Platinum-Catalyzed Intramolecular Spirocyclization of N-(Methylnaphthalenyl)propiolamides via Formal Aromatic Ene Reaction

Article abstract of DOI:10.1021/acs.orglett.1c00393

It has been established that an in situ-generated cationic platinum(II)/rac-BINAP complex catalyzes the intramolecular dearomative 5-endo spirocyclization of N-(methylnaphthalenyl)propiolamides via the deprotonation-protonation sequence (formal aromatic e

Full text of DOI:10.1021/acs.orglett.1c00393

pubs.acs.org/OrgLett
Letter
Platinum-Catalyzed Intramolecular Spirocyclization of
N‑(Methylnaphthalenyl)propiolamides via Formal Aromatic Ene
Reaction
Seiya Ouchi, Takumi Koshikawa, Yuki Nagashima, and Ken Tanaka*
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ABSTRACT: It has been established that an in situ-generated cationic platinum(II)/rac-BINAP complex catalyzes the
intramolecular dearomative 5-endo spirocyclization of N-(methylnaphthalenyl)propiolamides via the deprotonation−protonation
sequence (formal aromatic ene reaction). Mechanistic studies revealed that our previously reported dearomative 6-endo cyclization
followed by the Friedel−Crafts reaction is kinetically and thermodynamically unfavored, and thus, the 5-endo spirocyclization
proceeds selectively.
he catalytic dearomatization of arenes and heteroarenes
Tthrough C−C bond formation is a useful transformation
for the synthesis of complex aliphatic compounds from simple
aromatic compounds.1 In general, the dearomatization of
heteroarenes proceeds more easily than that of simple arenes
due to the low aromaticity of the heteroarenes. Thus, the
catalytic dearomatization of simple arenes through C−C bond
formation is a challenging target in organic synthesis. Many
examples of the catalytic C−C bond-forming dearomatization
reactions of phenol2 and aniline3 [X = O or NR; Z = H (Figure
1a)] derivatives giving cyclohexadienones and iminocyclohex-
adienes have been reported, but examples of the corresponding
reactions using their carbon analogues (toluene derivatives)
have been limited in number. The pioneering work on the
palladium-catalyzed allylative dearomatization reactions of
benzyl and cinnamyl chlorides [X = CHR or CHCHCH2;
Z = Cl (Figure 1a)] giving methylenecyclohexadienes was
reported by Bao and Yamamoto.4 Recently, Muto and
Yamaguchi utilized benzyl phosphonates5 and ammoniums6
propiolamides; stoichiometric amounts of iodine reagents
were required, and the naphthyl and electron-rich aryl groups
were not used presumably due to the possible electrophilic
halogenation of these arenes (Figure 1b).7 In 2014, Hoye
reported the thermal hexadehydro-Diels−Alder (HDDA)-
initiated aromatic ene reaction, while aromatization proceeds
after dearomatization (Figure 1b).8,9 Recently, You10 and
Luan11 reported the catalytic spirocyclization of toluene
derivatives via p-allyl intermediates and carbopalladation of
arynes (Heck-type reaction12),13 respectively (Figure 1b).
These reactions afforded the desired dearomatized spiro-
products in good yields (with high ee values in Ir catalysis),
while the carbonate or iodine leaving group and the strong
base were required.
On the contrary, in 2011, our research group reported the
palladium(II)-catalyzed atroposelective intramolecular 6-endo
cyclization of N-benzyl-N-(naphthalen-2-yl)propiolamides
[X = CHR; Z = OP(O)(OR)2 or CH2NMe3 Cl− (Figure 1a)]
+
Received: February 2, 2021
Published: February 17, 2021
for the transformation described above. In addition, the
dearomatization of toluene derivatives via C−H deprotonation
is advantageous due to its atom economical nature (Figure 1a).
As an example of such a transformation, Li reported the
iodinative spirocyclization reaction of N-(p-tolyl)-
https://dx.doi.org/10.1021/acs.orglett.1c00393
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Org. Lett. 2021, 23, 1934−1939
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Figure 2. Transition-metal-catalyzed alkyne hydroarylation and
dearomative spirocyclization reactions.
complex mixture of products other than 2a presumably due to
the electrophilic iodination of the electron-rich aryl and
naphthyl groups (entry 4). In the absence of rac-binap, the
yield of 2a decreased significantly (entry 5). Diphosphine
ligands other than rac-binap (entries 6−9) and silver salts other
than AgSbF6 (entries 10−12) were then examined, but the
yield of 2a was not improved. Finally, increasing the reaction
temperature to 40 °C could reduce the catalyst loading to 10
mol % (entry 13).
Figure 1. Dearomatization reactions of phenol, aniline, and toluene
With the optimized conditions in hand, the scope of the
platinum(II)-catalyzed intramolecular dearomative spirocycli-
zation of N-(1-methylnaphthalen-2-yl)propiolamides 1 leading
to dearomatized spirolactams 2 via the deprotonation−
protonation sequence (formal aromatic ene reaction) was
examined as summarized in Figure 3. For the substituent on
the nitrogen atom, a variety of benzyl and alkyl groups could
be employed (1a−e, entries 1−5, respectively). For the
substituent at the alkyne terminus, spirolactams 2a, 2f, and
2g bearing electron-rich aryl (2- and 4-methoxyphenyl and
thienyl) groups were obtained in yields higher than those of
spirolactams 2h−j bearing phenyl, naphthyl, and methyl
groups, respectively (entries 1, 6, and 7 vs 8−10, respectively).
Not only N-(1-methylnaphthalen-2-yl)propiolamides 1a−j but
also N-(2-methylnaphthalen-1-yl)propiolamides 3a−c could
also participate in this process (entries 11−13). Interestingly,
the reaction of N-(4-methylnaphthalen-1-yl)propiolamides 3d
afforded the corresponding dearomatized spirolactam 4d in a
yield (71%) higher than that of the corresponding hydro-
arylation product 5d (10%) (entry 14). Finally, the reactions of
aniline derivatives 6 were examined. Although the reaction of
N-methyl-N-(o-tolyl)propiolamide 6a gave the corresponding
hydroarylation product 8a as a sole product (entry 15),18 the
reaction of N-methyl-N-(p-tolyl)propiolamide 6b gave the
corresponding dearomatized spirolactam 7b in 21% yield as
well as hydroarylation product 8b in 20% yield (entry 16). The
preparative-scale reaction (1 mmol of 1a) also afforded 2a in
derivatives.
(Figure 2a, top).14 When using N-benzyl-N-(naphthalen-1-
yl)propiolamides and a cationic platinum(II) complex, the
catalytic dearomative intramolecular 6-endo cyclization
through CC bond formation at the ipso and ortho positions
of the acylamino group proceeded in high yields (Figure 2a,
bottom).15,16 In this paper, we disclose the platinum(II)-
catalyzed intramolecular dearomative spirocyclization (5-endo
cyclization) of N-(methylnaphthalenyl)propiolamides via the
deprotonation−protonation sequence [formal aromatic ene
reaction (Figure 2b)]. Importantly, in this transformation, the
naphthyl and electron-rich aryl groups are compatible and no
dearomative intramolecular 6-endo cyclization products were
generated, which are in contrast to the previously reported
iodinative spirocyclization7 and CC bond-forming dearoma-
tization, respectively.15,16
We first investigated the reaction of N-(1-methylnaphthalen-
2-yl)propiolamide 1a in the presence of π-electrophilic
reagents at room temperature (Table 1). Although no reaction
was observed by using a cationic palladium(II)/rac-binap
catalyst (entry 1), the use of a cationic platinum(II)/rac-binap
catalyst17 afforded dearomative spirocyclization product 2a in
64% yield (entry 2). The use of a cationic gold(I)/rac-binap
catalyst and 2 equiv of iodine7 decreased the yield of 2a
(entries 3 and 4). Importantly, the use of iodine generated a
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a
Table 1. Optimization of Reaction Conditions
entry
catalyst
yield (%)
1
2
[Pd(CH3CN)4](BF4)2/rac-BINAP
PtCl2(cod)/2AgSbF6/rac-BINAP
AuCl(SMe2)/AgSbF6/rac-BINAP
I2 (2 equiv)
0
64
39
b
3
c
d
4
25
5
6
6
7
8
9
10
11
12
PtCl2(cod)/2AgSbF6
PtCl2(PPh3)2/2AgSbF6
26
30
52
54
54
45
58
43
31
76
PtCl2(cod)/2AgSbF6/dppp
PtCl2(cod)/2AgSbF6/dppe
PtCl2(cod)/2AgSbF6/dppbz
PtCl2(cod)/2AgSbF6/dppm
PtCl2(cod)/2AgNTf2/rac-BINAP
PtCl2(cod)/2AgBF4/rac-BINAP
PtCl2(cod)/2AgOTf/rac-BINAP
PtCl2(cod)/2AgSbF6/rac-BINAP
e
13
a
1a (0.050 mmol), catalyst (0.010 mmol), and (CH2Cl)2 (1.0 mL)
b
were used. 1a (0.050 mmol), AuCl(SMe2)/AgSbF6 (0.015 mmol),
rac-BINAP (0.0075 mmol), and (CH2Cl)2 (1.0 mL) were used. In
CH3CN (1.0 mL) for 24 h. A complex mixture was generated other
than 2a. 1a (0.10 mmol), PtCl2(cod) (0.010 mmol), AgSbF6 (0.020
c
d
e
mmol), rac-BINAP (0.010 mmol), and (CH2Cl)2 (0.4 mL) were used
at 40 °C.
Figure 3. Platinum(II)-catalyzed dearomative spiroicyclization
reactions. Ar = 2-MeOC6H4. Reactions were conducted using a
substrate (0.10 mmol), PtCl2(cod) (0.010 mmol), AgSbF6 (0.020
mmol), rac-BINAP (0.010 mmol), and (CH2Cl)2 (0.4 mL) at 40 °C
a
for 72 h. 1a (1.0 mmol), PtCl2(cod) (0.10 mmol), AgSbF6 (0.20
mmol), rac-BINAP (0.10 mmol), and (CH2Cl)2 (4.0 mL) were used.
bA substrate (0.050 mmol), PtCl2(cod) (0.010 mmol), AgSbF6 (0.020
mmol), rac-BINAP (0.010 mmol), and (CH2Cl)2 (1.0 mL) were used.
good yield (entry 1). The thus obtained dearomatized
products were stable at room temperature under air for several
days.
The enantioselective spirocyclization was briefly examined as
shown in Figure 4. The reaction of N-(1-methylnaphthalen-2-
yl)propiolamide 1a using a cationic platinum(II)/(R)-BINAP
catalyst gave spirolactam 2a with a moderate ee value of 39%.
On the contrary, the reactions of N-(4-methylnaphthalen-1-
yl)propiolamides (+)-3d using a cationic platinum(II)/(R)-tol-
BINAP catalyst gave spirolactam (+)-4d with an improved ee
value of 71%.
To confirm this deprotonation−protonation sequence,
deuterium labeling studies were conducted. The reaction of
nondeuterated methyl-substituted N-(naphthalen-2-yl)-
propiolamide 1a in the presence of a large excess of an
external deuterium source (CD3OD, 4 equiv) furnished
partially deuterated product 2a-d with selective incorporation
Figure 4. Enantioselective reactions. Ar = 2-MeOC6H4. The data are
averages of two runs.
of deuterium in the vinylic position (Figure 5a). In addition,
the reaction of deuterated methyl-substituted N-(naphthalen-
2-yl)propiolamide 1a-d3 furnished partially deuterated product
2a-d2 (Figure 5b). No deuterium incorporation in the vinylic
position might be due to the protonation with the residual
water in the solvent. These results are consistent with the
formation of 2a via the deprotonation−protonation mecha-
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coordination of the cationic platinum(II) complex to the
alkyne triple bond of 1 could induce the 6-endo or 5-endo
cyclization to generate cation intermediate A or E, respectively.
The Friedel−Crafts-type reaction in A would afford
intermediate B, and proton transfer via intermediate C
would afford dearomative 5-endo cyclization product D; D
was not detected in any entry in Table 1 or Figure 3. In
contrast, proton transfer in E affords the observed dearomative
6-endo cyclization product 2 via intermediate F and
regenerates the platinum catalyst.
To gain detailed insight into the highly selective formation
of 2, we then performed a model calculation using 1h and the
Pt(PMe3)2 dication complex (Figures 6b). The calculation
revealed that complex IM1, generated by chelation of the
cationic platinum(II) complex to the alkyne and the carbonyl
group, requires a lower activation energy for the 5-endo
cyclization (5.6 kcal mol−1) giving IM2a than the 6-endo
cyclization (13.2 kcal mol−1) giving IM2b. In addition, the
Friedel−Crafts reaction affording 6-endo cyclization product
IM3b from IM2b is kinetically (ΔG⧧ = 35.6 kcal mol−1) and
thermodynamically (ΔG = 28.5 kcal mol−1) unfavored
probably due to both steric and electronic instability. On the
contrary, the formation of IM3a from IM2a may not be the
rate-limiting step due to the small DKIE values (Figure 5b,c).
These analyses could well explain the absence of 6-endo
cyclization products from 1 in the platinum catalysis presented
here.
In conclusion, we have established that a chiral cationic
platinum(II) complex, generated in situ from PtCl2(cod),
AgSbF6, and rac-BINAP, is a highly effective catalyst for the
intramolecular dearomative spirocyclization of N-
(methylnaphthalenyl)propiolamides via the deprotonation−
protonation sequence (formal aromatic ene reaction).
Importantly, the electron-rich aryl and naphthyl groups are
compatible in the spirocyclization presented here, which is in
Figure 5. Experimental mechanistic studies.
nism. Next, a deuterium kinetic isotope effect (DKIE) of the
intramolecular spirocyclization of 1a was measured. A DKIE
value, measured by comparing the initial rates obtained from
the reactions of 1a and 1a-d3, was 1.5 in the parallel reactions
(Figure 5b) and 1.3 in the competition reaction (Figure 5c),
which may not be the primary DKIE. These results would
suggest that the C−H deprotonation is not the rate-limiting
step in the intramolecular spirocyclization presented here.
Figure 6a depicts two possible dearomatization pathways for
N-(naphthalen-2-yl)propiolamide 1. We believe that the
Figure 6. Theoretical mechanistic studies. The changes in relative free energies calculated at the M06/6-31G** (C, H, O, N, and P) and SDD (Pt)
levels in the gas phase are shown in kilocalories per mole.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00393.
́
́
́
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AUTHOR INFORMATION
Corresponding Author
■
Ken Tanaka − Department of Chemical Science and
Engineering, Tokyo Institute of Technology, Tokyo 152-8550,
Japan; orcid.org/0000-0003-0534-7559;
Email: ktanaka@apc.titech.ac.jp
Authors
Seiya Ouchi − Department of Chemical Science and
Engineering, Tokyo Institute of Technology, Tokyo 152-
8550, Japan
Takumi Koshikawa − Department of Chemical Science and
Engineering, Tokyo Institute of Technology, Tokyo 152-
8550, Japan
Yuki Nagashima − Department of Chemical Science and
Engineering, Tokyo Institute of Technology, Tokyo 152-
8550, Japan; orcid.org/0000-0001-8470-5638
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00393
Quinones, N.; Mascarenas, J. L.; Gulías, M. Rhodium(III)-Catalyzed
̃ ̃
Notes
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Terminal Alkyne via an Intramolecular ipso-Friedel−Crafts Alkeny-
lation. Adv. Synth. Catal. 2014, 356, 2417−2421. (j) Rousseaux, S.;
García-Fortanet, J.; Del Aguila Sanchez, M. A.; Buchwald, S. L.
Palladium(0)-Catalyzed Arylative Dearomatization of Phenols. J. Am.
Chem. Soc. 2011, 133, 9282−9285. (k) Wu, Q. F.; Liu, W. B.; Zhuo,
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Angew. Chem., Int. Ed. 2011, 50, 4455−4458. (l) Nemoto, T.;
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Method for Synthesizing Spiro[4.5]cyclohexadienones through a Pd-
Catalyzed Intramolecular ipso-Friedel−Crafts Allylic Alkylation of
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Ishihara, K. Enantioselective Kita Oxidative Spirolactonization
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported partly by Grants-in-Aid for Scientific
Research (JP19H00893 to K.T. and JP20J20496 to T.K.) from
JSPS. The authors thank Mr. Juntaro Nogami (Tokyo Institute
of Technology) for his assistance with the structural analysis. A
generous allotment of computational resources from TSU-
BAME (Tokyo Institute of Technology) is gratefully acknowl-
edged.
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