Lewis acid catalyzed (3 + 2)-annulations of donor-acceptor cyclopropanes and ynamides

Article abstract of DOI:10.1021/ol500256n

The Sc(OTf)₃-catalyzed (3 + 2)-annulation of donor-acceptor cyclopropanes and ynamides is described, providing the corresponding cyclopentene sulfonamides in good to excellent yield. Deprotection and hydrolysis of the resulting ensulfonamides delivers 2,3-substituted cyclopentanones with high diastereoselectivity.

Full text of DOI:10.1021/ol500256n

Letter
pubs.acs.org/OrgLett
Terms of Use
Lewis Acid Catalyzed (3 + 2)-Annulations of Donor−Acceptor
Cyclopropanes and Ynamides
William D. Mackay, Meryem Fistikci, Ryan M. Carris, and Jeffrey S. Johnson*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States
S
* Supporting Information
ABSTRACT: The Sc(OTf)3-catalyzed (3 + 2)-annulation of
donor−acceptor cyclopropanes and ynamides is described,
providing the corresponding cyclopentene sulfonamides in
good to excellent yield. Deprotection and hydrolysis of the
resulting ensulfonamides delivers 2,3-substituted cyclopenta-
nones with high diastereoselectivity.
onor−acceptor (D−A) cyclopropanes continue to receive
significant attention as useful synthetic building blocks,
ring-opening byproduct in the annulation between D−A
cyclopropanes and enolsilanes through the use of bulky silyl
groups (TBDPS) on the enolsilane and ester groups
(adamantyl) on the D−A cyclopropane.4s The use of allenyl
silanes eliminates the potential for subsequent ring opening;
however, these trials are complicated by 1,2-silyl migrations,
providing a mixture of cyclopentane alkylidene and cyclohexene
annulation products.4f Ready and Qi have shown ynolsilanes to
be effective annulation partners for D−A cyclopropanes under
Lewis acidic conditions, providing access to highly substituted
cyclopentenones.4j
D
particularly for their ability to act as synthetic equivalents to
1,3-dipolar synthons in cycloaddition reactions (eq 1).1 The
A common embodiment of annulations involving D−A
cyclopropanes is the use of a 1,1-cyclopropane diester in
conjunction with a Lewis acid activator to create an activated
intimate ion pair (eq 3). The site-selective capture of this
intimate ion pair by ynamide “dipolarophiles” is the subject of
this paper. The preparation of useful functionalized cyclo-
penten-1-yl sulfonamides by these (3 + 2)-annulations is
demonstrated. Deprotection of the ensulfonamide reveals 2,3-
substituted cyclopentanones with high levels of diastereose-
lectivity. This strategy provides access to an important
structural motif resembling the products of diastereoselective
1,4-addition to 2-substituted cyclopentenones.
deployment of these carbogenic building blocks has been
widespread in the efficient assembly of heterocycles by (3 + n)-
annulation (eq 2, a or b ≠ carbon),2 but fewer cases have been
described for carbocycle assembly (a, b = carbon).3−5
Notable examples of the latter include the annulation
between Pd π-allyl activated vinyl D−A cyclopropanes and
electron-deficient alkenes.3a,c,d Marino and Laborde have
achieved silyloxycyclopropane ester activation via fluoride-
induced silyl ether cleavage, which enables annulation with
activated alkenes to provide cyclopentanes.3b
In the realm of Lewis acid activation of the acceptor group,
Snider has shown EtAlCl2 to effectively catalyze the annulation
between D−A cyclopropanes and methylenecyclohexane
derivatives,4b providing spiro-bicyclic products with the
regioselectivity controlled by the preferential formation of a
tertiary carbocation; however, a mixture of regioisomers was
observed upon annulation with internal alkenes. Several groups
have reported annulations between D−A cyclopropanes and
enolsilanes providing cyclopentanes; the products commonly
undergo subsequent ring-opening under the reaction con-
ditions to provide linear products.4k,n Tang has suppressed the
Ynamides (2) have been shown to be excellent partners for
(n + 2) annulations6 due to the high regioselectivity with which
they react. This selectivity is typically attributed to the major
zwitterionic resonance structure. Despite this advantageous
reactivity, ynamides have remained unutilized in (3 + 2)-
annulations with D−A cyclopropanes (Figure 1); therefore, we
initiated investigations to assess the feasibility of applying
ynamides in this manifold.
Both the D−A cyclopropanes (1a−m)7 and ynamides
(2a,b)8 were prepared in short order according to literature
procedures. The monosubstituted cyclopropanes (1a,b,d−j,m)
were prepared by successive Knoevenagel and Corey−
Chaykovsky condensations.7a The 2,2-disubstituted cyclo-
Received: January 23, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol500256n | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
Table 1. Substrate Scope
c
entry
R1
4-MePh
R2
R3
pdt
yield (%)
1
H (1a)
H (1a)
H (1b)
H (1b)
Me (1c)
Me (1c)
H (1d)
H (1e)
H (1f)
C5H11
Ph
3a
3b
3c
3d
3e
3f
>99
>99
2
4-MePh
4-OMePh
4-OMePh
4-OMePh
4-OMePh
2-OMePh
2,3-(CH2O2)Ph
2-furyl
d
3
C5H11
Ph
89 (86)
4
>99
64
5
C5H11
Ph
6
53
Figure 1. Proposed annulation.
7
C5H11
C5H11
C5H11
C5H11
Ph
3g
3h
3i
>99
64
8
9
46
propanes (1c,k,l) were prepared via rhodium-catalyzed (2 + 1)-
annulation between dimethyl diazomalonate decomposition
and alkenes.7b Ynamides (2a,b) were prepared via copper-
catalyzed oxidative cross coupling of TsNHMe and the
corresponding terminal alkyne.8
10
11
12
13
14
15
16
17
2-thienyl
2-thienyl
(E)-CHCHPh
4-ClPh
H (1g)
H (1g)
H (1h)
H (1i)
3j
84
3k
3l
93
C5H11
C5H11
C5H11
C5H11
C5H11
C5H11
69
e
3m
3n
3o
3p
3q
NR
e
4-NMe2Ph
Ph
H (1j)
NR
f
Working first with cyclopropane 1b and ynamide 2a, we set
out to optimize the title transformation. A brief screen of Lewis
acids revealed Sc(OTf)3 to be a superior promoter for the
reaction, providing complete starting material conversion with
catalyst loadings as low as 10 mol %. The efficacy of this
particular Lewis acid is congruent with our previously
demonstrated (3 + 2)-annulation of D−A cyclopropanes with
aldehydes.9 Attempts to lower the catalyst loading further were
met with incomplete consumption of 1b after 20 h. Two
equivalents of the ynamide were required in the annulation to
maximize product yields as ynamide hydrolysis was found to be
a competitive decomposition pathway (see the Supporting
Information).
With the optimized conditions in hand, we began to examine
the scope of the annulation (Table 1). The reaction proceeded
smoothly for a number of substrates, particularly for cyclo-
propanes bearing electron-rich aromatic groups (1a,b,d). This
observation is in agreement with our previous findings that
greater stabilization of the carbenium ion in the zwitterionic
indermediate provides faster reaction rates.9,10 However, there
is an apparent limit to the electron releasing ability of the donor
group toward promotion of the annulation. N,N-Dimethylani-
line-substituted cyclopropane 1j (entry 14), the most electron
rich of the substrates tested, failed to react after 100 h,
presumably due to a marked decrease in electrophilicity at the
donor site. This trend may also explain the yield discrepancy
between the p- and o-methoxyphenyl-substituted cyclopropanes
(entries 3 and 7).
Decreased yields were also observed for the 2-furyl-
substituted cyclopropane (entry 9). This iteration suffered
from significant amounts of unidentified side reactions and
starting material decomposition. A plausible degradation
pathway for 1f might be the competing Piancatelli rearrange-
ment, which has been previously observed for furyl-substituted
D−A cyclopropanes.11 Cyclopropanes bearing a vinyl donor
group (not shown) proceeded in low yields (<30%) upon
annulation with 2a under Lewis acidic conditions. These
annulation products were unable to be isolated cleanly, since no
conditions that were tested prevented coelution of the amide
resulting from the hydrolysis of 2a from the desired product.
Me (1k)
CCH (1l)
H (1m)
59 (90)
Ph
63
82
Ph
a
Reactions performed with 1.0 equiv of 1 and 2.0 equiv of 2 in dry
b
CH2Cl2 (0.1 M) with 0.10 equiv of Sc(OTf)3. Reactions were run for
18 h. Isolated yield. Run on 20 mmol scale of 1b. No reaction
observed after 100 h. Run with 3.0 equiv of 2a and 0.15 equiv of
Sc(OTf)3.
c
d
e
f
2,2-Disubstituted cyclopropanes (entries 5, 6, 15, and 16) all
suffered from diminished yields under the standard reaction
conditions, presumably due to a slower rate of annulation. Since
in situ ynamide hydrolysis is competitive with the annulation, at
extended reaction times the availability of the ynamide is
compromised. In these cases, the addition of 3 equiv of
ynamide (entry 15) resulted in dramatically increased yields of
3o. The alkynyl moiety, which has been shown to be an
effective donor for (3 + 2)-annulations between D−A
cyclopropanes and aldehydes,12 (entry 16) also functions as
an effective donor in the annulation with ynamides, providing
3p in 63% yield.
Our group has shown previously2d,9 that enantioenriched D−
A cyclopropanes transfer chirality to their annulation products
with high fidelity, undergoing complete inversion at the donor
site stereogenic center. As shown in Figure 2, this mechanistic
feature is also observed in the case of annulation with ynamides.
Stereospecific back-side capture of the intimate ion pair (eq 3)
would account for this finding.9
We then began to examine the feasilibity of performnig a
dynamic kinetic asymmetric transformation (DYKAT)13 of
Figure 2. Chirality transfer study.
B
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Letter
racemic D−A cyclopropanes and ynamides based on our
previous work in the cases of tetrahydrofurans2h and
pyrrolidines.2i However, we found this tactic to be ineffective
in the case of the title reaction, as the reactivity of 1b and 2a
were significantly hindered by the application of the
MgI2(pybox) catalyst system (Figure 3). Varying the electronic
Figure 5. NOE observations.
Unsubstituted ynamides (R3 = H) were not tested in the
annulation with D−A cyclopropanes, since the resultant
cyclopentanones 4 that would be accessed from these
substrates are analogous to the products of 1,4-addition to
cyclopentenone or the 1,4-reduction of β-substituted cyclo-
pentenones. There are already several excellent reports of
enantioselective variants of these reactions.14,15
In conclusion, we have shown ynamides to be suitable
partners in (3 + 2)-annulation with D−A cyclopropanes,
providing cyclopentene sulfonamide products. Subsequent
deprotection provides 2,3-substituted cyclopentanone products
with high stereoselectivity. Studies into the further develop-
ment of D−A cyclopropane annnulations are underway in our
group and will be reported in due course.
Figure 3. Proposed DYKAT.
profile of the pybox ligand by introducing halogens at the 4-
position (X = Cl, Br) had no effect on the annulation. In
addition, variation of the reaction solvent or temperature
showed no promise for increasing starting material conversion.
For example, treatment of 1b with 2a in refluxing CCl4 for 2 d
resulted in only trace degradation (<5%) of 1b. Notably, no
degradation of the ynamide was observed. This lack of reactivity
was attributed to unfavorable steric interactions between the
t
chiral ligand (R = Bu) and the approaching ynamide. In an
attempt to minimize this strain, less sterically demanding pybox
ligands (R = Pr, Bn) were evaluated, neither of which was
successful in promoting the annulation.
i
ASSOCIATED CONTENT
* Supporting Information
■
S
In an effort to provide synthetically attractive cyclo-
pentanones from the enamide products 3, the sulfonyl group
was first cleaved via single-electron reduction using sodium
naphthalenide. The resultant enamine was then hydrolyzed
under acidic conditions to provide cyclopentanones 4a−d as
single diastereomers (Figure 4).
Experimental details and analytical data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jsj@unc.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the NSF (CHE-1213082) for financial support.
■
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