Chapter+6+-+Addition+of+Isocyanide


 * Chapter 6: Addition of an Isocyanide: Formation of the Ugi Adduct**


 * 6.1 Introduction**

The study of isocyanide chemistry began in the mid-nineteenth century when allyl isocyanide was formed from allyl iodide and silver isocyanide (Ugi 2003). From that point, a small number of isocyanides were investigated, mostly because they were difficult to prepare. However, it wasn’t until the mid-twentieth century when isocyanides (36) were made widely available by the dehydration of formylamines (34) using an acyl halide (35) in the presence of a base (Ugi 1965, Ugi 2003).


 * Scheme 6.1** Synthesis of Isocyanides (Porcheddu 2005)

Isocyanide chemistry became extremely popular with the onset of four component combinatorial chemistry (4CC). With the availability of several isocyanides, many libraries of different compounds could easily be produced using simple one-pot procedures including the Ugi reaction (U-4CC).

In addition to the dehydration of formylamines, Armstrong proposed the synthesis of the “convertible isocyanide”, 1-isocyancyclohexene, in 1996 (Zhu 2005, Armstrong 1996). This isocyanide addresses the low availability of a variety of isocyanides. By using 1-isocyancyclohexene as the isocyanide input for the Ugi reaction, the Ugi adducts can be converted into a multitude of new products.

Our initial interest in using this convertible isocyanide to synthesize diketopiperazines from our Ugi adduct was subdued due to cost of the isocyanide and the difficulty in synthesis of the isocyanide. Hulme suggested (Hulme 1998) that benzyl isocyanide works just as well as Armstong's convertible isonitrile as well as n-butyl isocyanide and diethyl isocyanomethyl phosphonate. On account of this, we investigated the uses of other isocyanides in the Ugi reaction, including tert-butyl isocyanide which has been described in this chapter.


 * 6.2 Experimental**


 * 6.2.1 Materials and Reagents**

Piperonal was purchased from Sigma-Aldrich Chemical Company (Milwaukee, WI). 5-methylfurfurylamine (5-MFA) was purchased from Acros Organics (New Jersey). Boc-Gly-OH was purchased from Chem-Impex International (Wood Dale, IL). Tert-Butyl Isocyanide was purchased from Fluka Chemie (Steineheim, Switzerland). Deuterated chloroform with 0.03% v/v TMS was purchased from Cambridge Isotope Laboratories, Inc. (Andover, MA).


 * 6.2.2 Procedure**


 * 6.2.2.1 Synthesis (Holsey 2007A, Holsey 2007B)**


 * Scheme 6.2** Synthesis of the Ugi Adduct (38) using piperonal (16), 5-MFA (18), Boc-Gly-OH (17), and t-butyl isocyanide (37).

To four separate vials was added piperonal (16) (0.150 g, 1 mmol), 5-methylfurfurylamine (18) (111 uL, 1 mmol), Boc-Gly-OH (17) (0.175 g, 1 mmol), and tert-butyl isocyanide (37) (113 uL, 1 mmol) and diluted to 1 mL with methanol. To four separate vials was added piperonal (0.150 g, 1 mmol), 5-methylfurfurylamine (111 uL, 1 mmol), Boc-Gly-OH (0.175 g, 1 mmol), and tert-butyl isocyanide (113 uL, 1 mmol) and diluted to approximately 1 mL with CDCl3. Solutions in deuterated chloroform were used to take the spectra of the starting materials to ensure purity. To a separate 5 dram vial were added piperonal and 5-methylfurfurylamine solutions (in methanol) which were allowed to sit for approximately 3 hours. A 400uL sample of the reaction was removed and placed under high vacuum to eliminate solvent. One milliliter CDCl3 was added to the sample and HNMR spectra were taken to confirm the complete production of the imine (31). The Boc-Gly-OH solution (in methanol) was then added to the 5 dram vial. The 5 dram vial was shaken for approximately 30 seconds. The solution was allowed to sit for approximately 30 minutes. A 400 uL sample of the reaction was placed under high vacuum to eliminate solvent. One milliliter of CDCl3 was added to the sample and an NMR spectrum was taken of the reaction mixture. The tert-butyl isocyanide solution (in methanol) was then added to the 5 dram reaction vial. The reaction was then monitored by HNMR. The crystalline product (38) was isolated via suction filtration and rinsed in methanol. The product was dried via high vacuum, weighed, and dissolved in deuterated CDCl3 for NMR analysis. HNMR (300MHz, CDCl3) d 1.3 (9H, s), 1.4 (9H,s), 2.2 (3H, bs), 4.2 (2H, s), 4.4(2H, s), 5.6(1H, bs), 5.8 (3H, m), 6.0 (2H, d), 6.8 (3H, m); CNMR (CDCl3, 300MHz) d 13.7, 28.6, 28.8, 42.5, 43.1, 51.8, 63.0, 79.7, 102.4, 106.4, 108.4, 108.9, 110.4, 123.7, 128.7, 148.1, 151.9, 155.9, 168.9, 170.5; MALDI-TOFMS m/z cald for C26H35N3O7 501.5, obsvd 524.18 [M+Na]; m.p 172-174C, 163.7mg, 41.3% isolated yield.


 * The procedure was then repeated on a larger scale for further cyclization studies using the following data:**

To four separate volumetric flasks were added piperonal (16) (0.691 g, 4.6 mmol), 5-methylfurfurylamine (18) (510uL, 4.6 mmol), Boc-Gly-OH (17) (0.805 g, 4.6 mmol), and t-butyl isocyanide (37) (520 uL, 4.6 mmol) and diluted to mark to approximately 10 mL with methanol. HNMR (300MHz, CDCl3) d 1.3 (9H, s), 1.4 (9H,s), 2.2 (3H, bs), 4.2 (2H, s), 4.4(2H, s), 5.6(1H, bs), 5.8 (3H, m), 6.0 (2H, d), 6.8 (3H, m); 958mg, 41.3% isolated yield, m.p. 172C-174C


 * 6.2.2.2 MALDI TOFMS**

The MALDI Analysis was performed by William Erb and Dr. Kevin Owens in the Drexel University Chemistry Department (Owens 2007).


 * 6.2.3 Instrumentation**

All NMR spectra were taken on a 300 MHz Varian Inova at room temperature to determine whether the desired product was formed. Proton NMR spectra were taken using 16 scans and a 3.74 second acquisition time for CDCl3. The vacuum pump used was a duo seal vacuum pump (model 1400) manufactured by the Welch Scientific Company. Melting points were determined by a Mel-Temp apparatus. Matrix Assisted Laser Desorption Mass Spectrometry was performed on a Bruker Reflux III operating in reflectron mode. Fast Atom Bombardment Mass Spectrometry was performed using a VG Analytical VG70SE.


 * 6.3 Results and Discussion**

Twenty-four hours after adding the isocyanide, a 500uL sample of reaction solution was submitted for mass spectrometry analysis via fast atom bombardment (FAB) (Figure 6.1).
 * 6.3.1 FAB-MS**


 * Figure 6.1** FAB MS spectrum of reaction solution.

The results were inconclusive because an expected peak of 400 [M-101]+, corresponding to the loss of the BOC group (Perich 1994) was not present despite observing the expected [M+H]+ peak at 502 and [M+Na]+ peak at 524.


 * 6.3.2 NMR spectroscopy**

The addition of the Boc-Gly-OH only leads to minimal reversion to the aldehyde (**//8.3%//**). This is surprising because in previous experiments the imine completely reverted to aldehyde after 20 minutes when forming an imine between piperonal and t-butyl amine (Giammarco 2007, Mirza 2007) after adding the Boc-Gly-OH.

Approximately seventy minutes after tert-butyl isocyanide was added to the reaction, the triplet peak corresponding to the 13C-14N coupling (Weiger 1973, Taylor 1988) at 54.4 ppm (19.8Hz) in the CNMR disappeared which indicates that the reaction was moving toward formation of the Ugi adduct (Figure 6.2, 6.3)


 * Figure 6.2** Triplet peak of t-butyl isocyanide in CNMR spectra


 * Figure 6.3** Missing triplet peak 70 minutes after adding t-butyl isocyanide.

White crystals ([|Figure 6.4]) were seen at the bottom of the reaction vial twenty-four hours after the isocyanide was added.


 * Figure 6.4** Picture of Ugi Crystals formed at the bottom of reaction vial.

These crystals were removed from the solution, rinsed in methanol and dried via high vacuum (163.7mg). The melting point was determined to be 174°C. The crystals were then dissolved in 1 mL deuterated chloroform, and HNMR and CNMR spectra were taken. The proton assignments were made according to the following:

Singlets at 1.32 and 1.45- t-butyl protons of t-butyl isocyanide and Boc-Gly-OH Singlet at 2.2ppm- methyl group of 5-methylfurfurylamine Singlets at 4.2ppm and 4.4ppm- methylene groups of Boc-Gly-OH and 5-methylfurfurylamine. Broad singlet peak at 5.6 ppm- one NH group Multiplet at 5.8ppm- one NH group, chiral proton, and furan protons. Doublet at 6.0ppm- Methylene group of piperonal Multiplet at 6.8ppm- Aromatic protons (See figure 6.5)


 * Figure 6.5** HNMR spectra of Ugi Crystals.

From this spectrum it was determined that the Ugi product did form. A few drops of deuterated methanol (MeOH-d4) were added to the NMR tube of the dissolved crystals, ambiguity in the spectrum is eliminated with observation of the multiplet at 5.8ppm and at 5.6 ppm. The deuterium of the methanol exchanges with the protons of the amide groups, making them invisible to the NMR. With those signals suppressed, the integration of the multiplet at 5.8 ppm changes from 4 to 3 proton units and the broad singlet at 5.6ppm disappears ([|Figure 6.6]). The CNMR of the crystalline product was inconclusive because it was difficult to assign specific carbons to specific peaks ([|Figure 6.7]).


 * Figure 6.6** HNMR spectra of Ugi crystals with amide protons suppressed.




 * Figure 6.7** CNMR of Ugi crystalline product.

Results for the Ugi Adduct were obtained from MALDI TOFMS analysis using both CHCA and Dithranol matrices.
 * 6.3.2 MALDI TOFMS**

The [M]+ ion at m/z 501 and [M+H]+ ion at m/z 502 for the Ugi molecule is not seen because there are few places to protonate the molecule and produce a radical cation and the protonated product.There are peaks at m/z 508.17, 524.18, 540.14 indicating ions corresponding to the [M+Li]+, [M+Na]+, and [M+K]+ ([|Figure 6.8]). Fragment patterns are not expected because this method is a soft ionization technique.
 * 6.3.2.1 CHCA Matrix**


 * Figure 6.8** MALDI TOFMS of Ugi Product with CHCA Matrix.

We are able to see a small [M+H]+ peak at m/z 502.1, as well as peaks at m/z 509.1, 524.2, 540.1 corresponding to ions of [M+Li]+, [M+Na]+, and [M+K]+ ([|Figure 6.9]).
 * 6.3.2.1 Dithranol Matrix**


 * Figure 6.9** MALDI TOFMS of Ugi Product with Dithranol Matrix.

Based on the HNMR and MALDI TOFMS evidence, it is concluded that the Ugi product formed in this experiment. One of the important factors for completion of this reaction is the kinetics of the reaction once the Boc-protected amino acid is added. In other experiments, my colleagues Khalid Mirza and James Giammarco both showed (Giammarco 2007, Mirza 2007) that the aldehyde and imine interconvert during the course of the reaction, although it is unclear why this occurs. It is also unclear as to why the imine generated in this Ugi product does not intercovert. It may be important to conduct a kinetics study with this particular aldehyde and imine for at minimum 24 hours (Mirza and Giammarco used different aldehyde/amine combinations) to determine why interconversion did not occur for this aldehyde/amine combination.
 * 6.4 Conclusion**


 * 6.5 Reference List**

[|Armstrong, R. and Keating, T. Postcondensation modifications of Ugi four-component condensation products: 1-isocyanocyclohexene as a convertible isocyanide. Mechanism of conversion, synthesis of diverse structures, and demonstration of resin capture. J. Am. Chem. Soc., 118 (11), 2574, 1996] DOI:10.1021/ja953868b Giammarco, J. [|www.usefulchem.wikispaces.com/exp048] 2007 Holsey, A. [|www.usefulchem.wikispaces.com/exp052] 2007A Holsey, A [|www.usefulchem.wikispaces.com/exp059] 2007B Mirza, K. [|www.usefulchem.wikispaces.com/exp046] 2007 Owens, K.[|www.usefulchem.wikispaces.com/exp075] 2007 //[|Perich, J.W., et al. Fast atom bombardment mass spectra of some N-α-(t-Butoxycarbonyl)-O-(diorganylphosphono)-L-serines and O-(Diorganylphosphono)seryl-containing dipeptides and tripeptides” Australian Journal of Chemistry 47(2), 229, 1994] DOI:10.1071/CH9940229// [|Porcheddu, A. et al. Microwave-assisted synthesis of isonitriles: a general simple methodology. J. Org. Chem. 70(6), 2361, 2005] [|Taylor, M., Calvert, D., Hobbis, C. Carbon-13 to Nitrogen-14 coupling constants in some heterocyclic cations containing quaternary nitrogen atoms” Magnetic Resonance in Chemistry 26(7), 619, 1988] [|Ugi, I., Domling, A., and Werner, B. “The Chemistry of Isocyanides, their Multicomponent Reactions and their Libraries” Molecules 8, 53, 2003] [|Ugi, I. et al. Isonitrile Synthesis. Angew. Chem. Int. Ed. Eng. 4(6), 452, 1965] Ugi, I. Meyr, R., Angew. Chem, 70, 702, 1958 [|Weiger, F. and Roberts, J. Nuclear magnetic resonance spectroscopy. Spin-spin coupling of carbon to phosphorous, mercury, nitrogen, and other elements. J. Inorganic Chemistry 12(2), 313, 1973] Zhu, J., and Beinayme, H. [|Multicomponent Reaction]s Wiley-VCH ISBN 3-527-30806-7 2005

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