Preparative Scale Demonstration and Mechanistic Investigation of a Visible Light-Mediated Radical Smiles Rearrangement

Article abstract of DOI:10.1021/acs.oprd.6b00126

A visible light-mediated Smiles rearrangement providing the difluoroethanol motif has been shown to reliably operate on preparative scale up to 100 g of starting material. Mechanistic investigation has revealed the reaction proceeds predominantly via a radical chain process that in some instances can be initiated via visible light or thermal activation in the absence of a photocatalyst. The reaction was demonstrated in continuous flow, with visible light and thermal initiation using a thiophene substrate relevant to pharmaceutical development.

Full text of DOI:10.1021/acs.oprd.6b00126

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Full Paper
Preparative Scale Demonstration and Mechanistic Investigation
of a Visible Light-Mediated Radical Smiles Rearrangement
James J. Douglas, Martin J. Sevrin, Kevin Paul Cole, and Corey R. J. Stephenson
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00126 • Publication Date (Web): 01 Jun 2016
Downloaded from http://pubs.acs.org on June 14, 2016
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Preparative Scale Demonstration and Mechanistic
Investigation of a Visible Light-Mediated Radical
Smiles Rearrangement
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James J. Douglas,a,b† Martin J. Sevrin,a Kevin P. Coleb and Corey R. J. Stephenson*,a
aDepartment of Chemistry, University of Michigan, Ann Arbor, MI 48109
bSmall Molecule Design and Development, Lilly Research Laboratories, Eli Lilly and Company,
Indianapolis, IN 46285
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TOC GRAPHIC
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ABSTRACT
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A visible light-mediated Smiles rearrangement providing the difluoroethanol motif has been
shown to reliably operate on preparative scale up to 100 g of starting material. Mechanistic
investigation has revealed the reaction proceeds predominantly via a radical chain process that in
some instances can be can be initiated via visible light or thermal activation in the absence of a
photocatalyst. The reaction was demonstrated in continuous flow, with visible light and thermal
initiation using a thiophene substrate relevant to pharmaceutical development.
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Keywords: catalysis; photocatalysis; radical reactions; flow; scale
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Reactions mediated by visible light1 have become effective tools for both the preparation and late
stage functionalization of pharmaceutically relevant molecules.2 These methods have
demonstrated the unique disconnections enabled by photoredox catalysis, resulting in more
efficient synthetic routes, and providing access to previously challenging structural motifs. We
recently reported the development of a visible light-mediated radical Smiles rearrangement3 that
proceeded from bromodifluoro sulfonates such as 1 to give the corresponding difluoroethanol
motif, following C–Br bond reduction, rearrangement, and loss of SO2 (Scheme 1).2(e) The reaction
was primarily developed to address the synthesis of a challenging intermediate,4 however the
protocol also showed promising generality to a range of other heterocyclic scaffolds. We
speculated that the reaction was likely initiated by a C-Br bond reduction mediated by Ru(bpy)3Cl2,
of which there is substantial precedent.5 The possibility of a radical chain process playing a
significant role in the product formation was also present, especially given the short reaction time
and low catalyst loading (30 minutes, 0.01 mol%) that is atypical of methodologies using visible
light.7 In an isolated instance, the Smiles rearrangement was demonstrated on a 15 g scale;2(e)
however, most examples were performed on a scale more typical of an exploratory investigation
i.e. <1 g. Given the limited number of reports applying visible light-mediated methods at moderate
scale for example >10 g,8 combined with the currently unanswered questions concerning the
mechanism and its use in manufacture on scale > kg, we further explored the scalability of our
methodology.
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Scheme 1. Visible light-mediated radical Smiles rearrangement
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The previously published conditions were able to achieve an 89% isolated yield of thiophene 5 by
employing high dilution (0.07 M), with scale up conducted at 0.25 M resulting in lower yield of
69%, after hydrolysis of the methyl ester to the carboxylic acid. With the aim of demonstrating
this method at preparative scale, the 0.25 M conditions developed for 1 were evaluated further.
Due to the poor solubility of tributylamine (NBu3) in DMSO, even following the addition of formic
acid, it quickly became apparent that the biphasic reaction showed significant dependency on stir
rate at a 5 g scale. A reaction carried out at half the normal stir rate required 45 minutes for full
starting material consumption (not shown), compared to the normal 15 minute reaction time
(Table 1 Entry 1). Triethylamine (NEt3) provided a homogenous reaction solution, leading to a
comparable yield of 66%, along with a streamlined work up due to its more facile removal (Table
1 Entry 2).9
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Table 1. Reevaluation of previously reported reaction conditions.
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Temperature (°C)a
Entry Amine (1.5 equiv)
M
5 (%)b 6 (%)b
NBu3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
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0.25 70 (62) 24
0.25 70 (66) 22
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0.25 72
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0.25 66 15
0.25 66 (66) 15
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6c
7d
Reactions performed on 5 g scale and deoxygenated via sparging for 10 min with nitrogen.
a
Reaction time of 15 minutes unless otherwise stated. Refers to temperature when the light was
turned on. b Assay yield obtained via HPLC. Number in parentheses refers to isolated yield. c NEt3
and formic acid added dropwise over 20 minutes. d Reaction conducted using anhydrous solvent
and with molecular sieves. NBu3 = tributylamine NEt3 = triethylamine
In both sets of conditions the major side product was confirmed as the sulfonic acid 6 in
approximately 2025% yield. Monitoring the temperature of the reaction indicated a significant
exotherm from 25 °C to 35 °C over 5 minutes that could be eliminated by controlling the
temperature at 20 °C, resulting in a reduction in the quantity of 6 to 15 % (a/a % HPLC), but at the
expense of yield and rate, with 5% starting material remaining after 30 min (Table 1 Entry 3).
Increasing the reaction temperature to 50 °C led to a modest increase in the quantity of 6 to 24%
(a/a % HPLC) with limited change to the yield of 5 (Table 1 Entry 4). Previously at small scale
(<1 g) the sulfonic acid side product was controlled via the use of high dilution (0.07 M), that
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reproducibly led to less than 10% of 6 and allowed yields of 5 in the range of 85–95%. Revisiting
similar conditions, 0.10 M at a 5 g scale, 80% assay yield was obtained, however losses of the
product during the work up, due to the larger volume of DMSO, resulted in a similar isolated yield
of 66% (Table 1 Entry 5). Dropwise addition of the formic acid/NEt3 led to incomplete
consumption of 1 within 20 min (10% 1 remained) with a similar level of the sulfonic acid (Table
1 Entry 6).10 The formation of sulfonic acid 6 is postulated to be derived via -scission11 of the
carbon centered radical 2 following C–Br bond reduction (Scheme 2 (a)), although the possibility
of a further reduction of 2, followed by elimination of the sulfonate cannot be ruled out.12 The
formation of difluoroethylene13 at a similar rate to 5 could be observed in a closed NMR tube,
supporting this theory. Other mechanistic pathways for the formation of 6 such as hydrolysis from
adventitious water, appear unlikely as a reaction conducted with strictly anhydrous conditions
resulted in similar levels of 6 (Table 1, Entry 7). Equally, the sulfonate 1 is stable in the presence
of bromide at temperatures up to 50 °C, and slowly eliminates to the vinyl sulfonate 9 at 35 °C in
the presence of formic acid and triethylamine (Scheme 2 (b)).14
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Scheme 2. Control experiments exploring the potential origin of sulfonic acid 6 and
difluoroethylene 8.
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Proceeding with the current 0.25 M conditions (Table 1, Entry 2), greater insight into the
mechanism was gained by initiating the reaction using a CFL light to 25% consumption of starting
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material 1, then monitoring the reaction inside an NMR spectrometer with H and F NMR
spectroscopy (Figure 1). This revealed an efficient propagation mechanism in the absence of light,
with the consumption of starting material rising to 75% during the monitoring period, while clearly
showing the formation of product 5, sulfonic acid 6, and difluoroethylene 8 (Figure 1).15 Analysis
of the consumption of NEt3 and formic acid showed that predominantly formate is consumed (0.75
equiv vs 0.2 equiv of NEt3 relative to 1),16 suggesting that formate is likely the major terminal
reductant and H–atom donor.5(e), 17
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Figure 1. Plot of integration (1H or 19F NMR) for a reaction initiated with visible light for A: 0.5
min, B: 1.0 min, or C: 1.5 min, then monitored via NMR spectroscopy in the absence of light.
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1.1
A
Sulfonate 1
Product 5
0.9
B
1,1 difluoroethylene 8
C
Sulfonic acid 6
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0.5
0.3
0.1
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-0.1
Time (min)
Both the reaction temperature18 and conversion via HPLC indicated a reproducible 45 minute
initiation period that appeared to correlate to the rigor with which oxygen was removed prior to
the reaction (Figure 2). In the previously reported reaction protocol, oxygen levels were controlled
by evacuation of the headspace and backfilling with nitrogen, generally resulting in reproducibly
short reaction times (<30 min) for 1. Upon investigation of the deoxygenated reaction conditions
via prolonged sparging with nitrogen, identical reaction profiles and yields were observed (Figure
2) with photocatalyst loadings of 0.01 mol% and below, including no photocatalyst (Table 2,
5C). It was confirmed that thoroughly deoxygenated conditions were required for the reaction to
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proceed in the absence of photocatalyst, as multiple control experiments with no photocatalyst
failed to provide any consumption of starting material under the originally reported conditions, in
agreement with our previous findings.
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Figure 2. Plot of internal reaction temperature vs time showing oxygen dependent initiation and
the visible light-mediated background reaction.
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Not degassed
0.01 mol%
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Degassed 0.01
mol%
Degassed no
photocataylst
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Time (s)
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1015
Additionally, the reaction could be initiated thermally by heating to 45 °C for 15 minutes in the
absence of light, again providing similar yield (68%) and identical reaction profile (Table 2, 5C).
Given these findings, the updated conditions, both with and without Ru(bpy)3Cl2 (Table 2,
Conditions A and B) and thermally in the absence of light (Table 2, Conditions C) were tested
on a selected number of previously reported substrates 1012. Naphthalene sulfonate 10 behaved
analogously to the thiophene 5, with all three conditions leading to 57% yield of the product within
90 minutes (Table 2, Entry 2). For quinoline sulfonate 11, both conditions A and B led to initiation
of the reaction, but lower yields and longer reaction times were recorded when no photocatalyst
was added (54% vs. 76%, Table 2, Entry 3). The absence of photocatalyst proved detrimental for
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the styrenyl sulfonate 12, as no reactivity was observed under either thermal or deoxygenated
protocols (Table 2, Entry 4).19
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Table 2. Application of the developed conditions to other aryl and vinyl sulfonates.
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A: NEt3 (1.5 equiv), formic acid (1.5 equiv), Ru(bpy)3Cl2·6H2O (0.1 mol%), DMSO (0.25 M),
blue LED. B: NEt3 (1.5 equiv), formic acid (1.5 equiv), DMSO (0.25 M), deoxygenated via
sparging with nitrogen, blue LED. C: NEt3 (1.5 equiv), formic acid (1.5 equiv), DMSO (0.25 M),
deoxygenated via sparging with nitrogen. Reactions run on 5 g scale. Yields shown calculated via
19F spectroscopic analysis of the crude reaction mixture relative to trifluorotoluene unless
a
b
otherwise stated. NR indicates no reaction. Isolated yield. Reaction conducted with
c
Ru(bpy)3Cl2·6H2O (0.01 mol%) and deoxygenated via sparging with nitrogen. Irradiation via
white LED. d Reaction run on 0.5 g scale.
In light of these findings, it is proposed that the dominant mechanism for the formation of
thiophene 5 likely proceeds via either photochemical- or thermal homolysis of the C–Br bond to
give carbon centered radical 2.20 The homolysis would also lead to a bromine radical that would
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likely abstract a hydrogen atom from either NEt3 or formate, thus initiating another radical
chain.6(b) At this time the current mechanistic experiments cannot rule out the possibility of an
ionic fragmentation12 or an unwanted -scission of 2 accounting for the formation of sulfonic acid
6 and difluoroethylene 8, with the desired Smiles rearrangement providing the alkoxysulfonyl
radical 4.21 C–H abstraction of predominantly the formyl C-H of the formic acid NEt3 complex by
this species, followed by a polar loss of SO2 provides the Smiles product and the carboxyl radical
anion 17,22 which may reduce the sulfonate 1 to continue the chain and release CO2 (Figure 3).23
The fast rate of this reaction and general efficiency when compared to a previously reported radical
Smiles rearrangement (50 mol% AIBN initiator, 22 h, refluxing benzene)3(h) may result from the
lack of potential chain termination events, as even undesired pathways from 2 can lead to efficient
chain propagation via C–H abstraction.24 Furthermore, the identical rate of reaction in the absence
and presence of photocatalyst under deoxygenated conditions for thiophene 1, may imply that the
main role of Ru(bpy)3Cl2 was to consume molecular oxygen that otherwise inhibited the initiation
of the chain propagation, explaining the observed induction period.25
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Figure 3. Proposed mechanism accounting for the efficient reaction in the absence of Ru(bpy)3Cl2.
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Since they proved universally applicable to all substrates tested, the scale up of the Smiles
rearrangement proceeded using the general conditions A (0.25 M, 0.1 mol% Ru(bpy)3Cl2). The
thiophene substrate 5 gave comparable results at 22 g to those obtained on 5 g scale (69% yield
9.80 g, 89% a/a HPLC purity). Preparative scale reaction on 20 g of sulfonates 1012 afforded the
naphthalene, quinoline, and styrene products 1315 in good yields of 65%, 59%, and 61%
respectively (Scheme 3).26 This represents an attractive general route to these systems given the
wide availability of sulfonyl chlorides, and the ease of preparation of the requisite 2-bromo-2,2-
difluoroethanol.
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Scheme 3. Preparative scale reactions on a selection of aryl- and vinyl sulfonates.
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Products purified via flash column chromatography unless otherwise stated. a22 g of 1 used. 5 with
0.01mol% Ru(bpy)3Cl2 and a white LED. Obtained in 89% purity directly following work up
(purity measured by HPLC).
Our attention returned to the target thiophene with the aim of showcasing the photocatalyst-free
conditions in batch on 100 g scale. Sufficient quantities of starting material 1 could be readily
obtained at >250 g scale via the two-step reduction of ethyl bromodifluoroacetate and subsequent
sulfonate formation using the conditions previously reported.2(e) The Smiles rearrangement of 1
was conducted on 100 g using a commercially available 300 W white LED light27 in a conventional
5 L jacketed vessel and proceeded in similar fashion to the smaller scale reactions (Scheme 4).
Thiophene 5 was obtained in 64% isolated yield (43 g, 88% purity) after work up, with the major
impurity being the sulfonate 16 (Figure 3, 4% a/a HPLC) resulting from premature H-atom
abstraction of 2 prior to the Smiles rearrangement. At this time, no effort was made to develop an
improved isolation or purification procedure for 5, as it has been previously shown that the
carboxylic acid resulting from hydrolysis of 5 can be isolated in good purity. The current procedure
was primarily limited to 100 g scale by the volumes required for the work up and isolation, namely
the removal of DMSO and efficient recovery of 5. On small scale the distillation of DMSO
following the reaction was demonstrated to proceed without significant decomposition of the
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product. This strategy will likely be pursued further to address this current limitation with respect
to scale. One unattractive feature of this method is the low overall atom economy, as bromide and
SO2 are lost during the process. In the specfic case of thiophene 1, 39% of the mass is lost during
the Smiles rearrangement, however we do not believe this metric represents a critical feature at
this juncture. This study represents a proof of concept for this route and serves as a driving force
for the further application of visible light-mediated processes to our product pipeline.
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Scheme 4. 100 g scale visible light-mediated Smiles rearrangement conducted without
Ru(bpy)3Cl2.
While the facile Smiles rearrangement of 1 in batch at 100 g scale is a significant milestone with
respect to the implementation of visible light-mediated processes on scale, it does not imply a
general ability to operate at this scale. Indeed, previous efforts from our lab to scale a visible light-
mediated trifluoromethylation reaction to 100 g in batch resulted in significantly reduced yield.8(a)
The requirement for light to serve primarily as an initiator, combined with the observed efficiency
of the radical chain reaction in deoxygenated conditions, renders this specific transformation
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unusually amenable to batch scale up. This further underlines the need to understand both the role
of light and photocatalyst in the reaction mechanism before undertaking decisions with respect
scalability.28 In a general context, the use of visible light to either initiate or sustain a reaction on
large scale (i.e. >100 kg) using a traditional batch vessel raises a number of currently unanswered
engineering questions. While these can likely be overcome, the option to run this process in
continuous flow would provide an attractive alternative, especially considering that no specialty
(e.g. blue LED), or high intensity light source would be required.29 Using a commercially available
8 mL glass chip reactor comprising a 2.2 x 2.2 mm channel with static mixers and two cooling
channels, a yield of 65% (5.5 g over 140 min at 2.4 g·h-1) was obtained at a 10 min residence
time.16 It is of note that the rate enhancements typically observed in flow for visible light-mediated
processes are, as expected, not observed in this specific case, although the greater surface area to
volume ratio was sufficient to greatly reduce the exothermic event associated with the Smiles
rearrangement. With the ability of continuous processes to more safely handle exotherms, the
purely thermal initiation was investigated. Although it does not currently appear general, this is an
appealing option and indeed, conducting the reaction at 5560 °C in an 8 mL, 1/16" stainless steel
tubing reactor30 resulted in full consumption of 1 within a 5 minute residence time. Although
proceeding at a faster rate, the elevated temperature increased the quantity of the sulfonic acid 6
to 32% (a/a% HPLC), with the yield of 5 falling to 56% (Scheme 5).
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Scheme 5. Thermal and visible light-initiated radical Smiles rearrangement in flow.
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Conclusions
Further evaluation of a visible light-mediated radical Smiles rearrangement at preparative scale
has provided the synthetically useful difluoroethanol motif in moderate to good yield (50–69%)
and on scales up to 100 g of sulfonate starting material. Furthermore, investigations into the
mechanistic course of this reaction has indicated a radical chain propagation as the dominant
pathway leading to the desired product. With a thoroughly deoxygenated solution, this chain
propagation was found to be initiated either by visible light or thermally, in the absence of
photocatalyst, although this did not prove general to every substrate tested. With a thiophene
substrate relevant to pharmaceutical development, the reaction was demonstrated in flow, both
with visible light and thermal initiation. Although potentially an atypical example, this report has
demonstrated the scalability of a visible light-mediated reaction in batch up to 100 g, furthermore
highlighting the importance of mechanistic understanding when assessing the potential success of
visible light reactions at scale.
EXPERIMENTAL SECTION
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Synthesis of 2-bromo-2,2-difluoroethanol 18
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Note: 18 Appears to be a lachrymator and should be handled in a fume cupboard at all times.
Modified from the patent of Satoru et al.31 To a 5 L 4 necked round bottom flask fitted with a
nitrogen inlet, temperature probe and overhead stirrer was added sodium borohydride (30.4 g, 804
mmol, 1.1 equiv), tetrahydrofuran (1400 mL) and water (100 mL) to give a homogeneous solution
after stirring for 20 min. The solution was cooled in an ice/water bath to 1015 °C, after which
ethyl bromodifluoroacetate (148 g/ 93.7 mL, 730 mmol, 1.0 equiv) in a solution of THF (700 mL)
was added dropwise at approximately 5 mL/min via a peristaltic pump maintaining the internal
temperature at 1520 °C during the approximate 3 h addition period. The solution was stirred for
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0.5 h, after which a sample analyzed via H NMR indicated full consumption of ethyl
bromodifluoroacetate. The solution was cooled in an ice/water bath to 10 °C and HCl (5 mol/L,
150 mL, 750 mmol) was added dropwise via a peristaltic pump at 5 mL/min. The solution was
warmed to ambient temperature and stirred for 2 h, upon which time the pH was 23, so an
additional 40 mL of 5 M HCl was added and the solution stirred for an additional 1.5 h. 750 mL
of MTBE was added, the layers separated and the organic phase was washed with 350 mL of sat
NaHCO3, twice with 350 mL of sat NaCl then concentrated at 45 °C and 75 mbar to give a colorless
oil. The colorless oil was stored in a fridge overnight upon which time a white solid precipitated
from solution. Boron NMR spectroscopy indicated the solids were likely boron related and that
the solution did not contain detectable quantities of boron following filtration to give 18 as a
colorless 68% w/w solution in THF (135 g, 80% yield) with spectroscopic data in agreement with
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that previously reported.2(e) 1H NMR (400 MHz, CDCl3) δH 4.03 (m, 2H); F NMR (377 MHz,
CDCl3) δF −58.4 (t, J = 10.9 Hz, 2F).
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General procedure for the synthesis of arylsulfonates 1012: To a 1 L round bottom flask open
to air, was added sulfonyl chloride (96.2 mmol, 1.1 equiv), dichloromethane (640 mL), 4-
dimethylaminopyridine (1.07 g, 8.75 mmol, 0.1 equiv), 2-bromo-2,2-difluoroethanol (20.0 g, 87.5
mmol, 1.0 equiv) and triethylamine (14.6 mL, 105 mmol, 1.2 equiv). The reaction was stirred at
room temperature for 12 h. The reaction mixture was then washed with water (150 mL) and
saturated NaHCO3 (150 mL) and then dried with Na2SO4 before the solvent was removed in vacuo
to give crude product which was purified via silica gel chromatography to give the requisite
sulfonate.
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2-bromo-2,2-difluoroethyl naphthalene-1-sulfonate 10
Following the general procedure using naphthalene sulfonyl chloride (19.8 g, 87.5 mmol, 1.1
equiv), dichloromethane (580 mL), 4-dimethylaminopyridine (0.97 g, 7.95 mmol, 0.1 equiv), 2-
bromo-2,2-difluoroethanol (16.0 g, 79.5 mmol, 1.0 equiv, as a solution in THF) and triethylamine
(13.3 mL, 95.4 mmol, 1.2 equiv) for approximately 12 h and worked up to give crude product,
which was purified via column chromatography (10–30% EtOAc:Hexanes) to give 2-bromo-2,2-
difluoroethyl naphthalene-1-sulfonate as a viscous yellow oil (27.0 g, 97% yield). Spectroscopic
data in agreement with previous report.2(e) 1H NMR (400 MHz, CDCl3) δH 8.61 (d, J = 8.6 Hz,
1H), 8.28 (d, J = 7.4 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.71 (td, J = 7.8,
1.2 Hz, 1H), 7.63 (m, 1H), 7.55 (t, J = 7.8 Hz, 1H), 4.46 (t, J = 11.3 Hz, 2H); 19F NMR (377 MHz,
CDCl3) δF −57.3 (t, J = 10.9 Hz, 2F).
2-bromo-2,2-difluoroethyl quinoline-8-sulfonate 11
Following the general procedure using 8-quinolinesulfonyl chloride (21.9 g, 96.2 mmol, 1.1
equiv), dichloromethane (640 mL), 4-dimethylaminopyridine (1.07 g, 8.75 mmol, 0.1 equiv), 2-
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bromo-2,2-difluoroethanol (20.0 g, 87.5 mmol, 1.0 equiv, as a solution in THF) and triethylamine
(14.6 mL, 105 mmol, 1.2 equiv) for approximately 12 hours and worked up to give crude product
which was purified via silica plug eluting with dichloromethane to give a brown oil that was further
purified via recrystallization from hot hexanes to yield 2-bromo-2,2-difluoroethyl quinoline-8-
sulfonate as off-white needles (24.8 g, 81% yield). Spectroscopic data in agreement with previous
report. 2(e) 1H NMR (400 MHz, CDCl3) δH 9.12 (dd, J = 4.3, 1.8 Hz, 1H), 8.56 (dd, J = 7.3, 1.3 Hz,
1H), 8.31 (dd, J = 8.3, 1.7 Hz, 1H), 8.17 (m, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.61 (q, J = 8.4 Hz, 1H),
5.17 (t, J = 11.7 Hz, 2H); 19F NMR (377 MHz, CDCl3) δF −57.2 (t, J = 11.6 Hz, 2F).
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2 -bromo-2,2-difluoroethyl (E)-2-phenylethene-1-sulfonate 12
Following the general procedure using (E)-2-phenylethene-1-sulfonyl chloride (16.6 g, 81.8 mmol,
1.1 equiv), dichloromethane (640 mL), 4-dimethylaminopyridine (0.908 g, 7.44 mmol, 0.1 equiv),
2-bromo-2,2-difluoroethanol (17.0 g, 74.4 mmol, 1.0 equiv, as a solution in THF) and
triethylamine (12.4 mL, 89.2 mmol, 1.2 equiv) for approximately 12 h and worked up to give crude
product, which was purified via column chromatography (525% EtOAc:hexanes) and
recrystallized from hot hexanes to give 2 -bromo-2,2-difluoroethyl (E)-2-phenylethene-1-
sulfonate (11.8 g, 48% yield). Spectroscopic data in agreement with previous report. 2(e) 1H NMR
(400 MHz, CDCl3) δH 7.69 (d, J = 15.5 Hz, 1H), 7.50 (m, 5H), 6.81 (d, J = 15.5 Hz, 1H), 4.60 (t,
J = 11.4 Hz, 2H); 19F NMR (377 MHz, CDCl3) δF −57.4 (t, J = 11.6 Hz, 2F).
General procedure for the synthesis of difluoroethanol products 1315.
To a one neck 500 mL recovery flask placed within a 1 L jacketed beaker connected to a
recirculating chiller set to 20 °C with a stir bar was added a sulfonate substrate (56.8 mmol, 1.0
equiv), DMSO (230 mL), Ru(bpy)3Cl2·6H2O (43 mg, 0.06 mmol, 0.001 equiv), triethylamine (11.9
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mL, 85.2 mmol, 1.5 equiv), and formic acid (3.20 mL, 85.2 mmol, 1.5 equiv). The flask was
evacuated and then filled with N2 gas (×3) and then a NaOH bubbler was attached as the outlet
and N2 was continuously bubbled into the flask. The reaction mixture was stirred and irradiated
with a 72 W LED for the stated time (See Fig S5). The reaction mixture was diluted with ethyl
acetate (240 mL) and then washed with 1N HCl (480 mL). The aqueous layer was extracted with
ethyl acetate (2 x 240 mL). Organic layers were combined and washed with 1N HCl (240 mL),
sat. NaHCO3 (240 mL) and brine (240 mL). The solution was concentrated in vacuo to give the
crude product, which was purified via silica gel chromatography and/or recrystallization to give
the requisite Smiles rearrangement product.
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2,2-difluoro-2-(naphthalen-1-yl)ethan-1-ol 13
Following the general procedure using 2-bromo-2,2-difluoroethyl naphthalene-1-sulfonate (20.1
g, 57.2 mmol, 1.0 equiv), DMSO (380 mL), Ru(bpy)3Cl2·6H2O (43 mg, 0.06 mmol, 0.001 equiv),
triethylamine (12.0 mL, 85.9 mmol, 1.5 equiv), and formic acid (3.24 mL, 85.9 mmol, 1.5 equiv)
were reacted for 90 min and worked up to give the crude product which was purified via automated
column chromatography (220 g silica column, 0:100 EtOAc:hexanes to 7:93 EtOAc:hexanes) to
give 2,2-difluoro-2-(naphthalen-1-yl)ethan-1-ol 12 (6.97 g, 59% yield) as a viscous oil.
Spectroscopic data in agreement with previous report. 2(e) 1H NMR (400 MHz, CDCl3) δH 8.24 (d,
J = 8.2 Hz, 1H), 7.94 (m, 2H), 7.79 (d, J = 7.2 Hz, 1H), 7.56 (m, 3H), 4.24 (t, J = 13.7 Hz, 2H);
19F NMR (377 MHz, CDCl3) δF −102.18 (t, J = 13.6 Hz, 2F).
2,2-difluoro-2-(quinolin-8-yl)ethan-1-ol 14
Following the general procedure using 2-bromo-2,2-difluoroethyl quinoline-8-sulfonate (20.0 g,
56.8 mmol, 1.0 equiv), DMSO (240 mL), Ru(bpy)3Cl2·6H2O (43 mg, 0.06 mmol, 0.001 equiv),
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triethylamine (11.9 mL, 85.2 mmol, 1.5 equiv), and formic acid (3.20 mL, 85.2 mmol, 1.5 equiv)
were reacted for 90 min and worked up to give the crude product, which was purified via filtration
through a plug of silica and recrystallization from hot hexanes/ethyl acetate to give 2,2-difluoro-
2-(quinolin-8-yl)ethan-1-ol 11 (7.70 g, 65% yield) as a tan solid. Spectroscopic data in agreement
with previous report. 2(e) 1H NMR (400 MHz, CDCl3) δH 8.97 (dd, J = 4.2 Hz, 1H), 8.31 (dd, J =
8.4, 1.8 Hz, 1H), 8.15 (d, J = 7.4 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.55
(dd, J = 8.2, 4.3 Hz, 1H), 4.40 (t, J = 12.5 Hz, 2H); 19F NMR (377 MHz, CDCl3) δF −98.06 (t, J =
12.9 Hz, 2F).
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(E)-2,2-difluoro-4-phenylbut-3-en-1-ol 15
Following the general procedure using 2-bromo-2,2-difluoroethyl (E)-2-phenylethene-1-sulfonate
(20.1 g, 61.4 mmol, 1.0 equiv), DMSO (380 mL), Ru(bpy)3Cl2·6H2O (46 mg, 0.06 mmol, 0.001
equiv), triethylamine (12.9 mL, 92.2 mmol, 1.5 equiv), and formic acid (3.48 mL, 92.2 mmol, 1.5
equiv) were reacted for 90 min and worked up to give the crude product, which was purified via
automated column chromatography (220 g silica column, 0:100 EtOAc:hexanes to 10:90
EtOAc:hexanes) and recrystallization from hot hexanes to give (E)-2,2-difluoro-4-phenylbut-3-
en-1-ol 23 (43.5 g, 64% yield). Spectroscopic data agreed with previous report. 2(e) 1H NMR (400
MHz, CDCl3) δH 7.41 (m, 5H), 7.03 (dt, J = 16.3, 2.6 Hz, 1H), 6.27 (dt, J = 16.2, 11.3 Hz, 1H),
3.91 (t, J = 12.7 Hz, 2H); 19F NMR (377 MHz, CDCl3) δF −101.26 (t, J = 12.9 Hz, 2F).
Synthesis of methyl 3-((2-bromo-2,2-difluoroethoxy)sulfonyl)thiophene-2-carboxylate 1
To a 4 neck 5 L flask with a nitrogen inlet, a thermocouple, and an overhead stirrer was added
methyl-3-chlorosulfonyl-2-carboxylate (251 g, 1.04 mol, 1.1 equiv) and dichloromethane (1.90 L)
resulting in an endothermic dissolution and a heterogeneous solution. 4-Dimethylaminopyridine
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(11.6 g, 94.9 mmol, 0.10 equiv) was added to give a homogenous dark brown solution. 2-Bromo,2-
2-difluoro-ethanol (222 g, 949 mmol, 1.0 equiv, as a 69% w/w solution in THF) was added as a
solution in dichloromethane (500 mL). The solution was cooled in an ice/water bath to 10 °C and
triethylamine (115 g, 159 mL, 1.14 mol, 1.2 equiv) was added dropwise over 30 min. The light
brown homogenous solution was stirred for 2.5 h before being washed with 1N HCl (1.0 L),
saturated aqueous NaHCO3 (1.0 L), and brine (1.0 L) then concentrated to give a light brown solid
(crude material ~93% a/a by HPLC). The crude brown material was dissolved in ethyl acetate (350
mL) then heated to 40 °C. Heptane (300 mL) was added dropwise then the solution cooled to
ambient temperature over 1 h then in an ice/water bath resulting in precipitation of 1. The colorless
crystalline solids were filtered and washed with heptane (100 mL) then dried in a vacuum oven to
give 1 (135 g, 99% a/a by HPLC, 39% yield). Further quantities of 1 were recovered from the
filtrate via concentration and further cooling in an ice/water bath giving a combined quantity of 1
(284 g, 95% by HPLC, 78% yield) with spectroscopic data in accordance with that previously
reported. 2(e) 1H NMR (400 MHz, CDCl3) δH 7.62 (d, J = 5.1 Hz, 1H), 7.58 (d, J = 5.1 Hz, 1H),
4.85 (t, J = 11.7 Hz, 2H) and 3.95 (d, J = 0.2 Hz, 3H); 19F NMR (377 MHz, CDCl3) δF −57.6 (t, J
= 11.7 Hz, 2F).
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Synthesis of 3-((2-bromo-2,2-difluoroethoxy)sulfonyl)thiophene-2-carboxylate 5 on 100 g
scale without Ru(bpy)3Cl2.
To a 4 neck, 5 L jacketed flask fitted with a nitrogen inlet, a thermocouple, a condenser with the
outlet leading to a 5N NaOH scrubber, and an overhead stirrer with the jacket temperature set to
25 °C was added methyl 3-((2-bromo-2,2difluoroethoxy)sulfonyl)thiophene-2-carboxylate 1 (100
g, 98% purity, 268 mmol, 1.0 equiv) and DMSO (1.08 L). The light yellow homogenous solution
was deoxygenated via nitrogen sparging through a diffuser for 30 min. Triethylamine that had
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previously been deoxygenated via nitrogen sparging for 30 minutes (56.0 mL, 402 mmol, 1.5
equiv), and formic acid that had previously been deoxygenated via nitrogen sparging for 30
minutes (15.8 mL, 405 mmol, 1.5 equiv) were added causing an exotherm to approximately 30 C.
The reaction mixture was irradiated with a white LED work light and within 1 min the solution
began to change to a dark red that was accompanied with an exotherm to 45 C over 5 min and
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significant gas formation. After 20 min the temperature had returned to 28 C and the reaction was
shown to be complete by HPLC (65% assay yield). The solution was then sparged for 1 h to remove
SO2 with nitrogen before being removed from the reactor. To the reactor was added aqueous HCl
(1 mol/L, 2.15 L) and subsequently cooled to 5 C. The crude reaction solution was diluted with
ethyl acetate (1.08 L) and added to the 5 C aqueous HCl via a peristaltic pump over 1 h,
maintaining the internal reaction solution below 15 C. The layers were separated and the organic
layer washed with aqueous HCl (1 mol/L, 1.08 L), sat NaHCO3 (1.08 L), and brine (1.08 L) then
concentrated to give a 5 as a light brown solid (43.5 g, 88% purity by HPLC, 64% yield) with
spectroscopic data in accordance with that previously reported. 2(e) 1H NMR (400 MHz, CDCl3) δH
7.13 (s, 1H), 4.22 (t, J = 13.4 Hz, 2H), 3.88 (s, 3H), 2.49 (br s, 1H); 19F NMR (377 MHz, CDCl3)
−100.3 (t, J = 13.8 Hz, 2F).
ASSOCIATED CONTENT
Supporting Information. A full report of the mechanistic experiments, full experimental details,
and characterization data.
AUTHOR INFORMATION
Corresponding Author
*E-mail: crjsteph@umich.edu
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Present Addresses
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† AstraZeneca, Silk Road Business Park, Macclesfield SK10 2NA, United Kingdom
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Author Contributions
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The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
Funding Sources
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
gratefully acknowledged.
ACKNOWLEDGMENT
We thank Richard Miller for help conducting flow experiments, Jonas Buser for conducting the
NMR experiments and for identification of difluoroethylene, Matthew Embry, David Robbins,
Paul Dodson, and Michael Johnson for identification of sulfonic acid 6. We thank Greg Brown,
Odi Campos, and Stan Kolis for help with headspace mass spectrometry.
REFERENCES
1. For selected reviews see: (a) Tucker, J. W.; Stephenson, C. R. J. J. Org. Chem. 2012,
77, 1617–1622 (b) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322–
5363 (c) Nicewicz, D. A.; Nguyen, T. M. ACS Catal., 2014, 4, 355–360 (d) Douglas, J. J.; Nguyen,
J. D.; Cole, K. P.; Stephenson, C. R. J. Aldrichim. Acta 2014, 47, 16–27.
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2. For an accompanying review in this issue that summarizes these applications see:
Douglas, J. J.; Sevrin, M. J.; Stephenson, C. R. J. Org. Process Res. Dev. 2016, [insert DOI here].
Selected examples of the use of visible light in the preparation of pharmaceutical compounds see:
(a) Hari, D.P.; Hering, T.; König, B. Org. Lett. 2012, 14, 5334–5337 (b) Douglas, J. J.; Cole, K.
P.; Stephenson, C. R. J. J. Org. Chem. 2014, 79, 11631–11643 (c) Chu, L.; Lipshultz, J. M.;
MacMillan, D. W. C. Angew. Chem., Int. Ed. 2015, 54, 7929–7933 (d) Le, C.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2015, 137, 11938–11941 (e) Douglas, J. J.; Albright, H.; Sevrin, M. J.; Cole,
K. P.; Stephenson, C. R. J. Angew. Chem., Int. Ed 2015, 54, 14898–14902 (f) Haperin, S. D.;
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Nagib, D. A.; MacMillan, D. W. C. Nature 2011, 480, 224–228 (i) DiRocco, D. A.; Dukstra, K.;
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3. For the ionic Smiles rearrangement see: (a) Levy, A. A.; Rains, H. C.; Smiles, S. J.
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Tetrahedron Lett. 1970, 11, 1467–1469 (c) Wang, Z. In Comprehensive Organic Name Reactions
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M. K. J. Chem. Soc., Chem. Commun. 1991, 877–879 (f) Studer, A.; Bossart, M. Tetrahedron
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7. Typically, visible light-mediated methodologies employing Ru or Ir photocatalysts
operate with 0.5–2 mol% in 1–12 h, see ref 1(b)
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8. (a) Beatty, J. W.; Douglas, J. J.; Cole, K. P.; Stephenson, C. R. J. Nat. Commun. 2015,
6, 7919; See also ref 2(f) and 2(g).
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9. The removal of the tertiary amine prior to base wash and concentration was required to
prevent cyclization of the product to the corresponding lactone.
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10. As expected, under these conditions the quantity of 16, resulting from premature H-
atom abstraction of the radical 2 prior to the Smiles rearrangement was reduced (<2%).
11. Fouassier, J. P.; Burr, D. Macromolecules 1990, 23, 3615–3619.
12. Reductions of carbon centered radicals are typically observed when the resulting anion
can be delocalized into an adjacent pi system, for example see: Jovanovic, S. V.; Steenken, S.;
Simic, M. G. J. Phys. Chem. 1990, 94, 3583–3588. Such a reduction would also represent a chain
termination event in competition with other intermolecular processes, such as C–H abstraction
leading to 16. We kindly thank a reviewer for expanding upon this possibility
13. Difluoroethylene is a gas with boiling point 84 °C but shows significant organic
solubility.
14. For a full summary of control experiments and mechanistic investigations see the
supporting information.
15. This reaction failed to reach full conversion and could not be taken to completion with
further irradiation with light for 1 h.
16. Headspace mass spec identified the generation of carbon dioxide, sulfur dioxide and
difluoroethylene during the course of the reaction.
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17. See SI for further information.
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18. A significant exotherm (approximately 10 °C over 5 minutes) was observed under the
standard conditions that was consistent with the onset of the reaction.
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19. The ease of initiation appears to trend with the enthalpic gain following elimination to
the alkoxy sulfonyl radical from the cyclic intermediate such as 3.
20. We were unable to identify any trapping products resulting from the proposed
homolysis after visible light irradiation in the absence of NEt3/formic acid for 15 h with either
TEMPO (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl) or 2,4-di-tert-butylphenol.
21. (a) Chatgilialoglu, C.; Griller, D.; Rossini, S. J. Org. Chem., 1989, 54, 2734–2737 (b)
Qrareya, H., Protti, S., Fagoni, M. J. Org. Chem. 2014, 79, 11527–11533; See also ref 11.
22. The role of 17 as the major reductive species may not be general to all processes
employing formic acid/tertiary amine conditions. It is possible that alkoxy sulfonyl radical 4,
and sulfonyloxy radical 7 are particularly efficient at abstracting the C–H bond of formate.
23. (a) Beckwith, A. L. J., Norman R. O. C., J. Chem. Soc. B 1969, 400 (b) Surdhar, P, S.,
Mezyk, S. P., Armstrong, D. A., J. Phys. Chem. 1989, 93, 3360–3363 (c) Rosso, J. A.; Bertolotti,
S. G.; Braun, A. M.; Mártire, D. O., Gonzalez, M. C. J. Phys. Org. Chem. 2001, 14, 300–309.
24. Evidence for the radical nature of the reaction was obtained by the addition of TEMPO
(1.0 equiv) resulting in full inhibition after 2 h both with and without Ru(bpy)3Cl2.
25. (a) Juris, A.; Balzani, V.; Barigelletti, F.; Campagna, S.; Belser, P.; von Zelewsky, A.
Coordination Chemistry Reviews 1988, 84, 85–277 (b) DeRosa, M. C.; Crutchley, R. J.
Coordination Chemistry Reviews 2002, 233-234, 351–371.
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