Ruthenium(VIII)-Catalyzed ipso-Dearomative Spiro-Etherification and Spiro-Amidation of Phenols

Article abstract of DOI:10.1021/acs.orglett.9b01322

An open air ruthenium(VIII)-catalyzed oxidative spiro-etherification as well as spiro-amidation of phenols has been performed. The transformation works satisfactorily with both phenols and naphthols and thus exhibits a wide range of flexibility. The catalysis is performed in open air at room temperature with a yield of ≤95%.

Full text of DOI:10.1021/acs.orglett.9b01322

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ruthenium(VIII)-Catalyzed ipso-Dearomative Spiro-Etherification
and Spiro-Amidation of Phenols
Debayan Sarkar* and Nilendri Rout
Organic Synthesis and Molecular Engineering Laboratory, Department of Chemistry, National Institute of Technology, Rourkela,
Odisha 769008, India
S
* Supporting Information
ABSTRACT: An open air ruthenium(VIII)-catalyzed oxidative
spiro-etherification as well as spiro-amidation of phenols has been
performed. The transformation works satisfactorily with both phenols
and naphthols and thus exhibits a wide range of flexibility. The
catalysis is performed in open air at room temperature with a yield of
≤95%.
earomatization of arenes has been an important chemical
transformation, providing easy access to the alicyclic
Herein, we report the Ru(VIII)-catalyzed synthesis of spiro-
azacycles and spiro-oxacycles employing oxidative dearomati-
zation as the key step from easily available naphthols and
phenols (Figure 1).
D
framework found in biologically and pharmacologically active
compounds.1 Phenols and naphthols are readily available
chemical feedstocks for organic synthesis.2 Thus, catalytic
dearomatization of these arenols through C−heteroatom
bond-formation processes is a desired synthetic route for
accessing complex organic molecular targets.3 Efficient
construction of spirocyclic frameworks has been an important
challenge because of their presence in biologically active
natural products and pharmaceuticals. Among the various
spirocycles, spiro-oxacyclohexadienones and spiro-azacyclohex-
adienones are the primary targets.4 Extensive efforts were
focused on the development of efficient methods based on
hypervalent iodine reagents,5 ipso-halocyclization,6 radical
cyclization,7 arene−Ru complex-mediated dearomatization,8
and Cu-catalyzed oxygenation of R-azido-N-arylamides.9
The past decade has seen the prominent development of
hypervalent iodine catalysts being exhaustively employed in
such dearomatization reactions. Some important reports
included the catalytic intramolecular spirolactonization by
Ishihara10 and Kita.11 A quite generalized, tribromide-mediated
spiro-oxacyclization was reported by our group.12 Reterosyn-
thetically, it is envisaged that a preferred ipso-attack of a
tethered chain in a phenol can deliver spirocyclization that
proceeds via oxidative dearomatization. It would be inspiring if
the desired catalysis were an open air transformation.
Figure 1. Ru(VIII)-catalyzed dearomative spiro-etherification and
spiro-amidation.
Transition metal-catalyzed protocols have been limited
mainly to spiro-carbon cyclizations.9 Katsuki’s spiro-ether-
ification employing the Fe−Salan catalyst has been a direct way
to spiro-oxacylizations. Although the reaction is carried out in
open air, the required temperature is 90 °C.13 A recent report
by Vadola delineates a gold-catalyzed synthesis of spiroamides
that proceeds through a dearomative alkyne insertion;
however, the temperature required for the successful reaction
was 80 °C, and Ag(OTf)2 was employed as an activator with
moderate yields ranging from 35% to 80%.14
Our initial investigation started with 1-(3-ethyl-3-
hydroxypentyl)naphthalen-2-ol (xxi). The substrate (xxi) was
treated with RuCl3·3H2O in the presence of K2CO3 as a base
and KBrO3 as a co-oxidant along with phenyl trimethylammo-
nium iodide (PTAI) as the additive at room temperature that
delivered a 10% yield of the desired spiroether (Table 1, i).
Received: April 15, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01322
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Results of Optimization
Table 2. Substrate Scope of Spiro-Furano-Naphthalones
R
yield (%)
ammonium salt (additive)
oxidant
KBrO3
yield (%)
10
no
reaction
no
reaction
no
reaction
2(A)
2(B)
2(C)
2(D)
2(E)
2(F)
2(G)
2(H)
2(I)
-Me
92
75
95
89
94
90
92
92
96
98
85
75
95
82
a
-CH2-C6H4-F
-(CH2)2-CH3
-(CH2)4-CH3
−3-Me-C6H4
−4-Me-C6H4
-H
-Ph
-(CH2)7-CH3
-Et
-CH2-CH(CH3)2
−4-Br-C6H4
-CH2-CH2-C6H5
-CH2-C6H5
i
phenyl trimethylammonium iodide
tetrabutyl ammonium fluoride
(TBAF)
TBAF
TBAF
a
ii
m-CPBA
Na2O2
Oxone
KBrO3
a
iii
a
iv
a
v
tetrapropyl ammonium hydroxide
(TPAH)
TBAF
benzyl triethylammonium chloride
(BTEACl)
TBAF
60
a
vi
KBrO3
KBrO3
95
93
2(J)
a
vii
2(K)
2(L)
2(M)
2(N)
b
viii
KBrO3
(10 mol %)
KBrO3
10
c
ix
BTEACl
no
reaction
a
Reaction performed on a 0.5 mmol scale, with 1 equiv of substrate, 1
a
equiv of K2CO3, RuCl3·3H2O (10 mol %), BTAECl (10 mol %), and
1 equiv of KBrO3. The yield was determined after chromatographic
separation.
Reaction performed on a 0.5 mmol scale, with 1 equiv of substrate, 1
equiv of K2CO3, RuCl3·3H2O (10 mol %), additive (10 mol %), and 1
equiv of oxidant. Reaction performed on a 0.5 mmol scale, with 1
b
equiv of substrate, 1 equiv of K2CO3, RuCl3·3H2O (10 mol %),
c
additive (10 mol %), and 10 mol % oxidant. Reaction performed on a
and 2(B)]. Initial experiments with a focus on the
enantioselectivity variant were performed with 2(M) and
chiral (2R,4S,5R)-1-benzyl-2-[(S)-hydroxy(quinolin-4-yl)-
methyl]-5-vinylquinuclidin-1-ium bromide as the ammonium
salt under the same reaction conditions that produced 60% ee
and are still being explored.
0.5 mmol scale, with 1 equiv of substrate, 1 equiv of K2CO3, additive
(1 equiv), and KBrO3 (1 equiv). The reaction was carried out in the
absence of RuCl3·3H2O. The yield was determined after chromato-
graphic separation.
Methanol was used as the solvent of choice due to solubility
factors. Further optimization was investigated with the same
substrate and with varied oxidants like m-CPBA, sodium
peroxide, and oxone that produced no reaction (Table 1, ii−
iv). Replacing the additive with tetrapropyl ammonium
hydroxide (TPAH) improved the yield to 60% (Table 1, v).
This conveyed the requirement of an optimal dielectric
constant for a successful reaction. A detailed standardization
suggested TBAF and BTEACl with KBrO3 were the candidates
for the best combination (Table 1, vi). BTEACl was preferred
because it was less expensive than TBAF. Electron-donating or
-withdrawing substituents attached to the tethered chain did
not pose any effect in the reaction [Table 2, 2(A), 2(J), 2(L),
and 2(B)].
Repeating the reaction with only tetrapropyl ammonium
perruthenate [Ru(VII)] (10 mol %) in place of RuCl3·3H2O
without any co-oxidant did not produce any reaction. Addition
of one drop of a KBrO3 solution immediately triggered the
reaction (detailed reaction conditions are given in the
Supporting Information).
After the optimal reaction conditions had been achieved, we
attempted to generalize the reaction with different side chain
alcohols. Exposure of a wide range of side chain alcohols
delivered the corresponding spiroethers in excellent yields
(Table 2).
Reactions with electron-donating substituents in the side
chain [Table 2, 2(D), 2(F), and 2(K)] as well as a long carbon
chain [Table 2, 2(I)] promoted better yields compared to
those with electron-withdrawing substituents [Table 2, 2(L)
The substrate scope was further extrapolated with chiral
substrates bearing asymmetric centers under the optimized
reaction conditions (Table 3). The substitutent variety on the
alcohol was tolerated well with moderate diastereoselectivity
(4:1 dr) and excellent yield. Large substituents like aryls
delivered better diastereoselctivity. All entries (R,R-spiro-
furano-napthalones) were found to be the major diastereomer.
The stereochemical assignment was made on the basis of
nuclear Overhauser effect experiments. The detailed data are
given in the Supporting Information.
With an already established correlation with our previous
work on tribromide-cast dearomatizations,15 we sought to
explore the plausible effect of ammonium counterparts of the
additives on the diastereoselectivity of spiro-etherification in
naphthols. 1-(3-Hydroxy-5-phenylpentyl)naphthalen-2-ol
[3(P)] was chosen as the model substrate, and ipso-cyclization
was attempted in the presence of different ammonium salts.
The diastereoselectivity changed moderately with the
ammonium counterpart, which suggested a possible coordi-
nated key reactive intermediate (shown in the Supporting
Information).
The probable existence of moderate diastereoselectivity may
arise due to the presence of intimate ion pair arrangement of
the ammonium counterpart and the less sterically crowded
alkaloate, which attacks the exo face of the reactive
intermediate with minimal stereoelectronic repulsion (Figure
2).
A compatible combination of the coordinated ammonium
counterpart with an aliphatic alcohol followed by both π-
B
DOI: 10.1021/acs.orglett.9b01322
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 3. Substrate Scope of Diastereoselective Spiro-
a
Furano-Naphthalones
Figure 4. Spiroether conformation.
R
overall yield (%)
dr (4:5)
the thermodynamically stable reaction intermediate (R2) and
the conformational stability of the product that is achieved.
Spirocycles with a 1-naphthol backbone are rarely reported
in the literature. 4-Substituted 1-naphthols also delivered the
spiro-oxacycles under similar reaction conditions with
moderate to good yields (Table 4).
3(A)
3(B)
3(C)
3(D)
3(E)
3(F)
3(G)
3(H)
3(I)
-4-Me-C6H4
-Et
73
80
72
85
82
87
75
81
65
88
68
92
83
67
65
91
3:1 [4(A):5(A)]
3:1 [4(B):5(B)]
7:3 [4(C):5(C)]
4:1 [4(D):5(D)]
3:1 [4(E):5(E)]
3:1 [4(F):5(F)]
5:1 [4(G):5(G)]
8:1 [4(H):5(H)]
4:1 [4(I):5(I)]
3:1 [4(J):5(J)]
3:1 [4(K):5(K)]
3:1 [4(L):5(L)]
2:1 [4(M):5(M)]
7:3 [4(N):5(N)]
3:2 [4(O):5(O)]
4:1 [4(P):5(P)]
-Pr
-(CH2)4-CH3
-CH-(CH2)4
-(CH2)3-CH3
-(CH2)7-CH3
-CH-(CH2)5
-CH2-4-F-C6H4
-Ph
-CH-(CH3)2
-CH2-C6H4
-CH3
Table 4. Substrate Scope of Spiro-Oxacycles in 1-
a
Naphthols
3(J)
3(K)
3(L)
3(M)
3(N)
3(O)
3(P)
-C10H7
−4-F-C6H4
-CH2-CH2-C6H5
R1
R2
R3
yield (%)
a
Reaction performed on a 0.5 mmol scale, with 1 equiv of substrate, 1
7(A)
7(B)
7(C)
Ph
H
H
Et
Bn
Et
H
H
H
65
65
60
equiv of K2CO3, RuCl3·3H2O (10 mol %), BTAECl (10 mol %), and
1 equiv of KBrO3. The yield was determined after chromatographic
separation. Diastereoselectivity was measured for the mixture via
NMR, which is given in the Supporting Information.
a
Reaction performed on a 0.5 mmol scale, with 1 equiv of substrate, 1
equiv of K2CO3, RuCl3·3H2O (10 mol %), BTAECl (10 mol %), and
1 equiv of KBrO3. The yield was determined after chromatographic
separation.
Not only naphthols but also the developed protocol was
applicable in the case of properly substituted 2,6-disubstituted
phenols that delivered the cyclohexaoxaspirodienones in
excellent yields, but the ortho positions were required to be
substituted for a successful reaction (Table 5).
Figure 2. Reactive intermediate (R1).
With the wider substrate scope of spiro-etherification of
naphthols and phenols in hand, the next target was to expand
stackings (π-stacking 1 and π-stacking 2) and syn hydrogen−
hydrogen interaction was taken into consideration for the best
stereoselectivity (Figure 3). We further propose that from
varied projections of spiro-furans in Figure 4 conformation 4
suffers with minimal stereoelectronic interaction and thus is
more thermodynamically stable than 5 (Figure 4). Thus, the
overall diastereoselectivity achieved is a combination of both
Table 5. Substrate Scope of Synthesized Oxa-
Spirodienones
a
R1
R2
R3
R4
yield (%)
9(A)
9(B)
9(C)
9(D)
Pr
Me
Me
Me
Me
benzyl
Ph
H
benzyl
Ph
H
93
95
92
96
Me
Me
Pr
H
H
a
Reaction performed on a 0.5 mmol scale, with 1 equiv of substrate, 1
equiv of K2CO3, RuCl3·3H2O (10 mol %), BTAECl (10 mol %), and
1 equiv of KBrO3. The yield was determined after chromatographic
separation.
Figure 3. Proposed ion pairing of an alkoxide with a bulky
ammonium counterpart (R2).
C
DOI: 10.1021/acs.orglett.9b01322
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the synthetic utility of our methodology with different δ-amino
naphthols to perform the same ipso-cyclization to deliver the
spiro-azacyclodienones in good to excellent yields (Table 6).
Scheme 1. Catalytic Cycle for Oxidative Spiro-Etherification
a
Table 6. Substrate Scope of Synthesized Spiropyrrolidones
R
yield (%)
11(A)
11(B)
11(C)
11(D)
11(E)
11(F)
allyl
cyclohexyl
benzyl
butyl
propyl
86
95
95
92
91
82
4-Cl-C6H4
a
Reaction performed on a 0.5 mmol scale, with 1 equiv of substrate, 1
equiv of K2CO3, RuCl3·3H2O (10 mol %), BTAECl (10 mol %), and
1 equiv of KBrO3. The yield was determined after chromatographic
separation.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01322.
To the best of our knowledge, the catalysis involves a red−
ox cycle of Ru(III) to Ru(VIII).16
We may propose that the catalytic cycle continues with two-
phase oxidations of Ru(III) to Ru(VI) and Ru(VI) to Ru(VIII)
in the presence of KBrO3.
Copies of 1H and 13C NMR spectra of all new
compounds and EPR, CV, and UV data of related
reaction mixtures (PDF)
To further comply with the observation, regardless of
whether Ru(VIII) was the active species, the reaction mixture
was exposed to spectroscopic methods such as ultraviolet
(UV), cyclic voltammetry (CV), and electron paramagnetic
resonance (EPR) (details given in the Supporting Informa-
tion).
The combined data derived from EPR, UV, and CV
experiments complied and ruled out the possibilities of
Ru(VII) and the presence of Ru(VIII) as an active species in
the catalytic cycle.
From the experimental outcome mentioned above and the
proposed mechanism of ruthenium-catalyzed oxidative dear-
omatization of indoles,14 a mechanistic outlook is proposed.
The catalytic cycle begins with the oxidation of RuCl3·3H2O to
Ru(VIII) in the presence of KBrO3. The active species
Ru(VIII)O4 forms a hydrogen ruthenate complex with the
alcoholic naphthoxide and generates a spirofuran and
ruthenium(VI) oxide. The ruthenium(VI) oxide is further
oxidized to Ru(VIII) by KBrO3. We further propose that the
chiral ammonium counterpart of the additive maintains a
coordinated sphere throughout the catalytic cycle that
produces the moderate diastereoselectivity (Scheme 1).
In conclusion, open air in situ ruthenium(VIII)-catalyzed
ipso-dearomative spiro-etherification and spiro-amination of
phenols are reported. It is noteworthy that employing chiral
ammonium tribromides as additives tuned the stereoselective
outcome of spiro-oxacycles. Thus, it is clearly evident that fine-
tuning of the ammonium counterpart maintains an asymmetric
reaction sphere, and thus, better diastereoselectivity can be
achieved in spiro-cycle synthesis. The reaction has been also
successful with 1-naphthols as backbones. The asymmetric
version is presently being studied in our laboratories.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sarkard@nitrkl.ac.in.
ORCID
Debayan Sarkar: 0000-0003-2221-2912
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors sincerely acknowledge the Department of Science
and Technology (DST), Government of India (Grant EEQ/
2016/000518), and INSPIRE-DST, Government of India
(Grant 04/2013/000751). The authors thank Prof. Abhisek
Dey (IACS) for extending the support for the EPR facility.
N.R. thanks CSIR and DST for research fellowships.
REFERENCES
■
(1) (a) Zhuo, C. X.; Zhang, W.; You, S. L. Angew. Chem., Int. Ed.
2012, 51, 12662−12686. (b) Han, L.; Wang, H.; Luan, X. Org. Chem.
Front. 2018, 5, 2453−2457.
(2) (a) Wu, W.-T.; Zhang, L.; You, S.-L. Chem. Soc. Rev. 2016, 45,
1570−1580. (b) Fiege, H.; Voges, H. W.; Hamamoto, T.; Umemura,
S.; Iwata, T.; Miki, H.; Fujita, Y.; Buysch, H. J.; Garbe, D.; Paulus, W.
Ullmann’s Encyclopedia of Industrial Chemistry; Wiley, 2000.
́
(3) (a) Pouysegu, L.; Deffieux, D.; Quideau, S. Tetrahedron 2010,
66, 2235−2261. (b) Roche, S. P.; Porco, J. A., Jr Angew. Chem., Int.
Ed. 2011, 50, 4068−4093.
(4) (a) Rios, R. Chem. Soc. Rev. 2012, 41, 1060−1074. (b) Dohi, T.;
Maruyama, A.; Yoshimura, M.; Morimoto, K.; Tohma, H.; Kita, Y.
Angew. Chem., Int. Ed. 2005, 44, 6193−6196.
(5) (a) Dohi, T.; Maruyama, A.; Minamitsuji, Y.; Takenaga, N.; Kita,
Y. Chem. Commun. 2007, 12, 1224−1226. (b) Dohi, T.; Minamitsuji,
Y.; Maruyama, A.; Hirose, S.; Kita, Y. Org. Lett. 2008, 10, 3559−3562.
D
DOI: 10.1021/acs.orglett.9b01322
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(6) (a) Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2005, 127,
12230−12231. (b) Tang, B.-X.; Yin, Q.; Tang, R.-Y.; Li, J.-H. J. Org.
Chem. 2008, 73, 9008−9011.
́
́
(7) (a) Gonzalez-Lopez de Turiso, F.; Curran, D. P. Org. Lett. 2005,
7, 151−154. (b) Lanza, T.; Leardini, R.; Minozzi, M.; Nanni, D.;
Spagnolo, P.; Zanardi, G. Angew. Chem. 2008, 120, 9581−9584.
(8) (a) Pigge, F. C.; Coniglio, J. J.; Rath, N. P. Org. Lett. 2003, 5,
2011−2014. (b) Pigge, F. C.; Dhanya, R.; Hoefgen, E. R. Angew.
Chem. 2007, 119, 2945−2948.
(9) Chiba, S.; Zhang, L.; Lee, J.-Y. J. Am. Chem. Soc. 2010, 132,
7266−7267.
(10) (a) Uyanik, M.; Sasakura, N.; Kaneko, E.; Ohori, K.; Ishihara,
K. Chem. Lett. 2015, 44, 179−181. (b) Uyanik, M.; Yasui, T.; Ishihara,
K. Tetrahedron 2010, 66, 5841−5851. (c) Uyanik, M.; Yasui, T.;
Ishihara, K. Angew. Chem. 2010, 122, 2221−2223.
(11) (a) Dohi, T.; Maruyama, A.; Takenaga, N.; Senami, K.;
Minamitsuji, Y.; Fujioka, H.; Caemmerer, S. B.; Kita, Y. Angew. Chem.
2008, 120, 3847−3850. (b) Dohi, T.; Takenaga, N.; Nakae, T.;
Toyoda, Y.; Yamasaki, M.; Shiro, M.; Fujioka, H.; Maruyama, A.; Kita,
Y. J. Am. Chem. Soc. 2013, 135, 4558−4566.
(12) Sarkar, D.; Ghosh, M. K.; Rout, N. Org. Biomol. Chem. 2016,
14, 7883−7898.
(13) Oguma, T.; Katsuki, T. Chem. Commun. 2014, 50, 5053−5056.
(14) Vacala, T. L.; Carlson, P. R.; Arreola-Hester, A.; Williams, C.
G.; Makhoul, E. W.; Vadola, P. A. J. Org. Chem. 2018, 83 (3), 1493−
1501.
(15) Sarkar, D.; Ghosh, M. K.; Rout, N.; Kuila, P. New J. Chem.
2017, 41, 3715−3718.
(16) Zhou, X.-Y.; Chen, X.; Wang, L.-G.; Yang, D.; Li, J.-H. Synlett
2018, 29, 835−839.
E
DOI: 10.1021/acs.orglett.9b01322
Org. Lett. XXXX, XXX, XXX−XXX