Efficient construction of C=N double bonds via acceptorless dehydrogenative coupling

Article abstract of DOI:10.1002/adsc.201300455

The efficient construction of C=N double bonds has been achieved by the Ir-catalyzed intramolecular acceptorless dehydrogenative cross-coupling of tertiary amines and amides. An iridium/2-hydroxypyridine complex was identified as the highly efficient catalyst. A number of quinazolinone derivatives was prepared in excellent yields. An iridium-mediated C-H activation mechanism is proposed. This finding provides an unprecedented strategy for the direct imidation of sp3 C-H bonds.

Full text of DOI:10.1002/adsc.201300455

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DOI: 10.1002/adsc.201300455
Efficient Construction of C=N Double Bonds via Acceptorless
Dehydrogenative Coupling
Xiang Sun,a Yu Hu,a Shao-zhen Nie,a Yun-yun Yan,a Xue-jing Zhang,a
and Ming Yana,*
a
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University,
Guangzhou 510006, Peopleꢀs Republic of China
E-mail: yanming@mail.sysu.edu.cn
Received: May 24, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300455.
Abstract: The efficient construction of C=N double
bonds has been achieved by the Ir-catalyzed intra-
molecular acceptorless dehydrogenative cross-cou-
pling of tertiary amines and amides. An iridium/2-
hydroxypyridine complex was identified as the
highly efficient catalyst. A number of quinazolinone
derivatives was prepared in excellent yields. An iri-
green chemistry.[6] Zhou et al. reported the synthesis
of cyclic amidines via the acceptorless dehydrogena-
tion of alcohols and 2-aminobenzamides.[7] Liang et al.
developed an intermolecular acceptorless CDC reac-
tion of tertiary amines and ketones. The formation of
C C bonds was also achieved.[8] Recently we reported
À
an intramolecular CDC reaction of tertiary amines
and ketones. The construction of C=C double bonds
was achieved with iridium-diphosphine catalysts in
the absence of oxidants or hydrogen acceptors.[9 ] To
À
dium-mediated C H activation mechanism is pro-
posed. This finding provides an unprecedented
3
À
strategy for the direct imidation of sp C H bonds.
À
the best of our knowledge, the construction of C N
À
Keywords: C H functionalization; C=N double
bonds via acceptorless CDC reactions has never been
bond; dehydrogenative coupling; imidation; iridium
complexes
reported. As a continuous effort to develop new
À
methods for the direct functionalization of a-C H
bonds of amines, we extended the strategy to amide
derivatives. In this paper, we report the highly effi-
cient construction of C=N double bonds via iridium-
catalyzed acceptorless dehydrogenative coupling of
Nitrogen heterocycles are most important structural tertiary amines and amides.
units in natural products and synthetic drugs. Thus,
Iridium complexes are found to be efficient cata-
tremendous efforts have been made to develop syn- lysts for the catalytic dehydrogenations.[9] Initially, we
thetic methods towards nitrogen heterocycles.[1] Re- examined the reaction of tetrahydroisoquinoline-de-
À
cently the direct C H amidation has proven to be an rived benzamide 1a in the presence of [Cp*IrCl2]2
efficient strategy for the synthesis of various amines (Cp*=pentamethylcyclopentadienyl). To our delight,
and nitrogen heterocycles.[2] Most of these reactions quinazolinone 2a was obtained in good yield. TCD-
proceed via nitrene intermediates,[3] however, limited GC analysis indicated the release of hydrogen gas
substrate scope and low chemoselectivity were fre- during the reaction. Furthermore, a number of transi-
quently observed. In addition, the formation of ni- tion metal catalysts was screened and the results are
trene intermediates generally involves hypervalent summarized in Table 1. [IrACHTNUTRGNEUNG(cod)Cl]2(cod=1,5-cyclooc-
iodine reagents or other oxidants, so that oxidation- tadiene) provided a similar yield, however, the
sensitive functional groups are not tolerated. In reaction was significantly slower (Table 1, entry 2).
recent years, the cross dehydrogenative coupling IrACHTGNUTREN(NNUG cod)AHCTUNRTGEG(NNUN acac) (acac=acetylacetonate) and IrACHTUNGTRENNUNG(cod)-
(CDC) reaction has emerged as a powerful tool for
ACHTUNGTREN(NUGN hfacac) (hfacac=hexafluoroacetylacetonate) showed
organic synthesis.[4] The direct construction of C N low catalytic activity (Table 1, entries 3 and 4).
bonds via CDC has been successfully developed.[5] [Cp*RhCl2]2 was found to be completely inefficient
However, these CDC reactions generally require sac- (Table 1, entry 5). Several ruthenium complexes are
À
rificial oxidants or H-acceptors. The acceptorless also poor catalysts (Table 1, entries 6–8). PdACHTUNGTRENNUNG(OAc)2
CDC reaction via release of hydrogen gas is more at- provided 2a in low yield (Table 1, entry 9) and the
tractive from the view points of atom economy and deposition of Pd(0) particles was observed. The re-
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Table 1. Screen of catalysts.[a]
Table 2. Effect of nitrogen ligands.[a]
Entry
Catalyst
Time [h]
Yield [%][b]
1
2
3
4
5
6
7
8
N
2
86
89
6
18
-
8
-
<5
34
-
G
12
12
12
12
12
12
12
12
12
12
G
E
ACHTUNGTRENNUNG
A
R
G
9[c]
10
11[d]
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Entry
Ligand
Yield [%][b]
20
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L6
L7
L1
L1
L1
99
26
21
89
–
[a]
Conditions: 1a (0.2 mmol), catalyst (5 mol% metal), tri-
fluoroethanol (2 mL), argon atmosphere, 1008C, 12 h.
The yields were determined by H NMR using dimethyl
[b]
1
terephthalate as the internal standard.
Silvery metal particles were observed.
5 ꢂ molecular sieves were added.
–
[c]
[d]
91
98
94
87
8[c]
9[d]
10[e]
duction of Pd
ACHTUNGTRENNUNG(OAc)2 by 1a may account for this phe-
[a]
nomena. Pd(PPh3)2Cl2 did not show catalytic activity
ACHTUNGTRENNUNG
Conditions: 1a (0.2 mmol), [Cp*IrCl2]2 (2.5 mol%),
ligand (5 mol%), trifluoroethanol (2 mL), argon atmos-
phere, 1008C, 2 h.
The yields were determined by H NMR using dimethyl
terephthalate as the internal standard.
The reaction was carried out under an air atmosphere.
[Cp*IrCl2]2 (1 mol%) and L1 (2 mol%) were used.
[Cp*IrCl2]2 (0.1 mol%) and L1 (0.2 mol%) were used.
in this reaction (Table 1, entry 10). PtCl2 in combina-
tion with 5ꢂ molecular sieves gave 2a in low yield
(Table 1, entry 11).[10]
To improve the yield, a series of nitrogen ligands
was screened and the results are summarized in
Table 2. The addition of 2-hydroxypyridine (L1) led
to excellent yield (Table 2, entry 1). Fujita, Wang and
co-workers suggested that L1 can assist Ir-catalyzed
dehydrogenation by tautomerization.[11] In contrast, 8-
[b]
1
[c]
[d]
[e]
A variety of 2-aminobenzamide derivatives was ex-
hydroxyquinoline and 2-aminopyridine significantly amined and the results are summarized in Scheme 1.
decreased the yields (Table 2, entries 2 and 3). 2-Sulf- The benzamides with 2-tetrahydroisoquinolinyl (1a,
ACHTUNGTRENNUNGamidopyridine provided 2a in good yield (Table 2, 1b), 2-thienoACHTUNTGREN[NUGN 3,2-c]piperidinyl (1c) and 2-(isoindolin-
entry 4). 2,2’-Bipyridine and picolinic acid completely 2-yl) (1d) groups provided the expected products in
inhibited the reaction (Table 2, entries 5 and 6). Pro- excellent yields. 2-Tetrahydroisoquinolinylbenzamides
line is an efficient ligand and a good yield could be (1e–1k) are also suitable substrates and excellent
obtained (Table 2, entry 7). The reaction could also yields were generally obtained. 2-Tetrahydroisoquino-
be carried out under an air atmosphere and a similar linylpicolinamide (1l) afforded an excellent yield after
yield was obtained (Table 2, entry 8). The decrease of an extended reaction time. A good yield was also ob-
the [Cp*IrCl2]2 loading to 1 mol% and 0.1 mol% re- tained for 2-piperidinylbenzamide (1m). A lower
sulted in lower yields (94% and 87%, respectively) yield was observed for 2-pyrrolidinylbenzamide (1n).
(Table 2, entries 9 and 10).
2-Morpholinylbenzamide (1o) and 2-thiomorpholinyl-
The reaction solvent exerted a strong effect on the benzamide (1p) are unreactive. The lower electronic
reaction. Trifluoroethanol was identified as the best density of these two nitrogen heterocycles appears to
solvent. Lower yields were obtained in acetic acid and inhibit the reaction. 2-(Benzylamino)benzamide (1q)
ethanol (47% and 22%, respectively). Other solvents afforded the product 2q in a low yield.
such as toluene, dichloroethane, isopropyl alcohol,
2-Tetrahydroisoquinolinyl-benzenesulfonamide (3a)
DMF, and acetone are not compatible with the trans- is also applicable [Scheme 2, Eq. (1)]. The product 4a
formation.
was obtained in good yield when a higher catalyst
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Efficient Construction of C=N Double Bonds via Acceptorless Dehydrogenative Coupling
Scheme 2. Dehydrogenative coupling of 2-aminobenzene-
AHCTUNGTREGUNsNN ulfonamides.
ed (Scheme 4). 2-[3,4-Dihydroisoquinolin-2(1H)-yl]-
AHCTUNGTREGaNNUN niline (7a) gave imidazole derivative 8a in excellent
yield. However, the acetamide derivative 7b provided
an abnormal product 8b in good yield. On the other
hand, the reaction of the formamide derivative 7c af-
forded a mixture of 8a (44% yield) and 8b (16%
yield). The steric hindrance of the amide group ap-
pears to affect the regioselectivity of the dehydrogen-
ative coupling. In addition, the deacylation process
also occurred in these transformations.
The dehydrogenative coupling of 1a was found to
be reversible under an elevated pressure of hydrogen
gas. When the dehydrogenative reaction of 1a was
completed as indicated by TLC analysis, the reaction
mixture was charged with 10 atm hydrogen gas and
stirred at 608C for 12 h. The regeneration of 1a was
observed with 35% yield (Scheme 5). The result sug-
gests that iridium catalyst also promotes the hydroge-
nation of amidine 2a under an elevated pressure of
hydrogen gas.
We explored the intermolecular dehydrogenative
coupling of N-phenyltetrahydrogenisoquinoline and
benzamide, however, no reaction was observed. Be-
cause [IrACTHNURGTNEUNG(cod)Cl]2 also promotes the reaction effi-
Scheme 1. Dehydrogenative coupling of 2-aminobenzamide
derivatives.
ciently (Table 1, entry 2), [Cp*IrCl2]2 may be reduced
in situ by 1a to a catalytically active Ir(I) species. A
tentative reaction mechanism is proposed (Scheme 6).
The amide group coordinates with Ir(I) catalyst and
À
loading (12.5 mol%) was used. 2-(Piperidin-1-yl)ben- assists a C H insertion process.[12] The intermediate A
zenesulfonamide (3b) afforded the corresponding releases one molecule of hydrogen gas to give B. The
product 4b in moderate yield [Scheme 2, Eq. (2)].
reductive elimination leads to intermediate C. A hy-
À
Under the optimal reaction conditions, 2-tetrahy- dride transfer provides an Ir H species and iminium
droisoquinolinylbenzylamine (5a) provided the ex- intermediate D. The release of a second molecule of
pected product 6a in low yield [Scheme 3, Eq. (3)]. hydrogen gas provides the product 2a. Although the
Interestingly, the reaction of 2-tetrahydroisoquinoli- formation of an iminium species is also possible in the
nylbenzyl alcohol (5b) gave a dimer product 6b in low first step, the amide group-assisted C H insertion
yield [Scheme 3, Eq. (4)].
À
should be more favorable due to the avoidance of
To further illustrate the scope of the reaction, the charge separation. The intermediate C was never ob-
dehydrogenative coupling of 2-[3,4-dihydroisoquino- served in the reaction. The fast dehydrogenation of C
lin-2(1H)-yl]aniline derivatives (7a–7c) was investigat- may account for this result.
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Xiang Sun et al.
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Scheme 3. Dehydrogenative coupling of 2-tetrahydroisoquinolinylbenzylamine and 2-tetrahydroisoquinolinylbenzyl alcohol.
Scheme 4. Dehydrogenative coupling of 2-[3,4-dihydroisoquinolin-2(1H)-yl]aniline derivatives.
unprecedented strategy for the direct imidation of sp3
À
C H bonds.
Experimental Section
General Procedure for the Dehydrogenative
Coupling
Under an argon atmosphere, [Cp*IrCl2]2 (4.0 mg,
0.005 mmol) and 2-hydroxypyridine (1.0 mg, 0.01 mmol)
were stirred in dichloromethane (1 mL) at room tempera-
ture for 30 min. After the solvent had been removed under
vacuum, 1a (50.5 mg, 0.2 mmol) in trifluoroethanol (2 mL)
was added. The reaction mixture was stirred at 1008C for
2 h. The solvent was removed under vacuum and the residue
was purified by flash column chromatography over silica gel
to give the product 2a as a white solid; yield: 46.7 mg
Scheme 5. Reversibility of dehydrogenative coupling of 1a.
In conclusion, we have developed an intramolecular
acceptorless dehydrogenative coupling of tertiary
amines and amides. An iridium/2-hydroxypyridine
complex was identified as the highly efficient catalyst.
A number of quinazolinone derivatives was prepared
1
À
in excellent yields. An iridium-mediated C H activa-
(94%); mp 264.7–266.58C. H NMR (400 MHz, CDCl3): d=
tion mechanism is suggested. This finding provides an 8.59 (d, J=7.9 Hz, 1H), 8.43 (d, J=7.9 Hz, 1H), 7.76 (t, J=
4
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Efficient Construction of C=N Double Bonds via Acceptorless Dehydrogenative Coupling
Scheme 6. Proposed reaction mechanism.
7.2 Hz, 1H), 7.60–7.40 (m, 4H), 7.30 (d, J=7.4 Hz, 1H),
4.37 (t, J=6.6 Hz, 2H), 3.28 (t, J=6.6 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d=169.3, 155.0, 140.7, 135.7, 133.7,
132.7, 129.6, 129.1, 128.9, 127.8, 126.9, 125.8, 120.4, 113.8,
43.3, 27.1; IR (KBr): n=3070, 2949, 1634, 1601, 1521, 1486,
1454, 1415, 1350, 1118, 1035, 891, 754, 691 cmÀ1; HR-MS
(ESI): m/z=249.1025, calculated for C16H13N2O (M+H)+:
249.1022.
[3] For some reviews of nitrene chemistry, see: a) H. M. L.
Davies, J. R. Manning, Nature 2008, 451, 417–424;
b) H. M. L. Davies, M. S. Long, Angew. Chem. 2005,
117, 3584–3586; Angew. Chem. Int. Ed. 2005, 44, 3518–
3520.
[4] For some reviews of CDC reactions, see: a) C. J. Li,
Acc. Chem. Res. 2009, 42, 335–344; b) W. J. Yoo, C. J.
Li, Top. Curr. Chem. 2010, 292, 281–302; c) C. J.
Scheuermann, Chem. Asian J. 2010, 5, 436–451; d) C. S.
Yeung, V. M. Dong, Chem. Rev. 2011, 111, 1215–1292.
[5] For some recent examples for the direct construction of
À
C N bonds via CDC reactions, see: a) M. Miyasaka, K.
Acknowledgements
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Financial support of this research from the National Natural
Science Foundation of China (Nos. 20972195, 21172270) and
Guangdong Engineering Research Center of Chiral Drugs is
gratefully acknowledged.
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Efficient Construction of C=N Double Bonds via
7
Acceptorless Dehydrogenative Coupling
Adv. Synth. Catal. 2013, 355, 1 – 7
Xiang Sun, Yu Hu, Shao-zhen Nie, Yun-yun Yan,
Xue-jing Zhang, Ming Yan*
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