Unprecedented construction of C=C double bonds via Ir-catalyzed dehydrogenative and dehydrative cross-couplings

Article abstract of DOI:10.1021/ol4008469

Unprecedented constructions of C=C double bonds have been achieved by Ir-catalyzed intramolecular dehydrogenative and dehydrative cross-coupling of tertiary amines and ketones. The reactions are proposed to proceed via an Ir-mediated C-H activation mechan

Full text of DOI:10.1021/ol4008469

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Unprecedented Construction of
CdC Double Bonds via Ir-Catalyzed
Dehydrogenative and Dehydrative
Cross-Couplings
Shao-zhen Nie,†,§ Xiang Sun,†,§ Wen-tao Wei,† Xue-jing Zhang,† Ming Yan,*,† and
Jian-liang Xiao*,‡
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical
Sciences, Sun Yat-sen University, Guangzhou 510006, China, and Liverpool Centre
for Materials & Catalysis, Department of Chemistry, University of Liverpool,
Liverpool L69 7ZD, U.K.
yanming@mail.sysu.edu.cn; j.xiao@liv.ac.uk
Received March 28, 2013
ABSTRACT
Unprecedented constructions of CdC double bonds have been achieved by Ir-catalyzed intramolecular dehydrogenative and dehydrative cross-
coupling of tertiary amines and ketones. The reactions are proposed to proceed via an Ir-mediated CꢀH activation mechanism.
The construction of CꢀC bonds is the most important
transformation in organic synthesis. Despite the numerous
synthetic methods that have been developed, highly effi-
cient and atom economicalCꢀC bondformation reactions
are still challenging goals.1 In recent years, direct CꢀC
bond formations via cross dehydrogenative couplings
(CDCs) have exhibited great success.2,3 However, almost
all CDCs require sacrificial oxidants or H-acceptors. This
drawback decreases the practicability and atom economy
of CDCs. Oxidant-free or acceptorless CDCs are more
attractive, and also more challenging. In these reactions,
hydrogen gas is released as the only byproduct. So far only
one successful case was reported. In 2010, Liang et al.
developed a Pt-catalyzed intermolecular CDC reaction of
tertiary amines and carbon nucleophiles in the absence
of oxidants or H-acceptors.4 To the best of our knowledge,
the construction of CdC double bonds via an acceptorless
† Sun Yat-sen University.
‡ University of Liverpool.
(3) For selected recent examples of the construction of CꢀC bonds
via CDC reactions, see: (a) Kuhl, N.; Hopkinson, M. N.; Glorius, F.
Angew. Chem., Int. Ed. 2012, 51, 8230–8234. (b) Shi, Z.-Z.; Glorius, F.
Angew. Chem., Int. Ed. 2012, 51, 9220–9222. (c) Qin, X.-R.; Feng, B.-Y.;
Dong, J.-X.; Li, X.-Y.; Xue, Y.; Lan, J.-B.; You, J.-S. J. Org. Chem.
2012, 77, 7677–7683. (d) Bugaut, X.; Glorius, F. Angew. Chem., Int. Ed.
2011, 50, 7479–7481. (e) Alagiri, K.; Devadig, P.; Prabhu, K. R.; Prabhu.
Chem.;Eur. J. 2012, 18, 5160–5164. (f) Zhang, J.-M.; Tiwari, B.; Xing,
C.; Chen, X.-K.; Chi, Y. R. Angew. Chem., Int. Ed. 2012, 51, 3649–3652.
(g) Hu, H.-Y.; Liu, Y.; Zhong, H.; Zhu, Y.-L.; Wang, C.; Ji, M. Chem.;
Asian J. 2012, 7, 884–888. (h) Wang, P.; Rao, H.-H.; Hua, R.-M.; Li,
C.-J. Org. Lett. 2012, 14, 902–905. (i) Alagiri, K.; Prabhu, K. R. Org.
Biomol. Chem. 2012, 10, 835–842. (j) Zhang, G.; Zhang, Y.-H.; Wang, R.
Angew. Chem., Int. Ed. 2011, 50, 10429–10432.
§ S.-Z.N. and X.S. contributed equally.
(1) For reviews of ideal chemical synthesis, see: (a) Newhouse, T.;
Baran, P. S.; Hoffmann, R. W. Chem. Soc. Rev. 2009, 38, 3010–3021. (b)
Hendrickson, J. B. J. Am. Chem. Soc. 1975, 97, 5784–5800. (c) Trost,
B. M. Science 1991, 254, 1471–1477.
(2) For reviews of CDC reactions, see: (a) Li, C.-J. Acc. Chem. Res.
2009, 42, 335–344. (b) Li, Z.-P.; Bohle, D. S.; Li, C.-J. Proc. Natl. Acad.
Sci. U.S.A. 2006, 103, 8928–8933. (c) Li, C.-J.; Li, Z.-P. Pure Appl.
Chem. 2006, 78, 935–945. (d) Yoo, W.-J.; Li, C.-J. Top. Curr. Chem.
2010, 292, 281–302. (e) Scheuermann, C. J. Chem.;Asian J. 2010, 5,
436–451. (f) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215–
1292. (g) Zhang, M.; Zhang, A.-q. J. Heterocycl. Chem. 2012, 49, 721–
725. (h) Yang, L.; Huang, H.-M. Catal. Sci. Technol. 2012, 2, 1099–1112.
r
10.1021/ol4008469
XXXX American Chemical Society

Table 1. Ir-Catalyzed CDC Reaction of 1aa
Scheme 1. Ir-Catalyzed CDC Reaction of 1a
yield (%)b
entry
catalyst
solvent
3a
4a
1
2
3
4
5
6
[Cp*IrCl2]2
CF3CH2OH
CF3CH2OH
CF3CH2OH
AcOH
24
25
30
ꢀ
5
6a
ꢀ
6b
ꢀ
[Cp*IrCl2]2
25
29
34
6a
6b
AcOH
ꢀ
AcOH
ꢀ
a Reaction conditions: 1a (0.2 mmol), catalyst (0.005 mmol), solvent
(2 mL), refluxed for 24 h. b Isolated yield after column chromatography.
equilibrium toward 3a. Cyclometalated imido Ir(III) com-
plex 6a provided 3a in a similar yield (Table 1, entry 2).8
2-Hydroxy pyridine Ir(III)-complex 6b gave a slightly better
yield (Table 1, entry 3).9
A number of reaction solvents were screened. Toluene,
CH2Cl2, ether, THF, CH3CN, ethanol, and methanol
are not compatible with the transformation. The addition
of H-acceptors such as norbornene and β-nitrostyrene did
not exert a beneficial effect. On the contary they appeared
toinhibitthe reaction. Aceticacidwas foundtobea unique
reactionsolvent. Instead of product3a, anothercompound
4a was obtained (Table 1, entries 4ꢀ6). It was identified
as the CDC product, losing two molecules of hydrogen.
Logically, 3a can be generated by the further dehydrogena-
tion of 4a. However, the control test did not support this
hypothesis. The result implies that 3,4-dehydrogenation
occurs before the formation of the C1 double bond. The
reaction solvent exerts the strong effect on this step.
To improve the yield of the reaction, an extensive screen
of Ir and Rh complexes was carried out, and the results are
summarized in Table 2. [Ir(cod)Cl]2 (cod =1,5-cyclooctadiene)
was found to provide 4a with a better yield. In addition, a
new product 7a was obtained in 26% yield (Table 2, entry 2).
7a is generated via an interesting dehydrative coupling. By
contrast, the [Ir(cod)Cl]2-catalyzed reaction in trifluoroetha-
nol provided 3a in 29% yield and almost no product 4a, and
7a was obtained instead. Again, the reaction solvent showed
a significant effect on the product distribution. Other Ir(I)-
complexes, such as Ir(acac)(cod) (acac = acetylacetonate)
and Ir(hfacac)(cod) (hfacac = hexafluoroacetylacetonate)
provided 4a in similar yields. However, no product 7a was
obtained (Table 2, entries 3 and 4). [Rh(cod)Cl]2 is comple-
tely inefficient (Table 2, entry 5). Wilkinson’s catalyst failed
to catalyze the reaction (Table 2, entry 6).
CDC has never been developed. Here, we report the
efficient construction of CdC double bonds via an accep-
torless CDC between four sp3 CꢀH bonds of cyclic tertiary
amines and carbonyl compounds. Direct functionalization
of tertiary amines provided an efficient method for the
synthesis of biologically important amines.5 Ir-complexes
have been found to be active catalysts for the dehydrogena-
tion of alcohols and amines.6 The formation of strong IrꢀH
bonds contributes to their excellent catalytic activities.
We speculated that the reaction of tetrahydroisoquino-
line derivative 1a in the presence of Ir-catalysts may
provide N,O acetal 2 via an intramolecular hydride trans-
fer and cascade acetalization (Scheme 1).7 Initial reaction
of 1a in trifluoroethanol using [Cp*IrCl2]2 (Cp* =
pentamethylcyclopentadienyl) as the catalyst did not pro-
vide the expected product 2. Instead, zwitterionic product
3a was isolated in substantial yield (Table 1, entry 1). Its
structure was confirmed by NMR, MS, and IR spectral
studies. Although 3a can also exist in an equilibrium with
its tautomer 5, the IRspectrum indicated theabsence ofthe
carbonyl group and excluded this structure. The formation
of an extensive conjugated system may strongly drive the
(4) For acceptorless CDC reaction, see: (a) Shu, X.-Z.; Yang, Y.-F.;
Xia, X.-F.; Ji, K.-G.; Liu, X.-Y.; Liang, Y.-M. Org. Biomol. Chem. 2010,
8, 4077–4079.
(5) For reviews of direct functionalizations of tertiary amines, see:
(a) Campos, K. R. Chem. Soc. Rev. 2007, 36, 1069–1084. (b) Dobereiner,
G. E.; Crabtree, R. H. Chem. Rev. 2010, 110, 681–703. (c) Thansandote,
P.; Lautens, M. Chem.;Eur. J. 2009, 15, 5874–5883.
(6) For reviews of Ir-catalyzed dehydrogenation reactions, see:
(a) Chio, J.; MacArthur, A. H. R.; Brookhart, M.; Goldman, A. S.
Chem. Rev. 2011, 111, 1761–1779. (b) Choi, J.; Goldman, A. S. Top.
Organomet. Chem. 2011, 34, 139–168.
The results suggest that [Ir(cod)Cl]2 is a unique catalyst
for this transformation. Furthermore, the effect of nitrogen
and phosphine ligands was examined (Table 2, entries 7ꢀ14).
The addition of 2-hydroxyl-pyridine increased the yield
to 51% and completely inhibited the formation of product
(7) For reviews of the “borrowing hydrogen” strategy, see:
(a) Baehn, S.; Imm, S.; Neubert, L.; Zhang, M.; Neumann, H.; Beller,
M. ChemCatChem 2011, 3, 1853–1864. (b) Nixon, T. D.; Whittlesey,
M. K.; Williams, J. M. J. J. Chem. Soc., Dalton Trans. 2009, 38, 753–762.
(c) Dobereiner, G. E.; Crabtree, R. H. Chem. Rev. 2010, 110, 681–703.
(d) Hamid, M. H. S. A.; Slatford, P. A.; Williams, J. M. J. Adv. Synth.
Catal. 2007, 349, 1555–1575. (e) Saidi, O.; Blacker, A. J.; Farah, M. M.;
Marsden, S. P.; Williams, J. M. J. Angew. Chem., Int. Ed. 2009, 48, 7375–
(8) Wang, C.; Pettman, A.; Basca, J.; Xiao, J.-L. Angew. Chem., Int.
Ed. 2010, 49, 7548–7552.
(9) (a) Yamaguchi, R.; Ikeda, C.; Takahashi, Y.; Fujita, K. J. Am.
Chem. Soc. 2009, 131, 8410–8412. (b) Li, H.-X.; Jiang, J.-L.; Lu, G.;
Huang, F.; Wang, Z.-X. Organometallics 2011, 30, 3131–3141.
€
7378. (f) Neubert, L.; Michalik, D.; Bahn, S.; Imm, S.; Neumann, H.;
Atzrodt, J.; Derdau, V.; Holla, W.; Beller, M. J. Am. Chem. Soc. 2012,
134, 12239–12244.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Screen of Metal Complexes and Ligandsa
Table 3. Ir-Catalyzed CDC Reaction of Substrates 1aꢀ1ja
entry
metal complex
ligand
4ab
25
1
(Cp*IrCl2)2
[Ir(cod)Cl]2
Ir(acac)(cod)
Ir(hfacac)(cod)
[Rh(cod)Cl]2
Rh(Ph3P)3Cl
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
2c
3
39
37
4
37
5
trace
trace
51
6
7
2-hydroxyl-pyridine
1,10-phenanthroline
PPh3
8
46
9
59
10
11
12
13
14
15d
BINAP
60
DPPF
59
DPPE
71
DPPP
63
DPPB
44
DPPE
trace
a Reaction conditions: 1a (0.2 mmol), catalyst (0.005 mmol), ligand
(0.01 mmol), solvent (2 mL), refluxed for 24 h. b Isolated yield after
purification by flash-column chromatography. c Product 7a was obtained
in 26% yield. d Trifluoroethanol was used as the solvent.
7a (Table 2, entry 7). 1,10-Phenanthroline gave a lower yield
(Table 2, entry 8), while PPh3, BINAP, and DPPF [1,10-
bis(diphenylphosphino)ferrocene] provided improved yields
(Table 2, entries 9ꢀ11). A better yield was achieved with
DPPE [1,2-bis(diphenylphosphino)ethane] (Table 2, entry
12). DPPP [1,3-bis(diphenylphosphino)propane] and DPPB
[1,4-bis(diphenylphosphino)butane] are less efficient than
DPPE (Table 2, entries 13 and 14). The solvent acetic acid
is critical for the success of this transformation, since
[Ir(cod)Cl]2/DPPE gave only a trace amount of 4a in tri-
fluoroethanol (Table 2, entry 15).
A variety of tetrahydroisoquinoline derivatives 1aꢀ1j
were examined, and the results are summarized in Table 3.
Substitution on both aryl groups could be tolerated very
well (Table 3, entries 2ꢀ5). Thiophene derived substrate 1f
provided the product 4f in moderate yield. Propiophenone
derivative 1g gave a lower yield. Piperidine derived substrate
1h is also applicable, however, a low yield was obtained. In
this case, only one molecule of hydrogen was eliminated
(Table 3, entry 8). Morpholine derived substrate 1i is
unreactive (Table 3, entry 9). Oxime 1j derived from 1a
reacted smoothly, and the corresponding CDC product 4j
was obtained in good yield (Table 3, entry 10).
a Reaction conditions: 1aꢀ1j (0.2 mmol), catalyst (0.005 mmol),
ligand (0.01 mmol), acetic acid (2 mL), refluxed for 24 h. b Isolated yield
after column chromatography. c DPPP was used in this case. DPPE
provided lower yield (64%).
A preliminary investigation of this reaction was carried
out, and the results are summarized in Table 4. The trans-
formation was found to be quite sensitive to the substitu-
tion of the phenyl group. The 3-MeO substituted substrate
1b gave only an 8% yield of 7b together with CDC product
4b (Table 4, entry 2). Propiophenone derived substrate 1g
provided 7g in 24% yield (Table 4, entry 3). Benzophenone
derived substrate 1l afforded product 7l in 50% yield.
The dehydrative coupling product 7a and its analogs
were reported to possess attractive biological activities.10
(11) For directing group assisted CꢀH activations, see: (a) Engle, K. M.;
Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788–802. (b)
Patureau, F. W.; Glorius, F. Angew. Chem., Int. Ed. 2011, 50, 1977–1979. (c)
Yu, J.-Q.; Giri, R.; Chen, X. Org. Biomol. Chem. 2006, 4, 4041–4047.
(12) See the Supporting Information for the tentative reaction path-
way to product 3a.
(10) For the synthesis and biological activity of indolo[2,1-R]-
€
isoquinolines, see: (a) Lotter, A. N. C.; Pathak, R.; Sello, T. S.;
Fernandes, M. A.; Otterlo, W. A. L. V.; Koning, C. B. D. Tetrahedron
2007, 63, 2263–2274. (b) Kraus, G. A.; Gupta, V.; Kohut, M.; Singh, N.
Bioorg. Med. Chem. Lett. 2009, 19, 5539–5542. (c) Mahoney, S. J.;
Fillion, E. Chem.;Eur. J 2012, 18, 68–71.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 4. Ir-Catalyzed Dehydrative Couplinga
Scheme 3. Tentative Reaction Pathways to Products 4a and 7a
yield (%)b
entry
R1
R2
R3
7
4
1
2
3
4
5
Me
Me
Et
H
H
7a, 26
7b, 8
4a, 39
4b, 43
4g, 27
4k, 50
ꢀ
3-OMe
H
H
Me
H
7g, 12
7k, 20
7l, 50
Me
Ph
2-CF3
H
ꢀ
a Reaction conditions: Substrate (0.2 mmol), catalyst (0.005 mmol), acetic
acid (2 mL), refluxed for 24 h. b Isolated yield after column chromatography.
In this case, the competitive CDC was avoided, and thus a
better yield could be achieved.
GC-TCD analysis of the gas components in the [Ir(cod)-
Cl]2/DPPE catalyzed CDC of 1a confirmed the existence
of hydrogen gas. The fact suggests an acceptorless dehydro-
genative process. On the other hand, the intermolecular CDC
of N-phenyl-tetrahydroisoquinoline and acetophenone or
acetone did not occur with the [Ir(cod)Cl]2/DPPE catalyst.
When the reaction of 1a was stopped at 2, 4, and 8 h
respectively, the analysis of the reaction mixture indicated
the existence of partially dehydrogenated intermediate 8a.
The further transformation of 8a to 4a was observed after
an extended reaction period (Scheme 2). The result demon-
strates that 8a is the primary product of the reaction and it
is further dehydrogenated to give 4a.
the carbonyl group. The resulting intermediate E under-
goes a reductive elimination to give intermediate F, which
is readily dehydrated in acetic acid solvent to give product
7a. Nitrogen and phosphine ligands can exert a strong
effect on the selectivity for the two pathways.12
The tentative reaction pathway to product 4a is outlined
in Scheme 3. The carbonyl group works as a directing
group for the oxidative insertion of Ir(I) into the CꢀH
bond.11 The protonation of intermediate A with acetic acid
releases one molecule of hydrogen and generates inter-
mediateB. After elimination of one molecule ofacetic acid,
iridium enolate C is formed. The subsequent intramolecu-
lar addition of iridium enolate to an iminium cation gives
product 8a. Then Ir-catalyzed abstraction of a hydride
generates intermediate D, which eliminates a second mo-
lecule of hydrogen to provide product 4a. On the other
hand, the nucleophilic C1 of intermediateA can also attack
In conclusion, we have developed an intramolecular
CDC reaction of tertiary amines and ketones. The
construction of CdC double bonds was achieved with
Ir-catalysts in the absence of oxidants or hydrogen
acceptors. A number of tetrahydroisoquinoline derivatives
were prepared in good yields. A unique cross dehydrative
coupling reaction was also achieved to provide biologically
important indolo[2,1-R]isoquinolines. The diversified reaction
pathways could be realized via the change of the reaction
solvent, ligands, and iridium complexes. The reactions are
suggested to occur via a common Ir-mediated CꢀH activa-
tion step. The activation mechanism is potentially applicable
for direct functionalization of various tertiary amines.
Scheme 2. Variation of Reaction Components with Time
Acknowledgment. We thank the National Natural
Science Foundation of China (Nos. 20972195, 21172270)
and Guangdong Engineering Research Center of Chiral
Drugs for the financial support of this study.
Supporting Information Available. Experimental pro-
cedures, full spectroscopic data for all new products, and
deuterium-labeling experiment data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX