Aza-Diels-Alder reactions and synthetic applications of thio-substituted 1,3-dienes with arylsulfonyl isocyanates

Article abstract of DOI:10.1016/S0040-4039(00)01447-7

The first aza-Diels-Alder reactions of arylsulfonyl isocyanates with thio-substituted 1,3-dienes via the 3-sulfolene precursors 1 gave the cyclized products 3 with complete control of regio- and chemoselectivity. The cyclized products 3a and 4 underwent further interesting reactions with nucleophiles and bases to give useful heterocyclic compounds. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01447-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8323–8326
Aza-Diels–Alder reactions and synthetic applications of
thio-substituted 1,3-dienes with arylsulfonyl isocyanates
Shang-Shing P. Chou* and Chia-Cheng Hung
Department of Chemistry, Fu Jen Catholic University, Taipei 242, Taiwan, ROC
Received 28 June 2000; revised 21 August 2000; accepted 25 August 2000
Abstract
The first aza-Diels–Alder reactions of arylsulfonyl isocyanates with thio-substituted 1,3-dienes via the
3-sulfolene precursors 1 gave the cyclized products 3 with complete control of regio- and chemoselectivity.
The cyclized products 3a and 4 underwent further interesting reactions with nucleophiles and bases to give
useful heterocyclic compounds. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: aza-Diels–Alder reactions; 1,3-dienes; arylsulfonyl isocyanate.
Reactions of dienes with compounds containing CꢀN double bonds to give six-membered
aza-heterocycles have opened up a wide variety of opportunities for organic synthesis, in
particular for the construction of alkaloids and other natural products.1 In general, the use of
strongly electron-deficient imines is a prerequisite. This can sometimes be accomplished by the
attachment of an acyl2 or a sulfonyl group3 to the nitrogen. Although arylsulfonyl isocyanates
have an electron-deficient CꢀN moiety, their aza-Diels–Alder reactions with dienes were not
viable because the [2+2] cycloaddition or electrophilic substitution predominates.4 In this paper
we describe the first aza-Diels–Alder reactions of arylsulfonyl isocyanates with thio-substituted
1,3-butadienes to give the cyclized products with complete control of regio- and chemoselectiv-
ity. The cyclized products could undergo further interesting reactions with nucleophiles and
bases.
It is well established that 3-sulfolenes are useful precursors to 1,3-dienes.5 We have used this
method to synthesize many sulfur-substituted dienes.6 Herein we report that thio-substituted
3-sulfolenes 17 can undergo in situ thermal desulfonylation and subsequent cycloaddition with
arylsulfonyl isocyanates to give the cyclized products 2 and 3. The results are summarized in
Table 1.
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01447-7

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Table 1
Aza-Diels–Alder reactions of 3-sulfolenes 1 with arylsulfonyl isocyanates
Entry
1
R3
Conditiona
Yield (%)
1b,c
2b
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1c
Ts (5 equiv.)
Ts (3 equiv.)
Ts (3 equiv.)
Ts (5 equiv.)
PhSO2 (5 equiv.)
PhSO2 (5 equiv.)
PhSO2 (5 equiv.)
p-ClPhSO2 (5 equiv.)
Ts (5 equiv.)
Ts (3 equiv.)
Ts (3 equiv.)
Ts (3 equiv.)
Ts (5 equiv.)
PhSO2 (5 equiv.)
p-ClPhSO2 (5 equiv.)
Ts (5 equiv.)
110°C, 4.5 h
110°C, 4.5 h
110°C, 4.5 h
110°C, 4.5 h
110°C, 4 h
110°C, 4.5 h
110°C, 4.5 h
110°C, 4 h
130°C, 8 h
130°C, 8 h
150°C, 5 h
130°C, 12 h
130°C, 8 h
130°C, 8 h
130°C, 8 h
110°C, 4.5 h
2a (51), 3a (6)
3a (71)
3a (46)
3a (17)
3b (30)
3b (23)
3b (50)
3c (38)
2b (21), 3d (34)
3d (60)
3d (42)
3d (55)
3d (72)
3e (73)
3f (47)
3g (62)
3
4b,d
5
6b,d
7b
8
9b,c
10
11
12
13
14
15
16
a Unless noted otherwise, a mixture of the 3-sulfolene 1, the isocyanate and a catalytic amount of hydroquinone
(HQ) was heated at 110°C in toluene under nitrogen. If a higher temperature was needed, then a sealed tube was used.
After workup the crude product was purified by silica gel column chromatography using hexane/EtOAc/Et3N as
eluent.
b One equivalent of anhydrous NaHCO3 was also added.
c Triethylamine was not included in the eluent of the silica gel chromatography.
d THF was used as the solvent.
The cycloaddition of thio-substituted 3-sulfolene 1a with p-toulenesulfonyl isocyanate (PTSI)
could be carried out in refluxing toluene to give the cyclized product 2a and a small amount of
the double bond-isomerized product 3a (entry 1). Under this condition the diene was generated
in situ from desulfonylation of the 3-sulfolene 1a. In this reaction one equivalent of sodium
bicarbonate was present to remove the sulfur dioxide generated, and a catalytic amount of
1
hydroquinone (HQ) was used to prevent polymerization of the diene. Since the H NMR
spectrum of the crude product did not show the presence of 3a, its formation probably resulted
from the isomerization of 2a during silica gel chromatography. Indeed, when 10% of triethyl-
amine was included in the eluent of chromatography, complete isomerization to product 3a was
achieved (entry 2). If the cycloaddition was carried out in the absence of NaHCO3, only product
1
3a was obtained (entry 3), no trace of 2a being detected from the H NMR spectrum of the
crude product. Apparently, the sulfur dioxide generated from the reaction caused the isomeriza-
tion of 2a to 3a. Thus, both acid and base catalyzed the isomerization of 2 to 3. The
cycloaddition of 1a also proceeded with other arylsulfonyl isocyanates (entries 5–8).

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Polar solvents cannot be used for the cycloaddition because they react with the isocyanates.
It was found that toluene was a better solvent than THF (compare entries 2 with 4, and 6 with
7). Furthermore, the addition of sodium bicarbonate increased the yield (compare entries 2 with
3, and 5 with 7). The cycloaddition reactions of the bis(phenylthio)-substituted 3-sulfolene 1b with
arylsulfonyl isocyanates were similar to those of 1a, but required higher temperatures (entries
9–15). The reaction time and equivalents of arylsulfonyl isocyantes had some effects on the yields
of reaction. Under similar conditions, 3-sulfolene 1c5a reacted with PTSI to give the cyclized
product 3g in 62% yield (entry 16). Although the thio-substituted 1,3-dienes are unsymmetrical,
their aza-Diels–Alder reactions with arylsulfonyl isocyanates gave only one regioisomer, which
was shown by spectroscopic methods to be the ‘para’ adduct (with respect to the nitrogen).8 The
regiochemistry is consistent with that predicted either by a concerted or stepwise mechanism.1d
Under similar conditions, isoprene (5–10 equiv.) reacted with PTSI to give the cyclized product
3 only in 5–7% yield. Obviously, the thio-substituent enhances the reactivity of the diene toward
PTSI. We have also examined similar reactions with many other monosubstituted-dienes such as
2-trimethylsilyloxy-1,3-butadiene, 2-phenylsulfinyl-1,3-butadiene, 2-phenylsulfonyl-1,3-butadiene,
or disubstituted dienes derived from 1 (R1=NHAc, SOPh, SO2Ph, R2=H), but they all failed
to undergo aza-Diels–Alder reactions with PTSI. It appears that the thio-substituent on the diene
strikes a balance of reactivity with PTSI: an electron-donating group is needed to increase the
reactivity of cycloaddition, but too strong an electron-donating group leads to other reaction
pathways.
The cyclized product 3a contains an interesting structure of an a,b-unsaturated lactam, which
also bears a phenylthio leaving group at the b-position. The sulfide group in 3a could easily be
oxidized to the sulfone 4 by mCPBA (2.5 equiv.) in dichloromethane at room temperature in 98%
yield. The lactams 3a and 4 could react with various nucleophiles and bases to give addition,
substitution, or elimination products. The results are summarized in Table 2.
Table 2
Reactions of lactams 3a and 4 with nucleophiles and bases
Entry
3a or 4
Nu−/B−
Condition
Yield (%)
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3a
3a
4
4
4
4
4
Allyl-MgBr (4 equiv.)
MeLi (4 equiv.)
BuLi (4 equiv.)
THF, rt, 70 min
THF, rt, 1 h
THF, rt, 1 h
5a (91)
5b (66)
5c (60)
5d (23)
6a (90)
6b (91)
5e (88)
6c (76)
6d (93)
6e (63)
7 (89)
LiAlH4 (2.5 equiv.)
THF, rt, 5 h
MeLi (4 equiv.), CuI (4 equiv.)
BuLi (4 equiv.), CuI (4 equiv.)
Allyl-MgBr (4 equiv.)
NaN3 (1.1 equiv.)
NaCN (1.1 equiv.)
NaCH(CO2Me)2 (2 equiv.)
KF (10 equiv.)
THF, −78°C, 3 h
THF, −78°C, 3 h
THF, rt, 1 h
DMF, 0°C, 0.5 h
DMF, 0°C, 30 min
THF, −78°C, 1h; rt, 1 h
DMF, rt, 5 h
10
11

8326
The sulfide-substituted lactam 3a reacted with Grignard reagent, organolithium reagents and
hydride reducing agents to give the double addition products 5a–d (entries 1–4). Decreasing the
amount of the nucleophile only resulted in lower yields of 5a–d. Apparently, the monoaddition
intermediate readily undergoes an elimination to form an iminium ion which reacts with a
second nucleophile. The lactam 3a reacted with organocopper reagents to give the substitution
products 6a–b (entries 5–6). Attempted reactions of 3a with weaker nucleophiles (NaN3, NaCN
or Et2NH) led only to recovered starting material. The sulfone-substituted lactam 4 also yielded
the double addition product 5e with Grignard reagent (entry 7), but gave the substitution
products 6c–e with sodium azide, sodium cyanide and dimethyl malonate anion, respectively
(entries 8–10). Thus, the phenylsulfonyl group in 4 activates the nucleophilic addition and is also
a much better leaving group than the phenylthio group in 3a. Reactions of 4 with amines or
other bases led to the elimination product 7 (entry 11), which should be useful for reacting with
various dienes and dienophiles.9 Presumably, 7 was formed from 4 via a series of double bond
isomerization followed by elimination of the sulfone group.
In summary, we have carried out the first aza-Diels–Alder reactions of arylsulfonyl iso-
cyanates with thio-substituted 1,3-dienes via the 3-sulfolene precursors 1 to give the cyclized
products 3 with complete control of regio- and chemoselectivity. The cyclized products 3a and
4 underwent further interesting reactions with nucleophiles and bases to give useful heterocyclic
compounds.
Acknowledgements
Financial support of this work by the National Science Council of the Republic of China
(NSC 88-2113-M-030-005) is gratefully acknowledged.
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1
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