Tandem Synthesis of α-Diazoketones from 1,3-Diketones

Article abstract of DOI:10.1021/acs.joc.7b01187

A highly efficient synthesis of α-diazoketone was achieved by simply stirring the mixture of 1,3-diketone, TsN₃, and MeNH₂ in EtOH. It was a tandem reaction including a novel primary amine-catalyzed Regitz diazo transfer of 1,3-diket

Full text of DOI:10.1021/acs.joc.7b01187

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Note
A Tandem Synthesis of #-Diazoketones from 1,3-Diketones
Jianlan Zhang, Wenwen Chen, Dayun Huang, Xiaobao Zeng, Xinyan Wang, and Yuefei Hu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01187 • Publication Date (Web): 01 Aug 2017
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Page 1 of 13
The Journal of Organic Chemistry
Revised version for jo-2017-011876
July 28, 2017
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A Tandem Synthesis of -Diazoketones from 1,3-Diketones
Jianlan Zhang, Wenwen Chen, Dayun Huang, Xiaobao Zeng, Xinyan Wang,* Yuefei Hu*
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology
(Ministry of Education), Department of Chemistry, Tsinghua University,
Beijing 100084, P. R. China
Fax: +86-10-62771149; Tel: +86-10-62795380;
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E-mail: yfh@mail.tsinghua.edu.cn and wangxinyan@mail.tsinghua.edu.cn.
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Graphic Abstract
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aq. MeNH2, TsN3, EtOH
O
O
O
rt, 10 min to 4 h
N2
8
9
21 examples in 63-98%
Ar
Ar
Ar
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Abstract
A highly efficient synthesis of -diazoketone was achieved by simply stirring the mixture of 1,3-
diketone, TsN3 and MeNH2 in EtOH. It was a tandem reaction including a novel primary amine-
catalyzed Regitz diazo-transfer of 1,3-diketone and a novel primary amine-mediated C−C bond
cleavage of 2-diazo-1,3-diketone.
-Diazoketones 11,2 are important precursors of carbenes, carbenoids or 1,3-dipoles in
cyclopropanations, rearrangements, cycloadditions and insertions. They are also versatile substrates for
the synthesis of the complicated diazo compounds by electrophilic substitutions or couplings. As shown
in Scheme 1, the methods for their syntheses are limited to a narrow range in literature: (a) Arndt-Eistert
synthesis;2,3 (b) decomposition/oxidation of hydrazones;2,4 (c) fragmentation of triazenes;2,5 (d) C−C
bond cleavage of 1,3-diketones.2,6 The use of method-(a) is generally impeded by using the explosive
and toxic diazomethane. Method-(d) is one of the most often used diazomethane-free methods, but
structurally special 1,3-diketone is required (R = H or CF3).
Scheme 1. The common methods for the synthesis of 1.
O
O
NNHR
(a)
NHN=NR
Ar
Ar
(d)
O
O
O
+
Ar
O
N2
+
X
CH2N2
TsN3
Ar
Ar
R
1
X = Cl, OR, OH
R = H, CF3
-Diazoketone
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Recently, we found that when the solution of 1,3-diphenylpropane-1,3-dione (2a), benzylamine (3a)
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2
and TsN3 in DMF was stirred at room temperature for 25 min, the corresponding 2-diazo-1-
phenylethanone1a), benzamide (4a) and TsNH2 were produced in excellent yields (Scheme 2). This
result clearly indicated that both the diazotization of C2 and the C−C bond cleavage of 2a were
achieved in this process. It also implied that a highly efficient method for the synthesis of -
diazoketones 1 may be developed under mild conditions.
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Scheme 2. Diazotization of C2 and C−C bond cleavage of 2a.
BnNH2 (3a), TsN3
DMF, rt, 25 min
O
O
O
O
+
Ph
+
TsNH2
93%
N2
Ph
1a, 96%
NHBn
Ph
Ph
2a
4a, 95%
By carefully monitoring the above process, 2-diazo-1,3-diphenylpropane-1,3-dione (5a) was
separated as an intermediate. As shown in Scheme 3, when pre-made 5a was used as a substrate to react
with 3a, the desired 1a was obtained in 96% yield. This result indicated that the reaction in Scheme 2, in
fact, is a tandem reaction including a Regitz diazo-transfer7 of 2a and a C−C bond cleavage of 5a,
wherein 3a functioned as a base catalyst in the first step and as a reactant in the last step.
Scheme 3. A mild C−C bond cleavage of 5a.
BnNH2 (3a)
DMF, rt, 25 min
O
O
O
O
N2
+
Ph
Ph
Ph
1a, 96%
Ph
NHBn
N2
5a
4a, 95%
Investigation showed that no primary amine-catalyzed Regitz diazo-transfer has been reported in
literature. Although several protocols were reported to synthesize -diazoketones 1 via C−C bond
8
cleavage of 2-diazo-1,3-diketones (5) catalyzed by Al2O3 or an alkali metal hydroxide9 (such as LiOH,
NaOH or KOH), the precursor 5 must be prepared separately by Regitz diazo-transfer of 1,3-diketones
(2). This situation arose from the fact that the Regitz diazo-transfer can not be efficiently catalyzed by
Al2O3 and the hydroxides. Thus, our protocol provides a novel tandem synthesis of -diazoketones 1
from the corresponding 1,3-diketones (2).
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In order to understand this tandem reaction, different amines were tested. As shown in Table 1, all
aliphatic primary amines 3a-3e gave excellent results (entries 1-5). But, the secondary amine 3f gave a
mixture (entry 6) and the tertiary amine 3g gave the intermediate 5a in 92% yield as a single product
(entry 7). PhNH2 (3h) was completely inert to this reaction (entry 8). The results in entries 9 and 10
indicated that the primary amines could not be replaced by Al2O3 and aq. NaOH in this tandem reaction.
Finally, the aqueous solution of MeNH2 (3d) was chosen for further tests in the view of atom economy.
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Table 1. Effects of 3a-3h on the yield of 1a.a
amines 3a-3h
TsN3, DMF, rt, time
O
O
O
N2
0-96%
Ph
Ph
Ph
1a
2a
Amines and Nu-H
time
1a (%)b
entry
BnNH2 (3a)
n-BuNH2 (3b)
25 min
25 min
96
95
1
2
CH2=CHCH2NH2 (3c)
MeNH2 in H2O (3d)c
MeNH2 in THF (3e)d
(n-Bu)2NH (3f)
(n-Bu)3N (3g)
25 min
25 min
25 min
2 h
2 h
2 h
96
94
93
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7
8
mixture
92 (5a)
NR
PhNH2 (3h)
Al2O3
3 h
NR
9
aq. NaOH (1.0 M)
3 h
23%
10
aThe solution of 2a (1 mmol), TsN3 (1 mmol) and 3a-3h (1.2 mmol) in DMF (1 mL) was
stirred for the given times. bIsolated yields. c40% aqueous solution. d2 M solution in THF.
As shown in Table 2, all tested solvents were suitable for this reaction (entries 1-9). It seemed that
the process could be accelerated by water-miscible solvents (entries 6-9). The highest yield of 1a was
obtained by using EtOH as a solvent (entry 9).
Table 2. Effects of the solvents on the yield of 1a.a
1a (%)b
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entry
solvent
DCE
DCM
Toluene
EtOAc
MeCN
DMF
THF
NMP
EtOH
time
2 h
2 h
1 h
1 h
50 min
25 min
25 min
25 min
25 min
1
2
3
4
5
6
7
8
9
88
92
94
90
94
91
93
98
aThe solution of 2a (1 mmol), TsN3 (1 mmol) and 3d (1.2 mmol) in a given
solvent (1 mL) was stirred for the given times. bIsolated yields.
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Finally, the reaction scope was tested under the optimized conditions. As shown in Scheme 4, the
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2
steric effects were clearly observed from two groups of products 1b-1d and 1e-1g, in which the ortho-
substituents (1b and 1e) led to lower yields and longer reaction times. However, the electronic effects of
the substituents on aromatic rings had slight influences (1n and 1o). The products 1r-1u were
synthesized smoothly by using the corresponding heteroaryl substrates 2r-2u. In a 5-gram scale
synthesis, 1a was obtained in 95% yield after purification by a flash chromatography.
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Scheme 4. A novel tandem synthesis of 1a-1u.
40% aq. MeNH2 (3d), TsN3
O
O
O
EtOH, rt, 10 min to 4 h
63-98%
N2
Ar
Ar
Ar
1a-1u
2a-2u
Me
Me
Me
Br
1a
1ba
90%, 2 h
1c
1d
1e
63%, 4 h
98%, 25 min
91%, 40 min
93%, 0.5 h
Br
Br
F
Cl
I
1f
1g
1h
1i
1jb
96%, 20 min
88%, 10 min 97%, 10 min
98%, 10 min 92%, 10 min
MeO
MeO
MeO
MeO
MeO
1m
91%, 2 h
tBu
NC
1k
1l
1n
1o
OMe
97%, 1.5 h
89%, 1.5 h
85%, 40 min 83%, 10 min
H
N
N
O
S
1pa
1q
1r
1s
1t
1u
87%, 1 h 98%, 1.5 h 86%, 0.5 h 89%, 0.5 h 83%, 0.5 h 90%, 0.5 h
a 50 oC was used for better yield and shorter time. b DMF was used as a
solvent for better solubility of the substrate.
Unfortunately, 1,3-diketones 2v-2z were unsuitable substrates for this method. As shown in Scheme
5, 2v was converted into 1a as a major product isolated from a mixture. Although 2w-2z were quickly
converted into the corresponding 2-diazo-1,3-diketons 5w-5z in high yields, no further C−C bond
cleavages occurred.
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Scheme 5. Products from the substrates 2v-2z.
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5
6
7
8
O
O
O
O
O
O
O
O
O
O
Ph
2w
2x
2y
2z
2v
9
40% aq. MeNH2 (3d), TsN3
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EtOH, rt, 30 min
O
O
O
O
O
O
N2
N2
N2
N2
Ph
N2
5w, 87%
1a, 72%
O
O
O
5z, 91%
5x, 93%
5y, 90%
Based on the above results, a possible mechanism was proposed. As shown in Figure 1, the
intramolecular hydrogen bonds played critical roles, by which the geminal amino-alcohol structures in
6-9 were stabilized and the formation of 1,2,3-triazole by dehydration of 6-9 was stopped.10 Meanwhile,
the cyclization of 7 to 8 via a proton transfer also played a critical role, by which the charge-separated
resonance structure 9 was formed to finally lead the formation of 1a by C−C bond cleavage.
O
O
O
tandem reaction
N2
Ar
Ar
Ar
Ar
1
2
TsN3
O
ArCONHR (4)
O
H
H
O
O
O
Ar
Ar
RN
Ar
N2
5
N
N
9
RNH2 (3)
H
O
H
H
H
O
H
O
H
O
O
Ar
RN
Ar
Ar
Ar
N
RN
Ar
R
Ar
N
N
N
N
N
8
N
7
6
Figure 1. A proposed mechanism for the tandem reaction.
So far, the problems occurred in 2v-2z can be well explained by the proposed mechanism. Since the
methylketone group(s) in 2v and 2w can be enolized to form its own intramolecular hydrogen bond, by
which the formation of the intermediate 6 was blocked. Clearly, 5x-5z were inert because their
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molecules contain a three-atom plane, by which formation of the intermediate 6 was also blocked.
Furthermore, two reactions were predicted and realized as shown in Scheme 6: (a) 1-diazo-3,3-
dimethyl-2-butanone (11) was obtained when 1,3-di(tert-butyl)-propane-1,3-dione (10) was used as a
substrate; (b) a mixture of 1a and 1k was obtained from 1-phenyl-3-(4-methoxylphenyl)-propane-1,3-
dione (12). Both reactions gave strong supports to our proposed mechanism and the later reaction
indicated that this method may be unsuitable for unasymmetric diketones.
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Scheme 6. The predicated and realized reactions.
O
O
O
standard conditions, rt, 1 h
80%
N2
10
11
standard conditions
rt, 30 min
O
O
O
O
+
N2
N2
Ph
MeO-4-H4C6
Ph
C6H4-4-OMe
12
1a, 34%
1k, 63%
In conclusion, a novel synthesis of -diazoketones was achieved by simply stirring the mixture of
1,3-diketone, TsN3 and MeNH2 in EtOH. It was a tandem reaction including a novel primary amine-
catalyzed Regitz diazo-transfer of 1,3-diketone and a novel primary amine-mediated C−C bond
cleavage of 2-diazo-1,3-diketone. The method may have broad implications in organic synthesis due to
its high efficiency and convenience.
Experimental Section
All spectra of 1H (300 MHz) and 13C NMR (75 MHz) were recorded in CDCl3 and TMS was used
as an internal reference. All substrates 1,3-diketone 2a-2u, 10 and 12 are known compounds and some
of them were purchased directly. All of them can be prepared exactly by known procedures (see SI).
A typical procedure for preparation of 2-diazo-1-phenylethanone (1a). To a solution of 1,3-
diphenylpropane-1,3-dione (2a, 224 mg, 1 mmol) and TsN3 (197 mg, 1 mmol) in EtOH (1 mL) was
added MeNH2 (3d, 40% aqueous solution, 93 mg, 1.2 mmol). After the mixture was stirred at room
temperature for 25 min (monitored by TLC), the solvent was removed. The residue was purified by a
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o
flash chromatography [silica gel, 10% EtOAc in petroleum ether (60–90 C)] to give 143 mg (98%) of
product 1a as a yellow solid, mp 39−41 oC (lit.11a 38−40 oC). 1H NMR7.78−7.75 (m, 2H), 7.57−7.51
(m, 1H), 7.47−7.41 (m, 2H), 5.92 (s, 1H); 13C NMR 186.3, 136.6, 132.6, 128.6 (2C), 126.6 (2C), 54.1.
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9
The products 1b−1u and 11 were prepared by the similar procedure.
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1-(2-Methylphenyl)-2-diazoethanone (1b). Yellowish oil11b (144 mg, 90%), 1H NMR  7.38−7.31
(m, 2H), 7.26−7.18 (m, 2H), 5.58 (s, 1H), 2.49 (m, 3H); 13C NMR  190.0, 137.4, 136.6, 131.5, 130.7,
127.0, 125.6, 56.3, 20.1.
o
1-(3-Methylphenyl)-2-diazoethanone (1c). Yellow solid (145 mg, 91%), mp 59−61 C (lit.11c
64.2−64.8 oC). 1H NMR  7.59 (s, 1H), 7.53 (d, J = 6.5 Hz, 1H), 7.34−7.29 (m, 2H), 5.90 (s, 1H), 2.40
(s, 3H); 13C NMR  186.5, 138.5, 136.7, 133.4, 128.4, 127.2, 123.8, 54.0, 21.3.
o
1-(4-Methylphenyl)-2-diazoethanone (1d). Yellow solid (149 mg, 93%), mp 47−49 C (lit.11d
48−51 oC). 1H NMR  7.66 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 7.9 Hz, 2H), 5.89 (s, 1H), 2.40 (s, 3H); 13C
NMR  186.0, 143.4, 134.0, 129.2 (2C), 126.7 (2C), 53.7, 21.5.
1-(2-Bromophenyl)-2-diazoethanone (1e). Brown oil11e (142 mg, 63%), 1H NMR  7.62−7.59 (m,
1H), 7.45 (d, J = 7.2 Hz, 1H), 7.39−7.27 (m, 2H), 5.71 (s, 1H); 13C NMR  187.8, 139.5, 133.7, 131.7,
129.0, 127.5, 119.2, 57.4.
o
1-(3-Bromophenyl)-2-diazoethanone (1f). Yellow solid (216 mg, 96%), mp 72−74 C (lit.11c
73.5−75 oC). 1H NMR  7.90 (s, 1H), 7.67 (d, J = 8.3 Hz, 2H), 7.32 (t, J = 7.9 Hz, 1H), 5.89 (s, 1H); 13C
NMR  184.6, 138.4, 135.5, 130.2, 129.8, 125.2, 122.9, 54.6.
o
1-(4-Bromophenyl)-2-diazoethanone (1g). Yellow solid (198 mg, 88%), mp 124−126 C (lit.11f
13
130−133 oC). 1H NMR  7.65−7.56 (m, 4H), 5.89 (s, 1H); C NMR  185.0, 135.3, 131.9 (2C), 128.2
(2C), 127.6, 54.3.
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1-(4-Fluorophenyl)-2-diazoethanone (1h). Yellow solid (159 mg, 97%), mp 69−71 oC (lit.11g 72.5
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2
3
13
oC). 1H NMR  7.81−7.76 (m, 2H), 7.12 (t, J = 8.6 Hz, 2H), 5.88 (s, 1H); C NMR  184.8, 165.5 (d,
4
5
6
JCF = 252.4 Hz), 132.9 (d, JCF = 2.2 Hz), 129.1 (d, JCF = 8.6 Hz, 2C), 115.7 (d, JCF = 21.5 Hz, 2C), 54.1.
7
8
9
o
1-(4-Chlorophenyl)-2-diazoethanone (1i). Yellow solid (177 mg, 98%), mp 113−115 C (lit.11d
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1
114−115 oC). H NMR  7.70 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 5.89 (s, 1H); 13C NMR 
184.9, 139.0, 134.9, 128.9 (2C), 128.0 (2C), 54.3.
(4-Iodophenyl)-2-diazoethanone (1j). Yellow solid (250 mg, 92%), mp 110−112 oC (lit.11h 114 oC).
1H NMR  7.80 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H), 5.87 (s, 1H); C NMR  185.3, 137.9
13
(2C), 135.9, 128.1 (2C), 100.1, 54.3.
1-(4-Methoxyphenyl)-2-diazoethanone (1k). Yellow solid (171 mg, 97%), mp 84−86 C (lit.11i
o
85−86 oC). 1H NMR  7.73 (d, J = 8.9 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 5.86 (s, 1H), 3.85 (s, 3H); 13C
NMR  185.1, 163.2, 129.5, 128.7 (2C), 113.8 (2C), 55.4, 53.4.
1-(3,4-Dimethoxyphenyl)-2-diazoethanone (1l). Yellow solid (184 mg, 89%), mp 73−75 oC (lit.11j
77−78 oC). 1H NMR  7.44 (s, 1H), 7.27 (d, J = 7.9 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 5.89 (s, 1H), 3.93
(s, 6H); 13C NMR  185.1, 152.9, 149.1, 129.7, 120.2, 110.1, 109.4, 56.0, 55.9, 53.5.
1-(3,4,5-Trimethoxyphenyl)-2-diazoethanone (1m). Yellow solid (215 mg, 91%), mp 108−110
oC (lit.11k 101 oC). H NMR  7.01 (s, 2H), 5.90 (s, 1H), 3.90 (s, 9H); C NMR  185.3, 153.1 (2C),
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142.1, 132.0, 104.1 (2C), 60.9, 56.3 (2C), 54.0.
1-[4-(tert-butyl)phenyl]-2-diazoethanone (1n). Yellow solid (172 mg, 85%), mp 79−81 oC (lit.11g
82.5−83.5 oC). 1H NMR  7.70 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 5.89 (s, 1H), 1.33 (s, 9H);
13C NMR  186.0, 156.4, 134.0, 126.6 (2C), 125.5 (2C), 53.7, 35.0, 31.1 (3C).
1-(4-Cyanophenyl)-2-diazoethanone (1o). Yellow solid (142 mg, 83%), mp 146−148 C (lit.11g
o
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142−144 C). H NMR  7.87 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 7.9 Hz, 2H), 5.99 (s, 1H); C NMR 
184.2, 139.8, 132.4 (2C), 127.2 (2C), 117.8, 115.9, 55.3.
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1-(Naphthalen-1-yl)-2-diazoethanone (1p). Yellow solid (171 mg, 87%), mp 48−50 C (lit.11l
52−53 oC). 1H NMR  8.49 (d, J = 7.6 Hz, 1H), 7.95−7.92 (m, 2H), 7.62−7.42 (m, 4H), 5.70 (s, 1H); 13C
NMR  189.5, 135.5, 133.8, 131.8, 129.8, 128.3, 127.5, 126.5, 125.8, 125.4, 124.4, 57.1.
o
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1-(Naphthalen-2-yl)-2-diazoethanone (1q). Yellow solid (192 mg, 98%), mp 79−81 C (lit.11m
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81−83 C). H NMR  8.24 (s, 1H), 7.93−7.81 (m, 4H), 7.60−7.50 (m, 2H), 6.03 (s, 1H); C NMR 
186.1, 135.4, 133.9, 132.5, 129.3, 128.5, 128.1, 127.7, 127.5, 126.8, 123.0, 54.3.
1-(Pyridin-2-yl)-2-diazoethanone (1r). Brown oil11n (126 mg, 86%), H NMR  8.59−8.57 (m,
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1H), 8.09 (d, J = 7.9 Hz, 1H), 7.87−7.82 (m, 1H), 7.48−7.44 (m, 1H), 6.74 (s, 1H); C NMR  186.0,
152.3, 148.7, 137.0, 127.1, 120.7, 53.4.
o
1-(Pyrrol-2-yl)-2-diazoethanone (1s). Yellow solid (120 mg, 89%), mp 149−151 C. IR v 3255,
3110, 2116, 1584, 1537, 1415, 1362 cm-1; H NMR  10.2 (s, 1H), 7.02−7.01 (m, 1H), 6.64−6.61 (m,
1
1H), 6.24−6.21 (m, 1H), 5.63 (s, 1H); 13C NMR  176.8, 130.3, 124.0, 112.5, 110.4, 52.9. HRMS (ESI-
TOF) (m/z): calcd for C6H5N3O, [M-H]- 134.0360; found: 134.0359.
1-(Furan-2-yl)-2-diazoethanone (1t). Brown oil11h (113 mg, 83%), 1H NMR  7.50−7.49 (m, 1H),
7.14 (d, J = 3.8 Hz, 1H), 6.55−6.54 (m, 1H), 5.88 (s, 1H); 13C NMR  175.4, 151.6, 145.1, 114.4, 112.5,
54.0.
1-(Thiophen-2-yl)-2-diazoethanone (1u). Yellow solid (137 mg, 90%), mp 60−62 oC (lit.11o 61−64
oC). H NMR  7.60−7.58 (m, 1H), 7.52−7.51 (m, 1H), 7.12−7.09 (m, 1H), 5.84 (s, 1H); C NMR 
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178.8, 142.5, 132.1, 129.0, 128.0, 54.2.
1-Diazo-3,3-dimethyl-2-butanone (11). Yellow oil11p (101 mg, 80%), H NMR  5.43 (s, 1H),
1.15 (s, 9H); 13C NMR  201.2, 51.7, 42.5, 27.0.
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Supporting Information Available：1H and C NMR spectra for all products 1a-1u and 11.
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This material is available free of charge via the Internet at http://pubs.acs.org.
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Acknowledgment：This work was supported by NNSFC (Nos. 21472107 and 21372142).
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