Merging Br?nsted Acid and Hydrogen-Bonding Catalysis: Metal-Free Dearomatization of Phenols via ipso-Friedel-Crafts Alkylation to Produce Functionalized Spirolactams

Article abstract of DOI:10.1002/adsc.201701287

Intramolecular dearomative cyclization of phenols with α-diazoamide units for synthesizing functionalized spirolactams was developed by merging Br?nsted acid and hydrogen-bonding catalysis as an advantageous alternative to transition metal catalysis. This metal carbenoid-free strategy enables high chemoselectivity by suppressing potentially competing C?H insertion reactions and a Büchner reaction. Preliminary mechanistic studies were performed to elucidate the positive effect of the combined use of the catalysts, and extension to an asymmetric reaction was achieved. (Figure presented.).

Full text of DOI:10.1002/adsc.201701287

Title: Merging Brønsted Acid and Hydrogen-Bonding Catalysis:
Metal-Free Dearomatization of Phenols via ipso-Friedel-Crafts
Alkylation to Produce Functionalized Spirolactams
Authors: Shingo Harada, Irene Kwok, Hiroki Nakayama, Ayaka Kanda,
and Tetsuhiro Nemoto
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701287
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10.1002/adsc.201701287
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Merging Brønsted Acid and Hydrogen-Bonding Catalysis:
Metal-Free Dearomatization of Phenols via ipso-Friedel-Crafts
Alkylation to Produce Functionalized Spirolactams
Shingo Harada,a,* Irene Mei-Yi Kwok,a Hiroki Nakayama,a Ayaka Kanda,a and
Tetsuhiro Nemotoa,b,*
a
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan
Tel./fax: 81 43 226 2920; e-mail address: Sharada@chiba-u.jp (S. Harada), tnemoto@faculty.chiba-u.jp (T. Nemoto)
Molecular Chirality Research Center, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. Intramolecular dearomative cyclization of
phenols with -diazoamide units for synthesizing
functionalized spirolactams was developed by merging
Brønsted acid and hydrogen-bonding catalysis as an
advantageous alternative to transition metal catalysis. This
electrophiles. For example, O–H insertion
reactions,[8] esterifications of carboxylic acids,[9] and
nucleophilic
substitution
reactions[10]
are
representative transformations for the effective use of
diazonium cations generated from the diazo
functionality and Brønsted acid catalyst.
metal
carbenoid-free
strategy
enables
high
chemoselectivity by suppressing potentially competing C–
H insertion reactions and a Büchner reaction. Preliminary
mechanistic studies were performed to elucidate the
positive effect of the combined use of the catalysts, and
extension to an asymmetric reaction was achieved.
Catalytic dearomatization of phenol derivatives via
a
ipso-Friedel-Crafts-type reaction process has
proven to be one of the most straightforward
approaches to access the functionalized
spirocyclohexadienones as versatile synthetic
scaffolds.[11] Intramolecular phenol dearomatization
using transition-metal-catalyzed alkylation or
arylation reactions has been reported, with leading
examples by us,[11a] You,[11b] Buchwald,[11c] and
Luan.[11d] Given this background, we hypothesized
that spirocyclization of phenols with diazoamides
would be realized via protonation to generate
diazonium cations under Brønsted acid catalysis,
followed by ipso-Friedel-Crafts-type nucleophilic
alkylation. This transition metal and carbenoid-free
pathway would contribute to the chemoselectivity to
suppress C–H insertion reactions and a Büchner
reaction, which are competing processes in reactions
using metal carbenoid species.[5,12] Herein we
describe the development of an alternative method for
Keywords: Brønsted acid; diazo compounds; lactams;
carbenoids; dearomatization; spirocycles
Introduction
Spirocyclic molecular frameworks are pivotal
scaffolds for synthesizing an extensive range of
biologically important compounds. Among the cyclic
motifs, 2-azaspiro[4.5]decane derivatives are a highly
important class of compounds due to their ubiquity in
bioactive natural[1] and unnatural products[2] (Figure
1). The development of an efficient and
straightforward methodology for synthesizing
azaspirocyclic core structures with diverse
functionalities, therefore, continues to be an area of
great interest in the synthetic community.[3]
As part of our ongoing work aimed at developing
metal carbenoid reactions,[4] we recently reported a
highly chemoselective spirocyclization of phenols
with -diazoamides using a silver catalyst to produce
azaspirocyclic molecules.[5] Mechanistic analysis
revealed that high electrophilicity of the silver
carbenoid species was key to the success. Among the
various transformations using diazocompounds,[6]
Brønsted acid catalysis is a well-established process[7]
for the generation of diazonium cations as
spirocyclization using organocatalysis[13] via
a
dearomative ipso-Friedel-Crafts (DIFC) reaction to
produce functionalized spirolactams.
1
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10.1002/adsc.201701287
Advanced Synthesis & Catalysis
and availability.[18]
With the optimized conditions in hand, we next
investigated the scope and limitations of the
developed DIFC reaction (Scheme 2). In addition to
the model substrate 1a, other substrates bearing a
methyl group at the ortho- and meta-position of
phenols 1b-d were transformed into the
corresponding dearomatized compounds 2b-d in
excellent yields (82%-91%). Methoxy phenol could
also
be
applied,
in
which
case
azaspirocyclohexadienones containing an enol ether
unit were produced in good yield (2e-g, 68%-99%).
Electron-deficient phenol, however, was less reactive
in this spirocyclization reaction, indicating that
phenol dearomatization would proceed via the
Friedel-Crafts-type reaction (2h). α-Diazoacetamide
having removable substituent, such as PMB on the
amide nitrogen, were applicable (2i). In addition, the
δ-lactam 2j possessing an azaspiro[5.5]undecane
system was constructed with 30 mol % of 4 and 6 in
60% yield.
Figure 1 Biologically active molecules possessing a 2-
azaspiro[4.5]decane core
Table 1 Optimization of the reaction conditions
Scheme 1 Comparison of transition metal catalysis and
organocatalysis in the DIFC reaction.
Results and Discussion
The reaction conditions were optimized using
phenol derivatives with a diazoacetamide unit (1a) as
a
model substrate for development of the
dearomatization process (Table 1). At first, the
reaction using 10 mol% 2,2-diphenylacetic acid (3) as
a manageable solid catalyst was tested in acetonitrile
solvent at room temperature for 1 h, but no reaction
occurred (entry 1). We continued to examine
Brønsted acid catalysts, and revealed that the desired
DIFC reaction could be accelerated, depending on the
acidity of the catalysts (entries 1-5). All reactions
stopped before full conversion, however, even when
extremely strong acids such as Tf2NH or TfOH were
used. Schreiner’s thiourea (6) works as an effective
co-catalyst in some reaction systems.[14,15] Thus, we
investigated the effect of 6 in the presence of
Brønsted acid catalysts. Dramatic positive effects
were observed when 6 was used with relatively weak
Brønsted acid catalysts (entries 6-7). The use of
thiourea 6 only did not promote the spirocyclization
reaction at all[16] and fumaric acid (9) or (thio)urea 7,
8 were also ineffectual in this reaction (entries 9-12).
Although the reaction in entries 6 and 7 indicated
similar results, we decided to combine 6 and 4 as
mild Brønsted acid was the best cooperative catalyst
system[17] for dearomative spirocyclization from the
viewpoint of functional group tolerance, economy,
entry
1
2
3
4
5
6
7
8
catalyst(s)
3
2a [yield] recovered 1a
0%
97%
60%
59%
8%
10%
trace
2%
32%
33%
70%
73%
85%
85%
78%
0%
4
5
Tf2NH
TfOH
4 + 6
5 + 6
TfOH + 6
6
9 + 6
4 + 7
4 + 8
5%
9
100%
96%
50%
8%
10
11
12
2%
41%
78%
2
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10.1002/adsc.201701287
Advanced Synthesis & Catalysis
Table 2 Substrate scope
stereogenic center and enantiomeric ratio of 85:15.
Scheme 2 Enantioselective spirocyclizations. [a] Without
(S)-BINOL.
The reaction of Scheme 2 ceased before reaching
full conversion. To gain mechanistic insight, we
scrutinized side products of the DIFC reaction using
Brønsted acid and isolated O–H insertion product 11
generated from substrate 1a and 5.[21,22] Treatment of
10 with 6 did not afford 2a, indicating that 10 is not
an intermediate for the dearomatization process and
therefore a dead-end product.
[a]
[b]
The reaction was performed for 24 h. 30 mol% of 4
[c]
and 6 was used. The reaction was performed for 3 h in
the presence of 20 mol% of 4 and 6. PMB is p-
methoxybenzyl.
The
reaction
of
1k
possessing
a
dimethylphenylmethyl group on the amide in the
presence of a silver catalyst gives cycloheptatriene 10
formed through a Büchner reaction, which is specific
to the carbene reaction (eq 1).[5] To demonstrate the
utility of the developed catalyst system, we evaluated
the reaction of 1k using 4 and 6, which afforded 2k
without the production of 10.
Scheme 3 Isolation of O–H insertion product
Next, NMR experiments were performed to shed
light on the reaction mechanism and the positive
effect of merging the Brønsted acid and hydrogen-
bonding catalysis (table 3). The chemical shift of
vinyl protons of maleic acid 4 had the same value (δ
6.35) as that of 4 in the presence of thiourea 6 in
CD3CN solvent (entries 1,2). The value of a
conjugate base of maleic acid, generated from 4 and
Hünig's base, with 6 indicated a higher chemical shift
than that without 6 (δ 6.12 to δ 6.20, entries 3,4),
suggesting an interaction between the conjugate base
of 4 and 6 in acetonitrile.
To apply the reaction in asymmetric synthesis, we
investigated a chiral Brønsted acid[19] and hydrogen-
bonding donor catalyst.[20] The combination of
catalysts containing (S)-TRIP and (S)-BINOL[15b]
produced good yield and enantioselectivity,
furnishing (S)-2b with an all-carbon quaternary
3
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10.1002/adsc.201701287
Advanced Synthesis & Catalysis
Table 3 1H NMR analysis of 4 in CD3CN
recorded on a JEOL ecs 400 spectrometer, operating at 400
1
MHz for H NMR, and 100 MHz for 13C NMR. Chemical
entry
sample(s)
vinyl proton
shifts in CDCl3 were reported downfield from TMS (=0
1
ppm) for H NMR. For 13C NMR, chemical shifts were
of 4 (ppm)
reported in the scale relative to the solvent signal [CHCl3
(77.0 ppm)] as an internal reference. The enantiomeric
excess (ee) was determined by HPLC analysis. HPLC was
performed on JASCO HPLC systems consisting of the
following: pump, PU-980; detector, UV-970; mobile phase,
n-hexane/i-PrOH. Melting points were measured with a
SIBATA NEL-270 melting point apparatus. Column
chromatography was performed with silica gel 60 N
(spherical, neutral 63-210 mesh). ESI-TOF mass spectra
were measured on JEOL AccuTOF LC-plus JMS-T100LP.
Reactions were carried out in dry solvent under argon
atmosphere. Other reagents were purified by the usual
methods.
1
2
3
4
6.35
4
4 + 6
4 + i-Pr2NEt
4 + 6 +i-Pr2NEt
6.35
6.12
6.20
Based on the above-described mechanistic
information and the results shown in table 1, a
possible mechanism is depicted in Scheme 4. At first,
diazoamide 1 would be protonated by a Brønsted acid,
generating an ion pair of diazonium cation 12 and a
conjugate base of the acid catalyst. A nucleophilic
substitution reaction by the counteranion could give
O–H insertion product 14 as the dead-end product.
The interaction of conjugate base and thiourea would
work to suppress the undesired pathway and promote
the ipso-Friedel-Craft-type dearomatization by
lowering the electron density of the counteranion to
generate a loose ion pair.
General Procedure for the Spirocyclization
To a stirred solution of substrate 1c (61.8 mg, 0.25 mmol)
and Schreiner’s thiourea 6 (12.5 mg, 0.025 mmol) in
MeCN (2.5 mL) was added maleic acid 4 (2.9 mg, 0.025
mmol), and the reaction mixture was stirred for 1 h at room
temperature. The reaction was quenched with triethylamine
(0.1 mL) and concentrated under reduced pressure. The
crude residue was purified by flash chromatography on
silica gel to afford spirolactam 2c (47.6 mg, 87% yield),
(hexane / ethyl acetate as an eluent).
1H and 13C NMR, IR, and MS of products 2b, 2c, 2e, 2f,
2h, and 2k were identical to those reported.[5] For charts of
1H- and 13C-NMR spectra, see the Supporting Information.
2-Isopropyl-2-azaspiro[4.5]deca-6,9-diene-3,8-dione
(2a): 17.4 mg (85% yield); white powder; 103-104 °C; Rf
1
= 0.25 (EtOAc only); H NMR (400 MHz, CDCl3) δ 1.19
(d, J = 6.8 Hz, 6H), 2.59 (s, 2H), 3.39 (s, 2H), 4.47 (sep, J
= 7.0 Hz, 1H), 6.35 (d, J = 10.0 Hz, 2H), 6.93 (d, J = 10.0
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 19.7, 41.2, 41.5,
43.0, 49.6, 129.4, 149.8, 170.6, 184.9; IR (ATR)  2973,
2341, 1660, 1627, 1486, 1429, 1369, 1277, 1244, 1195,
1092, 862, 762, 711, 636 cm−1; HRMS (ESI-TOF) [M +
+
Na]+ calcd for C12H15NNaO2 m/z 228.0995, found
228.0997.
2-Isopropyl-7,9-dimethyl-2-azaspiro[4.5]deca-6,9-diene-
3,8-dione (2d): 21.4 mg (94% yield); pale yellow powder;
1
99-100 °C; Rf = 0.31 (hexane/EtOAc, 1/2); H NMR (400
MHz, CDCl3) δ 1.17 (d, J = 6.8 Hz, 6H), 1.92 (s, 6H), 2.52
(s, 2H), 3.34 (s, 2H), 4.45 (sep, J = 6.8 Hz, 1H), 6.68 (s,
2H); 13C NMR (100 MHz, CDCl3) δ 16.1, 19.7, 40.7, 41.8,
42.8, 49.8, 135.3, 145.2, 171.2, 186.3; IR (ATR)  2972,
2360, 1684, 1633, 1422, 1371, 1272, 1242, 1210, 1127,
1062, 909 cm−1; HRMS (ESI-TOF) [M + Na]+ calcd for
C14H19NNaO2+ m/z 256.1308, found 256.1306.
Scheme 4 Possible reaction pathways
2-Isopropyl-2-azaspiro[4.5]deca-6,9-diene-3,8-dione
(2g): 19.4 mg (73% yield); white powder; 175-176 °C; Rf
Conclusions
1
= 0.2 (hexane/EtOAc, 1/2); H NMR (400 MHz, CDCl3) δ
1.19 (d, J = 6.8 Hz, 6H), 2.62 (s, 2H), 3.42 (s, 2H), 3.69 (s,
6H), 4.49 (sep, J = 6.8 Hz, 1H), 5.87 (s, 2H); 13C NMR
(100 MHz, CDCl3) δ 19.7, 40.0, 42.7, 43.7, 51.8, 55.3,
117.4, 151.0, 171.2, 175.7; IR (ATR)  2971, 2358, 2346,
1669, 1652, 1620, 1424, 1366, 1282, 1238, 1197, 1108,
871 cm−1; HRMS (ESI-TOF) [M + Na]+ calcd for
C14H19NNaO4+ m/z 288.1206, found 288.1217.
2-(4-Methoxybenzyl)-2-azaspiro[4.5]deca-6,9-diene-3,8-
dione (2i): 5.5 mg (45% yield); yellow oil; Rf = 0.28
(EtOAc only); 1H NMR (400 MHz, CDCl3) δ 2.61 (s, 2H),
3.28 (s, 2H), 3.80 (s, 3H), 4.45 (s, 2H), 6.27 (d, J = 10.4
Hz, 2H), 6.84 (d, J = 10.4 Hz, 2H), 6.88 (d, J = 8.8 Hz,
2H), 7.19 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 41.1, 41.3, 46.3, 53.8, 55.3, 114.5, 127.7, 129.4,
129.7, 149.7, 159.6, 171.2, 184.7; IR (ATR)  2932, 2357,
1664, 1628, 1513, 1487, 1419, 1247, 1177, 1091, 1032,
862 cm−1; HRMS (ESI-TOF) [M + Na]+ calcd for
C17H17NNaO3+ m/z 306.1101, found 306.1106.
3-Isopropyl-3-azaspiro[5.5]undeca-7,10-diene-2,9-dione
(2j): 6.4 mg (60% yield); pale yellow powder; 88-90 °C;
Rf = 0.15 (hexane/EtOAc, 1/2); 1H NMR (400 MHz,
CDCl3) δ 1.20 (d, J = 6.8 Hz, 6H), 1.96 (t, J = 6.0 Hz, 2H),
2.45 (s, 2H), 3.40 (t, J = 6.0 Hz, 2H), 4.98 (sep, J = 6.8 Hz,
1H), 6.33 (d, J = 10.0 Hz, 2H), 6.85 (d, J = 10.0 Hz, 2H) ;
13C NMR (100 MHz, CDCl3) δ 19.2, 32.4, 37.4, 39.1, 40.5,
44.2, 129.5, 150.9, 165.7, 185.1 ; IR (ATR)  2930, 2359,
We developed a dearomative spirocyclization of
phenols possessing diazo functionality by merging
Brønsted acid and hydrogen-bonding catalysis. This
metal- and carbenoid-free methodology will
contribute to achieve high chemoselectivity by
suppressing C–H insertion reactions and Büchner
reactions. The DIFC cyclization was expanded to an
asymmetric reaction using chiral catalysts.
Mechanistic studies indicated an interaction between
the hydrogen-bonding catalyst and conjugate base of
the Brønsted acid. Total synthesis of bioactive
molecules using the developed dearomative
spirocyclization is underway.
Experimental Section
General Methods
IR spectra were recorded on a JASCO FT/IR 230 Fourier
transform infrared spectrophotometer, equipped with ATR
(Smiths Detection, DuraSample IR II). NMR spectra were
4
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10.1002/adsc.201701287
Advanced Synthesis & Catalysis
1663, 1627, 1495, 1453, 1368, 1323, 1216, 1175, 1096,
922, 858 cm−1; HRMS (ESI-TOF) [M + Na]+ calcd for
C13H17NNaO2+ m/z 242.1151, found 242.1143.
6.46 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 20.7, 45.7,
46.9, 47.3, 56.5, 103.4, 129.7, 134.1, 147.5, 166.6; IR
(ATR)  2970, 2359, 2101, 1586, 1516, 1419, 1370, 1326,
1201, 1113, 803, 734, 626 cm−1; HRMS (ESI-TOF) [M +
Isolation of O–H insertion product 11
+
To a stirred solution of substrate 1a (0.05 mmol, 11.7 mg)
in MeCN (0.5 mL, 0.1 M) was added phosphoric acid 5
(23.6 mg, 1 eq), and the reaction mixture was stirred for 1
h at room temperature. The reaction was quenched with
triethylamine (0.05 mL) and concentrated under reduced
pressure. The crude residue was purified by flash
chromatography on silica gel (hexane : ethyl acetate = 2:1
to 0:1, then ethyl acetate : methanol = 30 : 1 as eluent) to
afford 11 (5.2 mg, 15%) and 2a (6.4 mg, 62%).
Na]+ calcd for C14H19N3NaO4 m/z 316.1268, found
316.1263.
2-Diazo-N-(4-hydroxybenzyl)-N-(4-
methoxybenzyl)acetamide (1i): 2.0 g (46% yield); yellow
1
powder; 114-116 °C; Rf = 0.74 (hexane/EtOAc, 1/2); H
NMR (400 MHz, CDCl3) δ 3.81 (s, 3H), 4.40 (br d, 4H),
5.02 (s, 1H), 6.81 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.4 Hz,
2H), 7.05 (br d, 2H), 7.14(br d, 2H); 13C NMR (100 MHz,
CDCl3) δ 47.2, 49.0, 49.1, 55.3, 55.4, 114.4, 115.9, 128.0,
128.8, 156.1, 159.3, 166.9; IR (ATR)  3260, 2108, 1579,
1512, 1437, 1354, 1246, 1173, 1032, 825, 723, 612 cm−1;
N-(4-Hydroxybenzyl)-N-isopropyl-2-((2,4,8,10-tetra-
tert-butyl-6-oxidodibenzo[d,f][1,3,2]dioxaphosphepin-6-
yl)oxy)acetamide (11): white powder; 112-114 °C; Rf =
+
HRMS (ESI-TOF) [M + Na]+ calcd for C17H17N3NaO3
m/z 334.1162, found 334.1151.
1
0.2 (hexane/EtOAc, 2/1); H NMR (400 MHz, CDCl3) δ
1.09 (d, J = 6.0 Hz, 6H), 1.34 (s, 18H), 1.49 (s, 18H), 4.33
(br s, 2H), 4.65 (br s, 2H), 4.86 (br s, 1H), 5.55 (br s, 1H),
6.70 (d, J = 7.2 Hz, 2H), 7.01(br s, 2H), 7.17 (s, 2H), 7.48
(s, 2H); 13C NMR (100 MHz, CDCl3) δ 20.1, 31.2, 31.5,
34.7, 35.5, 43.8, 47.1, 66.7, 66.7, 115.9, 125.3, 126.6,
127.2, 130.1, 132.2, 140.3, 140.3, 144.4, 144.5, 148.0,
158.5, 166.2.; IR (ATR) 2959, 2360, 1669, 1518, 1458,
1364, 1280, 1172, 1064, 921 cm−1; HRMS (ESI-TOF) [M
+ Na]+ calcd for C40H56NO6PNa+ m/z 700.3737, found
700.3734.
2-Diazo-N-(4-hydroxyphenethyl)-N-isopropylacetamide
(1j): 165.7 mg (34% yield); yellow powder; 108-110 °C;
Rf = 0.63 (hexane/EtOAc,1/2); 1H NMR (400 MHz,
CDCl3) δ 1.18 (d, J = 6.8 Hz, 6H), 2.78 (t, J = 10.0 Hz,
2H), 3.27 (br d, 2H), 4.95 (br d, 1H), 5.03 (br d, 1H), 6.81
(d, J = 8.0 Hz, 2H), 7.03 (d, J = 7.0 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 20.9, 36.0, 44.6, 47.1, 47.5, 115.7,
129.7, 130.5, 155.1, 165.8; IR (ATR)  2978, 2360, 2341,
2105, 1576, 1516, 1431, 1358, 1231, 1164, 827, 645 cm−1;
+
HRMS (ESI-TOF) [M + Na]+ calcd for C13H17N3NaO2
Substrate Synthesis
m/z 270.1213, found 270.1211.
The substrates 1b, 1c, 1e, 1f, 1h and 1k were prepared
according to the reported procedure.[5] 1H and 13C NMR,
IR, and MS of products were identical to those reported.[5]
General Procedure for the synthesis of 1a, d, g, i, j: To a
stirred solution of 4-hydroxybenzaldehyde derivative in
MeOH (0.5 M) was added primary amine (1 eq), and the
reaction mixture was stirred for 24 h at room temperature.
Then NaBH4 (1.2 eq) was added to the mixture at 0 °C,
and stirring was continued for additional 3 h at 0 °C. The
reaction was quenched with water, concentrated under
reduced pressure to remove most of the MeOH, extracted
with EtOAc. The organic layer was acidified with 1 N
aqueous HCl, and the water layer was washed with EtOAc.
The aqueous solution was basified with 1 N aqueous
NaOH, extracted with EtOAc×3, washed with brine, dried
over Na2SO4, and concentrated under reduced pressure.
The obtained crude secondary amine was used for the next
step without further purification.
To a stirred solution of crude secondary amine in THF (0.5
M) were added Et3N (2 eq) and 2,5-dioxopyrrolidin-1-yl 2-
diazoacetate[23] at room temperature, and the reaction
mixture was stirred for 24 h at room temperature. The
reaction was quenched with N,N-dimethyl-1,3-propane-
diamine (2 eq), filtered through celite, concentrated under
reduced pressure. The crude residue was purified by flash
chromatography on silica gel to afford diazocarbonyl
compound 1.
Acknowledgements
This work was supported by the Sasakawa Scientific
Research Grant from The Japan Science Society, Futaba
Electronics Memorial Foundation, JSPS KAKENHI Grant
Numbers JP16K18840, JP15K07850.
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2-Diazo-N-(4-hydroxybenzyl)-N-isopropylacetamide
(1a): 421.8 mg (60% yield); yellow powder; 110-111 °C;
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CDCl3) δ 1.13 (d, J = 7.4 Hz, 6H), 4.30 (br d, 2H), 4.85 (br
d, 2H), 6.80 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 20.7, 45.1, 47.1, 47.6,
115.8, 127.6, 130.0, 155.4, 166.9; IR (ATR)  2978, 2459,
2104, 1575, 1515, 1427, 1354, 1234, 1203, 1169, 1070,
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1
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5
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10.1002/adsc.201701287
Advanced Synthesis & Catalysis
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6
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10.1002/adsc.201701287
Advanced Synthesis & Catalysis
UPDATE
Merging Brønsted Acid and Hydrogen-Bonding
Catalysis: Metal-Free Dearomatization of Phenols
via ipso-Friedel-Crafts Alkylation to Produce
Functionalized Spirolactams
Adv. Synth. Catal. Year, Volume, Page – Page
Shingo Harada,a,* Irene Mei-Yi Kwok,a Hiroki
Nakayama,a Ayaka Kanda,a and Tetsuhiro
Nemotoa,b,*
7
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