Synthesis of 2-(1-Alkoxyvinyl)anilines by Palladium/Norbornene-Catalyzed Amination Followed by Termination with Vinyl Ethers

Article abstract of DOI:10.1002/adsc.201600339

A palladium/norbornene-catalyzed ortho-amination and ipso vinyl ether termination reaction of iodoarenes is reported. The benzyl vinyl ether serves as an efficient alternative carbonyl source in palladium/norbornene catalysis for the final ipso termination reaction to give [1-(benzyloxy)vinyl]arenes, which readily undergo hydrolysis to deliver methyl ketones under aqueous acidic conditions. The final Heck termination reaction with vinyl ethers has high branched/linear selectivity. This reaction tolerates a range of iodoarene and O-benzoylhydroxylamine substrates, and it provides a convenient way to prepare o-acetylanilines. The synthetic utility of [1-(benzyloxy)vinyl]arenes and the corresponding ketones is briefly investigated. (Figure presented.).

Full text of DOI:10.1002/adsc.201600339

UPDATES
DOI: 10.1002/adsc.201600339
Synthesis of 2-(1-Alkoxyvinyl)anilines by Palladium/Norbornene-
Catalyzed Amination Followed by Termination with Vinyl Ethers
Jie Wanga and Zhenhua Gua,*
a
Department of Chemistry, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230036,
Peopleꢀs Republic of China
E-mail: zhgu@ustc.edu.cn
Received: March 29, 2016; Revised: June 6, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600339.
Abstract: A palladium/norbornene-catalyzed ortho-
amination and ipso vinyl ether termination reaction
of iodoarenes is reported. The benzyl vinyl ether
serves as an efficient alternative carbonyl source in
palladium/norbornene catalysis for the final ipso
termination reaction to give [1-(benzyloxy)vinyl]ar-
enes, which readily undergo hydrolysis to deliver
methyl ketones under aqueous acidic conditions.
The final Heck termination reaction with vinyl
ethers has high branched/linear selectivity. This re-
action tolerates a range of iodoarene and O-ben-
zoylhydroxylamine substrates, and it provides a con-
venient way to prepare o-acetylanilines. The syn-
thetic utility of [1-(benzyloxy)vinyl]arenes and the
corresponding ketones is briefly investigated.
ucts[5] were synthesized efficiently by many groups,
notably those of Catellani, Lautens and their co-work-
ers (Scheme 1a).
Ketones are an important type of functional group
and intermediates in organic synthesis, and various
biologically active molecules containing ketone moiet-
ies were discovered.[6] Recently the groups of Liang
and Dong as well as our own group independently re-
ported Pd/NBE-catalyzed ortho-acylation reactions by
the use of acid chlorides or (mixed) anhydrides.[7] In
contrast, we are aware of only one report using Pd/
NBE catalysis to introduce ketone functionality at the
ipso-position of iodoarenes.[8] Furthermore, this proto-
col was limited to the synthesis of 9H-fluoren-9-ones
by the use of 2-bromobenzoates (Scheme 1b). Given
the importance of aryl ketones, we report here a Pd/
NBE-catalyzed synthesis of acetophenones by ipso-
Heck termination with vinyl ethers (Scheme 1c).[9,10]
In our early work, we failed to synthesize ketones
under standard Pd/NBE catalysis conditions when we
used carbon monoxide as the carbonyl source, instead
obtaining a complicated mixture.[11] This failure may
Keywords: carbonyl compounds; Heck reaction;
norbornene; palladium; vinyl ethers
Palladium-catalyzed carbonylation is
a powerful reflect the fact that several intermediates in the cata-
method for synthesizing carbonyl compounds.[1] These lytic cycle, such as ArPdX and intermediates I and III
reactions are usually mild, efficient and tolerant of (Scheme 4), may react with carbon monoxide to give
different functional groups; they occasionally allow side products. Therefore, in order to introduce the
multiple bonds to be formed in a step-economical ketone functionality, in the present work we opted for
manner.
Palladium/norbornene
(NBE)-catalyzed a Heck reaction by the use of vinyl ethers. The pres-
transformations, first reported by Catellani and co- ent work also built on the seminal work of Dong and
workers in 1997,[2] are unique reactions which not co-workers in 2013, who reported a Pd/NBE-cata-
only furnish the classic cross-couplings, Heck reaction lyzed ortho-amination reaction in which O-benzoylhy-
or carbonylations etc., but also introduce functionality droxylamines served as the amination reagents.[4i] To
at the ortho-position via the norbornene-containing our delight, in the presence of Pd(OAc)2/NBE, Dave-
palladacycle intermediate. Such transformations have Phos and Cs2CO3, the reaction of 2-iodoanisole 1a,
become a popular method for constructing polysubsti- morpholine benzoate 2a and ethyl vinyl ether 3a gave
tuted arenes, particularly 1,2,3-trisubstituted ones. the expected terminal vinyl ether 4a in moderate
Simply by altering the termination reagents, which yield (Table 1, entry 1). Compound 4a was stable
can include alkenes, cyano anion, alkynes, electron- enough for regular column chromatographic purifica-
rich arenes, hydrazones, amides and ketones, many di- tion on silica gel. Palladium chloride showed compa-
versely substituted arenes,[3,4] as well as natural prod- rable efficiency as Pd(OAc)2, while the reaction with
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Table 1. Optimization of the reaction conditions.[a]
Entry Pd
Ligand
Solvent
3
4, Yield
1
Pd(OAc)2 DavePhos dioxane 3a 4a, 45%
2
3
PdCl2 DavePhos dioxane 3a 4a, 46%
Pd2(dba)3 DavePhos dioxane 3a 4a, 15%
4
5
6
PdCl2
PdCl2
PdCl2
DavePhos PhMe
DavePhos MeCN
DavePhos DMF
3a 4a, 27%
3a 4a, 44%
3a 4a, 32%
7
8
9
10
11
12
PdCl2
PdCl2
Pd(PPh3)4
PdCl2
TFP
PPh3
–
PPh3
PPh3
PPh3
dioxane 3a 4a, 47%
dioxane 3a 4a, 45%
dioxane 3a 4a, 42%
dioxane 3b 4b, 67%
dioxane 3c 4c, 84%[b]
dioxane 3c 4c, 24%
PdCl2[c]
PdCl2
[a]
The reaction was conducted with 0.20 mmol of 1a,
0.30 mmol of 2a, 0.60 mmol of 3, 0.60 mmol of norbor-
nene, 0.60 mmol of Cs2CO3, 5 mol% of PdCl2, and
10 mol% of phosphine in the indicated solvent (2.0 mL,
0.10 mol/L).
The regioisomer for the vinyl ether (linear product) was
detected. Branched:linear product ~20:1.
2 mol% of PdCl2 and 5mol% of PPh3 were used.
[b]
[c]
With the optimum reaction conditions in hand, we
investigated the substrate scope of this reaction re-
garding various iodoarenes and O-benzoylhydroxyl-
Scheme 1. Pd/NBE-catalyzed domino reactions.
AHCTUNGTRENNUNG
Pd2(dba)3 gave only 15% yield of 4a (entries 2 and 3). including methyl, phenyl, O-TBS, hydroxymethyl and
MeCN gave satisfactory results, while toluene and methoxymethoxy groups; the corresponding products
DMF proved to be unsuitable solvents for this trans- 4d–g were isolated in moderate to excellent yields.
formation (entries 4–6). Ligand screening showed that Both electron-withdrawing and electron-donating
both tris(2-furyl)phosphine (TFP) and PPh3 gave simi- groups were tolerated on 2-iodotoluene, although sub-
lar results (entries 7 and 8). Meanwhile, Pd(PPh3)4 strates with electron-withdrawing groups led to rela-
gave marginally lower yield than the PdCl2/PPh3 tively lower yields (4h–j). Using 1-iodonaphthalene in
system (entry 9). Vinyl ethers with higher boiling the reaction gave 4k in 93% yield. p-Iodoanisole was
points, such as n-butyl vinyl ether 3b and benzyl vinyl smoothly converted to the diamino product 4l in 63%
ether 3c led to higher isolated yields of the corre- yield. Evaluation of O-benzoylhydroxylamines
sponding products (entries 10 and 11). Thus, benzyl showed that piperidine and its derivatives containing
vinyl ether 3c was used in subsequent studies of sub- p-methyl, p-benzyl or 4-ethoxycarbonyl groups could
strate scope. During optimization of reaction condi- be efficiently introduced at the ortho-position with ex-
tions, dry and fresh distilled 1,4-dioxane was found to cellent yields (4m–p). Both primary and secondary
be critical for the reaction. Decreasing the loading of free alcohols were well tolerated (4q and 4r), and the
palladium catalyst to 2 mol% led to a significantly piperazine derivative 4s was synthesized in a highly
lower yield (entry 12).
efficient manner.
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Table 2. Substrate scope.[a]
Table 3. Hydrolysis to methyl ketones.
resulted in cleavage of both vinyl ether and the MOM
protective groups, giving 5g in quantitative yield.
The reaction was scaled up uneventfully by using
1.0 gram of 1-iodo-2-methoxybenzene (4.27 mmol) or
1-iodo-2-methylbenzene (4.59 mmol) under standard
reaction conditions. Good yields were obtained in
both cases (Scheme 2).
The synthetic utility of compounds 4 and 5 was
briefly investigated (Scheme 3). Vinyl ether 4t was ef-
ficiently acylated with trifluoroacetic anhydride, form-
ing 6 in 98% yield with a Z/E ratio near 1:1 and re-
tention of the vinyl ether moiety. The acetyl group
was further functionalized via classic aldol condensa-
tion with benzaldehyde to give chalcone analogue 7.
Compound 5g was converted to o-diacylbenzene de-
rivative 8 via hydrazone formation followed by
Pb(OAc)4-mediated oxidative rearrangement.[12] The
diketone 8 was readily transformed into phthalazine 9
in virtually quantitative yield.
A plausible catalytic cycle for our reaction is pro-
posed in Scheme 4 using 2-iodotoluene, 2a and 3c as
representative substrates. In the proposed mechanism,
oxidative addition of 2-iodotoluene with Pd(0) gives
an aryl-Pd(II) species, which generates a five-mem-
bered palladacycle I via NBE insertion and followed
À
by C H palladation. Oxidative addition of I with 2a
forms Pd(IV) complex II, which creates a C N bond
[a]
The reaction was conducted with 0.20 mmol of 1,
À
0.30 mmol of 2, 0.60 mmol of 3c, 0.60 mmol of norbor-
nene, 0.60 mmol of Cs2CO3, 5 mol% of PdCl2, and
10 mol% of PPh3 in dioxane (2.0 mL, 0.10 mol/L).
10 mol% of PdCl2 was used. TFP was the ligand and
4.0 mL of dioxane was used.
via reductive elimination.[13] Norbornene extrusion of
III gives ortho-aminated Pd(II) species IV, which un-
dergoes a classic Heck reaction with the benzyl vinyl
ether 3c to deliver the final product 4d. Polarization
of the C=C double bond in the vinyl ether may ex-
plain the observed high regioselectivity of the reac-
[b]
As expected, methyl aryl ketones were readily ob- tion.
tained from the [1-(benzyloxy)vinyl]arenes via acidic
In conclusion, we have described a reaction involv-
hydrolysis, and the corresponding products were ob- ing Pd/NBE-catalyzed ortho-amination and ipso vinyl
tained in yields of 88–99% (Table 3). Hydrolysis of 4g ether termination. Vinyl ethers are convenient and ef-
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Scheme 4. Plausible catalytic cycle.
ficient alternatives to carbon monoxide for introduc-
ing ipso ketone moieties during the Pd/NBE-cata-
lyzed process. Compounds 4 and 5 may be synthetical-
ly useful and can be transformed into vinyl ether 6,
chalcone derivatives and o-diacylanilines.
Scheme 2. Gram-scale reactions.
Experimental Section
Typical Procedure for the Palladium/Norbornene-
Catalyzed ortho-Amination and ipso Heck
Termination with Vinyl Ethers
A dried Schlenk tube was charged with 2-methoxyliodoben-
zene 1a (46.8 mg, 0.20 mmol, 1.0 equiv.), N-benzoyloxymor-
pholine 2a (62.0 mg, 0.30 mmol, 1.5 equiv.), benzyl vinyl
ether 3c (80.5 mg, 0.60 mmol, 3.0 equiv.), PdCl2 (1.8 mg,
0.01 mmol, 5 mol%), PPh3 (5.3 mg, 0.02 mmol, 10 mol%),
norbornene (56.5 mg, 0.60 mmol, 3.0 equiv.) and Cs2CO3
(196.0 mg, 0.60 mmol, 3.0 equiv.) in 1,4-dioxane (2.0 mL).
After stirring at 908C under an atmosphere of dry nitrogen
for 24 h, the reaction mixture was cooled to room tempera-
ture and filtered through a pad of celite with EtOAc as the
eluent. The filtrate was evaporated under reduced pressure,
and the residue was purified by column chromatography on
silica gel (petroleum ether/ethyl acetate=20:1) to give com-
pound 4c; yield: 54.4 mg (84%) (b/l=20:1).
Acknowledgements
We thank the ꢀ973ꢁ project from the MOST of China
(2015CB856600), NSFC (21272221, 21472179), and the Fun-
damental Research Funds for the Central Universities (WK
2060190026 and 3430000001) for financial support.
Scheme 3. Synthetic applications.
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Synthesis of 2-(1-Alkoxyvinyl)anilines by Palladium/
Norbornene-Catalyzed Amination Followed by Termination
with Vinyl Ethers
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Adv. Synth. Catal. 2016, 358, 1 – 7
Jie Wang, Zhenhua Gu*
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