Development of general catalytic allylation of acylhydrazones with pinacolyl allylboronate using an indium(I) catalyst

Article abstract of DOI:10.1021/ol702756k

Catalytic allylation of various acylhydrazones using a group 13 metal reagent (boron) in combination with a group 13 metal catalyst in its low-oxidation state (indium) has been developed. This operationally simple carbon-carbon bond-forming reaction displays remarkable substrate scope and functional group tolerance.

Full text of DOI:10.1021/ol702756k

ORGANIC
LETTERS
2008
Vol. 10, No. 5
737-740
Development of General Catalytic
Allylation of Acylhydrazones with
Pinacolyl Allylboronate Using an
Indium(I) Catalyst
Uwe Schneider, I-Hon Chen, and Shu¯ Kobayashi*
Department of Chemistry, School of Science and Graduate School of Pharmaceutical
Sciences, The UniVersity of Tokyo, The HFRE DiVision, ERATO, Japan Science and
Technology Agency (JST), Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
shu_kobayashi@chem.s.u-tokyo.ac.jp
Received November 14, 2007
ABSTRACT
Catalytic allylation of various acylhydrazones using a group 13 metal reagent (boron) in combination with a group 13 metal catalyst in its
low-oxidation state (indium) has been developed. This operationally simple carbon−carbon bond-forming reaction displays remarkable substrate
scope and functional group tolerance.
The development of innovative catalytic methods for efficient
carbon-carbon bond formation is of high importance in
modern organic synthesis.1 In this context, the chemistry of
indium in its low-oxidation state (I)2 is still in its infancy;3
only sporadic examples of its use as a stoichiometric reagent
have been reported.4 In addition, although organoindium
compounds tolerate many functional groups and have a low
toxicity, indium has been defined as a “rare metal”;5 thus
the development of indium-catalyzed reactions becomes
increasingly important. In an earlier report,6 we disclosed a
general catalytic allylation method for ketones through
catalytic activation of an allylboronate with indium(I). To
the best of our knowledge, this transformation represents the
first catalytic synthetic method involving the use of a catalytic
amount of indium(I). We subsequently aimed to extend this
conceptually novel catalytic activation of a group 13 metal
reagent (boron) with a group 13 metal catalyst in its low-
oxidation state (indium) to imine derivatives as electrophiles.
The allylation of imine derivatives is an important carbon-
carbon bond-forming transformation,7 since the correspond-
ing homoallylic amines and derivatives have proved to be
extremely useful intermediates in natural products syntheses8
and others.9 Typical protocols for the allylation of imines
involve the use of allylindium reagents generated in situ
(1) (a) Transition Metal Reagents and Catalysts: InnoVations in Organic
Synthesis; Tsuji, J., Ed.; Wiley: Chichester, 2000. (b) Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; Wiley-VCH: Weinheim, 2000.
(2) For recent reviews on the lower oxidation states of indium, see: (a)
Tuck, D. G. Chem. Soc. ReV. 1993, 22, 269. (b) Pardoe, J. A. J.; Downs,
A. J. Chem. ReV. 2007, 107, 2.
(3) In contrast, indium(III) derivatives are known to be commonly used
in “catalytic” quantities as Lewis acid catalysts: Loh, T.-P.; Chua, G.-L.
Chem. Commun. 2006, 2739.
(4) For most significant examples, see: (a) Araki, S.; Ito, H.; Katsumura,
N.; Butsugan, Y. J. Organomet. Chem. 1989, 369, 291. (b) Andrews, C.
G.; Macdonald, C. L. B. Angew. Chem., Int. Ed. 2005, 44, 7453. (c) Cooper,
B. F. T.; Andrews, C. G.; Macdonald, C. L. B. J. Organomet. Chem. 2007,
692, 2843. (d) Hill, M. S.; Hitchcock, P. B.; Pongtavornpinyo, R. Inorg.
Chem. 2007, 46, 3783.
(6) Schneider, U.; Kobayashi, S. Angew. Chem., Int. Ed. 2007, 46, 5909.
(7) For reviews on nucleophilic addition to imines, see: (a) Kobayashi,
S.; Ishitani, H. Chem. ReV. 1999, 99, 1069. (b) Alvaro, G.; Savoia, D. Synlett
2002, 651.
(8) For selected examples, see: (a) Ding, H.; Friestad, G. K. Synthesis
2005, 2815. (b) Kropf, J. E.; Meigh, I. C.; Bebbington, M. W. P.; Weinreb,
S. M. J. Org. Chem. 2006, 71, 2046.
(5) The Elements, 3rd ed.; Emsley, J., Ed.; Oxford Press: Oxford, 1998.
10.1021/ol702756k CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/07/2008

under Barbier-type conditions from the corresponding allyl
halides.10 More recently, these nucleophiles have been
accessed through transmetallation of allylpalladium11 and
allylmercury12 precursors. However, the major drawback of
these methods is the use of more than stoichiometric amounts
of indium metal or indium(I) halides. Moreover, other effi-
cient allylation methods rely on toxic allylstannanes13 or cor-
rosive allylsilanes14 and/or often require activated imine
derivatives.15 On the other hand, acylhydrazones16 are readily
available from the corresponding carbonyl compounds and
offer superior stability compared to imines. Unfortunately,
catalytic allylations of these electrophiles typically display
very limited substrate generality.17 We report here the general
catalytic allylation of N-benzoylhydrazones with an allylboro-
nate18 in the presence of a catalytic amount of indium(I).
Table 1. Examination of the Indium(I)-Catalyzed Allylation of
Model Hydrazone 1a with Allylboronate 2
entry
In catalyst (mol %)
additive (equiv)
yield (%)a
1
2
3
4
5
6
7
8
InI (5)
InI (5)
InI (5)
InI (0.5)
trace
40
MeOH (1)
MeOH (5)
MeOH (5)
MeOH (5)
MeOH (5)
MeOH (5)
MeOH (5)
99
93b
25
In(0) (5)
InI3 (5)
In(0) (3.3) + InI3 (1.7)
28
62
40
Our initial experiments were carried out in the reaction
of acetaldehyde-derived acylhydrazone 1a as a model
substrate in dry toluene (0.5 M) at room temperature (Table
1). On the basis of our previous results,6 we used com-
mercially available pinacolyl allylboronate (2; 1.5 equiv) as
a nucleophile and indium(I) iodide19 (5 mol %) as a catalyst.
a Isolated yields after preparative thin-layer chromatography (silica gel).
b Reaction time, 24 h.
The indium(I)-catalyzed reaction in dry toluene essentially
did not proceed (entry 1), whereas in the presence of 1 equiv
of methanol the desired homoallylic hydrazide 3a was cleanly
formed albeit in moderate yield (entry 2). However, the
indium(I)-catalyzed allylation proceeded smoothly when 5
equiv of methanol were added under otherwise identical
conditions (99% yield, entry 3). The significantly improved
results in the presence of methanol may be ascribed to the
increased solubility of hydrazone 1a, which is virtually
insoluble in toluene. Alternatively, methanol could play an
important role in the activation of allylboronate 220 or might
promote the catalyst turnover as a proton source.21 To our
delight, further examination of catalyst loading revealed that
use of as little as 0.5 mol % of indium(I) iodide gave the
desired addition product in 93% isolated yield, after pro-
longed reaction time (24 h, entry 4). In contrast, the non-
catalyzed transformation (in the absence of indium(I) iodide)
was found to provide product 3a in only 25% yield (entry
5). Various other solvents such as tetrahydrofuran, dimethoxy-
ethane, 1,4-dioxane, N,N-dimethylformamide, acetonitrile,
dimethyl sulfoxide, and water were investigated as well, but
such solvents proved to be significantly less effective than
the toluene-methanol system.22,23 These truly remarkable
catalytic results with indium(I) stand in sharp contrast to
literature reports that require at least stoichiometric amounts
of indium(I) reagents for indium-mediated Barbier-type4a and
Reformatsky-type24 reactions, metal-to-indium transmetal-
lations,11,12 or radical-generating reactions.25
(9) For selected examples of the use of homoallylic amines, see: (a)
Agami, C.; Couty, F.; Evano, G. Tetrahedron: Asymmetry 2000, 11, 4639.
(b) Schmidt, A. M.; Eilbracht, P. J. Org. Chem. 2005, 70, 5528. (c) Denhez,
C.; Vasse, J.-L.; Harakat, D.; Szymoniak, J. Tetrahedron: Asymmetry 2007,
18, 424.
(10) (a) Loh, T.-P.; Ho, D. S.-C.; Xu, K.-C.; Sim, K.-Y. Tetrahedron
Lett. 1997, 38, 865. (b) Foubelo, F.; Yus, M. Tetrahedron: Asymmetry
2004, 15, 3823. (c) Vilaivan, T.; Winotapan, C.; Banphavichit, V.; Shinada,
T.; Ohfune, Y. J. Org. Chem. 2005, 70, 3464. For related reviews on the
use of indium in organic synthesis, see: (d) Podlech, J.; Maier, T. C.
Synthesis 2003, 633. (e) Nair, V.; Ros, S.; Jayan, C. N.; Pillai, B. S.
Tetrahedron 2004, 60, 1959.
(11) (a) Cooper, I. R.; Grigg, R.; MacLachlan, W. S.; Sridharan, V.;
Thornton-Pett, M. Tetrahedron Lett. 2003, 44, 403. (b) Fontana, G.;
Lubineau, A.; Scherrmann, M.-C. Org. Biomol. Chem. 2005, 3, 1375.
(12) Chan, T. H.; Yang, Y. J. Am. Chem. Soc. 1999, 121, 3228.
(13) (a) Nakamura, H.; Nakamura, K.; Yamamoto, Y. J. Am. Chem. Soc.
1998, 120, 4242. (b) Gastner, T.; Ishitani, H.; Akiyama, R.; Kobayashi, S.
Angew. Chem., Int. Ed. 2001, 40, 1896. (c) Fernandes, R. A.; Stimac, A.;
Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 14133.
(14) (a) Nakamura, K.; Nakamura, H.; Yamamoto, Y. J. Org. Chem.
1999, 64, 2614. (b) Hamada, T.; Manabe, K.; Kobayashi, S. Angew. Chem.,
Int. Ed. 2003, 42, 3927. (c) Kobayashi, S.; Ogawa, C.; Konishi, H.; Sugiura,
M. J. Am. Chem. Soc. 2003, 125, 6610. (d) Berger, R.; Rabbat, P. M. A.;
Leighton, J. L. J. Am. Chem. Soc. 2003, 125, 9596. (e) Fernandes, R. A.;
Yamamoto, Y. J. Org. Chem. 2004, 69, 735. (f) Ding, H.; Friestad, G. K.
Synthesis 2004, 2216. (g) Ogawa, C.; Sugiura, M.; Kobayashi, S. Angew.
Chem., Int. Ed. 2004, 43, 6491. (h) Berger, R.; Duff, K.; Leighton, J. L. J.
Am. Chem. Soc. 2004, 126, 5686.
(15) (a) Ferraris, D.; Dudding, T.; Young, B.; Drury, W. J., III; Lectka,
T. J. Org. Chem. 1999, 64, 2168. (b) Ferraris, D.; Young, B.; Cox, C.;
Dudding, T.; Drury, W. J., III; Ryzhkov, L.; Taggi, A. E.; Lectka, T. J.
Am. Chem. Soc. 2002, 124, 67. (c) Taggi, A. E.; Hafez, A. M.; Lectka, T.
Acc. Chem. Res. 2003, 36, 10.
(16) (a) Oyamada, H.; Kobayashi, S. Synlett 1998, 249. (b) Sugiura, M.;
Kobayashi, S. Angew. Chem., Int. Ed. 2005, 44, 5176.
(17) For the use of more than a stoichiometric amount of indium metal
in enantioselective or diastereoselective allylations of acylhydrazones: (a)
Cook, G. R.; Maity, B. C.; Kargbo, R. Org. Lett. 2004, 6, 1741. (b) Cook,
G. R.; Kargbo, R.; Maity, B. Org. Lett. 2005, 7, 2767. (c) Tan, K. L.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2007, 46, 1315. (d) Kargbo, R.;
Takahashi, Y.; Bhor, S.; Cook, G. R.; Lloyd-Jones, G. C.; Shepperson, I.
R. J. Am. Chem. Soc. 2007, 129, 3846.
(18) For selected examples of the use of allylboron reagents in additions
to CdN bonds, see: (a) Li, S.-W.; Batey, R. A. Chem. Commun. 2004,
1382. (b) Sebelius, S.; Szabo´, K. J. Eur. J. Org. Chem. 2005, 2539. (c)
Dhudshia, B.; Tiburcio, J.; Thadani, A. N. Chem. Commun. 2005, 5551.
(d) Ramachandran, P. V.; Burghardt, T. E. Pure Appl. Chem. 2006, 78,
1397. (e) Wada, R.; Shibuguchi, T.; Makino, S.; Oisaki, Kanai, K. M.;
Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 7687. (f) Lou, S.; Moquist, P.
N.; Schaus, S. E. J. Am. Chem. Soc. 2007, 129, 15398.
(19) Anhydrous indium(I) iodide powder (99.999%; Aldrich) was selected
for its higher thermodynamic stability compared with other indium(I) halides.
(20) Methanol as a Lewis base could coordinate to the Lewis acidic boron
atom of allylboronate 2 to generate the corresponding allylborate; this species
might be activated for catalytic boron-to-indium transmetallation.
(21) Methanol could be necessary for the hydrolysis of the assumed
N-metal bond in the initially formed reaction product.
(22) It is noted that indium(I) iodide proved to be unstable in solvents
such as DME, DMF, DMSO, and water; this redox-disproportionation
process (formation of indium metal) is visible.
(23) After submission of our manuscript, the formation of a neutral
indium sub-halide cluster from indium(I) iodide in the presence of TMEDA
in toluene was reported: Green, S. P.; Jones, C.; Stasch, A. Angew. Chem.,
Int. Ed. 2007, 46, 8618.
738
Org. Lett., Vol. 10, No. 5, 2008

Next, we turned our attention to control experiments
because indium(I) is known to be prone to redox-dispropor-
tionation under certain conditions, thereby generating indium
metal and indium(III) in a molar ratio of 2:1.2 If this is the
case in our current system, indium metal might activate 1a
and/or 2 through single electron transfer, whereas indium-
(III) might activate 1a and/or 2 as a Lewis acid. However,
independent use of either indium metal or indium(III) iodide
proved to be less effective than indium(I) (entries 6 and 7).
This trend also holds true for the combined use of indium-
(0) (3.3 mol %) and indium(III) iodide (1.7 mol %) in a
molar ratio of 2:1 (40% yield, entry 8). These experiments
demonstrate that indium(I) is by far the most effective
catalyst tested and partially support the idea that indium(I)
might be the real catalyst in our system.
drazides 3 in excellent yields (entries 1-8). It is noted that
R,â-unsaturated substrates underwent exclusive 1,2-addition
(entries 9-11). Moreover, various aromatic hydrazones
including a heterocycle were shown to be smoothly allylated
with 2 by using the indium(I) catalyst system (entries
12-18). Additionally, ketone-derived hydrazones were also
converted into the corresponding tertiary homoallylic hy-
drazides in high yields (entries 19-21). Importantly, func-
tional groups such as silyloxy, methoxy, chloro, dimethyl-
amino, pyridine, and ester were compatible under the mild
conditions of this operationally simple indium(I)-catalyzed
carbon-carbon bond formation.26
With the aim to shed light on the reaction mechanism,
1
various control experiments were performed. H and 11B
NMR spectroscopic analysis of allylboronate 2 in dry
toluene-d8 (0.75 M) in the presence of indium(I) iodide (100
mol %) and dry methanol-d3 (3.33 equiv) indicated the
remarkably clean transformation of 2 into a single species,
allylindium(I),27,28 within 3 h at room temperature (see Sup-
porting Information, NMR experiment A). The identical
species was independently generated under Barbier-type
conditions from allyl bromide and indium metal (100 mol
%) in the same deuterated solvent system (see Supporting
Information, NMR experiment B). In addition, the Barbier-
type allylation of 1a with allyl bromide and a stoichiometric
amount of indium(0) resulted in the smooth generation of
3a as well (93% yield). Finally, 1H and 11B NMR monitoring
of the indium(I) iodide catalyzed allylation of 1a with 2
revealed the direct formation of product 3a. On the basis of
these control experiments, although some unclear points still
remain, we surmise that the active species in our reaction
system might be allylindium(I), generated in situ from 2
through catalytic boron-to-indium transmetallation.29 In this
context, it is noted that in the absence of methanol-d3, allyl-
boronate 2 proved to be stable in the presence of indium(I)
iodide in toluene-d8 at room temperature (see Supporting
Information, NMR experiment C); this observation is con-
sistent with the poor allylation result for 1a in toluene as a
sole solvent (trace yield; cf. Table 1, entry 1). Thus, methanol
likely plays a key role in the present mechanistic scenario,
through enabling the in situ formation of the catalytically
active species from 2 and indium(I) iodide.20
We then investigated the substrate generality for the
allylation of acylhydrazones 1 with pinacolyl allylboronate
(2) by using 5 mol % of indium(I) iodide under optimized
conditions (Table 2). Gratifyingly, it was found that the
Table 2. Substrate Scope for the Indium(I) Iodide Catalyzed
Allylation of Hydrazones 1 with Allylboronate 2
entry
hydrazone
R1
R2
yield (%)a
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
Me
n-pent
Ph-CH2-CH2
TBSO-CH2-CH2
i-Pr-CH2
i-Pr
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
99
93
99
96
97
99
93
93
82
78
quant
91
96
98
98
75
91
86
87
80
89
c-hex
t-Bu
9
CH2dCH
(E)-Ph-CHdCH
Ph-CtC
Ph
4-Cl-C6H4
4-MeO-C6H4
2-MeO-C6H4
4-NMe2-C6H4
1-naphthyl
3-pyridyl
-(CH2)5-
10
11
12
13
14
15
16
17
18
19
20
21
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
1t
In an additional experiment, we examined the indium(I)-
catalyzed allylation of acetophenone (4) with 2 in the present
toluene-methanol system at room temperature (Scheme 1).
Importantly, we found that the reaction proceeded smoothly,
Me
CO2Me
Me
Me
Scheme 1. Remarkable Solvent Effect in the Indium(I) Iodide
Catalyzed Allylation of Acetophenone (4) with Allylboronate 2
1u
a Isolated yields after preparative thin-layer chromatography (silica gel).
reaction displayed excellent generality, with various primary,
secondary, and tertiary aliphatic aldehyde-derived hydrazones
being transformed into the corresponding homoallylic hy-
a Isolated yields after preparative thin-layer chromatography
(silica gel).
(24) Babu, S. A.; Yasuda, M.; Shibata, I.; Baba, A. Org. Lett. 2004, 6,
4475.
(25) Ranu, B. C.; Mandal, T. Tetrahedron Lett. 2006, 47, 2859.
Org. Lett., Vol. 10, No. 5, 2008
739

providing the desired product 5 in 95% yield after 12 h. On
the other hand, compound 5 was formed in only 11% yield
after 24 h at room temperature when dry THF was used as
a solvent.30 The excellent allylation result under our newly
developed, milder reaction conditions constitutes a substantial
advance compared with our earlier report.6,31
In summary, we have developed highly efficient catalytic
allylation of N-benzoylhydrazones using a group 13 metal
reagent (boron) with a group 13 metal catalyst in its low-
oxidation state (indium). This transformation displays both
broad substrate scope and high functional group tolerance.
Importantly, the present toluene-methanol system proved
to be significantly more effective for ketone allylation than
the previously reported one.6 Further mechanistic studies and
the application to asymmetric catalysis are ongoing in our
laboratories.
(26) It is noted that in the absence of indium(I) iodide isolated yields
for several exemplified products (3h, 3l, 3o, 3r, 3t) did not exceed 15%.
(27) 1H NMR (toluene-d8, 400 MHz): δ ) 1.53-1.55 (m, 2H), 4.86-
4.97 (m, 1H), 5.62-5.73 (m, 2H) (see Supporting Information, charts 8
and 10).
(28) Allylindium(I) has been previously reported: see refs 11b and 12.
(29) This selective transmetallation process was detected as well with
11B NMR analysis, which unambiguously shows that the boron is stripped
off the allylic moiety (shift of the initial boron signal at ∼32 to ∼21 ppm
and ∼17 ppm; see Supporting Information, NMR experiment A).
(30) This poor allylation result is consistent with the observation that
allylboronate 2 is relatively stable in the presence of indium(I) iodide in
dry THF-d8 at room temperature; only a sluggish, non-selective boron-to-
indium transmetallation occurs (see Supporting Information, NMR experi-
ment D).
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research from Japan Society
of the Promotion of Sciences (JSPS).
Supporting Information Available: Experimental Sec-
tion and related spectra for the reported reaction. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(31) Indeed, in our earlier report on indium(I)-catalyzed ketone allylation,
heating to 40 oC and longer reaction times were required for full conversion
of ketone substrates.
OL702756K
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Org. Lett., Vol. 10, No. 5, 2008