Synthesis, crystal structure, and bioactivity of N-dichloroacetyl diazabicyclo compounds

Article abstract of DOI:10.1515/hc-2012-0174

A short and efficient route to synthesis of a series of N -dichloroacetyl diazabicyclo derivatives has been developed. The compounds were obtained by cycloaddition of levulinic acid or ester with diamine, followed by acylation with dichloroacetyl chloride. All products were characterized by IR, ¹H NMR, ¹³C NMR, MS, and elemental analysis. The single crystal of compound 4c was determined by X-ray crystallographic analysis. All compounds were tested for their herbicide safeners activity of protecting maize from injury with acetochlor.

Full text of DOI:10.1515/hc-2012-0174

ꢁ
ꢁꢁꢂ
DOI 10.1515/hc-2012-0174ꢀ
ꢀHeterocycl. Commun. 2013; 19(1): 75–78
Fei Ye, Guan-Yu Li, Li Ding, Ying Fu* and Zhi-Yong Xing
Synthesis, crystal structure, and bioactivity
of N-dichloroacetyl diazabicyclo compounds
Abstract: A short and efficient route to synthesis of a series
A variety of methods are available for synthesis of
of N-dichloroacetyl diazabicyclo derivatives has been substituted diazabicyclo derivatives [8, 9]. However,
developed. The compounds were obtained by cycloaddi- all these techniques have their own inherent disadvan-
tion of levulinic acid or ester with diamine, followed by tages, for example, the critical reaction conditions or
acylation with dichloroacetyl chloride. All products were the use of expensive reagents. Here, we developed a
1
13
characterized by IR, H NMR, C NMR, MS, and elemental convenient and efficient synthetic route to a series of
analysis. The single crystal of compound 4c was deter- diazabicyclic compounds 3a – fand their substituted
mined by X-ray crystallographic analysis. All compounds derivatives 4a – .f
were tested for their herbicide safeners activity of protect-
ing maize from injury with acetochlor.
Results and discussion
As can be seen from Scheme 1, product 3 was obtained
by cycloaddition of dicarbonyl compound 1 with diamine
Keywords: bioactivity; crystal structure; diazabicyclo;
N-dichloroacetyl; synthesis.
2
. The reaction proceeded well in ethanol with yields of
*
Corresponding author: Ying Fu, Department of Applied Chemistry,
4
5–85%. The yields were lower with n=3. Compound 4
Northeast Agricultural University, Harbin 150030, China,
e-mail: fuying@neau.edu.cn
was obtained in 50–87% yields by acylation of diazabi-
Fei Ye, Guan-Yu Li, Li Ding and Zhi-Yong Xing: Department of Applied cyclo compound 3 with dichloroacetyl chloride in toluene
Chemistry, Northeast Agricultural University, Harbin 150030, China
or CHCl . The structures of compounds 3 and 4 were con-
3
firmed by elemental analysis results and spectroscopic
1
techniques. In particular, H NMR spectra of compounds
Introduction
4a–f show a characteristic singlet for Cl CH- around δ 6.05.
2
1
3
In the C NMR spectra of the synthesized compounds
Diazabicyclic compounds are important synthons in 3 and 4, the signals for amide carbon atoms are observed
organic synthesis and biologically active materials [1–6] at δ 170 and δ 160.
including antibacterial agents, antibiotics, anti-cancer
Finally, the structure of 4c was solved by using X-ray
agents, and drug antagonists. In recent years, dichloro- crystallographic analysis. The single crystal of 4c was
acetyl diazabicyclic derivatives have become known as obtained by slow evaporation of ethanolic solution. The
herbicide safeners protecting crops from injury by chlo- molecular structure and the packing view of 4c are shown
rine acetamide herbicides, sulfonylurea herbicides, and in Figures 1 and 2, respectively. All bond lengths and
imidazolinone herbicides [7].
angles are in the expected ranges.
O
OEt
Me
HN
R1
O
Me
N
R1
O
O
NH2
Cl
2
HC
Cl
(
CH )
(CH )
2 n
R1
2 n
(CH2)n
N
Cl HC
N
NH2
2
O
O
Me
1
2
3a-f
4a-f
1
3d, 4d: n = 2; R1=
3e, 4e: n = 3; R1 = -(CH ) -
3
a, 4a: n = 2; R = -(CH ) -
2 2
3
3
b, 4b: n = 2; R1
=
2
3
1
3f, 4f: n = 3; R1 = -(CH2)2-
c, 4c: n = 2; R = -(CH ) -
2
4
Scheme 1
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7
6ꢀꢁꢁꢁꢂꢀF. Ye etꢃal.: N-Dichloroacetyl diazabicyclo compounds
Conclusion
C(3)
O(2)
C(2)
C(5)
A facile and efficient route for the synthesis of a series of
dichloroacetyl derivative 4 via cycloaddition and acylation
has been developed. The biological evaluation showed
that all compounds could protect maize from injury with
acetochlor to some extent.
CI(1)
C(10)
C(4)
C(11)
N(1)
C(9)
N(2)
C(6)
C(1)
O(1)
CI(2)
Experimental
C(8)
C(7)
The infrared (IR) spectra were taken on a KJ-IN-27G infrared spectro-
1
13
photometer using KBr pellets. The H NMR and C NMR spectra were
recorded on a Bruker AVANVE 300ꢀMHz nuclear magnetic resonance
spectrometer at 300ꢀMHz and 75 MHz, respectively. Mass spectra were
recorded on a Waters Xevo TQ mass spectrometer. Elemental analy-
sis was performed on a FLASH EA1112 elemental analyzer. Melting
points were determined on a Beijng Taike melting point apparatus
Figure 1ꢀStructure of 4c showing 30% probability ellipsoids.
(X-4) and uncorrected. All reagents were of analytical grade.
General procedure for the preparation
of compound 3
Ethyl levulinate (or ethyl 4-acetylbutyrate, 0.07 mol, 10.1 g) and di-
amine (0.25 mol) were mixed with 20ꢀmL EtOH. The mixture was
heated to reflux for 8 h, then concentrated under reduced pressure,
and the residue was subjected to column chromatography on silica
gel eluting with EtOAc and light petroleum (1:15). Analytically pure
product was obtained by crystallization from a mixture of ethanol
and hexanes.
5
-Methyl-8-oxa-1,4-diazabicyclo[3.3.0]octane (3a)ꢁOil; yield
-
1
1
7
0%; IR: ν 3250 (N-H), 2972–2874 (C-H), 1685ꢀcm (C O); H NMR
(
CDCl ): δ 3.68 (m, 1H, N-H), 3.25, 2.79–3.01 (2m, 4H, N-CH -CH -N),
3
2
2
Figure 2ꢀPacking view of 4c.
1
3
1
.78–2.50 (m, 4H, C-CH -CH -C), 1.39 (s, 3H, CH ); C NMR (CDCl ):
2
2
3
3
δ 176.0, 84.0, 47.1, 41.6, 35.2, 34.0, 24.8. Anal. Calcd for C H N O: C,
7
12
2
59.96; H, 8.63; N, 19.99. Found: C, 59.88; H, 8.55; N, 20.10.
Compounds 4a–f were evaluated for their protection
of maize against injury with 15 mg/kg acetochlor. The 3a-Methyl-decahydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-1-one
-
1
results are given in Table 1. Among the compounds tested, (3b)ꢁOil; yield 67%; IR: ν 3303 (N-H), 2964–2864 (C-H), 1677ꢀcm
1
(
C O); H NMR (CDCl ): δ 3.90 (m, 1H, N-H), 3.10 (m, 1H, N-CH), 2.63
4e showed the best activity against injury with acetochlor.
3
(
m, 1H, N-CH), 1.95–2.33 (m, 4H, C-CH -CH -C), 1.57–1.89, 1.17–1.26 (2m,
2
2
1
3
8
H, (CH ) ), 1.55 (s, 3H, CH ); C NMR (CDCl ): δ 178.6, 83.0, 56.8, 55.8,
2
4
3
3
Table 1ꢁEffect of compounds 4a–f on maize growth indexes.
3
8.8, 33.1, 27.8, 27.3, 25.8, 23.6, 20.0. Anal. Calcd for C H N O: C, 67.99;
11 18 2
H, 9.34; N, 14.43. Found: C, 67.94; H, 9.22; N, 14.51.
Products Plant height Plant fresh Root length of Root fresh
of recovery
rate (%)
weight of
recovery
rate (%)
the recovery
rate (%)
weight of 7-Methyl-10-oxa-1,6-diazabicyclo[5.3.0]decane (3c)ꢁWhite solid;
-1
recovery yield: 85%; mp 121–122°C; IR: ν 3305 (N-H), 2904–2854 (C-H), 1658ꢀcm
1
rate (%) (C O); H NMR (CDCl ): δ 3.97 (m, 1H, N-H), 2.36–2.96 (m, 4H,
3
1
3
2
×N-CH ), 1.23–1.97 (m, 8H, 4×CH ), 1.30 (s, 3H, CH ); C NMR (CDCl ):
2
2
3
3
ꢂa
ꢂb
ꢂc
ꢂd
ꢂe
ꢂf
ꢄꢄ.ꢅ
6ꢊ.ꢆ
ꢋ6.6
66.ꢌ
ꢇ6.ꢊ
ꢇꢈ.ꢋ
ꢄꢆ.ꢇ
ꢋꢄ.ꢌ
ꢋꢌ.ꢊ
6ꢇ.6
ꢄꢇ.ꢌ
ꢄ6.ꢈ
ꢄꢈ.ꢉ
6ꢆ.ꢅ
ꢋꢅ.ꢅ
6ꢄ.ꢈ
ꢄꢇ.ꢋ
ꢄꢋ.ꢈ
6ꢇ.6
6ꢊ.ꢋ
ꢋ6.ꢈ
66.ꢊ
ꢄꢌ.ꢆ
ꢄꢊ.ꢅ
δ 172.5, 77.8, 41.6, 38.3, 33.3, 32.3, 30.1, 27.8, 25.4. Anal. Calcd for
C H N O: C, 64.24; H, 9.59; N, 16.66. Found: C, 64.12; H, 9.68; N, 16.72.
9
16
2
3
a-Methyl-2,3,3a,4-tetrahydro-1H-benzo[d]pyrrolo[1,2-a]imida-
zol-1-one (3d)ꢁWhite solid; yield: 54%; mp 106–108°C; IR: ν 3326
-1
1
(
N-H), 2964–2906 (C-H), 1616 cm (C O); H NMR (CDCl ): δ 6.68–7.45
3
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F. Ye etꢃal.: N-Dichloroacetyl diazabicyclo compoundsꢀꢂꢁꢁꢁꢀ77
(
m, 4H, Ar-H), 4.19 (s, 1H, N-H), 2.37–2.82 (m, 4H, 2×CH ), 1.53 (s, 3H, 4-(Dichloroacetyl)-3a-methyl-2,3,3a,4-tetrahydro-1H-benzo[d]
2
1
3
CH ); C NMR (CDCl ): δ 173.7, 142.8, 128.6, 125.3, 120.2, 115.4, 110.6, pyrrolo[1,2-a]imidazol-1-one (4d)ꢁWhite solid; yield 55%; mp
3
3
-
1
1
8
5.6, 37.7, 33.6, 26.3. Anal. Calcd for C H N O: C, 70.18; H, 6.43; N, 135–137°C; IR: ν 3006–2981 (C-H), 1713 (C O), 1672ꢀcm (C O); H
4.89. Found: C, 70.06; H, 6.54; N, 14.81.
11 12 2
1
NMR (CDCl ): δ 7.20–7.66 (m, 4H, Ar-H), 6.46 (s, 1H, Cl CH), 2.60–2.89
3 2
m, 4H, C-CH -CH -C), 1.75 (s, 3H, CH ); C NMR (CDCl ): δ 172.6, 159.6,
1
3
(
2
2
3
3
6
-Methyl-10-oxa-1,5-diazabicyclo[4.4.0]decane (3e)ꢁWhite solid; 131.7, 130.3, 125.9, 125.5, 117.3, 114.4, 89.3, 64.5, 35.5, 33.4, 22.5; MS: m/z
-
1
+
yield: 52%; mp 52–54°C; IR: ν 3284 (N-H), 2947–2850 (C-H), 1612ꢀcm
298 [M+1] . Anal. Calcd for C H N O Cl : C, 52.34; H, 4.06; N, 9.40.
1
3
12
2
2
2
1
(
C O); H NMR (CDCl ): δ 4.69 (m, 1H, N-H), 1.56–2.13, (m, 12H, 6×CH ), Found: C, 52.30; H, 4.18; N, 9.31.
3
2
1
3
1
.49 (s, 3H, CH ); C NMR (CDCl ): δ 108.6, 70.7, 39.5, 39.1, 35.9, 32.6,
3
3
2
7.6, 21.9, 16.9. Anal. Calcd for C H N O: C, 64.24; H, 9.59; N, 16.66. 5-Dichloroacetyl-6-methyl-10-oxa-1,5-diazabicyclo[4.4.0]
9
16
2
Found: C, 64.32; H, 9.64; N, 16.55.
decane (4e)ꢁWhite solid; yield 50%; mp 115–116°C; IR: ν 2991–2873
C-H), 1685 (C O), 1623ꢀcm (C O); H NMR (CDCl ): δ 6.16 (s, 1H,
-1 1
(
3
6
-Methyl-2-oxa-1,7-diazabicyclo[4.3.0]nonane(3f)ꢁWhitesolid; Cl CH), 4.75, 4.00, 3.00–3.22 (3m, 4H, 2×CH -N), 1.71–2.50 (m, 8H,
2
2
-1
13
yield 45%; mp 87–89°C; IR: ν 3251 (N-H), 2960–2945 (C-H), 1628ꢀcm
4×CH ), 1.90 (s, 3H, CH ); C NMR (CDCl ): δ 170.5, 162.0, 77.8, 67.4,
2
3
3
1
+
(
4
C O); H NMR (CDCl ): δ 3.71–3.80 (m, 1H, N-H), 3.28, 2.44 (2m, 41.5, 33.2, 32.7, 31.6, 24.5, 22.4, 16.8; MS: m/z 279 [M+1] . Anal. Calcd
3
1
3
H, N-CH -CH -N), 1.39–2.35 (m, 6H, 3×CH ), 1.29 (s, 3H, CH );
C
for C H N O Cl : C, 47.47; H, 5.80; N, 10.07. Found: C, 47.39; H, 5.88;
2
2
2
3
11 16 2 2 2
NMR (CDCl ): δ 167.9, 77.5, 43.4, 42.2, 35.4, 30.4, 23.5, 17.7. Anal. Calcd N, 10.12.
3
for C H N O: C, 62.29; H, 9.16; N, 18.17. Found: C, 62.21; H, 9.25; N,
8
14
2
1
8.10.
7-Dichloroacetyl-6-methyl-2-oxa-1,7-diazabicyclo[4.3 .0 ]non-
ane (4f)ꢁWhite solid; yield 53%; mp 119–120°C; IR: ν 2985–2894
-1
1
(
C-H), 1703 (C O), 1643ꢀcm (C O); H NMR (CDCl ): δ 6.07 (s, 1H,
3
Cl CH), 4.61, 3.92, 3.68, 3.40 (4m, 4H, N-CH -CH -N), 1.64–2.50 (m,
2
2
2
General procedure for the preparation
of compound 4
13
6
6
H, 3×CH ), 1.62 (s, 3H, CH ); C NMR (CDCl ): δ 167.8, 160.7, 79.7,
2
3
3
+
6.5, 44.2, 40.3, 32.7, 30.6, 21.8, 17.7; MS: m/z 264 [M+1] . Anal. Calcd
for C H N O Cl : C, 45.45; H, 5.34; N, 10.61. Found: C, 45.54; H, 5.26;
1
0
14
2
2
2
Dichloroacetyl chloride (0.1 mmol) was added dropwise to a solution N, 10.56.
of compound 3 (0.05 mmol) in toluene (50 mL) at -10°C. The mixture
was treated with aqueous NaOH to pH 8–9 and stirred at room tem-
perature for 2 h. The organic phase was rinsed with water and dried
over anhydrous MgSO . Af er removal of the solvent under reduced
pressure, the residue was crystallized from a mixture of ethanol and
hexanes.
4
X-Ray data collection and structure
refinement
The X-ray data were collected on a Bruker AXS II CCD area-detector
diffractometer using graphite monochromated Mo Kα radiation
(λ=0.071073 nm) at 293(2) K. The structure was solved by direct
methods using SHELXS-97 and refined by full-matrix least-squares
on F2 using full-matrix least-squares procedures. Minimum and
maximum, final electron density were -0.606 and 0.883 eÅ . Sym-
metry equivalent reflections were used to optimize crystal shape
and size. Crystallographic data have been deposited at the Cam-
bridge Crystallographic Data Centre as supplementary publication
number CCDC 873817. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK [fax: + 44(1223)336033 or e-mail: deposit@ccdc.cam.ac.uk].
4
-Dichloroacetyl-5-methyl-8-oxa-1,4-diazabicyclo[3.3.0]octane
(
4a)ꢁWhite solid; yield 73%; mp 120–121°C; IR: δ 3020–2835 (C-H),
-1
1
1
701 (C O), 1689ꢀcm (C O); H NMR (DMSO-d ): δ 6.87 (s, 1H, Cl CH),
6
2
3
.30–4.03 (m, 4H, N-CH -CH -N), 2.22–2.71 (m, 4H, C-CH -CH -C), 1.54
2
2
2
2
1
3
(s, 3H, CH ); C NMR (DMSO-d ): δ 175.4, 160.4, 84.2, 67.3, 46.6, 39.4,
3
3
6
-3
+
3.3, 31.8, 23.0; MS: m/z 252 [M+1] . Anal. Calcd for C H N O Cl : C,
3.20; H, 4.84; N, 11.20. Found: C, 43.13; H, 4.75; N, 11.26.
9
12
2
2
2
4
4
-(Dichloroacetyl)-3a-methyl-decahydro-1H-benzo[d]
pyrrolo[1,2-a]imidazol-1-one (4b)ꢁWhite solid; yield: 87%; mp
-1
1
1
61–169°C; IR: ν 3010–2871 (C-H), 1681ꢀcm (C O); H NMR (CDCl ):
3
δ 6.15 (s, 1H, Cl CH), 4.24 (m, 2H, N-CH-CH-N), 1.42–2.78 (m, 12H,
2
13
6
5
×CH ), 1.77 (s, 3H, CH ); C NMR (CDCl ): δ 175.8, 161.1, 84.9, 64.3,
2
3
3
+
9.2, 52.7, 36.6, 32.5, 27.9, 25.9, 25.6, 17.6, 17.2; MS: m/z 306 [M+1] . Anal. Acknowledgments: This work was supported by the
Calcd for C H N O Cl : C, 51.30; H, 5.97; N, 9.21. Found: C, 51.42; H,
1
3
18
2
2
2
National Nature Science Foundation of China (No.
1101473), the Natural Science Foundation of Heilongji-
5.83; N, 9.15.
3
ang Province (B201212), the Science and Technology
Research Project of Heilongjiang Education Department
6
-Dichloroacetyl-7-methyl-10-oxa-1,6-diazabicyclo[5.3.0]
decane (4c)ꢁWhite solid; yield 70%; mp 157–159°C; IR: ν 2987–2825
C-H), 1704 (C O), 1693ꢀcm-1 (C O); H NMR (CDCl ): δ 6.19 (s, 1H, (No. 12521015), and the Research Science Foundation in
1
(
3
Cl CH), 3.99–4.13, 2.97–3.06 (2m, 4H, 2×CH -N), 1.62–2.59 (m, 8H, Technology Innovation of Harbin (2012RFQXN015).
2
2
1
3
4
4
×CH ), 1.87 (s, 3H, CH ); C NMR (CDCl ): δ 175.2, 163.3, 82.2, 67.2,
2
3
3
+
6.3, 40.1, 31.8, 29.3, 29.1, 25.5, 25.3; MS: m/z 280 [M+1] . Anal. Calcd
for C H N O Cl : C, 47.47; H, 5.80; N, 10.07. Found: C, 47.52; H, 5.74; Received December 2, 2012; accepted December 17, 2012; previously
1
1
16
2
2
2
N, 10.15.
published online February 19, 2013
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8ꢀꢁꢁꢁꢂꢀF. Ye etꢃal.: N-Dichloroacetyl diazabicyclo compounds
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