Palladium-catalyzed alkoxyamination of alkenes with use of N -fluorobenzenesulfonimide as oxidant

Article abstract of DOI:10.1021/jo101171g

Figure presented. A Pd-catalyzed alkoxyamination of protected aminoalkenes promoted by N-fluorobenzenesulfonimide is described. This mild transformation allows the direct formation of ethers from carbon-carbon double bonds. An unusual switch from exo to endo selectivity in polar solvents was discovered, allowing the selective formation of either regioisomer by careful choice of reaction conditions.

Full text of DOI:10.1021/jo101171g

pubs.acs.org/joc
SCHEME 1. Palladium-Catalyzed Diamination and Alkoxya-
mination
Palladium-Catalyzed Alkoxyamination of Alkenes
with Use of N-Fluorobenzenesulfonimide as Oxidant
Dmitry V. Liskin, Paul A. Sibbald, Carolyn F. Rosewall, and
Forrest E. Michael*
Department of Chemistry, University of Washington,
Box 351700, Seattle, Washington 98195-1700
michael@chem.washington.edu
Received July 1, 2010
TABLE 1. Nucleophile Scope
A Pd-catalyzed alkoxyamination of protected aminoalk-
enes promoted by N-fluorobenzenesulfonimide is described.
This mild transformation allows the direct formation of
ethers from carbon-carbon double bonds. An unusual
switch from exo to endo selectivity in polar solvents was
discovered, allowing the selective formation of either
regioisomer by careful choice of reaction conditions.
entry
[Pd]
R
% yield
1
2
3
4
5
6
Pd(TFA)2
Me
Eta
n-Pr
n-Bu
i-Pr
Ac
53 (4a)
63 (4b)
57 (4c)
66 (4d)
63 (4e)
55 (4f)
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
Pd(TFA)2
a9:1 EtOAc/EtOH.
We recently reported the diamination of protected amino-
alkenes using N-fluorobenzenesulfonimide (NFBS) as an
electrophilic nitrogen source (Scheme 1).6 When this reaction
was performed in THF, an unusual byproduct, 3, was iso-
lated from the reaction mixture. Compound 3 appears to
arise from nucleophilic incorporation of the THF solvent.
We reasoned that other oxygen nucleophiles might also be
incorporated under similar conditions. Gratifyingly, treat-
ment of substrate 1 under identical conditions in ethanol
provided the alkoxyamination product 4b in 52% yield
(Scheme 1, eq 3).
The effects of various palladium catalysts and additives
wereevaluated (see the Supporting Information). The optimal
conditions involved the use of either Pd(TFA)2 or PdCl2-
(MeCN)2 as catalyst. Radical scavengers such as BHT and
TEMPO have been shown to improve other NFBS-promoted
reactions but in this case did not improve the yield.6,7
A range of primary and secondary alcohols was success-
fully incorporated under mild conditions (Table 1). Acetic
acid could also be used to yield ester 4f in 55% yield. For
methanol and acetic acid incorporation, Pd(TFA)2 gave
better yields of the desired product, but for all other alcohols
PdCl2(MeCN)2 was the optimal catalyst.
The simultaneous addition of oxygen and nitrogen het-
eroatoms across a carbon-carbon double bond is a powerful
tool for the synthesis of biologically active molecules. Several
examples of these reactions have been previously reported,
most commonly aminohydroxylation1,2 and aminoacetoxy-
lation reactions.3,4 Direct introduction of an alkoxy group in
such a process is quite rare,5 but would greatly increase the
potential utility of this type of transformation by allowing
the direct formation of protected alcohols or ethers from
alkenes. Herein, we report an intramolecular Pd-catalyzed
alkoxyamination of unactivated alkenes under mild condi-
tions to yield nitrogen heterocycles.
(1) For selected reviews, see: (a) Kolb, H. C.; VanNieuwenhze, M. S.;
Sharpless, K. B. Chem. Rev. 1994, 94, 2483–2547. (b) Nilov, D.; Reiser, O.
Adv. Synth. Catal. 2002, 344, 1169–1173. (c) Bodkin, J. A.; McLeod, M. D.
J. Chem. Soc., Perkin Trans. 1 2002, 2733–2746. (d) Muniz, K. Chem. Soc.
Rev. 2004, 33, 166–174.
(2) Donohoe, T. J.; Lindsay-Scott, P. J.; Parker, J. S.; Callens, C. K. Org.
Lett. 2010, 12, 1060–1063. Donohoe, T. J.; Callens, C. K.; Thompson, A. L.
Org. Lett. 2009, 11, 2305–7.
(3) Stoichiometric: Backvall, J.-E. Acc. Chem. Res. 1983, 16, 335–342.
Catalytic: Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc. 2005,
127, 7690–7691. Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 7179–7181.
(4) Aminotrifluoroacetoxylation of alkenes, see: Lovick, H. M.; Michael,
F. E. J. Am. Chem. Soc. 2010, 132, 1249–1251.
(5) Intramolecular alkoxide (from alkenols): Szolcsanyi, P.; Gracza, T.
Chem. Commun. 2005, 3948. Desai, L. V.; Sanford, M. S. Angew. Chem., Int.
Ed. 2007, 46, 5737. Using TEMPO as alkoxy group: Fuller, P. H.; Kim,
J.-W.; Chemler, S. R. J. Am. Chem. Soc. 2008, 130, 17638–17639.
(6) Sibbald, P. A.; Michael, F. E. Org. Lett. 2009, 11, 1147–1149.
(7) Rosewall, C. F.; Sibbald, P. A.; Liskin, D. V.; Michael, F. E. J. Am.
Chem. Soc. 2009, 131, 9488–9489.
6294 J. Org. Chem. 2010, 75, 6294–6296
Published on Web 08/26/2010
DOI: 10.1021/jo101171g
r
2010 American Chemical Society

Liskin et al.
JOCNote
SCHEME 2. Direct Synthesis of Methyl and Isopropyl Ethers
TABLE 2. Effect of Halide on Regioselectivity
entry
[Pd]
additive (20 mol %)
4a:5aa
1
2
3
4
5
6
Pd(TFA)2
PdCl2(MeCN)2
PdCl2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
none
none
none
LiCl
LiBr
(n-Bu)4NBr
>20:1
1:2.5
1:0.7
1:1.8
1:1.8
1:2.2
aDetermined by 1H NMR spectroscopy
TABLE 3. Regioselectivity Changes with Solvent Polarity
aConditions: 10 mol % [Pd] (Pd(TFA)2 with MeOH; PdCl2(MeCN)2
with i-PrOH), 2 equiv of NFBS, ROH, 3 A MS, rt. b1:2 mixture of
˚
diastereomers.
SCHEME 3. Direct Formation of Bn and PMB Ethers
entry
cosolvent
vol % MeOH
4a:5aa
1
2
2
3
4
5
6
7
none
100
60
60
60
20
60
80
60
1:2.5
1:0.5
1:0.9
1:1.1
1:0.4
1:1.2
1:1.5
1:8
1,4-dioxane
CCl4
Et2O
EtOAc
EtOAc
EtOAc
DMF
Other aminoalkenes were suitable substratesfor thealkoxy-
amination reaction under standard conditions (Scheme 2).
Though the yields are moderate, the ability to directly form an
ether could save several synthetic steps over the corresponding
aminohydroxylation or aminoacetoxylation reaction.
To allow the efficient use of expensive or high-boiling
alcohols, reaction conditions to enable the use of smaller
quantities of alcohol nucleophile were examined. A screen of
cosolvents and conditions revealed that catalytic Pd(TFA)2
in benzene afforded the synthetically useful Bn and PMB
protected alcohols 4g and 4h in moderate yields with these
conditions (Scheme 3).
aDetermined by 1H NMR spectroscopy
SCHEME 4. Scope of 6-Endo Cyclizationa
aConditions: 10 mol % of PdCl2(MeCN)2, 2 equiv of NFBS, 9:1
DMF/ROH.
The change in catalyst when using MeOH or AcOH as the
nucleophile was due to a surprising change in regioselecti-
vity.8 The reaction of methanol with substrate 1 in the pre-
sence of catalytic PdCl2(MeCN)2 afforded a 1:1 mixture of
exo and endo cyclization products 4a and 5a, respectively
(eq 5). Under identical conditions, Pd(TFA)2 gave exclu-
sively exo product 4a. To test if the presence of the halide
counterion was responsible for the anomalous endo cycliza-
tion, a number of halide sources were added to the reaction
catalyzed by Pd(TFA)2 (Table 2). The addition of halides to
the reaction mixture always increased the amount of endo
cyclization product 5a.
Since the endo product was only observed when using
MeOH or AcOH as solvent, it appeared that the polarity of
the reaction mixture might have an influence on the exo/endo
selectivity. Addition of a less polar cosolvent favored for-
mation of exo product 4a, while addition of a more polar
solvent such as DMF promoted endo cyclization to form 5a
(Table 3).
Conditions were optimized for the selective formation of
the 6-endo cyclization products in DMF. Though the regios-
electivity is uniformly high, yields were moderate (Scheme 4).
The major byproduct of this reaction was diamination
product 2. The high yield of 10a is explained by the fact that
unsubstituted substrate 10 does not undergo diamination
under these conditions.
A plausible mechanism appears in Scheme 5. By analogy
to previous oxidative aminations,9 initial exoselective amino-
palladation occurs to generate complex I. Oxidative addition
of NFBS generates a Pd(IV) species II, which can undergo
nucleophilic substitution by the alcohol to generate the 5-exo
cyclization product. The origin of the 6-endo product is
(8) A substrate directed change in regiochemistry has been reported:
Sherman, E. S.; Chemler, S. R. Adv. Synth. Catal. 2009, 351, 467–471.
(9) Sibbald, P. A.; Rosewall, C. F.; Swartz, R. D.; Michael, F. E. J. Am.
Chem. Soc. 2009, 131, 15945–15951.
J. Org. Chem. Vol. 75, No. 18, 2010 6295

Liskin et al.
JOCNote
SCHEME 5. Proposed Mechanistic Cycle
Benzyl 2-(methoxymethyl)-4,4-dimethylpyrrolidine-1-carbox-
ylate (4a): clear oil, 52% yield; 1H NMR (500 MHz, CDCl3) δ
7.43-7.30 (m, 5H), 5.25-5.09 (m, 2H), 4.08-3.02 (m, 1H),
3.69-3.45 (m, 2H), 3.45-3.12 (m, 6H), 3.01 (d, J = 10 Hz, 1H),
1.87-1.78 (m, 1H), 1.78-1.71 (m, 1H), 1.09 (s, 3H), 0.98 (s, 3H);
13C NMR (125 MHz, CDCl3, observed as a mixture of rota-
mers, ∼1.5:1) δ 155.3, 136.9, 128.4, 127.8, 127.6, 74.3, 73.1, 66.8
(minor), 66.6 (major), 59.64 (minor), 59.1 (major), 57.0 (major),
56.3 (minor), 43.6 (minor), 42.4 (major), 37.4 (major), 37.1
(minor), 26.5, 25.9; FTIR (neat, cm-1) 2958, 2872, 1703, 1452,
1415, 1358, 1188, 1101; MS (EI) 277.2, (Mþ, 0.3%), 232.2 ([M -
CH2OCH3]þ, 27%), 188.2 ([M - PhCH2OCO]þ, 37%), 91.1
(Bnþ, 100%); HRMS (FAB) calcd for C16H24NO3 278.1756,
found 278.1761.
General Procedure for 6-Endo Alkoxyamination. Pd(TFA)2
(10 mol %, 0.025 mmol) and N-fluorobenzenesulfonimide
(0.158 g, 0.500 mmol, 2 equiv) were weighed into a 10 mL round-
bottomed flask containing a magnetic stir bar, capped with
a rubber septum, and placed under dry N2 gas. The substrate
(0.250 mmol) was dissolved in a mixture of 1 mL of the corre-
sponding alcohol and 4 mL of dimethylformamide and added to
the flask. The reaction was allowed to stir overnight and then
was diluted with ethyl acetate and separated from the sieves and
magnetic stirbar by transferring into another flask. The mixture
was concentrated under reduced pressure (0.1 Torr) at 50 °C and
chromatographed with 25:75 EtOAc/hexanes. The product was
collected and further purified by chromatography with a less
polar mixture of EtOAc/hexanes.
Benzyl 5-methoxy-3,3-dimethylpiperidine-1-carboxylate (5a):
colorless oil (38% yield); 1H NMR (500 MHz, CDCl3) δ 7.41-
7.29 (m, 5H), 5.20-5.10 (m, 2H), 4.36-4.34 (m, 0.5H), 4.23-
4.16 (m, 0.5H), 3.68-3.58 (m, 1H), 3.36 (d, J=18 Hz, 3H), 2.74-
2.63 (m, 0.5H), 2.65 (d, J=13.5 Hz), 1.80 (m, 1H), 1.21-1.16
(m, 1H), 0.98-0.89 (m, 6H); 13C NMR (125 MHz, CDCl3,
observed as a mixture of rotamers, ∼1.5:1) δ 155.6, 155.5, 136.8,
128.4, 128.0, 127.9, 127.8, 73.2 (minor), 72.8 (major), 67.1, 56.4
(major), 56.3 (minor), 55.0 (major), 54.9 (minor), 47.7, 43.8
(major), 43.8 (minor), 32.2 (major), 32.1, 28.2, 24.9, 24.7; FTIR
(neat, cm-1) 2929, 1700, 1430, 1200, 1090; MS (ES) 300 [M þ
Na]þ; HRMS (FAB) calcd for C16H24NO3 278.1756, found
278.1747.
currently unclear. One possibility is that under highly polar
reaction conditions, aziridinium species III could be generated
upon departure of the Pd, and preferential internal attack
would lead to selective formation of the 6-endo product.
In summary, we have successfully developed a Pd-cata-
lyzed alkoxyamination of protected aminoalkenes using
NFBS as oxidant. The regioselectivity could be controlled
by careful choice of catalyst and solvent, leading to selective
formation of either the 5-exo or 6-endo cyclization products.
The direct formation of benzyl and PMB protected alcohols
could also be achieved, potentially saving several synthetic
steps.
Experimental Section
General Procedure for 5-Exo Alkoxyamination. [Pd]10 (10mol%,
0.025 mmol) and N-fluorobenzenesulfonimide (0.158 g, 0.500
mmol, 2 equiv) were weighed into a 10 mL round-bottomed flask
˚
containing a magnetic stir bar and 3 A molecular sieves (10-15
sieves), capped with a rubber septum, and placed under dry N2
gas. The substrate (0.250 mmol) was dissolved in 5 mL of the
corresponding alcohol and added to the flask. The reaction was
allowed to stir overnight and then was diluted with ethyl acetate
and separated from the sieves and magnetic stirbar by transfer-
ring into another flask. The mixture was concentrated under
reduced pressure and chromatographed with 25:75 EtOAc/hex-
anes. The product was collected and further purified by chroma-
tography with a less polar mixture of EtOAc/hexanes.
Acknowledgment. We thank the University of Washington
and the National Science Foundation for financial support.
Supporting Information Available: Reaction conditions and
spectroscopic data. This material is available free of charge via
the Internet at http://pubs.acs.org.
(10) See the Supporting Information for Pd source.
6296 J. Org. Chem. Vol. 75, No. 18, 2010