A general, enantioselective synthesis of β- And γ-fluoroamines

Article abstract of DOI:10.1016/j.tetlet.2013.04.116

In this Letter, we describe a short, high yielding protocol for the enantioselective (87-96% ee) and general synthesis of β-fluoroamines and previously difficult to access γ-fluoroamines from commercial aldehydes via organocatalysis.

Full text of DOI:10.1016/j.tetlet.2013.04.116

Tetrahedron Letters 54 (2013) 3627–3629
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A general, enantioselective synthesis of b- and c-fluoroamines
Matthew C. O’Reilly a, Craig W. Lindsley a,b,
⇑
a Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA
b Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt Specialized Chemistry Center (MLPCN), Vanderbilt University Medical Center,
Nashville, TN 37232, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter, we describe a short, high yielding protocol for the enantioselective (87–96% ee) and general
Received 16 April 2013
Revised 24 April 2013
Accepted 26 April 2013
Available online 9 May 2013
synthesis of b-fluoroamines and previously difficult to access
via organocatalysis.
c
-fluoroamines from commercial aldehydes
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
b-fluoroamine
c
-fluoroamine
Enantioselective
Organocatalysis
Small molecule probes and drug candidates that contain one or
more chiral fluorine atoms are commonplace and represent a crit-
ical component of the medicinal chemists’ toolbox.1,2 In the con-
text of amine-containing ligands, introduction of a fluorine atom
however, the configurational instability of the a-chloroaldehyde
also necessitated immediate, one-pot use. To provide additional
flexibility, we developed an approach (Fig. 1, Eq. 2) that improved
yields and % ee for the synthesis of chiral morpholines and pipera-
either b- or
c- to the amine often maintains activity at the desired
zines by reducing the a-chloroaldehyde to an alcohol, converting
target while providing a 1–2 log reduction in pKa. That shift in elec-
tronic structure often results in diminished ancillary pharmacology
at cardiac ion channels, improved metabolic stability, enhanced
pharmacokinetics, and increased CNS penetration.1–3 In some
cases, introduction of a chiral b-fluoroamine, due to the almost
2-log impact on pKa, can diminish activity at the desired target;
the hydroxyl to a leaving group, displacing the leaving group with
an amino alcohol or diamine followed by base-induced
cyclization.16,17
These results led us to reflect on the b- and
lem, and apply this strategy to their asymmetric construction
(Fig. 2). Here, we envisioned standard organocatalytic -fluorina-
tion followed by reduction to the b-fluoroalcohol to provide a
c-fluoroamine prob-
a
however, moving the fluorine atom to the
c-position has been
shown to maintain the desired bioactivity, while still affording
the benefits of the b-fluoroamine congeners.1–6
Chiral -Fluoroamines via Organocatalysis
β
While we and others have made considerable advances in the
Me
O
•DCA
N
synthesis of chiral b-fluoroamines,7–13 the synthesis of
c-congen-
Me
Me
N
O
O
20 mol %
HNR2R3
R1
R2
ers still relies on classical DAST approaches which are plagued with
H
Ph
(1)
(2)
R1
N
R3
R1
rearranged and dehydrated products.1–6,14 Therefore, new syn-
H
NFSI,THF/ iPrOH
-20 °C
H
NaBH(OAc)3
F
F
thetic strategies to access these elusive, chiral
warranted.
c-fluoroamines were
(94-98% ee)
Chiral Morpholines and Piperazines via Organocatalysis
Previous work from our lab (Fig. 1) employed a one-pot protocol
to access chiral b-fluoroamines via organocatalysis in high yield
and % ee (Eq. 1); however, the configurational instability of the
Ph
Ph
R1
N
H
1. i) 10 mol %
NCS, DCM
R1
O
ii) NaBH4, MeOH
NBn
X
NBn
incipient
a-fluoroaldehyde required its immediate conversion to
KOtBu
-20 °C
R1
the b-fluoroamine.7,8 Later efforts utilized a similar strategy, but
Cl
X
H
2. i) Tf2O, lutidine
-78 °C
employed the analogous a-chloroaldehydes, to access chiral N-ter-
ii) diamine or
minal aziridines15 and chiral morpholines and piperazines;16
X = O, NBoc
75-98% ee
X = OH, NHBoc
aminoalcohol
-78 °C to rt
⇑
Corresponding author. Tel.: +1 615 322 8700; fax: +1 615 345 6532.
E-mail address: craig.lindsley@vanderbilt.edu (C.W. Lindsley).
Figure 1. First generation organocatalytic approach to chiral b-fluoroamines and
refined approach to chiral morpholines and piperazines.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.116

3628
M. C. O’Reilly, C. W. Lindsley / Tetrahedron Letters 54 (2013) 3627–3629
1. i) organocatalyst
(20 mol %)
1. Tf2O, lutidine
0 °C, 30 min
1. i) organocatalyst
(20 mol %)
O
NFSI, THF/IPA
ii) NaBH4
NFSI, THF/IPA
ii) NaBH4
R1
R1
OH
NHBn
2a-c
NH2
R1
R1
R1
2.
BnNH2
NHR
H
F
F
2. i) leaving group
2. i) leaving group
F
F
formation
formation
ii) -CN
4a-c
2
1
3
ii) RNH2
3. reduction
MeO
TBSO
NHBn
NHBn
Figure 2. Envisioned route to access both chiral b- and
organocatalysis.
c
-fluoroamines via
F
NHBn
F
F
2a, 84%a
2b, 96%a
2c, 96%a
94% eeb
90% eeb
94% eebc
Me
O
N
.
ayield following chromatography on a 1 mmol scale
DCA
Me
Me
b% ee determined by chiral HPLC analysis c% ee determined of the free alcohol
N
1.
H
Ph
O
(20 mol %)
R1
Scheme 2. Synthesis of chiral b-fluoroamines 2a–c.
R1
OH
H
NFSI, THF/IPA, -20 °C
2. NaBH4, DCM/EtOH, rt
F
1
4
CO2H
1. i)
MeO
N
H
(30 mol %)
OH
TBSO
OH
F
O
F
OH
NFSI (excess), THF, rt
TBSO
NHBn
F
TBSO
H
ii) NaBH4, DCM/EtOH, rt
77%
F
F
4a
4d
4b
4c
, 77%
, 65%
, 73%
2. i) Tf2O, lutidine, 0 °C
30 min
1c
5 81%
Me
ii) BnNH2
Me
OH
OH
OH
OH
8
Scheme 3. Synthesis of a b,b-difluoroamine 5.
F
F
F
F
4e
4f
4g
, 74%
, 75%
, 74%
, 69%
excess KCN
solvent, temp
(1.0 equiv.) KCN
solvent, temp
Scheme 1. Organocatalytic, enantioselective synthesis of b-fluoroalcohols 4a–g.
OTs
OTf
CN
CN
~50% conversion
full conversion
F
CN
CN
7
6
7
bench stable, chiral intermediate. Conversion of the hydroxyl to a
leaving group followed by SN2 displacement with an amine would
provide chiral b-fluoroamines 2, whereas a cyanide displacement,
followed by nitrile reduction, would afford rapid access to chiral
10 eq. KCN
20 mol %
18-crown-6
excess KCN
CN cat.18-crown-6
CN
F
F
F
DCM, reflux
MeCN, rt, 16 h
full conversion
9
9
~50% conversion
8
c-fluoroamines 3.
To validate this new approach, we prepared a number of b-flu-
Scheme 4. Optimization of b-fluoronitrile 8 synthesis.
oroalcohol substrates 4a–g under standard conditions in good
yields (65–77%) and high enantioselectivity (87–96% ee) as ex-
pected from literature precedent (Scheme 1).7,8,18–20 Conversion
to the corresponding triflate, and displacement with benzylamine
delivered the desired chiral b-fluoroamines 2a–c (Scheme 2) in
high yields (84–96%) and in excellent enantioselectivity (90–94%
ee). In essence, this new strategy sets the key stereocenter in a con-
formationally stabile way, affording the b-fluoroamines with
reproducibly high % ee, and higher yields than the first generation
chiral b-fluoroamine route.7
only 50% conversion accompanied by considerable decomposition.
Further surveying of reaction conditions and refinement led to the
discovery of optimal conditions (10 equiv KCN in the presence of
20 mol % 18-crown-6 at room temperature in MeCN for 16 h) to
fully convert triflate 8 to the desired fluoronitrile 9, without any
evidence of cyanide displacement of the fluoride.
With racemic 9 in hand, we then evaluated a number of reduc-
ing agents to provide the
c-fluoroamine. Interestingly, the vast
In some instances, a b,b-difluoroamines have been shown to be
an important pharmacophore,1–7 and we wanted to determine if
this new approach would grant access to this moiety as well. Here
majority of common methods for nitrile reduction (LiAlH4, DIBALH,
H2/Pd, Ni(0)/NaBH4) failed to reduce the b-fluoronitrile without
considerable decomposition or defluorination. Ultimately, good re-
sults were obtained with the milder conditions of InCl3/NaBH4,21,22
(Scheme 3), organocatalytic
a-fluorination with excess NFSI leads
to -difluorination, and reduction affords the b,b-difluoroalcohol.
a
,
a
delivering the
Having developed a route to racemic
was now directed at accessing chiral
and difficult to prepare pharmacophore. Here, the chiral b-fluoroal-
cohols 4a–g (Scheme 1) were converted into the corresponding tri-
flates, which were then displaced under the optimized cyanide
displacement conditions to deliver chiral b-fluoronitriles 9a–g in
yields ranging from 71% to 93% (Table 1). Our optimized reduction
c
-fluoroamines in yields up to 90%.
-fluoroamines, attention
-fluoroamines, an elusive
Conversion to the triflate and displacement with benzylamine pro-
vides the desired b,b-difluoroamine 5 from the difluoroalcohol in
81% yield, representing another improvement over our first gener-
ation methodology.7
While the ability to access b-fluoroamines was gratifying, our
main objective with this approach was to gain access to chiral c-
fluoroamines, a chemotype that is very challenging to prepare in
high enantioselectivity.1–8,14 We began our attempts with a race-
mic 4a congener and surveyed a variety of leaving groups for cya-
c
c
protocol with InCl3/NaBH4 smoothly provided the chiral c-fluoro-
amines 3a–g in excellent yields (73–90%) and enantioselectivity
(87–96% ee). The overall yields starting from commercial alde-
hydes 1 range from 40–58%. Of particular utility of this approach
is the commercial availability of both enantiomers of the organo-
nide displacement en route to c-fluoroamines. Interestingly, when
tosylate 6 was employed, all attempts (independent of cyanide
source, stoichiometry, solvent, and temperature) afforded a 1,2-
bis-cyano adduct 7 (Scheme 4). As more forcing conditions were
required for tosylate displacement, a competing displacement of
the fluoride by cyanide occurred. When triflate 8 was used, excess
KCN in refluxing DCM provided the desired b-fluoronitrile 9, but in
catalyst, enabling either enantiomer of the chiral
to be prepared. We were now able to access chiral b-fluoro- and
-fluoroamines, as well as b,b-difluoroamines, providing a range
of finely tuned amine basicity (with pKas of 10.7 (parent amine)
c-fluoroamine
c

M. C. O’Reilly, C. W. Lindsley / Tetrahedron Letters 54 (2013) 3627–3629
3629
Table 1
classical DAST chemistry, this work represents the only other ap-
proach for the enantioselective synthesis of -fluoroamines, an
Chrial
c
-fluoroamines 10a–g via organocatalysis
c
i) Triflic Anhydride, Lutidine
important pharmacophore in drug discovery and development.
Moreover, the chiral b-fluoronitrile linchpin offers rapid access to
a wide range of valuable fluorinated functional groups with subtle
perturbations of pKa and electronic properties. Additional refine-
ments are under development and will be reported in due course.
R1
R1
R1
NH2
InCl3, NaBH4
THF, rt
DCM, 0 °C, 30 min
OH
CN
9a-g
ii) KCN, 18-crown-6
F
4a g
F
F
3a-g
acetonitrile, rt
-
~16 h
Starting material
Yield of 9a–ga
Yield of 3a–gb
% eec
4a
4b
4c
4d
4e
4f
9a, 71%
9b, 92%
9c, 73%
9d, 93%
9e, 77%
9f, 82%
9g, 84%
3a, 87%
3b, 84%
3c, 86%
3d, 83%
3e, 90%
3f, 89%
3g, 73%
94%
87%
92%
96%
96%
95%
96%
Acknowledgments
The authors gratefully acknowledge funding from the Depart-
ment of Pharmacology, Vanderbilt University Medical Center and
the Warren Family & Foundation for funding the William K. War-
ren, Jr. Chair in Medicine.
4g
a
b
C
All reactions were performed on a 1.0 mmol scale.
All reactions were performed on a 0.5 mmol scale.
Supplementary data
Enantiomeric excess determined by 19F NMR using the (R)-Mosher amide of the
final amine.
Supplementary data (experimental details and characterization
data for all new compounds) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2013.04.116.
N
•
NaN3, Et3N HCl
N
Toluene, 70°C
F
HN
N
References and notes
11
, 77%
CN
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, 91%
Scheme 5. Synthesis of a b-fluoro tetrazole and a b-fluoro amide oxime.
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access a variety of fluorinated scaffolds using the nitrile as a handle.
To illustrate this idea, we performed common reactions to exem-
plify the b-fluoronitrile as a lynchpin providing access to other,
difficult to prepare, fluorinated moieties. As seen in Scheme 5, the
b-fluoronitrile 10 was used in a [3+2] cycloaddition with sodium
azide to provide b-fluorotetrazole 11, a common carboxylic acid
bioisostere.24 Additionally, hydrolysis of the nitrile with hydroxyl-
amine provided amide oxime 12, a precursor for oxadiazole synthe-
sis.25 Overall, the chiral b-fluoronitrile linchpin offers rapid entry to
a wide range of valuable fluorinated functional groups with subtle
perturbations of pKa and electronic properties.
In summary, we have developed a powerful extension of our
one-pot, chiral b-fluoroamine work, that overcomes issues related
to variable % ee due to configurationally unstable a-fluoroaldehy-
des, by a two-pot protocol that affords b-fluoroamines in high
yields and reproducibly high enantioselectivity (90–94% ee). A fur-
ther extension allows access to highly elusive and previously diffi-
24. Koguro, K.; Oga, T.; Mitsui, S.; Orito, R. Synthesis 1998, 6, 910–914.
25. Copp, R. R.; Abraham, B. D.; Farnham, J. G.; Twose, T. M. Org. Process Res. Dev.
2011, 15, 1344–1347.
cult to prepare chiral c-fluoroamines using a three-pot protocol in
good overall yields (40–58%) and excellent enantioselectivities
(87–96%) from commercial aldehydes. Importantly, outside of