[Molecules: 9] [Related articles/posters: 035 101 037 062 046 ]

From flatland to prochiral metalation. Aiming for new synthetic methodologies for aromatics and heteroaromatics

Victor Snieckus

The Guelph-Waterloo Centre for Graduate Work in Chemistry, University of Waterloo, Waterloo, Ontario, N2L 3G1, Canada

This cyperspace multilogue will concentrate on recent developments from our laboratories in a) extension of directed remote metalation (DreM) protocol for the regioselective synthesis of dibenzophosphorinones; b) anionic homo-Fries rearrangements for the construction of benzofuranones; c) sparteine-induced enantioselective lateral metalation of ortho-ethyl aryl O-carbamates and d) sparteine-mediated enantioselective metalation of diverse ferrocenes with planar chirality.

Updates of these areas are given schematically below and questions are raised for discussion.

(a) Regiospecific and general route to dibenzo[b,e]phosphorinones via anionic Friedel-Crafts and remote Fries rearrangement synthetic equivalents

As a rational extension of our DreM approach to thioxanthenone dioxides,1 we have prepared a variety of the analogous dibenzo[b,e]phosphorinones,2 a heretofore sparsely investigated class of compounds. (Scheme 1).

Scheme 1

ortho-Protected O-carbamoyl substrates undergo LDA-induced remote ring-to-ring carbamoyl migration followed by concomitant regioselective anionic cyclization to substituted phenyl dibenzo[b,e]-phosphorinones in moderate to good yield (Scheme 2).

Scheme 2

Of particular note is the double anionic-Friedel-Crafts equivalent to construct the pentacyclic phosphine oxide (Scheme 3), a possible starting point for novel ligand preparation. The biological profile of these systems is largely unknown. The dibenzophosphepinones, analogues of dibenzazepin antidepressents are also conveniently obtained.

Scheme 3

A carboxylate precursor (Scheme 4), prepared by two different routes, could be smoothly cyclized to give the parent tricycle in 75% yield, thereby enhancing the practical nature of this new chemistry.

Scheme 4

(b) Anionic homo-Fries rearrangements for the construction of benzofuranones

In 1983, the anionic equivalent of the ortho-Fries rearrangement of aryl O-carbamates was discovered in the context of their directed ortho metalation (DoM) chemistry.3 Recently, we have found an LDA-promoted O -> C carbamoyl transposition of methyl/benzyl-phenyl-O-carbamates, methylnapthyl-O-carbamates, and methylpyridyl-O-carbamates to provide a regiospecific and general route to hydroxyarylacetamides; this transposition reaction, in turn, permits an equally comprehensive new synthesis of 2(3H)-benzofuranones, naphthofuranones and 2(3H)-furopyridinones.(Scheme 5).

Scheme 5

(c) Sparteine-induced enantioselective lateral metalation of ortho -ethyl aryl O-carbamates

Stimulated by the results of Beak4 and Hoppe5 demonstrating that (-)-sparteine is an effective ligand for high asymmetric induction in lithiation-substitution reactions, we have initiated lateral metalation studies on 1-3 (Scheme 6).

Scheme 6

The 6-substituent in 1 and 2 is required to avoid competitive aryl C-H deprotonation.3a The 5-TBS carbamate 3 is designed to prevent 6-deprotonation (Scheme 7).

Scheme 7

Optimal conditions for lateral lithiation for carbamates 1 and 2 have been established (Scheme 8). Table 1 summarizes results of our current studies.

Scheme 8

Table 1 BusLi / (-)-sparteine-induced metalation of O-carbamate 2. Electrophiles, yields and enantioselectivities

A significant enantioenrichment based on remote silicon functionalization (3) predicted by molecular modelling and correlated with aryl C-O bond rotational barriers has been achieved (Figure 1)

Encouraged by these results, carbamate 3 was comprehensively studied by variation of reaction parameters and the optimum conditions were applied for generalization. The results are given in Scheme 9 and Table 2.

Scheme 9

Table 2 BusLi / (-)-sparteine-induced metalation of carbamate 3. Electrophiles, yields and enantioselectivities

(d) Sparteine-mediated enantioselective metalation of diverse ferrocenes with planar chirality

Ferrocene derivatives with planar chirality6a are of increasing significance in areas of asymmetric catalysis,6b enantioselective synthesis,6c and materials science.6d Methods for diastereoselective preparation of chiral ferrocenes using chiral directed metalation groups (DMGs) have been accumulating.7 In early 1996, we reported the first highly enantioselective synthesis of ferrocene derivatives with planar chirality by way of (-)-sparteine-mediated directed ortho metalation (DoM) of N,N-diisopropylferrocene-carboxamide (7).8

Almost simultaneously, Uemura reported N,N,N',N'-tetramethyl-1R,2R-cyclohexane-diamine as a chiral ligand in dimethylaminomethylferrocene metalation.9

Using the (-)-sparteine-induced metalation procedure we have prepared a variety of chiral ferrocenes 8 in excellent yield and with high enantioselectivity (Scheme 10) and (Table 3).

Scheme 10

Table 3 BuLi / (-)-sparteine induced metalation of N,N-diisopropyl ferrocenecarboxamide 7. Electrophiles, yields and enantioselectivities

The absolute configuration was established by single-crystal X-ray crystallographic analysis (Figures 2(a) and 2(b)).

<a href="0000024b.pdb"><IMG SRC="00000238.gif"></a>

We are currently investigating the use of the (-)-sparteine/BuLi complex in other ferrocene-DMG systems, e.g. the diethyl carbamate (-OCONEt2) (9) and diphenylphosphine oxide (-POPh2) (13). Preliminary metalation results of carbamate 9 are shown in Scheme 11 and Table 4.

Scheme 11

Table 4 Preliminary metalation results of carbamate 9

Preliminary metalation results of ferrocenylphosphine oxide 13 are specified in Scheme 12 and Table 5.

Scheme 12

Table 5 Metalation of ferrocenylphosphine oxide 13

Work in the design and synthesis of new chiral ferrocene derivatives and their application in catalysis is under active investigation.


  1. Beaulieu, F.; Snieckus, V. J. Org. Chem. 1994, 59, 6508.
  2. Gray, M.; Chapell, B. J.; Taylor, N. J.; Snieckus, V. Angew Chem. 1996, in press.
  3. (a) Sibi, M.P., Snieckus, V., J. Org. Chem., 1983, 48, 1935; (b) Snieckus, V., Chem. Rev., 1990, 90, 879.
  4. (a) Thayumanavan, S.; Lee, S.; Liu, C.; Beak, P. J. Am. Chem. Soc. 1994, 116, 9755; (b) Beak, P.; Kerrick, S.T.; Wu, S.; Chu, J. J. Am. Chem. Soc. 1994, 116, 3231 and references cited therein.
  5. Hoppe, D.; Hintze, F.; Tebben, P.; Paetow, M.; Ahrens, H.; Schwerdtfeger, J.; Sommerfeld, P.; Haller, J.; Guarnieri, W.; Kolczewski, S.; Hense, T.; Hoppe, I. Pure Appl. Chem. 1994, 66, 1479.
  6. (a) Togni, A.; Hayashi, T.; Eds. Ferrocenes: Homogeneous Catalysis, Organic Synthesis, Materials Science ; VCH: Weinheim, 1995; (b) Sawamura, M.; Ito, Y. Chem. Rev. 1992, 92, 857; (c) Nicolosi, G.; Patti, A.; Morrone, R.; Piattelli, M. Tetrahedron: Asymmetry 1994, 5, 1639; (d) Lion-Dagan, M.; Marx-Tibbon, S.; Katz, E.; Willner, I. Angew. Chem., Int. Ed. Engl. 1995, 34, 1604.
  7. (a) Marquarding, D.; Klusacek, H.; Gokel, G.; Hoffmann, P.; Ugi, I. J. Am. Chem. Soc. 1970, 92, 5389; (b) Rebière, F.; Riant, O.; Ricard, L.; Kagan, H.B. Angew. Chem. Int. Ed. Engl. 1993, 32, 568; (c) Riant, O.; Samuel, O.; Kagan, H.B. J. Am. Chem. Soc. 1993, 115, 5835; (d) Richards, C.J.; Damalidis, T.; Hibbs, D.E.; Hursthouse, M.B. Synlett 1995, 74; (e) Nishibayashi, Y.; Uemura, S. Synlett 1995, 79; (f) Sammakia, T.; Latham, H.A.; Schaad, D.R. J. Org. Chem. 1995, 60, 10.
  8. Tsukazaki, M.; Tinkl, M.; Roglans, A.; Chapell, B.J.; Taylor, N.J.; Snieckus, V. J. Am. Chem. Soc. 1996, 118, 685.
  9. Nishibayashi, Y.; Arikawa, Y.; Ohe, K.; Uemura, S. J. Org. Chem. 1996, 61, 1172.