Direct photochemical cross-coupling between aliphatic acids and BF3K salts

Article abstract of DOI:10.1039/c9cc09164e

We describe a novel photoredox hetero-coupling reaction of two C (sp³) radicals from aliphatic acids or BF₃K salts. The kinetic differences in radical persistence provide cross-selectivity, using an organic photoredox catalyst and an oxidant with visible light. This method exhibits broad scope, including several examples constructing sterically hindered C(sp³)-C(sp³) bonds.

Full text of DOI:10.1039/c9cc09164e

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Received 00th January 20xx,Direct photochemical cross-coupling between
aliphatic acids and BF3K salts
Accepted 00th January 20xx
Zhuming Sun, Bingqing Tang, Kevin K.-C. Liu and Hugh Y. Zhu*a
DOI: 10.1039/x0xx00000x
We describe a novel photoredox hetero-coupling reaction of two C
(sp3) radicals from aliphatic acids or BF3K salts. The kinetic
differences in radical persistence provide cross-selectivity, using an
organic photoredox catalyst and an oxidant with visible light. This
method exhibits broad scope, including several examples
constructing sterically hindered C(sp3)-C(sp3) bonds.
steric hindrance. In silico calculation of 19.3 kcal/mol for the
central bond of a 1a’-1a’ dimer predicted a low propensity for
self-dimerization (Scheme 1).9
To extend these results in the current study, we observed
that the benzyl radical 1b’ was readily generated from benzylic
BF3K salt 1b under the same photoredox conditions using
1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene
(4CzlPN),
forming the dimeric bibenzyl 1d.4a,10,11 With the addition of
persulfate salts as oxidant,12 carboxylic acid 1a directly coupled
with 1b in good yield, consistent with a reaction of persistent
radical 1a' with transient radical 1b’.13 Product 1c was isolated
in 65% yield (based on 1b, 0.3 mmol) under our optimized
conditions [4CzIPN (5 mmol%), acid 1a (2 equiv), Cs2CO3 (2
equiv), (NH4)2S2O8 (2 equiv), DMSO solvent, 2W blue LED
reactor).14 We also isolated bibenzyl 1d (~15% consumption of
1b), but did not detect a homodimer from 1a’. Considering the
transient nature of the radicals and their diffusion controlled
kinetics, the relatively high 65% yield was consistent with the
low propensity of 1a’ dimerization. To our best knowledge, this
is the first report of direct coupling of C (sp3)–C (sp3) between a
carboxylic acid and an organotrifluoroborate salt.
Carbon radical-based chemistry has flourished in recent years.1
Numerous publications have demonstrated the prowess of dual
photoredox/Ni catalysis protocols in constructing C(sp3)-C(sp2)
bonds.2 C(sp3)-C(sp3) bonds could be formed through C(sp3) radical
addition to  systems (Giese coupling).3 In theory, matching
persistent radicals with kinetically transient radicals may facilitate
synthetically useful hetero-couplings.4 In a seminal demonstration
of this concept, MacMillan attributed the high efficiency of -amino
C-H arylation to persistent aryl anion radicals C(sp2) coupling with
transient C(sp3) -amino radicals.5
subsequently reported synthesizing a variety of -amino ether
products through C(sp3)-C(sp3) coupling using
photoredox-
MacMillan's laboratory
a
hydrogen atom transfer (HAT) system, in which both radical coupling
partners formed at the same rate within the same “redox-neutral”
cycle.6 Other studies promoted radical cross-couplings by adding
external reducing agents.7 These impressive results spur
development of novel photoredox chemistry.
NHBoc
NHBoc
N
4-CzIPN (5 mmol%)
Cs2CO3 (2.0 equiv)
(NH4)2S2O8 (2.0 equiv)
NC
N
CN
N
OH
BF3-K+
+
N
DMSO (0.1 M), rt
30 min N2 bubbling
2W blue LED, Overnight
N
O
N
Cbz
Cbz
We sought to investigate direct photochemical C(sp3)-C(sp3)
radical coupling reactions using readily available precursors, such as
carboxylic acids and alkyltrifluoroborate salts. We proposed
generating two C(sp3) radicals in a decoupled manner with a
common photoredox catalyst, to enable hetero-coupling a persistent
radical (PR) with a transient radical (TR), in the presence of a
stoichiometric oxidant to recycle reduced photoredox catalyst.
In our separate study, we reported that the C(sp3) radical
generated from commercially available amino acid 1a directly
reacted with a number of sp2 aromatic substrates.8 We
reasoned that the resulting 1a’ had persistent radical character
due to hyperconjugation from neighboring heteroatoms and
1a
1b
1c (65%)
(2 eq)
(1 eq)
4CzIPN
NHBoc
+
1a
1b
N
Cbz
1a'
1b'
Cbz
N
BocHN
1c
N
1a' + 1a'
1d
(formed and verified)
NHBoc
Cbz
19.3 kcal/mol
Scheme 1. Optimized conditions for radical cross-coupling in a model system, and a
mechanistic proposition.
a Novartis Institute for Biomedical Research, 4218 Jinke Road, Pudong, Shanghai,
China. E-mail: hughzhu@hotmail.com
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
Next, we explored the scope of carboxylic acid substrates using
benzyl trifluoroborate 1b as the TR precursor (figure 1). In the case
of 2a with a quaternary acid starting material, the yield was slightly
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lower than its N-Boc amino acid counterpart 1a, suggesting a pyridines (4i-k) were all compatible. Adjusting the
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DOI: 10.1039/C9CC09164E
diminished stabilizing effect from only one -amino group. Other stoichiometry of the PR:TR precursor ratio from 2:1 to 1:2
cyclic amino acids gave yields ranging from 39% to 67% (2b-g), improved yields in some cases (4h, 4j, 4l-m, 4o & 4r). However,
exhibiting tolerance for several N-protecting groups (2d-f). only 4o showed a boost in yield with additional Cs2CO3.
Secondary radicals from acids with α-heteroatoms such as pipecolic Transient secondary radical derived from acids also afforded
acid (2i), tetrahydropyran-2-carboxylic acid (2j) and proline (2k) all cross-coupling products (4p-r). This acid-to-acid hetero-
successfully coupled with 1b. The scope further expanded to the coupling worked for other “PR” precursors as well (4s-t, 5a-b).
lactam from pyroglutamic acid (2l) and the acyclic amino acids N-Boc Even N-protected α-amino acids served as coupling partners,
alanine and phenylalanine (2h, 2m-n). Other functional groups such albeit in lower yields (5c-5e).
as alcohols, phenols, and electrophilic alkenes were tolerated, as
R1
OH
Standard condition
R2
BF3-K+
R2
R1
+
O
Nateglinide, Enoxolone or N-Boc methyldopa afforded good yields
(2o-q). We consistently observed minimal amount of dimer 1d
(~10%) and little or no PR dimers. For the preparations of 2i and 2k,
the yields substantially increased with 4 equivalents of cesium
carbonate. The additional loading of base promoting carboxylate
anion formation may maintain a higher concentration of persistent
radical, to complete more effectively with transient radical
dimerization.
(1 eq)
( 2 eq)
NHBoc
NHBoc
NHBoc
NHBoc
N
N
N
OMe
OMe
Boc
OMe
N
Me
Cbz
Cbz
Cbz
3b o-Me 33%
3c m-Me 45%
3d p-Me 52 %
3f 58 %
3a 68 %
NHBoc
3e 61 %
Me
NHBoc
NHBoc
NHBoc
Me
O
Me
N
N
N
N
Cbz
3j 29 %
(48 %)a
Cbz
Cbz
BF3-K+
Cbz
3i 56 %
R1 OH
R1
Standard condition
3h 40 %
(47%)a
+
3g 50 %
O
1
(2 eq)
2
1b
(1 eq)
Figure 2. Coupling between various acids and different BF3K salts. All isolated yields
calculated based on BF3K salt. No e.e. detected. a Cs2CO3 (4 equiv) was used.
R
NHBoc
BocHN
BocHN
N
N
N
R
Cbz
Boc
R1
OH
R2
OH
Standard condition
1c R = NHBoc, 65 %
2a R = Me, 41 %
2b 39 %
2c 61 %
2d R = Cbz, 67 %
2e R = CO2Me, 51 %
2f R = Boc, 42 %
R1
R2
+
O
O
( 2 eq)
( 1 eq)
NHBoc
BocHN
O
NHBoc
NHBoc
NHBoc
NHBoc
N
N
N
N
NH
N
O
Boc
N
N
X
N
N
N
N
2g 40 %
2h 53 %
2i 45 % (61 %)a
2j 43 %
Cbz
Cbz
Cbz
Cbz
4a X = Cl, 43 %
4b X = Br, 45 %
4c 50%
4d 41 %
NHBoc
4e 32 %
NHBoc
BocHN
N
O
NHBoc
N
NHBoc
NHBoc
H
Boc
OCF3
N
2k 21 % (37 %)a
2l 56 %
2m 57 %
2n 62 %
N
N
X
N
N
N
X
Cbz
Cbz
Cbz
Cbz
4j X = Cl, 43 %a
4k X = Br, 31 %
HO
HO
4g X = OH, 30 %
Me
4i 23 %
NHBoc
4f 32%
H
N
3a X = OMe, 49 %a
NHBoc
H
O
H
OMe
BocHN
BocHN
NHBoc
O
O
N
tBu
N
HO
N
N
Me
Cbz
Cbz
Cbz
Cbz
From Nateglinide
2o 53 %
From Enoxolone
From Methyldopa
2q 45 %
3b o-Me, 34 % (48 %)a
3c m-Me, 22 % (52 %)a
3d p-Me, 53 %
4o 25%
(50 %)a
(68 %)b
4p 32 %
d.r. = 2.3 : 1
4q 44 %
d.r. = 1.8 : 1
2p 60 % d.r. = 1:1
Figure 1. Coupling between different acids 1 and 1b. All isolated yields calculated on
BF3K salt. No e.e. detected. a Cs2CO3 (4 equiv) was used.
BocHN
NHBoc
N
NHBoc
N
Me
OnBu
O
N
N
N
N
Boc
Boc
Other BF3K salts were then surveyed (figure 2). As expected,
electron-donating substituents generally gave better yields, as
observed with 4-OMe benzyl radicals (3a, 3e, 3f). Methyl
substituted benzyl BF3K salts also coupled with piperidine
carboxylic acid (3b-d) and pyrrolidine carboxylic acid (3g-i). The
yield arising from the methoxymethyl BF3K salt under standard
conditions nearly doubled with 4 equivalents of Cs2CO3 (3j).
A variety of carboxylic acids were effective precursors for
the transient radical component, significantly broadening the
scope of coupling partners due to the greater availability of
carboxylic acids. Halogenated phenylacetic acids gave
acceptable yields (4a-b, figure 3). Acids containing other aryl
and heteroaryl groups such as pyrimidine (4c), pyrazine (4d),
triazole (4e), phenol (4g), phenol ethers (4f and 4h) and
Cbz
Cbz
4s 38%
5a 48 %
4r 40 %
(58 %)a
3i 56 %a
d.r. = 1.5 : 1
NHBoc
NHBoc
N
N
N
NHBoc
NHBoc
Boc
N
Boc
NHBoc
Cbz
5d 21 %
d.r. = 1.3 : 1
5c 25 %
d.r. = 1.6 :1
5e 26 %
5b 36 %
Figure 3. Coupling between two acids. All isolated yields (calculated based on
a
R2CO2H if not noted). No e.e. detected. R1CO2H : R2CO2H = 1: 2. Yield calculated
b
based on R1CO2H Cs2CO3 (4 equiv) was used.
We observed some nuance between acid-BF3K and acid-acid
coupling reactions. In acid-BF3K couplings, significant amounts
2 | J. Name., 2012, 00, 1-3
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of dimers from TR precursors were isolated, whereas from acid- radical mechanism. In fluorescent quenching VieewxpAretircilemOennlinte,
DOI: 10.1039/C9CC09164E
acid couplings, these dimers were seldom detected, suggesting carboxylic acids or BF3K salts reduced the 4CzlPN*-4CzlPN
2-
a lower concentration of transient radicals in acid-acid fluorescent signal, whereas S2O8 had no effect (figure 5, c).15
couplings. This also explained the yield boosts using two Based on this, we proposed a catalytic cycle (figure 5, d).
equivalents of the TR-precursor carboxylic acids (figure 3). On Irradiation transformed 4CzIPN into its long-lived excited-state
the contrary, increase in the equivalents of persistent radical 4CzIPN*, which acted as a strong oxidant (E1/2PC*/PC- = +1.35 V
precursor along with additional base may increase the yields in vs SCE) to convert 1a carboxylate anion and 1b into the
our acid-BF3K couplings. These observations reflect the respective radicals 1a’ and 1b’. The reduced radical anion
̄
complexity of kinetic control, and possibly other side reactions 4CzIPN•ˉ was subsequently oxidized by persulfate, regenerating
that we have not yet characterized.
ground state 4CzlPN.
As traditional methods are often unsuitable for constructing
hindered carbon-carbon bonds, we attempted tetrasubstituted
tertiary C(sp3) and quaternary C(sp3) couplings (figure 5). The simple
access to these congested structures further exemplified the value of
our photoredox strategy. For our general interest in drug discovery,
practical incorporation of C(sp3) may improve selectivity and
physicochemical properties of prospective drug candidates.16
a)
b)
BocHN
BocHN
O
Cl
BocHN
R
NHBoc
NHBoc
BF3-K+
CO2H
standard condition
(5.0 eq)
N
+
N
N
+
N
Cbz
N
N
Cbz
Boc
N
Cbz
Cbz
BocHN
6a 26 %
Cbz
Cbz
34%
7e
25%
7c
27%
7d
1b
1a
R = NHBoc 7a 41%
R = Me
1c 0 %
7b 30%
c)
Figure 5. Examples of tetrasubstituted tertiary and quaternary carbon bond formations
from acid-acid couplings (all isolated yields).
In conclusion, this novel C(sp3)-C(sp3) coupling reaction exhibits
relatively broad substrate scope and reasonably good isolated yields,
under mild conditions with simple operations. This method uses
inexpensive low-toxicity organic photoredox catalysts and
abundantly available carboxylic acid starting materials.17 By directly
enabling single-step access to under-explored chemical spaces, this
method may find applications in natural product synthesis and drug
discovery. Due to the complex nature of the kinetic conditions, these
results warrant additional experimentation and theoretical studies,
including evaluation of other photoredox catalysts, flow chemistry
for better kinetic control, and/or extensions to chiral induction.
We thank Drs. En Li and Amber Cai for the CNIBR Trainee
program (B.T.). We also thank Dr. Kian Tan (NIBR Cambridge) for
discussions and Prof. Frank McDonald (Emory University) for
proofreading. We additionally acknowledge assistance from Dr. Tian
Li, Mr. Tan Lin and Ms. Huiwen Deng.
d)
2-
SO4
+ SO4
4-CzIPN
2-
Cbz
S2O8
N
BocHN
1d
Reductive
Quenching
Cycle
N
NHBoc
4-CzIPN
Cbz
1a' + 1a'
1b' + 1b'
4-CzIPN*
NHBoc
Conflicts of interest
There are no conflicts to declare.
NHBoc
BocHN
cross-coupling
BF3-K+
+
-
CO2
+
N
N
N
Cbz
Cbz
1a
Cbz
1b
1b'
1c
1a'
a
b
c
Figure 4. Light on-off experiment. Radical trapping experiment. Fluorescent
Notes and references
quenching experiment. d Proposed reaction mechanism.
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J. Name., 2013, 00, 1-3 | 3
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