Novel design of 3,8-diazabicyclo[3.2.1]octane framework in oxidative sulfonamidation of 1,5-hexadiene

Article abstract of DOI:10.1016/j.tet.2014.04.095

1,5-Hexadiene reacts with trifluoromethanesulfonamide in the oxidative system (t-BuOCl+NaI) to give trans-2,5-bis(iodomethyl)-1- (trifluoromethylsulfonyl)pyrrolidine 5 and 3,8-bis(trifluoromethylsulfonyl)-3,8- diazabicyclo[3.2.1]octane 6. With arenesulfon

Full text of DOI:10.1016/j.tet.2014.04.095

Tetrahedron xxx (2014) 1e5
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Novel design of 3,8-diazabicyclo[3.2.1]octane framework in
oxidative sulfonamidation of 1,5-hexadiene
,
a
a
b
Bagrat A. Shainyan a , Mikhail Yu Moskalik , Vera V. Astakhova , Uwe Schilde
*
a A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Division of Russian Academy of Science, 1 Favorsky Street, Irkutsk 664033, Russian Federation
Institut fur Chemie, Universitat Potsdam, Karl-Liebknecht-Strasse 24-25, D-14476 Golm, Germany
b
€
€
a r t i c l e i n f o
a b s t r a c t
Article history:
1,5-Hexadiene reacts with trifluoromethanesulfonamide in the oxidative system (t-BuOClþNaI) to give
trans-2,5-bis(iodomethyl)-1-(trifluoromethylsulfonyl)pyrrolidine 5 and 3,8-bis(trifluoromethylsulfonyl)-
3,8-diazabicyclo[3.2.1]octane 6. With arenesulfonamides ArSO2NH2 (Ar¼Ph, Tol), the reaction stops at
the formation of the trans and cis isomers of 2,5-bis(iodomethyl)-1-(arenesulfonyl)pyrrolidine 7 and 8
(1:1). The cis isomers of 7 and 8 do not undergo cyclization to the corresponding 3,8-disubstituted 3,8-
diazabicyclo[3.2.1]octanes. The reaction with triflamide represents the first example of one-pot two-step
route to 3,8-diazabicyclo[3.2.1]octane system.
Received 28 February 2014
Received in revised form 14 April 2014
Accepted 29 April 2014
Available online xxx
Keywords:
Trifluoromethanesulfonamide
Arenesulfonamides
1,5-Dienes
Ó 2014 Elsevier Ltd. All rights reserved.
Cycloaddition
3,8-Diazabicyclo[3.2.1]octane
X-ray
1. Introduction
the substrates must be prepared in advance from commercially
available reagents. To the best of our knowledge only two examples
N,N0-Disubstituted 3,8-diazabicyclo[3.2.1]octanes (aza-analogs
of tropane) are actively investigated as substitutes for the
piperazine-based biologically active compounds with analgesic,
antiarrhythmic, antitussive, antitumor, and antiproliferative
activity;1e5 these results are partly summarized in the recent re-
view.6 However, since their first multi-step syntheses by Cignarella
et al. in 1960e1961,2e7 small progress has been made in the
methodology of construction of the 3,8-diazabicyclo[3.2.1]octane
framework.8 For example, the recently achieved diastereoselective
synthesis of 3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid in-
cluded cyclization of the separately prepared pyrrolidine derivative
followed by the reduction of the formed bicyclic adduct to the
target product in eight steps from pyroglutamic acid.9 An alterna-
tive synthetic strategy for the preparation of 3,8-diazabicyclo[3.2.1]
octane derivatives elaborated by Joule et al. and ascending to the
pioneering works by Katrizky10 is to react 3-oxidopyraziniums with
methyl acrylate or methacrylate.11 The formation of substituted 3,8-
bis(tosyl)-3,8-diazabicyclo[3.2.1]octanes in extremely low yields
from the properly substituted 2-benzoyl-1,4-bis(tosyl)piperazines
upon irradiation was also reported.12 The yields are moderate and
have been reported for the formation of 3,8-diazabicyclo[3.2.1]
octan-2-one derivatives by intramolecular cyclization reaction,
namely, from N,N0-diprotected 5-allyl-2-piperazinone in nine steps
with total yield of 23%13 and from 3-allyl-2-piperazinone in five
steps with total yield of 32%.14
2. Results and discussion
There are no examples of one-pot construction of 3,8-
diazabicyclo[3.2.1]octanes; neither are there examples of the
triflyl derivatives of 3,8-diazabicyclo[3.2.1]octanes. In continuation
of our systematic studies of triflamides15 and, in particular, of oxi-
dative triflamidation of alkenes and dienes,16 we report here the
reactions of 1,5-hexadiene 1 with trifluoromethanesulfonamide
(triflamide) 2, toluenesulfonamide (tosylamide) 3a, benzenesulfo-
namide 3b, and methanesulfonamide 4 in the presence of an oxi-
dant. The reaction was carried out under mild conditions (MeCN
solution, cooling) in the oxidative system (t-BuOClþNaI). Two
products were formed in the total isolated yield of 91%, which
were separated by column chromatography and assigned as
2,5-bis(iodomethyl)-1-(trifluoromethylsulfonyl)pyrrolidine 5 and
3,8-bis(trifluoromethylsulfonyl)-3,8-diazabicyclo[3.2.1]octane 6.
From 1H NMR before separation the products 5 and 6 are formed
in the ratio of 3:2. The 1H NMR spectra of the two products have the
* Corresponding author. E-mail addresses: bagrat@irioch.irk.ru (B.A. Shainyan),
us@chem.uni-potsdam.de (U. Schilde).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
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2
B.A. Shainyan et al. / Tetrahedron xxx (2014) 1e5
same number of signals but differ in that the signals of 5 are
broadened due to the flexibility of the five-membered ring, while
for the rigid bicyclic structure of 6 they are more narrow and better
resolved. The structure of product 6 was proved by the presence of
the signals of two different CF3 groups in the 13C and 19F NMR
spectra and, finally, by X-ray analysis (Fig. 1).
compound 5 to have the two iodomethyl groups trans to each other
with respect to the heterocyclic ring (Fig. 2).
Fig. 2. X-ray structure of trans-2,5-bis(iodomethyl)-1-(trifluoromethylsulfonyl)pyrro-
lidine 5. Beside the drawn 2R/5R enantiomer the 2S/5S enantiomer exists in the crystal.
This explains why compound 5 does not react with triflamide to
afford 6, but leaves open the question whether the final product 6 is
formed by pathway B or by pathway A via the transient cis isomer
of 5. Additional light was shed by the experiments with arene-
sulfonamides and methanesulfonamide. The reaction of 1 with
arenesulfonamides 3a,b proceeds in a different way than with tri-
flamide. In both cases, two products were formed in approximately
equal amounts (1:1.1 for 3a and 1:1.2 for 3b) and were identified as
the trans and cis isomers of 2,5-bis(iodomethyl)-1-(arenesulfonyl)
pyrrolidines 7 and 8 (Scheme 3).
Fig. 1. X-ray structure of 3,8-bis(trifluoromethylsulfonyl)-3,8-diazabicyclo[3.2.1]
octane 6.
The formation of 6 is the first example of assembling the
3,8-diazabicyclo[3.2.1]octane framework in one-pot procedure.
A priori, two mechanistic scenarios can be proposed for the for-
mation of the product of bicyclization 6, via the 2,5- (pathway A) or
1,6-cycloaddition (pathway B) to 1,5-hexadiene at the first step of
the reaction (Scheme 2).
Scheme 1. Mono and bicyclization in oxidative triflamidation of 1,5-hexadiene.
Scheme 2. Two possible routes to the product of bicyclization 6.
Scheme 3. Formation of isomeric products of arenesulfonamidation of 1,5-hexadiene.
In pathway A, the formation of 6 is possible only for the cis
The mixture of diastereomers 7a and 8a was separated by col-
umn chromatography and the structure of 8a was determined by
X-ray analysis (Fig. 3). Note, that because of non-planarity of the
pyrrolidine ring, the compound is not meso but exists in the crystal
as a mixture of enantiomers (in solution, the ring is vibrationally
averaged to planarity).
arrangement of the two iodomethyl groups in 2,5-bis(iodomethyl)-
1-(triflyl)pyrrolidine. Therefore, the structure of the isolated
compound 5 (Scheme 1) was of particular interest. A special
experiment showed that compound
5 does not react with
triflamide under the conditions in Scheme 1. X-ray analysis showed
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B.A. Shainyan et al. / Tetrahedron xxx (2014) 1e5
3
enantiomerically pure. For optically active substrate, the reaction is
enantioselective due to the presence of a chiral center.18b
No bicyclic products analogous to 6 are formed with arene-
sulfonamides. Moreover, neither isomer of 2,5-bis(iodomethyl)-1-
(tosyl)pyrrolidine 7a, 8a reacts with triflamide under the oxidative
conditions employed. 1H NMR analysis showed the presence of
unreacted triflamide and the isomers 7a, 8a in the same ratio as in
their mixture taken for the reaction. Formally, it can be considered
as an argument against pathway A and in favor of an alternative
route, e.g., pathway B in Scheme 2 as a route to compound 6.
However, the formation of both isomers 7 and 8 with arenesulfo-
namides 3 makes extremely improbable any mechanism of for-
mation of 6 avoiding the formation of the cis isomer of 5. Rather,
the absence of the products of bicyclization of the type 6 with
arenesulfonamides should be considered as a manifestation of the
difference between triflamide and other sulfonamides. Note also
that no reaction occurred with methanesulfonamide. As was em-
phasized,15 even a small difference in electron-acceptor ability of R
may result in principal changes in reactivity of RSO2NH2, in par-
ticular, in different courses of the reactions with alkenes in the
same oxidative system.16a,19 It was suggested that a strong acceptor
effect of the sulfonyl group brings sulfonamides to such a threshold
of reactivity after which even a moderate effect of the CF3 group
may cause the observed drastic changes.15 With this in mind, we
propose mechanism A to be operative, which can be detalized for
the formation of the products of mono and bicyclization as shown
in Scheme 6.
The inertness of methanesulfonamide 4 under the conditions
employed is, apparently, the result of its less electrophilic character
than sulfonamides 2, 3. Note that alkanesulfonamides are more
rarely than arenesulfonamides used as N1 sulfonamidation uni-
ts19e21 and usually show lower yields.20 The absence of bicyclic
products in the reaction with arenesulfonamides 3 and inactivity of
compounds 7 and 8 with respect to triflamide suggest that the
iodine substitution reaction is very sensitive to the electron-
acceptor ability of the RSO2 group in the molecule of
bis(iodomethyl)-1-(organylsulfonyl)pyrrolidine. Finally, the afore-
mentioned inertness of N-triflylpyrrolidine 5 to triflamide is in-
dicative that the last two steps of the iodine substitution and
cyclization in Scheme 6 are somehow interdependent, otherwise
we should see the products of mono or disubstitution of iodine in 5
by triflamide.
Fig. 3. X-ray structure of the two enantiomers of cis-2,5-bis(iodomethyl)-1-
tosylpyrrolidine 8a.
1H NMR spectra of the cis and trans isomers 7 and 8 are similar
in that they both show the ABX proton system but different in the
relative position of the signals. In one isomer the signals are spaced
by 1.2 ppm (4.1O2.9 ppm), practically as they are in compound 5,
being shifted upfield with respect to 5 by w0.2 ppm due to less
electron withdrawing ability of the tosyl versus the triflyl group.
This allowed us to assign the structure of this more abundant
product to the trans isomer 7a. The signals of the second (minor)
product, cis isomer 8a, are much closer to each other
(3.7O3.3 ppm). The signals of the CH2CH2 group of 8a are well
resolved and shifted upfield with respect to poorly resolved
CH2CH2 signals of 7a, which are closer to the corresponding non-
resolved signals of the trans isomer 5.
Diastereomers 7b and 8b could not be separated, so, the as-
signment was made based on the similarity of their 1H NMR signals
in the spectrum of the mixture of diastereomers to those of their
analogs 7a and 8a. The signals of the major trans-diastereomer 7b
are also spaced by 1.2 ppm (4.2O3.0 ppm) as in 7a, whereas for the
minor cis-diastereomer 8b they almost coincide with the corre-
sponding signals of 8a.
There are only two examples of the reaction of sulfonamides
with compounds containing the 1,5-diene motif. The first is the
gold(I) catalyzed hydroamination of 1,5-hexadienes leading to
w1:1.7 mixture of the cis and trans adducts (Scheme 4).17
3. Conclusions
Scheme 4. Au(I)-catalyzed heterocyclization of 1,5-dienes with tosylamide.
In summary, the reaction of 1,5-hexadiene with triflamide under
oxidative conditions affords trans-2,5-bis(iodomethyl)-1-(tri-
fluoromethylsulfonyl)pyrrolidine and 3,8-bis(trifluoromethylsul
fonyl)-3,8-diazabicyclo[3.2.1]octane, whereas with less electro-
philic arenesulfonamides the reaction stops at the isomeric 2,5-
The second is the formation of 2,5-diiodo-9-(trifluoromethy
lsulfonyl)-9-azabicyclo[4.2.1]nonane containing the pyrrolidine
motif by the reaction of oxidative triflamidation of 1,5-cyclo
octadiene (the cyclic analog of compound 1) (Scheme 5).16c
bis(iodomethyl)-1-(arenesulfonyl)pyrrolidines.
The
proposed
mechanism includes the formation of cis and trans isomers of 2,5-
bis(iodomethyl)-1-(organylsulfonyl)pyrrolidines. The trans isomer
is the final product both for triflamide and arenesulfonamides, while
the fate of the cis isomer depends on the substituent in the sulfonyl
group. The reaction with triflamide provides the first example of
one-pot assemblingof the 3,8-diazabicyclo[3.2.1]octane framework.
4. Experimental section
4.1. General
Scheme 5. Oxidative heterocyclization of 1,5-cyclooctadiene with triflamide.
Usually, 2,5-disubstituted pyrrolidines are prepared by hetero-
cyclization by substitution of Br7 or OTs18 groups in the
eCXeCeCeCXe motif by amines. What is important to our study is
that the cis and trans isomers are formed in comparable yields,7c,18b
unless the substrate, which is involved in heterocyclization, is
IR spectra were taken on a Bruker Vertex 70 spectrophotometer
in KBr. 1H, 13C, and 19F NMR spectra were recorded on a Bruker DPX
400 spectrometer at working frequencies 400 (1O), 100 (13S), and
376 (19F) MHz; 1H and 13C NMR chemical shifts are reported in parts
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4
B.A. Shainyan et al. / Tetrahedron xxx (2014) 1e5
Scheme 6. A tentative mechanism of mono and bicyclization during oxidative sulfamidation of 1,5-hexadiene.
per million downfield to TMS, and 19F NMR in ppm downfield to
CFCl3. The HRMS ESI spectra were recorded using a Micromass Q-
TOFmicro mass spectrometer in positive electrospray mode with an
electron energy of 70 eV. Elemental compositions were determined
by accurate mass measurement with standard deviation <5 ppm.
H3PO4 was used as reference compound. Elemental analysis on C, H,
and N was carried out on an elemental analyzer from Thermo-
Finnigan (Milan, Italy) model Flash EA. X-ray crystal structure de-
terminations were performed on an Imaging Plate Diffraction
System IPDS-2 (Stoe) at 210 K using graphite monochromatized Mo
(2H, d, J 12.4 Hz, CHBI), 2.18 (2H, m, CHA in CH2), 2.09 (2H, m, CHB in
CH2); dC (CD2Cl2) 120.2 (q, J 321.0 Hz, CF3), 119.8 (q, J 319.5 Hz, CF3),
58.4 (C1,5), 53.3 (C2,4), 27.8 (C6,7); dF (CDCl3) ꢁ75.71, ꢁ78.21; HRMS
calcd for C8H10F6N2O4S2 (Mþ) 375.9986. Found: 395.9983.
4.2.4. Reaction of 1,5-hexadiene with tosylamide 3a. t-BuOCl (4 mL,
35 mmol) was added dropwise to a solution of tosylamide 3a (2 g,
12 mmol), NaI (5.85 g, 35 mmol), and 1,5-hexadiene (1.4 mL,
12 mmol) in MeCN (80 mL) upon stirring in argon atmosphere in
the dark at ꢁ6ꢀS in the course of 6 h. Then the solvent was removed
under vacuum, the residue was dissolved in CHCl3, washed with
aqueous Na2S2O3, and dried over CaCl2. The solvent was removed
and the residue was purified from tarry admixtures by eluting on
a silica column (hexane/Et2O 2:1). The crude product (4.8 g, 81%)
consisted of the trans and cis isomers of 2,5-bis(iodomethyl)-1-
(tolylsulfonyl)pyrrolidine 7a and 8a in w2:1 ratio, which were
separated on a silica column to give fractions enriched with each
isomer, from which the analytically pure isomers (0.4 g of
(R,RþS,S)-2,5-bis(iodomethyl)-1-(tolylsulfonyl)pyrrolidine, 7a, and
0.28 g of (R,S)-2,5-bis(iodomethyl)-1-(tolylsulfonyl)pyrrolidine, 8a)
were isolated by crystallization from ethyl acetate.
Ka radiation.
4.2. Synthesis
4.2.1. Reaction of 1,5-hexadiene with triflamide 2. t-BuOCl (9.2 mL,
81 mmol) was added dropwise to a solution of triflamide 2 (4 g,
27 mmol), NaI (12.1 g, 81 mmol), and 1,5-hexadiene (3.2 mL,
27 mmol) in MeCN (120 mL) at 4ꢀS. The mixture was stirred for 24 h
in argon atmosphere in the dark, then concentrated on a rotary
evaporator, the residue treated with aqueous Na2S2O3 (80 mL),
extracted with ether (80 mL), the extract dried over CaCl2, the sol-
vent removed to give w9 g of dark brown residue, which was eluted
on a silica column (hexane, hexane/Et2O 1:1) to afford trans-2,5-
bis(iodomethyl)-1-(trifluoromethylsulfonyl)pyrrolidine 5 (7.02 g,
54%) and 3,8-bis(trifluoromethylsulfonyl)-3,8-diazabicyclo[3.2.1]
octane 6 (1.88 g, 37% with respect to triflamide, taking into account
the presence of two triflamide residues in the molecule). Analyti-
cally pure samples were obtained by crystallization from hexane.
4.2.5. (R,RþS,S)-2,5-Bis(iodomethyl)-1-(tolylsulfonyl)pyrrolidine,
7a. Colorless crystals, mp 133 ꢀC. IR spectrum of 7a is similar to that
of 8a; dH (CDCl3) 7.69 (2H, d, J 8.2 Hz, CHo), 7.29 (2H, d, J 8.2 Hz,
CHm), 4.13 (2H, m, CH), 3.67 (2H, dd, J 9.7, 2.7 Hz, CHAI), 2.94 (2H, t, J
9.7 Hz, CHBI), 2.45 (3H, s, CH3), 2.11 (2H, m, CHA in CH2), 2.04 (2H, m,
CHB in CH2). dC (CDCl3) 143.8 (Cp), 138.4 (C-1), 129.9 (Cm), 126.8 (Co),
62.1 (CH), 28.9 (CH2), 21.5 (CH3), 8.3 (CH2I). Anal. Calcd: C, 30.91; H,
3.39; N, 2.77. Found: C, 30.86; H, 3.41; N, 3.17.
4.2.2. trans-2,5-Bis(iodomethyl)-1-(trifluoromethylsulfonyl)pyrroli-
dine, 5. Colorless crystals, mp 96 ꢀC; nmax (KBr) 2985, 1384, 1225,
1202, 1190, 1146 cmꢁ1
;
dH (CDCl3) 4.33 (2H, br s, NCH), 3.70 (2H, m,
4.2.6. (R,S)-2,5-Bis(iodomethyl)-1-(tolylsulfonyl)pyrrolidine,
8a. Colorless crystals, mp 145 ꢀC. nmax 3039, 2944, 1599, 1447, 1343,
1206, 1164, 1091, 1026, 971, 817, 770, 706, 665, 580, 553; dH (CDCl3)
7.70 (2H, d, J 8.1 Hz, CHo), 7.33 (2H, d, J 8.1 Hz, CHm), 3.71 (2H, m,
CH), 3.56 (2H, dd, J 9.9, 3.0 Hz, CHAI), 3.27 (2H, t, J 9.9 Hz, CHBI), 2.42
(3H, s, CH3), 1.86 (2H, m, CHA in CH2), 1.69 (2H, m, CHB in CH2). dC
(CDCl3) 144.4 (Cp), 133.8 (C-1), 130.1 (Cm), 127.6 (Co), 63.1 (CH), 30.0
(CH2), 21.6 (CH3), 11.14 (CH2I); Anal. Calcd: C, 30.91; H, 3.39; N, 2.77.
Found: C, 30.41; H, 3.19; N, 3.19.
CHAI), 3.10 (2H, m, CHBI), 2.28 (4H, m, CH2); dH (C6D6) 3.91 (2H, br s,
NCH), 3.46 (4H, m, CHAI), 2.50 (2H, d, J 10.3 Hz, CHBI), 1.53 (2H, m,
CHA in CH2), 1.42 (2H, m, CHB in CH2); dC (CDCl3) 119.5 (q, J 323.6 Hz,
CF3), 63.5 (NC), 29.0 (br, CH2), 5.8 (br, CH2I); dF (CDCl3) ꢁ74.88;
HRMS calcd for C7H10F3I2NO2S (Mþ) 482.8474. Found: 482.8476;
Anal. Calcd: C, 17.41; H, 2.09; N, 2.90; S, 6.64. Found: C, 17.56; H,
2.12; N, 2.98; S, 6.98.
4.2.3. 3,8-Bis(trifluoromethylsulfonyl)-3,8-diazabicyclo[3.2.1]octane,
6. Colorless crystals, mp 153 ꢀC; nmax (KBr) 2967, 1388, 1229, 1191,
1103; dH (CDCl3) 4.43 (2H, s, NCH), 3.82 (2H, d, J 12.4 Hz, CHAI), 3.41
4.2.7. Reaction of 1,5-hexadiene with phenylsulfonamide 3b. To the
solution of 1 g (6.4 mmol) of benzenesulfonamide 3b, 0.75 mL
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B.A. Shainyan et al. / Tetrahedron xxx (2014) 1e5
5
(6.4 mmol) of 1,5-hexadiene and 2.9 g (19 mmol) of dry NaI in
MeCN (40 mL) 2.2 mL (19 mmol) of t-BuOCl was added dropwise in
argon atmosphere in the dark with cooling. The mixture was stirred
for 1 day, then treated with aqueous Na2S2O3 (80 mL), extracted
with ethyl acetate (80 mL), and dried over CaCl2. The solvent was
removed in vacuum to afford 2.5 g (80%) of dark residue, which was
purified on a silica column (0.063e0.200 mm) by gradual elution
with hexane, ether/hexane 1:1, ether. Triflamide (w0.2 g) was re-
covered and 1.5 g of 7b/8b was obtained. All trials to separate the
obtained mixture to pure diastereomers by column separation or
fractional crystallization failed. Mp 106.6ꢀS; nmax 3044, 2942, 1584,
1445, 1349, 1207, 1159, 1093, 1021, 979, 832, 775, 719, 667, 582, 569;
Anal. Calcd, %: S, 29.35; O, 3.08; N, 2.85; S, 6.53. Found, %: S, 29.74;
O, 3.03; N, 2.79; S, 6.54.
crystallographic data for this paper. These data can be obtained free
of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
The financial support of this work by the Russian Foundation for
Basic Research and Deutsche Forschungsgemeinschaft (Grants
RFBR 13-03-00055 and RFBR-DFG 11-03-91334) is greatly
acknowledged.
Supplementary data
Experimental details, spectroscopic data, and X-ray structural
information for new compounds (CCDC 931587 (5), 931588 (6),
980000 (8a)). Supplementary data related to this article can be
found at http://dx.doi.org/10.1016/j.tet.2014.04.095.
4.2.8. (R,S)-2,5-Bis(iodomethyl)-1-(benzenesulfonyl)pyrrolidine,
7b. dH (CDCl3) 7.86 (2H, d, J 7.3 Hz, CHo), 7.57 (3H, m, CHmþp), 4.20
(2H, m, CH), 3.70 (2H, dd, J 9.8, 2.5 Hz, CHAI), 3.00 (2H, t, J 10.0 Hz,
CHBI), 2.19 (2H, m, CHA in CH2), 2.07 (2H, m, CHB in CH2); dC (CDCl3)
136.9 (Cp), 133.6 (C-1), 129.6 (Cm), 127.8 (Cp), 62.3 (CH), 29.2 (CH2),
8.5 (CH2I).
References and notes
1. Barlocco, D.; Cignarella, G.; Tondi, D.; Vianello, P.; Villa, S.; Bartolini, A.; Ghe-
lardini, C.; Galeotti, N.; Anderson, D. J.; Kuntzweiler, T. A.; Colombo, D.; Toma, L.
J. Med. Chem. 1998, 41, 674.
4.2.9. (R,S)-2,5-Bis(iodomethyl)-1-(benzenesulfonyl)pyrrolidine,
8b. dH (CDCl3) 7.86 (2H, d, J 7.3 Hz, CHo), 7.57 (3H, m, CHmþp), 3.75
(2H, m, CH), 3.60 (2H, dd, J 9.9, 2.9 Hz, CHAI), 3.33 (2H, t, J 9.9 Hz,
CHBI), 1.90 (2H, m, CHA in CH2), 1.72 (2H, m, CHB in CH2); dC (CDCl3)
141.7 (Cp), 133.2 (C-1), 129.7 (Cm), 127.0 (Co), 63.3 (CH), 30.2 (CH2),
11.2 (CH2I).
ꢁ
ꢁ
ꢁ
2. (a) Villa, S.; Barlocco, D.; Cignarella, G.; Papp, G. J.; Balati, B.; Takacs, J.; Varro, A.;
^
ꢁ
Borosy, A.; Keseru, K.; Matyus, P. Eur. J. Med. Chem. 2001, 36, 495; (b) Artali, R.;
Barlocco, D.; Bombieri, G.; Meneghetti, F. Heterocycles 2002, 57, 439.
3. Filosa, R.; Peduto, A.; Caprariis, P.; Saturnino, C.; Festa, M.; Petrella, A.; Pau, A.;
Pinna, G. A.; La Colla, P.; Busonera, B.; Loddo, R. Eur. J. Med. Chem. 2007, 42, 293.
4. Cignarella, G.; Nathansohn, G. J. Org. Chem. 1961, 26, 1500.
5. (a) Garner, P.; Sunitha, K.; Shanthilal, T. Tetrahedron Lett. 1988, 29, 3525; (b)
Garner, P.; Arya, F.; Ho, W.-B. J. Org. Chem. 1990, 55, 412; (c) Garner, P.; Ho, W.-
B.; Shin, H. J. Am. Chem. Soc. 1992, 114, 2767; (d) Garner, P.; Ho, W.-B.; Shin, H. J.
Am. Chem. Soc. 1993, 115, 10742.
6. Grygorenko, O. O.; Radchenko, D. S.; Volochnyuk, D. M.; Tolmachev, A. A.;
Komarov, I. V. Chem. Rev. 2011, 111, 5506.
4.2.10. Reaction of 1,5-hexadiene with methanesulfonamide
4. Methanesulfonamide 4 (3 g, 32 mmol) and 14.2 g (95 mmol) of
NaI were dissolved in 120 mL of MeCN, the mixture was cooled
upon stirring to ꢁ35 ꢀC and 3.7 mL (32 mmol) of 1,5-hexadiene was
added. Then 11 mL (95 mmol) of t-BuOCl was added dropwise
under argon in the dark in the course of 10 min and the mixture was
stirred with TLC monitoring for 24 h. The spot of MeSO2NH2 did not
disappear. The mixture was treated as above and the residue ana-
lyzed by NMR, which revealed the presence of mainly the starting
material.
7. (a) Cignarella, G.; Kathansohn, G. G. Gazz. Chim. Ital. 1960, 90, 1406; (b)
Cignarella, G.; Nathansohn, G.; Occelli, E. J. Org. Chem. 1961, 26, 2747; (c)
Blackman, S. W.; Baltzly, R. J. Org. Chem. 1961, 26, 2750; (d) Schipper, E.;
Boehme, W. R. J. Org. Chem. 1961, 26, 3599; (e) Cignarella, G.; Occelli, E.; Cris-
tiani, G.; Paduano, L.; Testa, E. J. Med. Chem. 1963, 6, 764; (f) Cignarella, G.;
Occelli, E.; Testa, E. J. Med. Chem. 1965, 8, 326.
ꢂ
ꢂ
8. Paliulis, O.; Peters, D.; Miknius, L.; Sackus, A. Org. Prep. Proced. Int. 2007, 39, 86.
9. Pichlmair, S.; Mereiter, K.; Jordis, U. Tetrahedron Lett. 2004, 45, 1481.
10. Katritzky, A.; Dennis, N. Chem. Rev. 1989, 89, 827.
11. (a) Kiss, M.; Russell-Maynard, J.; Joule, J. A. Tetrahedron Lett. 1987, 28, 2187; (b)
Allway, P. A.; Sutherland, J. K.; Joule, J. A. Tetrahedron Lett. 1990, 31, 4781; (c)
Yates, N. D.; Peters, D. A.; Allway, P. A.; Beddoes, R. L.; Scopes, D. I. C.; Joule, J. A.
Heterocycles 1995, 40, 331; (d) Helliwell, M.; You, Y.; Joule, J. A. Acta Crystallogr.
2006, E62, o1293; (e) Helliwell, M.; You, Y.; Joule, J. A. Acta Crystallogr. 2006,
E62, o2318; (f) Helliwell, M.; Yun, Y.; Joule, J. A. Heterocycles 2006, 70, 87; (g)
Joomun, Z.; Raftery, J.; Delawarally, K.; Laulloo, S. J.; Joule, J. A. Arkivoc 2007, 51.
12. (a) Wessig, P.; Legart, F.; Hoffmann, B.; Henning, H.-G. Liebigs Ann. Chem. 1991,
979; (b) Liu, H.; Cheng, T.-M.; Zhang, H.-M.; Li, R.-T. Arch. Pharm. Pharm. Med.
Chem. 2003, 336, 510; (c) Singh, R. K.; Jain, S.; Sinha, N.; Mehta, A.; Naqvi, F.;
Agarwal, A. K.; Ananda, N. Tetrahedron Lett. 2007, 48, 545; (d) Huang, L. J.; Teng,
D. W. Chin. Chem. Lett. 2011, 22, 523.
4.3. X-ray measurements
Crystal data for 5: C7H10F3I2NO2S, Mr¼483.02 g molꢁ1, crystal
dimensions 0.50ꢂ0.45ꢂ0.40 mm, orthorhombic, space group Pbca,
3
ꢀ
ꢀ
a¼9.0384(4), b¼13.1528(6), c¼22.3699(8) A, V¼2659.3(2) A , Z¼8,
cmꢁ1
;
m
(Mo
K
a
)¼4.91 mmꢁ1
(
l
¼0.71073 A),
ꢀ
rcalcd¼2.413
g
T¼210 K; 2Qmax¼49.16ꢀ, 15,171 reflections measured, 2226 unique
(Rint¼0.0582), R¼0.0439, wR¼0.1125 (I>2
s(I)).
Crystal data for 6: C8H10F6N2O4S2, Mr¼376.30 g molꢁ1, crystal di-
13. Dinsmore, C. J.; Bergman, J. M.; Bogusky, M. J.; Culberson, J. C.; Hamilton, K. A.;
Graham, S. L. Org. Lett. 2001, 3, 865.
mensions 1.0ꢂ1.5ꢂ0.05 mm, triclinic, space group P1; a¼6.5267(5),
14. Rikimaru, K.; Mori, K.; Kan, T.; Fukuyama, T. Chem. Commun. 2005, 394.
15. Shainyan, B. A.; Tolstikova, L. L. Chem. Rev. 2013, 113, 699.
16. (a) Shainyan, B. A.; Moskalik, M. Y.; Starke, I.; Schilde, U. Tetrahedron 2010, 66,
8383; (b) Moskalik, M. Y.; Shainyan, B. A. Russ. J. Org. Chem. (Engl. Transl.) 2011,
47, 568; (c) Moskalik, M. Y.; Shainyan, B. A.; Schilde, U. Russ. J. Org. Chem. (Engl.
Transl.) 2011, 47, 1271; (d) Shainyan, B. A.; Moskalik, M. Y.; Astakhova, V. V. Russ.
J. Org. Chem. (Engl. Transl.) 2012, 48, 918; (e) Moskalik, M. Y.; Astakhova, V. V.;
Shainyan, B. A. Russ. J. Org. Chem. (Engl. Transl.) 2012, 48, 1530; (f) Moskalik, M.
Y.; Shainyan, B. A.; Astakhova, V. V.; Schilde, U. Tetrahedron 2013, 69, 705; (g)
Moskalik, M. Y.; Astakhova, V. V.; Shainyan, B. A. Russ. J. Org. Chem. (Engl. Transl.)
2013, 49, 761.
17. Zhang, J.; Yang, C.-G.; He, C. J. Am. Chem. Soc. 2006, 128, 1798.
18. (a) Marzi, M.; Misiti, D. Tetrahedron Lett. 1989, 30, 6075; (b) Takahata, H.; Ta-
kahashi, S.; Kouno, S.; Momose, T. J. Org. Chem. 1998, 63, 2224.
19. Minakata, S.; Morino, Y.; Oderaotoshi, Y.; Komatsu, M. Chem. Commun. 2006,
3337.
¼116.385(6)ꢀ,
b
¼91.289(7)ꢀ,
ꢀ
b¼11.0005(9ꢀ), c¼11.1688(10) A,
a
3
ꢀ
g
¼95.530(6) , V¼713.1(1) A , Z¼2, rcalcd¼1.753 g cmꢁ1
;
m
(Mo K
a
)¼
0.460 mmꢁ1
(
l
¼0.71073 A), T¼150 K; 2Qmax¼49.99ꢀ, 4612 re-
ꢀ
flections measured, 2356 unique (Rint¼0.0646), R¼0.0457,
wR¼0.1230 (I>2
s(I)).
Crystal data for 8a: C13H17I2NO2S, Mr¼505.14 g molꢁ1, crystal di-
mensions 0.8ꢂ0.7ꢂ0.4 mm, monoclinic, space group P21/n,
¼98.076(5)ꢀ,
ꢀ
a¼7.8509(6), b¼11.2192(5), c¼18.9203(12) A,
b
3
ꢀ
V¼1649.99(18) A , Z¼4, rcalcd¼2.033
g
cmꢁ1
;
m
(Mo
K
a
)¼
3.936 mmꢁ1
(l
¼0.71073 A), T¼210 K; 2Qmax¼50.00ꢀ, 10,389 re-
ꢀ
flections measured, 2826 unique (Rint¼0.1288), R¼0.0661,
wR¼0.1774 (I>2
s(I)).
20. Ando, T.; Kano, D.; Minakata, S.; Ryu, I.; Komatsu, M. Tetrahedron 1998, 54,
13485.
21. Nagamachi, T.; Takeda, Y.; Nakayama, K.; Minakata, S. Chem.dEur. J. 2012, 18,
12035.
For details of the data collection and the structure solution and
refinement, see Supplementary data. CCDC 931587 (5), CCDC
931588 (6), and CCDC 980000 (8a) contain the supplementary
Please cite this article in press as: Shainyan, B. A.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.04.095