Synthesis of substituted aryl amidines from aminoacetonitriles

Article abstract of DOI:10.1016/j.tetlet.2005.04.142

Aryl aminoacetonitriles are oxidized by NiO₂-H₂O or MnO₂ in the presence of a wide range of NH₂-containing compounds to afford aryl amidines, presumably via iminium intermediates. A 'one-pot' procedure for the preparation of heteroaryl amidines from N-containing heteroaryl halides through a process comprising sequential S_NAr substitution and oxidation has also been developed.

Full text of DOI:10.1016/j.tetlet.2005.04.142

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4919–4923
Synthesis of substituted aryl amidines from aminoacetonitriles
Zhiwei Yin, Zhongxing Zhang, Juliang Zhu, Henry Wong, John F. Kadow,
Nicholas A. Meanwell and Tao Wang*
Department of Chemistry, The Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford,
CT 06492, USA
Received 7 March 2005; accepted 8 April 2005
Available online 4 June 2005
Abstract—Aryl aminoacetonitriles are oxidized by NiO2–H2O or MnO2 in the presence of a wide range of NH2-containing com-
pounds to afford aryl amidines, presumably via iminium intermediates. A Ôone-potÕ procedure for the preparation of heteroaryl ami-
dines from N-containing heteroaryl halides through a process comprising sequential SNAr substitution and oxidation has also been
developed.
Ó 2005 Elsevier Ltd. All rights reserved.
Substituted aryl- and heteroaryl amidines are of interest
as synthetic targets1 and as structural elements with util-
ity in drug design.2 There is a dearth of simple and effi-
cient methodologies for accessing highly substituted aryl
amidines. Currently, the documented aryl amidine syn-
thesis has been limited to the coupling of an amine with
an imidoyl derivative3 or the reaction with an iminium
intermediate,4 both of which usually originated from
the corresponding amide. In this report, we would like
to describe the scope of a mild and novel protocol to
prepare N,N,N0-tri-substituted aryl- or heteroaryl ami-
dines from 2-substituted aminoacetonitriles and NH2-
containing compounds that has been optimized into a
practical and convenient one-pot procedure.
O
N
S
CN
N
S
NiO2-H2O
THF, r.t.
65%
NEt2
NEt2
2a
1a
Scheme 1.
CN
N
S
N Et
Et
3
Figure 1.
We have previously reported the formation of secondary
amides via oxidation of an aminoacetonitrile derivative
with NiO2–H2O under neutral conditions, as summa-
rized in Scheme 1.5 Several potential mechanistic path-
ways were proposed for this transformation in our
initial communication and while the exact mechanism
was not fully elucidated, a pathway involving a stabi-
lized iminium cation, represented by 3 in Figure 1, was
suggested. We hypothesized that if the iminium 3 was
indeed an intermediate, it should be susceptible to inter-
ception by exogenous nucleophiles. Of particularly
interest, the addition of an amine derivative provided
the potential for a synthesis of substituted amidines. In
order to examine this process, the N,N-diethylamino-
acetonitrile 1a was exposed to an excess of both NiO2–
H2O and n-propylamine in THF at room temperature.
As summarized in Scheme 2, the major product isolated
was the amidine 4a, obtained in 84% yield, as deter-
mined by LC–MS, with only small amounts of the
amides 2a (4%) and 5a (8%) detectable. This confirmed
that intermediate 3 could be trapped by a primary amine
to form a N,N,N0-tri-substituted amidine and prompted
a broader survey of reaction participants in order to
define the scope and utility of the procedure.
Keywords: Aryl amidine; Heteroaryl amidine; Condensation–oxida-
tion; Aminoacetonitrile; Nickel peroxide; Manganese oxide.
*
Table 1 summarizes the results of these studies that
demonstrate the generality of this process for the
Corresponding author. Tel.: +1 203 677 6584; fax: +1 203 677
7702; e-mail: wangta@bms.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.142

4920
Z. Yin et al. / Tetrahedron Letters 46 (2005) 4919–4923
NPr
+
NEt2
N
S
O
N
S
O
N
S
CN NiO2-H2O, n-PrNH2
THF, r.t., 30 min.
N
S
+
NEt2
NHPr
NEt2
4a
2a
5a
1a
84% (LC-MS)
48% (Isolated)
4% (LC-MS)
8% (LC-MS)
Scheme 2.
Table 1. The oxidation of heteroaryl aminoacetonitriles using NiO2–H2O or MnO2 in the presence of amines to afford amidine derivatives
CN
O
NY
Ar NEt2
Y-NH2
Ar
NiO2-H2O or MnO2
THF, 16 hours, r.t.
Ar
NEt2
NEt2
2
4
1
Entry
1
Y–NH2
NH4OH
1
Producta,b yield by using NiO2ꢀH2O/MnO2
NH
N
CN
NEt2
N
4b
S
NEt2
S
1a
59%c, 77%d / 57%d
NCN
4c
N
S
2
3
4
5
6
NC–NH2
1a
1a
1a
1a
1a
NEt2
64%c, 51%d / 58%d
NOMe
4d
NEt2
N
S
MeO–NH2, HCl salt
12%c, 15%d / 44%d
NNMe2
4e
N
S
Me2N–NH2
NEt2
35%c, 46%d / 57%d
N N
NEt2
N
S
N
4f
NH2
50%d / 54%d
NPh
4g
NEt2
N
S
Ph–NH2
62%c, 41%d / 25%d
N
NH
N
N
S
HN
N
N
7
8
1a
1a
4h
4i
NH2
NEt2
38%d / 23%d
N
N
N
N
N
N
N
S
NH2
NEt2
14%d / 16%d
NSO2NMe2
N
S
4j
9
Me2NSO2–NH2
1a
1a
NEt2
8%d / 12%d
NSO2Me
4k
N
S
10
MeSO2–NH2
NEt2
18%d / 26%c, 36%d

Z. Yin et al. / Tetrahedron Letters 46 (2005) 4919–4923
4921
Table 1 (continued)
Entry
Y–NH2
PrNH2
1
Producta,b yield by using NiO2ꢀH2O/MnO2
O
O
N
N
N
11
N
4l
NPr
1b
CN
66%d / 61%d
O
N
O
N
N
N
12
13
PrNH2
PrNH2
4m
NPr
1c
CN
97%d / 78%d
O
N
O
O
N
S
S
4n
NPr
1d
84%d / 46%d
CN
O
N
N
N
14
15
16
PrNH2
PrNH2
PrNH2
N
4o
Me
Me
NPr
1e
CN
28%d / 9%d
O
N
O
N
4p
NPr
1f
CN
70%d / 35%d
N
Cl
N
N
Cl
NEt2
4qe
NEt2
N
NPr
67%c, 73%d / 59%d
1g
CN
a Other compounds in reaction mixture after 16 hours at room temperature included amide 2 and unreacted starting material 1.
b Regiochemical structure was not determined.
c Isolated yield.
d LC–MS yield.
e Not degraded after 19 months.
preparation of novel aryl- and heteroaryl amidine deriv-
atives of diverse structure using two different oxidants
and a range of amine nucleophiles. As shown in Table
1, this procedure afforded products in low to good over-
all yields, as determined by LC–MS. Confirmation of
the LC–MS yields was obtained for 1–2 product(s)
(4a/4q, 4b, 4c, 4d, 4e, 4g and 4k) from each series
(ArC(@NR0)NR2, ArC(@NH)NR2, ArC(@NCN)NR2,
ArC(@NOR0)NR2, ArC(@NNR02)NR2, Ar(C@NAr0)NR2
and Ar(C@NSO2R0)NR2) by standard purification and
isolation methods. The iminium intermediates 5, gener-
ated by either NiO2–H2O or MnO2,6 were found to be
quite reactive and could readily be captured by primary
amines, anilines, heteroaromatic amines and sulfon-
amides. However, the yields of amidines varied and
appeared to correlate with the nucleophilicity of the
amine functionality. Consistent with this observation,
acylated amines such as EtCONH2, t-BuOCONH2,
MeNHCONH2 and Me2NCONH2, being very weak
nucleophiles were found to be unreactive partners (data
not shown). It would be anticipated that the conjugate
base would be more nucleophilic but these reagents
257a,b,i and unlikely to form under the mild reaction con-
ditions. In contrast, the more acidic cyanamide (pKa
DMSO
16.9, entry 2),7a,b sulfamide (entry 9) and methyl sulfon-
amide (pKaDMSO 17.5, entry 10)7a,b presumably reacted via
their more nucleophilic anionic forms after deprotona-
tion since the pKa
of water is in the range
DMSO
27–32.7a,b,i Primary amines,7a,c,d,h anilines,7a,b,d,e,h,i
hydroxylamines7a,d,h and hydrazines7a,d,f–h were ex-
pected to react more readily due to their intrinsically
higher nucleophilic nature, confirmed by the results
shown in entries 1, 3–8, 11–16. While substituted hydra-
zines and hydroxylamines provided the corresponding
amidine derivatives, neither hydrazine nor hydroxyl-
amine afforded products, presumably due to the domi-
nation of dehydrogenation of these reagents resulting
in the formation of N2 and NO.
It is also apparent from Table 1 that NiO2–H2O and
MnO2 behaved in a similar manner, with both oxidants
providing the desired products. However, the yield of
product varies and appears to be dependent upon the
identity of the individual reactants, with no overt reac-
tivity trends apparent. These data suggest that both
are only weakly acidic with pKa
values of about
DMSO

4922
Z. Yin et al. / Tetrahedron Letters 46 (2005) 4919–4923
O
N
CN
N
S
NiO2-H2O
THF, r.t.
N
S
N
NH2
+
+
8
H2N
S
2a
NEt2
NEt2
N
H
70%
1a
6a
20%
(LC-MS)
(LC-MS)
75%
reflux
N
(LC-MS)
N
N
S
NH2
N
S
NEt2
N
H
7a
Scheme 3. Imidazoline formation from aminoacetonitrile.
oxidants should be examined when applying this process
to new substrates in order to identify the optimal
conditions.
related heterocyclic amidines has been investigated.
These conditions13 allow for the construction of novel
aryl amidines and related heterocyclic amidines effec-
tively from the corresponding aryl aminoacetonitriles
or heterocyclic halides in a procedure that is both conve-
nient and rapid. The scope of substituted amidines that
could potentially be synthesized via these processes sug-
gest that this chemistry might be useful when attempting
to balance or improve pharmacokinetic, pharmaceutic
and safety parameters during a drug optimization cam-
paign.2 The extension of this methodology to the synthe-
sis of hydrocarbon-based aromatic amides from aryl
halides is under active investigation.
The scope of the reaction was extended to encompass
bis-nucleophilic partners, leading to the production of
heterocyclic amidines. For example, when ethylenedi-
amine was employed as the nucleophile, the imidazoline
6a8 was produced in 20% yield, as determined by LC–
MS (Scheme 3). This reaction presumably proceeds via
an intramolecular displacement of the diethylamino
moiety by the free primary amine in the newly-formed
N,N,N0-tri-substituted amidine 8. At elevated tempera-
tures, the amidine 6a underwent facile aromatization
to furnish imidazole 7a.9
Acknowledgements
This process for amidine formation could be combined
with the previously described SNAr-oxidation proto-
col5,10 to provide a convenient, single-pot process for
the production of heteroaryl amidines from heteroaryl
halides, as depicted in Schemes 4 and 5. In Scheme 4,
the anion of N,N-diethylaminoacetonitrile 10, prepared
by deprotonation with NaHDMS in THF, was treated
with 2-chlorobenzothiazole (9a) followed subsequently
by exposure to NiO2–H2O in the presence of n-propyl
amine to afford the benzothiazole amidine 4a in an iso-
lated yield of 35%.
The authors are very grateful to Dr. Li Pan for assis-
tance in obtaining exact mass spectral data.
Supplementary data
The supplementary data is available online with the pa-
per in ScienceDirect. Supplementary data associated
with this article can be found, in the online version at
doi:10.1016/j.tetlet.2005.04.142.
Similarly, the employment of a bis-nucleophile such as
ethylene diamine or 2-hydroxyethylamine instead of a
simple primary amine led to the formation of the
imidazoline 6a11 or oxazoline 11, respectively, via the
one-pot process that is summarized in (Scheme 5).8,12
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