Synthesis and Reactivity of Aziridines with Internal Dipolarophiles: An Approach to 1,4-Dihydrochromeno[4,3- b ]pyrroles and 3-Methylenechromano[4,3- b ]pyrroles

Article abstract of DOI:10.1055/s-0034-1378717

Aziridines derived from 2-(prop-2-yn-1-yloxy)- and 2-(buta-2,3-dien-1-yloxy)chalcones and from benzyl 2-(prop-2-yn-1-yloxy)- and 2-(buta-2,3-dien-1-yloxy)phenylacrylates were prepared in a stereoselective fashion. Their reactivity as azomethine ylide precursors was examined, leading to the synthesis of 1,4-dihydrochromeno[4,3-b]pyrrole and 3-methylenechromano[4,3-b]pyrrole derivatives through intramolecular 1,3-dipolar cycloaddition reactions.

Full text of DOI:10.1055/s-0034-1378717

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 2781–2790
2781
special topic
F. M. Ribeiro Laia, T. M. V. D. Pinho e Melo
Special Topic
Synthesis
Synthesis and Reactivity of Aziridines with Internal Dipolaro-
philes: An Approach to 1,4-Dihydrochromeno[4,3-b]pyrroles and
3-Methylenechromano[4,3-b]pyrroles
Fernanda M. Ribeiro Laia
Teresa M. V. D. Pinho e Melo*
Centro de Química de Coimbra, Department of Chemistry,
University of Coimbra, 3004-535 Coimbra, Portugal
tmelo@ci.uc.pt
Received: 09.04.2015
Accepted after revision: 01.05.2015
O
Published online: 24.06.2015
DOI: 10.1055/s-0034-1378717; Art ID: ss-2015-c0235-st
toluene, heat
N
Me
•
O
Abstract Aziridines derived from 2-(prop-2-yn-1-yloxy)- and 2-(buta-
2,3-dien-1-yloxy)chalcones and from benzyl 2-(prop-2-yn-1-yloxy)- and
2-(buta-2,3-dien-1-yloxy)phenylacrylates were prepared in a stereose-
lective fashion. Their reactivity as azomethine ylide precursors was ex-
amined, leading to the synthesis of 1,4-dihydrochromeno[4,3-b]pyrrole
and 3-methylenechromano[4,3-b]pyrrole derivatives through intramo-
lecular 1,3-dipolar cycloaddition reactions.
1
CHO
Me
O
H
CHO
O
N
N
CO2H
H
H
Me
toluene, heat
•
2
Key words polycycles, heterocycles, allenes, alkynes, cycloadditions,
ylides, pyrroles, chromenes
O
Me
O
N
CHO
toluene, heat
The chromene moiety is present in a variety of naturally
occurring compounds, many of which exhibit interesting
biological activities.1–3 Chromene-based derivatives have
been reported to show a broad spectrum of pharmacologi-
cal activities, including anticancer, antimicrobial, and anti-
hypertensive activities, making them important target mol-
ecules in medicinal chemistry.
We recently reported the reactivities of sarcosine and
1,3-thiazolidine-4-carboxylic acid toward salicylaldehyde-
derived alkynes and allenes, which gave access to chrome-
no[4,3-b]pyrrole and chromeno[2,3-b]pyrrole derivatives
(for example, compounds 1–3; Scheme 1). Decarboxylative
condensation of these secondary amino acids with 2-(prop-
2-yn-1-yloxy)benzaldehyde gave tetrahydrochromeno[4,3-
b]pyrroles through intramolecular 1,3-dipolar cycloaddi-
tion, whereas chromeno[2,3-b]pyrroles were obtained from
the reaction with 2-(propa-1,2-dien-1-yloxy)benzaldehyde.
On the other hand, sarcosine reacted with 2-(buta-2,3-
dien-1-yloxy)benzaldehyde to give the corresponding 3-
methylenechromano[4,3-b]pyrrole 2 (Scheme 1).4
3
Scheme 1 Synthesis of chromeno[4,3-b]pyrrole and chromeno[2,3-
b]pyrrole derivatives from sarcosine and salicylaldehyde-derived alkynes
or allenes
In continuation of our interest in the chemistry of
chromenes, we reported the synthesis of chromene deriva-
tives by pericyclic reactions of azafulvenium methides
bearing internal dipolarophiles (Scheme 2).5 Azafulvenium
methides bearing the (prop-2-yn-1-yloxy)phenyl substitu-
ent were converted into 2-[2-(2H-chromen-8-yl)vinyl]-1H-
pyrroles 5 through a sequence of rearrangements. These re-
active intermediates, which contain a more activated dipol-
arophile as well as the more activated 5-(trifluorometh-
yl)azafulvenium methide, participate in [8π+2π] cycloaddi-
tions to give 8,12a-dihydro-6H-chromeno[4,3-e]indolizines
6. A synthesis of chiral 3-(2H-chromen-8-yl)-1H,3H-pyrro-
lo[1,2-c]thiazoles by microwave-induced rearrangement of
3-[2-(prop-2-yn-1-yloxy)phenyl]-1H,3H-pyrrolo[1,2-c]thi-
azoles was also described.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2781–2790

2782
F. M. Ribeiro Laia, T. M. V. D. Pinho e Melo
Special Topic
Synthesis
ing methylenepyrrolidines 7, but they can also react by for-
mal [3+2] cycloadditions to give functionalized pyrroles 8.
The substitution pattern of the aziridine determines the
outcome of the reaction. In contrast with the reactivity ob-
served in toluene as a solvent, carrying out the reaction in
supercritical carbon dioxide resulted in formal [3+2] cyc-
loaddition becoming the preferred pathway.6c
Intramolecular cycloadditions of azomethine ylides
generated from aziridines containing double and triple C–C
bonds are known.7 However, the importance of chromene
derivatives justifies further exploration of the chemistry of
salicylaldehyde-derived aziridines with the aim of achiev-
ing greater structural diversity. In this context, we describe
thermal reactions of aziridines bearing terminal alkyne and
allene groups to give chromeno[4,3-b]pyrrole derivatives,
including 3-methylenechromano[4,3-b]pyrroles.
R2
R1
R3
N
R4
[8π+2π]
cycloadduct
O
6
strongly activated
dipolarophile or 1,7-dipole
R1
R1
MW
R2
R4
R2
1,2,4-Cl3C6H3
N
O2S
N
+
–
R4
R3
R3
O
O
via electrocyclization
R2
The synthesis of the target aziridines is outlined in
R1
R1
R2
Schemes
4
and 5. (2E)-1-Phenyl-3-[2-(prop-2-yn-1-
R4 = H
yloxy)phenyl]prop-2-en-1-one (10) was obtained from the
reaction of (2E)-3-(2-hydroxyphenyl)-1-phenylprop-2-en-
1-one (9) with propargyl bromide in refluxing ethanol in
the presence of potassium carbonate (Scheme 4). Treat-
ment of enone 10 with iodine and benzylamine, following a
known general procedure,8 gave trans-aziridine 11a as the
major product (93%), together with the corresponding cis-
isomer 11b, isolated in 6% yield. In the NOESY spectrum of
aziridine 11a, no connectivity was observed between pro-
tons H-2 and H-3, whereas the NOESY spectrum of aziri-
dine 11b showed cross-peaks between protons H-2 and H-
3, confirming the assignment of their stereochemistry.
Chalcone 10 was converted into (2E)-3-[2-(buta-2,3-dien-
1-yloxy)phenyl]-1-phenylprop-2-en-1-one (12) by Crabbé
homologation.9 The product was subsequently treated with
iodine and benzylamine to give aziridines 13 in good over-
all yield. The synthesis of the aziridine-2-carboxylates 19
and 20 required the initial preparation of benzyl (2E)-3-(2-
hydroxyphenyl)acrylate (16) through Wittig reaction of
phosphorus ylide 15 and salicylaldehyde (14). Compound
16 reacted with propargyl bromide in acetone at 50 °C in
the presence of a base to give the functionalized acrylate 17
in 99% yield. Attempts to obtain the corresponding aziridine
by treating acrylate 17 with iodine and benzylamine were
unsuccessful. However, bromination of alkene 17 with di-
bromine followed by treatment with benzylamine gave the
cis-aziridine 19 in moderate yield.10 The NOESY spectrum
of aziridine 19 corroborated the assignment of its stereo-
chemistry. Allene 18 was obtained from alkyne 17 in 76%
yield by the Crabbé reaction,9 and was then converted into
cis-aziridine 20 by successive reactions with dibromine and
benzylamine.10
R3
R3
N
H
via Claisen
rearrangement
N
H
4
5
O
O
R4
Scheme 2 Synthesis of chromene derivatives by pericyclic reactions of
azafulvenium methides
We surmised that the thermolysis of aziridines bearing
prop-2-yn-1-yloxyphenyl or buta-2,3-dien-1-yloxyphenyl
substituents might permit the synthesis of chromeno[4,3-
b]pyrroles with unusual substitution patterns. We recently
described the reactivity of buta-2,3-dienoates toward aziri-
dines (Scheme 3).6 We observed that allenoates can react as
the 2π-component in a [3+2] cycloaddition with azometh-
ine ylides generated from aziridines to give the correspond-
R4
•
R1
R1
N
CO2Bn
N
[3+2] cycloaddition
R2
R3
C–C bond cleavage
R2
R3
BnO2C
R4
R1 = Cy, t-Bu
BnO2C
7
2 = Ph
3 = COPh
•
R
R4
R
R4 = H, Me
R1
N
COPh
Ph
R1
+N
R4
R4
formal
[3+2] cycloaddition
C–N bond cleavage
Initially, we examined the thermal reactivity of aziri-
dine 11a (Table 1). The reaction was performed in tert-butyl
alcohol in the absence or presence of potassium tert-butox-
ide. The latter reaction conditions permitted the in situ
–
BnO2C
SH
BnO2C
8
Scheme 3 Cycloadditions of aziridines with allenoates to give meth-
ylenepyrrolidines and pyrroles
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2781–2790

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F. M. Ribeiro Laia, T. M. V. D. Pinho e Melo
Special Topic
Synthesis
generation of an allene moiety through isomerization of the
propargyl group. The optimized synthetic procedure for the
thermolysis in the presence of potassium tert-butoxide al-
lowed the synthesis of 1,4-dihydrochromeno[4,3-b]pyrrole
23 in 54% yield (Table 1, entry 4). Heterocycle 23 was ob-
tained on carrying out the reaction of aziridine 11a in the
absence of potassium tert-butoxide (entries 6–8). A more
efficient process was obtained by heating aziridine 11a in
refluxing tert-butyl alcohol for 27 hours, giving the target
compound in 64% yield (entry 8). When the reaction was
carried out in refluxing toluene for 27 hours or under mi-
crowave irradiation (toluene, 150 °C, 15 min), 1,4-dihydro-
chromeno[4,3-b]pyrrole 23 was obtained in modest yield
(29%).
OH
O
Ph
9
Br
K2CO3, EtOH
reflux, 4 h
•
O
O
(CH2O)n
O
O
i-Pr2NH, CuBr
Ph
Ph
1,4-dioxane
reflux, 1.5 h
10 84%
12 70%
Et2O
r.t., 2 h
I2, BnNH2
Et2O, r.t., 2.5 h
I2, BnNH2
•
Table 1 Synthesis of 1,4-Dihydrochromeno[4,3-b]pyrrole 23 from
Aziridine 11a in tert-Butyl Alcohol
Bn
Bn
O
O
1
N
N
Bn
O
O
2
3
t-BuOK
t-BuOH
heat
O
N
t-BuOH
heat
Ph
Ph
13a trans 75%
O
11a trans 93%
11b cis 6%
Ph
13b cis 9%
•
11a
Scheme 4 Synthesis of functionalized aziridines 11 and 13
O
H
O
H
O
+
N
O
+
N
–
–
O
Bn
Ph
Bn
Ph
OH
OH
21
OBn
22
Br
CO2Bn
CHO
PPh3
15
O
O
K2CO3
acetone
50 °C, 4.5 h
THF
r.t., 15.5 h
N
Ph
16 97%
14
Bn
23
•
Entry
t-BuOK (equiv)
Temp (°C)
Time
Yielda (%)
O
O
(CH2O)n
1
2
3
4
5
6
7
8
0.5
0.5
0.5
1.0
2.0
–
60
27 h
5 h
42
38
26
54
36
32
32
64
CO2Bn
CO2Bn
i-Pr2NH, CuBr
reflux
80 (MW)
60
1,4-dioxane
reflux, 3.5 h
20 min
47 h
24 h
3.5 h
5 h
18 76%
17 99%
60
1. Br2, CH2Cl2, overnight
2. BnNH2, EtOH, r.t., 4 d
reflux
reflux
reflux
•
–
Bn
Bn
N
–
27 h
O
O
1
N
a Isolated yield.
3
2
CO2Bn
CO2Bn
These results indicated that both the in situ generated
allene and the carbon–carbon triple bond can act as dipola-
rophiles in the cycloaddition of the azomethine ylide gener-
ated by conrotatory electrocyclic ring opening of aziridine
11a to give 1,4-dihydrochromeno[4,3-b]pyrrole 23 after
aromatization of the five-membered ring.
19 49%
Scheme 5 Synthesis of functionalized aziridines 19 and 20
20 36%
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2781–2790

2784
F. M. Ribeiro Laia, T. M. V. D. Pinho e Melo
Special Topic
Synthesis
The reactivity of aziridine 13a, which contains both an
aziridine ring and an allenic moiety, was also studied (Table
2). When the reaction was performed in refluxing tert-bu-
tyl alcohol for four hours, no products could be isolated (Ta-
ble 2, entry 1). However, on carrying out the reaction in re-
fluxing toluene for three hours, three products were ob-
tained: cycloadduct 24 (22% yield) and a 52:48 mixture of
the corresponding tautomeric derivative 25 and 1,4-dihy-
drochromeno[4,3-b]pyrrole 26 in 14% overall yield (entry
2). With a longer reaction time, this mixture was obtained
in 40% yield (entry 3). Derivatives 24, 25, and 26 were also
obtained by microwave irradiation at 150 °C for 15 minutes
(entry 4). The assignment of the stereochemistry of com-
pound 24 was supported by its NOESY spectrum (400
MHz), in which cross-peaks were observed between pro-
tons H-3a and H-9b. The reaction of aziridine 13a in reflux-
ing toluene for two hours with subsequent oxidation by us-
ing palladium/carbon in refluxing ethyl acetate for 2.5 days
gave cycloadduct 26 in 16% overall yield.
1,4-dihydrochromeno[4,3-b]pyrrole 23, resulting from the
inter- and intramolecular 1,3-dipolar cycloaddition, respec-
tively, were each obtained in 38% yield, and pyrrole 27 was
also isolated in a low yield. Similar results were obtained
when the reaction was carried out in refluxing toluene (en-
try 2). In the case of aziridine 13a, dimethyl acetylenedicar-
boxylate efficiently trapped the azomethine ylide, giving
pyrrole 28b in 74% yield together with pyrrole 27 in 10%
yield (entry 3). Pyrrole 27 was also obtained in low yield by
sealed-tube thermolysis of pyrrole 28b (240 °C, 4 h), indi-
cating that it is derived from compounds 28a and 28b.
Table 3 Thermolysis of Aziridines 11a and 13a in the Presence of Di-
methyl Acetylenedicarboxylatea
R
Bn
O
N
COPh
11a R =
13a R =
•
Table 2 Synthesis of Compounds 24–26 from Aziridine 13a
DMAD
heat
•
1. toluene
Bn
N
reflux, 2 h
2. Pd/C, EtOAc
reflux, 2.5 d
O
CO2Me
COPh
MeO2C
MeO2C
CO2Me
O
O
COPh
N
16%
+
+
Ph
Ph
N
N
Bn
heat
13a
Bn
Bn
O
23
3a
H
Me
Me
R1
H
27
O
O
O
O
O
O
28a R =
+
+
2
N
•
Ph
N
N
Ph
Ph
28b R =
H
9b
H
Bn
Bn
Bn
Entry
Aziridine
Solvent
Yieldb (%)
25
26
24
23
27
28
Entry Solvent
Temp
Time
Yielda (%)
1
2
3
11a
11a
13a
t-BuOH
toluene
t-BuOH
38
24
–
4
7
38 (28a)
30 (28a)
74 (28b)
24
25 + 26b
1
2
3
4
t-BuOH
toluene
toluene
toluene
reflux
reflux
reflux
4 h
3 h
–
–
10
22
–
14 (52:48)c
40 (55:45)c
18 (43:57)c
a Reaction conditions: reflux, 23 h.
b Isolated yield.
21 h
150 °C (MW)
15 min
<4
These results indicate that the terminal alkyne of aziri-
dine 11a is a more activated dipolarophile than the allenic
group of aziridine 13a. On the other hand, a more activated
dipole might ensure more-efficient synthesis of the
chromene derivatives. With this in mind, we extended our
study to other aziridines in which a carboxylate group re-
placed the benzoyl group (Scheme 6). Thermolysis of aziri-
dine 19 in refluxing tert-butyl alcohol for two hours did not
lead to any products. However, on increasing the reaction
time to 18 hours, we obtained a 69:31 mixture of com-
pounds 29 and 30 in 39% overall yield. The yield was im-
proved by performing the reaction in refluxing toluene for
a Isolated yield.
b Obtained together with 12, formed by elimination of BnNH2 from aziri-
dine 13a in variable amounts.
c Ratio determined by 1H NMR spectroscopy.
To evaluate the efficiency of the generation of the
azomethine ylides under the studied reaction conditions,
we carried out the thermal reactions of aziridines 11a and
13a in the presence of dimethyl acetylenedicarboxylate. On
performing the reaction of 11a in refluxing tert-butyl alco-
hol for 23 hours, we obtained the three products 23, 27, and
28a in 80% overall yield (Table 3, entry 1). Pyrrole 28a and
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2781–2790

2785
F. M. Ribeiro Laia, T. M. V. D. Pinho e Melo
Special Topic
Synthesis
two hours. Interestingly, when we carried out the thermol-
ysis of aziridine 19 in refluxing toluene for 29 hours, we ob-
tained the 1,4-dihydrochromeno[4,3-b]pyrrole 30 in high
yield (94%).
after aromatization of the initially formed cycloadducts.
Aziridines bearing terminal allenes allowed the stereoselec-
tive synthesis of 3-methylenechromano[4,3-b]pyrrole de-
rivatives.
O
CO2Bn
Flash column chromatography was performed on silica gel 60 as the
stationary phase. 1H NMR spectra were recorded on a Bruker Avance
III instrument operated at 400 MHz. 13C NMR spectra were recorded
on the same instrument operated at 100 MHz. Chemical shifts are ex-
pressed in ppm relatively to internal TMS. IR spectra were recorded
on a Nicolet 6700 Fourier-transform spectrophotometer. HRMS spec-
tra were obtained by electron impact (EI) or electrospray (ESI) meth-
ods using a Waters Micromass Autospec M (EI) and on a Bruker FTMS
APEXIII (ESI) ToF mass spectrometer. Melting points were determined
in open glass capillaries. Ylide 15 was prepared according to a report-
ed procedure.11
N
Bn
Bn
O
N
29
CO2Bn
30
heat
+
CO2Bn
O
19
N
Bn
toluene
reflux, 29 h
reaction
conditions
isolated yield
29/30
O
CO2Bn
t-BuOH, reflux, 2 h
t-BuOH, reflux, 18 h 39% (69:31)
toluene, reflux, 2 h 54% (54:46)
–
N
Benzyl (2E)-3-(2-Hydroxyphenyl)acrylate (16)
Bn
Salicylaldehyde (14; 1.56 mL, 14.62 mmol) was added to a solution of
ylide 15 (6.0 g, 14.62 mmol) in THF (100 mL), and the mixture was
stirred at r.t. for 15.5 h. The solvent was removed under reduced pres-
sure and the crude product was purified by flash chromatography
[silica gel, EtOAc–hexane (1:3 then 1:2)] to give a white solid; yield:
3.603 g (97%); mp 86.1–88.0 °C (EtOAc–hexane).
30 94%
3a
H
•
Bn
N
O
toluene, reflux
CO2Bn
O
2
IR (KBr): 3213, 1674, 1628, 1448, 1379, 1300, 1277, 1174 cm–1
.
N
H
CO2Bn
1H NMR (400 MHz, CDCl3): δ = 5.28 (s, 2 H), 6.72 (d, 3J = 16.0 Hz, 1 H),
6.78–6.80 (m, 1 H, Ar-H), 6.86–6.90 (m, 1 H, Ar-H), 7.13 (br s, 1 H),
7.18–7.22 (m, 1 H, Ar-H), 7.33–7.45 (m, 6 H, Ar-H), 8.11 (d, 3J = 16.0
Hz, 1 H).
Bn
9b
31
20
63% (4 h)
52% (24 h)
13C NMR (100 MHz, CDCl3): δ = 66.6, 116.5, 117.8, 120.6, 121.6, 128.3,
128.3, 128.7, 129.4, 131.6, 136.0, 141.7, 155.8, 168.7.
HRMS (EI): m/z [M+] calcd for C16H14O3: 254.0943; found: 254.0944.
Scheme 6 Synthesis of chromeno[4,3-b]pyrrole derivatives from aziri-
dines 19 and 20 by intramolecular 1,3-dipolar cycloaddition
(2E)-1-Phenyl-3-[2-(prop-2-yn-1-yloxy)phenyl]prop-2-en-1-one
(10)
Finally, we studied the reactivity of the cis-1-benzyl-3-
(buta-2,3-dien-1-yloxyphenyl)aziridine 20. On carrying out
the reaction in toluene at reflux for four hours, we obtained
the 3-methylenechromano[4,3-b]pyrrole 31 stereoselec-
tively in 63% yield. With a longer reaction time, a decrease
in the isolated yield was observed (52%). In the NOESY spec-
trum of compound 31, connectivity was observed between
protons H-9b and H-3a.
In conclusion, salicylaldehyde-derived aziridines bear-
ing terminal alkyne and allene groups were prepared, and
their thermal reactivity was explored. On thermolysis, the
azomethine ylides generated from the aziridines by conro-
tatory electrocyclic ring opening participated in intramo-
lecular cycloadditions to give chromeno[4,3-b]pyrrole de-
rivatives. Aziridine-2-carboxylates gave higher yields of the
target heterocycles than did the corresponding 2-benzoyl-
aziridines. On the other hand, the carbon–carbon triple
bond proved to be a more activated dipolarophile, leading
to the corresponding 1,4-dihydrochromeno[4,3-b]pyrroles
Anhydrous K2CO3 (1.356 g, 9.81 mmol) was added to a solution of
enone 9 (2.0 g, 8.92 mmol) in EtOH (20 mL), and the mixture was
stirred for 5 min at r.t. An 80% solution of propargyl bromide in tolu-
ene (1.46 mL, 13.54 mmol) was added and the mixture was refluxed
for 4 h under N2, then cooled to r.t. H2O (100 mL) was added to the
mixture and the aqueous layer was extracted with CH2Cl2 (3 × 80 mL),
dried (Na2SO4), and concentrated under reduced pressure. Purifica-
tion by flash chromatography [silica gel, EtOAc–hexane (1:4)] gave a
yellow solid; yield: 1.968 g (84%); mp 63.0–64.6 °C (EtOAc–hexane).
IR (KBr): 3249, 2116, 1655, 1601, 1570, 1277, 1217, 1020 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.55 (t, 4J = 2.2 Hz, 1 H), 4.79 (d, 4J = 2.2
Hz, 2 H), 7.02–7.06 (m, 2 H, Ar-H), 7.35–7.40 (m, 1 H, Ar-H), 7.47–7.51
(m, 2 H, Ar-H), 7.55–7.58 (m, 1 H, Ar-H), 7.64–7.65 (m, 1 H, Ar-H),
3
3
7.66 (d, J = 16.0 Hz, 1 H), 8.02–8.04 (m, 2 H, Ar-H), 8.09 (d, J = 16.0
Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 56.3, 76.0, 78.2, 112.8, 121.7, 123.4,
124.6, 128.5, 128.6, 129.5, 131.5, 132.6, 138.4, 140.0, 156.7, 191.0.
HRMS (EI): m/z [M]+ calcd for C18H14O2: 262.0994; found: 262.0990.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2781–2790

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F. M. Ribeiro Laia, T. M. V. D. Pinho e Melo
Special Topic
Synthesis
Benzyl (2E)-3-[2-(Prop-2-yn-1-yloxy)phenyl]acrylate (17)
procure. The mixture was stirred for 3.5 h, and the crude product was
purified by flash column chromatography [silica gel, EtOAc–hexane
(1:4)] to give a yellow oil; yield: 0.929 g (76%).
Anhydrous K2CO3 (1.584 g, 11.46 mmol) was added to a solution of
acrylate 16 (2.650 g, 10.42 mmol) in acetone (25 mL), and the mixture
was stirred for 5 min at r.t. An 80% soln of propargyl bromide in tolu-
ene (1.23 mL, 11.46 mmol) was added, and the mixture was heated at
50 °C for 4.5 h under N2 then cooled to r.t. H2O (120 mL) was added
and the aqueous layer was extracted with CH2Cl2 (3 × 100 mL), dried
(Na2SO4), and concentrated under reduced pressure. Purification by
flash chromatography [silica gel, EtOAc–hexane (1:4)] gave a white
solid; yield: 3.025 g (99%); mp 37.5–39.2 °C (EtOAc–hexane).
IR (film): 1957, 1711, 1161 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 4.61–4.64 (m, 2 H), 4.85–4.88 (m, 2 H),
5.25 (s, 2 H), 5.36–5.42 (m, 1 H), 6.60 (d, 3J = 16.4 Hz, 1 H), 6.89–6.97
(m, 2 H, Ar-H), 7.29–7.43 (m, 6 H, Ar-H), 7.48–7.51 (m, 1 H, Ar-H),
8.05 (d, 3J = 16.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 66.1, 66.2, 77.0, 86.9, 112.7, 118.5,
121.0, 123.8, 128.2, 128.3, 128.6, 129.1, 131.4, 136.3, 140.7, 157.2,
167.4, 209.4.
IR (KBr): 3224, 2114, 1705, 1628, 1308, 1275, 1219, 1167 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.54 (t, 4J = 2.4 Hz, 1 H), 4.77 (d, 4J = 2.4
Hz, 2 H), 5.28 (s, 2 H), 6.60 (d, 3J = 16.2 Hz, 1 H), 7.00–7.07 (m, 2 H, Ar-
H), 7.33–7.46 (m, 6 H, Ar-H), 7.54 (dd, 3J = 7.8 Hz, 4J = 1.4 Hz, 1 H, Ar-
H), 8.09 (d, 3J = 16.2 Hz, 1 H).
HRMS (EI): m/z [M]+ calcd for C20H18O3: 306.1256; found: 306.1254.
Aziridines 11, 13, 19, and 20; General Procedures
Method A: A solution of BnNH2 (4.7 equiv) in Et2O was slowly added to
a solution of I2 (1.1 equiv) and the appropriate chalcone in Et2O, and
the mixture was stirred at r.t. for the appropriate time. When the re-
action was complete (TLC), the mixture was filtered and the solution
was washed several times with H2O. The organic layer was dried (Na2-
SO4) and the solvent was evaporated. The crude product was purified
by flash column chromatography [silica gel, EtOAc–hexane (1:4)].
13C NMR (100 MHz, CDCl3): δ = 56.1, 66.2, 76.1, 78.2, 112.8, 118.8,
121.7, 124.0, 128.2, 128.3, 128.6, 129.0, 131.4, 136.3, 140.3, 156.3,
167.2.
HRMS (EI): m/z [M]+ calcd for C19H16O3: 292.1099; found: 292.1088.
Allenes 12 and 18; General Procedure
Allenes 12 and 18 were prepared according to a reported procedure.9
A mixture of the appropriated alkyne, paraformaldehyde, i-Pr2NH,
and anhydrous CuBr in 1,4-dioxane was refluxed for the appropriate
time then cooled to r.t. The mixture was then filtered and the precipi-
tate was washed with Et2O (25 mL). The organic phases were com-
bined and concentrated under reduce pressure to give a gum-like res-
idue that was treated with 1 M aq HCl to adjust its pH to 2–3. The
mixture was extracted with Et2O (3 × 30 mL) and the ether extracts
were combined, washed to neutrality with H2O (2 × 50 mL), and then
washed with sat. brine (2 × 50 mL). The organic layer was dried
(Na2SO4) and concentrated under reduced pressure to give a crude
product that was purified by flash column chromatography [silica gel;
EtOAc–hexane].
Method B: Br2 was added dropwise to a solution of the appropriated
alkene in CH2Cl2 at 0 °C. The mixture was stirred overnight at r.t., and
40% aq NaHSO3 solution was added. The organic phase was separated
and dried (Na2SO4), and the solvent was evaporated. The resulting di-
bromide was dissolved in EtOH (5 mL/mmol), BnNH2 (4.0 equiv) was
added, and mixture was stirred at r.t. for 4 d. When the reaction was
complete (TLC), H2O (10–15 mL) was added and the aqueous layer
was extracted with CH2Cl2 (3 × 15 mL), dried (Na2SO4), and concen-
trated under reduced pressure. The crude product was purified by
flash column chromatography [silica gel, EtOAc–hexane (1:4)].
{trans-1-Benzyl-3-[2-(prop-2-yn-1-yloxy)phenyl]aziridin-2-
yl}(phenyl)methanone (11a) and {cis-1-Benzyl-3-[2-(prop-2-yn-1-
yloxy)phenyl]aziridin-2-yl}(phenyl)methanone (11b)
(2E)-3-[2-(Buta-2,3-dien-1-yloxy)phenyl]-1-phenylprop-2-en-1-
one (12)
Prepared by Method A from I2 (1.426 g, 5.62 mmol) and chalcone 10
(1.340 g, 5.11 mmol) in Et2O (30 mL) and BnNH2 (2.62 mL, 24.02
mmol) in Et2O (4 mL). The mixture was stirred for 2.5 h and the prod-
uct was purified by flash chromatography [silica gel, EtOAc–hexane
(1:4)] to give, in order of elution, compound 11a [yield: 1.747 g (93%)]
as a yellow oil and compound 11b [yield: 0.120 g (6%)] as a white sol-
id.
Prepared from alkyne 10 (2.004 g, 7.64 mmol), paraformaldehyde
(0.574 g, 19.10 mmol), i-Pr2NH (2.14 mL, 15.28 mmol), and anhyd
CuBr (0.548 g, 3.82 mmol) in 1,4-dioxane (12 mL). The mixture was
stirred for 1.5 h, and the crude product was purified by flash column
chromatography [silica gel; EtOAc–hexane (1:4)] to give a yellow oil;
yield: 1.486 g (70%).
IR (film): 3062, 1957, 1660, 1600, 1213, 1017 cm–1
.
11a
IR (film): 3292, 2121, 1668, 1493, 1452, 1228, 1024 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 4.66–4.68 (m, 2 H), 4.86–4.89 (m, 2 H),
5.41–5.47 (m, 1 H), 6.95 (d, 3J = 8.4 Hz, 1 H, Ar-H), 6.98–7.02 (m, 1 H,
Ar-H), 7.33–7.37 (m, 1 H, Ar-H), 7.47–7.51 (m, 2 H, Ar-H), 7.55–7.59
(m, 1 H, Ar-H), 7.62–7.69 (m, 2 H), 8.01–8.03 (m, 2 H, Ar-H), 8.11 (d,
3J = 15.6 Hz, 1 H).
3
1H NMR (400 MHz, CDCl3): δ = 2.40 (br s, 1 H), 3.57 (d, J = 2.0 Hz, 1
H), 3.92 (d, 3J = 2.0 Hz, 1 H), 4.04 (d, 2J = 13.6 Hz, 1 H), 4.18 (d, 2J = 13.6
Hz, 1 H), 4.65 (d, 4J = 1.6 Hz, 2 H), 6.95–6.97 (m, 2 H, Ar-H), 7.14–7.23
(m, 4 H, Ar-H), 7.34–7.41 (m, 5 H, Ar-H), 7.48–7.52 (m, 1 H, Ar-H),
7.91–7.92 (m, 2 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 66.3, 76.9, 86.9, 112.8, 121.1, 123.2,
13C NMR (100 MHz, CDCl3): δ = 45.1, 46.9, 55.1, 56.2, 75.6, 78.7, 112.1,
121.6, 126.9, 127.1, 127.9, 128.2, 128.3, 128.4, 128.5, 128.5, 133.1,
138.4, 139.4, 156.1, 195.3.
124.4, 128.5, 129.5, 131.6, 132.5, 138.6, 140.5, 157.7, 191.2, 209.5.
HRMS (EI): m/z [M]+ calcd for C19H16O2: 276.1150; found: 276.1155.
Benzyl (2E)-3-[2-(Buta-2,3-dien-1-yloxy)phenyl]acrylate (18)
HRMS (EI): m/z [M]+ calcd for C25H21NO2: 367.1572; found: 367.1575.
Prepared from alkyne 17 (1.165 g, 3.99 mmol), paraformaldehyde
(0.299 g, 9.96 mmol), i-Pr2NH (1.12 mL, 7.98 mmol), and anhyd CuBr
(0.287 g, 2.0 mmol) in 1,4-dioxane (15 mL) according to the general
11b
Mp 102.7–103.8 °C (EtOH).
IR (KBr): 3282, 2129, 1680, 1450, 1242, 1230 cm–1
.
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2787
F. M. Ribeiro Laia, T. M. V. D. Pinho e Melo
Special Topic
Synthesis
1H NMR (400 MHz, CDCl3): δ = 2.45 (t, 4J = 2.4 Hz, 1 H), 3.46 (d, 3J = 7.2
Hz, 1 H), 3.59 (d, 3J = 7.2 Hz, 1 H), 3.75 (d, 2J = 13.6 Hz, 1 H), 4.03 (d, 2J =
13.6 Hz, 1 H), 4.48 (dd, 2J = 15.6 Hz, 4J = 2.4 Hz, 1 H), 4.57 (dd, 2J = 15.6
Hz, 4J = 2.4 Hz, 1 H), 6.73 (d, 3J = 8.0 Hz, 1 H, Ar-H), 6.87–6.91 (m, 1 H,
Ar-H), 7.07–7.11 (m, 1 H, Ar-H), 7.22–7.26 (m, 1 H, Ar-H), 7.30–7.39
(m, 4 H, Ar-H), 7.44–7.51 (m, 4 H, Ar-H), 7.93–7.95 (m, 2 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 46.1, 50.6, 55.7, 63.9, 75.5, 78.5, 110.6,
121.3, 123.6, 127.2, 128.0, 128.3, 128.4, 129.6, 132.8, 137.1, 138.2,
155.7, 193.4.
1H NMR (400 MHz, CDCl3): δ = 2.44 (t, 4J = 2.4 Hz, 1 H), 2.73 (d, 3J = 6.8
Hz, 1 H), 3.26 (d, 3J = 6.8 Hz, 1 H), 3.66 (d, 2J = 13.6 Hz, 1 H), 3.92 (d, 2J =
13.6 Hz, 1 H), 4.53 (dd, 2J = 15.6 Hz, 4J = 2.4 Hz, 1 H), 4.59 (dd, 2J = 15.6
Hz, 4J = 2.4 Hz, 1 H), 4.92 (d, 2J = 12.4 Hz, 1 H), 4.96 (d, 2J = 12.4 Hz, 1
H), 6.86–6.92 (m, 2 H, Ar-H), 7.04–7.07 (m, 2 H, Ar-H), 7.17–7.22 (m,
1 H, Ar-H), 7.24–7.27 (m, 4 H, Ar-H), 7.29–7.33 (m, 2 H, Ar-H), 7.42–
7.43 (m, 2 H, Ar-H), 7.47–7.49 (m, 1 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 44.3, 45.2, 56.0, 63.7, 66.3, 75.4, 78.7,
111.5, 121.2, 124.1, 127.3, 127.9, 128.1, 128.1, 128.3, 128.4, 128.4,
129.8, 135.8, 137.9, 156.0, 168.3.
HRMS (EI): m/z [M]+ calcd for C25H21NO2: 367.1572; found: 367.1580.
HRMS (EI): m/z [M]+ calcd for C26H23NO3: 397.1678; found: 397.1683.
{trans-1-Benzyl-3-[2-(buta-2,3-dien-1-yloxy)phenyl]aziridin-2-
yl}(phenyl)methanone (13a) and {cis-1-Benzyl-3-[2-(buta-2,3-
dien-1-yloxy)phenyl]aziridin-2-yl}(phenyl)methanone (13b)
Benzyl cis-1-Benzyl-3-[2-(buta-2,3-dien-1-yloxy)phenyl]aziridine-
2-carboxylate (20)
Prepared by Method A from I2 (0.276 g, 1.09 mmol) and chalcone 12
(0.272 g, 0.99 mmol) in Et2O (6 mL) and BnNH2 (0.51 mL, 4.65 mmol)
in Et2O (0.5 mL). The mixture was stirred for 2 h and the product was
purified by flash chromatography [silica gel, EtOAc–hexane (1:4)] to
give, in order of elution, compound 13a [yield: 0.285 g (75%)] as a yel-
low oil and compound 13b [yield: 0.035 g (9%)] as a pale-yellow solid.
Prepared by Method B from alkene 18 (0.90 g, 2.94 mmol) and Br2
(0.17 mL, 3.23 mmol) in CH2Cl2 (16 mL). Purification by flash chroma-
tography [silica gel, EtOAc–hexane (1:4)] gave a colorless oil; yield:
0.430 g (36%).
IR (film): 1957, 1749, 1720, 1495, 1454, 1184, 1167 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.72 (d, 3J = 6.8 Hz, 1 H), 3.26 (d, 3J = 6.8
Hz, 1 H), 3.66 (d, 2J = 13.6 Hz, 1 H), 3.92 (d, 2J = 13.6 Hz, 1 H), 4.40–4.51
(m, 2 H), 4.80–4.83 (m, 2 H), 4.94 (s, 2 H), 5.25–5.32 (m, 1 H), 6.75 (d,
3J = 8.0 Hz, 1 H, Ar-H), 6.85–6.89 (m, 1 H, Ar-H), 7.03–7.06 (m, 2 H, Ar-
H), 7.15–7.19 (m, 1 H, Ar-H), 7.23–7.27 (m, 4 H, Ar-H), 7.29–7.33 (m,
2 H, Ar-H), 7.42–7.47 (m, 3 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 44.5, 45.3, 63.8, 65.9, 66.3, 76.5, 87.3,
111.3, 120.5, 123.9, 127.3, 127.9, 128.1, 128.3, 128.4, 128.4, 129.5,
135.8, 138.0, 156.8, 168.4, 209.2.
13a
IR (film): 1957, 1668, 1493, 1452, 1230 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 3.58 (d, 3J = 2.6 Hz, 1 H), 3.92 (d, 3J = 2.6
Hz, 1 H), 4.06 (d, 2J = 13.8 Hz, 1 H), 4.21 (d, 2J = 13.8 Hz, 1 H), 4.55–4.56
(m, 2 H), 4.77–4.79 (m, 2 H), 5.25–5.32 (m, 1 H), 6.85 (d, 3J = 8.0 Hz, 1
H, Ar-H), 6.91–6.95 (m, 1 H, Ar-H), 7.15–7.25 (m, 4 H, Ar-H), 7.31–
7.37 (m, 3 H, Ar-H), 7.41–7.45 (m, 2 H, Ar-H), 7.52–756 (m, 1 H, Ar-H),
7.93–7.94 (m, 2 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 45.5, 46.8, 55.1, 65.9, 76.7, 87.2, 111.8,
120.9, 126.9, 127.0, 127.7, 128.2, 128.3, 128.5, 128.6, 133.1, 138.5,
139.5, 156.9, 195.4, 209.2.
HRMS (ESI): m/z [M + H]+ calcd for C27H26NO3: 412.19072; found:
412.19074.
Thermolysis of Aziridines 11a, 13a, 19, and 20; General Procedures
HRMS (ESI): m/z [M + H]+ calcd for C26H24NO2: 382.18042; found:
382.18016.
Method C: A solution of the appropriate aziridine in t-BuOH or tolu-
ene was refluxed until the reaction was complete (TLC). The solvent
was removed under reduced pressure and the crude product was pu-
rified by preparative TLC [EtOAc–hexane] or by flash chromatography
[silica gel, EtOAc–hexane].
13b
Mp 88.6–90.3 °C (EtOH).
IR (KBr): 1959, 1682, 1244, 1227 cm–1
.
Method D: A solution of t-BuOK (1.0 equiv) in t-BuOH (2 mL) was add-
ed dropwise to a solution of the appropriate aziridine in t-BuOH (8
mL). The mixture was heated at 60 °C for 47 h under N2 then cooled to
r.t. H2O (15 mL) was added, and the aqueous layer was extracted with
Et2O (3 × 15 mL). The organic layer was washed with sat. aq NH4Cl (15
mL), dried (Na2SO4), and concentrated in vacuum. The crude product
was purified by flash chromatography [silica gel, EtOAc–hexane].
1H NMR (400 MHz, CDCl3): δ = 3.45 (d, 3J = 7.0 Hz, 1 H), 3.59 (d, 3J = 7.0
Hz, 1 H), 3.76 (d, 2J = 13.8 Hz, 1 H), 4.03 (d, 2J = 13.8 Hz, 1 H), 4.35–4.41
(m, 1 H), 4.46–4.52 (m, 1 H), 4.82–4.87 (m, 2 H), 5.24–5.30 (m, 1 H),
6.65 (d, 3J = 8.0 Hz, 1 H, Ar-H), 6.83–6.87 (m, 1 H, Ar-H), 7.05–7.09 (m,
1 H, Ar-H), 7.22–7.26 (m, 1 H, Ar-H), 7.30–7.37 (m, 4 H, Ar-H), 7.45–
7.50 (m, 4 H, Ar-H), 7.92–7.95 (m, 2 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 46.3, 50.6, 64.0, 65.5, 76.7, 87.2, 110.5,
120.5, 123.3, 127.1, 128.0, 128.2, 128.2, 128.3, 128.4, 129.5, 132.7,
137.2, 138.2, 156.4, 193.4, 209.2.
(1-Benzyl-1,4-dihydrochromeno[4,3-b]pyrrol-2-yl)(phenyl)meth-
anone (23)
Prepared by Method C from aziridine 11a (78 mg, 0.21 mmol) in t-
BuOH (8 mL). The mixture was stirred for 27 h and the product was
purified by flash chromatography [silica gel, EtOAc–hexane (1:5)] to
give a pale-orange solid; yield: 50 mg (64%).
HRMS (EI): m/z [M]+ calcd for C26H23NO2: 381.1729; found: 381.1726.
Benzyl cis-1-Benzyl-3-[2-(prop-2-yn-1-yloxy)phenyl]aziridine-2-
carboxylate (19)
Alternatively, the product was prepared by Method D from aziridine
11a (78 mg, 0.21 mmol) and t-BuOK (24 mg, 0.21 mmol). Purification
by flash chromatography [silica gel, EtOAc–hexane (1:5)] gave a pale-
orange solid; yield: 42 mg (54%); mp 104.9–106.5 °C (Et2O–PE).
Prepared by Method B from alkene 17 (0.246 g, 0.84 mmol) and Br2
(0.05 mL, 0.88 mmol) in CH2Cl2 (5 mL). Purification by flash chroma-
tography [silica gel, EtOAc–hexane (1:4)] gave a white solid; yield:
0.164 g (49%); mp 86.6–87.8 °C (EtOAc–hexane).
IR (KBr): 1630, 1464, 1392, 1275, 725 cm–1
.
IR (KBr): 3253, 2129, 1734, 1194, 1169 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2781–2790

2788
F. M. Ribeiro Laia, T. M. V. D. Pinho e Melo
Special Topic
Synthesis
1H NMR (400 MHz, CDCl3): δ = 5.16 (s, 2 H), 5.98 (br s, 2 H), 6.66 (s, 1
H), 6.83–6.87 (m, 1 H, Ar-H), 7.01 (dd, 3J = 8.0 Hz, 4J = 1.2 Hz, 1 H, Ar-
H), 7.13–7.18 (m, 3 H, Ar-H), 7.22–7.35 (m, 4 H, Ar-H), 7.40–7.44 (m,
2 H, Ar-H), 7.49–7.53 (m, 1 H, Ar-H), 7.75–7.77 (m, 2 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 50.4, 65.2, 116.9, 117.6, 118.0, 118.4,
122.1, 122.9, 125.7, 127.2, 128.0, 128.9, 129.3, 129.4, 131.4, 132.0,
132.8, 138.3, 140.2, 155.1, 185.7.
HRMS (EI): m/z [M]+ calcd for C26H21NO3: 395.1521; found: 395.1524.
Benzyl 1-Benzyl-1,2,4,9b-tetrahydrochromeno[4,3-b]pyrrole-2-
carboxylate (29) and Benzyl 1-Benzyl-1,4-dihydrochromeno[4,3-
b]pyrrole-2-carboxylate (30)
Prepared by Method C from aziridine 19 (80 mg, 0.20 mmol) in tolu-
ene (5 mL). The reaction mixture was stirred for 2 h, and the product
was purified by flash chromatography [silica gel, EtOAc–hexane (1:4)]
to give a 54:46 mixture of compounds 29 and 30 as a yellow oil; total
yield: 43 mg (54%).
HRMS (ESI): m/z [M + H]+ calcd for C25H20NO2: 366.14886; found:
366.14873.
2
1H NMR (400 MHz, CDCl3): δ (29; major product) = 4.30 (d, J = 14.0
{1-Benzyl-3-methylene-1,2,3,3a,4,9b-hexahydrochromeno[4,3-
b]pyrrol-2-yl}(phenyl)methanone (24), (1-Benzyl-3-methyl-
1,3a,4,9b-tetrahydrochromeno[4,3-b]pyrrol-2-yl)(phenyl)meth-
anone (25), and (1-Benzyl-3-methyl-1,4-dihydrochromeno[4,3-
b]pyrrol-2-yl)(phenyl)methanone (26)
Hz, 1 H), 4.50 (br s, 1 H), 4.59 (d, 2J = 14.0 Hz, 1 H), 4.73 (d, 2J = 13.8 Hz,
1 H), 4.83 (d, 2J = 13.8 Hz, 1 H), 5.01–5.08 (m, 2 H), 5.17 (br s, 1 H),
5.66 (br s, 1 H), 6.90 (d, 3J = 8.0 Hz, 1 H, Ar-H), 6.94–6.98 (m, 1 H, Ar-
H), 7.07–7.33 (m, 11 H, Ar-H), 7.46 (d, 3J = 7.6 Hz, 1 H, Ar-H); δ (30;
minor product) = 5.15 (s, 2 H), 5.20 (s, 2 H), 5.88 (br s, 2 H), 6.79–6.83
(m, 1 H, Ar-H), 6.98–7.00 (m, 2 H), 7.07–7.13 (m, 3 H, Ar-H), 7.17–
7.19 (m, 1 H, Ar-H), 7.22–7.34 (m, 8 H, Ar-H).
Prepared by Method C from aziridine 13a (100 mg, 0.26 mmol) in tol-
uene (12 mL). The mixture was stirred for 3 h. Purification by prepar-
ative TLC [EtOAc–hexane (1:4)] gave, in order of elution, compound
24 [yield: 21.9 mg (22%)] as an orange oil and a 52:48 mixture of com-
pounds 25 and 26 [yield: 13.9 mg (14%)], also as an orange oil.
Benzyl 1-Benzyl-3-methylene-1,2,3,3a,4,9b-hexahydrochrome-
no[4,3-b]pyrrole-2-carboxylate (31)
Prepared by Method C from aziridine 20 (90 mg, 0.22 mmol) in tolu-
ene (5 mL). The mixture was stirred for 4 h, and the product was puri-
fied by flash chromatography [silica gel, EtOAc–hexane (1:8)] to give a
colorless oil; yield: 57 mg (63%).
24
IR (film): 1658, 1610, 1489, 1450, 1257, 1223 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 3.02–3.07 (m, 1 H), 3.98 (d, 2J = 12.4
Hz, 1 H), 4.05–4.17 (m, 2 H), 4.35 (d, 2J = 12.4 Hz, 1 H), 4.71–4.72 (m, 1
H), 4.79 (d, 3J = 5.2 Hz, 1 H), 5.01 (br s, 1 H), 5.07–5.08 (m, 1 H), 6.92–
6.98 (m, 2 H, Ar-H), 7.10–7.14 (m, 5 H, Ar-H), 7.22–7.26 (m, 1 H, Ar-
H), 7.30–7.34 (m, 2 H, Ar-H), 7.38 (dd, 3J = 7.6 Hz, 4J = 1.6 Hz, 1 H, Ar-
H), 7.42–7.44 (m, 2 H, Ar-H), 7.46–7.50 (m, 1 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 40.9, 49.8, 56.8, 63.0, 65.8, 109.7,
116.0, 117.0, 119.4, 126.0, 127.2, 127.5, 128.0, 128.1, 131.7, 131.8,
136.2, 137.7, 145.6, 154.0, 199.9.
IR (film): 1732, 1153, 1119, 1045 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.94–3.00 (m, 1 H), 3.87 (d, 2J = 12.8
2
Hz, 1 H), 4.00–4.04 (m, 2 H), 4.06 (s, 1 H), 4.29 (d, J = 12.8 Hz, 1 H),
4.52 (d, 3J = 4.8 Hz, 1 H), 5.10 (d, 2J = 12.0 Hz, 1 H), 5.15–5.18 (m, 2 H),
5.22–5.23 (m, 1 H), 6.89–6.95 (m, 2 H, Ar-H), 7.04–7.06 (m, 2 H, Ar-
H), 7.15–7.17 (m, 3 H, Ar-H), 7.20–7.40 (m, 7 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 39.9, 49.5, 56.5, 62.8, 65.3, 65.6, 109.8,
116.0, 118.9, 118.9, 126.0, 127.2, 127.3, 127.4, 127.5, 127.6, 128.1,
131.7, 134.7, 137.5, 144.5, 154.0, 170.1.
HRMS (EI): m/z [M]+ calcd for C26H23NO2: 381.1729; found: 381.1733.
HRMS (ESI): m/z [M + H]+ calcd for C27H26NO3: 412.19072; found:
412.19039.
Mixture of 25 + 26
1H NMR (400 MHz, CDCl3): δ (25; major product) = 1.75 (s, 3 H), 2.99–
3.03 (m, 1 H), 3.94 (d, J = 15.6 Hz, 1 H), 4.01–4.07 (m, 3 H), 4.24 (d,
2
3J = 8.4 Hz, 1 H), 6.75–7.48 (m, 12 H, Ar-H), 7.70–7.72 (m, 2 H, Ar-H);
δ (26; minor product) = 1.70 (s, 3 H), 5.12 (s, 2 H), 5.77 (s, 2 H), 6.84–
6.87 (m, 1 H, Ar-H), 7.01 (d, 3J = 8.0 Hz, 1 H, Ar-H), 7.06–7.08 (m, 2 H,
Ar-H), 7.12–7.16 (m, 1 H, Ar-H), 7.18–7.22 (m, 1 H, Ar-H), 7.25–7.30
(m, 3 H, Ar-H), 7.38–7.42 (m, 2 H, Ar-H), 7.48–7.52 (m, 1 H, Ar-H),
7.63–7.65 (m, 2 H, Ar-H).
(1-Benzyl-3-methyl-1,4-dihydrochromeno[4,3-b]pyrrol-2-yl)(phe-
nyl)methanone (26)
A solution of aziridine 13a (110 mg, 0.29) in toluene (5 mL) was re-
fluxed for 2 h then cooled to r.t. The solvent was removed under re-
duced pressure, and the crude product was dissolved in EtOAc (5 mL)
and treated with 5% Pd/C (62 mg, 0.03 mmol). The resulting mixture
was refluxed for 2.5 d then cooled to r.t. The mixture was filtered on
Celite to remove the oxidant and the solvent was evaporated under
reduced pressure. The crude product was purified by preparative TLC
[EtOAc–hexane (1:6)] to give a yellow oil; yield: 17 mg (16%).
Benzyl 1-Benzyl-1,4-dihydrochromeno[4,3-b]pyrrole-2-carboxyl-
ate (30)
Prepared by Method C from aziridine 19 (100 mg, 0.25 mmol) in tolu-
ene (5 mL). The mixture was stirred for 29 h, and the product was pu-
rified by flash chromatography [silica gel, EtOAc–hexane (1:4)] to give
a pale-yellow solid; yield: 93 mg (94%); mp 115.0–116.6 °C (EtOAc–
hexane).
IR (film): 1616, 1450, 1396 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.70 (s, 3 H), 5.12 (s, 2 H), 5.77 (s, 2 H),
6.84–6.87 (m, 1 H, Ar-H), 7.01 (d, 3J = 8.0 Hz, 1 H, Ar-H), 7.06–7.08 (m,
2 H, Ar-H), 7.12–7.16 (m, 1 H, Ar-H), 7.18–7.22 (m, 1 H, Ar-H), 7.25–
7.30 (m, 3 H, Ar-H), 7.38–7.42 (m, 2 H, Ar-H), 7.48–7.52 (m, 1 H, Ar-
H), 7.63–7.65 (m, 2 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 11.8, 50.0, 64.2, 117.4, 117.8, 122.0,
122.7, 123.9, 125.7, 127.1, 128.4, 128.6, 128.8, 128.9, 129.1, 130.9,
131.6, 131.9, 138.7, 140.8, 155.0, 187.9.
IR (KBr): 1703, 1697, 1271, 1211, 1184 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.15 (s, 2 H), 5.20 (s, 2 H), 5.88 (br s, 2
H), 6.79–6.83 (m, 1 H, Ar-H), 6.98–7.00 (m, 2 H), 7.07–7.13 (m, 3 H,
Ar-H), 7.17–7.19 (m, 1 H, Ar-H), 7.22–7.34 (m, 8 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 50.0, 65.3, 65.7, 113.9, 116.7, 117.9,
118.0, 122.0, 122.2, 123.7, 125.6, 127.2, 128.0, 128.1, 128.6, 128.8,
128.9, 131.3, 136.3, 138.1, 154.8, 160.5.
HRMS (ESI): m/z [M + H]+ calcd for C26H22NO2: 380.16451; found:
380.16491.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2781–2790

2789
F. M. Ribeiro Laia, T. M. V. D. Pinho e Melo
Special Topic
Synthesis
Thermolysis of Aziridines 11a and 13a in the Presence of Dimethyl
Acetylenedicarboxylate; General Procedure
1H NMR (400 MHz, CDCl3): δ = 3.20 (s, 3 H), 3.59 (s, 3 H), 4.53–4.56
(m, 2 H), 4.83–4.86 (m, 2 H), 5.12 (d, 2J = 15.4 Hz, 1 H), 5.20–5.27 (m, 1
H), 5.38 (d, 2J = 15.4 Hz, 1 H), 6.84–6.86 (m, 2 H, Ar-H), 6.96–7.02 (m,
2 H, Ar-H), 7.05–7.11 (m, 3 H, Ar-H), 7.26–7.28 (m, 1 H, Ar-H), 7.33–
7.42 (m, 3 H, Ar-H), 7.46–7.50 (m, 1 H, Ar-H), 7.59–7.61 (m, 2 H, Ar-
H).
A solution of the appropriate aziridine and DMAD (1.5 equiv) in t-
BuOH (15 mL) was refluxed for 23 h. The solvent was removed under
reduced pressure, and the crude product was purified by flash chro-
matography [silica gel, EtOAc–hexane (1:4)].
13C NMR (100 MHz, CDCl3): δ = 49.4, 51.4, 51.7, 65.8, 76.9, 86.9, 112.5,
113.4, 119.1, 120.6, 123.9, 127.0, 127.4, 128.1, 128.3, 129.0, 130.5,
131.1, 132.6, 132.9, 137.1, 138.6, 139.7, 156.4, 163.6, 164.9, 188.1,
209.2.
(1-Benzyl-1,4-dihydrochromeno[4,3-b]pyrrol-2-yl)(phenyl)meth-
anone (23), Dimethyl 1-Benzyl-4-phenyl-1H-pyrrole-2,3-dicarbox-
ylate (27), and Dimethyl 2-Benzoyl-1-benzyl-5-[2-(prop-2-yn-1-
yloxy)phenyl]-1H-pyrrole-3,4-dicarboxylate (28a)
HRMS (ESI): m/z [M + H]+ calcd for C32H28NO6: 522.19111; found:
Prepared from aziridine 11a (100 mg, 0.27 mmol) and DMAD (0.05
mL, 0.41 mmol). Purification by flash chromatography [silica gel,
EtOAc–hexane (1:4)] gave, in order of elution, compound 23 [yield: 38
mg (38%),] compound 27 [yield: 3 mg (4%)] as a yellow oil, and com-
pound 28a [yield: 52 mg (38%)] as a dark-orange oil.
522.19127.
Acknowledgment
Thanks are due to Fundação para a Ciência e a Tecnologia (FCT), Portu-
guese Agency for Scientific Research (Coimbra Chemistry Centre,
UID/QUI/00313/2013) for financial support. F.M.R.L. also acknowledg-
es the receipt of a Ph.D. research grant from FCT (SFRH/BD/69941/
2010). We thank the UC-NMR facility (www.nmrccc.uc.pt) for record-
ing the NMR data.
23
Identified by comparison with the specimen previously prepared (see
above).
27
IR (film): 1730, 1711, 1263, 1209 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 3.80 (s, 3 H), 3.82 (s, 3 H), 5.53 (s, 2 H),
6.94 (s, 1 H), 7.18–7.19 (m, 2 H, Ar-H), 7.23–7.39 (m, 8 H, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 51.8, 52.4, 52.5, 121.1, 122.3, 124.1,
125.7, 127.0, 127.3, 127.4, 127.9, 128.6, 128.8, 133.3, 136.9, 160.7,
167.3.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378717.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
HRMS (EI): m/z [M]+ calcd for C21H19NO4: 349.1314; found: 349.1314.
References
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.
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508.17568.
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yloxy)phenyl]-1H-pyrrole-3,4-dicarboxylate (28b)
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0.79 mmol). Purification by flash chromatography [silica gel, EtOAc–
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.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2781–2790

2790
F. M. Ribeiro Laia, T. M. V. D. Pinho e Melo
Special Topic
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2781–2790