Four Pathways in Radical Alkylation of Isocyanide with Simple Alcohol

Article abstract of DOI:10.1002/adsc.201900221

We demonstrated herein the four modes in free-radical C?C formation reaction of isocyanide with alcohol. The experimental results and DFT calculation revealed when and why one model opens. It would be instructive and valuable for radical alkylation with alcohol in organic synthesis. (Figure presented.).

Full text of DOI:10.1002/adsc.201900221

Title: Four Pathways in Radical Alkylation of Isocyanide with Simple
Alcohol
Authors: Shuai Liu, Fenghua Fan, Nengyong Wang, Dandan Yuan,
Yaxin Wang, Zaigang Luo, and Zhong-Quan Liu
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900221
Link to VoR: http://dx.doi.org/10.1002/adsc.201900221

10.1002/adsc.201900221
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Four Pathways in Radical Alkylation of Isocyanide with Simple
Alcohol
Shuai Liua,b†, Fenghua Fanc†, Nengyong Wanga, Dandan Yuana, Yaxin Wanga, Zaigang
Luob and Zhong-Quan Liu*a,c
a
State Key Laboratory Cultivation Base for TCM Quality and Efficacy, College of Pharmacy, Nanjing University of
Chinese Medicine, Nanjing 210023, P. R. China
E-mail: liuzhq@lzu.edu.cn
College of Chemical Engineering, Anhui University of Science and Technology, Huainan, Anhui 232001, P. R. China
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R.
These two authors contribute equally to this work.
b
c
†
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))
Cu(II)-catalyzed radical alkylation of diaryl isonitrile
with alcohol.[10]
Abstract: We demonstrated herein the four modes in
free-radical C-C formation reaction of isocyanide with
alcohol. The experimental results and DFT calculation
revealed when and why one model opens. It would be
instructive and valuable for radical alkylation with
alcohol in organic synthesis.
Keywords: Free-radical; C-C bond formation; Alcohol;
Isocyanide; DFT calculation
Scheme 1. Four major models in radical alkylation with
alcohol.
The radical alkylation using alcohol as the alkyl
source represents one of the most sustainable and
attractive conversions in synthetic organic
chemistry.[1] There are usually four pathways in these
In 2014, we reported
hydroxyalkylation of isocyanide with alcohol (eq. 1,
path A).[4c] Accidentally we found that
dehydroxylative alkylation occurred while the
temperature of reaction was raised to 140 oC (path B).
This surprising result stirred up our great interests
because both the mechanism and the potential
application in synthetic chemistry would be
attractive.
a radical-triggered
transformations (Scheme 1). Path
I
is the
a
hydroxyalkylation via C-centered radical
a
intermediate by direct hydrogen-atom-transfer (HAT)
of the α-hydroxyl C-H, which has been
well-developed by Tu,[2] Han and Pan,[3] and Liu [4] et
al.[5]
A
dehydroxylative
alkylation
via
spin-center-shift (SCS)[6] from the same intermediate
represents the second process, which is widely found
in biological system. Besides, an alkoxyl radical
intermediate could be often formed via one-electron
oxidation followed by deprotonation of alcohol.[7]
Path III is a decarbonylative alkylation via a
β-fragmentation of the alkoxyl radical.[8] The last
model is a δ-hydroxyalkylation via a 1,5-H shift.[9]
Recently, a variety of highly efficient systems
involving one of these processes have been developed.
However, several interesting questions were raised.
For example, what’s the relationship between each
other? What condition leads to what model? To the
best of our knowledge, studies focused on answering
these questions have never been reported so far.
Herein, we wish to report a first study on the
Initially we evaluated the substrate scope after
modification of the reaction conditions (Table 1 and
2). As illustrated in Table 1,
a
series of
6-ethylphenanthridines can be smoothly synthesized
in moderate to good yield (1-12).
connection between these pathways via
a
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900221
Advanced Synthesis & Catalysis
Table 1. Radical alkylation of isocyanide with ethanol.a
aTypical reaction conditions: isocyanide (1 equiv., 0.1
mmol), Cu(OAc)2 (5 mol%, 0.005 mmol), DCP (5 equiv.,
o
0.5 mmol), alcohol (5 mL), 140 C (measured temperature
of oil bath), sealed tube, 2 h., unless otherwise noted,
isolated yield.
aTypical reaction conditions: isocyanide (1 equiv., 0.1
mmol), Cu(OAc)2 (5 mol%, 0.005 mmol), DCP (dicumyl
peroxide) (5 equiv., 0.5 mmol), alcohol (5 mL), 140 C
(measured temperature of oil bath), sealed tube, 2 h.,
unless otherwise noted, isolated yield.
o
And then a set of control experiments were
carried out to study the detailed mechanism. Firstly, it
has been confirmed that the hydroxyalkylated
phenanthridine can not convert into dehydroxylative
product under the reaction conditions (eq. 2).
On the other hand, various simple alcohols
afforded the corresponding alkylated phenanthridines
under the typical conditions (Table 2). Interestingly,
along with the dehydroxylative alkylated product, a
decarbonylative alkylation phenanthridine was also
isolated (13-25). It is noteworthy that 1-pentanol gave
3 main products 14, 17 and 18. In addition, the more
β-substituents have in the primary alcohols, the more
decarbonylative products can be obtained. Secondary
alcohols only gave the dehydroxylative alkylation
phenanthridines (19-25).
Surprisingly, reaction of cyclopropyl methanol
with isonitrile led to product 13 in 67% yields under
the typical conditions (eq. 3). It seems undergo a
ring-opening decarbonylative alkylation, but the
detailed process is not clear.
Table 2. Radical alkylation of isocyanide with alcohol.a
Next we examined the relationship between
temperature variation and the yields of the products
(Figure 1). It can be seen from Figure 1 that A was
the major product when the temperature was lower
than 130oC. Product B became dominant while the
temperature higher than 130oC.
2
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900221
Advanced Synthesis & Catalysis
formed by dimerization of the spin trap
2-methyl-2-nitroso-propane (MNP). And the sextet
signal
should
belong
to
the
=
2-hydroxylethyl-tert-butylnitroxide radical (aN
16.25 G; aH = 3.85 G). It indicates that the
α-hydroxy-ethyl radical should be formed in this
reaction.
Figure 1. Diagram of yields with temperature variation.
In order to investigate the possible relationship
between the typical four models of alcohol involved
free radical reactions, the following experiments were
carried out (Figure 2). As expected, four products
have been obtained during the temperature variation
(70-160oC). Products A and D appeared at 80oC
while B and C were observed until 110oC. The
varying trends of A and B are similar to that of
ethanol.
Figure 3. Spin-trapping and EPR studies.
Based on these results and previous literatures,
we proposed the possible mechanisms for the
free-radical alkylation of biarylisonitriles. As
demonstrated in Scheme 2 that four main pathways
might be involved in the reactions. Path I and path II
start with the α-hydroxyl-C-centered radical A, which
was generated via hydrogen-atom transfer (HAT)
from alcohol. Radical addition of A to isocyanide and
then cyclization afforded radical C. Direct HAT or
deprotonation followed by single-electron oxidation
gave P1. The intermediate C would convert into D at
a higher temperature via a spin-center shift (SCS)
process.[6] Subsequently, hydrogen abstraction of
alcohol by D led to P2. On the other hand, an alkoxyl
radical B would produce under the conditions.
β-Fragmentation of B gave radical E by release of
HCHO, which is Path III. Then P3 was obtained via a
similar process to Path I. The last path began with
radical G which was formed by a 1,5-H atom shift of
B. Next a radical addition/cyclization cascade process
afforded H, which then gave P4 via
dehydrogenative rearomatization process.
a
Figure 2. Diagram of yields with temperature variation.
Furthermore, spin-trapping combined with
electron paramagnetic resonance (EPR) experiments
were designed to investigate the mechanism in details
(Figure 3). It can be seen from Fig. 3 that two radical
intermediates were clearly recorded by EPR (triplet
and sextet). The triplet signal should belong to
di-tert-butylnitroxide (DTBN) radical, which was
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900221
Advanced Synthesis & Catalysis
radical A (the barrier is 19.1 kcal/mol, which is
consistent with the KIE result.) and SCS (the barrier
is 35.9 kcal/mol) respectively. In cases of path III and
IV, the RDS is β-fragmentation (Fig. 5, the barrier is
17.0 kcal/mol) and the 1,5-H shift (Fig. 6, the barrier
is 14.6 kcal/mol) respectively. Thus, it is not difficult
to understand when and why one pathway occurs. At
a relatively lower temperature, the processes I, III and
IV which have relatively lower energetic barrier all
could happen. Path II began to dominate the reaction
with the increasing of the temperature. Nevertheless,
P1 and P2 were always the major product over P3
and P4. It should be due to the radical stability and
polarity. The SOMO-p (lone pair) delocalization
might make radical A more stable than the alkoxy
radical B and its derivatives F and H.[4d] Besides,
nucleophilic C-centered radical A could add to
electrophilic isocyanide directly. In contrast,
electrophilic alkoxy radical B couldn’t react with
isonitrile unless it converted into radical F via
β-fragmentation or radical H by 1,5-H shift. At a high
temperature, P2 became the predominant product
might be attributed to the entropy effect.
Scheme 2. Suggested mechanism.
Finally, the computed Gibbs free energy profile
for the four pathways in reaction of 1-pentanol (1)
with 2-isocyano-5-methyl-1,1'-biphenyl (2) have
been carried out (Figures 4-6, see also the SI). It can
be seen from Figure 4 that the rate-determining step
(RDS) in path I and path II is HAT from alcohol to
Figure 4. The Computed Gibbs Free Energy Profile for Path I and II.
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900221
Advanced Synthesis & Catalysis
Figure 5. The Computed Gibbs Free Energy Profile for Path III.
Figure 6. The Computed Gibbs Free Energy Profile for Path IV
In summary,
a free-radical alkylation of
isocyanide with simple alcohol was demonstrated,
which showed the diversity of radical addition
reaction of isonitriles.[11] We found that there were
four reaction modes that would afford four different
products. Then we investigated these pathways in
details. The experimental and computed results could
explain when and why one pathway occurs well.
Hence it might be instructive and valuable for field of
radical C-C bond formation with alcohol. Continuous
studies on controlled radical alkylation of other
molecules with alcohol are ongoing in our lab.
Experimental Section
General procedure: A mixture of biarylisonitriles (1
equiv., 0.1 mmol), Cu(OAc)2 (5 mol %, 0.005 mmol), DCP
(5 eq, 0.5 mmol) and alcohols (5 mL) was heated under
nitrogen at 140 oC (this temperature is measured outside of
the reaction mixture, it is the temperature of the oil bath)
for about 2 h in a sealed tube (25 mL). After the reaction
finished, the mixture was evaporated under vacuum and
purified by column chromatography to afford the desired
product.
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900221
Advanced Synthesis & Catalysis
Acknowledgements
Kamijo, M. Inoue, Chem. Sci. 2014, 5, 4339-4345; g) J.
Jin, D. W. C. MacMillan, Nature, 2015, 525, 87-90; h)
T. D. Neubert, Y. Schmidt, E. Conroy, D. Stamos, Org.
Lett. 2015, 17, 2362-2365; i) B. Niu, W. Zhao, Y. Ding,
Z. Bian, Jr., C. U. Pittman, A. Zhou, H. J. Ge, Org.
Chem. 2015, 80, 7251-7257; j) J.-K. Cheng, T.-P. Loh,
J. Am. Chem. Soc. 2015, 137, 42-45; (k) W. Hu, S. Sun,
J. Cheng, J. Org. Chem. 2016, 81, 4399-4405.
We thank the National Natural Science Foundation of China (No.
21672089, 21472080) for financial support.
References
[1] For reviews on selective functionalization of α-hydroxy
C-H bond in alcohol, see: a) S. Zhang, F. Zhang, Y.-Q.
Tu, Chem. Soc. Rev. 2011, 40, 1937-1949; b) X. Shang,
Z.-Q. Liu, Acta. Chim. Sin. 2015, 73, 1275-1282.
[6] For an excellent review on SCS, see: P. Wessig, O.
Muehling, Eur. J. Org. Chem. 2007, 2219-2232.
[7] For selected reviews on 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) K. Jia, Y. Chen, Chem. Commun. 2018,
54, 6105-6112, and the references therein.
[2] a) L. Shi, Y.-Q. Tu, M. Wang, F.-M. Zhang, C.-A. Fan,
Y.-M. Zhao, W.-J. Xia, J. Am. Chem. Soc. 2005, 127,
10836-10837; b) S.-Y. Zhang, Y. -Q. Tu, C.-A. Fan,
F.-M. Zhang, L. Shi, Angew. Chem. Int. Ed. 2009, 48,
8761-8765.
[8] For a recent review on β-scission of alkoxy radical, see:
a) M. Murakami, N. Ishida, Chem. Lett. 2017, 46,
1692-1700; for selected very recent examples, see: b) X.
Wu, M. Wang, L. Huan, D. Wang, J. Wang, C. Zhu,
Angew. Chem. Int. Ed. 2018, 57, 1640-1644; c) A. Hu,
Y. Chen, J.-J. Guo, N. Yu, Q. An, Z. Zuo, J. Am. Chem.
Soc. 2018, 140, 13580-13585; d) P. Natho, M. Kapun,
L. A. Allen, P. J. Parsons, Org. Lett. 2018, 20,
8030-8034; e) M. Wang, L. Huan, C. Zhu, Org. Lett.
2019, 21, 821-825.
[3] a) J.-C. Zhao, H. Fang, W. Zhou, J. Han, Y.-J. Pan, Org.
Chem. 2014, 79, 3847-3855; b) W. Zhou, P. Qian, J.
Zhao, H. Fang, J. Han, Y. Pan, Org. Lett. 2015, 17,
1160-1163; c) W. Zhou, S. Ni, H. Mei, J. Han, Y. Pan,
Org. Lett. 2015, 17, 2724-2727.
[4] a) Z.-Q. Liu, L. Sun, J. Wang, J. Han, Y. Zhao, B. Zhou,
Org. Lett. 2009, 11, 1437-1439; b) Z. Cui, X. Shang,
X.-F. Shao, Z.-Q. Liu, Chem. Sci. 2012, 3, 2853-2858;
c) Z. Li, F. Fan, J. Yang, Z.-Q. Liu, Org. Lett. 2014, 16,
3396-3399; d) Y. Tian, Z.-Q. Liu, Green Chem. 2017,
19, 5230-5235.
[9] J. W. Wilt, Free Radical Rearrangements in Free
Radicals, Ed. J. K. Kochi, John Wiley & Sons, 1973.
[5] a) C. A. Correia, L. Yang, C.-J. Li, Org. Lett. 2011, 13,
4581-4583; b) T. He, L. Yu, L. Zhang, L. Wang, M.
Wang, Org. Lett. 2011, 13, 5016-5019; c) D.-G. Yu, X.
Wang, R.-Y. Zhu, S. Luo, X.-B. Zhang, B.-Q. Wang, L.
Wang, Z.-J. Shi, J. Am. Chem. Soc. 2012, 134,
14638-14641; d) Y. Meng, L.-N. Guo, H. Wang, X.-H.
Duan, Chem. Commun. 2013, 49, 7540-7542; e) B.
Bohman, B. Berntsson, R. C. M. Dixon, C. D. Stewart,
R. A. Barrow, Org. Lett. 2014, 16, 2787-2789; f) Y.
Amaoka, M. Nagatomo, M. Watanabe, K. Tao, S.
[10] For selected recent reviews on free-radical reaction
with isocyanide, see: a) B. Zhang, A. Studer, Chem.
Soc. Rev. 2015, 44, 3505-3521, and references therein;
b) J. Lei, J. Huang, Q. Zhu, Org. Biomol. Chem. 2016,
14, 2593-2602; c) M. Giustiniano, A. Basso, V.
Mercalli, A. Massarotti, E. Novellino, G. C. Tron, J.
Zhu, Chem. Soc. Rev. 2017, 46, 1295-1357.
[11] G. P. Gomes, Y. Loginova, S. Z. Vatsadze, I. V.
Alabugin, J. Am. Chem. Soc. 2018, 140, 14272-14288.
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900221
Advanced Synthesis & Catalysis
COMMUNICATION
Four Pathways in Radical Alkylation of
Isocyanide with Simple Alcohol
Adv. Synth. Catal. Year, Volume, Page – Page
Shuai Liua,b†, Fenghua Fanc†, Nengyong Wanga,
Dandan Yuana, Yaxin Wanga, Zaigang Luob and
Zhong-Quan Liu*a,c
7
This article is protected by copyright. All rights reserved.