Synthesis of novel α-amino-N-substituted thioacetimidates

Full text of DOI:10.1021/jo0016935

J . Org. Chem. 2001, 66, 2865-2868
2865
Previous preparations of 1-imidoylbenzotriazoles com-
prise: (i) treatment of N-aryl secondary amides with
phosphorus oxychloride in the presence of triethylamine
and subsequent trapping of the resultant imidoyl chloride
with benzotriazole;6b (ii) treatment of amides with 1,1′-
sulfinylbenzotriazole6a,c (generated in situ from 1-tri-
methylsilylbenzotriazole and thionyl chloride); (iii) via a
benzotriazole-mediated Beckmann type rearrangement
of oximes.7
1-R-Amino-substituted 1-imidoylbenzotriazoles have
not been reported previously. We now disclose an efficient
novel synthetic route to such benzotriazoles 5a -k via
insertions of isonitriles 3a -d into the benzotriazole
nitrogen-carbon bond of N-(aminoalkyl)benzotriazoles
4a -f and subsequent nucleophilic displacement of the
benzotriazole moiety using thiols to give novel R-amino
thioacetimidates 1a -g.
Syn th esis of Novel r-Am in o-N-su bstitu ted
Th ioa cetim id a tes
Alan R. Katritzky,* Martin A. C. Button,‡ and
Sophie Busont§
Center for Heterocyclic Compounds, Department of
Chemistry, University of Florida, Gainesville, Florida 32611
katritzky@chem.ufl.edu
Received December 4, 2000
In tr od u ction
Glycineamidines 2 are useful synthetic building blocks
for the synthesis of aminoimidazoliums,1 aryliminopi-
perazine-2,3-diones,2 and novocaine derivatives.3 The
analogous R-amino-N-substituted thioacetimidates 1 are
also potentially useful intermediates; however, few of
them have been previously reported.4 R-Amino-thioace-
timidate derivatives were shown to exhibit herbicidal
activity.4b In general, thioimidates are known to be very
useful synthetic precursors in organic chemistry.4c
Resu lts a n d Discu ssion
N-(Aminoalkyl)benzotriazoles 4a -f were formed by
well-established procedures involving condensation of
benzotriazole, an aldehyde, and a secondary amine in
water (4a -d ),8 or by reflux under Dean-Stark conditions
in benzene (4e-f)9 (Scheme 1). Although they frequently
crystallized as the pure benzotriazol-1-yl isomer, such
N-(aminoalkyl)benzotriazoles usually exist in solution as
an equilibrating mixture of Bt1 and Bt2 isomers. The
reactivity of both isomers is identical or very similar,
since they both ionize to the same species.6e
Imidoyl halides are versatile intermediates5 and are
usually prepared by reaction of phosgene, thionyl chlo-
ride, oxalyl chloride, or phosphorus pentachloride with
amides.5 The major disadvantage of imidoyl halides is
their inherent instability and, since they are particularly
susceptible to hydrolysis, they are rarely isolated and
purified prior to use. 1-Imidoylbenzotriazoles provide
stable alternatives since they are substantially more
stable and easier to isolate than the corresponding
imidoyl halides.6 The benzotriazolyl moiety in imidoyl-
benzotriazoles can be exchanged for various nucleophiles,6a,d
and photolysis leads to 1,2-disubstituted benzimidazoles.6c
The isonitriles 3a -d were prepared from the corre-
sponding amides10 (92-99%) and were usually generated
and used in situ.
Reaction of the aromatic 3a -c or aliphatic isonitriles
3d with N-(aminoalkyl)benzotriazoles 4a -f in the pres-
ence of catalytic boron trifluoroetherate in THF at 20 °C
gave crude 1-imidoylbenzotriazoles 5a -k in excellent
yields (Table 1). Only the Bt1 isomers of imidoylbenzot-
riazoles 5a -i,k were observed even when a mixture of
the Bt1 and Bt2 isomers of N-(aminoalkyl)benzotriazoles
4a -f were used, a result of isomerization of the starting
materials. However, 5j was obtained as a mixture of the
Bt1 and Bt2 isomers. The reactions were complete within
1 h, and the products were purified by recrystallization
where possible (5a ,c,d ,f,h ,i,j) (87-97%). Compounds
5b,g,k were purified by flash column chromatography
(96%, 94%, and 87%, respectively). Attempts to purify
imidoylbenzotriazole 5e (45%) by column chromatogra-
phy afforded a significant amount of the corresponding
amide 6 (32%) as well as a trace of novel amidine 7 (5%)
(Scheme 1). In general, 1.05-1.10 equiv of the isonitrile
gave the products with approximately 95% purity fol-
lowing extractive workup. All 1-imidoylbenzotriazoles,
except 5k , could be used for the next step without
recrystallization or purification by column chromatogra-
phy.
‡ Present address: Charnwood Catalysis, PO Box 5775, Loughbo-
rough, Leicestershire, LE11 3WE, UK.
§ Present address: 3M Health Care Ltd, 3M House, Morley Street,
Loughborough, Leicestershire, LE11 1EP, UK.
(1) Korshin, E. E.; Soboleva, G. I.; Levin, Y. A.; Podval’nyi, E. A.;
Efremov, Y. Y. J . Org. Chem USSR (Engl. Transl.) 1993, 482.
(2) Korshin, E. E.; Soboleva, G. I.; Levin, Y. A.; Podval’nyi, E. A.;
Efremov, Y. Y. Bull. Acad. Sc. USSR 1991, 40, 212; as abstracted by
ISI.
(3) Kaufmann, H. P.; Budwig, J .; Mohnke, K. Chem. Ber. 1942, 75,
1585.
(4) (a) Takahata, H.; Takamatsu, T.; Chen, Y.-S.; Ohkubo, N.;
Yamazaki, T.; Momose, T.; Date. T. J . Org. Chem. 1990, 55, 3792. (b)
Entwistle, I. D. US Patent 4,131,449, 1978. (c) Neilson, D. G. In The
Chemistry of Amidines and Imidates; Patai, S., Rappoport, Z., Eds.;
J ohn Wiley and Sons: New York, 1991; Vol. 2.
(5) (a) Bonnet, R. In The Chemistry of the Carbon Nitrogen Double
Bond; Patai, S., Ed.; Interscience Publishers: London, 1970. (b) In The
Chemistry of Amides; Zabicky, J ., Ed.; Interscience Publishers: London,
1970.
(6) (a) Katritzky, A. R.; Stevens, C. V.; Zhang, G.-F.; J iang, J .; De
Kimpe, N. Heterocycles 1995, 40, 231. (b) Katritzky, A. R.; Rachwal,
S.; Offerman, R. J .; Najzarek, Z.; Yagoub, A. K.; Zhang, Y. Chem. Ber.
1990, 123, 1545. (c) Katritzky, A. R.; Yang, B.; Abonia, R.; Insuasty,
B. J . Chem. Res. (S) 1996, 540. (d) Katritzky, A. R.; Donkor, A.; Fang,
Y., Synthesis 2000, 14, 2029 (e) Katritzky, A. R.; Lan, X.; Yang, J . Z.;
Denisko, O. V. Chem. Rev. 1998, 98, 409.
(7) Katritzky, A. R.; Monteux, D. A.; Tymoshenko, D. O. Org. Lett.
1999, 1, 577.
(8) Katritzky, A. R.; Pilarski, B.; Urogdi, L. Org. Prep. Proced. Int.
1989, 21, 135.
(9) Katritzky, A. R.; Yannakopoulou, K.; Lue, P.; Rasala, D.; Urogdi,
L. J . Chem. Soc., Perkin Trans. 1 1989, 225.
(10) Katritzky, A. R.; Sutharchanadevi, M.; Urogdi, L. J . Chem. Soc.,
Perkin Trans. 1 1990, 1847.
10.1021/jo0016935 CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/29/2001

2866 J . Org. Chem., Vol. 66, No. 8, 2001
Notes
Sch em e 1a
a
For yields of 1a -g and 5a -k , see Tables 1 and 2. For compounds 4a -b,d -f Bt ) benzotriazol-1-yl (Bt1) and benzotriazol-2-yl (Bt2)
in ratios from 1:1 to 4:1. For compound 5j Bt ) Bt1:Bt2 in a 1:2.6 ratio.
Ta ble 1. 1-Im id oylben zotr ia zoles 5a -k
Ta ble 2. r-Am in o N-Su bstitu ted Th ioa cetim id a tes 1a -g
R1
R2
R3
R4
R5
yielda (%)
5
R1
R2
-(CH2)2O(CH2)2-
Me Me
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
R3
R4
yielda (%)
1
a
b
c
d
e
f
H
-(CH2)2O(CH2)2- 2,5-Cl2C6H3 4-MeC6H4
-(CH2)2O(CH2)2- 2,5-Cl2C6H3 C6H5CH2
Me
-(CH2)2O(CH2)2- 4-NO2C6H4 4-MeC6H4
-(CH2)2O(CH2)2- C6H5CH2
-(CH2)2O(CH2)2- C6H5CH2
44
53
92b
44
46
75
59
a
b
c
d
e
f
g
h
i
H
H
H
H
H
H
H
H
2,5-Cl2C6H3
2,5-Cl2C6H3
4-NO2-C6H4
3-NO2-C6H4
2,5-Cl2C6H3
3-NO2-C6H4
C6H5CH2
4-NO2-C6H4
3-NO2-C6H4
2,5-Cl2C6H3
2,5-Cl2C6H3
92
96b
93
H
H
H
H
H
Ph
2,5-Cl2C6H3
Ph
97
Me
Me
Ph
Ph
90 (45)c
91
4-MeC6H4
4-tBu-2-MeC6H3
g
iBu -(CH2)2O(CH2)2- 3-NO2C6H4 4-MeC6H4
-(CH2)2O(CH2)2-
-(CH2)5-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)5-
94b
88
87
a
b
Isolated by column chromatography unless stated. Isolated
iBu
Ph
H
by recrystallization.
j
k
89
87b
particularly evident for the CdN carbon at ca. 165-170
ppm and the adjacent methylene carbon at 58-64 ppm
in the 13C NMR spectra of thioacetimidates 1a ,c,d ,g and
1-imidoylbenzotriazole 5i. Sometimes the CdN carbon
signal was extremely broad and barely visible; therefore,
integration of the 13C NMR spectra became necessary in
order to verify the presence of these signals. The positions
of the CdN carbon signal in the 13C NMR spectra was
similar to that observed in previously reported 1-imi-
doylbenzotriazoles (typically around 155 ppm)6a,b and
thiazoles (typically around 165-170 ppm).11 Increased
acquisition times and temperatures of 60 °C for the NMR
acquisitions usually afforded better resolved spectra, but
occasionally led to decomposition, i.e., as in the case of
1a .
a
b
Isolated by recrystallization unless stated. Purified by flash
column chromatography. c Isolated by column chromatography,
crude yield ca. 90%, isolated yield 45% due to significant hydrolysis
to amide 6 (32%).
Attempts were unsuccessful in carrying out the analo-
gous isonitrile insertion reactions to prepare R-thio- or
R-alkoxy-N-substituted thioacetimidates from R-thio-
alkyl- and R-alkoxyalkyl-benzotriazoles, respectively.
R-Amino thioacetimidates 1a -g resulted from the
nucleophilic displacement in refluxing THF of the ben-
zotriazolyl moiety in 5a ,c,e,g,i by an appropriate ali-
phatic or aromatic thiolate anion, generated in situ from
a thiol and sodium methoxide (Scheme 1). Purification
by column chromatography on silica gel for compounds
1a ,b,d -g, and recrystallization for 1c, led to isolated
yields of 44-92% (Table 2). Since the starting material
5 and product 1 often have virtually identical retention
factors, they could not be separated by column chroma-
tography unless 5 was completely consumed.
Con clu sion
We have reported an efficient Lewis acid catalyzed
isonitrile insertion reaction leading to highly substituted
R-amino-substituted 1-imidoylbenzotriazoles 5a-k, stable
alternatives to imidoyl halides. Nucleophilic displacement
of the benzotriazolyl moiety in 5a ,c,e,g,i using a variety
of thiols led to novel highly functionalized R-amino
thioacetimidates 1a -g.
The structures of compounds 1a -g and 5a -k were
confirmed by H and 13C NMR and mass spectroscopy
1
and elemental analyses. Badly defined peaks and poorly
resolved H and 13C NMR spectra were often obtained at
1
room temperature for the pure R-amino thioacetimidates
1a -g and for 1-imidoylbenzotriazole 5i; this was due to
the slow rotation around the CdN double bond. This was
(11) Katritzky, A. R.; Ghiriviga, I.; Cundy, D. J . Heterocycles 1994,
38, 1041.

Notes
J . Org. Chem., Vol. 66, No. 8, 2001 2867
N-[1-(1H-Ben zotr ia zol-1-yl)-2-m or p h olin oeth ylid en e]-4-
n itr oa n ilin e (5c). Compound 5c was crystallized from ethanol
as pale yellow plates (93%), mp 164-165 °C; H NMR (CDCl3)
Exp er im en ta l Section
1
Gen er a l Com m en ts. Melting points were determined on a
hot-stage microscope and are uncorrected. 1H NMR spectra were
recorded on a 300 MHz spectrometer using tetramethylsilane
as the internal standard. The 13C NMR spectra were recorded
at 75 MHz on the same instrument with the solvent CDCl3 peak
as the internal reference. Elemental analyses (C, H, N) were
carried out on a Carlo Erba-1106 instrument. Column chroma-
tography was carried out on silica gel (230-400 mesh). THF was
distilled from Na and benzophenone under a nitrogen atmo-
sphere prior to use. N-(Aminoalkyl) benzotriazoles 4a -d were
prepared in high yields (63-95%) by condensation of benzotria-
zole, formaldehyde, and a secondary amine in water.8,12 N-
(Aminoalkyl)benzotriazoles 4e-f were prepared by reflux of
benzotriazole, an aldehyde, and a secondary amine under Dean-
Stark conditions in benzene.9 The isonitriles 3a -d were pre-
pared quantitatively from the corresponding amides using
phosphorus oxychloride in the presence of diisopropylamine at
-10 °C10 and used immediately, or, if stored under inert
atmosphere in the freezer, within 24 h.
1-(3-Meth yl-1-m or p h olin obu tyl)ben zotr ia zole (4e). Com-
pound 4e was crystallized from ethanol as white needles (63%);
it was present as a 1:1 mixture of Bt1 and Bt2 isomers, mp 89-
91 °C; 1H NMR (CDCl3) [for both isomers unless stated] δ 0.88-
1.02 (m, 12H), 1.36-1.58 (m, 2H), 2.12-2.46 (m, 4H), 2.56-2.70
(m, 8H), 3.60-3.79 (m, 8H), 5.51-5.68 (m, 2H), 7.35-7.44 (m,
3H, 2H for Bt1 isomer and 1H for Bt2 isomer), 7.48 (t, J ) 7.5
Hz, 1H, Bt2 isomer), 7.60 (d, J ) 8.9 Hz, 1H, Bt2 isomer), 7.86-
7.92 (m, 2H, Bt1 isomer), 8.09 (d, J ) 8.3 Hz, 1H, Bt2 isomer).
13C NMR (CDCl3) [for both isomers] δ 22.1, 22.3, 22.5, 24.6, 39.5,
39.7, 48.4, 48.9, 66.8, 66.9, 77.7, 84.6, 109.8, 118.1, 119.9, 123.7,
126.1, 127.2, 133.8, 143.4, 145.5. Anal. Calcd for C15H22N4O: C,
65.75; H, 8.09; N, 20.45. Found: C, 65.31; H, 8.28; N, 20.37.
δ 2.43-2.48 (m, 4H), 3.43-3.48 (m, 4H), 4.14 (s, 2H), 7.13 (d,
J ) 8.9 Hz, 2H), 7.54 (dt, J ) 1.0, 7.4 Hz, 1H), 7.64 (dt, J ) 1.0,
7.4 Hz, 1H), 8.15 (d, J ) 8.2 Hz, 1H), 8.30 (d, J ) 8.7 Hz, 2H),
8.41 (d, J ) 8.2 Hz, 1H). 13C NMR (CDCl3) δ 53.2, 54.9, 66.5,
115.1, 120.0, 120.1, 124.7, 125.9, 129.7, 131.1, 144.1, 146.5, 153.0,
153.3. Anal. Calcd for C18H18N6O3: C, 59.01; H, 4.95; N, 22.94.
Found: C, 59.18; H, 5.09; N, 23.21.
N-[1-(1H-Ben zotr ia zol-1-yl)-2-m or p h olin oeth ylid en e]-3-
n itr oa n ilin e (5d ). Compound 5d was crystallized from ethanol
as white plates (97%), mp 107-108 °C; 1H NMR (CDCl3) δ 2.45-
2.50 (m, 4H), 3.48-3.53 (m, 4H), 4.13 (s, 2H), 7.39 (d, J ) 8.4
Hz, 1H), 7.50-7.68 (m, 3H), 8.02-8.08 (m, 2H), 8.16 (d, J ) 8.1
Hz, 1H), 8.46 (d, J ) 8.4 Hz, 1H). 13C NMR (CDCl3) δ 53.2, 54.5,
66.6, 115.3, 115.5, 119.0, 120.1, 125.9, 126.6, 129.5, 129.7, 131.2,
146.6, 148.0, 148.5, 154.5. Anal. Calcd for C18H18N6O3: C, 59.01;
H, 4.95; N, 22.94. Found: C, 59.09; H, 5.03; N, 22.95.
N -[1-(1H -Be n zot r ia zol-1-yl)-2-(N -m e t h yla n ilin o)e t h -
ylid en e]-2,5-d ich lor oa n ilin e (5e). Compound 5e was obtained
as yellow plates following column chromatography using ethyl
acetate/hexanes (1:15) (45%), mp 110-112 °C; 1H NMR (CDCl3)
δ 2.66 (s, 3H), 5.19 (s, 2H), 6.40-6.46 (m, 3H), 6.74 (t, J ) 7.4
Hz, 1H), 6.90 (dd, J ) 2.4, 8.7 Hz, 1H), 7.17 (t, J ) 7.1 Hz, 2H),
7.28 (t, J ) 8.1 Hz, 1H), 7.51 (t, J ) 7.7 Hz, 1H), 7.61 (t, J ) 7.8
Hz, 1H), 8.16 (d, J ) 8.1 Hz, 1H), 8.39 (d, J ) 8.4 Hz, 1H). 13C
NMR (CDCl3) δ 39.8, 54.0, 112.2, 115.3, 117.7, 119.3, 120.0,
120.5, 124.0, 125.8, 129.2, 129.8, 129.9, 131.5, 132.5, 144.7, 146.4,
147.0, 153.8. Anal. Calcd for C21H17N5Cl2: C, 61.47; H, 4.18; N,
17.07. Found: C, 61.28; H, 4.15; N, 17.03.
N -[1-(1H -Be n zot r ia zol-1-yl)-2-(N -m e t h yla n ilin o)e t h -
ylid en e]-3-n itr oa n ilin e (5f). Compound 5f was crystallized
1
from ethanol as white plates (91%), mp 138-139 °C; H NMR
(CDCl3) δ 2.61 (s, 3H), 5.25 (s, 2H), 6.35 (d, J ) 7.8 Hz, 2H),
6.70 (dt, J ) 0.9, 6.9 Hz, 1H), 6.92-6.96 (m, 1H), 7.07-7.14 (m,
2H), 7.31 (t, J ) 8.1 Hz, 1H), 7.49-7.56 (m, 2H), 7.62 (dt, J )
1.2, 7.7 Hz, 1H), 7.76-7.82 (m, 1H), 8.17 (dd, J ) 1.2, 8.1 Hz,
1H), 8.34 (d, J ) 8.1 Hz, 1H). 13C NMR (CDCl3) δ 39.6, 52.9,
112.2, 112.6, 115.1, 118.0, 120.1, 123.8, 125.9, 129.0, 129.1, 129.8,
131.4, 146.4, 147.0, 147.4, 148.1, 152.5. Anal. Calcd for
C21H18N6O2: C, 65.27; H, 4.70; N, 21.75. Found: C, 65.33; H,
4.85; N, 21.80.
P r ep a r a tion of 1-Im id oylben zotr ia zoles 5a -k . Imidoyl-
benzotriazoles 5a -k were prepared by the reaction of N-
(aminoalkyl)benzotriazoles 4a -f and an appropriate isonitrile
3a -d . Boron trifluoride etherate (5-10 drops) was added to a
solution of N-(aminoalkyl)benzotriazole (5 mmol) in dry THF at
20 °C. After stirring for 10 min, 1.05-1.10 equiv of the crude
isonitrile (5.25-5.50 mmol) in THF was added. The reaction
mixture was stirred for 30 min to 1 h. Ethyl acetate was added,
and the organic layer was washed with three portions of water.
The organic layer was separated, dried over MgSO4, and filtered,
and the solvent was removed under reduced pressure to yield
the desired 1-imidoylbenzotriazole in a good yield. Further
purification was achieved by recrystallization with EtOH. In the
cases of 5b,g,e,k , flash column chromatography was used to get
an analytically pure sample; however, prolonged time on the
column led to rapid hydrolysis of the desired compound, as
demonstrated by the conversion of 5e f 6.
N-[1-(1H -Ben zot r ia zol-1-yl)-2-m or p h olin oet h ylid en e]-
ben zyla m in e (5g). Compound 5g was obtained as a pale yellow
oil following column chromatography using ethyl acetate/hex-
1
anes (1:3) (94%); H NMR (CDCl3) δ 2.63-2.67 (m, 4H), 3.63-
3.68 (m, 4H), 4.25 (s, 2H), 5.10 (s, 2H), 7.26-7.50 (m, 6H), 7.55
(dt, J ) 1.2, 7.7 Hz, 1H), 8.08 (d, J ) 8.1 Hz, 1H), 8.46 (d, J )
8.1 Hz, 1H). 13C NMR (CDCl3) δ 53.5, 53.8, 53.9, 66.8, 115.6,
119.6, 125.2, 126.9, 127.5, 128.5, 129.0, 131.6, 139.6, 146.5, 153.8.
HRMS (FAB) calcd for C19H21N5O: 336.1824. Found 336.1791.
N-[1-(1H -Ben zot r ia zol-1-yl)-2-p ip er id in oet h ylid en e]-4-
n itr oa n ilin e (5h ). Compound 5h was crystallized from ethanol
as white plates (88%), mp 155 °C (decomp); 1H NMR (CDCl3) δ
1.29 (br s, 6H), 2.36 (br s, 4H), 4.10 (s, 2H), 7.11 (d, J ) 9.0 Hz,
2H), 7.52 (t, J ) 7.8 Hz, 1H), 7.63 (t, J ) 7.4 Hz, 1H), 8.15 (d,
J ) 8.1 Hz, 1H), 8.28 (d, J ) 9.0 Hz, 2H), 8.41 (d, J ) 8.4 Hz,
1H). 13C NMR (CDCl3) δ 23.5, 25.7, 54.3, 55.7, 115.3, 120.1, 120.1
124.6, 125.8, 129.6, 131.3, 143.9, 146.6, 153.5, 154.2. Anal. Calcd
for C19H20N6O2: C, 62.62; H, 5.53; N, 23.06. Found: C, 62.52;
H, 5.67; N, 22.88. HRMS (FAB) calcd for C19H20N6O2: 365.1726.
Found 365.1693.
N-[1-(1H -Ben zot r ia zol-1-yl)-2-m or p h olin oet h ylid en e]-
2,5-d ich lor oa n ilin e (5a ). Compound 5a was crystallized from
1
ether as white plates (92%), mp 96-97 °C; H NMR (CDCl3) δ
2.43-2.48 (m, 4H), 3.41-3.45 (m, J ) 4.7 Hz, 4H), 4.16 (s, 2H),
7.05-7.12 (m, 2H), 7.39 (d, J ) 9.0 Hz, 1H), 7.51 (t, J ) 7.7 Hz,
1H), 7.63 (t, J ) 7.8 Hz, 1H), 8.14 (d, J ) 8.1 Hz, 1H), 8.51 (d,
J ) 8.4 Hz, 1H). 13C NMR (CDCl3) δ 53.3, 56.1, 66.6, 115.5, 120.0,
120.7, 123.0, 124.6, 125.8, 129.7, 130.3, 131.4, 132.5, 145.5, 146.5,
154.7. Anal. Calcd for C18H17Cl2N5O: C, 55.40; H, 4.39; N, 17.94.
Found: C, 55.46; H, 4.48; N, 17.95.
N-[1-(1H-Ben zotr iazol-1-yl)-2-dim eth ylam in oeth yliden e]-
2,5-d ich lor oa n ilin e (5b). Compound 5b was obtained as a pale
yellow oil following column chromatography using ethyl acetate/
hexanes (1:3) (96%); 1H NMR (CDCl3) δ 2.24 (s, 6H), 3.98 (s,
2H), 7.03-7.13 (m, 2H), 7.39 (d, J ) 8.4 Hz, 1H), 7.48 (t, J )
7.2 Hz, 1H), 7.61 (t, J ) 7.2 Hz, 1H), 8.13 (d, J ) 8.2 Hz, 1H),
8.51 (d, J ) 8.4 Hz, 1H). 13C NMR (CDCl3) δ 45.6, 55.9, 115.3,
119.9, 121.3, 123.3, 124.9, 125.5, 129.4, 130.5, 131.4, 132.6, 144.9,
146.4, 155.6. Anal. Calcd for C16H16Cl2N5: C, 55.18; H, 4.34; N,
20.11. Found: C, 54.85; H, 4.36; N, 19.96. HRMS (FAB) calcd
for C16H16Cl2N5 (M + 1): 348.0783. Found: 348.0788.
N-[1-(1H-Ben zotr ia zol-1-yl)-4-m eth yl-2-m or p h olin op en -
tylid en e]-3-n itr oa n ilin e (5i). Compound 5i was crystallized
from ethanol as pale yellow plates (87%), mp 150-153 °C; 1H
NMR (CDCl3) δ 0.88 (t, J ) 6.1 Hz, 6H), 1.58-1.73 (m, 1H),
1.74-1.92 (m, 2H), 2.50-2.65 (m, 4H), 3.47-3.64 (m, 4H), 4.61
(t, J ) 7.4 Hz, 1H), 7.21 (d, J ) 7.8 Hz, 1H), 7.42-7.58 (m, 3H),
7.89-7.98 (m, 2H), 8.12 (d, J ) 8.3 Hz, 2H). 13C NMR (CDCl3)
δ 22.5, 22.9, 26.0, 38.2, 51.0, 65.4, 67.1, 114.3, 115.4, 118.8, 120.2,
125.6, 125.9, 129.4, 129.4, 131.5, 146.2, 147.6, 148.7, 155.9. Anal.
Calcd for C22H26N6O3: C, 62.54; H, 6.20; N, 19.89. Found: C,
62.16; H, 6.50; N, 19.88.
N-[1-(Ben zotr iazolyl)-2-m or ph olin o-2-ph en yleth yliden e]-
2,5-d ich lor oa n ilin e (5j). This compound was crystallized from
ethanol as yellow microcrystals (89%), mp 186-187 °C, the
(12) (a) Burckhalter, J . H.; Stephens, V. C.; Hall, L. A. R. J . Am.
Chem. Soc. 1952, 74, 3868. (b) Smith, J . R. L.; Sadd, J . S. J . Chem.
Soc., Perkin Trans. 1 1975, 1181.

2868 J . Org. Chem., Vol. 66, No. 8, 2001
Notes
product was obtained as a mixture of Bt2 and Bt1 isomers (2.6:
1, respectively); H NMR (CDCl3) [both isomers unless stated]
δ 2.36-2.39 (m, 7H), 3.15 (s, 2H), 3.66-3.70 (m, 4H), 6.93 (d, J
) 7.9 Hz, 2H), 7.16 (d, J ) 7.9 Hz, 2H), 7.42 (d, J ) 7.9 Hz, 2H),
8.20 (d, J ) 7.9 Hz, 2H). 13C NMR (CDCl3) δ 21.2, 53.1, 63.1,
66.8, 119.9, 125.1, 125.3, 129.8, 135.9, 140.1, 144.1, 155.9, 167.4*
[*Quaternary carbon signal very small, but integration shows
it to be present. After attempted high-temperature NMR experi-
ments, this peak at ca. 168 ppm shows up more clearly, but
significant decomposition of the compound is observed by the
appearance of new signals in the aromatic region.] Anal. Calcd
for C19H21N3O3S: C, 61.44; H, 5.70; N, 11.31. Found: C, 61.17;
H, 6.07; N, 11.23.
1
δ 2.50-2.53 (m, 4H, Bt1 isomer), 3.11-3.14 (m, 4H, Bt2 isomer),
3.46-3.52 (m, 4H, Bt1 isomer), 3.67-3.70 (m, 4H, Bt2 isomer),
5.99 (s, 1H, Bt1 isomer), 6.17 (s, 1H, Bt2 isomer), 6.55-7.65 (m,
22H), 7.89 (d, J ) 8.3 Hz, 1H, Bt2 isomer) 8.09 (d, J ) 8.4 Hz,
1H, Bt1 isomer). 13C NMR (CDCl3) [both isomers] δ 48.9, 49.0,
67.1, 67.3, 109.4, 110.0, 110.4, 110.7, 113.6, 113.7, 117.6, 117.9,
119.7, 119.9, 120.0, 120.4, 123.9, 124.5, 127.8, 128.4, 128.5, 128.7,
128.8, 129.0, 129.6, 129.9, 130.2, 133.2, 133.5, 133.7, 134.5, 135.5,
140.8, 141.4, 143.3, 143.9, 145.2, 145.8. Anal. Calcd for C24H21
-
Cl2N5O: C, 61.81; H, 4.54; N, 15.02. Found: C, 61.71; H, 4.72;
N, 14.88.
4-Meth ylp h en yl N-Ben zyl-2-m or p h olin oth ioa cetim id a te
(1e). Compound 1e was obtained as pale yellow plates following
column chromatography using hexanes/ethyl acetate (3:1) (46%),
mp 73-75 °C; 1H NMR (CDCl3) (at 60 °C) δ 2.18-2.24 (m, 4H),
2.36 (s, 3H), 3.01 (s, 2H), 3.55-3.61 (m, 4H), 4.67 (s, 2H), 7.15
(d, J ) 7.9 Hz, 2H), 7.22-7.28 (m, 1H), 7.30-7.43 (m, 4H), 7.51
(d, J ) 8.1 Hz, 2H). 13C NMR (CDCl3) (at 60 °C) δ 21.1, 52.7,
56.7, 63.8, 66.8, 126.6, 126.7, 127.8, 128.3, 129.4, 136.0, 139.2,
139.6, 161.7. Anal. Calcd for C20H24N2OS: C, 70.55; H, 7.10; N,
8.23. Found: C, 70.32; H, 7.21; N, 8.00.
4-(ter t-Bu t yl)-2-m et h ylp h en yl N-b en zyl-2-m or p h olin o-
th ioa cetim id a te (1f). Compound 1f was obtained as a pale
orange oil after purification by column chromatography using
hexanes/ethyl acetate (3:1) (75%); 1H NMR (CDCl3) (at 60 °C) δ
1.31 (s, 9H), 2.10-2.20 (m, 4H), 2.45 (s, 3H), 3.00 (s, 2H), 3.46-
3.58 (m, 4H), 4.74 (s, 2H), 7.10-7.45 (m, 7H), 7.57 (d, J ) 2.0
Hz, 1H). 13C NMR (CDCl3) δ 21.1, 31.3, 34.4, 53.1, 57.0, 64.2,
66.9, 126.6, 126.7, 127.9, 128.4, 129.9, 130.2, 133.8, 139.6, 139.8,
149.7, 161.7. Anal. Calcd for C24H32N2OS: C, 72.68; H, 8.13; N,
7.06. Found: C, 73.28; H, 8.38; N, 7.44.
4-Meth ylph en yl N-(3-Nitr oph en yl)-2-m or ph olin o-(2-isobu -
tyl)th ioa cetim id a te (1g). Compound 1g was obtained as a pale
yellow oil following column chromatography using hexanes/ethyl
acetate (5:1) (59%); 1H NMR (CDCl3) δ 0.84 (t, J ) 7.4 Hz, 6H),
1.42-1.51 (m, 1H), 1.59-1.81 (m, 2H), 2.33 (s, 3H), 2.35-2.44
(m, 2H), 2.62-2.71 (m, 2H), 3.38 (dd, J ) 5.9, 8.1 Hz, 1H), 3.62-
3.68 (m, 4H), 7.09-7.18 (m, 3H), 7.35 (d, J ) 8.6 Hz, 2H), 7.45
(t, J ) 8.1 Hz, 1H), 7.64 (t, J ) 8.1 Hz, 1H), 7.88-7.94 (m, 1H).
13C NMR (CDCl3) δ 21.1, 22.4, 22.7, 25.0, 35.5, 48.8, 64.0, 67.4,
114.6, 118.4, 125.8, 125.8, 129.6, 129.8, 135.9, 139.9, 148.6, 150.7,
168.8. HRMS (FAB) for C23H29N3O3S calcd: 428.2008. Found:
428.2008.
N-(2,5-Dich lor oph en yl)-2-(N-m eth ylan ilin o)acetam ide (6).
Compound 6 was obtained as pale yellow prisms following
column chromatographic purification of compound 5e using
hexanes/ethyl acetate (15:1) (32%), mp 111-112 °C; 1H NMR
(CDCl3) δ 3.11 (s, 3H), 3.99 (s, 2H), 6.82 (d, J ) 7.8 Hz, 2H),
6.89 (t, J ) 7.4 Hz, 1H), 7.00 (dd, J ) 2.4, 8.4 Hz, 1H), 7.21 (d,
J ) 8.4 Hz, 1H), 7.32 (t, J ) 8.1 Hz, 2H), 8.53 (d, J ) 2.4 Hz,
1H), 9.16 (br s, 1H). 13C NMR (CDCl3) δ 40.1, 59.8, 112.0, 113.8,
119.5, 121.0, 124.6, 129.4, 129.6, 133.4, 134.8, 149.0, 168.9. Anal.
Calcd for C15H14N2Cl2O: C, 58.27; H, 4.56; N, 9.06. Found: C,
58.29; H, 4.55; N, 9.10.
N-[1-(1H-Ben zotr ia zol-1-yl)-2-p ip er id in oeth ylid en e]-2,5-
d ich lor oa n ilin e (5k ). Compound 5k was obtained as a pale
yellow oil following column chromatography using ethyl acetate/
hexanes (1:2) (87%); 1H NMR (CDCl3) δ 1.27 (br s, 6H), 2.36 (br
s, 4H), 4.11 (s, 2H), 7.02-7.12 (m, 2H), 7.34 (d, J ) 8.4 Hz, 1H),
7.47 (t, J ) 7.7 Hz, 1H), 7.60 (t, J ) 7.7 Hz, 1H), 8.12 (d, J ) 8.4
Hz, 1H), 8.51 (d, J ) 8.1 Hz, 1H). 13C NMR (CDCl3) δ 23.5, 25.6,
54.3, 56.8, 115.5, 119.8, 120.7, 122.8, 124.2, 125.5, 129.4, 130.0,
131.3, 132.2, 145.6, 146.4, 155.3. Anal. Calcd for C19H19Cl2N5:
N, 18.04. Found: N, 17.79. HRMS (FAB) calcd for C19H19Cl2N5:
388.1096. Found 388.1092.
P r ep a r a tion of r-Am in o Th ioa cetim id a tes 1a -g. 1-Imi-
doyl benzotriazole 5 (3 mmol), an appropriate thiol (1.1 equiv),
and sodium methoxide (1 equiv) were heated under reflux in
dry THF for 16-18 h under a nitrogen atmosphere. Ethyl acetate
was then added to the reaction mixture, which was washed with
1% NaOH, dried over MgSO4, and filtered. The solvent was
removed under reduced pressure to yield either an oily residue
that was purified by column chromatography on silica gel using
hexanes/ethyl acetate mixtures (1a ,b,d -g), or a solid which was
recrystallized from ethanol (1c).
4-Meth ylp h en yl
N-(2,5-Dich lor op h en yl)-2-m or p h oli-
n oth ioa cetim id a te (1a ). Compound 1a was obtained as yellow
needles following column chromatography using hexanes/ethyl
1
acetate (10:1) (44%), mp 88-90 °C; H NMR (CDCl3) δ 2.34 (s,
3H), 2.39-2.46 (m, 4H), 3.17 (s, 2H), 3.62-3.68 (m, 4H), 6.81
(br s, 1H), 6.94 (dd, J ) 2.2, 8.5 Hz, 1H), 7.14 (d, J ) 8.1 Hz,
2H), 7.24 (d, J ) 2.9 Hz, 1H), 7.43 (d, J ) 8.1 Hz, 2H). It was
not possible to obtain satisfactory 13C NMR spectra for this
compound due to poor resolution as explained in the text.
Attempts to heat the sample to either 60 °C (in CDCl3) or 100
°C (in CD3C6D5) led to substantial decomposition. Anal. Calcd
for C19H20Cl2N2OS: C, 57.72; H, 5.10; N, 7.09. Found: C, 57.69;
H, 5.19; N, 6.92.
Ben zyl N-(2,5-Dich lor op h en yl)-2-m or p h olin ot h ioa ce-
tim id a te (1b). Compound 1b was obtained as a pale yellow oil
following column chromatography using hexanes/ethyl acetate
(3:1) (53%); 1H NMR (CDCl3) δ 2.38-2.45 (m, 4H), 3.12 (s, 2H),
3.58-3.68 (m, 4H), 4.24 (s, 2H), 6.73 (d, J ) 2.5 Hz, 1H), 6.94
(dd, J ) 2.5, 8.5 Hz, 1H), 7.18-7.32 (m, 4H), 7.33-7.39 (m, 2H).
13C NMR (CDCl3) δ 34.3, 53.5, 61.1, 66.6, 120.3, 122.1, 123.9,
127.0, 128.4, 129.1, 130.5, 132.7, 137.5, 148.5, 172.7. Anal. Calcd
for C19H20Cl2N2OS: C, 57.72; H, 5.10; N, 7.09. Found: C, 57.75;
H, 5.22; N, 6.81. HRMS (FAB) calcd: 395.0752. Found: 395.0755.
P h en yl N′-(2,5-Dich lor op h en yl)-2-(N-m eth yl-N-p h en yl-
a m in o)th ioa cetim id a te (1c): Compound 1c was obtained as
white needles following recrystallization from EtOH/ethyl ace-
N′-(2,5-Dich lor op h en yl)-N-m eth yl-2-(N-m eth yla n ilin o)-
N-p h en yleth a n im id a m id e (7). This compound was obtained
as a pale yellow oil following column chromatography of com-
pound 5e using hexanes/ethyl acetate (15:1) (5%); 1H NMR
(CDCl3) δ 2.23 (s, 3H), 3.33 (s, 3H), 3.91 (s, 2H), 6.25 (d, J ) 8.5
Hz, 2H), 6.64 (d, J ) 2.5 Hz, 1H), 6.68 (d, J ) 7.3 Hz, 1H), 6.77
(dd, J ) 2.5, 8.5 Hz, 1H), 7.08-7.26 (m, 6H), 7.33-7.40 (m, 2H).
13C NMR (CDCl3) δ 38.7, 40.8, 53.2, 112.2, 116.9, 122.1, 123.1,
126.7, 126.9, 128.7, 129.6, 129.9, 132.3, 145.3, 147.5, 148.5, 157.8.
HRMS (FAB) for C22H21N3Cl2 calcd: 398.1191. Found: 398.1230.
1
tate (92%), mp 107-108 °C; H NMR (CDCl3) (at 60 °C) δ 2.30
(s, 3H), 4.11 (s, 2H), 6.64-6.77 (m, 4H), 6.89 (dd, J ) 1.8, 8.7
Hz, 1H), 7.18-7.24 (m, 3H), 7.29-7.35 (m, 3H), 7.50-7.54 (m,
2H). 13C NMR (CDCl3) (at 60 °C) δ 39.2, 58.8, 112.5, 117.3, 120.4,
122.1, 124.5, 128.4, 129.0, 129.4, 129.5, 130.6, 132.6, 135.4, 147.8,
148.7, 166.4. Anal. Calcd for C21H18Cl2N2S: C, 62.84; H, 4.52;
N, 6.98. Found: C, 62.45; H, 4.67; N, 6.86.
Ack n ow led gm en t. We thank Dr. C. Dennis Hall,
Mr. Boris Rogovoy, and Dr. Olga V. Denisko (University
of Florida) for their helpful advice and input.
4-Met h ylp h en yl N-(4-Nit r op h en yl)-2-m or p h olin ot h io-
a cetim id a te (1d ). Compound 1d was obtained as pale yellow
needles following column chromatography using hexanes/ethyl
acetate (4:1) (44%), mp 148-149 °C; 1H NMR (CDCl3) (at 60 °C)
J O0016935