Effects of Molecular Oxygen, Solvent, and Light on Iridium-Photoredox/Nickel Dual-Catalyzed Cross-Coupling Reactions

Article abstract of DOI:10.1021/acs.joc.5b01193

In order to achieve reproducibility during iridium-photoredox and nickel dual-catalyzed sp³-sp² carbon-carbon bond-forming reactions, we investigated the role that molecular oxygen (O₂), solvent and light-source (CF lamp o

Full text of DOI:10.1021/acs.joc.5b01193

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Article
The Effects of Molecular Oxygen, Solvent and Light on Iridium-
Photoredox/Nickel Dual-Catalyzed Cross-Coupling Reactions
Martins Sunday Oderinde, Adrian Varela-Alvarez, Brian Aquila, Daniel W. Robbins, and Jeffrey W. Johannes
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01193 • Publication Date (Web): 03 Jul 2015
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The Effects of Molecular Oxygen, Solvent and Light on Iridiumꢀ
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Photoredox/Nickel DualꢀCatalyzed CrossꢀCoupling Reactions
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Martins S. Oderinde,*† Adrian VarelaꢀAlvarez,† Brian Aquila,† Daniel W. Robbins,† Jeffrey W.
Johannes*†
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† Chemistry Department (Oncology), AstraZeneca Pharmaceuticals LP, 35 Gatehouse Drive, Waltham, MA. U.S.A. 02451
*Emails: martins.oderinde@astrazeneca.com; jeffrey.johannes@astrazeneca.com
TOC graphics:
Abstract:
In order to achieve reproducibility during iridiumꢀphotoredox and nickel dualꢀcatalyzed sp3ꢀsp2 carbonꢀcarbon bondꢀforming reactions, we
investigated the role that molecular oxygen (O2), solvent and lightꢀsource (CFꢀlamp or blue LED) play in a variety of Irꢀphotoredox mediated
transformations. The presence of O2 was discovered to be important for catalyst activation when airꢀstable Ni(II)ꢀprecatalysts were used in
DMF under CFꢀlamp irradiation; however, O2 was not required for catalysis when conducted with Ni(COD)2 in the same reaction system. O2 is
believed to promote rapid reduction of the Ni(II)ꢀprecatalyst by Ir(II) to Ni(0). In addition to O2, the effects that solvent and lightꢀsource have on
the dualꢀcatalyzed decarboxylative crossꢀcoupling reactions will be discussed. These findings have enabled us to develop a more robust dualꢀ
catalyzed decarboxylative crossꢀcoupling protocol.
Introduction:
Recent progress in photoredox chemistry has expanded the toolbox for carbonꢀcarbon bondꢀforming reactions. The ability of photoredox
transition metal complexes to engage in singleꢀelectron transfer (SET) processes upon excitation by visible light with both electronꢀreleasing
and electronꢀaccepting organic and organometallic compounds under mild conditions to generate reactive radical species make them
powerful synthetic tools.1ꢀ5 During the past decade, nickel catalysis has enabled the construction of various carbonꢀcarbon bonds via the
crossꢀcoupling of organometallic nucleophiles with various electrophiles including aryl, vinyl and alkyl halides.6 The easy accessibility of Ni(I)
and Ni(III) oxidation states in nickel catalysis also allows different modes of reactivity relative to the reactivity patterns of the wellꢀknown
palladium catalytic cycle.7
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Molander,8 MacMillan and Doyle9 recently reported their pioneering findings of Irꢀphotoredox/nickel dualꢀcatalysis in sp3ꢀsp2
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carbonꢀcarbon bond formation (Scheme 1). While Molander showed the crossꢀcoupling of potassium benzyltrifluoroborates with aryl
halides,8 MacMillan and Doyle demonstrated the decarboxylative crossꢀcoupling of αꢀamino acids with aryl halides.9 In the context of
medicinal chemistry, the construction of strategic bonds between readily accessible αꢀamino acids or potassium
benzyltrifluoroborates and aryl halides attracted our attention to these two protocols. In addition, we were intrigued by the use of airꢀ
stable NiCl2•glyme as the precatalyst for the crossꢀcoupling reactions. Our interest in the application of both protocols led us to
discover that O2 can play an important role in the decarboxylative crossꢀcoupling reactions under Irꢀphotoredox/Ni dualꢀcatalysis.
Specifically, we discovered that exposure of the reaction to O2 is crucial for the activation of the Ni(II)ꢀprecatalyst and the
reproducibility of the reaction under certain conditions. Due to this discovery, more thorough experimental and mechanistic
investigations of the Irꢀphotoredox/Ni dualꢀcatalysis as well as studies of the O2ꢀeffect on other Irꢀphotoredox carbonꢀcarbon bondꢀ
forming reactions were initiated.
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Herein, we report on the effects of molecular oxygen (O2), solvents and light on the Irꢀphotoredox and nickel dualꢀcatalyzed crossꢀ
coupling reactions.
Scheme 1. Reported dualꢀcatalyzed sp3ꢀsp2 crossꢀcoupling reactions.8,9
Results and Discussion:
We began our investigations by conducting the decarboxylative crossꢀcoupling reaction of BocꢀProꢀOH (1) and 4ꢀiodotoluene (2a)
following the reported protocol with the in-situ generated NiCl2•dtbbpy complex and photoredox catalyst IrꢀB with the rigorous
exclusion of O2 (Table 1).9 Surprisingly, no crossꢀcoupled product (3a) was formed and the 4ꢀiodotoluene (2a) was quantitatively
recovered (Table 1, entry 1). Likewise, no product was obtained when the reaction was conducted with a DMF:H2O (99:1) solvent
mixture in the absence of O2, suggesting that H2O does not initiate catalysis (entry 2). Based on these observations, we suspected
that O2 could be required for the catalysis to proceed.10ꢀ11 Gratifyingly, the expected crossꢀcoupled product (3a) was obtained in 69%
yield when the reaction mixture was not degassed (entry 3). Similarly, the decarboxylative crossꢀcoupling of BocꢀProꢀOH (1) and 4ꢀ
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bromoacetophenone (2b), which did not proceed under rigorously degassed conditions (entry 4), proceeded to give 3b in 95% yield
when the reaction mixture was not degassed (entry 5). The rate studies of this particular reaction showed 60% conversion to 3b in 5
hours (See SI for the rate curve). In contrast to IrꢀB, the following yields were obtained for 3b when the reaction was carried out with
other photoredox catalysts and NiCl2•dtbbpy under 26 W CFꢀlamp irradiation: IrꢀA (with O2 = 17%, without O2 = 0%), IrꢀC (with O2 =
82%, without O2 = 14%), and IrꢀD (with and without O2 = 0%). After further optimization studies with IrꢀB and NiCl2•dtbbpy, the
reaction concentration was increased to 0.04 M from 0.02 M, and the reaction time was significantly reduced from 72 hours to less
than 20 hours (See Table S1 in the SI for 12 substrate examples).
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To ensure that the O2ꢀeffect on this catalysis is not limited to the use of NiCl2•dtbbpy, we carried out the reaction of 1 and 2b with
in-situ generated NiI2•dtbbpy and Ni(OTf)2•dtbbpy. Similar to NiCl2•dtbbpy, no crossꢀcoupled product was obtained with either Ni(II)ꢀ
complexes in the absence of oxygen (Table 1, entries 6 and 7). Conversely, the crossꢀcoupled product (3b) was obtained in 30% and
50% yield respectively when neither reaction mixture was degassed (Table 1, entries 8 and 9).
Table 1. O2 Effect on the Irꢀphotoredox/nickel dualꢀcatalyzed decarboxylative crossꢀcoupling reaction.[a]
IrꢀB
, NiCl2•glyme,
dtbbpy, Cs2CO3,
X
O
N
+
N
Boc
Boc
R1
DMF, 26 W CFꢀlamp,
23 °C
R1
: R1 = Me
3b
OH
2a: R1 = Me, X = I
3a
1
: R1 = Ac, X = Br
: R1 = Ac
2b
Entry
X
R1
Condition[b]
none
Reaction Mixture
degassed
%Yield[c]
1
2
I
CH3
0
0
I
CH3
H2O[d]
none
degassed
3
I
CH3
not degassed[e]
degassed
69
0
4
Br
Br
Br
Br
Br
Br
Br
Br
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
none
5
none
not degassed[e]
degassed
>95
0
[f]
6
NiI2
[f]
7
Ni(OTf)2
degassed
0
[f]
8
NiI2
not degassed[e]
not degassed[e]
degassed
30
50
>95
>95
[f]
9
Ni(OTf)2
[f]
10
11
Ni(COD)2
[f]
Ni(COD)2
not degassed[e]
[a] Unless otherwise indicated, reactions were carried out with BocꢀProꢀOH (1) (0.6 mmol), aryl halide (2) (0.4 mmol), IrꢀB (1 mol%), NiCl2•glyme (10 mol%), dtbbpy
(15 mol%), DMF (10 mL), Cs2CO3 (0.6 mmol), and irradiated with one 26 W CFꢀlamp at room temperature for 20 hours; the reaction mixture was degassed either
by sparging with an argon or a nitrogen stream for at least 20 minutes or by three freezeꢀpumpꢀthaw cycles before irradiation. [b] Variation from standard condition
[a]. [c] Each reaction was repeated multiple times. DMF:H2O (99:1) mixture was used. [e] The headspace was purged with N2 for 10 seconds to remove excess
[d]
O2. [f] NiX2 (10 mol%) and dtbbpy (15 mol%) were used.
To this end, the quantitative recovery of the aryl halides (2a and 2b) in the absence of O2 led us to think that the presence of O2 may
be crucial for the activation of the Ni(II)ꢀprecatalyst to give an active Niꢀspecies (Ni(I) or Ni(0)), which initiates the Niꢀcycle. In such a
case, a reaction with a Ni(0)ꢀprecatalyst should proceed in the absence of O2. Indeed, the crossꢀcoupling reaction of 1 and 2b
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proceeded to give 3b in quantitative yield when Ni(COD)2 was used under O2ꢀfree conditions (all reagents were added inside an N2ꢀ
filled gloveꢀbox, Table 1, entry 10). Remarkably, when Ni(COD)2 was weighed out in air and used in the crossꢀcoupling reaction of 1
and 2b that was not degassed prior to irradiation, the reaction still proceeded to give 3b in quantitative yield (Table 1, entry 11). The
ability to carry out this dualꢀcatalysis with Ni(COD)2 in the presence of O2, shows the high tolerance of this catalysis to O2.
To better understand the role that O2 plays in this dualꢀcatalysis, additional control reactions were conducted. Hence, the reaction
of 1 and 2b under O2ꢀfree conditions that did not show any crossꢀcoupled product after 4 hours was initiated by introducing air into
the reaction mixture with a syringe. Further irradiation of the same reaction, resulted in the formation of 3b in 60% yield (Scheme 2a).
This shows that O2 is indeed required to promote the catalysis under this reaction condition. In addition, when the Irꢀphotoredox
mediated decarboxylative conjugate addition reaction of BocꢀProꢀOH (1) to malonate (4) was conducted in the absence of O2, a
diastereomeric mixture of 5 was obtained in 70% yield (Scheme 2b).12a Similarly, the Irꢀphotoredox mediated decarboxylative
arylation of BocꢀProꢀOH (1) with 1,4ꢀdicyanobenzene (6) gave 7 in 60% yield in the absence of O2 (Scheme 2c).12b However, the
yields of compounds 5 and 7 both increased to 90% and 92% respectively, when their reactions (Schemes 2b and 2c), were carried
out in the presence of O2. To the best our knowledge, this is also the first report of O2 effects and tolerance in both of these
synthetically useful reactions.
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Scheme 2. Control experiments to demonstrate O2 effect on Irꢀphotocatalysis.
To investigate whether O2 plays a role in other Irꢀphotoredox/Ni dualꢀcatalysis, we turned our attention to the reported dualꢀ
catalyzed crossꢀcoupling protocol of potassium benzyltrifluoroborate (8) and 4ꢀbromobenzonitrile (9) with Ni(COD)2 as the precatalyst
in acetoneꢀmethanolꢀ2,6ꢀlutidine solvents system.8a The crossꢀcoupling of potassium benzyltrifluoroborate (8) and 4ꢀ
bromobenzonitrile (9) under O2ꢀfree conditions (an N2ꢀfilled gloveꢀbox was used), gave the crossꢀcoupled product (10) in 80ꢀ91%
yield with either IrꢀA or IrꢀB and Ni(COD)2 dualꢀcatalyst (Scheme 3a).8a In order to gain a better understanding of the dualꢀcatalysis,
and in particular the catalysis with Ni(II)ꢀprecatalyst, we studied this reaction in DMF. When the dualꢀcatalyzed crossꢀcoupling of 8
and 9 was carried out in DMF with the rigorous exclusion of O2 with IrꢀA and NiCl2•dtbbpy precatalyst, the reaction proceeded to give
product (10) in 43% yield while the mass balance was the unreacted 4ꢀbromobenzonitrile (9) (Scheme 3b). Notably, the yield of 10
was not impacted in any significant way when either photoredox catalyst IrꢀB, or Ni(COD)2 precatalyst was used in the absence of O2
(Scheme 3b).13 These results imply that the NiCl2•dtbbpy precatalyst can be reduced by Ir(II) to the active Ni(0)•dtbbpy under this
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dualꢀcatalysis and in the absence of O2. Nonetheless, we considered the possibility of potassium benzyltrifluoroborate (8) activating
the NiCl2•dtbbpy to the Ni(0)•dtbbpy via a double transmetallation/reductive elimination mechanism.6,7 This alternate activation
mechanism was however ruled out after a reaction mixture of 20 mol% of 8 and 10 mol% NiCl2•dtbbpy failed to initiate the
decarboxylative crossꢀcoupling reaction of 1 and 2b in the absence of O2.
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Scheme 3. Dualꢀcatalyzed crossꢀcoupling reaction of potassium benzyltrifluoroborate and 4ꢀbromobenzontrile in the absence of O2.
To explain the drastically different oxygen dependencies of these two closely related catalytic systems, we suspected that in the case
of the decarboxylative crossꢀcoupling reaction, the carboxylate salt could be reacting rapidly with the NiX2•dtbbpy to form a new Ni(II)ꢀ
complex, which is not being reduced by Ir(II). In this regard, experiments to examine the effects of BocꢀProꢀOCs on the crossꢀ
coupling reaction of potassium benzyltrifluoroborate (8) and 4ꢀbromobenzonitrile (9) were carried out. When the crossꢀcoupling
reaction of potassium benzyltrifluoroborate (8) and 4ꢀbromobenzonitrile (9) was performed in the presence of in-situ generated Bocꢀ
ProꢀOCs (1.5:1.5:1.0 ratio of BocꢀProꢀOCs:8:9) and NiCl2•dtbbpy precatalyst with the rigorous exclusion of O2, only trace crossꢀ
coupled products were observed (Scheme 4). Conversely, when the same reaction was carried out in the presence of O2, catalysis
occurred to give products 10 and 7 in combined 64% yield (10:7 = 2:1). These control reactions show that the presence of Bocꢀ
ProꢀOCs prevents catalysis with NiCl2•dtbbpy precatalyst from occurring in the absence of O2.
Scheme 4. Effects of BocꢀProꢀOCs on the crossꢀcoupling reaction of potassium benzyltrifluoroborate and 4ꢀbromobenzontrile.
Infact, there is a ligand exchange reaction between NiCl2•dtbbpy (1.0 equiv.) and BocꢀProꢀOCs (15 equiv.) in DMF at room
temperature to give what is believed to be (BocꢀProꢀO)NiCl•dtbbpy (11) as indicated by in-situ mass spectroscopic analysis (m/z [Mꢀ
Cl]+ = 540.20 and 542.20 in 3:1 isotopic ratio indicating the presence of one Cl atom in the complex). The same mass peaks were
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also observed in reaction mixtures that did not proceed in the absence of O2. Unfortunately, the full characterization of complex 11 by
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other spectroscopic methods has so far been unsuccessful due to decomposition during isolation.
We recognized that O2 ‾ is known to be generated in-situ from the reduction of O2 in Irꢀphotoredox catalyzed reactions,11 hence
•
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•
weexamined if O2 ‾ activates the Ni(II)ꢀcomplex by reducing it via a SET process to give Ni(0)ꢀspecies and O2. However, no oxidative
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addition product was observed when 2 equiv. of KO2 was stirred with a mixture of NiCl2•dtbbpy, BocꢀProꢀOCs and 2a in DMF.
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Therefore, the inability to detect any oxidative addition product suggests that O2 ‾ is not reducing the Ni(II)ꢀcomplex to an active Niꢀ
species (See SI). Exploration of the literature revealed that molecular oxygen enhances the intersystem crossing (ISC) processes of
organic molecules (assisted intersystem crossing).14,15 We believe that the presence of O2 in all these photoredox reactions
enhanced the intersystem crossing (ISC) process of the excited singlet state of *Ir(III) to its excited triplet state, which has a longer
lifeꢀtime.1,14,15 An enhancement of the ISC process will result in a more efficient formation of the excited triplet state of *Ir(III) and a
faster reductive quenching of *Ir(III) by the carboxylate salt to give Ir(II) and carboxyl radical. In other words, the reductant Ir(II) will be
formed at a faster rate when the ISC process is enhanced. Therefore, the rate of reduction of NiCl2•dtbbpy by Ir(II) to Ni(0)•dtbbpy
must be faster than the rate of the ligand exchange reaction for the crossꢀcoupling reaction to have proceeded
.
Based on this hypothesis, we screened several ligands and solvents in search of a reaction protocol that tolerates O2 but does
not depend on O2 for catalyst activation when using Ni(II)ꢀprecatalyst (See Table S2 in the SI).
Table 2. Solvents and light effects on the Irꢀphotoredox/nickel dualꢀcatalyzed decarboxylative crossꢀcoupling reaction.[a]
Reaction
Entry
Light source
Solvent
%Yield[b],[c]
Mixture
degassed
degassed
degassed
degassed
1
2
3
4
26 W CFꢀlamp
26 W CFꢀlamp
26 W CFꢀlamp
34 W blue LEDs
DMF
MeCN
0
68
MeCN:DMF (4:1)
DMF
90
>95[d]
[a] Unless otherwise indicated, reactions were carried out with BocꢀProꢀOH (1) (0.6 mmol), aryl halide (2) (0.4 mmol), IrꢀB (1 mol%), NiCl2•glyme (10 mol%), dtbbpy
(15 mol%), solvent (10 mL), Cs2CO3 (0.6 mmol) at room temperature for 20 hours; the reaction mixture was degassed by sparging with a nitrogen stream for at
least 20 minutes. [b] Each reaction was repeated multiple times. [c] >95% yield was obtained when the reaction mixture was not degassed. [d] This reaction went to
completion within 5 hours.
Gratifyingly, we found that by simply carrying out the reaction in MeCN instead of DMF, the decarboxylative crossꢀcoupling reaction
of 1 and 2b with NiCl2•dtbbpy proceeded in the absence of O2 to give 3b in 68% yield (Table 2, entry 2). Unlike in DMF, the ligand
exchange reaction between NiCl2•dtbbpy and carboxylate salt is very slow in MeCN due to the poor solubility of the carboxylate salt.
The lower yield of the product in MeCN can also be attributed to the poor solubility of the carboxylate salt. Upon further optimization
studies, the use of 4:1 MeCN:DMF solvents mixture was found to be the ideal solvents combination for the reaction, and gave 3b in
90ꢀ95% yield with and without O2 (Table 2, entry 3).
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Interestingly, when the crossꢀcoupling reaction of 1 and 2b was carried out with NiCl2•dtbbpy in DMF with the rigorous exclusion
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8
9
of O2 and irradiated with blueꢀLEDs instead of CFꢀlamp, the crossꢀcoupled product 3b was obtained in quantitative yield in less than 5
hours (Table 2, entry 1 versus 4). In addition, when the crossꢀcoupling reaction of potassium benzyltrifluoroborate (8) and 4ꢀ
bromobenzonitrile (9) in the presence of in-situ generated BocꢀProꢀOCs (1.5:1.5:1.0 ratio of BocꢀProꢀOCs:8:9) and NiCl2•dtbbpy
precatalyst with the rigorous exclusion of O2 was repeated under blue LEDs irradiation, the aryl bromide (9) was quantitatively
converted to the crossꢀcoupled products 10 and 7 (Scheme 5). Under this condition, the amount of 7 observed in the products
mixture was also higher than 10 (10:7 = 1:1.3), which is in contrast to the result obtained under the CFꢀlamp irradiation (Scheme 4
versus Scheme 5). In metalꢀphotoredox catalyzed reactions, the irradiation with a monochromatic blueꢀLED has been reported to be
more efficient and produce reactions with faster rates than those irradiated with a broadꢀspectrum white CFꢀlamp.16 Therefore, similar
to our explanation of the molecular oxygen effect, we believe that the photoꢀinduced formation of the excited triplet state of *Ir(III) is
more efficient (longer lifetime and higher quantum yield)17 under blueꢀLED irradiation than CFꢀlamp irradiation. Consequently, the
SET quenching of the *Ir(III) by the carboxylate salt to give the reductant Ir(II) and the carboxyl radical as well as the reduction
processes of both the Ni(II) and Ni(I)ꢀspecies by Ir(II) to their corresponding Ni(I) and Ni(0)ꢀspecies are much faster under blueꢀLED
irradiation. The use of blueꢀLEDs in this dualꢀcatalytic process delivers a more efficient reaction than the use of CFꢀLamp and
molecular oxygen. It is important to note that we examined and ruled out reaction temperature as the source of the difference in the
outcome of the reactions performed in the absence of O2 under blueꢀLEDs and CFꢀlamp irradiations.
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That said, another notable aspect of the reaction in Scheme 5 is that both the αꢀamino and benzyl radicals are being generated
in the same reaction yet the reaction favors the Niꢀcatalyzed crossꢀcoupling rather than a combination reaction between these two
different radicals. Studies on the effects of 2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy, free radical (TEMPO) on these reactions, showed that
both the αꢀamino and benzyl radicals are indeed being generated and were trapped by TEMPO (Scheme 6). Hence, this observation
is a clear manifestation of persistent radical effect.18 In this catalytic reaction, the high energy fleeting carbonꢀcentred radicals react
selectively with the nickel species, which are the persistent radicals and are also present in a higher concentration than any carbonꢀ
centred radical whose concentration cannot be higher than that of the iridium catalyst.
Scheme 5. Effects of BocꢀProꢀOCs on the crossꢀcoupling reaction of potassium benzyltrifluoroborate (8) and 4ꢀbromobenzontrile (9).
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Scheme 6. TEMPO as a free radical trap of αꢀamino and benzyl radicals
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A plausible mechanism for the IrꢀB and Niꢀcomplex dualꢀcatalyzed decarboxylative crossꢀcoupling reaction is shown in Figure 1. The
visibleꢀlight induced photoexcitation of the singlet ground state Ir(III) gives an excited triplet state *Ir(III).1 The *Ir(III) (E red [*Ir(III)/Ir(II)]=
½
+1.21 V vs. SCE in MeCN)17 then accepts a single electron from an αꢀamino carboxylate salt (E red [BocꢀProꢀ OCs] = +0.95 V vs. SCE
½
in MeCN)12b to give the Ir(II) (reductive quenching) and a carboxyl radical.
Figure 1. Proposed mechanism of Irꢀphotoredox/Ni dualꢀcatalyzed decarboxylative crossꢀcoupling reaction.
This carboxyl radical spontaneously loses CO2 to give an αꢀamino radical. Under ideal reaction conditions as discussed above and
red
based on the known reduction potentials of the Ir(II)ꢀcomplex (E red [Ir(III)/Ir(II)] = –1.37 V vs. SCE in MeCN)17 and Ni(II)halides (E
½
½
[Ni(II)/Ni(0)] = –1.20 V vs. SCE in DMF),19 a two electron reduction of Ni(II) by Ir(II) to give Ni(0) via Ni(I) is a thermodynamically
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favorable process. From Ni(0)•dtbbpy (13), there are two possible ways by which the reaction can proceed. Ni(0)•dtbbpy (13) can
either undergo oxidative addition to the aryl halide9 or it can be trapped by an αꢀamino radical to give Ni(I)ꢀalkyl complex (14).8b,8c,20
The alkyl radical trap of the Ni(0)•dtbbpy (13) to give Ni(I)ꢀalkyl complex (14) appears to occur more rapidly and may also explain why
the reaction proceeded effectively with Ni(COD)2/dtbbpy precatalyst in the presence of O2. The Ni(I)ꢀalkyl complex (14) will then
undergo oxidative addition to aryl halide to give Ni(III)ꢀcomplex (15). The Ni(III)ꢀcomplex (15) will undergo reductive elimination to
deliver the product (ArꢀR) and regenerates the Ni(I)Xꢀcomplex (12), which turnsꢀover the Niꢀcycle.8b,8c,20 An alternate mechanistic
pathway wherein Ni(I)X•dtbbpy (12) is first trapped by an αꢀamino radical to give the corresponding Ni(II)ꢀspecies followed by its SET
reduction by Ir(II) to deliver the Ni(I)ꢀalkyl complex (14) and Ir(III) can not be ruled out.20
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Conclusion:
In conclusion, we have demonstrated the effect of O2 on a variety of Irꢀphotoredox mediated reactions. In order to render the
decarboxylative crossꢀcoupling reactions more practical and reproducible, we studied the effects of O2 on the Irꢀphotoredox and
nickel dualꢀcatalyzed crossꢀcoupling reactions. In our hands, no reaction was observed in the absence of O2 when Ni(II)ꢀprecatalyst
and CFꢀlamp were employed in the decarboxylative crossꢀcoupling reactions in DMF. This observation was attributed to the lack of
formation of an active Ni(I) or Ni(0)ꢀspecies under this reaction condition since reaction occurred with Ni(0)ꢀprecatalyst in the absence
of O2. The SET reduction of Ni(II)ꢀprecatalyst by Ir(II) is a thermodynamically favorable process as demonstrated by control
experiments. However, reaction may not proceed if the reductant Ir(II) is being produced at a rate that is slower than the undesired
ligand exchange reaction between the substrate/reagent and the Ni(II)ꢀprecatalyst, which produces a new Ni(II)ꢀcomplex with a
different reduction potential. Therefore, the presence of O2 in the reaction or the use of blueꢀLEDs for the irradiation can impact the
catalysis by enhancing the photoexcited *Ir(III) ISC process, which leads to a more rapid formation of the reductant Ir(II). Most
importantly, the presence of O2, type of solvent and light used for the Irꢀphotoredox reactions have more of an impact on the catalysis
than the feasibility of electron transfer. Finally, the decarboxylative crossꢀcoupling reaction with Ni(COD)2 precatalyst can be carried
out with high efficiency in the presence of O2. We hope that the new insights presented in this work regarding the effects of O2 and
blueꢀLEDs will enable further exploitation and development of these highly valued photocatalytic carbonꢀcarbon bondꢀforming
reactions for the easy access of pharmacophores in both academic and industrial settings.
Experimental Section:
General Methods. Reagents were purchased from commercial sources and were used as received unless otherwise stated. Irꢀ
complexes (IrꢀA, IrꢀB and IrꢀC) were synthesized following literature procedures.17 Reactions were monitored by reversed phase
UPLCꢀMS. All reactions were performed using borosilicate glass vials of appropriate sizes. 1Hꢀ and 13C{1H} NMR spectra were
recorded on 400 and 500 MHz spectrometers and were internally referenced to residual protio solvent signals (CDCl3 referenced at
1
7.26 and 77.0 ppm respectively, and CO(CD3)2 referenced at 2.05 and 29.9 ppm respectively). Data for H NMR are reported as
follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, b = broad), integration, and
coupling constant (Hz). Data for 13C{1H} NMR are reported in terms of chemical shift and no special nomenclature is used for
equivalent carbons. The HRMS were obtained using a hybrid quadrupole timeꢀofꢀflight mass spectrometer in ESI+ mode.
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[Ir(dF(CF3)ppy)2(bpy)]PF6 (IrꢀA). A mixture of Bisꢀ(µ)ꢀchlorotetrakis(2ꢀ(4,6ꢀdifluoromethylphenyl)ꢀpyridinatoꢀC2,N) diiridium(III)17 (300
4
mg, 0.20 mmol, 1.0 equiv.) and 2,2'ꢀbipyridine (79 mg, 0.50 mmol, 2.5 equiv.) in ethylene glycol (14 mL), was stirred and heated to reflux (150
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º
C) under gentle nitrogen flow for 18 hours. After cooling to room temperature, the mixture was transfered to a separatory funnel with water
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(100 mL) and washed with hexanes (3 x 100 mL). The yellow aqueous bottom phase was drained into an Erlenmeyer flask equipped with a
º
9
magnetic bar and placed in an oilꢀbath which had been preheated to 85 C and stirred at same temperature for 15 minutes. The flask was
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then immersed in an iceꢀbath and 20 mL of aqueous NH4PF6 solution (2.0 g in 20 mL of water) was added to the reaction mixture, producing
a yellowish precipitate. After cooling for 20 minutes in the iceꢀbath, the yellow product was collected by vacuum filtration, washed copiously
with water followed by hexanes and dried under vaccum. IrꢀA was obtained as a bright yellow solid in 389 mg (95% yield) and confirmed pure
by UPLCꢀMS and 1HꢀNMR. 1H NMR (400 MHz, acetoneꢀd6): δ 8.90 (d, J = 8 Hz, 2H), 8.62 (dd, J = 8 Hz, 3 Hz, 2H), 8.41 (m, 4H), 8.31 (d, J =
6 Hz, 2H), 7.97 (s, 2H), 7.81 (t, J = 6 Hz, 2H), 6.86 (ddd, J = 13 Hz, 9 Hz, 2 Hz, 2H), 5.97 (dd, J = 9 Hz, 2 Hz, 2H) ppm; 13C{1H} NMR (100
MHz, acetoneꢀd6): δ 168.7, 166.8, 164.5, 162.1, 156.9, 156.0, 152.5, 147.0, 141.6, 138.2, 130.1, 126.3, 124.9, 124.4, 121.7, 115.4, 100.3
ppm; 19FꢀNMR (282 MHz, acetoneꢀd6): δ 113.9, 106.1, 103.6, 72.8, 72.7, 69.6, 69.5 ppm; HRMS (ESI) m/z calcd for C34H18F10IrN4 [M+]
865.0996, found 865.1033.
[Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (IrꢀB). A mixture of Bisꢀ(µ)ꢀchlorotetrakis(2ꢀ(4,6ꢀdifluoromethylphenyl)ꢀpyridinatoꢀC2,N) diiridium(III)17
(850 mg, 0.57 mmol, 1.0 equiv.) and 4,4'ꢀdiꢀtertꢀbutylꢀ2,2'ꢀbipyridine (337 mg, 1.26 mmol, 2.2 equiv.) in ethylene glycol (40 mL), was stirred
º
and heated to reflux (150 C) under nitrogen for 18 hours. After cooling to room temperature, the mixture was transfered to a separatory
funnel with water (300 mL) and washed with hexanes (3 x 200 mL). The yellow aqueous bottom phase was drained into an Erlenmeyer flask
º
equipped with a magnetic bar and placed in an oilꢀbath, which had been preheated to 85 C and stirred at same temperature for 15 minutes.
The flask was then immersed an iceꢀbath and 20 mL of aqueous NH4PF6 solution (15.0 g in 150 mL of water) was added to the reaction
mixture, producing a yellowish precipitate. After cooling for 20 minutes in the iceꢀbath, the yellow product was collected by vacuum filtration,
washed copiously with water followed by hexanes and dried under vaccum. IrꢀB was obtained as a bright yellow solid in 1.24 g (96% yield)
and confirmed pure by UPLCꢀMS and 1HꢀNMR. 1H NMR (400 MHz, acetoneꢀd6): δ 8.93 (d, J = 8 Hz, 2H), 8.61 (dd, J = 9 Hz, 3 Hz, 2H), 8.40
(dd, J = 9 Hz, 2 Hz, 2H), 8.20 (d, J = 6 Hz, 2H), 7.76 ꢀ 7.86 (m, 4H), 6.89 (ddd, J = 13 Hz, 9 Hz, 2 Hz, 2H), 5.97 (dd, J = 9 Hz, 2 Hz, 2H), 1.43
(s, 18H) ppm; 13C{1H} NMR (100 MHz, acetoneꢀd6): δ 168.9, 166.5, 164.6, 162.2, 157.1, 156.8, 152.1, 146.8, 138.2, 127.9, 127.1, 125.1,
125.0, 123.6, 121.8, 115.6, 115.4, 100.3, 36.7 ppm; 19FꢀNMR (282 MHz, acetoneꢀd6): δ 113.8, 106.1, 103.6, 72.8, 72.7, 69.5, 69.4 ppm;
HRMS (ESI) m/z calcd for C42H34F10IrN4 [M+] 977.2248, found 977.2271. Characterization data for this compound matched that reported in the
literature.17
General Experimental Procedures:
Procedure A: A 20 mL vial was charged with Ir[dF(CF )ppy] (dtbbpy)PF (IrꢀB) (4.5 mg, 4.00 ꢁmol, 0.01 equiv.), NiCl2•glyme (8.76 mg, 0.04
3
2
6
mmol, 0.1 equiv.), 4,4'ꢀdiꢀtertꢀbutylꢀ2,2'ꢀbipyridine (16.1 mg, 0.06 mmol, 0.15 equiv.), 4ꢀbromoacetophenone (2b) (79.6 mg, 0.40 mmol, 1.0
equiv.), Cs2CO3 (195.0 mg, 0.60 mmol, 1.5 equiv.), BocꢀProꢀOH (1) (129.0 mg, 0.60 mmol, 1.5 equiv.), a magnetic stirring bar and DMF (10
mL). The headspace of the reaction mixture was purged with nitrogen for 10 seconds according to Figure S3, sealed, and wrapped with
parafilm. The reaction mixture was then irradiated for 20 hours with a 26 W CFꢀlamp clamped at approximately 2 cm away from the reaction
vial. The reaction mixture was quenched with saturated aqueous NaHCO solution (10 mL), extracted with Et O (3 x 100 mL). The combined
3
2
organic extracts were washed with water (3 x 25 mL), brine (50 mL), dried over anhydrous MgSO and concentrated in vacuo. Purification by
4
flash chromatography on silica gel, eluting with EtOAc and hexanes gradient afforded the desired product.
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Procedure B: A 20 mL vial was charged with Ir[dF(CF )ppy] (dtbbpy)PF (IrꢀB) (4.5 mg, 4.00 ꢁmol, 0.01 equiv.), Ni(COD)2 (11.0 mg, 0.04
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mmol, 0.1 equiv.), 4,4'ꢀdiꢀtertꢀbutylꢀ2,2'ꢀbipyridine (16.1 mg, 0.06 mmol, 0.15 equiv.), 4ꢀbromoacetophenone (2b) (79.6 mg, 0.40 mmol, 1.0
equiv.), Cs2CO3 (195.0 mg, 0.60 mmol, 1.5 equiv.), BocꢀProꢀOH (1) (129.0 mg, 0.60 mmol, 1.5 equiv.), a magnetic stirring bar and DMF (10
mL). The headspace of the reaction mixture was purged with nitrogen for 10 seconds according to Figure S3, sealed, and wrapped with
parafilm (Note: this procedure gave product with similar yield when conducted in the absence of molecular oxygen). The reaction mixture was
then irradiated for 20 hours with a 26 W CFꢀlamp clamped at approximately 2 cm away from the reaction vial. The reaction mixture was
quenched with saturated aqueous NaHCO solution (10 mL), extracted with Et O (3 x 100 mL). The combined organic extracts were washed
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with water (3 x 25 mL), brine (50 mL), dried over anhydrous MgSO and concentrated in vacuo. Purification by flash chromatography on silica
4
gel, eluting with EtOAc and hexanes gradient afforded the desired product.
Procedure C: A 20 mL vial was charged with Ir[dF(CF )ppy] (dtbbpy)PF (IrꢀB) (4.5 mg, 4.00 ꢁmol, 0.01 equiv.), NiCl2•glyme (8.76 mg, 0.04
3
2
6
mmol, 0.1 equiv.), 4,4'ꢀdiꢀtertꢀbutylꢀ2,2'ꢀbipyridine (16.1 mg, 0.06 mmol, 0.15 equiv.), 4ꢀbromoacetophenone (2b) (79.6 mg, 0.40 mmol, 1.0
equiv.), Cs2CO3 (195.0 mg, 0.60 mmol, 1.5 equiv.), BocꢀProꢀOH (1) (129.0 mg, 0.60 mmol, 1.5 equiv.), a magnetic stirring bar and
MeCN:DMF (8 mL:2mL). The headspace of the reaction mixture was purged with nitrogen for 10 seconds according to Figure S3, sealed, and
wrapped with parafilm (Note: this procedure gave product in good yield when conducted in the absence of molecular oxygen). The reaction
mixture was then irradiated for 20 hours with a 26 W CFꢀlamp clamped at approximately 2 cm away from the reaction vial. The reaction
mixture was quenched with saturated aqueous NaHCO solution (10 mL), extracted with Et O (3 x 100 mL). The combined organic extracts
3
2
were washed with water (3 x 25 mL), brine (50 mL), dried over anhydrous MgSO and concentrated in vacuo. Purification by flash
4
chromatography on silica gel, eluting with EtOAc and hexanes gradient afforded the desired product.
Procedure D: A 40 mL vial was charged with Ir[dF(CF )ppy] (dtbbpy)PF (IrꢀB) (4.5 mg, 4.00 ꢁmol, 0.01 equiv.), NiCl2•glyme (8.76 mg, 0.04
3
2
6
mmol, 0.1 equiv.), 4,4'ꢀdiꢀtertꢀbutylꢀ2,2'ꢀbipyridine (16.1 mg, 0.06 mmol, 0.15 equiv.), 4ꢀbromoacetophenone (2b) (79.6 mg, 0.40 mmol, 1.0
equiv), Cs2CO3 (195.0 mg, 0.60 mmol, 1.5 equiv), BocꢀProꢀOH (1) (129 mg, 0.60 mmol, 1.5 equiv.), a magnetic stirring bar and DMF (10 mL).
The reaction mixture was degassed either by sparging with nitrogen/argon stream for 20 ꢀ 30 minutes according to Figure S1 or by freezeꢀ
pumpꢀthaw technique according to Figure S2 (note: reaction proceeded with high efficiency without degassing, hence degassing is
unnecessary and a simple headspace purge is sufficient). The reaction mixture was then irradiated for 5 ꢀ 20 hours with 34 W BlueꢀLEDs as
shown in Figure S5. The reaction mixture was quenched with saturated aqueous NaHCO solution (10 mL), and extracted with Et O (3 x 100
3
2
mL). The combined organic extracts were washed with water (3 x 25 mL), brine (50 mL), dried over anhydrous MgSO and concentrated in
4
vacuo. Purification by flash chromatography on silica gel, eluting with EtOAc and hexanes gradient afforded the desired product.
tertꢀButyl 2ꢀ(pꢀtolyl)pyrrolidineꢀ1ꢀcarboxylate (3a). A 20 mL vial was charged with Ir[dF(CF )ppy] (dtbbpy)PF (IrꢀB) (4.5 mg, 4.00
3
2
6
ꢁmol, 0.01 equiv.), NiCl2•glyme (8.76 mg, 0.04 mmol, 0.1 equiv.), 4,4'ꢀdiꢀtertꢀbutylꢀ2,2'ꢀbipyridine (16.1 mg, 0.06 mmol, 0.15 equiv.), 4ꢀ
iodotoluene (2a) (89.0 mg, 0.40 mmol, 1.0 equiv.), Cs2CO3 (195.0 mg, 0.60 mmol, 1.5 equiv.), BocꢀProꢀOH (1) (129.0 mg, 0.60 mmol, 1.5
equiv.), a magnetic stirring bar and DMF (10 mL). The headspace of the reaction mixture was purged with nitrogen for 10 seconds according
to Figure S3, sealed, and wrapped with parafilm. The reaction mixture was then irradiated for 20 hours with a 26 W CFꢀlamp clamped at
approximately 2 cm away from the reaction vial. The reaction mixture was then quenched with saturated aqueous NaHCO solution (10 mL),
3
extracted with Et O (3 x 100 mL). The combined organic extracts were washed with water (3 x 25 mL), brine (50 mL), dried over anhydrous
2
MgSO and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 15% EtOAc and 85% hexanes gave 3a as
4
1
a colorless oil (89 mg, 85%). H NMR (400 MHz, CDCl3) rotameric mixture: δ 7.10 ꢀ 7.03 (m, 4H), 4.79 (br, 1H), 3.60 ꢀ 3.52 (m, 2H), 2.33 ꢀ
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2.25 (m, 4H), 1.91 ꢀ 1.79 (m, 3H), 1.24 (s, 9H) ppm; 13C{1H} NMR (125 MHz, CDCl3) rotameric mixture, resonances for minor rotamer are
enclosed in parenthesis: δ 154.7, 142.1 (141.1), 135.9, (129.0) 128.8, 125.4, 79.1, 61.0 (60.5), (47.3) 47.0, 36.0 (34.9), (28.6) 28.2, (23.4)
23.1, 21.0 ppm; HRMS (ESI) m/z calcd for C16H24NO2 [(M+H)+] 262.1802, found 262.1809. Characterization data matched that reported in the
literature.9a
tertꢀButyl 2ꢀ(4ꢀacetylphenyl)pyrrolidineꢀ1ꢀcarboxylate (3b). A 20 mL vial was charged with Ir[dF(CF )ppy] (dtbbpy)PF (IrꢀB) (4.5 mg,
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4.00 ꢁmol, 0.01 equiv.), NiCl2•glyme (8.76 mg, 0.04 mmol, 0.1 equiv.), 4,4'ꢀdiꢀtertꢀbutylꢀ2,2'ꢀbipyridine (16.1 mg, 0.06 mmol, 0.15 equiv.), 4ꢀ
bromoacetophenone (2b) (79.6 mg, 0.40 mmol, 1.0 equiv.), Cs2CO3 (195.0 mg, 0.60 mmol, 1.5 equiv.), BocꢀProꢀOH (1) (129.0 mg, 0.60 mmol,
1.5 equiv.), a magnetic stirring bar and DMF (10 mL). The headspace of the reaction mixture was purged with nitrogen for 10 seconds
according to Figure S3, sealed, and wrapped with parafilm. The reaction mixture was then irradiated for 20 hours with a 26 W CFꢀlamp
clamped at approximately 2 cm away from the reaction vial. The reaction mixture was then quenched with saturated aqueous NaHCO
3
solution (10 mL), extracted with Et O (3 x 100 mL). The combined organic extracts were washed with water (3 x 25 mL), brine (50 mL), dried
2
over anhydrous MgSO and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 20% EtOAc and 80%
4
hexanes gradient gave 3b as a colorless oil (110 mg, 95%). 1H NMR (400 MHz, CDCl3) rotameric mixture: δ 7.91 (d, J = 8.0 Hz, 2H), 7.27 (d,
J = 8.0 Hz, 2H), 4.97 and 4.82 (2 brs, 1H, rotamer), 3.70 ꢀ 3.51 (m, 2H), 2.60 (s, 3H), 2.38 ꢀ 2.32 (m, 1H), 1.94 ꢀ 1.76 (m, 3H), 1.46 (s, 3H),
1.19 (s, 6H) ppm; 13C{1H} NMR (100 MHz, CDCl3) rotameric mixture, resonances for minor rotamer are enclosed in parenthesis: δ 197.7,
154.4, 150.8 (149.8), 135.7, 128.4, 125.6, 79.5, 61.1 (60.7), 47.1, 35.9 (34.8), (28.4) 28.2, 26.6, (23.6) 23.3 ppm; HRMS (ESI) m/z calcd for
C17H24NO3 [(M+H)+] 290.1751, found 290.1759. Characterization data matched that reported in the literature.9a
Dimethyl 2ꢀ(1ꢀ(1ꢀ(tertꢀbutoxycarbonyl)pyrrolidinꢀ2ꢀyl)ethyl)malonate (5). Into
a
10 mL glass vial was added
Ir[dF(CF3)ppy)]2(dtbbpy)PF6 (IrꢀB) (11.2 mg, 10.0 ꢁmol, 0.01 equiv.), BocꢀProꢀOH (1) (215 mg, 1.00 mmol, 1.0 equiv.), dimethyl
ethylidenemalonate (4) (158 mg, 1.00 mmol, 1.0 equiv.), K2HPO4 (209 mg, 1.20 mmol, 1.2 equiv.), and 2.5 mL of DMF. The reaction mixture
was degassed by freezeꢀpumpꢀthaw technique according to Figure S2. The mixture was then irradiated for 20 hours with a 26 W fluorescent
lamp clamped at approximately 2 cm away from the reaction vial. The reaction mixture was then quenched with saturated aqueous NaHCO
3
solution (5 mL), extracted with Et O (3 x 50 mL). The combined organic extracts was washed with water (30 mL), brine (30 mL), dried over
2
anhydrous MgSO and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 20% EtOAc and 80% hexanes
4
gradient gave 5 as a pale yellow oil (231 mg, 70%). 1H NMR (400 MHz, CDCl3) mixture of diastereomers (1:1) and rotamers, hence see
spectra below: δ 3.98 ꢀ 3.80 (m, 0.38H), 3.73 ꢀ 3.71 (s,s,s, 6H), 3.67 ꢀ 3.27 (m, 2H), 3.16 – 3.00 (m, 1H), 2.86 ꢀ 2.77 (m, 0.53H), 2.75 – 2.60
(br, 0.21H), 2.59 – 2.50 (br, 0.18H), 2.01 – 1.90 (m, 0.78H), 1.88 – 1.63 (m, 3H), 1.48 (s, 9H), 1.38 (d, J = 6 Hz, 3H) ppm; 13 {1H} NMR (100
C
MHz, CDCl3) mixture of diastereomers and rotamers: δ 168.9, 168.5, 155.0, 154.6, 79.6, 79.0, 77.3, 77.2, 77.0, 76.7, 61.0, 60.5, 60.1, 55.0,
54.2, 53.7, 52.2, 52.1, 52.0, 47.6, 47.1, 46.6, 37.8, 37.1, 36.9, 36.7, 28.4, 28.2, 24.1, 23.4, 23.0, 14.5, 14.2, 13.9, 13.6 ppm; HRMS (ESI) m/z
calcd for C16H28NO6 [(M+H)+] 330.1911, found 330.1906.
tertꢀButyl 2ꢀ(4ꢀcyanophenyl)pyrrolidineꢀ1ꢀcarboxylate (7). A 40 mL vial was charged with Ir(dFppy)3 (IrꢀD) (6.19 mg, 8.12 µmol,
0.02 equiv.), CsF (185 mg, 1.22 mmol, 3.0 equiv.), terephthalonitrile (6) (52 mg, 0.41 mmol, 1.0 equiv.), BocꢀProꢀOH (1) (264 mg, 1.22 mmol,
3.0 equiv.) and anhydrous DMSO (20 mL). The reaction mixture was degassed by freezeꢀpumpꢀthaw technique according to Figure S2. The
mixture was then irradiated for 20 hours with a 26 W fluorescent lamp clamped at approximately 2 cm away from the reaction vial. Afterwhich,
the reaction mixture was diluted with saturated aqueous NaHCO solution (10 mL), extracted with Et O (3 x 100 mL). The combined organic
3
2
extracts were washed with water (3 x 25 mL), brine (50 mL), dried over anhydrous MgSO and concentrated in vacuo. Purification by flash
4
1
chromatography on silica gel, eluting with 15% EtOAc and 85% hexanes solvent gradient gave 7 as a colorless oil (67 mg, 60%). H NMR
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(400 MHz, CDCl3) δ 7.61 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 4.94, 4.78 (2 brs, 1H, rotamer), 3.64 ꢀ 3.60 (m, 2H), 2.38 ꢀ 2.36 (m, 1H),
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6
7
8
9
1.89 ꢀ 1.87 (m, 2H), 1.77 ꢀ 1.75 (m, 1H), 1.45 (s, 4H), 1.17 (s, 5H) ppm; 13 {1H} NMR (125 MHz, CDCl3) δ 154.2, 150.9, (149.7), 132.1, 126.2,
C
118.9, 110.4, 79.7, 61.3 (60.6), 47.6, 35.9, (34.7), (28.4), 28.1 (23.6), 23.2 ppm; HRMS (ESI) m/z calcd for C16N2O2H21 [(M+H)+] 273.1598,
found 273.1597. Characterization data matched that reported in the literature.12b
By Ir/Niꢀdualꢀcatalysis: A 20 mL vial was charged with Ir[dF(CF )ppy] (dtbbpy)PF (IrꢀB) (4.5 mg, 4.00 ꢁmol, 0.01 equiv.), NiCl2•glyme
3
2
6
10
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(8.76 mg, 0.04 mmol, 0.1 equiv.), 4,4'ꢀdiꢀtertꢀbutylꢀ2,2'ꢀbipyridine (16.1 mg, 0.06 mmol, 0.15 equiv.), 4ꢀbromobenzonitrile (9) (72.8 mg, 0.40
mmol, 1.0 equiv.), Cs2CO3 (195.0 mg, 0.60 mmol, 1.5 equiv.), BocꢀProꢀOH (1) (129.0 mg, 0.60 mmol, 1.5 equiv.), a magnetic stirring bar and
DMF (10 mL). The headspace of the reaction mixture was purged with nitrogen for 10 seconds according to Figure S3, sealed, and wrapped
with parafilm. The reaction mixture was then irradiated for 20 hours with a 26 W CFꢀlamp clamped at approximately 2 cm away from the
reaction vial. The reaction mixture was then quenched with saturated aqueous NaHCO solution (10 mL), extracted with Et O (3 x 100 mL).
3
2
The combined organic extracts were washed with water (3 x 25 mL), brine (50 mL), dried over anhydrous MgSO and concentrated in vacuo.
4
Purification by flash chromatography on silica gel, eluting with 25% EtOAc and 75% hexanes solvent gradient gave 7 as a colorless oil (104.6
mg, 96%).
4ꢀBenzylbenzonitrile (10). A 10 mL vial inside a nitrogenꢀfilled gloveꢀbox was charged with Ni(COD)2 (4.13 mg, 0.015 mmol, 0.03
equiv.), 4,4'ꢀdiꢀtertꢀbutylꢀ2,2'ꢀbipyridine (4.03 mg, 0.015 mmol, 0.03 equiv.), [Ir(dF(CF3)ppy)2(bpy)]PF6 (IrꢀA) (10.10 mg, 10.00 µmol, 0.02
equiv.), 4ꢀbromobenzonitrile (9) (91.0 mg, 0.50 mmol, 1.0 equiv.), BnBF3K (8) (119.0 mg, 0.60 mmol, 1.2 equiv.), a magnetic stirrer, 4.75 mL
of acetone, 0.25 mL of MeOH and 2,6ꢀdimethylpyridine (202 ꢁL, 1.75 mmol, 3.5 equiv). The vial was sealed, wrapped with parafilm and black
tape then removed from the gloveꢀbox. The reaction mixture was then irradiated for 24 hours with one 26 W fluorescent lamp clamped at
approximately 2 cm away from the reaction vial. UPLCꢀMS and 1HꢀNMR analysis of the crude reaction after 24 hours showed 95% conversion
to product. The crude mixture was filtered through a plug of celite, washed with EtOAc, concentrated in vacuo then purified by flash
1
chromatography on silica gel, eluting with 20% EtOAc and 80% hexanes gradient to give 10 as a colorless oil (88 mg, 91%). H NMR (400
MHz, CDCl3): δ 7.58 (d, J = 8.0 Hz, 2H), 7.25 ꢀ 7.34 (m, 5H), 7.17 (d, J = 8.0 Hz, 2H), 4.04 (s, 2H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ
146.7, 139.3. 132.2, 129.6, 128.9, 128.7, 126.6, 118.9, 110.1, 41.9 ppm; HRMS (ESI) m/z calcd for C14NH12 [(M+H)+] 194.0964, found
194.0958. Characterization data matched that reported in the literature.8a
Procedures for 4ꢀBenzylbenzonitrile (10) in Scheme 3B: With NiCl2•glyme: A 10 mL vial was charged with NiCl2•glyme (6.60 mg,
0.03 mmol, 0.06 equiv), 4,4'ꢀdiꢀtertꢀbutylꢀ2,2'ꢀbipyridine (9.7 mg, 0.04 mmol, 0.072 equiv.), [Ir(dF(CF3)ppy)2(bpy)]PF6 (IrꢀA) (10.0 mg, 10.00
µmol, 0.02 equiv.), 4ꢀbromobenzonitrile (9) (91.0 mg, 0.50 mmol, 1.0 equiv.), BnBF3K (8) (149.0 mg, 0.75 mmol, 1.5 equiv.), a magnetic stirrer,
and DMF (5 mL) was added. The vial was sealed, wrapped with parafilm and sparged with nitrogen for 20 minutes according to Figure S1.
The vial was again wrapped twice with parafilm and white tapes to prevent any airꢀleak into the reaction during irradiation. The reaction
mixture was then irradiated for 24 hours with a 26 W CFꢀlamp clamped at approximately 2 cm away from the reaction vial. UPLCꢀMS analysis
before work up and 1HꢀNMR analysis of the crude reaction after work up both showed 43% conversion to product (10).
With Ni(COD)2: A 10 mL vial was charged with [Ir(dF(CF3)ppy)2(bpy)]PF6 (IrꢀA) (10.1 mg, 10.00 µmol, 0.02 equiv.), 4ꢀbromobenzonitrile
(9) (91.0 mg, 0.50 mmol, 1.0 equiv.), BnBF3K (8) (149.0 mg, 0.75 mmol, 1.5 equiv.), a magnetic stirrer, and DMF (5 mL). The vial was sealed,
wrapped with parafilm and sparged with nitrogen for 15 minutes according to Figure S1. Then a mixture of Ni(COD)2 (8.25 mg, 0.03 mmol,
0.060 equiv.), and 4,4'ꢀdiꢀtertꢀbutylꢀ2,2'ꢀbipyridine (9.7 mg, 0.04 mmol, 0.072 equiv.) were added under argon atmosphere in one shot. The
vial was sealed, wrapped with parafilm and sparged for with nitrogen for another 10 minutes according to Figure S1. The vial was again
wrapped twice with parafilm and white tapes to prevent any airꢀleak into the reaction during irradiation. The reaction mixture was then
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irradiated for 24 hours with a 26 W CFꢀlamp clamped at approximately 2 cm away from the reaction vial. UPLCꢀMS analysis before work up
and 1HꢀNMR analysis of the crude reaction after work up both showed 49% conversion to product (10).
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tertꢀButyl 2ꢀ(4ꢀmethoxyphenyl)pyrrolidineꢀ1ꢀcarboxylate (17b): According to the general procedure A, Ir[dF(CF3)ppy]2(dtbbpy)PF6
(IrꢀB) (4.5 mg, 4.0 ꢁmol, 0.01 equiv), NiCl2•glyme (8.8 mg, 0.04 mmol, 0.10 equiv.), 4,4'ꢀdiꢀtertꢀbutylꢀ2,2'ꢀbipyridine (16.1 mg, 0.06 mmol, 0.15
equiv.), 4ꢀiodoanisole (96.0 mg, 0.40 mmol, 1.0 equiv.), BocꢀProꢀOH (1) (129.0 mg, 0.60 mmol, 1.5 equiv.), Cs2CO3 (195.6 mg, 0.60 mmol,
1.5 equiv.), and 10 mL of DMF were used. Purification by flash chromatography on silica gel, eluting with 15% EtOAc and 85% hexanes
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10
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1
gradient gave 17b as a colorless oil (83 mg, 75%). H NMR (400 MHz, CDCl3) rotameric mixture: δ 7.09 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 8.0
Hz, 2H), 4.90 and 4.74 (2 brs, 1H, rotamer), 3.80 (s, 3H), 3.61 ꢀ 3.51 (m, 2H), 2.28 (br, 1H), 1.92 ꢀ 1.78 (m, 3H), 1.47 (s, 3H), 1.21 (s, 6H)
ppm; 13C{1H} NMR (125 MHz, CDCl3) rotameric mixture, resonances for minor rotamer are enclosed in parenthesis: δ 158.3, 154.7, 137.3,
126.6, (113.8) 113.5, 79.1, 60.7 (60.1), 55.3, (47.3) 47.0, 36.1 (34.9), 30.6, (28.5), (23.5) 23.2 ppm; HRMS (ESI) m/z calcd for C16H24NO3
[(M+H)+] 278.1751, found 278.1764. Characterization data matched that reported in the literature.9a
tertꢀButyl 2ꢀ(4ꢀ(methoxycarbonyl)phenyl)pyrrolidineꢀ1ꢀcarboxylate (17c): According to the general procedure A,
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (IrꢀB) (4.5 mg, 4.0 ꢁmol, 0.01 equiv.), NiCl2•glyme (8.8 mg, 0.04 mmol, 0.1 equiv.), 4,4'ꢀdiꢀtertꢀbutylꢀ2,2'ꢀbipyridine
(16.1 mg, 0.06 mmol, 0.15 equiv.), methylꢀ4ꢀiodobenzoate (88.0 mg, 0.40 mmol, 1.0 equiv.), BocꢀProꢀOH (1) (129.0 mg, 0.60 mmol, 1.5
equiv.), Cs2CO3 (195.6 mg, 0.60 mmol, 1.5 equiv.), and 10 mL of DMF were used. Purification by flash chromatography on silica gel, eluting
1
with 25% EtOAc and 75% hexanes gradient gave 17c as a colorless oil (102.6 mg, 84%). H NMR (400 MHz, CDCl3) rotameric mixture: δ
7.97 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 4.97 and 4.80 (2 brs, 1H, rotamer), 3.92 (s, 3H), 3.65 ꢀ 3.52 (m, 2H), 2.37 ꢀ 2.31 (m, 1H),
1.92 ꢀ 1.77 (m, 3H), 1.47 (s, 3H), 1.16 (s, 6H) ppm; 13C{1H} NMR (125 MHz, CDCl3) rotameric mixture, resonances for minor rotamer are
enclosed in parenthesis: δ 166.9, 154.4, 150.6 (149.5), (129.8) 129.6, 128.5, 125.5, 79.5 (65.8), 61.2 (60.6), 51.9, (47.4) 47.1, 35.9 (34.7),
(29.8), (28.4) 28.1, (23.6) 23.3 ppm; HRMS (ESI) m/z calcd for C17H24NO4 [(M+H)+] 306.1700, found 306.1708. Characterization data
matched that reported in the literature.9a
tertꢀButyl
2ꢀ(4ꢀcyanoꢀ3ꢀfluorophenyl)pyrrolidineꢀ1ꢀcarboxylate
(17d):
According
to
the
general
procedure
A,
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (IrꢀB) (4.5 mg, 4.0 ꢁmol, 0.01 equiv.), NiCl2•glyme (8.8 mg, 0.04 mmol, 0.1 equiv.), 4,4'ꢀdiꢀtertꢀbutylꢀ2,2'ꢀbipyridine
(16.1 mg, 0.06 mmol, 0.15 equiv.), 4ꢀbromoꢀ2ꢀfluorobenzonitrile (82.0 mg, 0.40 mmol, 1.0 equiv.), BocꢀProꢀOH (1) (129.0 mg, 0.60 mmol, 1.5
equiv.), Cs2CO3 (195.6 mg, 0.6 mmol, 1.5 equiv.), and 10 mL of DMF were used. Purification by flash chromatography on silica gel, eluting
with 30% EtOAc and 70% hexanes solvent gradient gave 17d as a colorless oil (112.6 mg, 97%). 1H NMR (400 MHz, CDCl3) rotameric
mixture: δ 7.57 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 4.93 and 4.79 (2 brs, 1H, rotamer), 3.66 ꢀ 3.55 (m, 2H),
2.40 ꢀ 2.32 (m, 1H), 1.93 ꢀ 1.87 (m, 2H), 1.82 ꢀ 1.75 (m, 1H), 1.46 (s, 4H), 1.22 (s, 5H) ppm; 13C{1H} NMR (125 MHz, CDCl3) rotameric
mixture, resonances for minor rotamer are enclosed in parenthesis: δ (164.4) 162.3, (154.5) 154.37, 154.4 (153.5), 134.4, (133.5) 133.4,
121.9, (114.1) 114.0, 113.4 (99.4), (80.0), 79.9 (65.8), 60.9 (60.5), (47.5) 47.2, 35.8 (34.6), (28.4) 28.1, (23.7) 23.3 ppm; 19FꢀNMR (282 MHz,
CDCl3): δ ꢀ106.6 ppm; HRMS (ESI) m/z calcd for C16H20FN2O2 [(M+H)+] 291.1503, found 291.1522. Characterization data matched that
reported in the literature.9a
tertꢀButyl 2ꢀ(3,5ꢀbis(trifluoromethyl)phenyl)pyrrolidineꢀ1ꢀcarboxylate (17e): According to the general procedure A,
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (IrꢀB) (4.5 mg, 4.0 ꢁmol, 0.01 equiv.), NiCl2•glyme (8.8 mg, 0.04 mmol, 0.1 equiv.), 4,4'ꢀdiꢀtertꢀbutylꢀ2,2'ꢀbipyridine
(16.1 mg, 0.06 mmol, 0.15 equiv.), 1,3ꢀbis(trifluoromethyl)ꢀ5ꢀbromobenzene (118.0 mg, 0.40 mmol, 1.0 equiv.), BocꢀProꢀOH (1) (129.0 mg,
0.60 mmol, 1.5 equiv.), Cs2CO3 (195.6 mg, 0.60 mmol, 1.5 equiv.), and 10 mL of DMF were used. Purification by flash chromatography on
silica gel, eluting with 30% EtOAc and 70% hexanes solvent gradient gave 17e as a colorless oil (141 mg, 92%). 1H NMR (400 MHz, CDCl3)
rotameric mixture: δ 7.76 (s, 1H), 7.63 (s, 2H), 5.01 and 4.84 (2 brs, 1H, rotamer), 3.69 ꢀ 3.54 (m, 2H), 2.44 ꢀ 2.40 (m, 1H), 1.94 ꢀ 1.83 (m, 3H),
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1.46 (s, 3H), 1.16 (s, 6H) ppm; 13
C
{1H} NMR (125 MHz, CDCl3) rotameric mixture, resonances for minor rotamer are enclosed in parenthesis:
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5
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7
8
9
δ (158.2), (154.5) 154.2, 147.9 (146.8), 131.6 (q, J = 33.8 Hz), 125.9 (125.6), 123.3 (q, J = 271.3 Hz), (120.7) 120.6, (80.1) 80.0, 60.9 (60.3),
(47.4) 47.3, 36.1 (34.8), (28.3) 27.9, 23.5 (22.7) ppm; 19FꢀNMR (282 MHz, CDCl3): δ ꢀ62.9 ppm; HRMS (ESI) m/z calcd for C17NO2F6H20
[(M+H)+] 384.1393, found 384.1411. Characterization data matched that reported in the literature.9a
tertꢀButyl
2ꢀ(benzo[β]thiophenꢀ3ꢀyl)pyrrolidineꢀ1ꢀcarboxylate
(17f):
According
to
the
general
procedure
A,
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Ir[dF(CF3)ppy]2(dtbbpy)PF6 (IrꢀB) (4.5 mg, 4.0 ꢁmol, 0.01 equiv.), NiCl2•glyme (8.8 mg, 0.04 mmol, 0.1 equiv.), 4,4'ꢀdiꢀtertꢀbutylꢀ2,2'ꢀbipyridine
(16.1 mg, 0.06 mmol, 0.15 equiv.), 3ꢀbromobenzo[β]thiophene (85 mg, 0.40 mmol, 1.0 equiv.), BocꢀProꢀOH (1) (129.0 mg, 0.60 mmol, 1.5
equiv.), Cs2CO3 (195.6 mg, 0.60 mmol, 1.5 equiv.), and 10 mL of DMF were used. Purification by flash chromatography on silica gel, eluting
with 20% EtOAc and 80% hexanes solvent gradient gave 17f as a pale yellow oil (94 mg, 78%). Note: This compound contains inseparable
NꢀBocꢀpyrrolidine sideꢀproduct (see the 1HꢀNMR spectrum). 1H NMR (400 MHz, CDCl3) rotameric mixture: δ 7.77 (d, J = 8.0 Hz, 1H), 7.68 (d,
J = 8.0 Hz, 1H), 7.37 – 7.27 (m, 2H), 7.07 (br, s, 1H), 5.16 and 5.27 (2 brs, 1H, rotamer), 3.63 – 3.45 (m, 1H), 3.37 – 3.28 (m, 1H), 2.39 –
2.23 (m, 1H), 2.14 – 2.02 (m, 1H), 2.00 – 1.88 (m, 2H), 1.47 (s, 9H) ppm; 13 {1H} NMR (125 MHz, CDCl3) rotameric mixture, resonances for
C
minor rotamer are enclosed in parenthesis: δ (154.65) 154.4, 149.7 (149.1), 139.7, 138.9, 124.1, 123.6, 123.0, 122.2, (119.5) 119.3, 79.7
(78.0), 57.4 (57.0), (46.7) 46.3, 35.2 (34.2), (30.4), 28.5 (28.3), (23.9) 23.2 ppm; HRMS (ESI) m/z calcd for C17H22NO2S [(M+H)+] 304.1366,
found 304.1381.
tertꢀButyl 2ꢀ(4ꢀ(trifluoromethyl)pyridinꢀ2ꢀyl)pyrrolidineꢀ1ꢀcarboxylate (17g): According to the general procedure A,
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (IrꢀB) (4.5 mg, 4.0 ꢁmol, 0.01 equiv.), NiCl2•glyme (8.8 mg, 0.04 mmol, 0.1 equiv.), 4,4'ꢀdiꢀtertꢀbutylꢀ2,2'ꢀbipyridine
(16.1 mg, 0.06 mmol, 0.15 equiv.), 2ꢀchloroꢀ4ꢀ(trifluoromethyl)pyridine (72.6 mg, 0.40 mmol, 1.0 equiv.), BocꢀProꢀOH (1) (129.0 mg, 0.60
mmol, 1.5 equiv.), Cs2CO3 (195.6 mg, 0.60 mmol, 1.5 equiv.), and 10 mL of DMF were used. Purification by flash chromatography on silica
gel, eluting with 30% EtOAc and 70% hexanes solvent gradient gave 17g as a pale yellow oil (114 mg, 90%). 1H NMR (400 MHz, CDCl3)
rotameric mixture: δ 8.73 (d, J = 8.0 Hz, 1 H), 7.34 ꢀ 7.19 (br, s, 2H), 5.06 and 4.92 (2 brs, 1H, rotamer), 3.71 ꢀ 3.62 (m, 2H), 2.52 ꢀ 2.28 (m,
2H), 2.09 ꢀ 1.96 (m, 2H), 1.47 (s, 3H), 1.20 (s, 6H) ppm; 13 {1H} NMR (125 MHz, CDCl3) rotameric mixture, resonances for minor rotamer are
C
enclosed in parenthesis: δ 165.5 (164.5), (154.6) 154.3, (150.2) 150.1, 138.6, 122.5, (117.3) 117.1, 115.7, (79.7) 79.7, 62.7 (62.1), (47.4) 47.2,
34.2 (33.0), 29.7, 28.4, 28.0, (23.8) 23.4 ppm; 19FꢀNMR (282 MHz, CDCl3): δ ꢀ64.9 ppm; HRMS (ESI) m/z calcd for C15H20F3N2O2 [(M+H)+]
317.1471, found 317.1459.
tertꢀButyl 2ꢀ(4ꢀacetylphenyl)piperidineꢀ1ꢀcarboxylate (19a): According to the general procedure D with headspace purge,
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (IrꢀB) (4.5 mg, 4.0 ꢁmol, 0.01 equiv.), NiCl2•glyme (8.8 mg, 0.04 mmol, 0.1 equiv.), 4,4'ꢀdiꢀtertꢀbutylꢀ2,2'ꢀbipyridine
(16.1 mg, 0.06 mmol, 0.15 equiv.), 4ꢀbromoacetophenone (79.6 mg, 0.40 mmol, 1.0 equiv.), BocꢀPipꢀOH (18a) (138 mg, 0.60 mmol, 1.5
equiv.), Cs2CO3 (195 mg, 0.6 mmol, 1.5 equiv.), and 10 mL of DMF were used. The mixture was irradiated for 20 hours with 34 W blue LED
lights and fanned to reduce the temperature from the heat generated as shown in Figure S5. Purification by flash chromatography on silica
gel, eluting with 20% EtOAc and 80% hexanes solvent gradient gave 19a as a colorless oil (97 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 7.95
(d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 5.44 (s, 1H), 4.08 (d, J = 12.0 Hz, 1H), 2.76 (td, J = 12.0 Hz, J = 3.5 Hz, 1H), 2.61 (s, 3H), 2.32 ꢀ
2.29 (m, 1H), 1.96 ꢀ 1.89 (m, 1H), 1.65 ꢀ 1.52 (m, 3H), 1.47 (s, 9H), 1.39 ꢀ 1.33 (m, 1H) ppm; 13 {1H} NMR (125 MHz, CDCl3) δ 197.5, 155.4,
C
146.3, 135.3, 128.5, 126.5, 79.7, 53.3, 40.2, 28.3, 28.3, 26.5, 25.1, 19.2 ppm; HRMS (ESI) m/z calcd for C18NO3H26 [(M+H)+] 304.1907, found
304.1917. Characterization data matched that reported in the literature.9a
tert-butyl 3ꢀ(4ꢀacetylphenyl)morpholineꢀ4ꢀcarboxylate (19b): According to the general procedure D with headspace purge,
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (IrꢀB) (4.5 mg, 4.0 ꢁmol, 0.01 equiv.), NiCl2•glyme (8.8 mg, 0.04 mmol, 0.1 equiv.), 4,4'ꢀdiꢀtertꢀbutylꢀ2,2'ꢀbipyridine
(16.1 mg, 0.06 mmol, 0.15 equiv.), 4ꢀbromoacetophenone (79.6 mg, 0.40 mmol, 1.0 equiv.), BocꢀMorphꢀOH (18b) (139 mg, 0.60 mmol, 1.5
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equiv.), Cs2CO3 (195 mg, 0.60 mmol, 1.5 equiv.), and 10 mL of DMF were used. The mixture was irradiated for 20 hours with 34 W blue LED
lights and fanned to reduce the temperature from the heat generated as shown in Figure S5. Purification by flash chromatography on silica
gel, eluting with 20% EtOAc and 80% hexanes solvent gradient gave 19b as a colorless oil (86 mg, 70%). 1H NMR (400 MHz, CDCl3): δ 7.95
(d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 5.12 (br, 1H), 4.35 (d, J = 7.0 Hz, 1H), 3.91 ꢀ 3.87 (m, 2H), 3.83 ꢀ 3.80 (m, 1H), 3.61 (td, J = 12.0
Hz, J = 3.5 Hz, 1H), 3.11 (td, J = 12.0 Hz, J = 3.5 Hz, 1H), 2.60 (s, 3H), 1.47 (s, 9H) ppm; 13C{1H} NMR (125 MHz, CDCl3): δ 197.7, 154.8,
144.9, 136.0, 128.5, 127.8, 80.6, 68.9, 66.9, 53.3, 39.9, 28.4, 26.6 ppm; HRMS (ESI) m/z calcd for C17NO4H24 [(M+H)+] 306.1700, found
306.1714. Characterization data matched that reported in the literature.9a
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1ꢀ(4ꢀ(Tetrahydrofuranꢀ2ꢀyl)phenyl)ethanꢀ1ꢀone (19c): According to the general procedure
D
with headspace purge,
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (IrꢀB) (4.5 mg, 4.0 ꢁmol, 0.01 equiv.), NiCl2•glyme (8.8 mg, 0.04 mmol, 0.1 equiv.), 4,4'ꢀdiꢀtertꢀbutylꢀ2,2'ꢀbipyridine
(16.1 mg, 0.06 mmol, 0.15 equiv.), 4ꢀbromoacetophenone (79.6 mg, 0.40 mmol, 1.0 equiv.), tetrahydroꢀ2ꢀfuroic acid (18c) (69.7 mg, 0.60
mmol, 1.5 equiv.), Cs2CO3 (195 mg, 0.60 mmol, 1.5 equiv.), and 10 mL of DMF were used. The mixture was irradiated for 20 hours with 34 W
blue LED lights and fanned to reduce the temperature from the heat generated as shown in Figure S5. Purification by flash chromatography
on silica gel, eluting with 20% EtOAc and 80% hexanes solvent gradient gave 19c as a colorless oil (74 mg, 97%). 1H NMR (400 MHz,
CDCl3): δ 7.93 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 4.95 (t, J = 8.0 Hz, 1H), 4.11 (q, J = 8.0 Hz, 1H), 3.97 (q, J = 8.0 Hz, 1H), 2.60 (s,
3H), 2.40 ꢀ 2.34 (m, 1H), 2.04 ꢀ 1.99 (m, 2H), 1.81 ꢀ 1.74 (m, 1H) ppm; 13 {1H} NMR (125 MHz, CDCl3): δ 197.7, 149.2, 136.0, 128.4, 125.6,
C
80.1, 68.8, 34.7, 26.6, 25.9 ppm; HRMS (ESI) m/z calcd for C12H15O2 [(M+H)+] 191.1067, found 191.1048. Characterization data matched that
reported in the literature.9a
4ꢀ(Tetrahydrofuranꢀ2ꢀyl)benzonitrile (19d): According to the general procedure D with headspace purge, Ir[dF(CF3)ppy]2(dtbbpy)PF6
(IrꢀB) (4.5 mg, 4.0 ꢁmol, 0.01 equiv.), NiCl2•glyme (8.8 mg, 0.04 mmol, 0.1 equiv.), 4,4'ꢀdiꢀtertꢀbutylꢀ2,2'ꢀbipyridine (16.1 mg, 0.06 mmol, 0.15
equiv.), 4ꢀbromobenzonitrile (72.8 mg, 0.40 mmol, 1.0 equiv.), tetrahydroꢀ2ꢀfuroic acid (18c) (69.7 mg, 0.60 mmol, 1.5 equiv.), Cs2CO3 (195
mg, 0.60 mmol, 1.5 equiv.), and 10 mL of DMF were used. The mixture was irradiated for 20 hours with 34 W blue LED lights and fanned to
reduce the temperature from the heat generated as shown in Figure S5. Purification by flash chromatography on silica gel, eluting with 15%
1
EtOAc and 85% hexanes solvent gradient gave 19d as a colorless oil (62.4 mg, 90%). H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.0 Hz, 2H),
7.44 (d, J = 8.0 Hz, 2H), 4.94 (t, J = 8.0 Hz ,1H), 4.13 (dd, J = 15.0, 8.0 Hz , 1H), 3.98 (dd, J = 15.0, 8.0 Hz , 1H), 2.45 ꢀ 2.35 (m, 1H), 2.08 ꢀ
1.98 (m, 2H), 1.83 ꢀ 1.71 (m, 1H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ 149.2, 132.2, 126.2, 118.9, 110.9, 79.8, 68.9, 34.7, 25.9 ppm;
HRMS (ESI) m/z calcd for C11H12NO [(M+H)+] 174.0913, found 174.0935. Characterization data matched that reported in the literature.12b
Associated Content
Author Information
Corresponding Authors
*Email: martins.oderinde@astrazeneca.com; jeffrey.johannes@astrazeneca.com
Notes
The authors declare no competing financial interests.
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Acknowledgments
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We thank professor Mohammad Movassaghi (MIT) for helpful discussions, and Matthew Pompeo (Movassaghi group) for use of a
gloveꢀbox. M. S. Oderinde thanks the Natural Sciences and Engineering Research Council of Canada (NSERC) for his PDF award.
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Supporting Information
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The contents of Supporting Information include: (1) Expanded general materials and methods, (2) additional experimental procedures
for control reactions, (3) additional tables and graphs, (4) expanded discussions of peripheral findings and (5) copies of 1H, and
13C{1H} NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org.
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