Heteroaromatic sulfonates and phosphates as electrophiles in iron-catalyzed cross-couplings

Article abstract of DOI:10.1021/ol901975u

Employment of heteroaromatlc tosylates and phosphates as suitable electrophlles in iron-catalyzed cross-coupling reactions with alkyl Grignard reagents is reported. These reactions are performed at low temperature allowing good functional group tolerance

Full text of DOI:10.1021/ol901975u

ORGANIC
LETTERS
2009
Vol. 11, No. 21
4886-4888
Heteroaromatic Sulfonates and
Phosphates as Electrophiles in
Iron-Catalyzed Cross-Couplings
Thomas M. Gøgsig, Anders T. Lindhardt, and Troels Skrydstrup*
Center for Insoluble Protein Structures (inSPIN), Department of Chemistry and the
Interdisciplinary Nanoscience Center, Aarhus UniVersity, Langelandsgade 140,
8000 Aarhus C, Denmark
ts@chem.au.dk
Received August 26, 2009
ABSTRACT
Employment of heteroaromatic tosylates and phosphates as suitable electrophiles in iron-catalyzed cross-coupling reactions with alkyl Grignard
reagents is reported. These reactions are performed at low temperature allowing good functional group tolerance and full conversion is
achieved within minutes. In addition, an aryl-aryl cross-coupling utilizing a heteroaryl sulfamate electrophile is reported.
Heteroaromatic systems are important constituents of a wide
range of natural products, pharmaceuticals, and fine chemicals,
and hence methods for their functionalization are of high
interest.1,2 Transition-metal-catalyzed transformations repre-
sent a central strategy in this respect, and in particular Pd-
catalyzed reactions for the introduction of ring substituents
have demonstrated their worth.3 On the other hand, iron-
catalyzed cross-couplings employing heteroaromatic elec-
trophiles have been described to a lesser extent, with primary
focus on heteroaryl halides and a few triflates, even though such
catalytic protocols for coupling reactions with Grignard reagents
have been successfully applied to isocyclic aromatic ring systems.4
Heterocyclic alcohols represent interesting precursors to such
Fe-catalyzed coupling reactions as they allow for the possibility
of exploiting another class of commercially available substrates
with orthogonal substitution patterns compared to the aryl
halides.5 However, the use of the more common aryl triflates
suffers from certain drawbacks such as their instability and the
use of expensive triflating agents for their preparation. Hence,
replacement of the heteroaromatic triflate electrophiles with the
corresponding and more stable tosylates or phosphates would
increase the utility of such compounds.6-9
In this communication we report on the introduction of
2-pyridyl and 2-pyrimidyl tosylates and phosphates as viable
electrophiles in Fe-catalyzed cross-coupling reactions with
alkyl Grignard reagents. These reactions are performed under
conditions allowing good functional group tolerance.
(1) (a) Roth, H. J.; Kleemann, A. In Pharmaceutical Chemistry, Volume
1: Drug Synthesis; John Wiley and Sons: New York, 1988. (b) Sha, F.;
Huang, X. Angew. Chem., Int. Ed. 2009, 48, 3458. (c) Movassaghi, M.;
Hill, M. D.; Ahmad, O. K. J. Am. Chem. Soc. 2007, 129, 10096. (d) Karpov,
A. S.; Merkul, E.; Rominger, F.; Mu¨ller, T. J. J. Angew. Chem., Int. Ed.
Initial studies were focused on the coupling of n-
hexylmagnesium bromide with the crystalline 4,6-dimethyl-
pyrimidin-2-yl tosylate 1a prepared from the corresponding
alcohol with tosyl chloride.3g Using similar reaction condi-
tions as reported by the groups of Fu¨rstner and Cahiez with
2005, 44, 6951
.
(2) For some recent reviews, see: (a) Bagley, M. C.; Glover, C.; Merritt,
E. A. Synlett 2007, 2459. (b) Hill, M. D.; Movassaghi, M. Chem. Eur. J.
2008, 14, 6836
.
(3) (a) Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc.
2005, 127, 18020. (b) Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem.
Soc. 2008, 130, 9254. (c) Kakiya, H.; Yagi, K.; Shinokubo, H.; Oshima,
K. J. Am. Chem. Soc. 2002, 124, 9032. (d) Sasada, T.; Kobayashi, F.; Sakai,
N.; Konakahara, T. Org. Lett. 2009, 11, 2161. (e) Boudet, N.; Dubbaka,
S. R.; Knochel, P. Org. Lett. 2008, 10, 1715. (f) Pere´z-Balado, C.;
Willemsens, A.; Ormerod, D.; Aelterman, W.; Mertens, N. Org. Process.
Res. DeV. 2007, 11, 237. (g) Gøgsig, T. M.; Lindhardt, A. T.; Dekhane,
M.; Grouleff, J.; Skrydstrup, T. Chem. Eur. J. 2009, 15, 5950.
(4) (a) Fu¨rstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2002, 41, 609.
(b) Fu¨rstner, A.; Leitner, A.; Me´ndez, M.; Krause, H. J. Am. Chem. Soc.
2002, 124, 13856. (c) Hatakeyama, T.; Nakamura, M. J. Am. Chem. Soc.
2007, 129, 9844. (d) Quintin, J.; Franck, X.; Hocquemiller, R.; Figade`re,
B. Tetrahedron Lett. 2002, 43, 3547.
(5) Tobisu, M.; Chatani, N. Angew. Chem., Int. Ed. 2009, 48, 3565.
10.1021/ol901975u CCC: $40.75
Published on Web 09/28/2009
 2009 American Chemical Society

Fe(acac)3 as the catalyst in a solvent mixture of THF/NMP,
the desired coupling product 2a could be isolated in a
satisfactory 88% yield (Table 1, entry 1).4,10
Table 2. Heteroaromatic Tosylates in Iron-Catalyzed
Cross-Couplings
Table 1. Optimization of the Catalytic System
time
(min)
yield
(%)b
entrya
iron salt
solvent
1
2
Fe(acac)3
Fe(acac)3
None
THF/NMP
THF
THF/NMP
THF/NMP
DME
THF/NMP
THF/NMP
THF/NMP
THF/NMP
THF/NMP
15
60
88
not completec
not completec
3
240
60
c d
,
4
Fe(acac)3
Fe(acac)3
FeCl3
not complete
5
45
73
6
15
98
7
FeCl2
15
94
8
FeF3
60
no reaction
9
FeCl3
20
90e
96f
10
FeCl3
15
a 1a (0.6 mmol), NMP (5.4 mmol), and n-hexylmagnesium bromide
(1.1 mmol) in THF (2.5 mL). b Isolated yields. c Yield not determined due
to complex H NMR spectrum of crude reaction mixture. d Reaction run
1
with Fe(acac)3 (1 mol %). e Reaction run with n-hexylmagnesium bromide
(0.8 mmol). f Reaction run with n-hexylmagnesium bromide (0.9 mmol).
Lowering the catalytic loading or changing the solvent system
was nonrewarding and facilitated the formation of undesired
byproducts (entries 2-5). As observed by the group of Cahiez,
the presence of NMP as a cosolvent proved imperative for the
coupling to occur (entry 2).10 Turning to the iron(III) chloride
salt improved the reaction, and a nearly quantitative yield could
be secured after column chromatography (entry 6). An es-
sentially identical yield was obtained when n-hexylmagnesium
bromide (1.5 equiv) was added to the reaction mixture, attaining
full conversion within only 15 min (entry 10). On the other
hand, no reaction was observed when iron(III) fluoride was
applied, resulting in a sluggish reaction mixture, without the
formation of the characteristic dark brown solution upon
addition of the Grignard reagent (entry 8).
With these successful reaction conditions in hand, we set
out to test the generality of this iron-catalyzed cross-coupling
reaction, employing a variety of substituted heteroaromatic
tosylates as depicted in Table 2.
a 1a (0.6 mmol), NMP (5.4 mmol), and alkylmagnesium bromide (0.9
mmol) in THF (2.5 mL). b Isolated yields. c Reaction run with 4-pentenyl
magnesium bromide (1.8 mmol). d Reaction run with isobutyl-magnesium
bromide (1.8 mmol). e Reaction run with Fe(salen)Cl (5 mol %) and
cyclohexylmagnesium bromide (1.2 mmol) at 0 °C.
(6) For applications of tosylate electrophiles, see: (a) Hansen, A. L.;
Ebran, J.-P.; Ahlquist, M.; Norrby, P.-O.; Skrydstrup, T. Angew. Chem.,
Int. Ed. 2006, 45, 3349. (b) Shen, Q.; Ogata, T.; Hartwig, J. F. J. Am. Chem.
Soc. 2008, 130, 6586. (c) Munday, R. H.; Martinelli, J. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2008, 130, 2754. (d) Nguyen, H. N.; Huang, X.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11818. (e) Ackermann, L.;
Functional groups such as nitriles, esters, and amides are
well tolerated under the applied conditions, and the alkylated
products could be isolated in excellent yields (entries 1, 3
and 4). Switching from a pyridyl- to a pyrimidyl-based
aromatic core did not influence the outcome of the reaction
(entry 2). Alkenyl Grignard reagents represented by 4-pen-
tenylmagnesium bromide demonstrated equal reactivity
toward the heteroaromatic tosylates as described above
(entries 5, 7, 9, and 10). In addition, 2-quinaxolinyl tosylate
performed well, and a satisfactory 84% yield was obtained
(entry 6). A double coupling of the pyrimidyl ditosylate
shown in entry 8 was attempted, resulting in a nearly
Althammer, A. Org. Lett. 2006, 8, 3457
.
(7) For applications of phosphate electrophiles, see: (a) Hansen, A. L.;
Ebran, J.-P.; Gøgsig, T. M.; Skrydstrup, T. J. Org, Chem. 2007, 72, 6464.
(b) Gauthier, D.; Beckendorf, S.; Gøgsig, T. M.; Lindhardt, A. T.;
Skrydstrup, T. J. Org. Chem. 2009, 74, 3536. (c) Mousset, D.; Gillaizeau,
I.; Sabatie´, A.; Bouyssou, P.; Coudert, G. J. Org. Chem. 2006, 71, 5993
.
(8) Activated aryl tosylates have in a few examples been demonstrated
to be compatible in iron-catalyzed cross-couplings; see refs 4a and 4b.
(9) Cahiez and coworkers have recently described the coupling of dienol
phosphates with Grignard reagents under Fe-catalysis: Cahiez, G.; Habiak,
V.; Gager, O. Org. Lett. 2008, 10, 2389
.
(10) (a) Cahiez, G.; Marquais, S. Pure Appl. Chem. 1996, 68, 53. (b)
Cahiez, G.; Avedissian, H. Synthesis 1998, 1199
Org. Lett., Vol. 11, No. 21, 2009
.
4887

quantitative yield in only 14 min. Increasing the steric bulk
on the organomagnesium species did not influence the
outcome of the cross-coupling reaction (entries 11-13).
Despite the fact that 3 equiv of isobutylmagnesium bromide
was added to the reaction mixture, only the monoalkylated
quinoline-4-yl tosylate was detected (entry 12). Employment
of the more reactive Fe(salen)Cl complex was necessary in
order to obtain successful coupling when switching to a
secondary alkylmagnesium reagent (entry 13).4b Finally,
substrates such as vinyl-, allyl-, (1,3-dioxolan-2-yl-methyl)-,
and 3-(dimethylamino)-propylmagnesium halides did not
participate in this reaction. In the latter case, it may be
conceived that a coordination of the amine moiety to the
magnesium nucleus could possibly impede the desired
coupling. As reported by the group of Fu¨rstner an ethylene
spacer between the magnesium and the functional group
appears to be vital in order to obtain productive reactivity.4b
Enol phosphates derived from the corresponding ketones
or aldehydes have been shown to readily undergo iron-
catalyzed cross-coupling reactions with both alkyl and aryl
Grignard reagents.10,11 Thus, exploiting the same optimized
reaction conditions, we examined the utility of pyrimidyl
phosphates as coupling partners. As illustrated in Scheme
1, diethyl phosphates can be effectively employed to give
of the recent application of such derivatives in palladium-
catalyzed Suzuki-Miyaura and Negishi cross-couplings in
which they have been demonstrated to exhibit increased
reactivity compared to that of the corresponding tosylates.13
In the coupling with phenylmagnesium bromide, the
precatalyst Fe(acac)3 proved superior compared to FeCl3, and
NMP had a detrimental effect on the coupling yield. Instead,
a premixed solution of the Grignard reagent in THF and
TMEDA (N,N,N’,N’-tetramethylethylene-diamine) added
slowly to the cooled reaction mixture turned out to be crucial
to attain full conversion.14 Gratifyingly, this resulted in a
satisfying 81% isolated yield. Running the reaction at -40
°C produced the exact same result after only 10 min, proving
this cross-coupling to be very effective.
In conclusion we have demonstrated the usefulness of
heteroaromatic tosylates in iron-catalyzed alkylation reactions
with good functional group tolerance. Furthermore, we have
introduced heteroaromatic phosphates as viable electrophiles
displaying comparable reactivities as the corresponding tosy-
lates, and a single example of an effective aryl-aryl coupling
with a heterocyclic sulfamate was achieved. Work is now
underway in our laboratories to investigate the scope of both
Scheme 2
.
Heteroaromatic Sulfamate in Iron-Catalyzed
Cross-Couplings
Scheme 1
.
Heteroaromatic Phosphates in Iron-Catalyzed
Cross-Couplings
aryl phosphates and sulfamates, which will be reported in due
time.
Acknowledgment. We are deeply appreciative of generous
financial support from the Dansih National Research Foun-
dation, the Danish Natural Science Research Council and
Aarhus University.
Supporting Information Available: Experimental details
coupling products in excellent yields. These results demon-
strate to the best of our knowledge the first examples of aryl
phosphates as viable electrophiles in iron catalysis.
1
and copies of H NMR and 13C NMR spectra for all the
coupling products. This material is available free of charge
via the Internet at http://pubs.acs.org.
Finally, we studied the ability of the heteroaromatic
tosylates and phosphates to perform cross-coupling with
phenylmagnesium chloride. Unfortunately, severe formation
of undesired byproduct was detected (results not shown). In
addition to the expected homocoupling of the aryl Grignard
reagent,12 the formation of phenol was also observed,
potentially originating from a nucleophilic attack on the
sulfur center. In order to overcome this side reaction, we set
forth to search for an alternative electrophile. In this respect,
we examined the corresponding heteroaryl sulfamate because
OL901975U
(12) For papers regarding homocoupling of Grignard reagents, see: (a)
Cahiez, G.; Moyeux, A.; Buendia, J.; Duplais, C. J. Am. Chem. Soc. 2007,
129, 13788. (b) Cahiez, G.; Chaboche, C.; Mahuteau-Betzer, F.; Ahr, M.
Org. Lett. 2005, 7, 1943. (c) Xu, X.; Cheng, D.; Pei, W. J. Org. Chem.
2006, 71, 6637. (d) Nagano, T.; Hayashi, T. Org. Lett. 2005, 7, 491. (e)
Sapountzis, I.; Lin, W.; Kofink, C. C.; Despotopoulou, C.; Knochel, P.
Angew. Chem., Int. Ed. 2005, 44, 1654, and references therein.
(13) Albaneze-Walker, J.; Raju, R.; Vance, J. A.; Goodman, J. A.;
Reeder, M. R.; Liao, J.; Maust, M. T.; Irish, P. A.; Espino, P.; Andrews,
D. R. Org. Lett. 2009, 11, 1463, and references therein.
(14) (a) Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. J. Am. Chem.
Soc. 2004, 126, 3686. (b) Gue´rinot, A.; Reymond, S.; Cossy, J. Angew.
Chem., Int. Ed. 2007, 46, 6521.
(11) (a) Cahiez, G.; Gager, O.; Habiak, V. Synthesis 2008, 2636. (b)
Larsen, U. S.; Martiny, L.; Begtrup, M. Tetrahedron Lett. 2005, 46, 4261
.
4888
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