Synthesis and application of alkenylstannanes derived from base-sensitive cyclopropenes

Article abstract of DOI:10.1021/ol801486v

(Chemical Equation Presented) in the presence of stoichiometric potassium fluoride, a range of base-sensitive cyclopropenes undergo direct stannylation using (pentafluoroethyl)tributylstannane. The resulting stannylcyclopropenes serve as precursors to a variety of tetrasubstituted cyclopropenes that might otherwise be difficult to access using alternative methods.

Full text of DOI:10.1021/ol801486v

ORGANIC
LETTERS
2008
Vol. 10, No. 18
3993-3996
Synthesis and Application of
Alkenylstannanes Derived from
Base-Sensitive Cyclopropenes
Euan A. F. Fordyce,† Thomas Luebbers,‡ and Hon Wai Lam*,†
School of Chemistry, UniVersity of Edinburgh, The King’s Buildings, West Mains
Road, Edinburgh, EH9 3JJ, United Kingdom, and F. Hoffmann-La Roche Ltd.,
Grenzacherstrasse 124, CH-4070 Basel, Switzerland
h.lam@ed.ac.uk
Received July 1, 2008
ABSTRACT
In the presence of stoichiometric potassium fluoride, a range of base-sensitive cyclopropenes undergo direct stannylation using
(pentafluoroethyl)tributylstannane. The resulting stannylcyclopropenes serve as precursors to a variety of tetrasubstituted cyclopropenes that
might otherwise be difficult to access using alternative methods.
The high degree of strain inherent in the three-membered
ring of cyclopropenes confers upon these molecules a unique
and interesting range of reactivities, which has made them
the targets of significant investigation from chemists for many
years.1 A rich diversity of nucleophilic additions, substitu-
tions, rearrangements, cycloadditions, and ring-opening reac-
tions are among the typical reactions that cyclopropenes
undergo, and new variants of these processes continue to be
developed.1,2 Due to the versatility of these compounds, the
development of new methods that enable the synthesis of
functionalized cyclopropenes that are otherwise difficult to
access using conventional methods is in high demand.
In this regard, cyclopropenes containing a trialkylstannyl
substituent on one or both of the alkene carbons could
potentially serve as useful precursors to a range of other
cyclopropenes through Stille cross-coupling reactions.3-5
Surprisingly, only a few examples of these compounds have
been reported previously.6 The standard method to prepare
1- or 2-stannylcyclopropenes is through reaction of a
cyclopropenyllithium species with a trialkyltin chloride.6
† University of Edinburgh.
‡ Hoffmann-La Roche.
(1) For reviews, see: (a) Binger, P.; Bu¨ch, H. M. Top. Curr. Chem. 1987,
135, 77–151. (b) Baird, M. S. Cyclopropenes: Transformations (Houben-
Weyl); Thieme: Stuttgart, Germany, 1997; Vol. E17d/2, pp 2781-2790.
(c) Nakamura, M.; Isabe, H.; Nakamura, E. Chem. ReV. 2003, 103, 1295–
1326. (d) Fox, J. M.; Yan, N. Curr. Org. Chem 2005, 9, 719–732. (e) Rubin,
M.; Rubina, M.; Gevorgyan, V. Synthesis 2006, 1221–1245. (f) Rubin, M.;
Rubina, M.; Gevorgyan, V. Chem. ReV. 2007, 107, 3117–3179. (g) Marek,
I.; Simaan, S.; Masarwa, A. Angew. Chem., Int. Ed. 2007, 46, 7364–7376.
(2) For recent, selected examples of investigations into the reactivity of
cyclopropenes, see: (a) Alnasleh, B. K.; Sherrill, W. M.; Rubin, M. Org.
Lett. 2008, 10, 3231–3234. (b) Yan, N.; Liu, X.; Fox, J. M. J. Org. Chem.
2008, 73, 563–568. (c) Rubina, M.; Woodward, E. W.; Rubin, M. Org.
Lett. 2007, 9, 5501–5504. (d) Masarwa, A.; Stanger, A.; Marek, I. Angew.
Chem., Int. Ed. 2007, 46, 8039–8042. (e) Trofimov, A.; Rubina, M.; Rubin,
M.; Gevorgyan, V. J. Org. Chem. 2007, 72, 8910–8290. (f) Chuprakov, S.;
Malyshev, D. A.; Trofimov, A.; Gevorgyan, V. J. Am. Chem. Soc. 2007,
129, 14868–14869. (g) Hirashita, T.; Shiraki, F.; Onishi, K.; Ogura, M.;
Araki, S. Org. Biomol. Chem. 2007, 5, 2154–2158. (h) Giudici, R. E.;
Hoveyda, A. H. J. Am. Chem. Soc. 2007, 129, 3824–3825. (i) Smith, M. A.;
Richey, H. G., Jr. Organometallics 2007, 26, 609–616.
(3) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636–3638
.
(4) For selected reviews of the Stille reaction, see: (a) de Souza, M. V. N.
Curr. Org. Synth. 2006, 3, 313–326. (b) Espinet, P.; Echavarren, A. M.
Angew. Chem., Int. Ed. 2004, 43, 4704–4734. (c) Mitchell, T. N. Metal-
Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich, F., Eds.;
Wiley-VCH: Weinheim, 2004; Chapter 3. (d) Pattenden, G.; Sinclair, D. J.
J. Organomet. Chem. 2002, 653, 261–268. (e) Kosugi, M.; Fugami, K. J.
Organomet. Chem. 2002, 653, 50–53. (f) Duncton, M. A.; Pattenden, G.
J. Chem. Soc., Perkin Trans. 1 1999, 1235–1246. (g) Farina, V.; Krishna-
murthy, V.; Scott, W. J. Org. React. 1997, 50, 1–652. (h) Stille, J. K. Angew.
Chem., Int. Ed. Engl. 1986, 25, 508–524
.
(5) For Stille reactions of stannylcyclopropenes, see ref 6c
.
(6) (a) Kirms, M. A.; Primke, H.; Stohlmeier, M.; de Meijere, A. Recl.
TraV. Chim. Pays-Bas 1986, 105, 462–464. (b) Isaka, M.; Ejiri, S.;
Nakamura, E. Tetrahedron 1992, 48, 2045–2057. (c) Untiedt, S.; de Meijere,
A. Chem. Ber. 1994, 127, 1511–1515. (d) Eckert-Maksic´, M.; Golic´, M.;
Pasˇa-Tolic´, L. J. Organomet. Chem. 1995, 489, 35–41. (e) Eckert-Maksiæ,
M.; Elbel, S.; Stohlmeier, M.; Untiedt, S.; de Meijere, A. Chem. Ber. 1996,
129, 169–174.
10.1021/ol801486v CCC: $40.75
Published on Web 08/23/2008
2008 American Chemical Society

Although useful, this protocol is generally restricted to
cyclopropenes lacking base-sensitive functional groups (such
as esters) since these functional groups can often promote
undesired side-reactions such as cyclopropene ring-opening
(Scheme 1).7
alkyne using Bu3SnCF3 and catalytic KF.12 Since cyclopro-
penes often exhibit properties that are more similar in nature
to alkynes rather than alkenes,13 this procedure was deemed
to possess potential merit, and we therefore applied these
conditions to the stannylation of 1a. Although the use of
catalytic KF was not suitable, stoichiometric KF provided a
promising 54% conversion to 2a using Bu3SnCF3 in DMF
(entry 3). Further increases in conversion were realized by
raising the temperature (entry 4, and compare entries 5
and 6) and through the use of Bu3SnCF2CF3 (compare entries
3 and 4 with entries 5 and 6, respectively).11 The optimum
conditions employed Bu3SnCF2CF3 and stoichiometric KF
in DMF at 40 °C (entry 6).
Scheme 1. Ring-Opening of Cyclopropenyl Lithium Species
The generality of this procedure was investigated using
a variety of base-sensitive 1,3,3-trisubstituted cyclopro-
penes (Figure 1). Dimethyl malonate-derived cyclopro-
Although potential solutions to this problem might lie in
the inverse addition protocol employed by Eckert-Maksic´
and co-workers in the preparation of analogous silyl- and
germyl-substituted cyclopropenes7b,c or in the dianion ap-
proach using cyclopropene carboxylic acids described by Fox
and co-workers,8 the development of more user-friendly
cyclopropene stannylation procedures that proceed under
mild reaction conditions is an attractive goal. Herein, we
describe the efficient stannylation of base-sensitive cyclo-
propenes using the combination of (pentafluoroethyl)tribu-
tylstannane and stoichiometric potassium fluoride.
On the basis of our previous results involving the direct
silylation of base-sensitive cyclopropenes using (trifluorom-
ethyl)trimethylsilane as the silylating agent in conjunction
with substoichiometric quantities of Cu(acac)2 and dppe,9,10
our exploratory experiments began with attempted stanny-
lation of cyclopropene 1a using Bu3SnCF3 in place of
TMSCF3 (Table 1, entry 1). Unfortunately, only a low
Table 1. Optimization of Conditions for Stannylation of
Cyclopropene 1a
metal salt/ligand
entry (equiv of each)
Bu3SnX
(2 equiv)
temp convn
solvent (°C)
(%)a
Cu(acac)2/
Figure 1. Direct stannylation of various cyclopropenes. Reactions
1
dppe (0.05)
Cu(acac)2/
dppe (0.05)
KF (1.0)
Bu3SnCF3
THF
rt
10
were conducted using 0.20 mmol of cyclopropene, 0.20 mmol of
KF, and 0.40 mmol of BuSnCF2CF3. Cited yields are of isolated
material.
2
3
4
5
6
Bu3SnCF2CF3
Bu3SnCF3
Bu3SnCF3
Bu3SnCF2CF3
Bu3SnCF2CF3
THF
DMF
DMF
DMF
DMF
rt
rt
40
rt
40
25
54
67
84
98
KF (1.0)
KF (1.0)
KF (1.0)
a Determined by 1H NMR analysis of the unpurified reaction mixtures.
penes 1a-1d substituted with various aromatic groups or
an alkyl group smoothly underwent the reaction to provide
stannylcyclopropenes 2a-2d in good to excellent yield.
In addition to methyl esters, other tolerated functional
groups at C3 included ethyl esters and either electron-
rich or electron-deficient aromatics, resulting in stannyl-
cyclopropenes 2e-2h in 69-88% yield.
conversion to the desired product 2a was observed. Efforts
to increase the conversion through variation of the copper
source were unproductive. However, it was noticed that use
of Bu3SnCF2CF3 improved the conversion slightly (entry
2).11 Upon examining related reactions in the literature, we
encountered a single example of a direct stannylation of an
Two activating substituents (esters or aromatics) at C3 of
the cyclopropene are required for stannylation to proceed
3994
Org. Lett., Vol. 10, No. 18, 2008

efficiently.14 For example, cyclopropene 1i provided alk-
enylstannane 2i in only 29% yield (eq 1), while no reaction
was observed with 1j (eq 2).
Table 2. Stille Coupling Reactions of Stannylcyclopropenesa
Having developed a mild protocol for the direct stanny-
lation of base-sensitive cyclopropenes, the utility of the
resulting products was investigated. We have already dem-
onstrated that these stannylcyclopropenes undergo stereo- and
regioselective iron-catalyzed carbometalation-ring-opening
reactions to provide acyclic R,ꢀ,ꢀ′-trisubstituted alkenyl-
stannanes.15 In addition, treatment of 2d with I2 in Et2O
resulted in facile tin-iodine exchange to provide iodocy-
clopropene 3 in high yield (eq 3).16
However, our principal goal in this study was to establish
the utility of these stannane building blocks in the synthesis
of other tetrasubstituted cyclopropenes through Stille cou-
pling reactions.4,5 The only prior examples of these types of
reactions are those reported by Untiedt and de Meijere using
a limited selection of coupling partners,6c and it was therefore
of interest to ascertain whether more highly functionalized
cyclopropenes could be prepared using stannylcyclopropenes
2 and a wider selection of electrophiles. Fortunately, using
a combination of Pd2(dba)3 and Ph3As17 as the precatalyst
components, stannylcyclopropenes 2a, 2d, and 2h smoothly
underwent cross-coupling with a range of organic halides
(7) (a) Zrinski, I.; Gadanji, G.; Eckert-Maksic´, M. New J. Chem, 2003,
27, 1270–1276. (b) Zrinski, I.; Eckert-Maksic´, M. Synth. Commun. 2003,
33, 4071–4077. (c) Zrinski, I.; Novak-Coumbassa, N.; Eckert-Maksic´, M.
Organometallics 2004, 23, 2806–2809.
a Unless otherwise stated, reactions were conducted using 0.10 mmol
of stannylcyclopropene and 0.11 mmol of organic halide. b Isolated yield.
c Reaction conducted using 1.5 equiv of cinnamoyl chloride.
(8) Liao, L.; Yan, N.; Fox, J. M. Org. Lett. 2004, 6, 4937–4939.
(9) Fordyce, E. A. F.; Wang, Y.; Luebbers, T.; Lam, H. W. Chem.
Commun. 2008, 1124–1126.
(10) For the use of similar conditions in the trifluoromethylation of
aldehydes, see: Mizuta, S.; Shibata, N.; Ogawa, S.; Fujimoto, H.; Nakamura,
S.; Toru, T. Chem. Commun. 2006, 2575–2577.
(Table 2). Aromatic (entries 1, 3, 4, and 6) and heteroaro-
matic (entry 7) iodides were found to be effective electro-
philes, and as expected, the more reactive electron-deficient
iodoarenes resulted in higher yields (compare entries 1 and
6 with entries 3, 4, and 7).18 The use of an alkenyl iodide
provided diene 4b (entry 2) in 87% yield. Notably, acid
chlorides were also competent electrophiles, providing cy-
clopropenes 4e and 4h that would be difficult to prepare using
(11) The origin of the superiority of Bu3SnCF2CF3 over Bu3SnCF3 is
not understood at this time.
(12) Ishizaki, M.; Hoshino, O. Tetrahedron 2000, 56, 8813–8818.
(13) For example, cyclopropene alkene protons have a pKa of ∼30,
enabling metalation with strong bases much in the same fashion as terminal
alkynes. See: Fattahi, A.; McMarthy, R. E.; Ahmad, M. R.; Kass, S. R.
J. Am. Chem. Soc. 2003, 125, 11746–11750.
(14) For a a study of the effect of substituents at the 3-position on the
HOMO and LUMO energies of cyclopropenes, see: Diev, V. V.; Kostikov,
R. R.; Gleiter, R.; Molchanov, A. P. J. Org. Chem. 2006, 71, 4066–4077.
(15) Wang, Y.; Fordyce, E. A. F.; Chen, F. Y.; Lam, H. W. Angew.
Chem., Int. Ed. 2008, DOI: 10.1002/anie.200802391.
(16) Iodocyclopropene 3 was stable and could be purified by column
chromatography without noticeable decomposition.
(18) For a useful alternative preparation of these types of compounds,
see: Chuprakov, S.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2005,
127, 3714–3715.
(17) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585–9595.
Org. Lett., Vol. 10, No. 18, 2008
3995

existing methods (entries 5 and 8).1 In certain cases, we have
found that stannylcyclopropenes 2 sometimes undergo pro-
todestannylation during long-term storage. In light of this
observation, a one-pot direct stannylation-Stille cross-
coupling reaction that obviates the requirement for isolation
of the intermediate stannylcyclopropene was developed
(Scheme 2). Upon completion of the stannylation of cyclo-
continued at 40 °C to eventually provide cyclopropene 4a
in 66% overall yield.
In summary, a mild method for the direct stannylation of
cyclopropenes that employs Bu3SnCF2CF3 and KF has been
developed. By use of the Stille cross-coupling reaction, the
resulting stannylcyclopropenes serve as useful precursors to
a variety of highly functionalized tetrasubstituted cyclopro-
penes that might otherwise be difficult to prepare using
alternative methods. Utilization of cyclopropenes prepared
using these procedures in novel catalytic processes, along
with efforts to gain insight into the mechanism of the
stannylation reactions,19 will be the focus of future studies.
Scheme 2. One-Pot Direct Stannylation-Stille Coupling
Acknowledgment. This work was supported by the
University of Edinburgh, F. Hoffmann-La Roche, and the
EPSRC. The EPSRC National Mass Spectrometry Service
Centre at the University of Wales, Swansea, is thanked for
providing high-resolution mass spectra.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL801486V
propene 2a as observed by TLC analysis, a solution of
1-iodo-4-nitrobenzene (1.1 equiv), Pd2(dba)3 (2.5 mol %),
and Ph3As (10 mol %) in DMF was added, and heating was
(19) In the absence of further experiments, speculation about the
mechanism of these reactions would be premature at this stage.
3996
Org. Lett., Vol. 10, No. 18, 2008