Synthesis of C8-N9 annulated purines by iron-catalyzed C-H amination

Article abstract of DOI:10.1002/chem.201301248

Purine and simple: A short synthesis for substituted annulated purine derivatives based on an Fe-catalyzed direct amination reaction using oxygen as oxidant was developed (see scheme). Interestingly, iron proved to be superior to copper catalysis. Copyright

Full text of DOI:10.1002/chem.201301248

COMMUNICATION
DOI: 10.1002/chem.201301248
À
À
Synthesis of C8 N9 Annulated Purines by Iron-Catalyzed C H Amination
Jens Maes, Tom R. M. Rauws, and Bert U. W. Maes*[a]
Purine derivatives display a wide variety of biological ac-
tivities and the purine nucleus has been used as a template
for addressing a variety of biological targets.[1,2] Not surpris-
ingly, the development of efficient functionalization process-
es for the purine nucleus is a very active area of research.[3,4]
The biggest challenge in obtaining good purine-based
enzyme inhibitors and receptor (ant)agonists is to overcome
the lack of selectivity for a specific enzyme/receptor. Modifi-
cation of the substitution pattern and altering the purine
core can both result in an improved selectivity, as well as an
increased activity. Synthetic methods to construct new
purine-based scaffolds, which are easily post-decorated, are
thus very important. In this respect, it is surprising that het-
À
eroarenes annulated to C8 N9 of the purine core, in con-
[5]
À
trast to their C8 N7 regioisomers, have been rarely docu-
mented.[6–8] Derivatives of the pyrido
N
been reported as phosphodiesterase type 5 (PDE5) inhibi-
tors,[7] of which some had a better selectivity over PDE6 and
PDE1 than sildenafil,[7a] and as anti-neoplastics.[8] However,
the synthetic strategy to construct the scaffold does not
allow an efficient post-modification of the pyrimidine substi-
Scheme 1. Retrosynthesis of substituted pyridoACTHUNRTGNEUNG[1,2-e]purines.
tution pattern. Given the potential of substituted pyridoACTHNUTRGNEU[GN 1,2-
e]purines to interact selectively with enzymes and receptors,
we developed a short synthesis for substituted 1,3-bis(4-
methoxybenzyl)pyrido
based on an Fe-catalyzed direct amination reaction on easily
accessible 5-(pyridin-2-ylamino)pyrimidine-2,4(1H,3H)-
[1,2-e]purine-2,4
N
benzyl)-5-(pyridin-2-ylamino)pyrimidine-2,4
(3a), a low yield of 1,3-bis(4-methoxybenzyl)pyrido
e]purin-2,4(1H,3H)-dione (4a) was obtained under the
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
diones (3; Scheme 1). Oxygen (O2), the most sustainable ox-
idant available, could be used as oxidase in the process.[9]
Compounds 4 potentially allow further decoration in a late
stage of the synthesis by N-deprotection and subsequent de-
hydroxyhalogenation, making them especially useful for li-
brary synthesis.
Buchwald (25%) and Zhu conditions (28%; Table 1, en-
tries 1 and 2, respectively). Moreover, starting material re-
mained in the latter case, even with a higher catalyst loading
in comparison to the other literature procedures (Table 1,
entries 1–3). Application of the conditions reported by our
group gave a moderate yield of target compound 4a (57%)
but a significant amount of a side compound, N,N-bis(4-
Intramolecular Cu-catalyzed direct amination of arenes
2
À
with amidines involving sp C H activation using O2 as oxi-
methACHTNGUTERNNUoG xybenzyl)tricarbanodiimidic diamide (8), was isolated
dase has been reported by the groups of Buchwald (N-aryl-
benzamidines),[10a] Zhu (N-arylpyridin-2-amines),[10b] and
Maes (N-arylpyridin-2-amines).[10c] When these reaction con-
ditions were applied to our test substrate, 1,3-bis(4-methoxy-
(20%; Table 1, entry 3).[12] A closer look at the reaction mix-
tures conducted under the Buchwald and Zhu conditions re-
vealed that this side compound was also formed in 34% and
26% yield, respectively. To address this selectivity problem,
we turned our attention to the use of another base metal.
Iron was selected because it has advantages from the per-
spective of availability and price in comparison to copper;[13]
the crustal abundance of iron is around 1000 times higher
and its price is more than hundred times lower than that of
copper. Moreover, chemoselectivity of iron over copper in
the framework of benzylic oxidations has been previously
shown by our group.[14]
[a] J. Maes, Dr. T. R. M. Rauws, Prof. Dr. B. U. W. Maes
Organic Synthesis, University of Antwerp
Groenenborgerlaan 171, 2020 Antwerp (Belgium)
Fax : (+32)32653233
E-mail: bert.maes@ua.ac.be
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301248.
Chem. Eur. J. 2013, 00, 0 – 0
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Table 1. Optimization of the direct amination of 3a.[a]
the same result (Table 1, entry 7). The addition of pivalic
acid (PivOH) in a catalytic amount had no significant effect
on the yield of 4a (Table 1, entry 8); however, excess acid
decreased the yield significantly (Table 1, entry 9). Other
FeII and FeIII salts gave a lower or zero yield of the target
molecule (Table 1, entries 10–18), and in several cases a sub-
stantial amount of side compound 8 was formed. With
FeCl2·4H2O, only a trace of this side productwas detected in
the crude reaction mixture (by LC-MS). A solvent screening
(dimethylacetamide (DMA), DMF, anisole, ortho-xylene)
with the best catalyst (FeCl2·4H2O) at 1208C revealed that
Catalyst
Yield
of 4a
[%][b]
Yield
of 3a
[%][b]
Yield
of 8
[%][b]
1[c]
2[d]
3[e]
4
Cu
Cu(OAc)2
Cu(OAc)2·H2O
G
25
28
57
0
0
15
0
100
0
0
0
4
29
51
0
33
89
30
6
40
50
30
34
26
20
0
0
0
none
Table 2. Scope of the direct amination of 3.[a]
5
6
FeCl2·4H2O
FeCl3·6H2O
FeCl2 (99.998%)
FeCl2·4H2O
FeCl2·4H2O
68
64
68
73
19
0
7
0
8[f]
12
21
22
19
24
0
34
36
11
20
7
9[g]
10
[FeACHTUNGTRENNUNG
11
12
13
14
15
16
17
18
Fe
Fe
FeF2
Fe
Fe
U
58
25
0
25
30
27
12
17
R
Cat.
[mol%]
t
Substrate
Product
Yield
of 4
G
[h]
[%][b]
CHTUNGTRENNUNG
1
2
3
4
5
6
7
8
9
3-Me
4-Me
5-Me
5-Me
20
20
20
15
24
24
24
24
24
24
48
48
24
24
24
48
48
24
24
24
24
48
48
24
24
48
48
24
48
48
24
48
48
24
24
24
24
24
3b
3c
3d
3d
3e
3 f
3 f
3 f
3g
3h
3i
3i
3i
3j
3k
3l
3m
3m
3m
3n
3o
3o
3o
3p
3p
3p
3q
3q
3q
3r
4b
4c
4d
4d
4e
4 f
4 f
4 f
4g
4h
4i
4i
4i
4j
4k
4l
4m
4m
4m
4n
4o
4o
4o
4p
4p
4p
4q
4q
4q
4r
90
76
60
57
Fe2O3
(NH4)2FeII
4A
[FeII(CN)6]·3H2O
G
ACHTUNGTRENNUNG(SO4)2·6H2O
K CHTUNGTRENNUNG
[a] Conditions: Substrate (0.5 mmol), catalyst (15 mol%), DMSO (1 mL),
O2 atmosphere (balloon), 1208C, 18 h. [b] Yield of isolated product.
6-Me
20
0[c]
59[d]
71
3-OMe
3-OMe
3-OMe
4-OMe
5-OMe
3-Br
3-Br
3-Br
4-Br
5-Br
6-Br
4-Cl
4-Cl
4-Cl
5-Cl
5-CF3
5-CF3
5-CF3
4-COOMe
4-COOMe
4-COOMe
5-COOMe
5-COOMe
5-COOMe
3-Et
3-Et
3-Ph
3-Ph
isoquinolin-1-yl
20
[c] Cu
phere (balloon), 1008C, 20 h (ref. [10a]). [d] Cu
(NO3)3·9H2O (10 mol%), PivOH (5 equiv), DMF (1 mL), O2 atmosphere
(balloon), 1308C, 28 h (ref. [10b]). [e] Cu(OAc)2·H2O (15 mol%), 3,4,5-
ACHTUNGTRENNUNG
40[e]
40
AHCTUNGTRENNUNG
42[f]
39
ACHTUNGTRENNUNG
20
20
AHCTUNGTRENNUNG
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
64
trifluorobenzoic acid (TFBA; 15 mol%), DMSO (1 mL), O2 atmosphere
(balloon), 1208C, 18 h (ref. [10c]). [f] 15 mol% PivOH as additive.
[g] PivOH (5 equiv) as additive. [h] acac=acetylacetone.
20
30[g]
59
40[e]
40
73
64
76
20
20
20
À
Although Cu-catalyzed C N bond forming reactions in-
0[h]
57[i]
82
2
3
À
volving C H activation (sp and sp ) have received consider-
able interest,[10,15–17] the number of reported processes based
on iron as a catalyst is very limited.[18–26] The known Fe-cata-
20
40[e]
40
51
77
20
3
2
À
lyzed sp and sp C H amination reactions generally involve
nitrenoid formation. These intermediates are generated
from preactivated primary amines (e.g., from azides,[18] PhI=
NTs,[19] PhNO and PhNHOH,[20] by in situ oxidation of a pri-
mary amine with N-bromosuccinimide (NBS)[21] or PhI-
20
39[g]
33[j]
46[k]
49[l]
59[i]
39[f]
6[j]
40[e]
40
20
40[e]
40
ACHTUNGTRENNUNG
(OAc)2,[22] or by ring opening of an 2H-azirine[23]). However,
20
40[e]
40
5[m]
35[n]
86
85
91
the stoichiometric preactivation of the nitrogen reagent is
still a drawback from a sustainability perspective.[26] More-
over, this methodology cannot be applied to secondary
amines. Interestingly, our substrates 3 feature a secondary
amine (upon tautomerism).
A catalyst screening was performed on test substrate 3a
(Table 1). FeCl2·4H2O proved to be the best catalyst as full
conversion was obtained after 18 h at 1208C, providing 4a
in a good isolated yield (Table 1, entry 5). FeCl3·6H2O gave
a similar result, suggesting an initial oxidation occurs when
FeII salts are used (Table 1, entry 6). To exclude the possibil-
ity that a Cu impurity in the Fe catalyst was performing the
actual catalysis, a highly pure source was tested, which gave
20
15
20
15
3r
3s
3s
3t
4r
4s
4s
4t
84
93
20
[a] Conditions: Substrate (0.5 mmol), FeCl2·4H2O (X mol%), DMSO
(1 mL), O2 atmosphere (balloon), 1208C, Y h. [b] Yield of isolated prod-
uct. [c] No substrate recovered. [d] 24% substrate recovered. [e] In two
batches of 20 mol%, 2ꢁ24 h. [f] 6% substrate recovered. [g] 33% sub-
strate recovered. [h] Only substrate recovered. [i] 19% substrate recov-
ered. [j] 52% substrate recovered. [k] 29% substrate recovered. [l] 37%
substrate recovered. [m] 49% substrate recovered. [n] 14% substrate re-
covered.
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Iron-Catalyzed Synthesis of C8 N9 Annulated Purines
COMMUNICATION
Table 3. Comparison of iron versus copper in the direct amination of 3m.[a]
only in DMSO were good results achieved (See the
Supporting Information).
Next, the compatibility of our method for sub-
strates with substitution at the pyridine ring was
probed. Both electron-donating (Me, Et, Ph, OMe)
and electron-withdrawing groups (Cl, Br, COOMe,
CF3) were tested (Table 2). A uniform catalyst load-
ing (20 mol% FeCl2·4H2O) and a reaction time of
24 h were selected for these substituted substrates.
The catalyst loading was not optimized for each
substrate, although in several cases this could defi-
nitely be reduced as exemplified by the selected
cases that were tested (Table 2, entries 4, 31, and
33). Gratifyingly, under these conditions the corre-
Catalyst
Additive
Cat.
[%]
t
Yield
of 4m
[%][b]
Yield
of 3m
[%][b]
Yield
of 8
[h]
[%][b]
1
2
3
4
5
6
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
-
-
-
20
24
48
48
24
48
48
57
82
51
35
29
30
19
7
0
0
0
10
9
28
13
15
6
40[c]
40
Cu
Cu
Cu
N
TFBA
TFBA
TFBA
20
40[c]
40
0
sponding substituted 1,3-bis(4-methoxy
ACHTUNGTRENNbUNG enzyl)-
[a] Conditions: Substrate (0.5 mmol), catalyst (X mol%), additive (X mol%), DMSO
(1 mL), O2 atmosphere (balloon), 1208C, Y h. [b] Yield of isolated products. [c] In two
batches of 20 mol%, 2ꢁ24 h.
A
R
ACHTUNGTRENNUNG
generally obtained in moderate to good yields
(Table 2), thus supporting a wide functional group
compatibility of the new protocol. C6 substitution,
Table 4. Fundamental studies on 3a.[a]
which blocks the a-position to nitrogen, was not tolerated,
as exemplified for a methyl and a bromo substituent
(Table 2, entries 5 and 16). However, no steric effect due to
substituents in the challenging C3 position (Me, Et, Ph;
compare Table 2 entries 1, 30, and 32) was observed. Heter-
oatom-based groups in this position (OMe, Br; Table 2, en-
tries 6 and 11) require a higher catalyst loading (40 mol%)
and longer reaction time (48 h) to obtain full conversion
(Table 2, entries 7 and 13). For pyridine substitution featur-
ing stronger electron withdrawing groups (Cl, CF3,
COOMe), these conditions were usually also required
(Table 2, entries 17–29). The very challenging ester and tri-
fluoromethyl groups were tolerated by the protocol, al-
though under the best conditions some starting material re-
mained (Table 2, entries 23, 25, and 29). Interestingly, often
it was beneficial to add the additional catalyst in two por-
tions because it suppressed the formation of side compound
8 and increased the yield of 4 (See Table 2, entries 7 and 8,
18 and 19, 25 and 26, and the Supporting Information for
yield of 8). The protocol is chemoselective as halogens were
generally tolerated (Table 2, entries 11–20). Regioisomeric
Additive
Yield
Yield
of 3a
[%][b]
Yield
of 8
of 4a
[%][b]
[%][b]
1
2
3
–
68
8
9
0
69
57
0
7
9
TEMPO
Galvinoxyl
[a] Conditions: Substrate (0.5 mmol), catalyst (15 mol%), additive
(1 equiv), DMSO (1 mL), O2 atmosphere (balloon), 1208C, 18 h.
[b] Yield of isolated product.
fundamental experiments on substrate 3a (Table 4). Radical
inhibitors (TEMPO [(2,2,6,6-tetramethylpiperidin-1-yl)oxyl],
Galvinoxyl) were added to the cyclization reaction of 3a
and gave a significant reduction in conversion, hereby sup-
porting a radical reaction mechanism (Table 4, entries 2–3).
When a direct amination experiment was performed under
an Ar atmosphere with 40 mol% of FeIICl2·4H2O, no 4a was
formed. Interestingly, a similar experiment with 40 mol% of
FeIIICl3 gave an 18% yield of 4a. This experiment indicates
that FeIII initiates the catalytic cycle and that two metal ions
are required to make one molecule of the reaction product.
Oxygen acts as an oxidase, bringing reduced iron into the
original oxidation state and allowing a catalytic process to
occur. An intermolecular kinetic isotope effect with both
non-deuterated (3a) and deuterated substrate (3a-D), exe-
cuted in two different flasks, showed no kinetic isotope
halopyridoACHTUNGTRENNUNG[1,2-e]purin-2,4CAHTUNGTRENN(UGN 1H,3H)-diones (4i–n) are very
interesting compounds as they allow post functionalization
by Pd-catalyzed cross-coupling chemistry.
For substrates 3m, which did not convert completely
under the standard conditions (20% FeCl2·4H2O, 24 h), we
reinvestigated the use of copper. The reactions were per-
formed with the best copper-based catalytic system (Cu-
ACHTUNGTRENNUNG(OAc)2·H2O, 3,4,5-trifluorobenzoic acid (TFBA)) that was
identified for 4a synthesis, and with the same catalyst load-
ing as that used for the iron catalysis (Table 3, entries 1–3).
Copper catalysis resulted in systematically lower yields of
the target compound and complete decomposition of the
starting material, irrespective of the catalyst loading applied
(Table 3, entries 4–6). These results further support the su-
perior role of iron catalysts for the cyclization under study.
To gain insight into the reaction mechanism of the Fe-cat-
alyzed direct amination reaction we performed a number of
À
effect and therefore the rupture of the C H bond is not in-
volved in the rate-determining step (Scheme 2).
In accordance with these fundamental experiments, the
catalytic cycle in Scheme 3 is proposed. A radical mecha-
nism is also in accordance with the more difficult reactions
Chem. Eur. J. 2013, 00, 0 – 0
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B. U. W. Maes et al.
are currently underway in our laboratory. In addition ex-
tending the scope of the base-metal-catalyzed protocol for
the synthesis of other annulated purine scaffolds and study
of the pyrimidine post-functionalization potential are under
study.
Acknowledgements
Scheme 2. Determination of intermolecular KIE. PMB=para-methoxy-
benzyl.
This work was supported by the Institute for the Promotion of Innova-
tion by Science and Technology in Flanders (IWT-Flanders), the Fund
for Scientific Research (FWO-Flanders), the University of Antwerp
(BOF), and the Hercules Foundation. The research leading to these re-
sults has also received funding from the Innovative Medicines Initiative
(www.imi.euopa.eu) Joint Undertaking under grant agreement no.
115360, resources of which are composed of financial contribution from
the European Unionꢂs Seventh Framework Programme (FP7/2007-2013)
and EFPIA companiesꢂ in kind contribution.
À
Keywords: amination
catalysis · iron · purine
·
C H activation
·
homogeneous
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substituted substrates featuring a heteroatom (OMe and Br)
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and C5 substituents are expected to be similar. Alternative-
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which only exerts an inductive effect resulting in destabiliza-
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vations.
In summary, we have developed a sustainable direct ami-
nation protocol for substituted pyridoACTHNUTRGNE[NUG 1,2-e]purine synthesis
based on base-metal catalysis that does not require the pre-
activation of nitrogen and uses O2 as oxidant. The method
has excellent functional-group compatibility and the chemo-
selectivity towards halogens will allow post-functionalization
in the annulated ring. Further investigations to improve the
efficiency of the direct amination protocol (lower catalyst
loading, better tolerance of electron-withdrawing groups)
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Iron-Catalyzed Synthesis of C8 N9 Annulated Purines
COMMUNICATION
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Received: April 2, 2013
Published online: && &&, 0000
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
5
&
ÞÞ
These are not the final page numbers!

B. U. W. Maes et al.
Amination
J. Maes, T. R. M. Rauws,
B. U. W. Maes* ............... &&&& — &&&&
À
Synthesis of C8 N9 Annulated
Purine and simple: A short synthesis
for substituted annulated purine deriv-
atives based on an Fe-catalyzed direct
amination reaction using oxygen as
oxidant was developed (see scheme).
Interestingly, iron proved to be supe-
rior to copper catalysis.
À
Purines by Iron-Catalyzed C H
Amination
&
6
&
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!