Ruthenium-catalyzed C-H/O-H and C-H/N-H bond functionalizations: Oxidative annulations of cyclopropyl-substituted alkynes

Article abstract of DOI:10.1039/c2ob26250a

The chemical behavior of cyclopropyl-substituted alkynes has been probed using the reaction conditions of ruthenium-catalyzed oxidative C-H/O-H and C-H/N-H bond functionalizations. The oxidative annulations proceeded with complete conservation of all cyclopropane fragments and allowed for the one-step preparation of synthetically useful cyclopropyl-substituted isocoumarins and isoquinolones with high regioselectivities and chemical yields. The connectivities of the key heterocyclic products were unambiguously established by X-ray diffraction analysis. The Royal Society of Chemistry.

Full text of DOI:10.1039/c2ob26250a

Organic &
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Ruthenium-catalyzed C–H/O–H and C–H/N–H bond
functionalizations: oxidative annulations of
cyclopropyl-substituted alkynes†
Cite this: Org. Biomol. Chem., 2013, 11,
142
Monica Deponti,a Sergei I. Kozhushkov,a Dmitry S. Yufitb and Lutz Ackermann*a
The chemical behavior of cyclopropyl-substituted alkynes has been probed using the reaction conditions
of ruthenium-catalyzed oxidative C–H/O–H and C–H/N–H bond functionalizations. The oxidative annula-
tions proceeded with complete conservation of all cyclopropane fragments and allowed for the one-step
preparation of synthetically useful cyclopropyl-substituted isocoumarins and isoquinolones with high
regioselectivities and chemical yields. The connectivities of the key heterocyclic products were unambigu-
ously established by X-ray diffraction analysis.
Received 1st July 2012,
Accepted 11th October 2012
DOI: 10.1039/c2ob26250a
www.rsc.org/obc
pyridones, many of which possess valuable biological activi-
Introduction
ties3a–e and represent key structural scaffolds of naturally
Transition metal-catalyzed reactions have matured to being occurring compounds.3f–l Consequently, a number of valuable
among the most powerful tools in organic chemistry.1 Particu- protocols for intermolecular oxidative annulations with
larly, direct functionalizations2 of aromatic C–H bonds have alkynes 2 have been developed,4,5 with ruthenium-catalyzed4
received considerable recent attention as ecologically and cyclizations being among the most promising.
economically friendly synthetic methods, that avoid the use of
The attachment of a cyclopropyl fragment to heterocyclic
prefunctionalized starting materials. Yet, an even more sus- molecules frequently modifies their pharmacological proper-
tainable strategy is represented by the simultaneous transition ties and significantly enhances their biological activities.6 For
metal-catalyzed C–H/O–H or C–H/N–H bond functionalizations instance, a number of well-known antibacterial agents, such as
utilizing arenes or alkenes 1 (Scheme 1).
Ciprofloxacin, Sparfloxacin, Grepafloxacin and WIN-57294,
This approach allowed for the one-pot preparation of syn- contain a 1-cyclopropylquinolin-4(1H)-one moiety.6e,f However,
thetically useful heterocycles 3, such as substituted isoquinoli- the inherently high molecular strain in cyclopropanes
nones, isoquinolones, isocoumarins, α-pyrones and 2- (28.1 kcal mol−1)7 is reflected by some specificity to the chem-
istry of cyclopropane-containing molecules. As a consequence,
metal-mediated or -catalyzed reactions with participation of
(cyclopropylcarbinyl) metal intermediates proceeded almost
exclusively via opening of at least one cyclopropane ring,8
whereas formation of cyclopropane-containing compounds
was observed as a side reaction only. Given the remarkable bio-
logical activity of cyclopropyl-decorated heterocycles along
with the challenges associated with the use of cyclopropyl-sub-
Scheme 1 Oxidative annulations by C–H/O–H or C–H/N–H bond
stituted alkynes 2 in transition-metal catalysis, we, thus,
became attracted to exploring their unprecedented oxidative
annulations by metal-catalyzed C–H/Het–H bond functionali-
zation with rather inexpensive ruthenium catalysts, on which
we wish to report herein.
functionalizations.
aInstitut für Organische und Biomolekulare Chemie der Georg-August-Universität
Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany.
E-mail: lutz.ackermann@chemie.uni-goettingen.de; Fax: +49 (551) 396777
bDepartment of Chemistry, University of Durham, Durham, South Rd., DH1 3LE, UK.
E-mail: d.s.yufit@durham.ac.uk
†Electronic supplementary information (ESI) available: Experimental details of
syntheses and X-ray diffraction, 1H NMR spectra and 13C NMR spectra of new
Results and discussion
compounds. CCDC 901337 (6aa), 901338 (6ae), 901339 (7aa), 901340 (8aa) and
901341 (8ah). For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c2ob26250a
To elucidate the synthetic versatility of the transformation as
well as the influence and reactivity of cyclopropyl substituents
142 | Org. Biomol. Chem., 2013, 11, 142–148
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reaction manifold. Thus, the highest yield was observed for
the alkyne 2a in the reaction with the acid 4c, while the yield
decreased with alkyne 2e possessing an electron-withdrawing
substituent. However, the influence of the substituents in
benzoic acids 4 was found to be less pronounced.
No product formation was observed in the reactions of sub-
strate 4a with alkyne 2d and when using starting materials 4d
and 2a, while the corresponding isocoumarin 6dk was formed
in the reaction of 4d with diethylethyne in 31% yield.†
The influence of the cyclopropyl moieties upon the course
of chemical transformations by the stabilization of key reac-
tion intermediates due to conjugation is well documented.9
However, several representative experiments with p-anisic acid
(4b) and selected alkynes 2 (Table 1) indicated the cyclopropyl
substituents in the alkynes 2 to translate into a reduction of
their reactivity (entry 1), but demonstrated no significant influ-
ence onto the regioselectivity of the annulation. Indeed, the
Fig. 1 Substituted ethynylcyclopropanes 2, benzoic acids 4 and benzamides 5
used in C–H/Het–H bond functionalizations.
reaction with (pent-1-ynyl)cyclopropane (2h) furnished
a
in the alkynes 2, we set out to perform detailed synthetic and
structural studies on atom- and step-economical ruthenium-
catalyzed C–H/O–H and C–H/N–H bond functionalizations of
representative benzoic acids 4a–d and benzamides 5a–i with
various cyclopropylacetylenes 2 (Fig. 1).
We initiated our studies by exploring the reactivity of substi-
tuted benzoic acids 4 and cyclopropylarylethynes 2 in ruthe-
nium-catalyzed oxidative annulations4f (Scheme 2). Notably,
arylalkynes displaying a cyclopropyl substituent yielded the
desired product through the C–H/O–H bond functionalizations
1 : 1 mixture of the two regioisomeric isocoumarins 6bh and
7bh (entry 2), thereby indicating a negligible effect of steric
interactions10 in these annulations. Furthermore, the elec-
tronic effect of the cyclopropane appeared to be of less impor-
tance for the overall regioselectivity.
It is noteworthy that the rhodium-catalyzed annulation of
unsymmetrically substituted arylalkyl alkynes Alk–CuC–Ar
delivered mixtures of 3- and 4-arylsubstituted regioisomeric
products11,12 in ratios of 6 : 1 to 8 : 1.5i,j In spite of the pre-
viously reported almost exclusive formation of 3-arylsubsti-
tuted products,4e the cyclization of alkyne 2i afforded in our
hands heterocycles 7bi and 6bi in a ratio of 9.4 : 1 (Table 1,
entry 3).
In the ruthenium-catalyzed cyclizations of unsymmetrical
cyclopropylacetylenes the ratios of regioisomeric products 6
and 7 varied from 1 : 1 to 13 : 1 (Scheme 2 and Table 1). To
Table 1 Ruthenium-catalyzed C–H/O–H bond functionalizations with p-anisic
acid (4b) and selected substituted alkynes 2
Entry Alkyne R1
R2
Product 6/yield (%) Product 7/yield (%)
Scheme 2 Ruthenium-catalyzed C–H/O–H bond functionalizations with
1
2
3
2g
2h
2i
cPr cPr 6bg = 7bg
cPr nPr
7bg/27
6bh/7bh 1 : 1/53
7bi/5
benzoic acids 4 and (cyclopropylethynyl)benzenes 2. a[RuCl2(p-cymene)]2 (5 mol
Et
Ph
6bi/47
%).
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Fig. 2 Molecular structures of isocoumarins 6aa, 6ae and 7aa in the crystal13
(numbering does not correspond to the IUPAC rules).
elaborate spectroscopic criteria† for this group of cyclopropyl-
substituted heterocycles, the structures of cyclopropyliso-
coumarins 6aa, 6ae and 7aa have been unambiguously established
by X-ray diffraction analysis (Fig. 2). Notably, both 3-aryl-4-
cyclopropyl-substituted heterocycles 6aa and 6ae adopted
essentially the same conformations with the dihedral angles
C1–C2–C3–center (C4–C5) being equal to −99.5° and −96.8°,
respectively, while the dihedral angles between heterocyclic
and carbocyclic aromatic moieties were found to be 47.3 and
37.6°, respectively. In contrast, in 7aa the dihedral angle C1–
C2–C3–centre (C4–C5) = 179.4° with the angle between aro-
matic planes of 66.5°, i.e. with almost ideal conditions for the
conjugation of cyclopropyl and isocoumarin fragments.†
Somewhat similar tendencies were observed in ruthenium-
catalyzed C–H/N–H bond functionalizations in benzamides 5
with (cyclopropylethynyl)benzenes 2, the results of which are
summarized in Scheme 3. Generally, the oxidative annulations
occurred with high yields and synthetically useful regioselec-
tivity. While the catalytic system displayed a high functional
group tolerance, the attempted cyclization of amide 5a with
cyclopropylnaphthylalkyne 2d gave less satisfactory results.†
Furthermore, cyclopropylaryl alkynes 2c and 2e possessing
electron-withdrawing substituents on the aromatic rings deliv-
ered the corresponding products 8ac and 8ae, respectively, in
somewhat lower yield. However, a number of oxidative cycliza-
tions, including the reaction of the parent compounds 2a and
5a, proceeded in a regiospecific manner affording only regio-
isomers 8 (8aa, 8ac, 8ae, 8af and 8ca), while in the other cases
the ratio of heterocycles 8 and 9 varied from 9.8 (8ia) to 3.6
(8ab). Surprisingly, the best yield (83%) was obtained when uti-
lizing dicyclopropylacetylene (2g), which was less reactive in
the ruthenium-catalyzed isocoumarin synthesis (vide supra).
Unfortunately, the attempted synthesis of N-cyclopropyl-3(4)-
cyclopropylisoquinolones 8ea and 9ea occurred less efficiently.
Moreover, the benzamide 5e did not react with diphenylacety-
lene (tolane) under otherwise identical reaction conditions.
Remarkably, the nitrogen substituent had a considerable
effect on the outcome of the annulation. Thus, N-Me- (5a),
Scheme 3 Ruthenium-catalyzed C–H/N–H bond functionalizations in benza-
mides 5 with (cyclopropylethynyl)benzenes 2.
N-Et- (5b), N-nBu- (5d) and N-iso-propylbenzamides (5c) furn-
ished the corresponding isoquinolones 8 and 9 in the reac-
tions with the alkyne 2a in 71, 39, 39 and 23% yield,
respectively. This is in line with the values of steric substituent
constants of these alkyl groups, which are equal to 0, 0.86,
0.86 and 2.29, respectively.10 Yet, in contrast to the synthesis
of isocoumarins, the reaction of cyclopropyl-n-propyl alkyne
(2h) with benzamide 5a afforded a 2.75 : 1 mixture of 3-cyclo-
propyl (9ah) and 4-cyclopropylisoquinolones (8ah) (Scheme 3),
in spite of the steric substituent constants being equal to 0.89
(n-propyl) and 1.33 (cyclopropyl).10
The exact connectivities of the parent isoquinolone 8aa and
of the fundamentally important compound 8ah have been
established by X-ray diffraction analysis (Fig. 3). As for the
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Conclusions
In summary, we have examined the behavior of cyclopropyl-
substituted acetylenes in the ruthenium-catalyzed oxidative
C–H/O–H and C–H/N–H bond functionalizations and have
found these reactions to proceed with complete conservation
of all cyclopropane fragments. Thereby, these cyclizations
allowed the one-step preparation of synthetically useful cyclo-
propyl-substituted isocoumarins and isoquinolones in high
yields and regioselectivities.15
Experimental
Syntheses: general methods
Catalytic reactions were carried out using pre-dried glassware.
Triethylamine and tAmOH were distilled over CaH2 and
sodium, respectively. Anhydrous THF was obtained by distilla-
tion over sodium benzophenone ketyl. (Cyclopropylethynyl)
benzene (2a), 1-(cyclopropylethynyl)-3-methylbenzene (2b),
methyl 4-(cyclopropylethynyl)benzoate (2c), 1-(cyclopropylethy-
nyl)naphthalene (2d), 1-(cyclopropylethynyl)-4-methoxylben-
zene (2f), the previously unknown 1-(cyclopropylethynyl)-3-
(trifluoromethyl)benzene (2e), (pent-1-ynyl)cyclopropane (2h),
1,2-dicyclopropylethyne (2g), N-cyclopropylbenzamide (5e),
N,3-dimethylbenzamide (5f), 4-chloro-N-methylbenzamide
(5g), 4-methoxy-N-methylbenzamide (5h), 4-fluoro-N-methyl-
benzamide (5i) and [RuCl2(p-cymene)]2 were synthesized as
indicated in the ESI.† Other chemicals were obtained from
commercial sources and were used without further purifi-
cation. Yields refer to isolated compounds, estimated to be
>95% pure as determined by 1H-NMR and GC. TLC: Macherey-
Nagel, TLC plates Alugram® Sil G/UV254. Detection under UV
light at 254 nm. Chromatography: Separations were carried out
on Merck Silica 60 (0.040–0.063 mm, 70–230 mesh ASTM). All
IR spectra were recorded on a BRUKER ALPHA-P spectrometer.
MS: EI-MS: Finnigan MAT 95, 70 eV; ESI-MS: Finnigan LCQ.
High resolution mass spectrometry (HRMS): APEX IV 7T
FTICR, Bruker Daltonic. M.p.: Stuart® Melting Point Apparatus
SMP3 melting point apparatus, values are uncorrected. 1H,
13C, 19F NMR-spectra were recorded at 300 (1H), 75.5 {13C, APT
(Attached Proton Test)} and 283 MHz (19F), respectively, on a
Varian Unity-300 instrument.
Fig. 3 Molecular structures of isoquinolones 8aa and 8ah in the crystal13
(numbering does not correspond to the IUPAC rules).
Scheme 4 Regiochemistry-determining step of the ruthenium-catalyzed C–H/
Het–H and C–H/N–H bond functionalizations.
analogous isocoumarins 6aa and 6ae, heterocycles 9aa and
9ah adopted essentially the same conformations with the dihe-
dral angles C1–C2–C3–center (C4–C5) equal to 94.7° and
91.7°, respectively, i.e. without steric preconditions for conju-
gation, while the dihedral angle between heterocyclic and
phenyl aromatic moieties in 8aa was determined to be 63.2°.
It is particularly noteworthy that all the ruthenium-cata-
lyzed oxidative C–H/Het–H bond functionalizations proceeded
with complete conservation of all cyclopropane fragments.8,14
As a consequence, cyclopropylethynes can be utilized in ruthe-
nium-catalyzed C–H/Het–H bond functionalizations for the
preparation of valuable cyclopropyl-substituted heterocycles.
According to the mechanistic rationalizations generally
accepted for ruthenium-catalyzed C–H/Het–H bond functiona-
lization with alkynes,4a,b,d–g the regiochemistry-determining
step of these oxidative reactions is constituted by the insertion
of alkyne 2 into the ruthenium–carbon bond of key intermedi-
ate 10 to give the seven-membered ruthenacycle 11 (Scheme 4).
Thus, the observed regioselectivities can for instance be ration-
alized by the enhanced thermodynamic stability of regio-
isomer 11, in which the aryl substituent is in the neighboring
position to the ruthenium.
Synthesis of cyclopropyl-substituted isocoumarins 6 and 7
GENERAL PROCEDURE FOR RUTHENIUM-CATALYZED C–H/O–H BOND FUNC-
TIONALIZATIONS IN BENZOIC ACIDS 4 WITH ETHYNYLBENZENES 2. A suspen-
sion of acid 4 (2.00 mmol), alkyne 2 (1.00 mmol), [RuCl2(p-
cymene)]2 (15.5 mg, 2.5 mol%), KPF6 (36.8 mg, 20 mol%) and
Cu(OAc)2·H2O (300 mg, 1.50 mmol) in tAmOH (3.0 mL) was
stirred at 120 °C for 16 h. After cooling to ambient tempera-
ture, the reaction mixture was diluted with sat. aq. NH4Cl–NH3
solution (1 : 1, 50 mL) and extracted with EtOAc (4 × 25 mL).
The combined organic layers were washed with NH4Cl–NH3
solution (1 : 1, 2 × 20 mL) and dried over MgSO4. After fil-
tration and concentration of the solution under reduced
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pressure, the crude product was purified by column chromato- 131.9 (CH), 131.1 (CH), 129.0 (CH), 128.0 (C), 115.1 (C), 114.6
graphy on silica gel (n-hexane–EtOAc 25 : 1) to yield 6 and 7 as (CH), 113 0 (C), 107.1 (CH), 55.6 (CH3), 12.2 (CH), 7.8 (CH2); IR
colorless solids.
(ATR): 3009, 2925, 1713, 1600, 1231, 1044, 849, 723 cm−1; MS
4-CYCLOPROPYL-3-PHENYL-1H-ISOCHROMEN-1-ONE (6AA) AND 3-CYCLO- (EI) m/z (%): 292 (M+, 100), 277 (32), 264 (55), 195 (35), 152
PROPYL-4-PHENYL-1H-ISOCHROMEN-1-ONE (7AA). According to the (50); HRMS (EI) calcd for C19H16O3 (M+) 292.1099, found
general procedure, benzoic acid (4a) (490 mg, 4.0 mmol), 292.1105.
alkyne (2a) (284 mg, 2.0 mmol), [RuCl2(p-cymene)]2 (62.0 mg,
100 μmol), KPF6 (73 mg, 0.4 mmol) and Cu(OAc)2·H2O
Synthesis of cyclopropyl-substituted isoquinolones 8 and 9
(599 mg, 3.0 mmol) yielded compounds 6aa (353 mg, 67%)
GENERAL PROCEDURE FOR RUTHENIUM-CATALYZED C–H/N–H BONDS
and 7aa (64 mg, 11%) as colorless solids. 6aa: m.p. = FUNCTIONALIZATIONS IN BENZAMIDES 5 WITH (CYCLOPROPYLETHYNYL)BEN-
1
115–117 °C; H NMR (300 MHz, CDCl3) δ = 8.33 (dd, J = 8.0, ZENES 2. A mixture of benzamide 5 (0.50 mmol), acetylene 2
1.4 Hz, 1H), 8.12 (d, J = 8.2, 1H), 7.78 (td, J = 7.7, 1.41 Hz, 1H), (1.00 mmol), [RuCl2(p-cymene)]2 (15.3 mg, 25 μmol, 5.0 mol%)
7.76–7.72 (m, 2H), 7.50 (td, J = 7.7, 1.1 Hz, 1H), 7.46–7.37 (m, and Cu(OAc)2·H2O (200 mg, 1.00 mmol) in tAmOH (2.0 mL)
3H), 1.91 (tt, J = 8.1, 5.5 Hz, 1H), 1.00–0.87 (m, 2H), 0.26–0.06 was stirred at 100 °C under a nitrogen atmosphere for 22 h.
(m, 2H); 13C NMR (75 MHz, CDCl3) δ = 162.4 (C), 153.4 (C), After cooling the mixture to ambient temperature, the reaction
139.7 (C), 134.4 (CH), 133.2 (C), 129.5 (CH), 129.4 (CH), 129.3 mixture was diluted with aq. NH3 solution (75 mL, 1.0 wt%)
(CH), 127.8 (CH), 127.7 (CH), 124.5 (CH), 120.6 (C), 114.5 (C), and extracted with EtOAc (3 × 75 mL). The combined organic
9.9 (CH2), 9.0 (CH); IR (ATR): 3011, 2961, 2922, 2855, 1718, phase was washed with brine (50 mL) and dried over Mg2SO4.
1629, 1078, 700 cm−1; MS (EI) m/z (%): 262 (M+, 100), 247 (50), After filtration and concentration of the solution under
234 (35), 165 (65), 69 (25); HRMS (EI) m/z calcd for C18H14O2 reduced pressure, the crude product was purified by column
(M+) 262.0994, found 262.0988.
7aa: m.p. = 100–102 °C; 1H NMR (300 MHz, CDCl3) δ = 8.20 and 9 as colorless solids.
(dd, J = 7.9, 1.6 Hz, 1H), 7.57–7.33 (m, 7H), 6.95 (ddd, J = 8.1,
chromatography on silica gel (n-hexane–EtOAc 4 : 1) to yield 8
4-CYCLOPROPYL-2-METHYL-3-PHENYLISOQUINOLIN-1(2H)-ONE
(8AA).
1.1, 0.5 Hz, 1H), 1.70–1.56 (m, 1H), 1.21–1.12 (m, 2H), According to the general procedure, N-methylbenzamide (5a)
0.81–0.70 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.0 (C), 154.2 (135 mg, 1.0 mmol), alkyne 2a (284 mg, 2.0 mmol), [RuCl2(p-
(C), 138.8 (C), 134.4 (CH), 134.2 (C), 131.0 (2CH), 129.3 (CH), cymene)]2 (31 mg, 50 μmol), and Cu(OAc)2·H2O (399 mg,
128.8 (CH), 127.9 (CH), 126.7 (CH), 123.9 (CH), 119.5 (C), 115.0 2.0 mmol) yielded 8aa (185 mg, 71%) after column chromato-
(C), 12.0 (CH), 7.6 (CH2); IR (ATR): 3084, 3049, 3008, 2984, graphy as a colorless solid, m.p. = 139–141 °C; 1H NMR
1727, 1604, 1075, 672 cm−1; MS (EI) m/z (relative intensity): (300 MHz, CDCl3) δ = 8.49 (ddd, J = 8.0, 1.5, 0.6 Hz, 1H), 8.19
262 (M+, 50), 217 (45), 185 (40), 105 (55), 77 (100); HRMS (EI) (ddd, J = 8.3, 1.2, 0.6 Hz, 1H), 7.68 (ddd, J = 8.4, 7.1, 1.5 Hz,
calcd for C18H14O2 (M+) 262.0994, found 262.0996.
1H), 7.51–7.39 (m, 4H), 7.31–7.27 (m, 2H), 3.28 (s, 3H), 1.62 (tt,
The connectivities of compounds 6aa and 7aa were estab- J = 8.3, 5.6 Hz, 1H), 0.69–0.55 (m, 2H), 0.17–0.05 (m, 2H); 13C
lished by X-ray crystal structure analysis.13
NMR (75 MHz, CDCl3) δ = 162.8 (C), 142.9 (C), 138.0 (C), 135.7
4-CYCLOPROPYL-6-METHOXY-3-PHENYL-1H-ISOCHROMEN-1-ONE
(6BA) (C), 133.7 (CH), 129.9 (CH), 128.4 (CH), 128.4 (CH), 127.9 (CH),
AND 3-CYCLOPROPYL-6-METHOXY-4-PHENYL-1H-ISOCHROMEN-1-ONE (7BA). 126.2 (CH), 125.1 (C), 124.4 (CH), 115.0 (C), 34.2 (CH3), 10.5
According to the general procedure, p-anisic acid (4b) (152 mg, (CH), 8.7 (CH2); IR (ATR): 3081, 2994, 2957, 2924, 1643, 1587,
4.0 mmol), alkyne 2a (284 mg, 2.0 mmol), [RuCl2(p-cymene)]2 1025, 759 cm−1. MS (EI) m/z (%): 275 (M+, 32), 274 (100), 246
(31 mg, 50 μmol), KPF6 (73 mg, 0.4 mmol) and Cu(OAc)2·H2O (15), 198 (27), 77 (30); HRMS (EI) calcd for C19H17NO (M+)
(599 mg, 3.0 mmol) yielded 6ba (308 mg, 53%) and 7ba 275.1310, found 275.1298. The structure of compound 8aa was
(23 mg, 4%) after column chromatography as colorless solids. established by X-ray crystal structure analysis.13
6ba: m.p. = 144–146 °C; 1H NMR (300 MHz, CDCl3) δ = 8.27 (d,
4-CYCLOPROPYL-6-METHOXY-2-METHYL-3-PHENYLISOQUINOLIN-1(2H)-ONE
J = 8.8 Hz, 1H), 7.75–7.71 (m, 1H), 7.50 (d, J = 2.5 Hz, 1H), (8HA) AND 3-CYCLOPROPYL-6-METHOXY-2-METHYL-4-PHENYLISOQUINOLIN-1-
7.46–7.40 (m, 2H), 7.06 (dd, J = 8.8, 2.5 Hz, 1H), 3.97 (s, 2H), (2H)-ONE (9HA). According to the general procedure, 4-methoxy-
1.88 (tt, J = 8.1, 5.5 Hz, 1H), 0.98–0.88 (m, 1H), 0.23–0.15 (m, N-methylbenzamide (5h) (165 mg, 1.0 mmol), alkyne 2a
1H); 13C NMR (75 MHz, CDCl3) δ = 164.6 (C), 162.3 (C), 154.2 (284 mg, 2.0 mmol), [RuCl2(p-cymene)]2 (31 mg, 50 μmol), and
(C), 142.2 (C), 133.4 (C), 131.9 (CH), 129.6 (CH), 129.6 (CH), Cu(OAc)2·H2O (399 mg, 2.0 mmol) yielded 8ha (173 mg, 56%)
129.5 (CH), 127.9 (CH), 115.5 (CH), 114.4 (C), 113.9 (C), 107.7 and 9ha (9 mg, 3%) after column chromatography as colorless
1
(CH), 55.7 (CH3), 10.0 (CH2), 9.2 (CH); IR (ATR): 3005, 2956, solids. 8ha: m.p. = 135–137 °C; H NMR (300 MHz, CDCl3) δ =
2856, 1711, 1600, 1444, 1226, 831 cm−1; MS (EI) m/z (%): 292 8.39 (d, J = 8.9 Hz, 1H), 7.53 (d, J = 2.5 Hz, 1H), 7.48–7.37 (m,
(M+, 95), 217 (36), 215 (77), 105 (90), 77 (100); HRMS (EI) calcd 3H), 7.29–7.23 (m, 2H), 7.04 (dd, J = 8.9, 2.5 Hz, 1H), 3.91 (d,
for C19H16O3 (M+) 292.1099; found 292.1099.
J = 1.5 Hz, 3H), 3.24 (d, J = 1.4 Hz, 3H), 1.57 (tt, J = 8.2, 5.6 Hz,
7ba: m.p. = 126–128 °C; 1H NMR (300 MHz, CDCL3) δ = 1H), 0.63–0.54 (m, 2H), 0.13–0.05 (m, 2H); 13C NMR (75 MHz,
8.22 (d, J = 8.8 Hz, 1H), 7.54–7.34 (m, 5H), 6.94 (dd, J = 8.8, 2.5 CDCl3) δ = 162.3 (C), 162.2 (C), 143.5 (C), 140.0 (C), 135.6 (C),
Hz, 1H), 6.35 (d, J = 2.5 Hz, 1H), 3.72 (s, 3H), 1.67–1.55 (m, 129.9 (CH), 129.8 (CH), 128.3 (CH), 119.0 (C), 115.1 (C), 114.4
1H), 1.23–1.13 (m, 2H), 0.85–0.74 (m, 2H); 13C NMR (75 MHz, (C), 109.1 (C), 106.9 (CH), 55.2 (CH3), 33.9 (CH3), 10.4 (CH), 8.6
CDCl3) δ = 164.6 (C), 161.9 (C), 155.0 (C), 141.4 (C), 134.5 (C), (CH2); IR (ATR): 2991, 2939, 2914, 1639, 1604, 1275, 1027, 779,
146 | Org. Biomol. Chem., 2013, 11, 142–148
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725, 687 cm−1; MS (EI) m/z (%): 305 (M+, 52), 304 (84), 274
(100), 228 (68), 185 (20), 118 (30), 84 (40), 77 (46); HRMS (EI)
calcd for C20H19NO2 (M+) 305.1416; found: 305.1416.
Aldrichimica Acta, 2007, 40, 35–41; (t) I. V. Seregin and
V. Gevorgyan, Chem. Soc. Rev., 2007, 36, 1173–1193;
(u) L. Ackermann, Synlett, 2007, 507–526; (v) T. Satoh and
M. Miura, Chem. Lett., 2007, 36, 200–205.
9ha: m.p. = 145–147 °C; 1H NMR (300 MHz, CDCl3) δ = 8.39
(d, J = 8.9 Hz, 1H), 7.47–7.33 (m, 3H), 7.28 (d, J = 1.7 Hz, 1H),
7.25 (t, J = 1.5 Hz, 1H), 6.99 (dd, J = 8.9, 2.5 Hz, 1H), 6.59 (d, J =
2.5 Hz, 1H), 3.81 (s, 3H), 3.68 (s, 3H), 1.72 (tt, J = 8.3, 5.7 Hz,
1H), 0.75–0.66 (m, 2H), 0.34–0.25 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ = 162.6 (C), 162.3 (C), 140.8 (C), 138.9 (C), 137.3(C),
131.4 (CH2), 129.9 (CH), 128.3 (CH), 127.1 (CH), 119.4 (C),
118.7 (C), 115.0 (CH), 106.5 (CH), 55.2 (CH3), 32.1 (CH3), 14.0
(CH), 10.2 (CH2); IR (ATR): 3057, 2974, 2939, 2914, 1643, 1586,
1225, 1025, 781, 705 cm−1; MS (EI) m/z (%): 305 (M+, 94), 290
(100), 277 (33), 152 (21), 82 (13), 41 (10); HRMS (EI) calcd for
C20H19NO2 (M+) 305.1416; found: 305.1417.
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Acknowledgements
Support by Astra-Zeneca and the EPSRC (UK) is gratefully
acknowledged.
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