Synthesis of polysubstituted enynes through iron-catalyzed carbomagnesiation of conjugated diynes

Article abstract of DOI:10.1055/s-0033-1340476

Symmetrical and unsymmetrical conjugated diynes are chemo-, regio-, and stereoselectively carbomagnesiated with a ?Grignard reagent at room temperature in the presence of a catalytic amount of FeCl₂ without the need for an external ligand. The resulting magnesium intermediate can be further functionalized to give polysubstituted 1,3-enyne derivatives. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340476

LETTER
▌527
lSetyternthesis of Polysubstituted Enynes through Iron-Catalyzed Carbomagnesia-
tion of Conjugated Diynes
Iron-Catalyzed Carbomagnesiation of Diynes
Laurean Ilies, Takumi Yoshida, Eiichi Nakamura*
Department of Chemistry, School of Science, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
Fax +81(3)58006889; E-mail: nakamura@chem.s.u-tokyo.ac.jp
Received: 06.10.2013; Accepted after revision: 25.11.2013
phenylmagnesium bromide (1.2 equiv) in the presence of
Abstract: Symmetrical and unsymmetrical conjugated diynes are
FeCl2 (10 mol%) at only one of the two triple bonds to
produce trisubstituted conjugated diyne 2 in 68% yield
upon quenching with water, and a tetrasubstituted diyne 3
chemo-, regio-, and stereoselectively carbomagnesiated with a
Grignard reagent at room temperature in the presence of a catalytic
amount of FeCl2 without the need for an external ligand. The result-
ing magnesium intermediate can be further functionalized to give in 57% yield upon reaction with allyl bromide. We ob-
polysubstituted 1,3-enyne derivatives.
tained these products as single regio- and stereoisomers.
Although the material balance was not perfect, we neither
recovered the starting material nor found byproducts from
the diyne by GC, GC–MS, or NMR analysis. The reaction
produced a small amount of biphenyl, probably as a result
of oxidation of the Grignard reagent by Fe(II) at the begin-
ning of the reaction.
Key words: iron, catalysis, enynes, organometallic reagents, addi-
tion reactions
Polysubstituted conjugated enynes are structures of syn-
thetic interest in themselves1 and for medicinal chemistry2
and materials science.3 A conceptually straightforward
approach to these compounds4 includes regio- and stereo-
selective addition of an organometallic reagent across a
diyne, followed by stereospecific electrophilic trapping of
the resulting vinylmetal intermediate.5 There has, howev-
er, been a paucity of research activity in this area after
pioneering studies on an organozirconium-mediated reac-
tion by Hiyama,6 and Negishi and Takahashi7 in the
1990s. We report here an iron-catalyzed8 carbomagnesi-
ation reaction of a conjugated diyne9 with a Grignard re-
agent at ambient temperature, which proceeds chemo-,
regio-, and stereoselectively to produce a magnesium in-
termediate that then reacts with a variety of electrophiles
to give polysubstituted enynes.
Interestingly, in contrast to the poor performance of other
iron salts [Fe(acac)2 (23%), Fe(acac)3 (23%), FeCl3
(25%), FeF3 (5%), Fe(OTf)2 (12%), Fe(Oac)2 (28%)],
FeCl2 was found to be uniquely effective. We also noted
that FeCl2 is unique among the others for its poor solubil-
ity in diethyl ether, which was the best solvent among oth-
er common solvents screened (see the Supporting
Information). The presence of monophosphine, diphos-
phine, diamine, or carbene ligands retarded the reaction,
perhaps because they hamper the weak interaction be-
tween iron and the diyne substrate, as we speculated in the
hydromagnesiation study.10 Without the iron catalyst, no
conversion of the diyne took place. Other first-row transi-
tion metals used under the optimized conditions for FeCl2
were inefficient [CuCl (0%), Mn(OAc)2 (0%), Ni(acac)2
(10%), Co(acac)2 (5%)].
We previously reported an iron-catalyzed hydromagnesi-
ation of alkynes and diynes,10 where we speculated that
coordination of the substrate to the active iron species is
crucial for achieving reactivity and selectivity.11 With this
result in hand, we investigated the carbomagnesiation of a
diyne. After considerable experimentation on a prototype
reaction between bis(trimethylsilyl)-1,3-diyne (1) and
Grignard reagents (Scheme 1), we found that 1 reacts with
The scope of the carbomagnesiation reaction is summa-
rized in Table 1. The reaction proceeded exclusively on
only one triple bond for both symmetrical and unsymmet-
rical diynes. In all cases, the carbometalation reaction pro-
ceeded regioselectively to place the metal atom next to the
unreacted triple bond.7 The reaction proceeded in a syn
H2O
or
H2C=CHCH2Br
Ph
Me3Si
MgBr
Ph
E
PhMgBr (1.2 equiv)
FeCl2 (10 mol%)
Me3Si
SiMe3
Me3Si
Et2O, r.t., 3 h
1
SiMe3
SiMe3
2 E = H, 68%
3 E = allyl, 57%
(single isomer)
Scheme 1 Iron-catalyzed carbomagnesiation of 1,3-diynes followed by reaction of the magnesium intermediate with electrophiles
SYNLETT 2014, 25, 0527–0530
Advanced online publication: 08.01.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340476; Art ID: ST-2013-U0942-L
© Georg Thieme Verlag Stuttgart · New York

528
L. Ilies et al.
LETTER
fashion for disilyldiyne (entries 1–5) and dialkyldiyne reaction was not sensitive to steric bulk, thus a mesityl
(entry 8) derivatives, for which a mixture of stereoisomers group could also be introduced (entry 5). Methylmagne-
was reported in the zirconium-catalyzed reactions.6,7 In sium bromide (entry 7) reacted with moderate yield, and a
contrast, diaryldiynes showed a tendency toward isomeri- trace amount of regioisomer was observed. When an alkyl
zation, and a roughly 1:1 mixture of isomers was obtained Grignard reagent possessing a β-hydrogen was used, hy-
(see the Supporting Information). This problem requires dromagnesiation of the diyne mainly proceeded, as previ-
further investigation and will be the subject of future stud- ously observed.10
ies. An unsymmetrical diyne (entry 9) reacted with che-
The vinylmagnesium intermediate can be trapped by an
mo-, regio-, and stereoselectivity, and the product was
electrophile (Scheme 2). For example, when iodobenzene
obtained as a single isomer.
and a palladium catalyst were added after the carbomag-
Electron-rich (Table 1, entries 3 and 4) and electron-defi- nesiation was over, a tetraphenylated enyne was obtained
cient (entry 2) Grignard reagents reacted smoothly. The as a single product (Scheme 2, eq. 1). A nickel-catalyzed
Table 1 Iron-Catalyzed Carbomagnesiation of Conjugated Diynes with RMgBr followed by Protonolysisa
Entry
Diyne
R in RMgBr
Product
Yield (%)b
68 (X = H)
X
1
4-XC6H4
Me3Si
SiMe3
SiMe3
SiMe3
2
3
4
69 (X = F)
83 (X = OMe)
69 (X = Me)
Me3Si
SiMe3
5
Mes
65
Me3Si
SiMe3
Ph
Ph
Ph
Ph
Ph
6
7
8
Ph
Me
Ph
62
Ph
Ph
Ph
43c
55d
Ph
Ph
n-Bu
n-Bu
n-Bu
n-Bu
Ph
Ph
Ph
SiMe3
9
Ph
64
SiMe3
a Reaction conditions: conjugated diyne (0.3–0.4 mmol), FeCl2 (10 mol%) and Grignard reagent (1.2 equiv) in Et2O, r.t., 3 h. See the Supporting
Information for details.
b Isolated yield.
c An isomer was produced in 5% yield.
d An isomer was produced in 8% yield.
Synlett 2014, 25, 527–530
© Georg Thieme Verlag Stuttgart · New York

LETTER
Iron-Catalyzed Carbomagnesiation of Diynes
529
PhI (1.2 equiv)
PdCl2(PPh3)2
(10 mol%)
PhMgBr
cat. FeCl2
Ph
Ph
Ph
Ph
Ph
(1)
Et2O, r.t., 3 h
r.t., 12 h
Ph
46%
Ph
Ph
Br
PhMgBr
Ph
(1.5 equiv)
cat. FeCl2
(2)
Me3Si
SiMe3
Me3Si
NiCl2(dppe)
(10 mol%)
r.t., 12 h
Et2O, r.t., 3 h
SiMe3
43%
(containing <5% isomer)
PhMgBr
cat. FeCl2
1) ZnCl2
2) I2
Ph
I
Me3Si
SiMe3
(3)
r.t., 12 h
Et2O, r.t., 3 h
Me3Si
49%
SiMe3
Scheme 2
F. W.; Meyer, K.; Hübner, H.; Gmeiner, P. J. Med. Chem.
2013, 56, 5130.
cross-coupling with bromostyrene gave a stereodefined
dieneyne derivative (Scheme 2, eq. 2). We could also
transform the magnesium intermediate into an iodoenyne
(Scheme 2, eq. 3), which can be utilized as an electrophile
for coupling with a nucleophile.
(3) (a) Tykwinski, R. R.; Gholami, M.; Eisler, S.; Zhao, Y.;
Melin, F.; Echegoyen, L. Pure Appl. Chem. 2008, 80, 621.
(b) Gholami, M.; Tykwinski, R. R. Chem. Rev. 2006, 106,
4997. (c) Nielsen, M. B.; Diederich, F. Chem. Rev. 2005,
105, 1837.
In conclusion, we have developed conditions to effect
iron-catalyzed carbomagnesiation of a conjugated diyne
with an aryl Grignard reagent in diethyl ether at ambient
temperature.14 As observed for several iron-catalyzed re-
actions that we have reported recently,10,12 the reaction
conditions do not require an external ligand, probably be-
cause the substrate itself acts as a ligand to the iron cata-
lyst. Such simplicity of procedure, and the chemo-, regio-,
and stereoselectivity of the reaction, together with the
merits of iron catalysis13 make this reaction an attractive
alternative to the zirconium-catalyzed reactions.6,7 Con-
trol of selectivity for a broader range of substrates will be
the subject of future studies.
(4) See for example: (a) Kang, B.; Kim, D.; Do, Y.; Chang, S.
Org. Lett. 2003, 5, 3041. (b) Chinchilla, R.; Najera, C.
Chem. Rev. 2007, 107, 874. (c) Doucet, H.; Hierso, J.-C.
Angew. Chem. Int. Ed. 2007, 46, 834. (d) Suginome, M.;
Shirakura, A.; Yamamoto, A. J. Am. Chem. Soc. 2006, 128,
14438. (e) Yamauchi, Y.; Onodera, G.; Sakata, K.; Yuki,
M.; Miyake, Y.; Uemura, S.; Nishibayashi, Y. J. Am. Chem.
Soc. 2007, 129, 5175. (f) Hatakeyama, T.; Yoshimoto, Y.;
Gabriel, T.; Nakamura, M. Org. Lett. 2008, 10, 5341.
(5) For stoichiometric reactions, see: (a) Takahashi, T.; Xi, Z.;
Nishihara, Y.; Huo, S.; Kasai, K.; Aoyagi, K.; Denisov, V.;
Negishi, E. Tetrahedron 1997, 53, 9123. (b) Rosenthal, U.;
Burlakov, V. V.; Arndt, P.; Baumann, W.; Spannenberg, A.
Organometallics 2005, 24, 456; and references therein.
(c) Liu, Y.; Gao, H. Org. Lett. 2006, 8, 309. (d) Chen, J.; Liu,
Y. Tetrahedron Lett. 2008, 49, 6655. (e) Bredeau, S.;
Ortega, E.; Delmas, G.; Richard, P.; Frölich, R.; Donnadieu,
B.; Kehr, G.; Pirio, N.; Erker, G.; Meunier, P.
Acknowledgment
We thank MEXT for financial support (KAKENHI Specially Pro-
moted Research No. 22000008 to E.N., and a Grant-in-Aid for Sci-
entific Research on Innovative Areas No. 25105711 to L.I.).
Organometallics 2009, 28, 181. (f) Fu, X.; Liu, Y.; Li, Y.
Organometallics 2010, 29, 3012.
(6) Kusumoto, T.; Nishide, K.; Hiyama, T. Bull. Chem. Soc.
Jpn. 1990, 63, 1947.
(7) Takahashi, T.; Aoyagi, K.; Denisov, V.; Suzuki, N.;
Choueiry, D.; Negishi, E. Tetrahedron Lett. 1993, 34, 8301.
(8) (a) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev.
2004, 104, 6217. (b) Enthaler, S.; Junge, K.; Beller, M.
Angew. Chem. Int. Ed. 2008, 47, 3317. (c) Iron Catalysis in
Organic Chemistry; Plietker, B., Ed.; Wiley-VCH:
Weinheim, 2008. (d) Sherry, B. D.; Fürstner, A. Acc. Chem.
Res. 2008, 41, 1500. (e) Czaplik, W. M.; Mayer, M.;
Cvengros, J.; Jacobi von Wangelin, A. ChemSusChem 2009,
2, 396. (f) Nakamura, E.; Yoshikai, N. J. Org. Chem. 2010,
75, 6061. (g) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev.
2011, 111, 1293.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SuppInigfor
m
o
ti
References
(1) (a) Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100, 2901.
(b) Evans, P. A.; Murthy, V. S.; Roseman, J. D.; Rheingold,
A. L. Angew. Chem. Int. Ed. 1999, 38, 3175.
(2) (a) Krishnan-Natesan, S. Expert Opin. Pharmacother. 2009,
10, 2723. (b) Smith, A. L.; Nicolaou, K. C. J. Med. Chem.
1996, 39, 2103. (c) Hiller, C.; Kling, R. C.; Heinemann,
(9) For iron-catalyzed carbomagnesiation of alkynes, see:
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 527–530

530
L. Ilies et al.
LETTER
Y.; Hosomi, A. Angew. Chem. Int. Ed. 2001, 40, 621.
(b) Shirakawa, E.; Yamagami, T.; Kimura, T.; Yamaguchi,
S.; Hayashi, T. J. Am. Chem. Soc. 2005, 127, 17164.
(c) Zhang, D.; Ready, J. M. J. Am. Chem. Soc. 2006, 128,
15050. (d) Yamagami, T.; Shintani, R.; Shirakawa, E.;
Hayashi, T. Org. Lett. 2007, 9, 1045. (e) Matsumoto, A.;
Ilies, L.; Nakamura, E. J. Am. Chem. Soc. 2011, 133, 6557.
(f) Shirakawa, E.; Ikeda, D.; Masui, S.; Yoshida, M.;
Hayashi, T. J. Am. Chem. Soc. 2012, 134, 272. (g) Ilies, L.;
Matsumoto, A.; Kobayashi, M.; Yoshikai, N.; Nakamura, E.
Synlett 2012, 23, 2381.
1,4-bis(trimethylsilyl)-1,3-butadiyne (1; 78 mg, 0.40 mmol)
in Et2O (1.6 mL). After 15 min, a solution of phenyl-
magnesium bromide in Et2O (0.35 mL, 1.46 mol/L,
0.48 mmol) was added to the reaction mixture at r.t., and the
resulting mixture was stirred at r.t. for an additional 3 h, then
H2O (3.0 mL) was added. The organic phase was extracted
with EtOAc (3 × 5 mL), then the mixture was passed over a
pad of Florisil. The volatiles were removed in vacuo to
obtain an oily brown residue. The crude mixture was
purified by column chromatography (hexane 100%) to
afford the desired compound (74 mg, 68%) as a colorless oil.
GC analysis and 1H NMR analysis of the crude product
indicated that only one isomer was obtained.
(10) Ilies, L.; Yoshida, T.; Nakamura, E. J. Am. Chem. Soc. 2012,
134, 16951.
(11) Liu, P.; McCarren, P.; Cheong, P. H.-Y.; Jamison, T. F.;
Houk, K. N. J. Am. Chem. Soc. 2010, 132, 2050.
(12) (a) Nakamura, Y.; Ilies, L.; Nakamura, E. Org. Lett. 2011,
13, 5998. (b) Ilies, L.; Okabe, J.; Yoshikai, N.; Nakamura, E.
Org. Lett. 2010, 12, 2838.
(13) Nakamura, E.; Sato, K. Nat. Mater. 2011, 10, 158.
(14) Typical Procedure (Scheme 1): In an oven-dried Schlenk
tube, FeCl2 (5.0 mg, 0.040 mmol) was added to a solution of
(Z)-1-Phenyl-1,4-bis(trimethylsilyl)but-1-en-3-yne (2):
1H NMR (500 MHz, CDCl3): δ = 7.29–7.21 (m, 3 H), 7.05–
7.03 (m, 2 H), 6.14 (s, 1 H), 0.25–0.22 (m, 18 H); 13C NMR
(125 MHz, CDCl3): δ = 159.8, 145.1, 128.0, 126.7, 126.4,
122.0, 104.9, 100.5, –0.3, –0.4. GC MS (EI): m/z (%) = 272
(27), 257 (52), 199 (17), 155 (16), 73 (100).
Synlett 2014, 25, 527–530
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.