Pericyclic reactions of azafulvenium methides bearing internal dipolarophiles - synthesis of chromene and chromane derivatives

Article abstract of DOI:10.1002/ejoc.201403407

The reactivity of azafulvenium methides with internal dipolarophiles was explored as an approach to new chromene derivatives. 4,5-Dimethoxycarbonyl- and 5-ethoxycarbonyl- 4-phenylazafulvenium methides with a prop-2-ynyloxyphenyl substituent are converted into 2-[2-(2H-chromen- 8-yl)vinyl]-1H-pyrroles through a sequence of rearrangements. 4,5-Dimethoxycarbonylazafulvenium methide with a more-activated dipolarophile as well as the more-activated 5- (trifluoromethyl)azafulvenium methide with an unactivated alkyne could be trapped by [8π+2π] cycloadditions to afford 8,12a-dihydro-6H-chromeno[4,3-e]indolizines. 5-(Trifluoromethyl) azafulvenium methide with a 2-(3-methoxycarbonylprop- 2-enyloxy)phenyl substituent at C-1 participated in both intramolecular [8π+2π] and [4π+2π] cycloadditions to afford heterocycle-fused chromanes. The microwave-induced rearrangements of 3-[2-(prop-2-ynyloxy)phenyl]-1H,3Hpyrrolo[ 1,2-c]thiazoles afforded chiral 3-(2H-chromen-8-yl)- 1H,3H-pyrrolo[1,2-c]thiazoles.

Full text of DOI:10.1002/ejoc.201403407

FULL PAPER
DOI: 10.1002/ejoc.201403407
Pericyclic Reactions of Azafulvenium Methides Bearing Internal
Dipolarophiles – Synthesis of Chromene and Chromane Derivatives
[a]
[a]
[b]
Fernanda M. Ribeiro Laia, Maria I. L. Soares, Clara S. B. Gomes, and
Teresa M. V. D. Pinho e Melo*[
a]
Keywords: Cycloaddition / Pericyclic reactions / Fused-ring systems / Heterocycles / Microwave chemistry
The reactivity of azafulvenium methides with internal di-
polarophiles was explored as an approach to new chromene
derivatives. 4,5-Dimethoxycarbonyl- and 5-ethoxycarbonyl-
alkyne could be trapped by [8π+2π] cycloadditions to afford
8,12a-dihydro-6H-chromeno[4,3-e]indolizines. 5-(Trifluoro-
methyl)azafulvenium methide with
a 2-(3-methoxycarb-
4
-phenylazafulvenium methides with
oxyphenyl substituent are converted into 2-[2-(2H-chromen-
-yl)vinyl]-1H-pyrroles through a sequence of rearrange-
a
prop-2-ynyl-
onylprop-2-enyloxy)phenyl substituent at C-1 participated in
both intramolecular [8π+2π] and [4π+2π] cycloadditions to af-
ford heterocycle-fused chromanes. The microwave-induced
rearrangements of 3-[2-(prop-2-ynyloxy)phenyl]-1H,3H-
pyrrolo[1,2-c]thiazoles afforded chiral 3-(2H-chromen-8-yl)-
1H,3H-pyrrolo[1,2-c]thiazoles.
8
ments. 4,5-Dimethoxycarbonylazafulvenium methide with a
more-activated dipolarophile as well as the more-activated 5-
(
trifluoromethyl)azafulvenium methide with an unactivated
Introduction
electrocyclizations to afford bicyclic heterocycles, which un-
dergo ring-opening reactions to give substituted pyrroles
Aza- and diazafulvenium methide systems 1–7 were gen-
erated from 1H,3H-pyrrolo[1,2-c]thiazole 2,2-dioxides and
[
1a,1b,1d,1i]
(Scheme 2).
Recently, we became interested in the chemistry of
1H,3H-pyrazolo[1,5-c]thiazole 2,2-dioxides, respectively,
chromenes and described the reactions of sarcosine and 1,3-
thiazolidine-4-carboxylic acid with salicylaldehyde-derived
alkynes and allenes to form new chromeno[4,3-b]pyrrole
and are versatile building blocks for the synthesis of
pyrroles and pyrazoles (Scheme 1).[ These extended di-
poles can be intercepted by dipolarophiles. The 4,5-dimeth-
oxycarbonyl derivatives 1–6 participate exclusively in
1]
[
2]
and chromeno[2,3-b]pyrrole derivatives. The chromene
benzopyran) scaffold is frequently found in several natural
(
[
8π+2π] cycloadditions to give products resulting from the
products and bioactive compounds and has attracted great
attention. Chromenes and their derivatives are charac-
terized by a very broad spectrum of pharmacological activi-
ties, including anticancer, antimicrobial and antihyperten-
sive activities, and are also selective inhibitors of several
[
1a–1h]
addition across the 1,7-positions.
ducts include chlorin- and bacteriochlorin-type macrocycles
These 1,7-cycload-
[
1g]
(e.g., 8), which have relevance in medicinal chemistry. In
contrast with this chemical behaviour, 5-(trifluoromethyl)-
azafulvenium methides 7 can participate in both 1,7- and
[
3–5]
human proteins.
scopic properties, chromene derivatives can also be used as
In addition, owing to their spectro-
1
,3-dipolar cycloadditions.[1i–1k] Aza- and diazafulvenium
methides bearing methyl or benzyl groups at C-1 or C-7
undergo sigmatropic [1,8]H shifts to give vinylpyrroles and
vinylpyrazoles, respectively. Under flash vacuum pyrolysis
conditions, these heterocycles undergo interesting re-
arrangements.
[
6]
photochromic materials and dyes.
Bringing together our interest in the chemistry of
chromenes and in the study of pericyclic reactions of aza-
and diazafulvenium methides, the thermal reactivity of
azafulvenium methides bearing internal dipolarophiles was
explored as an approach to new chromene derivatives.
[
2]
[
1]
It was also previously observed that the cheletropic ex-
trusion of SO from 3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole
2
2,2-dioxides leads to 2-styryl-1H-pyrroles. In this case, aza-
fulvenium methides are generated and participate in 1,7-
Results and Discussion
[
[
a] Department of Chemistry, University of Coimbra,
3
004-535 Coimbra, Portugal
The strategy for the synthesis of 1H,3H-pyrrolo[1,2-c]thi-
azole 2,2-dioxides bearing internal dipolarophiles is out-
lined in Scheme 3. Aldehydes 15 were obtained from the
reaction of salicylaldehyde with the appropriate alkyl brom-
ide derivative in the presence of a base. The condensation
of aldehydes 15 with l-cysteine afforded the expected thi-
E-mail: tmelo@ci.uc.pt
http://www.uc.pt
b] Centro de Química Estrutural, Instituto Superior Técnico,
Universidade de Lisboa,
1
049-001 Lisboa, Portugal
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403407.
Eur. J. Org. Chem. 2015, 1341–1354
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1341

T. M. V. D. Pinho e Melo et al.
FULL PAPER
Scheme 1. Pericyclic reactions of aza- and diazafulvenium methides.
ine is lost, and the chirality at C-2 (C-3 in the product)
is retained to give 1H,3H-pyrrolo[1,2-c]thiazoles as single
[
1]
enantiomers with R configuration at C-3. The reactions
of thiazolidines 17a and 17b with dimethyl acetylenedicarb-
oxylate (18a) afford pyrrolo[1,2-c]thiazoles 19a and 19c in
96 and 91% yield, respectively. The reaction of thiazolidine
17a with the unsymmetrical dipolarophile ethyl phenyl pro-
piolate (18b) gives compound 19b as a single regioisomer.
The structural assignment of 19b was based on two-di-
mensional NOESY, heteronuclear multiple quantum corre-
lation (HMQC) and HMBC spectra (400 MHz). In the
HMBC spectrum, the methyl protons correlate with carbon
atoms C-5 (δ = 114.6 ppm) and C-6 (δ = 132.1 ppm) and
with the carbonyl carbon atom of the ester group at δ =
1
1
65.6 ppm, and the phenyl protons correlate with C-7 (δ =
17.8 ppm). It was established that the quaternary carbon
atoms with the chemical shifts of 117.8 and 132.1 ppm
correspond to C-7 and C-6, respectively, as connectivity was
observed between C-7 and the methylene protons (1-H), but
Scheme 2. Pericyclic reactions of azafulvenium methides.
azolidine-4-carboxylic acids 17 in high yields. 1H,3H- no correlation was observed between these protons and C-
Pyrrolo[1,2-c]thiazoles 19 were prepared by heating solu- 6. Finally, the NOESY spectrum shows cross-peaks be-
tions of thiazolidines 17 in acetic anhydride under reflux in tween the phenyl and methylene protons.
the presence of the appropriate dipolarophile. Under these
The oxidation of 1H,3H-pyrrolo[1,2-c]thiazoles 19 with
reaction conditions, the diastereoselective N-acylation of hydrogen peroxide in the presence of sodium tungstate af-
the thiazolidines occurs in situ and is followed by the gener- forded sulfones 20 in moderated yields. In the synthesis of
ation of bicyclic münchnones and subsequent 1,3-dipolar the sulfone 20a, the formation of the corresponding sulfox-
cycloaddition. The chirality at C-4 of the starting thiazolid- ide was detected in trace amounts.
1342
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 1341–1354

Pericyclic Reactions of Azafulvenium Methides
Scheme 3. Synthesis of 1H,3H-pyrrolo[1,2-c]thiazole 2,2-dioxides 20 and 22.
1H,3H-Pyrrolo[1,2-c]thiazole 21, containing an activated presence of sodium tungstate gave the target sulfones 26 in
triple bond, was obtained in 42% yield by a known general moderate-to-good yields.
[
7]
procedure, that is, the treatment of 19a with n-butyllith-
ium followed by the reaction with ethyl chloroformate. The
target sulfone 22 was obtained from compound 21 in 65%
yield by reaction with hydrogen peroxide in the presence of
sodium tungstate.
7-(Trifluoromethyl)-1H,3H-pyrrolo[1,2-c]thiazole 2,2-di-
oxides 26 were prepared by a previously reported general
methodology (Scheme 4).[1i] The reaction of thiazolidines
1
7 with 4-ethoxy-1,1,1-trifluorobut-3-ene-2-one (23),[8] pre-
pared from ethyl vinyl ether and trifluoroacetic anhydride
in the presence of pyridine, afforded thiazolidines 24 dia-
1
13
stereoselectively. At room temperature, the H and
C
NMR spectra of compounds 24 showed the presence of two
rotamers, as previously observed for other 1-butenylthiazol-
[
1i,1j]
idine derivatives.
7-(Trifluoromethyl)-1H,3H-pyrrolo-
[
1,2-c]thiazoles 25 were obtained as single enantiomers by
cyclization of thiazolidines 24 in the presence of trifluoro-
acetic anhydride. The stereochemistry of compounds 25 was
assigned by comparison with the structure of (R)-3-phenyl-
7-(trifluoromethyl)-1H,3H-pyrrolo[1,2-c]thiazole, prepared
by the same synthetic methodology, for which the absolute
configuration at C-3 has been unambiguously determined
by X-ray crystallography.[
1i]
The oxidation of 1H,3H-
Scheme 4. Synthesis of 7-(trifluoromethyl)-1H,3H-pyrrolo[1,2-c]-
pyrrolo[1,2-c]thiazoles 25 with hydrogen peroxide in the thiazole 2,2-dioxides 26.
Eur. J. Org. Chem. 2015, 1341–1354
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1343

T. M. V. D. Pinho e Melo et al.
FULL PAPER
Initially, we looked into the reactivity of 1H,3H-pyrrolo- Entry 5). A slight improvement of the yield was achieved
1,2-c]thiazole 2,2-dioxides 20 (Table 1). The microwave when sulfone 20b was irradiated at 260 °C for 10 or 15 min
[
(MW) irradiation of sulfone 20a for 10 min at 240, 250 and (Table 1, Entries 6 and 7).
260 °C afforded the 2-[2-(2H-chromen-8-yl)vinyl]-1H- The molecular structure of 27a was unambiguously es-
pyrrole 27a in 44, 47 and 34% yield, respectively (Table 1, tablished by X-ray crystallography (Figure 1). Its molecular
Entries 1–3). The best result was achieved by performing structure displays an E conformation around the C6–C7
the microwave irradiation at 240 °C over a period of 15 min
to give 1H-pyrrole 27a in 54% yield (Table 1, Entry 4). Un-
der these reaction conditions, sulfone 20b led to 2-[2-(2H-
chromen-8-yl)vinyl]-1H-pyrrole 27b in 18% yield (Table 1,
Table 1. Synthesis of 2-[2-(2H-chromen-8-yl)vinyl]-5-methyl-1H-
pyrroles 27.
Entry Sulfone Reaction conditions
Product, isolated yield [%]
1
2
3
4
5
6
7
20a
20a
20a
20a
20b
20b
20b
240 °C, 10 min
250 °C, 10 min
260 °C, 10 min
240 °C, 15 min
240 °C, 15 min
260 °C, 10 min
260 °C, 15 min
27a, 44
27a, 47
27a, Ͻ34
27a, 54
27b, 18
27b, 21
27b, 21
Figure 1. ORTEP-3 diagram of pyrrole 27a with 50% probability
ellipsoids. Selected bond lengths [Å] and angles [°]: N1–C2
1
.382(4), C2–C3 1.374(4), C3–C4 1.427(4), C4–C5 1.375(4), N1–
C5 1.363(4), C2–C6 1.443(4), C6–C7 1.326(5), C7–C8 1.463(4);
N1–C2–C6 122.5(3), C2–C6–C7 125.3(3), C6–C7–C8 126.8(3).
Scheme 5. Mechanism proposal for the synthesis of 2-[2-(2H-chromen-8-yl)vinyl]-5-methyl-1H-pyrroles 27.
344 Eur. J. Org. Chem. 2015, 1341–1354
1
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Pericyclic Reactions of Azafulvenium Methides
double bond. All distances and angles are within the ex- Table 2. Thermolysis of 1H,3H-pyrrolo[1,2-c]thiazole 2,2-dioxide
pected values for similar compounds.[
9]
20a.
The formation of 2-[2-(2H-chromen-8-yl)vinyl]-1H-
pyrroles 27 can be rationalized as outlined in Scheme 5. The
cheletropic extrusion of SO from sulfones 20 generates the
2
corresponding azafulvenium methides 28, which undergo
1,7-electrocyclization followed by ring opening to afford
styryl-1H-pyrroles 30. This reactivity has been observed
previously for the thermolysis of other 3-aryl-1H,3H-pyr-
rolo[1,2-c]thiazole 2,2-dioxides (see Scheme 2).[
1a,1b,1d,1i]
Styryl-1H-pyrroles 30, which have an aryl propargyl ether
substituent, are converted into the final 2-[2-(2H-chromen-
8-yl)vinyl]-1H-pyrroles 27. The process involves an initial
Claisen rearrangement of the aryl propargyl ether moiety
of compounds 30 to afford allenes 31. The enolization of
31 followed by a sigmatropic [1,5]-hydrogen shift gives
pyrroles 33, which undergo electrocyclization to form the
isolated products 27. The thermal cyclization of substituted
aryl propargyl ethers by sigmatropic Claisen rearrange-
ments has been described previously as a strategy for the
[
10]
synthesis of chromene derivatives,
natural products.
including bioactive
[
10e,10f]
Moreover, recent studies on the re-
arrangement of aryl propargyl ether to chromenes by theo-
retical DFT methods corroborate the mechanism propos-
al.[10g]
Styryl-1H-pyrrole 30 was postulated to be an intermedi-
ate of the synthesis of 2-[2-(2H-chromen-8-yl)vinyl]-5-
methyl-1H-pyrrole 27a. Thus, the thermolysis of sulfone
Entry Reaction conditions
Isolated yield [%]
27a
34
35[a]
2
0a under milder reaction conditions was explored with the
1
2
3
4
5
6
7
MW, 200 °C, 20 min
MW, 210 °C, 20 min
MW, 220 °C, 10 min
MW, 230 °C, 10 min
Sealed tube, 220 °C, 5 h
Sealed tube, 250 °C, 1 h
Sealed tube, 250 °C, 3 h
–
4
–
aim of isolating this intermediate. The microwave irradia-
tion at 200 °C for 20 min led to the target compound 34,
although in low yield (4%; Table 2, Entry 1). The reaction
at 210 °C allowed the isolation of 1H-pyrrole 27a and
styryl-1H-pyrrole 34 in trace amounts as an inseparable
mixture, and the unexpected 3-(chromen-8-yl)-1H,3H-
pyrrolo[1,2-c]thiazole 2,2-dioxide 35 was isolated in 24%
yield (Table 2, Entry 2). This heterocycle is formed by the
Claisen rearrangement of the aryl propargyl ether moiety
of sulfone 20a. These results indicate that the microwave-
trace
trace
24
31
18
34
24
25
27 (64:36)
46 (74:26)
trace
trace
trace
trace
trace
trace
[a] Obtained together with 20a in variable amounts.
The microwave-induced thermolysis of 1H,3H-pyrrolo-
induced SO extrusion from 20a at 200–210 °C is very un- [1,2-c]thiazole 2,2-dioxide 20c, which bears a terminal alk-
2
favourable and allows the isolation of sulfone 35. The irra- ene dipolarophile, was also studied. However, none of the
diation of 20a at 220 and 230 °C for 10 min led to sulfone studied reaction conditions allowed the isolation of prod-
35, but the formation of mixtures of 27a and 34 was also ucts.
observed (Table 2, Entries 3 and 4). Thus, under these reac- We also looked into the microwave-induced thermolysis
tion conditions, the generation of the azafulvenium of 1H,3H-pyrrolo[1,2-c]thiazole 2,2-dioxide 22, which bears
methides 28 becomes more favourable and leads to 1H- an activated internal dipolarophile (Scheme 6). Under the
pyrroles 27a and 34. The above-described results reinforce optimized reaction conditions for the generation of 4,5-di-
the mechanism proposal for the synthesis of 1H-pyrroles methoxycarbonylazafulvenium methide (MW, 240 °C,
27. The sealed-tube thermolysis of 20a afforded sulfone 35 15 min), cycloadduct 37 and 1H-pyrrole 38 were obtained
in low-to-moderate yield, and only traces of 27a and 34 in 22 and 25% yields, respectively. The same products were
could be detected (Table 2, Entries 5–7). Thus, under these obtained, although in lower yield, under irradiation at
reaction conditions, the generation of the 1,7-dipole is also 260 °C for 10 min. Of particular interest was the first obser-
very unfavourable; this agrees with previous results on the vation of the intramolecular trapping of an azafulvenium
generation of azafulvenium methides from the 4,5-dimeth- methide in a 1,7-dipolar cycloaddition reaction. Azafulven-
oxycarbonyl derivatives, which requires microwave irradia- ium methide 36 generated by SO extrusion from sulfone
2
tion. In all of the studied reactions, compound 35 was iso- 22 participated in an [8π+2π] cycloaddition reaction to give
lated together with the starting sulfone 20a, although a pure 6H-chromeno[4,3-e]indolizine 37. On the other hand, these
sample could be obtained and fully characterized.
results indicate that the thermal rearrangement of the aryl
Eur. J. Org. Chem. 2015, 1341–1354
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1345

T. M. V. D. Pinho e Melo et al.
FULL PAPER
Scheme 6. Microwave-induced thermolysis of 1H,3H-pyrrolo[1,2-c]thiazole 2,2-dioxide 22.
propargyl ethers to the corresponding chromenes is more target compounds is expected. The chiral 3-(2H-chromen-
favourable with a terminal alkyne than with an ester-substi- 8-yl)-1H,3H-pyrrolo[1,2-c]thiazole 40 was obtained in high
tuted alkyne such as 38.
yield (80–83%) as the single product of the microwave-in-
Sulfones 22 and 20a showed the same chemical behav- duced rearrangement of pyrrolo[1,2-c]thiazole 19a. A sim-
iour for microwave irradiation at 220 °C (Scheme 7). Three ilar result was obtained for 21, and the corresponding chiral
products were obtained: the 1,7-cycloadduct 37, styryl-1H- 1H,3H-pyrrolo[1,2-c]thiazole 41 could be obtained in 52%
pyrrole 38 and sulfone 39 as the major product.
yield. It is worth noting that the rearrangement of the (3-
ethoxycarbonylprop-2-ynyl)oxy derivative was less efficient
than the rearrangement of the compound bearing a prop-
2-ynyloxy substituent.
Scheme 7. Microwave-induced thermolysis of 1H,3H-pyrrolo[1,2-c]-
thiazole 2,2-dioxide 22.
Scheme 8. Synthesis of 3-(2H-chromen-8-yl)-1H,3H-pyrrolo[1,2-c]-
thiazoles 40 and 41.
The importance of the chromene derivatives led us to
explore the reactivity of 1H,3H-pyrrolo[1,2-c]thiazoles 19a
The study was extended to the reactivity of 5-(trifluoro-
and 21 under microwave irradiation (Scheme 8). Our goal methyl)azafulvenium methide 42 generated from 26a
was to synthesize 1H,3H-pyrrolo[1,2-c]thiazoles bearing a (Table 3). The high electronegativity of the CF group re-
3
chromene substituent at C-3 more efficiently. In this case, sults in quite different electron-density distribution and
no competitive sulfur dioxide extrusion can occur, as for significantly changes the reactivity of the azafulvenium
sulfones 20a and 22, and a more favourable synthesis of the methide when compared with that of the 4,5-dimeth-
1346
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 1341–1354

Pericyclic Reactions of Azafulvenium Methides
oxycarbonyl derivatives (see Scheme 1). The presence of the
trifluoromethyl group at the 5-position makes the azaful-
venium methide reactive enough to participate in intramo-
lecular [8π+2π] cycloaddition with the unactivated terminal
alkyne. The microwave irradiation of sulfone 26a afforded
1,7-dipolar cycloadduct 43 isolated as the major product
together with 2-[2-(2H-chromen-8-yl)vinyl]-1H-pyrrole 44.
The reaction at 220 °C afforded cycloadduct 43 in 23%
yield and an inseparable mixture of styryl-1H-pyrroles 44
and 45 in 12% yield (Table 3, Entry 1). An improvement of
the overall yield was achieved by carrying out the micro-
wave irradiation at 240 °C over a period of 15 min, which
led to cycloadduct 43 and 1H-pyrrole 44 in 33 and 16%
yield, respectively (Table 3, Entry 2). At higher temperature,
the same products were obtained in lower overall yield
(Table 3, Entry 3).
Scheme 9. Reactivity of 7-(trifluoromethyl)-1H,3H-pyrrolo[1,2-c]-
thiazole 2,2-dioxide (26b).
Table 3. Reactivity of 7-(trifluoromethyl)-1H,3H-pyrrolo[1,2-c]thi-
azole 2,2-dioxide (26a).
Conclusions
The microwave-induced thermolysis of 1H,3H-pyrrolo-
[1,2-c]thiazole 2,2-dioxides substituted at C-3 with allyloxy-
phenyl and prop-2-ynyloxyphenyl groups was studied.
These sulfones underwent cheletropic extrusion of SO to
2
give azafulvenium methide intermediates, which partici-
pated in pericyclic reactions to afford new chromene deriva-
tives.
4,5-Dimethoxycarbonyl- and 5-ethoxycarbonyl-4-phenyl-
azafulvenium methides with prop-2-ynyloxyphenyl sub-
stituents are converted into 2-[2-(2H-chromen-8-yl)-
vinyl]-1H-pyrroles through a sequence of rearrangements.
The process involves the formation of styryl-1H-pyrroles,
derived from the electrocyclization of the 1,7-dipole, fol-
lowed by the rearrangement of the aryl propargyl ether
moiety to form the chromene unit by an initial Claisen re-
arrangement.
A 4,5-dimethoxycarbonylazafulvenium methide with a
more-activated dipolarophile, namely, the 3-ethoxycarbon-
ylprop-2-ynyloxy group, could be trapped by [8π+2π] cyclo-
addition to afford an 8,12a-dihydro-6H-chromeno[4,3-e]-
indolizine derivative. The more-activated 5-(trifluoro-
methyl)azafulvenium methide does not require the acti-
vation of the carbon–carbon triple bond as it participates
in the intramolecular [8π+2π] cycloaddition with a terminal
alkyne. From these reactions, styryl-1H-pyrroles derived
from the electrocyclization of the in situ generated azaful-
venium methides were also isolated.
Entry
Conditions
Isolated yield [%]
44
43
[a]
1
2
3
220 °C, 15 min
240 °C, 15 min
260 °C, 10 min
23
33
21
16
13
[a] Isolated yield (44/45) 12% (67:33).
Finally, the thermolysis of 7-(trifluoromethyl)-1H,3H-
Interestingly, 5-(trifluoromethyl)azafulvenium methide
pyrrolo[1,2-c]thiazole 2,2-dioxide 26b, which has an acti- bearing
a
2-[(3-methoxycarbonylprop-2-enyl)oxy]phenyl
vated internal carbon–carbon double bond, was also ex- substituent at C-1 participated in both intramolecular
plored (Scheme 9). Microwave irradiation at 240 °C for [8π+2π] and [4π+2π] cycloadditions to form the corre-
15 min afforded an inseparable mixture of cycloadducts 47 sponding 6a,7,8,12a-tetrahydro-6H-chromeno[4,3-e]indoliz-
and 48 in 59% overall yield (33:67). Interestingly, 5-(tri- ine and 10-methyl-9-(trifluoromethyl)-6,6a,7,11a-tetra-
fluoromethyl)azafulvenium methide 46 participated in both hydrochromeno[3,4-b]pyrrolizine derivatives, respectively.
intramolecular [8π+2π] and [4π+2π] cycloadditions to af-
The microwave-induced rearrangement of 3-[2-(prop-2-
ford chromanes 47 and 48, respectively.
ynyloxy)phenyl]-1H,3H-pyrrolo[1,2-c]thiazoles allowed the
Eur. J. Org. Chem. 2015, 1341–1354
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1347

T. M. V. D. Pinho e Melo et al.
FULL PAPER
efficient synthesis of chiral 3-(2H-chromen-8-yl)-1H,3H- 62%) as a white solid; m.p. 61.6–63.8 °C. IR (KBr): ν˜ = 2952, 2871,
1
1
720, 1684, 1662, 1597, 1485, 1442, 1308, 1292, 1242, 1192, 1169,
pyrrolo[1,2-c]thiazoles.
–
1 1
3
018 cm . H NMR (400 MHz, CDCl ): δ = 3.76 (s, 3 H), 4.83
3
3
(
br. s, 2 H), 6.23 (d, J = 15.6 Hz, 1 H), 6.95 (d, J = 8.4 Hz, 1 H,
Ar-H), 7.04–7.08 (m, 1 H, Ar-H), 7.08–7.14 (m, 1 H), 7.52–7.56
Experimental Section
1
3
(
m, 1 H, Ar-H), 7.82–7.84 (m, 1 H, Ar-H), 10.52 (s, 1 H) ppm.
C
General Methods: Microwave reactions were performed in a CEM
Focused Synthesis System Discover S-Class microwave reactor with
closed 10 mL microwave vessels in the fixed-temperature mode. An
infrared surface detector measured the reaction temperatures dur-
ing microwave heating. The maximum irradiation power and pres-
sure were set to 200 W and 10 bar, respectively. Flash column
chromatography was performed with silica gel 60 as the stationary
phase. The 1H NMR spectra were recorded with an instrument
operating at 400 MHz, the C NMR spectra were recorded with
an instrument operating 100 MHz, and the 19F NMR spectra were
recorded with an instrument operating at 376 MHz. Chemical
shifts are expressed in ppm relative to internal tetramethylsilane
3
NMR (100 MHz, CDCl ): δ = 51.7, 66.8, 112.6, 121.4, 122.0, 125.0,
128.7, 135.9, 141.6, 160.1, 166.2, 189.1 ppm. HRMS (ESI): calcd.
[M + H]+ 221.08084; found 221.08147.
13 4
for C12H O
General Procedure for the Synthesis of 1,3-Thiazolidine-4-carboxylic
Acid Derivatives 17: A solution of the appropriate aldehyde in eth-
anol was added to a solution of l-cysteine in water. The reaction
mixture was stirred overnight at room temperature. The resulting
solid was collected by filtration and washed with diethyl ether. The
solid obtained in this way was pure enough to use in the next step
without recrystallization.
13
(
(
(
4R)-2-[2-(Prop-2-ynyloxy)phenyl]thiazolidine-4-carboxylic
17a): Prepared from aldehyde 15a (6.40 g, 40.0 mmol) in ethanol
30 mL) and l-cysteine (4.80 g, 40.0 mmol) in water (40 mL). Com-
Acid
(TMS), and coupling constants (J) are in Hertz. The IR spectra
were recorded with a Fourier transform spectrometer. Optical rota-
tions were measured with an Optical Activity AA-5 electrical pola-
rimeter. HRMS spectra were obtained with an electron impact (EI)
or electrospray (ESI) TOF mass spectrometer. Melting points were
recorded with a hot-stage microscope or by the open glass capillary
method. 4-Ethoxy-1,1,1-trifluoro-3-buten-2-one (23) was prepared
pound 17a (9.90 g, 94%) was obtained as a white solid. IR (KBr):
–
1 1
ν˜ = 3226, 1605, 1552, 1403, 1365, 1256 cm . H NMR (400 MHz,
]DMSO): Two diastereoisomers (62:38); major isomer: δ = 2.96–
[D
6
3
1
.03 (m, 1 H), 3.19–3.23 (m, 1 H), 3.56 (br. s, 1 H), 4.16–4.19 (m,
H), 4.84 (br. s, 2 H), 5.88 (s, 1 H), 6.95–7.06 (m, 2 H, Ar-H),
3
as described previously.[
8]
7.22–7.26 (m, 1 H, Ar-H), 7.43 (d, J = 7.2 Hz, 1 H, Ar-H) ppm;
minor isomer: δ = 2.96–3.03 (m, 1 H), 3.33–3.37 (m, 1 H), 3.56 (br.
General Procedure for the Synthesis of Salicylaldehyde Derivatives:
To a solution of salicylaldehyde in ethanol was added anhydrous
s, 1 H), 3.86–3.90 (m, 1 H), 4.84 (br. s, 2 H), 5.71 (s, 1 H), 6.95–
3
7
(
(
7
.06 (m, 1 H, Ar-H), 7.11 (d, J = 8.4 Hz, 1 H, Ar-H), 7.30–7.34
K
2
CO
at room temperature. The corresponding alkyl bromide was added,
and the reaction mixture was heated at reflux for 4 h under N
3
(1.1 equiv.), and the resulting mixture was stirred for 5 min
3
13
m, 1 H, Ar-H), 7.56 (d, J = 7.6 Hz, 1 H, Ar-H) ppm. C NMR
100 MHz, [D ]DMSO): major isomer: δ = 37.2, 55.7, 64.8, 65.0,
8.2, 79.2, 112.2, 120.9, 125.5, 128.1, 130.8, 154.1, 172.8 ppm;
minor isomer: δ = 38.1, 55.9, 65.4, 65.9, 78.4, 79.1, 112.8, 121.3,
27.2, 127.5, 129.1, 154.6, 172.3 ppm. HRMS (EI): calcd. for
S [M]+ 262.0538; found 262.0549.
6
2
atmosphere. After the reaction mixture cooled to room tempera-
ture, water was added, and the organic layer was extracted with
1
diethyl ether, dried with anhydrous Na
der reduced pressure.
2 4
SO and concentrated un-
13 3
C H12NO
(
4R)-2-[2-(Allyloxy)phenyl]thiazolidine-4-carboxylic Acid (17b): Pre-
O-Propargylsalicylaldehyde (15a):[7] Prepared from salicylaldehyde
11.13 mL, 100 mmol) and propargyl bromide (80% in toluene,
1.85 mL, 110 mmol) in ethanol (60 mL). Recrystallization from
diethyl ether afforded 15a (14.36 g, 90%) as a white solid; m.p.
pared from aldehyde 15b (4.880 g, 30.08 mmol) in ethanol (24 mL)
and l-cysteine (3.644 g, 30.08 mmol) in water (30 mL). Compound
(
1
1
7b (7.423 g, 93%) was obtained as a white solid. IR (KBr): ν˜ =
–1
1
6
2915, 1598, 1487, 1286, 1241 cm . H NMR (400 MHz, [D ]-
[
7]
6
1
7.7–69.6 °C (ref. 64–66 °C). IR (KBr): ν˜ = 3264, 2855, 1681,
DMSO): Two diastereoisomers (62:38); major isomer: δ = 2.92–
.98 (m, 1 H), 3.17–3.21 (m, 1 H), 4.13–4.16 (m, 1 H), 4.60–4.61
–1
1
592, 1449, 1287, 1219, 1191, 1006 cm . H NMR (400 MHz,
): δ = 2.58 (t, J = 2.0 Hz, 1 H), 4.83 (d, J = 2.0 Hz, 2 H),
.07–7.13 (m, 2 H, Ar-H), 7.55–7.59 (m, 1 H, Ar-H), 7.86 (dd, J
2
4
4
CDCl
7
=
3
3
3
(
m, 2 H), 5.26 (d, J = 10.4 Hz, 1 H), 5.49 (d, J = 16.0 Hz, 1 H),
3
5
7
.93 (s, 1 H), 6.01–6.10 (m, 1 H), 6.90–6.99 (m, 2 H, Ar-H), 7.19–
.23 (m, 1 H, Ar-H), 7.40 (d, J = 7.2 Hz, 1 H, Ar-H) ppm; minor
4
13
7.6 Hz, J = 1.2 Hz, 1 H, Ar-H), 10.49 (s, 1 H) ppm. C NMR
): δ = 56.3, 76.7, 77.7, 113.2, 121.6, 125.3, 128.4,
3
(100 MHz, CDCl
3
isomer: δ = 2.92–2.98 (m, 1 H), 3.33–3.37 (m, 1 H), 3.84–3.88 (m,
+
1
1
35.8, 159.7, 189.4 ppm. HRMS (EI): calcd. for C10
60.0524; found 160.0526.
H
8
O
2
[M]
3
3
1
H), 4.60–4.61 (m, 2 H), 5.26 (d, J = 10.4 Hz, 1 H), 5.45 (d, J
=
16.0 Hz, 1 H), 5.72 (s, 1 H), 6.01–6.10 (m, 1 H), 6.90–6.99 (m, 1
O-Allylsalicylaldehyde (15b):[11] Prepared from salicylaldehyde
3
H, Ar-H), 7.03 (d, J = 8.0 Hz, 1 H, Ar-H), 7.27–7.31 (m, 1 H, Ar-
3
13
(
6.10 mL, 57.24 mmol) and allyl bromide (5.20 mL, 60.09 mmol) in H), 7.50 (d, J = 7.2 Hz, 1 H, Ar-H) ppm. C NMR (100 MHz,
ethanol (30 mL). Compound 15b (8.83 g, 99%) was obtained as a
pale yellow oil. IR (film): ν˜ = 2862, 1684, 1300, 1295, 1238, 1220,
[D
6
]DMSO): major isomer: δ = 37.2, 65.1, 68.1, 111.8, 116.7, 120.3,
125.1, 128.1, 130.7, 133.5, 155.0, 172.8 ppm; minor isomer: δ =
–1 1
1
190, 1158, 1012, 1008, 994, 989, 756 cm . H NMR (400 MHz, 38.2, 65.5, 66.7, 68.5, 112.5, 117.3, 120.7, 126.8, 127.4, 129.2, 133.4,
CDCl
3
): δ = 4.65 (d, J = 2.8 Hz, 2 H), 5.33 (d, J = 10.4 Hz, 1 155.6, 172.3 ppm. HRMS (ESI): calcd. for C13H16NO S [M + H]
3
3
3
+
3
H), 5.45 (d, J = 17.2 Hz, 1 H), 6.02–6.12 (m, 1 H), 6.96–7.03 (m,
266.08454; found 266.08352.
4R)-2-(2-{[(E)-3-Methoxycarbonylprop-2-enyl]oxy}phenyl)thiazol-
idine-4-carboxylic Acid (17c): Prepared from aldehyde 15c (1.350 g,
.13 mmol) in ethanol (5 mL) and l-cysteine (0.743 g, 6.13 mmol)
3
2
H, Ar-H), 7.50–7.54 (m, 1 H, Ar-H), 7.83 (d, J = 7.6 Hz, 1 H,
(
13
Ar-H), 10.53 (s, 1 H) ppm. C NMR (100 MHz, CDCl
3
): δ = 69.1,
1
12.9, 118.0, 120.8, 125.1, 128.4, 132.4, 135.9, 160.9, 189.7 ppm.
6
+
10 2
HRMS (EI): calcd. for C10H O [M] 162.0681; found 162.0685.
in water (6 mL). Compound 17c (1.807 g, 91%) was obtained as a
white solid. IR (KBr): ν˜ = 3066, 1705, 1600, 1442, 1376, 1280,
1241 cm . H NMR (400 MHz, [D
O-(E)-(3-Methoxycarbonylprop-2-enyl)salicylaldehyde (15c): Pre-
pared from salicylaldehyde (1.93 mL, 18.08 mmol) and methyl
trans-4-bromo-2-butenoate (1.97 mL, 16.45 mmol) in ethanol
–
1 1
6
]DMSO): Two diastereoiso-
mers (65:35); major isomer: δ = 2.89–2.99 (m, 1 H), 3.18–3.23 (m,
3
(
10 mL). Recrystallization from diethyl ether afforded 15c (2.25 g, 1 H), 3.64 (br. s, 1 H), 3.69 (s, 3 H), 4.11 (t, J = 6.6 Hz, 1 H), 4.84
1348
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 1341–1354

Pericyclic Reactions of Azafulvenium Methides
3
(
(
br. s, 2 H), 5.97 (s, 1 H), 6.28 (d, J = 16.0 Hz, 1 H), 6.94–7.09
(m, 3 H), 7.30–7.38 (m, 1 H, Ar-H), 7.72–7.77 (m, 2 H, Ar-H),
3
13
m, 3 H), 7.20–7.23 (m, 1 H, Ar-H), 7.41 (d, J = 7.2 Hz, 1 H, Ar- 13.73 (br. s, 1 H) ppm. C NMR (100 MHz, [D
H) ppm; minor isomer: δ = 3.35–3.39 (m, 1 H), 3.42–3.48 (m, 1
H), 3.64 (br. s, 1 H), 3.68 (s, 3 H), 3.87–3.91 (m, 1 H), 4.86 (br. s,
6
]DMSO): major
conformer: δ = 31.6, 51.4, 61.7, 66.4, 69.5, 90.3, 112.1, 117.1 (q,
C,F = 290 Hz), 120.5, 121.1, 124.8, 127.1, 129.8, 143.4, 154.0,
J
3
2
2
7
H), 5.74 (s, 1 H), 6.22 (d, J = 16.0 Hz, 1 H), 6.94–7.09 (m, 3 H),
154.2, 165.7, 170.9, 175.4 (q, JC,F = 31.6 Hz) ppm; minor con-
3
.28–7.32 (m, 1 H, Ar-H), 7.53 (d, J = 7.2 Hz, 1 H, Ar-H) ppm. former: δ = 33.2, 51.4, 64.5, 65.7, 66.5, 90.9, 112.3, 117.2 (q, JC,F
1
3
6
C NMR (100 MHz, [D ]DMSO): major isomer: δ = 37.3, 51.4, = 290 Hz), 120.5, 121.3, 126.4, 127.7, 130.1, 143.5, 152.9, 155.2,
2
6
1
6
1
3
5.1, 65.2, 66.1, 111.6, 120.2, 120.6, 124.9, 128.1, 131.1, 143.8,
54.4, 165.8, 172.7 ppm; minor isomer: δ = 38.1, 51.4, 65.5, 66.4,
6.5, 112.3, 120.6, 121.0, 127.0, 127.3, 129.2, 143.6, 155.0, 165.8,
72.4 ppm. HRMS (ESI): calcd. for C15
24.09002; found 324.08996.
165.8, 169.6, 175.4 (q, JC,F = 31.6 Hz) ppm. HRMS (ESI): calcd.
for C19 19NO
H
6 3
F
S [M + H]+ 446.08797; found 446.08780.
General Procedure for the Synthesis of 1H,3H-Pyrrolo[1,2-c]thi-
azoles 19 and 25
H18NO
5
S [M + H]+
Method A: The appropriate 1,3-thiazolidine-4-carboxylic acid, di-
methyl acetylenedicarboxylate or ethyl 3-phenylpropiolate
(1.5 equiv.) and acetic anhydride were heated at 110–120 °C for 4 h,
unless indicated otherwise. The reaction mixture was cooled to
room temperature and diluted with CH Cl . The organic phase was
General Procedure for the Synthesis of 3-(3-Trifluoromethyl-3-oxo-
propenyl)thiazolidine-4-carboxylic Acid Derivatives 24: 4-Ethoxy-
1,1,1-trifluoro-3-buten-2-one (23) was added dropwise to a solution
of the appropriate thiazolidine-4-carboxylic acid in acetonitrile at
room temperature. After stirring for 24 h, the solution was filtered,
and the solvent was removed in vacuo. Diethyl ether and water
were added, and the two phases were separated. The aqueous phase
was further extracted with diethyl ether, the combined organic
2
2
washed with a saturated aqueous solution of NaHCO and water
3
and dried (MgSO ), and the solvent was evaporated. The crude
4
product was purified by flash chromatography (ethyl acetate/hex-
ane).
2 4
phases were dried with anhydrous Na SO , and the solvent was
removed in vacuo. The resulting solid was pure enough to use in
the next step without recrystallization.
Method B: To a stirred solution of the appropriate N-(unsaturated
ketone) thiazolidine-4-carboxylic acid under nitrogen in aceto-
nitrile was added trifluoroacetic anhydride dropwise at 0 °C. The
(
2R,4R,E)-2-[2-(Prop-2-ynyloxy)phenyl]-3-(3-trifluoromethyl-3-oxo- reaction mixture was stirred at room temperature for 6.5 h, and the
propenyl)thiazolidine-4-carboxylic Acid (24a): Prepared from 23 solvent was removed in vacuo. The resulting oil was purified by
1.277 g, 7.60 mmol) and thiazolidine 17a (2.0 g, 7.60 mmol) in flash chromatography (ethyl acetate/hexane).
(
acetonitrile (40 mL). Compound 24a (2.688 g, 92%) was obtained
as an orange solid; m.p. 121.0–123.0 °C (diethyl ether). IR (KBr):
ν˜ = 3278, 2920, 1743, 1543, 1531, 1460, 1265, 1228, 1190, 1149,
Dimethyl (3R)-5-Methyl-3-[2-(prop-2-ynyloxy)phenyl]-1H,3H-
pyrrolo[1,2-c]thiazole-6,7-dicarboxylate (19a): Prepared by method
A from thiazolidine 17a (1.317 g, 5.0 mmol) and dimethyl ace-
tylenedicarboxylate (18a; 0.92 mL, 7.5 mmol) in acetic anhydride
–1 1
1
093, 930, 760 cm . H NMR (400 MHz, [D
6
]DMSO): Two con-
2
formers (65:35 at T = 25 °C); major conformer: δ = 3.39 (dd, J =
(
20 mL). Purification by flash chromatography (ethyl acetate/hex-
3
11.6 Hz, J = 2.8 Hz, 1 H), 3.48 (s, 1 H), 3.52–3.56 (m, 1 H), 4.91–
ane, 1:3 to 1:1) afforded 19a (1.850 g, 96%) as a white solid; m.p.
4.94 (m, 3 H), 5.32 (br. s, 1 H), 6.15 (s, 1 H), 6.98–7.02 (m, 1 H,
25
9
3.3–95.2 °C (diethyl ether). [α]
D 2 2
= +290 (c = 1, CH Cl ). IR
Ar-H), 7.15–7.17 (m, 1 H, Ar-H), 7.31–7.35 (m, 1 H, Ar-H), 7.59
–1
(
KBr): ν˜ = 3270, 2946, 1725, 1702, 1443, 1295, 1230, 1094 cm .
H NMR (400 MHz, CDCl ): δ = 2.09 (s, 3 H), 2.56 (br. s, 1 H),
3
.82 (s, 3 H), 3.83 (s, 3 H), 4.27 (d, J = 15.0 Hz, 1 H), 4.36 (d, J
15.0 Hz, 1 H), 4.78 (d, J = 2.0 Hz, 2 H), 6.51 (d, J = 7.2 Hz, 1
3
3
(
d, J = 7.6 Hz, 1 H, Ar-H), 8.22 (d, J = 12.8 Hz, 1 H) ppm; minor
1
conformer: δ = 3.52–3.56 (m, 2 H), 3.61–3.65 (m, 1 H), 4.91–4.94
2
2
3
=
3
(
m, 2 H), 4.98 (br. s, 1 H), 5.49 (d, J = 12.6 Hz, 1 H), 6.53 (s, 1
4
3
H), 7.05–7.09 (m, 1 H, Ar-H), 7.17–7.20 (m, 1 H, Ar-H), 7.35–7.40
3
H, Ar-H), 6.60 (s, 1 H), 6.89–6.93 (m, 1 H, Ar-H), 7.03 (d, J =
3
3
(
1
m, 1 H, Ar-H), 7.69 (d, J = 12.6 Hz, 1 H), 7.77 (d, J = 7.2 Hz,
H, Ar-H) ppm. 13C NMR (100 MHz, [D
]DMSO): major con-
former: δ = 31.7, 56.0, 61.6, 69.6, 78.2, 78.7, 90.4, 112.7, 117.1 (q,
13
8
(
1
1
3
.4 Hz, 1 H, Ar-H), 7.27–7.31 (m, 1 H, Ar-H) ppm. C NMR
100 MHz, CDCl ): δ = 11.3, 29.5, 51.3, 51.5, 56.3, 59.2, 76.2, 78.0,
07.0, 112.5, 116.9, 122.1, 125.2, 129.1, 129.8, 130.8, 141.1, 153.7,
64.1, 165.3 ppm. HRMS (EI): calcd. for C20
85.0984; found 385.0982.
6
3
J
J
C,F = 290 Hz), 125.3, 127.2, 129.6, 153.8, 153.8, 170.9, 175.6 (q,
C,F = 31.6 Hz) ppm; minor conformer: δ = 33.4, 56.3, 64.4, 65.3,
+
5
H19NO S [M]
2
7
1
8.4, 78.8, 91.0, 113.1, 117.2 (q, JC,F = 290 Hz), 126.2, 128.3, 130.1,
2
Ethyl (3R)-5-Methyl-7-phenyl-3-[2-(prop-2-ynyloxy)phenyl]-1H,3H-
pyrrolo[1,2-c]thiazole-6-carboxylate (19b): Prepared by method A
from thiazolidine 17a (1.760 g, 6.68 mmol) and ethyl 3-phenylpro-
piolate (18b; 1.65 mL, 10.02 mmol) in acetic anhydride (27 mL).
The reaction mixture was stirred overnight, and purification by
52.4, 155.0, 169.6, 175.6 (q, JC,F = 31.6 Hz) ppm. HRMS (EI):
+
calcd. for C17
H
14NO
4
F
3
S [M] 385.0596; found 385.0592.
(
(
(
(
(
2R,4R,E,E)-2-{2-[(3-Methoxycarbonylprop-2-enyl)oxy]phenyl}-3-
3-trifluoromethyl-3-oxopropenyl)thiazolidine-4-carboxylic Acid
24b): Prepared from 23 (0.884 g, 5.26 mmol) and thiazolidine 17c flash chromatography (ethyl acetate/hexane, 1:4) afforded 19b
1.70 g, 5.26 mmol) in acetonitrile (28 mL). Compound 24b
2.106 g, 90%) was obtained as a pale yellow solid; m.p. 176.0–
2
5
(0.949 g, 34%) as a yellow oil. [α]
D 2 2
= +250 (c = 0.5, CH Cl ). IR
(film): ν˜ = 3284, 2979, 1697, 1489, 1294, 1159, 1107, 1022, 754,
–
1
1
3
1
1
76.5 °C (diethyl ether). IR (KBr): ν˜ = 2952, 1747, 1709, 1523,
700 cm . H NMR (400 MHz, CDCl
458, 1277, 1267, 1238, 1192, 1138, 1109, 1095, 920 cm . H NMR H, CO CH CH ), 2.27 (s, 3 H, Me), 2.53 (br. s, 1 H, CϵCH), 3.90
]DMSO): Two conformers (67:33 at T = 25 °C); (d, J = 13.2 Hz, 1 H, 1-H), 4.09–4.16 (m, 2 H, CO CH CH ), 4.20
), 6.57 (d, J =
3
): δ = 1.10 (t, J = 7.2 Hz, 3
–1 1
2
2
3
2
(
400 MHz, [D
6
2
2
3
2
3
2
3
major conformer: δ = 3.36 (dd, J = 11.8 Hz, J = 3.4 Hz, 1 H),
(d, J = 13.2 Hz, 1 H, 1-H), 4.79 (br. s, 2 H, OCH
2
2
3
3
(
.56 (dd, J = 12.0 Hz, J = 6.4 Hz, 1 H), 3.68 (s, 3 H), 4.89–4.92
m, 3 H), 5.34–5.36 (m, 1 H), 6.21–6.24 (m, 2 H), 6.96–7.00 (m, 1
H, Ar-H), 7.06–7.11 (m, 2 H, Ar-H), 7.30–7.38 (m, 1 H, Ar-H),
7.2 Hz, 1 H, Ar-H), 6.61 (s, 1 H, 3-H), 6.91–6.94 (m, 1 H, Ar-H),
3
7.04 (d, J = 8.0 Hz, 1 H, Ar-H), 7.24–7.38 (m, 6 H, Ar-H) ppm.
1
3
C NMR (100 MHz, CDCl
27.5 (C-1), 56.3 (OCH ), 58.6 (C-3), 59.4 (CO
s, 1 H) ppm; minor conformer: δ = 3.44–3.47 (m, 1 H), 3.62–3.65 (CϵCH), 78.2 (CϵCH), 112.4 (C-Ar), 114.6 (C-5), 117.8 (C-7),
3
): δ = 12.2 (Me), 14.1 (CO
2
CH
2
CH
3
),
3
3
7
.53 (d, J = 7.2 Hz, 1 H), 8.22 (d, J = 12.8 Hz, 1 H), 13.73 (br.
2
2
CH CH
2
3
), 76.1
(
m, 1 H), 3.68 (s, 3 H), 4.92 (br. s, 2 H), 5.00–5.01 (m, 1 H), 5.49 122.0 (C-Ar), 125.1 (C-Ar), 126.2 (C-Ar), 127.6 (C-Ar), 129.5 (C-
3
(d, J = 12.4 Hz, 1 H), 6.21–6.24 (m, 1 H), 6.65 (s, 1 H), 7.06–7.11
Ar), 129.6 (C-Ar), 130.0 (C-Ar), 132.1 (C-6), 132.4 (C-7a), 135.6
Eur. J. Org. Chem. 2015, 1341–1354
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1349

T. M. V. D. Pinho e Melo et al.
FULL PAPER
(
C-Ar), 153.6 (C-Ar), 165.6 (CO
2
CH
2
CH
3
) ppm. HRMS (EI): roformate (0.16 mL, 1.7 mmol) was slowly added to the reaction
+
calcd. for C25
Dimethyl (3R)-3-[2-(Allyloxy)phenyl]-5-methyl-1H,3H-pyrrolo-
1,2-c]thiazole-6,7-dicarboxylate (19c): Prepared by method A from
H
23NO
3
S [M] 417.1399; found 417.1395.
mixture, which was stirred for another 2 h at –78 °C. After warming
to room temperature, the reaction mixture was quenched with satu-
rated aqueous NH
organic layer was washed with water and brine and dried with
Na SO , and the solvent was removed in vacuo. Purification by
flash chromatography (ethyl acetate/hexane, 1:2) afforded 21
4
Cl solution and diluted with ethyl acetate. The
[
thiazolidine 17b (5.307 g, 20.0 mmol) and dimethyl acetylenedicar-
boxylate (18a; 3.69 mL, 30.0 mmol) in acetic anhydride (80 mL).
Purification by flash chromatography (ethyl acetate/hexane, 1:2) af-
forded 19c (7.074 g, 91%) as a white solid; m.p. 65.8–67.6 °C (di-
ethyl ether/hexane). [α]
1
CDCl ): δ = 2.10 (s, 3 H), 3.83 (s, 3 H), 3.84 (s, 3 H), 4.26 (d, J =
3
1
H), 5.32 (d, J = 10.4 Hz, 1 H), 5.43 (d, J = 17.6 Hz, 1 H), 6.00–
6
6
2
4
2
5
(
(
(
0.194 g, 42%) as a yellow oil. [α]
D 2 2
= +220 (c = 1, CH Cl ). IR
–
1 1
film): ν˜ = 2951, 1716, 1446, 1252, 1225, 1095 cm . H NMR
2
5
D
= +330 (c = 1, CH
2
1
Cl
2
). IR (KBr): ν˜ =
3
400 MHz, CDCl
3
): δ = 1.31 (t, J = 7.2 Hz, 3 H), 2.09 (s, 3 H),
731, 1725, 1452, 1295, 1205, 1091 cm–1. H NMR (400 MHz,
3
.83 (s, 3 H), 3.84 (s, 3 H), 4.22–4.37 (m, 4 H), 4.92 (s, 2 H), 6.50
2
3
(
d, J = 7.2 Hz, 1 H, Ar-H), 6.59 (s, 1 H), 6.92–6.96 (m, 1 H, Ar-
2
3
5.2 Hz, 1 H), 4.34 (d, J = 15.2 Hz, 1 H), 4.62 (d, J = 4.8 Hz, 2
3
H), 7.00 (d, J = 8.4 Hz, 1 H, Ar-H), 7.27–7.33 (m, 1 H, Ar-H)
3
3
1
3
ppm. C NMR (100 MHz, CDCl
3
): δ = 11.4, 14.0, 29.4, 51.4, 51.5,
6.0, 59.0, 62.5, 79.1, 80.8, 107.0, 112.3, 117.0, 122.6, 125.3, 129.3,
29.9, 130.8, 141.0, 152.7, 153.4, 164.0, 165.3 ppm. HRMS (EI):
S [M]+ 457.1195; found 457.1191.
3
.10 (m, 1 H), 6.48 (d, J = 7.2 Hz, 1 H, Ar-H), 6.61 (s, 1 H), 6.84–
5
1
.91 (m, 2 H, Ar-H), 7.24–7.28 (m, 1 H, Ar-H) ppm. 1 C NMR
3
(100 MHz, CDCl
3
): δ = 11.4, 29.5, 51.3, 51.5, 59.5, 69.0, 107.0,
12.0, 116.8, 117.9, 121.2, 124.9, 128.6, 129.8, 130.9, 132.6, 141.2,
5
54.6, 164.1, 165.4 ppm. HRMS (EI): calcd. for C20 21NO S
calcd. for C23H23NO
7
1
1
H
General Procedure for the Synthesis of 1H,3H-Pyrrolo[1,2-c]thiazole
+
[M] 387.1140; found 387.1142.
2
,2-Dioxides 20, 22 and 26: A mixture of Na WO ·2H O (1 m solu-
tion in water), C PO , (1 m solution in water), CH N[(CH
CH Cl (1 m solution in methanol) and aqueous 30% H was
2
4
2
6
H
5
3
H
2
3
2 7
) -
(
3R)-3-[2-(Prop-2-ynyloxy)phenyl]-7-(trifluoromethyl)-1H,3H-
3
]
3
2 2
O
pyrrolo[1,2-c]thiazole (25a): Prepared by method B from thiazolid-
ine 24a (1.180 g, 3.06 mmol) and trifluoroacetic anhydride
vigorously stirred at room temperature for 10 min. A solution of
the appropriate 1H,3H-pyrrolo[1,2-c]thiazole in ethyl acetate was
slowly added to the reaction mixture, and the resulting solution
was stirred at 45–50 °C. During the reaction, a new load of cata-
(0.51 mL, 3.67 mmol) in acetonitrile (25 mL). Purification by flash
chromatography (ethyl acetate/hexane, 1:3) afforded 25a (0.868 g,
8
8%) as a pale orange solid; m.p. 86.4–88.4 °C (ethyl acetate/hex-
2
5
2 2
lysts and H O was added, and the mixture was stirred again at
ane). [α]
D
= +175 (c = 1, CH
2
Cl
2
). IR (KBr): ν˜ = 3321, 1493, 1257,
): δ = 2.54 (br. s, 1
H), 4.17 (d, J = 13.6 Hz, 1 H), 4.28 (d, J = 13.6 Hz, 1 H), 4.77
–1
1
45–50 °C, unless otherwise indicated. The reaction was monitored
by TLC. After the reaction was complete, the mixture was cooled
to room temperature, and 40% (w/v) aqueous sodium hydrogen
sulfite solution was added to the reaction mixture. The organic
1
136, 1095 cm . H NMR (400 MHz, CDCl
3
2
2
(
(
=
br. s, 2 H), 6.45 (br. s, 1 H), 6.47 (br. s, 1 H), 6.73 (s, 1 H), 6.82
3
3
d, J = 7.2 Hz, 1 H, Ar-H), 6.94–6.97 (m, 1 H, Ar-H), 7.03 (d, J
8.0 Hz, 1 H, Ar-H), 7.29–7.33 (m, 1 H, Ar-H) ppm. 13C NMR
2 4
phase was separated and dried with anhydrous Na SO , and the
2
solvent was evaporated. The crude product was purified by flash
chromatography (ethyl acetate/hexane).
3
(100 MHz, CDCl ): δ = 28.2, 56.3, 60.2, 76.1, 78.0, 106.4 (q, JC,F
3
=
(
1
37.2 Hz), 111.4 (q, JC,F = 2.9 Hz), 112.3, 115.9, 122.0, 124.0
3
q, JC,F = 264 Hz), 126.3, 129.0, 129.9, 135.1 (q, JC,F = 4.0 Hz),
Dimethyl (3R)-5-Methyl-3-[2-(prop-2-ynyloxy)phenyl]-1H,3H-
pyrrolo[1,2-c]thiazole-6,7-dicarboxylate 2,2-Dioxide (20a): Prepared
54.3 ppm. 19F NMR (376 MHz, CDCl
): δ = –56.38 ppm. HRMS
3
+
(EI): calcd. for C16
H
12NOSF
3
[M] 323.0592; found 323.0596.
from pyrrolo[1,2-c]thiazole 19a (2.150 g, 5.58 mmol), H
1.55 mL, 16.74 mmol), Na WO ·2H O (5.58 μL, 5.58 μmol),
PO (5.58 μL, 5.58 μmol) and CH N[(CH CH Cl
5.58 μL, 5.58 μmol) in ethyl acetate (7 mL). After 1 d, a new load
of catalysts and H was added, and the reaction mixture was
2 2
O
(
2
4
2
(
3R,E)-3-{2-[(3-Methoxycarbonylprop-2-enyl)oxy]phenyl}-7-(tri-
C
6
H
5
3
H
2
3
2
)
7
3 3
]
fluoromethyl)-1H,3H-pyrrolo[1,2-c]thiazole (25b): Prepared by
method B from thiazolidine 24b (2.0 g, 5.22 mmol) and trifluoro-
acetic anhydride (0.87 mL, 6.26 mmol) in acetonitrile (40 mL). Pu-
rification by flash chromatography (ethyl acetate/hexane, 1:3) af-
forded 25b (1.394 g, 70%) as an orange solid; m.p. 109.4–111.1 °C
(
2
O
2
stirred for another 4 d. Purification by flash chromatography (ethyl
acetate/hexane, 1:1) afforded 20a (1.358 g, 58%) as a white solid;
2
5
ethyl acetate/hexane). [α]2
5
= +247 (c = 1, CH
m.p. 187.7–189.7 °C (diethyl ether). [α]D = +115 (c = 1, CH Cl ).
2
2
–
(
D
2
Cl
2
). IR (KBr): ν˜
1
IR (KBr): ν˜ = 3297, 1704, 1445, 1332, 1296, 1239, 1164, 1108 cm .
H NMR (400 MHz, CDCl ): δ = 2.17 (s, 3 H), 2.58 (s, 1 H), 3.84
(s, 3 H), 3.86 (s, 3 H), 4.38 (br. s, 1 H), 4.69 (d, J = 16.0 Hz, 1 H),
=
1712, 1495, 1444, 1277, 1261, 1246, 1119, 1097, 1043, 980,
1
–1
1
7
54 cm . H NMR (400 MHz, CDCl
3
): δ = 3.74 (s, 3 H), 4.15 (d,
3
2
2
2
J = 13.6 Hz, 1 H), 4.23 (d, J = 13.6 Hz, 1 H), 4.76 (br. s, 2 H),
3
4.81 (br. s, 2 H), 6.36 (br. s, 2 H), 6.98–7.01 (m, 1 H, Ar-H), 7.18
6
6
.21 (d, J = 15.6 Hz, 1 H), 6.46 (br. s, 1 H), 6.48 (br. s, 1 H), 6.74–
1
3
3
(br. s, 1 H, Ar-H), 7.42–7.46 (m, 1 H, Ar-H) ppm. C NMR
.78 (m, 2 H), 6.86 (d, J = 8.0 Hz, 1 H, Ar-H), 6.90–6.94 (m, 1
1
3
(100 MHz, CDCl ): δ = 11.3, 50.7, 51.7, 51.8, 56.8, 73.4, 76.5, 77.6,
H, Ar-H), 7.06–7.10 (m, 1 H), 7.25–7.29 (m, 1 H, Ar-H) ppm.
C
3
2
113.2, 115.7, 119.5, 122.3, 125.3, 128.2, 129.0, 132.0, 133.7, 156.1,
NMR (100 MHz, CDCl
37.2 Hz), 111.5 (q, 3
24.0 (q, JC,F = 264 Hz), 126.0, 128.7, 130.0, 135.2 (q, JC,F
3
): δ = 28.0, 51.7, 60.4, 66.7, 106.4 (q, JC,F
+
=
1
4
JC,F = 3.0 Hz), 111.7, 116.0, 121.7, 121.8,
163.2, 164.8 ppm. HRMS (EI): calcd. for C20
7
H19NO S [M]
3
417.0882; found 417.0894.
=
.0 Hz), 141.9, 154.6, 166.3 ppm. 1 F NMR (376 MHz, CDCl
–56.52 ppm. HRMS (EI): calcd. for C18
S [M]+
83.0803; found 383.0808.
9
): δ
3
Ethyl (3R)-5-Methyl-7-phenyl-3-[2-(prop-2-ynyloxy)phenyl]-1H,3H-
pyrrolo[1,2-c]thiazole-6-carboxylate 2,2-Dioxide (20b): Prepared
=
3 3
H16NO F
3
from pyrrolo[1,2-c]thiazole 19b (0.950 g, 2.28 mmol), H
Dimethyl (3R)-3-{2-[(3-Ethoxycarbonylprop-2-ynyl)oxy]phenyl}-5- (0.70 mL, 6.84 mmol), Na WO ·2H O (2.28 μL, 2.28 μmol),
(2.28 μL, 2.28 μmol) and CH N[(CH CH Cl
2 2
O
2
4
2
methyl-1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicarboxylate (21): A solu-
tion of pyrrolo[1,2-c]thiazole 19a (0.385 g, 1.0 mmol) in dry tetra-
hydrofuran (THF, 6 mL) was stirred at –78 °C for 10 min under a
nitrogen atmosphere. n-Butyllithium (0.60 mL, 1.50 mmol 2.5 m in
hexane) was slowly added to the reaction mixture, and the resulting
solution was stirred for 30 min at the same temperature. Ethyl chlo-
C
6
H
5
PO
3
H
2
3
2
)
7
3 3
]
(2.28 μL, 2.28 μmol) in ethyl acetate (8 mL) for 5 d. Purification
by flash chromatography (ethyl acetate/hexane, 1:3) afforded 20b
2
5
(0.436 g, 43%) as a pale yellow foam. [α]
D
= +110 (c = 1, CH
2
Cl
H NMR
3
): δ = 1.10 (t, J = 7.2 Hz, 3 H), 2.35 (s, 3 H),
2
).
–
1 1
IR (film): ν˜ = 3282, 2979, 1697, 1338, 1128 cm
.
3
(400 MHz, CDCl
1350
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 1341–1354

Pericyclic Reactions of Azafulvenium Methides
.57 (s, 1 H), 4.11–4.31 (m, 4 H), 4.79–4.89 (m, 2 H), 6.41 (br. s, 1
2
7.44–7.47 (m, 1 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl
3
): δ =
3
2
H), 6.63 (m, 1 H, Ar-H), 7.01–7.04 (m, 1 H, Ar-H), 7.19–7.21 (m, 49.7, 56.7, 74.8, 76.5, 77.7, 109.8 (q, JC,F = 2.6 Hz), 111.3 (q, JC,F
3
1
H, Ar-H), 7.28–7.38 (m, 5 H, Ar-H), 7.43–7.47 (m, 1 H, Ar-H)
= 37.6 Hz), 112.9, 119.1, 119.6, 122.1, 122.3 (q,
123.2 (q, JC,F = 265 Hz), 127.5, 132.0, 156.3 ppm. F NMR
(376 MHz, CDCl ): δ = –57.0 ppm. HRMS (ESI): calcd. for
S [M + H]+ 356.05627; found 356.05639.
JC,F = 3.8 Hz),
13
19
ppm. C NMR (100 MHz, CDCl
3
): δ = 12.3, 14.0, 49.2, 56.9, 59.8,
4.0, 76.4, 77.9, 113.2, 113.7, 119.3, 120.5, 122.3, 123.0, 127.0,
27.9, 129.5, 129.6, 131.7, 134.1, 135.2, 156.1, 164.9 ppm. HRMS
7
1
3
16 3 3
C H13NO F
+
(
5
ESI): calcd. for C25H24NO S [M + H] 450.13680; found
(
3R,E)-3-{2-[(3-Methoxycarbonylprop-2-enyl)oxy]phenyl}-7-(tri-
450.13697.
fluoromethyl)-1H,3H-pyrrolo[1,2-c]thiazole 2,2-Dioxide (26b): Pre-
Dimethyl (3R)-3-[2-(Allyloxy)phenyl]-5-methyl-1H,3H-pyrrolo- pared from pyrrolo[1,2-c]thiazole 25b (1.10 g, 2.87 mmol), H
1,2-c]thiazole-6,7-dicarboxylate 2,2-Dioxide (20c): Prepared from (0.88 mL, 8.61 mmol), Na WO ·2H O (2.87 μL, 2.87 μmol),
pyrrolo[1,2-c]thiazole 19c (2.0 g, 5.17 mmol), H (1.80 mL,
PO (2.87 μL, 2.87 μmol) and CH N[(CH CH Cl
5.51 mmol), Na WO ·2H O (5.17 μL, 5.17 μmol), C PO
(2.87 μL, 2.87 μmol) in ethyl acetate (8 mL). After 2 d, a new load
5.17 μL, 5.17 μmol) and CH N[(CH CH Cl (5.17 μL,
of catalysts and H was added, and the reaction mixture was
.17 μmol) in ethyl acetate (6.5 mL) for 65 h. Purification by flash
stirred for another day. Purification by flash chromatography (ethyl
chromatography (ethyl acetate/hexane, 1:1) afforded 20c (0.80 g, acetate/hexane, 1:2) afforded 26b (0.433 g, 36%) as a yellow solid;
m.p. 111.5–113.5 °C (ethyl acetate/hexane). [α] 2D 5 = +140 (c = 1,
). IR (KBr): ν˜ = 2987, 1709, 1446, 1335, 1254, CH Cl ). IR (KBr): ν˜ = 1732, 1335, 1311, 1282, 1255, 1190, 1173,
1113 cm–1
H NMR (400 MHz, CDCl ): δ = 3.75 (s, 3 H), 4.32 (d,
J = 15.6 Hz, 1 H), 4.52 (d,
H), 6.28 (d, J = 16.0 Hz, 1 H), 6.52 (s, 1 H), 6.59–6.61 (m, 2 H),
6.75 (d, J = 2.8 Hz, 1 H), 6.96–7.02 (m, 2 H, Ar-H), 7.08 (dt,
= 16.0, 3.6 Hz, 1 H), 7.40–7.44 (m, 1 H, Ar-H) ppm. 13C NMR
2 2
O
[
2
4
2
2
O
2
C
6
H
5
3
H
2
3
2
)
7
3 3
]
1
(
2
4
2
6
H
5
3 2
H
3
2
)
7
3
]
3
2 2
O
5
2
5
3
+
1
2
1
7%) as a white solid; m.p. 146.6–148.4 °C (diethyl ether). [α]
155 (c = 1, CH Cl
234, 1211, 1167, 1132 cm . H NMR (400 MHz, CDCl
D
=
2
2
2
2
–1
1
.
1
3
): δ =
3
2
2
2
J = 15.6 Hz, 1 H), 4.76–4.87 (m, 2
.18 (s, 3 H), 3.85 (s, 3 H), 3.87 (s, 3 H), 4.34 (pseudo-d, J =
3
3
6.0 Hz, 1 H), 4.67–4.71 (m, 3 H), 5.33 (pseudo-d, J = 10.4 Hz, 1
H), 5.47 (pseudo-d, J = 16.8 Hz, 1 H), 6.06 (br. s, 1 H), 6.39 (br.
3
3
3
J
3
s, 2 H), 6.92–6.96 (m, 1 H, Ar-H), 7.01 (d, J = 8.0 Hz, 1 H, Ar-
H), 7.39–7.43 (m, 1 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl
):
δ = 11.4, 50.6, 51.8, 51.8, 69.6, 73.6, 77.3, 111.9, 112.8, 115.7, 118.4,
(100 MHz, CDCl ): δ = 48.5, 50.8, 66.2, 73.7, 108.9 (q,
3
2
3
JC,F
=
3
2.7 Hz), 110.4 (q, JC,F = 37.6 Hz), 111.3, 118.1, 118.3, 120.9,
1
1
19.0, 121.4, 125.2, 127.9, 132.0, 132.2, 133.7, 157.0, 163.2, 121.2, 122.1 (q, JC,F = 264 Hz), 126.0, 131.0, 140.3, 155.6,
+
165.4 ppm. 19F NMR (376 MHz, CDCl ): δ = –57.09 ppm. HRMS
64.8 ppm. HRMS (EI): calcd. for C20
found 419.1047.
H
21NO
7
S [M] 419.1039;
3
5 3
H17NO F
S [M + H]+ 416.07740; found
(ESI): calcd. for C18
16.07792.
4
Dimethyl (3R)-3-{2-[(3-Ethoxycarbonylprop-2-ynyl)oxy]phenyl}-5-
methyl-1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicarboxylate 2,2-Dioxide
General Procedures for the Thermolysis of 1H,3H-Pyrrolo[1,2-c]thi-
azole 2,2-Dioxides
(
22): Prepared from pyrrolo[1,2-c]thiazole 21 (0.689 g, 1.51 mmol),
(0.42 mL, 4.53 mmol), Na WO ·2H O (1.51 μL, 1.51 μmol),
PO (1.51 μL, 1.51 μmol) and CH N[(CH CH Cl
1.51 μL, 1.51 μmol) in ethyl acetate (6 mL). After 2 d, a new load
of catalysts and H was added, and the reaction mixture was
H
2
O
2
2
4
2
Method A: A suspension of the appropriate 1H,3H-pyrrolo[1,2-c]-
thiazole 2,2-dioxide in 1,2,4-trichlorobenzene (1 mL) was irradiated
in the microwave reactor at the temperature and for the time indi-
cated in each case. After cooling to room temperature, the mixture
was purified by flash chromatography (hexane) to remove 1,2,4-
trichlorobenzene, followed by elution with ethyl acetate/hexane to
obtain the corresponding products.
C
6
H
5
3
H
2
3
2
)
7
3 3
]
(
2
O
2
stirred for another day. Purification by flash chromatography (ethyl
acetate/hexane, 1:1) afforded 22 (0.481 g, 65%) as a white foam.
2
5
[
α]
D
= +125 (c = 1, CH
2
Cl
2
). IR (film): ν˜ = 1716, 1252, 1227, 1211,
–1
1
3
1
3
2
(
1
132 cm . H NMR (400 MHz, CDCl ): δ = 1.31 (t, J = 7.2 Hz,
3
3
Method B: A suspension of the appropriate 1H,3H-pyrrolo[1,2-c]-
thiazole 2,2-dioxide in 1,2,4-trichlorobenzene (1 mL) was heated in
a sealed tube at the temperature and for the time indicated in each
case. After cooling to room temperature, the mixture was purified
by flash chromatography (hexane) to remove 1,2,4-trichlorobenz-
ene, followed by elution with ethyl acetate/hexane to obtain the
corresponding products.
H), 2.19 (s, 3 H), 3.85 (s, 3 H), 3.87 (s, 3 H), 4.25 (q, J = 7.2 Hz,
2
H), 4.32–4.36 (m, 1 H), 4.70 (d, J = 16.4 Hz, 1 H), 4.90–4.98
m, 2 H), 6.36 (br. s, 2 H), 7.01–7.05 (m, 1 H, Ar-H), 7.15–7.17 (m,
13
H, Ar-H), 7.44–7.48 (m, 1 H, Ar-H) ppm. C NMR (100 MHz,
): δ = 11.4, 14.0, 50.5, 51.8, 51.9, 56.6, 62.4, 73.3, 77.3, 79.4,
12.1, 113.2, 115.8, 119.7, 122.8, 125.7, 127.7, 132.1, 133.7, 152.7,
55.9, 163.1, 164.8 ppm. HRMS (ESI): calcd. for C23 S [M
CDCl
3
1
1
H
24NO
9
+
+
H] 490.11663; found 490.11640.
Dimethyl (E)-2-[2-(2H-Chromen-8-yl)vinyl]-5-methyl-1H-pyrrole-
3
,4-dicarboxylate (27a): Prepared by method A from 1H,3H-
(
3R)-3-[2-(Prop-2-ynyloxy)phenyl]-7-(trifluoromethyl)-1H,3H-
pyrrolo[1,2-c]thiazole 2,2-dioxide 20a (100 mg, 0.24 mmol). Com-
pound 20a was irradiated at 240 °C for 15 min. Purification by
flash chromatography (hexane and ethyl acetate/hexane, 1:2) af-
forded 27a (45.8 mg, 54 %) as a pale orange solid; m.p. 185.2–
pyrrolo[1,2-c]thiazole 2,2-Dioxide (26a): Prepared from pyrrolo[1,2-
c]thiazole 25a (0.5 g, 1.55 mmol), H (0.43 mL, 4.65 mmol),
Na WO ·2H O (1.55 μL, 1.55 μmol), C PO (1.55 μL,
.55 μmol) and CH N[(CH CH Cl (1.55 μL, 1.55 μmol) in ethyl
acetate (6 mL). After 2 d, a new load of catalysts and H was
2
O
2
2
4
2
6
H
5
3 2
H
1
3
2
)
7
3 3
]
1
1
2
5
87.2 °C (ethyl acetate/hexane). IR (KBr): ν˜ = 3257, 1712, 1699,
446, 1227, 1200, 1099 cm . H NMR (400 MHz, CDCl ): δ =
3
.39 (s, 3 H), 3.80 (s, 3 H), 3.85 (s, 3 H), 4.79 (br. s, 2 H), 5.73–
.78 (m, 1 H), 6.39 (d, J = 10.0 Hz, 1 H), 6.79–6.85 (m, 2 H, Ar-
2
O
2
–
1 1
added, and the reaction mixture was stirred for another 4 d. Purifi-
cation by flash chromatography (ethyl acetate/hexane, 1:4) afforded
2
acetate/hexane). [α]
3
3
6a (0.405 g, 73.5%) as a white solid; m.p. 111.5–113.3 °C (ethyl
3
H), 7.07 (d, J = 17.2 Hz, 1 H), 7.32–7.36 (m, 2 H), 9.21 (br. s, 1
H) ppm. C NMR (100 MHz, CDCl
1
1
2
5
D 2 2
= +95 (c = 1, CH Cl ). IR (KBr): ν˜ = 3300,
1
3
): δ = 12.7, 51.4, 51.7, 65.6,
13.0, 114.1, 116.7, 121.2, 121.5, 121.9, 122.6, 124.2, 124.7, 125.8,
26.2, 132.8, 135.6, 151.2, 165.6, 165.8 ppm. HRMS (EI): calcd.
–
1
1
3
282, 1342, 1284, 1254, 1194, 1117, 1105 cm
.
H NMR
2
(400 MHz, CDCl ): δ = 2.57 (br. s, 1 H), 4.37 (d, J = 15.6 Hz, 1
3
2
2
4
H), 4.51 (d, J = 15.6 Hz, 1 H), 4.76 (dd, J = 15.8 Hz, J = 1.6 Hz,
+
for C20
Ethyl (E)-5-[2-(2H-Chromen-8-yl)vinyl]-2-methyl-4-phenyl-1H-
H), 7.01–7.04 (m, 1 H, Ar-H), 7.16 (d, J = 8.4 Hz, 1 H, Ar-H), pyrrole-3-carboxylate (27b): Prepared by method A from 1H,3H-
5
H19NO [M] 353.1263; found 353.1263.
2
4
1
H), 4.83 (dd, J = 15.8, J = 1.6 Hz, 1 H), 6.45 (s, 1 H), 6.58 (d,
3
3
J = 2.8 Hz, 1 H), 6.63–6.65 (m, 1 H, Ar-H), 6.71 (d, J = 2.8 Hz,
3
1
Eur. J. Org. Chem. 2015, 1341–1354
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1351

T. M. V. D. Pinho e Melo et al.
FULL PAPER
pyrrolo[1,2-c]thiazole 2,2-dioxide 20b (90 mg, 0.20 mmol). Com-
pound 20b was irradiated at 260 °C for 10 min. Purification by
flash chromatography (hexane and ethyl acetate/hexane, 1:3) af-
forded 27b (16.0 mg, 21%) as an orange solid; m.p. 224.3–226.1 °C
Compound 38: Obtained as a yellow oil. IR (film): ν˜ = 3444, 1712,
1448, 1221, 1099 cm . H NMR (400 MHz, CDCl ): δ = 1.35 (t,
3
–
1 1
3
J = 7.2 Hz, 3 H), 2.41 (s, 3 H), 3.79 (s, 3 H), 3.84 (s, 3 H), 4.30
3
(q, J = 7.2 Hz, 2 H), 4.77–4.78 (m, 2 H), 6.78–6.80 (m, 1 H, Ar-
3
(
ethyl acetate/hexane). IR (KBr): ν˜ = 3282, 1664, 1431, 1161,
H), 6.89–6.92 (m, 1 H, Ar-H), 7.04 (d, J = 17.0 Hz, 1 H), 7.31 (d,
–1
1
3
3
3
3
1
3
5
6
095 cm . H NMR (400 MHz, CDCl
3
): δ = 1.07 (t, J = 7.2 Hz,
J = 17.0 Hz, 1 H), 7.41 (d, J = 7.6 Hz, 1 H, Ar-H), 7.76 (d, J =
3
13
H), 2.60 (s, 3 H), 4.10 (q, J = 7.2 Hz, 2 H), 4.84–4.85 (m, 2 H), 7.2 Hz, 1 H, Ar-H), 9.20 (br. s, 1 H) ppm. C NMR (100 MHz,
3
4
.77–5.81 (m, 1 H), 6.41 (dt, J = 9.6 Hz, J = 1.6 Hz, 1 H), 6.74– CDCl
3
): δ = 11.8, 13.2, 50.4, 50.7, 60.1, 63.7, 75.7, 76.2, 115.9,
3
.82 (m, 3 H), 6.87 (d, J = 16.8 Hz, 1 H), 7.17–7.20 (m, 1 H, Ar- 119.0, 120.3, 120.5, 123.7, 125.0, 125.3, 126.7, 130.3, 131.4, 134.3,
13
H), 7.30–7.38 (m, 5 H, Ar-H), 8.54 (br. s, 1 H) ppm. C NMR 150.2, 163.8, 164.4, 164.6 ppm. HRMS (EI): calcd. for C23H23NO
7
+
(
1
1
100 MHz, CDCl
3
): δ = 14.0, 14.0, 59.3, 65.6, 112.1, 117.1, 117.5,
21.2, 121.8, 122.6, 124.8, 124.9, 125.2, 125.4, 126.4, 126.5, 127.0,
27.4, 130.8, 135.1, 136.8, 150.7, 165.4 ppm. HRMS (EI): calcd.
[M] 425.1475; found 425.1473.
7
-Ethyl 10,9-Dimethyl 11-Methyl-8,12a-dihydro-6H-chromeno-
[
[
4,3-e]indolizine-7,9,10-tricarboxylate (37), (E)-Dimethyl 2-{2-
(3-Ethoxycarbonylprop-2-ynyl)oxy]styryl}-5-methyl-1H-pyrrole-
+
for C25
Dimethyl (E)-2-[2-(2H-Chromen-8-yl)vinyl]-5-methyl-1H-pyrrole-
,4-dicarboxylate (27a), Dimethyl (E)-2-Methyl-5-[2-(prop-2-ynyl-
oxy)styryl]-1H-pyrrole-3,4-dicarboxylate (34) and Dimethyl (3R)-3-
2H-Chromen-8-yl)-5-methyl-1H,3H-pyrrolo[1,2-c]thiazole-6,7-di-
carboxylate 2,2-Dioxide (35): Prepared by methods A and B from
H,3H-pyrrolo[1,2-c]thiazole 2,2-dioxide 20a (100 mg, 0.24 mmol).
3
H23NO [M] 385.1678; found 385.1685.
3
2
,4-dicarboxylate (38) and (3R)-Dimethyl 3-[4-(Ethoxycarbonyl)-
H-chromen-8-yl]-5-methyl-1H,3H-pyrrolo[1,2-c]thiazole-6,7-di-
3
carboxylate 2,2-Dioxide (39): Prepared by method A from 1H,3H-
pyrrolo[1,2-c]thiazole 2,2-dioxide 22 (100 mg, 0.20 mmol). Purifica-
tion by flash chromatography (hexane and ethyl acetate/hexane,
(
1
1:3) afforded, in order of elution, compounds 37, 38 and 39. The
Purification by flash chromatography (hexane and ethyl acetate/
hexane, 1:2) afforded, in order of elution, a mixture of compounds
reaction conditions and yields of the compounds are specified in
Scheme 7.
27a and 34 and sulfone 35. The reaction conditions and yields of
Compounds 37 and 38: Identified by comparison with the specimen
previously prepared (see above).
the compounds are specified in Table 2.
Compound 27a: Identified by comparison with the specimen pre-
viously prepared (see above).
Compound 39: Obtained as a white solid; m.p. 189.0–190.6 °C (ethyl
2
5
acetate/hexane). [α]
1
D 2 2
= +130 (c = 1, CH Cl ). IR (KBr): ν˜ = 1736,
1
Compound 34: Obtained as a yellow oil. H NMR (400 MHz,
–
1 1
716, 1699, 1460, 1448, 1335, 1238, 1213, 1196, 1132 cm . H
CDCl
3
): δ = 2.48 (s, 3 H), 2.54 (br. s, 1 H), 3.82 (s, 3 H), 3.86 (s, 3
3
NMR (400 MHz, CDCl
H), 3.85 (s, 3 H), 3.87 (s, 3 H), 4.30–4.36 (m, 3 H), 4.70 (d, J =
6.4 Hz, 1 H), 4.96 (br. s, 2 H), 6.23 (br. s, 2 H), 6.92–6.96 (m, 2 H,
Ar-H), 8.05 (d, J = 7.6 Hz, 1 H, Ar-H) ppm. C NMR (100 MHz,
CDCl ): δ = 11.4, 14.2, 50.6, 51.8, 51.9, 61.2, 65.3, 73.6, 112.1,
15.7, 118.1, 120.7, 122.2, 124.9, 126.6, 127.7, 128.8, 132.7, 133.6,
52.8, 163.1, 164.2, 164.8 ppm. HRMS (ESI): calcd. for
S [M + H]+ 490.11663; found 490.11737.
3
): δ = 1.37 (t, J = 7.2 Hz, 3 H), 2.20 (s, 3
4
H), 4.76 (d, J = 1.6 Hz, 2 H), 6.99–7.03 (m, 2 H, Ar-H), 7.12 (d,
2
3
3
J = 17.0 Hz, 1 H), 7.23–7.26 (m, 1 H, Ar-H), 7.38 (d, J = 17.0 Hz,
1
1
H), 7.61 (d, 3J = 7.6 Hz, 1 H, Ar-H), 8.63 (br. s, 1 H) ppm.
3
13
+
HRMS (EI): calcd. for C20
H
19NO
5
[M] 353.1263; found 353.1262.
3
Compound 35: Obtained as a white solid; m.p. 237.1–239.0 °C (ethyl
1
1
acetate/hexane). [α]2
958, 2925, 1732, 1703, 1448, 1342, 1211, 1132 cm . H NMR
400 MHz, CDCl ): δ = 2.21 (s, 3 H), 3.85 (s, 3 H), 3.87 (s, 3 H),
5
D
2 2
= +200 (c = 0.5, CH Cl ). IR (KBr): ν˜ =
–
1 1
2
(
23 9
C H24NO
3
2
2
9-(Trifluoromethyl)-8,12a-dihydro-6H-chromeno[4,3-e]indolizine
(43) and (E)-2-[2-(2H-Chromen-8-yl)vinyl]-3-(trifluoromethyl)-1H-
pyrrole (44): Prepared by method A from 1H,3H-pyrrolo[1,2-c]thi-
azole 2,2-dioxide 26a (100 mg, 0.28 mmol). Compound 26a was ir-
radiated at 240 °C for 15 min. Purification by flash chromatog-
raphy (hexane and ethyl acetate/hexane, 1:4) afforded, in order of
elution, compounds 43 (27.2 mg, 33%) and 44 (13.0 mg, 16%).
4
.33 (d, J = 16.4 Hz, 1 H), 4.69 (d, J = 16.4 Hz, 1 H), 4.94 (br.
s, 2 H), 5.84–5.88 (m, 1 H), 6.21 (br. s, 2 H), 6.44 (d, J = 10.0 Hz,
H), 6.81–6.85 (m, 1 H, Ar-H), 7.03 (d, J = 7.2 Hz, 1 H, Ar-H)
3
3
1
13
ppm. C NMR (100 MHz, CDCl
3
): δ = 11.4, 50.8, 51.8, 51.9, 66.3,
3.7, 111.9, 115.6, 117.3, 121.3, 121.8, 123.1, 123.2, 123.6, 127.9,
28.7, 133.7, 152.8, 163.2, 164.8 ppm. HRMS (ESI): calcd. for
S [M + H]+ 418.09550; found 418.09465.
7
1
20 7
C H20NO
Compound 43: Obtained as a yellow oil. IR (film): ν˜ = 1483, 1236,
7
[
2
-Ethyl 10,9-Dimethyl 11-Methyl-8,12a-dihydro-6H-chromeno-
4,3-e]indolizine-7,9,10-tricarboxylate (37) and Dimethyl (E)-
-{2-[(3-Ethoxycarbonylprop-2-ynyl)oxy]styryl}-5-methyl-1H-pyrr-
–
1 1
1
3
119, 1099 cm . H NMR (400 MHz, CDCl ): δ = 3.49 (pseudo-
2
2
d, J = 22.0 Hz, 1 H), 3.62 (pseudo-d, J = 22.0 Hz, 1 H), 4.75 (d,
2
2
J = 12.0 Hz, 1 H), 4.92 (d, J = 12.0 Hz, 1 H), 5.72 (br. s, 1 H),
ole-3,4-dicarboxylate (38): Prepared by method A from 1H,3H-
pyrrolo[1,2-c]thiazole 2,2-dioxide 22 (100 mg, 0.20 mmol). Com-
pound 22 was irradiated at 240 °C for 15 min. Purification by flash
chromatography (hexane and ethyl acetate/hexane, 1:3) afforded, in
order of elution, compounds 37 (22%) and 38 (25%).
3
5.99 (br. s, 1 H), 6.53 (d, J = 2.8 Hz, 1 H), 6.86–6.91 (m, 3 H),
3
7
.12 (d, J = 8.0 Hz, 1 H, Ar-H), 7.18–7.22 (m, 1 H, Ar-H) ppm.
1
3
3
C NMR (100 MHz, CDCl
3
): δ = 23.1, 53.0, 70.5, 107.1 (q, JC,F
2
=
3.0 Hz), 109.5 (q, JC,F = 36.0 Hz), 117.3, 118.4, 120.1, 121.1,
24.1, 124.5 (q, JC,F = 265 Hz), 125.7 (q, JC,F = 3.6 Hz), 125.8,
3
1
1
–
Compound 37: Obtained as a yellow oil. IR (film): ν˜ = 1718, 1444,
1
9
28.0, 129.4, 153.6 ppm. F NMR (376 MHz, CDCl
3
): δ =
–1
1
3
1
7
201, 1103 cm . H NMR (400 MHz, CDCl
.0 Hz, 3 H), 2.56 (s, 3 H), 3.06 (d, J = 14.0 Hz, 1 H), 3.18 (d, J
3
): δ = 1.01 (t, J =
+
55.92 ppm. HRMS (EI): calcd. for C16H12NOF [M] 291.0871;
3
2
2
found 291.0872.
2
=
14.0 Hz, 1 H), 3.83–3.85 (m, 8 H), 4.05 (d, J = 10.0 Hz, 1 H),
2
3
4.85 (d, J = 10.0 Hz, 1 H), 6.85 (s, 1 H), 6.95 (d, J = 8.4 Hz, 1
Compound 44: Obtained as an orange oil. IR (film): ν˜ = 3419, 1132,
–
1 1
H, Ar-H), 7.03–7.07 (m, 1 H, Ar-H), 7.25–7.28 (m, 1 H, Ar-H), 1101 cm . H NMR (400 MHz, CDCl
3
): δ = 4.87–4.88 (m, 2 H),
5.79–5.83 (m, 1 H), 6.42–6.45 (m, 2 H), 6.75 (br. s, 1 H), 6.87–6.89
.53 (d, 3J = 7.2 Hz, 1 H, Ar-H) ppm. C NMR (100 MHz,
CDCl ): δ = 12.1, 13.6, 37.6, 51.3, 51.5, 61.2, 63.6, 71.8, 105.2,
14.3, 116.4, 117.0, 117.9, 122.6, 125.7, 130.6, 134.4, 143.7, 145.0,
51.8, 163.7, 165.5, 167.5 ppm. HRMS (EI): calcd. for C23
13
7
3
3
3
(m, 2 H, Ar-H), 7.02 (d, J = 16.8 Hz, 1 H), 7.15 (d, J = 16.8 Hz,
1 H), 7.38–7.40 (m, 1 H, Ar-H), 8.66 (br. s, 1 H) ppm. C NMR
(100 MHz, CDCl
JC,F = 35.7 Hz), 116.2, 118.4, 120.8, 121.3, 122.0, 122.7, 124.1,
1
3
1
1
3
H
23NO
7
3
): δ = 65.7, 108.5 (q, JC,F = 3.2 Hz), 112.8 (q,
+
2
[M] 425.1475; found 425.1480.
1352
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 1341–1354

Pericyclic Reactions of Azafulvenium Methides
1
3
24.3 (q, JC,F = 265 Hz), 124.7, 125.7, 126.3, 129.8 (q, 3JC,F
=
X-ray Diffraction: A crystal of 27a was selected, covered with poly-
.5 Hz), 151.2 ppm. 19F NMR (376 MHz, CDCl
): δ = –55.00 ppm. fluoroether oil and mounted on a nylon loop. The crystallographic
[M] 291.0871; found
3
+
HRMS (EI): calcd. for C16
91.0875.
H
12NOF
3
data for this compound were collected at the IST by using graphite-
monochromated Mo-K radiation (λ = 0.71073 Å) with a Bruker
2
α
AXS-KAPPA APEX II diffractometer equipped with an Oxford
Cryosystem open-flow nitrogen cryostat at 150 K. The cell param-
eters were retrieved by using the Bruker SMART software and re-
fined by using Bruker SAINT on all observed reflections. Absorp-
tion corrections were applied with SADABS.[ Structure solution
and refinement were performed by direct methods with the pro-
Methyl 9-(Trifluoromethyl)-6a,7,8,12a-tetrahydro-6H-chromeno[4,3-
e]indolizine-7-carboxylate (47) and Methyl 10-Methyl-9-(trifluoro-
methyl)-6,6a,7,11a-tetrahydrochromeno[3,4-b]pyrrolizine-7-carb-
oxylate (48): Prepared by method A from 1H,3H-pyrrolo[1,2-c]thi-
azole 2,2-dioxide 26b (100 mg, 0.24 mmol). Compound 26b was ir-
radiated at 240 °C for 15 min. Purification by flash chromatog-
raphy (hexane and ethyl acetate/hexane, 1:3) afforded a 33:67 mix-
ture of 47 and 48 (49.9 mg, 59%) as a yellow oil.
12]
gram SIR2004,[ included in the WINGX-Version 1.80.05 and
SHELXL program packages.[ Except for the NH hydrogen atom,
all remaining hydrogen atoms were inserted at idealized positions
13]
[14]
15]
1
Compound 47: H NMR (400 MHz, CDCl
3
): δ = 2.77–2.86 (m, 2 and allowed to refine riding on their parent carbon atom with C–
H), 3.06–3.12 (m, 1 H), 3.20–3.26 (m, 1 H), 3.77 (s, 3 H), 4.03–4.09
H distances of 0.95, 0.98 and 0.99 Å for aromatic, methyl and
3
(
m, 1 H), 4.20–4.25 (m, 1 H), 5.21 (d, J = 4.4 Hz, 1 H), 6.35 (d, methylene H atoms, respectively, and with Uiso(H) = 1.2U (C). The
eq
3
3
[16]
J = 2.6 Hz, 1 H), 6.65 (d, J = 2.6 Hz, 1 H), 6.87–6.89 (m, 1 H,
Ar-H), 6.92–6.96 (m, 1 H, Ar-H), 7.16–7.26 (m, 2 H, Ar-H) ppm.
Compound 48: 1H NMR (400 MHz, CDCl
figure of the molecular structure was generated with ORTEP-III.
CCDC-1037887 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
3
): δ = 2.54 (s, 3 H),
.55–3.59 (m, 1 H), 3.81 (s, 3 H), 4.20–4.25 (m, 2 H), 4.37 (dd, J
2
3
3
3
=
12.0 Hz, J = 2.8 Hz, 1 H), 5.48 (d, J = 7.6 Hz, 1 H), 6.09 (s, 1
H), 6.87–6.89 (m, 1 H, Ar-H), 6.92–6.96 (m, 1 H, Ar-H), 7.16–7.26
3
(
m, 1 H, Ar-H), 7.34 (d, J = 8.0 Hz, 1 H, Ar-H) ppm.
General Procedure for the Synthesis of 3-(2H-Chromen-8-yl)-
H,3H-pyrrolo[1,2-c]thiazoles 40 and 41: A solution of the appro-
priate 1H,3H-pyrrolo[1,2-c]thiazole in 1,2,4-trichlorobenzene
1 mL) was irradiated in the microwave reactor at 240 °C for the
Acknowledgments
1
Thanks are due to the Fundação para a Ciência e a Tecnologia
(
FCT), the Portuguese Agency for Scientific Research (Coimbra
(
Chemistry Centre through the project Pest-OE/QUI/UI0313/2014
and Centro de Química Estrutural through the projects UID/QUI/
time indicated in each case. After cooling to room temperature, the
mixture was purified by flash chromatography (hexane) to remove
00100/2013 and RECI/QEQ-QIN70189/2012) and the Programa
1,2,4-trichlorobenzene, followed by elution with ethyl acetate/hex-
Operacional Potencial Humano, European Social Fund (POPH/
FSE) for financial support. F. M. R. L. and C. S. B. G. also
acknowledge the FCT for a PhD research grant (SFRH/BD/69941/
ane to obtain the corresponding products.
Dimethyl (3R)-3-(2H-Chromen-8-yl)-5-methyl-1H,3H-pyrrolo-
2010) and post-doctoral research grant (SFRH/BPD/64423/2009),
[
1,2-c]thiazole-6,7-dicarboxylate (40): Prepared from 1H,3H-
respectively. For obtaining the NMR spectroscopic data, the au-
thors acknowledge the UC-NMR facility, which is supported in
part by the FEDER – European Regional Development Fund
through the COMPETE Programme (Operational Programme for
Competitiveness) and by National Funds through FCT (grant
pyrrolo[1,2-c]thiazole 19a (100 mg, 0.26 mmol). Compound 19a
was irradiated for 15 min. Purification by flash chromatography
(
hexane and ethyl acetate/hexane, 1:2) afforded 40 (82.7 mg, 83%)
2
5
as a pale yellow solid; m.p. 130.9–133.3 °C (diethyl ether). [α]
D
=
+
310 (c = 1, CH
2 2
Cl ). IR (KBr): ν˜ = 2949, 1732, 1701, 1446, 1221,
–1
1
numbers
REEQ/481/QUI/2006,
RECI/QEQQFI/0168/2012,
1
3
205, 1161, 1095 cm . H NMR (400 MHz, CDCl
3
): δ = 2.12 (s,
H), 3.83 (s, 3 H), 3.84 (s, 3 H), 4.28 (d, J = 14.8 Hz, 1 H), 4.36
2
CENTRO-07-CT62-FEDER-002012, and RNRMN). C. S. B. G.
would like to thank Prof. M. Teresa Duarte for valuable discussions
on X-ray crystallography.
2
(d, J = 14.8 Hz, 1 H), 4.90 (br. s, 2 H), 5.79–5.83 (m, 1 H), 6.35
3
(d, J = 7.6 Hz, 1 H, Ar-H), 6.41–6.43 (m, 1 H), 6.50 (s, 1 H), 6.74–
3
13
6
.78 (m, 1 H, Ar-H), 6.90 (d, J = 7.2 Hz, 1 H, Ar-H) ppm.
): δ = 11.3, 29.6, 51.4, 51.5, 58.8, 65.9,
06.9, 116.9, 121.6, 122.4, 122.5, 124.1, 124.7, 126.9, 127.1, 130.8,
41.1, 150.1, 164.1, 165.4 ppm. HRMS (EI): calcd. for C20 19NO
5
C
NMR (100 MHz, CDCl
1
1
3
[
1] a) T. M. V. D. Pinho e Melo, M. I. L. Soares, A. M. d’A. Ro-
cha Gonsalves, H. McNab, Tetrahedron Lett. 2004, 45, 3889–
H
3893; b) T. M. V. D. Pinho e Melo, M. I. L. Soares, A. M. d’A.
+
[M] 385.0984; found 385.0986.
Rocha Gonsalves, J. A. Paixão, A. Matos Beja, M.
Ramos Silva, J. Org. Chem. 2005, 70, 6629–6638; c) T. M. V. D.
Pinho e Melo, M. I. L. Soares, C. M. Nunes, Tetrahedron 2007,
Dimethyl (3R)-3-[4-(Ethoxycarbonyl)-2H-chromen-8-yl]-5-methyl-
1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicarboxylate (41): Prepared from
1H,3H-pyrrolo[1,2-c]thiazole 21 (120 mg, 0.26 mmol). Compound
21 was irradiated for 20 min. Purification by flash chromatography
63, 1833–1841; d) M. I. L. Soares, T. M. V. D. Pinho e Melo,
Tetrahedron Lett. 2008, 49, 4889–4893; e) M. I. L. Soares,
S. M. M. Lopes, P. F. Cruz, R. M. M. Brito, T. M. V. D.
Pinho e Melo, Tetrahedron 2008, 64, 9745–9753; f) T. M. V. D.
Pinho e Melo, C. M. Nunes, M. I. L. Soares, J. A. Paixão, A.
Matos Beja, M. Ramos Silva, J. Org. Chem. 2007, 72, 4406–
4415; g) N. A. M. Pereira, S. M. Fonseca, A. C. Serra,
T. M. V. D. Pinho e Melo, H. D. Burrows, Eur. J. Org. Chem.
2011, 3970–3979; h) M. I. L. Soares, T. M. V. D. Pinho e Melo,
Curr. Microw. Chem. 2014, 1, 22–32; i) C. M. Nunes, M.
Ramos Silva, A. Matos Beja, R. Fausto, T. M. V. D.
Pinho e Melo, Tetrahedron Lett. 2010, 51, 411–414; j) W. J. Pe-
láez, T. M. V. D. Pinho e Melo, Tetrahedron 2013, 69, 3646–
3655; k) W. J. Peláez, A. J. Pepino, G. A. Argüello, T. M. V. D.
Pinho e Melo, Eur. J. Org. Chem. 2014, 2933–2941; l) M. I. L.
(
hexane and ethyl acetate/hexane, 1:2) afforded 41 (62.3 mg, 52%)
25
as a yellow oil. [α]
D
= +250 (c = 1, CH
444, 1228, 1194, 1097 cm . H NMR (400 MHz, CDCl ): δ =
.36 (t, J = 7.2 Hz, 3 H), 2.11 (s, 3 H), 3.83 (s, 3 H), 3.84 (s, 3 H),
.26–4.37 (m, 4 H), 4.86–4.95 (m, 2 H), 6.42 (d, J = 7.2 Hz, 1 H,
2
Cl
2
). IR (film): ν˜ = 1718,
–1 1
1
1
4
3
3
3
3
Ar-H), 6.50 (s, 1 H), 6.85–6.89 (m, 2 H), 7.88 (d, J = 7.6 Hz, 1 H,
Ar-H) ppm. 13C NMR (100 MHz, CDCl
): δ = 10.3, 13.2, 28.5,
0.4, 50.5, 58.1, 60.1, 63.9, 106.0, 115.9, 119.0, 120.9, 124.2, 125.8,
26.2, 126.7, 129.7, 130.7, 140.0, 149.2, 163.0, 163.4, 164.3 ppm.
3
5
1
+
HRMS (EI): calcd. for C23
57.1211.
7
H23NO S [M] 457.1195; found
4
Eur. J. Org. Chem. 2015, 1341–1354
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1353

T. M. V. D. Pinho e Melo et al.
FULL PAPER
Soares, C. M. Nunes, C. S. B. Gomes, T. M. V. D.
Pinho e Melo, J. Org. Chem. 2013, 78, 628–637.
2] F. M. Ribeiro Laia, C. S. B. Gomes, T. M. V. D. Pinho e Melo,
Tetrahedron 2013, 69, 10081–10090.
3] For reviews, see: a) T. Lee, Y. D. Gong, Molecules 2012, 17,
Schiedel, C. E. Muller, J. Med. Chem. 2013, 56, 5182–5197; i)
D. Harel, D. Schepmann, H. Prinz, R. Brun, T. J. Schmidt, B.
Wunsch, J. Med. Chem. 2013, 56, 7442–7448; j) Z. X. Pan, X.
He, Y. Y. Chen, W. J. Tang, J. B. Shi, Y. L. Tang, B. A. Song, J.
Li, X. H. Liu, Eur. J. Med. Chem. 2014, 80, 278–284.
[6] a) S. V. Paramonov, V. Lokshin, O. A. Fedorova, J. Photochem.
Photobiol. C: Photochem. Rev. 2011, 12, 209–236; b) N. Azizi,
M. Mariami, M. Edrisi, Dyes Pigm. 2014, 100, 215–221.
[7] S. Vedachalam, Q.-L. Wong, B. Maji, J. Zeng, J. Ma, X.-W.
Liu, Adv. Synth. Catal. 2011, 353, 219–225.
[
[
5
467–5496; b) S. A. Patil, R. Patil, L. M. Pfeffer, D. D. Miller,
Future Med. Chem. 2013, 5, 1647–1660; c) N. Thomas, S. M.
Zachariah, Asian J. Pharm. Clin. Res. 2013, 6, Supplement 2,
11–15; d) K. C. Nicolaou, J. A. Pfefferkorn, A. J. Roecker,
G. Q. Cao, S. Barluenga, H. J. Mitchell, J. Am. Chem. Soc.
2000, 122, 9939–9953.
[8] M. Hojo, R. Masuda, Y. Kokuryo, H. Shioda, S. Matsuo,
Chem. Lett. 1976, 499–502.
[
4] For examples of anticancer activity, see: a) A. R. Quesada,
M. D. G. Gravalos, J. L. F. Puentes, Br. J. Cancer 1996, 74,
[9] F. H. Allen, Acta Crystallogr., Sect. B 2002, 58, 380–388.
[10] a) K. C. Majumdar, R. Kumar Nandi, Tetrahedron 2013, 69,
6921–6957; b) W. K. Anderson, E. J. La Voie, J. Org. Chem.
1973, 38, 3832–3835; c) S. Yamaguchi, M. Ishibashi, K. Aka-
saka, H. Yokoyama, M. Miyazawa, Y. Hirai, Tetrahedron Lett.
2001, 42, 1091–1093; d) S. Yamaguchi, M. Maekawa, Y. Mu-
rayama, M. Miyazawa, Y. Hirai, Tetrahedron Lett. 2004, 45,
6971–6973; e) K. C. Nicolaou, H. Xu, M. Wartmann, Angew.
Chem. Int. Ed. 2005, 44, 756–761; Angew. Chem. 2005, 117,
766; f) M. Bruder, S. J. Smith, A. J. Blake, C. J. Moody, Org.
Biomol. Chem. 2009, 7, 2127–2134; g) V. Srinivasadesikan, J.-
K. Dai, S.-L. Lee, Org. Biomol. Chem. 2014, 12, 4163–4171.
[11] T. Shimizu, H. Yoshiyuki, Y. Kitora, K. Teramura, Bull. Chem.
Soc. Jpn. 1982, 55, 2450–2455.
677–682; b) M. Azizmohammadi, M. Khoobi, A. Ramazani,
S. Emami, A. Zarrin, O. Firuzi, R. Miri, A. Shafiee, Eur. J.
Med. Chem. 2013, 59, 15–22; c) S.-Q. Yin, M. Shi, T.-T. Kong,
C.-M. Zhang, K. Han, B. Cao, Z. Zhang, X. Du, L.-Q. Tang,
X. Mao, Z.-P. Liu, Bioorg. Med. Chem. Lett. 2013, 23, 3314–
3
319; d) K. R. Reddy, P. S. Rao, G. J. Dev, Y. Poornachandra,
C. G. Kumar, B. Narsaiah, Bioorg. Med. Chem. Lett. 2014, 24,
661–1663.
1
[
5] For other examples of pharmacological activities, see: a) H. N.
Eisohly, C. E. Turner, A. M. Clark, M. A. Eisohly, J. Pharm.
Sci. 1982, 71, 1319–1323; b) K. S. Atwal, G. J. Grover, F. N.
Ferrara, S. Z. Ahmed, P. G. Sleph, S. Dzwonczyk, D. E. Norm-
andin, J. Med. Chem. 1995, 38, 1966–1973; c) F. Cassidy, J. M.
Evans, M. S. Hadley, A. H. Haladij, P. E. Leach, G. Stemp, J.
Med. Chem. 1992, 35, 1623–1627; d) L. Zhi, C. M. Tegley,
K. B. Marschke, D. E. Mais, T. K. Jones, J. Med. Chem. 1999,
[12] G. M. Sheldrick, SADABS, Program for Empirical Absorption
Correction, University of Göttingen, Germany, 1996.
[13] SIR2004: M. C. Burla, R. Caliandro, M. Camalli, B. Carroz-
zini, G. L. Cascarano, L. De Caro, C. Giacovazzo, G. Polidori,
R. Spagna, J. Appl. Crystallogr. 2005, 38, 381–388.
4
2, 1466–1472; e) I. Torregroza, T. Evans, B. C. Das, Chem.
Biol. Drug Des. 2009, 73, 339–345; f) S. Endo, D. W. Hu, M.
Suyama, T. Matsunaga, K. Sugimoto, Y. Matsuya, O. El-Kab-
bani, K. Kuwata, A. Hara, Y. Kitade, N. Toyooka, Bioorg.
Med. Chem. 2013, 21, 6378–6384; g) S. S. Chaudhari, A. B. Ka-
dam, N. Khairatkar-Joshi, I. Mukhopadhyay, P. V. Karnik, A.
Raghuram, S. S. Rao, T. S. Vaiyapuri, D. P. Wale, V. M. Bho-
sale, G. S. Gudi, R. R. Sangana, A. Thomas, Bioorg. Med.
Chem. 2013, 21, 6542–6553; h) M. Funke, D. Thimm, A. C.
[14] L. J. Farrugia, J. Appl. Crystallogr. 1999, 32, 837–838.
[15] a) SHELX97 - Programs for Crystal Structure Analysis, release
97-2, University of Göttingen, Germany, 1998; b) G. M. Sheld-
rick, Acta Crystallogr., Sect. A 2008, 64, 112–122.
[16] L. J. Farrugia, J. Appl. Crystallogr. 1997, 30, 565.
Received: October 30, 2014
Published Online: January 15, 2015
1354
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 1341–1354