Microwave-assisted synthesis of N,N′-disubstituted acetamidine ligands

Article abstract of DOI:10.1080/00397910701465164

Under microwave activation, triethylorthoacetate reacts with the substituted anilines in the presence of acetic acid as a catalyst, producing acetamidine in moderate to high yields. The X-ray structures of the new amidines, N,N′-bis(3,5-dimethylphenyl)-ac

Full text of DOI:10.1080/00397910701465164

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Microwave‐Assisted Synthesis of
N,N′‐Disubstituted Acetamidine Ligands
Phimphaka Harding a , David J. Harding a , Harry Adams b & Sujittra
Youngme c
a Department of Chemistry , School of Science, Walailak University ,
Thasala, Thailand
b Department of Chemistry , University of Sheffield , Brook Hill, England
c Faculty of Science, Department of Chemistry , Khon Kaen University , Khon
Kaen, Thailand
Published online: 14 Aug 2007.
To cite this article: Phimphaka Harding , David J. Harding , Harry Adams & Sujittra Youngme (2007)
Microwave‐Assisted Synthesis of N,N′‐Disubstituted Acetamidine Ligands, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:16, 2655-2661, DOI:
10.1080/00397910701465164
To link to this article: http://dx.doi.org/10.1080/00397910701465164
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Synthetic Communicationsw, 37: 2655–2661, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701465164
Microwave-Assisted Synthesis of N,N0-
Disubstituted Acetamidine Ligands
Phimphaka Harding and David J. Harding
Department of Chemistry, School of Science, Walailak University,
Thasala, Thailand
Harry Adams
Department of Chemistry, University of Sheffield, Brook Hill, England
Sujittra Youngme
Faculty of Science, Department of Chemistry, Khon Kaen University,
Khon Kaen, Thailand
Abstract: Under microwave activation, triethylorthoacetate reacts with the substituted
anilines in the presence of acetic acid as a catalyst, producing acetamidine in moderate
to high yields. The X-ray structures of the new amidines, N,N0-bis(3,5-dimethylphe-
nyl)-acetamidine and N,N0-bis(p-tolyl)acetamidine, are also reported, revealing
polymeric chains supported by intramolecular H-bonds.
Keywords: amidine, microwave-assisted synthesis, one pot
Recently, amidines have been used as bridging ligands for the preparation of
transition-metal complexes, especially paddle-wheel complexes.[1–4] Rapid
synthesis of increasingly complex amidines is therefore of prime importance.
Taylor and Ehrhart reported an efficient synthesis of N,N0-disubstituted forma-
midines and acetamidines by refluxing ethyl orthoformate with alkylamines in
the presence of acetic acid as a catalyst at high temperature and subsequent
Received October 14, 2006
Address correspondence to Phimphaka Harding, Department of Chemistry, School
of Science, Walailak University, Thasala, Nakhon Si Thammarat 80161, Thailand.
E-mail: kphimpha@wu.ac.th
2655

2656
P. Harding et al.
Scheme 1. Synthesis of acetamidine.
distillation at 80–1508C under low pressure to remove the by-product, ethanol,
and excess starting material. However, this method is time-consuming,
requiring lengthy refluxing and extensive workup to isolate the product.[5] In
this communication, we report a novel method for the synthesis of N,N0-disub-
stituted acetamidines using a modified domestic microwave oven.[6,7]
Figure 1. Molecular structure of 1 with thermal ellipsoids at 50% probability. Hydro-
gen atoms have been omitted for clarity.

N,N0-Disubstituted Acetamidine Ligands
2657
Figure 2. Molecular structure of 2 with thermal ellipsoids at 50% probability.
Hydrogen atoms have been omitted for clarity.
Reflux of triethylorthoacetate and the desired aniline in the presence of
acetic acid as a catalyst under microwave irradiation at 850 W for 5–7 min
yields N,N0-disubstituted acetamidine, [RNC(Me)NHR] (R ¼ 3,5-dimethyl-
phenyl 1 and p-tolyl 2), shown in Scheme 1. The by-product, EtOH, is
easily removed by placing a receiver between the round-bottom flask and
the condenser and heating under microwave conditions at 850 W for a
further 2 or 3 min. The complete removal of EtOH is the key to high yield
and purity of the product. In general, yields are comparable or increased by
10–20% and reaction times are shortened to minutes rather than hours, with
isolated pure products obtained in most cases in less than an hour.
IR spectra of 1 and 2 show nNH at 3281 and 3301 cm21 respectively.
Additional bands are observed for the aromatic C55C and C-H stretches and
1
are comparable with other reported amidines.[5] The H NMR of the new
amidine 1 reveals two singlets in the aromatic region and a doublet for the
aromatic methyl groups slightly downfield of a singlet for the central
amidine methyl group. The presence of two peaks for the aromatic methyl
groups suggests that the acetamidine is asymmetric on the NMR timescale.
The amino hydrogen is not observed in the NMR spectrum, presumably due
to broadening.
Single-crystal X-ray diffraction studies of compounds 1 and 2 were under-
taken, and the molecular structures are shown in Figs. 1 and 2 respectively,
with selected bond lengths and angles given in Table 1 and crystal and refine-
ment data in Table 2. The structures closely resemble one another, differing
only in the substitution on the aromatic ring, and consequently the following
discussion is limited to the structure of 1. The amidine molecules adopt a

2658
P. Harding et al.
˚
Table 1. Selected bond lengths (A) and bond angles (8) of 1 and 2
Length
Angle
1
2
N(1)–C(1)
N(1)–C(2)
N(1)–H(1)
N(2)–C(1)
N(2)–C(8)
C(1)–C(14)
1.3727(18)
1.4122(18)
0.8800
1.363(3)
1.416(3)
0.8800
1.2906(18)
1.4293(18)
1.505(2)
1.295(3)
1.422(3)
1.499(3)
126.87(18)
116.6
C(1)–N(1)–C(2)
C(1)–N(1)–H(1)
C(2)–N(1)–H(1)
C(1)–N(2)–C(8)
N(2)–C(1)–N(1)
N(2)–C(1)–C(14)
N(1)–C(1)–C(14)
C(3)–C(2)–N(1)
C(7)–C(2)–N(1)
C(13)–C(8)–N(2)
C(9)–C(8)–N(2)
129.46(12)
115.3
115.3
116.6
118.61(12)
121.42(13)
125.55(13)
113.03(12)
123.90(13)
116.46(13)
120.05(14)
120.66(14)
118.63(18)
120.58(19)
124.65(19)
114.76(19)
119.40(18)
122.07(17)
120.3(2)
120.9(2)
trans-configuration with one of the aromatic rings orthogonal to the plane of
the acetamidine core (see Figs. 1 and 2). This arrangement is preferred
because of the presence of a weak intramolecular hydrogen bond between
the H-atom on N(1) and the imine nitrogen, N(2), on a neighboring
˚
molecule. The H-bond length is 2.26(4) and 2.25(6) A for 1 and 2 respectively.
In contrast to other reported amidines, the H-bond forms a zigzag chain, in
which neighboring amidines are almost orthogonal to one another, and not a
dimer of molecules.[8] The N(2)–C(1) bond is considerably shorter than the
˚
N(1)–C(1) bond (1.291, cf. 1.373 A) consistent with double and single
carbon–nitrogen bonds respectively (Table 1).
In conclusion, we have successfully synthesized N,N0-disubstituted
acetamidine ligands by microwave activation, reducing reaction times to a
matter of minutes rather than hours. X-ray crystal structures reveal that the
acetamidine molecules form polymeric chains through intramolecular
hydrogen bonds. The synthesis of more complex acetamidines is currently
under way in these laboratories.

N,N0-Disubstituted Acetamidine Ligands
2659
Table 2. Crystal and refinement data for RNC(Me)NHR (R ¼ 3,5-dmp 1 and p-tolyl 2)
Parameter
1
2
Empirical formula
Formula weight
Temperature
C18 H22 N2
266.38
C16 H18 N2
238.32
100(2) K
100(2) K
0.71073 A
˚
˚
0.71073 A
Wavelength
Crystal system
Space group
Unit cell dimensions
Orthorhombic
Pbca
Orthorhombic
Pbca
˚
˚
a ¼ 8.5708(9) A,
a ¼ 12.390(3) A,
a ¼ 908
a ¼ 908
˚
˚
b ¼ 15.7448(16) A,
b ¼ 9.1300(18) A,
b ¼ 908
b ¼ 908
˚
˚
c ¼ 23.201(2) A,
c ¼ 23.950(5) A,
g ¼ 908
g ¼ 908
3
˚
3
˚
Volume
Z
3130.8(6) A
2709.2(9) A
8
8
Density (calculated)
Absorption coefficient
F(000)
1.130 Mg/m3
0.066 mm21
1152
1.169 Mg/m3
0.069 mm21
1024
Crystal size
Theta range for data collection 1.76 to 27.538
0.32 ꢀ 0.18 ꢀ 0.14 mm3 0.32 ꢀ 0.10 ꢀ 0.09 mm3
1.70 to 30.988
216 ꢁ h ꢁ 17,
213 ꢁ k ꢁ 13,
229 ꢁ l ꢁ 34
53317
Index ranges
211 ꢁ h ꢁ 11,
219 ꢁ k ꢁ 17,
230 ꢁ l ꢁ 29
38695
Reflections collected
Independent reflections
Completeness to u ¼ 27.538
Absorption correction
3545 [R(int) ¼ 0.0706]
98.2%
4217 [R(int) ¼ 0.1169]
100.0%
Semi-empirical from
equivalents
0.9908 and 0.9791
Semi-empirical from
equivalents
0.9938 and 0.9782
Max. and min. transmission
Refinement method
Full-matrix least-squares Full-matrix least-squares
on F2
on F2
Data/restraints/parameters
Goodness of fit on F2
Final R indices [I . 2s(I)]
3545/0/186
1.048
4217/0/167
1.032
R1 ¼ 0.0491,
wR2 ¼ 0.1134
R1 ¼ 0.0733,
wR2 ¼ 0.1250
R1 ¼ 0.0875,
wR2 ¼ 0.1903
R1 ¼ 0.1884,
wR2 ¼ 0.2347
0.026(3)
R indices (all data)
23
˚
0.266 and 20.294 e. A
Largest diff. peak and hole
EXPERIMENTAL
A modified domestic microwave oven with a computer controller and infrared
thermometer was used for all experiments (details of the microwave reactor
are available at http://www.science.mju.ac.th/chemistry/research/weerachai/

2660
P. Harding et al.
reactor_eng.htm). Melting points were determined on a Stuart SMP3. Infrared
spectra (as KBr discs) were recorded on a Perkin-Elmer Spectrum One
1
infrared spectrophotometer in the range of 400–4000 cm21. H and 13C-1H
NMR spectra were recorded on a Bruker 300-MHz FT-NMR spectrometer
in CDCl3 with SiMe4 as an internal standard. Elemental analyses and electro-
spray ionization mass spectrometry (ESI MS) were carried out by the staff of
the School of Chemistry, University of Bristol, U.K.
Synthesis of N,N0-Bis(3,5-dimethylphenyl)acetamidine (1)
Method A
A mixture of triethylorthoacetate (2.0 cm3, 10.4 mmol), 3,5-dimethylaniline
(1.6 cm3, 20 mmol), and acetic acid (0.5 cm3) was placed in a microwave
oven equipped with a reflux condenser and heated at 850 W for 7 min. A
receiver was placed between the flask and the condenser, and the mixture
was heated under microwave conditions at 850 W for a further 2 or 3 min.
The volume was reduced under vacuum to yield a thick oil, and n-hexane
(10 cm3) was added. The solution was cooled to 08C, resulting in colorless
crystals (1.21 g, 45%).
Method B
Triethylorthoacetate (1 cm3, 5.2 mmol), 3,5-dimethylaniline (0.78 cm3,
10 mmol), and acetic acid (0.04 cm3) were refluxed at 1358C for 2 h. The
orange solution was distilled at 1408C in vacuo to remove EtOH and
starting material. The orange crystals were washed with cool n-hexane,
giving colorless crystals and an orange solution. The mixture was stored at
2208C overnight. The colorless crystals were filtered and dried in air; yield
0.619 g (47%).
Mp 160–161.58C. IR (KBr, cm21) 3301 w, 3270 w, 3152 w, 3096 w,
2917 w, 2861 w, 1636 s, 1567 s, 1467 s, 1344 s, 1157 s, 1047 m, 846 s, 691
1
s, 654 s. H NMR (CDCl3) d 6.78 (s, 3H, H-Ar), 6.68 (s, 3H, H-Ar), 2.28
(s, 12H, Ar-CH3), 1.98 (s, 3H, CH3). 13C NMR (CDCl3) d 155.07, 144.01,
139.52, 125.69, 120.05, 21.67, 18.85. Found: C, 81.5; H, 8.3; N, 10.6.
C18H22N2 calcd.: C, 81.2; H, 8.3; N, 10.5. Electrospray ionization (ESI)
mass data: m/z 267 [M þ H]þ.
Synthesis of N,N0-Bis(p-tolyl)acetamidine (2)
A mixture of triethylorthoacetate (2.0 cm3, 10.4 mmol), p-toluedine (2.12 g,
19.8 mmol), and acetic acid (0.5 cm3) was placed in a microwave oven
equipped with a reflux condenser and heated at 850 W for 5 min. A receiver

N,N0-Disubstituted Acetamidine Ligands
2661
was placed between the flask and the condenser, and the mixture was heated
under microwave conditions at 850 W for a further 2 or 3 min. The volume
was reduced under vacuum to yield a thick oil, and n-hexane (10 cm3) was
added. The solution was cooled to 08C, resulting in off-white crystals
(1.66 g, 70%).
Mp 102–1038C. IR (KBr, cm21): 3281 br, 3021 w, 2922 w, 2856 w, 1639
1
s, 1595 s, 1514 s, 1375 s, 1219 s, 1016 w, 817 s, 655 m, 506 s. H NMR
(CDCl3) d 7.14–7.05 (m, 8H, H-Ar), 2.32 (s, 6H, CH3), 2.00 (s, 3H, CH3).
13C NMR (CDCl3) d 180.87, 137.99, 135.64, 130.23, 124.07, 21.24, 17.39.
.
Found: C, 74.6; H, 7.4; N, 10.4. C16H18N2 0.75H2O calcd.: C, 74.6; H,
7.8; N, 11.1. Electrospray ionization (ESI) mass data: m/z 239 [M þ H]þ.
ACKNOWLEDGMENTS
We thank the Thailand Research Fund (MRG4780116) for financial support.
The University of Bristol is also gratefully acknowledged for CHN analysis
and MS services, and Weerachai Phutdhawong is acknowledged for assistance
with the microwave reactor.
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