Stereoselective formation of alkenyl halides via magnesium halide promoted ring opening of bis-activated cyclopropenes

Article abstract of DOI:10.1021/jo802475x

In the presence of stoichiometric magnesium halides, a range of bis-activated cyclopropenes undergo highly stereoselective ring-opening reactions to produce multisubstituted alkenyl halides. More highly functionalized compounds may be obtained by trapping

Full text of DOI:10.1021/jo802475x

targets and common structural components in numerous biologi-
cally active natural products and pharmaceuticals.3 The strain
energy of cyclopropenes may also be exploited in a host of
cycloaddition and rearrangement reactions, providing numerous
other molecules of interest.1
During our recent investigations into the development of
stereoselective carbometalation-ring-opening reactions of bis-
activated cyclopropenes to produce multisubstituted alkenes,2d
the reaction of cyclopropene 1a with commercially available
Grignard reagent 2 was conducted (eq 1). Instead of furnishing
products derived from addition of the nucleophilic alkyl
functionality of 2, the major product isolated in this reaction
was the alkenyl bromide 3a. We attributed this initially
surprising result to reaction of cyclopropene 1a with magnesium
bromide produced from the Schlenk equilibrium4 of the Grignard
reagent. This hypothesis was supported by reaction of 1a with
MgBr2 itself, which also produced 3a, but in 96% yield (eq 2).
Stereoselective Formation of Alkenyl Halides via
Magnesium Halide Promoted Ring Opening of
Bis-Activated Cyclopropenes
Yi Wang and Hon Wai Lam*
School of Chemistry, UniVersity of Edinburgh,
The King’s Buildings, West Mains Road,
Edinburgh, EH9 3JJ, United Kingdom
h.lam@ed.ac.uk
ReceiVed NoVember 5, 2008
In the presence of stoichiometric magnesium halides, a range
of bis-activated cyclopropenes undergo highly stereoselective
ring-opening reactions to produce multisubstituted alkenyl
halides. More highly functionalized compounds may be
obtained by trapping of the magnesium enolate intermediates
in situ.
This process is closely related to the results of Ma and co-
workers, who described a series of alkali metal halide induced
cyclopropene ring-opening-alkylation reactions that required
an alkali metal carbonate additive for highest yields (representa-
tive example shown in eq 3).5a However, their process differs
from ours in that simple protonolysis of the initial ring-opened
species was not described in their work.5a The majority of
examples described by Ma were conducted using a bis-activated
cyclopropene that was unsubstituted at the alkene, although four
results using trisubstituted cyclopropenes were reported (as in
eq 3).5a
Cyclopropenes, the smallest unsaturated carbocycles, are an
important class of building blocks for organic synthesis.1 The
high strain energy stored within the three-membered ring of
cyclopropenes may be harnessed in the design of novel chemical
transformations that are often unavailable to simple alkenes.1,2
For example, cyclopropenes are highly susceptible to a broad
range of addition reactions across the double bond1b to provide
functionalized cyclopropanes, which themselves are important
(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) Fisher, L. A.; Fox, J. M. J. Org. Chem. 2008, 73, 8474–
8478. (b) Sherill, W. M.; Rubin, M. J. Am. Chem. Soc. 2008, 130, 13804–13809.
(c) Fordyce, E. A. F.; Luebbers, T.; Lam, H. W. Org. Lett. 2008, 10, 3993–
3996. (d) Wang, Y.; Fordyce, E. A. F.; Chen, F. Y.; Lam, H. W. Angew. Chem.,
Int. Ed. 2008, 47, 7350–7353. (e) Pallerla, M. K.; Yap, G. P. A.; Fox, J. M. J.
Org. Chem. 2008, 73, 6137–6141. (f) Alnasleh, B. K.; Sherrill, W. M.; Rubin,
M. Org. Lett. 2008, 10, 3231–3234. (g) Yan, N.; Liu, X.; Fox, J. M. J. Org.
Chem. 2008, 73, 563–568. (h) Fordyce, E. A. F.; Wang, Y.; Luebbers, T.; Lam,
H. W. Chem. Commun. 2008, 1124–1126. (i) Rubina, M.; Woodward, E. W.;
Rubin, M. Org. Lett. 2007, 9, 5501–5504. (j) Masarwa, A.; Stanger, A.; Marek,
I. Angew. Chem., Int. Ed. 2007, 46, 8039–8042. (k) Trofimov, A.; Rubina, M.;
Rubin, M.; Gevorgyan, V. J. Org. Chem. 2007, 72, 8910–8920. (l) Chuprakov,
S.; Malyshev, D. A.; Trofimov, A.; Gevorgyan, V. J. Am. Chem. Soc. 2007,
129, 14868–14869. (m) Hirashita, T.; Shiraki, F.; Onishi, K.; Ogura, M.; Araki,
S. Org. Biomol. Chem. 2007, 5, 2154–2158. (n) Giudici, R. E.; Hoveyda, A. H.
J. Am. Chem. Soc. 2007, 129, 3824–3825.
To establish whether the serendipitous result of eq 2 could
be translated into a general and efficient process, a range of
bis-activated cyclopropenes 1a-1g were reacted with stoichio-
metric quantities of magnesium halides, and these results are
presented in Table 1. Using MgBr2, cyclopropenes 1a-1e
containing alkyl or aryl functionality on the alkene efficiently
underwent the ring-opening reaction to provide alkenyl bromides
(3) (a) Liu, H. W.; Walsh, C. T. Biochemistry of the Cyclopropyl Group In
The Chemistry of the Cyclopropyl Group; Rappoport, Z., Ed.; Wiley: Chichester,
UK, 1987; pp 959-1025. (b) Salaun, J. Top. Curr. Chem. 2000, 207, 1–67.
(4) Schlenk, W.; Schlenk, W., Jr. Chem. Ber. 1929, 62, 920–924.
10.1021/jo802475x CCC: $40.75
Published on Web 12/30/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1353–1355 1353

TABLE 1. Magnesium Halide Mediated Ring Openings of Various
Cyclopropenesa
SCHEME 1. Possible Mechanism
9 and 12). Unfortunately, no reaction occurred when MgF2 was
employed, presumably due to the low solubility of this salt.7
The stereochemical outcome of these reactions, where inver-
sion of configuration at the electrophilic vinylic center is
observed, suggests that an in-plane SN2-type mechanism8,9 (also
referred to as SNVσ9e) is operative, rather than an addition-
elimination process similar to that proposed in related cyclo-
propene carbometalation-ring-opening reactions.2d Although
SNVσ mechanisms had long been considered to be energetically
unfavorable compared to alternative pathways,10 a growing body
of theoretical8 and experimental9 work suggests that this process
is favorable in certain reactions.
Therefore, a possible mechanism for magnesium halide
promoted cyclopropene ring opening, using a dimethyl malo-
nate derived substrate for illustrative purposes, is outlined in
Scheme 1. It is likely that bidentate coordination of magnesium
halide to the cyclopropene (as in 4) promotes nucleophilic attack
by the halide ion to provide (via transition state 5) magnesium
enolate 6 that is protonated upon workup to furnish the product.
This mechanistic scenario suggested that trapping of the
magnesium enolates 6 to generate more highly functionalized
products might be possible, in similar fashion to the results of
Ma and co-workers (eq 3).5a Accordingly, various one-pot
multicomponent coupling reactions of bis-activated cyclopro-
penes, magnesium halides, and different electrophiles were
investigated. However, we found these enolates to be rather
unreactive, though Michael additions to ꢀ-unsubstituted enones
using acetonitrile as the solvent were possible, without the
requirement for additional basic additives (Scheme 2).5a
In summary, magnesium halide salts promote ring-opening
reactions of bis-activated cyclopropenes to provide trisubstituted
alkenyl halides with high stereoselectivities. The magnesium
enolates that are produced in these reactions may be trapped
with enones to result in more highly functionalized products.
Compared with related reactions,5a this work extends the scope
of the nucleophilic and electrophilic components to encompass
chloride anions and enones, respectively, increasing the range
of products that may be accessed.
a Reactions were carried out using 0.20 mmol of cyclopropene in
THF (2 mL). b A preparative scale reaction conducted using 2.00 mmol
of cyclopropene 1a in THF (20 mL) also provided 3a in 96% yield.
c Product isolated as an inseparable 9:1 Z:E mixture. d Reaction
conducted at 40 °C. e The product was accompanied by ca. 6% of an
inseparable regioisomeric impurity.
3a-3e, respectively, in good yields and with high stereoselec-
tivities6 (entries 1-5). In all cases, the bromide anion attacked
the least substituted carbon of the alkene with high selectivity,
though small quantities of regioisomeric products were observed
in a few cases (entries 10 and 11). This regioselectivity is
opposite to that seen in the large majority of cyclopropene
carbometalation and hydrometalation reactions described
previously1d but is consistent with the results of Ma and co-
workers (eq 3).5a Ring openings with MgI2 and MgCl2 also
occurred smoothly to furnish alkenyl halides 3f-3l (entries
6-12), though a reaction temperature of 40 °C was required in
the case of MgCl2 (entries 10-12). The ability to prepare alkenyl
chlorides is notable since this feature was not reported
previously.5a In addition to dimethyl malonate derived substrates
1a-1e, cyclopropenes 1f and 1g containing ethyl esters or a
phenylsulfone, respectively, were competent substrates (entries
Experimental Section
General Procedure A: Magnesium Halide Mediated Ring
Opening of Cyclopropenes. A solution of the appropriate cyclo-
(7) Reactions conducted using other fluoride salts such as ZnF2, KF, and
CsF in THF or MeCN at elevated temperatures also returned unchanged starting
material.
(8) (a) Glukhovtsev, M. N.; Pross, A.; Radom, L. J. Am. Chem. Soc. 1994,
116, 5961–5962. (b) Luchini, V.; Modena, G.; Pasquato, L. J. Am. Chem. Soc.
1995, 117, 2297–2300. (c) Kim, C. K.; Hyun, K. H.; Kim, C. K.; Lee, I. J. Am.
Chem. Soc. 2000, 122, 2294–2299. (d) Bach, R. D.; Baboul, A. G.; Schlegel,
H. B. J. Am. Chem. Soc. 2001, 123, 5787–5793.
(9) (a) Ochiai, M.; Oshima, K.; Masaki, Y. J. Am. Chem. Soc. 1991, 113,
7059–7061. (b) Okuyama, T.; Takino, T.; Sato, K.; Ochiai, M. J. Am. Chem.
Soc. 1998, 120, 2275–2282. (c) Ochiai, M.; Nishi, Y.; Hirobe, M. Tetrahedron
Lett. 2005, 46, 1863–1866. (d) Shiers, J. J.; Shipman, M.; Hayes, J. F.; Slawin,
A. M. Z. J. Am. Chem. Soc. 2004, 126, 6868–6869. (e) Miyauchi, H.; Chiba, S.;
Fukamizu, K.; Ando, K.; Narasaka, K. Tetrahedron 2007, 63, 5940–5953. See
also ref 5a.
(5) (a) Ma, S.; Zhang, J.; Cai, Y.; Lu, L. J. Am. Chem. Soc. 2003, 125, 13954–
13955. For halide-catalyzed cycloproprene ring-opening-cycloaddition reactions
with imines, see: (b) Ma, S.; Zhang, J.; Lu, L.; Jin, X.; Cai, Y.; Hou, H. Chem.
Commun. 2005, 909–911.
(6) The stereochemistries of alkenyl halides 3a, 3d, 3k, and 7a were
determined on the basis of NOESY experiments. See Supporting Information
for details.
(10) Kelsey, D. R.; Bergman, R. G. J. Am. Chem. Soc. 1971, 93, 1953–
1961.
1354 J. Org. Chem. Vol. 74, No. 3, 2009

SCHEME 2. One-Pot Cyclopropene Ring-Opening-Michael
Reactions
General Procedure B: One-Pot Magnesium Halide Medi-
ated Ring-Opening-Michael Reactions of Cyclopropenes. A
solution of the appropriate cyclopropene (0.20 mmol) in MeCN
(1 mL + 1 mL rinse) was added via cannula to a vial containing
the appropiate enone (0.40 mmol), MgBr2 (37 mg, 0.20 mmol),
and a stirrer bar. The resulting mixture was stirred at 40 °C for
18 h. After cooling to room temperature, the mixture was filtered
through a short plug of SiO2 (ca. 4 cm high × 2 cm diameter)
using EtOAc as eluent (ca. 50 mL), and the filtrate was concentrated
in vacuo. Purification of the residue by column chromatography
afforded the alkenyl halide product.
(Z)-Dimethyl 2-(2-bromo-1-phenylvinyl)-2-(3-oxobutyl)ma-
lonate (7a). The title compound was prepared according to General
Procedure B from cyclopropene 1a (46 mg, 0.20 mmol) and methyl
vinyl ketone (32 µL, 0.40 mmol) and purified by column chroma-
tography (10-30% EtOAc/hexane) to give a colorless oil (60 mg,
78%): IR (CHCl3) 2953, 1735 (CdO), 1613, 1491, 1437, 1366,
a The product was accompanied by ca. 5% of an inseparable regioiso-
meric impurity. b Yield in parentheses refers to a reaction conducted using
8.00 mmol of cyclopropene 1a.
1254, 1171, 1092, 1030 cm-1 1H NMR (360 MHz, CDCl3) δ
;
propene (0.20 mmol) in THF (1 mL + 1 mL rinse) was added via
cannula to a vial containing the appropriate magnesium halide (0.20
mmol) and a stirrer bar. The resulting mixture was stirred at the
indicated temperature for the indicated time and then filtered through
a short plug of SiO2 (ca. 4 cm high × 2 cm diameter) using EtOAc
as eluent (ca. 50 mL). After the filtrate was concentrated in vacuo,
purification of the residue by column chromatography afforded the
alkenyl halide product.
7.38-7.31 (3H, m), 7.07-7.05 (2H, m), 6.92 (1H, s), 3.71 (6H, s),
2.53-2.50 (2H, m), 2.27-2.24 (2H, m), 2.09 (3H, s); 13C NMR
(62.9 MHz, CDCl3) δ 206.6 (C), 169.5 (2 × C), 141.4 (C), 137.1
(C), 128.8 (2 × CH), 128.3 (2 × CH), 128.2 (CH), 112.3 (CH),
63.7 (C), 52.8 (2 × CH3), 39.0 (CH2), 29.9 (CH3), 28.2 (CH2);
HRMS (ES) exact mass calcd for C17H2079BrO5 [M + H]+ 383.0489,
found 383.0492.
(Z)-Dimethyl 2-(2-bromo-1-phenylvinyl)malonate (3a). The
title compound was prepared according to General Procedure A
from cyclopropene 1a (46 mg, 0.20 mmol) and MgBr2 (37 mg,
0.20 mmol) at room temperature for 2 h and purified by column
chromatography (hexane f 5% EtOAc/hexane) to give a colorless
oil (60 mg, 96%): IR (film) 2954, 2846, 1738 (CdO), 1620, 1491,
1437, 1265, 1201, 1151, 1076 cm-1; 1H NMR (360 MHz, CDCl3)
δ 7.41-7.38 (2H, m), 7.36-7.31 (3H, m), 6.75 (1H, d, J ) 0.6
Hz), 4.50 (1H, d, J ) 0.6 Hz), 3.76 (6H, s); 13C NMR (62.9 MHz,
CDCl3) δ 167.1 (2 × C), 138.1 (C), 137.2 (C), 128.4 (2 × CH),
128.3 (2 × CH), 128.2 (CH), 110.6 (CH), 58.8 (CH), 52.9 (2 ×
CH3); HRMS (EI) exact mass calcd for C13H1379BrO4 [M+]
311.9992, found 311.9992.
Acknowledgment. This work was supported by EaStCHEM
(The Edinburgh and St. Andrews Research School of Chemis-
try). 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 proce-
dures and full spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO802475X
J. Org. Chem. Vol. 74, No. 3, 2009 1355