Multiple Cycles to Afford Trimethyl Borate?

Acknowledgements TMK thanks Jackie and Les Stiner for financial support through the Ott-Stiner MS3 fellowship. ALK and RLL acknowledge support from GVSU-OURS, GVSU-CSCE, CLAS start-up funds, and the NSF for computational resources (CHE-1039925 to Midwest Undergraduate Computational Chemistry Consortium).

Talon M. Kosak, Andrew L. Korich, and Richard L. Lord Department of Chemistry, Grand Valley State University, Allendale, MI 49401

How Does BBr3 Cleave Ethers? A DFT Mechanistic Study

Abstract Nature provides us with a wide array of chemicals that have beneficial uses. Cyclization reactions are important in the man-made creation of these chemicals. Past research by S3 scholar Samantha Ellis in Prof. Korich's lab showed an unexpected cyclization reaction with o-alkynylanisoles in the presence of BBr3 instead of the expected demethylation reaction. We sought to understand this unusual reactivity using computational chemistry by comparing the energies of these competing pathways. However, we discovered that previously considered mechanisms for BBr3 assisted ether demethylation are incomplete. In this work we present an alternative mechanism for ether demethylation that has implications in a number of different reactions involving boron-containing reagents.

Introduction

Mechanisms of Ether Demethylation

Computational Methods Geometry optimizations were performed in the Gaussian09 program (G09.D01)9 at the B3LYP/6-31G(d) level of theory.10 Solvation effects were included using implicit solvation with the SMD model11 using dichloromethane as solvent. Stationary points on the potential energy surface were characterized as minima or saddle points by evaluating harmonic frequencies at the optimized geometries. Energy refinements with 6-311+G(d,p) included solvation and empirical dispersion corrections.12 Visualizations were made with GaussView 5.0.9 and CylView. 9. Gaussian 09, Revision D.01, Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Schuseria, G.E.; et al. 10. (a) Becke, A.D. J. Chem. Phys. 1993, 98, 5648. (b) Lee, C.; Yang, W.; Parr, R.G. Phys. Rev. B 1988, 37, 785. 11. Marenich, A.V.; Cramer, C.J.; Truhlar, D.G. J. Phys. Chem. B 2009, 113, 6378-6396. 12. (a) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys. 2010, 132, 154104. (b) Grimme, S.; Chem. Eur. J. 2012, 18, 9955-9964.

Mechanism of Dimethyl Ether Demethylation Can we form bromide for nucleophilic attack? - BBr3 loss of Br– not possible - Extra ether stabilizes “BBr2

+” - Extra BBr3 stabilizes “Br–” - “BBr2

+” may have 1 or 2 ethers What is the BBr4

– mechanism? Is this mechanism viable?

What do these transition states look like? Why does our mechanism matter? Unlike the Sousa-Silva or the intramolecular mechanism, our reaction pathway involving charged intermediates predicts that this process is catalytic in the ether-BBr3 adduct. If there is extra BBr3, do we need to stop with one cycle?

Conclusions and Future Work Identified new mechanistic pathway for dealkylation of ethers. Demonstrated feasibility of products of dealkylation undergoing multiple reaction cycles. Explained why our mechanism becomes more favorable for anisole. Preliminary results from computationally guided experiments support our three cycle mechanism. Test how o-alkynyl substituent affects pathway. Explore mechanisms for cyclization to afford benzofuran (see Matt Barylski’s poster)

Benzofurans (highlighted in red), and more generally 5- and 6-membered heterocycles containing oxygen and nitrogen, are important structural features in many natural products and man-made compounds that exhibit wide-ranging biological activities.1,2 Two examples include benzofuran-based cholinesterase inhibitors that are promising for retarding the progression of Alzheimer’s disease (top),3 and conjugated benzofurans and thiazolidinediones that normalize insulin and glucose levels in individuals with insulin-resistance (bottom).4 In both cases a benzofuran is linked to another moiety at either position 2 or 3 of the benzofuran ring. Thus, the efficient synthesis synthesis of 2,3-disubstituted benzofurans under mild conditions is highly desired. While cyclization mechanisms involving heavy metals like palladium and ruthenium are known, these metals are expensive and must be fully recovered if the drugs are to be used clinically.5,6 A catalyst based on less toxic and more abundant metals, or one that is metal-free, is of great interest. Reactions using I2, ICl, and organochalcogens have been reported.7 Recently, former S3 scholar Samantha Ellis and her advisor Prof. Andrew Korich identified that BBr3 is capable of catalyzing the electrophilic cyclization of o-alkynyl anisoles to form benzofurans in up to 70% yield.8 This reaction, which they happened upon by accident while studying covalent organic frameworks, is unprecedented. Our goal is to help them better understand this unusual reactivity. How does BBr3 cause the bonds to rearrange and form the benzofuran? Why does BBr3 demethylate one ether group to form the benzofuran ring but not the other? Can they control the regioselectivity of the 2,3-disubstitution such that the R and BBr2 groups are reversed in the product? We aim to answer these questions and more using computational chemistry. 1. Majumdar, K.C.; Chattopadhyay, S.K. Heterocycles in Natural Product Synthesis, 1st ed.; Wiley-VCH: New York, 2011. 2. Lamberth, C.; Dinges, J. Bioactive Hetercyclic Compound Classes: Pharmaceuticals and Agrochemicals (2 Volume Set), 1st ed.; Wiley-VCH: New York, 2011. 3. Rizzo, S.; Riviere, C.; Piazzi, L.; Bisi, A.; Gobbi, S.; Bartolini, M.; Andrisano, V.; Morroni, F.; Tarozzi, A.; Monti, J.-P.; Rampa, A. J. Med. Chem. 2008, 51, 2883-2886. 4. Reddy, K.A.; Lohray, B.B.; Bhushan, V.; Bajji, A.C.; Reddy, K.V.; Reddy, P.R.; Krishna, T.H.; Rao, I.N.; Jajoo, H.K.; Rao, N.V.S.M.; Chakrabarti, R.; Dileepkumar, T.; Rajagopalan, R. J. Med. Chem. 1999, 42, 1927-1940. 5. Wang, S.; Li, P.; Yu, L.; Wang, L. Org. Lett. 2011, 13, 5968-5971. 6. Lee, D.-H.; Kwon, K.-H.; Yi, C.S. J. Am. Chem. Soc. 2012, 134, 7325-7328. 7. Larock, R.C. In Acetylene Chemistry. Chemistry, Biology, and Material Science; Diederich, F.; Stang, P.J.; Tykwinski, R.R., Eds.; Wiley-VCS: New York, 2005. 8. Jackson, C.; Rogers, C.; Hammersma, Z.; Taylor, C.A.; Ellis, S.N.; Lord, R.L.; Korich, A.L. Preparation of Benzofuran Trifluoroborate Salts. Poster Presentation at 245th National Meeting of the American Chemical Society, New Orleans, LA.

Textbook Mechanism

BOBr

Br

H3C

H3CBr–

Dimer Mechanism

BOBrH3C

H3C BrBr

Intramolecular Mechanism

BOBrH3C

H3C BrBr

BOBrH3C

H3C BrBr

We started with modeling the ether demethylation because we wanted to understand the thermodynamics and kinetics of the expected reaction before we compared it to the observed reactivity. Sousa and Silva recently published a paper that challenged the commonly assumed mechanism for this reaction.12 We aimed to reproduce their results for the simplest ether, dimethyl ether. Our results confirm that the intramolecular mechanism is not possible. We reproduced the geometries, but not the energies, for their dimer mechanism. Finally, we explored alternatives to the textbook mechanism which we believe may be happening in reality. 13. Sousa, C.; Silva, P.J. Eur. J. Org. Chem. 2013, 5195-5199.

BBrBr

BrBBr

Br

+ Br

BOBr

Br+ Br

H3C

H3CBr BO

Br

Br

H3C

H3C

BOBr

Br+ BBr4

H3C

H3CBr BO

Br

Br

H3C

H3C+ BBr3

BOBr

Br+ BBr4

H3C

H3CBr BO

H3C

H3C+ BBr3 + CH3OCH3 O

Br

Br CH3

CH3

ΔG in kcal/mol+87.28

+38.30

+22.60

+5.96

BOBr

Br

H3C

H3CBr

H3C Br

BH3COBr

Br

BBrBr

O

Br Br

BOBr

Br

H3C

H3C

BOH3C

H3CO

Br

Br CH3

CH3

BBrBr

Br Br

O BBr

OBrCH3

CH3

CH3

H3C

BrBBr3

TS1b

O BBr2

CH3

H3C

BrBBr3

TS1a

BOBr

Br

H3C

H3CBr

Dimethyl Ether Demethylation

CH3

CH3

BH3COBr

Br

H3C Br

BH3COBr

OCH3

BBrBr

O

Br Br

BOO

Br

H3C

H3C

BOH3C

H3CO

O

Br CH3

CH3

BBrBr

Br Br

O BBr

OOCH3

CH3

CH3

H3C

BrBBr3

TS2b

O B

CH3

H3C

BrBBr3

TS2a

BOBr

Br

H3C

H3CBr

CH3

CH3

H3C

O CH3

H3CBrH3C

BH3COBr

OCH3

H3C Br

BH3COOCH3

OCH3

BBrBr

O

Br Br

BOO

O

H3C

H3C

BOH3C

H3CO

O

O CH3

CH3

BBrBr

Br Br

O BO

OOCH3

CH3

CH3

H3C

BrBBr3

TS3b

O B

CH3

H3C

BrBBr3

TS3a

BOBr

Br

H3C

H3CBr

CH3

CH3

H3C

O CH3

H3C

CH3

OH3C

CH3

H3C

CH3

!40$

!30$

!20$

!10$

0$

10$

20$

30$

40$

2 (CH3)2O2 BBr3

2 (CH3)2OBBr3

R1a

R1b

TS1a

TS1b

P1a

P1b

CH3OBBr2(CH3)2OBBr3

CH3Br

– CH3Br+ (CH3)2OBBr3

– CH3Br+ (CH3)2OBBr3

TS2a

TS3a

TS3b

TS2b

(CH3O)2BBr(CH3)2OBBr3

CH3Br

R2b

R2a

P2b

R3b

R3a P3b

(CH3O)3BBBr3

CH3Br

Cycle 2 Barriers TS2a: 23.60 kcal/mol TS2b: 32.68 kcal/mol Cycle 3 Barriers TS3a: 26.52 kcal/mol TS3b: 40.77 kcal/mol At least two cycles seem plausible “OCH3” vs. “Br” disfavors “b” pathway Substoichiometric BBr3 needed? Complicated by comproportionation14 BBr3 + (CH3O)2BBr à 2 CH3OBBr2 14. Roy, C.D. Aust. J. Chem. 2006, 59, 657-659.

Substrate Closer to Target: Anisole What about the target molecule? Is our mechanism favored? Intra-TS = 36.85 kcal/mol SS-TS1 = 29.72 kcal/mol TS1a = 24.83 kcal/mol TS1b = 23.17 kcal/mol Why? We no longer have to pay 5 kcal/mol to break the adduct apart when stabilizing our charged species which makes them more accessible.

!40$

!30$

!20$

!10$

0$

10$

20$

30$

40$

50$

Intramolecular$Sousa!Silva$Cycle$1a$Cycle$1b$

2 (CH3)2O2 BBr3

2 (CH3)2OBBr3

((CH3)2O)2BBr2+

BBr4–

(CH3)2OBBr3

(CH3)2OBBr2+

BBr4–

(CH3)2OBBr3

intra TS

SS-TS1

TS1a

TS1b

CH3Br((CH3)2O)(CH3O)BBr2

BBr3CH3Br

CH3OBBr2(CH3)2O

BBr3

SS-TS2

2 CH3OBBr22 CH3Br

CH3OBBr2(CH3)2OBBr3

ΔG(sol)

0"

5"

10"

15"

20"

25"

30"

35"

40"

Intramolecular"

Sousa5Silva"

Cycle"1a"

Cycle"1b"

2 CH3OPh2 BBr3

2 (CH3OPh)BBr3

(CH3OPh)BBr2+

BBr4–

CH3OPhBBr3

intra TS

SS-TS1

TS1a

TS1b

ΔG(sol)

(CH3OPh)BBr3BBr3

CH3OPh

(CH3OPh)2BBr2+

BBr4–

BBr3

OH3CO PhH3C

CH3BrPhOBBr2

PhBrCH3OBBr2

TMS

OMe

OMeO

O

OOB

O

OB

B

O OB

O

TMS

OMe

Desired Product - not isolated

Isolated Product

(HO)2B