Synthesis and thermal reactivity of pyrrolidine- and 2-pyrrolidinone-fused cyclic enediynes

Article abstract of DOI:10.1055/s-2006-950278

Various bicyclic enediynes containing pyrrolidine and pyrrolidinone moieties were synthesised. Thermal reactivity studies indicated the lowering of the onset temperature for Bergman cyclisation upon fusion of these heterocyclic systems onto the cyclic ene

Full text of DOI:10.1055/s-2006-950278

2804
LETTER
Synthesis and Thermal Reactivity of Pyrrolidine- and 2-Pyrrolidinone-Fused
Cyclic Enediynes
Pyrrolidine- and
asne-Fused
aCyclic Ene
b
diynes Roy, Amit Basak*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
E-mail: absk@chem.iitkgp.ernet.in
Received 7 June 2006
The retrosynthesis of the target molecules, as shown in
Abstract: Various bicyclic enediynes containing pyrrolidine and
pyrrolidinone moieties were synthesised. Thermal reactivity studies
indicated the lowering of the onset temperature for Bergman cycli-
sation upon fusion of these heterocyclic systems onto the cyclic
enediyne.
Scheme 1, has a common final intramolecular N-alkyla-
tion step. This was based upon the consideration of our
success in the synthesis of b-lactam-fused enediynes
involving a similar intramolecular N-alkylation between
the lactam N and propargyl halide.7
Key word: enediynes, pyrrolidines, pyrrolidinones, heterocyclic
systems, Bergman cyclisation
OH
X
N
O
Bicyclic enediynes are attractive targets1 because the
reactivity of their monocyclic counterparts towards
Bergman cyclisation (BC)2 can be perturbed by fusion of
another ring; the effect is significant if the fused ring is
small.3 Over the past few years, we have been interested
in the synthesis of nitrogen-containing cyclic enediynes,4
which have assumed significant importance in recent
years. These compounds possess a good thermal profile
under ambient conditions, especially the non-benzenoid
ones.5 Fusion of four-membered rings like b-lactams has
been reported to deactivate the parent enediyne system.6,7
This has prompted us to know whether similar effect
exists if the b-lactam ring is replaced by five-membered
heterocyclic systems like pyrrolidine or 2-pyrrolidinone
(g-lactam) rings. Thus, we have designed and subsequent-
ly synthesised enediynes 1–3. For comparison of thermal
reactivity, the enediyne 4 was synthesised (Figure 1).
Their synthesis and reactivity studies are reported herein.
N
O
H
NH
L-pyroglutamic acid
X
L
OH
N
O
H
X = H2
X = O
L-proline
Scheme 1
As a first step towards the synthesis of 1 and 2, the azides
5 and 9 were prepared from L-proline and L-pyroglutamic
acid, respectively. These were reduced with PPh3/water8
and the resulting amines were then protected as the
sulfonamides 6 and 10. The enediyne 1 was obtained as a
white solid in a single step when the sulfonamide tri-
fluoroacetate 7 was treated with enediynyl dibromide 8 in
the presence of anhydrous K2CO3 and DMF at 0.005 M
concentration (Scheme 2). This approach, however, failed
for the synthesis of enediyne 2. In this case, bisalkylation
of sulfonamide 10 yielded compound 16 because of the
reduced nucleophilicity of the amide nitrogen. The
scheme was modified and the synthesis was accomplished
as follows: a) initial N-alkylation of sulfonamide 10 with
protected bromoalcohol 11, b) conversion of the resulting
acyclic enediyne 12 into the bromide 15 in a three-step
protocol and c) final ring closure using NaH in THF under
high dilution condition (Scheme 3).
O
O
O
O
S
S
OH
N
N
NO2
NO2
N
N
O
O
N
2
4
1
3
O
S
O2N
The synthesis of the pyrrolidine-fused ten-membered ene-
diyne 3 was more challenging. In this case, the acetylenic
alcohol 19 was first prepared by the addition of TMS-
acetylide onto N-Boc prolinal 18. The alcohol 19 was then
protected as the THP ether 20 after fluoride-mediated de-
silylation. Attempted Sonogashira coupling9 of the alkyne
20 with dibromo- or diiodobenzene failed, very little cou-
pled product was obtained. When we changed the diha-
lobenzene to chloroeneyne alcohol 21 as the coupling
partner, the reaction took place smoothly at room temper-
ature to give the desired acyclic enediyne 22. This was
N
N
O2N
S
O
O
Figure 1
SYNLETT 2006, No. 17, pp 2804–2806
1
7
.1
0
.2
0
0
6
Advanced online publication: 09.10.2006
DOI: 10.1055/s-2006-950278; Art ID: D16106ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Pyrrolidine- and Pyrrolidinone-Fused Cyclic Enediynes
2805
1. Ph3P, THF, H2O
r.t., 20 h,
78%
converted to bromide 23 via mesylation, which was suc-
cessfully cyclised to the target enediyne 3 using K2CO3 in
DMF (Scheme 4). The enediyne 4 was prepared in a sin-
gle step by bis N-alkylation of ethylene diamine di-4-
nitrobenzene sulfonamide following our published proce-
dure.10 The structures of all enediynes 1–4 were con-
firmed by NMR and mass spectroscopic data.12
NHSO2Ar
N
Boc
L-proline
N3
N
Boc
2. ArSO2Cl, Et3N,
dry CH2Cl2, 0 °C,
30 min
6
5
TFA,
dry CH2Cl2
0 °C, 30 min
80%
NO2
Br
O
S
O
N
Br
O
OH
+
8
PCC
OH
TMS
MgBr
NHSO2Ar
N
H
N
Boc
N
H
H
dry CH2Cl2, 3 h
80%
N
Boc
K2CO3, DMF
70%
N
Boc
THF, 0 °C, 2 h
–
CF3CO2
7
85%
1
O
Si
N+
O–
17
19
18
Ar =
2. 3,4-DHP
PPTS
dry CH2Cl2
r.t.
1. KF, MeOH,
r.t., 8 h
Scheme 2
85%
80%
OTHP
OTHP
21
N3
O
N
H
L-Pyroglutamic acid
(PPh3)4Pd
n-BuNH2,CuI
OTHP
1. MsCl, Et3N
2. LiBr, THF
N
Boc
N
Boc
9
benzene, r.t.
72%
N
Boc
75%
1. Ph3P, THF, H2O
r.t., 20 h,
78%
20
23
Br
OH
22
2. ArSO2Cl, Et3N
dry CH2Cl2, 0 °C
30 min
1. TFA, CH2Cl2
0 °C
2. K2CO3, DMF
45%
OH
OH
N
80%
Cl
NSO2Ar
21
NH
11
3
NHSO2Ar
10
O
N
H
O
8
anhyd Cs2CO3
MeCN, r.t.
anhyd
Cs2CO3
MeCN, r.t.
Scheme 4
THPO
80%
The thermal reactivity of all the enediynes was studied
using differential scanning calorimetry.11 The onset
temperatures are shown in Table 1. The data clearly
demonstrated that fusion of five-membered rings like a
pyrrolidine or pyrrolidinone reduces the onset tempera-
ture for BC. The effect is more dramatic for the pyrroli-
dine system. This result is the opposite to what has been
observed so far for cyclic enediynes fused to small rings
(for example, an epoxide or b-lactam).3,6,7
12
85%
85%
O
S
O
Ar
O
N
N
H
H
PPTS, EtOH
50 °C
N
O
N
16
75%
Ar
O
S
i) MsCl
ii) Et3N
85%
O
Table 1 Thermal Reactivity of Enediynes 1–4 by DSC
NSO2Ar
O
NSO2Ar
N
H
O
N
H
LiBr,
Enediyne
Onset temp [T1, °C]
DT = T1[4] – T1 [1, 2, 3]
dry THF
r.t., 10 h
Br
RO
1
2
3
4
159
220
62
103
41
13
R = H
14
R = Ms
70%
200
–
15
262
NSO2Ar
NaH
anhyd THF
0 °C, 20 min
Br
N
O
In conclusion, we have developed synthetic routes to
pyrrolidine or pyrrolidone fused cyclic enediynes via
intramolecular N-alkylation strategy. The role of the five-
membered heterocyclic rings in reducing the onset tem-
perature for BC has also been successfully demonstrated.
65%
OTHP
11
2
Scheme 3
Synlett 2006, No. 17, 2804–2806 © Thieme Stuttgart · New York

2806
B. Roy, A. Basak
LETTER
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Acknowledgment
Author A.B. thanks DST, Government of India for a research grant.
B.R. is grateful to CSIR, Government of India for a Research
Fellowship.
References and Notes
(12) Spectroscopic Data: All new compounds were characterised
by spectroscopic and analytical data. Compound 1: 1H
NMR: d = 8.23 (2 H, dd, Jo,m = 6.9, 1.9 Hz), 8.00 (2 H, dd,
Jo,m = 6.9, 1.9 Hz), 7.32–7.07 (4 H, m), 4.68, 4.19 (2 H, ABq,
J = 18.8 Hz), 3.78, 3.52 (2 H, ABq, J = 16.6 Hz), 3.49–3.17
(5 H, m), 2.04–1.85 (4 H, m). 13C NMR: d = 150.0, 143.5,
130.5, 129.8, 128.8, 128.7, 127.9, 126.9, 124.7, 123.9, 90.5,
87.2, 84.0, 82.4, 59.2, 56.0, 50.2, 45.1, 28.2, 23.9. MS
(ES+): m/z = 436 [M + H+]. Compound 2: 1H NMR: d = 8.31
(2 H, dd, Jo,m = 7.0, 2.0 Hz), 7.98 (2 H, dd, Jo,m = 7.0, 2.0
Hz), 4.62 (2 H, dd, J = 18.6, 6.0 Hz), 4.33 (1 H, m), 4.21 (2
H, dd, J = 18.6,12 Hz), 3.79 (1 H, dd, J = 12.0, 3.4 Hz), 3.44
(1 H, t, J = 2.0 Hz), 2.65–2.37 (2 H, m), 2.27–2.15 (2 H, m).
13C NMR: d = 174.7, 150.3, 143.4, 130.6, 130.2, 128.9,
128.7, 128.4, 125.9, 124.6, 124.4, 87.2, 86.5, 84.9, 83.7,
54.8, 48.0, 38.0, 32.6, 29.4, 22.1. MS (ES+): m/z = 450 [M+
H+], 263 [M+ – SO2Ar]. Compound 3: d = 6.43 (1 H, d,
J = 10.8 Hz), 5.88–5.79 (2 H, m), 5.28 (1 H, d, J = 15.6 Hz),
4.51–4.42 (2 H, m), 4.12–4.04 (2 H, m), 3.69–3.41 (2 H, m),
2.25–2.14 (1 H, m), 1.97–1.88 (3 H, m). 13C NMR: d =
121.7, 120.8, 94.7, 93.0, 86.6, 83.4, 67.1, 65.0, 55.5, 54.7,
49.0, 32.0, 30.6, 23.7. MS (ES+): m/z = 170 [M – OH].
Compound 4: 1H NMR (200 MHz, CDCl3): d = 8.41 (2 H,
dd, J = 8.8 Hz), 8.07 (2 H, dd, J = 8.8 Hz), 7.28 (H, m), 4.28
(2 H, s), 3.66 (2 H, s). 1H NMR (200 MHz, DMSO-d6): d =
8.39 (2 H, d), 8.13 (2 H, dd, J = 8.8 Hz), 7.32 (2 H, m), 4.40
(2 H, s), 3.53 (2 H, s). 13C NMR (50 MHz, CDCl3): d =
150.3, 142.5, 130.7, 128.7, 124.7, 124.6, 85.7, 84.7, 46.3,
40.0. 13C NMR (50 MHz, DMSO-d6): d = 150.29, 142.4,
130.5, 129.2, 129.1, 124.9, 104.5, 86.7, 84.9, 45.7. MS
(ES+): m/z = 598 [M+ + H2O], 581 [M + H+], 394 [M+ –
SO2Ar].
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Synlett 2006, No. 17, 2804–2806 © Thieme Stuttgart · New York