Key words
Brønsted acid - PCCP - cyclopentadiene - dimethyl malonate - dimethyl acetylenedicarboxylate
Cyclopentadiene and its derivatives comprise a family of exceptionally important organic
molecules. Due to the stabilizing aromaticity of the cyclopentadienyl anion, the cyclopentadienes
are markedly more acidic compared to analogous hydrocarbons. The acidity of the cyclopentadiene
can be further increased through introduction of stabilizing groups, such as cyano
or carbonyl substituents.[1] Notably, the highly electron-deficient 1,2,3,4,5-pentacarbomethoxycyclopentadiene
(PCCP; 1), first reported by Otto Diels in 1942,[2] is approximately as acidic as HCl[1] (Figure [1]A).
Figure 1 PCCP (1) and selected derivatives
We recently reported that the PCCP scaffold offers a viable platform for organocatalysis.[3] One of the major attractive features of this scaffold is the fact that the carboxymethyl
substituents of 1 are readily derivatized, allowing facile access to a range of PCCP analogues (Figure
[1]B).[4] Using this strategy, we have developed chiral PCCP derivatives that act as Brønsted
acid catalysts for enantioselective Mukaiyama–Mannich and oxocarbenium aldol reactions[3a] and for the inverse-demand Diels–Alder cycloaddition of salicylaldehyde acetals.[3b] In addition, we have demonstrated that silylated PCCP derivatives can serve as effective
silicon Lewis acid catalysts to promote C–C bond-forming reactions.[3c] We are currently exploring the use of metal–PCCP complexes[5] as catalysts for a range of transformations.
As shown in Scheme [1], the established synthesis of PCCP 1 consists of two sequential reactions. In the first step, dimethyl malonate (DMM)
combines with three equivalents of dimethyl acetylenedicarboxylate (DMAD) to generate
an isomeric mixture of octacarbomethoxycycloheptadienes 2a and 2b.[6] In the second step, 2a and 2b undergo a base-mediated ring contraction to generate the potassium salt of PCCP,
3.[7] Upon protonation, PCCP (1) precipitates and can be collected by filtration.
Scheme 1 Synthesis of PCCP potassium salt 3 from dimethyl malonate and dimethyl acetylenedicarboxylate as reported by Diels
While this synthetic route makes use of relatively inexpensive reagents, a number
of issues make it highly inconvenient to run, particularly on a large scale. First,
formation of the octacarbomethoxycycloheptadienes 2a and 2b must be closely monitored due to the highly exothermic nature of this reaction and
the rapid precipitation of the products. Although the reaction requires heating to
achieve full conversion, the flask should nevertheless be cooled with an ice bath
until it ceases to reflux on its own. This precaution is very important: if the reaction
is not cooled and stirred efficiently, the mixture can erupt violently. Second, even
when highly pure starting materials are used, significant by-products are formed at
this stage, necessitating a recrystallization step prior to proceeding to step two.
This recrystallization results in a significant reduction in the yield of 2a and 2b and greatly extends the time of the overall procedure. When 2a and 2b are carried on to the next step without recrystallization, the second reaction yields
a nearly intractable mixture of the PCCP salt and undefined, dark, insoluble matter,
which significantly diminishes the yield of the product. When purified 2a and 2b are used, the second reaction generally proceeds smoothly, but high temperatures
are required due to the insolubility of 2a and 2b. Hot filtration is required to remove reaction by-products, and only after a slow,
overnight precipitation is the PCCP potassium salt obtained.
Given these significant drawbacks, we sought to develop an improved route to PCCP
(1) that would address the undesirable elements of this procedure and reduce the number
of steps and the time required to complete the synthesis. Herein, we report a simple,
one-pot procedure that delivers the PCCP potassium salt 3, and thus to 1 via protonation, in a single day.
We began by evaluating the conditions under which the two octacarbomethoxycycloheptadiene
isomers 2a and 2b can be formed. We aimed to determine whether 2a and 2b could be generated in solution in a synthetically useful yield. As shown in Table
[1], no alternative to the pyridine and acetic acid mixture employed by Diels (Table
[1], entry 1) was productive for the promotion of this reaction (entries 2–5). However,
when diethyl ether solvent was replaced with dichloromethane (entry 6), in which 2a and 2b are freely soluble, the reaction proceeded smoothly within three hours without heating.
Even on a large (~50 g) scale, where exothermic events are cause for significant concern,
a room temperature water bath was sufficient to keep the reaction under control.
Table 1 Investigation of Conditions under which 2a and 2b Form
|
|
Entry
|
Catalyst
|
Solvent
|
Yield (%)a
|
|
1
|
pyridine/AcOH
|
Et2O
|
74
|
|
2
|
DABCO/AcOH
|
Et2O
|
0
|
|
3
|
pyridine/HBr
|
Et2O
|
0
|
|
4
|
pyridine/TsOH
|
Et2O
|
0
|
|
5
|
2,6-lutidine/AcOH
|
Et2O
|
0
|
|
6
|
pyridine/AcOH
|
CH2Cl2
|
61
|
a Yields determined by 1H NMR spectroscopy.
We next sought to convert 2a and 2b into 3 in the same pot by the addition of organic bases to induce the ring contraction/fragmentation
events. A screen of amine bases revealed that DBU promoted formation of the desired
product; however, the use of stoichiometric DBU on a large scale is impractical. We
next examined the possibility of using aqueous base solutions in a biphasic mixture
with benzyltrimethylammonium chloride (BTMAC) as a phase-transfer catalyst. The reaction
was conducted with either aqueous 1 M KOH or saturated K2CO3 solution. With aqueous KOH, rapid conversion of the starting materials was observed
(60% in 2 h); however, significant decarboxylation of the PCCP product was detected
by NMR analysis. The reaction proceeded more slowly in saturated K2CO3 solution, but under these conditions, significant formation of 3 was observed within 16 hours. Conveniently, the PCCP salt precipitated out of the
reaction mixture without cooling. Protonation with aqueous HCl then delivered PCCP
acid 1, which was purified by recrystallization.
A key requirement of this project was to develop a synthetic route that was scalable
and high-yielding compared to the previously reported synthesis. On a 38.3 gram scale,
the new procedure delivered PCCP (1) in 48% (Scheme [2]), an improvement of 13% over an unoptimized Diels synthesis run on a similar scale.
Perhaps more importantly, the extreme inconvenience of the intractable material formed
in the two-pot synthesis (Scheme [2], left photo) has been eliminated in favor of a well-behaved homogeneous solution
(Scheme [2], right photo).
Scheme 2 Summary of the newly reported procedure for the synthesis of PCCP including visual
comparison of the reactions
In summary, PCCP (1) is a useful precursor to novel organic Brønsted and Lewis acid catalysts.[3]
[8] These organocatalysts offer a noteworthy alternative to chiral BINOL-based catalysts
and have an advantage in that they are significantly more straightforward and inexpensive
to access. While the PCCP methyl ester is commercially available, the high cost encourages
in-house production from inexpensive precursors. Our desire to more easily access
this useful scaffold led us to revisit an outdated and inconvenient synthetic methodology.
We have developed a convenient and rapid one-pot route to PCCP that delivers the product
in superior yield to the Diels synthesis. We anticipate that this improved synthesis
will encourage future applications of this unique molecule in organic synthesis.
Dimethyl acetylenedicarboxylate was acquired from Chem-Impex. All other reagents and
solvents were acquired from Sigma-Aldrich or Fisher Scientific. NMR spectra were recorded
on a Bruker AV500 spectrometer. Mass spectra were collected using a Thermo Scientific
Exactive DART-MS spectrometer.
1,2,3,4,5-Pentacarbomethoxycyclopentadiene (1)
To a flame-dried 3 L flask containing CH2Cl2 (840 mL) and a stir bar were added dimethyl acetylenedicarboxylate (82.6 mL, 95.8
g, 0.67 mol) and dimethyl malonate (76.7 mL, 88.2 g, 0.67 mol). Pyridine (2.75 mL,
2.7 g, 34 mmol) and AcOH (2.55 mL, 2.7 g, 44.8 mmol), dissolved in CH2Cl2 (10 mL) were added dropwise to the flask over 30 min. The reaction mixture was stirred
at rt for 3 h, during which time the solution darkened to a reddish brown. After 3
h, benzyltrimethylammonium chloride (518 mg, 2.8 mmol) was added along with sat. aq
K2CO3 (840 mL). Over the course of several hours, the biphasic mixture became viscous,
and stirring was increased as necessary to ensure thorough mixing of the phases. The
reaction was allowed to proceed for 16 h, during which time PCCP salt 3 precipitated. The heterogeneous mixture was filtered and the solid washed with CH2Cl2 (300 mL). The collected solid was dried in vacuo to furnish the PCCP salt 3. The PCCP acid 1 was acquired by dissolving 3 in H2O (4 mL/g) and treating this solution with concd HCl (2 mL/g). PCCP precipitated from
the acidified mixture and was filtered and dried in vacuo to remove all traces of
HCl. The resulting yellow powder was recrystallized from toluene/EtOAc to furnish
PCCP (1) as large, colorless crystals; yield: 38.3 g (48%).
1H NMR (CDCl3, 500 MHz): δ = 20.11 (s, 1 H), 4.06 (s, 6 H), 3.92 (s, 6 H), 3.79 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 172.3, 167.7, 163.1, 133.6, 117.6, 106.4, 55.6, 52.6, 51.9.
HRMS (DART-MS): m/z [M – H]– calcd for C15H15O10: 355.0671; found: 355.06125.
