Palladium(0)/copper(I)-catalyzed tandem cyclization of aryl 1-cyanoalk-5-ynyl ketone system: Rapid assembly of cyclopenta[b]naphthalene and benzo[b]fluorene derivatives

Article abstract of DOI:10.1002/adsc.201300107

We have developed a new and general approach to construct a variety of benzo[b]fluorene and cyclopenta-[b]naphthalene derivatives via the palladium(0)/copper(I)-catalyzed tandem cyclization of aryl 1-cyanoalk-5-ynyl ketone systems in an extremely efficient manner. The key operation lies in the copper(I)-catalyzed aerobic oxidation, which allows for activation of two successive intramolecular cycloadditions immediately after the Sonogashira coupling reaction has occurred. Copyright

Full text of DOI:10.1002/adsc.201300107

FULL PAPERS
DOI: 10.1002/adsc.201300107
Palladium(0)/Copper(I)-Catalyzed Tandem Cyclization of Aryl
1-Cyanoalk-5-ynyl Ketone System: Rapid Assembly of
Cyclopenta[b]naphthalene and Benzo[b]fluorene Derivatives
Ying-Chieh Wong,a Tzu-Ting Kao,a Yu-Cheng Yeh,a Bing-Siou Hsieh,a
and Kak-Shan Shiaa,*
a
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053,
Taiwan, R.O.C.
Fax : (+886)-37-586-456; e-mail: ksshia@nhri.org.tw
Received: February 2, 2013; Revised: April 10, 2013; Published online: April 30, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300107.
Abstract: We have developed a new and general ap- cycloadditions immediately after the Sonogashira
proach to construct a variety of benzo[b]fluorene coupling reaction has occurred.
and cyclopenta-[b]naphthalene derivatives via the
palladium(0)/copper(I)-catalyzed tandem cyclization
of aryl 1-cyanoalk-5-ynyl ketone systems in an ex- Keywords: arylnaphthalenes; benzo[b]fluorenes;
tremely efficient manner. The key operation lies in copper; cyclopenta[b]naphthalenes; palladium; radi-
the copper(I)-catalyzed aerobic oxidation, which cal cyclization; Sonogashira reaction; tandem reac-
allows for activation of two successive intramolecular tions
Introduction
antibiotic properties or potent antimitotic activities.[1,2]
Many effective synthetic methods have been devel-
Benzo[b]fluorene and arylnaphthalene nuclei, as typi- oped to construct these polycyclic frameworks, mainly
fied in Figure 1, are present in many naturally occur- making use of metal-catalyzed annulation or dehydro-
ring products exhibiting either a broad spectrum of Diels–Alder (DDA) cycloaddition as a key opera-
tion.[3,4] Recently we have successfully developed a va-
riety of annulation protocols to establish highly func-
tionalized polycyclic rings on the basis of a-activated
cross-conjugated cycloalkenone systems.[5] In one ap-
proach, when substrates 1 and 2 were individually
Figure 1. Natural products containing either benzo[b]fluor-
ene or arylnaphthalene skeletons.
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treated with oxidants tert-butyl hydroperoxide
(TBHP) and tetrabutylammonium iodide (TBAI)
under reflux in benzene, the corresponding tricyclic
compounds 3 and 4, containing a cyclopenta[b]naph-
thalene nucleus, could be synthesized effectively.[6]
Although the methodology described above is syn-
thetically useful, however, harsh reaction conditions
are necessary to drive the reaction to completion.
Herein, we wish to report that a mild Pd/Cu-catalyzed
radical cascade, proceeding via a sequence of Sonoga-
shira coupling followed by [4+1] and [4+2]cycload-
ditions,[7,8] has been developed to rapidly assemble cy-
clopenta[b]naphthalene and benzo[b]fluorene deriva-
tives, for which the synthetic scope is tremendously
broadened and extended as compared to the prior
version indicated above.[6]
Scheme 2. Proposed mechanism for an intramolecular
Cu(I)-catalyzed radical cascade under air.
the observed radical cyclization cascade. More impor-
tantly, the results also strongly suggest that the [4+
2]intramolecular cycloaddition is not the result of
Results and Discussion
That the Cu(I)-catalyzed aerobic oxidation could con- a Diels–Alder process. Upon exposure to air, similar
vert a-cyano esters to the corresponding a-keto esters experiments with an incremental addition of CuI in
has been reported by Kim et al.[9] Accordingly, the ini- DMF have been intensively studied, leading to find-
tial radical species was generated by abstracting hy- ings that the most appropriate catalytic amount of
drogen a to cyano with molecular oxygen mediated CuI is 20 mol% (Scheme 1). Moreover, it was noticed
by Cu(I) at ambient temperature. Given that a-cyano that, in the absence of CuI under air, substrate 2
esters bear a high similarity to a-cyano ketones in could spontaneously transform into product 4 in 5–
many facets of chemistry, such as Diels–Alder reac- 13% yield in 24 h when dissolved in commonly used
tion,[10] Conia-ene reaction,[11] reductive alkylation,[12] solvents including CH3COOEt, CH2Cl2, and DMF.
and metal-mediated annulations,[13] the reaction However, we found that the conversion rate was con-
system described above appears to be one of the po- stantly maintained at this level even if the reaction
tential alternatives to meet our purpose for seeking time was prolonged for more than two days under
a radical initiator allowing us to work under mild con- either air or oxygen.
ditions. This concept was tested and validated by the
As illustrated in Scheme 2, a plausible mechanism
use of 2 as a model compound. As illustrated in of the observed CuI-catalyzed aerobic cycloaddition
Scheme 1, when substrate 2 was reacted under cataly- is proposed using a-cyano ketone 2 as an example.
sis with CuI (20 mol%) in DMF under air at room The cyclization cascade is initiated by abstracting hy-
temperature, it was found to undergo an intramolecu- drogen, a to both cyano and carbonyl groups, with
lar cycloaddition efficiently to afford the expected molecular oxygen mediated by Cu(I) to generate radi-
product 4 in high yield (89%), the structure of which cal intermediate A and hydroperoxide anion, wherein
was unambiguously confirmed by the X-ray crystallo- Cu(I) is simultaneously oxidized into Cu(II). Inter-
graphic analysis.[14] In contrast, when the same reac- mediate A thus formed might undergo the first intra-
tion was carried out under a nitrogen atmosphere, molecular 5-exo-dig cyclization to produce vinyl radi-
product 4 was formed in less than 5% yield as deter- cal B, by which the ensuing [4+2]radical cycloaddi-
1
mined by H NMR analysis, indicating that CuI asso- tion could take place to afford the corresponding
ciated with O2 should play a critical role in promoting cyclic pentadienyl radical C. Finally, rearomatization
should occur through aromatic homolytic substitution
(AHS) to furnish product 4 with concomitant forma-
tion of hydrogen peroxide.[15] Meanwhile, Cu(II) is re-
duced to Cu(I) via an electron transfer from hydro-
peroxide anion to enter the next catalytic cycle.[16]
Although it can be converted into product 4 effi-
ciently under mild reaction conditions as indicated
above, substrate 2 and structurally related analogues
must be prepared via a three-step synthetic sequence,
involving Dess–Martin oxidation,[17] Knoevenagel
Scheme 1. CuI-catalyzed aerobic cycloaddition.
condensation,[18] and Sonogashira coupling,[7] starting
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Palladium(0)/Copper(I)-Catalyzed Tandem Cyclization of Aryl 1-Cyanoalk-5-ynyl Ketone System
functions, one for facilitating Sonogashira coupling
and one for triggering cycloaddition. The key inter-
mediate 5 was readily prepared via a modified proce-
dure of Knoevenagel condensation, in which benzoyl-
AHCTUNGTREGaNNNU cetonitrile (6) was first condensed with 4-pentyn-1-al
(7) to form the corresponding a,b-unsaturated enone
in situ followed by reduction with Hantzsch ester.[19]
Using 5 as a substrate, screening of reaction condi-
tions via combining the palladium and copper source
as catalyst with various parameters, including solvent,
temperature and base, was then extensively carried
out. Results are compiled in Table 1 and discussed as
follows. As indicated in entry 1, a reaction catalyzed
Scheme 3. Retrosynthetic analysis of cyclopenta[b]naphtha-
lene derivatives.
with PdCl2ACTHUNTRGNE(UNG PPh3)2 (2 mol%) and CuI (20 mol%) in
from commercially available 4-pentyn-1-ol and ben- DMF using NEt3 as base at elevated temperature
zoylacetonitrile. Attempts to simplify this linear ap- under air was first examined. Unfortunately, this com-
proach and further broaden the synthetic scope were bination failed to induce Sonogashira coupling, but
then made. According to the retrosynthetic analysis a Conia-ene reaction occurred instead, leading to
shown in Scheme 3, it was envisioned that a general product 8 in 45% yield. As such, under similar reac-
approach toward cyclopenta[b]naphthalene deriva- tion conditions an increase of PdCl2ACTHNUTRGEN(UGN PPh3)2 up to
tives I might be achievable by reacting a common in- 10 mol% was then tried to effect the coupling. To our
termediate 5 with various aryl iodides, respectively, in delight, the desired product 4 was obtained in 59%
a Pd(0)/Cu(I)-catalyzed system to direct both alkyn- yield through this minor modification (entry 2). Thus,
ACHTUNGTRENNUNGylation and subsequent cycloaddition in one pot, a primary concept that Pd(II) and Cu(I) metal might
wherein Cu(I) is expected to have dual independent work as cocatalyst to promote independently both al-
Table 1. Optimization of reaction conditions.
Entry
Catalyst
Base
Solvent
Temp. [oC]
Yield [%][b]
1[c]
2% PdCl
G
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
pyridine
DIEA
pyrrolidine
Cs2CO3
Na2CO3
DMF
DMF
DMF
DMF
DMF
DMF
THF
MeCN
toluene
dioxane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
80
80
80
80
–
2[c]
10% PdCl
10% Pd
G
59
68
75
72
76
63
59
55
63
80
50
75
90
<5
<5
3[c]
T
N
N
N
R
N
N
R
4[c]
5[c]
80
6[d]
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
7[d]
8[d]
9[d]
10[d]
11[d]
12[d]
13[d]
14[d]
15[d]
16[d]
R
R
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
[a]
All reactions were performed using substrate 5 (100 mg, 0.47 mmol), methyl-4-iodobenzoate (136 mg, 0.52 mmol) and
base (0.94 mmol) in the presence of catalyst, as indicated above, in 3 mL of solvent.
Isolated yields.
Reaction was complete in 1.5 h.
Reaction was complete in 3.5 h.
[b]
[c]
[d]
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kynylation and subsequent cyACTHNUGRTNEUNGclization was experimen-
tally validated. Encouraged with these findings, a con-
ventional Pd(0) coupling agent Pd(PPh3)4 instead of
PdCl2A(PPh3)2 was then applied as shown in entry 3.
AHCTUNGTRENNUNG
CHTUNGTRENNUNG
The operation resulted in product 4 in a higher yield
(68% vs. entry 2; 59%), implying that Pd(0) might be
a better surrogate for Pd(II) to catalyze Sonogashira
coupling in the presence of CuI. Along this line, an
incremental addition of PdACHTNUTRGNEUNG(PPh3)4 starting with
2 mol% up to 15 mol% has been investigated, leading
to findings that upon exposure to air, an amount of at
least 10 mol% of PdACHTNUGTRNEUGN(PPh3)4 was required to induce
the alkynylation effectively. As such, using 10 mol%
of Pd(0) as a fixed theme, the amount of CuI was fur-
ther adapted. When CuI was increased up to
30 mol% (entry 4), a slight increase in yield (75% vs.
entry 3; 68%) was obtained, but it was found to be
a ceiling amount in that the reaction yield dropped
immediately to 72% when 40 mol% of CuI was used
(entry 5). Later, we came to realize that when the re-
action conditions in entry 4, in fact, were allowed to
Figure 2. Preparation of aryl 1-cyanoalk-5-ynyl ketones 5a–j.
work at room temperature instead, affording product yields (51–95%). Thus, not only is the generality of
4 in almost an equal yield, but a longer reaction time the methodology attested but also a novel series of
was necessary for completing the conversion (entry 6; compounds containing a linear [6,6,5] tricyclic frame-
76%, 3.5 h vs. entry 4; 75%, 1.5 h). Accordingly, work has become accessible. It must be emphasized
screening of different solvents, including THF, MeCN, that the above isolated yields are obtained at least in
toluene, dioxane and CH2Cl2 at ambient temperature a three-step chemical transformation, so that even the
rather than at 808C was then conducted to check sol- lowest yield (51%) might be considered to be synthet-
vent effects (entries 7–11). Consequently, we found ically significant and useful. Although all reactions
that CH2Cl2 is superior to all solvents examined in took place in a predictable and efficient manner, in
terms of reaction yields (entry 11; 80%).
general, aryl iodides with an electron-donating group
Replacing triethylamine with other organic bases gave products [e.g., 9ab (92%), 9ad (82%), 9ap
using CH2Cl2 as a fixed solvent was then studied, re- (79%) and 9aq (85%)] in higher yields than those
sulting in findings that pyrrolidine could further in- containing an electron-withdrawing group [e.g., 9ah
crease the reaction yield by ~10% (entry 14; 90%). In (65%), 9ai (51%), 9ak (62%) and 9al (68%)]. Howev-
parallel, inorganic bases such as Cs2CO3 and Na2CO3 er, halogenated aryl and heteroaryl iodides contribut-
were also tested, but they appeared to be extremely ed to the corresponding products 9am (90%), 9an
incompatible with the current catalyst to promote the (87%), 9as (88%) and 9at (91%) in excellent yields
desired reaction (entries 15 and 16; <5%). An ex- though they belong to electron-deficient chemical en-
planation for this could be that organic bases might tities in nature. These outcomes might be attributed
help the catalyst to dissolve more homogeneously, to a compromise between Sonogashira reaction and
thus enhancing reaction yield more significantly. The the subsequent [4+2]cycloaddition during the reac-
reaction system [10 mol% PdACHTNUTRGNE(UNG PPh3)4/30 mol% CuI/ tion course in that aryl iodides containing electron-
pyrrolidine/CH2Cl2/room temperature) exhibited in withdrawing groups could facilitate the former by en-
entry 14 was considered as the optimum and adopted hancing oxidative addition of the Pd(0) metal to the
as a typical procedure for the following reactions. To carbon-halogen bond, but deactivate the latter via in-
examine the generality of this newly developed proto- ductive stabilization of the vinyl radical intermediate
col, many structurally diverse substrates 5a–j B, which is thought to assume a bent s-type structure
(Figure 2) were readily prepared in good to excellent (Scheme 2).[20] By inference, a maximum yield might
yields via a modified procedure of Knoevenagel con- be attainable once these two opposing effects could
densation as previously applied to the synthesis of in- reach a subtle balance as seen with products 9ab
termediate 5 (see Experimental Section for synthetic (92%), 9at (91%), 9bc (95%) and 9bd (95%). Com-
details).
pound 9bl formed with complete regioselectivity in
As listed in Table 2, treating 5a–j with various mon- 95% yield is apparently the result of a beneficial
osubstituted aryl iodides under optimized conditions effect of ambient temperature in that the same reac-
gave the corresponding cyclopenta[b]naphthalene de- tion performed at 808C in DMF resulted in the for-
rivatives 9aa–au and 9ba–bl in good to excellent mation of a complex isomeric mixture.[21]
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Palladium(0)/Copper(I)-Catalyzed Tandem Cyclization of Aryl 1-Cyanoalk-5-ynyl Ketone System
Table 2. Tandem annulation of aryl 1-cyanoalk-5-ynyl ketones under catalysis with Pd(0)/Cu(I) metal.
1
In addition, as evidenced by H NMR data with energy barrier imposed with the 2-methyl group on
two distinct methyl singlets, compound 9ac must be the phenyl ring. This explanation could be justified by
present in two atropisomers due to the rotational its isomer 9ab in which only a singlet is observed for
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Ying-Chieh Wong et al.
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the 4-methyl group allowing for free rotation. The ste-
reoelectronic feature of the substituent on the benzo-
yl portion might not dominate the yield of reaction as
demonstrated by products, such as 9bc (95%; p-CH3),
9bi (93%; p-CF3), 9bj (93%; p-CO2Me), 9bk (90%; p-
OCH3), and 9bl (95%; m,p-fused phenyl), containing
either an electron-withdrawing or electron-donating
group but resulting in almost an equal yield, presuma-
bly due to rearomatization occurring rapidly after in-
termediate C is formed (Scheme 2). Theoretically, the
methodology can be further extended to the construc-
tion of various tetracyclic benzo[b]fluorene deriva-
tives II after minor modifications as depicted in the
Scheme 6. One-pot synthesis of a-ester cyclopenta[b]naph-
thalene derivatives.
To broaden the synthetic utility, our above optimal
retrosynthetic analysis (Scheme 4). It is highly con- reaction conditions for the title compounds were fur-
ceivable that the common intermediate 10 could be ther applied to the corresponding a-ester compounds
prepared through reagents 6 and 11 by the modified as typified by substrate 16 in Scheme 6, synthetic pro-
Knoevenagel condensation as described previously. cedures of which are detailed in the Experimental
Compound 10 thus obtained should be able to couple Section. It was found that upon coupling with aryl io-
with a variety of arylacetylenes to provide the corre- dides, a-ester ketone 16 was allowed to take the same
sponding products in one pot. According to this syn- reaction mode, respectively, to afford the correspond-
thetic design, substrate 10 was experimentally realized ing products 17–19 in moderate yields (25–44%). Sim-
in 78% yield and benzo[b]fluorene derivatives 12–15 ilar results were obtained even when reaction time
were obtained in good to excellent yields (72–93%) was prolonged to overnight. Compared to their a-
as displayed in Scheme 5. By this approach, not only cyano counterparts 4, 9aa and 9ad formed in much
did benzo[b]fluorene derivatives become available, higher yields in shorter reaction times (82–90%;
but also the appended functionality, referred to as R, 3.5 h), such a distinct difference in the reaction out-
could be extended to various alkyl groups (e.g., 15) in come suggests that there might be a considerable dis-
addition to the regular aryl moieties.
crepancy in the homolytic bond-dissociation energy
between these two analogous systems in the initially
formed radical species (e.g., intermediate A in
Scheme 2).
However, as the same reaction was carried out
under a nitrogen atmosphere, Sonogashira coupling
products 20–22, precursors of compounds 17–19, were
obtained instead in excellent yields and stayed stable
even if the reaction time was extended overnight
(Figure 3), again supporting that the proposed [4+
2]intramolecular cyclization is not the result of
a Diels–Alder process.
For comparison, as the current reaction system
(Table 1, entry 14) was initially performed in the ab-
sence of air, it was found that at least 5 mol% of
Pd(0) was necessary to effect the Sonogashira cou-
pling (stage I) to afford intermediate 2 (~90%, 1.5 h)
Scheme 4. Retrosynthetic analysis of the formation of ben-
zo[b]fluorene derivatives.
1
as determined by crude H NMR data. Once coupling
reaction was complete, air was then introduced to fa-
cilitate the radical cyclization (stage II) to afford
product 4 (92%, 3.5 h). Although the one-pot reaction
Scheme 5. One-pot synthesis of benzo[b]fluorene deriva-
tives.
Figure 3. Formation of Sonogashira coupling products under
a nitrogen atmosphere.
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Palladium(0)/Copper(I)-Catalyzed Tandem Cyclization of Aryl 1-Cyanoalk-5-ynyl Ketone System
carried out in this manner could reduce the catalyst 2-Benzoylhept-6-ynenitrile (5)
loading to half the original amount, however, it would
result in a lower overall yield (83% vs. 90%) and
longer reaction time (5 h vs. 3.5 h).
To
a stirred solution of benzoylacetonitrile 6 (1.0 g,
6.8 mmol) and pent-4-ynal 7 (686 mg, 8.2 mmol) in EtOH
(100 mL) was added l-proline (312 mg, 2.7 mmol) and
Hantzsch ester (1.7 g, 6.8 mmol) sequentially in one portion.
The resulting mixture was stirred at 258C for 16 h. The reac-
tion solution was concentrated under reduced pressure, the
residue was purified by flash chromatography on silical gel
(33% CH2Cl2 in n-hexane) to afford intermediate 5 as a col-
orless oil; yield: 1.3 g (94%). IR (CH2Cl2): nmax =3294, 2937,
Conclusions
We have developed a new and general approach to
achieve a facile access to benzo[b]fluorene and cyclo-
penta[b]naphthalene derivatives via sequential Pd(0)/
Cu(I)-catalyzed radical cyclization of the aryl 1-cya-
noalk-5-ynyl ketone system. Accordingly, a library of
diverse arylnaphthalene lignan- and kinamycin-mim-
icking molecules can be rapidly established for the
purpose of screening new chemical entities with po-
tential antibacterial and/or anticancer activity. In ad-
dition, for further synthetic elaboration, polycyclic
compounds thus formed could increase the degree of
functionalization via reductive decyanation substitu-
tion below ambient temperature as demonstrated in
many historical cases.[5d,10d,11a,12]
2250, 2117, 1694 cmÀ1; H NMR (400 MHz, CDCl3): d=7.97
1
(d, J=8.0 Hz, 2H), 7.64 (t, J=7.6 Hz, 1H), 7.51 (dd, J=8.0,
7.6 Hz, 2H), 4.40 (dd, J=8.8, 5.6 Hz, 1H), 2.30 (td, J=6.8,
2.8 Hz, 2H), 2.24–2.05 (m, 2H), 1.97 (t, J=2.8 Hz, 1H),
1.86–1.72 (m, 2H); 13C NMR (100 MHz, CDCl3): d=190.5
(CO), 134.5 (CH), 133.7 (C), 129.0 (CH), 128.7 (CH), 117.0
ꢀ
(CN), 82.7 (CꢀC), 69.6 (C CH), 39.3 (CH), 28.5 (CH2),
25.4 (CH2), 17.6 (CH2); HR-MS (FAB): m/z=212.1076,
calcd. for C14H13NO [M+H]+: 212.1075.
2-(4-Methylbenzoyl)hept-6-ynenitrile (5a): colorless oil;
yield: 87%. IR (CH2Cl2): nmax =3293, 3035, 2936, 2249,
1689 cmÀ1 1H NMR (400 MHz, CDCl3): d=7.85 (d, J=
;
7.6 Hz, 2H), 7.29 (d, J=7.6 Hz, 2H), 4.37 (dd, J=8.8,
5.6 Hz, 1H), 2.41 (s, 3H), 2.28 (td, J=6.4, 2.8 Hz, 2H), 2.21–
2.03 (m, 2H), 1.96 (t, J=2.4 Hz, 1H), 1.85–1.70 (m, 2H);
13C NMR (100 MHz, CDCl3): d=190.0 (C), 145.5 (C), 131.1
ꢀ
(C), 129.6 (CH), 128.7 (CH), 117.2 (CN), 82.6 (C C), 69.5
Experimental Section
ꢀ
(C CH), 39.1 (CH), 28.5 (CH2), 25.3 (CH2), 21.5 (CH3),
17.5 (CH2); HR-MS (EI): m/z=225.1145, calcd. for
General Remarks
C15H15NO [M]+: 225.1154.
2-(2-Methoxybenzoyl)hept-6-ynenitrile (5b): white solid;
yield: 85%; mp 40–428C. IR (CH2Cl2): nmax =3291, 2944,
All reactions were performed under an atmosphere of nitro-
gen unless otherwise stated. All solvents were dried prior to
use and reagents were employed as received. Analytical thin
layer chromatography was performed on SiO2 60 F-254
plates and flash column chromatography was carried out
using SiO2 60 (particle size 0.040–0.055 mm, 230–400 mesh),
both of which are available from E. Merck. 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. Fourier transform infrared spectra (IR) were re-
corded on a Perkin–Elmer spectrum RX I FT-IR system
1
2246, 1678 cmÀ1; H NMR (400 MHz, CDCl3): d=7.74 (dd,
J=8.0, 1.6 Hz, 1H), 7.53 (td, J=8.0, 1.6 Hz, 1H), 7.04 (td,
J=8.0, 1.2 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 4.55 (dd, J=
8.8, 5.2 Hz, 1H), 3.95 (s, 3H), 2.25 (tt, J=6.8, 2.8 Hz, 2H),
2.17–2.08 (m, 1H), 2.02–1.94 (m, 1H), 1.93 (t, J=2.8 Hz,
1H), 1.84–1.67 (m, 2H); 13C NMR (100 MHz, CDCl3): d=
192.1 (CO), 158.4 (C), 135.2 (CH), 131.3 (CH), 124.5 (C),
ꢀ
ꢀ
121.1 (CH), 117.6 (CN), 111.6 (CH), 82.9 (C C), 69.2 (C
CH), 55.7 (CH3), 44.1 (CH), 28.0 (CH2), 25.7 (CH2), 17.8
(CH2); HR-MS (EI): m/z=241.1099, calcd. for C15H15NO2
[M]+: 241.1103.
1
and expressed in cmÀ1. H and 13C NMR spectra were re-
2-(4-Methoxybenzoyl)hept-6-ynenitrile (5c): white solid;
yield: 77%; mp 67–698C. IR (CH2Cl2): nmax =3291, 2938,
corded on a Varian Agilent 400 FT NMR spectrometer.
Chloroform-d and methanol-d were used as the solvent and
TMS (d=0.00 ppm) as an internal standard. Chemical shifts
are reported as d values in ppm as referenced to TMS. Mul-
tiplicities are recorded as s (singlet), d (doublet), t (triplet),
q (quartet), quint (quintet), sext (sextet), sept (septet), dd
(doublet of doublets), dt (doublet of triplets), br (broad), m
(multiplet). Coupling constants (J) are expressed in Hz.
HR-MS were measured on a JEOL JMS-HX110 spectrome-
ter and spectral data are recorded as m/z values. Melting
points were measured using an Electrothermal instrument.
2248, 1682 cmÀ1 1H NMR (400 MHz, CDCl3): d=7.94 (d,
;
J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 4.33 (dd, J=8.8,
6.0 Hz, 1H), 3.87 (s, 3H), 2.28 (td, J=6.8, 2.4 Hz, 2H), 2.21–
2.07 (m, 2H), 1.96 (t, J=2.8 Hz, 1H), 1.82–1.69 (m, 2H);
13C NMR (100 MHz, CDCl3): d=188.7 (CO), 164.5 (C),
ꢀ
131.1 (CH), 126.6 (C), 117.3 (CN), 114.2 (CH), 82.7 (C C),
ꢀ
69.5 (C CH), 55.6 (CH3), 38.9 (CH), 28.6 (CH2), 25.4
(CH2), 17.6 (CH2); HR-MS (EI): m/z=241.1105, calcd. for
C15H15NO2 [M]+: 241.1103.
2-(4-Chlorobenzoyl)hept-6-ynenitrile (5d): colorless oil;
yield: 90%. IR (CH2Cl2): nmax =3297, 3092, 2938, 2250,
1
1693 cmÀ1; H NMR (400 MHz, CDCl3): d=7.93 (dd, J=8.4,
1.2 Hz, 2H), 7.51 (dd, J=8.4, 1.2 Hz, 2H), 4.36 (dd, J=8.8,
5.6 Hz, 1H), 2.30 (td, J=6.4, 2.8 Hz, 2H), 2.22–2.04 (m,
2H), 1.97 (td, J=2.8, 1.2 Hz, 1H), 1.85–1.71 (m, 2H);
13C NMR (100 MHz, CDCl3): d=189.4 (C), 141.1 (C), 132.0
Preparation of Substrates
The general procedure for the synthesis of substrates 5 and
5a–j is demonstrated as follows using 5 as a typical example.
ꢀ
(C), 130.1 (CH), 129.4 (CH), 116.8 (CN), 82.6 (C C), 69.7
Adv. Synth. Catal. 2013, 355, 1323 – 1337
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1329

Ying-Chieh Wong et al.
FULL PAPERS
ꢀ
(C CH), 39.3 (CH), 28.3 (CH2), 25.3 (CH2), 17.6 (CH2);
1H), 7.98–7.94 (m, 2H), 7.89 (d, J=8.8 Hz, 1H), 7.85 (d, J=
8.0 Hz, 1H), 7.62 (td, J=8.0, 1.2 Hz, 1H), 7.56 (td, J=8.0,
1.2 Hz, 1H), 4.57 (dd, J=8.8, 5.6 Hz, 1H), 2.30 (td, J=6.8,
2.8 Hz, 2H), 2.27–2.08 (m, 2H), 1.98 (t, J=2.8 Hz, 1H),
1.89–1.75 (m, 2H); 13C NMR (100 MHz, CDCl3): d=190.4
(CO), 135.9 (C), 132.2 (C), 131.0 (C), 130.8 (CH), 129.7
(CH), 129.3 (CH), 129.0 (CH), 127.8 (CH), 127.2 (CH),
HR-MS (EI): m/z=245.0430, calcd. for C14H12ClNO [M]+:
245.0607.
4-(2-Cyanohept-6-ynoyl)benzonitrile (5e): white solid;
yield: 83%; mp 61–638C. IR (CH2Cl2): nmax =3290, 3096,
2930, 2232, 1701 cmÀ1; H NMR (400 MHz, CDCl3): d=8.07
1
(d, J=8.4 Hz, 2H), 7.82 (d, J=8.4 Hz, 2H), 4.35 (dd, J=8.4,
5.6 Hz, 1H), 2.31 (td, J=6.8, 2.8 Hz, 2H), 2.22–2.05 (m,
2H), 1.97 (t, J=2.8 Hz, 1H), 1.86–1.71 (m, 2H); 13C NMR
(100 MHz, CDCl3): d=189.7 (CO), 136.5 (C), 132.7 (CH),
ꢀ
ꢀ
123.7 (CH), 117.2 (CN), 82.7 (C C), 69.7 (C CH), 39.3
(CH), 28.7 (CH2), 25.4 (CH2), 17.6 (CH2); HR-MS (EI):
m/z=261.1148, calcd. for C18H15NO [M]+: 261.1154.
1-Benzoyl-2-methylenecyclopentanecarbonitrile (8): color-
less oil; yield: 45%. IR (CH2Cl2): nmax =2962, 2236, 1689,
ꢀ
129.0 (CH), 117.29 (CN), 117.26 (CN), 116.4 (C), 82.5 (C
ꢀ
C), 69.71 (C CH), 39.7 (CH), 28.0 (CH2), 25.1 (CH2), 17.4
1231 cmÀ1 1H NMR (400 MHz, CDCl3): d=8.07 (d, J=
;
(CH2); HR-MS (EI): m/z=236.0913, calcd. for C15H12N2O
[M]+: 263.0950.
7.6 Hz, 2H), 7.59 (t, J=7.2 Hz, 1H), 7.47 (t, J=7.6 Hz, 2H),
5.37 (s, 2H), 2.67–2.43 (m, 4H), 2.02–1.84 (m, 2H);
13C NMR (100 MHz, CDCl3): d=192.2 (CO), 148.6 (C),
133.7 (C), 133.6 (CH), 129.6 (CH), 128.5 (CH), 120.8 (CN),
113.5 (CH2), 55.8 (C), 38.6 (CH2), 32.1 (CH2), 23.6 (CH2);
HR-MS (EI): m/z=211.1001, calcd. for C14H13NO [M]+:
211.0997.
Methyl 4-(2-cyanohept-6-ynoyl)benzoate (5f): white solid;
yield: 79%; mp 62–648C. IR (CH2Cl2): nmax =3289, 2953,
2250, 1725, 1702 cmÀ1; H NMR (400 MHz, CDCl3): d=8.13
1
(d, J=8.8 Hz, 2H), 7.99 (d, J=8.8 Hz, 2H), 4.43 (dd, J=8.8,
5.6 Hz, 1H), 3.94 (s, 3H), 2.28 (td, J=6.8, 2.4 Hz, 2H), 2.22–
2.02 (m, 2H), 1.96 (t, J=2.4 Hz, 1H), 1.84–1.72 (m, 2H);
13C NMR (100 MHz, CDCl3): d=190.1 (CO), 165.7
(CO2Me), 136.9 (C), 135.0 (C), 130.1 (CH), 128.7 (CH),
116.6 (CN), 82.6 (C C), 69.8 (C CH), 52.6 (CH3), 39.7
(CH), 28.3 (CH2), 25.3 (CH2), 17.6 (CH2); HR-MS (EI): m/
z=269.1034, calcd. for C16H15NO3 [M]+: 269.1052.
Synthesis of Products
ꢀ
ꢀ
The general procedure for the synthesis of products 4, 9aa–
au and 9ba–bl is demonstrated as follows using 4 as a typical
example.
2-(4-(Trifluoromethyl)benzoyl)hept-6-ynenitrile
white solid; yield: 82%; mp 38–408C. IR (CH2Cl2): nmax
3297, 2939, 2251, 1702, 1326 cmÀ1 1H NMR (400 MHz,
(5g):
=
Methyl 4-(9a-Cyano-9-oxo-2,3,9,9a-tetrahydro-1H-
cyclopenta[b]naphthalen-4-yl)benzoate (4)
;
CDCl3): d=8.09 (d, J=8.4 Hz, 2H), 7.79 (d, J=8.4 Hz, 2H),
4.39 (dd, J=8.8, 5.6 Hz, 1H), 2.32 (td, J=6.4, 2.4 Hz, 2H),
2.25–2.07 (m, 2H), 1.98 (t, J=2.4 Hz, 1H), 1.87–1.73 (m,
2H); 13C NMR (100 MHz, CDCl3): d=189.8 (CO), 136.5
A
mixture of 2-benzoylhept-6-ynenitrile
0.47 mmol), methyl 4-iodobenzoate (135 mg, 0.52 mmol),
CuI (27 mg, 0.14 mmol), Pd(PPh3)4 (54 mg, 0.047 mmol) and
5
(100 mg,
AHCTUNGTRENNUNG
(C), 135.5 (q, 2JC,F =32.7 Hz, C), 129.1 (CH), 126.1 (CH),
pyrrolidine (78 mL, 0.94 mmol) in dichloromethane (3 mL)
was stirred under air at room temperature for 3.5 h. The
mixture was filtered through a pad of Celite and slica gel
and washed with CH2Cl2 (50 mL). The organic layer was
concentrated under reduced pressure to give the residue,
which was subjected to purification by flash chromatography
on silica gel (20% EtOAc in n-hexane) to afford compound
4 as a white solid; yield: 143 mg (90%); mp 181–1838C. IR
1
ꢀ
123.2 (q, JC,F =271.4 Hz, C), 116.6 (CN), 82.6 (C C), 69.8
ꢀ
(C CH), 39.8 (CH), 28.2 (CH2), 25.3 (CH2), 17.6 (CH2);
HR-MS (EI): m/z=279.0867, calcd. for C15H12F3NO [M]+:
279.0871.
2-(Thiophene-2-carbonyl)hept-6-ynenitrile (5h): white
solid; yield: 91%; mp 46–488C. IR (CH2Cl2): nmax =3293,
2937, 2249, 1668, 1412 cmÀ1 1H NMR (400 MHz, CDCl3):
;
(CH2Cl2): nmax =2952, 2228, 1723, 1608, 1596, 1284 cmÀ1
;
d=7.84 (dd, J=4.0, 1.2 Hz, 1H), 7.75 (dd, J=5.2, 1.2 Hz,
1H), 7.16 (dd, J=5.2, 4.0 Hz, 1H), 4.26 (dd, J=8.4, 6.0 Hz,
1H), 2.25 (td, J=6.8, 2.8 Hz, 2H), 2.21–2.04 (m, 2H), 1.96
(t, J=2.8 Hz, 1H), 1.82–1.67 (m, 2H); 13C NMR (100 MHz,
CDCl3): d=183.1 (CO), 140.5 (C), 136.2 (CH), 133.7 (CH),
128.6 (CH), 116.9 (CN), 82.6 (C C), 69.6 (C CH), 40.1
(CH), 29.0 (CH2), 25.3 (CH2), 17.5 (CH2); HR-MS (EI):
m/z=217.0555, calcd. for C12H11NOS [M]+: 217.0561.
1H NMR (400 MHz, CDCl3): d=8.11 (d, J=6.4 Hz, 2H),
7.95 (dd, J=7.6, 1.2 Hz, 1H), 7.48 (td, J=7.6, 1.2 Hz, 1H),
7.37 (td, J=7.6, 1.2 Hz, 1H), 7.35 (br, 2H), 6.83 (d, J=
7.6 Hz, 1H), 3.94 (s, 3H), 2.83–2.75 (m, 1H), 2.71–2.64 (m,
1H), 2.25–2.05 (m, 3H), 2.03–1.93 (m, 1H); 13C NMR
(100 MHz, CDCl3): d=193.1 (CO), 166.5 (CO2Me), 141.4
(C), 140.7 (C), 139.4 (C), 135.2 (CH), 132.5 (C), 130.0 (br,
CH), 129.9 (C), 128.5 (C), 128.4 (CH), 127.8 (CH), 126.8
(CH), 117.2 (CN), 52.2 (CH3), 51.4 (C), 33.2 (CH2), 29.5
(CH2), 22.4 (CH2); HR-MS (EI): m/z=343.1211, calcd. for
C22H17NO3 [M]+: 343.1208.
ꢀ
ꢀ
2-(Furan-2-carbonyl)hept-6-ynenitrile (5i): white solid;
yield: 94%; mp 40–428C. IR (CH2Cl2): nmax =3292, 2938,
2249, 1679, 1463 cmÀ1; H NMR (400 MHz, CDCl3): d=7.65
1
(dd, J=2.0, 1.2 Hz, 1H), 7.39 (dd, J=4.0, 1.2 Hz, 1H), 6.61
(dd, J=4.0, 2.0 Hz, 1H), 4.21 (dd, J=8.4, 6.0 Hz, 1H), 2.27
(td, J=6.8, 2.8 Hz, 2H), 2.20–2.04 (m, 2H), 1.95 (t, J=
2.8 Hz, 1H), 1.84–1.67 (m, 2H); 13C NMR (100 MHz,
CDCl3): d=179.0 (CO), 149.9 (C), 147.8 (CH), 119.9 (CH),
116.6 (CN), 113.2 (CH), 82.6 (C C), 69.5 (C CH), 39.5
(CH), 28.3 (CH2), 25.3 (CH2), 17.6 (CH2); HR-MS (EI):
m/z=201.0784, calcd. for C12H11NO2 [M]+: 201.0790.
4-Oxo-9-phenyl-2,3,3a,4-tetrahydro-1H-cyclopenta[b]-
naphthalene-3a-carbonitrile (9aa): white solid; yield: 90%;
mp 160–1628C. IR (CH2Cl2): nmax =2951, 2227, 1702, 1592,
1
1282 cmÀ1; H NMR (400 MHz, CDCl3): d=7.95 (dd, J=7.6,
ꢀ
ꢀ
1.2 Hz, 1H), 7.48 (td, J=7.6, 1.2 Hz, 1H), 7.44–7.39 (m,
3H), 7.34 (t, J=7.6 Hz, 1H), 7.33–7.10 (m, 2H), 6.91 (d, J=
7.6 Hz, 1H), 2.84–2.75 (m, 1H), 2.68–2.62 (m, 1H), 2.28–
2.20 (m, 1H), 2.18–2.04 (m, 2H), 2.03–1.90 (m, 1H);
13C NMR (100 MHz, CDCl3): d=193.5 (CO), 140.1 (C),
139.9 (C), 136.6 (C), 135.1 (CH), 133.2 (C), 128.7 (br, CH),
2-(2-Naphthoyl)hept-6-ynenitrile (5j): yellow solid; yield:
95%; mp 54–568C. IR (CH2Cl2): nmax =3294, 3058, 2936,
2247, 1686 cmÀ1 1H NMR (400 MHz, CDCl3): d=8.46 (s,
;
1330
asc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 1323 – 1337

Palladium(0)/Copper(I)-Catalyzed Tandem Cyclization of Aryl 1-Cyanoalk-5-ynyl Ketone System
128.6 (C), 128.1 (CH), 127.7 (CH), 127.1 (CH), 117.5 (CN),
51.3 (C), 33.3 (CH2), 29.5 (CH2), 22.4 (CH2); HR-MS (EI):
m/z=285.1158, calcd. for C20H15NO [M]+: 285.1154.
117.5 (CN), 113.6 (CH), 55.2 (OCH3), 51.3 (C), 33.3 (CH2),
29.5 (CH2), 22.4 (CH2); HR-MS (EI): m/z=315.1266, calcd.
for C21H17NO2 [M]+: 315.1259.
4-Oxo-9-p-tolyl-2,3,3a,4-tetrahydro-1H-cyclopenta[b]-
naphthalene-3a-carbonitrile (9ab): white solid; yield: 92%;
mp 147–1498C. IR (CH2Cl2): nmax =2974, 2227, 1704, 1592,
9-(4-Acetylphenyl)-4-oxo-2,3,3a,4-tetrahydro-1H-cyclo-
penta[b]naphthalene-3a-carbonitrile (9af): white solid;
yield: 87%; mp 169–1718C. IR (CH2Cl2): nmax =2974, 2227,
1
1285 cmÀ1; H NMR (400 MHz, CD3OD): d=7.93 (dd, J=
1685, 1265 cmÀ1 1H NMR (400 MHz, CDCl3): d=8.03 (d,
;
7.6, 1.2 Hz, 1H), 7.58 (td, J=7.6, 1.2 Hz, 1H), 7.42 (td, J=
7.6, 1.2 Hz, 1H), 7.30 (d, J=7.6 Hz, 2H), 7.14 (brm, 2H),
6.95 (d, J=7.6 Hz, 1H), 2.80 (ddd, J=18.4, 8.8 and 4.0 Hz,
1H), 2.61–2.55 (m, 1H), 2.40 (s, 3H), 2.34–2.11 (m, 2H),
2.09–1.98 (m, 2H); 13C NMR (100 MHz, CDCl3): d=193.5
(CO), 140.2 (C), 139.5 (C), 137.8 (C), 135.0 (CH), 133.4 (C),
133.0 (C), 129.3 (br, CH), 128.5 (C), 127.9 (CH), 127.4
(CH), 127.0 (CH), 117.5 (CN), 51.2 (C), 33.2 (CH2), 29.5
(CH2), 22.3 (CH2), 21.1 (CH3); HR-MS (EI): m/z=299.1314,
calcd. for C21H17NO [M]+: 299.1310.
J=7.2 Hz, 2H), 7.96 (dd, J=7.6, 1.2 Hz, 1H), 7.50 (td, J=
7.6, 1.2 Hz, 1H), 7.37 (t, J=7.6 Hz, 1H), 7.26 (brm, 2H),
6.84 (d, J=7.6 Hz, 1H), 2.83–2.76 (m, 1H), 2.72–2.62 (m,
1H), 2.64 (s, 3H), 2.26–2.07 (m, 3H), 2.01–1.94 (m, 1H);
13C NMR (100 MHz, CDCl3): d=197.5 (CO), 193.1 (CO),
141.7 (C), 140.7 (C), 139.4 (C), 136.8 (C), 135.3 (CH), 132.5
(C), 130.3 (br, CH), 128.8 (br, CH), 128.6 (C), 128.5 (CH),
127.9 (CH), 126.9 (CH), 117.3 (CN), 51.4 (C), 33.3 (CH2),
29.6 (CH2), 26.7 (CH3), 22.5 (CH2); HR-MS (EI): m/z=
327.1261, calcd. for C22H17NO2 [M]+: 327.1259.
4-Oxo-9-o-tolyl-2,3,3a,4-tetrahydro-1H-cyclopenta[b]-
naphthalene-3a-carbonitrile (9ac): white solid; yield: 85%;
mp 144–1468C. IR (CH2Cl2): nmax =2949, 2227, 1705, 1593,
9-(4-Cyanophenyl)-4-oxo-2,3,3a,4-tetrahydro-1H-cyclo-
penta[b]naphthalene-3a-carbonitrile (9ag): white solid;
yield: 84%; mp 170–1728C. IR (CH2Cl2): nmax =2973, 2228,
1
1282 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=7.96 (d, J=
1705, 1283 cmÀ1; H NMR (400 MHz, CDCl3): d=7.97 (dd,
7.6 Hz, 2H), 7.46 (tt, J=7.6, 1.2 Hz, 2H), 7.36–7.28 (m, 7H),
7.26–7.19 (m, 2H), 6.88 (d, J=7.6 Hz, 1H), 6.71 (d, J=
7.6 Hz, 1H), 6.68 (d, J=7.6 Hz, 1H), 2.72–2.61 (m, 3H),
2.50–2.42 (m, 1H), 2.30 (s, 3H), 2.27–1.96 (m, 8H), 1.85 (s,
3H); 13C NMR (100 MHz, CDCl3): d=193.49 (CO), 193.46
(CO), 140.4 (C), 140.1 (C), 139.9 (C), 139.5 (C), 137.3 (C),
135.7 (C), 135.6 (C), 135.4 (CH), 135.3 (CH), 135.2 (C),
132.8 (C), 132.4 (C), 130.44 (CH), 130.41 (CH), 130.1 (CH),
128.4 (C), 128.3 (CH), 128.2 (CH), 128.1 (C), 128.05 (CH),
128.03 (CH), 128.0 (CH), 127.8 (CH), 127.6 (CH), 126.5
(CH), 126.4 (CH), 126.3 (CH), 126.1 (CH), 117.4 (CN),
117.3 (CN), 51.4 (C), 51.1 (C), 33.5 (CH2), 33.2 (CH2), 29.2
(CH2), 29.1 (CH2), 22.2 (CH2), 22.1 (CH2), 19.3 (CH3), 18.9
(CH3); HR-MS (EI): m/z=299.1309, calcd. for C21H17NO
[M]+: 299.1310.
J=7.6, 1.6 Hz, 1H), 7.75 (d, J=7. 2 Hz, 2H), 7.51 (td, J=
7.6, 1.6 Hz, 1H), 7.40 (t, J=7.6 Hz, 1H), 7.39 (br, 2H), 6.78
(d, J=7.6 Hz, 1H), 2.82–2.75 (m, 1H), 2.71–2.65 (m, 1H),
2.24–2.05 (m, 3H), 2.03–1.94 (m, 1H); 13C NMR (100 MHz,
CDCl3): d=192.8 (CO), 141.6 (C), 141.4 (C), 138.9 (C),
135.3 (CH), 132.6 (CH), 131.9 (C), 130.1 (br, CH), 128.7
(CH), 128.5 (C), 128.0 (CH), 126.6 (CH), 118.3 (CN), 117.0
(CN), 112.2 (C), 51.4 (C), 33.2 (CH2), 29.6 (CH2), 22.4
(CH2); HR-MS (EI): m/z=310.1100, calcd. for C21H14N2O
[M]+: 310.1106.
9-(4-Formylphenyl)-4-oxo-2,3,3a,4-tetrahydro-1H-cyclo-
penta[b]naphthalene-3a-carbonitrile (9ah): white solid;
yield: 65%; mp 206–2088C. IR (CH2Cl2): nmax =2973, 2836,
2227, 1702, 1605, 1283 cmÀ1 1H NMR (400 MHz, CDCl3):
;
d=10.06 (s, 1H), 7.96 (dd, J=7.6, 1.6 Hz, 3H), 7.50 (td, J=
7.6, 1.6 Hz, 1H), 7.37 (td, J=7.6, 1.2 Hz, 1H), 7.28 (brm,
2H), 6.82 (d, J=7.6 Hz, 1H), 2.84–2.77 (m, 1H), 2.72–2.67
(m, 1H), 2.26–2.06 (m, 3H), 2.03–1.94 (m, 1H); 13C NMR
(100 MHz, CDCl3): d=193.0 (CO), 191.5 (CHO), 143.1 (C),
141.0 (C), 139.2 (C), 136.0 (C), 135.3 (CH), 132.3 (C), 130.1
(br, CH), 128.5 (CH), 127.9 (CH), 126.8 (CH), 117.2 (CN),
51.4 (C), 33.2 (CH2), 29.6 (CH2), 22.4 (CH2); HR-MS (EI):
m/z=313.1096, calcd. for C21H15NO2 [M]+: 313.1103.
9-(4-Methoxyphenyl)-4-oxo-2,3,3a,4-tetrahydro-1H-cyclo-
penta[b]naphthalene-3a-carbonitrile (9ad): white solid;
yield: 82%; mp 97–998C. IR (CH2Cl2): nmax =2969, 2227,
1706, 1608, 1513, 1248 cmÀ1 1H NMR (400 MHz, CDCl3):
;
d=7.93 (dd, J=7.6, 1.2 Hz, 1H), 7.48 (td, J=7.6, 2.4 Hz,
1H), 7.34 (td, J=7.6, 1.2 Hz, 1H), 7.17 (brm, 2H), 6.97 (d,
J=7.6 Hz, 1H), 6.96 (d, J=7.2 Hz, 2H), 3.84 (s, 3H), 2.86–
2.78 (m, 1H), 2.67–2.63 (m, 1H), 2.31–2.28 (m, 1H), 2.17–
2.05 (m, 2H), 1.99–1.95 (m, 1H); 13C NMR (100 MHz,
CDCl3): d=193.4 (CO), 159.1 (C), 140.2 (C), 139.4 (C),
135.0 (CH), 132.6 (C), 130.4 (br, CH), 128.5 (C), 128.4 (C),
127.8 (CH), 127.4 (CH), 126.9 (CH), 117.4 (CN), 113.9
(CH), 55.0 (OCH3), 51.1 (C), 33.1 (CH2), 29.5 (CH2), 22.2
(CH2); HR-MS (EI): m/z=315.1255, calcd. for C21H17NO2
[M]+: 315.1259.
4-(9a-Cyano-9-oxo-2,3,9,9a-tetrahydro-1H-cyclopenta[b]-
naphthalen-4-yl)benzoic acid (9ai): white solid; yield: 51%;
mp 202–2038C. IR (CH2Cl2): nmax =3441, 2228, 1691, 1609,
1285 cmÀ1 1H NMR (400 MHz, CDCl3): d=8.20 (d, J=
;
5.2 Hz, 2H), 7.97 (dd, J=7.6, 1.2 Hz, 1H), 7.51 (td, J=7.6,
1.2 Hz, 1H), 7.39 (td, J=7.6, 1.2 Hz, 1H), 7.26 (brm, 2H),
6.85 (d, J=7.6 Hz, 1H), 2.85–2.73 (m, 1H), 2.71–2.65 (m,
1H), 2.28–2.08 (m, 3H), 2.04–1.95 (m, 1H); 13C NMR
(100 MHz, CDCl3): d=193.1 (CO), 171.7 (CO2H), 142.5
(C), 140.8 (C), 139.3 (C), 135.3 (CH), 132.4 (C), 130.7 (br,
CH), 129.1 (C), 128.54 (C), 128.49 (CH), 127.9 (CH), 126.9
(CH), 117.2 (CN), 51.4 (C), 33.3 (CH2), 29.6 (CH2), 22.4
(CH2); HR-MS (EI): m/z=329.1061, calcd. for C21H15NO3
[M]+: 329.1052.
9-(3-Methoxyphenyl)-4-oxo-2,3,3a,4-tetrahydro-1H-cyclo-
penta[b]naphthalene-3a-carbonitrile (9ae): white solid;
yield: 78%; mp 117–1198C. IR (CH2Cl2): nmax =2961, 2227,
1
1700, 1594, 1284 cmÀ1; H NMR (400 MHz, CDCl3): d=7.96
(dd, J=7.6, 1.2 Hz, 1H), 7.51 (td, J=7.6, 1.2 Hz, 1H), 7.37
(t, J=7.6, 1.2 Hz, 2H), 6.95 (d, J=7.6 Hz, 3H), 6.62 (brm,
1H), 3.83 (s, 3H), 2.83–2.75 (m, 1H), 2.69–2.63 (m, 1H),
2.31–2.22 (m, 1H), 2.17–2.05 (m, 2H), 1.99–1.93 (m, 1H);
13C NMR (100 MHz, CDCl3): d=193.5 (CO), 159.8 (C),
140.0 (C), 139.9 (C), 138.0 (C), 135.2 (CH), 133.1 (C), 129.8
(br, CH), 128.5 (C), 128.1 (CH), 127.6 (CH), 127.1 (CH),
4-Oxo-9-[4-(trifluoromethyl)phenyl]-2,3,3a,4-tetrahydro-
1H-cyclopenta[b]naphthalene-3a-carbonitrile (9aj): brown
solid; yield: 79%; mp 150–1528C. IR (CH2Cl2): nmax =2974,
2228, 1703, 1596, 1324, 1284 cmÀ1
;
1H NMR (400 MHz,
Adv. Synth. Catal. 2013, 355, 1323 – 1337
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1331

Ying-Chieh Wong et al.
FULL PAPERS
CDCl3): d=7.97 (dd, J=7.6, 1.6 Hz, 1H), 7.72 (d, J=5.6 Hz,
2H), 7.51 (td, J=7.6, 1.2 Hz, 1H), 7.48 (br, 2H), 7.39 (td,
J=7.6, 1.2 Hz, 1H), 6.83 (d, J=7.6 Hz, 1H), 2.83–2.75 (m,
1H), 2.72–2.64 (m, 1H), 2.26–2.07 (m, 3H), 2.04–1.95 (m,
1H); 13C NMR (100 MHz, CDCl3): d=193.0 (CO), 141.0
(C), 140.5 (C), 139.4 (C), 135.3 (CH), 132.2 (C), 130.4 (q,
2JCÀF =32.0 Hz, C), 128.6 (C), 128.5 (CH), 128.0 (CH), 126.8
132.2 (C), 131.4 (br, CH), 128.6 (C), 128.2 (CH), 127.7
(CH), 126.8 (CH), 117.3 (CN), 115.8 (d, JC,F =21.4 Hz, CH),
2
51.3 (C), 33.3 (CH2), 29.5 (CH2), 22.4 (CH2); HR-MS (EI):
m/z=303.1065, calcd. for C20H14FNO [M]+: 303.1059.
9-[3-(Hydroxymethyl)phenyl]-4-oxo-2,3,3a,4-tetrahydro-
1H-cyclopenta[b]naphthalene-3a-carbonitrile (9ao): yellow
oil; yield: 86%; IR (CH2Cl2): nmax =3391, 2925, 2228, 1699,
1
1
(CH), 125.8 (br, CH), 123.9 (q, JCÀF =270.7 Hz, C), 117.2
1592, 1285 cmÀ1; H NMR (400 MHz, CDCl3): d=7.94 (dd,
(CN), 51.4 (C), 33.3 (CH2), 29.6 (CH2), 22.4 (CH2); HR-MS
(EI): m/z=353.1022, calcd. for C21H14F3NO [M]+: 353.1027.
9-(4-Nitrophenyl)-4-oxo-2,3,3a,4-tetrahydro-1H-cyclopen-
ta[b]naphthalene-3a-carbonitrile (9ak): yellow solid; yield:
62%; mp 171–1738C. IR (CH2Cl2): nmax =2953, 2228, 1703,
J=7.6, 1.2 Hz, 1H), 7.48 (td, J=7.6, 1.2 Hz, 1H), 7.39 (brm,
3H), 7.35 (td, J=7.6, 1.2 Hz, 1H), 7.04 (brm, 1H), 6.88 (d,
J=7.6 Hz, 1H), 4.70 (brs, 2H), 2.81–2.74 (m, 1H), 2.67–2.60
(m, 1H), 2.30 (brs, OH), 2.27–2.18 (m, 1H), 2.14–2.01 (m,
2H), 1.99–1.89 (m, 1H); 13C NMR (100 MHz, CDCl3): d=
193.5 (CO), 141.5 (C), 140.01 (C), 139.97 (C), 136.8 (C),
135.2 (CH), 133.1 (C), 128.9 (CH), 128.5 (C), 128.1 (CH),
127.6 (CH), 127.1 (CH), 126.6 (CH), 117.5 (CN), 64.7
(CH2), 51.3 (C), 33.3 (CH2), 29.5 (CH2), 22.3 (CH2); HR-MS
(EI): m/z=315.1266, calcd. for C21H17NO2 [M]+: 315.1259.
9-(4-Hydroxyphenyl)-4-oxo-2,3,3a,4-tetrahydro-1H-cyclo-
penta[b]naphthalene-3a-carbonitrile (9ap): yellow oil; yield:
79%. IR (CH2Cl2): nmax =3401, 2953, 2229, 1695, 1590,
1597, 1519, 1347, 1284 cmÀ1 1H NMR (400 MHz, CDCl3):
;
d=8.31 (d, J=7.2 Hz, 2H), 7.98 (dd, J=7.6, 1.6 Hz, 1H),
7.52 (td, J=7.6, 1.6 Hz, 1H), 7.47 (brm, 2H), 7.41 (t, J=
7.6 Hz, 1H), 6.78 (d, J=7.6 Hz, 1H), 2.83–2.76 (m, 1H),
2.72–2.65 (m, 1H), 2.24–2.08 (m, 3H), 2.04–1.96 (m, 1H);
13C NMR (100 MHz, CDCl3): d=192.7 (CO), 147.6 (C),
143.6 (C), 141.6 (C), 138.8 (C), 135.4 (CH), 131.6 (C), 130.4
(br, CH), 128.7 (CH), 128.5 (C), 128.0 (CH), 126.6 (CH),
124.0 (CH), 117.0 (CN), 51.4 (C), 33.2 (CH2), 29.6 (CH2),
22.4 (CH2); HR-MS (EI): m/z=330.1008, calcd. for
C20H14N2O3[M]+: 330.1004.
1285 cmÀ1 1H NMR (400 MHz, CDCl3): d=7.94 (d, J=
;
7.6 Hz, 1H), 7.49 (t, J=7.6 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H),
7.08 (brm, 2H), 6.97 (d, J=7.6 Hz, 1H), 6.91 (d, J=8.0 Hz,
2H), 6.28 (brm, OH), 2.80 (ddd, J=18.8, 9.6 and 4.0 Hz,
1H), 2.69–2.64 (m, 1H), 2.30–2.22 (m, 1H), 2.17–2.03 (m,
2H), 2.00–1.92 (m, 1H); 13C NMR (100 MHz, CDCl3): d=
194.0 (CO), 155.8 (C), 140.4 (C), 139.4 (C), 135.3 (CH),
132.9 (C), 130.6 (br, CH), 128.5 (C), 128.3 (C), 128.1 (CH),
127.6 (CH), 127.2 (CH), 117.6 (CN), 115.6 (CH), 51.2 (C),
33.3 (CH2), 29.6 (CH2), 22.4 (CH2); HR-MS (EI): m/z=
301.1109, calcd. for C20H15NO2 [M]+: 301.1103.
9-(3-Nitrophenyl)-4-oxo-2,3,3a,4-tetrahydro-1H-cyclopen-
ta[b]naphthalene-3a-carbonitrile (9al): white solid; yield:
68%; mp 155–1578C. IR (CH2Cl2): nmax =2953, 2227, 1702,
1
1529, 1349, 1282 cmÀ1; H NMR (400 MHz, CDCl3): d=8.27
(dd, J=8.8, 2.0 Hz, 1H), 7.98 (d, J=7.6, 1.2 Hz, 1H), 7.65
(brm, 3H), 7.52 (td, J=7.6, 1.2 Hz, 1H), 7.41 (t, J=7.6 Hz,
1H), 6.79 (d, J=7.6 Hz, 1H), 2.83–2.80 (m, 1H), 2.74–2.66
(m, 1H), 2.26–2.09 (m, 3H), 2.05–1.96 (m, 1H); 13C NMR
(100 MHz, CDCl3): d=192.6 (CO), 148.5 (C), 141.8 (C),
138.9 (C), 138.3 (C), 135.4 (CH), 131.3 (C), 130.0 (br, CH),
128.7 (CH), 128.5 (C), 128.0 (CH), 126.5 (CH), 123.2 (CH),
117.0 (CN), 51.4 (C), 33.2 (CH2), 29.6 (CH2), 22.4 (CH2);
HR-MS (EI): m/z=330.1009, calcd. for C20H14N2O3 [M]+:
330.1004.
9-(4-Aminophenyl)-4-oxo-2,3,3a,4-tetrahydro-1H-cyclo-
penta[b]naphthalene-3a-carbonitrile (9aq): yellow solid;
yield: 85%; mp 163–1658C. IR (CH2Cl2): nmax =3466, 3378,
2953, 2227, 1694, 1517, 1284 cmÀ1
;
1H NMR (400 MHz,
CDCl3): d=7.91 (dd, J=7.6, 1.2 Hz, 1H), 7.48 (td, J=7.6,
1.2 Hz, 1H), 7.32 (t, J=7.6 Hz, 1H), 7.01 (d, J=8.0 Hz,
3H), 6.72 (d, J=7.6 Hz, 2H), 3.77 (s, 2H), 2.81 (ddd, J=
18.8, 8.8 and 4.0 Hz, 1H), 2.67–2.60 (m, 1H), 2.32–2.23 (m,
1H), 2.16–1.90 (m, 3H); 13C NMR (100 MHz, CDCl3): d=
193.9 (CO), 146.3 (C), 140.6 (C), 139.0 (C), 135.1 (CH),
133.1 (C), 130.5 (br, CH), 128.8 (C), 127.9 (CH), 127.5
(CH), 127.2 (CH), 126.2 (C), 117.7 (CN), 114.9 (CH), 51.2
(C), 33.3 (CH2), 29.7 (CH2), 22.4 (CH2); HR-MS (EI): m/z=
300.1264, calcd. for C20H16N2O [M]+: 300.1263.
9-(4-Chlorophenyl)-4-oxo-2,3,3a,4-tetrahydro-1H-cyclo-
penta[b]naphthalene-3a-carbonitrile (9am): brown solid;
yield: 90%; mp 158–1598C: IR (CH2Cl2): nmax =2974, 2227,
1
1706, 1594, 1285 cmÀ1; H NMR (400 MHz, CDCl3): d=7.95
(dd, J=7.6, 1.6 Hz, 1H), 7.50 (td, J=7.6, 1.6 Hz, 1H), 7.42
(d, J=6.4 Hz, 2H), 7.37 (td, J=7.6, 1.2 Hz, 1H), 7.09 (brm,
2H), 6.88 (d, J=7.6 Hz, 1H), 2.83–2.75 (m, 1H), 2.71–2.63
(m, 1H), 2.27–2.05 (m, 3H), 2.02–1.93 (m, 1H); 13C NMR
(100 MHz, CDCl3): d=193.2 (CO), 140.5 (C), 139.7 (C),
135.3 (CH), 135.0 (C), 134.2 (C), 132.2 (C), 130.9 (br, CH),
129.1 (br, CH), 128.6 (C), 128.4 (CH), 127.8 (CH), 126.9
(CH), 117.3 (CN), 51.4 (C), 33.3 (CH2), 29.6 (CH2), 22.4
(CH2); HR-MS (EI): m/z=319.0761, calcd. for C20H14ClNO
[M]+: 319.0764.
9-(1H-indol-5-yl)-4-oxo-2,3,3a,4-tetrahydro-1H-cyclopen-
ta[b]naphthalene-3a-carbonitrile (9ar): yellow solid; yield:
81%; mp 206–2088C. IR (CH2Cl2): nmax =3408, 2952, 2227,
1
1696, 1591, 1286 cmÀ1; H NMR (400 MHz, CDCl3): d=8.27
(brm, 1H), 7.94 (d, J=7.6 Hz, 1H), 7.69 (brm, 1H), 7.46
(brm, 1H), 7.45 (t, J=7.6 Hz, 1H), 7.33 (t, J=7.6 Hz, 1H),
7.27 (brm, 1H), 6.97 (d, J=7.6 Hz, 1H), 6.83 (brm, 1H),
6.56 (brm, 1H), 2.83 (brm, 1H), 2.71–2.63 (m, 1H), 2.31–
2.22 (m, 1H), 2.18–2.02 (m, 2H), 1.99–1.89 (m, 1H);
13C NMR (100 MHz, CDCl3): d=194.1 (CO), 141.1 (C),
139.4 (C), 135.3 (C), 135.2 (CH), 134.1 (C), 128.7 (C), 128.0
(C), 127.9 (CH), 127.6 (CH), 127.5 (CH), 125.1 (CH), 124.2
(br, CH), 122.4 (br, CH), 120.5 (br, C), 117.9 (CN), 111.4
(CH), 102.8 (CH), 51.3 (C), 33.4 (CH2), 29.7 (CH2), 22.4
(CH2); HR-MS (EI): m/z=324.1260, calcd. for C22H16N2O
[M]+: 324.1263.
9-(4-Fluorophenyl)-4-oxo-2,3,3a,4-tetrahydro-1H-cyclo-
penta[b]naphthalene-3a-carbonitrile (9an): brown solid;
yield: 87%; mp 110–1128C. IR (CH2Cl2): nmax =2969, 2228,
1705, 1601, 1284, 1223 cmÀ1 1H NMR (400 MHz, CDCl3):
;
d=7.94 (dd, J=7.6, 1.6 Hz, 1H), 7.50 (td, J=7.6, 1.6 Hz,
1H), 7.36 (t, J=7.6, Hz, 1H), 7.20 (brm, 2H), 7.13 (brm,
2H), 6.87 (d, J=7.6 Hz, 1H), 2.82–2.63 (m, 1H), 2.72–2.63
(m, 1H), 2.27–2.06 (m, 3H), 2.03–1.94 (m, 1H); 13C NMR
1
(100 MHz, CDCl3): d=193.3 (CO), 162.4 (d, JCÀF
=
246.3 Hz, C), 140.4 (C), 139.9 (C), 135.2 (CH), 132.4 (C),
1332
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 1323 – 1337

Palladium(0)/Copper(I)-Catalyzed Tandem Cyclization of Aryl 1-Cyanoalk-5-ynyl Ketone System
4-Oxo-9-(thiophen-3-yl)-2,3,3a,4-tetrahydro-1H-cyclopen-
ta[b]naphthalene-3a-carbonitrile (9as): white solid; yield:
88%; mp 157–1598C. IR (CH2Cl2): nmax =2952, 2227, 1700,
3H), 3.86 (s, 3H), 2.87–2.79 (m, 1H), 2.69–2.63 (m, 1H),
2.33–2.24 (m, 1H), 2.20–1.94 (m, 3H); 13C NMR (100 MHz,
CDCl3): d=192.4 (CO), 159.8 (C), 142.2 (C), 141.1 (C),
131.6 (C), 131.3 (C), 131.1 (CH), 130.5 (CH), 130.2 (br,
CH), 128.1 (CH), 127.1 (C), 118.3 (CN), 117.5 (CN), 116.6
(C), 114.6 (CH), 55.3 (OCH3), 51.5 (C), 33.1 (CH2), 29.9
(CH2), 22.4 (CH2); HR-MS (EI): m/z=340.1220, calcd. for
C22H16N2O2 [M]+: 340.1212.
1
1593, 1285 cmÀ1; H NMR (400 MHz, CDCl3): d=7.93 (dd,
J=7.6, 1.6 Hz, 1H), 7.52 (td, J=7.6, 1.6 Hz, 1H), 7.40 (dd,
J=4.8, 3.2 Hz, 1H), 7.36 (td, J=7.6, 1.2 Hz, 1H), 7.26 (dd,
J=3.2, 1.2 Hz, 1H), 7.04 (d, J=7.6 Hz, 1H), 6.95 (dd, J=
4.8, 1.2 Hz, 1H), 2.92–2.84 (m, 1H), 2.71–2.64 (m, 1H),
2.42–2.33 (m, 1H), 2.17–1.95 (m, 3H); 13C NMR (100 MHz,
CDCl3): d=193.3 (CO), 140.3 (C), 139.9 (C), 136.5 (C),
135.2 (CH), 128.6 (C), 128.4 (C), 128.2 (CH), 127.7 (CH),
126.9 (CH), 125.9 (CH), 125.2 (CH), 117.4 (CN), 114.9
(CH), 51.3 (C), 33.3 (CH2), 29.8 (CH2), 22.4 (CH2); HR-MS
(EI): m/z=291.0712, calcd. for C18H13NOS [M]+: 291.0718.
4-Oxo-9-(pyridin-3-yl)-2,3,3a,4-tetrahydro-1H-cyclopen-
ta[b]naphthalene-3a-carbonitrile (9at): white solid; yield:
91%; mp 143–1458C. IR (CH2Cl2): nmax =2975, 2227, 1703,
7-Methyl-4-oxo-9-phenyl-2,3,3a,4-tetrahydro-1H-cyclo-
penta[b]naphthalene-3a-carbonitrile (9bc): white solid;
yield: 95%; mp 92–948C. IR (CH2Cl2): nmax =2963, 2227,
1
1698, 1600, 1281 cmÀ1; H NMR (400 MHz, CDCl3): d=7.85
(d, J=7.6 Hz, 1H), 7.40–7.38 (m, 4H), 7.16 (brm, 1H), 7.15
(d, J=7.6 Hz, 1H), 6.67 (s, 1H), 2.80–2.73 (m, 1H), 2.66–
2.63 (m, 1H), 2.27 (s, 3H), 2.25–2.03 (m, 3H), 1.97–1.93 (m,
1H); 13C NMR (100 MHz, CDCl3): d=193.0 (CO), 146.4
(C), 140.1 (C), 140.6 (C), 136.7 (C), 133.1 (C), 129.9 (br,
CH), 128.8 (CH), 128.6 (CH), 128.0 (CH), 127.7 (CH), 127.6
(CH), 126.2 (C), 117.6 (CN), 51.2 (C), 33.3 (CH2), 29.5
(CH2), 22.3 (CH2), 21.9 (CH3); HR-MS (EI): m/z=299.1305,
calcd. for C21H17NO [M]+: 299.1310.
1
1592, 1283 cmÀ1; H NMR (400 MHz, CDCl3): d=8.68 (br,
1H), 8.53 (brm, 1H), 7.98 (dd, J=7.6, 1.6 Hz, 1H), 7.67
(brm, 1H), 7.53 (td, J=7.6, 1.6 Hz, 1H), 7.45 (brm, 1H),
7.41 (t, J=7.6 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 2.84–2.79
(m, 1H), 2.72–2.66 (m, 1H), 2.28–2.09 (m, 3H), 2.06–1.99
(m, 1H); 13C NMR (100 MHz, CDCl3): d=192.8 (CO),
150.1 (br, CH), 149.4 (CH), 141.8 (C), 139.2 (C), 137.1 (br,
CH), 135.3 (CH), 132.5 (C), 129.9 (C), 128.52 (CH), 128.47
(C), 127.9 (CH), 126.5 (CH), 123.5 (CH), 117.1 (CN), 51.3
(C), 33.2 (CH2), 29.6 (CH2), 22.4 (CH2); HR-MS (EI): m/z=
286.1099, calcd. for C19H14N2O [M]+: 286.1106.
8-Oxo-4-phenyl-6,7,7a,8-tetrahydro-5H-indeno
phene-7a-carbonitrile (9bd): brown solid; yield: 95%; mp
141–1438C. IR (CH2Cl2): nmax =2951, 2228, 1669, 1411 cmÀ1
ACHTUNGTREN[NUNG 5,6-b]thio-
;
1H NMR (400 MHz, CDCl3): d=7.74 (d, J=5.2 Hz, 1H),
7.47–7.39 (m, 3H), 7.30–7.27 (m, 2H), 6.79 (d, J=5.2 Hz,
1H), 2.86 (ddd, J=18.8, 10.4 and 3.2 Hz, 1H), 2.72 (dd, J=
11.6, 6.4 Hz, 1H), 2.34–2.13 (m, 2H), 2.06–1.92 (m, 2H);
13C NMR (100 MHz, CDCl3): d=185.6 (CO), 150.9 (C),
144.0 (C), 137.3 (CH), 136.1 (C), 131.9 (C), 129.8 (C), 128.7
(br, CH), 128.6 (CH), 128.4 (CH), 127.3 (CH), 117.4 (CN),
53.5 (C), 33.5 (CH2), 28.5 (CH2), 22.3 (CH2); HR-MS (EI):
m/z=291.0717, calcd. for C18H13NOS [M]+: 291.0718.
9-(Naphthalen-2-yl)-4-oxo-2,3,3a,4-tetrahydro-1H-cyclo-
penta[b]naphthalene-3a-carbonitrile (9au): brown solid;
yield: 78%; mp 167–1698C. IR (CH2Cl2): nmax =2963, 2227,
1
1699, 1596, 1284 cmÀ1; H NMR (400 MHz, CDCl3): d=7.99
(dd, J=7.6, 1.6 Hz, 1H), 7.91–7.89 (m, 3H), 7.55–7.46 (m,
3H), 7.47 (td, J=7.6, 1.6 Hz, 1H), 7.36 (td, J=7.6, 0.8 Hz,
1H), 7.14 (brm, 1H), 6.93 (d, J=7.6 Hz, 1H), 2.86 (brm,
1H), 2.74–2.66 (m, 1H), 2.31–2.07 (m, 3H), 2.02–1.92 (m,
1H); 13C NMR (100 MHz, CDCl3): d=193.5 (CO), 140.4
(C), 140.1 (br, CH), 135.2 (CH), 134.0 (C), 133.3 (C), 133.1
(C), 132.8 (C), 129.6 (br, CH), 128.6 (C), 128.4 (CH), 128.2
(CH), 127.9 (CH), 127.7 (CH), 127.6 (CH), 127.2 (CH),
126.5 (CH), 126.4 (CH), 126.1 (C), 117.5 (CN), 51.4 (C),
33.3 (CH2), 29.6 (CH2), 22.4 (CH2); HR-MS (EI): m/z=
335.1306, calcd. for C24H17NO [M]+: 335.1310.
8-Oxo-4-phenyl-6,7,7a,8-tetrahydro-5H-indeno
furan-7a-carbonitrile (9be): white solid; yield: 62%; mp
156–1588C. IR (CH2Cl2): nmax =2953, 2229, 1677, 1428 cmÀ1
ACHTUNGTRENN[UNG 5,6-b]-
;
1H NMR (400 MHz, CDCl3): d=7.72 (d, J=1.6 Hz, 1H),
7.46–7.37 (m, 3H), 7.32–7.30 (m, 2H), 6.37 (d, J=1.6 Hz,
1H), 2.93 (ddd, J=18.4, 10.4 and 3.6 Hz, 1H), 2.71 (dd, J=
12.8, 6.4 Hz, 1H), 2.41–2.32 (m, 1H), 2.29–2.17 (m, 1H),
2.08–1.99 (m, 1H), 1.95–1.87 (m, 1H); 13C NMR (100 MHz,
CDCl3): d=178.6 (CO), 150.9 (CH), 144.8 (C), 144.6 (C),
140.9 (C), 135.0 (C), 128.7 (br, CH), 128.6 (2 x CH), 127.1
(C), 117.1 (CN), 110.2 (CH), 55.1 (C), 33.1 (CH2), 28.3
(CH2), 22.4 (CH2); HR-MS (EI): m/z=275.0937, calcd. for
C18H13NO2 [M]+: 275.0946.
9-(4-Cyanophenyl)-7-methoxy-4-oxo-2,3,3a,4-tetrahydro-
1H-cyclopenta[b]naphthalene-3a-carbonitrile (9ba): white
solid; yield: 94%; mp 182–1848C. IR (CH2Cl2): nmax =2945,
2228, 1690, 1592, 1262 cmÀ1
;
1H NMR (400 MHz, CDCl3):
7-Chloro-4-oxo-9-phenyl-2,3,3a,4-tetrahydro-1H-cyclopen-
ta[b]naphthalene-3a-carbonitrile (9bf): white solid; yield:
87%; mp 126–1288C. IR (CH2Cl2): nmax =2973, 2228, 1702,
d=7.99 (d, J=8.4 Hz, 1H), 7.74 (br, 2H), 7.52 (br, 1H),
7.24 (br, 1H), 6.87 (dd, J=8.4, 2.4 Hz, 1H), 6.22 (d, J=
2.4 Hz, 1H), 3.75 (s, 3H), 2.80–2.64 (m, 2H), 2.22–1.93 (m,
4H); 13C NMR (100 MHz, CDCl3): d=190.8 (CO), 165.4
(C), 142.6 (C), 141.6 (C), 141.3 (C), 132.6 (CH), 131.6 (C),
131.1 (br, CH), 130.8 (CH), 129.5 (br, CH), 121.7 (C), 118.3
(CN), 117.4 (CN), 113.0 (CH), 112.2 (C), 55.6 (OCH3), 51.3
(C), 33.4 (CH2), 29.6 (CH2), 22.3 (CH2); HR-MS (EI): m/z=
340.1210, calcd. for C22H16N2O2 [M]+: 340.1212.
1586, 1267 cmÀ1 1H NMR (400 MHz, CDCl3): d=7.89 (d,
;
J=7.6 Hz, 1H), 7.46–7.40 (m, 3H), 7.32 (dd, J=7.6, 2.0 Hz,
1H), 7.08 (br, 2H), 6.87 (d, J=2.0 Hz, 1H), 2.85–2.78 (m,
1H), 2.73–2.65 (m, 1H), 2.31–2.22 (m, 1H), 2.18–1.94 (m,
3H); 13C NMR (100 MHz, CDCl3): d=192.1 (CO), 141.9
(C), 141.6 (C), 135.8 (C), 132.2 (C), 130.0 (br, C), 129.1
(CH), 128.9 (CH), 128.4 (CH), 128.2 (CH), 127.8 (br, CH),
127.0 (CH), 126.8 (C), 117.0 (CN), 51.3 (C), 33.2 (CH2), 29.7
(CH2), 22.2 (CH2); HR-MS (EI): m/z=319.0761, calcd. for
C20H14ClNO [M]+: 319.0764.
9-(4-Methoxyphenyl)-4-oxo-2,3,3a,4-tetrahydro-1H-cyclo-
penta[b]naphthalene-3a,7-dicarbonitrile (9bb): yellow solid;
yield: 57%; mp 157–1598C. IR (CH2Cl2): nmax =2956, 2837,
2231, 1710, 1608, 1248 cmÀ1
;
1H NMR (400 MHz, CDCl3):
4-Oxo-9-phenyl-2,3,3a,4-tetrahydro-1H-cyclopenta[b]-
naphthalene-3a,7-dicarbonitrile (9bg): brown solid; yield:
80%; mp 207–2098C. IR (CH2Cl2): nmax =2972, 2231, 1711,
d=7.99 (d, J=7.6 Hz, 1H), 7.61 (dd, J=7.6, 1.2 Hz, 1H),
7.24 (brm, 1H), 7.23 (d, J=1.2 Hz, 1H), 6.99 (d, J=7.6 Hz,
Adv. Synth. Catal. 2013, 355, 1323 – 1337
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1333

Ying-Chieh Wong et al.
FULL PAPERS
1598, 1273 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=8.00 (d,
112.9 (CH), 112.8 (CH), 55.4 (OCH3), 51.0 (C), 33.5 (CH2),
29.5 (CH2), 22.1 (CH2); HR-MS (EI): m/z=315.1259, calcd.
for C21H17NO2 [M]+: 315.1259.
J=8.0 Hz, 1H), 7.63 (dd, J=8.0, 1.6 Hz, 1H), 7.50–7.43 (m,
3H), 7.18 (d, J=1.6 Hz, 1H), 7.14 (br, 2H), 2.82 (ddd, J=
18.8, 9.2 and 3.6 Hz, 1H), 2.71–2.65 (m, 1H), 2.32–1.95 (m,
4H); 13C NMR (100 MHz, CDCl3): d=192.3 (CO), 142.6
(C), 140.8 (C), 135.2 (C), 132.0 (C), 131.2 (CH), 130.5 (CH),
130.2 (br, C), 129.3 (CH), 128.8 (CH), 128.2 (CH), 118.4
(C), 117.5 (CN), 116.5 (CN), 51.5 (C), 33.1 (CH2), 29.8
(CH2), 22.4 (CH2); HR-MS (EI): m/z=310.1112, calcd. for
C21H14N2O [M]+: 310.1106.
7-Oxo-11-phenyl-7a,8,9,10-tetrahydro-7H-cyclopenta[b]-
phenanthrene-7a-carbonitrile (9bl): yellow solid; yield:
95%; mp 176–1788C. IR (CH2Cl2): nmax =3056, 2969, 2228,
1
1698, 1590, 1268 cmÀ1; H NMR (400 MHz, CDCl3): d=7.93
(d, J=8.8 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.79 (d, J=
8.0 Hz, 1H), 7.72 (brm, 1H), 7.52 (brm, 1H), 7.42 (t, J=
8.0 Hz, 1H), 7.34–7.30 (m, 2H), 7.13 (brm, 1H), 7.07 (t, J=
8.0 Hz, 1H), 6.56 (brm, 1H), 3.03 (ddd, J=18.4, 8.8 and
4.8 Hz, 1H), 2.63–2.57 (m, 1H), 2.43–2.27 (m, 2H), 2.15–
2.03 (m, 1H), 1.97–1.87 (m, 1H); 13C NMR (100 MHz,
CDCl3): d=194.7 (CO), 141.2 (C), 140.2 (C), 138.6 (C),
138.0 (C), 133.5 (C), 129.8 (C), 129.7 (CH), 128.6 (br, 2
x CH), 128.4 (CH), 128.2 (CH), 128.1 (br, CH), 127.7 (CH),
127.4 (C), 125.8 (CH), 122.3 (CH), 117.9 (CN), 51.0 (C),
32.7 (CH2), 31.2 (CH2), 23.7 (CH2); HR-MS (EI): m/z=
335.1316, calcd. for C24H17NO [M]+: 335.1310.
5-Methoxy-4-oxo-9-phenyl-2,3,3a,4-tetrahydro-1H-cyclo-
penta[b]naphthalene-3a-carbonitrile (9bh): white solid;
yield: 70%; mp 153–1558C. IR (CH2Cl2): nmax =2968, 2840,
2226, 1708, 1586, 1573, 1265 cmÀ1
;
1H NMR (400 MHz,
CDCl3): d=7.42–7.34 (m, 5H), 7.20 (brm, 1H), 6.88 (d, J=
8.4 Hz, 1H), 6.43 (d, J=7.6 Hz, 1H), 3.93 (s, 3H), 2.75 (ddd,
J=18.0, 8.8 and 3.6 Hz, 1H), 2.49 (ddd, J=13.2, 6.0 and
2.8 Hz, 1H), 2.33–2.16 (m, 2H), 2.08–1.90 (m, 2H);
13C NMR (100 MHz, CDCl3): d=192.0 (CO), 159.3 (C),
142.2 (C), 140.3 (C), 137.1 (C), 135.3 (CH), 133.7 (C), 129.4
(br, CH), 128.6 (CH), 128.0 (CH), 119.8 (CH), 118.0 (C), 2-(2-Iodobenzyl)-3-oxo-3-phenylpropanenitrile (10)
117.7 (CN), 111.7 (CH), 56.2 (OCH3), 52.8 (C), 32.3 (CH2),
To
a stirred solution of benzoylacetonitrile 6 (0.5 g,
29.9 (CH2), 23.1 (CH2); HR-MS (EI): m/z=315.1258, calcd.
3.6 mmol) and 2-iodobenzaldehyde 11 (1.0 g, 4.3 mmol) in
EtOH (20 mL) were added l-proline (83 mg, 0.72 mmol)
and Hantzsch ester (0.9 g, 3.6 mmol) sequentially in one por-
tion. The resulting mixture was stirred at 258C for 8 h. The
reaction solution was concentrated under reduced pressure,
the residue was purified by flash chromatography on silical
gel (33% CH2Cl2 in n-hexane) to afford product 10 as
a white solid; yield: 1.0 g (78%); mp 54–568C. IR (CH2Cl2):
for C21H17NO2 [M]+: 315.1259.
4-Oxo-9-phenyl-7-(trifluoromethyl)-2,3,3a,4-tetrahydro-
1H-cyclopenta[b]naphthalene-3a-carbonitrile (9bi): white
solid; yield: 93%; mp 64–668C. IR (CH2Cl2): nmax =2969,
2229, 1713, 1574, 1340, 1280 cmÀ1
;
1H NMR (400 MHz,
CDCl3): d=8.03 (d, J=8.0 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H),
7.44–7.40 (m, 3H), 7.14 (s, 1H), 7.11 (brm, 2H), 2.82 (ddd,
J=18.8, 9.6 and 4.0 Hz, 1H), 2.70–2.63 (m, 1H), 2.31–1.93
(m, 4H); 13C NMR (100 MHz, CDCl3): d=192.7 (CO),
nmax =3058, 2242, 1695 cmÀ1 1H NMR (400 MHz, CDCl3):
;
d=8.01 (dd, J=7.6, 1.2 Hz, 2H), 7.83 (dd, J=7.6, 1.6 Hz,
1H), 7.64 (tt, J=8.0, 1.2 Hz, 1H), 7.50 (dd, J=8.0, 7.6 Hz,
2H), 7.39 (dd, J=7.6, 1.6 Hz, 1H), 7.31 (td, J=7.6, 2.4 Hz,
1H), 6.97 (td, J=7.6, 2.4 Hz, 1H), 4.76 (dd, J=9.6, 6.0 Hz,
1H), 3.47 (dd, J=14.0, 6.0 Hz, 1H), 3.28 (dd, J=14.0,
9.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=189.7 (CO),
139.6 (CH), 138.2 (C), 134.5 (CH), 133.8 (C), 131.3 (CH),
129.4 (CH), 128.9 (CH), 128.8 (CH), 128.7 (CH), 116.4
(CN), 100.0 (C), 39.9 (CH2), 39.2 (CH); HR-MS (EI): m/z=
360.9965, calcd. for C16H12INO [M]+: 360.9964.
2
141.9 (C), 140.8 (C), 136.3 (q, JCÀF =32.8 Hz, C), 135.6 (C),
132.5 (C), 131.0 (C), 129.0 (br, 2 x CH), 128.7 (CH), 128.3
3
(CH), 126.9 (q, JC,F =3.8 Hz, CH), 124.0 (q, 3JC,F =3.8 Hz,
1
CH), 123.1 (q, JC,F =272.2 Hz, C), 116.8 (CN), 51.5 (C), 33.1
(CH2), 29.8 (CH2), 22.4 (CH2); HR-MS (EI): m/z=353.1030,
calcd. for C21H14F3NO [M]+: 353.1027.
Methyl 9a-cyano-9-oxo-4-phenyl-2,3,9,9a-tetrahydro-1H-
cyclopenta[b]naphthalene-6-carboxylate (9bj): white solid;
yield: 93%; mp 152–1548C. IR (CH2Cl2): nmax =2952, 2228,
1
1725, 1603, 1278 cmÀ1; H NMR (400 MHz, CDCl3): d=7.99
The general procedure for the synthesis of products 12,
13, 14 and 15 is demonstrated as follows using 12 as a typical
example.
(s, 2H), 7.56 (s, 1H), 7.46–7.39 (m, 3H), 7.28 (brm, 2H),
3.83 (s, 3H), 2.82 (ddd, J=18.8, 9.2 and 4.0 Hz, 1H), 2.69–
2.64 (m, 1H), 2.30–1.93 (m, 4H); 13C NMR (100 MHz,
CDCl3): d=193.2 (CO), 165.7 (CO2Me), 140.9 (C), 140.3
(C), 136.0 (C), 135.9 (C), 132.9 (C), 131.6 (C), 128.9 (2
x CH), 128.5 (br, CH), 128.4 (CH), 128.0 (CH), 127.8 (CH),
117.0 (CN), 52.5 (OCH3), 51.5 (C), 33.2 (CH2), 29.8 (CH2),
22.5 (CH2); HR-MS (EI): m/z=343.1209, calcd. for
C22H17NO3 [M]+: 343.1208.
10-Oxo-5-phenyl-10a,11-dihydro-10H-benzo[b]-
fluorene-10a-carbonitrile (12)
A mixture of 2-(2-iodobenzyl)-3-oxo-3-phenylpropanenitrile
10
0.52 mmol), CuI (27 mg, 0.14 mmol), PdAHCUTNGTRENNUNG
(170 mg,
0.47 mmol),
phenylacetylene
(58 mg,
(PPh3)4 (54 mg,
7-Methoxy-4-oxo-9-phenyl-2,3,3a,4-tetrahydro-1H-cyclo-
penta[b]naphthalene-3a-carbonitrile (9bk): white solid;
yield: 90%; mp 185–1878C. IR ( CH2Cl2): nmax =2968, 2840,
0.047 mmol) and pyrrolidine (78 mL, 0.94 mmol) in dichloro-
methane (3 mL) was stirred open to air at room tempera-
ture for 3 h. The mixture was filtered through a pad of celite
and slica gel and washed with CH2Cl2 (50 mL). The organic
layers were concentrated under vacuum to give the residue,
which was subjected to purification by flash chromatography
on silica gel (20% EtOAc in n-hexane) to afford the com-
pound 12 as a yellow solid; yield: 139 mg (89%); mp 232–
2348C; IR (CH2Cl2): nmax =3063, 2226, 1702, 1591,
2227, 1690, 1593, 1261 cmÀ1 1H NMR (400 MHz, CDCl3):
;
d=7.96 (d, J=8.4 Hz, 1H), 7.42–7.36 (m, 4H), 7.05 (m,
1H), 6.83 (dd, J=8.4, 2.4 Hz, 1H), 6.36 (d, J=2.4 Hz, 1H),
3.72 (s, 3H), 2.81–2.74 (m, 1H), 2.71–2.63 (m, 1H), 2.27–
2.18 (m, 1H), 2.14–2.02 (m, 2H), 1.99–1.90 (m, 1H);
13C NMR (100 MHz, CDCl3): d=191.3 (CO), 165.2 (C),
142.5 (C), 141.0 (C), 136.4 (C), 132.8 (C), 130.3 (CH), 130.29
(br, CH), 128.6 (CH), 128.0 (CH), 121.8 (C), 117.8 (CN),
1
1283 cmÀ1; H NMR (400 MHz, CDCl3): d=8.03 (dd, J=7.6,
1.2 Hz, 1H), 7.64–7.62 (m, 2H), 7.54–7.45 (m, 3H), 7.40 (dd,
1334
asc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 1323 – 1337

Palladium(0)/Copper(I)-Catalyzed Tandem Cyclization of Aryl 1-Cyanoalk-5-ynyl Ketone System
J=7.6, 1.2 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.22 (t, J=
7.6 Hz, 1H), 6.97 (t, J=8.0 Hz, 1H), 6.95 (t, J=8.0 Hz, 1H),
6.91 (d, J=7.6 Hz, 1H), 6.32 (d, J=8.0 Hz, 1H), 3.67 (s,
2H); 13C NMR (100 MHz, CDCl3): d=192.6 (CO), 143.2
(C), 140.7 (C), 138.0 (C), 136.4 (C), 135.9 (C), 135.4 (CH),
132.5 (C), 130.5 (CH), 129.8 (CH), 129.6 (CH), 129.2 (CH),
128.6 (CH), 128.4 (CH), 128.25 (C), 128.23 (CH), 127.8
(CH), 127.7 (CH), 127.6 (CH), 125.6 (CH), 124.7 (CH),
118.4 (CN), 51.5 (C), 37.3 (CH2); HR-MS (EI): m/z=
333.1154, calcd. for C24H15NO [M]+: 333.1154.
resulting mixture was heated to 808C for 16 h, and then
cooled to room temperature and quenched with water. The
aqueous phase was extracted with ethyl acetate (2ꢁ20 mL).
The combined organic extracts were washed with water and
brine, dried over anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure to give crude residue. The
crude trimethylsilane residue, without purification, was fur-
ther treated with TBAF (5.72 mL, 1M in THF) in THF
(50 mL) at À108C for 1 h and then cooled to room tempera-
ture and quenched with water. The aqueous phase was ex-
tracted with ethyl acetate (2ꢁ30 mL). The combined organic
extracts were washed with water and brine, dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced
pressure to give crude residue, which was subjected to pu-
rification by flash chromatography on silica gel with n-
hexane/ethyl acetate (8:1) to afford the desired product 16
as a colorless oil; yield: 0.49 g (73% over two steps). IR
(CH2Cl2): nmax =3294, 3062, 2981, 2938, 2117, 1735, 1686,
10-Oxo-5-[4-(trifluoromethyl)phenyl]-10a,11-dihydro-
10H-benzo[b]fluorene-10a-carbonitrile (13): yellow solid;
yield: 72%; mp 231–2338C. IR (CH2Cl2): nmax =2924, 2225,
1693, 1587, 1323, 1284 cmÀ1 1H NMR (400 MHz, CDCl3):
;
d=8.06 (dd, J=7.6, 1.6 Hz, 1H), 7.93 (d, J=7.6 Hz, 1H),
7.79–7.75 (m, 2H), 7.55 (td, J=7.6, 1.6 Hz, 1H), 7.45–7.39
(m, 2H), 7.27 (td, J=7.6, 1.2 Hz, 1H), 7.16 (d, J=7.6 Hz,
1H), 7.04 (t, J=7.6 Hz, 1H), 6.81 (d, J=7.6 Hz, 1H), 6.29
(d, J=7.6 Hz, 1H), 3.69 (s, 2H); 13C NMR (100 MHz,
CDCl3): d=192.2 (CO), 143.5 (C), 139.98 (C), 139.96 (C),
138.6 (C), 135.9 (C), 135.5 (CH), 131.2 (CH), 131.0 (C),
1
1597, 1448, 1221, 690 cmÀ1; H NMR (400 MHz, CDCl3): d=
7.98 (dd, J=8.4, 1.2 Hz, 2H), 7.58 (tt, J=8.8, 1.2 Hz, 1H),
7.47 (dd, J=8.8, 8.4 Hz, 2H), 4.32 (t, J=7.2 Hz, 1H), 4.14
(qd, J=7.2, 1.2 Hz, 2H), 2.24 (td, J=7.2, 2.4 Hz, 2H), 2.12
(ddd, J=11.2, 7.2, 5.2 Hz, 2H), 1.95 (t, J=2.4 Hz, 1H),
1.65–1.56 (m, 2H), 1.16 (td, J=7.2, 0.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=194.7 (CO), 169.6 (CO2Et), 135.9
2
130.9 (q, JCÀF =32.8 Hz, C), 130.1 (CH), 129.1 (CH), 128.7
(CH), 128.2 (C), 128.0 (CH), 127.8 (CH), 127.5 (CH), 126.9
1
(CH), 126.2 (CH), 125.8 (CH), 124.4 (CH), 123.9 (q, JC,F
=
270.6 Hz, C), 118.1 (CN), 51.6 (C), 37.3 (CH2); HR-MS
(EI): m/z=401.1023, calcd. for C25H14F3NO [M]+: 401.1027.
5-(4-Methoxyphenyl)-10-oxo-10a,11-dihydro-10H-ben-
zo[b]fluorene-10a-carbonitrile (14): yellow solid; yield:
88%; mp 196–1988C. IR (CH2Cl2): nmax =2956, 2226, 1701,
ꢀ
(C), 133.4 (CH), 128.6 (CH), 128.4 (CH), 83.4 (C C), 68.8
ꢀ
(C CH), 61.2 (CH2), 53.5 (CH), 27.7 (CH2), 26.1
N
(CH2), 13.8 (CH3); HR-MS (EI): m/z=258.1251, calcd. for
C16H18O3 [M]+: 258.1256
1510, 1283 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=8.02 (d,
The general procedure for the synthesis of products 17, 18
and 19 is demonstrated as follows using 17 as a typical ex-
ample.
J=7.6 Hz, 1H), 7.53 (t, J=7.6 Hz, 2H), 7.41–7.36 (m, 2H),
7.23 (t, J=7.6 Hz, 1H), 7.16 (d, J=6.8 Hz, 1H), 7.02–6.88
(m, 4H), 6.45 (d, J=7.6 Hz, 1H), 3.92 (s, 3H), 3.67 (s, 2H);
13C NMR (100 MHz, CDCl3): d=192.8 (CO), 159.7 (C),
143.1 (C), 141.1 (C), 138.2 (C), 136.6 (C), 135.3 (CH), 132.4 Ethyl 4-Oxo-9-phenyl-2,3,3a,4-tetrahydro-1H-cyclo-
(C), 131.8 (CH), 129.6 (CH), 129.5 (CH), 128.3 (CH), 128.29
(C), 127.9 (C), 127.8 (CH), 127.7 (CH), 127.6 (CH), 125.5
(CH), 124.7 (CH), 118.5 (CN), 115.3 (CH), 114.5 (CH), 55.3
(CH3), 51.6 (C), 37.3 (CH2); HR-MS (EI): m/z=363.1249,
calcd. for C25H17NO2 [M]+: 363.1259.
penta[b]naphthalene-3a-carboxylate (17)
A mixture of ethyl 2-benzoylhept-6-ynoate 16 (120 mg,
0.47 mmol), iodobenzene (105 mg, 0.52 mmol), CuI (27 mg,
0.14 mmol), PdACTHUNTRGNE(UNG PPh3)4 (54 mg, 0.047 mmol) and pyrrolidine
(78 mL, 0.94 mmol) in dichloromethane (3 mL) was stirred
under air at room temperature for 5 h. After reaction was
complete, the mixture was filtered through a pad of Celite
and slica gel, and washed with CH2Cl2 (50 mL). The organic
layer was concentrated under reduced pressure to give the
residue, which was subjected to purification by flash chro-
matography on silica gel (20% EtOAc in n-hexane) to
afford compound 17 as a colorless oil; yield: 25%; IR
(CH2Cl2): nmax =3061, 2963, 1738, 1704, 1594, 1444, 1287,
10-Oxo-5-propyl-10a,11-dihydro-10H-benzo[b]fluorene-
10a-carbonitrile (15): yellow solid; yield: 93%; mp 151–
1538C. IR (CH2Cl2): nmax =2965, 2223, 1700, 1593,
1
1286 cmÀ1; H NMR (400 MHz, CDCl3): d=7.99 (dd, J=7.6,
1.6 Hz, 1H), 7.72 (td, J=7.6, 1.6 Hz, 1H), 7.64 (d, J=
7.6 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.46–7.33 (m, 4H),
3.62, 3.56 (ABq, J=16.8 Hz, 1H each), 2.92 (ddd, J=14.0,
11.6 and 5.6 Hz, 1H), 2.76 (ddd, J=14.0, 11.6 and 5.6 Hz,
1H) 1.90–1.73 (m, 2H), 1.17 (t, J=7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=192.9 (CO), 143.2 (C), 140.2 (C),
136.8 (C), 136.2 (C), 135.6 (CH), 131.9 (C), 129.3 (CH),
128.7 (C), 128.3 (CH), 128.0 (CH), 127.9 (CH), 125.9 (CH),
125.2 (CH), 125.0 (CH), 118.4 (CN), 51.7 (C), 37.3 (CH2),
30.8 (CH2), 22.3 (CH2), 14.2 (CH3); HR-MS (EI): m/z=
299.1315, calcd. for C21H17NO [M]+: 299.1310.
1
1204, 1019, 775, 705 cmÀ1; H NMR (400 MHz, CDCl3): d=
7.88 (dd, J=1.2, 7.6 Hz, 1H), 7.49–7.34 (m, 5H), 7.26 (t, J=
7.6 Hz, 2H), 6.86 (d, J=7.6 Hz, 1H), 4.13–4.03 (m, 2H),
2.74–2.62 (m, 2H), 2.25–2.14 (m, 2H), 1.98–1.90 (m, 1H),
1.84–1.75 (m, 1H), 1.10 (t, J=7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=198.8 (CO), 169.3 (CO2Et), 144.1
(C), 140.7 (C), 137.9 (C), 133.9 (CH), 131.5 (C), 130.1 (C),
128.5 (CH), 127.6 (CH), 127.1 (CH), 126.7 (CH), 126.3
(CH), 66.0 (C), 61.9 (CH2), 31.8 (CH2), 30.5 (CH2), 22.6
(CH2), 13.8 (CH3); HR-MS (EI): m/z=332.1408, calcd. for
C22H20O3 [M]+: 332.1412.
Ethyl 2-Benzoylhept-6-ynoate (16)
To a stirred solution of ethyl 3-oxo-3-phenylpropanoate
(0.50 g, 2.60 mmol) and potassium carbonate (0.54 g,
3.90 mmol) in acetonitrile (13 mL) was added 5-iodopent-1-
ynyltrimethylsilane (0.83 g, 3.12 mmol) in one portion. The
Ethyl 9-[4-(methoxycarbonyl)phenyl]-4-oxo-2,3,3a,4-tetra-
hydro-1H-cyclopenta[b]naphthalene-3a-carboxylate
pale yellow oil; yield: 32%: IR (CH2Cl2): nmax =3063, 2953,
(18):
Adv. Synth. Catal. 2013, 355, 1323 – 1337
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1335

Ying-Chieh Wong et al.
2230, 1738, 1683, 1606, 1510, 1448, 1289, 1032, 833, 691 cmÀ1
;
FULL PAPERS
1721, 1608, 1434, 1282, 1114, 1019, 776 cmÀ1
;
1H NMR
(400 MHz, CDCl3): d=8.09 (d, J=6.4 Hz, 2H), 7.88 (dd, J=
1.6, 7.6 Hz, 1H), 7.40 (td, J=7.6, 1.6 Hz, 1H), 7.28 (td, J=
7.6, 1.2 Hz, 1H), 7.35 (br, 2H), 6.79 (d, J=7.6 Hz, 1H),
4.14–4.02 (m, 2H), 3.94 (s, 3H), 2.74–2.61 (m, 2H), 2.21–
2.13 (m, 2H), 1.99–1.87 (m, 1H), 1.85–1.76 (m, 1H), 1.09 (t,
J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=198.1
(CO), 168.8 (CO2Et), 166.6 (CO2Me), 144.7 (C), 142.8 (C),
139.8 (C), 133.9 (CH), 130.7 (C), 129.9 (C), 129.7 (CH),
129.3 (C), 127.3 (CH), 126.7 (CH), 125.9 (CH), 66.0 (C),
61.9 (CH2), 52.0 (CH3), 31.6 (CH2), 30.4 (CH2), 22.4 (CH2),
13.7 (CH3); HR-MS (EI): m/z=390.1460, calcd. for
C24H22O5 [M]+: 390.1467.
1H NMR (400 MHz, CDCl3): d=8.00 (dd, J=7.6, 1.2 Hz,
2H), 7.56 (tt, J=7.6, 1.2 Hz, 1H), 7.44 (t, J=7.6 Hz, 2H),
7.31–7.26 (m, 2H), 6.81–6.77 (m, 2H), 4.39 (t, J=7.2 Hz,
1H), 4.15 (qd, J=7.2, 1.6 Hz, 2H), 3.78 (s, 3H), 2.45 (t, J=
7.2 Hz, 2H), 2.21–2.15 (m, 2H), 1.72–1.64 (m, 2H), 1.17 (t,
J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=195.0
(CO), 169.8 (CO2Et), 159.0 (C), 136.1 (C), 133.4 (CH), 132.8
(CH), 128.7 (CH), 128.5 (CH), 115.8 (C), 113.7 (CH), 87.5
ꢀ
ꢀ
(C C), 80.9 (C C), 61.3 (CH2), 55.2 (CH3), 53.7 (CH), 28.1
(CH2), 26.6 (CH2), 19.1 (CH2), 13.9 (CH3); HR-MS (EI):
m/z=364.1677, calcd. for C23H24O4 [M]+: 364.1675.
Ethyl 9-(4-methoxyphenyl)-4-oxo-2,3,3a,4-tetrahydro-1H-
cyclopenta[b]naphthalene-3a-carboxylate (19): pale yellow
solid; yield: 44%; mp 91–938C. IR (CH2Cl2): nmax =3064,
2962, 1738, 1694, 1608, 1514, 1454, 1287, 1248, 1033,
Acknowledgements
1
774 cmÀ1; H NMR (400 MHz, CDCl3): d=7.87 (dd, J=1.2,
We are grateful to the National Health Research Institutes
and National Science Council of Taiwan (NSC-101-2113M-
400-003-MY2) for financial support.
8.0 Hz, 1H), 7.40 (td, J=8.0, 1.2 Hz, 1H), 7.26 (td, J=8.0,
1.2 Hz, 1H), 7.24 (br, 2H), 6.95 (d, J=8.0 Hz, 2H), 6.90 (d,
J=8.0 Hz, 1H), 4.12–4.04 (m, 2H), 3.86 (s, 3H), 2.75–2.60
(m, 2H), 2.25–2.13 (m, 2H), 1.97–1.90 (m, 1H), 1.83–1.77
(m, 1H), 1.10 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=198.8 (CO), 169.3 (CO2Et), 159.8 (C), 143.7 (C),
140.8 (C), 133.8 (CH), 131.0 (C), 130.1 (C), 129.3 (C), 127.0
(CH), 126.6 (CH), 126.2 (CH), 113.8 (CH), 65.8 (C), 61.8
(CH2), 55.2 (CH3), 31.7 (CH2), 30.5 (CH2), 22.5 (CH2), 13.7
(CH3); HR-MS (EI): m/z=362.1521, calcd. for C23H22O4
[M]+: 362.1518.
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Products 20, 21 and 22 are synthesized in a similar
manner as with 17, except that instead of exposure to air,
the reaction system is carried out under nitrogen.
Ethyl 2-benzoyl-7-phenylhept-6-ynoate (20): colorless oil;
yield: 97%: IR (CH2Cl2): nmax =3060, 2980, 2936, 2360, 1738,
1
1688, 1598, 1448, 1222, 758, 692 cmÀ1; H NMR (400 MHz,
CDCl3): d=8.00 (dd, J=7.6, 1.2 Hz, 2H), 7.57 (tt, J=7.6,
1.2 Hz, 1H), 7.45 (dd, J=7.6, 7.2 Hz, 2H), 7.37–7.34 (m,
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2H), 1.73–1.59 (m, 2H), 1.17 (t, J=7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=194.9 (CO), 169.7 (CO2Et), 136.0
(C), 133.4 (CH), 131.4 (CH), 128.6 (CH), 128.5 (CH), 128.1
ꢀ
ꢀ
(CH), 127.5 (CH), 123.6 (C), 89.1 (C C), 81.2 (C C), 61.3
(CH2), 53.6 (CH), 28.0 (CH2), 26.4 (CH2), 19.1 (CH2), 13.9
(CH3); HR-MS (EI): m/z=334.1572, calcd. for C22H22O3
[M]+: 334.1569.
Methyl 4-(6-benzoyl-7-ethoxy-7-oxohept-1-ynyl)benzoate
(21): colorless oil; yield: 90%. IR (CH2Cl2): nmax =3061,
2952, 2229, 1725, 1688, 1606, 1448, 1276, 770, 696 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=8.00 (d, J=10.4 Hz, 2H),
7.93 (d, J=10.4 Hz, 2H), 7.57 (tt, J=7.6, 1.2 Hz, 1H), 7.48–
7.38 (m, 4H), 4.37 (t, J=9.6 Hz, 1H), 4.15 (qd, J=9.2,
1.2 Hz, 2H), 3.90 (s, 3H), 2.49 (t, J=9.2 Hz, 2H), 2.22–2.15
(m, 2H), 1.70 (quint, J=9.2 Hz, 2H), 1.16 (td, J=9.2,
1.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=194.9 (CO),
169.8 (C), 166.6 (C), 136.0 (C), 133.5 (CH), 131.4 (CH),
129.3 (CH), 128.9 (C), 128.7 (CH), 128.6 (CH), 128.5 (C),
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92.6 (C C), 80.7 (C C), 61.4 (CH2), 53.7 (CH), 52.1 (CH3),
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1336
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Adv. Synth. Catal. 2013, 355, 1323 – 1337

Palladium(0)/Copper(I)-Catalyzed Tandem Cyclization of Aryl 1-Cyanoalk-5-ynyl Ketone System
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Adv. Synth. Catal. 2013, 355, 1323 – 1337
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asc.wiley-vch.de
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