Anti-Markovnikov Hydroarylation of Unactivated Olefins via Pyridyl Radical Intermediates

Article abstract of DOI:10.1021/jacs.7b03262

The intermolecular alkylation of pyridine units with simple alkenes has been achieved via a photoredox radical mechanism. This process occurs with complete regiocontrol, where single-electron reduction of halogenated pyridines regiospecifically yields the corresponding radicals in a programmed fashion, and radical addition to alkene substrates occurs with exclusive anti-Markovnikov selectivity. This system is mild, tolerant of many functional groups, and effective for the preparation of a wide range of complex alkylpyridines.

Full text of DOI:10.1021/jacs.7b03262

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Communication
Anti-Markovnikov Hydroarylation of Unactivated
Olefins via Pyridyl Radical Intermediates
Allyson J Boyington, Martin-Louis Riu, and Nathan T. Jui
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 04 May 2017
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Anti-Markovnikov Hydroarylation of Unactivated Olefins via Pyridyl
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Allyson J. Boyington, Martin-Louis Y. Riu, and Nathan T. Jui*
Department of Chemistry and Winship Cancer Institute, Emory University, Atlanta, GA 30322
Supporting Information Placeholder
ABSTRACT: The intermolecular alkylation of pyridine
Figure 1. Strategies for Anti-Markovnikov Hydroarylation
units with simple alkenes has been achieved via a photo-
redox radical mechanism. This process occurs with
of Simple Alkenes with Pyridines.
complete regiocontrol, where single-electron reduction
of halogenated pyridines regiospecifically yields the
corresponding radicals in programmed fashion, and rad-
ical addition to alkene substrates occurs with exclusive
anti-Markovnikov selectivity. This system is mild, toler-
ant of many functional groups, and effective for the
preparation of a wide range of complex alkylpyridines.
Bergman and Ellman (2007): Rh system for functionalization of 2-position
Rh(I)-catalyst
H
R
PCy3 •HCl
R
N
H
R
N
R
1
65 °C
pyridine
simple alkene
pyridine 2-alkylation
Nakao and Hiyama (2010): Dual catalytic system for functionalization of 4-position
N
Ni-NHC cat.
N
H
R
Lewis acid cat.
H
R
1
30 °C
Heteroaromatic units are important structural features in
bioactive small molecules, and pyridines are among the1
most highly-represented heterocycles in pharmaceuticals.
As a result, new methods for the construction of complex
pyridines from abundant precursors is an important
synthetic goal. Simple alkenes are ideal starting materials
because they are highly abundant and stable.
Hydroarylation, the addition of Ar–H across simple
alkenes, is an attractive strategy for the construction of
alkylarenes, and much progress has been made to enable
pyridine
simple alkene
pyridine 4-alkylation
This work: Simple alkene hydroarylation via pyridyl radical species
catalyst, light
H
N
R
N
H-atom source
room temp.
X
R
halopyridine
simple alkene
radical hydroarylation
Mild conditions, broad FG-tolerance
Selective alkylation at any position
a predictable and controllable manner) would be valuable,
particularly if it operated at ambient temperature with high
functional group tolerance. Here, we describe the
realization of these objectives.
2
–6
this type of process. While simple olefin hydroarylation
with pyridines remains challenging, Herzon and Shenvi
described radical-based systems that efficiently accomplish
selective formation of the branched alkylpyridine isomers
7,8
Our system is founded on the understanding that highly
reactive pyridyl radicals can be readily accessed via single
electron reduction of pyridyl halides.
have demonstrated that photoredox catalysts
(
Markovnikov selectivity).
To date, there are two distinct approaches to anti-
12–14
We and others
Markovnikov hydroarylation with pyridines that both
involve metal insertion into C–H bonds at elevated
temperature. Lewis, Bergman, and Ellman described the
ability of Rh(I) catalyst to accomplish the addition of 2-
substituted pyridines to a range of alkenes, via N-
15,16
are
capable of accomplishing (hetero)aryl radical formation
17–21
through this manifold.
Importantly, the resulting
radicals can be utilized in a number of valuable synthetic
processes. We recently demonstrated that nucleophilic
pyridyl radical species effectively engage a wide range of
electron-poor alkenes—in the presence of a stoichiometric
9
heterocyclic carbene intermediates. Importantly, this
approach delivers 2,6-disubstituted pyridines with complete
1
0
regiocontrol (Fig. 1). The groups of Nakao and Hiyama,
21
reductant—to give conjugate addition products. We
1
1
and Ong independently described a complementary
strategy for selective functionalization of the pyridyl 4-
questioned whether simple alkenes could be employed as
coupling partners for pyridyl radicals under a similar
mechanistic model. More specifically, reductive radical
formation followed by regioselective intermolecular
addition to simple alkenes and radical termination via
position that operates through
a bimetallic Lewis-
acid/Ni(0) cooperative catalytic system. An effective
method for simple alkene hydropyridylation that allows for
selective alkylation at any position on the pyridine ring (in
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hydrogen-atom transfer (HAT) would deliver linear
alkylpyridines, pathway that Weaver has nicely
demonstrated for 2-haloazoles and polyfluorinated arenes.
Table 2. Catalytic Olefin Hydroarylation: Halopyridine
a
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scope
a
1
8
1 mol%
R
R
A
B
[Ir(ppy)
2
dtbbpy]+
A
B
H
Because substituted pyridines containing halogenation at
any position (i.e. the 2-, 3-, 4-, 5-, or 6-position) are
n-hex
C
X
Hantzsch ester
C
n-hex
1
3,14,22
4 3 2
NH Cl, CF CH OH
available and radical formation is regiospecific,
the
halopyridine
1-octene
blue LED, 23 °C
hydroarylation product
outlined approach could grant access to all of the possible
regioisomeric hydroarylation products. Finally, pyridyl
radicals can be formed by the action of reducing
photoredox catalysts under very mild conditions, and they
display orthogonal reactivity to many functional groups.
H
H
N
H
N
N
n-hex
n-hex
n-hex
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2: X = Br, 86% yield
3: X = I, 80% yield
4: X = Br, 86% yieldb
We began our study by evaluating the coupling of 1-
octene (3 equiv) with 2-bromo-6-methylpyridine in the
presence of a slight excess (1.3 equiv) of Hantzsch ester
Me
N
Me
Me
H
H
N
H
(
HEH) and 1.0 mol% of the commercial photosensitizer
N
2
3
n-hex
n-hex
n-hex
Ir(ppy)
2
dtbbpy•PF
6
.
After irradiation with a commercial
blue LED for 16 h in a range of polar solvents, the desired
radical hydroarylation product (1) was observed, albeit in
low yield (Table 1, entries 1–5, 4–21% yield). In these
experiments, 2-picoline production (via hydrodehalogen-
ation) was a significant deleterious pathway. However, the
use of 2,2,2-trifluoroethanol as the solvent was uniquely
promising, delivering the desired octylpyridine 1 in 74%
yield (entry 6) without observable formation of picoline.
We found that the reaction outcome was greatly impacted
by the acidity/basicity of the reaction mixture. For
example, the addition of lutidine (1.0 equiv) had a strong
inhibitory effect on the reaction (entry 7, 4% yield) and the
addition of 2 equivalents of acetic acid or ammonium
chloride allowed for complete conversion of the bromo-
pyridine starting material (entries 8 and 9, 77% and 87%
yield, respectively). Importantly, the desired linear coupled
product was obtained with complete regiocontrol; the
5: X = Br, 66% yield
6: X = I, 70% yield
7: X = Br, 89% yield
Me
OH
Me
N
H
N
H
N
H
n-hex
: X = Br, 84% yieldb
Me
n-hex
9: X = Br, 82% yield
n-hex
8
10: X = Br, 40% yield
Boc
NH
Piv
3
F C
H
N
NH
H
H
N
N
n-hex
n-hex
1: X = I, 52% yield
n-hex
1
12: X = I, 54% yield
13: X =I, 53% yield
Cl
Br
Br
H
H
N
H
N
n-hex
N
n-hex
n-hex
16: X = Br, 57% yield
1
14: X = Br, 41% yield
15: X =Br, 43% yield
branched isomer was not detected by H NMR or GCMS.
Table 1. Optimization of Conditions for Simple Alkene
a
Hydroarylation
a
Conditions: Halopyridine (1.0 mmol), 1-octene (3.0 mmol),
Ir(ppy) dtbbpy•PF (1.0 mol%), Hantzsch ester (1.3 mmol), 2,2,2-
1
mol%
dtbbpy]+
Ir(ppy)
2
H
2
6
[
trifluoroethanol (10.0 mL), blue LED, 23 °C, 16 h, isolated yields
n-hex
Me
N
n-hex
b
Me
N
Br
Hantzsch ester
shown. Pyridine hydrochloride salt was used as starting material.
solvent, additive
blue LED, 23 °C
Having identified effective conditions for anti-
Markovnikov hydroarylation of octene, we studied the
scope of halogenated pyridines (pyridyl radical precursors).
The results are illustrated in Table 2. There is no apparent
requirement for specific substitution patterns (or lack
thereof) in this system, and unsubstituted or alkyl-
substituted pyridyl halides react to give mono-, di-, or
trialkylpyridines 2–9 with good efficiency (66–89% yield).
In general, alkylation of the 2- and 4-positions is achieved
through reductive radical formation from the corresponding
bromopyridines, and alkylation of the 3-position is most
efficient when the corresponding iodopyridines are
employed. Electron-donating substituents are tolerated,
including the phenol (10, 40% yield), carbamate (11, 52%
yield), or amide (13, 53% yield) groups. While the yields of
these products are lower, they exemplify the ability to
functionalize compounds with acidic N–H or O–H bonds.
In addition, the electron-poor 2-Iodo-5-trifluoromethyl
pyridine couples to give the desired product 12 in 54%
yield. Both 2,3- and 3,4-dibromopyridines underwent
bromopyridine
1-octene
alkylated pyridine 1
Entry
Solvent
Additive
Yield of 1b
1
2
3
4
5
6
7
8
9
25% H O/DMSO
—
4%
19%
5%
2
DMSO
DMF
—
—
CH CN
—
17%
21%
74%
4%
3
CH OH
—
3
CF CH OH
—
3
2
CF CH OH
lutidine (1 equiv)
AcOH (2 equiv)
3
2
CF CH OH
77%
87%
3
2
CF CH OH
NH Cl (2 equiv)
3
2
4
a
Conditions: 2-Bromo-6-methylpyridine (0.25 mmol), 1-octene
0.75 mmol), Ir(ppy) dtbbpy•PF (1.0 mol%), Hantzsch ester
0.325 mmol), 2,2,2-trifluoroethanol (2.5 mL), blue LED, 23 °C,
(
(
1
2
6
b
6 h. Yield determined by GC.
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1
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Table 3. Catalytic Olefin Hydroarylation: Scope of the Simple Alkene
1
mol% Ir[ppy]2dtbbpy+
EtO2C
CO2Et
1
mol% [Ir(ppy)2dtbbpy]+
H
R
N
N
I
Me
N
H
Me
NH4Cl, CF3CH2OH
blue LED, 23 °C
R
3-iodopyridine
alkene
Hantzsch ester
hydroarylation product
H
H
H
O
H
Boc
NH
H
N
OH
N
OH
N
N
N
OH
Me
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Me
19: 79% yield
Me Me
20: 83% yield
1
7: 78% yield
18: 76% yield
21: 71% yield
H
H
H
O
NBoc
H
N
N
Cl
N
P
N
N
SiMe3
OEt
OEt
4
H
O
22: 72% yield
23: 89% yield
24: 61% yield
25: 67% yield
2
6: 42% yield
H
Me
Me
N
Me
H
N
N
N
N
n-pent
n-pent
n-pent
H
H
H
2
7: 82% yield (>20:1 dr)
28: 73% yield
29 (2-Br-pyr): 91% yield
30 (3-I-pyr): 78% yieldb
31 (4-Br-pyr): 74% yieldb,c
Minor pathway: Radical arylation
Coupling of bromopyridines with aromatic substrates (5 equiv)
Me
HO
Me
H
N
*
N
Br
*
N
N
N
Me
MeO
Me
Me
3
2: 76% yield
32a: 12% yieldd
33: X = Br, 91% yielde
34: X = Br, 67% yieldd,e
35: X = Br, 74% yielde
a
Conditions: 3-Iodopyridine (1.0 mmol), alkene (3.0 mmol), Ir(ppy)
2 6 4
dtbbpy•PF (1.0 mol%), Hantzsch ester (1.3 mmol), NH Cl
b
c
(
2.0 mmol), 2,2,2-trifluoroethanol (10.0 mL), blue LED, 23 °C, 16 h, isolated yields shown. Yield determined by NMR. Pyridine
d
hydrochloride salt was used as starting material. 2:1 regioisomeric ratio (biaryl connectivity of the minor isomer is indicated by
e
the asterisk). Conditions: Bromopyridine (1.0 mmol), arene (5.0 mmol), Ir(ppy)
mmol), TFA (2.0 mmol), 2,2,2-trifluoroethanol (10.0 mL), blue LED, 23 °C, 16 h.
2 6
dtbbpy•PF (1.0 mol%), Hantzsch ester (1.3
selective activation of one of the C–Br bonds to ultimately
give products 14 and 16 in 41% and 57% yield,
respectively. This is noteworthy because it demonstrates
both preferential radical formation at the most electrophilic
S Ar reactivity
N
patterns ) and preservation of the second pyridylbromide
functional group for further synthetic elaboration.
alkenes methylenepiperidine and 2-methylheptene reacted
with 3-iodopyridine to give the corresponding 3-alkylated
products 25 and 30 in 67% and 78% yield, respectively. As
expected, alkylation of the 2- or 4-position of with 2-
methylheptene was possible when the 2- or 4-
bromopyridine substrates were employed (2-position: 29
(91% yield); 4-position: 31 (74% yield). When
allylbenzene was used as substrate, we observed efficient
alkene hydroarylation (32, 76% yield), accompanied by
2
4
2
-
and2 4-positions (which parallels
5
We investigated the scope of the olefin coupling partner
using 3-iodopyridine as radical precursor. As illustrated in
Table 3, these trifluoroethanol-based photoredox conditions
effectively couple a range of simple, unactivated alkenes.
Allylic carbamate (17, 78% yield), alcohol (18–20, 76–
83% yield), and ketone (21, 71% yield) derivatives are
tolerated, as are the silane (22, 72% yield), primary alkyl
chloride (23, 89% yield), and phosphonate (24, 61% yield)
groups. Again, we observed exclusive formation of the
linear (anti-Markovnikov) alkylpyridines in this system. In
addition to monosubstituted alkenes, the disubstituted
internal alkenes 2,5-dihydrofuran, norbornene, and
cyclohexene smoothly react to afford the desired products
1
2% yield of the 3-arylpyridine products 32a (2:1 mixture
of regioisomers). Simply substituting trifluoroacetic acid
for ammonium chloride under otherwise identical
conditions allowed for the efficient coupling of pyridyl
2
0,26–28
radical units with benzene derivatives (5 equiv).
While we have not extensively evaluated the scope of this
arylation process, a brief study indicated that a range of
phenylpyridine derivatives would be accessible using this
protocol (e.g. 33–35, 67–91% yield).
In contrast to our previous report in this area, where
pyridyl radical intermediates displayed nucleophilic
reactivity (through effective coupling with Michael
2
6–28 in useful yields (42–82%). The 1,1-disubstituted
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Scheme 1. Competition Experiments: Solvent Dictates Reactivity Profile of Pyridyl Radicals
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Nucleophilic Radical
in DMSO System
Electrophilic Radical
H
H
in CF CH OH System
(
1 equiv)
2 equiv)
3
2
O
O
Me
N
Me
Me
N
Br
O
Me
N
Me
OEt
Me
OEt
1
mol%
+
1 mol%
36: 47% yield
36: 2% yield
[
Ir(ppy)2dtbbpy]+
[Ir(ppy)2dtbbpy]+
(
Hantzsch ester
Hantzsch ester
OEt
H
H
2
5% H2O/DMSO
NH4Cl, CF3CH2OH
+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Me
N
: 0% yield
n-hex
blue LED, 23 °C
blue LED, 23 °C
Me
N
n-hex
n-hex
(2 equiv)
1
1: 68% yield
(ref 21)
(this work)
2
1
(1) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014, 57,
0257.
acceptors in aqueous DMSO), pyridyl radicals that are
generated in this system (slightly acidic trifluoroethanol as
solvent) preferentially react with electron-rich alkenes. To
1
(
(
2) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826.
3) Foley, N. A.; Lee, J. P.; Ke, Z.; Gunnoe, T. B.; Cundari, T. R. Acc.
Chem. Res. 2009, 42, 585.
2
9
clearly illustrate this differential behavior, we conducted
the competition experiments that are shown in Scheme 1.
Specifically, 2-bromo-6-methylpyridine was activated in
the presence of both 1-octene and ethyl crotonate (2
equivalents each). In aqueous DMSO without added acid,
we observed exclusive formation of the radical conjugate
addition product 36 (47% yield); and product 1 was not
formed. The use of trifluoroethanol solvent with added
ammonium chloride, resulted in highly-selective formation
of the octene hydroarylation product 1 (68% yield), along
(
4) Andreatta, J. R.; McKeown, B. A.; Gunnoe, T. B. J. Organomet.
Chem. 2011, 696, 305.
(
(
5) Crisenza, G. E. M.; Bower, J. F. Chem. Lett. 2016, 45, 2.
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(
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(
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3
0
with 2% yield of 36.
In conclusion, we have developed a mild catalytic system
that enables the general hydroarylation of simple alkenes
with pyridine units. This method allows for the installation
of alkyl substituents at any position of the pyridine rings,
and tolerates a wide range of functional groups. Key to this
development was the finding that the use of
trifluoroethanol as the solvent imparts electrophilic
character on the pyridyl radical intermediates. Further
mechanistic studies and the development of related
processes are ongoing in our laboratory.
(12) Holubek, J.; Volke, J. Collect. Czech. Chem. Commun. 1962, 27,
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(
(
(
13) Andrieux, C. P.; Blocman, C.; Dumas-Bouchiat, J. M.; Saveant, J.
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(
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ASSOCIATED CONTENT
Supporting Information.
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2016, 49, 1566.
Experimental procedures and spectral data are available
free of charge on the ACS Publications website.
(21) Aycock, R. A.; Wang, H.; Jui, N. T. Chem. Sci. 2017, 8, 3121.
(22) Costentin, C.; Robert, M.; Savéant, J. J. Am. Chem. Soc. 2004, 126,
1
6051.
AUTHOR INFORMATION
(
23) Lowry, M. S.; Hudson, W. R.; Pascal, R. A.; Bernhard, S. J. Am.
Chem. Soc. 2004, 126, 14129.
(24) In these cases, incomplete conversion of the dihalopyridine was
observed and not double alkylation or product dehalogenation.
Corresponding Author
njui@emory.edu
(
25) Burnett, J. F.; Zahler, R. E. Chem. Rev. 1951, 49, 273.
Notes
(26) Poelma, S. O.; Burnett, G. L.; Discekici, E. H.; Mattson, K. M.;
Treat, N. J.; Luo, Y.; Hudson, Z. M.; Shankel, S. L.; Clark, P. G.;
Kramer, J. W.; Hawker, C. J.; Read De Alaniz, J. J. Org. Chem.
The authors declare no competing financial interests.
2
016, 81, 7155.
ACKNOWLEDGMENT
(27) Seiple, I. B.; Su, S.; Rodriguez, R. A.; Gianatassio, R.; Fujiwara, Y.;
Sobel, A. L.; Baran, P. S. J. Am. Chem. Soc. 2010, 132, 13194.
This project was supported by funds from Emory Universi-
ty and Winship Cancer Institute.
(
28) Senaweera, S.; Weaver, J. D. J. Am. Chem. Soc. 2016, 138, 2520.
(29) For a discussion on radical nucleophilicity/electrophilicity, see:
Giese, B. Angew. Chem. Int. Ed. 1983, 22, 753.
(
30) The same selectivity is observed in trifluoroethanol without added
ammonium chloride, but conversion of starting material is lower.
REFERENCES
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