Palladium-catalyzed nitromethylation of aryl halides: An orthogonal formylation equivalent

Article abstract of DOI:10.1021/ol301713j

An efficient cross-coupling reaction of aryl halides and nitromethane was developed with the use of parallel microscale experimentation. The arylnitromethane products are precursors for numerous useful synthetic products. An efficient method for their direct conversion to the corresponding oximes and aldehydes in a one-pot operation has been discovered. The process exploits inexpensive nitromethane as a carbonyl equivalent, providing a mild and convenient formylation method that is compatible with many functional groups.

Full text of DOI:10.1021/ol301713j

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Palladium-Catalyzed Nitromethylation of
Aryl Halides: An Orthogonal Formylation
Equivalent
Ryan R. Walvoord, Simon Berritt, and Marisa C. Kozlowski*
Penn Merck High Throughput Experimentation Laboratory, Department of Chemistry,
University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States
marisa@sas.upenn.edu
Received June 21, 2012
ABSTRACT
An efficient cross-coupling reaction of aryl halides and nitromethane was developed with the use of parallel microscale experimentation.
The arylnitromethane products are precursors for numerous useful synthetic products. An efficient method for their direct conversion to the
corresponding oximes and aldehydes in a one-pot operation has been discovered. The process exploits inexpensive nitromethane as a carbonyl
equivalent, providing a mild and convenient formylation method that is compatible with many functional groups.
Nitroalkanes are compounds of unique and versatile
reactivity.1 Their ability to undergo powerful stereoselec-
tive carbonÀcarbon bond formation2 in addition to nu-
merous functional group transformations3 makes them
highly desirable synthetic intermediates. Despite this utility,
access to nitroalkanes remains synthetically challenging.1a,4
The coupling of aryl halides with nitromethane, an inex-
pensive and readily available solvent, would represent
an ideal method to prepare a wide variety of arylnitro-
methanes, precursors to an array of valuable compounds
(Scheme 1). In particular, we envisaged that by exploiting
the conversion of the nitro to carbonyl group, the Nef
reaction, this method would represent a novel, mild for-
mylation orthogonal to FriedelÀCrafts and lithiation/
formylation transforms.5 Furthermore, nitromethane is
more easily deployed as a formyl equivalent on a small
scale compared to carbon monoxide, a toxic gas that
requires tanks and often high temperatures and pressures.6
Herein, we describe the Pd-catalyzed coupling of aryl
halides with nitromethane to afford arylnitromethanes
and subsequent Sn(II)-mediated Nef reaction to provide
aryl oximes or aryl aldehydes.
Our primary challenge lay in developing a facile, robust
method to access arylnitromethanes. As observed in recent
(1) (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH:
New York, 2001. (b) Feuer, H., Nielsen, A. T., Eds. In Nitro Compounds:
Recent Advances in Synthesis and Chemistry; VCH Publishers: New York,
1990; Chapters 1À2. (c) Rosini, G.; Ballini, R. Synthesis 1988, 833–847.
(2) For recent reviews on CÀC bond formation with nitroalkanes,
see: (a) Marques-Lopez, E.; Merino, P.; Tejero, T.; Herrera, R. P. Eur. J.
Org. Chem. 2009, 2401–2420. (b) Ballini, R.; Bosica, G.; Fiorini, D.;
Palmieri, A.; Petrini, M. Chem. Rev. 2005, 105, 933–971. (c) Luzzio, F. A.
Tetrahedron 2001, 57, 915–945.
(5) For reviews on aromatic formylation, see: (a) Olah, G. A.;
Ohannesian, L.; Arvanaghi, M. Chem. Rev. 1987, 87, 671–686. (b)
Kantlehner, W. Eur. J. Org. Chem. 2003, 2530–2546 and references
therein. (c) Wakefield, B. J. Organolithium Methods; Academic Press: San
Diego, CA, 1988.
(3) (a) Seebach, D.; Colvin, E. W.; Lehr, F.; Weller, T. Chimia 1979,
33, 1–18. (b) Ballini, R.; Palmieri, A.; Righi, P. Tetrahedron 2007, 63,
12099–12121.
(4) Greger, J. G.; Yoon-Miller, S. J. P.; Bechtold, N. R.; Flewelling,
S. A.; MacDonald, J. P.; Downey, C. R.; Cohen, E. A.; Pelkey, E. T.
J. Org. Chem. 2011, 76, 8203–8214.
(6) (a) Shoenberg, A.; Heck, R. F. J. Am. Chem. Soc. 1974, 96, 7761–
€
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7764. (b) Klaus, S.; Neumann, H.; Zapf, A.; Strubing, D.; Hubner, S.;
Almena, J.; Riermeier, T.; Gross, P.; Sarich, M.; Krahnert, W.-R.;
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Sergeev, A. G.; Spannenberg, A.; Beller, M. J. Am. Chem. Soc. 2008, 130,
15549–15563.
r
10.1021/ol301713j
XXXX American Chemical Society

and higher congeners for which tBuMePhos17 or
tBuXPhos15b are effective, bis-tert-butyl ligands per-
formed poorly here with the exception of cataCXium
POMetBu, which was less consistent overall (see below).
Rather, the biscyclohexyl ligands XPhos and BrettPhos
were superior. These results are surprising since nitro-
methane is smaller, and it was expected that larger ligands
would be needed to force formation of the less favorable
C-bound vs O-bound palladium adduct.18
Scheme 1. Utility of the Products from the Coupling of Nitro-
methane with Aryl Halides
A detailed analysis of the HPLC data was crucial to
further optimization, revealing the formation of multiple
byproducts including debrominated substrate, aldehyde,
and decomposition products. Table 1 collects the con-
versions to the product and all the impurities relative to
an internal standard. While cataCXium POMetB gave
the highest conversion, there were also large amounts of
impurities. Using the difference of the product and im-
purity conversion (last column, Table 1) as a measure of
selectivity to the desired product, further optimization was
conducted with XPhos, which is also less costly than the
other two candidates.
studies utilizing these compounds,4,7 current methods to
generate arylnitromethanes (nitrite displacement of benzylic
bromides,8 oxidation of benzyl amines9 and oximes10) are
unsatisfactory,11 owing to poor efficiency, generality, and
availability of the corresponding substrates. We sought
to develop a less expensive12 and more reliable method
using nitromethane as a soft nucleophile in a palladium-
catalyzed cross-coupling.13 With the knowledge that this
cross-coupling had been described as problematic due
to low yields and multiple products,14 parallel microscale
experimentation15 was implemented to rapidly screen a
large number of conditions and draw out trends. Using
para-bromoanisole as a test substrate, 19 ligands, 4 sol-
vents, and 4 bases were initially assessed using 2 equiv of
nitromethane with Pd2dba3 at 80 °C.16 Unlike nitroethane
Table 1. Top Results from the Initial Screena
prod/ impurities/ impurities/
ligand
solvent
base
IS
IS
IS Àprod/IS
XPhos
THF
K3PO4
1.96
2.48
2.30
2.96
0.52
0.54
0.57
BrettPhos DME
K3PO4
1.75
cataXCium 1,4-dioxane NaOt-Bu 2.40
(7) Davis, T, A.; Johnston, J. N. Chem. Sci. 2011, 2, 1076–1077.
(8) (a) Kornblum, N.; Taub, B.; Ungnade, H. E. J. Am. Chem. Soc.
1954, 76, 3209–2111. (b) Kornblum, N.; Larson, H. O.; Blackwood,
R. K.; Mooberry, D. D.; Oliveto, E. P.; Graham, G. E. J. Am. Chem.
Soc. 1956, 78, 1497–1501. (c) Ballini, R.; Barboni, L.; Giarlo, G. J. Org.
Chem. 2004, 69, 6907–6908.
POMetB
XPhos
1,4-dioxane K3PO4
1.93
1.93
2.86
3.21
0.93
1.28
cataXCium 1,4-dioxane K3PO4
POMetB
(9) (a) Emmons, W. D. J. Am. Chem. Soc. 1957, 79, 5528–5530.
(b) Rozen, S.; Kol, M. J. Org. Chem. 1992, 57, 7342–7344.
(10) (a) Emmons, W. D.; Pagano, A. S. J. Am. Chem. Soc. 1955, 77,
4557–4559. (b) Bose, D. S.; Vanajatha, G. Synth. Commun. 1998, 28,
4531–4535.
(11) Independent work in our lab also showed that the AgNO2 or
NaNO2 methods provided the arylnitromethanes in low to moderate
yields (30À50%) for typical cases [BnBr, p-ClC6H4CH2Br, p-(t-Bu)-
C6H4CH2Br, m-CF3C6H4CH2Br] and purification was difficult due to
multiple byproducts. Activated or hindered systems (p-MeOBnBr,
1-NapCH2Br, 2-NapCH2Br) gave little (<20%) or no product. We
found that oxidation of the corresponding aryl oximes was also low
yielding (<20%).
(12) Superstoichiometric AgNO2 ($48/10 g via Sigma-Aldrich) is
typically employed.
(13) Prim, D.; Campagne, J.-M.; Joseph, D.; Andrioletti, B. Tetra-
hedron 2002, 58, 2041–2075.
(14) Vogl, E. M.; Buchwald, S. L. J. Org. Chem. 2002, 67, 106–111.
(15) (a) Dreher, S. D.; Dormer, P. G.; Sandrock, D. L.; Molander,
G. A. J. Am. Chem. Soc. 2008, 130, 9257–9259. (b) Metz, A. E.; Berritt,
S.; Dreher, S. D.; Kozlowski, M. C. Org. Lett. 2012, 14, 760–763.
(16) See the Supporting Information for additional details regarding
the high-throughput experimentation.
BrettPhos THF
BrettPhos 1,4-dioxane K3PO4
JohnPhos 1,4-dioxane K3PO4
Cs2CO3
1.66
1.82
1.87
3.08
3.33
4.22
1.42
1.51
2.34
a IS = Internal standard.
Postulating that increasing the effective concentration of
the nucleophile might improve rate and minimize decom-
position pathways, neat nitromethane was employed to
good effect, providing shorter reaction times and cleaner
reaction profiles. To further suppress aldehyde formation,
which requires water, molecular sieves were added. As a
result, the optimal conditions of Pd2dba3 with the
˚
XPhos ligand, Cs2CO3, powdered 3 A molecular sieves,
and 0.1 M nitromethane as solvent were discovered (Table 2).
(17) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 1360–1370.
(18) Liao, X.; Weng, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130,
195–200.
B
Org. Lett., Vol. XX, No. XX, XXXX

These optimized conditions were effective with sub-
strates possessing electron-donating and -withdrawing
groups (Table 2, entries 1À9), ortho-substituents (entries
7À9), and even highly sterically encumbered substrates
(entry 10). Ketones bearing acidic protons were well tol-
erated and did not exhibit competitive coupling or reaction
with nitromethane under the basic reaction conditions
(entry 8). As formation of ortho-substituted or electron-
rich arylnitromethanes via SN2 displacement of the corre-
sponding benzyl bromides has been shown to be a poor
process,19 this report allows greatly improved access to
a range of novel arylnitromethanes. Heteroaryls were also
well tolerated, although higher reaction temperatures
(70À80 °C) were needed (entries 11À14). In addition to
bromides, aryl iodides and triflates could be coupled
effectively (entries 15À16). On the other hand, chlorides
undergo reaction more slowly and require higher tempera-
tures (80 °C, entry 17). Since the rate with aryl bromides
was much faster relative to that of aryl chlorides, chloro-
substituted aryl bromides could be selectively coupled
(entries 18À19).
Table 2. Scope of Palladium-Catalyzed Nitromethane Coupling
With a robust method for accessing arylnitromethanes
in hand,20 we next elected to examine the Nef dispropor-
tionation21 to produce the aryl aldehydes. Conventional
Nef conditions,22 which proceed by hydrolysis of the re-
quisite primary aryl nitronic acid, are problematic for the
formation of aryl aldehydes.23 Indeed, exhaustive attempts
at utilizing hydrolytic Nef conditions failed on these sub-
strates, providing only recovered substrate. Use of com-
monly employed KMnO4 yielded significant amounts of
oxidatively coupled dimers,24 even when conducted under
extremely dilute conditions. We discovered that a modified
procedure using tin(II) chloride25 was most effective
and permitted a far wider range of functional groups to
be employed (Table 3). In this one-pot reaction, aryl
aldehydes with electron-donating (entries 1À2) and elec-
tron-withdrawing groups (entries 3À7) were readily pro-
duced. Notably, yields are high for the ketone and ester
(entries 5À6), which cannot be generated directly via
a Isolated yield after column chromatography. b Unoptimized. Con-
ductedat70°C. c Conducted at 80 °Cwith5 mol% Pd2dba3 and12mol%
XPhos. d Conducted at 50 °C with5 mol % Pd2dba3 and 12 mol % XPhos.
(19) (a) Kornblum, N.; Smiley, R. A.; Blackwood, R. K.; Iffland,
D. C. J. Am. Chem. Soc. 1955, 77, 6269–6280. (b) Kupchan, S. M.;
Wormser, H. C. J. Org. Chem. 1965, 30, 3792–3800. (c) Cameron, D. W.;
Crosby, I. T.; Feutrill, G. E.; Pietersz, G. A. Aust. J. Chem. 1992, 45,
2003–2024.
(20) After completion of this work, we discovered a related reaction
(only in the Supporting Information of: Burkhard, J. A.; Tchitchanov,
B. H.; Carreira, E. M. Ang. Chem. Int. Ed. 2011, 50, 5379–5382). The
conditions described therein [10 equiv of MeNO2, 1.5 mol % Pd2dba3,
6 mol % tBuMePhos, 1.1 equiv of Cs2CO3, DME, 50 °C, 16.5 h]
provided lower yields over longer reaction times (16.5 vs 5 h) with
p-bromoanisole (74% vs 93% from Table 2, entry 2) and much lower
yields with 2-bromomesitylene (<17% vs 97% Table 2, entry 9).
(21) For a review of recent Nef reactions, see: Ballini, R.; Petrini, M.
Tetrahedron 2004, 60, 1017–1047.
(22) Nef, J. U. Liebigs Ann. Chem. 1894, 280, 263–291.
(23) (a) Kornblum, N.; Brown, R. A. J. Am. Chem. Soc. 1965, 87,
1742–1747. (b) Kornblum, N.; Grahem, G. E. J. Am. Chem. Soc. 1951,
73, 4041–4043. (c) Semmelhack, M. F.; Keller, L.; Sato, T.; Speiss, E. J.;
Wulff, W. J. Org. Chem. 1985, 50, 5566–5574.
FriedelÀCrafts or lithiation/formylation chemistry. Synth-
esis of heteroarylaldehydes was also demonstrated (entry 8),
although incomplete conversion of the oxime intermediate
was observed in this unoptimized reaction.
The overall process, aryl halide to aryl aldehyde, repre-
sents a process complementary to FriedelÀCrafts reac-
tions,26 which is restricted to arenes with electron-donating
substituents at the ortho- or para-positions, and lithiation/
formylation,27 which is not compatible with many func-
tional groups. In addition, nitromethane is easier to employ
as a formylation equivalent relative to carbon monoxide.
(24) (a) Shechter, H.; Williams, F. T., Jr. J. Org. Chem. 1962, 27,
3699–3701. (b) Zhang, Z.; Yu, A.; Zhou, W. Bioorg. Med. Chem. 2007,
15, 7274–7280.
(25) (a) Urpi, F.; Vilarrasa, J. Tetrahedron Lett. 1990, 31, 7499–7500.
(b) Bartra, M.; Romea, P.; Urpi, F.; Vilarrasa, V. Tetrahedron 1990, 46,
587–594.
(26) Martinez, A. G.; Alvarez, R. M.; Barcina, J. O.; Cerero, S. M.;
Vilar, E. T.; Fraile, A. G.; Hanack, M.; Subramanian, L. R. J. Chem.
Soc., Chem. Commun. 1990, 1571–1572.
ꢀ
(27) Sice, J. J. Am. Chem. Soc. 1953, 75, 3697–3700.
Org. Lett., Vol. XX, No. XX, XXXX
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Table 3. Sn(II)-Mediated Nef Reaction
Scheme 2. One-Pot Formylation and Oxime Formation
experimentation proved useful to examining many vari-
ables in concert. The resultant mild method allows for
facile synthesis of a range of arylnitromethanes, a class
of useful materials that is difficult to obtain efficiently
through reported methods. A subsequent highly selective
Nef procedure provides easy access to the corresponding
oximes or aldehydes. A one-pot protocol telescoping the
cross-coupling and Nef reactions provides a mild, useful
alternative to formylation with carbon monoxide as well as
an expeditious entry to oximes. Additional efforts to
explore these processes and understand the key role of
the ligand are currently underway.
a Isolated yield after column chromatography. b Incomplete conver-
sion of the intermediate oxime was observed.
Reasoning that the nitromethane coupling and the Nef
reaction could be combined into a convenient, one-pot
process, para-bromoanisole was subjected to the coupling
conditions. Upon consumption of the starting material,
the solvent was removed, and the arylnitromethane was
directly subjected to the Nef conditions, generating the
aryl aldehyde (Scheme 2, top reaction) in good yield in a
one-pot process. Similarly, the one-pot process could be
halted at the oxime stage with the hindered substrate ortho-
bromotoluene in good yield (Scheme 2, bottom reaction).
Notably, this latter transformation provides a different
synthetic disconnection for generating oximes.
In conclusion, a highly selective monocoupling of nitro-
methane to aryl halides has been developed. The key to
developing this useful transformation was the recognition
of the unique reactivity of both nitromethane and the
reaction product under basic conditions. This study illus-
trates that selection of a system for further optimization by
relying on a singular outcome (e.g., product conversion)
is not the most advantageous. Rather, to optimize the
formation of product and simultaneously suppress the
formation of multiple byproducts, parallel microscale
Acknowledgment. We are grateful to the NSF for
funding of the High Throughput Laboratory (GOALI
CHE-0848460) and NIH (RO1GM087605) for financial
support. We thank Accelrys and Virscidian for providing
software for the high throughput screening and analysis.
Partial instrumentation support was provided by the NIH
for MS (1S10RR023444) and NMR (1S10RR022442). We
thank Dr. Spencer Dreher (Merck Research Laboratories)
for helpful discussions and Ms. Alison Metz (University of
Pennsylvania) for initial studies.
Supporting Information Available. Experimental pro-
cedures, full spectroscopic data for all new compounds,
and additional parallel microscale experimentation data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
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