Solvent-switched benzylic methylene functionalization: Addition, ring-opening, cyclization, and unexpected cleavage of C-O and C-C bonds

Article abstract of DOI:10.1021/ol401470y

Intermolecular benzylic methylene functionalization of exo-cyclic enol ethers has been achieved using imines as reagents and potassium tert-butoxide as the catalyst. Depending on the solvent used, the reaction proceeds by two pathways. In THF, an addition

Full text of DOI:10.1021/ol401470y

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Solvent-Switched Benzylic Methylene
Functionalization: Addition, Ring-Opening,
Cyclization, and Unexpected Cleavage of
CÀO and CÀC Bonds
Deng Yuan Li, Xue Song Shang, Guo Rong Chen, and Pei Nian Liu*
Shanghai Key Laboratory of Functional Materials Chemistry and Institute of Fine
Chemicals, East China University of Science and Technology, Meilong Road 130,
Shanghai, China
liupn@ecust.edu.cn
Received May 24, 2013
ABSTRACT
Intermolecular benzylic methylene functionalization of exo-cyclic enol ethers has been achieved using imines as reagents and potassium tert-
butoxide as the catalyst. Depending on the solvent used, the reaction proceeds by two pathways. In THF, an addition/elimination reaction of exo-
cyclic enol ethers with imines provides dihydroisobenzofuran derivatives in good yield. In DMSO, an addition/ring-opening/cyclization cascade
reaction occurs with unexpected cleavage of CÀO and CÀC bonds, affording isoquinolin-1(2H)-one products in high yield under ambient reaction
conditions.
The direct functionalization of the benzylic methylene
group has attracted increasing attention in recent years,
which usually involves transition metal salts or complexes
as catalysts.1 Some examples of transition-metal-free func-
tionalization at the benzylic methylene group have been
reported.2À5 In particular, diphenyl phosphate,3 MsOH,4
and chiral phosphoric acids5 have been described as efficient
catalysts for such transformations, in which the key step is
1,5-hydride transfer. In 2012, Walsh et al. reported that
LiN(SiMe3)2 could deprotonate the acidic hydrogen of
benzylic methylene in [(η6-benzylamine)Cr(CO)3]. The
resulting anion can be stabilized by delocalizing the
negative charge to Cr(CO)3, and undergo palladium-
catalyzed cross-coupling with aryl triflate.6
Recent years have seen increased interest in the direct
functionalization of endo-cyclic enol ethers, which has
furnished important, complex synthetic intermediates with
high efficiency.7 Functionalization of exo-cyclic enol
ethers, however, has rarely been investigated.8 Here we
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Chem. Soc. 2012, 134, 8074. (b) Balmond, E. I.; Coe, D. M.; Galan,
M. C.; McGarrigle, E. M. Angew. Chem., Int. Ed. 2012, 51, 9152. (c) Xu,
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2011, 133, 2100.
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Chem., Int. Ed. 2012, 51, 12307.
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r
10.1021/ol401470y
XXXX American Chemical Society

report the solvent-switched, direct benzylic methylene
functionalization of exo-cyclic enol ethers via addition to
imines using a potassium tert-butoxide (t-BuOK) catalyst.
In THF, the reaction proceeds via an addition/elimination
pathway; in DMSO, it proceeds via an addition/ring-
opening/cyclization cascade reaction with unexpected cleav-
age of CÀO and CÀC bonds.
reaction produced 4a in 90% yield in the presence of
20 mol % t-BuOK (entries 7 and 8). Decreasing catalyst
loading of t-BuOK to 10 mol % substantially reduced the
yield of 4a (entry 9).
Addition/elimination reactions of exo-cyclic enol ethers
with imines provide access to a new class of vinylogous
analogues of 3-arylideneisobenzofuran-1(3H)-one com-
pounds possessing antianxiety and anti-HIV activity.9 To
explore whether our solvent-switched approach might be
useful for synthesizing such analogues, we reacted exo-
cyclic enol ethers and substituted N-phenylmethanimines
in the presence of 1.2 equiv of t-BuOK for 3 h in THF in
sealed tubes at 110 °C. Products 3aÀ3m were obtained
exclusively in the Z-configuration at both the 1 and 3
positions, as indicated by single-crystal X-ray diffraction
analysis of 3d (see Supporting Information) and by com-
parison of 1H NMR spectra of the products. When the R3
substituent on the N-phenylmethanimine was a phenyl
group incorporating electron-donating moieties such as
OMe, NEt2, pyrrolidinyl, piperidinyl, or morpholinyl, the
addition/elimination reactions with exo-cyclic enol ether
1a gave the corresponding products 3aÀ3e in 84À96%
yield, while product 3f was obtained in only 69% yield
(Scheme 1).
First we focused on developing the intermolecular addi-
tion of exo-cyclic enol ether 1a to imine 2a (Table 1). In the
presence of commercially available t-BuOK as the catalyst,
reaction of 1a and 2a in THF at 80 °C afforded the
addition/elimination product 3a in 85% yield, as well as
the unexpected addition/ring-opening/cyclization cascade
reaction product 4a in 15% yield (entry 1). When the
reaction was carried out in a sealed tube at 110 °C and
the dosage of t-BuOK was increased to 1.2 equiv of 1a,
product 3a was obtained in up to 95% yield after 3 h
(entries 2 and 3). If the reaction was performed under rt in
THF, only an 11% yield was observed even after 12 h
(entry 4). To our surprise, when 1a and 2a were reacted in
the polar aprotic solvent DMF or DMSO with 20 mol %
t-BuOK as the catalyst, the yield of 3a decreased drama-
tically and the yield of addition/ring-opening/cyclization
cascade product 4a increased to 28% or 58% (entries 5 and 6).
These results indicate that the solvent plays a crucial role in
controlling the reaction pathway, allowing the same start-
ing materials to generate different types of products.
We also examined addition/elimination reactions be-
tween N-phenylmethanimine substituted with N,N-dimethyl-
aniline and the exo-cyclic enol ether 1a or derivatives of 1a
containing 4-Me, 4-MeO, 2-Cl, 2-MeO or naphthyl at
position R2. These reactions produced 3g-3l in 82À96%
yield. In contrast, reaction of the same imine with the
exo-cyclic enol ether derivative of 1a containing 6-F at
position R1 gave product 3m in only 52% yield.
Table 1. Investigation of the Reactions of 1a and 2a under
Various Conditionsa
Scheme 1. Addition/Elimination Reaction of exo-Cyclic Enol
Ethers 1 with Imines 2a
temp
time
(h)
yield
(3a, %)b
yield
(4a, %)b
entry
(°C)
solvent
1
80
110
110
rt
3
THF
85
15
2
3
THF
88
10
3c
4c
5
3
THF
95
trace
23
12
3
THF
11
80
80
60
rt
DMF
DMSO
DMSO
DMSO
DMSO
8
28
6
3
40
58
7
6
35
65
8
9d
6
trace
trace
90
rt
6
74
a Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), t-BuOK
(0.04 mmol), solvent (1.0 mL), unless otherwise noted. b Determined by
1H NMR integration. c t-BuOK (0.24 mmol) was used. d t-BuOK
(0.02 mmol) was used.
Encouraged by these results, we examined the reaction
of 1a and 2a in DMSO at lower temperature. At rt, the
a Reaction conditions: 1(0.2 mmol), 2(0.24 mmol), t-BuOk (0.24 mmol),
THF (1.0 mL), 110 °C, 3 h; isolated yields are shown.
(8) (a) Smith, J. G.; Dibble, P. W. J. Org. Chem. 1988, 53, 1841. (b)
Smith, J. G.; Welankiwar, S. S.; Chu, N. G.; Lai, E. H.; Sondheimer, S. J.
J. Org. Chem. 1981, 46, 4658. (c) Smith, J. G.; Welankiwar, S. S.; Shantz,
B. S.; Lai, E. H.; Chu, N. G. J. Org. Chem. 1980, 45, 1817.
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Tortoriello, J.; San Feliciano, A. Bioorg. Med. Chem. Lett. 2005, 15,
3483.
B
Org. Lett., Vol. XX, No. XX, XXXX

Changing the reaction solvent from THF to DMSO
caused the t-BuOK-catalyzed reactions of exo-cyclic enol
ethers with imines to proceed via an interesting addition/
ring-opening/cyclization cascade reaction. The result was
isoquinolin-1(2H)-one products, which have become in-
creasingly attractive synthetic targets because of their
antihypertensive10 and antitumor11 activity. Usually they
are synthesized through the cycloaddition of benzamides
and alkynes in the presence of transition metal catalysts
such as Ni,12 Cu,13 Rh,14 and Ru15 To explore our solvent-
switched system in greater detail, we first examined the
reactions of exo-cyclic enol ether 1awith N-phenylmethan-
imines substituted at position R2 with an unsubstituted
Ph or substituted phenyl groups. When the phenyl group
carried electron-donating substituents such as OMe,
i-Pr, SMe, pyrrolidinyl, piperidinyl, or morpholinyl, the
N-phenylmethanimines reacted with 1a to afford products
4aÀ4h in 78À91% yield (Scheme 2). In contrast, if position
R2 was occupied by unsubstituted Ph, a phenyl group with
electron-withdrawing fluoro or bromo substituents, or
naphthyl or pyridyl groups, the N-phenylmethanimine
reacted with 1a in THF to give single products 4iÀ4m in
78À85% yield, although the reactions could also proceed
smoothly in DMSO at lower yields.
Scheme 2. Addition/Ring-Opening/Cyclization Cascade
Reactions of exo-Cyclic Enol Ethers and Iminesa
When these reactions were carried out in DMSO using
1-phenylmethanimine substituted at position R3 with
4-Me-Ph, 4-MeO-Ph, or 3,5-Me2-Ph, the reaction with 1a
gave products 4nÀ4p in 89À92% yield. Note that product
structures were confirmed by single-crystal X-ray diffrac-
a Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), t-BuOk (0.04
mmol), DMSO (1.0 mL), room temperature, 6 h, unless otherwise noted;
isolated yields are shown. b THF was used as solvent at 80 °C for 3 h.
In the next phase of our study, we performed detailed
investigations of the mechanism of the solvent-switched
intermolecular benzylic methylene functionalization of the
exo-cyclic enol ethers. We obtained 75% deuteration of the
benzylic methylene in the presence of 4 equiv of t-BuOD
and 10 mol % t-BuOK (eq 1, Scheme 3), revealing the
acidity of the benzylic CÀH bond. When 1a and imine 2b
were reacted in DMSO with 20 mol % t-BuOK as the
catalyst, the addition product 5 was isolated after 2 h,
together with the isoquinolin-1(2H)-one 4i. Under similar
catalytic reaction conditions, isolated addition product 5
converted smoothly to isoquinolin-1(2H)-one 4i after 6 h
(eq 2, Scheme 3). These results clearly demonstrate that
addition product 5 is an intermediate in the cascade
reactions. A similar addition reaction seemed to occur in
the addition/elimination reactionof1aand 2a, inwhich the
formal CdN bond was cleaved and the byproduct phenyl-
amine was detected as the result of elimination. To clarify
the ring-opening step of the cascade reaction, we reacted
imine 2c with exo-cyclic enol ether 1b substituted with a
methyl group on the benzylic carbon. The only product
generated was 4w, and no addition/elimination product
was detected (eq 3, Scheme 3). This indicates that the ring
opening occurs selectively through sp3 CÀO cleavage. In
the reaction of 1a with 2a, volatile toluene was detected in
the reaction mixture by GC-MS. In addition, when the
exo-cyclic enol ether 1c bearing a naphthyl group reacted
with imine 2d, the nonvolatile byproduct 2-methyl-
naphthalene was isolated (eq 4, Scheme 3). These results
indicate formal cleavage of the CdC bond in the exo-cyclic
enol ether moiety and the unusual release of ArÀCH3.
1
tion analysis of 4o and the comparison of the H NMR
spectra (see Supporting Information). However, attaching
phenyl groups bearing electron-withdrawing substituents
to position R3 of 1-phenylmethanimine led to unsatisfac-
tory reactions with 1a.
At the same time, we also obtained good yields by
inserting an electron-withdrawing substituent on the enol
ether: a 6-fluoro-substituted exo-cyclic enol ether reacted
with various imines to give products 4qÀ4s in 78À91%
yield. Finally, we examined the reactivity of alkyl-
substituted imines in this reaction. N-Methyl, N-propyl,
and N-cyclohexyl substitutions on 1-phenylmethanimine
allowed the imine to react smoothly with 1a and generate
products 4tÀ4v in 82À95% yield. This suggests that alkyl
substituents on the imine exert minimal steric effects on
reaction efficiency.
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Wang, F.; Liu, H.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2009, 11, 2469.
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2011, 133, 6449. (b) Hyster, T. K.; Rovis, T. J. Am. Chem. Soc. 2010, 132,
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Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Mechanism Investigations of the Solvent-Switched
Reactions
Scheme 4. Proposed Mechanism of the Solvent-Switched
Reactions
amine elimination to afford product 3. When the solvent
is DMSO, however, proton H2 of intermediate C is
selectively deprotonated to produce the intermediate E.
Selectiveintramolecularsp3 CÀO bond cleavage then leads
to F. Proton exchange generates intermediate H, which
undergoes intramolecular nucleophilic addition to form
intermediate I. Unusual CÀC cleavage releases Ar1ÀCH3
and generates the isoquinolin-1(2H)-one product 4.
In summary, concise, solvent-switched transition-metal-
free benzylic methylene functionalization of exo-cyclic
enol ethers has been achieved using imines and a t-BuOK
catalyst. Notably, the solvent acts as a switch to trigger
different reaction pathways, affording two types of pro-
ducts from the same starting materials. In THF, addition/
elimination reactions of exo-cyclic enol ethers with imines
provide dihydroisobenzofuran derivatives in good to
excellent yields. In DMSO, a novel addition/ring-opening/
cyclization cascade reaction of the same reactants leads to
unexpected cleavage of CÀO and CÀC bonds, generating
high yields of isoquinolin-1(2H)-one products under ambi-
ent reaction conditions. These results provide new insights
into the functionalization of benzylic sp3 CÀH and support
the development of new strategies for constructing organic
skeletons via functionalization of exo-cyclic enol ethers.
When 1c and deuterated imine D-2d reacted in the
absence of t-BuOD or the presence of 10 equiv of t-BuOD,
the undeuterated product 4o was obtained in 75% yield, as
well as D-3n and deuterated 2-methylnaphthalene in 18%
yield (eq 5, Scheme 3). Under both sets of reaction condi-
tions, the deuteration ratio on the sole deuteron in D-3n
was >99%, indicating that no CÀD bond cleavage or
exchange occurred in the addition/elimination reaction
forming D-3n. Interestingly, the deuteration ratio on
2-methylnaphthalene was 38% in the absence of t-BuOD
and >99% in the presence of 10 equiv of t-BuOD,
indicating intermolecular proton migration rather than
intramolecular transfer.
When 1a was reacted with the methyl-substituted imine
2e, only the addition/elimination product 3o was formed,
withoutanyisoquinolin-1(2H)-oneproduct(eq6, Scheme3).
This shows that CÀH cleavage in the NdCÀH moiety is
crucial in the formation of the isoquinolin-1(2H)-one
product but not in the formation of 3o.
Acknowledgment. This work was supported by the Na-
tional Natural Science Foundation of China (Project Nos.
21172069 and 21190033), the Innovation Program of
Shanghai Municipal Education Commission (Project
No. 12ZZ050), the Basic Research Program of the Shang-
hai Committee of Science and Technology (Project No.
13NM1400802), and the Fundamental Research Funds
for the Central Universities.
Based on these experimental results, we propose
mechanisms for the solvent-switched reactions in Scheme 4.
First, deprotonation of exo-cyclic enol ethers 1 in the
presence of t-BuOK affords intermediate A, which adds
to imines 2 to produce B. The nitrogen anion B traps a
proton, leading to the key intermediate C. When the
solvent is THF, proton H1 of intermediate C is selectively
removed to generate intermediate D, which undergoes
Supporting Information Available. Experimental pro-
cedures, analysis data of the products, and crystallo-
graphic data (CIF) of 3d and 4o. This material is
available free of charge via the Internet at http://
pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX