Thermodynamic control of diastereoselectivity in the formal nucleophilic substitution of bromocyclopropanes

Article abstract of DOI:10.1021/ol100187c

(Figure Presented) A new, general, and chemoselective protocol for the formal nucleophilic substitution of 2-bromocyclopropylcarboxamides is described. A wide range of alcohols and phenols can be employed as pronucleophiles in this transformation, providi

Full text of DOI:10.1021/ol100187c

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1488-1491
Thermodynamic Control of
Diastereoselectivity in the Formal
Nucleophilic Substitution of
Bromocyclopropanes
Joseph E. Banning, Anthony R. Prosser, and Michael Rubin*
Department of Chemistry, UniVersity of Kansas, 1251 Wesoce Hall DriVe,
Lawrence, Kansas 66045-75832
mrubin@ku.edu
Received January 25, 2010
ABSTRACT
A new, general, and chemoselective protocol for the formal nucleophilic substitution of 2-bromocyclopropylcarboxamides is described. A
wide range of alcohols and phenols can be employed as pronucleophiles in this transformation, providing expeditious access to trans-
cyclopropanol ethers. A new mode of the selectivity control through a thermodynamic equilibrium is realized, alternative to the previously
described steric and directing modes.
Stereochemically defined and densely substituted cyclopro-
panes are readily available from the corresponding cyclo-
propenes via a number of highly diastereoselective additions
of various entities across the strained double bond.1,2 At the
same time, only a limited number of cyclopropenes can boast
a long shelf life, while most of the others are relatively short-
living species and require special handling. Trying to
circumvent this problem, we recently developed a process3
that allows us to generate reactive cyclopropene intermediates
2 in situ from a stable bromocyclopropane precursor 1 in
the presence of t-BuOK and catalytic 18-crown-6.4 Subse-
quent nucleophilic attack of 2 by an alkoxide provided
stereodefined cyclopropanol derivatives 3 in good yield
(Scheme 1, eq 1). It was shown that the diastereoselectivity
of the latter step could be efficiently controlled by either
steric or directing effect.3
While all of the previously reported examples involved
relatively stable, isolable 3,3-disubstituted cyclopropene
intermediates,4 the main goal of the present study was to
make this methodology applicable to more reactive, nonisol-
able monosubstituted cyclopropenes.5 Our initial experiment
demonstrated that treatment of disubstituted cyclopropane
4a (used as a mixture of trans- and cis-isomers, 2:1) with
excess t-BuOK provided tert-butyl ether 6aa in good yield
(Scheme 1, eq 2).3 Much to our surprise, the diastereose-
lectivity of the addition was opposite to that observed before
with all amide-containing substrates. Thus, instead of the
expected cis-selectivity, resulting from directing control, the
trans-diastereomer was obtained predominantly.6 We ratio-
nalized that this selectivity is governed by a thermodynami-
cally driven isomerization, involving deprotonation of the
(1) For reviews, see: (a) Rubin, M.; Rubina, M.; Gevorgyan, V. Chem.
ReV. 2007, 107, 3117. (b) Rubin, M.; Rubina, M.; Gevorgyan, V. Synthesis
2006, 1221. (c) Marek, I.; Simaan, S.; Masarwa, A. Angew. Chem., Int.
Ed. 2007, 46, 7364. (d) Fox, J. M.; Yan, N. Curr. Org. Chem. 2005, 9,
719
.
(2) For recent contributions, see: (a) Tarwade, V.; Liu, X.; Yan, N.;
Fox, J. M. J. Am. Chem. Soc. 2009, 131, 5382. (b) Sherrill, W. M.; Rubin,
M. J. Am. Chem. Soc. 2008, 130, 13804. (c) Alnasleh, B. K.; Sherrill, W. M.;
Rubin, M. Org. Lett. 2008, 10, 3231. (d) Levin, A.; Marek, I. Chem.
Commun. 2008, 4300. (e) Yan, N.; Liu, X.; Fox, J. M. J. Org. Chem. 2008,
73, 563. (f) Trofimov, A.; Rubina, M.; Rubin, M.; Gevorgyan, V. J. Org.
Chem. 2007, 72, 8910. (g) Simaan, S.; Marek, I. Org. Lett. 2007, 9, 2569
.
(3) Alnasleh, B. K.; Sherrill, W. M.; Rubina, M.; Banning, J.; Rubin,
M. J. Am. Chem. Soc. 2009, 131, 6906.
(5) There is a single precedent of formal substitution (Nu ) MeO) of
2-bromocyclopropanecarboxylic acid derivative, which provided marginal
yield and poor diastereoselectivity. See: Taylor, E. C.; Hu, B. Synth.
Commun. 1996, 26, 1041.
(4) For preparative synthesis of cyclopropenes via this route, see: Sherrill,
W. M.; Kim, R.; Rubin, M. Synthesis 2009, 1477.
10.1021/ol100187c  2010 American Chemical Society
Published on Web 03/10/2010

described transformation is puzzling, it was a long sought-
after solution that allowed for combining the 1,2-elimination
reaction and addition of an alkoxide, generated in situ from
an appropriate alcohol pronucleophile, in a sequential
chemoselective transformation (eq 5, Table 1).
Scheme 1
Table 1. Formal Nucleophilic Substitution of
Bromocyclopropanes with Alkoxidesa
no.
R1, R2
RO
product yield, %b
drc
1
2
3
4
5
6
7
8
t-Bu, H n-PrO
t-Bu, H MeOCH2CH2O
Et, Et MeOCH2CH2O
t-Bu, H CH2dCH(CH2)3O
morphd CH2dCH(CH2)3O
t-Bu, H m-NO2C6H4CH2O
6ab
6ac
6bc
6ad
6cd
6ae
6be
6bf
6ag
6ah
6ai
6aj
6ak
6al
71
97
87
85
84
81
93
87e
71
59
50
79
75
86
80
90
74
9:1
8:1
16:1
7:1
12:1
8:1
7:1
6:1
9:1
10:1
25:1
6:1
7:1
8:1
10:1
10:1
10:1
Et, Et
Et, Et
m-NO2C6H4CH2O
C6H4CH2O
acidic C-H in R-position to the amide function. We found
this result very exciting, since it opened the possibility for
exploiting a new mode of selectivity control. However, when
this reaction was performed in the presence of external
nucleophile source (ROH), a competing addition of two
nucleophiles across the conjugated double bond of mono-
substituted cyclopropene intermediate 5a was observed
(Scheme 1, eq 3), producing notable amounts of unwanted
tert-butoxide adduct 6aa. Apparently, nucelophilicity of even
such bulky base as tert-butoxide was significant enough to
cause addition across the extremely activated strained double
bond. To address this issue, we tested a series of alternative,
non-nucleophilic bases in this reaction; however, most of
them (such as NaH, LDA, and LiHMDS) were unable to
generate cyclopropene intermediate 5a. After substantial
experimentation, we discovered that the use of powedered
KOH allowed for smooth 1,2-elimination, with no subsequent
addition of the hydroxide ion to the cyclopropene double
bond (eq 4). Indeed, even after prolonged heating at 110
9
t-Bu, H i-PrO
t-Bu, H HCt C-CMe2O
t-Bu, H Ph3CO
10
11
12
13
14
15
16
17
t-Bu, H PhO
t-Bu, H p-MeOC6H4O
t-Bu, H p-BrC6H4O
t-Bu, H p-IC6H4O
t-Bu, H p-PhCOC6H4O
t-Bu, H p-NCC6H4O
6am
6an
6ao
a Reactions performed in 0.5 mmol scale unless specified otherwise.
b Isolated yields of diasteriomeric mixtures. c dr (trans:cis) determined by
GC or 1H NMR analysis of crude reaction mixtures. d morph ) morpholine
derivative, R1R2 ) (CH2CH2)2O. e Reaction performed in 8 mmol scale.
Thus, the reaction of bromocyclopropane 4a with KOH
in the presence of n-propanol and catalytic amounts of 18-
crown-6 proceeded smoothly affording trans-n-propoxide
adduct 6ab in good yield and high diastereoselectivity (eq
5, Table 1, entry 1). Other primary alkoxides, possessing
functional groups, such as a methyl ether or an isolated CdC
double bond, were transferred very efficiently, providing the
corresponding cyclopropanol ethers 6ac, 6bc, 6ad, and 6cd
in high yields (entries 2-5).7 meta-Nitrobenzyl-protected
cyclopropanols 6ae and 6be were also obtained in very good
yieds from the corresponding benzyl alcohol (entries 6-7).
The reaction with benzyl alcohol was easily scaled up to 8
mmol scale: product 6bf was obtained after vacuum distil-
lation in 87% yield (entry 8). The reaction of 6a with
secondary propanol also proceeded uneventfully, providing
isopropyl ether 6ag in good yield (entry 9). Much less
nucleophilic alkoxides generated from bulky tertiary prop-
argyl alcohol were also efficiently intercepted with cyclo-
°C, cyclopropene 8,4 generated from bromocyclopropane 7
in the presence of KOH and 18-crown-6, did not show any
traces of addition or decomposition (eq 4). Although such
extremely low nucleophilicity of hydroxide species in the
(7) Starting 2-bromocyclopropanecarboxamides are readily available
from the known 2,2-dibromocyclopropanecarbonyl chloride via reaction with
the corresponding amine, followed by partial reduction of halogen with
i-PrMgBr. See Supporting Information for details.
(6) For trans-selective formal nucleophilic substitution of 2-bromocy-
clopropanecarboxylate with tert-butoxide, see: Wiberg, K. B.; Barnes, R. K.;
Albin, J. J. Am. Chem. Soc. 1957, 79, 4994.
Org. Lett., Vol. 12, No. 7, 2010
1489

propene intermediate, affording product 6ah, albeit in a
somewhat lower yield (entries 10). Remarkably, no addition
of the acetylide species generated from terminal alkyne was
observed under the described reaction conditions.8 Finally,
an extremely sterically hindered trityl ether 6ai was prepared
successfully by the reaction of 6a with triphenylmethanol
(entry 11).
ethers (6ak, 6al, 6am, 6an, 6ao) in high yields (entires
13-17). Regardless of the nucleophile source, all these
additions provided trans-cyclopropylethers as major products
(Table 1). However, in some cases, relatively low basicity
of the non-nucleophlic hydroxide led to incomplete epimer-
ization of the minor cis-isomer of product 6 into the
thermodynamically more favorable trans-isomer (Table 1,
entries 8, 12). Neither addition of excess KOH to the reaction
mixture nor extension of the reaction time improved the
selectivity of this reaction. To address this issue, isolated
mixtures of products were treated with t-BuOK, which
allowed for significant improvement of the diastereomeric
ratios for all tested compounds without notable decomposi-
tion (Table 2, eq 6).
Table 2. t-BuOK-Assisted Epimerization Leading to
Improvement of Diastereomeric Ratiosa
dr before
dr after
material
treatment
treatment
balance, %
6ab
6ac
6ad
6ag
6aj
6al
6ao
6bf
9:1
8:1
7:1
9:1
6:1
8:1
10:1
6:1
39:1
19:1
19:1
16:1
>50:1
46:1
100
97
95
96
96
100
96
100
42:1
>50:1
a Material balance and diastereomeric ratios were determined by
quantitative GC analysis of crude reaction mixtures using n-decane as the
internal standard.
Having met succes with addition of alkoxides, we at-
tempted to extend this methodology to addition of aryloxide
species. We have previously shown that, in contrast to
alkoxides, softer phenoxides did not react as nucleophilic
components in the formal substitution reaction of bromocy-
clopropanes of type 1, mediated by t-BuOK (eq 1, Nu )
ArO).3,9 We rationalized that the aptitude toward addition
of these nucleophiles to the soft conjugated double bond of
cyclopropene intermediate 5 should be significantly higher.
To our delight, these expectations were realized to full extent.
Thus, the reaction between phenol and cyclopropylbromide
1a provided phenyl ether 6aj in good isolated yield and
diastereoselectivity (entry 12). Other aryloxides also reacted
smoothly producing the corresponding aryl cyclopropyl
Figure 1. Swain-Lupton LFER Studies for Formal Nucleophilic
Substitution of Bromocyclopropane 4a with Aryloxides.10
It also deserves noting that formal substitution with
phenoxides proceeded much slower and required higher
temperatures to achieve complete conversion, as compared
to analogous reactions with alkoxides. This difference can
be explained in terms of increased acidity of phenols, which
readily produce phenoxides and water by a stoichiometric
reaction with KOH. Although small amounts of moisture do
not adversly affect this transformation, formation of the
hydroxide-phenoxide “buffer” lowers the effective basisity
of the system. This, in turn, results in significant deceleration
of the dehydrobromination step, which is a rate-determining
(8) For direct transition metal-catalyzed addition of terminal alkynes
across the double bond of cyclopropenes, see: Yin, J.; Chisholm, J. D. Chem.
Commun. 2006, 632.
(9) For preparation of cyclopropyl ethers via alkylation of alcohols and
phenols with c-C3H5Br, see: (a) Chandru, H.; Sharada, A. C.; Bettadaiah,
B. K.; Ananda, K., C. S.; Rangappa, K. S.; Jayashree, K. Bioorg. Med.
Chem. 2007, 15, 7696. (b) Corbett, J. W.; Rauckhorst, M. R.; Qian, F.;
Hoffman, R. L.; Knauer, C. S.; Fitzgerald, L. W. Bioorg. Med. Chem. Lett.
2007, 17, 6250–6256. (c) Chiu, G.; Li, S.; Connolly, P. J.; Pulito, V.; Liu,
J.; Middleton, S. A. Bioorg. Med. Chem. Lett. 2007, 17, 3930. (d) van
Tilburg, E. W.; van der Klein, P. A. M.; von Frijtag Drabbe Kuenzel, J. K.;
de Groote, M.; Stannek, C.; Lorenzen, A.; Ijzerman, A. P. J. Med. Chem.
2001, 44, 2966
.
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Org. Lett., Vol. 12, No. 7, 2010

step in this reaction.11 The Swain-Lupton LFER parameters
obtained from a series of competing parallel reactions reveal
a profound negative F-value, indicating the diminution of
the negative charge in the anionic phenoxide reagent as a
result of addition to an electrophilic double bond (Figure
1).
reversible nucleophilic addition of an alkoxide or aryloxide
species. To clarify the mechanism, we performed a crossover
experiment employng a pair of 2-alkoxycyclopropane car-
boxamides 6ac and 6be, bearing different alkoxide and amide
groups. A mixture of these compounds was subjected to the
typical reaction conditions in the presence of either KOH or
t-BuOK as a base. In both cases no formation of crossover
products 6ae and 6bc was detected by GC analysis of crude
reaction mixtures (Scheme 2). These results strongly support
irreversibility of the nucleophilic addition step which, in turn,
suggests that thermodynamic control of the diastereoselec-
tivity in this reaction is exclusively realized via a base-assited
epimerization of the R-CH group.
Scheme 2
.
Crossover Experiments Demonstrating Irreversible
Addition of Alkoxide Speciesa
In conclusion, we have developed an efficient formal
substitution of 2-bromocyclopropanecarboxamides with both
hard and soft oxygen-based nucleophiles (alkoxides and
aryloxides) in the presence of powdered potassium hydroxide
and catalytic amounts of 18-crown-6. The reaction is tolerant
to steric hindrance and electronic properties of the nucleo-
phile and predominantly produces trans-products via a
thermodynamically driven base-assisted epimerization. This
new mode of the diastereoselectivity control is complemen-
tary to the previously reported cis-selective addition governed
by a directing effect of an amide function. Further develop-
ment of this methodology to employ S-, N-, and C-based
nucleophiles is currently underway in our laboratories.
a Conditions i: 6ac (50 µmol), 6be (50 µmol), 18-crown-6 ((5 µmol),
KOH (175 µmol), THF (500 µL), 85 °C, 48 h. Conditions ii: The same,
but KOH was replaced with t-BuOK (175 µmol).
We also questioned whether thermodynamic control of the
diastereoselectivity is realized via epimerization of the tertiary
carbon atom adjacent to the amide functionality, or via a
Acknowledgment. We thank the University of Kansas,
the National Science Foundation (EEC-0310689), and the
McNair Scholars Program (ARP) for financial support.
(10) σ(-)-Values used are derived from Swain-Lupton parameters
adopted from: (a) Swain, C. G.; Lupton, E. C., Jr. J. Am. Chem. Soc. 1968,
90, 4328. (b) Williams, S. G.; Norrington, F. E. J. Am. Chem. Soc. 1976,
98, 508.
Supporting Information Available: Experimental details.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(11) This was confirmed by the fact that the overall kinetic rate of the
transformation did not depend on electronic properties of the phenoxide
species.
OL100187C
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