Iron-mediated intramolecular metalative cyclization of α,β- unsaturated esters and amides. Versatile one-pot preparation of bicyclic ketoesters

Article abstract of DOI:10.1021/ol802170z

(Chemical Equation Presented) 2-Nonen-7-ynedioic or 2-decen-8-ynedioic acid derivatives were treated with an iron reagent generated from FeCl₂ and t-BuMgCl in a ratio of 1:4 to give cyclized products after hydrolysis, deuteriolysis, or the addition of carbonyl compounds. Upon reaction with the same iron reagent, 2,7-nonadienedioates afforded bicyclic ketoesters (and their enol forms) after the addition of s-BuOH or carbonyl compounds.

Full text of DOI:10.1021/ol802170z

ORGANIC
LETTERS
2008
Vol. 10, No. 21
5031-5033
Iron-Mediated Intramolecular Metalative
Cyclization of r,ꢀ-Unsaturated Esters
and Amides. Versatile One-Pot
Preparation of Bicyclic Ketoesters
Takeshi Hata, Naoki Hirone, Shiro Sujaku, Kirihiro Nakano, and Hirokazu Urabe*
Department of Biomolecular Engineering, Graduate School of Bioscience and
Biotechnology, Tokyo Institute of Technology, 4259-B-59 Nagatsuta-cho, Midori-ku,
Yokohama, Kanagawa 226-8501, Japan
hurabe@bio.titech.ac.jp
Received September 17, 2008
ABSTRACT
2-Nonen-7-ynedioic or 2-decen-8-ynedioic acid derivatives were treated with an iron reagent generated from FeCl2 and t-BuMgCl in a ratio of
1:4 to give cyclized products after hydrolysis, deuteriolysis, or the addition of carbonyl compounds. Upon reaction with the same iron reagent,
2,7-nonadienedioates afforded bicyclic ketoesters (and their enol forms) after the addition of s-BuOH or carbonyl compounds.
Cyclization of enynes and dienes derived from unsaturated
carbonyl compounds with a stoichiometric amount of a metal
species may produce synthetically useful functionalized
organometallic compounds, but reactions belonging to this
class are still limited, probably because of the poor compat-
ibility of a reactive metallic portion and the carbonyl group.1
Here, we report that an iron reagent, generated from FeCl2
and t-BuMgCl, is particularly useful for this type of
cyclization, in conjunction with another advantage that iron
is abundant, inexpensive, and nontoxic, which should
contribute to economical and sustainable organic synthesis.2
Treatment of (E)-2-nonen-7-ynedioic acid derivative 2 with
reagent 1 generated from FeCl2 and t-BuMgCl in a ratio of
1:43,4 afforded cyclized product 4 in good yield after aqueous
workup, with both carbonyl groups remaining untouched
(Scheme 1).5-8 When the aqueous workup was replaced with
deuteriolysis, dideuterated product 4-d2 was obtained, show-
ing the presence of the dimetalated intermediate 3. This
intermediate regioselectively reacted with carbonyl com-
pounds to give carbon chain-elongated products 5-7 in one
pot.9
Other products prepared from various (E)-2-nonen-7-
ynedioic acid derivatives according to Scheme 1 by hydroly-
sis are shown in Figure 1, where a dotted line refers to a
newly formed carbon-carbon bond. Cyclopentanes 4 and
8-10 having various ester and amide side chains were
obtained in good yields. While a benzyloxymethyl group in
the tether portion was not effective enough to control the
stereochemistry of product 11, a highly diastereoselective
(1) For functionalized titanacycles and their synthetic applications, see:
(a) Sato, F.; Urabe, H. In Titanium and Zirconium in Organic Synthesis;
Marek, I., Ed.; Wiley-VCH: Weinheim, 2002; pp 319-354. (b) Sato, F.;
Okamoto, S. AdV. Synth. Catal. 2001, 343, 759–784. (c) Sato, F.; Urabe,
H.; Okamoto, S. Chem. ReV. 2000, 100, 2835–2886. (d) Urabe, H.; Suzuki,
K.; Sato, F. J. Am. Chem. Soc. 1997, 119, 10014–10027. (e) Tanaka, R.;
Yuza, A.; Watai, Y.; Suzuki, D.; Takayama, Y.; Sato, F.; Urabe, H. J. Am.
Chem. Soc. 2005, 127, 7774–7780. For functionalized nickelacycles, see:
(f) Montgomery, J. Acc. Chem. Res. 2000, 33, 467–473. (g) Mahandru,
G. M.; Skauge, A. R. L.; Chowdhury, S. K.; Amarasinghe, K. K. D.; Heeg,
M. J.; Montgomery, J. J. Am. Chem. Soc. 2003, 125, 13481–13485.
(2) For reviews on iron-mediated organic reactions, see: (a) Enthaler,
S.; Junge, K.; Beller, M. Angew. Chem., Int. Ed. 2008, 47, 3317–3321. (b)
Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. ReV. 2004, 104, 6217–
6254. For enyne cyclization, see: (c) Michelet, V.; Toullec, P. Y.; Geneˆt,
J.-P. Angew. Chem., Int. Ed. 2008, 47, 4268–4315. For coupling reactions,
see: (d) Fu¨rstner, A.; Rube´n, M. Chem. Lett. 2005, 34, 624–629. For iron
carbonyl complexes, see: (e) Semmelhack, M. F. In Organometallics in
Organic Synthesis. A Manual, 2nd ed.; Schlosser, M., Ed.; John Wiley &
Sons: Chichester, 2002; pp 1006-1121.
10.1021/ol802170z CCC: $40.75
Published on Web 10/15/2008
2008 American Chemical Society

Scheme 1
.
Cyclization of Enynedioic Acid Derivative and
Subsequent Reactions
Figure 1. Products formed according to Scheme 1.
namically stable exo-alkoxycarbonyl group. The proposed
reaction course from 14 to 16 involves the iron-mediated
cyclization to form metallacycle 17, protonation to one of
its carbon-metal bonds, and Dieckmann condensation of 18
to 16. Proper choice of the proton source regarding its
reactivity and equivalents appeared critical for the efficient
conversion from 14 to 16, and we found that s-BuOH as
indicated in Scheme 2 attained a satisfactory and stable
product yield of 16 (50%).8,11-13
Figure 2 shows ketoesters prepared from various E,E-
dienedioates according to Scheme 2. The type of alcohol
portion of the starting esters did not affect the efficiency of
cyclization to give 19-21 in comparable yields. The yields
of 20 from the corresponding E,E- and Z,E-dienedioates (61
and 35%, respectively) show that the former is a more
preferable starting material than the latter. Differently
substituted ketoesters 16 and 22 and those having an oxa-
or aza-heterocycle 23 and 24 were produced in satisfactory
yields.
cyclization giving a single bicyclic compound 12 should be
also noted. Substituted cyclohexane 13 was similarly pro-
duced from the corresponding (E)- and (Z)-2-decen-8-
ynedioic acid derivatives in good yields, regardless of their
olefinic geometries.
When we attempted the cyclization of dienedioate 14 with
iron reagent 1 under the same conditions, the expected
cyclopentane 15 was not isolated after aqueous workup
(Scheme 2). Instead, the isolable product here was a bicyclic
ketoester 16 as a 1:1 mixture of tautomeric keto and enol
forms10 in varying yields between 17 and 32%. The ketoester
itself was a single isomer, which should have a thermody-
(3) For our recent work on iron-catalyzed addition of Grignard reagents
to dienoates and dienamides, see: (a) Fukuhara, K.; Urabe, H. Tetrahedron
Lett. 2005, 46, 603–606. (b) Okada, S.; Arayama, K.; Murayama, R.;
Ishizuka, T.; Hara, K.; Hirone, N.; Hata, T.; Urabe, H. Angew. Chem., Int.
Ed. 2008, 47, 6860–6864.
(4) The use of fewer equivalents of t-BuMgCl resulted in considerable
decrease in the product yield. It has been reported that FeCl2 and 4 equiv
of RCH2CH2MgX form a species of the formal composition of [Fe(MgX)2]n.
To the best of our knowledge, the use of t-BuMgCl for this purpose has
not been mentioned. (a) Bogdanovic´, B.; Schwickardi, M. Angew. Chem.,
Int. Ed. 2000, 39, 4610–4613. (b) Fu¨rstner, A.; Leitner, A.; Mendez, M.;
Krause, H. J. Am. Chem. Soc. 2002, 124, 13856–13863. (c) Fu¨rstner, A.;
Krause, H.; Lehmann, C. W. Angew. Chem., Int. Ed. 2006, 45, 440–444.
(5) Even with the metal species listed in ref 1, cyclization of enynedioic
acid derivatives to the products such as those in Scheme 1 and Figure 1
has not been reported.
(6) Other iron-mediated cyclizations of enynes and dienes are as follows.
In these reports, R,ꢀ-unsaturated carboxylic acid derivatives are not included
as the starting material. For the Pauson-Khand-type enyne cyclization, see:
(a) Pearson, A. J.; Dubbert, R. A. Organometallics 1994, 13, 1656–1661.
For [2 + 2] cyclization and polymerization of dienes, see: (b) Bouwkamp,
M. W.; Bowman, A. C.; Lobkovsky, E.; Chirik, P. J. J. Am. Chem. Soc.
2006, 128, 13340–13341. (c) Takeuchi, D.; Matsuura, R.; Park, S.; Osakada,
K. J. Am. Chem. Soc. 2007, 129, 7002–7003. Cyclization of diynes initiated
by iron-catalyzed carbometalation was recently reported: (d) Zhang, D.;
Ready, J. M. J. Am. Chem. Soc. 2006, 128, 1505–1506.
In the transformation of Scheme 2, the carbon-metal bond
in 17 is cleaved by a proton, which is followed by the second
cyclization. However, this proton may be replaced by another
electrophile. In fact, when a ketone or aldehyde was added
(9) Products 6 and 7 consisted of only two diastereoisomers out of four.
These diastereoisomers should be attributable to the stereochemistry between
the cyclopentane carbon and the carbon R to the ester group as similarly
observed for 5. In these cases, the assignment of stereochemistries to major
and minor isomers has not been done.
(10) Ketoesters in Scheme 2, Figure 2, and eq 1 are always an
approximately 1:1 mixture of keto and enol forms, of which only the former
is depicted for simplicity.
(11) Bicyclic ketoester 16 is a known key compound to pentalenolactone
F: Cane, D. E.; Thomas, P. J. J. Am. Chem. Soc. 1984, 106, 5295–5303
.
(12) For reviews on the preparation and synthetic utility of five-
membered bicyclic compounds, see: Mehta, G.; Srikrishna, A. Chem. ReV.
1997, 97, 671–719. Singh, V.; Thomas, B. Tetrahedron 1998, 54, 3647–
3692
.
(7) Iron-catalyzed Diels-Alder and Alder-ene reactions are also known.
(a) Genet, J. P.; Ficini, J. Tetrahedron Lett. 1979, 1499–1502. (b) tom Dieck,
H.; Diercks, R. Angew. Chem., Int. Ed. Engl. 1983, 22, 778–779. (c)
Baldenius, K.-U.; tom Dieck, H.; Ko¨nig, W. A.; Icheln, D.; Runge, T.
Angew. Chem., Int. Ed. Engl. 1992, 31, 305–307. (d) Takacs, J. M.;
Anderson, L. G.; Madhavan, G. V. B.; Seely, F. L. Angew. Chem., Int. Ed.
Engl. 1987, 26, 1013–1015. (e) Takacs, J. M.; Anderson, L. G.; Newsome,
P. W. J. Am. Chem. Soc. 1987, 109, 2542–2544. (f) Fu¨rstner, A.; Majima,
K.; Martin, R.; Krause, H.; Kattnig, E.; Goddard, R.; Lehmann, C. W. J. Am.
Chem. Soc. 2008, 130, 1992–2004.
(13) Dimerization of cinnamate esters to ketoesters has been reported:
(a) Kise, N.; Iitaka, S.; Iwasaki, K.; Ueda, N. J. Org. Chem. 2002, 67,
8305–8315, and references cited therein. (b) Takaki, K.; Beppu, F.; Tanaka,
S.; Tsubaki, Y.; Jintoku, T.; Fujiwara, Y. J. Chem. Soc., Chem. Commun.
1990, n/a, 516–517. (c) Jensen, S. R.; Kristiansen, A.-M.; Munch-Petersen,
J. Acta Chem. Scand. 1970, 24, 2641–2647. For intramolecular cyclization
of R,ꢀ-olefinic esters, see: (d) Shinohara, I.; Okue, M.; Yamada, Y.;
Nagaoka, H. Tetrahedron Lett. 2003, 44, 4649–4652. However, these
methods did not realize the concomitant incorporation of a second
constituent such as a carbonyl compound to the products as can be seen in
(8) For experimental details, see the Supporting Information.
27-30.
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Org. Lett., Vol. 10, No. 21, 2008

single stereoisomer having the hydroxyisopropyl group at
the exo position,8 and the same stereochemistry was assigned
to other products 28-30 based on that of 27. This transfor-
mation could be considered as an equivalent of the generation
and reaction of the dianion of ketoesters 19-2114 and is a
new entry to the existing methods.13
Scheme 2. Tandem Cyclization of Dienedioate
In conclusion, we reported new metalative cyclizations of
doubly functionalized enynes and dienes with a simple iron
reagent, which enable a tandem cyclization of dienedioates
affording bicyclic ketoesters in one pot. Further investigations
on the utility of the iron reagent and synthetic application
of the products are now in progress.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research on Priority Areas (No.16073208)
and a Grant-in-Aid for Young Scientists (B) (No. 20750071,
to T.H.) from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
Figure 2. Bicyclic ketoesters prepared according to Scheme 2.
Supporting Information Available: Experimental pro-
cedures and physical properties of products. This material
is available free of charge via the Internet at http://pubs.acs.org.
to metallacycle 26 generated from 25 and 1 (eq 1), an aldol-
type reaction followed by the Dieckmann condensation took
place to give bicyclic compounds 27-30 having an additional
hydroxyalkyl side chain. The ketoester 27 was virtually a
OL802170Z
(14) For the generation and reactions of dianions of ketoesters, see:
Thompson, C. M.; Green, D. L. C. Tetrahedron 1991, 47, 4223–4285.
Org. Lett., Vol. 10, No. 21, 2008
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