Rh-catalyzed aerobic oxidative cyclization of anilines, alkynes, and CO

Article abstract of DOI:10.1039/c7sc02181j

Transition-metal-catalyzed oxidative C-H cyclization of anilines has been an attractive and powerful strategy for the efficient construction of N-heterocycles. However, primary and tertiary anilines are rarely employed in this strategy due to the relative instability with strong oxidants or the presence of three C-N bonds. We describe here a novel Rh-catalyzed C-H cyclization of a wide range of anilines with alkynes and CO, using an aerobic oxidative protocol. Particularly, the simple primary anilines and readily prepared tertiary anilines could be easily converted to quinolin-2(1H)-ones, which are high value-added, biologically significant N-heterocycles, via C-N bond cleavage.

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Rh-catalyzed aerobic oxidative cyclization of anilines,alkynes, and CO†
a
a
a
a b
,
Xinyao Li, Jun Pan, Hao Wu, and Ning Jiao*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
5
Transition-metal-catalyzed oxidative C-H cyclization of anilines has been an attractive and powerful
strategy for the efficient construction of N-heterocycles. However, the primary and tertiary anilines are
rarely employed in this strategy due to the relatively unstability with strong oxidants or the presence of
three C-N bonds. By using aerobic oxidative protocol, we describe here a novel Rh-catalyzed C-H
cyclization of a wide range of anilines with alkynes and CO. Particularly, the simple primary anilines and
10 readily prepared tertiary anilines via C-N bond cleavage could be easily converted to quinolin-2(1H)-
ones, which are high value-added, biologically significant N-heterocycles.
Introduction
N-heterocyclic compounds are of great importance in
pharmaceuticals and are also versatile building blocks for natural
15 products, bioactive compounds, and drugs synthesis.1 Transition-
metal-catalyzed oxidative C-H cyclization of anilines and their
derivatives has recently emerged as one of the most attractive and
powerful strategy for efficient construction of N-heterocycles in
terms of atom and step economy.2-6 In the past decades, N-
20 monosubstituted secondary (2o amine) anilines and alkynes have
been extensively used in this field with the assistance of
stoichiometric oxidants in most cases (i, Scheme 1a).3,4 However,
despite the significances, the preparation of 2o anilines often
requires tedious multi-steps because the 3o amines would be
25 mainly obtained by the traditional substitution reaction. In addition,
the difficulty to remove R group in the formed N-heterocycles also
limit its further transformation.
In contrast, primary (1o) and tertiary (3o) anilines are more
readily available. However, only a few examples of oxidative
Scheme 1 Aerobic oxidative annulation strategies to construct
heterocycle.
30 cyclization reactions with 1o anilines have been reported (ii,
Scheme 1a),6 because of the unstability of these primary anilines
under strong oxidative conditions. And they usually prefer to
undergo acylation, hydroamination, and homocoupling.7 Moreover,
the C-H cyclization of alkynes with tertiary (3o) anilines which are
35 easily prepared is still unknown because one C−N bond cleavage
should be overcome in this process (iii, Scheme 1a).8 Whereas
most efforts on the field of the C−N bond cleavage of 3o anilines
were focused on the amination, alkylation, and arylation
50 transformation.9 Therefore, the practical oxidative C-H cyclization
of 1o and 3o anilines as stable chemicals to construct N-
heterocycles is very desired but still a challenging issue. In addition,
the transition-metal catalyzed C-H cyclization of anilines with
green and mild O2 as the oxidant10,11 is also very desired.
Herein, by using an aerobic oxidative strategy, we report an
efficient Rh-catalyzed C-H cyclization of simple anilines, alkynes,
and CO (Scheme 1b). The advantages of this protocol are threefold:
(1) A wide range of anilines are significantly employed in this
cyclization protocol and it enables new direct routes to N-H and N-
55
40 a State Key Laboratory of Natural and Biomimetic Drugs, Peking
University, School of Pharmaceutical Sciences, Peking University, Xue
Yuan Rd. 38, Beijing 100191, China.
60 R quinolin-2(1H)-ones, which represent an important class of
fused heterocyclic compounds found in many alkaloids.12,13 To the
best of our knowledge, this chemistry is the first straightforward
transformation of primary anilines to N-H quinolin-2(1H)-ones,
b State Key Laboratory of Elemento-organic Chemistry, Nankai University,
Weijin Rd. 94, Tianjin 300071, China
45 † Electronic Supplementary Information (ESI) available: Experimental
details and spectral data. See DOI: 10.1039/b000000x/
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mol%), and additive (y mol%) in PhCl (2 mL) under 1 atm CO/O2
whose synthesis usually suffered from multi-step synthesis
including protection and deprotection processes.13 In addition, the
inter-molecular C-H cyclization of tertiary anilines with alkynes
through C-N cleavage is still unknown till this case. (2) O2 is
successfully utilized as the sacrificial oxidant for the present
aerobic oxidative cyclizations in efficient ways to fulfill the
requirements of green chemistry.10,11 (3) In contrast to the well-
known two component aerobic oxidative cyclizations for N-
heterocycles such as indoles,3 this chemistry provides three
o
(v/v, 1 atm) at 130 C for 36 h. b Yields were determined by GC
analysis. c Isolated yields.
With the established aerobic oxidative conditions in hand, we
45 initially examined the scope of tertiary anilines 1 with alkynes 4
under Conditions A (Table 2). The reaction proved to be tolerant
of different substitution patterns on the aromatic core. In general,
both electron-donating and electron-withdrawing substituents of
anilines were well-tolerated under the current conditions (5a−h).
50 Anilines substituted with the halogens (F, Cl, and Br) afforded the
corresponding quinolin-2(1H)-ones in moderate to good yields
(5d−f), which could be used for further functionalization. In
addition, other alkynes were compatible to give the expected
products under the Conditions A in moderated efficiencies (5i, j).
55 The unsymmetrical aryl alkyl alkynes were also suitable for this
reaction, affording the corresponding products in good yields with
moderate regioselectivity (5k, l).
5
10 component cyclization approach to N-heterocycles with CO, which
has been used as a prominent C1 synthon in organic synthesis.14,15
Results and discussion
We initially chose N,N-dimethylaniline (1a), simple aniline (2a),
N-methylaniline (3a), and dec-5-yne (4a) as model substrates for
15 the investigation of C-H cyclization with CO (Table 1).
Considering the simple anilines could not well survive with strong
oxidant, we started the screening with O2 as the oxidant under
atmosphere pressure. Interestingly, we were excited that the
reaction of 1a catalyzed by [Rh(CO)2Cl]2 with catalytic amount of
20 Cu(OPiv)2 (10 mol%) afforded N-methyl-quinolin-2(1H)-one 5a
in 20% yield (entry 1, Table 1). Changing the mixed gas ratio and
screening ligands demonstrated that dppb performed best under
mixed gas of CO/O2 = 2:1, giving the product 5a in 60% yield
(entries 2-8). Finally, 5a was obtained in 72% yield under the
25 optimized conditions with catalytic amount of PivOH as the
additive (Conditions A, entry 9, Table 1). Control experiments
indicated that the Cu and Rh catalysts were both essential for this
transformation (entry 10, Table 1 and Table S1 in the ESI† for
details). Meanwhile, the C-H cyclization with primary aniline 2a
30 was also investigated. To our delight, under the similar conditions
(Conditions B, entry 11, Table 1), aniline (2a) was smoothly
converted into the corresponding N-H quinolin-2(1H)-one 6a in 67%
yield. Finally, under the optimized conditions (Conditions B, entry
12, Table 1), the reaction of N-methylaniline (3a) produced 5a in
35 85% yield.
Furthermore, we investigated the scope of N,N-dialkylanlines
that N-ethyl and N-benzyl groups were well compatible (5m, n).
60 Interestingly, when N-ethyl-N-methylaniline was treated with 4a,
two products 5m and 5a were obtained in 49% and 18% yields,
respectively. N-benzyl-N-ethylaniline was smoothly converted
into the products 5m and 5n in 37% and 23% yields, respectively.
It was worthy to note that N-methyl-N-(prop-2-yn-1-yl)-aniline
65 provided 5a, while N-methyl-N-phenylaniline afforded 5o as the
sole product in 31% yield, which could not be produced from
diphenylamine under Conditions B. The activation of N groups has
the order as Me > Bn > Et > Ph, indicating that the less sterically
hindered alkyl group is much more facile for cleavage.
70 Table 2 Substrate scope of tertiary anilinesa
Table 1 Optimization for the reaction of N,N-dimethylaniline (1a),
aniline (2a), N-methylaniline (3a) with dec-5-yne (4a)a
a Conditions A: see entry 9, Table 1. Isolated yields. b 4 (2 equiv.)
was employed.
On the basis of the optimization studies, we then evaluated the
75 scope and generality of primary anilines in this transformation
a Reaction conditions: aniline 1a-3a (0.3 mmol), alkyne 4a (0.45
40 mmol), Rh catalyst (2 mol%), Ligand (5 mol%), Cu catalyst (x
2
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suitable to such annulations, thus yielding the corresponding
products 5y-z in 62% yields. The unsymmetrical alkynes were also
40 suitable for this reaction, affording the corresponding products in
high yields with moderate regioselectivity (5k, l).
(Table 3). In general, primary anilines containing electron-
rich/deficient functional groups reacted smoothly to give N-H
quinolin-2(1H)-ones 6a−k in moderate to good yields.
Furthermore, a series of o-substituents can be well compatible and
the corresponding quinolin-2(1H)-ones were obtained in 40-79%
yields (6l−q). The present annulation proceeded well with
disubstituted aniline (6r). The current protocol could also be
applied to olefin-contained aniline, thereby allowing further
derivatization of the formed quinolin-2(1H)-one 6s. When the
Table 4 Substrate scope of secondary anilinesa
5
10 reaction was carried out using heterocyclic amine, the desired
product 6t was obtained in 20% yield. Besides, diarylalkyne
reacted smoothly to give the corresponding product 6u in moderate
yield. For the unsymmetrical aryl alkyl alkyne, its annulations gave
the desired compounds (5v, w) in 35-40% yields with moderate
15 regioselectivity. Interestingly, multi-substituted pyridin-2(1H)-one
6x could be constructed from the enamine through this synthetic
strategy albeit in low yield (15%, Table 3).
Table 3 Substrate scope of primary anilinesa
a Conditions B: see entry 12, Table 1. Isolated yields. b 3 (0.6 mmol)
45 and 4 (0.3 mmol) were employed.
After having been proven a wide substrate scope tolerance, this
present protocol was further applied to synthesize significant
intermediates and complex bioactive molecules. To be specific, the
mixture of 1a and 3a can be converted into the sole product 5a in
50 good yields (Scheme 2A), which demonstrates that the secondary
aniline could also be tolerated in the present protocol. Notably,
compound 7 known as a potential p38aMAP kinase inhibitor,16 can
be directly constructed in satisfactory yield through the present
protocol (Scheme 2B). Additionally, the significant intermediate 9
55 for supramolecular catalyst can be directly obtained through only
one step from corresponding primary aniline 8 under the current
standard Conditions B (Scheme 2C), In contrast, 9 was reported to
be prepared through six steps through Larock’s method including
the intermediacy of o-iodoamide.17 The current protocol could be
60 applied to late-stage construction of α 4 intergrin inhibitory 15
from aniline 3m and prepared alkyne 14, in 40% total yield with
four steps (Scheme 2D), which has potential utilities in medicinal
chemistry.18
To gain some preliminary understanding of the reaction
65 mechanism, several experiments were carried out under the
standard conditions. Upon treatment of the model reaction of 1a or
3a with 4a under standard condition with isotopically labeled
experiment, a H/D exchange of 6% in product 5a was found with
the addition of deuterated water, thereby implicating a reversible
70 cyclometalation mode [eqn (1)]. In addition, an intermolecular KIE
for the annulation reaction was determined to be kH/kD = 1.13 for
1a and 1.04 for 3a, indicating that the C(sp2)−H bond cleavage
should not be involved in the rate-determining step of the catalytic
cycle [eqn (2)].
20 a Conditions B: see entry 11, Table 1. Isolated yields. b 4 (3 equiv.)
was employed. c 2 (2 equiv.) and 4 (1 equiv.) were employed.
At this point, a range of secondary anilines 3 were fully
compatible as well under the Conditions B (Table 4). A variety of
N-methylanilines bearing electron-donating or electron-
25 withdrawing substituents on the phenyl ring underwent the
annulation to afford the corresponding quinolin-2(1H)-ones (5c-g,
5p-s) in moderate to excellent yields. For more broadly synthetic
interests, various functionalized groups, such as halides, free
carboxylic acid, esters, and nitriles were tolerated. In the case of
30 N-alkyl substituted anilines with PMB group, even with
cyclopropyl group, the desired quinolin-2(1H)-ones (5t, u) were
obtained successfully. Interestingly, tetrahydroquinoline,
tetrahydro-1H-benzo[b]azepine, and dihydrodibenzooxazepines
smoothly led to the more complex poly-heterocyclic compounds
35 (5v-x) in moderate to good yields, which are usually found in
nature products as the core structural motif and show possible
bioactivity. Diaryl-substituted alkynes also were proved to very
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Scheme
2
Further application to synthesize significant
intermediates and complex bioactive molecules. a) Et3N, DCM,
RT, 2 h, 99%; b) Tf2O, Py, DCM, RT, 1 h, 62%; c) MeCCTMS,
Pd(dppf)Cl2, CuI, iPr2NEt, DMF, 90 oC, 24 h, 98%.
5
Control experiments showed that no desired product was
observed in the absence or presence of CO, when formylated
aniline 16 was treated with 4a [eqn (3)]. These results indicate that
the formation of formylated aniline is not involved in this process.
10 In addition, carbamic chloride 17 also did not give the expected
product 5a through oxidative addition in the presence of Rh
catalyst [eqn (4)]. It is worthy to note that deuteration of N-methyl
groups have significant KIE, kH/kD = 2.53 for intramolecular KIE
and kH/kD = 2.00 for intermolecular KIE, indicating that the
15 C(sp3)−H bond cleavage might be involved in the rate-determining
step for tertiary anilines [eqn (5) and (6)]. Besides, when N,N’-
dibenzylaniline was employed, 5% yield of benzaldehyde (18) was
detected along with the expected product [eqn (7)]. This by-
product is likely to be generated from the in-site formed imine
20 intermediate through the oxidation of C(sp3)-H at the ortho
position of N atom. The kinetic experiments show that the initial
reaction rate of 3a is about three times that of 1a (Fig. 1), implying
the C-N bond cleavage of 1a was the key step.
can also be oxidated to Cu(II) using O2 in the presence of
carboxylic acid, with free energy of 19.9 kcal mol-1. This is
40 consistent with the expentmental observation that Cu catalyst plays
a pivotal role in the transformation.
Based on our preliminary mechanistic studies, we conducted the
25 density functional theory (DFT) calculation investigation into Rh-
catalyzed assembly of anilines, alkynes, and CO for quinolin-
2(1H)-one construction to better understand the mechanism of this
transformation.19 tBu group in acid and nBu groups in alkyne are
replaced by methyl groups to save computational time but without
30 sacrificing credibility. Initially, the direct aerobic oxidation of Rh(I)
to Rh(III) is calculated to be endergonic by 31.1 kcal mol-1 and the
generation of intermediate INT2 requires free energy of 34.2 kcal
mol-1, indicating the direct aerobic oxidation of Rh(I) is disfavor
(Fig. 2). However, Rh(I) can be easily oxidated to Rh(III) by Cu(II),
35 which is slightly endergonic by 11.6 kcal mol-1. The formed Cu(I)
Fig. 1 Annulation profile under Condition A or B: red circle for 1a;
45 black square for 3a.
4
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secondary aniline 3a to Rh(III) species is exogonic by 7.9 kcal mol-
1
to give stable complex INT4 that further dehydrogenation with
the release of HOAc to furnish INT5 endergonicly (Fig. 3). Then,
the consequent insertion of CO from Rh to aniline take place
20 through transition state TS1 with an activation free energy of 22.1
kcal mol-1 to afford INT6. The following H-abstraction through
transition state TS2 requires an activation free energy of only 1.8
kcal mol-1 to afford much more stable INT7. After the ligand
exchange of INT7 with alkyne 4, the formed rhodacycle complex
25 INT8 undergoes alkyne insertion through two stepwise pathways.
When C(Ar)-C(alkyne) bond was formed preferentially, it requires
an activation free energy of 20.0 kcal mol-1 to afford seven-
membered rhodacycle INT9. Finally, the reductive elimination is
facile through TS4 with energetic barrier of only 5.3 kcal mol-1
30 deliver the product 5 exogonicly, whilst regenerating the Rh(I)
catalyst. Alternatively, when C(CO)-C(alkyne) bond was formed
preferentially, transition state TS5 was high at 31.6 kcal mol-1 that
is 11.6 kcal mol-1 higher than TS3, albeit the consequent reductive
elimination occurs almost barrierlessly to provide the product 5.
35 The delivered Rh(I) species INT1 is reoxidized to Rh(III) complex
INT3 in the presence of Cu(II). Reviewing the whole energy
profiles, we found that the CO insertion and alkyne insertion in
Rh(III) species are disclosed as the key processes for this
transformation.
Fig. 2 Direct and Cu-assisted aerobic oxidation of Rh(I).
The C-N bond cleavage process with tertiary aniline is
interesting. On the basis of the previous results and our primary
experiments,9,20 the calculations showed that the Cu(II) species are
capable of oxidizing tertiary aniline through single electron
transfer (SET) and hydrogen atom transfer (HAT) pathways to give
the iminium-type intermediate, which requires a free energy of 8.8
kcal mol-1 (Fig. 3). The formed iminium-type intermediate is then
10 facilely hydrolyzed to be converted into the secondary aniline by
elimination of aldehyde as an exogonic process by 34.9 kcal mol-
1. Cu(I) catalyst is then reoxidized by oxygen to form Cu(II)
species in the presence of carboxylic acid, with free energy of 19.9
kcal mol-1.
5
40
15
When Rh(III) species INT3 is formed, the coordination of
Fig. 3 DFT-computed energy profiles for quinolin-2(1H)-one construction through Rh-catalyzed assembly of anilines, alkynes, and CO.
The energies discussed are Gibbs free energies in PhCl (ΔGsol). The numbers in the parentheses are Gibbs free energies in gas-phase (ΔG).
This synthetic strategy can be efficiently catalyzed by Rh-
45 catalysis system. However, Pd-catalysis system performs
the experimental observation. In addition, Ir-catalysis system has
been employed in recent report.4c The current calculational study
ineffective experimentally. Accordingly, the unreactive Pd- 55 indicated that the CO insertion catalyzed by Ir complex suffers
catalysis system was also calculated for comparison (Fig. 4, see the
ESI† for details). It is found that the Pd-catalysis system suffer
from high energetic barrier of 38.3 kcal mol-1 (TS9) in alkyne
50 insertion process due to the unstable quadridentate fashion of Pd
complex, though the CO insertion is facile with energetic barrier
of only 13.6 kcal mol-1 (TS7). This is qualitatively consistent with
from an activation free energy of 28.3 kcal/mol, which is 6.2
kcal/mol higher than that of Rh-catalysis, once again in agreement
with the experimental demand of 30 atm CO for Ir-catalysis.
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Page 6 of 8
2010, 132, 18326; (c) M. P. Huestis, L. Chan, D. R. Stuart and K.
Fagnou, Angew. Chem., Int. Ed., 2011, 50, 1338; (d) C. Wang, H. Sun,
Y. Fang and Y. Huang, Angew. Chem., Int. Ed., 2013, 52, 5795; (e) D.
Zhao, Z. Shi and F. Glorius, Angew. Chem., Int. Ed., 2013, 52, 12426;
(f) L. Ackermann and A. V. Lygin, Org. Lett., 2012, 14, 764; (g) J.
Chen, G. Song, C.-L. Pan and X. Li, Org. Lett., 2010, 12, 5426; (h) S.
Cai, K. Yang and D. Z. Wang, Org. Lett., 2014, 16, 2606; (i) P. Tao
and Y. Ji, Chem. Commun., 2014, 50, 7367; (j) Y. Kim and S. Hong,
Chem. Commun., 2015, 51, 11202.
For examples of N-heterocycle synthesis from three-components
cyclization of secondary anilines with alkynes and CO (1-30 atm),
using stoichiometric amount of BQ or copper salt as oxidant, see: (a)
J. Chen, K. Natte, A. Spannenberg, H. Neumann, M. Beller and X.-F.
Wu, Chem. Eur. J., 2014, 20, 14189; (b) X. Y. Li, X. W. Li and N. Jiao,
J. Am. Chem. Soc., 2015, 137, 9246; (c) F. Zhu, Y. Li, Z. Wang and
X.-F. Wu, Adv. Synth. Catal., 2016, 358, 3350; (d) J. Chen, J.-B. Feng,
K. Natte and X.-F. Wu, Chem. Eur. J., 2015, 21, 16370.
For examples of N-heterocycle synthesis from other N-containing
substrates: (a) R. Bernini, G. Fabrizi, A. Sferrazza and S. Cacchi,
Angew. Chem., Int. Ed., 2009, 48, 8078; (b) S. Würtz, S. Rakshit, J. J.
Neumann, T. Dröge and F. Glorius, Angew. Chem., Int. Ed., 2008, 47,
7230; (c) X. Xu, Y. Liu and C.-M. Park, Angew. Chem., Int. Ed., 2012,
51, 9372; (d) T. K. Hyster and T. Rovis, Chem. Sci., 2011, 2, 1606; (e)
T. K. Hyster and T. Rovis, J. Am. Chem. Soc., 2010, 132, 10565; (f) L.
Ackermann, A. V. Lygin and N. Hofmann, Angew. Chem., Int. Ed.,
2011, 50, 6379; (g) L. Ackermann, A. V. Lygin and N. Hofmann, Org.
Lett., 2011, 13, 3278; (h) Z. Shi, B. Zhang, Y. Cui and N. Jiao, Angew.
Chem., Int. Ed., 2010, 49, 4036; (i) Y. Wei, I. Deb and N. Yoshikai, J.
Am. Chem. Soc., 2012, 134, 9098; (j) L. Ackermann, L. Wang and A.
V. Lygin, Chem. Sci., 2012, 3, 177; (k) L. Wang and L. Ackermann,
Org. Lett., 2013, 15, 176; (l) S. Y. Hong, J. Jeong and S. Chang, Angew.
Chem., Int. Ed., 2017, 56, 2408; (m) K. Alex, A. Tillack, N. Schwarz
and M. Beller, Angew. Chem., Int. Ed., 2008, 47, 2304; (n) M. Shen,
B. E. Leslie and T. G. Driver, Angew. Chem., Int. Ed., 2008, 47, 5056;
(o) Á. M. Martínez, J. Echavarren, I. Alonso, N. Rodríguez, R. G.
Arrayás and J. C. Carretero, Chem. Sci., 2015, 6, 5802.
45
50
55
60
65
70
75
4
5
Fig. 4 DFT-computed transition state structures of CO insertion
and alkyne insertion in Rh and Pd catalysis system
Conclusions
5
In conclusion, a wide variety of anilines, especially the simple
primary and tertiary anilines were successfully employed in inter-
molecular C-H cyclization with alkynes and CO. This novel
protocol by Rh-catalysis provides a direct approach to N-H/N-
substituted quinolin-2(1H)-ones. The readily available anilines,
10 and the operationally simple conditions under 1 atm mixture of CO
and O2 make this protocol very practical, green, and sustainable.
This chemistry provides a direct route to quinolin-2(1H)-ones,
which are biologically significant N-heterocycles and useful
building blocks in organic synthesis. DFT calculations suggest that
15 the relay of CO insertion and alkyne insertion in Rh-catalysis are
disclosed as the key processes, while unreactive Pd-catalysis
suffers from high energetic barrier in alkyne insertion process due
to the unstable quadridentate fashion of Pd complex. Further
applications of this transformation are ongoing in our laboratory.
80 6 (a) Z. Shi, C. Zhang, S. Li, D. Pan, S. Ding, Y. Cui and N. Jiao, Angew.
Chem., Int. Ed., 2009, 48, 4572; (b) G. Zhang, H. Yu, G. Qin and H.
Huang, Chem. Commun., 2014, 50, 4331.
7
(a) G. Choudhary and R. K. Peddinti, Green Chem., 2011, 13, 3290;
(b) C. Zhang and N. Jiao, Angew. Chem., Int. Ed., 2010, 49, 6174.
85 8 For a C-H cyclization example with alkenes, see: (a) R. Shi, L. Lu, H.
Zhang, B. Chen, Y. Sha, C. Liu and A. Lei, Angew. Chem., Int. Ed.,
2013, 52, 10582; For some intra-molecular cyclization via C-N bond
cleavage, see: (b) D. Yue and R. C. Larock, Org. Lett., 2004, 6, 1037;
(c) B. Yao, Q. Wang and J. Zhu, Angew. Chem., Int. Ed., 2012, 51,
20 Acknowledgements
Financial support from National Basic Research Program of China
(973 Program) (grant No. 2015CB856600), National Natural
Science Foundation of China (No. 21325206, 21632001), National
Young Top-notch Talent Support Program, and Peking University
25 Health Science Center (No. BMU20160541) are greatly
appreciated. We thank Lingsheng Ai in this group for reproducing
the results of 5m, 6f, and 5v.
90
5170; (d) X.-F. Xia, L.-L. Zhang, X.-R. Song, Y.-N. Niu, X.-Y. Liu
and Y.-M. Liang, Chem. Commun., 2013, 49, 1410; (e) B. Yao, Q.
Wang and J. Zhu, Angew. Chem., Int. Ed., 2013, 52, 12992; (f) J. Sheng,
S. Li and J. Wu, Chem. Commun., 2014, 50, 578; (g) R. Shi, H. Niu,
L. Lu and A. Lei, Chem. Commun., 2017, 53, 1908.
95 9 (a) X. Zhao, D. Liu, H. Guo, Y. Liu and W. Zhang, J. Am. Chem. Soc.,
2011, 133, 19354; (b) Y. Kuninobu, M. Nishi and K. Takai, Chem.
Commun., 2010, 46, 8860; (c) J. Shearer, C. X. Zhang, L. Q. Hatcher
and K. D. Karlin, J. Am. Chem. Soc., 2003, 125, 12670; (d) S. Ueno,
N. Chatani and F. Kakiuchi, J. Am. Chem. Soc., 2007, 129, 6098; (e)
Notes and references
100
S. B. Blakey and D. W. C. MacMillan, J. Am. Chem. Soc., 2003, 125,
6046; (f) L.-G. Xie and Z.-X. Wang, Angew. Chem., Int. Ed., 2011, 50,
4901; C−N bond cleavage of amines: (g) Y. Xie, J. Hu, Y. Wang, C.
Xia and H. Huang, J. Am. Chem. Soc., 2012, 134, 20613; (h) M.-B. Li,
Y. Wang and S.-K. Tian, Angew. Chem., Int. Ed., 2012, 51, 2968.
105 10 (a) C.-J. Li and B. M. Trost, Proc. Natl. Acad. Sci., 2008, 105, 13197;
(b) P. T. Anastas and N. Eghbali, Chem. Soc. Rev., 2010, 39, 301. (c)
M. Costas, M. P. Mehn, M. P. Jensen and Jr. L. Que, Chem. Rev., 2004,
104, 939; (d) J. Piera and J. E. Backvall, Angew. Chem. Int. Ed., 2008,
47, 3506; (e) F. Cavani and J. H. Teles, ChemSusChem, 2009, 2, 508;
1
(a) T. Eicher and S. Hauptmann, The Chemistry of Heterocycles:
Structure, Reactions, Syntheses, and Applications, 2nd ed., Wiley-
VCH, Weinheim, 2003; (b) G. Jones, Comprehensive Heterocyclic
Chemistry II; A. R. Katritzky, C. W. Rees, E. F. V. Scriven, Eds.,
Pergamon Press: New York, 1996.
For reviews on C-H annulations, see: (a) L. Ackermann, Acc. Chem.
Res., 2014, 47, 281; (b) G. Song, F. Wang and X. Li, Chem. Soc. Rev.,
2012, 41, 3651; (c) T. Satoh and M. Miura, Chem. Eur. J., 2010, 16,
11212; (d) M. Gulñas and J. L. MascareÇas, Angew. Chem., Int. Ed.,
2016, 55, 11000; (e) N. Yoshikai and Y. Wei, Asian J. Org. Chem.,
2013, 2, 466.
30
35
2
110
(f) P. R. Ortiz de Montellano, Chem. Rev., 2010, 110, 932.
11 For examples on Rh-catalyzed aerobic oxidative annulations, see: (a)
G. Zhang, L. Yang, Y. Wang, Y. Xie and H. Huang, J. Am. Chem. Soc.,
2013, 135, 8850; (b) Y. Lu, H.-W. Wang, J. Spangler, K. Chen, P.-P.
Cui, Y. Zhao, W.-Y. Sun and J.-Q. Yu, Chem. Sci., 2015, 6, 1923; (c)
40 3 For examples of N-heterocycle synthesis from anilines and derivatives
with alkynes, see: (a) D. R. Stuart, M. Bertrand-Laperle, K. M. N.
Burgess and K. Fagnou, J. Am. Chem. Soc., 2008, 130, 16474; (b) D.
R. Stuart, P. Alsabeh, M. Kuhn and K. Fagnou, J. Am. Chem. Soc.,
6
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

View Article Online
DOI: 10.1039/C7SC02181J
Page 7 of 8
Chemical Science
Q. Jiang, C. Zhu, H. Zhao and W. Su, Chem. Asian J., 2016, 11, 356;
(d) G. Zhang, H. Yu, G. Qin and H. Huang, Chem. Commun., 2014,
50, 4331; (e) C.-Z. Luo, P. Gandeepan, J. Jayakumar, K. Parthasarathy,
Y.-W. Chang and C.-H. Cheng, Chem. Eur. J., 2013, 19, 14181; (f) J.
Jayakumar and C.-H. Cheng, Chem. Eur. J., 2016, 22, 1800.
Neumann and M. Beller, Angew. Chem., Int. Ed., 2010, 49, 7316; (c)
X. Fang, R. Jackstell and M. Beller, Angew. Chem., Int. Ed., 2013, 52,
14089; (d) K. Dong, X. Fang, R. Jackstell, G. Laurenczy, Y. Li and M.
Beller, J. Am. Chem. Soc., 2015, 137, 6053; (e) R. Giri and J.-Q. Yu,
J. Am. Chem. Soc., 2008, 130, 14082; (f) Z.-H. Guan, Z.-H. Ren, S. M.
Spinella, S. Yu, Y.-M. Liang and X. Zhang, J. Am. Chem. Soc., 2009,
131, 729; (g) C. E. Houlden, M. Hutchby, C. D. Bailey, J. G. Ford, S.
N. G. Tyler, M. R. Gagne, G. C. Lloyd-Jones and K. I. Booker-Milburn,
Angew. Chem., Int. Ed., 2009, 48, 1830; (h) J. S. Quesnel, A. Fabrikant
and B. A. Arndtsen, Chem. Sci., 2016, 7, 295; (i) Z.-H. Guan, M. Chen
and Z.-H. Ren, J. Am. Chem. Soc., 2012, 134, 17490; (j) W. Li, Z.
Duan, X. Zhang, H. Zhang, M. Wang, R. Jiang, H. Zeng, C. Liu and
A. Lei, Angew. Chem., Int. Ed., 2015, 54, 1893; (k) W. Li, C. Liu, H.
Zhang, K. Ye, G. Zhang, W. Zhang, Z. Duan, S. You and A. Lei,
Angew. Chem., Int. Ed., 2014, 53, 2443; (l) J. Tjutrins and B. A.
Arndtsen, Chem. Sci., 2017, 8, 1002.
35
40
45
5
12 (a) G. Claassen, E. Brin, C. Crogan-Grundy, M. T. Vaillancourt, H. Z.
Zhang, S. X. Cai, J. Drewe, B. Tseng and S. Kasibhatla, Cancer Lett.,
2009, 274, 243; (b) R. M. Forbis and K. L. Rinehart, J. Am. Chem. Soc.,
1973, 95, 5003; (c) A. L. Hopkins, J. Ren, J. Milton, R. J. Hazen, J. H.
Chan, D. I. Stuart and D. K. Stammers, J. Med. Chem., 2004, 47, 5912;
(d) A. Doleans-Jordheim, J.-B. Veron, O. Fendrich, E. Bergeron, A.
Montagut-Romans, Y.-S. Wong, B. Furdui, J. Freney, C. Dumontet
and A. Boumendjel, ChemMedChem, 2013, 8, 652; (e) R. W. Carling,
P. D. Leeson, K. W. Moore, J. D. Smith, C. R. Moyes, I. M. Mawer, S.
Thomas, T. Chan and R. Baker, J. Med. Chem., 1993, 36, 3397.
10
15
20
13 (a) D. V. Kadnikov and R. C. Larock, J. Org. Chem., 2004, 69, 6772;
(b) T. Iwai, T. Fujihara, J. Terao and Y. Tsuji, J. Am. Chem. Soc., 2010, 50 16 (a) J. DeRuiter, B. E. Swearingen, V. Wandrekar and C. A. Mayfield,
132, 9602; (c) R. Zeng and G. Dong, J. Am. Chem. Soc., 2015, 137,
1408; (d) J. Wu, S. Xiang, J. Zeng, M. Leow and X.-W. Liu, Org. Lett.,
2015, 17, 222; (e) R. Manikandan and M. Jeganmohan, Org. Lett.,
2014, 16, 3568; (f) B.-X. Tang, R.-J. Song, C.-Y. Wu, Z.-Q. Wang, Y.
J. Med. Chem., 1989, 32, 1033; (b) C. Peifer, R. Urich, V. Schattel, M.
Abadleh, M. Röttig, O. Kohlbacher and S. Laufer, Bioorg. Med. Chem.
Lett., 2008, 18, 1431.
17 E. Sheiban and K. Wärnmark, Org. Biomol. Chem., 2012, 10, 2059.
Liu, X.-C. Huang, Y.-X. Xie and J.-H. Li, Chem. Sci., 2011, 2, 2131; 55 18 T. Okuzumi, T. Yoshimura, E. Nakanishi, M. Ono and M. Murata,
(g) P. J. Manley and M. T. Bilodeau, Org. Lett., 2004, 6, 2433; (h) X.-
F. Yang, X.-H. Hu and T.-P. Loh, Org. Lett., 2015, 17, 1481.
Novel Phenylalanine Derivatives. WO 03/053926 A1, July 3, 2003.
19 Computational details and references are given in the Supporting
Information.
25 14 For reviews on carbonylation reactions, see: (a) X.-F. Wu, H.
Neumann and M. Beller, Chem. Soc. Rev., 2011, 40, 4986; (b) X.-F.
Wu and H. Neumann, ChemCatChem, 2012, 4, 447; (c) X.-F. Wu, X.
Fang, L. Wu, R. Jackstell, H. Neumann and M. Beller, Acc. Chem. Res.,
2014, 47, 1041; (d) Q. Liu, H. Zhang and A. Lei, Angew. Chem., Int.
20 (a) E. A. Lewis and W. B. Tolman, Chem. Rev., 2004, 104, 1047; (b)
L. M. Mirica, X. Ottenwaelder and T. D. P. Stack, Chem. Rev., 2004,
104, 1013; (c) S. T. Prigge, B. A. Eipper, R. E. Mains and L. M. Amzel,
Science, 2004, 304, 864; (d) W. Nam, Acc. Chem. Res., 2007, 40, 465;
(e) J.-S. Tian and T.-P. Loh, Angew. Chem., Int. Ed., 2010, 49, 8417;
(f) S. Guo, B. Qian, Y. Xie, C. Xia and H. Huang, Org. Lett., 2011, 13,
522; (g) S. Mahapatra, J. A. Halfen and W. B. Tolman, J. Am. Chem.
Soc., 1996, 118, 11575.
60
65
30
Ed., 2011, 50, 10788.
15 For examples of carbonylation reactions, see: (a) N. Chatani, T.
Asaumi, T. Ikeda, S. Yorimitsu, Y. Ishii, F. Kakiuchi and S. Murai, J.
Am. Chem. Soc., 2000, 122, 12882; (b) X.-F. Wu, P. Anbarasan, H.
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ARTICLE TYPE
Rh-catalyzed aerobic oxidative cyclization of anilines,alkynes, and CO†
Xinyao Li,a Jun Pan,a Hao Wu,a and Ning Jiao*a,b
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
5
ones, which are high valueꢀadded, biologically significant Nꢀheterocycles.
/
Transitionꢀmetalꢀcatalyzed oxidative CꢀH cyclization of anilines has been an attractive and powerful
10 strategy for the efficient construction of Nꢀheterocycles. However, the primary and tertiary anilines are
rarely employed in this strategy due to the relatively unstability with strong oxidants or the presence of
three CꢀN bonds. By using aerobic oxidative protocol, we describe here a novel Rhꢀcatalyzed CꢀH
cyclization of a wide range of anilines with alkynes and CO. Particularly, the simple primary anilines and
readily prepared tertiary anilines via CꢀN bond cleavage could be easily converted to quinolinꢀ2(1H)ꢀones,
15 which are high valueꢀadded, biologically significant Nꢀheterocycles.
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