Iron-catalyzed cross-coupling reactions of alkyl grignards with aryl sulfamates and tosylates

Article abstract of DOI:10.1021/ol303130j

The iron-catalyzed cross-coupling of aryl sulfamates and tosylates has been achieved with primary and secondary alkyl Grignards. This study of iron-catalyzed cross-coupling reactions also examines the isomerization and β-hydride elimination problems that are associated with the use of isopropyl nucleophiles. While a variety of iron sources were competent in the reaction, the use of FeF₃·3H₂O was critical to minimize nucleophile isomerization.

Full text of DOI:10.1021/ol303130j

ORGANIC
LETTERS
2013
Vol. 15, No. 1
96–99
Iron-Catalyzed Cross-Coupling Reactions
of Alkyl Grignards with Aryl Sulfamates
and Tosylates
Toolika Agrawal and Silas P. Cook*
Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington,
Indiana 47405-7102, United States
sicook@indiana.edu
Received November 13, 2012
ABSTRACT
The iron-catalyzed cross-coupling of aryl sulfamates and tosylates has been achieved with primary and secondary alkyl Grignards. This study of
iron-catalyzed cross-coupling reactions also examines the isomerization and β-hydride elimination problems that are associated with the use of
isopropyl nucleophiles. While a variety of iron sources were competent in the reaction, the use of FeF3•3H2O was critical to minimize nucleophile
isomerization.
Palladium-catalyzed cross-coupling reactions represent
over 60% of the carbonÀcarbon bond-forming reactions
used in medicinal chemistry today.1 This majority virtually
guarantees that every new clinical candidate will require a
process-scale implementation of a cross-coupling reaction.
The use of palladium raises the issue of residual contam-
ination that may affect subsequent transformations or
even the health of patients.2 As such, chemists need to
investigate new cross-couplingreactionscatalyzedbymore
benign metals. Iron, a historically important metal in
cross-coupling reactions,3 offers an appealing alternative
topalladium due toits low cost, broadavailability, and low
toxicity (Figure 1).4 Combined with an environmentally
friendly electrophile, iron-catalyzed cross-coupling reac-
tions could become the obvious alternative to palladium-
mediated processes.
The use of CÀO-based electrophiles provides an attrac-
tive cross-coupling partner that has been used widely
with Ni,5 and to a lesser extent with Pd.6 The ubiquity of
phenols and ketones combined with their favorable environ-
mental impact when compared to halogen substrates confers
clear advantages in using CÀO electrophiles. While triflates
and tosylates make up the majority of CÀO cross-coupling
(7) Antoft-Finch, A.; Blackburn, T.; Snieckus, V. J. Am. Chem. Soc.
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r
10.1021/ol303130j
Published on Web 12/17/2012
2012 American Chemical Society

substrates, other functional groups have also been inves-
tigated recently by the groups of Snieckus,7 Shi,8 Garg,9
Jarvo,10 and Watson,11 among others. Both triflates and
tosylates have been reported to function better than iodides
and bromides in iron-catalyzed cross-coupling reactions,12
but there are few reports of alternative CÀO electrophiles in
iron catalysis.13 Shi and co-workers first reported the iron-
catalyzed alkylation of alkenyl pivalates, but only one low
yielding example of an aryl pivalate was described.14 Very
recently, Garg and co-workers reported the first study of
iron-catalyzed sulfamate and carbamate alkylation.15 In
light of these recent developments, we thought it appro-
priate to report our findings regarding an iron-catalyzed
cross-coupling with aryl sulfamates and tosylates (Figure 1).
The methodology provides for the construction of Csp2ÀCsp3
bonds by coupling CÀO-based electrophiles with primary
and secondary Grignard reagents.
conditions were evaluated. In agreement with previous
work,14,15,18 N-heterocyclic carbene ligands were found
tobeuniquelyeffective forthistransformation (entries 1, 5,
and 6, Table 1) with 1,3-bis(2,6-diisopropylphenyl)-imidazol-
2-ylidene (IPr) providing the optimal yield (entry 1, Table 1).
Surprisingly, other ligands reported for iron-catalyzed
cross-coupling reactions, such as TMEDA,19 NMP,20 and
phosphines,21 as well as other polydentate amines such as
bipyridine and terpyridine, led to none of the desired
product (entries 7À12, Table 1). The transformation also
worked well with a number of alternative iron precatalysts
(entries 2À4, Table 1), albeit in lower yield than with
FeF3•3H2O. While lower catalyst loadings led to slightly
reduced yields, the exceptionally low cost of iron and ease
of catalyst removal made the use of 10 mol % loading
inconsequential. When 3 equiv of Grignard were used, the
reaction consistently returned a 5À10% lower yield.
Furthermore, the reaction proved unusually sensitive to
temperature, generally providing 15À20% lower yields
when reducing the temperature from 66 to 60 °C. During
the preparation of this manuscript, Garg and co-workers
reported the beneficial effect of DCM as an additive.15
Here we found the reaction proceeded well in the absence
of DCM.
Table 1. Deviation from Optimal Reaction Conditions
Figure 1. Iron-catalyzed CÀO activation.
To begin our studies, a suitable activating group was
required for the phenolic oxygen. Specifically, a functional
group capable of conferring selectivity to the CÀO bond
while, at the same time, being stable to the reaction con-
ditions was needed.16 The evaluation of pivalate (COtBu),
diethylcarbamate (CONEt2), diphenylphosphinate (POPh2),
t
Boc (CO2 Bu), and sulfamate (SO2NMe2) led quickly to
the identification of sulfamate as the optimal activating
group since nucleophilic displacement of the sulfamate by
the Grignard reagent was not observed. Furthermore, the
sulfamate moiety functions as an ideal directing group
for the site-selective functionalization of arenes.9c,17 With
p-phenylphenol sulfamate 1 as the model substrate, reaction
(11) Ehle, A. R.; Zhou, Q.; Watson, M. P. Org. Lett. 2012, 14, 1202.
€
(12) (a) Furstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2002, 41,
€
ꢀ
609. (b) Furstner, A.; Leitner, A.; Mendez, M.; Krause, H. J. Am. Chem.
€
Soc. 2002, 124, 13856. (c) Furstner, A.; Leitner, A. Angew. Chem., Int.
Ed. 2003, 42, 308. (d) Scheiper, B.; Bonnekessel, M.; Krause, H.;
a Yields obtained after silica gel chromatography.
€
Furstner, A. J. Org. Chem. 2004, 69, 3943. (e) Seidel, G.; Laurich, D.;
€
Furstner, A. J. Org. Chem. 2004, 69, 3950.
(13) (a) Cahiez, G.; Gager, O.; Habiak, V. Synthesis 2008, 2636.
(b) Hayashi, N.; Nakada, M. Tetrahedron Lett. 2009, 50, 232.
(14) Li, B.-J.; Xu, L.; Wu, Z.-H.; Guan, B.-T.; Sun, C.-L.; Wang,
B.-Q.; Shi, Z.-J. J. Am. Chem. Soc. 2009, 131, 14656.
(15) Silberstein, A. L.; Ramgren, S. D.; Garg, N. K. Org. Lett. 2012,
14, 3796.
(16) Yu, D.-G.; Li, B.-J.; Shi, Z.-J. Acc. Chem. Res. 2010, 43, 1486.
(17) Quasdorf, K. W.; Antoft-Finch, A.; Liu, P.; Silberstein, A. L.;
Komaromi, A.; Blackburn, T.; Ramgren, S. D.; Houk, K. N.; Snieckus,
V.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 6352.
(18) Hatakeyama, T.; Nakamura, M. J. Am. Chem. Soc. 2007, 129,
9844.
Org. Lett., Vol. 15, No. 1, 2013
97

After identifying FeF3•3H2O as the optimal iron pre-
catalyst and IPr as the optimal NHC ligand, we turned
our attention to the substrate scope (Table 2). Since aryl
tosylates provide good yields in iron/NMP-catalyzed
cross-coupling reactions12a,b and are considerably cheaper
than sulfamates, we explored the relative reactivity of aryl
tosylates and sulfamates. In general, naphthyl substrates
(entries 9, 10, 17, and 19, Table 2) provided higher yields of
the cross-coupled product than any of the phenyl sub-
strates (entries 1À8, 11À14, Table 2). Sterically hindered
electrophiles with a single ortho substituent provided low
yields (entries 11À12, Table 2) while bis-ortho substituted
substrates failed to react (entries 13À14, Table 2). Elec-
tron-rich aromatic rings (entries 1À2, Table2) gaveslightly
lower yields than electron-deficient aromatic rings (entries
5À8, Table 2). Heterocyclic substrates also gave moderate
yields under the reaction conditions (entries 15À16, Table 2).
All reactions with aryl sulfamates produced very few side
products with nearly quantitative yields based on recovered
starting material. Attempts to suppress premature catalyst
deactivation (e.g., slow Grignard addition, portionwise cat-
alyst addition, etc.) were unsuccessful. In contrast, while
reactions with aryl tosylates were much faster than those
with aryl sulfamates, the aryl tosylates produced more side
products and 5À10% of the corresponding phenol.
Table 2. Substrate Scope of Aryl Tosylates and Sulfamates
Previous work by Shi and co-workers found secondary
Grignards, such as isopropyl magnesium chloride, failed in
their iron-catalyzed cross-coupling reactions.19 Garg and
co-workers15 reported secondary Grignards to be compe-
tent nucleophiles in their iron-catalyzed cross-coupling
reactions with CÀO electrophiles, and others have ob-
served iron-catalyzed coupling reactions with secondary
Grignards and aryl/vinyl chlorides.12b,22 We were interested
in the branched-to-linear ratios of secondary Grignards, an
important problem in secondary alkyl cross-coupling
chemistry23 that has not been examined in iron-catalyzed
variants. Both the tosylate and sulfamate proved competent
electrophiles with cyclohexyl magnesium chloride to give
moderate-to-good yields of the cross-coupled product
(entries 2 and 5, Table 3). Interestingly, while isopropyl
magnesium chloride provided moderate branched selectiv-
ity with the sulfamate (entry 3, Table 3), the selectivity was
reversed with the corresponding tosylate (entry 6, Table 3).
Since the iron-catalyzed cross-coupling reaction seemed
relatively tolerant of different iron precatalysts (Table 1),
we investigated the formation of the branched product as a
function of the iron precatalyst (Table 4).
a All sulfamate reactions refluxed for 8 h, and tosylate reactions
refluxed for 3 h. b Yields obtained after silica gel chromatography.
c Starting tosylates were unstable.
branched selectivity by 6.5:1, FeCl3 reversed the selectivity
to favor the linear product by 1:5 (entries 1 and 2, Table 4).
Furthermore, both acetylacetonate (entry 3, Table 4) and
trifluoroborate (entry 5, Table 4) counterions exhibit
selectivity for the linear product whereas the triflate coun-
terion (entry 4, Table 4) shows almost equal formation of
branched and linear products with only a slight selectivity
for the linear product. These results suggest that the co-
ordination of the counterion to the active iron species has
an effect on the branched-to-linear selectivity. To corro-
borate this, silver salts were used to exchange the halide
counterions of both FeCl3 and FeF3 in situ. If full counter-
ion exchangewiththe noncoordinating counterion of SbF6
The branched-to-linear ratio was determined for the
coupling of an aryl sulfamate with isopropyl magnesium
chloride under the influence of different iron precatalysts.
Surprisingly, while FeF3•3H2O (entry 8, Table 4) favored
(19) Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. J. Am. Chem.
Soc. 2004, 126, 3686.
(20) Cahiez, G.; Avedissian, H. Synthesis 1998, 1199.
(21) Bedford, R. B.; Betham, M.; Bruce, D. W.; Danopoulos, A. A.;
Frost, R. M.; Hird, M. J. Org. Chem. 2005, 71, 1104.
(22) Ottesen, L. K.; Ek, F.; Olsson, R. Org. Lett. 2006, 8, 1771.
(23) (a) Joshi-Pangu, A.; Ganesh, M.; Biscoe, M. R. Org. Lett. 2011,
13, 1218. (b) Hayashi, T.; Konishi, M.; Kumada, M. Tetrahedron Lett.
1979, 1871.
98
Org. Lett., Vol. 15, No. 1, 2013

Table 3. Substrate Scope of Grignards
Table 4. Iron Precatalyst Effects on Branched-to-Linear
Selectivity
entry
catalyst
yield (%)a 3:4
1
2
3
4
5
6
7
8
FeCl3 (10 mol %)
79
70
85
76
80
76
43
65
0.2:1
0.3:1
0.2:1
0.9:1
0.3:1
0.2:1
1.1:1
6.5:1
FeCl3•6H2O (10 mol %)
Fe(acac)3 (10 mol %)
Fe(OTf)2 (10 mol %)
Fe(BF4)2•6H2O (10 mol %)
FeCl3 (10 mol %), AgSbF6 (30 mol %)
FeF3•3H2O (10 mol %), AgSbF6 (30 mol %)
FeF3•3H2O (10 mol %)
a Yields obtained after silica gel chromatography.
a Branched/linear ratio in parentheses.
In summary, the iron-catalyzed cross-coupling of aryl
sulfamates and tosylates has been achieved. The reaction
was shown to tolerate a number of iron precatalysts,
but the iron counterions had a significant influence on
branched-to-linear ratios with secondary Grignard reagents.
While reactions with the sulfamates produced nearly quan-
titative yields based on recovered starting material, further
investigations to determine the cause of catalyst deactivation
will lead to highly effective cross-coupling reactions. The
attractive features of CÀO electrophiles, combined with
cheap and environmentally friendly iron catalysis, provide
clear advantages for this methodology over existing cross-
coupling technology and should facilitate the development
of other iron-promoted transformations.
could be realized, then both of these reactions should give
similar yields and selectivity. When the reaction was run
with FeCl3 (10 mol %) and AgSbF6 (30 mol %), there is
virtually no change in yield relative to FeCl3 alone (entry 6
vs 1, Table 4), whereas the reaction with FeF3•3H2O
(10 mol %) and AgSbF6 (30 mol %) shows a marked decrease
in branched selectivity when compared to FeF3•3H2O
alone (entry 7 vs 8, Table 4). The lack of complete selec-
tivity reversal is likely due to incomplete AgF formation
since it has considerable solubility in THF, unlike AgCl.
This provides soluble fluoride ions that are available to
coordinate with iron to enhance the branched-to-linear
selectivity. A possible explanation for the unique branched-
to-linear selectivity for FeF3•3H2O is that the fluoride ion
strongly coordinates to the iron center to prevent open
coordination sites for β-agostic interactions, thereby slow-
ing down the isomerization of the alkyl Grignard. It is
noteworthy that reactions with FeF3•3H2O are the slow-
est, requiring the full 8 h at reflux, whereas reactions with
all other iron precatalysts are complete in 3 h or less. The
slower rate is consistent with the posibility of fewer open
coordination sites at iron with FeF3•3H2O during the
catalytic cycle.
Acknowledgment. Financial support for this work was
provided by Indiana University.
Supporting Information Available. Experimental pro-
cedures and spectral data for all new compounds are
provided. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 1, 2013
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