Pummerer Synthesis of Chromanes Reveals a Competition between Cyclization and Reductive Chlorination

Article abstract of DOI:10.1021/acs.orglett.9b02520

The competition between an unprecedented reductive chlorination and the Pummerer reaction was studied and applied to the synthesis of benzofused oxygen heterocycles including 3-aminochromanes and in the intramolecular chlorination of activated aromatic ri

Full text of DOI:10.1021/acs.orglett.9b02520

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Pummerer Synthesis of Chromanes Reveals a Competition between
Cyclization and Reductive Chlorination
́
́
́
Paola Acosta-Guzman, Alvaro Rodríguez-Lopez, and Diego Gamba-Sanchez*
Laboratory of Organic Synthesis, Bio and Organocatalysis, Chemistry Department, Universidad de los Andes, Cra 1 No. 18A-12
́
Q:305, Bogota 111711, Colombia
S
* Supporting Information
ABSTRACT: The competition between an unprecedented reductive chlorination and the Pummerer reaction was studied and
applied to the synthesis of benzofused oxygen heterocycles including 3-aminochromanes and in the intramolecular chlorination
of activated aromatic rings. The use of (COCl)2 as a Pummerer activator showed substantial activity, producing α-chlorinated
sulfides that can undergo Pummerer−Friedel−Crafts cyclization. If the aromatic ring has electron-donating groups in position
three, then the reaction follows a different pathway, yielding the reductive chlorination products, where the chlorine atom
comes from a sulfonium salt.
hromanes, which show diverse biological activities such
as antitumor, antioxidant, antibacterial, antifungal, and
anti-inflammatory effects, are privileged heterocycles in a
remarkable number of natural products and pharmaceutical
molecules.1 Figure 1 shows some examples of active
developing new and general methods to prepare them have
been made for many years; nevertheless, methods to access
functionalized chromanes remain limited.2
C
The Pummerer reaction and its variants3 have been
successfully used in the synthesis of heterocyclic compounds;4
however, the synthesis of benzofused oxygen heterocycles is
mainly accomplished by interrupted Pummerer approaches
(Scheme 1a).5
Classic Pummerer cyclizations using aromatic rings as
nucleophiles are extremely limited (Scheme 1b),6 presumably
because of the competition between nucleophiles and the
byproducts obtained7 but also because β-hydrogens are
undesirable because their elimination causes the formation of
vinyl sulfides. Recently, Carter and coworkers8 took advantage
of this fact by applying the vinyl sulfides effectively in a
Pummerer cyclization; unfortunately, the use of β-chiral
centers is impractical in Carter’s method. Another problem is
the use of highly deactivated aromatic rings (carrying electron-
withdrawing groups (EWGs)) as nucleophiles, whereas they
are almost unreactive in all aforementioned situations.
Inspired by those difficulties, we reasoned that eluding the
vinyl sulfide formation might be accomplished by reducing the
acidity of β-hydrogens and the basic character of counterion in
the Pummerer activator. Typical Pummerer activators are
acetic anhydride, trifluoroacetic anhydride, and triflic anhy-
dride; however, it was proven that oxalyl chloride may be used
as a Pummerer activator9 in an analogous process with Swern
Figure 1. Structures of selected bioactive chromanes and amino-
chromanes.
compounds with the chromane core in their structure:
Cromakalim is a potassium channel opener, alenespirone
reached phase II of pharmacological studies as a serotonin
receptor agonist, etamicastat reached phase II for hypertension
treatment, equol is a nonsteroidal estrogen metabolite
produced by humans from soy, which acts as a selective
agonist of ERβ, and sorbinil is an aldolase reductase inhibitor
used in the treatment of diabetes complications. Because of the
predominance of the chromane scaffold, considerable efforts in
Received: July 19, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02520
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Synthesis of Benzofused Heterocycles by
Pummerer Reaction, Previous and This Work
Scheme 2. Synthesis of Starting Materials
which should provide a suitable setup for cyclization.
Nevertheless, the treatment of 2a with oxalyl chloride afforded
in quantitative yield a new sulfide 6a issued from an
intramolecular reductive chlorination (Scheme 3).
Scheme 3. First Reductive Chlorination of Aromatics with
Sulfoxides
a
Isolated yield. The reaction was performed on a 1 mmol scale.
To the best of our knowledge, no chlorinations of aromatic
rings using chlorosulfonium salts have been described; in fact,
the reactions of sulfonium salts with phenols and phenol ethers
afford the alkylthioalkylation of the aromatic ring.10 Moreover,
the reactions of carbon, nitrogen, and oxygen nucleophiles with
sulfonium ions by the interrupted Pummerer pathway always
proceed by substitution on the sulfur atom, revealing new
chemistry and amazing developments.11 Similar aromatic
halogenations (with I and Br) presumably evolve by the in
situ formation of molecular halogens.12 In original works by
Swern13 and Corey14 (Corey−Kim oxidation), problems in the
oxidation of unsaturated alcohols were reported, probably due
to the presence of molecular chlorine in the reaction media;15
however, the chlorination of allyl and vinyl nucleophiles using
chlorosulfonium salts is very rare.16 Even if sulfonium salts are
known as electrophile sources,17 the interrupted Pummerer
reaction should be coexisting.
We then used highly activated aromatic rings (compounds
2b−f) under the same reaction conditions (see Scheme 4).
The reductive chlorination proceeded smoothly, and the
chlorinated sulfides were obtained in good to excellent yield
and with complete regioselectivity. Thus according to the
literature, four possible scenarios were envisaged to explain the
reductive chlorination: two using a nucleophilic chloride,
illustrated as routes a and b in Scheme 5 (interrupted
Pummerer approaches), one using an electrophilic chlorosul-
fonium salt (Scheme 5, route c), and one inspired by Jiao’s
work,12a where molecular halogen is formed in situ and acts as
the electrophile (Scheme 5, route d).
oxidation, forming highly reactive α-chlorinated sulfides and
generating the thionium ion, which is the key intermediate in
Pummerer chemistry. The counterion in this case is chloride,
which is less basic than acetate or trifluoroacetate, and thus
changing the CH3COO− or CF3COO− groups to Cl− should
be enough to reduce the elimination reaction and the cause of
vinyl sulfide formation. Consequently, in making this simple
change of reagents, we hoped to obtain the desired chromanes
(Scheme 1c). Herein we report the successful cyclization of
phenol ethers by the classic Pummerer reaction and our
preliminary studies on the competitive reductive chlorination
reaction issued from a special and unprecedented interrupted
Pummerer reaction.
The synthesis of the staring sulfoxides was accomplished by
the oxidation of the corresponding sulfides with NaIO4 in the
H2O/MeOH mixture. The sulfides were obtained by two
different methods, sequential nucleophilic substitutions with
thiophenol and the corresponding phenol (Scheme 2a) or the
Mitsunobu reaction of phenols with a phenyl cysteine
derivative (Scheme 2b). Yields were good to excellent, and
the reactions were performed on a 1 or 2 mmol scale in most
of the cases (sometimes they were performed on the gram
scale), showing the easy access to the starting materials and the
scalability of this process. Experimental details and data for
those experiments may be found in the Supporting
Information.
We mentioned that the previously described methods for
classic Pummerer cyclization in the synthesis of heterocycles
and carbocycles always used highly activated aromatic rings as
nucleophiles, so we started our study with compound 2a,
The regioselective chlorination of compound 2a makes
routes a and d the least plausible. The dication intermediate in
B
DOI: 10.1021/acs.orglett.9b02520
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Organic Letters
Letter
four is more nucleophilic than position 2,18 instigating the
reaction to proceed intermolecularly.
Scheme 4. Reductive Chlorination of Activated Aromatic
Rings
According to Jiao’s results12a the reaction between dimethyl
sulfoxide (DMSO) and hydrogen halides (HBr and HI)
generates the reduction of DMSO to dimethyl sulfide (DMS)
and the formation of molecular halogens, which are electro-
philic enough to react with highly activated aromatics. The
entire regioselectivity of our reaction suggests that in our case
the molecular halogen is not formed; however, we performed
the reaction with a polyfunctional substrate to demonstrate the
absence of molecular chlorine. Product 6f was isolated in 60%
yield, and the sole byproduct observed by careful analysis of
the crude 1H nuclear magnetic resonance (NMR) was
identified as the chromane issued by the reaction of a
thionium intermediate with the aromatic as a nucleophile (vide
infra). It is necessary to underscore that cyclization products
(chromanes) were not observed with either +I (compound 6c)
groups or with +M (compounds 6a,b) groups. Because the
chlorination on the double bond or the allylic carbon was not
observed, we ratify route (c) as being responsible for the
chlorination of aromatics.
a
Isolated yields.
Scheme 5. Plausible Pathways for Reductive Aromatic
Chlorination
Because we observed the chromane as a minor product in
the reaction of 2f, we reasoned that using less activated
aromatics should provide a suitable scenario for cyclization.
The reaction of compound 2g with oxalyl chloride (Scheme 6)
Scheme 6. Classic Pummerer Cyclization with an Unstable
α-Chlorosulfide as Intermediate
a
Isolated yield. The reaction was performed on a gram scale.
afforded a completely different product, the α-chlorinated
sulfide 7g (aliphatic chlorination). This compound is very
unstable and was identified via 1H NMR, which was measured
immediately after the evaporation of the solvent and the excess
of oxalyl chloride. Fortunately, the subsequent addition of BF3·
Et2O allowed us to isolate the desired chromane 8g in very
good yield.
With these results in hand, we decided to study the scope of
the reaction. To our delight, the cyclization may be performed
via a one-pot reaction, and it is a general reaction that can be
achieved with both electron-donating groups (EDGs) and
electron-withdrawing groups (EWGs); (see Scheme 7).
As demonstrated in Scheme 4, the use of strong EDGs
afforded the aromatic chlorination products. Consequently, we
started our screening of substrates using weakly deactivating
groups (I, Cl, and F), trying to induce the aliphatic
chlorination and then the formation of the thionium ion.
Fortunately, the reaction proceeded smoothly no matter the
position of the substituent, and the products 8h−j were
obtained in excellent yield. The use of EDGs in position two or
four also afforded the cyclization products in good to excellent
yield (products 8k−o). It is probable that when position two
has the influence of two activating groups, it is extremely
reactive, making the reaction with the chlorosulfonium salt
faster than the formation of the thionium ion and thus avoiding
the aliphatic chlorination. This is only possible with substrates
pathway b should be very unstable and consequently
unsuitable as a reaction intermediate; however, the usual
interrupted Pummerer reaction with phenols proceeds with the
oxygen as the nucleophile. Even if routes b and c should
provide the same products, it seems reasonable to expect that
route b provides the chlorination product in the less hindered
four-position because those products were not observed in the
crude reaction mixture (only products 6b−d were observed).
We can conclude that route c looks to be the most realistic for
the chlorination reaction. When the reaction is performed
using the 1-naphthol derivative (see compound 6e), position
C
DOI: 10.1021/acs.orglett.9b02520
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Letter
tion). Even though the eugenol was highly activated, it also
produced the corresponding chromane in extremely low yield
(detected by 1H NMR), indicating that aliphatic chlorination is
a competing reaction and the cyclization is feasible with any
substituents, with the exception of activating groups in position
three and rings with more than two activating groups, as
mentioned above.
Scheme 7. General Scope of Cyclization
In a nutshell, the reaction of type-2 compounds with oxalyl
chloride proceeds by the formation of a chlorosulfonium salt,20
which is a common intermediate for aromatic or aliphatic
chlorinations. When the phenol aromatic ring has extra EDGs
in position 3 or more than two EDGs as substituents, it is
nucleophilic enough to react with the chlorosulfonium salt,
yielding the aromatic chlorination product. On the contrary,
with less nucleophilic aromatics, the chlorosulfonium salt
participates in a typical Pummerer pathway, which means a β-
elimination to generate the electrophilic thionium ion,
followed by its reaction with chlorine, producing the aliphatic
chlorination. The BF3 is used to regenerate the thionium ion
and induce its cyclization.
Nevertheless, we needed to prove the compatibility of our
method with β-chiral centers. To this end, we chose 3-
aminochromanes because they are very important structures in
medicinal chemistry,1d,21 and the starting materials are easily
prepared from commercially available phenylcysteine, as shown
in Scheme 2 and in the Supporting Information.
Scheme 8 shows the results of the synthesis of 3-
aminochromanes. The reaction works as expected, but no
Scheme 8. Synthesis of 3-Aminochromanes
a
Isolated yields.
bearing an activating group in position three or with substrates
with more than two activated groups; however, the aromatic
1
chlorination products were observed in the crude H NMR
spectra as the minor products (<10%). The reaction of a
−NHBoc-substituted ring gave the product 8p in very low
yield, presumably because the Boc group is cleaved under the
reaction conditions, and thus we changed the group to a Cbz
group and obtained very good yields (product 8q), proving the
compatibility of our method with this protecting group. We
then turned our attention to moderate (MeCO) and strong
deactivators (NO2 and CF3). Pleasantly, the reaction worked
very well with moderate deactivators (product 8r) and the
strong EWG CF3 (product 8s). In the case of the NO2 group,
the reaction worked well enough compared with the previously
described Pummerer cyclizations (products 8t,u). Finally, we
used a tyrosine derivative (product 8v) to prove the tolerance
to other functional groups and to obtain a more functionalized
product, which may serve as a precursor to polycyclic
systems.19 The chromane was successfully obtained.
The reaction with sulfoxide 2w enabled us to isolate
compound 8w in excellent yield, and no chlorination of the
double bond or allylic carbon was observed, thereby
demonstrating the absence of molecular chlorine or radicals
in the reaction media. Compounds of Schemes 4 and 7 showed
an apparent generality: The more activated the ring (more
nucleophilic), the easier it reacted with the sulfonium salt to
afford the reductive chlorination product (aromatic chlorina-
a
Isolated yield.
control over the new chiral center was observed, and a 1:1
mixture of two diastereomers was obtained; however, the SPh
group was easily reduced in a one-pot procedure using a
mixture of NiCl2 and NaBH4, and the protected amino
chromanes (products 10a−c) were obtained in very good
overall yield and without racemization.22 This synthesis also
shows the versatility of the SPh group, which can be reduced,
oxidized, and used in further transformations, as demonstrated
in this category of heterocycles.2k
In summary, this work illustrates a new Pummerer
cyclization that provides a solution to previously described
problems in this kind of chemistry; we also successfully applied
the reaction to functionalized molecules carrying substituents
in both aromatic and aliphatic rings. Most importantly, this
method is compatible with chiral centers, which are β to the
sulfoxide. Finally, we showed our preliminary results in
reductive chlorinations of aromatic rings using sulfonium
salts as a source of electrophilic chlorine. The development of
this chemistry offers wonderful applications in synthetic
organic chemistry and is continuously growing, and we are
D
DOI: 10.1021/acs.orglett.9b02520
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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working to make this chlorination general and applicable in
highly functionalized molecules. The results will be reported in
due course.
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ASSOCIATED CONTENT
* Supporting Information
■
́
́
Sanchez, D.; Garzon-Posse, F. Pummerer-Type Reactions as Powerful
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Synthesis; John Wiley & Sons, Inc: 2015; pp 661−702.
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02520.
Complete experimental details and copies of 1H and 13
NMR spectra (PDF)
C
AUTHOR INFORMATION
■
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Corresponding Author
*E-mail: da.gamba1361@uniandes.edu.co.
ORCID
́
Diego Gamba-Sanchez: 0000-0001-5432-5108
Notes
The authors declare no competing financial interest.
(7) Parham, W. E.; Edwards, L. D. J. Org. Chem. 1968, 33, 4150−
4154.
ACKNOWLEDGMENTS
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(8) (a) Li, X.; Carter, R. G. Org. Lett. 2018, 20, 5541−5545. (b) Li,
Financial support for this work was provided by COLCIEN-
CIAS (project no. 1101-745-58974) and the Universidad de
los Andes. A.R.-L and P.A.-G acknowledge the Universidad de
los Andes and especially the Chemistry Department for their
fellowships.
X.; Carter, R. G. Org. Lett. 2018, 20, 5546−5549.
(9) Becerra-Cely, L.; Rueda-Espinosa, J.; Ojeda-Porras, A.; Gamba-
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[α]24 = −26.75 (c = 0.6; CHCl3).
D
F
DOI: 10.1021/acs.orglett.9b02520
Org. Lett. XXXX, XXX, XXX−XXX