D-Glucosamine in iron-catalysed cross-coupling reactions of Grignards with allylic and vinylic bromides: Application to the synthesis of a key sitagliptin precursor

Article abstract of DOI:10.1002/aoc.3327

A sustainable D-glucosamine ligand is successfully introduced into iron-catalysed C-C cross-coupling reactions for the first time. The Fe(acac)₂/D-glucosamine·HCl/Et₃N catalytic system was effective at 5 mol% loading in coupling reactions of Grignard reagents with organic bromides. Moderate to high efficiency was achieved with preserved stereochemistry when allyl (Csp³) or alkenyl (Csp²) bromides were coupled with phenylmagnesium (Csp²) or benzylmagnesium (Csp³) bromides. The catalytic system developed was also successfully applied for the novel and economic preparation of a Michael-acceptor-like starting material used in an alternative synthesis of the drug sitagliptin, a known blockbuster for the treatment of type II diabetes mellitus.

Full text of DOI:10.1002/aoc.3327

Full paper
Received: 26 February 2015
Revised: 4 April 2015
Accepted: 8 April 2015
Published online in Wiley Online Library: 22 May 2015
(wileyonlinelibrary.com) DOI 10.1002/aoc.3327
D-Glucosamine in iron-catalysed cross-coupling
reactions of Grignards with allylic and vinylic
bromides: application to the synthesis of a key
sitagliptin precursor
Matej Sovaa, Rok Frlana, Stanislav Gobeca, Gaj Stavberb
and Zdenko Časara,b,c
*
A sustainable D-glucosamine ligand is successfully introduced into iron-catalysed C–C cross-coupling reactions for the first time.
The Fe(acac)2/D-glucosamine·HCl/Et3N catalytic system was effective at 5 mol% loading in coupling reactions of Grignard reagents
with organic bromides. Moderate to high efficiency was achieved with preserved stereochemistry when allyl (Csp3) or alkenyl
(Csp2) bromides were coupled with phenylmagnesium (Csp2) or benzylmagnesium (Csp3) bromides. The catalytic system devel-
oped was also successfully applied for the novel and economic preparation of a Michael-acceptor-like starting material used in
an alternative synthesis of the drug sitagliptin, a known blockbuster for the treatment of type II diabetes mellitus. Copyright ©
2015 John Wiley & Sons, Ltd.
Additional supporting information may be found in the online version of this article at the publisher’s web-site
Keywords: cross-coupling; iron; glucosamine; Grignard reagent; catalysis
systems. To avoid the formation of possible side products, several
Introduction
ligands, additives[7a] and co-solvents (e.g. N-methyl-2-pyrrolidone
(NMP)[5b,5c]) have been used in combination with Fe (pre)catalysts.
Over the past decade, carbon–carbon bond-forming cross-coupling
reactions have become powerful and indispensable tools in mod-
ern and advanced organic synthesis.[1] One of the useful and com-
mon ways for single C–C bond formation is the coupling of an
organometallic nucleophile and an organic halide, generally in
the presence of a transition metal and/or a specific ligand system.[2]
Several transition metal catalysts have been applied for this
purpose.[1,2] However, the use of iron (Fe) has gained impetus over
the past decade as the cheapest, most environmentally friendly and
least toxic transition metal alternative.[3] Furthermore, Fe-catalysed
reactions have several advantages, such as high reaction rates, wide
scope of tolerated substrates and broad functional group compati-
bility under mild reaction conditions.[3] A large number of
Fe-catalysed cross-coupling reactions between an organic halide
and Grignard reagents have been reported, which started with
Kochi and co-workers in 1971[4] and was later followed by other
groups.[5–12] Among the various Fe precatalysts or catalysts, Fe(II)
and Fe(III) salts most commonly catalyse the reactions with the
highest levels of conversion.[3] Recently, Fe 1,3-diketonates
(especially Fe(acac)3) have been used as the most convenient
precatalysts, due to their low cost, commercial availability, stability
and relatively non-hygroscopic and non-toxic nature.[6a,6b,13] Iso-
lated Fe complexes with a variety of synthetically prepared
ligands,[14] including those with ‘artificial N,O-ligands’ (e.g. Fe
amine-bis(phenolate) complexes),[14c] have also been applied to
C–C cross-coupling reactions. However, additional synthetic efforts
are needed for their preparation, which makes them a second-
choice option in comparison with directly in situ formed Fe catalytic
N,N,N′,N′-Tetramethylethane-1,2-diamine (TMEDA), hexamethy-
lenetetramine (HMTA) and 1,4-diazabicyclo[2.2.2]octane (DABCO)
were shown to be the most promising ligands, as they show great
selectivity.[5f,5g,7a,9b,13] Although the mechanisms of Fe-catalysed
C–C cross-coupling reactions are still being investigated,[3c,15] the
exact mechanisms of action of the above-mentioned ligands and
additives remain elusive and under debate. For example, the initial
proposal of an Fe/TMEDA-based catalytic cycle by Nagashima and
co-workers[16] was recently revisited by Bedford et al.[17] Knowledge
of the actions of HMTA and NMP in these reactions is even more
slender. The positive effects of NMP have been assumed to
be associated with a reduction in the decomposition pathways
(i.e. β-hydride elimination) via stabilization of intermediate Fe
species.[5c] Moreover, only a few new original ligands have been
proposed for Fe-catalysed C–C cross-couplings in the past few
*
Correspondence to: Zdenko Časar, Lek Pharmaceuticals d.d., Sandoz
Development Center Slovenia, API Development, Organic Synthesis Department,
Kolodvorska 27, 1234 Mengeš, Slovenia. E-mail: zdenko.casar@sandoz.com
a Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000, Ljubljana,
Slovenia
b Lek Pharmaceuticals d.d., Sandoz Development Center Slovenia, API Development,
Organic Synthesis Department, Kolodvorska 27, 1234, Mengeš, Slovenia
c
Sandoz GmbH, Global Portfolio Management API, Biochemiestrasse 10, 6250,
Kundl, Austria
Appl. Organometal. Chem. 2015, 29, 528–535
Copyright © 2015 John Wiley & Sons, Ltd.

D-Glucosamine in iron-catalysed cross-coupling reactions
years.[18] In one of the latest studies by Cahiez et al., it was noted
that the discovery of specific new ligands is a forthcoming chal-
lenge for Fe-catalysed organic synthesis.[19]
Results and discussion
As a response to the challenge mentioned above, and in view of our
interest in the development of simple and especially more sustain-
able catalytic methodologies for C–C coupling reactions, our initial
study started with the screening of several different transition metal
catalysts in the presence of selected well-known ligands or ligand
systems (TMEDA[7a] and HMTA–TMEDA at 2/1[5f,5g]) in a model
non-optimized C–C coupling reaction. For this purpose, we used
methyl 4-bromocrotonate (1a) and phenylmagnesium bromide
(2a) to identify the catalytic systems with broad functional group
compatibility. Based on the data obtained (supporting information,
Table S1), Fe(acac)3 was selected as the catalyst, due to the high ef-
ficiency potential and the appropriate industrial applicability associ-
ated with it being environmentally friendlier due to its low toxicity.
In the continuation of our study, we focused on the search for new
specific ligands for Fe-catalysed organic reactions, to define a
cheap, simple and bio-inspired catalytic system that would be
efficient for our model reaction between 1a and 2a. Initially, we
performed screening of several natural molecules, including carbo-
hydrates, ascorbic and citric acids, amino acids, nicotinamide, re-
duced forms of alaninol and 3-picolylamine, and catechol as a
well-known Fe chelator,[20] and we compared their efficiencies with
those of some of the more well-known additives/ligands, such as
triethylamine (Et3N), DABCO, HMTA and TMEDA, and combinations
thereof.[9b] The data obtained are summarized in Table 1. It is worth
mentioning that carbohydrates and some basic amino acids are the
most bio-abundant groups of molecules that have environmentally
benign natures and can provide promising cost benefits for indus-
trial processes, and this is why they have high potential for use in
various synthetic applications. Chemists are using these very often
as the main precursors in the synthesis of natural compounds and
pharmaceutically important drugs, while significant progress has
been made in the field of selective catalytic reactions, where they
have important roles as efficient bio-based ligands.[21–25]
Substituted olefins represent an important structural motif in
organic chemistry. Their importance as principal building blocks in
organic synthesis, which enables many important functional group
interconversions, is widely recognized. Approaches to substituted
olefins from vinylic and allylic halides via cross-coupling reactions
using efficient, cheap and benign transition metal catalysts are
limited.[3o] In the context of iron catalysis, vinylic bromides were
cross coupled with Grignards using a very large excess of
reprotoxic NMP[5b,5c] or with iron catalyst based on the tedious-
to-prepare (on industrial scale) thiolate ligands,[19] while allylic
halides were efficiently coupled with Grignards only with highly
air-sensitive lithium ferrate complex[6i] or in moderate yields
with Fe(acac)3 (Scheme 1).[12b] In addition to vinyl halides, vinyl
triflates[6c,6g,6h,6j,12f,12g] and dienol phosphates[5h] have also been
used as substrates in cross-coupling reactions with Grignard
reagents for the construction of substituted olefins. In contrast to
vinyl halides, the coupling usually proceeds well in the presence
of Fe(acac)3 in pure THF or THF–NMP without the necessity of
additional ligand utilization. However, the use of expensive
trifluoromethanesulfonic anhydride or toxic diethoxyphosphoryl
chloride for the preparation of these substrates and lower atom
economy render these approaches less attractive for industrial
application. Therefore, a need exists to discover an efficient, robust
and benign catalytic system, which could be easily used in the
industrial setting in order to minimize waste streams.
Most of the sugars and amino acids used as ligands give similar
yields in comparison to the well-known ligands like TMEDA and
HMTA–TMEDA. To compare the efficiencies of ligands, the same
unoptimized reaction conditions were used for all entries in Table 1.
The substrate and Grignard reagent were used in 1:1 ratio to avoid
the possible influence of excess amounts of organomagnesium
reagent on the yield of the reaction and the formation of side
products. However, it is worth mentioning that part of the
organomagnesium reagent is probably consumed for the reduc-
tion of the iron catalyst and/or deprotonation of the chosen protic
additive. This is taken into consideration when we compare the ef-
ficiencies of selected ligands. Surprisingly, the highest yield among
the natural ligands is obtained when D-glucosamine hydrochloride
(D-GlcNÁHCl; Table 1, entry 3) and N,N-dimethylglycine (Table 1,
entry 7) are used as ligands in the catalytic system. It is well known
that both of these molecules work as efficient bidentate chelators
towards many metal ions in organometallic complexes, including
Fe.[26,27] On the other hand, D-glucosamine has also been reported
to be an efficient and green ligand for some metal-catalysed reac-
tions with palladium, in the well-known Heck reactions,[28] in
copper-catalysed synthesis of anilines from aryl halides[29] and in
N-arylation of imidazoles with aryl and heteroaryl bromides.[30]
However, to the best of our knowledge, D-glucosamine has never
been used in Fe-catalysed C–C coupling reactions. In our efforts to-
wards potential uses in industrial applications, D-glucosamine
might offer lower costs compared to N,N-dimethylglycine. In
addition, D-glucosamine has already been used for the synthesis
Scheme 1. Previously reported iron-catalysed cross-couplings of vinylic
and allylic halides with Grignards[3o] and the method developed herein.
Appl. Organometal. Chem. 2015, 29, 528–535
Copyright © 2015 John Wiley & Sons, Ltd.
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M. Sova et al.
Table 1. Ligands screened in the Fe(acac)3-catalysed C(sp2)–C(sp3) C–C
coupling model system
the literature, Et3N can also act as a ligand in Fe-catalysed C–C cou-
pling reactions of alkyl halides bearing β-hydrogens with Grignard
reagents, albeit at 10 mol% loading of Et3N.[9b] This might explain
the slightly higher efficiency of the reactions when Et3N is used.
However, when compared to other bases used (supporting infor-
mation, Table S2), only a slightly higher yield is obtained with
Et3N, which indicates clearly that the main contributing effect in
our catalytic system does not originate from the presence of Et3N.
Lower cost and better solubility of Et3N in THF compared to Cs2CO3
are the main reasons for the selection of Et3N as a base in all of the
further reactions. In our first set of experiments (supporting
information, Table S1), both Fe(II) and Fe(III) stabilized with
1,3-diketonates are effective in our model reaction. Additional
screening of four best ranked ligands with Fe(acac)2 shows the
highest yield for D-GlcNÁHCl (Table 1, entries 3 and 6–8). This obser-
vation can be explained by the recent study of Lefévre et al.,[15b]
where it was shown that additional equivalent of Grignard reagent
(e.g. PhMgBr) is consumed from Fe(acac)3 compared to Fe(acac)2 in
successive reductions to generate the active Fe(I) complex that cou-
ples with electrophiles (Fe(acac)2 is an intermediate in successive
reductions of Fe(acac)3 by Grignards towards Fe(I) species). This
could suggest that in the case of Fe(acac)3 part of the excess
Grignard is consumed for the reduction of Fe(acac)3 to Fe(acac)2
and generation of Ph–Ph by-product (which was also detected in
our case using NMR spectroscopy) instead for the desired reaction,
which results in lower observed yields. Accordingly, we performed
the reaction between 1a and 2a in the presence of the Fe(acac)2/
D-GlcNÁHCl/Et3N catalytic system, and we obtain a higher yield than
with the comparable Fe(III) analogue. Thus, we decided to use
Fe(acac)2 as the metal catalyst for all of our further experiments.
In the following optimization of Fe(acac)2/D-GlcNÁHCl/Et3N as the
selected catalytic system, the effects of catalyst and ligand loading,
reaction temperature and amount of Grignard reagent were exam-
ined for the cross-coupling reaction of a model system based on 1a
and 2a (Table 2). To demonstrate the efficiency of the assembled
catalytic system, we performed the reaction in the absence and
presence of a ligand and a base (Table 2, entries 1–3). We started
the optimization with 5 mol% metal catalyst and ligand at a tem-
perature of À20°C, which are standard conditions in similar metal-
based catalytic systems for C–C coupling reactions.[6b] Under these
conditions, a promising 60% conversion is achieved with Fe(acac)2/
D-GlcNÁHCl, and (E)-methyl-4-phenylbut-2-enoate (3) is isolated at a
43% yield (Table 2, entry 1). When Et3N is used in the absence of
D-GlcNÁHCl, 79% conversion is reached, and 3 is isolated at a 52%
yield (Table 2, entry 2). Moreover, as expected, the yield of 3 is
low when only Fe(acac)2 is used as the catalyst (Table 2, entry 3).
To explore potential synergistic effects of all of the tested species,
and to address the poor solubility of D-GlcNÁHCl in THF, our initial
reaction was run in the presence of 5 mol% of all of the ‘catalytic’
components. This combination enables excellent conversion
(92%), and 3 is obtained with a 60% isolated yield (Table 2, entry
4). These experiments also show that the addition rate of the
Grignard reagent has an important role as a critical factor in the ef-
ficiency of the cross-coupling reaction with the catalytic system de-
veloped (Table 2, entries 4 and 5).[7a] The best data are obtained
with the slow addition of the Grignard reagent (4ml hÀ1), although,
on the other hand, slower rates (<4 ml hÀ1) provide significantly
lower efficiency. Slow addition rates are generally preferred, to
avoid possible over-reduction of Fe species.[33]
,
Entry
Additive/ligand
Glucose
Yield (%)a b
1
30
2
Ribose
24
3
D-GlucosamineÁHCl
Phenylalanine
Proline
39 (43c)
4
26
5
20
6
Sarcosine (N-methylglycine)
N,N-Dimethylglycine
D,L-Pyroglutamic acid
Ascorbic acid
Citric acid
38 (35c)
7
39 (38c)
8
34 (27c)
10
11
12
13
14
15
16
17
18
19
10
5
Nicotinamide
Alaninol
8
26
5
Picolylamine
Catechol
5
DABCO
23
42
28
39
TMEDA
HMTA
HMTA–TMEDA (2/1)
aDetermined using HPLC analysis. 2,6-Dichlorobenzaldehyde and
phthalimide were used as internal standards.
bStandard reaction conditions: methyl 4-bromocrotonate 1a
(3.0 mmol), Fe(acac)3 (0.15 mmol), ligand (0.15 mmol), PhMgBr 2a
(3.0 mmol), anhydrous THF (20 ml), À20°C for 1 h, then room
temperature overnight. Although some of the used bio-based
ligands contain different numbers (2–5) of acidic protons which
can consume part of the used Grignard reagent, stoichiometric
amount of Grignard reagent 2 was used compared to substrate 1
for screening purposes. This result in the apparently lower
observed yields for catalytic systems based on bio-based ligands,
due to the partial consumption of Grignard in deprotonation of
acidic protons within the ligand.
cFe(acac)2 was used as the catalyst.
of several antibiotics and anticarcinogens.[30] Due to its apparent
advantages, we decided to use D-glucosamine as the potential li-
gand in our bio-inspired Fe-based catalytic system for C–C coupling
reactions.
The poor solubility of D-GlcNÁHCl in organic solvents is probably
one of the main reasons for the lower efficiency in the first experi-
ment. To circumvent the potential solubility problems, structurally
different bases were added to the Fe(acac)3/D-GlcNÁHCl couple
and the yields were determined using HPLC (supporting informa-
tion, Table S2). As expected, the addition of a base such as Et3N
to the reaction mixture deprotonates the D-GlcNÁHCl salt to its
neutral free base analogue (the pKa of D-glucosammonium ions is
ca 7.9–8.1[31] and the pKa of triethylammonium ions is ca 10.7[32]),
and increases its solubility as well as its possibility for iron chelation,
and consequently improves the yield from 39 to 50%. According to
To make the methodology even more economical, 1 mol%
Fe(acac)2 is used, where 87% conversion is detected and 3is obtained
with a moderate 50% isolated yield (Table 2, entry 6). Higher catalyst
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Appl. Organometal. Chem. 2015, 29, 528–535

D-Glucosamine in iron-catalysed cross-coupling reactions
Table 2. Effects of reaction conditions on Fe(acac)2/D-glucosamineÁ
HCl/Et3N-catalysed cross-coupling between 1a and 2a
Table 3. Fe(acac)2/D-glucosamineÁHCl/Et3N-catalysed C–C cross-cou-
pling of allyl and alkenyl bromides with Grignard reagents
Entry Fe
(acac)2 GlucosamineÁ (mol%) 2a
(mol%) HCl (mol%) (equiv.)
D-
Et3N PhMgBr, T (°C) Conversion Yield
(%)
(%)a
1
5
5
5
—
—
5
—
5
1
À20
À20
À20
À20
À20
À20
À20
À20
À20
0
60
79
50
92
88
87
88
93
79
95
49
99
97
98
43
52
20
60
39b
50
46
40
43
31
24
74
60
36
2
1
3
5
—
5
1
4
5
1
5
5
5
5
1
,
Entry
Substrate (1)
R1MgBr (2)
Product
Yield (%)a b
6
1
1
1
1
7
5
10
10
1
1
1a
1b
1b
1c
1c
1c
1d
1d
1e
1f
PhMgBr (2a)
PhMgBr (2a)
BnMgBr (2b)
PhMgBr (2a)
PhMgBr (2a)
BnMgBr (2b)
PhMgBr (2a)
BnMgBr (2b)
PhMgBr (2a)
PhMgBr (2a)
BnMgBr (2b)
PhMgBr (2a)
PhMgBr (2a)
BnMgBr (2b)
3
67
65
63
70
37c
84
79
40
80
72
92
83
70c
89
8
5
15
10
5
15
10
5
1
2
4
9
10
5
1
3
5
10
11
12
13
14
1
4
6
5
5
5
1
25
5
6
5
5
5
1.5
1.5
2.0
À20
À20
À20
6
7
2.5
2.5
2.5
7
8
5
5
5
8
9
aDetermined using HPLC analysis. 2,6-Dichlorobenzaldehyde was used
as internal standard. Standard reaction conditions: methyl
4-bromocrotonate 1a (3.0 mmol), Fe(acac)2 (1–10 mol%),
D-glucosamine hydrochloride (1–15 mol%), Et3N (1–15 mol%),
PhMgBr 2a (3.0–6.0 mmol, addition rate 4 ml hÀ1, anhydrous THF
(20 ml), À20°C, 1 h.
9
10
11
6
10
11
12
13
14
1f
1g
1g
1g
12
12
13
bAddition rate was 2 ml hÀ1
.
aYields were obtained after column chromatography (SiO2; diethyl
ether–petroleum ether = 1/10).
bStandard reaction conditions: substrate 1 (3.0 mmol), Fe(acac)2
(0.15 mmol), D-glucosamine hydrochloride (0.15 mmol), Et3N
(0.15 mmol), R1MgBr 2 (4.5 mmol; 1.5 equiv.), anhydrous THF
(20 ml), À20°C for 1 h, then slowly to room temperature for 1 h.
cFe(acac)3 was used as the catalyst.
and/or ligand loading (>5 mol%) does not improve the yield further
(Table 2, entries 7–9). Therefore, we decided to use the initial amounts
of 5 mol% Fe(acac)2 and D-GlcNÁHCl in the presence of Et3N for all of
the further experiments.
Next, we checked the effects of temperature on the reaction sys-
tem. It is known that a significant number of reported Fe-catalysed
reactions have been performed at temperatures below 0°C;[5–12]
however, it would be preferable to perform these reactions at am-
bient temperature. Unfortunately, the reaction temperatures be-
tween 0 and 25°C are not well tolerated, and result in decreased
reaction yields of 31 and 24%, respectively (Table 2, entries 10
and 11).
Last but not least, the amount of the Grignard reagent (2a) was
also studied. In many Fe-catalysed cross-coupling reactions re-
ported, up to 2 equiv. of Grignard reagents were often used.[5–12]
Accordingly, our reaction was performed in the presence of 1 to 2
equiv. of 2a. The data demonstrate that 3 is obtained with a higher
isolated yield of 74% when 1.5 equiv. of the Grignard reagent is
used (Table 2, entry 12). When lower catalyst loadings are used in
the presence of higher amounts of the Grignard reagents, lower ef-
ficiencies are again obtained (Table 2, entry 13). When 2 equiv. of 2a
is used, the yield does not exceed 36% (Table 2, entry 14).
Having defined this set of appropriate reaction conditions, we ex-
plored the efficiency and applicability of the developed catalytic
system for organic bromides. Several allyl and alkenyl bromides
and two different Grignard reagents (2a and benzylmagnesium
bromide, 2b) were used to examine the efficiencies of our catalytic
system in diverse Csp2/Csp3 C–C cross-coupling reactions (Table 3).
It is important to note here that, in most cases, the levels of
conversion are quantitative and the isolated yields are up to 92%.
Thus, the Fe(II)/D-GlcNÁHCl/Et3N bio-inspired catalytic system proves
to be relatively general with respect to different allyl or alkenyl bro-
mides, and provides a diverse set of useful products with high
yields (Table 3). Additionally, to test the selection of Fe(acac)2 as a
catalyst, we selected two substrates and performed the reaction
in the presence of Fe(acac)3 instead of Fe(acac)2 (Table 3; entries 5
and 13). As can be seen from the data obtained, the isolated yield
is lower in the case of Fe(acac)3, which confirms our initial findings
in the reaction between 1a and 2a.
The catalytic system developed proves to be efficient across the
structurally different allyl bromides 1a–d, and the target products
are obtained with 40 to 84% isolated yields (Table 3, entries 1–8).
The example shown in Table 3, entry 7, is of particular interest,
where high regioselectivity and efficiency are obtained when the
bromide 1d with an exocyclic double bond and an ester moiety is
reacted with 2a to product 8, which has not been achieved with
some previously developed catalytic methodologies. On the other
hand, the reaction with 2b (Table 3, entry 8) produces only 40%
pure isolated product 9. Among the selected allyl bromides 1a–d,
Appl. Organometal. Chem. 2015, 29, 528–535
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M. Sova et al.
the highest efficiency is obtained when cinnamyl bromide (1c) is
used as the substrate in the C–C coupling reaction with 2a or 2b,
where exclusively (E)-1,3-diphenylprop-1-ene (6) and (E)-1,4-
diphenylbut-1-ene (7) are obtained, with 70 and 84% isolated
yields, respectively (Table 3, entries 4 and 6). It is important to note
that these derivatives have been rarely studied within the frame of
iron catalysis.[3,6i,12b]
REACH Substance of Very High Concern (SVHC) list on 20 June
2011.[35a] The pharmaceutical industry has classified NMP as overall
hazardous[35b] and alternative amide-type solvents are already be-
ing investigated.[35c] Similarly, the operational simplicity advantage
of our method can also be noticed in comparison to Fe(II)
arylthiolate complexes,[19] where an additional Grignard-involving
step is needed for the preparation of Fe(II) arylthiolate precatalyst
from the iron source (e.g. FeCl2) and a foul-smelling mercaptan such
as 2-naphthalenethiol. In addition, these precatalysts work best at
5 mol% load in the presence of reprotoxic and hazardous NMP[35]
(7.5mol%) or expensive LiCl (200 mol%). Furthermore, in our case,
the same catalytic system also encompasses the ability to perform
previously less frequently studied Fe-catalysed coupling of
Grignard reagents with allyl halides in high efficiency.[3o] The pres-
ent highly efficient method described by Fürstner et al. for this type
of reaction uses the highly air-sensitive [Fe(C2H4)4][Li(tmeda)]2 lith-
ium ferrate complex at 5 mol% loading,[6i] while the Hashmi
method based on Fe(acac)3 operates with moderate efficiency.[12b]
Therefore, our method compares favourably with the existing
methods, due to its operational simplicity, albeit at slightly lower
attained yields compared to Fürstner et al.,[6i] but notably higher ef-
ficiencies compared to the Hashmi method.[12b]
In the past few years, iron catalysis has often been used for large-
scale applications and/or in the synthesis of industrially relevant
compounds.[36] Examples are 5-substituted 3-isoxazolol fibrinolysis
inhibitor AZD6564,[36a] a calcimimetic agent and calcium-sensing
receptor antagonist cinacalcet hydrochloride,[36b] highly selective
adenosine A2A receptor ligand antagonist ST1535,[36c] immu-
nosuppressive agent FTY720[36d] and a new heterocyclic dual
NK1/serotonin receptor antagonist.[36e] Encouraged by our results,
we wanted to determine whether the presented catalytic method-
ology based on Fe(II)/D-GlcNÁHCl/Et3N could be used for the prepa-
ration of a target intermediate, namely 4-(2,4,5-trifluorophenyl)
but-2-enoate (14), in an alternative process for the synthesis of
the oral antihyperglycemic drug sitagliptin phosphate (15).[37]
Compound 14 is a well-known precursor of sitagliptin chiral side
chain (Scheme 2). Sitagliptin phosphate can be assembled effi-
ciently in a concise manner from 14 either via asymmetric aza-
Michael addition strategy[37d,37f,37l] in five steps (including the salt
formation step) or via a lengthier borylation/alcohol amination
sequence comprising eight steps (Scheme 2).[37a,38] Previous syn-
thetic approaches to 14 are lengthy and consist of from three to
five synthetic steps (Scheme 2),[37b,37d,37f,37l] which makes the
abovementioned asymmetric aza-Michael addition strategy to-
wards sitagliptin rather long and less attractive from the industrial
point of view. Thus, a concise one-step synthesis of 14 from a com-
modity starting material such as 1a and the corresponding fluori-
nated aryl Grignard could mean the aza-Michael addition strategy
towards sitagliptin as a cost-effective six-step route. Namely, the
current benchmark routes to sitagliptin phosphate are four to five
steps long; however, they originate from more advanced starting
material 16, which already contains two atoms of the ‘side chain’.
Moreover, these routes use either costly Rh transition metal
catalyst[37c] or an expensive custom-made enzyme.[37e] The former
is prepared in several synthetic steps, while the enzyme preparation
requires specialized preparation and purification steps. All these
catalyst preparation steps in benchmark routes should be consid-
ered as complexity- and cost-generating factors in comparison to
the aza-Michael approach. Therefore, the starting material 1a was
reacted in the Fe(II)/D-GlcNÁHCl/Et3N-catalysed reaction with freshly
obtained 2,4,5-trifluoromagnesium bromide (2c) prepared via a
Grignard exchange reaction, and the target product 14a was
When alkenyl bromides 1e–g are used in the Fe(II)/D-GlcNÁHCl/
Et3N-catalysed cross-couplings, even higher efficiencies in compar-
ison to the allyl bromides 1a–d are obtained, and the conversions
are mostly quantitative (Table 3, entries 9–14). It is worth mention-
ing here that, in these cases, the methodology developed provides
very simple, economic, one-step synthesis to phenyl-substituted al-
kenes, where the desired products of 2-methyl-1-propylbenzene
(10), (E)-1,2-diphenylethene (11), (E)-1,3-diphenylprop-1-ene (6),
3-phenyl-1H-indene (12) and 3-benzyl-1H-indene (13) are prepared
at 72 to 92% isolated yields. Classical approaches to stilbene deriv-
atives also include bioactive compounds like resveratrol, pinosylvin
and pterostilbene, and these are usually more complicated
chemically, and require more chemical steps and/or operations,
while also showing variable stereoselectivities.[34] Various synthetic
strategies and methodologies to stilbenes have been developed
to date, which started with aldol-type condensations,[34a] Perkin
reactions,[34b,34c] the Wittig approach,[34d] Horner–Emmons
reactions[34c,34e] and, very recently, some modern Pd- and
Cu-catalysed Heck-type or Suzuki-type cross-couplings.[34f–34i] Fur-
thermore, it should be noted that the reactions catalysed with our
bio-inspired catalytic system are also fully stereoselective, as we
do not observe any changes in the E/Z ratio of the starting alkyl
or the alkenyl bromides 1e–g during the reactions. In all cases,
(E)-isomers are detected and confirmed with NMR spectroscopy.
We have also performed control experiments (in the absence of
Et3N) involving cross-coupling of alkenyl bromides 1e–g with
Grignards 2a and 2b (see supporting information for full details)
to verify the utility of D-GlcNÁHCl in the catalytic system. The ob-
tained results additionally affirm the beneficial role of D-GlcNÁHCl.
Indeed, when 1e–g react with 2a in the presence of Fe(acac)2, only
traces (0–11%) of products 10–12 are detected in the reaction
mixture, while the catalytic system based on Fe(acac)2/D-GlcNÁHCl
provides 30–68% of 10–12. When 1f and 1 g react with 2b in the
presence of Fe(acac)2 alone, 6 and 13 are formed in 54 and 48%
yields, respectively, while Fe(acac)2/D-GlcNÁHCl gives 10–19%
higher yields (73% for 6 and 58% for 13), which is also a notable dif-
ference from an industrial application perspective.
According to these data, our catalytic system complements the
Cahiez benchmark methods based on Fe(acac)3/THF/NMP (2–9
equiv.)[5c] or iron(II) arylthiolate complexes/NMP (7.5%) or LiCl
(2 equiv.)[19] for the coupling of Grignard reagents with alkenyl ha-
lides. Namely, our approach eliminates the necessity for the use of
2–9 equiv. (200–900%) of the NMP co-solvent in exchange for the
application of 5 mol% of D-GlcNÁHCl/Et3N, while 5 mol% of the
lower molecular weight Fe(acac)2 replaces 1 mol% of Fe(acac)3.
This is of great relevance when large-scale industrial processes are
considered, as enormous amounts of reprotoxic and hazardous
NMP solvent[5c,35] waste are eliminated in our method, while an
overall marginally higher amount of benign metallic catalyst waste
is generated. Namely, NMP is now known to cause reproductive
toxicity. According to Regulation (EC) No. 1272/2008 and amend-
ment by Regulation (EC) No. 790/2009, as of 1 December 2010,
NMP is listed and classified in Annex VI, Part 3, Table 3.1 as toxic
for reproduction category 1B (H360D: ‘May damage the unborn
child’). The European Chemicals Agency (ECHA) put NMP on the
wileyonlinelibrary.com/journal/aoc
Copyright © 2015 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2015, 29, 528–535

D-Glucosamine in iron-catalysed cross-coupling reactions
bromides makes this methodology industrially attractive from both
economic and environmental points of view.
Experimental
General remarks
Unless otherwise noted, all of the reactions were performed in dry,
round-bottomed flasks under an argon atmosphere. The chemicals
were from Sigma-Aldrich, TCI and Apollo Scientific, and they were
used without further purification. The reactions were conducted
in anhydrous THF, which was dried and purified by distillation over
Na before use. Analytical thin-layer chromatography (TLC) was
performed on Merck silica gel (60F254) plates (0.25mm). Column
chromatography was performed on silica gel 60 (particle
size, 240–400 mesh; Merck). 1H NMR spectra were recorded at 400
MHz, and 13C NMR spectra at 100 MHz, with a Bruker AVANCE III
1
400 MHz spectrometer in CDCl3. H NMR chemical shifts are re-
ported in parts per million (δ) relative to the solvent resonance used
as the internal standard (CDCl3, δ = 7.24 ppm). Data are reported
as follows: chemical shift, multiplicity (s, singlet; br s, broad singlet;
d, doublet; t, triplet; q, quartet; m, multiplet), coupling constants
(Hz) and integration. 13C NMR chemical shifts are reported in
ppm from the solvent resonance as the internal standard (CDCl3,
δ = 77.23ppm). HPLC analysis was performed using an Agilent
EclipsePlus C18, 150 × 4.6mm, 1.0ml minÀ1, injection volume 5 μl,
25°C, with absorbance measurement at 220 and 254 nm. Method:
CH3CN–H2O at 4/6 to CH3CN–H2O at 9/1 in 15 min, then 2.5min
at CH3CN–H2O at 9/1, then back to CH3CN–H2O at 4/6 at 18 min;
post-time 6 min.
Scheme 2. Straightforward synthesis of (E)-methyl-4-(2,4,5-trifluorophenyl)but-
2-enoate using the Fe(acac)2/D-GlcNÁHCl/Et3N catalytic system, and its use in an
alternative synthesis of sitagliptin phosphate.
successfully obtained with 75% isolated yield and exclusively in the
(E)-geometrical form (Scheme 2). It is worth mentioning that fluoro-
substituted Grignard reagents are very problematic for cross-
coupling reactions, due to very specific electronic effects of fluorine
atoms, as well as to their stability. This very encouraging result was
thus obtained by implementation of a simple and environmentally
friendlier catalytic system based on Fe and D-glucosamine in an im-
portant industrial application related to the improved economical
synthesis of sitagliptin phosphate,[38] where usually longer synthe-
ses with more complicated chemical steps are used for its
preparation.[37a,37d,37g,37j]
General experimental procedure for Fe(acac)2/D-GlcNÁHCl/
Et3N-Catalysed reaction of Grignard reagents with organic
bromides
A flame-dried and nitrogen-flushed flask equipped with a mag-
netic stirrer and a rubber septum was charged with anhydrous
Fe(acac)2 (0.15 mmol, 38 mg, dried 16 h under vacuum at 50°C),
D-(+)-glucosamine hydrochloride (0.15 mmol, 32 mg, dried 16 h
under vacuum at 50°C) and dry THF (20 ml). Then, anhydrous
Et3N (0.15 mmol, 0.021 ml) in THF (1 ml) was added, and the reac-
tion system was stirred at room temperature for 1 h. This was
then cooled to À20°C, at which point the starting material of sub-
strate 1a–g (3.0mmol) was added, with vigorous stirring for
10min. Grignard reagent 2 (1.5 equiv., 4.5mmol, 4.5 ml) was
added drop-wise (addition rate of 4 ml h–1) and, after 1 h, the re-
action system was slowly warmed to room temperature, when it
was quenched with methanol. Then 1 M HCl solution (30 ml)
was added to the reaction mixture, which was then extracted
with ethyl acetate (3× 50ml). The combined organic phases were
washed with brine (1× 30ml), dried over Na2SO4 and filtered, and
the solvent was evaporated. The residue was purified by flash
column chromatography using gradient elution (petroleum ether
to diethyl ether–petroleum ether, 1/10), to obtain the pure
products 3–13.
Conclusions
We have shown here that D-glucosamine is an efficient, sustainable
and cost-beneficial ligand alternative for Fe-catalysed cross-
coupling reactions of vinylic and allylic bromides. The Fe(acac)2/
D-GlcNÁHCl/Et3N catalytic system showed moderate to high effi-
ciency with preserved stereochemistry when allyl (Csp3) or alkenyl
(Csp2) bromides were coupled with phenylmagnesium (Csp2) or
benzylmagnesium (Csp3) bromides. To the best of our knowledge,
this is the first Fe-catalysed C–C coupling using an organometallic
nucleophile and a natural ligand such as D-glucosamine. Further-
more, the methodology presented was successfully applied to the
stereoselective synthesis of a key intermediate in the preparation
of the antidiabetic agent sitagliptin. This enables a facile and
benign six-step formal synthesis of sitagliptin phosphate from
commodity starting materials 1-bromo-2,4,5-trifluorobenzene and
methyl 4-bromocrotonate. The use of Fe as a non-toxic metal cata-
lyst and D-GlcNÁHCl as a simple and biocompatible sugar-type li-
gand in the presence of catalytic amounts of Et3N at 5 mol%
loading for C–C coupling reactions with various allyl and alkenyl
Protocol for preparation of methyl (E)-4-(2,4,5-trifluorophenyl)but-
2-enoate (14a)
A dry and nitrogen-flushed 250 ml flask equipped with a magnetic
stirrer and a rubber septum was charged with anhydrous THF
(7.0ml) and cooled to À20°C. Then, 1-bromo-2,4,5-trifluorobenzene
Appl. Organometal. Chem. 2015, 29, 528–535
Copyright © 2015 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

M. Sova et al.
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by slow addition of iPrMgCl (22.82 mmol, 11.41 ml; 2 M in THF). The
reaction temperature was maintained near À20°C and the reaction
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A flame-dried and nitrogen-flushed flask equipped with a
magnetic stirrer and a rubber septum was charged with anhydrous
Fe(acac)2 (0.15 mmol, 38 mg, dried 16 h under vacuum at 50°C),
D-(+)-glucosamine hydrochloride (0.15 mmol, 32 mg, dried 16h un-
der vacuum at 50°C) and dry THF (20 ml). Then, anhydrous Et3N
(0.15mmol, 0.021 ml) in THF (1ml) was added and the reaction
system was stirred at room temperature for 1 h. This was cooled
to À20°C, where starting material of methyl 4-bromocrotonate
(1a; 3.0mmol, 0.353ml) was added, with vigorous stirring for
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over Na2SO4 and filtered, and the solvent was evaporated. The res-
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elution (petroleum ether to diethyl ether–petroleum ether, 1/10),
to obtain 0.52 g (75% yield) pure product 14a.
All of the synthesized compounds 3–14a are known and
1
have been previously characterized in the literature.[38–49] The H
NMR and 13C NMR spectra of our compounds are consistent
with those previously reported and are included in the supporting
information.
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Acknowledgements
This study was supported by the Slovenian Research Agency (grant
P1-0208). In addition, the authors thank Lek Pharmaceuticals d.d.
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Supporting information
Additional supporting information may be found in the online ver-
sion of this article at the publisher’s web site. This includes
1
characterization data and H NMR and 13C NMR spectra of com-
pounds 3–14a as well as the experimental procedures leading to
the present synthetic method.
Appl. Organometal. Chem. 2015, 29, 528–535
Copyright © 2015 John Wiley & Sons, Ltd.
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