Reactions of active methylene compounds with benzhydrol during solvolysis in formic acid

Article abstract of DOI:10.1071/CH02157

Formic acid reacts with benzhydrol to give benzhydryl formate, which reacts with active methylene compounds in refluxing formic acid to give either C-alkylation or Ritter reaction products. The product formed is determined by the equilibrium enol content of the active methylene compound. These reaction conditions avoid the use of halogenated reaction solvents, and the pure products are isolated without recourse to chromatography.

Full text of DOI:10.1071/CH02157

CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2003, 56, 385–388
Reactions of Active Methylene Compounds with Benzhydrol
During Solvolysis in Formic Acid∗
Glen C. GullicksonA and David E. LewisA,B
A Department of Chemistry, University of Wisconsin—Eau Claire, Eau Claire, WI 54702–4004, USA.
B Author to whom correspondence should be addressed (e-mail: lewisd@uwec.edu).
Formic acid reacts with benzhydrol to give benzhydryl formate, which reacts with active methylene compounds
in refluxing formic acid to give either C-alkylation or Ritter reaction products. The product formed is determined
by the equilibrium enol content of the active methylene compound. These reaction conditions avoid the use of
halogenated reaction solvents, and the pure products are isolated without recourse to chromatography.
Manuscript received: 3 August 2002.
Final version: 14 November 2002.
Introduction
Ar
Ar
CO2H
CO2H
Ar
Ar
Ar
Ar
CO2H
CH2(CO2H)2
OH
Benzhydryl groups and their structural analogues form part
of the structure of a wide range of pharmaceuticals, making
methods for the incorporation of these groups into an exist-
ing carbon skeleton of relatively wide interest. For instance,
we required a convenient multi-gram synthesis of 2-alkyl-2-
cyano-3-aryl- and -3,3-diarylpropanoic acid derivatives for
use in the synthesis of a polycyclic alkaloid analogue. The
obvious method for the synthesis of these compounds, the
alkylation of cyanoacetic esters, was not easy to control with
reactive benzylic halides, which gave a mixture of the desired
compound along with recovered starting material and the
dialkylated compound in approximately equal proportions.
Potential reactant compatibility problems outside the scope
of this paper rendered the Michael addition of cuprates to
cinnamates unsuitable for this work.
150°C
(1)
(2)
(3)
Scheme 1. Solvent-free preparation of diarylpropanoic acids by Fossé.
Ar = p-HO-C6H4, p-(CH3)2N-C6H4, α-C10H7.
O
O
O
O
R1
R3
R1
R3
R
R2
X
R2
CoCl2 (0.2-0.75 eq)
o-C6H4Cl2 or CHCl3/⌬
(4)
(5)
Scheme 2. Cobalt-catalyzed preparation of diarylpropanoic acids by
Moreno-Mañas et al.
One intriguing, solvent-free method for the synthesis of
3,3-diarylpropanoic acid derivatives was reported by Fossé
in a series of papers between 1908 and 1910.[1] In these
papers, Fossé reported that the fusion of malonic acid with
a benzhyrol carrying two electron-rich aromatic rings gives
3,3-diarylpropanoic acids, Scheme 1, although the reaction
fails with benzhydrol itself.[2] Later workers showed that
the reaction does succeed with triphenylmethanol,[3] giving
3,3,3-triphenylpropanoic acid.
During the 1980s, Moreno-Mañas and his coworkers pub-
lished a series of papers on the C-alkylation of acetylacetone
by tertiary alkyl halides capable of undergoing SN1 sub-
stitution. These workers reported the cobalt(ii)-catalyzed
substitution of SN1-active alkyl halides (4) and the cor-
responding alcohols by active methylene compounds in
refluxing chlorocarbon solvents, Scheme 2.[5]
In the majority of their reports, it was the alkyl halide
which served as the alkylation substrate rather than the
alcohol. Their system for the direct substitution of alcohols
involved the use of anhydrous cobalt(ii) chloride in close to
stoichiometric quantities. The direct substitution of alcohols
in the presence of anhydrous cobalt chloride was reported
to fail in the presence of base.[5b] Based on these data, we
suggest that this reaction most likely involves the forma-
tion of the cobalt(ii) complex of the β-dicarbonyl compound,
In the 1960s, Cheeseman and his coworkers[4] revisited
the direct substitution of benzhydrol and observed that it
would react with amides, including sulfonamides, in the pres-
ence of an equimolar amount of p-toluenesulfonic acid to
give N-benzhydrylamides. Under these conditions, the ben-
zhydryl cation is almost certainly a key reactive intermediate
in the reaction.
∗ This paper is dedicated to Professor John H. Bowie on the occasion of his 65th birthday.
© CSIRO 2003
10.1071/CH02157
0004-9425/03/05385

386
G. C. Gullickson and D. E. Lewis
with concomitant formation of HCl which converts the alco-
hol to the alkyl chloride which then reacts with the metal
complex. In their initial paper,[5a] these workers had, in fact
used the pre-formed bis-acetylacetonatocobalt(ii) complexes
as substrates for the reaction with alkyl halides. The mecha-
nism of this reaction is not certain; the successful substitution
of 1-chloroadamantane by acetylacetone in the presence of
cobalt(ii) chloride suggests that it may involve free radical
intermediates.
The NMR evidence suggests that, as stated above, ben-
zhydryl formate (7) is the actual substrate for the reaction,
making formation of this ester critical to the success of the
substitution reaction. Evidence that this may be the case was
obtained by changing the reaction solvent for the reaction
between benzhydrol and acetylacetone to acetic acid, an ion-
izingsolventthatdoesnotconvertalcoholstoestersatauseful
rate in the absence of a strong acid catalyst. Under these con-
ditions, the formation of the substitution product was slowed
by much more than an order of magnitude (<5% conver-
sion after 48 h). This gives additional support to the postulate
that the initial esterification of the alcohol by formic acid is
critical to its success, and that the substitution reaction pro-
ceeds by solvolysis of the formate ester (7) to the benzhydryl
cation (8), which is then trapped by the enol form of the
active methylene compound. Of course, it must be borne in
mind that the observation may simply reflect the difference
in ionizing ability of the solvents: the Grunwald–Winstein
Y values[6] for the two solvents are very different (2.05 for
HCO2H and –1.64 for CH3CO2H), and could be consistent
with differences of up to three orders of magnitude in the
rates of solvolysis of similar substrates.
Results and Discussion
The simplicity of the Fossé reaction rendered it an attrac-
tive method for preparing some of the compounds which we
required. However, most of these compounds did not carry
two electron-rich aromatic rings. Therefore, in order to test
whether both electron-rich aromatic rings are essential for
the reaction to succeed, we attempted the reaction between
1-naphthylphenylmethanol and malonic acid, Fossé having
shown that the reaction succeeds when both aryl groups
are α-naphthyl.[1] The reaction failed, from which it may be
inferred that both electron-rich aromatic groups are, in fact,
essential for the reaction to occur.
This reaction was carried out with six active methylene
compounds chosen to exhibit the full range of common struc-
tural types: diethyl malonate (10) and Meldrum’s acid (11),[7]
β-diesters with very different equilibrium enol contents; ethyl
acetoacetate (12), a β-ketoester; ethyl cyanoacetate (13), an
α-cyanoester; acetylacetone (14), a β-diketone; and malonon-
itrile (15), an α-cyanonitrile. The results of the reactions are
gathered in Table 1.
Severalofthe3,3-diarylpropanoicacidsneededinourown
work carried no electron-releasing group in either ring, mak-
ing benzhydrol itself a good test compound to develop the
alkylation reaction. Although Cheeseman had reported suc-
cessful substitution of benzhydrol,[4] other functional groups
in our target molecule were potentially too sensitive to strong
acids (either sulfonic acids or hydrogen chloride) to use this
reaction. Even so, the results of Cheeseman[4] and Moreno-
Mañas[5] did suggest that direct substitution of benzhydrol
by the SN1 mechanism might provide a useful entry into
benzhydryl derivatives provided that suitable substrates and
reaction conditions could be identified. The formate ester in
the strongly ionizing solvent, formic acid, offered one such
possiblecombination.Accordingly, thereactionbetweenben-
zhydrol and active methylene compounds was studied using
formic acid as a strong ionizing solvent and a modest acid
catalyst. Each reaction was carried out by heating approxi-
mately 1 M solutions of benzhydrol and the active methylene
compound in formic acid under reflux.
The reactions of benzhydrol with ethyl acetoacetate (12)
and acetylacetone (14) gave the expected β-dicarbonyl com-
pounds (17) and (19) as the final products,[11] and Meldrum’s
acid (11) gave 3,3-diphenylpropanoic acid (16), almost cer-
tainly formed by hydrolysis and decarboxylation of the diox-
anedione initially formed by C-alkylation of the enol (this
type of formolysis and decarboxylation has been reported for
other β-diesters[12]). Surprisingly, however, neither diethyl
malonate, nor ethyl cyanoacetate, nor malononitrile gave any
C-alkylation products (which we had expected by analogy
with, for example, the reactions of these active methy-
lene compounds in the Knoevenagel and Claisen–Schmidt
condensations.[13] Diethyl malonate gave only dibenzhydryl
ether, and only after prolonged heating; ethyl cyanoacetate
and malononitrile gave the Ritter reaction[14] products (18)
and (20). N-Benzhydrylacetamide (18), obtained in the reac-
tion between ethyl cyanoacetate and benzhydrol, is most
likely formed from the initial Ritter reaction product by
subsequent acidolysis[15] of the ester group and decarboxy-
lation. Interestingly, despite the fact that formic acid is
known to hydrolyze nitriles to amides[16,17] and to carboxy-
late carbocations,[18,19] neither nitrile hydrolysis products
nor products of Koch–Haaf carboxylation of the benzhydryl
cation were isolated. These results indicate that there is an
apparent threshold enol content for the C-alkylation reaction
to occur, but the nature of the correlation between isolated
yield and reaction time is not straightforward. The equilib-
rium enol contents of the active methylene compounds in
Thin layer chromatography (TLC) monitoring revealed
that almost all the benzhydrol (6) is consumed within 20 min
under these reaction conditions, Scheme 3.The appearance of
resonances at δ 8.2 and 7.0 ppm and the loss of the benzhydrol
1
carbinol resonance in the H NMR spectrum are consis-
tent with benzhydryl formate (7) being the major component
(95%) of the reaction mixture at this point. Heating was con-
tinued until TLC analysis indicated that all the benzhydryl
formate had been consumed.
E
OH
R
E
O
R
Ph
Ph
Ph
Ph
Ph
Ph
HCO2H
OCHO
OH
Ph
⌬
Ph
(9)
(6)
(8)
(7)
Scheme 3. Preparation and solvolysis of benzhydryl formate with
trapping of benzhydryl cation by enols.

Reactions of Methylene Compounds with Benzhydrol During Solvolysis
387
Table 1. Reactions of benzhydrol with active methylene compounds
Active methylene
compound
Reaction
time (h)
Alkylation product
Yield (%)
Melting point
(literature value)
Ref.
CH2(CO2Et)2(10)
Me2C(OCO)2CH2 (11)
MeCOCH2CO2Et (12)
N≡CCH2CO2Et (13)
CH2(COMe)2(14)
CH2(CN)2 (15)
>48
–
0
44
61
80
73
60
–
5
5
5
6
6
Ph2CHCH2CO2H (16)
Ph2CHCH(Ac)CO2Et (17)
Ph2CH-NHCOMe (18)
Ph2CHCH(COMe)2 (19)
(Ph2CHNHCO)2CH2 (20)
144–146 (150)
85–86 (89–90)
144–146 (146–147)
115–117 (116)
234–235 (234–235)
[8]
[9]
[10]
[1a]
[4a]
Table 2. Enol content of active methylene compounds
as CDCl3 solutions using a JEOL Eclipse NMR spectrometer oper-
ating at 400 MHz; peak positions are reported as δ (ppm) downfield
from internal Me4Si; peaks marked as * were assigned on the basis
of HETCOR experiments. 13C NMR spectra were recorded as CDCl3
solutions at 100 MHz; peak positions are reported in ppm relative to
the centre peak of CDCl3 (77.1 ppm). TLC was carried out on Merck
Kieselgel 60F254. Gas chromatography–mass spectrometry was carried
out using a Hewlett-Packard 5890 Series II GC-MS. Formic acid (98%)
and diethyl malonate were used as obtained from EM Science; benzhy-
drol was used as obtained from ACROS Chemicals; ethyl acetoacetate
and ethyl cyanoacetate were used as obtained from J. T. Baker; 2,4-
pentanedione was used as obtained from Mallinckrodt; malononitrile
was used as obtained from Kay-Fries; Meldrum’s acid was prepared by
the literature method.[7]
Compound
% enol (MeOH)
Ref.
Observed reaction
(10)
(11)
(12)
(13)
(14)
7.7 × 10−3
[20]
[12]
[20]
[20]
[20]
95
C-alkylation
C-alkylation
Ritter reaction
C-alkylation
8.0–13.2
0.25
76.4
protic solvents are gathered inTable 2; only those compounds
with significant equilibrium enol content gave C-alkylation
products.
It is instructive to compare our results to those of Moreno-
Mañas. In our study, the evidence strongly suggests that the
substitution substrate is the formate ester, whose solvoly-
sis then serves as the source of the benzhydryl cation. The
mechanism of the Moreno-Mañas reaction, by contrast, is
less certain, and may involve free radical intermediates. In
general, our yields are comparable to or slightly lower than
those obtained by Moreno-Mañas and coworkers. However,
in our system it is not the halide, but the alcohol, which
is the substrate. Moreover, the products in our study are
obtained by simple crystallization, unlike the majority of the
Moreno-Mañas products, which required chromatographic
purification. Thus, our method offers the distinct practical
advantage of permitting reasonable yields of pure, crys-
talline materials to be obtained without the use of halogenated
solvents or the need for chromatography.
Standard Procedure for Reactions with Benzhydrol and
Active Methylene Compounds
A solution of benzhydrol (9.21 g, 50 mmol) and the active methylene
compound (50 mmol) in formic acid (40 mL) was stirred for 5–6 h under
reflux untilTLC analysis showed neither benzhydrol nor benzhydryl for-
mate. The resulting solution was poured into deionized water (50 mL),
and the mixture was stirred for 30 min.When the result was a waxy solid,
the water was decanted from the solid, and the crude solid was dried by
azeotropic distillation with toluene (30 mL) under a Dean–Stark water
separator. When the resultant material was an oil, the precipitate was
extracted into dichloromethane (50 mL), dried (Na2SO4), evaporated
under reduced pressure, and dissolved in hot toluene (30 mL). The hot
toluene solution was diluted with hexane until saturation. Cooling of the
solution gave crystals which were recovered by vacuum filtration and
recrystallized as necessary.
Reaction between Benzhydrol and Ethyl Cyanoacetate
From a solution of benzhydrol (9.21 g, 50 mmol) and ethyl cyanoacetate
(5.66 g, 50 mmol) refluxed in formic acid (40 mL) for 5 h, this proce-
dure gave N-diphenylmethylethanamide (18) (9.01 g, 80%) as white
crystals, mp 144–146◦C (lit.[10] 146–147◦C). νmax (KBr)/cm−1 3259,
3049, 1647, 1549. δH 7. 35–7. 21 (10 H, complex, ArH), 6.24 (1 H, d, J
8.1, Ph2CH), 6.03 (1 H, br d, NH). δC 169.1, 141.6, 128.8 (2 C), 127.6,
127.5 (2 C), 57.1, 23.5.
Conclusions
The reaction between benzhydrol and active methylene com-
pounds in refluxing formic acid provides a method for the
direct benzhydrylation of active methylene compounds via
benzhydryl formate.The active electrophile in these reactions
is the benzhydryl cation, which is formed by the solvolysis
of benzhydryl formate. Active methylene compounds with a
substantialequilibriumenolcontent(forexampleβ-diketones
andβ-ketoesters)reactwiththeelectrophileattheenolcarbon
to give C-benzhydryl derivatives. Nitriles react with the elec-
trophile to give amide, formed by a Ritter reaction between
the electrophile and the nitrile nitrogen atom. We are cur-
rently investigating the scope of this method for the synthesis
of N-benzhydrylamides by the Ritter reaction.
Reaction between Benzhydrol and Ethyl Acetoacetate
From a solution of benzhydrol (9.21 g, 50 mmol) and ethyl acetoacetate
(6.51 g, 50 mmol) refluxed in formic acid (40 mL) for 5 h, this proce-
dure gave ethyl 2-(diphenylmethyl)-3-oxobutanoate (17) (9.06 g, 61%)
as white crystals, mp 85–86◦C (lit.[9] 89–90◦C). νmax (KBr)/cm−1 3092,
3031, 3000, 2956, 1740, 1499, 1369, 1264, 1160, 764, 721. δH 7.30–
7.14 (10 H, complex, ArH), 4.76 (1 H, d, J12.2, Ph2CH*), 4.52 (1 H,
d, J 12.2, AcCH*), 3.92–4.03 (2 H, AB of ABX3, JAX 7.3, JBX 7.1,
OCH2CH3), 0.99 (3H, X of ABX3, JAX 7.3, JBX 7.1, OCH2CH3). δC
201.8, 167.7, 141.6, 141.3, 128.9 (2 C), 128.7 (2 C), 127.9 (2 C), 127.8
(2 C), 127.0, 126.9, 65.3, 61.6, 51.0, 30.1, 13.8.
Experimental
Reaction between Benzhydrol and 2,4-Pentanedione
Melting points were measured on a Fisher–Johns hotstage melting
point apparatus and are uncorrected. 1H NMR spectra were recorded
From a solution of benzhydrol (9.21 g, 50 mmol) and 2,4-pentanedione
(5.01 g, 50 mmol) refluxed in formic acid (40 mL) for 6 h, this procedure

388
G. C. Gullickson and D. E. Lewis
gave ethyl 2-(diphenylmethyl)-2,4-pentanedione (19) (9.71 g, 73%) as
white crystals, mp 115–117◦C (lit.[1a] 116◦C). νmax (KBr)/cm−1 3086,
3068, 3031, 3012, 2963, 2926, 1701, 1505, 1461, 1362, 1201, 1160,
752, 709. δH 7.31–7.25, 7.21–7.15 (10 H, complex, ArH), 4.81 (2 H, d,
J 12.3, Ph2CH*), 4.73 (1 H, d, J 12.3, Ac2CH*), 2.00 (6 H, s, CH3).
δC 203.0, 141.3 (2 C), 129.0 (4 C), 127.8 (4 C), 127.1 (2 C), 74.3, 51.0,
29.8 (2 C).
(d) R. Fossé, Ann. Chim. Phys. 1910, 18, 400; R. Fossé, Ann.
Chim. Phys. 1910, 18, 503; R. Fossé, Ann. Chim. Phys. 1910,
18, 531.
[2] R. Fossé, Compt. Rend. 1907, 145, 196.
[3] R. Adams, J. R. Johnson, C. F. Wilcox, Jr., Laboratory Experi-
ments in Organic Chemistry, 7th ed. 1979, p. 397 (MacMillan:
New York, NY).
[4] (a) G. W. H. Cheeseman, R. C. Poller, Analyst 1962, 87, 366.
(b) G. W. H. Cheeseman, R. C. Poller, J. Chem. Soc. 1962,
5277.
Reaction between Benzhydrol and Malononitrile
From a solution of benzhydrol (9.21 g, 50 mmol) and malononitrile
(1.65 g, 25 mmol) refluxedꢀin formic acid (40 mL) for 6 h, this proce-
dure (5 h reflux) gave N,N -bis(diphenylmethyl)propanediamide (20),
which was purified by recrystallization from 1-butanol to give white
crystals (6.52 g, 60%), mp 234–235◦C (lit.[4a] 234–235◦C). TLC analy-
sis (1 : 1 EtOAc/hexane) and 1H NMR analysis of the residue indicated
that it was a mixture of the malonamide 20 and the acetamide 18. νmax
(KBr)/cm−1 3308, 3092, 3061, 3031, 1647, 1536, 1493, 752, 709. δH
7.61 (2 H, d, J 8. 0, NH), 7.18–7.29 (20 H, complex, ArH), 6.19 (2 H, d,
J 8.2 Hz, Ph2CH), 3.26 (2 H, s, (RNHCO)2CH2). δC 166.1 (2 C), 141.1
(2 C), 128.8 (4 C), 127.6 (2 C), 127.3(4 C), 57.0 (2 C), 30.8.
[5] A. H. Fainberg, S. Winstein, J. Am. Chem. Soc. 1956, 78, 2770.
[6] (a) M. Moreno-Mañas, J. Marquet, Synthesis 1979, 348. (b) A.
Gonzalez, F. Güell, J. Marquet, M. Moreno-Mañas, Tetrahedron
Lett. 1985, 26, 3735. (c) J. Marquet, M. Moreno-Mañas, Chem.
Lett. 1981, 173. (d) P. De March, J. Marquet, M. Moreno-Mañas,
R. Pleixats, I. Ripoll, A. Truis, An. Quim., Ser. C 1983, 79,
15. (e) A. Gonzalez, M. Moreno-Mañas, Tetrahedron 1986, 42,
4253. (f ) J. Cervelló, J. Marquet, M. Moreno-Mañas, J. Chem.
Soc., Chem. Commun. 1987, 644.
[7] D. Davidson, S. A. Bernhard, J. Am. Chem. Soc. 1948, 70,
3426.
[8] F. N. Peters, Jr., E. Griffith, D. R. Briggs, H. E. French, J. Am.
Chem. Soc. 1925, 47, 449.
[9] H. Rupe, H. Kägi, Liebigs Ann. Chem. 1920, 420, 33.
[10] Beilsteins Handbuch der organischen Chemie 12, 1325; cites
H. L. Wheeler, Am. Chem. J. 1900, 26, 354.
Reaction between Benzhydrol and Meldrum’s Acid
From a solution of benzhydrol (9.21 g, 50 mmol) and Meldrum’s acid
(6.71 g, 46.6 mmol) refluxed in formic acid (40 mL) for 5 h, this proce-
dure (5 h reflux) gave 3,3-diphenylpropanoic acid (16) as white crystals
(4.64 g, 44%) mp 144–146◦C (lit.[8] 150◦C). Spectroscopic data of the
product were all in accord with the assigned structure.
[11] B. Loev, Chem. Ind. (London) 1964, 193.
[12] B. Eistert, W. Reiss, Chem. Ber. 1954, 87, 92.
[13] For a brief discussion of the Claisen–Schmidt and Knoevenagel
condensations, see: H. O. House, Modern Synthetic Reactions
2nd ed. 1972, pp. 632–653 (Benjamin: Menlo Park, CA).
[14] Review: L. I. Krimer, D. Cota, Org. React. 1969, 17, 213.
[15] G. E. Rehberg, Org. Synth., Coll. Vol. 3 1955, 33.
[16] F. Berke, J. Gnad, Liebigs Ann. Chem. 1968, 713, 212.
[17] F. Berke, H. Fleig, P. Pässler, Liebigs Ann. Chem. 1971, 749,
198.
[18] H. Koch, W. Haaf, Org. Synth., Coll. Vol. 5 1973, 20.
[19] W. Haaf, Org. Synth., Coll. Vol. 5 1973, 739.
[20] (a) A. Gero, J. Org. Chem. 1954, 19, 469; A. Gero, J. Org.
Chem. 1954, 19, 1960. (b) For an extensive discussion of
keto–enol tautomerism in active methylene compounds, see:
G. W. Wheland, Advanced Organic Chemistry, 3rd ed. 1960,
ch. 14, pp. 667–701 (John Wiley & Sons: New York, NY).
Acknowledgments
Financial support of this research by grants from Research
Corporation (Cottrell College Science Award No. CC4677),
the National Institutes of Health (Grant # 1 R15 DA013578–
01), and the University of Wisconsin—Eau Claire Office of
Research and Sponsored Programs is gratefully acknowl-
edged.
References
[1] (a) R. Fossé, Compt. Rend. 1907, 145, 1290. (b) R. Fossé,
Compt. Rend. 1908, 146, 1039; R. Fossé, Compt. Rend. 1908,
146, 1277. (c) R. Fossé, Bull. Soc. Chim. France 1909, 3, 1075.