Palladium(II)-catalyzed cycloamidination via C(sp2)-H activation and isocyanide insertion

Article abstract of DOI:10.1002/adsc.201200106

An efficient method for the synthesis of nitrogen heterocycles containing a cyclic amidine moiety has been developed. The process involves palladium-catalyzed C(sp²)-H activation and isocyanide insertion starting with readily accessible ortho-heteroarene-substituted aniline derivatives under mild conditions. Copyright

Full text of DOI:10.1002/adsc.201200106

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DOI: 10.1002/adsc.201200106
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À
Palladium(II)-Catalyzed Cycloamidination via C
G
Activation and Isocyanide Insertion
Yong Wanga and Qiang Zhua,*
a
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of
Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, Peopleꢀs Republic of China
Fax : (+86)-20-3201-5299; phone: (+86)-20-3201-5287; e-mail: zhu_qiang@gibh.ac.cn
Received: February 9, 2012; Revised: March 15, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200106.
Abstract: An efficient method for the synthesis of
nitrogen heterocycles containing a cyclic amidine
moiety has been developed. The process involves
from aza-Wittig reactions of corresponding imino-
phosphorane and isocyanates (path b Scheme 1).[8]
These methods suffer from lengthy synthetic steps,
harsh reaction conditions, and/or limited substrate
scope. As a result, an efficient and general method to
synthesize this important class of molecules starting
from readily available substrates is highly desirable.
2
À
palladium-catalyzed C
N
anide insertion starting with readily accessible
ortho-heteroarene-substituted aniline derivatives
under mild conditions.
À
Keywords: C H activation; cycloamidination; het-
eroaromatic compounds; isocyanides; palladium
The cyclic amidine moiety is a very common subunit
in many nitrogen-containing heteroaromatic com-
pounds exhibiting a wide range of bioactivities. For
example, gefitinib and erlotinib, bearing the general
structure of 4-anilinoquinazoline, are clinically ap-
proved anticancer drugs targeting EGFR tyrosine
kinase.[1] CX-4945, containing a substructure of 5-
anilinobenzo[c]ACHTUNGTRENNUNG[2,6]naphthyridine, is a first-in-class,
orally bioavailable ATP-competitive inhibitor of pro-
tein kinase CK2 in clinical trials for cancer.[2] 6-
Aminoindolo
ACHTUNGTRENNUNG[3,2-c]quinolines exhibit promising in-
hibitory activities against telomerase or DNA topoiso-
merase,[3] and 4-amino-pyrrolo
ACTHNUTRGNE[UNG 1,2-a]quinoxalines act
as antimalarial agents,[4] and agonists of 5-HT3 recep-
tors (Figure 1).[5]
The most widely used method to prepare this class
of molecules is nucleophilic substitution of the corre-
sponding chlorides with various amine nucleophiles
(path a, Scheme 1).[1–5] However, chlorination of lac-
tams needs acidic and hazardous phosphorus oxy-
chloride (POCl3) at reflux temperature.[6] In 2007,
Wan et al. reported a direct one-pot SNAr reaction of
heterocyclic amides and ureas with nucleophiles
mediated by stiochoimetric amounts of a phosphonium
reagent, such as BOP.[7] An alternative uncommon ap-
Figure 1. Examples of biologically active molecules contain-
proach was electrocylization of carbodiimides, derived ing a cyclic amidine subunit.
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dines via C H activation followed by isocyanide in-
sertion[12c], in which one of the NH groups in the ami-
dine moiety acted as
a
directing group. We
anticipated that when an analogous intramolecular
amino group is present, a cycloamidination product
will be formed following isocyanide insertion and tau-
tomerization (path c, Scheme 1). Herein, we wish to
report an efficient synthesis of 6-aminoindolo
ACHTUNGTRENNUNG[3,2-
c]quinolines and 4-aminopyrrolo[1,2-a]quinoxalines
AHCTUNGTRENNUNG
from readily available 2-(2-aminoaryl)indoles and 1-
(2-aminoaryl) pyrroles via Pd(II)-catalyzed sequential
C H activation and isocyanide insertion employing
Cu(II) as the stoichiometric oxidant. This method
allows the reaction to occur under mild conditions
À
Scheme 1. Approaches towards the cyclic amidine structure.
Isocyanides, acting as isoelectronic species of (508C), and a broad range of isocyanides and func-
carbon monoxide, have been successfully used in tional groups are tolerated.
Pd(0)-catalyzed amidination[9] and amidation reac-
We initiated the investigation by using 2-(2-amino-
tions.[10] Meanwhile, the transition metal-catalyzed ox- phenyl)indole 1a and tert-butyl isocyanide 2a as the
À
idative carbonylation of C H bonds using CO as C1 model substrates. Under our previously reported con-
source[11] is now recognized as an environmentally ditions [Pd
(OAc)2 (5 mol%) as catalyst, Cs2CO3
benign and atom economic alternative to traditional (1.5 equiv.) as base, in refluxing toluene under an
carbonylation reactions employing (pseudo)halogen- oxygen atmosphere],[12c] no trtace of the desired prod-
containing substrates. However, a similar process in- uct N-tert-butyl-6-aminoindolo
volving isocyanide insertion instead of CO is relative- obtained (entry 1, Table 1). Some Cu(II) salts were
ly undervalued.[12] Recently, we reported a Pd-cata- screened as the oxidant of Pd
(OAc)2 instead of O2 in
ACHTUNGERTN[NUNG 3,2-c]quinoline 3a was
AHCTUNGTRENNUNG
lyzed oxidative amidination reaction of N-arylami- the absence of base in THF (entries 2–5). It was intri-
Table 1. Optimization of the reaction conditions.[a]
Entry
Oxidant (equiv.)
O2
Temperature [oC]
Time [h]
Yield [%][b]
1[c]
2
3
4
5
120
70
70
70
70
50
25
50
50
50
50
50
50
8
2
2
8
2
3
6
2
0
0
0
0
65
69
51
40
31
79
0
Cu
Cu(OAc)2·H2O
Cu(OTf)2 (1.0)
Cu(TFA)2·xH2O (1.0)
Cu(TFA)2·xH2O (1.0)
Cu(TFA)2·xH2O (1.0)
(TFA)2·xH2O (1.0)
(TFA)2·xH2O (0.2)
(TFA)2·xH2O (1.0)
(TFA)2·xH2O (1.0)
(OAc)2 (1.0)/TFA (2.0)
T
A
U
E
R
N
U
6
7
8[d]
9[d]
10[e]
11[f]
12
13[g]
Cu
Cu
Cu
Cu
N
2
16
16
16
16
Cu
O2
A
50
0
[a]
Reaction conditions: 1a (0.2 mmol), tert-butyl isocyanide 2a (0.3 mmol), PdACTHUNRGTNEUNG(OAc)2 (5 mol%), THF (1 mL), under an air
atmosphere.
[b]
[d]
[e]
[f]
Isolated yield of 3a.[c] The reaction was performed in toluene in the presence of Cs2CO3 (1.5 equiv.).
The reaction was carried out under an oxygen atmosphere.
The reaction was carried out under an argon atmosphere.
In the absence of PdACTHNUTRGNENUG(OAc)2.
TFA (2.0 equiv.) was added. Trifluoroacetylation of the aniline occurred and 2-(2-trifluoroacetamidophenyl)indole was
obtained in 34% yield.
[g]
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Palladium(II)-Catalyzed Cycloamidination via C
ACHTUNGTRENUN(NG sp ) H Activation and Isocyanide Insertion
Table 2. Synthesis of 6-aminoindoloACTHUNGTRENNNUG
[3,2-c]quinolines.[a]
Entry
1
Substrate 1
Substrate 2
Product 3
Yield [%]
79
1a
1a
2b
3b
3c
2
3
2c
72
90
1a
1a
2d
3d
3e
4
2e
85
5
6
1a
1a
2f
2g
3f
3g
50[b]
81
7
1a
2h
3h
41
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Table 2. (Continued)
Entry
Substrate 1
Substrate 2
Product 3
Yield [%]
68
8
1a
2i
3i
9
1b: R=Me
2a
3j: R=Me
77
10
11
12
13
1c: R=F
2a
2a
2a
2a
3k: R=F
69
67
1d: R=Cl
1e: R=Br
1f: R=CF3
3l: R=Cl
3m: R=Br
3n: R=CF3
74
51[c]
14
15
1g
2a
3o
75
75
1h: R=Me
2a
3p: R=Me
16
17
1i: R=Cl
1j: R=CF3
2a
2a
3q: R=Cl
3r: R=CF3
81
80
[a]
Reaction conditions: 1 (0.2 mmol), isocyanide 2 (0.3 mmol), PdACHTNUGRTENNUG(OAc)2 (5 mol%), CuAHCTUNGTRENN(GUN TFA)2·xH2O (1.0 equiv.), THF
(1 mL), under balloon pressure of argon, at 508C for 16 h, yield of isolated 3.
The reaction time was 20 h.
The reaction time was 24 h.
[b]
[c]
guing that only copper trifluoroacetate hydrate
With the optimized reaction conditions established,
(1.0 equiv.) can act as an efficient oxidant at 708C, we next examined the generality of this cycloamidina-
producing the desired product 3a in 65% yield. The tion reaction (Table 2). The scope of isocyanide was
isolated yield of 3a was improved slightly to 69% by evaluated first. Alkyl isocyanides, such as isopropyl,
lowering the reaction temperature to 508C. The prod- cyclohexyl, n-butyl, 1-admantyl isocyanides reacted
uct was formed even at room temperature, but with with 1a smoothly to form the corresponding products
less efficiency (51%, entry 7). Changing the reaction in good yields (3b–3e). Ethyl isocyanoacetate was also
atmosphere from air to oxygen deteriorated the cycli- a suitable substrate for the reaction, providing the
zation. However, we were delighted to find that the product 3f in moderate yield. It is noteworthy that
yield of 3a was increased to 79% when the reaction the scope of alkyl isocyanide is normally narrow in
À
was performed under argon, albeit in an extended re- transition etal-catalyzed C H bond activation fol-
action time (entry 10). A control experiment in the lowed by isocyanide insertion.[9,10,12] Aryl isocyanides
absence of Pd
than copper was the catalyst of the process. A combi- acted with 1a to give 3g in good yield (81%), while
nation of Cu(OAc)2 (1.0 equiv.) and TFA (2.0 equiv.) less sterically hindered p-methylphenyl isocyanide fur-
also worked, but only a 50% yield of 3a was obtained nished the product 3h in a much lower yield (41%).
(entry 12). However, removal of Cu(OAc)2 hampered Importantly, benzyl isocyanide bearing a stereogenic
ACHTUNGTRENNUNG(OAc)2 confirmed that palladium rather were also tested. 2,6-Dimethylphenyl isocyanide re-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
the reaction completely, indicating that both copper center tolerated the reaction without any loss of enan-
salt and the counterion were crucial to the reaction tiomeric purity of the product 3i, owing to the neutral
(entry 13).
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Palladium(II)-Catalyzed Cycloamidination via C
ACHTUNGTRENUN(NG sp ) H Activation and Isocyanide Insertion
Table 3. Synthesis of 4-aminopyrroloACTHUNGTRENNNUG
[1,2-a]quinoxalines.[a]
Entry
1
Substrate 4
Substrate 2
Product 5
Yield [%]
40
4a: R=H
2a
5a: R=H
2
3
4
4b: R=Me
4c: R=Cl
4d: R=F
2a
2a
2a
5b: R=Me
5c: R=Cl
5d: R=F
44
53
49
5
4e
2a
5e
53
6
4a
2g
5f
52
[a]
Reaction conditions: 4 (0.2 mmol), isocyanide 2 (0.3 mmol), Pd
(1 mL), in argon, at 508C for 24 h, yield of isolated 5.
ACHTUNGTERNNUG(OAc)2 (5 mol%), CuAHCUTNGTREN(NUGN TFA)2·xH2O (1.0 equiv.), THF
and mild reaction conditions (see the Supporting In- when 2-phenylaniline or 2-(2-aminophenyl)benzofur-
formation for details). an was applied, no desired cyclization products were
We next focused on exploring the scope of substi- formed. When acetyl-protected 6 and 8 were used as
tuted 2-(2-aminophenyl)indoles. A range of substitu- substrates under more forcing conditions involving
ents including methyl, fluoro, chloro, and bromo on PdCl2 (10 mol%), CuCl2 (20 mol%), Cs2CO3
the para position of the aniline ring were tolerated, (1.5 equiv.), in toluene at 1108C in O2, the corre-
affording the corresponding products in good yields sponding cyclization products 7 and 9 were isolated in
(3j–3m). Nevertheless, the cycloamidination product 50% and 81% yield, respectively (Scheme 2).
3n was achieved in only 51% yield when a strong
A plausible reaction mechanism for this cycloamidi-
electron-withdrawing CF3 was present at the same nation process is illustrated in Scheme 3, using 2-(2-
place. This result indicates that the electron density aminophenyl)indole 1a and tert-butyl isocyanide 2a as
on the aniline nitrogen is crucial in the catalytic cycle. an example. The reaction is initiated by coordination
On the other hand, the electronic nature of substitu- of the aniline nitrogen with isocyanide ligated Pd(II),
ents on C-5 of indole 1 has little influence on the affording complex A. Subsequent electrophilic palla-
yield of the cyclization (3p–3r).
dation[13] of the indole ring furnishes Pd(II) intermedi-
The generality of the current cycloamidination re- ate B, followed by migratory insertion of an isocya-
action was further explored by employing 1-(2-amino- nide. The resulting cyclic imidoyl palladium inter-
phenyl)pyrrole as one of the reactants, and the results mediate C undergoes reductive elimination and tauto-
are summarized in Table 3. Substituted 1-arylpyrroles merization to generate the product 3a with simultane-
4 with both electron-donating Me and electron-with- ous formation of a Pd(0) species, which is reoxidized
drawing Cl, and F on the aniline ring were applicable to Pd(II) by Cu(II).
to the reaction, giving the corresponding 4-amino-
pyrrolo[1,2-a]quinoxaline derivatives in lower yields proach for the synthesis of 6-aminoindolo
when compared with their indole counterparts. line and 4-aminopyrrolo[1,2-a]quinoxaline derivatives
In conclusion, we have developed an efficient ap-
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
À
The attempts to expand the cycloamidination reac- via palladium(II)-catalyzed C H activation followed
tion to more general aryl substrates under the optimal by isocyanide insertion starting with readily available
reaction conditions were unsuccessful. For example, 2-(2-aminophenyl)indoles and 1-(2-aminophenyl)pyr-
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Scheme 2. Cyclization with acetyl-protected substrates.
Scheme 3. A plausible reaction mechanism.
3a: 1H NMR (400 MHz, CDCl3): d=8.82 (br, 1H), 7.92
(d, J=8.4 Hz, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.82 (d, J=
8.0 Hz, 1H), 7.55 (m, 2H), 7.43 (t, J=7.6 Hz, 1H), 7.38 (t,
J=7.6 Hz, 1H), 7.24 (m, 1H), 5.19 (br, 1H), 1.77 (s, 9H);
13C NMR (125 Hz, CDCl3): d=153.02, 146.37, 140.50,
137.74, 128.22, 127.46, 124.09, 122.18, 121.20, 120.87, 119.95,
119.39, 113.51, 111.39, 104.11, 52.13, 29.72; HR-MS (ESI):
roles, respectively. Due to the neutral and mild reac-
tion conditions, a broad range of indole and pyrrole
substrates and isocyanides are tolerated. In addition,
no racemization occurs at the benzylic position when
chiral 1-phenylethyl isocyanide is used. The current
strategy should provide a general approach to nitro-
gen heterocycles containing a cyclic amidine subunit. m/z=290.1654, calcd. for C19H20N3 [M+H]+: 290.1652.
Acknowledgements
Experimental Section
We are grateful to the National Science Foundation of China
General Procedure for the Synthesis of 3
(21072190) for financial support of this work. The authors
also thank Prof. Ke Ding for his assistance with HPLC anal-
ysis.
A
mixture of 2-(2-aminoaryl)-1H-indole
1 (0.2 mmol),
Pd
N
ACHTUNGTRENNUNG
0.2 mmol, 1.0 equiv.) and isocyanide 2 (0.3 mmol, 1.5 equiv.)
in THF (1.0 mL) was stirred at reflux temperature under
balloon pressure of argon for 16 h. EtOAc (20 mL) and am- References
monium hydroxide (15 mL) were added to the reaction mix-
ture. The organic phase was separated, and the aqueous
phase was further extracted with EtOAc (2ꢂ10 mL). The
combined organic phase was washed with brine and dried
over Na2SO4. The concentrated residue was purified by
column chromatography over silica gel using petroleum
ether/ethyl acetate (16:1–8:1) as eluent to give the desired
product 3.
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8 Palladium(II)-Catalyzed Cycloamidination via CACTHUNTGRNEUNG(sp ) H
Activation and Isocyanide Insertion
Adv. Synth. Catal. 2012, 354, 1 – 8
Yong Wang, Qiang Zhu*
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