Tuning chemoselectivity in iron-catalyzed sonogashira-type reactions using a bisphosphine ligand with peripheral steric bulk: Selective alkynylation of nonactivated alkyl halides

Article abstract of DOI:10.1002/anie.201104125

The incredible bulk: A highly C sp 3-center-selective alkynylation of nonactivated alkyl halides with the corresponding Grignard reagents is achieved by using the iron-phosphine complex 1. Primary and secondary alkyl iodides, bromides, and chlorides take

Full text of DOI:10.1002/anie.201104125

DOI: 10.1002/anie.201104125
Cross-Coupling
Tuning Chemoselectivity in Iron-Catalyzed Sonogashira-Type
Reactions Using a Bisphosphine Ligand with Peripheral Steric Bulk:
Selective Alkynylation of Nonactivated Alkyl Halides**
Takuji Hatakeyama, Yoshihiro Okada, Yuya Yoshimoto, and Masaharu Nakamura*
Alkynes are important structural units of various bioactive
molecules and organic electronic materials as well as of
versatile intermediates in organic synthesis.[1] We frequently
rely on the Sonogashira reaction to incorporate alkynyl units
into organic molecules in laboratory and industrial settings.[2]
Despite their prevalent use in the chemical synthesis, non-
activated alkyl halides with b-hydrogen atoms have remained
as difficult electrophiles for the cross-coupling reaction.
Considerable efforts have been devoted to address this
problem: Fu and co-workers recently employed a palla-
dium/copper catalyst composite with a bulky N-heterocyclic
carbene (NHC) ligand.[3] Glorius and co-workers[4] and Hu
and co-workers[5] have expanded the substrate scope by using
the palladium-NHC complex [{IBiox7PdCl2}2][4] and the
nickel-pincer complex [(MeNN2)NiCl] (bis[(2-dimethylami-
no)phenyl]amine nickel(II) chloride),[5] respectively. Oshima
and co-workers reported another noteworthy example of a
Sonogashira-type coupling of alkyl halides with alkynyl
Grignard reagents using a cobalt catalyst.[6] Based on the
ability of iron to couple a nonactivated alkyl halide with
various nucleophiles,[7–10] we would expect that iron would be
an efficient catalyst for the Sonogashira-type coupling of our
current focus. However, there has been no established
A recent mechanistic study reported by Nagashima and
our group showed that a diaryliron species, such as complex A
(Scheme 1), is a catalytically active species in the iron-
Scheme 1. Divalent iron diamine and bisphosphine complexes relevant
to iron-catalyzed cross-coupling of alkyl halides. Mes=2,4,6-trimethyl-
phenyl, tmeda=N,N,N’,N’-tetramethylethylene diamine, SciOPP=
spin-control-intended ortho-phenylene bisphosphine.[13]
catalyzed cross-coupling of alkyl halides.[14] Complex A
possesses the following characters: divalent oxidation state
(+ II), electronic charge neutrality, coordinative unsaturation
(14 electrons), and high spin state (S = 2). Complex A
homolytically cleaves the Csp3–halogen bond by a radical
mechanism, thus resulting in the observed high reactivity and
selectivity towards nonactivated alkyl halides. In analogy, we
designed new bisphosphine ligands bearing peripheral steric
bulk (SciOPPs), and prepared a divalent iron bisphosphine
complex B (Scheme 1). Complex B exhibits the above-
mentioned properties of the catalytically active species and
can be a good precatalyst for the coupling reaction; indeed,
various coupling reactions were successfully catalyzed by this
complex.[8n,15] The transmetalation reaction between B and
alkynyl metal reagents should also give rise to a reactive
alkynyliron intermediate for the desired Sonogashira-type
coupling reaction; however, in our previous work, we have
ꢀ
method for the Csp Csp3 coupling under iron catalysis, whereas
several groups, including us, successfully developed iron-
ꢀ
catalyzed Sonogashira-type Csp Csp2 couplings of conven-
tional unsaturated carbon electrophiles, such as aryl halides
and alkenyl halides.[11] We report herein a highly Csp3-selective
coupling reaction of nonactivated alkyl halides with alkynyl
Grignard reagents using an iron catalyst possessing a bisphos-
phine ligand with peripheral steric bulk. This ligand switches
ꢀ
the selectivity of the C C bond formation from an unsatu-
rated carbon center to a saturated carbon center.[8b,12]
ꢀ
observed that the Csp Csp2 coupling between an alkynyl
Grignard reagent and an alkenyl triflate or bromide pro-
ceeded in the absence of a ligand or a coordinating
additive.[11a] Thus, the issue of the chemoselectivity emerged
as an interesting point to explore.
To study the chemoselectivity, Csp3 center versus Csp2
center, we treated 4-bromo-1-cyclohexen-1-yl trifluorome-
thanesulfonate 1 with alkynylmagnesium reagent 2a in the
presence of various iron catalysts (Table 1). Electrophile 1 has
[*] Dr. T. Hatakeyama, Y. Okada, Y. Yoshimoto, Prof. M. Nakamura
International Research Center for Elements Science
Institute for Chemical Research, Kyoto University
Uji, Kyoto, 611-0011 (Japan)
E-mail: masaharu@scl.kyoto-u.ac.jp
[**] This work is granted by the Japan Society for the Promotion of
Science (JSPS) through the “Funding Program for Next Generation
World-Leading Researchers (NEXT Program),” initiated by the
Council for Science and Technology Policy (CSTP). Financial
support from Tosoh Finechem Corporations, the Noguchi Institute,
and a Grant-in-Aid for Scientific Research on Innovative Areas
“Integrated Organic Synthesis” is also acknowledged.
ꢀ
ꢀ
two potential reactive sites, Csp3 Br and Csp2 OTf. In the
presence of 5 mol% of FeCl2, the reaction between 1 and 2a
gave only 7% of Csp3-alkynylated 3, and 64% yield of Csp2
-
alkynylated 4 and 7% of the doubly alkynylated product 5
(Table 1, entry 1). Slow addition of Grignard reagent 2a
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201104125.
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Table 1: Chemoselective iron-catalyzed cross-coupling of 4-bromo-1-cyclohexen-1-yl trifluoromethanesulfonate (1) with (tert-butyldimethylsilyl)ethy-
nylmagnesium bromide (2a) in the presence of catalyst and additives.[a]
Entry
Catalyst
[mol%]
Additives
[mol%]
Solvent
T
[8C]
t
[h]
Yield [%][b]
Recovery
3
4
5
of 1 [%][b]
1
2
3
4
FeCl2 (5)
FeCl2 (5)
FeCl3 (3)
B (5)
–
–
THF
THF
THF
THF
60
60
60
60
60
45
120
60
2
7
18
0
65
70
0
64
31
89[d]
4
7
9
19
35
0
18
27
6[e]
30[e]
71[e]
2[c]
LiBr (120)
–
L1 (5)
IAd·HCl (5), CuI (5)
CuI (5), NaI (20)
–
2
5[e]
12[e]
2
2[c]
4[c]
4
5
B (5)
THF
1
6[f]
7[f]
8
[{(p-allyl)PdCl}2] (2.5)
[(MeNN2)NiCl][g] (5)
[Co(acac)3] (5)
DMF/Et2O
dioxane
TMEDA
88
26
3
0
0
13
16
3
0
10[e]
[a] Reactions were carried out on a 0.3–0.5 mmol scale. [b] Yields were determined by 1H NMR analysis using CH2Br2 as an internal standard, unless
otherwise noted. [c] Grignard reagent 2a was added dropwise over the time indicated. [d] Yield of the isolated product. [e] Yields were determined by
GLC analysis using decane as an internal standard. [f] Ethynyltriisopropylsilane and Cs2CO3 were used instead of 2a. [g] Bis[(2-dimethylamino)-
phenyl]amine nickel(II) chloride purchased from Sigma–Aldrich. acac=acetylacetonate, DMF=N,N’-dimethylformamide, Tf=trifluoromethanesul-
fonyl, THF=tetrahydrofuran.
slightly improved the yield of 3 (Table 1, entry 2).[8a] Addition
of LiBr (1.2 equiv), known as an effective additive for the
above-mentioned enyne coupling,[11a] resulted in the selective
secondary alkyl bromides with alkynyl Grignard reagents 2a–
e gave the desired product in good to excellent yields
(Table 2, entries 1–5). Notably the reactions with 2d and 2e,
which bear a less-bulky substituent, required a higher catalyst
loading and a longer addition period of the Grignard reagents
for completion. A secondary alkyl chloride, one of the
ꢀ
cleavage of Csp2 OTf to give 4 in 89% yield (Table 1, entry 3).
This chemoselectivity toward Csp2 electrophiles can be ration-
alized by the formation of an alkynylferrate intermediate.[8i,16]
The reaction in the presence of the divalent iron complex B
gave the desired Csp3 coupling product 3 in 65% yield along
with the formation of small amounts of 4 and 5 (Table 1,
entry 4). Addition of SciOPP ligand L1 (5 mol%) and the
prolongation of the addition period (2!4 h) of 2a further
improved the Csp3 selectivity to give 3 in 70% yield with the
minimal formation of 4 (1%) and 5 (2%; Table 1, entry 5).
challenging substrates in the Csp Csp3 coupling,[3–6] gave the
ꢀ
desired product in an acceptable yield (Table 2, entry 7). In all
the reactions examined, the reductive-cleavage by-product
(alkane) and the elimination by-product (alkene) were
obtained in 3–15% yields. The coupling reaction of an alkyl
bromide possessing an ethoxycarbonyl group occurred with
preservation of the ester functionality (Table 2, entry 8). With
ꢀ
ꢀ
Notably the literature methods for Csp Csp3 coupling based on
1-bromo-4-chlorobutane, C Br bond cleavage took place in
[3]
a Pd/Cu NHC catalyst and a Ni catalyst[5] gave the
preference to C Cl bond cleavage (Table 2, entry 9). 1-
ꢀ
ꢀ
unexpected Csp2-alkynylated product selectively (Table 1,
entries 6 and 7). The Co-catalyzed reaction[6] gave 3 in 10%
yield with 71% recovery of the substrate 1 (Table 1, entry 8).
These results clearly show that the combined use of an iron
catalyst and the phosphine ligand is effective for the selective
Bromo-4-(2-bromoethyl)benzene coupled with 2a with selec-
tive Csp3 Br bond cleavage (Table 2, entry 10). Notably the
Csp2 Br bond cleavage product was obtained in less than 1%
yield. The selective cleavage can be attributed to the radical
character of the organoiron species (see above) and the
difference in the stabilities of the resulting radical intermedi-
ates (alkyl versus aryl).
Taking advantage of the generation of alkyl radical
intermediates from the alkyl halide substrates, we carried
ꢀ
ꢀ
Csp Csp3 coupling reaction.[17]
ꢀ
Table 2 exemplifies the coupling reaction between various
alkyl halides and alkynyl Grignard reagents (2a–e; Scheme 2)
under the optimized reaction conditions. The reactions of
out
sequential
cyclization/cross-coupling
reactions[18]
(Table 2, entries 11 and 12). 3-(2-Bromo-1-butoxyethoxy)-3-
methyl-1-butene and N-(2-bromoethyl)-N-(2-propenyl)-4-
methylbenzenesulfonamide reacted with 2a to give the
corresponding ring-closure products in 81% and 92%
yields, respectively. The simple cross-coupling products with-
out the cyclization were not obtained.
A possible catalytic cycle based on our mechanistic
picture is shown in Scheme 3. The starting complex B is
treated with two equivalents of alkynyl Grignard reagent to
Scheme 2. Alkynyl Grignard reagents examined for the iron-catalyzed
cross-coupling of alkyl halides. See reactions in Table 2.
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Angew. Chem. Int. Ed. 2011, 50, 10973 –10976

Table 2: Cross-coupling of alkyl halides with alkynyl Grignard reagents.[a]
reactions, we believe that the iron center is not reduced
during the reaction and remains divalent in the ground state.
The catalytic cycle, thus, starts with the homolytic cleavage of
Entry Alkyl halide
RMgBr
Product
Yield
[%][b]
ꢀ
the Csp3 halogen bond of the alkyl halide by C to form an
alkyl radical (R·) and FeIII species D. This step is known as the
initial process in metal-catalyzed living radical polymeri-
zation reactions.[19,20] The trivalent intermediate D reacts with
the alkyl radical by release of the alkynyl radical, or much
more likely, by an addition/elimination or substitution
reaction of the alkyl radical at the ligating carbon center of
the alkynyl group, and gives the product and alkynyliron(II)
halide E. We cannot rule out the possibility of an alternative
pathway, in which the alkyl radical (R·) adds to the iron center
of D to form a FeIV intermediate, which may also undergo the
reductive elimination to give the product and E. Trans-
metalation with an alkynyl Grignard reagent regenerates the
reactive species C to complete the catalytic cycle. The
peripheral steric bulk[21] of the SciOPP ligand as well as the
slow addition of the Grignard reagents presumably sup-
presses the undesired ferrate formation and the side reactions,
1
2
2a
2b
88
83
3
2c
2d
86
64
4[c]
5[c]
6
2e
2b
68
83
7
8
2a
2a
69
81
ꢀ
such as the Csp2 OTf cleavage.
In summary, we have demonstrated that a Sonogashira-
type coupling of primary and secondary alkyl halides with
alkynyl Grignard reagents can be achieved in a highly
chemoselective manner by using an iron catalyst. The key to
this success is the use of a bisphosphine ligand bearing
peripheral steric bulk, which dramatically switches chemo-
selectivity from the Csp2-selective coupling to Csp3-selective
coupling. The present reaction can be applicable to secondary
alkyl halides, including less-reactive alkyl chlorides, which are
difficult substrates in previous methods. These synthetic
advantages, as well as the nonhazardous nature of the catalyst
and reagents make the present reaction suitable for the
practical synthesis of various functional molecules bearing
alkyne moieties.
9
2c
2a
2a
73
82
81
10
11
12[d]
2a
92
[a] Reactions were carried out according to the procedure for entry 4 in
Table 1 using 3–5 mol% of B on a 0.5–1.0 mmol scale, unless otherwise
noted. [b] Yield of the isolated product. [c] Grignard reagent was added
dropwise over 4 h in the presence of 20 mol% of B and 5 mol% of L1
[d] Grignard reagent was added dropwise over 4 h in the presence of
10 mol% of B. bn=benzyl, Ts=p-toluenesulfonyl.
Experimental Section
(Triisopropylsilyl)ethynylmagnesium bromide (0.80 mL, 0.78m in
THF, 0.62 mmol) was added dropwise using a syringe pump over
2 h at 708C to a THF solution (1.6 mL) of bromocycloheptane
form dialkynyliron(II) C. Because we did not observe any
trace formation of a diyne byproduct in the coupling
(73.5 mg, 0.42 mmol) and iron complex
B (12.7 mg, 12 mmol,
3.0 mol%). After addition of the Grignard reagent, the
reaction mixture was quenched by the addition of a
saturated aqueous solution of NH4Cl at room temper-
ature. The aqueous layer was extracted five times with
Et2O. The combined organic extracts were filtered
through a pad of Florisil and then concentrated in vacuo.
The crude product was purified by a reversed-phase
column chromatography (C18-bonded silica gel; eluents
20% H2O in MeOH and MeOH) to give (cycloheptyle-
thynyl)triisopropylsilane in 88% yield (0.102 g, 98% pure
by GC analysis).
Received: June 15, 2011
Published online: September 1, 2011
Keywords: alkynes · cross-coupling ·
homogeneous catalysis · iron
Scheme 3. A possible catalytic cycle for the iron-catalyzed Sonogashira-type cou-
pling.
.
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Communications
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