Synthesis of pyrrolo[2,1-f][1,2,4]triazin-4(3H)-ones: Rearrangement of pyrrolo[1,2-d][1,3,4]oxadiazines and regioselective intramolecular cyclization of 1,2-biscarbamoyl-substituted 1H-pyrroles

Article abstract of DOI:10.3762/bjoc.12.168

Pyrrolo[2,1-f][1,2,4]triazin-4(3H)-ones 12 have been easily prepared via nucleophile-induced rearrangement of pyrrolooxadiazines 11 and regioselective intramolecular cyclization of 1,2-biscarbamoyl-substituted 1H-pyrroles 10. In this work, we demonstrated

Full text of DOI:10.3762/bjoc.12.168

Synthesis of pyrrolo[2,1-f][1,2,4]triazin-4(3H)-ones:
Rearrangement of pyrrolo[1,2-d][1,3,4]oxadiazines and
regioselective intramolecular cyclization of
1,2-biscarbamoyl-substituted 1H-pyrroles
Kkonnip Son1,2 and Seong Jun Park*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 1780–1787.
1Research Center for Medicinal Chemistry, Korea Research Institute
of Chemical Technology (KRICT), 141 Gajeong-ro, Yuseong-gu,
Daejeon 305-600, Korea and 2Department of Chemistry, Sogang
University, 35 Baekbeom-ro, Mapo-gu, Seoul 121-742, Korea
doi:10.3762/bjoc.12.168
Received: 10 May 2016
Accepted: 19 July 2016
Published: 09 August 2016
Email:
Seong Jun Park* - sjunpark@krict.re.kr
Associate Editor: I. R. Baxendale
* Corresponding author
© 2016 Son and Park; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
intramolecular cyclization; pyrrolooxadiazines; pyrrolotriazinone;
rearrangement
Abstract
Pyrrolo[2,1-f][1,2,4]triazin-4(3H)-ones 12 have been easily prepared via nucleophile-induced rearrangement of pyrrolooxadiazines
11 and regioselective intramolecular cyclization of 1,2-biscarbamoyl-substituted 1H-pyrroles 10. In this work, we demonstrated that
the described synthetic approaches can be considered to be more facile and practical than previously reported procedures.
Introduction
Pyrrolo[2,1-f][1,2,4]triazin-4(3H)-ones have been considered to These skeletons are the key intermediates for the synthesis of
be biologically active compounds. For example, these nitrogen- pyrrolo[2,1-f][1,2,4]triazines, which have been shown to have
containing heterocycles have shown intriguing activities as outstanding biological activities [13-17]. Consequently, many
tankyrase inhibitors 1 [1,2], stearoyl CoA desaturase inhibitors research groups have developed synthetic approaches; two main
2 [3], Eg5 inhibitors 3 [4,5], melanin-concentrating hormone re- synthetic routes involve N-imine intermediates and could be
ceptor (MCH)-R1 antagonists 4 [6], and CRF1 receptor antago- considered for the preparation of pyrrolotriazinones (Figure 2).
nists 5 [7,8] (Figure 1). Notably, many patent applications have Based on the reported cyclization methods, however, the reac-
described pyrrolotriazinones as phosphoinositide 3-kinase tions require high temperatures and long reaction times (gener-
(PI3K) inhibitors 6 [9-12].
ally overnight) to obtain the desired products [1-12]. For exam-
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Figure 1: Bioactive pyrrolo[2,1-f][1,2,4]triazin-4(3H)-ones [1-12].
difficult to form the N-imine structure and to subsequently
perform intramolecular cyclization (Figure 2).
In our efforts to discover drugs that are PI3K inhibitors, a
Hutchison Medipharma patent caught our attention. They re-
ported that pyrrolotriazinones showed excellent inhibitory activ-
ities against PI3K enzymes [9]. However, their synthetic
method to prepare the target molecule 9 demonstrated a limited
scope, and involved high temperature, long reaction time, and
low yield (approach A, Scheme 1). Another synthetic approach,
reported by researchers at Infinity Pharmaceuticals Inc., has
been used to obtain triazinone 12a’ via rearrangement of oxadi-
azines 11a’ (approach B, Scheme 1) [10].
However, in our investigation of the reported rearrangement
reaction, the desired product 12a’ was not accessed (approach
B, Scheme 1). For the procedure using silica-gel column chro-
matography to afford triazinone 12a’ from the free amine-con-
taining oxadiazine 11a’ [10], compound 11a’ was not present
after the boc-deprotection reaction because of its instability in
Figure 2: General synthetic routes to pyrrolotriazinones [3-6,8,9,11].
ple, these cyclization methods involve procedures such as the acidic conditions.
microwave-assisted heating with NaOMe [1] and H2N-Ar [6] at
150–160 °C, refluxing with HC(OEt)3 [3] and xylene [4,5,8], Based on the literature and the attempts reported herein, it
stirring at 100 °C in the presence of either NaOH or KOH [4,9], should be highlighted that limitations exist for the preparation
and heating with POCl3 [11] (Figure 2). It is reasonable to of the desired compounds 12. Due to these difficulties, we have
consider that these harsh conditions are required because it is investigated the synthesis of pyrrolotriazinones 12 by using a
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Beilstein J. Org. Chem. 2016, 12, 1780–1787.
Scheme 1: Synthesis of pyrrolotriazinones 9 and 12 [9,10,18].
more convenient and facile approach than those that have been in good to excellent yield [9]. A reaction mixture of 14 with
previously reported in the literature [9-12].
NaOH, NH4Cl, and NaClO led to the formation of the
N-aminopyrrole 15 [11]. The addition of the NH2+ to the
nitrogen of pyrrole 14 by using the NaOH/NH4Cl/NaClO
Results and Discussion
Our studies started with the synthesis of aminopyrrolocarba- system [11] can be considered as a more practical method than
mate 10. The preparation of compound 10, which is illustrated others, such as those that use NH2Cl and HOSA [19]. In
in Scheme 2, involved chlorination of 3-chloro-1H-pyrrole-2- contrast to other substituents, 2-fluorophenyl and 4-cyano-
carboxylic acid (13) using the Vilsmeier reagent [9], followed phenyl groups caused low yields (15b: 15%, 15f: 31%). The
by further amination to produce 1H-pyrrole-2-carboxamide 14 N-aminopyrroles 15 were then reacted with EDC·HCl and Boc-
Scheme 2: Synthesis of aminopyrrolocarbamate 10.
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Beilstein J. Org. Chem. 2016, 12, 1780–1787.
L-alanine in THF to give the desired aminopyrrolocarbamate 10 Although initial attempts to synthesize pyrrolotriazinone 12a
in good to excellent yield [9].
regioselectively were not successful, it should be highlighted
that the regioisomers oxadiazine 11a and triazinone 12a could
To synthesize the desired pyrrolotriazinones 12 regioselective- be easily prepared under very mild conditions (0 °C for 5 min),
ly we initially considered the work of Mazurkiewicz [20,21]. whereas only the oxadiazine 11a had been obtained in other re-
He reported that a mixture of 4H-3,1-benzoxazines (O-imidoyl- ported procedures [10,12].
ation products) and 4-quinazolones (N-imidoylation products)
could be obtained after heating N-acylanthranilamides in The acid-promoted rearrangement of oxadiazine 11 to triazi-
CH2Cl2 under reflux with PPh3Br2 in the absence of triethyl- none 12 was also examined. However, the trial reaction was
amine. In his research, it was proved that HCl or HBr influ- not successful because compound 11 did not tolerate acidic
enced the rearrangement of benzoxazines to quinazolones. Im- conditions.
portantly, triethylamine was considered to be an HBr captor
[20,21].
Because of this result, the rearrangement reaction of
pyrrolooxadiazine 11a to pyrrolotriazinone 12a was explored
With regard to Mazurkiewicz’s work, the effect of Et3N on (Table 2). For nucleophile-induced cyclization, pyrrolidine,
intramolecular cyclization was explored, and the acid-assisted Li(Me3AlSPh) [22], NaSMe, and NaOMe were assessed.
rearrangement was also evaluated.
Attempting the Mazurciewitcz–Ganesan procedure [23], using
pyrrolidine as a nucleophile, was not successful (entry 1,
As shown in Table 1, although all of the obtained yields were Table 2). In the cases of Li[Me3AlSPh], NaSMe, and NaOMe,
influenced by the amount of Et3N, the attempt to synthesize the triazinone 12a was readily obtained after the nucleophilic-
compound 12a directly by optimizing the amount of base was addition/ring-closure reaction (entries 2–5, Table 2). For exam-
not successful. For example, no reaction was observed in the ple, similar to benzoxazine [22], treatment of 11a and 11d with
absence Et3N (entry 1, Table 1). When excess amounts of base lithium trimethyl(phenylsulfido)aluminate Li(Me3AlSPh) provi-
were used, compounds 11a and 12a were only obtained in low ded the desired pyrrolotriazinone, 12a and 12d, in excellent
yields (40% combined yield, entry 3, Table 1). Alternatively, yields and with retention of enantiomeric excesses (ee) (entries
when 2.5 equivalents of Et3N were used, the two regioisomers 2 and 3, Table 2). Interestingly, the rearrangement of oxadi-
11a and 12a were obtained in an excellent overall yield of 87% azine 11a with sodium thiomethoxide led to the desired com-
(entry 2, Table 1). In addition, the ratio of 11a to 12a was not pound 12a (92% yield, entry 4, Table 2), and retention of ee
significantly affected by reaction times and temperatures was observed. With sodium methoxide, the ee was not retained,
(entries 4–6, Table 1).
but the desired product 12a was obtained in excellent yield
Table 1: The studies on various reaction conditions.
Entry
Et3N (equiv)
Reaction conditions
Yield [%]a 11a (12a)
1
2
3
4
5
6
None
2.5
10
5
0 °C, 1 h → rt, 0.5 h
0 °C, 5 min
–b (–b)
53 (34)
11 (29)
68 (22)
63 (20)
59 (16)
0 °C, 5 min
0 °C, 5 min
5
0 °C, 1 h → rt, 6 h
reflux, 10 min
5
aAfter column chromatography, bnot obtained.
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Beilstein J. Org. Chem. 2016, 12, 1780–1787.
Table 2: Rearrangement of pyrrolooxadiazine 11 to pyrrolotriazinone 12.
Entry
1
R
Substrate/Product
Rearrangement conditions
Yield [%]a
–c
ee [%]b
–d
1. pyrrolidine, rt, 18 h
2. AcOH, CH3CN
Ph
11a/12a
2
3
4
5
Ph
4-F-Ph
Ph
11a/12a
11d/12d
11a/12a
11a/12a
Li(Me3AlSPh), THF, rt, 20 h
Li(Me3AlSPh), THF, rt, 20 h
NaSMe, THF/DMF, rt, 0.5 h
NaOMe, THF/DMF, rt, 3 h
90
69
92
85
99
99
99
88
Ph
aAfter column chromatography; bthe enantiomeric excess (ee) was determined after the amide coupling reaction of boc-deprotected 12 with
moscher’s acid; cnot obtained; dnot determined.
(entry 5, Table 2). Notably, it has proven that sulfur-based Next, the effect of different halogens on the regioselectivity of
reagents such as Li(Me3AlSPh) and NaSMe are efficient for the the cyclization of 10 was investigated (Table 3). In general, the
nucleophile-induced cyclization.
mixture of oxadiazines 11 and triazinones 12 was obtained in
Table 3: Investigation of regioselectivity.
Entry
R
X2
Products
Yield [%]a 11 (12)
1
2
3
phenyl
phenyl
phenyl
Cl
Br
I
11a (12a)
11a (12a)
11a (12a)
10 (87)
63 (18)
81 (13)
4
5
6
7
3-fluorophenyl
4-fluorophenyl
4-methoxyphenyl
4-cyanophenyl
Cl
Cl
Cl
Cl
11c (12c)
11d (12d)
11e (12e)
11f (12f)
11 (72)
15 (81)
20 (78)
43 (41)
8
2-fluorophenyl
3-fluorophenyl
4-fluorophenyl
4-methoxyphenyl
4-cyanophenyl
Br
Br
Br
Br
Br
11b (12b)
11c (12c)
11d (12d)
11e (12e)
11f (12f)
16 (29)
25 (68)
41 (19)
70 (10)
–b (–b)
9
10
11
12
13
14
4-methoxybenzyl
cyclopropyl
Br
Br
(12g)
(12h)
–b (60)
–b (66)
aAfter column chromatography; bnot obtained.
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Beilstein J. Org. Chem. 2016, 12, 1780–1787.
45–98% overall yield. The results show that the regioselectivity promoted rearrangement [20,21], because oxadiazine is not
is highly dependent on the halogen used. In particular, when stable under acidic conditions. In the case of the rearrangement
PPh3Cl2 was used, triazinones 12 (N-imidoylation product) of 11a to 12a, the mechanism of the nucleophile-induced cycli-
were more easily obtained than oxadiazines 11 (entries 1 and zation is proposed after considering Hart’s research on the syn-
4–6, Table 3). In the case of bromine, the O-imidoylation prod- thesis of fumiquinazolines [22]. It was shown that the nucleo-
ucts 11 were preferred over the N-imidoylation products 12, philicity of the N-acylnitrenium ion was increased when the
whereas for substrates with 2- and 3-fluorophenyl groups differ- oxygen ion was stabilized by counter ions such as lithium and
ent results were obtained (entries 2 and 8–11, Table 3). Based sodium. For the intramolecular cyclization step, it was shown
on the literature results [9-12,22-25] and the reactions that are that the regioselectivity depends on the halogen source (Br/Cl)
reported herein, the O-imidoylation product 11 is more acces- and neighboring groups of the N-acylnitrenium ions (electron-
sible than the N-imidoylation product 12 when PPh3-Br2/I2- withdrawing aryl and -donating alkyl substitutents). This is
Et3N/DIPEA systems are applied (entries 2, 3, 10 and 11, highlighted by the observation that the N-imidoylation product
Table 3).
(triazinone) 12 was preferentially obtained when a chlorine-
halogen source and electron-donating alkyl groups were used.
Interestingly, in the case of the 4-cyanophenyl group, it While further studies are required, we suggest the intermediates
appeared that the different reaction patterns might be a result of are N-acylnitrenium ions [26] and halogen-imine structures (the
the reagents PPh3Br2 and PPh3Cl2 (entries 7 and 12, Table 3). Vilsmeier type) [27,28].
For alkyl substituents (4-methoxybenzyl and cyclopropyl,
entries 13 and 14, Table 3), triazinones 12g and 12h were selec- Because oxadiazines 11 and triazinones 12 are non-crystalline,
tively prepared in over 60% yield. Based on these results, it is their exact structures were assigned by NMR spectroscopy (1H
possible to consider that due to the presence of electron-donat- and 13C). With the literature results alone [9-12] the identity of
ing groups, such as alkyl substituents, only the N-imidoylation the regioisomers could not be accurately confirmed; therefore,
products 12g, and 12h were formed.
the NMR studies were required. As shown in Table 4, different
NOEs were observed for compounds 11 and 12.
It is possible to propose a reaction mechanism after considering
our studies and the literature results (Figure 3) [20-28]. For ex- Upon examination of the 1H NMR spectra of oxadiazines 11
ample, it is not reasonable to consider Mazurkiewicz’s acid- and triazinones 12, different peak patterns of the NH protons
Figure 3: Probable mechanism for the synthesis of triazinone 12a.
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Beilstein J. Org. Chem. 2016, 12, 1780–1787.
Notably, we found that triazinones 12 can be readily accessed
under very mild conditions (0 °C, 5 min). The regioselectivity
was influenced by the identities of halogen sources of triphenyl-
phosphorane and the N-functional groups. For the rearrange-
ment reaction, it was demonstrated that triazinone 12a was
easily obtained when counter ions of oxygen such as lithium
and sodium were used. Finally, we predict that these methods
could be useful for the preparation of biologically active
pyrrolotriazinones and -triazines.
Table 4: NOE analysis of representative examples (11a/11d and 12a/
12d).
Supporting Information
Supporting Information File 1
Experimental and analytical data.
NOEs
Entry
R1
Product
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-12-168-S1.pdf]
Ha–Hb (%) Ha–Hc (%)
1
2
3
4
H
F
H
F
11a
11d
12a
12d
11
5
6
2
39
42
21
31
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