Oxidation of the inert sp3C-H bonds of tetrahydroisoquinolines through C-H activation relay (CHAR): construction of functionalized isoquinolin-1-ones

Article abstract of DOI:10.1039/d1cc00550b

A TBN/O₂-initiated oxidation of the relatively inert 3,4-C-H bonds of THIQs was accomplished, in which the existence of an α-phosphoric ester group is crucial to enable dioxygen trapping and intramolecular HAT (C-H activation relay,CHAR), reali

Full text of DOI:10.1039/d1cc00550b

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Oxidation of the inert sp3 C–H bonds of
tetrahydroisoquinolines through C–H activation
relay (CHAR): construction of functionalized
isoquinolin-1-ones†
Cite this: Chem. Commun., 2021,
57, 3347
Received 2nd February 2021,
Accepted 19th February 2021
Yuan Yuan, Shuwei Zhang, Zheng Sun, Yichun Su, Qiyuan Ma, Yu Yuan* and
DOI: 10.1039/d1cc00550b
Xiaodong Jia
*
rsc.li/chemcomm
A TBN/O2-initiated oxidation of the relatively inert 3,4-C–H bonds of starting materials are needed to generate the heteroatom-
THIQs was accomplished, in which the existence of an a-phosphoric centered radicals, which restricts the wide application of intra-
ester group is crucial to enable dioxygen trapping and intramolecular molecular HAT. So we questioned whether a carbon-centered
HAT (C–H activation relay, CHAR), realizing the synthesis of a free radical could be generated through oxidation of the active
series of isoquinolin-1-ones in high yields. The mechanistic study C–H bond under mild conditions, followed by intramolecular
confirmed that the formation of the 3,4-double bond is mediated by HAT to propagate further functionalization of the inert C–H
the CHAR process. This work provides a new strategy to achieve bond. However, a challenge exists. The radical intermediate
remote C–H bond activation.
derived from oxidation of the active C–H bond is commonly
more stable than that from the inert position; therefore, this
Recently, direct functionalization of C–H bonds has constituted process is generally unfavorable. However, in the presence of O2,
a promising atom- and step-economic strategy for the rapid the coupling between dioxygen and the radical center could
construction of complex and functionalized compounds.1,2 generate a peroxide radical (with rate constant of about
However, due to their inherently low reactivity, activation of 109 MÀ1 sÀ1) to initiate further intramolecular HAT.5a With this
the inactive sp3 C–H bonds remains a big challenge. As an strategy, named C–H activation relay (CHAR), we reported isatin
effective supplement to transition-metal catalysis, free radical synthesis by the aerobic oxidation of glycine esters in 2016, in
reactions show broad prospects in sp3 C–H bond activation and which the relatively inert C–H bond is activated through the
have been a focus of various research studies, which have CHAR process.7 We think that this strategy might be a new way
established numerous elegant methodologies.2–4 With the to realize remote C–H bond activation under mild conditions
deepening research, organic chemists have not been content (Fig. 1, eqn (2)).
with activation of the relatively active sp3 C–H bonds, such as
the C–H bonds adjacent to nitrogen or oxygen atoms, and the
activation of inactive and remote C–H bonds through
intramolecular hydrogen-atom transfer (HAT) has attracted
great attention.4
It is well known that the considerable difference in bond
dissociation energies (BDE) between the starting materials and
the products is one of the most important driving forces of
radical reactions.5 Therefore, heteroatom-centered radicals
must be initially generated to trigger further remote C–H
functionalization by intramolecular HAT (Fig. 1, eqn (1)).6
However, either harsh reaction conditions or prefunctionalized
School of Chemistry & Chemical Engineering, Yangzhou University,
Siwangting Road 180, Yangzhou, Jiangsu 225002, China.
E-mail: yyuan@yzu.edu.cn, jiaxd1975@163.com
† Electronic supplementary information (ESI) available: For experimental details
Fig. 1 Strategies for C–H activation relay.
and spectroscopic data. See DOI: 10.1039/d1cc00550b
This journal is © The Royal Society of Chemistry 2021
Chem. Commun., 2021, 57, 3347–3350 | 3347

View Article Online
Communication
ChemComm
According to our previous research,7,8 substrates suitable for
CHAR should meet several criteria: (1) at least one C–H bond in
the substrate should be active enough to be oxidized to a
radical under mild conditions; (2) the generated radical should
be stabilized to couple with dioxygen and not easily oxidized to
a carbocation; (3) the product should be as stable as possible to
provide sufficient driving force. Based on these considerations,
the functionalization of tetrahydroisoquinolines (THIQ)
aroused our interest. In the past decade, THIQs, as a kind of
model substrate, have been studied widely.9,10 However, most
research concentrated on functionalization of the C–H bond
adjacent to nitrogen (1-position), and the oxidation of C–H
bonds on the 3- or 4-position still remains unprecedented.
From the literature, we know that under mild conditions, a
radical center could be generated on the 1-position and
captured by dioxygen to provide the desired peroxide radical.
However, the existence of a-H and the relatively electron-rich
nature will accelerate generation of the iminium intermediate
through secondary electron transfer or elimination of a
peroxide, which will intercept the designed HAT (Fig. 1, eqn (3)).
So we reasoned that if an electron-withdrawing group is installed
on 1-position, on one hand, the radical intermediate would be
Scheme 1 Substrate scope of THIQs for the formation of isoquinolin-1-
ones.a a Reaction conditions: 1 (0.5 mmol), TBN (1 mmol), NHPI (20 mol%),
1,4-dioxane (5 mL), 80 1C under O2 for 24 h, isolated yield. b The yields
highlighted in red were obtained in the presence of 2 equivalents of
TEMPO instead of NHPI.
further stabilized by captodative effect, and on the other hand, the the phenyl ring, the reaction became messy, and only trace
formation of iminium intermediate would be inhibited, for the amount of the desired product was detected (2q). Although the
electron-withdrawing group will destabilize the electron-poor exact reason remains unknown, it is attributed to the oxidative
carbocation intermediate. If so, the desired HAT might occur deprotection of the N-PMP group, leading to the complicated
and achieve functionalization of the C–H bonds on the 3- and side-reactions. The reactions of N-alkyl THIQs were also tested,
4-positions. Considering the availability of the starting material, we and the desired products 2s and 2t were obtained in 52% and
decided to perform the reaction of an a-phosphorylated THIQ to 38% yields, respectively. These results show that even in the
test our design.
absence of N-aryl groups, which are beneficial to stabilizing the
At the outset, the aerobic oxidation of 1a was chosen as a generated radical intermediates, the current catalyst system can
model reaction to optimize the reaction conditions, and the be applied to more general substrates. Overall, the desired
results are provided in (ESI†). The results show that using TBN reaction was mainly intercepted by the direct oxidative Wittig
(tert-butylnitrite)/O2 as the catalyst system,11,12 the expected reaction, and reinforcing the intramolecular HAT is crucial to
product 2a was afforded in 69% isolated yield, although the increase the reaction efficiency. Fortunately, we accidentally
direct oxidative Wittig reaction is inevitable, giving the found that the addition of a stoichiometric amount of TEMPO
corresponding amide 3a in 9% yield (Scheme 1).12,13
can efficiently increase the yield of product 2 (catalytic amount of
With the best reaction conditions established, various sub- TEMPO is not beneficial to the reaction, see ESI†). Therefore,
stituted THIQs were evaluated. The alkyl electron-donating using 1c as the model substrate, the effect of TEMPO was
groups, such as methyl and tert-butyl, enhanced the conjugation studied, and when the amount of TEMPO was increased to
between the lone-pair electrons on nitrogen and the radical 2 equivalents, selectivity was obviously improved (for details,
intermediate, giving the desired products in higher yields, see ESI†). Then, some representative examples were tested in the
although the direct oxidative Wittig reaction was also inevitable presence of 2 equivalents of TEMPO, and in most cases, the
(2a–2c). The reaction efficiency was reduced by electron- reaction efficiency was improved dramatically (highlighted in
withdrawing groups, and the isoquinolin-1-ones were obtained red, Scheme 1). Although the exact reason remains unknown, the
in lower yields (2d–2g). The substituents on meta-position existence of TEMPO at high concentration might accelerate
could also be tolerated in this reaction, providing the expected formation of the CQC double bond, providing sufficient driving
products in acceptable yields (2h–2k). In the existence of force for the desired HAT.14
ortho-groups, the intramolecular HAT process was partly inhibited,
Encouraged by the success of 3,4-functionalization of
and the undesired 3l was obtained in 55% yield. Although no THIQs, we decided to introduce more functional groups on
3m was detected in the case of 1m, the yield of the desired the 3- or 4-position to provide platforms for later modification.
product 2m was also lower. The reaction of 3,4-dimethyl THIQ In 2018, Yan and co-workers reported an interesting synthesis
gave 2n in comparable yield, with poor selectivity. The substrates of 4-bromo-1,2-dihydroisoquinolines through
a
copper-
with ester and naphthyl groups were also suitable in this catalyzed atom-transfer process.15 Inspired by this work, the
reaction, affording the corresponding products in moderate model reaction of 1c was performed in the presence of copper
yields (2o–2p). When the methoxyl group was connected on catalyst, and as our design, the 4-bromodihydroisoquinolin-1-one
This journal is © The Royal Society of Chemistry 2021
3348 | Chem. Commun., 2021, 57, 3347–3350

View Article Online
ChemComm
Communication
Scheme 2 Substrate scope of THIQs for the formation of
4-bromoisoquinolin-1-ones.a a Reaction conditions: 1 (0.5 mmol), TBN
(1 mmol), NHPI (20 mol%), CuBr (1 equiv.), 1,4-dioxane (5 mL), 80 1C under
O2 for 24 h, isolated yield.
Scheme 3 Control experiments.
intermediate was observed by HRMS, suggesting that after the
HAT, a carbon-centered radical E (see ESI†) was formed. In
addition, the oxidative Wittig reaction leading to the formation
of the carbonyl group was also confirmed by the existence of
the corresponding phosphate. For the bromination reaction,
the reactions of 2a and 3a were conducted under the standard
conditions, respectively; however, no reaction occurred
(eqn (6)). These results showed that 2 and 3 are not the
intermediates, and the bromination process is prior to the
formation of 3,4-double bond. Based on these results and
the literature precedents,10–12 a radical-mediated mechanism
was proposed (see ESI†).
In summary, using TBN/O2 as the catalyst system, an unpre-
cedented C–H bond functionalization of THIQ was developed
through C–H activation relay process, synthesizing a series of
dihydroisoquinolin-1-ones and 4-bromodihydroisoquinolin-1-
ones. According to the mechanistic study, dioxygen trapping
and further intramolecular HAT process (CHAR) are key steps
to realize the functionalization of C–H bonds on the 3- and
4-positions. This CHAR strategy successfully avoids the use of
prefunctionalized starting material to generate heteroatom-
centered free radicals, accomplishing the shift of radical center
from the active position to the inert position. We believe that
CHAR might provide a useful way to accomplish remote C–H
bond activation. However, it should be confessed that the direct
Wittig reaction seriously affected the reaction efficiency, and
the introduction of phosphate ester group is far from the best
choice to implement the CHAR strategy. Further screening of
the a-substituents, attempts to construct more complicated
structures, and mechanistic studies are still underway in our
laboratory.
4c was obtained through copper-catalyzed atom-transfer
reaction.16 After optimization of the reaction conditions (see ESI†),
the results showed that 20 mol% of NHPI is sufficient to give the
desired product 4c in 60% yield (Scheme 2). It is worth noting that
CuBr might accelerate the formation of the desired product, and
no direct oxidative Wittig product 3c was detected.
Then, the reactions of various substrates were tested
(Scheme 2). Overall, both electron-donating and -withdrawing
groups are well tolerated in this reaction, providing the desired
products in acceptable yields (4a–4g). The substituents on meta-
and ortho-positions did not affect the reaction efficiency, and
the HAT proceeded smoothly to yield the 4-bromodihydro-
isoquinolin-1-ones (4h–4n and 4r). The ester group reduced
the reaction efficiency, giving the expected product in low
yield (4o). The electron-rich aryl groups were also tolerated in
this reaction, and the corresponding isoquinolin-1-ones were
isolated in moderate yields (4p–4q). This reaction could also be
applied to the N-alkyl THIQs (4s–4t), albeit the yields of the
desired products were lower.
To uncover the details of the reaction mechanism, several
control experiments were performed (Scheme 3). In the absence
of dioxygen and TBN, respectively, no reaction occurred even
in the presence of CuBr (eqn (1)–(3)), which suggested that
dioxygen and TBN are both crucial to initiate this C–H
functionalization. Using 3a as the starting material, no reaction
occurred under the standard conditions, indicating that 3a is
not the intermediate, and intramolecular HAT is the key
process to realize functionalization of the 3,4-C–H bonds
(eqn (4)). To observe the reaction intermediates, the reaction
mixture was detected by HRMS, and several important species
were confirmed to be involved in the reaction process (eqn (5)).
The existence of the peroxide intermediate implied the participation
of HAT process in functionalization of the 3,4-C–H bonds.
Under TBN-initiated reaction conditions, nitro radical, as a
This work was financially supported by the National Natural
Science Foundation of China (NNSFC, No. 21562038).
Conflicts of interest
persistent radical, will exist inevitably;11,12 therefore, a nitrated There are no conflicts to declare.
This journal is © The Royal Society of Chemistry 2021
Chem. Commun., 2021, 57, 3347–3350 | 3349

View Article Online
Communication
ChemComm
8 (a) K. He, T. Zhang, S. Zhang, Z. Sun, Y. Zhang, Y. Yuan and X. Jia,
Org. Lett., 2019, 21, 5030; (b) K. He, P. Li, S. Zhang, Q. Chen, H. Ji,
Y. Yuan and X. Jia, Chem. Commun., 2018, 54, 13232; (c) X. Jia, P. Li,
Y. Shao, Y. Yuan, H. Ji, W. Hou, X. Liu and X. Zhang, Green Chem.,
2017, 19, 5568.
9 For reviews of functionalization involving THIQs, see: (a) C.-Y.
Huang, H. Kang, J. Li and C.-J. Li, J. Org. Chem., 2019, 84, 12705;
(b) S. A. Girard, T. Knauber and C.-J. Li, Angew. Chem., Int. Ed., 2014,
53, 74; (c) C. Liu, H. Zhang, W. Shi and A. Lei, Chem. Rev., 2011,
111, 1780; (d) C. S. Yeung and V. M. Dong, Chem. Rev., 2011,
111, 1215.
10 Selected examples functionalization of THIQs: (a) W. Xie, B. Gong,
S. Ning, N. Liu, Z. Zhang, X. Che, L. Zheng and J. Xiang, Synlett,
2019, 2077; (b) M. Odachowski, M. F. Greaney and N. J. Turner, ACS
Catal., 2018, 8, 10032; (c) G. Kibriya, A. K. Bagdi and A. Hajra, J. Org.
Chem., 2018, 83, 10619; (d) M. R. Patil, N. P. Dedhia, A. R. Kapdi and
A. V. Kumar, J. Org. Chem., 2018, 83, 4477; (e) G. Oss, S. D. de Vos,
K. N. H. Luc, J. B. Harper and T. V. Nguyen, J. Org. Chem., 2018,
83, 1000; ( f ) B. Dutta, V. Sharma, N. Sassu, Y. Dang, C. Weerakkody,
J. Macharia, R. Miao, A. R. Howell and S. L. Suib, Green Chem., 2017,
19, 5350; (g) Z. Xie, X. Zan, S. Sun, X. Pan and L. Liu, Org. Lett., 2016,
18, 3944; (h) G.-Q. Xu, C.-G. Li, M.-Q. Liu, J. Cao, Y.-C. Luo and
P.-F. Xu, Chem. Commun., 2016, 52, 1190; (i) H. Wang, X. Li, F. Wu
and B. Wan, Tetrahedron Lett., 2012, 53, 681.
11 TBN initiated reactions: (a) X.-F. Wu, J. Schranck, H. Neumann and
M. Beller, Chem. Commun., 2011, 47, 12462; (b) X. Ma and Q. Song,
Org. Lett., 2019, 21, 7375; (c) Y. He, Z. Zheng, Y. Liu, J. Qiao, X. Zhang
and X. Fan, Org. Lett., 2019, 21, 1676; (d) B. Kilpatrick, M. Heller and
S. Arns, Chem. Commun., 2013, 49, 514; (e) P. Chaudhary, S. Gupta,
N. Muniyappan, S. Sabiahb and J. Kandasamy, Green Chem., 2016,
18, 2323; ( f ) X.-X. Peng, Y.-J. Deng, X.-L. Yang, L. Zhang, W. Yu and
B. Han, Org. Lett., 2014, 16, 4650; (g) T. Taniguchi, Y. Sugiura,
T. Hatta, A. Yajima and H. Ishibashi, Chem. Commun., 2013,
49, 2198; (h) Y.-F. Liang, X. Li, X. Wang, Y. Yan, P. Feng and
N. Jiao, ACS Catal., 2015, 5, 1956; (i) T. Shen, Y.-Z. Yuan and
N. Jiao, Chem. Commun., 2014, 50, 554; ( j) S. Maity, T. Naveen,
U. Sharma and D. Maiti, Org. Lett., 2013, 15, 3384.
Notes and references
1 For reviews of transition-metal enabled C–H bond activation, see:
(a) R. Shang, L. Ilies and E. Nakamura, Chem. Rev., 2017, 117, 9086;
(b) C. Cheng and J. F. Hartwig, Chem. Rev., 2015, 115, 8946;
(c) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110, 1147;
(d) D. Alberico, M. E. Scott and M. Lautens, Chem. Rev., 2007,
107, 174.
2 Selected reviews of radical C–H bond functionalization: (a) H. Wang,
X. Gao, Z. Lv, T. Abdelilah and A. Lei, Chem. Rev., 2019, 119, 6769;
(b) J. C. K. Chu and T. Rovis, Angew. Chem., Int. Ed., 2018, 57, 62;
(c) H. Yi, G. Zhang, H. Wang, Z. Huang, J. Wang, A. K. Singh and
A. Lei, Chem. Rev., 2017, 117, 9016; (d) Y.-F. Liang and N. Jiao, Acc.
Chem. Res., 2017, 50, 1640.
3 Recent progress of radical sp3 C–H bond activation: (a) J. B. Roque,
¨
Y. Kuroda, J. Jurczyk, L.-P. Xu, J. S. Ham, L. T. Gottemann,
C. A. Roberts, D. Adpressa, J. Saurı, L. A. Joyce, D. G. Musaev,
´
C. S. Yeung and R. Sarpong, ACS Catal., 2020, 10, 2929;
(b) E. E. Stache, V. Kottisch and B. P. Fors, J. Am. Chem. Soc.,
2020, 142, 4581; (c) A. F. Prusinowski, R. K. Twumasi,
E. A. Wappes and D. A. Nagib, J. Am. Chem. Soc., 2020, 142, 5429;
(d) F. Wang, X. Zhang, Y. He and X. Fan, J. Org. Chem., 2020,
85, 2220; (e) D. Anand, Z. Sun and L. Zhou, Org. Lett., 2020,
22, 2371; ( f ) H. Wang, Y. Li, Q. Lu, M. Yu, X. Bai, S. Wang,
H. Cong, H. Zhang and A. Lei, ACS Catal., 2019, 9, 1888;
(g) S. Liu, T. Shen, Z. Luo and Z.-Q. Liu, Chem. Commun., 2019,
55, 4027; (h) S. Tang, L. Zeng and A. Lei, J. Am. Chem. Soc., 2018,
140, 13128; (i) X. Wang, X. Qiu, J. Wei, J. Liu, S. Song, W. Wang and
N. Jiao, Org. Lett., 2018, 20, 2632; ( j) H. Wang, D. Zhang and
C. Bolm, Angew. Chem., Int. Ed., 2018, 57, 5863; (k) H. Yu, Z. Li
and C. Bolm, Org. Lett., 2018, 20, 2076; (l) P.-F. Yuan, Q.-B. Zhang,
X.-L. Jin, W.-L. Lei, L.-Z. Wu and Q. Liu, Green Chem., 2018, 20, 5464;
(m) X.-Q. Hu, J.-R. Chen and W.-J. Xiao, Angew. Chem., Int. Ed., 2017,
56, 1960.
4 (a) A. F. Prusinowski, R. K. Twumasi, E. A. Wappes and D. A. Nagib,
J. Am. Chem. Soc., 2020, 142, 5429; (b) A. N. Herron, D. Liu, G. Xia
and J.-Q. Yu, J. Am. Chem. Soc., 2020, 142, 2766; (c) P. Guo, Y. Li,
X.-G. Zhang, J.-F. Han, Y. Yu, J. Zhu and K.-Y. Ye, Org. Lett., 2020,
22, 3601; (d) D. Kurandina, D. Yadagiri, M. Rivas, A. Kavun,
P. Chuentragool, K. Hayama and V. Gevorgyan, J. Am. Chem. Soc.,
2019, 141, 8104; (e) B. Xu and U. K. Tambar, ACS Catal., 2019,
9, 4627; ( f ) M. Wang, L. Huan and C. Zhu, Org. Lett., 2019, 21, 821;
(g) Z.-Y. Ma, L.-N. Guo, Y. You, F. Yang, M. Hu and X.-H. Duan, Org.
Lett., 2019, 21, 5500; (h) B. J. Groendyke, A. Modak and S. P. Cook,
J. Org. Chem., 2019, 84, 13073; (i) X. Hu, G. Zhang, F. Bu, L. Nie and
A. Lei, ACS Catal., 2018, 8, 9370; ( j) X. Shen, J.-J. Zhao and S. Yu,
Org. Lett., 2018, 20, 5523; (k) L. Wang, Y. Xia, K. Bergander and
A. Studer, Org. Lett., 2018, 20, 5817; (l) D.-F. Chen, J. C. K. Chu and
T. Rovis, J. Am. Chem. Soc., 2017, 139, 14897.
12 Oxidative Wittig reaction: Y. Zhu, S. Lv, X. Ma, L. Zhang, L. Luo and
X. Jia, Asian J. Org. Chem., 2016, 5, 617.
13 It is worth noting that the desired product 2 and the side-product 3
could not be isolated by column chromatography and TLC, there-
fore, a mixture of 2 and 3 was obtained. The corresponding ratio was
determined by 1H NMR.
14 The aromaticity of the products might provide a strong driving force
to the oxidation of 3,4-C–H bonds.
5 (a) H. Togo, Advanced Free Radical Reactions for Organic Synthesis,
Elsevier, 2004; (b) P. Renaud and M. P. Sibi, Radicals in Organic
Synthesis, Wiley-VCH Verlag GmbH, 2001.
6 For BDEs, see: Y.-R. Luo, Handbook of Bond Dissociation Energy in 15 Q. Sun, Y.-Y. Zhang, J. Sun, Y. Han, X. Jia and C.-G. Yan, Org. Lett.,
Organic Compounds, CRC Press, Boca Raton, FL, 2002. 2018, 20, 987.
7 X. Jia, Y. Zhu, Y. Yuan, X. Zhang, S. Lu¨, L. Zhang and L. Luo, ACS 16 A review for copper-catalysed atom transfer radical process:
Catal., 2016, 6, 6033.
A. J. Clark, Chem. Soc. Rev., 2002, 31, 1.
This journal is © The Royal Society of Chemistry 2021
3350 | Chem. Commun., 2021, 57, 3347–3350