Palladium-Catalyzed 6-endo-Selective Oxycyclization-Alkene Addition Cascades of ortho-Alkynylarylcarboxamides and α,β-Unsaturated Carbonyl Compounds

Article abstract of DOI:10.1002/ejoc.201500797

Regio- and chemoselective palladium-catalyzed cyclization-coupling cascade reactions between ortho-alkynylarylcarboxamides and methyl vinyl ketone or acrylaldehyde are described. An initial 6-endo-oxypalladation of the triple bond is followed by a C-C cou

Full text of DOI:10.1002/ejoc.201500797

FULL PAPER
DOI: 10.1002/ejoc.201500797
Palladium-Catalyzed 6-endo-Selective Oxycyclization–Alkene Addition
Cascades of ortho-Alkynylarylcarboxamides and α,β-Unsaturated Carbonyl
Compounds
Youssef Madich,[a] Rosana Álvarez,*[b] and José M. Aurrecoechea*[a]
Keywords: Domino reactions / C–C coupling / Cyclization / Palladium / Regioselectivity / Oxygen heterocycles
Regio- and chemoselective palladium-catalyzed cyclization–
coupling cascade reactions between ortho-alkynylaryl-
carboxamides and methyl vinyl ketone or acrylaldehyde are
described. An initial 6-endo-oxypalladation of the triple bond
is followed by a C–C coupling to give structurally diverse
isochromenimines (and related heterosubstituted deriva-
tives), in which the α,β-unsaturated carbonyl moiety is incor-
porated as an alkyl-type exocyclic side chain. The coupling
products were obtained in 76–97% yield (average 86% yield)
without significant interference from Heck or alternative re-
giochemical pathways. In contrast to related cases, these cas-
cade reactions do not require the use of protic solvents and
excess amounts of halide additives, and they proceed effec-
tively under either PdCl2 catalysis in the presence of sub-
stoichiometric amounts of added KI or PdI2 catalysis without
any additive.
Introduction
Palladium-catalyzed heterocyclization–alkene addition
cascade reactions of nucleophile-tethered unsaturated sub-
strates I with α,β-unsaturated ketones and aldehydes have
been used in the synthesis of heterocyclic derivatives IV and
VII (depending on the exo or endo mode of cyclization), in
which an α,β-unsaturated carbonyl framework is incorpo-
rated as an alkyl-type exocyclic side chain (Scheme 1).[1] In
these reactions, substrate I undergoes an intramolecular nu-
cleopalladation, which is followed by an alkene insertion
and protonation of the resulting palladium enolate III/VI
(or their corresponding O-Pd enolates) to regenerate the
PdII catalyst.[2–5] The success of this process has normally
relied upon the selection of reaction conditions, typically
protic solvents and/or excess amounts of halide salt addi-
tives,[1] that effectively steer the transformation of interme-
diates III/VI towards palladium enolate protonation rather
than β-H elimination, a competing process that would lead
to the alternative Heck-type products.
Scheme 1. The exo and endo pathways for Pd-catalyzed hetero-
cyclization–alkene addition cascade reactions.
The Heck pathway is followed, for example, by ortho-
alkynylarylcarboxamides 3 (among other substrates) in pal-
ladium-catalyzed couplings with electron-deficient alkenes
under oxidative conditions (Scheme 2). These reactions
[a] Departamento de Química Orgánica II, Facultad de Ciencia y have been shown to afford either isobenzofuranimine-[6a] or
isochromenimine-type[6b–6d] products (i.e., 4 or 5, respec-
Tecnología, Universidad del País Vasco (UPV/EHU),
Apartado 644, 48080 Bilbao, Spain
tively) with high regioselectivity in each case. We now re-
port that, under modified reaction conditions, a new family
of products, namely, carbonyl derivatives 6, can be prepared
from the same substrates 3 and methyl vinyl ketone or
acrylaldehyde, as a result of the regioselective oxycycli-
zation–formal conjugate addition cascade reactions that
take place to the exclusion of the alternative Heck products
E-mail: jm.aurrecoechea@ehu.eus
http://www.ehu.eus/es/web/quimicaorganica2
[b] Departamento de Química Orgánica, Facultad de Química,
Universidade de Vigo,
Campus As Lagoas-Marcosende, 36310 Vigo, Spain
E-mail: rar@uvigo.es
http://webs.uvigo.es/delera/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500797.
6298
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Pd-Catalyzed Selective Oxycyclization–Alkene Addition Cascades
4/5 (Scheme 2). Structures 6 are representative of isochrom- stantial recovery of starting compound 3a (Table 1, En-
enimines (among other compounds), which are the subject tries 10 and 11). A control experiment further confirmed
of current synthetic interest because of their biological pro- the need of a palladium catalyst to trigger the reactivity of
files and for being nitrogen analogues of the biologically substrate 3a (Table 1, Entry 12).
interesting isocoumarins.[7] Interestingly, in contrast to the
related literature cases alluded to above,[1] the 3-to-6 cou-
pling reactions are effective without resorting to the use of
Table 1. Survey of conditions for palladium-catalyzed cyclization–
coupling cascade reactions of 3a and methyl vinyl ketone.[a]
excess amounts of halide salts. In fact, PdI2 alone as a cata-
lyst, without further additives, is enough to selectively direct
the reaction towards the formation of products 6 by follow-
ing the protonation pathway of VI to VII as depicted in
Scheme 1.
Entry [Pd]
Additive Atmosphere
[equiv.]
T
5a/6a[b] % Yield
5a, 6a
[°C], t [h]
1
2
3
4
5
6
7
8
PdCl2(PPh3)2 KI (0.5)
PdCl2(PPh3)2 KI (0.5)
air
80, 7
72:28
55:45
13:87
26:74
71, 20
46, 38[c]
10, 78
21, 59[c]
86
air
air
air
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
50, 42
50, 16
50, 16
50, 16
50, 16
50, 15
50, 16
50, 16
50, 16
50, 16
50, 13
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdI2
KI (0.5)
–
KI (0.5)
KI (0.3)
KI (0.1)
KI (0.05)
–
–
–
–
[d]
–
3:97
2:98
1:99
3:97
8:92
18:82
–
3, 84[c]
–, 89
1, 89
2, 86
9
10
11
12
PdCl2
PdBr2
–
1, 24[e]
5, 23[c,e]
4, Ͻ1[c,e]
[a] Relative amounts of reagents: Pd catalyst (5 mol-%), KI (equiv.
indicated above), and methyl vinyl ketone (6 equiv.). [b] The crude
Scheme 2. Palladium-catalyzed cyclization–coupling cascade reac-
tions of ortho-alkynylarylcarboxamides and electron-deficient alk-
enes.
1
product was used to determine 5a/6a. [c] Yields determined by H
NMR analysis of the crude product by using an internal standard.
1
[d] A trace amount of Heck product 5a was observed by H NMR
analysis of the crude mixture. [e] Amount of unreacted starting ma-
terial 3a: 64% in Entry 10, 46% in Entry 11, 89% in Entry 12.
Results and Discussion
Next, the scope of this reaction was investigated by using
We previously reported that under typical conditions for
the formation of alkenes 5, which included PdCl2(PPh3)2
as the catalyst with KI (0.5 equiv.) as the additive in N,N-
dimethylformamide (DMF) under air at 80 °C, the reaction
of 3a with methyl vinyl ketone provided 6a in 20% yield in
addition to the expected major product 5a (Table 1, En-
try 1).[6b,6c] We have subsequently found that the formation
of 6a is favored by lowering the reaction temperature and
using a phosphine-free palladium catalyst (Table 1, En-
tries 2 and 3). Thus, by using PdCl2 at 50 °C, 6a was already
obtained as the major product. However, when KI was
omitted from the reaction mixture, the selectivity dropped
(Table 1, Entry 4). A further improvement was realized
when the reaction was carried out under Ar, whereupon
6a was obtained almost exclusively in high isolated yield
(Table 1, Entry 5). Interestingly, KI amounts as low as
0.05 equiv. still delivered 6a with the same efficiency as
achieved by 0.5 equiv. (Table 1, Entries 6–8). Furthermore,
the formation of 6a was equally successful when PdI2 was
employed as the catalyst, even without the addition of KI
(Table 1, Entry 9). Significantly, under otherwise identical
reaction conditions, the similar use of PdCl2 and PdBr2 led
representative ortho-alkynylbenzamides 3 (Table 2). Ini-
Table 2. Reactions of 3 with methyl vinyl ketone under PdI2 cataly-
sis.[a]
Entry
3
R1
R2
t [h]
6, 7
% Yield
1
2
3
4
5
6
3a
3d
3e
3g
3h
3j
nBu
nBu
Ph
nhexyl
Ph
16
15
16
17
17
24
6a
6d
6e
6g
6h, 7h
6j, 7j
86
84
89
86
CH2Ph
pMeOC6H4 nhexyl
pCNC6H4
pMeC6H4
nhexyl
Ph
15, 75[b]
70, 18[c]
[a] Unless otherwise indicated, the reaction conditions were the
same as those of Table 1, Entry 9. [b] Amine 8h[8] (62% yield) was
to lower selectivity and sluggish reactivity along with sub- also isolated. [c] Amine 8j[8b] (5% yield) was also obtained.
Eur. J. Org. Chem. 2015, 6298–6305
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Y. Madich, R. Álvarez, J. M. Aurrecoechea
FULL PAPER
tially, the reaction conditions that employed PdI2 (Table 1, Table 3. Reactions of 3h with methyl vinyl ketone under PdCl2
catalysis with variable amounts of KI.[a]
Entry 9) were selected, as those were the simplest and af-
forded a high yield of coupling product 6a. The results pre-
sented in Table 2 confirm that PdI2 is indeed a competent
catalyst for the oxycyclization–alkene addition cascade re-
action. However, the data also reveals a limitation in its use.
For example, in the case of substrate 3h (Table 2, Entry 5),
the major coupling product was lactone 7h (75% isolated
yield) and not the expected isochromenimine 6h (15%
yield). Amine 8h[8] was also isolated in 62% yield. Similarly,
lactone 7j (18% yield) and amine 8j[8b] (5% yield) were also
Entry
KI [equiv.]
% Yield[b]
6
% Yield[b]
7
obtained in the case of substrate 3j (Table 2, Entry 6). It is
apparent that substrates derived from aromatic amines are
particularly prone to this side reaction. Nevertheless, de-
spite these shortcomings, the oxycyclization–conjugate ad-
dition cascade reactions were still efficient, as shown by the
combined yields of 6 and 7 (Ն90%) in those two cases.
The formation of lactone 7h was dependent on the
amount of iodide anion in the reaction mixture. The results
in Table 3 show a comparison between reactions of 3h that
were carried out under PdCl2 catalysis but with variable
1
2
3
4
0.05
0.10
0.30
0.50
9
47
89
47
13
–
85
98 (93)[c]
[a] Relative amounts of reagents: PdCl2 (5 mol-%), KI (as indicated
above), and methyl vinyl ketone (6 equiv.). [b] Yields were deter-
mined by H NMR analysis of the crude product by using an in-
1
ternal standard. [c] Isolated yield.
amounts of KI. In contrast to the formation of 6a, which try 4) to completely avoid the formation of lactone 7h.[9] In
efficiently occurred by using only 5 mol-% of KI (Table 1, a preparative run, under the conditions reported in Table 3,
Entry 8), the corresponding reaction of 3h required quanti- Entry 4, isochromenimine 6h was isolated in 93% yield (see
ties in the order of 50 mol-% of that additive (Table 4, En- Table 4).
Table 4. Reactions of 3 with methyl vinyl ketone or acrylaldehyde under PdCl2/KI catalysis.[a]
[a] Unless otherwise indicated, reaction conditions were the same as those of Table 3, Entry 4. [b] This reaction afforded a 95% yield of
a mixture of 6j and isomers as indicated by HPLC/HRMS analysis. From that mixture, a yield of 85% was estimated for 6j by 1H
NMR analysis using (3,4-dimethoxyphenyl)acetonitrile as the internal standard. Repeated column chromatography provided pure 6j for
characterization. [c] Reaction performed at 80 °C. [d] This product could not be purified by column chromatography because of decompo-
1
sition. The yield was estimated from the crude product by H NMR analysis using 1,2,4,5-tetramethylbenzene as the internal standard.
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Pd-Catalyzed Selective Oxycyclization–Alkene Addition Cascades
Using a combination of PdCl2 and KI (Table 3, Entry 4) (i.e., 6) products, respectively. Under the appropriate PdI2-
proved to be of general use for the conversion of structur- or PdCl2/KI-catalyzed conditions, the conjugate addition
ally diverse alkynylarylcarboxamides 3 (prepared from car- pathway operates to the exclusion of the alternative alkenyl-
boxamides 1 and alkynes 2, Scheme 2) into isochromenim- ation reaction, whereas PdBr2 or PdCl2 (without added KI)
ine (and related) heterocyclic structures 6 in yields that are much less effective. Although the effect of the iodide
ranged from high to very high (76–97% yield, average 87% anion on these reactions cannot be conveniently rational-
yield, Table 4). The reaction is compatible with alkyl or aryl ized at this point, these overall observations add to a
substituents at both the alkynyl terminus and the nitrogen number of recent reports that highlight the beneficial effect
atom (Table 4). Aryl substituents that have different elec- of iodide anions in cycloisomerizations[10] and other palla-
tronic characteristics are well tolerated, and all of the vari- dium-catalyzed reactions.[4,6b,6c,11]
ous combinations of R1-R2 groups, such as aryl-aryl, aryl-
An alternative mechanism for the formation of 6 could
alkyl, alkyl-aryl, and alkyl-alkyl, were successful. Similarly, involve a stepwise cycloisomerization–conjugate addition
the reaction is tolerant of other substituents at the benz- pathway through alkene 12, as similarly described for the
amide-type aryl ring, and various heterocyclic motifs were corresponding reactions of 2-alkynylanilines.[5] However,
readily incorporated into products 6 (i.e., 6k–6o). Finally, this pathway was effectively ruled out by the experiment
the application of the general conditions of Table 4 to acryl- shown in Scheme 4, in which cycloisomerization product
1
aldehyde as a coupling agent, instead of methyl vinyl 12a[7c] (derived from 3a) was recovered (86% yield by H
ketone, was examined. The coupling reaction between sub- NMR analysis and no formation of 6a) when submitted to
strate 3a and acrylaldehyde yielded the corresponding prod- the standard reaction conditions for the formation of 6.
uct 6p with comparably good results.
This reaction is remarkably regioselective for the 6-endo-
dig-type O-cyclization mode. In the case of 6j, other iso-
mers, which presumably result from the alternative 5-exo-
dig cyclization, were observed in small amounts by HPLC/
MS analysis, but the yield of this major isochromenimine
Scheme 4. Experiment to test an alternative mechanistic pathway.
product still remained quite high. Trace amounts of Heck
products 5 were also occasionally detected in the crude H
1
NMR spectrum. However, the formation of lactones 7 was
not observed under these conditions.
Conclusions
A reasonable reaction mechanism is shown in Scheme 3.
The pathways that lead to products 5 and 6 expectedly di-
verge at palladium enolate intermediate 11, which is formed
as a result of oxypalladation and alkene insertion steps
from initial coordinated complex 9. From 11, the competing
processes of β-H elimination and protonation would then
lead to alkenylation (i.e., 5) and formal conjugate addition
In summary, ortho-alkynylarylcarboxamides are suitable
substrates for oxypalladation–formal conjugate addition
cascade reactions by using methyl vinyl ketone or acryl-
aldehyde as the reaction partner. The overall process is cata-
lyzed by PdII and proceeds effectively either with PdCl2 and
KI as an additive or directly with PdI2 alone. In contrast,
when PdCl2 or PdBr2 catalysts are used without a KI addi-
tive, the reactions suffer from lower selectivity and reactiv-
ity. The initial intramolecular alkyne oxypalladation takes
place with high endo selectivity to yield isochromenimine-
type products. There is almost no interference from compet-
ing Heck-type products or alternative regiochemical path-
ways, and the reaction results in uniformly high yields of
coupling products. Amides derived from aromatic as well as
aliphatic amines participate with equal success, and various
heterocyclic motifs are readily incorporated into the final
products. This procedure complements those also high-
lighted in Scheme 2, in that it provides an additional entry
into the preparation of structurally diverse families of inter-
esting structures from a given set of starting materials by a
simple choice of catalyst and additive.
Experimental Section
General Methods: All reactions involving air- and moisture-sensi-
tive materials were performed under dry Ar. Triethylamine, di-
chloromethane, and toluene were distilled from CaH2 and purged
with Ar. Commercially sourced DMF (Ն99.8%) was kept over mo-
Scheme 3. Suggested mechanism for Pd-catalyzed oxycyclization–
coupling reactions of ortho-alkynylarylcarboxamides with methyl
vinyl ketone or acrylaldehyde.
Eur. J. Org. Chem. 2015, 6298–6305
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Y. Madich, R. Álvarez, J. M. Aurrecoechea
FULL PAPER
lecular sieves (MS, 4 Å) under Ar. Flash column chromatography
was carried out using silica gel (230–400 mesh). The 1H and 13C
NMR spectroscopic data were recorded at 25 °C with Bruker AV-
300 (300 MHz for 1H NMR and 75.4 MHz for 13C NMR) and
Bruker AV-500 spectrometers (500 MHz for 1H NMR and
125.7 MHz for 13C NMR) by using CDCl3 or [D6]acetone as the
the representative procedure for a reaction time of 16 h. The crude
product was purified by flash chromatography (silica gel saturated
with Et3N; hexanes/EtOAc/Et3N, from 89:10:1 to 74:25:1) to afford
6b (111 mg, 90 %) as a yellow solid; m.p. 75–77 °C. 1H NMR
(300 MHz, CDCl3): δ = 0.93 (t, J = 7.3 Hz, 3 H), 1.37–1.49 (m, 2
H), 1.59–1.69 (m, 2 H), 2.11 (s, 3 H), 2.64–2.69 (m, 2 H), 2.86–2.91
(m, 2 H), 3.45 (t, J = 7.1 Hz, 2 H), 3.87 (s, 3 H), 6.98 (d, J =
8.8 Hz, 2 H), 7.29–7.37 (m, 2 H), 7.43 (d, J = 8.8 Hz, 2 H), 7.48–
1
solvent and internal reference (CHCl3: δ = 7.26 ppm for H NMR,
CDCl3: δ = 77.0 ppm for 13C NMR; [D5]acetone: δ = 2.05 ppm for
1H NMR, [D6]acetone: δ = 29.84 ppm for 13C NMR). Coupling 7.53 (m, 1 H), 8.26 (dd, J = 7.4, 1.0 Hz, 1 H) ppm. 13C NMR
constants (J) are reported in Hertz (Hz). The DEPT sequence was
routinely used for multiplicity assignments for the 13C NMR. Infra-
red spectral data were obtained by using a thin film deposited onto
NaCl glass and then measured on a Jasco FT/IR 4100 in the inter-
val between 4000 and 600 cm–1. The data include only characteris-
tic absorptions. Electron impact mass spectra were obtained on a
Hewlett–Packard HP59970 instrument operating at 70 eV. Chemi-
cal ionization mass spectra were acquired on an Agilent 6890N gas
chromatograph coupled to a mass spectrometer with a Micromass
(75.5 MHz, CDCl3): δ = 14.0 (CH3), 20.8 (2 CH2), 29.9 (CH3), 33.0
(CH2), 43.4 (CH2), 46.0 (CH2), 55.3 (CH3), 109.5 (C), 113.8 (2 CH),
122.1 (CH), 124.8 (C), 126.5 (C), 126.9 (CH), 127.4 (CH), 130.0 (2
CH), 131.4 (CH), 133.1 (C), 150.0 (C), 150.3 (C), 160.1 (C), 207.5
(C) ppm. IR (film): ν = 1713 (s), 1660 (s), 1633 (m), 1602 (s) cm–1.
˜
MS (EI): m/z (%) = 377 (18) [M]+, 361 (17), 360 (73), 348 (12), 335
(13), 334 (45), 321 (16), 320 (74), 306 (22), 278 (13), 277 (14), 276
(69), 265 (16), 264 (100), 263 (11), 242 (14), 237 (11), 242 (14), 237
(11), 236 (29), 205 (10), 156 (15), 135 (80), 128 (56), 107 (11).
GCT time of flight analyzer. HPLC/MS data were obtained by HRMS (EI): calcd. for C24H27NO3 [M]+ 377.1991; found 377.1990.
using a binary Agilent G1312A pump with an Agilent DAD
Methyl 4-[(Z)-1-(Butylimino)-4-(3-oxobutyl)-1H-isochromen-3-yl]-
G1315B detector and a ZORBAX eclipse XDB-C8 (4.6ϫ150 mm,
benzoate (6c): Compound 3c (100 mg, 0.298 mmol) was used in the
5 μm) column. Samples were eluted by using a mixture of H2O
representative procedure for a reaction time of 16 h. The crude
(containing 0.1% formic acid) and acetonitrile (containing 0.1%
product was purified by flash chromatography (silica gel saturated
formic acid) from 70:30 to 10:90 over 30 min at a flow rate of
with Et3N; hexanes/EtOAc/Et3N, from 84:15:1 to 74:25:1) to afford
0.2 mLmin–1. Electrospray ionization mass spectra were obtained
6c (92 mg, 76 %) as a yellow solid; m.p. 98–100 °C. 1H NMR
(300 MHz, CDCl3): δ = 0.93 (t, J = 7.3 Hz, 3 H), 1.37–1.48 (m, 2
by a micrOTOF focus mass spectrometer (Bruker Daltonics) using
an Apollo II ESI source with a voltage of 4500 V applied to the
H), 1.60–1.68 (m, 2 H), 2.11 (s, 3 H), 2.65–2.70 (m, 2 H), 2.85–2.90
needle and a counter voltage between 100 and 150 V applied to the
(m, 2 H), 3.44 (t, J = 7.1 Hz, 2 H), 3.95 (s, 3 H), 7.31–7.41 (m, 2
capillary. Melting points were measured in open capillary tubes on
H), 7.52 (d, J = 7.6 Hz, 1 H), 7.58 (d, J = 8.4 Hz, 2 H), 8.14 (d, J =
a Büchi B-540 apparatus. The O-cyclized ring structure of com-
8.4 Hz, 2 H), 8.27 (d, J = 7.8 Hz, 1 H) ppm. 13C NMR (75.5 MHz,
pounds 6 was indicated by the absence of a carboxamide-type carb-
CDCl3): δ = 14.0 (CH3), 20.5 (CH2), 20.7 (CH2), 29.9 (CH3), 32.9
onyl carbon in the 13C NMR spectra.[12] Additionally, the IR imino
(CH2), 43.2 (CH2), 46.0 (CH2), 52.3 (CH3), 111.1 (C), 122.3 (CH),
group band was in the range of 1650–1665 cm–1, typical of six-
125.0 (C), 127.0 (CH), 128.0 (CH), 128.7 (2 CH), 129.7 (2 CH),
membered cyclic imidates,[12a] and 2D NMR correlations [COSY,
130.6 (C), 131.6 (CH), 132.5 (C), 138.3 (C), 149.2 (C), 149.4 (C),
heteronuclear single quantum correlation (HSQC), HMBC, and
166.4 (C), 207.0 (C) ppm. IR (film): ν = 1718 (s), 1661 (s), 1608
˜
NOESY] also displayed the expected data. X-ray analysis of a
single crystal confirmed the structural assignment of products 6j
and 6n (Figure S1, Supporting Information) and, by analogy, the
remainders of products 6.
(m) cm–1. MS (EI): m/z (%) = 405 (8) [M]+, 389 (16), 388 (59), 376
(17), 363 (23), 362 (74), 349 (15), 348 (62), 334 (20), 333 (18), 330
(11), 292 (14), 270 (24), 261 (19), 260 (100), 248 (11), 242 (14), 233
(14), 232 (18), 204 (20), 163 (31). HRMS (EI): calcd. for
C25H27NO4 [M]+ 405.1940; found 405.1944.
Representative Procedure for Heterocyclization-Alkene Addition
Cascade Reactions. Preparation of Isochromenimines-Type Products
6: To a solution of 3 (0.350 mmol) in DMF (3.0 mL) were added
3-buten-2-one or prop-2-enal (2.10 mmol), KI (29 mg,
0.175 mmol), and PdCl2 (3.1 mg, 18 μmol), and the resulting mix-
ture was then heated for the times indicated below at 50 °C under
Ar. The mixture was cooled to 25 °C, and a saturated NaCl solu-
tion (5 mL) was added. The mixture was extracted with EtOAc (3ϫ
10 mL), and the combined organic layers were dried with Na2SO4.
The solvent was removed, and the residue was purified by flash
chromatography (silica gel saturated with Et3N, mixtures of hex-
anes/EtOAc/Et3N) to afford products 6 in the yields reported in
Table 4. Alternatively, PdI2 (6.5 mg, 18 μmol) was used in place of
PdCl2/KI with the reaction times and yields indicated in Table 2.
Additional preparation and characterization details are given be-
low for the individual cases.
4-[(Z)-1-(Butylimino)-3-hexyl-1H-isochromen-4-yl]butan-2-one (6d):
Compound 3d[6a] (100 mg, 0.350 mmol) was used in the representa-
tive procedure for a reaction time of 15 h. The crude product was
purified by flash chromatography (silica gel saturated with Et3N;
hexanes/EtOAc/Et3N, 98:1:1) to afford 6d (107 mg, 86%) as a yel-
low oil. 1H NMR (300 MHz, CDCl3): δ = 0.87–0.98 (m, 6 H), 1.31–
1.48 (m, 8 H), 1.59–1.69 (m, 4 H), 2.16 (s, 3 H), 2.48 (t, J = 7.5 Hz,
2 H), 2.61–2.68 (m, 2 H), 2.75–2.81 (m, 2 H), 3.45 (t, J = 7.1 Hz,
2 H), 7.20 (d, J = 7.9 Hz, 1 H), 7.25–7.30 (m, 1 H), 7.43–7.48 (m,
1 H), 8.19 (d, J = 7.9 Hz, 1 H) ppm. 13C NMR (75.5 MHz, CDCl3):
δ = 14.0 (2 CH3), 19.9 (CH2), 20.8 (CH2), 22.5 (CH2), 27.4 (CH2),
28.9 (CH2), 30.1 (CH3), 30.4 (CH2), 31.6 (CH2), 32.9 (CH2), 43.0
(CH2), 45.8 (CH2), 108.1 (C), 121.3 (CH), 124.4 (C), 126.8 (2 CH),
131.3 (CH), 133.0 (C), 150.3 (C), 152.6 (C), 207.7 (C) ppm. IR
(film): ν = 1717 (s), 1664 (s), 1641 (m) cm–1. MS (EI): m/z (%) =
˜
4-[(Z)-1-(Butylimino)-3-phenyl-1H-isochromen-4-yl]butan-2-one
(6a):[6b] Compound 3a[13] (100 mg, 0.360 mmol) was used in the
representative procedure for a reaction time of 16 h. The crude
product was purified by flash chromatography (silica gel saturated
with Et3N; hexanes/EtOAc/Et3N, 90:8:2) to afford 6a[6b] (108 mg,
86%).
355 (11) [M]+, 326 (25), 313 (22), 312 (98), 299 (11), 298 (49), 271
(19), 270 (100), 256 (12), 243 (11), 242 (48), 214 (12), 212 (53), 186
(14), 184 (18), 172 (19), 168 (11), 158 (10), 156 (15), 144 (19), 143
(14), 130 (27), 129 (12), 128 (29), 116 (11), 115 (16). HRMS (EI):
calcd. for C23H33NO2 [M]+ 355.2511; found 355.2507.
4-[(Z)-1-(Butylimino)-3-(4-methoxyphenyl)-1H-isochromen-4-yl]but- 4-[(Z)-1-(Benzylimino)-3-phenyl-1H-isochromen-4-yl]butan-2-one
an-2-one (6b): Compound 3b (100 mg, 0.325 mmol) was used in
(6e): Compound 3e[14] (100 mg, 0.321 mmol) was used in the repre-
6302
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6298–6305

Pd-Catalyzed Selective Oxycyclization–Alkene Addition Cascades
sentative procedure for a reaction time of 18 h. The crude product
was purified by flash chromatography (silica gel saturated with
Et3N; hexanes/EtOAc/Et3N, from 95:3:2 to 92:6:2) to afford 6e
2.69 (m, 2 H), 2.81–2.86 (m, 2 H), 7.17 (d, J = 8.4 Hz, 2 H), 7.34
(d, J = 7.9 Hz, 1 H), 7.43 (t, J = 7.5 Hz, 1 H), 7.59–7.64 (m, 3 H),
8.38 (d, J = 7.9 Hz, 1 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ =
(113 mg, 92 %) as a yellow solid; m.p. 123–124 °C. 1H NMR 14.0 (CH3), 19.7 (CH2), 22.3 (CH2), 27.4 (CH2), 28.6 (CH2), 30.0
(300 MHz, CDCl3): δ = 2.11 (s, 3 H), 2.66–2.71 (m, 2 H), 2.88– (CH3), 30.1 (CH2), 31.4 (CH2), 42.8 (CH2), 106.1 (C), 109.9 (C),
2.93 (m, 2 H), 4.69 (s, 2 H), 7.21–7.26 (m, 1 H), 7.30–7.39 (m, 4
119.6 (C), 121.8 (CH), 123.0 (C), 123.3 (2 CH), 127.5 (CH), 128.0
H), 7.40–7.47 (m, 7 H), 7.56 (ddd, J = 7.9, 7.4, 1.4 Hz, 1 H), 8.42 (CH), 132.7 (2 CH), 133.0 (CH), 134.1 (C), 151.4 (C), 151.8 (C),
(dd, J = 7.9, 1.0 Hz, 1 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ
152.6 (C), 207.2 (C) ppm. IR (film): ν = 2222 (m, CϵN), 1715 (m),
˜
= 20.8 (CH2), 30.0 (CH3), 43.5 (CH2), 50.1 (CH2), 110.6 (C), 122.4 1660 (s), 1629 (s), 1592 (s) cm–1. MS (EI): m/z (%) = 400 (100)
(CH), 124.9 (C), 126.4 (CH), 127.4 (CH), 127.8 (CH), 127.9 (CH), [M]+, 357 (16), 344 (23), 343 (89), 330 (11), 315 (18), 287 (19), 285
128.3 (CH), 128.6 (CH), 128.9 (CH), 129.4 (CH), 131.9 (CH), 133.1 (12), 274 (13), 273 (68), 272 (36), 271 (17), 260 (39), 259 (10), 257
(C), 134.0 (C), 141.2 (C), 150.5 (C), 151.0 (C), 207.5 (C) ppm. IR
(22), 255 (15), 245 (37), 244 (25), 243 (39), 242 (28), 232 (18), 231
(film): ν = 1714 (s), 1658 (s), 1604 (m) cm–1. MS (EI): m/z (%) = (92), 230 (14), 229 (39), 225 (28). HRMS (EI): calcd. for
˜
381 (24) [M]+, 290 (15), 105 (46), 91 (100), 77 (10). HRMS (EI):
calcd. for C26H23NO2 [M]+ 381.1729; found 381.1721.
C26H28N2O2 [M]+ 400.2151; found 400.2153. Alternatively, the re-
action was conducted by using compound 3h[6a] (57.0 mg,
0.172 mmol), 3-buten-2-one (84 μL, 1.035 mmol), and PdI2
(3.10 mg, 8.6 μmol; Table 2, Entry 5), and the crude product was
purified by flash chromatography (silica gel saturated with Et3N;
hexanes/EtOAc/Et3N, from 92:7:1 to 40:59:1) to afford 7h[2]
(39.5 mg, 75%), 6h (8.5 mg, 15%), and 8h[8] (20 mg, 62%).
4-[(Z)-3-Hexyl-1-(phenylimino)-1H-isochromen-4-yl]butan-2-one
(6f): Compound 3f[7a] (100 mg, 0.327 mmol) was used in the repre-
sentative procedure for a reaction time of 16 h. The crude product
was purified by flash chromatography (silica gel saturated with
Et3N; hexanes/EtOAc/Et3N, 98.5:0.5:1 to 98:1:1) to afford 6f
1
4-[(Z)-1-(4-Chlorophenylimino)-3-hexyl-1H-isochromen-4-yl]butan-
2-one (6i): Compound 3i[6a] (100 mg, 0.294 mmol) was used in the
representative procedure for a reaction time of 18 h. The crude
product was purified by flash chromatography (silica gel saturated
with Et3N; hexanes/EtOAc/Et3N, from 98.5:0.5:1 to 97:2:1) to af-
(117 mg, 95%) as a yellow oil. H NMR (300 MHz, CDCl3): δ =
0.87 (m, 3 H), 1.24–1.31 (m, 6 H), 1.45–1.52 (m, 2 H), 2.18 (s, 3
H), 2.41 (t, J = 7.4 Hz, 2 H), 2.63–2.69 (m, 2 H), 2.79–2.85 (m, 2
H), 7.07 (t, J = 7.3 Hz, 1 H), 7.15 (d, J = 7.3 Hz, 2 H), 7.28–7.41
(m, 4 H), 7.53–7.59 (m, 1 H), 8.41 (dd, J = 7.8, 0.8 Hz, 1 H) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 14.0 (CH3), 19.8 (CH2), 22.4
(CH2), 27.3 (CH2), 28.7 (CH2), 30.1 (CH3), 30.2 (CH2), 31.5 (CH2),
43.0 (CH2), 109.1 (C), 121.5 (CH), 122.7 (2 CH), 123.3 (CH), 123.9
(C), 127.2 (CH), 127.8 (CH), 128.5 (2 CH), 132.3 (CH), 133.9 (C),
1
ford 6i (110 mg, 91%) as a yellow solid; m.p. 62–63 °C. H NMR
(300 MHz, CDCl3): δ = 0.85–0.90 (m, 3 H), 1.25–1.30 (m, 6 H),
1.45–1.52 (m, 2 H), 2.18 (s, 3 H), 2.41 (t, J = 7.4 Hz, 2 H), 2.63–
2.68 (m, 2 H), 2.80–2.85 (m, 2 H), 7.09 (d, J = 8.7 Hz, 2 H), 7.27–
7.32 (m, 3 H), 7.37–7.42 (m, 1 H), 7.55–7.60 (m, 1 H), 8.38 (d, J
= 8.0 Hz, 1 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 14.0
(CH3), 19.8 (CH2), 22.4 (CH2), 27.4 (CH2), 28.7 (CH2), 30.1 (CH3),
30.1 (CH2), 31.5 (CH2), 42.9 (CH2), 109.4 (C), 121.6 (CH), 123.6
(C), 124.1 (2 CH), 127.3 (CH), 127.8 (CH), 128.3 (C), 128.5 (2
CH), 132.5 (CH), 133.9 (C), 145.4 (C), 150.6 (C), 152.7 (C), 207.4
146.8 (C), 150.1 (C), 152.7 (C), 207.5 (C) ppm. IR (film): ν = 1717
˜
(s), 1660 (s), 1631 (s) cm–1. MS (EI): m/z (%) = 376 (20), 375 (77)
[M]+, 332 (14), 319 (22), 318 (100), 290 (12), 262 (12), 248 (22), 247
(12), 235 (14), 225 (16), 220 (18), 219 (12), 218 (27), 217 (19), 207
(15), 206 (74), 205 (10), 204 (31). HRMS (EI): calcd. for
C25H29NO2 [M]+ 375.2198; found 375.2197.
(C) ppm. IR (film): ν = 1716 (m), 1659 (s), 1630 (s) cm–1. MS (EI):
˜
m/z (%) = 411 (35) [M, 37Cl]+, 410 (29), 409 (100) [M, 35Cl]+, 366
(17), 354 (33), 353 (23), 352 (97), 324 (18), 296 (17), 284 (11), 283
(11), 282 (36), 281 (15), 280 (11), 269 (21), 266 (14), 256 (11), 255
(11), 254 (27), 253 (22), 252 (19), 242 (28), 241 (18), 240 (76), 238
(17), 225 (27), 218 (13), 217 (17), 205 (16), 204 (31), 203 (13).
HRMS (EI): calcd. for C25H2835ClNO2 [M]+ 409.1809; found
409.1808; calcd. for C25H2837ClNO2 [M]+ 411.1779; found
411.1782.
4-[(Z)-3-Hexyl-1-(4-methoxyphenylimino)-1H-isochromen-4-yl]but-
an-2-one (6g): Compound 3g[7a] (100 mg, 0.298 mmol) was used in
the representative procedure for a reaction time of 18 h. The crude
product was purified by flash chromatography (silica gel saturated
with Et3N; hexanes/EtOAc/Et3N, 97:2:1 to 91:8:1) to afford 6g
1
(117 mg, 97%) as a yellow oil. H NMR (300 MHz, CDCl3): δ =
0.85–0.90 (m, 3 H), 1.27–1.35 (m, 6 H), 1.51–1.58 (m, 2 H), 2.18
(s, 3 H), 2.42–2.47 (m, 2 H), 2.63–2.68 (m, 2 H), 2.80–2.85 (m, 2
H), 3.82 (s, 3 H), 6.89 (dd, J = 8.9, 2.1 Hz, 2 H), 7.19–7.29 (m, 3
H), 7.37 (t, J = 7.6 Hz, 1 H), 7.51–7.56 (m, 1 H), 8.40 (d, J =
7.9 Hz, 1 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 14.0 (CH3),
19.9 (CH2), 22.4 (CH2), 27.5 (CH2), 28.8 (CH2), 30.1 (CH3), 30.2
(CH2), 31.6 (CH2), 43.0 (CH2), 55.4 (CH3), 109.1 (C), 113.7 (2 CH),
121.5 (CH), 124.3 (2 CH, 1 C), 127.2 (CH), 127.6 (CH), 132.0
(CH), 133.7 (C), 139.6 (C), 149.5 (C), 152.7 (C), 155.9 (C), 207.6
4-[(Z)-3-Phenyl-1-(p-tolylimino)-1H-isochromen-4-yl]butan-2-one
(6j): Compound 3j[15] (100 mg, 0.321 mmol) was used in the repre-
sentative procedure for a reaction time of 17 h. The crude product
was purified by flash chromatography (silica gel saturated with
Et3N; hexanes/EtOAc/Et3N, from 95:4:1 to 92:7:1) to afford 6j
[85 % yield estimated by 1H NMR analysis using (3,4-dimeth-
oxyphenyl)acetonitrile as an internal standard; the isomeric rela-
tionship was confirmed by HPLC/HRMS analysis]. Column
chromatography was repeated to afford pure 6j as a yellow solid for
(C) ppm. IR (film): ν = 1716 (m), 1657 (s), 1632 (s), 1505 (s) cm–1.
˜
MS (EI): m/z (%) = 405 (100) [M]+, 390 (14), 349 (13), 348 (49),
237 (13), 236 (72), 234 (14), 204 (11), 123 (14). HRMS (EI): calcd.
for C26H31NO3 [M]+ 405.2304; found 405.2306.
1
characterization; m.p 139–141 °C. H NMR (300 MHz, CDCl3): δ
= 2.12 (s, 3 H), 2.30 (s, 3 H), 2.67–2.73 (m, 2 H), 2.91–2.96 (m, 2
4-[3-Hexyl-4-(3-oxobutyl)isochromen-1-ylidene]-(Z)-aminobenzo- H), 7.08 (d, J = 8.0 Hz, 2 H), 7.17 (d, J = 8.2 Hz, 2 H), 7.38–7.48
nitrile (6h): Compound 3h[6a] (100 mg, 0.303 mmol) was used in (m, 7 H), 7.60 (t, J = 7.7 Hz, 1 H), 8.48 (d, J = 7.9 Hz, 1 H) ppm.
the representative procedure for a reaction time of 18 h. The crude
product was purified by flash chromatography (silica gel saturated
with Et3N; hexanes/EtOAc/Et3N, 95:4:1 to 87:12:1) to afford 6h
13C NMR (75.5 MHz, CDCl3): δ = 20.6 (CH2), 20.9 (CH3), 29.8
(CH3), 43.3 (CH2), 110.0 (C), 122.3 (CH), 123.1 (2 CH), 124.7 (C),
127.9 (2 CH), 128.4 (2 CH), 128.7 (2 CH), 129.1 (2 CH), 129.2
(113 mg, 93 %) as a yellow solid; m.p. 93–95 °C. 1H NMR (CH), 132.2 (CH), 133.0 (C), 133.4 (C), 133.6 (C), 143.4 (C), 149.0
(300 MHz, CDCl3): δ = 0.85–0.89 (m, 3 H), 1.17–1.30 (m, 6 H), (C), 150.3 (C), 207.2 (C) ppm. IR (film): ν = 1713 (s), 1655 (s),
˜
1.41–1.47 (m, 2 H), 2.18 (s, 3 H), 2.42 (t, J = 7.4 Hz, 2 H), 2.64–
1630 (s), 1603 (m) cm–1. MS (EI): m/z (%) = 381 (99) [M]+, 325
Eur. J. Org. Chem. 2015, 6298–6305
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6303

Y. Madich, R. Álvarez, J. M. Aurrecoechea
(21), 324 (100), 296 (10). HRMS (EI): calcd. for C26H23NO2 [M]+ (CH2), 30.0 (CH3), 33.0 (CH2), 43.5 (CH2), 46.0 (CH2), 56.0 (CH3),
FULL PAPER
381.1729; found 381.1732. Alternatively, the reaction was con-
ducted by using compound 3j[15] (100 mg, 0.321 mmol), 3-buten-2-
one (156 μL, 1.93 mmol), and PdI2 (5.80 mg, 0.016 mmol; Table 2,
Entry 6). The crude product was purified by flash chromatography
(silica gel saturated with Et3N; hexanes/EtOAc/Et3N, from 95:4:1
56.2 (CH3), 104.3 (CH), 108.2 (CH), 110.1 (C), 118.2 (C), 127.2
(C), 128.4 (2 CH), 128.6 (2 CH), 128.9 (CH), 134.2 (C), 149.0 (C),
149.4 (C), 150.2 (C), 152.2 (C), 207.5 (C) ppm. IR (film): ν = 1713
˜
(s), 1663 (s), 1632 (m) cm–1. MS (EI): m/z (%) = 407 (12) [M]+, 391
(14), 390 (64), 365 (19), 364 (100), 350 (27), 294 (21), 293 (10), 188
to 49:50:1) to afford 7j[2] (17 mg, 18%) and a mixture of 6j and (12), 105 (10). HRMS (EI): calcd. for C25H29NO4 [M]+ 407.2097;
8j[8b] (93 mg, approximately 92:8). This mixture was dissolved in
EtOAc (20 mL), and the solution was washed with HCl (0.5 m solu-
tion, 2ϫ 5 mL), NaHCO3 (5 mL), and brine (5 mL). The organic
layer was dried with Na2SO4, and the solvent was removed to af-
ford 6j (86 mg, 70%).
found 407.2097.
4-[(Z)-1-(Butylimino)-3-phenyl-1H-pyrano[4,3-c]pyridin-4-yl]butan-
2-one (6n): Compound 3n[6b] (95 mg, 0.341 mmol) was used in the
representative procedure. The reaction was carried out at 80 °C. for
a reaction time of 24 h. The crude product was purified by flash
4-[(Z)-1-(4-Methoxyphenylimino)-3-thiophen-3-yl-1H-isochromen- chromatography (silica gel saturated with Et3N; hexanes/EtOAc/
4-yl]butan-2-one (6k): Compound 3k (100 mg, 0.300 mmol) was
used in the representative procedure for a reaction time of 16 h.
The crude product was purified by flash chromatography (silica gel
saturated with Et3N; hexanes/EtOAc/Et3N, from 84:15:1 to
Et3N, from 74:25:1 to 59:40:1) to afford 6n (99 mg, 83%) as a white
solid; m.p. 109–110 °C. H NMR (300 MHz, CDCl3): δ = 0.93 (t,
J = 7.2 Hz, 3 H), 1.38–1.48 (m, 2 H), 1.59–1.71 (m, 2 H), 2.11 (s,
3 H), 2.68–2.73 (m, 2 H), 2.90–2.95 (m, 2 H), 3.45 (t, J = 7.0 Hz,
2 H), 7.47 (m, 5 H), 8.02 (d, J = 5.1 Hz, 1 H), 8.58 (d, J = 5.1 Hz,
1
69:30:1) to afford 6k (104 mg, 86%) as a yellow solid; m.p. 138–
1
139 °C. H NMR (300 MHz, CDCl3): δ = 2.19 (s, 3 H), 2.74–2.80 1 H), 8.68 (s, 1 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 13.9
(m, 2 H), 3.04–3.09 (m, 2 H), 3.82 (s, 3 H), 6.88 (d, J = 8.8 Hz, 2
(CH3), 20.0 (CH2), 20.7 (CH2), 29.8 (CH3), 32.7 (CH2), 43.0 (CH2),
46.3 (CH2), 108.0 (C), 119.4 (CH), 127.7 (C), 128.5 (2 CH), 128.6
H), 7.21–7.23 (m, 3 H), 7.33–7.48 (m, 4 H), 7.56–7.61 (m, 1 H),
8.44 (d, J = 7.9 Hz, 1 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = (2 CH), 129.5 (CH), 131.4 (C), 133.3 (C), 144.9 (CH), 147.8 (C),
20.6 (CH2), 30.0 (CH3), 43.0 (CH2), 55.4 (CH3), 110.7 (C), 113.8
(2 CH), 122.3 (CH), 124.3 (2 CH), 124.6 (C), 125.6 (CH), 125.8
148.3 (CH), 151.8 (C), 206.7 (C) ppm. IR (film): ν = 1705 (s), 1663
˜
(s), 1619 (m) cm–1. MS (EI): m/z (%) = 348 (10) [M]+, 331 (44), 319
(CH), 127.2 (CH), 127.7 (CH), 127.9 (CH), 132.2 (CH), 133.7 (C), (11), 306 (11), 305 (42), 292 (14), 291 (81), 277 (11), 271 (17), 249
134.2 (C), 139.4 (C), 145.6 (C), 148.8 (C), 156.0 (C), 207.3 (C) ppm. (11), 247 (18), 243 (11), 236 (12), 235 (100), 207 (38), 206 (10).
IR (film): ν = 1711 (s), 1650 (s), 1624 (s), 1603 (m), 1504 (s) cm–1. HRMS (EI): calcd. for C22H24N2O2 [M]+ 348.1838; found
˜
MS (EI): m/z (%) = 403 (100) [M]+, 400 (15), 399 (60), 385 (23),
384 (76), 360 (15), 347 (17), 346 (71), 318 (14), 234 (10), 111 (98).
HRMS (EI): calcd. for C24H21NO3S [M]+ 403.1242; found
403.1241.
348.1837.
(Z)-4-(3-Phenyl-1-(phenylimino)-1H-benzo[4,5]thieno[2,3-c]pyran-4-
yl)butan-2-one (6o): Compound 3o (100 mg, 0.283 mmol) was used
in the representative procedure for a reaction time of 21 h. The
crude product was purified by flash chromatography (silica gel sat-
urated with Et3N, hexanes/EtOAc/Et3N, from 94:5:1 to 89:10:1) to
afford 6o (109 mg, 91%) as a yellow solid; m.p. 178–180 °C. 1H
NMR (300 MHz, CDCl3): δ = 2.11 (s, 3 H), 2.75–2.80 (m, 2 H),
3.21–3.26 (m, 2 H), 7.02–7.06 (m, 1 H), 7.25–7.34 (m, 4 H), 7.42–
7.52 (m, 7 H), 7.96 (d, J = 7.7 Hz, 1 H), 8.01 (d, J = 8.4 Hz, 1
H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 21.9 (CH2), 30.1
(CH3), 43.6 (CH2), 112.1 (C), 123.6 (CH), 123.8 (CH), 124.2 (CH),
125.4 (CH), 126.8 (CH), 128.5 (CH), 129.1 (CH), 129.4 (CH), 130.0
4-[(Z)-1-(Butylimino)-6-chloro-3-thiophen-3-yl-1H-isochromen-4-yl]-
butan-2-one (6l): Compound 3l (100 mg, 0.315 mmol) was used in
the representative procedure for a reaction time of 15 h. The crude
product was purified by flash chromatography (silica gel saturated
with Et3N; hexanes/EtOAc/Et3N, from 90:9:1 to 85:14:1) to afford
6l (104 mg, 85 %) as a white solid; m.p. 115–116 °C. 1H NMR
(300 MHz, CDCl3): δ = 0.95 (t, J = 7.3 Hz, 3 H), 1.39–1.49 (m, 2
H), 1.60–1.68 (m, 2 H), 2.19 (s, 3 H), 2.70–2.75 (m, 2 H), 2.94–2.99
(m, 2 H), 3.47 (t, J = 7.0 Hz, 2 H), 7.27–7.32 (m, 3 H), 7.40–7.43
(m, 1 H), 7.57–7.58 (m, 1 H), 8.18 (d, J = 8.3 Hz, 1 H) ppm. 13C (C), 132.8 (C), 135.3 (C), 135.9 (C), 142.6 (C), 145.5 (C), 147.3 (C),
NMR (75.5 MHz, CDCl3): δ = 14.0 (CH3), 20.5 (CH2), 20.8 (CH2), 152.3 (C), 207.0 (C) ppm. IR (film): ν = 1713 (s), 1647 (s), 1587
30.0 (CH3), 32.9 (CH2), 42.9 (CH2), 46.1 (CH2), 109.2 (C), 122.0
˜
(m) cm–1. MS (EI): m/z (%) = 423 (82) [M]+, 380 (12), 367 (23),
(CH), 123.2 (C), 125.7 (CH), 125.9 (CH), 127.2 (CH), 127.7 (CH), 366 (100), 338 (16), 260 (14). HRMS (EI): calcd. for C27H21NO2S
128.6 (CH), 134.4 (C), 134.8 (C), 137.9 (C), 146.9 (C), 148.7 (C),
[M]+ 423.1293; found 423.1291.
207.1 (C) ppm. IR (film): ν = 1713 (s), 1663 (s), 1595 (s) cm–1. MS
˜
(Z)-3-[1-(Butylimino)-3-phenyl-1H-isochromen-4-yl]propanal (6p):
Compound 3a[13] (150 mg, 0.541 mmol) was used in the representa-
tive procedure for a reaction time of 17 h. Saturated NaCl solution
(5 mL) was added, and the resulting mixture was extracted with
EtOAc (3ϫ 10 mL). The combined organic layers were washed
with saturated Na2S2O3 solution (5 mL) and dried with Na2SO4.
The solvent was evaporated to afford 6p, which was characterized
without further purification. The yield was determined to be 85%
by 1H NMR analysis using 1,2,4,5-tetramethylbenzene as the in-
[chemical ionization (CI)]: m/z (%) = 390 (31) [M + H, 37Cl]+, 389
(26), 388 (100) [M + H, 35Cl]+, 387 (21), 332 (13), 330 (21). HRMS
(CI): calcd. for C21H2335ClNO2S [M + H]+ 388.1138; found
388.1154; calcd. for C21H2337ClNO2S [M + H]+ 390.1109; found
390.1156.
4-[(Z)-1-(Butylimino)-6,7-dimethoxy-3-phenyl-1H-isochromen-4-yl]-
butan-2-one (6m): Compound 3m[6b] (100 mg, 0.296 mmol) was
used in the representative procedure for a reaction time of 19 h.
The crude product was purified by flash chromatography (silica gel
saturated with Et3N; hexanes/EtOAc/Et3N, from 89:10:1 to
1
ternal standard. H NMR (300 MHz, [D6]acetone): δ = 0.89–0.95
(m, 3 H), 1.37–1.49 (m, 2 H), 1.56–1.66 (m, 2 H), 2.77–2.83 (m, 2
74:25:1) to afford 6m (96 mg, 79%) as a yellow solid; m.p. 128– H), 2.88–2.94 (m, 2 H), 3.39–3.44 (m, 2 H), 7.38–7.62 (m, 8 H),
130 °C. 1H NMR (300 MHz, CDCl3): δ = 0.93 (t, J = 7.3 Hz, 3 H), 8.24–8.27 (m, 1 H), 9.71 (s, 1 H) ppm. 13C NMR (75.5 MHz, [D6]-
1.38–1.47 (m, 2 H), 1.59–1.68 (m, 2 H), 2.11 (s, 3 H), 2.65–2.70 (m,
acetone): δ = 14.3 (CH3), 20.0 (CH2), 21.4 (CH2), 33.9 (CH2), 44.1
2 H), 2.86–2.90 (m, 2 H), 3.43 (t, J = 7.2 Hz, 2 H), 3.93 (s, 3 H), (CH2), 46.6 (CH2), 111.0 (C), 123.6 (CH), 125.7 (C), 127.6 (CH),
3.99 (s, 3 H), 6.81 (s, 1 H), 7.44–7.48 (m, 5 H), 7.72 (s, 1 H) ppm.
128.5 (CH), 129.4 (2 CH), 129.6 (2 CH), 130.1 (CH), 132.5 (CH),
133.7 (C), 135.1 (C), 149.9 (C), 151.4 (C), 201.5 (CH) ppm. IR
13C NMR (75.5 MHz, CDCl3): δ = 14.0 (CH3), 20.6 (CH2), 20.8
6304
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Eur. J. Org. Chem. 2015, 6298–6305

Pd-Catalyzed Selective Oxycyclization–Alkene Addition Cascades
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[M + H]+, 333 (30), 332 (19), 316 (17), 291 (18), 290 (70). HRMS
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Acknowledgments
The authors thank the Spanish Ministerio de Economía y Compet-
itividad (MEC) (grant number CTQ2012-37734), Fondos Europeos
para el Desarrollo Regional (FEDER), and the Universidad del
País Vasco (fellowship to Y. M.) for financial support. SGIker
UPV/EHU is thanked for technical support (NMR facilities,
HRMS, and X-ray analyses).
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Received: June 16, 2015
Published Online: August 14, 2015
Eur. J. Org. Chem. 2015, 6298–6305
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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