Dication C(R1)-N(R2)2 synthons and their use in the synthesis of formamidines, amidines, and α-aminonitriles

Article abstract of DOI:10.1016/S0040-4020(00)00785-7

A combination of amides and 2-pyridinesulfonyl chloride was evaluated as synthons of the dication C(R¹)-N(R₂)2/2⁺. When the substrates were primary amines, high yields of formamidines and amidines were obtained. When the substrates were α-aminoamides, α-aminonitriles were obtained. Through this process, naturally occurring α-aminoacids can be transformed into chiral α-aminonitriles with complete retention of stereochemical configuration. All reactions proceed rapidly at room temperature, and normally finish within 10 min, with yields ranging from 80 to 95% for most cases. Among the sulfonyl chlorides examined, 2-pyridinesulfonyl chloride stands out in both reaction rate and selectivity of formamidine or amidine versus sulfonyl amide. The scope and limitations of the reaction among different types of amides as synthons and amines as substrates were examined. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00785-7

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 8253±8262
Dication C(R1)±N(R2)2 Synthons and their use in the Synthesis of
Formamidines, Amidines, and a-Aminonitriles
a
a
b
Lisheng Cai,a, Ying Han, Sumei Ren and Liangfu Huang
*
aDepartment of Chemistry, The University of Illinois at Chicago, Chicago, IL 60607, USA
bSynChem, Inc., 1700 South Mount Prospect Road, Desplaines, IL 60018, USA
Received 12 January 2000; revised 2 March 2000; accepted 3 March 2000
AbstractÐA combination of amides and 2-pyridinesulfonyl chloride was evaluated as synthons of the dication C(R1)±N(R2)221. When the
substrates were primary amines, high yields of formamidines and amidines were obtained. When the substrates were a-aminoamides,
a-aminonitriles were obtained. Through this process, naturally occurring a-aminoacids can be transformed into chiral a-aminonitriles
with complete retention of stereochemical con®guration. All reactions proceed rapidly at room temperature, and normally ®nish within
10 min, with yields ranging from 80 to 95% for most cases. Among the sulfonyl chlorides examined, 2-pyridinesulfonyl chloride stands out in
both reaction rate and selectivity of formamidine or amidine versus sulfonyl amide. The scope and limitations of the reaction among different
types of amides as synthons and amines as substrates were examined. q 2000 Elsevier Science Ltd. All rights reserved.
Formamidines, derivatives of the unstable imidic acid, have
been used as pharmacological agents,1 primarily as pesti-
cides like amitraz2 and histamine receptor antagonists.3
Their application as building blocks in polymers,4 bleaching
agents for paper,5 and ligands in transition metal complexes6
has also been noted. Their use as intermediates in organic
synthesis is quite diversi®ed,7 including as auxiliaries in
asymmetric synthesis,8 as protecting groups for primary
amines,9 as nitrogen-based nucleophiles,10 and as support
linkers in solid phase synthesis.11 A few general methods
are available for the synthesis of compounds of this type.
Coupling of N,N-dialkylformamides with primary amines
by a number of coupling agents including P2O5, PCl5,
PCl3, SOCl2, and acyl chlorides has been realized.12 In
other situations, ethyl N-cyanoformimidate was used to
form N2-aryl-N1-cyanoformamidines, which were converted
to a variety of N 2-aryl-N1-alkylformamidines with excess
alkyl or dialkylamines.13 Thiophenylimidic esters were
recently used in an alternative synthesis of formamidines.14
N,N-dialkylformamide dimethylacetals have also been used
to couple with primary amines directly under neutral con-
ditions.15 Earlier phenylisocyanate was reacted with N,N-
dimethylformamide to generate the formamidine through a
four-membered heterocyclic intermediate.16 This reaction
was further generalized to use other aryl isocyanates as
starting materials.17 Quite unexpectedly, (diamino-
methyl)di-tert-butylphosphine reacts with primary amines
to generate formamidines and di-tert-butyl-hydrophosphine
in moderate yields.18 Selective reduction of tri-substituted
ureas has also been used to synthesize 3-substituted forma-
midines in a number of cases.19 1,1-Addition of amines to
isocyanides catalyzed by AgCl at low temperature generates
stereospeci®c isomers of formamidines, which are different
from those generated by other methods.20 In our effort to
evaluate the application of the dication C(R1)±N(R2)2
synthons, we found a convenient and highly ef®cient synthe-
sis of a variety of formamidines, amidines and a-amino-
nitriles. Part of the results has been reported.21 Since our
initial report, other work using phosphorus-based coupling
agents such as PyBroP (Tri-pyrrole bromophosphorus
bromide) has appeared in the literature for the synthesis of
formamidines.22 Application of the synthons from the
combination of N,N-dimethylacrylamide/tri¯ic anhydride
and N,N-dimethylformamide/tri¯ic anhydride on activated
aromatic systems such as thiophenes23 or activated methyl-
ene groups such as cyclopentadienes24 has also been
reported. An interesting twist of the synthons has been
used in the synthesis of N,N-dibenzylformamidines.25
A
general scheme for the reaction of this paper is shown in
Scheme 1. We report the scope and limitation of the reaction
in the synthesis of formamidines, amidines and a-amino-
nitriles. The synthon C(R1)±N(R2)221 was generated from
the combination of an amide C(R1)(O)±N(R2)2 and a
Keywords: dication C(R1)±N(R2)2; a-aminonitriles; synthons.
* Corresponding author. Tel.: 11-312-996-3161; fax: 11-312-996-0431;
e-mail: cai@uic.edu
Scheme 1.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00785-7

8254
L. Cai et al. / Tetrahedron 56 (2000) 8253±8262
Scheme 2.
Table 1. Evaluation of coupling agents for the formation of 1c
Entry
Coupling agent
Time (min)
Yield (%)
95
Entry
4
Coupling agent
Time (min)
20±30
Yield (%)
89
1
1±2
2
3
2±5
90
5
6
CH3COCl
PhCOCl
5b
6b
2±5
,1a
,1a
CH3SO2Cl
a Pure amide was obtained.
3b
,1
76b
20±30
b A by-product, methyl sulfonyl amide, was formed.
coupling agent, either a sulfonyl chloride or acyl chloride.
Before our communication, only one report using the modi-
®ed Vilsmayer±Haack reagent R2NC(O)±H1ClSO2Ph in
the synthesis of trisubstituted N-(X-2-benzothiazolyl)for-
mamidines appeared.26 A isolated case for amide dehydra-
tion to nitriles upon dehydrative formamidine formation
was also reported.27
of the sulfonyl chloride by using methylsulfonyl chloride
increases the rate of the reaction, but decreases the yield of
formamidine, and formation of sulfonyl amide is observed
as shown in entry 3 in Table 1. Lowering the reactivity of
sulfonyl chloride by using 8-quinolinesulfonyl chloride
slows the reaction, although no difference in selectivity is
observed. However, acetyl chloride is a rather poor coupling
agent as shown in entry 5 and 6. Overall, sulfonyl chlorides
are better coupling agents than acyl chlorides. No experi-
ments based on acyl chlorides were performed any further.
The order of reagent addition is not important for this
reaction.
Evaluation of coupling agents
We used a reaction of forming formamidine as a typical
example to evaluate the ef®ciency of either a sulfonyl
chloride or an acyl chloride (Scheme 2). The reactivity of
2-pyridinesulfonyl chloride and p-toluenesulfonyl chloride
is optimal for the synthesis of formamidines, with the former
slightly favorable in rate and yield. Increasing the reactivity
Scope of formamidine formation
We selected the best coupling agent, 2-pyridinesulfonyl
Table 2. Scope of formamidine synthesis (all reaction ®nished within 5 min)
Entry
Amine
Product
Yield (%)
Entry
6
Amide
Product
Yield (%)
1
95
91
2
3
95
90
7
8
t-Bu-NH2
7a
38a
50a
4
5
91
94
9
80b
a 37% amide was isolated.
b Sulfonamide was the only product isolated.

L. Cai et al. / Tetrahedron 56 (2000) 8253±8262
8255
Table 3. Evaluation of coupling agents for the formation of 7c (all reaction ®nished within 5 min)
Entry
1
Coupling agent
Yield (%)
38a
Entry
3
Coupling agent
Yield (%)
CH3COCl 5b
,1b
2
,1b
a 37% amide was isolated.
b Pure amide was formed. No formamidine was detected by GCMS.
chloride, to evaluate the scope of the formamidine synthesis.
A variety of aromatic and aliphatic amines was ®rst
evaluated. The results are summarized in Table 2. It is
clear that aromatic amines are better substrates than ali-
phatic amines for this reaction in selectivity. The primary
side products are those of sulfonyl amides generated directly
from the reaction of the sulfonyl chloride and the amines.
For aromatic amines, no side products have been observed.
However, the amides become the major products even with
quite hindered aliphatic amines such as tert-butyl amine.
The stability of the formamidines from aliphatic amines is
much reduced. They are decomposed to the corresponding
amines when exposed to untreated silica gel. Diamines are
transformed into di-formamidines with the same ef®ciency
as the mono-ones. No effort was made to synthesize the
mono-amine mono-formamidine compounds. Secondary
amines, as expected, form amides only.
position of the formamidine group, the products are easily
cyclized to form the corresponding oxazoles upon air oxida-
tion. However, conjugated ester groups promote hydrolysis
of the formed formamidines even in basic conditions. This is
consistent with the electron-withdrawing property of the
group which activates the formamidine group toward
nucleophilic attack considerably. The corresponding forma-
mides are formed. When 2-nitroaniline was used, only a
small amount of the formamidine was formed; most of the
starting material was unchanged. Attempted reaction of
b-aminoalcohols, such as 2,2-diphenyl-2-amino-ethanol,
gave a mixture of products under the same conditions as
those for simple formamidine synthesis. No effort was
made to purify each compound in the mixture.
Reaction of derivatives of a-aminoacids
When a-aminoacids were used as amine substrates, no reac-
tion was observed. However, a-aminoesters undergo clean
transformation into a-formamidino esters (Scheme 3). No
loss of optical purity for the transformation and no side
products of sulfonamides have been observed for this
class of substrates. It is quite interesting to note that a nearby
electron-withdrawing ester group has such a strong
in¯uence on the course of the reaction, as compared with
other aliphatic amines such as tert-butyl amine.
In our effort to determine whether aliphatic amines prefer a
different coupling agent for this reaction, we evaluated a
few of coupling agents on formation of 7c. The results are
summarized in Table 3. Although not much difference is
observed between 2-pyridinesulfonyl chloride and
p-toluenesulfonyl chloride for aromatic substrates, only
the former gave any formamidine 7c. The other coupling
agents gave almost exclusively amides. This enforces our
selection of 2-pyridinesulfonyl chloride in the subsequent
evaluation of the scope of this reaction.
Synthesis of enantio-pure a-aminonitriles from
a-aminoacids
Tolerance of functional groups
When the substrates were changed to a-aminoamides, we
observed quantitative transformation into the formamidines
of a-aminonitriles instead (Scheme 4). This transformation
involves forming and breaking of 10 bonds, and is complete
in less than 10 min, with complete retention of the stereo-
chemical con®guration at the a-carbon center. Both
aromatic and aliphatic a-aminoamides proceed with high
ef®ciency. However, no reaction was observed when benza-
mide was used under identical conditions.
In order to test the generality of the formamidine synthesis,
different functional groups were added into the amine
substrates, including pyridine, phenol, and ester groups.
The results are summarized in Table 4. Both pyridine and
phenol or a combination of the two groups are well tolerated
for this reaction. No products from the direct reaction
between the OH group and 2-pyridinesulfonyl chloride
were observed. When the phenol group is at the ortho
Table 4. Tolerance of functional groups in formamidine synthesis (all reactions ®nished within 5 min)
Entry
1
Amine
Product
Yield (%)
87
Entry
3
Amine
Product
Yield (%)
79
2
88
4
63

8256
L. Cai et al. / Tetrahedron 56 (2000) 8253±8262
Scheme 3.
The reaction products were characterized by H, 13C{1H},
MS, and high resolution MS. It is interesting to note that
attempts to measure the IR band of the ±CN group fail to
give any notable peak around 2000±2400 cm21. The
stretching vibrations from the cyano group of a-amino-
nitriles appear in the region 2210±2250 cm21 in their IR
spectra.28 When an hydroxyl or acetyl group is the sub-
stitutent on nitrogen in the a-aminonitrile molecule, the
intensity of this band is considerably reduced. Our
experiments enforce the conclusion that IR spectroscopy
is not always a reliable method for con®rming the structure
of a-aminonitriles. However, the presence of an IR
absorption band in the region does suggest the existence
of a ±CN group because of limited overlap from other
groups.
to make through other synthetic routes, and are important
intermediates in organic synthesis. Chiral a-aminonitriles
have been used extensively as precursors for the
synthesis of amidine peptides, thiazoline peptides, and
tetrazole peptides, which show interesting biological
properties.31
1
Synthesis of chiral a-aminonitriles has been previously
realized from the dehydration of N-substituted a-amino-
amides with phosphorus oxychloride.32 The reaction con-
ditions include introduction of an N-o-nitrophenylsulfenyl
group (NPS), dehydration of the amide group, and
de-protection of the NPS group, with an overall yield
of 10±40%. Some earlier investigators employed benzyl-
oxycarbonyl, phthaloyl, or acetyl as an N-protecting
group.33
This reaction represents the reverse of the Strecker
synthesis.29 Since the starting materials were synthesized
from a-aminoacids (Scheme 5), it seems that there is no
synthetic value for this reaction. However, it provides a
cheap source of chiral pools from naturally occurring
a-aminoacids. Earlier work on the use of a-aminonitriles
has been reviewed.30 For example, they can serve as pre-
cursors to chiral a-aminoaldehydes, chiral a-amino-
alcohols, and chiral diamines, and all of them are dif®cult
Exploration of stoichiometric reaction and variation of
substituents on nitrogen of amides in the synthons
In the effort to expand the scope further, we studied the
formamidine formation reaction using solvents other than
neat N,N-dimethylformamide to explore the possibility of
using a stoichiometric quantity. It turned out that neat DMF
is critical to the success of the reaction. For example, no
Scheme 4.
Scheme 5.

L. Cai et al. / Tetrahedron 56 (2000) 8253±8262
8257
Scheme 6.
reaction was observed in a CH2Cl2/DMF (1:1) mixture. It is
also interesting to note that N,N-diethylformamide under the
same conditions gave no indication of the formation of the
corresponding formamidines. Other amides evaluated such
as CH2vCHC(O)NMe2 also gave no formamidines or
amidines, whether the amino substrates are 2-bromoaniline
or 2-hydroxyaniline.
for an amino group than for an amide group at the same
concentration. This is consistent with our observation that
formation of formamidines is only observed in neat DMF.
Any dilution of the amide group will tilt the balance in favor
of sulfonamide formation.
Compared with the experimental conditions of 100±1208
for P2O5, PCl5, or SOCl2 as coupling agents, this reaction
is advantageous for its mild experimental conditions, high
chemical yields, and short reaction times. In all of our reac-
tions, only one isomer is observed. The structures of all
unknown formamidines were con®rmed by high resolution
Formation of amidines
Success of the formamidine formation prompted us to
evaluate the synthesis of amidines. Under the same con-
ditions as those for the formation of formamidines, the
reaction of 2-bromoaniline gave the corresponding amidine
in high yield (Scheme 6). However, the reaction rate slows
down substantially. Other amines evaluated as substrates
such as aniline, 4-nitroaniline and 3,5-dimethylaniline
gave only the corresponding amides, without any par-
ticipation of N,N-dimethylacetamide. The reaction of
a-aminoamides, however, gave products too unstable to
be isolated.
1
MS, H NMR, and/or 13C{1H} NMR. Comparison of the
NMR spectra of 2c and 4c with literature assignments
con®rms the formation of the trans isomers. This is con-
sistent with a thermodynamically controlled reaction. In
analogy with the mechanism proposed for the formation
of formamidines by other coupling agents,34 a proposed
mechanism is shown on Scheme 8.
In conclusion, we have described a simple, convenient, and
ef®cient preparation of formamidines from primary amines
and N,N-dimethylformamide in the presence of sulfonyl
chlorides. Its advantages lie in: (a) the straightforwardness
and simplicity of the procedure; (b) the mildness of the
reaction conditions and excellent yields; and (c) the short
reaction time and chemoselectivity. The reaction scope of
formamidine formation is quite general with the amine
Attempts to synthesize cyclic amidines such as 24 as shown
in Scheme 7 fail to give the cyclic amidine under a variety of
solvents including CH2Cl2, CH2Cl2/HCl, CH3COOH, and in
neat state (2-pyridinesulfonyl chloride is a liquid at RT).
Exclusive formation of the sulfonamide is observed. It
appears that the sulfonyl chloride has a greater reactivity
Scheme 7.
Scheme 8. A possible mechanistic model.

8258
L. Cai et al. / Tetrahedron 56 (2000) 8253±8262
substrates, including compatibility with a variety of func-
tional groups. However, only DMF gives synthetically
useful and general reactions. Even a change from methyl
to ethyl in the formamide shuts down the formation of
formamidines all together. For a-aminoesters, clean trans-
formation into the corresponding formamidines is observed
without any interference from the ester group. The stereo-
chemical con®guration of the a-carbon is maintained. For
a-aminoamides, we observed a clean transformation into
a-aminonitriles with retention of the stereocenter. These
reactions expand the use of naturally occurring a-amino-
acids as chiral pools in organic synthesis. Only limited in
success was achieved in the synthesis of amidines by this
strategy. A mechanism consistent with the observations of
analogous coupling agents and all the experimental results
in this study is proposed.
General procedure for the formation of formamidine
15c±17c: All reactions were performed with 0.10 mmol of
amines and 0.30 mmol of Ar-SO2Cl in 0.5 mL DMF at rt.
The products were isolated by 20£20 cm TLC plates.
N,N-Dimethyl 20-bromoanilino formamidine (1c). 1H
NMR in CD3CN, d, 7.91 (s, 1H, NvCH±N), 7.73 (dd,
5
3JHHˆ6.1 Hz, JHHˆ0.7 Hz, 1H, Ar-H), 7.51±7.46 (m, 2H,
3
5
Ar-H), 7.31 (td, JHHˆ5.8 Hz, JHHˆ1.4 Hz, 1H, Ar-H),
3.48 (s, 3H, CH3), 3.29 (s, 3H, CH3). MS data, 226, 228
(20%, M1), 211, 213 (5%, M2CH13 ), 186, 184, 182
(20%, M2N(CH3)2), 157, 155 (M2CH(N)±NMe12 ), 147
(100%, M2Br1), 132, 131 (M2Br±Me1), 106 (40%), 76
(20%). HRMS for C9H11BrN2, found: 226.009; calcd:
226.011.
N,N-Dimethyl anilino formamidine (2c). 1H NMR in
3
CD3CN, d, 7.59 (s, 1H, NvCH±N), 7.22 (td, JHH
ˆ
5
3
7.0 Hz, JHHˆ1.8 Hz, 2H, Ar-H), 6.95 (t, JHHˆ7.2 Hz,
3
Experimental
1H, Ar-H), 6.90 (d, JHHˆ8.4 Hz, 2H, Ar-H), 2.96 (s, 6H,
CH3). MS data, 148 (55%, M1), 133 (25%, M2CH31), 120
(20%), 106 (40%), 104 (40%, M2NMe12 ), 77 (100%, Ph1),
73 (90%). HRMS for C9H12N2, found: 148.100; cald:
148.100.
2-Pyridinesulfonyl chloride was synthesized according to a
literature preparation with 84% isolated yield.35 This
compound is not stable at rt, and normally is kept in a
freezer. The other sulfonyl chlorides are commercially
available and used as received. DMF was purchased from
Fisher Scienti®c; N,N-diethylformamide, N,N-dimethyl
acrylamide, 2-bromoaniline, p-toluenesulfonyl chloride,
methylsulfonyl chloride, 8-quinolinesulfonyl chloride,
acetyl chloride, benzoyl chloride, aniline, 3,5-dimethyl
aniline, 2-naphthyl amine, 1,3-phenylenediamine, 1,10-
binaphthyl-2,20-diamine, t-butyl amine, 2-aminopyridine,
N,N-Dimethyl 30,50-dimethylanilino formamidine (3c).
1H NMR in CD3CN, d, 7.56 (s, 1H, NvCH±N), 6.62 (s,
1H, Ar-H), 6.52 (s, 2H, Ar-H), 2.94 (s, 6H, NCH3), 2.23 (s,
6H, CH3). MS data, 176 (100%, M1), 175 (65%, M2H1),
161 (40%, M2CH13 ), 148 (40%), 134 (90%), 105 (60%,
M2CH(N)±NMe12 ), 91(26%), 79 (57%), 77 (55%).
HRMS for C11H16N2, found: 176.131; calcd: 176.131.
2-hydroxy-aniline,
3-hydroxy-2-aminopyridine,
ethyl
1
N,N-Dimethyl 20-naphthylamino-formamidine (4c). H
NMR in CD3CN, d, 7.78±7.71 (m, 4H, Ar-H), 7.40 (td,
2-aminobenzoate, N,N-dimethylacetamide, 2-nitrophenol,
N,N-dimethyl bromoacetamide, and Pd/C were from
Aldrich. Dihydrogen (H2) and chlorine (Cl2) were from
Aga gases (Hammond, IN). All a-aminoamides were
synthesized according to a literature procedure from
a-aminoacids or a-aminoesters, which were obtained from
Aldrich.36
3JHHˆ7.2 Hz, JHHˆ1.2 Hz, 1H, Ar-H), 7.30 (td, JHH
ˆ
5
3
5
5
8.4 Hz, JHHˆ1.5 Hz, 1H, Ar-H), 7.26 (d, JHHˆ1.8 Hz,
3
5
1H, Ar-H), 7.20 (dd, JHHˆ8.7 Hz, JHHˆ2.1 Hz, 1H,
Ar-H), 3.01 (s, 6H, CH3). MS data, 198 (80%, M1), 183
(30%, M2CH13 ), 170 (40%), 156 (100%), 127 (70%,
M2CH(N)±NMe12 ). HRMS for C13H14N2, found:
198.116; calcd: 198.116.
1H and 13C{1H} NMR spectra were recorded on Bruker 200,
400, and 500 MHz and Varian 300 MHz NMR spectro-
meters. All chemical shifts were referenced by the residual
solvent peak(s) of deuterated solvents. All low resolution
MS data were obtained from a HP 5897 Mass spectrometer,
and all high resolution MS data from Mass Spectrometry
Center of The University of Illinois at Urbana.
1,3-Di-(N,N-dimethylformamidino)benzene (5c). 1H
NMR in CD3CN, d, 7.61 (s, 2H, NvCH±N), 7.07 (t,
3JHHˆ7.8 Hz, 1H, Ar-H), 6.53 (dd, JHHˆ7.5 Hz,
3
4JHHˆ1.8 Hz, 2H, Ar-H), 6.46 (t, JHHˆ2.4 Hz, 1H, Ar-H),
5
2.96 (s, 12H, CH3). MS data, 218 (100%, M1), 203 (10%,
M2CH13 ), 190 (30%), 176 (20%), 172 (15%, M2NMe12 ),
158 (10%), 147 (15%), 131 (30%, M22£NMe21H1).
HRMS for C12H18N4, found: 218.154; calcd: 218.153.
General procedure for the formation of formamidine 1c±
14c: All reactions were performed with 0.10 mmol of
amines and 0.15 mmol of Ar-SO2Cl in 0.5 mL DMF at
rt. Isolated yields were based on amines. After 1.5 equiv.
of a sulfonyl chloride was dissolved in DMF for 5 min, an
amine (1.0 equiv.) was added at room temperature. The
reaction mixture was stirred for the speci®ed time listed in
the tables or checked by TLC until the reaction was ®nished.
After the solvent was removed, K2CO3 solution (4M) was
added. The mixture was then extracted with ether. The ether
solution was dried over Na2SO4 and the solvent was
removed to generate the pure product. All of the products
2,20-Di-(N,N-dimethylformamidino)-1,10-binaphthyl (6c).
1H NMR in CD3OD, d, 7.81 (t, JHHˆ8.4 Hz, 4H, Ar-H),
3
3
7.42 (s, 2H, NvCH±N), 7.25 (td, JHHˆ7.3 Hz,
4JHHˆ0.9 Hz, 2H, Ar-H), 7.24 (d, JHHˆ8.7 Hz, 2H,
3
3
4
Ar-H), 7.13 (td, JHHˆ7.5 Hz, JHHˆ1.2Hz, 2H, Ar-H),
3
7.02 (d, JHHˆ8.7 Hz, 2H, Ar-H), 2.55 (s, 12H, CH3). MS
data, 394 (68%, M1), 350 (20%, M2NMe12 ), 323 (53%,
M2CH(N)±NMe12 ), 307 (30%, M22£NMe21H1), 294
(35%), 278 (M2CH(N)±NMe2±NMe2±H1), 265 (70%),
252 (35%, M22£CH(N)±NMe12 ), 224 (20%), 197 (40%).
HRMS for C26H26N4, found: 394.214; calcd: 394.216.
were characterized by H NMR, 13C{1H} NMR, MS, and
HRMS.
1

L. Cai et al. / Tetrahedron 56 (2000) 8253±8262
8259
N,N-Dimethyl tert-butylamino-formamidine (7c). 1H
NMR in CD3CN, d, 7.87 (NvCH±N), 2.90 (s, NCH3),
2.78 (s, NCH3), 2.27 (s, CH3). MS data, 128 (20%, M1),
113 (100%, M2CH13 ).
CDCl3, d, 168.1 (CCO2), 159.9 (HCON), 140.9 (CC), 135.0
(CH), 131.3 (CH), 123.5 (CH), 121.6 (CH), 115.9 (CC),
61.9 (OCH2), 14.6 (CH3). MS data, 193 (10%, M1), 165
(40%, M2CO1), 119 (100%, M2HCO2CH2CH3), 92
(30%, C6H4NH1H1), 65 (20%, C5H15 ). HRMS for
C10H11NO3, found: 193.074; calcd: 193.074.
N,N-Dimethyl a-methylbenzylamino-formamidine (8c).
1H NMR in CDCl3, d, 7.58 (s, 1H, NvCH±N), 7.38±7.12
3
(m, 5H, Ph), 4.42 (q, JHHˆ6.8 Hz, 1H, ±CH±N), 3.00 (s,
Methyl l-phenyl alanine a-(N0,N0-dimethylformami-
dino) carboxylate (14c). H NMR in CDCl3, d, 7.40±
3
1
6H, NCH3), 1.57 (d, JHHˆ6.8 Hz, 3H, C±CH3).
7.18 (m, 6H, Ar-H and HCN2), 4.89 (s, 1H, CH±N), 3.61
(s, 3H, OCH3), 2.83 (s, 6H, NCH3). MS data, 220 (1%, M1),
205 (1%, M2Me1), 161 (100%, M2CO2CH13 ). HRMS for
C12H16N2O2, found: 220.121; calcd: 220.121.
N,N-Diethyl 2-pyridinesulfonamide (9c). 1H NMR in
3
4
CDCl3, 8.66 (dd, JHHˆ4.6 Hz, JHHˆ1.8 Hz, 1H, Ar-H),
3
4
7.93 (dt, JHHˆ7.9 Hz, JHHˆ1.7 Hz, 1H, Ar-H), 7.86 (dt,
4
3JHHˆ7.7 Hz, JHHˆ1.7 Hz, 1H, Ar-H), 7.43 (ddd,
4
5
3JHHˆ7.0 Hz, JHHˆ4.7 Hz, JHHˆ1.1 Hz, 1H, Ar-H), 3.39
(q, 3JHHˆ7.2 Hz, 4H, CH2), 1.13 (t, 3JHHˆ7.2 Hz, CH3). MS
data, 199 (2%, M2CH13 ), 169, 107 (26%, M2C5H4N±
C2H15 ), 78 (78%, C5H4N1), 79 (61%, C5H5N1), 72 (100%,
N(CH2CH3)12 ).
l-Phenyl alanine a-(N0,N0-dimethylformamidino) nitrile
(15c). 1H NMR in CDCl3, d, 7.59 (s, 1H, NvCH±N), 7.44±
7.36 (m, 5H, Ar-H), 5.42 (s, 1H, ±CH(CN)±N), 2.95 (s, 6H,
CH3). 13C{1H} NMR, d, in CDCl3, 156.9 (CHN2), 137.9,
129.3, 128.8, 127.3, 119.9 (CN), 58.0. MS data, 187 (100%,
M1), 161 (5%, M2CN1), 147 (30%, M22CH13 ), 116 (95%,
M2CH(vN)NMe12 ), 106 (100%, Ph±CHNH12 ), 89
(Ph-C1), 77 (50%, Ph1), 71 (70%, CH(vN)NMe12 ).
HRMS, C11H13N3, found: 187.111; calcd: 187.111.
2-(N0,N0-Dimethylformamidino) pyridine (10c). 1H NMR
3
in CD3CN, d, 8.42 (s, 1H, NvCH±N), 8.17 (dd, JHH
ˆ
5
3
4.5 Hz, JHHˆ1.8 Hz, 1H, Ar-H), 7.53 (dd, JHHˆ5.7 Hz,
3
5
5JHHˆ0.9 Hz, 1H, Ar-H), 6.84 (dd, JHHˆ4.5 Hz, JHH
ˆ
3
5
1.5 Hz, 1H, Ar-H), 6.80 (dd, JHHˆ7.2 Hz, JHHˆ0.9 Hz,
1H, Ar-H), 3.06 (s, 3H, CH3), 3.00 (s, 3H, CH3). MS data,
149 (20%, M1), 134 (35%, M2CH31), 119 (5%,
M22£CH13 ), 105 (15%, M2NMe12 ), 93 (50%), 78 (70%,
M2CH(N)±NMe12 ), 73 (100%). HRMS for C8H11N3,
found: 149.096; calcd: 149.095.
l-Phenyl alanine a-aminoamide (15a).36 1H NMR in
CDCl3, d, 7.43±7.27 (m, 5H, Ar-H), 6.92 (brs, 1H, NH),
6.08 (brs, 1H, NH), 4.52 (s, 1H, CH(NH2)), 1.87 (s, 6H,
CH3).
l-Benzyl alanine a-(N0,N0-dimethylformamidino) nitrile
(16c). H NMR in CD3COCD3, d, 7.39 (m, 2H, o-H), 7.33
1
1
2-(N0,N0-Dimethylformamidino) phenol (11c). H NMR
in CD3COCD3, d, 7.93 (s, 1H, NvCH±N), 6.96 (dd,
(m, 2H, m-H), 7.32 (s, 1H, NvCH±N), 7.20 (m, 1H, p-H),
4.43 (m, 1H, ±CH(CN)±N), 3.02 (m, 2H, CH2), 2.85 (s, 6H,
CH3). 13C{1H} NMR in CD3COCD3, d, 157.2 (CHN2),
137.3, 130.2, 128.5, 127.1, 120.9 (CN), 56.9, 42.9. MS
data, 201 (15%, M1), 186 (1%, M2CH13 ), 174 (8%,
M2HCN1), 110 (100%, M2CH2Ph1), 91 (35%, PhCH12 ),
77 (10%, Ph1), 65 (20%, C5H51). HRMS, C12H15N3, found:
201.126; calcd: 201.127.
4
3
3JHHˆ9.9 Hz, JHHˆ2.2 Hz, 1H, Ar-H), 6.80 (td, JHH
ˆ
4
3
7.4 Hz, JHHˆ1.5 Hz, 1H, Ar-H), 6.73 (dd, JHHˆ7.9 Hz,
4JHHˆ1.6 Hz, 1H, Ar-H), 6.67 (td, 3JHHˆ7.5 Hz,
4JHHˆ1.6 Hz, 1H, Ar-H), 3.11 (s, 3H, CH3), 3.020 (s, 3H,
CH3). 13C{1H} NMR in CD3COCD3, d, 153.3 (NvCH±N),
150.9 (C±O), 138.2 (CC), 123.1 (CH), 120.1 (impurity),
119.6 (CH), 115.9 (CH), 113.3 (CH), 39.8 (CH3), 33.9
(CH3). MS data, 164 (70%, M1), 147 (18%, M2OH1),
120 (100%, M2N(CH3)12 ). HRMS for C9H12N2O, found:
164.094607; calcd: 164.094963. HRMS for M22H,
C9H10N2O, found: 162.079; calcd: 162.079.
l-Benzyl alanine a-aminoamide (16a).36 1H NMR in
CDCl3, d, 7.35±7.23 (m, 5H, Ar-H), 7.12 (brs, 1H, NH),
3
3
5.69 (brs, 1H, NH), 3.62 (dd, JHHˆ9.7 Hz, JHHˆ4.0 Hz,
3
3
1H, CH(NH)), 3.28 (dd, JHHˆ13.7 Hz, JHHˆ4.0 Hz, 1H,
3
3
CH2), 2.72 (dd, JHHˆ13.7 Hz, JHHˆ9.5 Hz, 1H, CH2),
3-Hydroxy-2-(N0,N0-dimethylformamidino) pyridine (12c).
1H NMR in CDCl3, d, 8.60 (s, 1H, NvCH±N), 7.76 (dd,
1.34 (brs, 2H, NH2).
4
3
3JHHˆ5.2 Hz, JHHˆ1.7 Hz, 1H, Ar-H), 7.10 (td, JHH
ˆ
l-Tryptophan a-(N0,N0-dimethylformamidino) nitrile
(17c). H NMR in CD3COCD3, d, 10.16 (brs, 1H, N±H),
4
3
1
7.9 Hz, JHHˆ1.7 Hz, 1H, Ar-H), 6.82 (dd, JHHˆ7.8 Hz,
4JHHˆ5.1 Hz, 1H, Ar-H), 3.15 (s, 3H, CH3), 3.11 (s, 3H,
CH3). MS data, 165 (50%, M1), 150 (18%, M2CH31),
121 (100%, M2N(CH3)21), 110 (100%, 3-OH-2-NH2-
Py1), 94 (30%, 3-OH-2-0-Py1), 82 (60%, C4H4NO, 71
(30%, CH(vN)(±NMe2)1), 55 (75%, C3H3O1). HRMS
for C8H11N3O, found: 165.090; calcd: 165.090. HRMS for
M22H, C8H9N3O, found: 163.074; calcd: 163.075.
3
3
7.64 (dd, JHHˆ6.4 Hz, 1H, Ar-H), 7.40 (td, JHHˆ6.6 Hz,
1H, Ar-H), 7.40 (s, 1H, NvCH±N), 7.29 (d, 4JHHˆ1.8 Hz,
1H, Ar-H), 7.11 (td, 3JHHˆ6.4 Hz, 4JHHˆ0.8 Hz, 1H, Ar-H),
3
4
7.03 (td, JHHˆ6.0 Hz, JHHˆ0.8 Hz, 1H, Ar-H), 4.47 (t,
2
3JHHˆ5.7 Hz, 1H, ±CH(CN)±N), 3.22 (ABd, JHH
ˆ
ˆ
3
2
14.8 Hz, JHHˆ6.2 Hz, 1H, CH2), 3.13 (ABd, JHH
3
14.2 Hz, JHHˆ5.8 Hz, 1H, CH2), 2.85 (s, 6H, CH3).
13C{1H} NMR in CD3COCD3, d, 157.1 (CHN2), 137.0,
128.1, 124.4, 124.2, 121.6, 121.5, 119.1, 119.0, 111.7,
111.6, 110.5, 56.8, 33.1. MS data, 240 (4%, M1), 130
(100%, M2CH(CN)(vN±CHNMe2)1). HRMS for
C14H16N4, found: 240.138; calcd: 240.137. HPLC analysis
on a chiracel OD column by isopropanol/hexane (5/95) gave
a retention time of 31.1 min.
Ethyl 2-(formylamino) benzoate (13c). 1H NMR in
3
CDCl3, d, 11.0 (brs, 1H, NH), 8.70 (d, JHHˆ8.4 Hz, 1H,
3
CH(O)), 8.51 (s, 1H, CHO), 8.06 (d, JHHˆ8.0 Hz, 1H,
3
Ar-H), 7.55 (t, JHHˆ7.8 Hz, 1H, Ar-H), 7.12 (t,
3
3JHHˆ7.7 Hz, 1H, Ar-H), 4.39 (q, JHHˆ7.0 Hz, 2H,
3
OCH2), 1.42 (t, JHHˆ7.1 Hz, 3H, CH3). 13C{1H} NMR in

8260
L. Cai et al. / Tetrahedron 56 (2000) 8253±8262
l-Tryptophan a-aminoamide (17a).36 1H NMR in
CD3COCD3, d, 8.30 (brs, 1H, ArN±H), 7.68 (d,
phenol (209 mg, 1.5 mmol) and N,N-dimethyl 2-bromo-
acetamide (500 mg, 3.0 mmol) were dissolved in acetone.
K2CO3 (5 equiv.) was added. The mixture was re¯uxed
overnight or as needed for complete reaction as checked
by TLC. The mixture was puri®ed on a silica gel column
eluated by ethyl acetate. The product was contaminated by
3
3JHHˆ7.8 Hz, 1H, Ar-H), 7.38 (d, JHHˆ7.7 Hz, 1H,
Ar-H), 7.25±7.08 (m, 4H, Ar-H, N±H), 5.66 (brs, 1H, N±
H), 3.73 (dd, 3JHHˆ4.1 Hz, 3JHHˆ9.2 Hz, 1H, CH(N)), 3.39
3
3
(dd, JHHˆ4.1 Hz, JHHˆ14.2 Hz, 1H, CH2), 2.94 (dd,
3
1
3JHHˆ9.2 Hz, JHHˆ14.2 Hz, 1H, CH2), 1.47 (brs, 2H,
N,N-dimethyl 2-bromoacetamide. H NMR in CDCl3, d,
3
3
NH2).
7.85 (d, JHHˆ8.1 Hz, 1H, Ar-H), 7.52 (t, JHHˆ7.6 Hz,
3
1H, Ar-H), 7.19 (d, JHHˆ8.3 Hz, 1H, Ar-H), 7.08 (t,
d-Tryptophan d-(N0,N0-dimethylformamidino) nitrile
(18c). H NMR in CD3COCD3, d, 10.14 (brs, 1H, N±H),
3JHHˆ7.7 Hz, 1H, Ar-H), 4.85 (s, 2H, CH2), 3.14 (s, 3H,
1
CH3), 2.97 (s, 3H, CH3).
3
4
7.62 (dd, JHHˆ7.9 Hz, JHHˆ0.4 Hz, 1H, Ar-H), 7.38 (td,
4
3JHHˆ7.2 Hz, JHHˆ0.6 Hz, 1H, Ar-H), 7.37 (s, 1H,
N,N-Dimethyl 20-aminophenoxo acetamide (22).37 N,N-
Dimethyl 20-nitrophenoxo acetamide (19) was dissolved in
methanol, and hydrogenated by H2 catalyzed by Pd/C (10%
Pd). The product was puri®ed by a silica gel column
elauated by ethyl acetate/hexane (1:1). The yield was
4
NvCH±N), 7.27 (d, JHHˆ2.2 Hz, 1H, Ar-H), 7.09 (td,
4
3
3JHHˆ6.5 Hz, JHHˆ0.9 Hz, 1H, Ar-H), 7.01 (t, JHH
ˆ
4
3
5.6 Hz, JHHˆ0.8 Hz, 1H, Ar-H), 4.47 (t, JHHˆ5.7 Hz,
2
3
1H, ±CH(CN)±N), 3.21 (ABd, JHHˆ14.8 Hz, JHH
ˆ
7.5 Hz, 1H, CH2), 3.10 (ABd, 2JHHˆ14.2 Hz,
3JHHˆ6.7 Hz, 1H, CH2), 2.81 (s, 6H, CH3). 13C{1H} NMR
in CD3COCD3, d, 157.1, 137.0, 128.1, 124.4, 124.2, 121.7,
121.5, 119.1, 119.0, 111.7, 111.6, 110.5, 56.8, 33.1. MS
data, 240 (4%, M1), 130 (100%, M2CH(CN)(vN±
CHNMe2)1). HRMS for C14H16N4, found: 240.137; calcd:
240.137. HPLC analysis on a chiracel OD column by
isopropanol/hexane (5/95) gave a retention time of
32.8 min.
90%. H NMR in CDCl3, d, 6.85 (t, JHHˆ8.1 Hz, 1H,
1
3
3
Ar-H), 6.83 (d, JHHˆ8.1 Hz, 1H, Ar-H), 6.74 (d,
3JHHˆ7.5, 1H, Ar-H), 6.70 (t, JHHˆ7.0 Hz, 1H, Ar-H),
3
4.73 (s, 2H, CH2), 4.02 (brs, 2H, NH2), 3.06 (s, 3H, CH3),
3.00 (s, 3H, CH3).
N,N-Dimethyl 20-(200-pyridylsulfonamido)phenoxo acet-
amide (23). N,N-Dimethyl 20-aminophenoxo acetamide
(22) (12 mg, 0.062 mmol) was dissolved in CH2Cl2, or
CH3COOH, or in neat state. 2-Pyridinesulfonyl chloride
(1.5±3 equiv.) was added in one portion at rt. The product
was puri®ed by a silica gel column. The yield was 90%. 1H
NMR in CDCl3, d, 8.85 (s, 1H, NH), 8.65 (d, 3JHHˆ4.5 Hz,
d-Tryptophan a-aminoamide (18a).36 1H NMR in
CD3COCD3, d, 8.23 (brs, 1H, ArN±H), 7.68 (d,
3
3JHHˆ7.6 Hz, 1H, Ar-H), 7.38 (d, JHHˆ8.0 Hz, 1H,
3
Ar-H), 7.25±7.08 (m, 4H, Ar-H, N±H), 5.57 (brs, 1H, N±
1H, Ar-H), 7.98 (d, JHHˆ7.7 Hz, 1H, Ar-H), 7.82 (t,
H), 3.73 (dd, 3JHHˆ4.1 Hz, 3JHHˆ9.2 Hz, 1H, CH(N)), 3.40
3JHHˆ6.9 Hz, 1H, Ar-H), 7.64 (dd, JHHˆ7.1 Hz, JHH
ˆ
3
4
3
3
3
4
(dd, JHHˆ4.1 Hz, JHHˆ14.2 Hz, 1H, CH2), 2.94 (dd,
2.4 Hz, 1H, Ar-H), 7.42 (dd, JHHˆ7.5 Hz, JHHˆ4.6 Hz,
3
3
1H, Ar-H), 7.02±6.96 (m, 2H, Ar-H), 6.84 (dd, JHH
3JHHˆ9.2 Hz, JHHˆ14.2 Hz, 1H, CH2), 1.45 (brs, 2H,
ˆ
4
NH2).
7.3 Hz, JHHˆ2.5 Hz, 1H, Ar-H), 4.64 (s, 2H, CH2O), 2.98
(s, 6H, NCH3).
N,N-Dimethyl 20-bromoanilino acetamidine (19c).
2-Bromoaniline (0.10 mmol) was dissolved in 0.25 mL
N,N-dimethyl acetamide. 2-Pyridinesulfonyl chloride
(0.20 mmol) was added into the above solution in one
portion. The mixture was stirred at rt for about 20 min.
The products were worked up as described above for the
synthesis of formamidines. 1H NMR in CD3CN, d, 7.49 (dd,
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3
3JHHˆ8.0 Hz, JHHˆ1.4 Hz, 1H, Ar-H), 7.19 (td, JHH
ˆ
4
3
7.4 Hz, JHHˆ1.4 Hz, 1H, Ar-H), 6.79 (td, JHHˆ7.7 Hz,
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3
4JHHˆ1.6 Hz, 1H, Ar-H), 3.03 (s, 6H, NMe2), 1.80 (s, 3H,
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