Mechanism of Ru(II)-Catalyzed Rearrangements of Allenyl- and Alkynylcyclopropanols to Cyclopentenones

Article abstract of DOI:10.1021/acs.orglett.6b03088

A comparison study of the Ru(II)-catalyzed rearrangements of allenyl- and alkynylcyclopropanols to the corresponding cyclopentenones has been undertaken with the aid of an alkyl substituent on the three-membered ring. These ring expansion reactions proceed with exceptional regioselectivity irrespective of the cis/trans stereochemistry of the substituents on the three-membered ring. β-Carbon elimination is the common feature in the absence of a chelating group at the 4′-position in the alkyne chain.

Full text of DOI:10.1021/acs.orglett.6b03088

Letter
pubs.acs.org/OrgLett
Mechanism of Ru(II)-Catalyzed Rearrangements of Allenyl- and
Alkynylcyclopropanols to Cyclopentenones
†
†
†
‡
,†
Eppa Gyanchander, Sridhar Ydhyam, Naresh Tumma, Ken Belmore, and Jin Kun Cha*
†Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States
‡Department of Chemistry, The University of Alabama, Tuscaloosa, Alabama 35487, United States
*
S Supporting Information
ABSTRACT: A comparison study of the Ru(II)-catalyzed rearrangements of
allenyl- and alkynylcyclopropanols to the corresponding cyclopentenones has
been undertaken with the aid of an alkyl substituent on the three-membered
ring. These ring expansion reactions proceed with exceptional regioselectivity
irrespective of the cis/trans stereochemistry of the substituents on the three-
membered ring. β-Carbon elimination is the common feature in the absence of
a chelating group at the 4′-position in the alkyne chain.
yclopentenones have long been utilized as versatile
intermediates for the preparation of functionalized
cyclopentane derivatives. The development of efficient
panols. We envisioned that Trost’s Ru-catalyzed ring expansion
of alkynylcyclopropanols 1 would also be applicable to that of
allenylcyclopropanols 5. As part of our continuing interest in
the use of cyclopropanols as masked homoenols in C−C bond
C
synthetic methods for cyclopentenones has been an active
1
10
area of research. In addition to the frequently used Nazarov
formation, we report herein comparative mechanistic studies
2
,3
and Pauson−Khand reactions, new approaches have recently
of the key ring-expansion reactions.
4
−7
emerged from transition-metal-catalyzed cycloisomerization.
The first question was whether 4 is capable of catalyzing the
hitherto-unknown cyclization of allenylcyclopropanols to
cyclopentenones. We undertook a survey of reaction conditions
with an unsubstituted allenylcyclopropanol to validate the
feasibility. The rearrangement of cyclopropanol 7a occurred by
the action of 4 alone (Table 1, entry 2), which was in contrast
A large body of work on one-carbon ring expansion of alkenyl-,
alkynyl-, and allenylcycloalkanols has dealt with cyclobutanol
derivatives, whereas related cyclopropanols have received
7
−9
limited attention.
One striking example is the Ru(II)-
catalyzed ring expansion of alkynylcyclopropanols 1, which
gives two different products 2 or 3 depending on the alkyne
11,12
to that of alkynylcyclopropanols.
Suitable reaction con-
6
ditions were THF at reflux (entries 3−5). Addition of In(OTf)
substituents (Scheme 1). Little detail was provided on the
3
resulted in a significant increase in rate (less than 30 min)
entry 1), and InCl was not as effective as In(OTf) (entry 6).
mechanism of the Trost cycloisomerization of alkynylcyclopro-
(
3
3
Interestingly, the highest yield of 8 (76%) was obtained with
TBS ether 7b (entry 7), which presumably underwent in situ
desilylation under the reaction conditions. The corresponding
acetate or methyl ether (structure not shown) was recovered
unchanged. A pronounced increase in reaction rate caused by
Scheme 1. Ring-Expansion Reactions
In(OTf) was also apparent for 7b (entries 7 and 8), but its
3
13
precise role was unclear. The reaction proceeded slowly in the
presence of base (entry 9), but its effect was smaller than in the
12
rearrangement of alkynylcyclopropanols. In the absence of
catalyst 4, no rearrangement was observed.
Along with cyclization of phenyl-substituted allenes 9a and
9
b, the regioselectivity of the rearrangement was next examined
by placing a substituent on the three-membered ring (Scheme
). The presence of an alkyl substituent on the cyclopropane
2
would not only broaden the scope but also serve as a useful
mechanistic probe. 1,2-trans-Dialkyl allenylcyclopropanols
11a−d were subjected to the aforementioned conditions and
Received: October 13, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03088
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Letter
Table 1. Cyclopentenone Formation from 7a and 7b
Scheme 3. Plausible Mechanism for the Reaction of 11 To
Give 12
a
b
entry
sm
conditions
4, In(OTf)3
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
7a
7a
7a
7a
7a
7a
7b
7b
7b
0.5
6
62
65
40
35
4
c
4, In(OTf)3
4, In(OTf)3
4
d
e
6
f
4, In(OTf)
6
−
3
g
4, InCl3
4
44
76
59
49
4
24
3
4, In(OTf)3
nones, as the previously reported examples possessed a
h
4, In(OTf) , Cs CO
3
6
6,17b
3
2
propargylic proton in the alkyl side chain.
However, little
a
b
The amount of each reagent was 5 mol %. Isolated yields are given.
was known about transition-metal-catalyzed isomerization of
c
d
The reaction was carried out at 50 °C. The reaction was carried out
18
e
alkynes to allenes. We next undertook a comparison study of
in toluene at 70 °C. The reaction was carried out in MeCN at 70 °C.
f
g
h
the key rearrangements by employing allenylcyclopropanols
A complex mixture was obtained. 5 mol %. 1.1 equiv.
and the corresponding alkynyl substrates having both cis- and
19
trans-dialkyl substituents (Scheme 4). An alkoxy group was
Scheme 2. Cyclization of Substituted Allenylcyclopropanols
Scheme 4. Cyclization of Allenyl- and Alkynylcyclopropanols
1
4
afforded cyclopentenones 12a−d in 56−68% yield. None of
the alternate 4-benzyloxyethyl regioisomer was found: the
observed regiochemistry was in accord with β-carbon
installed on the side chain to test the presumed intermediacy of
C (Scheme 3), which would trigger elimination of the alkoxy
substituent leading to 3-alkenyl-5-alkyl-2-cyclopentenones.
Allenylcyclopropanols 15a/16a and 15b/16b indeed under-
went cyclopentenone formation and concomitant elimination
of the benzyloxy moiety to afford 3-alkenylcyclopentenones 19
and 20, respectively, albeit in modest yields. There were
negligible differences between the cis and trans isomers.
1
0,15,16
elimination.
1,1-Allenyl derivatives 13a and 13b also
underwent the rearrangement to 14 in comparable yields. Easy
access to 2,3-disubstituted cyclopentenones is an obvious
advantage over the alkynylcyclopropanol route (Trost’s
method). Unlike cyclopropanols 7b, 9b, and 13b, however,
cyclization of the TBS ethers of 11a−d was very sluggish. A
plausible mechanism is shown in Scheme 3, which features β-
carbon elimination of ruthenium(II) alcoholate A to give
homoenolate B. Subsequent migratory insertion affords C. A
straightforward ligand exchange completes the catalytic cycle.
It was tempting to speculate that the Trost cyclization of
alkynylcyclopropanols might involve initial isomerization to the
corresponding allenylcyclopropanols en route to cyclopente-
In contrast, the corresponding reactions of the alkynyl
counterparts 17a,b and 18a,b gave a mixture of cyclo-
17a
20
pentenones 21a,b and cyclobutanones 22a,b. Both the
formation and the E configuration of the latter products were
6
unexpected in light of Trost’s original work. The E double-
bond geometry is indicative of a 1,2-alkyl shift, which is
commonly observed with alkynophilic transition metals, rather
than β-carbon elimination−migratory insertion. A benzyloxy
B
DOI: 10.1021/acs.orglett.6b03088
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Organic Letters
Letter
substituent at the homopropargylic position in 17a,b and 18a,b
is most likely responsible for the preponderance of four-
membered ring formation in marked contrast to literature
Scheme 6. Deuterium-Labeling Experiments
2
1
precedent. The alkoxy moiety is capable of chelation to the
metal, thus favoring formation of 22a,b via a 1,2-alkyl shift (II
→
VI) over β-carbon elimination (Scheme 5). The observed
Scheme 5. Plausible Mechanism for Trost Cyclization
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03088.
Experimental procedures and spectroscopic data for key
intermediates (PDF)
regiochemistry is presumably due to steric interactions that
could override the intrinsic migrating aptitude, as reported in a
related Au(I)-catalyzed rearrangement that is affected by the
cis/trans ring stereochemistry. Most importantly, the
formation of cyclopentenones 21a,b, free from elimination
AUTHOR INFORMATION
Corresponding Author
■
*
2
2
jcha@chem.wayne.edu
ORCID
(e.g., 19/20), is incongruent with the intermediacy of the
Jin Kun Cha: 0000-0003-4038-3213
Notes
corresponding allenes.
In the absence of a 4′-alkoxy substituent, β-carbon
elimination (I → III/IV) is the predominant pathway, leading
to the cyclopentenone product 21 with no elimination. A
plausible mechanism for the Trost cyclization could involve
addition of the alkylmetal to the alkynone functionality to give
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NSF (CHE-1265843) for generous financial
support and Drs. S. Blackstock and Q. Liang (University of
Alabama) for help with HRMS measurements.
23−25
V, followed by reductive elimination.
Proton (generated
during the formation of I from the cyclopropanol substrate)
may be necessary for the proposed cyclization IV → V, which
would account for the deleterious effects of base (Table 2 in the
Supporting Information vs Table 1). Although additional
studies are necessary, the proposed mechanism is consistent
with preliminary deuterium-labeling experiments (Scheme 6).
In summary, a plausible mechanism is advanced for the Trost
cycloisomerization of alkynylcyclopropanols to cyclopente-
nones. Also included are the new rearrangement of
allenylcyclopropanols to cyclopentenones and a comparative
mechanistic study of the rearrangements of alkynyl- and
allenylcyclopropanols. Noteworthy is the Ru(II) catalyst’s
propensity to induce β-carbon elimination, in contrast to
other alkynophilic transition metals. Additionally, the presence
of a chelating group at the 4′-position in the alkyne chain
triggers two-point complexation to the catalyst to favor a 1,2-
alkyl shift over β-carbon elimination to yield (E)-alkylidenecy-
clobutanones as the major product.
REFERENCES
■
(
1) For a review, see: Simeonov, S. P.; Nunes, J. P M.; Guerra, K.;
Kurteva, V. B.; Afonso, C. A. M. Chem. Rev. 2016, 116, 5744.
2) For reviews, see: (a) Habermas, K. L.; Denmark, S. E.; Jones, T.
K. Org. React. 1994, 45, 1. (b) Tius, M. A. Eur. J. Org. Chem. 2005,
2193. (c) Shimada, N.; Stewart, C.; Tius, M. A. Tetrahedron 2011, 67,
5851. (d) Frontier, A. J.; Collison, C. Tetrahedron 2005, 61, 7577.
(3) For reviews, see: (a) Brummond, K. M.; Kent, J. L. Tetrahedron
(
2
000, 56, 3263. (b) Blanco-Urgoiti, J.; An
Domínguez, G.; Perez-Castells, J. Chem. Soc. Rev. 2004, 33, 32.
c) Gibson, S. E.; Mainolfi, N. Angew. Chem., Int. Ed. 2005, 44, 3022.
d) Shibata, T. Adv. Synth. Catal. 2006, 348, 2328.
4) For representative examples, see: (a) Rautenstrauch, V. J. Org.
̃
́
orbe, L.; Perez-Serrano, L.;
́
(
(
(
Chem. 1984, 49, 950. (b) Shi, X.; Gorin, D. J.; Toste, F. D. J. Am.
Chem. Soc. 2005, 127, 5802. (c) Zhang, L.; Wang, S. J. Am. Chem. Soc.
2006, 128, 1442. (d) Pujanauski, B. G.; Bhanu Prasad, B. A.; Sarpong,
R. J. Am. Chem. Soc. 2006, 128, 6786. (e) Tanaka, K.; Fu, G. C. J. Am.
C
DOI: 10.1021/acs.orglett.6b03088
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Chem. Soc. 2001, 123, 11492. (f) Tanaka, K.; Fu, G. C. J. Am. Chem.
Soc. 2002, 124, 10296.
(c) Rummelt, S. M.; Radkowski, K.; Rosca, D.-A.; Fu
̈
rstner, A. J. Am.
Chem. Soc. 2015, 137, 5506. Intramolecular: (d) Trost, B. M.; Ball, Z.
T. J. Am. Chem. Soc. 2003, 125, 30. (e) Denmark, S. E.; Pan, W. Org.
Lett. 2002, 4, 4163. Also see: (f) Sudo, T.; Asao, N.; Yamamoto, Y. J.
Org. Chem. 2000, 65, 8919. (g) Chung, L. W.; Wiest, O.; Wu, Y.-D. J.
Org. Chem. 2008, 73, 2649.
(
5) (a) Owada, Y.; Matsuo, T.; Iwasawa, N. Tetrahedron 1997, 53,
1069. (b) Iwasawa, N.; Matsuo, T.; Iwamoto, M.; Ikeno, T. J. Am.
Chem. Soc. 1998, 120, 3903.
6) Trost, B. M.; Xie, J.; Maulide, N. J. Am. Chem. Soc. 2008, 130,
7258.
7) For reviews, see: (a) Gibson, S. E.; Lewis, S. E.; Mainolfi, N. J.
1
(
1
(
(25) An alternative pathway of migratory insertion in an uncommon
trans fashion (not shown) cannot be ruled out. A trans addition of
Rh−H to the tethered alkyne was proposed, albeit in one-carbon
Organomet. Chem. 2004, 689, 3873. (b) Aitken, D. J.; Eijsberg, H.;
Frongia, A.; Ollivier, J.; Piras, P. P. Synthesis 2014, 46, 1. (c) Mack, D.
J.; Njardarson, J. T. ACS Catal. 2013, 3, 272.
4
e,f
homologues.
(
8) (a) Clark, G. R.; Thiensathit, S. Tetrahedron Lett. 1985, 26, 2503.
(
(
b) Larock, R. C.; Reddy, C. K. J. Org. Chem. 2002, 67, 2027.
c) Yoshida, M.; Sugimoto, K.; Ihara, M. Tetrahedron 2002, 58, 7839.
(
(
9) Seiser, T.; Cramer, N. Angew. Chem., Int. Ed. 2008, 47, 9294.
10) (a) Das, P. P.; Belmore, K.; Cha, J. K. Angew. Chem., Int. Ed.
2
012, 51, 9517. (b) Parida, B. B.; Das, P. P.; Niocel, M.; Cha, J. K. Org.
Lett. 2013, 15, 1780. (c) Murali, R. V. N. S.; Rao, N. N.; Cha, J. K. Org.
Lett. 2015, 17, 3854. (d) Ydhyam, S.; Cha, J. K. Org. Lett. 2015, 17,
5
(
820.
11) Unlike alkynylcyclopropanols, treatment of allenylcyclopro-
5b
5a
panols with Co (CO) afforded 1,4-hydroquinones.
2
8
(
12) See the Supporting Information for the screening results of the
Trost cyclization.
13) See: (a) Trost, B. M.; Livingston, R. C. J. Am. Chem. Soc. 1995,
(
1
17, 9586. (b) Trost, B. M.; Livingston, R. C. J. Am. Chem. Soc. 2008,
1
30, 11970.
(
14) The COSY spectrum of 12 clearly shows the cross-peaks (a W
coupling) between the olefinic proton and the methylene protons. The
C5-substituted regiochemistry was confirmed by difference NOE
measurements, NOESY, HSQC, and HMBC.
(
15) For reviews, see: (a) Aïssa, C. Synthesis 2011, 2011, 3389.
(
(
b) Murakami, M.; Matsuda, T. Chem. Commun. 2011, 47, 1100.
c) Seiser, T.; Saget, T.; Tran, D. N.; Cramer, N. Angew. Chem., Int. Ed.
2
(
1
011, 50, 7740. (d) Ruhland, K. Eur. J. Org. Chem. 2012, 2683.
16) (a) Nishimura, T.; Uemura, S. J. Am. Chem. Soc. 1999, 121,
1010. (b) Matsumura, S.; Maeda, Y.; Nishimura, T.; Uemura, S. J.
Am. Chem. Soc. 2003, 125, 8862. (c) Nishimura, T.; Uemura, S. Synlett
004, 201.
17) (a) No β-hydride elimination of B (Scheme 3) was observed,
2
(
which precluded a Nazarov-type reaction pathway. (b) Alkynylcyclo-
propanols having SiR1 or COR substituents (Scheme 1) are believed
2
3
to rearrange via β-carbon elimination and subsequent migratory
insertion, as opposed to a 1,2-alkyl shift, which accounts for the
atypical Z geometry of the alkylidenecyclobutanone products.
(
18) See: (a) Wolf, J.; Werner, H. Organometallics 1987, 6, 1164.
(
b) Leeaphon, M.; Ondracek, A. L.; Thomas, R. J.; Fanwick, P. E.;
Walton, R. A. J. Am. Chem. Soc. 1995, 117, 9715. (c) Phadke, N.;
Findlater, M. Organometallics 2014, 33, 16.
(
19) Prepared by the methods of: (a) Racouchot, S.; Sylvestre, I.;
Ollivier, J.; Kozyrkov, Y. Y.; Pukin, A.; Kulinkovich, O. G.; Salaun, J.
̈
Eur. J. Org. Chem. 2002, 2160. (b) Lee, J.; Kim, H.; Cha, J. K. J. Am.
Chem. Soc. 1996, 118, 4198. (c) See the Supporting Information.
(
20) The E geometry and regiochemistry of 22a,b was unequivocally
1
determined by 1D and 2D H NMR spectroscopy.
21) It is interesting to note that no cyclobutanone formation was
(
reported for the cyclization of the one-carbon homologue, i.e., 5′-
6
benzyloxy-1′-pentynylcyclopropanol.
(
22) (a) Markham, J. P.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc.
2
005, 127, 9708. (b) Sordo, T. L.; Ardura, D. Eur. J. Org. Chem. 2008,
3
004.
(
23) There is precedent for Ru(IV) complexes. See: (a) Hartwig, J.
F.; Bergman, R. G.; Andersen, R. A. J. Am. Chem. Soc. 1990, 112, 3234.
b) Grellier, M.; Ayed, T.; Barthelat, J.-C.; Albinati, A.; Mason, S.;
Vendier, L.; Coppel, Y.; Sabo-Etienne, S. J. Am. Chem. Soc. 2009, 131,
633.
24) As an analogy, trans-hydrometalation reactions are well-
precedented. See: (a) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc.
001, 123, 12726. (b) Trost, B. M.; Ball, Z. T. Synthesis 2005, 853.
(
7
(
2
D
DOI: 10.1021/acs.orglett.6b03088
Org. Lett. XXXX, XXX, XXX−XXX