One-pot synthesis of functionalized 2,5-dihydrofurans via an amine-promoted Petasis borono-Mannich reaction

Article abstract of DOI:10.1021/ol402782f

A series of functionalized 2,5-dihydrofurans were efficiently synthesized via an amine-promoted Petasis borono-Mannich reaction of 4-substituted 1,2-oxaborol-2(5H)-ols with salicylaldehydes in high yields. The process, which combines a boronic acid-based Mannich reaction and a highly efficient intramolecular S_N2 cyclization, provides a one-step and efficient route toward 2,5-dihydrofurans from simple and stable starting materials.

Full text of DOI:10.1021/ol402782f

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
One-Pot Synthesis of Functionalized
2,5-Dihydrofurans via an Amine-Promoted
Petasis BoronoÀMannich Reaction
Chun-Xiao Cui,† Hui Li,‡ Xian-Jin Yang,*,† Jun Yang,*,‡ and Xiao-Qiang Li‡
Key Lab for Advanced Materials & Institute of Fine Chemicals, East China University of
Science and Technology, 130 Meilong Road, Shanghai 200237, China, and Shanghai
Institute of Organic Chemistry, Chinese Academy of Science, 345 Lingling Road,
Shanghai 200032, China
yxj@ecust.edu.cn; yangj@sioc.ac.cn
Received September 26, 2013
ABSTRACT
A series of functionalized 2,5-dihydrofurans were efficiently synthesized via an amine-promoted Petasis boronoÀMannich reaction of 4-substituted
1,2-oxaborol-2(5H)-ols with salicylaldehydes in high yields. The process, which combines a boronic acid-based Mannich reaction and a highly
efficient intramolecular SN2 cyclization, provides a one-step and efficient route toward 2,5-dihydrofurans from simple and stable starting materials.
2,5-Dihydrofurans are a class of useful and versatile
intermediates in organic syntheses. They also serve as
common structural building blocks in a wide variety of
bioactive natural and unnatural products.1,2 Moreover, a
large number of 2,5-dihydrofuran derivatives containing a
phenolic group at the 2-position are reported to possess a
diverse range of bioactivities. For instance, a new mono-
terpenylbenzenoid, 9,17-epoxyarnebinol (Figure 1), iso-
lated from the stem bark of Arnebia euchroma, has anti-
HCV and antibacterial activities.3 Dihydroshikonofuran
(Figure 1) isolated from the shikonin-free cell suspen-
sion of Lithospermum erythrorhizon4 and pteleifolins C
(Figure 1) isolated from Melicope pteleifolia, a traditional
Chinese medicine,5 also exhibit interesting biological activ-
ities. As a consequence, the development of practical
synthetic routes to access such compounds is of significant
interest.
Recently, several synthetic strategies for preparation
of 2,5-dihydrofurans have been reported, which include
RCM and Prins reactions, Ag(I)-catalyzed rearrangementÀ
cyclization, and Pd(0)-, Au(I)-, Ag(I)-, Hg(II)-, Au(III)-, or
Ru(III)-catalyzed cyclization reactions.6À17 However, some
† East China University of Science and Technology.
‡ Shanghai Institute of Organic Chemistry.
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Ogasawara, K. Synlett. 1995, 427. (d) Kim, S.; Kim, K. H. J. Chem. Soc.,
Perkin Trans. 1 1997, 1095. (e) Paolucci, C.; Musiani, L.; Venturelli, F.;
Fava, A. Synthesis. 1997, 1415. (f) Shieh, S.-J.; Fan, J.-S.; Chandrasekharam,
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r
10.1021/ol402782f
XXXX American Chemical Society

of these methods are still suboptimal because of the diffi-
culty in obtaining the raw materials, use of expensive
catalysts, and the harsh reaction conditions and multistep
synthetic procedures. Consequently, novel efficient methods
for synthesis of functionalized 2,5-dihydrofurans are much
needed.
Scheme 1
The Petasis boronoÀMannich reaction is a highly ver-
satile multicomponent reaction that utilizes readily avail-
able components capable of incorporating a wide range
of functional groups into the product. This method-
ology allows the synthesis of a large variety of interesting
molecules, including allylamines, amino acids, amino
ketones, amino alcohols, amino sugars, and several types
of heterocycles.18,19 Petasis and co-workers first reported
that organoboronic acids react with amines and salicylal-
dehydes to give amino phenols.20 Finn and co-workers
reportedthat a catalytic Petasis reaction of salicylaldehydes
and vinylboronic acids is applicable to the preparation
of 2H-chromenes.21 After then, Petasis and co-workers
described the synthesis of 2H-chromenes and 1,2-dihydro-
quinolines from arylaldehydes, amines, and alkenylboron
compounds.22 As far as we know, there is not any report
on the Petasis reaction of multisubstituted alkenyl boronic
acid. Moreover, no method for the construction of
2,5-dihydrofurans via Petasis reaction has been reported.
Scheme 2
Here in we report an efficient one-step synthetic route
toward 2,5-dihydrofuran derivatives via an amine-promoted
Petasis boronoÀMannich reaction of 4-substituted 1,2-
oxaborol-2(5H)-ols with salicylaldehydes.
The synthesis of 4-substituted 1,2-oxaborol-2(5H)-ols
was reported previously by our group.23 They can be easily
prepared through copper-catalyzed carbomagnesation
of propargyl alcohol, followed by the transmetalation of
magnesium to boron in a one-pot procedure (Scheme 1).
4-Phenyl-1,2-oxaborol-2(5H)-ol 1a, salicylaldehyde 2a,
and morpholine 3a were first chosen for a model reaction.
As shown in Scheme 2, the reaction took place after
the mixture was heated in C2H5OH at 85 °C for 24 h.
The isolated product was characterized as 2-(4-phenyl-2,5-
dihydrofuran-2-yl)phenol (4a), which is composed of a
2,5-dihydrofuran core. The effect of different solvents, the
temperature, and reaction time were then optimized, and
the results are summarized in Table 1. As shown in Table 1,
the reaction is very sensitive to solvents; 1,2-dichlor-
oethane was found to be the best solvent of the reaction
(Table 1, entry 6). We then noticed that the yield decreased
with fall of temperature (Table 1, entries 6, 13, and 14),
and the best reaction time was found to be 24 h as both
decreased (Table 1, entries 15 and 16) and increased
(Table 1, entry 17) reaction times led to decreased yields.
With the optimized reaction conditions in hand, we
studied whether using a range of other amines would yield
a better result. The results are summarized in Table 2.
Structurally different amines were tested (Table 2, entries
1À11), and we determined that, with electron-rich sec-
ondary amines such as cyclic amine and dibenzylamine,
moderate to good yields could be afforded (73À90%).
However, N-ethylbenzylamine, N-methylbenzylamine, and
diethylamine gave lowered yields (61%, 58%, and 56%,
respectively) (Table 2, entries 4À6).
Figure 1. Biologically active natural products with 2,5-dihydro-
furan unit, which might be synthesized via Petasis reaction.
(13) (a) Olsson, L. I.; Claesson, A. Synthesis 1979, 743. (b) Nikam,
S. S.; Chu, K. H.; Wang, K. K. J. Org. Chem. 1986, 51, 745.
(14) (a) Marshall, J. A.; Sehon, C. A. J. Org. Chem. 1995, 60, 5966. (b)
Marshall, J. A.; Yu, R. H.; Perkins, J. F. J. Org. Chem. 1995, 60, 5550.
(15) (a) Deng, Y.-Q.; Shi, Y.-L.; Ma, S.-M. Org. Lett. 2009, 11, 1205.
(b) Chen, B.; Lu, Z.; Chai, G. B.; Fu, C.-L.; Ma, S.-M. J. Org. Chem.
2008, 73, 9486. (c) Deng, Y.-Q.; Yu, Y.-H.; Ma, S.-M. J. Org. Chem.
2008, 73, 585.
(16) (a) Yoneda, E.; Kaneko, T.; Zhang, S. W.; Onitsuka, K.;
Takahashi, S. Org. Lett. 2000, 2, 441. (b) Trost, B. M.; Pinkerton,
A. B. J. Am. Chem. Soc. 1999, 121, 10842.
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Born, D. H.; Kang, D. J.; Lee, P. H. J. Org. Chem. 2010, 75, 7447.
ꢀ
(18) Zhu, J.; Bienayme, H. Multicomponent Reactions; Wiley-VCH:
Weinheim, 2005. For a review on the use of organoboron compounds, see:
Petasis, N. A. Multicomponent Reactions with Organoboron Compounds;
Wiley-VCH: Weinheim, 2005; pp 199À223.
When amines with a bulky steric hindrance were used as
catalyst, no product was given (Table 2, entries 7, 8, and 10).
(19) Candeias, N. R.; Montalbano, F.; Cal, P. M. S. D.; Gois,
P. M. P. Chem. Rev. 2010, 110, 6169.
(20) Petasis, N. A.; Boral, S. Tetrahedron Lett. 2001, 42, 539.
(21) Wang, Q.; Finn, M. G. Org. Lett. 2000, 2, 4063.
(22) Petasis, N. A.; Butkevich, A. N. J. Organomet. Chem. 2009, 694,
1747.
(23) Fang, G.-H.; Yan, Z.-J.; Yang, J.; Deng, M.-Z. Synthesis 2006,
7, 1148.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimization of Reaction Conditions
Table 3. Substrate Scopea
entry
solvent
C2H5OH
temp (°C)
time (h)
yieldb (%)
1a
2
85
85
85
85
85
85
100
100
60
50
85
90
60
40
85
85
85
24
24
24
24
24
24
24
24
24
24
24
24
24
24
6
34
52
21
64
31
90
29
14
62
26
40
50
55
6
Toluene
3
DMF
4
H2O
5
(CH3)2CHOH
ClCH2CH2Cl
HOCH2CH2OH
DMSO
6
7
8
9
(CF3)2CHOH
CH2Cl2
10
11
12
13
14
15
16
17
CH3CN
1,4-dioxane
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
79
86
87
12
48
a The reaction was performed with 4-phenyl-1,2-oxaborol-2(5H)-ol
1a (1.0 mmol), salicylaldehyde 2a (1.0 mmol), and morpholine 3a
(1.0 mmol) in C2H5OH (4 mL) at 85 °C for 24 h. b All yields were
determined by 1H NMR.
Table 2. Choice of Structure and Loading of Amines
entry
amines (equiv)
piperidine (1.0)
yieldb (%)
1a
2
65
pyrrolidine (1.0)
73
a The reaction was performed with 4-substituted 1,2-oxaborol-
2(5H)-ols 1 (1.0 mmol), salicylaldehydes 2 (1.0 mmol), and morpholine
3a (1.0 mmol) in 1,2-dichloroethane (4 mL) at 85 °C for 24 h. b Isolated
yields.
3
dibenzylamine (1.0)
N-ethylbenzylamine (1.0)
N-methylbenzylamine (1.0)
diethylamine (1.0)
diisopropylamine (1.0)
diphenylamine (1.0)
N-methylaniline (1.0)
benzhydrylamine (1.0)
morpholine (1.0)
83
4
61
5
58
6
56
7
n.d.
n.d.
15
Having identified morpholine 3a as a suitable amine for the
reaction, we next examined the effect of catalyst loading. It
is found that a gradual decrease of loading of the amine led
to gradual lowering of the yield (Table 2, entries 11À14).
Under the optimized conditions, the substrate scope
of the reaction was surveyed (Table 3). Employment of
various salicylaldehydes 2with electron-donating or electron-
withdrawing substituents on the aryl ring did not affect
thereaction performance(Table3, entries1À7). Moreover,
a salicylaldehyde bearing a bulky C2-substituent could
also afford the desired product in a good yield of 82%
8
9
10
11
12
13
14
n.d.
90
morpholine (0.5)
80
morpholine (0.3)
77
morpholine (0.1)
40
a The reaction was performed with 4-phenyl-1,2-oxaborol-2(5H)-ol
1a (1.0 mmol), salicylaldehyde 2a (1.0 mmol), and amine 3 (1.0 mmol) in
1,2-dichloroethane (4 mL) for 24 h at 85 °C. b All yields were determined
by 1H NMR.
Org. Lett., Vol. XX, No. XX, XXXX
C

electron-donating aryl R1 substituents on 1 gave the highest
yield (Table 3, entries 9 and 10), whereas alkyl R1 substitu-
tions led to slightly decreased yields (Table 3, entries 11 and
12). The structure of 4i was confirmed by X-ray single-
crystal diffraction (Figure 2).
A possible mechanism for the formation of functiona-
lized 2,5-dihydrofurans was then proposed as depicted in
Scheme 3. Initially, a nucleophilic addition of amine 3a to
salicylaldehydes 2 produces the key iminium intermediate
A. Coordination between the oxygen anion of phenolate
and the boron atom of 1 leads to the formation of a
tetracoordinate borate intermediate B. Subsequently, the
alkenyl carbanion moiety of boronic acids favorably at-
tacks the iminium ion, affording C. Then, after hydration
of intermediate C to afford D, an intramolecular SN2
reaction takes place, generating E and the recyclable amine
3a. Finally, hydrolysis of E gives rise to the cyclizated
product 4 through loss of a molecule of B(OH)3 in the
presence of a weak base.
Figure 2. X-ray crystal structure of 4i.
Scheme 3. Proposed Mechanism of the Reaction
In summary, we have developed an efficient and one-
step synthesis of functionalized 2,5-dihydrofurans via
an amine-promoted Petasis borono-Mannich reaction of
4-substituted 1,2-oxaborol-2(5H)-ols with salicylalde-
hydes. This approach represents a novel promising route
to preparing 2,5-dihydrofuran derivatives, broadening the
scope of the Petasis reaction. Further application of the
reaction in the construction of various other heterocycles is
in progress.
Acknowledgment. We are grateful to the Chinese Acad-
emy of Science, Chinese Natural Science Foundation
(Nos. 21372077, 20802088, 91017006, 90917017), for their
financial supports.
Supporting Information Available. Experimental de-
tails and characterization for all new compounds, and
crystal structure data (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
(Table 3, entry 3). Then, reactions were carried out with
a variety of differently substituted 1. The presence of
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX