Annelated Cyclobutanes by Fe-Catalyzed Cycloisomerization of Enyne Acetates

Article abstract of DOI:10.1002/anie.201806693

Cationic Fe complexes of the general type [(Ph₃P)₂Fe(CO)(NO)]X (X=BF₄, BAr^F₄) catalyze the redox-neutral cycloisomerization of 1,6- and 1,7-enyneacetates to afford bicyclic cyclobutanes under mild conditions in good yields and diastereoselectivities.

Full text of DOI:10.1002/anie.201806693

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Accepted Article
Title: Annelated cyclobutanes via Fe-catalyzed cycloisomerization of
enyne acetates
Authors: Bernd Plietker, Frederik Kramm, Johannes Teske, Franziska
Ullwer, and Wolfgang Frey
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201806693
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http://dx.doi.org/10.1002/ange.201806693

10.1002/anie.201806693
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Annelated cyclobutanes via Fe-catalyzed cycloisomerization of
enyne acetates
Frederik Kramm[a], Johannes Teske[a], Franziska Ullwer[a], Wolfgang Frey[a], and Bernd Plietker [a]*
Abstract: Cationic Fe-complexes of the general type
[(Ph3P)2Fe(CO)(NO)]X (X = BF4, BArF ) catalyze the redox-neutral
4
cycloisomerization of 1,6- and 1,7-enyneacetates to bicyclic
cyclobutanes under mild conditions in good yields and
diastereoselectivities.
Acccording to the Woodward-Hofmann-rules [2+2]-
cycloadditions between two olefins are thermally forbidden, yet
photochemically allowed.[1] As a consequence, photochemical
[2+2]-cycloadditions between two olefins represent the most
common and powerful strategy to form cyclobutanes.[2] Under
non-photochemical conditions highly reactive olefins like e.g.
ketenes can be used for a formal [2+2]-cycloaddition, however,
this strategy is hampered by the fact that these substrates
usually need to be prepared in-situ and that the high reactivity
limits the functional group tolerance.[3] Complementary to these
research lines, metal-catalyzed processes proved to be a valid
alternative strategy for obtaining functional cyclobutanes starting
from either enallenes or even dienes (Scheme 1).[4]
In 2011 Toste showed that a phosphoramidite (P*) Au(I)-
complex catalyzes the cycloisomerization of enallenes to the
corresponding bicyclo[3.2.0]heptanes in good yields and high
levels of enantioselectivity (eq. (1), Scheme 1).[5] In the same
year Chirik reported an intermolecular version of his previously
published[6] intramolecular (RPDI)Fe-catalyzed (RPDI = 2,6-(2,6-
R2-C6H3N=CMe)2C5H3N; R = Pr, Me) formal [2+2]-cycloaddition
Scheme 1 Cycloisomerization to form cyclobutanes – state of the art and this
work.[5,7]
i
of dienes to the corresponding cyclobutanes (eq. (2), Scheme
1).[7] Most recently, we found that enyneamides undergo a
At the outset of this study we hypothesized that the use of
less coordinating anions might increase the catalyst activity and
consequently the reactivity toward less electronrich N-allyl
propargylic acetates like 2. Amongst the tested additives
smooth
cycloisomerization
to
the
corresponding
allenylpyrrolidines in the presence of catalytic amounts of the
cationic Fe-complex [(Ph3P)2Fe(CO)(NO)]BF4 1*BF4 (eq. (3),
Scheme 1). This reaction however turned out to be limited to the
use of N-prenyl or -cinnamyl propargylic acetates, the
corresponding N-allyl derivatives did not show significant
conversions.[9] Triggered by this limitation we were wondering
whether more cationic Fe-complexes might enable the use of
less reactive N-allyl propargyl acetates. Much to our surprise we
did not find the expected allene but rather an unusual
azabicyclo[3.2.0]alkane as the major product (eq. (4), Scheme
1).[8]
(NaClO4, NaPF6, NaOTf, NaBPh4, NaSbF6, NaBArF ) only the
4
latter two showed conversion. However, we did not isolate the
expected allenyl pyrrolidine 4 but rather the corresponding
azabicyclo[3.2.0]heptane 3 (Scheme 2).[10,11]
[a]
[*]
M.Sc. Frederik Kramm, M.Sc. Johannes Teske, M.Sc. Franziska
Ullwer, Prof. Dr. Bernd Plietker,
Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring
55, DE-70569 Stuttgart (Deutschland)
corresponding author: Prof. Dr. Bernd Plietker,
e-mail: bernd.plietker@oc.uni-stuttgart.de
Scheme 2 Anion effect in Fe-catalyzed cycloisomerization of 1,6-enyne
acetate 2 (BArF4: tetrakis[3,5-bis(trifluoromethyl)phenyl]borate).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Subsequently, the optimized reaction conditions were
subjected to a set of enynes possessing different tethers, or
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10.1002/anie.201806693
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functional groups (Scheme 3). The reaction proved to be broadly
applicable leading to the corresponding structurally complex
annelated cyclobutanes 3 – 16 in moderate to good yields. Good
functional group tolerance was observed; esters, amides, or
halides are tolerated. Different linker units were employed,
however, only amide or malonate linkers were tolerated.
Employing oxygen as linking unit led to catalyst deactivation,
most likely through coordination to the metal center. Importantly,
different propargylic esters like phenylacetates, cinnamates or
even sorbates proved to be reactive which sets the stage for
further functionalization.
cycloisomerizations were achieved using the established 1*BF4
under otherwise identical conditions.
Scheme 4. Fe-catalyzed cycloisomerization of 1,7-enyneacetates.
A variety of six-four-membered bicyclic amides 17 – 23 were
obtained using 1*BF4 as a catalyst in moderate to good yields
starting from the corresponding homopropargylic amides. On the
contrary, homoallylic amides did not show any conversion. Even
tricyclic products 20 – 23 were obtained in good yields in a
straightforward manner. The relative configuration of the
complex products was unequivocally assigned through X-ray
spectroscopy, as exemplified by the X-ray structure of tricyclic
amide 20 (Figure 1).
Scheme 3. Fe-catalyzed cycloisomerization of 1,6-enyneacetates.
Moreover, both propargylic but also homopropargylic amides
can be employed leading to azabicyclo[4.2.0]octane motifs in
good yields and diastereoselectivities (Scheme 4). Interestingly,
catalyst 1*BArF4 which proved to be the optimum catalyst for the
formation of the azabiyclo[3.2.0]heptane products 3 - 16 led to
decomposition for the cycloisomerization of the corresponding
Figure 1. X-ray structure of tricyclic amide 20 (major E-isomer).
homopropargylic
acetates.
In
these
cases,
smooth
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The obtained products are interesting building blocks for
subsequent transformations. Pd-catalyzed hydrogenation for
example led to the formation of the corresponding saturated
bicyclic structure 24 in quantitative yields and good
diastereomeric ratio of 85 : 15 (eq. (1), Scheme 5). Ozonolysis
on the other hand proceeded smoothly to give the corresponding
cyclobutanone 25 in 82% yield, a reaction that could in principal
be achieved through the use of acetoxyketene 29 via a [2+2]-
cycloaddition (eq. (2), Scheme 5).[12] About 77% of the
corresponding benzaldehyde 26 as second C-C-bond scission
product was isolated which can be recycled to synthesize new
propargylic acetate 2 from alkyne 28 and acetic anhydride (eq.
(2), Scheme 3).
Scheme 6. Control experiments.
These control experiments and the previously reported
experiments[9] led us to propose the following preliminary
mechanistic picture (Scheme 7).
Scheme 5. Synthetic procedures involving azabicyclo[3.2.0heptanes as
building blocks.
Based on Toste’s and Chirik’s report on metal-mediated
formal [2+2]-cycloadditions between two olefins, we were
wondering whether the present reaction is the result of a Fe-
catalyzed
tandem
Rautenstrauch-rearrangement-[2+2]-
cycloaddition. However, test experiments clearly show that the
Fe-complex neither catalyzes the Rautenstrauch-rearrangement
of the structurally related amide 30 nor the formal [2+2]-
cycloaddition of allenylacetate 32 (Scheme 6, eq. (1) and (2)).
No reaction was observed.
Scheme 7. Mechanistic proposal.
Accordingly, upon coordination of the catalyst 1*BArF to the
4
alkyne in III a 1,2-oxyferration takes place leading to the
corresponding vinyl-Fe complex IV that tautomerizes to the Fe-
carbene species V. [2+2]-cycloaddition results in the formation of
metallacyclobutane VI which can exists in two different rotamers,
VI-A and VI-B. Depending on the nature of the substituent R1 a
1,3-acetoxymigration to VII or a [1,3]-metallotropic shift with
formation of the less strained metallacyclohexene IX takes place.
For R1 = H, the latter transformation is preferred. 1,2-Acetoxy
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W.-F. Zheng, P. P. Bora, G.-J. Sun, Q. Kang, Org. Lett. 2016, 18, 3694;
f) B. Ranieri, C. Obradors, M. Mato, A. M. Echavarren, Org. Lett. 2016,
18, 1614; L.-Y. Mei, Y. Wei, X.-Y. Tang, M. Shi, J. Am. Chem.
Soc. 2015, 137, 8131; g) J. M. Hoyt, V. A. Schmidt, A. M. Tondreau, P.
J. Chirik, Science 2015, 349, 960; h) V. A. Schmidt, J. M. Hoyt, G. W.
Margulieux, P. J. Chirik, J. Am. Chem. Soc. 2015, 137, 7903; i) S.
Suárez-Pantiga, C. Hernández-Díaz, M. Piedrafita, E. Rubio, J. M.
González, Adv. Synth. Catal. 2012, 354, 1651; j) M. Ebisawa, H.
Kusama, N. Iwasawa, Chem. Lett. 2012, 41, 786; k) M. R. Luzung, P.
Mauleón, F. D. Toste, J. Am. Chem. Soc. 2007, 129, 12402; l) H. Ohno,
T. Mizutani, Y. Kadoh, K. Miyamura, T. Tanaka, Angew. Chem. Int.
Ed. 2005, 44, 5113.
migration and deferration releases the azabicyclo[3.2.0]heptane
XII. For R1 = Ph steric repulsion between R1 and R2 disfavors
rotamer VI-B and thus favors the 1,3-acetoxymigration which
upon deferration leads to the observed allenylpyrrolidine VIII. At
this point we would like to emphasize that this is a preliminary
mechanistic picture that explains the results obtained in both
cycloisomerization reactions. More detailed studies are needed
and are part of our ongoing work.
We report here an unprecedented type of cycloisomerization
of 1,6- and 1,7-enyneacetates to the corresponding
bicyclo[3.2.0]- or [4.2.0]alkylamides in good to excellent yields
[5]
[6]
[7]
[8]
A. Z. González, D. Benitez, E. Tkatchouk, W. A. Goddard, F. D. Toste,
J. Am. Chem. Soc. 2011, 133, 5500.
using
a cationic Fe-NO-complex. Good functional group
M. W. Bouwkamp, A. C. Bowman, E. Lobkovsky, P. J. Chirik, J. Am.
Chem. Soc. 2006, 128, 13340.
tolerance and mild reaction conditions are characteristics of this
transformations. The Fe-catalyst is accessible in two steps from
Fe(CO)5 and can be handled under air for a short period of time
without special precautions. Future work will concentrate on the
development of an asymmetric version but also on a systematic
exploration and expansion of the catalytic scope.
S. K. Russell, E. Lobkovsky, P. J. Chirik, J. Am. Chem. Soc. 2011, 133,
8858.
To the best of our knowledge, only one example for such
a
cycloisomerization was reported by the group of Gung during their
investigation on enantioselective Au-catalyzed cycloisomerization of
1,6-enyneacetates to the corresponding bicyclo[4.1.0]alkylacetates:
B. W. Gung, L. N. Bailey, D. T. Craft, C. L. Barnes, K. Kirschbaum,
Organometallics 2010, 29, 3450.
Acknowledgements
[9]
J. Teske, B. Plietker, ACS Catal. 2016, 6, 7148.
[10] H. Nishida, N. Takada, M. Yoshimura, T. Sonoda, H. Kobayashi, Bull.
Chem. Soc. Jpn. 1984, 57, 2600.
The authors are grateful to the Deutsche Forschungs-
gemeinschaft for financial support, to the Fonds der Chemischen
Industrie (Kekulé-Ph.D. grant for Frederik Kramm), to the
Landesgraduiertenstiftung Baden-Württemberg (Ph.D. grant for
Franziska Ullwer), and to Dr. Wolfgang Frey for X-ray.
[11] For more details, please see supporting information.
[12] J: Finn (Merck Sharp & Dohme Corp.), WO/2015/038661, 2014.
Keywords: iron • isomerization • cyclobutane • enyne • catalysis
[1]
[2]
R. R. Woodward, R. Hoffmann, Angew. Chem. Int. Ed. 1969, 8, 781.
For recent reviews see: a) S. Poplata, A. Tröster, Y.-Q. Zou, T. Bach,
Chem. Rev. 2016, 116, 9748; b) N. Hoffmann, Photochem. Photobiol.
Sci. 2012, 11, 1613. For selected recent publications see: c) V. Mojr, G.
Pitrová, K. Straková, D. Prukała, S. Brazevic, E. Svobodová, I.
Hoskovcová, G. Burdziński, T. Slanina, M. Sikorski, R. Cibulka,
ChemCatChem 2018, 10, 849; d) Z. D. Miller, B. J. Lee, T. P. Yoon,
Angew. Chem. Int. Ed. 2017, 56, 11891; e) C. Wang, Z. Lu, Org. Lett.
2017, 19, 5888; R. Li, B. C. Ma, W. Huang, D. Wang, H. Lu, K.
Landfester, K. A. I. Zhang, ACS Catal. 2017, 7, 3097; f) S. K. Pagire, A.
Hossain, L. Traub, S. Kerres, O. Reiser, Chem. Commun. 2017, 53,
12072; g) A. E. Hurtley, Z. Lu, T. P. Yoon, Angew. Chem. Int. Ed. 2014,
53, 8991.
[3]
a) W.-F. Zheng, G.-J. Sun, L. Chen, Q. Kang, Adv. Synth. Catal. 2018,
360, 1790; b) X. Wu, H.-J. Wang, Y.-S. Huang, W.-D. Z. Li, Org. Lett.
2018, 20, 1871; c) J. M. Wiest, M. L. Conner, M. K. Brown, Angew.
Chem. Int. Ed. 2018, 57, 4647; d) H.-T. Zhu, S. Ke, N.-N. Zhou, M.-J.
Fan, D.-S. Yang, Org. Lett. 2016, 18, 4554; e) P. Rulliére, J. Griesel, C.
Poittevin, P. Cividino, S. Carrett, J.-F. Poisson, Org. Lett. 2016, 18,
2824; f) K. Chen, R. Sun, Q. Xu, Y. Wei, M. Shi, Org. Biomol. Chem.
2013, 11, 3949; g) M. R. Siebert, J. M. Osbourn, K. M. Brummond, D. J.
Tantillo, J. Am. Chem. Soc. 2010, 132, 11952; h) B. Alcaide, P.
Almendros, C. Aragoncillo, Chem. Soc. Rev. 2010, 39, 783.
[4]
a) Y. Yu, Y. Fu, F. Zhong, Green Chem. 2018, 20, 1743; b) W.-F.
Zheng, G.-J. Sun, L. Chen, Q. Kang, Adv. Synth. Catal. 2018, 360,
1790; c) L. Hu, H. Chen, J. Am. Chem. Soc. 2017, 139, 15564; d) M. R.
Fructose, A. Prieto, Tetrahedron 2016, 72, 355; J.-L. Hu, L.-W. Feng, L.
Wang, Z. Xie, Y. Tang, X. Li, J. Am. Chem. Soc. 2016, 138, 13151; e)
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10.1002/anie.201806693
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Frederik Kramm[a], Johannes Teske[a],
Franziska Ullwer[a], Bernd Plietker [a]
*
Page No. – Page No.
Annelated cyclobutanes via Fe-
catalyzed cycloisomerization of
enyne acetates
Cationic Fe-complexes of the general type [(Ph3P)2Fe(CO)(NO)]X (X = BF4, BArF )
4
catalyze the redox-neutral cycloisomerization of 1,6- and 1,7-enyneacetates to
bicyclic cyclobutanes under mild conditions in good yields and
diastereoselectivities.
This article is protected by copyright. All rights reserved.