Synthesis of benzo-fused lactams and lactones via Ru(II)-catalyzed cycloaddition of amide- and ester-tethered α,ω-diynes with terminal alkynes: Electronic directing effect of internal conjugated carbonyl group

Article abstract of DOI:10.1039/b402649g

In the presence of a catalytic amount of Cp*RuCl(cod), 1,6- and 1,7-diynes connected by an amide or an ester tether underwent cycloaddition with terminal alkynes at room temperature to give rise to cycloadducts in 40-93% yields with 63 : 37-83 : 17 regioisomer ratios.

Full text of DOI:10.1039/b402649g

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Synthesis of benzo-fused lactams and lactones via Ru(II)-catalyzed
cycloaddition of amide- and ester-tethered ꢀ,ꢁ-diynes with
terminal alkynes: electronic directing effect of internal conjugated
carbonyl group
Yoshihiko Yamamoto,*a Keisuke Kinpara,a Tomoaki Saigoku,a Hisao Nishiyamaa
and Kenji Itohb
a Department of Applied Chemistry, Department of Molecular Design and Engineering,
Graduate School of Engineering, Nagoya University, Chikusa, Nagoya 464-8603, Japan.
E-mail: yamamoto@apchem.nagoya-u.ac.jp; Fax: 81 52 789 3209; Tel: 81 52 789 3337
b Department of Molecular Design and Engineering, Graduate School of Engineering,
Nagoya University, Chikusa, Nagoya 464-8603, Japan.
Fax: 81 52 789 3209; Tel: 81 52 789 3337
Received 23rd February 2004, Accepted 11th March 2004
First published as an Advance Article on the web 7th April 2004
In the presence of a catalytic amount of Cp*RuCl(cod), 1,6- and 1,7-diynes connected by an amide or an ester tether
underwent cycloaddition with terminal alkynes at room temperature to give rise to cycloadducts in 40–93% yields
with 63 : 37–83 : 17 regioisomer ratios.
Introduction
Transition-metal-catalyzed [2 ϩ 2 ϩ 2] cyclotrimerization of
alkynes is straightforward and an atom-economical approach
to substituted benzene derivatives.1 One crucial disadvantage of
this potentially useful method is the difficulty in controlling
chemo- and regiochemistry.2 In this context, we have developed
the Ru()-catalyzed intramolecular alkyne cyclotrimerizations,
in which we have found that the cycloaddition of unsymmet-
rical 1,6-diynes 2 with terminal alkynes proceeded in the pres-
ence of a ruthenium precatalyst, Cp*RuCl(cod) (1) (Cp* = η5-
C5Me5, cod = 1,5-cyclooctadiene), at room temperature to
afford bicyclic benzenes 3 with good to excellent regioselectivity
(meta/ortho = 88 : 12–98 : 2) (Scheme 1).3
Scheme 2
almost no regioselectivity, although it has a bulky diphenyl-
methylene moiety adjacent to one of the two terminal alkynes
(Scheme 3). On the other hand, a carbonyl group directly
connected to the alkyne terminal is expected to exert a direct
electronic impact on the regioselectivity. To our surprise, such
an electronic effect has remained unevaluated. With these facts
in mind, we report herein the Ru()-catalyzed cycloaddition of
unsymmetrical diynes bearing a conjugated carbonyl group in
the tether with terminal alkynes (Fig. 1).
Scheme 1
In order to extend the Ru()-catalyzed cycloaddition, we
further explored the cycloaddition of amide- and ester-tethered
α,ω-diynes 4, which are readily prepared from propiolic acid
and propargyl compounds (Scheme 2), because this strategy
would provide an efficient entry into valuable heterocycles such
as isoindolinones and phthalides. Isoindolinone ring systems
have attracted considerable interest due to their biological
activity, including anti-inflammatory (indoprofen), anxiolytic
(pazinaclone), and protein kinase C inhibitor (staurosporine)
activities.4 The phthalide ring is also found in a biologically
active natural product, mycophenolic acid.5
Scheme 3
Results and discussion
At the outset of this study, an amide-diyne 4a (X = NBn) was
reacted with 4 equiv. 1-hexyne 5a in 1,2-dichloroethane (DCE)
containing 1 mol% 1 at room temperature for 0.5 h to afford the
expected isoindolinones 6aa and 7aa (Table 1, run 1). Interest-
ingly, the 1H NMR analysis of the crude product mixture
Unsymmetrical α,ω-diynes having no terminal substituent,
however, might afford regioisomeric cycloadducts unselectively.
In fact, an unsymmetrical propargyl ether derivative exhibited
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 2 8 7 – 1 2 9 4
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Table 1 Ru()-catalyzed cycloaddition of diynes 4 with alkynes 5
Run
X
R
Time/h
Product (yield, %)a 6/7b
1
2
3
4
5
6
7
8
NBn
NBn
NBn
NBn
NBn
O
nBu
0.5
2
2
1
1
2
2
0.5
6aa (51), 7aa (25)
6ab (31), 7ab (9)
6ac/7ac (93)
6ad/7ad (90)
6ae/7ae (63)
6ba/7ba (93)
6bc/7bc (87)
6ca/7ca (70)
63 : 37
tBu
80 : 20
80 : 20
64 : 36
64 : 36
70 : 30
75 : 25
78 : 22
Ph
CH2OMe
CH2NMe2
nBu
O
CMe2
Ph
nBu
Fig. 3 ORTEP drawing of 6ac.
a Isolated yields. b Regioisomer ratio was determined by 1H NMR
analysis of crude products.
Next we examined the influence of the electron-withdrawing
ability of the carbonyl group. Toward this end, diynes 4b and 4c
bearing an ester or a ketone carbonyl group were subjected to
the cycloaddition with terminal alkynes. An ester-diyne 4b7 was
reacted with 1-hexyne 5a or phenylacetylene 5c under similar
reaction conditions to afford phthalides 6ba/7ba and 6bc/7bc in
93 and 87% combined yields (Table 1, runs 6 and 7). The
observed regioselectivities are similar to those of corresponding
isoindolinones. In contrast, the regioisomer ratio was slightly
improved when a ketodiyne 4c was employed (run 8).
Indanones 6ca/7ca were obtained in 70% combined yield with
the ratio of 6ca : 7ca = 78 : 22. It is noteworthy that the present
regioselectivity increased in the order of 4a (X = NBn) ≅ 4b
(X = O) < 4c (X = CMe2), indicative of a carbonyl group with
stronger electron-withdrawing ability favoring the formation of
6 over 7.
Fig. 1 Starting materials used in this study.
In order to evaluate the cooperative effect of the terminal
substituents and the internal carbonyl group, variously substi-
tuted amide- and ester-diynes were examined with respect to the
cycloaddition with 1-hexyne 5a (Scheme 4). Under the same
reaction conditions with 4a, an amide 9a (X = NBn, R1 = Me,
R2 = H) possessing a methyl substituent at the electron-deficient
alkyne terminal furnished the expected regioisomer 10aa in
81% yield as a sole product. Similarly, an ester analogue 9b
(X = O, R1 = Me, R2 = H) gave rise to 10ba as a major product
(10ba : 11ba = 97 : 3). These results suggest that the steric direct-
ing effect of the terminal methyl substituent effectively sup-
pressed the formation of the minor regioisomers, resulting in
the selective formation of 10aa and 10ba. In striking contrast,
the reaction of 12a (X = NBn, R1 = H, R2 = Me) having a methyl
substituent on the other alkyne moiety required increased
catalyst loading (5 mol%) as well as a longer reaction time for
completion of the reaction. In addition, 14aa was obtained in
56% yield as a major product together with 13aa (12%). More-
over, the regioselectivity was decreased from 13aa : 14aa =
18 : 82 to 13ba : 14ba = 21 : 79, when a more electron-deficient
ester analogue 12b (X = O, R1 = H, R2 = Me) was employed in
place of 12a. In these cases, the electronic directing effect was
almost offset by the conflicting steric influence of the terminal
revealed that the cycloadduct 6aa, in which the n-butyl substit-
uent is placed in the para-position to the amide group, was
found preferably over the other regioisomer 7aa (6aa : 7aa =
63 : 37). This observation is in sharp contrast to the previously
repored Ni()-mediated cycloaddition of similar amide-diynes
with methyl propargyl ether giving rise to 50 : 50 regioisomer
mixtures.6 Separation with silica gel chromatography yielded
6aa and 7aa in 51 and 25% yields, respectively.
The generality of the present regioselectivity was examined
with respect to terminal alkynes as summarized in Table 1. In a
similar manner, sterically demanding tert-butylacetylene 5b was
reacted with 4a to afford 6ab and 7ab in 31 and 9% respective
yields (run 2). Interestingly, the regioselectivity was improved
up to 80 : 20, whereas the total yield was lower than that of 6aa/
7aa. Phenylacetylene 5c gave an inseparable mixture of bi-
phenyl analogues in excellent combined yield with the same
regioisomeric ratio of 6ac : 7ac = 80 : 20 (run 3). Alkynes 5d
and 5e bearing an ether or a tertiary amine functionality
also underwent the cycloaddition to form the corresponding
isoindolinones 6ad/7ad and 6ae/7ae, respectively, with the
regioisomer ratio similar to that of 6aa/7aa (runs 4 and 5).
The regiochemistry of the obtained products was determined
on the basis of 1H NMR (300 MHz, CDCl3) analysis. As
shown in Fig. 2, the diagnostic aromatic proton Ha appeared in
a lower magnetic field than Hb-Hd, because of the deshielding
effect of the adjacent carbonyl group. The Ha signals of the
major isomers 6 were observed as doublet peaks with a coup-
ling constant around 8 Hz, whereas those of the minor isomers
7 appeared as singlets. The major product derived from 4a and
5c was unambiguously assigned to 6ac by X-ray crystallo-
graphic analysis (Fig. 3).†
† Crystallographic data: A single crystal of 6ac (0.2 × 0.4 × 0.8 mm3)
suitable for X-ray analysis was obtained by recrystallization from
CHCl3–ether. The single crystal was mounted on a quartz fiber, and
diffraction data were collected in the θ range of 2.43–29.14Њ at 173 K
on a Brucker SMART APEX CCD diffractometer with graphite-
monochromated Mo Kα radiation (λ = 0.71073 Å). An absorption cor-
rection was made using SADABS. The structure was solved by direct
methods and refined by full-matrix least squares on F2 by using
SHELXTL. All non-hydrogen atoms were refined with anisotropic dis-
placement parameters. All hydrogen atoms were placed in calculated
positions. Final refinement details of 6ac [C21H17NO, Mw = 299.36];
space group P2(1), monoclinic; unit-cell dimensions a = 8.3987(6) Å,
b = 5.7449(4) Å, c = 15.9653(12) Å, β = 90.7740(10)Њ, V = 770.25(10) Å3;
Z = 2, Dcalc = 1.291 Mg mϪ3; Total 5753 reflections were measured and
3608 were independent [R(int) = 0.0236]. Final R1 = 0.0493, wR2
=
0.1318 [I > 2σ(I )], and GOF = 0.719 (for all data, R1 = 0.0506, wR2 =
0.1349).
CCDC reference numbers 224127. See http://www.rsc.org/suppdata/
ob/b4/b402649g/ for crystallographic data in.cif or other electronic
format.
Fig. 2 1H NMR chemical shifts of 6aa and 7aa.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 2 8 7 – 1 2 9 4
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Fig. 4 DFT-optimized geometries of model ruthenacycles 24 and 25a–c at the B3LYP/LACVP* level. Typical bond lengths (Å), angles (Њ) were
shown with natural charges (bold).
terminal alkyne 5 might afford ruthenacycle intermediates
22a–d, which subsequently undergo ring opening to result in
seven-membered ruthenacycles 23a–d.10 The final reductive
elimination affords the benzene regioisomers 6 and 7, and the
catalytically active species, Cp*RuCl, is restored. The regio-
chemistry of the cycloadducts might be determined by the
[2 ϩ 2] cycloaddition step. The access of the terminal alkyne to
the Ru–Cα bond on the same side with the carbonyl group gives
rise to 22a or 22b. On the other hand, 22c or 22d are produced,
when the terminal alkyne comes close to the ruthenacycle from
the other direction. The latter course seems favorable over the
former, because the methyl substituent on the electronically
neutral alkyne terminus in the diynes 12a,b had a deleterious
effect on both the reaction rate and the regioselectivity,
although the methyl substituent on the electron-deficient alkyne
terminal in 9a,b improved the regioselectivity (Scheme 4). In
addition, the repulsive interaction between the substituent R
and the chlorine ligand makes 22a and 22c less favorable than
22b or 22d, respectively. According to these analyses, path d
(21
22d
23d
6) is considered to be the major course of
the present cycloaddition.
In order to obtain further information on the regioselection
mechanism, we carried out the density functional study of the
ruthenacycle key intermediate. To this aim, the geometries of
model ruthenacycle complexes 25a–c bearing a cyclopenta-
dienyl ligand were optimized at the B3LYP/LACVP* level of
theory. The obtained geometries are outlined with those for
previously reported 243 in Fig. 4. Surprisingly, the ruthena-
cyclopentatriene moieties are almost symmetrical, although the
fused lactam, lactone, or cyclopentenone rings exhibited clearly
unsymmetrical geometries. Further calculations of natural
charges, however, uncovered the electronically unsymmetrical
environment of these ruthenacycles. With respect to the
ruthenacycle carbons, the natural charges are increased for the
red-colored carbons and decreased for the blue-colored ones.
With these results, we assumed that more negatively charged α
carbons are favorable for the [2 ϩ 2] cycloaddition with ter-
minal alkynes.
Scheme 4
methyl substituent. As a consequence, both the reaction rate
and regioselectivity were decreased to give rise to both regio-
isomers. Interestingly, an amide-diyne 15a (X = NBn, R1 = R2 =
Me) and an ester-diyne 15b (X = O, R1 = R2 = Me) reacted with
5a at room temperature for 1 h in the presence of 5 mol% 1 to
give rise to 83 : 17 and 90 : 10 regioisomer mixtures,8 whereas
they have methyl substituents on both alkyne termini.
The steric influence of an internal methyl substituent on the
regiochemistry was again not observed for the reaction of 18a
(Scheme 5). Isoindolinones 19aa/20aa were obtained with
almost the same isomer ratio to that observed for 5a.
The present regioselective cycloaddition was further
extended to 1,7-diynes 26a and 26b derived from ethynylaniline
and ethynylphenol, respectively (Scheme 7). In the presence of
10 mol% 1, 26a underwent cycloaddition with 5a at room tem-
perature for 1 h to afford the desired benzoquinolones 27aa/
1
28aa. To our delight, the H NMR analysis of the crude mix-
ture revealed that the regioselectivity of 27aa : 28aa = 83 : 17
was higher than that of the corresponding products from the
1,6-diyne 4a (Table 1, run 1). The chromatographic purification
gave 27aa and 28aa in 56 and 14% respective yields. With the
decreased catalyst loadings of 1–5 mol%, the reaction did not
complete within 15 h at room temperature. Analogously, 26b
reacted with 5a for 2 h to furnish inseparable coumarin regio-
isomers 27ba and 28ba in 41% combined yield. The crude regio-
isomer ratio of 27ba : 28ba = 82 : 18 was again higher than that
of the corresponding products from the ester-diyne 4b (Table 1,
run 6).
Scheme 5
Scheme 6 outlines the reaction mechanism of the cyclo-
addition of 4, which reasonably explains the observed regio-
selectivity. The cycloaddition might start with the formation of
a ruthenabicycle intermediate 21 from 1 and 4. As previously
proposed on the basis of the theoretical calculations,3,9 the [2 ϩ
2] cycloaddition of the ruthenacycle intermediate 21 with a
Apart from the regioselectivity issue, the ruthenium()-
catalyzed cycloadditions of the amide-diynes are highly
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 2 8 7 – 1 2 9 4
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Scheme 6
Scheme 8
(1 atm) at room temperature for 30 min to give rise to the
expected isoindoloisoquinoline 31 in 82% yield. The analytical
data of 31 were in good agreement with those reported in the
literature.12
Scheme 7
Conclusions
valuable, because they provide an efficient access to isoindol-
inone frameworks. In order to demonstrate its synthetic
potential, the present method was applied to the construction
of an isoindoloisoquinoline skeleton, which is found in neuv-
amine, an alkaloide stemming from Berberis darwinii, and its
derivatives (Scheme 8).11,12 The desired precursor, 1,6-diyne 30
was prepared from a readily available dihydroisoquinoline 29.13
In the presence of 1 mol% 1, 30 was reacted with acetylene
In conclusion, we successfully developed the mild and selective
synthesis of isoindolinone and phthalide derivatives by means
of the Ru()-catalyzed cycloaddition of the 1,6-diynes bearing
amide and ester tethers, and uncovered the unprecedented regio-
1
selectivity. The H NMR and X-ray crystallographic analyses
revealed that the cycloadducts, in which the substituent derived
from the terminal alkynes is placed in the para-position to the
carbonyl group, were formed preferentially. The regioselectivity
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 2 8 7 – 1 2 9 4
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varied depending on the tether group as well as substituents on
terminal alkynes. The carbonyl group with stronger electron-
withdrawing ability gave higher selectivity. Quinolone and
coumarin frameworks were also assembled successfully from
aniline- and phenol-derived 1,7-diynes. The synthetic potential
of the ruthenium catalysis was also demonstrated by the con-
struction of an isoindoloisoquinoline framework, which was
found in a naturally occurring alkaloid, neuvamine.
1.86 (3 H, t, J = 2.4), 2.92 (1 H, s), 4.74 (2 H, q, J 2.4); δC (75
MHz; CDCl3) 3.77, 54.45, 71.86, 74.09, 75.46, 84.45, 151.87;
ϩ
᎐
m/z (EI) no molecular ion peak 101 (M Ϫ CH C᎐CCO Ϫ 2H,
᎐
3
53), 69 (100).
15a. (Found: C, 79.99; H, 6.72; N, 6.21. C15H15NO requires
C, 79.97; H, 6.71; N, 6.22%); νmax/cmϪ1 2247, 1621 cmϪ1; δH (300
MHz; CDCl3) (syn/anti isomer mixture with ca. 55 : 45 ratio)
1.79 and 1.83 (3 H, t, J = 2.4), 2.00 and 2.03 (3 H, s), 4.05 and
4.20 (2 H, q, J 2.4), 4.71 and 4.88 (2 H, s), 7.27–7.40 (5 H, m);
δC (75 MHz; CDCl3) 3.48, 4.06 and 4.09, 32.72 and 37.90, 46.21
and 51.24, 72.72 and 72.82, 72.94 and 73.03, 79.92 and 80.78,
89.56 and 89.92, 127.35 and 127.64, 127.46, 128.19 and 128.33,
128.48, 135.75 and 135.88, 154.01; m/z (EI) 225 (Mϩ, 16), 172
(100), 149 (36).
Experimental
Flash chromatography was performed with a silica gel column
(Merck Silica gel 60) eluted with mixed solvents [hexane–
AcOEt]. 1H and 13C NMR spectra were obtained for samples in
CDCl3 solution at 25 ЊC on a Varian Mercury 300 spectrometer.
1H NMR chemical shifts (δ) are reported in ppm relative to the
singlet at 7.26 ppm for chloroform. Coupling constants (J) are
reported in Hz. Infrared spectra were recorded for CHCl3
sample solutions in 0.2 mm path length sodium chloride cavity
cells on a JASCO FT/IR-230 spectrometer. Mass spectra were
recorded on a JEOL JMS700 mass spectrometer. Elemental
analyses were performed by the Microanalytical Center of
Kyoto University and Instrumental Analysis Facility of
Nagoya University. Melting points were obtained on a Büchi
B-540 apparatus. CH2Cl2 and 1,2-dichloroethane was dried
over CaH2 and distilled. Cp*RuCl(cod) was prepared according
to the reported method.14
15b. (Found: C, 70.39; H, 6.10. C8H8O2 requires C, 70.57; H,
5.92%); νmax/cmϪ1 2242, 1712 cmϪ1; δH (300 MHz; CDCl3) 1.85
(3 H, t, J = 2.4), 1.98 (3 H, s), 4.70 (2 H, q, J 2.4); δC (75 MHz;
CDCl3) 3.68, 3.85, 53.88, 71.80, 72.21, 83.90, 86.43, 152.74; m/z
(EI) 137 (MHϩ, 25), 121 (17), 69 (100).
18a. (Found: C, 73.51; H, 6.20; N, 6.32. C14H13NOؒH2O
requires C, 73.34; H, 6.59; N, 6.11%); νmax/cmϪ1 3302, 2111,
1631 cmϪ1; δH (300 MHz; CDCl3) (syn/anti isomer mixture
with ca. 55 : 45 ratio) 1.16 and 1.33 (3 H, t, J = 7.2), 2.33
and 2.42 (1 H, d, J 2.4), 3.06 and 3.21 (1 H, s), 4.50 and 4.83
(1 H, d, J 16), 5.02 and 5.13 (1 H, d, J 16), 5.45 and 5.46 (1 H,
q, J 7.2), 7.27–7.40 (5 H, m); δC (75 MHz; CDCl3) 20.72
and 22.23, 42.30 and 45.57, 47.44 and 49.79, 73.40 and 73.90,
75.16 and 75.89, 79.16 and 79.97, 81.22 and 81.52, 127.06 and
127.17, 127.48 and 127.51, 128.23 and 128.38, 137.33 and
137.58, 152.94 and 153.18; m/z (EI) 212 (MHϩ, 81), 184 (100),
158 (31).
Representative procedure for preparation of diynes: Synthesis of
amide-diyne 9a
To a solution of N-benzylpropargylamine (1.54 g, 10.6 mmol),
DCC (2.48 g, 12 mmol), and DMAP (147 mg, 1.2 mmol) in dry
CH2Cl2 (20 cm3) was added a solution of 2-butynoic acid (965
mg, 11.5 mmol) in dry CH2Cl2 (10 cm3) at 0 ЊC. The reaction
mixture was stirred overnight. The resultant precipitates were
removed by filtration through a Celite pad, and the filtrate was
concentrated in vacuo. The residue was purified by silica gel
chromatography (hexane–AcOEt 6 : 1–3 : 1) to give 9a (1.98 g,
88%) as pale yellow oil (Found: C, 79.51; H, 6.33; N, 6.58.
C14H13NO requires C, 79.59; H, 6.20; N, 6.63%); νmax/cmϪ1
3306, 2250, 2198, 1621 cmϪ1; δH (300 MHz; CDCl3) (syn/anti
isomer mixture with ca. 3 : 2 ratio) 2.01 and 2.04 (3 H, s), 2.21
and 2.32 (1 H, t, J 2.4), 4.11 and 4.25 (2 H, d, J 2.4), 4.73 and
4.91 (2 H, s), 7.27–7.40 (5 H, m); δC (75 MHz; CDCl3) 4.03,
32.13 and 37.33, 46.23 and 51.19, 72.21 and 72.52, 72.80 and
72.96, 77.61, 89.88 and 90.19, 127.47 and 127.75, 128.16, 128.38
and 128.53, 135.31 and 135.49, 153.91; m/z (FAB) 212 (MHϩ,
100), 144 (28).
26a. (Found: C, 83.28; H, 5.25; N, 5.28. C18H13NO requires
C, 83.37; H, 5.05; N, 5.40%); νmax/cmϪ1 3301, 2112, 1640 cmϪ1
;
δH (300 MHz; CDCl3) 2.75 (1 H, s), 3.29 (1 H, s), 4.37 (1 H, d,
J 14.4), 5.54 (1 H, d, J 14.4), 6.83–6.86 (1 H, m), 7.18–7.34 (7 H,
m), 7.54–7.59 (1 H, m); δC (75 MHz; CDCl3) 51.34, 76.13,
79.14, 79.27, 82.89, 122.19, 127.60, 128.29, 128.45, 129.14,
129.20 130.11, 133.50, 135.86, 142.36, 152.99; m/z (EI) 212
(Mϩ Ϫ H, 42), 230 (68), 206 (100).
26b. (Found: C, 77.28; H, 3.91. C11H6O2 requires C, 77.64; H,
3.55%); νmax/cmϪ1 3300, 2128, 1737 cmϪ1; δH (300 MHz; CDCl3)
3.09 (1 H, s), 3.31 (1 H, s), 7.15 (1 H, dd, J 8.1 and 1), 7.26 (1 H,
dt, J 7.8 and 1.2), 7.40 (1 H, dt, J 8.1 and 1.8), 7.56 (1 H, dd,
J 7.5 and 1.8); δC (75 MHz; CDCl3) 73.88, 77.16, 77.78, 82.97,
116.05, 121.87, 126.54, 130.02, 133.63, 150.06, 150.70; m/z
(FAB) 171 (MHϩ, 100), 142 (29).
Other diynes were prepared in a similar manner.
9b. (Found: C, 68.77; H, 4.83. C7H6O2 requires C, 68.85; H,
4.95%); νmax/cmϪ1 3305, 2244, 2198, 1715 cmϪ1; δH (300 MHz;
CDCl3) 1.99 (3 H, d, J 0.3), 2.51 (1 H, t, J 2.4), 4.72 (2 H,
dd, J 2.4, 0.9); δC (75 MHz; CDCl3) 3.94, 52.95, 71.54, 75.57,
76.62, 87.06, 152.49; m/z (EI) no molecular ion peak 101
Cp*RuCl(cod)-catalyzed cycloaddition of 3,3-diphenyl-4-
oxahept-1,6-diyne with 1-hexyne
ϩ
᎐
(M Ϫ CH C᎐CCO Ϫ 2H, 93), 69 (100).
᎐
3
To a degassed solution of Cp*RuCl(cod) 1 (5.7 mg, 0.015
mmol) and 1-hexyne 5a (175.1 mg, 2.1 mmol) in dry 1,2-di-
chloroethane (1 cm3) was added a degassed solution of 3,3-di-
phenyl-4-oxahept-1,6-diyne (130.6 mg, 0.53 mmol) in dry
1,2-dichloroethane (2 cm3) by syringe over 10 min under Ar at
room temperature. The reaction mixture was stirred for 1 h. The
solvent was evaporated, and the crude products were purified
by silica gel chromatography (hexane–AcOEt 20 : 1) to give a
regioisomer mixture of cycloadducts (142 mg, 82%) as colorless
oil (Found: C, 87.70; H, 7.43. C24H24O requires C, 87.76; H,
7.37%); δH (300 MHz; CDCl3) 0.92 and 0.93 (3 H, t, J 7.2),
1.30–1.43 (2 H, m), 1.52–1.65 (2 H, m), 2.58–2.65 (2 H, m), 5.15
and 5.16 (2 H, s), 7.04–7.18 (3 H, m), 7.25–7.32 (10 H, m); m/z
(FAB) 327 (Mϩ-H, 35), 251 (100), 194 (57).
12a. (Found: C, 79.63; H, 6.20; N, 6.60. C14H13NO requires
C, 79.59; H, 6.20; N, 6.63%); νmax/cmϪ1 3299, 2112, 1629 cmϪ1
;
δH (300 MHz; CDCl3) (syn/anti isomer mixture with ca. 3 : 2
ratio) 1.80 and 1.83 (3 H, t, J = 2.4), 3.15 and 3.17 (1 H, s), 4.06
and 4.21 (2 H, q, J 2.4), 4.72 and 4.91 (2 H, s), 7.27–7.40 (5 H,
m); δC (75 MHz; CDCl3) 3.44, 32.81 and 37.93, 46.41 and 51.19,
72.44 and 72.55, 75.13 and 75.44, 79.38 and 79.60, 80.27 and
81.09, 127.46 and 127.50, 127.78 and 128.23, 128.38 and
128.52, 135.21 and 135.46, 152.62 and 152.70; m/z (FAB) 212
(MHϩ, 100), 143 (28).
12b. (Found: C, 68.68; H, 5.12. C7H6O2 requires C, 68.85; H,
4.95%); νmax/cmϪ1 3298, 2123, 1719 cmϪ1; δH (300 MHz; CDCl3)
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 2 8 7 – 1 2 9 4
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Representative procedure for Cp*RuCl(cod)-catalyzed cyclo-
addition of electron-deficient diynes with terminal alkynes:
synthesis of isoindolinones 7aa/8aa
122.62, 124.24, 127.42, 127.90, 128.54, 131.51, 132.45, 136.77,
138.24, 140.16, 168.04; m/z (EI) 280 (Mϩ, 100), 237 (25).
6ba/7ba. (Found: C, 75.63; H, 7.55. C12H14O2 requires C,
75.76; H, 7.42%); νmax/cmϪ1 1760, 1619 cmϪ1; δH (300 MHz;
CDCl3) (6ba) 0.94 (3 H, t, J 7.2), 1.30–1.42 (2 H, m), 1.58–1.67
(2 H, m), 2.74 (2 H, t, J 7.5), 5.28 (2 H, s), 7.58 (1 H, s), 7.34
(1 H, d, J = 7.8), 7.82 (1 H, d, J = 7.8); (7ba) 0.93 (3 H, t, J 7.2),
1.30–1.42 (2 H, m), 1.58–1.67 (2 H, m), 2.73 (2 H, t, J 7.5), 5.28
(2 H, s), 7.39 (1 H, d, J = 8.4), 7.50 (1 H, dd, J = 8.4 and 1.8),
7.73 (1 H, s); δC (75 MHz; CDCl3) (6ba) 13.88, 22.29, 33.40,
36.02, 69.42, 121.58, 125.31, 129.46, 146.90, 150.03, 170.92;
(7ae) 13.88, 22.16, 33.45, 35.25, 69.55, 121.68, 123.17, 124.86,
134.52, 143.89, 144.13, 170.92; m/z (FAB) 191 (MHϩ, 100), 147
(7).
To a degassed solution of Cp*RuCl(cod) 1 (1.9 mg, 0.005
mmol) and 1-hexyne 5a (164.3 mg, 2 mmol) in dry 1,2-dichloro-
ethane (2 cm3) was added a degassed solution of 4a (98.6 mg,
0.5 mmol) in dry 1,2-dichloroethane (3 cm3) by syringe over
15 min under Ar at room temperature. The reaction mixture
was stirred for 0.5 h. The solvent was evaporated, and the crude
products were purified by silica gel chromatography (hexane–
AcOEt 10 : 1) to give 7aa (34.7 mg, 25%) as a colorless solid
(mp. 61.1–61.8 ЊC). Further elution afforded 6aa (70.7 mg,
51%) as a colorless solid (mp. 59.5–60.2 ЊC; Found: C, 81.68; H,
7.73; N, 4.87. C19H21NO requires C, 81.68; H, 7.58; N, 5.01%);
νmax/cmϪ1 1679, 1624 cmϪ1; δH (300 MHz; CDCl3) (6aa) 0.92
(3 H, t, J 7.2), 1.26–1.42 (2 H, m), 1.55–1.66 (2 H, m), 2.68 (2 H,
t, J 7.5), 4.23 (2 H, s), 4.80 (2 H, s), 7.18 (1 H, s), 7.29–7.32 (6 H,
m), 7.82 (1 H, d, J 7.8 Hz); (7aa) 0.92 (3 H, t, J 7.2), 1.29–1.41
(2 H, m), 1.58–1.68 (2 H, m), 2.70 (2 H, t, J 7.5), 4.22 (2 H, s),
4.80 (2 H, s), 7.28–7.35 (7 H, m), 7.72 (1 H, s); δC (75 MHz;
CDCl3) (6aa) 13.96, 22.35, 33.66, 35.97, 46.38, 49.35, 122.47,
123.55, 127.45, 127.98, 128.35, 128.60, 130.11, 137.01, 141.43,
146.88, 168.40; (7aa) 13.98, 22.26, 33.70, 35.48, 46.46, 49.30,
122.34, 123.38, 127.48, 128.00, 128.62, 131.72, 132.58, 136.98,
138.49, 143.02, 168.51; m/z (FAB) 280 (MHϩ, 100), 202 (14).
6bc/7bc. (Found: C, 79.82; H, 4.96. C12H14O2 requires C,
79.98; H, 4.79%); νmax/cmϪ1 1762 cmϪ1; δH (300 MHz; CDCl3)
(6ba) 5.38 (2 H, s), 7.41–7.53 (3 H, m), 7.59–7.64 (2 H, m), 7.67–
7.68 (1 H, m), 7.73–7.77 (1 H, m), 7.98 (1 H, d, J = 8.1); (7bc)
5.38 (2 H, s), 7.38–7.53 (3 H, m), 7.57 (1 H, dd, J = 8.1, 0.8),
7.60–7.67 (2 H, m), 7.92 (1 H, dd, J = 8.1. 2.0), 8.14 (1 H, d,
J = 1.2); δC (75 MHz; CDCl3) (6ba) 69.56, 120.42, 124.23,
125.81, 127.31, 128.21, 128.44, 128.90, 139.39, 147.15, 170.72;
m/z (EI) 210 (Mϩ, 100), 181 (52), 153 (35).
6ca/7ca. (Found: C, 83.20; H, 9.40. C15H20O requires C,
83.28; H, 9.32%); νmax/cmϪ1 1704, 1609 cmϪ1; δH (300 MHz;
CDCl3); (6ca) 0.94 (3 H, t, J 7.2), 1.23 (6 H, s), 1.31–1.44 (2 H,
m), 1.56–1.68 (2 H, m), 2.68 (2 H, t, J 7.5), 2.96 (2 H, s), 7.19
(1 H, d, J 7.8), 7.22 (1 H, s), 7.67 (1 H, d, J = 7.8); (7ca) 0.92
(3 H, t, J 7.2), 1.23 (6 H, s), 1.31–1.44 (2 H, m), 1.56–1.68 (2 H,
m), 2.66 (2 H, t, J 7.5), 2.96 (2 H, s), 7.32 (1 H, d, J 7.8), 7.42
(1 H, dd, J = 7.8, 0.9), 7.57 (1 H, s); δC (75 MHz; CDCl3) (6ca)
13.98, 22.44, 25.40, 33.46, 36.19, 42.83, 45.61, 124.17, 126.15,
127.99, 135.43, 150.76, 152.49, 210.65; (7ca) 13.98, 22.28, 25.40,
33.59, 35.25, 42.59, 45.82, 123.59, 126.18, 133.10, 135.32,
142.26, 149.60, 210.65; m/z (FAB) 217 (MHϩ, 100), 147 (22).
6ab/7ab. (Found: C, 81.91; H, 7.47; N, 4.89. C19H21NO
requires C, 81.68; H, 7.58; N, 5.01%); νmax/cmϪ1 1679, 1626
cmϪ1; δH (300 MHz; CDCl3) (6ab) 1.34 (9 H, s), 4.25 (2 H, s),
4.80 (2 H, s), 7.27–7.36 (5 H, m), 7.39 (1 H, s), 7.51 (1 H, d,
J = 8.1), 7.82 (1 H, d, J = 8.1); (7ab) 1.37 (9 H, s), 4.25 (2 H, s),
4.82 (2 H, s), 7.27–7.36 (6 H, m), 7.57 (1 H, d, J 7.5), 7.94 (1 H,
s)]; δC (75 MHz; CDCl3) 13.96, 22.35, 33.66, 35.97, 46.38, 49.35,
122.47, 123.55, 127.45, 127.98, 128.35, 128.60, 130.11, 137.01,
141.43, 146.88, 168.40; m/z (FAB) 280 (MHϩ, 100), 249 (19).
6ac/7ac. (Found: C, 84.34; H, 5.83; N, 4.55. C21H17NO
requires C, 84.25; H, 5.72; N, 7.68%); νmax/cmϪ1 1681, 1672
cmϪ1; δH (300 MHz; CDCl3) (6ac) 4.33 (2 H, s), 4.83 (2 H,
s), 7.27–7.49 (8 H, m), 7.56–7.61 (3 H, m), 7.69 (1 H, dd,
J = 8.1 and 1.2), 7.96 (1 H, d, J = 8.1); (7ac) 4.31 (2 H, s), 4.84
(2 H, s), 7.28–7.50 (9 H, m), 7.63–7.66 (2 H, m), 7.76 (1 H, dd,
J = 7.1 and 1.5), 8.13 (1 H, d, J 1.5); δC (75 MHz; CDCl3) (6ac)
46.40, 49.45, 121.29, 123.97, 127.16, 127.19, 127.48, 127.79,
127.94, 128.60, 128.73, 131.28, 136.79, 140.17, 141.73, 144.47,
168.06; m/z (FAB) 280 (MHϩ, 100), 249 (19).
10aa. (Found: C, 81.87; H, 8.03; N, 4.64. C20H23NO requires
C, 81.87; H, 7.90; N, 4.77%); νmax/cmϪ1 1671 cmϪ1; δH (300
MHz; CDCl3) 0.92 (3 H, t, J 7.2), 1.28–1.41 (2 H, m), 1.53–1.64
(2 H, m), 2.62 (2 H, t, J 7.5), 2.73 (3 H, s), 4.17 (2 H, s), 4.76
(2 H, s), 6.98 (1 H, s), 7.01 (1 H, s), 7.27–7.32 (5 H, m);
δC (75 MHz; CDCl3) 13.96, 17.29, 22.37, 33.62, 35.76, 46.11,
48.79, 119.88, 127.22, 127.31, 127.94, 128.52, 130.22, 137.18,
137.21, 141.95, 146.29, 169.06; m/z (FAB) 294 (MHϩ, 100), 251
(16), 216 (70).
6ad/7ad. (Found: C, 76.50; H, 6.40; N, 5.13. C17H17NO2
requires C, 76.38; H, 6.41; N, 5.24%); νmax/cmϪ1 1682 cmϪ1
;
10ba/11ba. (Found: C, 76.39; H, 7.96. C13H16O2 requires C,
76.44; H, 7.90%); νmax/cmϪ1 1751 cmϪ1; δH (300 MHz; CDCl3)
(10ba) 0.93 (3 H, t, J 7.2), 1.29–1.42 (2 H, m), 1.56–1.66 (2 H,
m), 2.66 (3 H, s), 2.67 (2 H, t, J 7.8), 5.21 (2 H, s), 7.06 (1 H, s),
7.07 (1 H, s); (11ba) 0.94 (3 H, t, J 7.2), 1.29–1.42 (2 H, m),
1.56–1.66 (2 H, m), 2.66 (3 H, s), 2.67 (2 H, t, J 7.8), 5.19 (2 H,
s), 7.19 (1 H, d, J = 7.8), 7.41 (1 H, d, J = 7.8); δC (75 MHz;
CDCl3) (10ba) 13.93, 17.32, 22.34, 33.41, 35.87, 68.66, 118.93,
120.70, 130.91, 139.07, 147.38, 149.69, 171.09; m/z (EI) 204
(Mϩ, 20), 187 (100).
δH (300 MHz; CDCl3) (6ad) 3.41 (3 H, s), 4.26 (2 H, s), 4.53
(2 H, s), 4.80 (2 H, s), 7.27–7.43 (7 H, m), 7.82 (1 H, d, J = 7.8);
(7ad) 3.40 (3 H, s), 4.26 (2 H, s), 4.54 (2 H, s), 4.80 (2 H,
s), 7.27–7.43 (6 H, m), 7.52 (1 H, d, J 8.1), 7.85 (1 H, s);
δC (75 MHz; CDCl3) (6ad) 46.33, 49.32, 58.32, 74.16, 121.49,
123.62, 127.12, 127.45, 127.88, 128.57, 130.65, 136.77, 141.40,
141.98, 168.04; (7ad) 46.36, 49.27, 58.10, 74.06, 122.64, 122.79,
127.45, 127.91, 128.57, 131.78, 132.57, 136.77, 138.41, 140.43,
168.04; m/z (EI) 267 (Mϩ, 100), 236 (10), 190 (17), 176 (30), 163
(79).
13aa/14aa. (Found: C, 81.83; H, 7.93; N, 4.74. C20H23NO
6ae/7ae. (Found: C, 77.04; H, 7.58; N, 9.67. C18H20N2O
requires C, 81.87; H, 7.90; N, 4.77%); νmax/cmϪ1 1679 cmϪ1
;
requires C, 77.11; H, 7.19; N, 9.99%); νmax/cmϪ1 1682 cmϪ1
;
δH (300 MHz; CDCl3) (13aa) 0.94 (3 H, t, J 7.2), 1.33–1.45 (2 H,
m), 1.50–1.59 (2 H, m), 2.19 (3 H, s), 2.67 (2 H, t, J 7.5), 4.16
(2 H, s), 4.81 (2 H, s), 7.26 (1 H, d, J 8.1), 7.29–7.35 (5 H, m),
7.67 (1 H, d, J 8.1 Hz); (14aa) 0.92 (3 H, t, J 7.2), 1.28–1.41
(2 H, m), 1.56–1.67 (2 H, m), 2.24 (3 H, s), 2.67 (2 H, t, J 7.5),
4.13 (2 H, s), 4.81 (2 H, s), 7.13 (1 H, s), 7.26–7.35 (5 H, m), 7.55
(1 H, s); δC (75 MHz; CDCl3) (13aa) 14.05, 14.32, 22.75, 32.77,
33.11, 46.43, 49.04, 122.47, 123.55, 127.45, 127.98, 128.35,
δH (300 MHz; CDCl3) (6ae) 2.39 (6 H, s), 3.69 (2 H, s), 4.27
(2 H, s), 4.79 (2 H, s), 7.27–7.37 (6 H, m), 7.42 (1 H, d, J = 7.6),
7.85 (1 H, d, J = 7.6); (7ae) 2.45 (6 H, s), 3.81 (2 H, s), 4.27 (2 H,
s), 4.80 (2 H, s), 7.27–7.37 (6 H, m), 7.56 (1 H, s), 7.80 (1 H, s);
δC (75 MHz; CDCl3) (6ae) 45.21, 46.30, 49.27, 74.16, 63.96,
123.11, 123.44, 127.41, 127.88, 128.54, 128.80, 132.31, 136.81,
141.35, 142.27, 168.04; (7ae) 44.99, 46.33, 49.27, 74.06, 63.59,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 2 8 7 – 1 2 9 4
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128.60, 130.11, 137.01, 141.43, 146.88, 168.40; (7aa) 14.00,
17.56, 22.30, 33.77, 35.44, 46.44, 48.54, 120.89, 127.45, 127.97,
128.61, 131.94, 132.25, 132.69, 137.07, 137.44, 143.30, 168.88;
m/z (FAB) 294 (MHϩ, 100), 216 (13).
m), 2.81 (2 H, t, J 7.5), 7.30–7.51 (3 H, m), 7.91 (1 H, s), 8.05
(1 H, d, J 8.1), 8.09 (1 H, dd, J 7.8, 1.5), 8.32 (1 H, d, J 8.1);
(28ba) 0.95 (3 H, t, J 7.2), 1.32–1.48 (2 H, m), 1.65–1.76 (2 H,
m), 2.76 (2 H, t, J 7.5), 7.30–7.51 (5 H, m), 7.66 (1 H, dd, J 8.4,
1.8), 8.22 (1 H, d, J 1.8); δC (75 MHz; CDCl3) (27ba) 13.96,
22.41, 33.22, 36.26, 117.55, 118.00, 121.04, 122.54, 124.21,
129.32, 130.04, 130.37, 134.52, 135.27, 150.57, 151.18, 161.02;
m/z (EI) 252 (Mϩ, 100), 210 (78), 181 (57).
13ba/14ba. (Found: C, 76.25; H, 7.93. C13H16O2 requires C,
76.44; H, 7.90%); νmax/cmϪ1 1760 cmϪ1; δH (300 MHz; CDCl3)
(13ba) 0.92 (3 H, t, J 7.2), 1.28–1.40 (2 H, m), 1.53–1.66 (2 H,
m), 2.32 (3 H, s), 2.67 (2 H, t, J 7.8), 5.20 (2 H, s), 7.27 (1 H, s),
7.54 (1 H, s); (14ba) 0.95 (3 H, t, J 7.2), 1.36–1.46 (2 H, m),
1.51–1.62 (2 H, m), 2.25 (3 H, s), 2.71 (2 H, t, J 7.8), 5.22 (2 H,
s), 7.30 (1 H, d, J = 7.8), 7.66 (1 H, d, J = 7.8); δC (75 MHz;
CDCl3) (13ba) 13.95, 17.50, 22.24, 33.58, 35.26, 69.02, 122.34,
125.42, 130.25, 135.29, 142.95, 144.45, 171.53; m/z (EI) 204
(Mϩ, 100), 175 (96), 161 (91).
Synthesis of isoindoloisoquinoline 31
Synthesis of diyne 30. To a solution of trimethylsilylacetylene
(1.96 g, 20 mmol) in dry THF (39 cm3) was added a 1.6 M
hexane solution of nBuLi (12.8 cm3, 20 mmol) by a syringe
under Ar at Ϫ78 ЊC, and the solution was stirred for 30 min. To
this solution, BF3ؒOEt2 (2.84 g, 20 mmol) was added at Ϫ78 ЊC,
and the solution was stirred for 10 min. To this solution was
added a solution of dihydroisoquinoline 29 (1.91 g, 10 mmol) in
dry THF (6 cm3) at Ϫ78 ЊC, and the solution was stirred for 1 h
at this temperature, and for another 1 h at rt. The reaction was
quenched with 10% aqueous NaOH (30 cm3), and THF was
evaporated. The residue was then extracted with ether (20 cm3 ×
3). The combined organic layer was dried with K2CO3, and
concentrated in vacuo. The crude product was purified by silica
gel chromatography (hexane–AcOEt–MeOH 4 : 4 : 1) to give
trimethylsilylethynyltetrahydroisoquinoline (1.06 g, 40%) as
dark brown oil.
16aa/17aa. (Found: C, 82.26; H, 7.91; N, 4.63. C21H25NO
requires C, 82.04; H, 8.20; N, 4.56%); νmax/cmϪ1 1675 cmϪ1
;
δH (300 MHz; CDCl3) (16aa) 0.94 (3 H, t, J 7.2), 1.32–1.59 (4 H,
m), 2.13 (3 H, s), 2.62 (2 H, t, J 7.8), 2.70 (3 H, s), 4.11 (2 H, s),
4.78 (2 H, s), 6.99 (1 H, s), 7.29–7.37 (5 H, m); (17aa) 0.95 (3 H,
t, J 7.2), 1.32–1.59 (2 H, m), 2.19 (3 H, s), 2.65 (2 H, t, J 7.8),
2.73 (3 H, s), 4.06 (2 H, s), 4.78 (2 H, s), 7.06 (1 H, s), 7.29–7.37
(5 H, m), 7.55 (1 H, s); δC (75 MHz; CDCl3) (16aa) 13.73, 14.03,
16.93, 22.76, 32.83, 32.95, 46.13, 48.52, 126.95, 127.15, 127.32,
127.99, 128.55, 131.04, 134.49, 137.27, 141.11, 144.24, 169.61;
m/z (EI) 307 (Mϩ, 100), 250 (14), 216 (28).
The above obtained tetrahydroisoquinoline (950 mg, 3.5
mmol) was dissolved in MeOH (12 cm3) at room temperature,
and the solution was treated with KF (610 mg, 10.5 mmol) for
16 h. The reaction was quenched with aqueous NaHCO3 (15
cm3), and insoluble materials were removed by filtration
through a pad of Celite. After evaporation of MeOH, the resi-
due was extracted with AcOH (20 cm3 × 3), and the organic
layer was dried with K2CO3, and concentrated in vacuo. The
crude ethynyltetrahydroisoquinoline (626 mg, 82%) was sub-
mitted to the condensation with propiolic acid.
16ba/17ba. (Found: C, 76.92; H, 8.49. C14H18O2 requires C,
77.03; H, 8.31%); νmax/cmϪ1 1751 cmϪ1; δH (300 MHz; CDCl3)
(16ba) 0.96 (3 H, t, J 7.2), 1.34–1.61 (4 H, m), 2.19 (3 H, s), 2.61
(3 H, m), 2.66 (2 H, t, J 7.5), 5.16 (2 H, s), 7.05 (1 H, s); (17ba)
0.95 (3 H, t, J 7.2), 1.34–1.61 (4 H, m), 2.26 (3 H, s), 2.66 (2 H, t,
J 7.5), 5.12 (2 H, s), 7.20 (1 H, s); δC (75 MHz; CDCl3) (16ba)
13.65, 13.92, 16.81, 22.66, 32.52, 32.81, 68.36, 120.39, 126.76,
131.58, 136.15, 146.45, 147.40, 171.49; m/z (EI) 218 (Mϩ, 100),
203 (22), 189 (100).
To a solution of the above prepared ethynyltetrahydro-
isoquinoline (626 mg, 2.88 mmol), DCC (619 mg, 3.0 mmol),
and DMAP (36.7 mg, 0.3 mmol) in dry CH2Cl2 (5 cm3) was
added propiolic acid (210 mg, 3.0 mmol) at 0 ЊC. The reaction
mixture was stirred for 15 h at rt. After filtration of insoluble
materials, the solution was washed with aqueous NaHCO3
(20 cm3) and the aqueous layer was extracted with CHCl3
(20 cm3 × 3). The combined organic layer was dried with
K2CO3, and concentrated in vacuo. The crude product was
purified by silica gel chromatography (hexane–AcOEt 4 : 1–2 :
1) to give diyne 30 (228 mg, 30%) as a pale yellow solid (mp.
150.6–151.7 ЊC; Found: C, 66.94; H, 5.83; N, 4.96. C16H15NO3ؒ
H2O requires C, 66.89; H, 5.96; N, 4.88%); νmax/cmϪ1 3301,
2112, 1635 cmϪ1; δH (300 MHz; CDCl3) (syn/anti isomer mix-
ture with ca. 3 : 2 ratio) 2.36 and 2.47(1 H, d, J 2.4), 2.70–3.05
(2 H, m), 3.16 and 3.25 (1 H, s), 3.27–3.37 and 3.69–3.79 (1 H,
m), 3.56 and 3.87 (3 H, s), 3.87 and 3.90 (3 H, s), 4.44–4.54 and
4.57–4.66 (1 H, m), 6.09 and 6.21 (1 H, br s), 6.59 and 6.62 (1 H,
s), 6.76 and 6.77 (1 H, s); δC (75 MHz; CDCl3) 27.24 and 28.35,
36.48 and 41.70, 43.50 and 49.08, 55.79, 55.87 and 55.91, 71.55,
72.72 and 74.97, 79.32 and 80.19, 81.55 and 81.64, 109.25 and
109.52, 111.05 and 111.23, 123.96 and 124.08, 124.57 and
125.39, 147.79 and 147.93, 148.32 and 148.46, 151.39 and
151.48; m/z (EI) 269 (Mϩ, 100), 240 (50), 226 (25).
19aa/20aa. (Found: C, 82.15; H, 8.02; N, 4.49. C20H23NO
requires C, 81.87; H, 7.90; N, 4.77%); νmax/cmϪ1 1678 cmϪ1
;
δH (300 MHz; CDCl3) (19aa) 0.92 (3 H, t, J 7.2), 1.29–1.42 (2 H,
m), 1.42 (3 H, d, J 6.6), 1.56–1.66 (2 H, m), 2.69 (2 H, t, J 7.8),
4.24 (1 H, d, J 15), 4.33 (1 H, q, J 6.6), 5.33 (1 H, d, J 15), 7.15
(1 H, s), 7.24–7.34 (6 H, m), 7.79 (1 H, d, J 7.8); (20aa) 0.93
(3 H, t, J 7.2), 1.29–1.43 (2 H, m), 1.41 (3 H, d, J 6.9), 1.58–1.68
(2 H, m), 2.70 (2 H, t, J 7.5), 4.25 (1 H, d, J 15.3), 4.34 (1 H, q,
J 6.9), 5.33 (1 H, d, J 15.3), 7.24–7.32 (6 H, m), 7.34 (1 H, dd,
J 7.8, 1.5), 7.71 (1 H, d, J 0.6); δC (75 MHz; CDCl3) (19aa)
13.94, 18.08, 22.36, 33.66, 36.02, 43.62, 54.77, 121.63, 123.41,
127.28, 127.84, 128.34, 128.50, 129.11, 137.22, 147.01, 147.15,
167.92; m/z (EI) 293 (Mϩ, 100), 278 (44), 216 (25), 189 (24).
27aa/28aa. (Found: C, 84.23; H, 7.06; N, 4.02. C24H23NO
requires C, 84.42; H, 6.79; N, 4.10%); νmax/cmϪ1 1643 cmϪ1
;
δH (300 MHz; CDCl3) (27aa) 0.98 (3 H, t, J 7.2), 1.37–1.50 (2 H,
m), 1.68–1.78 (2 H, m), 2.84 (2 H, t, J 7.8), 5.67 (2 H, s), 7.21–
7.31 (7 H, m), 7.36–7.47 (1 H, m), 7.46 (1 H, dd, J 8.1, 1.5), 8.10
(1 H, s), 8.31 (1 H, d, J 8.1), 8.53 (1 H, d, J 7.8); (28aa) 0.96
(3 H, t, J 7.2), 1.34–1.47 (2 H, m), 1.66–1.74 (2 H, m), 2.81 (2 H,
t, J 7.8), 5.68 (2 H, s), 7.20–7.33 (7 H, m), 7.34–7.40 (1 H, m),
7.63 (1 H, dd, J 8.1, 1.8), 8.23 (1 H, d, J 8.7), 8.27 (1 H, dd,
J 8.1, 1.5), 8.43 (1 H, d, J 1.8); δC (75 MHz; CDCl3) (27aa)
14.03, 22.46, 33.49, 36.26, 46.33, 115.86, 119.44, 120.99, 122.24,
123.06, 123.19, 126.36, 126.96, 128.60, 128.66, 129.04, 129.20,
133.64, 136.55, 137.27, 147.93, 161.68; m/z (EI) 341 (Mϩ, 100),
264 (7), 235 (43).
Cp*RuCl(cod)-catalyzed reaction of 30 with acetylene. To a
degassed solution of Cp*RuCl(cod) 1 (1.1 mg, 0.003 mmol) in
dry 1,2-dichloroethane (1 cm3) was added a degassed solution
of 30 (88.6 mg, 0.3 mmol) in dry 1,2-dichloroethane (2 cm3) by
a syringe over 15 min under acetylene atmosphere at room tem-
perature. The reaction mixture was stirred for 0.5 h. The solvent
was evaporated, and the crude products were purified by silica
gel chromatography (hexane/AcOEt 1:1) to give 31 (71.9 mg,
27ba/28ba. (Found: C, 80.98; H, 6.34. C17H16O2 requires C,
80.93; H, 6.39%); νmax/cmϪ1 1726 cmϪ1; δH (300 MHz; CDCl3)
(27ba) 0.97 (3 H, t, J 7.2), 1.32–1.48 (2 H, m), 1.65–1.76 (2 H,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 2 8 7 – 1 2 9 4
1293

View Article Online
82%) as pink solids (mp. 172.6–173.4 ЊC, lit12 mp. 173 ЊC);
νmax/cmϪ1 1683 cmϪ1; δH (300 MHz; CDCl3) 2.77 (1 H, dt,
J 15.6, 3.9), 2.96–3.07 (1 H, m), 3.42 (1 H, ddd, J 13.2, 10.2,
4.5), 3.85 (3 H, s), 3.94 (3 H, s), 4.51 (1 H, ddd, J 12.9, 6, 3.6),
5.63 (1 H, s), 6.67 (1 H, s), 7.12 (1 H, s), 7.50 (1 H, t, J 7.5 Hz),
7.61 (1 H, dt, J 7.5, 1), 7.83 (1 H, dd, J 7.5, 0.6), 7.89 (1 H, dd,
J 7.5, 1); δC (75 MHz; CDCl3) 29.02, 38.13, 55.85, 56.13, 58.88,
108.50, 111.77, 122.84, 123.70, 125.79, 126.69, 128.23, 131.34,
132.51, 144.40, 147.60, 148.08, 167.60.
6 D. M. Duckworth, S. Lee-Wong, A. M. Z. Slawin, E. H. Smith and
D. J. Williams, J. Chem. Soc., Perkin Trans. 1, 1996, 815.
7 The Ni- and Rh-catalyzed cycloadditions of similar ester-diynes
have been reported, see: Y. Sato, K. Ohashi and M. Mori,
Tetrahedron Lett., 1999, 40, 5231; B. Witulski and A. Zimmermann,
Synlett, 2002, 1855.
8 The major isomers were tentatively assigned to 16 in the light of the
regioselectivity observed for other cases.
9 K. Kirchner, M. J. Calhorda, R. Schmid and L. F. Veiros, J. Am.
Chem. Soc., 2003, 125, 11721.
10 M. Paneque, M. L. Poveda, N. Rendón and K. Mereiter, J. Am.
Chem. Soc., 2004, 126, 1610.
11 E. Valencia, A. J. Freyer and M. Shamma, Tetrahedron Lett., 1984,
25, 599.
12 R. Alonso, L. Castedo and D. Domínguez, Tetrahedron Lett., 1985,
26, 2925.
Computational methods
The Q-chem 2.0 program15 in Spartan ’02 software package16
was used for geometry optimizations, and the NBO calculations
for the obtained geometries were performed with the Gaussian
98 program package.17 All geometries of ruthenacycles were
fully optimized by the Becke’s three-parameter hybrid density
functional method (B3LYP)18 with the LACVP* basis set. The
LACVP* basis set uses a double-ζ basis set with the relativistic
effective core potential of Hay and Wadt (LanL2 ECP)19 for Ru
and the 6-31G(d) basis sets20 for other elements. The NBO
calculations21 were performed at the same level of theory.
13 W. M. Whaley and T. R. Govindachan, Org. React., 1951, 6, 74.
14 N. Oshima, H. Suzuki and Y. Moro-oka, Chem. Lett., 1984,
1161.
15 J. Kong, C. A. White, A. I. Krylov, D. Sherrill, R. D. Adamson, T. R.
Furlani, M. S. Lee, A. M. Lee, S. R. Gwaltney, T. R. Adams,
C. Ochsenfeld, A. T. B. Gilbert, G. S. Kedziora, V. A. Rassolov,
D. R. Maurice, N. Nair, Y. Shao, N. A. Besley, P. E. Maslen,
J. P. Dombroski, H. Daschel, W. Zhang, P. P. Korambath, J. Baker,
E. F. C. Byrd, T. V. Voorhis, M. Oumi, S. Hirata, C.-P. Hsu,
N. Ishikawa, J. Florian, A. Warshel, B. G. Johnson, P. M. W.
Gill, M. Head-Gordon and J. A. Pople, J. Comp. Chem., 2000, 21,
1532.
Acknowledgements
16 Spartan ’02, version 1.0.2, Wavefunction, Inc., Irvine, CA, 2002.
17 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A.
Robb, J. R. Cheeseman, V. G. Zakrzewski, J. A. Montgomery, Jr.,
R. E. Stratmann, J. C. Burant, S. Dapprich, J. M. Millam, A. D.
Daniels, K. N. Kudin, M. C. Strain, O. Farkas, J. Tomasi, V. Barone,
M. Cossi, R. Cammi, B. Mennucci, C. Pomelli, C. Adamo,
S. Clifford, J. Ochterski, G. A. Petersson, P. Y. Ayala, Q. Cui,
K. Morokuma, P. Salvador, J. J. Dannenberg, D. K. Malick, A. D.
Rabuck, K. Raghavachari, J. B. Foresman, J. Cioslowski, J. V. Ortiz,
A. G. Baboul, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz,
I. Komaromi, R. Gomperts, R. L. Martin, D. J. Fox, T. Keith, M. A.
Al-Laham, C. Y. Peng, A. Nanayakkara, M. Challacombe, P. M. W.
Gill, B. G. Johnson, W. Chen, M. W. Wong, J. L. Andres,
C. Gonzalez, M. Head-Gordon, E. S. Replogle and J. A. Pople,
GAUSSIAN 98 (Revision A.11), Gaussian, Inc., Pittsburgh, PA,
2001.
We gratefully acknowledge financial support (14750677)
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
References and notes
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O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 2 8 7 – 1 2 9 4
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