Construction of spirofused tricyclic frameworks by NHC-catalyzed intramolecular stetter reaction of a benzaldehyde tether with a cyclic exsnone

Article abstract of DOI:10.1021/acs.joc.9b01403

Various benzaldehyde tethers with a cyclic enone were prepared from commercially available 2-hydroxybenzaldehydes via a three-step sequence involving triflate formation, Sonogashira cross-coupling, and regioselective hydrogenation. These substrates were t

Full text of DOI:10.1021/acs.joc.9b01403

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Article
Construction of Spiro-Fused Tricyclic Frameworks by NHC-Catalyzed
Intramolecular Stetter Reaction of Benzaldehyde Tether with a Cyclic Enone
Day-Shin Hsu, and Chiao-Yun Cheng
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01403 • Publication Date (Web): 09 Aug 2019
Downloaded from pubs.acs.org on August 10, 2019
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Construction of Spiro-Fused Tricyclic Frameworks by
NHC-Catalyzed Intramolecular Stetter Reaction of
Benzaldehyde Tether with a Cyclic Enone
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Day-Shin Hsu* and Chiao-Yun Cheng
Department of Chemistry and Biochemistry, National Chung Cheng University, Minhsiung, Taiwan 621
E-mail: chedsh@ccu.edu.tw
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RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
Keywords: Spiro compounds, enone-benzaldehydes, N-heterocyclic carbene, Stetter, cyclization
Bn
O
O
N
O
Cl
CHO
HO
S
A
Et N, EtOH, reflux
R
n
3
m
m
R
12 examples
X
X
n
30%87% yields
8,11,14
1517
Abstract: Various benzaldehyde tethers with a cyclic enone were prepared from commercially available
2-hydroxybenzaldehydes via a three-step sequence involving triflate formation, Sonogashira cross-
coupling and regioselective hydrogenation. These substrates were then exposed to an N-heterocyclic
carbene, whereupon intramolecular Stetter reaction proceeded smoothly to give various spiro-fused
tricyclic 1,4-diketones in 30%-87% yields. Furaldehyde and nicotinaldehyde derivatives also
participated in the reaction under the Stetter conditions.
Introduction
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Recently, spiro compounds have received much attention in organic and medicinal chemistry
because of their interesting conformational features and structural implications in biological systems.1
The asymmetric nature of the molecules, which is attributable to the chiral spiro carbon, is one of the
important criteria for biological activity. Spiro core systems are also found in a variety of natural
products with wide-ranging biological activities (Figure 1).2 Moreover, the unique structural features of
spiro compounds have been exploited for the synthesis of new catalysts and ligands with excellent
results.3 Consequently, the development of new and efficient strategies for constructing the spiro core
has become a major focal point for synthetic chemistry.4 Recently, we developed intramolecular
cyclizations of enone-aldehydes via samarium diiodide-mediated reductive cyclization5 and thiol-
mediated acyl radical cyclization6 to prepare spirocyclic γ-hydroxyketones and 1,4-diketones,
respectively (Scheme 1). As a continuation of our work, we report here the intramolecular Stetter
reaction of benzaldehyde tethers with a cyclic enone to construct various spiro-fused tricyclic 1,4-
diketones. The challenge in this strategy is the 1,4-addition of a Breslow intermediate7 to the β-
disubstituted enone, which is less reactive toward nucleophiles than are the corresponding β-mono-
substituted and unsubstituted enones due to steric hindrance.
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H
O
O
OH
O
O
MeO
nidemone
norascyronone A
O
OMe
O
O
HO
O
HN
O
fredericamycin A
O
O
O
OPPh2
OPPh2
OH
OH
P
OH
spirOP
spinol
spinol derived
phosphoric acid
Figure 1. Examples of natural products and chiral ligands containing a carbocyclic spiro skeleton
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Scheme 1. Strategies for constructing spiro skeletons
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5
previous work
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O
O
O
O
O
O
O
O
SmI2
OH
R
R
R
R
R
n
n
n
n
m
m
m
m
m
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n
O
O
thiol
O
R
O
AIBN
m
n
this work
O
O
N-heterocyclic
CHO
carbene
R
n
m
m
R
X
X
n
The Stetter reaction, which was discovered in 1976,8a,b involves the conjugate addition of an
aldehyde to an electron-deficient alkene to form a 1,4-dicarbonyl system in the presence of a catalytic
amount of N-heterocyclic carbene (NHC).8 This reaction can be performed in an asymmetric fashion by
utilizing a chiral NHC.9 NHCs used to prepare spirocyclic structures are well known;4i however, only a
few examples based on the Stetter reaction have been reported to date. A literature survey revealed that
Gravel and coworkers used domino intermolecular Stetter reaction–intramolecular Michael or aldol
reactions to construct the spiro bis-indane framework with a spiro[4.4]nonane core.10 Ye and coworker
employed NHC-catalyzed [4+1] annulation of phthalaldehyde and N-phenylmaleimide to form a
spirocyclic hydroxyindanone with a heterocyclic spiro[4.4]nonane structure via a tandem process
involving an intermolecular Stetter reaction, proton shift, and aldol reaction.11 Rovis and coworker
reported an intramolecular Stetter reaction to construct a heterocyclic spiro[4.4]nonane skeleton and
applied it to the total synthesis of (–)-cephalimysin A.12 Later, Zanardi and coworkers adopted an
intramolecular 1,6-Stetter reaction to prepare spiro[4.5]decanone derivatives.13 It is noteworthy that
these intramolecular Stetter reactions led to the formation of a five-membered ring in the spirocyclic
structures. In contrast to the literature procedures, our method results in the creation of a six-membered
ring in the spirocyclic skeletons.
Results and Discussion
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(a) Preparation of Sonogashira Cross-coupling Substrates. Our synthesis strategy toward
spiro precursors 8 involved the combination of enynones 4 and triflates 6, followed by selective
reduction of the triple bond. Therefore, the necessary enynones 4 were prepared from cyclic enones 1, as
outlined in Scheme 2. 1,2-Addition of the lithium acetylide, which was generated from
trimethylsilylacetylene and n-BuLi,14 to the ketone afforded tertiary allylic alcohols 2. Oxidation of 2
with PDC15 afforded enynones 3, and subsequent removal of the silyl group16 furnished the desired
conjugated enynones 4.
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Scheme 2. Preparation of conjugated cyclic enynones 4
TMS
, n-BuLi
PDC,
celite
TMS
THF,
0 oC to rt,
3 h
CH2Cl2,
rt, 36 h
O
OH
m
m
1a: m = 0
1b: m = 1
1c: m = 2
2a: m = 0 (89%)
2b: m = 1 (92%)
2c: m = 2 (93%)
O
O
KF, BTEAC
THF, rt, 1 h
m
m
TMS
3a: m = 0 (92%)
3b: m = 1 (93%)
3c: m = 2 (90%)
4a: m = 0 (86%)
4b: m = 1 (92%)
4c: m = 2 (84%)
On the other hand, triflates
6
were obtained from commercially available 2-
hydroxybenzaldehydes 5 in excellent yields by using phenylbis(trifluoromethanesulfonimide) as a
triflating reagent (Scheme 3).17a
Scheme 3. Preparation of triflates 6
R1
R1
R2
R3
OTf
PhNTf2,
DMAP
R2
R3
OH
Et3N,
rt, 0.5 h
CHO
CHO
R4
R4
5a: R1 = R2 = R3 = R4 = H
5b: R1 = OMe, R2 = R3 = R4 = H
5c: R1 = H, R2 = OMe, R3 = R4 = H
6a (91%)
6b (98%)
6c (99%)
6d (99%)
6e (98%)
6f (97%)
5d: R1 = R2 = H, R3 = OMe, R4 = H
5e: R1 = R2 = R3 = H, R4 = OMe,
5f: R1 = R2 = H, R3 = Me, R4 = H
5g: R1 = R2 = H, R3 = CO2Me, R4 = H 6g (87%)
(b) Preparation of Cyclic Enone-benzaldehydes. Coupling reactions of 4 and 6 were carried
out with triethylamine in the presence of bis(triphenylphosphine)palladium(II) dichloride and copper(I)
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iodide in DMF at 120 C.18 As an exception, the reaction of the triflate with an ester moiety reaction
occurred at room temperature (Table 1, entry 9). The desired coupling products 7 were obtained in
moderate to good yields. The coupling reaction of triflate 6e and enynone 4a gave the product in only
50% yield, probably because 4a was thermal unstable and easily decomposed under heat (entry 2). The
next step was selective hydrogenation at the triple bond.19 After screening multiple solvents for this
reaction, we found that is difficult to identify a common solvent system for the regioselective
hydrogenation. In all the solvents tested, either the reduction did not proceed or the double bond was
also reduced along with the triple bond. Therefore, selective reduction of the alkyne moiety with
hydrogen in the presence of 10% Pd/C was carried out in a suitable solvent, as indicated in Table 1 (0.1
M), at room temperature to furnish enone-benzaldehydes 8. Careful control of the reaction time for the
selective reduction of the triple bond is essential to prevent overreduction.
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Table 1. Preparation of aromatic spiro precursors 8
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O
O
4
5
6
7
8
9
O
1
4
R
R
4ac
H ,
Pd/C
2
3
2
R
R
OTf
CHO
CHO
m
4
3
m
4
3
R
R
R
R
solvent,
rt
PdCl (PPh ) ,
2
3 2
m
CHO
CuI, Et N, DMF,
3
1
1
R
R
temp, time
2
2
R
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R
6
7
8
1
2
3
4
a: R = R = R = R = H
1
2
3
4
b: R = OMe, R = R = R = H
1
2
3
4
c: R = H, R = OMe, R = R = H
1
2
3
4
d: R = R = H, R = OMe, R = H
1
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3
4
e: R = R = R = H, R = OMe,
1
2
3
4
f: R = R = H, R = OMe, R = H
1
2
3
4
g: R = R = H, R = CO Me, R = H
2
Sonogashira
temp / time
Hydrogenation
solvent / time
Entry
Triflate
6a
Enynone
4a: m = 0
4a: m = 0
4b: m = 1
4b: m = 1
Product 7 (yield)
7aa (65%)
Product 8 (yield)
o
1
2
3
4
5
6
7
8
i-PrOH : EtOAc (1:1) / 1 h 8aa (74%)
i-PrOH : EtOAc (1:1) / 1 h 8ea (70%)
120 C / 10 min
o
6e
7ea (50%)
120 C / 60 min
o
6a
7ab (92%)
EtOAc / 1 h
i-PrOH : EtOAc (1:1) / 1 h 8bb (83%)
MeOH : THF (1:1) / 1 h
MeOH : THF (1:1) / 2.5 h 8db (64%)
EtOAc / 2.5 h 8eb (62%)
8ab (91%)
120 C / 15 min
o
6b
7bb (77%)
120 C / 20 min
o
6c
6d
6e
6f
4b: m = 1
4b: m = 1
4b: m = 1
4b: m = 1
7cb (78%)
7db (81%)
7eb (81%)
7fb (72%)
8cb (90%)
120 C / 20 min
o
120 C / 40 min
o
120 C / 15 min
o
MeOH : THF (1:1) / 0.5 h 8fb (82%)
120 C / 40 min
9
6g
6a
4b: m = 1
4c: m = 2
rt / 30 min
7gb (76%)
7ac (77%)
MeOH : THF (1:1) / 1.5 h 8gb (86%)
i-PrOH : EtOAc (1:1) / 1 h 8ac (64%)
o
10
120 C / 30 min
In order to expand the substrate scope of the intramolecular Stetter reaction, heteroaromatic
aldehydes 11 and 14 were also prepared from the corresponding aryl iodide 920 and bromide 12,21
respectively, in good overall yields by using the same procedure, i.e., Sonogashira cross-coupling and
selective hydrogenation (Scheme 4).
Scheme 4. Preparation of heteroaromatic spiro precursors 11 and 14
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O
O
4
5
6
7
8
9
4b
CHO
I
H , Pd/C
2
CHO
PdCl (PPh ) ,
MeOH
2
3 2
O
rt, 0.5 h
56%
Et N, DMF,
rt, 1 h
72%
3
O
9
10
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O
CHO
O
11
O
O
4b
CHO
Br
CHO
H , Pd/C
2
PdCl (PPh ) ,
EtOAc,
rt, 3 h
N
2
3 2
Et N, DMF,
rt, 3 h
87%
3
N
13
12
57%
O
CHO
N
14
(c) Intramolecular Stetter Reaction. With these spiro precursors in hand, we first used 8ab to
optimize the reaction conditions. Compound 8ab was first treated with thiazolium salt A (0.2 equiv)22
and triethylamine (1.0 equiv) in ethanol (0.05 M) at room temperature. However, the reaction did not
proceed at this temperature even after 168 h, and the starting material was recovered (Table 2, entry 1).
o
Upon increasing the reaction temperature to 80 C, the intramolecular Stetter reaction proceeded
smoothly to give the desired product 15ab in 47% yield, along with the starting material, after 24 h
(entry 2). In refluxing ethanol, the reaction proceeded to completion within 24 h to afford 15ab in 85%
yield (entry 3). Decreasing the amount of thiazolium salt A from 0.2 equiv to 0.1 equiv under the same
conditions led to the formation of spiro compound 15ab in 49% yield over a longer reaction time (entry
4). Increasing the amount of triethylamine from 1.0 equiv to 2.0 equiv decreased the product yield (entry
5). Dilution of the reaction medium (0.01 M) also caused a decrease in the yield (entry 6). When other
alcoholic solvents such as i-PrOH and t-BuOH were employed, the reaction took a longer time to
complete and lower yields of the product were observed (entries 7–8). Moreover, the reaction did not
proceed in aprotic solvents (PhMe and THF) under the same conditions (entries 9–10). This was
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presumably due to the intermolecular hydrogen bonding between the carbonyl group of the enone and
the alcohol, which may increase the electrophilicity of the enone (Figure 2).23 In the absence of
hydrogen bonding, the enone moiety would not be sufficiently electrophilic to induce cyclization for the
formation of a six-membered ring under Stetter conditions. Next, we used another thiazolium salt B and
triazolium salt C, but the yields did not improve and a longer time was required for completion of the
reaction (entries 11–12). We also attempted to use a chiral tetracyclic triazolium salt D for the
asymmetry Stetter reaction. Unfortunately, when the reaction was carried out under the same conditions,
a complicated mixture of the products was observed (entry 13). The Stetter reaction did not proceed in
this case, probably due to the bulky Breslow intermediate, which does not readily undergo 1,4-addition
to the β-disubstituted enone. Changing the base from triethylamine to 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) also gave a complicated mixture of products (entry 14), whereas the use of
diisopropylethylamine and Cs2CO3 resulted in decreased yields (entries 15–16). Therefore, the best
yield for this reaction was obtained with 0.2 equiv of thiazolium salt A and 1.0 equiv of triethylamine in
refluxing ethanol for 24 h.
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Table 2. Conditions for attempted intramolecular Stetter reaction
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O
O
O
H
4
O
5
precatalyst (0.2 equiv)
6
7
8
base (1.0 equiv)
solvent (0.05 M), temp, time
8ab
15ab
9
entry
precatalyst
base
solvent
EtOH
EtOH
EtOH
temp
yield
time
10
11
12
13
14
15
16
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a
Et N
3
1
2
3
A
A
A
rt
168 h
24 h
24 h

o
b
Et N
80
C
47%
3
Et N
3
reflux
85%
c
Et N
4
5
6
A
EtOH
EtOH
reflux
reflux
reflux
48 h
24 h
36 h
49%
55%
60%
3
d
Et N
3
A
A
e
Et N
3
EtOH
Et N
3
7
A
i-PrOH
reflux
48 h
53%
b
Et N
8
9
A
A
A
t-BuOH
PhMe
THF
reflux
168 h
24 h
48 h
24%
3
o
a
Et N
80
C

3
a
Et N
3
10
reflux

Et N
11
12
13
14
B
C
D
A
EtOH
EtOH
EtOH
EtOH
reflux
reflux
reflux
reflux
72 h
36 h
24 h
24 h
60%
81%
3
Et N
3
f
Et N
3

f
DBU

15
16
A
A
DIPEA
Cs CO
EtOH
EtOH
reflux
reflux
48 h
24 h
62%
17%
2
3
aNo reaction. bReaction was not completed. cUsed 0.1 equiv of precatalyst A.
dUsed 2.0 equiv of Et3N. eReaction was carried In 0.01 M of EtOH.
fComplicated mixture.
C F
BF
6
5
4
N
N
Cl
BF
Bn
4
I
N
N
N
O
N
N
C F
6
5
N
HO
S
HO
S
A
B
C
D
Bn
OH
N
HO
S
H
RO
O
Figure 2. Intermolecular hydrogen bonding assists Stetter reaction
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With the optimized conditions in hand, we next used other enone-aldehydes in the reaction. Most
of these reactions were completed within 48 h and the desired spirocyclic products were produced in
moderate to good yields (Scheme 5). Reactions of benzaldehyde tethers with a five-, six-, and seven-
membered ring of the enone proceeded smoothly (15aa–15ac). Both electron-donating and electron-
withdrawing substituents at different positions on the phenyl ring were well tolerated under the
optimized conditions (15ea, 15bb–15gb). The reaction of substrate 8cb bearing a methoxy group at the
para-position of benzaldehyde was very sluggish (168 h) and a low yield (30%) of product 15cb was
obtained. This was presumably because the electron-donating group at the 4-position of the benzene ring
decreased the reactivity of benzaldehyde toward the NHC. Heterocyclic moieties such as furaldehyde
and nicotinaldehyde were compatible with these reaction conditions and gave the corresponding
cyclized products, albeit in slightly low yields (16, 17).
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12
13
14
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Scheme 5. Intramolecular Stetter reaction
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Bn
N
O
O
Cl
HO
S
O
A
CHO
(0.2 equiv.)
Et3N (1.0 equiv.)
EtOH (0.05 M), reflux, time
R
m
m
R
n
X
X
n
8,11,14
1517
O
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O
O
O
O
O
O
O
OMe
OMe
15aa (24 h / 74%)
15ea (24 h / 68%)
15ab (24 h / 85%)
15bb (24 h / 65%)
O
O
O
O
O
O
O
O
OMe
OMe
Me
OMe
15cb (168 h / 30%)
15db (24 h / 65%)
15eb (24 h / 87%)
15fb (48 h / 69%)
O
O
O
O
O
O
O
O
CO2Me
O
N
15gb (48 h / 68%)
15ac (24 h / 66%)
16 (36 h / 46%)
17 (24 h / 60%)
.
1
13
The structures of 15–17 were characterized by IR spectroscopy, H and C NMR, and low- and
high-resolution mass spectrometry. The 13C NMR spectra of these compounds showed spiroatom
absorptions at around 50 ppm in the 13C NMR spectra. Note that spiro compound 15ea has been used in
the total synthesis of the proposed structure of nidemone (Figure 3).24a
O
O
O
OMe
O
OH
MeO
nidemone
15ea
Figure 3. Application of 15ea to the total synthesis of nidemone
Conclusion
In summary, we have developed an efficient and general method for the preparation of spiro-
fused tricyclic 1,4-diketones. A variety of aromatic aldehydes underwent the intramolecular Stetter
reaction under NHC-catalyzed conditions. Intramolecular Stetter reactions for constructing a six-
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membered ring are known.9f However, to the best of our knowledge; this is the first example of the use
of the intramolecular Stetter reaction to construct a six-membered ring in spirocyclic structures. Our
methodology was also successfully applied to the total synthesis of nidemone.24 Efforts to develop an
asymmetric version of this reaction using chiral catalysts 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. Melting points are uncorrected. IR spectra
were recorded as films on KBr plates. 1H NMR spectra were obtained in CDCl3 at 400 MHz. 13C NMR
spectra were obtained at 100 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 Propargylic alcohols 2. To a stirred solution of
trimethylsilylacetylene (8.5 mL, 60.0 mmol) in THF (70 mL) under Ar atmosphere at 0 oC was added n-
BuLi (2.5 M in hexanes, 24.0 mL, 60.0 mmol). The mixture was stirred at room temperature for 0.5 h
o
and then cooled to 0 C. Cyclic enone 1 (50.0 mmol) was added to the reaction mixture and stirred at
room temperature for 3 h. The mixture was quenched with saturated aqueous NaCl solution and
extracted with Et2O. The combined extracts were washed with brine, dried over MgSO4, filtered and
concentrated. The residue was used in the next step without further purification. Analytically pure 2 was
purified by silica-gel chromatography.
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1-(Trimethylsilylethynyl)-2-cyclopenten-1-ol (2a). Chromatography (EtOAc/hexanes = 1:5); colorless
oil; 8.02 g; yield 89%; IR (neat) ν 3403, 3058, 2960, 2163, 1733, 1250, 1047, 860, 843 cm–1; 1H NMR
(400 MHz, CDCl3) δ 6.01–5.98 (m, 1H), 5.82–5.79 (m, 1H) , 2.58–2.49 (m, 1H), 2.46–2.38 (m, 2H),
2.18–2.12 (m, 1H), 2.05 (brs, 1H), 0.17 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 135.3, 134.7,
108.0, 88.6, 78.1, 41.0, 31.0, –0.1; MS (EI) m/z (% base peak) 180 (M+, 2), 165 (100), 163 (19), 147
(17), 145 (12), 105 (13), 99 (40), 75 (37), 73(25); HRMS (EI-TOF) m/z: [M]+ Calcd for C10H16OSi
180.0970; Found 180.0973.
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1-(Trimethylsilylethynyl)-2-cyclohexen-1-ol (2b).14 Chromatography (EtOAc/hexanes = 1:5); white
o
solid; 8.94 g; yield 92%; mp 39–40 C; IR (neat) ν 3358, 3031, 2954, 2158, 1250, 843 cm–1; 1H NMR
(400 MHz, CDCl3) δ 5.84–5.80 (m, 1H), 5.75–5.71 (m, 1H), 2.08–1.98 (m, 4H), 1.92–1.86 (m, 1H),
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1.79–1.71 (m, 2H), 0.16 (s, 9H); C{1H} NMR (100 MHz, CDCl3): δ 130.3, 129.9, 109.2, 87.7, 65.4,
37.8, 24.6, 19.0, –0.1; MS (EI) m/z (% base peak) 194 (M+, 3), 177 (100), 166 (36), 151 (35), 135 (8),
133 (8), 105 (7), 97 (21), 75 (42), 73 (34); HRMS (EI-TOF) m/z: [M]+ Calcd for C11H18OSi 194.1127;
Found 194.1124.
1-(Trimethylsilylethynyl)-2-cyclohepten-1-ol (2c). Chromatography (EtOAc/hexanes = 1:10); white
o
solid; 9.69 g; yield 93%; mp 54–55 C; IR (neat) ν 3380, 3026, 2930, 2856, 2163, 1446, 1250, 1025,
843, 759 cm–1; 1H NMR (400 MHz, CDCl3) δ 5.80–5.70 (m, 2H), 2.27–2.12 (m, 2H), 2.06 (brs, 1H),
1.97–1.82 (m, 4H), 1.79–1.70 (m, 1H), 1.49–1.40 (m, 1H), 0.17 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3): δ 137.4, 131.4, 107.5, 89.0, 71.4, 41.0, 27.4, 26.7, 25.6, –0.1; MS (EI) m/z (% base peak) 208
(M+, 5), 191 (100), 175 (3), 163 (3), 147 (2), 135 (5), 117 (10), 111 (7), 97 (7), 73 (29); HRMS (EI-TOF)
m/z: [M]+ Calcd for C12H20OSi 208.1283; Found 208.1280.
General Procedure for Preparation of Trimethylsilylenynones 3. A mixture of PDC (43.3 g, 115.0
mmol) and Celite (43.3 g) was added 2 (50.0 mmol) and CH2Cl2 (250 mL, 0.2 M) at room temperature.
The mixture was stirred at room temperature for 36 h. The mixture was then filtered through a pad of
Celite and washed with Et2O. The solvent was evaporated to give a crude product which was used in the
next step without further purification. Analytically pure 3 was purified by silica-gel chromatography.
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3-(Trimethylsilylethynyl)-2-cyclopenten-1-one (3a).24b Chromatography (EtOAc/hexanes = 1:10);
yellowish oil; 8.20 g; yield 92%; IR (neat) ν 2961, 2150, 1709, 1582, 1267, 1171, 848 cm–1; 1H NMR
(400 MHz, CDCl3) δ 6.28 (t, J = 1.9 Hz, 1H), 2.75–2.71 (m, 2H), 2.44–2.40 (m, 2H), 0.24 (s, 9H);
13C{1H} NMR (100 MHz, CDCl3): δ 208.6, 156.1, 136.3, 111.0, 99.4, 34.2, 32.0, –0.9; MS (EI) m/z (%
base peak) 178 (M+, 22), 163 (100), 133 (1), 119 (1), 107 (8), 97 (2), 83 (4), 77 (3), 75 (3); HRMS (EI-
TOF) m/z: [M]+ Calcd for C10H14OSi 178.0814; Found 178.0815.
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3-(Trimethylsilylethynyl)-2-cyclohexen-1-one (3b).25 Chromatography (EtOAc/hexanes = 1:10);
yellowish oil; 8.94 g; yield 93%; IR (neat) ν 2956, 2147, 1677, 1585, 1249, 845 cm–1; 1H NMR (400
MHz, CDCl3) δ 6.21 (t, J = 1.4 Hz, 1H), 2.46–2.37 (m, 4H) , 2.05–1.98 (m, 2H), 0.21 (s, 9H); 13C{1H}
NMR (100 MHz, CDCl3): δ 198.6, 142.9, 133.0, 105.9, 103.4, 37.2, 30.2, 22.5, –0.5; MS (EI) m/z (%
base peak) 192(M+, 56), 177 (100), 164 (37), 149 (52), 121 (11), 107 (8), 97 (12), 73 (14); HRMS (EI-
TOF) m/z: [M]+ Calcd for C11H16OSi 192.0970; Found 192.0973.
3-(Trimethylsilylethynyl)-2-cyclohepten-1-one (3c). Chromatography (EtOAc/hexanes = 1:10);
yellow oil; 9.29 g; yield 90%; IR (neat) ν 2956, 2138, 1664, 1590, 1252, 845 cm–1; 1H NMR (400 MHz,
CDCl3) δ 6.31 (s, 1H), 2.62–2.57 (m, 4H) , 1.87–1.78 (m, 4H), 0.21 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3): δ 203.1, 139.8, 137.1, 106.3, 102.2, 42.5, 34.0, 25.2, 21.1, –0.3; MS (EI) m/z (% base peak) 206
(M+, 20), 191 (100), 178 (22), 163 (42), 149 (9), 135 (7), 107 (7), 97 (8), 75 (11), 73 (16); HRMS (EI-
TOF) m/z: [M]+ Calcd for C12H18OSi 206.1127; Found 206.1128.
General Procedure for Preparation of Enynones 4. A mixture of 3 (50.0 mmol) and
benzyltriethylammonium chloride (BTEAC, 1.14 g, 5.00 mmol) in THF (100 mL, 0.5 M) at room
temperature was added 2 M KF (32.5 mL, 65.0 mmol). The reaction mixture was stirred at room
temperature for 1 h and extracted with Et2O. The combined extracts were washed with brine, dried over
MgSO4, filtered and concentrated. The crude product was purified by column chromatography on silica
gel to afford 4.
3-Ethynyl-2-cyclopenten-1-one (4a). Chromatography (Et2O/hexanes = 1:5); white solid; 4.56 g; yield
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86%; mp 55–56 C;24b IR (neat) ν 3194, 2926, 2854, 2095, 1701, 1664, 1578, 1435, 1285, 1177, 872,
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729 cm–1; 1H NMR (400 MHz, CDCl3) δ 6.32 (t, J = 1.7 Hz, 1H), 3.85 (s, 1H) , 2.75–2.71 (m, 2H),
2.42–2.39 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 209.1, 155.7, 137.7, 92.2, 78.9, 34.6, 32.2; MS
(EI) m/z (% base peak) 106 (M+, 100), 105 (12), 78 (47), 77 (20), 52 (15), 51 (13); HRMS (EI-TOF) m/z:
[M]+ Calcd for C7H6O 106.0419; Found 106.0420.
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3-Ethynyl-2-cyclohexen-1-one (4b).16 Chromatography (Et2O/hexanes = 1:5); yellow oil; 5.53 g; yield
92%; IR (neat) ν 3295, 2913, 2089, 1694, 1610, 855, 726 cm–1; 1H NMR (400 MHz, CDCl3) δ 6.21 (s,
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1H), 3.53 (s, 1H) , 2.44–2.36 (m, 4H), 2.03–1.97 (m, 2H); C{1H} NMR (100 MHz, CDCl3): δ 198.5,
142.2, 134.0, 87.1, 82.4, 37.3, 30.1, 22.4; MS (EI) m/z (% base peak) 120 (M+, 63), 92 (100), 91 (33), 64
(35), 63 (20), 58 (12), 51 (4); HRMS (EI-TOF) m/z: [M]+ Calcd for C8H8O 120.0575; Found 120.0578.
3-Ethynyl-2-cyclohepten-1-one (4c). Chromatography (Et2O/hexanes = 1:5); yellow oil; 5.64 g; yield
84%; IR (neat) ν 3250, 2940, 2086, 1658, 1593, 1259, 884 cm–1; 1H NMR (400 MHz, CDCl3) δ 6.34 (s,
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1H), 3.35 (s, 1H) , 2.62–2.58 (m, 4H), 1.89–1.72 (m, 4H); C{1H} NMR (100 MHz, CDCl3): δ 202.9,
138.7, 137.9, 85.1, 83.7, 42.6, 34.0, 25.3, 21.1; MS (EI) m/z (% base peak) 134 (M+, 19), 125 (31), 105
(42), 91 (71), 75 (100), 73 (44), 63 (19), 51 (14); HRMS (EI-TOF) m/z: [M]+ Calcd for C9H10O
134.0732; Found 134.0731.
General Procedure for Preparation of Trifluoromethanesulfonate 6. A mixture of 5 (5.00 mmol), N-
phenylbis(trifluoromethanesulfonimide) (1.97 g, 5.50 mmol), and 4-dimethylaminopyridine (DMAP)
o
(61 mg, 0.50 mmol) in CH2Cl2 (10 mL, 0.5 M) was added triethylamine (1.4 mL, 10.0 mmol) at 0 C.
The reaction mixture was stirred at room temperature for 0.5 h. Then the solvent was removed in vacuo
gave a residue, which was purified by silica-gel column chromatography on silica gel to afford 6.
2-Formylphenyl trifluoromethanesulfonate (6a).17a Chromatography (EtOAc/hexanes = 1:10);
colorless oil; 1.16 g; yield 91%; IR (neat) ν 1699, 1607, 1490, 1423, 1204, 1136, 1076, 899, 772 cm–1;
1H NMR (400 MHz, CDCl3) δ 10.27 (s, 1H), 8.01 (dd, J = 7.6, 2.0 Hz, 1H) , 7.73 (ddd, J = 8.2, 7.6, 2.0
Hz, 1H), 7.56 (dd, J = 7.6, 7.6 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ
186.5, 149.8, 135.9, 130.9, 128.9, 128.5, 122.4, 118.6 (q, J = 319 Hz); MS (EI) m/z (% base peak) 254
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(M+, 11), 253 (10), 189 (59), 185 (11), 162 (11), 120 (100), 104 (17), 92 (44), 81 (15), 69 (55), 65 (54);
HRMS (EI-TOF) m/z: [M]+ Calcd for C8H5F3O4S 253.9861; Found 253.9859.
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2-Formyl-6-methoxyphenyl trifluoromethanesulfonate (6b).17b Chromatography (EtOAc/hexanes =
9
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1:3); white solid; 1.39 g; yield 98%; mp 36–37 C; IR (neat) ν 1707, 1580, 1480, 1423, 1289, 1208,
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1137, 882, 785, 758 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.25 (s, 1H), 7.53 (dd, J = 8.0, 1.6 Hz, 1H),
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7.47 (dd, J = 8.0, 8.0 Hz, 1H), 7.31 (dd, J = 8.0, 1.6 Hz, 1H), 3.97 (s, 3H); C{1H} NMR (100 MHz,
CDCl3): δ 186.7, 151.6, 139.1, 129.5, 129.1, 121.2, 118.6, 118.6 (q, J = 319 Hz), 56.5; MS (EI) m/z (%
base peak) 284 (M+, 37), 225 (22), 151 (100), 136 (14), 108 (29), 92 (44), 65 (29); HRMS (EI-TOF) m/z:
[M]+ Calcd for C9H7F3O5S 283.9966; Found 283.9969.
2-Formyl-5-methoxyphenyl trifluoromethanesulfonate (6c).17c Chromatography (EtOAc/hexanes =
1:3); colorless oil; 1.41 g; yield 99%; IR (neat) ν 1699, 1612, 1505, 1428, 1249, 1212, 1139, 1075, 955,
831 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 7.95 (d, J = 8.7 Hz, 1H) , 7.03 (dd, J = 8.7, 2.4
Hz, 1H), 6.87 (d, J = 2.4 Hz, 1H), 3.93 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 185.4, 165.3, 151.3,
132.2, 121.8, 118.6 (q, J = 319 Hz), 114.2, 108.2, 56.2; MS (EI) m/z (% base peak) 284 (M+, 100), 283
(20), 219 (25), 151 (80), 150 (45), 134 (17), 108 (21), 95 (32), 69 (31); HRMS (EI-TOF) m/z: [M]+
Calcd for C9H7F3O5S 283.9966; Found 283.9965.
2-Formyl-4-methoxyphenyl trifluoromethanesulfonate (6d).17a Chromatography (EtOAc/hexanes =
1:3); colorless oil; 1.41 g; yield 99%; IR (neat) ν 1701, 1589, 1490, 1426, 1212, 1140, 1031, 870 cm–1;
1H NMR (400 MHz, CDCl3) δ 10.23 (s, 1H), 7.43 (d, J = 3.4 Hz, 1H) , 7.32 (d, J = 9.2 Hz, 1H), 7.20
(dd, J = 9.2, 3.4 Hz, 1H), 3.88 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 186.3, 159.3, 143.6, 129.3,
123.7, 122.2, 118.6 (q, J = 319 Hz), 113.0, 56.0; MS (EI) m/z (% base peak) 284 (M+, 35), 225 (7), 151
(100), 123 (23), 108 (19), 95 (25), 92 (16), 69 (18); HRMS (EI-TOF) m/z: [M]+ Calcd for C9H7F3O5S
283.9966; Found 283.9965.
2-Formyl-3-methoxyphenyl trifluoromethanesulfonate (6e).17d Chromatography (EtOAc/hexanes =
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1:3); white solid; 1.39 g; yield 98%; mp 70–71 C; IR (neat) ν 3105, 2925, 2782, 1692, 1610, 1476,
1426, 1276, 1202, 1139, 1064, 955, 833 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.46 (s, 1H), 7.59 (dd, J
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= 8.4, 8.0 Hz, 1H) , 7.06 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 3.98 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 187.0, 162.9, 148.0, 135.7, 118.6 (q, J = 319 Hz), 117.9, 114.5, 111.9, 56.6; MS (EI)
m/z (% base peak) 284 (M+, 60), 151 (100), 123 (22), 108 (25), 95 (27), 69 (28), 65 (17), 63 (8), 52 (8);
HRMS (EI-TOF) m/z: [M]+ Calcd for C9H7F3O5S 283.9966; Found 283.9965.
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2-Formyl-4-methylphenyl trifluoromethanesulfonate (6f).17e Chromatography (EtOAc/hexanes =
1:10); white solid; 1.30 g; yield 97%; mp 139–140 oC; IR (neat) ν 2868, 2764, 1705, 1606, 1488, 1428,
1214, 1140, 872, 615 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.23 (s, 1H), 7.78 (d, J = 2.1 Hz, 1H) , 7.50
13
(dd, J = 8.4, 2.1 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 2.45 (s, 3H); C{1H} NMR (100 MHz, CDCl3): δ
186.7, 147.9, 139.4, 136.4, 131.0, 128.1, 122.2, 118.6 (q, J = 319 Hz), 20.8; MS (EI) m/z (% base peak)
268 (M+, 67), 203 (41), 175 (16), 151 (18), 135 (100), 134 (48), 107 (52), 91 (15), 77 (99), 69 (62);
HRMS (EI-TOF) m/z: [M]+ Calcd for C9H7F3O4S 268.0017; Found 268.0020.
Methyl 3-formyl-4-trifluoromethylsulfonyloxybenzoate (6g).17f Chromatography (EtOAc/hexanes =
1:10); yellowish oil; 1.36 g; yield 87%; IR (neat) ν 3111, 2960, 1732, 1606, 1432, 1300, 1245, 1217,
1137, 1112, 919, 867, 609 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.29 (s, 1H), 8.65 (d, J = 2.2 Hz, 1H) ,
8.37 (dd, J = 8.6, 2.2 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 3.98 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3):
δ 185.7, 164.4, 152.1, 136.6, 132.4, 131.0, 128.4, 122.7, 118.5 (q, J = 319 Hz), 52.8; MS (EI) m/z (%
base peak) 312 (M+, 15), 281 (44), 217 (85), 189 (40), 178 (100), 162 (31), 136 (28), 120 (31), 119 (25),
92 (98), 69 (63), 58 (80); HRMS (EI-TOF) m/z: [M]+ Calcd for C10H7F3O6S 311.9915; Found 311.9917.
General Procedure for Sonogashira Cross-coupling. To a stirred solution of 6, 9, 12 (2.00 mmol),
bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2) (70 mg, 0.10 mmol), CuI (38 mg, 0.20
mmol), and 4 (4.00 mmol) in DMF (13 mL, 0.15 M) was added triethylamine (1.25 mL, 9.00 mmol)
under Ar atmosphere at room temperature. The reaction mixture was then stirred at room temperature or
heated in an oil bath to 120 oC for a period of time (see Table 1 and Scheme 4 for the duration of heating
and temperature). 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 to
afford 7, 10, 13.
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2-[(3-Oxocyclopent-1-en-1-yl)ethynyl]benzaldehyde (7aa). Chromatography (EtOAc/hexanes = 1:3);
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yellowish solid; 273 mg; yield 65%; mp 72–73 C; IR (neat) ν 3073, 2924, 2852, 2198, 1704, 1674,
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1580, 1175, 758 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.50 (s, 1H), 7.98 (d, J = 7.6 Hz, 1H) , 7.66–7.62
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(m, 2H), 7.58–7.53 (m, 1H), 6.44 (t, J = 2.2 Hz, 1H), 2.91–2.87 (m, 2H), 2.54–2.50 (m, 2H); C{1H}
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NMR (100 MHz, CDCl3): δ 208.9, 190.7, 155.5, 137.1, 136.0, 133.9, 133.6, 130.2, 128.0, 124.6, 99.4,
90.8, 34.8, 32.4; MS (EI) m/z (% base peak) 210 (M+, 30), 182 (100), 181 (84), 153 (86), 152 (40), 126
(41), 101 (10), 76 (17), 58 (16); HRMS (EI-TOF) m/z: [M]+ Calcd for C14H10O2 210.0681; Found
210.0680.
2-Methoxy-6-[(3-oxocyclopent-1-en-1-yl)ethynyl]benzaldehyde
(7ea).24a
Chromatography
o
(EtOAc/hexanes = 1:2); orange-red solid; 240 mg; yield 50%; mp 127–128 C; IR (neat) ν 2932, 2839,
1708, 1586, 1488, 1270, 1177, 753 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.58 (s, 1H), 7.52 (dd, J = 8.4,
7.6 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.40 (t, J = 1.6 Hz, 1H), 3.95 (s, 3H),
2.90–2.87 (m, 2H), 2.50–2.47 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 209.4, 189.2, 161.5, 156.5,
136.6, 134.5, 126.4, 125.0, 123.3, 113.1, 102.2, 89.4, 56.1, 34.8, 32.4; MS (EI) m/z (% base peak) 240
(M+, 16), 230 (8), 202 (10), 189 (11), 161 (12), 148 (100), 115 (7), 105 (8), 91 (22); HRMS (EI-TOF)
m/z: [M]+ Calcd for C15H12O3 240.0786; Found 240.0784.
2-[(3-Oxocyclohex-1-en-1-yl)ethynyl]benzaldehyde (7ab). Chromatography (EtOAc/hexanes = 1:5);
yellow solid; 413 mg; yield 92%; mp 59–60 oC; IR (neat) ν 3065, 2948, 2743, 2202, 1697, 1671, 1590,
1190, 765 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 7.87 (d, J = 7.8 Hz, 1H) , 7.56–7.52 (m,
2H), 7.48–7.43 (m, 1H), 6.27 (t, J = 1.6 Hz, 1H), 2.53 (dt, J = 6.1, 1.6 Hz, 2H), 2.41 (t, J = 6.8 Hz, 2H),
2.07–2.01 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 198.4, 190.9, 142.1, 136.0, 133.9, 133.5, 133.3,
129.8, 127.8, 125.0, 94.6, 94.5, 37.3, 30.2, 22.6; MS (EI) m/z (% base peak) 224 (M+, 67), 206 (11), 196
(28), 181 (21), 168 (100), 167 (31), 139 (71), 126 (9), 89 (5); HRMS (EI-TOF) m/z: [M]+ Calcd for
C15H12O2 224.0837; Found 224.0834.
3-Methoxy-2-[(3-oxocyclohex-1-en-1-yl)ethynyl]benzaldehyde
(7bb).
Chromatography
(EtOAc/hexanes = 1:3); yellow solid; 392 mg; yield 77%; mp 114–115 oC; IR (neat) ν 2943, 2841, 2195,
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1663, 1585, 1474, 1273, 1242, 1187, 756 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.48 (s, 1H), 7.55 (d, J
= 7.9 Hz, 1H), 7.47 (dd, J = 7.9, 7.9 Hz, 1H), 7.15 (d, J = 7.0 Hz, 1H), 6.37 (t, J = 1.6 Hz, 1H), 3.95 (s,
3H), 2.61 (dt, J = 6.3, 1.6 Hz, 2H), 2.47 (t, J = 6.7 Hz, 2H), 2.14–2.07 (m, 2H); 13C{1H} NMR (100
MHz, CDCl3): δ 198.5, 191.1, 160.8, 142.6, 137.1, 132.9, 130.7, 119.5, 115.7, 114.4, 98.9, 91.1, 56.3,
37.3, 30.3, 22.6; MS (EI) m/z (% base peak) 254 (M+, 19), 253 (12), 212 (9), 198 (13), 183 (13), 155 (8),
111 (13), 97 (18), 83 (16), 71 (19), 58 (100); HRMS (EI-TOF) m/z: [M]+ Calcd for C16H14O3 254.0943;
Found 254.0946.
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4-Methoxy-2-[(3-oxocyclohex-1-en-1-yl)ethynyl]benzaldehyde
(7cb).
Chromatography
o
(EtOAc/hexanes = 1:3); yellow solid; 397 mg; yield 78%; mp 96–97 C; IR (neat) ν 2946, 2838, 2753,
1684, 1592, 1297, 1225, 1025 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.25 (s, 1H), 7.83 (dd, J = 8.6, 2.8
Hz, 1H), 6.98–6.92 (m, 2H), 6.26 (t, J = 1.6 Hz, 1H), 3.84 (s, 3H), 2.52 (t, J = 5.9 Hz, 2H), 2.40 (dt, J =
13
7.5, 1.6 Hz, 2H), 2.09–2.02 (m, 2H); C{1H} NMR (100 MHz, CDCl3): δ 198.1, 189.3, 163.6, 142.0,
133.1, 129.8, 129.5, 126.8, 117.3, 116.3, 94.4, 94.0, 55.6, 37.1, 30.0, 22.4; MS (EI) m/z (% base peak)
254 (M+, 10), 222 (6), 198 (6), 155 (3), 85 (65), 83 (100), 58 (83); HRMS (EI-TOF) m/z: [M]+ Calcd for
C16H14O3 254.0943; Found 254.0943.
5-Methoxy-2-[(3-oxocyclohex-1-en-1-yl)ethynyl]benzaldehyde
(7db).
Chromatography
o
(EtOAc/hexanes = 1:3); yellow solid; 412 mg; yield 81%; mp 91–92 C; IR (neat) ν 2943, 2736, 1704,
1667, 1609, 1500, 1260, 1037 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 7.50 (d, J = 8.7 Hz,
1H), 7.39 (d, J = 2.6 Hz, 1H), 7.12 (dd, J = 8.7, 2.6 Hz, 1H), 6.28 (brs, 1H), 3.86 (s, 3H), 2.55 (dt, J =
6.0, 1.5 Hz, 2H), 2.44 (t, J = 6.7 Hz, 2H), 2.11–2.04 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ
198.4, 190.7, 160.7, 142.5, 137.5, 135.0, 132.6, 121.5, 117.6, 110.5, 95.0, 93.5, 55.7, 37.3, 30.3, 22.6;
MS (EI) m/z (% base peak) 254 (M+, 34), 226 (12), 211 (8), 198 (21), 183 (18), 155 (16), 127 (12), 113
(4), 58 (100); HRMS (EI-TOF) m/z: [M]+ Calcd for C16H14O3 254.0943; Found 254.0940.
2-Methoxy-6-[(3-oxocyclohex-1-en-1-yl)ethynyl]benzaldehyde
(7eb).
Chromatography
o
(EtOAc/hexanes = 1:2); orange-yellow solid; 412 mg; yield 81%; mp 114–116 C; IR (neat) ν 2945,
2874, 2195, 1688, 1664, 1572, 1470, 1295, 1258, 1188, 1136, 1062, 966, 793 cm–1; 1H NMR (400 MHz,
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CDCl3) δ 10.56 (s, 1H), 7.49 (dd, J = 8.4, 7.7 Hz, 1H), 7.16 (d, J = 7.7 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H),
6.32 (t, J = 1.4 Hz, 1H), 3.93 (s, 3H), 2.59 (dt, J = 6.1, 1.4 Hz, 2H), 2.44 (t, J = 6.7 Hz, 2H), 2.11–2.04
(m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 198.6, 189.2, 161.5, 143.0, 134.4, 132.9, 126.4, 125.1,
123.7, 112.8, 97.3, 93.1, 56.0, 37.4, 30.2, 22.6; MS (EI) m/z (% base peak) 254 (M+, 100), 239 (16), 225
(18), 211 (23), 198 (47), 165 (15), 155 (21), 139 (21), 127 (10); HRMS (EI-TOF) m/z: [M]+ Calcd for
C16H14O3 254.0943; Found 254.0943.
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5-Methyl-2-[(3-oxocyclohex-1-en-1-yl)ethynyl]benzaldehyde (7fb). Chromatography (EtOAc/hexanes
= 1:5); yellow solid; 343 mg; yield 72%; mp 63–64 oC; IR (neat) ν 2946, 2842, 2195, 1692, 1670, 1585,
1493, 1277, 1226 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 7.72 (brs, 1H), 7.47 (d, J = 7.9 Hz,
1H), 7.39 (d, J = 7.9 Hz, 1H), 6.29 (t, J = 1.4 Hz, 1H), 2.55 (dt, J = 6.0, 1.4 Hz, 2H), 2.44 (t, J = 6.7 Hz,
2H), 2.41 (s, 3H), 2.10–2.04 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 198.5, 191.1, 142.2, 140.6,
135.8, 134.8, 133.5, 133.0, 128.2, 122.3, 95.0, 93.9, 37.3, 30.3, 22.6, 21.5; MS (EI) m/z (% base peak)
238 (M+, 93), 223 (10), 210 (27), 195 (24), 182 (100), 153 (46), 139 (30), 115 (12), 84 (35), 85 (51);
HRMS (EI-TOF) m/z: [M]+ Calcd for C16H14O2 238.0994; Found 238.0995.
Methyl
3-formyl-4-[(3-oxocyclohex-1-en-1-yl)ethynyl]benzoate
(7gb).
Chromatography
(EtOAc/hexanes = 1:3); yellow solid; 429 mg; yield 76%; mp 101–102 oC; IR (neat) ν 2953, 2855, 1726,
1695, 1674, 1602, 1435, 1300, 1235, 1178, 1119, 766 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.45 (s, 1H),
8.55 (d, J = 1.7 Hz, 1H), 8.22 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 6.35 (t, J = 1.2 Hz, 1H), 3.94
(s, 3H), 2.58 (dt, J = 6.1, 1.2 Hz, 2H), 2.46 (t, J = 6.8 Hz, 2H), 2.14–2.07 (m, 2H); 13C{1H} NMR (100
MHz, CDCl3): δ 198.2, 189.9, 165.4, 141.5, 136.0, 134.2, 133.9, 133.7, 131.3, 129.2, 128.7, 96.8, 93.6,
52.7, 37.3, 30.1, 22.5; MS (EI) m/z (% base peak) 282 (M+, 29), 225 (49), 195 (20), 167 (18), 139 (20),
92 (100), 65 (45), 57 (23); HRMS (EI-TOF) m/z: [M]+ Calcd for C17H14O4, 282.0892; Found 282.0892.
2-[(3-Oxocyclohept-1-en-1-yl)ethynyl]benzaldehyde (7ac). Chromatography (EtOAc/hexanes = 1:3);
yellowish oil; 367 mg; yield 77%; IR (neat) ν 2924, 2852, 1699, 1592, 1464, 1260, 1190, 759 cm–1; 1H
NMR (400 MHz, CDCl3) δ 10.49 (s, 1H), 7.94 (d, J = 7.4 Hz, 1H) , 7.62–7.56 (m, 2H), 7.52–7.47 (m,
1H), 6.44 (brs, 1H), 2.74 (t, J = 5.9 Hz, 2H), 2.67 (t, J = 6.3 Hz, 2H), 1.97–1.83 (m, 4H); 13C{1H} NMR
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(100 MHz, CDCl3): δ 202.8, 191.0, 138.9, 137.3, 136.0, 133.8, 133.4, 129.5, 127.7, 125.5, 97.3, 91.4,
42.6, 34.0, 25.3, 21.1; MS (EI) m/z (% base peak) 238 (M+, 100), 210 (48), 195 (37), 181 (99), 167 (40),
152 (57), 139 (47), 126 (29), 115 (28), 85 (28), 71 (28), 58 (57); HRMS (EI-TOF) m/z: [M]+ Calcd for
C16H14O2 238.0994; Found 238.0996.
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2-[(3-Oxocyclohex-1-en-1-yl)ethynyl]-3-furaldehyde (10). Chromatography (EtOAc/hexanes = 1:3);
orange-yellow solid; 308 mg; yield 72%; mp 58–59 oC; IR (neat) ν 3128, 2951, 2188, 1677, 1426, 1243,
1134, 755 cm–1; 1H NMR (400 MHz, CDCl3) δ 9.98 (s, 1H), 7.45 (d, J = 2.0 Hz, 1H) , 6.78 (d, J = 2.0
Hz, 1H), 6.33 (brs, 1H), 2.54 (t, J = 6.1 Hz, 2H), 2.43 (t, J = 6.7 Hz, 2H), 2.11–2.04 (m, 2H); 13C{1H}
NMR (100 MHz, CDCl3): δ 197.9, 184.0, 145.8, 143.1, 140.3, 134.1, 130.8, 108.5, 97.0, 85.3, 37.3,
29.6, 22.5; MS (EI) m/z (% base peak) 214 (M+, 100), 186 (43), 185 (36), 158 (52), 157 (21), 129 (22),
128 (11), 102 (29), 58 (90); HRMS (EI-TOF) m/z: [M]+ Calcd for C13H10O3 214.0630; Found 214.0628.
2-[(3-Oxocyclohex-1-en-1-yl)ethynyl]nicotinaldehyde (13). Chromatography (EtOAc/hexanes = 1:10);
yellow solid; 392 mg; yield 87%; mp 88–89 oC; IR (neat) ν 3056, 2948, 2868, 1791, 1698, 1673, 1578,
1428, 1243, 966 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.49 (s, 1H), 8.82 (dd, J = 4.8, 1.8 Hz, 1H), 8.21
(dd, J = 7.9, 1.8 Hz, 1H), 7.45 (dd, J = 7.9, 4.8 Hz, 1H), 6.41 (t, J = 1.6 Hz, 1H), 2.60 (dt, J = 6.0, 1.6
Hz, 2H), 2.47 (t, J = 6.7 Hz, 2H), 2.14–2.07 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 198.0, 189.8,
154.5, 144.6, 140.9, 135.1, 134.6, 132.2, 124.1, 93.4, 93.1, 37.3, 29.9, 22.5; MS (EI) m/z (% base peak)
225 (M+, 69), 196 (37), 182 (18), 169 (100), 168 (46), 141 (36), 140 (24), 114 (15); HRMS (EI-TOF)
m/z: [M]+ Calcd for C14H11NO2 225.0790; Found 225.0789.
General Procedure for Regioselective Hydrogenation. To a mixture of 7, 10, 13 (100 mg) and 10%
Pd/C (20 mg) in flask was added solvent (0.1 M) (see Table 1 and Scheme 4 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 and Scheme 4 for the duration of hydrogenation). Filtration and concentration in vacuo gave a
residue, which was purified by column chromatography on silica gel to afford 8, 11, 14.
2-[(3-Oxocyclopent-1-en-1-yl)ethyl]benzaldehyde (8aa). Chromatography (EtOAc/hexanes = 1:2);
colorless solid; 75 mg; yield 74%; mp 54–55 oC; IR (neat) ν 3075, 2961, 2926, 2743, 1698, 1603, 1191,
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800, 756 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.17 (s, 1H), 7.82 (dd, J = 7.8, 1.0 Hz, 1H), 7.54 (ddd, J
= 7.8, 7.5, 1.3 Hz, 1H), 7.46 (ddd, J = 7.5, 7.5, 1.0 Hz, 1H), 7.29 (d, J = 7.5 Hz, 1H), 6.00 (t, J = 1.2 Hz,
1H), 3.32 (t, J = 8.0 Hz, 2H), 2.70 (t, J = 8.0 Hz, 2H), 2.66–2.63 (m, 2H), 2.44–2.41 (m, 2H); 13C{1H}
NMR (100 MHz, CDCl3): δ 210.0, 193.1, 181.5, 142.9, 134.7, 133.9, 133.7, 131.0, 129.9, 127.2, 35.3,
35.0, 31.6, 30.9; MS (EI) m/z (% base peak) 214 (M+, 5), 186 (100), 159 (14), 130 (19), 118 (21), 90
(16), 58 (15); HRMS (EI-TOF) m/z: [M]+ Calcd for C14H14O2 214.0994; Found 214.0997.
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2-Methoxy-6-(2-(3-oxocyclopent-1-en-1-yl)ethyl)benzaldehyde
(8ea).24a
Chromatography
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(EtOAc/hexanes = 1:2); white solid; 71 mg; yield 70%; mp 89–90 C; IR (neat) ν 2926, 2851, 1706,
1682, 1596, 1473, 1269, 1181, 1075, 792 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.62 (s, 1H), 7.43 (dd, J
= 8.4, 7.6 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 5.97 (s, 1H), 3.91 (s, 3H), 3.19 (t,
J = 8.0 Hz, 2H), 2.68–2.63 (m, 4H), 2.41–2.38 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 210.1,
192.1, 182.3, 163.6, 144.3, 134.9, 129.6, 123.2, 122.8, 109.9, 55.8, 35.3, 34.8, 31.8, 31.6; MS (EI) m/z
(% base peak) 244 (M+, 60), 216 (8), 187 (11), 163 (10), 148 (100), 109 (10), 96 (11), 83 (22), 58 (25);
HRMS (EI-TOF) m/z: [M]+ Calcd for C15H16O3 244.1099; Found 244.1100.
2-[(3-Oxocyclohex-1-en-1-yl)ethyl]benzaldehyde (8ab). Chromatography (EtOAc/hexanes = 1:5);
yellowish solid; 93 mg; yield 91%; mp 38–39 oC; IR (neat) ν 3028, 2939, 2868, 2741, 1695, 1667, 1599,
1453, 1252, 1193, 887, 756 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.14 (s, 1H), 7.79 (d, J = 7.5 Hz, 1H) ,
7.51 (dd, J = 7.8, 7.4 Hz, 1H), 7.41 (dd, J = 7.5, 7.4 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 5.87 (brs, 1H),
3.22 (t, J = 8.0 Hz, 2H), 2.47 (t, J = 8.0 Hz, 2H), 2.37–2.32 (m, 4H), 2.02–1.94 (m, 2H); 13C{1H} NMR
(100 MHz, CDCl3): δ 199.8, 192.9, 165.2, 143.1, 134.3, 133.8, 133.6, 131.1, 127.0, 126.0, 39.5, 37.2,
30.8, 29.6, 22.6; MS (EI) m/z (% base peak) 228 (M+, 28), 210 (15), 185 (32), 172 (29), 159 (39), 157
(36), 129 (41), 118 (86), 115 (19), 91 (85), 90 (19), 58 (100); HRMS (EI-TOF) m/z: [M]+ Calcd for
C15H16O2 228.1150; Found 228.1151.
3-Methoxy-2-[(3-oxocyclohex-1-en-1-yl)ethyl]benzaldehyde
(8bb).
Chromatography
o
(EtOAc/hexanes = 1:3); yellow solid; 84 mg; yield 83%; mp 68–69 C; IR (neat) ν 2943, 2730, 1695,
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7.10 (dd, J = 7.5, 1.2 Hz, 1H), 5.86 (brs, 1H), 3.86 (s, 3H), 3.26 (t, J = 8.0 Hz, 2H), 2.42–2.33 (m, 6H),
2.03–1.96 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 200.0, 192.8, 166.0, 157.8, 134.7, 131.8, 127.5,
125.8, 125.2, 115.6, 55.9, 38.2, 37.3, 29.6, 22.7, 22.5; MS (EI) m/z (% base peak) 258 (M+, 43), 215 (6),
189 (9), 161 (11), 149 (100), 148 (21), 115 (4), 91 (43), 84 (9), 58 (26); HRMS (EI-TOF) m/z: [M]+
Calcd for C16H18O3 258.1256; Found 258.1253.
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4-Methoxy-2-[(3-oxocyclohex-1-en-1-yl)ethyl]benzaldehyde (8cb). Chromatography (EtOAc/hexanes
o
= 1:3); yellowish solid; 91 mg; yield 90%; mp 47–48 C; IR (neat) ν 2940, 2868, 2736, 1682, 1600,
1566, 1250, 1106, 811 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 7.75 (d, J = 8.6 Hz, 1H), 6.90
(dd, J = 8.6, 2.4 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 5.89 (brs, 1H), 3.88 (s, 3H), 3.21 (t, J = 8.0 Hz, 2H),
2.49 (t, J = 8.0 Hz, 2H) 2.39–2.34 (m, 4H), 2.03–1.96 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ
199.9, 191.3, 165.3, 163.7, 145.8, 137.4, 127.3, 126.1, 116.9, 111.6, 55.5, 39.4, 37.3, 31.2, 29.7, 22.7;
MS (EI) m/z (% base peak) 258 (M+, 18), 215 (9), 202 (8), 189 (19), 176 (9), 148 (78), 121 (7), 91 (7),
58 (100); HRMS (EI-TOF) m/z: [M]+ Calcd for C16H18O3 258.1256; Found 258.1255.
5-Methoxy-2-[(3-oxocyclohex-1-en-1-yl)ethyl]benzaldehyde
(8db).
Chromatography
o
(EtOAc/hexanes = 1:3); yellow solid; 65 mg; yield 64%; mp 55–56 C; IR (neat) ν 2944, 2837, 2737,
1705, 1667, 1609, 1500, 1260, 1037, 885 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.12 (s, 1H), 7.29 (d, J
= 2.6 Hz, 1H), 7.14 (d, J = 8.5 Hz, 1H), 7.04 (dd, J = 8.5, 2.6 Hz, 1H), 5.84 (brs, 1H), 3.82 (s, 3H), 3.13
(t, J = 8.0 Hz, 2H), 2.43 (t, J = 8.0 Hz, 2H), 2.35–2.30 (m, 4H), 1.99–1.92 (m, 2H); 13C{1H} NMR (100
MHz, CDCl3): δ 199.8, 192.1, 165.1, 158.5, 135.4, 134.4, 132.2, 126.1, 120.3, 117.1, 55.5, 40.1, 37.3,
29.73, 29.72, 22.6; MS (EI) m/z (% base peak) 258 (M+, 22), 230 (9), 215 (16), 202 (12), 189 (25), 176
(23), 148 (100), 121 (10), 91 (10), 83 (13), 58 (74); HRMS (EI-TOF) m/z: [M]+ Calcd for C16H18O3
258.1256; Found 258.1256.
2-Methoxy-6-[(3-oxocyclohex-1-en-1-yl)ethyl]benzaldehyde (8eb). Chromatography (EtOAc/hexanes
= 1:2); colorless solid; 63 mg; yield 62%; mp 96–97 oC; IR (neat) ν 2930, 2856, 1728, 1682, 1667, 1595,
1473, 1267, 1076, 796 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.62 (s, 1H), 7.42 (dd, J = 8.4, 7.6 Hz, 1H),
6.87 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 5.87 (brs, 1H), 3.90 (s, 3H), 3.14–3.09 (m, 2H), 2.45
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(t, J = 7.9 Hz, 2H), 2.40–2.33 (m, 4H), 2.02–1.95 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 200.0,
192.1, 165.9, 163.5, 144.6, 134.9, 125.9, 123.3, 122.8, 109.8, 55.8, 39.4, 37.4, 32.0, 29.6, 22.7; MS (EI)
m/z (% base peak) 258 (M+, 19), 215 (11), 189 (19), 176 (15), 148 (100), 121 (8), 91 (11), 58 (42);
HRMS (EI-TOF) m/z: [M]+ Calcd for C16H18O3 258.1256; Found 258.1256.
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5-Methyl-2-[(3-oxocyclohex-1-en-1-yl)ethyl]benzaldehyde (8fb). Chromatography (EtOAc/hexanes =
1:3); yellowish oil; 83 mg; yield 82%; IR (neat) ν 2926, 2867, 2733, 1687, 1668, 1625, 1568, 1242,
1156, 885, 831 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.12 (s, 1H), 7.59 (d, J = 1.0 Hz, 1H), 7.31 (dd, J
= 7.7, 1.0 Hz, 1H), 7.14 (d, J = 7.7 Hz, 1H), 5.86 (brs, 1H), 3.18 (t, J = 8.0 Hz, 2H), 2.46 (t, J = 8.0 Hz,
2H), 2.40 (s, 3H), 2.37–2.33 (m, 4H), 2.02–1.95 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 199.7,
193.0, 165.2, 140.2, 136.8, 134.7, 134.6, 133.5, 131.1, 126.1, 39.7, 37.3, 30.4, 29.7, 22.7, 20.7; MS (EI)
m/z (% base peak) 242 (M+, 40), 199 (23), 186 (17), 173 (30), 171 (30), 133 (100), 132 (94), 105 (88),
83 (64), 77 (38), 58 (42); HRMS (EI-TOF) m/z: [M]+ Calcd for C16H18O2 242.1307; Found 242.1306.
Methyl
3-formyl-4-[(3-oxocyclohex-1-en-1-yl)ethyl]benzoate
(8gb).
Chromatography
(EtOAc/hexanes = 1:1); yellow solid; 87 mg; yield 86%; mp 106–108 oC; IR (neat) ν 2950, 2866, 1723,
1665, 1610, 1436, 1293, 1195, 1113, 762 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.19 (s, 1H), 8.47 (d, J
= 1.6 Hz, 1H), 8.16 (dd, J = 8.0, 1.6 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 5.88 (brs, 1H), 3.96 (s, 3H), 3.29
(t, J = 8.0 Hz, 2H), 2.49 (t, J = 8.0 Hz, 2H), 2.39–2.35 (m, 4H), 2.04–1.97 (m, 2H); 13C{1H} NMR (100
MHz, CDCl3): δ 199.7, 192.3, 165.8, 164.5, 148.0, 135.8, 134.4, 133.8, 131.5, 129.3, 126.2, 52.4, 39.1,
37.3, 31.1, 29.7, 22.6; MS (EI) m/z (% base peak) 286 (M+, 59), 255 (21), 243 (46), 230 (25), 217 (62),
215 (31), 176 (100), 171 (28), 143 (18), 133 (24), 110 (25); HRMS (EI-TOF) m/z: [M]+ Calcd for
C17H18O4, 286.1205; Found 286.1203.
2-[(3-Oxocyclohept-1-en-1-yl)ethyl]benzaldehyde (8ac). Chromatography (EtOAc/hexanes = 1:2);
yellowish oil; 65 mg; yield 64%; IR (neat) ν 2933, 2864, 2739, 1695, 1656, 1452, 1268, 1191, 756 cm–1;
1H NMR (400 MHz, CDCl3) δ 10.18 (s, 1H), 7.81 (dd, J = 7.4, 1.2 Hz, 1H) , 7.52 (ddd, J = 7.4, 7.4, 1.4
Hz, 1H), 7.43 (ddd, J = 7.4, 6.9, 1.2 Hz, 1H), 7.27 (d, J = 6.9 Hz, 1H), 5.93 (brs, 1H), 3.22 (t, J = 8.0 Hz,
2H ), 2.58 (t, J = 6.0 Hz, 2H ), 2.52 (t, J = 6.0 Hz, 2H ), 2.46 (t, J = 8.0 Hz, 2H ), 1.86–1.75 (m, 4H);
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13C{1H} NMR (100 MHz, CDCl3): δ 204.0, 192.9, 160.9, 143.4, 134.2, 133.9, 133.7, 131.2, 129.7,
127.0, 42.8, 42.3, 32.8, 31.7, 25.2, 21.3; MS (EI) m/z (% base peak) 242 (M+, 20), 224 (54), 214 (21),
185 (22), 159 (100), 129 (30), 118 (55), 109 (54), 91 (70); HRMS (EI-TOF) m/z: [M]+ Calcd for
C16H18O2 242.1307; Found 242.1306.
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2-[(3-Oxocyclohex-1-en-1-yl)ethyl]-3-furaldehyde (11). Chromatography (EtOAc/hexanes = 1:2);
yellow oil; 57 mg; yield 56%; IR (neat) ν 3126, 2924, 2851, 1674, 1425, 1253, 1124, 892, 755 cm–1; 1H
NMR (400 MHz, CDCl3) δ 9.92 (s, 1H), 7.32 (d, J = 2.0 Hz, 1H) , 6.68 (d, J = 2.0 Hz, 1H), 5.83 (brs,
1H), 3.19 (t, J = 7.6 Hz, 2H ), 2.62 (t, J = 7.6 Hz, 2H), 2.36–2.28 (m, 4H), 2.02–1.94 (m, 2H); 13C{1H}
NMR (100 MHz, CDCl3): δ 199.3, 184.7, 163.1, 162.6, 142.4, 126.5, 122.5, 108.8, 37.2, 35.9, 29.5,
24.9, 22.6; MS (EI) m/z (% base peak) 218 (M+, 17), 200 (11), 190 (9), 162 (13), 133 (7), 109 (100), 108
(26), 81 (18), 58 (17); HRMS (EI-TOF) m/z: [M]+ Calcd for C13H14O3 218.0943; Found 218.0946.
2-[(3-Oxocyclohex-1-en-1-yl)ethyl]nicotinaldehyde (14). Chromatography (EtOAc/hexanes = 2:1);
yellow oil; 58 mg; yield 57%; IR (neat) ν 3058, 2927, 2866, 1663, 1582, 1440, 1256, 1030, 755 cm–1;
1H NMR (400 MHz, CDCl3) δ 10.24 (s, 1H), 8.70 (dd, J = 4.8, 1.6 Hz, 1H) , 8.10 (dd, J = 7.7, 1.6 Hz,
1H), 7.37 (dd, J = 7.7, 4.8 Hz, 1H), 5.84 (brs, 1H), 3.43 (t, J = 7.9 Hz, 2H ), 2.66 (t, J = 7.9 Hz, 2H),
2.40 (t, J = 5.9 Hz, 2H), 2.35 (t, J = 6.7 Hz, 2H), 2.03–1.96 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3):
δ 199.8, 191.3, 164.9, 162.0, 153.2, 139.9, 129.2, 126.0, 122.1, 37.3, 37.2, 32.6, 29.7, 22.6; MS (EI) m/z
(% base peak) 229 (M+, 24), 201 (89), 200 (37), 173 (100), 172 (48), 144 (33), 130 (16), 117 (8), 93 (13),
77 (10); HRMS (EI-TOF) m/z: [M]+ Calcd for C14H15NO2 229.1103; Found 229.1106.
General Procedure for Intramolecular Stetter Reaction. To a stirred solution of 8, 11, 14 (0.13 mmol)
and thiazolium salt A (7 mg, 0.026 mmol) in absolute ethanol (2.6 mL, 0.05 M) was added triethylamine
(0.018 mL, 0.13 mmol) under Ar atmosphere at room temperature. The reaction mixture was then heated
in an oil bath for a period of time (see Scheme 5 for the duration of heating). The contents were cooled
to room temperature and the solvent was evaporated. The residue was purified by column
chromatography on silica gel to afford 15–17.
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3',4'-Dihydro-1'H-spiro[cyclopentane-1,2'-naphthalene]-1',3-dione
(15aa).
Chromatography
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o
(EtOAc/CH2Cl2 = 1:100); yellowish solid; 20.6 mg; yield 74%; mp 50–51 C; IR (neat) ν 3066, 2927,
1743, 1675, 1600, 1229, 1160, 746 cm–1; 1H NMR (400 MHz, CDCl3) δ 8.03 (dd, J = 8.0, 1.0 Hz, 1H),
7.49 (ddd, J = 8.0, 7.5, 1.0 Hz, 1H), 7.32 (dd, J = 8.0, 7.5 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 3.20–3.12
(m, 1H), 2.95 (ddd, J = 17.2, 5.0, 5.0 Hz, 1H), 2.80 (d, J = 17.8 Hz, 1H), 2.48–2.23 (m, 4H), 2.16–2.09
(m, 1H), 2.09 (d, J = 17.8 Hz, 1H), 2.03–1.94 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 216.6,
200.2, 143.2, 133.6, 130.7, 128.7, 128.0, 126.9, 49.9, 47.3, 36.1, 34.2, 30.5, 25.8; MS (EI) m/z (% base
peak) 214 (M+, 94), 196 (10), 185 (29), 171 (23), 157 (39), 142 (19), 129 (21), 119 (53), 118 (51), 91
(100), 58 (37); HRMS (EI-TOF) m/z: [M]+ Calcd for C14H14O2, 214.0994; Found 214.0995.
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8'-Methoxy-3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalene]-1',3-dione
(15ea).24a
o
Chromatography (EtOAc/hexanes = 1:1); white solid; 21.6 mg; yield 68%; mp 72–73 C; IR (neat) ν
2926, 2849, 1742, 1671, 1591, 1467, 1270, 1208, 1076, 962 cm–1; H NMR (400 MHz, CDCl3) δ 7.41
1
(dd, J = 8.4, 7.7 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 7.7 Hz, 1H), 3.90 (s, 3H), 3.16–3.07 (m,
1H), 2.93 (ddd, J = 17.1, 5.3, 5.3 Hz, 1H), 2.83 (d, J = 18.0 Hz, 1H), 2.54–2.42 (m, 2H), 2.34–2.16 (m,
2H), 2.10–2.03 (m, 2H), 1.97–1.89 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 217.0, 199.6, 161.3,
146.0, 134.4, 120.7, 120.2, 110.1, 55.9, 51.4, 47.9, 36.3, 34.1, 31.2, 26.8; MS (EI) m/z (% base peak)
244 (M+, 18), 216 (100), 189 (40), 173 (11), 148 (92), 115 (7), 90 (18); HRMS (EI-TOF) m/z: [M]+
Calcd for C15H16O3 244.1099; Found 244.1097.
3',4'-Dihydro-1'H-spiro[cyclohexane-1,2'-naphthalene]-1',3-dione
(15ab).
Chromatography
(EtOAc/CH2Cl2 = 1:100); yellowish oil; 25.2 mg; yield 85%; IR (neat) ν 3065, 2932, 1712, 1678, 1599,
1453, 1226, 741 cm–1; 1H NMR (400 MHz, CDCl3) δ 8.02 (dd, J = 8.0, 1.0 Hz, 1H), 7.48 (ddd, J = 7.7,
7.5, 1.0 Hz, 1H) , 7.31 (dd, J = 8.0, 7.5 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 3.16–3.07 (m, 1H), 2.92 (ddd,
J = 17.5, 4.5, 4.5 Hz, 1H), 2.81 (d, J = 14.4 Hz, 1H), 2.47–2.41 (m, 1H), 2.35–2.28 (m, 1H), 2.15–2.00
(m, 4H), 1.92–1.85 (m, 2H), 1.83–1.73 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 209.8, 200.0,
142.9, 133.6, 130.8, 128.7, 128.1, 126.9, 49.3, 48.7, 40.4, 33.0, 29.6, 24.9, 21.4; MS (EI) m/z (% base
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[M]+ Calcd for C15H16O2 228.1150; Found 228.1148.
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5'-Methoxy-3',4'-dihydro-1'H-spiro[cyclohexane-1,2'-naphthalene]-1',3-dione
(15bb).
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Chromatography (EtOAc/hexanes = 1:2); yellowish oil; 21.8 mg; yield 65%; IR (neat) ν 2924, 2851,
1714, 1680, 1583, 1470, 1262, 1062, 753 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.0 Hz, 1H),
7.27 (dd, J = 8.0, 8.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 3.86 (s, 3H), 3.00 (ddd, J = 18.3, 4.5, 4.5 Hz,
1H), 2.86–2.76 (m, 2H), 2.46–2.27 (m, 2H), 2.11 (d, J = 14.6 Hz, 1H), 2.09–2.00 (m, 2H), 1.89–1.74 (m,
4H); 13C{1H} NMR (100 MHz, CDCl3): δ 209.8, 200.3, 156.7, 131.9, 131.7, 127.1, 119.6, 114.2, 55.6,
48.9, 48.6, 40.5, 32.2, 29.5, 21.4, 18.8; MS (EI) m/z (% base peak) 258 (M+, 100), 215 (40), 189 (89),
161 (16), 148 (34), 120 (19), 90 (13), 58 (26); HRMS (EI-TOF) m/z: [M]+ Calcd for C16H18O3 258.1256;
Found 258.1253.
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6'-Methoxy-3',4'-dihydro-1'H-spiro[cyclohexane-1,2'-naphthalene]-1',3-dione
(15cb).
Chromatography (Et2O/hexanes = 1:2); colorless solid; 10.1 mg; yield 30%; mp 106–107 oC; IR (neat) ν
2933, 2852, 1712, 1668, 1599, 1256 cm–1; 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.8 Hz, 1H), 6.84
(dd, J = 8.8, 2.4 Hz, 1H), 6.67 (d, J = 2.4 Hz, 1H), 3.85 (s, 3H), 3.13–3.03 (m, 1H), 2.87 (ddd, J = 17.4,
4.5, 4.5 Hz, 1H), 2.81 (d, J = 14.6 Hz, 1H), 2.49–2.41 (m, 1H), 2.34–2.26 (m, 1H), 2.12 (d, J = 14.6 Hz,
1H), 2.13–1.98 (m, 3H), 1.93–1.86 (m, 2H), 1.80–1.75 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ
210.0, 198.7, 163.8, 145.4, 130.7, 124.5, 113.6, 112.4, 55.5, 49.1, 48.8, 40.5, 33.1, 29.8, 25.3, 21.5; MS
(EI) m/z (% base peak) 258 (M+, 78), 215 (27), 189 (100), 148 (70), 120 (11), 83 (18), 58 (35); HRMS
(EI-TOF) m/z: [M]+ Calcd for C16H18O3 258.1256; Found 258.1258.
7'-Methoxy-3',4'-dihydro-1'H-spiro[cyclohexane-1,2'-naphthalene]-1',3-dione
(15db).
Chromatography (EtOAc/CH2Cl2 = 1:100); yellowish solid; 21.8 mg; yield 65%; mp 79–80 oC; IR (neat)
ν 2937, 1714, 1677, 1608, 1496, 1419, 1275, 1244, 1028, 824 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.50
(d, J = 2.6 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.07 (dd, J = 8.4, 2.6 Hz, 1H), 3.82 (s, 3H), 3.09–3.00 (m,
1H), 2.85 (ddd, J = 17.3, 4.4, 4.4 Hz, 1H), 2.80 (d, J = 14.6 Hz, 1H), 2.49–2.27 (m, 2H), 2.13 (d, J =
14.6 Hz, 1H), 2.13–1.99 (m, 3H), 1.92–1.85 (m, 2H), 1.82–1.75 (m, 1H); 13C{1H} NMR (100 MHz,
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CDCl3): δ 209.8, 200.0, 158.5, 135.4, 131.6, 130.0, 122.2, 109.8, 55.5, 49.2, 48.7, 40.5, 33.3, 29.6, 24.1,
21.5; MS (EI) m/z (% base peak) 258 (M+, 100), 215 (44), 189 (79), 161 (17), 148 (24), 120 (51), 91 (9);
HRMS (EI-TOF) m/z: [M]+ Calcd for C16H18O3 258.1256; Found 258.1254.
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8'-Methoxy-3',4'-dihydro-1'H-spiro[cyclohexane-1,2'-naphthalene]-1',3-dione
(15eb).
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Chromatography (EtOAc/CH2Cl2 = 1:15); yellow solid; 29.2 mg; yield 87%; mp 99–100 oC; IR (neat) ν
1
2939, 1709, 1675, 1593, 1469, 1270, 1210, 1085, 963, 800 cm–1; H NMR (400 MHz, CDCl3) δ 7.39
(dd, J = 8.4, 7.2 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 7.2 Hz, 1H), 3.88 (s, 3H), 3.08–2.99 (m,
1H), 2.89 (ddd, J = 17.4, 5.1, 5.1 Hz, 1H), 2.84 (d, J = 14.6 Hz, 1H), 2.47–2.27 (m, 2H), 2.13 (d, J =
14.6 Hz, 1H), 2.13–1.75 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 210.3, 199.1, 161.2, 145.5, 134.2,
120.6, 120.5, 110.0, 55.9, 50.6, 48.7, 40.5, 32.2, 30.4, 25.7, 21.6; MS (EI) m/z (% base peak) 258 (M+,
62), 215 (14), 191 (49), 189 (77), 148 (100), 113 (16), 85 (27); HRMS (EI-TOF) m/z: [M]+ Calcd for
C16H18O3 258.1256; Found 258.1256.
7'-Methyl-3',4'-dihydro-1'H-spiro[cyclohexane-1,2'-naphthalene]-1',3-dione
(15fb).
Chromatography (Et2O/hexanes = 1:2); yellow oil; 21.7 mg; yield 69%; IR (neat) ν 3026, 2932, 2854,
1714, 1677, 1610, 1497, 1238, 1170, 821 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.84 (brs, 1H), 7.30 (dd,
J = 7.7, 1.5 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H), 3.11–3.02 (m, 1H), 2.88 (ddd, J = 17.4, 4.5, 4.5 Hz, 1H),
2.82 (d, J = 14.2 Hz, 1H), 2.49–2.41 (m, 1H), 2.35 (s, 3H), 2.35–2.28 (m, 1H), 2.13 (d, J = 14.2 Hz, 1H),
2.12–2.01 (m, 3H), 1.92–1.85 (m, 2H), 1.82–1.76 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 209.9,
200.2, 140.0, 136.6, 134.6, 130.6, 128.7, 128.2, 49.3, 48.7, 40.5, 33.0, 29.6, 24.5, 21.5, 20.9; MS (EI)
m/z (% base peak) 242 (M+, 100), 199 (46), 173 (96), 171 (15), 145 (18), 132 (63), 128 (14), 104 (34),
77 (8); HRMS (EI-TOF) m/z: [M]+ Calcd for C16H18O2 242.1307; Found 242.1307.
Methyl 1',3-dioxo-3',4'-dihydro-1'H-spiro[cyclohexane-1,2'-naphthalene]-7'-carboxylate (15gb).
Chromatography (EtOAc/hexanes = 1:3); yellow oil; 25.3 mg; yield 68%; IR (neat) ν 2956, 2924, 2851,
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1722, 1685, 1609, 1436, 1297, 1210, 1120, 759 cm–1; H NMR (400 MHz, CDCl3) δ 8.66 (brs, 1H),
8.12 (dd, J = 8.0, 1.3 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 3.91 (s, 3H), 3.17–3.10 (m, 1H), 2.98 (ddd, J =
18.0, 4.5, 4.5 Hz, 1H), 2.82 (d, J = 14.6 Hz, 1H), 2.47–2.41 (m, 1H), 2.35–2.29 (m, 1H), 2.14 (d, J =
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14.6 Hz, 1H), 2.10–2.04 (m, 3H), 1.92–1.77 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 209.4, 199.1,
166.2, 147.5, 134.0, 131.0, 129.7, 129.3, 129.2, 52.3, 49.2, 48.8, 40.5, 32.4, 29.5, 25.1, 21.4; MS (EI)
m/z (% base peak) 286 (M+, 81), 255 (16), 243 (53), 217 (100), 189 (12), 176 (55), 148 (11), 128 (13),
117 (11), 85 (9), 58 (13); HRMS (EI-TOF) m/z: [M]+ Calcd for C17H18O4 286.1205; Found 286.1204.
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3',4'-Dihydro-1'H-spiro[cycloheptane-1,2'-naphthalene]-1',3-dione
(15ac).
Chromatography
(EtOAc/CH2Cl2 = 1:100); yellowish oil; 20.8 mg; yield 66%; IR (neat) ν 3065, 2929, 2858, 1681, 1600,
1455, 1286, 1221, 915, 745 cm–1; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.0 Hz, 1H), 7.47 (ddd, J =
7.7, 7.4, 1.0 Hz, 1H), 7.31 (dd, J = 8.0, 7.4 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 3.12 (d, J = 13.0 Hz, 1H),
3.02–2.98 (m, 2H), 2.66 (ddd, J = 18.4, 5.7, 5.7 Hz, 1H), 2.46 (d, J = 13.0 Hz, 1H), 2.46–2.39 (m, 1H),
2.14–2.04 (m, 2H), 1.95 (ddd, J = 14.0, 5.2, 5.2 Hz, 1H), 1.89–1.75 (m, 5H); 13C{1H} NMR (100 MHz,
CDCl3): δ 212.8, 200.3, 142.9, 133.4, 130.8, 128.7, 128.3, 126.8, 50.0, 46.2, 43.9, 36.0, 32.4, 24.8, 24.4,
23.9; MS (EI) m/z (% base peak) 242 (M+, 100), 224 (20), 198 (14), 185 (39), 159 (98), 129 (27), 118
(66), 90 (37); HRMS (EI-TOF) m/z: [M]+ Calcd for C16H18O2, 242.1307; Found 242.1305.
6,7-Dihydro-4H-spiro[benzofuran-5,1'-cyclohexane]-3',4-dione
(16).
Chromatography
(EtOAc/CH2Cl2 = 1:100); colorless oil; 13.1 mg; yield 46%; IR (neat) ν 3124, 2943, 1712, 1673, 1597,
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1436, 1232, 1122, 955, 742 cm–1; H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 1.9 Hz, 1H), 6.65 (d, J =
1.9 Hz, 1H), 2.98–2.84 (m, 2H), 2.80 (d, J = 14.6 Hz, 1H), 2.47–2.39 (m, 1H), 2.32–2.27 (m, 1H), 2.13–
2.03 (m, 3H), 1.95–1.84 (m, 2H), 1.76–1.69 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 209.7, 196.1,
165.1, 143.3, 119.2, 107.2, 49.6, 47.9, 40.4, 32.6, 30.1, 21.8, 20.3; MS (EI) m/z (% base peak) 218 (M+,
100), 190 (19), 176 (20), 149 (55), 121 (7), 108 (73), 80 (23); HRMS (EI-TOF) m/z: [M]+ Calcd for
C13H14O3, 218.0943; Found 218.0942.
7',8'-Dihydro-5'H-spiro[cyclohexane-1,6'-quinoline]-3,5'-dione
(17).
Chromatography
(EtOAc/hexanes = 1:1); yellowish oil; 17.9 mg; yield 60%; IR (neat) ν 3065, 2941, 1712, 1684, 1582,
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1457, 1226, 762 cm–1; H NMR (400 MHz, CDCl3) δ 8.70 (dd, J = 4.8, 1.9 Hz, 1H), 8.29 (dd, J = 7.8,
1.9 Hz, 1H), 7.30 (dd, J = 7.8, 4.8 Hz, 1H), 3.32–3.22 (m, 1H), 3.14(ddd, J = 18.3, 4.6, 4.6 Hz, 1H),
2.81 (d, J = 14.6 Hz, 1H), 2.50–2.42 (m, 1H), 2.37–2.29 (m, 1H), 2.16 (d, J = 14.6 Hz, 1H), 2.14–2.06
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