`
`46
`
`45
`13.2 mL. 13.2 mmol), and Me2NH (5-6 equiv) was obtained
`Yield: 0.10 g (6% ).
`R_,0.18 (8% MeOWCHC13).
`a brown residue which was purified by flash column chro-
`mp 184o_l86o C. (recrystallized from MeOH).
`matography on Si02 gel (2.5% Me0HJCHC13) to give the
`desired product. The product was recrystallized from ethyl
`1H NMR (DMSO-d6) /5 1.87 (6H). 4.20 (dd, J=5.3, 15.3
`acetate/hexane to give light yellow cubic crystals.
`Yield: 1.20 g (40%).
`Hz. 2H), 4.44 (dd, J=6.2. 15.3 Hz. 2H), 5.28 (d, J=9.0 Hz,
`2H), 7.15-7 31 (m, lOH), 8.00 (d, J=9.0 Hz, 2H), 8.39 (dd,
`J=5.3. 6.2 Hz. 2H). 8.51 (s, lH).
`R_,039 (5% MeOWCHCl3).
`13C NMR (DMSO-~) 22.50 (2 C), 42.58 (2 C), 69.98 (2
`mp 104°-106° C.
`1H NMR (DMSO-~) /5 1.91 (s, 3H). 2.11 (s, 6H), 4.22 10 C), 126.73 (2 C). 127.23 (4 C), 128.22 (4 C), 139.08 (2 C),
`(dd, J=5.2.14.7 Hz, lH),434(dd,J=6.l,14.7 Hz, lH), 5.11
`167.60 (2 C). 169.57 (2 C) ppm.
`(d. J=8.3 Hz. lH), 7.23-7.31 (m. 5H), 8.18 (d. J=8.3 Hz,
`IR (KBr) 3300 (br), 1660 (br), 1530 (br), 1450, 740, 700
`lH), 8.55 (br s, lH).
`cm-1.
`13C NMR (DMSO-d6) 22.43, 40.33 (2 C), 42.28, 69.42,
`Mass spectrum (FD) 442 (M'+l).
`126.73, 127.27 (2 C), 128.21(2 C), 139.49, 168.49. 170.31 15
`Elemental analysis Calculated for C22H27N 50 5 59.85%
`ppm.
`C; 6.16% H; 15.86% N. Found 60.09% C; 5.93% H; 15.76%
`IR (KBr) 3280, 1670 (br), 1500 (br), 1460, 760, 700 cm-1.
`N.
`Mass spectrum 250 (M++l).
`Elemental analysis Calculated for C13H1gN30 2 62.63%
`C; 7 .68% H; 16.85% N. Found 62.82% C; 7.66% H; 16.69%
`N.
`
`20
`
`EXAMPLE55
`
`35
`
`40
`
`EXAMPLE56
`Improved Synthesis of 2-Acetamido-N-benzyl-2-(N-
`hydroxyamino )acetamide.
`2-Acetamido-N-benzyl-2-bromoacetamide (prepared
`from 2-acetamido-N-benzyl-2-ethoxyacetamide (3.00 g,
`Synthesis of 2-Acetamido-N-benzyl-2-(N-hydroxyamino) 25 12.0mmol)andBBr3 (1MinCH3Cl2, 17.2mL, 17.2mmol))
`was dissolved in THF (250 mL), cooled (-10° C.), and then
`acetamide.
`Using 2-acetamido-N-benzyl-2-ethoxyacetamide (2.00 g.
`added dropwise (30 min) to a suspension of NH20H (5-6
`, 8.8 ml., 8.8 mmol), and
`8.0 mmol). BBr3 (IM in CH2C12
`e~uiv)inTHF_(SOmL)_at-10° C. The reaction mixture was
`anhydrous NH20H (5-6 equiv) gave an oily residue. The
`stirred (30 rmn) at this temperature ~d then allowed_ to
`residue was separated into three components by flash chro- 30 warm to room temperature (1 h). The msoluble materials
`were filtered and the :filtrate was concentrated in vacuo. The
`matography on Si02 gel (7.5% MeOHJCHCI3).
`residue was separated into two components by flash column
`2-Aceiamido-N-benzyl-2-(N-hydroxyamino )acetamide.
`chromatography on Si02 gel (7.5% MeOWCHC13).
`Yield: O.l4 g (?%).
`2-Acetamido-N-benzyl-2-(N-hydroxyamino)acetamide.
`R_,0.30 (8% Me0WCHC13).
`Yield: 0.66 g (23%).
`mp 144o_146o C. (dee.) (recrystallized from EtOH).
`mp 144°-146° C. (dee.) (recrystallized from EtOH)
`1H NMR (DMSO-d,;) /5 1.88 (s, 3H), 431 (d, J=S.7 Hz,
`DimerB.
`2H), 5.08 (dd, J=4.4, 8.1 Hz, lH). 5.94 (dd, J=2.8, 4.4 Hz.
`Yield: 0.10 g (5%).
`lH), 7.19-7.35 (m, 5H). 7.5 (d,J=2.8 Hz, lH), 8.26 (d. J=8.l
`mp 184°-186° C. (recrystallized from MeOH).
`Hz. lH), 8.42 (t, J=5.7 Hz, lH).
`13C NMR (DMSO-d6) 22.69. 42.25, 67.86, 126.69,
`Dimer A was not observed under these conditions.
`127.14 (2 C), 128.18 (2 C), 139.08, 168.53, 169.67 ppm.
`IR (KBr) 3320 (br), 1660 (br), 1540 (br), 1460. 750, 700
`cm-1.
`Mass spectrum (FD) 238 (M++l).
`Elemental analysis Calculated for C11H15N30 3 55.69%
`C;637%H; 17.71%N.Found55.86% C;6.37% H; 1738%
`N.
`Dimer A.
`Yield: 0.05 g (3% ).
`R_, 0.27 (8% Me0WCHC13).
`mp 177°-179° C. (recrystallized from EtOH).
`1H NMR (DMSO-d6} o 1.82 (s. 6H), 4.25-4.34 (m. 4H), 55
`5.21 (d. 1=9.3 Hz. 2H) 7.20-73.3 (m, lOH), 8.16 (d, J=9.3
`Hz}H). 8.26 (t, J=5.8 Hz, 2H), 8.51 (s, lH).
`C NMR (DMSO-d,;) 22.54 (2 C), 42.30 (2 C), 67.55 (2
`C), 126.63 (2 C), 127.13 (4 C). 128.11 (4 C).139.02 (2 C),
`168.24 (2 C). 169.33 (2 C) ppm.
`IR (KBr) 3240 (br), 1640 (br), 1510 (br). 1450, 690 cm-1.
`Mass spectrum (FD) 442 (M++l).
`Elemental analysis Calculated for C22H27N50 5 59.85%
`C; 6.16% H; 15.86% N. Found 59.56% C; 6.08% H; 15.64% 65
`N.
`Dimer B.
`
`EXAMPLES?
`45 Synthesis of 2-Acetamido-N-benzyl-2-(N 2 -
`phenylhydrazino )acetamide.
`Using 2-acetamido-N-benzyl-2-ethoxyacetamide (2.00 g,
`8.0 mmol). BBr3 (lM in CH2Cl2 , 10.0 mL, 10.0 mmol), and
`phenylhydrazine (2.60 g, 24.0 mmol) gave a pale yellow oily
`50 residue which was purified by :flash column chromatography
`on Si02 gel (2% Me0WCHCI3) to give the desired product
`The product was recrystallized from chloroform/hexane as a
`light yellow solid.
`Yield: 0.75 g (29%).
`~0.26 (2% Me0WCHC13).
`mp 132°-134° C.
`1H NMR (DMSO-dJ /5 1.89 (s, 3H), 4.28 (d, J=5.8 Hz,
`2H). 4.89 (d. J=5.2 Hz, lH), 5.09 (dd. J=5.2. 7.4 Hz. lH),
`6.61 (t, J=7.4 Hz, lH). 6.70-7.28 (m, loH), 8.29 (d, J=7.4
`60 Hz. lH), 8.60 (t, 1=5.8 Hz, lH).
`) 22.88, 42.22, 66.22, 112.66 (2 C),
`13C NMR (DMSO-d6
`117.57, 126.65, 127.08 (2 C), 128.15 (2 C), 128.53 (2 C),
`139.12. 149.90, 168.66, 170.04 ppm.
`IR (KBr) 3300, 1640 (br), 1610, 1520 (br), 1460, 760, 700
`cm-1
`•
`Mass spectra (FD} 313 (M"+l).
`
`-25-
`
`
`
`5,654,301
`
`47
`Elemental analysis Calculated for C17H2oN40 2 65.37%
`C;6.45%H; 17.94%N.Found65.15% C;6.25% H; 17.71%
`N.
`
`EXAMPLE58
`
`48
`(5-6 equiv) in THF (55 mL) was then added. The reaction
`mixture was stirred at this temperature (30 min) and then at
`room temperature (1 h). The insoluble materials were fil(cid:173)
`tered and the filtrate was evaporated to dryness in vacuo. The
`5 oily residue obtained was purified by :fl.ash column chroma(cid:173)
`tography on Si02 gel (2% Me0H/CHC13) to give 1.10 g
`(27%) of the desired product as a yellow orange oil. The
`product was purified by a second :fl.ash column chromatog(cid:173)
`raphy on Si02 gel (2% MeOHJCHCl3 ) to give 0.72 g of the
`10 pure product as a white solid.
`R, 0.65 (3% MeOHJCHC13 ).
`mp 155°-157° C.
`1H NMR(CD3N02 ) o 1.98 (s,3H). 2.08 (s. 3H),4.39 (dd,
`15 J=6.l, 15.2 Hz, lH). 4.49 (dd.. J=6.1. 15.2 Hz, lH), 5.51 (d,
`J=7.8 Hz, lH), 7.15 (d, J=7.8 Hz, lH), 7.17-7.41 (m, 6H).
`13C NMR (CD3NO~ 12.28, 22.94, 44.26, 56.03, 128.46,
`128.60 (2 C), 129.77 (2 C), 140.17, 169.19, 171.06 ppm.
`IR (KBr) 3320. 1650 (br), 1520 (br), 1460, 750 cm-1
`.
`20 Mass spectrum (FD) 253 ~+1).
`Elemental analysis Calculated for C12H1 ~202S 57.12%
`C; 6.39% H; 11.10% N. Found 57 .06% C; 6.57% H; 11.28%
`N.
`
`• 25
`
`EXAMPLE61
`
`Synthesis of 2-Acetamido-N-benzyl-2-(Nz(cid:173)
`benzyloxycarbonylhydrazino )acetamide.
`Employing 2-acetamido-N-benzyl-2-ethoxyacetamide
`(3.00 g, 12.0 rnrnol). BBr3 (lM in CH2Cl2 , 15.0 mL. 15.0
`mmol), and benzyl carbazate (4.58 g, 27.6 mmol). 0.95 g
`(21 % ) of the desired product was obtained. The product was
`recrystallized from chlorofonn/hexane to give a white amor(cid:173)
`phous solid.
`R, 0.32 (2% MeOHJCHCI3).
`mp 152°-154° C.
`1H NMR (DMSO-dJ o 1.85 (s, 3H), 4.27 (d. J=4.4 Hz,
`2H). 5.00 (s, 2H), 5.14 (ddJ=3.L 8.0 Hz, lH), 5.23 (t, J=3.1
`Hz. lH), 7.25-7.35 (m, lOH), 8.26 (d, J=8.0 Hz, lH), 8.56
`(br s. lH), 8.66 (br s, lH).
`13C NMR (DMSO-d6 ) 22.71, 42.23, 65.56, 65.97, 126.69,
`127.16 (2 C), 127.61 (2 C), 127.77, 128.13 (2 C), 128.27 (2
`C), 136.74. 138.87, 168.04, 169.95 ppm.
`IR (KBr) 3325, 1620 (br), 1500 (br), 1440, 740, 680 cm-1
`Mass spectrum (FD) 371 (M++l).
`Elemental analysis Calculated for C19H22N4 0 4 61.61%
`C; 5.99% H; 15.13% N. Found 61.40% C; 6.21 % H; 15.39%
`N.
`
`Synthesis of 2-Acetamido-N-benzyl-2-(ethylrnercapto)
`acetamide.
`Using the procedure described for the synthesis of
`30 2-acetamido-N-benzyl-2-(methylmercapto)acetamide,
`2-acetamido-N-benzyl-2-ethoxyacetamide (2.00 g, 8.0
`mmol) and EtSH (0.65 g, 10.4 mmol) were converted to 0.80
`Synthesis of 2-Acetamido-N-benzyl-2-phenoxyacetarnide.
`g (38%) of the desired product. The compound was further
`Using 2-acetamido-N-benzyl-2-ethoxyacetamide (3.00 g,
`purified by recrystallization from chlorofoDilfhexane to give
`12.0 mmol). BBr3 (lM in CH2Cl2 , 15.0 mL, 15.0 mmol),
`35 a beige solid.
`and NaOPh (4.18 g. 30 mmol) gave a brown oily residue
`~0.60 (4% Me0HJCHC13).
`which was purified by flash column chromatography on
`mp 146°-148° C.
`Si02 gel using first CHC13 and then 2% MeOHJCHCl3 as the
`1H NMR (DMSO-~) o 1.56 (t. J=7.4 Hz, 3H), 1.88 (s,
`eluents to give the desired product. The compound was
`40 3H), 2.49-2.67 (m, 2H), 4.23 ( dd, J=5.9, 15.2 Hz, lH), 4.32
`recrystallized from chlorofonn/hexane.
`(dd, 1=5.9, 15.2 Hz, lH), 5.55 (cl. J=9.l Hz, lH). 7.20-7.35
`Yield: 0.80 g (22%).
`(m, 5H), 8.59 (d, J=9.l Hz, lH), 8.75 (t, 1=5.9 Hz, lH).
`R, 0.58 (3% Me0HJCHC13 ).
`13C NMR (DMSO-~) 14.73, 22.43, 23.73, 42.10, 53.70,
`mp 125°-128° C. (softens at 122° C.).
`126.87, 127.14 (2 C), 128.32 (2 C), 139.01, 167.89, 169.02
`1H NMR (DMSO-d6) o 1.83 (s, 3H), 4.35 (d. J=5.7 Hz,
`45 ppm.
`2H), 6.18 (d.. J=9.4 Hz, lH). 6.94-6.99 (m, 2H), 7.02-7.33
`IR (KBr) 3240, 1620 (br), 1510 (br), 1415, 680, 640 cm-1
`(m. SH), 8.98 (t, J=5.7 Hz. lH), 9.10 (d, J=9.4 Hz, lH).
`Mass spectrum (FD) 267 ~+1).
`13C NMR (DMSO-d6) 22.54, 42.24. 76.44, 116.09 (2 C),
`Elemental analysis Calculated for C13H18N20 2S.0.25
`121.78. 126.84, 127.26 (2 C). 128.25 (2 C), 128.44 (2 C),
`50 H~O 57.65% C; 6.88% H; 10.34% N. Found 57.48% C;
`138.84, 155.97, 166.63, 170.73 ppm.
`6.M% H; 10.28% N.
`IR (KBr) 3300, 1650 (br), 1600, 1530 (br), 1490. 1450,
`Preparation of Functionalized a-Heteroatom Substituted
`760, 700 cm-1.
`Amino Acids.
`General Procedure.
`Mass spectrum (FD) 299 (M",.+l).
`of 2-acetamido-2-(N,N ,N-
`A mixture
`Elemental analysis Calculated for C 17H18N20 3 .0.5 H20
`66.43% C; 6.23% H; 9.11 % N. Found 66.62% C; 6.23% H; 55 trimethylammonium)acetamide tetrafiuoroborate (1 eqiuv),
`9.16% N.
`and the nitrogen nucleophile (4-5 equiv) in MeOH (1
`mmol/1 mL) was stirred at 55°-60° C. (3 h). The solvent was
`removed in vacuo and the residue was purifted by flash
`column chromatography on Si02 gel using the indicated
`solvents as the eluent.
`Using this procedure the following examples were pre(cid:173)
`pared.
`
`EXAMPLE59
`
`•
`
`EXAMPLE60
`
`Synthesis of 2-Acetamido-N-benzyl-2-(methylrnercapto)
`acetamide.
`A cooled (-78° C.) solution or E~N (4.85 g, 48.0 rnmol)
`in THF (20 mL) was added to a cooled (-78° C.) solution of
`2-acetamido-N-benzyl-2-bromoacetamide (prepared from
`2-acetamido-N-benzyl-2-ethoxyacetamide (4.00 g, 16.0 65
`rnmol) and BBr3 (IM in CH2 Cl2 • 20.0 mL, 20.0 mmol)) in
`THF (275 mL). A cooled (-78° C.) solution of excess MeSH
`
`60
`
`EXAMPLE62
`
`Synthesis of 2-Acetamido-N-benzyl-2-(N-methoxyamino)
`acetamide.
`
`-26-
`
`
`
`5,654,301
`
`50
`1Y 0.39 (2% MeOH/CH03 ).
`mp 165°-167° C.
`1H NMR (DMSO-d6) 81.93 (s, 3H), 2.43 (s, 3H), 3.32 (s,
`3H). 4.25 (dd, J=5.9, 149 Hz, lH), 437 (dd, J=5.9. 14.9 Hz,
`lH), 5.19 (d, J=9.4 Hz, lH), 7.21-7.35 (m, 5H), 8.31 (d,
`J=9.4 Hz. lH), 8.56 (t, J=5.9 Hz, lH).
`13C NMR (DMSO-d6 ) 22.36, 39.68, 42.34, 59.16, 70.33,
`126.74, 127.41 (2 C), 128.21 (2 C). 139.30, 167.38, 170.30
`10 ppm.
`IR (KBr) 3300, 1640 (br). 1540 (br), 1460, 750, 700 cm-1 .
`Mass spectrum (FD) 266 (M++l).
`Elemental analysis Calculated for C13H1~303 58.85%
`C; 7.22% H; 15.84% N. Found 59.05% C; 7.37% H; 15.75%
`15 N.
`
`EXAMPLE65
`
`lidin )
`.
`Synthesis of 2-Acetarnido-N-benzyl-2-(N-isoxazo
`o
`acetarnide.
`
`49
`Using a MeOH solution of Me0NH2 (prepared from
`MeONH2.HO (2.83 g, 33.9 mmol) and NaOMe (l.41 g,
`26.l mmol)), and 2-acetamido-2-(N,N,N(cid:173)
`trimethylaromonium)acetamide tetra:fiuoroborate (2.70 g,
`7.67 mmol) gave an oily residue which was purified by flash 5
`column chromatography on Si02 gel (2% MeOH/CHC13) to
`give the desired product. The product was recrystallized
`from chlorofonn/hexane.
`Yield: 0.80 g (42%).
`1Y 0.23 (2% Me0H/CH03)
`mp 95°-97° C.
`1H NMR (DMSO-d6) 8 1.88 (s. 3H), 3.38 {s, 3H),
`4.22-4.41 (m.. 2H), 5.18 (dd. J=4.9, 7.8 Hz. lH). 6.78 (d,
`J=4.9 Hz. lH), 7.21-7.32 (m.. SH), 8.33 (d, J=7.8 Hz, lH).
`8.56 (br S, lH).
`13C NMR (DMSO-d6) 22.64, 42.28, 61.42, 66.25. 126.74,
`127.19 (2 C). 128.19 (2 C), 139.11. 167.95, 169.66 ppm.
`IR (KBr) 3300, 1650. 1620, 1510 (br), 1440, 750. 680
`cm-1.
`
`20
`
`Using 2-acetamido-2-(N,N,N-trimethylammonium)
`acetarnide tetra:fiuoroborate (1.60 g, 4.55 mmol). isoxazoli-
`dine (prepared from isoxazolidine hydrobromide (2.41 g,
`15.65 mmol) and NaOMe (0.70 g, 13.04 mmol)) gave the
`25 desired product. The product was recrystallized from
`chlorofonn/hexane to give a white amorphous solid.
`Yield: 0.80 g (64%).
`iyo.29 (4% MeOH/CH03)•
`mp 149°-151° C.
`1H NMR (DMSO-~) 8 1.91(s,3H), 2.05-2.20 (m.. 2H),
`2.45-2.89 (m, lH), 2.98-3.07 (m, lH), 3.74-3.90 (m.. 2H),
`4.25 ( dd, J=6. l, 15.3 Hz, lH), 4.35 ( dd, J=6. l, 15.3 Hz, lH),
`5.23 (d, J=9.2 Hz, lH), 7.15-7.35 (m, SH), 8.49 (d, J=9.2
`35 Hz, lH), 8.56 (br s, lH).
`13C NMR (DMSO-~) 22.26, 28.26, 42.15, 48.94, 66.19,
`68.77. 126.64, 127.02 (2 C), 128.13 (2 C), 139.22, 167.43,
`170.27 ppm.
`IR (KBr) 3400 (br), 3300, 1650, 1530, 1470, 740, 700.
`40 610 cm-1.
`Mass Spectrum (FD) 278 (M++l).
`Elemental analysis Calculated for C14H1~303 60.64%
`C; 6.91 % H; 15.15% N. Found 60.16% C; 7 .04% H; 15.07%
`N.
`45 Preparation of Functionalized cc-Heteroatom Substituted
`Amino Acids.
`General Procedure.
`2-Acetarnido-N-benzyl-2-ethoxyacetarnide (1 equiv) was
`suspended in E~O (100 mL/100 mmol), and then BF3.E~O
`50 (1.6-2.4 equiv) was rapidly added and the resulting solution
`was stirred (10 min). The nucleophile (H20 or EtSH)
`(l.6-4.0 equiv) was then added and the reaction was stirred
`at room temperature (18-48 h). The reaction was then
`quenched by the addition of an aqueous NaHC03 (100
`55 mLJlO mmol)/ice mixture. The experimental workup varied
`slightly for each compound and is described in the following
`examples along with the observed spectral properties.
`
`30
`
`Mass spectrum (FD) 252 <M++l).
`Elemental analysis Calculated for C12H17N303 57.63%
`C; 6.82% H; 16.72% N. Found 57.06% C; 6.63% H; 16.65%
`N.
`
`EXAMPLE63
`Synthesis of 2-Acetamido-N-benzyl-2-(N-(N(cid:173)
`methylhydroxyamino ))acetarnide.
`An MeOH solution (30 mL) ofMeNHOH (21.74 mmol)
`(prepared from MeNIIOH.HCl (2.36 g. 28.26 mmol) and
`NaOMe (l.17 g, 21.74 mmol)) and 2-acetamido-2-(N,N.N(cid:173)
`trimethylammonium)acetamide tetra:fiuoroborate (2.20 g.
`6.25 mmol) gave a residue which was pnrified by flash
`column chromatography on Si02 gel (6% Me0H/CHC13 ) to
`give the desired product as a white solid. The product was
`then purified by recrystallization from EtOH.
`Yield: 0.95 g (61%).
`1Y 0.32 (8% MeOH/CH03).
`mp 159°-161° C.
`1H NMR (DMSO-d6 ) o 1.95 (s. 3H), 2.43 (s. 3H), 4.26
`(dd, J=5.7. 15.1 Hz. lH), 4.35 (dd, J=5.7, 1.51 Hz, lH), 5.09
`(d, J=9.1 Hz, lH), 7.21-7.29 (m. 5H). 8.05 (s. lH), 8.18 (d,
`J=9.1 Hz, lH), 8.23 (t, J=5.7 Hz, lH).
`13C NMR (DMSO-d6 ) 22.40. 42.34, 43.92, 71.49. 126.62,
`127.12 (2 C), 128.12 (2 C), 139.14, 167.82. 170.28 ppm.
`IR (KBr) 3440 (br), 3300, 1640, 1530, 1460, 750, 700
`cm-1
`•
`Mass spectrum (FD) 252 (M++l).
`Elemental analysis Calculated for C12H17N30 3 57.36%
`C; 6.82% H; 16.72% N. Found 57.65% C; 6.59% H; 16.66%
`N.
`
`EXAMPLE64
`Synthesis of 2-Acetamido-N-benzyl-2-(N-(N,O(cid:173)
`methylhydroxyamino ))acetarnide.
`An MeOH solution (20 mL) ofMeNHOMe (17.39 rnmol)
`(prepared from MeNHOMe.HCl (2.20 g. 23.02 mmol) and 60
`NaOMe (0.94 g, 17.39 mmol)) and 2-acetarnido-2-(N.N,N-
`Synthesis of 2-Acetarnido-N-benzyl-2-hydroxyacetamide.
`trimethylammonium)acetamide tetrafluoroborate (2.10 g,
`Reacting 2-acetarnido-N-benzyl-2-ethoxyacetarnide (1.00
`5.97 mmol) gave a solid residue. Flash column chromatog-
`g, 4.0 mmol), BF3.E~O (0.91 g, 6.4 mmol) and H20 (0.12
`raphy of the solid on Si02 gel (2% MeOH/CH03 ) yielded
`g, 6.7 mmol) followed by aqueous NaHC03 workup gave an
`pure desired product. The product was recrystallized from 65 aqueous reaction mixture. The solution was then extracted
`EtOH.
`with EtOAc (3x50 mL), and the combined EtOAc extracts
`Yield: 1.30 g (82%).
`were dried (N~S04), and concentrated in vacuo. The resi-
`
`EXAMPLE66
`
`-27-
`
`
`
`5,654,301
`
`52
`accompanied by the evolution of heat. After stirring (5 min).
`the volatile materials were removed in vacuo. The residue
`was treated with a saturated aqueous NaHC03 solution (20
`mL). and the solid that remained was filtered and washed
`5 with H20 to give the desired product. The product was
`recrystallized from EtOH.
`Yield: 1.00 g (70%).
`R, 0.34 (8% Me0H/CHC13 ).
`10 mp 228°-230° C.
`1H NMR (DMSO-d6) o 1.90 (s, 3H). 4.30 (d. J=5.1 Hz.
`2H), 5.85 (d. J=8.0 Hz. lH). 7.21-7.35 (m, SH), 8.64 (d.
`J=8.0 Hz, lH), 8.75 (t, J=5.l Hz. lH), 10.04 (s, lH).
`13CNMR(DMSO-d6 )22.52,42.52, 57.42, 117.4 (q. JCF=
`15 288.3 Hz), 126.80, 127.16 (2 C). 128.21 (2 C), 138.93,
`156.14 (q, JCF=35.3 Hz), 166.3.9, 169.88 ppm.
`IR (KBr) 3300, 1720. 1660. 1520. 1380. 760, 700 cm-1
`Mass spectrum (FD) 318 (M++l).
`Elemental analysis Calculated for C 13H 14N 30 3F 3 49.21 %
`C; 4.45% H; 13.24% N. Found 49.48% C; 4.43% H; 13.10%
`N.
`
`•
`
`20
`
`EXAMPLE70
`
`51
`due was purified by flash column chromatography on Si02
`gel (3% Me0H/CHC13 ) to give the desired product as a
`white solid.
`Yield: 0.30 g (34%).
`R,0.14 (3% MeOH/CHCl3).
`mp 136°-138° C.
`1H NMR (DMSO-d6) o 1.85 (s, 3H), 4.29 (d, J=5.9 Hz,
`2H), 5.48 (dd. J=5.5, 8.6 Hz. lH). 6.47 (d, 1=5.5 Hz. lH),
`7.21-7.35 (m. SH), 8.52(t,1=5.9 Hz, lH), 8.59 (d, J=8.6 Hz.
`lH).
`13C NMR (DMSO-d6 ) 22.66, 41.99, 71.42, 126.66,
`127.22 (2 C). 128.13 (2 C), 139.20, 169.47, 169.62 ppm.
`IR (KBr) 3300. 1620.1530 (br), 1430 (br), 730, 690 cm-1
`.
`Mass spectrum, rn/e (relative intensity) 223 (M++L 1),
`163 (11), 134 (9), 106 (46), 91 (100), 77 (22), 65 (38).
`Elemental analysis Calculated for C 11H 14N20 3 59.45%
`C; 6.35% H; 12.61 % N. Found 59.24% C; 6.36% H; 12.50%
`N.
`
`EXAMPLE67
`
`Synthesis of 2-Acetamido-N-benzyl-2-(ethylrnercapto)
`acetamido.
`Using 2-acetamido-N-benzyl-2-ethoxyacetamide (2.00 g,
`8.0 mmol). BF3.E~O (2.72 g, 19.2 mmol) and EtSH (2.38 g,
`38.4 mmol) gave an aqueous reaction mixture. The solution
`was extracted with CHC13 (3x100 mL). The combined
`CHC13 layers were dried (N~SO 4), and then concentrated in
`vacuo to give the desired product as white solid.
`Yield: 1.90 g (89% ).
`R, 0.60 (4% Me0H/CHC13 ).
`mp 148°-149° C. (mixed melting point with an authentic
`sample, of Example 61 was undepressed).
`
`EXAMPLE68
`
`25 Synthesis of 2-Acetamido-N-benzyl-2-(N ,N ,N(cid:173)
`trimethylammonium)acetamide Tetrafluoroborate.
`A solution of 2-acetamido-N-benzyl-2-(N.N(cid:173)
`dimethylamino)acetarnide (1.93 g. 7.76 mmol) in
`nitromethane (7 mL) was added slowly to an ice cold
`30 solution of trimethyloxonium tetrafluoroborate ( 1.26 g, 8.54
`mmol) in nitromethane (6 mL). The reaction mixture was
`stirred at this temperature (15 min) and then at room
`temperature (2 h). Anhydrous E~O (-50 mL) was added the
`reaction mixture and the white solid that separated was
`35 filtered, washed with Et:?O, and dried in vacuo.
`Yield: 1.95 g (72%).
`mp 171°-173° C. (dee.).
`1H NMR (CD3NOJ o 2.14 (s, 3H), 3.18 (s. 9H). 4.50 (d.
`40 J=5.8 Hz, 2H), 5.70 (d, J=9.3 Hz, lH), 7.30-7.41 (m, SH),
`7.57 (d, J=9.3 Hz, lH), 7.70 (br s, lH).
`IR (KBr) 3300, 1680 (br), 1530, 1490, 710 cm-1
`Mass spectrum (FD) 264 ~)-
`Elemental analysis Calculated for C 14H 22N 3 0 2BF4
`47 .89% C; 6.31 % H; 11.97% N. Found 47.80% C; 6.33% H;
`12.00% N.
`
`•
`
`50
`
`EXA.1v1PLE 71
`Synthesis of 2-Acetamido-N-benzyl-2-(ethylmercapto)
`acetamide-S-oxide.
`A solution of m-chloroperbenzoic acid (LOO g (-65%).
`3.76 mmol) in CH20 2 (10 mL) was added dropwise into a
`stirred, cooled (-10° to -15° C.) CH2Cl2 solution (125 rnL)
`55 of 2-acetamido-N-benzyl-2-(ethylrnercapto)acetamide (LOO
`g, 3.76 mmol) under N 2• The reaction was stirred (30 min)
`at this temperature and then, the m-chlorobenzoic acid was
`precipitated as its ammonium salt by passing NH3 gas over
`the surface of the reaction solution. The excess NH3 was
`60 removed by passing N2 gas through the solution (20 min) at
`room temperature. The ammonium salt was filtered, and the
`filtrate was concentrated in vacuo. The residue was purified
`by flash chromatography on Si02 gel (2% Me0H/CH03) to
`give the desired product The product was recrystallized
`65 from chlorofonn/hexane as a white granular solid.
`Yield: 0.55 g (52%).
`R,0.23 (2% Me0H/CHC13).
`
`Synthesis of 2.2-Dicacetamido-N-benzylacetamide.
`Ac20 (1 mL) was added to a solution of 2-acetamido-N(cid:173)
`benzyl-2-aminoacetamide (1.10 g, 4.98 mmol) in dry pyri(cid:173)
`dine (10 rnL) and then CH2Cl2 (20 mL) was added. The
`mixture was stirred at room temperature (4 h) and then the
`volatile materials were removed in vacuo. The residue was
`then treated with a saturated aqueous NaHC03 solution (50
`mL). The white solid that remained was the desired product 45
`and-was filtered, dried (Na2S04). and recrystallized from
`MeOH.
`Yield: 1.20 g (92%).
`mp 265°-267° C. (dee.).
`1H NMR (DMSO-d6 ) o 1.84 (s. 6H), 4.26 (d, J=5.8 Hz,
`2H), 5.71 (t, J=7.6 Hz, lH), 7.20-7.31 (m. SH), 8.44 (d,
`J=7.6 Hz, 2H), 8.48 (t, J=5.8 Hz. lH).
`13C (DMSO-d6 ) 22.44 (2 C), 42.26, 56.99, 126.62, 127 .02
`(2 C), 128.12 (2 C), 139.15, 168.19. 169.39 (2 C) ppm.
`IR (KBr) 3260, 1530. 1500, 740, 690 cm-1
`Mass spectrum (FD) 264 (M++l).
`Elemental analysis Calculated for C 13H 17N3 0 3 59.30%
`C; 6.51 % H; 15.96% N. 59.16% C; 6.49% H; 15.86% N.
`
`•
`
`EXAMPLE69
`2-Acetamido-N-benzyl-2-
`of
`Synthesis
`trilluoroacetamidoact:tamide.
`Ice cold trifluoroacetic anhydride (8 rnL) was added in
`one portion to ice cold 2-acetamido-N-benzyl-2-
`aminoacetamide (l.00 g. 4.53 mmol). The reaction was
`
`-28-
`
`
`
`53
`
`5,654,301
`
`54
`EXAMPLE73
`
`mp 13S0-137° C.
`1H NMR (DMSO-~) o 1.15 (t, 1=7.5 Hz, 3H), 1.99 (s.
`3H), 2.49-2.56 (m, lH), 2.65-2.72 (m, lH), 4.34(d,1=S.7
`Hz. 2H), S.SS (d, J=9.S Hz, lH), 7.23-7.34 (m. SH), 8.74 (d,
`1=9.5 Hz, lH), 8.77 (t, 1=5.7 Hz, lH).
`13C NMR (DMSO-dJ 7.03, 22.34, 42.40, 42.47, 67.15,
`126.89, 127 2.7 (2 C), 128.24 (2 C), 138.55. 164.66, 170.18
`ppm.
`IR (KBr) 3300 (br), 1640 (br), lSlO (br), 1370, 1230,
`1100. 1020, 900 cm-1.
`Mass spectrum (FD) 283 (M++l).
`Elemental analysis Calculated for C 13H18N20 3S 55.30%
`C; 6.43% H; 9.92% N. Found SS.17% C; 6.38% H; 9.70%
`N.
`
`5
`
`EXAMPLE72
`
`Synthesis of 2-Acetamido-N-benzyl-2-(ethanesulfonyl)
`acetamide.
`An aqueous solution (20 mL) of Nal04 (3.00 g, 14.02
`rnmol) was added to a MeOH solution (20 mL) of
`2-acetamido-N-benzyl-2-(ethylmercapto )acetamide (0.9S g.
`3.S7 rnmol). The initial homogeneous solution rapidly
`became turbid. H20 (-10 mL) was then added dropwise
`10 until the system became homogeneous. The solution was
`stirred (18 h) atS0°--60° C.MeOH (SOmL) was added to the
`reaction solution and the precipitated salt was filtered and
`washed with MeOH (10 mL). The filtrate was concentrated
`and the remaining solution was extracted with CHC13 (3x50
`15 mL). The combined CHC13 extracts were dried (N32S04),
`and concentrated in vacuo. Time residue was purified by
`:flash chromatography on Si02 gel (1% Me0H/CHC13 ) to
`give the desiJ:ed product. The product was further purified by
`Synthesis of 2-Acetamido-N-benzyl-2-(S-ethylmercapto)
`recrystallization from EtOH:.
`acetamide-S-oxide.
`20 Yield: 0.34 g (32%).
`o 34 3%
`A solution of Nal04 (l.77 g, 8.27 mmol) in H20 (20 mL)
`OH/CHCI )
`~ ·
`0 Me
`3 ·
`(
`was added dropwise into a stirred solution of 2-acetamido-
`mp 161°-163° C.
`N-benzyl-2-(ethylmercapto)acetamide (2.00 g, 7.S2 mmol)
`1H NMR (DMSO-d6) o 1.22 (t, J=7.4 Hz, 3H), 1.99 (s,
`inMeOH (2S mL).Aprecipitate appearedrapidly. H20(-30
`mL) was added to the mixture to dissolve most of the
`3H),3.04-3.24 (m, 2H), 4.31(dd,1=S.7, 1S.3 Hz, lH), 4.41
`(dd, 1=S.7, lS.3 Hz, lH), 5.93(d,1=9.8 Hz, lH), 7.22-7.35
`suspension, and the reaction was stirred (4 h) at room
`(m, SH), 9.13 (t, J=S.7 Hz, lll), 9.17 (d, J=9.8 Hz, lH).
`temperature. The reaction was concentrated in vacuo and the
`13C NMR (DMSO-d6) S.72, 22.27, 42.63, 45.43, 69.14,
`remaining aqueous mixture was extracted with CHCI3
`127.02, 127.28 (2 C), 128.33 (2 C), 138.16, 161.88, 169.83
`(3x100 mL). The combined CHC13 extracts were dried
`(Na2S04) and the solvent was removed in vacuo. The oily 30 ppm.
`IR (KBr) 3300, 2940, 1660, 1S20, 1310.1230. 1120, 900
`residue (l.9S g, 92%) solidified on drying in vacuo. NMR
`analysis (DMSO-~) or the product showed that it was a 2:1
`cm-1.
`·
`mix~e of the two dias!ereomers of the desir~d product. The
`Mass spectrum (FD) 298 (M+).
`reaction was recrystallized from EtOAc to give nearly pure
`.
`diastereomer A (1.20 g) that was obtained from the
`Elemental analysis Calculated for C13H18N20 4S 52.33%
`m-chloroperbenzoic acid reaction. The EtOAc mother liquor 35 C; 6.08% H; 9.39% N. Found S2.S2% C; 6.06% H; 9.53%
`N.
`was concentrated and the remaining residue (0.7S g) was
`recrystallized from ethyl acetate/hexane to give a diastereo-
`meric mixture (0.41 g) of the two diastereomers A and :12. in
`Synthesis of 2-Acetamido-N-benzyl-2-(N ,N ,N-
`a 2:3 ratio, respectively.
`40 trimethylanimonium)acetamide Tetrafiuoroborate.
`~0.60 (4% Me0H/CHC13).
`A solution or 2-acetamido-N-benzyl-2-(N,N(cid:173)
`mp 13S0-l37° C. (softens at 117° C.).
`dimethylamino)acetamide (l.93 g, 7.76 mmol) in
`IR (KBr) 3300 (br). 1640 (br), lSlO (br), 1370, 1230,
`nitromethane (7 mL) was added slowly to an ice cold
`1100. 1020, 900 cm-1
`•
`45 solution of trimethyloxonium tetrafiuoroborate (1.26 g, 8.54
`mmol) in nitromethane (6 mL). The reaction mixture was
`Mass spectrum (FD) 283 (M++l).
`stirred at this temperature (15 min) and then at room
`Elemental analysis: Calculated for C 13H 18N 20 3S:
`5S30% C; 6.43% H; 9.92% N. Found: SS.S8% C; 6.49% H;
`temperature (2 h). Anhydrous Et20 (-SO mL) was added to
`the reaction mixture and the white solid that separated was
`9.97% N.
`The following NMR spectral properties have been 50 filtered. washed with E~O, and dried in vacuo.
`assigned to compounds A and~-
`Yield: l.9S g (72%).
`mp 171°-173° C. (dee.).
`Diastereomer A.
`1H NMR (DMSO-~) o 1.16 (t, J=7.S Hz, 3H), 2.00 (s,
`1H NMR (CD3NO~ o 2.14 (s, 3H), 3.18 (s, 9H), 4.SO (d,
`1=5.8 Hz, 2H), S.70 (d, J=9.3 Hz, lH), 7.30-7.41 (m, SH),
`3H), 2.49-2.72 (m, 2H), 4.28--4.39 (m, 2H), S.S6 (d, J=9.7
`55 7.S7 (d, 1=9.3 Hz, lH), 7.70 (br s, lH).
`Hz, lH), 7.21-7.34 (m, SH), 8.71-8.77 (m. 2H).
`IR (KBr) 3300, 1680 (br), 1S30, 1490, 710 cm-1
`13C NMR (DMSO-dJ 7.10, 22.43, 42.48, 42.57, 67.23,
`126.98, 127 36 (2 C), 128.33 (2 C), 138.63, 164.73, 170.2S
`Mass spectrum (FD) 264 ~-
`ppm.
`Elemental analysis
`Diastereomer B.
`Calculated for C14H2~30;BF4 47.89% C; 6.31% H;
`1H NMR (DMSO-~) 8 1.13 (t, 1=7.6 Hz. 3H). 1.94 (s.
`11.97% N. Found 47.80% C; 6.33% H; 12.00% N.
`3H), 2.49-2.72 (m, 2H), 4.28--4.39 (m. 2H), S.71(d,1=9.9
`Hz, lH). 7.21-7.34 (m, SH), 8.83(d,1=9.9 Hz, lH), 8.98 (t,
`J=S.6 Hz, lH).
`13C NMR (DMSO-d6) 6.47, 22.43, 41.53, 42.SS, 67.90, 65
`126.98. 127.36 (2 C), 128.33 (2 C), 13839, 164.43, 169.82
`ppm.
`
`25
`
`60
`
`EXAMPLE74
`
`•
`
`EXAMPLE7S
`Synthesis of 2-Acetamido-N-benzyl-2-(1-pyrrole)
`acetamide.
`A solution 2-acetarnido-N-benzyl-2-bromoacetarnide
`(prepared from 2-acetamido-N-benzyl-2-ethoxyacetamide
`
`-29-
`
`
`
`5,654,301
`
`56
`desired product. It was then recrystallized from EtOAc as a
`white solid: mp 158°-160° C.; ~0.51 (6% Me0H/CHC13 );
`1H NMR (DMSO-d6 ) o 1.93 (s, COCH3). 4.29(d,1=5.8 Hz.
`NH), 6.26 (s. C4H). 6.57(d,1=8.8 Hz, CH), 7.15-7.33 (m,
`5 5PhH). 7.48 (br s, C5 H), 7.76 (br s, C3H), 8.96(t,1=5.8 Hz.
`NH). 9.23 (d. 1=8.8 Hz, l\1H); 13C NMR (DMSO-d6) 22.41
`(COCH3 ). 42.40 (CH2), 65.51 (CH). 105.37 (C4 ), 126.87
`(C4 .). 127.14 (2C2 • or 2C3.). 128.25 (2C2 • or 2C3 .). 129.00
`(C5), 138.59 (C3). 139.17 (Cr)· 165.68 (CONH), 169.81
`10 (COCH3) ppm; mass spectrum. m/e (relative intensity) 273
`(W+l. 11), 272 (M+. 2), 139 (83). 138 (100), 92 (37).
`Anal. Calcdfor C14H 16N4 0 2 : C, 61.75; H, 5.92; N, 20.57.
`Found: C. 61.95; H, 5.%; N, 20.28.
`
`EXAMPLE78
`
`55
`(2.00 g. 8.0 mmol) andBBr3 (lM CH2Cl2 solution. 8.8 mL.
`8.8 mmol)) was prepared in THF (225 mL) and cooled to
`-78° C. It was then added under N2 gas atmosphere to a
`cooled (-78° C.) suspension of potassium pyrrole (2.71 g.
`25.8 mmol) in THF (25 rnL). The reaction mixture was
`stirred at -78° C. (1 h) and then at room temperature (1 h).
`H was then treated with water (10 mL) and acidified with 5%
`citric acid to pH 4.0 after which it was made basic with
`aqueous saturated Na2C03 solution. The aqueous mixture
`was extracted with EtOAc (2x250 mL) and the organic
`layers were dried (N~S04). The volatile materials were
`removed in vacuo and the residue was purified by flash
`column chromatography on silica gel using 3% MeOH/
`CHC~ as the eluant to give 0.4 g (18%) of the desired
`product. It was purified by recrystallization from EtOH: mp 15
`1H NMR
`182°-184° C.; ~ 0.44 (4% MeOH/CHCl3 );
`(DMSO-~) o 1.91 (s. COCH3 ). 4.30 (d, 1=5.5 Hz. CH2).
`6.01 (s, 2xC3H). 6.38 (d, 1=8.7 Hz, CH). 6.85 (s. 2xC2H),
`7.11-7.35 (m. 5PhH). 8.% (t, 1=5.5 Hz, NH), 9.14(d,1=8.7
`Hz. NH); 13C NMR (DMSO-d6) 22.22 (COCH3), 42.15
`(CH2), 62.86 (CH), 107.79 (2C3 ), 119.19 (2C2), 126.76
`(C4 .), 127.01 (2C2• or 2C3.). 128.11 (2C2 • or 2C3.), 13834
`(Cr). 166.37 (CONH). 169.41 (COCH3 ) ppm; mass
`spectrum. mle (relative intensity) 272 {W+l, 22), 271 (M+,
`100).
`Anal. Calcd for C15H17N30 2.0.2 H20: C, 65.53; H, 6.37;
`N. 15.28. Found: C. 65.80; H, 6.22; N. 15.13.
`
`25
`
`EXAMPLE76
`
`Synthesis of 2-Acetamido-N-benzyl-2-( 1-( 1.2,4-triazole))
`acetamide.
`Using 2-acetamido-N-benzyl-2-ethoxyacetamide (4.00 g,
`20 16.0 mmol), BBr3 (lM CH2Cl2 solution, 17.6 mL. 17.6
`mmol), E~N (4.85 g. 48.0 rnmol), and 1,2,4-triazole (l.43 g,
`20.8 mmol), 1.20 g (28%) of the desired product was
`obtained. It was recrystallized from EtOAc as an amorphous
`white solid: mp 146°-148° C.; R,0.48 (6% Me0H/CHC13 );
`1H NMR (DMSO-d6) o 1.85 (s, COCH3), 4.32 (br s. CH2),
`6.70(d,1=7.8 Hz, CH), 7.21-7.29 (m, 5PhH), 8.01 (s, C3H),
`8.57 (s, C5H), 9.04 (br s, NH), 9.39(d,1=7.8 Hz, NH); 13C
`NMR (DMSO-d6) 22.39 (COCH3 ), 42.59 (CH~, 65.02
`(CH), 126.97 (C4.), 127.25 (2C2. or 2C3.), 128.32 (2C2• or
`30 2C3 .). 138.47 (C1.), 143.93 (C5), 151.50 (C3 ), 164.77
`(CONH), 170.23 (COCH
`) ppm; mass spectrum, FD
`Synthesis of 2-Acetamido-N-benzyl-2-(1-imidazole)
`3
`(relative intensity) 275 (M++2, 12). 274 (W+l, 100), 273
`acetamide.
`Making use of the experimental procedure descrfoed in
`(11). 205 (19), 204 (13), 140 (67), 139 (31).
`Anal. Calcd for c
`: c, 57 .13; H, 5.53; N, 25.63.
`1sN5o
`the above ~xperiment, 2-acetamido-N-benzyl-2-
`H
`13
`2
`etho~yacetamide (2.00 g, 8.0 mmol). BBr3 (lM CH2Cl2 35 Found: C, 57.37; H. 5.66; N. 25.38.
`solution, 8.8 mL. 8.8 mmol). E~N (1.62 g, 1.60 mmol), and
`·
`·
`imidazole (0.60 g, 8.8 mmol) gave 0.60 g (30%) of the
`EXAMPLE 79
`desired product. It was recrystallized from ethyl acetate/
`hexane as a beige colored solid: mp 146°-148° C.; ~- (7%
`1H NMR (DMSO-d6) o 1.85 (s, COCH3 ),
`MeOH/CHC13 );
`4.30 (br s. CH2 ), 6.53 (d, 1=8.0 Hz, CH), 6.89 (s, C5 H),
`7.12-7.33 (m, C4H. 5PhH). 7.69 (s. C2H), 9.06 (br s, NH),
`9.29 (d, J=8.0 Hz, NH); 13C NMR (DMSO-dJ 22.28
`(COCH3 ), 42.36 (CH~. 61.18 (CH), 117.56 (C5 ), 126.92
`(C4 .). 127.16 (2C2• or 2C3 .), 128.19 (C4 ), 128.26 (2C2 • or
`2C3 .), 136.21 (C2 ), 138.27 (Cr), 165.72 (CONH), 169.77
`(COCH3 ) ppm; mass spectrum, FD (relative intensity) 274
`(M++2. 12). 273 (W+l, 77), 272 (100), 205 (34), 274 (18).
`Anal.CalcdforC14H1c;N4 0 2 :C,61.75;H,5.92;N.20.57.
`Found: C, 61.95; H. 6.09; N, 20.32.
`
`Synthesis of 2-Acetamido-N-benzyl-2-(1-tetrazole))
`acetamide.
`Making use of 2-acetamido-N-benzyl-2-ethoxyacetamide
`(3.00 g, 12.0 mmol). BBr3 (IM CH2Cl2 solution. 13.2 mL,
`13.2 mmol). E~N (2.42 g. 24.0 mmol), and tetrazole (l.10
`g, 15.6 mmol), 0.90 g (27%) of the desired product was
`obtained as a white solid. It was recrystallized from EtOH:
`1H NMR
`mp 169°-171° C.; R, 0.22 (4% Me0H/CHC13);
`(DMSO-~) o 1.97 (s, COCH3), 4.25-4.40 (m, CH~, 7.05
`(d, J=8.4 Hz. CH), 7.21-7.38 (m, 5PhH), 9.23(t,1=5.5 Hz,
`NH), 9.44 (s, CsH). 9.69 (d. 1=8.4 Hz. NH); 13C NMR
`50 (DMSO-d6) 22.38 (COCH3), 42.78 (CH2). 63.62 (CH),
`127.10 (C4'). 127.39 (2C2• or 2C3.), 128.38 (2C2 • or 2C3.),
`138.26 (Cr), 143.67 (C5 ), 163.88 (CONH). 170.62
`(COCH3), ppm; mass spectrum. FD (relative intensity) 275
`(W 79). 273 (14), 206 (100), 205 (50).
`Anal. Calcd for C1H 14N60 2 : C. 52.55; H, 5.15; N, 30.64.
`Found: C, 52.75; H. 5.33; N, 30.64.
`
`40
`
`45
`
`55
`
`EXAMPLE77
`Synthesis of 2-Acetamido-N-benzyl-2-( 1-pyrazole)
`acetamide.
`A solution of 2-acetamido-N-benzyl-2-bromoacetamide
`(prepared from 2-acetamido-N-benzyl-2-ethoxyacetamide
`(3.60 g, 14.4 mmol) and BBr3 (lM CH2Cl2 solution. 15.8
`mL. 15.8 mmol)) was prepared in THF (250 mL) and cooled
`Preparation of a-acetamido-N-benzyl-2-pyridylacetamide
`to -78° C. A solution of triethylamine (2.91 g, 28.8 mmo