Studies on the Synthesis of Specifically Fluorinated 4-Amino-pyridine Derivatives by Regioselective Nucleophilic Aromatic Substitution and Catalytic Hydrodefluorination

Article abstract of DOI:10.1002/adsc.201500393

The reactions of pentafluoropyridine and 2,4,6-trifluoropyridine with a series of primary and secondary amines were studied. Whereas the nucleophilic aromatic substitution of pentafluoropyridine occurs with high regioselectivity in all cases, providing the expected 4-aminopyridine derivatives in excellent yields, the regioselectivity of 2,4,6-trifluoropyridine is dependent on the steric hindrance of the attacking nucleophile. Small nucleophiles such as morpholine attack the 4-position of the pyridine ring with high preference, but more bulky diamines attack the 2- and 4-positions leading to the formation of three regioisomeric products. (R,R)-1,2-Diaminocyclohexane as moderately bulky diamine reacted with 2,4,6-trifluoropyridine to afford the desired bis(4-aminopyridinyl)cyclohexane derivative in 30% yield. For hydrodefluorination two methods were examined. A two-step procedure employing hydrazine and subsequently copper(II) sulfate removed just one fluorine substituent, but is not sufficiently high yielding for the reduction of more complex substrates. With the system titanocene difluoride as pre-catalyst and diphenylsilane as reducing agent we were able to selectively remove fluorine substituents at positions C-2 and C-4 of a variety of 4-aminopyridine derivatives. This protocol allows the synthesis of compounds such as the divalent chiral 4-(dimethylamino)pyridine (DMAP) analogue (R,R)-trans-N,N'-dimethyl-N,N'-bis(pyridin-4-yl)cyclohexane-1,2-diamine with fair overall yield.

Full text of DOI:10.1002/adsc.201500393

FULL PAPERS
DOI: 10.1002/adsc.201500393
Studies on the Synthesis of Specifically Fluorinated 4-Amino-
pyridine Derivatives by Regioselective Nucleophilic Aromatic
Substitution and Catalytic Hydrodefluorination
Gabriel Podolan,a Phillip Jungk,a,b Dieter Lentz,a Reinhold Zimmer,a
and Hans-Ulrich Reissiga,*
a
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustr. 3, 14159 Berlin, Germany
E-mail: hans.reissig@chemie.fu-berlin.de
Current address: Leibniz-Institut für Katalyse e.V. an der Universität Rostock (LIKAT), Albert-Einstein-Str. 29a, 18059
b
Rostock, Germany
Received: April 21, 2015; Revised: June 17, 2015; Published online: September 15, 2015
Dedicated to the memory of Prof. Manfred Schlosser.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500393.
Abstract: The reactions of pentafluoropyridine and amined. A two-step procedure employing hydrazine
2,4,6-trifluoropyridine with a series of primary and and subsequently copper(II) sulfate removed just
secondary amines were studied. Whereas the nucleo- one fluorine substituent, but is not sufficiently high
philic aromatic substitution of pentafluoropyridine yielding for the reduction of more complex sub-
occurs with high regioselectivity in all cases, provid- strates. With the system titanocene difluoride as pre-
ing the expected 4-aminopyridine derivatives in ex- catalyst and diphenylsilane as reducing agent we
cellent yields, the regioselectivity of 2,4,6-trifluoro- were able to selectively remove fluorine substituents
pyridine is dependent on the steric hindrance of the at positions C-2 and C-4 of a variety of 4-aminopyri-
attacking nucleophile. Small nucleophiles such as dine derivatives. This protocol allows the synthesis of
morpholine attack the 4-position of the pyridine ring compounds such as the divalent chiral 4-(dimethyl-
with high preference, but more bulky diamines amino)pyridine (DMAP) analogue (R,R)-trans-N,N’-
attack the 2- and 4-positions leading to the formation dimethyl-N,N’-bis(pyridin-4-yl)cyclohexane-1,2-di-
of three regioisomeric products. (R,R)-1,2-Diamino- amine with fair overall yield.
cyclohexane as moderately bulky diamine reacted
with 2,4,6-trifluoropyridine to afford the desired
bis(4-aminopyridinyl)cyclohexane derivative in 30% Keywords: catalysis; fluorine; hydrodefluorination;
yield. For hydrodefluorination two methods were ex- nucleophilic aromatic substitution; pyridines
Introduction
aminocyclohexane or by other methods.[6] However,
taking the detour via specifically fluorinated amino-
Aminopyridine derivatives are important compounds pyridine derivatives we could finally prepare these
in organic synthesis either as final targets, as reagents target compounds with reasonable efficacy.[7]
or as intermediates.[1] The most famous derivative of
In this full report we want to disclose a detailed de-
this class of heterocycles is 4-(dimethylamino)pyridine scription of our approach to these compounds that in-
(DMAP),[2] very frequently employed as an efficient volves the well known regioselective nucleophilic sub-
Brønsted base in stoichiometric or catalytic
amounts.[3,4] This compound can also function as
a powerful Lewis base, for example, in the stabiliza-
tion of nanoparticles and nanotubes.[5] We were inter-
ested in the synthesis of the new divalent DMAP ana-
logues A (Scheme 1) but could not access these new
compounds by conventional substitution reactions
starting from 4-halopyridines and trans-1,2-di- Scheme 1. Divalent 4-(dimethylamino)pyridine analogues A.
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Gabriel Podolan et al.
stitutions[8] of 2,4,6-trifluoropyridine or of penta-
fluoropyridine with the required amines. Subsequent-
ly, we describe the experiments to achieve partial or
full catalytic hydrodefluorination (HDF)[9] with
known or new catalytic systems to reach our final
goal. A series of partially fluorinated aminopyridine
derivatives was prepared that may also be of interest
as building blocks in medicinal chemistry. It is well es-
tablished that due to their high electronegativity fluo-
rine atoms strongly alter the physical, chemical and
biological properties of compounds[10] and a high per-
centage of newly registered drugs or crop protection
products contain at least one fluorine atom.
Results and Discussion
Nucleophilic displacement of fluorine in highly fluori-
nated pyridine derivatives and related heteroaromatic
compounds occurs very readily since the heterocyclic
system is strongly activated by the presence of the ni-
trogen atom and the electron-withdrawing fluorine
substituents. The regioselectivity of the aromatic nu-
cleophilic substitution processes has been carefully
studied. The site-reactivity of pentafluoropyridine (1)
follows the sequence 4-fluorine>2-fluorine@ 3-fluo-
rine substituent. The reactions of 1 with various nu-
cleophiles were summarized and discussed in detail.[8]
Scheme 3. Model reactions of pentafluoropyridine (1) and
2,4,6-trifluoropyridine (2) with morpholine leading to
amino-substituted pyridines 6–9 (Morph=morpholinyl).
2,4,6-Trifluoropyridine (2) was also found to undergo ucts 7 and 8, or with the assistance of sodium amide
nucleophilic substitution preferentially or exclusively as stronger base the symmetrical trisubstituted com-
at the 4-position.[8] Two typical examples[8i,e] are pre- pound 8, exclusively. These transformations confirm
sented in Scheme 2 revealing the high regioselectivity the high regioselectivity in favor of the 4-substituted
and the efficacy of this process.
compounds. The subsequent substitution of primarily
formed 4-aminopyridine derivative 6 requires an
excess of the amine and harsher conditions and finally
leads to 2,4,6-trismorpholino-substituted product 8.
We then investigated the reactivity of vicinal di-
amines such as the stereoisomers of cyclohexane-1,2-
diamine. The cis-compound 10 and four equivalents
of electrophile 1 provided the expected divalent ami-
nopyridine derivative 11 in excellent yield
(Scheme 4). The corresponding (R,R)-stereoisomer 12
gave under similar conditions the enantiopure diva-
lent compound (R,R)-13 in 99% yield. Similar results
were obtained with the 1,2-diamino-1,2-diphenyl-
ethane derivatives 14 and (S,S)-16 which provided the
meso-compound 15 and the (S,S)-configured product
17 with high efficacy. Although all transformations re-
quired heating to reflux in tetrahydrofuran to achieve
these excellent yields, the examples of Scheme 4 con-
Scheme 2. Regioselective nucleophilic aromatic substitution
of pentafluoropyridine (1) and 2,4,6-trifluoropyridine (2)
leading to 4-dimethylaminopyridine derivatives 3 and 4.[8i,e]
Starting with pyridine derivatives 1 and 2 and with firm the high regioselectivity of nucleophilic substitu-
morpholine 5 as model nucleophile we obtained the tion reactions of pentafluoropyridine (1).
expected monosubstitution products 6[8i] and 9, when
Next we studied the substitutions employing N-
the reactions were performed at room temperature methyl-substituted 1,2-diamines. Probably due to the
(Scheme 3). On the other hand, reaction of 1 with higher steric hindrance the conversions of racemic
a large excess (46 equivalents) of morpholine fur- precursor rac-18 and of meso-compound 20 into com-
nished either a mixture of di- and trisubstituted prod- pounds rac-19 and 21, respectively, were less efficient
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Studies on the Synthesis of Specifically Fluorinated 4-Aminopyridine Derivatives
Scheme 6. Nucleophilic aromatic substitution of 2,4,6-tri-
fluoropyridine (2) with 1,2-diamine 22 leading to regioiso-
meric compounds 24, 25 and 26.
ance with the literature reporting a yield of 89% for
this compound.[8i]
Whilst the substitutions employing 1 as strong elec-
trophile occurred with very high regioselectivity even
with the sterically more hindered secondary amines
rac-18, 20 and 22, this was no longer the case for the
reactions of these nucleophiles with 2,4,6-trifluoropyr-
idine (2). The reaction of four equivalents of this pyri-
dine derivative with 1,2-diamine 22 furnished a mix-
ture of the 2,2-, the 2,4-, and the 4,4-disubstituted
products 24–26 in a good overall yield of 85%
(Scheme 6). Although the three isomeric products
were separable by column chromatography, the syn-
thesis of the desired compound 26 was not very effi-
cient.
Scheme 4. Synthesis of divalent bis(tetrafluoropyridin-4-yl)-
substituted 1,2-diamines 11, (R,R)-13, 15, and (S,S)-17 by
nucleophilic substitution of 1 with 1,2-diamines.
The low regioselectivity became fatal when the ster-
ically more hindered N-methylated 1,2-diaminocyclo-
hexane derivative rac-18 was employed (Scheme 7).
The desired 4,4-disubstituted product rac-31 was only
obtained in 1% yield. The two other regioisomers rac-
Scheme 5. Synthesis of divalent bis(tetrafluoropyridin-4-yl)-
substituted 1,2-diamines rac-19, 21 and 23 by substitution of
compound 1.
(Scheme 5). In comparison, the acyclic N,Nꢀ-dimethyl-
substituted diamine 22 furnished the expected prod-
Scheme 7. Nucleophilic aromatic substitutions of 2,4,6-tri-
fluoropyridine (2) with trans-1,2-diaminocyclohexane deriva-
uct 23 almost quantitatively; this result is in accord- tives 18 and 12.
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Scheme 8. Hydrodefluorination of 4-morpholinopyridines 6, 34 and 9 by the two-step method employing hydrazine and
copper sulfate.[11]
27 and rac-29 were isolated in 12% and 7% yield, re- (2) becomes unfavorable when bulky secondary
spectively, demonstrating that the substitution is not amines (such as 18) are employed; in contrast, the re-
only unselective, but also quite inefficient. Gratifying- action at C-2 (or C-6) is less hampered because the
ly, the sterically less hindered primary diamine 12 – adjacent nitrogen atom is unsubstituted. When less
studied as racemic compound and as enantiopure bulky primary amines are used this effect could be
(R,R)-isomer – behaved much more productively, al- partially overcome and the 4-substitution occurs in
lowing a synthetically reasonable access to com- a higher percentage providing the expected products.
pounds rac-32 and (R,R)-32. The process is still not
With the library of oligofluorinated aminopyridine
regioselective and the undesired isomers 28 and 30 derivatives in hand, we started to study the hydrode-
are formed in relatively high amounts, nevertheless, fluorination of these compounds. The final goal was
this route to the desired compound 32 is straightfor- the preparation of totally defluorinated compounds,
ward considering the simplicity of the method. Again, either in one step or in a multi-step fashion, but we
the three regioisomers were easily separated by were also interested whether specifically fluorinated
column chromatography.
aminopyridines will be accessible by the applied
In summary, our results demonstrate an unexpect- methods. The first results with morpholino-substituted
edly high effect of the steric hindrance of the attack- model compounds 6 and 9 as well as with intermedi-
ing nucleophile on the regioselectivity of the nucleo- ate 34 are collected in Scheme 8. The two-step
philic aromatic substitution with compound 2. To the method of Schlosser et al.[8e,11] consists in a regioselec-
best of our knowledge, results showing a similarly tive nucleophilic substitution of fluoride by hydrazine
strong effect are not known. Apparently, the electron- delivering the 2-hydrazinopyridine derivatives. Subse-
ically favored attack at C-4 of 2,4,6-trifluoropyridine quent treatment with copper sulfate at 1108C replaces
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Studies on the Synthesis of Specifically Fluorinated 4-Aminopyridine Derivatives
the hydrazine moiety by a hydrogen atom. By this
method trifluoro compound 34, difluoro compound 36
and monofluoro compound 39 were obtained in mod-
erate to good overall yields. An attempt to introduce
two hydrazine substituents at C-2 and C-6 of com-
pound 6 under forcing conditions to give 37 was not
successful, thus precluding the direct two-fold de-
fluorination of 6 to 36.
After these encouraging first results we applied this
method to divalent aminopyridines 23 and rac-19. In
both cases, we observed a substitution with hydrazine
at C-2 of both pyridine rings of the substrates, quanti-
tatively leading to the desired intermediates 40 and
42. Treatment of these compounds with copper sulfate
provided the expected products 41 and 43 in moder-
ate yields. Although the two examples demonstrate
that the selective removal of one fluorine substituent
per pyridine ring is also possible for divalent sub-
strates, the results of Scheme 8 and Scheme 9 indicate
that a complete removal by this two-step method
would be laborious and probably inefficient.
We also tried to reduce model compound 6 with an
excess of samarium diiodide in tetrahydrofuran,[12]
however, no conversion was observed up to tempera-
tures of 708C. Next, we examined a catalytic hydrode-
fluorination method (HDF)[9] recently developed for
fluoroalkenes[13] employing the pre-catalyst [Cp2TiF2]
and diphenylsilane as reducing agent.[14] As test sub-
strates we again used simple 4-morpholinopyridines 6
and 9 and identified 1,4-dioxane and 1108C as opti-
mal conditions. Under these conditions 15 mol% of
the pre-catalyst were sufficient to convert both com-
pounds into partially or completely defluorinated
products 36 and 44 with excellent efficacy
(Scheme 10).
Table 1 summarizes details of our optimization ex-
periments. The use of 1,2-dimethoxyethane as solvent
led to a considerable decrease of the reaction rate
(entry 4). Full conversion of 6 into 36 was observed
only after 96 h (92% yield). The full defluorination of
compound 6 to 44 could not be achieved by this
method. Higher pre-catalyst loadings and longer reac-
tion times caused decomposition of precursor 6 and/
or the possible intermediates (entry 5).
Scheme 9. Two-step hydrodefluorinations of divalent amino-
pyridine derivatives 23 and rac-19.
Table 1. Catalytic HDF of pyridine derivatives 6 and 9 ac-
cording to Scheme 10.
Entry Compound T
t
Cp2TiF2
[mol%]
Product, Yield
[8C] [h]
1
2
6
6
6
6
6
9
80
90
110 24
110 96
110 30
110 24
168
120
50
24
15
15
100
15
no reaction
36, 81%
36, 95%
36, 92%
decomposition
44, 98%
3
4[a]
5
Scheme 10. Catalytic hydrodefluorination of model sub-
strates 6 and 9 under optimized conditions employing the
[Cp2TiF2]/diphenylsilane system.
6
[a]
1,2-Dimethoxyethane as solvent.
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Gabriel Podolan et al.
Scheme 11. Catalytic HDF of divalent octafluoro-substituted pyridines 23, rac-19 and (S,S)-17.
We then turned our attention to the divalent ami- four fluorine atoms from the precursors in reasonable
nopyridine derivatives and applied the optimized con- reaction times.
ditions to compounds 23, rac-19 and (S,S)-17
Although the N,N’-dimethyl derivative 31 was di-
(Scheme 11). Gratifyingly, the method smoothly rectly available by the aromatic nucleophilic substitu-
worked for the two octafluorinated substrates furnish- tion (Scheme 7) the low yield of 1% strongly limits
ing the expected tetrafluoro-substituted products 45 the access to this compound. We therefore tried
and rac-46 in good yields. Surprisingly, substrate a two-fold N-alkylation of rac-32 in order to gain rac-
(S,S)-17 with the 1,2-diphenylamino backbone did not 31. Unexpectedly, the first attempt employing a reduc-
afford product 47, but it underwent complete decom- tive amination with formaldehyde and formic acid fur-
position. The benzylic positions in the backbone of nished the interesting bicyclic compound rac-50
this substrate possibly lead to side reactions and (Scheme 13). Gratifyingly, the direct N-methylation of
hence they are not compatible with the reaction con- (R,R)-32 was very efficient, when sodium hydride and
ditions of this catalytic HDF method.
methyl iodide were employed. The N-alkylated com-
To our great pleasure 2,6-tetrafluorinated divalent pounds rac-50 and (R,R)-31 underwent the catalytic
pyridine derivatives 26 and 32 were very efficiently HDF with excellent efficacy affording the two new di-
converted into the fully defluorinated target com- valent DMAP-analogues 51 and (R,R)-52 in more
pounds 48 and 49 in excellent yields (Scheme 12). It than 90% yield. An alkylation of (R,R)-32 with 2-io-
should be noted that for the HDF reactions illustrated dopropane in order to prepare an analogue of (R,R)-
in Scheme 11 and Scheme 12 30 mol% of pre-catalyst 52 with an altered conformation was not successful.
Cp2TiF2 are used, in order to guarantee removal of
Scheme 12. Complete catalytic HDF of divalent tetrafluoro-substituted divalent pyridines 26 and rac-32.
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Studies on the Synthesis of Specifically Fluorinated 4-Aminopyridine Derivatives
Scheme 13. N-Alkylations of compounds rac-32 and (R,R)-32 and subsequent catalytic HDF affording divalent DMAP-ana-
logues rac-51 and (R,R)-52.
purified by flash chromatography (FLC) on silica gel (32–
63 mm). Unless otherwise stated, yields refer to chromato-
Conclusions
graphically homogeneous and spectroscopically pure materi-
In this report we have demonstrated that pentafluoro-
pyridine (1) and 2,4,6-trifluoropyridine (2) are suita-
ble starting materials for the short, fairly efficient and
versatile syntheses of a library of simple and complex
als (1H NMR spectroscopy). NMR spectra were recorded
with JEOL (ECX 400, Eclipse 500) instruments. Chemical
shifts are reported relative to TMS (1H: d=0.00 ppm) and
CDCl3 (13C: d=77.0 ppm). Integrals are in accordance with
fluorinated 4-aminopyridine derivatives. The removal
of all or selected fluorine atoms of the resulting com-
pounds by catalytic hydrodefluorination[15] or by pro-
assignments; coupling constants are given in Hz. 13C NMR
1
spectra are H-decoupled and in most cases 19F-decoupled.
Multiplicity is indicated as follows: s (singlet), d (doublet), t
(triplet), m (multiplet), mc (centered multiplet), dd (doublet
of doublet), br s (broad singlet). MS and HR-MS analyses
were performed with a Varian Ionspec QFT-7 instrument
(ESI-FT ICR-MS). Elemental analyses were carried out
with a Vario EL Elemental Analyzer. Melting points were
measured with a Reichert apparatus (Thermovar) and are
uncorrected.
À
cesses activating the C F bond leads to new 4-amino-
pyridine derivatives with unusual substitution pat-
terns. The complete hydrodefluorination of com-
pounds such as (R,R)-31 led to the desired divalent
analogue of 4-(dimethylamino)pyridine (R,R)-52 that
is of interest as a new enantiopure Lewis base and
ligand.[16]
Experimental Section
General Procedure 1 (GP1)
A solution of the amine with pentafluoropyridine (1) or
2,4,6-trifluoropyridine (2) in THF or in CH2Cl2 was stirred
with Et3N (4 equiv.) under an Ar atmosphere at room tem-
perature or heated to 708C for a certain period of time.
After cooling to room temperature the reaction was
quenched by water addition. Extraction with Et2O, solvent
evaporation provided the crude product that was purified by
flash chromatography (FLC).
General Methods
Reactions were generally performed under argon in flame-
dried flasks. Solvents and reagents were added by syringes.
Solvents were dried using standard procedures. Reagents
were purchased and were used as received without further
purification unless otherwise stated. Reactions were moni-
tored by thin-layer chromatography (TLC). Products were
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(125 MHz, CDCl3): d=48.7, 51.1 (2 t, CH2N), 67.0, 67.5 (2 t,
CH2O), 136.6 (mc, C-4), 138.6 (mc, C-3), 143.6 (mc, C-2);
19F NMR (376 MHz, CDCl3): d=À148.8 (mc, 2F, 3-F); IR
À
General Procedure 2 (GP2)
4-Substituted tetrafluoropyridine and hydrazine monohy-
drate were dissolved in ethanol and stirred for the required
time under reflux. The mixture was concentrated and the
residue was dissolved in CH2Cl2 and washed with water. The
organic phase was dried and concentrated to give the crude
hydrazine derivative. The crude product was suspended in
water and the solution of CuSO4·5H2O in water was added
drop-wise. The resulting mixture was refluxed for 1 h, after
cooling down, ammonia solution (25%) was added until
pH 9 was reached. Extraction with EtOAc, concentration
and purification by FLC furnished the resulting pyridine de-
rivative.
˜
(ATR): n=2965–2825 (C H), 1595, 1565 (C=C, C=N), 1485,
1185, 1110 (C F) cmÀ1; HR-MS (ESI-TOF): m/z=371.1897,
À
calcd. for C17H24F2N4O3: 371.1889 [M+H]+, m/z=393.1716,
calcd. for [M+Na]+: 393.1709; anal. calcd. (%) for
C17H24F2N4O3 (370.4): C 55.13, H 6.53, N 15.13; found C
55.22, H 6.44, N 15.40.
Sodium amide (0.490 g, 12.5 mmol, 5 equiv.) was suspend-
ed in morpholine (10 mL, 115 mmol, 46 equiv.), pyridine de-
rivative 1 (0.420 g, 2.50 mmol) was added and the resulting
mixture was heated under reflux for 24 h. The reaction was
quenched with saturated aqueous NH4Cl solution, then ex-
traction (EtOAc) and FLC (hexanes/EtOAc, 4:1) gave 8 as
a colorless solid; yield: 717 mg (78%).
General Procedure 3 (GP3)
2,6-Difluoro-4-morpholinopyridine (9): According to
GP1, morpholine (0.360 g, 4.00 mmol) and Et3N (1.40 mL,
10.0 mmol, 2.5 equiv.) were dissolved in CH2Cl2 (9 mL). A
solution of 2 (0.540 g, 4.00 mmol) in CH2Cl2 (2 mL) was
added and the mixture was stirred overnight at room tem-
perature. Work-up and FLC (hexanes/EtOAc 3:1) gave 9 as
a colorless solid; yield: 0.711 g (89%); mp 201–2028C;
1H NMR (500 MHz, acetone-d6): d=3.43 (t, J=5.1 Hz, 4H,
CH2N), 3.77 (t, J=5.1 Hz, 4H, CH2O), 6.37 (mc, 2H, 3-H, 5-
H); 13C NMR (125 MHz, acetone-d6): d=47.3 (t, CH2N),
66.7 (t, CH2O), 89.5 (mc, C-3), 163.2 (t, JC,F =12.0 Hz, C-4),
164.5 (dd, JC,F =235, 21.6 Hz, C-2); 19F NMR (376 MHz, ace-
˜
The substrate, titanocene difluoride, diphenylsilane and dry
1,4-dioxane were put into a Schlenk flask or a flask
equipped with a J. Young PTFE valve and the resulting mix-
ture was subsequently degassed by the freezing vacuum
pump method. Subsequently, the mixture was shortly heated
with a heat gun until the yellow color changed into dark-
brown and the solution was then stirred at 1108C for the re-
quired period (controlled by TLC). The reaction was
quenched with MeOH and water was added. Extraction
with Et2O, drying with Na2SO4 and concentration furnished
the crude product. Purification by FLC furnished the de-
sired product.
tone-d6): d=À73.0 (s,
2 F, 2-F); IR (ATR): n=3125
2,3,5,6-Tetrafluoro-4-morpholinopyridine (6): According
to GP1, morpholine (1.31 g, 15.0 mmol) was dissolved in
THF (40 mL). A solution of 1 (2.54 g, 15.0 mmol) and Et3N
(5.25 mL, 37.5 mmol, 2.5 equiv.) in THF (4 mL) was added
and the resulting mixture was stirred overnight at room tem-
perature. Work-up and FLC (hexanes/EtOAc 5:1) afforded
6 as a colorless solid; yield: 3.49 g (99%, Lit[8i] 90%); mp
À
À
(=C H), 2970–2865 (C H), 1660–1530 (C=C, C=N), 1450,
1235, 1210, 1120 (C F) cmÀ1; HR-MS (ESI-TOF): m/z=
À
201.0832, calcd. for C9H10F2N2O: 201.0834 [M+H]+, m/z=
223.0652, calcd. for [M+Na]+: 223.0653; anal. calcd. (%) for
C9H10F2N2O (200.2): C 54.00, H 5.04, N 13.99; found C
54.19, H 5.19, N 14.08.
1
51–538C, Lit.[8i] 71–738C. H NMR (500 MHz, CDCl3): d=
cis-N,N’-Bis(2,3,5,6-tetrafluoropyridin-4-yl)cyclohexane-
1,2-diamine (11): According to GP1, cis-cyclohexane-1,2-di-
amine (10) (0.100 g, 0.870 mmol) and Et3N (0.490 mL,
3.48 mmol, 4 equiv.) were dissolved in THF (5 mL). A solu-
tion of 1 (0.565 g, 3.34 mmol, 4 equiv.) in THF (1 mL) was
added and the mixture was stirred for 24 h under reflux.
Work-up and FLC (hexanes/EtOAc 6:1) afforded 12 as a col-
orless solid; yield: 0.348 g (97%); mp 92–948C. 1H NMR
(500 MHz, CDCl3): d=1.56–1.74 (m, 6H, CH2), 1.85–1.91
(m, 2H, CH2), 4.26 (mc, 2H, CH), 4.69 (mc, 2H, NH);
13C NMR (125 MHz, CDCl3): d=21.3 (t, CH2), 29.2 (t,
CH2), 54.0 (dt, JC,F =4.4 Hz, CH), 131.7 (mc, C-2/C-3), 136.7
(mc, C-4), 144.3 (mc, C-2/C-3); 19F NMR (376 MHz, CDCl3):
d=À162.3 (mc, 4F, 3-F), À93.1 (mc, 4F, 2-F); HR-MS (ESI-
TOF): m/z=413.1033, calcd. for C16H12F8N4: 413.1012 [M+
H]+, m/z=435.0839, calcd. for [M+Na]+: 435.0832.
3.48 (mc, 4H, CH2N), 3.81 (mc, 4H, CH2O). The data agree
with those of the literature.[17] 13C NMR (125 MHz, CDCl3):
d=50.5 (t, CH2N), 67.0 (t, CH2O), 135.1, 139.3, 144.9 (3 mc,
C-2, C-3, C-4); 19F NMR (376 MHz, CDCl3): d=À154.3 (mc,
2F, 3-F), À92.6 (mc, 2F, 2-F).
3,5,6-Trifluoro-2,4-dimorpholinopyridine (7) and 3,5-Di-
fluoro-2,4,6-trimorpholinopyridine (8): Morpholine (10.0 g,
115 mmol, 46 equiv.),
1 (0.420 g, 2.50 mmol) and Et3N
(2.08 mL, 15.0 mmol, 6 equiv.) were mixed and heated under
reflux overnight. Work-up and FLC (hexanes/EtOAc 6:1)
afforded 7 [yield: 0.45 g (59%)] and 8 [yield: 0.36 g (39%)]
as colorless solids.
1
7: mp 94–978C; H NMR (500 MHz, CDCl3): d=3.31 (mc,
4H, CH2N), 3.36 (mc, 4H, CH2N), 3.78 (mc, 8H, CH2O);
13C NMR (125 MHz, CDCl3): d=48.4, 50.8 (2 t, CH2N),
66.8, 67.3 (2 t, CH2O), 132.7 (mc, C-6), 138.6, 139.8, 143.3,
146.3 (4 mc, C-2, C-3, C-4, C-5); 19F NMR (376 MHz,
CDCl3): d=À161.2, À143.1 (2mc, 2F, 3-F, 5-F), À92.7 (mc,
À
(R,R)-N,N’-Bis(2,3,5,6-tetrafluoropyridin-4-yl)cyclohex-
ane-1,2-diamine (13): According to GP1, (R,R)-cyclohex-
ane-1,2-diamine (12) (0.100 g, 0.870 mmol) and Et3N
(0.490 mL, 3.48 mmol, 4 equiv.) were dissolved in THF
(5 mL). A solution of 1 (0.565 g, 3.34 mmol, 4 equiv.) in
THF (1 mL) was added and the mixture was stirred for 24 h
under reflux. Work-up and FLC (hexanes/EtOAc 5:1) af-
forded 13 as a colorless solid; yield: 0.360 g (99%); mp 125–
˜
1F, 6-F); IR (ATR): n=2985–2860 (C H), 1620–1560 (C=C,
C=N), 1470, 1190, 1110 (C F) cmÀ1; HR-MS (ESI-TOF):
À
m/z=304.1258, calcd. for C13H16F3N3O2: 304.1267 [M+H]+,
m/z=326.1105, calcd. for [M+Na]+: 326.1087; anal. calcd.
(%) for C13H16F3N3O2 (303.3): C 51.48, H 5.32, N 13.86;
found C 51.55, H 5.51, N 14.02.
1
1278C; [a]2D0: +103.4 (c=1.5, CHCl3). H NMR (500 MHz,
8: mp 130–1328C; 1H NMR (500 MHz, CDCl3): d=3.29
(mc, 12H, CH2N), 3.78 (mc, 12H, CH2O); 13C NMR
CDCl3): d=1.42 (mc, 4H, CH2), 1.89 (mc, 2H, CH2), 2.24
(mc, 2H, CH2), 3.77 (mc, 2H, CH), 4.49 (mc, 2H, NH);
3222
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Adv. Synth. Catal. 2015, 357, 3215 – 3228

FULL PAPERS
Studies on the Synthesis of Specifically Fluorinated 4-Aminopyridine Derivatives
13C NMR (125 MHz, CDCl3): d=24.6 (t, CH2), 34.2 (t,
CH2), 59.4 (mc, CH), 131.0 (mc, C-2/C-3), 137.0 (mc, C-4),
144.1 (mc, C-2/C-3); 19F NMR (376 MHz, CDCl3): d=
À162.4 (mc, 4F, 3-F), À93.2 (mc, 4F, 2-F); HR-MS (ESI-
TOF): m/z=413.1002, calcd. for C16H12F8N4: 413.1012 [M+
H]+, m/z=435.0836, calcd. for [M+Na]+: 435.0832.
[M+Na]+: 463.1139; anal. calcd. (%) for C18H16F8N4 (440.3):
C 49.10, H 3.66, N 12.72; found: C 49.12, H 3.45, N 12.87.
cis-N,N’-Dimethyl-N,N’-bis(2,3,5,6-tetrafluoropyridin-4-
yl)cyclohexane-1,2-diamine (21): According to GP1, cis-
N,N’-dimethylcyclohexane-1,2-diamine
(20)
(0.100 g,
0.70 mmol) and Et3N (0.40 mL, 2.81 mmol, 4 equiv.) were
dissolved in THF (5 mL). A solution of 1 (0.26 g, 1.54 mmol,
2.2 equiv.) in THF (2 mL) was added and the resulting mix-
ture was stirred for 2 d under reflux. Work-up and FLC
(hexanes/EtOAc 15:1) afforded 21 as a brownish foam;
meso-N,N’-Bis(2,3,5,6-tetrafluoropyridin-4-yl)-1,2-diphe-
nylethane-1,2-diamine (15): According to GP1, meso-1,2-di-
phenylethane-1,2-diamine (14) (0.150 g, 0.710 mmol) and
Et3N (0.400 mL, 2.83 mmol, 4 equiv.) were dissolved in THF
(5 mL). A solution of 1 (0.458 g, 2.72 mmol, 4 equiv.) in
THF (1 mL) was added and the mixture was stirred for 24 h
under reflux. Work-up and FLC (hexanes/EtOAc 6:1) af-
forded 15 as a slightly yellow solid; yield: 0.361 g (quant.);
mp 176–1788C. 1H NMR (500 MHz, acetone-d6): d=5.78
(mc, 2H, CH), 6.74 (mc, 2H, NH), 7.24 (mc, 2H, Ph), 7.34
(mc, 4H, Ph), 7.72 (mc, 4H, Ph); 13C NMR (125 MHz, ace-
tone-d6): d=62.4 (dt, JC,F =4.9 Hz, CH), 127.8 (d, Ph), 128.2
(d, Ph), 128.6 (d, Ph), 131.3 (mc, C-2/C-3), 136.0 (mc, C-4),
140.2 (s, Ph), 144.0 (mc, C-2/C-3); 19F NMR (376 MHz,
CDCl3): d=À161.6 (mc, 4F, 3-F), À96.8 (mc, 4F, 2-F); HR-
MS (ESI-TOF): m/z=511.1170, calcd. for C24H14F8N4 [M+
H]+: 511.1169, m/z=533.0991, calcd. for [M+Na]+:
533.0988.
(S,S)-N,N’-Bis(2,3,5,6-tetrafluoropyridin-4-yl)-1,2-diphe-
nylethane-1,2-diamine (17): According to GP1, (S,S)-1,2-di-
phenylethane-1,2-diamine (16) (0.150 g, 0.710 mmol) and
Et3N (0.400 mL, 2.83 mmol, 4 equiv.) were dissolved in THF
(5 mL). A solution of 1 (0.458 g, 2.72 mmol, 4 equiv.) in
THF (1 mL) was added and the mixture was stirred for 24 h
under reflux. Work-up and FLC (hexanes/EtOAc 5:1) af-
forded 17 as a colorless solid; yield: 0.355 g, (98%); 159–
1618C; [a]2D0: À62.1 (c=1.3, CHCl3). 1H NMR (500 MHz,
CDCl3): d=5.14 (br s, 2H, NH), 5.28 (mc, 2H, CH), 6.96
(mc, 4H, Ph), 7.21–7.33 (m, 6H, Ph); 13C NMR (125 MHz,
CDCl3): d=63.1 (dt, JC,F =4.1 Hz, CH), 127.3 (d, Ph), 129.1
(d, Ph), 129.2 (d, Ph), 131.8 (mc, C-2/C-3), 136.4 (mc, C-4),
136.5 (s, Ph), 144.2 (mc, C-2/C-3); 19F NMR (376 MHz,
CDCl3): d=À160.8 (mc, 4F, 3-F), À92.5 (mc, 4F, 2-F); HR-
MS (ESI-TOF): m/z=511.1171, calcd. for C24H14F8N4:
511.1169 [M+H]+, m/z=533.1001, calcd. for [M+Na]+:
533.0988.
1
yield: 0.127 g (41%). H NMR (400 MHz, CDCl3): d=1.51
(mc, 2H, CH2), 1.77–1.81 (m, 4H, CH2), 2.02–2.10 (m, 2H,
CH2), 2.76 (mc, 6H, CH3), 3.72–3.83 (m, 2H, CH); 13C NMR
(125 MHz, CDCl3): d=23.9 (t, CH2), 28.4 (t, CH2), 38.9 (q,
CH3), 61.2 (d, CH), 134.2, 138.2, 145.4 (3 mc, C-2, C-3, C-4);
19F NMR (376 MHz, CDCl3): d=À155.1 (mc, 4F, 3-F), À95.8
(mc, 4F, 2-F); HR-MS (ESI-TOF): m/z=441.1324, calcd. for
C18H16F8N4: 441.1320 [M+H]+.
N,N’-Dimethyl-N,N’-bis(2,3,5,6-tetrafluoropyridin-4-yl)-
ethane-1,2-diamine (23): According to GP1, N,N’-dimethyl-
ethylene-1,2-diamine (22) (0.29 g, 3.30 mmol) and Et3N
(1.87 mL, 13.3 mmol, 4 equiv.) were dissolved in THF
(20 mL). A solution of pentafluoropyridine (1) (1.13 g,
6.68 mmol, 2 equiv.) in THF (15 mL) was added and the re-
sulting mixture was stirred overnight at room temperature.
Work-up and following FLC (hexanes/ethyl acetate 6:1) af-
forded product 23 as a colorless solid; yield: 1.28 g (99%,
lit.[8i] 90%); mp 140–1418C (lit.[8i] 139–1408C). 1H NMR
(CDCl3, 500 MHz): d=3.15 (t, J=3.3 Hz, 6H, CH3), 3.64 (s,
4H, CH2); 13C NMR (CDCl3, 125 MHz): d=40.8 (q, CH3),
52.7 (t, CH2), 134.5, 139.8, 145.1 (3 s, C-2, C-3, C-4);
19F NMR (CDCl3, 471 MHz): d=À155.3 (mc, 4F, 3-F), À92.7
À
˜
(mc, 4F, 2-F); IR (ATR): n=2990–2835 (C H), 1630, 1530
(C=C, C=N), 1460, 1260, 1220, 1130, 1115 (C F) cmÀ1; HR-
À
MS (ESI-TOF): m/z=387.0826, calcd. for C14H10F8N4:
387.0850 [M+H]+, m/z=409.0649, calcd. for [M+Na]+:
409.0670; anal. calcd. (%) for C14H10F8N4 (386.2): C 43.53, H
2.61, N 14.51; found: C 43.49, H 2.51, N 14.39.
N,N’-Dimethyl-N,N’-bis(4,6-difluoropyridin-2-yl)ethane-
1,2-diamine (24), N,N’-dimethyl-N-(2,6-difluoropyridin-4-
yl)-N’-(4,6-difluoropyridin-2-yl)ethane-1,2-diamine (25) and
N,N’-dimethyl-N,N’-bis(2,6-difluoropyridin-4-yl)ethane-1,2-
diamine (26): According to GP1, N,N’-dimethylethylene-1,2-
diamine (22) (0.220 g, 2.50 mmol) and Et3N (1.40 mL,
10.0 mmol, 4 equiv.) were dissolved in THF (20 mL). A solu-
tion of 2 (0.670 g, 5.00 mmol, 2 equiv.) in THF (5 mL) was
added and the mixture was stirred overnight under reflux.
Work-up and FLC (hexanes/EtOAc 12:1, 8:1, 3:1) afforded
24 (yield: 0.143 g, 18%), 25 (yield: 0.235 g, 30%) and 26
(0.290 g, 37%) as a colorless solids.
rac-trans-N,N’-Dimethyl-N,N’-bis(2,3,5,6-tetrafluoropyri-
din-4-yl)cyclohexane-1,2-diamine (19): According to GP1,
rac-trans-N,N’-dimethylcyclohexane-1,2-diamine
(18)
(0.280 g, 1.97 mmol) and Et3N (1.11 mL, 7.90 mmol,
4 equiv.) were dissolved in THF (20 mL). A solution of
1 (1.33 g, 7.87 mmol, 4 equiv.) in THF (5 mL) was added
and the resulting mixture was stirred for 2 d under reflux.
Work-up and FLC (hexanes/EtOAc 15:1) afforded 19 as
a colorless solid; yield: 0.400 g (46%); mp 216–2178C.
1H NMR (500 MHz, CDCl3): d=1.36 (mc, 2H, CH2), 1.71–
1.73 (m, 2H, CH2), 1.82–1.94 (m, 2H, CH2), 2.11–2.13 (m,
2H, CH2), 2.76 (t, JHF =3.1 Hz, 6H, CH3), 3.58–3.69 (m, 2H,
CH); 13C NMR (125 MHz, CDCl3): d=25.1 (t, CH2), 30.2 (t,
CH2), 33.5 (q, CH3), 61.9 (d, CH), 134.6, 140.7, 145.2 (3 mc,
C-2, C-3, C-4); 19F NMR (376 MHz, CDCl3): d=À154.2 (mc,
1
24: mp 177–1788C; H NMR (500 MHz, acetone-d6): d=
2.99 (s, 6H, CH3), 3.71 (s, 4H, CH2), 5.85 (mc, 2H, 3-H/5-
H), 5.96 (mc, 2H, 3-H/5-H); 13C NMR (125 MHz, acetone-
d6): d=37.2 (q, CH3), 47.6 (t, CH2), 84.6 (ddd, JC,F =42.3,
24.8 Hz, C-3/C-5), 89.9 (ddd, JC,F =23.8, 5.7 Hz, C-3/C-5),
158.4 (dd, JC,F =20.1, 14.0 Hz, C-2), 163.7 (dd, JC,F =233,
18.3 Hz, C-6), 172.9 (dd, JC,F =254, 14.8 Hz, C-4); 19F NMR
(376 MHz, acetone-d6): d=À98.7 (mc, 2F, 4-F), À65.5 (mc,
À
À
˜
4F, 3-F), À92.7 (mc, 4F, 2-F); IR (ATR): n=2955–2835 (C
˜
2F, 6-F); IR (ATR): n=3120, 3100 (=C H), 2925–2810
À
À
H), 1635, 1525 (C=C, C=N), 1465, 1220, 1160, 1110 (C F)
(C H), 1710–1510 (C=C, C=N), 1455, 1260, 1180, 1110
cmÀ1
;
HR-MS (ESI-TOF): m/z=441.1315, calcd. for
(C F) cmÀ1; HR-MS (ESI-TOF): m/z=315.1240, calcd. for
À
C18H16F8N4: 441.1320 [M+H]+, m/z=463.1136, calcd. for
C14H14F4N4: 315.1227 [M+H]+, m/z=337.1060, calcd. for
Adv. Synth. Catal. 2015, 357, 3215 – 3228
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3223

FULL PAPERS
Gabriel Podolan et al.
[M+Na]+: 337.1047; anal. calcd. (%) for C14H14F4N4 (314.3):
(2 s, 3 H each, CH3), 4.22, 4.87 (2 mc, 1 H each, CH), 6.01
(mc, 1H, 3’-H/5’-H), 6.15 (mc, 1H, 3’-H/5’-H), 6.26 (br s, 2H,
3-H/5-H); 13C NMR (125 MHz, acetone-d6): d=25.4, 25.7,
29.7, 29.9 (4 t, CH2), 32.3 (q, CH3), 58.9 (d, CH), 84.5 (ddd,
C 53.50, H 4.49, N 17.83; found: C 53.31, H 4.57, N 17.90.
1
25; mp 194–1958C; H NMR (500 MHz, acetone-d6): d=
3.08 (s, 3H, CH3), 3.10 (s, 3H, CH3), 3.69 (mc, 2H, CH2),
3.81 (mc, 2H, CH2), 6.06 (mc, 1H, 3’-H/5’-H), 6.19 (mc, 1H,
3’-H/5’-H), 6.25 (br s, 2H, 3-H/5-H); 13C NMR (125 MHz,
acetone-d6): d=37.5, 38.8 (2 q, CH3), 47.6, 49.9 (2 t, CH2),
84.6 (ddd, JC,F =42.7, 25.1 Hz, C-3’/C-5’), 88.2 (mc, C-3/C-5),
89.9 (ddd, JC,F =23.9, 5.6 Hz, C-3’/C-5’), 159.7 (dd, JC,F =20.3,
14.1 Hz, C-2’), 162.2 (dd, JC,F =12.0 Hz, C-4), 164.1 (dd,
J
J
C,F =43.7, 25.2 Hz, C-3’/C-5’), 88.2 (mc, C-3/C-5), 90.0 (ddd,
C,F =24.0, 5.3 Hz, C-3’/C-5’), 159.6 (dd, JC,F =20.7, 14.3 Hz,
C-2’), 162.0 (t, JC,F =12.2 Hz, C-4), 164.3 (dd, JC,F =231,
17.9 Hz, C-6’), 164.5 (dd, JC,F =233, 21.9 Hz, C-2/C-6), 173.5
(dd, JC,F =253, 14.1 Hz, C-4’); 19F NMR (376 MHz, acetone-
d6): d=À100.3 (mc, 1 F, 4’-F), À73.7 (mc, 2F, 2-F), À66.4 (d,
À
˜
J
C,F =232, 18.1 Hz, C-6’), 164.7 (dd, JC,F =234, 22.2 Hz, C-2/
J
F,F =22.9 Hz, 1 F, 6’-F); IR (ATR): n=2935, 2860 (C H),
C,F =252, 14.6 Hz, C-4’); 19F NMR
1620, 1570, 1545 (C=C, C=N), 1495, 1240 1190, 1120 (C F)
À
C-6), 173.4 (dd,
J
(376 MHz, acetone-d6): d=À100.3 (mc, 1F, 4’-F), À73.6 (s,
cmÀ1
;
HR-MS (ESI-TOF): m/z=369.1699, calcd. for
2F, 2-F), À66.6 (d, JF,F =22.9 Hz, 1F, 6’-F); IR (ATR): n=
C18H20F4N4: 369.1697 [M+H]+, m/z=391.1524, calcd. for
[M+Na]+: 391.1516; anal. calcd. (%) for C18H20F4N4 (368.4):
C 58.69, H 5.47, N 15.21; found: C 58.74, H 5.64, N 15.09.
˜
À
À
3100 (=C H), 2925–2815 (C H), 1620–1510 (C=C, C=N),
1450, 1265, 1170, 1150, 1120 (C F) cmÀ1; HR-MS (ESI-
À
1
TOF): m/z=315.1239, calcd. for C14H14F4N4: 315.1227 [M+
H]+, m/z=337.1061, calcd. for [M+Na]+: 337.1047; anal.
calcd. (%) for C14H14F4N4 (314.3): C 53.50, H 4.49, N 17.83;
found: C 53.43, H 4.49, N 17.78.
31: mp 196–1978C; H NMR (500 MHz, acetone-d6): d=
1.59–1.69 (m, 2H, CH2), 1.82–1.87 (m, 6H, CH2), 2.80 (s,
6H, CH3), 4.27 (mc, 2H, CH), 6.31 (s, 4H, 3-H/5-H);
13C NMR (125 MHz, acetone-d6): d=25.2 (t, CH2), 29.5 (t,
CH2), 32.1 (q, CH3), 59.1 (d, CH), 88.3 (mc, C-3/C-5), 161.9
(t, JC,F =12.2 Hz, C-4), 164.5 (dd, JC,F =233, 21.9 Hz, C-2);
19F NMR (376 MHz, acetone-d6): d=À73.4 (s, 4F, 2-F); IR
1
26: mp 188–1898C; H NMR (500 MHz, acetone-d6): d=
3.08 (s, 6H, CH3), 3.82 (s, 4H, CH2), 6.14 (mc, 4H, 3-H/5-
H); 13C NMR (125 MHz, acetone-d6): d=39.2 (q, CH3), 49.8
À
À
˜
(t, CH2), 88.3 (dd, JC,F =45.5 Hz, C-3/C-5), 161.5 (t, JC,F
=
(ATR): n=3085 (=C H), 2930, 2860 (C H), 1635, 1545,
12.2 Hz, C-4), 164.4 (dd, JC,F =234, 21.9 Hz, C-2); 19F NMR
(376 MHz, acetone-d6): d=À73.2 (s, 4F, 2-F); IR (ATR):
1510 (C=C, C=N), 1445, 1220, 1190, 1130 (C F) cmÀ1; HR-
À
MS (ESI-TOF): m/z=369.1699, calcd. for C18H20F4N4:
369.1697 [M+H]+, m/z=391.1521, calcd. for [M+Na]+:
391.1516.
À
À
˜
n=3100 (=C H), 2925–2855 (C H), 1735–1520 (C=C,
C=N), 1440, 1240, 1170 (C F) cmÀ1; HR-MS (ESI-TOF):
À
m/z=315.1201, calcd. for C14H14F4N4: 315.1227 [M+H]+,
m/z=337.1023, calcd. for [M+Na]+: 337.1047; calcd. (%)
for C14H14F4N4 (314.3): C 53.50, H 4.49, N 17.83; found: C
53.31, H 4.49, N 17.60.
rac-trans- or (R,R)-N,N’-Bis(4,6-difluoropyridin-2-yl)cy-
clohexane-1,2-diamine (28), rac-trans- or (R,R)-N-(2,6-di-
fluoropyridin-4-yl)-Nꢀ-(4,6-difluoropyridin-2-yl)cyclohexane-
1,2-diamine (30) and rac-trans- or (R,R)-N,N’-bis(2,6-di-
fluoro-pyridin-4-yl)cyclohexane-1,2-diamine (32): According
to GP1, rac-trans-12 (0.500 g, 4.38 mmol) and Et3N
(2.45 mL, 17.5 mmol, 4 equiv.) were dissolved in THF
(10 mL). A solution of 2 (2.33 g, 17.5 mmol, 4 equiv.) in
THF (5 mL) was added and the resulting mixture was
stirred for 36 h under reflux. Work-up and FLC (hexanes/
EtOAc 6:1, 4:1, 1:1) afforded 28 (yield: 0.200 g, 13%), 30
(yield: 0.616 g, 41%) and 32 (yield: 0.370 g, 25%) as color-
less solids.
rac-trans-N,N’-Dimethyl-N,N’-bis(4,6-difluoropyridin-2-
yl)cyclohexane-1,2-diamine (27), rac-trans-N,N’-dimethyl-
N-(2,6-difluoropyridin-4-yl)-N’-(4,6-difluoropyridin-2-yl)cy-
clohexane-1,2-diamine (29) and rac-trans-N,N’-dimethyl-
N,N’-bis(2,6-difluoropyridin-4-yl)cyclohexane-1,2-diamine
(31): According to GP1, rac-trans-18 (1.12 g, 7.85 mmol) and
Et3N (4.41 mL, 31.4 mmol, 4 equiv.) were dissolved in THF
(100 mL). A solution of 2 (4.18 g, 31.4 mmol, 4 equiv.) in
THF (5 mL) was added and the mixture was refluxed for
72 h. Work-up and FLC (hexanes/EtOAc 15:1, 10:1, 5:1) af-
forded 27 (yield: 0.358 g, 12%), 29 (yield: 0.202 g, 7%) and
31 (0.026 g, 1%) as colorless solids.
The experiment was also performed with (R,R)-12 to give
the enantiopure products in almost identical yields: 13% for
28, 45% for 30 and 30% for 32.
27: mp 74–768C; 1H NMR (500 MHz, acetone-d6): d=
1.47 (mc, 2H, CH2), 1.77–1.83 (m, 6H, CH2), 2.75 (s, 6H,
CH3), 4.81 (br s, 2H, CH), 5.97 (mc, 2H, 3-H/5-H), 6.09 (mc,
2H, 3-H/5-H); 13C NMR (125 MHz, acetone-d6): d=25.3 (t,
CH2), 30.0 (t, CH2), 31.0 (q, CH3), 56.0 (d, CH), 84.2 (ddd,
28: mp 141–1438C [147–1498C for the R,R-isomer, [a]2D0:
1
+68.5 (c=1.04, CHCl3)]; H NMR (500 MHz, CDCl3): d=
1.24–1.35 (m, 2H, CH2), 1.36–1.43 (m, 2H, CH2), 1.77 (mc,
2H, CH2), 2.14 (mc, 2H, CH2), 3.55 (mc, 2H, CH), 5.68 (mc,
2H, 3-H/5-H), 5.81 (mc, 2H, 3-H/5-H); 13C NMR (125 MHz,
CDCl3): d=24.6 (t, CH2), 32.6 (t, CH2), 55.7 (d, CH), 85.0
(ddd, JC,F =41.7, 24.9 Hz, C-3/C-5), 90.1 (mc, C-3/C-5), 158.6
J
C,F =43.9, 25.2 Hz, C-3/C-5), 89.0 (ddd, JC,F =23.9, 5.5 Hz,
C-3/C-5), 159.8 (dd, JC,F =20.7, 14.4 Hz, C-2), 164.3 (dd,
J
C,F =231, 18.0 Hz, C-6), 173.5 (dd, JC,F =253, 14.1 Hz, C-4);
(ddd, JC,F =20.7, 14.2 Hz, C-2), 164.1 (ddd, JC,F =235,
19F NMR (376 MHz, acetone-d6): d=À100.5 (mc, 2F, 4-F),
17.2 Hz, C-6), 172.2 (ddd, JC,F =256, 14.0 Hz, C-4); 19F NMR
(376 MHz, CDCl3): d=À98.7 (mc, 2F, 4-F), À66.8 (mc, 2F,
6-F); HR-MS (ESI-TOF): m/z=341.1384, calcd. for
C16H16F4N4: 341.1389 [M+H]+.
˜
À66.4 (d, JF,F =23.2 Hz, 2F, 6-F); IR (ATR): n=3105
À
(=C H), 2930, 2860, 2815 (C-H), 1625, 1565 (C=C, C=N),
1495, 1190, 1160, 1115 (C F) cmÀ1; HR-MS (ESI-TOF):
À
m/z=369.1699, calcd. for C18H20F4N4: 369.1697 [M+H]+,
m/z=391.1516, calcd. for [M+Na]+: 391.1516; anal. calcd.
(%) for C18H20F4N4 (368.4): C 58.69, H 5.47, N 15.21; found:
C 58.81, H 5.56, N 15.12.
30: mp 137–1398C [131–1338C for the R,R-isomer, [a]2D0:
1
+135.4 (c=1.04, CHCl3)]; H NMR (500 MHz, CDCl3): d=
1.23–1.47 (m, 4H, CH2), 1.77–1.86 (m, 2H, CH2), 2.08 (mc,
1H, CH2), 2.19 (mc, 1H, CH2), 3.12 (dt, J=10.0, 8.6 Hz, 1H,
CH), 3.89 (dt, J=10.0, 8.9 Hz, 1H, CH), 4.75 (mc, 1H, NH),
5.74 (s, 2H, 3-H/5-H), 5.91 (mc, 2H, 3’-H/5’-H), 6.02 (mc,
1
29: mp 105–1078C; H NMR (500 MHz, acetone-d6): d=
1.48–1.64 (m, 2H, CH2), 1.74–1.90 (m, 6H, CH2), 2.77, 2.79
3224
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Adv. Synth. Catal. 2015, 357, 3215 – 3228

FULL PAPERS
Studies on the Synthesis of Specifically Fluorinated 4-Aminopyridine Derivatives
1H, NH); 13C NMR (125 MHz, CDCl3): d=24.1 (t, CH2),
24.9 (t, CH2), 31.6 (t, CH2), 32.9 (t, CH2), 54.1 (d, CH), 59.6
(d, CH), 86.0 (ddd, JC,F =41.7, 24.9 Hz, C-3’/C-5’), 87.8 (mc,
C-3/C-5), 91.7 (ddd, JC,F =22.4, 5.6 Hz, C-3’/C-5’), 158.6
(ddd, JC,F =19.9, 14.3 Hz, C-2’), 159.7 (ddd, JC,F =11.9 Hz, C-
4), 163.4 (ddd, JC,F =237, 20.3 Hz, C-2/C-6), 164.1 (ddd,
CH2N), 67.2 (t, CH2O), 134.4 (s, C-4), 135.1 (d, C-2), 136.2
(s, C-3); 19F NMR (CDCl3, 376 MHz): d=À137.8 (s, 2F, 3-
À
À
˜
F); IR (ATR): n=3030 (=C H), 2955, 2920, 2855 (C H),
À
1600, 1550, 1505 (C=C, C=N), 1450, 1250, 1150, 1115 (C F)
cmÀ1
;
HR-MS (ESI-TOF): m/z=201.0839, calcd. for
C9H10F2N2O: 201.0834 [M+H]+.
J
C,F =236, 17.1 Hz, C-6’), 172.1 (ddd, JC,F =257, 13.9 Hz, C-
2-Fluoro-4-morpholinylpyridine (39): According to GP2,
2,6-difluoro-4-morpholinylpyridine (9) (0.100 g, 0.50 mmol)
and hydrazine monohydrate (0.500 g, 10.0 mmol, 20 equiv.)
were dissolved in ethanol (7 mL) and stirred for 4 h under
reflux. The mixture was concentrated and the residue was
dissolved in CH2Cl2 (50 mL) and washed with water (2”
50 mL). The organic phase was dried and concentrated to
give 38 as a yellow solid; yield: 84 mg (79%). The crude
product 38 (53 mg, 0.25 mmol) was suspended in water
(1 mL) and the solution of CuSO4·5H2O (0.41 g, 1.62 mmol,
6.5 equiv.) in water (10 mL) was added drop-wise. The re-
sulting mixture was heated to reflux for 1 h. Purification by
FLC (hexanes/EtOAc 2:1, 1:1) furnished pyridine 39 as a col-
orless solid; yield: 15 mg (33%, 26% over 2 steps); mp 153–
1548C. 1H NMR (500 MHz, CDCl3): d=3.29 (mc, 4H,
CH2N), 3.82 (mc, 4H, CH2O), 6.18 (d, J=1.4 Hz, 1H, 3-H),
6.54 (mc, 1H, 5-H), 7.90 (d, J=6.1 Hz, 1H, 6-H); 13C NMR
(125 MHz, CDCl3): d=46.4 (t, CH2N), 66.3 (t, CH2O), 92.1
(d, C-3), 106.5 (d, C-5), 147.8 (d, C-6), 159.4 (s, C-4), 165.9
(s, C-2); 19F NMR (376 MHz, CDCl3): d=À68.9 (s, 1F, 2-F);
À
4’); 19F NMR (376 MHz, CDCl3): d=À98.2 (mc, 1F, 4’-F),
À71.2 (s, 2F, 2-F), À66.8 (mc, 1F, 6’-F); HR-MS (ESI-TOF):
m/z=341.1382, calcd. for C16H16F4N4: 341.1389 [M+H]+.
32: mp 259–2618C [250–2528C for R,R-isomer, [a]2D0:
+89.2 (c=0.60, MeOH]; 1H NMR (500 MHz, acetone-d6):
d=1.36–1.55 (m, 4H, CH2), 1.76 (mc, 2H, CH2), 2.06–2.12
(m, 2H, CH2), 3.54 (mc, 2H, CH), 6.04 (s, 4H, 3-H/5-H),
6.56 (br s, 2H, NH); 13C NMR (125 MHz, acetone-d6): d=
24.4 (t, CH2), 32.1 (t, CH2), 56.5 (d, CH), 87.4 (mc, C-3/C-5),
160.9 (ddt, JC,F =12.1 Hz, C-4), 163.3 (dd, JC,F =233, 20.8 Hz,
C-2); 19F NMR (376 MHz, acetone-d6): d=À73.8 (s, 4F, 2-
F); HR-MS (ESI-TOF): m/z=341.1380, calcd. for
C16H16F4N4: 341.1389 [M+H]+.
2,3,5-Trifluoro-4-morpholinylpyridine (34): According to
GP2, 2,3,5,6-tetrafluoro-4-morpholinylpyridine (6) (0.470 g,
2.00 mmol) and hydrazine monohydrate (2.00 g, 40.0 mmol,
20 equiv.) were dissolved in ethanol (12 mL) and stirred for
3 h under reflux. The mixture was concentrated and the resi-
due was dissolved in CH2Cl2 (75 mL) and washed with water
(2”50 mL). The organic phase was dried and concentrated
to give crude 33 as a yellow solid; yield: 0.469 g (94%). The
crude product 33 (0.124 g, 0.50 mmol) was suspended in
˜
IR (ATR): n=3110, 3020 (=C H), 2975, 2960, 2925, 2860
À
(C H), 1610, 1550, 1505 (C=C, C=N), 1450, 1195, 1120
(C F) cmÀ1; HR-MS (ESI-TOF): m/z=183.0924, calcd. for
À
water (1 mL) and
a
solution of CuSO4·5H2O (0.81 g,
C9H11FN2O: 183.0928 [M+H]+, m/z=205.0741, calcd. for
[M+Na]+: 205.0748, m/z=221.0491, calcd. for [M+K]+:
221.0487, m/z=387.1590, calcd. for [2M+Na]+: 387.1603;
anal. calcd. (%) for C9H11FN2O (182.2): C 59.33, H 6.09, N
15.38; found: C 59.34, H 5.92, N 15.22.
3.25 mmol, 6.5 equiv.) in water (5 mL) was added drop-wise.
The resulting mixture was heated to reflux for 1 h. Purifica-
tion by FLC (hexanes/EtOAc 2:1) gave pyridine 34 as a col-
orless solid; yield: 90 mg (78% over 2 steps); mp 33–348C.
1H NMR (500 MHz, CDCl3): d=3.43 (mc, 4H, CH2N), 3.80
(mc, 4H, CH2O), 7.66 (mc, 1H, 2-H); 13C NMR (125 MHz,
CDCl3): d=50.5 (t, CH2N), 67.1 (t, CH2O), 128.2 (d, C-6),
137.7 (s, C-4), 149.8, 150.0 (2 s, C-2, C-3), 150.6 (s, C-5);
19F NMR (471 MHz, CDCl3): d=À150.7 (mc, 1F, 3-F),
N,N’-Dimethyl-N,N’-bis(2,3,5-trifluoropyridine-4-yl)-
ethane-1,2-diamine (41): According to GP2, pyridine deriva-
tive 23 (0.193 g, 0.50 mmol) and hydrazine monohydrate
(1.00 g, 20.0 mmol, 40 equiv.) were dissolved in ethanol
(10 mL) and stirred for 3 h under reflux. The mixture was
concentrated and the residue was dissolved in CH2Cl2
(50 mL) and washed with water (2”50 mL). The organic
phase was dried and concentrated to give 40 as a yellow
solid; yield: 203 mg. The crude product 40 (0.183 g,
0.45 mmol) was suspended in water (1 mL) and a solution of
CuSO4·5H2O (1.45 g, 5.80 mmol, 13 equiv.) in water (16 mL)
was added drop-wise. The resulting mixture was refluxed for
1 h. Purification by FLC (hexanes/EtOAc 10:1) provided
pyridine 41 as a yellow solid; yield: 68 mg (44% over 2
˜
À139.4 (mc, 1F, 5-F), À89.9 (mc, 1F, 2-F); IR (ATR): n=
À
2965–2860 (C H), 1615, 1565, 1510 (C=C, C=N), 1450, 1255,
1180, 1120, 1100 (C F) cmÀ1; HR-MS (ESI-TOF): m/z=
À
219.0749, calcd. for C9H9F3N2O: 219.0749 [M+H]+, m/z=
241.0575, calcd. for [M+Na]+: 241.0559; anal. calcd. (%) for
C9H9F3N2O (218.2): C 49.55, H 4.16, N 12.84; found: C
49.44, H 4.22, N 12.95.
3,5-Difluoro-4-morpholinylpyridine (36): According to
GP2, 2,3,5-trifluoro-4-morpholinylpyridine (34) (0.110 g,
0.50 mmol) and hydrazine monohydrate (1.00 g, 20.0 mmol,
40 equiv.) were dissolved in ethanol (7 mL) and stirred for
48 h under reflux. The mixture was concentrated and the
residue was dissolved in CH2Cl2 (50 mL) and washed with
water (2”50 mL). The organic phase was dried and concen-
trated to give 35 as a red solid (yield: 93 mg). The crude
product was suspended in water (10 mL) and the solution of
CuSO4·5H2O (0.66 g, 2.63 mmol, 6.5 equiv.) in water
(10 mL) was added drop-wise. The resulting mixture was
heated to reflux for 1 h. Purification by FLC (hexanes/
EtOAc 10:1) gave pyridine 36 as a colorless solid; yield:
1
steps); mp 113–1148C. H NMR (500 MHz, CDCl3): d=3.15
(t, J=3.3 Hz, 6H, CH3), 3.64 (s, 4H, CH2), 7.61 (mc, 2H, 2-
H); 13C NMR (125 MHz, CDCl3): d=40.8 (q, CH3), 52.5 (t,
CH2), 128.1 (d, C-6), 137.1 (s, C-2), 137.3 (s, C-4), 150.0 (s,
C-5), 169.4 (s, C-3); 19F NMR (376 MHz, CDCl3): d=À153.5
(mc, 2F, 3-F), À142.0 (mc, 2F, 5-F), À92.3 (mc, 2F, 2-F); IR
À
˜
(ATR): n=3015–2835 (C H), 1610, 1560, 1525 (C=C, C=N),
1455, 1240, 1215, 1110 (C F) cmÀ1; HR-MS (ESI-TOF):
À
m/z=351.1046, calcd. for C14H12F6N4: 351.1039 [M+H]+,
m/z=373.0866, calcd. for [M+Na]+: 373.0858; anal. calcd.
(%) for C14H12F6N4 (350.3): C 48.01, H 3.45, N 16.00; found:
C 40.08, H 3.44, N 16.11.
1
35 mg (35% over 2 steps); mp 56–588C. H NMR (500 MHz,
CDCl3): d=3.39 (mc, 4H, CH2N), 3.81 (mc, 4H, CH2O), 8.15
rac-trans-N,N’-Dimethyl-N,N’-bis(2,3,5-trifluoropyridine-
4-yl)cyclohexane-1,2-diamine (43): According to GP2, pyri-
(s, 2H, 2-H); 13C NMR (CDCl3, 125 MHz): d=50.6 (t,
Adv. Synth. Catal. 2015, 357, 3215 – 3228
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3225

FULL PAPERS
Gabriel Podolan et al.
dine derivative rac-19 (0.220 g, 0.50 mmol) and hydrazine
monohydrate (1.00 g, 20.0 mmol, 40 equiv.) were dissolved
in ethanol (10 mL) and stirred for 3 h under reflux. The mix-
ture was concentrated and the residue was dissolved in
CH2Cl2 (50 mL) and washed with water (2”75 mL). The or-
ganic phase was dried and concentrated to give 42 as
a yellow solid; yield: 230 mg. The crude product 42 (0.205 g,
0.44 mmol) was suspended in water (1 mL) and a solution of
CuSO4·5H2O (1.43 g, 5.74 mmol, 13 equiv.) in water (20 mL)
was added drop-wise. The resulting mixture was heated to
reflux for 1 h. Purification by FLC (hexanes/EtOAc 15:1)
provided pyridine 43 as a colorless solid; yield: 100 mg
1108C. Product 45 was isolated after FLC (hexanes/EtOAc
1:1) as a colorless solid; yield: 112 mg (55%); mp 146–
1
1488C. H NMR (500 MHz, CDCl3): d=3.04 (t, J=2.9 Hz,
6H, CH3), 3.53 (s, 4H, CH2), 8.04 (s, 4H, 2-H, 6-H);
13C NMR (CDCl3, 125 MHz): d=40.8 (q, CH3), 52.5 (t,
CH2), 134.3 (s, C-4), 134.9 (d, C-2), 152.1 (s, C-3); 19F NMR
˜
(CDCl3, 376 MHz): d=À138.3 (s, 4F, 3-F); IR (ATR): n=
À
À
3010 (=C H), 2920, 2850 (C H), 1600, 1525 (C=C, C=N),
1460, 1225, 1190, 1150 (C F) cmÀ1; HR-MS (ESI-TOF):
À
m/z=315.1226, calcd. for C14H14F4N4: 315.1227 [M+H]+.
rac-trans-N,N’-Dimethyl-N,N’-bis(3,5-difluoropyridin-4-
yl)cyclohexane-1,2-diamine (46): According to GP3, rac-19
(600 mg, 1.36 mmol), titanocene difluoride (88 mg,
0.41 mmol, 30 mol%), diphenylsilane (1.51 mL, 8.16 mmol,
6 equiv.) and dry 1,4-dioxane (6 mL) were stirred for 18 h at
1108C. Product 46 was isolated after FLC (hexanes/EtOAc
4:1) as a colorless solid; yield: 345 mg (69%); mp 134–
1
(50% over two steps); mp 118–1198C. H NMR (500 MHz,
CDCl3): d=1.35 (mc, 2H, CH2), 1.65–1.74 (m, 2H, CH2),
1.83–1.89 (m, 2H, CH2), 2.08–2.11 (m, 2H, CH2), 2.70 (t, J=
3.1 Hz, 6H, CH3), 3.58–3.60 (m, 2H, CH), 7.64 (mc, 2H, 6-
H); 13C NMR (125 MHz, CDCl3): d=25.3 (t, CH2), 30.2 (t,
CH2), 33.3 (q, CH3), 61.7 (d, CH), 128.3 (d, C-6), 136.9 (s, C-
2), 138.5 (s, C-4), 150.1 (s, C-3), 151.1 (s, C-5); 19F NMR
(376 MHz, CDCl3): d=À150.6 (mc, 2F, 3-F), À139.1 (mc, 2F,
1
1358C. H NMR (500 MHz, CDCl3): d=1.33 (mc, 2H, CH2),
1.62–1.71 (m, 2H, CH2), 1.83–1.86 (m, 2H, CH2), 2.08–2.11
(m, 2H, CH2), 2.66 (t, J=2.7 Hz, 6H, CH3), 3.55 (mc, 2H,
CH), 8.08 (br s, 4H, 2-H, 6-H); 13C NMR (125 MHz,
CDCl3): d=25.4 (t, CH2), 30.2 (t, CH2), 33.4 (q, CH3), 61.5
(d, CH), 134.8 (d, C-2), 135.4 (s, C-4), 152.0 (s, C-3);
19F NMR (376 MHz, CDCl3): d=À137.5 (s, 4 F, 3-F); IR
À
˜
5-F), À90.5 (mc, 2F, 2-F); IR (ATR): n=2940–2830 (C H),
À1
À
1610, 1515 (C=C, C=N), 1455, 1250, 1210, 1140 (C F) cm
;
HR-MS (ESI-TOF): m/z=405.1523, calcd. for C18H18F6N4:
405.1508 [M+H]+, m/z=427.1347, calcd. for [M+Na]+:
427.1328; anal. calcd. (%) for C18H18F6N4 (404.4): C 53.47, H
4.49, N 13.86; found: C 53.33, H 4.40, N 13.72.
À
À
˜
(ATR): n=3055 (=C H), 2925–2855 (C H), 1600, 1515
(C=C, C=N), 1425, 1200, 1145, 1150 (C F) cmÀ1; HR-MS
À
3,5-Difluoro-4-morpholinopyridine (36): According to
GP3, 2,3,5,6-tetrafluoro-4-morpholinopyridine (6) (50 mg,
0.21 mmol), titanocene difluoride (7 mg, 0.032 mmol,
15 mol%), diphenylsilane (0.235 mL, 1.27 mmol, 6 equiv.)
and dry 1,4-dioxane (2 mL) were stirred for 18 h at 1108C.
The product was isolated after FLC (hexanes/ethyl acetate
4:1, 1:1) as a colorless solid; yield: 40 mg (95%); mp 56–
588C. 1H NMR (500 MHz, CDCl3): d=3.39 (mc, 4H,
CH2N), 3.81 (mc, 4H, CH2O), 8.15 (s, 2H, 2-H); 13C NMR
(125 MHz, CDCl3): d=50.6 (t, CH2N), 67.2 (t, CH2O), 134.4
(s, C-4), 135.1 (d, C-2), 136.2 (s, C-3); 19F NMR (376 MHz,
(ESI-TOF): m/z=369.1693, calcd. for C18H21F4N4: 369.1697
[M+H]+.
N,N’-Dimethyl-N,N’-bis(pyridin-4-yl)ethane-1,2-diamine
(48): According to GP3, N,N’-dimethyl-N,N’-bis(2,6-
difluoropyridine-4-yl)ethane-1,2-diamine
(26)
(145 mg,
0.46 mmol), titanocene difluoride (30 mg, 0.14 mmol,
30 mol%), diphenylsilane (0.51 mL, 2.76 mmol, 6 equiv.) and
dry 1,4-dioxane (3 mL) were stirred for 24 h at 1108C. Prod-
uct 48 was isolated after FLC [CH2Cl2/MeOH/NH3 in
MeOH (7N), 95:5:2] as a colorless solid; yield: 99 mg
(89%); mp 114–1158C. 1H NMR (400 MHz, CDCl3): d=
2.92 (s, 6H, CH3), 3.53 (s, 4H, CH2), 6.43 (dd, J=4.9,
1.6 Hz, 4H, 3-H), 8.21 (dd, J=4.9, 1.6 Hz, 4H, 2-H);
13C NMR (125 MHz, CDCl3): d=38.2 (q, CH3), 48.6 (t,
CH2), 106.5 (d, C-3), 150.3 (d, C-2), 153.1 (s, C-4); IR
˜
CDCl3): d=À137.8 (s, 2F, 3-F); IR (ATR): n=3030
À
À
(=C H), 2955, 2920, 2855 (C H), 1600, 1550, 1505 (C=C,
C=N), 1450, 1250, 1150, 1115 (C F) cmÀ1; MS (ESI-TOF):
À
m/z=201.0839, calcd. for C9H10F2N2O: 201.0834 [M+H]+.
4-Morpholinopyridine (44): According to GP3, 2,6-di-
fluoro-4-morpholinopyridine (9) (100 mg, 0.50 mmol), tita-
nocene difluoride (16 mg, 0.08 mmol, 15 mol%), diphenylsi-
lane (0.28 mL, 1.50 mmol, 3 equiv.) and dry 1,4-dioxane
(2 mL) were stirred for 18 h at 1108C. Product 44 was isolat-
ed after FLC (CH2Cl2/MeOH 95:5) as a colorless solid;
yield: 80 mg (98%); mp 105–1078C (lit.[18] 112–1158C).
1H NMR (500 MHz, CD3OD): d=3.30 (t, J=8.1 Hz, 4H,
CH2N), 3.77 (t, J=8.1 Hz, 4H, CH2O), 6.81 (d, Jꢀ6 Hz,
2H, 3-H), 8.13 (d, Jꢀ6 Hz, 2H, 2-H); 13C NMR (125 MHz,
CD3OD): d=45.7 (t, CH2N), 66.1 (t, CH2O), 108.1 (d, C-3),
À
À
À
˜
(ATR): n=3090–3030 (=C H), 2990, 2805 (C H), 1605,
1520 (C=C, C=N) cmÀ1; HR-MS (ESI-TOF): m/z=243.1604,
calcd. for C14H18N4: 243.1610 [M+H]+; anal. calcd. (%) for
C14H18N4 (242.2): C 65.73, H 7.68, N 21.90; found: C 65.72,
H 7.72, N 22.08.
rac-trans-N,N’-Bis(pyridin-4-yl)cyclohexane-1,2-diamine
(49): According to GP3, rac-trans-N,N’-bis(2,6-difluoropyri-
din-4-yl)cyclohexane-1,2-diamine (32) (50 mg, 0.15 mmol),
titanocene difluoride (10 mg, 0.04 mmol, 30 mol%), diphe-
nylsilane (0.163 mL, 0.88 mmol, 6 equiv.) and dry 1,4-diox-
ane (2 mL) were stirred for 20 h at 1108C. Product 49 was
isolated after FLC [EtOAc/MeOH/NH3 in MeOH (7N),
95:5:2] and HPLC (RP, MeOH/H2O, 70:30) as a colorless
solid; yield: 33 mg (83%); mp 293–2958C. 1H NMR
(400 MHz, CD3OD): d=1.30–1.45 (m, 4H, CH2), 1.79 (mc,
2H, CH2), 2.05 (mc, 2H, CH2), 3.34–3.41 (m, 2H, CH), 6.44
(d, J=5.8 Hz, 4H, 3-H), 7.82 (d, J=4.7 Hz, 4H, 2-H);
13C NMR (101 MHz, CD3OD): d=25.9 (t, CH2), 33.3 (t,
CH2), 57.1 (d, CH), 108.5 (d, C-3), 149.2 (d, C-2), 155.8 (s,
C-4); HR-MS (ESI-TOF): m/z=269.1770, calcd. for
C17H21N4: 269.1761 [M+H]+.
˜
148.8 (d, C-2), 155.9 (s, C-4); IR (ATR): n=3025 (=C H),
À
2965–2880 (C H), 1600–1535 (C=C, C=N), 1450, 1365, 1235,
cmÀ1
;
HR-MS (ESI-TOF): m/z=165.1034, calcd. for
C9H13N2O: 165.1028 [M+H]+.
N,N’-Dimethyl-N,Nꢀ-bis(3,5-difluoropyridin-4-yl)ethane-
1,2-diamine (45): According to GP3, N,N’-dimethyl-N,N’-
bis(2,3,5,6-tetrafluoropyridin-4-yl)ethane-1,2-diamine
(23)
(250 mg, 0.65 mmol), titanocene difluoride (43 mg,
0.20 mmol, 30 mol%), diphenylsilane (0.73 mL, 3.90 mmol,
6 equiv.) and dry 1,4-dioxane (4 mL) were stirred for 18 h at
3226
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FULL PAPERS
Studies on the Synthesis of Specifically Fluorinated 4-Aminopyridine Derivatives
3a,7a-rac-trans-1,3-Bis(2,6-difluoropyridin-4-yl)octahydro-
1H-benzo[d]imidazole (rac-50): To a stirred solution of com-
pound rac-32 (70 mg, 0.206 mmol) in formaldehyde (1.8 mL
of a 37% w/v solution in water, 20.6 mmol, 100 equiv.),
formic acid (63 mg, 1.36 mmol, 6.7 equiv.) was added and
the resulting mixture was heated to reflux for 24 h. The re-
action was quenched by water (30 mL) and extracted with
CH2Cl2 (3”50 mL). The product rac-50 was obtained after
FLC (hexanes/EtOAc 3:1) as a colorless solid; yield: 51 mg
(70%); mp 192–1948C. 1H NMR (400 MHz, CDCl3): d=
1.50–1.67 (m, 4H, CH2), 2.02 (mc, 2H, CH2), 2.64 (mc, 2H,
CH2), 3.34 (mc, 2H, CH), 4.75 (s, 2H, N-CH2-N), 6.15 (s,
4H, 3-H); 13C NMR (101 MHz, CDCl3): d=24.0 (t, CH2),
30.0 (t, CH2), 65.9 (d, CH), 70.7 (t, CH2), 91.6 (mc, C-3),
159.2 (dd, J=11.1 Hz, C-4), 162.9 (dd, J=240, 20.0 Hz, C-
2); 19F NMR (376 MHz, CDCl3): d=À68.9 (s, 4F, 2-F); MS
(ESI-TOF): m/z=375.1208, calcd. for C17H16F4N4Na:
375.1209 [M+Na]+.
C-2), 153.7 (s, C-4); HR-MS (ESI-TOF): m/z=297.2082,
calcd. for C18H24N4: 297.2079 [M+H]+.
Copies of NMR spectra of all compounds can be found in
the Supporting Information.
Acknowledgements
Generous support of this work by the Deutsche Forschungs-
gemeinschaft (SFB 765 “Multivalency” and GRK 1582 “Flu-
orine as Key Element”) and Bayer HealthCare is most grate-
fully acknowledged. We also thank Dr. Moritz F. Kühnel for
experimental advice and helpful discussions and Mrs. V.
Rojek for preliminary experiments.
References
(R,R)-trans-N,N’-Dimethyl-N,N’-bis(2,6-difluoropyridin-
4-yl)cyclohexane-1,2-diamine (31): Enantiopure (R,R)-trans-
N,N’-bis(2,6-difluoropyridin-4-yl)cyclohexane-1,2-diamine
(32) (320 mg, 0.94 mmol) was dissolved in THF (10 mL) and
NaH (228 mg, 6.65 mmol, 70% in mineral oil, 7 equiv.) was
added at room temperature and the resulting mixture was
stirred for 30 min. Then, methyl iodide (820 mg, 5.78 mmol,
6 equiv.) was added drop-wise and the resulting mixture was
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addition and extraction (3”50 mL, CH2Cl2) and chromato-
graphic purification (hexanes/EtOAc, 6:1) gave the product
(R,R)-31; yield: 295 mg (85%); mp 201–2038C; [a]2D0: +105.7
(c=1.4, CHCl3).
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0.085 mmol),
titanocene
difluoride
(4 mg,
0.02 mmol, 20 mol%), diphenylsilane (0.094 mL, 0.51 mmol,
6 equiv.) and dry 1,4-dioxane (2 mL) were stirred for 48 h at
1108C. Product 51 was isolated after FLC [EtOAc/NH3 in
MeOH (7N), 95:5] as a slightly yellow solid; yield: 22 mg
(92%); mp 216–2188C. 1H NMR (400 MHz, CD3OD): d=
1.52 (mc, 4H, CH2), 1.97 (mc, 2H, CH2), 2.64 (mc, 2H, CH2),
3.25 (mc, 2H, CH), 4.73 (s, 2H, N-CH2-N), 6.66 (d, J=
4.6 Hz, 4H, 3-H), 8.33 (d, J=4.4 Hz, 4H, 2-H); 13C NMR
(101 MHz, CD3OD): d=24.3 (t, CH2), 30.3 (t, CH2), 65.6 (d,
CH), 71.6 (t, CH2), 101.8 (d, C-3), 150.2 (d, C-2), 153.2 (s, C-
4); HR-MS (ESI-TOF): m/z=281.1766, calcd. for C17H21N4:
281.1761 [M+H]+.
(R,R)-trans-N,N’-Dimethyl-N,N’-bis(pyridin-4-yl)cyclo-
hexane-1,2-diamine (52): According to GP3, (R,R)-N,N’-di-
methyl-N,N’-bis(2,6-difluoropyridin-4-yl)cyclohexane-1,2-di-
amine (31) (24 mg, 0.065 mmol), titanocene difluoride
(5 mg, 0.02 mmol, 30 mol%), diphenylsilane (0.073 mL,
0.39 mmol, 6 equiv.) and dry 1,4-dioxane (2 mL) were stirred
for 24 h at 1108C. Product 52 was isolated after FLC
[CH2Cl2/MeOH/NH3 in MeOH (7N), 95:5:2] as a slightly
yellow solid; yield: 18 mg (95%); mp 269–2718C; [a]2D0:
1
+157.3 (c=0.50, MeOH). H NMR (500 MHz, CDCl3): d=
1.42–1.48 (m, 2H, CH2), 1.56–1.62 (m, 2H, CH2), 1.89–1.94
(m, 4H, CH2), 2.59 (s, 6H, CH3), 3.83 (dd, J=5.8, 3.1 Hz,
2H, CH), 6.49 (d, Jꢀ6 Hz 4H, 3-H), 8.20 (d, Jꢀ6 Hz, 4H,
2-H); 13C NMR (126 MHz, CDCl3): d=25.2 (t, CH2), 29.2 (t,
CH2), 30.5 (q, CH3), 58.0 (d, CH), 106.7 (d, C-3), 150.1 (d,
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Adv. Synth. Catal. 2015, 357, 3215 – 3228