One-Pot Cascade Synthesis of Fused Nitrogen-Containing Heterocycles in Aqueous Media - Utility of N -Protective Groups in Intramolecular Diels-Alder Reaction of Furan

Article abstract of DOI:10.1055/s-0035-1562458

A metal-free, thermal, intramolecular Diels-Alder (IMDA) reaction of furan in aqueous media without the use of microwave irradiation was investigated. Protection of the amine functionality and the cycloaddition reaction were performed as a one-pot, two-component process. Various nitrogen-protecting groups and their electronic and steric effects on the cycloaddition reaction were studied. The protection-intramolecular Diels-Alder reaction sequence proceeds under environmentally benign aqueous conditions, which are tolerated by substrates with a broad range of nitrogen-protecting groups such as benzyloxycarbonyl (Cbz), trityl, tert-butoxycarbonyl (Boc), trifluoroacetyl, tosyl, mesyl, and p-nosyl [(4-nitrophenyl)sulfonyl]. This study allowed the development of a stereoselective, tandem allylamine isomerization-Diels-Alder cycloaddition sequence leading to the rapid assembly of complex nitrogen-containing heterocycles in a simple one-pot process.

Full text of DOI:10.1055/s-0035-1562458

SYNTHESIS
0
0
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9
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1
1
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-
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1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–H
paper
A
A. Demircan et al.
Paper
Synthesis
One-Pot Cascade Synthesis of Fused Nitrogen-Containing Hetero-
cycles in Aqueous Media – Utility of N-Protective Groups in Intra-
molecular Diels–Alder Reaction of Furan
Aydin Demircan*a
Muhammet K. Kandemira
Medine Colaka
Muhsin Karaarslanb
O
X
O
R
R
X
PG
H
N
exo
IMDA
H2O
N
n
n
n
N
H
X
O
R
a Department of Chemistry, Nigde University, Kampus,
51240, Nigde, Turkey
ademircan@nigde.edu.tr
b Department of Chemistry, Aksaray University, Kampus,
68000, Aksaray, Turkey
PG
n = 1, 2
R = H, Me
X = Br, Cl
PG = Ts, Ms, p-nosyl, o-nosyl, Boc, trityl, COCF3, Cbz
Received: 18.03.2016
Accepted after revision: 01.06.2016
Published online: 22.07.2016
tions rather than isoindoles under high pressure.4 DABCO-
catalyzed thermal cycloadditions have also been studied.
Thermal IMDA cyclization of furans tethered to allenamides
without the need for any catalyst was reported; metal assis-
tance for the rapid assembly of highly functionalized nitro-
gen heterocycles was reported by Hsung as well.5 Cascade
cycloadditions between tosylated furylamines and allenyl
esters and various π-systems were used for the synthesis of
structurally interesting aza heterocycles.6 A one-pot proto-
col for the synthesis of fused heterocycles from furan-teth-
ered allenes via a two-component reaction by the use of al-
dehydes and furan-tethered terminal alkynes was also very
recently published.7
In the past ten years we have been examining a different
facile thermal intramolecular Diels–Alder reaction with fu-
ran-cored compounds towards the synthesis of epoxyisoin-
doles with tethered heteroatoms. We initially found that fu-
ran-tethered bromoalkenes linked by oxygen undergo [4+2]
cycloaddition, giving fused systems in moderate yields (16–
22%) and obstructing radical reactions (Scheme 1).8a Later
we discovered that sulfur-containing tethered bromoalke-
nyl furans also undergo this process in hot toluene in rather
good yields (up to 75%).8b
DOI: 10.1055/s-0035-1562458; Art ID: ss-2016-z0170-op
Abstract A metal-free, thermal, intramolecular Diels–Alder (IMDA) re-
action of furan in aqueous media without the use of microwave irradia-
tion was investigated. Protection of the amine functionality and the cy-
cloaddition reaction were performed as a one-pot, two-component
process. Various nitrogen-protecting groups and their electronic and
steric effects on the cycloaddition reaction were studied. The protec-
tion–intramolecular Diels–Alder reaction sequence proceeds under en-
vironmentally benign aqueous conditions, which are tolerated by sub-
strates with a broad range of nitrogen-protecting groups such as
benzyloxycarbonyl (Cbz), trityl, tert-butoxycarbonyl (Boc), trifluoroace-
tyl, tosyl, mesyl, and p-nosyl [(4-nitrophenyl)sulfonyl]. This study al-
lowed the development of a stereoselective, tandem allylamine isomer-
ization–Diels–Alder cycloaddition sequence leading to the rapid
assembly of complex nitrogen-containing heterocycles in a simple one-
pot process.
Key words cycloaddition, cascade reactions, intramolecular Diels–Al-
der reaction, heterocycles, furan
The intramolecular Diels–Alder (IMDA) reaction of fu-
ran has always been used as a versatile methodology to-
wards the synthesis of complex structures. A double bond
adds to the conjugated diene of the furan ring (a [4+2] cyc-
loaddition), so the product always has a fused ring system.1
Thermal IMDA reactions of furan and furan derivatives with
different dienophiles play an important role in the synthe-
sis of complex molecules, as shown by the numerous publi-
cations dealing with different kinds of dienes and dieno-
philes.2
Related methodologies have been reported for the IMDA
reaction of furan. Due to the importance of fused nitrogen-
containing heterocycles, cycloaddition reactions between
double or triple bonds and dienes by using transition-metal
catalysis was studied by Fernandes and co-workers.3 Early
reports dealt with lactone- or lactam-fused side ring forma-
O
R
R
Br
O
toluene
90–110 °C
4 d
X
Br
X
X = O, S
2
1
Scheme 1 Intramolecular Diels–Alder reaction of furan with an oxy-
gen- or sulfur-linked alkenyl side chain
These series of investigations encouraged us to intro-
duce nitrogen into the tethered system and investigate its
reactivity. Experiments showed rather interesting results,
where nitrogen-tethered furans without N-protective
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

B
A. Demircan et al.
Paper
Synthesis
groups do not undergo the Diels–Alder cycloaddition; the
structures of some synthesized IMDA cycloadducts were
also elucidated by NOE.9 Subsequently, we showed that this
facile thermal IMDA reaction can be utilized to construct
fused building blocks, giving more complex tetracyclic
structures. The aromatization of the IMDA cycloadducts
was also carried out by using the boron trifluorate–diethyl
ether complex in diethyl ether at –78 °C.10 Herein, we re-
port a two-component, one-pot protection–IMDA reaction
sequence under aqueous conditions with various protective
groups and proceeding without the assistance of metal cat-
alysts or microwave irradiation.
Recent reports show that two-component, one-pot cas-
cade reactions giving fused cycloadducts are currently of
interest to provide easy access to heterocycles bearing ni-
trogen.11 The first step of the reaction is protection,12 which
is then followed by intramolecular Diels–Alder cycloaddi-
tion. The features of this one-pot procedure might make it a
powerful synthetic approach to the construction of fused
heterocycles containing nitrogen with increased molecular
diversity and complexity.13
1) with 2,3-dibromopropene in the presence of potassium
carbonate in boiling tetrahydrofuran gave (furfuryl)(bro-
moallyl)amines 3 (n = 1; R = H, Me) (Scheme 2). As expect-
ed, these (bromoallyl)amines 3 with unprotected secondary
amine tethers did not undergo thermal IMDA reactions,
even when forced under harsher conditions. Therefore, we
converted them into tertiary amines 4g,h by using tri-
phenylmethyl as protective group. This was achieved by us-
ing triethylamine in dichloromethane at 0 °C to room tem-
perature to give precursors 4g,h in good yields (Scheme 2).
However, it was realized that heating the reaction mixture
for two days in boiling dichloromethane gave mixtures of
cycloadducts 5g,h with the cycloaddition precursors 4g,h
(3:1 ratio).
We then decided to use different bulky protective
groups to accelerate the intramolecular Diels–Alder cyc-
loaddition process. To evaluate this possibility, we explored
the formation of bicyclic ring systems with fused five- and
six-membered rings or two fused six-membered rings (Ta-
ble 1). Moreover, we intended to explore the effect of the
various protecting groups on this transformation, since this
thermally driven alkenyl [4+2]-cycloaddition reaction rep-
resents a unique opportunity, with much broader synthetic
potential than previous work, by giving an unambiguous
stereoselective structure.15
We initially started our synthetic investigations with
the N-triphenylmethyl-protected adducts 4g,h and 5g,h
(Table 1, entries 7 and 8), for which protocols involving
metal catalysts such as zinc, aluminum, gold, or platinum
were not very useful.14 Alkylation of furfurylamines 7 (n =
Table 1 Scope of Synthesis of Products 4 and 5 from 3
X
X
X
PG
N
+
i
R
R
O
NH
n
O
N
n
O
R
PG
n
3
4
5
Entry
1
3
R
X
n
Protective group (PG)a
Conditions i
K2CO3, H2O
Products 4/5
4a/5a
Yield 4/5 (%)
O
O
3a
3b
Me
H
Cl
Br
1
1
50:50
Cbz
O
S
2
3
K2CO3, H2O
K2CO3, H2O
4b/5b
4c/5c
26:74
47:53
O
Ms
O2N
O
3b
3d
H
H
Br
Cl
1
1
S
O
o-nosyl
O2N
O
4
K2CO3, H2O
4d/5d
34:66
S
O
o-nosyl
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

C
A. Demircan et al.
Paper
Synthesis
Table 1 (continued)
Entry
3
R
X
n
Protective group (PG)a
Conditions i
K2CO3, H2O
Products 4/5
4e/5e
Yield 4/5 (%)
O
5
3b
H
Br
1
30:70
S
O
Ts
O
6
7
3f
Me
H
Br
Br
1
1
K2CO3, H2O
Et3N, CH2Cl2
4f/5f
26:74
34:66
S
O
Ts
Ph
Ph
3b
4g/5g
Ph
trityl
Ph
Ph
8
9
3f
Me
H
Br
Br
Cl
1
1
1
Et3N, CH2Cl2
Et3N, CH2Cl2
Et3N, CH2Cl2
4h/5h
4k/5k
38:62
45:55
43:57
Ph
trityl
F3C
O
3b
3d
trifluoroacetyl
F3C
O
10
H
4m/5m
trifluoroacetyl
O
11
12
3n
3p
Me
Me
Cl
Br
2
2
Et3N, CH2Cl2, 60°C
4n/5n
4p/5p
40:60
38:62
O
Boc
O
K2CO3, H2O
S
O
Ts
NO2
O
13
3n
Me
Cl
2
K2CO3, H2O
4r/5r
35:65
S
O
p-nosyl
a Abbreviations: o-nosyl = (2-nitrophenyl)sulfonyl; p-nosyl = (4-nitrophenyl)sulfonyl.
X
O
R
IMDA
(exo)
R
O
n
O
NH2
n
protection
HN
iii
i, ii
PG
N
n
n = 2
O
N
n
O
X
O
R
R
R
PG
X
6
7
3
4
5
R = Me
n = 1, 2
R = H, Me
IMDA
O
R
n
N
H
X
8
Scheme 2 Reagents and conditions: (i) MeNO2, NaOH, MeOH, H2O, –10 °C, 80%; (ii) LiAlH4, THF, reflux, 12 h, 54%; (iii) K2CO3, THF, 2,3-dibromopropene
or 2,3-dichloropropene, reflux, 2 d.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

D
A. Demircan et al.
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Synthesis
To prepare the furylethyl derivatives 4n,p,r and 5n,p,r
(n = 2, R = Me; Table 1, entries 11-13), a Henry reaction
with commercially available 5-methyl-2-furfural was used
to give α,β-unsaturated nitro compounds. The resulting yel-
low, crystalline nitro compounds were then reduced to the
corresponding primary amines 7 in 50–56% yield by em-
ploying lithium aluminum hydride. Treatment of primary
amines 7 (n = 1, n = 2, R = H, Me) with 2,3-dibromopropene
or 2,3-dichloropropene in the presence of potassium car-
bonate in boiling tetrahydrofuran provided the correspond-
ing (bromoallyl)- and (chloroallyl)amines 3 in good yields
(Scheme 2).16
undergo intramolecular cyclization; subsequent removal of
the protecting group produces the thermodynamically un-
stable acyclic free amine.18
Several conclusions may be drawn concerning the reac-
tivity of the furan dienes in the IMDA reaction. For success-
ful synthesis, the furan diene and dienophile need to be
geometrically disposed for π-overlap. The cycloaddition
process is heavily dependent on the protective groups and
their electronic and steric properties, presumably because
the steric and electronic effects are the driving force in the
cycloaddition process. Five-and-six- and six-and-six-mem-
bered fused rings can be formed with significant protective
group variations. In addition, substitution on the dieno-
phile (Br and Cl) and diene part (Me and H) do not appear
to retard the reaction.
A wide range of protective groups on the furan-tethered
bromo- and chloro-alkenes are tolerated in this thermal
IMDA reaction. Protection and cycloaddition reactions are
performed as a one-pot process with the furan-tethered N-
haloalkenes and protective groups participating in a two-
component reaction. The groups Boc, trityl, trifluoroacetyl,
tosyl, mesyl, and nosyl behave as driving forces and acceler-
ate the cycloaddition process in addition to providing pro-
tection. Furthermore, reactions involving sulfonyl protec-
tive groups (tosyl, o- and p-nosyl, mesyl) and the Cbz
groups are rather facile and can be carried out in aqueous
media, thus being an environmentally friendly methodolo-
gy giving the desired solid products. Further investigations
on expanding the scope of this IMDA cycloaddition step
with theoretical work followed by a multicomponent Ugi
reaction, also in aqueous media, for natural product synthe-
sis are in progress.
All subsequent nitrogen-protection and cycloaddition
reactions were performed in a one-pot procedure and mon-
itored by thin-layer chromatography until no further prog-
ress was detected (Table 1). Reactions involving sulfonyl
protecting groups (mesyl, nosyl, and tosyl) and the Cbz
group were carried out in water in the presence of potassi-
um carbonate at 98–100 °C under continuous stirring for
four days (entries 1–6, 12, and 13). The mixtures were usu-
ally purified by flash column chromatography and charac-
1
terized by using H and 13C NMR and IR spectroscopy. The
structure of a key compound was unambiguously deter-
mined by using single-crystal X-ray diffraction.17
We assume that ring constraints dictate that the cycliza-
tion is exo selective, and no variation in selectivity was ob-
served in this regard. The structure of previous X-ray analy-
sis indicated that subsequent IMDA cycloaddition of furan
indeed took place with the distal and proximal double bond
of the allyl moiety bearing a halogen atom in a quaternary
position.17a,b The crystal structure is stabilized by weak Van
der Waals interactions and two C–H···O intermolecular hy-
drogen bonds forming ring motifs in three-dimensional
networks, as can be seen in Figure 1.17c
Solvents and reagents were freshly distilled as follows: THF and Et2O
were distilled from sodium/benzophenone; CH2Cl2 and toluene were
distilled from CaH2. Reactions were monitored by TLC, using pre-coat-
ed silica plates (Macharey Nagel sil G UV254). Compounds were visual-
ized by using UV fluorescence, alkaline KMnO4 solution or acidic ceri-
um(IV) sulfate solution. Column chromatography was carried out
Macharey Nagel Kieselgel 60 (230–240 mesh). 1H NMR spectra were
recorded on a Bruker 400 MHz DPX 400 spectrometer at the chemis-
try department of the Ataturk University, Erzurum and on a Bruker
Avance III 500 MHz spectrometer at the molecular biology and genet-
ic departments of the Yildiz Technical University Istanbul. The chemi-
cal shifts are quoted in ppm, as δ values downfield from TMS or rela-
tive to the residual solvent resonance. IR spectra were recorded on a
Perkin-Elmer BXII spectrophotometer; solid and liquid samples were
recorded as thin films on ATR apparatus. Electron ionization mass
spectra (EI, 70 eV) were obtained on a Fisions VG Autospec mass spec-
trometer at NU central research laboratory.
Figure 1 ORTEP depiction of molecule 5f
It is also noteworthy that whereas the acyclic adducts
have higher Rf values on TLC plates and are liquids, the cyc-
loadducts show lower Rf values and are generally solid,
crystalline materials. All reactions reported here are per-
formed quantitatively under proper conditions and yields
presented are of isolated, purified products, not NMR yields
as presented in previous works. N-Allylfurfurylamines
bearing the appropriate N-protecting group can thermally
Benzyl (3aR,6S,7aR)-7a-Chloro-6-methyl-1,6,7,7a-tetrahydro-3a,6-
epoxyisoindole-2(3H)-carboxylate (5a)
To a mixture of 3a (0.55 g, 2.96 mmol), CH2Cl2 (15 mL), and H2O (35
mL), benzyl chloroformate (0.6 g, 3.55 mmol) was added portionwise
at r.t., and the mixture was stirred for 30 min. K2CO3 (0.37 g, 3.55
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

E
A. Demircan et al.
Paper
Synthesis
mmol) was then added and the reaction mixture was stirred for 2 h at
r.t. It was then warmed to 98 °C and stirred for 2 d. The reaction mix-
ture was cooled to r.t., and then 10% aq NaOH (40 mL) was added; the
mixture was extracted with EtOAc (3 × 15 mL) and washed with brine
(40 mL). The combined organic fractions were dried over MgSO4, fil-
tered, and concentrated under reduced pressure. The residue was
subjected to flash column chromatography; this gave a yellow gel
product; yield: 0.47 g (50%).
(3aR,6S,7aR)-7a-Chloro-2-[(2-nitrophenyl)sulfonyl]-1,2,3,6,7,7a-
hexahydro-3a,6-epoxyisoindole (5d)
According to GPI, the title compound 5d was collected as a white
powder; yield: 0.24 g (66%); mp 139.6–140.2 °C.
TLC: Rf = 0.42 (hexane–EtOAc, 6:4).
IR (ATR): 3203 (m, =CH), 3025.7 (m, =CH), 2928 (m, –CH), 2873 (m,
–CH), 1542 (s, –NO2), 1443 (s, benzene), 1151 (s, C–O), 783 (C–Cl) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.13–7.95 (m, 1 H), 7.78–7.56 (m, 3 H),
6.59 (dd, J = 5.7, 1.8 Hz, 1 H), 6.47 (d, J = 5.8 Hz, 1 H), 5.12 (dd, J = 4.7,
1.8 Hz, 1 H), 4.26 (d, J = 12.1 Hz, 1 H), 4.22 (d, J = 11.4 Hz, 1 H), 3.91 (d,
J = 12.1 Hz, 1 H), 3.70 (d, J = 11.4 Hz, 1 H), 2.57 (dd, J = 12.5, 4.7 Hz, 1
H), 1.68 (d, J = 12.5 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 148.3, 137.9, 133.6, 132.9, 132.2,
131.8, 130.4, 124.3, 96.8, 81.1, 77.3, 62.3, 47.5, 41.1.
TLC: Rf = 0.56 (hexane–EtOAc, 8:2).
IR (ATR): 2941 (m, CHarom), 2883 (m, CHaliph), 23587 (m, –CH), 1702 (s,
C=O), 1498, 1149 (s, C–O), 734 (s, C–Cl) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.39–7.37 (m, 5 H), 6.49–6.41 (m, 2 H),
5.17 (dd, J = 5.0 Hz, 2 H), 4.24–4.05 (m, 2 H), 3.67 (d, J = 12.0 Hz, 2 H),
2.32–2.24 (m, 2 H), 1.62 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 154.6, 140.8, 136.6, 128.5, 127.9, 96.5,
95.8, 89.3, 74.9, 73.9, 65.2, 61.1, 47.7, 46.2, 29.7, 19.0.
(3aR,6S,7aR)-7a-Bromo-2-tosyl-1,2,3,6,7,7a-hexahydro-3a,6-ep-
oxyisoindole (5e)
Mesyl, Tosyl, and Nosyl Cycloadducts 5b–f; General Procedure GPI
According to GPI the title compound 5e was obtained as pale yellow
To a mixture of the appropriate 3 (1 equiv) and tosyl, mesyl, or nosyl
chloride (1.2 equiv) in distilled H2O (30 mL), K2CO3 (1.2 equiv) was
added portionwise at r.t. The reaction mixture was warmed to 98 °C
after stirring for 10 min at r.t. and then stirred for 2–4 d; monitoring
was done by TLC. The reaction mixture was cooled to r.t., quenched
with EtOAc (100 mL), and extracted with EtOAc (2 × 75 mL). The com-
bined organic phases were dried over Na2SO4 and filtered and evapo-
rated under reduced pressure. The residue was subjected to flash col-
umn chromatography (n-hexane–EtOAc).
crystals; yield: 0.26 g (70%); mp 142–146 °C.
TLC: Rf = 0.38 (hexane–EtOAc, 7:3).
IR (ATR): 2982 (m, =C–H), 2168 (m, SO), 1972 (m, SO), 1660 (s, C=C),
1593, 1337, 1152, 1091 (s, C–O), 702 (s, C–Br) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.66 (d, J = 8.3 Hz, 2 H), 7.24 (dd, J = 8.5,
0.6 Hz, 2 H), 6.40 (dd, J = 5.8, 1.8 Hz, 1 H), 6.34 (d, J = 5.8 Hz, 1 H), 4.94
(dd, J = 4.7, 1.8 Hz, 1 H), 4.05 (d, J = 11.3 Hz, 1 H), 4.00 (d, J = 12.0 Hz, 1
H), 3.66 (d, J = 12.0 Hz, 1 H), 3.43 (d, J = 11.3 Hz, 1 H), 2.36 (d, J = 4.8
Hz, 1 H), 2.34 (s, 3 H), 1.62 (d, J = 12.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 143.8, 137.3, 134.7, 134.3, 129.9,
127.7, 127.6, 97.2, 81.0, 80.9, 63.5, 63.3, 47.5, 41.7, 21.7.
(3aR,6S,7aR)-7a-Bromo-2-(methylsulfonyl)-1,2,3,6,7,7a-hexahy-
dro-3a,6-epoxyisoindole (5b)
According to GPI, the title compound 5b was obtained as light brown
crystals; yield: 0.22 g (74%); mp 132–136 °C.
N-(2-Bromoprop-2-en-1-yl)-4-methyl-N-[(5-methylfuran-2-
yl)methyl]benzenesulfonamide(4f) and (3aR,6S,7aR)-7a-Bromo-6-
methyl-2-tosyl-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole (5f)
TLC: Rf = 0.4 (hexane–EtOAc, 6:4).
IR (ATR): 2929 (m, C–H), 2157 (m, SO), 1980 (m, SO), 1629 (s, C=C)
697 (s, C–Br) cm–1
.
According to GPI, the acyclic product 4f was collected as a pale yellow
liquid; yield: 0.1 g (26%); and 5f as pale yellow crystals; yield: 0.28 g
(74%).
1H NMR (500 MHz, CDCl3): δ = 6.50 (dd, J = 5.8, 1.8 Hz, 1 H), 6.42 (d, J =
5.8 Hz, 1 H), 5.09 (dd, J = 4.7, 1.8 Hz, 1 H), 4.06 (dd, J = 12.0, 3.9 Hz, 2
H), 3.75 (d, J = 12.3 Hz, 1 H), 3.59 (d, J = 11.7 Hz, 1 H), 2.84 (s, 3 H),
2.51 (dd, J = 12.8 Hz, 4.7 Hz, 1 H), 1.71 (d, J = 12.8 Hz, 1 H).
4f
TLC: Rf = 0.86 (hexane–EtOAc, 7:3).
13C NMR (126 MHz, CDCl3): δ = 137.5, 133.8, 97.1, 80.9, 63.6, 63.5,
IR (ATR): 2918 (m, C–H), 2161 (m, SO), 1978 (m, SO), 1629 (s, C=C),
47.3, 41.4, 35.6.
1090 (s, C–O), 701 (s, C–Br) cm–1
.
(3aR,6S,7aR)-7a-Bromo-2-[(2-nitrophenyl)sulfonyl]-1,2,3,6,7,7a-
hexahydro-3a,6-epoxyisoindole (5c)
1H NMR (400 MHz, CDCl3): δ = 7.68 (d, J = 8.0 Hz, 2 H), 7.27–7.24 (m, 2
H), 6.0 (d, J = 3.0 Hz, 1 H), 5.88 (d, J = 5.2 Hz, 1 H), 5.79 (d, J = 3.0 Hz, 1
H), 5.61 (d, J = 5.2 Hz, 1 H), 4.38 (s, 2 H), 3.99 (s, 2 H), 2.41 (s, 3 H), 2.08
(s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 152.6, 147.0, 143.4, 137.4, 129.6,
127.9, 119.3, 111.3, 106.4, 54.4, 43.6, 21.7, 13.6.
According to GPI, the title compound 5c was collected as a white
powdery solid; yield: 0.21 g (53%); mp 139.4–140.2 °C.
TLC: Rf = 0.5 (hexane–EtOAc, 6:4).
IR (ATR): 3097 (m, =CH), 3021 (m, =CH), 2856 (s, –CH), 1544 (s, –NO2),
1457 (s, –NO2), 1156 (s, C–O), 683.3 (s, C–Br) cm–1
.
5f
1H NMR (400 MHz, CDCl3): δ = 8.07–8.03 (m, 1 H), 7.74–7.64 (m, 3 H),
6.55 (dd, J = 5.7, 1.8 Hz, 1 H), 6.49 (d, J = 5.7 Hz, 1 H), 5.13 (dd, J = 4.7,
1.8 Hz, 1 H), 4.32 (dd, J = 11.8, 5.9 Hz, 2 H), 3.93 (d, J = 12.0 Hz, 1 H),
3.77 (d, J = 11.7 Hz, 1 H), 2.55 (dd, J = 12.8, 4.7 Hz, 1 H), 1.76 (d, J = 12.8
Hz, 1 H).
Mp 150–152 °C.
TLC: Rf = 0.4 (hexane–EtOAc, 7:3).
IR (ATR): 2980 (m, =C–H), 2163 (m, SO), 1977 (m, SO), 1658 (s, C=C),
1598, 1337, 1158, 1090 (s, C–O), 700 (s, C–Br) cm–1
.
13C NMR (100 MHz, CDCl3): δ = 148.3, 137.3, 133.9, 133.6, 132.2,
131.7, 130.4, 124.3, 97.0, 81.0, 63.5, 63.2, 47.5, 40.9.
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1H NMR (400 MHz, CDCl3): δ = 7.74 (d, J = 8.0 Hz, 2 H), 7.31 (d, J = 8.0
Hz, 2 H), 6.39 (d, J = 5.6 Hz, 1 H), 6.30 (d, J = 5.6 Hz, 1 H), 4.13 (d, J =
12.0 Hz, 1 H), 4.01 (d, J = 12.0 Hz, 1 H), 3.72 (d, J = 12.0 Hz, 1 H), 3.57
(d, J = 12.0 Hz, 1 H), 2.41 (s, 3 H), 2.14 (d, J = 12.0 Hz, 1 H), 1.82 (d, J =
12.0 Hz, 1 H), 1.51 (s, 3 H).
(2-Bromoprop-2-en-1-yl)[(5-methylfuran-2-yl)methyl](tri-
tyl)amine (4h) and (3aR,6S,7aR)-7a-Bromo-6-methyl-2-trityl-
1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole (5h)
According to GPII, the product 4h was obtained as a white gel; yield:
0.18 g (38%); and cyclized product 5h was obtained as a white pow-
der; yield: 0.92 g (62%).
13C NMR (100 MHz, CDCl3): δ = 143.8, 140.4, 134.9, 134.7, 129.9,
127.7, 96.9, 89.4, 65.9, 63.6, 47.7, 47.6, 21.7, 19.2.
4h
Trityl Cycloadducts 4g,h and 5g,h; General Procedure GPII
TLC: Rf = 0.82 (hexane–Et2O, 8:2).
Triphenylmethyl chloride (1.1 equiv) was added to the corresponding
amine (1 equiv) in CH2Cl2 (10 mL), and stirred for 5 min at 0 °C, fol-
lowed by addition of Et3N (1.1 equiv). The reaction mixture was
stirred for 4 h at r.t., and then the solvent was removed under reduced
pressure. The residue was dissolved in toluene (20 mL), and stirred for
2–4 d at 108 °C. The reaction was monitored by TLC and then 10% aq
NaOH (10 mL) was added, and the mixture was extracted with EtOAc
(3 × 15 mL). The combined organic phases were washed with brine,
dried over MgSO4, and filtered. The solvent was removed under re-
duced pressure, and the residue was subjected to flash column chro-
matography.
IR (ATR): 3042 (w, C–H), 2948 (w, C–H), 1594 (w, C=C), 1445 (m, C–N),
704 (s, C–Br) cm–1
.
1H NMR (400 MHz, CDI3): δ = 7.60 (m, 6 H), 7.30 (m, 6 H), 7.18 (m, 3
H), 6.52 (d, J = 5.6 Hz, 1 H), 6.17 (d, J = 5.6 Hz, 1 H), 3.78 (d, J = 11.6 Hz,
1 H), 3.62 (d, J = 11.6 Hz, 1 H), 2.63 (d, J = 12.0 Hz, 1 H), 2.33 (d, J = 12.0
Hz, 1 H), 1.93 (d, J = 12.5 Hz, 1 H), 1.77 (d, J = 12.5 Hz, 1 H), 1.38 (s, 3
H).
13C NMR (100 MHz, CDI3): δ = 142.5, 138.6, 137.1, 129.4, 129.3, 127.6,
127.5, 126.2, 96.7, 88.2, 74.5, 69.5, 60.5, 46.8, 46.3, 19.1.
5h
2-Bromo-N-(2-furylmethyl)-N-tritylprop-2-en-1-amine (4g) and
(3aR,6S,7aR)-7a-Bromo-2-trityl-1,2,3,6,7,7a-hexahydro-3a,6-ep-
oxyisoindole (5g)
Mp 159–161 °C.
TLC: Rf = 0.42 (hexane–EtOAc, 8:2).
IR (ATR): 3026 (s, CHarom), 2916 (s, C–H), 2850 (s, C–H), 1489 (s, C=C),
According to GPII, the product 4g was obtained as a viscous white gel;
yield: 0.55 g (34%); and the cyclized product 5g was obtained as a
white powder; yield: 0.3 g (66%).
1445 (m, C=C), 1157 (s, C–O), 757 (s, CHarom), 696 (s, C–Br) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.60–7.55 (m, 6 H), 7.30–7.28 (m, 6 H),
7.19–7.14 (m, 3 H), 6.53 (d, J = 5.5 Hz, 1 H), 6.17 (d, J = 5.6 Hz, 1 H),
3.79 (d, J = 11.7 Hz, 1 H), 3.62 (d, J = 10.8 Hz, 1 H), 2.64 (d, J = 11.7 Hz,
1 H), 2.33 (d, J = 10.8 Hz, 1 H), 1.93 (d, J = 12.6 Hz, 1 H), 1.77 (d, J = 12.5
Hz, 1 H), 1.38 (s, 3 H).
4g
TLC: Rf = 0.88 (hexane–Et2O, 8:2).
IR (ATR): 3049 (w, C–H), 2943 (w, C–H), 1593 (w, C=C), 1446 (m, C–N),
13C NMR (100 MHz, CDI3): δ = 134.8, 133.8, 131.5, 130.9, 129.9, 128.4,
68.6, 60.6, 35.9, 33.3, 19.6, 14.4.
705 (s, C–Br) cm–1
.
1H NMR (400 MHz, CDI3): δ = 7.65 (d, J = 1.62 Hz, 4 H), 7.62–7.58 (m, 6
H), 7.49–7.44 (m, 3 H), 7.36–7.24 (m, 6 H), 6.35 (dd, J = 3.0, 1.62 Hz, 1
H), 6.23 (d, J = 3.0 Hz, 1 H), 6.04 (s, 1 H), 5.96 (s, 1 H), 3.88 (s, 2 H), 3.66
(s, 2 H).
13C NMR (100 MHz, CDI3): δ = 142.6 136.7, 135.6, 129.6, 127.8, 126.5,
97.2, 80.5, 74.7, 66.7, 60.7, 46.8, 40.1.
Trifluoroacetyl-Protected Cycloadducts 4k,m and 5k,m; General
Procedure GPIII
To 2-bromo-N-(2-furylmethyl)prop-2-en-1-amine (3b) or 2-chloro-
N-(2-furylmethyl)prop-2-en-1-amine (3d) (3.85 mmol, 1 equiv) in
CH2Cl2 (15 mL) was added Et3N (7.7 mmol, 1.8 equiv). TFAA (3.85
mmol, 1equiv) in CH2Cl2 (5 mL) was added to the reaction mixture at
0 °C. The mixture was stirred at r.t. for 2 h and then brought to reflux
for 3 d at 72 °C. Subsequently, H2O (20 mL) was added to the reaction
mixture; this was followed by extraction with CH2Cl2 (3 × 15 mL). The
combined organic phases were dried with Na2SO4, filtered, and con-
centrated under reduced pressure. The residue was subjected to flash
column chromatography.
MS (EI, 70 eV): m/z (%) = 459 [M+(81Br), 12%], 457 [M+(79Br), 11%], 217
[M+ – trityl, 100%], 215 [M+ – trityl, 100%].
5g
Mp 125–127 °C.
TLC: Rf = 0.45 (PE–Et2O, 8:2).
IR (ATR): 3003 (w, C–H), 2950 (w, C–H), 1585 (w, C=C), 1479 (m, C–N),
705 (s, C–Br) cm–1
.
N-(2-Bromoallyl)-2,2,2-trifluoro-N-(2-furylmethyl)acetamide(4k)
and 1-[(3aR,6S,7aR)-7a-Bromo-1,6,7,7a-tetrahydro-3a,6-epoxyiso-
indol-2(3H)-yl]-2,2,2-trifluoroethanone (5k)
1H NMR (400 MHz, CDI3): δ = 7.52–7.49 (m, 6 H), 7.28–7.19 (m, 6 H),
7.12–7.07 (m, 4 H), 6.46 (d, J = 5.2 Hz, 1 H, AB), 6.25 (dd, J = 5.2, 3.2 Hz,
1 H, AB), 3.79 (dd, J = 12.0, 4.7 Hz, 1 H), 3.57 (dd, J = 10.7, 4.7 Hz, 1 H),
2.60 (dd, J = 12.0, 4.70 Hz, 2 H) 2.25–2.11 (m, 1 H), 1.58 (dd, J = 12.0,
4.8 Hz, 1 H).
According to GPIII, the acyclic products 4k was obtained as a brown
oil; yield: 0.54 g (45%); and the cyclized product 5k was obtained as a
yellow oil; yield: 0.66 g (55%).
13C NMR (100 MHz, CDI3): δ = 142.6, 136.7, 135.6, 129.6, 127.8, 126.5,
97.2 80.5, 74.7, 66.7, 60.7, 46.7, 40.0.
4k
TLC: Rf = 0.63 (hexane–EtOAc, 7:3).
MS (EI, 70 eV): m/z (%) = 459 [M+(81Br), 18%], 457 [M+(79Br), 17%], 379
[M+ – (81Br), 36%], 381 [M+ – (79Br), 34%], 137 [M+ – (81Br + Trityl),
100%].
IR (ATR): 2945 (w, CHarom), 1693 (s, C=O), 1449 (m, C=C), 1203 (s, C–
O), 1015 (s, C–F), 692 (s, C–Br) cm–1
.
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1H NMR (400 MHz, CDCl3): δ = 7.46–7.34 (m, 1 H), 6.38–6.33 (m, 1 H),
6.35–6.30 (m, 1 H), 5.80 (dd, J = 9.9, 1.6 Hz, 1 H), 5.76–5.68 (m, 1 H),
4.62 (d, J = 7.9 Hz, 2 H), 4.30 (s, 1 H), 4.25 (s, 1 H).
Prop-2-en-1-amines 3n,p (n = 2); General Procedure GPIV
To a stirred solution of 5-methyl-2-(2-aminoethyl)furan (5.6 mmol, 2
equiv) in THF (15 mL) was added 2,3-dichloropropene or 2,3-dibro-
mopropene (2.8 mmol, 1 equiv), and the resulting solution was heat-
ed to reflux for 12 h. A portion of K2CO3 (1.76 g, 12.8 mmol) was then
added, and the reaction mixture was heated at reflux for a further 48
h. On cooling, a precipitate was formed, which was washed with Et2O
(3 × 15 mL). The filtrate was extracted with 10% aq NaOH (15 mL) and
the combined organic phases were dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was subjected to
flash column chromatography.
13C NMR (100 MHz, CDCl3): δ = 148.0, 143.6, 143.3, 120.7, 119.9,
110.9, 110.5, 110.3, 52.6, 41.9. MS (EI, 70 eV): m/z (%) = 232 [M+
(
–
79Br), 20], 192 [M+ – (79Br + CH2CCH2), 100]
5k
TLC: Rf = 0.44 (hexane–EtOAc, 7:3).
IR (ATR): 2918 (w, CHarom), 2851 (w, C–H), 1688 (s, C=O), 1452 (s, C=C),
1203 (s, C–O), 1045 (s, C–F), 700 (s, C–Br) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.64 (dd, J = 1.6 Hz, J = 5.6 Hz, 1 H),
6.48 (d, J = 5.6 Hz, 1 H), 5.12 (dd, J = 1.6 Hz, J = 4.6 Hz, 1 H), 4.38 (d, J =
12.0 Hz, 1 H), 4.35 (d, J = 12.8 Hz, 1 H), 4.01 (d, J = 12.0 Hz, 1 H), 3.87
(d, J = 12.8 Hz, 1 H), 2.62 ( dd, J = 4.6, 12 Hz, 1 H), 1.74 (d, J = 12.0 Hz, 1
H).
13C NMR (100 MHz, CDCl3): δ = 138.5, 132.9, 132.6, 117.7, 94.7, 81.5,
62.1, 47.3, 42.1, 41.4.
2-Chloro-N-[2-(5-methylfuran-2-yl)ethyl]prop-2-en-1-amine (3n)
According to GPIV, product 3n was obtained as a colorless oil; yield:
0.13 g (63%).
TLC: Rf = 0.26 (PE–Et2O, 7:3).
IR (ATR): 3342 (br, NH), 2928 (s, C=C, CH), 1740 (s, C=C), 742 (s, C–Cl)
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.92 (d, J = 3.0 Hz, 1 H), 5.80 (d, J = 3.0
Hz, 1 H), 5.62 (s, 1 H), 5.44 (s, 1 H), 3.40 (s, 2 H), 2.86–2.79 (m, 4 H),
2.35 (s, 3 H), 1.80 (s, NH).
MS (EI, 70 eV): m/z (%) = 232 [M+ – (79Br), 25], 192 [M+ – (79Br +
CH2CCH2), 100].
13C NMR (100 MHz, CDCl3): δ = 153.0, 151.2, 136.8, 121.2, 109.2,
108.2, 61.0, 49.3, 31.0, 15.6.
N-(2-Chloroallyl)-2,2,2-trifluoro-N-(2-furylmethyl)acetamide
(4m) and 1-[(3aR,6S,7aR)-7a-Chloro-1,6,7,7a-tetrahydro-3a,6-ep-
oxyisoindol-2(3H)-yl]-2,2,2-trifluoroethanone (5m)
MS (EI, 70 eV): m/z (%) = 201 [M+(37Cl), 12], 199 [M+(35Cl), 36], 151
[M+(CH2NHCH2C37ClCH2), 31], 149 [M+, (CH2NHCH2C35ClCH2), 96].
According to GPIII, the acyclic products 4m was obtained as a dark
yellow oil; yield: 0.14 g (43%); and the cyclized product 5m was ob-
tained as a yellow gel; yield: 0.19 g (57%).
2-Bromo-N-[2-(5-methylfuran-2-yl)ethyl]prop-2-en-1-amine (3p)
According to GPIV, product 3p was obtained as a pale yellow oil;
4m
yield: 0.17 g (68%).
TLC: Rf = 0.66 (hexane–EtOAc, 7:3).
TLC: Rf = 0.24 (PE–Et2O, 7:3).
IR (ATR): 3339 (br, NH), 2921 (s, CH), 1742 (s, C=C), 774 (s, C–Br) cm–1
.
IR (ATR): 2938 (w, CHarom), 1695 (s, C=O), 1452 (m, C=C), 1198 (s, C–
O), 1011 (s, C–F), 537 (s, C–Cl) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.90 (d, J = 3.0 Hz, 1 H), 5.83 (d, J = 3.0
Hz, 1 H), 5.65 (s, 1 H), 5.44 (s, 1 H), 3.40 (s, 2 H), 2.84–2.80 (m, 4 H),
2.30 (s, 3 H), 1.82 (s, NH).
13C NMR (100 MHz, CDCl3): δ = 155.0, 153.2, 135.8, 120.2, 109.2,
108.5, 60.0, 49.7, 31.2, 16.0.
1H NMR (400 MHz, CDCl3): δ = 7.44–7.32 (m, 1 H), 6.38–6.34 (m, 1 H),
6.35–6.30 (m, 1 H), 5.56–5.42 (m, 1 H), 5.39–5.32 (m, 1 H), 4.62 (d, J =
8.0 Hz, 2 H), 4.23 (s, 1 H), 4.19 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 148.5, 148.0, 143.6, 143.2, 116.2,
115.8, 110.8, 110.5, 52.3, 43.3.
MS (EI, 70 eV): m/z (%) = 232 [M+ – (35Cl), 22], 192 [M+ – (35Cl +
MS (EI, 70 eV): m/z (%) = 245 [M+(81Br), 27], 243 [M+(79Br), 28], 150
[M+(CH2NHCH2C81BrCH2), 100], 148 [M+, (CH2NHCH2C79BrCH2), 100].
CH2CCH2), 100].
tert-Butyl (4aS,7S,8aR)-8a-Chloro-7-methyl-1,3,4,7,8,8a-hexahy-
dro-2H-4a,7-epoxyisoquinoline-2-carboxylate (5n)
5m
TLC: Rf = 0.44 (hexane–EtOAc, 7:3).
To a stirred solution of 3n (0.56 g, 2.3 mmol) and Boc2O (0.55 g, 2.5
mmol) in CH2Cl2 (10 mL) was added DMAP (30 mg, 0.25 mmol) at 0
°C. The reaction mixture was stirred for 2 h at r.t. and then brought to
reflux at 72 °C for 2 d. The reaction mixture was then cooled to r.t.
and concentrated under reduced pressure. The residue was subjected
to flash column chromatography; this afforded the title compound as
a pale yellow gel; yield: 0.41 g (60%).
IR (ATR): 2919 (w, CHarom), 2851 (w, C–H), 1688 (s, C=O), 1452 (s, C=C),
1203 (s, C–O), 1045 (s, C–F), 708 (s, C–Cl) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.65 (dd, J = 1.6, 5.6 Hz, 1 H), 6.51 (d, J =
5.6 Hz, 1 H), 5.18 (dd, J = 1.6, 4.8 Hz, 1 H), 4.42 (d, J = 12.4 Hz, 1 H),
4.35 (d, J = 12.0 Hz, 1 H), 4.01 (d, J = 12.4 Hz, 1 H), 3.87 (d, J = 12.0 Hz,
1 H), 2.64 ( dd, J = 4.8, 12 Hz, 1 H), 1.78 (d, J = 12.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 138.5, 138.4, 133.0, 132.7, 81.5, 81.4,
61.3, 47.3, 42.1, 41.2.
TLC: Rf = 0.30 (hexane–Et2O, 7:3).
IR (ATR): 3012 (w, C–H), 2948 (w, C–H), 1585 (w, C=C), 1479 (m, C–N),
740 (C–Cl) cm–1
.
MS (EI, 70 eV): m/z (%) = 232 [M+ – (35Cl), 22], 192 [M+ – (35Cl +
CH2CCH2), 100].
1H NMR (400 MHz, CDI3): δ = 6.57 (d, J = 5.6 Hz, 1 H), 6.36 (d, J = 5.6
Hz, 1 H), 4.66–4.63 (m, 1 H), 4.60–4.44 (m, 1 H), 3.47–3.43 (m, 3 H),
2.67–2.59 (m, 2 H), 1.82 (s, 3 H), 1.77 (s, 9 H).
13C NMR (100 MHz, CDI3): δ = 149.0, 139.0, 138.0, 105.0, 87.0, 80.0,
62.0, 57.0, 48.0, 39.0, 29.9, 28.5, 19.3.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

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A. Demircan et al.
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Synthesis
(4aS,7S,8aR)-8a-Bromo-7-methyl-2-tosyl-2,3,4,7,8,8a-hexahydro-
1H-4a,7-epoxyisoquinoline (5p)
(2) (a) Gulbrandsen, H. S.; Hennum, M.; Osheka, M.; Read, M. L.;
Gundersen, L.-L. Eur. J. Org. Chem. 2014, 36, 8182. (b) Lewis, F.
W.; Harwood, L. M. Targets Heterocycl. Syst. 2012, 16, 1–30.
(c) Zubkov, F. I.; Nikitina, E. V.; Galeev, T. R.; Zaytsev, V. P.;
Khrustalev, V. N.; Novikov, A. R.; Orlova, D. N.; Varlamov, A. V.
Tetrahedron 2014, 70, 1659. (d) Padwa, A.; Flick, A.; Andrew, C.
Adv. Heterocycl. Chem. 2013, 110, 1.
Prop-2-en-1-amine 3p (0.65 g, 2.66 mmol) and tosyl chloride (0.6 g,
3.20 mmol) were dissolved in distilled H2O (50 mL). K2CO3 (0.46 g, 3.2
mmol) was added and the reaction mixture was stirred at 98 °C for 4
d. Product 5p was collected as pale yellow crystals; yield: 0.66 g
(62%).
(3) Fernandez, I.; Mascerenas, J. L. Org. Biomol. Chem. 2012, 10, 699.
(4) (a) Parker, K. A.; Adamchuk, M. R. Tetrahedron Lett. 1978, 19,
1689. (b) Rogers, C.; Keay, B. A. Can. J. Chem. 1993, 71, 611.
(c) Isaacs, N. S.; Van der Beeke, P. Tetrahedron Lett. 1982, 23,
2147.
(5) Lohse, A. G.; Hsung, R. P. Org. Lett. 2009, 11, 3430.
(6) Hu, J.; Tian, B.; Wu, X.-Y.; Tong, X.-F. Org. Lett. 2012, 14, 5074.
(7) Zhang, Y. Y.; Hao, J.; Shi, M. Org. Chem. Front. 2015, 2, 349.
(8) (a) Demircan, A.; Parsons, P. J. Synlett 1998, 1215. (b) Demircan,
A.; Parsons, P. J. Heterocycl. Commun. 2002, 8, 531.
TLC: Rf = 0.22 (hexane–EtOAc, 8:2).
IR (ATR): 3014 (w, C–H), 2948 (s, C–H), 1585 (w, C=C), 1479 (m, C–N),
708 (C–Br) cm–1
.
1H NMR (400 MHz, CDI3): δ = 7.60 (d, J = 8.0 Hz, 2 H), 7.26 (d, J = 8.0
Hz, 2 H), 6.23 (d, J = 5.6 Hz, 1 H), 6.07 (d, J = 5.6 Hz, 1 H), 4.07 (d, J = 2.0
Hz, 1 H), 3.73–3.70 (m, 1 H), 2.64 (m, 2 H), 2.52 (m, 2 H), 2.36 (s, 3 H),
1.95 (d, J = 12.8 Hz, 1 H), 1.71 (d, J = 12.8 Hz, 1 H), 1.44 (s, 3 H).
13C NMR (100 MHz, CDI3): δ = 143.9, 140.1, 138.1, 134.2, 129.9, 127.8,
87.4, 87.2, 60.3, 58.8, 48.7, 42.7, 25.4, 21.8, 19.1.
(9) Demircan, A.; Karaarslan, M.; Turac, E. Heterocycl. Commun.
2006, 8, 233.
(10) Karaarslan, M.; Gokturk, E.; Demircan, A. J. Chem. Res. 2007, 2,
117.
(4aS,7S,8aR)-8a-Chloro-7-methyl-2-[(4-nitrophenyl)sulfonyl]-
2,3,4,7,8,8a-hexahydro-1H-4a,7-epoxyisoquinoline (5r)
The same procedure as that for 5p was applied, with p-nitrotosyl
chloride and 3n used for the IMDA reaction. Product 5r was obtained
as pale yellow crystals; yield: 0.23 g (65%); mp 170–172 °C.
(11) (a) Feng, W.; Jiang, D.; Kee, C.-W.; Liu, H.; Tan, C. C.-H. Chem.
Asian J. 2016, 11, 390. (b) Williams, D. R.; Klein, J. C. Org. Lett.
2016, 18, 420. (c) Benallou, A.; El Alaoui El Abdallaoui, H.;
Garmes, H. Tetrahedron 2016, 72, 76. (d) Zhao, G.; He, M.; Li, H.;
Duan, S. H.; Yuan, Z.; Xie, X.; She, X. Chem. Commun. 2015, 51,
17321. (e) Kim, K. H.; Lim, J. W.; Moon, H. R.; Kim, J. N. Bull.
Korean Chem. Soc. 2014, 35, 3254. (f) Richey, B.; Mason, K. M.;
Meyers, M. S.; Luesse, S. B. Tetrahedron Lett. 2016, 57, 492.
(12) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in
Organic Synthesis, 4th ed.; Wiley: Hoboken, 2007.
TLC: Rf = 0.2 (hexane–EtOAc, 8:2).
IR (ATR): 3217 (m, =CH), 2972.9 (m, –CH), 1606.7 (s, C–Harom), 1528 (s,
–NO2), 1102 (s, C–O), 795 (s, –NO2) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.42–8.28 (m, 2 H), 8.08–7.97 (m, 2 H),
6.37 (d, J = 1.2 Hz, 2 H), 4.08 (d, J = 11.3 Hz, 1 H), 3.97 (d, J = 12.0 Hz, 1
H), 3.77 (d, J = 12.0 Hz, 1 H), 3.57 (d, J = 11.3 Hz, 1 H), 2.18 (d, J = 12.6
Hz, 1 H), 1.75 (d, J = 12.6 Hz, 1 H), 1.52 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 150.1, 143.3, 132.9, 132.4, 130.9,
128.5, 124.5, 124.3, 96.3, 74.3, 68.1, 47.7, 47.3, 38.7, 23.7.
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Acknowledgment
The authors are grateful to The Scientific and Technological Research
Council of Turkey TUBITAK (PN: 107T831) for financial support of this
work. We thank Dr. Davit Jishkariani at the University of Pennsylva-
nia, USA, for proofreading.
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metry 1996, 7, 3397.
Supporting Information
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Crystallogr., Sect. E 2011, 67, o994. (b) Temel, E.; Demircan, A.;
Arslan, H.; Büyükgüngör, O. Acta Crystallogr., Sect. E 2011, 67,
o1304. (c) Alaşalvar, C.; Demircan, A.; Koşar, B.; Pekacar, A. I.;
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Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562458.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H