Photoredox-mediated Minisci C-H alkylation of N-heteroarenes using boronic acids and hypervalent iodine

Article abstract of DOI:10.1039/c6sc02653b

A photoredox-mediated Minisci C-H alkylation reaction of N-heteroarenes with alkyl boronic acids is reported. A broad range of primary and secondary alkyl groups can be efficiently incorporated into various N-heteroarenes using [Ru(bpy)₃]Cl₂ as photocatalyst and acetoxybenziodoxole as oxidant under mild conditions. The reaction exhibits excellent substrate scope and functional group tolerance, and offers a broadly applicable method for late-stage functionalization of complex substrates. Mechanistic experiments and computational studies suggest that an intramolecularly stabilized ortho-iodobenzoyloxy radical intermediate might play a key role in this reaction system.

Full text of DOI:10.1039/c6sc02653b

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DOI: 10.1039/C6SC02653B
EDGE ARTICLE
Photoredox-Mediated Minisci C−H Alkylation of N-
Heteroarenes Using Boronic Acids and Hypervalent
Iodine
Cite this: DOI: 10.1039/x0xx00000x
Guo-Xing Li,a Christian A. Morales-Rivera,b Yaxin Wang,a Fang Gao,a Gang He,a
Peng Liu*b and Gong Chen*a, c
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
A photoredox-mediated Minisci C−H alkylation reaction of N-heteroarenes with alkyl boronic
acids is reported. A broad range of primary and secondary alkyl groups can be efficiently
incorporated into various N-heteroarenes using [Ru(bpy)3]Cl2 as photocatalyst and
acetoxybenziodoxole as oxidant under mild conditions. The reaction exhibits excellent
substrate scope and functional group tolerance, and offers a broadly applicable method for late-
stage functionalization of complex substrates. Mechanistic experiments and computational
studies suggest that an intramolecularly stabilized ortho-iodobenzoyloxy radical intermediate
might play a key role in this reaction system.
www.rsc.org/
Introduction
2-
N-heteroarenes are common structural motifs in natural
products, drug molecules, organic materials and ligands for
metal catalysts.1 Synthetic methods which enable the selective
functionalization of the C−H bonds of N-heteroarenes could
greatly facilitate their applications in these areas.2 Among the
different types of C−H functionalizations, C−H alkylations
could provide more stereochemically diverse modifications.3
Over the past few years, the C−H functionalization of electron-
deficient heteroarenes via addition of carbon-centered radicals
under oxidative conditions, known as the Minisci reaction, has
undergone a remarkable renaissance, offering increasingly
powerful methods for synthesizing alkyl-substituted
heteroarenes (Scheme 1).4 While the classical Minisci
alkylation reaction involves alkyl carboxylic acids and halides,
Baran recently demonstrated that aryl boronic acids are also
viable reagents in Minisci-type C−H arylation reactions using
R−CO2H :
R−B(OH)2
R−BF3K :
[Ag], S2O8 classic Minisci
2-
:
[Ag], S2O8
Mn(OAc)3
TBHP
(Baran)
(Molander)
(Baran)
R−SO2M :
O
[Ir] photoredox (DiRocco)
OR'
R
O
for methylation, ethylation
and cyclopropylation
R2
N
N
H
[Ir] photoredox (MacMillan)
& thiol organocatalysis
using primary alcohols in excess
R−OH
R1
This
work
B(OH)2
Bl:
R2
(1.5 equiv)
R1
I
BI-OAc (Ox), visible light
Ru(bpy)3Cl2 (1 mol%)
O
HFIP, 30 o
C
O
2-
Ag(I)/S2O8 oxidant.5 Molander demonstrated that alkyl
Scheme 1. Minisci C−H alkylation of N-heteroarenes.
trifluoroborates, particularly secondary alkyl trifluoroborates,
can effect efficient Minisci alkylation using Mn(OAc)3
oxidant.6 In addition, Minisci C−H alkylation transformations
have been achieved using a variety of other alkylating reagents,
including sulfinates, aldehydes, and even simple alkanes, using
different radical initiators and oxidants.7
More recently, DiRocco reported the first photoredox-
mediated Minisci alkylation reaction of N-heteroarenes using
peroxides as the alkylating reagent.8 MacMillan demonstrated a
Minisci alkylation reaction of N-heteroarenes using primary
alcohols as the alkylation reagent, via photoredox- and organo-
catalysis.9a However, despite these significant advances,
practical and broadly applicable methods for Minisci C−H
alkylation of N-heteroarenes capable of coupling complex alkyl
groups are still lacking. Herein, we report a photoredox-
mediated Minisci C−H alkylation reaction of N-heteroarenes
with a variety of easily accessible primary and secondary alkyl
boronic acids. Its high efficiency, broad substrate scope,
excellent functional group tolerance, and mild operation
conditions make it particularly suitable for late-stage
functionalization of complex substrates such as drug molecules.
This journal is © The Royal Society of Chemistry 2013
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reactions, using butyl boronic acid 2a or trifluoroborate 2b
under the visible light (VL) irradiation (Table 1). We were
delighted to find that the desired C2-alkDyOlaIt:e1d0.1p0r3Vo9ied/wCu6AcSrttCic30lea2O6nc5la3inBne
be formed in excellent yield with 2a using [Ru(bpy)3]Cl2
photocatalyst and BI-OAc oxidant under optimized conditions
(entry 5). Alkylation with 2b proceeded in lower yield (entry
6). In comparison with Bl-OAc, hydroxylbenziodoxole (BI-
OH) gave slightly lower yield, methoxylbenziodoxole (Bl-
OMe) was notably less effective, BI-N3 gave low yield,
chlorobenziodoxole (Bl-Cl) and PhI(OAc)2 showed little
reactivity (entries 7-11). Hexafluoroisopropanol (HFIP) solvent
is critical for obtaining high yield (entries 3-5). No 3a was
formed in the absence of either Ru catalysis or light irradiation
(entries 13-14). Formation of 3a was completely suppressed
when 2 equiv of TEMPO was added, forming side product O-
butyl TEMPO in 16% yield (entry 15).
With the optimized conditions in hand, we next explored the
substrate scope (Scheme 2). As seen in 3c-3l, a range of
primary alkyl boronic acids reacted with 4-chloroquinoline 3 to
give C2-alkylated products in good to excellent yield.
Methylation with MeB(OH)2 gave moderate yield (see 3b).
Primary alkyl radicals are more challenging reactants in Minisci
reactions than secondary alkyl radicals due to their lower
stability and nucleophilicity.18 We were pleased to observe that
primary alkyl substituents carrying various functional groups,
including alkyl bromide, aryl iodide, ester, amide, carbamate,
terminal alkyne, and benzyl chloride, can be incorporated in
good yield (see 3g-3l). As seen in 3m-3r, the alkylation
reactions of secondary alkyl boronic acids are much faster than
the primary and typically proceed in good to excellent yield
under the standard conditions. In contrast to alkylation,
arylation with PhB(OH)2 gave product 3s in low yield (21%).
As seen in 4-11, alkylation of pyridines and pyridine-based
heteroarenes selectively took place at C2 and/or C4 positions. A
mixture of C2-substituted 4a and C4-substituted 4b was
obtained for unsubstituted quinoline. Alkylation of 2-
methylquinoline selectively occurred at C4 to give 9 in
excellent yield. In general, electron-deficient N-heteroarenes
show higher reactivity toward alkylation. For instance,
cyclohexylation of 4-t-butylpyridine predominantly resulted in
mono-alkylation (see 5b) while cyclohexylation of 4-CF3-
pyridine gave 2,6-dialkylated 8 in excellent yield using 3 equiv
of boronic acid. A variety of other N-heteroarenes can also be
alkylated in good yield and regioselectivity (see 12-20). For
instance, a purine riboside substrate was selectively alkylated at
C6 to give 12 in excellent selectivity;7d and a pyrrole-fused
pyrimidine was selectively alkylated on the electron-deficient
pyrimidine ring to give 14 in good yield. Without protection of
the NH group, benzimidazole can be alkylated at C2 to give 20
in good yield.
Results and Discussion
Although alkyl boron reagents are readily available and are
well-known precursors for alkyl radicals, they have been rarely
applied in photoredox-mediated C−C coupling reactions.10-13 In
2012, Akita reported that alkyl trifluoroborates or cyclic
triolborates can couple with 2,2,6,6-tetramethylpiperidinyl-1-
oxy (TEMPO) or Michael acceptors under Ru or Ir photoredox
catalysis.11 In 2015, Chen reported
a
decarboxylative
alkenylation of alkyl trifluoroborates with vinyl carboxylic
acids using a hypervalent iodine oxidant, acetoxybenziodoxole
(BI-OAc), under Ru photoredox catalysis.12a More recently,
Molander achieved coupling of alkyl trifluoroborates with aryl
halides by merging photoredox with Ni cross-coupling
catalysis.13 During our recent investigation of radical-mediated
sp3 C−H azidation reactions, we discovered that
azidobenziodoxole (Bl-N3) can be readily activated by visible
light in the presence of [Ru(bpy)3]Cl2, initiating a radical chain
reaction.14 Intrigued by the unique radical reactivity of
benziodoxole reagents with photocatalysts, we questioned
whether they can facilitate Minisci C−H alkylation with alkyl
boron reagents under photoredox-mediated conditions. 15-17
Table 1. Minisci C−H alkylation of 1 under visible light.
Cl
Cl
N
Bu-B(OH)2 2a
or Bu-BF3K 2b
(1)
oxidants, solvent, Ar
visible light
N
H
1
3a
entry reagents (equiv)
solvents
t (oC)
/time (h)
yield(%)a
3a
1
2
3
2a (1.5), AgNO3 (0.2), K2S2O8 (3) DCM/H2O
30 / 24
18
30
33
2b (1.5), Mn(OAc)3 (2.5), TFA (1) AcOH/H2O 50 / 18
2a (1.5), Bl-OAc (2), Ru(bpy)3Cl2 DCM
30 / 24
30 / 24
30 / 24
30 / 24
30 / 24
30 / 24
30 / 24
(0.01), VLb
4
5
6
7
8
9
2a (1.5), Bl-OAc (2), Ru(bpy)3Cl2 CH3CN
(0.01), VL
2a (1.5), Bl-OAc (2), Ru(bpy)3Cl2 HFIP
(0.01), VL, Ar
2b (1.5), Bl-OAc (2), Ru(bpy)3Cl2 HFIP
(0.01), VL
2a (1.5), Bl-OH (2), Ru(bpy)3Cl2
38
88 (82c)
59
HFIP
82
(0.01), VL
2a (1.5), Bl-OMe (2), Ru(bpy)3Cl2 HFIP
(0.01), VL
2a (1.5), Bl-N3 (2), Ru(bpy)3Cl2
61
HFIP
25
(0.01), VL
10 2a (1.5), Bl-Cl (2), Ru(bpy)3Cl2
(0.01), VL
11 2a (1.5), PhI(OAc)2 (2),
Ru(bpy)3Cl2 (0.01), VL
12 2a (1.5), Bl-OAc (2), Ir(ppy)3 (0.01), HFIP
HFIP
HFIP
30 / 24
30 / 24
30 / 24
<2
<2
22
VL
13 2a (1.5), Bl-OAc (2), VL
14 2a (1.5), Bl-OAc (2), Ru(bpy)3Cl2
(0.01), in darkness
HFIP
HFIP
30 / 24
30 / 24
<2
<2
15 2a (1.5), Bl-OAc (2), TEMPO (2), HFIP
30 / 24
<2
Ru(bpy)3Cl2 (0.01), VL
As shown in Scheme 3, this Minisci C−H alkylation can be
readily applied to functionalize complex natural products and
drug molecules.2c, 8, 9a For instance, quinine with a free OH and
vinyl group can be selectively alkylated at C2 position with
both ethyl and cyclohexyl groups in excellent yield (see 21).
Camptothecin can be selectively alkylated at the C4 position of
(a) Yields are based on 1H-NMR analysis on a 0.2 mmol scale; (b)
VL: compact household fluorescent bulb, 20W; (c) Isolated yield.
We commenced our investigation with C−H butylation of 4-
chloroquinoline 1, a common model substrate for Minisci
2 | J. Name., 2012, 00, 1-3
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(HO)2B
O
N
R1
(1.5 equiv)
N
N
R2
N
R
R:
N
R
View Article Online
BI-OAc (2 equiv)
HO
N
Ph
O
N
(2)
DOI: 10.1039/C6SC02653B
R1
22a, 42% (24h)
Cy, 22b, 50% (12h)
caffeine
H
quinine
Ru(bpy)3Cl2 (1 mol%)
HFIP, visible light, Ar, 30 o
Conditions Aa
MeO
R2
C
R: Et, 21a, 81% (24h)
Cy, 21b, 90% (8h)
N
I
R: Bu, 3a, 82%
Me, 3b, 46%b
Et, 3c, 80%
Pr, 3d, 85%
i-Bu, 3e, 78%
Oct, 3f, 73%
(24h)
Cl
N
O
4 Br
3h, 60%
(24h)
HN
O
R
R:
3g, 60% (24h)
4O
R
O
N
N
N
OAc
Br
R
O
NHCbz
24a, 51% (7h)
N
H2N
N
N
O
OH
camptothecin
3i, 77%
(24h)
4
4 Br
OAc
Famciclovir
O
O
24b, 65% (5h)
R: Et, 23a, 60% (48h)
Cy, 23b, 91% (5h)
H
Cy, 24c, 50% (4h)
Et, 24d, 70% (4h)
N
Cl
3l, 52%
(24h)
3j, 55% (10h)c
3k, 74% (10h)
Cl
NH
OH
O
N
Fenarimol
R1=Et, R2=H, 25a, 11%
R1=H, R2=Et, 25b, 14%
R1=Et, R2=Et, 25c, 16%
(24h)
O
S
Cl
R1
NTs
Fasudil
N
N
3n, 56% 3o, 82%
3p, 87%
3m, 88%
3q, 88%
3s, 21%d
3r, 86%
(3h)
N
(24h)
(10h)
(1h)
(1h)
(1h)
(24h)
R: Et, 26, 61% (10h)a
R2
R
CbzHN
Scheme 3. Minisci C-H alkylation for functionalization of
natural products and drug molecules. Isolated yield on 0.2
mmol scale under the standard conditions with 1.5 equiv of R-
B(OH)2 (see Scheme 2). (a) Product was isolated in N-Boc
protected form.
NHCbz
N
R
N
N
4b, 11%e
R: Oct, 5a, 52% (48h)f
Cy, 5b, 53% (16h)f
4a, 39%
+
Cy
N
CF3
N
N
N
the pyridine ring (see 23). Caffeine, a challenging substrate for
previous Minisci reactions, can be selectively alkylated at C2
(see 22).7b Alkyl chains carrying an alkynyl or alkyl bromide
group can be installed at C6 of Famciclovir in good yield (see
24a, 24b). Fasudil carrying a free secondary NH group was
selectively alkylated at C1 in good yield (see 26).
Cy
Cy
Cy
N
Cy
Pr
8, 82% (2h)i
6, 70% (24h)g
7, 63% (1h)h
Pr
Cy
N
R
N
Cl
N
R: Et, 10a, 80% (24h)
Cy, 10b, 96% (1h)
11, 62% (24h)
9, 93% (2h)
Control experiments and density functional theory (DFT)
calculations have been carried out to probe the mechanism of
this photoredox-mediated Minisci alkylation with alkyl boronic
acids and Bl-OAc oxidant.19 As shown in Scheme 4A, we were
surprised to observe that reaction of 1 with BuB(OH)2 and 1
equiv of benzoyl peroxide in HFIP under visible light
irradiation without photocatalyst also gave the alkylated
product 3a in 20% yield along with 11% yield of arylated side
product 3s, which is presumably formed from PhŸ via the
decarboxylation of BzOŸ. In comparison with BuB(OH)2,
BuBF3K showed much lower reactivity. Furthermore, 3a was
formed as the only C−H functionalized product in 38% yield
when ortho-iodobenzoyl peroxide 27 (highly explosive) was
used as the oxidant for reaction of 1 with BuB(OH)2 under the
same conditions.20 These experiments suggest that benzoyloxy
radicals can react with alkyl boronic acids to generate the
requisite alkyl radical for the subsequent C−H alkylation. As
shown in Scheme 4B, our DFT calculation showed that oxidant
Bl-OAc can be readily reduced by photoexcited Ru(II)* via
single electron transfer (SET) to form a radical anion
intermediate Bl-1, which then can undergo I−O bond cleavage
to form radical Bl-2 and acetate anion via pathway a or form
Bl-3 and acetoxy radical AcOŸ via pathway b.21 Formation of
Bl-2 is considerably more thermodynamically favorable than
formation of AcOŸ. Although a pair of interconvertible radical
Pr
OMe
Cl
I
N
N
N
R
N
N
AcO
N
N
O
MeO2C
N
Pr
N
H
12, 60%
R: Pr, 13a, 72% (24h)
Cy, 13b, 90% (1h)
14, 62% (24h)
(24h)j
AcO OAc
N
Cy
Cl
N
S
R
Cl
N
R
N
N
R: Pr, 16a, 64% (24h)
Cy, 16b, 78% (10h)
R: Pr, 15a, 82% (24h)
Cy, 15b, 88% (2h)
17, 65% (2h)
N
N
O
Ph
N
Cy
N
H
NH
18, 67% (24h)
N
Ph
19, 64% (24h)
20, 76% (10h)
Scheme 2. Substrate scope of photoredox-mediated C−H
alkylation of N-heteroarenes. (a) Isolated yield on 0.2 mmol
scale; (b) 2 equiv of MeB(OH)2, 48h; (c) 2 equiv of RB(OH)2;
(d) 1.5 equiv of PhB(OH)2; (e) 1 equiv of RB(OH), 2,4-
dialkylated product was formed in <5% yield; (f) 2,6-
dialkylated product was formed in <3% yield; (g) 2,2’-
dialkylated product was formed in <5% yield; (h) 4.5 equiv of
CyB(OH)2; (i) 3 equiv of CyB(OH)2. (j) other alkylated
regioisomer was formed in <5% yield.
This journal is © The Royal Society of Chemistry 2012
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A)
Calculation also revealed that Bl-2 is notably more stable than
O
O
benzoyloxy radical BzOŸ and is much less prone to undergo
O
View Article Online
Cl
N
Cl
N
3s
11%
7%
decarboxylation to form the corresponding aryl radical, which
O
(1 equiv)
DOI: 10.1039/C6SC02653B
could cause the C−H arylation side reaction.25 Similar to the
nucleo-homolytic substitution reaction of more reactive
alkylboranes with O-centered radicals, Bl-2 could react with the
less Lewis-acidic boronic acids to form an alkyl radical RŸ via
a radical “ate” transition state.26-28 The DFT calculation showed
that this is a facile process at ambient temperature and highly
exothermic (Scheme 4D).
BuB(OH)2 or BuBF3K
(1.5 equiv)
+
Bu
3a,
BuB(OH)2: 20%
BuBF3K: ~5%
Ph
HFIP, Ar, 30 oC, 24h
visible light
Cl
(without Ru(II))
I
O
N
O
O
1
27 (1 equiv)
(explosive!)
O
I
3a (38%)
no arylated side product formed
~50% unreacted 1 recovered
BuB(OH)2 (1.5 equiv)
I
Bl-OAc
OH
B
same as above
O
HO
R
SET 1
Ru(III)
O
B)
Ru(II)∗
Ru(II)
Bl-2
I
O
ΔG
R
B
I
a
b
O
O
+
+
= −24.2
photoredox
cycle
OH
OH
TS
O
O
O
light
O
O
I
Bl-2
Bl-3
AcO
I
SET
Bl-OAc
O
O
ΔG
= 0.0
O
Ru(II)* Ru(III)
O
ΔG
N
H
H
Bl-1
= −16.4
SET 2
O
ΔG = −18.7
H
R
R
O
AcO
+ H+
R
N
29
N
H
H
31
30
C)
ΔG‡ = 15.3
ΔH‡ = 16.9
Bl-2
stabilized by
a secondary O…
I
I
Scheme 5. Proposed mechanism.
I
O
bonding interaction
O
CO2
28 (o-I)Ph
Bl-2
Based on the above studies, we propose that the reaction
with boronic acid substrates is initiated with the SET from
photoexcited Ru(II)* to Bl-OAc (Scheme 5). The resulting Bl-2
reacts with boronic acid to form a RŸ, which then undergoes
nucleophilic addition reaction with protonated N-heteroarenes
to form a σ-complex. Single-electron oxidation of this
intermediate by Ru(III) and deprotonation gives the final C−H
alkylated product and closes the photoredox cycle.29
spin density
ΔG = −2.1
ΔH = 9.3
over both O and I
vs
vs
ΔG‡ = 6.9
ΔH‡ = 7.2
Bl-4
I
cyclic I-centered radical
(I−O distance ca. 2.1-2.2 Å)
cannot be located
O
O
O
CO2
Ph
ΔG = −8.6
ΔH = 1.7
BzO
O
by calculation
D)
ΔG
(ΔH)
15.3
(1.6)
Conclusions
TS-1
In summary, we have developed a photoredox-mediated
Minisci C−H alkylation reaction of N-heteroarenes with easily
accessible alkyl boronic acids. A broad range of alkyl groups,
including challenging primary alkyl groups, can be readily
incorporated into various N-heteroarenes with high efficiency
under mild conditions. These reactions exhibit excellent
substrate scope and functional group tolerance, and offer a
broadly applicable method for the late-stage functionalization
of complex substrates. Mechanistic studies have revealed that
acetoxybenziodoxole serves as a facile precursor for an ortho-
iodobenzoyloxy radical intermediate under photoredox
catalysis. The unique property of this intramolecularly
stabilized benzoyloxy radical might be critical for the efficient
transformation of usually less reactive alkyl boronic acids to
form alkyl radicals. Further mechanistic studies and application
of benziodoxole reagents in other photoredox-mediated reaction
systems are currently underway.
I
0.0
(0.0)
TS-1
O
OH
B
Bl-2 + BuB(OH)2
O
OH
−22.2
(−21.3)
29
Scheme 4. Mechanistic studies. DFT calculations were
performed at the M06-2X/6-311++G(d,p)-
SDD/SMD(HFIP)//M06-2X/6-31+G(d)-SDD level of theory.
All energies are in kcal/mol.
species, I-centered radical Bl-4 and O-centered radical Bl-2,
have been invoked in a number of previous studies,22 the
postulated cyclic structure of Bl-4 with a typical I−O bond
length of ca. 2.1-2.2 Å cannot be located in our DFT calculation
(Scheme 4C).23 Instead, the acyclic radical intermediate Bl-2 is
stabilized by a secondary I−O bonding interaction (~2.6 Å) and
its spin density is distributed between the O and I atoms.24
4 | J. Name., 2012, 00, 1-3
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Acknowledgements
Ishihara and P. S. Baran, Nature 2012, 492, 95; (c) A. P. Antonchick
and L. Burgmann, Angew. Chem., Int. Ed. 2013, 52, 3267; (d) R.
View Article Online
We gratefully thank the State Key Laboratory of Elemento-
Organic Chemistry at Nankai University and the University of
Pittsburgh for financial support of this work.
Xia, M.-S. Xie, H.-Y. Niu, G.-R. Qu and H.-M. Guo, Org. Lett.
DOI: 10.1039/C6SC02653B
2014, 16, 447; (e) W.-M. Zhao, X.-L. Chen, J.-W. Yuan, L.-B. Qu,
L.-K. Duan and Y.-F. Zhao, Chem. Commun. 2014, 50, 2018; (f) R.-
J. Tang, L. Kang and L. Yang, Adv. Synth. Catal. 2015, 357, 2055;
(g) T. McCallum and L. Barriault, Chem. Sci. 2016, 7, 4754.
D. A. DiRocco, K. Dykstra, S. Krska, P. Vachal, D. V. Conway and
M. Tudge, Angew. Chem., Int. Ed. 2014, 53, 4802.
Notes and references
8
9
a
State Key Laboratory and Institute of Elemento-Organic Chemistry,
Collaborative Innovation Center of Chemical Science and Engineering
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J. Name., 2012, 00, 1-3 | 5

Chemical Science
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Journal Name
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29 The control experiment in Scheme 4A suggest that the reaction of
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mechanisms under our reaction conditions. It is plausible that that
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easily oxidizable alkyl trifluoroborates to give the alkyl radical and
Ru(II). Such process has been proposed in the previous studies of
Bl-mediated photoredox-catalyzed reaction system using alkyl
trifluoroborates (ref 12). Formation of alkyl radical via SET
oxidation of alkyl trifluoroborates by Ru(III) or Ir(X) have been
6 | J. Name., 2012, 00, 1-3
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