Generation of strong, homochiral bases by electrochemical reduction of phenazine derivatives

Article abstract of DOI:10.1039/b313995f

Electrochemical reduction of enantiomerically pure amino- and alkoxy-phenazine derivatives forms strongly basic radical anions which give asymmetric induction in the conversion of 3,4-epoxytetrahydrothiophene-1,1- dioxide 7 into the allylic ester 9 with f

Full text of DOI:10.1039/b313995f

Generation of strong, homochiral bases by electrochemical reduction of
phenazine derivatives†
A. Mateo Alonso, Roberto Horcajada, Helen J. Groombridge, Reshma Mandalia, Majid Motevalli,
James H. P. Utley* and Peter B. Wyatt*
Department of Chemistry, Queen Mary, University of London, Mile End Road, London, UK E1 4NS.
E-mail: p.b.wyatt@qmul.ac.uk; j.utley@qmul.ac.uk; Fax: 44 20 78827794; Tel: 44 20 78823267
Received (in Cambridge, UK) 4th November 2003, Accepted 18th December 2003
First published as an Advance Article on the web 20th January 2004
Electrochemical reduction of enantiomerically pure amino- and
alkoxy-phenazine derivatives forms strongly basic radical
anions which give asymmetric induction in the conversion of
3,4-epoxytetrahydrothiophene-1,1-dioxide 7 into the allylic
ester 9 with facile regeneration of the phenazine.
The first and second E0 values of 21.10 and 22.05 V in DMSO vs.
SCE, observed for compound 6a, are typical and indicate the
feasibility of generating phenazine radical anions in the presence of
other reactants.
+
Reaction between an added carbon acid such as Ph3PCH3 and
the radical-anion formed at the first reduction potential results in
loss of reversibility of the first peak and a consequent doubling of
the peak height. This is characteristic of the well established DISP
mechanism, set out in steps (1) to (4) as follows, in which the
second electron transfer (step 3) involves a second equivalent of the
radical-anion.
Electrochemical reduction of neutral substrates (‘probases’) gen-
erates radical-anions and dianions which may be used as bases in
synthetic transformations.1 Previous studies have shown that the
radical-anion of phenazine is able to deprotonate phosphonium ions
+
such as Ph3PCH3 at conveniently measurable rates.2 There have
not hitherto been any descriptions of the use of electrogenerated
bases in asymmetric reactions. We now report the synthesis of some
C2-symmetric homochiral phenazine derivatives, the radical-anions
of which exhibit enantioselectivity in the rearrangement of a
prochiral epoxide.
The known3 1,6-dichlorophenazine 1 underwent palladium-
catalysed amination with chiral amines to give enantiomerically
pure 1,6-diaminophenazine derivatives 2 (Scheme 1).
Phen + e2 ? Phen·2
Phen·2 + HA ? HPhen· + A2
HPhen· + Phen·2 ? HPhen2 + Phen
HPhen2 + HA ? H2Phen + A2
(1)
(2)
(3)
(4)
It is of note that although each phenazine undergoes reduction to
a 5,10-dihydrophenazine product in the course of acting as an
Readily available4 1,6-dimethoxyphenazine underwent quantita-
tive conversion into 1,6-dihydroxyphenazine 3 using hot BBr3.
Cyclophane systems were obtained by alkylation of 3 using
terminal diiodides under conditions of high dilution (Schemes 2 and
3). Thus the planar chiral compound 4 was initially obtained as a
racemate, as shown by chiral HPLC; resolution of 4 was achieved
through flash chromatographic separation of the diastereoisomeric
N-acyldihydrophenazines, 5a and 5b, followed by acid hydrolysis
and re-aromatisation. Use of an enantiomerically pure bis-
alkylating agent derived from (R,R)-cyclohexane-1,2-diol, fol-
lowed by chromatographic separation, gave the two bridged
phenazines 6a and 6b as pure stereoisomers. Single crystal X-ray
diffraction studies were performed on compounds (2)-(pS)-4, 5b,
6a and 6b and the sense of planar chirality in these substances was
thus defined relative to the established central chirality, which is
derived from (R,R)-cyclohexane-1,2-diol and (R)-a-methoxyphe-
nylacetic acid.‡
Cyclic voltammetry in aprotic solvents showed the phenazine
derivatives to be reduced in two one-electron steps, the first being
chemically reversible at modest scan rates ( < 1 V s21) and the
second becoming reversible at higher scan rates (up to 100 V s21).
Scheme 2 Reagents and conditions: (i) I[CH2CH2O]3CH2CH2I, K2CO3,
DMF, 80 °C, 30 h, 14%; (ii) H2 (balloon), 10% Pd–C, CH2Cl2, 20 °C, 30
min; then (R)-a-methoxyphenylacetyl chloride (3.1 equiv.), pyridine (3.8
equiv.), 14% for 5a and 19% for 5b; (iii) 1.3 M HCl, EtOH–H2O (2 : 1),
reflux, 3 d, 31%; (iv) 6.7 M HCl, EtOH–H2O (2 : 1), reflux, 7 d, 34%.
Scheme 1 Reagents and conditions: (i) RCH(Me)NH2 (2.2 equiv.), t-
BuONa (2.4 equiv.), Pd2(dba)3 (2 mol%), (R)-(2)-BINAP (5 mol%),
toluene, 99% (R = Ph) or 55% (R = 1-naphthyl).
† Electronic supplementary information (ESI) available: procedure for
conversion of 7 into 9 using electrochemical reduction of 6a to generate the
chiral base; crystallographic data for (pS)-4, 5b, 6a and 6b. See http://
www.rsc.org/suppdata/cc/b3/b313995f/
Scheme 3 Reagents and conditions: (i) (R,R)-1,2-bis(3-iodopropoxy)-
cyclohexane, K2CO3, DMF, 80 °C, 30 h, 5% for 6a and 5% for 6b.
412
C h e m . C o m m u n . , 2 0 0 4 , 4 1 2 – 4 1 3
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

reaction conditions. The ester product 9 was isolated by flash
chromatography and its ee was determined by chiral HPLC (Table
1). Phenazine derivatives were recovered by air oxidation and
chromatography.
We have established the principle that bases formed by
electrochemical reduction of chiral phenazines with either amino or
alkoxy substitution are able to effect rearrangement of the epoxide
7 with modest, but significant, enantiomeric excess. Greatest
selectivity is seen with the bridged compounds 6a and 6b, although
the data suggest that the stereochemical outcome is controlled more
by the presence of chiral centres than by the planar chirality.
Addition of Lewis acidic metal salts was examined: Li+ increased
the yields of rearrangement product but did not improve the best ee
values, whereas Mg2+ and Yb3+ salts were unhelpful, perhaps
because they introduced water as a competing proton source.
We thank Queen Mary, University of London (studentship for
R.H.), the EPSRC (A.M.A. project studentship and MS measure-
ments at the National Mass Spectrometry Service Centre, Swan-
sea), the EPSRC National Crystallography Service for data
collection and the Nuffield Foundation (H.G., Undergraduate
Research Bursary) for support.
Scheme 4
Table 1 Conversion of epoxide 7 into ester 9 using electrogenerated
basesa
Yield
of 9
Recovery
of probase
Probase
Additiveb
eec of 9
(R,R)-2a
(S,S)-2a
(R,R)-2b
(+)-(pR)-4
(+)-(pR)-4
(2)-(pS)-4
6a
6a
6a
6a
6a
—
—
—
—
LiClO4
—
—
LiClO4
—
—
50d
50d
63
33
53
38
43
77
39
48d
0
+8
28
72
+18
< 10
+20
< 10
+34
+28
+32
+28
74
71
78
57
100
100
100
67
Notes and references
‡ Crystal data for (2)-(pS)-4. C20H22N2O5, M = 370.40, Orthorhombic, a
= 10.0266(3), b = 11.8433(4), c = 14.9627(5) Å, a = 90.00, b = 90.00,
g = 90.00°, V = 1776.79(10) Å3, space group P212121, Z = 4, Dc = 1.385
Mg m23, m = 0.100 mm21, reflections measured 14029, reflections unique
4047 with Rint = 0.0493, T = 120(2) K, final R indices [I > 2 S(I)] R1 =
0.0412, wR2 = 0.0841 and for all data R1 = 0.0661, wR2 = 0.0927. Crystal
data for 5b. C29H31N2O7, M = 519.56, Monoclinic, a = 8.429(7), b =
15.650(14), c = 9.980(9) Å, a = 90.00, b = 105.40(4), g = 90.00°, V =
1269.2(19) Å3, space group P21, Z = 2, Dc = 1.271 Mg m23, m = 0.098
Yb(OTf)3
—
LiClO4
Mg(OTf)2
6b
6b
6b
63
72
19
+16
+24
< 10
100
80
100
a Experiments were conducted in DMSO with Bu4NPF6 as supporting
electrolyte unless indicated otherwise. b 3 equiv. relative to probase.
c Determined by chiral HPLC on Daicel Chiralpak OT-(+) eluted with 9 : 1
hexane : propan-2-ol; a positive ee value indicates an excess of the (R)-
enantiomer, which we have synthesised independently and found to have a
longer retention time than the (S)-form. d DMF was used as solvent.
mm21, reflections measured 3776, reflections unique 3408 with Rint
=
0.0063, T = 160(2) K, final R indices [I > 2 S(I)] R1 = 0.0457, wR2 =
0.1151 and for all data R1 = 0.0541, wR2 = 0.1210. Crystal data for 6a.
C24H28N2O4, M = 408.48, Monoclinic, a = 7.436(11), b = 17.116 (12), c
= 8.713(13) Å, a = 90.00, b = 105.712(14), g = 90.00°, V = 1068(2) Å3,
space group P21, Z = 2, Dc = 1.271 Mg m23, m = 0.087 mm21, reflections
measured 3892, reflections unique 2938 with Rint = 0.0171, T = 160(2) K,
final R indices [I > 2 S(I)] R1 = 0.0329, wR2 = 0.07580 and for all data
R1 = 0.0485, wR2 = 0.0818. Crystal data for 6b. C24H28N2O4, M =
408.48, Orthorhombic, a = 13.3625(4), b = 16.2726(5), c = 19.4817(7) Å,
a = 90.00, b = 90.00, g = 90.00°, V = 4236.2(2) Å3, space group P212121,
Z = 8, Dc = 1.281 Mg m23, m = 0.087 mm21, reflections measured 20623,
reflections unique 8921 with Rint = 0.0818, T = 120(2) K, final R indices
[I > 2 S(I)] R1 = 0.0844, wR2 = 0.1970 and for all data R1 = 0.1842, wR2
= 0.2376. CCDC 223727–223730. See http://www.rsc.org/suppdata/cc/b3/
b313995f/ for crystallographic data in .cif or other electronic format.
electrogenerated base, regeneration of the initial phenazine is
efficiently achieved by brief air oxidation. This means that
investment in the synthesis of relatively complex phenazine
derivatives is not wasted and they can be recovered from product
mixtures.
Cyclic voltammetry and digital simulation, assuming the DISP
mechanism, allow the measurement of rate constants for the rate-
limiting proton transfer step (step 2). Self-consistent rate constant
data, which will be discussed elsewhere, were obtained over a
variety of experimental conditions (concentration of phenazine
derivative and carbon acid, cyclic voltammetric sweep speed).
The rearrangement of the epoxide 7 to the isomeric allylic
alcohol was used to test the ability of the electrogenerated chiral
bases to effect enantioselective deprotonation. This epoxide
rearrangement is known to occur in the presence of moderate bases
such as barium carbonate.5 Therefore the intermediate alkoxide 8,
which might have acted as an alternative base, was trapped by in
situ acylation (Scheme 4). 2,4,6-Trimethylbenzoic anhydride was
used for this purpose, since unlike the less hindered benzoic
anhydride, it did not react with the phenazine radical ions under the
1 J. H. P. Utley and M. F. Nielsen, Electrogenerated Bases, in Organic
Electrochemistry, Ed H. Lund and O. Hammerich, Marcel Dekker Inc.,
New York, 2001.
2 A.-P. Bettencourt, A. M. Freitas, M. I. Montenegro, M. F. Nielsen and J.
H. P. Utley, J. Chem. Soc., Perkin Trans. 2, 1998, 515–522.
3 I. J. Pacher and M. C. Kloetzel, J. Am. Chem. Soc., 1951, 73,
4958–4961.
4 E. Breitmaier and U. Hollstein, J. Org. Chem., 1976, 41, 2104–2108.
5 W. R. Sorenson, J. Org. Chem., 1959, 24, 1796–1798.
C h e m . C o m m u n . , 2 0 0 4 , 4 1 2 – 4 1 3
413