The Interrupted Pummerer Reaction in a Sulfoxide-Catalyzed Oxidative Coupling of 2-Naphthols

Article abstract of DOI:10.1002/anie.201903492

A benzothiophene S-oxide catalyst, generated in situ by sulfur oxidation with H₂O₂, mediates the oxidative coupling of 2-naphthols. Key to the catalytic process is the capture and inversion of reactivity of a 2-naphthol partner, using an interrupted Pummerer reaction of an unusual benzothiophene S-oxide, followed by subsequent coupling with a second partner. The new catalytic manifold has been showcased in the synthesis of the bioactive natural products, (±)-nigerone and (±)-isonigerone. Although Pummerer reactions are used widely, their application in catalysis is rare, and our approach represents a new catalytic manifold for metal-free C?C bond formation.

Full text of DOI:10.1002/anie.201903492

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Accepted Article
Title: The interrupted Pummerer reaction in a sulfoxide-catalyzed
oxidative coupling of 2-naphthols
Authors: Zhen He, Alex P Pulis, and David John Procter
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201903492
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10.1002/anie.201903492
Angewandte Chemie International Edition
COMMUNICATION
The interrupted Pummerer reaction in a sulfoxide-catalyzed
oxidative coupling of 2-naphthols
Zhen He, Alexander P. Pulis, and David J. Procter*
Abstract: A benzothiophene S-oxide catalyst, generated in situ by
sulfur oxidation with H2O2, mediates the oxidative coupling of 2-
naphthols. Key to the catalytic process is the capture and inversion
of reactivity of a 2-naphthol partner, using an interrupted Pummerer
reaction of an unusual benzothiophene S-oxide, followed by
subsequent coupling with a second partner. The new catalytic
manifold has been showcased in the synthesis of the bioactive
natural products, (±)-nigerone and (±)-isonigerone. Although
Pummerer reactions are used widely, their application in catalysis is
rare, and our approach represents a new catalytic manifold for
metal-free C–C bond formation.
side reactions (e.g. classical Pummerer chemistry)9 and
rearrangements of sulfonium intermediates A and B.5b-5c,6a-6t,10
Here we describe the realization of an interrupted
Pummerer catalytic manifold in a carbon-carbon bond-forming,
oxidative coupling of 2-naphthols that delivers important 1,1'-bi-
2-naphthols (BINOLs) (Scheme 1B). The BINOL motif is one of
the most recognizable and well-established ligand architectures
in catalysis,11 in addition to being found in bioactive molecules,
natural products12 and functional materials.13 BINOLs are most
efficiently formed by oxidative coupling of 2-naphthols and
various stoichiometric and catalytic processes, including
excellent catalytic enantioselective variants, have been
employed.11h,14 To our knowledge no metal-free, organocatalytic
synthesis of BINOLs has been reported. The process constitutes
Carbon-carbon bond formation underpins almost every synthetic
undertaking1 and oxidative processes that unite two nucleophilic
partners,2 at the expense of a C–H bond in each partner, are at
the forefront of synthetic technology. Such couplings are
typically achieved using stoichiometric metals, or metal
catalysts,2 however, metal-free processes that do not rely on
expensive metal catalysts, and do not generate metallic waste,
are desirable.3,4
a
rare example of a catalytic Pummerer process, uses
synthetically under-explored benzothiophene S-oxides,6r,6t,15 and
employs inexpensive H2O2 as the terminal oxidant. The high
functional group compatibility of the process has been exploited
in the synthesis of (±)-nigerone and related natural products.
The Pummerer reaction,5 including its so-called interrupted
variant,6 involves the activation of sulfoxides and the subsequent
transformation of the resultant sulfonium salts. As tools for
synthesis, the family of Pummerer processes continues to find
widespread application en route to important targets, including
natural products, bioactive molecules and advanced materials.5
It is therefore surprising that the use of Pummerer reactions to
drive catalysis is rare,7 and the use of sulfoxides to catalyze
carbon-carbon bond formation via Pummerer processes has not
been described. We postulated that sulfoxides could serve as
catalysts for oxidative union of two carbon nucleophiles through
the operation of an interrupted Pummerer process (Scheme 1A).
In such a process, activated sulfoxide derivatives A would
engage nucleophile partners in an interrupted Pummerer
reaction to form sulfonium salts B. A reversal of natural reactivity
is made possible through the formation of B: the first nucleophile
becomes electrophilic and is now activated for coupling with a
second, liberating the coupled product and a sulfide leaving
group. Selective oxidation of the sulfide would render the
process catalytic in the sulfur species. Although interrupted
Pummerer reactions generally operate under mild conditions
with a range of nucleophiles, the proposed catalytic cycle in
which sulfonium species must be regenerated presents acute
challenges. For example, selective oxidation and electrophilic
activation of sulfur must be possible in the presence of other
nucleophiles,8 and interrupted Pummerer reactivity must out-run
A. Catalytic Nu−Nu coupling by Interrupted Pummerer reaction
Nu
Nu
Nu
Nu
H
Nu
H
interrupted
Pummerer
S
coupling
R
R
B
– H
– HOE
OE
S
Umpolung of Nu reactivity
S
R
R
R
R
A
[O]
E
O
S
electrophilic
activation
oxidation
R
R
B. This work: Benzothiophene S-oxide-catalyzed, metal-free C–C coupling
Me
–via
Me
S
R
R
OH
3a 10 mol%
S
O
OH
OH
R
I
1
H2O2, TFAA
2
n catalysis by interrupted Pummerer reaction
n application in the total synthesis of nigerone
R
Scheme 1. The Interrupted Pummerer reaction in sulfoxide-catalyzed
oxidative couplings. (A) A new approach to nucleophile-nucleophile coupling
that uses a sulfoxide catalyst to reverse the natural reactivity of one partner. (B)
The realization of an interrupted Pummerer catalytic manifold in a carbon-
carbon bond-forming, oxidative coupling of 2-naphthols that delivers important
1,1'-bi-2-naphthols.
As a prelude to our studies in catalysis, we first investigated
the ability of sulfoxides to mediate the homocoupling of 2-
naphthols in a stoichiometric process. In particular, the studies
were designed to ascertain whether; (i) 2-naphthols would
undergo nucleophilic addition to the activated sulfoxide (cf. A)
through oxygen or through carbon in an SEAr fashion;16 (ii) if the
reaction occurred through oxygen, would the resultant
aryloxysulfonium salts I now act as electrophiles and couple with
[*]
Dr. Z. He, Dr. A. P. Pulis and Prof. Dr. D. J. Procter
School of Chemistry, University of Manchester
Oxford Rd, Manchester, M13 9PL (UK)
E-mail: david.j.procter@manchester.ac.uk
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201903492
Angewandte Chemie International Edition
COMMUNICATION
a second equivalent of 2-naphthol. Thus, 2-naphthol (1a) and a
variety of sulfoxides 3 were combined in the presence of the
electrophilic activator TFAA (Figure 1). Pleasingly, when 3-
methyl benzothiophene S-oxide (3a) was employed in CH2Cl2,
the desired coupling product 2a was formed in high isolated
yield (87%). Dibenzothiophene S-oxide (3b) also produced 2a
but in slightly lower yield. The use of DMSO (3c), phenyl methyl
sulfoxide (3d), and diphenyl sulfoxide (3e) produced complex
mixtures thus highlighting the importance of the thieno moiety in
3a and 3b for efficient coupling (vide infra). Finally,
benzothiophene S-oxides 3f and 3g bearing bulky substrates at
C3 proved less effective in the coupling than 3a. The C3
substituent is likely to play a role in disfavoring the competing
rearrangement of aryloxysulfonium salts I.6r,6t
For a catalytic process, chemoselective oxidation of the
sulfide byproduct, to the sulfoxide and not the sulfone, by a
convenient terminal oxidant in the presence of the other
nucleophilic reaction components is crucial. H2O2 and TFAA6r,6t
were added in one portion to a solution of 2-naphthol (1a) and
10 mol% of sulfide 3a’. Pleasingly, 2a was obtained in 45% yield
(Table 1, entry 1). However, significant quantities of sulfone 3a’’
were formed thus limiting catalytic turnover. Adding the oxidant
and activator in portions greatly improved reaction efficiency and
product 2a was isolated in 84% yield (entry 2). Control
experiments revealed that 3a’, TFA, and TFAA were all essential
for the reaction to proceed (entry 3-5). Other terminal oxidants
(e.g. UHP and tBuOOH) were less effective (entry 6-7).
A. Homocouplinga
3a' (10 mol%)
H2O2 (1.25 equiv)
R
O
S
OH
TFAA (1.25 equiv)
OH
OH
2 x
R
3
R
R
CH2Cl2/TFA(1:1)
0 oC to rt
R
TFAA
OH
OH
OH
1
2
CH2Cl2
−40 °C to rt
R1
2d, R1 = Br, 75%
S
1a
2a
2e, R1 = CO2Me, 52%b
2f, R1 = CN, 35%c
OH
OH
O
S
O
S
O
S
O
S
2g, R1 = Ph, 82%
O
S
OH
OH
2h, R1 = 1-naphthyl, 65%
2i, R1 = 9-phenanthryl, 70%
2j, R1 = p-OMeC6H4, 90%
2k, R1 = p-CF3C6H4, 55%b
Me
Me
Me
R1
2a, R1 = H, 84%
2b, R1 = nC10H21, 67%
2c, R1 = OMe, 40%
Me
2l, 76%d
3a
3b
3e
<15%a
3c
<15%b
3d
<15%a
S
90% (87%)
84%
2m, R2 = OMe, 58%
2n, R2 = OH, 47%
2o, R2 = Br, 80%
2p, R2 = nC10H21, 51%
2q, R2 = Ph, 80%
O
S
O
S
HO
R2
R2
OH
OH
S
S
OH
2r, R2 = p-OMeC6H4, 62%
2s, R2 = 1-naphthyl, 60%
3g
(52%)
3f
(44%)
2t, 64%d X-ray
R3
OH
OH
OH
CO2Et
Figure 1. Preliminary studies: stoichiometric sulfoxide mediated oxidative
coupling. Reaction conditions: 1a (0.20 mmol), 3 (0.11 mmol), CH2Cl2 (1.0 mL),
at –40 °C; TFAA (0.17 mmol) then added and stirred for 15 min; warmed to rt.
Yield determined by 1H NMR analysis of the crude reaction mixture. Isolated
yield in parentheses. [a] Complex mixture formed.
MeO
CO2Et
OH
OH
OH
OH
OH
OH
OH
OH
R3
2u, R3 = Br, 65%b
CO2Et
MeO
CO2Et
2v, R3 = CO2Me, 60%e,
58%f X-ray
OH
Table 1. Optimization of the sulfoxide-catalyzed oxidative homocoupling.[a]
2w, R3 = OH, 50%
2x, R3 = Ph, 50%
2z, 69%g
2aa, 80%g
2y, 62%
S
X-ray
O
O
B. Cross-couplingh
Me
OH
3a' (10 mol%)
S
OH
OH
3a' (20 mol%)
H2O2 (2.5 equiv)
TFAA (2.5 equiv)
H
OH
R4
R5
TFAA, H2O2
CH2Cl2/TFA
0 °C to rt
R5
R4
Me
OH
+
1a
2a
3a''
1
4
CH2Cl2/TFA(1:1)
0 oC to rt
(1 equiv)
(1 equiv)
Entry
Changes to conditions
Yield 2a (%)
5
1
2
3
4
5
6
7
H2O2 and TFAA added in one portion
45
90 (84)
trace
trace
0
R4
MeO
OH
MeO
none
no 3a’
OH
OH
OMe
OH
MeO
OMe
MeO
MeO
OMe
no TFA
R5
OMe
no TFAA
OMe
5a, 42%
OMe
OMe
5b, 41%
5c, R4 = H, 48%
5e, R5 = H, 55%
5f, R5 = OMe, 50%
UHP was used instead of H2O2
tBuOOH (5.5 M) was used instead of H2O2
85
5d, R4 = OMe, 47%
45
Figure 2. Substrate scope for the sulfoxide-catalyzed oxidative coupling of 2-
naphthols. [a] Reaction conditions: (0.2 mmol), 3a’ (0.02 mmol) in
[a] Reaction condition: 1a (0.2 mmol), 3a’ (0.02 mmol), CH2Cl2/TFA (0.5/0.5
mL), 0 ºC; 30% aqueous H2O2 (0.25 mmol) and TFAA (0.25 mmol) added in
five portions over 2 h; warmed to rt. Yield determined by 1H NMR analysis of
the crude reaction mixture. Isolated yield in parentheses.
1
CH2Cl2/TFA (0.5/0.5 mL), at 0 °C; then 30% H2O2 aqueous (0.25 mmol) and
TFAA (0.25 mmol) were added separately in five portions over 2 h; warmed to
rt. [b] 20 mol% catalyst 3a’ was used. [c] Dibenzothiophene 3b’ was used as
the precatalyst and Tf2O was used instead of TFAA. [d] without 3a’. [e] Used
CH2Cl2/TFA (1.0/1.0 mL) and heated to 50 oC. [f] 1.6 g of 1v used. [g] H2O2
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10.1002/anie.201903492
Angewandte Chemie International Edition
COMMUNICATION
and TFAA were added in five portions over 10 min. [h] Reaction conditions: 1
(0.1 mmol), 4 (0.1 mmol) and 3a’ (0.02 mmol) in CH2Cl2/TFA (0.5/0.5 mL), at
0 °C; then 30% H2O2 aqueous (0.25 mmol) and TFAA (0.25 mmol) were
added separately in five portions over 2 h and then warmed to rt.
Scheme 2. (A) Proposed catalytic cycle. (B) Probing the intermediacy of an
aryloxysulfonium salt.
Based on the above results, and our previous studies,6r,6t
we propose the catalytic cycle set out in Scheme 2A.
Benzothiophene S-oxide 3a reacts with TFAA to form activated
sulfoxides II, which we have observed by NMR (See Supporting
Information).18 Subsequently, 2-naphthols 1a react through
oxygen with II in an interrupted Pummerer process to form
aryloxysulfonium salts I.6r,6t The intermediacy of I is supported by
the formation of cross-coupled product 7 from the stepwise
Using 10 mol% of 3a’, a range of 2-naphthols 1, bearing
electron neutral, electron rich and electron poor substituents at a
variety of positions on the ring system, underwent smooth
coupling to give BINOLs 2 in moderate to good yield (Figure 2A).
Ester (2e, 2v), methoxy (2c, 2j, 2m, 2r, 2z), cyano (2f), bromo
(2d, 2o, 2u), trifluoromethyl (2k), and additional free hydroxyl
(2n, 2w, 2z, 2aa) functional groups were well tolerated.
Interestingly, the coupling of 2-naphthols
benzothiophene substituent (formation of 2l and 2t) did not
require addition of an external benzothiophene as
1 containing a
addition of phenol
6
to one equivalent of activated
benzothiophene S-oxide 3a, and subsequent addition of 2-
naphthol (Scheme 2B). Formation of the aryloxysulfonium salts I,
bearing a benzothiophene leaving group on oxygen, allows the
reversal, or umpolung, of the normal nucleophilic reactivity of C1
of 2-naphthols. Thus, the now electrophilic naphthol moiety in I
engages with another equivalent of 2-naphthol 1 to form a new
carbon-carbon bond in III, which undergoes rearomatization to
form BINOLs 2. The liberated benzothiophene is selectively re-
oxidized with H2O2/TFA to complete the catalytic cycle. Key to
the process is the lack of aromaticity in the five-membered ring
in benzothiophenium salts I:19 Upon carbon-carbon bond
formation and concurrent expulsion of benzothiophene,
aromaticity is regained – a driving force that is absent when
sulfoxides 3c-e are used.
a
benzothiophene S-oxide catalyst is likely formed in situ from the
substrates. Crucially, products bearing 3,3’ disubstitution, a key
motif for the function of the most powerful BINOL based
ligands,11 were successfully formed (2u-x). The catalytic
coupling worked well on gram scale: 1.6 g of 1v produced 2v
(0.93 g) with similar efficiency as to that achieved on a smaller
scale. We also achieved the coupling of highly oxygenated 2-
napthols 1z and 1aa to give BINOLs 2z and 2aa in high yield. A
previously reported attempt to oxidatively couple 1z, to give 2z,
using a copper catalyst was unsuccessful.14s Notably, the results
from reactions using 10 mol% of 3a’ were highly consistent with
those obtained from reactions using stoichiometric 3a.17 This
underscores the remarkable selectivity achieved in the stages of
the catalytic process. Our sulfoxide-catalysis approach can also
be used in C–H/C–H-type cross-coupling between 2-naphthols
and arene partners; the combination of 2-naphthols with various
electron-rich arene partners gave the desired cross-coupled
products (5a-5f) in moderate yield (Figure 2B). 2-Naphthol
homocoupling products were also observed (See Supporting
Information).
OMe OH
3a' (10 mol%)
CO2Et
OMe OH
H2O2 (1.25 equiv)
TFAA (1.25 equiv)
CO2Et
OH
MeO
MeO
OH
OH
CH2Cl2/TFA(1:1)
0oC to rt
MeO
8
CO2Et
9
50%
OMe OH
X-ray
NaH, DMSO, THF 40%
Me
A. Proposed mechanism for the sulfoxide-catalyzed oxidative coupling of 2-naphthols
OMe O
OMe OH
O
O
S
X-ray
O
Me
Me
piperidine
cat.
Me
O
MeO
OH
MeO
MeO
OH
OH
H2O2
Me
H
H
2
O
MeO
O
Me
MeCHO
Tol
S
1
S
III
OMe OH
O
OMe OH
O
O
Me
10
isonigerone 25%
Me
S
CF3CO2
O
S
3a
OMe O
OMe OH
O
O
TFAA
O
I
Me
MeO
MeO
OH
OH
MeO
MeO
O
O
Me
Me
OH
S
O
O
O
CF3CO2
interrupted
Pummerer
CF3
OMe O
OMe OH
O
II
1
X-ray
X-ray
Me
nigerone 19%a
NaOH, MeOH, 57%
B. Mechanistic probe for the formation of intermediate I
bisisonigerone 41%
Me
OH
OH
Me
MeO
OMe
OH
TFAA
S
O
Scheme 3. Total synthesis of (±)-nigerone and (±)-isonigerone.
CH2Cl2
1a
3a
OMe
S
O
–40oC to rt
OMe
OH
We have applied the sulfoxide-catalyzed method in a short
synthesis of (±)-nigerone and (±)-isonigerone, bisnaphthopyrone
natural products isolated from mold and exhibiting antitumor20
and antibacterial21 activity (Scheme 3). Kozlowski employed 2-
MeO
MeO
cf. I
7 91%
6
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10.1002/anie.201903492
Angewandte Chemie International Edition
COMMUNICATION
naphthol 8 in the only reported total synthesis of nigerone.22 2-
Naphthol 8 underwent metal-free, sulfoxide-catalyzed oxidative
coupling, delivering complex BINOL 9 in 50% isolated yield.
Inspired by Kozlowski’s route, 9 was transformed into bis-
sulfoxide 10 which subsequently underwent piperidine mediated
aldol reaction and cyclization to form a mixture of the natural
[5]
a) T. Yanagi, K. Nogi, H. Yorimitsu, Tetrahedron Lett. 2018, 59, 2951-
2959; b) H. Yorimitsu, Chem. Rec. 2017, 17, 1156-1167; c) A. P. Pulis,
D. J. Procter, Angew. Chem. 2016, 128, 9996-10014; Angew. Chem. Int.
Ed. 2016, 55, 9842-9860; d) L. H. S. Smith, S. C. Coote, H. F. Sneddon,
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2401-2432.
products, isonigerone, bis-isonigerone and nigerone, in
a
combined 85% yield. Heating the mixture of isonigerone and bis-
isonigerone in the presence of NaOH allowed equilibration and
formation of the thermodynamic product, (±)-nigerone in 57%
yield. The concise route to (±)-nigerone hinges on the high
chemoselectivity of the sulfoxide-catalyzed oxidative coupling:
the additional free hydroxyl group in 8 was incompatible with
earlier catalytic couplings thus protection and later deprotection
of the group was essential.22 Our approach constitutes the first
synthesis of isonigerone, and also enabled us to characterize all
three natural products by X-ray crystallographic analysis, thus
lending further support to their structural assignment.23
In summary, we have developed a metal-free, sulfoxide-
catalyzed, oxidative coupling of 2-naphthols using inexpensive
H2O2 as the terminal oxidant. Key to our approach is the use of a
benzothiophene S-oxide catalyst that captures and inverts the
reactivity of one partner by means of an interrupted Pummerer
reaction. The resultant aryloxysulfonium salts undergo
subsequent coupling with a second partner, driven by the regain
of aromaticity upon expulsion of benzothiophene. The
chemoselectivity of the new catalytic manifold has been
showcased in a concise approach to the natural product (±)-
nigerone and its congeners. As a new strategy for inducing
carbon-carbon formation between nucleophilic partners, and a
rare example of the use of a Pummerer process in catalysis, the
method provides a blueprint for future metal-free, catalytic
couplings.
[6]
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Acknowledgements
We thank EPSRC (Postdoctoral Fellowship to Z.H.; Established
Career Fellowship to D.J.P.) and The University of Manchester
(Lectureship to A.P.P.) for their generous support.
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Keywords: • sulfoxide • catalysis • Pummerer • Metal-free •
oxidative coupling • BINOLs
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Entry for the Table of Contents
COMMUNICATION
Me
Zhen He, Alexander P. Pulis, and David
J. Procter*
–via
(also cross-coupling)
Me
S
R
R
Page No. – Page No.
S
OH
10 mol%
OH
OH
OH
O
R
The interrupted Pummerer reaction in
a sulfoxide-catalyzed oxidative
coupling of 2-naphthols
H2O2, TFAA
0 °C to rt
n catalysis by interrupted Pummerer reaction
n application in synthesis of natural products
34 examples
A benzothiophene S-oxide catalyst, generated in situ using H2O2, mediates the
oxidative coupling of 2-naphthols, thus exemplifying a strategy for coupling
nucleophilic partners. Key to the catalytic process is the capture and inversion of
reactivity of one partner, using an interrupted Pummerer reaction, followed by
subsequent coupling with a second partner. The new catalytic manifold has been
showcased in the synthesis of bioactive natural products. Although Pummerer
reactions are used widely, their application in catalysis is rare.
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