DABCO-catalyzed synthesis of 3-bromo-/3-iodo-2H-pyrans from propargyl alcohols, dialkyl acetylene dicarboxylates, and N-bromo-/N-iodosuccinimides

Article abstract of DOI:10.1016/j.tetlet.2014.11.111

The DABCO-catalyzed reaction of propargyl alcohols with dialkyl acetylene dicarboxylates and N-bromo-/N-iodosuccinimides under mild conditions has been developed. The reactions give 3-bromo-/3-iodo-2H-pyrans in up to 98% yield.

Full text of DOI:10.1016/j.tetlet.2014.11.111

Tetrahedron Letters 56 (2015) 401–403
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
DABCO-catalyzed synthesis of 3-bromo-/3-iodo-2H-pyrans from
propargyl alcohols, dialkyl acetylene dicarboxylates, and N-bromo-/
N-iodosuccinimides
⇑
⇑
Qinglei Chong, Chunxiang Wang, Dongping Wang, Haolong Wang, Fan Wu, Xiaoyi Xin , Boshun Wan
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The DABCO-catalyzed reaction of propargyl alcohols with dialkyl acetylene dicarboxylates and N-bromo-/
N-iodosuccinimides under mild conditions has been developed. The reactions give 3-bromo-/3-iodo-2H-
pyrans in up to 98% yield.
Received 21 October 2014
Revised 17 November 2014
Accepted 23 November 2014
Available online 28 November 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
2H-pyrans
N-Iodosuccinimide
N-Bromosuccinimide
Heterocycles
Cyclization
Introduction
reactions6 for the synthesis of 3-bromo-/3-iodo-2H-pyrans using
organic base DABCO as a catalyst (Scheme 1, Eq. 2).
2H-Pyran and its analogues have been widely used in various
areas such as materials, medicines, and agricultural chemicals.1
As a precursor, 3-bromo-/3-iodo-2H-pyrans are important inter-
mediates for the synthesis of 2H-pyran derivatives.2 To the best
of our knowledge, there are no examples of the synthesis of mono-
cyclic 3-bromo-/3-iodo-2H-pyrans from propargyl alcohols, since
they can undergo an electrocyclic ring-opening to give 1-oxatri-
enes in the presence of transition metal or at elevated tempera-
tures.3 Therefore, the development of attractive synthetic
methods for the synthesis of monocyclic 3-bromo-/3-iodo-2H-pyr-
ans is of great significance.
Results and discussions
In the course of our continuing investigation into the transfor-
mation of propargyl alcohols 1 to O-heterocycles, we found that
treatment of the model substrate 1a and 2a (R1 = Ph, R2 = 4-
IC6H4, R3 = Me) with N-iodosuccinimide (NIS) and 5 mol % DABCO
(1,4-diazabicyclo[2.2.2]octane) in dichloromethane for 12 h,
a
new style heterocycle, 3-iodo-2H-pyran, was obtained in 39% yield
(Table 1, entry 1). Only DABCO among all the tested bases could
selectively afford the 2H-pyran compound after 12 h (Table 1,
entries 1–6). The reaction did not proceed in the absence of DABCO
(Table 1, entry 7). Delightfully, the product was obtained in a
satisfactory yield (88%, Table 1, entry 8) when the reaction was
conducted in a 1:1:1.5 molar ratio (1a:2a:NIS) at 40 °C. Increasing
the amount of NIS or lowering the temperature did not improve
the product yield (Table 1, entries 9–11). The structure was unam-
biguously confirmed by single-crystal X-ray diffraction analysis of
its derivative 3j.7
With this result in hand, we explored the scope of this reaction,
and the results are shown in Table 2.8 When R1 groups were the
phenyl group, R2 groups bearing different substituents: neutral
groups (Table 2, entries 2–3), halogen groups (Table 2, entries 1
and 6–10), the cyano-group (Table 2, entry 11) were well tolerated,
The groups of Toste4 and Kirsch3c,5 have reported a convenient
method for the synthesis of monocyclic 2H-pyrans via Ag(I) or
Au(I)-catalyzed propargyl-Claisen rearrangement (Scheme 1, Eq.
1). It should be noted that the transition metals are essential and
the corresponding 2H-pyrans with bromine or iodine are not inves-
tigated. Herein, this study will focus on the reaction of propargyl
alcohols, dialkyl acetylene dicarboxylates, and N-bromo-/N-
iodosuccinimides in one pot, as well as the discovery of new
N-bromo-/N-iodosuccinimides-induced electrophilic cyclization
⇑
Corresponding authors. Tel.: +86 411 84379260; fax: +86 411 84379223.
E-mail addresses: xyxin@dicp.ac.cn (X. Xin), bswan@dicp.ac.cn (B. Wan).
http://dx.doi.org/10.1016/j.tetlet.2014.11.111
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

402
Q. Chong et al. / Tetrahedron Letters 56 (2015) 401–403
Table 2
Previous work:
Scope of synthesis of 3-bromo-/3-iodo-2H-pyransa
R1
CO2R4
R3
R1
R1
CO2R3
+
DABCO (5 mol%)
CO2R3
R3
X
X
N
S (1.5 equiv)
+
R2 OH
X = I, Br
R2
O
CO2R3
CO2
R2 OH
3
1
2
R1
R1
(TFP)AuCl + AgBF4
or AgSbF6
CO2R4
R3
Entry
R1
R2
R3
NXS
Yieldb (%)
CO2R4
R3
(1)
(2)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeC6H4
4-ClC6H4
Ph
Ph
Ph
4-IC6H4
Me
Et
Et
Et
Et
Et
Et
Et
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NBS
NBS
NBS
NBS
NBS
NBS
88 (3a)
82 (3b)
63 (3c)
85 (3d)
32 (3e)
49 (3f)
88 (3g)
87 (3h)
82 (3i)
98 (3j)
89 (3k)
77 (3l)
93 (3m)
73 (3n)
55 (3o)
97 (3p)
72 (3q)
96 (3r)
92 (3s)
R2
O
R2
O
+
3-MeC6H4
4-MeC6H4
1-naphthyl
2-naphthyl
2-FC6H4
This work:
R1
R1
CO2R3
DABCO (5 mol%)
CO2R3
X
X
N
S (1.5 equiv)
X = I, Br
R2
O
CO2
R3
R3
3-FC6H4
CO2
R2 OH
4-ClC6H4
2,3-Cl2C6H3
2,3-Cl2C6H3
4-CNC6H4
Ph
9
Scheme 1. Synthesis of 2H-pyran.
10
11
12
13
14
15
16
17
18
19
Table 1
Ph
a
Screening of the reaction conditions
3-MeC6H4
1-naphthyl
3-FC6H4
2,3-Cl2C6H3
Ph
Ph
CO2Me
Ph
Base (5 mol%)
I
CO2Me
CO2Me
I
N S (x equiv)
Ph
4-ClC6H4
4-FC6H4
+
4-IC6H4
O
3a
CO2Me
4-IC6H4 OH
2,3-Cl2C6H3
1a
2a
a
Conditions:
1 (0.5 mmol), 2 (0.5 mmol), DABCO (5 mol %), NIS, or NBS
(0.75 mmol), under Ar for 12 h, 40 °C for NIS (50 °C for NBS).
b
Entry
Base
x
Yieldb (%)
Isolated yields.
1
2
3
4
5
6
7
8
DABCO
DBU
NMM
NEt3
K2CO3
NaOAc
—
DABCO
DABCO
DABCO
DABCO
1
1
1
1
1
1
1
1.5
6
39
N.R.c
N.R.c
N.R.c
N.R.c
N.R.c
N.R.c
88
Ph
CO2Me
CO2Me
4-IC6H4
Ph
O
CO2Me
Ph
6a
DABCO (5 mol%)
CH2Cl2 40 °C
CO2Me
(1)
+
CO2Me
,
9
10
11
43
4-IC6H4 OH
4-IC6
H4
8
1.5
49
CO2Me
1a
2a
O
9d
11a
68%
a
Conditions: 1a (0.5 mmol), 2a (0.5 mmol), base (5 mol %), NIS (x equiv), CH2Cl2
Ph
CO2Me
Ph
DABCO (5 mol%)
(2 mL), under argon atmosphere for 12 h, 40 °C.
I
CO2Me
CO2Me
I
N S (1.5 equiv)
b
+
Isolated yields.
N.R. = No reaction.
25 °C.
(2)
°
C
CH2Cl2 90
,
c
O
OH
1b
CO2Me
2a
(in sealed tube)
d
3t
52%
Ph
DABCO (5 mol%)
CO2Me
+
1b
2a
°
C
CH2Cl2 25
(3)
,
and the desired products were obtained with good to excellent
yields. Naphthalene was also suitable for this process (Table 2,
entries 4–5). Aryl R1 groups also appeared quite tolerant with dif-
ferent substituents (Table 2, entries 12–13). When N-bromosuccin-
imide (NBS) was used instead of NIS at 40 °C, this reaction was not
completive even with a longer reaction time (48 h). Therefore we
raised the temperature to 50 °C and the products were obtained
in satisfactory yields (Table 2, entries 14–19).
O
CO2Me
6b
6c
and
DABCO (5 mol%)
NIS (1.5 equiv)
:
=
:
0.59
3t 6c
1
°
C
CH2Cl2 90
,
(in sealed tube)
(4)
6b
6c
and
NIS (1.5 equiv)
:
=
:
0.58
3t 6c
1
°
C
CH2Cl2 90
,
To elucidate the mechanism of this protocol, many experiments
were carried out. The results are shown in Scheme 2. We found
that the treatment of the model substrate 1a and 2a without NIS
in dichloromethane for 12 h, dimethyl 5-(4-iodobenzyl)-4-phenyl-
furan-2,3-dicarboxylate 11a instead of dimethyl 2-((1-(4-iodo-
phenyl)-3-phenylprop-2-ynyl)oxy)maleate 6a, was obtained in
68% yield (Scheme 2, Eq. 1). It is noteworthy that when R2 was
hydrogen atom, this cyclization could also proceed in a sealed tube
(Scheme 2, Eq. 2). Fortunately, the addition products 6b and 6c
were easily obtained from propargyl alcohol 1b (Scheme 2, Eq.
3). When 6b and 6c were allowed to react under 90 °C, the corre-
sponding products 3t and 6c were generated in a 1:0.59 ratio as
determined by 1H NMR analysis (Scheme 2, Eq. 4). In contrast, in
the absence of DABCO, almost the same ratio of 3t and 6c were
(in sealed tube)
Scheme 2. Mechanistic studies.
detected by 1H NMR spectroscopy (Scheme 2, Eq. 4), indicating that
DABCO was dispensable in the transformation of the intermediate
6 to the final product.
On the basis of these experimental results, a plausible reaction
mechanism is depicted in Scheme 3. Initially, intermediate 49 is
formed from DABCO and dialkyl acetylene dicarboxylates 2. Then,
the zwitterionic 4 is attacked by propargyl alcohol 1 to form 5.
After release the DABCO catalyst, propargyl vinyl ether 610 is
abstracted. Intermediate 6 undergoes electrophilic cyclization with

Q. Chong et al. / Tetrahedron Letters 56 (2015) 401–403
403
X
N
R1
O
O
R1
N
X
CO2R3
CO2R3
CO2R3
CO2R3
CO2R3
( X=Br/I)
2
N
R2
O
R2
O
6
CO2R3
( DABCO)
7
O
O
O
N
8
R1
CO2R3
R3O2C
CO2
R3
O
N
N
8
R2
O
R1
CO2R3
R1
CO2R3
H
N
X
R3
CO2
X
N
4
N
R2
O
3
CO2R3
R2
O
CO2R3
OH
R2
H
5
N
O
O
9
R1
1
10
Scheme 3. Proposed mechanism.
NIS (or NBS) to furnish 7 and succinimide anion 8.6 Subsequent
cyclization of cation 7 generates cation 9. The succinimide anion
8 traps a proton of 9 to form succinimide 10 and releases product
3.
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Conclusion
In summary, we have developed an efficient entry to 3-bromo-/
3-iodo-2H-pyrans via an efficient N-bromo-/N-iodosuccinimide-
induced organic base DABCO catalyzed electrophilic cyclization
reaction of propargyl alcohols with dialkyl acetylene dicarboxyl-
ates in up to 98% yield. The mechanism involving the electrophilic
cyclization step was established. The easily and commercially
available starting materials, mild reaction conditions, combined
with operational feasibility, make this method practical. This study
provides a framework for further explorations of 3-bromo-/3-iodo-
2H-pyrans derivatives.
5. Menz, H.; Kirsch, S. F. Org. Lett. 2006, 8, 4795.
6. (a) Xin, X. Y.; Wang, D. P.; Wu, F.; Li, X. C.; Wan, B. S. J. Org. Chem. 2013, 78,
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7. CCDC 988280 (3j) contains the supplementary crystallographic data for this
Letter. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
8. (a) General experimental procedure for the synthesis of 3-bromo-/3-iodo-2H-
pyrans 3: Propargyl alcohols 1 (0.5 mmol), dialkyl acetylene dicarboxylates 2
(0.5 mmol) and DABCO (0.025 mmol) were placed in a dried flask. NBS or NIS
(0.75 mmol) in CH2Cl2 (2 mL) was added slowly. The resulting mixture was
stirred at 40 °C (for NIS) or 50 °C (for NBS) under argon atmosphere until the
consummation of raw material 1 detected by TLC. The solvent was evaporated
under vacuum and the crude product was directly purified by silica gel flash
column chromatography (eluent: 4:1 petroleum ether/ethyl acetate) to give
the desired compound 3.
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (21172218) for financial support.
Supplementary data
9. (a) Nair, V.; Bindu, S.; Sreekumar, V.; Rath, N. P. Org. Lett. 2003, 5, 665; (b) Fan,
M. J.; Li, G. Q.; Liang, Y. M. Tetrahedron 2006, 62, 6782.
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Chong, Q. L.; Xin, X. Y.; Wang, C. X.; Wu, F.; Wang, H. L.; Shi, J. C.; Wan, B. S. J.
Org. Chem. 2014, 79, 2105.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.11.
111.
References and notes
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