Mild boronic acid catalyzed Nazarov cyclization of divinyl alcohols in tandem with Diels-Alder cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2012.10.100

Boronic acid catalysis (BAC) was applied to a sequential Nazarov cyclization of divinyl alcohols/Diels-Alder cycloadditions leading to the preparation of highly functionalized bicyclic compounds in a highly diastereoselective fashion. In these one-pot transformations, highly functionalized dienes were generated in situ through boronic acid catalyzed Nazarov cyclizations of divinyl alcohols and were subsequently trapped with different dienophiles such as maleic anhydride and phenylmaleimide. The tandem reactions proceed directly from divinyl alcohols under very mild reaction conditions using air-stable catalysts, and as such this methodology represents a greener alternative to existing methods employing strong Lewis and Bronsted acids.

Full text of DOI:10.1016/j.tetlet.2012.10.100

Tetrahedron Letters 54 (2013) 91–94
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Mild boronic acid catalyzed Nazarov cyclization of divinyl alcohols in tandem
with Diels–Alder cycloaddition
⇑
Hongchao Zheng, Michal Lejkowski, Dennis G. Hall
Department of Chemistry, Gunning-Lemieux Chemistry Centre, 4-010 Centennial Centre for Interdisciplinary Science, University of Alberta, Edmonton, Alberta, Canada T6G 2G2
a r t i c l e i n f o
a b s t r a c t
Article history:
Boronic acid catalysis (BAC) was applied to a sequential Nazarov cyclization of divinyl alcohols/Diels–
Alder cycloadditions leading to the preparation of highly functionalized bicyclic compounds in a highly
diastereoselective fashion. In these one-pot transformations, highly functionalized dienes were generated
in situ through boronic acid catalyzed Nazarov cyclizations of divinyl alcohols and were subsequently
trapped with different dienophiles such as maleic anhydride and phenylmaleimide. The tandem reactions
proceed directly from divinyl alcohols under very mild reaction conditions using air-stable catalysts, and
as such this methodology represents a greener alternative to existing methods employing strong Lewis
and Brønsted acids.
Received 1 October 2012
Accepted 23 October 2012
Available online 1 November 2012
Keywords:
Boronic acids
Carbocycles
Diels–Alder cycloadditions
Divinyl alcohols
Nazarov cyclization
Ó 2012 Elsevier Ltd. All rights reserved.
Hydroxyl is a poor leaving group and therefore pre-activation
with recourse to intermediary functionalities such as halides and
pseudo-halides (e.g., sulfonates, oxyphosphonium) is usually
required for nucleophilic substitution.1 The consideration of
atom- and step-economy and the use of environmentally friendlier
reactions are becoming a key theme in many research areas. In this
regard, the ACS Green Chemistry Institute Pharmaceutical Roundtable
ranked ‘alcohol activation for nucleophilic substitution’ as the sec-
ond most important priority area for green chemistry research.2
Highly Lewis acidic electron-deficient arylboronic acids 1 are
emerging as a promising new class of organocatalysts for the direct
activation of alcohols by facilitating the complete or partial ioniza-
tion of the C–O bond (Scheme 1).3–5 This concept of covalent hy-
droxyl activation has been successfully applied to a broad range
of classical chemical transformations, including Friedel–Crafts
alkylations,3a–c 1,3-transpositions of allylic alcohols,3d Meyer–
Schuster rearrangements of propargylic alcohols,3d and a variety
of cationic cyclizations of allylic alcohols.3e Faster reactions, milder
reaction conditions, and increased selectivity are the main benefits
provided by boronic acid catalysis (BAC). Inspired by these
successful examples, we sought to expand the BAC concept to
other synthetically useful organic reactions, such as the Nazarov
cycloaddition, and further demonstrate its mildness and
versatility.
Ar
B
ArB(OH)2
δ-
O
R1
R2
ArB(OH)3
R3
(1, cat.)
OH
R3
:Nu
electrophilic activation electrophilic activation
δ+
R2
R1
or
R3
:Nu
R1
OH
R2
SN1' pathway SN2' pathway
Scheme 1. The concept of hydroxyl activation using boronic acid catalysis.
tion, upon activation with a Lewis or Brønsted acid, the divinyl ke-
tone substrate 2 generates a hydroxyl-substituted pentadienyl
cation 3 as a key intermediate, which then undergoes a 4p-electrocyclic
ring closure to furnish the cyclopentenone 4 as the final product
(Scheme 2).6 It can be envisioned that a pentadienyl cation 6 can
be generated from a different class of substrates, divinyl alcohols
5, under boronic acid catalysis (Scheme 2). Subsequently, the
formed pentadienyl cations 6 can undergo the Nazarov cyclization
to provide synthetically useful cyclic dienes 8 via the elimination of
cyclopentyl allylic cations 7 (Scheme 2). Although the Nazarov
reactions of divinyl ketone substrates have been studied exten-
sively,6 there are only sporadic reports of using divinyl alcohols
of type 5 as starting materials.7 Moreover, nearly all methods in
the literature require either strongly acidic or toxic metal based
catalysts. Therefore, a milder and environmentally friendlier alter-
native is highly desirable. As part of our program aimed at explor-
ing the use of boronic acids as catalysts and stoichiometric reaction
promoters,8 herein we report a mild and efficient Nazarov cycliza-
tion of divinyl alcohols in tandem with Diels–Alder cycloadditions
to afford highly functionalized bicyclic compounds in a single
operation.
The Nazarov cyclization is a widely employed chemical trans-
formation allowing the synthesis of cyclopentenones such as 4
from divinyl ketone 2 (Scheme 2).6 In the classical Nazarov reac-
⇑
Corresponding author. Tel.: +1 780 492 3141; fax: +1 780 492 8231.
E-mail address: dennis.hall@ualberta.ca (D.G. Hall).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.100

92
H. Zheng et al. / Tetrahedron Letters 54 (2013) 91–94
Table 1
classical Nazarov reaction:
Optimization of reaction conditions in the boronic acid catalyzed sequential Nazarov
H
cyclization/Diels–Alder reactiona
O
O
OH
4π e−
O
H+ or LA
cyclization
O
B(OH)2
F
O
2
3
4
Ph
Ph
OH
Ph
F
F
9
O
O
our proposal
:
(1.0 equiv)
F
R1
O
ArB(OH)2
Ar
4π e−
cyclization
R1
OH
solvent, additive
50 oC, 16 h
Ph
Ph
R2
R3
R5
R4
R2
R3
R5
R4
Ph
O
5a
10a
Entry
Solvent
Catalyst (mol %)
Additive
Yieldb (%)
OH
OH
OH
6
5
B
1
2
3
4
5
6
7
8
DMF
EtOAc
THF
Acetone
Hexanes
DCE
Toluene
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
20
20
20
20
20
20
20
20
10
5
20
20
20
20
20
20
No additive
No additive
No additive
No additive
No additive
No additive
No additive
No additive
No additive
No additive
12
16
31
58
85
88
90
95
71
41
32
83
R1
R1
R1
R2
R3
R2
R3
R5
R5
R4
R2
R5
R4
-H+
or
R4
R3
9
8
7
10
11
12
13
14
15
16
4 Å Molecular sievesc
H2O (1.0 equiv)
ZrCl4 (20 mol %)
TsOH (20 mol %)
TsOH (20 mol %)
No additive
Scheme 2. Proposed boronic acid catalyzed Nazarov cyclizations.
d
—
31e
39f
0g
B(OH)2
F
a
Reaction conditions: Unless specified, the reaction was performed with divinyl
F
F
Ph
Ph
Ph
Ph
alcohol 5a (0.2 mmol), maleic anhydride (0.2 mmol), and tetrafluorophenylboronic
OH
Ph
F
acid 9 (0.01–0.04 mmol) at 50 °C in a solvent (1 mL) for 16 h.
b
9
(20 mol%)
Isolated yields of product 10a after purification by silica gel column
+
chromatography.
DCM, rt, 48 h
Ph
Ph
c
4 Å Molecular sieves (200 mg) were employed as the additive.
A complex mixture was obtained.
Sixty percentage of hydrolysis product (dicarboxylic acid) was isolated as the
Ph
Ph
d
5a
8a
8b
E
91% (1:2.2)
side product.
f
The reaction was performed in the absence of boronic acid catalyst 9 and 55% of
Scheme 3. A preliminary test for the boronic acid catalyzed Nazarov cyclization.
hydrolysis product (dicarboxylic acid) was isolated as the side product.
g
The reaction was performed in the absence of boronic acid catalyst 9.
As a preliminary test, the Nazarov reaction of divinyl alcohol 5a
was found to proceed smoothly at room temperature using elec-
tron deficient arylboronic acid 9 as the catalyst, providing mixtures
of polysubstituted cyclopentadienes 8a and 8b in excellent yield
(Scheme 3). This result showed the suitability of electron deficient
arylboronic acid 9 as a catalyst to promote the Nazarov reaction.
Maleic anhydride is a remarkably good dienophile and as such it
was employed as a model partner to trap the formed dienes 8 (Ta-
ble 1). Although the Nazarov reactions of divinyl alcohols could
proceed smoothly at room temperature (Scheme 3), a slightly high-
er reaction temperature (50 °C) was necessary to ensure the com-
pletion of the subsequent Diels–Alder cycloaddition within a
reasonable time (Table 1). In the first round of optimization, sev-
eral solvents were evaluated in the sequential Nazarov cycliza-
tion/Diels–Alder trapping of model divinyl alcohol 5a catalyzed
by 9 (Table 1). Although some non-polar aprotic or halogenated
solvents like toluene, hexanes, or 1,2-dichloroethane were quite
effective, the highly polar aprotic solvent nitromethane was supe-
rior (Table 1, entry 8). A lower yield was obtained when a lower
catalyst loading was employed (Table 1, entries 9 and 10). Further-
more, the use of dehydrating agents such as molecular sieves was
detrimental, while excess water showed a subtle influence on the
reaction (Table 1, entries 11 and 12). Then, a number of simple
additives were screened but none provided any observable rate
acceleration (Table 1, entries 13 and 14). Interestingly, when a
strong Brønsted acid like p-TsOH was used as the additive or as
the catalyst, the formed cycloadduct 10a could further undergo
hydrolysis to provide the corresponding dicarboxylic acid as the
major product (Table 1, entries 14 and 15). This result provides evi-
dence for the mildness of our BAC methodology. Finally, a control
run in the absence of boronic acid catalyst 9 led to no product for-
mation (Table 1, entry 16).
Using the optimal conditions of entry 8,9 the scope of substi-
tuted divinyl alcohols was explored using maleic anhydride as
the dienophile (Table 2, entries 1–6). In the event, a wide selection
of substituted divinyl alcohols was tolerated. In all cases, the de-
sired cycloadduct 10 was obtained in excellent yield as a single iso-
mer (Table 2, entries 1–5). However, a trivinyl alcohol afforded a
low yield of the desired product due to the competition between
two possible Nazarov cyclizations (Table 2, entry 6). Phenylmale-
imide is also suitable as a dienophile for trapping the formed cyclo-
pentadienes 8 (Table 2, entries 7–10). Compared with maleic
anhydride, it exhibited lower efficiency for the sequential Nazarov
cyclization/Diels–Alder trapping (Table 2, entries 7–10). NMR
experiments were performed on 10d to determine the relative ste-
reochemistry of the cycloadducts. From the 1H NMR spectrum, Ha,
Hb, and Hc could be identified as the signals at 2.99, 3.52, and
4.22 ppm, respectively. Then the strong NOE correlations of Ha
M
Hb and Ha M Hc clearly indicated that the produced cycloadducts
10 corresponded to the endo isomer (Fig. 1). To address the origin
of the stereoselectivity in this sequential process, a control exper-
iment was conducted (Scheme 4). When one isomer 8b was re-
subjected to the reaction conditions, a mixture of two isomers
was obtained. This result confirms that a thermodynamic equili-
bration between two isomers is occurring under the reaction con-
ditions, likely via 1,5-H shift. The subsequent Diels–Alder reaction
is most likely under kinetic control and favored with the less steri-
cally hindered isomer 8a, thus providing the cycloadduct 10a as
the exclusive diastereomer (Scheme 4).

H. Zheng et al. / Tetrahedron Letters 54 (2013) 91–94
93
Table 2
Acknowledgments
Substrate scope in the boronic acid catalyzed sequential Nazarov cyclization/Diels–
Alder reactiona
This research was generously funded by the Natural Sciences
and Engineering Research Council (NSERC) of Canada and the Uni-
versity of Alberta. H.Z. thanks the Alberta Ingenuity Foundation for
a Graduate Scholarship and the University of Alberta for a Queen
Elizabeth II Graduate Scholarship.
B(OH)2
O
F
X
Ph
R
F
F
OH
R
F
O
O
(1.0 equiv)
9 (20 mol%)
Supplementary data
X
CH3NO2
Ph
50 oC, 16 h
Ph
Ph
O
5
Supplementary data (experimental procedures, NMR spectra)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2012.10.100.
10
Entry
R
X
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
Ph
n-Bu
Me
CH2CH@CH2
C„CPh
CH@CH2
Ph
n-Bu
Me
CH2CH@CH2
O
O
O
O
O
O
NPh
NPh
NPh
NPh
10a
10b
10c
10d
10e
10f
10g
10h
10i
95
88
91
85
87
30
58
62
60
55
References and notes
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10j
a
Unless specified, the reaction was performed with divinyl alcohol 5 (0.2 mmol),
maleic anhydride or phenylmaleimide (0.2 mmol), and tetrafluorophenylboronic
acid 9 (0.04 mmol) at 50 °C in nitromethane (1 mL) for 16 h.
b
Isolated yields of product 10 after purification by silica gel column
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Whiting, A. Acc. Chem. Res. 2009, 42, 756–768; (b) Charville, H.; Jackson, D.;
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chromatography.
Ha
Ph
Hb
Ha: 2.99 ppm
O
Hb: 3.52 ppm
Hc
O
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B. J. Am. Chem. Soc. 1963, 85, 2230–2236; (b) Letsinger, R. L.; Dandegao, S.;
Morrison, J. D.; Vullo, W. J. J. Am. Chem. Soc. 1963, 85, 2223–2227; (c) Letsinger,
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Hc: 4.22 ppm
Ph
O
10d
Figure 1. Illustration of NOE correlations for 10d.
Ph
Ph
Ph
Ph
Ph
Ph
9 (20 mol%)
CH3NO2, 50 oC, 16 h
Ph
+
Ph
Ph
8b
8a
8b
(1:2)
O
O
Ph
Ph
Ph
reaction
O
O
Ph
Ph
Ph
Ph
conditions
(1.0 equiv)
O
Ph
Ph
8b
8a
O
10a
sterically favored diene
Scheme 4. Control experiment to address the origin of the stereoselectivity in the
boronic acid catalyzed sequential Nazarov cyclization of divinyl alcohols/Diels–
Alder reaction.
In summary, we have reported the application of boronic acid
catalysis for the direct activation of allylic alcohols in a sequential
Nazarov cyclization/Diels–Alder reaction involving divinyl alcohols
as the substrates. These Nazarov cyclizations produce highly func-
tionalized cyclic dienes and bicyclic cycloadducts effectively using
an air-stable boronic acid catalyst under mild reaction conditions.
Therefore, it represents an environmentally advantageous alterna-
tive to existing methods employing strong Lewis and Brønsted
acids. Further studies of this reaction process will be aimed at
applying the BAC concept to ‘interrupted’ Nazarov cyclizations.
8. (a) Refs. 3d–e, 5o, 5r,s, and 5v.; (b) Zheng, H.; Hall, D. G. Tetrahedron Lett. 2010,
51, 4256–4259.
9. Typical experimental procedure for the boronic acid catalyzed sequential Nazarov
cyclization of divinyl alcohols/Diels–Alder trapping: To a solution of the divinyl
alcohol 5a (68 mg, 0.2 mmol) and maleic anhydride (20 mg, 0.2 mmol) in
nitromethane (1 mL) at room temperature was added 2,3,4,5-tetrafluorophenyl

94
H. Zheng et al. / Tetrahedron Letters 54 (2013) 91–94
boronic acid 9 (8 mg, 0.04 mmol). The resulting solution was stirred at 50 °C for
3.67 (d, J = 8.2 Hz, 1H), 3.22 (s, 1H), 1.75 (s, 3H), 1.50 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 170.8, 170.2, 141.3, 139.9, 135.9, 135.4, 133.8, 130.4, 129.2, 129.2,
128.4, 128.2, 127.9, 127.58, 127.57, 127.4, 78.4, 67.8, 60.6, 54.7, 52.3, 16.5, 14.6;
IR (Microscope, cmÀ1) 3059, 3030, 2968, 2930, 1859, 1778, 1560, 1494, 1448;
HRMS (EI) for C29H24O3: calcd 420.1726; found 420.1733.
16 h. Upon evaporation of the solvent under reduced pressure, the residue was
purified by silica gel column chromatography (EtOAc/Hexanes = 1:10) to give
the anhydride 10a (80 mg, 95%) as a white solid: 1H NMR (400 MHz, CDCl3) d
7.43–7.37 (m, 2H), 7.36-7.16 (m, 11H), 7.03–6.98 (m, 2H), 4.35 (d, J = 8.2 Hz, 1H),