Acceptorless dehydrogenation of nitrogen heterocycles with a versatile iridium catalyst

Article abstract of DOI:10.1002/anie.201300292

Gas up: A cyclometalated iridium complex is found to catalyze the dehydrogenation of various benzofused N-heterocycles, thus releasing H ₂. Driven by as low as 0.1 mol % catalyst, the reaction affords quinolines, indoles, quinoxalines, isoquinolines, and β-carbolines in high yields. Copyright

Full text of DOI:10.1002/anie.201300292

Angewandte
Chemie
Communications
Synthetic Methods
J. Wu, D. Talwar, S. Johnston, M. Yan,
J. Xiao*
&&&& — &&&&
Acceptorless Dehydrogenation of
Nitrogen Heterocycles with a Versatile
Iridium Catalyst
Gas up: A cyclometalated iridium com-
plex is found to catalyze the dehydrogen-
ation of various benzofused N-hetero-
cycles, thus releasing H2. Driven by as low
as 0.1 mol% catalyst, the reaction affords
quinolines, indoles, quinoxalines, isoqui-
nolines, and b-carbolines in high yields.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
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DOI: 10.1002/anie.201300292
Synthetic Methods
Acceptorless Dehydrogenation of Nitrogen Heterocycles with
a Versatile Iridium Catalyst**
Jianjun Wu, Dinesh Talwar, Steven Johnston, Ming Yan, and Jianliang Xiao*
Dedicated to Professor Richard J. Puddephatt on the occasion of his 70th birthday
Catalytic dehydrogenation (CDH) is one of the most
important reactions in the manufacturing of commodity
chemicals.[1] For instance, annually approximately 17 million
tons of styrene are produced by CDH of ethyl benzene.
However, CDH has been much less used in the synthesis of
fine chemicals, pharmaceuticals, and agrochemicals, although
it offers considerable benefits with respect to atom economy
and environmental impact because of the avoidance of
stoichiometric oxidants. In recent years, CDH of alkanes,
alcohols, and amines has been realized with metal complexes,
although sacrificial hydrogen acceptors and additives are
Scheme 1. Cyclometalated iridium complexes and hypothesized dehy-
frequently used.[2] However, homogeneous catalysts capable
drogenation of N-heterocycles.
of dehydrogenating heterocycles are very rare, and those
catalysts that are active are mostly heterogeneous ones, which
usually show poor functionality tolerance and require harsh
reaction conditions.[3,4] More recently, Fujita and Yamaguchi
reported the first example of homogeneous dehydrogenation
of tetrahydroquinolines using a [Cp*Ir(2-hydroxypyridine)]
catalyst.[5] A limitation is that only a few examples of 1,2,3,4-
tetrahydroquinolines were demonstrated and the reaction
conditions were relatively forcing [2 mol% catalyst for 20 h in
refluxing p-xylene (bp 1388C) or 5 h in mesitylene (bp
1658C)]. Given the importance of nitrogen-containing aro-
matics in numerous naturally occurring alkaloids and syn-
thetic pharmaceuticals, and as potential hydrogen storage
materials,[6] developing a single catalytic system with higher
CDH activity and wider scope would be of significant interest.
We recently reported that the cyclometalated [Cp*IrIII]/
imino complexes 1 are excellent catalysts for reductive
amination (Scheme 1).[7] They readily form hydrides under
H2 pressure or when treated with formate, and could produce
H2 with the aid of an acid. Inspired by the Fujita work, we
envisioned that when reacted with an amine, 1 could undergo
b-hydrogen elimination, thus generating an imino bond and
H2 upon protonation.[8] It would be interesting to test if
1 could be exploited for the CDH of not only tetrahydroqui-
nolines but other N-heterocycles as well.
We started the investigation choosing 2-methyl-1,2,3,4-
tetrahydroquinoline (2a) as a model substrate. As expected,
in the absence of a catalyst, formation of 2-methyl-quinoline
(3a) was not detected in 2,2,2-trifluoroethanol (TFE; bp
788C) after 2 h at reflux (Table 1, entry 1). After screening
a variety of precatalysts and solvents (entries 2–19), we were
pleased to observe that complex 1d, which bears electron-
donating OMe groups, did catalyze efficient CDH of 2a in
TFE, thus furnishing 88% conversion in 2 hours. Full
conversion, along with release of H2, was reached with
0.1 mol% overnight (entry 7).[9] Other complexes or solvents
were less effective.
TFE appears to play multiple roles in the CDH. It may
promote the dissociation of chloride from and hence the
coordination of 2a to 1d before CDH takes place [Eq. (1)].[10]
[*] J. Wu,[+] D. Talwar,[+] S. Johnston, Prof. J. Xiao
Department of Chemistry, University of Liverpool
Liverpool L69 7ZD (UK)
E-mail: jxiao@liv.ac.uk
In support of this view, addition of a chloride salt inhibits the
CDH (Table 1, entry 20). However, adding a silver or sodium
salt did not improve the activity of 1d when the reaction was
carried out in toluene (entries 21 and 22). We noted that
strong reflux is necessary for higher conversions, and remark-
ably, when nitrogen was bubbled through the solution, the
CDH occurred even at room temperature, thus affording
52% conversion overnight. These observations indicate that
the CDH is rate-limited by the step of dihydrogen forma-
tion,[8a,11] which we consider to be facilitated by TFE through
protonation of the intermediate hydride [Eq. (2)].[12] Consis-
Prof. M. Yan
Institute of Drug Synthesis and Pharmaceutical Process
School of Pharmaceutical Sciences, Sun Yat-sen University
Guangzhou 510006 (China)
[+] These authors contributed equally to this work.
[**] We thank the EPSRC and the University of Liverpool for a DTA
studentship, Dr. Weijun Tang, Yi Zhang, and Dr. Jonathan H.
Barnard for assistance and the EPSRC NMSSC at Swansea
University for mass analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300292.
2
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Table 1: Screening catalysts for the CDH of 2a.[a]
Table 2: CDH of tetrahydroquinolines by 1d.[a]
Conv. [%][b]
Entry
2
R1
R2
Yield [%][b]
Entry
Catalyst
Additive
Solvent
1[c]
2
3
4
5
none
[{Cp*IrCl2}2]
IrCl3·3H2O
1a
1b
1c
1d
1e
1 f
1d
1d
1d
1d
1d
1d
1d
1d
–
–
–
–
–
–
–
–
–
–
-
–
–
-
–
–
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
DFE
EtOH
iPrOH
MeOH
H2O
n.r.
3
1
2a
2b
2c
2d
2e
2 f
2g
2h
2i
2-Me
H
H
H
H
H
Me
OMe
F
Cl
H
95 (3a)
87 (3b)
72 (3c)
87 (3d)
94 (3e)
97 (3 f)
93 (3g)
94 (3h)
81 (3i)
92 (3j)
2[c]
3[c]
4
<1
42
74
25
88
29
72
23
4
<1
14
3
n.r.
n.r.
<1
n.r.
<1
56
6
3-Me
4-Me
2-Me
2-Me
2-Me
2-Me
2-CH2OH
2-Ph
5
6
7
8
9
10
6
7[d]
8
9
10
11
12
13
14
15[c]
16[c]
17
18[c]
19[e]
20[f]
21
22[c]
2j
H
11
2k
2l
92 (3k)
88 (3l)
THF
12
DMF
MeCN
toluene
p-xylene
TFE
–
–
–
1d
1d
1d
1d
13[c]
2m
81 (3m)
TBAC
AgBF4
NaBF4
toluene
toluene
[a] Reaction conditions: 2 (0.5 mmol) and 1d (0.1 mol%) in TFE (3 mL)
stirred at reflux under nitrogen for 20 h. [b] Yield of isolated product.
[c] Used 1 mol% 1d.
1d
n.r.
[a] Reaction conditions: 2a (0.5 mmol) and catalyst (1 mol%) in solvent
(3 mL) stirred at reflux under nitrogen for 2 h; 1 mol% additive when
used. [b] Determined by NMR spectroscopy. [c] No reaction observed.
[d] Full conversion with 0.1 mol% 1d overnight. [e] 2a (1.0 mmol) and
catalyst (2 mol%), reflux, 20 h. [f] Used 20 mol% TBAC. Cp*=C5Me5,
DFE=difluoroethanol, DMF=N,N-dimethylformamide, n.r.=no reac-
tion, TBAC=tetrabutylammonium chloride, THF=tetrahydrofuran.
(entries 11 and 12). Notably, the 2,2’-biquinoline 3m, a well-
known diamine ligand, was generated along with liberation of
4 equivalents of H2 from the octahydro form 2m (entry 13).
The catalyst is chemoselective, as seen in the CDH of 2i,
bearing a primary alcohol group, thus affording 3i with
exclusive selectivity towards the N-heterocyclic ring (entry 9).
Isoquinolines and b-carbolines find broad pharmaceutical
applications.[16] They can be obtained by traditional oxidation
of the easily accessible tetrahydro or 3,4-dihydro analogues.[17]
Following the CDH of 2, we examined tetrahydroisoquino-
lines and tetrahydro-b-carbolines (4). These substrates are
challenging to fully dehydrogenate, because of their tendency
to form stable imine intermediates.[18] Table 3 shows that 4 can
be dehydrogenated to isoquinolines (5) in good to excellent
yields in general at a 0.1 mol% catalyst loading (entries 1–8).
Among the substrates examined, only the nonsubstituted 4a
and sterically demanding 4e necessitated a higher catalyst
loading of 1 mol%. In the case of the former, 5a was obtained
in only 30% yield. Worth noting is that the tetrahydroharman
4i was fully dehydrogenated to give the aribine 5i, an
important b-carboline (entry 9), and 4j was converted into 5j
(entry 10) in high yield.
tent with this, the CDH became progressively slower when
alcohols of lower acidity were used, for example, TFE
(pKa 12.5) versus 2,2-difluoro-ethanol (DFE; pKa 13.1), and
ethanol (pKa 15.8; entries 7, 10, and 11). Thus, CDH by 1d
appears mechanistically distinct from that by the Fujita–
Yamaguchi catalyst.[8,13]
With the 1d/TFE catalytic system in hand, we first
subjected a variety of tetrahydroquinolines (2) to the CDH
(Table 2). These were dehydrogenated to give quinolines
generally in excellent yields with 0.1 mol% of 1d. Lower
yields were obtained with the nonsubstituted 2b and 3-
methyl-1,2,3,4-tetrahydroquinoline (2c), even at a higher
catalyst loading of 1 mol% (entries 2 and 3).[14] All the 6-
substituted substrates afforded high yields (entries 5–8),
regardless of the nature of the substituent. The less basic 2j
was also dehydrogenated (entry 10). The acridine 3k and the
1,2,3,4-tetrahydro variant 3l, used as antitumor drugs and an
analogue of acetylcholinesterase inhibitor,[15] were obtained
from 2k and 2l, respectively, in good to excellent yields
We next became interested in the CDH of 3,4-dihydro-
isoquinolines (6), which can be produced by the classical
Bischler–Napieralski reaction (Table 4).[19] Although high
yields were achieved, surprisingly a high catalyst loading
(1 mol%) was required (entries 1–6). Under the reaction
conditions used for 4 (Table 3), CDH of 6 was hardly
detectable, thus suggesting that the reaction of 4 does not
proceed via the intermediacy of 6.
Apart from CDH, we found that 1d also catalyzes the
hydrogenation of 6a into 4b with excellent conversion at
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Table 3: CDH of tetrahydroisoquinolines and tetrahydro-b-carbolines by
1d.[a]
three forms of isoquinoline by hydrogenation and dehydro-
genation using a single catalyst (1d; Scheme 2).
Bearing in mind that there are diverse ways for the
preparation of indolines,[20] direct CDH adds a valuable
alternative to the strategies of indole synthesis. Using 1d,
various indoline derivatives could be dehydrogenated, thus
affording indoles in excellent yields (Table 5). In particular,
sterically demanding 2,3-dimethyl- and 2-phenylindolines
were dehydrogenated to indoles in 96% yield (entries 5 and
7). However, as with 4a, the nonsubstituted 8a was more
difficult to dehydrogenate.
Entry
4
R1
R2
Yield [%][b]
1[c,d]
2
3
4a
4b
4c
4d
4e
4 f
H
1-Me
1-iPr
3-Me
H
H
H
H
H
H
OMe
OMe
30 (5a)
90 (5b)
92 (5c)
93 (5d)
82 (5e)
95 (5 f)
93 (5g)
96 (5h)
4
5[c]
6
1-tBu
1-cyclohexyl
1-cyclohexyl
1-Ph
7
8
4g
4h
Table 5: CDH of indoline derivatives by 1d.[a]
9[c]
10
4i
4j
93 (5i)
95 (5j)
Entry
8
R1
R2
Yield [%][b]
1[c]
2
8a
8b
8c
8d
8e
8 f
8g
H
H
H
H
OMe
Cl
H
H
91 (9a)
95 (9b)
93 (9c)
90 (9d)
96 (9e)
98 (9 f)
96 (9g)
3[d]
4
[a] The reaction conditions were the same as those in Table 2 except for
using 4. [b] Yield of isolated product. [c] 1 mol% 1d used. [d] Yield as
determined by NMR spectroscopy.
2-Me
2-Me, 3-Me
3-Me
2-Ph
5
6
7
H
H
Table 4: CDH of 3,4-dihydroisoquinolines by 1d.[a]
[a] The reaction conditions were the same as those in Table 2 except for
using 8. [b] Yield of the isolated product. [c] Used 1 mol% 1d. [d] Used
0.5 mol% 1d.
Entry
6
R1
R2
Yield [%][b]
Traditional synthesis of quinoxalines makes use of reac-
tions such as condensation and oxidative cyclization.[21] CDH
is not known for this. We therefore investigated the dehydro-
genation of tetrahydroquinoxalines (10; Table 6). The CDH
1
2
3
4
5
6a
6b
6c
6d
6e
1-Me
1-iPr
1-cyclohexyl
1-cyclohexyl
1-Ph
H
H
H
OMe
OMe
89 (5b)
92 (5c)
93 (5 f)
94 (5g)
95 (5h)
Table 6: CDH of tetrahydroquinoxalines by 1d.[a]
6
6 f
81 (5i)
[a] The reaction conditions were the same as those in Table 2 except for
R1
R2
Yield [%][b]
using 6 and 1 mol% 1d. [b] Yield of isolated product.
Entry
10
1
2
3
10a
10b
10c
10d
10e
10 f
10g
2-Me
2-Ph
2-Me, 3-Me
2-Me, 3-Ph
2-Ph, 3-Ph
H
H
H
H
H
H
5-Me
6-Me
92 (11a)
79 (11b)
93 (11c)
85 (11d)
82 (11e)
62 (11 f)
64 (11g)
208C and 1 atm H2 pressure (Scheme 2). The highly stable 5b
was hydrogenated as well, although more forcing reaction
conditions were needed. Together with the results in Tables 3
and 4, these results weave a unique network which links the
4[c]
5[c]
6
7
H
[a] The reaction conditions were the same as those in Table 2 except for
using 10. [b] Yield of the isolated product. [c] Used 1 mol% 1d.
worked, giving rise to good to excellent yields of the
quinoxalines 11 with 0.1 mol% of 1d. However, a higher
catalyst loading was necessary for the sterically bulky 10d and
10e.
To showcase the synthetic utility of the CDH, we applied
the protocol to a rapid total synthesis of two well-known
alkaloids, papaverine and harmine. Papaverine is an opium
alkaloid antispasmodic drug, clinically used for the treatment
of vasospasm and occasionally for erectile dysfunction.[22]
Scheme 2. Hydrogenation/dehydrogenation-linked interchangeable
transformations between isoquinoline and derivatives.
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Harmine is a major b-carboline alkaloid found in pegunam
harmala extract. It is an inhibitor of monoamine reuptake
system and has also shown cytotoxic activities against a series
of tumor cell lines.[23] Our synthesis of papaverine started with
the condensation of homoveratric acid and homoveratryl-
amine under microwave-assisted, neat conditions, thus gen-
erating the corresponding amide in almost quantitative yield
(Scheme 3). The amide was then treated with POCl3 to
1H NMR spectrum. Under the normal refluxing conditions
(Table 2), 3a was obtained with deuterium incorporation at
the C3 and methyl position. On this basis, CDH of 2a is
suggested to proceed by the pathway shown in Scheme 5a. At
Scheme 3. Synthesis of papaverine by CDH. MW=microwave.
Scheme 5. Proposed pathways for the CDH of tetrahydroquinolines,
and tetrahydro- and dihydroisoquinolines.
furnish a cyclic imine by the Bischler–Napieralski reaction.[19]
The last step of the synthesis was accomplished by 1d-
catalyzed CDH of the 3,4-dihydroisoquinoline (see the
Supporting Information for details). The three-step synthesis,
employing commercially available materials with an overall
yield of 78%, appears to offer a most efficient and econom-
ically sound method for this significant alkaloid.[24]
low temperature, 2a is in equilibrium with 2a1, which is
probably protonated by or hydrogen-bonded with the
medium, and 2a2, with the equilibrium strongly favoring 2a.
At high temperature 2a1 isomerizes to 2a4 by acid catalysis,
which hydrogenates 2a3, thus resulting in the formation of 3a
and 2a.
Scheme 4 shows the synthesis of harmine starting with
a
Pictet–Spengler reaction[19] of acetaldehyde with 6-
When 4b was subjected to CDH with 0.1 mol% of 1d in
refluxing TFE for a short time, both 6a and 5b were observed.
However, 6a showed no observable CDH under these
reaction conditions, although it gave 4b and 5b at 1 mol%
of 1d. In contrast, using of 0.1 mol% of 1d but in the presence
of 4c (Table 3), 6a was converted into 4b and 5b, thus
showing that 6a can readily undergo CDH, probably by 4b, if
a hydride donor such as 4c is present. These observations
suggest that the CDH of 4b involves a pathway as shown in
Scheme 5b, where 4b can be dehydrogenated into either 6a
or 4b1. But it is 4b1 which gives rise to the product 5b. The
formation of 5b from 6a proceeds by its first reduction to 4b.
When 6a alone is dehydrogenated, it is likely to be reduced to
4b in the first place by TFE,[27] a solvent of well-known
resistance to oxidation. This explains why 6 is more difficult to
reduce than 4.
methoxytryptamine. CDH of the resulting tetrahydroharmin
by 1d afforded the target alkaloid, with an overall yield of
Scheme 4. Synthesis of harmine by CDH.
In summary, we have developed a versatile catalyst for the
oxidant-free, acceptorless CDH of various benzofused N-
heterocycles. The high activity and broad substrate scope of
the catalytic system make the protocol a promising alternative
for laboratory and industrial applications, and this is rein-
forced by the ease of operation, atom economy, and environ-
mental benefits offered by CDH.
57% (see the Supporting Information for details). In com-
parison with other known methods,[25] this concise synthesis of
harmine using commercially available materials is high-
yielding and less wasteful under mild reaction conditions.
Preliminary mechanistic studies of CDH of 2a and 4b
shed light on how these CDH reactions may take place (see
the Supporting Information for details). In the presence of 1d
in [D3]TFE, 2a undergoes rapid H–D exchange at the C2-
position at room temperature.[26] However, no other species
were observed apart from 2a and trace amounts of 3a in the
Received: January 12, 2013
Revised: April 16, 2013
Published online: && &&, &&&&
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[11] In line with dihydrogen formation being turnover-limiting, Ir-H
was observed in the 1H NMR spectrum at RT, 5 min after mixing
2a with 1d (1 mol%) in TFE in a NMR tube, along with ca. 4%
of 3a.
[12] TFE can hydrogen bond with and protonate metal hydrides, thus
forming M-(H2): a) E. I. Gutsul, N. V. Belkova, M. S. Sverdlov,
L. M. Epstein, E. S. Shubina, V. I. Bakhmutov, T. N. Gribanova,
R. M. Minyaev, C. Bianchini, M. Peruzzini, F. Zanobini, Chem.
Eur. J. 2003, 9, 2219; b) M. Besora, A. Lledꢀs, F. Maseras, Chem.
Soc. Rev. 2009, 38, 957.
[13] To further demonstrate that the high activity of this CDH results
from the combination of 1d and TFE, that is, a solvent-assisted
CDH, we compared 1d and the Fujita–Yamaguchi catalyst.
Under the conditions of Table 1, the later afforded less than 2%
conversion. In contrast, the conversion was less than 1% with
the former but 77% with the latter under Fujitaꢁs conditions
(2 mol%, p-xylene, reflux, 20 h).
[14] X.-B. Zhang, Z. Xi, Phys. Chem. Chem. Phys. 2011, 13, 3997.
[15] a) G. Cholewinski, K. Dzierzbicka, A. M. Kolodziejczyk, Phar-
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Chen, Chem. Biol. 1995, 2, 621.
Keywords: dehydrogenation · hydrogen · hydrogenation ·
iridium · nitrogen heterocycles
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[25] R. S. Kusurkar, S. K. Goswami, Tetrahedron 2004, 60, 5315.
[26] This suggests again that dehydogenation, without releasing H2, is
a fast process. Also see Ref. [11].
[27] When 1d was heated in TFE at 608C, an Ir-H hydride resonance
was observed at d = À10.10 ppm along with trifluoroacetalde-
hyde in the 1H NMR spectrum (see the Supporting Information).
[9] Formation of H2 was confirmed by GC analysis and quantified
with the water displacement method. Please see the Supporting
Information for details.
[10] Alcohols are known acceptors for halide anions, see: a) D. K.
Smith, Org. Biomol. Chem. 2003, 1, 3874; b) J. W. Ruan, J. L.
Xiao, Acc. Chem. Res. 2011, 44, 614.
6
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