Studies on the stability of cycloprop-2-ene carboxylate dianions and reactions with electrophiles

Article abstract of DOI:10.1021/jo801683n

(Chemical Equation Presented) Dianions are generated from alkyllithium reagents and cycloprop-2-ene carboxylic acids, and these dianions can be functionalized by electrophiles at the vinylic position. In a previous report, we described that such dianions could be generated and reacted with electrophiles in Et₂O or THF. Upon further study, it was found that there were reproducibility issues for those reactions that were carried out in Et₂O. Working under the assumption that an impurity may have promoted these reactions, a detailed study was undertaken to determine the effect of variables on the generation, stability, and reactivity of cycloprop-2-ene carboxylate dianions. It has been found that certain additives can have a substantial effect on the chemistry of cycloprop-2-ene carboxylate dianions. In particular, it was determined that amine N-oxide additives have a beneficial effect both on the stability of cycloprop-2-ene carboxylate dianions and on the rates that such dianions undergo alkylation. Conditions for reacting dianions with a broad range of electrophiles are described.

Full text of DOI:10.1021/jo801683n

Studies on the Stability of Cycloprop-2-ene Carboxylate Dianions
and Reactions with Electrophiles
Laural A. Fisher and Joseph M. Fox*
Brown Laboratories, Department of Chemistry and Biochemistry, UniVersity of Delaware,
Newark, Delaware 19716
jmfox@udel.edu
ReceiVed July 31, 2008
Dianions are generated from alkyllithium reagents and cycloprop-2-ene carboxylic acids, and these dianions
can be functionalized by electrophiles at the vinylic position. In a previous report, we described that
such dianions could be generated and reacted with electrophiles in Et2O or THF. Upon further study, it
was found that there were reproducibility issues for those reactions that were carried out in Et2O. Working
under the assumption that an impurity may have promoted these reactions, a detailed study was undertaken
to determine the effect of variables on the generation, stability, and reactivity of cycloprop-2-ene
carboxylate dianions. It has been found that certain additives can have a substantial effect on the chemistry
of cycloprop-2-ene carboxylate dianions. In particular, it was determined that amine N-oxide additives
have a beneficial effect both on the stability of cycloprop-2-ene carboxylate dianions and on the rates
that such dianions undergo alkylation. Conditions for reacting dianions with a broad range of electrophiles
are described.
Introduction
tion,4 and desymmetrization5 provide broad access to enantio-
merically enriched cyclopropenes. These methods provide access
to chiral cyclopropenes from terminal alkynes, but there are
relatively few methods that provide access to chiral cyclopro-
penes with two alkene substituents. This discrepancy prompted
Eckert-Maksic,6a-c Lam,6d Gevorgyan,7 and us8 to investigate
protocols for converting “terminal” cyclopropenes into “internal”
cyclopropenes.9 Gevorgyan and co-workers have described an
elegant, Pd-catalyzed method for accessing chiral, internal
cyclopropenes by the direct arylation of alkyl cycloprop-2-ene
carboxylates.7a In more recent work, Gevorgyan and co-workers
have also described a variant of the Morita-Baylis-Hillman
reaction that converted methyl 2-butyl-1-(p-nitrophenyl)-3-
trimethylsilylcycloprop-2-ene carboxylate into an internal cy-
clopropene using benzaldehyde as the electrophile.7b It is well
Chiral cyclopropenes have emerged as important intermedi-
ates for the stereocontrolled synthesis of functionalized cyclo-
propane derivatives.1 Accordingly, much attention has been
focused recently on the preparation of cyclopropenes in enan-
tiomerically enriched form, and recently developed methods for
enantioselective cyclopropenation,2 resolution,3 kinetic resolu-
(1) Selected reviews on the reaction chemistry of cyclopropenes: (a) Rubin,
M.; Rubina, M.; Gevorgyan, V. Chem. ReV. 2007, 107, 3117. (b) Rubin, M.;
Rubina, M.; Gevorgyan, V. Synthesis 2006, 1221. (c) Halton, B.; Banwell, M. G.
In The Chemistry of the Cyclopropyl Group; Patai, S., Rappoport, Z., Eds.; Wiley:
Chichester, UK, 1987; pp 1224-1339. (d) Baird, M. S. Top. Curr. Chem. 1988,
144, 137. (e) Nakamura, M.; Isobe, H.; Nakamura, E. Chem. ReV 2003, 103,
1295. (f) Fox, J. M.; Yan, N. Curr. Org. Chem. 2004, 9, 719. (g) Marek, I.;
Simaan, S.; Masarwa, A. Angew. Chem., Int. Ed. 2007, 46, 7364.
(2) (a) Doyle, M. P.; Protopopova, M.; Mu¨ller, P.; Ene, D.; Shapiro, E. A.
J. Am. Chem. Soc. 1994, 116, 8492. (b) Mu¨ller, P.; Imoga¨ı, H. Tetrahedron:
Asymmetry 1998, 9, 4419. (c) Doyle, M. P.; Ene, D. G.; Forbes, D. C.; Pillow,
T. H. Chem. Commun. 1999, 1691. (d) Timmons, D. J.; Doyle, M. P. J.
Organomet. Chem. 2001, 617, 98. (e) Doyle, M. P.; Hu, W. Tetrahedron Lett.
2000, 41, 6265. (f) Doyle, M. P.; Hu, W. H. Snylett 2001, 1364. (g) Imoga¨ı, H.;
Bernardinelli, G.; Gra¨nicher, C.; Moran, M.; Rossier, J. C.; Mu¨ller, P. HelV.
Chim. Acta 1998, 81, 1754. (h) Davies, H. M. L.; Lee, G. H. Org. Lett. 2004,
6, 1233. (i) Luo, Y.; Horikawa, M.; Kloster, R. A.; Hawryluk, N. A.; Corey,
E. J. J. Am. Chem. Soc. 2004, 126, 8916. (j) Lou, Y.; Remarchuk, T. J.; Corey,
E. J. J. Am. Chem. Soc. 2005, 127, 14223. (k) Weatherhead-Kloster, R. A.; Corey,
E. J. Org. Lett. 2006, 8, 171.
(5) Zhang, F.; Fox, J. M. Org. Lett. 2006, 8, 2965.
(6) (a) Zrinski, I.; Novak-Coumbassa, N.; Eckert-Maksic, M. Organometalics
2004, 23, 2806. (b) Zrinski, I.; Eckert-Maksic, M. Synth. Commun. 2003, 33,
4071. (c) Zrinski, I.; Gadanji, G.; Eckert-Maksic, M. New J. Chem. 2003, 27,
1270. (d) Fordyce, E. A. F.; Wang, Y.; Luebbers, T.; Lam, H. W. Chem Commun.
2008, 1124. (e) Fordyce, E. A. F.; Luebbers, T.; Lam, H. W. Org. Lett. 2008,
18, 3993.
(7) (a) Chuprakov, S.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2005,
127, 3714. (b) Chuprakov, S.; Malyshev, D. A.; Trofimov, A.; Gevorgyan, V.
J. Am. Chem. Soc. 2007, 129, 14868.
(3) Liao, L.-a.; Zhang, F.; Yan, N.; Golen, J. A.; Fox, J. M. Tetrahedron
2004, 60, 1803.
(4) Liao, L.-a.; Zhang, F.; Dmitrenko, O.; Bach, R. D.; Fox, J. M. J. Am.
Chem. Soc. 2004, 126, 4490.
(8) Liao, L.-a.; Yan, N.; Fox, J. M. Org. Lett. 2004, 6, 4937.
(9) In analogy to the common nomenclature of alkynes, we refer to
cyclopropenes with a single alkene substituent as “terminal” cyclopropenes and
to those with two alkene substituents as “internal” cyclopropenes.
8474 J. Org. Chem. 2008, 73, 8474–8478
10.1021/jo801683n CCC: $40.75 2008 American Chemical Society
Published on Web 10/14/2008

Cycloprop-2-ene Carboxylate Dianions
TABLE 1. Effects of Various Parameters on Dianion Alkylation.
entry
alkyllithium
solvent
before Mel addition after Mel addition yield of 3c (%)
1
2
3
4
5
6
7
8
MeLi (1.6 M in Et2O)
MeLi (“homemade” from Li with low Na content 1.1 M in Et2O) Et2O
MeLi (“homemade” from Li with high Na content 1.1 M in Et2O) Et2O
s-BuLi (1.4 M in cyclohexane)
MeLi (1.6 M in Et2O)
MeLi (1.6 M in Et2O)
s-BuLi (1.4 M in cyclohexane)
s-BuLi (1.4 M in cyclohexane)
s-BuLi (1.4 M in cyclohexane)
s-BuLi (1.4 M in cyclohexane)
MeLi (1.6 M in Et2O)
Et2O
9 mina
9 mina
9 mina
30 mina
20 min
20 min
20 min
20 min
20 min
30 min
20 min
20 min
20 min
20 min
30 min
7
0
5
Et2O
6
Et2O (0.16 M in 1)d 4 mina
46
88e
86
68
10
0
THF
THF
THF
THF
THF
9 mina
10 min (0 °C)b
30 min (18 °C)b
60 min rt (21 °C)b
120 min rt (21 °C)b
9
10
11
Et2O (0.16 M in 1)d 4 min
H2O (0.7 equiv)
64
12
MeLi (1.6 M in Et2O)
Et2O (0.16 M in 1)d 4 min
MeOH (3.5 equiv)
30 min
56
a Unless noted otherwise, reactions were all carried out on the same scale (0.016 mmol of 1 in 10 mL of solvent). In representative reactions, internal
temperatures were typically measured to be 0-5 °C after 9 min. After 30 min, the internal temperature had reached rt. b Internal temperature of the
reaction at the time when Mel was added. c Yields and conversions were measured by 1H NMR. d Reactions carried out at 0.16 M (1 mL solvent) had
e
1
reached 0-5 °C after 4 min. The yield measured by H NMR was slightly lower than the isolated yield in later experiments (see Table 4).
established that cyclopropenes are acidic at the vinylic position
and can be functionalized through deprotonation/electrophilic
capture.10 Eckert-Maksic and co-workers demonstrated that alkyl
cycloprop-2-ene carboxylates can be generated and captured by
silyl and germanyl electrophiles that were available for in situ
reactivity.6a-c However, that protocol was limited to electro-
philes that could be introduced prior to the introduction of base:
the anions underwent ring-opening fragmentation when the
electrophile was introduced subsequent to the addition of base.
Lam has recently described a Cu-catalyzed method for silylation
of cyclopropenes using TMSOTf,6d and a KF-mediated method
for the stannylation of cyclopropenes by Bu3SnC2F5.6e The
cyclopropenes produced by the latter method can be further
elaborated via Stille couplings.6e Our group described a
procedure for anion formation/capture that utilized the dianions
of cycloprop-2-ene carboxylic acids. For example, 1-phenyl-2-
butyl-3-methylcycloprop-2-ene carboxylic acid (3) is produced
by alkylation of dianion (2), which is derived from 1-phenyl-
2-butylcycloprop-2-ene carboxylic acid (1) (eq 1).
to room temperature prior to the addition of the electrophile.
Although the majority of the experiments in our prior work
involved racemic cyclopropenes, it was demonstrated that the
dianion of nonracemic 1,2-diphenylcycloprop-2-ene carboxylic
acid undergoes alkylation by MeI with excellent transfer of
stereochemistry.8 Overall, the reactions were operationally
straightforward and did not require special precautions.
Recently, we became aware that the protocols that employed
Et2O as solvent could not be consistently repeated (see Table 1
of the 2004 publication:8 all three entries in row 1, and the first
entry in row 2). As all of the protocols in the earlier work had
been reproduced prior to publication, it seemed possible that
an adventitious and essential impurity may have been present
in the earlier experiments. Accordingly, a study was undertaken
to determine the effects of different additives on the stability
and reactivity of the dianions. It was determined that amine
N-oxides dramatically enhance both the reactivity and the
stability of dianions from cycloprop-2-ene carboxylic acids.
Conditions are described for reacting dianions with a variety
of electrophiles, and the scope and limitations of the method
are described.
Results and Discussion
We reported previously that 3 could be prepared by adding
ethereal MeLi (2.2 equiv) to a 0.016 M solution of 1 in Et2O at
-78 °C, permitting the resulting solution to warm to room
temperature, and subsequently adding MeI or MeOTs and
allowing the mixture to stir for 30 min.8 The product 3 was
obtained in good yield (81%) upon acidic workup and chro-
matography. However, our more recent experiments have
produced 3 in only low yield (Table 1, entries 1-3). The MeLi
that was used in the published procedure was prepared from
MeI/Li wire in Et2O.8 However, low yields (0-7%) were
obtained regardless of the source or type of MeLi: attempts were
made using commercially available MeLi from various vendors,
and MeLi prepared from several grades of Li wire. A low yield
of 3 was also obtained in an experiment that was carried out
with s-BuLi instead of MeLi (Table 1, entry 4). However, it
Dianions such as 2 were found to be relatively stable toward
ring-opening fragmentation, and hence could be reacted with a
relatively wide range of electrophiles that included alkyl halides
and aldehydes. The dianions could also be coupled to aryl
iodides upon transmetalation with ZnCl2 under Pd-catalyzed
conditions. In general, dianions were formed from cycloprop-
2-ene carboxylic acids by using MeLi at -78 °C in Et2O or
THF. For most reactions, the dianions were allowed to warm
(10) (a) Nakamura, M.; Isobe, H.; Nakamura, E. Chem. ReV. 2003, 103, 1295.
(b) Closs, G. L.; Closs, L. E. J. Am. Chem. Soc. 1963, 85, 99. (c) Avezov, I. B.;
Bolesov, I. G.; Levina, R. Y. J. Org. Chem. (USSR), Engl. Transl. 1974, 10,
2129. (d) Isaka, M.; Matsuzawa, S.; Yamago, S.; Ejiri, S.; Miyachi, Y.;
Nakamura, E. J. Org. Chem. 1989, 54, 4727. (e) Kirms, M. A.; Primke, H.;
Stohlmeier, M.; de Meijere, A. Recl. TraV. Chim. Pays-Bas. 1986, 105, 462. (f)
Schipperijn, A. J.; Smael, P. Recl. TraV. Chim. Pays-Bas. 1973, 92, 1159.
J. Org. Chem. Vol. 73, No. 21, 2008 8475

Fisher and Fox
TABLE 2. Discovery that N-Oxides Promote Dianion Alkylation
TABLE 3. The Effect of NMO on the Stability of the Dianion of 1
in THF
amount of 1
in THF/NMO
time elapsed after
Etl addition
time/internal
tempa
time/internal
amount of 1
remaining (%)
tempa
entry
solvent
yield of 5a(%)
remaining (%)
1
2
3
4
5
6
7
8
9
Et2Ob
9 min
9 min
10c
15 min/21 °C
30 min/23 °C
45 min/24 °C
60 min/24 °C
32
27
20
12
15 min/18 °C
30 min/24 °C
45 min/24 °C
60 min/24 °C
74
58
44
38
Et2O, 12-C-4 (6%)b
9c
THF
THF
THF
30 min
2.5 h
30 min, 35 °C
30 min
1.5 h
32c
45d
34d
34c
34d
53c
81e
72e
THF/TMEDA (2 equiv)
THF/TMEDA (2 equiv)
a Time was measured from the point at which the dry ice bath was
removed.
THF/TMANO (2 equiv) 30 min
THF/NMO (2 equiv)
THF/HMPA (2 equiv)
30 min
30 min
introduced to the system via reaction of oxygen with MeLi.11
However, the addition of methanol also resulted in only a modest
improvement in the yield of 3 in Et2O (56%, Table 1, entry
12). The effect of adding LiI was also analyzed for reaction of
EtI with the dianion of 1 in THF, but there was no benefit.12
The effect of amines or amine N-oxides on alkylation
reactions was also considered. While the addition of TMEDA
did not provide any benefit for the formation of 5 (Table 2,
entries 6 and 7), the inclusion of amine N-oxides had a
significant effect. The yield of 5 increased to 51% when
trimethylamine N-oxide was included (Table 2, entry 8), and
to 81% when N-methylmorpholine N-oxide (NMO) was in-
cluded (Table 2, entry 9). NMO has been used as a less-toxic
alternative to HMPA for promoting vinyl alumination
reactions.13a Quinuclidine N-oxide has also been used as a
general alternative to HMPA for a range of reactions, including
dianion reaction.13b,c Indeed, the use of HMPA as a cosolvent
also has a beneficial effect on the yield of 5 (72%, Table 2,
entry 10). DMSO and 1,3-dimethylimidazolidinone are also
commonly employed as HMPA alternatives, but these cosolvents
were ineffective for the synthesis of 5.
10
a Yield estimated by analysis of the crude 1H NMR spectrum. b The
reaction was carried out at 0.016 M. c By TLC analysis, only 5 and 4
were detected. d Only traces of remaining 4 were detected by TLC
analysis. Uncharacterized decomposition products were observed in the
NMR spectrum of the crude mixture. e Isolated yield; compound 4 was
not detected by TLC analysis.
was possible to obtain 3 in moderate yield (46%) when the
reaction was carried out at higher concentration (0.16 M) in
Et2O (Table 1, entry 5). A high yield (88%) of 3 was obtained
when THF was used as the solvent instead of Et2O (Table 1,
entry 6).
The results displayed in entries 7-10 in Table 1 demonstrate
that the dianion of 1 is not stable for long periods at room
temperature. In these experiments, the dianion of 1 was
generated with s-BuLi at -78 °C and permitted to stir while
warming to room temperature for variable amounts of time
before quenching with MeI. In a reaction where MeI was added
10 min after the cold bath was removed (internal temperature
of 0 °C), 3 was produced in 86% yield (Table 1, entry 7).
However, in a reaction where MeI was added 30 min after the
cold bath was removed (internal temperature of 18 °C), the yield
was only 68% (Table 1, entry 8). In experiments where the time
prior to MeI addition was increased to 1 and 2 h, the yields of
3 were measured as 10% and 0%, respectively (Table 1, entries
9 and 10). Collectively, the results in Table 1 suggest that the
dianion of 1 is only moderately stable at room temperature, and
that the rate of dianion decomposition is comparable to the rate
of alkylation by MeI when Et2O is the solvent.
A conclusion from the experiments outlined in Table 2 is
that dianion alkylation is accelerated by the inclusion of NMO.
The experiments outlined below determined that NMO also has
a beneficial effect on the stability of dianions. Thus, the dianion
of 1 was generated at -78 °C with MeLi in THF (0.16 M) in
the presence of an internal standard (mesitylene). The cold bath
was removed and the dianion was permitted to warm to an
internal temperature of 23 °C: at timed intervals aliquots were
1
taken, quenched, and analyzed by H NMR (Table 3). Only
27% of 1 remained after the cold bath had been removed for
30 min, and only 12% of 1 remained after 60 min. However,
58% and 38% of 1 remained after 30 and 60 min, respectively,
in a similar experiment in which NMO was included.
From these experiments, it is concluded that the stability and
reactivity of cycloprop-2-ene carboxylate dianions can be
influenced by additives. Efforts are ongoing in our laboratories
to determine other additives that promote dianion stability and
reactivity toward electrophiles.
We had also reported previously that cyclopropene 5 could
be synthesized from EtI and the dianion of 4, which was
prepared from MeLi in Et2O with a catalytic amount of 12-
crown-4. However, in more recent experiments we obtained 5
in low yield (9-10%) in Et2Oswith or without 12-crown-4
(Table 2, entries 1 and 2). Using THF as the solvent (0.16 M)
resulted in only a modest improvement (32%, Table 2, entry
3). Increasing the temperature to 35 °C did not increase the
yield (34%, Table 2, entry 5), and prolonged reaction times
resulted in only a minor improvement (45%, Table 2, entry 4).
(11) Liu, X.; Fox, J. M. J. Am. Chem. Soc. 2006, 128, 5600.
(12) A 0.016 M solution of 1 was deprotonated by using 2.2 equiv of MeLi
(1.47 M in Et2O) and after warming to 0-5 °C EtI (2.6 equiv) and LiI (5 equiv)
were added. The reaction was then allowed to stir for 30 min while warming to
room temperature. Aqueous workup and analysis of the crude 1H NMR spectrum
indicated a 30% yield of 9 with the balance being unreacted starting material.
(13) (a) Ramachandran, P. V.; Reddy, M. V. R.; Rudd, M. T. Chem. Commun.
1999, 1979. (b) O’Neil, I. A.; Lai, J. Y. Q.; Wynn, D. Chem. Commun. 1999,
59. (c) O’Neil, I. A.; Bhamra, I.; Gibbons, P. D. Chem. Commun. 2006, 4547.
Studies were carried out to determine the effect of additives
on the fate of the dianion alkylation. We focused initially on
additives that may have reasonably been present as impurities
in our earlier experiments. Adding water provided only a modest
benefit for the reaction of 1 with MeI in Et2O (64%, Table 1,
entry 11). It was also speculated that methanol may have been
8476 J. Org. Chem. Vol. 73, No. 21, 2008

Cycloprop-2-ene Carboxylate Dianions
TABLE 4. Reactions of Dianions with Electrophiles
NMO was also not required for the reaction to form 4 via a
cross-coupling reaction. Transmetalation was accomplished by
adding anhydrous ZnCl217 to the dianion of 1-phenylcycloprop-
2-ene carboxylic acid at -78 °C and stirring for 10 min;
subsequent cross-coupling with iodobenzene under Pd-catalyzed
conditions (-78 °C f rt) gave 4 in 83% yield. We note that
the dianion of 1-phenyl-cycloprop-2-ene carboxylic acid de-
composes at temperatures above -40 °C, and it should be
combined with electrophiles at low temperature for effective
reactivity. In our prior report,8 the dianion of 1-phenylcycloprop-
2-ene carboxylic acid was warmed to 0-5 °C before electro-
philes were added. It is plausible that an impurity in the earlier
study may have stabilized the dianion at higher temperatures.18
Reactions of the dianion of 4 with primary alkyl halides did
require NMO to achieve high conversion of starting material.
As described previously, 5 was obtained in high yield only when
NMO was included. The dianion of 4 also reacted to completion
with butyl iodide to give 8 in 76% yield when NMO was
included in the reaction. The analogous reaction of the dianion
of 4 with butyl bromide only went to ∼50% conversion (by
TLC analysis) after 45 min: 8 was obtained in 48% isolated
yield. Running the reaction for 2 h and increasing the amount
of butyl bromide to 5.5 equiv resulted in a 72% isolated yield,
with the remainder being unreacted starting material (TLC
analysis). Further increasing the reaction time did not improve
the yield.
Several electrophiles were tried unsuccessfully. The dianion
of 4 did not react with styrene oxide, 1,2-epoxydecane, or
2-cyclohexen-1-one. These reactions resulted only in returned
starting material. Attempts to facilitate these reactions by adding
CuI were unsuccessful, and resulted in decomposition. The
reaction of the dianion of 1 with N-methoxy-N-methylbenzamide
gave the product of O-acylation without C-acylation. Attempts
to add a secondary halide, 2-iodopropane, to either the dianion
of 1 or 4 gave products in <30% yield, and the products could
not be isolated in pure form. Ethyl R-bromoacetate and
N-ethylmaleimide were also unsuccessful and resulted only in
unreacted starting material. The addition of propionyl chloride
to the dianion of 1 resulted in decomposition. The reactions of
the dianion of 4 with benzyl bromide or benzyl iodide did not
proceed to completion (<50% conversion). Although the
product was detected by 1H NMR analysis of the crude reaction
mixtures, the product decomposed during flash chromatography
and could not be isolated in pure form.
a NMO (2 equiv) was added prior to the addition of MeLi.
With a clearer understanding of the factors that govern the
reactivity and stability of dianions, the scope of reactivity toward
various electrophiles was determined (Table 4). In experiments
where the starting cyclopropene was chiral, racemic material
was utilized. While MeLi was used in general to effect
deprotonation, the nature of the alkyllithium was not important.
In THF the reactions of dianions proceed in high yield with a
variety of alkyllithium bases: commercial MeLi, “homemade”
MeLi from Li with low Na content, “homemade” MeLi from
Li with high Na content, s-BuLi, and n-BuLi.14,15 It was not
necessary to use NMO in the reactions of dianions with highly
reactive electrophiles such as aldehydes (which gave 12 and
13), ketones (which gave 14), MeI (which gave 3, 6, and 7),
and MOMCl. It was possible to achieve selective C-alkylation
to give 10 with 1.1 equiv of MOMCl, albeit in modest yield
(53%).16 However, both the vinylic and carboxylate anions could
be alkylated to give 11 in 73% yield when excess MOMCl (4.0
equiv) was utilized.
Conclusions
A systematic study on the generation, stability, and reactivity
of cycloprop-2-ene carboxylate dianions is described. The nature
of the organolithium base used to deprotonate cycloprop-2-ene
carboxylic acids is not a significant variable, but the solvent
plays a major role in the efficiency of reactions toward
electrophiles. Additionally, N-oxide additives have a dramatic
influence on the stability and reactivity of the dianions.
(14) The dianion of 1 was generated with commercial MeLi, “homemade”
MeLi from Li with low Na content, “homemade” MeLi from Li with high Na
content, and commercial s-BuLi. In all cases, reaction with MeI gave 3 in 90-
97% yield.
Experimental Section
(15) The dianion of 4 was generated by using n-BuLi in the presence of
NMO. Reaction with BuI produced compound 8 in 72% yield.
(16) Increasing the amount of MOMCl to 1.5 equiv only led to larger amounts
of the dialkylated product. NMO did not help to improve this selectivity.
(17) The quality of the ZnCl2 was found to be very important for the
transmetalation/Pd(PPh3)4 coupling reaction of aryl halides. Initial attempts to
use a commercial 1.0 M solution in Et2O resulted in recovered starting material
and only trace amounts of product. Anhydrous beads of ZnCl2 (10 mesh) were
found to give optimal results in the coupling reaction.
Representative Procedures: 1-Phenyl-2-butyl-3-methylcyclo-
prop-2-ene Carboxylic Acid (3). To a dried 10-mL round-bottomed
(18) Decomposition of the dianion of 1-phenylcycloprop-2-ene carboxylic
acid (generated with MeLi at-78 °C in THF) occurs rapidly when the solution
is warmed by an ice bath: within 2 min the solution turns black. In our prior
report, a yellow solution was obtained when the solution was warmed to 0-5
°C.
J. Org. Chem. Vol. 73, No. 21, 2008 8477

Fisher and Fox
flask was added (()-1-phenyl-2-butylcycloprop-2-ene carboxylic
acid (35 mg, 0.16 mmol). Freshly distilled THF (1 mL) was added
via syringe, and the solution was cooled in a bath of dry ice/acetone.
The solution was allowed to stir and MeLi (0.22 mL of a 1.6 M
solution in Et2O, 0.35 mmol) was added via syringe. After the
mixture had stirred at -78 °C for 10 min, the dry ice/acetone bath
was removed and the mixture was gradually allowed to warm until
an internal temperature of 0-5 °C was reached (3 min on this scale).
To the red solution was added MeI (60 mg, 26 µL, 0.42 mmol) via
syringe. After being stirred at room temperature for 30 min, the
reaction was quenched with water, and aq 3 M HCl was added to
render the solution acidic (pH 1-2). The organic phase was
separated and the aqueous phase was extracted three times with
CH2Cl2. The combined organics were dried (Na2SO4), filtered, and
concentrated. The residue was chromatographed on silica gel
(5-15% ethyl acetate in hexanes) to provide 36 mg (97%) of the
title compound as a white solid (mp 59-62 °C). A similar
experiment starting with 100 mg of (()-1-phenyl-2-butylcycloprop-
2-ene carboxylic acid gave 99 mg (93%) of the title compound.
The spectroscopic properties were identical with those described
previously.8
10 min, the dry ice/acetone bath was replaced by a -40 °C bath,
and the mixture was allowed to stir for 30 s. To the red solution
was added cyclooctanone (107 mg, 111 µL, 0.845 mmol) via
syringe. The cold bath was removed and stirring was continued
for 5 min. The reaction was quenched with water, and aq 3 M HCl
was added to render the solution acidic (pH 1-2). The organic
phase was separated and the aqueous phase was extracted three
times with ethyl acetate. The combined organics were dried
(Na2SO4), filtered, and concentrated. The residue was chromato-
graphed on silica gel (5-20% ethyl acetate in hexanes) to provide
68 mg (73%) of the title compound as a waxy solid, mp 97-102
°C. An identical experiment gave 63 mg (68%) of the title
compound. Minor impurities were detected at 2.18, 1.24, and 0.85
ppm. 1H NMR (DMSO-d6, 400 MHz) δ 11.89 (br s, 1H), 7.31-7.34
(m, 2H), 7.20-7.24 (m, 3H), 7.10-7.14 (m, 1H), 4.99 (br s, 1H),
1.74-1.82 (m, 2H), 1.64-1.70 (m, 2H), 1.44-1.55 (m, 6H),
1.31-1.41 (m, 4H); 13C NMR (DMSO-d6, 100 MHz) δ 176.2 (C),
142.5 (C), 128.6 (CH, 2 carbons), 127.3 (CH, 2 carbons), 125.5
(CH), 125.2 (C), 97.6 (CH), 72.6 (C), 35.0 (CH2), 34.8 (CH2), 33.9
(C), 27.8 (CH2), 27.5 (CH2), 24.1 (CH2), 21.3 (CH2), 21.0 (CH2);
IR(CHCl3, cm-1) 3028, 2928, 2856, 1686, 1474, 1232, 1028;
HRMS-CI(NH3) m/z [M + H], calcd for C18H23O3 287.1647, found
287.1657.
1,2-Diphenylcycloprop-2-ene Carboxylic Acid (4). To a dried 25-
mL round-bottomed flask was added 1-phenylcycloprop-2-ene
carboxylic acid (77 mg, 0.48 mmol). Freshly distilled THF (3 mL)
was added via syringe, and the solution was cooled in a bath of
dry ice/acetone. The solution was allowed to stir and MeLi (0.66
mL of a 1.6 M solution in Et2O, 1.1 mmol) was added via syringe.
After the mixture had stirred at -78 °C for 10 min, the dry ice/
acetone bath was replaced by a -40 °C bath, and the mixture was
allowed to stir for 2 min at this temperature. The mixture was again
cooled to -78 °C, and to the red solution was added ZnCl2 (79
mg, 0.58 mmol). After the mixture was stirred at -78 °C for 5
min, Pd(PPh3)4 (28 mg, 0.024 mmol) and iodobenzene (225 mg,
124 µL, 1.10 mmol) were added. The dry ice/acetone bath was
again removed and the reaction was stirred overnight at room
temperature for 16 h. The reaction was then quenched with water,
and aq 3 M HCl was added to render the solution acidic (pH 1-2).
The organic phase was separated and the aqueous phase was
extracted three times with ethyl acetate. The combined organics
were dried (Na2SO4), filtered, and concentrated. The residue was
chromatographed on silica gel (5-30% ethyl acetate in hexanes)
to provide 92 mg (81%) of the title compound as a white solid, mp
138-140 °C (lit.3 mp 136-138 °C). An identical experiment gave
85 mg (75%) of the title compound. The spectroscopic properties
were identical with those described previously.3
1,2-Diphenyl-3-butylcycloprop-2-ene Carboxylic Acid (8). To a
dried 25- mL round-bottomed flask was added (()-1,2-diphenyl-
cycloprop-2-ene carboxylic acid (114 mg, 0.483 mmol) and
N-methylmorpholine N-oxide (113 mg, 0.966 mmol). Freshly
distilled THF (3 mL) was added via syringe, and the solution was
cooled in a bath of dry ice/acetone. The solution was allowed to
stir and MeLi (0.67 mL of a 1.6 M solution in Et2O, 1.1 mmol)
was added via syringe. After the mixture had stirred at -78 °C for
10 min, the dry ice/acetone bath was removed and the mixture was
gradually allowed to warm until the internal reaction temperature
had reached 0-5 °C (5 min on this scale). To the blue solution
was added BuI (232 mg, 144 µL, 1.26 mmol) via syringe. After
being stirred at room temperature for 45 min, the reaction was
quenched with water, and aq 3 M HCl was added to render the
solution acidic (pH 1-2). The organic phase was separated and
the aqueous phase was extracted five times with CH2Cl2. The
combined organics were dried (Na2SO4), filtered, and concentrated.
The residue was chromatographed on silica gel (10-15% ethyl
acetate in hexanes) to provide 113 mg (80%) of the title compound
as a white solid (mp 143-145.5 °C). An identical experiment gave
102 mg (72%) of the title compound. A similar experiment starting
with 38 mg of (()-1,2-diphenylcycloprop-2-ene carboxylic acid
and reacting with BuBr (120 mg, 95 µL, 0.89 mmol) for 2 h gave
35 mg (73%) of the title compound. A repetition of the experiment
with BuBr gave the title compound in 70% yield. 1H NMR (DMSO-
d6, 400 MHz) δ 12.07 (br s, 1H), 7.46-7.53 (m, 4H), 7.37-7.42
(m, 1H), 7.30-7.33 (m, 2H), 7.22-7.26 (m, 2H), 7.13-7.17 (m,
1H), 2.69-2.84 (m, 2H), 1.63-1.71 (m, 2H), 1.33-1.42 (m, 2H),
0.88 (t, J ) 7.5 Hz, 3H); 13C NMR (DMSO-d6, 100 MHz) δ 175.6
(C), 141.9 (C), 129.1 (CH), 128.8 (CH), 128.1 (CH), 127.8 (CH, 2
carbons), 126.3 (C), 125.8 (CH), 115.1 (C), 108.3 (C), 34.5 (C),
Acknowledgment. For financial support of this work we
thank NIGMS (NIH R01 GM068650-01A1). We are extremely
grateful to Rick Danheiser and his co-workers, who first alerted
us to difficulties with our previously published protocols that
were carried out in Et2O.
29.1 (CH2), 24.0 (CH2), 21.8 (CH2), 13.6 (CH3); IR (neat, cm-1
)
2933, 1684, 1495, 1236, 965; HRMS-CI(NH3) m/z [M + H] calcd
for C20H21O2 293.1542, found 293.1533.
Supporting Information Available: Full experimental and
characterization details for all compounds, as well as copies of
1H NMR and 13C NMR spectra for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1-Phenyl-2-(1-hydroxycyclooctyl)cycloprop-2-ene Carboxylic Acid
(14). To a dried 25-mL round-bottomed flask was added 1-phenyl-
cycloprop-2-ene carboxylic acid (52 mg, 0.33 mmol). Freshly
distilled THF (2 mL) was added via syringe, and the solution was
cooled in a bath of dry ice/acetone. The solution was allowed to
stir and MeLi (0.45 mL of a 1.6 M solution in Et2O, 0.72 mmol)
was added via syringe. After the mixture had stirred at -78 °C for
JO801683N
8478 J. Org. Chem. Vol. 73, No. 21, 2008