Nitroethylation of vinyl triflates and bromides

Article abstract of DOI:10.1021/ol401747u

A two-carbon homologation of vinyl triflates and bromides for the synthesis of homoallylic nitro products is described. This palladium-catalyzed double coupling of nitromethane exploits the anion stabilizing and leaving group properties of nitromethane, generating the homo allyl nitro products via a tandem cross-coupling/π-allylation sequence. The resultant process provides a mild and convenient entry to nitroethylated products, which are versatile precursors to β,γ-unsaturated carbonyls, homoallylic amines, and nitrile oxides.

Full text of DOI:10.1021/ol401747u

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Nitroethylation of Vinyl Triflates
and Bromides
Rosaura Padilla-Salinas, Ryan R. Walvoord, Sergei Tcyrulnikov, 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 20, 2013
ABSTRACT
A two-carbon homologation of vinyl triflates and bromides for the synthesis of homoallylic nitro products is described. This palladium-catalyzed
double coupling of nitromethane exploits the anion stabilizing and leaving group properties of nitromethane, generating the homo allyl nitro
products via a tandem cross-coupling/π-allylation sequence. The resultant process provides a mild and convenient entry to nitroethylated
products, which are versatile precursors to β,γ-unsaturated carbonyls, homoallylic amines, and nitrile oxides.
Recently, we reported a highly versatile and robust
cross-coupling reaction of aryl halides with nitromethane.1
This work provided simple access to a range of useful
Scheme 1. Nitromethane Homologation
arylnitromethane building blocks and exploited nitro-
methane as a formyl equivalent to directly afford aryl
aldehydes or oximes (Scheme 1a). While exploring the
use of vinyl bromides to further expand the scope, an
unexpected, two-carbon homologated reaction product
wasencountered. Herein, we communicatethe resultsfrom
this investigation wherein palladium-catalyzed coupling of
vinyl halides and enol triflates with nitromethane affords
nitroethylated products (Scheme 1b).
Nitromethane has been shown to react as a nucleophile
for the Pd-catalyzed substitution reactions with allyl ace-
tates, phenyl ethers, esters, and carbonate derivatives.2
In addition, allyl nitro compounds have been observed to
undergo ionization to form a PdÀπ-allyl complex.3,4 How-
triflates or halides has not been previously reported.2c,f,5
(1) Walvoord, R. R.; Berritt, S.; Kozlowski, M. C. Org. Lett. 2012,
14, 4086–4089.
(2) (a) Wade, P. A.; Hinney, H. R.; Amin, N. V.; Vail, P. D.; Morrow,
ever, accessing homoallylic nitroalkanes directly from vinyl
S. D.; Hardinger, S. A.; Saft, M. S. J. Org. Chem. 1981, 46, 765–770. (b)
Such a tandem process provides access to an array of
nitroethylated compounds, which are versatile precursors
Wade, P. A.; Morrow, S. D.; Hardinger, S. A. J. Org. Chem. 1982, 47, 365–
367. (c) Deardoff, D. R.; Savin, K. A.; Justman, C. J.; Karanjawala, Z. E.;
Sheppeck, J. E., II; Hager, D. C.; Aydin, N. J. Org. Chem. 1996, 61, 3616–
3622. (d) Rieck, H.; Helmchen, G. Angew. Chem., Int. Ed. Engl. 1996, 34,
2687–2689. (e) Giambastiani, G.; Giovanni, P. J. Org. Chem. 1998, 63,
9608–9609. (f) Trost, B. M.; Surivet, J. Angew. Chem., Int. Ed. 2000, 39,
3122–3124. (g) Uozumi, Y.; Suzuka, T. J. Org. Chem. 2006, 71, 8644–8646.
(3) (a) Tamura, R.; Hegedus, L. S. J. Am. Chem. Soc. 1982, 104,
3727–3729. (b) Ono, N.; Hamamoto, I.; Kaji, A. J. Chem. Soc., Chem.
Commun. 1982, 821–822.
(4) Tamura, R.; Kamimura, A.; Ono, N. Synthesis 1991, 6, 423–434.
(5) Select examples: (a) Aleksandrowicz, P.; Piotrowska, H.; Sas, W.
Tetrahedron 1982, 38, 1321–1327. (b) Maki, K.; Kanai, M.; Shibaski, M.
Tetrahedron 2007, 63, 4250–4257. (c) Grenning, A. J.; Tunge, J. A. Org.
Lett. 2010, 12, 740–742. (c) Grenning, A. J.; Tunge, J. A. Angew. Chem.,
Int. Ed. 2011, 50, 1688–1691.
r
10.1021/ol401747u
XXXX American Chemical Society

Scheme 2. Utilization of Nitroethylated Products
Scheme 4. Proposed Mechanism
to β,γ-unsaturated carbonyls, homoallylic amines, and
other useful functionality (Scheme 2).
Our studies began with the discovery that the palladium-
catalyzed nitromethylation of β-bromostyrene gave rise to
an unexpected product (Scheme 3). Instead of obtaining
the allylnitro species, the nitroethylated product was iso-
lated in moderate yield (54%).
employing trialkylphosphine ligands do not catalyze this
initial cross-coupling step.2a
Further study of the transformation from Scheme 3
revealed that the nitroethylated product decomposed
under the reaction conditions over time as observed by GC
analysis (see Supporting Information). Additionally, sub-
jecting the nitroethylated product to the reaction conditions
for 6 h led to only a 68% mass recovery. The low stability of
the product coupled with the potential multiple pathways
available from the Pd η3 π-allyl intermediate (Scheme 5) and
the need to simultaneously optimize two very different
transformations (cross-coupling vs π-allylation; see above)
prompted us to utilize parallel microscale (10 μmol of
vinyl halide, 100 μL reaction volume) experimentation to
screen conditions. In addition to being able to rapidly
assess the impact of different combinations of base, solvent,
palladium source, and ligand on product formation,
LCMS analysis of the reaction profiles provides insight into
which sets of conditions give rise to undesired reaction
pathways.
Due to the low stability of β-bromostyrene and its
nitroethylated products, the screening focused on the more
stable3aasa testsubstrate(Table1). Fora general process,
vinyltrifluoromethanesulfonates are also preferred be-
cause they are more easily obtained (via enolization of
the ketone) than the corresponding vinyl bromides. A
variety of bis-tert-butyl and biscyclohexyl ligands were
selected for screening that are known to promote the first
step of the process (nitromethylation of the aryl halide).1
Based on the efficiencyofPPh3 in the C-alkylation of allylic
acetates with (phenylsulfonyl)nitromethane,2a the combi-
nation of PPh3 with Xantphos, BINAP, CataCXium
POMetB, JohnPhos, BrettPhos, or XPhos was also exam-
ined. Withthese ligands, six different bases (2.4 equiv) were
screened.
Scheme 3
The formation of the nitroethylated product is postu-
lated to arise from a tandem cross-coupling/π-allylation
mechanism (Scheme 4). Notably, the intermediate allylni-
tro compound was never observed in any of the studies
conducted, indicating that it undergoes facile oxidative
ionization under the reaction conditions. Utilizing nitro-
methane as a traceless coupling partner to homologate the
vinyl moiety by one carbon and to incorporate a leav-
ing group to allow formation of π-allyl intermediate V
(Scheme 4) and a second homologation is a unique feature
of this process.
Notably, the two palladium-catalyzed CÀC bond form-
ing events proceed via different mechanisms (oxidative
addition/transmetalation/reductive elimination vs oxida-
tive ionization/outer sphere nucleophilic attack), and there
is no expectation that a single palladium-ligand species
would effectively catalyze both portions.6 For example, with
the exception of CataCXium POMetB, bidentate and bis-
tert-butyl-ligands performed poorly in the nitromethyla-
tion of aryl halides.1 Indeed, typical π-allylation conditions
Select results from this screen are listed in Table 1. In
general, K3PO4 and Cs2CO3 were the most efficient bases
(Table 1, entries 5À8). Bis-tert-butyl ligands (Table1, en-
tries 1 and 8) and a mixed ligand system (Table 1, entry 11)
performed poorly (<3.0 product/internal standard).
(6) For reviews of sequential catalyzed processes, see: (a) Fogg, D. E.;
dos Santos, E. N. Coord. Chem. Rev. 2004, 248, 2365–2379. (b) Lee, J.;
Na, Y.; Han, H.; Chang, S. Chem. Soc. Rev. 2004, 33, 302–312.
(c) Wasilke, J.; Obrey, S. J.; Baker, T.; Bazan, G. C. Chem. Rev. 2005,
105, 1001–1020.
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Org. Lett., Vol. XX, No. XX, XXXX

The use of chloride ion additives was explored since it is
well documented that chloride ions are critical for coupling
enol triflates.7,8 The allylPdOTfLn intermediate formed
after oxidative addition of the enol triflate is proposed to
undergo a counterion exchange.9 Indeed, performing the
reaction in the presence of excess chloride ions (10 equiv
KCl) led to improved isolated yields and rates provid-
ing good results for both vinyl triflates and bromides
(Scheme 6).
Scheme 5. Potential Reaction Pathways from the π-Allyl Nitro
Intermediate
Scheme 6. Use of KCl in the Nitroethylation
Table 1. Product/Internal Standard Ratios from Initial Screening
The optimized conditions did not prove to be broadly
applicable to other alkene, diene, and β- and R-styrene
substrates affording the desired product in <50% yield
(see Supporting Information). Incomplete conversion
of starting material and byproducts were observed in
most cases. Thus, lead ligands from the initial screen
were assessed with a variety of alkene substrates to
draw out reactivity trends (Table 2). Indeed, the yields
could be improved to a >50% yield for each substrate
class.10
Dienes, disubstituted alkenes, and di- and trisubstituted
β-bromostryene derivatives fall into class A where the
XPhos ligand performed best (Table 2). R-Bromostyrenes
and R-tetralone substrates comprise class B, for which
the CataCXium POMetB and DavePhos ligands are
superior. SPhos is most effective for β-tetralone sub-
strates (class C). As expected, the addition of a potas-
sium chloride additive is most effective for enol triflates
derived from β-tetralones and did not improve the out-
come for vinyl bromides.
In an effort to understand the discrete reaction steps, the
allyl nitro species for the corresponding β-tetralone was
synthesized and subjected to the reaction conditions. The
desired nitroethylated product was isolated in 14% yield
(Scheme 7) suggesting that slow formation of the allyl nitro
intermediate is necessary. Oxidative ionization of the allyl
nitro ostensibly competes with other pathways such as
dimerization, the products from which could be identified
in LCMS of the HTE screen. Once the π-allyl species does
form, however, nucleophilic attack is highly regioselective
for the primary position. The branched product was not
observed here (Scheme 7) or with any of the other sub-
strates studied.
Biscyclohexyl (DavePhos and SPhos) phosphine ligands
and CataCXium POMetB were superior (Table 1, entries
5À7), even though they are not highly effective in typical
π-allylations. The top three results were scaled up
(0.360 mmol scale) using Cs2CO3 and afforded the
desired product in 51À72% isolated yield (Table 1).
Complete conversion was observed with DavePhos
and SPhos while incomplete conversion was observed
with CataCXium POMetB. The SPhos ligand proved
most effective, offering enhanced reactivity and cleaner
reaction profiles in comparison to DavePhos and Cat-
aCXium POMetB.
(8) Scott, W. J.; Crisp, G. T.; Stille, J. K. J. Am. Chem. Soc. 1984, 106,
4630–4632.
(9) (a) Jutand, A.; Mosleh, A. Organometallics 1995, 14, 1810–1817.
ꢀ
(b) Jutand, A.; Negri, S. Organometallics 2003, 22, 4229–4237. (c)
Jutand, A. Appl. Organometal. Chem. 2004, 18, 574–582.
˚
(10) 3 A MS suppressed aldehyde formation from water. See ref 1.
(7) Solvation of the metal ion to enhance the nucelophilicity of
nitromethane with the use of ethereal solvents did not improve the yield.
Org. Lett., Vol. XX, No. XX, XXXX
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Table 2. Palladium-Catalyzed Nitroethylation
Scheme 7. One-Carbon Homologation from the Putative
Allylnitro Intermediate
Scheme 8. Nitroethylation of an Aryl Halide
2-bromonaphthalene was subjected to the reaction con-
ditions (Scheme 8). Small amounts of the anticipated
nitroethylated product were observed indicating the
potential of such substrates.
In conclusion, a tandem cross-coupling/π-allylation of
alkenyl bromides and triflates with nitromethane has been
developed. Examining the reactivity of a variety of alkene
substrates with selected conditions obtained from a test
substrate proved to be an effective strategy for rapid
optimization of different substrate classes. This method
allows for facile nitroethylation of both enol triflates,
readily available from the corresponding ketones, and
bromides to afford versatile homoallylic nitro building
blocks.
Acknowledgment. We are grateful to the National In-
stitutes of Health (GM-087605) and the National Science
Foundation (CHE-105544) for financial support of this
research. R.P.S. gratefully acknowledges a Gates Millenium
Scholar Fellowship. The NSF provided for funding
of the High Throughput Laboratory (GOALI CHE-
0848460). Partial instrumentation support was pro-
vided by the NIH for MS (1S10RR023444) and NMR
(1S10RR022442) and by the NSF for an X-ray diffrac-
tometer (CHE 0840438).
a Isolated yields. b Conversion determined by 1H NMR. c 10 equiv of
KCl added.
To probe whether a similar reaction pathway is
feasible with benzylic11 vs allylic nitro intermediates,
(11) (a) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122,
9546–9547. (b) Nettekoven, U.; Hartwig, J. F. J. Am. Chem. Soc. 2002,
124, 1166–1167. (c) Johns, A. M.; Utsunomiya, M.; Incarvito, C. D.;
Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 1828–1839. (d) Kuwano,
R.; Kondo, Y.; Matsuyama, Y. J. Am. Chem. Soc. 2003, 125, 12104–
12105. (e) Trost, B. M. J . Am. Chem. Soc. 2010, 132, 15534–15536. (f)
Trost, B. M.; Czabaniuk, L. C. J. Am. Chem. Soc. 2012, 134, 5778–
5781.
Supporting Information Available. Experimental pro-
cedures and spectral 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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