Cross-coupling reactions through the intramolecular activation of Alkyl(triorgano)silanes

Article abstract of DOI:10.1002/anie.201000816

(Figure Presented) Cross-Si-ing the Jordan: Cross-coupling reactions of 2-(2-hydroxyprop-2-yl)phenylsubstituted alkylsilanes with a variety of aryl halides proceed in the presence of palladium and copper catalysts. The use of K₃PO₄ base allows for highly chemoselective alkyl coupling with both primary and secondary alkyl groups (Alk).

Full text of DOI:10.1002/anie.201000816

Angewandte
Chemie
DOI: 10.1002/anie.201000816
Cross-Coupling
Cross-Coupling Reactions through the Intramolecular Activation of
Alkyl(triorgano)silanes**
Yoshiaki Nakao,* Masahide Takeda, Takuya Matsumoto, and Tamejiro Hiyama*
Silicon-based cross-coupling reactions have received much
attention in terms of their chemoselectivity, reagent stability,
and the nontoxicity associated with organosilicon reagents,
and many efforts have resulted in the extensive development
of cross-coupling reactions with alkenyl- and arylsilane
compounds in the last decade.[1] Despite the widespread use
of these alkyl cross-coupling strategies in organic synthesis,[2]
the silicon-based methods have relied on the use of polyfluo-
rinated alkylsilane reagents, which are moisture-, acid-, and
base-sensitive, and require the use of a highly nucleophilic
and expensive fluoride activator.[3] Herein, we report a
palladium/copper-catalyzed alkyl-cross-coupling reaction
using 2-(2-hydroxyprop-2-yl)phenyl-substituted alkylsilanes,
which are highly stable tetraorganosilicon reagents that
transfer both primary and secondary alkyl groups with the
Scheme 1. Cross-coupling of 2-(hydroxymethyl)phenyl-substituted
methylsilanes with 4-chlorobenzonitrile (2a).
aid of K3PO4 as a mild base.
We have previously reported that 2-(hydroxymethyl)-
phenyl-substituted alkenyl- and arylsilanes cross-couple with
a range of electrophiles.[4] Therefore, we began by examining
the palladium-catalyzed methylation of aryl halides using a
structurally modified alkylsilane reagent, trimethyl[2-(2-
hydroxyprop-2-yl)phenyl]silane (1; Scheme 1). The reaction
of 1 (1.5 mmol) with 4-chlorobenzonitrile (2a, 1.0 mmol) in
the presence of Pd(OAc)2 (1 mol%), Qphos (2.1 mol%),[5]
and K3PO4 (2.5 mmol) in tetrahydrofuran at 1008C for
2 hours gave 4-methylbenzonitrile (3a) in 88% yield, as
nyl]silane (1’) under identical conditions resulted in the
oxidation of 1’ and reduction of 2a to almost-exclusively
afford 5 and 6, respectively.
These results prompted us to examine the methylation of
a range of aryl electrophiles (Table 1).[8] A variety of func-
tional groups were tolerated in the reaction, including nitro,
formyl, keto, and ester groups (Table 1, entries 1–5). For the
methylation of some aryl halides, 1,1’-bis(diphenylphosphi-
no)ferrocene (DPPF)[9] gave better yields (Table 1, entries 2
and 4). Use of copper(II) hexafluoroacetylacetonate hydrate
[Cu(hfacac)2] as a co-catalyst was effective for the methyl-
ation of 2’d, whilst competitive a-arylation of the acetyl
group[10] was observed in its absence. Activation of the silicon
reagents by a base other than fluoride allowed silyl ethers to
participate in the coupling reaction, with the protecting group
being completely retained (Table 1, entry 6). In most cases,
silicon residue 4a was observed in good yields. The highly
sterically demanding 2-chloro-meta-xylene (2j) was methy-
lated successfully (Table 1, entry 10). Performing the reaction
on a 10 mmol scale allowed isolation of 4a by distillation in
64% yield; the resultant residue was purified by flash
chromatography on silica gel to give methylated arene 3k in
89% yield (Table 1, entry 11). Recovered 4a was treated with
methyllithium to give 1 in 88% yield,[8] which demonstrates
the facile synthesis of this methylsilane reagent. Heteroaryl
electrophiles also underwent the methylation in modest to
good yields (Table 1, entries 12 and 13).
1
estimated by H NMR spectroscopy. It is worth noting that
À
the very strong Si Me bond of the tetraorganosilicon reagent
À
is activated exclusively over the Si Ar bond with the aid of
the metal catalysts and the mild base.[6,7] Indeed, no coupling
of the aryl group was observed under these reaction
conditions. Formation of cyclic silyl ether 4a in 93% yield
was calculated based on the conversion of 1 (95%), both
estimated by GC analysis. Cyclic silyl ether 4a was subse-
quently used as a starting material for synthesizing alkylsi-
lanes through ring-opening reactions with alkyl lithium
reagents. The presence of the benzylic methyl groups in 1 is
essential: the reaction of trimethyl[2-(hydroxymethyl)phe-
[*] Dr. Y. Nakao, M. Takeda, T. Matsumoto, Prof. Dr. T. Hiyama
Department of Material Chemistry, Graduate School of Engineering
Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510 (Japan)
Fax: (+81)75-383-2445
E-mail: yoshiakinakao@npc05.mbox.media.kyoto-u.ac.jp
thiyama@z06.mbox.media.kyoto-u.ac.jp
We then turned our attention to the general alkylation of
aryl halides based on this reagent design. First, butylation was
examined with butyl[2-(2-hydroxyprop-2-yl)phenyl]diisopro-
pylsilane (7a), wherein the three methyl groups on the silicon
atom of 1 are substituted by one butyl group and two,
[**] This work was supported financially by a Grant-in-Aid for Creative
Scientific Research and Priority Areas “Synergy of Elements” from
MEXT.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201000816.
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Table 1: Methylation of aryl halides with 1.
Table 2: Butylation of aryl halides with 7a.
Entry
2 (R)
Time Yield of 3
[h]
Yield
of 4
À
Entry
X Ar
t [h]
Yield of 8 [%][a]
Yield of 4b [%][b]
[%][a]
[%][b]
1[c]
2
3
2a
2’b
2’c
2’d
2’g
2’j
2
1
1
1
1
5
2
1
81 (8aa)
84 (8ab)
96 (8ac)
98 (8ad)
79 (8ag)
82 (8aj)
73 (8al)
76 (8am)
86
87
90
>95
>95
>95
>95
>95
1
2b
3
77 (3b)
73
4
5
2[c]
3
2b (H)
2d (Me)
2’d (Me)
2e
3
3
1
4
70 (3c)
53 (3d)
>95 (3d)
84 (3e)
>95
75
94
6[d]
7
4[c,d]
5
2’l
2’m
8
94
(OtBu)
[a] Yield of isolated product based on 2 or 2’. [b] Estimated by GC based
on consumed 7a. [c] Run with 7a (1.5 mmol) and Qphos (2.1 mol%).
[d] Run with 7a (1.5 mmol) and DPPF (2.1 mol%). [f] Run at 508C.
6
7
2 f
8
77 (3 f)
63 (3g)
>95
2g
8
4
90
Table 3: Alkylation of 2’a with functionalized alkylsilanes.
8
9
2h (Me)
70 (3h)
68 (3i)
86
81
2i (MeO) 18
10
2j
18
10
59 (3j)
69
11[e]
2’k
89[f] (3k)
64[f]
Entry
7
Yield of 3 Yield of 4 [%][b]
[%][a]
12[g]
13
2l
4
65 (3l)
>95
1
7b 93 (8ba)
7c 76 (8ca)
>95
95
2
3[c]
2’m
16
75 (3m)
82
7d 73 (8da)
85
[a] Estimated by 1H NMR spectroscopy based on 2 (X=Cl) or 2’ (X=Br).
[b] Estimated by GC or 1H NMR analysis based on consumed 1. [c] Run
with DPPF (2.1 mol%) instead of Qphos. [d] Run with 4-bromoaceto-
phenone (2’d) in the presence of [Cu(hfacac)2] (3.0 mol%). [e] Run on a
10 mmol scale. [f] Yield of isolated product. [g] Run with 2.0 mmol of 1.
4
5
7e 86 (8ea)
>95
>95
7 f
92 (8 fa)
[a] Yield of isolated product based on 2’a. [b] Estimated by GC based on
consumed 7. [c] Run with 7d (1.5 mmol), 2a (1.0 mmol), and Qphos
(2.1 mol%) instead of 2’a and DPPF.
presumably less reactive, isopropyl groups.[8] The presence of
[Cu(hfacac)2] (3 mol%) was found to be crucial to give the
corresponding butylated arenes in good yields (Table 2);[8] its
absence induced O-arylation and the Brook rearrangement of
7a rather than the desired reaction pathway, which suggests
that the alkyl copper species might play an important role in
the copper-to-palladium transmetalation step. The scope of
aryl halides that can be used in the reaction was found to be
similar to the methylation reaction under these conditions.
Furthermore, functionalized alkylsilane reagents also reacted
successfully with 2’a in good yields (Table 3).[8]
Finally, we extended the scope of this cross-coupling
reaction to consider the intramolecular activation of secon-
dary alkylsilanes. Compared with cross-coupling reactions of
secondary-alkyl electrophiles,[11] the development of comple-
mentary protocols using secondary-alkyl nucleophiles has
relied on the use of highly nucleophilic alkylmagnesium[9,12]
alkylzinc,[13] or alkylmanganese[14] reagents. On the other
hand, stable, isolatable, and storable nucleophiles that
participate in such cross-coupling reactions is limited to
secondary alkylboron reagents.[15–17] To the best of our
knowledge, silicon-based cross-coupling reactions have
never been performed with secondary alkylsilanes.[18] There-
fore, triisopropyl[2-(2-hydroxyprop-2-yl)phenyl]silane (9a)
was prepared[8] and reacted with 4-bromobenzonitrile (2’a;
Table 4). To our delight, reaction under the standard reaction
conditions in the presence of the copper catalyst gave an 18:1
mixture of 4-isopropylbenzonitrile (10aa) and 4-propylben-
zonitrile (10’aa) in 74% yield as estimated by 1H NMR
spectroscopy. The latter would be derived from b-hydride
elimination of an (aryl)isopropylpalladium(II) intermediate
followed by re-insertion of the resultant propene that
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Chemie
corresponding coupling product. Further purification was performed
by preparative GPC to remove impurities in some cases.
coordinates to the palladium center to give an (aryl)n-
propylpalladium(II) species, which reductively eliminates
the n-propylarene.[12] Use of tert-butyl alcohol as the solvent
slightly increased the yield of 10aa, and performing the
Received: February 10, 2010
Revised: March 12, 2010
Published online: May 7, 2010
Table 4: Alkylation of aryl bromides with sec-alkylsilanes.
Keywords: copper · cross-coupling · palladium · silicon
.
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Entry
9
2’
t [h] Yield of 10 [%][a]
Yield of 4
(isopropyl/n-propyl ratio)[a] [%][b]
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1
2
3
9a
9a
9a
9a
9a
9a 2’m
9b
9c
2’a
2’d
2’g
2’h
2’l
75
50
123
3
190
3
84 (78[c]) (10aa, >20:1)
79 (71[c]) (10ad, >20:1)
70 (10ag, 17:1)
90 (10ah, >20:1)
69 (10al, 16:1)
91 (4b)
>95 (4b)
85 (4b)
>95 (4b)
89 (4b)
>95 (4b)
99[e] (4c)
92[e] (4d)
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4[d]
5
6[d]
7[d]
8[d]
82 (10am, 20:1)
2’a
2’a
3
3
84[c] (10ba)
78[c] (10ca)
[a] Estimated by 1H NMR spectroscopy based on 2’. [b] Estimated by GC
based on consumed 9. [c] Yield of isolated product based on 2’. [d] Run
at 1008C. [e] Yield of isolated product based on consumed 9.
reaction at lower temperature gave a better isopropyl/n-
propyl ratio, although a longer reaction time was required for
the reaction to proceed to completion (Table 4, entry 1). The
optimized reaction conditions also worked effectively for the
isopropylation of other aryl bromides (Table 4, entries 2–6) as
well as cyclopentyl- and cyclohexylsilanes (9b and 9c;
Table 4, entries 7 and 8) to give a variety of arenes that
contain a secondary alkyl substituent.[8]
À
[7] For other examples of Si Me bond activation, see: a) I. Ojima,
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In conclusion, we have demonstrated that 2-(2-hydroxy-
prop-2-yl)phenyl-substituted alkylsilanes selectively transfer
an alkyl group to facilitate the alkylation of a range of aryl
halides with the aid of palladium/copper catalysis and K3PO4
as a mild activator. The development of other alkylsilane
reagents, such as 2-pyrrolidyl, 2-pyperidyl, and cyclopropylsi-
lanes for not only cross-coupling reactions but also metal-
catalyzed carbonyl-addition reactions[19] based on this reagent
design is currently underway.
[8] See the Supporting Information for the full scope of substrates
investigated and for details about the preparation of the silicon
reagents.
[9] For a pioneering report on the use of DPPF for alkyl cross-
coupling reactions, see: T. Hayashi, M. Konishi, Y. Kobori, M.
Kumada, T. Higuchi, K. Hirotsu, J. Am. Chem. Soc. 1984, 106,
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Experimental Section
General procedure for the cross-coupling of alkylsilanes with aryl or
alkenyl bromides: Aryl or alkenyl bromide (1.0 mmol), n-dodecane
(an internal standard, 88 mg, 0.50 mmol), and tetrahydrofuran (1.0–
2.0 mL) were added sequentially by syringe to a mixture of K3PO4
(0.53 g, 2.5 mmol), [Cu(hfacac)2] (15 mg, 30 mmol), DPPF (23 mg,
42 mmol), Pd(OAc)2 (2.2 mg, 10 mmol), and an alkylsilane reagent
(1.3 mmol) under an argon atmosphere in a screw-capped 3 mL vial
that was sealed with a PTFE septum; the resulting mixture was stirred
at 50–1008C. After the specified time period, the mixture was filtered
through a pad of silica gel and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel to afford the
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Communications
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