The remarkable effect of a simple ion: Iodide-promoted transfer hydrogenation of heteroaromatics

Article abstract of DOI:10.1002/chem.201201517

I can do it! Accelerated by simple iodide ions, rhodium-catalysed transfer hydrogenation can be readily performed on quinolines, isoquinolines and quinoxalines, affording the tetrahydro products in high yields with low catalyst loading (see scheme). Copyright

Full text of DOI:10.1002/chem.201201517

COMMUNICATION
DOI: 10.1002/chem.201201517
The Remarkable Effect of a Simple Ion: Iodide-Promoted Transfer
Hydrogenation of Heteroaromatics
Jianjun Wu,[a] Chao Wang,[b] Weijun Tang,[a] Alan Pettman,[c] and Jianliang Xiao*[a]
Dedicated to Professor Marty Cowie on the occasion of his 65th birthday
Among a variety of heteroaromatics, 1,2,3,4-tetrahydro-
quinolines, -isoquinolines and -quinoxalines are three signifi-
cant substructures in many bioactive compounds and have
attracted a great deal of attention in research concerning
pharmaceuticals, agrochemicals, dyes and fragrances, as well
as hydrogen-storage materials.[1] They can be directly ac-
cessed by hydrogenation from commercially available quino-
lines, isoquinolines and quinoxalines. Traditionally, stoichio-
metric metal hydrides and reactive metals are used as reduc-
ing reagents.[2] Apart from producing copious waste and
using often hazardous reagents, these methods suffer from
limited substrate scope, incompatibility with functionality
and poor chemoselectivity.
A more attractive method is to use catalytic hydrogena-
tion. Over the past several decades, a number of homogene-
ous and heterogeneous catalysts have been applied to the
hydrogenation of heteroaromatics, including the asymmetric
version.[3–7] The need for high H2 pressure, high reaction
temperature or high catalyst loading is typical of metal-cata-
lysed hydrogenation. Obviating the need for hydrogen gas,
transfer hydrogenation (TH) offers an alternative. However,
only a few catalysts have been reported thus far that allow
for the TH of heteroaromatics, and in all cases the catalyst
loading is relatively high (ꢀ0.5%).[8] Furthermore, in either
hydrogenation or TH, there appears to be no catalyst capa-
ble of reducing all three classes of heteroaromatics: quino-
lines, isoquinolines and quinoxalines. Herein, we disclose
a highly effective catalyst system, enabled by a simple ion,
IÀ, which shows unprecedented activity in the reduction of
these heteroaromtics under mild conditions.
formate as the hydrogen source.[8f] Excellent enantioselectiv-
ities were obtained with Rh–Ts-dpen catalyst,
a
[Cp*RhCl(Ts-dpen-H)][9] (Ts-dpen=N-(p-toluenesulfonyl)-
1,2-diphenylethylenediamine).[10] Following this success, we
attempted the ATH of quaternary quinoline salts, aiming to
directly obtain chiral N-substituted 1,2,3,4-tetrahydroquino-
lines. We chose the N-methyl-2-methylquinoline iodide salt
as a benchmark substrate and Rh–Ts-dpen as the catalyst
(1 mol%). There was little reduction using sodium formate
as the reductant in water at 408C in 24 h, under which qui-
nolines were readily reduced.[8f] Somewhat surprisingly,
changing the aqueous formate to the azeotropic HCO2H/
NEt3 mixture led to an excellent isolated yield of 95% but
a very low enantiomeric excess (ee) value of 5% for the tet-
rahydro product. Interestingly, similar conversion was also
observed under identical conditions with [(Cp*RhCl2)2] as
catalyst, without adding the Ts-dpen ligand. Thus, the low ee
value might result from the diamine ligand in Rh–Ts-dpen
being replaced by the iodide anion in the salt during the re-
action. Bearing in mind the unusual effects of iodide docu-
mented in catalysis[11] and the scarcity of effective catalysts
for TH of heteroaromatics,[8] we thought it would be inter-
esting to explore whether [(Cp*RhCl2)2] in combination
with the iodide ion would lead to a simple but active cata-
lyst.
Choosing 2-methylquinoline 1a (pKa 5.4) as a model sub-
strate, which is expected to be protonated when using
formic acid (pKa 3.6) as the reductant, the TH was first car-
ried out with 0.05 mol% [(Cp*RhCl2)2] in the azeotropic
HCO2H/NEt3 at 408C. The reduction was insignificant, with
the conversion of 1a being only 6% (Table 1, entry 2), indi-
cating that iodide might indeed be necessary. To our delight,
in the presence of 1 or even 0.1 equivalent of an iodide salt,
tetrabutylammonium iodide (TBAI), full conversion was ob-
served (Table 1, entries 3 and 4). In contrast, the analogous
bromide salt TBAB is much less effective (Table 1, entry 5)
and the chloride TBAC is ineffective (entry 6). The cheaper
KI was equally effective, showing that it is the iodide ion
that promotes the catalysis (Table 1, entry 7). Remarkably,
in the presence of KI, the metal loading could be decreased
to 0.01 mol% without affecting the conversion (Table 1,
entry 8). At an even a lower loading of 0.001 mol% of rho-
dium with 0.5 equivalent of KI added, a moderate conver-
sion of 71% was still obtained, albeit in a longer reaction
We recently reported the first example of asymmetric
transfer hydrogenation (ATH) of quinolines in water with
[a] J. Wu, Dr. W. Tang, Prof. J. Xiao
Department of Chemistry, University of Liverpool
Liverpool L69 7ZD (UK)
E-mail: j.xiao@liv.ac.uk
[b] Dr. C. Wang
School of Chemistry & Chemical Engineering
Shaanxi Normal University, Xiꢀan 710062 (P.R. China)
[c] Dr. A. Pettman
Chemical R & D, Global Research & Development, Pfizer
Sandwich, Kent CT13 9NJ (UK)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201517.
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Table 1. Effect of iodide on the TH of 1a.[a]
Entry
Metal, mol%[b]
t [h]
Additive, equiv
Conv. [%][c]
1
2
3
4
5
6
7
8
none
12
12
12
15
15
15
15
12
48
12
12
12
none
none
NR[d]
6
100
100
42
Rh, 0.1
Rh, 0.1
Rh, 0.1
Rh, 0.1
Rh, 0.1
Rh, 0.1
Rh, 0.01
Rh, 0.001
Ir, 0.01
Ru, 0.01
RhCl3, 0.01
TBAI, 1.0
TBAI, 0.1
TBAB, 0.1
TBAC, 0.1
KI, 0.1
KI, 0.2
KI, 0.5
KI, 0.2
KI, 0.2
8
100
100
71
<1
<1
NR[d]
9
10
11
12
KI, 0.2
[a] Reaction conditions: 1a (0.5 mmol), HCO2H/NEt3 azeotrope (3 mL),
408C. [b] Rh=[(Cp*RhCl2)2], Ir=[(Cp*IrCl2)2] and Ru=[{RuCl2ACHNUTRGTEG(NNUN p-
Figure 2. Effect of IÀ on the TH of 1a (0.8 mmol) catalysed by
cymene)}2]; number refers to Rh content. [c] Determined by 1H NMR
spectroscopy. [d] No reaction observed.
~
&
*
[(Cp*RhX2)2] (0.5 mol%) ( X=Cl,
X=I,
X=Cl plus 20 mol%
KI). Reactions were carried out in the HCO2H/NEt3 azeotrope (5 mL) at
408C.
time (Table 1, entry 9). This yields a turnover number
(TON) close to 7.1ꢂ104, which is, to the best of our knowl-
edge, the highest TON value ever reported in catalytic re-
duction of heteroaromatics. However, under similar condi-
tions, other metal compounds, such as [(Cp*IrCl2)2] and
to 1a; thereafter the rate decreased with more iodide
added, suggesting that the iodide is involved in the turn-
over-limiting step or steps prior to this step. This finds sup-
port in the conversion-time profiles shown in Figure 2, ob-
tained using as catalysts [(Cp*RhCl2)2], [(Cp*RhI2)2] and
[(Cp*RhCl2)2] in the presence of 20 mol% KI (1 mol% rho-
dium in each case). Clearly, the iodo dimer catalysed signifi-
cantly faster hydrogenation than its chloro analogue. More
interestingly, the kinetics for these two catalysts appears to
be distinctively different. With the chloro catalyst, the re-
duction appears to be zero order in [1a], whereas in the
case of the iodo catalyst, the profile suggests rate depend-
ence on [1a]. In the presence of excess IÀ (20 mol% KI),
the reduction became still faster, with the initial rate being
approximately 7 times that obtained with [(Cp*RhI2)2] and
approximately 40 times that with [(Cp*RhCl2)2] alone.
These results suggests that in the presence of excess IÀ, an
active Cp*Rh-iodo catalyst is generated from [(Cp*RhCl2)2]
and its presence alters the hydrogenation kinetics, with the
turnover rate limited by hydride formation with
[(Cp*RhCl2)2] but more likely by hydride transfer when
iodide is added.
[{RuCl2ACHTUNGTRENNUNG(p-cymene)}2], failed to catalyse the reduction
(Table 1, entries 10–12).
The beneficial effect of iodide in asymmetric hydrogena-
tion with H2 has been noted in a number of instances,
though the mechanistic details remain to be delineate-
d.[5a,h,11,12] Few examples of an iodide effect in TH are
known or have been studied, however.[8d,13] We therefore de-
cided to take a further look into the rate acceleration by
iodide. Figure 1 shows the effect of iodide concentration [IÀ]
on the conversion of 1a to 2a at 4.5 h in the HCO2H/NEt3
azeotrope. A dramatic increase in the reaction rate was ob-
served when [IÀ] was increased, up to 20 mol% with respect
A plausible mechanism is shown in Scheme 1. The key
feature is that the substrate, which is most likely to be pro-
Figure 1. Effect of the concentration of iodide on the TH of 1a
(0.5 mmol) catalysed by [Cp*RhCl2]2 (0.005 mol%). Reactions were car-
ried out in the HCO2H/NEt3 azeotrope (3 mL) for 4.5 h at 408C.
Scheme 1. Suggested mechanism for the Cp*RhIII-I catalysed TH of quin-
oline.
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Iodide-Promoted Transfer Hydrogenation
COMMUNICATION
tonated under the reaction conditions, is reduced by an
Having identified the optimised conditions, we subjected
a variety of quinoline derivatives to the TH. As can be seen
from Table 2, the reduction affords good to excellent yields
at 408C with 0.01–0.1 mol% catalyst. Notably, the reaction
can be carried out in air; degassing did not show any detect-
able difference. Quinolines bearing various alkyl substitu-
ents at the 2-position (1a–f) proceeded successfully to give
the corresponding hydrogenated products in excellent yields
(Table 2, entries 1–6). Pleasingly, good to excellent yields
were obtained for quinolines with bulky substituents at the
2-position (1g–k; Table 2, entries 7–11), and in particular,
1,2,3,4-tetrahydro-2-tert-butylquinoline (2i) was obtained
with 99% yield. In homogeneous hydrogenation, the best
result reported previously for this substrate was 43% con-
À
anionic diiodo Rh H hydride, probably via a 1,4-addition
pathway as indicated by deuterium labelling (see the Sup-
porting Information).[14] The anionic charge is likely to make
the hydride more hydridic, and this would be reinforced by
the stronger bonding of the soft iodide to RhIII and its stron-
ger “trans” effect than the hard chloride,[15] facilitating hy-
dride transfer to the substrate. Increasing [IÀ] increases the
concentration of the hydride and hence the rate; however,
when [IÀ] becomes too high, the equilibrium shown in
Scheme 1 will favour the triiodo species, decreasing the con-
centration of active catalyst and so the rate. Therefore,
a maximum is expected in the conversion–[IÀ] profile seen
in Figure 1.
Table 2. TH of quinolines with [(Cp*RhCl2)2]–KI in the HCO2H/NEt3 azeotrope.[a]
Entry
1
Product
S/C[b]
t [h]
Yield [%][c]
91
Entry
14
Product
S/C[b]
t [h]
Yield [%][c]
92
10000
12
10000
24
2
3
4
10000
10000
10000
15
12
15
93
93
96
15
16
17
10000
10000
10000
12
24
48
83
73
83
5
6
10000
10000
15
10
84
72
18
19
10000
10000
15
20
89
69
7
10000
15
91
20
10000
12
95
8
9
10000
10000
12
15
93
99
21
22
5000
12
24
98
71
10000
10
11
10000
10000
15
11
85
96
23
24
1000
1000
48
48
98
98
12
13
10000
10000
12
12
76
74
25
26
1000
5000
26
12
94
88
[a] Reaction conditions: 1 (0.5 mmol), [(Cp*RhCl2)2] (0.025–0.25 mmol), KI (0.1–0.8 mmol), HCO2H/NEt3 azeotrope solution (3 mL), 408C, 12–48 h.
[b] Substrate/rhodium molar ratio. [c] Yields of isolated products.
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J. Xiao et al.
version with 2 mol% of a rhodium catalyst in 48 h.[8g] The
isolated C=C bond in 1v, which is challenging in hydrogena-
tion with molecular hydrogen, was tolerated (Table 2,
entry 22). Also interestingly, 2,3-disubstituted and 3-substi-
tuted quinolines (1s, 1t and 1z; Table 2, entries 18, 19 and
26) and an example of fused quinolines (1u; entry 21) can
be smoothly reduced. A problem was encountered with the
less basic 2-arylquinolines (1w–y), where good yields were
obtained with a higher metal and iodide loading and
a longer reaction time (Table 2, entries 23–25). To showcase
the practicability of this methodology, we tried the TH of
5.0 g of 1a with 0.01 mol% rhodium (1.0 mg). The reduction
afforded 2a in 97% isolated yield in 24 h at 408C.
catalyst loading was necessary for some of these substrates,
however. Thus, using 0.2 mol% rhodium loading, good to
excellent yields were obtained for a range of tetrahydroiso-
quinolines (4a–d; Table 3, entries 1–4). This represents the
lowest metal loading reported in metal-catalysed hydrogena-
tion of this class of substrates. Excellent yields were also ob-
served in the reduction of several quinoxalines (3e–i;
Table 3, entries 5–9) with as low as 0.02 mol% rhodium
loading. The accelerating effect of iodide was again noted.
Thus, no reaction was observed in the TH of 3a and 3e
when the iodide salt was omitted.
In conclusion, we have developed a new protocol for the
reduction of quinolines, isoquinolines and quinoxalines. En-
abled by the simple iodide ion, which accelerates the hydro-
genation presumably by altering the reaction mechanism,
the protocol is efficient, practical and operationally simple,
providing a valuable alternative to currently used methods
for heterocycle reduction.
The more challenging quinoxalines and particularly iso-
quinolines were next attempted (Table 3). The latter struc-
tures have not been reduced, until now, to tetrahydroisoqui-
nolines under TH due to their stable aromaticity. Higher
Table 3. TH of isoquinolines and quinoxalines with [(Cp*RhCl2)2]–KI in
HCO2H/NEt3.[a]
Acknowledgements
We are grateful to Pfizer for funding (J.W.), AstraZeneca for support,
Dr. Xiaofeng Wu for assistance in NMR spectroscopy, and the EPSRC
National Mass Spectrometry Service Centre for mass analysis.
Keywords: formic acid · heterocycles · hydrogenation ·
iodine · rhodium
Entry
1
Product
S/C[b]
500
t [h]
Yield [%][c]
83
24
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95
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Iodide-Promoted Transfer Hydrogenation
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Received: May 1, 2012
Published online: && &&, 0000
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J. Xiao et al.
Transfer Hydrogenation
J. Wu, C. Wang, W. Tang, A. Pettman,
J. Xiao* ........................ &&&& — &&&&
The Remarkable Effect of a Simple
Ion: Iodide-Promoted Transfer Hydro-
genation of Heteroaromatics
I can do it! Accelerated by simple
iodide ions, rhodium-catalysed transfer
hydrogenation can be readily per-
formed on quinolines, isoquinolines
and quinoxalines, affording the tetra-
hydro products in high yields with low
catalyst loading (see scheme).
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ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!