Cascade Radical Cyclization to Vinylogous Carbonates/Carbamates for the Synthesis of Oxa- and Aza-Angular Triquinanes: Diastereoselectivity Depends on the Ring Size of Radical Precursor

Article abstract of DOI:10.1055/s-0036-1589541

An efficient strategy was developed for the stereoselective construction of oxa- and aza-angular triquinanes employing a cascade 5 - exo - trig radical cyclization to vinylogous carbonates and carbamates. The radical precursors are readily prepared from 2-(hydroxymethyl)cyclopentenone/cyclohexenones. High diastereoselectivity is observed for the formation of angular oxa- and azatriquinanes. Diastereoselectivity drops when six-membered radical precursors are used. The strategy is found to be useful to incorporate synthetically challenging moieties such as spiroindoline, lactone-bearing, and uracil-fused angular triquinanes in a concise manner.

Full text of DOI:10.1055/s-0036-1589541

SYNTHESIS
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1
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1
0
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–N
special topic
A
en
S. J. Gharpure et al.
Special Topic
Synthesis
Cascade Radical Cyclization to Vinylogous Carbonates/Carbamates
for the Synthesis of Oxa- and Aza-Angular Triquinanes: Diastereo-
selectivity Depends on the Ring Size of Radical Precursor
Santosh J. Gharpure*a
P. Niranjanab
Suheel K. Porwalc
Bz
EtO2C
H
EtO2C
O
N
O
n-Bu3SnH
n-Bu3SnH
( )n
X
H
( )n
N
Y
Y
H
AIBN, C6H6,
reflux
AIBN, C6H6,
reflux
H
a Department of Chemistry, Indian Institute of Technology
Bombay, Powai, Mumbai 400076, India
sjgharpure@iitb.ac.in
G
X
n = 1, 2
O
b Department of Chemistry, Indian Institute of Technology,
Madras, Chennai 600036, India
(dr > 19:1)
X,Y = O, NTs
G = radical precursor
(n = 1, dr > 19:1)
(n = 2, dr > 4:1)
c Department of Chemistry, DIT University, Dehradun,
Dehradun 248009, India
Stereoselective construction of oxa- and azatriquinanes
dr is dependent on ring size of the radical precursors
Vinylogous carbonates and carbamates are good radical acceptors
Published as part of the Special Topic Modern Radical Methods
and their Strategic Applications in Synthesis
Dedicated to Professor Sambasivarao Kotha, IIT Bombay, on the
occasion of his 60th birthday.
Received: 10.06.2018
Accepted after revision: 03.07.2018
Published online: 11.07.2018
ably less attention from synthetic chemists.2 The majority
of the strategies developed in past few decades give access
to either aza- or oxatriquinanes. Far less attention has been
paid to develop strategies that would incorporate both oxy-
gen and nitrogen in the same molecule.
DOI: 10.1055/s-0036-1589541; Art ID: ss-2018-c0397-st
Abstract An efficient strategy was developed for the stereoselective
construction of oxa- and aza-angular triquinanes employing a cascade
5-exo-trig radical cyclization to vinylogous carbonates and carbamates.
The radical precursors are readily prepared from 2-(hydroxymethyl)cy-
clopentenone/cyclohexenones. High diastereoselectivity is observed for
the formation of angular oxa- and azatriquinanes. Diastereoselectivity
drops when six-membered radical precursors are used. The strategy is
found to be useful to incorporate synthetically challenging moieties
such as spiroindoline, lactone-bearing, and uracil-fused angular
triquinanes in a concise manner.
X
H
Y
linear
HO
angular
propellane
X, Y = O, NR
hetero-triquinanes
O
H
O
O
H
R1
O
R2
Me(H2C)6
O
O
O
O
O
O
O
Key words oxatriquinanes, azatriquinanes, vinylogous carbonates, vi-
nylogous carbamates, cascade/tandem radical cyclization, stereoselec-
tive synthesis
OH
C(CH3)3
O
H
O
O
OH
OH
HO
syringolide 2
bilobalide
R1 = H, R2 = OH anislactone A
R1 = OH, R2 = H anislactone B
Triquinanes have attracted considerable attention from
organic chemists due to their unique and synthetically
challenging framework, which is also present in many natu-
ral products.1 Generally, triquinanes are classified into three
types depending on the stereochemical arrangement of the
five-membered rings present, namely, linear-, angular-, and
propellane-type (Figure 1). In addition, many of these
triquinanes display versatile biological activity. After the
discovery and synthesis of the first polyquinane natural
product, hirsutic acid C, significant progress has been made
on the synthesis of carbocyclic polyquinanes. Substantial
efforts have been directed towards the synthesis of carbo-
cyclic triquinane frameworks as they constitute the core of
many sesquiterpene natural products. In contrast, the het-
eroatom-substituted triquinanes have attracted consider-
Figure 1 Carbocyclic and heterocyclic triquinanes and triquinane natu-
ral products
Such methods would be particularly useful as not only
these heteroatom-substituted polyquinanes were thought
to be more interesting from the point of view of their bio-
logical activity, but also many of these entities have proved
to be useful intermediates for the synthesis of their carbo-
cyclic analogues.3 As a result, stereoselective synthesis of
heteroatom-substituted angular triquinanes continues to
be an important and interesting area of research. We dis-
close here full details of our approach to the synthesis of
oxa- and azatriquinanes.4j
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

B
S. J. Gharpure et al.
Special Topic
Synthesis
In continuation of our interest on using vinylogous car-
bonates and carbamates in the synthesis of cyclic ethers
and amines,4 we envisioned that the heterocyclic angular
triquinanes could be synthesized via a cascade radical cy-
clization (Figure 2). It was argued that a radical precursor
such as iodide 1 could be rapidly assembled from the readi-
ly available cyclopentenone derivatives 2 via a short se-
quence involving: (i) hydroxymethylation of the enone 2 us-
ing Baylis–Hillman reaction, (ii) conversion of the resultant
alcohol into the vinylogous carbonate, (iii) Luche reduction
of the enone moiety to the allyl alcohol, and (iv) Mitsunobu
reaction of the resultant alcohol.
enone (6).5,6 Reaction of the Baylis–Hillman adduct 6 with
ethyl propynoate in the presence of N-methylmorpholine
(NMM) in dry CH2Cl2 gave the vinylogous carbonate 7 in
72% yield (Scheme 2). The alcohol 8 could be readily ob-
tained from the enone 7 by Luche reduction using NaBH4
and CeCl3·7H2O in methanol.7 Repetition of this three-step
sequence on the known cyclopentenone derivative 9 fur-
nished the alcohol 12, through the intermediacy of the al-
cohol 10 and the keto-vinylogous carbonates 11.8,9
R
R
R
R
aq. HCHO
cat. DMAP,
THF, rt
OH
O
O
I
5: R = H
9: R = Me
6: R = H 45%
10: R = Me 26%
CO2Et
1.Baylis–Hillman
reaction
2. Vinylogous carbonate
R
H
Y
Tandem
5-exo-trig
X
H
NMM
CO2Et CH2Cl2,
rt
radical
cyclization
3. Luche reduction
4. Mitsunobu reaction
Y
R
O
R
X
EtO2C
R
EtO2C
R
CO2Et
3
1
2
NaBH4
CeCl3⋅7H2O
R
R
Figure 2 Retrosynthesis for heterocyclic angular triquinanes 3
MeOH,
–10 °C
O
O
O
HO
8: R = H 92%
12: R = Me 92%
7: R = H 72%
11: R = Me 69%
It was expected that the intramolecular radical cycliza-
tion of iodide 1 would lead to the formation of oxa-angular
triquinane 3 through a cascade process. The reaction would
involve initial formation of a radical from the iodide radical
precursor 1, which would undergo a 5-exo-trig radical cy-
clization to generate a new radical intermediate 4. The radi-
cal intermediate 4 upon second 5-exo-trig cyclization to the
vinylogous carbonate/carbamate moiety would generate a
new radical, which on reduction with n-Bu3SnH would give
the heteroatom-substituted angular triquinane derivative 3
(Scheme 1).
Scheme 2 Synthesis of alcohol precursors
With the cyclopentenol derivatives 8 and 12 in hand, in-
troduction of the radical precursor moiety was carried out
by Mitsunobu reaction.10,11 Thus, the alcohol 8 upon reac-
tion with diisopropyl azodicarboxylate (DIAD), PPh3, and
2-iodophenol (13), led to the corresponding iodide 17 in
72% yield (Table 1, entry 1). Similarly, alcohols 8 and 12
with various nucleophiles such as 2-iodophenol (13), 1-
iodo-2-naphthol (14), and 2-iodo-N-tosylaniline (15) fur-
nished the corresponding iodides 17–21 in good yields (Ta-
ble 1, entries 2–5). On the other hand, Mitsunobu reaction
of the alcohols 8 and 12 using N-tosylpropargylamine (16)
gave the alkyne tethered precursors 22 and 23, respectively,
in good yield (Table 1, entries 6 and 7).
EtO2C
EtO2C
EtO2C
H
n-Bu3SnH
AIBN, C6H6
reflux
H
5-exo-trig
n-Bu3SnH
Y
Y
Y
5-exo-trig
X
X
X
X, Y = O, NTs
To synthesize an O-propargyl-tethered vinylogous car-
bonate substrate, the alcohol 12 was reacted with NaH and
propargyl bromide. However, rather than the requisite
propargyl ether, acetal 24 was obtained as the major prod-
uct (Scheme 3). The product was formed by the base-pro-
moted oxa-Michael addition of the hydroxy group to the vi-
nylogous carbonate moiety.
I
1
4
3
Scheme 1 Rationale for proposed cascade radical cyclization for the
formation of heterocyclic angular triquinanes
We initiated our studies with the synthesis of the re-
quired radical precursors. To expand the scope, three points
of structural variations were considered, namely, modifica-
tion in cyclopentenone structure, nature of radical precur-
sor, and final acceptor as vinylogous carbonate or carba-
mate. Baylis–Hillman reaction of readily available cyclo-
EtO2C
Br
O
O
O
NaH, DMF
pent-2-enone
(5)
and
formalin
using
4-
0 °C to rt,
50%
OH
12
(dimethylamino)pyridine as the catalyst following litera-
ture protocol furnished 2-(hydroxymethyl)cyclopent-2-
CO2Et
24
Scheme 3 Acetal formation by oxa-Michael addition
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

C
S. J. Gharpure et al.
Special Topic
Synthesis
Table 1 Synthesis of Iodides and Alkynes for Radical Cyclization
protected as its THP ether 25 using dihydropyran and PPTS.
Luche reduction of the enone using CeCl3·7H2O and NaBH4
to the alcohol 26, followed by propargylation using NaH
and propargyl bromide gave the ether 27. THP protection of
the ether 27 was removed using PPTS and MeOH to yield
the alcohol 28. The alcohol 28 thus obtained was treated
with ethyl propynoate in the presence of N-methylmorpho-
line in dry CH2Cl2 to furnish the corresponding vinylogous
carbonate 29 in 91% yield (Scheme 4).
Nu-H
DIAD, PPh3,
THF, rt
EtO2C
EtO2C
R
O
R
R
G
O
Y = O, NTs
R
G = Radical precursor
Y
HO
8: R = H
17–23
12: R = Me
Entry Sub- Nucleophile
strate
Yield Iodides and alkynes
(%)a
OH
I
O
O
HO
I
O
NaBH4
O
CO2Et
1
2
8
72
54
CeCl3·7H2O,
MeOH, –10 °C,
84%
PPTS
CH2Cl2
0 °C to rt,
82%
THPO
OH
OTHP
25
O
17
18
13
OH
6
26
DMF
0 °C to rt,
88%
Br
I
I
I
O
NaH
12
CO2Et
CO2Et
13
O
O
O
CO2Et
PPTS
MeOH
O
O
NMM, CH2Cl2
rt, 91%
I
O
rt, 53%
OTHP
OH
OH
CO2Et
29
28
27
3
4
8
62
65
O
Scheme 4 Synthesis of O-propargyl tethered vinylogous carbonate 29
14
19
I
For the synthesis of substrates bearing a vinylogous car-
bamate moiety, the Baylis–Hillman adduct 10 was envis-
aged to be an appropriate starting material. Thus, reaction
of the alcohol 10 with DIAD, PPh3, and N-Boc protected sul-
fonamide gave the amino enone 30 in 74% yield. The Boc
group in enone 30 was deprotected using DMSO at 150 °C
to yield the amine 31.12 Treatment of the amine 31 with
ethyl propynoate and DMAP in dry CH2Cl2 furnished the
keto-vinylogous carbamate 32 in 85% yield. Chemoselective
reduction of the enone 32 using NaBH4 and CeCl3·7H2O in
methanol at –10 °C gave the desired alcohol 33 in excellent
yield (Scheme 5).
I
O
OH
12
CO2Et
O
14
20
NHTs
Ts
I
N
I
5
6
12
59
65
CO2Et
O
15
21
Ts
N
H
N
8
CO2Et
Ts
Ts
16
O
22
Ts
Boc
N
H
O
DMSO
Ts
N
Ts
PPh3, DIAD
THF, rt, 74%
OH
150 °C
88%
N
H
N
Boc
NHTs
31
O
O
7
12
80
CO2Et
10
30
16
O
23
DMAP
CH2Cl2
85%
CO2Et
a Isolated yield.
EtO2C
EtO2C
NaBH4,
CeCl3·7H2O
N
Ts
N
Ts
An alternate sequence for the synthesis of the alkyne 29
was conceived to circumvent this problem. Towards this
end, the hydroxy group of the Baylis–Hillman adduct 6 was
MeOH
–10 °C
92%
32
33
O
HO
Scheme 5 Synthesis of alcohol bearing vinylogous carbamate 33
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

D
S. J. Gharpure et al.
Special Topic
Synthesis
Table 2 Synthesis of Iodide/Alkyne Tethered Vinylogous Carbamates
34–36
formed in comparable efficiencies with a variety of radical
precursors. In general, vinylogous carbonates proved to be
better acceptors in this tandem radical cyclization process
than the vinylogous carbamates and thus the yields were
better in the former cases.
Nu-H
DIAD, PPh3,
THF, rt
EtO2C
EtO2C
NTs
G
Y = O, NTs
G = Radical precursor
NTs
H
n-Bu3SnH,
Y
HO
Y
Z
X
EtO2C
AIBN
33
34–36
H
CO2Et
C6H6, reflux
G
X
Entry Substrate Nucleophile
Yield Iodides and alkynes
(%)a
Z
X = C, C(CH3)2
Y, Z = O, NTs
G = radical precursor
Y
17–23, 29, 34–36
37-47
dr >19:1
OH
1
33
33
62
I
EtO2C
EtO2C
EtO2C
I
O
H
H
H
H
CO2Et
H
H
13
O
O
O
N
34
Ts
O
O
O
2
65
73
NHTs
Ts
I
I
N
37, 72%
EtO2C
39, 74%
38, 61%
CO2Et
EtO2C
EtO2C
H
H
H
H
15
H
H
N
35
O
O
O
Ts
3
33
H
N
Ts
SnBu3
N
Ts
41, 67%
N
O
N
Ts
Ts
16
CO2Et
40, 60%
42, 70%
EtO2C
EtO2C
H
N
EtO2C
36
H
H
Ts
H
H
H
Ts
N
O
a Isolated yield.
O
SnBu3
H
For the installation of a radical precursor, the alcohol 33
was subjected to Mitsunobu reaction with different nucleo-
philes. Thus, Mitsunobu reaction of the alcohol 33 with
2-iodophenol (13), 2-iodo-N-tosylaniline (15), and N-tosyl-
propargylamine (16) furnished the products 34, 35, and 36,
respectively, in good yields (Table 2, entries 1–3).
N
O
SnBu3
O
Ts
43, 81%
44, 72%
45, 48%
Ts
Ts
H
N
N
EtO2C
EtO2C
SnBu3
H
H
N
N
Having the requisite radical precursors 17–23, 29, 34–
36 in hand, attention was turned towards the tandem radi-
cal cyclization reaction of these precursors.13,14 The results
are summarized in the Scheme 6.4j Slow addition of a solu-
tion of n-Bu3SnH and AIBN in benzene using syringe pump
to a refluxing solution of the iodide 17 and AIBN in ben-
zene, gratifyingly yielded the oxatriquinane 37 in 72% yield
as the only detectable diastereomer.4j The structure of the
triquinane 37 rests secured from its spectral data (see the
Supporting Information to ref 4j). Similarly, various radical
precursors were successfully employed in this reaction.
Thus, the iodide derived from iodophenol, iodonaphthol,
and protected iodoaniline also participated efficiently in
this tandem radical cyclization giving triquinanes 38–45
and 46. Not only aryl iodides but also the alkynes could act
as radical precursors and furnished the triquinanes 42–44
and 47 bearing tributylstannyl substitution. Having a gem-
dimethyl substitution on the cyclopentene ring did not af-
fect the reactivity and oxa- and azatriquinanes were
46, 49%
47, 45%
Ts
Ts
Scheme 6 Synthesis of heteroatom-substituted angular triquinanes
Heteroatom-substituted triquinanes 41, 45, and 46 are
particularly noteworthy as they incorporate spirocyclic in-
doline moiety, which is part structure of many bioactive
molecules.15–17 In all the cases, the triquinane formation
proceeded with good to moderate yields and excellent dias-
tereoselectivity.
To further confirm the structure of the triquinanes 42–
44, 47 they were subjected to proto-destannylation reac-
tion (Scheme 7). Thus, treatment of angular triquinanes 42–
44 with silica gel in CH2Cl2 furnished the heteroatom sub-
stituted angular triquinane 48–50, respectively, in good
yield. Alternatively, proto-destannylation of the vinylstan-
nanes 47 could also be achieved using 4-toluenesulfonic
acid (PTSA) in MeOH to furnish angular triquinane 51.4j
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

E
S. J. Gharpure et al.
Special Topic
Synthesis
come of the smaller five-membered rings present in the
structure, which are devoid of significant conformational
flexibility.
EtO2C
H
EtO2C
SiO2
EtO2C
H
PTSA
MeOH
R
R
H
H
H
H
CH2Cl2
Ts
R
R
N
Y
Y
rt
rt
3 days
3 days
N
SnBu3
X
H
H
X
CO2Et
Ts
H
42–44,47
51, 76%
48–50
Y
Y
H
H
X
X
CO2Et
H
EtO2C
EtO2C
EtO2C
H
H
H
H
H
O
A
B
H
O
O
Figure 4 Transition state structures for the tandem radical cyclization
reaction
N
N
O
Ts
Ts
48, 72%
49, 62%
50, 62%
To test this hypothesis, two types of substrates for radi-
cal cyclization were envisaged. To ascertain the importance
of olefin or aryl ring for getting high stereoselectivity, a
substrate devoid of olefin or aryl ring on the radical precur-
sor was prepared. On the other hand, to check the effect of
conformational flexibility, instead of starting with Baylis–
Hillman adducts of cyclopentenone derivative, it was decid-
ed to prepare substrates starting from cyclohexenone deriv-
atives. It was argued that not only these substrates will help
us to understand the stereochemical outcome better but
also expand the scope of this strategy.
The bromide 52 was thought to be a useful substrate to
test the importance of olefin or aryl ring to impart higher
stereoselectivity. The bromide 52 was readily assembled by
reacting the alcohol 12 with ethyl vinyl ether and N-bromo-
succinimide (NBS) in dry CH2Cl2. Reaction of the bromide
52 using n-Bu3SnH and AIBN in refluxing benzene, however,
furnished predominantly the simple reduction product
without cyclization. Hence, the tandem radical cyclization
was attempted using modified radical cyclization condi-
tions, which rely on generating n-Bu3SnH in situ. Reaction
of the bromide 52 with sodium cyanoborohydride, tribut-
yltin chloride, and catalytic AIBN in refluxing t-BuOH in-
deed furnished a diastereomeric mixture of ether 53. Crude
sample of the ether 53 was subjected to Jones oxidation to
furnish the dioxatriquinane 54 as a 4:1 mixture of diaste-
reomers in 56% yield over two steps (Scheme 8). Outcome
of this experiment clearly suggests that the steric interac-
tion between aryl ring/olefin moiety and the incipient
(ethoxycarbonyl)methyl group arising from vinylogous car-
bonates/carbamates is important for getting good diastere-
oselectivity. The triquinane 54 is also particularly interest-
ing as it gave an entry into lactone-bearing oxatriqui-
nanes.4j
Scheme 7 Proto-destannylation of heteroatom substituted angular
triquinanes
Stereochemical outcome of the radical cyclization reac-
tion was established based on the H NMR data. Further,
1
single crystal X-ray diffraction studies on the heteroatom
substituted triquinanes 38, 41, 46, 49, and 514j (Figure 3)
unambiguously confirmed the assigned stereochemistry of
the products. As can be noticed, the product oxa- and aza-
triquinanes 38–47 had the hydrogens on carbons cis to each
other.20
Figure 3 ORTEP picture of the oxatriquinane 494j
The stereochemical outcome of this reaction can be ra-
tionalized as follows.4j The first 5-exo-trig radical cycliza-
tion happens on the cyclopentene moiety generating the
cis-diquinane as expected. The next step of the tandem rad-
ical cyclization is the diastereoselectivity determining step.
The two diastereomers can arise from two possible transi-
tion state structures A and B. We reasoned that the transi-
tion state structure B leading to the trans-product suffers
from steric interaction between the aryl ring or the olefin
moiety and the incipient (ethoxycarbonyl)methyl group
(Figure 4). On the other hand, the transition state structure
A is free from such an interaction and hence of lower ener-
gy. Naturally, it would lead to the cis product preferentially.
We believed that the pronounced difference in the interac-
tions in transition state structures A and B could be an out-
To test the effect of conformational flexibility on the
stereochemical outcome of the tandem radical cyclization,
synthesis of the iodides 59 and 60 was undertaken. Baylis–
Hillman reaction of cyclohex-2-enone (55) using formalin
and catalytic amount of DMAP in THF furnished 2-(hy-
droxymethyl)cyclohex-2-enone (56). The alcohol 56 was
treated with ethyl propynoate in the presence of N-methyl-
morpholine in dry CH2Cl2 to obtain the corresponding viny-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

F
S. J. Gharpure et al.
Special Topic
Synthesis
crude reaction mixture. Similarly, radical cyclization on the
iodide 60 bearing a bigger naphthyl ring rather than the
phenyl ring did not improve the diastereoselectivity and
the product 62 was obtained in moderate yield and diaste-
reoselectivity (dr = 4:1) (Scheme 11).
EtO2C
EtO2C
O
O
NBS, CH2Cl2
72%
O
O
Br
HO
12
52
EtO
CO2Et
EtO2C
H
EtO2C
H
AIBN,
t-BuOH,
reflux
NaBH3CN
n-Bu3SnCl
H
H
n-Bu3SnH
O
+
O
O
EtO2C
H
EtO2C
AIBN
C6H6, reflux
65%
O
I
H
O
O
Jones reagent
acetone
H
H
dr = 4:1
O
O
59
61
61'
0 °C, 56%
(two steps)
O
O
CO2Et
O
EtO2C
H
EtO2C
H
O
OEt
54 (dr = 4:1)
53
H
H
n-Bu3SnH
Scheme 8 Synthesis of lactone bearing oxatriquinane 54
+
O
O
O
I
AIBN
C6H6, reflux
33%
O
O
dr = 4:1
logous carbonate 57 in 91% yield. Luche reduction of the
enone 57 using NaBH4 and CeCl3·7H2O in methanol at –10 °C
gave the corresponding alcohol 58 in 95% yield (Scheme 9).
60
62
62'
Scheme 11 Tandem radical cyclization of iodides 59 and 60
1. aq. HCHO
cat. DMAP
THF, rt, 64%
To further expand the scope of this tandem radical cy-
clization, it was decided to change the acceptor from vinylo-
gous carbonate/carbamate to vinylogous urea. It was
thought that the iodide 66 would be an appropriate precur-
sor to test this strategy.18,19 The synthesis of the iodide be-
gan with the Baylis–Hillman adduct 6. Protection of the hy-
droxy group of the alcohol 6 using acetic anhydride fur-
nished the acetate 63. Luche reduction of the enone 63 gave
the alcohol 64, which on Mitsunobu reaction using 2-io-
dophenol (13) gave rise to the corresponding ether and
subsequent hydrolysis of the acetate group using K2CO3
gave yielded the alcohol 65. Mitsunobu reaction of the alco-
hol 65b using N-benzoyluracil furnished the requisite io-
dide 66 in good overall yield. When the iodide 66 was sub-
jected to standard radical cyclization condition, the uracil-
fused oxatriquinane 67 was obtained in good yield and ex-
cellent diastereoselectivity (Scheme 12).4j This demonstrat-
ed that vinylogous urea could also be used as a radical ac-
ceptor in tandem radical cyclization for the synthesis of an-
gular triquinane.
CO2Et
O
CO2Et
O
NaBH4
CO2Et
2.
CeCl3·7H2O
MeOH, –10 °C
95%
O
NMM, CH2Cl2
rt, 91%
O
OH
55
57
58
Scheme 9 Synthesis of vinylogous carbonate 58 from cyclohexenone
The alcohol 58 was converted into the iodide 59 by the
Mitsunobu reaction using DIAD, PPh3, and 2-iodophenol
(13). On the other hand, when 1-iodo-2-naphthol (14) was
used as the nucleophile, the iodide 60 was obtained in 57%
yield (Scheme 10).
EtO2C
I
OH
EtO2C
OH
14
I
EtO2C
O
13
O
O
I
O
DIAD, PPh3
THF, rt
57%
DIAD, PPh3
THF, rt
68%
O
I
OH
In conclusion, a tandem 5-exo-trig radical cyclization-
based strategy for the construction of novel heterocyclic an-
gular triquinanes was developed. The heterocyclic angular
triquinanes were obtained in moderate to good yields and
excellent diastereoselectivity. This method gave access to
lactone-bearing oxatriquinanes. It was observed that the di-
astereoselectivity of cascade radical cyclization was affect-
ed by the ring size, with less flexible smaller rings giving
higher selectivity. Further, this method has been utilized for
the synthesis of conformationally constrained uracil-fused
angular triquinane.
59
58
60
Scheme 10 Synthesis of radical precursors 59 and 60
The iodides 59 and 60 were then subjected to the stan-
dardized tandem radical cyclization conditions. Thus, a
slow addition of a solution of n-Bu3SnH and AIBN in ben-
zene to a refluxing solution of the iodide 59 and AIBN in
benzene yielded the cyclized product 61 in 65% yield, albeit
with lower diastereoselectivity (dr = 4:1). The diastereose-
1
lectivity was determined based on H NMR analysis of the
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

G
S. J. Gharpure et al.
Special Topic
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.58 (d, J = 12.8 Hz, 1 H), 5.76–5.70 (m,
1 H), 5.23 (d, J = 12.8 Hz, 1 H), 4.80–4.78 (m, 1 H), 4.73–4.67 (m, 1 H),
4.53–4.40 (m, 2 H), 4.15 (q, J = 7.2 Hz, 2 H), 3.67–3.53 (m, 2 H), 3.47–
3.32 (m, 2 H), 2.10 (ABX, J = 13.6, 7.2 Hz, 1 H), 1.79 (ABX, J = 13.6, 4.4
Hz, 1 H), 1.30–1.18 (m, 6 H), 1.14 (m, 3 H), 1.06 (m, 3 H).
13C NMR (100 MHz, CDCl3, DEPT): δ = 167.90 (C), 162.15 (CH), 144.39
(CH), 135.82 (C), 102.63 (CH), 97.19 (CH), 80.38 (CH), 67.54 (CH2),
61.68 (CH2), 59.93 (CH2), 46.24 (CH2), 43.90 (C), 32.13 (CH2), 29.63
(CH3), 28.82 (CH3), 15.38 (CH3), 14.47 (CH3).
NaBH4
CeCl3·7H2O
Ac2O, DMAP
Et3N, CH2Cl2
70%
OH
OAc
OAc
MeOH, –10 °C
74%
O
O
OH
6
63
64
1. 2-Iodophenol
PPh3 , DIAD
2. K2CO3
MeOH
80%
THF, rt
63%
O
O
Bz
O
Bz
O
Bz
N
N
N
OR
HRMS (ESI): m/z [M + H]+ calcd for C17H28O5Br: 391.1120; found:
391.1121.
n-Bu3SnH
AIBN
H
N
H
O
O
N
H
N
C6H6, reflux
55%
PPh3, DIAD,
THF, 0 °C to rt
71%
O
2-(Hydroxymethyl)-4,4-dimethylcyclopent-2-enone (10)
I
O
O
Reaction of 4,4-dimethylcyclopent-2-enone (9; 800 mg, 7.27 mmol)
with aq HCHO (2.2 mL, 29.08 mmol) and DMAP (89 mg, 0.73 mmol)
in THF (20 mL) at rt as described for the alcohol 64j followed by purifi-
cation of the residue by column chromatography (silica gel,
EtOAc/hexanes, 1:4) gave the alcohol 10 (260 mg, 26%) as a colorless
liquid; Rf = 0.5 (EtOAc/hexanes, 1:4).
67
(dr > 19:1)
66
65a: R = OAc
65b: R = H
I
Scheme 12 Synthesis of uracil-fused oxatriquinane 67
IR (neat): 3414, 2960, 2928, 2868, 1699, 1641, 1463, 1409, 1364,
1347, 1294, 1206, 1154, 1084, 1003 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.25 (t, J = 1.6 Hz, 1 H), 4.30 (d, J = 1.2
Hz, 2 H), 2.31 (br s, 1 H), 2.30 (s, 2 H), 1.21 (s, 6 H).
13C NMR (100 MHz, CDCl3, DEPT): δ = 209.70 (C), 168.26 (CH), 141.84
.
Melting points are recorded using sigma melting point apparatus in
capillary tubes and are uncorrected. IR spectra were recorded on
Nicolet 6700 spectrophotometer and Jasco FT-IR-4100 spectropho-
1
tometer. H (400 MHz) and 13C (100 MHz) spectra were recorded on
Bruker Avance 400 spectrometer and 1H (500 MHz) and 13C (125
MHz) spectra were recorded on Bruker Avance 500 spectrometer
both referenced to residual CHCl3. In the 13C NMR spectra, the nature
of the carbons (C, CH, CH2 or CH3) was determined by recording the
DEPT-135 experiment and is given in parentheses. CHN analysis was
carried out using Elemental analyser VSM-VT. HRMS measurements
were carried out using MicromassQ-ToF instrument using direct inlet
mode. Analytical TLC was performed on glass plates (7.5 × 2.5 and
7.5 × 5.0 cm) coated with Merck silica gel G containing 13% CaSO4 as
binder or on pre-coated 0.2 mm thick Merck 60 F245 silica plates and
various combinations of EtOAc and hexane were used as eluent. Visu-
alization of spots was accomplished by exposure to I2 vapor and UV
light. All compounds were purified using silica gel [Acme silica gel
(100–200 mesh)] column chromatography. All small-scale dry reac-
tions were carried out using standard syringe septum technique. Dry
THF was obtained by distillation over Na/benzophenone ketyl. Dry
CH2Cl2 and DMF were prepared by distilling over CaH2. AIBN obtained
from spectrochem was recrystallized from Et2O and stored at 0–5 °C
in the dark. All the commercial reagents were used as such without
further purification. Compounds 7, 8, 17, 37–47, 53, 54, 67, were pre-
viously reported by us.4j
(C), 57.34 (CH2), 50.90 (CH2), 39.49 (C), 28.12 (2 CH3).
HRMS (ESI): m/z [M + H]+ calcd for C8H13O2: 141.0916; found:
141.0912.
Ethyl (E)-3-[(3,3-Dimethyl-5-oxocyclopent-1-enyl)methoxy]acry-
late (11); Typical Procedure 1 (TP1)
Following the procedure for 7.4j To a magnetically stirred solution of
10 (230 mg, 1.64 mmol) in CH2Cl2 (5 mL) were added ethyl propy-
noate (183 μL, 1.81 mmol) and NMM (197 μL, 1.81 mmol) at rt and
the mixture was stirred for 4 h (TLC control). Evaporation of the sol-
vent and purification of the residue by column chromatography (sili-
ca gel, EtOAc/hexanes, 1:9) gave the vinylogous carbonate 11 (265 mg,
69%) as a colorless liquid; Rf = 0.5 (EtOAc/hexanes, 1:5).
IR (neat): 2960, 1707, 1624, 1462, 1405, 1367, 1325, 1284, 1204,
1132, 1049 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.57 (d, J = 12.4 Hz, 1 H), 7.35 (t, J = 1.2
Hz, 1 H), 5.25 (d, J = 12.4 Hz, 1 H), 4.50 (d, J = 1.2 Hz, 2 H), 4.15 (q,
J = 7.2 Hz, 2 H), 2.32 (s, 2 H) 1.27 (s, 3 H), 1.25 (s, 3 H), 1.23 (s, 3 H).
13C NMR (100 MHz, CDCl3, DEPT): δ = 206.99 (C), 169.58 (CH), 167.55
(C), 161.77 (CH), 137.78 (C), 97.86 (CH), 64.59 (CH2), 59.97 (CH2),
50.66 (CH2), 39.78 (C), 28.11 (2 CH3), 14.44 (CH3).
Ethyl (E)-3-{[(5S*)-5-(2-bromo-1-ethoxyethoxy)-3,3-dimethylcy-
clopent-1-en-1-yl]methoxy}acrylate (52)
HRMS (ESI): m/z [M + H]+ calcd for C13H19O4: 239.1283; found:
239.1286.
To a magnetically stirred solution of the N-bromosuccinimide (166
mg, 0.92 mmol) in dry CH2Cl2 (5 mL) was added ethoxyethene (152
μL, 2.1 mmol), and cooled the reaction mixture to 0 °C. To this, alco-
hol 34 (202 mg, 0.84 mmol) in dry CH2Cl2 (5 mL) was added dropwise
and allowed to stir for 6 h. Evaporation of the solvent and purification
of the residue on a silica gel column using ethyl acetate/hexanes (1:9)
as eluent furnished the bromoacetal 52 (238 mg, 73%) as a colorless
liquid; Rf = 0.6 (EtOAc/hexanes, 1:9).
Ethyl (E)- 3-[(5-Hydroxy-3,3-dimethylcyclopent-1-enyl)me-
thoxy]acrylate (12); Typical Procedure 2 (TP2)
Following the procedure for 8.4j To a cold –10 °C, magnetically stirred
solution of 11 (265 mg, 1.11 mmol) and CeCl3·7H2O (438 g, 1.34
mmol) in MeOH (10 mL) was added NaBH4 (51 mg, 1.34 mmol) por-
tionwise. The solvent was removed under reduced pressure and the
residue was extracted with EtOAc. The organic layer was washed with
brine and dried (anhyd Na2SO4). The solvent was evaporated under
IR (neat): 3089, 3033, 2960, 2931, 2870, 1710, 1627, 1459, 1373,
1326, 1284, 1234, 1198, 1131, 1049 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

H
S. J. Gharpure et al.
Special Topic
Synthesis
reduced pressure and the residue was purified by column chromatog-
raphy (silica gel, EtOAc/hexanes, 1:5) to furnish the alcohol 12 (245
mg, 92%) as a colorless liquid; Rf = 0.5 (EtOAc/hexanes, 1:5).
13C NMR (100 MHz, CDCl3, DEPT): δ = 167.91 (C), 162.19 (CH), 155.59
(C), 137.74 (C), 135.88 (CH), 135.37 (C), 131.47 (CH), 130.41 (CH),
130.10 (C), 128.31 (CH), 128.24 (CH), 124.63 (C), 115.31 (CH), 97.51
(CH), 89.54 (C), 84.95 (CH), 67.88 (CH2), 59.93 (CH2), 31.24 (CH2),
30.91 (CH2), 14.46 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C21H22O4I: 465.0563; found:
465.0573.
IR (neat): 3434, 2955, 2868, 1703, 1629, 1457, 1373, 1324, 1288,
1197, 1137, 1047 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 12.8 Hz, 1 H), 5.72 (s, 1 H),
5.25 (d, J = 12.4 Hz, 1 H), 4.83 (dd, J = 7.2, 4.4 Hz, 1 H), 4.48 (q, J = 12.4
Hz, 2 H), 4.15 (q, J = 7.2 Hz, 2 H), 2.17 (ABX, J = 13.6, 7.2 Hz, 1 H), 1.62
(ABX, J = 13.6, 4.0 Hz, 1 H), 1.26 (t, J = 7.2 Hz, 3 H), 1.54 (s, 3 H), 1.05
(s, 3 H).
Ethyl (E)- 3-{[5-(1-Iodonaphthalen-2-yloxy)-3,3-dimethylcyclo-
pent-1-enyl]methoxy}acrylate (20)
13C NMR (100 MHz, CDCl3, DEPT): δ = 167.98 (C), 162.25 (CH), 143.58
(CH), 137.35 (C), 97.23 (CH), 76.72 (CH), 67.97 (CH2), 59.99 (CH2),
49.64 (CH2), 43.60 (CH2), 29.96 (CH3), 28.88 (CH3), 14.46 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C13H21O4: 241.1440; found:
241.1435.
Reaction of the alcohol 12 (108 mg, 0.45 mmol) with PPh3 (236 mg,
0.90 mmol), 1-iodo-2-naphthol (14; 182 mg, 0.68 mmol), and DIAD
(177 μL, 0.90 mmol) in THF (3 mL) at rt for 6 h as described for TP3
and purification of the residue by column chromatography (silica gel,
EtOAc/hexanes, 1:9) furnished the iodide 20 (135 mg, 65%) as a color-
less liquid; Rf = 0.5 (EtOAc/hexanes, 1:9).
IR (neat): 2954, 2865, 1703, 1620, 1592, 1554, 1499, 1459, 1427,
Ethyl (E)- 3-{[5-(2-Iodophenoxy)-3,3-dimethylcyclopent-1-
enyl]methoxy}acrylate (18); Typical Procedure 3 (TP3)
1323, 1260, 1235, 1122, 1040, 1019, 1005 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.13 (d, J = 8.8 Hz, 1 H), 7.79 (d, J = 9.2
Hz, 1 H), 7.73 (d, J = 8.0 Hz, 1 H), 7.61 (d, J = 12.8 Hz, 1 H), 7.53 (t,
J = 8.0 Hz, 1 H), 7.38 (t, J = 8.0 Hz, 1 H), 7.15 (d, J = 8.8 Hz, 1 H), 5.94 (s,
1 H), 5.44 (dd, J = 7.2, 3.2 Hz, 1 H),) 5.30 (d, J = 12.4 Hz, 1 H), 4.70 (AB,
J = 12.8 Hz, 1 H), 4.65 (AB, J = 12.8 Hz, 1 H), 4.12 (q, J = 7.2 Hz, 2 H),
2.31 (ABX, J = 14.0, 7.2 Hz, 1 H), 2.02 (ABX, J = 13.6, 3.2 Hz, 1 H), 1.26
(s, 3 H), 1.23 (t, J = 7.2 Hz, 3 H), 1.17 (s, 3 H).
13C NMR (100 MHz, CDCl3, DEPT): δ = 167.87 (C), 162.14 (CH), 155.58
(C), 145.18 (CH), 135.90 (CH), 134.84 (C), 131.44 (CH), 130.32 (CH),
130.00 (C), 128.29 (CH), 128.22 (CH), 124.54 (C), 114.98 (CH), 97.46
(CH), 89.21 (C), 84.19 (CH), 67.79 (CH2), 59.90 (CH2), 46.65 (CH2),
44.55 (C), 29.69 (CH3), 28.99 (CH3), 14.44 (CH3).
Following the procedure for 17.4j To a magnetically stirred solution of
the alcohol 12 (146 mg, 0.60 mmol) in THF (5 mL) were added succes-
sively PPh3 (319 mg, 1.22 mmol) and 2-iodophenol (13; 161 mg, 0.72
mmol), followed by dropwise addition of DIAD (239 μL, 1.22 mmol)
over a period of 10 min at rt. The mixture was stirred at rt for 6 h (TLC
control). The solvent was evaporated under reduced pressure and the
residue was purified by column chromatography (silica gel, EtOAc/
hexanes, 1:9) to furnish the iodide 18 (138 mg, 54%) as a colorless liq-
uid; Rf = 0.5 (EtOAc/hexanes, 1:9).
IR (neat): 2957, 2865, 1709, 1628, 1584, 1468, 1369, 1322, 1280,
1238, 1131, 1045 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.76 (dd, J = 7.6, 1.6 Hz, 1 H), 7.59 (d,
J = 12.4 Hz, 1 H), 7.29–7.25 (m, 2 H), 6.79 (dd, J = 8.4, 1.2 Hz, 1 H), 6.70
(td, J = 7.6, 1.2 Hz, 1 H), 5.90 (s, 1 H), 5.28 (d, J = 12.4 Hz, 1 H), 5.26
(dd, J = 6.8, 3.2 Hz, 1 H), 4.60 (s, 1 H), 4.14 (q, J = 7.2 Hz, 2 H), 2.26
(ABX, J = 13.6, 7.2 Hz, 1 H), 1.91 (ABX, J = 13.6, 3.2 Hz, 1 H), 1.25 (t,
J = 7.2 Hz, 3 H), 1.22 (s, 3 H), 1.15 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C23H26O4I: 493.0876; found:
493.0886.
Ethyl (E)- 3-({5-[N-(2-Iodophenyl)-4-methylphenylsulfonamido]-
3,3-dimethylcyclopent-1-enyl}methoxy)acrylate (21)
13C NMR (100 MHz, CDCl3, DEPT): δ = 167.93 (C), 162.19 (CH), 156.95
(C), 145.10 (CH), 139.73 (CH), 134.72 (C), 129.49 (CH), 122.66 (CH),
113.23 (CH), 97.45 (CH), 87.49 (C), 83.27 (CH), 67.73 (CH2), 59.93
(CH2), 46.33 (CH2), 44.56 (C), 29.72 (CH3), 28.98 (CH3), 14.49 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C19H24O4I: 443.0719; found:
443.0712.
Reaction of the alcohol 12 (106 mg, 0.44 mmol) with PPh3 (231 mg,
0.88 mmol), 2-iodo-N-tosylaniline (15; 181 mg, 0.49 mmol), and
DIAD (174 μL, 0.88 mmol) in THF (5 mL) at rt for 6 h as described for
TP3 and purification of the residue by column chromatography (silica
gel, EtOAc/hexanes, 1:9) furnished the iodide 21 (155 mg, 59%) as a
colorless liquid; Rf = 0.4 (EtOAc/hexanes, 1:9).
IR (neat): 2981, 2958, 2868, 2306, 1705, 1624, 1577, 1493, 1464,
1398, 1367, 1347, 1327, 1266, 1200, 1161, 1137, 1092, 1049, 1021
Ethyl (E)- 3-{[5-(1-Iodonaphthalen-2-yloxy)cyclopent-1-enyl]me-
thoxy}acrylate (19)
cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.93 (dd, J = 6.4, 1.2 Hz, 1 H), 7.62 (d,
J = 6.8 Hz, 2 H), 7.55 (d, J = 10.4 Hz, 1 H), 7.35 (td, J = 6.4, 1.2 Hz, 1 H),
7.27 (d, J = 7.2 Hz, 2 H), 7.10–7.05 (m, 2 H), 5.69 (br s, 1 H), 5.27 (dd,
J = 7.2, 4.4 Hz, 1 H), 5.05 (d, J = 10.0 Hz, 1 H), 4.26–4.14 (m, 4 H), 2.43
(s, 3 H), 2.20 (ABX, J = 11.6, 7.6 Hz, 1 H), 2.05 (ABX, J = 11.6, 4.4 Hz, 1
H), 1.30 (t, J = 5.6 Hz, 3 H), 0.96 (s, 3 H), 0.48 (s, 3 H).
Reaction of the alcohol 8 (151 mg, 0.72 mmol) with PPh3 (374 mg,
1.43 mmol), 1-iodo-2-naphthol (14; 211 mg, 0.78 mmol), and DIAD
(281 μL, 1.43 mmol) in THF (4 mL) at rt for 6 h as described TP3 and
purification of the residue by column chromatography (silica gel, EtO-
Ac/hexanes, 1:9) furnished the iodide 19 (206 mg, 62%) as a colorless
liquid; Rf = 0.5 (EtOAc/hexanes, 1:9).
13C NMR (125 MHz, CDCl3, DEPT): δ = 167.84 (C), 162.04 (CH), 145.56
(CH), 144.21 (C), 143.85 (CH), 141.09 (CH), 139.64 (C), 138.07 (C),
134.15 (C), 133.04 (CH), 130.38 (CH), 129.78 (2 CH), 128.95 (CH),
128.43 (2 CH), 106.49 (C), 97.14 (CH), 68.14 (CH2), 59.97 (CH2), 43.17
(CH2), 42.65 (C), 29.51 (CH3), 27.90 (CH3), 21.69 (CH3), 14.54 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C26H31NO5SI: 596.0968; found:
596.0957.
IR (neat): 3063, 2976, 2929, 2864, 1781, 1703, 1625, 1499, 1457,
1388, 1328, 1270, 1235, 1129, 1046 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.13 (d, J = 8.8 Hz, 1 H), 7.80 (d, J = 8.8
Hz, 1 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.60 (d, J = 12.4 Hz, 1 H), 7.54 (t,
J = 7.2 Hz, 1 H), 7.38 (t, J = 7.2 Hz, 1 H), 7.19 (d, J = 8.8 Hz, 1 H), 6.15 (s,
1 H), 5.44 ((t, J = 4.8 Hz, 1 H),) 5.30 (d, J = 12.8 Hz, 1 H), 4.75 (AB,
J = 12.8 Hz, 1 H), 4.71 (AB, J = 12.8 Hz, 1 H), 4.16 (q, J = 7.2 Hz, 2 H),
2.72–2.63 (m, 1 H), 2.56–2.42 (m, 2 H), 2.19–2.10 (m, 1 H), 1.23 (t,
J = 7.2 Hz, 3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

I
S. J. Gharpure et al.
Special Topic
Synthesis
Ethyl (E)- 3-({5-[4-Methyl-N-(prop-2-ynyl)phenylsulfonamido]cy-
clopent-1-enyl}methoxy)acrylate (22)
1H NMR (400 MHz, CDCl3): δ = 7.04 (s, 1 H), 4.61–4.58 (m, 2 H), 4.21–
4.17 (m, 1 H), 3.83–3.77 (m, 1 H), 3.40–3.36 (m, 1 H), 1.93–1.90 (m, 2
H), 1.82–1.79 (m, 2 H), 1.76–1.67 (m, 1 H), 1.59–1.55 (m, 2 H), 1.38–
1.32 (m, 1 H), 1.31–1.21 (m, 2 H).
13C NMR (100 MHz, CDCl3, DEPT): δ = 206.52 (C), 157.75 (CH), 143.80
(C), 98.54 (CH), 61.69 (CH2), 61.46 (CH2), 34.62 (CH2), 30.81 (CH2),
26.52 (CH2), 25.76 (CH2), 19.55 (CH2).
Reaction of the alcohol 8 (60 mg, 0.28 mmol) with PPh3 (148 mg, 0.57
mmol), N-tosylpropargylamine (16; 71 mg, 0.34 mmol), and DIAD
(108 μL, 0.57 mmol) in THF (2 mL) at rt for 6 h as described for TP3
and purification of the residue by column chromatography (silica gel,
EtOAc/hexanes, 1:4) furnished the alkyne 22 (74 mg, 65%) as a color-
less liquid; Rf = 0.5 (EtOAc/hexanes, 1:4).
HRMS (ESI): m/z [M + H]+ calcd for C11H17O3: 197.1178; found:
IR (neat): 3303, 2982, 2934, 1714, 1631, 1504, 1462, 1381, 1331,
197.1168.
1235, 1154, 1120, 1043 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.79 (d, J = 8.4 Hz, 2 H), 7.46 (d, J = 12.4
Hz, 1 H), 7.28 (d, J = 8.4 Hz, 2 H), 6.05 (s, 1 H), 5.06 (d, J = 12.8 Hz, 1 H),
5.00–4.97 (m, 1 H), 4.24–4.12 (m, 5 H), 3.91 (d, J = 2.4 Hz, 2 H), 2.49–
2.43 (m, 1 H), 2.42 (s, 3 H), 2.17–2.10 (m, 2 H), 1.93–1.89 (m, 1 H),
1.28 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3, DEPT): δ = 167.79 (C), 161.99 (CH), 143.76
(C), 137.51 (C), 135.99 (CH), 129.70 (2 CH), 127.61 (2 CH), 97.10 (CH),
79.81 (C), 72.29 (C), 67.32 (CH2), 63.68 (CH), 59.97 (CH2), 32.24 (CH2),
31.14 (CH2), 27.62 (CH2), 21.95 (CH), 21.65 (CH3), 14.48 (CH3).
2-[(Tetrahydro-2H-pyran-2-yloxy)methyl]cyclopent-2-enol (26)
Reduction of 25 (120 mg, 0.61 mmol) using NaBH4 (28 mg, 0.73
mmol) and CeCl3·7H2O (241 mg, 0.73 mmol) in MeOH (10 mL) at
–10 °C as described for TP2 followed by purification of the residue by
column chromatography (silica gel, EtOAc/hexanes, 1:9) furnished the
alcohol 26 (99 mg, 84%) as a colorless liquid; Rf = 0.5 (EtOAc/hexanes,
1:9).
IR (neat): 3418, 2941, 2859, 1656, 1448, 1386, 1351, 1321, 1267,
1204, 1125, 1030 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C21H26NO5S: 404.1532; found:
404.1535.
1H NMR (400 MHz, CDCl3): δ = 5.62–5.61 (m, 1 H), 4.81–4.93 (m, 1 H),
4.62 (t, J = 3.2 Hz, 1 H), 4.52–4.49 (m, 1 H), 4.46–4.42 (m, 1 H), 4.12
(dd, J = 12.4, 5.2 Hz, 1 H), 3.82–3.73 (m, 1 H), 3.38–3.31 (m, 1 H),
2.10–2.09 (m, 1 H), 2.08–1.96 (m, 2 H), 1.83–1.76 (m, 1 H), 1.68–1.61
(m, 1 H), 1.53–1.49 (m, 2 H), 1.33–1.27 (m, 1 H), 1.26–1.22 (m, 2 H).
Ethyl (E)- 3-({3,3-Dimethyl-5-[4-methyl-N-(prop-2-ynyl)phenyl-
sulfonamido]cyclopent-1-enyl}methoxy)acrylate (23)
13C NMR (100 MHz, CDCl3, DEPT): δ = 143.87 (C), 130.60 (CH), 98.50
(CH), 78.00 (CH), 64.99 (CH2), 62.18 (CH2), 34.05 (CH2), 30.97 (CH2),
30.32 (CH2), 25.74 (CH2), 19.82 (CH2).
HRMS (ESI): m/z [M + Na]+ calcd for C11H18O3Na: 221.1154; found:
221.1146.
Reaction of the alcohol 12 (108 mg, 0.45 mmol) with PPh3 (236 mg,
0.90 mmol), N-tosylpropargylamine (16; 141 mg, 0.68 mmol), and
DIAD (177 μL, 0.90 mmol) in THF (3 mL) at rt for 6 h as described for
TP3 and purification of the residue by column chromatography (silica
gel, EtOAc/hexanes, 1:4) furnished the alkyne 23 (155 mg, 80%) as a
colorless liquid; Rf = 0.4 (EtOAc/hexanes, 1:4).
IR (neat): 3273, 2956, 2868, 1754, 1704, 1621, 1454, 1333, 1281,
2-{[5-(Prop-2-ynyloxy)cyclopent-1-enyl]methoxy}tetrahydro-2H-
pyran (27)
1199, 1163, 1126, 1092, 1065, 1046, 1017 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 8.4 Hz, 2 H), 7.44 (d, J = 12.4
Hz, 1 H), 7.28 (d, J = 8.4 Hz, 2 H), 5.77 (d, J = 1.2 Hz, 1 H), 5.08–5.02 (m,
2 H), 4.20–4.10 (m, 4 H), 4.01 (ABX, J = 18.4, 2.4 Hz, 1 H), 3.89 (ABX,
J = 18.4, 2.4 Hz, 1 H), 2.42 (s, 3 H), 2.18 (t, J = 2.4 Hz, 1 H), 1.97 (ABX,
J = 14.4, 8.8 Hz, 1 H), 1.78 (ABX, J = 14.4, 6.4 Hz, 1 H), 1.27 (t, 3 H), 1.12
(s, 3 H), 1.02 (s, 3 H).
13C NMR (100 MHz, CDCl3, DEPT): δ = 167.73 (C), 161.92 (CH), 145.11
(CH), 143.72 (C), 137.54 (C), 133.26 (C), 129.67 (2 CH), 127.57 (2 CH),
97.06 (CH), 79.90 (C), 72.80 (C), 67.23 (CH2), 64.08 (CH), 59.93 (CH2),
43.40 (C), 42.24 (CH2), 32.28 (CH2), 29.24 (CH), 21.82 (CH3), 21.63
(CH3), 14.48 (CH3).
To a cold (0 °C) magnetically stirred suspension of NaH (85 mg 60% in
mineral oil, 1.29 mmol) in dry DMF (2 mL), a solution of the alcohol
26 (235 mg, 1.19 mmol) in dry DMF (3 mL) was added and the mix-
ture was stirred at rt for 30 min. 80% Propargyl bromide in toluene
(264 μL, 2.37 mmol) was added slowly over a period of 15–20 min
and the mixture was stirred overnight at rt. The reaction was
quenched with water at 0 °C and extracted with Et2O. The combined
organic layer was washed with brine and dried (anhyd Na2SO4). Evap-
oration of the solvent under reduced pressure and purification of the
residue by column chromatography (silica gel, EtOAc/hexanes, 1:19)
furnished the propargyl ether 27 (245 mg, 88%) as a colorless liquid;
Rf = 0.5 (EtOAc/hexanes, 1:19).
HRMS (ESI): m/z [M + H]+ calcd for C23H30NO5S: 432.1845; found:
IR (neat): 3287, 3260, 2941, 2855, 2115, 1450, 1353, 1263, 1202,
432.1853.
1179, 1120, 1075, 1029 cm–1
.
2-[(Tetrahydro-2H-pyran-2-yloxy)methyl]cyclopent-2-enone (25)
1H NMR (400 MHz, CDCl3): δ = 5.77 (t, J = 2.8 Hz, 1 H), 4.73 (t, J = 2.8
Hz, 1 H), 4.69–4.58 (m, 2 H), 4.58–4.52 (m, 1 H), 4.19 (t, J = 10.8 Hz, 1
H), 4.03–3.90 (m, 2 H), 3.89–3.78 (m, 2 H), 3.44–3.63 (m, 1 H), 2.02–
2.01 (m, 1 H), 1.96–1.86 (m, 1 H), 1.84–1.72 (m, 2 H), 1.67–1.58 (m, 2
H), 1.42–1.35 (m, 1 H), 1.34–1.22 (m, 2 H).
13C NMR (100 MHz, CDCl3, DEPT): δ = 142.35 (C), 130.78 (CH), 98.39
(CH), 83.94 (CH), 81.15 (C), 73.84 (CH), 64.22 (CH2), 63.50 (CH2), 61.39
(CH2), 56.34 (CH2), 30.92 (CH2), 30.33 (CH2), 25.90 (CH2), 19.49 (CH2).
To a magnetically stirred solution of 2-(hydroxymethyl)cyclopent-2-
enone (6; 109 mg, 0.97 mmol) in CH2Cl2 (5 mL) was added PPTS (49
mg, 0.19 mmol) at 0 °C followed by addition of dihydropyran (155 μL,
1.71 mmol) and the mixture was stirred for 12 h (TLC control). Evapo-
ration of the solvent and purification of the residue by column chro-
matography (silica gel, EtOAc/hexanes, 1:9) furnished the product 25
(156 mg, 82%) as a colorless liquid; Rf = 0.5 (EtOAc/hexanes, 1:9).
HRMS (ESI): m/z [M + Na]+ calcd for C14H20O3Na: 259.1310; found:
259.1320.
IR (neat): 2943, 2868, 1700, 1641, 1559, 1540, 1523, 1453, 1442,
1356, 1288, 1257, 1200, 1123, 1076, 1025 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

J
S. J. Gharpure et al.
Special Topic
Synthesis
[5-(Prop-2-ynyloxy)cyclopent-1-enyl]methanol (28)
N-[(3,3-Dimethyl-5-oxocyclopent-1-enyl)methyl]-4-methylben-
zenesulfonamide (31)
To a magnetically stirred solution of 27 (140 mg, 0.59 mmol) in MeOH
(5 mL) was added PPTS (140 mg, 0.59 mmol) at rt and the mixture
was stirred for overnight (TLC control). Evaporation of the solvent and
purification of the residue by column chromatography (silica gel, EtO-
Ac/hexanes, 1:4) furnished the product 28 (48 mg, 53%) as a colorless
liquid; Rf = 0.5 (EtOAc/hexanes, 1:4).
A magnetically stirred solution of the carbamate 30 (140 mg, 0.36
mmol) in DMSO (3 mL) was heated at 150 °C and the mixture was
stirred for 1.5 h (TLC control). The mixture was diluted with water
and extracted with Et2O. The organic layer was washed with brine
and dried (anhyd Na2SO4). The solvent was evaporated under reduced
pressure and purification of the residue by column chromatography
(silica gel, EtOAc/hexanes, 3:7) furnished the amine 31 (94 mg, 88%)
as a colorless solid; Rf = 0.5 (EtOAc/hexanes, 3:7); mp 76–78 °C.
IR (neat): 3633, 3551, 3466, 2987, 2087, 1559, 1451, 1376, 1243,
1051 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.87 (s, 1 H), 4.79–4.75 (m, 1 H), 4.27
(br s, 2 H), 4.24 (ABX, J = 15.6, 2.4 Hz, 1 H), 4.12 (ABX, J = 15.6, 2.0 Hz,
1 H), 2.52–2.45 (m, 1 H), 2.42 (t, J = 2.4 Hz, 1 H), 2.30–2.29 (m, 1 H),
2.26–2.18 (m, 1 H), 1.94–1.85 (m, 1 H), 1.70–1.67 (m, 1 H).
13C NMR (100 MHz, CDCl3, DEPT): δ = 143.06 (C), 131.48 (CH), 84.96
(CH), 80.37 (C), 74.25 (C), 60.54 (CH2), 56.36 (CH2), 30.34 (CH2), 30.14
(CH2).
IR (neat): 3270, 2959, 2921, 2866, 1690, 1641, 1598, 1495, 1435,
1409, 1326, 1306, 1289, 1207, 1185, 1155, 1093, 1019 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.71 (d, J = 8.0 Hz, 2 H), 7.29 (d, J = 8.0
Hz, 2 H), 7.11 (s, 1 H), 3.77 (d, J = 5.6 Hz, 2 H), 2.41 (s, 3 H), 2.16 (s, 2
H), 1.10 (s, 6 H).
13C NMR (100 MHz, CDCl3, DEPT): δ = 208.75 (C), 169.35 (CH), 143.59
(C), 137.82 (C), 137.05 (C), 129.81 (2 CH), 127.24 (2 CH), 50.42 (CH2),
39.37 (C), 38.84 (CH2), 27.80 (2 CH3), 21.54 (CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C9H12O2Na: 175.0735; found:
175.0741.
HRMS (ESI): m/z [M + H]+ calcd for C15H20NO3S: 294.1164; found:
294.1169.
Ethyl (E)- 3-{[5-(Prop-2-ynyloxy)cyclopent-1-enyl]methoxy}acry-
late (29)
Ethyl (E)- 3-{N-[(3,3-Dimethyl-5-oxocyclopent-1-enyl)methyl]-4-
methylphenylsulfonamido}acrylate (32)
Reaction of 28 (45 mg, 0.30 mmol) with ethyl propynoate (33 μL, 0.33
mmol) and NMM (35 μL, 0.33 mmol) in CH2Cl2 (3 mL) at rt as de-
scribed TP1 followed by purification of the residue by column chro-
matography (silica gel, EtOAc/hexanes, 1:9) gave the vinylogous car-
bonate 29 (70 mg, 91%) as a colorless liquid; Rf = 0.5 (EtOAc/hexanes,
1:9).
Reaction of 31 (92 mg, 0.31 mmol) with ethyl propynoate (35 μL, 0.34
mmol) and DMAP (7 mg, 0.06 mmol) in CH2Cl2 (3 mL) at rt as de-
scribed for TP1 followed by purification of the residue by column
chromatography (silica gel, EtOAc/hexanes, 1:9) gave the vinylogous
carbonate 32 (110 mg, 85%) as a colorless liquid; Rf = 0.5 (EtOAc/hex-
anes, 1:9).
IR (neat): 2986, 2944, 2909, 2085, 1889, 1742, 1642, 1626, 1448,
1374, 1301, 1243, 1098, 1048 cm–1
.
IR (neat): 2959, 2922, 2869, 1702, 1620, 1597, 1493, 1447, 1364,
1H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 12.4 Hz, 1 H), 5.97 (br s, 1
H), 5.26 (d, J = 12.4 Hz, 1 H), 4.69 (t, J = 3.6 Hz, 1 H), 4.50 (br s, 2 H),
4.21–4.09 (m, 4 H), 2.54–2.46 (m, 1 H), 2.42 (m, 1 H), 2.35–2.29 (m, 1
H), 2.26–2.17 (m, 1 H), 1.95–1.87 (m, 1 H), 1.26 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3, DEPT): δ = 167.98 (C), 162.43 (CH), 138.60
(C), 134.33 (CH), 97.28 (CH), 83.40 (CH), 80.32 (C), 74.24 (C), 67.83
(CH2), 59.91 (CH2), 56.59 (CH2), 30.53 (CH2), 29.89 (CH2), 14.50 (CH3).
1283, 1255, 1152, 1089, 1062 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.12 (d, J = 14.0 Hz, 1 H), 7.70 (d, J = 8.4
Hz, 2 H), 7.33 (d, J = 8.4 Hz, 2 H), 7.02 (d, J = 1.2 Hz, 1 H), 4.90 (d,
J = 14.0 Hz, 1 H), 4.18–4.12 (m, 4 H), 2.43 (s, 3 H), 2.29 (s, 2 H), 1.26 (t,
J = 7.2 Hz, 3 H), 1.13 (s, 6 H).
13C NMR (100 MHz, CDCl3, DEPT): δ = 207.46 (C), 169.53 (CH), 167.03
(C), 145.26 (C), 141.08 (CH), 135.75 (C), 135.10 (C), 130.41 (2 CH),
127.41 (2 CH), 99.05 (CH), 60.35 (CH2), 50.63 (CH2), 41.47 (CH2), 39.59
(C), 28.05 (2 CH3), 21.73 (CH3), 14.46 (CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C14H18O4Na: 273.1103; found:
273.1109.
HRMS (ESI): m/z [M + H]+ calcd for C20H26NO5S: 392.1532; found:
392.1515.
tert-Butyl [(3,3-Dimethyl-5-oxocyclopent-1-enyl)methyl](to-
syl)carbamate (30)
Reaction of the alcohol 10 (225 mg, 1.61 mmol) with PPh3 (842 mg,
3.21 mmol), tert-butyl tosylcarbamate (479 mg, 1.77 mmol), and
DIAD (633 μL, 3.21 mmol) in THF (5 mL) at rt for 12 h as described for
TP3 and purification of the residue by column chromatography (silica
gel, EtOAc/hexanes, 1:4) furnished the carbamate 30 (423 mg, 74%) as
a colorless solid; Rf = 0.5 (EtOAc/hexanes, 1:4); mp 92–94 °C.
Ethyl (E)- 3-{N-[(5-Hydroxy-3,3-dimethylcyclopent-1-enyl)meth-
yl]-4-methylphenylsulfonamido}acrylate (33)
Reduction of 32 (85 mg, 0.21 mmol) using NaBH4 (10 mg, 0.26 mmol)
and CeCl3·7H2O (85 g, 0.26 mmol) in MeOH (5 mL) at –10 °C as de-
scribed for TP2 followed by purification of the residue by column
chromatography (silica gel, EtOAc/hexanes, 3:7) furnished the alcohol
33 (80 mg, 92%) as a colorless liquid; Rf = 0.5 (EtOAc/hexanes, 3:7).
IR (neat): 2961, 2928, 2868, 1732, 1708, 1644, 1596, 1458, 1362,
1303, 1247, 1163, 1092, 1024 cm–1
.
IR (neat): 3424, 2954, 2924, 2861, 1706, 1620, 1446, 1361, 1308,
1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 8.0 Hz, 2 H), 7.31 (d, J = 8.0
Hz, 2 H), 7.20 (s, 1 H), 4.57 (d, J = 1.6 Hz, 2 H), 2.44 (s, 3 H), 2.34 (s, 2
H), 1.35 (s, 9 H), 1.22 (s, 6 H).
13C NMR (100 MHz, CDCl3, DEPT): δ = 207.30 (C), 167.87 (CH), 150.63
(C), 144.58 (C), 139.67 (C), 136.90 (C), 129.40 (2 CH), 128.37 (2 CH),
84.54 (C), 50.80 (CH2), 42.53 (CH2), 39.27 (C), 28.16 (CH3), 28.05 (CH3),
28.02 (CH3), 27.92 (2 CH3), 21.73 (CH3).
1286, 1258, 1154, 1089, 1054 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.10 (d, J = 14.0 Hz, 1 H), 7.70 (d, J = 8.0
Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2 H), 5.44 (s, 1 H), 5.14 (d, J = 14.0 Hz, 1 H),
4.72 (dd, J = 7.6, 4.4 Hz, 1 H), 4.23–4.14 (m, 3 H), 3.95 (d, J = 16.8 Hz, 1
H), 2.42 (s, 3 H), 2.12 (ABX, J = 13.6, 7.2 Hz, 2 H), 1.60 (ABX, J = 13.6,
4.4 Hz, 1 H), 1.27 (t, J = 7.2 Hz, 3 H), 1.07 (s, 3 H), 0.97 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C20H28NO5S: 394.1688; found:
394.1691.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

K
S. J. Gharpure et al.
Special Topic
Synthesis
13C NMR (100 MHz, CDCl3, DEPT): δ = 167.23 (CH), 145.15 (C), 143.29
(CH), 141.53 (CH), 135.46 (C), 135.06 (C), 130.33 (2 CH), 127.41 (2
CH), 99.45 (CH), 76.07 (CH), 60.31 (CH2), 48.79 (CH2), 44.51 (CH2),
43.50 (C), 29.80 (CH3), 28.97 (CH3), 21.74 (CH3), 14.49 (CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C20H27NO5NaS: 416.1508; found:
416.1504.
Ethyl (E)- 3-[N-({3,3-Dimethyl-5-[4-methyl-N-(prop-2-ynyl)phe-
nylsulfonamido]cyclopent-1-enyl}methyl)-4-methylphenylsul-
fonamido]acrylate (36)
Reaction of the alcohol 33 (92 mg, 0.15 mmol) with PPh3 (123 mg,
0.47 mmol), N-tosylpropargylamine (16; 59 mg, 0.28 mmol), and
DIAD (92 μL, 0.0.47 mmol) in THF (3 mL) at rt for 6 h as described for
TP3 and purification of the residue by column chromatography (silica
gel, EtOAc/hexanes, 1:4) furnished the iodide 36 (100 mg, 73%) as a
colorless liquid; Rf = 0.5 (EtOAc/hexanes, 1:4).
Ethyl (E)- 3-(N-{[5-(2-Iodophenoxy)-3,3-dimethylcyclopent-1-
enyl]methyl}-4-methylphenylsulfonamido)acrylate (34)
IR (neat): 3283, 2955, 2919, 2872, 1706, 1623, 1491, 1452, 1358,
Reaction of the alcohol 33 (61 mg, 0.16 mmol) with PPh3 (81 mg, 0.31
mmol), 2-iodophenol (13; 38 mg, 0.17 mmol), and DIAD (61 μL, 0.31
mmol) in THF (3 mL) at rt for 6 h as described for TP3 and purification
of the residue by column chromatography (silica gel, EtOAc/hexanes,
1:4) furnished the iodide 34 (57 mg, 62%) as a colorless liquid; Rf = 0.5
(EtOAc/hexanes, 1:4).
1340, 1290, 1162, 1090, 1058 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.10 (d, J = 14.0 Hz, 1 H), 7.79 (d, J = 8.4
Hz, 2 H), 7.70 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H), 7.29 (d,
J = 8.0 Hz, 2 H), 5.38 (d, J = 1.2 Hz, 1 H), 4.99 (t, J = 1.2 Hz, 1 H), 4.95 (d,
J = 9.6 Hz, 1 H), 4.20–4.10 (m, 4 H), 3.80 (ABX, J = 18.4, 2.4 Hz, 1 H),
3.68 (ABX, J = 18.8, 2.4 Hz, 1 H), 2.44 (s, 3 H), 2.43 (s, 3 H), 2.21 (t,
J = 2.4 Hz, 1 H), 1.80–1.69 (m, 2 H), 1.28 (t, J = 7.2 Hz, 3 H), 1.00 (s, 3
H), 0.91 (s, 3 H).
13C NMR (100 MHz, CDCl3, DEPT): δ = 167.21 (C), 145.13 (C), 143.78
(C), 142.55 (CH), 141.59 (CH), 135.28 (C), 130.82 (C), 130.38 (2 CH),
129.67 (2 CH), 127.68 (CH), 127.34 (2 CH), 127.38 (2 CH), 98.96 (CH),
79.70 (C), 64.87 (CH), 60.30 (CH2), 44.87 (CH2), 43.30 (C), 41.58 (CH2),
33.01 (C), 32.21 (CH2), 29.39 (CH3), 29.04 (CH3), 21.85 (CH3), 21.70
(CH3), 14.50 (CH3).
IR (neat): 2955, 2923, 2865, 1704, 1620, 1581, 1568, 1468, 1439,
1363, 1308, 1273, 1236, 1152, 1089, 1056, 1016 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.13 (d, J = 14.0 Hz, 1 H), 7.74–7.71 (m,
3 H), 7.28–7.20 (m, 3 H), 6.67 (d, J = 8.0 Hz, 2 H), 5.37 (s, 1 H), 5.31 (d,
J = 14.0 Hz, 1 H), 5.03 (dd, J = 7.2, 2.8 Hz, 1 H), 4.25 (q, J = 18.0 Hz, 2
H), 4.11 (q, J = 7.2 Hz, 2 H), 2.38 (s, 3 H), 2.11 (ABX, J = 14.0, 6.8 Hz, 1
H), 1.77 (ABX, J = 13.6, 2.8 Hz, 1 H), 1.21 (t, J = 7.2 Hz, 3 H), 1.01 (s, 3
H), 0.97 (s, 3 H).
13C NMR (100 MHz, CDCl3, DEPT): δ = 167.50 (C), 156.48 (C), 144.89
(C), 143.73 (CH), 141.30 (CH), 139.74 (CH), 135.58 (C), 131.60 (C),
130.24 (2 CH), 129.43 (CH), 127.56 (2 CH), 122.54 (CH), 112.72 (CH),
99.63 (CH), 87.36 (C), 83.49 (CH), 60.14 (CH2), 46.05 (CH2), 44.88
(CH2), 44.39 (C), 29.69 (CH3), 28.92 (CH3), 21.72 (CH3), 14.51 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C30H37N2O6S2: 465.0563; found:
465.0573.
2-(Hydroxymethyl)cyclohex-2-enone (56)
To a magnetically stirred solution of cyclohex-2-enone (55; 2 g, 20.81
mmol) in THF was added aq HCHO (4.3 mL, 41.61 mmol), followed by
portionwise addition of catalytic amount of DMAP (254 mg, 2.08
mmol) and the mixture was stirred for 5 d. The mixture was diluted
with CH2Cl2 and acidified with aq 1 M HCl. The organic layer was sep-
arated and washed with aq NaHCO3 and brine and dried (anhyd
Na2SO4). Evaporation of the solvent under reduced pressure and puri-
fication of the residue by column chromatography (silica gel,
Et2O/CH2Cl2, 3:7) furnished the alcohol 56 (1.65 g, 64%) as a colorless
liquid; Rf = 0.5 (Et2O/CH2Cl2, 3:7).
HRMS (ESI): m/z [M + Na]+ calcd for C26H30NO5SINa: 618.0787; found:
618.0798.
Ethyl (E)- 3-[N-({5-[N-(2-Iodophenyl)-4-methylphenylsulfonami-
do]-3,3-dimethylcyclopent-1-enyl}methyl)-4-methylphenylsul-
fonamido]acrylate (35)
Reaction of the alcohol 34 (109 mg, 0.28 mmol) with PPh3 (145 mg,
0.55 mmol), 2-iodo-N-tosylaniline (15; 124 mg, 0.33 mmol), and
DIAD (109 μL, 0.55 mmol) in THF (5 mL) at rt for 6 h as for described
TP3 and purification of the residue by column chromatography (silica
gel, EtOAc/hexanes, 3:7) furnished the iodide 35 (135 mg, 65%) as a
colorless solid; Rf = 0.5 (EtOAc/hexanes, 3:7); mp 82–84 °C.
IR (neat): 3447, 2937, 2870, 1667, 1388, 1251, 1172, 1138, 1072, 911,
860, 803 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.93 (t, J = 4.0 Hz, 1 H), 4.22 (d, J = 5.2
IR (neat): 2979, 2955, 2930, 2867, 1736, 1709, 1625, 1597, 1464,
Hz, 2 H), 2.75 (t, J = 6.4 Hz, 1 H), 2.45–2.36 (m, 3 H), 2.02–1.96 (m, 3
H).
1451, 1363, 1319, 1285, 1260, 1164, 1090, 1057, 1019 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.02 (d, J = 13.6 Hz, 1 H), 7.84–7.86 (m,
3 H), 7.53 (dd, J = 8.0, 1.2 Hz, 1 H), 7.44 (d, J = 8.4 Hz, 2 H), 7.40–7.36
(m, 1 H), 7.16 (br s, 1 H), 7.24 (d, J = 8.0 Hz, 2 H), 7.11 (d, J = 8.4 Hz, 2
H), 6.98–6.94 (m, 1 H), 5.07–5.02 (m, 2 H), 4.96 (d, J = 13.6 Hz, 1 H),
4.96 (AB, J = 13.6 Hz, 1 H), 4.10–4.05 (m, 1 H), 3.91 (AB, J = 13.6 Hz, 1
H), 2.32 (s, 3 H), 2.29 (s, 3 H), 2.05 (ABX, J = 14.0, 9.2 Hz, 1 H), 1.78
(ABX, J = 14.0, 6.0 Hz, 1 H), 1.18 (t, J = 7.2 Hz, 3 H), 0.74 (s, 3 H), 0.33 (s,
3 H).
13C NMR (100 MHz, CDCl3, DEPT): δ = 167.40 (C), 144.94 (C), 144.13
(C), 142.60 (CH), 141.76 (CH), 140.55 (CH), 139.13 (C), 137.23 (C),
135.52 (C), 134.69 (CH), 131.63 (C), 130.57 (CH), 130.32 (2 CH),
129.57 (2 CH), 129.40 (CH), 128.79 (2 CH), 128.47 (CH), 128.40 (C),
127.58 (2 CH), 99.32 (CH), 69.35 (CH), 60.26 (CH2), 47.07 (CH2), 43.13
(CH2), 42.33 (C), 29.46 (CH3), 28.03 (CH3), 21.76 (CH3), 14.52 (CH3).
13C NMR (100 MHz, CDCl3, DEPT): δ = 200.83 (C), 147.20 (CH), 138.30
(C), 62.05 (CH2), 38.30 (CH2), 25.72 (CH2), 22.80 (CH2).
HRMS (ESI): m/z [M + H]+ calcd for C7H11O2: 127.0759; found:
127.0759.
Ethyl (E)- 3-[(6-Oxocyclohex-1-enyl)methoxy]acrylate (57)
To a magnetically stirred solution of 56 (500 mg, 3.99 mmol) in dry
CH2Cl2 (10 mL) were added NMM (427 μL, 4.36 mmol) and ethyl pro-
pynoate (440 μL, 4.36 mmol) at rt and the mixture was stirred for 4 h
(TLC control). Evaporation of the solvent and purification of the resi-
due by column chromatography (silica gel, EtOAc/hexanes, 1:4) fur-
nished the alcohol 57 (811 mg, 91%) as a colorless liquid; Rf = 0.5
(EtOAc/hexanes, 1:4).
IR (neat): 2938, 1707, 1678, 1630, 1455, 1395, 1283, 1136, 1047 cm–1
.
HRMS (ESI): m/z [M + Na]+ calcd for C33H37N2O6S2INa: 771.1036;
found: 771.1028.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

L
S. J. Gharpure et al.
Special Topic
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.58 (d, J = 12.4 Hz, 1 H), 7.03 (t,
J = 4.02 Hz, 1 H), 5.26 (d, J = 12.4 Hz, 1 H), 4.53 (s, 2 H), 4.15 (q, J = 7.2
Hz, 2 H), 2.49–2.42 (m, 4 H), 2.03 (quin, J = 6.4 Hz, 2 H), 1.26 (t, J = 7.2
Hz, 3 H).
13C NMR (100 MHz, CDCl3, DEPT): δ = 198.08 (C), 167.85 (C), 162.16
(CH), 148.33 (CH), 134.11 (C), 97.57 (CH), 67.98 (CH2), 59.98 (CH2),
38.15 (CH2), 25.88 (CH2), 22.73 (CH2), 14.48 (CH3).
Ethyl (E)- 3-{[6-(1-Iodonaphthalen-2-yloxy)cyclohex-1-enyl]me-
thoxy}acrylate (60)
Reaction of the alcohol 58 (151 mg, 0.72 mmol) with PPh3 (374 mg,
1.43 mmol), 1-iodo-2-naphthol (14; 211 mg, 0.78 mmol), and DIAD
(281 μL, 1.43 mmol) in THF (4 mL) at rt for 6 h as described for TP3
and purification of the residue by column chromatography (silica gel,
EtOAc/hexanes, 1:9) furnished the iodide 60 (206 mg, 57%) as a color-
less liquid; Rf = 0.5 (EtOAc/hexanes, 1:9).
HRMS (ESI): m/z [M + H]+ calcd for C12H17O4: 225.1127; found:
IR (neat): 2976, 2932, 2873, 1706, 1622, 1592, 1500, 1459, 1324,
225.1122.
1280, 1260, 1236, 1130, 1045, 1000 cm–1
.
Ethyl (E)- 3-[(6-Hydroxycyclohex-1-enyl)methoxy]acrylate (58)
1H NMR (400 MHz, CDCl3): δ = 8.14 (d, J = 8.8 Hz, 1 H), 7.79 (d, J = 8.8
Hz, 1 H), 7.73 (d, J = 8.8 Hz, 1 H), 7.59 (d, J = 12.4 Hz, 1 H), 7.53 (t,
J = 8.4 Hz, 1 H), 7.39 (t, J = 7. 6 Hz, 1 H), 7.21 (d, J = 8.8 Hz, 1 H), 6.16
(br s, 1 H), 5.27 (d, J = 12.4 Hz, 1 H), 5.00 (br s, 1 H), 4.75 (d, J = 11.6
Hz, 1 H), 4.36 (d, J = 11.6 Hz, 1 H), 4.11 (qd, J = 7.2, 2.0 Hz, 2 H), 2.26–
2.25 (m, 1 H), 2.15–2.13 (m, 1 H), 2.10–2.03 (m, 1 H), 2.01–1.96 (m, 1
H), 1.82–1.76 (m, 1 H), 1.70–1.66 (m, 1 H), 1.23 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3, DEPT): δ = 167.91 (C), 162.14 (CH), 155.72
(C), 135.93 (C), 133.53 (CH), 131.88 (C), 131.65 (CH), 130.47 (CH),
130.34 (C), 128.29 (CH), 128.19 (CH), 124.76 (CH), 116.01 (CH), 97.53
(CH), 90.63 (C), 72.96 (CH), 72.94 (CH2), 59.90 (CH2), 28.15 (CH2),
25.37 (CH2), 18.13 (CH2), 14.46 (CH3).
To a cold (–10 °C), magnetically stirred solution of 57 (751 mg, 3.35
mmol) and CeCl3·7H2O (1.21 g, 3.69 mmol) in MeOH (10 mL) was add-
ed NaBH4 (127 mg, 3.35 mmol) portionwise. The solvent was re-
moved under reduced pressure and residue was extracted with EtOAc.
The organic layer was washed with brine and dried (anhyd NaSO4).
The solvent was evaporated under reduced pressure and purification
of the residue by column chromatography (silica gel, EtOAc/hexanes,
3:7) furnished the alcohol 58 (715 mg, 95%) as a colorless liquid; Rf =
0.5 (EtOAc/hexanes, 3:7).
IR (neat): 3412, 2935, 1690, 1619, 1453, 1373, 1324, 1282, 1123,
1044 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C22H24O4I: 479.0719; found:
479.0714.
1H NMR (400 MHz, CDCl3): δ = 7.58 (d, J = 12.8 Hz, 1 H), 5.92 (t, J = 3.6
Hz, 1 H), 5.25 (d, J = 12.4 Hz, 1 H), 4.53 (AB, J = 11.6 Hz, 1 H), 4.28 (AB,
J = 11.6 Hz, 1 H), 4.21–4.19 (m, 1 H), 4.16 (q, J = 7.2 Hz, 2 H), 2.10–2.02
(m, 3 H), 1.84–1.74 (m, 2 H), 1.72–1.67 (m, 1 H), 1.63–1.58 (m, 1 H),
1.25 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3, DEPT): δ = 168.03 (C), 162.28 (CH), 134.28
(C), 131.61 (CH), 97.23 (CH), 73.64 (CH2), 64.88 (CH), 59.96 (CH2),
31.69 (CH2), 25.37 (CH2), 17.85 (CH2), 14.41 (CH3).
Angularly-Fused Bis-ether 61; Typical Procedure 4 (TP4)
Following the procedure for 37.4j To a magnetically stirred, refluxing
solution of iodide 59 (707 mg, 1.48 mmol) and AIBN (48.5 mg, 0.3
mmol) in benzene (40 mL) was added a solution of with n-Bu3SnH
(796 μL, 2.96 mmol) and AIBN (48.5 mg, 0.3 mmol) in benzene (30
mL) over a period of 3 h under a nitrogen atmosphere. The mixture
was further refluxed until completion (ca. 3 h, TLC control). It was
then cooled, diluted with Et2O, washed with 2% aq NH3 and brine, and
the organic layer was dried (anhyd Na2SO4). Evaporation of the sol-
vent under reduced pressure gave a residue that was purified by col-
umn chromatography (silica gel, EtOAc/hexanes, 1:9) to furnish the
angularly-fused bis-ether 61 (286 mg, 65%; dr = 4:1) as a colorless liq-
uid; Rf = 0.5 (EtOAc/hexanes, 1:19).
HRMS (ESI): m/z [M + H]+ calcd for C12H19O4: 227.1283; found:
227.1286.
Ethyl (E)- 3-{[6-(2-Iodophenoxy)cyclohex-1-enyl]methoxy}acry-
late (59)
Reaction of the alcohol 58 (430 mg, 1.90 mmol) with PPh3 (997 mg,
3.80 mmol), 2-iodophenol (13; 460 mg, 2.09 mmol), and DIAD (748
μL, 3.80 mmol) in THF (7 mL) at rt for 6 h as described for TP3 and
purification of the residue by column chromatography (silica gel, EtO-
Ac/hexanes, 1:9) furnished the iodide 59 (550 mg, 68%) as a colorless
liquid; Rf = 0.5 (EtOAc/hexanes, 1:9).
IR (neat): 2932, 2865, 1733, 1596, 1469, 1370, 1271, 1229, 1181,
1136, 1024 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.32 (dd, J = 7.2, 0.8 Hz, 1 H), 7.17 (td,
J = 7.6, 1.2 Hz, 1 H), 6.93 (t, J = 7.6 Hz, 1 H), 6.83 (d, J = 7.6 Hz, 1 H),
4.70 (dt, J = 8.0, 5.2 Hz, 1 H), 4.42 (t, J = 2.8 Hz, 1 H), 4.16 (q, J = 7.2 Hz,
2 H), 4.13 (AB, J = 8.8 Hz, 1 H), 3.93 (AB, J = 8.8 Hz, 1 H), 2.66 (ABX,
J = 15.6, 8.0 Hz, 1 H), 2.47 (ABX, J = 15.6, 5.2 Hz, 1 H), 2.30 (dd, J = 16.8,
2.0 Hz, 1 H), 1.84–1.81 (m, 1 H), 1.71–1.65 (m, 1 H), 1.64–1.58 (m, 2
H), 1.56–1.52 (m, 1 H), 1.26 (t, J = 7.2 Hz, 3 H), 1.12 (dd, J = 13.2, 2.8
Hz, 1 H).
13C NMR (100 MHz, CDCl3, DEPT): δ = 171.47 (C), 158.36 (C), 136.86
(C), 128.55 (CH), 122.92 (CH), 121.25 (CH), 109.93 (CH), 82.66 (CH),
72.62 (CH2), 60.85 (CH2), 53.74 (C), 47.24 (CH), 35.96 (CH2), 26.21
(CH2), 24.19 (CH), 22.37 (CH2), 18.63 (CH2), 14.31 (CH3).
IR (neat): 2936, 1702, 1623, 1575, 1463, 1373, 1320, 1273, 1232,
1122, 1045 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.77 (dd, J = 7.6, 1.2 Hz, 1 H), 7.57 (d,
J = 12.8 Hz, 1 H), 7.30–7.26 (m, 1 H), 6.88 (d, J = 7.6 Hz, 1 H), 6.71 (td,
J = 7.6, 1.2 Hz, 1 H), 6.13–6.12 (m, 1 H), 5.25 (d, J = 12.4 Hz, 1 H), 4.84
(br s, 1 H), 4.66 (dd, J = 11.6, 0.8 Hz, 1 H), 4.32 (d, J = 11.6 Hz, 1 H),
4.14 (q, J = 7.2 Hz, 2 H), 2.23–2.21 (m, 1 H), 2.13–2.12 (m, 1 H), 2.04–
1.99 (m, 1 H), 1.89–1.76 (m, 2 H), 1.67–1.62 (m, 1 H), 1.25 (t, J = 7.2
Hz, 3 H).
13C NMR (100 MHz, CDCl3, DEPT): δ = 167.92 (C), 162.14 (CH), 156.92
(C), 139.72 (CH), 133.27 (CH), 131.65 (C), 129.54 (CH), 122.95 (CH),
114.06 (CH), 97.33 (CH), 88.27 (C), 72.77 (CH2), 71.73 (CH), 59.88
(CH2), 27.57 (CH2), 25.26 (CH2), 17.99 (CH2), 14.45 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C18H23O4: 303.1596; found:
303.1600.
HRMS (ESI): m/z [M + H]+ calcd for C18H22O4I: 429.0563; found:
429.0562.
Angularly-Fused Bis-ether 62
Reaction of the iodide 60 (105 mg, 0.22 mmol) with n-Bu3SnH (118
μL, 0.44 mmol) and AIBN (14 mg, 0.09 mmol) in benzene (30 mL) as
described TP4 followed by purification of the residue by column chro-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

M
S. J. Gharpure et al.
Special Topic
Synthesis
matography (silica gel, EtOAc/hexanes, 1:9) furnished the angularly-
fused bis-ether 62 (25 mg, 33%; dr = 4:1) as a colorless liquid; Rf = 0.7
(EtOAc/hexanes, 1:9).
[5-(2-Iodophenoxy)cyclopent-1-enyl]methyl Acetate (65a)
Reaction of the alcohol 64 (160 mg, 1.03 mmol) with PPh3 (537 mg,
2.05 mmol), 2-iodophenol (13; 226 mg, 1.03 mmol), and DIAD (403
μL, 2.05 mmol) in THF (5 mL) at rt for 6 h as described for TP3 and
purification of the residue by column chromatography (silica gel,
EtOAc/hexanes, 1:9) furnished the iodide 65a (235 mg, 63%) as a col-
orless liquid; Rf = 0.5 (EtOAc/hexanes, 1:9).
IR (neat): 2978, 2932, 2867, 1735, 1623, 1592, 1519, 1480, 1461, 1373,
1348, 1300, 1260, 1185, 1164, 1134, 1120, 1049, 1029, 1010 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.22 (d, J = 8.4 Hz, 1 H), 7.81 (d, J = 8.4
Hz, 1 H), 7.72 (d, J = 8.4 Hz, 1 H), 7.52 (t, J = 8.4 Hz, 1 H), 7.31 (t, J = 7.6
Hz, 1 H), 7.15 (d, J = 8.8 Hz, 1 H), 4.92 (td, J = 8.4, 5.2 Hz, 1 H), 4.61 (AB,
J = 8.8 Hz, 1 H), 4.52 (br s, 1 H), 4.14 (q, J = 7.2 Hz, 2 H), 4.05 (AB, J = 8.8
Hz, 1 H), 2.70 (ABX, J = 15.6, 8.4 Hz, 1 H), 2.50 (ABX, J = 15.6, 5.2 Hz, 1
H), 2.35 (dt, J = 14.0, 2.4 Hz, 1 H), 2.01 (dt, J = 12.8, 5.2 Hz, 1 H), 1.77–
1.69 (m, 2 H), 1.64–1.60 (m, 3 H), 1.26 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3, DEPT): δ = 171.36 (C), 156.83 (C), 130.52 (2
C), 130.28 (CH), 129.38 (CH), 127.39 (CH), 126.54 (C), 122.99 (CH),
122.44 (CH), 112.57 (CH), 83.04 (CH), 79.46 (CH), 70.22 (CH2), 60.76
(CH2), 55.70 (C), 48.00 (CH), 36.39 (CH2), 26.21 (CH2), 22.62 (CH2),
18.63 (CH2), 14.39 (CH3).
IR (neat): 3058, 2934, 2854, 1741, 1580, 1568, 1469, 1439, 1365,
1306, 1275, 1239, 1160, 1119, 1051, 1033, 1017 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.81 (dd, J = 8.0, 1.2 Hz, 1 H), 7.35–7.30
(m, 1 H), 6.90 (d, J = 8.4 Hz, 1 H), 6.75 (t, J = 7.2 Hz, 1 H), 6.12 (s, 1 H),
5.33 (t, J = 4.4 Hz, 1 H), 4.93 (AB, J = 13.2 Hz, 1 H), 4.84 (AB, J = 13.2 Hz,
1 H), 2.70–2.60 (m, 1 H), 2.52–2.48 (m, 2 H), 2.09 (s, 3 H), 2.11–2.07
(m, 1 H).
13C NMR (100 MHz, CDCl3, DEPT): δ = 170.93 (C), 157.10 (C), 139.75
(CH), 137.89 (C), 134.85 (CH), 129.46 (CH), 122.62 (CH), 113.46 (CH),
87.63 (C), 84.36 (CH), 61.18 (CH2), 30.90 (CH2), 30.77 (CH2), 21.14
(CH3).
HRMS (ESI): m/z [M + H]+ calcd for C22H25O4: 353.1753; found:
HRMS (ESI): m/z [M + Na]+ calcd for C14H15O3NaI: 380.9964; found:
353.1750.
380.9954.
(5-Oxocyclopent-1-enyl)methyl Acetate (63)
To a cold (0 °C) magnetically stirred solution of 2-(hydroxymethyl)cy-
clopent-2-enone (6; 249 mg, 2.22 mmol) in dry CH2Cl2 (5 mL) were
added successively, Et3N (728 μL, 0.67 mmol) and DMAP (54 mg, 0.44
mmol), followed by dropwise addition of Ac2O (420 μL, 4.44 mmol)
over a period of 15 min and the mixture was stirred overnight at rt.
The mixture was diluted with EtOAc (50 mL) and organic layer was
washed with water and brine and dried (anhyd NaSO4). Evaporation
of the solvent under reduced pressure and purification of the residue
by column chromatography (silica gel, EtOAc/hexanes, 1:4) furnished
the acetate 63 (342 mg, 70%) as a colorless liquid; Rf = 0.5 (EtOAc/hex-
anes, 1:4).
[5-(2-Iodophenoxy) cyclopent-1-enyl]methanol (65b)
To a magnetically stirred solution of 65a (231 mg, 0.65 mmol) in
MeOH (5 mL) was added K2CO3 (134 mg, 0.97 mmol) at rt and the
mixture was stirred overnight (TLC control). Evaporation of the sol-
vent and purification of the residue by column chromatography (sili-
ca gel, EtOAc/hexanes, 1:4) furnished the product 65b (160 mg, 80%)
as a colorless solid; Rf = 0.5 (EtOAc/hexanes, 1:4); mp 74–76 °C.
IR (neat): 3435, 2953, 2926, 2813, 2725, 1593, 1470, 1436, 1384,
1350, 1276, 1241, 1350, 1276, 1241, 1165, 1123, 1057, 1033,
1018 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 8.0 Hz, 1 H), 7.30 (t, J = 8.0
Hz, 1 H), 6.88 (d, J = 8.0 Hz, 1 H), 6.72 (t, J = 7.6 Hz, 1 H), 6.04 (t, J = 1.2
Hz, 1 H), 5.34 (t, J = 3.2 Hz, 1 H), 4.40 (s, 2 H), 2.60–2.42 (m, 3 H), 2.11
(t, J = 5.6 Hz, 1 H), 2.04–1.98 (m, 1 H).
13C NMR (100 MHz, CDCl3, DEPT): δ = 156.84 (C), 141.90 (C), 139.67
(CH), 133.15 (CH), 129.55 (CH), 122.67 (CH), 113.34 (CH), 87.41 (C),
85.55 (CH), 60.39 (CH2), 31.17 (CH2), 30.72 (CH2).
IR (neat): 2924, 2854, 1590, 1459, 1416, 1317, 1267, 1120, 1041 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.58–7.56 (m, 1 H), 4.74 (d, J = 1.2 Hz, 2
H), 2.65–2.63 (m, 2 H), 2.45–2.43 (m, 2 H), 2.07 (s, 3 H).
13C NMR (100 MHz, CDCl3, DEPT): δ = 207.85 (C), 170.78 (C), 161.19
(CH), 141.28 (C), 57.99 (CH2), 34.81 (CH2), 26.99 (CH2), 20.94 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C8H11O3: 155.0708; found:
HRMS (ESI): m/z [M + Na]+ calcd for C12H13O2NaI: 338.9858; found:
155.0710.
338.9857.
(5-Hydroxycyclopent-1-enyl)methyl Acetate (64)
Reduction of 63 (140 mg, 0.91 mmol) using NaBH4 (41 mg, 1.09
mmol) and CeCl3·7H2O (357 mg, 1.09 mmol) in MeOH (5 mL) at –10 °C
as described TP2 followed by purification of the residue by column
chromatography (silica gel, EtOAc/hexanes, 3:7) furnished the alcohol
64 (100 mg, 74%) as a colorless liquid; Rf = 0.5 (EtOAc/hexanes, 3:7).
3-Benzoyl-1-{[5-(2-iodophenoxy)cyclopent-1-enyl]methyl}pyrim-
idine-2,4(1H,3H)-dione (66)
Reaction of the alcohol 65b (70 mg, 0.22 mmol) with PPh3 (116 mg,
0.44 mmol), 3-benzoylpyrimidine-2,4(1H,3H)-dione (60 mg, 0.28
mmol), and DIAD (89 μL, 0.44 mmol) in THF (7 mL) at rt for 12 h as
described for TP3 and purification of the residue by column chroma-
tography (silica gel, EtOAc/hexanes, 2:3) furnished the iodide 66 (85
mg, 71%) as a colorless solid; Rf = 0.5 (EtOAc/hexanes, 2:3); mp 52–54 °C.
IR (neat): 3410, 2930, 2846, 1732, 1630, 1584, 1446, 1412, 1373,
1242, 1123, 1039 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.89–5.88 (m, 1 H), 4.81 (AB, J = 12.8
Hz, 1 H), 4.74 (s, 1 H), 4.63 (AB, J = 12.8 Hz, 1 H), 2.50–2.42 (m, 1 H),
2.39 (br s, 1 H), 2.34–2.28 (m, 1 H), 2.08 (s, 3 H), 1.81–1.74 (m, 2 H).
IR (neat): 3058, 2931, 2854, 1747, 1704, 1663, 1596, 1582, 1467,
1440, 1381, 1341, 1238, 1175, 1118, 1073, 1048, 1035, 1020 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 7.6 Hz, 2 H), 7.80 (dd,
J = 7.6, 1.6 Hz, 1 H), 7.62 (t, J = 7.2 Hz, 1 H), 7.45–7.41 (m, 3 H), 7.29
(td, J = 8.4, 1.2 Hz, 1 H), 6.84 (dd, J = 8.4, 0.8 Hz, 1 H), 6.75 (td, J = 8.4,
1.2 Hz, 1 H), 6.05 (s, 1 H), 5.77 (d, J = 8.0 Hz, 1 H), 5.24 (d, J = 4.0 Hz, 1
H), 4.70 (AB, J = 15.6 Hz, 1 H), 4.62 (AB, J = 15.6 Hz, 1 H), 2.66–2.59 (m,
1 H), 2.54–2.44 (m, 2 H), 2.04–1.98 (m, 1 H).
13C NMR (100 MHz, CDCl3, DEPT): δ = 171.53 (C), 140.89 (C), 133.41
(CH), 76.72 (CH), 61.14 (CH2), 33.31 (CH2), 29.94 (CH2), 20.97 (CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C8H12O3Na: 179.0684; found:
179.0684.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

N
S. J. Gharpure et al.
Special Topic
Synthesis
13C NMR (100 MHz, CDCl3, DEPT): δ = 168.91 (C), 162.58 (C), 156.27
(C), 149.90 (C), 144.59 (CH), 139.79 (CH), 136.71 (C), 135.60 (CH),
135.12 (CH), 131.52 (C), 130.53 (2 CH), 129.77 (CH), 129.21 (2 CH),
123.06 (CH), 113.53 (CH), 102.35 (CH), 87.38 (C), 84.43 (CH), 46.72
(CH2), 30.81 (CH2), 30.76 (CH2).
HRMS (ESI): m/z [M + Na]+ calcd for C23H19N2O4NaI: 534.0287; found:
537.0265.
83, 323. (q) Bandaru, A.; Kaliappan, K. P. Synlett 2012, 23, 1473.
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Pohmakotr, M. Angew. Chem. Int. Ed. 2014, 53, 2212.
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Shukla, M. K. Eur. J. Org. Chem. 2011, 6632. (f) Gharpure, S. J.;
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Funding Information
We thank SERB, New Delhi, for financial support.
)(
Acknowledgment
We thank Mr. V. Ramkumar of the Department of Chemistry, IIT Ma-
dras, for the crystallographic data. We thank CSIR, New Delhi, for the
award of research fellowships to P.N. and S.K.P.
Supporting Information
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Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1589541.
S
u
p
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S
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given in the Supporting Information.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N