chain extension-mannich reactions with sulfonyl imines acknowledgments this work would not have been...

Chain Extension-Mannich Reactions with Sulfonyl Imines

AcknowledgmentsThis work would not have been possible without the help of Dr. Zercher, Deepthi Bhogadhi, Rekha Chhetri, and Kaushik Bala for their help and support in lab. I would also like to thank the Department of Chemistry, UNH, for funding.

Brittney Hutchinson, Dr. Charles Zercherbsl28@wildcats.unh.edu; Parsons Hall, 23 Academic Way, Durham NH 03824

Introduction Investigation into tandem chain extended- Mannich reactions have provided insight into some organic synthesis pathways. Researchers have looked into the demonstration of functional groups and their ability to stabilize intermediates. Zinc organometallic intermediates are common in the Zercher tandem chain-extension research. The zinc-enolates formed in this process have shown the ability to stabilize the intermediates.5

The Jacobe Mannich Variation focused on trapping of the chain extension intermediate with different activated imines. Jacobe used imines that were activated with either a phosphoryl group or a carbamate (Boc) group. Although yields were low, this proved that Mannich reactions could be carried out much like aldol reactions. 2

Scheme 3: Synthesis of chain extension with sulfone activated imine

References 1. Egar, W.; Zercher, C.K.; Williams, C.M. A Mechanistic Investigation into the Zinc Carbenoid-

mediated Homologation Reaction by DFT methods: Is a Classical Donor-Acceptor Cyclopropane Intermediate Involved? J. Org. Chem. 2010, 75, 7322-7331.

2. Jacobine, A.M.; Puchlopek, A.L.A.; Zercher, C.K., Briggs, J.B.; Jasinski, J.P.; Butcher, R.J. Tandem Chain Extension-Mannich Reaction: An Approach to β-proline Derivatives. Tetrahedron 2012, 68, 7799-7805.

3. Lu, K.; Ohyum, K.; Phosphine-Catalyzed [2+4] Annulation: Synthesis of Ethyl 6-Phenyl-1-Tosyl-1,2,5,6-Tetrahydropyridine-3-Carboxylate. Org. Synth, 2009, 86, 212-224.

4. Mazzone, J.R. PhD. Dissertation, University of New Hampshire, 2011.5. Spencer, C. PhD. Dissertation, University of New Hampshire, 2013.

Results and Discussion The synthesis of the sulfonyl activated imine was successful with a 70.5% yield. However, for the other two reactions the outcome wasn’t the same. Synthesis 2 has proven to be difficult for a number of reasons. The synthesis has worked once, and chain extension reaction was completed. However, the chain extended material was then lost during column purification.

Conclusions Compared to the Jacobe study done on phosphoryl imines, the sulfonyl imine activated group allowed the reaction to proceed at a faster rate. The rate was decreased from 48 hours (phosphoryl imine) to 34 hours (sulfonyl imine). The reaction is hypothesized to proceed quicker with the sulfonyl imine because of the electron withdrawing abilities of sulfur.

Future Work • Synthesize the chain extension-Mannich reaction

product using the sulfonyl imine• Raise reaction yields• Experimentation on the activated imine.• Further investigation into the applications of the

sulfonyl imine

R1 OR2

O OO

R1 OR2

OZn

X

R1 OR2

O O

ZnX

Zn

X

R1 OR2

O OZn

X

R1 O

Zn

OR2

XO

R1 OR2

O

HO

EtZnCH2I EtZnCH2I

Path APath B

H+

Zinc- Carbenoid Mediated Chain ExtensionFigure 1 demonstrates the proposed mechanism of a chain extension reaction. This mechanism is supported through computational work done by Zercher, Egar, and Williams.1 Pathway B shows conversion to the chain extended material by a direct conversion to the chain extended organometallic intermediate. Pathway A proceeds via a donor-acceptor cyclopropane formation and is found to be the lower energy conversion.

Scheme 1: Synthesis of (E)-N-Benzylidene-4-methylbenzenesulfonamide3

Scheme 2: Synthesis of Methyl-4-4-dimethyl-3-oxopentanoate4

Figure 1: Proposed mechanism of Zinc mediated chain extension5

Figure 2: 1H NMR of Methyl-4-4-dimethyl-3-oxopentanoate

Figure 3: 1H NMR of (E)-N-Benzylidene-4-methylbenzenesulfonamide

CHO+

Me

SNH2

OBF3Et2O

benzenereflux, 14 h

NS

Me

OOO

70.5%

O

O O

O O

O ONaH

PinacoloneDimethyl

Carbonate

90oC+

18 hr

NS

Me

OO

O

O O+

O

O

O

Ph NH

SO

O

Et2Zn (3 equiv)CH2I2 (3 equiv)

RT, 34 hrs

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000

6500PROTONpurrified NMR

CH3 CH3

CH3O

CH3

O O

Methyl 4,4- dimethyl- 3- Oxopentanoate

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

0

100

200

300

400

500

600

700

800

900

1000

PROTON BH-01-01

NS

Me

OO