Synthesis of α-aminocarbonyl compounds via hetero dielsalder reaction

Article abstract of DOI:10.1246/cl.170970

A synthetic route to α-aminoketone derivatives via a hetero DielsAlder reaction is described. Diacylhydrazine was oxidized by tert-butyl hypochlorite in the presence of pyridine. After evaporation, the hetero DielsAlder reaction with diene was carried out without isolation of the azodicarbonyl compound. Quantitative hetero DielsAlder reaction was possible with 1 equivalent of diene when Hf(OTf)₄ or AgOTf was used as the catalyst. The NN bond of the product was cleaved by SmI₂-reduction in the presence of tert-BuOH in THF. Further, ozonolysis of the C=C double bond afforded the α-aminoketone derivative in excellent yield.

Full text of DOI:10.1246/cl.170970

CL-170970
Received: October 16, 2017 | Accepted: November 4, 2017 | Web Released: December 22, 2017
Synthesis of α-Aminocarbonyl Compounds via Hetero Diels-Alder Reaction
Masayoshi Sakurai,1 Nobuhiro Kihara,*1 Nobuhiro Watanabe,2 Yoshihiro Ikari,2 and Toshikazu Takata3
1Department of Chemistry, Faculty of Science, Kanagawa University, 2946 Tsuchiya, Hiratsuka, Kanagawa 259-1293, Japan
2Department of Applied Chemistry, Faculty of Engineering, Osaka Prefecture University,
1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan
3Department of Polymer Chemistry, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8550, Japan
E-mail: kihara@kanagawa-u.ac.jp
A synthetic route to α-aminoketone derivatives via a hetero
Diels-Alder reaction is described. Diacylhydrazine was oxidized
by tert-butyl hypochlorite in the presence of pyridine. After
evaporation, the hetero Diels-Alder reaction with diene was
carried out without isolation of the azodicarbonyl compound.
Quantitative hetero Diels-Alder reaction was possible with
1 equivalent of diene when Hf(OTf)4 or AgOTf was used as the
catalyst. The N-N bond of the product was cleaved by SmI2-
reduction in the presence of tert-BuOH in THF. Further,
ozonolysis of the C=C double bond afforded the α-aminoketone
derivative in excellent yield.
unstable, diacylhydrazine 2a was used as its precursor. Selective
oxidation of 2a in the presence of 3 and subsequent HDA
reaction of 1a with 3 were investigated. However, 3 was more
easily oxidized than 2a regardless of the oxidant, and no HDA
product 4a was obtained (eq 1).
O
H
[O]
N
Ar
+
oxidation of 3
Ar
N
H
O
3
O
N
O
N
2a
Ar
Ar
ð1Þ
O
N
Ar
tBu
Ar =
Ar
N
O
1a
4a
Keywords: α-Aminocarbonyl compound
Hetero Diels–Alder reaction
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To avoid the oxidation of diene, the oxidation of 2a was
Azodicarbonyl compound
carried out before the addition of 3. The formation of
azodicarbonyl compound was easily confirmed by the change
from white suspension to orange-red solution. Since 1a, which
was produced by the oxidation of 2a, decomposed during the
purification procedure, a volatile oxidant was used for the
oxidation of 2a, and 1a was isolated simply by evaporation. As
a volatile oxidant, tert-butyl hypochlorite was found to be the
most effective.3 For quantitative oxidation, the use of excess
hypochlorite was necessary. Addition of a catalytic amount of
pyridine greatly accelerated the oxidation of 2a. Thus, 2a was
α-Aminocarbonyl compounds are important synthetic inter-
mediates, which have been used as building blocks for the
synthesis of nitrogen-containing compounds.1 While the oxida-
tion of α-aminoalcohol derivatives has been widely used to
obtain α-aminocarbonyl compounds,1a-1k aldol reaction using an
azodicarbonyl compound as the electrophile has also attracted
much attention1l-1n because of its potential application in
asymmetric synthesis. In the latter process, however, one of the
two nitrogen atoms in the electrophile is discarded. We noted
that hetero Diels-Alder (HDA) reaction2 can be used instead
of the aldol reaction for the preparation of α-aminocarbonyl
compounds. Thus, reduction of the N-N bond in the HDA
product, followed by ozonolysis, can be a straightforward and
atom-economical method for the synthesis of α-aminocarbonyl
compounds from azodicarbonyls (Scheme 1), although such an
approach for α-aminocarbonyl compounds has not been reported.
First, the HDA reaction of azodicarbonyl 1a with 2,3-
dimethylbutadiene 3 was investigated. Since 1a is thermally
t
treated with 3 equiv of BuOCl and 12 mol % of pyridine in
dichloromethane at 0 °C. After evaporation of volatiles, the
residue was dissolved in dichloromethane, and 3 was added to
initiate the HDA reaction.
When an excess of 3 was used, the HDA product 4a was
obtained in good yield. However, from the viewpoint of atom
efficiency, the HDA reaction with 1 equiv of 3 was investigated.
The results are summarized in Table 1. In the absence of a
catalyst, the yield was moderate even at elevated temperatures.
Thus, the reaction was carried out in the presence of a Lewis
acid at 0 °C. It was found that Hf(OTf)4 was the most effective
Lewis acid, with which 4a was obtained quantitatively. The
amount of Hf(OTf)4 could be reduced to 18 mol % without loss
of the yield. AgOTf was also an effective catalyst to obtain 4a
Oxidation route:
OH
O
[O]
NHCOR'
NHCOR'
R
R
t
almost quantitatively. Further, the amount of BuOCl could be
Aldol route:
1) base
reduced to 2 equiv without loss of the yield. Due to less
availability of Hf(OTf)4, AgOTf was used as the Lewis acid in
the following experiments.
The HDA reaction was carried out using various diacyl-
hydrazines. The results are summarized in Table 2. When a
substituted benzoyl group was used as the acyl group, the yield
of the HDA product strongly depended on the substituent on
the benzene ring. The electron-withdrawing ester group in 2c
O
O
COR'
O
[H]
N
COR'
NHCOR'
R
2) R'CON=NCOR'
R
N
R
H
This work:
COR'
R
O
1) HDA
N
N
+
NHCOR'
2) [H]
3) O3
R
R'OC
R
t
inhibited the oxidation with BuOCl, and no HDA product was
Scheme 1. Approaches to α-aminocarbonyl compounds.
obtained. Halogen-substituted HDA products were obtained in
144 | Chem. Lett. 2018, 47, 144–147 | doi:10.1246/cl.170970
© 2018 The Chemical Society of Japan

Table 1. HDA reaction with a stoichiometric amount of diene in
the presence of Lewis acida
Table 2. HDA reaction with 3 using various diacylhydazinesa
R1
N N
R2
H
1) 3 equiv tBuOCl, 14 mol% py
R1
N
O
O O
N
R2
N
Ar
Ar
Ar
Lewis acid
0 oC, CH2Cl2
H
2) 1 equiv 3, 40 mol% of AgOTf
Ar
N
+
N N
2
O
1a
3
4
4a
Yield
/%
Yield
/%
2
R1, R2
R1 = R2 =
2
i
R1, R2
tBu
Ar =
R1 = R2 =
b
Time
/h
Yieldb
/%
Lewis acid (mol %)
CH3
O
none
none
17
6
16
17
3
3
4
4
3
1
1
2
1
1
1
0
69c
30
29
25
9
17
23
14
100
100
23
95
97d
79e
95
3
CH3
O
(51)b
CH3
Ga(OTf)3 (41)
In(OTf)3 (41)
Sc(OTf)3 (40)
Y(OTf)3 (40)
La(OTf)3 (41)
Yb(OTf)3 (40)
Cp2Zr(OTf)2 (40)
Hf(OTf)4 (39)
Hf(OTf)4 (18)
NbCl5 (43)
R1 = R2 =
R1 = R2 =
c
j
O
COOMe
0
0
O
R1 = R2 =
R1 = R2 =
d
e
k
l
O
F
86
88
98
94
OtBu
O
O
R1 = R2 =
R1 = R2 =
AgOTf (40)
AgOTf (40)
AgOTf (40)
O
O
Cl
aAfter the treatment of 2a with 3 equiv of tBuOCl and 12 mol %
of pyridine at 0 °C for 1 h, the volatiles were evaporated before
the addition of dichloromethane, 1.0 equiv of 3, and Lewis acid.
R1 = R2 =
O
f
m
n
OtBu
R1 =
bIsolated yield. In a sealed tube at 90 °C. 2 equiv of BuOCl
c
d
t
R2 =
e
t
OMe
was used. 1 equiv of BuOCl was used.
0
96c
O
O
excellent yields even if an electronegative fluorine atom was
introduced. The effect of the electron-donating methoxy group
was complicated. When a MeO group was introduced at the
p-position, quantitative oxidation of 2f occurred, although no
HDA product was obtained, probably because the p-MeO group
increased the electron density of 1f to suppress the HDA
reaction. m-MeO derivative 2g gave the HDA product 4g in
good yield. When o-MeO derivative 2h was oxidized, the
product 1h was fairly unstable, and decomposed immediately
with releasing N2, and no HDA product was obtained. When
2 had aliphatic acyl groups (2i and 2j), the oxidized product 1
was extremely unstable and decomposed immediately. Thus,
oxidation of 2i was carried out for 5 min before the addition
of 3 to furnish HDA product 4i in 51% yield. When 2 had
urethane-type acyl groups (2k, 2l, and 2m), the HDA product
was obtained almost quantitatively. Under the same reaction
R1 = R2 =
R1 = R2 =
g
O
O
OMe
S
97
0
0
O
CH3
h
R1 = R2 =
MeO
O
aAfter the treatment of 2 with 3 equiv of BuOCl and 12 mol %
of pyridine at 0 °C for 1 h, the volatiles were evaporated before
the addition of dichloromethane, 1.0 equiv of 3, and 40 mol %
of AgOTf. Oxidation was carried out for 5 min before HDA
reaction. Without pyridine.
t
b
c
t
conditions, sulfonyl hydrazine 2n was not oxidized by BuOCl.
was added to the system, 5k and 5l were obtained, although
the yields were low.
Reductive cleavage of the N-N bond of 4 was selectively
carried out using 3 equiv of SmI2 in the presence of 1.5 equiv
of tBuOH.4 The results are shown in Table 3. Diamide 5
was obtained almost quantitatively from benzoyl-type HDA
products, except for 4g, in which the electron-donating methoxy
group hindered the reduction of the N-N bond by SmI2. Because
of the high electron density of the urethane group, the reduction
of 4k and 4l did not occur under the standard reaction
conditions. When hexamethylphosphoric triamide (HMPA)
Ozonolysis of the C=C double bond was then examined.
α-Aminocarbonyl compound 6 was obtained in excellent yield
when ozonolysis was carried out at ¹98 °C, although a by-
product with an undefined structure was observed when the
reaction was carried out at ¹80 °C. The results are summarized
in Table 4. When 6m was subjected to the ozonolysis, two
α-aminocarbonyl compounds were simultaneously obtained in
excellent yields.
Chem. Lett. 2018, 47, 144–147 | doi:10.1246/cl.170970
© 2018 The Chemical Society of Japan | 145

a
Table 3. Cleavage of N-N bond of HDA product with SmI2
R1
R2
R1
N
40 mol% AgOTf
0 °C, CH2Cl2
R1
N N
R2
R1
HN NH
R2
N
N
N
R2
+
3.0 equiv SmI2, 1.5 equiv tBuOH
THF
1
8
9
a : 98 %
b : 91 %
m : 70 %
4
5
4
Temperature/°C
Time/h
Yield/%
R1
HN
R2
NH
a
b
d
e
g
i
k
l
m
r.t.
50
r.t.
r.t.
r.t.
3
3
2
2
2
95
92
90
90
52
47
8b
15b
76
t
3.0 equiv SmI2, 1.5 equiv BuOH
THF
10
a : 80 %
b : 97%
m : 90 %
50
1
reflux
reflux
r.t.
15
18
2
O
H
O3 then Me2S
R1
N
aReactions were carried out in THF with 3.0 equiv of SmI2 and
1.5 equiv of BuOH. In the presence of 10 equiv of HMPA.
N
R2
H
CH2Cl2/ MeOH = 4 /1
-98 °C
t
b
O
11
a : 96 %
b : 73 %
m : 88 %
Scheme 2. Synthesis of bis(α-aminocarbonyl) compounds.
Table 4. Ozonolysis of C=C bonda
R1
HN NH
R2
When hexa-2,4-diene was used as the diene, alanine
derivative 7 was obtained from 2a using the standard procedure
(eq 2). Since hexa-2,4-diene is less reactive than 3, the yield of
HDA product was 50% when 1 equiv of diene was used. The
yield of HDA product increased to 83% when 3 equiv of diene
was used at 60 °C in 1,2-dichloroethane.
O
O3 then Me2S
RHN
CH2Cl2/ MeOH = 4 / 1
-98 °C
6
5
5
a
O3/equiv
14.6
Product
Yield/%
80
tBu
O
O
O
H
N
1) tBuOCl, py
Ar
N
H
CHO
2a
CH3
2) hexa-2,4-diene, AgOTf
3) SmI2, tBuOH, 46%
4) O3 then Me2S, 85%
ð2Þ
O
7
CH3
6.4
b
H
N
80
96
90
When exo-olefinic diene 8 was used for the HDA reaction,
bifunctional α-aminoketone 11 was obtained easily (Scheme 2).
When 1m was used as the azodicarbonyl compound, an
asymmetrically protected 1,8-diamino-2,6-diketone, which is
difficult to prepare quantitatively by other methods, was
obtained in good yield.
In summary, we have demonstrated a novel atom-econom-
ical approach for the synthesis of α-aminocarbonyl compounds
using diacylhydrazine as the nitrogen source. Since the hetero
Diels-Alder reaction of the azodicarbonyl compound proceeds
quantitatively with 1 equiv of diene in the presence of an
appropriate Lewis acid, this system is also expected to be
extended to Diels-Alder polymerization.
H3C
CH3
O
F
8.8
8.2
d
e
O
H
N
CH3
O
Cl
O
H
N
CH3
CH3
O
8.2
40
g
i
O
H
N
90
62
99
91
MeO
O
O
H
Me
N
Me
O
Supporting Information is available on http://dx.doi.org/
10.1246/cl.170970.
8.2
m
O
H
N
CH3
CH3
O
References and Notes
O
H
1
Selected recent examples: a) A. Vasseur, R. Membrat, D.
Gatineau, A. Tenaglia, D. Nuel, L. Giordano, ChemCatChem
2017, 9, 728. b) A. H. Khan, J. S. Chen, Org. Lett. 2015, 17,
3718. c) R. A. Rodriguez, D. B. Steed, Y. Kawamata, S. Su,
P. A. Smith, T. C. Steed, F. E. Romesberg, P. S. Baran, J. Am.
tBuO
N
O
aAfter the treatment of 5 with ozone in CH2Cl2-MeOH (4/1,
v/v) at ¹98 °C, dimethyl sulfide was added.
146 | Chem. Lett. 2018, 47, 144–147 | doi:10.1246/cl.170970
© 2018 The Chemical Society of Japan

Chem. Soc. 2014, 136, 15403. d) N. Armanino, M. Lafrance,
E. M. Carreira, Org. Lett. 2014, 16, 572. e) K. Chung, S. M.
Banik, A. G. De Crisci, D. M. Pearson, T. R. Blake, J. V.
Olsson, A. J. Ingram, R. N. Zare, R. M. Waymouth, J. Am.
Chem. Soc. 2013, 135, 7593. f) J. Bredihhina, P. Villo, K.
Andersons, L. Toom, L. Vares, J. Org. Chem. 2013, 78,
2379. g) F. Liu, F. Li, A. Ma, E. Dobrovetsky, A. Dong,
C. Gao, I. Korboukh, J. Liu, D. Smil, P. J. Brown,
S. V. Frye, C. H. Arrowsmith, M. Schapira, M. Vedadi, J.
Jin, J. Med. Chem. 2013, 56, 2110. h) M. Ettaoussi, A.
Sabaouni, B. Pérès, E. Landagaray, O. Nosjean, J. A. Boutin,
D.-H. Caignard, P. Delagrange, P. Berthelot, S. Yous,
ChemMedChem 2013, 8, 1830. i) D. N. Mai, B. R. Rosen,
J. P. Wolfe, Org. Lett. 2011, 13, 2932. j) A. Bøgevig, I. M.
Pastor, H. Adolfsson, Chem.®Eur. J. 2004, 10, 294.
k) S. Campestrini, F. D. Furia, G. Modena, J. Org. Chem.
1990, 55, 3658. l) J.-P. Genet, C. Greck, D. Lavergne, in
Modern Amination Methods, ed. by A. Ricci, Wiley-VCH,
Weinheim, 2000, Chap. 3. doi:10.1002/9783527613182.
ch3. m) T. Vilaivan, W. Bhanthumnavin, Molecules 2010,
15, 917. n) N. Kumaragurubaran, K. Juhl, W. Zhuang, A.
Bøgevig, K. A. Jørgensen, J. Am. Chem. Soc. 2002, 124,
6254.
S. M. Weinreb, in Comprehensive Organic Synthesis, ed. by
L. A. Paquette, Pargamon, Oxford, 1991, Vol. 5, pp. 426-
430. doi:10.1016/B978-0-08-052349-1.00129-3.
a) C. J. Moody, Adv. Heterocycl. Chem. 1982, 30, 1. b) N.
Rabjohn, Org. Synth. Coll. Vol. 1955, 3, 375; See also: J. C.
Kawev, Org. Synth. Coll. Vol. 1963, 4, 411.
a) M. J. Burk, J. E. Feaster, J. Am. Chem. Soc. 1992, 114,
6266. b) J. Souppe, L. Danon, J. L. Namy, H. B. Kagan,
J. Organomet. Chem. 1983, 250, 227.
2
3
4
Chem. Lett. 2018, 47, 144–147 | doi:10.1246/cl.170970
© 2018 The Chemical Society of Japan | 147