Asymmetric Cyclization of N-Sulfonyl Alkenyl Amides Catalyzed by Iridium/Chiral Diene Complexes

Article abstract of DOI:10.1021/acs.orglett.6b01954

Iridium/chiral diene complexes efficiently catalyzed the asymmetric cyclization of N-sulfonyl alkenyl amides to give the corresponding 2-pyrrolidone derivatives with high enantioselectivity. A mechanistic study revealed that the reaction proceeds via nucleophilic attack of the amide on the alkene moiety.

Full text of DOI:10.1021/acs.orglett.6b01954

Letter
pubs.acs.org/OrgLett
Asymmetric Cyclization of N‑Sulfonyl Alkenyl Amides Catalyzed by
Iridium/Chiral Diene Complexes
Midori Nagamoto, Tomoyuki Yanagi, Takahiro Nishimura,* and Hideki Yorimitsu
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
S
* Supporting Information
ABSTRACT: Iridium/chiral diene complexes efficiently catalyzed the asymmetric
cyclization of N-sulfonyl alkenyl amides to give the corresponding 2-pyrrolidone
derivatives with high enantioselectivity. A mechanistic study revealed that the
reaction proceeds via nucleophilic attack of the amide on the alkene moiety.
a
Table 1. Ir-Catalyzed Asymmetric Cyclization of 1a
irect addition of N−H bonds to C−C unsaturated bonds,
Dwhich is known as hydroamination, has attracted much
attention, as it represents an atom-efficient approach to the
synthesis of various nitrogen-containing compounds.1 Primary
and secondary amides have been often used as nucleophiles in
the hydroamination reactions catalyzed by transition metal
complexes. Although there have been many successful examples
of the addition of amides to unactivated alkenes,2 the
asymmetric variant is still a challenging objective.3−5
Widenhoefer and co-workers reported gold-catalyzed hydro-
amination reactions including the asymmetric addition of
amides to alkenes.3a,d Hartwig and co-workers reported iridium-
catalyzed asymmetric addition of benzamides to bicyclic
alkenes.3b In this context, we recently reported iridium-
catalyzed asymmetric cyclization of alkenoic acids leading to
γ-lactones.6 The reaction of 4-pentenoic acid derivatives in the
presence of an iridium/chiral bisphosphine complex in an
amide solvent gave the corresponding lactones with good
enantioselectivity. We next focused on the asymmetric addition
of amide nucleophiles toward the synthesis of chiral γ-lactams,
which are often found in natural products and biologically
active compounds.7 Although various methodologies for the
stereoselective synthesis of γ-lactams have been developed,
there have been few reports on the catalytic enantioselective
synthesis of 2-pyrrolidone derivatives in an intramolecular
manner.8 Herein we report the asymmetric cyclization of N-
sulfonyl alkenyl amides catalyzed by iridium/chiral diene
complexes.
It was found that the cyclization of an N-sulfonyl 4-
pentenamide, which bears a highly acidic N−H bond,
proceeded to give the corresponding 2-pyrrolidone under the
same reaction conditions as the cyclization of 4-pentenoic acid.
Treatment of N-tosyl-2,2-diphenyl-4-pentenamide (1a) in the
presence of [IrCl(coe)2]2 (5 mol % of Ir, coe = cyclooctene)
and (R)-DTBM-segphos in N-methylpyrrolidone (NMP) at
100 °C for 20 h gave 2a in 91% yield albeit with 7% ee (Table
1, entry 1). An iridium complex [IrCl(cod)]2 (cod = 1,5-
cyclooctadiene), which has a chelating diene ligand, also
displayed high catalytic activity at 80 °C (entry 2). These
results encouraged us to examine chiral diene ligands to achieve
the high enantioselectivity in the present reaction. Recently, we
yield
ee
entry
Ir catalyst
[IrCl(coe)2]2/
(R)-DTBM-segphos
solvent
NMP
(%)
(%)
b
1
91
7
2
3
4
5
6
7
8
9
[IrCl(cod)]2
NMP
92
92
92
83
99
98
0
−
40
[IrCl((S,S)-Me-tfb*)]2
[IrCl((S,S)-Ph-tfb*)]2
[IrCl((S,S)-Fc-tfb*)]2
[IrCl((S,S)-Me-tfb*)]2
[IrCl((S,S)-Me-tfb*)]2
[IrCl((S,S)-Me-tfb*)]2
[IrCl((S,S)-Me-tfb*)]2
NMP
NMP
1
NMP
25
35
41
−
TMU
DMA
toluene
1,4-dioxane
0
−
a
Reaction conditions: Amide 1a (0.10 mmol) and Ir catalyst (5 mol %
of Ir) in solvent (0.40 mL) at 80 °C for 20 h. Isolated yields are shown.
The ee was determined by chiral HPLC analysis. At 100 °C. NMP =
N-methylpyrrolidone. TMU = 1,1,3,3-tetramethylurea. DMA = N,N-
b
dimethylacetamide.
have developed chiral diene ligands based on a tetrafluoro-
benzobarrelene (tfb) framework, which have been successfully
applied to Rh- and Ir-catalyzed asymmetric reactions.9 The tfb
ligand substituted with methyl groups was a promising one; the
reaction in the presence of [IrCl((S,S)-Me-tfb*)]2 gave 2a in
92% yield with 40% ee (entry 3). Other tfb ligands substituted
Received: July 6, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01954
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
with phenyl and ferrocenyl groups decreased the enantiose-
lectivity (entries 4 and 5). The reactions in other amide
solvents such as TMU and DMA proceeded to give 2a in high
yields with similar levels of ee to that obtained in the reaction in
NMP (entries 6 and 7). In contrast, no reaction occurred in
nonpolar solvents such as toluene and 1,4-dioxane (entries 8
and 9).
The enantioselectivity was further improved by modifying
the arenesulfonyl groups on the amide (Table 3). In the
a
Table 3. Effect of Substituents on Nitrogen
It is likely that the high catalytic activity in amide solvents
might be derived from the coordination ability or the weak
basicity of the amides. It was found that the reaction in
nonpolar solvents proceeded with good enantioselectivity in the
presence of an amine. Thus, the reaction in toluene in the
presence of 10 mol % of triethylamine gave 2a in 40% yield
entry
R
yield (%)
ee (%)
1
2
3
4
5
6
7
8
SO2(4-MeC6H4) (1a)
SO2(2-MeC6H4) (1b)
SO2(2-MeOC6H4) (1c)
SO2(2-EtOC6H4) (1d)
SO2(2-i-PrOC6H4) (1e)
SO2(2-CyOC6H4) (1f)
SO2Me (1g)
89 (2a)
58 (2b)
75 (2c)
95 (2d)
95 (2e)
96 (2f)
88 (2g)
60 (2h)
92 (2e)
95 (2e)
68
77
73
84
87
84
1
with 60% ee (Table 2, entry 1). The use of Hunig’s base
̈
a
Table 2. Effect of Amines
CO2t-Bu (1h)
1
b
9
1e
89
91
bc
,
10
1e
a
Reaction conditions: Amide 1 (0.10 mmol), [IrCl((S,S)-Me-tfb*)]2
(5 mol % of Ir), and A2 (10 mol %) in toluene (0.40 mL) at 80 °C for
20 h. Isolated yields are shown. The ee was determined by HPLC
b
c
analysis. At 60 °C. A2 (5 mol %).
entry
additive
yield (%)
ee (%)
1
Et3N
43
12
96
95
>99
92
89
38
92
>99
8
60
11
26
51
53
60
68
21
64
65
8
presence of amine A2, the reaction of 1b having an ortho-
toluenesulfonyl group gave 2b with 77% ee (entry 2). We
tested several ortho-alkoxybenzenesulfonyl groups, whose steric
bulkiness can be changed by the alkyl groups. The reactions of
amides 1c−f having methoxy-, ethoxy-, isopropoxy-, and
cyclohexyloxybenzenesulfonyl groups gave 2c, 2d, 2e, and 2f
with 73, 84, 87, and 84% ee, respectively (entries 3−6). In
contrast, the sterically less bulky methanesulfonyl group
significantly decreased the enantioselectivity (1% ee, entry 7).
Besides N-sulfonyl alkenyl amides, N-Boc alkenyl amide 1g also
reacted to give 2g in 60% yield, albeit with a very low ee (entry
8).10 The cyclization of 1e smoothly proceeded at 60 °C to give
2e in 92% yield with 89% ee (entry 9). The use of the same
amount of the amine (5 mol %) as the Ir catalyst improved the
enantioselectivity to 91% ee (entry 10).11
The results obtained for the iridium-catalyzed asymmetric
cyclization of N-(2-isopropoxybenzenesulfonyl)alkenyl amides
are summarized in Table 4. Several amides substituted at the 2-
position underwent the cyclization in the presence of amine A2
to give the corresponding lactams with good enantioselectivity.
The reactions of the amides 1e, 1i−l bearing aryl groups gave
the lactams 2e, 2i−l in 89−97% yield with 88−91% ee,
regardless of electronic properties of the aryl groups (entries
1−5). The reactions of alkyl-substituted amides were relatively
slow, but the cyclizations of 1m and 1n, having benzyl and n-
hexyl groups at the 2-position, gave 2m and 2n, respectively, in
good yields with high enantioselectivity (entries 6 and 7). The
reactivity of 1o and 1p, having sterically less bulky cyclic
pentamethylene and dimethyl groups, was not high even at 80
°C (entries 8 and 9), indicating that the strong Thorpe−Ingold
effect is necessary for the present cyclization.12 The amides 1q
and 1r having a benzene ring and a diene moiety also
participated in the reaction to give 2q and 2r, respectively, in
high yields (entries 10 and 11).
2
i-Pr2NEt
Me2NEt
Me2NBn
Me2Ni-Pr
A1
3
4
5
6
7
A2
8
A3
9
(R)-A4
(S)-A4
pyridine
DBU
10
11
12
13
30
0
14
−
Na2CO3
a
Reaction conditions: Amide 1a (0.10 mmol), [IrCl((S,S)-Me-tfb*)]2
(5 mol % of Ir), and additive (10 mol %) in toluene (0.40 mL) at 80
°C for 20 h. Isolated yields are shown. The ee was determined by
chiral HPLC analysis. DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene.
dramatically decreased the yield and enantioselectivity, whereas
N,N-dimethylethylamine enhanced the reactivity to give 2a in
96% yield with 26% ee (entries 2 and 3). Further screening of
amines revealed that tertiary amines bearing dimethyl groups
and a bulky alkyl group enhanced the enantioselectivity while
maintaining the high yield. The reaction in the presence of
N,N-dimethylbenzylamine and N,N-dimethylisopropylamine
gave 2a in high yields with moderate enantioselectivity (entries
4 and 5). Sterically bulkier A1 and A2, having a 5-nonyl and a
1,3-diphenylpropan-2-yl group, increased the enantioselectivity
to 60 and 68% ee, respectively (entries 6 and 7). However, a
diphenylmethyl group of A3 significantly decreased the yield
and enantioselectivity (entry 8). The enantioselectivity was not
influenced by the absolute configuration of chiral amine A4; the
reactions in the presence of (R)- and (S)-A4 gave (−)-2a with
64 and 65% ee, respectively (entries 9 and 10). Pyridine and
DBU reduced both the yield and enantioselectivity (entries 11
and 12). An inorganic base was not effective for the present
reaction (entry 13).
The present catalyst system can also be applied to the
cyclization of N-sulfonyl-N′-alkenyl urea 4 prepared from
allylamine 3, giving the corresponding 2-imidazolidinone
derivative 5 (eq 1). Although the iridium/cod complex
B
DOI: 10.1021/acs.orglett.6b01954
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 4. Substrate Scope
Scheme 1. Stereochemistry of the Addition
entry
R
yield (%)
ee (%)
b
1
Ph (1e)
96 (2e)
89 (2i)
97 (2j)
89 (2k)
91 (2l)
92 (2m)
90 (2n)
38 (2o)
25 (2p)
93 (2q)
81 (2r)
88
89
90
91
90
86
80
82
74
81
23
2
3
4
5
4-MeC6H4 (1i)
4-MeOC6H4 (1j)
4-FC6H4 (1k)
4-ClC6H4 (1l)
Bn (1m)
c
6
d
7
n-hexyl (1n)
−(CH2)5− (1o)
Me (1p)
e
8
d
Scheme 2. Plausible Catalytic Cycle
9
10
11
1q
1r
a
Reaction conditions: Amide 1 (0.20 mmol), [IrCl((S,S)-Me-tfb*)]2
(5 mol % of Ir), and A2 (5 mol %) in toluene (0.80 mL) at 60 °C for
20 h. Isolated yields are shown. The ee was determined by HPLC
b
c
d
analysis. 5-Fold scale reaction (1.0 mmol of 1e). For 48 h. A2 (10
e
mol %) at 80 °C for 48 h. At 80 °C for 48 h.
exhibited a high catalytic activity, iridium/chiral diene
complexes displayed low catalytic activity and enantioselectiv-
ity.
goes reductive elimination to give 2a and regenerates catalyst
A.13 The presence of amines is crucial for the reaction, as they
increase the nucleophilicity of the amide moiety to promote the
cyclization of intermediate B.18
In summary, we have developed the asymmetric cyclization
of N-sulfonyl alkenyl amides using Ir/chiral diene complexes to
give 2-pyrrolidones with good enantioselectivity. A mechanistic
study revealed that the reaction proceeds via nucleophilic attack
of the amide to the alkene moiety.
To gain some insight into the mechanism, we focused on the
stereochemistry of the addition. The reaction involving alkene
activation13 leads to an anti-addition product, whereas a
mechanism involving oxidative addition and alkene insertion14
leads to a syn-addition product (Scheme 1a). We conducted a
deuterium-labeling experiment to determine the stereochemis-
try by using norbornene carboxamide 1s as a model substrate
(Scheme 1b). The amide 1s was treated with a large excess of
D2O to give deuterated amide 1s-d, which was directly
subjected to the catalytic conditions after concentration under
vacuum. The cyclization product was obtained in a moderate
yield, where the deuterium was incorporated at the exo-
position.15 This result indicates that the reaction proceeds via
nucleophilic attack of the amide to the alkene moiety, which is
activated by coordination to the iridium.
The catalytic cycle is postulated as illustrated in Scheme 2.
The amide 1a reacts with the amine to generate an ammonium
salt.16 Iridium catalyst A activates an alkene moiety to generate
complex B, and a nucleophilic attack of the nitrogen gave
alkyliridium(I) intermediate C.17 Protonation of intermediate C
forms alkylhydridoiridium(III) intermediate D, which under-
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01954.
Experimental procedures and compound characterization
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tnishi@kuchem.kyoto-u.ac.jp.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.6b01954
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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(10) The cyclization of 2,2-diphenylpent-4-enamide (R = H) did not
proceed.
(11) The absolute configuration of 2e was determined to be R, which
was assigned by comparison of the specific rotation of 1,5-dimethyl-
3,3-diphenyl-2-pyrrolidinone after detosylation and methylation. See
the Supporting Information for details.
(12) The cyclization of nonsubstituted N-tosyl-4-pentenamide (R =
H) did not proceed.
(13) For an example of iridium-catalyzed hydroamination via alkene
activation, see: Hesp, K. D.; Tobisch, S.; Stradiotto, M. J. Am. Chem.
Soc. 2010, 132, 413.
(14) For examples of iridium-catalyzed hydroamination via oxidative
addition of a N−H bond, see refs 4b, 5d, and 5f.
(15) The reaction in the presence of additional D2O (20 equiv) gave
2s with 70% D (exo). See the Supporting Information for details.
(16) An NMR experiment showed that 1a reacted with Et3N to give
an ammonium salt. See the Supporting Information for details.
(17) Another deuterium-labeling experiment indicates the reversi-
bility of the C−N bond formation. See the Supporting Information for
details.
(18) The enantioselectivity is influenced by the steric property of the
amine probably because the ammonium salt forms a tight ion pair in
the nonpolar solvent and remains in the vicinity of the amide moiety in
the cyclization step.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI Grant Number
JP15H03810. M.N. thanks the JSPS for Research Fellowship
for Young Scientists.
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DOI: 10.1021/acs.orglett.6b01954
Org. Lett. XXXX, XXX, XXX−XXX