The alkynyl moiety as a donor for donor-acceptor cyclopropanes

Article abstract of DOI:10.1021/ol400809n

The first trans-selective [3 + 2]-cycloaddition of a new type of donor-acceptor cyclopropane with aldehydes is presented. 2,2-Disubstituted cyclopropanes, bearing an alkyne moiety as the sole donor entity, were transformed to highly substituted tetrahydro

Full text of DOI:10.1021/ol400809n

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
The Alkynyl Moiety as a Donor for
DonorꢀAcceptor Cyclopropanes
€
Stefan Haubenreisser, Peter Hensenne, Sebastian Schroder, and Meike Niggemann*
Institute of Organic Chemistry, RWTH Aachen University, 52074 Aachen, Germany
niggemann@oc.rwth-aachen.de
Received March 27, 2013
ABSTRACT
The first trans-selective [3 þ 2]-cycloaddition of a new type of donorꢀacceptor cyclopropane with aldehydes is presented. 2,2-Disubstituted
cyclopropanes, bearing an alkyne moiety as the sole donor entity, were transformed to highly substituted tetrahydrofurans in the presence of a
catalytic amount of Ca(NTf2)2/Bu4NPF6. The protocol allows for an easy access to tetrahydrofurans bearing a versatile alkyne substituent at the
quarternary 2-position under very mild reaction conditions.
The diastereoselective generation of complex hetero-
cycles from donorꢀacceptor (DA) cyclopropanes1 has
emerged as an efficient strategy and a number of [3 þ n]-
cycloaddition reactions has been described over the past
decade.2 Despite the progress in the investigation of 2-sub-
stituted-cyclopropane-1,1-diesters, reactions involving the
analogous 2,2-disubstituted species such as 1 (Scheme 1)
remain scarce,3 even though the thus generated hetero-
cycles 3 contain a highly interesting quaternary stereocen-
ter. Furthermore, with the exception of three examples,3a,b
these inquiries are limited to cyclopropanes bearing a phenyl-
moiety as the donor entity. The reactions were generally
found to proceed with high diastereoselectivity, predictably
yielding cis-configured heterocycles, orienting the substituent
R4 of the former dipolarophile on the same side of the newly
formed ring as the former donor group.
(1) For donorꢀacceptor cyclopropane reviews, see: (a) Carson,
C. A.; Kerr, M. A. Chem. Soc. Rev. 2009, 38, 3051–3060. (b) Yu, M.;
Pagenkopf, B. L. Tetrahedron 2005, 61, 321–347. (c) Reissig, H.-U.;
Zimmer, R. Chem. Rev. 2003, 103, 1151–1196.
(2) (a) Zhu, W.; Fang, J.; Liu, Y.; Ren, J.; Wang, Z. Angew. Chem., Int.
Ed. 2013, 52, 2032–2037. (b) Miyake, Y.; Endo, S.; Moriyama, T.; Sakata,
K.; Nishibayashi, Y. Angew. Chem., Int. Ed. 2013, 52, 1758–1762. (c)
Benfatti, F.; de Nanteuil, F.; Waser, J. Org. Lett. 2012, 14, 386–389. (d)
Xing, S.; Li, Y.; Li, Z.; Liu, C.; Ren, J.; Wang, Z. Angew. Chem., Int. Ed.
2011, 50, 12605–12609. (e) Schneider, T. F.; Werz, D. B. Org. Lett. 2011, 13,
1848–1851. (f) Ivanova, O. A.; Budynina, E. M.; Chargarovskiy, A. O.;
Trushkov, I. V.; Melnikov, M. Ya. J. Org. Chem. 2011, 76, 8852–8868. (g)
Lebold, T. P.; Kerr, M. A. Pure Appl. Chem. 2010, 82, 1797–1812. (h)
Campbell, M. J.; Johnson, J. S.; Parsons, A. T.; Pohlhaus, P. D.; Sanders,
S. D. J. Org. Chem. 2010, 75, 6317–6325. (i) Christie, S. D. R.; Cummins, J.;
Elsegood, M. R. J.; Dawson, G. Synlett 2009, 257–259. (j) Pohlhaus, P. D.;
Sanders, S. D.; Parsons, A. T.; Li, W.; Johnson, J. S. J. Am. Chem. Soc.
2008, 130, 8642–8650. (k) Agrawal, D.; Yadav, V. K. Chem. Commun. 2008,
6471–6488. (l) Ivanova, O. A.; Budynina, E. M.; Grishin, Y. K.; Trushkov,
I. V.; Verteletskii, P. V. Angew. Chem., Int. Ed. 2008, 47, 1107–1110. (m)
Parsons, A. T.; Campbell, M. J.; Johnson, J. S. Org. Lett. 2008, 10, 2541–
2544. (n) Gupta, A.; Yadav, V. K. Tetrahedron Lett. 2006, 47, 8043–8047.
(o) Christie, S. D. R.; Davoile, R. J.; Elsegood, M. R. J.; Fryatt, R.; Jones,
R. C. F.; Pritchard, G. J. Chem. Commun. 2004, 2474–2475.
Scheme 1. Proposed Cycloaddition with Quaternary Donor
Sitesa
a Alkynyl moiety as the sole donor moiety, R2 = aliphatic.
We have recently developed a novel calcium catalyst as a
sustainable alternative to traditionally used, expensive,
rare, and oftentimes highly toxic transition metal catalysts
for organic synthesis. Through the choice of appropriate
counteranions, we were the first to successfully apply
calcium salts as highly efficient Lewis acidic catalysts for
the transformation of π-activated alcohols and olefins.4
Having thus in hand a new Lewis acidic catalyst that provides
(3) (a) Smith, A. G.; Slade, M. C.; Johnson, J. S. Org. Lett. 2011, 13,
1996–1999. (b) Xing, S.; Pan, W.; Liu, C.; Ren, J.; Wang, Z. Angew.
Chem., Int. Ed. 2010, 49, 3215–3218. (c) Carson, C. A.; Kerr, M. A. Org.
Lett. 2009, 11, 777–779. (d) Sibi, M. P.; Ma, Z.; Jasperse, C. P. J. Am.
Chem. Soc. 2005, 127, 5764–5765.
r
10.1021/ol400809n
XXXX American Chemical Society

higher activity than most of the previously known ones, we
envisioned a systematic investigation of the transformation of
a new type of 2,2-disubstituted DA-cyclopropane 1, bearing
an alkyne as the sole donor entity, which might be highly
beneficial in several ways. First, the alkyne moiety is devel-
oped into a versatile functional handle, also due to the
tremendous success witnessed in the area of noble metal
catalysis.5 Hence, the obtained products represent highly
interesting building blocks for further conversion into natural
products. Second, the minor steric extension of this new
donor moiety might account for a thus unprecedented
trans-diastereoselectivity in the [3 þ 2]-cycloaddition toward
heterocycles 3.
was completed after 5 min at room temperature affording
tetrahydrofuran 3a in 95% yield with a good stereoselectivity
of 87:13 in favor of the trans-configured heterocycle. Other
alkaline earth metal triflimides as well as LiNTf2 showed very
low or no reactivity (entries 1ꢀ4). Among other additives,
the PF6ꢀ salt gave the best results (entries 5ꢀ7). As already
mentioned in previous publications,4f,g the hexafluoro-
phosphate salt is required to form the much more soluble
CaNTf2PF6 species via an anion exchange reaction (entry 8).
Only noncoordinating, polar solvents such as 1,2-dichloro-
ethane (DCE) were found suitable. Sn(OTf)2 promoted the
reaction. However, the diastereoselectivity was poor in the
presence of this catalyst that proved highly efficient regarding
both conversion and selectivity, in previous studies with a
phenyl-donor moiety (entries 12/13).3a Similar results were
obtained in the presence of Sc(OTf)3 that efficiently promotes
this type of reaction, a single example also showcasing a 2,2-
disubstituted cyclopropane.3b Here, in the presence of the
additive the isolated yield was low due to oligomerization
side reactions, or in the absence of the additive the diaste-
reoselectivity was poor and, interestingly, in favor of the
cis-configured tetrahydrofuran (entries 14/15). Formation of
a hidden Brønsted acid6 as a catalytic species was ruled out by
NMR experiments (see Supporting Information (SI)).
Our studies began with the optimization of the reaction
conditionsfor the [3 þ 2]-cycloaddition of cyclopropane1a
Table 1. Optimization of the Reaction Conditions
entrya Lewis acid
additive
time
16 h
yield [%]
dre
1
2
3
4
5
6
7
Mg(NTf2)2
Bu4NPF6
10
70:30
87:13
ꢀ
Ca(NTf2)2 Bu4NPF6
5 min
16 h
95
n.r.
70
Table 2. Reaction of Cyclopropane 1a with Aldehydes
Ba(NTf2)2
LiNTf2
Bu4NPF6
Bu4NPF6
Bu4NSbF6
Bu4NBF4
48 h
87:13
88:12
87:13
ꢀ
Ca(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
30 min
30 min
89
84
PhMe2HNþ 16 h
n.r.
ꢀ
B(C6F5)4
8
Ca(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
Sn(OTf)2
Sn(OTf)2
Sc(OTf)3
Sc(OTf)3
ꢀ
16 h
n.r.
n.r.
79
ꢀ
9b
Bu4NPF6
Bu4NPF6
Bu4NPF6
Bu4NPF6
ꢀ
16 h
ꢀ
10c
11d
12
13
14
15
4 h
82:18
ꢀ
16 h
n.r.
72
45 min
30 min
10 min
15 min
57:43
61:39
86:14
45:55
85
Bu4NPF6
ꢀ
61
92
a p-Anisaldehyde 2a (0.2 mmol) and cyclopropane 1a (0.1 mmol)
were added to a Lewis acid (5 mol %) and an additive (5 mol %) in DCE
(0.5 mL) at rt and stirred for the indicated time. b Reaction run in Et2O.
c Reaction run in toluene. d Reaction run in MeNO2. e Determined by
1H NMR spectroscopy.
with p-anisaldehyde 2a (Table 1). In the presence of 5 mol %
of Ca(NTf2)2 and 5 mol % of Bu4NPF6 the cycloaddition
(4) (a) Capitta, F.; Begouin, J.-M.; Wu, X.; Niggemann, M. Org.
Lett. 2013, 15, 1370–1373. (b) Haven, T.; Kubik, G.; Haubenreisser, S.;
Niggemann, M. Angew. Chem., Int. Ed. 2013, 52, 4016–4019. (c) Kena
Diba, A.; Begouin, J.-M.; Niggemann, M. Tetrahedron Lett. 2012, 53,
6629–6632. (d) Meyer, V. J.; Niggemann, M. Chem.;Eur. J. 2012, 18,
4687–4691. (e) Meyer, V. J.; Niggemann, M. Eur. J. Org. Chem. 2011,
3671–3674. (f) Haubenreisser, S.; Niggemann, M. Adv. Synth. Catal.
2011, 353, 469–474. (g) Niggemann, M.; Meel, M. J. Angew. Chem., Int.
Ed. 2010, 49, 3684–3687. (h) Niggemann, M.; Bisek, N. Chem.;Eur. J.
2010, 16, 11246–11249.
(5) (a) de Mendoza, P.; Echavarren, A. M. Pure Appl. Chem. 2010, 82,
801–820. (b) Yamamoto, Y.; Gridnev, I. D.; Patil, N.; Jin, T. Chem. Commun.
2009, 5075–5087. (c) Abu Sohel, S. Md.; Liu, R.-S. Chem. Soc. Rev. 2009, 38,
2269–2281. (d) Kitamura, T. Eur. J. Org. Chem. 2009, 1111–1125.
a Aldehyde 2 (0.2 mmol) and cyclopropane 1a (0.1 mmol) were added
to Ca(NTf2)2 (5 mol %) and Bu4NPF6 (5 mol %) in DCE (0.5 mL) at rt
and stirred for the indicated time. b Reaction run at 50 °C. c Determined
by 1H NMR spectroscopy.
B
Org. Lett., Vol. XX, No. XX, XXXX

To investigate the scope of the cycloaddition, a series of
different aldehydes were reacted with cyclopropane 1a
(Table 2). Aromatic aldehydes, bearing an electron-with-
drawing group at the aryl moiety (2b), showed no difference
in reactivity compared to p-anisaldehyde 2a. Cinnamalde-
hyde 2c proved equally suitable as a dipolarophile, providing
high yields and good selectivity. The less reactive o-nitrocin-
namaldehyde 2d showed no reactivity at room temperature,
but cycloaddition could be achieved at 50 °C within 10 min.
Aliphatic aldehydes were suitable substrate; however, the
tetrahydrofurans 3e/f were obtained in moderate yields
because of their fragility under the reaction conditions in
combination with their considerably lower nucleophilicity.
We further explored the scope of the [3 þ 2]-cycloaddi-
tion with regard to differently substituted cyclopropanes
(Table 3). Special emphasis was given to both the second
substituent at the quaternary donor site and the electronic
properties of the alkyne. Cyclopropane 1b afforded the
desired tetrahydrofurans 3g and 3h in high yield. Once
again, the trans-diastereomers, orienting the former donor
moiety and the former aldehyde substituent on either side
of the just formed tetrahydrofuran ring, were predomi-
nant. Due to the sterically more demanding n-propyl
substituent, the diastereoselectivity is even higher in these
cases. The electron-withdrawing benzyloxy substituent in 1c
reduced the reactivity to some degree, but the high reactivity
of the calcium catalyst accounts for an acceptable conver-
sion of these deactivated substrates to the highly interesting
building blocks 3i and 3j. The diastereoselectivity was again
excellent. The phenyl substituted cyclopropane 1d afforded
tetrahydrofuran 3k in high yield and diastereoselectivity.
Alteration of the electronic properties of the alkyne moiety
revealed the suitability of a broad range of different sub-
stituents R1 for the presented [3 þ 2]-cycloaddition. Electron-
withdrawing substituents in an aryl substituent such as in
1e had no significant influence on the reaction outcome.
Interestingly, an electron-rich aryl moiety was nonbeneficial
for the reaction outcome. In this case the highly electron-rich
alkyne moiety in 1f seems to be entangled in side reactions,
which could be suppressed to some extent at lower reaction
temperatures. Much to our delight, the more electron-poor
aliphatic alkyne donors in 1g and 1h also successfully
promoted the reaction with high yield and good stereose-
lectivity although a slightly higher reaction temperature
(50 °C) was required. All aldehydes, even the ones that
showed only moderate reactivity in the reaction with cyclo-
propane 1a, proved to be good dipolarophiles in the reaction
with 1h (see Table 4). In analogy to the previously proposed
considerations for this reaction family,2h,j the mechanism of
the reaction was outlined as depicted in Figure 1.
Table 3. Reaction of Cyclopropanes 1 with Aldehydes
a Aldehyde 2 (0.2 mmol) and cyclopropane 1 (0.1 mmol) were added
to Ca(NTf2)2 (5 mol %) and Bu4NPF6 (5 mol %) in DCE (0.5 mL) and
stirred for the time indicated. b Reaction run at 0 °C. c Reaction run at
50 °C. d Determined by 1H NMR spectroscopy.
Coordination of the calcium Lewis acid induces the
formation of the intimate contact ion pair 4. The approach
of the aldehyde occurs in such a way that the arising 1,3-
diaxial steric clash is minimized, by orienting the slender
alkyne moiety in 5 on the same side as the aldehyde
hydrogen atom. A 120° bond rotation followed by ring
closure via an envelope transition state then yields the
trans-tetrahydrofuran 3. Due to the already favorable
pseudoaxial orientation of the two larger groups R2 and
R4 the steric penalty in 6 is kept at a minimum and ring flip
events therefore are unlikely.
As opposed to the observations made in previous
studies,2j longer reaction times proved to be beneficial for
(6) Dang, T. T.; Boeck, F.; Hintermann, L. J. Org. Chem. 2011, 76,
9353–9361.
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C

Scheme 2. Prolonged Reaction Time and Diastereoselectivitya
Table 4. Reaction of Cyclopropane 1h with Aldehydes
a Trans/cis-mixtures of tetrahydrofurans 3a or 3p (0.1 mmol) were
added to Ca(NTf2)2 (5 mol %) and Bu4NPF6 (5 mol %) in DCE (0.5 mL)
and stirred for 16 h at 50 °C; dr determined by 1H NMR spectroscopy.
substituent, both of them being electron-rich, equilibration
to the thermodynamically more stable trans-product oc-
curs, whereas no such event was observed in the case of 3p.
This process proceeds via a ring-opening reaction that is
facilitated by the coordination of the calcium Lewis acid to
the tetrahydrofuran oxygen atom (for a mechanistic ratio-
nale, see SI).2j Bond rotation in the ring opened species
followed by reoccurring ring closure then accounts for the
transformation of the unfavorable cis- to the more stable
trans-product. The intermediary cationic ring opened spe-
cies is highly stabilized by the two electron releasing
substituents in the tetrahydrofuran 3a, which are thus
facilitating the overall process. Due to the much poorer
stabilizing abilities of the substituents in the case of 3p,
either ring opening is prevented or the subsequent bond
rotation is slow in comparison to the reoccurring ring
closure. An equilibration of tetrahydrofuran 3p seems
therefore prohibited. These findings also explain the di-
minished diastereoselectivities in the cycloadditions of
cyclopropane 1h with sterically less demanding aldehydes.
In summary we have developed a calcium-catalyzed
[3 þ 2]-cycloaddition of aldehydes with a new type of
quaternary donor site cyclopropanes, bearing an alkyne
moiety as the sole donor entity. By taking advantage of the
marginal steric extension of this new donor, the tetrahy-
drofurans could be obtained with excellent trans-diaste-
reoselectivities for the first time. Thereby, an unprecedented
general access has been granted to highly substituted
tetrahydrofurans bearing an alkyne moiety as a versatile
functional handle at the quarternary 2-position. Further
exploration of the scope of other dipolarophiles for this
type of reaction are currently underway in our laboratory.
a Aldehyde 2 (0.2 mmol) and cyclopropane 1h (0.1 mmol) were added
to Ca(NTf2)2 (5 mol %) and Bu4NPF6 (5 mol %) in DCE (0.5 mL) and
stirred for the time indicated. b Determined by 1H NMR spectroscopy.
Figure 1. Mechanistic rationale.
the diastereoselectivity in our studies. Further investiga-
tions of this initial observation were conducted by expos-
ing diastereomeric mixtures trans-/cis-3a and trans-/cis-3p
to the reaction conditions (see Scheme 2). As confirmed by
computational analysis on the B3LYP6-31Gþ(d,p) level
of theory (see SI) tetrahydrofurans trans-3a and trans-3p
are the more stable stereoisomers, due to the minimized
1,3-diaxial strain between the alkynyl substituent and the
former aldehyde hydrogen atom. In the case of the tetra-
hydrofuran 3a that bears an aryl and an arylalkynyl
Supporting Information Available. Experimental pro-
cedures, full characterization of products, NMR spectra,
computational methods, additional information. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX