Highly regioselective Ru(II)-catalyzed [3+2] spiroannulation of 1-aryl-2-naphthols with alkynes via a double directing group strategy

Article abstract of DOI:10.1016/j.tetlet.2021.153050

A highly regioselective Ru(II)-catalyzed [3+2] spiroannulation of 1-aryl-2-naphthols with internal alkynes was developed by using a novel double directing group strategy. This method was compatible with many functional groups, thus affording a variety of sterically congested spirocyclic molecules in high yields.

Full text of DOI:10.1016/j.tetlet.2021.153050

Tetrahedron Letters 71 (2021) 153050
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Tetrahedron Letters
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Highly regioselective Ru(II)-catalyzed [3+2] spiroannulation of
1-aryl-2-naphthols with alkynes via a double directing group strategy
⇑
Jiamao Hao, Yicong Ge, Liuqing Yang, Jing Wang, Xinjun Luan
Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education, College of Chemistry & Materials Science, Northwest University, Xi’an 710127, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly regioselective Ru(II)-catalyzed [3+2] spiroannulation of 1-aryl-2-naphthols with internal alky-
nes was developed by using a novel double directing group strategy. This method was compatible with
many functional groups, thus affording a variety of sterically congested spirocyclic molecules in high
yields.
Received 25 February 2021
Revised 25 March 2021
Accepted 28 March 2021
Available online 31 March 2021
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
C–H activation
Dearomatization
Double Directing Groups
Ruthenium
Transition metal-catalyzed C–H functionalization is a rapidly
growing field with research going into many different areas [1].
Due to the ubiquity of C–H bonds in the starting arenes, selective
cleavage of a specific C–H bond is difficult, but highly desirable.
One approach to address such an issue is the use of a directing
group (DG), which directs a metal catalyst to be proximal to a cer-
tain C–H bond, leading to selective activation and subsequent func-
tionalization. As a result, a myriad of useful and economical
transformations of readily available aromatic compounds have
been successfully developed [2–3]. However, there are still some
challenging problems to be solved. For example, extension of this
approach to meta-substituted aromatic molecules was only
partially successful. Activation of the sterically more encumbered
C–H bond is less favorable, and the reactions with substrate I gen-
erally led to a single product II, or a regioisomeric mixture of II and
III (Scheme 1a) [4–5]. Presumably, if the R substituent can serve as
a second DG, the more difficult activation of C–H bond at the more
bulky site of I’ might be realized by chelating binding with two DGs
for the formation of desired intermediate B’ (Scheme 1b). If one DG
binds more strongly with the metal catalyst, competitive side reac-
tion for generating metallacyclic A’ or C’ might take place [6].
Therefore, the key to the development of such reactions is to iden-
tify two suitable DGs. Until now, very few examples within that
category have been disclosed [7]. Stimulated by the previous works
from our and other groups [8], in which phenolic DG was used for
promoting Ru(II), Rh(III) or Pd(II)-catalyzed dearomatizing [3+2]
spiroannulation of 1-aryl-2-naphthols with alkynes, we planned
to explore a complementary protocol by functionalizing C–H bond
at the more crowded site through the incorporation of a second
DG2 at the meta-position of their upper aryl ring. Herein, we pre-
sent the successful execution of our new double directing group
strategy for the regioselective construction of a number of steri-
cally congested spirocycles by using two phenolic and acetylamino
DGs (Scheme 1c).
As outlined in the reaction proposal, the main task was to find a
suitable DG2. Therefore, we began the study by testing a series of
biaryl substrates 1 bearing another common DG besides the phe-
nolic DG under our prior Ru(II)-catalysis conditions [8a], and the
results are summarized in the Table 1. When equipped with an
acetyl group (1I), the C–H activation took place at its para-
position, leading to the less bulky product 3I in 40% yield, with
no formation of the desired 4I. Similar outcomes were observed
when oxime ether and amide DGs (1II and 1III) were involved.
These results indicated that the DGs for the generation of five-
membered ruthenacycles might not be suitable for the double
directing group strategy. Much to our delight, an acetylamino
DG, which was widely used to activate C–H bonds for generating
six-membered metallacycles [9], could promote the formation of
anticipated product 4a in 26% yield. However, regioisomeric 3a
was observed as the major product under the tested conditions.
This experiment proved the feasibility of developing a double
directing group strategy via the generation of two six-membered
ruthenacycle-fused intermediate.
To improve the regiochemistry for the formation of 4a, further
optimization on the reaction parameters were performed (Table 2).
⇑
Corresponding author.
E-mail address: xluan@nwu.edu.cn (X. Luan).
https://doi.org/10.1016/j.tetlet.2021.153050
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

J. Hao, Y. Ge, L. Yang et al.
Tetrahedron Letters 71 (2021) 153050
Scheme 1. Reaction development based on the C–H activation of meta-substituted arenes.
Table 1
Exploring DG2 for the Double Directing Group Strategy.a
a
Isolated yields.
Gratifyingly, the desired 4a could be selectively generated as a sin-
gle product in 80% yield, with a catalytic system consisting of
[RuCl2(p-cymene)2] (5 mol%), AgSbF6 (20 mol%), Cu(OAc)2 (2.1
equiv), and KOAc (2.1 equiv) in THF at 130 °C for 12 h (entry 1).
Control experiments indicated that Pd(OAc)2 and [Cp*RhCl2]2 led
to poor results in terms of both reactivity and regioselectivity (en-
tries 2–3). Replacing Cu(OAc)2 with oxidants such as Ag2O and BQ
gave inferior performance (entries 4–5). Notably, the runs by using
NaOAc, Cs2CO3 and K2CO3 as the base revealed that both the cation
and anion of KOAc was important for maintaining a good reaction
performance (entries 6–8). Further studies on the solvent screen-
ing showed that THF was crucial for the desired transformation,
and no better results were obtained by other solvents (entries 9–
13).
With the optimized reaction conditions in hand, the scope with
respect to biaryl substrates 1 was first examined (Table 3). The
experimental results indicated that many functional groups could
be tolerated on both aromatic fragments, thus providing a series
of spirocyclic molecules 4b-m in 63–85% yields with excellent
regioselectivity (>19:1 rr for all cases). Specifically, the upper aryl
ring could be diversely substituted with electron-neutral methyl
group (4b), electron-donating methoxy group (4e), or an elec-
tron-withdrawing group such as fluoro (4c), trifluoromethoxy
(4d), chloro (4f) and trifluoromethyl (4g) groups, and the C–H bond
cleavage regioselectively took place at the more sterically con-
gested site. Moreover, substrates 1h-m, which were equipped with
different substituent at the naphthol ring respectively, were suit-
able for the desired [3+2] spiroannulation as well. Notably, formyl,
ester, and thienyl groups, which might coordinate with the Ru(II)-
catalyst in the reaction, didn’t affect the efficiency for the forma-
tion of their corresponding products 4j-l.
Having examined the scope of phenolic substrates, we moved to
evaluate the performance of alkynes (Table 4). Overall, the titled Ru
(II)-catalyzed C–H activation/naphthol dearomatization tandem
reaction could proceed smoothly to produce the desired products
4a’-l’ in moderate to good yields. In general, all the products were
generated as single regioisomers. Notably, a wide range of func-
tional groups such as methyl (4a’), tert-butyl (4b’), methoxy (4c’),
fluoro (4d’,j’), chloro (4e’,i’), trifluoromethyl (4f’) and ester (4g’)
groups were well accommodated. It should be noted that the use
2

J. Hao, Y. Ge, L. Yang et al.
Tetrahedron Letters 71 (2021) 153050
Table 2
Optimization of the Reaction Conditions.a
Entry
Variations from standard conditions
3aYield (%)b
4aYield (%)b
1
2
3
4
5
6
7
8
none
0
80
12
18
0
Pd(OAc)2 instead of [RuCl2(p-cymene)2]
[Cp*RhCl2]2 instead of [RuCl2(p-cymene)2]
Ag2O instead of Cu(OAc)2
BQ instead of Cu(OAc)2
NaOAc instead of KOAc
Cs2CO3 instead of KOAc
K2CO3 instead of KOAc
DMF instead of THF
36
33
30
16
0
36
11
6
5
7
0
6
9
54
14
48
20
24
46
31
66
9
10
11
12
13
PhMe instead of THF
1,4-dioxane instead of THF
DCE instead of THF
tAmOH instead of THF
a
Performed on 0.2 mmol scale.
Isolated yield.
b
Table 3
Scope of 1-Aryl-2-naphthols.a
a
Isolated yields.
3

J. Hao, Y. Ge, L. Yang et al.
Tetrahedron Letters 71 (2021) 153050
Table 4
Scope of Alkynes.a
a
Isolated yields.
of more bulky alkynes didn’t shut down the reaction, and sterically
more congested products 4j’-k’ could be obtained in acceptable
yields. Moreover, the alkyne containing heterocyclic groups
behaved well in the [3+2] spiroannulation, affording the desired
product 4l’ in 70% yield. In the end, it needed to mention that
replacement of aromatic substituents of internal alkynes with
either one or two aliphatic groups was unsuccessful, and no antic-
ipated product was not observed.
the [3+2] spiroannulation didn’t proceed at all, while two com-
pounds 6 and 7 were isolated in 37% and 22% yield, respectively.
These cyclic products were formed by activating different C–H
bonds with the assistance of those two directing groups, respec-
tively. The outcome clearly amplified the power of this new double
directing strategy for the titled challenging transformation.
In conclusion, we have successfully developed a new Ru(II)-cat-
alyzed [3+2] spiroannulation with
a double directing group
To demonstrate the importance on the combination of these
two DGs for the titled reaction, we studied the process by using
a new substrate 5, which contains the hydroxyl and acetylamino
group in the distant positions. As it is shown in the Scheme 2,
approach. This current process is featured by the introduction of
acetylamino group as a second DG2, thus reversing conventional
regiochemistry of the previously reported [3+2] spiroannulations
between 1-aryl-2-naphthols and internal alkynes. Noteworthy, this
4

J. Hao, Y. Ge, L. Yang et al.
Tetrahedron Letters 71 (2021) 153050
Scheme 2. Control Experiment with 5.
e) C. Sambiagio, D. Schönbauer, R. Blieck, T. Dao-Huy, G. Pototschnig, P. Schaaf,
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4083–4086;
work also represents a rare example of the challenging activation
of C–H bond at the more bulky site of meta-substituted arenes
through the involvement of two directing groups.
b) B. Li, S. Fang, D. Huang, B. Shi, Org. Lett. 19 (2017) 3950–3953;
c) Q. Wang, S. An, Z. Deng, W. Zhu, Z. Huang, G. He, G. Chen, Nat. Catal. 2 (2019)
793–800;
Declaration of Competing Interest
d) Q. Wang, W. Zhu, Q. Sun, G. He, G. Chen, Chin. J. Chem. 39 (2021) 571–576.
[4] a) G. Zhang, L. Yang, Y. Wang, Y. Xie, H. Huang, J. Am. Chem. Soc. 135 (2013)
8850–8853;
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
b) S. Luo, F. Luo, X. Zhang, Z. Shi, Angew. Chem. Int. Ed. 52 (2013) 10598–10601;
c) L. Castro, N. Chatani, Chem. Lett. 44 (2015) 410–421;
d) Y. Liang, X. Wang, Y. Yuan, Y. Liang, X. Li, N. Jiao, ACS Catal. 5 (2015) 6148–
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Acknowledgements
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[5] a) S. Mochida, K. Hirano, T. Satoh, M. Miura, J. Org. Chem. 76 (2011) 3024–3033;
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We thank the National Natural Science Foundation of China
(21925108) and the Key Laboratory Project of Xi’an
(201805058ZD9CG42).
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Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153050.
c) C. Ghosh, P. Nagtilak, M. Kapur, Org. Lett. 21 (2019) 3237–3241.
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