Tandem processes in C-aryl ketenes and ketenimines triggered by [1,5]-Hydride-like migration of an acetalic hydrogen atom

Article abstract of DOI:10.1002/ejoc.201301501

Heating a range of suitably substituted diazoacetoacetates produced a family of 2-(1,3-dioxolan-2-yl)phenyl ketenes that, under thermal conditions, smoothly underwent a [1,5]-H shift/6π-electrocyclic ring-closure sequence to give 1H-2- benzopyrans. The ap

Full text of DOI:10.1002/ejoc.201301501

FULL PAPER
DOI: 10.1002/ejoc.201301501
Tandem Processes in C-Aryl Ketenes and Ketenimines Triggered by [1,5]-
Hydride-Like Migration of an Acetalic Hydrogen Atom
Angel Vidal,*[a] Marta Marin-Luna,[a] and Mateo Alajarin[a]
Keywords: Ketenes / Sigmatropic rearrangement / Electrocyclic reactions / Cyclization / Nitrogen heterocycles
Heating a range of suitably substituted diazoacetoacetates
produced a family of 2-(1,3-dioxolan-2-yl)phenyl ketenes
that, under thermal conditions, smoothly underwent a [1,5]-
H shift/6π-electrocyclic ring-closure sequence to give 1H-2-
benzopyrans. The application of such processes to ketenes,
produced by replacing the phenyl scaffolding with a thio-
phene ring, afforded thienopyrans. The aza-Wittig reaction
of these 2-(1,3-dioxolan-2-yl)phenyl and thienyl ketenes with
N-aryliminophosphoranes provided analogous ketenimines
that transform into the respective 1(2H)isoquinolinones and
thienopyridinones under similar thermal conditions, follow-
ing the same type of cascade sequence.
into the final quinolines 3a (X = N; Y = CR1R2), quinazo-
lines 3b (X = N; Y = NAr), or dihydronaphthalenes 3c (X
= CR; Y = CR1R2) through a 6π electrocyclization reaction
(Scheme 1). DFT studies have shown that the initial [1,5]-H
shifts of these sequences can be denoted as intramolecular
hydride transfers. This characterization of the hydrogen mi-
gration step is essentially based on the weakening and po-
larization of the acetalic C–H bond by the hyperconjugative
interaction of its σ*(C-H) orbital with the lone-pair elec-
trons at the vicinal heteroatoms of the acetalic function.
Introduction
Ketenimines are a special class of nitrogenated hetero-
cumulenes that were first synthesized by Staudinger.[1] Their
C=C=N cumulenic system confers a high reactivity to the
members of this class of organic compounds,[2] which are
able to undergo a wide variety of transformations that are
of particular interest in the building of nitrogen heterocy-
cles.[3] These reactions are mainly based on the addition of
nucleophiles and free radicals to the electrophilic sp-hy-
bridized central carbon atom of the heterocumulenic func-
tion, and also on the participation of ketenimines in pericy-
clic processes such as cycloadditions, electrocyclic ring-clo-
sures and sigmatropic rearrangements.
In the last decade, our research group has been engaged
in the study of tandem processes initiated by [1,j]-H sigma-
tropic shifts toward heterocumulenic functional groups,
such as ketenimines and carbodiimides,[4] allene functions[5]
and carbon–carbon double bonds activated by electron-
withdrawing groups.[6] Some of these works are based on
acetalic ketenimines 1a (X = N; Y = CR1R2), carbodiimides
1b (X = N; Y = NAr), and allenes 1c (X = CR; Y =
CR1R2), which, under thermal activation, undergo a tan-
dem sequence consisting of a [1,5]-H shift[4d,7] followed by
a 6π electrocyclic ring-closure (6π-ERC). In the 1,5-H shift
step the hydrogen atom placed at the acetalic carbon is
transferred to the electrophilic central carbon atom of the
(hetero)cumulenic moiety to give the corresponding ortho-
(aza)xylylenes 2. These reactive intermediates easily convert
Scheme 1. Previously studied tandem processes in acetalic keten-
imines, carbodiimides, and allenes.
Having established an efficient preparation of protected
quinolones 3a by the tandem sequence starting from N-2-
(1,3-dioxolan-2-yl)phenyl ketenimines 1a (X = N; Y =
CR1R2), we reasoned that a similar transformation should
occur by starting from the regioisomeric ketenimines of ge-
neral structure A (Figure 1), in which the terminal N and
C atoms of the ketenimine function are interchanged when
compared with the atom connectivity in the isomeric struc-
tures 1a. To experimentally check this idea, we addressed
[a] Departamento de Química Orgánica, Universidad de Murcia,
Facultad de Química, Regional Campus of International Excel-
lence “Campus Mare Nostrum”,
Espinardo, 30100 Murcia, Spain
E-mail: vidal@um.es
http://www.um.es/web/quimica
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301501.
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Tandem Processes in C-Aryl Ketenes and Ketenimines
the synthesis and thermal activation of ketenimines of type Table 1. 1H-2-benzopyrans 6 and thieno[3,2-c]pyrans 11.
A, which should be reasonably accessible from the respec-
tive ketenes B.
n
R1
R2
R3
Yield [%][a]
6a
6b
1
1
1
1
1
2
H
H
CH3O
OCH2O
OCH2O
H
H
H
H
CH3CH2
CH3
CH3CH2
CH3CH2
CH3
CH3CH2
CH3CH2
CH3
55
73
55
43
50
70
43
60
6c
6d
6e
6f
H
11a
11b
Figure 1. General structure of C-[2-(1,3-dioxolan-2-yl)]phenyl ket-
enimines A and their expected precursor ketenes B.
[a] Yields of the conversions 5Ǟ6 and 10Ǟ11.
As a result of this experimental work, we disclose here
that under mild thermal treatment several examples of ket-
enimines of general structure A, generated by aza-Wittig
reaction of 2-(1,3-dioxolan-2-yl)phenyl ketenes B and N-
aryl iminophosphoranes, transform into 1(2H)-isoquinol-
ines by a [1,5]-H shift/6π-ERC cascade sequence. We will
also show that ketenes B, under comparable thermal acti-
vation, undergo similar [1,5]-H/6π-ERC tandem transfor-
mations to afford 1H-2-benzopyrans.
Structural determination of spiro[1H-2-benzopyran-1,2Ј-
[1,3]-dioxolanes] 6a–e and spiro[1H-2-benzopyran-1,2Ј-
[1,3]-dioxane] 6f was carried out on the basis of their ana-
lytical and spectroscopic data. In their 1H NMR spectra the
C(3)H proton resonates at δ = 7.66–7.80 ppm as a singlet.
Significant chemical shifts from the 13C NMR spectra of
compounds 6 are those corresponding to the sp3 quaternary
carbon C1 (δ = 107.4–108.6 ppm), accounting for its bond-
ing to three oxygen atoms, and the sp2 methine carbon C3
(δ = 150.7–152.8 ppm).
It seems reasonable that, upon heating, diazoacetoacet-
ates 5 should undergo the initially expected Wolff re-
arrangement leading to ketenes 7, which, under the thermal
reaction conditions, undergo [1,5]-H migration of the acet-
alic hydrogen atom to the central carbon atom of the ketene
fragment, resulting in ortho-xylylenes 8. These reactive in-
termediates further cyclize through 6π electrocyclic ring-
closure to give the final cyclic orthoesters 6 (Scheme 3). The
presence of the electron-withdrawing alkoxycarbonyl group
at the Cβ carbon atom of the ketene unit should have an
activating effect in the [1,5]-H shift step, because this mech-
anistic step is interpreted as a hydride-like H atom mi-
gration to the electrophilic sp-hybridized carbon atom of
the ketene; similar processes have been found with other
[1,5]-H shifts occurring in ketenimines and carbodiimides
1.[4]
Results and Discussion
We first prepared the new diazoacetoacetate derivatives
5, bearing ethylenedioxy or propylenedioxy substituents,
starting from acetalic aldehydes 4 by following the simple
and efficient one-pot procedure recently reported by Steel’s
group.[8] Treatment of solutions of 2-(1,3-dioxolan-2-yl)-
benzaldehydes 4a–c and 2-(1,3-dioxan-2-yl)benzaldehyde 4d
in dimethyl sulfoxide with ethyl and methyl diazoacetate, in
the presence of a catalytic amount of 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU), provided the respective aldol-
type products, α-diazo-β-hydroxy carbonyl compounds,
which were oxidized in situ by the action of 2-iodoxybenz-
oic acid (IBX) to the diazoacetoacetates 5, which were iso-
lated in low to moderate yields. Not unexpectedly, heating
of solutions of diazodicarbonyl compounds 5 in toluene at
reflux temperature afforded 1H-2-benzopyrans 6, in moder-
ate to good yields (Scheme 2, Table 1).
Scheme 2. Preparation of 1H-2-benzopyrans 6.
Scheme 3. Proposed mechanism for the conversions 5Ǟ6.
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We then studied similar [1,5]-H shift/6π-ERC sequences
by replacing the ortho-phenylene scaffold with a thiophene
ring. Thus, we combined a ketene fragment and a 1,3-di-
oxolane group at the respective C2 and C3 carbon atoms
of a thiophene ring. By treating 3-(1,3-dioxolan-2-yl)thio-
phene-2-carboxaldehyde (9) with ethyl and methyl diazo-
acetate, a small quantity of DBU and 2-iodoxybenzoic acid,
in dimethyl sulfoxide solution at room temperature, the ex-
pected diazoacetoacetates 10 were conveniently prepared.
By following the planned Wolff rearrangement/[1,5]-H shift/
6π electrocyclization sequences, when heated in toluene at
reflux temperature, compounds 10 were transformed into
the respective 4H-thieno[3,2-c]pyrans 11 (Scheme 4). Cyclic
orthoesters 11 were thus obtained in moderate yields
(Table 1).
Scheme 4. Preparation of 4H-thieno[3,2-c]pyrans 11.
Scheme 5. Preparation of 1H-2-benzopyrans 16 and 21.
In efforts to extend the scope and versatility of this syn-
thetic methodology, we decided to study similar transfor- an example closely related to those reported herein, α,β-
mations of additional 1,3-dioxolane-ketenes having substit- unsaturated ketenes with hydrogen atoms at the allylic posi-
uents at their Cβ carbon atom other than the alkoxycarb- tion have been shown to undergo [1,5]-H sigmatropic shifts
onyl group, such as the electron-withdrawing diphenylphos- to afford conjugated 2,4-dienals.[9] Additionally, the degen-
phoryl Ph2P(O) or a plain phenyl group. Thus, the reaction erate rearrangement of conjugated ketene aldehydes by re-
of methyl 2-(1,3-dioxolan-2-yl)benzoate (12) with lithiated versible migration of the aldehydic hydrogen to the Cα atom
methyl diphenylphosphane oxide in tetrahydrofuran pro- of the ketene fragment has also been disclosed.[10]
vided β-ketophosphane oxide 13. Subsequent diazo trans-
Following our experiments with ketenes, we then under-
fers to the reactive methylene group of 13 by treatment with took an exploration of the initially planned chemical trans-
p-toluenesulfonyl azide, using triethylamine as base, gave α- formations of analogous ketenimines. For the synthesis of
diazo-β-ketophosphane oxide 14 (Scheme 5). On the other the new ketenimines (general structure A in Figure 1), we
hand, bromo–lithium exchange of 2-bromobenzaldehyde selected the efficient protocol based on aza-Wittig reaction
ethylene acetal 17 with n-butyllithium, in diethyl ether, and between iminophosphoranes and ketenes. To this end, we
further transmetalation of the resulting aryllithium with envisaged the use of some of the ketenes taking part as reac-
zinc chloride, afforded the corresponding organozinc deriv- tive (non-isolated) intermediates in the sequences repre-
ative. Cross-coupling of this organometallic reagent with sented in Schemes 3, 4 and 5, obtained via the Wolff re-
phenylacetyl chloride catalyzed by tetrakis(triphenylphos- arrangement of the respective diazoacetoacetate derivatives.
phane)palladium(0) furnished aryl ketone 18. To ac- Clearly, such a strategy is based upon the reasonable expec-
complish the required diazo transfer, ketone 18 was treated tation that the easy aza-Wittig process between the imino-
with p-toluenesulfonyl azide in the presence of triethyl- phosphorane and the ketene generated in situ to yield ket-
amine. Finally, heating diazo compounds 14 and 19 in tolu- enimines, would occur more rapidly than the competitive
ene at reflux gave the respective benzopyrans 16 and 21 [1,5]-H shift toward the ketene fragment. Pleasingly, we
(Scheme 5), substituted at C4 by either a diphenyl phos- found that mixtures of diazo compounds 5 and 10 and a
phoryl or a phenyl group, presumably via ketenes 15 and range of N-aryliminophosphoranes heated in toluene solu-
20 (not isolated), resulting in the first instance of the ex- tion gave rise to the desired spiroisoquinolines 22 and thien-
pected Wolff rearrangements.
opyridine 24, respectively. The putative ketenimine interme-
Several cases of sigmatropic hydrogen shifts on ketenes diates were detected spectroscopically (IR ν = 2000 cm–1)
˜
have been previously disclosed in the chemical literature. In in the reaction medium during the first stages of these reac-
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Tandem Processes in C-Aryl Ketenes and Ketenimines
1
tions. Compound 24 was identifiable in the H NMR spec- As reasoned above for ketenes 7, the presence of the alkoxy-
trum of the final reaction mixture but could not be isolated carbonyl group at the Cβ carbon atom of the ketenimine
as such, undergoing hydrolysis of the acetal group during should have a positive influence on the hydrogen transfer
its chromatographic purification by silica gel column step.
chromatography, finally giving thieno[3,2-c]pyridin-4(5H)-
one 25. This was also the case for spiroisoquinolines 22e–
g, which were isolated and characterized as the isoquinol-
ones 23e–g (Scheme 6, Table 2).
Scheme 7. Mechanistic sequence explaining the formation of iso-
quinolines 22.
Finally, we targeted the preparation of ketenimine 29,
bearing two different 1,3-dioxolane functions as potential
hydride sources, placed at the ortho position of the two
phenyl rings linked at both ends, sp2-carbon and nitrogen
atoms, of the ketenimine unit. The objective was to investi-
gate the competition between the two possible alternative
Scheme 6. Preparation of isoquinolines 22, isoquinolones 23, and
thieno[3,2-c]pyridine-4(5H)-one 25.
Table 2. Isoquinolines 22 and isoquinolones 23.
Ar
R1
R2
R3
Yield [%]
22a 4-CH3–C6H4
22b 4-CH3–C6H4
22c 4-CH3O-C6H4
H
H
H
H
H
H
H
H
CH3CH2
CH3
CH3CH2
CH3CH2
CH3CH2
CH3
99
70
65
90
60
60
80
22d
23e
23f
1-naphthyl
4-CH3–C6H4
4-CH3–C6H4
OCH2O
OCH2O
OCH2O
23g 4-CH3O-C6H4
CH3CH2
A mechanistic sequence explaining the formation of iso-
quinolines 22 is depicted in Scheme 7. Thus, diazoaceto-
acetates 5 transform into ketenes 7 through a thermally
activated Wolff rearrangement. Next, the generated ketenes
react in situ with the N-aryliminophosphorane giving rise
to ketenimines 26. A [1,5]-H shift from the acetalic function
to the electrophilic central carbon atom of the ketenimine
moiety provides the transient ortho-xylylenes 27, and subse-
quent 6π electrocyclic ring-closure affords isoquinolines 22. Scheme 8. Preparation of isoquinoline 31.
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A. Vidal, M. Marin-Luna, M. Alajarin
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types of [1,5]-H shift/6π-ERC tandem sequences that are tenimines is the terminus of the initial shift. The reactive
conceivable in this substrate. When a mixture of diazoace- intermediates resulting from these H-shifts subsequently
toacetate 5a and iminophosphorane 28 was heated in tolu- undergo rapid ring-closing 6π electrocyclization to give a
ene solution, after purification by column chromatography variety of new spiroheterocyclic compounds. Thus, we have
of the final reaction mixture, only isoquinoline 31 was iso- shown that 2-(1,3-dioxolan-2-yl)phenyl ketenes and 3-(1,3-
lated, albeit in low yield (45%; Scheme 8).
dioxolan-2-yl)-2-thienyl ketenes undergo [1,5]-H shifts/6π-
Formation of isoquinoline 31 is the result of a [1,5]-H ERC tandem sequences to afford new 1H-2-benzopyrans
shift/6π-ERC sequence triggered by migration of the hydro- and thieno[3,2-c]pyrans, respectively. Moreover, we have
gen atom at the 1,3-dioxolane moiety, which connects with also demonstrated that ketenimines resulting from the aza-
the benzene ring at the sp2-carbon atom of the keteminine. Wittig reaction of these ketenes and N-aryliminophosphor-
While not identifying large differences between the two anes give rise to isoquinolines and thienopyridines through
available [1,5]-H shifts in ketenimine 29, we rationalized similar cascade sequences.
that the exclusive formation of isoquinoline 31 (as ascer-
tained by NMR analyses of the crude reaction mixture) was
due to the more facile 6π-electrocyclization of the ortho-
xylylene 30, with formation of a new C–N bond, when com-
Experimental Section
General: All melting points are uncorrected. Infrared (IR) spectra
were recorded as Nujol emulsions or neat. H NMR spectra were
pared with that of the alternative ortho-azaxylylene type 32.
In the latter case, the 6π-ERC process would be less facile
because it occurs with steric buttressing in the formation of
the new C–C bond between two completely substituted sp2-
carbon atoms, to give the quinoline ring (Scheme 9). It has
been previously stated that the 6π-electrocyclization of con-
jugated 1-azahexatrienes is exceedingly facile.[11]
1
recorded in CDCl3 at 300 or 400 MHz; 13C NMR spectra were
recorded in CDCl3 at 75 or 100 MHz. The chemical shifts are ex-
pressed in ppm relative to Me4Si (δ = 0.00 ppm) for 1H, and the
chemical shifts for 13C are reported relative to the resonances of
CDCl3 (δ = 77.1 ppm). 31P NMR spectra were recorded in CDCl3
at 121.4 MHz, using H3PO4 as internal reference.
Materials: 2-(1,3-Dioxolan-2-yl)benzaldehyde (4a),[12] 2-(1,3-diox-
olan-2-yl)-4-methoxybenzaldehyde (4b),[13] 6-(1,3-dioxolan-2-yl)-
1,3-benzodioxole-5-carbaldehyde (4c),[14] 2-(1,3-dioxan-2-yl)benz-
aldehyde (4d),[15] 3-(1,3-dioxolan-2-yl)thiophene-2-carbaldehyde
(9),[16] methyl 2-(1,3-dioxolan-2-yl)benzoate (12),[17] and 2-(tri-
phenylphosphoranylideneamino)benzaldehyde ethylene acetal
(28)[4f] were prepared following published experimental procedures.
General Procedure for the Preparation of 1H-2-Benzopyrans 6 and
Thieno[3,2-c]pyrans 11: To a solution of ethyl diazoacetate (0.06 g,
0.58 mmol) or methyl diazoacetate (0.058 g, 0.58 mmol) in di-
methyl sulfoxide (4 mL) at room temperature were added in suc-
cession DBU (0.007 mL, 0.05 mmol), the appropriate aldehyde 4
(0.49 mmol), and a solution of IBX (0.27 g, 0.97 mmol) in dimethyl
sulfoxide (5 mL). The mixture was stirred at room temperature for
10 h, then the reaction was quenched with aqueous NaHCO3
(10 mL) and extracted with dichloromethane (3ϫ 20 mL). The
combined organic layers were washed with aqueous NaHCO3 (3ϫ
60 mL) and with water (60 mL), dried with MgSO4, filtered, and
concentrated in vacuo. The resulting crude product was purified by
column chromatography on silica gel (hexanes/ethyl acetate, 4:1
v/v) to afford the corresponding diazoacetoacetates 5 and 10.
A solution of diazoacetoacetate 5 or 10 (0.5 mmol) in anhydrous
toluene (15 mL) was heated at reflux temperature for 2 h. After
cooling, the solvent was removed under reduced pressure and the
resulting material was purified by column chromatography on silica
gel.
Scheme 9. The two alternative [1,5]-H shift/6π-ERC sequences in
ketenimine 29.
4-Ethoxycarbonylspiro(1H-2-benzopyran-1,2Ј-[1,3]-dioxolane) (6a):
Eluent for column chromatography: hexanes/ethyl acetate (4:1 v/v),
1
yield 72 mg (55%); white prisms; m.p. 50–52 °C (diethyl ether). H
NMR (300 MHz, CDCl3, 25 °C): δ = 1.34 (t, J = 7.2 Hz, 3 H),
4.23–4.43 (m, 6 H), 7.34 (t, J = 7.5 Hz, 1 H), 7.43–7.52 (m, 2 H),
7.77 (s, 1 H), 8.35 (d, J = 8.1 Hz, 1 H) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 14.3, 60.3, 65.5, 107.7 (s), 120.2 (s), 124.0, 124.4,
124.7 (s), 127.5, 128.5 (s), 130.2, 152.7, 165.4 (s) ppm. IR (Nujol):
Conclusions
We have disclosed a series of new tandem processes in-
volving 1,3-dioxolane functions as hydride-releasing units,
occurring under thermal conditions, in which the heterocu-
ν = 1711 (vs), 1617 (vs), 1492 (s), 1452 (s) cm–1. HRMS (ESI):
˜
mulenic sp-hybrized central carbon atom of ketenes and ke- calcd. for C14H15O5 [M + H]+ 263.0914; found 263.0922.
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Tandem Processes in C-Aryl Ketenes and Ketenimines
4-Methoxycarbonylspiro(1H-2-benzopyran-1,2Ј-[1,3]-dioxolane)
(6b): Eluent for column chromatography: hexanes/ethyl acetate (4:1
v/v), yield 90 mg (73 %); yellow prisms; m.p. 68–70 °C (diethyl
ether). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 3.83 (s, 3 H), 4.26–
4.34 (m, 2 H), 4.36–4.45 (m, 2 H), 7.35 (td, J = 0.9, 7.5 Hz, 1 H),
7.45–7.53 (m, 2 H), 7.77 (s, 1 H), 8.35 (d, J = 8.1 Hz, 1 H) ppm.
13C NMR (75 MHz, CDCl3, 25 °C): δ = 51.4, 65.5, 107.6 (s), 120.2
(s), 124.0, 124.4, 124.6 (s), 127.5, 128.4 (s), 130.2, 152.8, 165.9
H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 14.4, 60.9, 65.3,
105.3 (s), 121.3 (s), 123.1, 123.4 (s), 125.9, 150.1, 164.8 (s) ppm. IR
(Nujol): ν = 1704 (vs), 1604 (vs), 1428 (vs) cm–1. HRMS (ESI):
˜
calcd. for C12H13O5S [M + H]+ 269.0478; found 269.0486.
4H-Thieno[3,2-c]pyran 11b (R3 = CH3): Eluent for column
chromatography: hexanes/ethyl acetate (4:1 v/v), yield 76 mg (60%);
white prisms; m.p. 108–110 °C (diethyl ether). 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 3.85 (s, 3 H), 4.25–4.34 (m, 2 H), 4.36–4.44 (m,
2 H), 7.02 (d, J = 5.4 Hz, 1 H), 7.28 (d, J = 5.4 Hz, 1 H), 7.71 (s,
1 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 51.8, 65.3, 105.0
(s), 121.3 (s), 123.1, 123.4, 125.9, 133.0 (s), 150.3, 165.2 (s) ppm.
(s) ppm. IR (Nujol): ν = 1714 (vs), 1618 (vs), 1492 (s), 1452
˜
(m) cm–1. HRMS (ESI): calcd. for C13H13O5 [M + H]+ 249.0757;
found 249.0764.
IR (Nujol): ν = 1708 (vs), 1603 (vs), 1459 (vs) cm–1. HRMS (ESI):
4-Ethoxycarbonyl-7-methoxyspiro(1H-2-benzopyran-1,2Ј-[1,3]-di-
oxolane) (6c): Eluent for column chromatography: hexanes/ethyl
acetate (4:1 v/v), yield 80 mg (55%); white prisms; m.p. 77–79 °C
˜
calcd. for C11H11O5S [M + H]+ 255.0322; found 255.0328.
1
Preparation of 2-Diphenylphosphanyl-1-[2-(1,3-dioxolan-2-yl)phen-
yl]ethanone (13): To a solution of methyl(diphenyl)phosphane oxide
(0.55 g, 2.5 mmol) in THF (20 mL), at –78 °C, nBuLi (2.6 m in n-
hexane, 1 mL, 2.5 mmol) was added, and the resulting mixture was
stirred for 1 h. A solution of methyl 2-(1,3-dioxolan-2-yl)benzoate
12 (0.4 g, 1.92 mmol) in THF (20 mL) was added through a drop-
ping funnel. The reaction mixture was stirred at –78 °C for 1 h,
then quenched with saturated aqueous NH4Cl (20 mL). The or-
ganic layer was separated and the aqueous layer was extracted with
ethyl acetate (2ϫ 50 mL). The combined organic layer was washed
with brine (50 mL), dried with MgSO4, and the solvent was evapo-
rated under reduced pressure. The residue was purified by silica gel
column chromatography (hexanes/ethyl acetate, 1:9 v/v), yield
(diethyl ether). H NMR (300 MHz, CDCl3, 25 °C): δ = 1.32 (t, J
= 7.2 Hz, 3 H), 3.81 (s, 3 H), 4.24–4.38 (m, 6 H), 7.00–7.02 (m, 2
H), 7.66 (s, 1 H), 8.28 (d, J = 9.3 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 14.3, 55.3, 60.1, 65.4, 107.8 (s), 108.9,
116.3, 119.9 (s), 121.5 (s), 125.7, 126.2 (s), 150.7, 158.9 (s), 165.5
(s) ppm. IR (Nujol): ν = 1709 (vs), 1613 (vs), 1505 (vs), 1299
˜
(vs) cm–1. HRMS (ESI): calcd. for C15H17O6 [M + H]+ 293.1020;
found 293.1028.
4-Ethoxycarbonyl-6,7-(methylenedioxy)spiro(1H-2-benzopyran-
1,2Ј-[1,3]-dioxolane) (6d): Eluent for column chromatography: hex-
anes/ethyl acetate (4:1 v/v), yield 66 mg (43%); white prisms; m.p.
1
113–115 °C (diethyl ether). H NMR (300 MHz, CDCl3, 25 °C): δ
= 1.33 (t, J = 7.2 Hz, 3 H), 4.21–4.40 (m, 6 H), 5.96 (s, 2 H), 6.94
(s, 1 H), 7.70 (s, 1 H), 7.91 (s, 1 H) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 14.3, 60.3, 65.3, 101.4, 104.5, 104.6, 107.5 (s),
118.5 (s), 120.3 (s), 123.6 (s), 146.8 (s), 149.2 (s), 151.3, 165.4
1
0.46 g (61%); yellow oil. H NMR (300 MHz, CDCl3, 25 °C): δ =
3.79–3.90 (m, 4 H), 4.08 (d, J = 14.7 Hz, 2 H), 6.04 (s, 1 H), 7.27–
7.45 (m, 8 H), 7.56 (d, J = 7.5 Hz, 1 H), 7.67–7.78 (m, 5 H) ppm.
13C NMR (75 MHz, CDCl3, 25 °C): δ = 45.9 (d, J = 58.5 Hz), 64.7,
100.4, 126.4, 128.3, 128.6 (d, J = 12.1 Hz), 128.5, 130.6 (d, J =
9.8 Hz), 130.9, 131.7 (d, J = 2.3 Hz), 131.8 (d, J = 102.4 Hz, s),
136.3 (s), 138.6 (s), 196.0 (d, J = 5.9 Hz, s) ppm. 31P NMR
(s) ppm. IR (Nujol): ν = 1708 (vs), 1630 (m), 1485 (vs), 1407
˜
(s) cm–1. HRMS (ESI): calcd. for C15H15O7 [M + H]+ 307.0812;
found 307.0825.
4-Methoxycarbonyl-6,7-(methylenedioxy)spiro(1H-2-benzopyran-
1,2Ј-[1,3]-dioxolane) (6e): Eluent for column chromatography: hex-
anes/ethyl acetate (4:1 v/v), yield 73 mg (50%); white prisms; m.p.
(121.4 MHz, CDCl , 25 °C): δ = 26.95 ppm. IR (Neat): ν = 1686
˜
3
(vs), 1636 (s), 1437 (vs), 1395 (m) cm–1. HRMS (ESI): calcd. for
C23H22O4P [M + H]+ 393.1250; found 393.1259.
1
131–133 °C (diethyl ether). H NMR (300 MHz, CDCl3, 25 °C): δ
Preparation of 2-Phenyl-1-[2-(1,3-dioxolan-2-yl)phenyl]ethanone
(18): 2-Bromobenzaldehyde ethylene ketal 17 (2 g, 8.73 mmol) was
dissolved in anhydrous diethyl ether (25 mL) and the solution was
cooled with stirring to –70 °C. n-Butyllithium (2.6 m in n-hexane,
3.85 mL, 10 mmol) was added dropwise, keeping the internal tem-
perature at –65 °C, and the reaction mixture was stirred for 1 h
(forming a yellow solution). Zinc chloride (1.0 m in diethyl ether,
10 mL) was cooled to 0 °C and added dropwise, keeping the in-
ternal temperature at –55 °C. The reaction mixture was warmed to
room temperature and stirred at that temperature for 1 h. After
cooling at 0 °C tetrakis(triphenylphosphane)palladium(0) (0.49 g,
5 mol-%) was added followed by dropwise addition by using a can-
nula of phenylacetyl chloride (1.23 g, 8 mmol) in anhydrous diethyl
ether (14 mL). The reaction mixture was then warmed to room
temperature and stirring was continued for 20 h, affording a yellow
solution that was poured into a mixture of saturated aqueous
NaHCO3 (50 mL) and ethyl acetate (50 mL). The organic phase
was separated and the aqueous layer was then back-extracted with
ethyl acetate (2 ϫ 25 mL). The organic layers were combined,
washed with brine (50 mL), and dried with anhydrous MgSO4. The
solvent was removed under reduced pressure to afford a crude oil
that was purified by silica gel column chromatography (hexane/
= 3.81 (s, 3 H), 4.23–4.28 (m, 2 H), 4.34–4.42 (m, 2 H), 5.98 (s, 2
H), 6.94 (s, 1 H), 7.70 (s, 1 H), 7.90 (s, 1 H) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 51.5, 65.4, 101.5, 104.6, 104.7, 107.4
(s), 118.6 (s), 120.4 (s), 123.6 (s), 146.9 (s), 149.3 (s), 151.5, 165.9
(s) ppm. IR (Nujol): ν = 1713 (vs), 1632 (m), 1596 (m), 1503
˜
(vs) cm–1. HRMS (ESI): calcd. for C14H13O7 [M + H]+ 293.0656;
found 293.0663.
4-Ethoxycarbonylspiro(1H-2-benzopyran-1,2Ј-[1,3]-dioxane) (6f):
Eluent for column chromatography: hexanes/ethyl acetate (4:1 v/v),
1
yield 97 mg (70%); white prisms; m.p. 68–70 °C (diethyl ether). H
NMR (300 MHz, CDCl3, 25 °C): δ = 1.37 (t, J = 7.2 Hz, 3 H),
1.58–1.63 (m, 1 H), 2.28–2.43 (m, 1 H), 4.00 (ddd, J = 1.2, 5.1,
10.5 Hz, 2 H), 4.31 (q, J = 7.2 Hz, 2 H), 4.47 (td, J = 1.5, 11.7 Hz,
2 H), 7.34 (td, J = 1.5, 7.8 Hz, 1 H), 7.43 (td, J = 1.5, 7.8 Hz, 1
H), 7.62 (dd, J = 1.5, 7.5 Hz, 1 H), 7.81 (s, 1 H), 8.31 (dd, J = 1.5,
7.8 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 14.4,
24.0, 60.3, 60.9, 108.6 (s), 110.8 (s), 123.9, 124.3, 126.8 (s), 127.6,
128.3 (s), 129.7, 151.8, 165.6 (s) ppm. IR (Nujol): ν = 1709 (vs),
˜
1617 (vs), 1331 (vs), 1291 (vs) cm–1. HRMS (ESI): calcd. for
C15H17O5 [M + H]+ 277.1071; found 277.1078.
4H-Thieno[3,2-c]pyran 11a (R3 = CH3CH2): Eluent for column
chromatography: hexanes/ethyl acetate (4:1 v/v), yield 58 mg (43%); ethyl acetate, 7:3 v/v), yield 0.66 g (31 %); yellow oil. 1H NMR
white prisms; m.p. 92–94 °C (diethyl ether). 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 1.36 (t, J = 7.2 Hz, 3 H), 4.22–4.45 (m, 6 H),
7.02 (d, J = 5.1 Hz, 1 H), 7.28 (d, J = 5.1 Hz, 1 H), 7.72 (s, 1
(300 MHz, CDCl3, 25 °C): δ = 3.96 (br. s, 4 H), 4.18 (s, 2 H), 6.20
(s, 1 H), 7.23–7.34 (m, 5 H), 7.38 (dd, J = 1.2, 7.6 Hz, 1 H), 7.40–
7.49 (m, 2 H), 7.65–7.68 (m, 1 H) ppm. 13C NMR (75 MHz,
Eur. J. Org. Chem. 2014, 878–886
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
883

A. Vidal, M. Marin-Luna, M. Alajarin
FULL PAPER
CDCl3, 25 °C): δ = 49.3, 65.2, 101.2, 126.9, 127.1, 127.3, 128.5,
4Ј-Methoxycarbonyl-2Ј-(4-methylphenyl)spiro(1,3-dioxolane-2,1Ј-
[1ЈH]isoquinoline) (22b): Eluent for column chromatography: hex-
anes/ethyl acetate (9:1 v/v), yield 82 mg (70%); white prisms; m.p.
128.7, 129.8, 130.6, 134.1 (s), 136.6 (s), 139.2 (s), 202.5 (s) ppm. IR
(Neat): ν = 1617 (vs), 1697 (vs), 1601 (m), 1496 (s) cm–1. HRMS
˜
(ESI): calcd. for C17H17O3 [M + H]+ 269.1172; found 269.1176.
152–154 °C (diethyl ether). H NMR (300 MHz, CDCl3, 25 °C): δ
1
= 2.40 (s, 3 H), 3.57–3.62 (m, 2 H), 3.76 (s, 3 H), 4.03–4.08 (m, 2
H), 7.21–7.24 (m, 2 H), 7.27 (d, J = 7.2 Hz, 1 H), 7.35 (d, J =
8.4 Hz, 2 H), 7.41–7.50 (m, 2 H), 7.81 (s, 1 H), 8.59 (d, J = 8.1 Hz,
1 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 21.2, 50.9, 66.2,
98.7 (s), 113.5 (s), 123.6, 124.6, 125.6, 128.1 (s), 129.1, 129.5, 129.7,
General Procedure for the Preparation of 1H-2-Benzopyrans 16 and
21: p-Toluenesulfonyl azide (0.2 g, 1.05 mmol) and Et3N (0.2 mL,
1.4 mmol) were added to a solution of 13 or 18 (0.7 mmol) in anhy-
drous acetonitrile (20 mL) at room temperature. The mixture was
stirred at room temperature for 12 h, then the reaction was
quenched with 10% aqueous NaOH (20 mL) and extracted with
ethyl acetate (3 ϫ 20 mL). The combined organic extracts were
washed with brine (2ϫ 20 mL) and dried with MgSO4. The solvent
was evaporated under reduced pressure and the residue was puri-
fied by silica gel column chromatography (hexanes/ethyl acetate,
4:1 v/v) to afford the corresponding diazo compounds 14 and 19.
129.9 (s), 138.3 (s), 139.4 (s), 144.1, 166.8 (s) ppm. IR (Nujol): ν =
˜
1693 (vs), 1621 (vs), 1605 (vs), 1511 (vs) cm–1. HRMS (ESI): calcd.
for C20H20NO4 [M + H]+ 338.1387; found 338.1392.
4Ј-Ethoxycarbonyl-2Ј-(4-methoxylphenyl)spiro(1,3-dioxolane-2,1Ј-
[1ЈH]isoquinoline) (22c): Eluent for column chromatography: hex-
anes/ethyl acetate (4:1 v/v), yield 83 mg (65%); white prisms; m.p.
1
A solution of the diazo compound 14 or 19 (0.5 mmol) in anhy-
drous toluene (15 mL) was heated at reflux temperature for 3 h.
After cooling, the solvent was removed under reduced pressure and
the resulting material was purified by column chromatography on
silica gel.
115–117 °C (diethyl ether). H NMR (400 MHz, CDCl3, 25 °C): δ
= 1.31 (t, J = 7.2 Hz, 3 H), 3.58–3.61 (m, 2 H), 3.85 (s, 3 H), 4.05–
4.08 (m, 2 H), 4.26 (q, J = 7.2 Hz, 2 H), 6.93–6.96 (m, 2 H), 7.29
(td, J = 1.2, 8.0 Hz, 1 H), 7.39–7.41 (m, 2 H), 7.44 (td, J = 1.6,
7.6 Hz, 1 H), 7.47 (dd, J = 1.2, 8.0 Hz, 1 H), 7.79 (s, 1 H), 8.60 (d,
J = 8.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
14.6, 55.5, 59.6, 66.2, 98.8 (s), 113.5 (s), 114.1, 123.6, 124.7, 125.5,
128.0 (s), 129.1, 129.9 (s), 131.0 (s), 134.5 (s), 144.0, 159.4 (s), 166.4
4-Diphenylphosphanylspiro(1H-2-benzopyran-1,2Ј-[1,3]-dioxolane)
(16): Eluent for column chromatography: hexanes/ethyl acetate (1:1
1
v/v), yield 97 mg (50%). H NMR (300 MHz, CDCl3, 25 °C): δ =
(s) ppm. IR (Nujol): ν = 1693 (vs), 1619 (vs), 1509 (vs) cm–1
.
˜
4.26–4.36 (m, 4 H), 6.51 (d, J = 9.9 Hz, 1 H), 7.22–7.31 (m, 1 H),
7.41–7.52 (m, 8 H), 7.71–7.78 (m, 5 H) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 65.5, 107.0 (d, J = 112.5 Hz, s), 120.0, 124.8,
125.0 (d, J = 5.8 Hz, s), 127.8, 128.7 (d, J = 12.3 Hz), 130.2, 131.7
(d, J = 106.7 Hz, s), 132.0 (d, J = 9.7 Hz, s), 132.1, 152.6 (d, J =
22.6 Hz, s) ppm. 31P NMR (121.4 MHz, CDCl3, 25 °C): δ =
HRMS (ESI): calcd. for C21H22NO5 [M + H]+ 368.1487; found
368.1492.
4Ј-Ethoxycarbonyl-2Ј-(1-naphthyl)spiro(1,3-dioxolane-2,1Ј[1ЈH]-
isoquinoline) (22d): Eluent for column chromatography: hexanes/
ethyl acetate (4:1 v/v), yield 0.12 g (90%); white prisms; m.p. 153–
155 °C (diethyl ether). 1H NMR (400 MHz, CDCl3, 25 °C): δ =
1.27 (t, J = 7.2 Hz, 3 H), 3.05 (q, J = 7.6 Hz, 1 H), 3.76–3.80 (m,
1 H), 3.91–3.96 (m, 1 H), 4.04 (q, J = 7.6 Hz, 1 H), 4.20–4.29 (m,
2 H), 7.34 (td, J = 1.2, 7.6 Hz, 1 H), 7.49–7.57 (m, 5 H), 7.75 (dd,
J = 1.2, 7.2 Hz, 1 H), 7.82 (s, 1 H), 7.91–7.98 (m, 3 H), 8.70 (dd,
J = 0.8, 8.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ
= 14.5, 59.7, 65.8, 66.5, 99.1 (s), 113.8 (s), 123.8, 124.3, 124.7,
125.3, 125.7, 126.7, 127.2, 127.9, 128.2 (s), 128.6, 129.2, 129.3,
130.1 (s), 132.3 (s), 134.3 (s), 138.2 (s), 144.3 (s), 166.4 (s) ppm. IR
27.46 ppm. IR (Nujol): ν = 1749 (m), 1608 (vs), 1490 (m), 1437
˜
(vs) cm–1. HRMS (ESI): calcd. for C23H20O4P [M + H]+ 391.1094;
found 391.1101.
4-Phenylspiro(1H-2-benzopyran-1,2Ј-[1,3]-dioxolane) (21): Eluent
for column chromatography: hexanes/ethyl acetate (4:1 v/v), yield
1
89 mg (67 %); white prisms; m.p. 123–125 °C (diethyl ether). H
NMR (300 MHz, CDCl3, 25 °C): δ = 4.29–4.48 (m, 4 H), 6.72 (s,
1 H), 7.12–7.15 (m, 1 H), 7.33–7.42 (m, 7 H), 7.57–7.60 (m, 1
H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 65.4, 118.1 (s),
119.6 (s), 122.9, 124.8, 125.8 (s), 127.4, 127.5, 128.6, 129.7, 129.8,
(Nujol): ν = 1695 (vs), 1615 (vs), 1450 (s), 1394 (s) cm–1. HRMS
˜
(ESI): calcd. for C24H22NO4 [M + H]+ 388.1543; found 388.1558.
132.0 (s), 135.2 (s), 140.1 ppm. IR (Nujol): ν = 1631 (vs), 1604
˜
(m), 1494 (vs) cm–1. HRMS (ESI): calcd. for C17H15O3 [M + H]+
267.1016; found 267.1020.
4-Ethoxycarbonyl-6,7-(methylenedioxy)-2-(4-methylphenyl)-
1(2H)-isoquinolinone (23e): Eluent for column chromatography:
hexanes/ethyl acetate (9:1 v/v), yield 74 mg (60%); white prisms;
m.p. 130–132 °C (diethyl ether). 1H NMR (300 MHz, CDCl3,
25 °C): δ = 1.36 (t, J = 7.2 Hz, 3 H), 2.42 (s, 3 H), 4.34 (q, J =
7.2 Hz, 2 H), 6.10 (s, 2 H), 7.31 (m, 4 H), 7.81 (s, 1 H), 8.14 (s, 1
H), 8.32 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ =
14.4, 21.2, 60.8, 102.1, 104.1, 106.3, 106.8 (s), 121.5 (s), 126.6,
130.1, 131.9 (s), 138.2 (s), 138.7 (s), 139.0, 148.0 (s), 152.8 (s), 161.3
General Procedure for the Preparation of Isoquinolines 22, 23 and
31, and Thieno[3,2-c]pyridine 25: A solution of the appropriate di-
azoacetoacetate 5 or 10 (0.35 mmol) and triphenyliminophos-
phorane (0.35 mmol), in anhydrous toluene (10 mL), was heated at
reflux temperature for 2 h. After cooling, the solvent was removed
under reduced pressure and the resulting crude material was puri-
fied by column chromatography on silica gel.
4Ј-Ethoxycarbonyl-2Ј-(4-methylphenyl)spiro(1,3-dioxolane-2,1Ј-
[1ЈH]isoquinoline) (22a): Eluent for column chromatography: hex-
anes/ethyl acetate (9:1 v/v), yield 0.12 g (99%); white prisms; m.p.
(s), 165.4 (s) ppm. IR (Nujol): ν = 1715 (vs), 1664 (vs), 1488 (vs),
˜
1463 (vs) cm–1. HRMS (ESI): calcd. for C20H18NO5 [M + H]+
352.1179; found 352.1186.
1
130–132 °C (diethyl ether). H NMR (300 MHz, CDCl3, 25 °C): δ
= 1.29 (t, J = 7.2 Hz, 3 H), 2.39 (s, 3 H), 3.57–3.61 (m, 2 H), 4.02–
4.07 (m, 2 H), 4.24 (q, J = 7.2 Hz, 2 H), 7.21–7.25 (m, 2 H), 7.27–
7.32 (m, 1 H), 7.34–7.37 (m, 2 H), 7.40–7.49 (m, 2 H), 7.80 (s, 1
4-Methoxycarbonyl-6,7-(methylenedioxy)-2-(4-methylphenyl)-
1(2H)-isoquinolinone (23f): Eluent for column chromatography:
hexanes/ethyl acetate (9:1 v/v), yield 71 mg (60%); white prisms;
H), 8.60 (dd, J = 0.9, 8.4 Hz, 1 H) ppm. 13C NMR (75 MHz, m.p. 213–215 °C (diethyl ether). 1H NMR (300 MHz, CDCl3,
CDCl3, 25 °C): δ = 14.5, 21.2, 59.5, 66.1, 98.9 (s), 113.5 (s), 123.6, 25 °C): δ = 2.42 (s, 3 H), 3.87 (s, 3 H), 6.12 (s, 2 H), 7.30 (m, 4 H),
124.5, 125.5, 128.0 (s), 129.0, 129.5, 129.6, 129.9 (s), 138.3 (s), 139.4
7.83 (s, 1 H), 8.16 (s, 1 H), 8.33 (s, 1 H) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 21.3, 51.9, 102.1, 104.1, 106.4, 106.6 (s), 121.6
(s), 126.6, 130.1, 131.8 (s), 138.2 (s), 138.8 (s), 139.3, 148.1 (s), 152.9
(s), 143.8 (s), 166.4 (s) ppm. IR (Nujol): ν = 1690 (vs), 1620 (vs),
˜
1604 (vs), 1511 (vs) cm–1. HRMS (ESI): calcd. for C21H22NO4 [M
+ H]+ 352.1543; found 352.1555.
(s), 161.3 (s), 165.8 (s) ppm. IR (Nujol): ν = 1720 (vs), 1699 (vs),
˜
884
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 878–886

Tandem Processes in C-Aryl Ketenes and Ketenimines
1488 (vs), 1462 (m) cm–1. HRMS (ESI): calcd. for C19H16NO5 [M
+ H]+ 338.1023; found 338.1032.
Comprehensive Organic Functional Group Transformations
(Eds.: A. R. Katritzky, O. Meth-Cohn, C. W. Rees), Pergamon,
Cambridge, UK, 1995, vol. 3, p. 555–610; h) H. Perst, Sci.
Synth. 2006, 23, 781–898; i) E. J. Yoo, S. Chang, Curr. Org.
Chem. 2009, 13, 1766–1776; j) P. Lu, Y. Wang, Synlett 2010,
165–173; k) P. Lu, Y. Wang, Chem. Soc. Rev. 2012, 41, 5687–
5705.
4-Ethoxycarbonyl-2-(4-methoxylphenyl)-6,7-(methylenedioxy)-
1(2H)-isoquinolinone (23g): Eluent for column chromatography:
hexanes/ethyl acetate (4:1 v/v), yield 0.10 g (80%); white prisms;
m.p. 181–183 °C (diethyl ether). 1H NMR (400 MHz, CDCl3,
25 °C): δ = 1.36 (t, J = 7.2 Hz, 3 H), 3.86 (s, 3 H), 4.34 (q, J =
7.2 Hz, 2 H), 6.11 (s, 2 H), 7.00 (d, J = 8.8 Hz, 2 H), 7.34 (d, J =
8.8 Hz, 2 H), 7.80 (s, 1 H), 8.13 (s, 1 H), 8.32 (s, 1 H) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 14.4, 55.6, 60.8, 102.0, 104.0,
106.2, 106.8, 114.6, 121.5 (s), 127.9, 131.9 (s), 133.5 (s), 139.1, 148.0
[3] a) P. Molina, M. Alajarin, A. Vidal, J. Feneau-Dupont, J. P.
Declerq, J. Org. Chem. 1991, 56, 4008–4016; b) M. Alajarin,
A. Vidal, F. Tovar, Tetrahedron Lett. 2000, 41, 7029–7032; c)
M. Alajarin, A. Vidal, F. Tovar, Targets Heterocycl. Syst. 2000,
4, 293–326; d) M. Alajarin, M. Marin-Luna, A. Vidal, Eur. J.
Org. Chem. 2012, 5637–5653.
[4] a) M. Alajarin, A. Vidal, M.-M. Ortin, Tetrahedron Lett. 2003,
44, 3027–3030; b) M. Alajarin, A. Vidal, F. Tovar, Tetrahedron
2005, 61, 1531–1537; c) M. Alajarin, P. Sanchez-Andrada, A.
Vidal, F. Tovar, J. Org. Chem. 2005, 70, 1340–1349; d) M. Ala-
jarin, A. Vidal, M.-M. Ortin, Tetrahedron 2005, 61, 7613–7621;
e) M. Alajarin, B. Bonillo, M.-M. Ortin, P. Sanchez-Andrada,
A. Vidal, R.-A. Orenes, Org. Biomol. Chem. 2010, 8, 4690–
4700; f) M. Alajarin, B. Bonillo, M.-M. Ortin, P. Sanchez-And-
rada, A. Vidal, Org. Lett. 2006, 8, 5645–5648; g) M. Alajarin,
B. Bonillo, M.-M. Ortin, P. Sanchez-Andrada, A. Vidal, Eur.
J. Org. Chem. 2011, 1896–1913; h) M. Alajarin, B. Bonillo, P.
Sanchez-Andrada, A. Vidal, D. Bautista, Org. Lett. 2009, 11,
1365–1368; i) M. Alajarin, B. Bonillo, P. Sanchez-Andrada, A.
Vidal, J. Org. Chem. 2010, 75, 3737–3750; j) M. Alajarin, B.
Bonillo, M. Marin-Luna, P. Sanchez-Andrada, A. Vidal, R.-A.
Orenes, Tetrahedron 2012, 68, 4672–4681; k) M. Alajarin, B.
Bonillo, R.-A. Orenes, M.-M. Ortin, A. Vidal, Org. Biomol.
Chem. 2012, 10, 9523–9537.
(s), 152.8 (s), 159.6 (s), 161.4 (s), 165.4 (s) ppm. IR (Nujol): ν =
˜
1712 (vs), 1662 (vs), 1488 (s), 1465 (vs) cm–1. HRMS (ESI): calcd.
for C20H18NO6 [M + H]+ 368.1134; found 368.1123.
7-Ethoxycarbonyl-5-(4-methylphenyl)thieno[3,2-c]pyridin-4(5H)-one
(25): Eluent for column chromatography: hexanes/ethyl acetate (9:1
v/v), yield 60 mg (55 %); white prisms; m.p. 163–165 °C (diethyl
ether). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.36 (t, J = 7.2 Hz,
3 H), 2.42 (s, 3 H), 4.39 (q, J = 7.2 Hz, 2 H), 7.31 (m, 4 H), 7.42
(d, J = 5.4 Hz, 1 H), 7.67 (d, J = 5.4 Hz, 1 H), 8.16 (s, 1 H) ppm.
13C NMR (75 MHz, CDCl3, 25 °C): δ = 14.3, 21.2, 61.4, 106.6 (s),
124.8, 126.5, 127.6, 130.0, 130.1 (s), 137.7 (s), 138.6, 138.9 (s), 145.1
(s), 158.6 (s), 164.3 (s) ppm. IR (Nujol): ν = 1701 (vs), 1664 (vs),
˜
1510 (vs) cm–1. HRMS (ESI): calcd. for C17H16NO3S [M + H]+
314.0845; found 314.0845.
Isoquinoline 31: Eluent for column chromatography: hexanes/ethyl
[5] M. Alajarin, B. Bonillo, M. Marin-Luna, P. Sanchez-Andrada,
A. Vidal, Chem. Eur. J. 2013, 19, 16093–16103.
[6] M. Alajarin, M. Marin-Luna, A. Vidal, Adv. Synth. Catal.
2011, 353, 557–562.
acetate (4:1 v/v), yield 61 mg (45%); white prisms; m.p. 150–152 °C
1
(diethyl ether). H NMR (300 MHz, CDCl3, 25 °C): δ = 1.30 (t, J
= 7.2 Hz, 3 H), 3.33–3.40 (m, 1 H), 3.61–3.67 (m, 1 H), 3.86–4.10
(m, 5 H), 4.13–4.22 (m, 1 H), 4.24–4.29 (m, 2 H), 5.95 (s, 1 H),
7.29 (td, J = 1.2, 7.5 Hz, 1 H), 7.43–7.55 (m, 5 H), 7.75–7.72 (m,
1 H), 7.80 (s, 1 H), 8.64 (d, J = 8.1 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 14.6, 59.6, 65.4, 65.7, 65.8, 66.6, 98.9
(s), 100.0, 113.3 (s), 123.7, 124.7, 125.6, 127.6, 128.0 (s), 129.2,
129.3, 129.8, 130.0 (s), 131.4, 137.6 (s), 140.1 (s), 144.2, 166.4
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(s) ppm. IR (Nujol): ν = 1689 (vs), 1621 (vs), 1485 (s), 1453
˜
(s) cm–1. HRMS (ESI): calcd. for C23H24NO6 [M + H]+ 410.1598;
found 410.1583.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra of compounds 6, 11, 16,
21–23, 25 and 31.
Acknowledgments
This work was supported by the Spanish Ministerio de Ciencia e
Innovación (MICINN) (project number CTQ2008-05827/BQU)
and Fundación Seneca-CARM (project project number 08661/PI/
08).
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Received: October 3, 2013
Published Online: December 2, 2013
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