Cobalt(II)-Catalyzed Aerobic Oxidation of Terminal-Capped Alkynyl α-Cyano Alkanone Systems. An Oxygen-Mediated Radical Chain Reaction

Article abstract of DOI:10.1021/acs.joc.6b01837

A new N-hydroxyphthalimide (NHPI)/Co(II)-catalyzed protocol, mechanistically involving a sequence of α-hydrogen abstraction, 5-exo-dig cyclization, oxygen capture, hydrogen transfer, and 1,4-dehydration, has been developed to facilitate aerobic oxidation of aryl-, silyl-, and alkyl-capped alkynyl α-cyano alkanone systems to the corresponding highly functionalized products in an effective manner, thus turning this novel chain reaction, originally occurring spontaneously in low yields, into a practical methodology.

Full text of DOI:10.1021/acs.joc.6b01837

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Article
Cobalt(II)-Catalyzed Aerobic Oxidation of Terminal-capped Alkynyl alpha-
Cyano Alkanone Systems. An Oxygen-mediated Radical Chain Reaction
Jing-Kai Huang, Ying-Chieh Wong, Tzu-Ting Kao, Chen-Tso Tseng, and Kak-Shan Shia
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01837 • Publication Date (Web): 17 Oct 2016
Downloaded from http://pubs.acs.org on October 19, 2016
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Cobalt(II)ꢀCatalyzed Aerobic Oxidation of Terminalꢀcapped
Alkynyl αꢀCyano Alkanone Systems. An Oxygenꢀmediated Radical
Chain Reaction
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JingꢀKai Huang,† YingꢀChieh Wong,† TzuꢀTing Kao, ChenꢀTso Tseng, and KakꢀShan Shia*
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes,
Miaoli County 35053, Taiwan, R.O.C.
ABSTRACT: A new NHPI/Co(II)ꢀcatalyzed protocol, mechanistically involving a sequence of
αꢀhydrogen abstraction, 5ꢀexoꢀdig cyclization, oxygen capture, hydrogen transfer and 1,4ꢀ
dehydration, has been developed to facilitate aerobic oxidation of arylꢀ, silylꢀ and alkylꢀcapped
alkynyl αꢀcyano alkanone systems, respectively, to the corresponding highly functionalized
products in an effective manner, thus turning this novel chain reaction, originally occurring
spontaneously in low yields, into a practical methodology.
INTRODUCTION
Since compound 1 was discovered to undergo aerobic oxidation spontaneously to afford α,βꢀ
unsaturated acylsilane 2 in ca. 30% yield upon exposure to air, attempts have been made to
optimize reaction conditions, leading to findings that substrate 1 could convert to product 2 more
effectively under catalysis with pyridine at one atmosphere of oxygen (Scheme 1).1
Scheme 1. Trimethylsilylꢀcapped Aerobic Oxidation.
O
O
O
TMS
CN
CN
pyridine (10 mol%)
1 atm O2, rt, 12 h
70%
H
TMS
1
2
The generality of the autoxidative reaction has been verified by a variety of silylꢀcapped alkynyl
αꢀcyano cycloalkanones as reported previously.1 However, we found that the TMSꢀfree αꢀcyano
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cyclohexanone 3 and its αꢀester counterparts 4 and 5 were rather stable under air, suggesting that
both the αꢀcyano group and TMS functionality are required to induce the observed autoxidation.
To expand the scope of this interesting type of reaction, attempts to cap the
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terminal acetylene with various functionalities were then made. In one approach, when the
acetylene was capped with a phenyl group, the expected transformation of substrate 6 to enone 7
was found to proceed spontaneously in ca. 7% yield under air (Scheme 2). Even if reactant 6
stood on bench or was dissolved in a commonly used solvent, including ethyl acetate,
dichloromethane or dimethylformamide, for more than two days under air, its conversion rate
into 7 maintained at this level and starting material was recovered intact by ca. 90%. When
optimal reaction conditions developed previously (Scheme 1) were applied to substrate 6, a
complex mixture was obtained and the yield of product 7 was barely improved as analysed by 1H
NMR.
Scheme 2. Phenylꢀcapped Aerobic Oxidation.
Screening of reaction conditions was then extensively carried out. Consequently, a commonly
effective procedure was developed to realize the desired aerobic oxidation, wherein the terminal
acetylene unit of the titled systems allowed to be capped with either an aryl, silyl or alkyl
functionality. Results and discussion are presented as follows.
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RESULTS AND DISCUSSION
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Given that aforementioned aerobic reactions are triggered via a free radical cascade process,
metal catalysts or oxidants reported to serve as useful radical initiators in air, including
CuO/dibenzoyl peroxide (DBP), Mn(III)/Co(II)/O2, diꢀtꢀbutyl peroxide, TBAI/TBHP, CuI,
Mn(OAc)3, I2, CAN, and Nꢀhydroxyphthalimide (NHPI),2ꢀ8 are first examined. Using substrate 6
as an initial model, screening results are listed in Table 1. Though the desired product 7, except
for treatment with Mn(OAc)3 (entry 4), was mainly obtained in all cases examined, a side
product, benzoic acid 8, was accompanied in 17ꢀ45% yields. In fact, the direct oxidative
cleavage of alkynes into carboxylic acids under metal catalysis has been well documented,9
which might account for the low yield of product 7. As indicated in entry 9, the reaction system
(10 mol% Co(OAc)2/20 mol% NHPI/PhH/air), giving rise to product 7 in 61% yield, is
tentatively considered the system of choice and is applied to an array of substrates to verify its
synthetic generality.
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Table 1. Screening of Reaction Conditions.
entry
1
reagent
ꢀ
solvent
PhH
time (h)
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7 / 8 yield (%)b
~7 / ꢀ
2
3
10% TBAI/1.0 equiv TBHP
20% CuI
PhH
DMF
PhH
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51 / 45
20 / 17
27 / 37
9 / ꢀ
4
2.0 equiv Mn(OAc)3
10% I2
5
PhH
6
2.0 equiv CAN
MeOH
PhH
33 / 17
50 / 35
39 / 27
61 / 30
42 / 25
7
20% NHPI
8
10% Cu(acac)2/20% NHPI
10% Co(OAc)2/20% NHPI
10% Co(OAc)2/20% NHPI
PhH
9
PhH
DMF
10
aAll reactions were performed using substrate 6 (0.35 mmol) and 10~20 mol% catalyst in 1 mL of solvent as
indicated above; the resulting mixture was vigorously stirred at room temperature under air. bYields are for isolated,
chromatographically pure products.
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As shown in Scheme 3, compound 6 and various arylꢀcapped substrates 9–13 were readily
prepared from compound 1 via a twoꢀstep sequence, involving deprotection of the trimethylsilyl
group followed by Sonogashira coupling with an aryl iodide, in an overall yield of 35~62%.10,11
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Scheme 3. Preparation of Arylꢀcapped Alkynes.
As compiled in Table 2, the present methodology is applicable for the acetylene unit capped with
various aryls, irrespective of the stereoelectronic nature of the para substituent, affording the
corresponding products in 35~61% yields (entries 1–7). Product 20 was unambiguously
determined by the Xꢀray analysis,12 lending strong support to the structural elucidation for this
series of compounds by the use of conventional spectroscopic methods (1H, 13C, IR and HRMS).
Similarly, acyclic substrates 16–18, readily prepared in good to excellent yields according to
synthetic procedures reported in the literature,4b,5b,13 were also subjected to this newly developed
protocol. As a result, desired products 26–28 were obtained in 28~40% yields, structures of
which were fully confirmed by the Xꢀray analysis.14,15 It is noteworthy that different from cyclic
substrates (e.g. compound 1), the spontaneous conversion rate of acyclic substrates 16–18 are
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thoroughly undetectable by H NMR analysis. Though above autoxidative products seem to be
isolated in low to moderate yields (28~61%) , however, unlike a regular reaction with a simple
mechanistic insight, the inherent reactivity of this unique reaction comprises a fiveꢀstep domino
transformation, including αꢀhydrogen abstraction, 5ꢀexoꢀdig cyclization, oxygen capture,
hydrogen transfer and 1,4ꢀdehydration. Even if 28% is the lowest reaction yield in all cases
examined in Table 2, the average yield of each transformation is as high as 78%. In general, the
corresponding side products, benzoic acids, were obtained in 25~ 40% for the current procedure.
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Table 2. Autoxidation of Arylꢀcapped Alkynyl αꢀCyano Alkanones.
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aYields were for isolated, chromatographically pure products. bThe structure was confirmed by Xꢀray
crystallographic analysis.
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Since the acetylene unit capped with an aryl group was found prone to oxidative cleavage, we
assumed that a trialkylsilyl group providing more steric hindrance might retard the approach of
active oxygen radical species (e.g., M–OꢀO⋅) to lessen the side effect. As such, this newly
developed protocol was also employed to reinvestigate trialkylsilylꢀcapped counterparts
containing a TMS,1 TES or TBDMS functionality. Results are listed in Table 3. As TMSꢀcapped
αꢀcyano ketones 1, 29, 30, and 35 were treated with Co(II)ꢀcatalyzed conditions, corresponding
acylsilanes 2 (entry 2; 68% vs. 70%), 36 (entry 1; 55% vs. 59%), 37a/37b (entry 3; 46% vs. 28%)
and 42 (entry 8; 44% vs. 21%) were produced in almost equal or better yields as compared to
those obtained by previous reaction conditions (10 mol% pyridine/1 atm O2/rt), thus
demonstrating that this newly developed method is more efficient and practical. Moreover, when
the TMS group of substrate 1 was replaced with a bulkier TES or TBDMS group, the similar
aerobic oxidation could proceed with equal facility, affording the corresponding products 39
(entry 5; 73%) and 41 (entry 7; 75%), respectively, in a slightly higher yields than their TMS
counterpart 2 (entry 2; 68%). These results seem to reflect our argument that the steric hindrance
of the terminal silyl group might hamper active oxygen radicals to access the acetylene unit, thus
lessening its oxidative cleavage and resulting in higher yields. In addition, acylsilane products
containing a bulkier TES or TBDMS group are much more stable than those containing a TMS
group in that upon longꢀterm exposure to light, the former remain intact but the latter are slowly
decomposed to the corresponding α,βꢀunsaturated aldehydes, presumably due to Norrish Type I
cleavage.1,16
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Table 3. Autoxidation of Silylꢀcapped Alkynyl αꢀCyano Alkanones.
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aYields were for isolated, chromatographically pure products. bThe yields in the parenthesis are those of the reaction
carried out under previous conditions in ref. 1 (10 mol% pyridine/1 atm O2/rt).cThe structure was confirmed by Xꢀ
ray crystallographic analysis.20,21,22
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Using the transformation of compound 17 into 27 as a typical example, the proposed mechanism
is depicted in Scheme 4. The chain reaction is initiated by abstracting hydrogen α to the cyano
and ketone group of 17 via phthalimide Nꢀoxyl (PINO) radical, generated under catalysis with
Co(II)/NHPI in the presence of oxygen,8a to form radical intermediate A, which could
immediately undergo 5ꢀexoꢀdig addition to produce vinyl radical B.17,18,19 Subsequently, an
oxygen molecule is captured by vinyl radical B to provide vinyl peroxyl radical C by which the
hydrogen of NHPI is abstracted to form hydroperoxide D followed by 1,4ꢀdehydration to give
product 27 and restart the catalytic cycle (pathway A). Alternatively, radical C might take
pathway B to form dioxetane radical E which could decompose to furnish 1,3ꢀdiketone I, leading
to carboxylic acid J via hydrolysis, and acyl radical F, leading to benzoic acid G via
oxygenation.6,9,23 2ꢀcyanoꢀ1,3ꢀdiketone I, a coꢀproduct of benzoic acid G, appeared unstable and
prone to hydrolysis in the presence of moisture to afford the corresponding acid J as detected by
LCꢀMass (see S37ꢀS38 in Supporting Information).
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Scheme 4. Proposed Mechanism for Aerobic Oxidation with NHPI/Co(II) Acetate.
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To confirm the mechanism, authentic sample I was then prepared according to Scheme 5.
Intermediate H was synthesized via a modified procedure of Knoevenagel condensation
followed by deprotection with TsOH in 80% over two steps.4b,5b Hydroxyl H was then oxidized
with PCC to afford cyclic βꢀhydroxyl ketone, which without purification was further oxidized
with DMP to afford the desired 2ꢀcyanoꢀ1,3ꢀdiketone I in 39% over two steps. Compound I thus
obtained was found to be hydrolysed in CDCl3 in a couple of hours to form the corresponding
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1
carboxylic acid J as verified by H and 13C spectra shown in Figure S1 in Supporting
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Information. Neverthless, the clean H and C spectrum of I could be timely recorded (see S34
in Supporting Information). The above results lend strong support to the mechanism proposed in
Scheme 4.
Scheme 5. Preparation of Authentic Sample 2ꢀCyanoꢀ1,3ꢀdiketone I.
More intriguingly, when substrates 43 and 44 (Scheme 6) were designed to make the pendant
acetylene unit get closer to the reacting αꢀcarbon center via the ThorpeꢀIngold effect, the
expected chain reaction occurred almost instantly after an usual workup of 1,4ꢀconjugate
addition of the Grignard reagent, furnishing desired products 45 and 46 in 42% and 38% yields
in one pot, respectively, structures of which were unambiguously confirmed by the Xꢀray
crystallographic analysis.24,25 Obviously, a gemꢀdimethyl group installed at the γ position could
force the acetyleneꢀcontaining linker to adopt a constrained conformation like intermediate A
(Scheme 4), thus accelerating the chain reaction in an efficient fashion.
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Scheme 6. Reaction Rate Enhanced by ThorpeꢀIngold Effect.
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When the above optimal reaction system was further extended to substrates capped with an alkyl
group such as 47 and 48 (Scheme 7), readily prepared by 1,4ꢀconjugate addition of an
appropriate Grignard reagent to 2ꢀcyanoꢀ2ꢀcyclohexenone in good yields,26 the corresponding
products 49 and 50 were obtained in 21% and 26% yields, respectively. Also emphasized is the
fact that upon exposure to air over two days, not a trace of substrates 47 and 48 was
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spontaneously converted into products 49 and 50 as determined by H NMR analysis. These
results suggest that the new methodology is synthetically more useful than the previous one in
that it can activate the latent autoxidative reaction rather than just enhance it. However, the
formation of products 51 and 52 is somewhat unexpected because similar products are not
observed in both silylꢀcapped and arylꢀcapped series. In light of stereochemistry, they are
tentatively assigned as trans isomers based on our previous studies on Coniaꢀene reactions with
the same substrates in the presence of Lewis acids such as ZnI2.26b
Scheme 7. Unexpected Coniaꢀene Reactions in Alkylꢀcapped Series.
Above outcomes might be rationalized as follows. As illustrated in Figure 1 base on Hartreeꢀ
Fock quantum mechanic calculation (see S39 in Supporting Information),27 vinyl radical I with
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the relatively highest energy is supposed to be more reactive than its counterparts II and III, and
thus could randomly capture either an oxygen molecule to continue the chain reaction or abstract
a hydrogen atom from the reaction environment to terminate it.
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Figure 1. Relative energy of vinyl radicals I, II and III base on HartreeꢀFock quantum mechanic
calculation.
We also observed that the trialkylsilylꢀcapped series usually afforded the corresponding products
in higher yields than their arylꢀ and alkylꢀcapped counterparts. An explanation could be that in
addition to the steric hindrance of the silyl group making oxidative cleavage of the alkyne unit
more difficult, a unique stabilizing force provided by the Si element through delocalization with
its d orbital or lowꢀlying σ* (SiꢀC) antiꢀbonding orbital might render trialkylsilyl vinyl radicals
existing longer, thus trapping oxygen more efficiently.1,18,23 For comparison purposes, αꢀcyano
ester 53 and βꢀketo ester 54, structurally analogous to αꢀcyano ketone 35 (Table 3, entry 8, 44%),
were also synthesized and subjected to the same reaction conditions. As a result, both substrates
53 and 54 (Figure 2) were recovered intact over a period of 24 h at room temperature or under
heating in refluxing benzene for 10 h, the poor reactivity of which might be ascribed to higher
bond dissociation energy (BDE) as compared with substrate 35.
Figure 2. Bond dissociation energy of substrates 35, 53 and 54.
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CONCLUSION
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Our continued investigation on terminalꢀcapped alkynyl αꢀcyano alkanone systems has
culminated in a legitimate protocol (10 mol% Co(OAc)2/20 mol% NHPI/PhH/air), by which an
aerobic chain reaction, regardless of whether its spontaneous conversion rate is detectable, can
be promoted in an effective fashion. Also demonstrated is the fact that the substituent capped on
the terminal acetylene of the titled systems is structurally variable and not restricted to the
trialkylsilyl group, originally recognized to be one of essential elements. Nevertheless, there is
no doubt that the Si element of the trialkylsilyl group may play an extraordinary role in inducing
the radical chain reaction although the underlying cause remains to be determined.
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EXPERIMENTAL SECTION
General Experimental Procedure. All reactions were performed under air unless otherwise
stated. All solvents and reagents were employed as received without further purification.
Analytical thin layer chromatography was performed on SiO2 60 Fꢀ254 plates and flash column
chromatography was carried out using SiO2 60 (particle size 0.040ꢀ0.055 mm, 230–400 mesh).
Visualization was performed under UV irradiation at 254 nm followed by staining with aqueous
potassium permanganate (KMnO4 (3 g) and K2CO3 (20 g) in 300 mL of H2O containing 5 mL of
an aqueous solution of NaOH (5%, w/v)) and charring by heat gun. Infrared spectra (IR) were
recorded on a FTꢀIR spectrometer and expressed in cmꢀ1. 1H NMR spectra were recorded at 400
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MHz and C NMR spectra at 100 MHz. Chloroformꢀd were used as the solvent and TMS (δ =
0.00 ppm) as an internal standard. Chemical shifts are reported as δ values in ppm as referenced
to TMS. Multiplicities are recorded as s (singlet), d (doublet), t (triplet), q (quartet), quint
(quintet), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), qd (quartet of
doubles), tt (triplet of triplets), ddd (doublet of doublet of doublets), m (multiplet), br (broad).
Coupling constants (J) are expressed in Hz. HRMS was obtained on a triple quadrupole mass
analysis using electrospray ionization (ESI) source or a double quadrupole mass analysis using
electron impact (EI) source, and spectral data were recorded as m/z values. Melting points were
measured using an Electrothermal instrument.
Preparation of Substrates. The general procedure for 1,4ꢀconjugate addition in the synthesis of
compounds 1, 31–34, 45 and 46 is demonstrated as follows using 1 as a typical example.1
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2ꢀOxoꢀ6ꢀ(4ꢀ(trimethylsilyl)butꢀ3ꢀynyl)ꢀcyclohexanecarbonitrile (1): To a stirred solution of αꢀ
cyanoꢀ2ꢀcyclohexenone (302 mg, 2.50 mmol) in THF (5 mL) was added freshly prepared (4ꢀ
butyꢀ1ꢀnyl)trimethylsilane magnesium chloride solution (6.0 mL, 0.92 M in THF, 5.50 mmol)
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dropwise at –30 C. After stirring for 10 min at the same temperature, TMSCl (0.95 mL, 7.50
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mmol) was introduced in one portion. The resulting mixture was stirred for another 1 h at –30 oC.
Saturated NH4Cl solution (8 mL) was added to quench the reaction. The aqueous layer was
separated and extracted with diethyl ether (3 × 15 mL). The combined organic extracts were
washed with brine, dried over MgSO4, filtered and concentrated to give the crude residue, which
was purified by flash chromatography on silica gel using EtOAc/nꢀhexane (1:9) as eluant to
afford substrate 1 (476 mg, 77% yield, a mixture of keto isomers in a ratio of 1:2 (cis : trans)) as
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a yellowish oil. H NMR (600 MHz, CDCl3) major isomer: δ 3.33 (d, J = 11.6 Hz, 1H), 2.56–
2.52 (m, 1H), 2.38–1.80 (m, 6H), 1.74–1.33 (m, 4 H), 0.08 (s, 9H); minor isomer: δ 3.52 (d, J =
4.5 Hz, 1H); 13C NMR (150 MHz, CDCl3) major isomer: δ 200.0, 115.7, 105.1, 86.0, 49.6, 42.2,
40.3, 32.9, 27.0, 22.7, 16.8, ꢀ0.1 (3C); minor isomer: δ 200.9, 115.4, 104.7, 86.2, 47.5, 40.9, 38.8,
30.4, 28.8, 22.6, 17.0, –0.3 (3C); IR (neat): 2249, 2174, 1728 cmꢀ1; HRMS (EI): m/z calcd for
C14H21NOSi: 247.1392 [M]+; found: 247.1391.
2ꢀOxoꢀ5ꢀ(4ꢀ(triethylsilyl)butꢀ3ꢀynyl)ꢀcyclopentanecarbonitrile (31): A mixture of keto
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isomers in a ratio of 1:5 (cis : trans) was obtained as a yellowish oil; 372 mg, 54% yield; H
NMR (400 MHz, CDCl3) major isomer: δ 2.93 (d, J = 12.4 Hz, 1H), 2.58–2.27 (m, 4H), 2.17–
1.86 (m, 2H), 1.73–1.64 (m, 2H), 1.59–1.49 (m, 1H), 0.94 (t, J = 8.0 Hz, 9H), 0.54 (q, J = 8.0 Hz,
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6H); minor isomer: δ 3.38 (d, J = 7.6 Hz, 1H); C NMR (100 MHz, CDCl3) major isomer : δ
205.9, 116.0, 106.1, 83.3, 45.9, 41.7, 37.1, 32.7, 27.0, 17.5, 7.4 (3C), 4.3 (3C); minor isomer: δ
206.3, 114.2, 105.9, 83.8, 44.2, 38.4, 36.1, 29.6, 26.4, 17.9, 7.3 (3C), 4.2 (3C); IR (neat): 2955,
2875, 2245, 2173, 1759, 1459, 726; HRMS (EI): m/z calcd for C16H25NOSi: 275.1705 [M]+;
found: 275.1709.
2ꢀOxoꢀ6ꢀ(4ꢀ(triethylsilyl)butꢀ3ꢀynyl)ꢀcyclohexanecarbonitrile (32): A mixture of keto isomers
in a ratio of 1:1.5 (cis : trans) was obtained as a yellowish oil; 441 mg, 61% yield; 1H NMR (400
MHz, CDCl3) major isomer: δ 3.32 (d, J = 11.2 Hz, 1H), 2.76–2.68 (m, 1H), 2.63–2.57 (m, 1H),
2.46–1.99 (m, 5H), 1.90–1.55 (m, 4H), 0.95 (t, J = 8.0 Hz, 9H), 0.55 (q, J = 8.0 Hz, 6H); minor
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isomer: δ 3.51 (d, J = 4.4 Hz, 1H); C NMR (100 MHz, CDCl3) major isomer: δ 200.0, 115.7,
106.0, 83.3, 49.6, 42.2, 40.3, 33.0, 28.8, 24.7, 16.9, 7.3 (3C), 4.3 (3C); minor isomer: δ 200.8,
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115.4, 105.7, 83.4, 47.5, 40.8, 38.8, 30.5, 27.0, 24.6, 17.0, 7.3 (3C), 4.3 (3C); IR (neat): 2955,
2877, 2241, 2173, 1728, 1458, 1239, 740 cmꢀ1; HRMS (EI): m/z calcd for C15H22NOSi: 260.1471
[M–Et]+; found: 260.1477.
2ꢀ(4ꢀ(tertꢀButyldimethylsilyl)butꢀ3ꢀynyl)ꢀ5ꢀoxocyclopentanecarbonitrile (33): A mixture of
keto isomers in a ratio of 1:4 (cis : trans) was obtained as a yellowish oil; 241 mg, 35% yield; 1H
NMR (400 MHz, CDCl3) major isomer: δ 2.92 (d, J = 12.4 Hz, 1H), 2.60–2.30 (m, 4H), 2.06–
1.83 (m, 2H), 1.74–1.64 (m, 2H), 1.59–1.49 (m, 1H), 0.89 (s, 9H), 0.05 (s, 6H); minor isomer: δ
3.38 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) major isomer: δ 205.9, 116.0, 105.6, 84.2,
45.9, 41.7, 37.1, 32.7, 27.0, 25.9 (3C), 17.4, 16.3, ꢀ4.6 (2C); minor isomer: δ 206.2, 114.2, 105.5,
83.8, 44.2, 40.5, 36.1, 29.6, 26.4, 25.9 (3C), 17.8, 16.6, –4.6 (2C); IR (neat): 2954, 2858, 2242,
2173, 1759, 1463, 776; HRMS (EI): m/z calcd for C12H16NOSi: 218.1001 [M–tBu]+; found:
218.0991.
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2ꢀ(4ꢀ(tertꢀButyldimethylsilyl)butꢀ3ꢀynyl)ꢀ6ꢀoxocyclohexanecarbonitrile (34): A mixture of
keto isomers in a ratio of 1:3 (cis : trans) was obtained as a yellowish oil; 239 mg, 33% yield; 1H
NMR (400 MHz, CDCl3) major isomer: δ 3.31 (d, J = 11.2 Hz, 1H), 2.68–2.56 (m, 2H), 2.46–
1.99 (m, 5H), 1.90–1.55 (m, 4H), 0.89 (s, 9H), 0.05 (s, 6H); minor isomer: δ 3.51 (d, J = 4.8 Hz,
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1H); C NMR (100 MHz, CDCl3) major isomer: δ 199.9, 115.7, 105.6, 84.4, 49.7, 42.3, 40.4,
33.0, 28.9, 26.0 (3C), 24.8, 17.0, 16.4, –5.7 (2C); minor isomer: δ 200.8, 115.5, 105.2, 84.5, 47.5,
41.0, 38.9, 30.7, 27.1, 26.0 (3C), 24.9, 17.1, 16.2, –5.3 (2C); IR (neat): 2952, 2858, 2248, 2173,
1730, 1463, 1251, 776 cmꢀ1; HRMS (EI): m/z calcd for C13H18NOSi: 232.1158 [M–tBu]+; found:
232.1148.
7,7ꢀDimethylꢀ4ꢀoxoꢀ3ꢀ((trimethylsilyl)carbonyl)ꢀ3a,4,5,6,7,7aꢀhexahydroꢀ1Hꢀindeneꢀ3aꢀ
carbonitrile (45): Compound 45 was obtained directly after an usual work up of 1,4ꢀconjugate
addition. Yellow soild; 304 mg, 42% yield; m.p. 95–96 oC; 1H NMR (400 MHz, CDCl3): δ 6.93
(t, J = 2.4 Hz, 1H), 3.02 (m, 1H), 2.89 (ddd, J = 10.0, 8.0, 1.6 Hz, 1H), 2.72 (ddd, J = 18.4, 8.0,
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3.2 Hz, 1H), 2.42–2.30 (m, 2H), 1.94–1.81 (m, 2H), 1.47 (s, 3H), 0.98 (s, 3H), 0.30 (s, 9H); C
NMR (100 MHz, CDCl3): δ 229.7, 201.7, 146.2, 145.7, 118.8, 59.5, 54.5, 36.5, 34.8, 34.6, 32.4,
28.4, 27.9, –1.9 (3C); IR (CH2Cl2): 2962, 2240, 1731, 1595, 1250, 848 cmꢀ1; HRMS (EI): m/z
calcd for C16H23NO2Si: 289.1498 [M]+; found: 289.1489.
9,9ꢀDimethylꢀ4ꢀoxoꢀ3ꢀ((trimethylsilyl)carbonyl)ꢀ3a,4,9,9aꢀtetrahydroꢀ1Hꢀ
cyclopenta[b]naphthaleneꢀ3aꢀcarbonitrile (46): Compound 46 was obtained directly after an
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usual work up of 1,4ꢀconjugate addition. Yellow solid; 321 mg, 38% yield; m.p. 136–137 oC; 1H
NMR (400 MHz, CDCl3): δ 7.80 (dd, J = 7.6, 1.2 Hz, 1H), 7.56 (td, J = 7.6, 1.2 Hz, 1H), 7.36 (d,
J = 7.6 Hz, 1H), 7.30 (td, J = 7.6, 1.2 Hz, 1H), 6.81 (dd, J = 3.2, 2.4 Hz, 1H), 3.22 (t, J = 9.0 Hz,
1H), 2.88 (ddd, J = 19.2, 9.2, 3.2 Hz, 1H), 2.19 (ddd, J = 19.2, 9.2, 2.4 Hz, 1H), 1.48 (s, 6H),
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0.21 (s, 9H); C NMR (100 MHz, CDCl3): δ 229.3, 187.2, 149.2, 148.7, 144.3, 134.5, 132.2,
129.2, 127.0, 125.3, 120.0, 56.0, 55.0, 37.0, 36.8, 33.6, 25.4, –2.0 (3C); IR (CH2Cl2): 2966, 2903,
2239, 1685, 1599, 1377, 1250, 849 cmꢀ1; HRMS (EI): m/z calcd for C20H23NO2Si: 337.1498 [M]+;
found: 337.1499.
The general procedure for Sonogashira coupling in the synthesis of substrates 6 and 9–15 is
demonstrated as follows using 9 as a typical example.
Methyl 4ꢀ(4ꢀ(2ꢀcyanoꢀ3ꢀoxocyclohexyl)butꢀ1ꢀynyl)benzoate (9): A mixture of 2ꢀoxoꢀ6ꢀ(4ꢀ
(trimethylsilyl)butꢀ3ꢀynyl)cyclohexanecarbonitrile 1 (1.0 g, 4.0 mmol) was treated with TBAF
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(4.8 mL, 1M in THF) in THF (20 mL) at 0 C for 1 h and then cooled to room temperature and
quenched with water. The aqueous phase was extracted with ethyl acetate (2 × 30 mL). The
combined organic extracts were washed with water and brine, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure to give the crude residue, which without
purification, was further treated with methyl 4ꢀiodobenzoate (1.25 g, 4.8 mmol), CuI (76 mg,
0.40 mmol), Pd(PPh3)4 (462 mg, 0.40 mmol) and pyrrolidine (0.67 ml, 8.0 mmol) in CH2Cl2 (15
mL) under nitrogen at room temperature for 6 h. The mixture was filtered through a pad of celite
and slica gel followed by washing with CH2Cl2 (50 mL). The organic solution was concentrated
under reduced pressure to give the crude residue, which was subjected to purification by flash
chromatography on silica gel using 30% EtOAc in nꢀhexane as eluant to afford a mixture of keto
isomers in a ratio of 1: 3 (cis : trans) as a yellowish oil (630 mg, 51% yield). 1H NMR (400 MHz,
CDCl3) major isomer: δ 7.93 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 3.88 (s, 3H), 3.32 (d, J
= 11.6 Hz, 1H), 2.64–2.47 (m, 2H), 2.33–2.03 (m, 4H), 1.90–1.67 (m, 5H); minor isomer: δ 3.55
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(d, J = 4.4 Hz, 1H); C NMR (100 MHz, CDCl3) major isomer: δ 200.0, 166.4, 131.3 (2C),
129.2 (2C), 128.9, 128.0, 115.7, 91.4, 81.0, 52.0, 49.6, 42.1, 40.1, 33.1, 28.8, 24.6, 16.4; IR
(neat): 2950, 2248, 1721, 1606, 1437, 1279, 1110 cmꢀ1; HRMS (ESI): m/z calcd for C19H20NO3:
310.1443 [M+H]+; found: 310.1438.
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The general procedure for Knoevenagel condensation using Hantzsch ester as a reducing agent in
the synthesis of substrates 16–18 and 35 is demonstrated as follows using 16 as a typical
example.13
2ꢀ(Cyclohexanecarbonyl)ꢀ7ꢀphenylheptꢀ6ꢀynenitrile (16): To a stirred solution of 3ꢀ
oxohexanenitrile (755 mg, 6.8 mmol) and 5ꢀphenylpentꢀ4ꢀynal (1.3 g, 8.2 mmol) in EtOH (100
mL) was added Lꢀproline (312 mg, 2.7 mmol) and Hantzsch ester (1.7 g, 6.8 mmol) sequentially
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in one portion. The resulting mixture was stirred at 25 C for 16 h. The reaction solution was
concentrated under reduced pressure, which was purified by flash chromatography on silica gel
using 33% CH2Cl2 in nꢀhexane as eluant to afford substrate 16 as a paleꢀyellow oil; 1.40 g, 70%
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yield; H NMR (400 MHz, CDCl3): δ 7.38–7.36 (m, 2H), 7.27–7.25 (m, 3H), 3.60 (dd, J = 8.4,
5.6 Hz, 1H), 2.73 (tt, J = 11.2, 3.6 Hz, 1H), 2.48 (t, J = 6.8 Hz, 2H), 2.13–1.65 (m, 8H), 1.42–
1.17 ppm (m, 6H); 13C NMR (100 MHz, CDCl3): δ 203.5, 131.4, 128.2, 127.7, 123.4, 117.3, 88.2,
81.7, 49.1, 41.7, 28.5, 28.3, 27.8, 25.7, 25.4, 25.2, 25.1, 18.7; IR (neat): 2934, 2242, 1722, 1450
cmꢀ1; HRMS (ESI): m/z calcd for C20H24NO: 294.1858 [M+H]+; found: 294.1845.
Methyl 4ꢀ(6ꢀcyanoꢀ7ꢀcyclohexylꢀ7ꢀoxoheptꢀ1ꢀynyl)benzoate (17): Yellow oil; 1.39 g, 58%
yield; 1H NMR (400 MHz, CDCl3): δ 7.94 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 3.89 (s,
3H), 3.58 (dd, J = 8.4, 6.0 Hz, 1H), 2.74 (tt, J = 10.8, 3.2 Hz, 1H), 2.50 (t, J = 6.8 Hz, 2H), 2.12–
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1.65 (m, 8H), 1.43–1.17 ppm (m, 6H); C NMR (100 MHz, CDCl3): δ 203.3, 166.4, 131.3,
129.3, 129.0, 128.1, 117.2, 91.6, 81.1, 52.0, 49.1, 41.6, 28.4, 28.2, 27.7, 25.5, 25.3, 25.2, 25.1,
18.8; IR (neat): 2934, 2241, 1731, 1715, 1607, 1436, 1308, 1109 cmꢀ1; HRMS (EI): m/z calcd for
C22H25NO3: 351.1834 [M]+; found: 351.1830.
2ꢀ(Cyclohexanecarbonyl)ꢀ7ꢀ(4ꢀmethoxyphenyl)heptꢀ6ꢀynenitrile (18): Yellow oil; 1.21 g,
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55% yield; H NMR (400 MHz, CDCl3): δ 7.29 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 8.8, Hz, 2H),
3.77 (s, 3H), 3.60 (dd, J = 8.4, 5.6 Hz, 1H), 2.72 (tt, J = 10.8, 3.2 Hz, 1H), 2.45 (t, J = 6.8 Hz,
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2H), 2.10–1.93 (m, 2H), 1.89–1.86 (m, 2H), 1.79–1.63 (m, 4H), 1.41–1.15 ppm (m, 6H); C
NMR (100 MHz, CDCl3): δ 203.5, 159.1, 132.8, 117.3, 115.5, 113.8, 81.5, 56.6, 55.1, 49.1, 41.7,
28.5, 28.3, 27.8, 25.7, 25.4, 25.2, 25.1, 18.7; IR (neat): 2934, 2241, 1720, 1606, 1510, 1450,
1247, 834 cmꢀ1; HRMS (ESI): m/z calcd for C21H26NO2: 324.1958 [M+H]+; found: 324.1952.
2ꢀ(Cyclohexanecarbonyl)ꢀ7ꢀ(trimethylsilyl)heptꢀ6ꢀynenitrile (35): Colorless oil; 1.42g, 72%
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yield; H NMR (400 MHz, CDCl3): δ 3.57 (dd, J = 8.8, 5.6 Hz, 1H), 2.72 (tt, J = 11.2, 3.6 Hz,
1H), 2.28 (t, J = 6.8 Hz, 2H), 2.01–1.86 (m, 4H), 1.81–1.61 (m, 4H), 1.41–1.18 (m, 6H), 0.12
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ppm (s, 9H); C NMR (100 MHz, CDCl3): δ 203.5, 117.3, 105.3, 86.0, 49.2, 41.8, 28.6, 28.4,
27.7, 25.5, 25.3, 25.2, 19.1, 0.0; IR (neat): 2935, 2176, 1723, 1451, 1250, 844 cmꢀ1; HRMS (EI):
m/z calcd for C17H27NOSi: 289.1862 [M]+; found: 289.1867.
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Synthesis of Products. The general procedure for autoxidative annulation in the synthesis of
products 7, 19–28, 38–42 and 49–52 was demonstrated as follows using 7 as a typical example.
3ꢀBenzoylꢀ4ꢀoxoꢀ3a,4,5,6,7,7aꢀhexahydroꢀ1Hꢀindeneꢀ3aꢀcarbonitrile (7): A mixture of 2ꢀoxoꢀ
6ꢀ(4ꢀphenylbutꢀ3ꢀynyl)cyclohexanecarbonitrile 6 (125 mg, 0.50 mmol), Co(OAc)2 (7 mg, 0.04
mmol) and Nꢀhydroxyphthalimide (13 mg, 0.08 mmol) in benzene (1 mL) was stirred under air
at room temperature for 12 h. The mixture was filtered through a pad of celite and slica gel
followed by washing with CH2Cl2 (2 × 20 mL). The organic layer was concentrated under
reduced pressure to give the residue, which was subjected to purification by flash
chromatography on silica gel using EtOAc/nꢀhexane = 2/5 as eluant to afford product 7 (81 mg,
61% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J = 7.2 Hz, 2H), 7.56 (t, J =
7.2 Hz, 1H), 7.44 (t, J = 7.2 Hz, 2H), 6.83 (t, J = 2.8 Hz, 1H), 3.29–3.23 (m, 1H), 2.98 (ddd, J =
18.4, 6.8, 2.8 Hz, 1H), 2.77 (dt, J = 13.6, 6.0 Hz, 1H), 2.48–2.40 (m, 2H), 2.14–2.06 (m, 1H),
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2.02–1.94 (m, 2H), 1.68–1.59 (m, 1H); C NMR (100 MHz, CDCl3): δ 201.1, 190.2, 149.1,
140.0, 137.2, 132.7, 128.9, 128.4, 117.8, 59.7, 50.4, 38.4, 38.2, 27.0, 24.0; IR (neat): 2929, 2238,
1726, 1646, 1343 cmꢀ1; HRMS (EI): m/z calcd for C17H15NO2: 265.1103 [M]+; found: 265.1098.
Methyl 4ꢀ(3aꢀcyanoꢀ4ꢀoxoꢀ3a,4,5,6,7,7aꢀhexahydroꢀ1Hꢀindeneꢀ3ꢀcarbonyl)benzoate (19):
Colorless oil; 99 mg, 61% yield; 1H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 8.8 Hz, 2H), 7.77 (d,
J = 8.8 Hz, 2H), 6.81 (t, J = 2.8 Hz, 1H), 3.93 (s, 3H), 3.28 (quint, J = 6.4 Hz, 1H), 2.97–2.90 (m,
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1H), 2.86–2.78 (m, 1H), 2.48–2.39 (m, 2H) 2.19–1.92 (m, 3H), 1.69–1.61 (m, 1H); C NMR
(100 MHz, CDCl3): δ 201.2, 189.7, 166.0, 150.1, 140.8, 140.0, 133.4, 129.6, 128.7, 117.7, 59.1,
52.4, 50.5, 38.2, 38.1, 26.6, 23.9; IR (neat): 2953, 2234, 1725, 1651, 1282, 1109 cmꢀ1; HRMS
(ESI): m/z calcd for C19H18NO4: 324.1236 [M+H]+; found: 324.1227.
3ꢀ(4ꢀCyanobenzoyl)ꢀ4ꢀoxoꢀ3a,4,5,6,7,7aꢀhexahydroꢀ1Hꢀindeneꢀ3aꢀcarboꢀ nitrile (20): White
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solid; 73 mg, 50% yield; m.p. 149–150 C; H NMR (400 MHz, CDCl3): δ 7.82 (d, J = 8.0 Hz,
2H), 7.75 (d, J = 8.0 Hz, 2H), 6.80 (t, J = 2.8 Hz, 1H), 3.31 (quint, J = 6.4 Hz, 1H), 2.92 (ddd, J
= 18.8, 7.6, 2.8 Hz, 1H), 2.87–2.80 (m, 1H), 2.49–2.39 (m, 2H), 2.23–2.16 (m, 1H), 2.15–2.06
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(m, 1H), 2.00–1.92 (m, 1H), 1.71–1.63 (m, 1H); C NMR (100 MHz, CDCl3): δ 201.2, 188.8,
149.9, 140.8, 139.8, 132.3, 129.3, 117.8, 117.5, 115.9, 58.7, 50.6, 38.1, 37.8, 26.2, 23.9; IR
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(CH2Cl2 cast): 2941, 2232, 1731, 1651, 1250 cmꢀ1; HRMS (ESI): m/z calcd for C18H15N2O2:
291.1134 [M+H]+; found: 291.1129.
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3ꢀ(4ꢀMethoxybenzoyl)ꢀ4ꢀoxoꢀ3a,4,5,6,7,7aꢀhexahydroꢀ1Hꢀindeneꢀ3aꢀcarbonitrile
(21):
Colorless oil; 62 mg, 42% yield; 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.0 Hz, 2H), 6.90 (d,
J = 8.0 Hz, 2H), 6.78 (t, J = 2.8 Hz, 1H), 3.88 (s, 3H), 3.21 (quint, J = 6.4 Hz, 1H), 3.00 (ddd, J
= 18.4, 7.2, 2.8 Hz, 1H), 2.71–2.64 (m, 1H), 2.47–2.40 (m, 2H), 2.05–1.81 (m, 3H), 1.64–1.56
(m, 1H); 13C NMR (100 MHz, CDCl3): δ 201.2, 188.7, 163.5, 147.2, 139.9, 131.5, 129.8, 117.9,
113.8, 60.3, 55.5, 50.4, 38.5, 38.4, 27.3, 24.0; IR (neat): 2960, 2239, 1727, 1599, 1261, 1026 cmꢀ
1; HRMS (ESI): m/z calcd for C18H18NO3: 296.1287 [M+H]+; found: 296.1281.
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3ꢀ(4ꢀFluorobenzoyl)ꢀ4ꢀoxoꢀ3a,4,5,6,7,7aꢀhexahydroꢀ1Hꢀindeneꢀ3aꢀcarbonitrile
(22):
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Colorless oil; 57 mg, 40% yield; H NMR (400 MHz, CDCl3): δ 7.78 (dd, J = 8.8, 5.6 Hz, 2H),
7.12 (t, J = 8.8 Hz, 2H), 6.79 (t, J = 2.8 Hz, 1H), 3.26 (quint, J = 6.0 Hz, 1H), 2.96 (ddd, J = 18.4,
7.2, 2.8 Hz, 1H), 2.80–2.73 (m, 1H), 2.48–2.39 (m, 2H), 2.15–2.07 (m, 1H), 2.00–1.93 (m, 2H),
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1.67–1.59 (m, 1H); C NMR (100 MHz, CDCl3): δ 201.3, 188.7, 165.5 (d, JCꢀF = 253.1 Hz),
148.8, 139.7, 133.4 (d, 4JCꢀF = 3.0 Hz), 131.6 (d, 3JCꢀF = 9.2 Hz), 117.8, 115.6 (d, 2JCꢀF = 22.2 Hz),
59.6, 50.4, 38.2 (2C), 26.8, 23.9; IR (neat): 2945, 2239, 1726, 1648, 1598, 1230 cmꢀ1; HRMS
(EI): m/z calcd for C17H14FNO2: 283.1009 [M]+; found: 283.1012.
3ꢀ(4ꢀMethylbenzoyl)ꢀ4ꢀoxoꢀ3a,4,5,6,7,7aꢀhexahydroꢀ1Hꢀindeneꢀ3aꢀcarbonitrile
(23):
Colorless oil; 56 mg, 40% yield; 1H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 8.4 Hz, 2H), 7.25 (d,
J = 8.4 Hz, 2H); 6.85 (t, J = 2.4 Hz, 1H), 3.28–3.22 (m, 1H), 3.02 (ddd, J = 18.4, 6.8, 2.4 Hz,
1H), 2.78–2.70 (m, 1H), 2.52–2.43 (m, 2H), 2.42 (s, 3H), 2.13–2.03 (m, 1H), 2.02–1.90 (m, 2H),
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1.69–1.60 (m, 1H); C NMR (100 MHz, CDCl3): δ 201.2, 189.8, 148.4, 143.7, 140.0, 134.5,
129.2, 129.1, 117.9, 59.9, 50.4, 38.5, 38.3, 27.2, 24.0, 21.6 ; IR (neat): 2949, 2238, 1725, 1643
cmꢀ1; HRMS (EI): m/z calcd for C18H17NO2: 279.1259 [M]+; found: 279.1261.
4ꢀBenzoylꢀ3ꢀoxoꢀ1,2,3,3a,6,6aꢀhexahydropentaleneꢀ3aꢀcarbonitrile (24): Colorless oil; 48 mg,
38% yield; 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 7.2 Hz, 2H), 7.56 (t, J = 7.2 Hz, 1H), 7.44
(t, J = 7.2 Hz, 2H), 6.74 (t, J = 2.4 Hz, 1H), 3.51–3.45 (m, 1H), 3.21 (ddd, J = 19.6, 8.0, 2.4 Hz,
1H), 2.68 (dt, J = 19.6, 2.4 Hz, 1H), 2.62–2.48 (m, 2H), 2.46–2.37 (m, 1H), 1.85–1.76 (m, 1H);
13C NMR (100 MHz, CDCl3): δ 204.1, 189.6, 148.8, 137.3, 137.1, 132.9, 128.9, 128.4, 117.4,
58.6, 46.3, 40.1, 36.3, 26.7; IR (neat): 2958, 2239, 1750, 1652 cmꢀ1; HRMS (EI): m/z calcd for
C16H13NO2: 251.0946 [M]+; found: 251.0948.
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4ꢀ(4ꢀMethoxybenzoyl)ꢀ3ꢀoxoꢀ1,2,3,3a,6,6aꢀhexahydropentaleneꢀ3aꢀcarbonitrile
Colorless oil; 49 mg, 35% yield; 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 7.2 Hz, 2H), 6.93 (d,
(25):
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J = 7.2 Hz, 2H), 6.65 (t, J = 2.4 Hz, 1H), 3.86 (s, 3H), 3.48–3.43 (m, 1H), 3.20 (ddd, J = 19.2,
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7.6, 2.4 Hz, 1H), 2.66 (dt, J = 19.2, 2.4 Hz, 1H), 2.64–2.36 (m, 3H), 1.83–1.74 (m, 1H); C
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NMR (100 MHz, CDCl3): δ 204.3, 188.2, 163.6, 146.3, 137.3, 131.5, 129.7, 117.4, 113.7, 59.1,
53.5, 46.3, 40.0, 36.4, 26.8; IR (neat): 2920, 2241, 1753, 1641 cmꢀ1; HRMS (ESI): m/z calcd for
C17H16NO3: 282.1152 [M+H]+; found: 282.1125.
2ꢀBenzoylꢀ1ꢀ(cyclohexanecarbonyl)cyclopentꢀ2ꢀenecarbonitrile (26): Colorless oil; 62 mg,
40% yield; 1H NMR (400 MHz, CDCl3): δ 7.45 (d, J = 7.6 Hz, 2H), 7.58 (t, J = 7.6 Hz, 1H), 7.46
(t, J = 7.6 Hz, 2H), 6.89 (t, J = 2.4 Hz, 1H), 3.36 (tt, J = 11.2, 3.2 Hz, 1H), 2.95–2.80 (m, 2H),
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2.63–2.56 (m, 1H), 2.40–2.32 (m, 1H), 2.10–1.69 (m, 4H), 1.52–1.17 ppm (m, 6H); C NMR
(100 MHz, CDCl3): δ 206.4, 190.1, 150.1, 143.2, 137.0, 132.7, 128.8, 128.4, 120.1, 57.6, 48.7,
36.1, 33.5, 29.1, 28.7, 27.9, 25.6, 25.6, 24.9; IR (neat): 2933, 2856, 2237, 1719, 1643, 1449 cmꢀ1;
HRMS (EI): m/z calcd for C20H21NO2: 307.1572 [M]+; found: 307.1585.
Methyl 4ꢀ(5ꢀcyanoꢀ5ꢀ(cyclohexanecarbonyl)cyclopentꢀ1ꢀenecarbonyl)benzoate (27): White
o
1
solid; 66 mg, 36% yield; m.p. 124–126 C; H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 8.0 Hz,
2H), 7.77 (d, J = 8.0 Hz, 2H), 6.86 (t, J = 2.8 Hz, 1H), 3.93 (s, 3H), 3.35 (tt, J = 11.2, 3.2 Hz,
1H), 2.95–2.82 (m, 2H), 2.65–2.59 (m, 1H), 2.41–2.34 (m, 1H), 2.10–2.04 (m, 2H), 1.84–1.70
13
(m, 3H), 1.49–1.20 ppm (m, 5H); C NMR (100 MHz, CDCl3): δ 206.3, 189.5, 166.0, 151.0,
143.1, 140.6, 133.5, 129.6, 128.7, 119.9, 57.5, 52.4, 48.7, 36.1, 33.6, 29.2, 27.9, 25.6, 25.6, 24.9;
IR (CH2Cl2 cast): 2935, 2856, 2237, 1723, 1646, 1283, 1108 cmꢀ1; HRMS (EI): m/z calcd for
C22H23NO4: 365.1627 [M]+; found: 365.1643.
1ꢀ(Cyclohexanecarbonyl)ꢀ2ꢀ(4ꢀmethoxybenzoyl)cyclopentꢀ2ꢀenecarbonitrile (28): White
o
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solid; 47 mg, 28% yield; m.p. 118–120 C; H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 9.2 Hz,
2H), 6.91 (d, J = 9.2 Hz, 2H), 6.81 (t, J = 2.4 Hz, 1H), 3.85 (s, 3H), 3.35 (tt, J = 10.8, 3.2 Hz,
1H), 2.89–2.84 (m, 2H), 2.61–2.54 (m, 1H), 2.39–2.32 (m, 1H), 2.11–2.02 (m, 2H), 1.83–1.69
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(m, 4H), 1.49–1.19 ppm (m, 4H); C NMR (100 MHz, CDCl3): δ 206.6, 188.6, 163.4, 148.5,
143.3, 131.3, 129.7, 120.3, 113.7, 57.9, 55.5, 48.8, 36.1, 33.5, 29.2, 27.9, 25.7, 25.6, 24.9; IR
(CH2Cl2 cast): 2934, 2855, 2237, 1720, 1634, 1600, 1259, 1028 cmꢀ1; HRMS (ESI): m/z calcd.
for C21H24NO3: 338.1756 [M+H]+; found: 338.1746.
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3ꢀOxoꢀ4ꢀ((triethylsilyl)carbonyl)ꢀ1,2,3,3a,6,6aꢀhexahydropentaleneꢀ3aꢀcarbonitrile
Yellow oil; 90 mg, 62% yield; 1H NMR (400 MHz, CDCl3): δ 6.89 (t, J = 2.8 Hz, 1H), 3.40–3.34
(38):
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(m, 1H), 3.19 (ddd, J = 19.6, 8.4, 2.8 Hz, 1H), 2.59 (dt, J = 19.6, 2.8 Hz, 1H), 2.43–2.39 (m, 2H),
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2.36–2.26 (m, 1H), 1.77–1.69 (m, 1H), 0.93 (t, J = 8.0 Hz, 9H), 0.77 (q, J = 8.0 Hz, 6H); C
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NMR (100 MHz, CDCl3): δ 230.1, 203.7, 148.1, 144.7, 117.3, 57.3, 45.8, 40.5, 35.7, 26.4, 7.2
(3C), 3.1 (3C); IR (neat): 2919, 2238, 1754, 1590, 1460, 737 cmꢀ1; HRMS (EI): m/z calcd for
C16H23NO2Si: 289.1498 [M]+; found: 289.1494.
4ꢀOxoꢀ3ꢀ((triethylsilyl)carbonyl)ꢀ1,4,5,6,7,7aꢀhexahydroindeneꢀ3aꢀcarbonitrile (39): Yellow
solid; 111 mg, 73% yield; m.p. 59–60 oC; 1H NMR (400 MHz, CDCl3): δ 7.01 (t, J = 2.8 Hz, 1H),
3.13–3.06 (m, 1H), 2.96 (ddd, J = 18.8, 6.8, 2.8 Hz, 1H), 2.68–2.62 (m, 1H), 2.43 (ddd, J = 18.4,
4.8, 2.8 Hz, 1H), 2.23–2.16 (m, 1H), 2.06–2.00 (m, 1H), 1.92–1.85 (m, 2H), 1.56–1.50 (m, 1H),
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0.96 (t, J = 8.0 Hz, 9H), 0.80 (q, J = 8.0 Hz, 6H); C NMR (100 MHz, CDCl3): δ 230.3, 201.0,
148.0, 147.5, 117.8, 58.4, 49.9, 38.8, 38.1, 27.1, 24.3, 7.2 (3C), 3.1 (3C); IR (CH2Cl2 cast): 2955,
2875, 2235, 1733, 1576, 1457, 1239, 850 cmꢀ1; HRMS (EI): m/z calcd for C17H25NO2Si:
303.1655 [M]+; found: 303.1644.
4ꢀ((tertꢀButyldimethylsilyl)carbonyl)ꢀ3ꢀoxoꢀ1,2,3,3a,6,6aꢀhexahydropentaleneꢀ3aꢀ
o
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carbonitrile (40): Yellow solid; 100 mg, 69% yield; m.p. 85–86 C; H NMR (400 MHz,
CDCl3): δ 6.92 (t, J = 2.8 Hz, 1H), 3.41–3.35 (m, 1H), 3.21 (ddd, J = 19.6, 8.4, 2.8 Hz, 1H), 2.62
(dt, J = 19.6, 2.8 Hz, 1H), 2.45–2.41 (m, 2H), 2.37–2.30 (m, 1H), 1.78–1.70 (m, 1H), 0.90 (s,
9H), 0.27 (s, 3H), 0.26 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 229.4, 203.6, 148.4, 145.1, 117.3,
57.4, 45.8, 40.5, 35.8, 26.5 (3C), 26.4, 16.8, –5.4, –5.7; IR (CH2Cl2 cast): 2954, 2858, 2242,
2174, 1759, 1589, 1251, 839 cmꢀ1; HRMS (ESI): m/z calcd for C16H24NO2Si: 290.1576 [M+H]+;
found: 290.1568.
3ꢀ((tertꢀButyldimethylsilyl)carbonyl)ꢀ4ꢀoxoꢀ3a,4,5,6,7,7aꢀhexahydroꢀ1Hꢀindeneꢀ3aꢀ
o
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carbonitrile (41): Yellow solid; 114 mg, 75% yield; m.p. 93–94 C; H NMR (400 MHz,
CDCl3): δ 7.01 (t, J = 2.8 Hz, 1H), 3.12–3.06 (m, 1H), 2.95 (ddd, J = 18.8, 6.8, 2.8 Hz, 1H), 2.67
(dt, J = 13.2, 6.4 Hz, 1H), 2.43 (ddd, J = 18.8, 5.2, 2.8 Hz, 1H), 2.24–2.17 (m, 1H), 2.07–2.00 (m,
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1H), 1.93–1.87 (m, 2H), 1.57–1.48 (m, 1H), 0.93 (s, 9H), 0.29 (s, 3H), 0.26 (s, 3H); C NMR
(100 MHz, CDCl3): δ 229.6, 201.0, 148.6, 147.9, 117.9, 58.5, 49.9, 38.8, 38.1, 27.0, 26.4 (3C),
24.3, 16.7, –5.4, –5.7; IR (CH2Cl2 cast): 2931, 2239, 1728, 1583, 1251, 840 cmꢀ1; HRMS (EI):
m/z calcd for C17H25NO2Si: 303.1655 [M]+; found: 303.1643.
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1ꢀ(Cyclohexanecarbonyl)ꢀ2ꢀ((trimethylsilyl)carbonyl)cyclopentꢀ2ꢀenecarbonitrile
Yellow oil; 67 mg, 44% yield; 1H NMR (400 MHz, CDCl3): δ 7.06 (t, J = 2.8 Hz, 1H), 3.34 (t, J
(42):
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= 10.8, 3.2 Hz, 1H), 2.94–2.81 (m, 2H), 2.52–2.45 (m, 1H), 2.30–2.22 (m, 1H), 2.19–1.97 (m,
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2H), 1.83–1.73 (m, 4H), 1.54–1.36 (m, 4H), 0.28 ppm (s, 9H); C NMR (100 MHz, CDCl3): δ
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229.7, 206.5, 150.0, 148.5, 120.3, 56.1, 48.70, 35.6, 33.7, 29.7, 29.3, 27.8, 25.7, 24.9, ꢀ2.05 (3C);
IR (neat): 2935, 2235, 1719, 1585, 1250, 846 cmꢀ1; HRMS (EI): m/z calcd. for C17H25NO2Si:
303.1655 [M]+; found: 303.1650.
4ꢀOxoꢀ3ꢀpropionylꢀ3a,4,5,6,7,7aꢀhexahydroꢀ1Hꢀindeneꢀ3aꢀcarbonitrile (49): Colorless oil;
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23 mg, 21% yield; H NMR (400 MHz, CDCl3): δ 7.06 (t, J = 2.4 Hz, 1H), 3.19 (quint., J = 6.8
Hz, 1H), 2.92 (ddd, J = 18.4, 7.2, 2.8 Hz, 1H), 2.80ꢀ2.67 (m, 3H), 2.45ꢀ2.38 (m, 1H), 2.35–2.28
(m, 1H), 2.12–2.04 (m, 1H), 2.02–1.92 (m, 2H), 1.65–1.56 (m, 1H), 1.13(t, J = 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ 201.4, 196.1, 146.4, 141.5, 117.8, 58.5, 50.6, 38.0, 37.9, 31.8, 26.7,
24.2, 7.7; IR (neat): 2940, 2238, 1729, 1671, 1369 cmꢀ1; HRMS (ESI): m/z calcd for C13H16NO2:
218.1176 [M+H]+; found: 218.1177.
3ꢀButyrylꢀ4ꢀoxoꢀ3a,4,5,6,7,7aꢀhexahydroꢀ1Hꢀindeneꢀ3aꢀcarbonitrile (50): Colorless oil; 30
mg, 26% yield; 1H NMR (400 MHz, CDCl3): δ 7.05 (t, J = 2.4 Hz, 1H), 3.19 (quint., J = 6.4 Hz,
1H), 2.92 (ddd, J = 18.4, 6.8, 2.4 Hz, 1H), 2.76ꢀ2.63 (m, 3H), 2.42 (ddd, J = 18.4, 5.6, 2.8 Hz,
1H), 2.35–2.28 (m, 1H), 2.12–2.01 (m, 1H), 1.98–1.92 (m, 2H), 1.73–1.56 (m, 3H), 0.96 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 201.3, 195.7, 146.3, 141.9, 117.8, 50.6, 40.5, 38.1,
37.9, 26.7, 24.2, 17.5, 13.7; IR (neat): 2956, 2932, 2242, 1729, 1669, 1375 cmꢀ1; HRMS (ESI):
m/z calcd for C14H18NO2: 232.1332 [M+H]+; found: 232.1333.
Eꢀ4ꢀOxoꢀ3ꢀpropylideneoctahydroꢀ1Hꢀindeneꢀ3aꢀcarbonitrile (51):26b Colorless oil; 33mg,
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32% yield; H NMR (400 MHz, CDCl3): δ 5.65 (tt, J = 7.6, 20 Hz, 1H), 2.90–2.84 (m, 1H),
2.65–2.52 (m, 3H), 2.50–2.41 (m, 1H), 2.11 (quint., J =7.6 Hz, 1H), 2.03–1.94 (m, 3H), 1.93–
1.84 (m, 2H), 1.69–1.55 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 202.4,
134.1, 133.0, 118.9, 57.3, 52.5, 38.5, 30.7, 28.7, 25.8, 24.9, 22.1, 13.4; IR (neat): 2940, 2234,
1714, 1458, 1240cmꢀ1; HRMS (ESI): m/z calcd for C13H18NO: 204.1383 [M+H]+; found:
204.1384.
Eꢀ3ꢀButylideneꢀ4ꢀoxooctahydroꢀ1Hꢀindeneꢀ3aꢀcarbonitrile (52):26b Colorless oil; yield: 30
mg, 28%; 1H NMR (400 MHz, CDCl3): δ 5.69 (tt, J = 7.6, 2.0 Hz, 1H), 2.90–2.84 (m, 1H), 2.65–
2.49 (m, 3H), 2.48–2.41 (m, 1H), 2.11–1.84 (m, 6H), 1.68–1.55 (m, 2H), 1.43–1.35 (m, 2H),
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0.90 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3): δ 202.5, 134.7, 131.6, 118.9, 57.5, 52.6,
38.5, 30.8, 30.6, 28.8, 26.0, 25.0, 22.3, 13.7; IR (neat): 2960, 2932, 2234, 1716, 1453, 1235 cmꢀ1;
HRMS (ESI): m/z calcd for C14H20NO: 218.1539 [M+H]+; found: 218.1540.
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Synthesis of the authentic sample I .
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2ꢀ(cyclohexanecarbonyl)ꢀ6ꢀhydroxyhexanenitrile (H): To a stirred solution of 3ꢀcyclohexylꢀ3ꢀ
oxopropanenitrile (1.51 g, 10 mmol) and 4ꢀ((tetrahydroꢀ2Hꢀpyranꢀ2ꢀyl)oxy)butanal (1.72 g, 10
mmol) in EtOH (50 mL) was added Lꢀproline (230 mg, 2 mmol) and Hantzsch ester (2.54 g, 10
o
mmol) sequentially in one portion. The resulting mixture was stirred at 25 C for 16 h. The
reaction solution was concentrated under reduced pressure followed by rapid chromatography on
silical gel (CH2Cl2) to afford the crude product. To a stirred solution of the crude product in
methanol (50 mL) was added pꢀTsOH (380 mg, 2 mmol) in one portion. The resulting mixture
o
was stirred at 25 C for 10 h. The reaction solution was concentrated under reduced pressure to
give the crude residue, which was purified by chromatography on silica gel using EtOAc/nꢀ
Hexane = 1/3 to 1/1 as eluant to afford compound H (1.78 g, 80% yield over 2 steps) as a
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colorless oil; H NMR (400 MHz, CDCl3): δ 3.68 (t, J = 6.0 Hz, 2H), 3.52 (dd, J = 8.0, 6.0 Hz,
1H), 2.75 (tt, J = 10.8, 3.2 Hz, 1H), 1.95–1.15 (m, 16H); 13C NMR (100 MHz, CDCl3): δ 203.8,
117.3, 61.4, 48.8, 41.9, 31.4, 28.1, 28.0, 25.2, 24.9, 23.1; IR (neat): 3422, 2934, 2858, 2243,
2198, 1719, 1450 cmꢀ1; LRMS (ESI): m/z = 224 [M+H]+, 246 [M+Na]+, 469 [2M+Na] +; HRMS
(ESI): m/z calcd for C13H22NO2: 224.1645 [M+H]+; found: 224.1651.
1ꢀ(cyclohexanecarbonyl)ꢀ2ꢀoxocyclopentanecarbonitrile (I): To a stirred solution of 2ꢀ
(cyclohexanecarbonyl)ꢀ6ꢀhydroxyhexanenitrile H (447 mg, 2 mmol)in dry CH2Cl2 (20 mL) were
o
added celite (2 g) and PCC (1.08 g, 5 mmol) sequentially in one portion at 0 C. The resulting
o
mixture was stirred at 25 C for 3 h. The reaction mixture was filtrated with a pad of silica gel
and then the filtrate was concentrated under reduced pressure to give the crude βꢀhydroxy ketone.
To the solution of the βꢀhydroxy ketone in dry CH2Cl2 (20 mL) was added DMP (848 mg, 2
o
o
mmol) in one portion at 0 C. The resulting mixture was stirred at 25 C for 1 h. The reaction
o
mixture was quenched with 10% Na2S2O3(aq) solution (10 mL) at 0 C for 30 min. The organic
layer was washed with saturated NaHCO3(aq) solution and brine, dried over MgSO4(s), filtered and
concentrated to give the crude residue, which was purified by chromatography on silica gel using
EtOAc/nꢀhexane (3/20) as eluant to afford 2ꢀcyanoꢀ1,3ꢀdiketone I (171 mg, 39% yield over 2
1
steps) as a colorless oil; H NMR (400 MHz, CDCl3): δ 3.15 (tt, J = 10.8, 3.6 Hz, 1H), 2.74
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(quint, J = 6.8 Hz, 1H), 2.47 (t, J = 7.6 Hz, 2H), 2.43 (quint, J = 6.8 Hz, 1H); 2.19–2.06 (m, 2H),
13
2.04–1.96 (m, 1H), 1.87–1.69 (m, 4H), 1.45–1.16 (m, 5H); C NMR (100 MHz, CDCl3): δ
7
8
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204.1, 201.3, 116.5, 60.3, 48.9, 36.9, 32.9, 29.2, 28.1, 25.2, 25.0, 24.8, 19.6; IR (neat): 2934,
2857, 2239, 1761, 1715, 1450 cmꢀ1; LRMS (ESI): m/z = 220 [M+H]+, 242 [M+Na]+.
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5ꢀcyanoꢀ6ꢀcyclohexylꢀ6ꢀoxohexanoic acid (J): 2ꢀcyanoꢀ1,3ꢀdiketone I (22 mg, 0.1 mmol) was
hydrolysed to acid J upon exposure to air in CDCl3 over 48 h at roon temperature. The solution
was concentrated to give the crude residue which was purified by chromatography on silica gel
using EtOAc as eluant to afford acid J (18 mg, 75% yield) as a colorless oil; 1H NMR (400 MHz,
CDCl3): δ 3.54 (dd, J = 8.0, 6.0 Hz, 1H), 2.49 (tt, J = 10.8, 3.2 Hz, 1H), 2.44 (t, J = 6.8 Hz, 2H)
13
2.15–1.69 (m, 8H), 1.49–1.16 (m, 7H); C NMR (100 MHz, CDCl3): δ 203.3, 178.6, 117.2, 49.2,
41.8, 33.0, 28.5, 28.3, 27.8, 25.4, 25.3, 25.1, 21.9; LRMS (ESI): m/z = 260 [M+Na]+; HRMS
(ESI): m/z calcd for C13H18NO3: 236.1292 [MꢀH]ꢀ; found: 236.1284.
ASSOCIATED CONTENT
Supporting Information
1H and 13C NMR spectra of all new compounds including compounds I and J, Xꢀray
crystallographic analysis of products 20, 27, 28, 39ꢀ41, 45 and 46, geometries of vinyl radicals I,
II, III and compounds 35, 53 and 54 along with Cartesian atom coordinates, absolute energies,
and BDE are provided. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: ksshia@nhri.org.tw.
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We are grateful to the National Health Research Institutes and Ministry of Science and
Technology of Taiwan (MOSTꢀ103ꢀ2113ꢀMꢀ400ꢀ002ꢀMY3) for financial support.
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7.729(15) Å, b = 7.756(14) Å, c = 12.50(3) Å, V = 730(2) Å3, space group P ꢀ1, Z = 2, a total of
4725 reflections were collected in the range 1.67 to 25.03o. Of these, 2465 were independent; for
the observed data, wR2 = 0.2474, R1 = 0.1106.
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(14) Crystallographic data for 27 (CCDC 962910): C22H23NO4, Mw = 365.41, triclinic, a =
19.901(11) Å, b = 9.308(5) Å, c = 10.561(6) Å, V = 1907.7(19) Å3, space group P 21/c, Z = 4, a
total of 9435 reflections were collected in the range 2.43 to 25.14o. Of these, 3383 were
independent; for the observed data, wR2 = 0.2170, R1 = 0.0972.
(15) Crystallographic data for 28 (CCDC 968701): C21H23NO3, Mw = 337.40, triclinic, a =
7.7230(3) Å, b = 21.7910(10) Å, c = 10.8617(4) Å, V = 1809.62(13) Å3, space group P 21/n, Z =
4, a total of 12081 reflections were collected in the range 2.82 to 25.03o. Of these, 3183 were
independent; for the observed data, wR2 = 0.0952, R1 = 0.0381.
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(19) Colvin, E. W. Silicon in Organic Synthesis, Butterworths, 1981.
(20) Crystallographic data for 39 (CCDC 883936): C17H25NO2Si, Mw = 303.47, triclinic, a =
17.6278(10) Å, b = 8.0278(5) Å, c = 12.3398(7) Å, V = 1693.79(17) Å3, space group P 21/c, Z =
4, a total of 11381 reflections were collected in the range 2.80 to 25.24o. Of these, 3008 were
independent; for the observed data, wR2 = 0.1027, R1 = 0.0579.
(21) Crystallographic data for 40 (CCDC 971513): C16H23NO2Si, Mw = 289.44, triclinic, a =
7.1377(10) Å, b = 12.3260(18) Å, c = 18.630(3) Å, V = 1634.6(4) Å3, space group P 21/n, Z = 4,
a total of 8759 reflections were collected in the range 1.98 to 25.15o. Of these, 2915 were
independent; for the observed data, wR2 = 0.1830, R1 = 0.0815.
(22) Crystallographic data for 41 (CCDC 966268): C17H25NO2Si, Mw = 303.47, triclinic, a =
19.146(14) Å, b = 7.452(6) Å, c = 12.716(9) Å, V = 1755(2) Å3, space group C c, Z = 4, a total of
4110 reflections were collected in the range 2.95 to 25.02o. Of these, 2443 were independent; for
the observed data, wR2 = 0.0922, R1 = 0.0564.
(23) Sun, M.; Salomon, R. G. J. Am. Chem. Soc. 2004, 126, 5699–5708.
(24) Crystallographic data for 45 (CCDC 885581): C16H23NO2Si, Mw = 289.44, triclinic, a =
11.211(10) Å, b = 12.349(11) Å, c = 12.562(11) Å, V = 1607(3) Å3, space group P ꢀ1, Z = 4, a
total of 6252 reflections were collected in the range 1.86 to 27.38o. Of these, 6252 were
independent; for the observed data, wR2 = 0.2574, R1 = 0.1046.
(25) Crystallographic data for 46 (CCDC 886563): C20H23NO2Si, Mw = 337.48, triclinic, a =
26.426(12) Å, b = 26.426(12) Å, c = 7.039(4) Å, V = 7.039(4) Å3, space group R 3, Z = 9, a total
of 8174 reflections were collected in the range 1.54 to 25.00o. Of these, 2311 were independent;
for the observed data, wR2 = 0.0799, R1 = 0.0744.
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Chang, C.ꢀP.; Shia, K.ꢀS. Org. Biomol. Chem. 2011, 9, 4778–4781. (c) Fleming, F. F.; Zhang, Z.
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O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.;
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