Hydroxoiridium-Catalyzed Hydroalkylation of Terminal Alkenes with Ureas by C(sp3)?H Bond Activation

Article abstract of DOI:10.1002/anie.201702169

Direct alkylation of a methyl group, on di- and trisubstituted ureas, with terminal alkenes by C(sp³)?H bond activation proceeded in the presence of a hydroxoiridium/bisphosphine catalyst to give high yields of the corresponding addition products. The hydroxoiridium/bisphosphine complex generates an amidoiridium intermediate by reaction with ureas having an N?H bond.

Full text of DOI:10.1002/anie.201702169

Angewandte
Communications
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International Edition: DOI: 10.1002/anie.201702169
German Edition: DOI: 10.1002/ange.201702169
À
C H Activation
Hydroxoiridium-Catalyzed Hydroalkylation of Terminal Alkenes with
3
À
Ureas by C(sp ) H Bond Activation
Daisuke Yamauchi, Takahiro Nishimura,* and Hideki Yorimitsu
3
À
Abstract: Direct alkylation of a methyl group, on di- and
the amidoiridium species for the activation of the C(sp ) H
bond of a methyl group adjacent to a nitrogen center. Herein
we report that a hydroxoiridium/bis(phosphine) complex can
3
À
trisubstituted ureas, with terminal alkenes by C(sp ) H bond
activation proceeded in the presence of a hydroxoiridium/
bisphosphine catalyst to give high yields of the corresponding
addition products. The hydroxoiridium/bisphosphine complex
generates an amidoiridium intermediate by reaction with ureas
catalyze the hydroalkylation reaction of terminal alkenes with
ureas by C(sp ) H bond activation. The method provides an
easy access to biologically active compounds containing an
3
À
having an N H bond.
amino group or a urea moiety.[13]
À
Treatment of 1-methyl-1,3-diphenylurea (1a) with
4-methoxystyrene (2a) in the presence of [{Ir(OH)(cod)}2]
(5 mol% of Ir, cod = 1,5-cyclooctadiene) and 1,2-bis(diiso-
propylphosphino)benzene (dippbz; 5 mol%) in 1,4-dioxane
at 708C for 6 hours gave the hydroalkylation product 3aa in
92% yield (Table 1, entry 1). The alkylation occurred at the
methyl group and the other possible reaction sites, such as the
ortho positions of the two benzene rings, were inert. Biden-
tate triarylphosphine ligands, 1,2-bis(diphenylphosphino)ben-
zene (dppbz), and rac-binap, were less effective than dippbz
(entries 2 and 3). The use of dppb, dppf, and xantphos resulted
R
ecent rapid progress in transition-metal-catalyzed direct
À
functionalization reaction of unactivated C H bonds has
opened up new possibilities for achieving highly atom-
efficient transformations in synthetic organic chemistry.[1]
Although many studies have realized the reactions by
2
3
À
À
C(sp ) H activation, selective C(sp ) H functionalization is
still a challenging objective in this field.[2] The alkylation of
3
À
C(sp ) H bonds with alkenes is obviously one of the useful
À
C C bond formation reactions, and in view of the site
À
selectivity of the C H bond activation, the alkylation of the
3
[3]
À
C(sp ) H bonds adjacent to a nitrogen center has been
developed by using transition-metal catalysis[4–8] as well as
radical reactions.[9,10] With respect to the directed C(sp ) H
3
À
Table 1: Iridium-catalyzed hydroalkylation of 2a with the ureas 1.[a]
alkylation catalyzed by late transition metals, ruthenium-
catalyzed alkylations of the C(sp ) H bond of 2-(N-alkyl-
3
À
amino)pyridines with alkenes were reported by the groups of
Jun[5a] and Murai,[5b] independently. Shibata and co-workers
have developed enantioselective hydroalkylation of alkenes
3
À
by secondary C(sp ) H bond activation of N-2-(alkylamino)-
pyridines catalyzed by cationic iridium/chiral bis(phosphine)
complexes.[6b,c,e]
Recently, we reported that a hydroxoiridium/chiral diene
complex catalyzes asymmetric alkylation of N-sulfonylbenza-
mides with vinyl ethers.[11] The reaction involves an
amidoiridium(I) species as a key intermediate derived from
the neutral hydroxoiridium and benzamide, and the key
Entry
Ligand
Solvent
1
Yield [%][b]
À
species undergoes oxidative addition of an ortho-C H bond
1
2
3
4
5
dippbz
dppbz
rac-binap
dppb
dppf
xantphos
–
dippbz
dippbz
dippbz
dippbz
dippbz
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
toluene
1a
1a
1a
1a
1a
1a
1a
1a
1b
1a
1a
1a
92
4
26
0
0
0
31
0
0
49
12
0
to form an aryl(hydrido)iridium(III) species. We also
reported asymmetric hydroarylation of vinyl ethers using
À
aryl-substituted azoles, containing an N H bond as a directing
group, catalyzed by a hydroxoiridium/chiral bis(phosphine)
complex.[12] The reaction also involves the formation of an
amidoiridium species as an essential intermediate. In this
context, we found that ureas are suitable substrates in forming
6
7
8[c]
9
10
11
12
MeCN
1,2-dichloroethane
[*] D. Yamauchi, Dr. T. Nishimura, Prof. Dr. H. Yorimitsu
Department of Chemistry, Graduate School of Science
Kyoto University, Sakyo, Kyoto 606-8502 (Japan)
E-mail: tnishi@kuchem.kyoto-u.ac.jp
[a] Reaction conditions: 1 (0.10 mmol), 2a (0.12 mmol), [{Ir(OH)-
(cod)}2] (5 mol% of Ir), and ligand (5 mol%) in 1,4-dioxane (0.1 mL) at
1
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201702169.
708C for 6 h. [b] Determined by H NMR spectroscopy. [c] Performed
with [{IrCl(cod)}2] (5 mol% of Ir) and NaBArF (10 mol%) instead of
4
[{Ir(OH)(cod)}2].
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in no formation of the addition product (entries 4–6). [{Ir-
(OH)(cod)}2] itself displayed a low catalytic activity in the
absence of dippbz, thus giving 3aa in 31% yield (entry 7). A
cationic complex generated from [{IrCl(cod)}2], dippbz, and
adducts 3ai and 3aj, respectively, in high yields, although
the use of two equivalents of alkenes was needed because of
the isomerization of the alkene moieties (entries 9 and 10).
The vinyl silane 2k, vinyl ether 2l, and N-vinyl amide 2m and
imide 2n also reacted with 1a to give the addition products in
good yields (entries 11–14). The reaction of an electron-
deficient alkene, diethyl vinylphosphonate (2o), gave 3ao in
83% yield (entry 15), while ethyl acrylate (2p) was less
reactive, thus resulting in 39% yield of the adduct 3ap, even
in the presence of 10 mol% of the Ir/dippbz catalyst
(entry 16). Isoprene (2q) also reacted with 1a to give rise to
addition product 3aq in 80% yield, where the vinyl group of
isoprene selectively participated in the reaction (entry 17).
The present catalytic system was also applicable to the
reactions of several ureas (1) with para-methoxystyrene (2a;
Table 3). A variety of functional groups on aromatic rings (X)
of the ureas were tolerated in the reaction, thus giving high
yields of the adducts 3ca–ka (entries 1–9). The ureas having
alkyl groups (Y) adjacent to the N-methyl moiety reacted
with 2a in the presence of KOSiMe3, as a base, to give
NaBArF [ArF = 3,5-(CF3)2C6H3] had no catalytic activity
4
(entry 8). In addition, the reaction of 1,3-dimethyl-1,3-diphe-
nylurea (1b) did not take place under the present catalytic
conditions (entry 9). These results indicate that the formation
of the amidoiridium species from the hydroxoiridium and
trisubstituted urea is essential for the present reaction. The
reaction in toluene gave the addition product in 49% yield
(entry 10), while the other solvents such as acetonitrile and
1,2-dichloroethane were ineffective (entries 11 and 12).
Table 2 summarizes the results obtained for the hydro-
alkylation of several terminal alkenes 2 with 1-methyl-1,3-
diphenylurea (1a). The para-substituted styrenes with elec-
tron-donating (MeO, Me) and electron-withdrawing groups
(Cl, Br) are all good substrates for giving the corresponding
addition products 3aa–ae in high yields (entries 1–5). The
reaction of 2,3,4,5,6-pentafluorostyrene (2 f) required
a higher catalyst loading because of the slow reaction and
catalyst deactivation (entry 6). The meta- and ortho-methoxy-
substituted styrenes 2g and 2h, respectively, also reacted with
1a to give the corresponding 3ag and 3ah in high yields
(entries 7 and 8). The reactions of 1-octene (2i) and vinyl-
cyclohexane (2j) proceeded to give the corresponding
Table 3: Iridium-catalyzed hydroalkylation of 2a with the ureas 1.[a]
Table 2: Iridium-catalyzed hydroalkylation of the alkenes 2 with 1a.[a]
Entry
2
R
3
Yield [%][a]
1
2
3
4
5
2a
2b
2c
2d
2e
2 f
2g
2h
2i
4-MeOC6H4
Ph
4-MeC6H4
4-ClC6H4
4-BrC6H4
C6F5
3-MeOC6H4
2-MeOC6H4
n-hexyl
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
95
92
99
95
93
87
91
93
88
88
93
72
6[b]
7[c]
8[c]
9[d,e]
10[d,e]
11
12[d,f]
2j
2k
2l
c-hexyl
SiEt3
OnBu
3aj
3ak
3al
13[c]
2m
3am
89
14[b,f]
2n
3an
83
15[b,d,f]
16[b,d,f]
17[e]
2o
2p
2q
PO(OEt)2
CO2Et
3ao
3ap
3aq
83
39
80
=
C(CH3) CH2
[a] Reaction conditions: 1a (0.20 mmol), 2 (0.24 mmol), [{Ir(OH)-
(cod)}2] (5 mol% of Ir), and dippbz (5 mol%) in 1,4-dioxane (0.2 mL) at
708C for 20 h. Yield is that of the isolated product. [b] [{Ir(OH)(cod)}2]
(10 mol% of Ir) and dippbz (10 mol%) were used. [c] For 48 h.
[d] Performed with toluene (0.2 mL). [e] 2 (0.40 mmol) was used. [f] At
808C.
[a] Reaction conditions: 1 (0.20 mmol), 2a (0.24 mmol), [{Ir(OH)-
(cod)}2] (5 mol% of Ir), and dippbz (5 mol%) in 1,4-dioxane (0.2 mL) at
708C for 20 h. Yield is that of isolated product. [b] For 48 h. [c] At 808C.
[d] Me3SiOK (10 mol%) was added. [e] Performed in toluene (0.2 mL).
[f] 2a (0.48 mmol) was used. Ts=p-toluenesulfonyl.
2
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addition products 3la–na (entries 10–12).[14] The reactivity of
the N-methyl-N-phenyl ureas 1o and 1p, having aryl groups
(Z) at another nitrogen atom, was high (entries 13 and 14),
while the alkyl-substituted ureas 1q and 1r displayed
relatively low reactivity (entries 15 and 16). Double alkyla-
tion of 1,1-dimethyl-3-phenylurea (1s) with 2a proceeded to
give 3sa in 95% yield (entry 17). 1,3-Dimethylurea (1t) is also
a good substrate to undergo the alkylation with 2a, thus
giving 3ta in 88% yield (entry 18). The reaction did not take
place at all with 1u, which has a tosyl group on the nitrogen
À
atom. The alkylation of a secondary alkyl C H bond of either
1v or 1w was not observed, and neither N-phenylpivalamide
(1x) nor the thiourea 1y were reactive under the present
catalytic conditions.
The present alkylation reaction can be applied to the
straightforward synthesis of some biologically active com-
pounds (Scheme 1). For example, the reaction of the urea 1z
Scheme 2. Deuterium-labeling experiments.
3 hours gave [D3]1a containing deuterium at the methyl
group (42% D).[17] 2H NMR spectroscopic analysis of [D3]1a
clearly showed that the deuterium was incorporated only into
the methyl group and the other possible reaction sites, such as
the ortho positions of the two benzene rings, did not contain
deuterium. In contrast, H–D exchange of 1v was hardly
À
observed, thus indicating that the secondary C H activation
does not occur under the present catalytic conditions
(Scheme 2b).[18] The reaction of 1a with deuterated alkene
[D3]2a at 708C for 2 hours gave 3aa in 35% yield, and partial
H–D exchange was observed at the three methylene groups of
3aa, the methyl group of 1a, and the vinyl group of alkene
À
[D3]2a (Scheme 2c). These results indicate that the C H
activation forming a hydridoiridium species and the alkene
insertion are reversible.
The catalytic cycle proposed for the present hydroalkyla-
tion of the alkene 2 with 1a is illustrated in Scheme 3. The
Scheme 1. Synthesis of biologically active compounds. DMSO=di-
methyl sulfoxide.
with 3-(trifluoromethyl)styrene (2r) gave the alkylation
product 3zr in 75% yield. Hydrolysis of 3zr by aqueous
KOH gave the corresponding amine, and then, treatment of
the resulting amine with HCl in Et2O gave rac-Cinacalcet
hydrochloride (4), which is a drug that acts as a calcimimetic
agent (Scheme 1a).[15] The urea 3ts, which shows an anti-
secretory and antiulcer activities, was prepared from 1,3-
dimethylurea (1t) and the N-allylpyridazinone 2s in 90%
yield (Scheme 1b).[16]
À
C H activation under the present catalytic system was
found to occur only at the methyl group of 1a (Scheme 2a).
Thus, treatment of 1a with D2O (20 equiv) in the presence of
[{Ir(OH)(cod)}2] and dippbz in 1,4-dioxane at 708C for
Scheme 3. Plausible catalytic cycle.
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À
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À
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À
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3
3
À
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À
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was efficiently catalyzed by a hydroxoiridium/bisphosphine
complex, which generates an amidoiridium intermediate by
À
reaction with ureas having an N H bond. The methyl group
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Acknowledgments
This work was supported by JSPS KAKENHI Grant No.
15H03810.
3, 704.
3
À
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À
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Conflict of interest
N. Chatani, F. Kakiuchi, S. Murai, Organometallics 1997, 16,
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2009, 11, 1821; d) T. Shibata, H. Hirashima, M. Kasagawa, K.
Tsuchikama, K. Endo, Synlett 2011, 2171.
The authors declare no conflict of interest.
À
Keywords: alkenes · C H activation · iridium ·
reaction mechanisms · synthetic methods
À
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À
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4
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[17] A partial deuterium incorporation into the NH group of [D3]1a
in Scheme 2a was observed after evaporation of the reaction
mixture.
[11] M. Hatano, Y. Ebe, T. Nishimura, H. Yorimitsu, J. Am. Chem.
Soc. 2016, 138, 4010.
[12] D. Yamauchi, T. Nishimura, H. Yorimitsu, Chem. Commun.
2017, 53, 2760.
[18] The H–D exchange was also not observed for either 1w or 1x.
[13] M. I. El-Gamal, M. Ashrafuddin Khan, H. Tarazi, M. S. Abdel-
Maksoud, M. M. Gamal El-Din, K. Ho Yoo, C.-H. Oh, Eur. J.
Med. Chem. 2017, 127, 413.
Manuscript received: February 28, 2017
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
À
C H Activation
D. Yamauchi, T. Nishimura,*
H. Yorimitsu
&&&& — &&&&
Hydroxoiridium-Catalyzed
Hydroalkylation of Terminal Alkenes with
3
À
Ureas by C(sp ) H Bond Activation
Direct alkylation of a methyl group, on di-
high yields of the corresponding addition
products. The hydroxoiridium/bisphos-
phine complex generates an amidoiri-
dium intermediate by reaction with ureas
and trisubstituted ureas, with terminal
3
À
alkenes by C(sp ) H bond activation
proceeded in the presence of a hydroxo-
iridium/bisphosphine catalyst to give
À
having an N H bond.
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!