Rapid Access to Nitrogenous Heterobicycles via RhIII-Catalyzed Isomerization from Alkynes to Allenes

Article abstract of DOI:10.1002/chem.201701704

We show that N-alkynylnitrones are efficiently converted to nitrogenous heterobicyclic compounds with a nitrogen atom at the bridgehead position by using a Rh^III-catalyst. Our mechanistic studies suggest that the reaction proceeds via an allene

Full text of DOI:10.1002/chem.201701704

A Journal of
Accepted Article
Title: Rapid Access to Nitrogenous Heterobicycles via Rh(III)-catalyzed
Isomerization from Alkynes to Allenes
Authors: Itaru Nakamura, Keisuke Takeda, Yoshinori Sato, and
Masahiro Terada
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10.1002/chem.201701704
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COMMUNICATION
Rapid Access to Nitrogenous Heterobicycles via Rh(III)-catalyzed
Isomerization from Alkynes to Allenes
Itaru Nakamura,*[a] Keisuke Takeda,[b] Yoshinori Sato,[b] and Masahiro Terada[a,b]
(a) Allylation using in situ generated allenes by metal catalyst
Abstract: We have disclosed that N-alkynylnitrones are efficiently
converted to nitrogenous heterobicyclic compounds having
a
cat. M
(Pd, Rh)
H-M
NuH
·
nitrogen atom at the bridgehead position by using a Rh(III)-catalyst.
Our mechanistic studies suggest that the reaction proceeds via an
allene intermediate, which is generated in situ through Rh(III)-
catalyzed isomerization of the alkyne group.
Nu
M
- H-M
fast
Allene
H-X
(b) Cascade reactions via [3+2] cycloaddition of in situ generated allene (this work)
N
cat. M
[3+2]
N
1,3-N
N
N
O
O
O
Allenes have been frequently utilized in organic synthesis as three-
carbon units owing to their high reactivity.[1] However, due to the
inherent instability of this functional group, construction of highly
functionalized organic molecules from functionalized allene species
has been limited. In situ generation of allenes is one of the most
effective solutions for this problem. Particularly, isomerization of
alkynes by using transition metal catalysts, such as Pd0,[2] RhI,[3,4]
and RuII,[5] has been widely utilized as an efficient and robust method
to transiently generate allenes (Scheme 1a). These methodologies
have been typically utilized as allylation reactions, because the
generated allene rapidly undergoes addition of the metal hydride that
is formed during the isomerization process, leading to the
thermodynamically stable π-allylmetal intermediate.[1b] Accordingly,
we envisioned that the generated allene A could be captured by a
properly placed nitrone group in an intramolecular manner, and the
expected cycloadduct B would rapidly rearrange via N-O bond
cleavage, leading to nitrogenous heterobicycle C, which is beneficial
for drug discovery (Scheme 1b).[6] Herein, we report that N-(4-
hexynyl)nitrones 1 undergo cycloisomerization by the aid of rhodium
catalysts, producing nitrogenous heterobicycles 2, in good to
acceptable yields [Eq(1)].
·
O
C
B
A
Scheme 1. Transformations via metal-catalyzed in situ generation of allenes
R1
O
cat. Rh
N
O
(1)
R2
N
R2
R1
2
1
efficiency of the present reaction, To our surprise, the use of Br2 and
LiBr as additive improved the chemical yield (entries 4 and 5), while
the reaction in the absence of the Br additive did not afford the
desired product at all (entry 6). The reaction with I2 afforded the
product in lower yield than that using Br2 (entry 7). These results
encouraged us to examine RhIII as a catalyst, which is expected to
be generated through oxidation of RhI by Br2. To our delight, the
reaction using RhBr3·2H2O in place of [RhCl(cod)]2 afforded the
desired product 2a in good yield even in the absence of the
additional bromine source (entries 8 and 9). In sharp contrast, the
reaction using RhCl3 was sluggish (entry 10). It should be noted that
only dppp {1,3-bis(diphenylphosphino)propane} exhibited good
catalytic activity and THF gave the best result among the solvents
we tested (see SI).
Initially, the previously reported reaction conditions using Pd and
Rh catalysts were applied to the benzaldoxime 1a and we found that
the conditions using a rhodium catalyst reported by Breit afforded
the 1-azabicyclo[3.2.1]octan-6-one 2a having a nitrogen atom at the
bridgehead with excellent diastereoselectivity, albeit in low chemical
yields. Among Brønsted acids examined as a potential hydrogen
source, only HBr showed improved catalytic activity (entry 3), while
other protic acids, such as carboxylic acids and HCl, were ineffective
(see SI). Thus, the reaction was conducted in the presence of
several bromine sources in order to know if bromine atom affects on
Next, the optimal reaction conditions (Table 1, entry 9) were
applied to various substrates, as summarized in Table 2. An
electron-deficient aromatic group was efficient as a substituent at the
nitrone carbon atom. The p-cyanophenyl group gave the desired
product in good yield (entry 5). Bromo, chloro, and naphthyl groups
were tolerated under the reaction conditions. While reaction of
substrate 1i having an electron-rich p-anisyl group at R1 afforded 2i
in low yield (entry 8), 1j having an alkyl substituent at R1 did not
afford the desired product under the present reaction conditions
(entry 9). Both electron-rich and electron-poor aromatic substituents
were applicable as substituents at R2, affording the heterobicycles in
good to acceptable yields (entries 12-14), while that having an alkyl
group resulted in low chemical yield (entry 15). It should be noted
that the substrate having an ethyl group, instead of a methyl group,
at the alkyne terminus was not converted to the desired product at
all.
[a]
[b]
Prof. Dr. I. Nakamura, Prof. Dr. M. Terada
Research and Analytical Center for Giant Molecules, Graduate
School of Science
Tohoku University
6-3 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8578 Japan
E-mail: itaru-n@m.tohoku.ac.jp
K.Takeda, Y. Sato
Department of Chemistry, Graduate School of Science
Tohoku University
6-3 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8578 Japan
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201701704
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COMMUNICATION
Table 1. Optimization of reaction conditions
Table 2. RhIII-catalyzed reaction of 1b-p[a]
Ph
10 mol % RhBr3·2H2O
20 mol % dppp
R1
[conditions]
O
O
N
N
O
N
O
Ph
Ph
N
Ph
R2
R2
THF, 100 °C
48 h
R1
THF, 120 °C
2a
(dr = >99:1)
2
1a
1
Entry
Conditions (mol %)
Pd(PPh3)4 (10), BzOH (10)
Yield [%][a]
<1
Entry
1
R1
R2
Time
[h]
2
Yield
[%][b
1
2
3
4
5
6
7
8
9
10
1
1b
1c
1d
1e
1f
p-ClC6H4
p-BrC6H4
p-FC6H4
p-F3CC6H4
p-NCC6H4
3,5-(F3C)2C6H3
2-naphthyl
p-MeOC6H4
Cy
Ph
30
48
24
20
24
24
24
24
24
24
24
24
24
24
24
2b
2c
2d
2e
2f
55
37
48
63
65
64
42
20
<1
33
51
49
46
58
25
[RhCl(cod)]2 (5), dppp (11), BzOH (50)
[RhCl(cod)]2 (5), dppp (11), HBr (10)[b]
[RhCl(cod)]2 (5), dppp (11), Br2 (10)[c]
[RhCl(cod)]2 (5), dppp (11), LiBr (10)
[RhCl(cod)]2 (5), dppp (11)
16[d]
43 (37)
51
2
Ph
3
Ph
4
Ph
33
5
Ph
<1
6
1g
1h
1i
Ph
2g
2h
2i
[RhCl(cod)]2 (5), dppp (11), I2 (10)
RhBr3·2H2O (10), dppp (20)
49 (29)
40
7
Ph
8
Ph
RhBr3·2H2O (10), dppp (10)[e]
RhCl3·2H2O (10), dppp (20)
51 (49)
7
9
1j
Ph
-
10
11
12
13
14
15
1k
1l
Ph
p-F3CC6H4
p-MeOC6H4
p-ClC6H4
p-F3CC6H4
p-MeOC6H4
iBu
2k
2l
[a] Yields were determined by 1H NMR using dibromomethane as an
internal standard. Isolated yield is in parentheses. [b] 47% HBr aqueous
solution was used. [c] Br2-1,4-dioxane complex was used. [d] 15% of 1a
was recovered. [e] At 120 °C for 24 h.
Ph
1m
1n
1o
1p
p-NCC6H4
p-NCC6H4
p-NCC6H4
Ph
2m
2n
2o
2p
The rhodium-catalyzed reaction of the N-(5-hexynyl)nitrone
3a, in which the position of the alkynyl group was shifted by one
carbon in comparison to 1a, gave the identical product 2a to that
of the N-(4-hexynyl)nitrone 1a (Scheme 2a). These results
clearly support intermediacy of the same allene intermediate 4a.
Moreover, when the N-(4-pentynyl)nitrone 5 was treated with the
standard conditions of Crabbe allene synthesis,[7] the
heterobicycle 2a was obtained, albeit in low chemical yield
(Scheme 2b), supporting the in situ generation of the allene
group. A mass spectrum corresponding to [RhBr2(dppp)]+ was
detected in the reaction of 1a under the optimal reaction
conditions (Table 1, entry 9), suggesting that RhIII coordinated by
bromine atoms exists in the reaction media, presumably serving
as a real catalytic species for the present reaction.
[a] The reactions of 1b-p (0.4 mmol) were carried out in the presence of 10
mol % of RhBr3·2H2O and 20 mol % of dppp in THF (2.0 mL) at 120 °C. [b]
Isolated yields.
We propose a tentative reaction mechanism based on the
reactivity of the rhodium catalyst as a π-acid, as illustrated in
Scheme 3. First, the RhIII catalyst is coordinated by the triple
bond of substrate 1, forming the σ,π-complex 6. The π-
coordination enhances acidity of the methyl group at the alkyne
terminus, facilitating elimination of the proton.[8] The resulting
Ph
cat. Rh(III), dppp
51% yield
N
O
allenylrhodium
species
7
immediately
undergoes
Ph
protodemetallation leading to the allene intermediate 4. Next,
intramolecular [3+2] cycloaddition between the generated allene
and the pendant nitrone leads to the bicyclic intermediate 8,
having a 5-methylenisoxazolidine ring.[10] Finally, [1,3]-nitrogen
rearrangement involving N-O bond cleavage leads to the
1a
(a)
Ph
Ph
O
cat. Rh(III), dppp
10% yield
N
N
N
Ph
O
O
·
product 2.
The excellent diastereoselectivity is probably
Ph
Ph
because both R1 and R2 are formally located at equatorial
positions in the forming 6-membered ring in the [3+2]
cycloaddition process as shown in intermediate 4’. We consider
that the in situ generated allene was effectively utilized for [3+2]
cycloaddition not only because the nitrone is located at a
suitable position in the key intermediate 4/4’ but also because
the present catalyst system based on π-acid RhIII is free from
generation of metal hydride species, which cause the typical
allylation reaction.
Ph
2a
3a
4
(b)
Ph
(CH2O)n
N
Ph
O
CuI, Pr NH
i
2
dioxane, reflux
12% yield
5
Scheme 2. Mechanistic studies
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10.1002/chem.201701704
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R1
RhBr3L
Keywords: rhodium • rearrangement • allene • heterocycles •
R1
O
·
N
N
O
R2
R2
R2
N
cascade reaction
R1
O
·
R2
R2
4'
1
4
[3+2]
[1]
a) A. Lledó, A. Pla-Quintana, A. Roglans, Chem. Soc. Rev. 2016, 45,
2010-2023; b) S. Kitagaki, F.Inagaki, C. Mukai, Chem. Soc. Rev. 2014,
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S. Yu, S. Ma, Angew. Chem. Int. Ed. 2012, 51, 3074-3112; e) N.
Krause, A. S. K. Hashmi, Modern Allene Chemistrym Wiley-VCH,
Weinheim, 2004. h) R. Zimmer, C. U. Dinesh, E. Nandanan, F. A.
Khan, Chem. Rev. 2000, 100, 3067-3126.
R1
O
N
R1
R1
N
O
8
HBr
N
O
RhBr2L
·
Br
RhBr2L
[1,3]-nitrogen
rearrangement
R2
R2
O
7
H
N
R1
6
2
[2]
[3]
a) B. M. Trost, W. Brieden, K. H. Baringhaus, Angew. Chem., Int. Ed.
Engl. 1992, 31, 1335–1336; b) I. Kadota, A. Shibuya, Y. S. Gyoung, Y.
Yamamoto, J. Am. Chem. Soc. 1998, 120, 10262–10263; L. M. Lutete,
I. Kadota, Y. Yamamoto, J. Am. Chem. Soc. 2004, 126, 1622-1623; d)
N. T. Patil, H. Wu, I. Kadota, Y. Yamamoto, J. Org. Chem. 2004, 69,
8745-8750.
Scheme 3. A plausible mechanism
In conclusion, we have successfully developed a new
method to generate allene intermediates by using a RhIII catalyst.
Since the reaction rapidly constructs nitrogenous heterobicyclic
skeletons in a single operation under mild reaction conditions,
the present method is potentially useful for the synthesis of new
classes of heterocyclic compounds, which is beneficial for drug
discovery.[11]
a) A. Lumbroso, P. Koschker, N. R. Vautravers, B. Breit, J. Am. Chem.
Soc. 2011, 133, 2386-2389; b) U. Gellrich, A. Meißner, A. Steffani, M.
Kähny, H.-J. Drexler, D. Heller, D. A. Plattner, B. Breit, J. Am. Chem.
Soc. 2014, 136, 1097-1104; c) P. Koschker, M. Kähny, B. Breit, J. Am.
Chem. Soc. 2015, 137, 3131-3137; d) P. Koschker, B. Breit, Acc. Chem.
Res. 2016, 49, 1524-1536; e) F. A. Cruz, Z. Chen, S. I. Kurtoic, V. M.
Dong, M. Chem. Commun. 2016, 52, 5836-5839.
[4]
[5]
[6]
Rhodium-catalyzed isomerization of internal alkynes, R. Shintani, W.-L.
Duan, S. Park, T. Hayashi, Chem. Commun. 2006, 3646-3647.
T, Liang, K. D. Nguyen, W. Zhang, M. J. Krische, J. Am. Chem. Soc.
2015, 137, 3161-3164.
Experimental Section
a) M. C. Aversa, G. Cum, N. Uccella, J. Chem. Soc., Chem. Commun.
1971, 156-157; b) A. Padwa, Y. Tomioka, M. K. Venkatramanan,
Tetrahedron Lett. 1987, 28, 755-758; c) A. Padwa, M. Matzinger. Y.
Tomioka, M. K. Venkatramanan, J. Org. Chem. 1988, 53, 955-963.
P. Crabbé, H. Fillion, D. André, J.-L. Luche, J. Chem. Soc., Chem.
Commun., 1979, 859-860.
To a mixture of 1f (120.9 mg, 0.4 mmol), RhBr3·2H2O (15.1 mg, 0.04
mmol), and dppp (33.0 mg, 0.08 mmol) was added THF (2.0 mL) under
argon atmosphere and the mixture was stirred at 120 °C for 24 hours.
After cooling to room temperature, the mixture was filtered through a
short pad of silica gel using ethyl acetate. After removing solvents in
vacuo, the crude product was purified by flash silica gel column
chromatography using hexane/ethyl acetate (10/1), affording 2f (78.1 mg,
0.26 mmol) in an analytically pure form.
[7]
[8]
[9]
Z. Wang, Y. Wang, L. Zhang, J. Am. Chem. Soc. 2014, 136, 8887-8890.
Typical π-acidic catalysts, such as [(PPh3)AuNTf2] and PtCl4, did not
promote the present reaction.
[10] Attempts to observe the cycloaddition intermediate 8 was unsuccessful.
Indeed, our preliminary calculations suggested that the product 2a is
38.3 kcalmol-1 more stable than the cycloaddition intermediate 8a.
[11] a) B. S. Bhatti, J.-P. Strachan, S. R. Breining, C. H. Miller, P. Tahiri, P.
A. Crooks, N. Deo, C. S. Day, W. S. Caldwell, J. Org. Chem. 2008, 73,
3497-3507; b) A. Mallick, A. P. J. Pal, Y. D. Vankar, Tetrahedron Lett.
2013, 54, 6549-6552.
Acknowledgements
This work was supported by JSPS KAKENHI Grant Number
JP16H00996 in Precisely Designed Catalysts with Customized
Scaffolding.
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10.1002/chem.201701704
Chemistry - A European Journal
COMMUNICATION
Layout 2:
COMMUNICATION
Itaru Nakamura,* Keisuke Takeda,
Yoshinori Sato, Masahiro Terada
R1
cat. RhBr3 / dppp
O
Page No. – Page No.
N
O
N
R2
R2
via alkyne-allene
isomerization
R1
Rapid Access to Nitrogenous
Heterobicycles via Rh(III)-catalyzed
Isomerization from Alkyne to Allene
RhIII catalyst rapidly constructs heterobicycles from N-alkynylnitrones.
Mechanistic studies suggest that the present transformation proceeds via in situ
generation of allene intermediate through Rh-catalyzed isomerization of alkyne.
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