Synthesis of 1-aminoisoquinolines via Rh(III)-catalyzed oxidative coupling

Article abstract of DOI:10.1021/ol2018505

[RhCp*Cl₂]₂ can catalyze the oxidative coupling of N-aryl and N-alkyl benzamidines with alkynes to give N-substituted 1-aminoisoquinolines in high selectivity.

Full text of DOI:10.1021/ol2018505

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4636–4639
Synthesis of 1-Aminoisoquinolines via
Rh(III)-Catalyzed Oxidative Coupling
Xiaohong Wei,†,‡ Miao Zhao,† Zhengyin Du,‡ and Xingwei Li*,†
Dalian Institute of Chemical Physics, The Chinese Academy of Sciences, Dalian, 116023,
P.R. China, and College of Chemistry and Chemical Engineering,
Northwest Normal University, Lanzhou 730070, P. R. China
xwli@dicp.ac.cn
Received July 10, 2011
ABSTRACT
[RhCp*Cl2]2 can catalyze the oxidative coupling of N-aryl and N-alkyl benzamidines with alkynes to give N-substituted 1-aminoisoquinolines in
high selectivity.
Transition-metal catalyzed organic reactions via activa-
tion of CÀH bonds have attracted increasing attention.1
This process is attractive in that CÀH bonds are ubiqui-
tous and prefunctionalization of CÀH bonds is no longer
necessary. Therefore, selective and efficient functionaliza-
tion of CÀH bonds under mild conditions has been long
sought, and this should allow the construction of complex
molecules in an energy-efficient and step-economic fash-
ion. Significant progresses have been made, and this topic
has been extensively reviewed.2 Among the various pro-
mising activation strategies is the utilization of a proximal
directing group, which facilitates the activation of sub-
strate ortho CÀH bonds. By utilizing this strategy with
oxygen and nitrogen directing groups, rhodium complexes
havestood out asefficient catalysts in the functionalization
of CÀH bonds using unsaturated coupling partners.3
Recently, Rh(III)-catalyzed oxidative CÀH functiona-
lization of arenes with alkynes has been increasingly
explored, which allowed for the synthesis of a broad
spectrum of heterocycles.4 A number of research groups,
including ours,5 have successfully applied this method to
the synthesis of isoquinolines,6 isoquinolones,5c,7 indoles,8
isocoumarins,9 indenols,4b,d pyrroles,10 and pyridones.5d,11
† The Chinese Academy of Sciences.
‡ Northwest Normal University.
(1) For recent reviews, see: (a) Wencel-Delord, J.; Droge, T.; Glorius,
F. Chem. Soc. Rev. 201110.1039/c1cs15083a. (b) Yeung, C. S.; Dong, V. M.
Chem. Rev. 2011, 111, 1215. (c) Lyons, T. W.; Sanford, M. S. Chem. Rev.
2010, 110, 1147. (d) Sun, C. L.; Li, B. J.; Shi, Z.-J. Chem. Commun 2010,
46, 677. (e) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int.
Ed. 2009, 48, 9792.
(2) (a) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2009, 48, 5094. (b) Xu, L. M.; Li, B.-J.; Yang, Z.; Shi,
Z.-J. Chem. Soc. Rev. 2010, 39, 712. (c) Chen, X.; Engle, K. M; Wang,
D. H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (d) Zhang, M.
Adv. Syn. Cat 2009, 351, 2243. (e) Alberico, D.; Scott, M. E.; Lautens, M.
Chem. Rev. 2007, 107, 3013. (f) Ackermann, L. Chem. Rev. 2011, 111,
1315.
(3) For recent reviews, see: (a) Colby, D. A.; Bergman, R. G.; Ellman,
J. A. Chem. Rev. 2010, 110, 624. (b) Satoh, T.; Miura, M. Chem.;Eur. J.
2010, 37, 11212. (c) Satoh., T.; Ueura, K.; Miura, M. Pure Appl. Chem.
2008, 80, 1127. For individule reports, see:(d) Tsai, A. S.; Tauchert,
M. E.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2011, 133, 1248.
(e) Patureau, F. W.; Besset, T.; Glorius, F. Angew. Chem., Int. Ed. 2011,
50, 1064. (f) Li, Y.; Li, B. J.; Wang, W. H.; Huang, W. P.; Zhang, X. S.;
Chen, K.; Shi, Z.-J. Angew. Chem., Int. Ed. 2011, 50, 2115.
(4) (a) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F. J. Am.
Chem. Soc. 2011, 133, 2350. (b) Patureau, F. W.; Besset, T.; Kuhl, N.;
Glorius, F. J. Am. Chem. Soc. 2011, 133, 2154. (c) Huestis, M. P.; Chan,
L.; Stuart, D. R.; Fagnou, K. Angew. Chem., Int. Ed. 2011, 50, 1338. (d)
Muralirajan, K.; Parthasarathy, K.; Cheng, C.-H. Angew. Chem., Int.
Ed. 2011, 50, 4169. (e) Stuart, D. R.; Alsabeh, P.; Kuhn, M.; Fagnou, K.
J. Am. Chem. Soc. 2010, 132, 18326. (f) Mochida, S.; Hirano, K.; Satoh,
T.; Miura, M. Org. Lett. 2010, 12, 5776. (g) Fukutani, T.; Hirano, K.;
Satoh, T.; Miura, M. Org. Lett. 2009, 11, 5198. For pioneering work on
Rh(III)-mediated stoichiometric CÀH activation and functionalization,
see:(h) Davies, D. L.; Al-Duaij, O.; Fawcett, J.; Giardiello, M.; Hilton,
S. T.; Russell, D. R. Dalton Trans. 2003, 4132. (i) Li, L.; Brennessel,
W. W.; Jones, W. D. Organometallics 2009, 28, 3492. (j) Li, L.;
Brennessel, W. W.; Jones, W. D. J. Am. Chem. Soc. 2008, 130, 12414.
(5) (a) Chen, J.; Song, G.; Pan, C.-L.; Li, X. Org. Lett. 2010, 12, 5426.
(b) Wang, F.; Song, G.; Li, X. Org. Lett. 2010, 12, 5430. (c) Song, G.;
Chen, D.; Pan, C.-L.; Crabtree, R. H.; Li, X. J. Org. Chem. 2010, 75,
7487. (d) Su, Y.; Zhao, M.; Han, K.; Song, G.; Li, X. Org. Lett. 2010, 12,
5462. (e) Zhang, X. P.; Chen, D.; Zhao, M.; Zhao, J.; Jia, A. Q.; Li, X.
Adv. Synth. Catal. 2011, 353, 719. (f) Wang, F.; Song, G.; Du, Z.; Li, X.
J. Org. Chem. 2011, 76, 2926.
r
10.1021/ol2018505
Published on Web 08/03/2011
2011 American Chemical Society

Despite the success, it is still necessary to explore substrates
with readily installed directing groups that lead to other-
wise less accessible structures.
benzamidines and alkynes, leading to 1-(alkylamino)- and
1-(arylamino) isoquinolines.
Recent studies by Miura and Satoh,7b Rovis,7a and us5c
indicated that Rh(III) can catalyze the oxidative CÀH
activation of N-aryl benzamides (PhC(O)NHAr) in the
C-ring. We feel that N-aryl benzamidines are structurally
related and should undergo analogous reactions with
alkynes. However, these two classes of substrates are
intrinsically different in that N-aryl benzamidines are
essentially bifunctional with two NÀH bonds. In addition,
the low thermostability of benzamidines might cause
complications. Thus, at least three oxidation products
(AÀC) can be expected when 1a reacts with PhCtCPh
(eq 1). Moreover, further coupling of these products with a
second equivalent of PhCtCPh is also possible. We herein
report the successful isolation of type A products.
Figure 1. Rh(III)-catalyzed synthesis of isoquinolines.
Isoquinolines are key structural motifs in compounds
with important biological activity, and they are also im-
portant organic building blocks.12 Recently, Fagnou,6a
Miura and Satoh,6b Chiba,13 and We5e have successfully
applied Rh(III) catalysts to the synthesis of isoquinolines
via a CÀH activation pathway (Figure 1). However, these
products are generally less functionalized at the 1-position.
To expend the synthetic utility of Rh(III) catalysis, we aim
to prepare less accessible 1-aminoisoquinolines.14 We
noted that the nitrogen in benzamide can act as an efficient
directing group for CÀH activation in metal-catalyzed
oxidative cyclization.15 However, no oxidative cross-cou-
pling has been reported. We now report Rh(III)-catalyzed
oxidative CÀC and CÀN coupling between N-substituted
Table 1. Screening of Conditionsa,b
entry
oxidant
x
solvent
temp (°C)
yield (%)c
(6) (a) Guimond, N.; Fagnou, K. J. Am. Chem. Soc. 2009, 131, 12050.
(b) Fukutani, T.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. Chem.
Commun. 2009, 44, 5141.
(7) (a) Hyster, T. K.; Rovis, T. J. Am. Chem. Soc. 2010, 132, 10565.
(b) Mochida, S.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. Chem.
Lett. 2010, 39, 744. (c) Guimond, N.; Gorelsky, S. I.; Fagnou, K. J. Am.
Chem. Soc. 2011, 133, 6449.
(8) (a) Stuart, D. R.; Alsabeh, P.; Kuhn, M.; Fagnou, K. J. Am.
Chem. Soc. 2010, 132, 18326. (b) Stuart, D. R.; Bertrand-Laperle, M.;
Burgess, K. M. N.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 16474.
(9) (a) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9, 1407. (b)
Ueura, K.; Satoh, T.; Miura, M. J. Org. Chem. 2007, 72, 5362.
(10) Rakshit, S.; Patureau, F. W.; Glorius, F. J. Am. Chem. Soc.
2010, 132, 9585.
1
Ag2CO3
4
acetone
acetone
acetone
o-xylene
DMF
tAmOH
MeCN
DME
120
90
13
25
38
58
14
37
28
45
74
47
2
Ag2CO3
4
3
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
2.5
2.5
2.5
2.5
2.5
2.5
4
90
4
100
100
110
120
90
5
6
7
8
9
10d
THF
85
4
THF
85
(11) Hyster, T. K.; Rovis, T. Chem. Sci. 2011, 2, 1606.
a Reaction conditions: 1a (0.3 mmol), diphenyl acetylene (1.05 equiv),
oxidant(2.1 equiv for Cu(OAc)2 or1.3 equivfor Ag2CO3), solvent (3 mL),
13 h, sealed tube under N2. b No evidence for the formation of products of
types B and C. c Isolated yield. d 1a (0.3 mmol), PhCtCPh (1.05 equiv),
Cu(OAc)2 (2.1 equiv), [RhCp*Cl2]2 (4 mol %), AgSbF6 (16 mol %), THF
(3 mL), 13 h, sealed tube under N2.
(12) Hwang, S.; Lee, Y.; Lee, P. H.; Shin, S. Tetrahedron Lett. 2009,
50, 2305. (b) Gao, H.; Zhang, J. Adv. Synth. Catal. 2009, 351, 85. (c)
Fischer, D.; Tomeba, H.; Pahadi, N. K.; Patil, N. T.; Yamamoto, Y.
Angew. Chem., Int. Ed. 2007, 46, 4764. (d) Konno, T.; Chae, J.; Miyabe,
T.; Ishihara, T. J. Org. Chem. 2005, 70, 10172. (e) Korivi, R. P.; Cheng,
C.-H. Org. Lett. 2005, 7, 5179. (f) Churruca, F.; SanMartin, R.; Carril,
M.; Urtiaga, M. K.; Solans, X.; Tellitu, I.; Domınguez, E. Org. Lett.
2005, 7, 3178. For a recent review, see:(g) Giri, P.; Kumar, G. S. Mini-
Rev. Med. Chem. 2010, 10, 568.
(13) (a) Wang, Y.-F.; Toh, K. K.; Lee, J.-Y.; Chiba, S. Angew. Chem.,
Int. Ed. 2011, 50, 5927. (b) Too, P. C.; Wang, Y.-F.; Chiba, S. Org. Lett.
2010, 12, 5688. (c) Too, P. C.; Chua, S. H.; Wong, S. H.; Chiba, S. J. Org.
Chem. 201110.1021/jo200897q.
(14) (a) Yin, J. J.; Xiang, B. P.; Huffman, M. A.; Raab, C. E.; Davies,
I. W. J. Org. Chem. 2007, 72, 4554. (b) Xie, X. M.; Zhang, T. Y.; Zhang,
Z. G. J. Org. Chem. 2006, 71, 6522.
(15) (a) Xiao, Q.; Wang, W. H.; Liu, G.; Meng, F. K.; Chen, J. H.;
Yang, Z.; Shi, Z.-J. Chem.;Eur. J. 2009, 15, 7292. (b) Brasche, G.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 1932. For a recent
review, see ref 2d.
We commenced our studies with the oxidative coupling
of N-phenylbenzamidine (1a) and PhCtCPh. The condi-
tions that are optimal for the coupling of N-phenylbenza-
mide and alkynes were applied first (Ag2CO3, [RhCp*Cl2]2
(4 mol %), acetone, 120 °C).5c Although a full conversion
was reached (Table 1, entry 1), product 2aa was isolated in
only 13% yield together with an unindentifiable yellow
mixture, indicative of a low selectivity. By lowering the
Org. Lett., Vol. 13, No. 17, 2011
4637

temperature to 90 °C, the yield of 2aa is slightly increased
(entry 2). When Cu(OAc)2 was used as an oxidant, a
comparable isolated yield was achieved with 2.5 mol %
loading of the catalyst (entry 3). Further optimization
using solvents such as MeCN, DME, o-xylene, DMF,
and tert-AmOH all failedtogivesyntheticallyviableyields.
The well-studied cationic catalyst system [RhCp*Cl2]2
(4 mol %)/AgSbF6 (16 mol %) also failed to give syntheti-
cally acceptable yield. Fortunately, using THF as a solvent
(85 °C) and Cu(OAc)2 as an oxidant, product 2aa was
isolated in 74% yield with 4 mol % catalyst loading (entry 9).
The structure of compound 2aa was determined as an
isoquinoline (type A) on the basis of NMR spectroscopy.16
Under these optimized conditions, 2aa is the only major
product that can be isolated, although the unidentifiable
yellow mixture still exists. In all cases, no evidence for the
formation of products of types B and C could be obtained,
and no such products were isolated.
(Scheme 2). A series of N-aryl benzamidines was examined
first. Benzamidines with para-substituted (including halo-
gens) N-phenyl groups coupled smoothly with PhCtCPh
to give the correponding product in yield ranging from 62
to84% (2ba, 2ca, 2da, 2ea, and 2fa), wherethe highestyield
was obtained for N-(para-fluorophenyl)benzamidine. How-
ever, there seems to be no direct correlation between the
electronic parameter of the para-substitutent and the
reaction yield, which might be ascribed to the presence of
the unidentifiable coupling product in each reaction.
Further examinations indicated that the reaction yield is
not significantly affected by the steric bulk of the N-aryl
Scheme 2. Coupling of Benzamidines with PhCtCPha,b
With the optimized conditions in hand, we explored the
coupling of benzamidine 1a with other alkynes (Scheme 1).
Coupling with symmetrically substituted diarylacetylenes,
including di(2-thiophenyl)acetylene, afforded the desired
products in moderate to good yield (52À74%). The cou-
pling of1awith4-octyneproceededsmoothly, and product
Scheme 1. Coupling of 1a with Alkynea,b,c
a Reaction conditions: 1a (0.3 mmol), diphenyl acetylene (1.05 equiv),
Cu(OAc)2 (2.1 equiv), THF (3 mL), sealed tube under N2, 13 h.
b No product of type B or C could be isolated.
c 1a (0.3 mmol), diphenyl acetylene (1.05 equiv), Cu(OAc)2 (2.1
equiv), acetone (3 mL), 110 °C, sealed tube under nitrogen.
a Reaction conditions: 1a (0.3 mmol), diphenyl acetylene (1.05 equiv),
Cu(OAc)2 (2.1 equiv), solvent (3 mL), 13 h, sealed tube under nitrogen.
b Isolated yield.
d 1a (0.3 mmol), diphenyl acetylene (2.1 equiv), Cu(OAc)2 (4.2 equiv),
acetone (3 mL), sealed tube under nitrogen.
e 24 h.
c No product of type B or C could be isolated.
group in the benzamidine when o-Me (2ga) and o-OMe
(2ha) are introduced, and these products were isolated in
good yield. However, essentially no reaction occurred
when N-(1-naphthyl)benzamidine was subjected to the
standard conditions. Only by moving to harsh conditions
(acetone, 110 °C) was the desired product obtained in 50%
yield (2ia).
To better define the scope of this coupling reaction, two
benzamidines with a sterically less accessible C-ring were
examined. Fusing an extra phenyl ring to the C-phenyl
(1m) caused significant differences in reactivity and selectivity.
2ad was obtained in 55% yield. Unsymmetrically substi-
tuted alkyne PhCtCnPr reacted to afford a mixture of two
regioisomers (2ag) in 59% yield and in 4:1 ratio. In
contrast, 2af was isolated (57%) as a single isomer using
an unsymmetrical thiophenyl-substituted alkyne.
The scope and limitations of this reaction were further
defined using diphenylacetylene as a coupling partner
(16) On the basis of the 13C NMR spectrum of compound 2da, the
structure was further confirmed, where the presence of 13CÀ19F cou-
pling can help rule out structures B and C.
4638
Org. Lett., Vol. 13, No. 17, 2011

Essentially no reaction between 1m and PhCtCPh oc-
curred under the standard conditions (THF, 85 °C), How-
ever, a clean reaction did proceed in acetone at 110 °C(24h),
N-aryl group, the substrate is bifunctional, so that side
reaction products such as types B and C can be possible,
while those are suppressed for N-alkyl substrates. In
addition, since the tBu group is distal to the reaction site,
its steric bulk is well-tolerated. Thus N-tert-Bu and N-Cy
benzamidines coupled with PhCtCPh in high yield for
substrates bearing different para substituents in the C-ring
(2paÀ2ta). Significantly, 2qa was even isolated in nearly
quantitative yield when a m-Me group was introduced to
the C-phenyl ring, and the product corresponds to CÀH
activation at a less hindered position (2qa). Further studies
indicated that this coupling reaction is significantly af-
fected by the steric bulk of the C-ring. For example, no
reaction occurred when a Me group was introduced to the
ortho position of N-tert-Bu benzamidine. In line with this
observation, by fusing an extra phenyl ring to the C-pehyl
ring of the benzamidine, this coupling is also less efficient
since product 2ua was isolated in 38% yield.
Competition reactions have been carried out to explore
some details of this reaction. The competition between
substrates 1s and 1p in the reaction with an equimolar
amount of PhCtCPh afforded 2sa and 1pa in 1:2.1 ratio,
indicating that this coupling is favored for benzamidines
with electron-rich C-aryl rings. This observation seems to
suggest that the benzamidine nitrogen is metalated as a
neutral donor and this parallels that in the oxidative coupling
of N-aryl-2-aminopyridines with alkynes,5a where chelation
assistance is believed to be offered by the neutral pyridine
ring nitrogen. This observation is in contrast to that in the
oxidative coupling of N-aryl benzamides and alkynes,7a
where the nitrogen metalated as an anionic group.
1
and H NMR analysis of the isolated product revealed
the incorporation of two alkynes units, even though only
1.05equiv was provided. Simple optimization byproviding
an excess of PhCtCPh and Cu(OAc)2 afforded this
product in 73% yield. The structure of this indole-functio-
nalized isoquinoline 2ma was unambiguously confirmed
byX-raycrystallography(seetheSupportingInformation).
Analogously, substrate 1n reacted to afford 2na in 44%
isolated yield. In both cases, we falied to isolate the 1:1
oxidative coupling product (Type A). We reasoned that the
isolation of the 2-fold oxidative coupling product is due to
steric assistance. After the formation of the 1-(phenyl-
amino)isoquinoline intermediate (Scheme 3), the steric
repulsion between the o-Me and the N-phenyl group
renders these two groups distal to each other, leading to a
conformation that is exactly favored for CÀH activation.
With this conformational assistance, the isoquonoline ring
nitrogen coordinated to the Rh(III) to give an intermediate
in which the ortho CÀH bond in the N-phenyl ring is
pointed favorable to the metal center, leading to cycloma-
talation and eventually CÀC andCÀN formation. Oxidative
coupling between the closely related N-aryl-2-aminopyridines
and alkynes has been reported by us using [RhCp*Cl2]2 as
a catalyst.5a In contrast, we attempted but failed to further
oxidatively couple 2aa with PhCtCPh using [RhCp*Cl2]2
as a catalyst even under harsh conditions. Clearly, the
entropic effect and the favored steric assistance are of great
importance for further CÀH activation.
In summary, we have achieved the synthesis of N-
substituted 1-aminoisoquinolines via Rh(III)-catalyzed
oxidative coupling of N-aryl and N-alkyl benzamidines
with alkynes. This reaction occurred via ortho CÀH acti-
vation of the C-aryl ring. The coupling of N-aryl benza-
midines gave functionalized isoquonilines in moderate to
good yield, and N-tBu and N-Cy benzamidines showed
even higher efficiency and selectivity. A broad scope of
substrates has been defined. In both cases steric bulk of the
C-aryl ring has a significant influence on the reaction
selectivity and efficiency. Given the wide presence of
isoquinolines in natural products and in organic synthesis,
the current reactions are likely to find synthetic utility.
Scheme 3. Formation of Two-fold Oxidative Coupling Products
Although N-benzylbenzamidine coupled with PhCt
CPh to give 2oa in moderate yield, even higher reactivity
and selectivity of the coupling were observed when we
moved to other N-alkyl benzamidines. Compound 2pa is
the exclusive product in the coupling between N-tert-
butylbenzamidine and PhCtCPh (87% isolated yield),
and essentially no side product could be detected (GC-
MS). The differences for benzamidines with N-Ph and
N-tBu groups indicate that the selectivity of this reaction
is significantly affected by the N-substituent. In the case of
Acknowledgment. We thank the Dalian Institute of
Chemical Physics, Chinese Academy of Sciences for finan-
cial support.
Supporting Information Available. General experimen-
tal procedure and characterization data of the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 17, 2011
4639