Diastereoselective functionalisation of benzoannulated bicyclic sultams: Application for the synthesis of cis-2,4-diarylpyrrolidines

Article abstract of DOI:10.3762/bjoc.5.69

The cis-dibromination of unsaturated bicyclic bridgehead sultams 5a and 5b, and experiments designed to understand the cisstereochemical outcome of these reactions, are described. In the case of 5b, a novel solvent dependent carbocation rearrangement occu

Full text of DOI:10.3762/bjoc.5.69

Diastereoselective functionalisation of benzo-
annulated bicyclic sultams: Application for
the synthesis of cis-2,4-diarylpyrrolidines
Susan Kelleher, Pierre-Yves Quesne and Paul Evans*
Full Research Paper
Open Access
Address:
Beilstein Journal of Organic Chemistry 2009, 5, No. 69.
Centre for Synthesis and Chemical Biology, School of Chemistry and
Chemical Biology, University College Dublin, Dublin 4, Ireland
doi:10.3762/bjoc.5.69
Received: 04 August 2009
Accepted: 08 October 2009
Published: 25 November 2009
Email:
Paul Evans* - paul.evans@ucd.ie
* Corresponding author
Associate Editor: J. Aubé
Keywords:
© 2009 Kelleher et al; licensee Beilstein-Institut.
License and terms: see end of document.
cyclic sulfonamides; diastereoselective alkene functionalisation;
double reduction; Pd-mediated cross coupling
Abstract
The cis-dibromination of unsaturated bicyclic bridgehead sultams 5a and 5b, and experiments designed to understand the cis-
stereochemical outcome of these reactions, are described. In the case of 5b, a novel solvent dependent carbocation rearrangement
occurs with the formation of 18b. cis-Dibromides 13a and 13b undergo regioselective dehydrobromination, and the participation of
the resultant vinyl bromide 24a in lithiation and Pd-coupling chemistry is described. In the case of the latter, hydrogenation of the
styryl products afforded a single diastereoisomer. These compounds were then studied under dissolved metal reduction conditions,
in which the cleavage of both N–S and C–S bonds takes place to afford cis-2,4-diaryl-substituted pyrrolidines 35–37.
Introduction
Substituted pyrrolidine ring systems represent a common struc- In this sequence, the sulfonyl moiety not only serves as an
tural motif in a range of biologically active compounds, amino protecting group but also facilitates the diastereose-
including pharmaceutical agents and natural products. In rela- lective intramolecular carbon–carbon bond formation. In this
tion to these general targets, we have recently developed a present study we demonstrate that this general concept may be
method that enables the construction of aryl-substituted extended enabling the diastereoselective preparation of 2,4-
pyrrolidines, featuring the double reduction of cyclic aromatic diaryl-substituted pyrrolidines from more readily available,
sulfonamides [1-4]. As illustrated in Scheme 1, a Heck albeit racemic, substrates.
(Heck–Mizoroki) cyclisation [5-9] was employed to form the
cyclic sulfonamide. Subsequently, it was shown that high Results and Discussion
stereofacial bias was achieved on hydrogenation, generating 2 Bicyclic aromatic cyclic sulfonamides 5a and 5b were formed
as a single diastereoisomer. Treatment under dissolved metal according to the 3-step sequence previously described [1-3,10].
reduction conditions afforded the cis-disubstituted pyrrolidine. Originally, inclusion of triphenylphosphine was employed,
Page 1 of 11
(page number not for citation purposes)

Beilstein Journal of Organic Chemistry 2009, 5, No. 69.
Scheme 1: The diastereoselective intramolecular Heck-hydrogenation and double reduction sequence as a means of accessing cis-disubstituted
pyrrolidine 3.
however, optimisation of this reaction with the exclusion of newly substituted alkene [13-15]. Thus, following complete
PPh3 gave products 5a and 5b in 82 and 65% yields, respect- Heck cyclisation, as judged by TLC analysis, the reaction was
ively, which are comparable with the phosphine-based method simply stirred under a hydrogen atmosphere in order to afford
(5a: 84% and 5b: 76% with PPh3) [11]. Standard alkenyl hydro- the corresponding saturated bicycles 6a and 6b in yields of 61
genation (not shown) then gave the saturated bicycles 6a and 6b and 52% respectively. In terms of efficiency this one-pot
which were used as substrates for the N–S and C–S bond process is competitive compared with those from the original
cleavage forming arylsubstituted pyrrolidines [1-3]. In relation two-step, two-pot process (Scheme 2).
to this sequence attempts to achieve a reductive Heck cyclisa-
tion employing ammonium formate [12], gave only the product Functionalisation of the N-sulfonyl enamines 5a and 5b was
of bromine-hydrogen exchange 4c (where X = H). Therefore, a subsequently studied with the ultimate aim of introducing
one-pot method was developed based on recent reports which substituents, in a stereoselective fashion, to the masked
demonstrate that the residual palladium catalyst in Heck reac- pyrrolidine ring. Thus, epoxidation of 5a and 5b (Scheme 3)
tions may effectively mediate the addition of hydrogen to the using m-CPBA proceeded smoothly for both substrates and as
Scheme 2: The synthesis of 5a and 5b by an intramolecular Heck cyclisation reaction.
Scheme 3: Diastereoselective epoxidation of 5a and 5b.
Page 2 of 11
(page number not for citation purposes)

Beilstein Journal of Organic Chemistry 2009, 5, No. 69.
Figure 1: X-ray structure of 7a; including a view along the S=O···C–O axis (Diamond representations) [O2···C9: 2.850(2) Å].
hoped, occurred under complete stereocontrol (de >95%). The results were encountered using chloroform or dichloromethane
stereochemical outcome was confirmed by single-crystal X-ray as reaction solvents (e.g. Entries 1–3). Furthermore, separation
crystallography (Figure 1, and see crystallographic data). The of the different diastereoisomers by column chromatography
use of in situ generated trifluoromethyl-methyldioxirane was proved difficult. The unusual stereochemical outcome of this
also investigated and in the case of 5a, very efficient formation bromination process was carefully studied by a combination of
of 7a was observed [16,17].
NOE analysis, using the diagnostic 12a-CH2 signal, and X-ray
crystallography which helped to substantiate the structures of
Unfortunately, however, under a variety of conditions it proved the minor 1,2-trans-diastereoisomers 14a and 15a (see crystal-
impossible to elaborate these species. For example, reductive lographic data). Optimum conditions, forming 13a as the major
ring-opening using triethylsilane, conditions previously reported diastereomer, were ultimately found (Scheme 4). Thus, addi-
for N-sulfonylamino-α,β-epoxides [18,19], led only to recovery tion of bromine to the compound in toluene at low temperature
of starting material and not the hoped for alcohol 8. A similar gave 13a in 75% isolated yield and high diastereoselectivity as
outcome was observed under both Sakurai-type conditions and observed by 1H NMR spectroscopy of the crude reaction mix-
treatment with potassium cyanide. It seems probable that these ture (Entry 4).
failures reflect a combination of the inability of the N-lone pair
to stabilise the developing α-carbocation (the resultant N-sul- In an attempt to further understand the mechanism of this
fonyl iminium ion would be anti-Bredt) and in addition the lone bromination reaction, a bromo-methanolysis reaction was
pair is perpendicular to the p-orbital resulting from C–O bond carried out (Entry 5). Interestingly, regio- and diastereose-
cleavage. Furthermore, it also appears that the aromatic ring, lective formation of the cis-16a was observed in good yield.
based on the fold of the molecule, represents a steric barrier When 13a was taken up in methanol no conversion into 16a, via
blocking the approach to the C–O σ* orbital. Since the bicyclic an SN1-type process, was observed. The use of THF as solvent
structure was implicated in the lack of epoxide reactivity, led to the formation of compound 17a, albeit in low yield, in
double reduction of 7a was then considered. It was hoped that which a molecule of the solvent has been incorporated (Entry
following N–S bond cleavage, the now electron rich amino 6). For X-ray crystal structure of 13a see Figure 2.
species would form an imine 9 that would then undergo further
reduction to afford 11. However, in the event the only isolable
product was 12. Although the yield for this process was low, the
isolated product indicated that C11 underwent reduction,
presumably prior to N–S bond cleavage.
Based on a recent report from Paquette [20], the dibromination
of 5a and 5b was subsequently considered. We felt that bromin-
ation of the double bond would lead to further possibilities for
subsequent functionalisation. This report indicated that the
treatment of 5a with neat bromine gave the cis-1,2-dibromide
13a in quantitative yield. It was also reported that under more
standard brominating conditions mixtures of diastereoisomeric
Figure 2: X-ray crystal structure of 13a (Diamond representation).
1,2-dibromides were formed. In our hands broadly similar
Page 3 of 11
(page number not for citation purposes)

Beilstein Journal of Organic Chemistry 2009, 5, No. 69.
Scheme 4: cis-Selective dibromination of 5a (NOE indicated by arrows).
The analogous functionalisation of alkene 5b was then ingly, none of this rearranged type of product was observed for
considered. In toluene (Scheme 5, Entry 1), the optimal solvent 5a under identical conditions. The yield for this process was
for the cis-dibromination of 5b, as hoped, selective formation of increased to 87% when an excess of Br2 (10 equiv) was
13b was observed (>90% by 1H NMR spectroscopy of the employed. The bromo-methanolysis reaction, performed as
crude mixture). It should be noted that whilst the selectivity of described above, gave a mixture of compounds 16b and 19b in
this reaction is good, it did prove difficult to perform in a repro- 58% and 37% yields, respectively (Entry 3). The structure of
ducible manner based on the limited solubility of 5b in toluene 19b was also confirmed by X-ray crystallography (see Figure 3
and competing benzyl bromide formation in some instances.
and crystallographic data).
When the same reaction was conducted in chloroform, the Based on the results obtained we propose a mechanistic explan-
formation of 18b as the major product (42% yield) was ation illustrated in Scheme 6 to account for the products
observed (Entry 2). The identity of this compound was deter- formed. It seems reasonable to speculate that the cis-1,2-
mined by single crystal X-ray crystallography (Figure 3). Strik- dibromide formation results from the slow reaction of the
Scheme 5: Dibromination studies of 5b.
Page 4 of 11
(page number not for citation purposes)

Beilstein Journal of Organic Chemistry 2009, 5, No. 69.
Figure 3: X-ray crystal structures of 18b and 19b (Diamond representations).
Scheme 6: Possible explanation for the products formed in the dibromination of 5a and 5b.
bromonium ion 20 with bromide due to the blocking of the tive mechanism of stabilisation has been suggested in which
lower face by the aromatic ring (route c). Indeed, the epoxide one of the sulfonyl oxygen atoms may act as a Lewis base and
7a (Figure 1) may be considered a bromonium ion model and in doing so stabilise the positive charge [22,23]. Inspection of
inspection of this representation demonstrates the pronounced the X-ray structure obtained for compounds 7a and 7b (not
fold of this structure. Consequently, since the SN2 process is shown) indicates that this stabilisation mechanism may be
retarded the bromide may then intercept either carbocation 21, possible based on the distance between the carbon atom of the
or 22 in an SN1 sense, from the less hindered, top face, forming epoxide and its closest sulfonyl oxygen atom (see Figure 1).
13a and 13b. Using methanol as the solvent the cis-1,2-difunc-
tionalised compounds 16a and 16b were formed regioselect- In the case of carbocation 22, the benzylic bond appears to be
ively (none of the products resulting from methanolysis of 22 aligned with the empty p-orbital, consequently, when the
were detected). The regiochemical outcome of this process aromatic ring is substituted with the +M methoxy substituents
suggests that either the carbocation adjacent to nitrogen is ener- the results obtained indicate that a Wagner–Meerwein-type
getically more stable, or that it is more reactive under these rearrangement occurs to generate carbocation 23. Depending on
conditions. In relation to the N-sulfonyl group and its ability to the conditions this species is then intercepted, again diastereose-
stabilise an α-carbocation, N-sulfonyl iminium ions have been lectively, by bromide or methanol, affording 18b and 19b,
implicated in many instances [18,19,21]. However, in this respectively. In the case of 5b in chloroform and methanol this
particular case, based on the conformation of the rigid bicyclic carbocation rearrangement takes place faster than any nucleo-
molecule, this mode of stabilisation is not feasible. An alterna- philic interception of species 21 and 22. (A hydride shift from
Page 5 of 11
(page number not for citation purposes)

Beilstein Journal of Organic Chemistry 2009, 5, No. 69.
the bridging CH2 to carbocation 21 was also considered; graphic data). Although the yields described during this
however, based on the regioselective formation of compound sequence are low at this stage, the successful epimerisation
19b this mechanism was discounted.) The remarkable observed demonstrates that this approach represents a stereo-
contrasting behaviour for compound 5b in chloroform and complementary method to those described in Scheme 1 and
toluene appears to be explained based on the polarity of the Scheme 8.
respective solvents. Toluene with a low dielectric constant
favours formation of 13b whereas the more polar chloroform
facilitates the rearrangement chemistry via carbocation 22. This
type of terpene-like carbocation rearrangement has been
reported for molecules which might be considered related to our
[2.2.1]-bicyclic systems and has been termed a molecular
somersault [24].
Regioselective elimination of the cis-dibromides 13a and 13b
with TBAF, according to Paquette’s procedure [20], gave the
vinyl bromides 24a and 24b in good yields, respectively
(Scheme 7). Vinyl bromide 24a was then subjected to lithiation
Figure 4: X-ray structure of 26 (Diamond representation).
with t-BuLi, followed by a CO2 quench. The desired carboxylic
acid recovered from this reaction was only formed in low yields
possibly due to issues with competing directed ortho-lithiation With the lithiation chemistry described above proving ineffi-
[25]. Notwithstanding, this acid was transformed into the cor- cient, palladium chemistry was subsequently considered. The
responding methyl ester 25 using a Steglich-type esterification. vinyl bromide 24a was reported to participate in Sonagashira
Alkenyl reduction of the α,β-unsaturated ester under standard alkynylation chemistry; however, yields of the resultant enyne
conditions gave the product of hydrogenation as an undeter- were low [20]. Therefore, we decided to investigate
mined 3:1 mixture of diastereoisomers. The likely explanation Suzuki–Miyaura cross-coupling reaction as a means of incorp-
for this mixture of products, based on the high levels of diaste- orating alternative structural features into our masked
reoselectivity observed in the similar examples discussed pyrrolidine ring. Under standard conditions, the reactivity of a
herein, is that the initially formed product begins to undergo series of commercially available aryl and alkenyl boronic acids
epimerisation in order to place the larger (CO2Me) substituent with 24a was investigated. Pleasingly, it was found that in the
on the least hindered face. Consequently, the complete epimer- case of the aryl boronic acids, good yields of the resultant styryl
isation of this material was investigated using NaOMe (1 M) adducts 27–30 were observed. It was found that employment of
based on a literature report [26]. Pleasingly, the hoped for the boronic acids in excess (approximately 5 equiv) in conjunc-
process did indeed lead to the formation of one diastereomer of tion with base work-up gave the desired products in good yields
carboxylic acid 26, which was formed from the methyl ester on with no starting material 24a, or the product of
hydrolysis following work-up (see Figure 4 and crystallo- bromine–hydrogen exchange 5a. Unfortunately, under identical
Scheme 7: Lithiation–CO2 quench approach for the synthesis of 26 from vinyl bromide 24a.
Page 6 of 11
(page number not for citation purposes)

Beilstein Journal of Organic Chemistry 2009, 5, No. 69.
Scheme 8: Suzuki–Miyaura cross-coupling of 24a and the diastereoselective hydrogenation of the resultant styrene adducts.
conditions no cross-coupled products were obtained following
several attempts using Z-crotyl boronic acid and vinyl boronic
acid.
Hydrogenation of the trisubstituted alkene in compounds 27–30
was carried out in DMF due to the poor solubility of these com-
pounds in more standard solvents. These reactions also proved
rather slow. Nevertheless, after 72 h under a hydrogen atmos-
phere in the presence of Pd/C, moderate to good yields of com-
pounds 31–34 were achieved. As predicted, the addition of
hydrogen took place in a diastereoselective manner and the
adducts were formed as single diastereoisomers. This sense of
diastereoselectivity was confirmed by a series of NOE experi-
ments and the single X-ray crystal structure obtained for
compound 31 (see Figure 5 and crystallographic data). Poor
conversion was observed when the one-pot reductive-palla-
dium method, analogous to that described in Scheme 2, was
attempted.
Figure 5: X-ray crystal structure of 31 (Diamond representation).
The double reduction of compounds 31–34 was next
considered. Cleavage of both the S–N and S–C bonds would
result in the formation of a series of cis-diaryl-substituted The successful double reduction of compounds 31–33 was
pyrrolidine ring containing compounds. Consequently, treat- observed in moderate/low yields. In the case of compound 31, a
ment of each compound under the currently optimal conditions significant amount of the product 39 of benzylic cleavage was
(lithium in liquid ammonia at −78 °C) gave the products of also detected. This type of product was not observed for the
reduction which were converted into the corresponding tosyl more electron rich, methoxy-containing substituents, presum-
derivatives to aid characterisation and purification (Scheme 9). ably since the Birch-type radical anionic intermediate, which
Scheme 9: Attempted sulfonamide double reduction of compounds 31–34.
Page 7 of 11
(page number not for citation purposes)

Beilstein Journal of Organic Chemistry 2009, 5, No. 69.
enables the elimination of the amino group, is disfavoured in Calcd for C10H9NO3S: C, 53.80; H, 4.06; N, 6.27. Found: C,
this instance. In the case of compound 34, trace amount of the 53.63; H, 4.04; N, 6.06.
hoped for product 38 was detected. However, in this case the
major product 40 stems from the partial reduction of the naph- (±)-(1S,10R,11R)-10,11-Dibromo-8-thia-9-azatricyclo-
thyl ring in addition to cleavage of the sulfonyl tether.
[7.2.1.02,7]dodeca-2(7),3,5-triene-8,8-dioxide (13a) [20]: To a
solution of alkene 5a (50 mg, 0.24 mmol, 1.2 equiv) in PhMe
(10 mL) at −78 °C, Br2 (0.01 mL, 0.20 mmol, 1 equiv) was
Conclusion
In summary, the work described demonstrates that we were able added. The reaction mixture was stirred for 15 h during which
to utilise the functionalisation of bicyclic sulfonamide 5a time, room temperature was reached. The reaction was
featuring a Suzuki coupling and a diastereoselective hydrogena- quenched with a saturated solution of Na2SO3 (10 mL) and
tion to construct cis-2,4-diarylpyrrolidines in a diastereose- H2O (10 mL) was added. The resultant aqueous layer was then
lective manner. The epimerisation reaction which led to the further extracted with CH2Cl2 (2 × 10 mL) and the combined
formation of carboxylic acid 26 demonstrates, in principle, how organic extracts were dried over MgSO4. Filtration followed by
the trans-2,4-substituted series might also be accessible. The solvent removal in vacuo afforded the crude product, which was
cis-diastereoselective dibromination of the bridgehead sultams purified by flash column chromatography (c-Hex–EtOAc; 9:1)
5a and 5b was also studied from a mechanistic perspective and affording 13a (55 mg, 75%) as a colourless solid. mp 174–176
related to this an unusual molecular somersault was uncovered, °C (EtOAc), lit. 185–188 °C [20]; Rf = 0.6 (c-Hex–EtOAc; 1:1);
the occurrence of which was dependent on the electronic nature 1H NMR (400 MHz, CDCl3): δ 3.66 (s, 1H, 1-CH), 4.10 (d, J =
of the aryl motif and of the reaction solvent.
13.0 Hz, 1H, 12a-CH2), 4.30 (d, J = 13.0 Hz, 1H, 12b-CH2),
4.66 (d, J = 6.0 Hz, 1H, 11-CH), 6.47 (d, J = 6.0 Hz, 1H,
10-CH), 7.35 (d, J = 7.0 Hz, 1H, ArH), 7.50–7.60 (m, 2H,
Experimental
Representative experimental procedures are shown for com- ArH), 7.81 (d, J = 7.0 Hz, 1H, ArH); 13C NMR (100 MHz,
pounds 7a, 13a, 18b, 24a, 27, 31, 35, 39. For full experimental CDCl3): δ 52.3 (CH), 52.8 (CH2), 57.8 (CH), 67.6 (CH), 126.6
details see accompanying Supporting Information.
(CH), 126.7 (CH), 130.5 (CH), 133.7 (CH), 134.9 (C), 135.9
(C); υmax (CH2Cl2/cm−1) (NaCl) 3010, 2977, 1446, 1344, 1324,
(±)-(1S,10R,11R)-Epoxy-8-thia-9-azatricyclo[7.2.1.02,7]- 1300, 1263, 1234, 1206, 1162, 1077; Anal. Calcd for
dodeca-2(7),3,5-triene-8,8-dioxide (7a): To a solution of C10H9Br2NO2S: C, 32.70; H, 2.45; N, 3.89; Br, 43.60. Found:
alkene 5a (252 mg, 1.22 mmol, 1 equiv) in CH2Cl2 (50 mL) at C, 32.66; H, 2.31; N, 3.41; Br, 43.27.
0 °C, 70% (w/w) m-CPBA (1.68 g, 6.82 mmol, 5.5 equiv) was
added. The reaction mixture was stirred for 72 h during which (±)-(1R,11R,12S)-11,12-Dibromo-4,5-dimethoxy-8-thia-9-
time room temperature was reached. The reaction was quenched azatricyclo[7.2.1.02,7]dodeca-2(7),3,5-triene-8,8-dioxide
with a saturated Na2SO3 solution (15 mL) which was basified (18b): To a solution of alkene 5b (75 mg, 0.28 mmol, 1 equiv)
after 0.5 h with a saturated NaHCO3 solution (15 mL). H2O (10 in CHCl3 (10 mL) at −78 °C, Br2 (0.15 mL, 2.80 mmol, 10
mL) was added and the aqueous layer was then extracted with equiv) was added. The reaction mixture was stirred for 15 h
CH2Cl2 (2 × 20 mL). The combined organic extracts were dried during which time, room temperature was reached. The reac-
over MgSO4. Filtration followed by solvent removal in vacuo tion was quenched with a saturated solution of Na2SO3 (20 mL)
afforded the crude product, which was purified by flash column and H2O (20 mL) was added. The aqueous layer was then
chromatography (c-Hex–EtOAc; 5:1) affording 7a (179 mg, further extracted with CH2Cl2 (2 × 20 mL) and the combined
66%) as a colourless solid. Recrystallisation from EtOAc gave organic extracts were dried over MgSO4. Filtration followed by
crystals suitable for X-ray crystallographic analysis. mp solvent removal in vacuo afforded the crude product, which was
164–165 °C (EtOAc); Rf = 0.45 (c-Hex–EtOAc; 1:1); 1H NMR purified by flash column chromatography (c-Hex–EtOAc; 5:1)
(300 MHz, CDCl3): δ 3.27 (d, J = 4.0 Hz, 1H, 1-CH), 3.35 (dd, affording 18b (104 mg, 87%) as a colourless solid. Recrystal-
J = 4.0, 12.5 Hz, 1H, 1H, 12a-CH2), 3.65 (s, 1H, 11-CH), 3.92 lisation from EtOAc gave crystals suitable for X-ray crystallo-
(d, J = 12.5 Hz, 1H, 12b-CH2), 5.03 (s, 1H, 10-CH), 7.19 (d, J = graphic analysis. mp 225 °C (EtOAc); Rf = 0.6 (c-Hex–EtOAc;
6.5 Hz, 1H, ArH), 7.40–7.47 (m, 2H, ArH), 7.67–7.80 (m, 1H, 1:1); 1H NMR (500 MHz, CDCl3): δ 3.86 (s, 1H, 1-CH), 3.91
ArH); 13C NMR (100 MHz, CDCl3): δ 39.5 (CH), 49.4 (CH2), (s, 3H, CH3), 3.96 (s, 3H, CH3), 4.13 (dd, J = 5.0, 8.0 Hz, 1H,
57.8 (CH), 65.4 (CH), 127.0 (CH), 127.7 (CH), 130.1 (CH), 11-CH), 4.20 (dd, J = 5.0, 15.0 Hz, 1H, 10a-CH2), 4.60 (dd, J =
132.5 (CH), 135.3 (C), 136.3 (C); υmax (CH2Cl2/cm−1) (KCl) 8.0, 15.0 Hz, 1H, 10b-CH2), 6.32 (s, 1H, 12-CH), 6.70 (s, 1H,
3067, 3037, 1472, 1381, 1335, 1246, 1205, 1170, 1061, 1007, ArH), 7.19 (s, 1H, ArH); 13C NMR (125 MHz, CDCl3): δ 44.0
935, 916, 855, 811, 792, 767, 750, 715, 609; m/z (ES) required (CH), 56.3 (CH), 56.4 (CH3), 58.5 (CH3), 58.9 (CH), 64.5
224.0379 (MH+, 100%); found 224.0381 (−1.1 ppm); Anal. (CH2), 107.8 (CH), 108.5 (CH), 126.3 (C), 130.2 (C), 150.4
Page 8 of 11
(page number not for citation purposes)

Beilstein Journal of Organic Chemistry 2009, 5, No. 69.
(C), 153.2 (C); υmax (CH2Cl2/cm−1) (NaCl) 3096, 2975, 1593, (CH), 127.1 (CH), 127.3 (CH), 128.3 (CH), 129.2 (CH), 129.7
1444, 1326, 1260, 1203, 1164, 1044; Anal. Calcd for (CH), 131.7 (CH), 134.7 (C), 140.8 (C), 147.0 (C); υmax
C12H13Br2NO4S: C, 33.75; H, 3.07; N, 3.28. Found: C, 33.69; (CH2Cl2/cm−1) (KCl) 3063, 1965, 1592, 1452, 1327, 1162,
H, 2.99; N, 3.17.
1029, 948; m/z (ES) required 284.0733 (MH+, 100%); found
284.0745 (−4.3 ppm); Anal. Calcd for C16H13NO2S: C, 67.84;
10-Bromo-8-thia-9-azatricyclo[7.2.1.02,7]dodeca-2,4,6,10- H, 4.59; N, 4.95. Found: C, 67.69; H, 4.65; N, 4.84.
tetraene-8,8-dioxide (24a) [20]: Compound 13a (1.04 g, 2.83
mmol, 1 equiv) in THF (15 mL) was treated with a 1 M solu- (±)-(1S,10R)-10-Phenyl-8-thia-9-azatricyclo[7.2.1.02,7]-
tion of TBAF in THF (20 mL, 20.00 mmol, 7 equiv) for 15 h. dodeca-2(7),3,5-triene-8,8-dioxide (31): 10% (w/w) Pd/C (98
The solvent was removed in vacuo and CH2Cl2 was added (30 mg, 0.09 mmol, 15 mol %) was added to a solution of the
mL). The organic layer was washed with a saturated solution of alkene 27 (173 mg, 0.61 mmol, 1 equiv) in DMF (20 mL). The
NaHCO3 (30 mL), the aqueous phase further extracted with mixture was degassed before stirring under a hydrogen atmos-
CH2Cl2 (30 mL) and the combined organic layers were dried phere (1 atm) at room temperature for 72 h. Filtration through
over MgSO4. Filtration followed by solvent removal in vacuo Celite® and solvent removal in vacuo gave 32 (77 mg, 44%) as
afforded the crude product, which was purified by flash column a colourless crystalline solid. mp 131–134 °C (EtOAc); Rf = 0.5
chromatography (c-Hex–EtOAc; 1:1) affording 24a (700 mg, (c-Hex–EtOAc; 1:1); 1H NMR (400 MHz, CDCl3): δ 2.36 (ddd,
86%) as a colourless solid. mp 188–192 °C (CH2Cl2); Rf = 0.3 J = 2.0, 7.5, 13.0 Hz, 1H, CH2), 2.73 (ddd, J = 7.5, 10.0, 13.0
(c-Hex–EtOAc; 1:1); 1H NMR (400 MHz, CDCl3): δ 3.29 (t, J Hz, 1H, CH2), 3.43 (dd, J = 3.5, 7.5 Hz, 1H, CH), 3.56 (dd, J =
= 4.0 Hz, 1H, CH), 4.37 (dd, J = 4.0, 12.0 Hz, 1H, 12a-CH2), 3.5, 12.5 Hz, 1H, CH2), 4.53 (dd, J = 2.0, 12.5 Hz, 1H, CH2),
4.59 (d, J = 12.0 Hz, 1H, 1H, 12b-CH2), 6.68 (d, J = 4.0 Hz, 5.05 (dd, J = 7.5, 10.0 Hz, 1H, CH), 7.13–7.19 (m, 2H, ArH),
1H, 11-CH), 7.12 (d, J = 7.5 Hz, 1H, ArH), 7.42 (t, J = 7.5 Hz, 7.22–7.29 (m, 4H, ArH), 7.36 (dt, J = 1.0, 7.0 Hz, 1H, ArH),
1H, ArH), 7.50 (t, J = 7.5 Hz, 1H, ArH), 7.77 (d, J = 7.5 Hz, 7.48 (dt, J = 1.0, 7.5 Hz, 1H, ArH), 7.66 (d, J = 7.5 Hz, 1H, 1H,
1H, ArH); 13C NMR (100 MHz, CDCl3): δ 43.9 (CH), 65.5 ArH); 13C NMR (100 MHz, CDCl3): δ 37.7 (CH2), 40.1 (CH),
(CH2), 125.0 (C), 125.4 (CH), 127.4 (CH), 130.2 (CH), 132.1 59.1 (CH2), 66.4 (CH), 125.8 (CH), 127.0 (CH), 127.9 (CH),
(CH), 134.5 (C), 135.9 (CH), 139.3 (C); υmax (CH2Cl2/cm−1) 128.2 (CH), 128.3 (CH), 129.8 (CH), 132.6 (CH), 135.1 (C),
(NaCl) 3102, 2924, 1591, 1452, 1338, 1168, 1054, 925, 866, 137.2 (C), 142.1 (C); υmax (CH2Cl2/cm−1) (KCl) 3042, 2956,
749; m/z (ES) required 285.9549 (MH+(Br79), 100%); found 2342, 1954, 1876, 1596, 1452, 1324, 1163, 1087, 975; m/z (ES)
285.9537 (+4.1 ppm); Anal. Calcd for C10H8BrNO2S: C, 41.96; required 284.0894 (MH+, 100%); found 284.0902 (−2.7 ppm).
H, 2.80; N, 4.90; Found: C, 41.97; H, 2.77; N, 4.71.
(±)-(2R,4S)-2,4-Diphenyl-1-(toluene-4-sulfonyl)pyrrolidine
10-Phenyl-8-thia-9-azatricyclo[7.2.1.02,7]dodeca-2,4,6,10- (35) and N-(2,4-diphenylbutyl)-4-methylbenzenesulfon-
tetraene-8,8-dioxide (27): Under N2, a mixture of the amide (39): Under N2 at −78 °C liquid NH3 (ca. 100 mL) was
compound 24a (500 mg, 1.75 mmol, 1 equiv), phenylboronic treated with lithium wire (10 mg, 1.43 mmol, 5 equiv). This
acid (1.073 g, 8.80 mmol, 5 equiv), Pd(OAc)2 (20 mg, 0.09 mixture was stirred for 1 h before a solution of 31 (80 mg, 0.28
mmol, 5 mol %), PPh3 (47 mg, 0.18 mmol, 10 mol %) and mmol, 1 equiv) in THF (5 mL) was introduced dropwise. Stir-
Cs2CO3 (1.714 g, 5.26 mmol, 3 equiv) in a mixture of ring was continued at −78 °C for 20 min before solid NH4Cl
THF:H2O (10:1) (25 mL) was heated to reflux for 15 h. On (ca. 5 g) was added. The NH3 was allowed to evaporate and
cooling Et2O (20 mL) and H2O (20 mL) were added and the Et2O (25 mL) and H2O (25 mL) were added to the residue. The
resultant aqueous layer was further extracted with Et2O (2 × 20 resultant aqueous layer was further extracted with Et2O (2 × 25
mL) and the combined organic extracts were washed with a 2 M mL) and the combined organic extracts were dried over MgSO4.
NaOH solution (20 mL) and dried over MgSO4. Filtration Filtration, followed by solvent removal under reduced pressure,
followed by solvent removal under reduced pressure gave the afforded a colourless oil. At 0 °C the crude material was treated
crude product, which was purified by flash column chromato- with Et3N (0.06 mL, 0.43 mmol, 1.5 equiv) and TsCl (53 mg,
graphy (c-Hex–EtOAc; 5:1) affording 27 (314 mg, 63%) as a 0.28 mmol, 1 equiv) in CH2Cl2 (10 mL). The mixture was
colourless solid. mp 120–122 °C (EtOAc); Rf = 0.55 stirred for 3 h during which time, room temperature was
(c-Hex–EtOAc; 1:1); 1H NMR (400 MHz, CDCl3): δ 3.44 (t, J reached. CH2Cl2 (20 mL) and H2O (20 mL) were added and the
= 4.0 Hz, 1H, CH), 4.27 (dd, J = 4.0, 12.0 Hz, 1H, CH2), 4.70 resultant aqueous layer was further extracted with CH2Cl2 (2 ×
(d, J = 12.0 Hz, 1H, CH2), 6.82 (d, J = 4.0 Hz, 1H, CH), 7.17 20 mL). The combined organic extracts were dried over
(d, J = 7.5 Hz, 1H, ArH), 7.31–7.39 (m, 3H, ArH), 7.40–7.47 MgSO4, which was removed by filtration. The solvent was
(m, 2H, ArH), 7.69–7.71 (m, 3H, ArH); 13C NMR (100 MHz, removed under reduced pressure and purification of the residue
CDCl3): δ 43.3 (CH), 64.3 (CH2), 110.0 (C), 125.3 (CH), 126.6 by flash column chromatography (c-Hex–EtOAc; 4:1) gave
Page 9 of 11
(page number not for citation purposes)

Beilstein Journal of Organic Chemistry 2009, 5, No. 69.
initially 35 (21 mg, 20%) as a colourless oil. Rf = 0.45 M = 253.27; monoclinic, P21/n; a = 14.7519(16) Å, b =
(c-Hex–EtOAc; 3:1); 1H NMR (400 MHz, CDCl3): δ 2.05 (ddd, 9.6485(10) Å, c = 15.2476(16) Å; U = 2163.8(4) Å3; T = 100(2)
app. dt, J = 10.0, 12.5 Hz, 1H, CH2), 2.43 (s, 3H, CH3), K; Z = 8; 37265 reflections measured, 4487 unique (Rint =
2.63–2.72 (m, 1H, CH2), 2.90–3.02 (m, 1H, CH), 3.51 (t, J = 0.0384). The final wR2 was 0.1158 (all data). CCDC reference
11.0 Hz, 1H, CH2), 4.16 (ddd, J = 1.0, 7.0, 11.0 Hz, 1H, CH2), number 742471. Crystal structural data for compound 31:
4.82 (dd, J = 7.0, 10.0 Hz, 1H, CH), 7.12 (d, J = 7.0 Hz, 2H, C16H15NO2S; M = 285.35; orthorhombic, P212121; a =
ArH), 7.20–7.36 (m, 10H, ArH), 7.63 (d, J = 8.0 Hz, 2H, ArH); 9.3949(7) Å, b = 10.7576(8) Å, c = 13.5221(10) Å; U =
13C NMR (100 MHz, CDCl3): δ 21.5 (CH3), 43.7 (CH), 44.4 1366.63(18) Å3; T = 180(2) K; Z = 4; 16599 reflections meas-
(CH2), 55.9 (CH2), 64.5 (CH), 126.4 (CH), 127.0 (CH), 127.1 ured, 4468 unique (Rint = 0.0157). The final wR2 was 0.0852
(CH), 127.3 (CH), 127.4 (CH), 128.4 (CH), 128.7 (CH), 129.6 (all data). CCDC reference number 742470.
(CH), 135.7 (C), 139.0 (C), 142.5 (C), 143.3 (C); υmax
(CH2Cl2/cm−1) 3059, 2926, 1599, 1494, 1432, 1342, 1289,
Supporting Information
1254, 1158, 1093, 1027; m/z (ES) required 378.1535 (MH+,
100%); found 378.1528 (+1.1 ppm). Further elution gave 39 (51
Supporting information features experimental procedures
mg, 48%) as a colourless oil. Rf = 0.35 (c-Hex–EtOAc; 3:1); 1H
and spectroscopic analyses for compounds 6a, 6b, 7a, 7b,
NMR (300 MHz, CDCl3): δ 1.77–1.88 (m, 1H, CH2), 1.90–2.00
13a, 13b, 16a, 16b, 17a, 18b, 19b, 24a, 24b, 25–37, and
(m, 1H, CH2), 2.34–2.49 (m, 5H, CH3, CH2), 2.63–2.72 (m,
39.
1H, CH), 3.00 (app. ddt, J = 4.5, 9.0 Hz, 1H, CH2), 3.27 (app.
Supporting Information File 1
ddt, J = 5.5, 8.0 Hz, 1H, CH2), 4.21 (dd, J = 4.0, 4.5 Hz, 1H,
NH), 7.01–7.06 (m, 4H, ArH), 7.13–7.35 (m, 8H, ArH), 7.62 (d,
J = 8.0 Hz, 2H, ArH); 13C NMR (100 MHz, CDCl3): δ 21.5
(CH3), 33.1 (CH2), 35.0 (CH2), 45.0 (CH), 48.5 (CH2), 125.9
(CH), 127.0 (CH), 127.3 (CH), 127.8 (CH), 128.3 (CH), 128.35
(CH), 129.0 (CH), 129.6 (CH), 137.0 (C), 141.0 (C), 141.5 (C),
143.3 (C); υmax (CH2Cl2/cm−1) 3360, 2043, 2932, 1599, 1493,
1431, 1327, 1222, 1159, 1087, 810; m/z (ES) required 380.1666
(MH+, 100%); found 380.1684 (−4.8 ppm).
Diastereoselective functionalisation of benzo-annulated
bicyclic sultams: application for the synthesis of
cis-2,4-diarylpyrrolidines.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-5-69-S1.pdf]
Acknowledgements
We would like to acknowledge UCD for the provision of a post-
Crystallographic data
graduate scholarship. Additionally Dr. Helge Müller-Bunz is
Crystal structural data for compound 7a: C10H9NO3S; M = thanked for X-ray crystallography and Dr. Jimmy Muldoon is
223.24; orthorhombic, Pbca; a = 8.9434(12) Å, b = 12.1447(16) thanked for assistance with NMR spectroscopy.
Å, c = 17.0400(2) Å; U = 1850.8(4) Å3; T = 100(2) K; Z = 8;
References
1. Evans, P.; McCabe, T.; Morgan, B. S.; Reau, S. Org. Lett. 2005, 7,
15241 reflections measured, 2019 unique (Rint = 0.0514). The
final wR2 was 0.1169 (all data). CCDC reference number
43–46. doi:10.1021/ol0480123
742466. Crystal structure data for compound 13a:
2. Evans, P. J. Org. Chem. 2007, 72, 1830–1833. doi:10.1021/jo062189o
C10H9NO2SBr2; M = 367.06; monoclinic, P21/c; a =
3. Kelleher, S.; Muldoon, J.; Müller-Bunz, H.; Evans, P. Tetrahedron Lett.
11.1268(11) Å, b = 8.6567(8) Å, c = 12.5715(12) Å; U =
2007, 48, 4733–4736. doi:10.1016/j.tetlet.2007.05.015
1129.8(19) Å3; T = 100(2) K; Z = 4; 11016 reflections meas-
ured, 2808 unique (Rint = 0.0407). The final wR2 was 0.0671
(all data). CCDC reference number 742467. Crystal structural
data for compound 18b: C12H13NO4SBr2; M = 427.11; mono-
clinic, P21/n; a = 11.462(2) Å, b = 10.4508(18) Å, c =
12.0450(2) Å; U = 1405.2(4) Å3; T = 100(2) K; Z = 4; 11889
reflections measured, 2867 unique (Rint = 0.0378). The final
wR2 was 0.0946 (all data). CCDC reference number 742468.
Crystal structural data for compound 19b: C13H16NO5SBr; M =
378.24; monoclinic, P21/c; a = 15.9581(19) Å, b = 10.6318(13)
Å, c = 17.8100(2) Å; U = 2889.5(6) Å3; T = 100(2) K; Z = 8;
65857 reflections measured, 8789 unique (Rint = 0.0329). The
final wR2 was 0.0712 (all data). CCDC reference number
742469. Crystal structural data for compound 26: C11H11NO4S;
4. Zeng, W.; Chemler, S. R. J. Org. Chem. 2008, 73, 6045–6047.
doi:10.1021/jo801024h
5. Knowles, J. P.; Whiting, A. Org. Biomol. Chem. 2007, 5, 31–44.
doi:10.1039/b611547k
(see for recent reviews).
6. Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106, 4644–4680.
doi:10.1021/cr0683966
(see for recent reviews).
7. Gibson, S. E.; Middleton, R. J. Contemp. Org. Synth. 1996, 3,
447–471. doi:10.1039/CO9960300447
(see for recent reviews).
8. Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945–2964.
doi:10.1021/cr020039h
(see for recent reviews).
Page 10 of 11
(page number not for citation purposes)

Beilstein Journal of Organic Chemistry 2009, 5, No. 69.
9. Link, J. T. Org. React. 2002, 60, 157–534.
doi:10.1002/0471264180.or060.02
(see for recent reviews).
10.Grigg, R.; Sridharan, V.; York, M. Tetrahedron Lett. 1998, 39,
4139–4142. doi:10.1016/S0040-4039(98)00709-6
11.de Vries, A. H. M.; Mulders, J. M. C. A.; Mommers, J. H. M.;
Henderickx, H. J. W.; de Vries, J. G. Org. Lett. 2003, 5, 3285–3288.
doi:10.1021/ol035184b
12.McAlonan, H.; Montgomery, D.; Stevenson, P. J. Tetrahedron Lett.
1996, 37, 7151–7154. doi:10.1016/0040-4039(96)01564-X
13.Bielawski, C. W.; Louie, J.; Grubbs, R. H. J. Am. Chem. Soc. 2000,
122, 12872–12873. doi:10.1021/ja001698j
14.Leclerc, J.-P.; André, M.; Fagnou, K. J. Org. Chem. 2006, 71,
1711–1714. doi:10.1021/jo0523619
15.Ibarguren, O.; Zakri, C.; Fouquet, E.; Felpin, F.-X. Tetrahedron Lett.
2009, 50, 5071–5074. doi:10.1016/j.tetlet.2009.06.084
16.Fenster, M. D. B.; Dake, G. R. Org. Lett. 2003, 5, 4313–4316.
doi:10.1021/ol035566h
17.Yang, D.; Wong, M.-K.; Yip, Y.-C. J. Org. Chem. 1995, 60, 3887–3889.
doi:10.1021/jo00117a046
18.Kamenecka, T. M.; Danishefsky, S. J. Chem.–Eur. J. 2001, 7, 41–63.
doi:10.1002/1521-3765(20010105)7:1<41::AID-CHEM41>3.0.CO;2-D
19.Li, S.; Yamamura, S. Tetrahedron 1998, 54, 8691–8710.
doi:10.1016/S0040-4020(98)00479-7
20.Dura, R. D.; Paquette, L. A. J. Org. Chem. 2006, 71, 2456–2459.
doi:10.1021/jo0526587
21.Berti, G.; Marsili, A. Tetrahedron 1966, 22, 2977–2988.
doi:10.1016/S0040-4020(01)82275-4
(see for example).
22.Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817–3856.
doi:10.1016/S0040-4020(00)00159-9
23.Ungureanu, I.; Bologa, C.; Chayer, S.; Mann, A. Tetrahedron Lett.
1999, 40, 5315–5318. doi:10.1016/S0040-4039(99)01002-3
24.Qiu, J.; Silverman, R. B. J. Med. Chem. 2000, 43, 706–720.
doi:10.1021/jm9904755
25.Blanchet, J.; Macklin, T.; Ang, P.; Metallinos, C.; Snieckus, V.
J. Org. Chem. 2007, 72, 3199–3206. doi:10.1021/jo062385v
26.Seto, H.; Fujioka, S.; Koshino, H.; Suenaga, T.; Yoshida, S.;
Watanabe, T.; Takatsuto, S. J. Chem. Soc., Perkin Trans. 1 1998,
3355–3358. doi:10.1039/a805945d
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.5.69
Page 11 of 11
(page number not for citation purposes)