Control of 6-Exo and 7-Endo cyclizations of alkynylamides using platinum and bismuth catalysts

Article abstract of DOI:10.1002/asia.201100209

The rules of cyclization: Alkynylamides are regioselectively cycloisomerized into piperazin-2-one and 1,4-diazepan-2-one derivatives by using catalytic amounts of appropriate metal catalysts. A 6-exo-dig addition proceeds in the presence of Bi(OTf)₃, while the 7-endo-dig addition occurs with PtCl₂ for the same substrate. (see scheme; Ns=o- nitrobenzenesulfonyl, Ts=p-toluenesulfonyl, Cbz=benzyloxycarbonyl, DCE=dichloroethane) Copyright

Full text of DOI:10.1002/asia.201100209

DOI: 10.1002/asia.201100209
Control of 6-Exo and 7-Endo Cyclizations of Alkynylamides using Platinum
and Bismuth Catalysts
Anne-Lise Girard, Taro Enomoto, Shinsuke Yokouchi, Chihiro Tsukano, and
Yoshiji Takemoto*[a]
Piperazin-2-one and 1,4-diazepan-2-one scaffolds are fea-
tured in biologically active natural products and pharma-
ceutical compounds,[1] such as peptidomimetics,[2] com-
pounds with potential to reverse multi-drug resistance in
cancer treatments (ardeemins),[3] antibiotics (caprazami-
cins),[4] sedatives, and tranquilizers (diazepam)[5] . These
exo-dig/7-endo-dig cyclization.[9] To our knowledge, the hy-
droamidation of terminal alkynes has never been described
for the synthesis of 1,4-diazepan-2-one and piperazin-2-one
with control of diastereoselectivity.[10] The palladium- and
gold-catalyzed cyclization of substituted alkynylamides has
been reported by our research group and several other
groups.[11,12] However, these conditions have not previously
been applied to terminal alkynes. Herein, we report the de-
velopment of highly selective syntheses of 1,4-diazepan-2-
ones or piperazin-2-ones by an intramolecular hydroamida-
tion of 2-(prop-2-ynylamino)acetamides, in which regioselec-
tivity is dependent on the Lewis acid catalyst employed.
Initially, we investigated the cyclization of N-Ns alkynyla-
mide (Ns=o-nitrobenzenesulfonyl (nosyl)) 1a with different
catalytic systems in 1,2-dichloroethane (DCE) at 708C and
at room temperature (Table 1). A catalyst screening re-
vealed that the 6-exo-dig N-cyclized product 2a and the 7-
endo-dig N-cyclized product 3a were produced in different
ratios depending on the Lewis acids used.[13] Surprisingly,
when PtCl2 was used as a catalyst,[14] 3a was obtained in
67% yield with only trace quantities of 2a generated
(Table 1, entry 1). In contrast, the reaction using PtCl4 gave
2a as the major product (entry 2). Other platinum catalytic
systems tested were not effective at promoting cyclization
(entries 3 and 4). When a cationic gold catalyst[15] was em-
ployed, 3a was also the major product but lower regioselec-
tivity was obtained compared to that of PtCl2 (entry 5). By
using AgNTf2 as a (Tf=CF3SO2) catalyst resulted in low re-
activity and selectivity, and by-products were observed
structures have therefore attracted considerable attention as
important pharmacophores in the field of drug discovery.
Diverse synthetic methods have been developed for the con-
struction of these N-heterocyclic structures, by means of lac-
tamization, the Mitsunobu reaction, reductive amination,
and Ugi reactions.[6,7] While piperazin-2-ones are homolo-
gous with 1,4-diazepan-2-ones, however, to date no reports
on the synthesis of both motifs from the same compound
have been reported. To establish a simple and unified
method to generate these constructs, we investigated the
Lewis acid catalyzed heteroannulation of 2-(prop-2-ynylami-
no)-acetamide. While there are a number of reports on the
5-exo-dig/6-endo-dig cyclization of this precursor,[8] there are
relatively few reporting the control of the competitive 6-
(entry 6). [PdACTHNUTRGNEUNG
(PhCN)2Cl2][16] did not promote conversion to
the cyclized products at room temperature and only degra-
dation products were observed upon heating (entry 7).
When metals considered to be borderline according to the
hard and soft acids and bases (HSAB) principle,[17] such as
[a] Dr. A.-L. Girard, T. Enomoto, S. Yokouchi, Dr. C. Tsukano,
Prof. Dr. Y. Takemoto
Graduate School of Pharmaceutical Sciences
Kyoto University
Yoshida, Sakyo-ku, Kyoto 606-8501 (Japan)
Fax : (+81)075-753-4569
CuI, Cu
ACHUTGTNERN(NUG OTf)2, or InACHTUNGTERN(NUGN OTf)3 were employed, the starting ma-
terial was recovered in over 80% yield (Table 1, entries 8–
[18]
10). In sharp contrast, the reaction with Bi
G
pro-
E-mail: takemoto@pharm.kyoto-u.ac.jp
ceeded slowly at room temperature, and afforded the 6-exo-
cyclized product 2a as a single product in 75% yield
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100209.
Chem. Asian J. 2011, 6, 1321 – 1324
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1321

COMMUNICATION
Table 1. Screening of Lewis acid catalysts for the hydroamidation of sub-
Table 2. Investigation of selective 6-exo-dig/7-endo-dig hydroamidation of
substrates 1b–k.[a,b]
strate 1a.[a]
Entry
Catalyst
Yield [%][b]
3a
Entry
Starting Material
R1
Conditions A[a]
Yield [%][c]
Conditions B[a]
Yield [%][c]
2a
SMR[c]
R
R2
H
1
PtCl2
PtCl4
1
48
–
67
15
trace
–
59
8
–
–
–
–
–
–
2[d]
3
1
2
3
1b pNs
1c pNs
1d pNs
2b
2c
2d
82%
80%
73%
3b
70%
62%
59%
Pt
Pt
U
99
4[d]
5[d]
6
–
–
[e]
AuP
A
E
20
12
–
–
7
17
75
81
–
27
H
H
3c
3d
[e]
7
8
9
10
11[d]
12
E
–
99
82
80
E
E
Bi
Bi
U
–
–
–
4
5
6
7
8
9
10
11
1e pNs CH2OBn
1 f pNs iBu
1g pNs iPr
H
H
H
H
H
H
2e
2 f
67%
63%
3e
3 f
62%
64%
[a] Ns=nitrobenzenesulfonyl, Bn=benzyl, Tf=trifluoromethanesulfonyl,
cod=cyclooctadiene, o-biPh=ortho-biphenyl, DCE=dichloroethane.
[b] Isolated yield. [c] SMR=starting material recovered. [d] Reaction
performed at room temperature instead of 708C. [e] Decomposition.
2g 81%[d]
3g 45%[e]
1h pNs Me
2h 89%[f]
3h
3i
3j
3k
3l
0%
73%
47%
40%
70%
1i Ts
Bn
2i
84%
1j Cbz Bn
1k pNs Bn
1l pNs Bn
2j 46%[d]
Bn 2k 41%[f]
iBu 2l 43%[f]
(entry 11). It is noteworthy that BiACTHNUTRGNENUG(OTf)3 resulted in the op-
[a] Conditions A: BiACTHNUTRGNEUNG(OTf)3 (10–30 mol%), 1,2-dichloroethane, 708C, 24 h.
Conditions B: PtCl2 (10 mol%), 1,2-dichloroethane, 708C, 24 h. [b] iBu=iso-
butyl, iPr=isopropyl, Ts=p-toluenesulfonyl, Cbz=benzyloxycarbonyl.
[c] isolated yield. [d] H2O (5 equiv) was added. [e] 6-Exo-cyclized product 2g
was obtained in 32% yield. [f] TfOH (10 mol%) was added.
posite regioselectivity to that of PtCl2. By heating at 708C,
the reaction reached completion to give piperazin-2-one 2a
in 81% yield (entry 12). The 6-exo-dig/7-endo-dig cyclization
could therefore be controlled simply by choice of catalyst.[19]
Our attention was next directed toward the exploration of
the substrate scope of the hydroamidation. 2-(Prop-2-ynyla-
s A and B). The steric bulk of the substituents on the amide
affected the yield. When secondary amides 1k and 1l were
employed, moderate to good yields were obtained (en-
tries 10 and 11, conditions A and B). It should be noted that
in a few cases of the bismuth-catalyzed cyclization, the addi-
tion of five equivalents of water or catalytic amounts of tri-
fluoromethanesulfonic acid (TfOH) gave better yields as
well as complete conversion (entries 6, 7, and 9–11, condi-
tions A).[20,21] Based on these results, both cyclizations dis-
played excellent regioselectivity and either piperazin-2-ones
or 1,4-diazepan-2-ones could be readily obtained from the
same substrates, 1a–f and 1i–l.
Proposed mechanisms for each cyclization are presented
in Scheme 1. Initially, p activation of the triple bond occurs
in both catalytic processes to produce intermediate 4. Both
6-exo-dig and 7-endo-dig ring-closing modes are favored by
Baldwinꢁs rules.[22] In the case of 6-exo cyclization, nucleo-
philic addition of the amide to the internal carbon triple
bond is thought to occur to form intermediate 5. Subsequent
protodemetalation followed by isomerization of the exocy-
clic double bond to the endocyclic position gives the ob-
served product 2. The addition of H2O or TfOH could pro-
mote protodemetalation, thereby yielding the desired prod-
ucts in better yields than in the absence of an additive.[21]
On the other hand, two possible reaction pathways can be
envisioned for 7-endo cyclization. The p-activated alkyne 4
mino)acetamides 1b–l were treated with PtCl2 or BiACTHNURTGNENG(U OTf)3
at 708C. Representative results are shown in Table 2. First
we tested various substitutions at the amide a-position (R1).
The bismuth-catalyzed reaction proved to be less sensitive
to R1 substitution, as various amino acid derivatives 1b–h
converted into piperazine-2-ones 2b–h in yields of 63 to
89% (Table 2, entries 1–7, conditions A). A benzyl group
could be employed for the protection of an alcohol in 1e
(entry 4, conditions A).
Interestingly, 6-exo cyclization was not observed in the
case of a glycine derivative (R1 =H, not shown). The plati-
num-catalyzed cyclizations of l-DOPA derivative 1b (R1 =
CH2ACHTUNGTRENNUNG(3,4-ACHTUNGTRENNUNG(MeO)2C6H3)), methyl tyrosine derivative 1c, chlor-
ophenylalanine derivative 1d, serine derivative 1e, and leu-
cine derivative 1 f (R1 =iBu) showed comparable reactivities
to the phenylalanine derivative 1a (entries 1–5, condi-
tions B). On the other hand, treatment of valine derivative
1g (R1 =iPr) with PtCl2 gave the 7-endo-cyclized product 3g
as well as significant quantities of the 6-exo-cyclized product
2g (entry 6, conditions B). Alanine derivative 1h did not cy-
clize under the standard conditions (entry 7, conditions B).
These results indicate that a bulky R1 group is required in
the platinum-catalyzed cyclization. para-Tosyl or benzyloxy-
carbonyl (Cbz) groups could be employed instead of a para-
nosyl group in both cyclizations (entries 8 and 9, condition-
1322
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 1321 – 1324

Control of 6-Exo and 7-Endo Cyclizations
Ministry of Education, Culture, Sports, Science, and Technology of Japan,
and A.-L. G. thanks the JSPS for a Postdoctoral Fellowship.
Keywords: bismuth · cyclization · heterocycles · piperazin-2-
one · platinum
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This work was supported in part by a Grant-in-Aid for Scientific Re-
search (B) (Y.T.) and “Targeted Proteins Research Program” from the
Chem. Asian J. 2011, 6, 1321 – 1324
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
1323

Y. Takemoto er al.
COMMUNICATION
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Received: February 26, 2011
Published online: May 5, 2011
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Chem. Asian J. 2011, 6, 1321 – 1324