Preparation of 1-tosyloxy-4-substituted-2-butenes using Ag(I) salts

Article abstract of DOI:10.1016/j.tetlet.2015.05.100

Abstract The trans-fluoro-2-butenyl group has been previously utilized as an N-substituent on several nortropanes for imaging the dopamine transporter with positron emission tomography. We report here a simplified and shorter synthesis of trans-1-tosyloxy

Full text of DOI:10.1016/j.tetlet.2015.05.100

Tetrahedron Letters 56 (2015) 4480–4482
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Tetrahedron Letters
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Preparation of 1-tosyloxy-4-substituted-2-butenes using Ag(I) salts
⇑
Jeffrey S. Stehouwer , Mark M. Goodman
Center for Systems Imaging, Department of Radiology and Imaging Sciences, Emory University, WWHC 209, 1841 Clifton Rd NE, Atlanta, GA 30329, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The trans-fluoro-2-butenyl group has been previously utilized as an N-substituent on several nortropanes
for imaging the dopamine transporter with positron emission tomography. We report here a simplified
and shorter synthesis of trans-1-tosyloxy-4-substituted-2-butenes using Ag(I) salts. This methodology
was also applied to the synthesis of the cis-isomers. Furthermore, these procedures allow for the recovery
of the majority of the Ag(I) ions.
Received 5 May 2015
Revised 22 May 2015
Accepted 26 May 2015
Available online 30 May 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Fluorobutenyl-tosylate
N-Fluorobutenyl-nortropane
Fluorine-18
Positron emission tomography
Several N-(E)-fluoro-2-butenyl-nortropanes (Scheme 1) have
been previously reported as high affinity ligands of the dopamine
transporter (DAT) and which can be radiolabeled with fluorine-
18 for imaging the DAT with positron emission tomography
(PET).1–4 trans-1,4-Ditosyloxy-2-butene (1) was initially prepared
by multi-step syntheses and then reacted with tetrabutylammo-
nium fluoride to give trans-4-fluoro-1-tosyloxy-2-butene (2) which
was then reacted with the various nortropanes to provide the N-
(E)-fluoro-2-butenyl-nortropanes (Scheme 1).1–4 Radiolabeling
was performed by reacting 1 with K18F/K2.2.2 to give [18F]2, which
was then reacted with the various nortropanes to give the 18F PET
tracers.1,3,5 Subsequently, trans-4-chloro-1-tosyloxy-2-butene (3)
was prepared and reacted with the tolyl-nortropane to provide
the N-(E)-chloro-2-butenyl-nortropane that could then be used
as a one-step 18F-radiolabeling precursor.6 The preparation of 1,
2, and 3 all require multiple synthetic steps.2–4,6 Herein, we report
a simplified synthesis of 1, 2, and trans-4-bromo-1-tosyloxy-2-
butene (4), which can serve as a replacement for 3, all of which
can be obtained in 1 or 2 steps from commercially available
trans-1,4-dibromo-2-butene (5) using Ag(I) salts.7–9 Additionally,
we have applied this methodology to the synthesis of the cis-iso-
mers using commercially available cis-1,4-dichloro-2-butene (6).
Furthermore, these procedures allow for the recovery of the major-
ity of the Ag(I) ions which would reduce the cost if these com-
pounds were to be prepared commercially.
This reaction was significantly faster (3 h) than a similar reaction
with 1,4-dibromobutane which took 17 h to afford 1,4-ditosy-
loxybutane in 91% yield.10 The proposed mechanism8,9 of the
reaction of silver salts with alkyl iodides involves an ion-pair
intermediate in the transition state. Presumably, the carbocation
formed from 5 is stabilized by being in an allylic position which
accelerates the reaction relative to the non-stabilized carbocation
that is formed from 1,4-dibromobutane. When 5 was reacted with
AgOTs (1 equiv) in refluxing CH3CN for 2 h (Scheme 2), compound
4 was obtained in 56% yield and compound 1 was obtained in 20%
yield. Thus, the product distribution of 1 and 4 can be controlled by
the ratio of AgOTs employed and the reaction time. When com-
pound 4 was reacted with AgF (1.1 equiv) in refluxing CH3CN for
2 h, compound 2 was obtained in 51% yield and compound 1 was
obtained in 15% yield. The fact that 1 was obtained from this reac-
tion suggests that AgOTs was formed in situ and then reacted with
4. AgOTs could be formed in situ if the fluoride ion displaced the
tosylate group from 4 or 2 by an SN2 mechanism. The nucleophilic-
ity of AgF was tested by reacting 1 with AgF (1.2 equiv) in refluxing
CH3CN for 2 h which afforded 2 in 27% yield (unreacted 1 was
recovered in 59% yield). Thus, the fluoride ion of AgF is capable
of nucleophilic displacement of a tosylate group. This was repeated
by reacting 1 with KF/18-crown-6 in refluxing CHCl3 for 16 h
which produced 2 in 38% yield (unreacted 1 was recovered in
33% yield). Thus, it is not clear if AgF reacts with alkyl bromides
through an SN2 mechanism, through the previously proposed
ion-pair mechanism,8,9 or a combination of both. For example, in
the reaction of 4 with AgF, fluoride ion could displace the tosylate
group of 4 to give 1-bromo-4-fluoro-2-butene which would then
react with in situ-generated AgOTs to give 2. Alternatively, Ag
As shown in Scheme 2, reaction of 5 with AgOTs (2.5 equiv) in
refluxing CH3CN for 3 h afforded 1 in 95% yield after silica gel
purification (see Supplementary data for experimental details).
⇑
Corresponding author. Tel.: +1 404 712 1201.
E-mail address: jstehou@emory.edu (J.S. Stehouwer).
http://dx.doi.org/10.1016/j.tetlet.2015.05.100
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

J. S. Stehouwer, M. M. Goodman / Tetrahedron Letters 56 (2015) 4480–4482
4481
TsO
AgOTs
OTs
-
Cl
OTs
Cl
TsO
(2.6 equiv)
1
X
H
6
7
18/19F
N
N
O
O
54%
AgOTs
(1.2 equiv)
34%
TsO
TsO
KF/18-C-6
(44%)
OMe
OMe
18/19F
2
or
R
R
X = F,18F,Cl
R = F,Cl,Br,I,Me
AgF
X
R = F,Cl,Br,I,Me
Cl
F
TsO
TsO
Cl
9
3
Scheme 3.
Scheme 1.
ion could abstract bromide from 4 to give the ion pair8,9 which
would then react with fluoride to give 2.
Herein, we have described improvements in the preparation of
1,4-substituted-2-butenes. Previously, compound 1 was obtained
by ditosylation of trans-1,4-dihydroxy-2-butene1–5,11,12 which
was obtained by reduction of 1,4-dihydroxy-2-butyne,1,4,13,14
reduction of dimethylfumarate,2,5 hydrolysis of trans-1,4-diace-
toxy-2-butene,3,11,15,16 or cross-metathesis of allyl alcohol.12 The
previous methods all required multiple steps whereas our new
method allows 1 to be obtained in high yield after a single step
and mild conditions from commercially available 5. This new
methodology also provides a simplified preparation of 7 compared
to the previously reported procedure.17 Furthermore, we have
developed a simple method of preparing unsymmetrical 1,4-sub-
stituted-2-butenes which only relies on adjusting the ratio of
Ag(I) salt to starting material and using shorter reaction times.
Compound 2 can now easily be obtained in a single step with a
2-h reaction time followed by a simple purification. This method-
ology also affords easy access to 4 which otherwise would have
to be prepared from trans-1,4-dihydroxy-2-butene6 or by reduc-
tion of methyl 4-bromocrotonate to give trans-1-bromo-4-hy-
droxy-2-butene18 followed by tosylation of the alcohol.
Additionally, these procedures allow for the simple preparation
of 7, 8, and 9 which now provides easier access to cis-halo-2-
butenylamines.19,20
Compound 2 can also be prepared directly from 5 in one step by
the following three methods (performed side-by-side on the same
day and with the same molar scale of 5; see experimental details in
Supplementary data): (1) Compound 4 was prepared in situ by
refluxing 5 and AgOTs (1 equiv) for 1 h in CH3CN, and then con-
verted to 2 by the addition of AgF (1.25 equiv) and refluxing for
1 h. After purification, 2 was obtained in 40% yield and 1 was
obtained in 27% yield. (2) 1-Bromo-4-fluoro-2-butene was pre-
pared in situ by refluxing 5 and AgF (1.3 equiv) for 1 h in CH3CN,
and then converted to 2 by the addition of AgOTs (1 equiv) and
refluxing for 1 h. After purification, 2 was obtained in 27% yield
and 1 was obtained in 16% yield. This method was repeated on a
separate day and on a slightly larger scale and afforded 2 in 40%
yield and 1 in 10% yield. (3) Compound 5, AgOTs (1 equiv), and
AgF (1.3 equiv) were stirred for 2 h in refluxing CH3CN. After purifi-
cation, 2 was obtained in 24% yield and 1 was obtained in 21%
yield. Thus, various procedures have been developed that allow 2
to be prepared from 1, 4, or 5. In all cases the sample of 2 had
minor baseline impurities in the 1H NMR spectrum (see Figs. S6–
S10, Supplementary data) with the least amount of impurities
when 2 was prepared from 5 by Methods 2 and 3, and more impu-
rities when 2 was prepared from 4. The amount of impurities did
not increase with storage as 2 was shown to be stable for >1 year
In summary, we have developed a simplified and shorter proce-
dure for the preparation of 1, 2, and 4 which allows these com-
pounds to be prepared in
a single step from commercially
when stored in
a freezer (Fig. S6, Supplementary data).
available 5 and Ag(I) salts. These procedures also allow for the
recovery of the Ag(I) halides and any unreacted AgOTs.
Furthermore, these procedures can be used to prepare 7 and 8 from
commercially available 6, and compound 9 can be prepared from 7
using KF/18-crown-6. In all cases of our new methodology stereo-
chemical integrity is maintained.
Furthermore, the impurities did not interfere with the ability to
use 2 as an N-alkylating agent.
These procedures were then applied to the preparation of the
cis-isomers (Scheme 3). Reaction of 6 with AgOTs (2.6 equiv) in
refluxing CH3CN for 15 h afforded 7 in 54% yield after purification
(a mixture of 7 and 8 was also isolated). The lower yield of 7 and
longer reaction time required relative to the preparation of 1
may be the result of lower reactivity of chlorides relative to bro-
mides during formation of the ion-pair intermediate.8,9
Compound 8 was obtained in 34% yield after reacting 6 with
AgOTs (1.2 equiv) in refluxing CH3CN for 75 min. Conversion of
8–9 using AgF was not successful, and attempted preparation of
9 directly from 6 was also not successful after several attempts,
except for one instance where 9 was obtained in 2% yield.
Therefore, 9 was prepared from 7 using KF/18-crown-6 in CHCl3
and was obtained in 44% yield after purification (with 40% recovery
of unreacted 7).
Acknowledgements
This research was sponsored by NIH/NIMH (1-R21-MH-66622-
01 and 2U19 MH069056).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.05.
100.
References and notes
Br
AgOTs (2.5 equiv)
95%
TsO
Br
OTs
1. Chen, P.; Kilts, C. D.; Camp, V. M.; Ely, T. D.; Keil, R.; Malveaux, E.; Votaw, J.;
Hoffman, J. M.; Goodman, M. M. J. Labelled Compd. Radiopharm. 1999, 42, S400.
2. Dollé, F.; Emond, P.; Mavel, S.; Demphel, S.; Hinnen, F.; Mincheva, Z.; Saba, W.;
Valette, H.; Chalon, S.; Halldin, C.; Helfenbein, J.; Legaillard, J.; Madelmont, J.-C.;
Deloye, J.-B.; Bottlaender, M.; Guilloteau, D. Bioorg. Med. Chem. 2006, 14, 1115–
1125.
5
1
AgF (27%)
or
AgOTs (1 equiv)
AgF
AgOTs
(1 equiv)
56%
KF/18-C-6
(38%)
(~1.25 equiv)
(24 - 40%)
3. Stehouwer, J. S.; Daniel, L. M.; Chen, P.; Voll, R. J.; Williams, L.; Plott, S. J.; Votaw,
J. R.; Owens, M. J.; Howell, L.; Goodman, M. M. J. Med. Chem. 2010, 53, 5549–
5557.
TsO
TsO
AgF (1.1 equiv)
51%
Br
F
4
2
4. Goodman, M. M.; Chen, P. WO 2000064490 A1, 2000.
5. Dollé, F.; Hinnen, F.; Emond, P.; Mavel, S.; Mincheva, Z.; Saba, W.; Schöllhorn-
Peyronneau, M.-A.; Valette, H.; Garreau, L.; Chalon, S.; Halldin, C.; Helfenbein,
Scheme 2.

4482
J. S. Stehouwer, M. M. Goodman / Tetrahedron Letters 56 (2015) 4480–4482
J.; Legaillard, J.; Madelmont, J.-C.; Deloye, J.-B.; Bottlaender, M.; Guilloteau, D. J.
Labelled Compd. Radiopharm. 2006, 49, 687–698.
12. Edwards, G. A.; Culp, P. A.; Chalker, J. M. Chem. Commun. 2015, 515–518.
13. Miller, A. E. G.; Biss, J. W.; Schwartzman, L. H. J. Org. Chem. 1959, 24, 627–630.
14. Organ, M. G.; Cooper, J. T.; Rogers, L. R.; Soleymanzadeh, F.; Paul, T. J. Org. Chem.
2000, 65, 7959–7970.
6. Dollé, F.; Helfenbein, J.; Hinnen, F.; Mavel, S.; Mincheva, Z.; Saba, W.;
Schöllhorn-Peyronneau, M.-A.; Valette, H.; Garreau, L.; Chalon, S.; Halldin, C.;
Madelmont, J.-C.; Deloye, J.-B.; Bottlaender, M.; Le Gailliard, J.; Guilloteau, D.;
Emond, P. J. Labelled Compd. Radiopharm. 2007, 50, 716–723.
7. Emmons, W. D.; Ferris, A. F. J. Am. Chem. Soc. 1953, 75, 2257.
8. Hoffmann, H. M. R. J. Chem. Soc. 1965, 6748–6753.
9. Hammond, G. S.; Hawthorne, M. F.; Waters, J. H.; Graybill, B. M. J. Am. Chem.
Soc. 1960, 82, 704–711.
10. Stehouwer, J. S.; Birnbaum, M. S.; Voll, R. J.; Owens, M. J.; Plott, S. J.; Bourke, C.
H.; Wassef, M. A.; Kilts, C. D.; Goodman, M. M. 2015, Unpublished results.
11. Asuma, Y.; Suzuki, T.; Hidaka, T.; Asada, K.; Miyake, R.; Dekishima, Y.;
Kawabata, H. US 2013/0096339 A1; PCT/JP2011/053285, 2013.
15. Raphael, R. A. J. Chem. Soc. 1952, 401–405.
16. Bouquillon, S.; Muzart, J. Eur. J. Org. Chem. 2001, 3301–3305.
17. Malanga, C.; Pagliai, L.; Menicagli, R. Synth. Commun. 1990, 20, 2821–2826.
18. Kinoshita, M.; Takami, H.; Taniguchi, M.; Tamai, T. Bull. Chem. Soc. Jpn. 1987, 60,
2151–2161.
19. Casara, P.; Marchal, P.; Wagner, J.; Danzin, C. J. Am. Chem. Soc. 1989, 111, 9111–
9113.
20. Hsin, L.-W.; Webster, E. L.; Chrousos, G. P.; Gold, P. W.; Eckelman, W. C.;
Contoreggi, C.; Rice, K. C. J. Labelled Compd. Radiopharm. 2000, 43, 899–908.