exp064



=Objective= To synthesize a Ugi adduct from [|3,4-dimethoxybenzaldehyde], [|5-methylfurfurylamine], [|Benzylisocyanide] and [|Boc-Gly-OH] in methanol using Ugi 4CR. =Procedure= Dissolved [|3,4-dimethoxybenzaldehyde] (Veratradlehyde) (332mg, 2mmol) and [|5-methylfurfurylamine](5-MFA) (244uL, 2.2mmol, 10% excess ) in 4mL methanol-d4 in a 4mL volumetric flask, immediately transferred the contents to a 25mL Erlenmeyer flask, The reaction is allowed to sit for about 6 hours without stirring to form the imine. A solution of [|Boc-Gly-OH](350mg, 2mmol), and [|Benzylisocyanide](240uL, 2mmol) is made up in 4ml volutmeric flask in methanol-d4. This solution of Boc-Gly-OH and benzylisocyanide is added to the preformed Imine. The reaction mix is allowed to sit undisturbed overnight, when the Ugi product is obtained. The product is recrystallized from a small amount of methanol and saved in a 1 dram vial. UCExp64C-C30H37N3O7 ; White solid; tert-butyl (2-{[2-(benzylamino)-1-(3,4-dimethoxyphenyl)-2-oxoethy​ l][(5-methylfuran-2-yl)methyl]amino}-2-oxoethyl)carbamate : M.Pt- 176-177C; 1H NMR ( ppm, 500MHz, CDCl3) 1.44 (s, 9H), 2.1 (s, 3H), 3.72 (s, 3H), 3.86 (s, 3H), 4.196 (s, 2H), 4.32-4.64 (m, 4H), 5.64-5.46, (s, 2H), 6.70-6.82 (m, 2H), 6.83-6.93 0(m, 1H), 7.15-7.40 (m, 8); 13C NMR ( ppm, CDCl3) 13.3, 28.2, 42.5, 42.8, 43.5, 55.67, 55.8, 63.1, 79.5, 106.2, 108.8, 110.7, 112.7, 122.3, 126.4, 127.4, 127.6, 128.5, 137.9, 147.7, 148.9, 149.2, 151.7, 155.7, 169.28, 170.150; IR (cm-1) 3250.01, 1692.10, 1665.94, 1644.09, 1516.65, 1147.11; HRMS (CI-methane): //m/z// calcd for C30H37N3O7 (M+H) 552.270976 Da, found 552.270854 Da.:

=Results=

(Reactant NMRs from Exp054) [|H NMR] [|C NMR] [|H NMR] [|Homodecoupled HNMR spectrum] [One of the furan protons is irradiated to decouple from the methyl group conifrming its position] [|C NMR] [|Tentative assignments] [|H NMR] Signature triplet at 4.68ppm. J = 2.2Hz [|C NMR] [|H NMR] [|C NMR]
 * Veratraldehyde**
 * 5-Methyl furfurylamine**
 * Benzyl isocyanide**
 * Boc-Gly-OH**

[|HNMR -13min] [|H NMR - 5h 15min] [|C NMR - 6h 15min] [|C NMR- 7h 06min] [|H NMR- 7h 10min] [|H NMR- 24h 00min]
 * 64A** (Veratraldehyde + 5-Methyl furfurylamine)

Benzylisocyanide + Boc-Gly-OH in CD3OD [|H NMR]

[|t = 03min] [|t = 09min] [|t = 12min] [|t = 15min] [|t = 24min] [|t = 31min] [|t = 37min] [|t = 46min] [|t = 59min] [|t = 1h 06min] [|t= 1h 52min] [solid in the NMR tube]
 * 64B** (Boc-Gly-OH + Benzyl Isonitrile + 64A) [H NMR analysis]

First batch of crystals -179 mg [|H NMR in CDCl3] [|H NMR in CDCl3 / CD3OD] [|64C Overlay] [|64C 13C-NMR] [|CNMR from Exp060C]
 * 64C** [**C30 H37 N3 O7**]

//**should get one HMR in pure methanol -d4 to see the shifts in the monitoring NMRs**// Melting Point : 176-177C [|64C -DEPT spectrum] (//**beautiful! - looks like you figured this out**//) [|64C [DEPT]] all protonated carbon along a single scale [|Ugi Product 64C-2]

Mass analysis - Ionization Source- CI (methane) [|Nominal mass] [|High Res] [|Elemental analysis] [|High Res] [|MS- pdf] [|Exp064C-IR]

Second batch of crystals -304 mg Melting point :176-178C 43%, 478.7mg (179.5+304.2; 64C and 64C-2) =Discussion=
 * 64C** **-2**
 * Yield**

=Conclusion=
 * 1) [|Imine Assignments] and her is [|mechanism of imine formation (general)] (animation from MSU Chemistry)
 * 2) Proton NMR of 64C in CD3Cl3 accounts for all 37 attached protons. After the addition of CD3OD the integration of the peaks account for only 35 protons, suggesting 2 labile protons (amide N-H) as expected. **//There are a few problems with that - first the reaction was done in methanol-d4 so there should be no N-H's to exchange. Adding the methanol-d4 would not change the total number of H's because any exchanged ones would show up as CD3OH. Now adding a bit of methanol-d4 does shift a few peaks, for example in the furan region removing the overlap between the furan H and the chiral benzylic H. It is worth taking the spectrum in pure methanol-d4 to get some reproducible values that can be compared with the reaction monitoring samples.//**
 * 3) 13CNMR of 64C shows exactly 26 signals which are as expected for the ugi product 64C. **//Good - now list them and identify which are what from the DEPT//**
 * 4) Proton NMR [|assignments for 64C.] There are 3 diastereotopic CH2's between 4.0-4.8ppm range, the protons on these carbons (d,e,f in the image) are diastereotopic coupling with each other. //[coupling would not happen with the N-H's but with each other//**//.//** //2 singlets don't couple differently with a next door H; then you have a set of doublets that do - this should be the benzylic CH2 since [|Alicia's 2 CH2s] were just singlets].// There is an enantiomeric proton at 5.6 ppm ( i in the image) overlapping with one of the furan protons, however after adding deuterated methanol (CD3OD) to the sample it becomes visible.
 * A pure product was prepared via a 4 component Ugi reaction. The experiment was successful.

=Log=

2007-03-02
12:41 : Dissolved 332mg (2mmol) of veratraldehyde in CD3OD in a clean 4ml volumetric flask added 244uL (2.2mmol) 5-methyl frufurylamine to it and immediately made it up to the 4ml mark with CD3OD. This is **64A**. 12:54 : Obtained H NMR of 64A t = 13min 17:56 : Obtained H NMR of 64A t = 5h 15min 18:56 : Obtained C NMR of 64A t = 6h 15min 19:47 : Obtained C NMR of 64A t = 7h 06min 19:51 : Obtained H NMR of 64A t = 7h 10min

2007-03-03
12:41 : Obtained H NMR of 64A t = 24h 00min 13:30 : Made up a solution of 350mg (2mmol) Boc-Gly-OH and 240uL (2mmol) Benzylisocyanide in CD3OD in a 4ml volumetric flask. 14:00 : Obtained a H NMR of the solution of Boc-Gly-OH and Benzylisocyanide 14:35 : Added the solution of Benzylisocyanide and Boc-Gly-OH to 64A (preformed imine solution), this is **64B** 14:38 : Obtained H NMR of 64B [t = 03min] 14:44 : Obtained H NMR of 64B [t = 09min] 14:47 : Obtained H NMR of 64B [t = 12min] 14:50 : Obtained H NMR of 64B [t = 15min] 14:59 : Obtained H NMR of 64B [t = 24min] 15:06 : Obtained H NMR of 64B [t = 31min] 15:12 : Obtained H NMR of 64B [t = 37min] 15:21 : Obtained H NMR of 64B [t = 46min] 15:34 : Obtained H NMR of 64B [t = 59min] 15:41 : Obtained H NMR of 64B [t = 01h 06min] 16:17 : Obtained H NMR of 64B [t = 1h 52min] 16:27 : A [|solid mass] has appeared in the erlenmyer flask containing the reaction mixture **64B**. 17:38 : The solid was filtered through a buchner funnel and washed with methanol. This is [|64C (179.5mg)]. The mother liquor (**64D**) is set on a steam bath to concentrate it for further crystallization. 18:35 : Obtained H NMR of **64C** (~30mg) in CDCl3 (800uL, 0.03% V/V TMS). 18:50 : Added CD3OD (200uL, 0.053% V/V TMS) in the same NMR tube containing **64C** in CDCl3, and obtained H NMR.

2007-03-07
13:00 : The filterate **64D** (mother liquor) was concentrated on a steam bath when it became thick and cloudy, this was filtered through a buchner funnel, washed with ice cold methanol and dried (by letting the product sit in an oven maintained at 80C for 7min. (**//- these harsh conditions should be avoided - always just dry on the high vac pump//**).A filterate was again collected (**64E**) 17:00 : Obtained a second batch of white solid...Ugi product, **64C-2** (//304mg//)- Yield : 43.8%

2007-03-08
12:00 : Concentrated the mother liquor **64E** on a steam bath - **//again should use a rotovap then high vac to avoid decomposing the product - give weight and appearance of 64E when dry//**

2007-03-09
15:50 : [|64E (mother liquor)] has started to develop solid again. =Tags= [|Benzylisocyanide] [|InChI=1/C8H7N/c1-9-7-8-5-3-2-4-6-8/h2-6H,7H2] [|Veratradehyde][|InChI=1/C9H10O3/c1-11-8-4-3-7(6-10)5-9(8)12-2/h3-6H,1-2H3] [|Boc-Gly-OH][|InChI=1/C7H13NO4/c1-7(2,3)12-6(11)8-4-5(9)10/h4H2,1-3H3,(H,8,11)(H,9,10)] [|5-methylfurfurylamine][|InChI=1/C6H9NO/c1-5-2-3-6(4-7)8-5/h2-3H,4,7H2,1H3] ugi054:[|InChI=1/C30H37N3O7/c1-20-12-14-23(39-20)19-33(26(34)18-32-29(36)40-30(2,3)4)27(22-13-15-24(37-5)25(16-22)38-6)28(35)31-17-21-10-8-7-9-11-21/h7-16,27H,17-19H2,1-6H3,(H,31,35)(H,32,36)]

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