Calcium-catalyzed cycloisomerization of enynes

Article abstract of DOI:10.1002/adsc.201300253

A cycloisomerization of enynes with a benign calcium catalyst is presented exploring a complementary reactivity to that usually found in transition and noble metal-catalyzed reactions. Thereby, a systematic investigation of the π-activation of alkynes with reactive carbocations has been realized and ketones of various ring sizes were easily accessed. We are certain that these basic investigations will pave the way for the elaboration of further reactions based on the reaction principles discovered in the area of noble metal catalysis. Copyright

Full text of DOI:10.1002/adsc.201300253

COMMUNICATIONS
DOI: 10.1002/adsc.201300253
Calcium-Catalyzed Cycloisomerization of Enynes
Vera J. Meyer,a Liang Fu,a Fabian Marquardt,a and Meike Niggemanna,*
a
Institute for Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax : (+49)-241-8092-127; phone: (+49)-241-8094-688; e-mail: niggemann@oc.rwth-aachen.de
Received: March 28, 2013; Revised: May 14, 2013; Published online: July 12, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300253.
Abstract: A cycloisomerization of enynes with
a benign calcium catalyst is presented exploring
a complementary reactivity to that usually found in
transition and noble metal-catalyzed reactions.
Thereby, a systematic investigation of the p-activa-
tion of alkynes with reactive carbocations has been
realized and ketones of various ring sizes were
easily accessed. We are certain that these basic in-
vestigations will pave the way for the elaboration of
further reactions based on the reaction principles
discovered in the area of noble metal catalysis.
Figure 1. Outline for the p-activation of alkynes with reac-
tive carbocations.
sence of any transition metal or stoichiometric re-
agent, might be achieved by the p-activation of al-
kynes with reactive carbocations (cf. Figure 1), there-
by again generating a highly reactive vinyl cation that
sets the stage for subsequent cycloisomerization reac-
tions in analogy to the parent gold- and iodine-medi-
ated reactions. We have recently demonstrated that
skeletal rearrangements normally granted by noble
Keywords: calcium catalysis; cycloisomerization;
enynes; noble metal catalysis; vinyl carbocations
The efficient introduction of scaffold diversity and metal bound non-classical cations can be highly prolif-
complexity, while preferentially departing from ic also in the absence of the metal.[4] It has been dem-
simple and readily available starting materials in onstrated by some scattered literature precedents that
a minimum of chemical operations, is one of the most the generation of a vinyl cation via attack of a carbo-
challenging missions of modern organic synthesis. Ad- cation onto a triple bond is indeed feasible.[5] Never-
dressing this objective, the field of noble metal cataly- theless a systematic investigation of the observed re-
sis has witnessed a veritable boom within the last activity is lacking despite its high value as a starting
decade. Due to the peculiar abilities of noble metals point for the rich follow-up chemistry that is conceiv-
as p-acids for carbophilic activation, a wide range of able.
conceptually new reaction types has been discov-
As a new branch of sustainable metal catalysis, the
ered.[1] Reactive intermediates in gold-catalyzed reac- application of early main group metals as an alterna-
tions have been described either as cationic or carbe- tive to traditionally used, expensive, rare and often
noid species.[2] In the cationic rendition, the initially highly toxic transition metal catalysts has emerged
formed reactive species is a gold-stabilized vinyl within the last couple of years. Among the other early
cation, generated by the attack of the gold catalyst main group metals, calcium seems to be particularly
onto the alkyne moiety. Skeletal rearrangements of privileged, which is reflected by a considerable inten-
this non-classical vinyl cation then account for the ac- sification of research around the analysis of the
cessibility of a multitude of unusual frameworks such nature of calcium complexes[6] and the exploration of
as vinylcyclopropanes or strained bridgehead cyclobu- its potential as a catalyst.[7] Taking part in these ef-
tenes. One possibility to generate a similar reactivity forts, we have recently developed a novel calcium cat-
is the activation of the alkyne moiety with one or alyst for organic synthesis.[8] The choice of appropri-
more equivalents of electrophilic iodine sources, thus ate counter-anions allowed for a first successful appli-
generating an analogous iodine-stabilized vinyl cation cation of calcium salts as highly efficient catalysts for
species.[3] Even higher degrees of complexity from the transformation of environmentally benign p-acti-
acyclic polyunsaturated precursors, also in the ab- vated alcohols and olefins. Having thus in hand a new
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
ÞÞ
These are not the final page numbers!

Vera J. Meyer et al.
COMMUNICATIONS
Table 1. Optimization of the reaction conditions.
Entry[a]
Solvent
Additive
H2O source (mol%)
Ratio 2:3
Yield [%][b]
1
2
3
4
5
6
7
8
DCM
toluene
DCE
Bu4NPF6
Bu4NPF6
Bu4NPF6
Bu4NPF6
Bu4NBF4
Bu4NSbF6
Me2PhNH·B
Bu4NPF6
Bu4NPF6
Bu4NPF6
Bu4NPF6
HNTf2
–
–
–
–
–
–
–
0:100
0:100
0:100
61:39
77:23
59:41
–
58:42
100:0
100:0
60:40
59:41
40:60
35:66
40:60
50
75
50
90
76
86
–
83
87
88
85
89
68
45
68
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
(C6F5)4
H2O (100)
9
MgSO4·xH2O (100)
MgSO4·xH2O (10)
MgSO4·7H2O(10)
–
10
11
12[c]
13[c]
14[c]
15[c]
HNTf2, Bu4NPF6
HNTf2
HNTf2, Bu4NPF6
–
MgSO4·xH2O (100)
MgSO4·xH2O (100)
[a]
Additive, H2O source and Ca
stirred for 18 h at 508C.
Isolated yield.
ACHTUNGTREN(NNUG NTf2)2 were added at room temperature to enyne 1 (0.25 mmol) in 1.5 mL of solvent and
[b]
[c]
In the absence of CaACHTNUTRGEN(UNG NTf2)2.
Lewis acidic catalyst, which provides access to reac- tivity that is complementary to the cycloisomerization
tive cationic intermediates from olefinic precursors reactions of enynes usually found in transition and
with higher activity than most of the previously noble metal catalysis.
known catalysts, including transition metal-based
Our studies began with the optimization of the re-
Lewis acids, we envisaged a systematic investigation action conditions for the cycloisomerization reaction
of the p-activation of alkynes with reactive carboca- of model compound 1 (see Table 1). In the presence
tions.
of 5 mol% of CaACTHNGUTERNN(UG NTf2)2 and 5 mol% of Bu4NPF6 in
A first model reaction has been designed according dichloromethane (entry 1) none of the desired prod-
to the following considerations (see Figure 1). An uct was detected even after prolonged reaction times,
olefin moiety in I serves as the carbocation precursor and only ketone 3 was formed in a moderate yield as
as we have demonstrated the high activity of the cal- a result of water addition after direct activation of the
cium catalyst for the transformation of this entity into alkyne in 1 by the calcium catalyst. A change of sol-
reactive carbocations in previous publications.[8b,d] To vent to nitromethane (entry 4) improved the results.
control the regioselectivity of the alkyne attack, the In order to suppress the undesired background reac-
olefin in I is tethered to the alkyne moiety, thereby tion to ketone 3 completely, different additives were
forcing the resulting vinyl cation in III into an exocy- screened (entries 5–7) and special emphasis was given
clic position, as its inclusion in a small to medium- to the amount of water that is present in the reaction
sized ring is prohibited by sp-hybridization. In addi- mixture. The best results were obtained with the ini-
tion, the substituent R ought to be electron-rich, thus tial Bu4NPF6 additive in the presence of conventional,
stabilizing an adjacent positive charge. The highly re- non-dried MgSO4·xH2O as a slowly releasing source
active vinyl cation III will be intercepted by a water of H2O (entries 9–10). To ensure reproducibility of
molecule thus yielding the ketone IV via its corre- the results the solvent was partly dried via filtration
sponding enol. In addition to providing a systematic through a pad of basic alumina, thereby adjusting
investigation of the p-activation of alkynes with reac- a leveled content of residual water. Reaction of the
tive carbocations the envisioned study explores a reac- model compound in the presence of HNTf2 as the cat-
2
asc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Calcium-Catalyzed Cycloisomerization of Enynes
Table 2. Cycloisomerization of 1,6-enynes.
alyst leads to a significant drop of both conversion
and selectivity (entries 12–15). A simple protonation
of the NTf2 anion, leading to what has recently been
À
coined as a hidden Brønsted acid as the active catalyt-
ic species in the calcium-catalyzed reactions is thus
unlikely.[9] Nevertheless, as water is present in the re-
action mixture, a partial or full hydration of the Ca2+
ion leading to the strong acidification of the coordi-
nated water molecule cannot be ruled out, thereby
generating a Lewis acid/Brønsted acid cooperative
catalyst system providing different activity than either
the Lewis acid or the Brønsted acid alone.
Entry[a]
1
Product
Yield [%][b]
85
To showcase the scope of the reaction a series of
different enynes was cyclized under the optimized re-
action conditions (see Table 2 and Table 3). Different
electronic properties of the arene moiety stabilizing
the intermediary vinyl cation were found to be well
tolerated. Other electron-donating groups than the
methoxy substituent in model compound 1 such as
the free hydroxy group in 4d or even the acid-labile
OTBS moiety in 4c proved suitable. Cyclization pre-
cursors with a simple unsubstituted phenyl group
(entry 1) as well as electron-withdrawing substituents,
such as a chlorine atom (entry 5) and a CF3 moiety
(entry 6) reacted in good to excellent yields. Enynes
with non- or alkyl-substituted alkynes were found to
give complex reaction mixtures, presumably due to in-
sufficient stabilization of the cationic charge of the re-
active vinyl cation. Similar results were obtained
when 1,2- and mono-substituted olefins were used as
precursors for the formation of the initial carbocation.
The chemoselectivity of the reaction proved to be
excellent. Highly reactive groups such as ketones and
even aldehydes were found to interfere by no means
with the desired reaction pathway (entries 7–9).
In a second series, 1,5- and 1,7-enynes were cyclized
to ketones of different ring sizes (see Table 3). Once
more, different electronic properties of the arene
moiety were well tolerated and 5-membered rings
were readily obtained (entries 1–3). Presumably due
to the unfavourable ring size, the yields of 7-mem-
bered carbocycles from 1,7-enynes were found to be
insufficient in the presence of 5 mol% of the calcium
catalyst. Nevertheless, increasing the catalyst loading
to 10 mol% delivered the desired products 7d and 7e
in synthetically useful yields.
2
3
4
5
6
72
66
71
72
60
7
8
70
72
9
60
52
10
To exclude a mechanistic scenario involving the hy-
drolysis of the alkyne to the corresponding ketone
(such as in 3) followed by an aldol-type addition to
the carbocation, the ketone 8 was synthesized and
submitted to the optimized reaction conditions (see
Scheme 1).
11
12
81 (5k, R=Me)
50 (5l, R=Ac)
The reaction proceeded cleanly to the cyclic olefin
9 in 76% yield, and no trace of the cycloisomerization
product 5a was detected. The formation of 9 follows
a carbonyl-ene fragmentation pathway (for a reaction
scheme see the Supporting Information).
[a]
10 mol% MgSO4·H2O, 5 mol% Bu4NPF6 and 5 mol%
Ca(NTf2)2 were added at room temperature to enyne 4
(0.25 mmol) in 1.5 mL of MeNO2 and stirred for 18 h at
508C.
Isolated yield.
ACHTUNGTRENNUNG
[b]
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3
ÞÞ
These are not the final page numbers!

Vera J. Meyer et al.
COMMUNICATIONS
Table 3. Cycloisomerization of 1,5-/1,7-enynes.
tion of further reactions based on the reaction princi-
ples discovered in the area of noble metal catalysis.
Experimental Section
General Procedure
The enyne (0.25 mmol) and MgSO4·xH2O (10 mol%) were
suspended in 1.5 mL of nitromethane. Bu4NPF4 (5 mol%)
and CaACHTNUTGRENUNG(NTf2)2 (5 mol%) were added at room temperature
Entry[a]
1
Product
Yield [%][b]
83
and stirred at 508C overnight (18 h). For the isolation of the
product, 5 mL of saturated NaHCO3 solution is added, the
aqueous phase extracted with dichloromethane, the com-
bined organic phases dried over Na2SO4 and concentrated
under vacuum. The crude product was purified by column
chromatography.
2
94
82
Acknowledgements
3
This work was supported by the Deutsche Forschungsgemein-
schaft (DFG). Liang Fu receives funding from the China
Scholarship Council (CSC).
4[c]
57
77
References
5[c]
[1] Selected references: a) A. Fꢁrstner, P. W. Davies,
Angew. Chem. 2007, 119, 3478; Angew. Chem. Int. Ed.
2007, 46, 3410; b) A. S. K. Hashmi, Chem. Rev. 2007,
107, 3180; c) D. J. Gorin, B. D. Sherry, D. F. Toste, Chem.
Rev. 2008, 108, 3351; d) E. Jimenez-Nunez, A. M. Echa-
varren, Chem. Rev. 2008, 108, 3326; e) P. Y. Toullec, V.
Michelet, Top. Curr. Chem. 2011, 302, 31.
[2] a) A. Fꢁrstner, L. Morency, Angew. Chem. 2008, 120,
5108; Angew. Chem. Int. Ed. 2008, 47, 5030; b) A. S. K.
Hashmi, Angew. Chem. 2008, 120, 6856; Angew. Chem.
Int. Ed. 2008, 47, 6754; c) A. M. Echavarren, Nature
Chem. 2009, 1, 431; d) D. Benitez, N. D. Shapiro, E.
Tkatchouk, Y. M. Wang, W. A. Goddard, F. D. Toste,
Nature Chem. 2009, 1, 482.
[a]
10 mol% MgSO4·xH2O, 5 mol% Bu4NPF6 and 7.5 mol%
Ca(NTf2)2 were added at room temperature to enyne 6
(0.25 mmol) in 1.5 mL of MeNO2 and stirred for 18 h at
ACHTUNGTRENNUNG
508C.
Isolated yield.
10 mol% CaACHTUNGTRENNUNG(NTf2)2 were used.
[b]
[c]
[3] Selected references: a) Y. Yamamoto, I. D. Gridnev,
N. T. Patil, T. Jin, Chem. Commun. 2009, 45, 5075; b) B.
Godoi, R. F. Schumacher, G. Zeni, Chem. Rev. 2011,
111, 2937; c) S. Hummel, S. F. Kirsch, Beilstein J. Org.
Chem. 2011, 7, 849.
Scheme 1. Control experiment confirming the proposed re-
action pathway.
[4] T. Haven, G. Kubik, S. Haubenreisser, M. Niggemann,
Angew. Chem. Int. Ed. 2013, 52, 4016.
[5] a) W. S. Johnson, L. R. Hughes, J. A. Kloek, T. Niem, A.
Shenvi, J. Am. Chem. Soc. 1979, 101, 1281; b) W. S.
Johnson, T. M. Yarnell, R. F. Myres, D. R. Morton, S. G.
Boots, J. Org. Chem. 1980, 45, 1254; c) A. Furstner, H.
Szillat, B. Gabor, R. Mynott, J. Am. Chem. Soc. 1998,
120, 8305; d) A. Balog, S. J. Geib, D. P. Curran, J. Org.
Chem. 1995, 60, 345; e) Y. H. Liu, S. L. Zhou, G. J. Li, B.
Yan, S. H. Guo, Y. B. Zhou, H. Zhang, P. G. Wang, Adv.
Synth. Catal. 2008, 350, 797; f) T. Jin, M. Himuro, Y. Ya-
mamoto, Angew. Chem. 2009, 121, 6007; Angew. Chem.
Int. Ed. 2009, 48, 5893; g) T. Jin, J. Uchiyama, M.
Himuro, Y. Yamamoto, Tetrahedron Lett. 2011, 52, 2069;
In summary, a systematic investigation of the p-ac-
tivation of alkynes with reactive carbocations is pre-
sented that explores a reactivity that is complementa-
ry to that usually found in transition and noble metal-
catalyzed cycloisomerization reactions of enynes. In
the presence of 5 mol% of a benign calcium catalyst,
ketones of various ring sizes are readily accessed from
1,5-, 1,6- and 1,7-enynes. We are certain that these
basic investigations will pave the way for the elabora-
4
asc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Calcium-Catalyzed Cycloisomerization of Enynes
h) X.-C. Wang, R. L. Yan, M.-J. Zhong, Y.-M. Liang, J.
Org. Chem. 2012, 77, 2064.
mann, A. G. M. Barrett, M. S. Hill, P. A. Procopiou, J.
Am. Chem. Soc. 2012, 134, 2193; d) T. D. Nixon, B. D.
Ward, Chem. Commun. 2012, 48, 11790; e) B. Liu, T.
Roisnel, J.-F. Carpentier, Y. Sarazin, Chem. Eur. J. 2013,
19, 2784.
[6] Selected references: a) K. K. Yan, B. M. Upton, A.
Ellern, A. D. Sadow, J. Am. Chem. Soc. 2009, 131,
15110; b) M. Westerhausen, Z. Anorg. Allg. Chem. 2009,
635, 13; c) P. Jochmann, T. S. Dols, T. P. Spaniol, L.
Perrin, L. Maron, J. Okuda, Angew. Chem. 2009, 121,
5825; Angew. Chem. Int. Ed. 2009, 48, 5715; d) S.
Harder, Chem. Rev. 2010, 110, 3852; e) O. Michel, H.
Kaneko, H. Tsurugi, K. Yamamoto, K. W. Tçrnroos, R.
Anwander, K. Mashima, Eur. J. Inorg. Chem. 2012, 998.
[7] Selected references: a) M. R. Crimmin, M. Arrowsmith,
A. G. M. Barrett, I. J. Casely, M. S. Hill, P. A. Procopiou,
J. Am. Chem. Soc. 2009, 131, 9670; b) S. Kobayashi, Y.
Yamashita, Acc. Chem. Res. 2011, 44, 58; c) C. Brink-
[8] Selected references: a) M. Niggemann, M. J. Meel,
Angew. Chem. 2010, 122, 3767; Angew. Chem. Int. Ed.
2010, 49, 3684; b) M. Niggemann, N. Bisek, Chem. Eur.
J. 2010, 16, 11246; c) S. Haubenreisser, M. Niggemann,
Adv. Synth. Catal. 2011, 353, 469; d) A. Kena Diba, J.-M.
Begouin, M. Niggemann, Tetrahedron Lett. 2012, 53,
6629.
[9] T. T. Dang, F. Boeck, L. Hintermann, J. Org. Chem.
2011, 76, 9353.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
5
ÞÞ
These are not the final page numbers!