C(sp)-C(sp3) bond formation through cu-catalyzed cross-coupling of N -tosylhydrazones and trialkylsilylethynes

Article abstract of DOI:10.1021/ja3004792

Copper-catalyzed cross-coupling of N-tosylhydrazones with trialkylsilylethynes leads to the formation of C(sp)-C(sp³) bonds. Cu carbene migratory insertion is proposed to play the key role in this transformation.

Full text of DOI:10.1021/ja3004792

Communication
pubs.acs.org/JACS
C(sp)−C(sp3) Bond Formation through Cu-Catalyzed Cross-Coupling
of N-Tosylhydrazones and Trialkylsilylethynes
Fei Ye,† Xiaoshen Ma,† Qing Xiao,† Huan Li,† Yan Zhang,† and Jianbo Wang*,†,‡
†Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering
of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, China
‡State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
S
* Supporting Information
has also been applied to C(sp)−C(sp3) bond formation.7
ABSTRACT: Copper-catalyzed cross-coupling of N-
tosylhydrazones with trialkylsilylethynes leads to the
formation of C(sp)−C(sp3) bonds. Cu carbene migratory
insertion is proposed to play the key role in this
transformation.
Although remarkable progress has been made, we have
considered that it is still highly desirable to develop novel
approaches for C(sp)−C(sp3) bond formation, preferably by
using simple and cheap catalysts and easily available starting
materials.
Recently, N-tosylhydrazones, which are easily prepared from
aldehydes or ketones, have emerged as a new type of cross-
coupling partner in transition-metal-catalyzed reactions.8−14 In
this area, we reported the Cu(I)-catalyzed direct C−H bond
benzylation or allylation of 1,3-azoles with N-tosylhydrazones.11
We also developed the Cu(I)-catalyzed cross-coupling of
terminal alkynes and N-tosylhydrazones, which leads to the
formation of allenes.12−14 These reactions are proposed to
follow a similar pathway that involves Cu carbene formation
and subsequent migratory insertion. Herein we further report
the Cu(I)-catalyzed cross-coupling of N-tosylhydrazones and
trialkylsilylethynes (eq 2), which leads to the formation of
ethynylation products. This reaction represents a highly
efficient and practical approach for C(sp)−C(sp3) bond
formation.
In the course of the investigation of the Cu(I)-catalyzed
synthesis of allenes through cross-coupling of N-tosylhydra-
zones and terminal alkynes,12 we observed that using
trimethylsilylethyne (2a) as the cross-coupling partner allowed
the ethynylation product 3a to be isolated, while the
corresponding allene 4 was not detected (eq 3). This result
he Sonogashira reaction has been established as a
T
powerful tool for incorporating an alkynyl moiety into
organic molecules since its discovery in 1975.1 Because alkynes
are an important structural unit of various bioactive molecules
and are frequently used as synthetic intermediates and
precursors for natural products as well as for organic electronic
materials,2 enormous efforts have been devoted to the
enhancement of this method over the past decades. Despite
the great success of the Sonogashira reaction in the
construction of C(sp)−C(sp2) bonds, the corresponding
coupling with nonactivated alkyl halides, namely, the
construction of C(sp)−C(sp3) bonds, has remained a
considerable challenge. This is mainly due to the reluctance
of alkyl halides to undergo oxidative addition and the
propensity to have unproductive β-hydride elimination of the
alkylmetal intermediates.
In spite of the challenges, significant progress has been made
in this area recently (eq 1). Eckhardt and Fu first reported the
is similar to the previous report by Suarez and Fu on Cu(I)-
catalyzed reaction of terminal alkynes with α-diazo carbonyl
compounds, which gives 3-alkynoates as the major products.15
In view of the importance of C(sp)−C(sp3) bond formation,
we decided to optimize this ethynylation reaction.16 With N-
tosylhydrazone 1a and trimethylsilylethyne 2a as the substrates,
it was found that the alkyne product 3a could be isolated in
75% after optimization of the reaction conditions (eq 3).
Sonogashira coupling of primary alkyl halides by employing a
Pd/N-heterocyclic carbene catalyst system.3 Following this
pioneering work, Glorius and co-workers further expanded the
scope of the coupling reaction to secondary alkyl bromides, also
with a Pd/N-heterocyclic carbene catalyst system.4 More
recently, Hu and co-workers introduced a Ni(II) pincer
complex as the catalyst, expanding the Sonogashira coupling
to primary alkyl chlorides.5 Other coupling reactions for
C(sp)−C(sp3) bond formation, such as those using organo-
metallic reagents, have also been extensively explored recently.6
Besides, inter- or intramolecular decarboxylative cross-coupling
Received: January 16, 2012
Published: March 16, 2012
© 2012 American Chemical Society
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Next, we proceeded to explore the scope of the N-
tosylhydrazones for the reaction with 2a. As shown in Scheme
1, the reaction was efficient with a series of N-tosylhydrazones
Scheme 2. Cross-Coupling of N-Tosylhydrazones Derived
from Ketones
a b
,
Scheme 1. Cross-Coupling of N-Tosylhydrazones Derived
a b
,
from Aromatic Aldehydes and Trimethylsilylethyne
a
Unless otherwise noted, the reaction conditions were the following:
N-tosylhydrazone 5a−l (0.6 mmol), alkyne 2a or 2b (0.4 mmol), CuI
(20 mol %), LiOtBu (1.12 mmol), dioxane (5 mL), 110 °C, 1 h; TIPS
b
c
= triisopropylsilyl. Isolated yields are shown. The reaction was
carried out with N-tosylhydrazone (0.72 mmol) and LiOtBu (1.2
mmol).
a
Unless otherwise noted, the reaction conditions were the following:
elevated temperature. It is noteworthy that the reactions with
substrates bearing a bulky group such as a tert-butyl group also
proceeded smoothly (Scheme 3, 6r, 6u). To our delight, the
cross-coupling reactions of N-tosylhydrazones derived from
cyclic ketones such as cyclopentanone and cyclohexanone also
gave moderate to good yields (Scheme 3, 6x−z).
N-tosylhydrazone 1a−o (0.88 mmol), alkyne 2a (0.4 mmol), CuI (20
b
mol %), LiOtBu (1.4 mmol), dioxane (5 mL), 90 °C, 1 h. Isolated
c
d
yields are shown. The reaction was run at 110 °C. The reaction was
run with N-tosylhydrazone (0.48 mmol) and LiOtBu (1.0 mmol).
derived from aromatic aldehydes. Both electron-withdrawing
groups such as chloro, cyano, ester, and nitro groups (Scheme
1, 3b, 3c, 3i, 3j) and electron-donating groups such as N,N-
dimethylamino and alkoxyl groups (Scheme 1, 3d, 3m) were all
tolerated under the reaction conditions, and moderate to good
yields of the corresponding ethynylation products were
obtained. It is noteworthy that N-tosylhydrazones bearing
heterocyclic substituents were also suitable substrates for this
reaction (Scheme 1, 3l, 3n, 3o).
The scope of the coupling reaction can be extended to N-
tosylhydrazones derived from aromatic ketones (Scheme 2).
The reaction was found to be only slightly affected by the
substituents on the aromatic ring. To our delight, the
cyclopropyl moiety could also survive the reaction conditions
(Scheme 2, 6c). It was also noted that a slightly improved yield
could be obtained when triisopropylsilylethyne (2b) was used
instead of 2a (Scheme 2, compare 6g and 6k).
Encouraged by these results, we further proceeded to explore
the cross-coupling reactions with N-tosylhydrazones derived
from aliphatic aldehydes and ketones. As shown by the results
summarized in Scheme 3, both straight-chain and β-branched
substrates can be reacted smoothly under the same reaction
conditions (Scheme 3, 6m−p, 6s−t, 6v−w); however, the
relatively lower boiling point contributes to the diminished
yield in the case of 6s. The reaction with α-alkenyl-substituted
N-tosylhydrazone 5q afforded the expected 1,4-enyne product
6q. The low yield in this case is presumably due to the
unstability of the in situ-generated diazo intermediate at
Finally, since the transformation of a ketone or aldehyde to
the corresponding N-tosylhydrazone is highly efficient, a one-
pot cross-coupling reaction was then performed starting from
aldehyde or ketone without separation of the N-tosylhydrazone.
As shown in Scheme 4, the one-pot reactions afforded the
desired coupling products in good yields. It is noteworthy that
these two-step transformations can be viewed as reductive
cross-couplings of ketones or aldehydes with terminal alkynes.
A plausible mechanism to account for the Cu(I)-catalyzed
coupling (Scheme 5) is proposed on the basis of our
understanding of the Cu-catalyzed cross-coupling reaction of
N-tosylhydrazones.12 In the presence of base and Cu(I) salt,
copper acetylide A is formed from the trialkylsilylethyne.
Reaction of copper acetylide A with diazo substrate B, which is
generated in situ from the N-tosylhydrazone in the presence of
base, leads to the formation of copper carbene species C.
Migratory insertion of the alkynyl group at the carbenic carbon
gives intermediate D. Subsequently, protonation affords the
ethynylation product.
It is noted that in our previous study, in which the alkynes
used in the cross-coupling bear substituents other than a silyl
group, the protonation occurred preferentially at the sp carbon
to afford the trisubstituted allene product.12 Thus, the
trialkylsilyl substituent plays a vital role in the alkyne formation.
To gain some insights into the effect of substituents, tert-butyl-
substituted alkyne 9 was subjected to the identical reaction
conditions with N-tosylhydrazone 5m (eq 4). The reaction
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Scheme 3. Cross-Coupling with N-Tosylhydrazones Derived
from Aliphatic Aldehydes and Ketones
Scheme 4. One-Pot Cross-Coupling Starting from Ketones
or Aldehydes
ab
,
a b
,
a
Unless otherwise noted, the reaction conditions were the following:
7a−f (2.2 mmol) and N-tosylhydrazine (1 equiv) were reacted in 5
mL of dioxane for 0.5 h at 60 °C; next, to the reaction mixture were
added trialkylsilylethyne (4 mmol), CuI (20 mol %), LiOtBu (22
mmol), and dioxane (35 mL), and the mixture was heated under N2
b
c
for 1 h at 110 °C. Isolated yields are shown. The reaction was run
d
with 7b, 7e, or 7f (6.0 mmol) and LiOtBu (16 mmol). The reaction
was run with cyclohexenone 7g (0.72 mmol), 2b (0.4 mmol), and
LiOtBu (2.0 mmol).
Scheme 5. Proposed Reaction Mechanism
a
Unless otherwise noted, the reaction conditions were the following:
N-tosylhydrazone 5m−z (0.88 mmol), alkyne 2a or 2b (0.4 mmol),
CuI (20 mol %), LiOtBu (1.4 mmol), dioxane (5 mL), 110 °C, 1 h.
b
c
Isolated yields are shown. The yield refers to the 10 times scaled-up
d
e
reaction (0.77 g of 6m was obtained). CuI (40 mol %). The reaction
was run with N-tosylhydrazone (0.6 mmol) and LiOtBu (1.12 mmol).
f
The solution of N-tosylhydrazone in 4 mL of dioxane was added with
g
a syringe pump. A 25% yield of alkyne was recovered.
ketones and the silyl substituent of the coupling products can
be readily removed,17 we consider this transformation to be a
practically useful method for converting carbonyl functionality
into an ethynyl group.
afforded allene 10 in good yield. By comparison with the result
obtained using the trimethylsilyl-substituted ethyne (Scheme 3,
6m), it can be concluded that steric effects do not account for
the alkyne/allene selection because Me3Si and Me3C have
similar steric bulkiness. However, the details of the mechanism
are ambiguous at present and will be the subject of future study.
In conclusion, we have developed a novel strategy for the
formation of C(sp)−C(sp3) bonds starting from N-tosylhy-
drazones and trialkylsilylethynes, with CuI as the catalyst. This
C(sp)−C(sp3) bond-forming reaction is mechanistically differ-
ent from other transition-metal-catalyzed cross-coupling
reactions with terminal alkynes. β-Hydride elimination, which
is a common challenge for the cross-coupling with alkyl halides,
is not a problem in the cross-coupling with N-tosylhydrazones.
The salient feature of this coupling reaction is that a
complicated ligand is not required and simple CuI can be
used as the catalyst. In view of the fact that N-tosylhydrazones
are easily prepared from the corresponding aldehydes or
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, characterization data, and copies of
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
wangjb@pku.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project was supported by the 973 Program
(2009CB825300), the RFDP and the NSFC.
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