Regioselective Iron-Catalysed Cross-Coupling Reaction of Aryl Propargylic Bromides and Aryl Grignard Reagents

Article abstract of DOI:10.1002/adsc.201901203

An iron-catalysed Kumada-type cross-coupling reaction between aryl substituted propargylic bromides and arylmagnesium reagents has been developed. Propargylic coupling products were the main or only outcome, and propargyl/allene regioselectivity was shown to depend on the electronic nature of the substituents on the triple bond of the substrate and on the arylmagnesium halide. Best selectivities were observed when electron donating substituents were present in either reagent. The process is stereoespecific, occurs with configuration inversion and no carbon-based radicals seem to be involved in the mechanism. (Figure presented.).

Full text of DOI:10.1002/adsc.201901203

Title: Regioselective Iron-Catalyzed Cross-Coupling Reaction of Aryl
Propargylic Bromides and Aryl Grignard Reagents
Authors: Inés Manjón-Mata, María Teresa Quirós, Elena Buñuel, and
Diego Jesus Cardenas Morales
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10.1002/adsc.201901203
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Regioselective Iron-Catalyzed Cross-Coupling Reaction of Aryl
Propargylic Bromides and Aryl Grignard Reagents
Inés Manjón-Mata,a M. Teresa Quirós,a* Elena Buñuela and Diego J. Cárdenasa*
a
Department of Organic Chemistry, Facultad de Ciencias, Universidad Autónoma de Madrid, Institute for Advanced
Research in Chemical Sciences (IAdChem), Avd. Francisco Tomás y Valiente 7, Campus de Cantoblanco, 28049,
Madrid, Spain.
E-mail: mariat.quiros@uam.es, diego.cardenas@uam.es
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201
electrophiles with an oxygen leaving group.[7]
a
stereospecific Cu-catalyzed reaction of aryl Grignard
reagents and propargylic ammonium salts.[8]
Abstract. An iron-catalysed Kumada-type cross-coupling
reaction between aryl substituted propargylic bromides and Furthermore, in 2017 Tortosa developed
arylmagnesium reagents has been developed. Propargylic
coupling products were the main or only outcome, and
propargyl/allene regioselectivity was shown to depend on
the electronic nature of the substituents on the triple bond
of the substrate and on the arylmagnesium halide. Best
selectivities were observed when electron donating
substituents were present in either reagent. The process is
stereoespecific, occurs with configuration inversion and no
carbon-based radicals seem to be involved in the
mechanism.
Nevertheless, iron catalysis constitutes a more
convenient alternative, since this metal is economic,
abundant and nontoxic.[9] In 2004, Fürstner published
a Fe-catalysed Kumada cross-coupling reaction of
alkyl halides with aryl Grignard reagents to obtain
alkane derivatives,[10] in which only three examples
were reported using propargylic halides as substrates.
The iron complex used as catalyst was an ate
complex containing Fe(-II) that was previously
prepared and was reported to be an air-sensitive
crystalline material. Among these examples, the only
one with an aryl substituent in the terminal position
of the alkyne led to the propargylic coupling product
with moderate regioselectivity (Scheme 1a).
Racemization was observed when starting from an
enantiopure substrate, which was attributed to a
radical manifold.
Keywords: cross-coupling; Grignard reagents; Iron;
homogeneous catalysis; propargylic bromides
Cross-coupling processes are possibly the most
powerful tool in organic synthesis for the generation
of new C–C bonds. Among the wide variety of
substrates able to undergo this transformation,
propargylic derivatives represent a major challenge,
due to the difficulty of developing selective
methodologies for the formation of propargylic vs
allenic derivatives. The most thoroughly studied
metal catalyst in cross-coupling chemistry is by far
palladium. In fact, there are multiple examples of
cross-coupling reactions of propargyl derivatives
selective to the allenic product catalysed by this
metal.[1] However, the need of more sustainable,
selective and economic catalysts has shifted the
attention of chemists towards other first row
transition metals. And indeed, this transformation has
been also achieved using a variety of metal catalyst,
such as Ni,[2] Cu[3] and Fe.[4]
Regarding the direct cross-coupling of propargylic
derivatives in order to form the propargylic coupling
products, there are scarce examples in the literature.
In 2008, Fu described a Ni-catalyzed Negishi cross-
coupling reaction of secondary propargylic bromides
with alkyl- and arylzinc reagents.[5] Later that year,
they developed the enantioselective version of that
reaction,[6] which in 2012 was extended to
Scheme 1. Fe-catalyzed Kumada-type reactions using aryl-
substituted propargylic derivatives.
1
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10.1002/adsc.201901203
Advanced Synthesis & Catalysis
In 2016, the same group extended the reaction to 1-
alkynylcyclopropyl tosylates using aryl- and
alkylmagnesium reagents,[11] obtaining excellent
propargyl:allene ratios, except in the case of phenyl-
and benzyl-magnesium reagents, in which a decrease
of the regioselectivity was observed (Scheme 1b).
Lastly, in 2018, our group described a new method
using aryl and alkyl propargylic bromides together
with alkyl Grignard reagents (Scheme 1c).[12] The
factors governing the regioselectivity were studied
and it was concluded that it mainly depends on the
electronic nature of the substituent on the triple bond,
and better ratios were obtained when primary
propargylic substrates were used.
In view of the limited number of examples found
in the literature dealing with cross-coupling processes
of propargylic bromides with aryl Grignard reagents,
in this work, we report a new study on the
regioselectivity of the reaction using aryl substituted
propargylic derivatives as electrophiles and
arylmagnesium halides as nucleophiles in a Fe-
catalysed process (Scheme 1d).
Firstly, we decided to test if the reaction conditions
previuosly optimized in our group for alkyl Grignard
reagents [2.5 mol% of Fe(OAc)2 as catalyst, 6 mol%
of IMes (formed by deprotonation of 1,3-bis(2,4,6-
trimethylphenyl)-imidazolium) as ligand, in THF at –
78 °C],[12] led to good results when using PhMgBr.
To our delight, the reaction of propargylic bromide
1a under these conditions furnished product 3a with
an excellent regioselectivity and a good yield that we
did not manage to beat by tuning the reaction
conditions (Scheme 2).[13] The use of different NHC
ligands to try to improve the yields provided worse
results in terms of conversion, yield and
regioselectivity. Only the SIPr (1,3-bis(2,6-
diisopropylphenyl)imidazolidene) gave a slightly
better yield (78%), but showed a decrease in the
regioselectivity from > 98:2 to 92:8, which made us
decide to continue with IMes (see SI for details).
Worth of mentioning is that the best result obtained
for the alkyl Grignard reagent was a 85:15 mixture of
propargylic 2a and allenic regioisomers with a 51%
yield.
biaryl species does not necesarily infer the formation
of low valent iron species, since it can be caused by
the quenching of arylated iron species.[14] The
relatively high amount of this compound suggests
that a non-desired secondary reaction is taking place,
which accounts for the need of more than one
equivalent of the Grignard reagent.
Control experiments were carried out to ensure the
need of ligand and iron source. The absence of
IMes·HCl led to worse yields and incomplete
transformation of 1a. Besides, the reaction did not
occur without Fe(OAc)2, and propargylic derivative
1a was recovered unaltered (see SI for details).
With an iron catalytic system in hand, able to
promote the formation of propargylic products with
excellent regioselectivity, we sought to explore the
reaction scope using different aryl-substituted
propargylic bromides (Table 1).
Phenyl substituted primary and secondary
bromides 1a and 1e led to excellent regioselectivities
and moderate yields to 3a and 3e propargylic
products (entries 1 and 5). A similar trend was
observed with an electron-donating group in the
para- position of the aryl substrates 1b and 1f (entries
2 and 6). However, substrates with deactivated rings
(1c, 1g, 1h and 1i) reacted with lower but still useful
regioselectivity (entries 3, 7, 8 and 9). Surprisingly,
substrate 1d bearing an electron-withdrawing p-CN
group (entry 4), gave the propargylic product 3d with
excellent regioselectivity. It is worth noting that
substrates with functional groups potentially sensitive
to the Grignard reagents, such as esters or nitriles,
were well-tolerated (entries 3, 4, 8 and 9).
Table 1. Fe-catalyzed Kumada-type reactions using
different aryl-substituted propargylic bromides.
Entry Sub. 1
R1
R2
3:4
Yield
(%)
ratioa)
1
2
H
H
H
H
H
Me
Me
Me
Me
Me
Cy
tBu
> 98:2 72
1a
1b
1c
1d
1e
1f
1g
1h
1i
p-OMe
p-CO2Me
p-CN
H
p-Me
m-OMe
p-CO2Me
p-CN
H
93:7
88:12
55
66
3b)
4c)
5
> 98:2 58
> 98:2 55
> 98:2 88
6
7
8
84:16
82:18
72:28
65:35
--
50
74
68
57
--
9c)
10d)
Scheme 2. Fe-catalyzed Kumada-type reactions of 1a with
alkyl- and aryl-Grignard reagents.
1j
1k
11e)
H
a)
3:4 ratio was determined by 1H NMR of the crude
mixture. b) 84% conversion. c) Reaction time was 2 days.
d)
Biphenyl derived from the homocoupling of the
Grignard reagent was isolated from the reaction
mixture (~ 40% yield), which could indicate that
reduction of Fe catalyst may be taking place under
the reaction conditions. However, the formation of
Nucleophile homocoupling by-product could not be fully
separated by column chromatography. Starting material
recovered.
e)
2
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10.1002/adsc.201901203
Advanced Synthesis & Catalysis
As a general rule, it can be observed that reactivity
and regioselectivity seem to depend on the electronic
nature of the aromatic ring. Worse yields and
selectivities were obtained with electron withdrawing
substituents. In addition, substitution in the ipso-
position of the bromide does not seem to have a
major impact on the propargyl vs allene selectivity in
the case of a methyl group (entries 1 and 5). Bulkier
substituents, such as cyclohexyl led to a decrease in
the selectivity (entry 10) and no reaction was
11
12
1g
1h
> 98:2 (5k:6g)
38b)
66
> 98:2 (5l:6h)
a)
1
5:4 and 5:6 ratios were determined by H NMR of the
b)
crude mixtures. Nucleophile homocoupling by-product
could not be fully separated by column chromatography.
p-CO2Me aryl substituted Grignard reagent led to
worse yields and regioselectivities when compared to
phenylmagnesium bromide. The selectivity is
completely lost with primary bromides 1a and 1b
(entries 1 and 2) and a total inversion of the
regioselectivity was obtained using the p-CO2Me aryl
substituted primary propargylic bromide 1c (entry 3),
which led to allenic product 4c. In contrast,
secondary bromides 1e-1h provided better propargyl
vs allene ratios (entries 4-6), with phenyl derivative
1e showing an excellent regioselectivity towards the
propargylic product 5e (> 98:2 ratio).
t
observed when a Bu group was introduced in that
position (entry 11).[15]
The methodology was also studied for propargylic
substrates bearing an alkyl substituent in the alkyne.
In the case of 1l, the reaction proceeds to the
formation of the allene 4l as the major product.
Secondary propargylic bromide 1m led to similar
selectivity. However, in that case, conversion and
yield dropped off.
These results are similar to those obtained using
phenylmagnesium bromide, suggesting that the
secondary bromides are less affected by the electronic
richness of the aryl Grignard reagent.
Contrarily, the (4-methoxyphenyl)magnesium
bromide provided higher regioselectivities and yields
than p-CO2Me aryl substituted Grignard reagent, and
the same trend was observed regarding the
substitution at the ipso position of the bromide with a
methyl group. Using primary derivatives 1a-1c,
propargylic compounds 5a-5c were obtained as the
major products with moderate yields and ratios
between 80:20 and 90:10 (entries 7-9). Secondary
propargylic bromide 1e led to products 5e:6c with a
90:10 ratio and a 47% yield (entry 10). The
regioselectivity towards the propargylic product was
excellent when secondary bromides 1g and 1h were
used (entries 11 and 12). Although similar
regioselectivities were expected using the
methoxyphenyl Grignard derivative when compared
with phenylmagnesium bromide, the reaction of this
Grignard reagent with phenyl-substituted substrates
1a and 1e (entries 7 and 10) provided worse results.
To assess the feasibility of the methodology in a
preparative scale, the reaction was performed starting
from a gram of substrates 1a and 1h with phenyl
magnesium bromide. Coupling products 3:4 were
obtained with no significant reduction of the yields.
However, in the case of products 3a:4a a decrease in
the regioselectivity from 98:2 to 87:13 was observed
(Scheme 4).
Scheme 3. Fe-catalyzed Kumada-type reaction of alkyl
substituted propargylic bromides.
In order to elucidate the importance of the
substitution in the Grignard reagent, [(4-
(methoxycarbonyl)phenyl] magnesium chloride and
(4-methoxyphenyl)magnesium bromide were tested
with different propargylic derivatives (Table 2. Please,
note that the same allene can be obtained in some
cases from differently substituted electrophiles and
nucleophiles, and that the compound is named as 4
instead of 6 if it already appears in Table 1).
Table 2. Fe-catalysed Kumada-type reactions using
different aryl Grignard reagents.
Entry
Sub. 1
Ar–MgX 5:4 or 5:6 ratioa) Yield
(%)
1
2
3
4
5
6
7
8
53:47 (5a:4c)
55:45 (5b:6a)
> 2:98 (5c:6b)
> 98:2 (5d:4h)
87:13 (5e:6c)
88:12 (5f:6d)
80:20 (5g:4b)
85:15 (5h:6e)
87:13 (5i:6b)
90:10 (5j:6f)
26
55
33
40
36
40
60
48b)
52
47
1a
1b
1c
1e
1g
1h
1a
1b
1c
1e
Scheme 4. Gram-scale Fe-catalyzed Kumada-type reaction
of selected substrates.
9
10
3
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10.1002/adsc.201901203
Advanced Synthesis & Catalysis
Previous works on this type of iron catalysed
Kumada cross-couplings suggest the participation of
radical species in the reaction mechanism.[16] To test
whether carbon-based radicals were formed in our
reaction conditions, we performed the reaction of the
propargylic bromide 1b in the presence of TEMPO
(Scheme 5).
as an enantiopure mixture of propargyl:allene (R)-
3h:4h 84:16, in which racemization was not observed
by chiral HPLC (Scheme 7a).
Alkyl and aryl Grignard reagents sometimes show
different reactivity features.[18] In fact, Neidig isolated
an Fe(II) complex with two alkyl ligands coming
from the (1,3-dioxan-2-ylethyl)magnesium bromide,
under our same conditions.[19] This complex has one
the oxygens of both dioxane rings coordinated to the
Fe-centre, which gives an additional stability. But
that is not possible when aryl Grignard derivatives
are used. In order to explore whether the nature of the
nucleophile could affect the stereoselectivity of the
process, the reaction of the enantiomerically pure
electrophile was also performed with (1,3-dioxan-2-
ylethyl)magnesium bromide, and similar results were
obtained (Scheme 7b). These experiments allow to
discard the possibility of a radical oxidative addition.
Besides, analysis of the stereochemistry of the
product revealed that the process takes place with
configuration inversion,[8,20] meaning that a SN2 type
oxidative addition is a more feasible pathway. Allenic
product was also obtained in its enantiopure form, but
absolute configuration was not determined.
Scheme 5. Influence of TEMPO in Fe-catalyzed Kumada-
type reaction of propargylic bromides.
The reaction was completely inhibited and no
coupling products, neither propargylic nor allenic,
were obtained. Substrate 1b was recovered mostly
unaltered. However, traces of compounds 7 and 8,
resulting from the coupling of the TEMPO with C-
centred radicals coming from nucleophile and
1
electrophile, were detected by H-NMR and GC-MS.
Although the formation of these C-centred radicals in
the reaction media could not be fully ruled out, the
low amounts of 7 and 8 encountered suggest that this
is not the main manifold of the process. The
inhibition of the reaction could be due to the
formation of radical metal complexes from the
catalyst.
To further explore the idea of a non-radical
mechanism,[17] the reaction was performed with a
propargylic tosylate, which cannot be activated
though homolytic cleavage. At a temperature of -78
ºC, this substrate was unreactive. However, at -30 ºC,
both bromide and tosylate gave similar reactivity in
the presence of the iron catalyst (Scheme 6),
providing worse yield and regioselectivity when
compared to the reaction at -78 ºC (See SI for further
details).
Scheme 7. Use of enantiomerically pure substrate (R)-1f in
the Fe-catalyzed Kumada-type reaction.
Multiple articles deal with the mechanism of Fe-
catalysed cross-coupling reactions and the oxidation
22]
state of the active species.[21] Thus, Fe(I),[18b,
23]
24]
Fe(II),[19,
or even Fe(-II)[18a,
complexes have
been proposed, detected or isolated. In the present
case, the experimental evidence suggests the
formation of radical iron species, which is compatible
with an Fe(I/III) catalytic cycle (Scheme 8). Even so,
a Fe(0/II)[25] cycle cannot be discarded, since high
spin Fe(II) species could be also formed.[26] More
studies would be necessary in order to ascertain the
nature of the catalytically-active Fe species.
Scheme 6. Comparison of the reactivity of propargylic
bromides vs propargylic tosylates.
As the final test to ensure the absence of C-based
radicals, the reaction was carried out using an
enantiomerically pure propargylic bromide (R)-1h
(Scheme 7). The corresponding product was obtained
4
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10.1002/adsc.201901203
Advanced Synthesis & Catalysis
45, 5573-5575; e) J. Zhao, Y. Yu, S. Ma, Chem. Eur. J.
2010, 16, 74-80; f) Z. S. Chen, X. H. Duan, L. Y. Wu,
S. Ali, K. G. Ji, P. X. Zhou, X. Y. Liu, Y. M. Liang,
Chem. Eur. J. 2011, 17, 6918-6921; g) Y. Yang, K. J.
Szabò, J. Org. Chem. 2016, 81, 250-255; h) Z. Zhang,
S. Mo, G. Zhang, X. Shao, Q. Li, Y. Zhong, Synlett
2017, 28, 611-614.
Scheme 8. Simplified mechanistic proposal for Fe-
catalyzed Kumada-type reaction.
[2] R. Soler-Yanes, I. Arribas-Álvarez, M. Guisán-Ceinos,
E. Buñuel, D. J. Cárdenas, Chem. Eur. J. 2017, 23,
1584-1590.
[3] a) H. Ohniya, U. Yokobon, Y. Makida, M. Sawamura,
Org. Lett. 2011, 13, 6312-6315; b) U. Yokobon, H.
Ohniya, M. Sawamura, Organometallics 2012, 31,
7909-7913; c) S. Ma, Q. Liu, X. Tang, Y. Cai, Asian J.
Org. Chem. 2017, 6, 1209-1212; d) M. Guisán-Ceinos,
V. Martín-Heras, R. Soler-Yanes, D. J. Cárdenas, M.
Tortosa, Chem. Commun. 2018, 54, 8343-8346.
In conclusion, we have developed a Fe-catalysed
Kumada-type cross-coupling reaction of aryl
substituted propargylic bromides and aryl Grignard
reagents with substrates underexplored in this kind of
chemistry. The reaction shows high regioselectivities
towards the propargylic coupling product in most of
the cases and tolerates the presence of nitrile and
ester groups in both propargylic and Grignard
reagents. The formation of the allenic product
depends on the electronic properties of the
substituents on the aromatic rings of both reagents.
Besides, experiments confirming the chirality transfer
from reagent to product have been performed,
suggesting that no carbon-based radicals are formed
in the proccess and opening the posibility of new
reactivities under Fe catalysis. However, further
[4] a) S. N. Kessler, J. E. Bäckvall, Angew. Chem. Int. Ed.
2016, 55, 3734-3738; b) S. N. Kessler, F. Hundemer, J.
E. Bäckvall, ACS Catal. 2016, 6, 7448-7451.
[5] S. W. Smith, G. C. Fu, Angew. Chem. Int. Ed. 2008, 47,
9334-9336.
[6] S. W. Smith, G. C. Fu, J. Am. Chem. Soc. 2008, 130,
12645-12647.
studies are necessary to propose
mechanism.
a
detailed
[7] A. J. Oelke, J. Sun, G. C. Fu, J. Am. Chem. Soc. 2012,
134, 2966-2969.
[8] M. Guisán-Ceinos, V. Martín-Heras, M. Tortosa, J. Am.
Chem. Soc. 2017, 139, 8448-8451.
Experimental Section
[9] a) C. Bolm, J. Legros, J. L. Paith, L. Zani, Chem. Rev.
2004, 104, 6217-6254; b) A. Fürstner, R. Martín, Chem.
Lett. 2005, 34, 624-629; c) I. Bauer, H. J. Knölker,
Chem. Rev. 2015, 115, 3170-3387; d) A. Guérinot, J.
Cossy in Ni- and Fe-Based Cross-Coupling Reactions
(Eds: A. Correa) CrossMark, Switzerland, 2016, pp.
47-121; e) J. Legros, B. Figadère, Phys. Chem. Rev.
2018, 3, 2365-6581.
General procedure: Formation of the active iron catalyst:
To a solution of iron (II) acetate (2.5 mol%) and 1,3-
dimesityl-1H-imidazol-3-ium chloride (6 mol%) in dry and
Ar-degassed THF (1 mL/mmol) at 50 °C under argon
atmosphere, 0.3 equivalents of arylmagnesium bromide
were added dropwise. The mixture was stirred for 5 min.
Reaction procedure: After cooling at -78 °C, a solution of
the corresponding propargylic bromide (1.0 equiv) in dry
and Ar-degassed THF (4 mL/mmol) was added, followed
by the dropwise addition of arylmagnesium bromide (1.5 -
2.0 equiv). The reaction was stirred at -78 °C and
monitored by TLC until completion (16 h to 2 d). Saturated
aqueous NH4Cl solution was added (2 mL) and the
aqueous layer was extracted with CH2Cl2 three times. The
combined organic layers were dried over anhydrous
MgSO4 and the solvent was evaporated under vacuum. The
product was purified by column chromatography in silica
gel.
[10] R. Martín, A. Fürstner, Angew. Chem. Int. Ed. 2004,
43, 3955-3957.
[11] D. J. Tindall, H. Krause, A. Fürstner, Adv. Synth.
Catal. 2016, 358, 2398-2403.
[12] P. Domingo-Legarda, R. Soler-Yanes, M. T. Quirós, E.
Buñuel, D. J. Cárdenas, Eur. J. Org. Chem. 2018,
4900-4904.
Acknowledgements
[13] The reaction was also tried with an aromatic
organozinc reagent (p-methoxyphenylzinc bromide),
but a complex reaction mixture was obtained, where
none of the coupling products could be identified (see
SI for details).
We thank Spanish MINECO for funding (grant CTQ2016-79826-
R and a Juan de la Cierva contract to M. T. Q.) and the CAM for
a contract to I. M.-M.
[14] J. D. Sears, P. G. N. Neate, M. L. Neidig, J. Am.
Chem. Soc. 2018, 140, 11872-11883.
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5
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10.1002/adsc.201901203
Advanced Synthesis & Catalysis
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10.1002/adsc.201901203
Advanced Synthesis & Catalysis
COMMUNICATION
Regioselective Iron-Catalyzed Cross-Coupling
Reaction of Aryl Propargylic Bromides and Aryl
Grignard Reagents
Adv. Synth. Catal. Year, Volume, Page – Page
Inés Manjón-Mata, M. Teresa Quirós,* Elena
Buñuel and Diego J. Cárdenas*
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