`
`J. Org. Chem. 1992,57, 1082-1087
`A New Route to the Synthesis of Amino Acids through the Mercury
`Cyclization of Chiral Amidals
`
`Rosa Amoroso, Giuliana Cardillo,* Claudia Tomasini, and Paola Tortoreto
`Dipartimento di Chimica "G. Ciamician", Universitd di Bologna, Centro per lo Studio della Fisica delle
`Macromolecole, via Selmi 2, 40126 Bologna, Italy
`Received August 2, 1991
`
`By means of the mercury cyclization of the unsaturated amidals 3a-0, obtained from the reaction of 1,3,5-
`tris-[ (S)-phenylethyl]hexahydrotriazine (1) and a,@-unsaturated acyl chlorides, diastereomeric mixtures of im-
`idazolidin-4ones 5-8 and perihydropyrimidin-4-ones 4-10 have been synthesized and easily separated by flash
`,chromatography. The subsequent hydrolysis under acid conditions of the separated heterocycles affords respectively
`D or L a- and @-amino acids. The regicchemistry of the cyclization has been studied, depending on the substituents
`of the double bond. Furthermore the absolute confiiation of the newly introduced stereogenic center has been
`attributed on the basis of the 'H NMR spectra of the heterocycles.
`
`idazolidin-4-ones and 6-Substituted Perihydro-
`pyrimidin-4-ones. The amid& 3a-e have been obtained
`through simple steps, starting from the chiral 1,3,5-tris-
`[(s)-l-phenylethyl]hexahydrotriazine, 1.7 It is known that
`1,3,5-hexahydrotriazines are highly reactive compounds
`which afford, by treatment with acyl chlorides, the cor-
`responding N-alkyl-N-(chloromethy1)amides in quantita-
`tive yieldsa8 Thus 1 was obtained simply by treating
`(23)-1-phenylethylamine either with a 40% aqueous solu-
`tion of formaldehyde or with solid paraformaldehyde in
`dichloromethane. This compound can be utilized without
`further purification, nevertheless, the crystallization from
`petroleum ether afforded a white solid (mp 52-54 "C; [a]D
`-70.3"; c = 2, CHC13).
`
`Ph
`
`Me
`
`Introduction
`Recently many synthetic procedures describing the
`electrophile-promoted cyclofunctionalization of unsatu-
`rated substrates containing an internal nucleofde has been
`reported.'
`In the last years we have been interested in this kind
`of approach, assaciated to the use of commercially available
`(5')-1-phenylethylamine as a chiral source to synthesize
`enantiomerically pure compounds. This strategy affords
`diastereomeric mixtures of heterocycles that can be easily
`separated by flash chromatography. Moreover, starting
`from the appropriate unsaturated carbamate, urea, or
`amide,2 cyclic compounds have been synthesized, with the
`carbon-hydrogen bond of the phenylethyl group eclipsing
`the adjacent carbonyl function of the heterocycle. This
`particular situation favors the identification of the absolute
`configuration of the newly formed stereogenic center
`through the comparison of 'H NMR shifts of the couples
`of diastereomers.
`In a preliminary account of this work3 we reported the
`synthesis of D- and L-alanine starting from chiral ami-
`Now we report an extension of this strategy to
`substrates containing substituted double bonds, further
`transformations of the organometallic intermediates, and
`the experimental details, in order to extend this method
`to the synthesis of a- and &amino acids.
`Results and Discussion
`A. Synthesis and Separation of 5-Substituted Im-
`
`a: CH20 (40% in H20)/0 "C
`PhAMe
`b: (CH20),/CH2C12
`1
`The hexahydrotriazine 1 reacted smoothly with 2,3-un-
`saturated acyl chlorides in dry dichloromethane a t 0 "C
`under argon to give the corresponding N-[(S)-1-phenyl-
`ethyl]-N-(chloromethy1)amides 2a-e. The displacement
`of the chloride group was performed directly by adding the
`mixture to a saturated solution of ammonia in dry di-
`chloromethane and continuing to bubble gaseous ammonia
`in the reaction mixture for 20 min. After filtration of
`ammonium chloride and concentration of the liquid, the
`amino group was protected by reaction with benzyl chlo-
`roformate in a heterogeneous solution of dichloromethane
`and aqueous NaHC03 at 0 "C. The amidals 3a-e were
`purified by chromatography on neutral alumina or silica
`gel and obtained as colorless oils in yields ranging from
`60 to 80% from the triazine 1.
`The synthesis of enantiomerically pure (R)- or @)-a-
`amino acids draws increasing attentions in the recent
`years.g Thus in order to synthesize the optically active
`N-substituted imidmlidin-4ones that are proteded forms
`of a-amino acids, the amidal 3a was cyclized in dry di-
`chloromethane, utilizing Hg(TFA)2 (1.1 equiv) as electro-
`philea5 The reaction was complete in 20 min at room
`
`(1) (a) Bartlett, P. A. Tetrahedron 1980,36,2. (b) Bartlett, P. A. In
`Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New York,
`1984; Vol. 3. (c) Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321.
`(2) For carbamates, see: (a) Cardillo, G.; Orena, M.; Sandri, S.; To-
`masini, C. Tetrahedron 1987, 43, 2505. (b) Bongini, A.; Cardillo, G.;
`Orena, M.; Porzi, G.; Sandri, S. Tetrahedron 1987,43,4377. For ureas
`and isoureas see: (c) Bruni, E.; Cardillo, G.; Orena, M.; Sandri, S.; To-
`masini, C. Tetrahedron Lett. 1989,30,1679. (d) Cardillo, G.; Orena, M.;
`Penna, M.; Sandri, S.; Tomasini, C. Synlett 1990,543. (e) Cardillo, G.;
`Orena, M.; Penna, M.; Sandri, S.; Tomasini, C. Tetrahedron 1991, 47,
`2263. For amides see: (0 Cardillo, G.; Hashem, M. A.; Tomasini, C. J.
`Chem. SOC., Perkin Trans. 1 1990, 1487.
`(3) Amoroso, R.; Cardillo, G.; Tomasini, C. Tetrahedron Lett. 1990,
`31, 6413.
`(4) For the use of acetals to extend the nucleophilicity of an hydroxyl
`group, see: (a) Overman, L. E.; Campbell, C. B. J. Org. Chem. 1974,39,
`1474. (b) Stork, G., Kowalski, C.; Garcia, G. J. Am. Chem. SOC. 1975,97,
`3258.
`(5) For the w e of amidals in cyclofunctionalization reactions, see:
`Harding, K. E.; Marman, T. H.; Nam, D. H. Tetrahedron 1988,44,5605
`and references therein.
`(7) Zaugg, H. E. Synthesis 1984,85 and 181.
`(6) For an alternative strategy for the Synthesis of amino acids starting
`(8) Gronowitz, S.; Lidert, Z. Synthesis 1979, 810.
`from chiral amidals, see: (a) Polt, R.; Seebach, D. J. Am. Chem. SOC.
`(9) (a) O'Donnell, M. J., Ed. a-Amino Acids Synthesis; Tetrahedron
`Simposia in Print number 33; Pergamon: Oxford, 1988; p 5253. (b)
`1989, 111, 2622. (b) Juaristi, E.; Quintana, D.; Lamatach, B.; Seebach,
`D. J. Org. Chem. 1991, 56, 2553. (c) Konopelski, J. P.; Chu, K. S.;
`Williams, R. M. Synthesis of Optically Active a-Amino Acids; Pergamon:
`Negrete, G. R. J. Org. Chem. 1991,56, 1355.
`Oxford, 1989.
`0022-326319211957-1082$03.00/0 0 1992 American Chemical Society
`
`IPR2014-01126- Exhibit 1030 p. 1
`
`
`
`Mercury Cyclization of Chiral Amidals
`
`O R '
`
`
`
`Ph 0
`
`R'
`
`1
`
`+
`
`c
`
`i
`
`u
`
`~
`
`
`
`M e A N u R
`
`2
`
`1) NH3/CH&12
`2) ClCbz
`NaHCO3 (aq.)
`
`a: R=H; R'=H
`b: R=CH$ R'=H
`C: R = CH;CH&Hj; R' = H
`d: R=Ph; R'=H
`e: R = CH3; R' = CH3
`
`Me
`
`I
`'NHCbz
`
`(2)
`
`Figure 1.
`
`J. Org. Chem., Vol. 57, No. 4, 1992 1083
`
`Me Hb
`
`Me
`
`Me
`
`X=O,NR
`
`3
`temperature, and then the solvent was evaporated and
`replaced with dry acetonitrile. The cleavage of the C-Hg
`bond was performed under the usual conditions'" by
`adding 1.1 equiv of NaBH4 a t 0 OC. The mercury was
`removed by filtration, and the analysis of the crude mix-
`ture by 'H NMR and capillary column gas chromatography
`showed, as expeded,l0 the signals of two diastereomers in
`1:l ratio. The diastereomeric mixture, separated on silica
`gel, afforded pure 5a and 5b in 80% total yield. The
`enantiomeric purity and the absolute confiigwation of each
`compound were established by 'H NMR analysis.
`When the organomercury compound 4a was treated with
`NaBH4 in DMF under 02," a 1:l mixture of 5-(hydroxy-
`methyl)imidazolidin-4ones 6a and 6b was obtained. After
`the usual workup, the mixture was separated on silica gel
`(cyclohexane/ethyl acetate, 8 2 , as eluant), and 6a and 6b
`have been obtained in 60% overall yield.
`
`(1 'S ,5 S) - a
`
`Figure 2.
`
`Table I. Synthesis of 5-Substituted Imidazolidin-4-ones
`
`1) HS(TFA)2
`3a-c 2) " 4 4
`
`~
`
`O w -
`PhyNVNCbz
`
`
`
`O W R
`+ phyNyNCbz
`
`
`
`Me
`( 1 'S,5 S) -a
`
`Me
`(l'S,SR)-b
`
`R
`
`[ah, deg
`
`b
`a
`total yield, %
`product
`-43.7
`-89.3
`H
`78
`5
`6
`-20.9
`-88.2
`OH
`61
`-92.0
`+95.3
`73
`7
`CH8
`-96.1
`-26.7
`81
`8
`(CHACH3
`Hg(TFA)2 in &chloromethane was complete in 2 h. After
`reduction with NaBH4, a mixture of 6-phenylperihydro-
`pyrimidin-Cones, 9a and 9b, was obtained in 80% yield
`and 2 1 diastereomeric ratio, as shown by GC-MS and 'H
`NMR analyses. The chromatographic separation appeared
`to be troublesome, and only the more abundant diaste-
`PhYNVNCbz
`reomer 9a could be obtained pure. The IR absorption at
`D PhYNVNCbz
`1650 cm-l c o n f i i e d the formation of six-membered rings.
`Me
`Me
`Similar results have been obtained starting from 38. In
`+
`fact, after cyclization with Hg(Tl?A)2 and reduction with
`NaBH4, the perihydropyrimidin-4-one 10 was obtained
`pure in 80% overall yield.
`O W O H
`2) separation PhYNVNCbz
`phYNVNCbz
`Me
`+
`
`Me
`
`4a
`
`5a
`
`5b
`
`1 ) NaBH4
`2) separation
`
`1) NaBHd02
`
`0 -'.OH
`
`4a
`
`4a
`
`6b
`6a
`In order to establish the influence of a substituent on
`the double bond for the ring size formation, the amidals
`3b and 3c have been cyclized with HB(TFA)~ in dry di-
`chloromethane. The cyclization proceeds with the for-
`mation of imidazolidin-4-ones as proven by the IR ab-
`sorption at 1690 an-', characteristic of fivemembered rings
`of this class of compounds.
`When electron factors are overwhelming, as in the am-
`id& 3d and 3e, the cyclization proceeds with the formation
`of six-membered rings. The cyclization of 3d with
`
`(10) For enantioselective cyclizations starting from chiral amidals, see:
`(a) Harding, K. E.; Hollingaworth, D. R.; Reibenspies, J. Tetrahedron
`Lett. 1989,30,4775. (b) Takacs, J. M.; Helle, M. A.; Yang, L. Tetrahe-
`dron Lett. 1989, 30, 1777. (c) Amoroso, R.; Cardillo, G.; Tomasini, C.
`Tetrahedron Lett. 1991,32,1971.
`(11) Hill, C. L.; Whitesides, G. M. J. Am. Chem. SOC. 1974, 96,870.
`
`3d 3j separation PhyNxNCbz
`
`PhyNyNCbz
`
`M e k Hb
`
`+
`
`Me Ha Hb
`
`(i's,6s)-Qa
`
`(l1S,6R)-9b
`
`2:l diastereomeric ratio
`
`1 ) Hg(TFA)z
`2)NaBH4
`
`3e
`
`O Y - 6
`PhYNwNCbz
`Me 10
`B. 'H NMR Study on 5-Substituted Imidazolidin-
`4-ones and 6-Substituted Perihydropyrimidin-4-ones.
`In preceding works it has been hypothesized through 'H
`NMR analysis that the (S)-phenylethyl group assumes a
`rigid conformation with the hydrogen eclipsing the adja-
`cent carbonyl group.2a,b This observation has been con-
`
`(4)
`
`IPR2014-01126- Exhibit 1030 p. 2
`
`
`
`1084 J. Org. Chem., Vol. 57, No. 4, 1992
`Table 11. 'H NMR Data of Imidazolidin-4-ones 6-8 in CDClt at 300 MHz
`
`Amoroso et al.
`
`(1 'S ,5 S)
`
`(1'S,5R)
`
`a
`
`Ph Me Ha Hb
`
`b
`
`6th
`R
`product
`4 i b
`CH3
`4.41-4.48"
`4.70
`Sa
`CHpOH
`6a
`4.42-4.50"
`4.70-4.72'
`CHpCH3
`7a
`4.65-4.66"
`4.44451"
`(CHz),CH3
`8a
`4.45-4.50"
`4.64-4.65"
`CH3
`4.31
`4.74-4.81"
`5b
`CHpOH
`6b
`4.35
`4.72-4.80"
`CHpCH3
`7b
`4.27
`4.77-4.85"
`(CHJ3CH3
`8b
`4.77-4.85"
`4.25
`" Owing to the presence of two conformers, two chemical shift values are reported.
`
`h i e
`4.20
`4.16-4.27"
`4.25-4.32"
`4.25-4.32"
`4.24
`4.19-4.24
`4.32
`4.32
`
`JW, Hz
`6.5
`5.6
`6.0
`6.0
`6.5
`6.0
`6.0
`5.7
`
`Table 111. Hydrolysis of Compounds 5-8b
`
`( 1 'S,6 S) - 9 a
`Figure 3.
`
`(l1S,6R):9b
`
`firmed by MM2P12 calculations for perihydrooxazin-2-ones
`and oxazolidin-Zones containing the (S)-l-phenylethyl-
`amine moiety.13
`In a similar way as a result of this conformation, the
`absolute confiiation at C5 of imidazolidin-4-ones 5-8 may
`be easily attributed on the basis of the shielding effect
`exerted by the phenyl group of the (9-1-phenylethylamine
`on Ha of the heterocycle. Moreover an additional shielding
`effect is exerted by the substituent R, which shifts upfield
`Hb in compounds 5-8a and Ha in compounds 5-8b. The
`combination of those two effeds yields a A6Ha,m larger in
`5-8b then in 5-8a.
`Moreover, due to the presence of the N-carbamate
`protecting group, the 'H NMR spectra recorded at room
`temperature in CDC13 at 300 MHz show a mixture of ro-
`tamers in ratios ranging from 2:l to l:l.I4
`In Table I1 are
`collected the more significant 'H NMR data for imida-
`zolidin-4-ones 5-8a and 5-8b.
`Owing to the same conformational effect of the phe-
`nylethyl moiety, the absolute configuration of perihydro-
`pyrimidin-4-ones 9a and 9b can be attributed. The
`structural assignment of 9a and 9b is made on the basis
`of the nonequivalence of Ha and Hb, assuming that the
`chemical shift of the hydrogen resonating upfield strongly
`depends on the shielding of the phenyl ring of the 1's
`stereogenic center.
`The phenyl group on 1's shields Ha, which resonates
`always upfield in 9a and 9b [gal 6 b 4.31, 6Hb 5.05; 9b, 6%
`4.58, 6Hb 4.951; moreover, due to the additional shielding
`
`effect of the substituent at C6, A b ~ ~ , m in 9a is larger then
`in 9b. The result of a nuclear Overhauser effect (NOEDIF)
`experiment performed on 9a confirmed the stereochemical
`
`(12) Auinger, N. L.; Yuh, Y. H. Program MM2P (QCPE), updated by
`Rohrer D. C. (1984).
`(13) Bongini, A.; Cardillo, G.; Orena, M.; Porzi, G.; Sandri, S. Chem-
`istry Lett. 1988, 87.
`(14) Hiemstra, H.; Fortgene, H. P.; Stegenga, S.; Speckamp, W. N.
`Tetrahedron. Lett. 1986,26, 3151.
`
`st+u3
`R
`yield, I [ c u ] ~ , O deg
`product
`material
`CH3
`73
`11
`5b
`-14.1
`CHpOH
`6b
`12
`65
`-13.9
`CHpCH3
`71
`7b
`13
`-7.6
`(CHz),CH3
`80
`8b
`14
`-20.5
`"The [aID values are in agreement with those of commercial
`samples.
`assignment. In fact the irradiation of Hd (6 2.71) caused
`the enhancement of Ha (6 4.31)) showing the cis relation-
`ship between Hd and Ha.
`Furthermore the coupling constants of &-% and I&-&
`
`in 9a (&cad = 11 Hz, J H ~ H ~ = 6 Hz) show that the phenyl
`substituent occupies the equatorial position. The same
`trend is observed for 9b (JHc,Hd = 5.5 HZ, J H ~ , H ~
`= IO HZ).
`D. Hydrolysis of Imidazolidin-4-ones 5-8b and
`Perihydropyrimidin-4-ones 9-10. The correct attrib-
`ution of the stereochemistry of the imidazolidin-Cones is
`confirmed by
`the hydrolysis of
`the compounds
`(l'S95R)-5-8b. The hydrolysis was conducted under acid
`conditions to avoid racemization and represents an easy
`step to the synthesis of a-amino acids. Thus the imida-
`zolidin-40nes7 dissolved in methanol and 11 M HC1, were
`refluxed for 24 h to furnish in quantitative yield a mixture
`of the corresponding a-amino acids hydrochlorides and
`(8)-l-phenylethylamine hydrochloride.
`The (S)-l-phenylethylamine was separated during the
`workup, by treatment with aqueous sodium carbonate
`followed by extraction with ethyl acetate. On the other
`hand the purification of the amino acid from sodium
`chloride was performed on a column of BIORAD AG
`50W-X2 resin using NH40H (0.015 M) as eluant. The
`resulta of the hydrolysis of compounds 5-8b are reported
`in Table III. The values of [a]D are in perfect agreement
`with those reported for commercial samples.
`The hydrolysis under acid conditions of the 2:l mixture
`of (1's ,6S)-9a and (1's ,6R)-9b afforded the 8-phenyl-
`alanine 15. In fact after elution from the column resin with
`NH40H (1.5 M), 15 was obtained in 70% yield and 33%
`-6.9'; C = 0.8, HZO)],
`[ [ a ] ~ -2.3'; C = 0.7, H20
`[ a ] ~
`
`IPR2014-01126- Exhibit 1030 p. 3
`
`
`
`Mercury Cyclization of Chiral Amidals
`confirming that the more abundant heterocycle 9a has a
`1'S,6S configuration.
`In the same manner from the 6,6-dimethylperihydro-
`pyrimidin-4-one, 10, the 3-amino-3-methylbutanoic acid,
`16, was obtained in 75% yield.
`1) MeOwHCl 11 M
`gb 2)ionexchangeresin
`
`'0
`
`9a
`
`+
`
`15
`[a]D = -2.3' (C= 0.7 Hfl)
`e.e. = 33 %
`
`1) MeOwHClllM
`2) ion exchange resin
`
`10
`
`'0
`
`(5)
`
`16
`In conclusion this work describes the preparation of
`enantiomerically pure amino acids through simple steps
`and under mild conditions, by means of the formation of
`intermediate chiral imidazolidin-4-ones and perihydro-
`pyrhnidin-4-0nes. Nevertheless the c y c l o f u n c t i o n a l i n
`of substrates containing electron-deficient double bonds
`requires the use of Hg(TFA)2 as electrophile.
`Experimental Section
`General Methods.
`'H NMR and 13C NMR spectra were
`recorded at 300 and 75 MHz, respectively. Chemical shifts are
`reported in ppm relative to the solvent. Infrared spectra were
`recorded with a Perkin-Elmer 682 infrared spectrometer. Melting
`points were determined in open capillaries and are uncorrected.
`GCMS analyses were performed with a cross-linked methyl sil-
`icone column. Flash chromatography was performed with silica
`gel 60 (230-400 mesh). Tetrahydrofuran ("HF) was distilled from
`sodium benzophenone ketyl. Methylene chloride and DMF were
`distilled over CaH2 and stored over molecular sieves. Other
`solvents were used as purchased. (S)-1-Phenylethylamine was
`purchased by Janssen and distilled.
`1,3,&Tris[ (S)-phenylethyl]hexahydrotriazine, 1. Method
`A. To an aqueous solution of formaldehyde (40%, 133 mmol,
`10 mL) was added (3-1-phenylethylamine (100 mmol,12.9 mL)
`at 0 OC. The solution was stirred for 15 min until a yellowish solid
`precipitated. After 30 min CH2Clz was added, and the organic
`layer was separated, dried over Na804, and concentrated under
`vacuum. Hexahydrotriazine 1 was obtained pure in quantitative
`yield (3.95 g) as a low-melting solid and directly used without
`further purification. Recrystallization from petroleum ether
`afforded a white solid.
`Method B. To a solution of (s)-l-phenylethylam.ine (100 "01,
`12.9 mL) in CH2C12 (30 mL) was added solid paraformaldehyde
`(100 mmol,3.00 9). The homogeneous solution was dried over
`sodium sulfate and concentrated. Hexahydrotriazine 1 was ob-
`tained in quantitative yield (3.9 g) as a low-melting solid and
`directly used without further purification. Recrystallization from
`petroleum ether afforded a white solid mp 52-54 'C; 'H NMR
`(CDCld 6 1.23 (d, 3 H, J = 7 Hz, NCHCHS), 3.35 ( ~ , 2 H, NCHN),
`3.70 (q, 1 H, J = 7 Hz, NCHCH3), 7.20 (m, 5 H, Ph); 13C NMR
`(CDClS) 6 20.08,59.38,69.98, 126.67, 127.31, 128.06, 144.29; [a]D
`-70.3" (c = 2, CHClJ. Anal. Calcd for CnHS3N3: C, 81.16; H,
`8.32; N, 10.52. Found: C, 81.09; H, 8.29; N, 10.49.
`General Procedure for the Preparation of Amidal3. A
`solution of acyl chloride (45 mmol) in dry CHzCl2 (10 mL) was
`added dropwise to a solution of hexahydrotriazine 1 (15 mmol,
`5.98 g) in dry CHzC12 (30 mL) at 0 "C and under argon. After
`20 min at 0 "C, TLC analysis of the reaction mixture showed a
`single spot corresponding to the N-(chloromethy1)-N- [ (S)-
`phenylethyllamide 2.
`Meanwhile in a 500-mL four-necks flask dry CH2C12 (200 mL)
`was saturated with gaseous NHB. The solution of N-(chloro-
`methyl)-N-[ (S)-phenylethyllamide 2 in CH2C12 was added
`dropwise at 0 "C, bubbling NH3. After 20 min a white precipitate
`
`(15) Graf, E.; Boeddeker, H. Liebigs Ann. Chem. 1958,613,111.
`
`J. Org. Chem., Vol. 57, No. 4, 1992 108s
`(ammonium chloride) was formed and the bubbling waa stopped.
`The mixture was filtered, and the white solid was washed with
`CH2C12. The liquid was concentrated under vacuum, and the
`corresponding N-(aminomethyl)-N- [(SI-phenylethyllamide was
`obtained.
`To a solution of N-(aminomethyl)-N-[ (S)-phenylethyllamide
`in CHIC& (50 mL) and aqueous NaHC03 (50 mL) was added
`benzyl chloroformate (18 mmol, 2.55 mL) in CHzC12 (10 mL)
`dropwise at 0 OC. The mixture waa stirred for 10 min at room
`temperature and then separated in a funnel. The organic layer
`was dried over NazS04 and concentrated, and the residue was
`chromatographed on silica gel or neutral alumina (cyclohexane-
`/ethyl acetate in different ratios). The amidal3 was obtained
`in good yield as a colorless oil.
`(9)-N-( 1-Phenyleth-1-y1)-N-[[(benzyloxycarbonyl)-
`amino]methyl]acrylamide (3a): chromatography on neutral
`alumina (cyclohexaue/ethyl acetate, 91); 60% yield from hexa-
`hydrotriazine 1; IR ( f i i ) 3440,3300,1700,1650 cm-'; 'H NMR
`(CDClJ 6 1.68 (d, 3 H, J = 7.1 Hz, NCHCHS), 4.58 (8, 2 H,
`NCHZN), 5.06 (8, 2 H, OCH2Ph), 5.23 (9, 1 H, J = 7.1 Hz,
`CHSCHN), 5.75 (d, 1 H, J = 10 Hz, NCOCH-CHH), 6.06 (be,
`1 H, NH), 6.39 (d, 1 H, J = 15 Hz, COCHECHH), 6.64 (dd, 1
`H, J = 10 Hz, J = 15 Hz, NCOCH-CH2), 7.30 (m, 10 H, Ph);
`13C NMR (CDClS) 6 18.12, 50.40, 55.16, 66.45, 126.75, 127.73,
`127.87,128.09,128.31,128.47,128.75,128.91,136.40,140.18,1&.59,
`
`168.37; [ a ] ~ -115.4'
`(c = 1, CHCl,). Anal. Calcd for C&IaNzO3:
`C, 70.99; H, 6.55; N, 8.28. Found C, 70.94; H, 6.49; N, 8.24.
`( S ) - N - ( 1-Phenyleth-1-y1)-N-[ [ (benzyloxycarbonyl)-
`amino]methyl]crotonamide (3b): chromatography on silica gel
`(cyclohexane/ethyl acetate, 91); 67% yield from hexahydmthine
`1; IR (film) 3440,3300,1730,1660,1620 CJD-'; 'H NMR (CDC18)
`6 1.63 (d, 3 H, J = 7.1 Hz, CHSCHN), 1.84 (d, 3 H, J = 6 Hz,
`CH3CH=CH), 4.53 (m, 2 H, NCH2N), 5.01 (a, 2 H, OCHah), 5.18
`(4, 1 H, J = 7.1 Hz, CH&HN), 6.08 (bs, 1 H, NH), 6.31 (d, 1 H,
`J = 11 Hz, OCCH-CH), 6.95 (dq, 1 H, J = 6 Hz, J = 11 Hz,
`OCCH=CH), 7.28 (m, 10 H, Ph); '3c NMR (CDClJ 6 15.47,18.27,
`50.44,55.02,66.58, 121.63, 126.75, 127.22, 127.60,127.83, 128.01,
`
`128.41, 128.65,140.21, 142.97, 155.27, 168.20; [ a ] ~ -111.5" (C =z
`1, CHCh). Anal. Calcd for CllHaN203: C, 71.57; H, 6.86; N, 7.95.
`Found C, 71.49; H, 6.79; N, 7.88.
`(S )-N-( 1-Phenyleth-1-y1)-N-[ [ (benzyloxycarbonyl)-
`amino]methyl]hex-2-enamide (3c): chromatography on silica
`gel (cyclohexane/ethyl acetate, 91); 72% yield from hexa-
`hydrotriazine 1; IR (fii) 3440,3300,1730,1660,1620 cm-l; 'H
`NMR (CDCIS) 6 0.93 (t, 3 H, J = 7.4, Hz, CH3CH2CHz), 1.49 (m,
`2 H, CHSCHzCHz), 1.69 (d, 3 H, J = 7.0 Hz, CHSCHN), 2.19 (4,
`2 H, J = 7.4 Hz, CH3CH2CH2), 4.54 (m, 2 H, NCH2N), 5.01 (s,
`2 H, OCHzPh), 5.22 (4, 1 H, J = 7.0 Hz, CHSCHN), 6.08 (bs, 1
`H, NH), 6.31 (d, 1 H, J = 11 Hz, OCCHdH), 6.95 (dq, 1 H, J
`= 7 Hz, J = 11 Hz, OCCH=CH), 7.28 (m, 10 H, Ph); 13C NMR
`(CDClS) 6 13.36, 18.17, 21.13, 34.19, 50.34, 54.84, 66.20, 120.15,
`1~.39,127.21,127.50,127.65,128.06,128.30,136.10,140.11,147.35,
`155.18, 168.10; ["ID -95.5'
`(c = 1.8, CHCIS). Anal. Calcd for
`C.JI&2OS: C, 72.61; H, 7.42; N, 7.36. Found C, 72.58; H, 7.39;
`N, 7.32.
`(9)-N-( 1-Phenyleth-1-y1)-N-[ [ (benzyloxycarbonyl)-
`amino]methyl]cinnamamide (3d): chromatography on silica
`gel (cyclohexane/ethyl acetate, 91); 80% yield from hexa-
`hydrotriazine 1; IR (film) 3420,3300,1720,1640,1600 cm-'; 'H
`NMR (CDClS) 6 1.79 (d, 3 H, J = 6.8 Hz, NCHCH,), 4.78 (m, 2
`H, NCHZN), 5.10 (8, 2 H, OCHZPh), 5.36 (9, 1 H, J 6.8 Hz,
`NCHCHS), 6.12 (bs, 1 H, NH), 6.91 (d, 1 H, OCCH-CH), 7.35
`(m, 15 H, Ph), 7.75 (d, 1 H, OCCH=CH); 13C NMR (CDCI,) 6
`18.75, 51.03,55.57,66.74,117.38,126.77, 127.94,128.12,128.50,
`128.84,1~.88,1~.00,140.37,143.69,157.28,169.12; [ a ] ~ =-148.9"
`(C = 2, CHC13). Anal. Calcd for CzsHmNz03: C, 75.34; H, 6.32;
`N, 6.76. Found C, 75.30; H, 6.28; N, 6.71.
`( S ) - N - ( 1-Phenyleth-1-y1)-N-[[(benzyloxycarbonyl)-
`amino]methyl]-3-methylcrotonamide (38): chromatography
`on silica gel (cyclohexane/ethyl acetate, 85:15); 72% yield from
`hexahydrotriazine 1; IR (film) 3440,3300,1730,1660,1620 cm-';
`'H NMR (CDClJ 6 1.67 (d, 3 H, J = 7.1 Hz, CHSCHN), 1.86 (8,
`3 H, CHSC-), 2.01 ( ~ , 3 H, CHSC-), 4.53 (ABX, 2 H, J = 4.2
`Hz, J = 13.5 Hz, NCHZN), 5.07 (8, 2 H, OCH2Ph), 5.19 (9, 1 H,
`J = 7.1 Hz, CH&HN), 5.56 ( 8 , l H, OCCH=C), 6.04 (d, 1 H, J
`= 7 Hz, NH), 7.28 (m, 10 H, Ph); '% NMR (CDClJ 6 18.11,20.32,
`
`IPR2014-01126- Exhibit 1030 p. 4
`
`
`
`1086 J. Org. Chem., Vol. 57, No. 4, 1992
`21.75,48.13, 55.47,66.50, 118.41, 126.07, 127.02, 127.47, 128.36,
`
`128.44, 128.56, 140.11, 148.49, 155.27, 165.91; [ a ] ~ -110.8’ (C
`2, CHCl,). Anal. Calcd for C ~ H d 2 0 3 : C, 72.11; H, 7.15; N, 7.64.
`Found C, 72.13; H, 7.17; N, 7.67.
`General Procedure for Cyclization. To a stirred solution
`of amidal 3 (3.0 ”01)
`in dry CH2Clz (60 mL) was added
`at room temperature and under argon. After
`Hg(TFA), (3.2 “01)
`20 min the reaction was complete, and the solvent was evaporated
`and replaced with CH&N (200 mL). The solution was cooled
`at 0 OC, and solid N&H4 (3.2 mmol, 121 mg) was added. After
`30 min at 0 ‘C, elemental mercury precipitated and was filtered,
`water was added, and the organic layer was separated, dried, and
`concentrated under vacuum, and the crude product was chro-
`matographed on silica gel (cyclohexane/ethyl acetate in different
`ratios). The heterocycles 5 and 7-10 were obtained as liquids or
`low melting solids.
`1-(Benzyloxycarbonyl)-3-( l’-phenyleth-l’-yl)-5-methyl-
`imidazolidin-4-0110s (sa and 5b): overall yield 78%; isolated
`ratio 1:l.
`(1’S,5S)-5a: IR (film) 1710,1690 cm-’; ‘H NMR (CDCl,) 6
`(mixture of rotamers) 1.44 (d, 3 H, J = 6.8 Hz, OCCHCH,, major
`rotamer), 1.50 (d, 3 H, J = 6.8 Hz, OCCHCH,, minor rotamer),
`1.56 (d, 3 H, J = 7.1 Hz, NCHCHJ, 4.20 (q, 1 H, J = 6.8 Hz, HJ,
`4.41 (d, 1 H, J = 6.5 Hz, Ha, minor rotamer), 4.48 (d, 1 H, J =
`6.5 Hz, Ha, major rotamer), 4.70 (d, 1 H, J = 6.5 Hz, Hb), 5.09
`(AB, 2 H, OCHph, minor rotamer), 5.16 (AB, 2 H, OCH2Ph, major
`rotamer), 5.54 (q, 1 H, J = 7.1 Hz, NCHCHS), 7.32 (m, 10 H); 13C
`NMR (CDClS) 6 (major rotamer) 16.00,17.39,48.89,54.91,57.98,
`67.31,127.18,128.18,128.42,128.67,128.94,136.04,138.78,154.03,
`170.47; (minor rotamer) 16.00, 16.48, 48.66, 55.07, 57.65,67.13,
`127.18,128.18,128.42,128.67,128.94,136.04,138.78,153.27,170.47;
`(c = 0.1, CHCl,). Anal. Calcd for C&2zNz03: c,
`[.ID
`-89.3’
`70.99; H, 6.55; N, 8.28. Found C, 71.04; H, 6.58; N, 8.34.
`(l’S,5R)-5b IR (film) 1710, 1690 cm-’; ‘H NMR (CDC1,) 6
`(mixture of rotamers) 1.38 (d, 3 H, J = 6.4 Hz, OCCHCH,, major
`rotamer), 1.46 (d, 3 H, J = 6.4 Hz, OCCHCH,, minor rotamer),
`1.56 (d, 3 H, J = 7.1 Hz, NCHCHJ, 4.24 (9, 1 H, J = 6.4 Hz, HJ,
`4.31 (d, 1 H, J = 6.5 Hz, Ha, 4.74 (d, 1 H, J = 6.5 Hz, Hb, minor
`rotamer), 4.81 (d, 1 H, J = 6.5 Hz, Hb, major rotamer), 5.13 (AB,
`2 H, OCHzPh, minor rotamer), 5.17 (AB, 2 H, OCHzPh, major
`rotamer), 5.54 (q, 1 H, J = 7.1 Hz, NCHCH,), 7.33 (m, 10 H); 13C
`NMR (CDC13) 6 (major rotamer) 15.93,17.41,48.67,54.94,57.97,
`67.32,126.95,128.17,128.45, 128.70,128.97,136.08,138.93,154.05,
`170.53; (minor rotamer) 15.93, 16.57, 48.38, 55.08, 57.58, 67.32,
`126.95,128.17,128.45,128.70,128.97,136.08,138.93,153.27,170.53;
`[a]D -43.7’ (c = 0.1, CHCl,). Anal. Calcd for CmHz2NZ03: c,
`70.99; H, 6.55; N, 8.28. Found: C, 70.98; H, 6.43; N, 8.27.
`1-(Benzyloxycarbonyl)-3-( l’-phenyleth-l’-yl)-5-ethyl-
`imidazolidin-4-0110s (7a and 7b): overall yield 73%; isolated
`ratio 1:l.
`(1’8,5S)-7a: mp 55-57 ‘C; IR (film), 1710,1690 cm-’; ‘H NMR
`(CDClJ 6 (mixture of rotamers) 0.83 (t, 3 H, J = 7.4 Hz, CHZCH,,
`major rotamer), 0.85 (t, 3 H, J = 7.4 Hz, CH2CH3, minor rotamer),
`1.58 (d, 3 H, J = 7.1 Hz, NCHCH3), 1.98 and 2.08 (m, 2 H,
`CH2CH3), 4.25 (t, 1 H, J = 6.2 Hz, H,, major rotamer), 4.32 (t,
`1 H, J = 6.2 Hz, I-&, minor rotamer), 4.44 (d, 1 H, Ha, J = 6.0 Hz,
`minor rotamer), 4.51 (d, 1 H, &, J = 6.0 Hz, major rotamer), 4.65
`(d, 1 H, Hb, J = 6.0 Hz, major rotamer), 4.66 (d, 1 H, Hb, J = 6.0
`Hz, minor rotamer), 5.13 (AB, 2 H, OCHzPh), 5.56 (q, 1 H,
`NCHCH3, J = 7.1 Hz), 7.30 (m, 10 H, Ph); 13C NMR (CDCl,) 6
`(major rotamer) 7.17,16.11,23.82,48.96,58.93,59.65,67.33,127.23,
`128.10,128.21,128.40,128.67,128.94,136.03,138.67,154.12,169.60;
`(minor rotamer) 7.31,16.11,22.89,48.69,58.51,59.78,67.11,127.23,
`128.10,128.21,128.40,128.67,128.94,136.03,138.67,154.12,169.60,
`[“ID +95.3’ (c = 0.1, CHC13). Anal. Calcd for C21H24N203: C,
`71.57; H, 6.86; N, 7.95. Found: C, 71.61; H, 6.88; N, 7.97.
`(ltS,5R)-7b: IR (film) 1710,1690 cm-’; ‘H NMR (CDCl,! 6
`(mixture of rotamers) 0.68 it, 3 H, J = 7.4 Hz, CHzCH3, major
`rotamer), 0.75 (t, 3 H, J = 7.4 Hz, CHzCH3, minor rotamer), 1.59
`(d, 3 H, J = 7.1 Hz, NCHCH,), 1.92 (m, 2 H, CH2CH3), 4.27 (d,
`1 H, J = 6.0 Hz, Ha), 4.32 (t, 1 H, J = 6.1 Hz, H,), 4.77 (d, 1 H,
`J = 6.0 Hz, Hb, minor rotamer), 4.85 (d, 1 H, J = 6.0 Hz, Hb, major
`rotamer), 5.16 (AB, 2 H, OCH2Ph), 5.57 (9, 1 H, J = 7.1 Hz,
`NCHCHJ, 7.32 (m, 10 H, Ph); 13C NMR (CDC13) 6 (major ro-
`tamer) 7.24, 15.93,23.96,48.93,58.92,59.77,67.41, 127.20, 128.14,
`128.28,128.49,128.76,128.95,136.14,138.98,154.12,169.74; (minor
`
`Amoroso et al.
`rotamer) 7.41,15.93,23.05,48.61,58.45,59.89,67.41,127.20,128.14,
`128.28,128.49, 128.76, 128.95, 136.14,138.98, 154.12,169.74; [U]D
`(c = 0.1, CHCl,). Anal. Calcd for CzlHuNz09: C, 71.57;
`-92.0’
`H, 6.86; N, 7.95. Found C, 71.61; H, 6.92; N, 7.98.
`1-(Benzyloxycarbonyl)-3-( 1’-phenyleth-1‘-y1)-5-butyl-
`imidazolidin-4-ones (ea and 8b): overall yield 81%; isolated
`ratio 1:l.
`(ltS,5S)-8a: mp 50-52 “C; IR (film) 1710,1690 cm-’; ‘H NMR
`(CDCl,) 6 (mixture of rotamers) 0.85 (t, 3 H, J = 7.2 Hz, CH3C-
`H2CHzCH2, major rotamer), 0.87 (t, 3 H, J = 7.2 Hz, CH3CHzC-
`H2CH2, minor rotamer), 1.26 (m, 4 H, CH3CH2CH2CHz), 1.59 (d,
`3 H, J = 7.2 Hz, NCHCHJ, 1.92 (m, 2 H, CH3CH2CH2CH2), 4.25
`(t, 1 H, J = 6.3 Hz, H,, major rotamer), 4.32 (t, 1 H, J = 6.3 Hz,
`I-&, minor rotamer), 4.45 (d, 1 H, J = 6.0 Hz, Ha, minor rotamer),
`4.50 (d, 1 H, J = 6.0 Hz, Ha, major rotamer), 4.64 (d, 1 H, J =
`6.0 Hz, Hb, major rotamer), 4.65 (d, 1 H, J = 6.0 Hz, Hb, minor
`rotamer), 5.13 (AB, 2 H, OCHzPh), 5.55 (q, 1 H, J = 7.2 Hz,
`NCHCH,), 7.30 (m, 10 H, Ph); 13C NMR (CDCI,) 6 (major ro-
`tamer) 13.72, 15.93, 20.42, 25.14,30.45,48.77, 58.69,58.83,66.98,
`126.73,127.71,127.88,128.14,128.42,135.82,138.40,153.76,169.16;
`(minor rotamer) 13.46,15.93,22.11,25.35,29.30,48.55,58.57,59.64,
`66.74,126.73,127.71,127.88,128.14,128.42,135.82,138.40,153.75,
`
`169.16; [ a ] ~ -26.7’ (C 2, CHC13). hid. cdcd for C&.&&&
`C, 72.61; H, 7.42, N, 7.36. Found C, 72.66; H, 7.48; N, 7.40.
`(l’S,SR)-8b: IR (film) 1710,1690 cm-’; ‘H NMR (CDC13) 6
`(mixture of rotamers) 0.76 (t, 3 H, J = 7.2 Hz, CH3CH2CHzCHz,
`minor rotamer), 0.85 (t, 3 H, J = 7.2 Hz, CH3CH2CH2CH2, major
`rotamer), 1.20 (m, 2 H, CH3CHzCHzCHz), 1.60 (d, 3 H, J = 7.0
`Hz, NCHCH,), 1.88 (m, 2 H, CH&HzCH2CH2), 2.15 (m, 2 H,
`CH&H&H2), 4.25 (d, 1 H, J = 5.7 Hz, HJ,4.32 (t, 1 H, J = 6.3
`Hz, H,), 4.77 (d, 1 H, J = 5.7 Hz, Hb, minor rotamer), 4.85 (d,
`1 H, J = 5.7 Hz, Hb, major rotamer), 5.14 (AB, 2 H, OCH2Ph),
`5.58 (q, 1 H, J = 7.0 Hz, NCHCH,), 7.30 (m, 10 H, Ph); ‘9c NMR
`(CDCl,) 6 (major rotamer) 13.85, 16.11,22.42,25.51,29.65,48.98,
`58.81,59.11,67.40, 126.21, 127.01, 128.07, 128.30, 128.54, 128.69,
`135.89,138.35,144.90,169.60; (minor rotamer) 13.68,16.11,21.60,
`25.75,30.08,48.57,58.34,59.26,67.40,126.21,127.01,128.07,128.30,
`128.54,128.69,135.89,138.35, 144.90,169.60, [.ID
`-95.1’ (C = 0.5,
`CHCl,). Anal. Calcd for CBHzaNz03: C, 72.61; H, 7.42; N, 7.36.
`Found C, 72.62; H, 7.50, N, 7.38.
`1-(Benzyloxycarbonyl)-3-( 1’-phenyleth- l’-yl)-6-phenyl-
`perihydropyrimidin-4-ones (Sa and Sb): overall yield 80% ;
`isolated ratio 2:l.
`(lrS,6S)-9a: IR (film) 1710, 1650 cm-l; ‘H NMR (CDCI,) 6
`1.58 (d, 3 H, J = 7.2 Hz, NCHCH,), 2.71 (dd, 1 H, &daC = 11
`HZ, JHd,He = 15.5 HZ, Hd), 2.95 (dd, 1 H, JHeac = 6 HZ, JHs,Hd =
`15.1 Hz, b), 4.31 (d, 1 H, J = 13.2 Hz, HJ, 5.05 (d, 1 H, J = 13.2
`Hz, Hb), 5.10 (m, 3 H, H, + OCH2Ph), 5.86 (q, 1 H, J = 7.2 Hz,
`NCHCH,), 7.35 (m, 15 H, Ph); 13C NMR (CDC1,) 6 16.26,50.51,
`53.20,67.74,125.55,125.73,127.10,127.31,127.72,127.84, 127.96,
`128.09,128.28,128.40,128.58,128.74,128.79,128.88,135.72,139.13,
`159.26, 169.50; [a]D -45.9’
`(c = 0.5, CHC13). Anal. Calcd for
`C&IaN203: C, 75.34, H, 6.32; N, 6.76. Found C, 75.38; H, 6.34;
`N, 6.81.
`(1’8,6R)-9b: IR (film) 1710,1650 cm-’; ‘H NMR (CDCl,) 6
`1.58 (d, 3 H, J = 7.2 Hz, NCHCHJ, 2.79 (dd, 1 H, JH~,H,
`10
`HZ, Jfi Hd = 15 H2, He), 2.98 (dd, 1 H, JHd,Hc = 5.5 HZ, JHd,He
`15 Hz, k,), 4.58 (d, 1 H, J = 12.1 Hz, Ha), 4.95 (d, 1 H, J = 12.1
`Hz, Hb), 5.02 (m, 3 H, H, + OCHZPh), 5.93 (q, 1 H, J = 7.2 Hz,
`NCHCH3), 7.35 (m, 15 H, Ph); 13C NMR (CDClJ 6 16.26, 50.51,
`54.65,67.99,125.55,127.10,127.31, 127.59,127.72, 127.84,127.96,
`128.09,128.28,128.40,128.58,128.74,128.79,128.88,135.72,139.13,
`159.50, 169.50.
`1-(Benzyloxycarbonyl)-3-( 1’-phenyleth- l’-yl)-6,6-di-
`methylperihydropyrimidin-4-ones (10): yield 75% ; IR (film)
`1710, 1650 cm-’; ‘H NMR (CDClJ 6 1.44 (8, 3 H, CH,CN), 1.47
`( ~ , 3 H, CHSCN), 1.48 (d, 3 H, J =i 7.1 Hz, CHBCHN), 2.54 (AB,
`2 H, OCCH,C), 4.50 (d, 1 H, J = 13.2 Hz, Ha), 4.81 (d, 1 H, J =
`13.2 Hz, Hb), 5.05 (AB, 2 H, OCHzPh), 5.82 (9, 1 H, J = 7.1 HZ,
`NCHCH3), 7.26 (m, 10 H, Ph); NMR (CDClJ 6 16.38, 26.48,
`47.85, 49.75, 53.09, 55.35, 66.99, 126.94, 127.48, 127.88, 127.99,
`128.34,128.39,135.94,139.60,169.50; [ a ] ~ -51.7’
`
`(C = 3, CHClS).
`Anal. Calcd for CzzHzsN203: C, 72.11; H, 7.15; N, 7.64. Found
`C, 72.17; H, 7.20; N, 7.69.
`l-(Benzyloxycarbonyl)-3-( 1’-phenyleth-1’-y1)-5-(hydroxy-
`methyl)imidazolidin-4-ones (6a and 6b). To a stirred so