Mild and phosphine-free iron-catalyzed cross-coupling of nonactivated secondary alkyl halides with alkynyl grignard reagents

Article abstract of DOI:10.1021/ol501087m

A simple protocol for iron-catalyzed cross-coupling of nonactivated secondary alkyl bromides and iodides with alkynyl Grignard reagents at room temperature has been developed. A wide range of secondary alkyl halides and terminal alkynes are tolerated to a

Full text of DOI:10.1021/ol501087m

Letter
pubs.acs.org/OrgLett
Mild and Phosphine-Free Iron-Catalyzed Cross-Coupling of
Nonactivated Secondary Alkyl Halides with Alkynyl Grignard
Reagents
Chi Wai Cheung, Peng Ren, and Xile Hu*
Laboratory of Inorganic Synthesis and Catalysis, Institute of Chemical Sciences and Engineering, Ecole Polytecnique Fed
́ ́
erale de
Lausanne (EPFL), ISIC-LSCI, BCH 3305, Lausanne 1015, Switzerland
S
* Supporting Information
ABSTRACT: A simple protocol for iron-catalyzed cross-
coupling of nonactivated secondary alkyl bromides and iodides
with alkynyl Grignard reagents at room temperature has been
developed. A wide range of secondary alkyl halides and
terminal alkynes are tolerated to afford the substituted alkynes
in good yields. A slight modification of the reaction protocol also allows for cross-coupling with a variety of primary alkyl halides.
lkynes are versatile intermediates in the syntheses of
natural products, biologically active molecules, and
is rare.6a To the best of our knowledge, there is only a single
report by Nakamura on iron-catalyzed synthesis of substituted
alkynes via the cross-coupling of secondary alkyl halides with
alkynyl Grignard reagents (eq 1a).6a However, the reactions
A
functional materials.1 Therefore, the development of stream-
lined and practical syntheses of substituted and functionalized
alkynes is highly desirable. Whereas aryl- and vinyl-substituted
alkynes are routinely prepared by palladium-catalyzed Sonoga-
shira coupling,1a,2 alkyl-substituted alkynes are harder to access
through similar reactions due to two factors: (i) oxidative
addition of alkyl halides is comparatively slow;3 (ii) the
competitive and nonproductive β-hydride elimination of alkyl
group is facile in metal alkyl intermediates.3 Until now, there
have been less than a handful of reports of Pd-4 and Ni-
catalyzed5 Sonogashira coupling of alkyl halides, the most
advanced of which is Liu’s Ni-based method to afford a broad
range of secondary alkyl-substituted alkynes.5b Consequently, a
number of alternatives of Sonogashira coupling have been
developed to access alkyl-substituted alkynes.6−12 Among them,
alkyl−alkynyl organometallic coupling reactions are most
straightforward and versatile.6−8,10 These include the coupling
of alkyl halides with organometallic reagents,6,7 the coupling of
haloalkynes with organometallic reagents,8 and the oxidative
coupling of alkynyl nucleophiles.10 Despite the advances of the
above-mentioned synthetic methodologies in the construction
of C(sp3)−C(sp) bond, several limitations exist: (i) Coupling
of nonactivated secondary alkyl halides remains difficult
compared with primary ones. (ii) The terminal alkynes
employed in the reported methods are generally limited to
silylethynes and arylethynes, while the coupling of function-
alized alkylethynes is challenging. (iii) The transition-metal-
catalyzed reactions usually employ costly phosphine- and
nitrogen-based ligands.
required an iron complex with a bis(phosphine) ligand, an
elevated temperature (70 °C), and a slow, dropwise addition of
Grignard reagents over 2 h. Furthermore, only several examples
of cyclic secondary alkyl halides and sterically hindered alkynes
were demonstrated. Herein, we report the phosphine-ligand-
free iron-catalyzed cross-coupling of nonactivated secondary
alkyl bromides and iodides with alkynyl Grignard reagents at
room temperature, exhibiting a broad scope on both alkyl
halides and terminal alkynes (more than 50 examples, eq 1b).
We commenced our investigation by attempting the cross-
coupling of iodocyclohexane with 1-propynylmagnesium bro-
mide in N-methylpyrrolidone (NMP) solvent at room
temperature (Table S1, Supporting Information). Various
iron(III) and iron(II) salts were tested as the catalysts. While
most of the iron salts catalyzed the reaction to yield the desired
product, 1-propynylcyclohexane (1), iron(II) bromide was the
optimal catalyst (Table S1, entry 10, Supporting Information).
In the past decade, iron catalysis has generated significant
interest for C−C cross-coupling reactions thanks to the
abundance, low toxicity, and low cost character of iron.13
Although iron catalysis has been widely employed for the
formation of C(sp2)−C(sp2), C(sp3)−C(sp2), and C(sp3)−
C(sp3) bonds,13 iron-catalyzed C(sp3)−C(sp) bond formation
Received: April 15, 2014
Published: April 22, 2014
© 2014 American Chemical Society
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Letter
a
Upon further optimization, we were able to achieve the highest
yield of 1 (86%) in the presence of 10 mol % of FeBr2 and 1.5
equiv of alkynyl Grignard reagent in a more diluted solution
(Table S1, entry 19, Supporting Information). Significantly, a
slow, dropwise addition of Grignard reagent as in the
Nakamura protocol was unnecessary. The replacement of
NMP with other solvents [for example, tetrahydrofuran (THF),
1,4-dioxane, and N,N-dimethylformamide (DMF)] only
provided 1 in low yields.14 While bis[2-(N,N-dimethylamino)-
ethyl] ether (O-TMEDA)6c and tetramethylethylenediamine
(TMEDA)15 have been reported to enhance the yield of
transition-metal-catalyzed alkylation of Grignard reagents, they
did not promote the yield of 1 in our protocol (Table S1,
entries 31 and 36, Supporting Information).14 Thus, no additive
is employed in our protocol. We further examined other
transition-metal catalysts (Mn,16 Co,6b Ni,6c,d,7 Cu,8b Ag,12
Cr,17 and Pd6e) which have been employed in various C−C
cross-coupling reactions (Table S1, entries 39−48, Supporting
Information); however, they either promoted the reaction to
afford 1 in a trace to modest yield or did not catalyze the
reaction at all. Their catalytic inactivity further suggests that
they are unlikely to be the metal impurities present in FeBr2 to
catalyze the reaction. Without FeBr2, no product was observed
(Table S1, entry 21, Supporting Information), further
suggesting FeBr2 as a genuine precatalyst.
Scheme 1. Scope of Six-Membered Cyclic Alkyl Halides
With the optimized conditions in hand, we then explored the
substrate scope (Scheme 1). This iron-catalyzed protocol
tolerates a wide range of six-membered cyclic alkyl iodides,
including cyclohexyl, bicyclo[2.2.1]heptyl, Boc-protected piper-
idinyl, and tetrahydrofuranyl moieties. The cyclic rings bearing
various substituents (alkyl, ester, carbamate, and functionalized
aryl groups) (2f−h,k,l,n,o,u−x) are also suitable coupling
partners. In the presence of higher loading of FeBr2 (20 mol %)
and O-TMEDA additive, bromocyclohexane gave a yield similar
to that using iodocyclohexane (2c). In addition, a variety of
aryl-, silyl-, and alkylethynes readily react with EtMgBr to
generate the corresponding alkynyl Grignard reagents for
subsequent cross-coupling reactions, affording the substituted
alkynes in moderate to excellent yields. Electron-rich, -neutral,
and -deficient arylethynes, as well as trialkylsilylethynes with
varying steric properties (SiMe3, SiEt3, and SiiPr3), are well
tolerated. Furthermore, alkylethynes containing both simple
hydrocarbon (hexyl, nonyl) and functionalized groups
(tetrahydropyran, carbazole, morpholine, substituted aryl
ether, and cyclohexenyl) couple efficiently. Double alkynylation
of 1,4-diiodocyclohexnae proceeded smoothly when excess
Grignard reagent was added (2m). The biologically related
molecule, cholestene, can also be alkynylated (2y). The
diastereomeric ratios of the alkyne products are enhanced
compared to the corresponding alkyl iodides, especially when
sterically hindered alkynyl groups are adopted (2f,h,k,u,v,x).
However, the use of less bulky alkylethynyl groups results in a
decrease of the diastereomeric ratio of the products
(2g,l,m,y).18 When extremely high purity (99.999%) FeBr2
was used in the coupling reactions, similar yields of substituted
alkyne products were obtained as compared to the use of FeBr2
in 98% purity (2o,s,w), further supporting that FeBr2 is the best
catalyst to promote the reactions.
a
Reaction conditions: alkyl halide (1 mmol), alkynyl-MgBr (0.5 M in
THF, 1.5 mmol, 3 mL), FeBr2 (98% purity, 10 mol %), NMP (4 mL),
N2 atm, rt, 16 h; yields are of isolated products; diastereomeric ratios
(dr) of product and RX determined by H NMR or GCMS; major
diastereoisomers are shown. FeBr2 (20 mol %), O-TMEDA (2
equiv). Major diasteroisomer could not be determined. FeBr2 (20
1
b
c
d
e
mol %), alkynyl-MgBr (0.5 M in THF, 3 mmol, 6 mL). FeBr2
(99.999% purity) used.
compounds. Further, acyclic alkyl halides, even when bearing
aryl, ester, amine, carbamate, and olefin functional groups,
reacted smoothly to yield the substituted alkynes (3f−v). The
more sterically hindered acyclic alkyl iodides afforded the
products in higher yields in the presence of higher loading of
FeBr2 and O-TMEDA (3t−v). To our knowledge, this method
enables the first Fe-catalyzed cross-coupling of acyclic
secondary alkyl halides with alkynyl Grignard reagents.
We then studied the scope of smaller and larger cyclic as well
as acyclic alkyl halides (Scheme 2). Halo-substituted azetidine,
cyclopentane, dihydroindene, cycloheptane, and cyclooctane
were shown to be compatible coupling partners (3a−e) despite
the ring strains and/or steric hindrance of these cyclic
To demonstrate the practicality of this Fe-catalyzed
alkynylation of secondary alkyl halides, the coupling was
performed at higher mmol scales. Both 4-iodotetrahydropyran
(eq 2a,b) and tert-butyl 4-iodopiperidine-1-carboxylate (eq 2c)
(5−20 mmol, up to 4.2 g) reacted with (trimethylsilyl)-
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Scheme 2. Scope of Cyclic and Acyclic Secondary Alkyl
a
Halides.
intermediate.23 A single-electron transfer from the Fe center
of the Fe−ate complex to alkyl halide initiates the carbon−
halogen bond cleavage, generating an alkyl radical. The
recombination of alkyl radical to the Fe(alkynyl-ate)
intermediate forms an Fe(alkynyl-ate)(alkyl) species, which
subsequently undergoes reductive elimination to generate the
alkyl-substituted alkyne product. While the identity of the Fe
species during catalysis is unclear, after the reaction the solution
remained clear and no insoluble iron(0) particles were
observed.
The application of this protocol to the cross-coupling of
nonactivated primary alkyl halides was also examined. Further
optimization of the original protocol showed that the use of
THF solvent in conjunction with 2 equiv of O-TEMDA
efficiently facilitated the coupling of primary alkyl halides with
alkynyl Grignard reagents.14 Under the modified conditions, a
number of functionalized primary alkyl halides were found to
couple with various arylethynyl-, silylethynyl-, and alkylethy-
nylmagnesium bromides (Scheme 3).
a
Reaction conditions: alkyl halide (1 mmol), alkynyl-MgBr (0.5 M in
THF, 1.5 mmol, 3 mL), FeBr2 (98% purity, 10 mol %), NMP (4 mL),
N2 atm, rt, 16 h; yields are of isolated products. FeBr2 (20 mol %), O-
TMEDA (2 equiv). Reaction conditions: alkyl halide (0.5 mmol),
alkynyl-MgBr (0.5 M in THF, 0.75 mmol, 1.5 mL), NMP (2.0 mL).
b
c
In the Fe-catalyzed reaction protocols (Schemes 1−3), the
cross-coupling of secondary alkyl iodides generally proceeds
smoothly without the addition of O-TMEDA additive, whereas
a
Scheme 3. Scope of Primary Alkyl Halides
ethynylmagnesium bromide to give the corresponding sub-
stituted alkynes without significant diminishment of yields.
To gain mechanistic insight for the Fe-catalyzed coupling of
secondary alkyl halides with alkynyl Grignard reagents, we
employed enantioenriched (3-iodobutyl)benzene as the cou-
pling partner (eq 3).19 Only a racemic mixture of substituted
alkynes was obtained. Additionally, a radical clock substrate,
cyclopropylmethyl bromide, reacted to give the ring-opening
product in the Fe-catalyzed alkynylation (eq 4). These results
are consistent with the radical mechanism proposed in Fe-6a,20
and Ni-catalyzed5b,6c,21 C−C cross-coupling reactions with
alkyl halides. The enhancement of diastereomeric ratios of
substituted alkyne products in the Fe-catalyzed alkynylation of
3- and 4-substituted iodocyclohexanes further supports the
radical pathway (Scheme 1), as similar results have been
demonstrated in radical-based Ni-catalyzed coupling reac-
tions.5b,22 We propose that the reaction mechanism of this
phosphine-free Fe-catalyzed protocol would be similar to that
proposed in Nakamura’s system.6a FeBr2 first reacts with the
alkynyl Grignard reagent to form an Fe(alkynyl-ate)
a
Reaction conditions: alkyl halide (1 mmol), alkynyl-MgBr (0.5 M in
THF, 1.5 mmol, 3 mL), FeBr2 (98% purity, 20 mol %), O-TMEDA (2
mmol), THF (4 mL), N2 atm, rt, 16 h; yields are of isolated products.
b
FeBr2 (10 mol %).
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(7) For Ni-catalyzed coupling of propargyl halides with organozinc
reagents, see: Smith, S. W.; Fu, G. C. Angew. Chem., Int. Ed. 2008, 47,
9334.
(8) For transition-metal-catalyzed coupling of haloalkynes with
organometallic reagents, see the following. (i) Pd-catalyzed reactions:
(a) Thaler, T.; Guo, L.-N.; Mayer, P.; Knochel, P. Angew. Chem., Int.
Ed. 2011, 50, 2174. (ii) Cu-catalyzed reactions: (b) Cahiez, G.; Gager,
O.; Buendia, J. Angew. Chem., Int. Ed. 2010, 49, 1278.
the addition of O-TMEDA can promote the coupling with
secondary alkyl bromides, primary halides, and sterically
hindered alkyl iodides.14 We propose that O-TMEDA would
stabilize the reactive alkynyl Grignard reagents from decom-
position,6c prior to the Fe-mediated activation of less reactive
secondary alkyl bromides and primary alkyl halides as well as
sterically hindered alkyl iodides to generate the corresponding
alkyl radicals. Some reactions only generate moderate yields of
products despite a 100% conversion, probably due to a
competing β-hydride elimination from Fe−alkyl intermediate
to give alkene and the Fe-mediated reduction of the alkyl halide
to give akane.24
In summary, we have developed a general method for the
iron-catalyzed cross-coupling reactions of nonactivated secon-
dary alkyl halides with alkynyl Grignard reagents at ambient
conditions. This method is compatible with a wide range of
readily accessible secondary alkyl halides and terminal alkynes.
Additionally, the modified reaction protocol can be utilized in
the cross-coupling reactions of nonactivated primary alkyl
halides. Thanks to the use of environmentally benign and
inexpensive iron catalyst along with the mild conditions of this
protocol, we anticipate that this chemistry will be applicable to
the convenient synthesis of functionalized alkyne motifs in
pharmaceutical and materials chemistry.
(9) For metal-free coupling of arylsulfonylacetylenes with organo-
́
metallic reagents, see: Ruano, J. L. G.; Aleman, J.; Marzo, L.; Alvarado,
C.; Tortosa, M.; Díaz-Tendero, S.; Fraile, A. Chem.Eur. J. 2012, 18,
8414.
(10) For synthesis of alkynes via oxidative coupling, see the following.
With two organometallic reagents: (a) Zhao, Y.; Wang, H.; Hou, X.;
Hu, Y.; Lei, A.; Zhang, H.; Zhu, L. J. Am. Chem. Soc. 2006, 128, 15048.
With one organometallic reagent: (b) Chen, M.; Zheng, X.; Li, W.;
He, J.; Lei, A. J. Am. Chem. Soc. 2010, 132, 4101.
(11) For synthesis of alkynes from N-tosylhydrazones, see: Ye, F.;
Ma, X.; Xiao, Q.; Li, H.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2012,
134, 5742.
(12) For synthesis of alkynes from ethynylbenziodoxolones and
aliphatic carboxylic acids, see: Liu, X.; Wang, Z.; Cheng, X.; Li, C. J.
Am. Chem. Soc. 2012, 134, 14330.
(13) For examples, see: (a) Bolm, C.; Legros, J.; Paih, J. L.; Zani, L.
Chem. Rev. 2004, 104, 6217. (b) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem.
Rev. 2011, 111, 1293. (c) Hatakeyama, T.; Hashimoto, T.;
Kathriarachchi, K. K. A. D. S.; Zenmyo, T.; Seike, H.; Nakamura, M.
Angew. Chem., Int. Ed. 2012, 51, 8834. (d) Furstner, A.; Martin, R.
̈
ASSOCIATED CONTENT
* Supporting Information
Spectral and experimental data. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
Chem. Lett. 2005, 34, 624. (e) Sherry, B. D.; Furstner, A. Acc. Chem.
̈
S
Res. 2008, 41, 1500.
(14) See the Supporting Information for experimental details.
(15) (a) Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. J. Am.
Chem. Soc. 2004, 126, 3686. (b) Cahiez, G.; Habiak, V.; Duplais, C.;
Moyeux, A. Chem. Int. Ed. 2007, 46, 4364.
(16) (a) Kang, S.-K.; Kim, J.-S.; Choi, S.-C. J. Org. Chem. 1997, 62,
4208. (b) Cahiez, G. Gager, O.; Lecomte, F. Org. Lett. 2008, 10, 5255.
(17) Steib, A. K.; Kuzmina, O. M.; Fernandez, S.; Flubacher, D.;
Knochel, P. J. Am. Chem. Soc. 2013, 135, 15346.
(18) We propose that the Fe(alkynyl-ate) intermediate containing
the less bulky alkynyl group could not sterically differentiate
significantly the substituted cyclohexyl radical prior to the coupling
reaction, thereby generating a lower diasteromeric ratio of the product.
(19) The deviation of the yields of 3f was presumably due to the use
of different scales of enantioenriched substrates.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xile.hu@epfl.ch.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work is supported by a European Research Council
(ERC) starting grant (no. 257096).
■
(20) For examples, see: (a) Furstner, A.; Martin, R.; Krause, H.;
̈
Seidel, G.; Goddard, R.; Lehmann, C. W. J. Am. Chem. Soc. 2008, 130,
8773. (b) Noda, D.; Sunada, Y.; Hatakeyama, T.; Nakamura, M.;
Nagashima, H. J. Am. Chem. Soc. 2009, 131, 6078. (c) Hatakeyama, T.;
Hashimoto, T.; Kondo, Y.; Fujiwara, Y.; Seike, H.; Takaya, H.;
Tamada, Y.; Ono, T.; Nakamura, M. J. Am. Chem. Soc. 2010, 132,
10674.
(21) (a) Hu, X. Chem. Sci. 2011, 2, 1867. (b) Breitenfeld, J.; Ruiz, J.;
Wodrich, M. D.; Hu, X. J. Am. Chem. Soc. 2013, 135, 12004.
(22) Perez Garcia, P. M.; Di Franco, T.; Orsino, A.; Ren, P.; Hu, X.
Org. Lett. 2012, 14, 4286.
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