Iron-catalyzed coupling of aryl sulfamates and aryl/vinyl tosylates with aryl grignards

Article abstract of DOI:10.1021/ol5024344

The iron-catalyzed coupling of aryl sulfamates and tosylates with aryl Grignard reagents is reported for the first time. The methodology employs air-stable, low-cost FeF₃·3H₂O and the N-heterocyclic carbene ligand IPr·HCl as the preligand to form a long-lived catalyst upon treatment with aryl Grignards. The reaction provides a range of cross-coupled products in good-to-excellent yields. In contrast to previous reports with aryl chlorides, these reactions proceed with low levels of Grignard homocoupling regardless of the iron source.

Full text of DOI:10.1021/ol5024344

Letter
pubs.acs.org/OrgLett
Iron-Catalyzed Coupling of Aryl Sulfamates and Aryl/Vinyl Tosylates
with Aryl Grignards
Toolika Agrawal and Silas P. Cook*
Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana 47405-7102, United States
S
* Supporting Information
ABSTRACT: The iron-catalyzed coupling of aryl sulfamates and
tosylates with aryl Grignard reagents is reported for the first time.
The methodology employs air-stable, low-cost FeF3·3H2O and the
N-heterocyclic carbene ligand IPr·HCl as the preligand to form a
long-lived catalyst upon treatment with aryl Grignards. The reaction
provides a range of cross-coupled products in good-to-excellent
yields. In contrast to previous reports with aryl chlorides, these
reactions proceed with low levels of Grignard homocoupling
regardless of the iron source.
a
raditionally, cross-coupling reactions to form biaryls have
overwhelmingly depended on palladium catalysis, but
Scheme 1. Iron-Catalyzed Biaryl Couplings
T
increasing costs and the concern of residual contamination have
prompted the investigation of alternative metals.1 Iron, one of
the earliest catalysts reported in cross-coupling reactions,2 offers
an appealing alternative to palladium due to its low cost, broad
availability, and low toxicity.3 More importantly, iron possesses
significantly different reactivity than Pd, Ni, or Cu, thereby
offering the potential to fill the reactivity gaps of known
methods.
Alkenyl or aryl halides are frequently used as the electro-
philes in Pd-, Ni-, and Cu-catalyzed cross-coupling reactions
due to their relatively high reactivity. However, the
disadvantages associated with the preparation, handling, and
disposal of organohalides raise environmental and regulatory
concerns for the pharmaceutical industry.4 Thus, much effort
has been directed to the search for alternatives to organo-
halides.5 Among these, C−O-based electrophiles are partic-
ularly attractive due to the unparalleled natural abundance and
low cost of carbonyl and phenol compounds.6 Since nontriflate,
C−O-based electrophiles offer significant benefits over triflate
electrophiles,7 extensive efforts with Ni7,8 and, to a lesser
extent, Pd9 have focused on activating Csp2−O bonds.
Although iron-catalyzed cross-coupling reactions generally
perform better with aryl triflates and tosylates than with
iodides and bromides,10 few reports on the use of alternate C−
O electrophiles exist.11
While iron-catalyzed cross-coupling reactions represent
something of the “holy grail” of coupling chemistry, iron-
catalyzed biaryl couplings remain rare.10b,12 While reports of
iron-catalyzed Suzuki couplings provided ample excitement,13
residual palladium proved to be the true catalyst.14 The direct
coupling of aryl halides and aryl Grignard reagents in the
presence of ferric or ferrous precatalysts is low yielding
(Scheme 1a).10a This has generally been ascribed to the weak
reducing properties of aryl Grignards relative to alkyl
Grignards15 and extensive homocoupling of aryl Grignards.16
a
(a) A single example of electron-deficient aryl chloride coupling led
to significant homocoupling of the phenyl Grignard.10a (b) Excess
phenylmagnesium bromide or sacrificial ethylmagnesium bromide can
affect the coupling of aryl chlorides with aryl Grignard reagents.17 (c)
The direct coupling of C−O-based electrophiles and aryl Grignard
reagents is reported here.
Nakamura overcomes the reduction problem by using sacrificial
alkyl Grignard to produce low-valent iron species capable of
entering the catalytic cycle for coupling (Scheme 1b).17 The
importance of C−O-based electrophiles combined with the
complete lack of iron-catalyzed examples prompted us to
investigate this possibility (Scheme 1c).
Based on Nakamura’s use of sacrificial alkyl Grignard,12b,17
we investigated his conditions in the context of C−O-based
electrophiles and aryl Grignards. Unfortunately, these con-
Received: August 16, 2014
© XXXX American Chemical Society
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Letter
ditions produced no detectable biaryl formation. On reducing
the time for iron reduction from 4 h to 2 min, biaryl coupling
was observed along with extensive coupling of the sacrificial
alkyl Grignard reagent with aryl sulfamate, thereby demonstrat-
ing the significant reactivity difference of aryl sulfamates
compared to aryl chlorides (see the Supporting Information).
Reducing the equivalents of sacrificial alkyl Grignard relative to
iron suppressed the alkyl-coupling side reaction and provided
high yield (92%) of biaryl product (Table 1, entry 9).
Scheme 2. Aryl Sulfamate Cross-Coupling with Aryl
Grignard Reagents
Table 1. Evaluation of Iron Precatalysts in the Coupling of
Aryl Sulfamate 3 and 4-(Methoxyphenyl)magnesium
Bromide in the Presence of Sacrificial n-Butylmagnesium
Chloride as the Reductant
a
Isolated yields after silica chromatography.
For the biaryl coupling of aryl chlorides, metal fluorides (Fe,
Co, Ni) have been documented to overcome the undesired
homocoupling of aryl Grignard nucleophiles.12b,17 Interestingly,
aryl sulfamates react with a wide range of iron precatalysts
without appreciable homocoupling side-product formation,
thereby demonstrating the enhanced rate of aryl sulfamate
coupling relative to aryl chlorides under these conditions. While
the homocoupling of aryl Grignard proved a nonissue, iron
precatalysts other than FeF3 proved inferior in terms of
conversion to product (Table 1). The superior performance of
FeF3 stems from the longer catalyst lifetime of the active
catalyst derived from FeF3, demonstrating an important role of
fluoride ions in stabilizing the active iron species.
With these optimized conditions in hand, the exploration of
substrate scope could commence. Disappointingly, these
optimized conditions provided poor yields for all substrates
beyond p-phenylphenyl sulfamate (3, Supporting Information).
While exploring the source of this underperformance, we
determined that removing the sacrificial alkyl Grignard from the
reaction generally led to significant improvement in yields
(Scheme 2).
a
FeF3·3H2O (10 mol %), IPr·HCl (20 mol %), ArMgBr (3 equiv),
b
THF (0.1 M), reflux, 16 h. FeF3·3H2O (10 mol %), IPr·HCl (20 mol
%), ArMgBr (4 equiv), THF (0.1 M), reflux, 24 h. Yield in
parentheses refer to reactions run at 1g scale. No starting material left
after 16 h. NMR yield using 1,3,5-trimethoxybenzene as an internal
c
d
e
f
standard. Reaction run for 48 h.
slightly better than electron-rich sulfamates (Scheme 2, 11 and
18), 3,5-bis(trifluoromethyl)phenol sulfamate (Scheme 2, 15)
proved to be an exception. While o-cresol sulfamate (Scheme 2,
13) coupled in good yield, 2,6-xylenyl sulfamate (Scheme 2,
16) does not react under these conditions. Surprisingly, 2-
naphthyl sulfamate (Scheme 2, 12) reacts significantly better
than 1-naphthyl sulfamate (Scheme 2, 19). Overall, the
reactions proceed cleanly with no observable side products
(unreacted starting sulfamate is observed in the case of <50%
yield substrates) and less than 5% Grignard homocoupling in
each case. Moreover, the reaction is scalable with comparable
In the coupling reaction without sacrificial alkyl Grignard,
both electron-rich (Scheme 2, 5 and 7) and electron-deficient
(Scheme 2, 9) aryl Grignard reagents proceeded well. However,
the reaction was found to be sensitive to sterics as ortho-
substituted aryl Grignard reagent (Scheme 2, 8) led to a poor
yield of the coupled product. Although electron-deficient
sulfamates (Scheme 2, 10, 14, and 17) were found to be
B
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Letter
yields obtained when the reaction is performed on a 1-g scale
(Scheme 2, 12). Since aryl tosylates represent synthetically
attractive C−O-based electrophiles, we evaluated the coupling
conditions in the context of these electrophiles. While tosylates
reacted much faster than the corresponding sulfamates,
extensive phenol formation was observed along with lower
overall conversion (Scheme 3). Moreover, a conjugated vinyl
tosylate also proved competent in the reaction to form
compound 20.18
C−O-based electrophiles and aryl Grignard reagents without
sacrificial alkyl Grignard reductant, we evaluated other Grignard
nucleophiles lacking β-hydrogens. We were pleased to find that
methylmagnesium bromide couples well under our conditions
(94% yield, Scheme 4). Strangely, allylmagnesium bromide and
benzylmagnesium bromide do not couple and remain under
investigation.
Scheme 4. Coupling of Aryl Sulfamate 3 with
Methylmagnesium Bromide
Scheme 3. Aryl Tosylate Cross Coupling with Aryl Grignard
Reagents
It should be noted that significant differences exist between
reactions performed in the presence of sacrificial alkyl Grignard
and reactions performed without. While it is too early to
speculate about the mechanistic implications, reduction of the
precatalyst system with sacrificial alkyl Grignard produced a
shorter-lived catalyst that ceased turnover after approximately
6−8 h, whereas by simply relying on the aryl Grignard coupling
partner for reducing equivalents, the resulting catalyst system
continued operating past 24 h. Such behavior may be related to
the low-valent oxidation state of iron produced by alkyl
Grignard reduction15,24 versus aryl Grignard reduction.25
In summary, we have developed the first iron-catalyzed direct
coupling of aryl sulfamates and tosylates with aryl Grignard
reagents. Although the reaction was shown to tolerate a number
of iron precatalysts with no significant homocoupling of aryl
Grignard, fluoride counterions were found to be necessary to
achieve high yields of the desired cross-coupled product.
Moreover, reactions performed without prereduction of FeF3
work better in almost all cases. Further efforts will be directed
toward understanding the reaction mechanism and expanding
the scope of this interesting transformation.
ASSOCIATED CONTENT
* Supporting Information
■
S
Description of procedures and spectral data for all new
compounds is described. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
a
1
Yield determined by H NMR using 1,3,5-trimethoxybenzene as an
*E-mail: sicook@indiana.edu.
Notes
b
internal standard. 12% homocoupling of the Grginard reagent
observed.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The original Kochi coupling combined vinyl bromide with
methylmagnesium bromide.2 Iron catalysis has also been used
to couple methyl Grignard reagents with alkenyl triflates,10e,19
heteroaryl chlorides,10e acid chlorides,10e 4-pyrones,20 and vinyl
cyclopropanes.21 However, examples of iron-catalyzed methyl
Grignard coupling with phenyl electrophiles remain rare. New
methyl installation technologies are critically needed to address
the dearth of methyl coupling methodologies22 and allow
exploration of the “magic” methyl effect in medicinal
chemistry.23 Bolstered by the ability of this system to couple
■
We acknowledge generous funding from Indiana University in
support of this work. We also gratefully acknowledge the
American Chemical Society Petroleum Research Fund (PRF
52233-DNI1) and NSF-CAREER Award (CHE-1254783) for
partial support of this work. We also thank Eli Lilly for the
Grantee Award.
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