Comparative performance evaluation and systematic screening of solvents in a range of Grignard reactions

Article abstract of DOI:10.1039/c3gc40702k

The solvent effect on the Grignard reaction of benzyl, aryl and heteroaromatic substrates has been systematically evaluated based on reaction efficiency, ease of subsequent work-up, safety and greenness. 2-Methyltetrahydrofuran (2-MeTHF), which can be derived from renewable resources, had at least an equal if not a superior overall process most notably in suppressing the Wurtz coupling by-product from the benzyl Grignard reactions. It is therefore a recommended alternative solvent to Et₂O and THF for the preparation of most Grignard reagents and their subsequent reactions.

Full text of DOI:10.1039/c3gc40702k

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Comparative performance evaluation and systematic
screening of solvents in a range of Grignard reactions†
Cite this: DOI: 10.1039/c3gc40702k
Asha Kadam,a Mylinh Nguyen,a Michael Kopach,b Paul Richardson,c Fabrice Gallou,d
Zhao-Kui Wane and Wei Zhang*a
The solvent effect on the Grignard reaction of benzyl, aryl and heteroaromatic substrates has been sys-
tematically evaluated based on reaction efficiency, ease of subsequent work-up, safety and greenness.
2-Methyltetrahydrofuran (2-MeTHF), which can be derived from renewable resources, had at least an equal
if not a superior overall process most notably in suppressing the Wurtz coupling by-product from the
benzyl Grignard reactions. It is therefore a recommended alternative solvent to Et2O and THF for the
preparation of most Grignard reagents and their subsequent reactions.
Received 14th April 2013,
Accepted 3rd May 2013
DOI: 10.1039/c3gc40702k
www.rsc.org/greenchem
evaluate solvents for Grignard reactions. In 2011, the Zhang
group at UMass Boston was awarded a grant from GCIPR to
1 Introduction
The American Chemical Society’s Green Chemistry Institute carry out this targeted research and development. Preliminary
Pharmaceutical Roundtable (GCIPR) was developed in 2005 to results of these R&D efforts were presented at the 16th Annual
encourage the integration of green chemistry and engineering Green Chemistry and Engineering Conference.1 Herein we
into the pharmaceutical industry and to promote sustainable report the full set of results, which includes explorations of
manufacturing. GCIPR presently has 16 member companies benzyl, aryl and heteroaromatic Grignard reactions.
including contract research/manufacturing organizations,
1.1 Background of the Grignard reaction
generic pharmaceuticals, and related companies. In 2009,
GCIPR identified that a preponderance of commonly used
organometallic reagents was supplied in solvents lacking
greenness from an environmental and process safety perspec-
tive. Unfortunately, the solvent used for the organometallic
reagent biases a process towards a less green position from the
outset of development. Frequently these sub-optimal solvents
persist through the development lifecycle all the way through
to commercial manufacturing. To address these issues, a
GCIPR team was assembled with the objective to catalyse sup-
pliers to provide organometallic reagents in the greenest poss-
ible solvent. In 2010, feedback was received from several
organometallic reagent suppliers that the strongest impact
could be realized by conducting independent research and
publishing the findings with head to head performance com-
parisons between different solvents. Based on this feedback,
Victor Grignard and Paul Sabatier received the Nobel Prize in
1912 for the discovery of what was later called the Grignard
reaction.2 The classic Grignard reaction is an organometallic
reaction in which alkyl- or aryl-magnesium halides (Grignard
reagents) add to carbonyl groups of aldehydes and ketones to
generate a new carbon–carbon bond. In addition to the broad
applications on a research scale, Grignard reactions have also
been adapted to a large scale and are the pivotal steps in the
manufacture of numerous complex molecules. From
a
pharmaceutical perspective, the Grignard reaction has been
employed as a key step in numerous syntheses such as that of
tramadol,3 ravuconazole,4 naproxen,5 ibuprofen,6 aprepitant,7
droloxifene,8 and tamoxifen9 (Fig. 1). For each molecule shown
in Fig. 1, the bond prepared by the Grignard reaction is
highlighted.
the GCIPR developed
a research grant to systematically
Despite significant utility, Grignard reactions present chal-
lenges particularly on scaling-up. From a safety standpoint,
the initiation step is often hard to control, and is strongly
exothermic as is the subsequent Grignard reaction. In some
instances research scale chemistry has been recently carried
out using continuous flow methods to alleviate the exotherm
hazards of the Grignard reaction.10 Furthermore, the solvents
typically employed such as Et2O and THF have low boiling
points, and are capable of forming peroxides, which are both
hazardous as well as detrimental to the reaction. In addition,
aDepartment of Chemistry, University of Massachusetts Boston, Boston,
Massachusetts 02125, USA. E-mail: wei2.zhang@umb.edu
bEli Lilly and Company, Indianapolis, Indiana 46285, USA
cPfizer-La Jolla, 10777 Science Center Drive, La Jolla, California 92122, USA
dNovartis Pharma AG, Postfach, CH-4002 Basel, Switzerland
ePfizer-Cambridge, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140,
USA
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3gc40702k
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equilibrium. THF and in particular Et2O are not optimal sol-
vents for scale-up work due to their potential for peroxide for-
mation, as well as physical hazards such as their low boiling
points and flashpoints. An ideal alternative solvent would
present an improved reaction profile, and allow for an opera-
tionally simpler work-up. From an environmental standpoint,
the optimal solvent would also be one with a better safety
profile, and ideally available from renewable sources.13
Aycock14 has presented initial data showing the promising
nature of 2-MeTHF for Grignard reactions, and Clarke15 has
employed Grignard reagents of significantly enhanced concen-
trations (up to 5 M) in cross-coupling chemistry using this
solvent. 2-MeTHF can be derived from a renewable source,16 is
more stable to acids and bases than THF, is less prone to per-
oxide formation, and is immiscible with water thus enabling
an easier phase-split for work-up.17 Cyclopentylmethyl ether
(CPME), which can be produced directly from cyclopentene,
has also been promoted as a potential alternative solvent for
Grignard reactions.18 CPME is resistant to peroxide formation,
and like 2-MeTHF it is more easily dried than typical ethereal
solvents due to formation of an azeotrope with water. Merck
recently reported the results of oral toxicity studies for
2-MeTHF and CPME.19 For both these solvents the results were
negative for genotoxicity and mutagenicity which should assist
in favourable long-term ICH classifications. Although widely
promoted as greener solvents, only a handful of Grignard
reagents are available in 2-MeTHF or CPME. Despite the initial
promising results demonstrated for 2-MeTHF and CPME, to
the best of our knowledge, no systematic and unbiased evalu-
ation of solvent performance of a range of solvents has been
reported in the literature. For the purpose of comparison,
other solvents such as diethoxymethane (DEM),20 toluene, and
diglyme are also included in our study (Table 1).
Fig. 1 Pharmaceutical syntheses featuring the Grignard reaction.
the reactions typically use the reactive Grignard metal, and the
product profile is often complicated by the symmetrical homo
(Wurtz) coupling by-product and the proteo by-product result-
ing from direct reduction of the substrate or unfavourable
water ingress into the reaction. The amounts of oxygen and
moisture intake are also key parameters impacting both the
success of the initial reagent formation and subsequent pro-
cesses of Grignard reactions. Numerous methods have been
devised to initiate sluggish Grignard reactions.11 All these
derive from the common theme of weakening the passivation
layer of magnesium oxide, thereby exposing highly reactive
magnesium to the organic halide.
1.2 Selection of substrates and solvents for Grignard
reactions
Because of the broad use in the pharmaceutical and fine
chemicals industry, benzyl, aryl and heteroaromatic halides
were identified as the representative substrates to systemati-
2 Results and discussion
cally evaluate the solvent effect for the Grignard reactions. The The approach used in this study was to evaluate Grignard reac-
reaction solvent is the key component in the formation of the tions of the selected substrates in the seven solvents shown in
Grignard reagent and reaction. From a process standpoint, the Table 1. The Grignard reagents were generated by reacting the
solvent typically represents the largest fraction of the process alkyl- or aryl-halides with commercial grade magnesium turn-
mass12 and as such its judicious selection for work-up, safety, ings. The in situ generated Grignard reagents were allowed to
cost and reaction profile is critical. Numerous Grignard react with the electrophile. In the solvent screening reactions,
reagents are available commercially, and as previously men- the reaction mixtures were analysed by GC-MS or LC-MS to
tioned the vast majority of these are offered either as THF or determine the ratio of the product and by-products. Gram-
Et2O solutions. The use of commercially prepared Grignard scale reactions were then conducted under optimized con-
solutions provides an advantage for the synthetic chemist in ditions in selected solvents to examine the ease of product iso-
that the hazardous initiation step is removed. However, it lation and determine the yield. Other than solvents, key
causes problems in that the subsequent Grignard reactions are parameters such as temperature and activators were also evalu-
also performed in these solvents, though co-solvents can be ated. It is important to note in these systems that the reaction
introduced for purposes of solubility or reactivity. It has long of the magnesium metal with the aryl or alkyl halide forms the
been recognized that the solvent in which a Grignard reagent Grignard reagent, and is not classified as the actual Grignard
is formed has a significant effect on its reactivity due to the reaction, though both processes are often carried out sequen-
formation of potential aggregates with a chelating solvent, and tially and impurities generated from the Grignard reagent for-
a redistribution of organomagnesium species in the Schlenk mation step are carried into the Grignard reaction.
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Table 1 Physical property of solvents used for Grignard reactions
Boiling point
(°C)
Flash point
(°C)
Dipole moment
(D)
Dielectric
constant
Solubility in
Solubility of water in
water (g 100 g−1
)
solvent (g 100 g−1
)
Et2O
THF
DEM
2-MeTHF
CPME
Toluene
Diglyme
35
66
88
−45
−14
−7
11
−1
4
1.15
1.63
4.2
7.6
6.5
mis
4.2
14
1.1
0.05
mis
1.2
mis
1.3
4.4
0.3
80
1.38
1.27
0.36
1.6
7.0
4.8
2.4
7.2
106
111
162
67
mis
2.1 Benzyl Grignard reactions
Reactions in CPME and DEM gave a small amount of the
Grignard product using DIBAl-H in THF as an activator
(entries 4 and 5).
Grignard reaction of benzyl chloride in Et2O or 2-MeTHF
improved the product to Wurtz coupling by-product ratio to
90 : 10 (Table 3, entries 1 and 3), but it still remained 30 : 70
for the THF system (entry 2). Reactions in CPME, DEM,
toluene, and diglyme afforded some limited amounts of the
Grignard product by using DIBAL-H as an activator (entries
4–7).
The high yield and chemoselectivity in 2-MeTHF and Et2O
cannot be explained solely based on polarity, since solvents
with higher and lower dielectric constants produce much
greater quantities of the Wurtz by-product. Rather the aggrega-
tion state of the Grignard reagent is likely a key contributor.
Overall, the equivalent performance of 2-MeTHF to Et2O jus-
tifies the preferential usage of 2-MeTHF for the benzyl
Grignard class of reaction, since Et2O has a much lower
boiling point, a lower flashpoint, and a higher propensity for
peroxide formation.
After the solvent screening reactions, gram-scale reactions
of benzyl chloride were carried out under optimized con-
ditions in the selected solvents for product isolation (Table 4).
As expected, excellent yields of the Grignard product were
obtained from the reactions in both Et2O (94%) and 2-MeTHF
(90%), but due to a significant amount of the Wurtz by-
product, the yield was poor in THF (27%). Low product yields
were obtained from the CPME (45%) and DEM (45%) systems
using DIBAL-H in THF as an activator. We also conducted the
reactions in a hybrid solvent system by generating the
Grignard reagent in 2-MeTHF and adding the electrophile
2-butanone in CPME or toluene. Compared to the reactions in
the single CPME or toluene solvent, which did not afford the
Benzyl Grignard reactions are well-known and have been uti-
lized for the synthesis of important pharmaceutical com-
pounds such as propoxyphene21 and several selective
norepinephrine inhibitors.22 A major issue associated with
benzyl Grignard reagents is the generation of substantial quan-
tities of the undesired Wurtz coupling by-product, especially
from the more reactive benzyl bromides. In our experiments,
the in situ generated benzyl Grignard reagents from either
benzyl bromide or chloride were allowed to react with 2-buta-
none in different solvents to evaluate the solvent effect
(Scheme 1).
A screening using the full range of selected solvents was
carried out to determine whether the desired product was
observed prior to the optimization of reaction conditions for
the subsequent scale-up reaction and product isolation. The
reaction mixtures were analysed by GC-MS to determine the
ratio of the product and the Wurtz coupling by-product. Using
iodine as an activator, only the reactions in Et2O, THF, and
2-MeTHF gave the desired Grignard product 2. GC-MS analysis
indicated that the Et2O and 2-MeTHF systems both gave an
80 : 20 ratio of the product to the Wurtz coupling by-product
(Table 2, entries 1 and 3). Interestingly, the chemoselectivity is
reversed to a 30 : 70 ratio in the THF system (entry 2).
Scheme 1 Benzyl Grignard reaction.
Table 3 Solvent screening of benzyl chloride Grignard reaction
Table 2 Solvent screening of benzyl bromide Grignard reaction
2 : 1 Ratioa
Entry
Solvent
Activator
2 : 1 ratioa
Entry
Solvent
Activator
1
2
3
4
5
6
7
Et2O
THF
2-MeTHF
CPME
DEM
Toluene
Diglyme
I2
I2
I2
90 : 10
30 : 70
90 : 10
48 : 52
55 : 45
30 : 70
20 : 80
1
2
3
4
5
6
7
Et2O
THF
2-MeTHF
CPME
DEM
Toluene
Diglyme
I2
I2
I2
80 : 20
30 : 70
80 : 20
35 : 65
20 : 80
—
DIBAL-H
DIBAL-H
DIBAL-H
DIBAL-H
DIBAL-H
DIBAL-H
I2 or DIBAL-H
I2 or DIBAL-H
—
a Determined by GC-MS.
a Determined by GC-MS.
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exposed to non-ideal storage conditions prior to the receipt of
these materials by the customer. Because of these issues, sup-
pliers who produce Grignard reagents are encouraged to esta-
blish expiry date specifications and re-test these reagents if they
exceed the expiry date. While 2-MeTHF contained much less
Wurtz by-product and no benzene pentan-1-ol or related by-
product, the amount of benzyl alcohol was relatively high, indi-
cating strong oxygen sensitivity. Overall, these data support the
optimal preparation of benzyl Grignard reagents in 2-MeTHF.
However, based on the apparent air sensitivity, purchase of
commercial solutions of benzyl Grignard reagents is not re-
commended, and rather in situ preparation with 2-MeTHF and
direct use appear the best option.
2.2.1 Aryl Grignard reactions for benzyl alcohol. The use
of aryl Grignard reagents in organic chemistry is also well
established in the literature, and has been exploited in the syn-
thesis of a number of important pharmaceutical compounds
such as naproxen,5 emend (aprepitant),7 droloxifene,8 and
tamoxifen.9 It is another important transformation we have
selected for the investigation of the solvent effect. In a similar
manner to that described above, the reaction of the in situ pre-
pared Grignard reagent of 3-bromoanisole with 2-butanone in
seven different solvent systems was evaluated (Scheme 2).
The results summarized in Table 6 indicate that the reac-
tion proceeded well in Et2O, THF or 2-MeTHF using iodine as
the initiator and heating the reaction to 45 °C (entries 1–3).
For CPME, DEM, toluene, and diglyme solvent systems, no
reaction was observed even when the reaction was heated to
60 °C. Utilizing DIBAL-H in THF as the initiator, it was
observed that an almost identical yield could be obtained to
that with iodine when the reaction was run in 2-MeTHF
(entries 3 and 4). It was also found that acceptable yields of
Table 4 Benzyl chloride Grignard reaction
Entry
Solvent
Activator
2a
1
2
3
4
5
6
7
Et2O
THF
2-MeTHF
CPME
I2
I2
I2
94%
27%
90%
45%
45%
60%
51%
DIBAL-H
DIBAL-H
I2
I2
DEM
2-MeTHFb/CPMEc
2-MeTHFb/Toluenec
a Isolated yield calculated based on the electrophile limiting reagent.
b Solvent for Grignard reagents. c Solvent for electrophiles.
Grignard product using I2 as an activator, the hybrid systems
gave 60% and 51% product yields for the reactions involving
CPME and toluene respectively as the secondary solvents
(entries 6 and 7).
Since ethereal benzylmagnesium chloride solutions are
available from several commercial sources, we thought it was
important to assess the purity of the reagent. Seven benzyl-
magnesium chloride preparations in THF, 2-MeTHF and Et2O
were purchased from five suppliers. The benzyl Grignard solu-
tions obtained from commercial suppliers were analysed by
HPLC and titration (Table 5) within one month of the receipt
of the samples.23 For all preparations, substantial quantities of
impurities were observed by LC analysis and titration con-
firmed that the strength of these Grignard reagents was con-
sistently 25–50% below the label claim. For the THF systems,
the Wurtz by-product 3 was the major observed impurity
ranging from 12–33%. In addition, two additional impurities,
benzyl alcohol 4 and benzene pentan-1-ol 5, were prominent.
Benzyl alcohol 4 is likely formed by the known reaction of the
Grignard reagent with oxygen, followed by hydrolysis whereas
benzene pentan-1-ol 5 is likely produced from a radical reac-
tion between THF and the Grignard reagent. This impurity was
observed in all THF preparations, and as expected not
observed in the 2-MeTHF and Et2O preparations. Interestingly,
internal preparation of 1 M benzyl magnesium chloride THF
solutions reveals only trace amounts (<0.1%) of 2-benzene pen-
tanol after 3 months of ambient storage under nitrogen. These
data imply that the commercially purchased benzyl mag-
nesium chloride THF solutions were of significant age and/or Scheme 2 Anisole Grignard reaction.
Table 5 Commercial benzyl magnesium chloride impurity analysis
Supplier
Solvent
Label purity (M)
Titrated purity (M)
HPLC purity (%)
3 (%)
4 (%)
5 (%)
A (Batch1)
A (Batch1)
A (Batch1)
B
C
D
E
THF
THF
THF
THF
THF
Et2O
2-MeTHF
2.0
2.0
2.0
1.5
1.5
1.0
1.0
1.2
1.1
1.1
0.75
0.91
0.75
0.65
58.6
44.4
46.8
52.3
76.5
62.2
76.6
24.5
33.1
33.0
16.5
12.3
14.1
6.6
6.5
16.1
13.2
14.7
1.6
20.8
15.1
9.8
5.95
5.9
15.1
5.7
0.0
0.0
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Table 6 Grignard reaction of anisole bromide
Entry
Solvent
Tempa (°C)
Activator
7b (%)
1
2
3
4
5
6
7
8
Et2O
THF
25–35
25–45
25–45
25–45
60
60
60
I2
I2
I2
79
68
75
72
72
60
70
30
2-MeTHF
2-MeTHF
CPME
DEM
Diglyme
CPME
DIBAL-H
DIBAL-H
DIBAL-H
DIBAL-H
DIBAL-Hc
Scheme 3 Knochel’s method for bromoanisole Grignard reaction.
60
a For generating Grignard reagents. b Isolated yield. c In toluene.
range of temperatures, though under none of the examined
reaction conditions was the desired product observed.
Knochel’s method to generate the aryl Grignard reagent was also
evaluated using 3-bromoanisole as the substrate (Scheme 3).25
Due to the ready commercial availability of the requisite
Grignard reagent in THF, this was the solvent used for evalu-
ation. As shown in Scheme 3, the reaction proceeds smoothly
to provide a similar yield to that obtained above (Table 6, entry 3).
However, this method does possess several advantages such
as (1) no initiator is required, (2) the reactions proceed at
ambient temperature, and most notably (3) only a trace
amount of the Wurtz coupling product was observed. It is
important to note that this reagent is also commercially avail-
able in 2-MeTHF.
2.2.2 Aryl Grignard reactions for benzyl tramadol. To
further examine the solvent effect for aryl Grignard reactions,
our attention was turned to the synthesis of tramadol,3 which
is a well-known analgesic for the treatment of pain, and an
important model compound in opioid research. Tramadol is
marketed as a racemic mixture with the final step of the syn-
thesis featuring a Grignard reaction of (3-methoxy)phenyl-
magnesium bromide with racemic 2-((dimethylamino)methyl)
cyclohexanone to afford tramadol as a mixture of diastereo-
mers in an 80 : 20 ratio in favour of the desired cis isomer. The
desired compound is then obtained by recrystallization as its
hydrochloride salt.3 Not only will this study enable a further
comparison of the ability of the solvents screened to promote
the Grignard reaction, but it will also allow us to examine
whether the solvent has any influence on the diastereomeric
ratio obtained from the reaction. Previous studies have demon-
strated that it is possible to increase the amount of the cis-8 by
addition of an inorganic lithium salt and use of DEM as a
co-solvent,26 though we felt it would be instructive to learn if
any variations were observed in different reaction solvents
(Scheme 4).
the desired product could be realized using solvents such as
CPME, DEM, and diglyme albeit at an elevated temperature
(entries 5–7). At this juncture, it became critical to determine
whether this is an effect which could be attributed purely to
the nature of the initiator, or a more subtle co-solvent effect
given that we had utilized the commercially available DIBAL-H
in THF solution. Switching to the alternative preparation of
the DIBAL-H in toluene (entry 8), and hence eliminating the
ethereal co-solvent, we observed a significant drop in yield
demonstrating again the benefit of employing such a solvent.
However, clearly the judicious selection of the initiator is
important as well given that no reaction is observed for sol-
vents such as CPME when iodine was utilized.
Overall the results show equivalent performance of
2-MeTHF to THF and Et2O for the aryl Grignard chemistry.
Given the other advantages associated with the employment of
2-MeTHF as a solvent one should make this the preferred
choice for the aryl Grignard reaction class. CPME and DEM
have been promoted as new green solvent alternatives, and
have been demonstrated in certain cases to be effective sol-
vents for Grignard chemistry. In the current evaluation of aryl
Grignard reactions though, these solvents are shown to be sig-
nificantly inferior to Et2O, THF and 2-MeTHF. The observed
differences in reactivity here cannot be simply explained in
terms of polarity, but instead reflect complex solvent pertur-
bations of the Schlenk equilibrium leading to changes in
aggregation state of the reactive magnesium species. Glymes
have also been promoted as solvents or additives for Grignard
reactions,24 though on inspection, the inferior results obtained
using diglyme are not difficult to rationalize. The reaction
would be perceived to be favoured in terms of both the polarity
and the donating effect of the solvent. However, one would
expect the actual rate of the reaction to be slow due to the
greater amount of energy required to displace the strongly
coordinating solvent from the reaction intermediates. This is
reflected to some degree in the elevated temperature required
to promote this reaction, and suggests that although the reac-
tions may be slow, the lowered reactivity potentially offers the
opportunity to obtain higher selectivity using such solvents.
Experiments were also conducted in a series of solvents to
examine the potential to use 3-chloroanisole to generate the
Grignard reagent. Reactions were carried out in Et2O, THF and
2-MeTHF using either iodine or DIBAL-H as an initiator in a
Small-scale reactions for solvent screening were carried out
to determine whether the desired product was observed prior
to optimization of the most promising conditions for scale-up,
product isolation, and determination of the diastereomeric
ratio. The results obtained were similar to our earlier findings
with Et2O, THF and 2-MeTHF standing out for further evalu-
ation. For the gram-scale reactions, mild heating was applied
to push the reactions to completion (Table 7, entries 1–3).
The yield with 2-MeTHF was slightly higher than the other two
solvents possibly reflecting a more facile work-up and iso-
lation. Examining the diastereomeric ratio for the reactions in
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Scheme 5 Grignard reaction of 3-methyl thiophene.
Scheme 4 Grignard reaction for tramadol.
Table 7 Grignard reaction for tramadol
both the overall yield and the regioselectivity of the initial
deprotonation. Shown in Scheme 5 is the deprotonation and
trapping steps being performed in the solvent under investi-
gation. It is important to note however that the i-PrMgCl is in
itself supplied as a 2 M THF solution, and given this, there is
always an ethereal solvent present under the reaction con-
ditions. However, the solvent ratio in the deprotonation is
approximately 1 : 1 THF–screening solvent, and in addition the
electrophile (DMF or benzaldehyde) in the trapping step is
introduced as a solution in the screening solvent.
Entry Solvent
Tempa (°C) Activator Yieldb (%) 8 cis : transc
1
2
3
4
5
Et2O
THF
2-MeTHF 25–45
CPME
DEM
25–35
25–45
I2
I2
I2
70
67
78
80 : 20
80 : 20
83 : 17
80 : 20
85 : 15
60
60
DIBAL-H 66
DIBAL-H 52
a For generating Grignard reagents. b Isolated yield. c Determined
by LC.
As it has been previously documented, several by-products
such as Wurtz coupling or the proteo derivative can arise from
the intermediate Grignard species. In addition, it is possible
to obtain regioisomeric species arising from deprotonation
and trapping at the 2-position of the thiophene. Experiments
were conducted evaluating two electrophiles (DMF and benz-
aldehyde). The results obtained by trapping with DMF under
Bouvealt formylation24 conditions to provide the aldehyde are
summarized in Table 8. All the solvents investigated per-
formed well to give a high yield of product 10 in a regioselec-
tive fashion. It was noticed that 2-MeTHF does provide a
slightly higher yield of the desired product (entry 3). Taking
into account the other advantages of employing this solvent,
such as ease of work-up, and the fact that as noted previously,
i-PrMgCl is also available as a solution in this solvent, this
should be made the solvent of choice for conducting this type
of chemistry. In a similar manner, the reaction was conducted
using benzaldehyde as the electrophile, and the results are
also summarized in Table 8. Once again, all the solvents per-
formed well in this reaction providing the desired product 11
in good yield, and in a regioselective fashion. 2-MeTHF was
2-MeTHF (83 : 17) and THF (80 : 20) indicated a slight enhance-
ment in the formation of the desired cis-8 in 2-MeTHF. In
agreement with the previous exploration of aryl Grignards, it
was also possible to get relatively good yields of the desired
products in CPME or DEM solvents at slightly elevated temp-
erature (60 °C) using DIBAL-H in THF as the initiator.
2.3 Heteroaromatic Grignard reactions
Heteroaromatic systems are of paramount importance in the
pharmaceutical industry and it is important to assess the
effect of solvents on the Grignard reaction performed on such
substrates. 3-Methyl thiophene was selected as the substrate
for deprotonation and subsequent functionalization through
the Grignard reaction. Several studies have been reported on
this system involving Li or Mg-based deprotonations as well as
transmetallation approaches.27 The conditions including
temperature and additives have been shown to have a dramatic
effect on both the regioselectivity and the subsequent reactivity
of the intermediate organometallic species. Workers at Amgen
have recently reported a practical, robust method to access
metallothiophenes, and their utilization in the regioselective
synthesis of 2,4-disubstituted thiophenes.28 Under the
reported optimized conditions, treatment of a slight excess of
3-methylthiophene with i-PrMgCl (1.1 equiv.) and 2,2,6,6-tetra-
methylpiperidine (TMP-H) (0.13 equiv.) in THF at 66 °C fol-
lowed by trapping of the intermediate species in excess solvent
at reduced temperature led to moderate to good yields of the
desired thiophenes with excellent regioselectivity. We felt that
this study serves as an excellent starting point to probe this
Table 8 Reaction of 9 with DMF or benzaldehyde
Entry
Solvent
10a (%)
11a (%)
1
2
3
4
5
6
7
Et2O
THF
2-MeTHF
CPME
DEM
Toluene
Diglyme
67
67
72
60
54
50
—
78
80
82
70
65
65
68
chemistry in a variety of solvents paying particular attention to a Isolated yield.
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noted to slightly outperform the other solvents evaluated in reaction was observed and the temperature increased to 45 °C.
the chemistry. The remaining 3-bromoanisole solution was added slowly over
Of additional interest in this chemistry was the ability to 40 min while maintaining the temperature around 45 °C. The
tune the reaction conditions to also obtain the corresponding Grignard reagent was generated as a pale yellow solution after
ketone through a Mg-mediated Oppenauer oxidation of the the complete addition of 3-bromoanisole. The formation of a
intermediate alcohol. This has been reported by Knochel,29 Grignard complex was confirmed by extracting an aliquot and
and it is believed that the role of LiCl in the system is crucial diluting in methanol for GC-MS analysis. The Grignard
in promoting this reaction. The LiCl is proposed to solubilise complex was stirred for 30 min at 25 °C and then cooled to
the intermediate alkoxide in the reaction solvent as well as 0 °C. A solution of 2-butanone (5 g, 6.9 mmol in 6 mL of
activate the carbonyl function of benzaldehyde by acting as a 2-MeTHF) was added slowly maintaining the temperature below
Lewis acid.
0 °C. The reaction mixture was stirred at room temperature for
4 h and then poured into a beaker containing 10 g of NH4Cl in
80 mL of ice water. The mixture was extracted with ether
(3 × 30 mL) and the combined organic layers were dried over
Na2SO4 and concentrated in vacuo. The resulting crude
product was purified by flash chromatography over silica gel
eluting with 7 : 3 hexane–ethyl acetate to yield product 7 as a
colorless oil (9.4 g, 75%).31
3 Experimental section
General procedure for the Grignard reactions of benzyl halides
with 2-butanone
Magnesium turnings (2.33 g, 9.7 mmol) and iodine (0.57 g,
0.45 mmol) were placed in a dry, nitrogen flushed 50 mL flask
equipped with a magnetic stirrer, a thermometer and a
septum. The flask was warmed to 40 °C for 5 min to partially
vaporize the iodine. To the reaction mixture was added 1 mL
of 2-MeTHF and then cooled to 0 °C. A continuous stream of
dry nitrogen was passed via a septum to avoid moisture.
A portion of 10% of a benzyl chloride solution (11.56 g,
9.01 mmol in 10 mL of 2-MeTHF) was added in a dropwise
fashion. The exothermic reaction was observed and the temp-
erature increased to 10–15 °C. The remaining benzyl chloride
solution was added slowly over 40 min by maintaining the
temperature below 10 °C. A grey suspension of the Grignard
reagent was generated after the complete addition of benzyl
chloride. The formation of a Grignard complex was confirmed
by extracting an aliquot and diluting in methanol for GC-MS
analysis. The Grignard complex was stirred at 0 °C for 30 min
and then a solution of 2-butanone (3.24 g, 4.5 mmol in 8 mL
of 2-MeTHF) was added slowly maintaining the temperature
below 5 °C. The reaction mixture was stirred at room tempera-
ture for 4 h and then poured into a beaker containing 10 g of
NH4Cl in 80 mL of ice water. The mixture was extracted with
ether (3 × 30 mL) and the combined organic layers were dried
over Na2SO4 and concentrated in vacuo. The resulted crude
product was purified by flash chromatography over silica gel
eluting with 7 : 3 hexane–ethyl acetate to yield product 2 as a
colorless oil (6.7 g, 90%).30 The isolation of the product was
carried out to determine an accurate yield.
Knochel’s method for the Grignard reaction of 3-bromoanisole
with 2-butanone
A solution of i-PrMgCl·LiCl (1.33 M in THF, 2.6 mL, 2.6 mmol)
was charged to a dry 10 mL round bottom flask equipped with
a magnetic stirrer and a septum under a nitrogen atmosphere.
The 3-bromoanisole (482 mg, 2.6 mmol) was added to a single
portion. The reaction mixture was stirred at room temperature
for 8 h. The conversion to the Grignard complex was checked
by GC-MS. The reaction mixture was cooled to 0 °C and a solu-
tion of 2-butanone (205 mg, 2.86 mmol in 1 mL of THF) was
added slowly maintaining the temperature below 5 °C. After
the reaction mixture was stirred at room temperature for about
4 h, it was poured into a beaker containing 0.5 g of NH4Cl
in 12 mL of ice water. After extracting with ether (3 × 5 mL),
the combined organic layers were dried over Na2SO4 and
concentrated in vacuo to give product 7 as a colorless oil
(280 mg, 60%).
General procedure for the Grignard reaction of tramadol
Magnesium turnings (250 mg, 1.04 mmol) and iodine (61 mg,
0.048 mmol) were placed in a dry, nitrogen flushed 25 mL
flask equipped with a magnetic stirrer, a thermometer and a
septum. The flask was warmed to 40 °C for 5 min to partially
vaporize the iodine. A continuous stream of dry nitrogen was
passed via a septum to avoid moisture. 10% of a 3-bromo-
anisole solution (1.805 g, 0.97 mmol in 1 mL of 2-MeTHF) was
slowly added at room temperature. An exothermic reaction was
observed and the temperature increased to 45 °C. The remain-
der of 3-bromoanisole solution was added in a dropwise
General procedure for the Grignard reaction of 3-bromoanisole
with 2-butanone
Magnesium turnings (2.33 g, 9.7 mmol) and iodine (0.57 g, fashion over 10 min maintaining the temperature at 45 °C.
0.45 mmol) were placed in a dry, nitrogen flushed 50 mL flask The Grignard reagent was generated as a pale yellow solution.
equipped with a magnetic stirrer, a thermometer and a The formation of the Grignard complex was confirmed by
septum. The flask was warmed to 40 °C for 5 min to partially extracting an aliquot and diluting in methanol for GC-MS ana-
vaporize the iodine. A continuous stream of dry nitrogen was lysis. The Grignard complex was stirred for an additional
passed via a septum to avoid moisture. To the flask, 10% of 30 min at 25 °C and then cooled to 0 °C. A solution of 2-di-
3-bromoanisole solution (16.88 g, 9.07 mmol in 10 mL of methylamino methyl cyclohexanone (1.151 g, 0.7 mmol, in
2-MeTHF) was slowly added at room temperature. An exothermic
1
mL of 2-MeTHF) was added slowly maintaining the
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temperature below 5 °C. The reaction mixture was stirred at
room temperature for 4 h and then poured into a beaker con-
4 Conclusions
taining 1.5 g of NH4Cl in 30 mL of ice water. The mixture was In this study, we performed the systematic study focusing on
extracted with ether (3 × 5 mL) and the combined organic the solvent effect on a series of Grignard-type reactions. In
layers were dried over Na2SO4 and concentrated in vacuo. The addition, we have looked at both the effects of the initiators
crude product was dissolved in 5 mL of toluene and cooled in employed, and the reaction conditions in these systems. In the
an ice bath. The pH was adjusted to 0 by addition of 6 N HCl. reactions that we have studied, 2-MeTHF has consistently
Two layers were obtained with an aqueous layer containing the either out-performed or performed in an equivalent manner to
hydrochloride salt of tramadol. To the aqueous phase was typical reaction solvents such as Et2O and THF. Given this,
added 10 mL of EtOAc and then NH4OH to reach pH 9. The 2-MeTHF should be the solvent of choice for such reactions
aqueous layer was extracted with ether (3 × 5 mL). The com- from both safety and environmental standpoints. In addition,
bined organic layers were dried over Na2SO4 and concentrated we have demonstrated that the judicious selection of the
in vacuo to give product 8 as a brown-colored oil (1.4 g, 78%)3 initiator including its preparation (such as DIBAL-H in THF)
with a diastereomeric ratio of 83 : 17 (cis : trans) as determined enables solvents such as CPME, DEM and diglyme to be
by LC-MS.
employed in Grignard couplings. Finally, hybrid solvent
systems consisting of 2-MeTHF with toluene, CPME and
diglyme have the potential to broaden the scope of solvent
systems for the Grignard reaction. Utilization of such systems
could have a dramatic effect in terms of facilitating the work-
Grignard reaction of 3-methyl thiophene with DMF
A solution of 3-methyl thiophene (1.47 g, 15 mmol) in 6 mL of up, and isolation of the desired products from these reactions.
THF was charged into a 50 mL round bottom flask equipped Based on the data presented, organometallic reagent suppliers
with a thermometer and a stirrer under a slow stream of nitro- are encouraged to collect data to support manufacture and
gen. To the solution was added 2,2,6,6-tetramethylpiperidine storage of Grignard reagents in greener solvents such as
(0.252 mL, 1.5 mmol) in a single portion followed by addition 2-MeTHF.
of iso-propylmagnesium chloride in THF (2.00 M, 6.33 mL,
12.70 mmol) over 10 min keeping the temperature below
Acknowledgements
30 °C. The mixture was heated at reflux for 24 h. After cooling
the Mg–thiophene complex to 0 °C, DMF (1.6 mL, 21 mmol) in
7.2 mL of THF was added over 40 min. After being stirred at
0 °C for a further 30 min, the reaction mixture was quenched
with 5.6 mL of water followed by addition of 6 N HCl to adjust
the pH to 2. The aqueous layer was extracted with methyl tert-
butyl ether (MTBE) and the crude compound purified by flash
chromatography over silica gel eluting with 7 : 3 hexane–MTBE
to give product 10 as a pale yellow colored oil (1.7 g, 67%).27
WZ thanks ACS Green Chemistry Institute Pharmaceutical
Roundtable for research grant support.
Notes and references
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A solution of 3-methyl thiophene (1.47 g, 15 mmol) in 6 mL of
THF was charged into a 50 mL round flask equipped with a
thermometer and a stirrer under a slow stream of nitrogen. To
the solution was added 2,2,6,6-tetramethylpiperidine
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mixture was quenched with 5.6 mL of water followed by
addition of 6 N HCl to adjust the pH to 2. The aqueous layer
was extracted with methyl tert-butyl ether (MTBE) and the
crude compound was purified by flash chromatography over
silica gel eluting with 7 : 3 hexane–MTBE to give product 11 as
a brown colored oil (3.4 g, 80%).27
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