Halogenation reagents initiating ring opening of vinylidenecyclopropanes: Easy access to halogenated tetrahydropyrans

Article abstract of DOI:10.1055/s-0030-1259715

A novel synthetic protocol that uses halogenation reagents (NBS, NIS and selectfluor) to initiate intramolecular ring-opening reactions of diarylvinylidenecyclopropanes (VDCPs) connected to alcohol-bearing chains has been developed. The approach provides

Full text of DOI:10.1055/s-0030-1259715

LETTER
995
Halogenation Reagents Initiating Ring Opening of Vinylidenecyclopropanes:
Easy Access to Halogenated Tetrahydropyrans
H
alogenated Tetrahydro
e
pyrans i Yuan, Min Shi*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin
Lu, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: mshi@mail.sioc.ac.cn
Received 31 August 2010
Dedicated to Professors Xiyan Lu and Lixin Dai
hydrobromination products in good yields (Scheme 1).7
Abstract: A novel synthetic protocol that uses halogenation re-
More recently, we have found an efficient intramolecular
ring-opening reaction of VDCPs 2 tethered to alcohol-
bearing chains under gold catalysis that gives the corre-
agents (NBS, NIS and selectfluor) to initiate intramolecular ring-
opening reactions of diarylvinylidenecyclopropanes (VDCPs) con-
nected to alcohol-bearing chains has been developed. The approach
provides a variety of halogenated tetrahydropyran derivatives in sponding functionalized tetrahydropyran derivatives 3 in
moderate to good yields (Scheme 2).3c Herein, we wish to
moderate to good yields under mild conditions. Plausible reaction
mechanisms are proposed on the basis of previous literature and the
substrate scope has been carefully examined.
report a novel use of halogenation reagents such as NBS
or NIS to initiate ring-opening reactions of 2 under mild
conditions, affording halogenated tetrahydropyran deriv-
atives in moderate to good yields.
Key words: vinylidenecyclopropanes, halogenation, hydroxyl
group, ring opening, tetrahydropyrans
R
R
R
Tetrahydropyrans are found widely in a variety of natural-
ly occurring and biologically active compounds, and syn-
thetic methodologies for producing tetrahydropyrans and
their derivatives have attracted much attention. As a re-
sult, many useful synthetic methods have been ex-
plored.1,2 For example, it has been reported that
tetrahydropyrans could be formed from intermolecular/in-
tramolecular nucleophilic attack of a pre-nucleophile con-
taining a hydroxyl group on an alkyne under the catalysis
of transition metals,3 or from allylic ethers through 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) mediated
oxocarbenium ion formation with subsequent intramolec-
ular nucleophilic addition in a highly diastereocontrolled
way,4 or by a cross-metathesis of common alkenes con-
taining a hydroxyl group, followed by iodocyclization.5
However, to the best of our knowledge, examples of syn-
thetic methods that generate tetrahydropyran rings by
means of ring-opening reactions of highly strained small
rings are rare.3c Therefore, to extend the synthetic ap-
proach to tetrahydropyran rings, we attempted to establish
a new general method to access this interesting structural
motif under mild conditions through ring-opening reac-
tions of highly strained small rings, such as vinylidene-
cyclopropanes (VDCPs) with an attached alcohol moiety.
Br
NBS (1.2 equiv)
OH
MeCN–H2O (3:1), r.t.
R
1
R = H, Me, Cl, F, OMe
Scheme 1 Hydrobromination of vinylidenecyclopropanes 1 by
NBS and water in acetonitrile
Ar1
Ar3
Ar3
H
Ar1
Ar2
[(Ph3PAu)3O]BF4 (4 mol%)
AgOTf (4 mol%)
Ar2
HO
O
1,4-dioxane, 60 °C
2
3
45–59% yield
Scheme 2 Au(I)-catalyzed intramolecular addition–ring opening of
VDCPs 2
Initial experiments on the intramolecular ring-opening re-
actions of VDCPs 2 were performed by exposing VDCP
2a (0.2 mmol) to NBS (1.2 equiv) in CH2Cl2 (2.0 mL) at
room temperature (20 °C). To our delight, it was found
that, under these conditions, the corresponding brominat-
ed tetrahydropyran derivative 4a8 was obtained in 20%
yield after three hours (Table 1, entry 1). We then attempt-
ed to optimize the reaction by adjusting the conditions; the
results of these experiments are shown in Table 1. Chang-
ing the solvent to acetonitrile improved the yield of 4a to
61% after three hours (Table 1, entry 2). Other solvents,
such as tetrahydrofuran (THF), toluene or N,N-dimethyl-
formamide (DMF) did not facilitate the formation of 4a
(Table 1, entries 3–5). Moreover, we found that increas-
Over the past several years, we and others have been
studying the chemical transformations of VDCPs, which
are highly strained small rings that are readily accessible.6
For example, previously, we have reported the hydrobro-
mination of vinylidenecyclopropanes 1 by N-bromosuc-
cinimide (NBS) and water in acetonitrile to afford
SYNLETT 2011, No. 7, pp 0995–0999
x
x.
x
x.
2
0
1
1
Advanced online publication: 10.03.2011
DOI: 10.1055/s-0030-1259715; Art ID: W31710ST
© Georg Thieme Verlag Stuttgart · New York

996
W. Yuan, M. Shi
LETTER
Table 1 Optimizing the Reaction Conditionsa
yield of 4a (Table 1, entry 9). Examination of the reaction
time and the reaction temperature revealed that this NBS-
initiated reaction was best carried out at room temperature
(20 °C) for three hours; shortening the reaction time or
raising the reaction temperature did not improve the yields
of 4a (Table 1, entries 10–12). Ultimately, it was found
that the ring-opening product 4a was obtained in 70%
yield when VDCP 2a (0.2 mmol) tethered to an alcohol-
bearing chain was used to react with NBS (1.2 equiv) in
MeCN (2.0 mL) within three hours at room temperature
(20 °C), using NaHCO3 (1.0 equiv) as an additive; these
conditions were thus established as the optimal reaction
conditions for this transformation.
Ph
Ph
Ph
Ph
Br
NBS (x equiv), additive (1.0 equiv)
Ph
solvent, temp, time
HO
O
2a
4a
Entry
x
Solvent
Temp Time Additive
Yield of 4a
(°C)
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
30
(h)
(%)b
1
2
1.2 CH2Cl2
1.2 MeCN
1.2 THF
3
–
–
–
–
–
–
–
20
61
trace
3
3
3
3
Under these optimal reaction conditions, we then exam-
ined the substrate scope of this novel ring-opening reac-
tion by employing a variety of VDCPs 2; the results of
these experiments are outlined in Table 2. As can be seen
from Table 2, all the VDCPs examined reacted smoothly
with NBS to yield the corresponding tetrahydropyran de-
rivatives 4 in moderate to good yields. For diphenyl-
vinylidenecyclopropanes 2b–g, bearing electron-
withdrawing or electron-donating groups on the aromatic
rings of Ar3, the corresponding products 4b–g were ob-
tained in 44–61% yields (Table 2, entries 2–7). In the case
of VDCP 2g, the corresponding product 4g was obtained
in 44% yield, presumably due to the steric hindrance of
the meta-substituent Br atom on the aromatic ring (Ar3).
Similarly, introducing electron-donating or moderately
electron-withdrawing groups onto the aromatic rings of
Ar1 and Ar2 also afforded the corresponding tetrahydro-
pyran derivatives 4h–j in moderate to good yields
(Table 2, entries 8–10). For unsymmetrical diarylvi-
nylidenecyclopropane 2k, the corresponding tetrahydro-
pyran derivative 4k was obtained as a pair of
diastereoisomers with a ratio of 1:1 in 52% total yield un-
der identical conditions (Table 2, entry 11).
4
1.2 toluene
1.2 DMF
1.5 MeCN
1.8 MeCN
1.2 MeCN
1.2 MeCN
1.2 MeCN
1.2 MeCN
1.2 MeCN
3
5
3
5
6
3
42
40
70
32
53
65
43
7
3
8
3
NaHCO3
Et3N
9
3
10
11
12
1
NaHCO3
NaHCO3
NaHCO3
2
3
a Reagents and conditions: 2a (0.2 mmol), NBS (x equiv) and additive
(1.0 equiv) were added into a flask under argon, then solvent (2.0 mL)
was added into the flask via syringe.
b Isolated yield.
ing the amount of NBS employed also did not favor the
formation of 4a (Table 1, entries 6 and 7). When NaHCO3
was included as an additive, it was found that 4a could be
obtained in 70% yield (Table 1, entry 8), although using
triethylamine (Et3N) as an additive failed to improve the
Table 2 Intramolecular Ring-Opening Reactions of VDCPs 2 with NBSa
Ar1
Ar1
Ar2
Br
Ar3
Ar3
NBS (1.2 equiv), NaHCO3 (1.0 equiv)
MeCN, r.t., 3 h
Ar2
HO
O
2
4
Entry
Ar1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ar2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ar3
Starting material
Yield of 4 (%)b
1
2
3
4
5
6
7
Ph
2a
2b
2c
2d
2e
2f
70
56
61
59
59
52
44
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
3-BrC6H4
2g
Synlett 2011, No. 7, 995–999 © Thieme Stuttgart · New York

LETTER
Halogenated Tetrahydropyrans
997
Table 2 Intramolecular Ring-Opening Reactions of VDCPs 2 with NBSa (continued)
Ar1
Ar1
Ar2
Br
Ar3
Ar3
NBS (1.2 equiv), NaHCO3 (1.0 equiv)
MeCN, r.t., 3 h
Ar2
HO
O
2
4
Entry
8
Ar1
Ar2
Ar3
Starting material
Yield of 4 (%)b
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
4-MeC6H4
4-MeOC6H4
4-ClC6H4
Ph
Ph
Ph
Ph
Ph
2h
2i
63
43
39
52c
9
10
11
2j
2k
a Reagents and conditions: 2 (0.2 mmol), NBS (1.2 equiv), NaHCO3 (1.0 equiv), Ar, MeCN (2.0 mL), r.t., 3 h.
b Isolated yield.
c E/Z isomeric mixture (ratio 1:1).
A mechanistic explanation for the intramolecular ring ucts. As shown in Table 3, VDCPs 2b and 2c were also
opening of VDCP 2a in the presence of NBS is proposed suitable substrates for this reaction under the standard
in Scheme 3 using 2a as a model. Firstly, a three-mem- conditions, giving the iodinated tetrahydropyran deriva-
bered cyclic bromonium ion A is formed by the electro- tives 5b and 5c in 70–81% yields, respectively (Table 3,
philic addition of a Br+ ion (generated in situ from NBS) entries 2 and 3).
onto 2a,9 which undergoes intramolecular nucleophilic
addition of the hydroxyl group onto the cyclopropane, ac-
Ph
Ph
Ph
Cl
Ph
companied by a ring-opening process to afford the corre-
sponding cationic intermediate B. Deprotonation of B
with NaHCO3 furnishes the corresponding vinyltetra-
hydropyran derivative 4a (Scheme 1).
NCS (1.2 equiv),
Ph
NaHCO3 (1.0 equiv)
Ph
HO
MeCN, r.t., 3 h
O
2a
4a'
Scheme 4 The reaction of VDCP 2a with NCS
O
N
Br
Table 3 Intramolecular Ring-Opening Reactions of VDCPs 2 with
Ph
Ph
NISa
+
Br
Ph
Ph
Ph
Ph
Br
Ph
O
NBS
Ar1
Ph
Ph
Ar1
Ar2
I
Ar3
Ar3
NIS (1.2 equiv),
NaHCO3 (1.0 equiv)
+
O
HO
Ar2
HO
HO
H
2a
A
MeCN, r.t., 3 h
O
B
2
5
NaHCO3
Entry Ar1
Ar2
Ar3
Starting Product Yield of 5
material
(%)b
Ph
Ph
Br
Ph
1
2
3
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2a
5a
5b
5c
80
O
4-FC6H4
2b
70
4a
4-MeC6H4 2c
81
Scheme 3 A plausible mechanism for the intramolecular ring ope-
ning of VDCP 2a with NBS
a Reagents and conditions: 2 (0.2 mmol), NIS (1.2 equiv), NaHCO3
(1.0 equiv), Ar, MeCN (2.0 mL), r.t., 3 h.
b Isolated yield.
These results also stimulated us to investigate the reaction
of VDCPs 2 with other halogenation reagents. Thus, we
utilized N-chlorosuccinimide (NCS) to replace NBS in the
ring-opening reaction of VDCP 2a, but found that no re-
action occurred under identical conditions, presumably
due to the fact that NBS is more reactive than NCS
(Scheme 4). Using N-iodosuccinimide (NIS) to replace
NBS afforded the corresponding iodinated product 5a in
80% yield, together with traces of unidentified byprod-
In our previous work, we investigated the details of the re-
action between VDCPs 1 and N-fluorodibenzenesulfon-
imide (NFSI).9 Therefore, we also examined the reaction
of VDCPs 2 with NFSI under the standard conditions.
However, we found that the reaction was rather sluggish
and complex product mixtures were formed. We then
utilized
1-chloromethyl-4-fluoro-1,4-diazoniabicyclo-
Synlett 2011, No. 7, 995–999 © Thieme Stuttgart · New York

998
W. Yuan, M. Shi
LETTER
[2.2.2]octane bis(tetrafluoroborate) (Selectfluor) as the
fluorination reagent in this reaction and found that the re-
action proceeded efficiently in MeCN at 60 °C within
three hours, affording the expected fluorinated product 6a
in 72% yield (Table 4, entry 1). Examination of substrate
scope of this interesting fluorination reaction revealed
that, as for diphenylvinylidenecyclopropanes 2b–d bear-
ing electron-withdrawing or electron-donating groups on
their aromatic rings of Ar3, the corresponding fluorinated
products 6b–d could be obtained in 43–72% yields
(Table 4, entries 2–4). Similarly, introducing moderately
electron-donating or electron-withdrawing groups onto
the aromatic rings of Ar1 and Ar2 also afforded the corre-
sponding fluorinated tetrahydropyran derivatives 6e and
6f in moderate to good yields (Table 4, entries 5 and 6).
F
N+
N+
N
N+
F+
+
Cl
Cl
Selectfluor
Ph
Ph
F+
Ph
Ph
Ph
Ph
F
F+
Ph
Ph
Ph
+
O
HO
HO
H
C
D
2a
Ph
Ph
F
Ph
A plausible mechanism for the intramolecular ring open-
ing of VDCPs 2 with Selectfluor is shown in Scheme 5 us-
ing 2a as a model. The fluoric cation F+ is first generated
from Selectfluor under the standard reaction conditions,11
which adds to a double bond of 2a to give the correspond-
ing three-membered cationic intermediate C.10 Intramo-
lecular nucleophilic addition of the hydroxyl group onto
the cyclopropane combined with a ring-opening process,
affords the corresponding cationic intermediate D, which
undergoes deprotonation to furnish the corresponding
O
6a
Scheme 5 A plausible mechanism of the intramolecular ring ope-
ning of VDCPs 2a with Selectfluor
under mild conditions.12 Plausible reaction mechanisms
have been proposed on the basis of previous investiga-
tions and literature data, and the substrate scope has been
carefully examined. These reactions provide an alterna-
tive synthetic approach to functionalized tetrahydropyran
derivatives from easily available highly strained small
rings. Efforts are in progress to further elucidate the mech-
anistic details of this reaction and to determine its scope
and limitations.
fluorinated
vinyltetrahydropyran
derivative
6a
(Scheme 5).
Table 4 Intramolecular Ring-Opening Reactions of VDCPs 2 with
Selectfluora
Ar1
Ar1
Ar2
F
Ar3
Ar3
Selectfluor (1.2 equiv)
MeCN, 60 °C, 3 h
Ar2
HO
O
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
2
6
Entry Ar1
Ar2
Ar3
Starting
material
Yield of 6
(%)b
Acknowledgment
1
2
3
4
5
6
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2a
2b
2c
72
72
63
43
47
64
We thank the Shanghai Municipal Committee of Science and Tech-
nology (08dj1400100-2), the National Basic Research Program of
China (973)-2009CB825300, and the National Natural Science
Foundation of China (20872162, 20672127, 20732008, 20821002
and 20702013).
4-ClC6H4
4-BrC6H4
4-MeOC6H4 2d
4-ClC6H4 4-ClC6H4 Ph
4-MeC6H4 4-MeC6H4 Ph
2e
References and Notes
2f
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a Reagents and conditions: 1 (0.2 mmol), Selectfluor (1.2 equiv), Ar,
MeCN (2.0 mL), 60 °C, 3 h.
b Isolated yield.
In conclusion, we have developed a novel application of
halogenation reagents such as NBS, NIS, and Selectfluor
that initiates intramolecular ring-opening reactions of dia-
rylvinylidenecyclopropanes (VDCPs) 2 tethered to alco-
hol-bearing chains, to give a variety of halogenated
tetrahydropyran derivatives in moderate to good yields
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Synlett 2011, No. 7, 995–999 © Thieme Stuttgart · New York

LETTER
Halogenated Tetrahydropyrans
999
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syringe. The mixture was stirred for 3 h at r.t., then the
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by flash column chromatography on silica gel column
(petroleum ether–EtOAc, 20:1) to give 4 in moderate to
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Synlett 2011, No. 7, 995–999 © Thieme Stuttgart · New York

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