Visible-Light-Driven Photocatalytic Initiation of Radical Thiol-Ene Reactions Using Bismuth Oxide

Article abstract of DOI:10.1021/acs.orglett.5b03184

A nontoxic and inexpensive photocatalytic initiation of anti-Markovnikov hydrothiolation of olefins using visible light is reported. This method is characterized by low catalyst loading, thereby enabling a mild and selective method for radical initiation in thiol-ene reactions between a wide scope of olefins and thiols.

Full text of DOI:10.1021/acs.orglett.5b03184

Letter
pubs.acs.org/OrgLett
Visible-Light-Driven Photocatalytic Initiation of Radical Thiol−Ene
Reactions Using Bismuth Oxide
Olugbeminiyi O. Fadeyi,* James J. Mousseau, Yiqing Feng, Christophe Allais, Philippe Nuhant,
Ming Z. Chen, Betsy Pierce, and Ralph Robinson
Worldwide Medicinal Chemistry, Pfizer, 445 Eastern Point Road, Groton, Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: A nontoxic and inexpensive photocatalytic initiation of anti-
Markovnikov hydrothiolation of olefins using visible light is reported. This
method is characterized by low catalyst loading, thereby enabling a mild and
selective method for radical initiation in thiol−ene reactions between a wide
scope of olefins and thiols.
rganosulfur compounds are widely present in nature and
play important roles in many biological structures and
activated carbon−carbon double bonds.9 The high efficiency
and orthogonality of thiol−ene chemistry has led to increased
utility in polymer functionalization, macromolecular synthesis,
biological applications, and functionalization of biomaterials.10
Growing concerns about the environment and energy use
have spurred extensive efforts to make chemical processes more
sustainable and “green”. Examples include employing sunlight
or low energy visible light to promote reactivity and performing
synthetic transformations without the use of rare, expensive,
and potentially toxic elements, especially in the pharmaceutical
industry.11
O
functions.1,2 Sulfur containing functional groups such as
thioether, thioester, and disulfide are found in a number of
natural products, for example the disulfide depsipeptide FK228
(romidepsin, anticancer);3 the thioester depsipeptide largazole
(anticancer);4 and pharmaceutical agents such as ranitidine
(Zantac, antiulcer),5 NCH-31 (antitumor),6 and the cyclic
tetrapeptide disulfide SCOP (HDAC inhibitor) (Figure 1).7
Pioneering work by Yoon12 and Stephenson13 on radical
thiol−ene coupling of alkenes and thiols (Scheme 1) using
visible-light-absorbing ruthenium polypyridyl complex (Ru-
(bpz)32+ and Ru(bpy)3Cl2) photocatalysts constitutes a striking
development of chemical transformations promoted by low-
cost energy.14 However, both methodologies require the use of
Scheme 1. Visible light-photoredox radical thiol−ene
reaction
Figure 1. Bioactive sulfur-containing compounds.
Disulfide-containing linkers are now used in antibody−drug
conjugates (ADCs), which are used as targeted cell-based
immunotherapeutics.8 Lastly, organosulfur compounds com-
monly serve as useful synthetic intermediates, with applications
in chemical biology, medicinal, and polymer chemistry.1,2
A common way to construct carbon−sulfur bonds is via the
thiol−ene reaction, a prototypical “click reaction” that effects
the anti-Markovnikov radical addition of thiol across non-
Received: September 30, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03184
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Organic Letters
Letter
rare, expensive, and toxic metals (Scheme 1). More recently,
Greaney and co-workers reported the use of the naturally
abundant and nontoxic metal oxide TiO2 for thiol−ene
coupling, but the protocol requires a nanoparticulate form of
TiO2 and the substrate scope was limited (Scheme 1).15 We
were interested in finding an alternative photoredox catalytic
initiation to promote hydrothiolation, one that is not only mild,
cheap, and nontoxic but also more efficient and suitable for
late-stage functionalization of biologically relevant molecules.
Upon perusal of the literature, we were inspired by the work of
transformation (entries 3, 7, and 8). The background reaction
was observed in the absence of the bismuth photocatalyst and
BrCCl3 (entry 7) but in only 35% conversion after 24 h.
Interestingly, the thiol−ene reaction proceeded highly
efficiently under sunlight (entry 10). Importantly, lowering of
the catalyst loading had no impact on the overall performance
of this protocol (entry 9), but due to reaction operational
simplicity, 3 mol % was utilized as the optimal catalyst loading.
Stoichiometric thiol (entry 11) or excess olefin (entry 12) still
afforded practical but much lower conversion.18 Finally, an
evaluation of solvents revealed that the reaction performed best
in DMF and DMSO (entries 3−4).
With the optimized conditions in hand, we next sought to
evaluate the scope of the reaction using a variety of thiols and
olefins. As depicted in Table 2, a range of structurally diverse
alkenes 4 and thiols 5 gave the desired thioether product
(Scheme 2, 6a−6r). Both aliphatic alkene and styrene
̀
Pericas and co-workers in which inexpensive and nontoxic
bismuth-based materials were used as photocatalysts for the
direct asymmetric alkylation of aldehydes.16 Based on this
precedent, we sought to develop a mild photocatalytic method
for alkene hydrothiolation utilizing visible light activation and a
bismuth oxide photocatalyst. It is worth noting that during our
̀
work in this area Pericas reported the use of the bismuth oxide
photocatalysts for the atom transfer radical addition (ATRA)
reaction of organobromides to alkenes.17
Scheme 2. Bismuth Oxide Photocatalytic Initiation of
Radical Thiol−Ene Reaction: Representative Substrate
Scope
We first set out to determine if bismuth oxide (Bi2O3) would
catalyze the visible light initiated radical thiol−ene reaction and
optimize the reaction conditions (Table 1). Initial investigation
Table 1. Bismuth Oxide Photocatalytic Initiation of Radical
a
Thiol−Ene Reaction: Optimization Studies
b
entry
condition
time (h)
solvent
conv (%)
1
0 mol % BrCCl3
5 mol % BrCCl3
as shown
24
12
12
12
12
12
24
24
12
6
DMF
DMF
DMF
DMSO
MeCN
MeOH
DMF
DMF
DMF
DMF
DMF
DMF
<5
90
2
c
3
>95
4
as shown
>95
37
41
35
0
5
as shown
6
as shown
7
0 mol % Bi2O3/BrCCl3
no light
8
c
9
1 mol % Bi2O3
1 mol % Bi2O3/sunlight
1 mol % Bi2O3/1 equiv of 2
1 mol % Bi2O3/2 equiv of 1
>95
d
10
11
12
>95
e
20
20
75
66
a
All reactions were performed on a 0.5 mmol scale, alkene (1.0 equiv),
b
thiol (4.0 equiv), and solvent (0.7 mL). Conversion of all reactions
determined by NMR analysis of the crude reaction mixture. 91%
isolated yield. 94% isolated yield. 55% isolated yield.
c
d
e
a
into the proposed Bi2O3 catalyzed thiol−ene reaction focused
on the reaction of 5-hexen-1-ol 1 and benzyl mercaptan 2
(Table 1). Irradiation of the alkene and thiol in the presence of
photocatalyst Bi2O3 (3 mol %) produced only poor conversion
to the addition product after 24 h (Table 1, entry 1). However,
we were delighted to find that addition of 5 mol % of a single
electron acceptor bromotrichloromethane (BrCCl3) provided
the desired thioether 3 in excellent conversion (Table 1, entry
2) after 12 h. Utilization of BrCCl3 to promote the generation
of the thiyl radical was previously reported by Stephenson and
co-workers.13 It is presumed that the trichloromethyl radical
generated from the photocatalyst abstracts the hydrogen atom
of the mercaptan to give the electrophilic thiyl radical
intermediates that undergo addition reaction with alkene 1 to
give the desired thioether 3. Control experiments highlighted
the essential roles of the photocatalyst, BrCCl3, and light in this
All reactions were performed on a 0.5 mmol scale, alkene (1.0 equiv),
thiol (4.0 equiv) and solvent (0.7 mL). Shown are yields after
chromatography. 1 mol % of photocatalyst used.
b
substrates possessing various functional groups (including
pyridine-based heteroaromatics, alcohols, esters, carboxylic
acids, Boc-protected amines, and boronic pinacol esters) react
smoothly under the optimized reaction conditions to afford
radical−thiolene adducts with the expected anti-Markovnikov
regioselectivity in generally high yields. Interestingly, allyl
boronic ester functionality was well-tolerated as exemplified by
the preparation of the useful synthetic intermediate for Suzuki
couplings 6q in 89% yield.
As shown in Scheme 2, we found that a broad range of thiol
substrates readily participate as coupling partners in the radical
B
DOI: 10.1021/acs.orglett.5b03184
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
thiol−ene protocol. Alkyl (Scheme 2, 6a, 6b, and 6g) and
benzyl thiols (6c, 6q, 6p, and 6o) all delivered the
corresponding thioether products in good to excellent yields
(82%−96% yield). Bulkier thiols such as cyclohexyl (6l) and
tertiary thiols (6k, 6m, and 6n) gave the desired thiolene
adducts in moderate to good yields (48%−89%). Thiol
substrates with more acidic thiols such as methyl thioglycolate
(6h), Boc-protected cysteine (6d, 6e, 6f, and 6j), and acyl thiol
(6i and 6r) all proceeded smoothly in nearly quantitative yields.
Given the broad generality and operational simplicity shown
in the scope of the photocatalytic initiation of the radical thiol−
ene reaction, we were keen to explore the synthetic application
of our methodology to late-stage diversification of advanced,
highly functionalized, complex biomolecules and active
pharmaceutical agents. As illustrated in Scheme 3, a variety of
variety of complex drug-like molecules could be accessed via
late-stage functionalization by employing this mild technology.
Proposed mechanistic details for the photocatalytic initiation
of the radical thiol−ene reaction are depicted in Scheme 4. It
Scheme 4. Proposed Mechanism for Bismuth Oxide Thiol−
Ene Reaction
Scheme 3. Late-Stage Diversification of Complex
a
Biomolecules and Active Pharmaceutical Agents
has been established that irradiation of bismuth oxide with
visible light leads to the creation of positive holes (h+) on the
surface of the semiconductor due to the photoexcitation of
electrons from the valence to the conduction band.16,17 We
propose here that the photoexcited electrons induce reductive
cleavage of the bromotrichloromethane to generate trichlor-
omethyl radicals that readily abstract the thiol hydrogen atom
producing the thiyl radical, which in turn initiates the radical
thiol−ene process.12
In summary, we have developed a mild, inexpensive, and
nontoxic visible light-driven photocatalytic initiation system of
hydrothiolation of alkenes using Bi2O3 with wide functional
group compatibility. This methodology lent itself in the late-
stage hydrothiolation of useful complex biomolecules. To
highlight the robustness of this technology, we achieved the
synthesis of relevant pharmaceutical agents. Further biological
application of this methodology is in progress and will be
reported in due course.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03184.
Complete preparatory and analytical data for all new
compounds (PDF)
a
Conditions: 4 (1.0 equiv), 5 (4.0 equiv) in DMF (0.7 M). Yields are
b
1H and 13C NMR spectra (PDF)
of isolated product. 1 mol % of photocatalyst used
AUTHOR INFORMATION
■
complex biologically relevant scaffolds readily undergo the
hydrothiolation transformation to provide the useful glyco-
chemistry substrates tetra-O-acetyl-pyran 7 and tetra-O-acetyl-
β-D-glucopyranoside 8, Fmoc-protected amino acid 9, and
linear tetrapeptide 10 in 65%, 74%, 91%, and 75% yields,
respectively. Notably, the reaction is compatible with N-Fmoc-
protected amino acid basic and acidic groups, with no effect on
the rate or overall performance of the protocol. Additionally, we
applied our protocol to the synthesis of the S-acetyl protected
precursor to NCH-31 (a potent antitumor agent) 11, the cyclic
tetrapeptide SCOP (a potent HDAC inhibitor) 12, and the
glycosyl sulfonamide 13 (a potent carbonic anhydrase (hCA IX
and hCA XII) inhibitor (Scheme 3). This demonstrated that a
Corresponding Author
*E-mail: Olugbeminiyi.fadeyi@pfizer.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are very grateful to Joe Tucker and Steve Wright, Pfizer Inc,
for helpful conversations. This paper is dedicated to Professor
Amos B. Smith, III, Rhodes-Thompson professor of chemistry
at the University of Pennsylvania, for his recent 2015 Allan R.
Day award.
C
DOI: 10.1021/acs.orglett.5b03184
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(15) Bhat, V. T.; Duspara, P. A.; Seo, S.; Abu Bakar, N. S. B.;
Greaney, M. F. Chem. Commun. 2015, 51, 4383.
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DOI: 10.1021/acs.orglett.5b03184
Org. Lett. XXXX, XXX, XXX−XXX