Preparation of highly reactive pyridine- and pyrimidine-containing diarylamine antioxidants

Article abstract of DOI:10.1021/jo301013c

We recently reported a preliminary account of our efforts to develop novel diarylamine radical-trapping antioxidants (Hanthorn, J. J. et al. J. Am. Chem. Soc. 2012, 134, 8306-8309) wherein we demonstrated that the incorporation of ring nitrogens into diphenylamines affords compounds which display a compromise between H-atom transfer reactivity to peroxyl radicals and stability to one-electron oxidation. Herein we provide the details of the synthetic efforts associated with that report, which have been substantially expanded to produce a library of substituted heterocyclic diarylamines that we have used to provide further insight into the structure-reactivity relationships of these compounds as antioxidants (see the accompanying paper, DOI: 10.1021/jo301012x). The diarylamines were prepared in short, modular sequences from 2-aminopyridine and 2-aminopyrimidine wherein aminations of intermediate pyri(mi)dyl bromides and then Pd-catalyzed cross-coupling reactions of the amines and precursor bromides were the key steps to yield the diarylamines. The cross-coupling reactions were found to proceed best with Pd(η³-1-PhC₃H ₄)(η⁵-C₅H₅) as precatalyst, which gave higher yields than the conventional Pd source, Pd₂(dba) ₃.

Full text of DOI:10.1021/jo301013c

Article
pubs.acs.org/joc
Preparation of Highly Reactive Pyridine- and Pyrimidine-Containing
Diarylamine Antioxidants
Jason J. Hanthorn,† Luca Valgimigli,§ and Derek A. Pratt*,†,‡
†Department of Chemistry, Queen’s University, 90 Bader Lane, Kingston, Ontario, Canada K7L 3N6
§Department of Organic Chemistry “A. Mangini”, University of Bologna, 40126, Bologna, Italy
‡Department of Chemistry, University of Ottawa, 10 Marie Curie Pvt., Ottawa, Ontario, Canada K1N 6N5
S
* Supporting Information
ABSTRACT: We recently reported a preliminary account of our efforts to develop novel diarylamine radical-trapping
antioxidants (Hanthorn, J. J. et al. J. Am. Chem. Soc. 2012, 134, 8306−8309) wherein we demonstrated that the incorporation of
ring nitrogens into diphenylamines affords compounds which display a compromise between H-atom transfer reactivity to
peroxyl radicals and stability to one-electron oxidation. Herein we provide the details of the synthetic efforts associated with that
report, which have been substantially expanded to produce a library of substituted heterocyclic diarylamines that we have used to
provide further insight into the structure−reactivity relationships of these compounds as antioxidants (see the accompanying
paper, DOI: 10.1021/jo301012x). The diarylamines were prepared in short, modular sequences from 2-aminopyridine and 2-
aminopyrimidine wherein aminations of intermediate pyri(mi)dyl bromides and then Pd-catalyzed cross-coupling reactions of
the amines and precursor bromides were the key steps to yield the diarylamines. The cross-coupling reactions were found to
proceed best with Pd(η3-1-PhC3H4)(η5-C5H5) as precatalyst, which gave higher yields than the conventional Pd source,
Pd2(dba)3.
nitrogen atoms into the aryl rings, which enables their
substitution with strongly electron-donating groups to weaken
the N−H bond and accelerate the rate of the formal H-atom
transfer reaction in eq 1. Both modifications are believed to be
key to optimizing reactivity, since ring substitution alone results
in compounds that undergo one-electron oxidation by O2 in
the air or by product hydroperoxides thereby rendering them
useless as antioxidants. In fact, we showed that analogues of 1
bearing either ring carbons or nitrogens at the positions
indicated by X, Y, and Z in 2 were characterized by oxidation
potentials that increased systematically with the number of N-
atoms from less than 1 V to >1.5 V (vs NHE), while their
reactivity to peroxyl radicals decreased only 6-fold at most
(from 1.8 × 105 M−1s−1 for 1 to 3.0 × 104 M−1s−1 for 2 with X
= Y = Z = N in chlorobenzene at 37 °C). This permitted the
design of diarylamines bearing strongly electron-donating N,N-
dialkylamino groups (3) that were stable in air and reacted with
peroxyl radicals with temperature-independent rate constants
up to 200-fold greater than those measured for 1 under the
same conditions.
INTRODUCTION
■
Diarylamines (Ar2NH) are among the most important additives
to petroleum-derived products.1 They are radical-trapping
antioxidants which slow hydrocarbon autoxidation, the
archetype free-radical chain reaction, through initial donation
of their aminic H-atom to chain-carrying peroxyl radicals (eq
1).2 Subsequent reaction of the aminyl radical with another
peroxyl radical leads to nonradical products at ambient
temperatures (eq 2) and nitroxide radicals at elevated
temperatures (>120 °C, eq 3).3 The latter reaction is key to
the catalytic antioxidant activity of alkylated diphenylamines
(1), which has made them the additives of choice to lubricating
oils of combustion engines and in other high-temperature
applications.
Ar2NH + ROO• → Ar2N• + ROOH
(1)
Ar2N• + ROO• → nonradical products
(2)
Ar2N• + ROO• → Ar2NO• + RO•
In a recent communication,4 we described preliminary results
of our attempts to improve the reactivity of diarylamine
antioxidants. Our strategy involves the incorporation of
(3)
Received: May 29, 2012
Published: July 12, 2012
© 2012 American Chemical Society
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RESULTS AND DISCUSSION
I. Preparation of 3-Pyridyl and 5-Pyrimidyl Bromides.
■
2-Aminopyridine and 2-aminopyrimidine were employed as
common starting materials for each of the pyridyl and pyrimidyl
halides because of their commercial availability and low cost.
Synthesis of the various pyridyl bromides began with
bromination of the 5-position of 2-aminopyridine using NBS/
NH4OAc.14 This intermediate was either alkylated by reductive
amination with appropriate aldehydes to prepare 5-bromo-2-
N,N-dialkylaminopyridines (4) or subjected to nonaqueous15
diazotization/halo-dediazoniation to afford 2,5-dibromopyri-
dine (Scheme 2). This compound served as the precursor to all
These exciting results prompted us to carry out a thorough
study of the structure−reactivity relationships in these
compounds. First, it was of interest to determine the optimal
location of the ring nitrogen atoms. In our preliminary work,
we studied only 3-pyridyl- and 5-pyrimidylamines, but clearly
other arrangements are possible and should be investigated.
Second, it was of interest to determine the relative reactivities
of unsymmetrically substituted compounds as compared to the
symmetric compounds studied to date. Third, it was necessary
to expand the type of ring substituents that we have studied in
order to establish well-defined structure−reactivity relation-
ships that will provide meaningful insights into their chemistry
and potential usefulness. Therefore, in addition to the alkyl-
and N,N-dialkylamino-substituted compounds we studied in
our preliminary report (i.e., 2 and 3),4 we sought to prepare
alkoxyl-substituted compounds as well as the unsubstituted
(parent) compounds. The compounds of interest are shown in
Chart 1.
Scheme 2. Preparation of Relevant Pyri(mi)dyl Halides 4−
a
11
Chart 1. Target Heterocyclic Diarylamines
It should be pointed out that few of these heterocyclic
diarylamines have been described in the literature,5 and prior to
our preliminary report,4 their radical chemistry had never been
explored. Diarylamines can be prepared by a variety of
methods, including Smiles rearrangements of amides,6 Chap-
man rearrangement of imino ethers,7 and addition of
phenylmagnesium halides to nitrobenzenes8 or nitrosyl
chlorides.9 We sought a modular synthetic strategy involving
intermediates that could be used in multiple combinations to
build up a small library that could be used to survey a broad a
series of ring structures and substitutions (cf. Scheme 1).
a
Key: (a) NBS, NH4OAc, MeCN, rt, 5 min, pyr: 85−90%; pym:
quant; (b) pyr: RCHO, Na(CN)BH3, MeCN, reflux, 1−12 h (82%, R
= C5H11); pym: NaH, RI, THF, rt, overnight (85%, R = Me); (c)
Me3(Bn)NBr, t-BuONO, CH2Br2, rt, overnight, pyr: 77−83%; pym:
30−40%; (d) pym: HI, CH2Cl2, 0 °C, 80−85%; (e) (i) NaOH, Br2,
H2O, rt, 50−60%, (ii) POCl3, PhNEt2, reflux, 4h, 75−85%, (iii) HI,
CH2Cl2, 0 °C, 80−85%; (f) ROH, Na, rt, 1−12 h, quant; (g) RZnI,
Cl2Pd(PPh3)2, DMF/THF, rt, overnight, pyr (Br): 72% (R = C6H13),
pym (I) 81%, (R = C6H13); (h) alkyne, CuI, Cl2Pd(PPh3)2, Et3N,
MeCN, rt, 1−12 h, quant.
Scheme 1. Library Approach to Heterocyclic Diarylamines
other substituted pyridines: 2-alkoxy-5-bromopyridines (6)
were obtained by nucleophilic substitution with an appropriate
sodium alkoxide,16 and 2-alkynyl-5-bromopyridine (8) and 2-
alkyl-5-bromopyridines (10) were prepared via Sonogashira17
and Negishi18 cross-coupling reactions, respectively.
The pyrimidyl bromides were prepared in a similar manner,
beginning with bromination of 2-aminopyrimidine. N-Alkyla-
tion could not be achieved by reductive amination (presumably
due to the decreased nucleophilicity of the amine) and was
instead accomplished using NaH and an appropriate alkyl
halide to give 5. Nonaqueous diazotization/halo-dediazoniation
was used to prepare 5-bromo-2-halopyrimidines15 but in
diminished yield relative to the analogous reaction with the
2-aminopyridine (again, presumably due to the decreased
Transition-metal-catalyzed (i.e., Pd, Cu, Ni, Fe) cross-coupling
reactions of aryl halides and amines appeared to be the most
convenient and versatile approach to accomplish this.10−12
Herein we describe the application of this approach to the
synthesis of a library of diarylamines that has enabled detailed
studies of their radical-trapping antioxidant activities (see the
accompanying paper, DOI: 10.1021/jo301012x).4,13
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a
Table 1. Copper-Catalyzed Amination of 2-Substituted 5-Bromopyridnes and 5-Bromopyrimidines
a
Method A: 1.2 equiv of BnNH2, 1.5 equiv of K2CO3, 0.1 equiv of CuI, 0.2 equiv of L-proline, DMSO (1 mL/1.2 mmol of ArBr) heated to 80 °C
under argon. Method B: 1.5 equiv of NH4OH, 1.5 equiv of K2CO3, 0.2 equiv of CuI, 0.4 equiv of L-proline, DMSO (1 mL/1 mmol ArBr) heated to
90 °C in a sealed tube. Isolated yields.
b
nucleophilicity of the amine group). Alternatively, 2-pyrimidi-
none could serve as a precursor to 5-bromo-2-halopyrimi-
dines19 or as a substrate for alkylation to generate 5-bromo-2-
alkoxypyrimidines (7).20 Introduction of an alkyne substituent
at the 2-position to give 9 proceeded satisfactorily under
Sonogashira conditions, but alkylation using Negishi conditions
was unselective. Since reduction of the 2-alkynylpyrimidyl
bromide 9 to the corresponding 2-alkylpyrimidyl bromide 11
was complicated by competing removal of the bromine, we
turned to 5-bromo-2-iodopyrimidine as a precursor for the
cross-coupling reactions and saw a dramatic improvement in
selectivity and yields.
II. Preparation of 3-Aminopyridines and 5-Amino-
pyrimidines. With the substituted pyridyl and pyrimidyl
bromides in hand, we attempted to install the amine
functionality using a two-step procedure involving first a
copper-catalyzed amination with benzylamine followed by
reductive cleavage of the benzyl group.15 This method is
attractive because the N-benzyl intermediate is stable to
oxidative degradation, an attribute lacking in the more
electron-rich primary amines, which can undergo significant
degradation upon prolonged storage. We found that CuI, L-
proline, and K2CO3 in DMSO at 80 °C were general conditions
that afforded benzyl-protected amines in good yields from each
of 4−11 as well as the unsubstituted 3-bromopyridine and 5-
bromopyrimidine. While removal of the benzyl group to afford
the corresponding primary amines was easily achieved using
Pd/C and ammonium formate in refluxing methanol for the
more electron-rich compounds (R = NR2, OR), these
conditions were ineffective for the less electron-rich com-
pounds (R = H, alkyl, alkynyl). Increasing catalyst loading, or
changing to Pd(OH)2 or Raney nickel as catalyst, did not
improve the outcome up to several atmospheres of H2.
the two-step benzylamination/hydrogenation sequence had
failed at the latter step, presumably since the less electron-rich
substrates are more reactive to substitution. The results are
summarized in Table 1. Although the reactions generally
proceeded with excellent conversions, the isolated yields reflect
the difficulty associated with the purification of the more polar
and/or oxidizable substrates and as such, the more electron-rich
amines were generally carried through without purification.
III. Preparation of Diarylamines. A large number of
phosphine ligands have been developed for Pd-catalyzed C−N
bond-forming reactions, and indeed, our original ligand screen
showed a broad structural variety of phosphines were useful
when coupling substituted bromopyri(mi)dines with aniline
(e.g., BINAP, Josiphos, SPhos, DPPF). However, 2-dicyclohex-
ylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos)11 gave con-
sistently good results, showing the least sensitivity to the
electronics of the aryl bromides, and had the added benefit of
being air-stable and therefore easily handled. Based on these
results, we settled on a catalytic system of 2 mol % of Pd2(dba)3
as a palladium source along with 4 mol % of XPhos as a ligand.
A series of dialkylamino-substituted pyridine- and pyrimidine-
based diarylamines were prepared, with varied alkyl groups to
improve solubility in hydrocarbons, as shown in Table 2. The
conversions were very good for nearly all of the substrates
shown, the exception being 2-aminopyrimidine 30; however,
the isolated yields in some cases do not reflect the conversion
because of difficulty with purification and/or sensitivity to
oxidation in solution. We surmise that the poor reactivity of 2-
aminopyrimidine is due its relatively low pKa (6.8)25 and
corresponding poor nucleophilicity. Switching nucleophile and
electrophile by using N,N-dimethylbenzene-1,4-diamine and 2-
bromopyrimidine as the coupling partners also resulted in poor
yields due to competing reduction of the aryl bromide by the
highly electron-rich arylamine.
To circumvent this problem, we attempted to install the
desired primary amine directly. After screening reported
conditions for the amination of aryl bromides with “NH2
equivalents” LiHMDS,21 ZnHMDS,22 Li/NaNH2,12 and tert-
butyl carbamate23 with either copper or palladium as catalysts
with mixed results, we found that aqueous ammonia, in
combination with CuI, L-proline, and K2CO3 in DMSO at 90
°C, was most effective.24 Coincidently, this procedure was only
successful for those pyridyl and pyrimidyl bromides for which
A similar set of compounds were prepared having alkyl
substituents that will allow us to explore the effect of
heteroatom incorporation on stability and reactivity using the
industry standards (4,4′-dialkyldiphenylamines) as a baseline
for comparison (Table 3). The isolated yields for these
compounds are generally quite good. As noted previously,
compounds with unsubstituted pyrimidines (e.g., 45) can be
difficult to purify by chromatography.
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Table 2. N,N-Dialkylamino-Substituted Diarylamines
Prepared by Palladium-Catalyzed Cross-Couplings of Aryl
Bromides and Arylamines
Table 3. Alkyl-Substituted Diarylamines Prepared by
Palladium-Catalyzed Cross-Couplings of Aryl Bromides and
Arylamines
a
Conditions: ArBr (1.0 mmol), ArNH2 (1.1 mmol), Pd (2 mol %),
XPhos (4 mol %), NaOtBu (1.4 mmol) in degassed toluene (2 mL)
b
heated to 90 °C. Reactions done using Pd(η3-1-PhC3H4)(η5-C5H5)
(65).
a
Conditions: ArBr (1.0 mmol), ArNH2 (1.1 mmol), Pd (2 mol %),
XPhos (4 mol %), NaOtBu (1.4 mmol) in degassed toluene (2 mL)
b
heated to 90 °C. Reactions done using Pd(η3-1-PhC3H4)(η5-C5H5)
with the pyrimidine ring to be effective as an antioxidant.
However, none of these compounds gave the desired result.
It should be pointed out that upon preparation of each series
of diarylamines, we could readily see that with increasing
nitrogen incorporation into the aromatic rings, the diarylamines
were much more stable to oxidation. For example, on
comparing the series of symmetrically substituted diarylamines
in Table 2, compounds 33 and 34 became intensely colored
(because of formation of the corresponding radical cation, vide
supra) almost immediately upon exposure to air in solution,
while compounds 35, 36, 37, and 38 were bench stable.
Although the Pd2(dba)3/XPhos catalyst system was effective
for the preparation of the bulk of the diarylamines shown in
Tables 2−4, we found that the little used Pd(η3-1-PhC3H4)(η5-
C5H5) precatalyst (65)26,27 afforded higher isolated yields in
essentially all cases where a direct comparison was made. We
suggest that the increased yields from the 65/XPhos system can
be attributed to the rapid and irreversible formation of the active
PdL2 catalyst27 compared to when Pd2(dba)3 is used, which
remains in equilibrium with PdL2. Although a detailed
quantitative comparison of the performance of these two Pd
precatalysts in Buchwald−Hartwig amination chemistry is well
beyond the objectives of our work, we did monitor the reaction
progress of three representative reactions under otherwise
identical conditions to provide some insight into their differing
performance. The first two reactions (Figure 1A,B) were
randomly chosen from the many examples given above, and the
third was selected because it was a particularly problematic
(65).
To round out the series, a set of alkoxy-substituted
compounds were prepared that should have reactivities/
stabilities in between the dialkylamino and alkyl compounds
(Table 4). In the case of alkoxy-substituted compounds, the
reaction becomes more complicated because the alkoxide
represents a reasonable leaving group and when in the
electrophilic 2-position of a pyridine or pyrimidine ring and
in the presence of a nucleophilic amine coupling partner a
competing SNAr reaction can occur. This is reflected in some of
the isolated yields, although we found the use of bulkier alkyl
groups helped to minimize the undesired substitution reaction.
Unfortunately, the symmetrical 2-alkoxypyrimidine com-
pound (64) could not be prepared by the C−N coupling
approach as the amines always underwent nucleophilic
substitution at the 2-position prior to the desired coupling.
Because products were obtained for 56, 61 and 63, compounds
which also feature 2-alkoxypyrimidine rings, we suspect the
desired coupling reaction is sluggish due to the arylamine
coupling partner not readily participating in the catalytic cycle.
We attempted to decrease the rate of nucleophilic substitution
relative to that of amine ligation to palladium by using relatively
bulky alkyl substituents (−OCy, −OMeCy, −OBn, −OEtPh,
etc.), keeping in mind that the substituent must be small
enough to allow conjugation of the oxygen p-orbital (lone pair)
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The reaction progress data clearly show higher rates of
catalyst turnover when 65 is used in place of Pd2(dba)3 as the
precatalyst. Since the catalyst in both cases is likely the same
[Pd(XPhos)2], the different rates must arise from different
concentrations of the catalyst available to turnover. This is
consistent with the observed rapid irreversible formation of PdL2
from 65 and phosphine ligands.27 It is interesting to note that
the initial rates of the reactions utilizing 65 are slowed due to
the presence of an induction period. We ascribe this induction
period to the undesired formation of coordination complexes
between the Lewis basic pyridines and 65 in competition with
reductive elimination to form the active PdL2 species (Scheme
3). A recent report comparing 65 with other Pd precatalysts for
Table 4. Alkoxy-Substituted Diarylamines Prepared by
Palladium-Catalyzed Cross-Couplings of Aryl Bromides and
Arylamines
Scheme 3. Proposed Origin of the Induction Periods
Observed in Reactions Shown in Figure 1
the Suzuki−Miyaura coupling of bromoanisole and phenyl-
boronic acid did not display induction periods, presumably
because of the lack of competitively coordinating substrates.29
Unlike with 65, the formation of inactive coordination
complexes with Pd2(dba)3 remains in continuous equilibrium
with formation of PdL2; each intermediate (e.g., (dba)PdL2)30
can form new complexes with Lewis bases. This equilibrium
may explain why the product yields are much lower than
reactions using 65 for A−C in Figure 1; the concentration of
active catalyst never reaches a sustained level suitable for
catalysis to occur. The relative Lewis basicities of the substrates
support this explanation, as the yields obtained with Pd2(dba)3
as the precatalyst are lower for the reactions with 3-
aminopyridine as a substrate (Figure 1A,C) than for 2-
hexynylpyridine (Figure 1B).
a
Conditions: ArBr (1.0 mmol), ArNH2 (1.1 mmol), Pd (2 mol %),
XPhos (4 mol %), NaOtBu (1.4 mmol) in degassed toluene (2 mL)
b
heated to 90 °C. Reactions done using Pd(η3-1-PhC3H4)(η5-C5H5)
(65).
literature reaction (Figure 1C); the diarylamine product could
be obtained in a modest 56% yield but required high precatalyst
loading (Pd(OAc)2, 15 mol %), large amounts of ligand
(XantPhos, 30 mol %), and long reaction time (48 h) and
utilized 3-iodo-2-chloropyridine as a more reactive coupling
partner than the corresponding 3-bromo-2-chloropyridine
(which we used below).28 In each case, we monitored reaction
progress under typical preparative conditions at regular time
intervals by gas chromatography using hexadecane as an
internal standard. The results are shown in Figure 1.
CONCLUSIONS
■
We have presented a simple, modular approach for the
preparation of substituted pyridine- and pyrimidine-based
■
●
Figure 1. Comparative reaction profiles for a series of cross-coupling reactions where either 65 ( ) or Pd2(dba)3 ( , grey) was used as a precatalyst.
Reactions A and B: Pd (1 mol %), XPhos (2 mol %), ArBr (1 mmol), ArNH2 (1.1 mmol), NaOtBu (1.4 mmol) in toluene (2 mL) at 80 °C. Reaction
C: Pd (3 mol %), XPhos (6 mol %), ArBr (1 mmol), ArNH2 (1.3 mmol), NaOtBu (1.4 mmol) in toluene (3 mL) at 100 °C. All reactions were done
with 0.1 mmol hexadecane as an internal standard. Data were fit to sigmoidal functions; no attempt was made to analyze the kinetics of these
reactions.
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N5-Benzyl-N2,N2-dimethylpyrimidine-2,5-diamine (19): yield
187 mg, 82%; yellow solid; mp 89−90 °C; H NMR (CDCl3, 400
diarylamine radical-trapping antioxidants. General conditions
for Cu-catalyzed amination of pyridyl and pyrimidyl bromides
have been described that are best carried out by choosing an
appropriate nitrogen nucleophile to match the electronics of
the aryl bromide. We have also described general conditions for
Pd-catalyzed Buchwald−Hartwig aminations that are effective
for electronically diverse aryl bromides and arylamines and that
are greatly enabled by the use of the unconventional Pd(η3-1-
PhC3H4)(η5-C5H5) precatalyst. These synthetic efforts have
permitted extensive quantitative measurements of the effects of
nitrogen incorporation on the oxidative stability of diarylamines
as well as kinetic and thermodynamic measurements to
determine their reactivity with alkyl and peroxyl radicals,
which are detailed in the accompanying manuscript (DOI:
10.1021/jo301012x).13
1
MHz) δ ppm 7.93 (s, 2H), 7.36−7.24 (m, 5H), 4.25 (s, 2H), 3.11 (s,
6H); 13C NMR (CDCl3,100 MHz) δ ppm 144.5, 144.5, 138.5, 132.5,
128.7, 127.6, 127.5, 49.7, 37.6; HRMS (EI) m/z calculated for
C13H16N4 228.1375, found 228.1373.
N5-Benzyl-N2,N2-diethylpyrimidine-2,5-diamine (20): yield
1
184 mg, 72%; yellow solid; mp 89−90 °C; H NMR (CDCl3, 400
MHz) δ ppm 7.93 (s, 2H), 7.37−7.27 (m, 5H), 4.24 (s, 2H), 3.55 (q, J
= 7.0 Hz, 4H), 3.41 (brs, 1H), 1.15 (t, J = 7.0 Hz, 6H); 13C NMR
(CDCl3, 100 MHz) δ ppm 156.6, 145.0, 139.0, 132.5, 128.7, 127.5,
127.4, 49.9, 41.9, 13.2; HRMS (EI) m/z calcd for C15H20N4 256.1688,
found 256.1668.
Direct Amination of Pyri(mi)dyl Bromides. To a tube equipped
with a threaded Teflon screw-cap were added ArBr (1.0 mmol), CuI
(0.2 mmol), L-proline (0.4 mmol), and K2CO3 (1.5 mmol). The vessel
was evacuated and backfilled with argon before DMSO (1 mL) was
added. After the mixture was stirred a few minutes, NH4OH (28%, 1.5
mmol) was added, the tube was sealed and the reaction heated to 90
°C for 12 h. After cooling, the reaction was quenched with water and
extracted with Et2O. The organics were washed with brine and dried
over MgSO4. Column chromatography (EtOAc/hexanes/Et3N eluent)
afforded pure products.
EXPERIMENTAL SECTION
■
General Methods. Reagents were purchased from commercial
suppliers and used without further purification, unless otherwise
indicated. Pd(η3-1-PhC3H4)(η5-C5H5) (65) was synthesized from
[Pd(η3-1-PhC3H4)Cl]2 and sodium cyclopentadienide as described by
Fraser et al.29 Column chromatography was carried out using flash
silica gel (60 Å, 40−63 μm, 500 m2/g). 1H and 13C NMR were
recorded at 25 °C on a spectrometer operating at 400 and 100 MHz,
respectively, unless otherwise indicated. High-resolution mass spectra
were obtained by electron-impact ionization in combination with a
single quadrupole mass analyzer.
6-(Hex-1-ynyl)pyridin-3-amine (16): yield 165 mg, 95%; yellow
semisolid; 1H NMR (CDCl3, 300 MHz) δ ppm 8.02 (s, 1H), 7.16 (d, J
= 8.3 Hz, 1H), 6.88 (dd, J = 2.1, 8.3 Hz, 1H), 3.80 (s, 2H), 2.41 (t, J =
6.6 Hz, 2H), 1.44−1.64 (m, 4H), 0.93 (t, J = 7.1 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ ppm 141.4, 137.2, 133.6, 127.1, 121.3, 88.5, 30.6,
22.0, 19.0, 13.6; HRMS (EI) m/z calcd for C11H14N2 174.1157, found
174.1150.
Cu-Catalyzed Benzylamination of Pyri(mi)dyl Bromides. To a
Schlenk flask were added ArBr (1.0 mmol), CuI (0.2 mmol), L-proline
(0.4 mmol), and K2CO3 (1.5 mmol). The flask was evacuated and
backfilled with argon before degassed DMSO (1.5 mL) was added.
After a few minutes of stirring, BnNH2 (1.2 mmol) was added and the
reaction heated to 80 °C until completion, as determined by TLC. The
reaction was cooled, quenched with water, and extracted with Et2O.
The combined organics were washed twice with water, washed with
brine, and dried over MgSO4. Column chromatography (EtOAc/
hexanes eluent) afforded pure products.
1
6-Hexylpyridin-3-amine (17): yield 158 mg, 89%; yellow oil; H
NMR (CDCl3, 400 MHz) δ ppm 7.95 (t, J = 1.6 Hz, 1H), 6.86−6.85
(m, 2H), 3.56 (bs, 2H), 2.60 (t, J = 8.0 Hz, 2H), 1.63−1.55 (m, 2H),
1.28−1.19 (m, 6H), 0.82 (t, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 100
MHz) δ ppm 152.3, 140.1, 136.5, 122.4, 122.4, 37.2, 31.6, 30.0, 28.9,
22.4, 13.9; HRMS (EI) m/z calcd for C11H18N2 178.1470, found
178.1475.
3-Aminopyridine (18): yield 265 mg, 93%; peach-colored solid.
Spectral data are consistent with those of commercially obtained
material.
N5-Benzyl-N2,N2-dimethylpyridine-2,5-diamine (12): yield 168
mg, 74%; yellow solid; mp 69−70 °C; 1H NMR (CDCl3, 400 MHz) δ
ppm 7.74 (d, J = 2.9 Hz, 1H), 7.38−7.31 (m, 4H), 7.28−7.25 (m, 1H),
6.95 (dd, J = 8.9, 2.9 Hz, 1H), 6.48 (dd, J = 8.9, 0.6 Hz, 1H), 4.27 (s,
2H), 3.56 (brs, 1H), 2.99 (s, 6H); 13C NMR (CDCl3, 100 MHz) δ
ppm 154.2, 139.5, 135.6, 133.4, 128.6, 127.5, 127.2, 124.8, 107.0, 49.6,
38.9; HRMS (EI) m/z calcd for C14H17N3 227.1422, found 227.1419.
N5-Benzyl-N2,N2-dipentylpyridine-2,5-diamine (13): yield 294
mg, 87%; yellow needles; mp 32−33 °C; 1H NMR (CDCl3, 400
MHz) δ ppm 7.71 (d, J = 2.8 Hz, 1H), 7.38−7.28 (m, 5H), 6.92 (dd, J
= 9.0, 2.8 Hz, 1H), 6.36 (d, J = 9.0 Hz, 1H), 4.25 (s, 2H), 3.45 (brs,
1H), 3.34 (t, J = 7.6 Hz, 4H), 1.55 (qt, J = 7.6 Hz, 4H), 1.37−1.24 (m,
9H), 0.89 (t, J = 7.0 Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ ppm
152.5, 139.6, 134.7, 133.5, 128.3, 127.6, 126.9, 124.8, 106.1, 49.6, 48.8,
29.2, 27.4, 22.5, 14.0; HRMS (EI) m/z calcd for C22H33N3 339.2518,
found 339.2519.
N-Benzyl-6-methoxypyridin-3-amine (14): yield 133 mg, 62%;
white solid; mp 62−64 °C; 1H NMR (CDCl3, 400 MHz) δ ppm 7.59
(d, J = 2.8 Hz, 1H), 7.38−7.32 (m, 4H), 7.30−7.28 (m, 1H), 6.99 (dd,
J = 8.8, 2.8 Hz, 1H), 6.61 (dd, J = 8.8, 0.6 Hz, 1H), 4.29 (s, 2H), 3.86
(s, 3H); 13C NMR (CDCl3, 100 MHz) δ ppm 157.4, 139.1, 139.0,
130.4, 128.7, 127.5, 127.4, 125.8, 110.8, 53.3, 49.1; HRMS (EI) m/z
calcd for C13H14N2O 214.1106, found 214.1104.
2-(Phenethoxy)pyrimidin-5-amine (21): yield 109 mg, 51%;
1
white solid; mp 78−79 °C; H NMR ((CD3)2CO, 400 MHz) δ ppm
8.03 (s, 2H), 7.34−7.27 (m, 4H), 7.22−7.18 (m, 1H), 4.54 (brs, 1H),
4.40 (t, J = 7.1 Hz, 2H), 3.04 (t, J = 7.1 Hz, 2H); 13C NMR
((CD3)2CO, 100 MHz) δ ppm 146.8, 140.7, 130.9, 130.1, 128.0, 69.1,
37.1; HRMS (EI) m/z calcd for C12H13N3O 215.1059, found
215.1060.
2-(Cyclohexyloxy)pyrimidin-5-amine (22): yield 133 mg, 69%;
white solid; mp 94−96 °C; 1H NMR (CDCl3, 400 MHz) δ ppm 8.02
(s, 2H), 4.87−4.80 (m, 1H), 3.35 (brs, 2H), 2.01−1.97 (m, 2H),
1.81−1.76 (m, 2H), 1.58−1.49 (m, 3H), 1.43−1.22 (m, 3H); 13C
NMR (CDCl3, 100 MHz) δ ppm 159.2, 146.3, 134.7, 74.7, 31.7, 25.6,
23.8; HRMS (EI) m/z calcd for C10H15N3O 193.1215, found
193.1206.
2-(Hex-1-ynyl)pyrimidin-5-amine (23): yield 150 mg, 84%;
1
yellow solid; H NMR (CDCl3, 400 MHz) δ ppm 8.12 (s, 2H), 3.94
(brs, 2H), 2.39 (t, J = 7.0 Hz, 2H), 1.58 (qt, J = 7.0 Hz, 2H), 1.45 (qt,
J = 7.2 Hz, 2H), 0.89 (t, J = 7.2 Hz); 13C NMR (CDCl3, 100 MHz) δ
ppm 143.6, 142.7, 139.0, 87.4, 30.2, 22.0, 18.8, 13.5; HRMS (EI) m/z
calcd for C10H13N3 175.1109, found 175.1108.
6-Hexylpyrimidin-5-amine (24): yield 104 mg, 58%; off-white
1
solid; mp 107−108 °C; H NMR (CDCl3, 400 MHz) δ ppm 8.13 (s,
N-Benzyl-6-butoxypyridin-3-amine (15): yield 194 mg, 80%;
1
2H), 6.34 (brs, 2H), 2.81 (t, J = 7.7 Hz, 2H), 1.73 (qt, J = 7.7 Hz, 2H),
1.33−1.27 (m, 6H), 0.84 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100
MHz) δ ppm 161.9, 143.4, 137.7, 38.4, 31.6, 29.0, 28.9, 22.5, 14.0;
HRMS (EI) m/z calcd for C10H17N3 179.1423, found 179.1407.
5-Aminopyrimidine (25): yield 63 mg, 66%; pale-yellow solid.
Spectral data are consistent with those of commercially obtained
material.
reddish solid; mp 51−52 °C; H NMR (CDCl3, 400 MHz) δ ppm
7.60 (d, J = 2.8 Hz, 1H), 7.38−7.28 (m, 5H), 6.99 (dd, J = 8.8, 2.8 Hz,
1H), 6.63 (d, J = 8.8 Hz, 1H), 4.29 (s, 2H), 4.17 (t, J = 6.8 Hz, 2H),
3.79 (brs, 1H), 1.78 (qt, J = 7.2 Hz, 2H), 1.03 (t, J = 7.2 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) δ ppm 157.3, 139.0, 138.8, 130.5, 128.6,
127.4, 127.3, 125.6, 110.8, 67.4, 49.0, 22.4, 10.5; HRMS (EI) m/z
calcd for C16H20N2O 242.1419, found 242.1419.
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Deprotection of N-benzylamines. To a solution of benzyl-
protected amine (1.0 mmol) in EtOH (5 mL) degassed with argon
were added 10% Pd/C (10 wt %) and ammonium formate (5.0
mmol). The solution was heated to reflux until completion, as
determined by TLC. When complete, the solution was cooled, diluted
with EtOAc, and filtered through a pad of silica. No further
purification was attempted because of oxidative instability and
difficulty associated with chromatographing these compounds.
General Procedure for Synthesis of Diarylamines. To a
Schlenk flask were added 59 (or Pd2dba3, 0.005−0.02 mmol) and
XPhos (Pd/L = 1:2). The flask was evacuated and backfilled with
argon before degassed toluene (2 mL) was added and the solution
heated to 60 °C. After 10 min, ArBr (1.0 mmol), ArNH2 (1.1 mmol),
and NaOtBu (1.4 mmol) were added, and the reaction was heated to
the desired temperature. Once complete, the mixture was cooled and
quenched by filtering through Celite. Column chromatography
(EtOAc/hexanes eluent with 1−5% Et3N added depending on
substrate) afforded pure products.
N5-(4-(Dimethylamino)phenyl)-N2,N2-dimethylpyridine-2,5-
diamine (34): yield 159 mg, 62%; dark green solid; mp 111−112 °C;
1H NMR (CDCl3, 400 MHz) δ ppm 7.94 (d, J = 2.8 Hz, 1H), 7.28
(dd, J = 8.9, 2.8 Hz, 1H), 6.86−6.82 (m, 2H), 6.72−6.68 (m, 2H),
6.57 (dd, J = 8.9, 0.5 Hz, 1H), 6.39 (brs, 1H), 2.99 (s, 6H), 2.82 (s,
6H); 13C NMR (CDCl3, 100 MHz) δ ppm 157.2, 147.4, 141.2, 138.8,
133.5, 131.2, 119.7, 116.5, 107.8, 42.7, 39.6; HRMS (EI) m/z calcd for
C15H20N4 256.1688, found 256.1674.
N5-(4-(Dimethylamino)phenyl)-N2,N2-dimethylpyrimidine-
2,5-diamine (35): yield 223 mg, 87%; yellow needles; mp 116−117
1
°C; H NMR (DMSO-d6, 400 MHz) δ ppm 8.15 (s, 2H), 7.15 (brs,
1H), 6.74 (dd, J = 2.4, 6.8 Hz, 2H), 6.65 (dd, J = 2.4, 6.8 Hz, 2H), 3.07
(s, 3H), 2.77 (s, 3H); 13C NMR (DMSO-d6,100 MHz) δ ppm 158.0,
149.6, 144.7, 136.2, 128.8, 116.5, 114.5, 41.1, 37.0; HRMS (EI) m/z
calcd for C14H19N5 257.1640, found 257.1632.
N5-(6-(Dimethylamino)pyridin-3-yl)-N2,N2-dimethylpyridine-
2,5-diamine (36): yield 185 mg, 72%; pale-green plates; mp 113−114
°C; 1H NMR (CDCl3, 400 MHz) δ ppm 7.91 (d, J = 2.4 Hz, 2H), 7.15
(dd, J = 2.8, 8.8 Hz, 2H), 6.46 (d, J = 8.8 Hz, 2H), 4.96 (brs, 1H), 3.02
(s, 12H); 13C NMR (CDCl3,100 MHz) δ ppm 155.7, 139.1, 131.3,
121.4, 106.4, 38.7; HRMS (EI) m/z calcd for C14H19N5 257.1640,
found 257.1646.
N1,N1-Dimethyl-N4-phenylbenzene-1,4-diamine (26): yield
197 mg, 93%; off-white needles. Spectral data are consistent with
those in the literature.31
N1,N1-Dimethyl-N4-(pyridin-3-yl)benzene-1,4-diamine (27):
yield 158 mg, 74%; yellow needles; mp 145−147 °C; 1H NMR
((CD3)2CO, 400 MHz) δ ppm 8.23 (d, J = 2.6 Hz, 1H), 7.91 (dd, J =
4.5, 1.2 Hz, 1H), 7.20 (ddd, J = 8.3, 2.6, 1.2 Hz, 1H), 7.13 (brs, 1H),
7.10−7.06 (m, 3H), 6.79−6.75 (m, 2H), 2.89 (s, 6H); 13C NMR
((CD3)2CO, 100 MHz) δ ppm 149.3, 144.9, 140.9, 139.4, 133.4,
125.3, 124.6, 124.5, 121.1, 115.6, 42.1; HRMS (EI) m/z calcd for
C13H15N3 213.1266, found 213.1257.
N5-(6-(Dimethylamino)pyridin-3-yl)-N2,N2-diethylpyrimi-
dine-2,5-diamine (37): yield 260 mg, 91%; metallic green solid; mp
102−103 °C; 1H NMR (CDCl3, 400 MHz) δ ppm 8.11 (s, 2H), 7.87
(d, J = 2.8 Hz, 1H), 7.10 (dd, J = 2.8, 8.8 Hz, 1H), 6.46 (d, J = 8.8 Hz,
1H), 4.74 (brs, 1H), 3.58 (q, J = 7.0 Hz, 4H), 3.03 (s, 3H), 1.18 (t, J =
7.0 Hz, 6H); 13C NMR (acetone-d6, 100 MHz) δ ppm 159.5, 157.1,
152.0, 139.5, 134.2, 131.2, 129.5, 108.0, 43.5, 39.6, 14.5; HRMS (EI)
m/z calcd for C15H22N6 286.1906, found 286.1907.
N1,N1-Dipropyl-N4-(pyrimidin-5-yl)benzene-1,4-diamine
N5-(2-(Diethylamino)pyrimidin-5-yl)-N2,N2-diethylpyrimi-
dine-2,5-diamine (38): yield 246 mg, 78%; yellow needles; mp 72−
1
(28): yield 251 mg, 93%; greenish solid; mp 79−80 °C; H NMR
(DMSO-d6, 400 MHz) δ ppm 8.45 (s, 1H), 8.27 (s, 2H), 8.00 (brs,
1H), 7.02−6.98 (m, 2H), 6.66−6.61 (m, 2H), 3.19 (t, J = 7.4 Hz, 4H),
1.51 (sextet, J = 7.5 Hz, 4H), 0.88 (t, J = 7.4 Hz, 6H); 13C NMR
(DMSO-d6, 100 MHz) δ ppm 147.5, 144.5, 141.1, 140.8, 128.3, 122.7,
112.5, 52.2, 19.9, 11.2; HRMS (EI) m/z calcd for C16H22N4 270.1845,
found 270.1837.
1
73 °C; H NMR ((CD3)2CO, 400 MHz) δ ppm 8.11 (s, 4H), 6.24
(brs, 1H), 3.62 (q, 7.0 Hz, 8H), 1.14 (t, 7.0 Hz, 12H); 13C NMR
((CD3)2CO, 100 MHz) δ ppm 159.5, 151.3, 131.5, 43.5, 14.5; HRMS
(EI) m/z calcd for C16H25N7 315.2171, found 315.2150.
1
4-Butyl-N-phenylaniline (39): yield 213 mg, 95%; yellow oil; H
N1,N1-Dimethyl-N4-(pyridin-2-yl)benzene-1,4-diamine (29):
yield 170 mg, 80%; green solid; mp 129−130 °C; 1H NMR
(CDCl3, 400 MHz) δ ppm 8.13 (ddd, J = 5.0, 1.9, 0.9 Hz, 1H),
7.39 (ddd, J = 8.7, 7.2, 1.9 Hz, 1H), 7.18 (d, J = 8.7 Hz, 1H), 6.75 (d, J
= 8.6 Hz, 1H), 6.65−6.55 (m, 3H), 2.94 (s, 6H); 13C NMR (CDCl3,
100 MHz) δ ppm 158.0, 148.3, 148.1, 137.5, 129.6, 124.9, 113.7,
113.6, 106.7, 50.0; HRMS (EI) m/z calcd for C13H15N3 213.1266,
found 213.1260.
NMR (CDCl3, 400 MHz) δ ppm 7.27−7.23 (m, 2H), 7.10 (d, J = 6.0
Hz, 2H), 7.04−7.02 (m, 4H), 6.89 (t, J = 7.2 Hz, 1H), 5.68 (brs, 1H),
2.57 (t, J = 6.7 Hz, 2H), 1.63−1.57 (m, 2H), 1.37 (sextet, J = 7.4 Hz,
2H), 0.94 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ ppm
143.8, 140.4, 136.0, 129.3, 129.2, 120.3, 118.7, 116.9, 34.9, 33.8, 22.3,
14.0; HRMS (EI) m/z calcd for C16H19N 225.1517, found 225.1495.
6-Hexyl-N-phenylpyridin-3-amine (40): yield 223 mg, 88%; off-
white semisolid; 1H NMR (CDCl3, 400 MHz) δ ppm 8.31 (d, J = 2.4
Hz, 1H), 7.37 (dd, J = 8.4, 2.5 Hz, 1H), 7.28−7.23 (m, 2H), 7.04−
7.00 (m, 3H), 6.93 (tt, J = 7.4, 1.0 Hz, 1H), 5.92 (brs, 1H), 2.73 (t, J =
7.8 Hz, 2H), 1.70 (qt, J = 7.4 Hz, 2H), 1.37−1.26 (m, 6H), 0.88 (t, J =
6.9 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ ppm 155.0, 142.9, 140.1,
137.1, 129.4, 125.4, 122.5, 121.0, 117.1, 37.5, 31.7, 30.0, 29.0, 22.5,
14.0; HRMS (EI) m/z calcd for C17H22N2 254.1783, found 254.1796.
2-Heptyl-N-phenylpyrimidin-5-amine (41): yield 223 mg, 83%;
N1,N1-Dipropyl-N4-(pyrimidin-2-yl)benzene-1,4-diamine
1
(30): yield 121 mg, 45%; dark green solid; mp 84−86 °C; H NMR
(CDCl3, 400 MHz) δ ppm 8.33 (d, J = 4.8 Hz, 2H), 7.34−7.30 (m,
2H), 6.97 (brs, 1H), 6.62−6.22 (m, 2H), 6.59 (t, J = 4.8 Hz, 1H), 3.21
(t, J = 7.6 Hz, 4H), 1.65−1.55 (m, 4H), 0.92 (t, J = 7.4 Hz, 6H); 13C
NMR (CDCl3, 100 MHz) δ ppm 161.2, 158.1, 145.4, 127.2, 123.4,
112.3, 111.4, 53.2, 20.4, 11.4; HRMS (EI) m/z calcd for C16H22N4
270.1844, found 270.1864.
1
off-white solid; mp 71−72 °C; H NMR (CDCl3, 400 MHz) δ ppm
N2,N2-Dimethyl-N5-phenylpyridine-2,5-diamine (31): yield
200 mg, 94%; yellow solid; mp 134−136 °C; 1H NMR (CDCl3,
400 MHz) δ ppm 8.07 (d, J = 2.6 Hz, 1H), 7.36 (dd, J = 8.9, 2.7 Hz,
1H), 7.20−7.16 (m, 2H), 6.80−6.76 (m, 3H), 6.54 (d, J = 9.3 Hz,
1H), 5.35 (brs, 1H), 3.09 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
ppm 156.7, 146.5, 143.6, 133.9, 129.3, 127.5, 118.8, 114.3, 106.1, 38.5;
HRMS (EI) m/z calcd for C13H15N3 213.1266, found 213.1275.
N2,N2-Dimethyl-N5-phenylpyrimidine-2,5-diamine (32): yield
8.49 (s, 2H), 7.30 (t, J = 7.5 Hz, 2H), 7.04 (d, J = 7.5 Hz, 2H), 7.01 (t,
J = 7.4 Hz, 1H), 5.61 (brs, 1H), 2.90 (t, J = 7.7 Hz, 2H), 1.80 (qt, J =
7.6 Hz, 2H), 1.41−1.27 (m, 8H), 0.87 (t, J = 6.8 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ ppm 164.0, 146.4, 141.6, 135.3, 129.7, 122.3,
117.8, 38.6, 31.8, 29.4, 29.1, 28.9, 22.6, 14.1; HRMS (EI) m/z calcd for
C17H23N3 269.1892, found 269.1873.
N-Phenylpyridin-5-amine (42): yield 160 mg, 94%; peachy solid;
mp 139−140 °C; 1H NMR (CDCl3, 400 MHz) δ ppm 8.38 (d, J = 2.8
Hz, 1H), 8.16 (dd, J = 4.6, 1.2 Hz, 1H), 7.41 (ddd, J = 8.3, 2.8, 1.2 Hz,
1H), 7.33−7.28 (m, 2H), 7.16 (ddd, J = 8.3, 4.6, 0.4 Hz, 1H), 7.10−
7.07 (m, 2H), 6.99 (tt, J = 7.4, 1.1 Hz, 1H), 5.88 (brs, 1H); 13C NMR
(CDCl3, 100 MHz) δ ppm 141.9, 141.8, 140.1, 139.8, 129.5, 123.7,
123.4, 122.0, 118.3; HRMS (EI) m/z calcd for C11H10N2 170.0844,
found 170.0820.
1
199 mg, 93%; yellow solid; mp 111−112 °C; H NMR (CDCl3, 400
MHz) δ ppm 8.26 (s, 2H), 7.21−7.16 (m, 2H), 6.80 (tt, J = 7.3, 1.0
Hz, 1H), 6.73−6.70 (m, 2H), 5.23 (brs, 1H), 3.20 (s, 6H); 13C NMR
(CDCl3, 100 MHz) δ ppm 159.9, 155.0, 146.4, 129.4, 125.3, 119.1,
113.9, 37.4; HRMS (EI) m/z calcd for C12H14N4 214.1218, found
214.1197.
N1-(4-(Dimethylamino)phenyl)-N4,N4-dimethylbenzene-1,4-
diamine (33): yield 226 mg, 89%; beige solid. Spectral data are
consistent with those in the literature.32
N-Phenylpyrimidin-5-amine (43): yield 140 mg, 82%; white
solid; mp 214−215 °C; 1H NMR ((CD3)2CO, 400 MHz) δ ppm 8.61
(s, 1H), 8.55 (d, J = 1.6 Hz, 2H), 7.72 (brs, 1H), 7.35−7.30 (m, 2H),
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7.20−7.18 (m, 2H), 6.99 (tt, J = 7.4, 1.0 Hz, 1H); 13C NMR
((CD3)2CO, 100 MHz) δ ppm 152.0, 146.1, 143.6, 140.8, 131.4,
123.9, 120.1; HRMS (EI) m/z calcd for C10H9N3 171.0796, found
171.0789.
N-(4-Butylphenyl)pyridin-3-amine (44): yield 165 mg, 73%;
pale yellow solid; mp 78−79 °C; 1H NMR (CDCl3, 400 MHz) δ ppm
8.33 (d, J = 2.8 Hz, 1H), 8.11 (dd, J = 4.6, 1.2 Hz, 1H), 7.35 (ddd, J =
8.2, 2.8, 1.2 Hz, 1H), 7.16−7.11 (m, 3H), 7.02 (dt, J = 8.4, 2.2 Hz,
2H), 5.67 (brs, 1H), 2.58 (t, J = 7.8 Hz, 2H), 1.63−1.55 (m, 2H), 1.36
(sextet, J = 7.4 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ ppm 140.9, 140.6, 139.1, 137.3, 129.4, 123.7, 122.6,
119.3, 100.0, 34.9, 33.8, 22.3, 14.0; HRMS (EI) m/z calcd for
C15H18N2 226.1470, found 226.1469.
N-(4-Butylphenyl)pyrimidin-5-amine (45): yield 140 mg, 62%;
off-white solid; mp 161−162 °C; 1H NMR (CDCl3, 400 MHz) δ ppm
8.72 (s, 1H), 8.49 (s, 2H), 7.17 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.4
Hz, 2H), 5.76 (brs, 1H), 2.60 (t, J = 7.7 Hz, 2H), 1.64−1.56 (m, 2H),
1.36 (sextet, J = 7.5 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ ppm 149.6, 143.8, 139.2, 138.7, 137.5, 129.7,
120.1, 35.0, 33.7, 22.3, 13.9; HRMS (EI) m/z calcd for C14H17N3
227.1422, found 227.1421.
Bis(4-octylphenyl)amine (46): yield 350 mg, 86%; beige solid.
Spectral data are consistent with those reported in the literature.33
N-(4-Butylphenyl)-6-hexylpyridin-3-amine (47): yield 192 mg,
62%; pale yellow solid; mp 39−40 °C; 1H NMR (CDCl3, 400 MHz) δ
ppm 8.28 (d, J = 2.6 Hz, 1H), 7.32 (dd, J = 8.4, 2.8 Hz, 1H), 7.08 (d, J
= 8.4 Hz, 2H), 7.02 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 8.4, 2.8 Hz, 2H),
5.60 (brs, 1H), 2.72 (t, J = 7.8 Hz, 2H), 2.56 (d, J = 7.6 Hz, 2H),
1.73−1.68 (m, 2H), 1.62−1.54 (m, 2H), 1.40−1.29 (m, 8H), 0.93 (d, J
= 7.3 Hz, 3H), 0.88 (d, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
δ ppm 154.4, 140.2, 139.3, 137.8, 136.3, 129.3, 124.6, 122.6, 118.1,
37.4, 34.9, 33.8, 31.7, 30.1, 29.1, 22.6, 22.3, 14.1, 14.0; HRMS (EI) m/
z calcd for C21H30N2 310.2409, found 310.2406.
((CD3)2SO, 100 MHz) δ ppm 141.2, 139.4, 139.1, 123.8, 122.7;
HRMS (EI) m/z calcd for C10H9N3 171.0797, found:171.0787.
Dipyrimidin-5-ylamine (53): yield 133 mg, 77%; off-white solid;
1
mp 226−228 °C; H NMR ((CD3)2SO, 400 MHz) δ ppm 8.88 (brs,
1H), 8.75 (s, 2H), 8.66 (s, 4H); 13C NMR ((CD3)2SO, 100 MHz) δ
ppm 150.9, 145.0, 137.0; HRMS (EI) m/z calcd for C8H7N5 173.0702,
found 173.0692.
4-Methoxy-N-phenylaniline (54): yield 179 mg, 90%; white
solid. Spectral data are consistent with those reported in the
literature.34
6-Methoxy-N-phenylpyridin-3-amine (55): yield 186 mg, 93%;
yellow oil; 1H NMR (CDCl3, 400 MHz) δ ppm 8.00 (dd, J = 2.8, 0.4
Hz, 1H), 7.45 (dd, J = 8.8, 2.8 Hz, 1H), 7.25−7.20 (m, 2H), 6.88−
6.84 (m, 3H), 6.72 (dd, J = 8.8, 0.4 Hz, 1H), 5.44 (brs, 1H), 3.93 (s,
3H); 13C NMR (CDCl3, 100 MHz) δ ppm 160.2, 144.8, 139.7, 133.2,
132.8, 129.4, 120.0, 115.4, 111.0, 53.5; HRMS (EI) m/z calcd for
C12H12N2O 200.0950, found 200.0934.
2-(Cyclohexyloxy)-N-phenylpyrimidin-5-amine (56): yield 153
1
mg, 57%; white needles; mp 164−165 °C; H NMR (CDCl3, 400
MHz) δ ppm 8.38 (s, 2H), 7.26−7.22 (m, 2H), 6.92−6.86 (m, 3H),
5.39 (brs, 1H), 4.98−4.91 (m, 1H), 2.07−2.03 (m, 2H), 1.86−1.80
(m, 2H), 1.65−1.57 (m, 5H), 1.47−1.26 (m, 3H); 13C NMR (CDCl3,
100 MHz) δ ppm 161.0, 152.7, 144.0, 131.3, 129.6, 120.7, 115.5, 75.4,
31.6, 25.5, 23.9; HRMS (EI) m/z calcd for C16H19N3O 269.1528,
found 269.1520.
N-(4-Methoxyphenyl)pyridin-3-amine (57): yield 196 mg, 98%;
pale red solid; mp 123−125 °C; 1H NMR (CDCl3, 400 MHz) δ ppm
8.25 (d, J = 2.4 Hz, 1H), 8.06 (dd, J = 4.7, 1.3 Hz, 1H), 7.20 (ddd, J =
8.3, 2.4, 1.3 Hz, 1H), 7.10 (d, J = 4.7 Hz, 1H), 7.09−7.06 (m, 2H),
6.90−6.86 (m, 2H), 5.58 (brs, 1H), 3.81 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ ppm 155.9, 141.7, 140.66, 140.64, 138.4, 134.3, 123.6,
122.7, 121.1, 114.8, 55.5; HRMS (EI) m/z calcd for C12H12N2O
200.0950, found 200.0932.
N-(4-Butylphenyl)-2-hexylpyrimidin-5-amine (48): yield 261
mg, 84%; off white solid; mp 73−74 °C; 1H NMR (CDCl3, 400 MHz)
δ ppm 8.44 (s, 2H), 7.12 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H),
5.54 (brs, 1H), 2.88 (t, J = 7.8 Hz, 2H), 2.57 (t, J = 7.7 Hz, 2H), 1.79
(qt, J = 7.7 Hz, 2H), 1.62−1.55 (m, 2H), 1.40−1.30 (m, 8H), 0.93 (d,
J = 7.3 Hz, 3H), 0.88 (d, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100
MHz) δ ppm 154.3, 140.2, 139.4, 137.8, 136.2, 129.3, 124.5, 122.5,
118.0, 37.5, 34.9, 33.7, 31.7, 30.0, 29.0, 22.5, 22.3, 14.0, 13.9; HRMS
(EI) m/z calcd for C20H29N3 311.2362, found 311.2360.
N-(4-Methoxyphenyl)pyrimidin-5-amine (58): yield 175 mg,
87%; purple needles; mp 211−212 °C; H NMR (CDCl3, 400 MHz)
δ ppm 8.69 (s, 1H), 8.35 (s, 2H), 7.13−7.09 (m, 2H), 6.93−6.89 (m,
2H), 5.47 (brs, 1H), 3.82 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
ppm 156.7, 1450.0, 143.0, 139.9, 132.7, 123.4, 115.1, 55.6; HRMS (EI)
m/z calcd for C11H11N3O 201.0902, found 201.0904.
Bis(4-methoxyphenyl)amine (59): yield 219 mg, 96%; white
needles. Spectral data are consistent with those reported in the
literature.35
1
Bis(6-hexylpyridin-3-yl)amine (49): yield 288 mg, 85%; light red
solid; mp 44−45 °C; 1H NMR (CDCl3, 400 MHz) δ ppm 8.27 (d, J =
2.8 Hz, 2H), 7.29 (dd, J = 8.4, 2.8 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H),
5.96 (brs, 1H), 2.71 (t, J = 7.8 Hz, 4H), 1.68 (qt, J = 7.8 Hz, 4H),
1.35−1.28 (m, 12H), 0.86 (t, J = 6.8 Hz, 6H); 13C NMR (CDCl3, 100
MHz) δ ppm 155.4, 139.7, 136.9, 124.8, 122.7, 37.5, 31.7, 30.0, 29.0,
22.5, 14.0; HRMS (EI) m/z calcd for C22H33N3 339.2674, found
339.2685.
6-Methoxy-N-(4-methoxyphenyl)pyridin-3-amine (60): yield
133 mg, 58%; reddish oil; H NMR (CDCl3, 400 MHz) δ ppm 7.89
1
(d, J = 2.8 Hz, 1H), 7.31 (dd, J = 8.8, 2.8 Hz, 1H), 6.90−6.87 (m, 2H),
6.83−6.80 (m, 2H), 6.67 (d, J = 8.8 Hz, 1H), 5.32 (brs, 1H), 3.90 (s,
3H), 3.77 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ ppm 159.1, 154.4,
137.4, 136.6, 134.9, 130.7, 119.2, 114.8, 110.8, 55.6, 53.5; HRMS (EI)
m/z calcd for C13H14N2O2 230.1055, found 230.1042.
2-Phenethoxy-N-(4-phenethoxyphenyl)pyrimidin-5-amine
1
(61): yield 345 mg, 84%; white solid; mp 143−144 °C; H NMR
2-Heptyl-N-(6-hexylpyridin-3-yl)pyrimidin-5-amine (50):
1
(CDCl3, 400 MHz) δ ppm 8.29 (d, J = 1.2 Hz, 2H), 7.35−7.29 (m,
8H), 7.23−7.20 (m, 2H), 7.02−6.98 (m, 2H), 6.90−6.86 (m, 2H),
4.47 (t, J = 7.0 Hz, 2H), 4.17 (t, J = 6.9 Hz, 2H), 3.09−3.04 (m, 4H);
13C NMR (CDCl3, 100 MHz) δ ppm 155.7, 150.2, 141.2, 136.6, 130.9,
130.2, 128.1, 121.0, 117.4, 70.7, 69.5, 37.4, 37.0; HRMS (EI) m/z
calcd for C26H25N3O2 411.1947, found 411.1931.
yield 250 mg, 71%; white solid; mp 64−65 °C; H NMR (CDCl3,
400 MHz) δ ppm 8.44 (s, 2H), 8.33 (d, J = 2.8 Hz, 1H), 7.35 (d, J =
8.4, 2.8 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 5.69 (brs, 1H), 2.90 (t, J =
7.8 Hz, 2H), 2.75 (d, J = 7.8 Hz, 2H), 1.83−1.67 (m, 4H), 1.39−1.27
(m, 14H), 0.89−0.85 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ ppm
164.5, 156.5, 146.0, 140.1, 135.8, 135.0, 125.5, 123.0, 38.7, 37.5, 31.8,
31.7, 29.9, 29.3, 29.1, 29.0, 28.9, 22.63, 22.57, 14.07, 14.06; HRMS
(EI) m/z calcd for C22H34N4 354.2784, found 354.2773.
Bis(6-methoxypyridin-3-yl)amine (62): yield 226 mg, 98%; pale
1
yellow oil; H NMR ((CD3)2CO, 400 MHz) δ ppm 7.89 (d, J = 2.8
Bis(2-heptylpyrimidin-5-yl)amine (51): yield 299 mg, 81%;
Hz, 2H), 7.41 (dd, J = 8.8, 2.8 Hz, 2H), 6.96 (brs, 1H), 6.69 (d, J = 8.8
Hz, 2H), 3.83 (s, 6H); 13C NMR ((CD3)2CO, 100 MHz) δ ppm
160.8, 137.7, 137.2, 131.6, 112.5, 54.4; HRMS (EI) m/z calcd for
C12H13N3O2 231.1008, found 231.0996.
1
white solid; mp 103−104 °C; H NMR (CDCl3, 400 MHz) δ ppm
8.48 (s, 4H), 5.58 (brs, 1H), 2.92 (t, J = 7.6 Hz, 4H), 1.84−1.76 (m,
4H), 1.36−1.28 (m, 16H), 0.87 (t, J = 6.4 Hz, 6H); 13C NMR
(CDCl3, 100 MHz) δ ppm 165.5, 146.6, 134.1, 38.7, 31.7, 29.3, 29.1,
28.8, 22.6, 14.1; HRMS (EI) m/z calcd for C22H35N5 369.2893, found
369.2892.
N-(6-Butoxypyridin-3-yl)-2-phenethoxypyrimidin-5-amine
1
(63): yield 156 mg, 43%; off-white solid; H NMR ((CD3)2CO, 400
MHz) δ ppm 8.30 (d, J = 1.2 Hz, 2H), 7.92 (d, J = 2.9 Hz, 1H), 7.48
(dd, J = 8.8, 2.9 Hz, 1H), 7.35−7.29 (m, 4H), 7.23−7.19 (m, 1H),
7.05 (brs, 1H), 6.71 (d, J = 8.5 Hz, 1H), 4.48 (t, J = 7.0 Hz, 2H), 4.24
(d, J = 6.6 Hz, 2H), 3.08 (t, J = 7.0 Hz, 2H), 1.75−1.68 (m, 2H), 1.47
(st, J = 7.5 Hz, 2H), 0.96 (t, J = 7.4 Hz, 3H); 13C NMR ((CD3)2CO,
Dipyridin-3-ylamine (52): yield 152 mg, 89%; off-white solid; mp
129−131 °C; 1H NMR ((CD3)2SO, 400 MHz) δ ppm 8.56 (brs, 1H),
8.37 (d, J = 2.4 Hz, 2H), 8.08 (dd, J = 4.6, 1.2 Hz, 2H), 7.50 (ddd, J =
8.3, 2.4, 1.2 Hz, 2H), 7.26 (dd, J = 8.3, 4.6 Hz, 2H); 13C NMR
6915
dx.doi.org/10.1021/jo301013c | J. Org. Chem. 2012, 77, 6908−6916

The Journal of Organic Chemistry
Article
100 MHz) δ ppm 162.0, 161.2, 150.2, 140.6, 138.7, 138.6, 136.4,
136.3, 135.6, 135.9, 132.26, 132.13, 130.9, 130.2, 128.1, 112.8, 69.5,
67.1, 37.0, 33.0, 21.0, 15.1; HRMS (EI) m/z calcd for C21H24N4O2
364.1899, found 364.1895.
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ASSOCIATED CONTENT
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(28) Patriciu, O. I.; Finaru, A. L.; Massip, S.; Leger, J. M.; Jarry, C.;
Guillaumet, G. Eur. J. Org. Chem. 2009, 3753.
S
* Supporting Information
Nuclear magnetic resonance spectra for compounds 12−63.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(29) Fraser, A. W.; Besaw, J. E.; Hull, L. E.; Baird, M. C.
Organometallics 2012, 31, 2470.
(30) Amatore, C.; Jutand, A. Coordin. Chem. Rev. 1998, 178, 511.
(31) Hill, L. L.; Smith, J. A.; Brown, W. S.; Moore, L. R.; Guevera, P.;
Pair, E. S.; Porter, J.; Chou, J.; Wolterman, C. J.; Craciun, R.; Dixon, D.
A.; Shaughnessy, K. H. Tetrahedron 2008, 64, 6920.
(32) Pratt, D. A.; DiLabio, G. A.; Valgimigli, L.; Pedulli, G. F.; Ingold,
K. U. J. Am. Chem. Soc. 2002, 124, 11085.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dpratt@uottawa.ca.
(33) Tasios, N.; Grigoriadis, C.; Hansen, M. R.; Wonneberger, H.; Li,
C.; Spiess, H. W.; Mullen, K.; Floudas, G. J. Am. Chem. Soc. 2010, 132,
7478.
Notes
The authors declare no competing financial interest.
(34) Carroll, M. A.; Wood, R. A. Tetrahedron 2007, 63, 11349.
(35) McNulty, J.; Cheekoori, S.; Bender, T. P.; Coggan, J. A. Eur. J.
Org. Chem. 2007, 1423.
ACKNOWLEDGMENTS
■
We are grateful for the support of the Natural Sciences and
Engineering Research Council of Canada, the Ontario Ministry
of Research and Innovation, and the Canada Research Chairs
program for grants to D.A.P. L.V. thanks the University of
Bologna and MIUR (Rome) for grants. Lastly, we acknowledge
Michael Baird and Andrew Fraser of Queen’s University for
kindly providing a sample of 65 for use in preliminary
experiments.
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