A visible-light-mediated radical smiles rearrangement and its application to the synthesis of a difluoro-substituted spirocyclic ORL-1 antagonist

Article abstract of DOI:10.1002/anie.201507369

A visible-light-mediated radical Smiles rearrangement has been developed to address the challenging synthesis of the gem-difluoro group present in an opioid receptor-like 1 (ORL-1) antagonist that is currently in development for the treatment of depressio

Full text of DOI:10.1002/anie.201507369

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Angewandte
Communications
International Edition: DOI: 10.1002/anie.201507369
German Edition: DOI: 10.1002/ange.201507369
Photocatalysis
AVisible-Light-Mediated Radical Smiles Rearrangement and its
Application to the Synthesis of a Difluoro-Substituted Spirocyclic
ORL-1 Antagonist
James J. Douglas, Haley Albright, Martin J. Sevrin, Kevin P. Cole, and Corey R. J. Stephenson*
Abstract: A visible-light-mediated radical Smiles rearrange-
ment has been developed to address the challenging synthesis
of the gem-difluoro group present in an opioid receptor-like 1
(
ORL-1) antagonist that is currently in development for the
treatment of depression and/or obesity. This method enables
the direct and efficient introduction of the difluoroethanol
motif into a range of aryl and heteroaryl systems, representing
a new disconnection for the synthesis of this versatile moiety.
When applied to the target compound, the photochemical step
could be conducted on 15 g scale using industrially relevant
[
Ru(bpy) Cl ] catalyst loadings of 0.01 mol%. This trans-
3 2
formation is part of an overall five-step route to the antagonist
that compares favorably to the current synthetic sequence and
demonstrates, in this specific case, a clear strategic benefit of
photocatalysis.
Scheme 1. Previously reported route towards 1 and the proposed
photochemical radical Smiles rearrangement. AIBN=azobis(isobutyro-
nitrile).
I
n recent years, there has been an exponential increase in the
number of transformations mediated by visible-light photo-
with classical methods including nucleophilic or electrophilic
fluorination of pre-functionalized substrates. Direct ben-
[
1]
[6]
catalysis; however, there remain to be only few reports
detailing its application to agrochemical or pharmaceutical
zylic CÀH fluorination strategies, typically employing either
[
2]
[7]
[8]
synthesis. Key to the expansion of this mode of catalysis is
the demonstration of a strategic benefit when compared to
other routes, most likely showcased by the ability of photo-
catalysis to provide new synthetic disconnections. We aimed
to test the potential advantage of photocatalysis in the
transition metals or non-metal promoters, have recently
been reported. Chen and co-workers have shown that visible-
[
9]
light photocatalysis is a potentially viable method; however,
their method requires the use of 3.0 equivalents of Select-
fluor II. An appealing strategy to address the high step count,
low yield, and the use of specialized fluorinating reagents for
the fluorination sequence would be to start from pre-
fluorinated thiophene 3.
[3]
synthesis of difluoro-substituted spirocyclic thiophene 1,
a building block in the synthesis of an opioid receptor-like 1
(
ORL-1) antagonist that is currently in development for the
[4]
treatment of depression and/or obesity (Scheme 1).
A
This route could make use of ethyl bromodifluoroacetate
as an inexpensive, readily available source of the requisite
production campaign demonstrated rapid access to the
carbocyclic framework 2 in good yield and on multi-kilogram
scale. However, the benzylic fluorination of 2 proved to be
a challenge, requiring four synthetic steps in an overall 25%
yield. Furthermore, this sequence included an AIBN initiated
radical bromination, utilized 2.6 equivalents of Deoxo-Fluor
[10]
benzylic gem-difluoromethyl group, diverting the key step
[
11]
from CÀF to CÀC bond formation. CÀH
or directed
[12]
[13]
coupling strategies as well as radical arylation methods
are well documented (Scheme 2), but proved poorly selective
in the context of 1. Specifically, employing coupling con-
[
5]
[14]
as the fluoride source, and required chromatographic
purification. Benzylic fluorination remains a general problem,
ditions originally introduced by Kobayashi and co-workers,
treatment of 4-bromo-2-chlorothiophene with superstoichio-
metric amounts of copper and ethyl bromodifluoroacetate led
[15]
[
*] Dr. J. J. Douglas, H. Albright, M. J. Sevrin, Prof. C. R. J. Stephenson
Department of Chemistry, University of Michigan
Ann Arbor, MI 48109 (USA)
primarily to functionalization at the five position. Radical
arylation is generally limited to the 5-position of the hetero-
aromatic compound; in our system, with both the 2- and 5-
E-mail: crjsteph@umich.edu
Homepage: www.umich.edu/~crsgroup/
Dr. J. J. Douglas, Dr. K. P. Cole
Small Molecule Design and Development
Lilly Research Laboratories, Eli Lilly and Company
Indianapolis, IN 46285 (USA)
[16]
positions blocked, the desired product was not obtained.
Given the need for selectivity and step efficiency, we surveyed
methods that would lead directly and regiospecifically to the
difluoromethyl group. The Smiles rearrangement is an intra-
molecular nucleophilic substitution reaction that occurs
exclusively at the ipso position of an activated aromatic
Supporting information and ORCID(s) from the author(s) for this
article are available on the WWW under http://dx.doi.org/10.1002/
anie.201507369.
[17]
leaving group, typically a sulfonate. Radical versions of the
[
18]
Smiles rearrangement have also been demonstrated and
1
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sulfonyl chlorides (> 1000 commercially available) and the
[
16]
ready access to bromodifluoroethanol, we envisioned this
as a general method for the synthesis of the difluoroethanol
motif (Scheme 2).
Our envisioned reaction mechanistically proceeds by
quenching of the excited state of a photocatalyst such as
2
+
II /I
[
Ru(bpy)3] (E1/2 * =+ 0.77 V vs. SCE; bpy = bipyridine)
by a suitable electron donor, such as [NBu ][HCO H], to
3
2
I
II/I
/2
generate the strongly reducing Ru species (E
= À1.33 V
1
[21]
vs. SCE; Scheme 3). Single-electron reduction of thiophene
Scheme 2. Approaches to the difluoroethanol motif.
4 provides the desired difluoromethyl radical and regenerates
the Ru photocatalyst. The newly formed radical may then
II
undergo intramolecular ipso addition/elimination with the
sulfonate group (Scheme 1) to give 5, with subsequent
H atom abstraction followed by polar extrusion of SO2
leading to the desired product.
can proceed without the requirement for a strongly electron-
withdrawing group adjacent to the sulfonate. Tada et al. have
developed an AIBN initiated (50 mol%) rearrangement
using stoichiometric Bu SnH, conditions we did not deem to
At this juncture, we cannot rule out the possibility of
radical chain processes contributing to the formation of the
3
[19]
be applicable in our setting. Given the extensive literature
detailing visible-light-mediated reductive dehalogena-
product, especially given the low photocatalyst loading and
[
1a,20]
[22]
tion,
rearrangement from a difluorobromo sulfonate such as 4
Scheme 1). Furthermore, given the wide availability of
we were confident of developing a radical Smiles
the short reactions times for 6 (see below).
These con-
ditions (0.01 mol% initiator, 1 h) are in contrast to those of
(
the classical chain process using Bu SnH, which requires
3
Scheme 3. Mechanistic proposal for the photocatalyzed radical Smiles
rearrangement.
Table 1: Optimization of the reaction conditions.
Entry Electron/H atom source Solvent Cat.
6
7
[%]
[
a]
[a]
[
mol%] [%]
[
b]
[c]
1
2
3
4
5
6
7
iPr NEt
DMA
1.0
43
28
<2
<2
<2
<2
36
53
67
86
95
94 (89)
2
[
c]
iPr NEt
DMSO 1.0
DMSO 1.0
DMSO 1.0
DMSO 1.0
DMSO 0.01
2
[
c]
[c]
iPr NEt, HCO H
2
2
[
c]
[c]
NBu3, HCO H
2
[
d,e]
[f]
[f]
NBu3, HCO H
NBu3, HCO H
NBu3, HCO H
2
[
d,e]
[f]
[f]
[g]
2
[
f]
[f]
DMSO
–
>98 <2
2
All reactions were performed at 0.14m with 1.0 mol% of the photo-
catalyst without degassing unless otherwise stated. [a] Yield determined
19
by F NMR spectroscopic analysis of the crude reaction mixture using
PhCF as the internal standard. [b] Reaction degassed by freeze–pump–
Scheme 4. Substrate scope. [a] [Ru(bpy) ]Cl (0.01 mol%). [b] Tf O
3
3
2
2
thaw cycles. [c] 2.5 equiv. [d] 0.07m. [e] 1 h. [f] 1.5 equiv. [g] Yield of
isolated product. DMA=dimethylacetamide, DMSO=dimethyl sulfox-
(1.1 equiv), pyridine (1.6 equiv), MeCN, 08C to RT; then NH OH
4
(10 equiv), 508C. [c] Yield determined by F NMR spectroscopic anal-
1
9
ide.
ysis of the crude reaction mixture with PhCF as the internal standard.
3
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a significantly larger amount of initiator (AIBN, 50 mol%),
longer reaction times (22 h), and elevated temperature
readily obtained on > 20 g scale and was isolated by
crystallization in 64% yield (Scheme 5). Whereas the low
catalyst loading and fast reaction time associated with the
radical Smiles rearrangement of 6 are ideal from a synthetic
perspective, the dilute reaction conditions limited the assess-
ment of this reaction on larger scale. Conducting the reaction
at increased concentrations (0.26m) led to competitive
formation of the sulfonic acid, resulting in consistently
[
19]
(
808C). In our system, propagation may occur following
H atom abstraction from NBu by 5 to give an a-aminoalkyl
3
radical, which has previously been shown to be a competent
[22b, 23]
reductant of CÀBr bonds.
Initial studies on employing sulfonate 4 yielded no
observable rearrangement product, providing only moderate
consumption of starting material amongst a complex mix-
19
lower yields (70–75% by F NMR spectroscopy). This issue
could be mitigated by a two-step, one-pot photocatalyzed
Smiles rearrangement/ester hydrolysis sequence on 15 g scale
[16]
ture. Considering the structural features required for an
[19]
efficient radical Smiles rearrangement as well as both the
[24]
cost and availability of sulfonyl chlorides,
we continued our investigations with thio-
[
25]
phene 6. Employing conditions similar to
those previously developed for the reduc-
[20a]
tion of activated alkyl bromides
gave
a promising 36% yield (Table 1, entry 1).
Switching to DMSO as the solvent gave an
improved yield of 53% without the need for
[
26]
degassing. The addition of formic acid,
[20a]
a known H atom source,
led to full
consumption of the starting material
(
entry 3), and following a switch to NBu
3
[20b]
as the electron/H atom source,
the
Scheme 5. Application to the synthesis of 3. DMAP=dimethylaminopyridine, NMP=
N-methylpyrrolidone.
desired product 7 was formed in 86%
yield (entry 4). Increased dilution gave full
starting material consumption within one
hour (entry 5), even with a 100-fold reduced
catalyst loading (entry 6). A reaction conducted in the
absence of photocatalyst returned unreacted 6 (entry 7).
We next applied our optimized procedure to a range of
other aromatic and heteroaromatic substrates (Scheme 4).
Good yields were obtained for an alternative thiophene with
application to the synthesis of 1 (8, 87%) as well as a more
complex thiophene substrate (9, 64%). Extended aromatic
systems reacted efficiently, presumably owing to a lower
penalty associated with dearomatization upon radical ipso
addition (11 and 12, 72% and 60%). Other heterocyclic
systems typically found in pharmaceutical targets, such as
thiazole 14, pyrrole 15, and furan 16, could be obtained in
moderate to good yield (45%, 43%, and 73%, respectively).
We also explored the limits of this method and found that
benzene-derived substrates or heterocycles lacking radical-
stabilizing groups provided low to moderate yields (17–21,
with industrially relevant catalyst loadings (0.01 mol%),
yielding 69% of the thiophenecarboxylic acid 24 without
[31]
purification. The silver-catalyzed decarboxylation
pro-
ceeded to give thiophene difluoroethanol 3 in 73% yield
following distillation (Scheme 5).
Efforts to realize the subsequent transformation of 3 into
spirocyclic thiophene 1 proved challenging, potentially owing
to the decreased nucleophilicity of the hydroxy group, which
is now proximal to a difluoromethyl substituent.
We progressed by investigating the possibility of elimi-
nating the downstream chlorination step by repeating the
three-step sequence with the corresponding chlorinated
sulfonyl chloride, providing the target thiophene 26 in 28%
[32]
overall yield.
26 could be converted into the required
spirocyclic material 1 by lithiation, addition to N-Boc-4-
piperidinone 27 in 60% yield, followed by concurrent
spirocyclization/Boc deprotection in 59% yield (Scheme 6).
This unoptimized five-step sequence addresses many of the
undesirable features of the current synthetic route. Most
importantly, the challenging benzylic fluorination can be
[27]
<
10–34%). Whereas the difluoroethanol motif is featured
in a number of biologically active compounds such as
[
28]
Abediterol,
it is also used as a precursor to the more
[
29]
common difluoroethylamine group. Access to this motif by
a two-step triflation–amination sequence was
demonstrated on representative Smiles products
9
and 12, providing the corresponding amines in
good yield (10 and 13). Finally, we also applied the
Smiles rearrangement to a single example of
[
18b]
a vinyl sulfonate (64% yield; Scheme 4c)
to
[30]
afford the vinyl difluoroethanol motif featured
in the prostaglandin analogue Tafluprost.
Following the establishment of this procedure
as a general method, we returned to target
compound 1. The starting material 6 could be Scheme 6. Synthesis of spirocyclic thiophene 1.
1
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accomplished by switching this key transformation to a CÀC
rather than a CÀF bond formation. This allows the use of ethyl
bromodifluoroacetate to introduce the gem-difluoro group,
directly and regiospecifically accessing the difluoroethanol
motif under mild conditions using low catalyst loadings.
In conclusion, we have developed a visible-light-mediated
radical Smiles rearrangement that addresses a current and
pressing challenge associated with the synthesis of a key
starting material for an ORL-1 antagonist. The method is
general for other aromatic and heteroaromatic substrates,
allowing rapid and efficient access to the benzylic difluor-
oethanol motif from widely available sulfonyl chlorides.
Preliminary assessment of this method with regards to the
target compound has been demonstrated on significant scale
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15 g) and proceeds with short reaction times (as low as 0.5 h)
and industrially relevant catalyst loadings (0.01 mol%).
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This research was supported by a Lilly Innovation Fellowship
Award to J.J.D. from Eli Lilly and Company. Financial
support for this research from the NIH-NIGMS (R01-
GM096129), the Camille Dreyfus Teacher-Scholar Award
Program, Eli Lilly, and the University of Michigan is grate-
fully acknowledged. This material is based upon work
supported by the National Science Foundation Graduate
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[
Keywords: catalysis · heterocycles · photocatalysis ·
radical reactions · rearrangement
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[
[
[
[
24] 2-Carbomethoxy-3-thiophenesulfonyl chloride is available at
approximately $250–300 per kg.
25] We anticipated that the unwanted methyl ester at the 2-position
could be readily hydrolyzed and decarboxylated.
26] A reaction left open to air gave 24% of the desired product after
a prolonged (20 h) reaction time.
27] In cases where the Smiles rearrangement did not proceed
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(48% on a single attempt at 5 g scale at 0.5m).
Received: August 7, 2015
Published online: October 16, 2015
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