Formation of cyclic sulfonamides via an unusual 8-endo-trig Heck olefination reaction

Article abstract of DOI:10.1016/j.tetlet.2008.10.004

The synthesis of the novel benz[c]azocines, 11a and 11b was achieved following an 8-endo-trig selective intramolecular Heck reaction. Optimisation of this reaction demonstrated that inclusion of both tetra-n-butylammonium sulfate and water was essential f

Full text of DOI:10.1016/j.tetlet.2008.10.004

Tetrahedron Letters 49 (2008) 7187–7190
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Formation of cyclic sulfonamides via an unusual 8-endo-trig
Heck olefination reaction
*
}
Johannes E. M. N. Klein, Helge Muller-Bunz, Yannick Ortin, Paul Evans
Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin, Dublin 4, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of the novel benz[c]azocines, 11a and 11b was achieved following an 8-endo-trig selective
intramolecular Heck reaction. Optimisation of this reaction demonstrated that inclusion of both tetra-
n-butylammonium sulfate and water was essential for its success. No products from the corresponding
7-exo-trig process were encountered under these conditions.
Received 3 September 2008
Revised 22 September 2008
Accepted 1 October 2008
Available online 7 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
We have recently become interested in the preparation of cyclic
sulfonamide-containing compounds1 and have employed the pal-
ladium-catalysed intramolecular Heck (Heck–Mizoroki) olefin-
ation reaction for their synthesis. More generally, it is well
appreciated that this reaction represents a useful method for the
preparation of 5- and 6-membered cyclic compounds following
5-exo-trig and 6-exo-trig cyclisation processes.2 Several literature
reports also exist describing the successful 7-exo-trig palladium-
mediated Heck-type cyclisation (i.e., the conversion of 1 to 3 and
2 to 4), a noteworthy feature of which is the formation of a quater-
nary stereogenic centre (Scheme 1).3 The motivation being that
this type of spiro-benz[c]azepine architecture is found in several
nitrogen-based natural products of biological interest. More rare
are examples of 8-endo-trig cyclisations, however, in certain in-
stances it appears possible that the corresponding 8-membered
ring-containing products may also form competitively. For exam-
ple, Rigby demonstrated that for one substrate class, 7- and 8-
endo-trig cyclisations occur in preference to their exo-counterparts
under Jeffery-type conditions (see 5 to 6, Scheme 1).4 This regio-
chemical outcome is reversed under more standard conditions.
Similarly, Gibson has shown that dehydroamino acid derived sub-
strates, in which the intermediate palladium species resulting from
exo-carbopalladation are unable to undergo b-hydride elimination,
generate reasonable to good yields of the products resulting from
endo-cyclisation.5 At first sight, these reports appear surprising
since, based on a combination of entropic and thermodynamic
O
O
O
O
endo
I
→
1
3: Pd2(dba)3, dppe,
exo
R
R
TlOAc, MeCN, 90 ºC;3a,b
R
R
7
X
2
→
N
N
4: Pd(OAc)2, PPh3,
X
'
R
R'
K2CO3, MeCN, 130 ºC3c
1: R = -OCH2O-,
X = CH2, R' = Boc;
3: 56%;
4: 67%
2: R = H, X = CO, R' = Me
NHCy
O
I
O
O
Pd(OAc)2 (0.1 equiv.),
O
n-Bu4NCl (2 equiv.),
N
8
NHCy
N
KOAc, DMF, 100 ºC4
O
5
O
6: 30%
Scheme 1. Literature examples of 7-exo and 8-endo-trig intramolecular Heck reactions.
* Corresponding author.
E-mail address: paul.evans@ucd.ie (P. Evans).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.004

7188
J. E. M. N. Klein et al. / Tetrahedron Letters 49 (2008) 7187–7190
(1) Et3N, CH2Cl2,
0 ºC to rt, 85-92%;
O2
S
R
R
SO2Cl
Br
H2N
R
R
N
+
Me
(2) NaH, MeI, DMF,
0 ºC to rt, 95-96%
Br
8
7a: R = OMe;
7b: R = H
9a: R = OMe;
9b: R = H
(1) n-BuLi, THF, -78 ºC;
(2) NH4Cl, or I2, 93-99%
O2
S
O2
cat. Pd(OAc)2,
or Pd(dba)2
S
NMe
R
NMe
R
R
O2
R
R
S
N
see Table 1
R
Me
X
12a: R = OMe, X = H;
12b: R = H, X = H;
13a: R = OMe, X = I
10a: R = OMe;
10b: R = H
11a: R = OMe;
11b: R = H
Scheme 2.
considerations, the formation of ‘medium’ ring-containing hetero-
cycles (8–10 membered) remains a synthetic challenge.6
tion of the product of bromine-hydrogen exchange 12a (entry 2)
whose structure was confirmed independently on treatment of
9a with n-BuLi followed by aqueous acidic work-up. This result
suggested that although the required oxidative addition was occur-
ring, the following cyclisation was slow, consequently enabling
‘protonation’ of the putative aryl-palladium(II) intermediate. Sup-
port for this hypothesis came by way of the X-ray crystal structure
of 9a, which indicates a large distance between the alkene and
reactive sp2-centre in the solid state (Fig. 1). Based on the work
of Jeffery8 and the indication that inclusion of tetraalkylammo-
nium salts drastically altered the regiochemical outcome of a series
of related intramolecular Heck processes4 (see Scheme 1), tetra
n-butylammonium hydrogensulfate was next investigated. Disap-
pointingly, the formation of complex mixtures of products was ob-
served again (entry 3). However, this situation was improved when
water was included. The use of solvent mixtures including water
was shown by Genêt and co-workers to lead to significant reversals
in the regiochemistry of Heck cyclisation reactions, and even the
products of 6-endo-trig cyclisation were obtained with reasonable
selectivity over their 5-exo-trig counterparts.9 Accordingly, treat-
ment of 9a in a DMF–water (9:1) mixture (entry 4) led to the for-
mation of two products which proved to be 12a and the hoped for
cyclic species 11a (ratio 25:75). Sulfonamide 11a could be obtained
in pure form by recrystallisation from a mixture of dichlorometh-
ane-pentane (ca. 1:4), and its structure was confirmed by X-ray
crystallography.10
Consequently, we decided to investigate whether an intra-
molecular Heck reaction might be useful for the synthesis of cyclic
sulfonamides containing 7- or 8-membered rings. The alkenyl sub-
strate chosen to test this sequence was the commercially available
cyclohexenylethylamine 8. Thus, sulfonamide formation was per-
formed with both 2-bromo-4,5-dimethoxybenzenesulfonyl chlo-
ride1a 7a and 2-bromobenzenesulfonyl chloride 7b. N-Alkylation
under standard conditions then afforded the corresponding
N-methyl compounds 9a and 9b (Scheme 2).
Substrate 9a was then subjected to standard Heck conditions in
the hope that a regioselective cyclisation would occur (Table 1, en-
try 1). In the event, using catalytic amounts of either Pd(OAc)2 or
Pd(dba)2, starting material 9a was completely consumed. How-
ever, although mass spectrometry confirmed the formation of a
species with the expected molecular weight, NMR spectroscopy
indicated that complex mixtures of products were formed in con-
trast to the conversion of 2 into 43c (Scheme 1) that was success-
fully reported under similar conditions. Furthermore, these
species proved to be inseparable by flash column chromatography.
It seemed likely that the mixture comprised of 8-membered ring-
containing compound 11a and the corresponding 7-membered
ring-containing compound 10a, probably as mixture of alkene
regioisomers (the isomerisation of alkenes following Heck olefin-
ation has frequently been encountered2,7). Palladium-catalysed
hydrogenation, however, failed to significantly simplify these mix-
tures. Therefore, we set out to systematically screen various alter-
native conditions in the hope that the selectivity of this reaction
might improve. Use of triethylamine as the base led to the forma-
It should be noted that this reaction proceeded most effectively
in a sealed tube in the absence of oxygen. If the amount of the
additive was increased (entry 5), then preferential formation of
the protonated species 12a was observed. Conducting the reaction
Table 1
Entry
Substrate
Conditionsa
Ratio 10:11:12
Yieldb (%)
Conversionc (%)
1
2
3
9a
9a
9a
9a
9a
9a
9a
13a
9b
K2CO3 (2 equiv), DMF (or DMSO, or MeCN), 110 °C, 24 h
Et3N (10 equiv), DMF, 110 °C, 24 h
CM
0:0:100
CM
0:75:25
0:15:85
0:55:45
15:60:25
0:70:30
0:60:40
ND
57
ND
60–100
88
87
100
100
100
100
100
100
K2CO3 (2 equiv), n-Bu4NHSO4(0.3 equiv), DMF, 110 °C, 24 h
K2CO3 (2 equiv), n-Bu4NHSO4 (0.3 equiv), DMF–H2O (9:1), 110 °C, 24 h
K2CO3 (2 equiv), n-Bu4NHSO4 (1 equiv), DMF–H2O (9:1), 110 °C, 24 h
K2CO3 (2 equiv), n-Bu4NHSO4 (0.3 equiv), H2O, 110 °C, 24 h
K2CO3 (2 equiv), DMF–H2O (9:1), 110 °C, 24 h
4d
5d
6d
7d
8d
9d
90 (55%)e
70
74
ND
77
96
K2CO3 (2 equiv), n-Bu4NHSO4 (0.3 equiv), DMF–H2O (9:1), 110 °C, 24 h
K2CO3 (2 equiv), n-Bu4NHSO4 (0.3 equiv), DMF–H2O (9:1), 110 °C, 24 h
a
Pd(OAc)2 (0.1 equiv) [or Pd(dba)2 (0.1 equiv)], PPh3 (0.2 equiv), solvent (0.1 M), degassed for 0.5 h under a steady N2 stream.
After purification by flash column chromatography.
Based on recovered starting material.
Reactions performed under N2 in a sealed tube.
Isolated yield following recrystallisation; CM = complex mixture; ND = not determined.
b
c
d
e

J. E. M. N. Klein et al. / Tetrahedron Letters 49 (2008) 7187–7190
7189
C11
C12
C8
C10
C9
C9
O3
S
C13
C8
C5
C17
C4
O2
C14
C5
C6
C16A
C15A
C11
C12
C13
C6
C4
C3
N
C15
O4
C10
C3
O4
O1
O2
C1
C2
C14
C7
O3
C1
C16
N
Br
C2
S
C17
C7
O1
Figure 1. X-ray crystallographic structures of 11a and its precursor 9a (Diamond representations).
O2
S
O2
S
NMe
NMe
NMe
R
R
R
R
MeO
MeO
DDQ (2.2 equiv.),
PhMe, 110 ºC, 24 h
11a: R = OMe;
11b: R = H
14a: R = OMe; 62%
14b: R = H; 24% (2 steps)
15
Scheme 3.
in water as the sole solvent (entry 6) proved to be less selective in
terms of formation of 12a. Omission of the ammonium additive did
prove to generate the adduct 11a, which, as above, was accompa-
nied by 12a. However, this reaction also formed significant
amounts of an impurity attributed to the 7-membered species
10a (entry 7). Since the rate of halogen-palladium oxidative addi-
tion might be expected to alter the ratio of these products, a bro-
mine-iodine exchange was performed to afford 13a from 9a.
However, it was found that under the optimised conditions, this
structural change did not alter the outcome of the Heck reaction
in terms of the product ratio (entry 8). Finally, a similar reactivity
pattern was observed for substrate 9b. For example, as entry 9
indicates, under the optimised conditions, the 8-membered species
11b was formed in conjunction with 12b (60:40). In this instance,
separation of these compounds was not possible since 11b proved
not to be a solid. Notable additional points concerning this cyclisa-
tion process are that omission of triphenylphosphine11 from the re-
agents in entry 1 resulted in no turnover and 9a was recovered and
that the Heck reactions attempted with the NH sulfonamide pre-
cursors to 9a and 9b under the optimised, 8-endo selective condi-
tions (entry 5) resulted both in only moderate conversion and in
the formation of mixtures of products.12
tate an unusual 8-endo-trig intramolecular Heck reaction, which
allows the preparation of a novel heterocyclic ring system.15
Acknowledgements
We would like to thank UCD for financial support and Dr. Dilip
Rai for high resolution mass spectrometry.
Supplementary data
Full experimental procedures, spectroscopic data and X-ray
crystallographic structures of 9a, 11a and 12a are available. Sup-
plementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2008.10.004.
References and notes
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The novel benz[c]thiaazocine dioxide 11a was further converted
into 14a following oxidation with DDQ in 62% yield (Scheme 3).13
This compound can be considered a sulfonamide analogue of the
natural product buflavine 15, a rare example of a naturally occur-
ring Amaryllidaceae alkaloid possessing the dibenz[c,e]azocine
skeleton.14 Similarly, the previously inseparable mixture of 11b
and 12b was treated with DDQ and 14b proved now to be isolable
(24% yield from 9b).
In summary, we have discovered that inclusion of both tetra-n-
butylammonium hydrogensulfate and water is required to facili-

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J. E. M. N. Klein et al. / Tetrahedron Letters 49 (2008) 7187–7190
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10. CCDC reference numbers: 11a; 700643; 9a; 700644; 12a; 700645.
15. Examples of heterocycles of this type are scarce.