The iron-catalyzed construction of 2-aminopyrimidines from alkynenitriles and cyanamides

Article abstract of DOI:10.1039/c3cc44422h

Several cycloaddition catalysts and reagents were surveyed for their effectiveness toward cyclizing alkynenitriles with cyanamides. Catalytic amounts of FeI₂, ^iPrPDAI and Zn were found to effectively catalyze the [2+2+2] cycloaddition of a variety of cyanamides and alkynenitriles to afford bicyclic 2-aminopyrimidines.

Full text of DOI:10.1039/c3cc44422h

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Page 1 ofJ3ournal Name
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ARTICLE TYPE
The Iron-Catalyzed Construction of 2-Aminopyrimidines from
Alkynenitriles and Cyanamides
Timothy K. Lane,a Minh H. Nguyen,a Brendan R. D’Souza,a Nathan A. Spahna and Janis Louiea*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
niobium Lewis acid to afford pyrimidines from an alkyne and two
50 nitriles (equation 1).14 While this method is regioselective, it
requires an excess of NbCl5 that must be added in six portions
over the course of the reaction. Additionally, yields are moderate
and this system is limited to aromatic nitriles. Nevertheless,
based on the reactivity of Nb complexes, pyrimidine formation
55 likely involves a nucleophilic attack of the nitrile nitrogen onto a
Nb coordinated alkyne complex rather than a Nb catalyzed
cycloaddition reaction. Such a scarcity of examples in this area
led us to seek a new metal-catalyzed [2+2+2] cycloaddition
method for the creation of cyclic compounds with two
60 heteroatoms.
Several cycloaddition catalysts and reagents were surveyed
for their effectiveness toward cyclizing alkynenitriles with
cyanamides. Catalytic amounts of FeI2, iPrPDAI and Zn were
found to effectively catalyze the [2+2+2] cycloaddition of a
10 variety of cyanamides and alkynenitriles to afford bicyclic 2-
aminopyrimidines.
Since the 1948 report by Reppe of acetylene cyclotrimerization in
the presence of a transition metal, the field of [2+2+2]
cycloaddition has grown immensely.1 Today, a myriad of
15 carbocycles can be created from various combinations of
unsaturated hydrocarbons.2 The next development in this field
was the incorporation of heteroatoms into cyclic products.
Heterocycles (such as pyridones,3 piperidines,4 pyridines5 etc) of
great complexity can now be synthesized from numerous
20 coupling partners.6 These systems supply a highly efficient
method to form multiple bonds in a single step and are of
paramount importance in organic synthesis.
(1)
(2)
The domain of [2+2+2] cycloaddition is poised to enter a new
step in its evolution. Cyclic compounds with multiple
25 heteroatoms constitute another vast collection of compounds
attracting considerable interest. Such motifs are abound in
pharmaceuticals, natural products, and other biologically active
compounds as well as in polymers and supramolecules.7 Despite
such importance, the use of [2+2+2] cycloaddition for the
30 construction of these compounds has received little attention.
Such a reaction requires the incorporation of two heteroatom
coupling partners to one hydrocarbon coupling partner.
However, the latter substrates are typically more reactive in
cycloaddition and lead to products that exclude the less reactive
35 heteroatom coupling partner.8 For example, the combination of
alkynes and excess nitriles in the presence of a variety of [2+2+2]
cycloaddition catalysts affords either pyridines or substituted
benzenes, or a mixture of thereof.9 Even when employing nitrile
as a solvent, incorporation of multiple nitrogen atoms is typically
65
(3)
Our group demonstrated that cyanamides perform
exceptionally well in Ni- and Fe-catalyzed cycloadditions with
diynes (equation 2).15,16 Additionally, we showed that utilizing
alkynenitriles aid in the incorporation of nitrogen into
40 not observed.10
Despite this significant obstacle, limited
70 cycloaddition products when using an iron catalyst.17 We report
herein a novel Fe-catalyzed cycloaddition reaction between
alkynenitriles and cyanamides to provide 2-aminopyrimidines
examples demonstrate that strategies to access cyclic compounds
with multiple heteroatoms are possible. The first example by
Hoberg involved the cycloaddition of an alkyne and two
isocyanates in the presence of stoichiometric Ni(0) producing a
(equation 3).
The abundant biological activity of 2-
aminopyrimidines make such a reaction desirable because
75 complex substitution patterns can be obtained from simple
starting materials.18,19
45 pyrimidine dione.11
Our lab revisited this reactivity and
successfully developed the first catalytic [2+2+2] route to
pyrimidine diones.12 This work was later followed up by Kondo
and co-workers.13 A more recent example by Obora utilizes a
We began by surveying the field of [2+2+2] transition metal
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DOI: 10.1039/C3CC44P42a2gHe 2 of 3
catalysts under their previously developed conditions (Table 1).20
FeI2, 10 mol % iPrPDAI, 30 mol % Zn dust in toluene at 40 °C
(Equation 4).
Table 1 Catalyst/Reagent Screening
35
Entry Substrates (equiv)
Conditionsa
5 mol % Rh(cod)2BF4/BINAP
15 mol % CoCp(CO)2
% yield 3ab
1
2
3
1a (1), 2a (2)
1a (1), 2a (5)
1a (1), 2a (3)
n.d.c
n.d.
n.d.
10 mol % CoCl2, 10 mol % dppe
20 mol % Zn
4
5
1a (1), 2a (1.5) 10 mol % Ni(cod)2, 20 mol % SIPr
1a (1), 2a (1.5) 10 mol % Ni(cod)2, 20 mol % IMes
n.d.
n.d.
6
7
8
9
10
11
12
13
14
1a (1), 2a (1.5) 10 mol % Ni(cod)2, 10 mol % Xantphos
1a (1), 2a (1.5) 2 mol % Cp*RuCl(cod)
n.d.
n.d.
trace
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
1a (1), 2a (3)
1a (1), 2a (3)
1a (1), 2a (3)
1a (1), 2a (3)
1a (1), 2a (3)
1a (1), 2a (3)
1a (1), 2a (3)
2 mol % [Ir(cod)Cl]2, 4 mol % DPPF
1.2 equiv NbCl5
5 mol % Ph3PAuOPOF2
(4)
5 mol % AuCl3, 1.1 equiv MsOH
5 mol % AuPEt3Cl, 5 mol % AgSbF6
10 mol % AgOTf, 10 mol % CuBr
10 mol % FeI2, 20 mol % dppp
20 mol % Zn
Table 2 Substrate Scope
15
16
17
1a (1), 2a (3)
1a (1), 2a (2)
1a (1), 2a (2)
10 mol % FeI2, 20 mol % dppp
20 mol % Zn, 20 mol % ZnI2
20 mol % Fe(OAc)2, 40 mol % Zn,
26 mol % p-OMe, iPrPDAIm
10 mol % FeCl2, 20 mol % MesPDAI
20 mol % Zn
n.d.
trace
16d
a
c
Detailed conditions available in SI or ref. 20. b Detected by GC/MS.
n.d. = not detected. d NMR yield.
5
Rhodium, cobalt, nickel, and ruthenium catalysts (entries 1-7)
were ineffective while iridium (entry 8) only afforded a trace of
3a as detected by GCMS. Additionally, niobium, gold, silver and
Cu reagents provided no products (entries 9-13). FeI2/dppp was
ineffective (entries 14-15). However, our previous Fe(OAc)2/p-
10 OMe,iPrPDAI system17,21 provided a trace of 2-aminopyrimidine
(entry 16). Curiously, our FeCl2/MesPDAI catalyst (entry 17),
under the conditions used to produce 2-aminopyridines,16
afforded 2-aminopyimidine 3a (Figure 1) in 16 % NMR yield.
This result was auspicious considering the low cost, high
15 terrestrial abundance and relatively low toxicity of iron as
compared to other metal catalysts.
Fig. 1 Ortep of 3a
Expensive and highly toxic benzene was replaced with toluene
20 at the outset of optimization.22 We initially identified Fe(OAc)2
as the optimum iron source; however, subsequent optimization
with Fe(OAc)2 was unproductive. We then turned to FeI2, which
allowed for significant improvements. Decreasing concentration,
increasing cyanamide loading to 3 equiv and ensuing ligand
25 optimization led to sound improvements in yields. Phosphine,
amine, carbene and bisimine ligands were ineffective while PDI
a
Conditions: 5 mol % FeI2, 10 mol % iPrPDAI, 30 mol % Zn dust,
b
c
40 toluene, 40 °C. Reaction progress monitored by GC. Conditions: 5
mol % FeI2, 10 mol % iPrPDAI, 30 mol % Zn dust, 30 mol % ZnI2,
toluene, 40 °C. d n.d. = not detected.
Our final optimized conditions were applied to various
combinations of substrates (Table 2). The model substrates 1a
45 and 2a afforded 3a in 90 % yield in 12 hours (entry 1); however,
ligands could only afford traces of product.23
Reducing
temperature to 40 °C and increasing Zn dust loading to 30 mol %
allowed for catalyst loading to be reduced to 5 mol %. At lower
30 concentrations, the reduction of iron pre-catalyst by Zn is perhaps
more difficult leading to the necessity for higher loading. Our
final conditions utilize a 1:3 ratio of alkynenitrile with 5 mol %
other substrates required extended reaction times.
Cyclic
cyanamides were incorporated providing 3b, 3c, and 3d in 40, 82,
and 35 % yields, respectively (entry 2-4). Me/Ph-cyanamide 2e
provided 3e in 40 % yield over 3 days (entry 5). Under our

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Page 3 of 3
ChemComm
J.-M. Lehn, G. Baum, D. Genske Angew. Chem. Int. Ed. 1997, 36,
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standard conditions, 1b was unreactive. However, in the
presence of 30 mol % ZnI2, 3f was obtained in 27 % yield (entry
6). While ZnI2 is known to aid in cobalt catalysis by stabilizing
Co(I) species,24 its effect in iron-catalyzed reactions remains
unclear.8,25 Applying ZnI2 to all reactions involving 1a resulted
in increased reaction times and decreased yields. This conflicting
result has been observed in a previous study.25 Finally, the
challenging terminal alkynenitrile 1c failed to react under these
conditions (entry 7). Efforts to replace the cyanamide substrate
8
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16 T. K. Lane, B. R. D’Souza, J. Louie J. Org. Chem., 2012, 77, 7555.
17 B. R. D’Souza, T. K. Lane, J. Louie Org. Lett., 2011, 13, 2936.
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Chem. Rev., 2010, 79, 655; (b) M. D. Hill, M. Movassaghi, Chem.‒
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3-component cyclizations of 4-CH3PhCCH with either
2
equivalents of free nitriles (i.e., PhCN) or cyanamides (i.e., 2a).
Although yields are modest in many cases, this work
demonstrates that bicyclic 2-aminopyrimidines with complex
15 substitution patterns can be prepared through Fe-catalyzed
cycloaddition chemistry. In some cases however, yields are high
indicating that this system could be synthetically useful if
optimization is done on a case-by-case basis.
Conclusions
20 We have disclosed the first catalytic [2+2+2] cycloaddition to
produce aromatic diazaheterocycles.
What is especially
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cycloaddition catalyst for nitrile incorporation, can now
incorporate multiple nitriles into aromatic products. Furthermore,
25 traditionally more efficient catalysts were ineffective toward this
strategy of 2-aminopyrimidine synthesis. We are actively
studying the properties of iron/PDAI catalysts in the hope that a
better understanding of these systems will lead to improved
yields and expanded substrate scopes.
30 Notes and references
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Org. Chem., 2006, 3917; (b) For CpCo(CO)2 (entry 2) L. V. R.
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a The University of Utah, 315 S. 1400 E. RM. 2020, Salt Lake City, UT
84102, USA. Fax:801-581-8433; Tel:801-581-6681; E-mail:
louie@chem.utah.edu
† Electronic Supplementary Information (ESI) available: [details of any
35 supplementary information available should be included here]. See
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