Indium(I) iodide-catalyzed regio- and diastereoselective formal α-addition of an α-methylallylboronate to N-acylhydrazones

Article abstract of DOI:10.1039/b802153h

Indium(I) iodide was found to catalyze the formal α-addition of an α-methylallylboronate to various N-acylhydrazones, in the presence of an alcohol additive, to afford the corresponding anti-α-adducts with high regio- and diastereoselectivity in high yiel

Full text of DOI:10.1039/b802153h

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Indium(I) iodide-catalyzed regio- and diastereoselective formal a-addition
of an a-methylallylboronate to N-acylhydrazonesw
Shu¯ Kobayashi,* Hideyuki Konishi and Uwe Schneider
Received (in Cambridge, UK) 6th February 2008, Accepted 31st March 2008
First published as an Advance Article on the web 17th April 2008
DOI: 10.1039/b802153h
Indium(I) iodide was found to catalyze the formal a-addition of
an a-methylallylboronate to various N-acylhydrazones, in the
presence of an alcohol additive, to afford the corresponding anti-
a-adducts with high regio- and diastereoselectivity in high yields.
In an initial experiment, a-methylallylboronate 2 (1.5 equiv)
reacted with acetaldehyde-derived N-benzoylhydrazone 1a in
dry toluene (0.5 M) in the presence of 5 mol% of indium(I)
iodide11 as a catalyst and 5 equiv of MeOH as an additive
(Table 1). The reaction proceeded smoothly to afford the
corresponding product in high yield. Surprisingly, the major
product was revealed to be not the expected g-adduct, but the
a-adduct 3a (entry 1). In contrast, the reaction in the absence
of indium(I) iodide proceeded sluggishly and gave the g-adduct
predominantly. These results indicated that the indium(I)
catalyst played a crucial role in achieving this unusual
a-selectivity.
We next turned our attention to investigate the effect of
alcohol additives and solvents (Table 2). An alcohol additive
has already been suggested to be important for the activation
of an allylboronate.9 A clear trend was revealed; as the steric
demand of alcohols was increased, the diastereoselectivities
were substantially improved, although the reaction became
more sluggish (entries 1–5). 2-Propanol was found to be the
additive of choice to obtain the desired product with satisfac-
tory diastereoselectivity (entry 4). Phenol and ethylene glycol
were also tested, but resulted in lower yields and diastereo-
selectivities compared with 2-propanol (entries 6 and 7). The
possibility that the alcohol might work as a proton source to
activate the N-acylhydrazone seemed unlikely, because low
reactivity and diastereoselectivity were observed when a more
acidic alcohol was used (entry 8). As for the solvent, it was
found that toluene gave better diastereoselectivity, although a
low reaction rate was observed (entries 9 and 10).
Addition of allylic metal nucleophiles to CQN double bonds
is one of the most important reactions to afford homoallylic
amine derivatives, which can be useful synthetic building
blocks as well as biologically active compounds,1 and various
allylmetal reagents have been used to perform these C–C bond
formations.2 When a substituted allylmetal nucleophile is
used, the regioselectivity of this reaction emerges as an im-
portant issue since two types of products can be obtained:
a-adduct and g-adduct. Hence, regioselective formation of
both a- and g-adducts is desired with regard to improving
efficiency and decreasing by-products. The ratio of a- to g-
adducts is known to depend on the nature of the allylmetal
reagents used;3 in this context, allylic boron and silicon
nucleophiles are of particular importance since they readily
form C–C bonds via a six-membered transition state, affording
g-adducts exclusively.4
Recently, our group has uncovered enantioselective allyla-
tion of iminoesters catalyzed by a chiral zinc complex.5 Inter-
estingly, the products obtained indicated that the addition
formally took place at the a-position of allylic boronates. It is
quite rare for catalytic addition reactions of allylic boronates
to imine derivatives to afford a-adducts regioselectively.
Furthermore, this successful transformation provides the pos-
sibility of obtaining various homoallylamine products from
a-substituted allylboronates,4,6 which has not received so
much attention. In two earlier reports, we have described as
well the catalytic use7 of indium(I) iodide for effective allyla-
tion of ketones8 and N-acylhydrazones9,10 with an allylbor-
onate. On the basis of this concept involving two group 13
elements, we report here indium(I)-catalyzed additions of a-
substituted allylic boronates to N-acylhydrazones. This reac-
tion showed broad substrate generality and could afford
formal a-adducts regioselectively with high anti-selectivity.
Next, the substrate scope for N-acylhydrazones using
a-methylallylboronate 2 was examined in the presence of 5
mol% of the indium(I) catalyst (Table 3). Although a slight
amount of g-adduct was observed in several entries, the
Table 1 Addition of an a-methylallylboronate to an N-acylhydra-
zone
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. E-mail:
shu_kobayashi@chem.s.u-tokyo.ac.jp; Fax: +81 3 5684 0634; Tel:
+81 3 5841 4790
Entry
InI
Time/h
Yield (%)
a : g
92 : 8
13 : 87
syn : anti
1
2
+
À
6
36
87
36
16 : 84
16 : 84
w Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b802153h
ꢀc
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Table 2 Effect of alcohols and solvents
Entry
Alcohol
Yield (%)
a : g
syn : anti
1
2
3
4
5
6
7
8
—
MeOH
EtOH
i-PrOH
t-BuOH
PhOH
HOCH2CH2OH
HFIPc
MeOH
MeOH
9
57
86
29
8
20
25
17
96
23
b
499 : o1
499 : o1
499 : o1
499 : o1
499 : o1
499 : o1
499 : o1
499 : o1
499 : o1
499 : o1
7 : 93
13 : 87
12 : 88
3 : 97
o1 : 499
15 : 85
33 : 67
18 : 82
37 : 63
20 : 80
9a
10ab
a
Reaction was conducted at rt. Toluene was used as a solvent.
HFIP = hexafluoroisopropanol.
c
Scheme 1 Assumed catalytic cycle.
reactions were highly regio- and diastereoselective to afford
anti-a-adducts12 in all cases. Since aliphatic imines generally
suffer from poor stability,2,9,10 successful transformation of
stable aliphatic hydrazones is particularly noteworthy (entries
1–4). Concerning aromatic hydrazones, both electron-donat-
ing and electron-withdrawing groups on the aromatic ring did
not markedly affect the reaction rate and selectivity (entries
5–8). Moreover, a,b-unsaturated substrates reacted smoothly
to afford the desired 1,2-adducts in high yields (entries 9 and
10). Furthermore, glyoxylate- and pyruvate-derived hydra-
zones were found to be excellent substrates (entries 11 and 12).
An assumed catalytic cycle as well as a transition state for
formal a-addition with anti-selectivity is shown in Scheme 1.
The catalytic cycle is initiated by boron-to-indium trans-
metallation at the g-position of an allylic boronate to generate
(Z)-crotylindium (4); an alcohol may accelerate this trans-
metallation. This (Z)-configured indium species 4 reacted then
with an acylhydrazone via a cyclic six-membered transition
state3g,12 to afford anti-crotylated adduct 5, which was proto-
nated to give the product 313 accompanied by regeneration of
indium(I) iodide.14 Thus, two g-additions give the formal
a-addition product.15
Finally, it was confirmed that the InI-catalyzed regio- and
diastereoselective addition reaction could be applied to a
ketone. When acetophenone (6) was used as an electrophile,
addition of a-methylallylboronate 2 took place in high yield
with complete a-selectivity and high diastereoselectivity
(Scheme 2). In this case, the syn-adduct 7 was obtained
predominantly.16
In summary, we have discovered that indium(I)-catalyzed
addition of an a-methylallylboronate to N-acylhydrazones
proceeded smoothly to give formal a-adducts with high
Table 3 Substrate scope for InI-catalyzed formal a-addition of a-methylallylboronate 2 to N-acylhydrazones 1
Entry
R1
R2
Conditions
Product
Yield (%)
a : g
syn : anti
1
2
3
PhCH2CH2
n-C7H15
c-Hex
t-Bu
Ph
4-MeOC6H4
4-ClC6H4
2-MeOC6H4
CH2QCH
PhCRC
EtO2C
H
H
H
H
H
H
H
H
H
H
H
Me
b
Toluene, rt, 48 h
Toluene, rt, 48 h
Toluene, rt, 24 h
CH2Cl2, 0 1C, 48 h
CH2Cl2, 0 1C, 24 h
CH2Cl2, 0 1C, 24 h
CH2Cl2, 0 1C, 24 h
CH2Cl2, À20 1C, 72 h
CH2Cl2, 0 1C, 36 h
CH2Cl2, 0 1C, 36 h
CH2Cl2, 0 1C, 12 h
CH2Cl2, 0 1C, 72 h
c
3c
3d
3e
3f
3b
3g
3h
3i
85
94
97
88
97
98
96
75
85
99
98
95
97 : 3
96 : 4
94 : 6
95 : 5
99 : 1
499 : o1
499 : o1
499 : o1
499 : o1
499 : o1
499 : o1
91 : 9
5 : 95
8 : 92
7 : 93
3 : 97
6 : 94
9 : 91
4 : 96
6 : 94
9 : 91
5 : 95
2 : 98
8 : 92c
4a
5b
6
7
8
9
3j
3k
3l
10
11
12
a
MeO2C
3m
MeOH was used instead of i-PrOH. 10 mol% of InI was used. Tentatively assigned.
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Konishi and M. Sugiura, J. Am. Chem. Soc., 2003, 125, 6610; (f) R.
Berger, P. M. A. Rabbat and J. L. Leighton, J. Am. Chem. Soc.,
2003, 125, 9596; (g) C. Ogawa, M. Sugiura and S. Kobayashi,
Angew. Chem., Int. Ed., 2004, 43, 6491; (h) R. Berger, K. Duff and
J. L. Leighton, J. Am. Chem. Soc., 2004, 126, 5686; (i) A. E. Taggi,
A. M. Hafez and T. Lectka, Acc. Chem. Res., 2003, 36, 10; (j) S. W.
Li and R. A. Batey, Chem. Commun., 2004, 1382; (k) S. Sebelius
and K. J. Szabo, Eur. J. Org. Chem., 2005, 2539; (l) B. Dhudshia, J.
Tiburcio and A. N. Thadani, Chem. Commun., 2005, 5551; (m) P.
V. Ramachandran and T. E. Burghardt, Pure Appl. Chem., 2006,
78, 1397; (n) R. Wada, T. Shibuguchi, S. Makino, K. Oisaki, M.
Kanai and M. Shibasaki, J. Am. Chem. Soc., 2006, 128, 7687.
4 L. Carosi and D. G. Hall, Angew. Chem., Int. Ed., 2007, 46, 5913,
and references cited therein.
Scheme 2 InI-catalyzed formal a-addition of a-methylallylboronate 2
to ketone 6.
anti-selectivity. A catalytic cycle and a six-membered transi-
tion state involving two g-additions are proposed. Moreover,
this unusual regioselectivity was also observed when a ketone
was used as an electrophile. Further mechanistic investigations
on this catalytic activation of a group 13 metal reagent (boron)
with the same group 13 metal in its low-oxidation state
(indium) and its application to asymmetric catalysis are now
in progress.
5 M. Fujita, T. Nagano, U. Schneider, T. Hamada, C. Ogawa and S.
Kobayashi, J. Am. Chem. Soc., 2008, 130, 2914.
6 (a) H. Ito, S. Ito, Y. Sasaki, K. Matsuura and M. Sawamura, J.
Am. Chem. Soc., 2007, 129, 14856; (b) F. Peng and D. G. Hall,
Tetrahedron Lett., 2007, 48, 3305; (c) L. Carosi, H. Lachance and
D. G. Hall, Tetrahedron Lett., 2005, 46, 8981; (d) R. W. Hoffmann
and J. J. Wolff, Chem. Ber., 1991, 124, 563; (e) R. W. Hoffmann
and B. Landmann, Chem. Ber., 1986, 119, 1039.
7 For recent reviews on the stoichiometric use of indium as reagent
in organic synthesis, see: (a) J. Podlech, Synthesis, 2003, 633; (b) V.
Nair, Tetrahedron, 2004, 60, 1959.
H.K. thanks the JSPS for a fellowship for Japanese junior
scientists.
8 U. Schneider and S. Kobayashi, Angew. Chem., Int. Ed., 2007, 46,
5909.
9 U. Schneider, I.-H. Chen and S. Kobayashi, Org. Lett., 2008, 10,
737.
Notes and references
10 For the use of N-acylhydrazones in organic synthesis, see: (a) H.
Oyamada and S. Kobayashi, Synlett, 1998, 249; (b) M. Sugiura and
S. Kobayashi, Angew. Chem., Int. Ed., 2005, 44, 5176.
11 Anhydrous indium(I) iodide powder (99.999%; Aldrich) was
selected for its higher thermodynamic stability compared with
other indium(I) halides.
12 (a) S. Kobayashi and R. Hirabayashi, J. Am. Chem. Soc., 1999,
121, 6942; (b) R. Hirabayashi, C. Ogawa, M. Sugiura and S.
Kobayashi, J. Am. Chem. Soc., 2001, 123, 9493.
13 Alternatively, intermediate 5 might be converted to product 3
through proton transfer from protonated hydrazone 1.
14 For a recent report on the formation of a neutral indium sub-halide
cluster from indium(I) iodide in the presence of TMEDA in
toluene, see: S. P. Green, C. Jones and A. Stasch, Angew. Chem.,
Int. Ed., 2007, 46, 8618.
15 The reaction of an enantiomerically enriched boronate with 1b
gave an almost racemic product. Details are shown in ESI.
16 K. Takaki, T. Kusudo, S. Uebori, T. Nishiyama, T. Kamata, M.
Yokoyama, K. Takehira, Y. Makioka and Y. Fujiwara, J. Org.
Chem., 1998, 63, 4299.
1 (a) C. Agami, F. Couty and G. Evano, Tetrahedron: Asymmetry,
2000, 11, 4639; (b) H. Ding and G. K. Friestad, Synthesis, 2005,
2815; (c) A. M. Schmidt and P. Eilbracht, J. Org. Chem., 2005, 70,
5528; (d) J. E. Kropf, I. C. Meigh, M. W. P. Bebbington and S. M.
Weinreb, J. Org. Chem., 2006, 71, 2046; (e) C. Denhez, J.-L. Vasse,
D. Harakat and J. Szymoniak, Tetrahedron: Asymmetry, 2007, 18,
424.
2 For reviews on nucleophilic addition to imines, see: (a) S. Kobaya-
shi and H. Ishitani, Chem. Rev., 1999, 99, 1069; (b) G. Alvaro and
D. Savoia, Synlett, 2002, 651; (c) S. Kobayashi, M. Sugiura, U.
Schneider, R. Matsubara, J. S. Fossey and Y. Yamashita, in
Comprehensive Organometallic Chemistry III, ed. I. Ojima and T.
Hiyama, pp. 403–491.
3 (a) H. Nakamura, K. Nakamura and Y. Yamamoto, J. Am. Chem.
Soc., 1998, 120, 4242; (b) T. Gastner, H. Ishitani, R. Akiyama and
S. Kobayashi, Angew. Chem., Int. Ed., 2001, 40, 1896; (c) R. A.
Fernandes, A. Stimac and Y. Yamamoto, J. Am. Chem. Soc., 2003,
125, 14133; (d) T. Hamada, T. Manabe and S. Kobayashi, Angew.
Chem., Int. Ed., 2003, 42, 3927; (e) S. Kobayashi, C. Ogawa, H.
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