Chemoselective Asymmetric Intramolecular Dearomatization of Phenols with α-Diazoacetamides Catalyzed by Silver Phosphate

Article abstract of DOI:10.1021/jacs.7b04813

We report asymmetric dearomatization of phenols using Ag carbenoids from α-diazoacetamides. The Ag catalyst promoted intramolecular dearomatization of phenols, whereas a Rh or Cu catalyst caused C-H insertion and a Büchner reaction. Studies indicated Ag carbenoids have a carbocation-like character, making their behavior and properties unique. Highly enantioselective transformations using Ag carbenoids have not been reported. We achieved a Ag carbenoid-mediated chemo- and highly enantioselective phenol dearomatization with substrate generality for the first time.

Full text of DOI:10.1021/jacs.7b04813

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Communication
Chemoselective Asymmetric Intramolecular Dearomatization of
Phenols with #-Diazoacetamides Catalyzed by Silver Phosphate
Hiroki Nakayama, Shingo Harada, Masato Kono, and Tetsuhiro Nemoto
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b04813 • Publication Date (Web): 17 Jul 2017
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Chemoselective Asymmetric Intramolecular Dearomatization of Pheꢀ
nols with αꢀDiazoacetamides Catalyzed by Silver Phosphate
Hiroki Nakayama,† Shingo Harada,*,† Masato Kono,† and Tetsuhiro Nemoto*,†,‡
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†Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan
‡Molecular Chirality Research Center, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Supporting Information Placeholder
lysts were utilized for CADA reactions of phenols to con-
ABSTRACT: We report an asymmetric dearomatization of
phenols using Ag carbenoids generated from α-
struct chiral ortho-spirolactone structures.11 Enantiocontrol
at the para-position in these reactions remains difficult,
however, due to the remote distance from the chiral envi-
ronment created by O-bound iodine(III).12 In sharp contrast,
para-substituted phenols can directly react with chirally
modified electrophiles at the ipso-position to construct the
chiral center at the para-position. Extensive efforts recently
focused on the development of the CADA processes based on
this strategy.13,14,15 The presence of substituents at the meta-
position of phenols, however, was prerequisite to achieve
efficient enantiodiscrimination of the Re/Si face of the car-
bon at the para-position.
diazoacetamides. The Ag catalyst preferentially promoted an
intramolecular dearomatization of phenols, while a Rh or Cu
catalyst caused a C–H insertion and a Büchner reaction. Ex-
perimental and computational studies indicated the Ag car-
benoids have a carbocation-like character, making their be-
havior and properties quite unique. Highly enantioselective
transformations using Ag carbenoids have not yet been re-
ported. We achieved a Ag carbenoid-mediated chemo- and
highly enantioselective phenol dearomatization with broad
substrate generality for the first time.
Scheme 1. Chemoselective reactions of arenes with met-
al carbenoids
Achieving a high level of chemoselectivity enhances synthet-
ic efficiency by reducing the number of steps needed to pro-
tect the functional groups and minimize undesired byprod-
ucts, which contributes to step and atom economy. Notably,
controlling the chemoselectivity in divergent reactions pro-
moted by extremely reactive chemical species is a rewarding
challenge in modern organic chemistry.
Metal carbenoids are highly active carbon species with diver-
gent reactivity.1 Recently, several groups succeeded in con-
trolling the chemoselectivity of metal carbenoid-mediated
reactions against arenes. Reisman developed a substrate-
controlled arene cyclopropanation (Scheme 1a).2 Using α-
diazo-β-ketonitriles as substrates,3 the cyclopropanation was
preferentially promoted over the C–H insertion. The devel-
opment of catalyst-controlled chemoselective reactions of
metal carbenoids and their mechanistic studies is also re-
ported. Che developed Ru-catalyzed intramolecular primary
(1°) C–H insertion in contrast to a Rh-catalyzed reaction pre-
ferring secondary (2°) C–H insertion or a Büchner reaction
(Scheme 1b).4,5 Liu, Zhang and Lan, Shi independently re-
ported chemo- and site-selective alkylations of phenols using
a Au catalyst with a phosphite ligand (Scheme 1c).6,7 While
methods to control the reactivity of metal carbenoids con-
tinue to be developed,8,9 the development of chemo- and
highly enantioselective reactions of arenes with metal carbe-
noids has remained an unsolved challenge.
esp is α,α,α’,α’-tetramethyl-1,3-benzenedipropanoate. n.d. is
not described.
Catalytic asymmetric dearomatization (CADA)10 reactions of
phenols are particularly powerful strategies for assembling
versatile three-dimensional cyclic architectures from widely
available aromatic feedstocks. Chiral hypervalent iodine cata-
We envisioned that chemoselective dearomatization reac-
tions of phenols could be realized using an electrophilic met-
al carbenoid if the competing Büchner reaction or the C–H
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insertion could be controlled by the appropriate selection of
Interestingly, it proceeded smoothly to produce the opposite
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metal and ligands. Herein, we report intramolecular CADA
reactions using chiral Ag phosphate, and describe the first
successful examples of discrimination of the enantiotopic
face of the carbon at the para-position on the phenolic ring
without a substituent at the meta-position.
To assess the chemoselectivity in divergent reactions, we
began our studies using α-diazoamide 1a as a model sub-
strate possessing 1°, 2°, and 3° C–H bonds as well as a phenol
unit (Table 1). The reaction of 1a in the presence of 5 mol %
Rh2(OAc)4 in CH2Cl2 at room temperature gave tropone 3a
through a Büchner reaction and 1° and 3° C–H insertion
products 4a and 5a in 26%, 15%, and 17% yield, respectively
enantiomer of 2a as a major product without a significant
loss of chemoselectivity (51% yield, 81:19 er, entry 5).18 To
confirm the effect of Ag metal without phosphate, AgSbF6
was utilized, which exhibited a different chemoselectivity
from those obtained using a Rh or Cu catalyst (entries 1 and 2
vs 6). In addition, to eliminate the possibility of Brønsted
acid catalysis, 2,6-di-tert-butylpyridine was used as an addi-
tive in the reaction conditions of entries 5 and 6, and similar
results were observed (entries 5 vs 7, 6 vs 8). These results
indicate that the Ag catalyst promoted the dearomatization
process preferentially. Examples of Ag carbenoids used in
synthetic organic chemistry and its mechanistic investiga-
tions are quite limited, despite the known unique reactivities
of Ag carbenoids compared with other metals.19 Moreover,
no highly enantioselective reactions with Ag carbenoid have
been reported,19 leading us to conduct the study using a (S)-
TRIPAg catalyst. Next, solvent screening revealed that a polar
solvent was appropriate for the reaction system; the yield
increased to 61% in 2-butanone (entry 14) while no further
improvement was observed in other solvents (entries 9-13).
Comprehensive examination of additives revealed that ben-
zoic acid effectively increased the yield to 89% without de-
creasing the er (entry 15).
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(entry 1). Using Cu(NCMe)4PF6 as
a catalyst, azaspi-
ro[4.5]decane derivative 2a was obtained in only 6% yield
(entry 2). The reaction with (2,4-t-Bu2C6H3O)3PAuCl and
AgSbF6, utilized by Liu and Zhang6a provided 2a in 52% yield
(entry 3). To expand the asymmetric reaction,16 a catalyst
system using (2,4-t-Bu2C6H3O)3PAuCl and (S)-TRIPAg for
generation of the chiral counteranion17 in situ was examined,
furnishing 2a with enantiomeric ratio (er) of 28:72 (entry 4).
The absolute configuration of the major enantiomer of 2a
was determined to be S by Mosher’s ester analysis after some
transformations.16 To investigate the effect of Ag salt, the
reaction was performed using only (S)-TRIPAg as a catalyst.
Table 1. Optimization of the reaction conditions
entry
catalyst
additive
solvent
temp
(°C)
rt
rt
rt
rt
rt
rt
rt
rt
0
0
0
0
0
0
0
time
(h)
16
6
16
16
1
22
16
22
3
24
24
24
20
21
yield (%)a
er of 2a
(R:S)
–
–
–
28:72
81:19
–
80:20
–
88:12
69:31
93:7
90:10
95:5
95:5
95:5
2a
0
6
52
84
51
3a
26
20
0
0
15
7
4a
5a
17
16
0
0
0
0
0
0
0
0
0
0
0
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Rh2(OAc)4
Cu(NCMe)4PF6
(ArO)3PAuCl/AgSbF6
(ArO)3PAuCl/(S)-TRIPAg
(S)-TRIPAg
–
–
–
–
–
–
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
THF
15
25
0
0
0
5
AgSbF6
(S)-TRIPAg
AgSbF6
(S)-TRIPAg
(S)-TRIPAg
(S)-TRIPAg
(S)-TRIPAg
(S)-TRIPAg
30
45
28
49
57
44
48
55
61
2,6-t-Bu2pyb
5
3
0
2
2,6-t-Bu2pyb
–
–
–
–
–
–
15
3
13
5
7
8
0
0
0
0
0
0
0
EtOAc
acetone
2-butanone
2-butanone
(S)-TRIPAg
(S)-TRIPAg
Benzoic acidc
48
89d
0
aDetermined by 1H-NMR analysis of the crude mixture. b10 mol % of 2,6-t-Bu2py was used. c1 equiv. dIsolated yield. Ar is 2,4-t-Bu2C6H3.
without cyclopropanation (2k and 2m). Substrates contain-
With the optimal reaction conditions in hand, we next inves-
tigated the substrate scope of this chemoselective CADA
reaction using Ag catalysis (Table 2). We tested the reaction
using phenols possessing a substituent at the ortho-position
instead of at the meta-position. To our delight, when using
1b, a high level of enantiocontrol as well as high chemoselec-
tivity was observed, furnishing 2b in 93% yield. Electron-
deficient ortho-halophenols were also applicable to the
CADA reaction with a larger amount of catalyst (7~10 mol %)
for full conversion (2e-2h). In addition, α-diazoacetamides
having removable substituents such as PMB on the amide
nitrogen were applicable in a highly selective manner afford-
ing the products in good yield (2i, 81%).20 The six-membered
ring formation also proceeded with 10 mol % of the catalyst,
producing azaspiro[5.5]undecane structure 2l. Potentially
reactive terminal alkene was tolerated in the CADA reaction
ing the biphenyl system 1n-q were also effective for this reac-
tion, affording the corresponding products 2n-q in excellent
yields and with high enantioselectivity. Naphthol derivative
1r was also applied in this reaction, but there was room for
improvement in the yield. It is worth emphasizing that the
architecture of spirolactam bearing an all-carbon quaternary
stereogenic center is ubiquitous in bioactive molecules.21
We next performed the following experiments to gain mech-
anistic insight into the developed CADA reaction. The reac-
tion of 1s bearing a dimethylphenylmethyl group on the am-
ide under the optimum conditions using the Ag catalysis
gave 2s and cycloheptatriene 6 formed through Büchner re-
action, which is specific to the carbene reaction22 (eq 1), indi-
cating the generation of Ag carbenoid. The production of
tropone 3a from 1a also supports it (Table 1).
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Table 2. Substrate scope
makes the Ag carbenoid carbon more carbocationic to facili-
1
2
3
4
tate the electrophilic addition to phenol (path A). These val-
ues of Ag carbenoid are very close to those of Au carbe-
noid,26,27 rationalizing the observed similar chemoselectivity
(entries 3, 4).
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Scheme 2. Proposed reaction pathways
c
a5 mol % of catalyst was used. bFor 24 h. 7 mol % of catalyst
was used. dFor 48 h.
Figure 1. LUMO map for Rh and Ag carbenoids
We also studied an asymmetric induction of the CADA reac-
tion. No nonlinear effects were observed when the enantio-
meric excess of the (S)-TRIPAg was changed.16 A kinetic
study was also performed, and the reaction rate showed a
first-order dependency on the catalyst.16 These findings sug-
gest the involvement of a single catalyst in the enantio- and
rate-determining step. In addition, higher enantioselectivi-
ties were observed when phenols were substituted at the
ortho-position compared with meta-substituted phenols (2b
vs 2a, 2c vs 2d). Furthermore, the anisole derivative 7 was not
converted into the corresponding dearomatized product 2b
(eq 3, 4),28 indicating that the interaction between the phe-
nolic hydroxyl group and catalyst, and the CADA reaction
proceed through a cyclophane-like transition state via hy-
drogen bonding29 to realize the remote stereocontrol (Figure
2).
Plausible reaction pathways for this reaction are shown in
Scheme 2. There are two possible pathways to form 2a. One
is electrophilic addition of the metal carbenoids to the para-
position of phenol accompanied by dearomatization to gen-
erate Int-1 (path A), followed by proto-demetalation (path
B). The other is ring-opening of cyclopropane Int-2 (path C),
which could be formed through concerted arene cyclopropa-
nation with a metal carbenoid (path D) or conjugate addition
to enone from Int-1 (path E). Tropone 3a is formed by the
Büchner reaction and subsequent autoxidation through path
F, indicating that path F is more favorable than path C when
using a Rh or Cu catalyst (Table 1, entries 1, 2). On the other
hand, the Ag-catalyzed reaction produced 2a preferentially.
If the formation of 2a from Int-2 is postulated, (S)-TRIPAg
must be an effective catalyst for path C. Thus, to test this
hypothesis, we performed the reaction using
a
Rh2(OAc)4/(S)-TRIPAg mixed catalyst system, where Int-2
generated by the Rh catalyst is expected to undergo ring-
opening reaction to afford 2a in the presence of the Ag cata-
lyst. Under these conditions, 2a was not isolated at all (eq 2).
This result provides support that 2a was formed through
path B. The finding that benzoic acid improved the yield of
2a by promoting path B while suppressing the production of
3a also supports this mechanism (entries 14, 15). We there-
fore propose a stepwise mechanism based on the electro-
philic addition of Ag carbenoid to phenol followed by proto-
demetalation.
To elucidate the origin of the metal-dependent chemoselec-
tivity, we performed a LUMO map23 analysis based on DFT
calculations at the M06 level with the 6-311G* basis set
(LANL2TZ(f) basis set for Rh, Ag)16 (Figure 1). The LUMO
map clearly shows that Ag carbenoid has higher electro-
philicity (deeper blue) than the Rh carbenoid. In addition,
the Ag–carbene bond order is 0.29 lower than that of the Rh
complex,24 indicating weak back donation from Ag to the
vacant carbene π-orbital. As a result, the longer distance25
Figure 2. Plausible working model
In summary, we developed an asymmetric intramolecular
dearomatization of phenol derivatives using Ag carbenoids.
The methodology provides facile access to functionalized
chiral spirolactams possessing an all-carbon quaternary ste-
reogenic center with a high level of enantiocontrol regardless
of the substituted position on the phenol ring. Experimental
3
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and theoretical studies indicated that the carbocation-like
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character facilitated the electrophilic addition of Ag carbe-
noid to phenol, realizing chemoselective promotion of the
phenol dearomatization pathway. Further studies taking
advantage of the specific properties of metal carbenoids are
underway in our laboratory.
(10) This term was coined by prof. Shu-Li You, see: (a) Zhuo, C.-X.;
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
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Experimental procedures and spectral data (PDF)
(13) CADA reactions based on the ipso-Friedel-Crafts-type addition,
see: (a) Nemoto, T.; Ishige, Y.; Yoshida, M.; Kohno, Y.; Kanematsu,
M.; Hamada, Y. Org. Lett. 2010, 12, 5020. (b) Wu, Q.-F.; Liu, W.-B.;
Zhuo, C.-X.; Rong, Z.-Q.; Ye, K.-Y.; You, S.-L. Angew. Chem. Int. Ed.
2011, 50, 4455. (c) Zhuo, C.-X.; You, S.-L. Angew. Chem. Int. Ed. 2013,
52, 10056. (d) Nan, J.; Liu, J.; Zheng, H.; Zuo, Z.; Hou, L.; Hu, H.;
Wang, Y.; Luan, X. Angew. Chem. Int. Ed. 2015, 54, 2356. (e) Wang,
S.-G.; Liu, X.-J.; Zhao, Q.-C.; Zheng, C.; Wang, S.-B.; You, S.-L. An-
gew. Chem. Int. Ed. 2015, 54, 14929. (f) Yin, Q.; Wang, S.-G.; Liang,
X.-W.; Gao, D.-W.; Zheng, J.; You, S.-L. Chem. Sci. 2015, 6, 4179. (g)
Cheng, Q.; Wang, Y.; You, S.-L. Angew. Chem. Int. Ed. 2016, 55, 3496.
(h) Shen, D.; Chen, Q.; Yan, P.; Zeng, X.; Zhong, G. Angew. Chem.
Int. Ed. 2017, 56, 3242.
(14) CADA reactions via metallacycle intermediates, see: (a) Rous-
seaux, S.; García-Fortanet, J.; Del Aguila Sanchez, M. A.; Buchwald, S.
L. J. Am. Chem. Soc. 2011, 133, 9282. (b) Xu, R.-Q.; Gu, Q.; Wu, W.-T.;
Zhao, Z.-A.; You, S.-L. J. Am. Chem. Soc. 2014, 136, 15469. (c) Yang, L.;
Zheng, H.; Luo, L.; Nan, J.; Liu, J.; Wang, Y.; Luan, X. J. Am. Chem.
Soc. 2015, 137, 4876. (d) Zheng, J.; Wang, S.-B.; Zheng, C.; You, S.-L. J.
Am. Chem. Soc. 2015, 137, 4880. (e) Du, K.; Guo, P.; Chen, Y.; Cao, Z.;
Wang, Z.; Tang, W. Angew. Chem. Int. Ed. 2015, 54, 3033. (f) Bai, L.;
Yuan, Y.; Liu, J.; Wu, J.; Han, L.; Wang, H.; Wang, Y.; Luan, X. An-
gew. Chem. Int. Ed. 2016, 55, 6946.
AUTHOR INFORMATION
Corresponding Author
tnemoto@faculty.chiba-u.jp, Sharada@chiba-u.jp
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by the Sasakawa Scientific Research
Grant from The Japan Science Society, the Nagai Memorial
Research Scholarship from the Pharmaceutical Society of
Japan, Futaba Electronics Memorial Foundation, Grant-in-
Aid from the Tokyo Biochemical Research Foundation, JSPS
KAKENHI Grant Numbers JP16K18840 and 15K07850.
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(20) PMB group in 2m and 2n could be removed with CAN in 84%
and 97% yield, respectively.16
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(23) The absolute value of the Kohn-Sham LUMO is mapped onto
an electron density surface.
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(28) The reaction of eq 4 gave a complex mixture, however, mass
measurement of the mixture exhibited a peak at m/z 1008.5316,
which is in good agreement with total mass of [7 − N2 + TRIP + Na+]
(calculated 1008.5302).16
(29) Chen, M.; Sun, J. Angew. Chem. Int. Ed. 2017, 56, 4583.
A graphic for the TOC
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