Intramolecular hydroamination of alkynic sulfonamides catalyzed by a gold-triethynylphosphine complex: Construction of azepine frameworks by 7-exo-dig cyclization

Article abstract of DOI:10.3762/bjoc.7.106

The gold-catalyzed, seven-membered ring forming, intramolecular hydroamination of alkynic sulfonamides has been investigated. The protocol, with a semihollow-shaped triethynylphosphine as a ligand for gold, allowed the synthesis of a variety of azepine de

Full text of DOI:10.3762/bjoc.7.106

Intramolecular hydroamination of alkynic sulfon-
amides catalyzed by a gold–triethynylphosphine
complex: Construction of azepine frameworks by
7-exo-dig cyclization
Hideto Ito, Tomoya Harada, Hirohisa Ohmiya and Masaya Sawamura*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 951–959.
Department of Chemistry, Faculty of Science, Hokkaido University,
Sapporo 060-0810, Japan
doi:10.3762/bjoc.7.106
Received: 23 April 2011
Accepted: 17 June 2011
Published: 08 July 2011
Email:
Masaya Sawamura* - sawamura@sci.hokudai.ac.jp
* Corresponding author
This article is part of the Thematic Series "Gold catalysis for organic
synthesis".
Keywords:
azepine; cyclization; gold catalyst; hydroamination;
triethynylphosphine
Guest Editor: F. D. Toste
© 2011 Ito et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The gold-catalyzed, seven-membered ring forming, intramolecular hydroamination of alkynic sulfonamides has been investigated.
The protocol, with a semihollow-shaped triethynylphosphine as a ligand for gold, allowed the synthesis of a variety of azepine
derivatives, which are difficult to access by other methods. Both alkynic sulfoamides with a flexible linear chain and the benzene-
fused substrates underwent 7-exo-dig cyclization to afford the nitrogen-containing heterocyclic seven-membered rings, such as
tetrahydroazepine and dihydrobenzazepine, in good yields.
Introduction
Nitrogen-containing heterocyclic seven-membered rings are straightforward and efficient [17,18]. Specifically, gold-
found in many biologically active natural products and pharma- catalyzed intramolecular hydroaminations of alkynes, alkenes
ceuticals, such as (−)-tuberosutemonin (1) [1-6], related and allenes show remarkable efficiency [19-28]. Unfortunately,
Stemona alkaloids [7], Cephalotaxus alkaloid (−)-cephalotaxine however, the application of these methodologies to the syn-
(2) [8-12], and SB-462795 (3) (Figure 1) [13-16]. Among a thesis of the N-heterocyclic seven-membered ring compounds is
number of different approaches for the construction of N-hete- hampered by the low efficiency of seven-membered ring forma-
rocyclic compounds, metal-catalyzed intramolecular hydro- tions. Despite extensive studies on the gold-catalyzed intramol-
amination of unactivated C–C multiple bonds is particularly ecular hydroamination of alkynes [19-51], seven-membered
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Beilstein J. Org. Chem. 2011, 7, 951–959.
ring formation is rare and is limited to the cases where the sub-
strate is preorganized for cyclization: The substrates must have
geminal disubstitution or ring fusion within a linker chain
connecting the attacking nitrogen atom and the alkyne moiety.
It should be noted, however, that 7-“endo”-dig cyclizations of
(o-alkynyl)phenylacetamides and a diynamide were achieved
with gold and palladium complexes [39,46,52,53], and the zinc-
catalyzed 7-exo-dig cyclization was reported specifically for a
propargyl ether substrate [54].
Figure 2: Semihollow-shaped triethynylphosphine L1.
sulfonamides. This article describes the results of the optimiz-
ation of reaction conditions, exploration of substrate scope, and
some mechanistic experiments.
Results and Discussion
Reaction conditions
The reaction conditions were optimized for the cyclization of
N-(6-heptyn-1-yl)-p-toluenesulfonamide (4a) (Table 1). The
triethynylphosphine–gold complex [Au(NTf2)(L1)] (0.5 mol %)
catalyzed the cyclization of 4a (0.2 mmol) efficiently in CH2Cl2
(1.0 mL) at 25 °C (100% convn. of 4a) to afford 4,5,6,7-tetra-
Figure 1: Azepine frameworks found in natural products and pharma-
ceuticals.
Previously, we reported that semihollow-shaped triethyl- hydroazepine derivative 5a with 18 h reaction time in 82%
nylphosphine L1 (Figure 2) exerted marked acceleration effects isolated yield (Table 1, entry 1). This reaction seemed to
in the gold(I)-catalyzed Conia-ene reactions of acetylenic keto proceed through 7-exo-dig cyclization, but an exomethylene-
esters and enyne cycloisomerizations. The new catalytic system type cyclic product 6a, which is a possible product of the 7-exo-
has expanded the scope of the reactions to six- and seven- dig cyclization [57], was not observed. The reaction under four-
membered ring formations, which had been difficult with the times-diluted conditions did not proceed to full conversion in
conventional catalytic systems [55]. Furthermore, we found that the same reaction time (Table 1, entry 2). The reaction time was
L1–gold(I) complex efficiently catalyzed the cyclization of shortened to 9 h by heating at 80 °C, but this caused a slight
internal alkyne substrates, which had also been difficult due to decrease in the isolated yield of 5a (79%) (Table 1, entry 3).
the steric repulsion between a nucleophilic center and a terminal
substituent on the alkyne moiety [56]. We proposed that the Among other solvents examined, toluene gave a result compa-
cavity in the ligand forces the nucleophilic center closer to the rable with CH2Cl2 (Table 1, entries 1 and 4). On the other hand,
gold-bound alkyne, resulting in the entropy-based rate enhance- polar and potentially coordinating solvents such as THF and
ment. Recently, we further developed the gold(I)-catalyzed MeCN were not effective in this reaction (Table 1, entries 5 and
7-exo-dig cyclization of acetylenic silyl enol ethers with 6). The effect of the counter anion of the cationic gold complex
L1 [57].
is shown in Table 1, entries 1 and 7–9. While OTf− was as
effective as NTf2− (Table 1, entry 7), SbF6− and BF4− inhibited
In this context, we expected that the use of L1 as a ligand in the the reaction completely (Table 1, entries 8 and 9).
gold-catalyzed intramolecular hydroamination of alkynes would
enable the construction of nitrogen-containing heterocyclic The ligand effect is evaluated in Table 1, entries 1 and 10–14.
seven-membered rings, and we applied the triethynylphos- The reaction proceeded slowly, even with a conventional phos-
phine–gold(I) catalytic systems to the synthesis of azepine phine ligand PPh3, such that the starting material was not fully
derivatives through intramolecular hydroamination of alkynic consumed even after 24 h and the yield was as low as 26% (Ta-
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Beilstein J. Org. Chem. 2011, 7, 951–959.
Table 1: Optimization of reaction conditions for the gold-catalyzed intramolecular hydroamination of 4a.
entry
Au cat. (mol %)
solvent (mL)
temp. (°C)
time (h)
convn. (%)a yield orf 5 (%)a,b
1
[Au(NTf2)(L1)] (0.5)
[Au(NTf2)(L1)] (0.5)
[Au(NTf2)(L1)] (0.5)
[Au(NTf2)(L1)] (0.5)
[Au(NTf2)(L1)] (0.5)
[Au(NTf2)(L1)] (0.5)
[Au(OTf)(L1)] (0.5)
[Au(SbF6)(L1)] (0.5)
[Au(BF4)(L1)] (0.5)
[Au(NTf2)(PPh3)] (0.5)
[Au(NTf2)(PPh3)] (5.0)
CH2Cl2 (1.0)
CH2Cl2 (4.0)
DCE (1.0)
25
25
80
25
25
25
25
25
25
25
25
25
25
25
18
18
9
100
87
100
98
29
0
90 (82)
85
2
3
83 (79)
97
4
toluene (1.0)
THF (1.0)
18
18
18
18
18
18
24
18
18
18
18
5
24
6
MeCN (1.0)
CH2Cl2 (1.0)
CH2Cl2 (1.0)
CH2Cl2 (1.0)
CH2Cl2 (1.0)
CH2Cl2 (1.0)
n. d.
90 (80)
n. d.
n. d.
22 (26)
66 (64)
39
7
100
14
7
8
9
10
11
12
13
14
29
100
54
41
53
[Au(NTf2){P(OPh)3}] (0.5) CH2Cl2 (1.0)
[Au(NTf2)(X-Phos)] (0.5)
[Au(NTf2)(IPr)] (0.5)
CH2Cl2 (1.0)
CH2Cl2 (1.0)
41
41
aDetermined by 1H NMR. bIsolated yield in parentheses.
ble 1, entry 10). Increasing the catalyst loading of improvement of the reaction kinetics and not the thermal
[Au(NTf2)(PPh3)] to 5.0 mol % caused full consumption of 4a, stability of the catalyst. Although it was reported that
but the cyclization product was obtained only in 64% yield (Ta- Au(NTf2)(IPr) was somewhat unstable in the gold-catalyzed
ble 1, entry 11). The low yield relative to the conversion value intermolecular hydroamination of alkyne under heating condi-
is probably due to oligomerization and/or product decomposi- tions [59], the deactivation of the gold catalyst with IPr and
tion as suggested by TLC and 1H NMR analysis of the crude X-Phos was not significant under the present reaction condi-
mixture. A phosphite ligand P(OPh)3, which is comparable to tions: The reactions with X-Phos and IPr ligands reached 100%
triethynylphosphine L1 in electron-donor ability [58], was and 84% conversions after 58 h, respectively (see Supporting
slightly more effective than PPh3, but was far less effective than Information File 1 for reaction profiles with longer reaction
L1 (Table 1, entry 12). Bulky and strongly electron-donating times).
ligands such as X-Phos and IPr were as effective as the elec-
tron-deficient ligand P(OPh)3 (Table 1, entries 13 and 14). Effect of N-substituents
Accordingly, it is concluded that the acceleration effect by L1 is While alkynic o-nitrotoluenesulfonamide 4b did not react at all
not due to an electronic effect rather a steric effect.
with 0.5 mol % of [Au(NTf2)(L1)] at room temperature
(Table 2, entry 1), this substrate underwent 7-exo-dig cycliz-
The time–conversion profiles shown in Figure 3 clearly indi- ation upon increasing catalyst loading to 2.5 mol % and heating
cate that the high catalytic efficiency with L1 is due to the at 80 °C, giving N-nosylazepine derivative 5b in 76% isolated
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Beilstein J. Org. Chem. 2011, 7, 951–959.
yield (Table 2, entry 2). N-Benzyloxycarbonyl (Cbz) and
N-acetylazepine derivatives 5c and 5d were obtained in low
yields through the cyclization of substrates 4c and 4d (Table 2,
entries 3 and 4). On the other hand, the reactions of the
substrates bearing N-tert-butoxycarbonyl (Boc) or N-p-
methoxybenzyl (PMB) groups (4e,f) did not give the desired
products at all (Table 2, entries 5 and 6). It seems that the re-
activity of the substrates is affected by the balance between
nucleophilicity of the nitrogen atom and acidity of the N–H
bond as well as a steric factor.
Effect of substituents in acyclic linkers
Next, we explored the substrate scope by introducing one or
two substituents in the acyclic linker chain of the alkynic
N-tosylsulfonamide 4a (Table 3). The introduction of the
substituents at the α or β positions relative to the alkyne moiety
caused a significant decrease in the reactivity, but the cycliz-
ation of the substituted alkynic sulfonamide 4g–l proceeded
smoothly, with 2.5–5.0 mol % catalyst loading at 80 °C, into
full substrate conversion. Specifically, the substrate bearing an
α-Me group (4g) derived from L-alanine was quantitatively
converted into 2,7-dimethyltetrahydroazepine 5g with
2.5 mol % of [Au(NTf2)(L1)] (99% isolated yield, Table 3,
entry 1). Although the substitution with bulkier iPr or Bn
Figure 3: Time–conversion profiles for the gold-catalyzed cyclization
of 4a with L1, X-Phos and IPr ligands.
Table 2: Effect of N-substitutents.
entry
R
Au cat. (mol %)
solvent
temp. (°C)
time (h)
convn. (%)a yield of 5 (%)a
1
2
3
4
5
6
Ns (4b)
Ns (4b)
Cbz (4c)
Ac (4d)
Boc (4e)
PMB (4f)
0.5
2.5
2.5
2.5
2.5
2.5
CH2Cl2
DCE
DCE
DCE
DCE
DCE
25
80
80
80
80
80
18
18
24
24
24
24
0
100
97
63
17
0
n. d.
76b
33
18
n. d.
n. d.
aDetermined by 1H NMR. bIsolated yield.
954

Beilstein J. Org. Chem. 2011, 7, 951–959.
groups at the α-position in 4h and 4i resulted in even lower Although the starting material was fully consumed after 3 h or
reactivities, the corresponding cyclization products 5h and 5i 6 h, using the respective catalysts, L1 was superior to IPr with
were obtained in high or good yields (Table 3, entries 2 and 3). respect to both reaction time and product yield. The reaction of
The substrates (4j–l) with geminal disubstitution at the β-carbon N-tosylbenzamide 4n with L1 afforded the benzene-fused
also participated in the 7-exo-dig cyclization in good yields (Ta- ε-caprolactam 6n within an exomethylene structure in 97%
ble 3, entries 4–6). Among the cyclization products (5a–l) yield in an isomerically pure form (vide infra for discussion)
described above, only the β,β-diphenyl-substituted sulfonamide (Table 4, entry 3). Sulfonamide 4o, with a cyclohexane-fused
5k was contaminated with a small amount of exomethylene pro- linker, also participated in the cyclization to form
duct 6k (Table 3, entry 5).
azabicylo[5.4.0]decene 5o in 76% yield along with a small
amount of exomethylene isomer 6o (5o/6o 98:2, Table 4,
It should be noted that the geminal disubstitution in 4j–l caused entry 4).
a drastic decrease in the ease of the cyclization, which necessi-
tated much more harsh reaction conditions (5 mol % Au, 80 °C, Effect of ring sizes
4–12 h, Table 3, entries 4–6) than those for the reaction of the We also evaluated the triethynylphosphine L1, X-Phos, and IPr
parent substrate 4a (0.5 mol % Au, 25 °C, 18 h, Table 1, entry for an acceleration effect in the six-membered, ring forming,
1). This means that the Thorpe–Ingold effect did not operate in gold-catalyzed hydroamination of N-(5-hexyn-1-yl)-p-toluene-
the present case and that the substituents caused steric repul- sulfonamide 7. As expected from entropy considerations, the
sion hindering the cyclization.
six-membered ring formations of 7 with these ligands were gen-
erally much faster than the seven-membered ring formations of
4: The reaction with 0.5 mol % catalyst loading at room
Construction of bicyclic frameworks
Next, we applied the gold(I)–triethynylphosphine L1 complex temperature completed within 1 h irrespective of the ligand
to the construction of bicyclic frameworks such as benzazepine used. When the catalyst loading was reduced to 0.1 mol %,
(Table 4). The cyclization of o-alkynyl benzylsulfonamide 4m however, the superiority of L1 to X-Phos and IPr became
proceeded with both [Au(NTf2)(L1)] and [Au(NTf2)(IPr)] to significant, as shown in Table 5. The reaction with L1 at room
give a benzazepine derivative 5m (Table 4, entries 1 and 2). temperature afforded the six-membered ring product 8 in 91%
Table 3: Cyclization of alkynic sulfonamides with an acyclic linker.a
entry
substrate
Au cat. (mol %)
time (h) convn. (%)b product
yield (%)c
1
2
3
R = Me (4g)
R = iPr (4h)
R = Bn (4i)
2.5
5.0
5.0
8
12
12
100
100
100
R = Me (5g)
R = iPr (5h)
R = Bn (5i)
99
88
71
4
5
6
R = Me (4j)
5.0
5.0
5.0
4
4
100
100
100
R = Me (5j)
77
69d
66
R = Ph (4k)
R = Ph (5k)
R = –(CH2)5– (4l)
12
R = –(CH2)5– (5l)
aReaction conditions: 4, 0.1 mmol; [Au(NTf2)(L1)], 2.5 or 5 mol %; DCE, 1.0 mL; 80 °C.
bDetermined by 1H NMR.
cIsolated yield.
dMixture of 5k and 6k in 92:8 ratio.
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Beilstein J. Org. Chem. 2011, 7, 951–959.
Table 4: Cyclization of alkynic sulfonamide with a ring-fused linker.a
entry
substrate
Au cat. (mol %)
time (h)
convn. (%)b
product
yield (%)c
1
2
[Au(NTf2)(L1)] (2.5)
3
6
100
100
86
58
4m
4m
5m
5m
[Au(NTf2)(IPr)] (2.5)
3
4
[Au(NTf2)(L1)] (5.0)
[Au(NTf2)(L1)] (2.5)
3
100
100
97
6n
5o
4n
4o
17
76d
aReaction conditions: 4, 0.1 mmol; DCE, 1.0 mL; 80 °C.
bDetermined by 1H NMR.
cIsolated yield.
dMixture of 5o and 6o in 98:2 ratio.
isolated yield after 2 h (Table 1, entry 1). On the other hand, the
reaction with X-Phos did not reach full conversion (76%
convn.) even after 12 h and gave 8 in only 70% yield (Table 5,
entry 2). The use of IPr ligand resulted in even lower conver-
sion (68%) and isolated yield (58%) (Table 5, entry 3).
Table 5: 6-exo-dig cyclization of sulfonamide 7.
The triethynylphosphine ligand L1 was also evaluated for the
eight-membered ring formation of sulfonamide 9, which is
much more challenging than the seven-membered ring forma-
tion of 4. The reaction required 5 mol % catalyst loading under
heating conditions (80 °C) in 1,2-dichloroethane for a reason-
able conversion rate to afforded an eight-membered ring
azocine derivative 10 in 15% isolated yield (Scheme 1). It
should be noted that the reaction produced significant amounts
of unidentified oligomeric side products.
time
(h)
convn.
(%)a
yield of 8
entry
Ligand
(%)a,b
1
2
3
L1
2
12
12
100
76
100 (91)
76 (70)
67 (58)
X-Phos
IPr
68
aDetermined by 1H NMR. bIsolated yield in the parentheses.
Alkene isomerization
We carried out alkene isomerization experiments to clarify how
tetrahydroazepines 5 formed via the 7-exo-dig cyclization of 4.
One possible reaction pathway is the alkene isomerization of an
exomethylene product 6. To test this possibility, we synthe-
sized 6a through another route (see Supporting Information
File 1) and subjected it to the standard reaction conditions of the
gold–triethynylphosphine-catalyzed cyclization of alkynic
sulfonamide with or without N-tosyl aniline 7 as an external
Scheme 1: 8-exo-dig cyclization of sulfonamide 9.
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Beilstein J. Org. Chem. 2011, 7, 951–959.
major pathway to 5. Instead, a possible reaction pathway from
4a to 5a is illustrated in Figure 4. First, the cationic gold center
coordinates with 4a to form the gold–alkyne complex A.
Intramolecular nucleophilic attack of the nitrogen atom affords
the 7-exo-dig cyclization product B with an exocyclic C–C
double bond. The protonated N-sulfonylenamide B tautomer-
izes to iminium ion C through 1,3-proton shift, or through an
alternative pathway via a gold(I)–carben intermediate (D).
Then, re-tautomerization affords the protonated N-sulfonylen-
amide E with an endocyclic C–C double bond. Finally,
protodemetalation of E give the N-sulfonylenamide 5a, which is
thermodynamically more stable than 6a.
It should be noted that the reaction of the N-tosylbenzamide 4n
afforded exceptionally the exomethylene isomer 6n. One
conceivable reason is that the alkene isomerisation was
prevented due to a ring strain in the seven-membered ring of 5n,
of which six out of seven atoms are sp2-hybridized.
Scheme 2: Isomerization experiments of 6a.
Conclusion
We demonstrated that the 7-exo-dig intramolecular hydroamin-
proton source (Scheme 2). Although 6a was indeed isomerized ation of ω-alkynic N-alkyl-N-sulfonamides is efficiently
into 5a to some extent in both cases, the main reaction was catalyzed by a gold(I) complex coordinated with the semi-
decomposition to give complex mixtures. The exomethylene hollow-shaped triethynylphopshine ligand L1, and that the
substrate 6a appeared to be unstable at room temperature even cyclization protocol provides a new efficient route to
in the absence of the gold-catalyst.
N-containing seven-membered ring compounds. The protocol is
applicable to the reaction of alkynic sulfonamides with an
According to these results, the formation of exomethylene com- acyclic or ring-fused linker chain with various substitution
pound 6 and subsequent alkene isomerisation should not be a patterns. Evaluation of the ligand effect in the gold catalysis
Figure 4: Possible pathway for the gold-catalyzed conversion of 4a into 5a.
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Beilstein J. Org. Chem. 2011, 7, 951–959.
with different ligands and substrates strongly suggested that the Acknowledgements
rate enhancement by the triethynylphosphine would be due to a This work was supported by Grants-in-Aid for Scientific
steric factor which enforces a nucleophilic center close to a Research on Priority Area “Chemistry of Concerto Catalysis”
gold-activated alkyne moiety.
from MEXT. H.I. thanks JSPS for a fellowship.
Experimental
Preparation of [Au(NTf2)(L1)]
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