A simple, catalytic H2-hydrogenation method for the synthesis of fine chemicals; hydrogenation of protoporphyrin IX dimethyl ester

Article abstract of DOI:10.1016/j.tetlet.2006.05.083

A conceptually simple H₂-hydrogenation protocol is introduced for the high-yield preparation of a natural product derivative. Protoporphyrin IX dimethyl ester is hydrogenated to the mesoporphyrin analogue in N,N-dimethylacetamide under H₂ (1 atm) at 80 °C within 30 min. The reaction is catalyzed by commercial RuCl₃, without the need for the use of phosphine- and/or carbene-based ligands.

Full text of DOI:10.1016/j.tetlet.2006.05.083

Tetrahedron Letters 47 (2006) 5119–5122
A simple, catalytic H2-hydrogenation method for
the synthesis of fine chemicals; hydrogenation of
protoporphyrin IX dimethyl ester
Ju´lio S. Rebouc¸as and Brian R. James*
Department of Chemistry, The University of British Columbia, 2036 Main Mall, Vancouver, BC, Canada V6T 1Z1
Received 22 April 2006; revised 12 May 2006; accepted 12 May 2006
Available online 6 June 2006
Abstract—A conceptually simple H2-hydrogenation protocol is introduced for the high-yield preparation of a natural product deriv-
ative. Protoporphyrin IX dimethyl ester is hydrogenated to the mesoporphyrin analogue in N,N-dimethylacetamide under H2
(1 atm) at 80 °C within 30 min. The reaction is catalyzed by commercial RuCl3, without the need for the use of phosphine- and/
or carbene-based ligands.
Ó 2006 Elsevier Ltd. All rights reserved.
Catalytic hydrogenations are key reactions for organic
synthesis in both laboratory and industrial scales.1–8
Because H2 is the cleanest reducing agent, there has been
a great deal of interest in developing robust homogeneous
catalysts to attain efficient H2-hydrogenations of a variety
of C@C, C@O, and C@N functionalities.1–11 Histori-
cally, the catalysts in these systems ‘evolved’ from simple
late-transition metal salts to platinum metal-based
complexes containing phosphine as ligands;2,8,9 more
recently, carbene-containing species have received
attention due to their ability to mimic the reactivities of
their phosphine counterparts.12 This catalyst evolution
was initially driven by interests in the organometallic
chemistry of reaction intermediates and coincided with
the development of very active catalysts such as the
so-called Wilkinson’s catalyst;9 this represented the origins
of the usual phosphine/platinum–metal combination that
has dominated the hydrogenation literature since the
mid-1960s.1,2,8,9 Whereas in most of the hydrogenation
systems the appropriate choice of the phosphine repre-
sents a means of controlling catalytic efficiency and/or
selectivity,1–11 the actual role of the phosphine ligands is
not always obvious and, in some cases, these ligands
may play no role.13,14 Our group, for example, while
studying the catalytic properties of some Ni(II)-phos-
phine complexes for hydrogen transfer hydrogenation
of ketones, observed that simple NiX2 salts had compara-
ble (X = Cl) or even higher activity (X = Br, I) than
Ni-phosphine complexes themselves.13,14 Evidently,
depending on the catalytic conditions (solvent, tempera-
ture, additives, substrate), efforts in designing ligand
systems for metal complex catalysts may be unnecessary.
It was first reported in the 1960s that N,N-dimethylacet-
amide (DMA) solutions of RuCl3 were able to perform
H2-hydrogenation of simple olefins (e.g., maleic and
fumaric acids) under mild conditions.15–22 Despite the
intrinsic, conceptual advantages of the RuCl3–DMA
method, that is, no need to prepare ligands or their me-
tal complexes and the low-cost of Ru (compared to the
other platinum group metals), there has been no report
on the use of this protocol for organic synthesis. In this
communication, the convenience of this simple, phos-
phine-free, RuCl3-based method is explored for the
high-yield preparation of mesoporphyrin IX dimethyl
ester (H2mesoPIX-DME) via H2-hydrogenation of pro-
toporphyrin IX dimethyl ester (H2PPIX-DME), which
involves reduction of vinyl to ethyl groups (Scheme 1).
Because such reduction results in a more stable com-
pound than the parent H2PPIX,23 H2mesoPPIX and
its metal complexes have been extensively used in a vari-
ety of chemical, biological, and clinical studies.24–51 The
choice of mesoPIX is sometimes dictated by the incom-
patibility of the vinyl groups of PPIX with the harsh
conditions required for the synthesis of heme
analogues.24 Whereas mesoPIX complexes have been
traditionally used for studies of reconstituted heme
proteins and enzymes (e.g., myoglobin and horseradish
*
Corresponding author. Tel.: +1 604 822 6645; fax: +1 604 822
4827; e-mail: brj@chem.ubc.ca
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.083

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J. S. Rebouc¸as, B. R. James / Tetrahedron Letters 47 (2006) 5119–5122
H2mesoPIX is comparable to those of Methods A and B
Me
Me
(Table 1), the amount of Pt per vinyl group is almost
stoichiometric and the 16 h reaction time is long (likely
because of the low temperature used in this method).
Me
Me
Me
Me
N
NH
N
NH
N
N
H2
Catal.
HN
HN
Method D emerged as an adaptation of the PtO2-cata-
lyzed reduction of ‘RuCl3’ by H2 in DMF,58 where the
organic substrate H2PPIX-DME replaced the inorganic
substrate ‘RuCl3’. In this Method, H2PPIX-DME and
PtO2 in DMF were warmed at 60 °C for 30 min under
H2 (1 atm).59 The end of the reaction was detected by
the disappearance of the UV–vis bands for H2PPIX-
DME; the appearance of a small band at ꢀ650 nm at
high conversions indicated that reduction of the vinyl
groups was accompanied also by some reduction at
the ring as reported previously in Methods A and
B;54,57 the nature of this ‘chlorin’-type compound was
not investigated further, but the impurity can easily be
removed by filtration through a neutral Al2O3 plug
using CHCl3 (containing 0.75% EtOH) as eluent. The
compromise between heating time and product selectiv-
ity has been noted.54,57 Nevertheless, the H2mesoPIX
yield in Method D is close to that of Method C, using
ꢀ5 times less catalyst load than that used in C; further-
more, the experimental setup for Method D is conve-
nient as DMF and PtO2 are used as received, and the
work-up procedure is simple. Although no effort was
made to recover the PtO2 catalyst, in larger scale reac-
tions PtO2 may be filtered off after hydrogenation is
completed. Of note, a drawback of Method D is that
PtO2 should not be exposed to mixtures of O2 (air)
and H2 as a fire may occur; the experimental procedure
thus requires flushing with N2 at the beginning and at
the end of the catalytic hydrogenation.59
Me
Me
R = CH2CH2CO2Me
R
R
R
R
H2PPIX-DME
H2mesoPIX-DME
Scheme 1.
peroxidases),24–36 mesoPIX derivatives have also been
particularly useful in studying enzymes such as ferroche-
latase37–40 and heme oxygenase (HO),41–43 in following
heme trafficking within living cells,44 and in understand-
ing aspects of the synthesis of antihemostatics by blood-
sucking insects.45 The clinical use of a mesoPIX
complex, Sn(mesoPIX)Cl2, for the treatment of hyper-
bilirubinemia in infants (neonatal jaundice) relies on
the potent inhibitory effect that this compound exerts
on HO.46,47 Such an effect has also been explored for
functional imaging of HO gene expression in living
animals.48 Of note, Sn(mesoPIX)Cl2 is a stronger HO
inhibitor than is Sn(PPIX)Cl2.41
The H2-hydrogenation of H2PPIX-DME, or its chloro-
Fe(III) complex, has been traditionally accomplished by
using one of three literature protocols (A,52 B,53,54 and
C;55 Table 1). In Method A, which is an optimized pro-
tocol52 of Taylor’s procedure,57 Fe(PPIX)Cl is hydroge-
nated in 90% formic acid using wet PdO as catalyst, and
quantitative demetalation of the protohemin occurs con-
comitantly; although the method affords H2PPIX in rel-
ative high yields, it uses high loadings of Pd per vinyl
group (Table 1). A modification uses Pd on carbon
(Pd/C) as catalyst and anhydrous formic acid as solvent
(Method B); the course of the reaction needs to be mon-
itored spectrophotometrically as over-reduction may
occur to yield a chlorin-type compound that shows a
UV–vis band at ꢀ650 nm.54 In an attempt to prevent
the formation of side-products that generally accompa-
nied the earlier hydrogenations and contaminated the
isolated products,56 Baker et al.55 proposed that the
hydrogenation of Fe(PPIX)Cl be carried out in aqueous
KOH solution (0.2 mol LÀ1) catalyzed by PtO2 (Method
C); the crude hydrogenation product is then demetalated
with concd H2SO4. Indeed, although over-reduction has
not been observed in Method C55 and the yield of
Given that for the preparation of small quantities of
H2mesoPIX-DME on a laboratory-scale, recovery and
recycling of the catalyst are not usually a concern, the
use of a homogeneous catalyst (vs a heterogeneous
one) is justified. The modification of the vinyl groups
of H2PPIX-DME and its Zn(II) or Ni(II) complexes
via homogeneous catalysis has received some attention
recently. For example, Pereira and coworkers60,61 found
that homogeneous hydroformylation of M(PPIX-DME)
(M = H2, Ni, Zn) can be efficiently accomplished by the
use of Rh-phosphine catalysts, while Dolphin and co-
workers62 reported that olefins and M(PPIX-DME)
(M = H2, Zn) undergo cross-metathesis reactions cata-
lyzed by Grubbs-type, Ru-phosphine/carbene catalysts.
Table 1. Catalytic hydrogenation of protoporphyrin IX derivatives under 1 atm H2
Method
Catalyst (mmol metal)
Solvent (volume)
Vinyl group/catalyst
T/°C
t/min
% Yield
Ref.
Aa
Bb
Ca
Db
Eb
PdO (57.1)
Pd/C (0.705)
PtO2 (8.81)
PtO2 (0.014)
‘RuCl3’ (0.008)
HCO2H (3 L)
2.15
4.80
1.39
7.43
8.75
96
50
25
60
80
60
45
960
30
82c
95c,d
85e
81c
86c
52
53,54
55
This work
This work
HCO2H(anhydrous) (120 mL)
KOH(aq) (1.5 L)
DMF (50 mL)
DMA (10 mL)
30
a Using Fe(PPIX)Cl as starting material; acidic demetalation of crude product mixture yields H2mesoPIX.
b Using H2PPIX-DME as starting material.
c Isolated as H2mesoPIX-DME.
d Purity has been questioned.56
e Isolated as H2mesoPIX.

J. S. Rebouc¸as, B. R. James / Tetrahedron Letters 47 (2006) 5119–5122
5121
RuIII(H)2
RuIII
H2
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[Ligands (Cl-, DMA) omitted]
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´
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od D) by these phosphine complexes would result in the
introduction of an extra step in the synthetic protocol
for H2-hydrogenation of H2PPIX-DME, that is, the
preparation and isolation or purchase of these expensive
catalysts. In order to maintain the relative simplicity of
Method D, an alternative, RuCl3-based catalytic system
was investigated. The ability of DMA or DMF solutions
of RuCl3 to catalyze the H2-hydrogenation of simple
olefins has long been recognized,22 but applications in
organic synthesis have remained unexplored. Whereas
the kinetic and mechanistic aspects of this phosphine-
free, RuCl3-based hydrogenation system are relatively
complex (Scheme 2),15–21 the experimental one-pot pro-
cedure is simple: DMA solutions of RuCl3 are warmed
to 60–80 °C and reacted with H2 (1 atm) for 1–2 h to
generate a Ru(I)–DMA complex in situ; substrate
hydrogenation is then initiated by addition of the
olefin.15,18 A successful H2-hydrogenation of H2PPIX-
DME via this method (Method E; Table 1) was
accomplished.63 Indeed, Method E combines all the
advantages listed for Method D with one additional
feature: Ru is the cheapest of the platinum group metals,
and indeed RuCl3 can often be acquired free as ‘on loan’
material from several suppliers. Analogously to methods
A, B, and D, formation of the over-reduced, chlorin-
type product (band at ꢀ650 nm) is observed at
high conversion. The work-up procedure for Method
E is identical to that of Method D and the isolated
H2mesoPIX-DME samples from either method are
indistinguishable. The convenient and efficient
H2-hydrogenation of H2PPIX-DME via Method E
represents the first example of the use of the simple,
phosphine-free, RuCl3–DMA catalytic system in organ-
ic synthesis of fine chemicals.
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Acknowledgments
We thank the NSERC of Canada for financial support
and Colonial Metals Inc. for a loan of RuCl3ÆxH2O.
J.S.R. acknowledges Fundac¸ao CAPES (The Ministry
˜
of Education of Brazil) and The University of British
Columbia for graduate scholarships.
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MeOH, and collected by elution with CH2Cl2; a black
solid (presumably PtO2) remained on the Celite pad. The
CH2Cl2 solution was evaporated to dryness and the
resulting solid was dissolved in ꢀ5 mL of CHCl3 (used
as received, containing 0.75% EtOH). This solution was
percolated through a neutral Al2O3 (Brockmann activity I)
plug. The filtrate was collected and evaporated to dryness.
The purple solid was further dried in an Abderhalden
pistol (EtOH) overnight. Yield: 24.7 mg (81%). Charac-
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63. The apparatus described above59 was charged with
‘RuCl3’ (1.91 mg, 0.008 mmol in Ru) and DMA (10 mL),
and the mixture was warmed to 80 °C with magnetic
stirring. The resulting brownish-red solution was flushed
10 min with Ar and then a slow flow of H2 was introduced
at 80 °C for 1.5 h, during which time the color changed to
pale yellow. H2PPIX-DME (20.7 mg, 0.035 mmol), con-
tained in a glass half-capsule, was then added. After
30 min, the UV–vis spectrum of a sample aliquot showed
complete conversion. The mixture was cooled to room
temperature, flushed with Ar for 5 min, opened to the
atmosphere, and concentrated to ꢀ5 mL. The work-up
procedure for isolation of H2mesoPIX-DME was identical
to that described above,59 except that Ru salts were
eliminated in the H2O/MeOH washings. Yield: 17.9 mg
(86%). Anal. Calcd for H2mesoPIX-DME, C36H42N4O4:
C, 72.70; H, 7.12; N, 9.42. Found: C, 72.91; H, 7.11; N,
57. Taylor, J. F. J. Biol. Chem. 1940, 135, 569–595.
9.74. UV–vis (CH2Cl2): 398 nm (loge/L molÀ1 cmÀ1
,
58. Judd, R. J.; Cao, R.; Biner, M.; Armbruster, T.; Burgi,
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5.15), 498 (4.10), 532 (3.94), 568 (3.76), 620 (3.61). IR
H.-B.; Merbach, A. E.; Ludi, A. Inorg. Chem. 1995, 34,
5080–5083.
(KBr): 3314 cmÀ1 (mNH), 1735 (mCO). 1H NMR (CDCl3): d
3
10.10, 10.09 (2 s, 4H, meso-H), 4.42 (t, 4H, JHH = 7.59
3
59. A 125 mL three-neck-round-bottom flask fitted with a
reflux condenser and an oil-bubbler was charged with
H2PPIX-DME (30.9 mg, 0.052 mmol), PtO2 (3.21 mg,
0.014 mmol), and DMF (50 mL), and the mixture was
warmed to 60 °C with magnetic stirring. The purple
solution was flushed with N2 for 10 min before H2 was
introduced. The mixture was kept at 60 °C under a slow
flow of H2 for 30 min, when the UV–vis spectrum of a
sample of the mixture showed complete conversion to
H2mesoPIX-DME (the 630 nm band of H2PPIX-DME is
replaced by the 620 nm band of H2mesoPIX-DME57). The
Hz, CH2CH2CO2), 4.08 (q, 4H, JHH = 7.62, CH2CH3),
3.65 (s, 6H, CO2CH3), 3.64, 3.62 (2s, 12H, CH3), 3.28 (t,
3
3
4H, JHH = 7.59, CH2CO2), 1.85 (t, 6H, JHH = 7.62,
CH2CH3). ESI-MS (9:1 MeOH/CH2Cl2, positive mode):
m/z 595 (100%, [H2mesoPIX-DME+H]+). Spectroscopic
data agree with those reported.52,54,64,65
64. Smith, K. M. In Porphyrins and Metalloporphyrins; Smith,
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