Zirconium-catalyzed Nagata reaction for the synthesis of 2-aryl-1,3,2-aryldioxaborins via a mild three-component condensation of phenols, aldehydes, and boronic acid

Article abstract of DOI:10.1016/j.tetlet.2010.06.035

An efficient ZrCl₄-catalyzed ortho-hydroxyalkylation of phenols with aldehydes promoted by 3,5-bis(trifluoromethyl)phenyl boronic acid, leading to the formation of 2-aryl-1,3,2-aryldioxaborins, was investigated and optimized. The reaction afforded the desired aryldioxaborins in good to excellent yields under mild conditions at room temperature. The electron-deficient boronic acid promoter was essential. Electron-rich phenols react faster, and both alkyl and aryl aldehydes are suitable substrates. The resulting aryldioxaborins can be further elaborated to produce substituted saligenols, 2-ethoxy chromans, and 2-substituted phenols.

Full text of DOI:10.1016/j.tetlet.2010.06.035

Tetrahedron Letters 51 (2010) 4256–4259
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Zirconium-catalyzed Nagata reaction for the synthesis
of 2-aryl-1,3,2-aryldioxaborins via a mild three-component
condensation of phenols, aldehydes, and boronic acid
*
Hongchao Zheng, Dennis G. Hall
Department of Chemistry, Gunning-Lemieux, Chemistry Centre, 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:
An efficient ZrCl4 catalyzed ortho-hydroxyalkylation of phenols with aldehydes promoted by 3,5-bis
(trifluoromethyl)phenyl boronic acid, leading to the formation of 2-aryl-1,3,2-aryldioxaborins was inves-
tigated and optimized. The reaction afforded the desired aryldioxaborins in good to excellent yields under
mild conditions at room temperature. The electron-deficient boronic acid promoter was essential.
Electron-rich phenols react faster, and both alkyl and aryl aldehydes are suitable substrates. The resulting
aryldioxaborins can be further elaborated to produce substituted saligenols, 2-ethoxy chromans and
2-substituted phenols.
Received 2 May 2010
Accepted 7 June 2010
Available online 11 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
OH R2
ortho-Quinone methides 1 (Scheme 1) are versatile motifs in or-
ganic synthesis, as they are known to be very reactive intermedi-
ates with applications in the total synthesis of natural products.1
Following their generation, ortho-quinone methides (1) can under-
go a wide variety of chemical transformations. For instance, they
can be reduced to give o-alkylphenols 3;2b or they can be trapped
by alcohols/thiols and carbon nucleophiles to generate phenol
derivatives 4 and 5.2a,b A Friedel–Crafts reaction between 1 and
aromatic compounds furnished the corresponding phenols 6.2a
OH Nu
R3
X
R2
R1
(X =O, S)
R1
:Nu
4
5
R3XH
acid
OH
O
B
heat
.
Moreover, intermediates
1 can also be fused with different
or acid
R2
O
O
R2
t-BuNH2 BH3
dienophiles inter- and intramolecularly to deliver the Diels–Alder
cycloadducts 7.2b A major issue with ortho-quinone methides 1 is
their high reactivity, therefore, they are usually produced from a
stable precursor in situ and used directly in the synthesis.
2-Aryl-1,3,2-aryldioxaborins (2) are very stable at room tempera-
ture, however, they can generate ortho-quinone methides (1)
under thermolytic or acidic conditions.2 Surprisingly, only a few
approaches for the preparation of 2-aryl-1,3,2-aryldioxaborins 2
have been reported until now. The Peer group synthesized 2 from
the three-component condensation of phenylboronic acid, phenol
and paraformaldehyde by employing a carboxylic acid as the cata-
lyst under reflux in benzene.3 The Nagata group later modified the
reaction conditions (refluxing toluene) to extend the substrate
scope to various aldehydes.4 The harsh reaction conditions, how-
ever, hampered further applications to sensitive, polymerizable
AlCl3
R2
R1
R1
3
1
R1
2
OR4
R5
ArH
OR4
R5
R2
OH Ar
O
R2
R1
R1
6
7
Scheme 1. 2-Aryl-1,3,2-aryldioxaborin 2 as versatile synthetic intermediates.
aldehydes. Dufresne and co-workers developed
a novel dic-
and sensitivity to humidity of this surrogate limited its general
application. Recently, Naimi-Jamal et al. reported that microwave
irradiation can promote the transformation to 2 on the surface of
acidic alumina, which results in environmentally harmful acidic
alumina waste.6 An effective approach to synthesize 2 under sim-
ple and practical conditions at room temperature was envisioned.
hlorophenylborane as the phenylboronic acid surrogate to perform
this reaction smoothly at 0 °C or room temperature.5 The high cost
* 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 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.035

H. Zheng, D. G. Hall / Tetrahedron Letters 51 (2010) 4256–4259
4257
As part of our program aimed at exploring the use of boronic acids
L.A.
as catalysts and promoters for amidation7 and cycloadditions,8 we
herein report an efficient construction of 2-aryl-1,3,2-aryldioxabo-
rin (2) catalyzed by ZrCl4 under mild ambient conditions.
OR'
B
OR'
B
CF3
CF3
CF3
CF3
O
O
O
O
Initially, different arylboronic acids were screened. Interest-
ingly, 3,5-bis(trifluoromethyl)phenylboronic acid (8) was identi-
fied as the most active one amongst over 70 boronic acids. It
reacted with phenol and hexanal to deliver the desired aryldioxab-
orin 2a in 10% yield promoted by propionic acid at 50 °C with 4 Å
molecular sieves.9 Inspired by this intriguing result, we examined
different reaction conditions. Representative results are summa-
rized in Table 1.10 Several common dehydrating additives were se-
lected to scavenge the water produced from the condensation
reaction (Table 1, entries 1–3), and MgSO4 led to the best yield of
product 2a at 25 °C. Unfortunately, the reaction was not Brønsted
acid dependent so that the reaction yield could not be improved
by changing different Brønsted acids (Table 1, entries 3–5). It is as-
sumed that the reaction mechanism involves a [3,3]-sigmatropic
rearrangement pathway (A, Fig. 1).4 Lewis acid catalyzed [3,3]-sig-
matropic rearrangements are well documented in the literature.11
In the event, Cu(OTf)2 was found to improve the reaction yield
(Table 1, entry 6), and dichloromethane was found to give the best
result after further screening of various solvents (Table 1, entries
7–10). Different Lewis acids were tested to further improve the
R
R
R' = Ar or H
R' = Ar or H
B
A
Figure 1. Proposed intermediates A (left, without Lewis acid catalysis) and B (right,
with Lewis acid catalysis) for the formation of 2-aryl-1,3,2-aryldioxaborins 2.
reaction rate at room temperature (Table 1, entries 11–21). To
our satisfaction, zirconium tetrachloride ZrCl4 (5 mol %) gave the
best yield (60%), and it also was found that excess hexanal
(3.0 equiv) was essential to drive the reaction to completion (Table
1, entry 22). Control experiments showed that no desired product
was formed in the absence of Lewis acid or 8 as the reactant. The
detailed mechanism towards how the Lewis acid catalyzes the for-
mation of 2-aryl-1,3,2-aryldioxaborins 2 is unclear. This reaction is
proposed to proceed through a closed six-membered chairlike
transition state B (Fig. 1), which is based on our previous mecha-
nistic studies of Lewis acid-catalyzed allylboration.12 In this transi-
tion state, the electron-deficient aryl substituent of 8 combines
with Lewis acid coordination to render the boron atom more elec-
trophilic and further favor aldehyde activation.
Table 1
With the optimized conditions in hand,13 more synthetically
useful phenols and aldehydes were investigated (Table 2).
Aliphatic, and electron-poor aromatic aldehydes are tolerated
(Table 2, entries 1–3 and entries 5–8). Linear aldehydes proceeded
Optimization of reaction conditions for three-component condensationa
F3C
CF3
OH
HO
OH
catalyst,
additive
B
B
O
O
+
+ RCHO
(1 equiv)
º
solvent, 25 C
0.1 M, 24 h
Table 2
R
F3C
CF3
(1 equiv)
Substrate scope studies for ZrCl4-catalyzed three-component condensationa
(1 equiv)
F3C
ZrCl4 (5 mol%)
MgSO4 (5 equiv)
solvent (0.1 M)
24 h
CF3
8
(R = n-C5H11
)
2a
OH
HO
OH
B
Entry
Additive
Solvent
Catalystb
Yieldc (%)
B
+
+ R2CHO
(3 equiv)
O
O
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22f
M.S.d
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
EtOH
C2H5COOH
C2H5COOH
C2H5COOH
CCl3COOH
CF3COOH
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
ZnBr2
SnCl2
Yb(OTf)3
CuBr
ZrCl4
ZrCl4
0
R1
(1 equiv)
R2
Na2SO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
M.S.d
Trace
10
F3C
CF3
(1 equiv)
R1
Prdt
13
8
2
NDe
30
Entry
R1
=
R2
=
Solventb
Temp (°C)
Yieldc (%)
0
EtOAc
Et2O
Trace
5
33
Trace
6
42
13
53
48
Trace
7
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
H
H
H
H
H
H
H
H
H
n-C5H11
CH2Cl2
CH2Cl2
DCE
25
25
50
50
50
25
25
25
50
25
25
25
25
25
25
50
50
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
60
68
63
0
PhCH2CH2
(C2H5)2CH
(CH3)3C
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
EtOH
EtOAc
Et2O
CH2Cl2
CH2Cl2
CH2Cl2
DCE
Ph
DCE
36
76
58
71
Trace
80
75
70
78
83
87
53
0
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
4-MeOC6H4
PhCH2CH2
PhCH2CH2
PhCH2CH2
PhCH2CH2
PhCH2CH2
PhCH2CH2
PhCH2CH2
PhCH2CH2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
Naphd
Naphe
2-CH3
4-CH3
2-OMe
4-OMe
4-Cl
ZrCl4
ZrCl4
ZrCl4
ZrCl4
ZrCl4
ZrCl4
Trace
Trace
31
Na2SO4
MgSO4
60
a
Reaction conditions: the mixture of phenol (1.0 mmol), 3,5-bis(trifluoro-
4-NO2
DCE
methyl)phenylboronic acid (1.0 mmol), hexanal (1.0 mmol), 4 Å molecular sieves
(1.0 g) or other additives (5.0 mmol) and catalyst (0.05 mmol or 0.3 mmol) in the
given solvent was stirred at 25 °C for 24 h.
a
Reaction conditions: the mixture of phenols (1.0 mmol), 3,5-bis(trifluoro-
methyl)phenylboronic acid (1.0 mmol), aldehydes (3.0 mmol), MgSO4 (5.0 mmol)
and ZrCl4 (0.05 mmol) in the given solvent was stirred at the given reaction tem-
perature for 24 h.
b
For Brønsted acids, 30 mol % catalyst loading was used. For Lewis acids, 5 mol %
catalyst loading was used.
c
b
Isolated yields of product purified by recrystallization of crude mixture from
DCE: 1,2-dichloroethane.
c
diethyl ether/n-pentane (1:3).
Isolated yields of product purified by recrystallization of crude mixture from
d
M.S.: 4 Å molecular sieves.
A complex mixture was obtained.
3.0 mmol (3 equiv) hexanal was used.
diethyl ether/n-pentane (1:3).
e
d
Substituted phenol: 1-naphthol.
Substituted phenol: 2-naphthol.
f
e

4258
H. Zheng, D. G. Hall / Tetrahedron Letters 51 (2010) 4256–4259
to react smoothly under optimized conditions (Table 2, entries 1
and 2). For the more hindered aldehyde, it was necessary to use
1,2-dichloroethane as a solvent at elevated temperature (50 °C)
(Table 2, entry 3). No desired product was observed with pivalalde-
hyde neither in the crude reaction mixture nor after work up
(Table 2, entry 4). This lack of reactivity is likely as a result of steric
hindrance. Compared to aliphatic aldehydes, benzaldehyde gave
the desired product 2e in moderate yield even at 50 °C (Table 2, en-
try 5). It was found that the electronic properties of substituents
played an important role for the reactivity. Thus, electron-
withdrawing aromatic aldehydes delivered products 2f–h in good
yields under optimized conditions (Table 2, entries 6–8), and
electron-donating aromatic aldehydes showed lower reactivity
(Table 2, entry 9).
We next examined the substrate scope of this methodology
with a panel of substituted phenols in the presence of hydrocinna-
maldehyde. 1-Naphthol and 2-naphthol gave the aryldioxaborins
2j and 2k in good yields (Table 2, entries 10 and 11). Interestingly,
only one regioisomer was obtained with 2-naphthol both in crude
reaction mixture and after work up, which revealed that the 1-po-
sition of 2-naphthol is more reactive than the 3-position. The reac-
tivity of substituted phenols was found to be dependent on the
electronic properties of the substituents. Electron-rich phenols
gave the desired aryldioxaborins 2l–o in excellent yields (Table 2,
entries 12–15). Halogen (Cl) substituted phenol gave the desired
product 2p in good yield under elevated temperature (Table 2, en-
try 16). The electron-poor 4-nitro-phenol however, showed no
reactivity (Table 2, entry 17).
excellent yield.2 Thermolysis of the dioxaborin 2b or 2e gave the
corresponding ortho-quinone methides 1 as the intermediates,
which were trapped by ethyl vinyl ether to afford the desired
2-ethoxy chromans 10 or 11 in good yields.2 Michael addition of
allyl trimethylsilane to the ortho-quinone methide generated
in situ from dioxaborin 2a in the presence of boron trifluoride
etherate at 70 °C gave the desired 2-substituted phenol 12 in good
yield.2
Although the underlying mechanism of this new catalytic
process remains to be elucidated, it can be concluded that the
electronic properties of substituents have a large impact on the
reactivity of all three reactants. The electron-withdrawing CF3
groups make boronic acid 8 more acidic, thus favoring the forma-
tion of six-membered chair-like transition state B (Fig. 1). The
improved nucleophilicity of the phenols by electron-donating
groups and the increased electrophilicity of the aldehydes
decorated with electron-withdrawing groups favor the [3,3]-sig-
matropic rearrangement process.
In summary, we have identified a mild and effective approach
for the preparation of aryldioxaborins 2 using ZrCl4 as the catalyst
and electron-deficient boronic acid 8 as the promoter. A wide
range of aldehydes and phenols are suitable as substrates. Further
studies of this reaction process will be aimed at clarifying the
mechanism, developing a chiral Lewis for producing optically pure
aryldioxaborins, and its application to the total synthesis of biolog-
ically important molecules.
Acknowledgments
Further applications of 2-aryl-1,3,2-aryldioxaborin 2 to the
preparation of more synthetically and biologically useful deriva-
tives are shown in Scheme 2. The substituted saligenol 9 was
obtained by hydrolytic oxidation (30% H2O2) of dioxaborin 2b in
This research was generously funded by the Natural Sciences
and Engineering Research Council (NSERC) of Canada (E.W.R. Stea-
cie Memorial Fellowship to D.G.H.), and the University of Alberta.
H.Z. thanks the Alberta Ingenuity Foundation for a Graduate
Scholarship.
F3C
CF3
Supplementary data
OH OH
30% H2O2
THF, 2 h
B
Supplementary data (experimental procedures, NMR spectra)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.06.035.
O
O
9
95%
2b
References and notes
1. For reviews of ortho-quinone methide 1 in synthesis, see: (a) Selenski, C.;
Pettus, T. R. R. o-Quinone Methides. In Science of Synthesis; Griesbeck, A. G., Ed.;
Georg Thieme: Stuttgart, 2006; pp 831–899; (b) Van de Water, R. W.; Pettus, T.
R. R. Tetrahedron 2002, 58, 5367–5405; (c) Boger, D. L.; Weinreb, S. N. Hetero
Diels–Alder Methodology in Organic Synthesis; Academic Press: San Diego, 1987;
(d) Desimoni, G.; Tacconi, G. Chem. Rev. 1975, 75, 651–692; For examples of
ortho-quinone methide 1 in natural product synthesis, see: (e) Lumb, J.-P.;
Choong, K. C.; Trauner, D. J. Am. Chem. Soc. 2008, 130, 9230–9231; (f) Bulger, P.
G.; Bagal, S. K.; Marquez, R. Nat. Prod. Rep. 2008, 25, 254–297; (g) Lumb, J.-P.;
Trauner, D. J. Am. Chem. Soc. 2005, 127, 2870–2871; (h) Rodriguez, R.; Moses, J.
E.; Adlington, R. M.; Baldwin, J. E. Org. Biomol. Chem. 2005, 3, 3488–3495; (i)
Rodriguez, R.; Adlington, R. M.; Moses, J. E.; Cowley, A.; Baldwin, J. E. Org. Lett.
2004, 6, 3617–3619; (j) Adlington, R. M.; Baldwin, J. E.; Mayweg, A. V. W.;
Pritchard, G. J. Org. Lett. 2002, 4, 3009–3011.
F3C
CF3
sealed tube
240 C, 12 h
O
OEt
OEt
º
B
+
O
O
R
R
R = Ph(CH2)2, 10, 86%, (anti:syn = 1:1)
R = Ph, 11, 78%, (anti:syn = 1:1)
2b
R = Ph(CH2)2,
R = Ph, 2e
2. (a) Chambers, J. D.; Crawford, J.; Williams, H. W. R.; Dufresne, C.; Scheigetz, J.;
Bernstein, M. A.; Lau, C. K. Can. J. Chem. 1992, 70, 1717–1732; (b) Lau, C. K.;
Williams, H. W. R.; Tardiff, S.; Dufresne, C.; Scheigetz, J.; Belanger, P. C. Can. J.
Chem. 1989, 67, 1384–1387.
3. Peer, H. G. Recl. Trav. Chim. Pays-Bas. 1960, 79, 825–835.
4. Nagata, W.; Okada, K.; Aoki, T. Synthesis 1979, 365–368.
5. Lau, C. K.; Mintz, M.; Bernstein, M. A.; Dufresne, C. Tetrahedron Lett. 1993, 34,
5527–5530.
6. Naimi-Jamal, M. R.; Mirzaei, M.; Bolourtchian, M.; Sharifi, A. Synth. Commun.
2006, 36, 2711–2717.
F3C
CF3
.
BF3 Et2O
OH
(4 equiv)
B
TMS
(4 equiv.)
O
O
+
ClCH2CH2Cl,
70 C, 18 h
R
º
R
7. Al-Zoubi, R. M.; Marion, O.; Hall, D. G. Angew. Chem., Int. Ed. 2008, 47, 2876–
2879.
8. (a) Zheng, H.; McDonald, R.; Hall, D. G. Chem. Eur. J. 2010, 16, 5454–5460; (b)
Zheng, H.; Hall, D. G. Tetrahedron Lett. 2010, 51, 3561–3564.
9. For detailed information about the screening of arylboronic acids, see
Supplementary data Section 2.1.
R = n-C5H11
R = n-C5H11
12
2a
72%
Scheme 2. Synthetic applications of 2-aryl-1,3,2-aryldioxaborin 2.

H. Zheng, D. G. Hall / Tetrahedron Letters 51 (2010) 4256–4259
4259
10. For detailed information about the screening of reaction conditions, see
Supplementary data Section 2.
11. For recent reviews, see: (a) Castro, A. M. M. Chem. Rev. 2004, 104, 2939–3002;
(b) Nubbemeyer, U. Synthesis 2003, 961–1008.
12. Rauniyar, V.; Hall, D. G. J. Am. Chem. Soc. 2004, 126, 4518–4519.
13. Typical experimental procedure for ZrCl4 catalyzed synthesis of 2-aryl-1,3,2-
phase was further extracted with dichloromethane (2 Â 20 mL). The combined
organic phase was dried over anhydrous Na2SO4, filtered and evaporated under
reduced pressure. The residue was recrystallized from diethyl ether/n-pentane
(1:3) to afford the title 2-aryl-1,3,2-aryldioxaborin 2a (250 mg, 60%) as a white
solid: 1H NMR (400 MHz, CDCl3) d 8.40 (s, 2H), 8.00 (s, 1H), 7.28 (t, J = 7.7 Hz,
1H), 7.15–7.08 (m, 2H), 7.06 (d, J = 7.6 Hz, 1H), 5.33 (dd, J = 7.2, 4.2 Hz, 1H),
2.02–1.81 (m, 2H), 1.60–1.44 (m, 2H), 1.42–1.26 (m, 4H), 0.89 (t, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 148.4, 134.2, 131.0 (q, JC–F = 32.8 Hz), 128.9,
126.0, 125.5, 124.9, 123.7, 123.6 (q, JC–F = 272.9 Hz), 118.0, 73.6, 39.4, 31.6,
23.9, 22.6, 14.0; 11B NMR (128 MHz, CDCl3) d 26.4; 19F NMR (376 MHz, CDCl3) d
À63.3; IR (Microscope, cmÀ1) 3053, 2956, 2935, 2861, 1618, 1590; HRMS (EI)
for C20H19BF6O2: calcd 416.13824; found 416.13754.
aryldioxaborins via
a three-component condensation: a mixture of 3,5-
bis(trifluoromethyl)phenylboronic acid (258 mg, 1.0 mmol), phenol (94 mg,
1.0 mmol), hexanal (300 mg, 3.0 mmol), MgSO4 (600 mg, 5.0 mmol) and ZrCl4
(12 mg, 0.05 mmol) in dichloromethane (10 mL) was stirred at 25 °C for 24 h.
The reaction mixture was filtered to remove MgSO4. The filtrate was diluted
with dichloromethane (30 mL) and washed with H2O (30 mL). The aqueous