Regioselective 2-Amination of Polychloropyrimidines

Article abstract of DOI:10.1021/acs.orglett.6b00799

The regioselective amination of substituted di- and trichloropyrimidines affording the 2-substituted products is reported. While aryl- and heteroarylamines require the use of a dialkylbiarylphosphine-derived palladium catalyst for high efficiency, more nucleophilic dialkylamines produce 2-aminopyrimidines under noncatalyzed S_NAr conditions. The key is the use of 5-trimethylsilyl-2,4-dichloropyrimidine as a surrogate for the parent dichloropyrimidine. For more challenging cases, the 2-chloro-4-thiomethoxy analogues were prepared and exclusively afford the desired 2-aminated-4-thiomethoxypyrimidine products.

Full text of DOI:10.1021/acs.orglett.6b00799

Letter
pubs.acs.org/OrgLett
Regioselective 2‑Amination of Polychloropyrimidines
Sean M. Smith and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139,
United States
S
* Supporting Information
ABSTRACT: The regioselective amination of substituted di-
and trichloropyrimidines affording the 2-substituted products
is reported. While aryl- and heteroarylamines require the use of
a dialkylbiarylphosphine-derived palladium catalyst for high
efficiency, more nucleophilic dialkylamines produce 2-amino-
pyrimidines under noncatalyzed SNAr conditions. The key is
the use of 5-trimethylsilyl-2,4-dichloropyrimidine as a
surrogate for the parent dichloropyrimidine. For more
challenging cases, the 2-chloro-4-thiomethoxy analogues were
prepared and exclusively afford the desired 2-aminated-4-
thiomethoxypyrimidine products.
olysubstituted pyridimines,1 especially 2- and 4-amino-
2
Ppyrimidines, constitute important biological and pharma-
ceutical compounds that are being increasingly studied in
materials research. Yet, despite their demonstrated importance,
general methods for the selective preparation of 2- and 4-
aminopyridimines from simple starting materials remain under-
developed. Our laboratory has long been interested in the use of
palladium catalysis for the catalytic formation of carbon−
nitrogen bonds, particularly within the context of the selective
functionalization of heterocycles. Using this approach, the site-
selective coupling between an amine and a 2,4-dichloropyr-
idimine derivative represents an attractive and potentially
generalizable route to access 2- or 4-aminopyridimines.
Figure 1. Regioselective amination of substituted 2,4-dichloropyrimi-
dines.
Importantly, the 2- and 4-aminopyridimine products accessed
by such a strategy contain a reactive aryl-chloride bond that is
available for further synthetic manipulation.
The major challenge associated with selective 2- or 4-
aminopyridimine synthesis via palladium-catalyzed amination is
the discrimination of the two aryl-chloride bonds in 2,4-
dichloropyridimine compounds.3 A number of previous studies
from other laboratories have highlighted the often poor levels of
regioselectivity observed when utilizing such an approach.4,5
Peng recently described the most general reported method for
the highly selective synthesis of 4-amino-2-chloropyridimine
compounds: a 6-aryl substituent is required for such selectivity
(Figure 1).6 However, no general method for the synthesis of 2-
amino-4-chloropyridimine derivatives from 2,4-dichloropyrimi-
dines has been reported to date.7 This is primarily a consequence
of the inherent reactivity of 2,4-dichloropyridimine compounds,
which tend to undergo substitution at the more reactive 4-
position.5 We describe herein several strategies to access a variety
of 2-amino-4-chloropyridimines selectively.
we screened these and other phosphine ligands in an attempt to
identify a catalyst system capable of the selective amination at the
2-position of 2,4-dichloropyridimine. No catalyst system was
found to override the inherent tendency toward 4-substitution of
2,4-dichloropyridimine. We speculated that placement of a
suitable substituent at the 5-position of the pyridimine ring,
together with the use of larger dialkylbiarylphosphines, might
direct the reaction to the desired 2-position due to these
combined steric effects (Figure 1). We reasoned that a 5-
trimethylsilyl (TMS) group would be ideal for this substrate-
guided approach given (a) its ease of incorporation; (b) its large
size and hence its ability to direct reactions away from its adjacent
positions; and (c) its ease of removal (vide infra) and thus
potential as a traceless directing group. We therefore prepared
2,4-dichloro-5-(trimethylsilyl)pyrimidine (1) by simple silyla-
As part of our work on C−N cross-coupling methods, we have
developed a family of dialkylbiarylphosphine ligands that have
found widespread use in the amination of heterocycles.8 Initially,
Received: March 18, 2016
© XXXX American Chemical Society
A
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Letter
tion of the 5-bromo derivative (85%, Table 1) and began our
amination studies.
Scheme 1. Regioselective Amination of 1 by Aryl and
Heteroarylamines
a
a
Table 1. Regioselective Amination of 1 by Aniline
entry
P:L
solvent
temp (°C)
2a yield (%)
1
no catalyst
no catalyst
P1:L1
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
THF
80
22
32
34
39
45
35
2
100
80
3
4
P2:L2
80
5
P3:L3
80
6
P4:L4
80
b
bc
,
a
7
P5:L5
80
83, 78
All regioselectivities were >99:1 2-:4-aminated product and were
determined by GC analysis of the crude reaction material. Isolated
8
P5:L5
80
65
73
71
<3
b
yields are reported and are an average of two runs. Reaction was run
at 80 °C. Reaction was run at 100 °C.
9
P5:L5
CPME
100
100
60
c
10
11
P5:L5
toluene
P5:L5
NMP
a
Reaction conditions unless otherwise noted: 1 (0.25 mmol), aniline
(56−64%). Five-membered heterocycles, such as substituted
aminopyrazole and aminobenzothiazole, afforded 2h and 2i (60
and 51% yields, respectively) with no formation of regioisomer
observed.
When secondary amines were employed as coupling partners,
they were found to proceed efficiently under noncatalyzed
nucleophilic aromatic substitution conditions. For example,
using N-methylaniline as a coupling partner without a palladium
catalyst afforded 2j in 67% yield (Scheme 2). Addition of P6:L6
(RuPhos) combination provided a minor increase in yield (84%,
> 99:1 regioselectivity).8a,12
(0.28 mmol), Cs2CO3 (0.38 mmol), P (2.5 μmol), L (2.5 μmol), and
solvent (0.5 mL). Yields are expressed as an average of two runs and
1
were determined by H NMR analysis of the crude reaction mixture.
b
c
Represents isolated yield as an average of two runs. Reactions were
run on a 1.0 mmol scale.
Given the susceptibility of electron-deficient pyrimidines such
as 1 toward nucleophilic aromatic substitution,4,5 noncatalyzed
amination was first explored. Thus, 1 in combination with
Cs2CO3 and aniline in 2-MeTHF gave 2a in low yield at both 80
and 100 °C (Table 1, entries 1 and 2, respectively) with
noticeable formation of the minor 4-substituted regioisomer (3−
4%). Little improvement was realized with palladium precatalysts
P1−P39 in conjunction with dialkylbiaryl phosphines L1−L3
(34−35%, entries 3−5). Catalyst system P4:L4, which previously
has demonstrated high efficiency in C−N cross-coupling
reactions of primary amines,10 also yielded pyrimidine 2a in
low yield (35%, entry 6). The yield was greatly improved with P5
in combination with L5 (tBuBrettPhos, 1:1 ratio, 1 mol %),
giving 2a in 83% yield with no formation of the 4-substituted
product (entry 7) observed. Using P5:L5, no improvement in
yield was observed employing other ethereal solvents such as
THF or CPME (entries 8 and 9) or aromatic solvents such as
toluene (entry 10). More polar solvents (NMP, entry 11)11
resulted in greatly diminished yields of 2a.
Scheme 2. Noncatalyzed and Palladium-Catalyzed Amination
a
of 1 with Secondary Amines
Having identified P5:L5 as a highly active catalyst system for
the 2-selective amination of 1, the reactions of a series of other
aryl and heteroarylamine cross-coupling amines were evaluated.
Amination of 1 with p-toluidine under the optimized conditions
led to exclusive formation of 2b in high yield (81%, Scheme 1).
More electron-deficient arylamines gave the respective 2-
substituted products 2c and 2d in reasonable yield (69−75%).
Electron-deficient heteroarylamines also served as good cross-
coupling partners, resulting in the exclusive formation of the
respective 2-aminated products 2e−2g in slightly lower yields
a
Regioselectivities were determined by GC analysis of the crude
reaction material. Isolated yields are reported and are an average of
two independent runs. Reaction was run with 1% P6:L6.
b
B
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This nucleophilic aromatic substitution protocol was ame-
nable to a broad range of amine coupling partners. Amination of
1 by more nucleophilic piperidine afforded 2k in excellent yield
and regioselectivity (97%, >99:1) in the absence of a palladium
catalyst. Additionally, sterically encumbered 2-methylpiperidine
as well as morpholine, N-Boc-protected piperazine, and acyclic
N,N-dibutylamine produced the respective 2-aminated products
2l−2o in excellent yields and exceptional levels of regioselectivity
(95−98%, 97:3−99:1 2-/4-aminated product). Nucleophilic
aromatic substitution by pyrrolidine gave 2p with slightly
diminished regioselectivity (92:8), likely a consequence of its
relatively smaller size. The regioselectivity of this transformation
was improved to 97:3 (2-/4-aminated product) when P6:L6 was
included in the reaction.
Scheme 4. Regioselective Amination of Substituted Di- and
Trichloropyrimidines
a
Amination of trichloropyrimidine analogue 3 by morpholine
afforded the 2-aminopyrimidine regioisomer 4 in high yield and
regioselectivity (80%, >99:1 regioselectivity, Scheme 3).
a
Regioselectivities were determined by GC analysis of the crude
reaction material. Isolated yields are reported as an average of two
independent runs. Reaction was run with 2% P5:L5.
Scheme 3. Amination and Subsequent Functional Group
Elaboration of 1 and 3
b
again, lower regioselectivity was observed for 5-allyl-2,4,6-
trichloropyrimidine compared to the 5-TMS analogue.
As highlighted by the results with substrates 12 and 14,
relatively smaller 5-substituents on the pyrimidine ring have a
detrimental effect on the levels of 2-selectivity in the amination of
polychloropyrimidines. In the complete absence of a 5-
substituent (15), the 4-aminated product 16 predominates
(64%), with only 20% of the desired 2-aminated regioisomer
formed (Scheme 5).
Scheme 5. Amination of 2-Chloro-4-thiomethoxypyrimidine
(17)
Protodesilylation of 4 produced heterocycle 5 (84%),14
a
dichloropyrimidine that has demonstrated high efficiency in
C−C cross-couplings to provide access to 4,6-di(hetero)aryl-2-
morpholinopyrimidines.15
Additional synthetic utility of the products accessed via this
method is also highlighted in Scheme 3. For example, the 5-TMS
blocking group used in substrate 2k was cleanly cleaved by
treatment with TBAF (6, 93%). Desilylated pyrimidine 6 was
then coupled to PhB(OH)2 to afford 8 (82%), demonstrating the
value of this method for accessing 4-aryl-2-aminopyrimidine
structures in a regioselective manner. Additionally, 2k was
smoothly converted to the 5-iodopyrimidine analogue 7 by
reaction with ICl in CCl4 (96%).13
A variety of other 5-substituted dichloropyrimidines showed
the same preference for 2-amination as 1. For instance, amination
of dichloropyrimidines containing 5-TES, i-Pr, and Ph
substitution with aniline using P5:L5 gave the respective 2-
aminated products 9−11 (65−80%, Scheme 4). A noticeably
lower yield and selectivity were observed for the amination of
2,4-dichloro-5-methylpyrimidine (44% and 3:1 2-/4-substituted
pyrimidine). The lower yield of 12 is most likely explained by the
relatively smaller size of the 5-methyl substituent. Aminated
products 13 and 14 were obtained in high yield (75 and 85%,
respectively) from 5-substituted trichloropyrimidines. Once
To overcome the inherent preference for 4-substitution of
unbiased 2,4-dichloropyrimidines, a thiomethoxy substituent
was installed at the 4-position of 15 by nucleophilic aromatic
substitution with NaSMe (17, 72%, Scheme 5). Numerous
examples of metal-mediated aryl- and heteroaryl-SMe activation
in C−C cross-coupling led us to believe that we could carry out 2-
amination by piperidine followed by palladium-catalyzed C−C
cross-coupling at the 4-position.16 Amination of 17 by piperidine
gave 2-amino-4-thiomethoxypyrimidine 18 in excellent yield
(94%) followed by conversion to 8 (63%) via palladium-
catalyzed C−C cross-coupling.
We also utilized the 4-thiomethoxy-installation strategy for the
2-selective palladium-catalyzed amination of 6-substituted
pyrimidine substrates 20 and 21 (products 23 and 24, Figure
2). Products 23 and 24 were obtained with complete 2-
selectivity, as compared to 2,4-dichloropyrimidine substrate 19,
which led to a mixture of the 2- and 4-aminated pyrimidine
products (22, 40%, 1:2 2-/4-aminopyrimidine).
C
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Letter
(2) (a) Selvam, T. P.; James, C. R.; Dniandev, P. V.; Valzita, S. K. Res.
Pharm. 2012, 2, 1. (b) Tavares, F. X.; Boucheron, J. A.; Dickerson, S. H.;
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and references cited therein.
Figure 2. Selective palladium-catalyzed amination of substituted 2-
chloro-4-thiomethoxypyrimidines.
(3) For reviews on regioselective cross-couplings of polyhalogenated
heterocycles, see: (a) Rossi, R.; Bellina, F.; Lessi, M. Adv. Synth. Catal.
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̈
In summary, we have developed several effective approaches
for the preparation of 2-aminopyrimidines through the
amination of substituted polychloropyrimidines and chlorothio-
methoxy pyrimidines. Palladium-catalyzed aminations of 5-
substituted di- and trichloropyrimidines by aryl and heteroaryl-
amines afford the 2-substituted products in excellent levels of
regioselectivity. More nucleophilic dialkylamines also exhibit 2-
amination but do not require a palladium catalyst for a
regioselective reaction. For chloropyrimidines without sterically
encumbering 5-substituents, an attractive alternative route
utilizing readily prepared 2-chloro-4-thiomethoxypyrimidine
analogues results in exclusive 2-amination. Taken together,
these methods should aid the further development of function-
alized 2-aminopyrimidines in application-focused research.
(4) For recent examples, see: (a) Joubran, L.; Jackson, W. R.; Campi, E.
M.; Robinson, A. J.; Wells, B. A.; Godfrey, P. D.; Callaway, J. K.; Jarrot, B.
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K. D.; Castillo, R.; Gregory, M.; Vazir, H.; May, J. M.; Anderson, M. B.
Bioorg. Med. Chem. Lett. 2002, 12, 3635. (d) Schomaker, J. M.; Delia, T.
J. J. Heterocycl. Chem. 2000, 37, 1457.
(5) Recent computational work has sought to explain the observed
preference for coupling at the 4-chloro position, see: (a) Garcia, Y.;
Schoenebeck, F.; Legault, C. Y.; Merlic, C. A.; Houk, K. N. J. Am. Chem.
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Tanaka, T.; Ohtaka, H. J. Chem. Soc., Perkin Trans. 1 1991, 1279.
(8) (a) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27. (b) Surry, D.
S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338. (c) Martin, R.;
Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461.
(9) For the preparation of precatalysts P1−P5, see: (a) Bruno, N. C.;
Tudge, M. T.; Buchwald, S. L. Chem. Sci. 2013, 4, 916. (b) Bruno, N. C.;
Buchwald, S. L. Org. Lett. 2013, 15, 2876.
(10) (a) Maiti, D.; Fors, B. P.; Henderson, J. L.; Nakamura, Y.;
Buchwald, S. L. Chem. Sci. 2011, 2, 57. (b) Fors, B. P.; Watson, D. A.;
Biscoe, M. R.; Buchwald, S. L. J. Am. Chem. Soc. 2008, 130, 13552.
(11) Catalyzed or noncatalyzed aminations carried out in more polar
solvents such as NMP resulted in desilylation as well as decomposition
of 1. The same observation was made when aminations were carried out
with relatively stronger bases such as LDA and LiHMDS.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00799.
Synthetic procedures, characterization of products, and
NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sbuchwal@mit.edu.
Notes
The authors declare the following competing financial
interest(s): MIT has patents on some of the ligands and
precatalysts described in this work from which S.L.B. as well as
former or current co-workers receive royalty payments.
(12) Fors, B. P.; Davis, N. R.; Buchwald, S. L. J. Am. Chem. Soc. 2009,
131, 5766.
̈
(13) Farha, O. K.; Yazaydin, A. O.; Eryazici, I.; Malliakas, C. D.; Hauser,
B. G.; Kanatzidis, M. G.; Nguyen, S. T.; Snurr, R. Q.; Hupp, J. T. Nat.
Chem. 2010, 2, 944.
(14) Desilylation of 4 in THF with TBAF resulted in substantial
amounts of nucleophilic aromatic substitution, affording the respective
fluorinated pyrimidine product. Using a less polar solvent such as
toluene circumvented this issue.
ACKNOWLEDGMENTS
■
Research reported in this publication was supported by Merck
and Co. We thank Dr. Aaron C. Sather (MIT), Dr. Jeffery Bandar
(MIT), Dr. Michael T. Pirnot (MIT), and Dr. Yi-Ming Wang
(MIT) for aid in the preparation of this manuscript.
(15) (a) Martínez, M. M.; Perez-Caaveiro, C.; Pena-Lopez, M.;
́
́
̃
Sarandeses, L. A.; Sestelo, J. P. Org. Biomol. Chem. 2012, 10, 9045.
(b) Liu, M.; Su, S. − J.; Jung, M. − C.; Qi, Y.; Zhao, W. − M.; Kido, J.
Chem. Mater. 2012, 24, 3817.
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