Lithium phosphonate umpolung catalysts: Do fluoro substituents increase the catalytic activity?

Article abstract of DOI:10.3762/bjoc.7.138

Fluorinated and nonfluorinated phosphonates are employed as precatalysts in lithium phosphonate catalyzed cross benzoin couplings. Surprisingly, a decreased catalytic activity for the fluorinated precatalysts compared to the nonfluorinated systems is observed. Furthermore, the ring size of six, seven and nine membered ring catalysts appears not to be crucial for their catalytic activity.

Full text of DOI:10.3762/bjoc.7.138

Lithium phosphonate umpolung catalysts: Do fluoro
substituents increase the catalytic activity?
Anca Gliga, Bernd Goldfuss* and Jörg M. Neudörfl
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1189–1197.
Department für Chemie, Universität zu Köln, Greinstr. 4, D-50939
Köln, Germany
doi:10.3762/bjoc.7.138
Received: 09 June 2011
Accepted: 17 August 2011
Published: 31 August 2011
Email:
Bernd Goldfuss* - goldfuss@uni-koeln.de
* Corresponding author
Associate Editor: M. Rueping
Keywords:
© 2011 Gliga et al; licensee Beilstein-Institut.
License and terms: see end of document.
benzoin coupling; catalytic activity; fluoro effects; lithium
phosphonates; umpolung
Abstract
Fluorinated and nonfluorinated phosphonates are employed as precatalysts in lithium phosphonate catalyzed cross benzoin
couplings. Surprisingly, a decreased catalytic activity for the fluorinated precatalysts compared to the nonfluorinated systems is
observed. Furthermore, the ring size of six, seven and nine membered ring catalysts appears not to be crucial for their catalytic
activity.
Introduction
Since the discovery of the cyanide catalyzed benzoin reaction mechanisms, show comparable activities for lithium phospho-
by Liebig and Wöhler in 1832 [1], acyloin-type reactions nate and cyanide [19,20].
evolved as powerful tools for couplings of acylanion equiva-
lents with carbon electrophiles. In addition to cyanide [2-5] and Recently, we introduced fenchol based phosphonates as precata-
nucleophilic carbene catalysts (e.g. thiazolium salts) [6-17], lysts, which are similarly accessible as fencholate metal cata-
lithium phosphonates were found to catalyze cross acyloin type lysts [21-25], in the benzoin coupling (Scheme 2) [26]. A strong
couplings of acylsilanes with aldehydes [18]. The catalytic increase of the catalytic activity was observed for a benzylic
cycle proposed by Johnson et al. [18] (Scheme 1) suggests that fencholate, when the benzylic positions were occupied by CF3-
a potential metallophosphonate catalyst must act as a nucleo- groups (92% versus 19% yield, Scheme 2) [26]. This increased
phile, an anion (d1-synthon) stabilization group, and as well as a reactivity is thought to arise from a favored formation of the
leaving group (nucleofuge). Comparative computational assess- carbanionic d1-synthon intermediate, due to the electron with-
ments of carbanionic d1-species, which have been proposed as drawing effect of the CF3 groups. A comparison of fluorinated
crucial intermediates according to the Lapworth and Breslow and nonfluorinated TADDOL phosphonates (which were used
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Beilstein J. Org. Chem. 2011, 7, 1189–1197.
Scheme 1: Proposed catalytic cycle of the lithium phosphonate catalyzed cross benzoin coupling [18].
by Johnson's group) as precatalysts in benzoin coupling does ized with diol 4 [27] and the analogous nonfluorinated
not show any difference in reactivity (Scheme 2). In contrast the 2-(hydroxymethyl)phenol (5) as precursor.
enantioselectivity is clearly higher with the fluorinated
TADDOL precatalyst (Scheme 2).
Biphenyl-based fluorinated and nonfluorinated systems (6 [28-
30], 7 and 8, Scheme 3) were chosen as precursors for the syn-
Here, we analyze the effect of fluoro substituents on the thesis of nine ring phosphonates. The synthesis of these diols
catalytic activity by using different fluorinated and nonfluori- was realized by a double ortho lithiation of biphenyl and subse-
nated phosphonates as precatalysts in the benzoin coupling.
quent addition to the corresponding carbonyl compound. By
this procedure, two asymmetric carbon centres and a chiral axis,
which is fixed by intramolecular hydrogen bonds (6: Intramole-
Results and Discussion
As precursors for six, seven and nine membered ring phospho- cular O1–O2 distance 2.83 Å, 7: Intramolecular O1–O2 dis-
nates, diols 1–4, and 6–8 were synthesized (Scheme 3). The tance 2.81 Å, Figure 1 and Figure 2, respectively), are gener-
synthesis of diol 1 was conducted by an ortho lithiation of ated. Chiral HPLC and X-ray analyses revealed one pair of
1,1,1,3,3,3-hexafluoro-2-phenylpropan-2-ol and subsequent enantiomers for diol 6 and 7 (HPLC (Daicel-OD-H, 90:10
addition of the in situ generated carbanion to formaldehyde. For n-hexane/isopropanol; flow 0.5 mL/min): 6: tR1 = 10.4 min; tR2
comparison, a nonfluorinated diol precursor 2 was synthesized. = 13.2 min (racemate); 7: tR = 22.1 min; X-ray structures shown
Diol 3 was used as the precursor to investigate the influence of in Figure 1 and Figure 2, respectively) and an additional meso
aromatic fluoro substituents. Six ring phosphonates were real- product for diol 8 (HPLC: tR2 = 22.4 min; tR3 = 30.6 min (race-
Scheme 2: Phosphonate as precatalysts in benzoin coupling [18,26].
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Beilstein J. Org. Chem. 2011, 7, 1189–1197.
Scheme 3: Synthesis of diols 1–4, 6–7; diol 5 is commercially available.
Figure 1: X-ray crystal structure of 6. (M)-(S,S) and (P)-(R,R) pair of enantiomers; intermolecular O1–O2 distance 2.81 Å; intramolecular O1–O2 dis-
tance 2.83 Å. Ellipsoids correspond to 50% probability levels. Hydrogen atoms are omitted for clarity.
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Beilstein J. Org. Chem. 2011, 7, 1189–1197.
Figure 2: X-ray crystal structure of 7. (M)-(S,S) and (P)-(R,R) pair of enantiomers; intermolecular O1–O2 distance 2.80 Å; intramolecular O1–O2 dis-
tance 2.81 Å. Ellipsoids correspond to 50% probability levels. Hydrogen atoms are omitted for clarity.
mate); tR1 = 9.1 min). A dimer associated by a hydrogen bond is The conformational stability of the biphenyl axis can be demon-
apparent for the enantiomeric pair (6: intermolecular O1–O2 strated by the energy difference of the optimized structures
distance 2.81 Å, 7: intermolecular O1–O2 distance 2.80 Å, (B3LYP 6-31G*) (Table 1) (between (M)-(S,S); (P)-(R,R) and
Figure 1 and Figure 2, respectively). The favored formed enan- (P)-(S,S); (M)-(R,R) for 6 Erel = 3.6 kcal/mol; for 7 Erel = 4.3
tiomeric pair has the same configuration (R,R or S,S) for both kcal/mol). The alternative diastereomers, with different configu-
benzylic carbon centres, which defines the conformation of the rations at the benzylic carbon (M)-(R,S); (P)-(R,S), are energeti-
biphenyl axis (M(inus) for S,S and P(lus) for R,R).
cally disfavored (Table 1). For these diastereomers two possible
Table 1: Optimized structures of diols 6 and 7.
diol 6
(M)-(R,S);
(P)-(R,S)
R→Sa
(M)-(R,S);
(P)-(R,S)
S→Ra
diastereomer
(M)-(S,S); (P)-(R,R)
(P)-(S,S); (M)-(R,R)
Erel [kcal/mol]b
0
+3.6
+1.8
+1.4
diol 7
(M)-(R,S);
(P)-(R,S)
R→Sa
M)-(R,S);
(P)-(R,S)
S→Ra
diastereomer
(M)-(S,S); (P)-(R,R)
(P)-(S,S); (M)-(R,R)
Erel [kcal/mol]b
0
+4.3
+4.4
+4.7
aDirection of hydrogen bond; bB3LYP 6-31G*.
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Beilstein J. Org. Chem. 2011, 7, 1189–1197.
directions of the hydrogen bond were considered, that is (M)-
(R,S); (P)-(R,S) with the hydrogen bond from S→R giving Erel
= 1.4 kcal/mol and (M)-(R,S); (P)-(R,S) with the hydrogen bond
from R→S giving Erel = 1.8 kcal/mol for 6; equivalently Erel =
4.7 kcal/mol and Erel = 4.4 kcal/mol in the respective cases for
7. Similar biphenyl conformation stabilities were found for 1,1′-
biphenyl-2,2′-bisterpenols (terpenol moiety: (−)-Fenchol, (−)-
menthol, (−)-verbenol und (−)-carvol) [31,32]. The energy
differences of the terpene-based conformers are between 5.1
and 5.8 kcal/mol [32,33] (B3LYP/6-31++G**:AM1).
Scheme 4: Synthesis of phosphonates 9–15.
phonates (Table 2). In general, 1J(P–H) coupling constants
increase with the electronegativity of the substituents [33]. The
The conversion of diols 1–5, 7, and 8 to the desired phospho- influence of electronegativity results from the change in s-char-
nates can be achieved by twofold addition to phosphorus acter, given that the Fermi-contact is the dominant coupling
trichloride and subsequent hydrolysis. Diol 6 could not be mechanism [33]. According to Bent’s rule [34] electron with-
converted under the employed conditions (Scheme 4).
drawing substituents require more p-character in the bonding
orbitals, which leads to an increased s-character in the bonding
The strong inductive effect of the fluoro substituents is clearly P–H orbital. The smallest influence on the coupling constant is
visible from the 1J(P–H) coupling constants, which are signifi- apparent for phosphonate 11, in which the fluoro substituents
cantly increased compared to the nonfluoro-substituted phos- are not in close proximity to the phosphorous atom (five bonds
Table 2: 1J(P–H) coupling constants for phosphonates 9–15.
seven membered ring
phosphonate
9
10
11
1J(P–H) [Hz]
705.3
755.0
720.0
six membered ring
phosphonate
12
13
1J(P–H) [Hz]
723.0
758.0
nine membered ring
phosphonate
14
15
1J(P–H) [Hz]
713.2
754.7
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Beilstein J. Org. Chem. 2011, 7, 1189–1197.
distance). The largest 1J(P–H) coupling constant was detected The lithium phosphonate catalyzed benzoin reaction (Scheme 5)
for phosphonate 13. Thereby an additional electron with- with phosphonates 9–15 as precatalysts led to the benzoin prod-
drawing effect of the phenoxy group causes the further increase uct in low to moderate yields (5–44%) (Figure 5). The supposed
in the 1J(P–H) coupling constant. All synthesized phosphonates increase in catalytic activity, which was observed for fenchol-
were identified by 31P NMR, especially characteristic are the based phosphonate (Scheme 2) [21] with fluoro-substituted
phosphorus–hydrogen and phosphorus–fluoro couplings.
phosphonates as precatalysts, could not be confirmed. The
highest yield was achieved with phosphonate 14 as precatalyst
For phosphonates 14 and 15 (Figure 3) a doublet splitting (44%). Contrary to expectations this yield is twice as high as the
caused by the 1J(P–H) coupling ~700 Hz was observed in the yield achieved with phosphonate 15. The reduction of the
31P NMR spectra. The protons in the benzylic position (phos- nucleophilic character of the phosphorus nucleophile in the first
phonate 14) effect a 3J(P–H) coupling (12.5 Hz) and the CF3 step of the catalytic cycle, and of the d1-synthon in the third
groups in this position (phosphonate 15) a 4J(P–F) coupling step of the catalytic cycle (Scheme 1), could explain these
(14.3 Hz) (Figure 3).
results. The increased 1J(P–H) coupling constants for the CF3
substituted phosphonates (10, 13, 15, Table 2) suggest an
A crystal structure was obtained for phosphonate 15, which increase in s-character at the phosphorus atom, which confirms
shows the (M)-(R,S) diastereomers (Figure 4).
a reduction in nucleophilic character. In contrast to the fenchol-
Figure 3: 31P NMR of phosphonate 14 (a) and 15 (b).
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Beilstein J. Org. Chem. 2011, 7, 1189–1197.
Figure 4: X-ray crystal structure of 15. (M)-(R,S) diastereomer; ellipsoids correspond to 50% probability levels. Hydrogen atoms are omitted for
clarity.
Scheme 5: Lithium phosphonate catalysts in cross benzoin coupling.
based phosphonates [26] the best result was achieved by a nine phosphorus lone pair in the active anionic catalysts [33]. A rise
membered ring phosphonate instead of a seven membered ring of catalytic activity due to the inductive effect of CF3
phosphonate. It can be concluded that the ring size is not of substituents, as was observed before for a fenchol-based phos-
basic importance to the catalytic activity.
phonate (Scheme 2) [26], was not realized with the phospho-
nates employed herein. Instead a reduction of catalytic activity
was apparent with fluorinated phosphonates compared to the
Conclusion
Three types of cyclic fluorinated and nonfluorinated phospho- nonfluorinated phosphonates. This can be explained by a
nates were synthesized and used as precatalysts in cross benzoin weaker nucleophilic character of the phosphorus nucleophile, as
couplings with yields ranging from 5 to 44%. The inductive a consequence of the increased s-character. Comparisons of
effect of CF3 substituents in benzylic position of phosphonates phosphonates with different ring sizes show that the nine ring
10, 13 and 15 gives rise to increased 1J(P–H) couplings in P–H phosphonates result in higher yields than do the six and seven
precatalysts and hence points to increased s-character at the ring phosphonates.
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Figure 5: Phosphonate precatalysts 9–15 in cross benzoin coupling.
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