Microwave-assisted Piloty-Robinson synthesis of 3,4-disubstituted pyrroles

Article abstract of DOI:10.1021/jo070389+

(Chemical Equation Presented) The synthesis of N-acyl 3,4-disubstituted pyrroles can be accomplished directly from hydrazine and an aldehyde via a Piloty-Robinson pyrrole synthesis. The use of microwave radiation for the cyclization and pyrrole formation

Full text of DOI:10.1021/jo070389+

cycle with various substitution patterns.11,12 Many established
approaches for the synthesis of pyrroles are based on the
venerable Paal-Knorr13-16 and Hantzsch17 reactions, which
were developed in the late 19th century. Even with the
substantial work in this area spanning the last hundred years,
new reports that provide efficient and versatile access to pyrroles
continue to appear, underscoring the importance of this hetero-
cycle in various areas of science.18-20 For example, contem-
porary strategies for the construction of pyrroles include
transition-metal-mediatedandmulticomponentcouplingroutes.16,21-25
The symmetric 3,4-disubstitued pyrrole core has special interest
since the combination of these monomers with an aldehyde
results in highly substituted porphyrins. These resulting 4-fold
symmetric macrocycles are key molecules that are the basis for
a large variety of synthetic and physiochemical studies.6,26,27
Over the last three decades, two compounds have emerged as
useful model systems in the investigations of general properties
ofmetalloporphyrinatederivatives: octaethylporphyrin(H2OEP)28-33
and tetraphenylporphyrin (H2TPP).34 For example, iron com-
plexes of octaethylporphyrin have received significant attention
due to its homology to heme b of the heme proteins.26,35,36
Although H2OEP is a more appropriate model compound due
to its substitution pattern and homology to the heme cofactor,
Microwave-Assisted Piloty-Robinson Synthesis of
3,4-Disubstituted Pyrroles
Benjamin C. Milgram,† Katrine Eskildsen,‡
Steven M. Richter,§ W. Robert Scheidt,‡ and
Karl A. Scheidt*,†
Department of Chemistry, Northwestern UniVersity, 2145
Sheridan Road, EVanston, Illinois 60208, Department of
Chemistry and Biochemistry, UniVersity of Notre Dame, Notre
Dame, Indiana 46556, and Abbott Laboratories, Process Safety
Laboratory, 1401 Sheridan Road, North Chicago, Illinois 60064
scheidt@northwestern.edu
ReceiVed February 27, 2007
(10) Merz, A.; Schwarz, R.; Schropp, R. AdV. Mater. 1992, 4, 409-
411.
(11) Jones, R. A., Ed. Pyrroles. Part I: The Synthesis and the Physical
and Chemical Aspects of the Pyrrole Ring; Wiley: New York, 1990; Vol.
48, Part 1.
(12) Jones, R. A., Ed. Pyrroles. Part 2. The Synthesis, ReactiVity, and
Physical Properties of Substituted Pyrroles; Wiley: New York, 1992; Vol.
48, Part 2.
(13) Paal, C. Chem. Ber. 1885, 367-371.
(14) Knorr, L. Chem. Ber. 1885, 18, 299-311.
(15) Amarnath, V.; Anthony, D. C.; Amarnath, K.; Valentine, W. M.;
Wetterau, L. A.; Graham, D. G. J. Org. Chem. 1991, 56, 6924-6931.
(16) Braun, R. U.; Zeitler, K.; Muller, T. J. J. Org. Lett. 2001, 3, 3297-
3300.
The synthesis of N-acyl 3,4-disubstituted pyrroles can be
accomplished directly from hydrazine and an aldehyde via
a Piloty-Robinson pyrrole synthesis. The use of microwave
radiation for the cyclization and pyrrole formation greatly
reduces the time necessary for this process and facilitates
moderate to good yields from hydrazine for the correspond-
ing 3,4-disubstituted products (5-12). By simple hydrolysis,
the free N-H pyrroles can be accessed after the Piloty-
Robinson reaction and then used directly in the synthesis of
octaethylporphyrin (H2OEP, 14) and octaethyltetraphenylpor-
phyrin (H2OETPP, 15).
(17) Hantzsch, A. Chem. Ber. 1890, 23, 1474-1483.
(18) Tang, J. S.; Verkade, J. G. J. Org. Chem. 1994, 59, 7793-7802.
(19) Lash, T. D.; Bellettini, J. R.; Bastian, J. A.; Couch, K. B. Synthesis
1994, 170-172.
Pyrroles with substituents at C3 and C4 are important
compounds for the synthesis of pharmaceuticals, natural
products,1-5 and porphyrins.6-10 Consequently, there are numer-
ous general methods to access this important aromatic hetero-
(20) Yu, M.; Pagenkopf, B. L. Org. Lett. 2003, 5, 5099-5101.
(21) Buchwald, S. L.; Wannamaker, M. W.; Watson, B. T. J. Am. Chem.
Soc. 1989, 111, 776-777.
(22) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc.
2001, 123, 2074-2075.
(23) Bharadwaj, A. R.; Scheidt, K. A. Org. Lett. 2004, 6, 2465-2468.
(24) Dhawan, R.; Arndtsen, B. A. J. Am. Chem. Soc. 2004, 126, 468-
469.
* To whom correspondence should be addressed. Tel: 847-491-6659.
† Northwestern University.
‡ University of Notre Dame.
(25) Agarwal, S.; Knolker, H. J. Org. Biomol. Chem. 2004, 2, 3060-
3062.
§ Abbott Laboratories.
(1) LeQuesne, P. W.; Dong, Y.; Blythe, T. A. In Alkaloids: Chemical
and Biological PerspectiVes; Pelletier, S. W., Ed.; Elsevier: Amsterdam,
The Netherlands, 1999; Vol. 13.
(2) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435-446.
(3) Sanchez, C.; Zhu, L. L.; Brana, A. F.; Salas, A. P.; Rohr, J.; Mendez,
C.; Salas, J. A. Proc. Nat. Acad. Sci. U.S.A. 2005, 102, 461-466.
(4) Nishizawa, T.; Gruschow, S.; Jayamaha, D. H. E.; Nishizawa-Harada,
C.; Sherman, D. H. J. Am. Chem. Soc. 2006, 128, 724-725.
(5) Hinze, C.; Kreipl, A.; Terpin, A.; Steglich, W. Synthesis 2007, 608-
612.
(26) Buchler, J. W. Angew. Chem., Int. Ed. 1978, 17, 407-423.
(27) Scheidt, W. R.; Reed, C. A. Chem. ReV. 1981, 81, 543-555.
(28) Eisner, U.; Lichtarowicz, A.; Linstead, R. P. J. Chem. Soc. 1957,
733-739.
(29) Inhoffen, H. H.; Fuhrhop, J. H.; Voigt, H.; Brockman, H. Liebigs
Ann. Chem. 1966, 695, 133-139.
(30) Whitlock, H. W.; Hanauer, R. J. Org. Chem. 1968, 33, 2169-2171.
(31) Paine, J. B.; Kirshner, W. B.; Moskowitz, D. W.; Dolphin, D. J.
Org. Chem. 1976, 41, 3857-3860.
(32) Paine, J. B.; Dolphin, D. J. Org. Chem. 1988, 53, 2787-2795.
(33) Sessler, J. L.; Mozaffari, A.; Johnson, M.; Fischer, J.; Winterfeldt,
E. Org. Synth. 1992, 70, 68-74.
(6) Kadish, K. M., Smith, K. M., Guilard, R., Eds. The Porphyrin
Handbook; Academic Press: San Diego, CA, 2000.
(7) Smith, K. M. In ComprehensiVe Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vol. 4, p 377.
(8) Ono, N.; Kawamura, H.; Bougauchi, M.; Maruyama, K. Tetrahedron
1990, 46, 7483-7496.
(34) Adler, A. D.; Longo, F. R.; Finarelli, J. D.; Goldmach, J.; Assour,
J.; Korsakoff, L. J. Org. Chem. 1967, 32, 476.
(35) Ellison, M. K.; Schulz, C. E.; Scheidt, W. R. J. Am. Chem. Soc.
2002, 124, 13833-13841.
(36) Hu, C. J.; Roth, A.; Ellison, M. K.; An, J.; Ellis, C. M.; Schulz, C.
E.; Scheidt, W. R. J. Am. Chem. Soc. 2005, 127, 5675-5688.
(9) Ono, N.; Miyagawa, H.; Ueta, T.; Ogawa, T.; Tani, H. J. Chem. Soc.,
Perkin Trans. 1 1998, 1595-1601.
10.1021/jo070389+ CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/14/2007
J. Org. Chem. 2007, 72, 3941-3944
3941

SCHEME 1
H2TPP is more widely used due in part to its convenient
synthesis from pyrrole and benzaldehyde.37 An inexpensive and
reliable synthesis of H2OEP and related porphyrin derivatives
remains a challenging goal since it relies on an efficient route
to the requisite 3,4-disubstituted pyrroles. In our continuing
studies on metalloporphyrinate compounds (W.R.S.), we typi-
cally synthesize H2OEP by way of 3,4-diethylpyrrole. The H2-
OEP synthesis procedures reported independently by Inhoffen,29
Whitlock,30 Dolphin,31 and Sessler33 all provide access to H2-
OEP, but the synthesis of the monomer precursor 3,4-dieth-
ylpyrrole remains challenging due to the number of synthetic
steps, the cost of the starting materials, or both. In all these
approaches, 2-carboxy- or 2,5-bis-carboxy-pyrroles are con-
verted into the key 3,4-diethylpyrrole, which is then employed
in the subsequent H2OEP syntheses.
aromatization to generate the desired N-acylated pyrrole core
with substitution at C3 and C4 (3) and benzamide (4).
A key goal in streamlining our approach was to determine
the optimal set of reaction conditions that would minimize the
number of purification steps while still providing pure N-
aroylpyrroles from simple and inexpensive starting materials.
Given the well-known propensity for pyrroles to undergo
oxidative processes over prolonged reaction times and temper-
atures, we sought to employ a rapid heating step to induce the
Piloty-Robinson sequence which could potentially increase the
yield and ease purification. Accessing symmetrical azines (2)
is easily accomplished by the slow addition of aqueous
hydrazine (1 equiv) to a 0 °C ethereal solution of an aldehyde
(1, 2 equiv). After removal of the water (anhydrous potassium
carbonate), the reaction is filtered and the solvent is removed
under reduced pressure to afford the unpurified azines in >90%
yield.
With a quick route to the symmetrical precursors, we initially
examined the reaction of the azine derived from butyraldehyde
with benzoyl chloride using microwave conditions in order to
optimize the thermal parameters. We chose to omit additional
solvent since Baldwin had reported earlier that pyridine was
used to promote the acylation/rearrangement step of the Piloty
sequence, and we anticipated that the pyridine alone would
facilitate adequate mixing and heat transfer in the microwave-
assisted reaction. Accordingly, the heating of the azine, benzoyl
chloride (2 equiv), and pyridine (3.7 equiv) in a sealed
microwave reaction vessel provides a dark suspension that can
be passed through a coarse fritted funnel with the aid of ethyl
acetate. The filtrate was concentrated in vacuo, passed through
a short pad of silica gel using chloroform and then initially
purified by distillation to afford the symmetric N-benzoyl pyrrole
(3, Ar ) Bz, R ) Et). After surveying various times and thermal
parameters, we determined that heating reaction mixtures
containing 3-5 mmol of azine for 30-60 min at 180 °C (as
measured by the internal infrared sensor of the microwave
apparatus) provided the best yields for the desired pyrroles.
Larger scale reactions (25-30 mmol of azine) required longer
reaction times to convert all of the bis-acylated materials (II)
to products.
With our interests in the efficient syntheses of nitrogen
heterocycles (K.A.S.),23,38-40 we recognized that a straightfor-
ward and reliable strategy to 3,4-diethylpyrrole would
provide for a streamlined H2OEP synthesis with a minimal
number of purification steps. A facile route to the desired 3,4-
disubstituted heterocycles is the Piloty-Robinson pyrrole
synthesis that involves the conversion of ketone-derived azines
into pyrroles.41-43 A seminal study by Baldwin in 1982
expanded this useful reaction sequence to include azines derived
from aldehydes.44 The reported two-step process delivers
symmetric N-benzoylpyrroles but suffers from the elevated
temperatures (140 °C) and prolonged reaction times (3 days)
required for low to moderate yields of products (<35%).
With the emergence of microwave irradiation as a useful tool
in organic synthesis, we sought to apply this technique to this
reaction.45-53 In this paper, we report the use of microwave
radiation in the Piloty-Robinson pyrrole synthesis to afford
disubstituted N-acylpyrroles (Scheme 1). The overall sequence
involves the synthesis of a symmetric azine (2) followed by
exposure of the unpurified material to 2 equiv of an aroyl
chloride and pyridine. With the aid of significant thermal energy,
the acylation of the azine nitrogen atoms under these conditions
promotes tautomerization to intermediate I and then subsequent
[3,3]-sigmatropic rearrangement delivers a 1,4-bis imine (II).
This acyclic intermediate then undergoes cyclization and
(37) The cost of tetraphenylporphyrin (Sigma-Aldrich) is $21 per mmol.
The cost of 2,3,4,7,8,12,13,17,18-octaethylpophyrin (Sigma-Aldirch) is $245
per 1 mmol.
(38) Galliford, C. V.; Beenen, M. A.; Nguyen, S. T.; Scheidt, K. A. Org.
Lett. 2003, 5, 3487-3490.
(39) Galliford, C. V.; Scheidt, K. A. J. Org. Chem. 2007, 72, 1811-
1813.
(40) Galliford, C. V.; Scheidt, K. A. Chem. Comm. 2007, 631-633.
(41) Piloty, O. Chem. Ber. 1910, 43, 489.
(42) Robinson, R.; Robinson, G. M. J. Chem. Soc. 1918, 43, 639-644.
(43) Posvic, H.; Dombro, R.; Ito, H.; Telinski, T. J. Org. Chem. 1974,
39, 2575-2580.
(44) Baldwin, J. E.; Bottaro, J. C. J. Chem. Soc., Chem. Commun. 1982,
624-625.
(45) Kuhnert, N. Angew. Chem., Int. Ed. 2002, 41, 1863-1866.
(46) Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002, 35,
717-727.
With the microwave parameters optimized, we surveyed the
reaction scope as a function of different acid chlorides and
different starting aldehydes (Table 1). In all cases, the unpurified
azine is carried directly into the Piloty-Robinson reaction.
While the reaction is limited to aromatic acid chlorides in the
cases we have examined, the use of butyraldehyde produces
the corresponding 3,4-diethylpyrroles in moderate yields based
on the amount of aldehyde used (entries 1-4). A short survey
(47) Lew, A.; Krutzik, P. O.; Hart, M. E.; Chamberlin, A. R. J. Comb.
Chem. 2002, 4, 95-105.
(48) Hayes, B. L. Aldrichim. Acta 2004, 37, 66-77.
(49) Xu, Y.; Guo, Q.-X. Heterocycles 2004, 63, 903-974.
(50) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250-6284.
(51) de la Hoz, A.; Diaz-Ortiz, A.; Moreno, A. Chem. Soc. ReV. 2005,
34, 164-178.
(52) Molteni, V.; Ellis, D. A. Curr. Org. Synth. 2005, 2, 333-375.
(53) Roberts, B. A.; Strauss, C. R. Acc. Chem. Res. 2005, 38, 653-661.
3942 J. Org. Chem., Vol. 72, No. 10, 2007

TABLE 1. Scope of N-Aroylpyrrole Synthesisa
SCHEME 2. Synthesis of H2OEP and H2OETPP from
N-Benzoyl-3,4-diethylpyrrole
saturated aldehyde (e.g., butyraldehyde). Notably, the process
uses inexpensive starting materials and requires only two
purification stepssone for the N-aroylpyrrole and the second
for the final porphyrin product.
a 1 equiv of azine, 2.1 equiv of ArCOCl, 3.7 equiv of pyridine. Heated
by microwave at 180 °C for 30 min. b Isolated yields calculated from azine
after purification. c 180 °C for 1 h.
An attractive feature of this reaction sequence is that it
delivers the N-acylated pyrroles. Importantly, the placement of
an electron-withdrawing substituent on the pyrrole nitrogen
deactivates the pyrrole core toward unwanted side reactions and
can induce crystallinity to ease purification. In this manner, the
N-benzoylated pyrroles from the Piloty-Robinson synthesis can
be stored indefinitely with only minimal precautions to exclude
air or moisture. The removal of the benzoyl group can be cleanly
accomplished in high yield by exposure of the N-benzoylated
pyrroles to aqueous KOH in ethanol (Scheme 2, eq 2). After
15-20 min, the reaction is diluted with water and extracted
with hexanes. A wash of the organic layer with aqueous sodium
bicarbonate removes any remaining benzoic acid, thereby
affording >95% pure N-H pyrrole without purification.
Due to the potential issues with hydrazine and related
nitrogenous compounds, we examined the safety and thermo-
dynamic parameters of the Piloty-Robinson reaction using
calorimetry. Based on our initial differential scanning calorim-
etry, the only intermediate in the overall process that has an
exothermic event below 300 °C is the unpurified azine (see the
Supporting Information for details). For the azine derived from
butyraldehyde and hydrazine hydrate, an exothermic event is
observed at 240 °C. We have also used reaction calorimetry to
study the azine formation and Piloty-Robinson sequence. Not
surprisingly, the addition of hydrazine hydrate to the butyral-
dehyde in the azine formation is exothermic, with a heat of
reaction of -692 J/g butyraldehyde. The heat generation for
this process can be controlled by cooling the reaction to 0 °C
and the addition rate of hydrazine. With the use of a chemical
reactivity calorimeter, the thermal parameters of the benzoyl
chloride addition were determined. The combination of the acid
chloride and azine in the presence of pyridine is exothermic
with the heat of reaction being -1383 J/g azine. Overall, the
of the aldehyde structure of indicates that changes in the length
or substitution does not greatly impact the overall yield of the
process. Currently, the pyridinium chloride produced in the
reaction and high temperatures rule out the use of highly
sensitive protecting groups on either reaction component, but
the overall sequence should be amenable to a variety of different
functional groups. It should be noted that while the maximum
reaction flask size for the microwave reactor used in these
studies is a 20 mL vessel, the process can be performed five
times to afford significant amounts (∼20 g) of unpurified
pyrrole.
This material can be taken directly into the synthesis of
various porphyrins, including octaethylporphyrin (H2OEP, 14)
and octaethyltetraphenylporphyrin (H2OETPP, 15). After the
hydrolysis of 5, the exposure of the unpurified N-H pyrrole
(13) to aqueous formaldehyde and oxygen with benzene as
solvent generates the desired H2OEP macrocycle in 51% yield
after recrystallization.54-56 By integrating our approach with the
porphyrin synthesis described by Smith,57 we can also access
the more substituted H2OETPP from the initial porphyrinogen
formation with BF3‚OEt (76%) and subsequent oxidation with
DDQ (68%, 51% overall yield from 5). The combination of
our Piloty-Robinson protocol with these hydrolysis and cy-
clization steps affords a streamlined, four-step porphyrin
synthesis starting from hydrazine, benzoyl chloride, and a
(54) Rothemund, P. J. Am. Chem. Soc. 1939, 61, 2912-2915.
(55) Rothemund, P. J. Am. Chem. Soc. 1936, 58, 625-627.
(56) Sessler, J. L.; Mozaffari, A.; Johnson, M. R. Org. Synth. 1992, 70,
242-249.
(57) Barkigia, K. M.; Berber, M. D.; Fajer, J.; Medforth, C. J.; Renner,
M. W.; Smith, K. M. J. Am. Chem. Soc. 1990, 112, 8851-8857.
J. Org. Chem, Vol. 72, No. 10, 2007 3943

was cooled to 0 °C, and hydrazine hydrate (17 mL, 350 mmol)
was added dropwise over 30 min. The reaction was warmed to 23
°C and stirred for 30 min. The water produced in the reaction was
then removed by pipet, and anhydrous potassium carbonate was
added to dry the reaction further. The mixture was filtered, and
the resulting solution was concentrated carefully under reduced
pressure (400 mbar) to afford the 1,2-dibutylidenehydrazine (42 g,
300 mmol) which is used directly in the subsequent Piloty-
Robinson reaction.
To a dry 20 mL microwave vial equipped with a magnetic stir
bar were added unpurified azine (3.76 g, 27 mmol) and pyridine
(8.1 mL, 100 mmol). Benzoyl chloride (6.7 mL, 58 mmol) was
then added slowly and the vial capped with a rubber septum. The
vial was shaken vigorously and then heated in the microwave for
60-75 min at 170 °C (as recorded via the IR sensor of the
microwave apparatus). After heating, the vessel was cooled, diluted
with ethyl acetate (1 L), and filtered through a course frit funnel.
The above microwave procedure was repeated five times, and the
resulting combined solution was concentrated under reduced
pressure. The remaining material was dissolved in chloroform and
filtered through a 400 mL silica gel pad to remove the benzamide.
The eluent (2 L) was collected and removed under reduced pressure
to afford a brown residue. This material was purified by vacuum
distillation (145-155 °C/200 mT), yielding 15.9 g (52%) of (3,4-
diethyl-1H-pyrrol-1-yl)(phenyl)methanone (5) as a tan oil that
crystallized upon standing: Rf ) 0.71 (20:80 ethyl acetate/hexanes);
mp ) 43 °C; IR (film) 2965, 1688, 1377, 1317, 1274, 1246, 1136,
FIGURE 1. Adiabatic calorimetry self-heating data for Piloty-
Robinson reaction mixture. Accelerating rate calorimetry (ARC) was
performed with a TIAX accelerating rate calorimeter in a glass test
cell (in blue) and a titanium test cell (in red). See the Supporting
Information for details.
formation of the azine and subsequent Piloty-Robinson se-
quence can be performed safely at laboratory scale with current
commercial microwave reactors equipped with appropriate
temperature control and safety precautions associated with
operating at elevated pressures. If traditional heating protocols
are employed (i.e., non-microwave), then metal contact should
be avoided since adiabatic testing of the Piloty-Robinson
sequence in titanium test cells (accelerating rate calorimetry)
led to a significant increase in exothermic activity (Figure 1.)
In summary, we have developed a concise and cost-effective
synthesis of symmetric 3,4-disubstituted pyrroles based on the
Piloty-Robinson synthesis. The use of microwave radiation
allows for short reaction times that deliver N-benzoylated
pyrroles from hydrazine and a saturated aldehyde in moderate
yields with a single purification. The products from this
acylation/rearrangement/cyclization can be converted to the free
N-H pyrroles using basic conditions and the unpurified pyrroles
have been used directly in the synthesis of octaethylporphyrin
(H2OEP) and octaethyltetraphenylporphyrin (H2OETPP). The
methodology detailed in this study should facilitate the synthesis
of highly substituted porphyrin derivatives for use in bioinor-
ganic chemistry and materials research.
1
884, 807, 717, 668 cm-1; H NMR (500 MHz, CDCl3) δ 7.72 (d,
J ) 7.3 Hz, 2H), 7.57 (dd, J ) 7.3 Hz, 1H), 7.50 (dd, J ) 7.3 Hz,
2H), 7.00 (s, 2H), 2.43 (q, J ) 7.3 Hz, 4H), 1.21 (t, J ) 7.3 Hz,
6H); 13C NMR (125 MHz, CDCl3) δ164.7, 133.8, 131.7, 130.8
129.2 128.3 117.4 18.4 13.4; LRMS (ESI) mass calcd for C15H17-
NO [M]+ 227.3, found [M + H]+ 228.5.
Acknowledgment. Support for this research has been
provided by the NSF (CAREER CHE-0348979 to K.A.S.) and
the NIH (GM 38401 to W.R.S.). K.A.S. thanks Abbott
Laboratories, Amgen, Boehringer-Ingelheim, and 3M for gener-
ous research support. B.C.M. thanks Northwestern University
and Sigma-Aldrich for summer research fellowships. Funding
for the NU Analytical Services Laboratory has been furnished
in part by the NSF (CHE-9871268).
Supporting Information Available: Experimental procedures
and spectral data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Experimental Section
(3,4-Diethyl-1H-pyrrol-1-yl)(phenyl)methanone (5). To a round-
bottom flask equipped with a magnetic stir bar were added diethyl
ether (90 mL) and butyraldehyde (64 mL, 710 mmol). The solution
JO070389+
3944 J. Org. Chem., Vol. 72, No. 10, 2007