Silyl-mediated photoredox-catalyzed Giese reaction: Addition of non-activated alkyl bromides

Article abstract of DOI:10.1039/c8sc02253d

The emergence of photoredox catalysis has enabled the discovery of mild and efficient conditions for the generation of a variety of radical reaction platforms. Herein is disclosed the development of a conjugate addition reaction of non-activated alkyl bromides to Michael acceptors under visible-light photoredox catalysis. Optimization of the reaction was achieved using high-throughput experimentation (HTE) tools to enable the identification of mild, general and practical reaction conditions. A diverse set of alkyl bromides was successfully added to cyclic or acyclic α,β-unsaturated esters and amides. The features of this transformation allowed also access to a key intermediate of Vorinostat, an HDAC inhibitor used to fight cancer and HIV.

Full text of DOI:10.1039/c8sc02253d

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Silyl-Mediated Photoredox-Catalyzed Giese Reaction: addition of
non-activated alkyl bromides
Abdellatif ElMarrouni,*a Casey B. Rittsb and Jaume Balsells*b
Received 00th January 20xx,
Accepted 00th January 20xx
The emergence of photoredox catalysis has enabled the discovery of mild and efficient conditions for the generation of a
variety of radical reaction platforms. Herein is disclosed the development of a conjugate addition reaction of non-activated
alkyl bromides to Michael acceptors under visible-light photoredox catalysis. Optimization of the reaction was achieved
using high-throughput experimentation (HTE) tools to enable the identification of mild, general and practical reaction
conditions. A diverse set of alkyl bromides was successfully added to cyclic or acyclic α,β-unsaturated esters and amides.
The features of this transformation allowed also access to a key intermediate of Vorinostat®, an HDAC inhibitor used to
fight cancer and HIV.
DOI: 10.1039/x0xx00000x
www.rsc.org/
alkenes (Scheme 1). While these synthetic methods allow
access to a broad diversity of substrates, there is still an
opportunity to expand the scope of this synthetic
transformation to additional families of organic compounds
Introduction
The development of general and modular synthetic methods
requiring minimal activating groups for reactivity has the
potential to dramatically expand the Medicinal Chemistry
toolbox and accelerate the discovery of new small molecule
therapeutics.1 As part of this strategy, the formation of C(sp3)–
C(sp3) bonds remains one of the most challenging synthetic
transformations2 with many bond disconnections still lacking
robust methodology, a wide substrate scope and functional
group tolerance. The conjugate addition reaction exemplifies
this vacancy,3 suffering from limiting reaction conditions,
moslty related to the use of strong bases, that obstruct its use
in parallel or library synthesis for Medicinal Chemistry
applications. Recent advances in photoredox catalysis have
demonstrated generation of carbon-centered radicals under
mild conditions4 which have substantially filled the existing
methodology gaps on conjugate addition reactions to electron-
deficient olefins, also known as the Giese reaction.5 Several
research groups have recently reported on the generation of
carbon-centered radicals from a diverse set of functional
handles such as alkyl trifluoroborate salts,6 carboxylic acids,7
secondary and tertiary alcohols8 or organosilicates9 and
demonstrated their utility in addition reactions to different
that are widely available as building blocks in Medicinal
Chemistry such as haloalkanes.
CurrentPhotoredox Giese Reaction
R1
R2
X
EWG
R1
R2
EWG
+
photoredox
catalyst
R3
R3
Alkylated product
Michael
acceptor
Radical
precursor
X = CO2H, BF3K, OH, Si-(cathecol)2Y+
This work: Giese reaction usingnon-activated alkyl bromides
O
O
(Me3Si)3SiH
R1
R2
Br
R1
R2
+
R
R
photoredox
catalyst
R3
R3
Alkyl
Michael
Alkylated
product
bromides
acceptor
Scheme 1 Synthesis of C-C bonds through photocatalytic Giese reaction
The thermal generation of primary and other radicals from
alkylbromides mediated by tributyltin hydride or
tris(trimethylsilyl)silane as radical initiators have been widely
studied.10 The radical reactions initiated using triethylborane
and oxygen have been also described.11 Reactions mediated by
metals such as indium, nickel, samarium, chromium, and zinc
additives to promote the reduction of halogen-containing
derivatives have been also reported.12
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in MeCN as solvent. Under these initial set of conditions, the
More recently, seminal work by MacMillan and co-workers13 addition of alkylbromide
to amide furnished the desired
demonstrated the generation of alkyl radicals from alkyl product in 35% yield amongst various side products. This
bromides through halogen-atom abstraction via result reinforced our photoredox mechanistic hypothesis.
photocatalytically generated tris(trimethylsilyl)silyl radical However, to make sure the reaction occurred under
species. With these considerations in mind, we became photoredox catalysis, we performed series of control
2
1
3
a
a
interested in developing a method for the generation of non- reactions wherein we independently set up reactions in the
activated alkyl radicals in a practical and efficient manner to absence of light, photocatalyst and/or silane (entries 2-4, Table
use them as nucleophiles in
transformation. This reaction would allow the construction of were recovered. Interestingly, a test reaction without base
new C(sp3)–C(sp3) bonds and provide access to a wide range of resulted in the formation of the coupled product
in 30% yield
a photoredox Giese-type 1). In all cases, no reaction was observed and starting materials
3
valuable compounds including clinical candidates and together with a significant increase in side-products (entry 5,
analogues thereof.14 Herein, we describe the development, Table 1).
optimization and scope of a photoredox promoted Giese
addition of alkylbromides to α,β-unsaturated amides and Ensuing optimization of the main reaction parameters aimed
esters.
at improving the ratio of desired product to side-products
while reaching complete conversion. For this optimization
study, we applied High-Throughput Experimentation (HTE)15
techniques using the Aldrich® Micro Photochemical Reactor
which allows for up to 16 reactions to be run in parallel under
uniform lighting conditions. Both the amounts of desired
product as well as unreacted starting materials were measured
in these experiments as this provided a better understanding
of mass balance and overall reaction performance.
Table 1 Initial reaction screening[a]
O
Me
Ph
Br
(Me3Si)3SiH
O
N
H
Ir[dF(CF3)ppy]2(dtbbpy)PF 6
Me
Ph
N
H
1
+
Na2CO3, MeCN
3
N
Bz
N
25 °C, 16h
Bz
O
2
(Me3Si)3SiH
O
Me
Ph
Br
Major Side-products
N
H
photocatalyst
Me
Ph
O
N
H
1
O
+
Ph
Me
H
Ph
Me
N
H
O
N
H
O
H
Me
Me
Ph
Na2CO3, solvent
3
N
Ph
N
N
H
N
Bz
N
H
Bz
25 °C, 16h
Bz
2
Me3Si
Me3Si
Si
SiMe3
4
5
6
N
Bz
Entry
Conditions
As shown
No light
Yield 1[b]
0%
Yield 2[b]
0%
Yield 3[b]
35%
0%.
1
2
3
4
5
100%
100%
100%
8%
100%
100%
100%
21%
No silane
No [Ir] cat
No base
0%
0%
30%
[a] N-phenylmetacrylamide (1) (1.0 equiv.), (4-bromopiperidin-1-
yl)(phenyl)methanone (2) (1.0 equiv.), Na2CO3 (2.0 equiv.), (Me3Si)3SiH (1.0
equiv.) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1 mol%) in MeCN, Aldrich® Micro
Photochemical Reactor (ring) for 16h. [b] Assay yields for product and
remaining starting materials were determined using HPLC techniques.
Figure
1 Photocatalyst and solvent screening: N-phenylmetacrylamide (1), (4-
bromopiperidin-1-yl)(phenyl)methanone (2), Na2CO3 (2.0 equiv.), (Me3Si)3SiH,
photocatalyst (1 mol%), Aldrich® Micro Photochemical Reactor (ring) for 16h. [a] Assay
yields for desired product was determined using standard HPLC techniques.
Reaction optimization
An initial screen of photocatalysts across different solvents
(Figure 1) revealed that Ir[dF(CF3)ppy]2(dtbbpy)PF6 was a
superior catalyst in the solvents tested. This screening also
exposed MeOH (35% yield) and MeCN (38% yield) as the two
ideal solvents. Although reactions in THF or 2-propanol (IPA)
performed similarly to MeCN (36% and 38% yield respectively),
starting materials were completely consumed in these
To evaluate this transformation, we first turned our attention
to the reaction of phenylacrylamide
derivative as a model system. Initially, these reactants were
subjected to the silyl mediated photoredox catalysis reaction
conditions, using mol% Ir[dF(CF3)ppy]2(dtbbpy)PF6 as
1 and 4-bromopiperidine
2
1
photocatalyst, equimolar amounts of (Me3Si)3SiH and Na2CO3
2 | J. Name., 2012, 00, 1-3
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reactions and there was a significant increase of the amount of desired reaction pathway over side-reactions, thus maximizing
side-products. the yield.
Having unveiled an optimized photocatalyst and two preferred We therefore examined the ratio of Michael acceptor
solvents, we decided to study the effect of bases in the alkyl bromide in presence of different amounts of silane (See
reaction (see Table S2 in the Supporting Information). While Figure 2 and Table S4 in the Supporting Information). This
the reaction proceeded in the absence of base, higher yields screening revealed that a slight excess of alkyl bromide (1.5
were obtained when 2 equiv. of inorganic bases such as to 3 equiv.) led to the best yields with little impact of the
Na2CO3 (49% yield), Li2CO3 (51% yield) or KF (52% yield) were amount of silane. An excess of Michael acceptor was
1 and
2
2
1
used. We selected Na2CO3 since it is more commonly available deleterious in all cases. The use of 0.78 equiv. of (Me3Si)3SiH
in chemistry laboratories. Organic bases (2,6-lutidine, DIPEA, showed full consumption of the limiting reagent and a cleaner
Et3N, Barton’s base16) were significantly less efficient and led reaction profile (74% yield with 3 equiv. of bromide
to an increase of side-products (see Table S2 in the Supporting
2).
O
Information). In all cases, MeOH was superior to MeCN and
(Me3Si)3SiH
O
Me
Ph
Br
thus we pursued the rest of the optimization study in MeOH.
N
H
Ir[dF(CF3)ppy]2(dtbbpy)PF6
Me
Ph
N
H
1
A further round of optimization focused on the impact of
variable amounts of (Me3Si)3SiH (see Table S3 in the
Supporting Information). While the reaction did not occur
without silane, an excess of this reagent proved detrimental
for this transformation, leading to a significant increase of
+
Na2CO3, MeOH
3
N
N
Bz
25 °C
Bz
2
dehalogenated side-product
4 and conjugate addition of silane
to the Michael acceptor 6.
O
(Me3Si)3SiH
O
Me
Ph
Br
N
H
Ir[dF(CF3)ppy]2(dtbbpy)PF6
Me
Ph
N
H
1
+
Na2CO3, MeOH
3
N
N
Bz
25 °C, 16h
Bz
2
Figure 3 Visible-light source comparison: N-phenylmetacrylamide (1) (1.0 equiv.), (4-
bromopiperidin-1-yl)(phenyl)methanone (2) (1.5 equiv.), Na2CO3 (2.0 equiv.),
(Me3Si)3SiH, Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1 mol%) in MeOH .[a] Assay yields for desired
product was determined using standard HPLC techniques. [b] Ring = Aldrich® Micro
Photochemical Reactor. [c] Lamp = Kessil® A160WE Tuna Blue Light. [d] Reactor =
13.2W Merck Photoreactor.
Before engaging in the study of the scope of this
transformation, we decided to evaluate the performance of
this reaction using different visible-light sources. This is an
important factor to ensure reproducibility of this methodology
since light source setups differ from one research laboratory to
another. We used three different devices differing in light
intensity: i) the Aldrich® Micro Photochemical Reactor; ii) the
previously reported setup based on Kessil® lamps with fans;
and iii) the integrated Photoreactor recently developed by
Merck scientists in collaboration with MacMillan’s group.17
Reactions were run under the optimized conditions and
monitored over 24 h. While all reactions reached similar yields
on the three devices tested, drastic differences were observed
in the reaction rates. Remarkably, the reaction was complete
Figure 2 Reactant ratio screening: N-phenylmetacrylamide (1), (4-bromopiperidin-1-
yl)(phenyl)methanone (2), Na2CO3 (2.0 equiv.), (Me3Si)3SiH, Ir[dF(CF3)ppy]2(dtbbpy)PF6
(1 mol%) in MeOH, Aldrich® Micro Photochemical Reactor (ring) for 16h. [a] Assay
yields for desired product was determined using standard HPLC techniques.
The best results were observed using between 0.5 equiv. to
1.0 equiv. of (Me3Si)3SiH. Yields of desired product declined
when using more than 1.0 equiv. of silane, as larger amounts
of side-products were observed. This non-obvious behavior
prompted us to explore the performance of the reaction using
variable amounts of the two key reactants, hypothesizing that after 30 minutes in the integrated photoreactor, compared to
the 24 h required for the Aldrich® Micro Photochemical
Reactor (Figure 3). Changes in the reaction rate are attributed
excess amounts of one of the reactants might favor the
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to the different intensity of the light sources, which has been tolerated a variety of substituents and functional groups
optimized in the integrated photoreactor.
including cyclopropyl, ester, primary Boc amine and
phosphonate. Although most products were isolated in
moderate yields, this transformation overcomes one of the
main synthetic gaps of the existing photoredox conjugate
addition methods. In addition, this method allowed access to
biologically relevant phosphonates 13 and 14 with antimalarial
properties in a single step.18 Unactivated secondary alkyl
bromides generate more stable radicals than primary ones
Reaction scope
Using the optimized conditions and performing the reactions
in the integrated photoreactor, we began to explore the scope
of the reaction focusing on a variety of primary, secondary and
tertiary alkyl bromides (Table 2). We were pleased to find that
which led to higher isolated yields for compounds 16-22 (Table
2). Among these products, several unfunctionalized cyclic and
linear alkanes were installed successfully in addition to small
synthetically useful yields. The reaction conditions successfully cyclic ethers such as tetrahydropyran and oxetane groups.
primary alkyl bromides provided the desired products 7-15 in
Table 2 Scope of alkyl bromides[a].[b]
CF3
F
(Me3Si)3SiH (0.75 equiv)
O
tBu
O
N
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1 mol%)
Me
Ph
Br
N
N
N
H
Me
Ph
F
F
IrIII
PF6
tBu
N
H
+
N
Na2CO3 (2 equiv), MeOH [0.2M]
25 °C, 1h, Photoreactor
1
F
Alkyl bromides
CF3
7-25
Ir[dF(CF3)ppy]2(dtbbpy)PF6
1° alkyl bromides
O
O
O
O
Me
Ph
Me
Ph
Me
Ph
Me
Ph
N
H
N
H
N
H
Me
O
N
H
Me
Me
Ph
Ph
O
10, 41%
8, 47%
9, 49%
7, 63%
O
O
O
O
O
Me
Ph
Me
Ph
Me
F
Ph
Me
Ph
Me
Ph
N
H
N
H
N
H
N
H
O
F
N
H
EtO
EtO
P
P
Ph
BocN
H
F3C
EtO
EtO
O
12, 35%
15, 81%
11, 43%
14, 52%
13, 57%
2° alkyl bromides
3° alkyl bromides
O
O
O
O
O
Me
Ph
Me
Ph
Me
Ph
Me
Ph
Me
Ph
N
H
N
H
N
H
N
H
N
H
Me
Me
Me
Me
Me
Me
Me
16, 69%
18, 76%
17, 68%
Me
24, 59%
23, 66%
O
O
O
O
O
Me
Ph
Me
Ph
Me
Ph
Me
Ph
Me
Ph
N
H
N
H
N
H
N
H
N
H
H
Ph
Me
O
H
O
Me
Me
22, 70%
25, 69%
19, 87%
20, 55%
21, 86%
H
[a] N-phenylmetacrylamide (1) (1.0 equiv.), alkyl bromide (1.5 – 3.0 equiv.), Na2CO3 (2.0 equiv.), (Me3Si)3SiH (0.75 equiv.) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1 mol%) in
MeOH, integrated Photoreactor (reactor). [b] Yields corresponding to isolated and analytically pure products.
4 | J. Name., 2012, 00, 1-3
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Table 3 Michael acceptor scope.[a],[b]
The use of tertiary alkyl bromides enabled the synthesis of
quaternary centers from small alkyl groups such as tBu or 2-
methylbutane (23-24, Table 2). Likewise, this methodology
O
R1
allowed access to the adamantyl derivative 25, an exotic
moiety used often by Medicinal Chemists to increase drug-like
qualities of a lead compound, without increasing toxicity.19
O
A
(Me3Si)3SiH (0.75 equiv)
R1
Ir[dF(CF )ppy]2(dtbbpy)PF6 (1 mol%)
3
A
Michael acceptors
+
Br
The reaction scope was further explored by testing a variety of
Michael acceptors including esters and amides. Bromide
Na2CO3 (2 equiv), MeOH [0.2M]
25 °C, 1h, Photoreactor
2
successfully reacted with diverse acceptors including fumarate,
malonate, mono- and di-substituted acrylates, furanone and
maleimide (26-34, Table 3). We were also pleased to find that
26-43
Alkyl bromides
primary, secondary and tertiary alkyl bromides such as
tetrahydropyran, adamantyl and ethylbenzene reacted with
different α,β-unsaturated esters such as acrylates, fumarates
BzN
BzN
BzN
CO2Et
CO2Me
CO2Me
CO2Me
CO2Et
Me
and malonates to provide the desired products 35-43 in good
26, 87%
28, 73%
27, 49%
yields (Table 3). The examples shown on Tables 2 and 3
demonstrate the robustness of this transformation with a
variety of alkyl bromides as well as Michael acceptors.
BzN
BzN
CO2Et
BzN
Me
CO2Bn
NBz
O
Tolerability of functional groups on both coupling partners,
such as unprotected alcohols, esters or Boc-protected amines
also surpasses that of traditional methods using
organometallic species. Finally, short reaction times using the
Merck integrated Photoreactor render this methodology highly
practical for synthetic chemists.
CF3
O
30, 44%
29, 61%
31, 62%
BzN
CO2Et
Me
O
HO
HN
CO2Et BzN
O
32, 73%
33, 53%
MeO2C
34, 40%
Mechanistic studies
Me
CO2Bn
CO2Et
A plausible mechanism for the visible light-mediated Giese
addition is proposed on Scheme 2. The generation of an initial
CO2Me
O
Me
O
CO2Et
O
carbon-based radical
A from an alkyl bromide under
35, 69%
36, 58%
37, 89%
photoredox conditions has been explained previously by
MacMillan13 in the context of their cross-electrophile coupling.
Oxidation of bromide by the photocatalyst generates an
electrophilic bromine radical13 which is capable of abstracting
hydrogen from (Me3Si)3SiH,20 generating the silyl radical
species [(Me3Si)3Si•].10 Subsequent halogen abstraction from
Me
CO2Bn
CO2Me
CO2Me
EtO2C
CO2Et
Me
H
H
H
H
H
H
alkyl bromide
radical species
reaction of with an acceptor to generate radical
2
would provide the corresponding nucleophilic
and the bromosilane byproduct. Giese
is also well
38, 56%
39, 72%
40, 72%
H
H
H
A
A
B
CO2Me
CO2Me
established. The presence of stoichiometric (Me3Si)3SiH in the
reaction presents two potential reaction pathways for this
radical species to be reduced to the final product of the
EtO2C
CO2Et
Me
CO2Bn
Ph
Me
41, 38%
Ph
Ph
reaction,
species [IrII] to provide anion
resulting in the desired product
3
: i) single-electron transfer (SET) from reductant
, followed by protonation
; ii) radical propagation
43, 75%
42, 45%
C
3
[a] Michael acceptor (1.0 equiv.), alkyl bromide (1.5 – 3.0 equiv.), Na2CO3 (2.0
equiv.), (Me3Si)3SiH (0.75 equiv.) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1 mol%) in
MeOH, integrated Photoreactor (reactor). [b] Yields corresponding to isolated
and analytically pure products.
mechanism via hydrogen atom abstraction from (Me3Si)3SiH
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directly generating product 3 and, consequently, regenerating result does not support the existence of an efficient radical
the stabilized silyl radical species [(Me3Si)3Si•].
chain and is in line with the observations of the deuteration
experiments.
Better understanding of this part of the mechanism was
important since this is the stereodetermining step in the
reaction and we envisioned that a rapid way to discern
between these two pathways could be the utilization of
deuterated reagents in the reaction. Therefore, we performed
A. Control experiment
O
O
(Me3Si)3SiH
Ir[dF(CF3)ppy)2(dtbbpy)PF6
H
H
Ph
Ph
Me
Me
Me
N
Me
Me
Me
N
H
H
separate experiments using deuterated solvent (CD3
CH3O ) and (Me3Si)3Si (Scheme 3).
OD and
D
D
Me
Me
Na2CO3, MeOD
23
23
(Me3Si)3SiBr
BzN
(Me3Si)3Si
(Me3Si)3SiH
B. Quenching experiments
Br
O
2
Me
Ph
(Me3Si)3SiH
N
H
O
O
Ir[dF(CF3)ppy)2(dtbbpy)PF6
R
Br
Br
Ph
1
Ph
Me
Me
N
N
+
H
H
BzN
SET
Me
Me
Me
Br
Na2CO3, MeOH
Me
A
1
Me
IrIII
Oxidant
23
IrII
Reductant
Me
O
when (Me3Si)3SiD
when MeOD or CD3OD
only R = H
R = H/D (1:9)
Ph
N
H
Scheme 3 Deuterated NMR experiments: A. control experiment; B. reaction of amide 1
BzN
Me
B
with t-butyl bromide using deuterated reagents.
SET
Major
pathway
(Me3Si)3SiH
IrIII
Minor
pathway
Medicinal Chemistry application
Photoredox
Catalyst
O
Ph
N
H
To demonstrate the potential value of this methodology on a
Medicinal Chemistry application, we utilized this
transformation to access Vorinostat® (44),23 an oncology drug
approved for the treatment of cutaneous T-cell lymphoma
(CTCL), and currently being studied as part of a possible
strategy to cure HIV infection.24 From a Medicinal Chemistry
perspective, derivatization of suberic acid 45 using
conventional amide bond formation strategies easily enabled
SAR exploration of both terminal carboxylic acids on the
compound.23a However, derivatization or substitution on most
positions of the methylene chain would be much more
challenging synthetically, slowing down SAR efforts. The
present chemistry enables a non-obvious bond disconnection
via Giese addition and, using the standard reaction conditions
described, enabled the synthesis of the Vorinostat® precursor
46 in a single step from commercially available bromovalerate
47 and acrylamide 48. The photoredox product 46 was
BzN
Me
C
(Me3Si)3Si
H
O
Ph
N
H
BzN
Scheme 2 Plausible mechanism
Me
3
tButyl bromide was chosen as
a
substrate for these
experiments due to the unambiguous assignment of the 1H-
NMR spectra (see Supporting Information). While the reaction
with (Me3Si)3SiD led to insignificant incorporation of
deuterium into the desired product, the experiments in CH3O
D
resulted predominantly in the formation of deuterated
coupled product. A control experiment subjecting purified
product 23 to the reaction conditions using deuterated
obtained in 48% yield after
1 hr using the integrated
photoreactor. Within the Vorinostat® chemical space, this
disconnection could be used by Medicinal Chemists to quickly
explore additional sites of chemical diversity such as
methanol (CD3OD) showed no deuterium incorporation, thus
excluding the possibility of a base-catalyzed H/D scrambling
after the product initially formed (Scheme 3). These results
suggest that the major pathway to convert radical species B to
substitution on the
α or β positions of the acrylamide or
additional chain lengths, to name a few, exemplifying the
value of this methodology on biologically relevant chemical
motifs.
desired product is likely to occur through anion via SET
3
C
reduction by the [IrII] photocatalyst. Determination of
quantum yield is also informative in characterizing chain
processes in visible light photoredox catalysis.21 Using recently
developed LED-NMR methodology,22 and under slightly
modified reaction conditions, (see Supporting Information) we
determined the quantum yield for the reaction is φ = 0.45. This
6 | J. Name., 2012, 00, 1-3
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ml/min. The fractions were concentrated to provide pure
products.
O
HO
OH
O
45
Conflicts of interest
(3 steps)
Ref. 11b
There are no conflicts to declare.
O
H
N
Ph
HO
N
H
Acknowledgements
O
Vorinostat (44)
We thank L. C. Campeau and Prof. D. W. C. MacMillan for
helpful discussions. We thank Janine Brouillette and James
Small for support with NMR characterization. We thank Yining
Ji and Mikhail Reibarhk for their help with quantum yield
experiments. We thank James J. Perkins, Antonella Converso,
Mark E. Layton and Michael VanHeyst for reviewing the paper.
Ref. 11d
O
MeO
Ph
N
H
O
46, 48%
Standard
conditions[a]
Notes and references
O
MeO
Br
Ph
1
(a) T. Cernak, K. D. Dykstra, S. Tyagarajan, P. Vachal and S. W. Krska,
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Discovery Today 2009, 14, 731; (d) J. S. Carey, D. Laffan; C. Thomson
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+
N
H
O
47
48
Scheme 4 Versatile approach to Vorinostat® through photocatalytic conjugate addition.
[a] 48 (1.0 equiv.), 47 (3.0 equiv.), Na2CO3 (2.0 equiv.), (Me3Si)3SiH (0.75 equiv.) and
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1 mol%) in MeOH, integrated Photoreactor (reactor), 1 hr.
2
3
(a) See review and references therein: E. Geist, A. Kirschning, and T.
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Conclusions
In conclusion, we have developed
a Giese addition of
unactivated alkyl bromides to α,β-unsaturated esters and
amides mediated by photoredox catalysis. We have also
demonstrated that this transformation proceeds under mild
conditions to provide numerous primary, secondary and
tertiary products, including, biologically relevant compounds
such as Vorinostat®.
4
5
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Experimental
General procedure
In a vial were added N-phenylmetacrylamide (
mmol, 1.0 equiv.), (4-bromopiperidin-1-yl)(phenyl)methanone
) (250 mg, 0.93 mmol, 1.5 equiv.), Na2CO3 (131 mg, 1.24
1) (100 mg, 0.62
(
2
mmol, 2.0 equiv.) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (7 mg, 0.006
mmol, 0.01 equiv.). MeOH (2 mL) was added followed by
(Me3Si)3SiH (145 µL, 0.46 mmol, 0.75 equiv.). The vial was
purged with nitrogen and then sealed. The vial was placed in
the integrated photoreactor (100% intensity, 6000rpm fan,
1000 rpm stirring) until the starting acceptor was completely
consumed (1h). After the reaction was completed, volatiles
were removed at reduced pressure. The resulting residue was
dissolved in DMSO (1 mL), filtered and purified by HPLC: eluted
with a 15 minute gradient of 90% water/MeCN (0.1% TFA) to
5% water/MeCN (both 0.1% TFA) with a flow rate of 25
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