Asymmetric Synthesis of Monofluorinated 1-Amino-1,2-dihydronaphthalene and 1,3-Amino Alcohol Derivatives

Article abstract of DOI:10.1021/acs.orglett.5b03671

Enantioenriched 1-amino-4-fluoro-1,2-dihydronaphthalene derivatives are accessed via two complementary synthetic strategies. The careful optimization of the reaction conditions required for the elimination step in one route has allowed both the identification of an anchimerically assisted reaction pathway and, more importantly, access to a divergent reaction pathway toward fluorinated 1,3-amino alcohols from a common intermediate just by adjusting the number of equivalents of base used.

Full text of DOI:10.1021/acs.orglett.5b03671

Letter
pubs.acs.org/OrgLett
Asymmetric Synthesis of Monofluorinated 1‑Amino-1,2-
dihydronaphthalene and 1,3-Amino Alcohol Derivatives
Ruben Lazaro,†,‡ Raquel Roman,† Daniel M. Sedgwick,† Gunter Haufe,§ Pablo Barrio,*,†
́
́
́
̈
and Santos Fustero*,†,‡
†Departamento de Química Organ
‡Laboratorio de Molec
ulas Organicas, Centro de Investigacion
§Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat, Corrensstrasse 40, D-48149 Munster, Germany
́
ica, Universidad de Valencia, E-46100 Burjassot, Spain
Príncipe Felipe, E-46012 Valencia, Spain
́
́
́
̈
̈
̈
S
* Supporting Information
ABSTRACT: Enantioenriched 1-amino-4-fluoro-1,2-dihydronaph-
thalene derivatives are accessed via two complementary synthetic
strategies. The careful optimization of the reaction conditions
required for the elimination step in one route has allowed both the
identification of an anchimerically assisted reaction pathway and,
more importantly, access to a divergent reaction pathway toward
fluorinated 1,3-amino alcohols from a common intermediate just by adjusting the number of equivalents of base used.
he increasing importance of organofluorine chemistry is
T
unquestionable.1 The impact that organofluorine com-
pounds have had in key industrial fields such as the
pharmaceutical,2 agrochemical,3 or materials industries4 makes
it hard to conceive our everyday life without them. The vast
developments in the synthesis of monofluorinated organic
compounds during the past decade have recently been covered
by Paquin.5 Specifically, fluorolefins display an array of features
that have made them valuable building blocks in organic
synthesis6 found in antidiabetes and anti-HIV drugs, among
others (Figure 1).7 Perhaps the most characteristic feature of
Figure 2. Proposed retrosynthesis for 1-amino-1,2-dihydronaphthalene-
derived vinyl fluorides.
common precursor from our recently reported one-pot
allylation/RCM procedure, which has already been transformed
into the corresponding bromolefin en route toward the synthesis
of sertraline.10e Herein, we describe the transformation of such
intermediates into the corresponding new benzo-fused vinyl-
fluoride analogues13 along with some insight into the mechanism
of the elimination step leading to it (Figure 2).
We began our study by subjecting N-acetylated substrate 1a to
the reaction conditions originally developed by Olah for the
bromofluorination of olefins, affording 2a in moderate yield and
complete diastereoselectivity (Scheme 1).14,15 The relative
Scheme 1. Preliminary Experiment
Figure 1. Fluorolefin-containing drugs and bioisosterism with amides.
fluorolefins is their bioisoterism with an amide group (Figure
1).7c,8 The stereoelectronic resemblance between these two
subunits allows the introduction of fluorolefins in peptidomi-
metics, mimicking an amide bond without suffering from
proteolytic degradation.9
In our continuing effort to expand the use of 2-halobenzalde-
hyde derivatives in the context of diversity-oriented synthesis
(DOS),10−12 we envisioned the asymmetric synthesis of fluorine
containing 1-amino-1,2-dihydronaphthelene derivatives as a new
synthetic challenge (Figure 2). Specifically, we aimed to use a
Received: December 26, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03671
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Organic Letters
Letter
configuration of the two new stereocenters was ascertained by
means of 2D-NMR NOESY experiments (see the Supporting
Information). The exchange of the protecting group was essential
given that the tert-butylsulfinyl group proved incompatible with
the reaction conditions (HF·Py). t-BuOK-mediated elimination
proceeded uneventfully, affording the desired vinyl fluoride 3a in
moderate yield(Scheme1).16 Theformation ofthe latter madeus
question if the elimination of HBr, required to obtain the target
molecule, mightproceedwiththeparticipationoftheneighboring
amineprotectinggroup,17 sincedirectE2eliminationisprecluded
due to the lack of a proton in the benzylic position anti to the
bromine atom (see Scheme 2).18
conditions reported by Vasella (K2CO3, MeOH/H2O)20b
afforded the tricyclic structure 11a in a moderate 60% yield
which could be improved to 88% through the use of NaH in DMF
(Scheme 3).20a This intermediate was then subjected to further
elimination, with NaH in DMF once again being the optimal
condition (Scheme 3). In view of the observed results, we
considered carrying out both elimination steps in a tandem
fashionbyusingexcessNaHinDMF,affordingfluoroolefin12ain
aquantitativeyield(Scheme3). Althoughthesynthesisof12awas
our initial objective, the ability to isolate 11a in excellent yield
permitted the diversification of molecular architectures obtain-
able by our methodology (vide infra).
With these optimized reaction conditions in hand, we studied
the scope and limitations of this transformation using bromo- and
fluorotrifluoroacetamides 10a−g. These compounds were
synthesized from various substrates 14a−g affordable by our
previously described one-pot methodology10e following a three-
step procedure with only one chromatographic purification
(Scheme 4). Most compounds were obtained in good to excellent
Scheme 2. Evidence for an Anchimeric Assistance Pathway
Scheme 4. Optimized Synthesis of Substrates 10a−h
Should this be correct, the reaction would only take place with
amine protecting groups able to undergo similar processes. In
order to find some preliminary support for our hypothesis, we
carried out the reaction sequence on the unprotected derivative
4a (Scheme 2). In addition, the corresponding phthalimide
derivative was also tested, since imides are known not to
participate as neighboring groups in processes of this kind
(Scheme 2). The corresponding bromofluoro compounds were
then synthesized in moderate yield and subjected to elimination
conditions using t-BuOK as the base (Scheme 2).19 In agreement
with our hypothesis, the formation of vinyl fluorides 6a or 9a was
not observed (Scheme 2).
Related anchimeric assistance processes have been reported in
the literature by several authors with the corresponding dibromo
derivatives.20 Inspired by these reports, we selected the
trifluoroacetyl protecting group due to its enhanced participation
in neighboring group processes along with its ease of removal by
treatment with K2CO3 in MeOH/H2O. The corresponding
trifluoroacetylated substrate 10a was then synthesized, and the
reaction conditions for the elimination step were subsequently
optimized (Scheme 3). First, we found that the reaction
a
Yields for the second three-step, one-purification reaction sequence.
overall yields for a three-step procedure (10a,c−e); however, the
introduction of a moderately electron-donating methyl group at
position 6 in 10f resulted in a significantly lower yield along with a
diminished diastereoselectivity (Scheme 4). Nevertheless, for all
of the other examples the diastereoselectivities ranged from good
to excellent. Compounds 10b and 10g could not be isolated, so
the crude material from this three-step reaction sequence was
used in a fourth step (vide infra).
Having prepared an array of bromofluoro derivatives 10, we
subjected them to the optimized reaction conditions shown in
Scheme 3 for the synthesis of the corresponding fluoroolefins 12.
The reactions proceeded in good to excellent yields (69 → 99%)
with electron-neutral (10a), electron-deficient (10b−e), or
moderately electron-rich substrates (10f). Interestingly, com-
pounds 12b and 12g were obtained in good yields via a four-step
sequence with a sole chromatographic purification from 13b,g
due to the instability of the corresponding bromofluoro
intermediates 10b,g (Scheme 5).
Scheme 3. Optimization of the Reaction Conditions for
Substrate 7a
As mentioned previously, the isolation of 11a in an excellent
>99% yield and complete diastereo- and enantiopurity
encouraged us to explore one further reaction pathway. TFA-
mediated hydrolysis of cyclic trifluoroimidates of this kind
provides a straightforward access to cis-1,3-amino alcohols.22
B
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Organic Letters
Letter
Scheme 5. Scope and Limitations21
Scheme 7. New Strategy, Initial Steps
inconvenient. In light of this unanticipated and undesired
outcome, we decided to carry out the condensation with the
chiral auxiliary on bromofluoro intermediates 16a,b followed by
elimination and asymmetric allylation using a three-step/one-
purification procedure in synthetically acceptable yields and
excellent diastereoselectivities (Scheme 7).
However, to the best of our knowledge, this transformation has
never been applied to the synthesis of fluorine-containing 1,3-
amino alcohols. Thus, various representative tricyclic oxazocines
11a,c,d were synthesized by using 1 equiv of NaH (see Scheme
3)19 and treated with TFA inwet THF affording all-cis fluorinated
1,3-amino alcohols 14a,c,d in quantitative yields and with
complete control over both the relative and the absolute
stereochemistry (Scheme 6).
AfterfailingataccomplishingthefinalRCMonsubstrate 18a,23
we were pleased to find that by simply exchanging the protective
group at the nitrogen to acetyl (78−99% yield) the desired
transformation could be afforded in90% yield (Scheme 8).19 This
reaction sequence was also applied to the synthesis of a
substituted derivative 3e with similar results (Scheme 8).
Scheme 6. Synthesis of Stereodefined Fluorinated 1,3-Amino
Alcohols
Scheme 8. Final RCM Step
The results reported herein allow the rapid and stereoselective
assembly of two unprecedented and interesting fluorinated
scaffolds based on the dihydro- or tetrahydronaphthalene
backbone, more specifically benzo-fused aminofluoroolefins and
fluorinated 1,3-amino alcohols, respectively. The synthesis of the
common substrates for both these families of compounds 10a−h
was achieved by means of our one-pot condensation/
asymmetric/allylation/RCM procedure10e followed by a three-
step reaction sequence consisting of deprotection/bromofluori-
nation/reprotection reactions requiring a single purification, thus
maximizing the efficiency of our approach. Fine-tuning the
amount of base used for the elimination step was key for the
discovery of these two divergent pathways. In addition, we have
set up an alternative reaction sequence toward fluoroalkene
containing 1-amino-1,2-dihydronaphthalene derivatives by re-
versing the reaction sequence. Furthermore, we have reported for
the first time the synthesis of OFVBA. A synthetic procedure that
allows us to overcome this molecule’s instability is in progress in
our laboratories and will be reported in due course.
Finally, we set out to reduce the number of steps necessary to
afford benzo-fused fluoroolefin derivatives like 12 or 3. Based on
our own experience, we envisioned that o-(1-fluorovinyl)-
benzaldehyde derivatives (OFVBA) could serve as starting
materials for our condensation/asymmetric allylation/RCM
sequence (Figure 3).
Figure 3. Alternative retrosynthetic approach.
Astonishingly, we found that 2-(1-fluorovinyl)benzaldehyde
derivativeswerenotknowncompounds, soourfirstchallengewas
to set up a suitable synthetic route toward such promising
fluorinated building blocks. First, 2-vinylbenzaldehyde was
treated with HF·Py/NBS affording the corresponding 1,2-
bromofluoro compound 16a in just 1 min in a moderate 52%
yield (Scheme 7). t-BuOK-mediated elimination afforded the
desired OFVBA 17a in a poor 35% yield (Scheme 7), which
proved to be instable and volatile making its handling somewhat
ASSOCIATED CONTENT
■
S
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.5b03671.
C
DOI: 10.1021/acs.orglett.5b03671
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Experimental procedures, characterization of all new
Letter
Chemical Biology; Ojima, I., Ed.; Blackwell Publishing, Inc., 2009; p 257.
Original papers:. (c) Allmendinger, T.; Furet, P.; Hungerbuhler, E.
̈
compounds, copies of HPLC chromatograms, and NMR
spectra (1H, 13C, and 19F) (PDF)
Tetrahedron Lett. 1990, 31, 7297. (d) Allmendinger, T.; Furet, P.;
Hungerbuhler, E. Tetrahedron Lett. 1990, 31, 7297. (e) Bartlett, P. A.;
̈
Otake, A. J. Org.Chem. 1995, 60, 3107. (f)Welch, J. T.;Lin, J. Tetrahedron
1996, 52, 291. (g) Veenstra, S. J.; Hauser, K.; Felber, P. Bioorg. Med.
Chem. Lett. 1997, 7, 351. (h) Zhao, K.; Lim, D. S.; Funaki, T.; Welch, J. T.
Bioorg. Med. Chem. 2003, 11, 207. (i) Urban, J. J.; Tillman, B. G.; Cronin,
W. A. J. Phys. Chem. A 2006, 110, 11120. (j) Couve-Bonnaire, S.; Cahard,
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: pablo.barrio@uv.es.
*E-mail: santos.fustero@uv.es.
Notes
(10) (a) Barrio, P.; Ibanez, I.; Herrera, L.; Roman
́
, R.; Catalan
Fustero, S. Chem. - Eur. J. 2015, 21, 11579. (b) Fustero, S.; Lazaro, R.;
Aiguabella, N.; Riera, A.; Simon-Fuentes, A.; Barrio, P. Org. Lett. 2014,
16, 1224. (c) Fustero, S.; Ibanez, I.; Barrio, P.; Maestro, M. A.; Catalan
́
, S.;
̃
The authors declare no competing financial interest.
́
́
ACKNOWLEDGMENTS
■
́
, S.
̃
We are grateful to the Spanish MINECO (CTQ2013-43310) and
Generalitat Valenciana (PROMETEOII/2014/073) for financial
support. R.L. and D.M.S. thank the Spanish Government and the
Generalitat Valenciana for predoctoral fellowships.
Org. Lett. 2013, 15, 832. (d) Fustero, S.; Rodríguez, E.; Laz
Herrera, L.; Catalan
(e) Fustero, S.; Lazaro, R.; Herrera, L.; Rodríguez, E.; Mateu, N.; Barrio,
P. Org. Lett. 2013, 15, 3770. (f) Fustero, S.; Herrera, L.; Lazaro, R.;
́
aro, R.;
́
, S.; Barrio, P. Adv. Synth. Catal. 2013, 355, 1058.
́
́
Rodríguez, E.; Maestro, M. A.; Mateu, N.; Barrio, P. Chem. - Eur. J. 2013,
19, 11776. (g) Fustero, S.; Rodríguez, E.; Herrera, L.; Asensio, A.;
Maestro, M. A.; Barrio, P. Org. Lett. 2011, 13, 6564. (h) Fustero, S.;
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