Synthesis of functionalized 3-chloro-1-naphthols via Friedel-Crafts acylation of vinyl chlorides

Article abstract of DOI:10.1016/j.tetlet.2012.01.011

Friedel-Crafts type cyclization of vinyl chlorides was developed into a general method for the synthesis of functionalized naphthols. The chloro functional group contained within these products allowed for further elaboration via cross-coupling reactions,

Full text of DOI:10.1016/j.tetlet.2012.01.011

Tetrahedron Letters 53 (2012) 1550–1552
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Tetrahedron Letters
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Synthesis of functionalized 3-chloro-1-naphthols via Friedel–Crafts acylation
of vinyl chlorides
⇑
⇑
Xin Linghu , Mark McLaughlin , Cheng-yi Chen, Robert A. Reamer, Lisa Dimichele, Ian W. Davies
Department of Process Research, Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Friedel–Crafts type cyclization of vinyl chlorides was developed into a general method for the synthesis of
functionalized naphthols. The chloro functional group contained within these products allowed for fur-
ther elaboration via cross-coupling reactions, leading to increased structural complexity.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 30 November 2011
Revised 3 January 2012
Accepted 4 January 2012
Available online 11 January 2012
Keywords:
Friedel–Crafts acylation
Vinyl chloride
3-Chloro-1-naphthols
Introduction
OH
O
FG
FG
F-C cyclization
OH
The Friedel–Crafts acylation of arenes is a thoroughly estab-
lished technique for the synthesis of aromatic ketones.1–8 Intramo-
lecular acylation with alkenes as nucleophiles has also proven
highly useful in the formation of ring-systems.9–14 While previous
studies demonstrated the use of electron enriched alkenes as effi-
cient nucleophiles, few Friedel–Crafts acylation reactions with
electron deficient alkene species have been reported. As part of a
continuing effort to develop efficient approaches to functionalized
organic intermediates, we recently became interested in the use of
alternative nucleophilic components to the commonly used arene
ring. In particular, we sought to investigate the use of electron defi-
cient vinyl chlorides as the nucleophilic component in intramolec-
ular Friedel–Crafts acylation reactions. Herein, we disclose the
results from our work in this area, which demonstrate the utility
of intramolecular Friedel–Crafts acylation of vinyl chlorides for
the synthesis of various functionalized naphthols.
Cl
Cl
2
1
Figure 1. Access to naphthols via vinyl chloride Friedel–Crafts acylation.
a chloro-group in a 1,3-relationship to a hydroxy was attractive
since this type of disubstituted naphthalene is difficult to prepare
by other means.15
Numerous reports from the Knochel group have established the
utility of Mg–I exchange for the preparation of functionalized aro-
matic compounds.16–19 Using this technology, it was possible to
access various functionalized substrates containing the desired
vinyl chloride and carboxylic acid subunits in convenient fashion
via quenching of aryl-MgX species with 2-chloro-3-iodopropene
in the presence of a Cu catalyst (Scheme 1).20 This reaction
Results and discussion
O
O
Figure 1 depicts the basic process that we set out to develop into
a general method for the preparation of naphthols. To our knowl-
edge, there are no literature examples of the direct synthesis of
naphthols via this kind of vinyl chloride Friedel–Crafts reaction.
Furthermore, the potential to generate naphthol products bearing
O
I
FG
OR b or c
FG
FG
a
OH
OR
Cl
Cl
3
1
4
R = Me, Et or t-Bu
⇑
Corresponding authors. Tel.: +1 732 594 1439; fax: +1 732 594 1499 (X.L.); tel.:
Scheme 1. Synthesis of chloroallyl Friedel–Crafts cyclization substrates via Mg–I
exchange chemistry. (a) i-PrMgCl/THF, CuCNÁ2LiCl, 2-chloro-3-iodopropene. (b) 10%
NaOH, MeOH. (c) TFA, CH2Cl2.
+1 732 594 2001; fax: +1 732 594 1499 (M.M.).
E-mail addresses: xin_linghu@merck.com (X. Linghu), mark_mclaughlin@
merck.com (M. McLaughlin).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.011

X. Linghu et al. / Tetrahedron Letters 53 (2012) 1550–1552
1551
Table 2
sequence with methyl or ethyl ester 4 normally afforded modest
Synthesis of functionalized chloronaphtholsa
yields of substituted benzoic acids due to formation of allene
by-products during basic hydrolysis via an E1cb pathway (Table 1,
entries 1–4). Alternative alkylation and acidic hydrolysis of t-butyl
analogues could improve the overall yields (entries 5 and 6).
Intramolecular Friedel–Crafts acylation reactions using these
substrates was initially processed in two separated steps of acid
chloride formation and intramolecular Friedel–Crafts acylation.
However, isolation of acid chloride intermediates sometimes cost
a significant reduction of yields for the final product. Improved re-
sults were obtained with conducting the two-step sequence in one
pot fashion by treating the intermediate acid chloride in-situ with
AlCl3. Reactions normally gave a mixture of dichloroketone 5 and
desired chloronaphthol 2. Upon being subject to longer reaction
time or a basic workup, dichloroketone can be converted to the de-
sired chloronaphthol product completely. As shown in Table 2,
substrates bearing different functional groups display the same
reactivity.
Several methodologies have been developed to functionalize
unprotected chloro-phenols or naphthols via C–C or C–X (X = O,
N, or S) bond formations.21 To further demonstrate the principal
possibility of the application of 3-chloronaphthol in organic syn-
thesis, we elaborated one example of Pd-catalyzed C–N bond for-
mation at 3rd position of naphthols, as shown in the Scheme 2.
With steric bulky t-butyl Xphos ligand, hydroxy group was toler-
ated under an amination condition.21e 3-morpholine substituted
O
O
OH
FG
FG
FG
a
OH
+
Cl
Cl
Cl
2
5
Cl
b
Entry
1
Benzoic acids
Yieldb (%)
OH
89
Cl
2a
OH
Br
2
3
4
92
93
83
Cl
Cl
2b
OH
Me
2c
OH
MeO
MeO
Cl
2d
OH
Table 1
Synthesis of chloroallyl benzoic acid substrates
5
6
83
83
Entry
Iodo ester
Benzoic acids
Yielda (%)
Cl
F
Cl
O
O
2e
OH
OH
OEt
O
1
67
I
Cl
Cl
2f
O
a
Carboxylic acid (1.0 equiv), oxalyl chloride (1.5 equiv), cat. DMF, and AlCl3
(2.0 equiv).
Br
OMe
OMe
OH
OH
b
2
3
4
5
6
64
69
73
92
83
Isolated yield of analytically pure material.
I
Br
Cl
O
O
OH
OH
H
N
[Pd (dba) ]
Me
Me
3 , t-BuXphos
2
+
NaOtBu
toluene, 100 °C
80%
I
O
Cl
N
2a
O
6
Cl
O
O
Scheme 2. Elaboration of functionalized chloronaphthols via C–N bond formations.
MeO
MeO
MeO
MeO
OH
OMe
I
naphthol can be directly derived from the chloro-precursor in a
high yield.
Cl
O
I
O
OtBu
OH
Conclusion
Cl
Cl
F
In summary, we have described the facile synthesis of 3-chloro-
1-naphthols from readily available starting materials by an intra-
molecular Friedel–Crafts acylation of vinyl chloride. The meta-sub-
stitution pattern produced using this chemistry is not readily
achievable through alternative approaches. Moreover, the resul-
tant aryl chloride functionality was demonstrated to be a useful
synthetic handle to access to multisubstituted naphthalene system
via cross-coupling chemistry.
Cl
O
F
O
I
OtBu
OH
Cl
Isolated yield of analytically pure material over two steps.
a

1552
X. Linghu et al. / Tetrahedron Letters 53 (2012) 1550–1552
Experimental section
Supplementary data
Typical experimental procedure for 2-(2-chloroallyl)-benzoic
acid formation 1: A dry, N2 flushed 25 mL round-bottomed flask,
equipped with a magnetic stirring bar, was charged with aryl iodide
3 (1 mmol) in anhydrous THF (5 mL), and cooled to À40 °C. i-PrMgCl
(2 M in THF, 2 mmol) was slowly added. After 0.5 h, CuCNÁ2LiCl
(premixed CuCN and 1 M LiCl in THF) (0.1 mmol) was added. After
5 min, at the same temperature, 2-chloro-3-iodo-propene (2 mmol)
was added and the reaction mixture allowed to warm to rt. The reac-
tion mixture was quenched with sat. NH4Cl (20 mL) and extracted
with MTBE (2 Â 20 mL). The combined organic fractions were
washed with brine (10 mL), then dried over Na2SO4, and concen-
trated in vacuo. The crude product was used in the next step after
a silica plug treatment or without further purification.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.01.011.
References and notes
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At rt, to a solution of ester 4 from the last step (1 mmol) in
MeOH (10 mL) was added 10% NaOH (5 mL). After 20 h, the reac-
tion was acidified with concentrated HCl to pH 2. After removing
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Acknowledgment
High Resolution Mass Spectroscopy analysis support from Tho-
mas J. Novak is gratefully acknowledged.