Ammonium Salt-Catalyzed Highly Practical Ortho-Selective Monohalogenation and Phenylselenation of Phenols: Scope and Applications

Article abstract of DOI:10.1021/acscatal.8b00327

An ortho-selective ammonium chloride salt-catalyzed direct C-H monohalogenation of phenols and 1,1′-bi-2-naphthol (BINOL) with 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) as the chlorinating agent has been developed. The catalyst loading was low (down to 0.01 mol %) and the reaction conditions were very mild. A wide range of substrates including BINOLs were compatible with this catalytic protocol. Chlorinated BINOLs are useful synthons for the synthesis of a wide range of unsymmetrical 3-aryl BINOLs that are not easily accessible. In addition, the same catalytic system can facilitate the ortho-selective selenylation of phenols.

Full text of DOI:10.1021/acscatal.8b00327

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Ammonium Salt Catalyzed Highly Practical Ortho-Selective Mono-
Halogenation and Phenylselenation of Phenols: Scope and Applications
Xiaodong Xiong, and Ying-Yeung Yeung
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00327 • Publication Date (Web): 15 Mar 2018
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Ammonium Salt Catalyzed Highly Practical Orthoꢀ
Selective MonoꢀHalogenation and Phenylselenation
of Phenols: Scope and Applications
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Xiaodong Xiong, Ying-Yeung Yeung*
Department of Chemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong
(China)
ABSTRACT: An orthoꢀselective ammonium chloride saltꢀcatalyzed direct CꢀH monoꢀ
halogenation of phenols and 1,1′ꢀbiꢀ2ꢀnaphthol (BINOL) with 1,3ꢀdichloroꢀ5,5ꢀ
dimethylhydantoin (DCDMH) as the chlorinating agent has been developed. The catalyst loading
was low (down to 0.01 mol%) and the reaction conditions were very mild. A wide range of
substrates including BINOLs were compatible with this catalytic protocol. Chlorinated BINOLs
are useful synthons for the synthesis of a wide range of unsymmetrical 3ꢀaryl BINOLs that are
not easily accessible. In addition, the same catalytic system can facilitate the orthoꢀselective
selenylation of phenols.
KEYWORDS: ammonium salt, BINOL, halogenation, orgnaocatalysis, phenol, mechanism,
selenylation
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1. INTRODUCTION
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Halogenated phenols, naphthols, and their derivatives (e.g. BINOLs) are widely found in
numerous natural products,1ꢀ4 pharmaceuticals,5ꢀ7 bioactive compounds and fine chemicals.8ꢀ12
They are also frequently employed as the key precursors in various chemical transformations.13ꢀ
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In the fields of agrochemical and drug discovery, chlorinated compounds are frequently
employed to enhance the biological properties.11ꢀ12 Moreover, halogenated BINOLs (e.g. 3,3’ꢀ
dihalogenated BINOLs) are very useful ligand precursors.16ꢀ19
Direct CꢀH halogenation of phenols using electrophilic halogen source is a common method to
prepare halogenated phenols. However, treatment of phenols with halogen sources usually give a
mixture of polyhalogenated products with paraꢀhalogenated products preferentially obtained due
to their inherent selectivity resulted from the electronic property and steric demand.20ꢀ25 Despite
the fact that orthoꢀhalogenated phenols and BINOLs are privileged building blocks, direct CꢀH
halogenations to generate the orthoꢀselective halogenated products remain highly challenging;
26ꢀ27
harsh conditions and multiꢀstep chemical operations are often required.
Thus, the
development of a mild, efficient and regioselective method to access orthoꢀhalogenated phenols
has received continuous attention from the synthetic community.
Among the existing methods, orthoꢀmetalation (e.g. lithiation) is a prominent strategy for the
preparation of orthoꢀhalogenated phenols. However, this strategy often suffers from harsh
reaction conditions and narrow substrate scope.28ꢀ29 Transition metalꢀcatalyzed directed CꢀH
halogenations emerged as highly atomꢀ and stepꢀeconomic methods for CꢀX (X= Cl, Br, I) bonds
formation and significant progress was demonstrated by the examples of orthoꢀselective
halogenation of aniline.30ꢀ32 However, the application of these strategies in the orthoꢀ
halogenation of phenols and BINOLs remain underexploited. Research efforts on using nonꢀ
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metal promotors/catalysts in the orthoꢀselective halogenation of phenols are also sporadic.
Fujisaki reported the pioneer work on an amineꢀcatalyzed orthoꢀbromination of 2ꢀsubstituted
phenols with Nꢀbromosuccinimide (NBS) as the stoichiometric halogen source.33 Later,
Sheldon34 and Snider35 independently disclosed that the orthoꢀchlorination of a few phenols
could be achieved using amines as the catalysts and SO2Cl2 as the halogen source at elevated
temperature. Recently, seminal study has shown that the use of 10 mol% of Nagasawa’s bisꢀ
thiourea catalyst could promote the chlorination through dual activation of both the phenol and
Nꢀchlorosuccinimide (NCS) to yield the corresponding orthoꢀhalogenated compounds in
moderateꢀtoꢀgood regioselectivity.36 Although some advancements have been achieved in this
area, drawbacks including the use of strongly acidic reagent and relatively expensive catalyst,
and limited substrate scope hampered their synthetic applications and largeꢀscale production.
Consequently, the development of a sophisticated catalytic protocol aiming at high efficiency,
selectivity, and practicality together with wide substrate scope of the orthoꢀhalogenation is
highly desired. Herein, we are pleased to describe a mild and highly practical catalytic protocol
for orthoꢀselective halogenation of phenols and naphthols. Ammonium chloride salts were used
as catalysts that are inexpensive and easy to handle. This method can be applied to prepare
valuable BINOL ligands at large scale. In addition, the protocol was applied to the first case of
organocatalytic orthoꢀselective selenylation of phenols (Scheme 1).
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2. RESULTS AND DISCUSSION
2.1 Reaction optimization
It has been reported that ammonium salts 1, which can easily be prepared from inexpensive
amines and hydrochloric acid, are extremely effective for highly regioselective orthoꢀ
chlorination of anilines and the in situ generated halogenating agent A is believed to be the active
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Scheme 1. Organocatalytic orthoꢀselective halogenation of phenols and BINOLs
species.37 We anticipated that phenols or BINOLs, which have acidic protons, could interact with
the species A and direct the CꢀH monoꢀhalogenation at the orthoꢀposition (Scheme 1). It is
worthꢀmentioning that as compared with anilines, halogenation of phenols is nonꢀtrivial since
halogenating agents can oxidize phenol compounds readily.38
o
Phenol (2a) was chosen as the model substrate and the reaction was conducted at 0 C.
Toluene and 1,3ꢀdichloroꢀ5,5ꢀdimethylhydantoin (DCDMH) were used as the solvent and the
halogenation source, respectively. The reaction was sluggish in the absence of catalyst (Table 1,
entries 1 and 2). Nonetheless, we are delighted to realize that the desired orthoꢀchlorinated
product 3a was obtained in 97% isolated yield by employing 1 mol% of ammonium salt catalyst
1a (entry 3). Notably, only negligible amount of chlorinated isomers was detected. The less
bulky ammonium salt 1b gave slightly lower orthoꢀselectivity (entry 4). Ammonium salt 1c that
is derived from Hünig's base still gave appreciable orthoꢀselectivity although the reaction was
relatively sluggish (entry 5). Poorer orthoꢀselectivity was observed when employing the
ammonium salt with a bromide (1d) or an acetate (1e) counter anion, suggesting that the chloride
anion in 1a might play an important role in dictating the siteꢀselectivity (entries 6 and 7). While
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the tetraalkylammonium salt 1f could promote the chlorination of phenol (2a), pꢀchlorophenol
(3b) was found to be the major product (entry 8). Since no observable catalyst degradation was
noticed during the reaction, we attempted to lower the catalyst loading of 1a and studied the
efficiency of the orthoꢀchlorination of 2a. It was found that the reaction could still proceed
smoothly at a 0.05 mol% catalyst loading to give 3a in 96% yield, although a relatively longer
reaction time (16 h) was found to be necessary to give reasonably high conversion (entry 9). To
our delight, 90% of 3a could still be obtained when just 0.01 mol % of 1a was applied (entry 10).
The relatively low reaction rate could be compensated by increasing the reaction temperature
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from 0 to 25 C but a slight decrease in the orthoꢀselectivity was observed (entry 11). We have
also conducted the reaction using iPr2NH instead of 1a and poor ortho/paraꢀselectivity was
observed, which further highlighted the crucial role of ammonium salt in this catalytic protocol
(entry 12). Thus, the conditions in Table 1, entry 3 were then chosen for the exploration of scope
indicated in the following sections.
Table 1. Catalyst Optimizationa
entry Catalyst (loading)
yield of 3a (%)b ratio (2a/3a/3b/3c/3d)c
1
ꢀ
ꢀ
trace
<5
>99/0/0/0/0
>95/5/0/0/0
2d
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1a (1 mol%)
1b (1 mol%)
1c (1 mol%)
1d (1 mol%)
1e (1 mol%)
1f (1 mol%)
97
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95
0/98/0/1/1
0/93/4/0/1
5/65/9/21/1
1/90/4/1/1
16/74/9/0/1
2/30/65/3/0
2/>95/3/0/0
5/91/4/0/0
0/94/2/2/2
23/65/22/0/0
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9e
10d
11f
12
1a (0.05 mol%)
1a (0.01 mol%)
1a (0.01 mol%)
iPr2NH (10 mol%) 62
a
Reactions were carried out with phenol (2a) (0.2 mmol), catalyst 1 (1 mol%), and DCDMH
o
b
c
(0.2 mmol) in toluene (3 mL) in the absence of light at 0 C. Isolated yield of 3a. The ratios
were determined by GC/MS analysis. d The reaction time was 24 h. e The reaction time was 16 h.
f The reaction was conducted at 25 oC for 6 h. DCDMH = 1,3ꢀdichloroꢀ5,5ꢀdimethylhydantoin.
2.2 Exploration of the ortho-chlorination scope
We then examined the generality of catalyst 1a in this transformation and the results are
summarized in Table 2. In general, high siteꢀselectivity at the orthoꢀposition of phenol was
observed. A series of paraꢀsubstituted phenols 2b–2h bearing either electronꢀwithdrawing or
electronꢀdonating groups were well tolerated, providing the desired monoꢀchlorinated products
3b–3h in excellent yields. For the metaꢀsubstituted phenolic substrates 2i–2k, chlorination
proceeded smoothly at the sterically less hindered C(6) position to give 3i–3k with high siteꢀ
selectivity. On the other hand, for the metaꢀsubstituted substrates with substituents including
ester, ketone, aldehyde and boronic ester (2l–2p), the orthoꢀchlorination happened selectively at
the sterically more congested C(2) position, furnishing the monoꢀchlorinated products 3l–3p in
good isolated yields. These phenomena could be attributed to the syngeneic directing effect
(potentially through hydrogen bonding) of the OH and the metaꢀsubstituted functional groups
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(see Section 2.8). The chlorination of the sterically hindered orthoꢀsubstituted substrates 2q–2w
worked equally well to furnish the corresponding orthoꢀchlorinated compounds 3q–3w in goodꢀ
toꢀexcellent yields. 3,5ꢀ and 3,6ꢀdisubstitued substrates 2x–2z also were also compatible with
this methodology.
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Under the optimized reaction conditions, 3aa could also be obtained smoothly when using the
naphthyl substrates 2aa. Resorcinol (2ac) could also readily undergo double orthoꢀchlorination
to yield 3ac. This method was found to be applicable to the lateꢀstage modification of estrone
derivative 2ad to give the orthoꢀselective chlorination products 3ad in 68% yield. The
practicalities of this catalytic protocol were demonstrated by the gramꢀscale reactions with 2g, 2l,
2u, and 2y as the substrates and excellent product yields of 3g, 3l, 3u, and 3y were still obtained.
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Table 2. Substrate scope of the orthoꢀchlorination of phenols a
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a
Reactions were carried out with substrate 2 (0.1 mmol), catalyst 1a (1 mol%, 0.001 mmol),
o
and DCDMH (0.1 mmol) in toluene (2 mL) in the absence of light at 0 C. The yields were
b
isolated yields (average of two trials) of the pure oꢀchlorinated products. 5 mmol% catalyst 1a
was used. c The yield was determined based on the TBS ether derivative. d 0.2 mmol of DCDMH
e
f
was used. The ratio was measured on the crude sample by GC/MS with internal standard.
Some starting material was recovered.
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Further experimentations revealed that achieving orthoꢀchlorination of phenol or naphthol with
high regioselectivity and functional group compatibility is not a trivial task using literature
methods. For instance, phenol 2ae that contains an amine functionality returned sluggish reaction
when the classical 2,2,6,6ꢀtetramethylpiperidine (TMP)/SO2Cl2 protocol was employed.34ꢀ35 On
the other hand, the newly developed ammonium salt catalyst system gave the orthoꢀchlorinated
product 3ae smoothly (Scheme 2, eq 1). In addition, ammonium salt 1a could effectively
catalyze the orthoꢀchlorination of 2af that bears an unprotected hydroxyl group, giving 3af in
71% isolated yield. In contrast, sluggish reaction together with dirty mixture was observed when
applying the TMP/SO2Cl2 protocol34ꢀ35 to the substrate 2af (Scheme 2, eq 2). Monoꢀchlorination
of naphthol 2ab at the orthoꢀposition is also not straightforward in which multiꢀchlorinated
products were obtained when employing the TMP/SO2Cl2 protocol34ꢀ35 (Scheme 2, eq 3), but the
monoꢀchloronaphthol 3ab could be obtained in high selectivity using our approach. We
speculate that the undesirable outcomes using the TMP/SO2Cl2 protocol could be attributed to
the presence of HCl that could protonate the substrates.
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Scheme 2. Orthoꢀchlorination of 2ab, 2ae and 2af
Interestingly, double orthoꢀchlorination of the biphenols 4a–4b, tetraphenylene 4c39 and rigid
biaryl 4d–4e proceeded readily to provide the corresponding bisꢀorthoꢀchlorinated products 5a–
5e (Table 3). These are very useful intermediates for the preparation of biphenol derivatives,40ꢀ42
which is an important class of ligands that have been extensively applied in various metalꢀ
catalyzed asymmetric reactions.43ꢀ46 Particularly, 5d has been proven to be an exceptionally
potent ligand than its bromine derivative in the enantioselective alkene metathesis;47 the
literature procedure for the preparation of 5d from the corresponding biphenol 4d is tedious
(through the classical approach MOMꢀprotection→lithiation→deprotection sequence). On the
other hand, 5d could be prepared from the direct orthoꢀchlorination of 4d in a single chemical
operation using the ammonium salt catalytic system. The potential application of the orthoꢀ
chlorination catalytic protocol appears to be quite broad not only with regard to the synthesis of
symmetrical orthoꢀchlorinated biphenol derivatives, but also in terms of the preparation of
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unsymmetrical monoꢀchlorinated BINOLs and biphenols with high orthoꢀselectivity. To our
delight, chlorination at the orthoꢀposition of the naphthol and phenol moieties in 6a–6g
proceeded smoothly, giving the corresponding monoꢀchlorinated products 7a–7g in good
isolated yields (Table 3). However, a mixture of chlorinated product was obtained when simple
BINOL was used as the substrate.
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Table 3. Orthoꢀchlorination of biphenols 4 and unsymmetrical BINOLs 6a
a Reactions were carried out with substrate (0.1 mmol), catalyst 1a (1 mol%, 0.001 mmol), and
o
DCDMH (0.2 mmol) in toluene (2 mL) in the absence of light at 0 C. The yields were isolated
yields (average of two trials). b 20 mol% catalyst 1a was used. c 10 mol% catalyst 1a was used. d
The reaction was carried out at 25 oC. e 1 mol % catalyst 1a was used.
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2.3 One-pot sequential ortho-halogenation
Despite our success in demonstrating the excellent performance of the ammonium chloride salt
1a in catalyzing the monoꢀchlorination of phenols and BINOLs with high orthoꢀselectivity, we
sought to explore the versatility of this catalytic halogenation protocol in the oneꢀpot synthesis of
2ꢀchloroꢀ6ꢀbromophenols 8 via a sequential orthoꢀselective chlorination and bromination (Table
4). In this process, the phenol substrates 2 were subjected to the standard 1aꢀcatalyzed orthoꢀ
chlorination conditions followed by the addition of the other halogen source Nꢀ
bromosuccinimide (NBS). Other than simple phenol, this oneꢀpot chemical operation was
applied to the halogenations of a variety of metaꢀand paraꢀsubstituted phenols and the
corresponding bisꢀorthoꢀhalogenated phenols 8 were obtained smoothly in all these cases. Again,
the reaction was found to be readily scalable through the gramꢀscale trail in the formation of
compound 8g. These multiꢀhalogenated compounds are attractive building blocks in the
synthesis of bioactive compounds and functional materials.48ꢀ50
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Table 4. Substrate scope of the sequential oneꢀpot orthoꢀhalogenationa
5
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9
OH
OH
1. 1a (1 mol%), DCDMH
toluene, 0 oC, 4 h
2. NBS, 1 h
H
H
Cl
Br
R
R
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3 or 8
2
OH
OH
OH
OH
OH
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Br
MeO
Br
8f (91%)
Cl
I
O
8g (93%)
(95% @ 1.5 g scale)
3s (55%)
8e (96%)
8i (68%)b
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OH
OH
OH
OH
OH
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Br Cl
Br
Br
Me
Ph
H
F
F
Br
O
O
O
F
8j (54%)b
8k (58%)b
8l (60%)b
8v (52%)
8z (50%)
8ag (85%)
a Reactions were carried out with phenol substrate 2 (0.1 mmol), catalyst 1a (1 mol%, 0.001
mmol), and DCDMH (0.1 mmol) in toluene (2 mL) in the absence of light at 0 C for 4 h. NBS
o
(0.1 mmol) was then added followed by additional 1 h stirring. The yields were isolated yields
(average of two trials) after the twoꢀstep reaction. b 5 mol% 1a was used.
2.4 Utilities of the ortho-chlorinated phenols and BINOLs
The orthoꢀchlorinated phenols and naphthols are very useful building blocks for the synthesis
of functional molecules. For example, oꢀchloronaphthol 3ab could readily undergo Suzukiꢀ
Miyaura crossꢀcoupling/intramolecular transesterification to provide lactone 9 in 82% yield in
which the lactone skeleton 9 widely exists in natural products and has been used as the starting
material for the preparation of axially chiral biaryl compounds (Scheme 3, eq 1).51ꢀ52 In addition,
chlorophenol 3v could undergo selective intramolecular coupling to form benxofuran 10 in 75%
yield.53ꢀ54 Subsequent crossꢀcoupling of 10 with tꢀbutylacetylene gave the functionalized
benxofuran 11, which is an important constitutional unit of organic lightꢀemitting diode materials
(Scheme 3, eq 2).55
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Scheme 3. Preparation of functional polycyclic compounds from the orthoꢀchlorinated naphthol
3ab and phenol 3v
Another key application of these products is the preparation of ligands. For instance, 5a is an
excellent starting material to prepare biphenol ligands 14 in which this type of ligand has been
extensively applied in various metalꢀcatalyzed asymmetric reactions and exhibits much better
enantioselectivity than binaphthol in some cases (Scheme 4, eq 1).43ꢀ46 However, the limited
structure diversity, partly due to the impractical synthetic sequence, often hinders their
applications. Indeed, the functionalization of common biphenol ligands was mainly introduced
with the same groups at 3,3’ꢀ and 5,5′ꢀpositions through lithiation/halogen exchange.
Nevertheless, biphenol 15 could readily be obtained by a simple orthoꢀchlorination/paraꢀ
bromination of 4a. The structure of 15 was confirmed unambiguously by an Xꢀray
crystallographic study. Compound 15 contains two halogen handles with different reactivity
towards crossꢀcoupling reaction (Scheme 4, eq 1). A sequential crossꢀcoupling reaction of 15
(after methylation) with different boronic acids could give rise to biphenol ligand 18. This
method provides an easy access to the highly functionalized biphenol ligands.56ꢀ61
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Scheme 4. Preparation of biphenol ligands
Other than the preparation of biphenol ligands, the ammonium salt catalytic protocol could be
applied to the preparation of chiral unsymmetrical BINOLs and biphenols in which these ligands
were found to have superior performance in some challenging reactions.16ꢀ19 For example, it has
been demonstrated that the unsymmetrical monoꢀsubstituted chiral ligands BINOL (R)ꢀ19 have
superior performance in some asymmetric reactions as compared with the corresponding
symmetrical 3,3′ꢀaryl BINOLs.56ꢀ61 Starting from the orthoꢀhalogenated compounds (R)ꢀ7b and
(R)ꢀ7f, coupling reactions using different boronic acids followed by hydrolysis under basic
condition gave a series of chiral ligands (R)ꢀ19 (Scheme 5). Typically, the synthesis of these type
of special ligands involves the use of very moisture sensitive organolithium or Grignard reagents
at very low temperature, which is tedious and nonꢀtrivial for largeꢀscale production.54ꢀ59 On the
other hand, the present catalytic protocol is operationally simply with high synthetic
convenience.
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Ar
Cl
1. ArB(OH)2, Pd(OAc)2, S-Phos
K3PO4 3H2O, THF, 65 oC
OH
OH
OH
OTs
2. NaOH, MeOH/H2O, 70 oC
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(R)-7b, (R)-7f
Ph
(R)-19
Ar
Ph
Ph
OR
OH
OH
OH
OH
OH
OH
(R)-19bref 57-58, Ar = 4-Me-C6H4 (74%)
(R)-19cref 59, Ar = 3,5-Ph2-C6H3(78%)
BBr3
CH2Cl2
0 oC
(R)-19d, R = Me (65%)
(R)-19eref 60, R = H (96%)
(R)-19aref 56 (59%)
Scheme 5. Preparation of monoꢀsubstituted BINOL ligands 19
In addition, this method could offer an easy access to the unsymmetrical diꢀsubstituted 3,3’ꢀ
aryl BINOLs. For instance, the 3ꢀaryl substituted compound 21 could be efficiently prepared by
the palladium catalyzed crossꢀcoupling reaction of the methylated compound 20 (prepared from
the orthoꢀchlorination of 6c in gramꢀscale) with 4ꢀmethylphenyl boronic acid (Scheme 6). After
removal of the nosyl group in 21 to give 22, the naphthol moiety in 22 could undergo the orthoꢀ
selective chlorination to give 23 in 79% yield. Subsequent crossꢀcoupling reaction and
demethylation furnished the unsymmetrical 3,3’ꢀaryl BINOL 25. Again, this synthetic avenue is
readily scalable since the key starting material (R)ꢀ7c could be prepared in gramꢀscale using the
ammonium salt catalytic protocol.
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Scheme 6. Preparation of unsymmetrical BINOL ligands
2.5 Exploration of the ortho-selenylation scope
Further evaluation of the ammonium chloride salt showed that catalyst 1a could catalyze the
direct CꢀH orthoꢀselenylation of phenols with Nꢀ(phenylseleno)phthalimide (NPSP) as the
electrophile. As shown in Table 5, phenols with diverse functionalities were proved compatible
under this catalytic protocol and could react smoothly with the selenium reagent NPSP to furnish
the corresponding orthoꢀselenylated phenols 26. Interestingly, allylꢀsubstituted substrate 2al,
which is known to readily undergo selenoetherification,62 was wellꢀtolerated under this reaction
to generate the orthoꢀselenylated product 26al. For the substrates that have relatively lower
reactivity, the less sterically hindered ammonium salt catalyst 1b was required to ensure a
reasonable rate of selenylation, furnishing 26r and 26s in good yields. In the case of the metaꢀ
substituted phenol substrates, monoselenylation could be achieved in moderateꢀtoꢀexcellent
yields (26j, 26ai, 26aj, 26ae) with ammonium salt catalyst 1c. The selenylation of naphthols was
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Table 5. Substrate scope of the orthoꢀselenylationa
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a
Reactions were carried out with phenol substrate (0.1 mmol), catalyst 1a (10 mol%, 0.01
o
mmol), NPSP (0.2 mmol) and 3Å MS (10 mg) in toluene (2 mL) in the absence of light at 0 C.
b
c
The yields were isolated yields (average of two trials). 1b was used as the catalyst. 1c was
used as the catalyst. d The reactions were conducted at –10 oC.
also explored, delivering the corresponding orthoꢀselective monoꢀselenylated compounds in
good yields (26aa-26ab). It is worthꢀmentioning that aryl selenides are the scaffolds of many
bioactive compounds.63ꢀ64 Although transition metalꢀcatalyzed orthoꢀselective selenylation of
arenes could be achieved with specific directing groups,65ꢀ66 using phenol as a substrate remains
unknown, potentially due to the unfavorable highꢀstrain CꢀH activation process. On the other
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hand, this report represents the first report of organocatalytic orthoꢀselective selenylation of
5
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phenols.
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2.6 Structural Requirement of Substrate
Instead of phenol (2a), anisole (27) was used as the substrate. Sluggish reaction was observed
and poor siteꢀselectivity with pꢀchloroanisole (28) as the major product was realized (Scheme 7,
eq 1). A similar reaction was performed using 30 as the substrate. Monoꢀchlorinated product at
the orthoꢀposition of the phenol moiety in 30 was obtained exclusively, giving 31 in 96% yield
(Scheme 7, eq 2). Although methoxy group has a strong electronꢀdonating effect that enables
aromatic halogenation,67 the strong preference of chlorination at the phenol moiety in 30
suggests that the OH group might provide a strong directing effect in the reaction. These results
suggest that the hydroxyl handle in phenol might play a crucial role in the ammonium salt
catalyzed orthoꢀchlorination, potentially through the hydrogenꢀbond interaction with the active
species. Poor reactivity of the selenylation were also observed when anisole (27) was used as the
substrate (Scheme 7, eq 3).
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Scheme 7. Examination of anisoleꢀcontaining substrates
2.7 Active Species in The Catalytic Cycle
It was noticed that both secondary amineꢀderived ammonium salt 1a and tertiary amineꢀ
derived ammonium salt 1c could catalyze the chlorination of phenols with certain level of orthoꢀ
selectivity (Table 1, entries 4 and 5). However, quaternary ammonium salt 1f was found to be
ineffective in the promotion of orthoꢀchlorination of phenol (2a) (Table 1, entry 8). We then
attempted to probe the active species in order to get a better understanding on the catalytic cycle.
Upon mixing 1a and DCDMH in CDCl3, new proton signals that correspond to species A were
observed (Scheme 8, eq 1). However, the same species could not be obtained when mixing 1a
with Nꢀchlorosuccinimide (NCS), attributable to the relatively weaker electrophilicity of the Cl
in NCS (See SI). Indeed, replacing DCDMH with NCS in the orthoꢀchlorination of 2a returned
sluggish transformation (Scheme 8, eq 2). Thus, we believe that effective formation of the active
species A might be the key of high orthoꢀselectivity.
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Scheme 8. Experiments on probing the active species
Species A might degrade to give iPr2NCl (through the elimination of HCl) or chlorine, and
either of them might act as the chlorinating agent in the reaction. However, chlorination of
phenol (2a) using iPr2NCl as the stoichiometric reagent gave poor orthoꢀselectivity. Using
Et4NCl3 as the chlorinating agent also returned sluggish reaction. These results suggest that
iPr2NCl or chlorine is not responsible for the observed orthoꢀselectivity, which is different from
the mechanistic proposal in the literature method.34ꢀ35 For the selenylation, species B was also
identified upon mixing 1a and NPSP (Scheme 8, eq 1) (See SI). Again, phenylselenium chloride
might be formed through the degradation of species B. However, selenylation of phenol using
PhSeCl gave only trace amount of 26a, which indicates that PhSeCl might not be the active
selenylation species in the orthoꢀselenylation reaction (Scheme 8, eq 2).
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2.8 Plausible Catalytic Cycle
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8
9
Based on the abovementioned studies, it appears that species A and B are the active
intermediates in the orthoꢀselective halogenation and selenylation of phenols, respectively. A
plausible catalytic cycle is constructed as illustrated in Scheme 9. We believe that species A or B
could be formed in the reaction between 1a and DCDMH or NPSP, respectively (Scheme 9). We
suspect that the counter ion of the ammonium salts might play an important role in controlling
the selectivity since ammonium salts 1d and 1e gave poorer selectivity (Table 1, entries 6 and
7).68 A possible explanation is that the chloride anion in 1a might be a better hydrogenꢀbond
acceptor to interact with the phenolic proton, which could enhance the electron density of the
phenol system (i.e. intermediate D). The hydrogen bond interaction might then bring the
electrophilic halogen or selenium close proximity to the orthoꢀposition of phenols and allow an
effective atom transfer (intermediate E) to yield the desired orthoꢀfunctionalized products.
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In terms of the siteꢀselectivity with 3ꢀcarbonyl substituted substrates 2l–2o that gave rise to the
products 3l–3o with the Cl at the sterically more congested C(2), we suspect that the carbonyl
unit might provide a directing effect through a weak interaction with species A. This speculation
is supported by the fact that in the 13C NMR study (See SI), an appreciable downfieldꢀshift of the
carbonyl carbon signal of acetophenone was observed when mixing species C with acetophenone
(Scheme 9, eq 1). The weak interaction could be attributed to the halogenꢀbond interaction69ꢀ70
between the electrophilic Cl in species C and the carbonyl oxygen. Thus, we suspect that the
synergistic effect of the OH group and the carbonyl group in 2l–2o might promote the halogen
transfer at C(2) to yield the desired products 3l–3o (Scheme 9, eq 2). For the case of resorcinol
(2ac) (Table 2), it appears that the synergistic effect of the two hydroxyl groups in bringing the
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Cl atom to the C(2) position might be disfavored, potentially due to the rigid pseudo fourꢀ
membered ring transition state (Scheme 9, eq 3).
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9
H Cl-
O+
iPr iPr
OH
OH
Ar
N
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X
H
SePh
Cl
R2
H
or
R2
R2
E
H Cl-
Cl-
N+
O
iPr iPr
N+
X
H
R2
H
H
H
1a
D
SePh
N
Cl
N
OH
O
O
O
O
H
or
R2
N
Cl-
N+
Cl-
Cl
or
N
DCDMH
NPSP
H
Cl
H
SePh
A
B
198.1 ppm
Et
3.08 ppm
3.63 ppm
O
Et
Et
N+
Cl
O
Cl-
HH
Et
HH
Et
acetophenone
DCDMH
CD2Cl2
(1)
Et
Et
N+
H
N+
Cl-
Cl-
Cl
198.7 ppm
C
OH
OH
H
O
O
2
Cl
6
2
6
A
H
R1
H
N
H
Cl-
R1
(2)
(3)
H
Cl
Cl-
O Cl N+
O
O
R1
O
3
3
R
R
R1
2l 2o
R
R
3l 3o
-
-
OH
H
O
O
6
2
A
H
H
H
H O
H
N
R
H O
Cl
Cl N+ Cl-
Cl-
3
OH
R
R
R
2ac
Scheme 9. Plausible catalytic cycle
3. CONCLUSIONS
In summary, we have demonstrated that the ammonium chloride salts are powerful
organocatalysts for highly orthoꢀselective halogenation and selenylation of phenols and BINOLs.
The substrate scope is very board and the catalytic protocol provides an expeditious avenue
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towards the preparation of highly functionalized biphenols and unsymmetrical BINOL ligands.
Further investigation on the application of this catalytic protocol to other reactions is underway.
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AUTHOR INFORMATION
Corresponding Authors
*Eꢀmail for Y.ꢀY. Yeung: yyyeung@cuhk.edu.hk
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge.
Experimental details, CIF files, spectroscopic and analytical data for new compounds. (PDF)
ACKNOWLEDGMENTS
We thank the Hong Kong Special Administrative Region University Grant Council (RGC Ref.
No. CUHK14315716), The Chinese University of Hong Kong Direct Grant (Project code:
4053203), and Research Fellowship Scheme (Project code: 4200486) for financial supports. The
equipment was partially supported by the Faculty Strategic Fund for Research from the Faculty
of Science of the Chinese University of Hong Kong. This paper is dedicated to Professor Elias J.
Corey in the occasion of his 90th birthday.
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