Synthesis of N-Substituted 3-Amino-4-halopyridines: A Sequential Boc-Removal/Reductive Amination Mediated by Br?nsted and Lewis Acids

Article abstract of DOI:10.1021/acs.joc.7b02966

N-Substituted 3-amino-4-halopyridines are valuable synthetic intermediates, as they readily provide access to imidazopyridines and similar heterocyclic systems. The direct synthesis of N-substituted 3-amino-4-halopyridines is problematic, as reductive aminations and base-promoted alkylations are difficult in these systems. A high yielding deprotection/alkylation protocol mediated by trifluoroacetic acid and trimethylsilyl trifluoromethanesulfonate is described, providing access to a wide scope of N-substituted 3-amino-4-halopyridines. This protocol furnishes many reaction products in high purity without chromatography. Similar reductive amination conditions were also established for deactivated anilines.

Full text of DOI:10.1021/acs.joc.7b02966

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Note
Synthesis of N-Substituted-3-amino-4-halopyridines: a Sequential Boc-
Removal/Reductive Amination Mediated by Brønsted and Lewis Acids
Christopher Alexander Wilhelmsen, Alexandre Dylan
Crawford Dixon, John Daniel Chisholm, and Daniel A. Clark
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 08 Jan 2018
Downloaded from http://pubs.acs.org on January 8, 2018
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Synthesis of N-Substituted-3-amino-4-halopyridines: a
Sequential Boc-Removal/Reductive Amination Mediated by
Brønsted and Lewis Acids
Christopher A. Wilhelmsen, Alexandre D.C. Dixon,* John D. Chisholm and Daniel A. Clark*
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Department of Chemistry, 1-014 Center for Science and Technology, Syracuse University,
Syracuse, New York 13244
addixon@syr.edu
Abstract:
NꢀSubstitutedꢀ3ꢀaminoꢀ4ꢀhalopyridines are valuable synthetic intermediates, as they readily
provide access to imidazopyridines and similar heterocyclic systems. The direct synthesis of Nꢀ
substitutedꢀ3ꢀaminoꢀ4ꢀhalopyridines is problematic, as reductive aminations and base promoted
alkylations are difficult in these systems. A high yielding deprotection/alkylation protocol
mediated by trifluoroacetic acid and trimethylsilyl trifluoromethanesulfonate is described,
providing access to a wide scope of Nꢀsubstitutedꢀ3ꢀaminoꢀ4ꢀhalopyridines. This protocol
furnishes many reaction products in high purity without chromatography. Similar reductive
amination conditions were also established for deactivated anilines.
NꢀSubstituted imidazo[4,5ꢀc]pyridine derivatives have engendered notable interest in
drug discovery, as they often possess significant and varied biological activity.1 Selective
approaches to Nꢀsubstituted imidazo[4,5ꢀc]pyridines are coveted,2 as a mixture of regioisomers
(Scheme 1) is typically obtained upon base promoted alkylation.2ꢀ3 Recently a selective synthesis
of Nꢀsubstituted imidazo[4,5ꢀc]pyridines employing
a
palladium catalyzed tandem
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amidation/cyclization as the key step was developed.4 This method utilizes Nꢀsubstitutedꢀ3ꢀ
aminoꢀ4ꢀhalopyridines as the reaction starting material, thus more effective methods to access
pyridines like 4 became a priority.
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Scheme 1. Use of NꢀSubstitutedꢀ3ꢀAminoꢀ4ꢀHalopyridines in the Regioselective Synthesis of Nꢀ
Substituted Imidazo[4,5ꢀc]pyridines
Initially attempts were made to alkylate 3ꢀaminoꢀ4ꢀchloropyridine using reductive
amination conditions that have provided high yields in similar pyridine systems (AcOH and
NaBH(OAc)3 are typically effective for 3ꢀaminoꢀ2ꢀchloropyridine,5 for example), but these
reactions showed poor conversion or failed completely. This lack of reactivity is attributed to the
higher basicity of the 3ꢀaminoꢀ4ꢀchloropyridine (the pKa of 4ꢀchloropyridinium has been
reported as 3.83,6 while 2ꢀchloropyridinium has a pKa of 0.757), allowing it to act as a buffer,
slowing imine formation or decelerating reduction of the imine by limiting protonation.
Therefore a threeꢀstep procedure involving protection as a carbamate, baseꢀpromoted alkylation
and acidꢀmediated deprotection was carried out to yield Nꢀsubstituted 3ꢀaminoꢀ4ꢀ
chloropyridines. This alkylation protocol gave only moderate yields in most cases (typically 40ꢀ
50%).4a An investigation was therefore initiated to expand and strengthen alkylation protocols to
access Nꢀalkylatedꢀ3ꢀaminoꢀ4ꢀhalopyridines.
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At first these studies were hindered by the gradual decomposition of 3ꢀaminoꢀ4ꢀ
chloropyridine under ambient conditions, forcing constant repurification to achieve meaningful
isolated yields. This prompted the search for a bench stable, easily functionalized starting
material that could be prepared and stored on large scale. Starting from the inexpensive 3ꢀ
aminopyridine, 5, monoprotection with diꢀtertꢀbutyldicarbonate afforded the NꢀBocꢀ3ꢀ
aminopyridine 6 in excellent yield on 20 g scale. This material was purified by recrystallization
and could be used in the next step without chromatography (Scheme 2). The carbamate serves as
a useful directing group for lithiation at the pyridine 4ꢀposition, with subsequent electrophilic
halogenation (employing hexachloroethane, 1,2ꢀdibromoethane, or iodine respectively) affording
NꢀBocꢀ3ꢀaminoꢀ4ꢀhalopyridines on large scale (up to 100 mmol). Quéginer and coꢀworkers
previously reported a similar directed metalation with a pivalate,8 however the removal of the
Boc group is a more facile process compared to that of pivalate and similar amide directing
groups.8ꢀ9 In addition, the Bocꢀprotected 3ꢀaminoꢀ4ꢀhalopyridine could be stored under ambient
conditions with no special precautions for up to six months without noticeable degradation.
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Scheme 2. Optimized Synthesis of NꢀBocꢀ3ꢀAminoꢀ4ꢀHalopyridines
A reinvestigation of the reductive amination protocol was undertaken with the goal to
improve access to Nꢀsubstituted 3ꢀaminoꢀ4ꢀchloropyridine systems. Reductive amination
remains one of the simplest, mildest, and most economical methods for forming C−N
bonds.1a,5b,10 However, there are still limitations to this chemistry. Generally, less nucleophilic
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amines require stronger acids to facilitate the conversion to the imine/iminium.5b,10a Selectivity
between the reduction of the imine and carbonyl reactant decreases with increased acid strength,
however, which may hinder product formation.10b Despite this limitation, working in highly
acidic media also presented an opportunity to facilitate Bocꢀremoval in situ, so the reductive
amination with stronger Brønsted acids was initially evaluated. Sodium triacetoxyborohydride
was used as the reducing agent for its selective reactivity.10a,10b,11 Other reducing agents such as
sodium borohydride and sodium cyanoborohydride were less effective. Trifluoroacetic acid
(TFA) is known to deprotect tertꢀbutyl carbamates and mediate reductive amination for weakly
basic amines, so it was evaluated first (Table 1).5,9b Boc removal from substrate 7 was complete
within minutes in neat TFA (10 equiv). The corresponding pyridinium salt 11 could be isolated
at this stage upon concentration in vacuo. Given that ammonium salts have been previously
reported to facilitate reductive amination,10a pyridinium trifluoroacetate 11 was subjected to
reductive amination conditions and provided a 45% yield of the desired product 10a (Table 1,
entry 1). The reduction of the imine was sluggish, as a significant amount of imine 14 was also
detected. The addition of more TFA favored the reduction of the imine (Table 1, entries 2ꢀ4),
though excess TFA led to competitive reduction of the aldehyde, leaving unreacted amine 12
along with moderate amount of desired pyridine 10a (Table 1, entry 4) in the product mixture.
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Table 1. Reaction Conditions for Deprotection and Reductive Amination of 9
Cl
1) TFA (10 equiv)
Cl
then conc.
NHBn
10a
NHBoc
2) PhCHO (2 equiv)
DCM, additive
9
N
N
3) NaBH(OAc)3 (3 equiv)
9
Cl
Cl
Cl
Cl
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NHEt
NH2
NH2
N
Ph
11
12
13
14
N
N
H
N
N
-
CF3CO2
Additive
(Equiv)
10aa 12a 13a 14a
Entry
1
2
ꢀ
45
53
63
30 55
19 12
12 32 12
10 31 21
53 15 10
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
45
33
TFA (1)
3
4
TFA (2)
TFA (10)
ꢀ
ꢀ
9
28
ꢀ
5b
6b
7b
8b
9
BF3•OEt2 (5)
TiCl4 (5)
ꢀ
ꢀ
ꢀ
ꢀ
4
ꢀ
ꢀ
AlCl3 (5)
TMSOTf (5)
TMSOTf (2)
TfOH (1)
90
50 33
ꢀ
ꢀ
ꢀ
20
10
11
TMSOTf (1.1) 55
ꢀ
aYield as determined using 1H NMR with a mesitylene internal standard. bLewis acids were used
to deprotect the Boc group without TFA.
Attention became focused on the use of Lewis acids for both deprotection and reductive
amination. Presumably, a more oxophilic Lewis acid would preferentially activate the carbonyl
partner in the presence of the basic pyridine. Several strong Lewis acids that have been reported
to both cleave Boc groups12 and facilitate reductive aminations13 were screened to mediate
conversion of 9 to 10a (Table 1, entries 5ꢀ8). Boc removal was rapid with boron trifluoride
diethyl etherate, titanium (IV) chloride, and aluminum trichloride, being complete in minutes.
However, these Lewis acids were ineffective at mediating the reductive amination. Instead,
competitive reduction of the aldehyde occurred with benzyl alcohol being observed by TLC and
1
crude H NMR. Interestingly, an ethylated byproduct 13 was observed in some cases, evidently
resulting from reaction with decomposing sodium triacetoxyborohydride.10b,11b,13d
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Further screening revealed that TMSOTf demonstrated promising reactivity (Table 1,
entry 8) in the reductive amination, providing 53% yield of 10a. Presumably TMSOTf facilitates
condensation of the amine and the carbonyl partner while minimizing the reversibility of imine
formation (a similar argument has been adopted when TMSOAc was employed in reductive
amination10d). An even better result was obtained when the pyridinium trifluoroacetate was used
as the starting material, with a 90% yield of 10a being observed. Experiments employing TfOH
(Table 1, entry 11) provided a lower yield than with TMSOTf (Table 1, entry 10), likely because
the water generated by imine formation is not effectively scavenged. Excess of both TMSOTf
and the aldehyde was required to prevent competitive ethylation (Table 1, entry 11).
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Under the optimized conditions a 79% isolated yield with the benzyl substituted amine
10a (Table 2) was achieved. A large scale reaction using this substrate was performed on a 15
mmol scale, which provided an 83% isolated yield of pyridine 10a without column
chromatography. This protocol demonstrated excellent substrate tolerance. High yields were
obtained with haloꢀsubstituted aryl aldehydes (Table 2, 10b-e) and with electronꢀdeficient
aldehydes (Table 2 10f-h). Cinnamyl substrate 10i was isolated with a 76% yield and the transꢀ
olefin was maintained during the reduction. Biphenyl functionality was introduced with an 86%
isolated yield of 10j. Numerous electron rich carbonyl substrates (Table 2, 10k-t) were also
evaluated with good results. The furfuryl substrate, 10k, showed tolerance of acidic reaction
conditions and acidic purification conditions (55% isolated yield). pꢀTolyl, piperonyl, and 2,3ꢀ
dimethoxybenzyl (DMB) substrates (Table 2, 10l-n) also gave product in excellent yields. Acid
labile substrates 2,4ꢀ (10o) and 2,5ꢀDMB (10p),9b were obtained without the addition of
TMSOTf in a reduced reaction time of 1 hour. The sterically encumbering neopentyl amine, 10q,
was obtained in 85% yield from pivaldehyde. Enolizable aliphatic aldehydes (Table 2, 10r-s)
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also participate and gave good to moderate yields without using TMSOTf. These substrates are
often prone to overalkylation10f in reductive aminations and require chromatography.
Cyclohexanone also performed well under the reaction conditions, providing a 75% yield of
cyclohexylamine 10t. In addition, 4ꢀbromoꢀ3ꢀaminopyridine and 4ꢀiodoꢀ3ꢀaminopyridine gave
good yields with a variety of carbonyl substrates under analogous conditions (Table 2, 15a-d and
16a-d). Most benzylic amine products are accessed with greater than 95% purity (as determined
by 1H NMR) without chromatography.
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Table 2. Substrate scope for oneꢀpot Bocꢀremoval/Reductive amination
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aReaction performed on a 15 mmol scale. bNo TMSOTf was added.
Given the excellent yields obtained with the 4ꢀhaloꢀ3ꢀaminopyridines, the optimized
conditions were also evaluated with some aniline substrates that have been reported10b,13d to be
slow to undergo reductive amination due to electronic and/or steric reasons (Table 3).
Tribromoaniline provided the benzylated product 17 in 96% yield under these conditions.
Reductive amination of 2,4ꢀdinitroaniline provided 63% yield of 18, while 2,6ꢀdiisopropylaniline
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proceeded, yielding 70% of 19. The excellent yield with these difficult substrates is again
attributed to the use of TMSOTf, which facilitates imine formation, removes water, and produces
the strong acid TfOH, activating the imine for reduction. TMSOTf has only rarely been utilized
in reductive amination reactions,13d,13e but these results indicate that this Lewis acid should be
investigated in difficult cases where the amine partner is deactivated and/or significantly
hindered.
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Table 3. Reductive Aminations with Hindered Aniline Substrates
Entry
X
Br
Y
Br
H
Z
% Yield
1
2
3
Br
96 (17)
NO2
NO2 63 (18)
70 (19)
iꢀPr iꢀPr
H
In summary, an efficient, general procedure for the reductive amination of 3ꢀaminoꢀ4ꢀ
haloꢀpyridines is disclosed. A useful single vessel protocol has been devised using NꢀBocꢀ3ꢀ
aminoꢀ4ꢀhalopyridines as the starting materials. Acidꢀmediated precipitation followed by
formation of the free base provided the monoꢀalkylated amines in high purity. This protocol was
used in the efficient synthesis of Nꢀalkylated 3ꢀaminoꢀ4ꢀhalopyridines, and may be of use in
similar systems which resist reductive amination under standard conditions.
Experimental Section
General procedure A
To a round bottom flask equipped with a magnetic stir bar and rubber septum, was added, Nꢀ
Bocꢀ3ꢀaminoꢀ4ꢀhalopyridine (1 equiv) followed by neat TFA (10 equiv.) via syringe.
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CAUTION: Vigorous gas evolution and an exothermic reaction occurs. The Bocꢀremoval was
monitored by thin layer chromatography (3ꢀaminoꢀ4ꢀhalopyridines have an Rf = 0.20 in 1:1 ethyl
acetate: hexanes). The reaction mixture was concentrated in vacuo and the crude oil was
dissolved in ethyl acetate and concentrated in vacuo three times to yield the solid pyridinium
trifluoroacetate salt. DCM (0.5 M) was added to form a slurry to which the carbonyl (2 equiv)
and TMSOTf (2 equiv) were added, sequentially. The mixture was stirred for 1 hour at ambient
temperature before sodium triacetoxyborohydride (3 equiv) was added as a single portion. The
mixture was allowed to stir at rt for 24 hours. The reaction mixture was quenched by the addition
of 20 mL of NaOH(aq) (20% w/v) and 20 mL of DCM. The resulting two layers were separated
and the aqueous layer was extracted with DCM (3 x 15 mL). The combined organic layers were
washed with 30 mL of brine, dried over magnesium sulfate, filtered through a coarse porosity
fritted funnel and concentrated in vacuo. The crude material was dissolved in 25 mL of diethyl
ether and 2 mL of 1M HCl in ether (2 equivalents) was added dropwise to the vigorously stirring
ether solution at room temperature. The resulting slurry was allowed to stir for 1 hour in a 0 °C
(ice/water) and solvent was removed by needle filtration. The resulting solid was washed with an
additional 25 mL of diethyl ether and needle filtered again. The resulting salt was treated with 20
mL of (20% w/v) NaOH(aq) and 20 mL of DCM. The aqueous layer was extracted with 15mL
DCM and the combined organic layers were dried over anhydrous magnesium sulfate, filtered
through a coarse porosity fritted funnel and concentrated in vacuo to yield pure product.
General Procedure B
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To a round bottom flask equipped with a magnetic stir bar and rubber septum, was added, Nꢀ
Bocꢀ3ꢀaminoꢀ4ꢀhalopyridine (1 equiv) then added TFA (10 equiv) via syringe, neat. CAUTION:
Vigorous gas evolution and an exothermic reaction occurs. The Bocꢀremoval was monitored by
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thin layer chromatography (3ꢀaminoꢀ4ꢀhalopyridines have an Rf = 0.20 in 1:1 ethyl acetate:
hexanes). The reaction mixture was concentrated in vacuo. The crude oil was dissolved in ethyl
acetate and concentrated in vacuo three times to yield the solid pyridinium trifluoroacetate salt.
DCM (0.5 M) then the carbonyl (2 equiv) were added to form a slurry mixture. Reaction stirred
for 1 hour before adding sodium triacetoxyborohydride (2 equiv). Reduction was allowed to
occur for 1 hour. The reaction was quenched and collected with (20% w/v) NaOH(aq) and DCM.
The resulting two layers were separated and the aqueous layer was extracted with DCM (3 x 15
mL). The combined organic layers were washed with brine, dried over anhydrous magnesium
sulfate, filtered through a coarse porosity fritted funnel and concentrated in vacuo.
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General Procedure C
To a round bottom flask equipped with a magnetic stir bar and rubber septum, was added, Nꢀ
Bocꢀ3ꢀaminoꢀ4ꢀhalopyridine (1 equiv) then added TFA (10 equiv) via syringe, neat. CAUTION:
Vigorous gas evolution and an exothermic reaction occurs. The Bocꢀremoval was monitored by
thin layer chromatography (3ꢀaminoꢀ4ꢀhalopyridines have an Rf = 0.20 in 1:1 ethyl acetate:
hexanes). The reaction mixture was concentrated in vacuo. The crude oil is dissolved in ethyl
acetate and concentrated in vacuo three times to yield the solid pyridinium trifluoroacetate salt.
DCM (0.5 M) then the carbonyl (1.1 equiv) were added to form a slurry mixture. Reaction was
stirred for 1 hour before adding sodium triacetoxyborohydride (3 equiv). Reduction was allowed
to occur for 24 hours. The reaction was quenched and collected with 20% (w/v) NaOH aqueous
solution and DCM. The resulting two layers were separated and the aqueous layer was extracted
three times with DCM (3 x 15 mL). The combined organic layers were washed with brine, dried
over magnesium sulfate, filtered through a coarse porosity fritted funnel and concentrated in
vacuo. The crude mixture was dissolved in 25 mL of diethyl ether. 2 mL of 1M ethereal
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hydrogen chloride (2 equivalents) was added dropwise to the vigorously stirring ether solution at
room temperature. The resulting slurry was allowed to stir for 1 hour in a 0 °C iceꢀwater bath.
Slurry was removed from ice bath and stirring, and was subject to needle filtration. The resulting
solid was treated with an additional 25 mL of diethyl ether and needle filtered again. The
resulting wash was discarded and the pyridinium salt was collected with 20 mL (20% w/v)
NaOH(aq) and 20 mL DCM. The aqueous layer was extracted once more with 15 mL DCM. The
combined organics were dried over anhydrous magnesium sulfate, filtered through a coarse
porosity fritted funnel and concentrated in vacuo.
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General Procedure for directed metalation
A flameꢀdried 3 neck round bottom flask equipped with a magnetic stir bar, addition funnel,
immersion thermometer, and septum was charged with NꢀBocꢀ3ꢀaminopyridine and 1,2
dimethoxyethane (~0.3 M). The reaction mixture was cooled to ꢀ78 °C (dry ice/acetone) and n-
BuLi (2.4 eq, hexanes solution) was added dropwise to yield an opaque mixture that was allowed
to warm to ꢀ20 °C and stir for 2 hours. The reaction mixture was again cooled to ꢀ78 °C and a
solution of electrophilic halogen source (1.5 eq) in 1,2 dimethoxyethane (~1.6 M) was added
dropwise. The resulting solution was allowed to warm to room temperature with removal of
cooling bath and stir overnight. The reaction was quenched by the addition of saturated
ammonium chloride and the layers were separated. The aqueous layer was extracted 3 times with
methyl tertꢀbutyl ether. The combined organic layers were washed with brine, dried over
anhydrous magnesium sulfate, filtered through a coarse porosity fritted filter, and then
concentrated in vacuo. The crude material was adsorbed onto silica gel and loaded directly onto
silica gel column, eluting with 30% ethyl acetate: hexanes.
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N-Boc-3-Aminopyridine (6). A 250 mL, 3ꢀneck round bottom flask equipped with 100 mL
addition funnel and magnetic stir bar was charged with 3ꢀaminopyridine (20 g, 213 mmol),
isopropanol (60 mL), and water (23 mL), and the mixture was cooled to 0 °C in an iceꢀwater
bath. The addition funnel was charged with a solution of diꢀtertꢀbutyl dicarbonate (53 g, 244
mmol) in isopropanol (30 mL). Gas evolution occurred during the dropwise addition. Upon
completion of the dropwise addition, the reaction was removed from ice bath, allowed to warm
to room temperature and stirred overnight. Reaction was concentrated in vacuo and the resulting
thick oil was dissolved in methyl tertꢀbutyl ether. The resulting two layers were separated with a
separatory funnel. The aqueous layer was extracted with methyl tertꢀbutyl ether three times. The
collected organic was washed with brine, dried over anhydrous magnesium sulfate, filtered
through a coarse porosity fritted filter, then concentrated in vacuo to yield 35.5 grams of white
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solid (86%): Compared to literature data14 mp 115ꢀ117 °C; H NMR (400 MHz, CDCl3) δ 8.43
(d, J = 2.4 Hz, 1H), 8.28 (dd, J = 4.7, 1.4 Hz, 1H), 7.97 (d, J = 7.0 Hz, 1H), 7.24 (dd, J = 8.4,
4.7 Hz, 1H), 6.57 (bs, 1H), 1.53 (s, 9H).
N-Boc-3-Amino-4-chloropyridine (7). Following the general procedure for directed metalation
using hexachloroethane as the electrophile on a 100 mmol (19.43 gram) scale, a yield of 14.55
grams of an pale yellow solid was obtained (64%): mp:105ꢀ106 °C; Rf 0.52 (1:1 ethyl
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acetate:hexanes); H NMR (400 MHz, CDCl3) δ 9.36 (s, 1H), 8.20 (d, J = 5.2 Hz, 1H), 7.29 (d, J
= 5.2, 1H), 6.83 (bs, 1H), 1.55 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 152.0, 144.2, 142.2,
132.7, 131.1, 123.8, 82.1, 28.4. IR (KBr pellet) ν = 3224, 3135, 2973, 1725, 1573, 1085 cmꢀ1;
Anal. Calcd for C10H13ClN2O2: C, 52.52; H, 5.73; N, 12.25; Found: C, 52.45; H, 5.47; N, 12.32.
N-Boc-3-Amino-4-bromopyridine (8). Following the general procedure for directed metalation
using 1,2ꢀdibromoethane as the electrophile on a 60 mmol (11.66 gram) scale, a yield of 8.63
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grams of a white solid was obtained (53%): mp 108ꢀ109 °C; Rf 0.41 (1:1 ethyl acetate: hexanes);
1H NMR (400 MHz, CDCl3) δ 9.31 (s, 1H), 8.10 (d, J =5.2 Hz, 1H), 7.45 (d, J =5.2 Hz, 1H),
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6.83 (bs, 1H), 1.54 (s, 9H); C NMR (100 MHz, CDCl3) δ 152.0, 144.3, 142.3, 133.9, 127.1,
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122.2, 82.1, 28.4; IR (KBr pellet) 3228, 3125, 1974, 1727, 1568, 1456, 1164 cmꢀ1; Anal. Calcd
for C10H13BrN2O2: C, 43.97; H, 4.80; N, 10.26. Found: C, 43.78; H, 4.81; N, 10.00.
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N-Boc-3-Amino-4-iodopyridine (9). Following the general procedure for directed metalation
using iodine as the electrophile on a 60 mmol (11.66 gram) scale, a yield of 10.23 grams of a
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pale yellow solid was obtained (53%): mp: 87ꢀ88 °C; Rf 0.41 (1:1 ethyl acetate: hexanes); H
NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 7.91 (d, J =5.1 Hz, 1H), 7.69 (d, J =5.1 Hz, 1H), 6.66
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(bs, 1H), 1.55 (s, 9H); C NMR (100 MHz, CDCl3) δ 152.2, 144.6, 142.1, 136.6, 133.7, 99.7,
82.0, 28.4; IR (KBr pellet) 3381, 3068, 2980, 1726, 1561, 1509, 1250 cmꢀ1; Anal. Calcd for
C10H13N2IO2: C, 37.52; H, 4.09; N, 8.75. Found: C, 37.78; H, 4.05; N, 8.74;
3-Amino-4-chloropyridinium trifluoroacetate (11). A 25 mL round bottom flask and magnetic
stir bar was charged with NꢀBocꢀ3ꢀaminoꢀ4ꢀchloropyridine (228mg, 1.0 mmol) and TFA (741
ꢁL, 10 mmol). Upon completion of the Bocꢀremoval, the yellow solution was concentrated in
vacuo to yield 231 mg of a pale yellow solid (95%): mp 134ꢀ135 °C; Rf 0.12 (50% ethyl acetate :
hexanes); 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 7.91 (d, J = 5.8 Hz, 1H), 7.58 (d, J = 5.84
Hz, 1H); 13C NMR (100 MHz, (CD3)2SO) δ 159.2 (q, JCꢀF = 34.1 Hz), 144.2, 131.0, 130.4, 129.7,
126.6, 116.6 (q, JCꢀF = 293.4 Hz); 19F NMR (376.5 MHz, CDCl3) δ ꢀ76.2; IR (KBr, pellet) 3375,
3196, 3044, 2644, 2112, 1675, 1560, 1489, 1206; Anal. Calcd for C7H6ClF3N2O2: C, 34.66; H,
2.49; N, 11.55. Found: C, 34.63; H, 2.65; N, 11.51.
N-(Ethyl)-3-amino-4-chloropyridine (13). To a 100 mL flameꢀdried roundꢀbottom flask
equipped with a magnetic stir was charged with NꢀBocꢀ3ꢀaminoꢀ4ꢀchloropyridine (1.14 grams, 5
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mmol) and DMF (0.5M). The resulting mixture was cooled to 0 °C (iceꢀwater) and sodium
hydride (60% by wt, 300 mg, 7.5 mmol) was added (CAUTION: gas evolution). After 1 hour,
bromoethane (0.56 mL, 7.5 mmol) was added dropwise via syringe at 0 °C. After addition was
complete the cooling bath was removed and the reaction mixture was allowed to warm to room
temperature. After 30 minutes at room temperature the reaction mixture was quenched with 10
mL water. The resulting layers were separated and the aqueous layer was extracted with ethyl
acetate (3 x 15 ml). The organic layers were collected, washed with 30 mL brine, dried over
anhydrous magnesium sulfate, filtered through a coarse porosity fritted funnel and concentrated
in vacuo to yield a yellow oil. The crude mixture was diluted in 10 mL DCM and 3.5 mL of TFA
was added dropwise via syringe. The reaction was monitored by TLC and upon completion the
reaction was quenched with water and (20% w/v) NaOH(aq) was added until the aqueous layer
was pH 8. The aqueous layer was extracted with DCM (3 x 15 mL). The combined organic
layers were washed with brine, dried over anhydrous magnesium sulfate, filtered through a
coarse porosity fritted funnel, and concentrated in vacuo. The crude material was subjected to
flash column chromatography (2.5cm x 15cm) eluted with 1L 10% ethyl acetate: hexanes
solution to yield 224 mg of white solid (29%). mp 26ꢀ27 °C; Rf = 0.4 (1:1 ethyl acetate:
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hexanes); H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.87 (d, J = 4.8 Hz, 1H), 7.17 (d, J = 5.2
Hz, 1H), 4.09 (s, 1H), 3.29ꢀ3.26 (m, 2H), 1.34 (t, J = 14.4 Hz, 3H) 13C NMR δ (100 MHz,
CDCl3) δ 140.6, 138.4, 133.4, 127.3, 123.7, 38.0, 14.7; IR (KBr, pellet) 3410, 2969, 1579, 1507,
1414, 1325 cmꢀ1; Anal. Calcd for C7H9ClN2: C, 53.68; H, 5.79; N, 17.89. Found: C, 53.72; 5.74;
N, 17.88.
N-(Benzyl)-3-amino-4-chloropyridine (10a). Following general procedure A: 193 mg of pale
yellow solid containing 5% of pyridine A was collected. 10a could be further purified via flash
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column chromatography, eluting with 3% ethyl acetate: 3% triethylamine: 3% benzene: 91%
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hexanes to yield 173 mg of pale yellow crystalline solid (79%). mp 100ꢀ103 °C; Rf 0.42 (50%
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ethyl acetate: hexanes); H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.90 (d, J = 5.1 Hz, 1H),
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7.38 ꢀ 7.29 (m, 5H), 7.20 (d, J = 5.1 Hz, 1H), 4.62 (bs, 1H), 4.46 (d, J = 5.7 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 140.3, 138.9, 137.9, 133.8, 128.9, 127.7, 127.6, 127.4, 123.8, 47.7; IR
(KBr, pellet) 3428, 1636, 1579, 1259; Anal. Calcd for C12H11ClN2: C, 65.91; H, 5.07; N, 12.81.
Found. C, 65.79; H, 5.08; N, 12.80.
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In addition, a 15 mmol scale reaction for 10a was performed following general procedure A:
Following the workꢀup and purification via general procedure A: product was recrystallized in
10% methanol: hexanes solution to yield 2.73 g of pale yellow solid (83%).
Following the Bocꢀremoval protocol to yield 3ꢀaminopyridinium trifluoroacetate, the salt was
recrystallized using ethyl acetate and subject to conditions following general procedure A:
pyridinium salt (121 mg, 0.5 mmol), DCM (0.5 M), benzaldehyde (102 ꢁL, 1 mmol), then
TMSOTf (181 ꢁL, 1 mmol) were combined in a 25 mL roundꢀbottom flask, equipped with stir
bar and rubber septum, and allowed to stir for 1 hr at rt. Sodium triacetoxyborohydride (318 mg,
1.5 mmol) was added in one portion and allowed to stir for 24 hr. Following the workꢀup and
purification via general procedure A, 90 mg of white solid was obtained (83%).
N-(4-Bromobenzyl)-3-amino-4-chloropyridine (10b). Following general procedure A: 273 mg
of pale orange crystalline solid was obtained (92%): mp 104ꢀ105 °C; Rf 0.65 (50% ethyl acetate:
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hexanes); H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.91 (d, J = 4.8 Hz, 1H), 7.50ꢀ7.47 (m,
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2H), 7.23ꢀ7.19 (m, 2H), 7.20 (d, J = 5.1 Hz, 1H), 4.63 (bs, 1H), 4.43 (d, J = 5.8 Hz, 2H); C
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NMR (100 MHz, CDCl3) δ 140.2, 139.4, 137.0, 133.9, 132.2, 129.1, 127.9, 124.0, 121.7, 47.2;
IR (KBr, pellet) 3244, 1577, 1512, 1407, 1329, 1234, 1073 cmꢀ1; Anal. Calcd for C12H10BrClN2:
C, 48.43; H, 3.39; N, 9.41. Found. C, 48.43; H, 3.49; N, 9.58.
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N-(2-Chlorobenzyl)-3-amino-4-chloropyridine (10c). Following general procedure A: 10c was
further purified via flash column chromatography eluted with 3% ethyl acetate: 3%
triethylamine: 3% benzene: 91% hexanes afforded 196 mg of pale yellow crystalline solid
(77%): mp 81ꢀ83 °C; Rf 0.47 (50% ethyl acetate: hexanes); 1H NMR (400 MHz, CDCl3) δ 8.01
(s, 1H), 7.93 (d, J = 5.1 Hz, 1H), 7.46ꢀ7.38 (m, 2H), 7.30ꢀ7.27 (m, 2H), 7.23 (d, J = 5.1 Hz, 1H),
4.79 (bs, 1H), 4.61 (d, J = 6.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 140.1, 139.3, 135.2,
134.0, 133.6, 130.0, 129.1, 129.0, 127.9, 127.3, 124.0, 45.5; IR (KBr, pellet) 3245, 3068, 2955,
1583, 1558, 1509, 1417, 1330, 1259, 1069 cmꢀ1; Anal. Calcd for C12H10Cl2N2: C, 56.94; H, 3.98;
N, 11.07. Found. C, 56.91; H, 3.98; N, 11.09.
N-(4-Fluorobenzyl)-3-amino-4-chloropyridine (10d). Following general procedure A: 10d was
recrystallized in 30:1 hexanes: ethyl acetate afforded 180 mg of slight yellow crystalline solid
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(76%): mp 80ꢀ83 °C; Rf 0.37 (50% ethyl acetate: hexanes); H NMR (400 MHz, CDCl3) δ 7.99
(s, 1H), 7.90 (d, J = 5.1 Hz, 1H), 7.35ꢀ7.31 (m, 2H), 7.20 (d, J = 5.1 Hz, 1H), 7.07ꢀ7.03 (m, 2H),
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4.60 (bs, 1H), 4.43 (d, J = 5.6 Hz, 2H); C NMR (100 MHz, CDCl3) δ 162.5 (d, JCꢀF= 244.8
Hz), 140.2, 139.2, 133.9, 133.7 (d, JCꢀF= 3.2 Hz), 129.1 (d, JCꢀF= 8.0 Hz), 127.8, 123.9, 115.9 (d,
JCꢀF= 21.6 Hz), 47.2; 19F NMR (376.5 MHz, CDCl3) δ ꢀ115.3; IR (KBr, pellet) 3321, 3054, 2913,
1579, 1506, 1325, 1228, 1070 cmꢀ1; Anal. Calcd for C12H10ClFN2: C, 60.90; H, 4.26; N, 11.84.
Found. C, 60.92; H, 4.31; N, 11.87.
N-(4-Chlorobenzyl)-3-amino-4-chloropyridine (10e). Following general procedure A: 10e was
further purified via flash column chromatography eluted with 3% acetone: 3% triethylamine: 3%
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benzene: 91% hexanes afforded 208 mg of slight orange crystalline solid (82%): mp 93ꢀ95 °C; Rf
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0.50 (50% ethyl acetate: hexanes); H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.90 (d, J = 5.1
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Hz, 1H), 7.35ꢀ7.30 (m, 4H), 7.20 (d, J = 5.1 Hz, 1H), 4.63 (bs, 1H), 4.44 (d, J = 5.7 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 140.2, 139.3, 136.5, 133.9, 133.6, 129.2, 128.7, 127.9, 124.0, 47.2;
IR (KBr, pellet) 3436, 3235, 2847, 1578, 1513, 1489, 1416, 1330, 1089 cmꢀ1; Anal. Calcd for
C12H10Cl2N2: C, 56.94; H, 3.98; N, 11.07. Found: C, 57.08; H, 4.03; N, 10.75.
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N-(4-Cyanobenzyl)-3-amino-4-chloropyridine (10f). Following general procedure A: 10f was
further purified via flash column chromatography eluted with 3% ethyl acetate: 3%
triethylamine: 3% benzene: 91% hexanes, then recrystallized in hexanes to afford 178 mg of pale
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yellow crystalline solid (73%): mp 107ꢀ108 °C; Rf 0.20 (50% ethyl acetate: hexanes); H NMR
(400 MHz, CDCl3) δ 7.93ꢀ7.87 (m, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.22
(d, J = 5.0 Hz, 1H), 4.79 (bs, 1H), 4.56 (d, J = 6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
143.7, 139.7, 133.8, 132.8, 128.1, 127.7, 124.1 (2 overlapping), 118.7, 111.8, 47.3; IR (KBr,
pellet) 3236, 3055, 2226, 1577, 1508, 1327, 1239, 1069, 823, 692, 556 cmꢀ1; Anal. Calcd for
C13H10ClN3: C, 64.07; H, 4.14; N, 17.24. Found. C, 64.07; H, 4.16; N, 17.43.
N-(4-Nitrobenzyl)-3-amino-4-chloropyridine (10g). Following general procedure A: 10g was
further purified via silica plug eluted with 50% ethyl acetate: hexanes afforded 240 mg of green
solid (91%): mp 118ꢀ119 °C; Rf 0.28 (50% ethyl acetate: hexanes); 1H NMR (400 MHz, CDCl3)
δ 8.24ꢀ8.21 (m, 2H), 7.93 (d, J = 5.1 Hz, 1H), 7.88 (s, 1H), 7.54ꢀ7.52 (m, 2H), 7.23 (d, J = 5.1
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Hz, 1H), 4.81 (bs, 1H), 4.61 (d, J = 6.0 Hz, 2H); C NMR (100 MHz, CDCl3) δ 147.7, 145.7,
139.9, 139.8, 133.7, 128.2, 127.8, 124.3, 124.1, 47.2; IR (KBr, pellet) 3221, 3071, 2925, 1579,
1516, 1345, 1069 cmꢀ1; Anal. Calcd for C12H10ClN3O2: C, 54.66; H, 3.82; N, 15.94. Found. C,
54.63; H, 3.84; N, 16.14.
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N-(4-(Trifluoromethyl)benzyl)-3-amino-4-chloropyridine (10h). Following general procedure
A: 10h was further purified via flash column chromatography eluted with a gradient elution of
10% to 30% ethyl acetate: hexanes, affording 209 mg of white crystalline solid (73%): mp 94ꢀ96
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°C; Rf 0.31 (50% ethyl acetate: hexanes); H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.91 (d, J
= 5.1 Hz, 1H), 7.61 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 5.1 Hz, 1H), 4.73
(bs, 1H), 4.55 (d, J = 5.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) 142.2 (q, JCꢀF = 1.4 Hz), 140.0,
139.5, 133.9, 130.2 (q, JCꢀF = 32.3 Hz), 128.0, 127.5, 126.0 (q, JCꢀF= 3.8 Hz), 124.2 (q, JCꢀF
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270.4 Hz), 124.0, 47.3; 19F NMR (376.5 MHz, CDCl3) δ ꢀ63.1; IR (KBr, pellet) 3272, 3054,
2942, 1619, 1582, 1507, 1414 cmꢀ1; Anal. Calcd for C13H10ClF3N2: C, 54.47; H, 3.52; N, 9.77.
Found. C, 54.23; H, 3.49; N, 9.90.
N-Cinnamyl-3-amino-4-chloropyridine (10i). Following general procedure A: 10i was further
purified via flash column chromatography eluted with 3% ethyl acetate: 3% triethylamine: 3%
benzene: 91% hexanes afforded 185 mg of white solid (76%): mp 65ꢀ67 °C; Rf 0.28 (50% ethyl
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acetate: hexanes); H NMR (400 MHz, CDCl3): δ 8.10 (s, 1H), 7.91 (d, J =5.1 Hz, 1H), 7.39ꢀ
7.36 (m, 2H), 7.34ꢀ7.30 (m, 2H), 7.27ꢀ7.23 (m, 1H), 7.20 (d, J =5.1 Hz, 1H), 6.66 (d, J =15.9
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Hz, 1H), 6.31 (dt, J =15.9, 5.8 Hz, 1H), 4.44 (bs, 1H), 4.08 (td, J =5.8, 1.5 Hz, 1H); C NMR
(100 MHz, CDCl3): δ 140.4, 139.0, 136.6, 134.0, 132.7, 128.8, 128.0, 127.8, 126.6, 125.5, 123.9,
45.7; IR (KBr, pellet) 3274, 3055, 3020, 2936, 1576, 1552, 1071 cmꢀ1; Anal. Calcd for
C14H13ClN2: C, 68.71; H, 5.35; N, 11.45. Found: C, 68.75; H, 5.41; N, 11.46.
N-(4-Phenylbenzyl)-3-amino-4-chloropyridine (10j). Following general procedure A: 10j was
further purified via flash column chromatography eluted with 3% ethyl acetate: 3%
triethylamine: 3% benzene: 91% hexanes afforded 220 mg of offꢀwhite crystalline solid (87%):
mp 98ꢀ100 °C; Rf 0.53 (50% ethyl acetate: hexanes); 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H),
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7.91 (d, J = 5.1 Hz, 1H), 7.60ꢀ7.57 (m, 4H), 7.47ꢀ7.43 (m, 4H), 7.38ꢀ7.33 (m, 1H), 7.21 (d, J =
5.1 Hz, 1H), 4.66 (bs, 1H), 4.43 (d, J = 5.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 140.8,
140.7, 140.3, 139.9 136.9, 133.8, 128.8, 128.0, 127.8, 127.6, 127.4, 127.1, 123.8, 47.4; IR (KBr,
pellet) 3270, 1581, 1514, 1487, 1418, 1259 cmꢀ1; Anal. Calcd for C18H15ClN2: C, 73.34; H, 5.13;
N, 9.50. Found: C, 73.45; H, 5.15; N, 9.83.
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N-(Furfuryl)-3-amino-4-chloropyridine (10k). Following general procedure A: 10k was
further purified via flash column chromatography eluted with 1% ethyl acetate: 1%
triethylamine: 1% benzene: 97% hexanes then crystallized in of hexanes to afford 114 mg of off
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white solid (55%): mp 59ꢀ61 °C; Rf 0.47 (50% ethyl acetate: hexanes); H NMR (400 MHz,
CDCl3) δ 8.13 (s, 1H), 7.92 (d, J = 5.1 Hz, 1H), 7.39 (dd, J = 1.8 Hz, 0.8 Hz, 1H), 7.19 (d, J =
5.1 Hz, 1H), 6.34 (dd, J = 3.2 Hz, 1.8 Hz, 1H), 6.29 (dd, J = 3.2 Hz, 0.8 Hz, 1H), 4.60 (bs, 1H),
4.45 (d, J = 5.9 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 151.3, 142.6, 140.1, 139.4, 134.0,
128.1, 124.0, 110.6, 107.9, 40.9; IR (KBr, pellet) 3431, 3199, 3075, 3014, 2953, 1581, 1556,
1517, 1438 cmꢀ1; Anal. Calcd for C10H9ClN2O: C, 57.57; H, 4.35; N, 13.43. Found: C, 57.51; H,
4.35; N, 13.68.
N-(4-Methylbenzyl)-3-amino-4-chloropyridine (10l). Following general procedure A: 204 mg
of 10l was obtained as a pale orange crystalline solid (88%): mp 80ꢀ82 °C; Rf 0.50 (50% ethyl
acetate: hexanes); 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.88 (d, J = 5.1 Hz, 1H), 7.26 (d,
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J = 8.0 Hz, 2H), 7.20ꢀ7.16 (m, 3H), 4.57 (bs, 1H), 4.41 (d, J = 5.6 Hz, 2H), 2.35 (s, 3H); C
NMR (100 MHz, CDCl3) δ 140.5, 138.9, 137.6, 134.9, 133.9, 129.7, 127.7, 127.5, 123.9, 47.6,
21.2; IR (KBr, pellet) 3238, 3079, 3018, 2930, 2850, 1577, 1512, 1415, 1332, 1262 cmꢀ1; Anal.
Calcd for C13H13ClN2: C, 67.10; H, 5.63; N, 12.04. Found: C, 67.21; H, 5.61; N, 12.19.
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N-(Piperonyl)-3-amino-4-chloropyridine (10m). Following general procedure A: 10m was
purified via flash column chromatography eluted with 3% ethyl acetate: 3% triethylamine: 3%
benzene: 91% hexanes to afford 224 mg of white crystalline solid (86%): mp 88ꢀ92 °C; Rf 0.52
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(50% ethyl acetate: hexanes); H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.89 (d, J = 5.1 Hz,
1H), 7.19 (d, J = 5.1 Hz, 1H), 6.87ꢀ6.77 (m, 3H), 5.96 (d, J = 1.7 Hz, 2H), 4.57 (bs, 1H), 4.36 (d,
J = 5.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 148.3, 147.3, 140.3, 139.1, 134.0, 131.8, 127.8,
123.9, 120.8, 108.7, 108.0, 101.3, 47.7; IR (KBr, pellet) 3412, 2901, 1578, 1501, 1416, 1245 cmꢀ
1; Anal. Calcd for C13H11ClN2O2: C, 59.44; H, 4.22; N, 10.66. Found. C, 59.36; H, 4.25; N,
10.65.
N-(2,3-Dimethoxybenzyl)-3-amino-4-chloropyridine (10n). Following general procedure A:
10n was further purified via flash column chromatography eluted with 10% ethyl acetate:
hexanes, then 20% ethyl acetate: hexanes to afford 232 mg of pale yellow crystalline solid
(83%): mp 76ꢀ79 °C; Rf 0.44 (50% ethyl acetate: hexanes); 1H NMR (400 MHz, CDCl3) δ 8.09
(s, 1H), 7.88 (d, J = 5.1 Hz, 1H), 7.17 (d, J = 5.1 Hz, 1H), 7.03 (t, J = 7.9 Hz, 1H), 6.91 (dd, J =
7.7 Hz, 1.5 Hz, 1H), 6.88 (dd, J = 8.1 Hz, 1.5 Hz, 1H), 4.67 (bs, 1H), 4.47 (d, J = 6.0 Hz, 2H),
3.90 (s, 3H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.0, 147.4, 140.5, 138.8, 134.0,
131.6, 127.8, 124.4, 123.9, 120.8, 112.3, 61.0, 55.9, 43.0; IR (KBr, pellet) 3387, 2997, 2964,
2933, 2831, 1582, 1510, 1480, 1449, 1418 cmꢀ1; Anal. Calcd for C14H15ClN2O2: C, 60.33; H,
5.42; N, 10.05. Found. C, 60.10; H, 5.59; N, 9.90.
N-(2,4-Dimethoxybenzyl)-3-amino-4-chloropyridine (10o). Following general procedure B:
10o was further purified via flash column chromatography eluted with 10% ethyl acetate:
hexanes to afford 97 mg of slight yellow crystalline solid (70%): mp 70ꢀ71 °C; Rf 0.37 (50%
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ethyl acetate: hexanes); H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.85 (d, J = 5.1 Hz, 1H),
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7.18 (d, J = 8.9 Hz, 1H), 7.15 (d, J = 5.1 Hz, 1H), 6.48 (d, J = 2.3 Hz, 1H), 6.44 (dd, J = 8.2 Hz,
2.4 Hz, 1H), 4.67 (brth, J = 5.4 Hz, 1H), 4.38 (d, J = 6.1 Hz, 2H), 3.85 (s, 3H), 3.78 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 160.7, 158.7, 140.8, 138.6, 134.3, 129.9, 127.8, 123.8, 118.5, 104.2,
98.9, 55.5, 55.5, 42.9; IR (KBr, pellet) 3246, 1620, 1582, 1510, 1209 cmꢀ1; Anal. Calcd for
C14H15ClN2O2: C, 60.33; H, 5.42; N, 10.05. Found: C, 59.99; H, 5.52; N, 9.97.
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N-(2,5-Dimethoxybenzyl)-3-amino-4-chloropyridine (10p). Following general procedure B:
10p was further purified via flash column chromatography eluted with 10% ethyl acetate:
hexanes to afford 106 mg of slight yellow crystalline solid (76%): mp 70ꢀ71 °C; Rf 0.37 (50%
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ethyl acetate: hexanes); H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.86 (d, J = 5.1 Hz, 1H),
7.16 (d, J = 5.1 Hz, 1H), 6.86 (d, J = 2.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 6.77 (dd, J = 8.8 Hz,
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3.0 Hz, 1H), 4.76ꢀ4.73 (m, 1H), 4.43 (d, J = 6.2 Hz, 2H), 3.84 (s, 3H), 3.74 (s, 3H); C NMR
(100 MHz, CDCl3) δ 153.7, 151.6, 140.5, 138.7, 134.1, 127.7, 127.1, 123.7, 115.3, 112.6, 111.3,
55.8, 55.7, 43.0; IR (KBr, pellet) 3278, 3063, 2997, 2956, 2836, 1577, 1501, 1417, 1270, 1235
cmꢀ1; Anal. Calcd for C14H15ClN2O2: C, 60.33; H, 5.42; N, 10.05. Found. C, 60.28; H, 5.42; N,
9.95.
N-(2,2-Dimethylpropyl)-3-amino-4-chloropyridine (10q). Following general procedure A: 10q
was further purified via flash column chromatography eluted with 1% ethyl acetate: 1%
triethylamine: 1% benzene: 97% hexanes to afford 136 mg of pale yellow crystalline solid
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(68%): mp 35ꢀ37 °C; Rf 0.51 (50% ethyl acetate: hexanes); H NMR (400 MHz, CDCl3) δ 8.05
(s, 1H), 7.84 (d, J = 5.1 Hz, 1H), 7.15 (d, J = 5.1 Hz, 1H), 4.21 (bs, 1H), 3.01 (d, J = 6.0 Hz,
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2H), 1.03 (s, 9H); C NMR (100 MHz, CDCl3) δ 141.3, 138.2, 133.6, 127.4, 123.8, 55.2, 32.2,
27.6; IR (KBr, pellet) 3427, 3224, 2961, 2864, 2502, 1580, 1517, 1417 cmꢀ1; Anal. Calcd for
C10H15ClN2: C, 60.45; H, 7.61; N, 14.10. Found: C, 60.43; H, 7.50; N, 14.17.
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N-(n-Butyl)-3-amino-4-chloropyridine (10r). Following general procedure C: 10r was further
purified via flash column chromatography eluted with 1% ethyl acetate: 1% triethylamine: 1%
benzene: 97% hexanes to afford 125 mg of offꢀwhite crystalline solid (68%): mp 38ꢀ39 °C; Rf
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0.43 (50% ethyl acetate: hexanes); H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.86 (d, J = 4.6
Hz, 1H), 7.16 (d, J = 5.0 Hz, 1H), 4.15 (bs, 1H), 3.25ꢀ3.21 (m, 2H), 1.71ꢀ1.64 (m, 2H), 1.50ꢀ
1.41 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 140.7, 138.2, 133.4,
127.2, 123.7, 43.1, 31.4, 20.2, 13.8; IR (KBr, pellet) 3309, 2953, 2935, 2868, 1580, 1555, 1484,
1410 cmꢀ1; Anal. Calcd for C9H13ClN2: C, 58.54; H, 7.10; N, 15.17. Found C, 58.54; H, 7.11; N,
15.22.
N-(Cyclohexylmethyl)-3-amino-4-chloropyridine (10s). Following general procedure C: 10s
was further purified via flash column chromatography eluted with 10% ethyl acetate: hexanes to
afford 180 mg of slight yellow crystalline solid (80%): mp 67ꢀ70 °C; Rf 0.59 (50% ethyl acetate:
hexanes); 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.83 (d, J = 5.1 Hz, 1H), 7.14 (d, J = 5.1,
1H), 4.25 (brs, 1H), 3.06 (t, J = 6.2 Hz, 2H), 1.86ꢀ1.57 (m, 6H), 1.32ꢀ1.12 (m, 3H), 1.06ꢀ0.94 (m,
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2H); C NMR (100 MHz, CDCl3) δ 140.8, 138.1, 133.5, 127.3, 123.8, 50.0, 37.5, 31.2, 26.6,
26.0; IR (KBr, pellet) 3383, 3054, 2923, 2845, 1577, 1508, 1459 cmꢀ1; Anal. Calcd for
C12H17ClN2: C, 64.14; H, 7.63; N, 12.47. Found. C, 64.12; H, 7.54; N, 12.18.
N-(Cyclohexyl)-3-amino-4-chloropyridine (10t). Following general procedure A: 10t was
further purified via flash column chromatography eluted with 3% acetone: 3% triethylamine: 3%
benzene: 91% hexanes afforded 79 mg of white crystalline solid (75%): mp 64ꢀ65 °C; Rf 0.68
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(50% ethyl acetate: hexanes); H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.82 (d, J = 5.1 Hz,
1H), 7.15 (d, J = 5.1 Hz, 1H), 4.09 (d, J = 7.1 Hz, 1H), 3.41ꢀ3.38 (m, 1H), 2.09ꢀ2.05 (m, 2H),
1.81ꢀ1.76 (m, 2H), 1.69ꢀ1.64 (m, 1H), 1.44ꢀ1.37 (m, 2H), 1.31ꢀ1.20 (m, 3H); 13C NMR (100
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MHz, CDCl3) δ 139.9, 138.0, 134.1, 127.4, 124.1, 51.4, 33.3, 25.9, 24.9; IR (KBr, pellet) 3410,
3051, 2932, 2852, 1578, 1506, 1449, 1414 cmꢀ1; Anal. Calcd for C11H15ClN2: C, 62.70; H, 7.18;
N, 13.30. Found. C, 62.84; H, 7.18; N, 13.29.
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N-(Benzyl)-3-amino-4-bromopyridine (15a). Following general procedure A: 15a was further
purified via flash column chromatography, eluted with 10% ethyl acetate: 90% hexanes to yield
197 mg of pale purple crystalline solid (75%): mp 102ꢀ103 °C; Rf 0.44 (50% ethyl acetate:
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hexanes); H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.79 (d, J =5.1 Hz, 1H), 7.38ꢀ3.36 (m,
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5H), 7.34ꢀ7.28 (m, 1H), 4.65 (bt, 1H), 4.46 (d, J =5.6 Hz, 2H); C NMR (100 MHz, CDCl3) δ
141.5, 139.2, 138.0, 133.8, 129.0, 127.9, 127.5, 127.2, 118.6, 48.0; IR (KBr, pellet) 3331, 3051,
2360, 1577, 1508, 1453, 1413, 1256 cmꢀ1; Anal. Calcd for C12H11BrN2: C, 54.77; H, 4.21; N,
10.65; Found: C, 54.79; H, 4.21; N, 10.66.
N-(4-Methylbenzyl)-3-amino-4-bromopyridine (15b). Following general procedure A: 15b
was recrystallized in hexanes to afford 229 mg of pale orange crystalline solid (83%): mp 85ꢀ86
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°C; Rf 0.44 (50% ethyl acetate: hexanes); H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.79 (d, J
= 5.0 Hz, 1H), 7.35 (d, J = 5.1 Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 4.60
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(bs, 1H), 4.41 (d, J = 5.6 Hz, 2H), 2.35 (s, 3H); C NMR (100 MHz, CDCl3) δ 141.5, 139.0,
137.6, 134.9, 133.8, 129.7, 127.5, 127.2, 118.6, 47.7, 21.3; IR (KBr, pellet) 3424, 3250, 3055,
3020, 2935, 2850, 1575, 1550, 1508, 1452, 1412 cmꢀ1; Anal. Calcd for C13H13BrN2: C, 56.34; H,
4.73; N, 10.11. Found: C, 56.40; H, 4.74; N, 10.04.
N-(4-Chlorobenzyl)-3-amino-4-bromopyridine (15c). Following general procedure A: 15c was
further purified via silica plug eluted with 50% ethyl acetate: hexanes, then recrystallized with
hexanes afforded 213 mg of an offꢀwhite crystalline solid (72%): mp 87ꢀ88 °C; Rf 0.40 (50%
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= 5.7 Hz, 2H); C NMR (100 MHz, CDCl3) δ 141.2, 139.4, 136.5, 133.8, 133.6, 129.2, 128.7,
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cmꢀ1; Anal. Calcd for C12H10BrClN2: C, 48.43; H, 3.39; N, 9.41. Found: C, 48.41; H, 3.43; N,
9.36.
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N-(2,3-Dimethoxybenzyl)-3-amino-4-bromopyridine (15d). Following general procedure A:
15d was further purified via silica plug eluted with 50% ethyl acetate: hexanes, then
recrystallized in hexanes to afford 257 mg of pale orange solid (80%): mp 83ꢀ85 °C; Rf 0.32
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(50% ethyl acetate: hexanes); H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.77 (d, J = 5.1 Hz,
1H), 7.33 (d, J = 5.1 Hz, 1H), 7.03 (t, J = 7.9 Hz, 1H), 6.92ꢀ6.87 (m, 2H), 4.69 (bs, 1H), 4.48 (d,
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J = 5.9 Hz, 2H), 3.90 (s, 3H), 3.88 (s, 3H); C NMR (100 MHz, CDCl3) δ 158.0, 147.4, 141.6,
138.9, 133.9, 131.6, 127.2, 124.3, 120.8, 118.6, 112.3, 61.0, 56.0, 43.1; IR (KBr, pellet) 3260,
3086, 2955, 2932, 1573, 1544, 1480, 1413, 1274 cmꢀ1; Anal. Calcd for C14H15BrN2O2: C, 52.03;
H, 4.68; N, 8.67. Found: C, 52.14; H, 4.81; N, 8.84.
N-(Benzyl)-3-amino-4-iodopyridine (16a). Following general procedure A: 16a was further
purified via flash column chromatography, eluted with 10% ethyl acetate: 90% hexanes to yield
238 mg of offꢀwhite crystalline solid (77%): mp 90ꢀ92 °C; Rf 0.44 (50% ethyl acetate: hexanes);
1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.60 (d, J=4.8 Hz, 1H ), 7.58 (d, J=5.2 Hz, 1H),
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7.38ꢀ3.36 (m, 4H), 7.34ꢀ7.28 (m, 1H), 4.53 (bs, 1H), 4.46 (d, J =5.6 Hz, 2H); C NMR (100
MHz, CDCl3) δ 143.8, 139.4, 137.9, 133.8, 132.8, 129.0, 127.8, 127.4, 95.1, 48.2; IR (KBr,
pellet) 3328, 3061, 3015.6, 2908, 1564, 1540, 1502, 1452, 1409 cmꢀ1; Anal. Calcd for C12H11IN2:
C, 46.47; H, 3.58; N, 9.03. Found: C, 46.46; H, 3.61; N, 9.02.
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N-(4-Methylbenzyl)-3-amino-4-iodopyridine (16b). Following general procedure A: 16b was
further purified via silica plug eluted with 50% ethyl acetate: hexanes, then recrystallized in
hexanes to afford 253 mg of a pale orange crystalline solid (78%): mp 65ꢀ66 °C; Rf 0.47 (50%
ethyl acetate: hexanes); 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.60 (d, J=4.8 Hz, 1H), 7.57
(d, J=4.8 Hz, 1H), 7.25 (d, J = 7.9 Hz, 2H), 7.17 (d, J = 7.9 Hz, 2H), 4.46 (bs, 1H), 4.41 (d, J =
5.4 Hz, 2H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.9, 139.3, 137.5, 134.9, 133.8,
132.9, 129.7, 127.5, 95.1, 48.1, 21.3; IR (KBr, pellet) 3396, 3034, 2908, 2855, 1564, 1503, 1417
cmꢀ1; Anal. Calcd for C13H13IN2: C, 48.17; H, 4.04; N, 8.64. Found: C, 48.16; H, 3.93; N, 8.53.
N-(4-Chlorobenzyl)-3-amino-4-iodopyridine (16c). Following general procedure A: 303 mg of
16c was obtained as a white crystalline solid (88%): mp 107ꢀ114 °C; Rf 0.40 (50% ethyl acetate:
hexanes); 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.61 (d, J=4.8 Hz, 1H), 7.59 (d, J=5.2 Hz,
1H), 7.34 (d, J=8.6 Hz, 2H), 7.29 (d, J=8.6 Hz, 2H), 4.52 (bs, 1H), 4.44 (d, J = 5.6 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 143.6, 139.7, 136.5, 133.8, 133.6, 132.8, 129.2, 128.7, 95.3, 47.7; IR
(KBr, pellet) 3389, 3043, 2929, 2868, 1559, 1497, 1446 cmꢀ1; Anal. Calcd for C12H10ClIN2: C,
41.83; H, 2.93; N, 8.13. Found: C, 41.76; H, 2.98; N, 8.05.
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N-(2,3-Dimethoxybenzyl)-3-amino-4-iodopyridine (16d). Following general procedure A: 317
mg of 16d was obtained as a brown/red solid (85%): mp 118ꢀ120 °C; Rf 0.35 (50% ethyl acetate:
hexanes); 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.58 (d, J= 5.0 Hz, 1H), 7.56 (d, J=5.0 Hz,
1H), 7.03 (t, J = 8.0 Hz, 1H), 6.89 (td, J=8.9, 1.5 Hz, 2H), 4.57 (bs, 1H), 4.47 (d, J = 5.8 Hz,
2H), 3.91 (s, 3H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.0, 147.4, 144.0, 139.2, 133.8,
131.5, 124.3, 120.7, 112.3, 95.1, 61.0, 56.0, 43.5; IR (KBr, pellet) 3413, 3001, 2970, 2935, 2834,
1561, 1479, 1410, 1270 cmꢀ1; Anal. Calcd for C14H15IN2O2: C, 45.42; H, 4.08; N, 7.57. Found:
C, 45.50; H, 4.09; N, 7.55.
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N-Benzyl-2,4,6-tribromoaniline (17): An ovenꢀdried 10 mL round bottom flask with magnetic
stir bar was charged with 2,4,6ꢀtribromoaniline (330 mg, 1 mmol), benzaldehyde (0.20 mL, 2
mmol), and CH2Cl2 (2 mL, 0.5 M). Trimethylsilyl trifluoromethanesulfonate (0.36 mL, 2 mmol)
was added in one portion and the mixture was stirred for 1 hour. To the mixture was added
sodium triacetoxyborohydride (636 mg, 3 mmol) and the reaction was stirred 18 hours, before
diluting with 10 mL CH2Cl2 and quenching with 20 mL of 20% (m/v) NaOH(aq). The aqueous
layer was extracted 3 times with 10 mL portions of CH2Cl2. The combined organics were dried
with MgSO4, filtered and concentrated in vacuo. The resulting oil was further purified via flash
column chromatography (silica deactivated with a 1% triethylamine : 99% hexanes solution),
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eluting 402 mg of 17 with hexanes as a clear oil (96%): Rf 0.59 (10% ethyl acetate:hexanes); H
NMR (400 MHz, CDCl3) δ 7.61 (s, 2H), 7.40ꢀ7.27 (m, 5H), 4.41 (s, 2H), 4.15 (bs, 1H); 13C
NMR (100 MHz, CDCl3) δ 144.2, 139.1, 135.1, 128.8, 128.3, 127.8, 117.7, 114.4, 52.2; IR
(NaCl, thin film) ν = 3051, 2983, 1264 cmꢀ1; Anal. Calcd for C13H10Br3N: C, 37.18; H, 2.40; N,
3.34. Found: C, 37.04; H, 2.44; N, 3.30.
N-Benzyl-2,4-dinitroaniline (18): An ovenꢀdried 10 mL round bottom flask with magnetic stir
bar was charged with 2,4ꢀdinitroaniline (183 mg, 1 mmol), benzaldehyde (0.20 mL, 2 mmol),
and CH2Cl2 (2 mL, 0.5 M). Trimethylsilyl trifluoromethanesulfonate (0.36 mL, 2 mmol) was
added in one portion and the mixture was stirred for 1 hour. To the mixture was added sodium
triacetoxyborohydride (636 mg, 3 mmol) and the reaction was stirred 18 hours, before diluting
with 10 mL CH2Cl2 and quenching with 20 mL of 20% (m/v) NaOH(aq). The aqueous layer was
extracted 3 times with 10 mL portions of CH2Cl2. The combined organics were dried with
MgSO4, filtered and concentrated in vacuo. The resulting crude solid was triturated with 10 mL
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of Et2O and 171 mg of 18 was collected by filtration as a yellow solid (63%): Compared to
literature data15 1H NMR (400 MHz, CDCl3) δ 9.17 (d, J = 2.6 Hz, 1H), 8.91 (bs, 1H), 8.24 (dd,
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J = 9.5, 2.6 Hz, 1H), 7.43ꢀ7.33 (m, 5H), 6.91 (d, J = 9.5 Hz, 1H), 4.65 (d, J = 5.6 Hz, 2H); C
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NMR (100 MHz, CDCl3) δ 148.3, 136.7, 135.7, 131.0, 130.5, 129.5, 128.5, 127.2, 124.4, 114.5,
47.7.
N-Benzyl-2,6-diisopropylaniline (19): An ovenꢀdried 10 mL round bottom flask with magnetic
stir bar was charged with 2,4ꢀdinitroaniline (183 mg, 1 mmol), benzaldehyde (0.20 mL, 2 mmol),
and CH2Cl2 (2 mL, 0.5 M). Trimethylsilyl trifluoromethanesulfonate (0.36 mL, 2 mmol) was
added in one portion and the mixture was stirred for 1 hour. To the mixture was added sodium
triacetoxyborohydride (636 mg, 3 mmol) and the reaction was stirred 18 hours, before diluting
with 10 mL CH2Cl2 and quenching with 20 mL of 20% (m/v) NaOH(aq). The aqueous layer was
extracted 3 times with 10 mL portions of CH2Cl2. The combined organics were dried with
MgSO4, filtered and concentrated in vacuo. The crude oil was further purified via flash column
chromatography (silica deactivated with a 1% triethylamine : 99% hexanes solution), eluting a
mixture of benzyl alcohol: 19, which was purified further through the acidification/freebase
method in General procedure A. This yielded 187 mg of 19 as a clear oil (70%): Compared to
literature data16 1H NMR (400 MHz, CDCl3) δ 7.42ꢀ7.28 (m, 5H), 7.12 (m, 3H), 4.05 (s, 2H),
3.31 (sept, J = 6.2 Hz, 2H), 3.15 (bs, 1H), 1.23 (d, J = 6.2 Hz, 12H) ; 13C NMR (100 MHz,
CDCl3) δ 143.0, 142.9, 140.3, 128.7, 128.1, 127.6, 124.2, 123.8, 56.2, 27.9, 24.4.
Acknowledgements
Acknowledgement is made to the National Institute of General Medical Sciences (R15ꢀ
GM116054) for partial financial support. We thank the Chisholm and Totah research groups
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(Syracuse University) for copious sharing of chemicals, instrumentation, and pertinent
discussions. We thank Ijaz Ahmed, Patrick J. Heaphy, Rachel Wilson, and Breanna Tomiczek
for preliminary deprotection/reductive amination studies. We thank Tomas Smith for the
synthesis of compound 13.
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Associated Content
Supporting Information
1H and 13C NMR spectra available for compounds 7, 8, 9, 10aꢀ10t, 11, 13, 15aꢀ15d, 16aꢀ
16d, 17, 18 (1H NMR only), and 19 (1H NMR only)
19F NMR spectra available for compounds 10d, 10h, and 11
Author information
Corresponding Author
*Eꢀmail: addixon@syr.edu
ORCID
Alexandre D. C. Dixon: 0000ꢀ0002ꢀ3390ꢀ7640
References
1.
(a) Khaksar, S.; Heydari, A.; Tajbakhsh, M.; Vahdat, S. M. J. Fluorine Chem. 2010, 131,
1377. (b) Dvorak, C. A.; Apodaca, R.; Barbier, A. J.; Berridge, C. W.; Wilson, S. J.;
Boggs, J. D.; Xiao, W.; Lovenberg, T. W.; Carruthers, N. I. J. Med. Chem. 2005, 48,
2229. (c) Temple, C., Jr.; Rose, J. D.; Comber, R. N.; Rener, G. A. J. Med. Chem. 1987,
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