NHC-Mediated Synthesis of Tricyclic Spirocarbocycles via an Intramolecular Stetter Reaction of Cyclic Enal-Enones

Article abstract of DOI:10.1021/acs.joc.9b02881

A general and efficient method for the synthesis of tricyclic spirocarbocycles is described. Various cyclic enal-enones were reacted with an N-heterocyclic carbene, and an intramolecular Stetter reaction proceeded smoothly to give various tricyclic spiro-

Full text of DOI:10.1021/acs.joc.9b02881

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Note
NHC-Mediated Synthesis of Tricyclic Spirocarbocycles via
an Intramolecular Stetter Reaction of Cyclic Enal-Enones
Day-Shin Hsu, and Suz-Ping Liang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02881 • Publication Date (Web): 03 Dec 2019
Downloaded from pubs.acs.org on December 10, 2019
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NHC-Mediated Synthesis of Tricyclic Spirocarbocycles
via an Intramolecular Stetter Reaction of Cyclic Enal-
Enones
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Day-Shin Hsu* and Suz-Ping Liang
Department of Chemistry and Biochemistry, National Chung Cheng University, Minhsiung, Taiwan 621
E-mail: chedsh@ccu.edu.tw
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BF4
O
O
N
N
C6F5
O
N
CHO
B
o
Et3N, EtOH, reflux
m
m
31%72% yields
n
o
n
6
11
Abstract: A general and efficient method for the synthesis of tricyclic spirocarbocycles is described.
Various cyclic enal-enones were reacted with an N-heterocyclic carbene and an intramolecular Stetter
reaction proceeded smoothly to give various tricyclic spiro-1,4-diketones in 31–72% yields. The ring
size of the spiro compounds can be easily controlled using different cyclic enals and enones, or by
altering the length of the carbon tether.
Over the past two decades, the broad application of N-heterocyclic carbenes (NHCs) in organic
synthesis has become an important synthetic tool.1 Among these, the nucleophilic carbene can transform
an aldehyde into an acyl anion equivalent via polarity reversal, which enables the aldehyde to react with
several different electrophiles.2 In particular, the conjugate addition of the acyl anion derived from an
aldehyde to an electron-deficient alkene is called the Stetter reaction, which is one of the highly explored
reactions in the field of NHC-organocatalysis, and provides efficient access to unique 1,4-dicarbonyl
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compounds.3 1,4-Dicarbonyl compounds are important synthons for the synthesis of natural products4
and the Stetter reaction offers a practical route to the synthesis of this class of compounds.
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Recently, our research work has focused on the development of a general and efficient method to
prepare spiro compounds because there are many natural products that contain spiro structures, which
exhibit a wide range of biological activities.5,6 Due to their importance in nature, the synthesis of spiro
compounds has become a major focal point in synthetic chemistry. For this reason, there has been a
great deal of research interest in developing a multitude of methods for their synthesis.7 We have
reported an efficient synthesis of spiro tricyclic 1,4-diketones via a NHC-catalyzed intramolecular
Stetter reaction of various aromatic aldehydes tethered to a cyclic enone (Scheme 1).8 In our ongoing
interest in this research field, we planned to apply a similar synthetic strategy on other substrates. A
literature review revealed that only a few examples have been reported to date based on the
intramolecular Stetter reaction of aliphatic aldehydes in the construction of the spiro skeletons.9 This
prompted our group to develop a general intramolecular Stetter reaction of α,β-unsaturated aldehydes
tethered to a cyclic enone to obtain various tricyclic spirocarbocycles. α,β-Unsaturated aldehydes were
used as substrates rather than their corresponding saturated aldehyde derivatives because their cyclized
products, tricyclic spirocarbocycles, contain at least one functional group in each ring, which can be
used for further functional group transformations or carbon side-chain elongation reactions. In addition,
natural products przewalskin B10a and holophyllin A10b possess a tricyclic carbon framework and exhibit
some interesting biological properties (Figure 1).10 Thus, this methodology is of potential synthetic use
for the syntheses of przewalskin B, holophyllin A, and other related natural products.
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Scheme 1. Synthetic strategies used to construct spiro skeletons
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Previous work
Bn
Cl
4
5
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9
N
O
O
HO
O
S
CHO
(0.2 equiv.)
R
m
Et N (1.0 equiv.)
m
3
R
X
n
X
EtOH, reflux
n
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This work
O
O
O
N-heterocyclic
carbene
CHO
o
m
m
n
o
n
O
O
O
OH
O
O
OH
H
H
HO C
2
przewalskin B
holophyllin A
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Figure 1. Examples of natural products containing a tricyclic spirocarbocycle
The precursors, cyclic enal-enones 6, were prepared from commercially available α-
carbomethoxycycloalkanones 1. Conversion of the ketone moiety into the vinyl triflate using sodium
hydride and triflic anhydride gave 2 in good to excellent yields (Table 1).11 The coupling reaction of 2
and 38 was performed using two different reaction conditions. For enynones 3a–b, the coupling reaction
was carried out using triethylamine and tetrabutylammonium fluoride (TBAF) in the presence of
bis(triphenylphosphine)palladium(II) dichloride in THF at 80 C under microwave irradiation.12
However, using the same reactions conditions for enynone 3c did not give the desired coupling product.
Thus, the coupling reaction of enynone 3c was carried out using triethylamine and the same palladium
catalyst, PdCl2(PPh3)2, in dimethylformamide (DMF) at 120 C for 1 h.13 The desired coupling products
4 were obtained in good yield. The next step was the selective hydrogenation of the triple bond using
5% Pd/BaSO4 in MeOH/THF at room temperature to furnish the corresponding α,β-unsaturated ester-
enones 5, with the exception of 4aa, which was performed at 0 C (entry 1).14 Careful control of the
reaction time and the solvent system used for the selective reduction of the triple bond were essential to
prevent further reduction of the conjugated double bond. The next stage was the conversion of the ester
group into the requisite aldehyde. This was achieved upon treating 5 with DIBAL-H followed by
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oxidation of the resulting allylic alcohol with MnO2 to give the desired cyclic enal-enone 6 in good
overall yields.
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Table 1. Preparation of the aliphatic spiro precursors 6
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CO Me
CO Me
2
2
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TfO
O
Tf O, NaH
2
Conditions A
PdCl (PPh ) ,
o
O
Et O, 0
C
2
n
n
2
3 2
1 h
TBAF, Et N, THF,
H ,
Pd/BaSO
1ac
2ac
3
2
2a (92%)
2b (85%)
2c (95%)
CO Me
o
2
W, 80 C, 45 min
4
m
+
MeOH/THF
rt, time
Conditions B
O
PdCl (PPh ) ,
2
3 2
n
Et N, DMF,
3
4
o
120 C, 1 h
m
3ac
O
O
CO Me
CHO
1. DIBAL-H, CH Cl ,
2
2
2
o
70 C, 3 h
m
m
2. MnO , CH Cl ,
rt, 8 h
2
2
2
n
n
5
6
Sonogashira reaction
/ Product 4 (yield)
Hydrogenation
MeOH:THF / time
Enynone
Entry
Triflate
2a: n = 0
2a: n = 0
2a: n = 0
2b: n = 1
Product 5 (yield) Product 6 (yield)
a
3a: m = 0
3b: m = 1
3c: m = 2
3a: m = 0
3b: m = 1
3c: m = 2
3a: m = 0
1
2
3
4
1:2 / 1.5 h
5aa (70%)
5ab (71%)
5ac (67%)
5ba (78%)
6aa (64%)
6ab (60%)
6ac (55%)
6ba (58%)
A / 4aa (70%)
A / 4ab (78%)
B / 4ac (72%)
A / 4ba (71%)
1:2 / 45 min
1:5 / 2 h
1:2 / 1 h
2b: n = 1
2b: n = 1
2c: n = 2
1:15 / 1 h
1:5 / 2.5 h
5
6
7
5bb (80%)
5bc (60%)
5ca (70%)
6bb (60%)
6bc (65%)
6ca (60%)
A / 4bb (75%)
B / 4bc (73%)
A / 4ca (70%)
1:2 / 1.5 h
aReaction was carried out at 0 oC.
In order to extend the scope of the intramolecular Stetter reaction, a cyclic enal-enone containing
a one-carbon tether (6bd) was also prepared from triflate 2b. This was accomplished by the reduction of
the ester group using DIBAL-H followed by oxidation of the resulting alcohol with MnO2 to obtain
aldehyde 8b (Scheme 2). A Wittig reaction of 8b with phosphorus ylide 9 followed by treatment with
HF afforded cyclohexenone 10bd.15 Conversion of the triflate to the methyl ester was performed using
CO and methanol in the presence of tris(dibenzylideneacetone)dipalladium–chloroform
(Pd2(dba)3CHCl3)16 to give 5bd in 78% yield. Using other palladium catalysts in the carbonylation
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reaction (e.g., Pd(OAc)2,17 Pd(PPh3)4 ) gave the desired product, but in low yields. Finally, the ester
and ketone moieties in 5bd were reduced by using excess DIBAL-H and the resultant allyl alcohol
groups were oxidized to conjugate aldehyde and ketone, respectively, by MnO2.
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Scheme 2. Preparation of the spiro precursor 6bd containing a one-carbon tether
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CO2Me
CH2OH
TfO
DIBAL-H
TfO
MnO2
Et2O, 0 o
0.5 h
C
CH2Cl2,
rt, 8 h
85%
2b
7b
OTBS
1.
PPh3
9
O
78 oC to 0 oC,
CHO
TfO
TfO
2 h
2. HF NEt3,
THF, 0 oC, 8 h
59% (3 steps)
10bd
8b
1. DIBAL-H,
CH2Cl2,
70 oC, 3 h
OMe
CO, Et3N,dppf,
Pd2(dba)3 CHCl3,
MeOH
DMF, 65 oC,
O
O
2. MnO2,
CH2Cl2,
rt, 8 h
12 h
78%
5bd
62%
O
O
6bd
With the precursors in hand, we first used 4bb to examine the Stetter reaction conditions.
Compound 4bb was treated with thiazolium salt A (0.5 equiv) and triethylamine (1.0 equiv) in refluxing
ethanol (0.1 M). However, these reaction conditions gave a complicated mixture of products containing
trace amounts of the desired product (11bb) after 48 h of reaction (Table 2, entry 1). Increasing the
amount of thiazolium salt A from 0.5 equiv to 1.0 and 2.0 equiv under the same conditions led to the
same results (entries 2–3). We then turned to use triazolium salt B (0.5 equiv) instead of thiazolium salt
A in refluxing ethanol. Gratifyingly, the intramolecular Stetter reaction proceeded smoothly under these
reaction conditions and gave the desired product 11bb in 30% yield along with the recovered starting
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material in 35% yield (entry 4). Increasing the amount of triazolium salt B from 0.5 equiv to 1.0 equiv
under the same reaction conditions led to the formation of spiro compound 11bb in 65% yield (entry 5).
When the reaction was carried out using 2.0 equiv of triazolium salt B, the reaction was completed in 14
h and the product formed in 78% yield (entry 6). Increasing the amount of triethylamine from 0.5 equiv
to 1.0 equiv decreased the product yield (entry 7). When other alcoholic solvents such as MeOH, i-PrOH,
and t-BuOH were employed, lower yields of the product were observed (entries 8–10). Changing the
base from triethylamine to Cs2CO3 in refluxing ethanol or DMF at 90 C resulted in the recovery of the
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starting material (entries 11–12), whereas the use of KHMDS in toluene at 90 C gave a complicated
mixture of products (entry 13). Although the best yield was observed using 2.0 equiv of triazolium salt
B and 0.5 equiv of triethylamine in ethanol at reflux (entry 6), the amount of triazolium salt B used was
considerable. Thus, in the subsequent reactions of other enal-enone substrates, we used 1.0 equiv of
triazolium salt B and 0.5 equiv of triethylamine in refluxing ethanol for 48 h (entry 5). In contrast to our
previous study on aromatic aldehydes, aliphatic aldehydes require a stoichiometric amount of NHC to
carry out the intramolecular Stetter reaction.19 This is probably due to aliphatic aldehydes being more
reactive towards a nucleophile or base, which will cause some undesired reactions. As a consequence, a
large amount of the NHC was needed to perform the Stetter reaction in order to diminish these side
reactions.
Table 2. Reaction conditions for the attempted intramolecular Stetter reaction
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O
O
O
H
4
O
5
NHC precursor (equiv)
6
7
base (0.5 equiv)
solvent (0.1 M), reflux, time
8
6bb
11bb
9
NHC
precursor
entry
1
base
Et3N
solvent
EtOH
temp
time
yield
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tracea
A (0.5)
A (1.0)
A (2.0)
B (0.5)
B (1.0)
B (2.0)
B (1.0)
reflux 48 h
reflux 48 h
reflux 48 h
reflux 48 h
reflux 48 h
reflux 14 h
reflux 48 h
tracea
tracea
30%b
65%
Et3N
Et3N
Et3N
Et3N
Et3N
2
3
4
5
6
7
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
78%
Et3Nc
Et3N
26%
8
B (1.0)
MeOH
reflux 48 h
27%
Et3N
9
B (1.0)
B (1.0)
B (1.0)
B (1.0)
B (0.5)
i-PrOH reflux 48 h
t-BuOH reflux 48 h
40%
10%d
e
Et3N
10
11
Cs2CO3
Cs2CO3
KHMDS
EtOH
reflux 48 h
48 h
90 o
90 o
C
e
a
12
13
DMF
PhMe
48 h
C
aComplicated mixture. b4bb was recovered in 35% yield. c1.0 equiv of Et3N
was used. d4bb was recovered in 20% yield. eNo reaction.
BF4
Bn
Cl
N
N
N
C6F5
N
HO
S
B
A
With the optimized conditions in hand, we next used other enal-enones in the reaction. The
desired tricyclic spirocycles were produced in moderate to good yields (Scheme 3). The reactions of
enal-enones with a two-carbon tether proceeded smoothly (11aa–ca). The reaction also proceeded well
on a gram scale (11bb) without any significant influence on the product yield (61%). The reaction of the
enal-enones with a one-carbon tether (6bd) gave product 11bd in low yield (31%). This was presumably
because 6bd is an active hydrogen compound, which contains two electron-withdrawing groups at the
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connected carbon atom leading to an increase in the acidity of the hydrogen atom, which can easily
undergo deprotonation under the Stetter reaction conditions to cause some undesired side reactions.
Scheme 3. The intramolecular Stetter reaction
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BF
4
N
O
O
N C F
6
5
N
O
B
CHO
(1.0 equiv.)
o
Et N (0.5 equiv.)
EtOH (0.1 M), reflux, 48 h
3
m
m
n
o
n
6
11
O
O
O
O
O
O
11aa (72%)
11ab (66%)
11ac (58%)
O
O
O
O
O
O
11ba (66%)
11bb ( 65%)
(61%, gram scale)
11bc (54%)
O
O
O
O
11ca (60%)
11bd (31%)
.
The structures of tricyclic spirocarbocycles 11 were characterized using IR spectroscopy, 1H and
13C NMR, and low- and high-resolution mass spectrometry. The C NMR spectra of these compounds
13
showed two ketone carbonyl and a spirocarbon signals at around 200–220 and 50 ppm, respectively. It is
noteworthy mentioning that tricyclic spiro-1,4-diketone 11ba contains the same tricyclic carbon
framework as przewalskin B and holophyllin A. Therefore, compound 11ba could be used toward the
syntheses of przewalskin B and holophyllin A.
Conclusions
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We have developed a general and efficient method for the preparation of tricyclic
spirocarbocycles. A variety of α,β-unsaturated aldehydes underwent an intramolecular Stetter reaction
under NHC-mediated conditions to form five- and six-membered rings. The ring size of the spiro
compounds can be easily controlled by either using different cyclic enals or enones, or by altering the
length of the carbon tether. Although a stoichiometric amount of NHC was used in the Stetter reaction,
this methodology provides a way to readily access various ring sizes of tricyclic spiro-1,4-diketones.
Efforts to use this methodology toward the total syntheses of przewalskin B, holophyllin A, and other
related natural products are now in progress.
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Experimental Section
General Information. Unless stated otherwise, reagents were obtained from commercial sources and
used without further purification. All reactions were performed under an argon or nitrogen atmosphere
in anhydrous solvents, which were dried prior to use following standard procedures. Reactions were
monitored by thin-layer chromatography on 0.25 mm E. Merck silica gel plates (60F-254) using 7%
ethanolic phosphomolybdic acid as developing agent. Merck silica gel 60 (particle size 0.040–0.063 mm,
230–400 mesh) was employed for flash chromatography. IR spectra were recorded as films on KBr
1
plates. H NMR spectra were obtained in CDCl3 at 400 MHz or 500 MHz. 13C NMR spectra were
obtained at 100 MHz or 125 MHz. Chemical shifts were reported in δ (ppm) using solvent resonance as
the internal reference. High resolution mass spectra (HRMS) were obtained on a TOF MS instrument
with an EI source.
General Procedure for Preparation of Enol Triflates 2. A suspension of NaH (50.0 mmol, 60%
dispersion in mineral oil, 5.0 equiv) in Et2O (40 mL) was cooled to 0 °C and added a solution of 1 (10.0
o
mmol, 1.0 equiv) in Et2O (30 mL). The mixture was stirred at 0 C for 40 min and then added
trifluoromethanesulfonic anhydride (20.0 mmol, 2.0 equiv). After stirred at 0 oC for 1 h, the mixture was
o
quenched carefully with saturated aqueous NH4Cl at 0 C and extracted with Et2O. The combined
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extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was
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purified by column chromatography on silica gel (EtOAc/hexanes) to afford 2.
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8
Methyl
2-(trifluoromethylsulfonyloxy)cyclopent-1-enecarboxylate
(2a).11
Chromatography
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(EtOAc/hexanes = 1:15); colorless oil; 2.52 g; yield 92%; IR (neat) ν 2957, 1729, 1669, 1428, 1355,
1212, 1142, 1032, 1010, 928, 846, 767 cm–1; 1H NMR (400 MHz, CDCl3) δ 3.78 (s, 3H), 2.77–2.66 (m,
4H), 2.05–1.99 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 162.7, 154.0, 122.9, 118.3 (q, J = 318 Hz),
51.8, 32.7, 29.1, 18.8; MS (EI) m/z (% base peak) 274 (M+, 34), 243 (49), 179 (41), 141 (30), 109 (100),
85 (49), 69 (84), 59 (45); HRMS (EI-TOF) m/z: [M]+ Calcd for C8H9F3O5S 274.0123; Found 274.0124.
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Methyl
2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate
(2b).11
Chromatography
(EtOAc/hexanes = 1:20); colorless oil; 2.45 g; yield 85%; IR (neat) ν 2954, 2870, 1730, 1670, 1422,
1361, 1289, 1245, 1210, 1140, 1093, 1043, 897, 819 cm–1; 1H NMR (400 MHz, CDCl3) δ 3.75 (s, 3H),
2.48–2.42 (m, 2H), 2.40–2.35 (m, 2H), 1.79–1.72 (m, 2H), 1.66–1.61 (m, 2H); 13C{1H} NMR (100
MHz, CDCl3): δ 165.0, 151.7, 122.7, 118.2 (q, J = 318 Hz), 51.9, 28.5, 26.0, 22.1, 20.9; MS (EI) m/z (%
base peak) 288 (M+, 10), 257 (67), 219 (8), 193 (3), 168 (6), 155 (47), 139 (13), 123 (100), 95 (34), 79
(36), 67 (34), 59 (32); HRMS (EI-TOF) m/z: [M]+ Calcd for C9H11F3O5S 288.0279; Found 288.0279.
Methyl
2-(trifluoromethylsulfonyloxy)cyclohept-1-enecarboxylate
(2c).11
Chromatography
(EtOAc/hexanes = 1:15); colorless oil; 2.87 g; yield 95%; IR (neat) ν 2925, 2854, 1728, 1652, 1614,
1423, 1353, 1284, 1209, 1140, 1096, 1004, 866, 760 cm–1; 1H NMR (400 MHz, CDCl3) δ 3.78 (s, 3H),
2.58 (t, J = 5.5 Hz, 2H), 2.52 (t, J = 5.4 Hz, 2H), 1.80–1.61 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3):
δ 166.1, 155.0, 127.8, 118.3 (q, J = 317 Hz), 52.2, 33.9, 30.6, 27.9, 25.2, 23.7; MS (EI) m/z (% base
peak) 302 (M+, 10), 271 (53), 233 (6), 169 (27), 153 (68), 137 (100), 109 (54), 81 (80); HRMS (EI-TOF)
m/z: [M]+ Calcd for C10H13F3O5S 302.0436; Found 302.0435.
General Procedure for Sonogashira Cross-Coupling. (i) Conditions A. A mixture of 2a–c (3.50
mmol, 1.0 equiv), 3a–b (4.20 mmol, 1.2 equiv), bis(triphenylphosphine)palladium(II) dichloride
(Pd(PPh3)2Cl2) (246 mg, 0.35 mmol, 0.1 equiv), TBAF (915 mg, 3.50 mmol, 1.0 equiv), and
triethylamine (1.46 mL, 10.50 mmol, 3.0 equiv) in THF (5 mL) in a sealed reaction vessel was irradiated
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with microwave (110 W) maintained at 80 C for 45 min, the temperature was monitored with an
internal probe. The contents were cooled to room temperature, quenched with saturated aqueous NH4Cl,
and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4,
filtered and concentrated under reduced pressure. The crude product was purified by column
chromatography on silica gel (EtOAc/hexanes) to afford 4aa–4ab, 4ba–4bb, 4ca.
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(ii) Conditions B. To
a
stirred solution of 2a–b (2.00 mmol, 1.0 equiv),
bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2) (140 mg, 0.20 mmol, 0.1 equiv), and 3c
(2.40 mmol, 1.2 equiv) in DMF (20 mL, 0.10 M) was added triethylamine (0.84 mL, 6.00 mmol, 3.0
equiv) under Ar atmosphere at room temperature. The reaction mixture was then heated in an oil bath to
120 oC for 1 h. The contents were cooled to room temperature and the solvent was evaporated in vacuo
to give a residue. The crude product was purified by column chromatography on silica gel
(EtOAc/hexanes) to afford 4ac, 4bc.
Methyl 2-((3-oxocyclopent-1-en-1-yl)ethynyl)cyclopent-1-enecarboxylate (4aa). Conditions A;
chromatography (EtOAc/hexanes = 1:3); yellow oil; 564 mg; yield 70%; IR (neat) ν 2951, 2852, 2189,
1705, 1614, 1572, 1435, 1252, 1170, 862, 762 cm–1; 1H NMR (400 MHz, CDCl3) δ 6.37 (t, J = 1.8 Hz,
1H), 3.81 (s, 3H), 2.87–2.73 (m, 6H), 2.51–2.48 (m, 2H), 2.06–1.98 (m, 2H); 13C{1H} NMR (100 MHz,
CDCl3): δ 209.2, 164.4, 156.3, 141.1, 136.6, 132.9, 99.8, 93.7, 51.7, 38.6, 34.8, 33.5, 32.4, 22.4; MS (EI)
m/z (% base peak) 230 (M+, 100), 215 (67), 199 (48), 187 (92), 171 (31), 159 (18), 141 (19), 128 (33),
115 (45), 87 (18); HRMS (EI-TOF) m/z: [M]+ Calcd for C14H14O3 230.0943; Found 230.0946.
Methyl 2-((3-oxocyclohex-1-en-1-yl)ethynyl)cyclopent-1-enecarboxylate (4ab). Conditions A;
chromatography (EtOAc/hexanes = 1:3); yellow oil; 667 mg; yield 78%; IR (neat) ν 2950, 2185, 1705,
1673, 1613, 1579, 1435, 1238, 1188, 1133, 963, 888, 765 cm–1; 1H NMR (400 MHz, CDCl3) δ 6.28 (brs,
1H), 3.80 (s, 3H), 2.80–2.70 (m, 4H), 2.57–2.52 (m, 2H), 2.47–2.43 (m, 2H), 2.11–1.95 (m, 4H); 13C{1H}
NMR (100 MHz, CDCl3): δ 198.6, 164.5, 142.9, 140.5, 133.2, 132.8, 97.4, 95.1, 51.5, 38.7, 37.3, 33.5,
30.2, 22.5, 22.2; MS (EI) m/z (% base peak) 244 (M+, 100), 229 (20), 215 (32), 201 (81), 183 (16), 173
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(32), 157 (20), 128 (36), 115 (25), 91 (13); HRMS (EI-TOF) m/z: [M]+ Calcd for C15H16O3 244.1099 ;
Found 244.1096.
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Methyl 2-((3-oxocyclohept-1-en-1-yl)ethynyl)cyclopent-1-enecarboxylate (4ac). Conditions B;
chromatography (EtOAc/hexanes = 1:5); yellow oil; 372 mg; yield 72%; IR (neat) ν 2944, 2864, 2187,
1704, 1660, 1609, 1580, 1437, 1245, 1133, 878 cm–1; 1H NMR (400 MHz, CDCl3) δ 6.35 (brs, 1H),
3.77 (s, 3H), 2.76–2.61 (m, 8H), 2.01–1.80 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 202.9, 164.6,
139.9, 139.8, 137.0, 133.7, 100.4, 92.0, 51.6, 42.5, 38.8, 33.9, 33.4, 25.2, 22.3, 21.1; MS (EI) m/z (%
base peak) 258 (M+, 3), 218 (61), 190 (8), 176 (26), 175 (20), 149 (70), 108 (100), 91 (20), 79 (45);
HRMS (EI-TOF) m/z: [M]+ Calcd for C16H18O3 258.1256; Found 258.1259.
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Methyl 2-((3-oxocyclopent-1-en-1-yl)ethynyl)cyclohex-1-enecarboxylate
(4ba). Conditions A;
chromatography (EtOAc/hexanes = 1:3); yellow oil; 607 mg; yield 71%; IR (neat) ν 2940, 2862, 2187,
1707, 1612, 1576, 1435, 1275, 1235, 1170, 1061, 860, 759 cm–1; 1H NMR (400 MHz, CDCl3) δ 6.24
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(brs, 1H), 3.73 (s, 3H), 2.78–2.72 (m, 2H), 2.43–2.30 (m, 6H), 1.66–1.60 (m, 4H); C{1H} NMR (100
MHz, CDCl3): δ 209.2, 166.9, 156.8, 136.8, 135.8, 127.3, 104.1, 90.8, 51.6, 34.6, 32.4, 31.6, 26.3, 21.4,
21.3; MS (EI) m/z (% base peak) 244 (M+, 51), 229 (36), 213 (16), 201 (100), 185 (14), 173 (9), 155 (5),
141 (10), 128 (27), 115 (18), 91 (11), 71 (12); HRMS (EI-TOF) m/z: [M]+ Calcd for C15H16O3 244.1099;
Found 244.1101.
Methyl 2-((3-oxocyclohex-1-en-1-yl)ethynyl)cyclohex-1-ene-1-carboxylate (4bb). Conditions A;
chromatography (EtOAc/hexanes = 1:5); yellow oil; 678 mg; yield 75%; IR (neat) ν 2944, 2864, 2187,
1718, 1671, 1610, 1582, 1432, 1300, 1231, 1187, 1137, 963, 887, 760 cm–1; 1H NMR (500 MHz,
CDCl3) δ 6.21 (t, J = 1.5 Hz, 1H), 3.77 (s, 3H), 2.51–2.48 (m, 2H), 2.42–2.35 (m, 4H), 2.35–2.34 (m,
2H), 2.07–2.01 (m, 2H), 1.67–1.64 (m, 4H); 13C{1H} NMR (125 MHz, CDCl3): δ 198.7, 167.2, 143.4,
136.5, 132.4, 127.6, 99.4, 94.5, 51.7, 37.3, 31.8, 30.3, 26.4, 22.5, 21.5, 21.4; MS (EI) m/z (% base peak)
258 (M+, 97), 243 (41), 227 (29), 215 (100), 187 (30), 171 (20), 142 (73), 128 (44), 115 (43), 91 (32),
77 (37); HRMS (EI-TOF) m/z: [M]+ Calcd for C16H18O3 258.1256; Found 258.1257.
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Methyl 2-((3-oxocyclohept-1-en-1-yl)ethynyl)cyclohex-1-enecarboxylate (4bc). Conditions B;
chromatography (EtOAc/hexanes = 1:5); yellow oil; 398 mg; yield 73%; IR (neat) ν 2939, 2864, 2182,
1708, 1657, 1582, 1432, 1231, 1054, 878, 753 cm–1; 1H NMR (400 MHz, CDCl3) δ 6.31 (brs, 1H), 3.77
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(100 MHz, CDCl3): δ 203.0, 167.3, 140.4, 136.5, 135.9, 127.9, 97.3, 96.3, 51.7, 42.5, 34.0, 31.9, 26.4,
25.3, 21.6, 21.5, 21.2; MS (EI) m/z (% base peak) 272 (M+, 20), 257 (11), 244 (8), 229 (32), 218 (26),
201 (18), 190 (100), 163 (20), 149 (17), 129 (25), 122 (68), 101 (46), 91 (36), 79 (85), 59 (74), 55 (58);
HRMS (EI-TOF) m/z: [M]+ Calcd for C17H20O3 272.1412; Found 272.1410.
Methyl 2-((3-oxocyclopent-1-en-1-yl)ethynyl)cyclohept-1-enecarboxylate (4ca). Conditions A;
chromatography (EtOAc/hexanes = 1:3); yellow oil; 633 mg; yield 70%; IR (neat) ν 2941, 2861, 2185,
1712, 1660, 1439, 1248, 1126, 911, 881 cm–1; 1H NMR (400 MHz, CDCl3) δ 6.27 (brs, 1H), 3.77 (s,
3H), 2.80–2.76 (m, 2H), 2.63–2.55 (m, 4H), 2.45–2.42 (m, 2H), 1.84–1.78 (m, 2H), 1.60–1.53 (m, 4H);
13C{1H} NMR (100 MHz, CDCl3): δ 209.2, 167.9, 156.9, 143.4, 135.9, 132.3, 105.5, 91.7, 51.9, 36.4,
34.7, 32.4, 32.0, 30.0, 25.7, 25.3; MS (EI) m/z (% base peak) 258 (M+, 5), 244 (53), 230 (82), 215 (71),
199 (42), 187 (100), 171 (27), 159 (28), 145 (19), 128 (35), 115 (53), 91 (27), 77 (24); HRMS (EI-TOF)
m/z: [M]+ Calcd for C16H18O3 258.1256; Found 258.1253.
General Procedure for Regioselective Hydrogenation. To a mixture of 4 (2.00 mmol, 1 equiv) and
5% Pd/BaSO4 (1.00 g, 0.50 mmol, 0.25 equiv) in flask was added solvent (0.05 M) (see Table 1 for the
solvent used). The reaction mixture was then stirred under a hydrogen balloon at room temperature for a
period of time (see Table 1 for the duration of hydrogenation). Filtration and concentration in vacuo
gave a residue, which was purified by column chromatography on silica gel (EtOAc/hexanes) to afford 5.
Methyl 2-(2-(3-oxocyclopent-1-en-1-yl)ethyl)cyclopent-1-enecarboxylate (5aa). Chromatography
(EtOAc/hexanes = 1:3); yellowish oil; 328 mg; yield 70%; IR (neat) ν 2948, 2861, 1708, 1616, 1436,
1188, 1115, 841, 768 cm–1; 1H NMR (400 MHz, CDCl3) δ 5.97 (t, J = 1.3 Hz, 1H), 3.71 (s, 3H), 2.89 (t,
J = 7.7 Hz, 2H), 2.65–2.55 (m, 6H), 2.50 (t, J = 7.7 Hz, 2H), 2.42–2.39 (m, 2H), 1.87–1.79 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3): δ 210.1, 181.9, 166.3, 157.7, 129.7, 128.4, 51.1, 37.8, 35.4, 33.5,
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31.6, 31.4, 27.4, 21.4; MS (EI) m/z (% base peak) 234 (M+, 10), 219 (12), 203 (18), 192 (25), 174 (39),
146 (18), 131 (26), 109 (100), 96 (50), 79 (46), 69 (36); HRMS (EI-TOF) m/z: [M]+ Calcd for C14H18O3
234.1256; Found 234.1253.
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(EtOAc/hexanes = 1:3); yellowish oil; 353 mg; yield 71%; IR (neat) ν 2950, 2868, 1709, 1670, 1433,
1256, 1192, 1115, 1041, 966, 887, 770 cm–1; 1H NMR (400 MHz, CDCl3) δ 5.85 (brs, 1H), 3.70 (s, 3H),
2.79 (t, J = 7.9 Hz, 2H), 2.63–2.56 (m, 2H), 2.50–2.45 (m, 2H), 2.37–2.32 (m, 6H), 2.00–1.94 (m, 2H),
1.85–1.77 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 200.0, 166.3, 165.7, 158.0, 128.1, 125.8, 51.0,
38.0, 37.3, 36.1, 33.4, 29.4, 27.4, 22.6, 21.4; MS (EI) m/z (% base peak) 248 (M+, 8), 216 (21), 188 (35),
160 (40), 123 (100), 110 (86), 91 (37), 79 (57), 77 (37); HRMS (EI-TOF) m/z: [M]+ Calcd for C15H20O3
248.1412; Found 248.1409.
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Methyl 2-(2-(3-oxocyclohept-1-en-1-yl)ethyl)cyclopent-1-enecarboxylate (5ac). Chromatography
(EtOAc/hexanes = 1:3); yellowish oil; 352 mg; yield 67%; IR (neat) ν 2932, 2854, 1729, 1708, 1656,
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1435, 1347, 1258, 1194, 1113, 1038, 848 cm–1; H NMR (400 MHz, CDCl3) δ 5.91 (brs, 1H), 3.71 (s,
3H), 2.78 (t, J = 7.7 Hz, 2H), 2.65–2.55 (m, 4H), 2.51–2.45 (m, 4H), 2.33 (t, J = 7.7 Hz, 2H), 1.87–1.76
(m, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 204.0, 166.3, 161.4, 158.3, 129.5, 128.0, 51.0, 42.2, 39.2,
38.1, 33.5, 32.5, 28.2, 25.2, 21.5, 21.3; MS (EI) m/z (% base peak) 262 (M+, 3), 230 (24), 202 (29), 173
(26), 147 (29), 137 (57), 124 (100), 109 (43), 108 (31), 91 (30), 79 (73), 67 (42), 55 (38); HRMS (EI-
TOF) m/z: [M]+ Calcd for C16H22O3 262.1569; Found 262.1567.
Methyl 2-(2-(3-oxocyclopent-1-en-1-yl)ethyl)cyclohex-1-enecarboxylate (5ba). Chromatography
(EtOAc/hexanes = 1:3); yellowish oil; 387 mg; yield 78%; IR (neat) ν 2932, 2859, 1708, 1616, 1435,
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1279, 1232, 1180, 1075, 1049, 841, 766 cm–1; H NMR (400 MHz, CDCl3) δ 5.97 (brs, 1H), 3.71 (s,
3H), 2.70–2.55 (m, 6H), 2.45–2.42 (m, 2H), 2.34–2.29 (m, 2H), 2.21–2.15 (m, 2H), 1.70–1.59 (m, 4H);
13C{1H} NMR (100 MHz, CDCl3): δ 209.9, 182.4, 168.5, 148.2, 129.2, 125.3, 51.0, 35.1, 32.9, 32.1,
31.4, 31.2, 26.2, 21.98, 21.97; MS (EI) m/z (% base peak) 248 (M+, 4), 217 (21), 206 (28), 189 (19), 165
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(13), 152 (56), 121 (12), 109 (100), 96 (52), 93 (40), 58 (56); HRMS (EI-TOF) m/z: [M]+ Calcd for
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C15H20O3 248.1412; Found 248.1411.
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(5bb). Chromatography
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1450, 1432, 1279, 1232, 1076, 966, 887, 760 cm–1; H NMR (400 MHz, CDCl3) δ 5.88 (brs, 1H), 3.70
(s, 3H), 2.56–2.51 (m, 2H), 2.38–2.25 (m, 6H), 2.20–2.10 (m, 2H), 1.99–1.96 (m, 2H), 1.80–1.58 (m,
6H); 13C{1H} NMR (100 MHz, CDCl3): δ 199.9, 168.9, 166.1, 148.6, 125.6, 125.4, 51.2, 37.3, 36.9,
33.3, 31.5, 29.7, 26.4, 22.7, 22.3, 22.2; MS (EI) m/z (% base peak) 262 (M+, 2), 230 (10), 202 (13), 174
(13), 152 (48), 123 (48), 110 (100), 93 (37), 79 (26); HRMS (EI-TOF) m/z: [M]+ Calcd for C16H22O3
262.1569; Found 262.1567.
Methyl 2-(2-(3-oxocyclohept-1-en-1-yl)ethyl)cyclohex-1-enecarboxylate (5bc). Chromatography
(EtOAc/hexanes = 1:5); yellowish oil; 332 mg; yield 60%; IR (neat) ν 2930, 2861, 1709, 1658, 1440,
1231, 1075, 1049, 850 cm–1; 1H NMR (400 MHz, CDCl3) δ 5.92 (brs, 1H), 3.71 (s, 3H), 2.60–2.55 (m,
2H), 2.54–2.45 (m, 4H), 2.34–2.25 (m, 4H), 2.16–2.12 (m, 2H), 1.82– 1.77 (m, 4H), 1.62–1.58 (m, 4H);
13C{1H} NMR (100 MHz, CDCl3): δ 204.2, 168.9, 162.1, 148.7, 129.2, 125.2, 51.3, 42.3, 39.9, 34.1,
32.7, 31.6, 26.4, 25.2, 22.23, 22.20, 21.3; MS (EI) m/z (% base peak) 276 (M+, 4), 258 (8), 244 (13), 231
(7), 216 (14), 201 (9), 187 (12), 165 (14), 152 (34), 137 (69), 124 (100), 109 (54), 93 (38), 81 (46), 79
(44), 55 (50); HRMS (EI-TOF) m/z: [M]+ Calcd for C17H24O3 276.1725; Found 276.1722.
Methyl 2-(2-(3-oxocyclopent-1-en-1-yl)ethyl)cyclohept-1-enecarboxylate (5ca). Chromatography
(EtOAc/hexanes = 1:5); yellowish oil; 367 mg; yield 70%; IR (neat) ν 2924, 2852, 1709, 1678, 1616,
1436, 1287, 1258, 1201, 1107, 1038, 840 cm–1; H NMR (400 MHz, CDCl3) δ 5.96 (brs, 1H), 3.70 (s,
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13C{1H} NMR (100 MHz, CDCl3): δ 209.9, 182.1, 169.9, 152.7, 131.8, 129.4, 51.3, 35.4, 35.3, 34.6,
32.2, 31.8, 31.5, 29.9, 26.2, 25.5; MS (EI) m/z (% base peak) 262 (M+, 7), 231 (13), 220 (24), 203 (32),
179 (11), 166 (82), 159 (18), 135 (13), 109 (100), 96 (74), 79 (38), 67 (22), 55 (16); HRMS (EI-TOF)
m/z: [M]+ Calcd for C16H22O3 262.1569; Found 262.1572.
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General Procedure for Preparation of Enol-Enones 6. To a stirred solution of 5 (2.00 mmol, 1.0
equiv) in CH2Cl2 (10 mL) at –70 oC under Ar atmosphere was added diisobutylaluminum hydride (6.00
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CH2Cl2. The combined organic extracts were washed with brine, dried over MgSO4, filtered and
concentrated under reduced pressure to give a residue. A mixture of the resulting crude product (2.00
mmol, 1.0 equiv) and MnO2 (40.0 mmol, 20.0 equiv) in CH2Cl2 (10 mL) was stirred at room
temperature for 8 h. The mixture was filtered through a pad of Celite. The filtrate was concentrated in
vacuo to give a residue, which was purified by column chromatography on silica gel (EtOAc/hexanes) to
afford 6.
2-(2-(3-Oxocyclopent-1-en-1-yl)ethyl)cyclopent-1-ene-1-carbaldehyde
(6aa). Chromatography
(EtOAc/hexanes = 1:2); yellowish oil; 261 mg; yield 64%; IR (neat) ν 2954, 2923, 2856, 1707, 1670,
1
1612, 1436, 1260, 1184, 1024, 799, 722 cm–1; H NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 6.00 (brs,
1H), 2.90 (t, J = 7.9 Hz, 2H), 2.66–2.56 (m, 8H), 2.45–2.40 (m, 2H), 1.92–1.84 (m, 2H); 13C{1H} NMR
(100 MHz, CDCl3): δ 209.4, 187.4, 180.1, 163.1, 139.3, 130.0, 38.1, 35.2, 32.0, 31.5, 30.4, 26.0, 21.3;
MS (EI) m/z (% base peak) 204 (M+, 4), 190 (2), 176 (5), 162 (5), 147 (7), 133 (10), 109 (100), 96 (70),
81 (29), 67 (27); HRMS (EI-TOF) m/z: [M]+ Calcd for C13H16O2 204.1150; Found 204.1148.
2-(2-(3-Oxocyclohex-1-en-1-yl)ethyl)cyclopent-1-ene-1-carbaldehyde
(6ab).
Chromatography
(EtOAc/hexanes = 1:3); yellowish oil; 262 mg; yield 60%; IR (neat) ν 2929, 2856, 1661, 1427, 1249,
1190, 796, 752 cm–1; 1H NMR (400 MHz, CDCl3) δ 9.98 (s, 1H), 5.88 (brs, 1H), 2.80 (t, J = 7.7 Hz, 2H),
2.64–2.55 (m, 4 H), 2.43 (t, J = 7.7 Hz, 2H), 2.36 (t, J = 6.7 Hz, 2H), 2.31 (t, J = 5.8 Hz, 2H), 2.04–1.96
(m, 2H), 1.90–1.83 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 199.4, 187.5, 163.8, 163.6, 139.2,
126.3, 38.2, 37.2, 36.3, 30.3, 29.5, 25.9, 22.6, 21.3; MS (EI) m/z (% base peak) 218 (M+, 6), 200 (4),
190 (6), 161 (7), 147 (9), 131 (14), 121 (10), 110 (100), 108 (66), 95 (8), 79 (26), 58 (40); HRMS (EI-
TOF) m/z: [M]+ Calcd for C14H18O2 218.1307; Found 218.1305.
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2-(2-(3-Oxocyclohept-1-en-1-yl)ethyl)cyclopent-1-ene-1-carbaldehyde
(6ac).
Chromatography
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(EtOAc/hexanes = 1:3); yellowish oil; 256 mg; yield 55%; IR (neat) ν 2926, 2859, 1660, 1447, 1354,
1256, 1194, 1030 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 5.92 (brs, 1H), 2.80 (t, J = 7.7 Hz,
2H), 2.63–2.55 (m, 6H), 2.46–2.40 (m, 4H), 1.92–1.75 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ
203.6, 187.5, 163.9, 159.4, 139.1, 129.9, 42.2, 39.3, 38.2, 32.7, 30.3, 26.7, 25.2, 21.3, 21.2; MS (EI) m/z
(% base peak) 232 (M+, 11), 218 (12), 203 (4), 174 (11), 161 (11), 149 (31), 137 (45), 124 (43), 108
(100), 98 (72), 79 (62), 67 (58), 55 (52); HRMS (EI-TOF) m/z: [M]+ Calcd for C15H20O2 232.1463;
Found 232.1465.
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2-(2-(3-Oxocyclopent-1-en-1-yl)ethyl)cyclohex-1-ene-1-carbaldehyde
(6ba).
Chromatography
(EtOAc/hexanes = 1:2); yellowish oil; 253 mg; yield 58%; IR (neat) ν 2932, 2861, 1702, 1665, 1616,
1436, 1235, 1183, 843 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.10 (s, 1H), 5.99 (brs, 1H), 2.81 (t, J = 8.1
Hz, 2H), 2.63–2.58 (m, 4 H), 2.44–2.41 (m, 2H), 2.30–2.18 (m, 4H), 1.68–1.57 (m, 4H); 13C{1H} NMR
(100 MHz, CDCl3): δ 209.5, 190.2, 180.4, 157.4, 134.6, 129.9, 35.3, 33.5, 32.0, 31.6, 29.7, 22.4, 22.0,
21.5; MS (EI) m/z (% base peak) 218 (M+, 13), 206 (5), 190 (35), 161 (17), 147 (13), 122 (100), 109
(36), 96 (55), 79 (52), 58 (38); HRMS (EI-TOF) m/z: [M]+ Calcd for C14H18O2 218.1307; Found
218.1305.
2-(2-(3-Oxocyclohex-1-en-1-yl)ethyl)cyclohex-1-ene-1-carbaldehyde
(6bb).
Chromatography
(EtOAc/hexanes = 1:3); yellowish oil; 279 mg; yield 60%; IR (neat) ν 2933, 2861, 1665, 1626, 1423,
1
1371, 1250, 1233, 1191, 964, 887 cm–1; H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H), 5.87 (brs, 1H),
2.72 (t, J = 8.0 Hz, 2H), 2.45–2.17 (m, 10 H), 2.04–1.95 (m, 2H), 1.70–1.55 (m, 4H); 13C{1H} NMR
(100 MHz, CDCl3): δ 199.5, 190.2, 164.0, 157.7, 134.5, 126.2, 37.8, 37.2, 32.0, 29.71, 29.68, 22.6, 22.4,
22.0, 21.5; MS (EI) m/z (% base peak) 232 (M+, 7), 214 (3), 204 (5), 189 (4), 175 (4), 163 (12), 135 (11),
122 (73), 110 (100), 91 (23), 79 (41), 58 (38), 55 (10); HRMS (EI-TOF) m/z: [M]+ Calcd for C15H20O2
232.1463; Found 232.1465.
2-(2-(3-Oxocyclohept-1-en-1-yl)ethyl)cyclohex-1-ene-1-carbaldehyde
(6bc).
Chromatography
(EtOAc/hexanes = 1:3); yellowish oil; 320 mg; yield 65%; IR (neat) ν 2933, 2864, 1704, 1661, 1447,
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1382, 1211, 1068, 802 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 5.91 (brs, 1H), 2.70 (t, J = 8.0
Hz, 2H), 2.58 (t, J = 6.0 Hz, 2H), 2.45–2.36 (m, 4H), 2.29–2.17 (m, 4H), 1.84–1.77 (m, 4H), 1.70–1.55
(m, 4H); 13C NMR (100 MHz, CDCl3): δ 203.7, 190.3, 159.6, 158.0, 134.5, 129.9, 42.2, 40.9, 33.0, 32.1,
30.5, 25.2, 22.3, 22.0, 21.6, 21.2; MS (EI) m/z (% base peak) 246 (M+, 5), 228 (5), 218 (5), 189 (6), 175
(4), 163 (21), 135 (7), 124 (100), 122 (46), 109 (15), 95 (20), 79 (25), 67 (16); HRMS (EI-TOF) m/z:
[M]+ Calcd for C16H22O2 246.1620; Found 246.1621.
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2-(2-(3-Oxocyclopent-1-en-1-yl)ethyl)cyclopent-1-ene-1-carbaldehyde
(6ca).
Chromatography
(EtOAc/hexanes = 1:2); yellowish oil; 279 mg; yield 60%; IR (neat) ν 2924, 2849, 1755, 1705, 1663,
1
1613, 1447, 1280, 1185, 966, 887, 845 cm–1; H NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 6.00 (brs,
1H), 2.87 (t, J = 8.1 Hz, 2H), 2.64–2.57 (m, 4 H), 2.50–2.41 (m, 6H), 1.83–1.76 (m, 2H), 1.70–1.56 (m,
2H), 1.45–1.38 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 209.5, 189.5, 180.3, 163.7, 140.5, 130.0,
36.9, 35.3, 32.4, 32.3, 31.6, 30.7, 26.0, 25.9, 24.5; MS (EI) m/z (% base peak) 232 (M+, 1), 204 (2), 181
(3), 169 (4), 149 (13), 136 (10), 125 (10), 109 (37), 96 (58), 81 (55), 69 (79), 55 (100); HRMS (EI-TOF)
m/z: [M]+ Calcd for C15H20O2 232.1463; Found 232.1463.
2-(Hydroxymethyl)cyclohex-1-en-1-yl trifluoromethanesulfonate (7b).17 To a stirred solution of 2b
o
(880 mg, 3.05 mmol) in Et2O (7.6 mL) at 0 C under Ar atmosphere was added diisobutylaluminum
hydride (9.10 mL, 9.10 mmol, 1.0 M solution in hexanes). After stirred at 0 oC for 0.5 h, the mixture was
quenched with EtOAc and 1 M HCl. The solution was extracted with Et2O. The combined organic
extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure.
The crude product was purified by column chromatography on silica gel (EtOAc/hexanes = 1/8) to
afford 7b (675 mg, 85%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.20 (s, 2H), 2.37–2.30 (m, 4H),
1.81–1.63 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 144.1, 129.9, 118.3 (q, J = 317 Hz), 59.7, 27.6,
26.4, 22.9, 21.4.
2-Formylcyclohex-1-en-yl trifluoromethanesulfonate (8b, 80b). A mixture of 7b (880 mg, 3.41 mmol)
and MnO2 (5.93 g, 68.2 mmol) in CH2Cl2 (5 mL) was stirred at room temperature for 8 h. The mixture
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was filtered through a pad of Celite. The filtrate was concentrated in vacuo to give a crude product 8b,
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which was immediately used in the next step without further purification.
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2-((3-Oxocyclohex-1-en-1-yl)methyl)cyclohex-1-en-1-yl trifluoromethanesulfonate (10bd).
A
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mixture of cyclohexanone (471 mg, 4.91 mmol), trimethylsilyl trifluoromethanesulfonate (1.09 g, 4.91
mmol), and PPh3 (1.29 g, 4.91 mmol) in THF (8.2 mL) was stirred at room temperature for 1.5 h and
then cooled to –78 oC. n-BuLi (1.80 mL, 4.41 mmol, 2.5 M solution in hexanes) was added dropwise to
the reaction mixture and stirred for another 1 h. Crude 8b (3.41 mmol) was then added to the mixture
and it was stirred at room temperature for 2 h. The reaction mixture was quenched with water and the
solvent was evaporated. The residue was then dissolved in EtOAc and washed successively with water,
brine and dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was
dissolved in THF (8.2 mL) and added Et3N3HF (2.4 mL, 14.73 mmol) at 0 oC. The mixture was stirred
at 0 oC for 8 h and extracted with EtOAc. The combined organic extracts were washed with brine, dried
over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by
column chromatography on silica gel (EtOAc/hexanes = 1/5) to afford 10bd (669 mg, 59% over 3 steps)
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as a yellow oil. IR (neat) ν 2943, 2866, 1675, 1629, 1409, 1211, 1140, 1022, 887, 817 cm–1; H NMR
(400 MHz, CDCl3) δ 5.84 (s, 1H), 3.06 (s, 2H), 2.40–2.35 (m, 4H), 2.26 (t, J = 6.0 Hz, 2H), 2.09–1.90
(m, 4H), 1.82–1.75 (m, 2H), 1.67–1.60 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 199.5, 161.4,
145.5, 127.1, 125.9, 118.2 (q, J = 317 Hz), 38.8, 37.2, 29.3, 28.7, 27.5, 23.0, 22.5, 21.6; MS (EI) m/z (%
base peak) 339 (M+ + H, 0.3), 257 (6), 172 (58), 107 (31), 91 (76), 83 (22), 69 (100), 65 (37), 58 (21);
HRMS (EI-TOF) m/z: [M]+ Calcd for C14H17F3O4S 338.0800; Found 338.0797.
Methyl 2-((3-oxocyclohex-1-en-1-yl)methyl)cyclohex-1-enecarboxylate (5bd). To a stirred solution
of 10bd (500 mg, 1.48 mmol) in MeOH (13.1 mL) and DMF (4.6 mL) was saturated with CO (Caution:
Carbon monoxide is an extremely flammable and toxic gas. All manipulations with carbon monoxide
must be performed in a well-ventilated fume hood. Keep shield and/or hood sash between reaction
vessel and laboratory worker.).20 A solution of tris(dibenzylideneacetone)dipalladium(0)-chloroform
adduct (155 mg, 0.15 mmol) and 1,1’-bis(diphenylphosphino)ferrocene (164 mg, 0.30 mmol) in DMF
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(4.6 mL) and triethylamine (0.41 mL, 2.94 mmol) were added to the reaction mixture. The mixture was
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heated in an oil bath to 65 C for 12 h. The contents were cooled to room temperature and then added
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saturated aqueous NH4Cl. The aqueous layer was extracted with Et2O. The combined organic extracts
were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude
product was purified by column chromatography on silica gel (EtOAc/hexanes = 1/10) to afford 5bd
(285 mg, 78%) as a yellow oil. IR (neat) ν 2932, 2856, 1709, 1670, 1429, 1232, 1187, 1069, 1045, 966,
888, 759 cm–1; 1H NMR (400 MHz, CDCl3) δ 5.78 (brs, 1H), 3.69 (s, 3H), 3.36 (s, 2H), 2.38–2.29 (m,
6H), 2.10–2.01 (m, 2H), 1.99–1.90 (m, 2H), 1.62–1.55 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ
200.0, 168.6, 164.6, 144.6, 127.7, 125.7, 51.4, 43.1, 37.4, 31.8, 29.8, 26.5, 22.6, 22.1, 22.0; MS (EI) m/z
(% base peak) 248 (M+, 46), 217 (39), 188 (90), 171 (26), 160 (100), 145 (27), 131 (21), 117 (22), 105
(18), 91 (43), 79 (24), 77 (22), 55 (15); HRMS (EI-TOF) m/z: [M]+ Calcd for C15H20O3 248.1412;
Found 248.1409.
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2-((3-Oxocyclohex-1-en-1-yl)methyl)cyclohex-1-ene-1-carbaldehyde (6bd). To a stirred solution of
o
5bd (286 mg, 1.15 mmol) in CH2Cl2 (5.8 mL) at –70 C under Ar atmosphere was added
o
diisobutylaluminum hydride (3.45 mL, 3.45 mmol, 1.0 M solution in hexanes). After stirred at –70 C
for 3 h, the mixture was then stirred at 0 oC for 10 min. The reaction mixture was quenched with water
and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSO4,
filtered and concentrated under reduced pressure to give a residue. A mixture of the crude product and
MnO2 (2.00 g, 23.0 mmol) in CH2Cl2 (5.8 mL) was stirred at room temperature for 8 h. The mixture was
filtered through a pad of Celite. The filtrate was concentrated in vacuo to give a residue, which was
purified by column chromatography on silica gel (EtOAc/hexanes = 1/3) to afford 6bd (156 mg, 62%
over 2 steps) as a yellowish oil. IR (neat) ν 2934, 2859, 1712, 1667, 1626, 1447, 1238, 1190, 1137, 967,
888, 736 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 5.85 (brs, 1H), 3.44 (s, 2H), 2.38 (t, J = 6.7
Hz, 2H), 2.32–2.24 (m, 4H), 2.20–2.16 (m, 2H), 2.07–2.01 (m, 2H), 1.67–1.62 (m, 4H); 13C{1H} NMR
(100 MHz, CDCl3): δ 199.3, 190.4, 162.3, 153.2, 136.4, 127.1, 40.0, 37.2, 32.3, 29.8, 22.6, 22.5, 21.9,
21.5; MS (EI) m/z (% base peak) 218 (M+, 12), 205 (25), 188 (19), 177 (19), 161 (30), 149 (100), 136
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(49), 129 (32), 109 (55), 97 (83), 85 (83), 71 (91), 57 (96), 55 (74); HRMS (EI-TOF) m/z: [M]+ Calcd
for C14H18O2 218.1307; Found 218.1310.
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General Procedure for Intramolecular Stetter Reaction. A suspension of triazolium salt B (182 mg,
0.50 mmol, 1.0 equiv) in absolute ethanol (2.5 mL) was added triethylamine (0.035 mL, 0.25 mmol, 0.5
equiv) under Ar atmosphere at room temperature. After stirred at room temperature for 10 min, a
solution of 6 (0.50 mmol, 1.0 equiv) in absolute ethanol (2.5 mL) was added. The reaction mixture was
then heated in an oil bath to reflux for 48 h. The contents were cooled to room temperature and then
added saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc. The combined organic
extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure.
The crude product was purified by column chromatography on silica gel (EtOAc/hexanes) to afford 11.
2',3',6',7'-Tetrahydrospiro[cyclopentane-1,5'-indene]-3,4'(1'H)-dione (11aa). Chromatography
(EtOAc/hexanes = 1:3); yellow oil; 74 mg; yield 72%; IR (neat) ν 2957, 2924, 2854, 1743, 1704, 1654,
1456, 1394, 1259, 1167, 887 cm–1; 1H NMR (400 MHz, CDCl3) δ 2.73 (d, J = 18.2 Hz, 1H), 2.65–2.20
(m, 9H), 2.17–1.83 (m, 6H); 13C{1H} NMR (125 MHz, CDCl3): δ 217.3, 199.3, 164.4, 136.1, 49.4, 46.9,
37.7, 36.3, 34.5, 30.4, 29.4, 24.0, 21.8; MS (EI) m/z (% base peak) 204 (M+, 61), 176 (100), 149 (42),
148 (26), 133 (12), 108 (100), 91 (30), 79 (58), 77 (26); HRMS (EI-TOF) m/z: [M]+ Calcd for C13H16O2
204.1150; Found 204.1150.
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2',3',6',7'-Tetrahydrospiro[cyclohexane-1,5'-indene]-3,4'(1'H)-dione
(11ab).
Chromatography
(EtOAc/hexanes = 1:4); yellow oil; 72 mg; yield 66%; IR (neat) ν 2936, 2855, 1712, 1656, 1515, 1391,
1228, 940, 887 cm–1; 1H NMR (400 MHz, CDCl3) δ 2.71 (d, J = 14.6 Hz, 1H), 2.58–2.22 (m, 8H), 2.03
(d, J = 14.6 Hz, 1H), 2.03–1.83 (m, 7H), 1.68–1.60 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 210.4,
199.2, 164.0, 135.9, 48.9, 48.2, 40.5, 37.6, 33.3, 30.1, 29.3, 23.4, 21.8, 21.7; MS (EI) m/z (% base peak)
218 (M+, 77), 190 (7), 176 (27), 175 (21), 149 (80), 147 (12), 108 (100), 91 (17), 79 (43), 75 (25), 58
(22); HRMS (EI-TOF) m/z: [M]+ Calcd for C14H18O2 218.1307; Found 218.1304.
2',3',6',7'-Tetrahydrospiro[cycloheptane-1,5'-indene]-3,4'(1'H)-dione
(11ac). Chromatography
(EtOAc/hexanes = 1:3); yellow oil; 67 mg; yield 58%; IR (neat) ν 2926, 2854, 1742, 1698, 1661, 1515,
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1456, 1388, 1260, 1195, 1028, 803 cm–1; H NMR (400 MHz, CDCl3) δ 3.00 (d, J = 12.9 Hz, 1H),
2.66–2.30 (m, 9H), 2.07–2.00 (m, 1H), 1.96–1.76 (m, 7H), 1.66–1.56 (m, 2H); 13C{1H} NMR (100 MHz,
CDCl3): δ 213.2, 199.7, 163.7, 135.4, 50.0, 45.9, 43.8, 37.6, 36.5, 33.3, 29.5, 24.6, 23.9, 23.4, 21.8; MS
(EI) m/z (% base peak) 232 (M+, 10), 214 (3), 197 (2), 177 (13), 149 (79), 127 (7), 108 (100), 99 (13),
85 (36), 71 (38), 57 (20); HRMS (EI-TOF) m/z: [M]+ Calcd for C15H20O2 232.1463; Found 232.1460.
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3',4',5',6',7',8'-Hexahydro-1'H-spiro[cyclopentane-1,2'-naphthalene]-1',3-dione
(11ba).
Chromatography (EtOAc/hexanes = 1:4); yellow oil; 72 mg; yield 66%; IR (neat) ν 2923, 2859, 1742,
1657, 1459, 1379, 1224, 1168, 1075, 967, 845, 799 cm–1; H NMR (500 MHz, CDCl3) δ 2.70 (d, J =
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18.0 Hz, 1H), 2.44–2.36 (m, 2H), 2.29–2.12 (m, 7H), 2.07–1.99 (m, 1H), 1.98 (d, J = 18.0 Hz, 1H),
1.94–1.86 (m, 2H), 1.68–1.63 (m, 2H), 1.59–1.54 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3): δ 217.4,
200.9, 156.0, 130.4, 48.8, 47.5, 36.2, 33.2, 31.6, 30.7, 28.2, 22.3, 22.0, 21.9; MS (EI) m/z (% base peak)
218 (M+, 19), 190 (100), 163 (12), 147 (4), 122 (62), 105 (4), 91 (12), 79 (28), 77 (9), 58 (17); HRMS
(EI-TOF) m/z: [M]+ Calcd for C14H18O2 218.1307; Found 218.1306.
3′,4′,5′,6′,7′,8′-Hexahydro-1′H-spiro[cyclohexane-1,2′-naphthalene]-1′,3-dione
(11bb).
Chromatography (EtOAc/hexanes = 1:3); yellow oil; 76 mg; yield 65%; IR (neat) ν 2930, 2856, 1712,
1654, 1634, 1445, 1385, 1217, 1178, 940, 844 cm–1; H NMR (400 MHz, CDCl3) δ 2.68 (d, J = 14.5
1
Hz, 1H), 2.45–2.00 (m, 9H), 2.01 (d, J = 14.5 Hz, 1H), 1.92–1.80 (m, 4H), 1.70–1.50 (m, 5H); 13C{1H}
NMR (125 MHz, CDCl3): δ 210.4, 200.6, 155.4, 130.4, 48.9, 48.3, 40.5, 32.1, 31.5, 30.2, 27.6, 22.3,
22.1, 21.9, 21.6; MS (EI) m/z (% base peak) 232 (M+, 67), 190 (39), 189 (24), 163 (94), 122 (100), 110
(7), 91 (22), 79 (53), 58 (52); HRMS (EI-TOF) m/z: [M]+ Calcd for C15H20O2 232.1463; Found
232.1466.
3',4',5',6',7',8'-Hexahydro-1'H-spiro[cycloheptane-1,2'-naphthalene]-1',3-dione
(11bc).
Chromatography (EtOAc/hexanes = 1:3); yellow oil; 67 mg; yield 54%; IR (neat) ν 2958, 2927, 2851,
1735, 1716, 1518, 1459, 1378, 1260, 1083, 1020, 967, 802, cm–1; 1H NMR (400 MHz, CDCl3) δ 2.97 (d,
J = 13.0 Hz, 1H), 2.67–2.55 (m, 1H), 2.41–2.32 (m, 1H), 2.34 (d, J = 13.0 Hz, 1H), 2.30–1.98 (m, 7H),
1.90–1.45 (m, 11H); 13C{1H} NMR (100 MHz, CDCl3): δ 213.3, 201.0, 155.2, 129.9, 50.5, 45.2, 43.8,
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36.7, 31.7, 31.5, 27.6, 24.5, 23.9, 22.5, 22.2, 21.9; MS (EI) m/z (% base peak) 246 (M+, 6), 211 (3), 197
(4), 177 (15), 163 (15), 149 (63), 141 (10), 127 (16), 122 (26), 113 (23), 99 (28), 85 (75), 71 (100), 57
(78); HRMS (EI-TOF) m/z: [M]+ Calcd for C16H22O2 246.1620; Found 246.1620.
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3′,4′,6′,7′,8′,9′-Hexahydrospiro[benzo[7]annulene-2,1'-cyclopentane]-1,3'(5H)-dione
(11ca).
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Chromatography (EtOAc/hexanes = 1:3); yellow oil; 70 mg; yield 60%; IR (neat) ν 2920, 2848, 1742,
1651, 1514, 1449, 1375, 1249, 1153, 964, 834 cm–1; 1H NMR (400 MHz, CDCl3) δ 2.69 (d, J = 18.2 Hz,
1H), 2.62–2.18 (m, 9H), 2.07–1.75 (m, 6H), 1.57–1.50 (m, 2H), 1.42–1.35 (m, 2H); 13C{1H} NMR (100
MHz, CDCl3): δ 217.4, 200.2, 161.9, 136.2, 48.0, 47.5, 36.6, 36.3, 33.2, 32.2, 30.7, 30.0, 26.2, 25.4,
24.3; MS (EI) m/z (% base peak) 232 (M+, 0.5), 219 (2), 204 (1), 181 (5), 169 (7), 149 (15), 131 (14),
119 (17), 109 (42), 96 (82), 83 (59), 69 (100), 55 (99); HRMS (EI-TOF) m/z: [M]+ Calcd for C15H20O2
232.1463; Found 232.1460.
4',5',6',7'-Tetrahydrospiro[cyclohexane-1,2'-indene]-1',3(3'H)-dione
(11bd).
Chromatography
(EtOAc/hexanes = 1:3); yellow oil; 34 mg; yield 31%; IR (neat) ν 2929, 2854, 1699, 1643, 1430, 1398,
1
1276, 1226, 1073, 905, 755 cm–1; H NMR (400 MHz, CDCl3) δ 2.65 (d, J = 13.7 Hz, 1H), 2.48–2.10
(m, 7H), 2.05–1.93 (m, 2H), 1.85–1.40 (m, 8H); 13C{1H} NMR (100 MHz, CDCl3): δ 211.0, 208.9,
171.0, 136.1, 51.5, 48.7, 42.7, 40.9, 32.2, 28.3, 24.0, 22.0, 21.5, 20.0; MS (EI) m/z (% base peak) 218
(M+, 29), 190 (6), 175 (10), 161 (10), 149 (100), 147 (9), 136 (6), 105 (5), 91 (13), 79 (9), 58 (72);
HRMS (EI-TOF) m/z: [M]+ Calcd for C14H18O2 218.1307; Found 218.1310.
Acknowledgement. We thank the Ministry of Science and Technology (MOST) of the Republic of
China for financial support (MOST 102-2113-M-194-001-MY3).
Supporting Information Available: Copies of 1H and 13C NMR for compounds 2, 4–6, 7b, 10bd, and
11.
References:
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(1) (a) Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.; Rovis, T. Organocatalytic
5
6
Reactions Enabled by N-Heterocyclic Carbenes. Chem. Rev. 2015, 115, 9307–9387. (b) Tang,
7
8
9
W.; Du, D. Access to Spiro and Fused Indole Derivatives from α,β-Unsaturated Aldehydes
Enabled by N-Heterocyclic Carbene Catalysis. Chem. Rec. 2016, 16, 1489−1500. (c) Zhang, C.-
H.; Hooper, J. F.; Lupton, D. W. N-Heterocyclic Carbene Catalysis via the α,β-Unsaturated Acyl
Azolium. ACS Catal. 2017, 7, 2583−2596 and references cited therein.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2) (a) Enders D, Breuer K. In Addition of Acyl Carbanion Equivalents to Carbonyl Groups and
Enones. Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Eds.; Comprehensive Asymmetric Catalysis
I–III; Springer-Verlag: Berlin, 1999; Vol. III, pp 1093–1104. (b) Johnson, J. S. Catalyzed
Reactions of Acyl Anion Equivalents. Angew. Chem. Int. Ed. 2004, 43, 1326–1328. (c) Vora, H.
U.; Rovis, T. Asymmetric N-Heterocyclic Carbene (NHC) Catalyzed Acyl Anion Reactivity.
Aldrichimica Acta 2011, 44, 3–11. (d) Biju, A.T.; Kuhl, N.; Glorius, F. Extending NHC-
Catalysis: Coupling Aldehydes with Unconventional Reaction Partners. Acc. Chem. Res. 2011,
44, 1182–1195. (e) Bugaut, X.; Glorius, F. Organocatalytic Umpolung: N-Heterocyclic Carbenes
and Beyond. Chem. Soc. Rev. 2012, 41, 3511–3522. (f) Menon, R. S.; Biju, A. T.; Nair, V.
Recent Advances in N-heterocyclic Carbene (NHC)-Catalysed Benzoin Reactions. Beilstein J.
Org. Chem. 2016, 12, 444–461.
(3) (a) Stetter, H.; Kuhlmann, H. Addition von Aliphatischen, Heterocyclischen und Aromatischen
Aldehyden an α,β-Ungesättigte Ketone, Nitrile und Ester. Chem. Ber. 1976, 109, 2890–2896. (b)
Stetter, H.; Kuhlmann, H. Addition Aliphatischer, Heterocyclischer und Aromatischer Aldehyde
an Butenon. Chem. Ber. 1976, 109, 3426–3431. (c) Ciganek, E. Esters of 2,3-Dihydro-3-
oxobenzofuran-2-acetic Acid and 3,4-Dihydro-4-oxo-2H-1-benzopyran-3-acetic Acid by
Intramolecular Stetter Reactions. Synthesis 1995, 1311–1314. (d) Webber, P.; Krische, M. J. The
Catalytic Asymmetric Intramolecular Stetter Reaction. Chemtracts 2007, 19, 262–269. (e) Read
de Alaniz, J.; Rovis, T. The Catalytic Asymmetric Intramolecular Stetter Reaction. Synlett 2009,
24
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Page 25 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1189–1207. (f) Yetra, S. R.; Patra, A.; Biju, A. T. Recent Advances in the N-Heterocyclic
Carbene (NHC)-Organocatalyzed Stetter Reaction and Related Chemistry. Synthesis 2015, 47,
1357–1378. (g) Ghosh, A.; Patra, A.; Mukherjee, S.; Biju, A. T. Synthesis of 2-Aryl
Naphthoquinones by the Cross-Dehydrogenative Coupling Involving an NHC-Catalyzed endo-
Stetter Reaction. J. Org. Chem. 2019, 84, 1103–1110.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4) (a) Tomioka, K.; Koga, K. Noncatalytic Additions to α,β-Unsaturated Carbonyl Compounds, In
Asymmetric Synthesis, Vol. 2; Morrison, J. D., Ed.; Academic Press: New York, 1983, 201–224.
(b) Yoshikoshi, A.; Miyashita, M. Oxoalkylation of Carbonyl Compounds with Conjugated
Nitro Olefins. Acc. Chem. Res. 1985, 18, 284–290. (c) Rosini, G.; Ballini, R. Functionalized
Nitroalkanes as Useful Reagents for Alkyl Anion Synthons. Synthesis 1988, 833–847.
(5) (a) Hsu, D.-S.; Hsu, C.-W. Spiranes Synthesis Based on Samarium Diiodide-Mediated Reductive
Cyclization. Tetrahedron Lett. 2012, 53, 2185–2188. (b) Hsu, D.-S.; Chen, C.-H.; Hsu, C.-W.
Synthesis of Spiranes by Thiol-Mediated Acyl Radical Cyclization. Eur. J. Org. Chem. 2016,
2016, 589–598.
(6) (a) Marshall, J.A.; Brady, S. F.; Andersen, N. H. In The Chemistry of Spiro[4.5]decane
Sesquiterpenes; Herz, W.; Grisebach, H.; Kirby, G. W. Ed.; Fortschritte der Chemie Organischer
Naturstoffe; Springer-Verlag: New York, 1974; Vol. 31, pp 283–376. (b) Martín, J. D.; Darias, J.
In Algal Sesquiterpenoids; Scheuer, P. J., Ed.; Marine Natural Products: Chemical and
Biological Perspectives; Academic: New York, 1978; Vol. I, pp 125–171. (c) Erickson, K. L. In
Constituents of Laurencia; Scheuer, P. J., Ed.; Marine Natural Products: Chemical and
Biological Perspectives; Academic: New York, 1983; Vol. V, pp131–257. (d) Fraga, B. M.
Natural Sesquiterpenoids. Nat. Prod. Rep. 2012, 29, 1334–1366. (e) Blunt, J. W.; Copp, B. R.;
Keyzers, R. A.; Munro, M. H. G.; Prinsep, M. R. Marine Natural Products. Nat. Prod. Rep. 2014,
31, 160–258.
25
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Page 26 of 28
1
2
3
4
5
6
7
8
9
(7) (a) Krapcho, A. P. Synthesis of Carbocyclic Spiro Compounds via Intramolecular Alkylation
Routes. Synthesis 1974, 383–419. (b) Krapcho, A. P. Synthesis of Carbocyclic Spiro Compounds
via Rearrangement Routes. Synthesis 1976, 425–444. (c) Sannigrahi, M. Stereocontrolled
Synthesis of Spirocyclics. Tetrahedron 1999, 55, 9007–9071. (d) Pradhan, R.; Patra, M.; Behera,
A. K.; Mishra, B. K.; Behera, R. K. A Synthon Approach to Spiro Compounds. Tetrahedron
2006, 62, 779–828. (e) Kotha, S.; Deb, A. C.; Lahiri, K.; Manivannan, E. Selected Synthetic
Strategies to Spirocyclics. Synthesis 2009, 165–193. (f) Rios, R. Enantioselective Methodologies
for the Synthesis of Spiro Compounds. Chem. Soc. Rev. 2012, 41, 1060–1074. (g) Undhein, K.
Preparation and Structure Classification of Heteraspiro[m.n]alkanes. Synthesis 2014, 46, 1957–
2006. (h) Undhein, K. Stereoselective Reactions in Preparation of Chiral α-
Heteraspiro[m.n]alkanes. Synthesis 2015, 47, 2497–2522. (i) Liu, Y.; Zhang, X.; Zeng, R.;
Zhang, Y.; Dai, Q.-S.; Leng, H.-J.; Gou, X.-J.; Li, J.-L. Recent Advances in the Synthesis of
Spiroheterocycles via N-Heterocyclic Carbene Organocatalysis. Molecules 2017, 22, 1882.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(8) Hsu, D.-S.; Cheng, C.-Y. Construction of Spirofused Tricyclic Frameworks by NHC-Catalyzed
Intramolecular Stetter Reaction of a Benzaldehyde Tether with a Cyclic Enone. J. Org. Chem.
2019, 84, 10832–10842.
(9) (a) Orellana, A.; Rovis, T. Towards the Total Synthesis of FD-838: Modular Enantioselective
Assembly of the Core. Chem. Commun. 2008, 730–732. (b) Lathrop, S. P.; Rovis, T. A
Photoisomerization-Coupled Asymmetric Stetter Reaction: Application to the Total Synthesis of
Three Diastereomers of (–)-Cephalimysin A. Chem. Sci. 2013, 4, 1668–1673. (c) Dell’Amico, L.;
Rassu, G.; Zambrano, V.; Sartori, A.; Curti, C.; Battistini, L.; Pelosi, G.; Casiraghi, G.; Zanardi,
F. Exploring the Vinylogous Reactivity of Cyclohexenylidene Malononitriles: Switchable
Regioselectivity in the Organocatalytic Asymmetric Addition to Enals Giving Highly
Enantioenriched Carbabicyclic Structures. J. Am. Chem. Soc. 2014, 136, 11107–11114.
26
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6
7
8
9
(10) (a) Xu, G.; Hou, A.-J.; Zheng, Y.-T.; Zhao, Y.; Li, X.-L.; Peng, L.-Y.; Zhao, Q.-S. Przewalskin
B, a Novel Diterpenoid with an Unprecedented Skeleton from Salvia przewalskii Maxim. Org.
Lett. 2007, 9, 291–293. (b) Kim, C. S.; Shin, B.; Kwon, O. W.; Kim, S. Y.; Choi, S. U.; Oh, D.-
C.; Kim, K. H.; Lee, K. R. Holophyllin A, a Rearranged Abietane-Type Diterpenoid from the
Rrunk of Abies holophylla. Tetrahedron Lett. 2014, 55, 6504–6507.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
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51
52
53
54
55
56
57
58
59
60
(11) Petersen,M. D.; Boye, S. V.; Nielsen,E. H.; Willumsen, J.; Sinning, S.; Wiborg, O.; Bols, M.
Synthesis, Inhibition and Binding of Simple non-Nitrogen Inhibitors of Monoamine Transporters.
Bioorg. Med. Chem. 2007, 15, 4159–4174.
(12) Mori, A.; Kawashima, J.; Shimada, T.; Suguro, M.; Hirabayashi, K.; Nishihara, Y. Non-
Sonogashira-Type Palladium-Catalyzed Coupling Reactions of Terminal Alkynes Assisted by
Silver(I) Oxide or Tetrabutylammonium Fluoride. Org. Lett. 2000, 19, 2935–2937.
(13) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. A Convenient Synthesis of Acetylenes: Catalytic
Substitutions of Acetylenic Hydrogen with Bromoalkenes, Iodoarenes, and Bromopyridines.
Tetrahedron Lett. 1975, 16, 4467–4470. (b) Chinchilla, R.; Nájera, C. Recent Advances in
Sonogashira Reactions. Chem. Soc. Rev. 2011, 40, 5084–5121.
(14) Nicolaou, K. C.; Sun, Y.-P.; Peng, X.-S.; Polet, D.; Chen, D. Y.-K. Total Synthesis of (+)-
Cortistatin A. Angew. Chem. Int. Ed. 2008, 47, 7310–7313.
(15) Kozikowxski, A. P.; Jung, S. H. Phosphoniosilylation: An Efficient and Practical Method for the
β-Functionalization of Enones. J. Org. Chem. 1986, 51, 3400–3402.
(16) Reisman, S. E.; Ready, J. M.; Hasuoka, A.; Smith, C. J.; Wood, J. L. Total Synthesis of (±)-
Welwitindolinone A Isonitrile. J. Am. Chem. Soc. 2006, 128, 1448–1449.
27
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The Journal of Organic Chemistry
Page 28 of 28
1
2
3
4
5
6
7
8
(17) Gagnier, S. V.; Larock, R. C. Palladium-Catalyzed Carbonylative Cyclization of Unsaturated
Aryl Iodides and Dienyl Triflates, Iodides, and Bromides to Indanones and 2-Cyclopentenones. J.
Am. Chem. Soc. 2003, 125, 4804–6507.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(18) Furuichi, N.; Hara, H.; Osaki, T.; Mori, H.; Katsumura, S. Highly Efficient Stereocontrolled
Total Synthesis of the Polyfunctional Carotenoid Peridinin. Angew. Chem. Int. Ed. 2002, 41,
1023–1026.
(19) (a) Trost, B. M.; Shuey, C. D.; Dininno, F.; Mcelvain, S. S. A Stereocontrolled Total Synthesis
of (±)-Hirsutic Acid C. J. Am. Chem. Soc. 1979, 101, 1284–1285. (b) McErlean, C. S. P.; Willis,
A. C. Application of an Intramolecular Stetter Reaction to Access trans,syn,trans-Fused Pyrans.
Synlett 2009, 233–236.
(20) National Research Council; Prudent Practices in the Laboratory: Handling and Management of
Chemical Hazards, Updated Version; The National Academies Press: Washington, DC, 2011.
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