Novel and potent Lewis acid catalyst: Br2-catalyzed Friedel-Crafts reactions of naphthols with aldehydes

Article abstract of DOI:10.1080/00397911.2016.1139723

A discovery that the inexpensive Br₂ can serve as a potent Lewis acid catalyst for bis(2-hydroxy-1-naphthyl)methanes synthesis is presented. Under the catalysis of Br₂ at room temperature, naphthols reacted smoothly with various aldehydes with high efficiency and broad substrate scope. This reaction used to require highly acidic conditions and/or high temperature and/or pressure, and sometimes featured poor yields. Moreover, theoretical calculations suggested that Br₂ is a potent Lewis acid to activate the carbonyl group, yet it was not the primary cause for the remarkable activity of Br₂ in the current communication.

Full text of DOI:10.1080/00397911.2016.1139723

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Novel and potent Lewis acid catalyst: Br2-catalyzed
Friedel–Crafts reactions of naphthols with
aldehydes
Deqiang Liang, Jingjing Li, Yanni Li, Baoling Wang, Ping Cheng & Sha Luo
To cite this article: Deqiang Liang, Jingjing Li, Yanni Li, Baoling Wang, Ping Cheng & Sha
Luo (2016): Novel and potent Lewis acid catalyst: Br2-catalyzed Friedel–Crafts reactions of
naphthols with aldehydes, Synthetic Communications
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Date: 26 February 2016, At: 04:02

SYNTHETIC COMMUNICATIONS®
http://dx.doi.org/10.1080/00397911.2016.1139723
Novel and potent Lewis acid catalyst: Br2-catalyzed
Friedel–Crafts reactions of naphthols with aldehydes
Deqiang Lianga, Jingjing Lia, Yanni Lia, Baoling Wanga, Ping Chengb, and Sha Luoa
aDepartment of Chemistry, Kunming University, Kunming, China; bSchool of Environmental and Chemical
Engineering, Shanghai University, Shanghai, China
ABSTRACT
ARTICLE HISTORY
Received 11 November 2015
A discovery that the inexpensive Br2 can serve as a potent Lewis acid
catalyst for bis(2-hydroxy-1-naphthyl)methanes synthesis is presented.
Under the catalysis of Br2 at room temperature, naphthols reacted
smoothly with various aldehydes with high efficiency and broad
substrate scope. This reaction used to require highly acidic conditions
and/or high temperature and/or pressure, and sometimes featured
poor yields. Moreover, theoretical calculations suggested that Br2 is a
potent Lewis acid to activate the carbonyl group, yet it was not the
primary cause for the remarkable activity of Br2 in the current
communication.
KEYWORDS
Alkylation; bromine effect;
C–C coupling; homogeneous
catalysis
GRAPHICAL ABSTRACT
Introduction
Halogens are of critical importance and have been well studied.[1] In this regard, expensive
molecular iodine is much safer than other halogens, is convenient to use, and has wide
applications as a catalyst in modern synthetic chemistry.[1,2] Elemental bromine is
cheap but more volatile and corrosive. In sharp contrast, though, there is an increasing
tendency to explore the utility of N-bromosuccinimide (NBS)[3] and other solid alternatives
to Br2.[4–6] Br2 itself has rarely been used in a catalytic manner except as an oxidant.[7–9]
CONTACT Deqiang Liang and Yanni Li
ldq5871@126.com; suliyn@163.com
Department of Chemistry, Kunming
University, 2 Puxin Road, Kunming 650214, P. R. China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
© 2016 Taylor & Francis

2
D. LIANG ET AL.
Scheme 1. Previously reported bis(2-hydroxy-1-naphthyl)methanes synthesis.
Those alternatives are associated with higher costs and/or tedious steps of preparations,
and yet are no match for Br2 in many cases.
We believe that chemists’ distaste for Br2 hinders the development of science. Not long
ago, the abnormal catalytic performances of HBr in some C–C coupling processes was sur-
prising, and some attributed it to the counterion effect.[10,11] On the other hand, Jamison
et al. reported a N-bromosuccinimide (NBS)– or Br2-catalyzed synthesis of cyclic carbo-
nates from epoxides and CO2, and they pointed out that the epoxides were activated by
electrophilic bromine.[12] Although in this work the catalytic activity of Br2 was not unique,
we suggest that Br2 might serve as a novel and potent Lewis acid, which was subsequently
confirmed by the extremely high efficiency of Br2 in activating carbonyl compounds.[13,14]
Nevertheless, the curious bromine effect is far from well understood and further inquiries
are needed.
Friedel–Crafts alkylation is one of the most important and fundamental tools for the
construction of aromatic C–C bonds and was found to be acidity dependent.[15] In this
field, the synthesis of xanthenes from electron-rich β-naphthols and aldehydes was well
established.[16–18] In comparison, bis(2-hydroxy-1-naphthyl)methane derivatives are
biologically important and exhibit a broad range of bioactivities,[19–21] but from the same
materials their synthesis was seldom reported (Scheme 1).[22–24] Moreover, these reac-
tions featured harsh conditions, such as strongly acidic conditions[22,23] and high
temperature[22,24] and/or pressure,[24] and sometimes featured poor yields.[23] Very
recently, Wang et al. achieved this transformation at ambient temperature by using only
10 mol% of HBr as the catalyst.[10] Despite this contribution, the development of more
mild protocols still remains highly important and challenging. Inspired by the aforemen-
tioned curious bromine effect,[10–14] and in an effort to gain further insights into it, we
examined the catalytic power of Br2 in this transformation. Herein, we present a mild and
efficient Br2-catalyzed synthesis of bis(2-hydroxy-1-naphthyl)methane derivatives
(Scheme 1), and while theoretical calculations proved that Br2 as a novel Lewis acid
possesses significant acidity, it might not be the primary cause of the unique performance
of Br2.
Results and discussion
We began our study with β-naphthol 1a and 4-nitrobenzaldehyde 2a as model substrates
(Table 1). Preliminary results showed that in the presence of 5 mol% of Br2 in MeCN at
room temperature, this Friedel–Crafts reaction did not reach completion after 24 h, afford-
ing expected benzylidene biphenol 3a in only 72% yield, which was, however, much
greater than the one achieved in the case of 5 mol% HBr as catalyst (entry 1).[10] When

SYNTHETIC COMMUNICATIONS®
3
Table 1. Optimization of reaction conditionsa.
Entry
Acid (mol%)
Solvent
Time (h)
Yield of 3ab (%)
1
Br2 (5)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
CH2Cl2
EtOAc
THF
24
7.0
72 (36)c
2
Br2 (10)
81 (76)c
3
Br2 (10)
24
97 (95)d (90)e
4
BF3 · Et2O (10)
FeCl3 (10)
SnCl4 (10)
Br2 (10)
24
Trace
Nr
5
24
6
24
Nr
96 (Nr)c (43)f
38
7
12 (24)f
24
8
Br2 (10)
9
Br2 (10)
24
Trace
10
11
Br2 (10)
DMF
EtOH
24
Trace
Br2 (10)
24
Nr
aUnless otherwise noted, all reactions were run using 1.0 mmol of 1a and 0.55 mmol of 2a in 5.0 mL of solvent at room
temperature.
bIsolated yields.
cResults from Wang et al.,[10] wherein the same loading of HBr (40% aqueous) was used instead of Br2.
d0.012 mL of H2O was additionally added under otherwise identical conditions.
eThe reaction was run under otherwise identical conditions except that 10 mol% of HBr (40% aqueous) was used as catalyst
instead of Br2.
fThe reaction was run under otherwise identical conditions except that 10 mol% of anhydrous HBr (33% solution in acetic
acid) was used instead of Br2.
the catalyst loading was increased to 10 mol%, thin-layer chromatography (TLC) revealed
that after 7 h 1a was mostly consumed, and 3a was isolated in 81% yield (entry 2). To our
delight, by prolonging the reaction time to 24 h, nearly quantitative yield of 3a could be
obtained (90% yield with Wang’s catalyst, entry 3). Notably, when the same amount of
water contained in aqueous HBr at the same loading was additionally added, the reaction
was hardly affected (note d, entry 3). An evaluation of some typical Lewis acids demon-
strated that, at the loading of 10 mol%, BF3 · Et2O (entry 4), FeCl3 (entry 5), and SnCl4
(entry 6) all showed little or no activity. So did CuBr2, Bu4NBr, and a series of Brønsted
acids, including HCl, HI, HBF4, HPF6, trifluoroacetic acid (TFA), TsOH, H2SO4, and
TfOH.[10] Next, other solvents were screened. Somewhat surprisingly, CH2Cl2, the use of
which led to totally retarded reaction in Wang’s work and provided only a moderate yield
after 24 h with anhydrous HBr as the catalyst, was superior to MeCN in the present study
and within 12 h bis(2-hydroxy-1-naphthyl)methane 3a was generated in 96% yield (entry
7). While the reaction run in ethyl acetate was sluggish, producing product 3a in only 38%
yield after 24 h (entry 8), employment of tetrahydrofuran (THF, entry 9), N,N-dimethylfor-
mamide (DMF, entry 10), or ethanol (entry 11) proved fruitless.
Under the optimized reaction conditions (entry 7, Table 1), a variety of bis(2-hydroxy-1-
naphthyl)methane derivatives 3 were synthesized from β-naphthols 1 and aldehydes 2. As
summarized in Table 2, aromatic aldehydes 2a–e bearing electron-withdrawing substitu-
ents, such as the nitro group (entries 1 and 2) and halogen atoms (entries 3–5), at the para,
meta, or ortho positions all reacted efficiently with β-naphthol 1a to furnish the desired

4
D. LIANG ET AL.
Table 2. Scope of the Br2-catalyzed bis(2-hydroxy-1-naphthyl)methanes synthesisa.
Entry
1
R1
2
R2
t (h)
3
Yield of 3b (%)
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
H
H
H
H
H
H
H
H
H
H
Br
Br
Br
2a
2b
2c
2d
2e
2f
4-NO2Ph
3-NO2Ph
4-ClPh
2-ClPh
4-BrPh
Ph
4-MePh
4-MeOPh
2-Furyl
H
12
12
12
6.0
12
24
24
24
1.0
6.0
24
24
24
3a
3b
3c
3d
3e
3f
96
90
2
3
92
4
91
5
94
6
86
7c
8c
9
2g
2h
2i
3g
3h
83
70
Complex
92
10
11c
12c
13
2j
3i
3j
3k
3l
2a
2c
2j
4-NO2Ph
4-ClPh
H
77
45
84
aUnless otherwise noted, all reactions were run using 1.0 mmol of 1, 0.55 mmol of 2, and 0.1 mmol of Br2 in 5.0 mL of solvent
at room temperature.
bIsolated yields.
cThe reaction was run at 40 °C.
biphenols 3a–e in excellent yields. The reaction of electron-neutral benzaldehyde 2f with
1a gave corresponding product 3f in 86% yield (entry 6), whereas in the cases of aromatic
aldehydes 2g and h with electron-donating substituents, a little greater temperature of 40 °
C was required to obtain products 3g and h in good yields (entries 7 and 8). Even this was
remarkable, considering that electron-rich aromatic aldehydes were challenging substrates
and they did not participate in Wang’s reactions to yield the desired products.[10] It thus
represented a significant advantage of the current method. Unfortunately, the use of the
heteroaromatic aldehyde 2i resulted in a complex mixture (entry 9). It is worthy of notice
that aliphatic paraformaldehyde 2j was also adept in efficiently furnishing the related pro-
duct 3i in 92% yield within 6 h (entry 10). Then, the reaction was extended to 6-bromo-
naphthalen-2-ol 1b, and the desired biphenols 3j–l were synthesized from 1b and various
aldehydes in moderate to good yields (entries 11–13), though in the cases concerning aro-
matic aldehydes, a slightly elevated temperature was required. These aryl bromides (entries
5 and 11–13) and chlorides (entries 3, 4, and 12) could facilitate further elaboration to
more interesting molecules.
α-Naphthol 4 could also participate in this Br2-catalyzed Friedel–Crafts reaction
(Scheme 2). 4-Nitrobenzaldehyde 2a and 4-chlorobenzaldehyde 2c were selected to react
with 4, and the corresponding biphenol products 5a and b and their isomers 6a and b were
produced in high to excellent overall yields, though poor ortho/para selectivities were
observed.
Although in many cases, trace amounts of brominated by-products[25] were observed, in
the present protocol the possibility that HBr generated in situ was the true catalyst could be
ruled out, since with CH2Cl2 as solvent aqueous HBr was totally inactive and anhydrous

SYNTHETIC COMMUNICATIONS®
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Scheme 2. Reactions of α-naphthol with aldehydes.
Figure 1. Charge calculations for acid-activated carbonyl carbon of 4-nitrobenzaldehyde.
HBr in AcOH was far less active (notes c and f, entry 7, Table 1), whereas the catalytic
activity of Br2 was not affected by a minute quantity of water (note d, entry 3, Table 1).
In an effort to gain insight into the extraordinary performance of Br2, theoretical
calculations of the power of a range of Brønsted and Lewis acids in activating the carbonyl
group were carried out (Fig. 1; for details see Table S1). 4-Nitrobenzaldehyde 2a was used
as the model substrate. Upon coordination of the carbonyl oxygen atom to acids, the
positivity of the carbonyl carbon was enhanced. Various theoretical methods, including
B3LYP[26]/6–31 þ G(d,p),[27] B3LYP/def2-TZVP,[28] and M062X[29]/def2-TZVP, confirmed
that the positive charge on the carbonyl carbon activated by Br2 was more or less on par
with the ones with other strong acids as activater. This might be related to the high
electronegativity in combination with high polarizability of the element of bromine. Be that
as it may, Br2 seemed not to be so superior, and when the solvent effect of MeCN was con-
sidered (acids were all compared in MeCN as solvent; see Table 1 and Wang’s work[10]), the
trend was basically unaffected (M062X/def2-TZVPþMeCN[30]). These results suggested
that Br2, similar to I2, was indeed a potent Lewis acid; however, in the present reaction
acidity might not be the primary cause of the unique activity of Br2, the origin of which
remains unclear at this stage. Further exploration still needs to be carried out.
Conclusion
In conclusion, we have demonstrated that Br2 could act as a novel and potent Lewis acid
catalyst in Friedel–Crafts reactions of naphthols, and have developed a mild and efficient
synthesis of biologically important bis(2-hydroxy-1-naphthyl)methane derivatives.

6
D. LIANG ET AL.
Theoretical calculations suggested that Br2 did possess the significant power to activate the
carbonyl group, yet it might not be the primary cause for the remarkable activity of Br2
presented here. This work might inspire more novel Br2-catalyzed reactions and provide
further clues for the understanding the curious bromine effect, further studies toward
which are under way in our laboratory.
Experimental
Chemicals were all purchased from commercial sources and used without treatment. TLC
was carried out using silica-gel GF254 plates. Products were purified by column chroma-
tography over silica gel. 1H NMR and 13C NMR spectra were recorded at 25 °C on a Bruker
AscendTM 400 spectrometer in CDCl3/DMSO using tetramethylsilane (TMS) as internal
standard. High-resolution mass spectra (HRMS) were obtained using a Bruker microTOF
II Focus spectrometer (ESI). Products 3a, 3c, 3f, 3i, 3j, 5a, 5b, 6a, and 6b are known com-
pounds and their spectral data can be found in the literature.[10]
Optimization of all molecular geometries, vibrational analyses, and Mulliken atomic
(MA) charges were calculated at B3LYP and M06-2X functions with the 6-31 þ G(d,p)
and def2TZVP basis sets by using Gaussian 09 program. A natural bonding orbital (NBO)
analysis for structures was also performed to determine the natural population atomic
(NPA) charges by using the NBO 3.1 package implemented in Gaussian 09. All calculated
structures were true minima (i.e., no imaginary frequencies). Solvent effect at M06-2X/
def2TZVP level was calculated using the solvent model density (SMD) approach.[30]
General procedure (taking the synthesis of 3b as an example)
A solution of Br2 (0.0051 mL) in CH2Cl2 (1.0 mL) was added to a stirred solution of
β-naphthol 1a (144 mg, 1.0 mmol) and 3-nitrobenzaldehyde 2b (83 mg, 0.55 mmol) in
CH2Cl2 (4.0 mL), and the mixture was stirred for 12 h at ambient temperature. After 1a
was consumed, as indicated by TLC, the reaction mixture was quenched with saturated
aqueous Na2S2O3 (0.5 mL) and water (20.0 mL), and extracted with CH2Cl2 four times.
The residue obtained after evaporation of the solvent was purified by column chromato-
graphy on silica gel (petroleum ether–ethyl acetate ¼ 12:1, v/v) to afford benzylidene
biphenol 3b as an off-white solid (202 mg, 96% yield).
1,1′-((3-Nitrophenyl)methylene)dinaphthalen-2-ol (3b)
1
Off-white solid: mp 174–175 °C (dec.). H NMR (400 MHz, DMSO) δ ¼ 7.10–7.25 (m, 7H),
7.48 (d, J ¼ 4.9 Hz, 2H), 7.70 (d, J ¼ 8.9 Hz, 2H), 7.74 (d, J ¼ 7.7 Hz, 2H), 7.83 (s, 1H), 8.00–
8.03 (m, 1H), 8.13 (d, J ¼ 8.5 Hz, 2H), 10.39 (bs, 2H); 13C NMR (100 MHz, DMSO) δ ¼ 154.0,
148.0, 147.7, 135.5, 134.5, 129.4, 128.93, 128.86, 126.5, 123.7, 123.0, 122.5, 120.5, 119.9, 119.5,
þ
41.7. HRMS (ESI-TOF) calcd. for C27H20NO4 ([MþH]þ) 422.1387; found 422.1393.
Funding
This work was supported by the Applied Basic Research Programs of Yunnan Science and Tech-
nology Department (2014FD039), the Research Foundation for Introduced Talents of Kunming

SYNTHETIC COMMUNICATIONS®
7
University (YJL13001 and YJL15003), and the Foundation for Innovative Scientific Research Team
of Kunming University (2015CXTD03).
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