Iron-Catalyzed Regio- And Stereoselective Substitution of γ,δ-Epoxy-α,β-unsaturated Esters and Amides with Grignard Reagents

Article abstract of DOI:10.1021/ol100022w

Chemical Equetion Presentation When γ,δ-epoxy-α,β- unsaturated esters or amides were treated with 2 equiv of Grignard reagents in the presence of 10-24 mol % FeCl₂, regio- and stereoselective substitution of the epoxide moiety with the Grignard reagent occurred to give exclusively δ-hydroxy-γ-alkyl or aryl-α,β-unsaturated esters or amides in good yields.

Full text of DOI:10.1021/ol100022w

ORGANIC
LETTERS
2010
Vol. 12, No. 5
1012-1014
Iron-Catalyzed Regio- and Stereoselective
Substitution of γ,δ-Epoxy-r,ꢀ-unsaturated
Esters and Amides with Grignard
Reagents
Takeshi Hata, Rie Bannai, Mamoru Otsuki, 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 January 5, 2010
ABSTRACT
When γ,δ-epoxy-r,ꢀ-unsaturated esters or amides were treated with 2 equiv of Grignard reagents in the presence of 10-24 mol % FeCl2,
regio- and stereoselective substitution of the epoxide moiety with the Grignard reagent occurred to give exclusively δ-hydroxy-γ-alkyl or
aryl-r,ꢀ-unsaturated esters or amides in good yields.
Diene monoepoxides are useful building blocks in organic
synthesis, and their utility has been explored by many
research groups.1 Although their functionalized counterparts,
such as γ,δ-epoxy-R,ꢀ-unsaturated carboxylic acid derivative
1 in eq 1, are often more useful than simple compounds,2
their reaction with organometallic reagents has not been
amply reported, probably because of the poor compatibility
of the functional group with metallic reagents.3,4 Here we
report that iron-catalyzed substitution of these diene monoe-
(3) With methyl- or ethylaluminum reagents: (a) Miyashita, M.; Hoshino,
M.; Yoshikoshi, A. J. Org. Chem. 1991, 56, 6483–6485. (b) Shanmugam,
P.; Miyashita, M. Org. Lett. 2003, 5, 3265–3268. For application to natural
product synthesis, see: (c) Komatsu, K.; Tanino, K.; Miyashita, M. Angew.
Chem., Int. Ed. 2004, 43, 4341–4353. (d) Nakamura, R.; Tanino, K.;
(1) (a) Olofsson, B.; Somfai, P. In Aziridines and Epoxides in Organic
Synthesis; Yudin, A. K., Ed.; Wiley-VCH: Weinheim, 2006; pp 315-347.
For substitution of epoxides with Grignard reagents, see: (b) Urabe, H.;
Sato, F. In Handbook of Grignard Reactions; Silverman, G. S., Rakita,
P. E., Eds.; Marcel Dekker: New York, 1996; pp 577-632.
Miyashita, M. Org. Lett. 2003, 5, 3579–3582
.
(4) With organocopper reagents (which shows different regioselection
to form allyl alcohols rather than homoallyl alcohols): Hirai, A.; Matsui,
A.; Komatsu, K.; Tanino, K.; Miyashita, M. Chem. Commun. 2002, 1970–
(2) Substitution of functionalized diene monoepoxides with various
nucleophiles has been reported. With oxygen or nitrogen nucleophiles: (a)
Yu, X.-Q.; Yoshimura, F.; Ito, F.; Sasaki, M.; Hirai, A.; Tanino, K.;
Miyashita, M. Angew. Chem., Int. Ed. 2008, 47, 750–754. (b) Miyashita,
M.; Mizutani, T.; Tadano, G.; Iwata, Y.; Miyazawa, M.; Tanino, K. Angew.
Chem., Int. Ed. 2005, 44, 5094–5097. (c) Fagnou, K.; Lautens, M. Org.
Lett. 2000, 2, 2319–2321. (d) Tsuda, T.; Horii, Y.; Nakagawa, Y.; Ishida,
T.; Saegusa, T. J. Org. Chem. 1989, 54, 977–979. With active methylene
compounds under Pd catalysis (which shows different regioselection to form
allyl alcohols rather than homoallyl alcohols): (e) Tsuji, J.; Kataoka, H.;
Kobayashi, Y. Tetrahedron Lett. 1981, 22, 2575–2578. (f) Nemoto, H.;
Ibaragi, T.; Bando, M.; Kido, M.; Shibuya, M. Tetrahedron Lett. 1999, 40,
1319–1322. With hydride under Pd catalysis: (g) Oshima, M.; Yamazaki,
H.; Shimizu, I.; Nisar, M.; Tsuji, J. J. Am. Chem. Soc. 1989, 111, 6280–
6287. With electron: (h) Molander, G. A.; Bella, B. E. L.; Hahn, G. J. Org.
Chem. 1986, 51, 5259–5264. (i) Yadav, J. S.; Shekharam, T.; Srinivas, D.
Tetrahedron Lett. 1992, 33, 7973–7976.
1971
.
(5) For reviews on iron-promoted organic reactions, see: (a) Correa, A.;
Manchen˜o, O. G.; Bolm, C. Chem. Soc. ReV. 2008, 37, 1108–1117. (b)
Enthaler, S.; Junge, K.; Beller, M. Angew. Chem., Int. Ed. 2008, 47, 3317–
3321. (c) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. ReV. 2004, 104,
6217–6254. For diene, enyne, and diyne cyclizations, see: (d) Michelet,
V.; Toullec, P. Y.; Geneˆt, J.-P. Angew. Chem.Int. Ed 2008, 47, 4268–4315.
For coupling reactions, see: (e) Sherry, B. D.; Fu¨rstner, A. Acc. Chem. Res.
2008, 41, 1500–1511. (f) Fu¨rstner, A.; Martin, R. Chem. Lett. 2005, 34,
624–629
.
(6) For iron-catalyzed or -mediated reactions from our laboratory, see:
(a) Okada, S.; Arayama, K.; Murayama, R.; Ishizuka, T.; Hara, K.; Hirone,
N.; Hata, T.; Urabe, H. Angew. Chem., Int. Ed. 2008, 47, 6860–6864. (b)
Hata, T.; Hirone, N.; Sujaku, S.; Nakano, K.; Urabe, H. Org. Lett. 2008,
10, 5051–5053. (c) Fukuhara, K.; Urabe, H. Tetrahedron Lett. 2005, 46,
603–606
.
10.1021/ol100022w  2010 American Chemical Society
Published on Web 02/09/2010

poxides with Grignard reagents satisfactorily took place to
give homoallyl alcohols as single isomers.5,6
Table 1. Preparation of Various Homoallyl Alcohols According
The outcome of the preliminary investigation is shown
by eq 1, in which amide 1 was allowed to react with
PhMgBr in the presence of iron salts or other metallic
catalysts. While a few iron salts proved particularly useful
for this reaction (entries 2-5), routine catalysts1,2 were
found ineffective (entries 6-12).7 Considering its cost and
simplicity (free from organic ligands), we adopted 10-20
mol % of FeCl2 as the best catalyst and obtained the desired
homoallyl alcohol 2 in 62% isolated yield and as a single
isomer (entry 4).8
to eqs 1 and 2
This reaction is also applicable to ester 3 as shown in eq
2. The stereochemistry of product 5 was unambiguously
verified by its derivatization to known lactone 6.9
The high selectivity observed above is valid to various
γ,δ-epoxy-R,ꢀ-unsaturated carboxylic acid derivatives and
Grignard reagents as shown in Table 1, thus affording the
desired products as virtually single isomers. Besides ethyl
ester 3 and diethylamide 1, t-butyl ester 7 and N,N-
dibenzylamide 8 participated in the substitution as well to
give 16 and 18 (entries 4 and 7). In addition to aryl delivery
(entries 1, 2, 4-7, and 12), alkyl or alkenyl Grignard reagents
afforded single homoallyl alcohols in good yields (entries
3, 8, 10, 11, and 13-18). One exception was ethynyl
Grignard reagent (entry 9), which gave the coupling product
20 in good yield, but its diastereoselectivity was moderate.
While the reactions of entries 1-13 always started with
trans-epoxides, cis epoxides 10-12 could be utilized equally
well to give the homoallyl alcohols 25-27 as single isomers
(entries 14-16), among which product 26 is a known
compound.3a Even trisubstituted epoxides 13 and 14 reacted
a Isolated yields. A single isomer was always produced, except for entry
9. b Same diastereoselectivity was observed before and after purification.
Stereochemical assignment to the diastereoisomers has not been done.
c PhMgBr (2.3 equiv) or MeMgBr (1.9 equiv) was used.
smoothly with a Grignard reagent to produce the desired
products 28 and 29 in high yields (entries 17 and 18).
Synthetic versatility of Grignard reagents makes this
transformation more attractive as illustrated in eq 3.10
Coupling of functionalized Grignard reagent 31 generated
from (chloromethyl)iodobenzene (30)11 and diene monoep-
(7) Unsuitable copper catalysis for this purpose was expected from the
results of ref 4. See, for example: Buchwald, S. L.; Bolm, C. Angew. Chem.,
Int. Ed 2009, 48, 5586–5587.
(8) Other regio- and stereoisomers were not detected in a crude reaction
1
mixture after careful analysis by H NMR spectroscopy.
(10) As cited in reference 3 this type of carbon-carbon bond formation
is so far viable with only methyl- or ethylaluminum reagents.
(11) Delacroix, T.; Be´rillon, L.; Cahiez, G.; Knochel, P. J. Org. Chem.
2000, 65, 8108–8110.
(9) Nagumo, S.; Ono, M.; Kakimoto, Y.; Furukawa, T.; Hisano, T.;
Mizukami, M.; Kawahara, N.; Akita, H. J. Org. Chem. 2002, 67, 6618–
6622.
Org. Lett., Vol. 12, No. 5, 2010
1013

oxide 1 afforded alkoxide 32, which spontaneously under-
went cyclization to yield the isochroman derivative 33. The
somewhat low diastereoselectivity (92:8) of 33 may arise
from vinylogous enolization of intermediate 32 at a higher
temperature necessary for the cyclization step.
active, functionalized allyl mesylate 37. As can be seen from
eq 5, the stereochemical integrity of 37 was partially lost
during the reaction through 38 to give product 39 as a single
regioisomer with a lower ee value.14 Thus, the highly
selective overall inversion of stereochemistry in the reaction
of the functionalized diene monoepoxide with a Grignard
reagent is noteworthy from both synthetic and mechanistic
points of view.
The present reaction should proceed via π-allyliron
intermediate 3512,13 generated from 34 with inversion of
configuration of the allylic epoxide carbon (eq 4). Subsequent
migration of the R group from iron to the allyl ligand with
retention of configuration should have resulted in the
exclusive production of 36 with the observed stereochemistry.
To see the generality of this stereochemical outcome, we
turned our attention to a similar substitution of an optically
In conclusion, the iron-catalyzed substitution of γ,δ-
epoxy-R,ꢀ-unsaturated esters and amides with Grignard
reagents proceeded with inversion of configuration. As
Grignard reagents are one of the most versatile organo-
metallic reagents, this method is a novel entry to the
practical preparation of stereodefined functionalized ho-
moallyl alcohols.
(12) Iron-catalyzed allylic substitution with Grignard reagents has been
reported. (a) Kauffmann, T. Angew. Chem., Int. Ed. Engl. 1996, 35, 386–
403. (b) Yanagisawa, A.; Nomura, N.; Yamamoto, H. Synlett 1991, 513–
514. (c) Urabe, H.; Inami, H.; Sato, F. J. Chem. Soc., Chem. Commun.
1993, 1595–1597. (d) Nakamura, M.; Matsuo, K.; Inoue, T.; Nakamura, E.
Org. Lett. 2003, 5, 1373–1375. With functionalized (achiral) allyl bromide,
see: (e) Fu¨rstner, A.; Martin, R.; Krause, H.; Seidel, G.; Goddard, R.;
Lehmann, C. W. J. Am. Chem. Soc. 2008, 130, 8773–8787. With
alkynylepoxides, see: (f) Fu¨rstner, A.; Me´ndez, M. Angew. Chem., Int. Ed.
2003, 42, 5355–5357. (g) Fu¨rstner, A.; Kattnig, E.; Lepage, O. J. Am. Chem.
Soc. 2006, 128, 9194–9204. With vinylcyclopropanes, see: (h) Sherry, B. D.;
Acknowledgment. This work was supported by a Grant-
in-Aid for Young Scientists (B) (20750071, to T.H.) and a
Grant-in-Aid for Scientific Research (B) (21350027) from
JSPS.
Fu¨rstner, A. Chem. Commun. 2009, 7116–7118
.
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.
(13) Regio- and stereochemical aspects of iron-catalyzed allylic substitu-
tion with soft nucleophiles such as malonates and amines have been
disclosed. (a) Silverman, G. S.; Strickland, S.; Nicholas, K. M. Organo-
metallics 1986, 5, 2117–2124. (b) Xu, Y.; Zhou, B. J. Org. Chem. 1987,
52, 974–977. (c) Zhou, B.; Xu, Y. J. Org. Chem. 1988, 53, 4419–4422. (d)
Plietker, B. Angew. Chem., Int. Ed. 2006, 45, 1469–1473. (e) Plietker, B.
Angew. Chem., Int. Ed. 2006, 45, 6053–6056. (f) Åkermark, B.; Sjo¨gren,
M. P. T. AdV. Synth. Catal. 2007, 349, 2641–2646. (g) Plietker, B.; Dieskau,
A.; Mo¨ws, K.; Jatsch, A. Angew. Chem., Int. Ed. 2008, 47, 198–201. For
review, see: (h) Plietker, B.; Dieskau, A. Eur. J. Org. Chem. 2009, 775–
OL100022W
(14) To the best of our knowledge, this is the first example disclosing
the stereochemical course of iron-catalyzed allylic substitution at an optically
active system with Grignard reagent, which is categorized as a hard
nucleophile.
787
.
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