J. Org. Chem. 1995,60, 2642-2644
2642
A n Efficient Synthesis of Aromatic
Scheme 1
Acetonyl Imines Joel Morris* and Donn G . Wishka Medicinal Chemistry Research, The Upjohn Company, Kalamazoo, Michigan 49001 MeLi-LiBr toluene / ether -78 to 0 oc
Received January 3, 1995
The condensation of primary amines with aldehydes or ketones represents the classical method for the synthesis of imines or Schiff bases.l Various Lewis acid2 promoters and dehydrating agents3 have been utilized to provide a measure of predictability and reliability to this process. Reactions of aromatic amines with a ~ e t o n e ,oRen ~ ~ . performed ~ in the absense of a catalyst,4ab can be beset with long reaction times4aand the significant formation of undesired by product^.^" The development of an alternative synthesis of the (tert-butylaminolpyridine HIV-1 reverse transcriptase inhibitor intermediate 35 prompted the need for a n efficient preparation of acetonyl imine 2 from pyridylamine 1. The original route to 3 involved a two-step tert-butylamine synthesis6 that utilized the ability of a n a-amino nitrile to act as a precursor for the in situ generation of imine 2.7 Herein, we describe a n efficient synthesis of aromatic acetonyl imines and present the application of this process to the preparation of 3 (Scheme 1). Utilizing the related benzyl protected piperidine 48 as our intial substrate, we first attempted the use of 2,2dimethoxypropane as a n acetone equivalent. Heating 4 neat in the presence of 2,2-dimethoxypropane (pTsOH, 80 "C,17 h) resulted in a n 81%recovery of the primary amine. Reasoning that conditions that produce a n irreversible shift in the equilibrium toward the imine were preferred, 2-methoxypropene was chosen to serve as both a n acetone source as well as a methanol sink to drive the reaction. Although no reaction was observed when 4 was stirred in 2-methoxypropene with 5 mol % pyri-
4
. .-
dinium p-toluenesulfonate (PF'TS) at rt, heating the mixture a t 100 "C(4 h, sealed tube) afforded a quantitative yield of acetonyl imine 5. (1)(a) Schiff, H.Ann. 1864, 131,118.(b) Layer, R. W. Chem. Reu. 1963,63,489. (2)(a) AgI: Kuhn, R.; Schretzmann, H. Chem. Ber. 1957,90,557. (b) ZnCl2: Duffaut, N.; Dupin, J.-P. Bull. Chim. SOC.Fr. 1966,3205. (c) TiC14: Weingarten, H.; Chupp, J. P.; White, W. A. J . Org. Chem. 1967,32,3246.(d) BuzSnClp: Stetin, C.; de Jeso, B.; Pommier, J. C. Synth. Commun. 1982,12,495.(e) TMSOTf: Morimoto, T.; Sekiya, M. Chem. Lett. 1985,1371.(0 PhN(AlCl&: Eisch, J. J.; Sanchez, R. J. Org. Chem. 1986,51,1848. (3)Molecular sieves: (a) Kyba, E. P. Org. Prep. Proc. Int. 1970,2, 149.(b) Roelofsen, D. P.; Bekkum, H. V. Red. Trau. Chim. Pays-Bas 1972,91,605. MgSOl and CaSO1: (c) Meister, W.; Guthrie, R. D.; Maxwell, J. L.; Jaeger, D. A.; Cram, D. J. J. Am. Chem. SOC.1969,91, 4452. (4)(a) Chong, R. J.; Siddiqui, M. A.; Snieckus, V. Tetrahedron Lett. 1986,5323-5326.(b)Nagawa, Y.;Honda, K.; Nakanishi, H. Synthesis 1987,905.(c) Eaton, D. R.; Tong, J . P. K. Znorg. Chem. 1980,19,740.
3
N&
Our initial attempt to apply this method to the formation of imine 2 proved less than satisfactory due to the formation of significant amounts of byproducts discernible in the crude lH N M R spectrum. However, we found that the addition of 1 no1 equiv of E t a to the mixture allowed the reaction to proceed normally, providing a quantitative recovery of 2 (Scheme 1). The 'H and I3C NMR spectra of unpurified 2 were impeccably clean and demonstrated the complete stability of the N-Boc protecting group to the reaction conditions. Increasing the amount of PPTS catalyst from 5 to 10 mol % resulted in a substantial increase in the reaction rate (35 h 16 h). The generality of this process was established by the extension of this strategy to a series of aromatic amines 8 (Table 1).With the exception of 2-aminopyridine (6d), which afforded a complex mixture under the reaction conditions, the imines 7 were produced cleanly in excellent yield. Several experiments performed with 3-amino2-chloropyridine (8a)suggest that the role of EtsN in this process may simply be to provide a less acidic ~ a t a l y s t . ~ In one run using only 10 mol % of Et3N in addition to 10 mol % of PPTS, a quantitative recovery of imine 7a was obtained uneventfully. The use of 10 mol % Et3NHf TsO- as the sole catalyst was also successful, although the product was contaminated with small amounts of byproducts.1° Treatment of acetonyl imine 2 with MeLi-LiBr complex (4 equiv, -78 "C to rt, etherholuene) afforded the corresponding (tert-buty1amino)pyridine3 in 82% yield.'l Whereas the employment of similar conditions for the transformation of 7a to 8a proceeded in 70% yield, the related conversion with 7b gave only a n optimized 27% recovery of 8b (Scheme 2). The lower yield in the latter reaction can be attributed to the relative increase in the amount of deprotonation of the more sterically accessible imine.
-
(5)Romero, D. L.;Morge, R. A.; Biles, C.; Berrios-Pena, N.; May, P. D.; Palmer, J. R.; Johnson, P. D.; Smith, H. W.; Busso, M.; Tan, C.-K.; Voorman, R. L.; Reusser, F.; Althaus, I. W.; Downey, K. M.; So, A. G.; Resnick, L.; Tarpley, W. G.; Aristoff, P. A. J . Med. Chem. 1994,37, 999. (6)Genin, M. J.; Biles, C.; Romero, D. L. Tetrahedron Lett. 1993, 4301. (7)Overman, L. E.; Burk, R. M. Tetrahedron Lett. 1984,1635. (8)Romero, D. L.; Mitchell, M. A.; Thomas, R. C.; Palmer, J. R.; Tarpley, W. G.; Aristoff, P. A. WO 91/09849,1991. (9)Formation of acetonyl imine 5 is apparently successful in the absence of Et3N due to the presence of a basic piperidine nitrogen in aminopyridine 4. (10)This hygroscopic catalyst was prepared in 93% yield by the addition of 1.2 equiv of Et3N to an azeotropically dried solution of p-toluenesulfonic acid monohydrate in benzene (rt). (11)By monitoring the reaction by TLC, it appeared that quenching the reaction at -10 "C might allow for isolation of the tert-butylamine with the N-Boc group intact.
0022-3263/95/1960-2642$09.00/00 1995 American Chemical Society
J. Org. Chem., Vol. 60,No. 8, 1995 2643
Notes Table 1. Synthesis of Aromatic Acetonyl Imines
OMe
R-NHz
PPTS, EbN
6 entry a b c d e f
A , l0OQC-
starting amine 3-amino-2-chloropyridine 3-aminopyridine 3-aminoquinoline 2-aminopyridine 4-bromoaniline 1-aminonaphthalene
NqMe Me
R'
7
reaction time, h 9 9 16 3.5 5 5.5
% yield of imine 100 100 100 complex mixture 99 97
Scheme 2
A
N
%
N
MeLi-LiBr
7a R = C I 7b R = H
Ba R = CI, 70% 8b R=H,27%
In summary, the reaction of aromatic amines with 2-methoxypropene in the presence of PP'l'S and Et3N provides the corresponding acetonyl imines in excellent yield.
Experimental Section NMR IR spectra were taken as a Nujol mull. 'H and spectra were obtained in CDC13 a t 300 MHz. TLC was performed on Merck precoated glass plates on silica gel 60-F254 and stained with a solution of 75 g of ammonium molybdate, 2.5 g of ceric sulfate, and 500 mL of 10% HzS04 (v/v). Column (flash) chromatography was performed with Merck silica gel 60 (230-400 mesh). Caution: Sealed tube reactions with 2-methoxypropene at 100 "C m a y develop significant pressure and should be performed behind a suitable safety shield (weighted base, polycarbonate type). Representative Procedure for the Preparation of Aromatic Acetonyl Imines: [2-[ l-(tert-Butyloxycarbonyl)-4piperazinyl]pyridin-3-yll(l-methylethylidene)amine(2).A solution of l-(tert-butyloxycarbonyl)-4-(3-aminopyridin-2-y1)piperazine (1)(4.44 g, 15.95 mmol) in 7.6 mL of CHC13 in a 48 mL screw cap pressure tube (Ace Glass, No. 8648) was diluted with 7.6 mL of 2-methoxypropene (79.4 mmol). Et3N (2.2 mL, 15.9 mmol) and PPTS (400 mg, 1.59 mmol) were added, and the mixture was warmed to 100 "C for 16 h. After cooling to rt, the mixture was poured into 50 mL of 50% saturated N a ~ C 0 3and extracted with 3 x 50 mL of EtzO. The combined organics were dried over K&O3 and concentrated in U ~ C U Oto provide 5.08 g (100%) of 2 as an amber viscous oil: 'H NMR 6 1.48 ( 8 , 9H), 1.75 ( s , 3H), 2.20 (s, 3H), 3.22 (m, 4H), 3.44 (m, 4H), 6.82-6.89 (m, 2H), 7.99-8.01 (m, 1H); 13C NMR 6 21.1, 28.4, 44.0, 47.6, 79.7, 117.9, 127.5, 137.9, 142.6, 152.7, 155.0, 170.5; IR 1697, 1663, 1579, 1233 cm-l; HRMS calcd for C17H26N402 318.2056, found 318.2055. (2-Chloropyridin-3-y1)( 1-methylethylidenelamine (7a): yield 2.53 g (100%)from 1.93 g (15 mmol) of 6a;'H NMR 6 1.82 (s,3H), 2.30 (s,3H), 7.07-7.10 (m, lH), 7.18-7.22(m, lH), 8.108.12 (m, 1H); '3C NMR 6 21.7, 28.3, 122.9, 128.9, 141.5, 144.1, 144.5, 173.4; IR 1668, 1397, 1241 cm-I; HRMS calcd for CsH9ClNz 168.0454, found 168.0454. 3-Pyridinyl(l-methylethylidene)amine(7b): yield 2.01 g (100%) from 1.41 g (15 mmol) of 6b; 'H NMR 6 1.84 (s, 3H), 2.23 (s, 3H), 7.04-7.08 (m, lH), 7.22-7.30 (m, lH), 8.05-8.07 (m, lH), 8.31-8.33 (m, 1H); I3C NMR6 20.9, 28.7, 123.5, 127.0, (12)Examination of the 'H NMR from the unpurified reaction mixture (which employed inverse addition conditions) showed a 1:2 ratio of tert-butylamine to imine.
141.4,144.7,147.0,171.5;IR 1664,1586,1237 cm-'; HRMS calcd for CsHloN2 134.0844, found 134.0852. 3-Quinolinyl(l-methylethylidene)amine(74: yield 1.84 g (100%) from 1.44 g (10 mmol) of 6c;'H NMR 6 1.88 (s, 3H), 2.27 (s, 3H), 7.40 (d, J = 2.4 Hz, lH), 7.48-7.53 (m, lH), 7.587.64(m,lH),7.73(d,J=8Hz,lH),8.07(d, J=8Hz,lH),8.46 (d, J = 2.4 Hz, 1H); 13C NMR 6 21.7, 28.8, 122.8, 127.0, 127.2, 127.7, 128.4, 129.2, 144.3, 145.2, 145.6, 172.1; IR 1664, 1615, 1438, 1244 cm-1; HRMS calcd for ClzHlzNz 184.1000, found 184.0999. (4-Bromophen-l-yl)(l-methylethylidene)amine (7e):yield 2.09 g (99%) from 1.72 g (10 mmol) of 6e; 'H NMR 6 1.80 (s, 3H), 2.17 (s, 3H), 6.57-6.61 (m, 2H), 7.37-7.42 (m, 2H); 13C NMR 6 20.7, 28.6, 116.1, 121.5, 131.9, 150.4, 170.0; IR 1663, 1595, 1397, 1234 cm-l; HRMS calcd for CgHloBrN 210.9997, found 210.9993. 1-Naphthyl(1-methylethy1idene)amine(70:yield 1.77 g (97%) from 1.43 g (10 mmol) of 6f;mp 103-104 "C; 'H NMR 6 1.75 (s, 3H), 2.34 (s, 3H), 6.70 (d, J = 7 Hz, lH), 7.37-7.48 (m, 3H), 7.55 (d, J = 8 Hz, lH), 7.73 (d, J = 8 Hz, 1H); 13C NMR 6 21.0, 28.5, 109.6, 113.9, 123.2, 123.4, 125.3, 125.9, 126.0, 128.0, 134.2, 147.6, 170.6; IR 1664, 1573, 1243 cm-l. Anal. Calcd for C13H13N: C, 85.21; H, 7.15; N, 7.64. Found: C, 85.21; H, 7.10; N, 7.68. [2-[N-Methyl-N[l-(phenylmethyl)piperidin4yl]amino] pyridin-3-yl] (1-methylethy1idene)amine(5). 4W-MethylN-(3-aminopyridin-2-yl)aminol-l-(phenylmethyl)piperidine (4) (5.1 g, 17.2 mmol) was combined with 2-methoxypropene (8.2 mL, 86 mmol) and PPTS (0.22 g, 0.86 mmol) in a sealed tube under Nz and heated a t 100 "C for 4 h. The reaction mixture was allowed to cool to rt and was partitioned between 50 mL of 50% saturated Na2C03 and 3 x 25 mL of Et2O. The combined organics were dried over anhydrous KzCO3 and concentrated in uucuo to provide 5.78 g (100%) of 5: 1H NMR 6 1.48-1.52 (m, 2H), 1.73 (s, 3H), 1.81-2.02 (m, 4H), 2.18 (s, 3H), 2.78 (s, 3H), 2.91-2.95 (m, 2H), 3.45-3.53 (m, 3H), 6.70-6.81 (m, 2H), 7.247.31 (m, 5H), 7.96-7.98 (m, 1H); 13C NMR 6 20.9, 28.5, 29.2, 31.2, 53.5, 56.7, 63.1, 115.5, 127.0, 127.4, 128.2, 129.1, 137.0, 138.5, 142.4,154.0,169.5;Rf0.26,50% acetonehexane; IR 1663, 1579, 1208 cm-l; HRMS calcd for C21H24N4 336.2314, found 336.2320. 1 4 3 4 l,l-Dimethylethyl)aminolpyridin-2-yllpiperazine (3). A solution of 2 (5.04 g, 15.8 mmol) in 120 mL of dry toluene a t -78 "C was treated with MeLi-LiBr complex (63.6 mL, 95 mmol, 1.5 M in EtzO), and the mixture was slowly warmed t o rt. After 2.5 h a t rt, the reaction was carefully quenched with 100 mL of water. The aqueous layer was extracted with 3 x 50 mL of CH2C12, and the combined organics were dried over K2C03 and concentrated in uacuo. Chromatography on 250 g of silica gel, eluting with 6% MeOWCHzClz 0.4% concentrated NH4OH afforded 3.03 g (82%)of 3: 'H NMR 6 1.39 (s, 9H), 3.00 (m, 8H), 4.62 (bs, lH), 6.83-6.87 (m, lH), 7.02-7.05 (m, lH), 7.66-7.68 (m, 1H); 13C NMR 6 29.6, 46.7, 50.4, 50.9, 118.1, 119.6, 134.6,136.1,151.8;Rf0.35,10% MeOW CHzClz 0.4% concentrated NH4OH; IR 3338,1575,1224 cm-I. Anal. Calcd for C13H~2N4(+ 0.9% HzO): C, 66.03; H, 9.48; N 23.69. Found: C, 65.72; H, 9.43; N, 23.36. 2-Chloro-3-[ (1,l-dimethylethy1)aminolpyridine @a). A solution of 7a (1.26 g, 7.5 mmol) in 50 mL of dry toluene a t -78 "C was treated rapidly dropwise with MeLi-LiBr complex (25 mL, 37.5 mmol, 1.5 M in EtzO), and the mixture was slowly warmed to 0 "C. After 1 h a t 0 "C the reaction was carefully quenched with 50 mL of water. The aqueous layer was extracted with 2 x 50 mL of CH2C12, and the combined organics were dried over &COS and concentrated in uacuo. Chromatography on 50 g of silica gel, eluting with 25% ethyl acetatehexanes, afforded 0.97 g (70 %) of 8a: 1H NMR 6 1.40 ( s , 9H), 4.40 (bs, lH), 7.027.06 (m, lH), 7.15-7.18 (m, lH), 7.66-7.69 (m, 1H); 13C NMR 6 29.2, 51.1,119.9,122.6,135,8,138.2,139.4;Rf0.64,50% acetone/ hexanes; IR 3418,1583,1499,1213 cm-l; HRMS calcd for C9H13ClNz 184.0767, found 184.0769. 34(1,l-Dimethylethy1)aminolpyridine(8b). A solution of 7b (0.724 g, 5.4 mmol) in 8 mL of dry toluene (+ 2 mL toluene rinse) was added slowly dropwise (30 min, syringe drive) to a solution of MeLi-LiBr complex (18 mL, 27 mmol, 1.5 M in Et201 in 40 mL of toluene a t -25 "C. The reaction was allowed to slowly warm to -5 "C. The mixture was carefully quenched with 25 mL of water. The aqueous layer was extracted with 2 x 25
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+
+
2844 J. Org. Chem., Vol. 60,No. 8,1995 mL of CH2C12, and the combined organics were dried over KzCO3 and concentrated in uucuo. Chromatography on 75 g of silica
Additions and Corrections Supplementary Material Available: Copies of lH NMR spectra of 2, 3, 5, 7a-c, 7e,f, 8a,b (10pages). This material is contained in libraries on microfiche, immediately follows this article in the microfilm version of the journal, and can be ordered from the ACS; see any current masthead page for ordering information.
gel, eluting with 35% acetonehexanes + 1% Et3N afforded218 mg (27%) of8b: NMR 6 1.35 (8, 9H), 3.59 (bs, 1H), 7.027.08 (m, 2H), 7.97-7.99 (m, 1H); 13C NMR 6 29.9, 51.5, 122.7, 123.3, 139.3, 143.0; Rf 0.42, 50% acetonehexanes f 1%Et3N; IR 3396, 1584, 1482, 1227 cm-l; HRMS calcd for C ~ H ~ ~ N Z 151.1235, found 151.1223. J0950036N
Additions and Corrections Vol. 59, 1994
Louis D. Quin*and Stefan Jankowski. 0-Ethyl Phosphoramidic Acids with Sterically Demanding N-Substituents: Useful Precursors of Ethyl Metaphosphate on Thermolysis.
Page 4408, column 1, line 3 of experimental section, replace EtzNH with Et3N. Line 6, replace EbNH.HC1 with Et3N*HC1. Following line 9, replace one OH of the phosphoramidic acid precursor of 17 by OEt. J0944015P
Carole A. Bewley and D. John Faulkner*. Theonegramide, an Antifungal Glycopeptide from the Philippine Lithistid Sponge Theonella swinhoei.
Page 4849, Chart 1. The methyl group in the AHMP residue (F) in theonegramide (2) should be at C-6. Theonellamide F (1) was also drawn incorrectly.
fo H~NOC'
J0954002R
"
H
James A Marshall* and Chad E. Bennett. Synthesis of Furans by SN~'Cyclization of y-Alkynyl Allylic Alcohol Derivatives.
Page 6133. Incorrect numbers were assigned to compounds 13a, 13b, and 14 in the Experimental Section of this paper. The corrected version should read as follows. (2)-6-Hydroxy-l-hexyl-1,4-dimethyl-4-hexen-2ynyl 2,6-Dimetho~ybenzoate(13b). The procedure described for benzoate 4b was followed with 2.00 g (5.91 mmol) of (Z)-l-((tert-butyldimethylsilyl)oxy)-3,6dimethyl-2-dodecen-4-yn-6-oll and 3.56 g (17.7 mmol) of 2,6-dimethoxybenzoyl chloride for 47 h. The product was purified by flash chromatography on silica gel (10%EtOAc-hexane, followed by 25%EtOAc-hexane) to yield 2.64 g (89%) of benzoate as a yellow oil: lH NMR (300 MHz, CDCl3) 6 7.23 (t, J = 8.4 Hz), 6.51 (d, J = 8.4 Hz),5.73(dt,J=1.5,4.9Hz),4.38(dt,J=1.3,5.1Hz), 3.78 (s), 1.85 (9,J = 1.3, 1.4 Hz), 1.79 (SI, 1.52-1.28 (m), 0.87 (m), 0.05 (m). The procedure described for alcohol 6b was followed with 2.64 g (5.25 mmol) of the foregoing benzoate for 45 h. The product was purified by flash chromatography on silica gel (25% EtOAc-hexane, followed by 50% EtOAc-hexane) to yield 0.541 g (27%) of a pure benzoate 13b and 1.190 g (58%)of slightly impure benzoate 13b: 'H NMR (300 MHz, CDCl3) 6 7.24 (t, J = 8.4 Hz), 6.52 ( d , J = 8 . 4 H z ) , 5 . 9 1 ( d t , J = 1 . 5 , 5 . 3 H z ) , 4 . 2 9 ( d J, = 6 . 9 Hz), 3.79 (s), 2.01-1.92 (m), 1.88 (d, J = 1.5 Hz), 1.77 (s), 1.70 (SI, 1.53-1.28 (m), 0.87 (t, J = 6.7 Hz). Anal. Calcd for C23H3205: C, 71.11; H, 8.30. Found: C, 70.86; H, 8.32. (E)-2-(2-Methyl-l-octenyl)-3-methylfuran (14): A. Cyclization of MOM Ether 13a with KO-t-Bu in THF. Procedure A described for furan 6 was followed with 0.255 g (0.950 mmol) of MOM ether 13a for 3.75 h. The product was purified by flash chromatography on silica gel (2.5% EtOAc-hexane) to yield 0.164 g (84%)of furan 14 a s a 1 : l mixture of E and 2 isomers: lH NMR (300 MHz, CDC13) 6 7.27 (d, J = 1.8 Hz), 7.25 (s), 6.19 (d, J = 2.6 Hz), 6.18 (d, J = 2.0 Hz), 5.92 (s), 5.90 (s), 2.43 (t, J = 7.5 Hz), 2.12 (t, J = 7.5 Hz), 1.99 (SI, 1.86 (d, J = 1.3 Hz), 1.46-1.28 (m), 0.86 (m). B. Cyclization of 2,6-Dimethoxybenzoate 13b with KOH-Aliquot 336. Procedure D described for furan 6 was followed with 0.196 g (0.504 mmol) of benzoate 13b a t 55-65 "C for 1.75 h. The product was purified by flash chromatography on silica gel (2.5% EtOAc-hexane) to yield 0.081 g (78%)of furan 14, a light yellow oil, as a 60:40 mixture of E and 2 isomers. 509540035
