An anti-Baldwin 3-Exo-dig cyclization: Preparation of vinylidene cyclopropanes from electron-poor alkenes

Article abstract of DOI:10.1021/ja803553a

Stabilized carbanions undergo an uncommon 3-exodig cyclization onto propargyl halides through an S_N2′ substitution. Propargyl iodides as electrophiles are necessary to achieve good yields (36-95%) for most substrates, although the usefulness of chlorides and bromides is documented. A variety of monocyclic and bicyclic vinylidene cyclopropanes can be prepared. These products are not available by standard carbene methodology. Copyright

Full text of DOI:10.1021/ja803553a

Published on Web 06/27/2008
An “Anti-Baldwin” 3-Exo-Dig Cyclization: Preparation of Vinylidene
Cyclopropanes from Electron-Poor Alkenes
Matthew J. Campbell, Patrick D. Pohlhaus, Geanna Min, Kohsuke Ohmatsu, and Jeffrey S. Johnson*
Department of Chemistry, UniVersity of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290
Received December 26, 2007; E-mail: jsj@unc.edu
Table 1. Screen of 3-Exodig Cyclization Reaction Variablesa
Baldwin’s rules are routinely used as a first round of analysis to
predict the propensity of cyclization for a given system.1 Although
exceptions are not uncommon,2 these stereoelectronic guidelines
continue to occupy a prominent and useful role in synthetic
planning. We report in this Communication a rare example of the
3-exo-dig cyclization mode as a method to prepare vinylidene
entry
substrate
reagentb
time (h)
solvent
yield (%)c
cyclopropanes from electron-poor alkenes. To our knowledge, only
isolated examples of 3-exo-dig reactions have been reported in the
literature, with all involving nucleophilic attack of a heteroatom
onto a pendant alkyne.3
1
2
3
4
5
6
7
8
9
10
1b
1b
1b
1b
2b
2b
2b
2b
2b
2b
TBAF
Cs2CO3
Cs2CO3
K2CO3/18-c-6
TBAF
TBAF
TBAT
TBAT
Cs2CO3
22
22
22
23
0.1
0.5
3
2
2.5
5
THF
13
35
33d
43
78d
77
77
82
59
46
DMF
MeCN
DMF
THF
MeCN
MeCN
DMF
DMF
DMF
Vinylidene cyclopropanes (VCPs) can be prepared from electron-
rich alkenes using carbenes derived from propargylic halides4a,b
or dibromocyclopropanes4c and have been utilized as valuable
intermediates in organic synthesis.5 Electron-deficient alkenes are
unable to undergo this reaction, because of the electrophilic nature
of the carbene. In the course of a recent synthetic study we had
cause to seek an efficient preparation of these allenes (e.g., 3a)
and considered that 1,3-dicarbonyls and their enolic congeners (e.g.,
1a) might undergo SN2′ cyclization with a pendant propargyl halide,
a process predicted to be disfavored under Baldwin’s rules.
K2CO3/18-c-6
a Conditions: Silyl enol ether 1b and 2b (1.0 equiv) and reagent (3.0
equiv) in solvent (0.03 M) at room temperature. b 18-c-6
)
1,4,7,10,13,16-hexaoxacyclooctadecane. TBAF ) tetrabutylammonium
fluoride. TBAT ) tetrabutylammonium triphenyldifluorosilicate. TASF
)
tris(dimethylamino)sulfonium difluorotrimethylsilicate. c Yield
determined by GLC analysis against an internal standard. d Yield
determined by isolation.
Scheme 1. Attempted Cyclization of Propargyl Chlorides
Initial investigations revealed that silyl enol ether 1a did undergo
3-exo-dig cyclization in the presence of an excess of TBAF, albeit
in variable yields (eq 1).6 In an attempt to expand the scope of this
transformation, we were surprised to find silyl enol ether 1b, which
lacks the 4-isopropyl substituent, was considerably more resistant
to cyclization with TBAF in THF, yielding only 13% of 3b (Table
1, entry 1). Seeking improvement, a number of weak bases and
fluoride sources were examined. Best results were obtained using
carbonates and phosphates in conjunction with a noncoordinating
cation. DMF was found to be the optimal solvent, as the use of
other polar aprotic solvents resulted in diminished yields.
Unfortunately, exposure of 1c and 1d to Cs2CO3 in DMF led to
only trace quantities of bicycles 3c and 3d, respectively (Scheme
1). In need of more active substrates, we probed the identity of the
propargylic leaving group. Iodide/chloride exchange was facile
using the Finkelstein reaction.7 For the cyclization of 2b, weak,
noncoordinating bases in DMF were again effective, with reaction
times being significantly shorter than with 1b (Table 1, entries
5-10). Fluoride sources were the most effective promoters. The
best reagent/solvent combinations were TBAF in THF or MeCN
and TBAT in DMF or MeCN; however, TBAF in THF was chosen
for further experiments for the combination of efficiency and rapid
reaction rate that these conditions engendered.
Using the propargylic iodides,8 a variety of VCPs could be
prepared from the corresponding silyl enol ethers in fair to excellent
yields in 5 min (Scheme 2). Our structural assignment of these
products as VCPs was confirmed by an X-ray crystallographic study
of the 2,4-dinitrophenylhydrazone derived from 3b.9 Unexpectedly,
replacement of the keto ester moiety with a lactone ester or keto
nitrile attenuated the efficiency of the cyclization (3c and 3f). We
were initially unable to prepare products from secondary or tertiary
halides, because of difficulty in preparing the substrate iodides.
Fortunately, a secondary chloride and tertiary bromide were
successfully cyclized with TBAF although the reactions were more
sluggish, requiring 9 and 0.75 h, respectively. We believe these
hindered halides are less prone to intermolecular side-reactions than
the primary halides, leading to efficient intramolecular cyclization.
A slight modification of the reaction conditions was required to
extend this methodology to acyclic systems. Only 8% of 3i was
formed when TBAF was added to a solution of the corresponding
iodide in THF, with oligomers being the main byproducts. We
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9180 J. AM. CHEM. SOC. 2008, 130, 9180–9181
10.1021/ja803553a CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Further Transformations of VCP Products
Scheme 2. Scope of the 3-Exo-Dig Cyclization of Propargyl
Halidesa,b
product VCPs from electron-poor alkenes has limited any study of
their synthetic utility which, in light of the unique display of reactive
functionality, could be substantial.
a Conditions: Silyl enol ether propargyl iodide (1.0 equiv) and TBAF
(1.2 equiv) in THF (0.05 M) at room temperature unless otherwise noted.
b Values represent isolated yields (average of at least two experiments).
c Substrate for cyclization was the unsilylated diester. d TBAF (2.0 equiv).
e Propargyl chloride was used. f Propargyl bromide was used. g Syringe pump
addition (0.04 mmol/min) of diester 2 to TBAF (2.0 equiv) in THF (0.07
M).
Acknowledgment. This work was supported by the NSF (Grants
CHE-0239363 and CHE-0749691). X-ray crystallography was
performed by Dr. Peter White. K.O. acknowledges a Research
Fellowship for Young Scientists from the Japan Society for the
Promotion of Science. J.S.J. is an Alfred P. Sloan Fellow and a
Camille-Dreyfus Teacher Scholar.
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.
References
(1) (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734–736. (b)
Baldwin, J. E.; Cutting, J.; Dupont, W.; Kruse, L.; Silberman, L.; Thomas,
R. C. J. Chem. Soc., Chem. Commun. 1976, 736–738. (c) Baldwin, J. E.;
Thomas, R. C.; Kruse, L. I.; Silberman, L. J. Org. Chem. 1977, 42, 3846–
3852.
(2) For selected examples: (a) Ichikawa, J.; Lapointe, G.; Iwai, Y. Chem.
Commun. 2007, 2698–2700. (b) Salem, B.; Klotz, P.; Suffert, J. Org. Lett.
2003, 5, 845–848. (c) Robin, S.; Rousseau, G. Eur. J. Org. Chem. 2000,
3007–3011. (d) Doan, H. D.; Gallon, J.; Piou, A.; Vate`le, J.-M. Synlett 2007,
983–985. (e) Janda, K. D.; Shevlin, C. G.; Lerner, R. A. Science 1993, 259,
490–493. (f) Bogen, S.; Fensterbank, L.; Malacria, M. J. Am. Chem. Soc.
1997, 119, 5037–5038.
(3) Oxygen: (a) Berg, T. C.; Gundersen, L. -L.; Eriksen, A. B.; Malterud, K. E.
Eur. J. Org. Chem. 2005, 4988–4994. (b) Reisch, J.; Zappel, J.; Henkel, G.;
Ekiz-Gu¨cer, N. Monatsh. Chem. 1993, 124, 1169–1175. Nitrogen: (c)
Inokuchi, T.; Matsumoto, S.; Tsuji, M.; Torii, S. J. Org. Chem. 1992, 57,
5023–5027. Phosphorus: (d) Breen, T. L.; Stephan, D. W. J. Am. Chem.
Soc. 1995, 117, 11914–11921.
Figure 1. Conformational analysis of cyclization.
reasoned that intermolecular substitution was dominant without the
conformational constraints found in the cyclic systems that orient
the alkyne in the reactive conformation. The use of high dilution
conditions was predicted to disfavor intermolecular alkylation and
select for the desired intramolecular cyclization. Because of the
fast cyclization rate, we were able to use syringe pump addition of
the iodide to a solution of TBAF in THF over 40 min. The volume
of THF was kept at a manageable level while still operating under
low substrate concentrations ([R-I]t ≈ 10-4 M). The linear
substrates cyclized in good yields using this procedure.
The efficiency with which 1a undergoes cyclization relative to
1b can be explained through analysis of the competing half-chair
conformations (Figure 1). Keq is expected to be larger for 1a than
1b as a consequence of an unfavorable gauche interaction in the
diequatorial conformation. This results in a higher concentration
of the reactive diaxial conformation.
Preliminary experiments show that these VCPs can undergo
selective addition reactions such as hydroboration, hydrogenation,
and iodination (Scheme 3). It was necessary to reduce the ketone
when using metal-catalyzed processes to prevent ring opening of
the cyclopropane via ꢀ-carbon elimination.
(4) (a) Hartzler, H. D. J. Am. Chem. Soc. 1961, 83, 4990–4996. (b) Bleiholder,
R. F.; Shechter, H. J. Am. Chem. Soc. 1964, 86, 5032–5033. (c) Isagawa,
K.; Mizuno, K.; Sugita, H.; Otsuji, Y. J. Chem. Soc., Perkin Trans. 1 1991,
2283–2285.
(5) (a) Zhang, Y.-P.; Lu, J.-M.; Xu, G.-C.; Shi, M. J. Org. Chem. 2007, 72,
509–516. (b) Shi, M.; Lu, J.-M. J. Org. Chem. 2006, 71, 1920–1923, and
references therein.
(6) Pohlhaus, P. D., Ph.D. Thesis, University of North Carolina at Chapel Hill:
Chapel Hill, NC, 2006.
(7) Finkelstein, H. Ber. Dtsch. Chem. Ges. 1910, 43, 1528.
(8) Enolsilane substrates were prepared by TBSOTf-promoted conjugate addition
of alkynyltrimethylaluminates to enones. Diester substrates were prepared
either by alkylation of dimethyl malonate or the conjugate addition of
alkynyldiethylalanes to Knoevenagel condensation products. Full preparative
details are given in the Supporting Information.
(9) CCDC 671491 contains the supplementary crystallographic data for this
compound. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
In conclusion, we have described simple and efficient 3-exo-dig
cyclizations of propargylic halides possessing a suitably placed
active methine. The prior dearth of reactions for accessing the
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