarboxylate (13b) was synthesized as described for 13a
using 1-(2′,2′,2′-trichloromethylcarbonylamino)-5-ethyl-1″-enecyclo-
hex-5-ene (11b) (0.10 g, 0.37 mmol). Purification by flash column
chromatography (petroleum ether/diethyl ether, 11:9) gave diethyl 1-
(2′,2′,2′-trichloromethylcarbonylamino)-1,2,3,4-tetrahydronaphtha-
lene-7,8-dicarboxylate (13b) (0.095 g, 58%) as a yellow solid: Rf (50%
diethyl ether/petroleum ether) 0.49; mp 134−136 °C; IR (neat) 3318,
1
1454, 1236, 1117, 1071, 1028, 1011, 988, 910, 860, 758 cm−1; H
NMR (500 MHz, CDCl3) δ 3.76 (dd, 1H, J 11.9, 3.1 Hz), 3.92 (d, 1H,
J 11.9 Hz), 4.25 (d, 1H, J 15.9 Hz), 4.42−4.49 (m, 2H), 5.15 (d, 1H, J
17.9 Hz), 5.16 (d, 1H, J 11.1 Hz), 5.86 (d, 1H, J 5.1 Hz), 6.28 (dd, 1H,
J 17.9, 11.1 Hz), 6.94 (br d, 1H, J 5.6 Hz) ppm; 13C NMR (126 MHz,
CDCl3) δ 45.4 (CH), 65.2 (CH2), 68.4 (CH2), 92.5 (C), 114.5
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2940, 1690, 1597, 1520, 1366, 1258, 1134, 1011, 826 cm−1; H NMR
(500 MHz, CDCl3) δ 1.36 (t, 3H, J 7.2 Hz), 1.38 (t, 3H, J 7.2 Hz),
1.71−1.97 (m, 3H), 2.23−2.30 (m, 1H), 2.84 (ddd, 1H, J 17.7, 11.5,
6.2 Hz), 2.94−3.03 (m, 1H), 4.29−4.48 (m, 4H), 5.30 (dt, 1H, J 7.1,
3.5 Hz), 6.74 (d, 1H, J 7.1 Hz), 7.28 (d, 1H, J 8.1 Hz), 7.90 (d, 1H, J
8.1 Hz) ppm; 13C NMR (126 MHz, CDCl3) δ 13.9 (CH3), 14.2
(CH3), 17.3 (CH2), 27.8 (CH2), 29.6 (CH2), 46.4 (CH), 61.6 (CH2),
62.4 (CH2), 92.5 (C), 127.0 (C), 129.8 (CH), 130.7 (CH), 130.9 (C),
137.3 (C), 143.4 (C), 160.3 (C), 165.4 (C), 168.2 (C) ppm; MS m/z
438 (MH+, 73), 390 (100), 371 (77), 356 (70), 275 (25), 271 (18),
231 (11), 153 (10), 69 (70); HRMS (CI) calcd for
C18H2135Cl237ClNO5 (MH+), 438.0459, found 438.0456.
methyl 1-(2′,2′,2′-trichloromethylcarbonylamino)-2,3-dihydroindene-
7-carboxylate (13e) (0.075 g, 52%) as a red solid: Rf (50% diethyl
ether/petroleum ether) 0.57; mp 108−110 °C; IR (neat) 3279, 2949,
1
1
1711, 1689, 1533, 1432, 1290, 1136, 818 cm−1; H NMR (500 MHz,
CDCl3) δ 2.23 (ddt, 1H, J 14.0, 8.6, 2.4 Hz), 2.43 (dq, 1H, J 14.0, 8.6
Hz), 2.90 (ddd, 1H, J 16.4, 8.6, 2.4 Hz), 3.19 (dt, 1H, J 16.4, 8.6 Hz),
3.82 (s, 3H), 5.68 (td, 1H, J 8.6, 2.4 Hz), 6.90 (br d, 1H, J 5.1 Hz),
7.34 (t, 1H, J 7.6 Hz), 7.44 (d, 1H, J 7.6 Hz), 7.86 (d, 1H, J 7.6 Hz)
ppm; 13C NMR (126 MHz, CDCl3) δ 30.7 (CH2), 31.7 (CH2), 52.5
(CH), 57.4 (CH3), 92.9 (C), 127.4 (C), 129.3 (CH), 129.5 (CH),
129.6 (CH), 141.4 (C), 146.7 (C), 160.9 (C), 166.7 (C) ppm; MS m/
z 336 (MH+, 100), 302 (16), 257 (12), 175 (98), 137 (54), 121 (38),
81 (6); HRMS (CI) calcd for C13H1335Cl3NO3 (MH+), 335.9961,
found 335.9952.
Diethyl 4-(2′,2′,2′-trichloromethylcarbonylamino)-
isochroman-5,6-dicarboxylate (13c). Diethyl 4-(2′,2′,2′-
trichloromethylcarbonylamino)isochroman-5,6-dicarboxylate (13c)
was synthesized as described for 13a using 1-(2′,2′,2′-trichlorome-
thylcarbonylamino)-5-ethyl-1″-ene-1,4-dihydro-1H-pyran (11c)
(0.082 g, 0.30 mmol). Purification by flash column chromatography
(petroleum ether/ethyl acetate, 7:3) gave diethyl 4-(2′,2′,2′-
trichloromethylcarbonylamino)isochroman-5,6-dicarboxylate (13c)
(0.056 g, 42%) as a brown solid: Rf (50% ethyl acetate/petroleum
ether) 0.63; mp 141−143 °C; IR (neat) 3322, 2978, 2938, 1724, 1695,
Methyl 1-(2′,2′,2′-trichloromethylcarbonylamino)-1,2,3,4-
tetrahydronaphthalene-8-carboxylate (13f). Methyl 1-(2′,2′,2′-
trichloromethylcarbonylamino)-1,2,3,4-tetrahydronaphthalene-8-car-
boxylate (13f) was synthesized as described for 13e using 1-(2′,2′,2′-
trichloromethylcarbonylamino)-5-ethyl-1″-enecyclohex-5-ene (11b)
(0.10 g, 0.37 mmol). Purification by flash column chromatography
(petroleum ether/diethyl ether, 7:3) gave methyl 1-(2′,2′,2′-
trichloromethylcarbonylamino)-1,2,3,4-tetrahydronaphthalene-8-car-
boxylate (13f) (0.085 g, 66%) as a colorless solid: Rf (50% diethyl
ether/petroleum ether) 0.56; mp 133−135 °C; IR (neat) 3324, 2933,
1
1598, 1522, 1369, 1287, 1260, 1150, 1093, 822 cm−1; H NMR (500
MHz, CDCl3) δ 1.36 (t, 3H, J 7.4 Hz), 1.38 (t, 3H, J 7.4 Hz), 3.82 (dd,
1H, J 12.2, 2.2 Hz), 4.24 (br d, 1H, J 12.2 Hz), 4.30−4.40 (m, 3H),
4.42−4.51 (m, 1H), 4.78 (d, 1H, J 16.1 Hz), 4.95 (d, 1H, J 16.1 Hz),
5.22 (br d, 1H, J 7.8 Hz), 7.06 (br d, 1H, J 7.8 Hz), 7.21 (d, 1H, J 8.2
Hz), 7.98 (d, 1H, J 8.2 Hz) ppm; 13C NMR (126 MHz, CDCl3) δ 13.9
(CH3), 14.2 (CH3), 44.8 (CH), 61.8 (CH2), 62.6 (CH2), 67.9 (CH2),
69.2 (CH2), 92.2 (C), 125.7 (CH), 128.0 (C), 128.3 (C), 130.3 (CH),
137.0 (C), 140.2 (C), 160.7 (C), 165.0 (C), 167.4 (C) ppm; MS m/z
438 (MH+, 100), 404 (70), 398 (62), 370 (27), 251 (17), 113 (22), 73
(76); HRMS (CI) calcd for C17H1935Cl3NO6 (MH+), 438.0278, found
438.0275.
Diethyl 4-(2′,2′,2′-trichloromethylcarbonylamino)-1,2,3,4-
tetrahydro-2-(p-toluenesulfonyl)isoquinoline-5,6-dicarboxy-
late (13d). Diethyl 4-(2′,2′,2′-trichloromethylcarbonylamino)-1,2,3,4-
tetrahydro-2-(p-toluenesulfonyl)isoquinoline-5,6-dicarboxylate (13d)
was synthesized as described for 13a using 3-(trichloromethylcarbo-
nylamino)-1,2,3,6-tetrahydro-1-(p-toluenesulfonyl)-5-ethyl-1″-enepyri-
dine (11d) (0.090 g, 0.21 mmol). Purification by flash column
chromatography (petroleum ether/diethyl ether, 3:7) gave diethyl 4-
(2′,2′,2′-trichloromethylcarbonylamino)-1,2,3,4-tetrahydro-2-(p-
toluenesulfonyl)isoquinoline-5,6-dicarboxylate (13d) (0.060 g, 48%)
as a red solid: Rf (100% diethyl ether) 0.67; mp 172−174 °C; IR
(neat) 3323, 2988, 1716, 1507, 1267, 1164, 1018, 753 cm−1; 1H NMR
(500 MHz, CDCl3) δ 1.35 (t, 3H, J 7.2 Hz), 1.36 (t, 3H, J 7.2 Hz),
2.44 (m, 3H), 2.70 (dd, 1H, J 12.6, 2.4 Hz), 3.77 (d, 1H, J 15.8 Hz),
4.10 (br d, 1H, J 12.6 Hz), 4.27−4.48 (m, 4H), 4.85 (d, 1H, J 15.8
Hz), 5.43 (br d, 1H, J 8.5 Hz), 7.06 (d, 1H, J 8.5 Hz), 7.26 (d, 1H, J
8.0 Hz), 7.35 (d, 2H, J 8.2 Hz), 7.73 (d, 2H, J 8.2 Hz), 7.97 (d, 1H, J
8.0 Hz) ppm; 13C NMR (126 MHz, CDCl3) δ 13.9 (CH3), 14.1
(CH3), 21.6 (CH3), 45.5 (CH), 47.9 (CH2), 48.6 (CH2), 61.9 (CH2),
62.7 (CH2), 92.0 (C), 127.7 (CH), 127.9 (2 × CH), 128.3 (C), 128.6
(C), 130.1 (2 × CH), 130.4 (CH), 132.3 (C), 137.2 (C), 137.7 (C),
144.6 (C), 161.0 (2 × C), 167.2 (C) ppm; HRMS (ESI) calcd for
C24H2435Cl3N2O7S (M−H−), 589.0375, found 589.0371.
1
1726, 1695, 1517, 1431, 1285, 1262, 1137, 754 cm−1; H NMR (500
MHz, CDCl3) δ 1.72−1.82 (m, 1H), 1.85−1.98 (m, 2H), 2.15−2.22
(m, 1H), 2.84 (ddd, 1H, J 17.1, 10.7, 5.8 Hz), 2.94 (dt, 1H, J 17.1, 4.6
Hz), 3.87 (s, 3H), 5.77 (dt, 1H, J 6.3, 4.3 Hz), 6.68 (d, 1H, J 6.3 Hz),
7.30−7.34 (m, 2H), 7.86 (dd, 1H, J 6.0, 3.1 Hz) ppm; 13C NMR (126
MHz, CDCl3) δ 18.1 (CH2), 28.5 (CH2), 29.8 (CH2), 46.8 (CH3),
52.6 (CH), 92.8 (C), 128.0 (CH), 129.2 (CH), 131.8 (C), 133.4
(CH), 133.7 (C), 139.2 (C), 160.4 (C), 168.1 (C) ppm; HRMS (ESI)
calcd for C14H1435Cl3NNaO3 (MNa+), 371.9931, found 371.9925.
1-(2′,2′,2′-Trichloromethylcarbonylamino)-1,2,3-
trihydrocyclopent[a]naphthalene-6,9-dione (14a). 1-(2′,2′,2′-
Trichloromethylcarbonylamino)-4-ethyl-1″-enecyclopent-5-ene (11a)
(0.071 g, 0.28 mmol) was dissolved in toluene (10 mL) and p-
benzoquinone (0.034 g, 0.37 mmol) was added. The reaction mixture
was stirred at 115 °C for 72 h. The solution was then cooled to room
temperature, and manganese oxide (0.244 g, 2.80 mmol) was added
with a silicon carbide bar. The mixture was stirred at 115 °C in a
microwave reactor for 2 h. The solution was then cooled to room
temperature, and the solvent was evaporated under a vacuum.
Purification by flash column chromatography (petroleum ether/diethyl
ether, 1:1) gave 1-(2′,2′,2′-trichloromethylcarbonylamino)-1,2,3-
trihydrocyclopent[a]naphthalene-6,9-dione (14a) (0.076 g, 75%) as
a yellow solid: Rf (50% diethyl ether/petroleum ether) 0.35; mp 153−
155 °C; IR (neat) 3350, 2926, 1688, 1663, 1510, 1298, 1078, 820
cm−1; 1H NMR (500 MHz, CDCl3) δ 2.48−2.61 (m, 2H), 3.03 (ddd,
1H, J 17.4, 8.7, 2.8 Hz), 3.52 (dt, 1H, J 17.4, 8.7 Hz), 5.62 (ddd, 1H, J
8.7, 6.4, 2.8 Hz), 6.90 (d, 1H, J 10.3 Hz), 6.96 (d, 1H, J 10.3 Hz), 7.47
(br d, 1H, J 6.4 Hz), 7.67 (d, 1H, J 7.9 Hz), 8.11 (d, 1H, J 7.9 Hz)
ppm; 13C NMR (126 MHz, CDCl3) δ 30.5 (CH2), 31.5 (CH2), 57.2
(CH), 92.9 (C), 127.9 (C), 128.3 (CH), 130.3 (CH), 131.9 (C),
138.3 (CH), 138.8 (CH), 140.7 (C), 154.2 (C), 161.0 (C), 184.4 (C),
186.2 (C) ppm; HRMS (ESI) calcd for C15H1035Cl237ClNNaO3
(MNa+), 381.9589, found 381.9578.
Methyl 1-(2′,2′,2′-trichloromethylcarbonylamino)-2,3-dihy-
droindene-7-carboxylate (13e). 1-(2′,2′,2′-Trichloromethylcarbo-
nylamino)-4-ethyl-1″-enecyclopent-4-ene (11a) (0.11 g, 0.43 mmol)
was dissolved in toluene (6 mL) and transferred to a Schlenk tube
containing anhydrous zinc chloride (0.059 g, 0.43 mmol) and
hydroquinone (0.014 g, 0.13 mmol). Methyl propiolate (0.12 mL,
1.29 mmol) was added, and the tube was purged with argon. The
reaction mixture was stirred at 140 °C for 9 days. The solution was
then cooled to room temperature, and 2,3-dichloro-5,6-dicyanobenzo-
quinone (0.21 g, 0.95 mmol) was added. The tube was resealed under
argon and stirred at 115 °C for 24 h. The solution was cooled to room
temperature, and the solvent was then evaporated. Purification by flash
column chromatography (petroleum ether/diethyl ether, 12:9) gave
1-(2′,2′,2′-Trichloromethylcarbonylamino)-1,2,3,4-
tetrahydrobenz[a]naphthalene-7,10-dione (14b). 1-(2′,2′,2′-Tri-
chloromethylcarbonylamino)-1,2,3,4-tetrahydrobenz[a]naphthalene-
7,10-dione (14b) was synthesized as described for 14a using 1-
(2′,2′,2′-trichloromethylcarbonylamino)-5-ethyl-1″-enecyclohex-5-ene
(11b) (0.070 g, 0.34 mmol). Purification by flash column
chromatography (petroleum ether/diethyl ether, 5:4) gave 1-
(2′,2′,2′-trichloromethylcarbonylamino)-1,2,3,4-tetrahydrobenz[a]-
naphthalene-7,10-dione (14b) (0.084 g, 66%) as a yellow solid: Rf
(50% diethyl ether/petroleum ether) 0.30; mp 165−167 °C; IR (neat)
1
3345, 2947, 1709, 1663, 1586, 1512, 1304, 1096, 822 cm−1; H NMR
(400 MHz, CDCl3) δ 1.80−1.97 (m, 3H), 2.33−2.47 (m, 1H), 2.89−
3.00 (m, 1H), 3.04−3.14 (m, 1H), 5.90−5.96 (m, 1H), 6.76 (br d, 1H,
7204
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J 6.4 Hz), 6.88 (d, 1H, J 10.2 Hz), 6.92 (d, 1H, J 10.2 Hz), 7.57 (d, 1H,
J 8.1 Hz), 8.09 (d, 1H, J 8.1 Hz) ppm; 13C NMR (126 MHz, CDCl3) δ
17.8 (CH2), 27.9 (CH2), 30.7 (CH2), 47.1 (CH), 92.9 (C), 126.9
(CH), 129.6 (C), 132.5 (C), 135.2 (C), 135.3 (CH), 136.4 (CH),
140.4 (CH), 146.3 (C), 160.5 (C), 184.8 (C), 186.4 (C) ppm; MS m/
z 372 (MH+, 36), 338 (30), 304 (10), 268 (15), 243 (84), 229 (100),
213 (60), 162 (75), 128 (40); HRMS (CI) calcd for C16H1335Cl3NO3
(MH+), 371.9961, found 371.9960.
1.75−1.92 (m, 3H), 2.37−2.46 (m, 2H), 2.85−2.95 (m, 1H), 3.04 (dt,
1H, J 17.7, 4.7 Hz), 5.85−5.90 (m, 1H), 6.73 (s, 1H), 6.75 (d, 1H, J
5.9 Hz), 7.50 (d, 1H, J 8.1 Hz), 8.07 (d, 1H, J 8.1 Hz) ppm; 13C NMR
(126 MHz, CDCl3) δ 17.9 (CH2), 27.8 (CH2), 29.2 (3 × CH3), 30.5
(CH2), 35.1 (C), 47.2 (CH), 93.1 (C), 127.3 (CH), 129.4 (C), 134.3
(C), 134.4 (C), 134.9 (CH), 135.5 (CH), 145.4 (C), 156.3 (C), 160.4
(C), 184.7 (C), 187.1 (C) ppm; MS m/z 428 (MH+, 5), 408 (6), 370
(29), 285 (100), 162 (58), 128 (48), 71 (31); HRMS (CI) calcd for
C20H2135Cl3NO3 (MH+), 428.0587, found 428.0584.
4-(2′,2′,2′-Trichloromethylcarbonylamino)-1,2,3,4-tetrahy-
dro-2-(p-toluenesulfonyl)benzo[f ]isoquinoline-5,8-dione
(14c). 4-(2′,2′,2′-Trichloromethylcarbonylamino)-1,2,3,4-tetrahydro-
2-(p-toluenesulfonyl)benzo[f]isoquinoline-5,8-dione (14c) was syn-
thesized as described for 14a using 3-(trichloromethylcarbonylamino)-
1,2,3,6-tetrahydro-1-(p-toluenesulfonyl)-5-ethyl-1″-enepyridine (11d)
(0.075 g, 0.18 mmol). The reaction mixture was stirred at 115 °C for
72 h. The solution was then cooled to room temperature, and 2,3-
dichloro-5,6-dicyanobenzoquinone (0.088 g, 0.39 mmol) and a silicon
carbide bar were added. The mixture was stirred at 115 °C in a
microwave reactor for 2 h. Purification by flash column chromatog-
raphy (petroleum ether/ethyl acetate, 3:1) gave 4-(2′,2′,2′-trichlor-
omethylcarbonylamino)-1,2,3,4-tetrahydro-2-(p-toluenesulfonyl)-
benzo[f ]isoquinoline-5,8-dione (14c) (0.045 g, 48%) as a brown solid:
Rf (50% ethyl acetate/petroleum ether) 0.51; mp 192−194 °C; IR
(neat) 3329, 2924, 1707, 1663, 1593, 1508, 1303, 1165, 1096, 1071,
961, 816 cm−1; 1H NMR (500 MHz, CDCl3) δ 2.44 (s, 3H), 2.77 (dd,
1H, J 12.6, 2.8 Hz), 3.94 (d, 1H, J 16.1 Hz), 4.12 (ddd, 1H, J 12.6, 2.8,
1.7 Hz), 4.85 (d, 1H, J 16.1 Hz), 6.07 (dt, 1H, J 7.6, 2.8 Hz), 6.91−
6.97 (m, 3H), 7.38 (d, 2H, J 8.2 Hz), 7.55 (d, 1H, J 8.2 Hz), 7.75 (d,
2H, J 8.2 Hz), 8.18 (d, 1H, J 8.2 Hz) ppm; 13C NMR (126 MHz,
CDCl3) δ 21.6 (CH3), 46.5 (CH), 48.2 (CH2), 48.4 (CH2), 92.3 (C),
127.7 (CH), 127.9 (2 × CH), 129.6 (C), 130.1 (2 × CH), 132.4
(CH), 132.4 (C), 133.1 (2 × C), 136.7 (CH), 140.3 (CH), 140.5 (C),
144.5 (C), 161.1 (C), 184.2 (C), 185.6 (C) ppm; HRMS (ESI) calcd
for C22H1735Cl3N2NaO5S (MNa+), 548.9816, found 548.9813.
7-tert-Butyl-4-(2′,2′,2′-trichloromethylcarbonylamino)-1,3-
dihydro-4H-benzo[f ]isochromene-5,8-dione (14f). 7-tert-Butyl-
4-(2′,2′,2′-trichloromethylcarbonylamino)-1,3-dihydro-4H-benzo[f ]-
isochromene-5,8-dione (14f) was synthesized as described for 14a
using 1-(2′,2′,2′-trichloromethylcarbonylamino)-5-ethyl-1″-ene-1,4-di-
hydro-1H-pyran (11c) (0.070 g, 0.26 mmol) and 2-tert-butyl-p-
benzoquinone (0.051 g, 0.31 mmol). The solution was then cooled to
room temperature, and 2,3-dichloro-5,6-dicyanobenzoquinone (0.129
g, 0.57 mmol) and a silicon carbide bar were added. The mixture was
stirred at 115 °C in a microwave reactor for 2 h. Purification by flash
column chromatography (petroleum ether/diethyl ether, 11:9) gave 7-
tert-butyl-4-(2′,2′,2′-trichloromethylcarbonylamino)-1,3-dihydro-4H-
benzo[f ]isochromene-5,8-dione (14f) (0.064 g, 57%) as a yellow
solid: Rf (50% diethyl ether/petroleum ether) 0.24; mp 192−194 °C;
IR (neat) 3379, 2969, 1708, 1661, 1592, 1513, 1274, 1250, 1091, 908,
819 cm−1; 1H NMR (500 MHz, CDCl3) δ 1.34 (s, 9H), 3.79 (dd, 1H,
J 12.3, 2.3 Hz), 4.34 (dd, 1H, J 12.3, 1.2 Hz), 4.85 (d, 1H, J 16.2 Hz),
5.00 (d, 1H, J 16.2 Hz), 5.78 (br d, 1H, J 7.4 Hz), 6.77 (s, 1H), 6.90
(d, 1H, J 7.4 Hz), 7.44 (d, 1H, J 8.1 Hz), 8.17 (d, 1H, J 8.1 Hz) ppm;
13C NMR (126 MHz, CDCl3) δ 29.2 (3 × CH3), 35.4 (C), 45.9 (CH),
68.3 (CH2), 68.9 (CH2), 92.6 (C), 127.9 (CH), 129.1 (C), 130.0
(CH), 130.6 (C), 134.5 (C), 135.4 (CH), 142.1 (C), 156.6 (C), 161.0
(C), 184.3 (C), 186.4 (C) ppm; MS m/z 430 (MH+, 43), 396 (21),
287 (20), 245 (37), 207 (32), 162 (95), 128 (62), 85 (65), 73 (100);
HRMS (CI) calcd for C19H1935Cl3NO4 (MH+), 430.0380, found
430.0370.
7-tert-Butyl-1-(2′,2′,2′-trichloromethylcarbonylamino)-
1,2,3-trihydrocyclopent[a]naphthalene-6,9-dione (14d). 7-tert-
Butyl-1-(2′,2′,2′-trichloromethylcarbonylamino)-1,2,3-
trihydrocyclopent[a]naphthalene-6,9-dione (14d) was synthesized as
described for 14a using 1-(2′,2′,2′-trichloromethylcarbonylamino)-4-
ethyl-1″-enecyclopent-4-ene (11a) (0.071 g, 0.28 mmol) and 2-tert-
butyl-p-benzoquinone (0.054 g, 0.33 mmol). Purification by flash
column chromatography (petroleum ether/diethyl ether, 7:3) gave 7-
tert-butyl-1-(2′,2′,2′-trichloromethylcarbonylamino)-1,2,3-
trihydrocyclopent[a]naphthalene-6,9-dione (14d) (0.079 g, 68%) as a
yellow solid: Rf (50% diethyl ether/petroleum ether) 0.53; mp 198−
200 °C; IR (neat) 3325, 2954, 1680, 1661, 1597, 1504, 1290, 1250,
7-tert-Butyl-4-(2′,2′,2′-trichloromethylcarbonylamino)-
1,2,3,4-tetrahydro-2-(p-toluenesulfonyl)benzo[f ]isoquinoline-
5,8-dione (14g). 7-tert-Butyl-4-(2′,2′,2′-trichloromethylcarbonylami-
no)-1,2,3,4-tetrahydro-2-(p-toluenesulfonyl)benzo[f ]isoquinoline-5,8-
dione (14g) was synthesized as described for 14a using 3-
(trichloromethylcarbonylamino)-1,2,3,6-tetrahydro-1-(p-toluenesul-
fonyl)-5-ethyl-1″-enepyridine (11d) (0.091 g, 0.21 mmol) and 2-tert-
butyl-p-benzoquinone (0.083 g, 0.51 mmol). The solution was then
cooled to room temperature, and 2,3-dichloro-5,6-dicyanobenzoqui-
none (0.252 g, 1.11 mmol) and a silicon carbide bar were added. The
mixture was stirred at 115 °C in a microwave reactor for 3 h.
Purification by flash column chromatography (petroleum ether/ethyl
acetate, 3:1) gave 7-tert-butyl-4-(2′,2′,2′-trichloromethylcarbonylami-
no)-1,2,3,4-tetrahydro-2-(p-toluenesulfonyl)benzo[f ]isoquinoline-5,8-
dione (14g) (0.056 g, 44%) as a yellow solid: Rf (50% ethyl acetate/
petroleum ether) 0.53; mp 187−189 °C; IR (neat) 3335, 2959, 1717,
1
1068, 910, 816 cm−1; H NMR (500 MHz, CDCl3) δ 1.36 (s, 9H),
2.48−2.57 (m, 2H), 3.00 (ddd, 1H, J 17.1, 7.8, 3.7 Hz), 3.49 (dt, 1H, J
17.1, 8.8 Hz), 5.54−5.61 (m, 1H), 6.77 (s, 1H), 7.50 (d, 1H, J 5.5 Hz),
7.63 (d, 1H, J 7.9 Hz), 8.11 (d, 1H, J 7.9 Hz) ppm; 13C NMR (126
MHz, CDCl3) δ 29.4 (3 × CH3), 30.4 (CH2), 31.4 (CH2), 35.7 (C),
57.1 (CH), 92.9 (C), 127.5 (C), 128.8 (CH), 130.1 (CH), 133.5 (C),
134.1 (CH), 139.8 (C), 153.4 (C), 158.1 (C), 161.0 (C), 184.4 (C),
187.0 (C) ppm; MS m/z 413 (M+, 12), 378 (57), 268 (30), 252 (100),
237 (41), 185 (23), 165 (22), 143 (13), 115 (22), 84 (79), 49 (76);
HRMS (EI) calcd for C19H1835Cl3NO3 (M+), 413.0352, found
413.0354.
1
1655, 1522, 1454, 1339, 1254, 1161, 964, 818 cm−1; H NMR (500
MHz, CDCl3) δ 1.33 (s, 9H), 2.44 (s, 3H), 2.75 (dd, 1H, J 12.6, 2.8
Hz), 3.92 (d, 1H, J 16.0 Hz), 4.12 (ddd, 1H, J 12.6, 2.8, 1.7 Hz), 4.83
(d, 1H, J 16.0 Hz), 6.04 (dt, 1H, J 7.4, 2.8 Hz), 6.76 (s, 1H), 6.92 (d,
1H, J 7.4 Hz), 7.37 (d, 2H, J 8.4 Hz), 7.50 (d, 1H, J 8.2 Hz), 7.75 (d,
2H, J 8.4 Hz), 8.16 (d, 1H, J 8.2 Hz) ppm; 13C NMR (126 MHz,
CDCl3) δ 21.6 (CH3), 29.2 (3 × CH3), 35.4 (C), 46.5 (CH), 48.2
(CH2), 48.3 (CH2), 92.4 (C), 127.9 (2 × CH), 128.1 (CH), 129.2
(C), 130.1 (2 × CH), 130.9 (C), 132.0 (CH), 132.5 (C), 134.8 (C),
135.5 (CH), 139.6 (C), 144.5 (C), 156.6 (C), 161.1 (C), 184.1 (C),
186.3 (C) ppm; HRMS (ESI) calcd for C26H2535Cl237ClN2NaO5S
(MNa+), 607.0412, found 607.0414.
1-(2′,2′,2′-Trichloromethylcarbonylamino)-1,2,3,4-
tetrahydrobenz[a]anthracene-7,12-dione (14h). 1-(2′,2′,2′-Tri-
chloromethylcarbonylamino)-1,2,3,4-tetrahydrobenz[a]anthracene-
7,12-dione (14h) was synthesized as described for 14a using 1-
(2′,2′,2′-trichloromethylcarbonylamino)-5-ethyl-1″-enecyclohex-5-ene
(11b) (0.036 g, 0.14 mmol) and 1,4-naphthoquinone (0.042 g, 0.20
mmol). The reaction mixture was then cooled to room temperature,
8-tert-Butyl-1-(2′,2′,2′-trichloromethylcarbonylamino)-
1,2,3,4-tetrahydrobenz[a]naphthalene-7,10-dione (14e). 8-tert-
Butyl-1-(2′,2′,2′-trichloromethylcarbonylamino)-1,2,3,4-
tetrahydrobenz[a]naphthalene-7,10-dione (14e) was synthesized as
described for 14a using 1-(2′,2′,2′-trichloromethylcarbonylamino)-5-
ethyl-1″-enecyclohex-5-ene (11b) (0.10 g, 0.37 mmol) and 2-tert-
butyl-p-benzoquinone (0.073 g, 0.47 mmol). Purification by flash
column chromatography (petroleum ether/diethyl ether, 7:3) gave 8-
tert-butyl-1-(2′,2′,2′-trichloromethylcarbonylamino)-1,2,3,4-
tetrahydrobenz[a]naphthalene-7,10-dione (14e) (0.092 g, 58%) as a
yellow solid: Rf (50% diethyl ether/petroleum ether) 0.61; mp 128−
130 °C; IR (neat) 3225, 2957, 1705, 1661, 1607, 1541, 1341, 1252,
1
1121, 1078, 816 cm−1; H NMR (500 MHz, CDCl3) δ 1.34 (s, 9H),
7205
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and 2,3-dichloro-5,6-dicyanobenzoquinone (0.13 g, 0.60 mmol) and a
silicon carbide bar were added. The mixture was stirred at 115 °C in a
microwave reactor for 4 h. Purification by flash column chromatog-
raphy (petroleum ether/diethyl ether, 13:7) gave 1-(2′,2′,2′-
trichloromethylcarbonylamino)-1,2,3,4-tetrahydrobenz[a]anthracene-
7,12-dione (14h) (0.034 g, 54%) as a colorless solid: Rf (50% diethyl
ether/petroleum ether) 0.48; mp 180−182 °C; IR (neat) 3335, 2922,
5,6,7,8-tetrahydroquinoline-2-carboxylate (15c) (0.030 g, 40%) as a
colorless oil: Rf (50% diethyl ether/petroleum ether) 0.23; IR (neat)
1
3345, 2926, 2361, 1707, 1506, 1314, 1258, 1086, 1024, 820 cm−1; H
NMR (400 MHz, CDCl3) δ 1.40 (t, 1H, J 7.1 Hz), 1.62 (dtd, 1H, J
12.7, 11.3, 4.7 Hz), 1.93−2.09 (m, 2H), 2.85−3.02 (m, 2H), 4.37 (dq,
1H, J 10.8, 7.1 Hz), 4.45 (dq, 1H, J 10.8, 7.1 Hz), 4.79 (dt, 1H, J 10.9,
4.7 Hz), 7.62 (d, 1H, J 7.9 Hz), 8.01 (d, 1H, J 7.9 Hz), 8.48 (br s, 1H)
ppm; 13C NMR (101 MHz, CDCl3) δ 14.2 (CH3), 19.8 (CH2), 27.6
(CH2), 27.8 (CH2), 53.0 (CH), 61.7 (CH2), 92.9 (C), 124.1 (CH),
136.8 (C), 138.1 (CH), 145.3 (C), 154.1 (C), 162.1 (C), 164.9 (C)
ppm; HRMS (ESI) calcd for C14H1535Cl3N2NaO3 (MNa+), 387.0040,
found 387.0036.
1
2361, 1701, 1668, 1589, 1501, 1327, 1290, 818 cm−1; H NMR (400
MHz, CDCl3) δ 1.86−1.97 (m, 3H), 2.37−2.47 (m, 1H), 2.91−3.03
(m, 1H), 3.05−3.17 (m, 1H), 6.00−5.96 (m, 1H), 6.79 (br d, 1H, J 6.3
Hz), 7.59 (d, 1H, J 8.2 Hz), 7.73−7.79 (m, 2H), 8.20−8.27 (m, 2H),
8.32 (d, 1H, J 8.2 Hz) ppm; 13C NMR (126 MHz, CDCl3) δ 17.8
(CH2), 28.1 (CH2), 30.9 (CH2), 47.6 (CH), 93.0 (C), 126.5 (CH),
127.6 (CH), 127.7 (CH), 131.6 (C), 132.2 (C), 133.7 (CH), 134.2
(C), 134.4 (CH), 134.9 (C), 135.5 (CH), 135.8 (C), 146.5 (C), 160.6
(C), 183.1 (C), 184.6 (C) ppm; HRMS (ESI) calcd for
C20H1435Cl3NNaO3 (MNa+), 443.9931, found 443.9919.
7-(2′,2′,2′-Trichloromethylcarbonylamino)-6,7-dihydro-2-(p-
toluenesulfonyl)-5H-cyclopenta[b]pyridine (15a). 1-(2′,2′,2′-Tri-
chloromethylcarbonylamino)-4-ethyl-1″-enecyclopent-4-ene (11a)
(0.024 g, 0.094 mmol) was dissolved in p-xylene (4 mL) and
transferred to a sealable vial containing anhydrous zinc chloride (0.013
g, 0.094 mmol) and hydroquinone (0.001 g, 0.0094 mmol). p-
Toluenesulfonyl cyanide (0.026 g, 0.14 mmol) was added, and the vial
was purged with argon and sealed. The reaction mixture was stirred at
125 °C for 24 h. The solution was then cooled to room temperature,
and the solvent was evaporated. Purification by flash column
chromatography (petroleum ether/ethyl acetate, 1:1) gave 7-
(2′,2′,2′-trichloromethylcarbonylamino)-6,7-dihydro-2-(p-toluenesul-
fonyl)-5H-cyclopenta[b]pyridine (15a) (0.024 g, 58%) as a green
solid: Rf (50% diethyl ether/petroleum ether) 0.45; mp 124−126 °C;
IR (neat) 3335, 2926, 1699, 1518, 1420, 1302, 1144, 1076, 816 cm−1;
1H NMR (500 MHz, CDCl3) δ 1.91−2.05 (m, 1H), 2.41 (s, 3H),
2.91−3.10 (m, 3H), 5.10−5.18 (m, 1H), 7.19 (br d, 1H, J 4.6 Hz),
7.30 (d, 2H, J 8.2 Hz), 7.84 (d, 1H, J 8.1 Hz), 7.93 (d, 2H, J 8.2 Hz),
8.09 (d, 1H, J 8.1 Hz) ppm; 13C NMR (101 MHz, CDCl3) δ 21.7
(CH3), 28.0 (CH2), 32.4 (CH2), 56.2 (CH), 92.3 (C), 121.4 (CH),
129.2 (2 × CH), 129.7 (2 × CH), 134.5 (CH), 135.6 (C), 141.0 (C),
144.9 (C), 158.1 (C), 161.9 (C), 162.6 (C) ppm; HRMS (ESI) calcd
for C17H1535Cl3N2NaO3S (MNa+), 454.9761, found 454.9747.
8-(2′,2′,2′-Trichloromethylcarbonylamino)-5,6,7,8-tetrahy-
dro-2-(p-toluenesulfonyl)quinoline (15b). 8-(2′,2′,2′-Trichloro-
methylcarbonylamino)-5,6,7,8-tetrahydro-2-(p-toluenesulfonyl)-
quinolone (15b) was synthesized as described for 15a using 1-
(2′,2′,2′-trichloromethylcarbonylamino)-5-ethyl-1′-enecyclohex-5-ene
(11b) (0.035 g, 0.13 mmol) and p-toluenesulfonyl cyanide (0.035 g,
0.20 mmol). The reaction mixture was heated at 160 °C for 18 h.
Purification by flash column chromatography (petroleum ether/ethyl
acetate, 11:9) gave 8-(2′,2′,2′-trichloromethylcarbonylamino)-5,6,7,8-
tetrahydro-2-(p-toluenesulfonyl)quinoline (15b) (0.030 g, 54%) as a
colorless solid: Rf (50% ethyl acetate/petroleum ether) 0.44; mp 85−
87 °C; IR (neat) 3335, 2926, 1705, 1510, 1316, 1155, 1078, 814 cm−1;
1H NMR (500 MHz, CDCl3) δ 1.59 (qd, 1H, J 11.5, 4.2 Hz), 1.97−
8-(2′,2′,2′-Trichloromethylcarbonylamino)-2-(dichlorometh-
yl)-5,6,7,8-tetrahydroquinoline (15d). 8-(2′,2′,2′-Trichloromethyl-
carbonylamino)-2-(dichloromethyl)-5,6,7,8-tetrahydroquinoline (15d)
was synthesized as described for 15a using 1-(2′,2′,2′-trichlorome-
thylcarbonylamino)-5-ethyl-1′-enecyclohex-5-ene (11b) (0.035 g, 0.13
mmol) and trichloroacetonitrile (0.078 mL, 0.78 mmol). The reaction
mixture was heated at 160 °C for 18 h. Purification by flash column
chromatography (petroleum ether/diethyl ether, 2:1) gave 8-(2′,2′,2′-
trichloromethylcarbonylamino)-2-(dichloromethyl)-5,6,7,8-tetrahydro-
quinoline (15d) (0.043 g, 67%) as a colorless oil: Rf (50% diethyl
ether/petroleum ether) 0.49; IR (neat) 3343, 2930, 2361, 1705, 1503,
1
1462, 1408, 1256, 1215, 1088, 926, 818 cm−1; H NMR (500 MHz,
CDCl3) δ 1.62−1.72 (m, 1H), 1.87−2.08 (m, 2H), 2.75−2.83 (m,
1H), 2.84−2.95 (m, 2H), 4.81 (dt, 1H, J 10.5, 5.3 Hz), 6.67 (s, 1H),
7.60 (d, 1H, J 8.1 Hz), 7.65 (d, 1H, J 8.1 Hz), 8.01 (br s, 1H) ppm;
13C NMR (126 MHz, CDCl3) δ 19.9 (CH2), 27.7 (CH2), 27.9 (CH2),
52.6 (CH), 71.2 (CH), 92.9 (C), 120.2 (CH), 134.1 (C), 138.9 (CH),
153.0 (C), 155.1 (C), 162.1 (C) ppm; HRMS (ESI) calcd for
C12H1135Cl5N2NaO (MNa+), 396.9206, found 396.9191.
7-(2′,2′,2′-Trichloromethylcarbonylamino)-5,6-
dihydrocyclopenta[c]pyridazine (16a). 1-(2′,2′,2′-Trichlorome-
thylcarbonylamino)-4-ethyl-1″-enecyclopent-4-ene (11a) (0.13 g,
0.41 mmol) was dissolved in toluene (10 mL), and di-tert-butyl
azodicarboxylate (0.15 g, 0.63 mmol) was added. The reaction mixture
was stirred at 115 °C for 18 h. The solution was then cooled to room
temperature, and the solvent was then evaporated. Purification by flash
column chromatography (petroleum ether/diethyl ether, 3:2) gave a
colorless oil. The oil was dissolved in degassed chloroform (12 mL)
and cooled to 0 °C. Bromine (0.10 mL, 2.03) was then added
dropwise. The ice bath was then removed, and the mixture was stirred
for 3 h as the reaction was allowed to warm to room temperature. The
reaction mixture was quenched with a 10% aqueous solution of sodium
sulfite (15 mL), stirred for 0.5 h, and then basified with a saturated
solution of sodium hydrogencarbonate (30 mL). The aqueous layer
was then extracted with chloroform (4 × 75 mL). The organic layers
were combined, dried (MgSO4) and concentrated to give a yellow oil.
Purification by flash column chromatography (dichloromethane/
methanol, 25:1) gave 7-(2′,2′,2′-trichloromethylcarbonylamino)-5,6-
dihydrocyclopenta[c]pyridazine (16a) (0.072 g, 51%) as a brown oil:
1
IR (neat) 3327, 2955, 1695, 1518, 1393 1263, 820 cm−1; H NMR
(400 MHz, CDCl3) δ 1.91−2.05 (m, 1H), 2.87−3.12 (m, 3H), 5.32
(td, 1H, J 8.5, 5.2 Hz), 7.36 (d, 1H, J 5.1 Hz), 7.74 (br s, 1H), 8.97 (d,
1H, J 5.1 Hz) ppm; 13C NMR (101 MHz, CDCl3) δ 28.2 (CH2), 31.8
(CH2), 56.0 (CH), 92.1 (C), 123.3 (CH), 142.0 (C), 150.6 (CH),
162.4 (C), 164.3 (C) ppm; HRMS (ESI) calcd for C9H835Cl3N3NaO
(MNa+), 301.9625, found 301.9631.
2.05 (m, 2H), 2.42 (s, 3H), 2.75 (dq, 1H, J 11.5, 4.8 Hz), 2.85−2.97
(m, 2H), 4.76 (dt, 1H, J 11.5, 4.8 Hz), 7.31 (d, 2H, J 8.2 Hz), 7.69 (d,
1H, J 8.0 Hz), 7.76 (br d, 1H, J 3.8 Hz), 7.91 (d, 2H, J 8.2 Hz), 8.09
(d, 1H, J 8.0 Hz) ppm; 13C NMR (126 MHz, CDCl3) δ 19.8 (CH2),
21.7 (CH3), 27.7 (CH2), 27.9 (CH2), 52.7 (CH), 92.6 (C), 120.8
(CH), 129.1 (2 × CH), 129.8 (2 × CH), 135.5 (C), 137.2 (C), 139.0
(CH), 145.0 (C), 155.4 (C), 156.2 (C), 161.9 (C); HRMS (ESI) calcd
for C18H1835Cl3N2O3S (MH+), 447.0098, found 447.0093.
Ethyl 8-(2′,2′,2′-trichloromethylcarbonylamino)-5,6,7,8-tet-
rahydroquinoline-2-carboxylate (15c). Ethyl 8-(2′,2′,2′-trichlor-
omethylcarbonylamino)-5,6,7,8-tetrahydroquinoline-2-carboxylate
(15c) was synthesized as described for 15a using 1-(2′,2′,2′-
trichloromethylcarbonylamino)-5-ethyl-1′-enecyclohex-5-ene (11b)
(0.056 g, 0.21 mmol) and ethyl cyanoformate (0.12 mL, 1.25
mmol). The reaction mixture was heated at 160 °C for 72 h.
Purification by flash column chromatography (petroleum ether/diethyl
ether, 1:1) gave ethyl 8-(2′,2′,2′-trichloromethylcarbonylamino)-
8-(2′,2′,2′-Trichloromethylcarbonylamino)-5,6,7,8-tetrahy-
drocinnoline (16b). 8-(2′,2′,2′-Trichloromethylcarbonylamino)-
5,6,7,8-tetrahydrocinnoline (16b) was synthesized according to the
above procedure using 1-(2′,2′,2′-trichloromethylcarbonylamino)-5-
ethyl-1″-enecyclohex-5-ene (11b) (0.11 g, 0.41 mmol) and di-tert-
butyl azodicarboxylate (0.12 g, 0.51 mmol). Purification by flash
column chromatography (dichloromethane/methanol, 25:1) gave 8-
(2′,2′,2′-trichloromethylcarbonylamino)-5,6,7,8-tetrahydrocinnoline
(16b) (0.079 g, 66%) as a colorless oil: IR (neat) 3339, 2947, 2361,
1
1697, 1508, 1377, 1265, 1090, 818, 731 cm−1; H NMR (500 MHz,
CDCl3) δ 1.67−1.76 (m, 1H), 1.93−2.08 (m, 2H), 2.81−2.97 (m,
3H), 5.01 (dt, 1H, J 10.3, 5.0 Hz), 7.27 (d, 1H, J 5.1 Hz), 8.29 (br s,
7206
dx.doi.org/10.1021/jo401182r | J. Org. Chem. 2013, 78, 7199−7207

The Journal of Organic Chemistry
Article
1H), 9.04 (d, 1H, J 5.1 Hz) ppm; 13C NMR (126 MHz, CDCl3) δ 19.2
(CH2), 27.1 (CH2), 27.6 (CH2), 51.8 (CH), 92.5 (C), 126.6 (CH),
137.9 (C), 150.6 (CH), 157.7 (C), 162.2 (C) ppm; HRMS (ESI)
calcd for C10H1035Cl3N3NaO (MNa+), 315.9782, found 315.9776.
(14) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masumune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183.
(15) Grafton, M. W.; Farrugia, L. J.; Senn, H. M.; Sutherland, A.
Chem. Commun. 2012, 48, 7994.
(16) Hernan
1164.
̀
dez, E.; Galan, A.; Rovira, C.; Veciana, J. Synthesis 1992,
ASSOCIATED CONTENT
■
S
* Supporting Information
(17) Ishizaki, M.; Hoshino, O. Tetrahedron 2000, 56, 8813.
(18) Overman, L. E.; Carpenter, N. E. In Organic Reactions;
Overman, L. E., Ed.; Wiley: Hoboken, NJ, 2005; Vol. 66, pp 1−107
and references therein.
(19) (a) Poulsen, C. S.; Madsen, R. Synthesis 2003, 1. (b) Diver, S.
T.; Giessert, A. J. Chem. Rev. 2004, 104, 1317. (c) Villar, H.; Frings,
M.; Bolm, C. Chem. Soc. Rev. 2007, 36, 55.
(20) Tandem processes involving an Overman rearrangement and a
metathesis reaction have been previously reported by us. See ref 15
and: (a) Swift, M. D.; Sutherland, A. Org. Lett. 2007, 9, 5239.
(b) McGonagle, F. I.; Brown, L.; Cooke, A.; Sutherland, A. Org.
Biomol. Chem. 2010, 8, 3418. (c) Ahmad, S.; Thomas, L. H.;
Sutherland, A. Org. Biomol. Chem. 2011, 9, 2801. (d) Ahmad, S.; Swift,
M. D.; Farrugia, L. J.; Senn, H. M.; Sutherland, A. Org. Biomol. Chem.
2012, 10, 3937. (e) Ahmad, S.; Sutherland, A. Org. Biomol. Chem.
2012, 10, 8251.
1H and 13C NMR spectra for all new compounds and crystal
data (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: Andrew.Sutherland@glasgow.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the University of Glasgow (University
Scholarship to M.W.G.) is gratefully acknowledged.
(21) Fustero, S.; Bello, P.; Miro,
Eur. J. 2012, 18, 10991.
́
J.; Simon
́
, A.; del Pozo, C. Chem.
(22) For the synthesis of diene 11d, it was found that a separate
Overman rearrangement (89% yield) and RCEYM reaction (with HG-
II, 5 mol % and 1,7-octadiene, 67% yield) was more efficient overall
than the one-pot tandem process.
(23) One-pot Diels−Alder cycloadditions/oxidation sequences have
been previously reported. For example, see: (a) Kotha, S.;
Sreenivasachary, N.; Brahmachary, E. Tetrahedron Lett. 1998, 39,
2805. (b) Kotha, S.; Sreenivasachary, N.; Brahmachary, E. Eur. J. Org.
Chem. 2001, 787. (c) Kotha, S.; Meshram, M.; Tiwari, A. Chem. Soc.
Rev. 2009, 38, 2065. (d) Kurhade, S. E.; Sanchawala, A. I.; Ravikumar,
V.; Bhuniya, D.; Reddy, D. S. Org. Lett. 2011, 13, 3690.
(24) The regiochemistry of the Diels−Alder step for compounds 13f
and 15d was established by NOE experiments (see Supporting
Information for full details). The regiochemical outcome for all other
compounds (13e and 15a−c) was determined using standard one- and
two-dimensional NMR spectroscopy.
(25) See Supporting Information for ORTEP drawing of 14e. The
structure has been deposited with the Cambridge Crystallographic
Data Centre, with code CCDC 930479.
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