A comprehensive picture of the one-electron oxidation chemistry of enols, enolates and α-carbonyl radicals: oxidation potentials and characterization of radical intermediates

DOI: 10.1016/j.tet.2009.10.039

Source and publish data:

Tetrahedron p. 10842 - 10855 (2009)

Update date:2022-08-02

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Authors:

Schmittel, Michael

Lal, Mukul

Lal, Rupali

R?ck, Maik

Langels, Anja

Rappoport, Zvi

Basheer, Ahmad

Schlirf, Jens

Deiseroth, Hans-J?rg

Fl?rke, Ulrich

Gescheidt, Georg

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Article abstract of DOI:10.1016/j.tet.2009.10.039

Oxidation potentials of 40 enols, enolates and some selected α-carbonyl radicals are presented along with their characterization by various techniques as applicable (X-ray, EPR, ENDOR, general TRIPLE, magnetic susceptibility measurements, UV-vis, fast sca

Full text of DOI:10.1016/j.tet.2009.10.039

Tetrahedron 65 (2009) 10842–10855

Contents lists available at ScienceDirect

Tetrahedron

journal homepage: w ww.elsevier.com/locate/tet

A comprehensive picture of the one-electron oxidation chemistry of enols,

enolates and a-carbonyl radicals: oxidation potentials and characterization

of radical intermediates

Michael Schmittel ^a, Mukul Lal , Rupali Lal , Maik Ro¨ck , Anja Langels , Zvi Rappoport ,

Ahmad Basheer ^d, Jens Schlirf ^e, Hans-Jo¨rg Deiseroth ^e, Ulrich Flo¨rke ^f, Georg Gescheidt ^g

Department of Chemistry, Organische Chemie I, Universitat Siegen, Adolf-Reichwein-Str., D-57068 Siegen, Germany

^bInstitut fu¨r Organische Chemie und Biochemie, Universita¨t Freiburg, Albertstr. 21, 79104 Freiburg, Germany

^cInstitut fu¨r Organische Chemie der Universita¨t Wu¨rzburg, Am Hubland, D-97074 Wu¨rzburg, Germany

^dInstitute of Chemistry, The Hebrew University, IL-91904 Jerusalem, Israel

^eDepartment of Chemistry, Anorganische Chemie I, Universita¨t Siegen, Adolf-Reichwein-Str., D-57068 Siegen, Germany

^fDepartment of Chemistry, Anorganische und Analytische Chemie, Universita¨t Paderborn, Warburger Str. 100, D-33098 Paderborn, Germany

^gInstitut fu¨r Physikalische und Theoretische Chemie, TU Graz, Technikerstrasse 4/I, A–8010 Graz, Austria

a r t i c l e i n f o

a b s t r a c t

Article history:

Oxidation potentials of 40 enols, enolates and some selected a-carbonyl radicals are presented along

Received 22 June 2009

Received in revised form

21 September 2009

Accepted 9 October 2009

Available online 4 November 2009

with their characterization by various techniques as applicable (X-ray, EPR, ENDOR, general TRIPLE,

magnetic susceptibility measurements, UV–vis, fast scan cyclic voltammetry, isotope effects). The model

compounds comprise representatives of stable simple enols linked to a multitude of substituents (alkyl,

alkenyl, alkynyl, aryl, heteroaryl, propargyl alcohols) and of stable simple enols of amides. The results

allow to clarify the primary reaction pathway of enol radical cations as a rapid deprotonation anddif

warranted by the redox potential and the strength of the oxidantda follow-up oxidation of the resultant

-carbonyl radical to the

early correlated with AM1 computed ionization potentials after correction for solvation. The correlation

allows a reliable prediction of oxidation potentials of radicals including -carbonyl radicals. After com-

a-carbonyl cation. Moreover, the experimental oxidation potentials were lin-

puting redox potentials of relevant radicals, the possibility of one-electron transfer between enolates and

ﬂavin and the involvement of various radicals of ascorbic acid in oxidation processes were assessed.

1. Introduction

In contrast, the one-electron oxidation of enol derivatives, such

as enol ethers,¹²in particular enol silanes,¹³and enol esters,¹⁴has

Enols, enolates and

-carbonyl radicals constitute derivatives of

received much wider coverage, but will not be addressed here.

Theoretical and experimental investigations have established

that the thermochemical stability order of keto/enol tautomers can

be inverted upon one-electron oxidation in the gas phase¹⁵or in

solution.^8a,eAs a consequence, enols are much more readily oxi-

the carbonyl group, one of the most important functional groups in

synthetic organic transformations, but the rich and rewarding

facets of their preparative one-electron oxidation chemistry are

only surfacing slowly.¹While the oxidative transformations of

enolates leading to intra-²and intermolecular³C–C bond formation

have already reached some importance as demonstrated by the

synthesis of hirsutene,⁴acremoauxin A^5aand palau’amine,^5bthe

dized than the tautomeric ketones (E_ox(ketone)

E_ox

(enol)þ1.0 V),^8aallowing for a selective oxidation of the enol

present in minute amounts in the tautomeric equilibrium. In a

reaction system designed for rapid enolization, e.g. in the presence

of acid, the ketone may now be transformed quantitatively via an

enol radical cation as intermediate, opening new synthetic

perspectives.⁷

one-electron oxidation of enols and

a-carbonyl radicals has

remained largely unexplored.^1,6–9Despite such shortcomings,

-carbonyl radicals¹⁰and enol radical cations have been invoked as

reactive intermediates in biological processes.¹¹

One reason why so little is known about the one-electron oxi-

dation chemistry of enols in solution is connected to their facile

tautomerization to the thermodynamically more stable keto form.

To outmaneuver this problem we chose

kinetically stable enols, some of which had initially been inspected

b,b-dimesitylethenols as

* Corresponding author. Tel.: þ49 271 7404356; fax: þ49 271 7403270.

E-mail address: schmittel@chemie.uni-siegen.de (M. Schmittel).

doi:10.1016/j.tet.2009.10.039

M. Schmittel et al. / Tetrahedron 65 (2009) 10842–10855

10843

by Fuson and Rowland¹⁶and more recently investigated in depth by

Mes

RLi

Rappoport et al.¹⁷Importantly, both the enol and keto tautomers of

many of these systems can be obtained in tautomerically pure form.

Herein, we wish to present a study on the oxidation of 40 stable

enols (Chart 1), some of which have been synthesized for the ﬁrst

time. We will present the characterization of the enols and their

Mes

E6: R = n-butyl

E9: R = p-C₆H₄Br

E12: R = 2-MeO-5-BrC₆H₃

radical cations, enolates and a-carbonyl radicals by cyclic voltam-

The alkynylated enols E29–E31 were synthesized in reasonable

yields (31–80%) by Grignard addition of the corresponding TIPS

protected acetylenes to dimesitylketene. The u-hydroxy enols E32–

E34 were obtained in good yields (78–86%) by deprotection of the

enols E29–E31 with 10% sulfuric acid in methanol.

metry (CV), EPR/ENDOR, UV-vis and magnetic susceptibility mea-

surements. Along with some results on the preparative one-electron

oxidation of enolates this will provide a comprehensive picture of

the enol one-electron oxidation chemistry. Some of the CV results

have been described in preliminary communications, but will be

repeated here to describe the full picture.^6,8a

TIPS

Mes

H₂SO₄, RT,

BrMg

Mes

Stable enols with sterically bulky groups in the -position

24 h, methanol

Mes

TIPS

E32: n = 1

E33: n = 2

E34: n = 3

E29: n = 1

E30: n = 2

E31: n = 3

E1: R = Ph

E5: R = Me

E6: R = n-Bu

E7: R = t-Bu

E8: R = Ph

E15: R = CH=CH₂

E16: R = CH=CHMe

E17: R = CH=C(Me)₂

E2: R = p-Tol

E3: R = p-An

E4: R = Mes

E9: R = p-C₆H₄Br

E10: R = p-Tol

E11: R = p-An

E18: R =

E12: R = 2-OMe-5-BrC₆H₃E19: R =

E13: R = p-C₆H₄N(Me)₂

E14: R = Mes

p-An

E20: R =

The enols were characterized by IR, ¹H NMR, ¹³C NMR and ele-

mental analysis/HRMS. Suitable single crystals were obtained for

E29 and E34 and analyzed by X-ray analysis (Fig. 1).

Mes

Het-Ar

Mes

OH Mes

Mes Mes

Mes

E21: Het-Ar = 2-C₄H₃S

E22: Het-Ar = 3-C₄H₃S

E23: Het-Ar = 2-tetrahydro

benzthiophene

E24: Het-Ar = 2-C₄H₃O

E25: Het-Ar = 2-C₅H₄N

E26: Het-Ar = 3-C₅H₄N

E27: Het-Ar = 8-quinoline

E28

TIPS

E29: n = 1

E30: n = 2

E31: n = 3

E32: n = 1

E33: n = 2

E34: n = 3

Stable enols based on amides with electron withdrawing groups in -position

C₆F₅NH

NH₂

E37

E36

E35

Figure 1. Molecular structure of (a) E29 and (b) E34 as obtained by X-ray single crystal

analysis. Data are reported in Tables 10 and 11 (see Experimental part).

E40

CCl₃

2.2. Cyclic voltammetric investigations of b,b-dimesityl enols

E39

E38

At low scan rates (v¼50–500 mV s^ꢀ1) CV investigations of all

enols displayed two oxidation waves. The ﬁrst, an irreversible wave

was readily assigned to the oxidation of the enol E (fourth column

in Table 1) and the second wave (mostly partially reversible) to the

oxidation of benzofuran derivatives B formed rapidly in the course

of the enol oxidation (Fig. 2). According to our earlier mechanistic

investigations^8a–dthe formation of benzofurans B can be un-

derstood in terms of the following mechanism (Scheme 1).

Chart 1. List of enols in the present investigation.

2. Results

2.1. Synthesis and characterization of enols

The synthesis of all enols, except for E2, E3, E6, E9, E12 and E29–

E34, has been described elsewhere.^{8b,c,18,19–21}Enols E2 and E3 were

prepared by following the synthetic protocol to enol E1 that had

initially been reported by Fuson et al.²²LAH reduction of the cor-

responding aryl mesityl ketene allowed the isolation of the tauto-

merically pure (99%) enol E2 in 17% yield after chromatography. In

contrast, enol E3 could only be prepared in a mixture with the

corresponding aldehyde (75% enol). Unfortunately, this enol/alde-

hyde mixture decomposed quite rapidly presumably due to aut-

oxidation of the readily oxidizable (vide infra) enol tautomer.

Mes

SOCl₂

pyridine

LAH

E2: R = p-tolyl

E3: R = p-anisyl

Mes

E6, E9 and E12 were readily obtained from dimesitylketene and

the corresponding alkyl or aryl lithium reagents following pro-

cedures developed mainly by Fuson and Rappoport.^16,17b,23

Scheme 1. Mechanism of the oxidation of stable

b,b-dimesityl enols E or enolates A.

10844

M. Schmittel et al. / Tetrahedron 65 (2009) 10842–10855

Table 1

chemical reaction involving

a second electron transfer. In-

Oxidation potentials (either E_paor E vs ferrocene) of enols and derivatives carrying

1/2

terestingly, in some of the model systems containing strong elec-

tron donating groups or ﬁve-membered heterocycles, no oxidation

wave for the benzofuran was observed. Instead an oxidation wave

at higher anodic potentials was observed for these enols, which was

bulky groups in the b-position. All cyclic voltammograms were recorded in aceto-

nitrile at v¼100 mV s^-1at room temperature unless noted differently (uncertainty

ꢃ10 mV s^ꢀ1

)

Model system

E_paof

enols

E/V_Fc

E^o₁^x_/2of

enols

E/V_Fc

1/2

due to the oxidation of the dihydrofuranyl cations X^{D 25}

enolates

A/V_Fc

a-carbonyl

radicals R^ꢁ/V_Fc

E10

E11

ꢀ0.66^a

þ0.63^a

þ0.70

þ0.64

þ0.48

þ0.68^c

þ0.59

þ0.64^c

þ0.61^c

þ0.58

þ0.57^c

þ0.52

þ0.82^k

n.d.^b

2.3. Cyclic voltammetric investigation of enols derived from

amides

n.d.^b

ꢀ0.73^c

ꢀ0.90^c

ꢀ0.87

ꢀ1.01^c

ꢀ0.83^c

ꢀ0.78

ꢀ0.86^c

ꢀ0.89

þ0.36^c

þ0.21^c

þ0.14

þ0.15^c

þ0.24^c

þ0.29

þ0.22^c

þ0.31

þ0.85^j

þ0.96^j

n.d.^b

The use of electron-withdrawing groups in the b-position has

been utilized for the ﬁrst time by Rappoport et al.¹⁹to generate

enols derived from amides. The high enol content (>90%) in non-

polar solvents enabled us to investigate their electrochemical

properties (Fig. 3, Table 2). All enols E35–E40 exhibited an irre-

versible oxidation wave between E_pa¼1.23–1.49 V_Fc(except for E37,

which showed two oxidation waves). An EC_irrelectrode kinetics

was obtained for enols E35–E40 based on the diagnostic criteria by

Nicholson and Shain.²⁴However, since the HOMO of E35–E40 is

dominated by their enamine character, these enols behave differ-

ently than the other enols upon oxidation.

0.73ⁿ

þ0.67^h,i

n.d.^b

þ0.64^h,j

þ0.568^h,k

þ0.586^l,m

n.d.^b

þ0.76^j

n.d.^b

þ1.09^l

n.d.^b

E12

E13

E14

E15

E16

E17

E18

E19

E20

E21

E22

E23

E24

E25

E26

E27

E28

E29

E30

E32

E33

E34

n.d.^b

þ0.61

ꢀ0.96

ꢀ0.75^c

ꢀ0.78

ꢀ0.84

ꢀ0.92

ꢀ0.60

ꢀ0.62

ꢀ0.66

ꢀ0.78^f

ꢀ0.99^f

ꢀ0.77^f

ꢀ0.78^f

ꢀ0.78

ꢀ0.72

ꢀ0.56

ꢀ0.76^l

ꢀ0.61

ꢀ0.55

ꢀ0.56

ꢀ0.63

þ0.09

þ0.26^c

þ0.27

þ0.23

þ0.14

þ0.38

þ0.31

þ0.16

þ0.24^f

n.d.^b

þ0.13

þ0.76^c

þ0.69^d

þ0.64^d

þ0.51^d

þ0.72^d

þ0.68^d

þ0.13^e

þ0.53^f

þ0.58^f

þ0.27^f

þ0.11

þ0.37

þ0.01

þ1.38^o

þ0.35

þ0.32

þ0.34

þ0.31

þ0.30

þ0.46^f

þ0.50^f

þ0.46,þ0.75^g

þ0.36,þ0.76^g

þ0.02,þ0.53^g

þ0.945

þ0.69

þ0.67

þ0.84

þ0.71

þ0.74

Figure 3. A representative cyclic voltammogram observed for enols derived from

amides (i.e. of E40) in dichloromethane at a scan rate of 100 mV s^ꢀ1

Determined at v¼480 V s^ꢀ1

Not determined.

From Ref. 6.

From Ref. 18.

Ferrocene residue is oxidized.

From Ref. 20.

Table 2

Oxidation potentials of enols E35–E40 (derived from amides) in dichloromethane at

a scan rate of 100 mV s^ꢀ1

Enol

E_pa1/V_Fc

E_pa2/V_Fc

Shift^a/V_Fc

1.45

From Ref. 19 (low potential¼hydrogen bonded species, high potential¼no

hydrogen bond).

E35

E36

E37

E38

E39

E40

1.49

1.38

1.23

1.32

1.38

1.24

From Ref. 26.

Determined at v¼14,000 V s^ꢀ1

1.40

1.19 (E_pa1), E_pa2-disappears

Determined at v¼10,000 V s^ꢀ1

Determined at v¼12,000 V s^ꢀ1

Determined at v¼4000 V s^ꢀ1

In dichloromethane.

Determined at v¼1000 V s^ꢀ1

Shift in the oxidation potential observed upon addition of 2,6-di-tert-

Determined at v¼600 V s^ꢀ1

butylpyridine.

2.4. Characterization of enol radical cations in solution

For some of the enols (E8, E10, E11 and E14) it was possible to

follow the reactivity of their radical cations in acetonitrile using

fast scan cyclic voltammetry (FSCV).²⁶At scan rates beyond

4000 V s^ꢀ1their irreversible oxidation waves turned reversible

(Fig. 4, Table 3). The different degree of reversibility at various

scan rates was utilized for the determination of the rate con-

stants k_fapplying the Nicholson–Shain formalism and assuming

a rate determining ﬁrst-order process. The enol radical cation

E11^ꢁ^Dproved to be the one with the longest lifetime both in

Figure 2. Representative cyclic voltammograms of a b,b-dimesityl enol showing the

two typical oxidation waves at 100 mV s^-1scan rate; wave I shows the enol oxidation

and wave II the oxidation of the benzofuran as a follow-up oxidation product of the

enol (in some cases oxidation of dihydrofuranyl cations). (a) CV of E32 in acetonitrile,

(b) multiple scan of E32.

acetonitrile (

¼6ꢂ10^ꢀ5s) and dichloromethane (

¼1.9ꢂ10^ꢀ2s). A

The enol oxidation wave exhibited a linear shift of the anodic

peak potential with log v and a decreasing ratio I_pa/v^1/2with in-

creasing scan rate. These diagnostic criteria²⁴point to the occur-

rence of a reversible electron transfer followed by a fast irreversible

primary kinetic isotope effect KIE¼2.6 was found when com-

paring the follow-up reactions of E11^ꢁ^Dand [OD]–E11^ꢁ^D. UV–vis

investigations on E11^ꢁ^Dprovided two absorptions, at

¼404 nm

and

¼520 nm.

M. Schmittel et al. / Tetrahedron 65 (2009) 10842–10855

10845

2.5. Oxidation of the enolates and characterization of the

-carbonyl radicals

Deprotonation of the enols E with 1 equiv of tetramethyl-

ammonium hydroxide yielded the corresponding enolates A. For all

enolates with mesityl groups in the -position, the cyclic voltam-

mogramms showed a reversible oxidation (Fig. 6). Their half wave

oxidation potentials E lie between ꢀ0.55 and ꢀ1.02 V_Fc(Table 1).

1/2

They are much lower than those observed for enolates with

-electron-withdrawing groups.²⁷

Figure 4. Typical fast scan cyclic voltammogram obtained for a

scan rate¼2000 V s^ꢀ1, solvent: acetonitrile.

b,b-dimesityl enol: E11,

Table 3

Results of fast scan CV investigations with bulky

-dimesityl enols in acetonitrile

Figure 6. Cyclic voltammograms that show the typical behavior of enolates with bulky

-dimesityl groups, (a) completely reversible redox wave of enolate A12, (b) scan rate

dependence of the oxidation wave of enolate A12, (i) 20 mV s^ꢀ1, (ii) 50 mV s^ꢀ1, (iii)

100 mV s^ꢀ1, (iv) 200 mV s^ꢀ1and (v) 500 mV s^ꢀ1

b,b

Compound

v/Vs^ꢀ1

I_pc/I_pa/s

E8^ꢁ^D

14,000

10,000

4,000

0.20

0.21

0.47

0.25

6ꢂ10^ꢀ5

8ꢂ10^ꢀ5

6ꢂ10^ꢀ5

4ꢂ10^ꢀ4

E10^ꢁ^D

E11^ꢁ^D

E14^ꢁ^D

8,000

Aside from the reversible oxidation wave of the enolates, an

irreversible oxidation wave at higher anodic potential (E_pabetween

þ0.01 and þ1.38 V_Fc) was observed that was assigned to the oxi-

Oxidation of E11 by tris(p-bromophenyl)aminium (TBPA^ꢁ^D) in

dichloromethane at ꢀ100 ^ꢄC yielded E11^ꢁ^Dthat exhibited a rather

long lifetime. While only an unresolved EPR signal could be ob-

served, it was possible to detect well-resolved ENDOR and general

TRIPLE (Fig. 5) spectra providing the isotropic hyperﬁne coupling

constants (hfcs). Moreover, the comparison with the spectra of the

corresponding deuterated derivative [OD]–E11^ꢁ^Dpermitted further

insight into the electron distribution of E11^ꢁ^D(Table 4). The struc-

ture of E11^ꢁ^Dwill be discussed below in comparison to that of

radicals R4^ꢁ–R14^ꢁ.

dation of the a-carbonyl radical (Table 1).

For a few selected enolates the formation of the

a-carbonyl

radicals was furthermore corroborated by EPR/ENDOR and mag-

netic susceptibility measurements. For EPR/ENDOR experiments

the a-carbonyl radicals were generated by one-electron oxidation

of enolates A4, A5, A7, A8, A10, A11 and A14 in dichloromethane

using 1 equiv of the weak oxidant tri(p-anisyl)aminium hexa-

red

ﬂuorophosphate (E ¼0.16 V_Fc). Upon addition of the oxidant to

1/2

the enolate a red color emerged immediately. The UV–vis spec-

trum of R7^ꢁexhibited two absorptions at l₁¼353 nm and

l₂¼480 nm with l₁showing a hypsochromic shift of about 17 nm

compared to the enolate spectrum. The

-carbonyl radical R11^ꢁ

revealed bathochromically shifted absorptions at l₁¼425 nm and

l₂¼584 nm.

The structural assignment of the neutral radicals R4^ꢁ, R5^ꢁ, R7^ꢁ,

R8^ꢁ, R10^ꢁ, R11^ꢁand R14^ꢁwas established by using the hyperﬁne

data obtained by EPR/ENDOR/general TRIPLE. An example is

shown in Figure 7 for R4^ꢁ; the complete set of hyperﬁne data is

summarized in Table 5. The formation of a

-carbonyl radicals in R7^ꢁ

and R11^ꢁwas further quantiﬁed by magnetic susceptibility mea-

surements using the Evans’ NMR shift method,²⁸attesting 85ꢃ2%

(R7^ꢁ) and 87ꢃ2% (R11^ꢁ) conversion to the

a-carbonyl radical.

Figure 5. ENDOR spectra of [OH]–E11^ꢁ^Dand [OD]–E11^ꢁ^D

Table 4

Coupling constants (hfc/mT) for E11^ꢁ^Dand [OD]–E11^ꢁ^Dobtained by the ENDOR and

general TRIPLE spectra in dichloromethane

Mes(p)

Mes(o)

Mes(m)

An(o)

An(p)

An(m)

O–H

E11^ꢁ^D

0.307

0.308

0.30

0.226

0.229

0.15

0.151

0.150

0.11

0.109

0.107

0.10

0.080

0.076

0.08

0.052

–

0.0

[OD]-E11^ꢁ^D

Calc^a

0.0

Figure 7. Experimental and simulated EPR, ENDOR and general TRIPLE spectra of

-carbonyl radical R4^ꢁ.

UB3LYP/6–31G**.

10846

M. Schmittel et al. / Tetrahedron 65 (2009) 10842–10855

Table 5

g-Values of some a-carbonyl radicals at 213–253 K

Coupling constants ¹H hfc/mT

Mes

Compound

g-Values

[Fe(Phen)₃]

Acetonitrile

R4^ꢁ

2.00370

2.00303

0.234 ^a; 0.181 ^b; 0.136 ^b; 0.106 ^c; 0.069

0.221 ^a; 0.177 ^b; 0.149 ^b; 0.116 ^c; 0.096;

0.075

R5^ꢁ

Mes

R7^ꢁ

R8^ꢁ

2.00352

2.00262

0.278 ^a; 0.155 ^b; 0.107 ^b; 0.040 ^c; 0.016

0.225 ^a; 0.199 ^b; 0.170 ^b; 0.142 ^c; 0.108;

0.085

R = n-Bu

R = p-C₆H₄Br

B6 (86%)

B9 (96%)

E12 R = 2-OMe-5-BrC₆H₃B12 (75%)

R10^ꢁ

2.00339

0.226 ^a; 0.203 ^b; 0.170 ^b; 0.108 ^c; 0.086;

0.010

R11^ꢁ

R14^ꢁ

2.00274

2.00325

0.227 ^a; 0.203 ^b; 0.170 ^b; 0.111 ^c; 0.087

0.194 ^a; 0.165 ^b; 0.132 ^b; 0.106 ^c; 0.085;

0.062; 0.25; 0.14; 0.04

R11^ꢁ

Calcd

0.23 ^a; 0.16 ^b; 0.12 ^b; 0.16 ^c; 0.09

CV investigations on benzofurans B6 and B9 showed partially

reversible waves appearing at E ¼0.92 and 0.90 V_Fc, respectively.

1/2

p-CH₃–Mes.

The position and form of the wave were identical to that of ben-

zofurans B formed during the cyclic voltammetric investigation of

enols and enolates.

o-CH₃–Mes (the four o-CH₃groups in the Mes substituents are pairwise

equivalent).

m-H-Mes. The small hfcs are attributed to protons of the remaining substituents.

3. Discussion

3.1. Structural features of the enols

2.6. Oxidation of enolate A7 with ﬂavin

The basic structural features of b,b-dimesityl enols (C]C, C–O

Flavin cofactors (FAD and FMN) are known to serve as biological

oxidants, e.g. in enzymatic reactions involving dehydrogenations

bond lengths, etc.) do not alter dramatically upon changes of sub-

stituents. Hence, it is not surprising to see that all bond lengths,

bond angles and torsional angles in E29 and E34 have almost

identical values (see Experimental part, Tables 10 and 11). It is

noteworthy that the two enols are even similar with regard to the

HOC]C torsional angle. Both, E29 and E34 prefer an anticlinal

conformation of the enolic hydroxyl group in the solid state. The

-lactate dehydrogenase, general acyl-coenzyme

de-

hydrogenase, glutaryl-CoA and butyryl-CoA dehydrogenase).²⁹

Enolates are suggested to be the key intermediates in these

oxidations, although the oxidation by ﬂavin cofactors should be

very endergonic.¹⁰

latter preference may arise due to OH/

the unsaturated triple bond. This interaction is dominating over the

OH/ interactions with the enol double bond as well as the b-

mesityl group, the latter being possible in a syn conformation. In

addition, the anticlinal OH group in E29 is involved in in-

termolecular hydrogen bonding in the solid.

p interactions with

+e , +H

-e , -H

+e , +H

-e , -H

Fl_Ox

Fl_Seq

Fl_Red

3.2. Oxidation potentials of enols

An analysis of the oxidation potentials of enols E1–E34 indicates

that a common trend does not exist between the substitution

pattern and the oxidation potentials of the enols. However, some

interesting features were observed in smaller subgroups. For enols

E8, E10, E11, and E14 a linear relationship was observed between

the calculated IP_aand the experimentally determined oxidation

potentials (E_pa).¹⁹As anticipated, the calculated IP_aas well as the

oxidation potentials decreased with increasing electron-donating

With the oxidation potentials of enolates and

radicals being known through the present work, we planned to

mimic the enzymatic oxidation of enolates by Fl_Oxusing an

a-carbonyl

endergonic oxidation in solution. Thus, a solution of Fl_Ox(E_1/2

–0.21 V_Ag/AgCl³⁰) was added to A7 (E ¼–0.83 V_Ag/AgCl) in equi-

1/2

molar amounts under inert atmosphere. Although electron

transfer is endergonic by 620 mV, a deep red coloration was

observed after warming the reaction mixture to 50 ^ꢄC. EPR

characterization of the solution indicated the presence of a radi-

cal species at g¼2.0035 with a coupling of 1.5 G and a spectral

ability of the

E4, E5, E14 and E28, an unusual

observed. For E14 (E_pa¼0.76 V_Fc) with three mesityl groups in

and -position, the oxidation potential was found to be higher than

when the -mesityl group was replaced by a hydrogen (E4:

E_pa¼0.68 V_Fc) or with a methyl group as in E5 (E_pa¼0.68 V_Fc). In-

terestingly, enol E28 (formally the -mesityl in E14 is replaced by

a-aryl ring. Moreover, within a small set of enols, i.e.

-effect of a methyl group was

b,b

width of 30.7 G, which was similar to that of the

a-carbonyl

radical R7^ꢁ, generated by oxidation of enolate A7 with the ami-

nium salt. Addition of sodium bicarbonate to the solution of A7

and Fl_Oxfollowed by extraction in DCM afforded the enol E7 in

74% yield. In contrast, formation of the benzofuran derivative B7

was not observed.

a methyl group) has an oxidation potential, which is anodically

shifted by almost 200 mV (E_pa¼0.95 V_Fc). Comparison of the oxi-

dation potentials of enols E1–E3 reveals that with increasing

2.7. Preparative scale oxidation of enols

electron-donating ability of the

tential shifts cathodically by more than 200 mV. Attaching a triple

bond in the -position (E18–E20, E29, E30, E32–E34) has little or

b-substituent the oxidation po-

The benzofuran derivatives B6, B9 and B12 were isolated after

oxidation of the corresponding enols (E6, E9 and E12) with

2 equiv of [Fe(Phen)₃]^3þ(Phen¼1,10-phenanthroline) in acetoni-

trile under inert atmosphere. Compounds B6, B9 and B12 were

obtained in good yields and characterized by ¹H NMR, ¹³C NMR, IR,

and HRMS.

no effect on the oxidation potential except for E20 due to the ad-

ditional ferrocene substituent. Within the series E15–E17, a ca-

thodic shift of up to 180 mV was observed (E15: E_pa¼0.69 V_Fc, E16:

E_pa¼0.64 V_Fc, E17: E_pa¼0.51 V_Fc) as the number of terminal methyl

groups at the a-vinyl group increases.

M. Schmittel et al. / Tetrahedron 65 (2009) 10842–10855

10847

Unusually low oxidation potentials were observed for all enols

meta protons of the mesityl substituent and to further protons of

the substituents at C(1), which only carry a minor amount of spin.

The structural differences between the parent enol, the corre-

sponding radical cation and the neutral radical can be followed by

regarding some signiﬁcant torsion angles and bond lengths of the

calculated geometries of E11, E11^ꢁ^D, and R11^ꢁ(Scheme 2, Table 6).

with heteroaromatic rings in the a-position. This behavior in enols

E21–E25 is due to the enhanced electron density in the enol itself.²⁰

In contrast, in enols E26–E27 it is primarily due to OH/N hydrogen

bonding.¹⁹

3.3. Radical cation E11^ꢁ^Dand neutral radicalsdstructural

considerations

Mes

It has been possible to observe enol radical cations in solution by

Mes

p-An Mes

p-An

both CV and EPR/ENDOR.²⁶For E11^ꢁ^D, the life times lie in the range

E11

R11

between 19 ms (dichloromethane) and 400 ms (acetonitrile) as

Scheme 2. Compounds E11, E11^ꢁ^Dand R11^ꢁ.

established by CV. Our investigations nicely complement the laser

ﬂash photolysis characterization of the 4-methoxyphenylacetone

enol radical cation by Schepp⁹that exhibited a lifetime of 200

ms in

The torsional angle between the bonds b–a–d (Scheme 2) is

a suitable indicator for the planarity of the molecule in respect to

the twist about the central C(1)–C(2) bond. The closer this angle is

to 180^ꢄ, the more planar the molecule. The neutral enol E11 with

a formal conjugated double bond (bond length 1.367 Å) represents

a virtually planar system, whereas the radical cation E11^ꢁ^Dpos-

sesses an elongated double bond (1.423 Å) and a more pronounced

deviation from planarity (angle b–a–d¼155^ꢄ). Finally, radical R11^ꢁ

acetonitrile. Fortunately, under our experimental conditions, the

radical cation E11^ꢁ^Dwas sufﬁciently long-lived to be characterized

by EPR/ENDOR and TRIPLE resonance. Although the multiplicity of

the hfcs in E11^ꢁ^Dcould not be directly determined by the analysis of

the unresolved EPR signal, structural information was obtained by

comparison with the deuterated derivative [OD]-E11^ꢁ^Dand calcu-

lated values. The highest ¹H hfc of 0.307 mT was attributed to six

equivalent protons of the two p-CH₃groups of the mesityl sub-

stituents agreeing rather well with that of the dimesityl methyl

radical (0.331 mT).³¹The values 0.226 (6H) and 0.151 (6H) mT were

assigned to two sets of ortho methyl groups of the mesityl sub-

stituents (dimesityl methyl 0.207 mT); due to steric hindrance in

E11^ꢁ^D, two different ¹H hfcs were attributed to the two symmet-

rically non-equivalent ortho methyl groups of the mesityl sub-

stituents. The ¹H hfc of 1.09 mT stems from the meta protons. This

allotment of the ¹H hfcs is compatible with the overall width of the

unresolved EPR signal of E11^ꢁ^Dand reﬂects a marked ‘diaryl methyl‘

radical character of E11^ꢁ^Dwith the highest spin population residing

at C(2). A much smaller spin population in the remainder of the

molecules is indicated by comparison with the results on [OD]–

E11^ꢁ^D. While all hfcs remain virtually unchanged, the smallest

coupling constant of 0.052 mT vanished indicating that it has to be

connected with the proton of the enol OH. These ﬁndings corrob-

orated a twisted geometry for E11^ꢁ^Dalong the C(1)–C(2) double

bond, which is consistent with results of DFT (UB3LYP/6-31G**)

geometry optimizations and the corresponding spin distribution.

This also points to a distonic character of E11^ꢁ^D: whereas the spin

resides in the dimesityl methyl radical moiety, the positive charge is

predominately located at C(1) and in the anisyl substituent.

mirrors a carbon-centered dimesityl radical with an

a-carbonyl

substituent. In R11^ꢁ, the C(1)–C(2) bond length further increases to

1.483 Å and the carbonyl CO bond approaches a double bond

(1.238 Å). Remarkably, the out-of-plane angles for the two mesityl

substituents are almost identical in R11^ꢁand E11^ꢁ^D. Therefore, the

lower ¹H hfcs for R11^ꢁcompared to E11^ꢁ^Dcan only be rationalized

by an increase of the

character at the radical center C(2) in R11^ꢁ

causing attenuated delocalization onto the two mesityl

substituents.

Extensive investigations on enols containing electron-with-

drawing groups in the

follow-up reactions of

are predominantly of the radical type, which is in agreement with

previous investigations.³³In contrast,

-carbonyl radicals derived

from -dimesityl enols are kinetically stable due to the bulky

b-position (as in E35–E40) reveal that the

-carbonyl radicals derived from these enols

b,b

groups preventing dimerization. This is clearly demonstrated by

the fully reversible enolate oxidation wave in the CV for E1–E34.

With a-carbonyl radicals derived from b,b-dimesityl enols it was

thus possible for the ﬁrst time to measure their oxidation potentials

directly by cyclic voltammetry. They agree qualitatively with the

reduction potentials of three related

a-carbonyl cations determined

by Okamoto.³⁴All

a-carbonyl radicals (Table 1) showed an irre-

The spin distribution in the neutral radicals R4^ꢁ, R5^ꢁ, R7^ꢁ, R8^ꢁ,

R10^ꢁ, R11^ꢁand R14^ꢁis similar to that of E11^ꢁ^Dbut with attenuated ¹H

hfcs in the mesityl substituents. Here, at least partly resolved EPR

spectra allowed the determination of the multiplicities of the hfcs.

Generally, the spectra are dominated by line patterns, which can be

traced back to three sets of ¹H hfcs of ca. 0.2–0.25, 0.14–0.19, and ca.

0.1 mT, each due to six equivalent protons. In agreement with the

calculations (see Table 6) and related bi(aryl)methyl radicals,³²the

biggest hfcs have to be assigned to two virtually equivalent para

CH₃groups of the two mesityl substituents whereas the smaller

ones have to stem from two sets of the non-equivalent ortho-CH₃

groups. The remaining deﬁnitely smaller hfcs are ascribed to the

versible oxidation wave under cyclic voltammetric conditions due

to fast follow-up reactions of the corresponding carbocations.

These reactions furnished the benzofuran derivatives B (Scheme

1),^7,8,18,25,35some of which were isolated and investigated earlier.

Partially reversible to irreversible oxidation waves were observed

for the benzofuran derivatives.

3.4. Comparison of oxidation potentials of

a-carbonyl

radicals with other carbon-centered radicals

Due to the kinetic stability of a-carbonyl radicals we were able

to directly measure their oxidation potentials^33ain solution,

whereas in general the determination of oxidation potentials of

simple carbon-centered radicals requires complicated experimen-

tal set-ups. A while ago, Wayner et al.³⁶developed a technique to

measure oxidation and reduction potentials of carbon-centered

Table 6

Selected calculated bond lengths/Å and angles/^ꢄfor E11, E11^ꢁ^D, and R11^ꢁ(UB3LYP/6-

31G**). For numbering, see Scheme 2

a/Å

c/Å

b/Å

Out-of plane

Torsional angle

angle of mesityl

substituents/deg

(b–a–d)/deg

radicals but published data on a series, which did not include a-

E11

1.367

1.423

1.483

1.375

1.343

1.238

1.508

1.480

1.475

166

155

146

carbonyl radicals. With the knowledge of oxidation potentials of

various carbon-centered radicals³⁶and our values at hand we were

interested to establish a correlation between measured oxidation

E11^ꢁ^D

R11^ꢁ

10848

M. Schmittel et al. / Tetrahedron 65 (2009) 10842–10855

potentials in solution and gas phase ionization potentials. When we

calculated the gas phase ionization potentials of the carbon-cen-

tered radicals described by Wayner et al.³⁶using a time inexpensive

method (AM1, Spartan programme) and plotted them against the

oxidation potentials measured in solution, a linear plot with

a rather poor correlation coefﬁcient of R²¼0.88 was obtained.

However, when the gas phase ionization potentials were cor-

9.0

7.5

IP / eV

rected for the solvation term D

E^A_so^C_l^N_v(Eq. 1) using the Born equation,

6.0

an improved correlation R²¼0.92 was found between the IP_a^corr

versus the measured oxidation potential (Eq. 2). The corrected

ionization potentials were about 1.6–2.4 eV lower than the gas

phase ionization potentials.

IP_a^corr

IP_a^gas

4.5

IP^C_a^orr¼ IP^g_a^as

ꢀ

E_solv

(1)

ACN

-1.5

0.0

1.5

E_pa/ V_SCE

Figure 8. Plot of IP (eV) against E_pa(V_SCE) of carbon-centered radicals including the

-carbonyl radicals derived from b,b-dimesityl enolates. Dots [C] represent a plot of

IP^C_a^orr¼ 0:93E_paþ 5:48

(2)

IP_a^gasagainst E_pawhile dots [-] depict the plot of IP_a^corr(IP^g_a^ascorrected for solvation

term) against E_pa(V_SCE).

The validity of Eq. 2 was checked by predicting the oxidation po-

-carbonyl radicals 41^ꢁ–44^ꢁ, whose oxidation potentials

their concentrations in biological systems may approach unity or

even favor enol formation. Enols have been invoked in a number

of reactions carried out by racemases.³⁸Typically, under bio-

chemical conditions rapid equilibration of the keto/enol/enolate

system³⁹and its breakdown may occur by one of the following

three ways: (a) reversible reaction with an electrophile leading to

tentials of

had been measured indirectly by Le-Moing by the reduction of

stable carbocations.³⁷Importantly, the calculated oxidation po-

tentials using Eq. 2 were in close agreement with the experimen-

tally determined values (Table 7).

bond formation/cleavage

to the carbonyl groups⁴⁰(e.g. de-

carboxylation⁴¹), (b) eliminations leading to

a,b-unsaturated

R₁

R₂

carbonyl compounds,⁴²(c) oxidations leading to loss of one or

R₁

42 Ph

two electrons.⁴³

pAn

R₂

Although involvement of enols as one-electron transfer donors

in biological systems is not yet widely established, radical cations of

simple enols and enol ethers are known to play a vital role in DNA

damage.⁴⁴In addition, enol radical cations have been invoked in

transformations carried out by coenzyme B₁₂dependent enzymes

such as ribonucleotide reductase, diol and glycerol dehydratase and

ethanol-amine ammonia lyase.⁴⁵

Table 7

Comparison of calculated and experimental solution oxidation potentials of a-car-

bonyl radicals.³⁷The computed values were obtained by Eq. 2. The solvation term

was obtained using the classical Born equation

The oxidation potentials of our model enols (with or without

System IP^g_a^as/eV

E^A_So^C_l^N_v/eV IP^g_a^as

ꢀD

E^A_so^C_l^N_v/eV Calculated Experimental

electron-withdrawing group in the

b-position) strongly suggest

E_1/2/V_SCE

that a biological oxidation would not occur directly from the enol

form (oxidation potentials of simple enols would be much higher

41^ꢁ

42^ꢁ

43^ꢁ

44^ꢁ

8.80

8.56

8.30

8.09

1.87

1.77

1.72

1.64

6.93

6.79

6.58

6.45

1.56

1.41

1.18

1.04

1.52

1.48

1.19

1.15

than those of

b,b-dimesityl enols), but may occur from the corre-

sponding enolates, which are more than 1.5 V (w35 kcal mol^ꢀ1

)

easier to oxidize. Also model studies suggest that hydrogen bond-

ing to enols may shift the oxidation potentials of enols by up to

500 mV.¹⁹Generation of an enolate not only generates a better

electron donor, it also allows the system to act as either one- or

two-electron transfer reagent, with the second transfer involving

Thus, Eq. 2 can be used for predicting the oxidation potentials of

other carbon-centered radicals. However, from the data in Table 7 it

is also clear that deviations between 10 and 110 mV may exist be-

tween calculated and experimentally determined oxidation poten-

the

a-carbonyl radical as reducing agent.

tials. To improve the correlation, we ﬁnally combined the

a-carbonyl

Formation of R7^ꢁ, as described in Section 2.6, is in line with

radicals reported by Orliac-Le-Moing et al.,³⁷some representative

electron transfer between Fl_Oxand enolate A7. The lack of benzo-

carbonyl radicals from Table 1 and Wayner’s data. Again, it was

necessary to include a solvent correction (Eq. 3, R²¼0.94) providing

only a slight change in the overall equation (Fig. 8).

furan formation clearly indicates that further oxidation of the

a-carbonyl radical by Fl_Seqor Fl_Oxdid not occur in solution. Radical

addition reactions between the Fl_Seqand various simple radicals are

well known, but such a process can be excluded for the sterically

crowded R7^ꢁ. Thus, after one-electron transfer the reaction stops.

Interestingly, investigations by Armstrong and Rizwan⁴⁶indicated

IP^C_a^orr¼ 0:93E_paþ 5:50

(3)

Interestingly, in the plot of Figure 8 the oxidation potentials of

-carbonyl radicals derived from -dimesityl enols fall in the

that the

a-carbonyl radical obtained by dehydration of ethylene

b,b

glycol radical did neither add to the Fl_Seqnor undergo further ox-

idation, which is in agreement with the above result.

same range as benzyl radicals (simple as well as benzannulated

ones).

Obviously, the oxidation of enolates by an enzyme might pro-

ceed in an entirely different manner, as conformational changes in

the protein or hydrogen bonding to the semiquinone Fl_Seqcan

potentially bring about a distinct anodic shift in the oxidation po-

tential, allowing for a second electron transfer from the substrate to

yield Fl_Red. Nevertheless, as the protonated semiquinone form of

the riboﬂavin (Fl_Seq) was unable to oxidize the electron rich

3.5. Biological relevance of oxidation potentials of enols,

enolates and a-carbonyl radicals

The enol forms of simple carbonyl compounds are present at

exceedingly low concentration in solution (K_enol¼10^ꢀ8), however,

M. Schmittel et al. / Tetrahedron 65 (2009) 10842–10855

10849

-carbonyl radical R7^ꢁ, which upon oxidation undergoes a fast fol-

low-up reaction, the one-electron oxidation of an -carbonyl rad-

Recent theoretical calculations revealed that approximately 40%

of the unpaired spin resided on the O2 position in the ascorbic acid

radical 46a^ꢁ.⁵¹It was also predicted that hydrogen bonding occur-

ring at O2 and O3 atoms would lead to a signiﬁcant redistribution of

spin density in the free radical 46a^ꢁ. Interestingly, due to an ab-

sorption at 290 nm, the presence of 46c^ꢁwas established under

pulse radiolytic conditions. The spectrum was shifted hyp-

sochromically by 70 nm in comparison to 46a^ꢁ.⁵²Earlier pulse ra-

diolytic investigations in nitrous oxide saturated solution between

pH 3.0 and 4.5 showed two OH–radical adducts (46b^ꢁand 46d^ꢁ) in

addition to the ascorbate radical anion.⁵³The OH–radical adduct

46b^ꢁformed by addition of the hydroxyl radical to C3 of 46. Radical

46b^ꢁwas found to exhibit a doublet of lines in the EPR that is pH

dependent. Equally, the adduct 46d^ꢁcould form by addition of the

hydroxyl radical to the C2 position of 46. It is apparent from Scheme

3 that a large number of potential secondary electron donors can be

written for ascorbic acid radical, some of which have the structure

ical derived from a thioester (simpliﬁed model for the enzyme

substrate) can now be assessed realistically. The oxidation potential

of the a-carbonyl radical 45 derived from methyl thioacetate, used

here as a simple mimic for the enzyme substrate of a de-

hydrogenase, is predicted to be 1.92 V_SCE(from Eq. 3). This value is

clearly far out of range, so that oxidation of 45 by Fl_Seqor Fl_Oxis

impossible. The results thus show that ﬂavins may trigger a one-

electron oxidation of enolates, but they do not have the oxidation

power to oxidize a-carbonyl radicals.

E_pa= 1.92 V_SCE

IP_pa^gas= 9.62 eV

E_solv^ACN= 2.29 eV

a-carbonyl radicals or a,a

⁰-dicarbonyl radicals. It would be of

much interest to know, which of these radicals participate in the

follow-up electron transfers.

To get a closer insight we computed oxidation potentials of

radicals 46a^ꢁ–46d^ꢁ. To our surprise, 46a^ꢁhas still a high oxidation

potential around 1.75 V_SCE, even though it is shifted w1000 mV

The data of this manuscript also allow to get better insight into

the action of vitamin C. Ascorbic acid (vitamin C), an important

two-electron donor system, has found a broad range of applications

in various ﬁelds ranging from photographic developing agents,⁴⁷

metal ion sensors to its famous utility as a biological antioxidant.

While the electron donating ability of ascorbic acid is well accepted,

the mechanism by which it donates the electron is, however, still

not well understood, mostly due to the multitude of possible re-

ductants (Scheme 3).

cathodically compared to that of a prototypical a,a-dicarbonyl alkyl

radical (2.72 V_SCEfor cyclohexanedione radical).^1aRadical 46c^ꢁ

(1.26 V_SCE) was found to be w500 mV cathodically shifted in

comparison to 46a^ꢁ, with its oxidation potential being similar to

that of a-carbonyl radicals with one a-electron-withdrawing group.

The oxidation potential of radical 46b^ꢁ(1.37 V_SCE) is similar to that

of 46c^ꢁin line with our expectations. The 110 mV anodic shift of the

oxidation potential could be due to the fact that in 46c^ꢁthe

a-car-

bonyl radical is of a ketone type while in 46b^ꢁit is of the ester type.

Most likely, 46c^ꢁis the strongest reducing agent in acetonitrile. Of

different range is the oxidation potential of radical 46d^ꢁ, which was

calculated to be 0.20 V_SCEin acetonitrile but requires water to form.

The oxidation potential of 46d^ꢁis similar to that of an

a-hydrox-

yalkyl radical,⁵⁴as reported by Wayner et al.,⁵⁵all of them placed in

the range of ꢀ0.61 V_SCEto þ0.38 V_SCEdepending on the sub-

stituents. It was also noted that the oxidation potentials of

-e

-H⁺

a-hydroxyalkyl radicals are strongly dependent on the solvent used

+H₂O

-H₂O

and are signiﬁcantly lower in water than those obtained in aceto-

nitrile.⁵⁶The main reason for this large solvent effect was attributed

to the better ion solvation properties of water compared to that of

acetonitrile. In water, not only the reducing power of 46a^ꢁ–46c^ꢁis

distinctly stronger, but deprotonation reactions are possible due to

the higher basicity of the solvent. Thus, radicals 46a^ꢁ–46c^ꢁmay af-

+H⁺

-H⁺

46a

46b

-H⁺

1,4-H-shift

+H⁺

-e

-H⁺

-e

-H⁺

+H⁺

ꢁ

ford the dehydroascorbate radical anion 46a^Lby deprotonation

46a

and dehydration. The latter species is such a strong reductant that it

should become the dominant secondary reducing species in water.

-e

46c

-H⁺

4. Conclusion

-e

-H₂O +H₂O

+H⁺

An extensive electrochemical investigation on 40 model enols

was carried out by cyclic voltammetry showing a range of E_pafrom

0.13 to 0.95 V_Fc. A few of the resulting enol radical cations were

characterized by spectroscopic means (EPR, ENDOR). For the ﬁrst

time, oxidation potentials of enols derived from amides were

reported. Their high E_papotentials suggest that the two additional

electron-withdrawing groups play an important role in the oxida-

tion. Electronically seen, these systems are not only enols, but

equally enamines.

-H₂O

-e

+H₂O

-H₂O

+H₂O

46d

Scheme 3. The various possible radicals that are formed after one-electron oxidation

of ascorbic acid (46).

ꢁ

The radical anionic ascorbate 46a^Lhas been invoked as an

important intermediate after one-electron transfer,⁴⁸as support

was gained by a mechanistic investigation based on two-di-

mensional voltammetry.⁴⁹The half wave potentials were found to

be strongly pH dependent (0.76 V_SCEat pH 2.1 and 0.3 V_SCEat pH

6.7,⁴⁹1.13 V_SCEin DMF⁵⁰).

The oxidation potentials of the enolates proved to be lower than

those of the enols by about 1.1–1.6 V, which allowed an easy access

a-carbonyl radicals by oxidation of the enolates. The radicals

were characterized by various techniques, such as EPR, ENDOR,

magnetic susceptibility and cyclic voltammetry.

10850

M. Schmittel et al. / Tetrahedron 65 (2009) 10842–10855

A different reactivity under oxidative conditions was observed

-carbonyl radicals derived from enols with -electron-with-

drawing groups as compared those with -electron-donating

groups. While -carbonyl radicals derived from the latter type of

enols, e.g. -dimesityl enols, are easily oxidized and undergo re-

actions typical of carbocations, -carbonyl radicals derived from

enols with -electron-withdrawing groups will typically undergo

for

b,b

radical follow-up reactions.

Using stable and hindered enols, it was possible to measure the

oxidation potentials of a wide range of a-carbonyl radicals. A cor-

relation was obtained, when AM1 calculated ionization potentials

corrected for the solvation term were plotted against the experi-

mentally determined oxidation potentials of

correlation was useful in predicting the oxidation potential of the

-carbonyl radical derived from a simple thioester, a mimic for

a-carbonyl radicals. The

Mes

E14

the enzyme substrate in dehydrogenases, suggesting that while the

ﬁrst electron transfer between the riboﬂavin derivatives FAD or FMN

is possible, the second electron transfer would be very difﬁcult.

Rather, the radical intermediate will undergo a hydrogen atom

transferora radicaladditiontothe cofactor underenzyme conditions.

The correlation was also used to compute oxidation potentials of

various ascorbic acid radicals formed after one-electron transfer or

addition of hydroxyl radical to ascorbic acid. It was found that 46c^ꢁ

had the lowest oxidation potentials of all possible neutral radicals

in acetonitrile. Considering all species, however, it is the ascorbate

radical anion, which has the lowest oxidation potential and thus is

the strongest reducing agent.

Chart 2. List of radicals used in Figure 8 for the correlation of IP_a^gaswith the experi-

mentally determined oxidation potential.

obtained by subtracting the heats of formation (DH_f) of the cation

was corrected for the solvation term (IP_a^gas

ꢀ

E^A_so^C_l^N_v). The solvation

term (D

E^A_so^C_l^N_v) was obtained from the Born equation (Table 9):

ꢀ

ꢁ

ꢀN_LZ²e²

ACN

solv

1 ꢀ

(4)

In brief, oxidation potentials of enolates, a-carbonyl radicals and

enols can provide valuable insight into their role as intermediates

in preparative and enzymatic processes.

Details to Eq. 4:

is the dielectric constant of the solvent;

ACN¼acetonitrile; r is the ionic radius of the carbocation, which

was obtained from the surface area of the carbocation; N_Lis the

Avogadro’s number and e is the charge of an electron.

5. Experimental

5.1. Cyclic voltammetry

5.3. DFT computations

All CV measurements were carried out with a three-electrode

system with 1 mm platinum disc electrode as working electrode,

a Pt wire counter electrode and a Ag reference electrode all being

placed into the solution. The cyclic voltammograms were recorded

at various scan rates using a manifold of starting and reversal po-

tentials. For determination of the oxidation potentials, ferrocene or

triphenylpyrylium tetraﬂuoroborate or decamethylferrocene was

added as internal standard. Tetra-n-butylammonium hexa-

ﬂuorophosphate was used as electrolyte. For fast scan cyclic vol-

tammetry investigations, 385 mg (1.00 mmol) of supporting

For the calculations of the isotropic hyperﬁne coupling con-

stants the UB3LYP/6-31G* level of theory was applied using the

Gaussian 94 program suite.⁵⁸

Table 8

Calculation of gas phase adiabatic ionization potential of various radicals and their

corresponding cations using the semiempirical method (AM1, Spartan)

Radical

Radical (R)

H_f/kcal mol^ꢀ1

Cation (C)

H_f/kcal mol^ꢀ1

IP^g_a^as(CꢀR)/

IP^g_a^as/eV

kcal mol^ꢀ1

electrolyte, 50

mmol of substrate and 4.0 mL of solvent were used.

ꢀ6.1

61.9

28.8

ꢀ22.8

ꢀ38.2

ꢀ49.2

ꢀ46.2

21.6

174.8

269.2

206.0

158.0

131.0

111.6

125.5

174.7

109.1

173.2

262.3

262.0

300.7

281.6

270.3

274.0

270.6

161.9

117.3

146.2

173.1

165.8

200.0

183.8

180.9

207.3

177.2

180.8

169.2

160.8

171.7

153.1

176.4

173.2

192.7

192

202.5

183.7

180.6

187.9

188.3

167.8

161.6

145.9

175.9

173.8

172.7

170

7.85

8.99

7.68

7.84

7.34

6.97

7.45

6.64

7.65

7.51

8.36

8.33

8.78

7.97

7.83

8.15

8.17

7.28

7.01

6.33

7.63

7.54

7.45

7.37

Fast scan cyclic voltammograms were carried out at 5,10 and 25

Au ultramicro electrodes, with a Pt wire serving as counter elec-

trode and a Ag wire as a pseudo-reference electrode. Standard CVs

were recorded using a Princeton Applied Research Model 362

potentiostat with a Philips model PM 8271xYt-recorder for scan

rates <1 V s^ꢀ1. For fast scan cyclic voltammetry, a Hewlett Packard

(HP) Model 331A4 Function Generator was used, connected to

a three-electrode potentiostat developed by Amatore et al.⁵⁷Data

were recorded by an HP 54510 A digitizing oscilloscope linked to

a 486DX33 computer using the HP data transfer program Scopelink.

For generating enolates (under preparative as well as for cyclic

voltammetry) tetramethylammonium hydroxide (25% solution in

methanol) was used as base.

ꢀ67.3

R4^ꢁ

R5^ꢁ

R8^ꢁ

R14^ꢁ

0.0

69.6

70.0

98.2

97.9

89.7

86.1

82.3

ꢀ5.9

ꢀ44.3

0.3

ꢀ2.8

ꢀ8.0

27.3

5.2. Computations

For the correlation in Figure 8, radicals (see Chart 2) with known

oxidation potentials were computed by AM1 (Spartan). The corre-

sponding cation was also optimized at the same level of compu-

tation (Table 8). The adiabatic ionization potential (IP_a^gas) was

13.8

M. Schmittel et al. / Tetrahedron 65 (2009) 10842–10855

10851

Table 9

and the crude product (2.23 g, 8.31 mmol, 80%) precipitated. The

crude product consisted of the desired enol E3 and its tautomeric

aldehyde (55:45, as determined by GC on an SE30, 25 m). Separa-

tion of the tautomers failed due to the rapid tautomerization rate.

Solvent corrected adiabatic ionization potential of various radicals used in Figure 8

using the surface area method for incorporating the radius in the Born equation. The

last column represents the experimentally determined oxidation potential of the

corresponding radicals in acetonitrile, determined either by Wayner et al.³⁶or in the

present work

¹H NMR (250 MHz, CDCl₃):

d 2.10 (s, 6H, o-Mes–CH₃), 2.31 (s, 3H,

p-Mes–CH₃), 3.79 (s, 3H, CH₃O), 5.04 (s, 1H, OH), 6.60–7.00 (m, 7H,

Ar–H, CHOH).

ACN

Radical Surface Radius

area/Å²r/Å

E^A_so^C_l^N_v/eV (IP^g_a^as

ꢀ

E^A_so^C_l^N_v)/eV

solv

1/2

kcal mol^ꢀ1

V_SCE

110.5

103.6

118.5

82.8

124.2

160.3

99.9

107.3

113.0

163.3

154.0

173.5

224.9

231.4

196.3

196.9

165.1

195.0

163.4

325.4

342.2

396.8

438.4

2.97

2.87

3.07

2.57

3.14

3.57

2.827

2.921

3.00

3.60

3.50

3.728

4.23

4.29

3.95

3.96

3.62

3.94

3.61

5.09

5.23

5.62

5.91

53.58

55.45

51.84

61.92

50.68

44.586

56.29

54.48

53.04

44.20

45.47

42.69

37.62

37.09

40.29

40.19

43.96

40.39

44.08

31.26

30.43

28.32

26.93

2.32

2.402

2.25

2.69

2.20

1.93

2.445

2.36

2.30

1.921

1.97

1.85

1.63

1.61

1.75

1.74

1.91

1.75

1.91

1.36

1.32

1.23

1.17

5.52

6.59

5.44

5.16

5.14

5.04

5.01

4.28

5.35

5.59

6.39

6.36

6.93

6.34

6.22

6.40

6.42

5.37

5.26

4.42

6.27

6.22

6.26

6.20

0.09

6.3. 1,1-Dimesityl-1-hexen-2-ol (E6)

0.80

-0.04

ꢀ0.24

ꢀ0.45

ꢀ0.10

ꢀ0.60

ꢀ1.03

ꢀ0.08

0.51

1.03

1.11

1.63

1.01

0.56

0.72

0.97

ꢀ0.44

ꢀ0.55

ꢀ1.12

0.76

0.59

0.63

To a solution of dimesitylketene (1.50 g, 5.39 mmol) in dry ether

(30 mL), kept at 0 ^ꢄC in an inert atmosphere,1.4 M n-butyllithium in

hexane (3.9 mL, 5.50 mmol) was added dropwise. The mixture was

stirred for additional 1.5 h at 0 ^ꢄC and 1 h at room temperature.

After the mixture had been hydrolyzed by adding half-saturated aq

NH₄Cl solution (10 mL), the aqueous layer was extracted with

diethyl ether (3ꢂ15 mL). The combined organic layers were dried

and the solvent was removed in vacuo. The remaining brown oil

was chromatographed twice on silica gel using cyclohexane/ethyl

acetate (1:1) and cyclohexane/DCM (2:1) as eluent. Yield: 789 mg

(43%). IR (neat): 3524 (s, OH), 3474 (s, OH), 2926 (s, C–H), 1626 (s),

R4^ꢁ

R5^ꢁ

R8^ꢁ

R14^ꢁ

1450 (s), 1375 (m), 1227 (m), 1176 (m), 851 (m) cm^ꢀ1

¹H NMR

(200 MHz, CDCl₃):

0.83 (t, J¼7 Hz, 3H, 6-CH₃), 1.29 (m, 2H, 5-CH₂),

1.56 (m, 2H, 4-CH₂), 2.15 (m, 14H, o-Mes–CH₃þ3-CH₂), 2.37 (s, 6H,

p-Mes–CH₃), 4.93 (s, 1H, OH), 6.80 (s, 2H, Mes–H), 6.85 (s, 2H, Mes–

H). ¹³C NMR (CDCl₃, 63 MHz):

d 13.9, 18.4, 20.8, 20.9, 21.0, 22.8, 29.3,

31.2, 109.1, 129.0, 129.9, 132.3, 135.2, 135.3, 136.5, 138.4, 139.0, 152.4.

HRMS (70 eV): calcd 336.2453, found 336.2454.

0.66

5.4. EPR, ENDOR, and general TRIPLE

6.4. 1-(4-Bromophenyl)-2,2-dimesitylethenol (E9)

EPR spectra were taken on a Varian E9 spectrometer whereas

the ENDOR and general TRIPLE measurements were performed on

a Bruker ESP300 instrument. All instruments were equipped with

variable temperature units. EPR simulations were performed with

the public domain program WinSim.

In an inert atmosphere, a solution of 2.45 M n-butyllithium in

hexane (2.60 mL, 6.36 mmol) was added quickly to an ice-cooled

solution of 1,4-dibromobenzene (1.50 g, 6.36 mmol) in dry ether

(30 mL). A solution of dimesitylketene (1.67 g, 6.00 mmol) in dry

ether (30 mL) was added after 1 min. Stirring was continued for 3 h

at 0 ^ꢄC and for an additional hour at room temperature. The mix-

ture was hydrolyzed with half-saturated NH₄Cl solution (50 mL),

washed with ether (3ꢂ30 mL), and evaporated after drying the

organic layer (MgSO₄). Chromatography of the remaining oil on

silica gel using cyclohexane/ethyl acetate (3:1) as the eluent and

crystallization from ethanol yielded the pure E9. Yield: 1.11 g (40%).

Mp 161–163 ^ꢄC. IR (KBr): 3506 (s, OH), 2916 (s, C–H), 1610 (s, C]C),

6. Synthesis

6.1. Z-2-Mesityl-2-(p-tolyl)ethenol (E2)⁵⁹

In an inert atmosphere lithium aluminum hydride (700 mg,

18.4 mmol) was added to mesityl-p-tolyl ketene (2.20 g,

8.86 mmol) in anhydrous THF (40 mL). Stirring in an ice bath was

continued until gas evolution stopped. Then the reaction mixture

was stirred for 1 h at room temperature and stirred for additional

2 h at 80 ^ꢄC. After cooling the solution was hydrolyzed with water

(10 mL). After drying (MgSO₄) the solvent was removed in vacuo.

The crude product was chromatographed under medium pressure

(medium pressure liquid chromatography) with n-hexane/

dichloromethane (1:2) as the eluent. Yield: 390 mg (17%). Mp 86–

86.5 ^ꢄC. Purity by GC (OV17, 25 m): 99%. IR (CCl₄): 3480 (vs, OH),

2900 (s, C–H), 1610 (vs, C]C), 1590 (m, C]C), 1420 (w), 1365 (w),

1290 (w), 1180 (m), 1130 (vs), 1060 (vs), 870 (w). ¹H NMR (250 MHz,

1484, 1214, 1060, 1009, 849, 835, 741 cm^ꢀ1

¹H NMR (250 MHz,

CDCl₃): 1.90 (s, 3H, Mes–CH₃), 2.20 (s, 3H, Mes–CH₃), 2.27 (s, 12H,

Mes–CH₃), 5.15 (s, 1H, OH), 6.68 (s, 2H, Mes–H), 6.89 (s, 2H, Mes–H),

7.18 (d, 2H, J¼9 Hz, Ar–H), 7.28 (d, 2H, J¼9 Hz, Ar–H). ¹³C NMR

(CDCl₃, 63 MHz):

d 20.6, 20.8, 21.2, 112.2, 122.2, 129.4, 129.9, 130.2,

130.8, 132.5, 134.9, 135.3, 136.1, 137.0, 137.9, 139.0, 149.3. Elemental

analysis for C₂₆H₂₇BrO: calcd C 71.72%, H 6.25%; found C 71.62%,

H 5.97%.

6.5. 1-(5-Bromo-2-methoxyphenyl)-2,2-dimesityl-

ethenol (E12)

CDCl₃):

d 2.10 (s, 6H, o-Mes–CH₃), 2.28 (s, 3H, p-Mes–CH₃), 2.32 (s,

3H, p-Tol–CH₃), 4.26 (d, J¼14 Hz, OH), 6.95 (s, 2H, Mes–H), 6.95 (d,

To a solution of 2.3 M n-butyllithium (5.52 mL, 12.7 mmol) in

dry diethyl ether (70 mL) kept at ꢀ20 ^ꢄC was added a solution of

4-bromo-1-methoxybenzene (2.40 g, 12.7 mmol) in dry ether

(18 mL) under an argon blanket. After stirring for 30 min at this

temperature a solution of dimesitylketene (3.52 g, 12.7 mmol) in

dry ether (20 mL) was added and stirring continued for an addi-

tional 90 min at ꢀ18 ^ꢄC. Then, while stirring, the temperature was

slowly raised to room temperature over 60 min and kept for

120 min. The reaction mixture was poured in ice water (200 mL)

and acidiﬁed with concd HCl (1 mL) and 2 N HCl (20 mL). The

aqueous layer was extracted with diethyl ether (200 mL) and the

J¼14 Hz, 1-H), 7.00 (m_AB, 4H, Tol–H). ¹³C NMR (CDCl₃, 63 MHz):

19.8, 21.1, 21.2, 116.9, 124.5, 128.4, 129.0, 129.4, 130.0, 135.0, 135.5,

138.4, 138.5. HRMS (70 eV): calcd 252.1512, found 252.1510.

6.2. Z-2-(p-Anisyl)-2-mesitylethenol (E3)²²

In an inert atmosphere, 1-mesityl-2-(4-methoxyphenyl)-

ethylene glycol (3.00 g, 10.4 mmol), glacial acetic acid (30 mL) and

concentrated hydrochloric acid (8 mL) were reﬂuxed for 1 h. After

cooling the reaction mixture was hydrolyzed with water (300 mL)

10852

M. Schmittel et al. / Tetrahedron 65 (2009) 10842–10855

combined organic layers were extracted with concd NH₄Cl solution,

dried (MgSO₄) and evaporated. The residue was chromatographed

on silica gel to separate off the dimesitylacetic acid. A second

6.8. 1,1-Dimesityl-7-(triisopropylsilyloxy)hept-1-en-

3-yn-2-ol (E31)

chromatography on silica gel (0.060–0.200

m) under medium

Triisopropylsilyloxy-4-pentyne (2.0 g, 8.3 mmol) was added to

ethylmagnesium bromide, generated from ethyl bromide (1.0 g,

9.2 mmol) and magnesium (0.20 g, 8.3 mmol) in 20 mL of dry THF

at room temperature. After the effervescence of hydrogen gas had

stopped, 25 mL of a solution of dimesitylketene (2.5 g, 9.0 mmol) in

THF was added. The reaction mixture was stirred at room tem-

perature for 12 h and quenched with water. The reaction mixture

was extracted with dichloromethane (2ꢂ25 mL), dried over Na₂SO₄

(anhyd) and concentrated affording a brown oil. Yield: 3.73 g (86%).

pressure (ﬂow 10 mL min^ꢀ1, 10 bar) with cyclohexane/DCM (1:2) as

eluent yielded enols E11 and E12.⁶⁰Pure E12 (301 mg, 13%) was

obtained after crystallization from petroleum ether. Mp

201–201.5 ^ꢄC. IR (CCl₄) 3500 (vs), 3000, 2910, 2830, 1600 (vs), 1590,

1440, 1270, 1210, 1180, 1060, 1030, 850 cm^ꢀ1

¹H NMR (400 MHz,

1.60–2.70 ([including signals at 1.90 (s, 6H), 2.14 (s, 3H),

CDCl₃)

2.27 (s, 3H)], total 18H, coalescence, Mes–CH₃), 3.47 (s, 3H, CH₃O),

5.32 (s, 1H, OH), 6.60 (d, J¼9.9 Hz, 1H, m-aryl–H), 6.61 (s, 2H,

Mes–H), 6.82 (s, 2H, Mes–H), 7.25 (dd, J¼9.9 and 1.0 Hz, 1H, p-aryl–

H), 7.37 (d, 1H, J¼1.0 Hz, o-aryl–H). ¹³C NMR (CDCl₃, 100 MHz):

¹H NMR (CDCl₃, 200 MHz):

d (ppm): 1.03 (s, 21H, 8 and 9-H),1.64 (q,

J¼6 Hz, 2H, 2-H) 1.99–2.28 (br s, coalescence, 18H, 10a and 10b-H),

2.38 (t, J¼7 Hz, 2H, 3-H), 3.53 (t, J¼6 Hz, 2H, 1-H), 4.72 (br s, 1H,

OH), 6.77 (br s, coalescence, 2H, 14-H), 6.86 (br s, coalescence, 2H,

20.8, 20.9, 21.2, 55.3, 112.2, 112.9, 115.2, 127.9, 128.9, 129.0, 129.8,

132.2, 133.0, 134.5, 135.2, 135.5, 136.7, 139.0, 146.1, 156.3. MS

(70 eV): m/z (%)¼467 (29), 466 (100), 465 (30), 464 (98). HRMS

(70 eV) of C₂₇H₂₉⁷⁹BrO₂: calcd 464.1351, found 464.1370.

15-H). ¹³C NMR (CDCl₃, 50 MHz):

d (ppm) 12.9, 16.8, 19.0, 21.8, 21.9,

32.4, 62.4, 94.2, 120.5, 129.9, 130.0, 130.7, 132.6, 135.1, 135.7, 136.8,

138.1, 139.5.

6.6. 1,1-Dimesityl-5-(triisopropylsilyloxy)pent-1-en-

3-yn-2-ol (E29)

6.9. 5,5-Dimesitylpent-4-en-2-yne-1,4-diol (E32)

Triisopropylsilyloxy-2-propyne (1.07 g, 5.04 mmol) was added to

ethylmagnesium bromide, generated from ethyl bromide (0.600 g,

5.50 mmol) and magnesium (0.133 g, 5.50 mmol) in 10 mLTHF (dry),

at room temperature. After the effervescence of hydrogen gas had

stopped, 15 mL of a solution of dimesitylketene in THF (1.31 g,

4.71 mmol) was added. The reaction mixture was stirred at room

temperature for 12 h and quenched with water. The reaction mixture

was extracted with dichloromethane (2ꢂ25 mL), dried over Na₂SO₄

(anhyd) and concentrated yielding a colorless solid. It was recrys-

tallized from hot pentane. Yield: 0.900 g (39%), mp 98–99 ^ꢄC, IR

(NaCl): 3269 (br s, OH), 2919, 2864 (alkyl), 2214 (alkyne),1612 (C]C),

1463, 1368, 1247, 1138, 1062 (aromatic), 1015, 882, 852, 725, 689,

1,1-Dimesityl-5-(triisopropylsilyloxy)pent-1-en-3-yn-2-ol

(0.40 g, 0.82 mmol) was added to a solution of aqueous acidic

methanol, prepared by dissolving 5 mL of 10% sulfuric acid in 15 mL

of methanol. The reaction mixture was stirred for 12–14 h and

monitored by TLC. After the complete consumption of starting

material, the reaction mixture was quenched with solid NaHCO₃

and concentrated. The residue was extracted with dichloromethane

(2ꢂ25 mL), dried over Na₂SO₄(anhyd) and concentrated. The crude

product was puriﬁed by column chromatography with 60: 40

ether/hexane mixture as eluent (R_f¼0.5). Yield: 0.23 g (84%). Mp

154–155 ^ꢄC. IR (NaCl): 3413 (s, OH, non-hydrogen bonded), 3197 (br

s, OH, hydrogen bonded), 2957, 2919, 2857 (alkyl), 2219 (alkyne),

1610 (C]C), 1474, 1445, 1375, 1262, 1203, 1178, 1097, 1046, 998, 967,

584 cm^ꢀ1. ¹H NMR (CDCl₃, 200 MHz):

d 0.98 (s, 21H, 7-H), 2.12–2.25

(br s, coalescence,18H, 8-H), 4.43 (s, 2H,1-H), 4.71 (br s,1H, OH), 6.77

900, 856, 805, 594. ¹H NMR (CDCl₃, 200 MHz):

d 1.60 (br s, 1H, OH),

(br s, coalescence, 2H, 11-H), 6.86 (br s, coalescence, 2H, 13-H). ¹³C

2.17–2.24 (br s, coalescence, 18H, 6a and 6b-H), 4.28 (s, 2H, 1-H),

4.85 (s, 1H, OH), 6.80 (br s, coalescence, 2H, 9-H), 6.86 (br s, co-

NMR (CDCl₃, 50 MHz): d 12.9 (C-6),18.9 (C-7), 21.8 (C-8a), 22.2 (C-8b),

53.3 (C-1), 81.6 (C-2), 91.6 (C-3), 122.2 (C-4), 130.0 (C-5), 130.1, 130.7,

132.3, 134.6, 135.1, 137.0, 138.3, 139.4. Elemental analysis for

C₃₂H₄₆O₂Si(490.79):calcdC78.31%, H9.45%;foundC78.16%, H9.70%.

alescence, 2H, 10-H). ¹³C NMR (CDCl₃, 50 MHz):

d 21.8, 22.2, 52.4,

82.8, 90.9, 122.5, 130.0, 130.2, 130.8, 132.0, 134.6, 134.8, 137.4, 138.5,

139.4. Elemental analysis for C₂₃H₂₆O₂(334.45): calcd C 82.60%,

H 7.84%, found C 82.25%, H 8.09%.

6.7. 1,1-Dimesityl-6-(triisopropylsilyloxy)hex-1-en-

3-yn-2-ol (E30)

6.10. 6,6-Dimesitylhex-5-en-3-yn-1,5-diol (E33)

Triisopropylsilyoxy-3-butyne (2.0 g, 8.8 mmol) was added to

ethylmagnesium bromide, generated from ethyl bromide (1.1 g,

10 mmol) and magnesium (0.24 g, 10 mmol) in 20 mL of dry THF at

room temperature. After the effervescence of hydrogen gas had

stopped, 25 mL of a solution of dimesitylketene (2.5 g, 9.0 mmol) in

THF was added. The reaction mixture was stirred at room tem-

perature for 12 h and quenched with water. The reaction mixture

was extracted with dichloromethane (2ꢂ25 mL), dried over Na₂SO₄

(anhyd) and concentrated yielding a colorless crystalline solid,

which was recrystallized from hot pentane. Yield: 1.4 g (31%). Mp

126–128 ^ꢄC. IR (NaCl): 3273 (br s, OH), 2956, 2916, 2863 (alkyl),

2727, 2214 (alkyne), 1721, 1610 (C]C), 1561, 1474, 1370, 1241, 1137,

1060 (aromatic), 1015, 965, 902, 885, 851, 828, 764, 696, 641, 567,

1,1-Dimesityl-6-(triisopropylsilyloxy)hex-1-en-3-yn-2-ol (0.60 g,

1.2 mmol) was added to a 20 mL solution of aqueous acidic methanol,

prepared by dissolving 5 mL of 10% sulfuric acid to 15 mL of metha-

nol. The reaction mixture was stirred for 12–14 h, while monitoring it

by TLC. After complete consumption of the starting material the re-

action mixture was quenched with solid NaHCO₃. The concentrated

residue was extracted with dichloromethane (2ꢂ25 mL), and dried

over Na₂SO₄(anhyd). The crude product was puriﬁed by column

chromatography with ether/hexane 60:40 as eluent (R_f¼0.5). Yield:

325 mg (78%). Mp 192–194 ^ꢄC. IR (ﬁlm): 3430 (s, OH, non-hydrogen

bonded), 3173 (br s, OH, hydrogen bonded), 3017, 2995, 2958, 2916

(alkyl), 2853, 2214 (alkyne),1611 (C]C),1475,1439,1373,1355,1289,

1238, 1165, 1138, 1035, 902, 849, 821, 735, 683, 582 cm^ꢀ1. ¹H NMR

506 cm^ꢀ1

¹H NMR (CDCl₃, 200 MHz):

1.04 (s, 21H, 7 and 8-H),

(CDCl₃, 200 MHz): d 1.6 (br s, 1H, OH), 2.17–2.24 (br s, coalescence,

2.12–2.25 (br s, coalescence, 18H, 9a and 9b-H), 2.49 (t, J¼7 Hz, 2H,

2-H), 3.68 (t, J¼7 Hz, 2H, 1-H), 4.73 (br s, 1H, OH), 6.76 (br s, co-

alescence, 2H, 12-H), 6.86 (br s, coalescence, 2H, 14-H). ¹³C NMR

18H, 7a and 7b-H), 2.49 (t, J¼6 Hz, 2H, 2-H), 3.57 (t, J¼6 Hz, 2H, 1-H),

4.88 (br s, 1H, OH), 6.82 (br s, coalescence, 2H, 10-H), 6.86, (br s, co-

alescence, 2H,12-H).¹³C NMR (CDCl₃, 50 MHz):

d 21.8, 25.0, 36.9, 61.7,

(CDCl₃, 50 MHz):

130.0, 130.7, 132.5, 135.0, 135.5, 136.9, 138.1, 138.3, 139.4.

12.9, 18.9, 21.8, 22.3, 24.9, 62.6, 91.1, 120.0, 129.9,

90.8, 121.4, 130.9, 132.1, 135.3, 135.4, 137.9, 138.3, 139.4, 139.6. HRMS

for C₂₄H₂₈O₂: calcd 348.2089, found 348.2093.

M. Schmittel et al. / Tetrahedron 65 (2009) 10842–10855

10853

6.11. 7,7-Dimesitylhept-6-en-4-yne-1,6-diol (E34)

acetonitrile was added. After 5 min, the reaction mixture was

quenched with saturated NaHCO₃solution (5.0 mL) and extracted

with CH₂Cl₂(2ꢂ10 mL). The combined organic layer was washed

twice with saturated NaCl solution (2ꢂ10 mL) and dried over

NaSO₄. The crude product was puriﬁed by column chromatogra-

phy on silica gel (cyclohexane/CH₂Cl₂2:1). Yield: 10.0 mg (75%). IR

(CCl₄): 2915 (vs, C–H), 2850 (s), 1610 (m, C]C), 1590 (m, C]C),

1445 (s), 1250 (s), 1190 (m), 1120 (s), 1065 (s), 1040 (vs), 860 (w),

1,1-Dimesityl-7-(triisopropylsilyloxy)hept-1-en-3-yn-2-ol

(2.0 g, 3.9 mmol) was added to a solution of aqueous acidic meth-

anol, prepared by dissolving 5 mL of 10% sulfuric acid to 15 mL of

methanol. The reaction mixture was stirred for 12–14 h while

monitoring it by TLC. After complete consumption of the starting

material the reaction mixture was quenched with solid NaHCO₃.

The residue was extracted with dichloromethane (2ꢂ25 mL) and

dried over Na₂SO₄(anhyd). The crude product was puriﬁed by

column chromatography with DCM/ether 90:10 (R_f¼0.7). Yield:

1.2 g (86%). Mp 141–142 ^ꢄC. IR (ﬁlm): 3435 (s, OH, non-hydrogen

bonded), 2952, 2223 (alkyne), 1609 (C]C), 1474, 1454, 1350, 1239,

1193, 1137, 1054, 1032, 993, 899, 849, 819, 733, 564 cm^ꢀ1. ¹H NMR

820 (m). ¹H NMR (250 MHz, CDCl₃):

d 1.88 (s, 3H, p-Mes–CH₃), 1.95

(s, 6H, o-Mes–CH₃), 2.29 (s, 3H, 4-Bf–CH₃), 2.37 (s, 3H, 6-Bf–CH₃),

2.44 (s, 3H, 7-Bf–CH₃), 3.45 (s, 3H, OCH₃), 6.68 (d, 1H, J¼10 Hz,

m-aryl–H), 6.75 (s, 1H, 5-Bf–H), 6.85 (s, 2H, Mes–H), 7.32 (dd, 1H,

J¼10, 4 Hz, p-aryl–H), 7.50 (d,1H, J¼4 Hz, o-aryl–H).¹³C NMR (CDCl₃,

100 MHz):

d 11.6, 17.3, 19.1, 20.6, 21.2, 55.3, 112.5, 113.3, 117.2, 118.9,

(CDCl₃, 200 MHz):

1.21 (br s, 1H, OH), 1.63 (q, J¼6 Hz, 2H, 2-H)

123.2,125.1,126.3,127.8,128.7,130.5,132.3,133.0,136.7,137.5,146.4,

154.4, 156.5. MS (70 eV): m/z (%)¼465 (28), 464 (100), 463 (30), 462

(98). HRMS (70 eV) for C₂₇H₂₇O₂⁷⁹Br: calcd 462.1194, found:

462.1201.

2.12–2.25 (br s, coalescence, 18H, 8a-H and 8b-H), 2.36 (t, J¼6 Hz,

2H, 3-H), 3.45 (t, J¼6 Hz, 2H, 1-H), 4.84 (br s, 1H, OH), 6.80 (br s,

coalescence, 2H, 12-H), 6.86 (br s, coalescence, 2H, 13-H). ¹³C NMR

(CDCl₃, 50 MHz):

130.7, 132.4, 135.3, 135.7, 137.0, 138.2, 139.4. Elemental analysis for

C₂₅H₃₀O₂(362.5): calcd C 82.83%, H 8.34%, found C 82.30%, H 8.66%.

21.9, 22.1, 31.5, 62.2, 78.3, 93.4, 120.8, 129.8,

Crystal structure determination of E29: colorless crystals, size

1.60ꢂ0.90ꢂ0.70 mm³. C₃₂H₄₆O₂Si (M_r¼490.8), triclinic, space

group Pꢀ1 with a¼8.407(2) Å, b¼14.957(3) Å, c¼25.124(5) Å,

¼80.63(3)^ꢄ,

¼80.70(3)^ꢄ,

¼74.22(3)^ꢄ, V¼2976.6(11) Å³, Z¼4,

6.12. 2-(n-Butyl)-3-mesityl-4,6,7-trimethylbenzofuran (B6)

D_calcd¼1.095 g cm^ꢀ3

¼0.71073 Å. Intensity data were measured on

an STOE-IPDS1 diffractometer. A total of 36,317 reﬂections were

Two test tubes were loaded with enol E6 (572 mg, 169

and [Fe(phen)₃](PF₆)₃(349 mg, 338 mol), then to each CH₃CN

mol)

collected to a maximum 2

value of 28.08^ꢄat 173(2) K; ꢀ11ꢅhꢅ11,

ꢀ19ꢅkꢅ19, ꢀ33ꢅlꢅ33. Data reduction and absorption correction

from equivalents.⁶⁰The structure was solved by direct methods⁶¹

and reﬁned by full-matrix least-squares on F². All non-hydrogen

atoms were given anisotropic displacement parameters; hydrogen

atoms were located from difference Fourier maps and reﬁned at

idealized positions riding on their parent atoms. The reﬁnement

(3.0 mL) was added by syringe. The oxidant solution was added to

the enol solution. After 1 min the reaction was quenched with

saturated NaHCO₃solution (2.0 mL) and extracted with CH₂Cl₂

(2ꢂ15 mL). The combined organic layer was washed twice with

saturated NaCl solution (2ꢂ10 mL) and dried over MgSO₄(anhyd).

The crude product was puriﬁed by chromatography on silica gel

(cyclohexane/CH₂Cl₂2:1) as yellow-greenish oil. Yield: 49.1 mg

(86%). IR (neat): 2922 (s, C–H), 2861 (m), 1609 (m), 1455, 1377, 1094,

converged at R1 (I>2

(I))¼0.054, wR2 (all data)¼0.1712 for 13,315

independent reﬂections and 660 variables. Min/max height in ﬁnal

F-map ꢀ0.50/0.76 e Å^ꢀ3

976, 851 (m). ¹H NMR (200 MHz, CDCl₃):

0.88 (t, J¼7 Hz, 3H, 4⁰⁰-

E29 (aP324) crystallizes triclinic in the space group P₁with two

CH₃), 1.35 (m, 2H, 3⁰⁰-CH₃), 1.66 (m, 2H, 2⁰⁰-CH₃), 1.85 (s, 3H, p-Mes–

CH₃), 2.02 (s, 6H, o-Mes–CH₃), 2.34 (s, 6H, 4þ6-Bf-CH₃), 2.43 (s, 3H,

7-Bf-CH₃), superimposed 2.47 (t, J¼7 Hz, 3H, 1⁰⁰-CH₃), 6.72 (s, 1H, 5-

formula units in the asymmetric unit. Intermolecular hydrogen

bonds leading to dimers were observed in the solid state.

Bf–H), 6.93 (s, 2H, Mes–H). ¹³C NMR (CDCl₃, 50 MHz):

d 11.4, 13.8,

17.1, 19.0, 20.5, 21.1, 26.4, 29.9, 114.7, 116.7, 124.8, 125.5, 127.5, 127.6,

130.1, 131.2, 136.8, 138.0, 153.4, 153.8. HRMS (70 eV) for C₂₄H₃₀O:

calcd 334.2296, found: 334.2295.

Table 10

Bond lengths, bond and dihedral angles in E29 (two formula)

Bonds

d/pm^a

d/pm^b

Angles

Angle^a/^ꢄ

Angle^b/^ꢄ

C1]C2

]C–O1

C^C

135.2

137.0

119.1

82.0

134.6

137.4

119.8

82.0

C]C–O1

C–O1–H

HOC]C

120.26

109.47

174.25

ꢀ10.58

119.70

109.47

160.35

ꢀ9.33

6.13. 2-(4-Bromophenyl)-3-mesityl-4,6,7-trimethyl-

benzofuran (B9)

O1–H

O1C]CC6

To a solution of enol E9 (30.0 mg, 68.8

mmol) in acetonitrile

Eq. 1.

Eq. 2.

(3.0 mL), a solution of [Fe(phen)₃](PF₆)₃(142 mg, 138

mmol) was

added under nitrogen. The reaction mixture was quenched with

saturated NaHCO₃(2.0 mL) and extracted with CH₂Cl₂(2ꢂ15 mL).

The combined organic layer was washed twice with saturated NaCl

solution (2ꢂ10 mL), and dried over MgSO₄. The crude product was

puriﬁed by chromatography on silica gel (cyclohexane/DCM 2:1).

Crystal structure determination of E34: colorless crystals, size

0.40ꢂ0.35ꢂ0.35 mm³. C₂₅H₃₀O₂(M_r¼362.5), triclinic, space group

Pꢀ1 with a¼8.0809(6) Å, b¼9.7154(7) Å, c¼14.4476(11) Å,

Yield: 28.7 mg (96%). ¹H NMR (200 MHz, CDCl₃):

1.86 (s, 3H,

¼82.184(2)^ꢄ,

¼81.136(1)^ꢄ,

¼69.744(1)^ꢄ, V¼1047.2(1) Å³, Z¼2,

p-Mes–CH₃), 1.99 (s, 6H, o-Mes–CH₃), 2.37þ2.38 (2s, 6H, 4- and

D_calcd¼1.150 g cm^ꢀ3

¼0.71073 Å. Intensity data were measured on

6-Bf–CH₃), 2.51 (s, 3H, 7-Bf–CH₃), 6.76 (s, 1H, 5-Bf–H), 6.97 (s, 2H,

a Bruker-AXS SMART APEXCCD diffractometer. A total of 6148 re-

Mes–H), 7.37 (s, 4H, Ar–H). ¹³C NMR (CDCl₃, 50 MHz):

11.5, 16.9,

ﬂections were collected to a maximum 2q

value of 26.4^ꢄat

19.1, 20.8, 21.3, 117.1, 121.4, 125.1, 125.4, 125.6, 127.1, 127.4, 127.7,

128.7, 129.2, 130.1, 130.5, 130.8, 132.5, 133.2, 137.2, 137.6, 146.9,

153.6. HRMS (70 eV): calcd 432.1089, found: 432.1093.

150(2) K; h ꢀ8/þ10, k ꢀ7/þ12, l ꢀ18/þ17. Data reduction and ab-

sorption correction from equivalents.⁶¹The structure was solved by

direct methods⁶²and reﬁned by full-matrix least-squares⁶²on F².

All non-hydrogen atoms were given anisotropic displacement

parameters; hydrogen atoms were located from difference Fourier

maps and reﬁned at idealized positions riding on their parent

6.14. 2-(5-Bromo-2-methoxyphenyl)-3-mesityl-4,6,7-

trimethylbenzofuran (B12)

atoms. The reﬁnement converged at R1 (I>2

(I))¼0.043, wR2 (all

To a solution of enol E12 (13.4 mg, 28.8

mmol) in acetonitrile

data)¼0.121 for 4168 independent reﬂections and 252 variables.

(10.0 mL), a solution of [Fe(phen)₃](PF₆)₃(88.8 mg, 86.2

mmol) in

Min/max height in ﬁnal

F-map ꢀ0.18/0.22 e Å^ꢀ3

10854

M. Schmittel et al. / Tetrahedron 65 (2009) 10842–10855

Chiba, K. Org. Lett. 2009, 11, 1033–1035; (e) Moeller, K. D. Synlett 2009, 1208–

Table 11

1218.

Bond lengths d, bond and dihedral angles in E34

13. Enol silanes: (a) Schmittel, M.; Keller, M.; Burghart, A. J. Chem. Soc., Perkin Trans.

2 1995, 2327–2333; (b) Einaga, H.; Nojima, M.; Abe, M. Main Group Met. Chem.

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J. Org. Chem. 2007, 72, 5486–5492; (l) Avetta, C. T.; Konkol, L. C.; Taylor, C. N.;

Dugan, K. C.; Stern, C. L.; Thomson, R. J. Org. Lett. 2008, 10, 5621–5624.

14. Enol esters: (a) Shono, T.; Matsumura, Y.; Nakagawa, Y. J. Am. Chem. Soc. 1974,

96, 3532–3536; (b) Shono, T.; Okawa, M.; Nishiguchi, I. J. Am. Chem. Soc. 1975,

97, 6144–6147; (c) Schmittel, M.; Heinze, J.; Trenkle, H. J. Org. Chem. 1995, 60,

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7482–7488.

Bonds

d/pm

Angles

Angle/^ꢄ

C1]C2

]C–O1

C^C

134.7

137.3

119.4

84.0

C]C–O1

C–O1–H

HOC]C

OC]CC6

121.43

109.42

163.62

4.82

O1–H

The crystallographic data (excluding structure factors) have

been deposited with the Cambridge Crystallographic Data Centre as

supplementary publication nos. CCDC 752574 (E29) and 752432

(E34). Copies of the data can be obtained, free of charge, on ap-

plication to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: þ44

(0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).

Acknowledgements

For generous ﬁnancial support we are indebted to the DFG

(priority programdRadicals in enzymatic catalysis), the BASF (fel-

lowship to M.R.), the Volkswagen-Stiftung, the Fonds der Chem-

ischen Industrie and University of Siegen. We thank Prof. Dr. J. P.

Dinnocenzo (Rochester) for help with the magnetic susceptibility

measurements.

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Supplementary data

Supplementary data associated with this article can be found in

online version at doi:10.1016/j.tet.2009.10.039.

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