Surgical Cleavage of Unstrained C(sp3)?C(sp3) Bonds in General Alcohols for Heteroaryl C?H Alkylation and Acylation

Article abstract of DOI:10.1002/adsc.201900975

We reported herein a predictable and surgical cleavage of carbon-carbon bond in alcohols. A wide range of 1°, 2° and 3° alcohols including sugars and steroids without ring strain or steric hindrance were all compatible with this system. Also it offered a green and practical strategy for generation of alkyl/acyl radicals using alcohols as the sources. Besides, the features of visible-light-initiation, catalyst and metal free, excellent selectivity and mild conditions make it valuable and attractive. (Figure presented.).

Full text of DOI:10.1002/adsc.201900975

Title: Surgical Cleavage of Unstrained C(sp3)-C(sp3) Bonds in General
Alcohols for Heteroaryl C-H Alkylation and Acylation
Authors: Yaxin Wang, Le Yang, Shuai Liu, Lixia Huang, and Zhong-
Quan Liu
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10.1002/adsc.201900975
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Surgical Cleavage of Unstrained C(sp3)-C(sp3) Bonds in General
Alcohols for Heteroaryl C-H Alkylation and Acylation
Yaxin Wang,a Le Yang,a Shuai Liu,a Lixia Huang,a and Zhong-Quan Liu a*
a
State Key Laboratory Cultivation Base for TCM Quality and Efficacy, College of Pharmacy, Nanjing University of
Chinese Medicine, Nanjing 210023, China.
E-mail: liuzhq@lzu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. We reported herein a predictable and surgical Besides, the features of visible-light-initiation, catalyst and
cleavage of carbon-carbon bond in alcohols. A wide range of metal free, excellent selectivity and mild conditions make it
1o, 2o and 3o alcohols including sugars and steroids without valuable and attractive.
ring strain or steric hindrance were all compatible with this
system. Also it offered a green and practical strategy for
generation of alkyl/acyl radicals using alcohols as the
sources.
Keywords: Free-Radical; C-C Bond Cleavage; Alcohols;
Sugars; C-H Alkylation; C-H Acylation
cleavage of the unstrained C(sp3)-C(sp3) bond in
1o, 2o and 3o alcohols for heteroaryl C-H
alkylation and acylation (Scheme 1).
Introduction
The development of highly efficient strategy for
selective carbon-carbon (C-C) bond cleavage
could have profound impacts on synthetic organic
chemistry, petroleum cracking and biomass
conversion.[1,2] Among those established methods,
the C-C bond breaking occurs via alcohols
represents one of the most successful modes. In
general, there are three fashions in the cleavage
of a C-C bond adjacent to the hydroxyl group.
The first mode is the cationic fragmentation such
as the retro-Prins-type reaction and the well-
known pinacol rearrangement etc. The second
type is the anionic fragmentation such as the
Eschenmoser fragmentation. And the last one is
the β-scission of an alkoxy radical derived from
an alcohol.[3] Recently, advances in the alkoxy-
radical driven C-C bond fragmentation have been
made by Chiba,[4] Zhu,
Chen,[6] and others.[7]
[5]
These effective systems provide novel and
attractive strategies for synthetic organic
chemistry. However, most of these systems are
limited in 2o and 3o alcohols either with ring-
strain or crowded steric hindrance (Scheme 1).
The β-C-C bond fragmentation of the alkoxy
radical from unstrained alcohols especially 1o
alcohols remains a great challenge. To the best of
our knowledge, only three primary alcohols were
reported to undergo β-scission of the
corresponding alkoxy radical very recently.[8]
Furthermore, selective radical fragmentation of
the C-C bond adjacent to primary hydroxyl group
in sugars has never been reported so far. Herein
we wish to report a general and highly selective
Scheme 1. Alcohol C-C bond cleavage via β-scission of
alkoxy radical.
Results and Discussion
Selective cleavage of unstrained C(sp3)-C(sp3)
bond in 2-Me-butanol for lepidine C-H alkylation.
In the 70s and 80s of the last century, the
pioneering studies on photo-irradiation-induced C-C
cleavage in alcohols via alkoxy radicals had been
revealed by Suginome and Suárez et al.[9] However,
these systems were suffered from excess heavy
1
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10.1002/adsc.201900975
Advanced Synthesis & Catalysis
metals, limited substrate scope and relative low
efficiency. Inspired by these studies and the
hypervalent iodine mediated radical processes,[10] we
began to question whether the combination of
illumination with hypervalent iodine chemistry could
be applied to break the unstrained C(sp3)-C(sp3)
bonds in challenging 1o alcohols. If it works, general
alcohols could be used as greener and safer alkyl
radical sources than traditional reagents such as
haloalkane and alkylmetallic reagents etc. Initially, a
Minisci-type reaction[11] of lepidine 1 and 2-Me-
butanol 2 in the presence of hypervalent iodine under
photo-irradiation was examined (Table 1). However,
2 equiv. of (diacetoxyiodo)benzene (PIDA) exhibited
no reactivity (entry 1). Oxygen atoms in the primary
alcohols have lower electron density compared with
those in the reported cyclic alcohols and tertiary
alcohols, thus an array of hypervalent iodine reagents
were screened (entries 2-12). As analyzed above, we
were delighted to find that the desired product 3 was
obtained in 95% yield when 2.0 equiv. of
[bis(trifluoroacetoxy)iodo]benzene (PIFA) with more
deficient electron instead of PIDA was applied (entry
2). This result prompted us to evaluate the effect of
different substituents of hypervalent iodine (III)
reagents on the yield of alkylation products. Other
aryliodine bis(trifluoroacetate) also gave product 3 in
moderate to excellent yield, which showed that the
electronegativity and the position of the substituent
on the phenyl have little effect on the reaction
efficiency (entry 3 to entry 8). I(OCOCF3)3 or
C4F9I(OCOCF3)2 could not promote C-C bond
cleavage of 2-Me-butanol under the irradiation of
blue light (entry 9 entry 10). In contrast to acyclic
hypervalent iodine reagents, cyclic hypervalent
iodine reagents such as hydroxybenziodoxole BIOH,
entry
1
reagent (equiv), reaction time, temp
2 (5), PIDA (2.0), 12 h, 20 o
2 (5), PIFA (2.0), 12 h, 20 o
2 (5), p-Me-PhI(OCOCF3)2, 12 h, 20 o
2 (5), p-F-PhI(OCOCF3)2, 12 h, 20 oC
solvent
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
3 %
3' %
0
C
0
95
2
C
0
(89)b
3
C
70
65
78
68
61
80
0
0
4
0
5
2 (5), p-Br-PhI(OCOCF3)2, 12 h, 20 o
2 (5), p-Cl-PhI(OCOCF3)2, 12 h, 20 o
2 (5), o-Cl-PhI(OCOCF3)2, 12 h, 20 o
C
0
6
C
C
0
7
0
8
2 (5), m-Cl-PhI(OCOCF3)2, 12 h, 20 o
C
0
9
2 (5), I(OCOCF3)3 (2.0), 12 h, 20 oC
2 (5), C4F9I(OCOCF3)2 (2.0), 12 h, 20 o
0
10
11
12
13
14
15
16
17
18
19
20
21
C
0
0
2 (5), cyclic [IIII] reagentsc (2.0), 12 h, 20 o
C
0
0
2 (5), BIN3(2.0), 12 h, 20 oC
4
18
0
2 (5), PIFA (1.5), 12 h, 20 o
2 (5), PIFA (1.5), 12 h, 20 o
2 (5), PIFA (1.5), 12 h, 20 o
C
C
C
56
43
21
0
DCM
(0.5)
DCM
(0.3)
15
20
0
2 (5), PhI (0.2), Oxone (0.3), CF3COOH (0.3),
DCM
solventd
DCM
12 h, 20 oC
2 (5), PIFA (1.5), 12 h, 20 o
C
<10
93
44
0
0
2 (5), PIFA (2.0), 12 h, 20 oC, UV (365 nm, 24
0
W)
2 (5), PIFA (2.0), 12 h, 20 oC, CFL (White, 24
DCM
0
W)
2 (5), PIFA (2.0), 12 h, 20 oC, in darkness
DCM
0
acetoxybenziodoxole
BIOAc
and
93
2 (5), PIFA (2.0), 2 h, 20 o
C
DCM
0
(85)b
chloroxybenziodoxole BICl exhibited no reactivity
(entries 11). Interestingly, when Zhdankin reagent
BIN3 was used, main product 3’ was produced via
hydrogen atom transfer process of 2-Me-butanol
(entries 12). Reducing amount of PIFA obviously
dropped yield of the reaction (entries 13). Increasing
reaction concentration led to an increased yield of by-
products 3’ (entries 14 and entries 15). The strategy
via in situ generation of PIFA using a catalytic
amount of iodobenzene with oxone did not work
(entries 16). Then different solvents such as DMF,
DMSO, THF and acetone were evaluated to be less
efficient than DCM (entries 17). Furthermore the
light source had a remarkable impact on this reaction
(entries 18-20). Irradiation of black light (UV 365 nm,
24 W) with higher energy gave comparable results
(entries 18). However, with white light (CFL, 24 W),
the yield was significantly reduced (entries 19). No
reaction occurred in darkness (entries 20). Finally we
found that the reaction could complete in 2 hours
(entry 21) and be easily scaled up to gram level
without decreasing efficiency (See SI).
[a] Yields are based on 1H-NMR analysis of reaction
mixture on a 0.1 mmol scale at a 0.2 M concentration
unless specified otherwise using ACS grade solvents under
an air atmosphere. Source of light: 24 W blue LEDs. [b]
Isolated yield. [c] Cyclic hypervalent iodine [IIII] reagents
were used. [d] Other solvents such as DMF, DMSO,
acetone and THF were used.
Substrate Scope and Selectivity.
Selective cleavage of unstrained C(sp3)-C(sp3)
bonds in alcohols for lepidine C-H alkylation and
acylation. With the optimized conditions in hand, we
then explored the scope of this system. As shown in
Scheme 2, a wide range of 1o, 2o and 3o alcohols
without ring strain or steric hindrance were all
compatible with this reaction. Initially a series of
cyclic and acyclic 1o alcohols were examined (4-17).
The cleavage of the C(sp3)-C(sp3) bond in alcohols
Table 1. Surgical cleavage of unstrained C(sp3)-C(sp3)
bond in 2-Me-butanol for lepidine C-H alkylation.
2
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10.1002/adsc.201900975
Advanced Synthesis & Catalysis
underwent smoothly and the corresponding alkylated
Lepidine were obtained in high to quantitative yields
(4-9). In addition, alcohols with diverse functional
groups, such as unprotected hydroxyl, ether, ester,
ketone and even amide were also screened (10-17).
At the beginning, the reactions failed to conduct by
using these substrates under standard conditions. But
the problems were solved soon by replacing the
solvent dichloromethane (DCM) with glycol dimethyl
ether (GDE). The possible reason is the strong
coordination between hypervalent iodine and alcohols
bearing more than one heteroatoms, which makes it
difficult to produce alkoxy radical. The O-atoms in
ether solvents might preferentially coordinate with
the I-atom, and hence prevent the strong coordination
between alcohols and PIFA. By using GDE as the
solvent, functionalized alcohols were also effective
substrates. It’s noteworthy that unprotected diols
were amenable to this system (11 and 12). Especially
it could achieve the β-hydroxyl alkylation of
heteroarene (12), which cannot be reached in the
previous Minisci-type reactions.[11] Besides, the
unstrained C(sp3)-C(sp3) bonds in α-hydroxy ketones
and α-hydroxy amides could also cleave to produce
corresponding acyl radicals and amide radicals, and
subsequently achieve lepidine C2-H acylation and
amidation reactions (15-17). Then we examined
various secondary and tertiary alcohols (18-26).
Under the optimal reaction conditions, they all can
afford the expected alkylated and/or acylated
heteroarenes via the selective C-C bond cleavage.
The diol compounds could also react smoothly (22-
24). Interestingly, when a diol with a primary and a
secondary hydroxyl groups was used as a substrate,
the secondary hydroxyl group preferentially reacted
with PIFA to give the corresponding alkylated
lepidine (23 and 24). This selectivity might be due to
the nucleophilicity of the O-atoms. Furthermore,
another attractive selectivity is the C-C bond cleavage.
It can be seen from 23 and 24 that the β-
fragmentation of the C-C bond occurred where a
more stable alkyl radical would form. For example, it
was not an isopropyl but a quaternary carbon that
alkylated to heteroarene because the 3o C-centered
radical is stable than the 2o one. Also the desired
products were isolated in excellent yields with
tertiary alcohols (25 and 26).
Scheme 2. C-H alkylation of lepidine by selective
cleavage of unstrained C(sp3)-C(sp3) bonds in alcohols.
3
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10.1002/adsc.201900975
Advanced Synthesis & Catalysis
Selective cleavage of unstrained C(sp3)-C(sp3)
monoalkylation and dialkylation in excellent yield
(46).
bonds in sugars and steroids for heteroaryl C-H
alkylation and acylation. The selective C-C bond
cleavage via β-fragmentation of alkoxy radical has
been successfully applied in skeletal modification of
sugars and steroids derivatives.[3, 9, 10] However, most
of these systems were limited in breaking the C-C
bond (C1-C2) adjacent to the secondary hydroxyl
group. To the best of our knowledge, the selective C-
C bond cleavage via β-scission of the primary alkoxy
radical in sugars has not been realized before. Based
on the results of Scheme 2, we began to apply this
strategy in sugars and steroids (Scheme 3).
Fortunately, for the first time, we successfully
incorporated a series of cyclic and/or linear sugars
and steroids into heteroarenes via primary alkoxy
radical-promoted selective cleavage of unstrained
C(sp3)-C(sp3) bond. As shown in Scheme 3, both
cyclic sugar Ribofuranoside (27) and linear sugars
such as Glycerol (28) and Xylitol (29 and 30) were
compatible with this system. It is worth noting that
only one configurational isomer was observed in
these reactions. This unique selectivity should be due
to the stereo-electronic effect (anomeric effect). The
hyperconjugation effect between electrons in SOMO
and p-orbital of the vicinal O-atom makes the radical
addition occurred at the axial direction. Interestingly,
this protocol can realize selective C-C bond cleavage
in one same sugar molecule (29 and 30). For example,
(2,2,2',2'-tetramethyl-[4,4'-bi(1,3-dioxolan)]-5-
yl)methanol and bis(2,2-dimethyl-1,3-dioxolan-4-
yl)methanol gave the corresponding products 29 and
30 respectively in good yields. In addition, steroid
Pregnenolol acetate was also evaluated to be effective
substrate, which reacted with lepidine to afford the
expected product in 56% yield (31). Thus this method
provided a new strategy for skeletal modification of
sugars and steroids compounds.
Selective cleavage of unstrained C(sp3)-C(sp3)
bonds in 2-Me-butanol for heteroaryl C-H
alkylation. Next, a variety of heteroarenes were
tested. As depicted in Scheme 4, alkylation of
pyridines and quinolines heteroarenes selectively
took place at C2 and/or C4 positions, while
isoquinoline solely preferred the C1 position (see 32-
36). In general, the electronic effect of substituents in
heteroarenes had little impact on the reaction (34b vs
34c). Other heteroarenes, such as quinoxaline,
phthalazine, quinazoline, benzoquinoline and
phenanthridine, were also proved to be suitable
substrates (see 36-41). Various functional groups
including unprotected hydroxyl or phenolic hydroxyl,
ether, benzoate or acetate, halogen, sulfonic acid,
amide, sulfonamide and even olefins were tolerated.
This Minisci C–H alkylation can also be successfully
applied to functionalize complex natural products and
drug molecules (42-46). For instance, fenazaquin,
quinoxyfen, fasudil and quinine can be selectively
alkylated at the specific position of the heteroaryl
ring in good yield under standard reaction conditions
(42-45). N,N-dibenzoyl-famciclovir resulted in
Scheme 3. C-H alkylation of lepidine by selective
cleavage of unstrained C(sp3)-C(sp3) bonds in sugars
or steroids.
4
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10.1002/adsc.201900975
Advanced Synthesis & Catalysis
mechanism was proposed (Scheme 5D). Firstly,
nucleophilic substitution reaction of PIFA with
alcohol produced intermediate A. Then photo-
irradiated homolysis of A afforded an alkoxy radical
by liberating PhI. Subsequently, the alkoxy radical
underwent a β-fragmentation to give an alkyl radical
and formaldehyde. Next addition of alkyl radical to a
protonated heteroarene generated a radical cation B,
which then conducted single electron oxidation
followed by deprotonation to yield the final product.
The by-products such as iodobenzene and aldehydes
or ketones were isolated and/or detected.
Scheme 4. Substrate scope of heteroarenes.
Mechanistic Studies.[12]
As demonstrated in Scheme 5, a set of experiments
were designed to study the mechanism in details.
Initially, mixing 2 with PIFA in CDCl3 immediately
led to a metastable intermediate 47, which was
1
speculated by crude H-NMR and 13C-NMR (eq 1).
However, reaction of PIDA and alcohol 2 could not
yield intermediate 47 (eq 2) (see the SI). These
results could explain the fact that PIDA exhibited no
reactivity in the cleavage of C(sp3)-C(sp3) bond in
alcohol (entry 1, Table 1). Subsequently reaction of
intermediate 47 with lepidine smoothly gave the
expected product 3 in 73% yields (eq 3). Then a
radical clock experiment was conducted (eq 4). The
PIFA promoted reaction of lepidine with 2-
cyclopropylethan-1-ol (48) afforded the ring-opening
product 49 in 65% yield and 2-formyl lepidine 49’ in
10% (see the SI), which clearly supported a free-
radical pathway involving β-scission of alkoxyl
radical.
Scheme 5. Mechanistic studies.
Conclusion
In summary, we have developed a visible-light-
induced highly selective cleavage of unstrained
C(sp3)-C(sp3) bonds in general alcohols, especially
for challenging primary alcohols. Through this
strategy, a wide range of 1o, 2o and 3o alcohols
including sugars and steroids without ring strain or
steric hindrance can be utilized as more sustainable
and safer alkyl radical precursors than traditional
ones. As depicted in this work, an efficient heteroaryl
C-H alkylation and/or acylation could be achieved by
Finally, based on the results of control experiments
9-11]
and the previous literatures,[3,
a plausible
5
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10.1002/adsc.201900975
Advanced Synthesis & Catalysis
a Minisci-type reaction of heterocycles with alcohols.
Besides, the features of metal and photo-catalyst free,
scalability and compatibility of diverse functional
groups make it very attractive to synthetic organic
chemistry. Most importantly, this protocol can be
used to break a given C-C bond selectively even in
sugars and complex natural products, which would
have great potential for application in biomass
conversions. Future studies on exploring catalytic
hypervalent iodine systems are ongoing in our lab.
Zhao, Chem. Sci. 2017, 8, 3885-3890. (e) J. Liu, X. Qiu,
X. Huang, X. Luo, C. Zhang, J. Wei, J. Pan, Y. Liang,
Y. Zhu, Q. Qin, S. Song, N. Jiao, Nat. Chem. 2019, 11,
71-77. (f) J. Zhu, J. Wang, G. Dong, Nat. Chem. 2019,
11, 45-51. (g) A. Xia, X. Qi, X. Mao, X. Wu, X. Yang,
R. Zhang, Z. Xiang, Z. Lian, Y. Chen, S. Yang, Org.
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[3] For recent reviews on C-C fragmentation via alkoxy
radical, see: (a) J. Hartung, Eur. J. Org. Chem. 2001,
619-632. (b) J. Hartung, T. Gottwald, K. špehar,
Synthesis 2002, 1469-1498. (c) M. Murakami, N. Ishida,
Chem. Lett. 2017, 46, 1692-1700. (d) K. Jia, Y. Chen,
Chem. Commun. 2018, 54, 6105-6112.
Experimental Section
Lepidine 1 (28.6 mg, 0.2 mmol, 1.0 equiv) and 2-
methylbutanol 2 (88.0 mg, 1.0 mmol, 5.0 equiv) were first
dispersed in 1 mL DCM. PIFA (171.6 mg, 0.4 mmol, 2.0
equiv) was then added. The reaction was irradiated with 24
W blue LEDs and kept at rt under fan cooling for 2 h.
After the reaction completion monitored by TLC, the
mixture was quenched by addition of saturated NaHCO3
until pH>8 and then extracted with DCM (3 x 2 mL). The
combined organic extracts were washed by brine, dried
over Na2SO4, filtered, concentrated, and purified by flash
column chromatography on silica gel (eluted with
hexane/acetone (v/v 20:1)) to give the desired product
(isolated yield 85%).
[4] (a) S. Chiba, Z. Cao, S. A. A. El Bialy, K. Narasaka,
Chem. Lett. 2006, 35, 18-19. (b) Y.-F. Wang, S. Chiba,
J. Am. Chem. Soc. 2009, 131, 12570-12752.
[5] (a) J. Yu, H. Zhao, S. Liang, X. Bao, C. Zhu, Org.
Biomol. Chem. 2015, 13, 7924-7927. (b) H. Zhao, X.
Fan, J. Yu, C. Zhu, J. Am. Chem. Soc. 2015, 137, 3490-
3493. (c) R. Ren, H. Zhao, L. Huan, C. Zhu, Angew.
Chem. Int. Ed. 2015, 54, 12692-12696. (d) R. Ren, Z.
Wu, Y. Xu, C. Zhu, Angew. Chem. Int. Ed. 2016, 55,
2866-2869.
[6] (a) K. F. Jia, F. Y. Zhang, H. C. Huang, Y. Y. Chen, J.
Am. Chem. Soc. 2016, 138, 1514-1517. (b) K. F. Jia, Y.
Pan, Y. Y. Chen, Angew. Chem. Int. Ed. 2017, 56,
2478-2481.
Acknowledgements
This project is supported by National Natural Science
Foundation of China (No. 21672089).
[7] (a) A. Ilangovan, S. Saravanakumar, S.
Malayappasamy, Org. Lett. 2013, 15, 4968-4971. (b) Z.
Ye, M. Dai, Org. Lett. 2015, 17, 2190-2193. (c) J.-J.
Guo, A. Hu, Y. Chen, J. Sun, H. Tang, Z. Zuo, Angew.
Chem. Int. Ed. 2016, 55, 15319-15322. (d) H. G. Yayla,
H. Wang, K. T. Tarantino, H. S. Orbe, R. R. Knowles,
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Supporting Information.
7
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FULL PAPER
Surgical Cleavage of Unstrained C(sp3)-C(sp3)
Bonds in General Alcohols for Heteroaryl C-H
Alkylation and Acylation
Adv. Synth. Catal. Year, Volume, Page – Page
Yaxin Wang,a Le Yang,a Shuai Liu,a Lixia Huang,a
and Zhong-Quan Liu a*
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