S1

Convenient Access to 5-Membered Cyclic Iminium Ions:

Evidence for a Stepwise [4+2] Cycloaddition Mechanism

Jared L. Freeman, Margaret A. Brimble* and Daniel P. Furkert*

School of Chemical Sciences and Maurice Wilkins Centre for Molecular Biodiscovery

University of Auckland, 23 Symonds Street, Auckland 1142, New Zealand.

*Corresponding authors: d.furkert@auckland.ac.nz, m.brimble@auckland.ac.nz

Supporting Information

S2 1H and 13C NMR Spectra

S30 NOESY Spectra for 18a, 18b, 18c and 20

S35 X-ray structure for 20

S36 Calculation of relative energies for endo adduct 20 and epimeric exo adduct

S37 Table of attempted reactions with 18a

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry.This journal is © The Royal Society of Chemistry 2019

S2

Iodide 6c

INHTs

6c

INHTs

6c

S3

Keto Ester 7c

O O

OEt

7cNHTs

O O

OEt

7cNHTs

S4

N-Boc Ester 5a

NBoc

CO2Et

5a

NBoc

CO2Et

5a

S5

N-Cbz Ester 5b

NCbz

CO2Et

5b

NCbz

CO2Et

5b

S6

N-Ts Ester 5c

NTs

CO2Et

5c

NTs

CO2Et

5c

S7

Alcohol 8a

NBoc

8aOH

NBoc

8aOH

S8

Alcohol 8b

NCbz

8bOH

NCbz

8bOH

S9

Alcohol 8c

NTs

8cOH

NTs

8cOH

S10

Methyl ether 9a

NBoc

9aOMe

NBoc

9aOMe

S11

Methyl ether 9b

NCbz

9bOMe

NCbz

9bOMe

S12

Methyl ether 9c

NTs

9cOMe

NTs

9cOMe

S13

N-Boc enecarbamate 10a

N

NH

Boc

10a

N

NH

Boc

10a

S14

N-Tosyl enecarbamate 10c

N

NH

Ts

10c

N

NH

Ts

10c

S15

Diels-Alder adduct 11a

NHBocO

11a

NHBocO

11a

S16

Diels-Alder adduct 11c

NHTsO

11c

NHTsO

11c

S17

Adduct 12

NTs

12

S18

Aldehyde 15

O

15

OBz

O

15

OBz

S19

Enone 17a

O

17a

OBz

O

17a

OBz

S20

Enone 17b

O

17b

OBz

O

17b

OBz

S21

Silyloxy diene 13a

OTBS

13a OBz

OTBS

13a OBz

S22

Mixture of Silyloxy dienes 13a-b

OTBS

BzO

13b

OTBS

13a OBz

+

OTBS

BzO

13b

OTBS

13a OBz

+

S23

N-Boc enecarbamate adduct 18a

N

BzO

Boc

OTBS18a

S24

N-Cbz enecarbamate adduct 18b

N

BzO

Cbz

OTBS18b

N

BzO

Cbz

OTBS18b

S25

N-Ts enecarbamate adduct 18c

N

BzO

Ts

OTBS18c

N

BzO

Ts

OTBS18c

S26

N-Ts enone 19

NTs

O

OBz

19

NTs

O

OBz

19

S27

N-Ts bicyclic ketone 20

N

BzO

Ts

O20

N

BzO

Ts

O20

S28

Vinyl triflate 21

N

BzO

Ts

OTf21

N

BzO

Ts

OTf21

S29

Vinyl triflate 21

N

BzO

Ts

OTf21

S30

Enamine 22

Impurity

X

Impurity

X

Impurity

X

Impurity

X

N

BzO

Ts

22

N

BzO

Ts

22

S31

N-Boc Enecarbamate adduct 18a

Expanded below

nOe

NBoc

H

OBz OTBS

H H

nOe

18a

S32

N-Cbz Enecarbamate adduct 18b

Expanded below

nOe

NCbz

H

OBz OTBS

H H

nOe

18b

S33

N-Ts Enecarbamate adduct 18c

Expanded below

nOe

NTs

H

OBz OTBS

H H

nOe

18c

S34

N-Ts bicyclic ketone 20

Expanded below

nOe

NTs

H

OBz OTBS

H H

nOe

20

S35

Crystallization. Single crystals of N-Ts bicyclic ketone (20) were obtained by slow recrystallization of a solution of the compound in ethyl acetate.

Figure S1. ORTEP diagram drawn with 50% ellipsoid probability of the crystal structure of N-Ts bicyclic ketone 20.

Table S1. Crystal data and structure refinement details for N-Ts bicyclic ketone 20.

Empirical formula C24H26NO6SFormula weight 456.52Temperature (K) 293(2)Wavelength (A) 1.54184Crystal system MonoclinicSpace group P 21/c

a (Å) 11.1279(2)b (Å) 6.76700(10)c (Å) 29.5619(4) (°) 90.000 (°) 97.0730(10)(°) 90.000

V (Å3) 2209.14(6)Z 4

Dc (Mg/m3) 1.373F(000) 964

μ (mm-1) 1.655θmax (°) 67.734

Total reflections 22389Unique reflections 3991

Reflections [I > 2σ(I)]] 3991Parameters 298

Rint 0.0355Goodness-of-fit 0.869R [F2 > 2σ(F2)] 0.0325

wR (F2, all data) 0.0874

C3

C4

C5

C6

C7

C8

C9

C10

S36

Calculations:

Assuming a late transition state, the relative energies of the possible formal endo and exo epimers, 20 and epi-20, should be indicative of the thermodynamically favoured product. For each epimer, point energies (HF, basis set 6-31+G*) were calculated for the equilibrium geometry (AM1) obtained after a conformer search (MMFF).

The results suggest that the observed isomer is 4.31 kcal/mol lower in energy than the potential epimer epi-20, that was not observed experimentally.

Figure S2. Calculated energies for possible formal endo and exo epimers, 20 and epi-20.

endo epimer (20) exo epimer (epi-20)

Relative energy(kcal/mol) 0.00 4.31

sole product not observed

N

H H

SO

O

HO

O

ON

H H

S

O

O

O

O

O

HH

H

H

H

20 epi-20

S37

Table S2. Attempted conditions for iminium Diels-Alder reaction of 9a.

BocN

OTBS

OBz13a

9a

N53

6H

OBz

Boc

OTBS18a

conditions

OMe

Entry Lewis acid (equiv.) Conditions Result

1 BF3·OEt2 (1.1)a,c CH2Cl2, −78 °C -e

2 BF3·OEt2 (5)a,c CH2Cl2, −78 °C -e

3 BF3·OEt2 (10)a,c CH2Cl2, −78 °C 18a (4%)

4 BF3·OEt2 (1.1)b,c CH2Cl2, −78 °C -e

5 Sc(OTf)3 (0.1)b,c CH2Cl2, −78 °C -e

6 Sc(OTf)3 (0.05)b,c CH2Cl2, −78 °C -e

7 Sc(OTf)3 (0.05)b,d CH2Cl2, 0 °C -e

8 Sc(OTf)3 (0.05)b,d CH3CN, −40 °C -e

9 TMSOTf (0.2)b,d CH2Cl2, −78 °C -e

10 Et2AlCl (0.2)b,c CH2Cl2, −78 °C -e

11 LiBF4 (0.4)a,d CH2Cl2, 0 °C -e

a Method A: Lewis acid added to methyl ether 9a and stirred for 5 min, prior to diene 13a addition. b Method

B: Lewis acid added to a mixture of methyl ether 9a and diene 13a. c Reaction quenched using TEA (10

equiv.) at −78 °C. d Reaction quenched using TEA (10 equiv.) at 0 °C. e Iminium precursor 9a consumed;

no desired product 18a observed.