Rapid, general access to chiral β-fluoroamines and β,β-difluoroamines via organocatalysis

Article abstract of DOI:10.1021/ol802930q

A rapid, general route to enantiopure β-fluoroamines and β,β-difluoroamines has been developed employing organocatalysis in both a twopot and a one-pot procedure. Both chemical yields (64-82%) and enantioselectivity (94-98% ee) were excellent and represen

Full text of DOI:10.1021/ol802930q

ORGANIC
LETTERS
2009
Vol. 11, No. 4
943-946
Rapid, General Access to Chiral
ꢀ-Fluoroamines and ꢀ,ꢀ-Difluoroamines
via Organocatalysis
Olugbeminiyi O. Fadeyi and Craig W. Lindsley*
Departments of Chemistry and Pharmacology, Vanderbilt UniVersity,
NashVille, Tennessee 37232
craig.lindsley@Vanderbilt.edu
Received December 19, 2008
ABSTRACT
A rapid, general route to enantiopure ꢀ-fluoroamines and ꢀ,ꢀ-difluoroamines has been developed employing organocatalysis in both a two-
pot and a one-pot procedure. Both chemical yields (64-82%) and enantioselectivity (94-98% ee) were excellent and represent a significant
improvement in the art of preparing chemically diverse ꢀ-fluoroamines from readily available precursors.
The incorporation of ꢀ-fluoroamines into drug candidates has
increased dramatically in the past 5 years, with >150
fluorinated drug candidates in phase II and phase III clinical
trials.1 The role of the ꢀ-fluorine atom is diverse and has
been shown to enhance binding interactions, improve meta-
bolic stability, increase CNS penetration, and eliminate
ancillary ion channel activity by attenuating amine basicity
(pKa).1-5 The inductive effects of a ꢀ-fluorine atom are
pronounced, lowering the pKa of a linear aliphatic amine (pKa
∼10.7) to pKa ∼9.0 with a single ꢀ-flourine to pKa ∼7.3
with ꢀ,ꢀ-difluoro substitution. These effects are general and
additive, with a ꢀ-CF3 moiety lowering the pKa to ∼5.7.1-6
dines with nucleophilic flouride sources8 and the hydroflu-
orination of olefins,9 deliver ꢀ-fluoroamines but lack generality/
substrate scope, require starting materials that are not readily
available, or in the latter case, do not provide access to
enantiopure ꢀ-fluoroamines. The route most utilized involves
the treatment of ketones or secondary alcohols with DAST,
(diethylamino)sulfur trifluoride, to provide ꢀ,ꢀ-difluoroamine
and ꢀ-fluoroamines (with inversion of stereochemistry),
respectively.1-10 However, this methodology requires the
synthesis of enantiopure secondary alcohols and then suffers
from the formation of rearranged and dehydrated products,
which in many published cases greatly diminished yields of
the desired ꢀ-fluoroamines.10 In this Letter, we describe
general and high-yielding protocols to deliver enantiopure
ꢀ-fluoroamines and ꢀ,ꢀ-difluoroamines employing organo-
catalysis and readily available starting materials.
Despite the importance of the ꢀ-fluoroamine moiety, there
are few synthetic methods in the literature for their prepara-
tion.1-7 Two common methods, the ring opening of aziri-
We were attracted to the classical MacMillan work11 where
organocatlysis was employed to deliver enantioselective
(91-99% ee) R-fluoroaldehydes 4 by treatment of an
(1) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359–4369.
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Chem 2004, 5, 559–572
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K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637–643
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O.; Zunino, F. Chem. Commun. 2007, 3198–3200.
(10) Hsin, L.-W.; Chang, L-T.; Rothman, R. B.; Dersch, C. M.; Jacobson,
(6) Morgenthaler, M.; Schweizer, E.; Hoffman-Roder, F.; Benini, F.;
Martin, R. E.; Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerili,
D.; Schneider, J.; Hiedrich, F.; Kansy, M.; Muller, K. ChemMedChem 2007,
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(11) Beeson, T. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127,
(7) Percy, J. M. Sci. Synth. 2005, 34, 379–416
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8826–8828.
10.1021/ol802930q CCC: $40.75
Published on Web 01/21/2009
2009 American Chemical Society

aldehyde 1 with NFSI (N-fluorobenzenesulfonamide) 2 and
catalytic chiral imidazolidinone ligand 3 (Scheme 1).
for the R-fluorination, with a quick aqueous workup prior
to the reductive amination step. Conversion and enantiose-
lectivity to the desired ꢀ-fluoroamine were excellent, but
about 20% of the undesired ꢀ,ꢀ-difluoroamine was observed.
To avoid this side product, we decreased the equivalents for
NFSI from 5.0 to 3.0 (entry 2), to 2.0 (entry 3), and finally
to 1.5 (entry 4). Only in the latter case was the ꢀ,ꢀ-
difluoroamine side product eliminated; moreover, the success
of the R-fluorination was not hindered by decreasing the
equivalents of costly NFSI, and workup was greatly im-
proved. Other solvent systems were evaluated, with acetone
(entry 6) proving to be generally useful, while CH2Cl2 (entry
7) suffered diminished yields (37%) and low ee (84%).
Ultimately, optimal conditions for the two-step sequence
(entry 10) employed 1.0 equiv of NFSI in THF at -20 °C
for 24 h, followed by a quick aqueous workup, suspension
of the resulting R-fluoroaldehyde in ClCH2CH2Cl with 6 and
NaB(OAc)3H at ambient temperature to provide enantiopure
(>99% ee) 7 with 96% conversion and 80% isolated yield.
As shown in Tables 2 and 3, this two-pot protocol is
general with respect to the amine component, providing
Scheme 1. Organocatalytic R-Fluorination of Aldehydes
If these chiral R-fluoroaldehydes 4 were subjected to a
reductive amination protocol, we surmised that chiral
ꢀ-fluroamines would result, and depending on the chirality
of the imidazolidinone ligand, either the (S)- or (R)-ꢀ-
fluoroamine would be delivered. Moreover, there are thou-
sands of commercially available amines and aldehydes to
employ as reactants, providing improved generality in terms
of substrate scope. Surprisingly, this powerful extension of
the MacMillan enantioselective R-fluorination of aldehydes
has never been described.
Table 2. Scope of HNR1R2 in the Enantioselective Synthesis of
(S)-ꢀ-Fluoroamines
We first explored the effect of NFSI equivalents, solvent,
and temperature on a prototypical R-fluorination reaction and
subsequent reductive amination sequence employing orga-
nocatalyst 3 with phenylpropanal 5 and Boc-piperazine 6 to
produce chiral ꢀ-fluoroamine 7 (Table 1). Our initial attempt
(entry 1) employed the conditions prescribed by MacMillan11
Table 1. Optimization of Organocatalytic R-Flourination/
Reductive Amination Sequence
entrya 2 (equiv) solvent temp (°C) time (h) convn (%)b ee (%)c
1d
2d
3d
4
5.0
3.0
2.0
1.5
1.5
1.5
1.5
1.5
1.2
1.0
THF
-20
-20
-20
24
24
24
24
3
12
3
3
3
24
24
99
98
99
97
98
91
37
89
99
96
>98
>98
>99
>98
>98
>96
84
THF
a All reactions were performed on a 0.5 mmol scale and proceeded to
complete conversion. b Yield after chromatography. c Enantiomeric excess
was determined using chiral stationary phase HPLC. See Supporting
Information for complete details.
THF
THF
5
THF
4
6
acetone
CH2Cl2
EtOAc
THF
24
7
24
8
24
95
9
-20
-20
>99
>99
yields from 65-82% employing both primary and secondary
amines, which include therapeutically relevant GPCR privi-
leged structures.12 Importantly, the (S)-imidazolidinone
catalyst 3 provides the corresponding (S)-ꢀ-fluoroamines
7a-f in 95->99% ee (Table 2), whereas the (R)-imidazo-
10
THF
a All reactions were performed on a 0.05 mmol scale. b Conversion
determined by LC/MS and 1H NMR. See Supporting Information for
complete details. c Enantiomeric excess was determined using chiral
stationary phase HPLC. d R,R-Difluoro product was observed.
944
Org. Lett., Vol. 11, No. 4, 2009

Table 3. Scope of HNR1R2 in the Enantioselective Synthesis of
(R)-ꢀ-Fluoroamines
Table 4. Scope of ꢀ-Fluoroamine Synthesis via Organocatalysis
a All reactions were performed on a 0.05 mmol scale and proceeded to
complete conversion. b Yield after chromatography. c Enantiomeric excess
was determined using chiral stationary phase HPLC. See Supporting
Information for more details.
lidinone catalyst 3 provides the corresponding (R)-ꢀ-fluo-
roamines 8a-e in 87->95% ee (Table 3).
At this point, we wanted to explore the scope of this new
methodology to produce ꢀ-fluoroamines employing alterna-
tive aldehydes and to determine if this new strategy would
allow access to tertiary ꢀ-fluoroamines, a moiety inaccessible
through DAST and other known chemistries.8-10 We envi-
sioned that these transformations might require alternative
organocatalysts to (S)- and (R)-3, so we assembled a catalyst
screening kit composed of compounds 9-13 for evaluation
(Figure 1).
a All reactions were performed on a 0.05 mmol scale and proceeded to
complete conversion. b Yield after chromatography. c Enantiomeric excess
was determined using chiral stationary phase HPLC. d Not determined.
e Diastereomer ratios were measured by 19F NMR. See Supporting Informa-
tion for complete details.
chiral ꢀ-fluoramines in good isolated yields (58-92%) and
with high enantioselectivities (>96%ee). If the aldehyde
bears a ꢀ-stereogenic center, as in 15f, the ꢀ-fluoroine is
still installed with high ee (>95%) but with a 1.2:1 dr.
Compounds 15h and 15i represent transformations that all
known standard ꢀ-fluoroamine methodology cannot produce:
tertiary ꢀ-fluoroamines.8-10 Standard conditions with (S)-3
provide excellent chemical yield for installation of the tertiary
ꢀ-fluoroamine but suffer from low enantioselectivity (15%
ee). Catalysts 9, 10, and 13 provided poor conversion
(<25%) and low ee. Like (S)-3, catalysts 11 and 12 installed
the tertiary ꢀ-fluoroamine in good chemical yields, but the
maximum ee observed was 31% with catalyst 11. A similar
Figure 1. Organocatalysts examined in determining the scope of
ꢀ-fluoroamine synthesis.
As shown in Table 4, the methdology appears general with
respect to both aldehyde and amine component, affording
Org. Lett., Vol. 11, No. 4, 2009
945

trend was observed in the synthesis of tertiary ꢀ-fluoroamine
15i. Our standard methodolgy with (S)-3 provided good
conversion but only 17% ee. Switching to the tetrazole
catalyst 11 provided the desired tertiary ꢀ-fluoroamine 15i
in comparable yield but with improved ee (40%). Thus, our
new methodology allows access to tertiary ꢀ-fluoroamines
with modest % ee, as opposed to existing methods that are
unable to install tertiary ꢀ-fluoroamines.
Table 6. ꢀ,ꢀ-Difluoroamine Synthesis via Organocatalysis
Our attention now turned to developing a one-pot orga-
nocatalytic approach to ꢀ-fluoroamines to avoid the aqueous
workup step. As shown in Table 5, this was smoothly
Table 5. One-Pot ꢀ-Fluoroamine Synthesis via Organocatalysis
entrya
solvent
THF
CH3CN
CH2Cl2
DCE
THF/i-PrOH
temp (°C) time (h) yield (%)b ee (%)c
1
2
3
4
5
24
24
3
3
45
36
12
0
>95
>95
ndd
ndd
>96
24
24
-20
24
24
3
65
a All reactions were performed on a 0.05 mmol scale. b Yield after
chromatography. c Enantiomeric excess was determined using chiral station-
ary phase HPLC. d Not determined.
accomplished by application of 1.0 equiv of NFSI, at -20
°C for 3 h in 10% i-PrOH/THF, followed by direct addition
of 1.0 equiv of mono-Boc-piperazine 6 and 2.2 equiv of
NaB(OAc)3H for 16 h. The desired ꢀ-fluoroamine 7 was
delivered in 65% isolated yield and with >96% ee. The Boc
protecting groups remained intact, highlighting the mild
conditions of this one-pot procedure.
Finally, there are many examples in the literature where a
ꢀ,ꢀ-difluoroamine is required to address a specific liability
of a candidate molecule.1-6 On the basis of an earlier
observation of ꢀ,ꢀ-difluoroamine formation (Table 1) when
excess NFSI was employed, we quickly developed a two-
pot route to rapidly access this valuable moiety. In this
instance (Table 6), aldehydes 16 were treated with 2 equiv
of NFSI and 40 mol % DL-proline in 10% i-PrOH/THF at
room tempertaure for 24 h to provide R,R-difluoroaldehydes
17. After a quick aqueous workup, the resulting oils were
resuspended in DCE, amine and NaB(OAc)3H were added,
and the reaction was allowed to stir at room temperature for
16 h to provide ꢀ,ꢀ-difluoroamines 18 in isolated yields
ranging from 64% to 77%.
a All reactions were performed on a 0.05 mmol scale and proceeded to
complete conversion. b Yield after chromatography.
method, and without rearranged and dehydrated side prod-
ucts. Moreover, our new methodology allows for the first
synthesis of tertiary ꢀ-fluoroamines with enantioselectivities
up to 40%. Furthermore, slight modification of our protocol
provides rapid, high-yielding access to ꢀ,ꢀ-difluoroamines.
Overall, these novel strategies for the synthesis of ꢀ-fluo-
roamines and ꢀ,ꢀ-difluoroamines, from readily available
precursors, represents a significant improvement in the art
to access these therapeutically relevant moieties.
Acknowledgment. This work was supported, in part, by
the Department of Pharamacology and Vanderbilt University.
Funding for the NMR instrumentation was provided in part
by a grant from NIH (S10 RR019022).
In summary, we have developed a powerful extension of
the MacMillan enantioselective R-fluorination of aldehydes
for the general enantioselective synthesis of ꢀ-fluoroamines
in yields and % ee far exceeding that of any other reported
Supporting Information Available: Experimental pro-
cedures, characterization data, chiral LC traces, and 1H, 19F,
and 13C NMR spectra for all new compounds, 7a-f, 15a-i,
and 18a-d. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) Patchett, A. A.; Nargund, R. Annu. Rep. Med. Chem. 2000, 35,
289–298.
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