TABLE 1. Oxidative Coupling of 2 under Different
Experimental Conditions
Reactivity of Methyl
Mandelate-Ti(IV)-enediolate: Oxidative
Homocoupling versus Aldol and Direct
Mannich-Type Syn-Diastereoselective
Condensation
Angelo Clerici, Nadia Pastori, and Ombretta Porta*
molar ratio
TiCl4
yield (%)a
3 (meso/dl)
no reaction
Dipartimento di Chimica, Materiali e Ingegneria Chimica
“Giulio Natta”, Politecnico di Milano, Sezione Chimica,
Via Mancinelli 7, 20131 Milano, Italy
entry
(method)b
2
base
1
1 (i)
1
1
1
1
1
1
1
1
1
1
1
2
1
1
-
1
2
3
3
3
3
2 (i)
9 (83:17)
-
-
-
-
-
30
-
Received September 29, 2004
3 (i)
62 (80:20)
4 (i)
quant (83:17)
quant (95:5)
60 (83:17)
5 (i)
6 (i)c
7 (ii)
8 (ref 3)d
14 (only meso)
59 (92:8)
a Material balance g95%; quant means 1H NMR purity of the
crude residue is g95%; the remainder to 100% is the starting
material 2; yields and isomer ratios are calculated from the peak
area of the COOCH3 proton singlets (δ, ppm): 3-meso, 3.85; 3-dl,
3.79; 2, 3.74; 1, 3.98. b Method i: slow addition (15 min) of TiCl4
to 2 followed by the base addition (5 min). Method ii: addition of
the base (10 min) to 2 followed by TiCl4 addition (5 min.). c DIPEA
instead of TEA was used. d From 1/TiCl3/pyridine/THF.
the heterolytic cleavage of Ti(IV)-chelated diol B, afford-
ing C and the starting 1.5
In the absence of any reactive partner, both 1 and C
are partially recycled to A, the former by Ti(III) reduction
and the latter by Ti(IV) oxidation affording dimethyl 2,3-
dihydroxy-2,3-diphenylbutanedioate 3 (59%; meso/dl, 98:
2) and 2 (6%).3 Conversely, in the presence of a suitable
electrophile, C is drained from the cycle to afford 4 or
5.3-5
We now report our preliminary results on the reactivity
of C when it is directly generated from methyl mandelate
2 and TiCl4/TEA (or DIPEA, N,N-diisopropylethylamine)
at room temperature (Scheme 1, paths b). The results
obtained, either in the absence or in the presence of
electrophiles, show that the chemo- and stereoselectivity
of C generated by the previous and the present methods
are quite similar.
Oxidative Coupling of 2. When 3 equiv of TEA was
added to a CH2Cl2 solution of 2 and TiCl4 (1 equiv each),
dimer 3 is formed in quantitative yield after NH4Cl
hydrolysis of B. The amount of TEA strictly controlled
the yield of 3 (Table 1, method i, entries 1-4), whereas
the use of DIPEA resulted in a lower yield (entry 6). Two
equivalents of TiCl4 slightly improved the meso/dl ratio
(entry 5).
The reaction conditions that involve reverse order of
addition (TEA followed by TiCl4, method ii, entry 7)
furnished 1 as the main oxidation product. Both products
distribution (formation of 3 and 1) and stereoselectivity
(only 3-meso) observed are in accord with the radical
mechanism shown in Scheme 1 (paths b).
Methyl mandelate undergoes quantitative oxidative homo-
coupling on treatment with TiCl4/amine at room tempera-
ture. In the presence of ArCHO, quantitative syn-diastereo-
selective aldol condensation takes over the dimerization,
whereas exclusive Mannich-type syn-diastereoselective reac-
tion is observed in the presence of both ArCHO and PhNH2.
The subsequent reactions of the title intermediate do not
depend on how it is generated.
Scattered examples of Li-enolate and silylenol ether1
homocoupling promoted by TiCl4 have been reported.
More recently, oxidative coupling of simple Ti(IV)-eno-
lates from phenylacetic acid derivatives have appeared.2
Since Ti(IV)-enolates can play an important role in
carbon-carbon bond formation, understanding all as-
pects of their reactivities is an important goal.
In the course of our studies, we have found that TiCl3/
pyridine/THF reduction of methyl phenylglyoxylate 1, in
the presence of aldehydes or imines (formed in situ),
undergoes aldol3 or direct Mannich-type4 condensations.
According to the mechanism of Scheme 1 (paths a), we
suggested Ti(IV)-enediolate C3,4 to be the reactive inter-
mediate. Ti(III)-reductive dimerization of 1, via coupling
of the intermediate radical A, is followed in tandem by
(1) (a) Inaba, S.; Ojima, I. Tetrahedron Lett. 1977, 23, 2009-2012.
(b) Wallace, I. H. M.; Chan, T. H. Tetrahedron 1983, 39, 847-853. (c)
Ojima, I.; Brandstadter, S. M.; Donovan, R. Chem. Lett. 1992, 1591-
1594.
(2) (a) Matsamura, Y.; Nishimura, M.; Hiu, H.; Watanabe, M.; Kise,
N. J. Org. Chem. 1996, 61, 2809-2811. (b) Kise, N.; Kumada, K.; Terao,
Y.; Ueda, N. Tetrahedron 1998, 54, 2697-2708.
(3) Clerici, A.; Clerici. L.; Malpezzi, L.; Porta, O. Tetrahedron 1995,
51, 13385-13400.
(4) Clerici, A.; Clerici. L.; Porta, O. Tetrahedron Lett. 1995, 36,
5955-5958.
The Ti(IV)-enolate C, once formed from 2, is oxidized,
via metal to ligand electron transfer (ET), to the stabi-
(5) Clerici, A.; Clerici. L.; Porta, O. J. Org. Chem. 1995, 60, 480-
481.
10.1021/jo048279f CCC: $30.25 © 2005 American Chemical Society
Published on Web 03/31/2005
4174
J. Org. Chem. 2005, 70, 4174-4176