Synthesis of Malononitrile-Substituted Diarylmethines via 1,6-Addition of Masked Acyl Cyanides to para -Quinone Methides

Article abstract of DOI:10.1055/s-0036-1590947

An efficient method for the synthesis of malononitrile-substituted diarylmethines through 1,6-conjugate addition of para -quinone methides with masked acyl cyanide (MAC) reagents has been developed. Under mild conditions, the scalable reaction occurs in good to excellent yields providing a straightforward access to a series of malononitrile-substituted diarylmethines. The synthetic utility of this protocol has been demonstrated in the synthesis of bioactive compounds.

Full text of DOI:10.1055/s-0036-1590947

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–I
paper
A
en
K. Zhao et al.
Paper
Synthesis
Synthesis of Malononitrile-Substituted Diarylmethines via
1,6-Addition of Masked Acyl Cyanides to para-Quinone Methides
Kun Zhaoa
Ying Zhia
OH
O
R'
R'
R'
R'
Ph
OH
Ai Wangb
Dieter Enders*a
HN
R =
Ph
Nu
OR
CN
2
CN
+
cannabinoid CB1
receptor antagonist
CN
NC
1,6-addition
unmask
a Institute of Organic Chemistry, RWTH Aachen University,
Landoltweg 1, 52074 Aachen, Germany
enders@rwth-aachen.de
b Institute of Inorganic Chemistry, RWTH Aachen University,
Landoltweg 1, 52074, Aachen, Germany
Ar
Ar
R
OR
HN OH
R =
O
p-QMs
MAC
70–99% yield
17 examples
histone deacetylase
inhibitor
Received: 06.10.2017
Accepted: 09.10.2017
Published online: 23.11.2017
DOI: 10.1055/s-0036-1590947; Art ID: ss-2017-z0645-op
Stoltz and co-workers (Scheme 1, b).6h Despite the fact that
masked acyl cyanides have been used successfully in reac-
tions as described above, it is still desirable to explore the
reactivity of MAC reagents as nucleophiles with novel elec-
trophiles, such as 1,6-Michael acceptors.7
Abstract An efficient method for the synthesis of malononitrile-
substituted diarylmethines through 1,6-conjugate addition of para-
quinone methides with masked acyl cyanide (MAC) reagents has been
developed. Under mild conditions, the scalable reaction occurs in good
to excellent yields providing a straightforward access to a series of malo-
nonitrile-substituted diarylmethines. The synthetic utility of this proto-
col has been demonstrated in the synthesis of bioactive compounds.
a) Selected d1 synthons and equivalent reagents:
N
H
O
O
OR
O
N
S
S
H
R
NC
CN
H
R
Key words diarylmethines, 1,6-addition, masked acyl cyanides, para-
quinone methides, malononitrile-substituted diarylmethines
3
2
1
1,3-dithianes
formaldehyde hydrazones
masked acyl cyanide
b) Umpolung reactions employing MACs:
The umpolung of the natural reactivity of functional
groups is a powerful concept in chemistry and of enormous
value in the synthesis strategy of organic molecules.1 Since
the pioneering work of Corey and Seebach in the mid
1960s,2 significant attention has been paid to this basic re-
search field and several acyl anion equivalents, such as 1,3-
dithianes 13 and aldehyde N,N-dialkylhydrazones 2,4 have
been developed and employed in a large number of chemi-
cal transformations (Scheme 1, a). Meanwhile, much effort
has also been devoted to the use of alkoxymalononitriles 3
in umpolung reactions, termed masked acyl cyanide (MAC)
reagents.5 Compared with the common acyl anion equiva-
lents, MACs can exhibit both nucleophilic (d1) and electro-
philic (a1) reactivity, thus serving as carbon monoxide
equivalents. Not surprising this unique property has at-
tracted much interest among chemists.6 In 2013, the Rawal
group disclosed a squaramide-catalyzed 1,4-addition reac-
tion between masked acyl cyanides and α,β-unsaturated
aryl ketones.6e In 2014, the same group reported an organo-
catalytic 1,2-addition of MAC reagents to N-Boc-ald-
imines.6f Very recently, the iridium-catalyzed allylic alkyla-
tion reaction of masked acyl cyanides was achieved by
OR
NC
O
R2
CN
CN
∗
OR
O
R1
NC
∗
R'
a
c
R'
OCO2Me
R1
R2
OR
1,4-addition
allylic alkylation
NC
CN
1,2-addition
NBoc
1,6-addition
unknown
3
MAC
b
R'
this work
NHBoc
∗
CN
OR
R'
NC
Scheme 1 Selected d1 synthons and reports based on MAC reagents
During the past several years, para-quinone methides
(p-QMs)8 have emerged as important vinylogous Michael
acceptors due to their intrinsic reactivities,9,10 and applica-
tions of p-QMs in domino reactions have also been
achieved. However, to the best of our knowledge, the reac-
tion between p-QMs and MAC reagents has not been
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

B
K. Zhao et al.
Paper
Synthesis
reported so far. We envisioned that a 1,6-addition of MAC
reagents 3 to p-QMs 4 might occur in the presence of a suit-
able base (Scheme 2, a). This reaction could provide a facile
access to malononitrile-substituted diarylmethines 5,
which after unmasking would deliver acyl cyanide interme-
diates 6, amenable to interception by a wide range of nucleo-
philes to afford the products 7 (Scheme 2, b). Furthermore,
based on this proposed strategy the synthesis of several
bioactive compounds (8 and 9)11 and natural products
(10)12 should be possible (Scheme 2, c).
with a series of organic bases (e.g., Et3N, DIPEA, DBU) re-
vealed that organic bases had a negative influence on the
efficiency of this 1,6-addition, delivering 5a in 32–44%
yields (entries 6–8). Once the best base was established, the
effect of the solvent was investigated and we found that
other solvents failed to further improve the yield of this
transformation (entries 10–15).
Table 1 Optimization of the Reaction Conditionsa
OH
O
tBu
tBu
OH
tBu
tBu
O
OTBS
CN
R
R
R
R
base
CN
CN
OTBS
+
OR
1,6-addition
base
solvent, r.t.
NC
+
CN
CN
NC
CN
Ar
Ar
4a
3a
5a
OR
4
3
5
Entry
Base
Solvent
Time (h)
Yield(%)b
a)
unmasking
b)
1
2
Na2CO3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
Et2O
48
48
4
69
88
97
96
98
32
44
39
46
94
51
62
97
45
88
K2CO3
Cs2CO3
K3PO4
NaOH
Et3N
OH
OH
3
R
R
R
R
4
12
1
nucleophilic
interception
5
CN
Nu
Ar
6
24
24
2
O
Ar
O
7
DIPEA
DBU
7
6
8
c)
OH
9
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
48
24
48
12
2
OH
OH
Br
OH
OH
10
11
12
13
14
15
Br
CCl4
Ph
Br
H
CHCl3
DCE
NHOH
N
Ph
O
2
MeO
O
O
OH
bromophenol
natural product (10)
MeOH
2
cannabinoid CB1
receptor antagonist (8)
histone deacetylase
inhibitor (9)
1,4-dioxane
24
a All reactions were conducted with 0.2 mmol of 4a, 0.24 mmol of 3a, and
20 mol% of base in 2 mL of solvent at r.t.
Scheme 2 Project design and selected bioactive and natural products
b Yield of isolated 5a after column chromatography.
To test our hypothesis, we chose the readily available
para-quinone methide 4a and TBS-MAC 3a as the standard
substrates to carry out the screening of the reaction condi-
tions (Table 1). The initial experiment was done using sodi-
um carbonate (0.2 equiv) as base in dichloromethane at
room temperature. To our delight, the proposed 1,6-addi-
tion occurred and the expected adduct 5a was isolated in a
good yield of 69% (Table 1, entry 1). It turned out that the
choice of an ideal base is crucial for the success of this 1,6-
addition, and therefore a systematic screening of the base
was conducted. First, several commonly used inorganic bas-
es (e.g., K2CO3, Cs2CO3, K3PO4, NaOH) were examined, and
all of them afforded the desired product 5a in comparable
yields (entries 2–5). Especially, when 20 mol% of NaOH was
used, a very clean reaction was observed and the adduct 5a
was obtained in 98% yield (entry 5). Further optimization
With the optimal conditions found (Table 1, entry 5),
the substrate scope of this 1,6-addition was investigated
and the results are shown in Scheme 3. First, we evaluated
the scope of the p-QM component. Generally, a broad range
of p-quinone methides reacted with 3a to afford the corre-
sponding adducts 5a–o in good to excellent yields (70–
99%). In detail, p-QMs bearing electron-neutral (R = H),
electron-donating (R = Me, OMe), or electron-withdrawing
groups (R = Cl, Br, NO2) in the para and ortho positions of
the benzene ring easily underwent this 1,6-addition reac-
tion furnishing the desired products 5a–h in 88–99% yields.
A bulky substituent (2-OTBS) was well tolerated and the ex-
pected product 5i could be isolated in 97% yield. Further-
more, the disubstituted p-QMs were suitable substrates for
this transformation, and the corresponding adducts 5j,k
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

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K. Zhao et al.
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Synthesis
were obtained with excellent results. Moreover, we found
that p-quinone methides, containing furyl and naphthyl
moieties, could be processed to deliver the products 5l and
5m in 70% and 95% yield, respectively. Replacing the bulky
tert-butyl R′ substituents of the p-QMs by isopropyl or
methyl groups did not influence the efficiency of this 1,6-
addition reaction (5n, o). In terms of the MAC reagents, the
MOM-MAC 3b displays a similar reactivity in this reaction
providing the product 5p in nearly quantitative yield. Nota-
bly, the p-quinone methide derived from ferrocene carbox-
aldehyde also underwent this reaction smoothly to its cor-
responding adduct 5q, and the structure of 5q was con-
firmed by NMR as well as X-ray crystallographic analysis.13
A gram-scale reaction using the standard conditions
worked very well with the same efficiency, and the desired
compound 5a was obtained in 96% yield.
Malononitrile-Substituted Diarylmethines 5; General Procedure
A 10 mL glass tube equipped with a stirring bar was charged with p-
QMs 4 (0.40 mmol, 1.0 equiv), MAC reagents 3 (0.48 mmol, 1.2 equiv),
NaOH (0.08 mmol, 20 mol%), and CH2Cl2 (4.0 mL). The resulting solu-
tion was stirred at r.t. for 1 h. The solvent was evaporated under re-
duced pressure and the crude product was directly purified by flash
column chromatography (PE/EtOAc from 50:1 to 30:1) to provide the
desired products 5a–q.
2-[(tert-Butyldimethylsilyl)oxy]-2-[(3,5-di-tert-butyl-4-hydroxy-
phenyl)(phenyl)methyl]malononitrile (5a)
According to the general procedure, 5a was obtained as a light yellow
wax (0.194 g, 99%).
IR (ATR): 3630, 2954, 2240, 2056, 1955, 1735, 1596, 1439, 1366, 1317,
1253, 1128, 1008, 840, 786, 696 cm–1
.
Because MAC adducts can be considered as versatile
precursors for the synthesis of carboxylic acid derivatives,
we turned our attention to this issue (Scheme 4, a). Un-
masking compound 5k and addition of methylamine pro-
vided the amide 7a in 94% yield. Similarly, the methyl ester
7b could be synthesized via methanolysis of adduct 5a.
Treatment of 7b with AlCl3 in benzene (60 °C) for 1 hour
successfully removed the tert-butyl groups, delivering
product 7c in 96% yield. Furthermore, the utility of this
novel 1,6-addition was demonstrated with the synthesis of
bioactive compounds (Scheme 4, b). First, the cannabinoid
CB1 receptor inverse agonist 8 and histone deacetylase in-
hibitor 9 could be efficiently synthesized from 7c in 71%
and 68% yield, respectively. The unmasking of adduct 5a
with AcOH-buffered TBAF gave the carboxylic acid 7d re-
flecting the basic α-phenolic phenyl acetic acid skeleton of
natural products, such as the bromophenol derivative 10.
In conclusion, we have developed a novel 1,6-conjugate
addition reaction between p-QMs and MAC reagents. With
this new scalable protocol a variety of diarylmethine deriv-
atives could be easily synthesized in good to excellent
yields. Based on this method, we accomplished the synthe-
sis of the cannabinoid CB1 receptor antagonist 8 and the
histone deacetylase inhibitor 9.
Commercially available compounds were used without further purifi-
cation. Solvents were distilled using standard procedures. Flash col-
umn chromatography was performed with silica gel SIL G-25 UV254
(size 0.040–0.063 mm) from Machery & Nagel. For the TLC silica gel
60 F254 plates from Merck, Darmstadt, were used. The compounds on
the TLC plates were identified under UV light (254 nm) and by stain-
ing with anisaldehyde staining reagent. 1H and 13C NMR spectra were
recorded on Varian Gemini 300, Varian Mercury 300, Varian Inova
400, and Varian Inova 600 instruments at r.t. Mass spectra were re-
corded on the spectrometer SSQ7000 from Finnigan at 70 eV, whereas
HRMS data (ESI) were collected with a ThermoFisher Scientific LTQ-
Orbitrap XL apparatus. IR spectra were recorded using the ATR tech-
nique on a PerkinElmer FT-IR Spectrum 100 spectrophotometer.
Melting points were measured with a Büchi 510 instrument.
Scheme 3 Evaluation of the substrate scope. Reagents and conditions:
Unless otherwise noted, the reactions were conducted with 0.4 mmol
of 4 (1.0 equiv), 0.48 mmol of 3 (1.2 equiv), and 20 mol % of NaOH in
CH2Cl2 (4.0 mL) at r.t. Yields are those of the isolated products 5 after
column chromatography.
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K. Zhao et al.
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Synthesis
OH
OH
tBu
tBu
tBu
tBu
CN
TBAF
H
MeO
MeO
N
MeO
MeO
Me
THF, MeNH2
0 °C, 2 h
OTBS
O
CN
7a, 94%
5k
OH
OH
OH
tBu
tBu
tBu
tBu
TBAF
THF/MeOH
AlCl3
C6H6, 60 °C
OMe
CN
OTBS
OMe
Ph
Ph
O
O
CN
7b, 96%
7c, 96%
5a
a
b
OH
OH
OH
1. MeOH, NaOH
NH2OH, KOH
Ph
THF/MeOH (1:1)
2. Et3N, HATU
Ph
H
NH-OH
N
OMe
Ph
Ph
Ph
Ph
2
H2N
O
O
Ph
O
7c
2
8, 71%
9, 68%
OH
OH
OH
Br
OH
tBu
tBu
tBu
tBu
OH
TBAF
Br
Br
OH
CN
CN
OTBS
THF/H2O/AcOH
0 °C, 24 h
O
MeO
O
OH
5a
7d, 83%
bromophenol natural
product 10
Scheme 4 Unmasking of MAC adducts and synthesis of bioactive compounds; HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyri-
dinium 3-oxide hexafluorophosphate
1H NMR (600 MHz, CDCl3): δ = 7.57 (d, J = 7.8 Hz, 2 H), 7.39–7.36 (m, 2
H), 7.33 (d, J = 7.2 Hz, 1 H), 7.31 (s, 2 H), 5.24 (s, 1 H), 4.44 (s, 1 H), 1.42
(s, 18 H), 0.79 (s, 9 H), 0.22 (s, 3 H), 0.21 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 153.8 (2 C), 138.0, 135.8, 133.2, 129.4
(2 C), 129.3 (2 C), 126.3 (2 C), 126.1, 115.4, 115.3, 67.8, 61.5, 34.4 (2
C), 30.2 (6 C), 25.2 (3 C), 21.1, 18.0, –4.7 (2 C).
13C NMR (150 MHz, CDCl3): δ = 153.9 (2 C), 136.2, 135.9 (2 C), 129.5 (2
C), 128.7 (2 C), 128.2, 126.4 (2 C), 125.8, 115.3, 67.7, 61.7, 34.4 (2 C),
30.2 (6 C), 25.2 (3 C), 18.0, –4.7 (2 C).
MS (EI): m/z (%) = 309.2 (100) [M – C9H15N2OSi]+ = [C22H29O]+.
HRMS (EI): m/z [M – C9H15N2OSi]+ calcd for C22H29O: 309.2213; found:
309.2216.
MS (EI): m/z (%) = 295.2 (100) [M – C9H15N2OSi]+ = [C21H27O]+.
HRMS (EI): m/z [M – C9H15N2OSi]+ calcd for C21H27O: 295.2056; found:
2-[(tert-Butyldimethylsilyl)oxy]-2-[(3,5-di-tert-butyl-4-hydroxy-
phenyl)(4-methoxyphenyl)methyl]malononitrile (5c)
295.2057.
According to the general procedure, 5c was obtained as a light yellow
solid (0.200 g, 96%); mp 103–105 °C.
2-[(tert-Butyldimethylsilyl)oxy]-2-[(3,5-di-tert-butyl-4-hydroxy-
phenyl)(p-tolyl)methyl]malononitrile (5b)
IR (ATR): 3623, 3464, 2946, 2328, 2066, 1741, 1609, 1438, 1233, 1133,
According to the general procedure, 5b was obtained as a wax (0.187
824 cm–1
.
g, 93%).
1H NMR (600 MHz, CDCl3): δ = 7.50 (d, J = 8.4 Hz, 2 H), 7.30 (s, 2 H),
6.91 (d, J = 8.4 Hz, 2 H), 5.23 (s, 1 H), 4.39 (s, 1 H), 3.81 (s, 3 H), 1.42 (s,
18 H), 0.80 (s, 9 H), 0.22 (s, 3 H), 0.22 (s, 3 H).
IR (ATR): 3625, 3459, 2943, 2338, 2094, 1741, 1378, 1218, 1129, 827
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.46 (d, J = 8.4 Hz, 2 H), 7.31 (s, 2 H),
7.18 (d, J = 8.4 Hz, 2 H), 5.21 (s, 1 H), 4.39 (s, 1 H), 2.33 (s, 3 H), 1.42 (s,
18 H), 0.80 (s, 9 H), 0.22 (s, 6 H).
13C NMR (150 MHz, CDCl3): δ = 159.5 (2 C), 153.8, 135.9 (2 C), 130.6 (2
C), 128.2, 126.3 (2 C), 126.2, 115.4, 115.3, 114.0 (2 C), 67.9, 61.0, 55.3,
34.4 (2 C), 30.2 (6 C), 25.2 (3 C), 18.0, –4.7 (2 C).
MS (EI): m/z (%) = 325.2 (100) [M – C9H15N2OSi]+ = [C22H29O2]+.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

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K. Zhao et al.
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Synthesis
HRMS (EI): m/z [M – C9H15N2OSi]+ calcd for C22H29O2: 325.2162;
found: 325.2158.
1H NMR (400 MHz, CDCl3): δ = 7.80 (dd, J = 8.0, 1.6 Hz, 1 H), 7.32 (s, 2
H), 7.31–7.24 (m, 1 H), 7.03–6.97 (m, 1 H), 6.90 (d, J = 8.0 Hz, 1 H),
5.20 (s, 1 H), 5.13 (s, 1 H), 3.83 (s, 3 H), 1.41 (s, 18 H), 0.80 (s, 9 H),
0.22 (s, 3 H), 0.22 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 156.9 (2 C), 153.7, 135.6, 129.2, 129.0,
126.8 (2 C), 125.8, 125.2, 120.5, 115.6, 115.5, 111.1, 67.7, 55.5, 52.7,
34.4 (2 C), 30.2 (6 C), 25.2 (3 C), 18.0, –4.7, –4.8.
2-[(4-Bromophenyl)(3,5-di-tert-butyl-4-hydroxyphenyl)methyl]-
2-[(tert-butyldimethylsilyl)oxy]malononitrile (5d)
According to the general procedure, 5d was obtained as a wax (0.201
g, 88%).
MS (EI): m/z (%) = 325.3 (100) [M – C9H15N2OSi]+ = [C22H29O2]+.
HRMS (ESI): m/z [M + Na]+ calcd for C31H44N2O3SiNa+: 543.3013;
IR (ATR): 3518, 2939, 2317, 2099, 1740, 1605, 1467, 1369, 1130, 827,
701 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.51 (d, J = 8.4 Hz, 2 H), 7.43 (d, J = 8.4
Hz, 2 H), 7.25 (s, 2 H), 5.25 (s, 1 H), 4.40 (s, 1 H), 1.41 (s, 18 H), 0.80 (s,
9 H), 0.24 (s, 3 H), 0.21 (s, 3 H).
found: 543.3005.
2-[(tert-Butyldimethylsilyl)oxy]-2-[(2-chlorophenyl)(3,5-di-tert-
13C NMR (100 MHz, CDCl3): δ = 154.0 (2 C), 136.1, 135.3, 131.8 (2 C),
131.1 (2 C), 126.3 (2 C), 125.3, 122.5, 115.1, 115.0, 67.4, 61.1, 34.4 (2
C), 30.1 (6 C), 25.2 (3 C), 18.0, –4.7 (2 C).
butyl-4-hydroxyphenyl)methyl]malononitrile (5h)
According to the general procedure, 5h was obtained as a wax (0.194
g, 92%).
MS (EI): m/z (%) = 373.1 (100) [M – C9H15N2OSi]+ = [C21H26BrO]+.
IR (ATR): 3626, 2937, 2350, 1745, 1440, 1133, 797 cm–1
.
HRMS (EI): m/z [M – C9H15N2OSi]+ calcd for C21H26BrO: 373.1162;
found: 373.1160.
1H NMR (400 MHz, CDCl3): δ = 8.00 (dd, J = 8.0, 1.6 Hz, 1 H), 7.41 (dd,
J = 8.0, 1.2 Hz, 1 H), 7.38–7.31 (m, 1 H), 7.27 (s, 2 H), 7.26–7.23 (m, 1
H), 5.24 (s, 1 H), 5.15 (s, 1 H), 1.40 (s, 18 H), 0.80 (s, 9 H), 0.25 (s, 3 H),
0.22 (s, 3 H).
2-[(tert-Butyldimethylsilyl)oxy]-2-[(3,5-di-tert-butyl-4-hydroxy-
13C NMR (100 MHz, CDCl3): δ = 154.0 (2 C), 135.8, 134.9, 134.6, 130.3,
129.1, 128.7, 126.9, 126.8 (2 C), 124.1, 115.3, 115.1, 67.3, 56.4, 34.4 (2
C), 30.1 (6 C), 25.2 (3 C), 18.0, –4.7, –4.8.
phenyl)(4-nitrophenyl)methyl]malononitrile (5e)
According to the general procedure, 5e was obtained as a light yellow
solid (0.203 g, 95%); mp 115–116 °C.
MS (EI): m/z (%) = 329.3 (100) [M – C9H15N2OSi]+ = [C21H26ClO]+.
HRMS (ESI): m/z [M + Na]+ calcd for C30H41ClN2O2SiNa+: 547.2519;
IR (ATR): 3554, 2938, 2324, 2228, 2186, 2047, 1993, 1948, 1739, 1600,
1525, 1434, 1351, 1223, 1122, 995, 840, 792, 695 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.24 (d, J = 8.8 Hz, 2 H), 7.74 (d, J = 8.8
Hz, 2 H), 7.23 (s, 2 H), 5.31 (s, 1 H), 4.58 (s, 1 H), 1.40 (s, 18 H), 0.80 (s,
9 H), 0.27 (s, 3 H), 0.22 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 154.4 (2 C), 147.6, 143.5, 136.4, 130.4
(2 C), 126.3 (2 C), 124.3, 123.7 (2 C), 114.9, 114.8, 67.1, 61.1, 34.5 (2
C), 30.1 (6 C), 25.1 (3 C), 18.0, –4.6, –4.7.
found: 547.2526.
2-[(tert-Butyldimethylsilyl)oxy]-2-({2-[(tert-butyldimethylsilyl)-
oxy]phenyl}(3,5-di-tert-butyl-4-hydroxyphenyl)methyl)malono-
nitrile (5i)
According to the general procedure, 5i was obtained as a brown solid
(0.240 g, 97%); mp 130–132 °C.
MS (EI): m/z (%) = 340.3 (100) [M – C9H15N2OSi]+ = [C21H26NO3]+.
IR (ATR): 3610, 2948, 2864, 2334, 2048, 1994, 1928, 1735, 1596, 1444,
HRMS (ESI): m/z [M + Na]+ calcd for C30H41N3O4SiNa+: 558.2759;
found: 558.2744.
1258, 1121, 919, 833, 781 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.90 (d, J = 7.2 Hz, 1 H), 7.32 (s, 2 H),
7.21–7.18 (m, 1 H), 7.04–7.01 (m, 1 H), 6.85 (d, J = 7.8 Hz, 1 H), 5.19 (s,
2 H), 1.40 (s, 18 H), 1.03 (s, 9 H), 0.80 (s, 9 H), 0.28 (s, 3 H), 0.23 (s, 3
H), 0.19 (s, 6 H).
13C NMR (150 MHz, CDCl3): δ = 153.8, 153.5, 135.5 (2 C), 128.9, 128.7,
127.2, 127.0 (2 C), 125.5, 121.0, 118.5, 115.6, 115.4, 67.7, 52.2, 34.4 (2
C), 30.1 (6 C), 25.9 (3 C), 25.2 (3 C), 18.3, 18.0, –4.0, –4.3, –4.8, –4.9.
2-[(tert-Butyldimethylsilyl)oxy]-2-[(3,5-di-tert-butyl-4-hydroxy-
phenyl)(o-tolyl)methyl]malononitrile (5f)
According to the general procedure, 5f was obtained as a light yellow
solid (0.190 g, 94%); mp 132–136 °C.
IR (ATR): 3627, 2937, 2325, 2088, 1739, 1613, 1443, 1125, 831 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 8.0 Hz, 1 H), 7.30–7.25 (m, 1
H), 7.22 (s, 2 H), 7.21–7.15 (m, 2 H), 5.20 (s, 1 H), 4.66 (s, 1 H), 2.29 (s,
3 H), 1.38 (s, 18 H), 0.80 (s, 9 H), 0.23 (s, 3 H), 0.21 (s, 3 H).
MS (EI): m/z (%) = 425.4 (100) [M – C9H15N2OSi]+ = [C27H41O2Si]+.
HRMS (ESI): m/z [M + Na]+ calcd for C36H56N2O3Si2Na+: 643.3722;
found: 643.3705.
13C NMR (100 MHz, CDCl3): δ = 153.8 (2 C), 136.7, 135.7, 135.3, 131.1,
127.8, 127.0 (2 C), 126.9, 126.1, 124.8, 115.6, 115.5, 67.6, 56.7, 34.3 (2
C), 30.1 (6 C), 25.2 (3 C), 20.2, 18.0, –4.6, –4.7.
MS (EI): m/z (%) = 309.3 (100) [M – C9H15N2OSi]+ = [C22H29O]+.
HRMS (ESI): m/z [M + K]+ calcd for C31H44N2O2SiK+: 543.2804; found:
2-[Benzo[d][1,3]dioxol-5-yl(3,5-di-tert-butyl-4-hydroxyphe-
nyl)methyl]-2-[(tert-butyldimethylsilyl)oxy]malononitrile (5j)
According to the general procedure, 5j was obtained as a colorless sol-
id (0.200 g, 94%); mp 116–119 °C.
543.2792.
IR (ATR): 3629, 2931, 2324, 2093, 1740, 1453, 1241, 1121, 1035, 806,
696 cm–1
.
2-[(tert-Butyldimethylsilyl)oxy]-2-[(3,5-di-tert-butyl-4-hydroxy-
phenyl)(2-methoxyphenyl)methyl]malononitrile (5g)
1H NMR (600 MHz, CDCl3): δ = 7.30 (s, 2 H), 7.08–7.04 (m, 2 H), 6.82
(d, J = 9.0 Hz, 1 H), 5.97 (s, 2 H), 5.25 (s, 1 H), 4.37 (s, 1 H), 1.44 (s, 18
H), 0.82 (s, 9 H), 0.25 (s, 3 H), 0.24 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 153.9 (2C), 147.9, 147.6, 136.0, 129.8,
126.2 (2 C), 126.0, 123.2, 115.3, 109.8, 108.3, 101.2, 67.8, 61.3 (2 C),
34.4 (2 C), 30.2 (6 C), 25.2 (3 C), 18.1, –4.6, –4.7.
According to the general procedure, 5g was obtained as a light yellow
solid (0.204 g, 98%); mp 123–125 °C.
IR (ATR): 3793, 3623, 3332, 2937, 2304, 2077, 1904, 1599, 1451, 1246,
1131, 1033, 783 cm–1
.
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MS (EI): m/z (%) = 339.3 (100) [M – C9H15N2OSi]+ = [C22H27O3]+.
2-[(tert-Butyldimethylsilyl)oxy]-2-[(4-hydroxy-3,5-diisopropyl-
phenyl)(phenyl)methyl]malononitrile (5n)
HRMS (ESI): m/z [M + Na]+ calcd for C31H42N2O4SiNa+: 557.2806;
According to the general procedure, 5n was obtained as a light yellow
found: 557.2797.
solid (0.179 g, 97%); mp 113–115 °C.
2-[(tert-Butyldimethylsilyl)oxy]-2-[(3,5-di-tert-butyl-4-hydroxy-
phenyl)(3,4-dimethoxyphenyl)methyl]malononitrile (5k)
IR (ATR): 3518, 2950, 2864, 2322, 2101, 1739, 1599, 1461, 1364, 1303,
1263, 1199, 1125, 996, 943, 887, 831, 790, 697 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.56 (d, J = 7.8 Hz, 2 H), 7.39–7.36 (m, 2
H), 7.34–7.32 (m, 1 H), 7.22 (s, 2 H), 4.88 (s, 1 H), 4.48 (s, 1 H), 3.15
(hept, J = 6.8 Hz, 2 H), 1.27 (d, J = 7.0 Hz, 12 H), 0.86 (s, 9 H), 0.27 (s, 3
H), 0.26 (s, 3 H).
According to the general procedure, 5k was obtained as a wax (0.210
g, 97%).
IR (ATR): 3627, 2922, 2858, 2332, 2223, 2003, 1945, 1736, 1595, 1517,
1443, 1361, 1256, 1130, 1027, 935, 846, 784, 666 cm–1
.
13C NMR (150 MHz, CDCl3): δ = 150.2 (2 C), 136.1, 133.8, 129.6 (2 C),
128.6 (2 C), 128.2, 127.4, 124.9 (2 C), 115.3, 115.2, 67.7, 61.4, 27.3 (2
C), 25.2 (4 C), 22.6 (3 C), 18.1, –4.6, –4.7.
MS (EI): m/z (%) = 267.2 (100) [M – C9H15N2OSi]+ = [C19H23O]+.
HRMS (ESI): m/z [M + Na]+ calcd for C28H38N2O2SiNa+: 485.2595;
1H NMR (400 MHz, CDCl3): δ = 7.33 (s, 2 H), 7.15–7.10 (m, 2 H), 6.86
(d, J = 8.0 Hz, 1 H), 5.22 (s, 1 H), 4.37 (s, 1 H), 3.88 (s, 3 H), 3.86 (s, 3 H),
1.41 (s, 18 H), 0.78 (s, 9 H), 0.21 (s, 3 H), 0.20 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 153.8 (2 C), 149.0, 148.8, 135.9, 128.5,
126.3 (2 C), 126.0, 122.1, 115.5, 115.4, 112.5, 111.1, 68.0, 61.4, 55.8 (2
C), 34.4 (2 C), 30.2 (6 C), 25.2 (3 C), 18.0, –4.7 (2 C).
found: 485.2580.
MS (EI): m/z (%) = 355.3 (100) [M – C9H15N2OSi]+ = [C23H31O3]+.
2-[(tert-Butyldimethylsilyl)oxy]-2-[(4-hydroxy-3,5-dimethylphe-
nyl)(phenyl)methyl]malononitrile (5o)
HRMS (ESI): m/z [M + Na]+ calcd for C32H46N2O4SiNa+: 573.3119;
found: 573.3109.
According to the general procedure, 5o was obtained as a light yellow
solid (0.132 g, 81%); mp 93–95 °C.
2-[(tert-Butyldimethylsilyl)oxy)-2-[(3,5-di-tert-butyl-4-hydroxy-
phenyl)(furan-2-yl)methyl]malononitrile (5l)
IR (ATR): 3626, 2935, 2216, 1911, 1739, 1592, 1438, 1219, 1010, 793
cm–1
.
According to the general procedure, 5l was obtained as a dark yellow
1H NMR (400 MHz, CDCl3): δ = 7.51–7.49 (m, 2 H), 7.38–7.28 (m, 3 H),
7.12 (s, 2 H), 4.70 (s, 1 H), 4.38 (s, 1 H), 2.21 (s, 6 H), 0.87 (s, 9 H), 0.26
(s, 3 H), 0.25 (s, 3 H).
solid (0.134 g, 70%); mp 113–114 °C.
IR (ATR): 3629, 2941, 2326, 2087, 1973, 1740, 1579, 1439, 1226, 1138,
1037, 842 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 152.4 (2 C), 136.1, 129.8 (2 C), 129.5 (2
C), 128.6 (2 C), 128.2, 127.1, 123.2, 115.1, 115.0, 67.4, 60.6, 25.1 (3 C),
18.1, 16.0 (2 C), –4.8 (2 C).
MS (EI): m/z (%) = 211.2 (100) [M – C9H15N2OSi]+ = [C15H15O]+.
HRMS (EI): m/z [M]+ calcd for C24H30N2O2Si: 406.2071; found:
1H NMR (600 MHz, CDCl3): δ = 7.47 (d, J = 1.8 Hz, 1 H), 7.37 (s, 2 H),
6.53 (d, J = 3.0 Hz, 1 H), 6.40 (dd, J = 3.0, 1.8 Hz, 1 H), 5.29 (s, 1 H), 4.56
(s, 1 H), 1.44 (s, 18 H), 0.79 (s, 9 H), 0.24 (s, 3 H), 0.18 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 154.4 (2 C), 149.1, 142.9, 135.9, 126.8
(2 C), 123.4, 114.9, 114.8, 110.7, 110.1, 67.2, 55.9, 34.4 (2 C), 30.1 (6
C), 25.1 (3 C), 18.0, –4.7, –4.9.
406.2050.
MS (EI): m/z (%) = 285.2 (100) [M – C9H15N2OSi]+ = [C19H25O2]+.
2-[(4-Bromophenyl)(3,5-di-tert-butyl-4-hydroxyphenyl)methyl]-
2-(methoxymethoxy)malononitrile (5p)
HRMS (ESI): m/z [M + Na]+ calcd for C28H40N2O3SiNa+: 503.2700;
found 503.2693.
According to the general procedure, 5p was obtained as a yellow solid
(0.197 g, 99%); mp 104–106 °C.
2-[(tert-Butyldimethylsilyl)oxy]-2-[(3,5-di-tert-butyl-4-hydroxy-
phenyl)(naphthalen-1-yl)methyl]malononitrile (5m)
IR (ATR): 3622, 2956, 2647, 2256, 2163, 2006, 1920, 1730, 1589, 1439,
1312, 1237, 1160, 1109, 1022, 928, 831, 768 cm–1
.
According to the general procedure, 5m was obtained as a colorless
1H NMR (400 MHz, CDCl3): δ = 7.51 (d, J = 8.4 Hz, 2 H), 7.41 (d, J = 8.4
Hz, 2 H), 7.27 (s, 2 H), 5.29 (s, 1 H), 5.04 (s, 2 H), 4.53 (s, 1 H), 3.42 (s, 3
H), 1.43 (s, 18 H).
solid (0.205 g, 95%); mp 153–154 °C.
IR (ATR): 3625, 3459, 2943, 2323, 2099, 1740, 1599, 1372, 1220, 1125,
779 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 154.1 (2 C), 136.2, 135.3, 131.9 (2 C),
131.1 (2 C), 126.2 (2 C), 125.2, 122.5, 113.0, 112.9, 96.4, 69.6, 59.1,
57.4, 34.5 (2 C), 30.2 (6 C).
MS (EI): m/z (%) = 373.2 (100) [M – C5H5N2O2]+ = [C21H26BrO]+.
HRMS (ESI): m/z [M + Na]+ calcd for C26H31N2O3BrNa+: 521.1410;
1H NMR (400 MHz, CDCl3): δ = 8.11 (d, J = 7.2 Hz, 1 H), 8.01 (d, J = 8.4
Hz, 1 H), 7.88–7.80 (m, 2 H), 7.59–7.42 (m, 3 H), 7.31 (s, 2 H), 5.32 (s, 1
H), 5.20 (s, 1 H), 1.37 (s, 18 H), 0.81 (s, 9 H), 0.24 (s, 3 H), 0.20 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 154.0 (2 C), 135.7, 134.1, 132.6, 131.6,
129.1, 128.8, 126.8 (2 C), 126.6, 125.7, 125.2, 125.1, 124.9, 122.8,
115.6, 115.5, 67.9, 56.1, 34.3 (2 C), 30.1 (6 C), 25.3 (3 C), 18.1, –4.6,
–4.7.
found: 521.1397.
MS (EI): m/z (%) = 345.2 (100) [M – C9H15N2OSi]+ = [C25H29O]+.
HRMS (EI): m/z [M – C9H15N2OSi]+ calcd for C25H29O: 345.2213; found:
Cyclopenta-2,4-dien-1-yl{5-[2,2-dicyano-1-(3,5-di-tert-butyl-4-
hydroxyphenyl)-2-(methoxymeth-oxy)ethyl]cyclopenta-1,3-dien-
1-yl}iron (5q)
345.2205.
According to the general procedure, 5q was obtained as a dark red sol-
id (0.229 g, 91%); mp 114–116 °C.
IR (ATR): 3592, 3096, 2955, 2246, 2053, 1735, 1662, 1439, 1304, 1234,
1157, 1119, 1046, 974, 918, 889, 820, 754, 666 cm–1
.
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1H NMR (400 MHz, CDCl3): δ = 7.38 (s, 2 H), 5.30 (s, 1 H), 4.97–4.90
(m, 2 H), 4.42–4.40 (m, 1 H), 4.33–4.30 (m, 1 H), 4.22–4.18 (m, 2 H),
4.14 (s, 1 H), 3.80 (s, 5 H), 3.35 (s, 3 H), 1.50 (s, 18 H).
13C NMR (100 MHz, CDCl3): δ = 153.9 (2 C), 135.8 (2 C), 127.1, 126.2 (2
C), 113.2, 96.1, 83.3, 71.3, 70.3, 69.2, 68.9 (5 C, Cp), 68.7, 67.9, 57.0,
56.0, 34.5 (2 C), 30.4 (6 C).
Methyl 2-(4-Hydroxyphenyl)-2-phenylacetate (7c)
A solution of alcohol 7b (100 mg, 0.28 mmol) and AlCl3 (224 mg, 1.68
mmol) in anhyd benzene (0.018 M, 16.0 mL) was stirred at 60 °C for 1
h. H2O (3 mL) and EtOAc (3 mL) were added and the layers were sepa-
rated. The aqueous layer was extracted with EtOAc (3 × 5 mL) and the
combined organic layers were dried (anhyd Na2SO4) and filtered. The
solvent was removed and the crude product was purified by flash
chromatography (PE/Et2O 25:1) to give 7c (65 mg, 96%) as a colorless
oil.
MS (ESI): m/z = 551.2 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C30H36FeN2O3Na+: 551.1973;
found: 551.1948.
IR (ATR): 3421, 2969, 2324, 2096, 1733, 1610, 1361, 1209, 1003, 815,
707 cm–1
.
2-(3,5-Di-tert-butyl-4-hydroxyphenyl)-2-(3,4-dimethoxyphenyl)-
N-methylacetamide (7a)
1H NMR (600 MHz, CDCl3): δ = 7.34–7.26 (m, 5 H), 7.17 (d, J = 9.0 Hz, 2
H), 6.77 (d, J = 9.0 Hz, 2 H), 4.97 (s, 1 H), 4.82 (s, 1 H), 3.74 (s, 3 H).
In a 10 mL glass tube equipped with a stirring bar, 5k (85 mg, 0.15
mmol) and MeNH2 [100 mg, 0.6 mmol, 33% (w/w) in EtOH] were dis-
solved in THF (1.2 mL) in an ice bath. TBAF (0.17 mL, 0.17 mmol, 1 N
in THF) was added dropwise to the solution at 0 °C. The reaction mix-
ture was allowed to stir for 2 h and then quenched with sat. aq NH4Cl
(1 mL). The mixture was extracted with Et2O (3 × 10 mL), the com-
bined Et2O layers were dried (anhyd Na2SO4), and the solvent was
evaporated. The residue was purified by flash column chromatogra-
phy (PE/Et2O 4:1) to afford 7a (86 mg, 94%) as a wax.
13C NMR (150 MHz, CDCl3): δ = 173.3, 154.7, 138.8, 130.9, 129.9 (2 C),
128.6 (2 C), 128.4 (2 C), 127.2, 115.4 (2 C), 56.1, 52.3.
MS (EI): m/z (%) = 242.1 (20) [M]+ = [C15H14O3]+, 183.1 (100) [M
– C2H3O2]+ = [C13H11O]+.
HRMS (ESI): m/z [M + Na]+ calcd for C15H14O3Na+: 265.0835; found:
265.0827.
2-(3,5-Di-tert-butyl-4-hydroxyphenyl)-2-phenylacetic Acid (7d)
IR (ATR): 3313, 2916, 2854, 2333, 2088, 1923, 1733, 1649, 1515, 1459,
In a 10 mL glass tube equipped with a stirring bar, 5a (49 mg, 0.1
mmol) was dissolved in a mixed solvent of H2O (0.1 mL), THF (0.1 mL),
and AcOH (0.2 mL) in an ice bath. In a separate vial, TBAF (0.12 mmol,
0.12 mL, 1 N in THF) was dissolved in a mixture of THF (0.48 mL) and
H2O (0.6 mL). The resulting solution of TBAF [0.1 M in THF/H2O (1:1)]
was added dropwise to the solution at 0 °C. The reaction mixture was
allowed to stir for 24 h and then diluted with H2O (0.5 mL). The mix-
ture was extracted with Et2O (2 × 5 mL), dried (anhyd Na2SO4), and
the solvent was evaporated. The crude product was purified by flash
column chromatography (PE/Et2O 5:1) to afford 7d (28 mg, 83%) as a
colorless solid; mp 157–169 °C.
1375, 1234, 1177, 1104, 1046, 982, 884, 807, 725 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.03 (s, 2 H), 6.82 (d, J = 2.0 Hz, 1 H),
6.80–6.73 (m, 2 H), 5.69 (br s, 1 H), 5.14 (s, 1 H), 4.74 (s, 1 H), 3.82 (s, 3
H), 3.80 (s, 3 H), 2.78 (d, J = 4.8 Hz, 3 H), 1.37 (s, 18 H).
13C NMR (100 MHz, CDCl3): δ = 173.5, 152.9, 148.9, 148.0, 135.9 (2 C),
132.6, 130.0, 125.3 (2 C), 120.9, 112.2, 111.1, 58.6, 55.9, 55.8, 34.3 (2
C), 30.2 (6 C), 26.6.
MS (EI): m/z (%) = 413.4 (7) [M]+ = [C25H35NO4]+, 355.3 (100) [M
– C2H4NO]+ = [C23H31O3]+.
HRMS (ESI): m/z [M + Na]+ calcd for C25H35NO4Na+: 436.2458; found:
436.2445.
IR (ATR): 3625, 2942, 2092, 1714, 1432, 1209, 905, 703 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.37–7.31 (m, 4 H), 7.29–7.26 (m, 1 H),
7.15 (s, 2 H), 5.17 (s, 1 H), 4.95 (s, 1 H), 1.40 (s, 18 H).
13C NMR (150 MHz, CDCl3): δ = 178.6, 153.2, 138.5, 135.9, 128.6 (2 C),
Methyl 2-(3,5-Di-tert-butyl-4-hydroxyphenyl)-2-phenylacetate
(7b)
128.5 (2 C), 128.3, 127.3 (2 C), 125.4 (2 C), 56.8, 34.4 (2 C), 30.2 (6 C).
MS (ESI): m/z = 363.2 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C22H28O3Na+: 363.1931; found:
363.1927.
In a 10 mL glass tube equipped with a stirring bar, 5a (155 mg, 0.31
mmol) was dissolved in a mixture of THF (2.2 mL) and MeOH (1.1 mL)
in an ice bath. TBAF (0.35 mL, 0.35 mmol, 1 N in THF) was added
dropwise to the solution at 0 °C. The reaction mixture was allowed to
stir for 2 h and then quenched with sat. aq NH4Cl (1 mL). The mixture
was extracted with Et2O (3 × 10 mL), the combined Et2O layers were
dried (anhyd Na2SO4), and the solvent was evaporated. The residue
was purified by flash column chromatography (PE/Et2O 30:1) to af-
ford 7b (105 mg, 96%) as a wax.
N-(3,3-Diphenylpropyl)-2-(4-hydroxyphenyl)-2-phenylacetamide
(8)
To a solution of compound 7c (42 mg, 0.17 mmol) in MeOH (1.7 mL)
was added NaOH (21 mg, 0.52 mmol) and the reaction mixture was
heated to 90 °C for 12 h. The solution was cooled to r.t. and concen-
trated. To the residue, H2O (5 mL) was added and then extracted with
Et2O (3 × 10 mL). The aqueous phase was adjusted to pH 1 with aq 1 M
HCl and extracted with EtOAc (3 × 10 mL). The combined organic lay-
ers were washed with brine, dried (anhyd Na2SO4) and concentrated
to give the acid compound, which was used directly in the next step
without further purification.
IR (ATR): 3625, 2946, 2651, 2325, 2084, 1934, 1744, 1566, 1440, 1354,
1197, 703 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.35–7.30 (m, 4 H), 7.27–7.24 (m, 1 H),
7.13 (s, 2 H), 5.16 (s, 1 H), 4.94 (s, 1 H), 3.74 (s, 3 H), 1.41 (s, 18 H).
13C NMR (150 MHz, CDCl3): δ = 173.5, 153.0, 139.2, 135.8, 129.0,
128.5 (2 C), 128.4 (2 C), 127.0 (2 C), 125.2 (2 C), 56.9, 52.2, 34.4 (2 C),
30.3 (6 C).
MS (EI): m/z (%) = 354.3 (35) [M]+ = [C23H30O3]+, 295.2 (100) [M
In a glass tube, to a solution of the above obtained acid (23 mg, 0.1
mmol), Et3N (50 mg, 0.5 mmol), 3,3-diphenylpropan-1-amine (42 mg,
0.2 mmol) in DMF (1 mL) was added HATU (76 mg, 0.2 mmol) at r.t.
and the reaction mixture was stirred for 4 h. The reaction was
quenched with aq NaHCO3 and extracted with EtOAc (3 × 10 mL). The
combined organic layers were washed with brine, dried (anhyd
– C2H3O2]+ = [C21H27O]+.
HRMS (ESI): m/z [M + Na]+ calcd for C23H30O3Na+: 377.2087; found:
377.2082.
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Synthesis
Na2SO4), and concentrated. The residue was purified by column chro-
matography over silica gel (CH2Cl2/MeOH 10:1) to give 8 (30 mg, 71%)
as a colorless solid; mp 153–155 °C.
(5) For selected examples, see: (a) Nemoto, H.; Kubota, Y.;
Yamamoto, Y. J. Org. Chem. 1990, 55, 4515. (b) Nemoto, H.;
Kawamura, T.; Miyoshi, N. J. Am. Chem. Soc. 2005, 127, 14546.
(c) Nemoto, H.; Ma, R.; Kawamura, T.; Kamiya, M.; Shibuya, M.
J. Org. Chem. 2006, 71, 6038. (d) Nemoto, H.; Ma, R.; Kawamura,
T.; Yatsuzuka, K.; Kamiya, M.; Shibuya, M. Synthesis 2008, 3819.
(e) Nemoto, H.; Kawamura, T.; Kitasaki, K.; Yatsuzuka, K.;
Kamiya, M.; Yoshioka, Y. Synthesis 2009, 1694.
(6) For applications of MAC reagents in total synthesis (ref. 6a–d)
and recent reports (ref. 6e–h), see: (a) Nemoto, H.; Ma, R.;
Suzuki, I.; Shibuya, M. Org. Lett. 2000, 2, 4245. (b) Roche, S. P.;
Faure, S.; Aitken, D. J. Angew. Chem. Int. Ed. 2008, 47, 6840.
(c) Yamatsugu, K.; Kanai, M.; Shibasaki, M. Tetrahedron 2009,
65, 6017. (d) Yamatsugu, K.; Yin, L.; Kamijo, S.; Kimura, Y.;
Kanai, M.; Shibasaki, M. Angew. Chem. Int. Ed. 2009, 48, 1070.
(e) Yang, K. S.; Nibbs, A. E.; Türkmen, Y. E.; Rawal, V. H. J. Am.
Chem. Soc. 2013, 135, 16050. (f) Yang, K. S.; Rawal, V. H. J. Am.
Chem. Soc. 2014, 136, 16148. (g) Kagawa, N.; Nibbs, A. E.; Rawal,
V. H. Org. Lett. 2016, 18, 2363. (h) Hethcox, J. C.; Shockley, S. E.;
Stoltz, B. M. Org. Lett. 2017, 19, 1527.
(7) For selected reviews and highlights on 1,6-addition reactions,
see: (a) Biju, A. T. ChemCatChem 2011, 3, 1847. (b) Silva, E. M. P.;
Silva, A. M. S. Synthesis 2012, 44, 3109. (c) Lear, M. J.; Hayashi, Y.
ChemCatChem 2013, 5, 3499. (d) Chauhan, P.; Kaya, U.; Enders,
D. Adv. Synth. Catal. 2017, 359, 888.
(8) For selected reviews on para-quinone methides, see: (a) Peter,
M. G. Angew. Chem. Int. Ed. 1989, 28, 555. (b) Toteva, M. M.;
Richard, J. P. Adv. Phys. Org. Chem. 2011, 45, 39. (c) Parra, A.;
Tortosa, M. ChemCatChem 2015, 7, 1524.
IR (ATR): 3852, 3621, 3537, 3319, 3031, 2923, 2870, 2473, 2297, 2184,
2125, 2068, 1974, 1888, 1739, 1614, 1516, 1444, 1363, 1230, 1085,
1029, 964, 834, 793, 740, 698 cm–1
.
1H NMR (600 MHz, CD3OD): δ = 7.30–7.20 (m, 9 H), 7.18–7.16 (m, 4
H), 7.13–7.09 (m, 4 H), 6.74 (d, J = 9.0 Hz, 2 H), 4.85 (s, 1 H), 3.87 (t, J =
7.8 Hz, 1 H), 3.13 (t, J = 7.2 Hz, 2 H), 2.25–2.22 (m, 2 H).
13C NMR (151 MHz, CD3OD): δ = 173.8, 156.2, 144.4, 140.2, 130.5 (2
C), 129.5 (2 C), 128.4 (2 C), 128.1 (4 C), 128.0 (2 C), 127.4 (4 C), 126.5,
125.8 (2 C), 114.8 (2 C), 57.0, 48.4, 37.9, 34.5.
MS (ESI): m/z = 422.2 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C29H28NO2+: 422.2115; found:
422.2120.
N-Hydroxy-2-(4-hydroxyphenyl)-2-phenylacetamide (9)
To a solution of 7c (24 mg, 0.1 mmol) and hydroxylamine (50% in H2O,
0.1 mL) in THF/MeOH (1:1, 0.8 mL) was added KOH (23 mg, 0.4
mmol). The mixture was stirred at r.t. for 2 h, acidified to pH 7 with
aq 1 M HCl, diluted with EtOAc (5 mL), and washed with H2O (1 mL).
The organic layer was separated, dried (anhyd Na2SO4), filtered, and
concentrated. The residue was purified by flash column chromatogra-
phy (CH2Cl2/MeOH 10:1) to afford 9 (17 mg, 68%) as a colorless solid;
mp 157–160 °C.
IR (ATR): 3620, 3351, 3220, 2921, 2855, 2664, 2313, 2108, 1893, 1656,
1609, 1509, 1442, 1358, 1212, 1107, 1033, 984, 887, 836, 798, 726,
690 cm–1
.
(9) For selected reports of non-enantioselective reactions, see:
(a) Gai, K.; Fang, X.; Li, X.; Xu, J.; Wu, X.; Lin, A.; Yao, H. Chem.
Commun. 2015, 51, 15831. (b) López, A.; Parra, A.; Jarava-Bar-
rera, C.; Tortosa, M. Chem. Commun. 2015, 51, 17684.
(c) Ramanjaneyulu, B. T.; Mahesh, S.; Anand, R. V. Org. Lett.
2015, 17, 3952. (d) Reddy, V.; Anand, R. V. Org. Lett. 2015, 17,
3390. (e) Yuan, Z.; Fang, X.; Li, X.; Wu, J.; Yao, H.; Lin, A. J. Org.
Chem. 2015, 80, 11123. (f) Zhang, X.-Z.; Du, J.-Y.; Deng, Y.-H.;
Chu, W.-D.; Yan, X.; Yu, K.-Y.; Fan, C.-A. J. Org. Chem. 2016, 81,
2598. (g) Molleti, N.; Kang, J. Y. Org. Lett. 2017, 19, 958.
(h) Zhang, Z.-P.; Dong, N.; Li, X. Chem. Commun. 2017, 53, 1301.
(10) For selected reports on enantioselective reactions, see: (a) Chu,
W.-D.; Zhang, L.-F.; Bao, X.; Zhao, X.-H.; Zeng, C.; Du, J.-Y.;
Zhang, G.-B.; Wang, F.-X.; Ma, X.-Y.; Fan, C.-A. Angew. Chem. Int.
Ed. 2013, 52, 9229. (b) Caruana, L.; Kniep, F.; Johansen, T. K.;
Poulsen, P. H.; Jørgensen, K. A. J. Am. Chem. Soc. 2014, 136,
15929. (c) Jarava-Barrera, C.; Parra, A.; López, A.; Cruz-Acosta,
F.; Collado-Sanz, D.; Cárdenas, D. J.; Tortosa, M. ACS Catal. 2015,
6, 442. (d) Lou, Y.; Cao, P.; Jia, T.; Zhang, Y.; Wang, M.; Liao, J.
Angew. Chem. Int. Ed. 2015, 54, 12134. (e) Wang, Z.; Wong, Y. F.;
Sun, J. Angew. Chem. Int. Ed. 2015, 54, 13711. (f) Deng, Y.-H.;
Zhang, X.-Z.; Yu, K.-Y.; Yan, X.; Du, J.-Y.; Huang, H.; Fan, C.-A.
Chem. Commun. 2016, 52, 4183. (g) Dong, N.; Zhang, Z.-P.; Xue,
X.-S.; Li, X.; Cheng, J.-P. Angew. Chem. Int. Ed. 2016, 55, 1460.
(h) He, F.-S.; Jin, J.-H.; Yang, Z.-T.; Yu, X.; Fossey, J. S.; Deng, W.-P.
ACS Catal. 2016, 6, 652. (i) Li, X.; Xu, X.; Wei, W.; Lin, A.; Yao, H.
Org. Lett. 2016, 18, 428. (j) Wong, Y. F.; Wang, Z.; Sun, J. Org.
Biomol. Chem. 2016, 14, 5751. (k) Zhang, X.-Z.; Deng, Y.-H.; Yan,
X.; Yu, K.-Y.; Wang, F.-X.; Ma, X.-Y.; Fan, C.-A. J. Org. Chem. 2016,
61, 5655. (l) Zhao, K.; Zhi, Y.; Wang, A.; Enders, D. ACS Catal.
2016, 6, 657. (m) Zhao, K.; Zhi, Y.; Shu, T.; Valkonen, A.;
Rissanen, K.; Enders, D. Angew. Chem. Int. Ed. 2016, 55, 12104.
1H NMR (600 MHz, DMSO-d6): δ = 10.83 (s, 1 H), 9.28 (s, 1 H), 8.89 (s,
1 H), 7.28–7.25 (m, 4 H), 7.22–7.16 (m, 1 H), 7.10 (d, J = 8.4 Hz, 2 H),
6.67 (d, J = 8.4 Hz, 2 H), 4.56 (s, 1 H).
13C NMR (150 MHz, DMSO-d6): δ = 168.9, 156.6, 141.0, 130.6, 129.9 (2
C), 128.7 (2 C), 128.6 (2 C), 127.0, 115.4 (2 C), 53.0.
MS (ESI): m/z = 266.1 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C14H13NO3Na+: 266.0788; found:
266.0792.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590947.
S
u
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References
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

I
K. Zhao et al.
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(13) CCDC 1566735 contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge from
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/getstructures.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I