The benzyne aza-claisen reaction

Article abstract of DOI:10.1002/anie.200901410

Adding an aryne to a tertiary allylamine affords oallylaniline products of an aza-Claisen rearrangement. The aryne simultaneously provides the π component for the rearrangement and the quaternization event that lowers the activation energy for the sigmatr

Full text of DOI:10.1002/anie.200901410

Angewandte
Chemie
DOI: 10.1002/anie.200901410
Rearrangement
The Benzyne Aza-Claisen Reaction**
Alastair A. Cant, Guillaume H. V. Bertrand, Jaclyn L. Henderson, Lee Roberts, and
Michael F. Greaney*
The aza-Claisen (or 3-aza-Cope) rearrangement of allylen-
amines is a powerful, atom-efficient method for the synthesis
of functionalized amines.[1] The scope of the reaction, how-
ever, has yet to be fully realized because of the forcing
reaction conditions necessary to achieve rearrangement.
Simple rearrangement of allylenamines requires very high
reaction temperatures (> 2008C) and is seldom used as a
preparative method.[2] Charge-accelerated aza-Claisen rear-
rangements, however, take place under milder reaction
conditions and have been widely studied in terms of substrate
range, stereocontrol, and application to the synthesis of
complex molecules.[3,4] The basic nitrogen atom provides the
site for charge acceleration, usually through protonation,
quaternization, or Lewis acid coordination. Even so, simple
allylaniline aza-Claisen reactions require stoichiometric
amounts of Lewis acids such as BF3.OEt2 and reaction
temperatures well in excess of 1008C (Scheme 1).[5]
Our interest in aryne chemistry[6] led us to speculate that
the addition of benzyne to a tertiary allylamine could set up
an aza-Claisen rearrangement pathway, thus creating a novel
route to functionalized anilines. The electrophilic aryne
would react rapidly with the nitrogen nucleophile to afford
the zwitterion 2. This key intermediate could undergo direct
rearrangement through a 6-endo intramolecular SN2’ reaction
to produce aniline 3 (path A). Alternatively, protonation of 2
by the solvent would afford the ammonium salt 4, which could
rearrange via the conventional charge-accelerated aza-
Claisen pathway to produce the same aniline product 3
(path B). In one pot, we would take readily available tertiary
Scheme 1. The aza-Claisen rearrangement and proposed benzyne reac-
tion. Sol=solvent.
benzocarbazole 8 in 12% yield (Scheme 2). Initial DA
reaction and subsequent N-arylation gave the intermediate
zwitterion 7, which undergoes rearrangement in a manner
À
À
allylamines and form one aryl C N bond and one aryl C C
bond without recourse to metal catalysts or stoichiometric
amounts of Lewis acid promoters.
Precedent for the addition of tertiary allylamines to
benzyne can be found in seminal work from Wittig and
Behnisch on the benzyne Diels–Alder (DA) reaction of
pyrroles.[7–9] When studying the DA reaction of N-methyl
pyrroles with excess benzyne, Wittig isolated the novel
[*] A. A. Cant, G. H. V. Bertrand, J. L. Henderson, Dr. M. F. Greaney
School of Chemistry, University of Edinburgh
King’s Buildings, West Mains Road, Edinburgh, EH93JJ (UK)
Fax: (+44)131-650-4743
Scheme 2. Wittig’s pyrrole Diels–Alder reaction and subsequent rear-
rangement. THF=tetrahydrofuran.
E-mail: michael.greaney@ed.ac.uk
Dr. L. Roberts
that is exactly analogous to path A in Scheme 1. Although the
yield of the transformation was low, we were encouraged by
this early precedent which accounts for three sequential
reactions in one pot, and which was achieved in an era
predating purification involving chromatographic methods.
We began our investigations into the aryne aza-Claisen
rearrangement using benzyne precursor 9a[10] and N-allylpi-
Discovery Chemistry, Pfizer Global R&D, Sandwich (UK)
[**] We thank Pfizer, CRUK, and the University of Edinburgh for funding
as well as the EPSRC mass spectrometry service at the University of
Swansea. Jordi Rull and Fabien Ehret are thanked for preliminary
work in the area.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200901410.
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peridine 10a as substrates, with cesium fluoride used to
Scheme 1. Alternative mechanisms of allyl transfer corre-
sponding to overall s insertion could be discounted.[11,12]
We next examined the scope of the reaction with respect
to the aryne structure. Methylenedioxy benzyne and naph-
thyne derivatives were both good substrates, and produced
the aza-Claisen products in 57% and 79% yield (Table 2,
generate the key aryne reactive intermediate. After a screen
of the reaction solvents and temperatures, we were pleased to
observe that heating in a toluene/acetonitrile mixture at
1108C afforded the desired aza-Claisen product 11a in an
excellent 92% yield (Table 1, entry 1). The reaction was
Table 2: Investigation of the reaction scope with respect to the aryne 9.[a]
Table 1: Aryne aza-Claisen rearrangement using benzyne precursor 9a
and amines 10.[a] Tf =triflate, Tol=toluene.
Entry
1
Aryne precursor
Product
Yield [%][b]
Entry
1
Amine
Product
Yield [%][b]
92
9b
9c
9d
11h 57
10a
10b
10c
11a
11b
11c
2
3
11i 79
11j 76
2
62
65
3[c]
11k
4
10d
11d
91
4
5
9e
79[c]
5
10e
10 f
11e
11 f
74
31
11k’
9 f
11l 40
6[d]
[a] Reaction conditions: aryne precursor (1 equiv), 1-allylpiperidine
(1.5 equiv), and CsF (3 equiv) in toluene (0.75 mL) and MeCN
(0.25 mL). Reactions were carried out on a 0.2 mmol scale and heated
at reflux for 48 hours in a sealed tube. [b] Yield of isolated product.
[c] Products isolated as a 2.3:1 ratio of 11k/11k’.
[a] Reaction conditions: o-trimethylsilylphenyl triflate (1 equiv), amine
(1.5 equiv), and CsF (3 equiv) in toluene (0.75 mL) and MeCN
(0.25 mL). Reactions were carried out on a 0.2 mmol scale and heated
to 1108C for 48 hours in a sealed tube. [b] Yield of isolated product.
[c] Prestirred at room temperature for 24 hours. [d] Reaction was
performed in DME at reflux.
entries 1 and 2). The naphthyne substrate showed good
regiocontrol, with the nucleophilic addition of amine occur-
ring cleanly at the more sterically accessible b position. The
electron-rich dimethoxy aryne substrate 9d provided valuable
insight into the mechanism of the benzyne aza-Claisen
rearrangement (Table 2, entry 3). Whilst the Claisen product
was isolated in good yield, the position of both allyl and amine
groups was incommensurate with the position of the aryne
triple bond. The regioselectivity of amine addition is exclu-
sively distal to the methoxy group, as expected,[13] but the
subsequent rearrangement to the 1,2,4,5-tetrasubstituted
arene 11j indicates that the incipient anion is being quenched
prior to aza-Claisen rearrangement (path B in Scheme 1).
viable for a range of simple tertiary allylamines, with the
morpholine, diethyl, and aniline derivatives 10b–d under-
going smooth rearrangement in good to excellent yields
(Table 1, entries 2–4). We examined a substituted allyl sub-
strate with the cyclohexenyl amine 10e, which afforded the
tricyclic aniline 11e in 74% yield (Table 1, entry 5). The crotyl
derivative 10 f likewise underwent successful rearrangement,
albeit in low yield owing to significant deallylation taking
place to produce N-phenylpiperidine (Table 1, entry 5). The
methyl group did, however, act as a marker to prove that the
reaction was taking place as envisioned in path A or B in
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Table 3: Synthesis of medium-ring amines using the benzyne aza-
Claisen rearrangment.[a]
Similar behavior was observed for the methoxyaryne sub-
strate 9e, which produced a mixture of aniline products 11k
and 11k’ in a ratio of 2.3:1 (Table 2, entry 4). The 2,3-pyridyne
precursor 9 f was not viable in the reaction; initial nucleo-
philic addition of the amine was observed but the subsequent
aza-Claisen rearrangement did not take place under the
reaction conditions. Instead, deallylation occurred and a
moderate yield of 2-(piperidin-1-yl)pyridine 11l was isolated
after 48 hours.
To shed further light on the aza-Claisen rearrangement/
SN2’ reaction dichotomy we examined the reaction of 9a and
10a at room temperature. Stirring the reaction for 24 hours in
the presence of CsF and subsequent filtration, concentration,
and chromatography afforded the triflate salt 12a in 71%
yield (Scheme 3). As suspected, the zwitterion 2 is being
Entry
1
Amine
Product
Yield [%][b]
41
13a
13b
13c
14a
14b
14c
2[c]
40
28
3
[a] Reaction conditions: o-trimethylsilylphenyl triflate (1 equiv), amine
(1.5 equiv), and CsF (3 equiv) in toluene (0.75 mL) and MeCN
(0.25 mL). Reactions were carried out on a 0.2 mmol scale and were
stirred for 24 hours at room temperature and then heated at reflux for
48 hours in a sealed tube. [b] Yield of isolated product. [c] 2 equivalents
of o-trimethylsilylphenyl triflate to 1 equivalent of amine was used. Bn=
benzyl.
Scheme 3. Salt formation from benzyne and tertiary allylamine.
DME=1,2-dimethoxyethane.
14c being isolated in 17% yield after RCM with a reaction
time of one week.[15]
Finally, we were interested in reexamining Wittigꢀs
benzyne pyrrole DA system in light of our results on the
aza-Claisen rearrangement. A repeat of Wittigꢀs procedure
using magnesium treatment of o-bromofluorobenzene as the
benzyne source gave a complex product mixture from which
the benzocarbazole product 8 could be isolated by column
chromatography in 22% yield, along with a trace amount of
the a-naphthylamine 17.[16] Repeating the reaction using the
O-triflato silane method for benzyne generation developed by
Kobayashi and co-workers[10] unexpectedly produced the a-
naphthylamine 17 in good yield (Scheme 4). The complete
absence of any benzocarbazole product when using aryne
precursor 9a highlights the important role played by the
reagents used to generate the aryne in the subsequent
evolution of intermediates 15 and 16. The increased basicity
protonated by the acetonitrile component of the reaction
solvent, which was verified by conducting the reaction in
CD3CN and observing deuterium incorporation in the salt
12b. The triflate salt 12a was productive in the aza-Claisen
rearrangement, and produced high yields of aniline 11a when
heated under the established reaction conditions. Salt 12a is
likewise formed in non-acidic solvents such as DME, although
subsequent aza-Claisen rearrangement in ethereal solvents
was found to be less efficient.
We extended the benzyne aza-Claisen reaction to cyclic
tertiary amines of the type 13 (Table 3). This strategy, which
has been demonstrated for stable alkynes such as dimethyl-
acetylene dicarboxylate,[14] affords benzannulated medium-
ring amines in a single step, and would complement published
ring-closing metathesis (RCM) routes to these biologically
active motifs.[15] In the event, the proline derivatives 13a and b
were treated with benzyne precursor 9a to successfully
produce the corresponding nine-membered ring compounds
14a and b in moderate yield (Table 3, entries 1 and 2). It was
possible in the case of 13b to start with the secondary amine
and generate the tertiary amine in situ using two equivalents
of benzyne precursor, which then rearranged to the N-phenyl
benzazonine product 14b in 40% overall yield.
Nicotinic acid precursors to ten-membered rings proved
more recalcitrant substrates, with the N-benzyl substrate 13c
affording a 28% yield of benzazecine 14c as a representative
example (Table 3, entry 3). This inefficiency in the formation
of ten-membered rings has also been observed in the RCM
approach to benzazecines, with the Z-N-benzoyl analogue of
Scheme 4. Diels–Alder benzyne aza-Claisen reaction.
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Communications
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In conclusion, we have discovered a new benzyne aza-
Claisen rearrangement of tertiary allylamines. The aryne
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Experimental Section
Synthesis of 1-(2-allylphenyl)piperidine 11a: 2-(Trimethylsilyl)phenyl
trifluoromethanesulfonate (90 mg, 0.30 mmol, 1 equiv) was then
added to N-allylpiperidine (56 mg, 0.45 mmol, 1.5 equiv), cesium
fluoride (137 mg, 0.9 mmol, 3 equiv), toluene (1.12 mL), and aceto-
nitrile (0.38 mL) were placed in a sealed carousel tube under
nitrogen. The reaction mixture was heated to 1108C for 48 h.
Filtration and concentration in vacuo gave a crude product that was
purified by flash column chromatography on silica gel (hexanes, dry
loaded) to afford 9a (55 mg, 92%) as a colorless oil. 1H NMR
(360 MHz, CDCl3): d = 7.23–7.17 (2H, m), 7.08 (1H, dd, J = 1.3,
7.9 Hz), 7.03 (1H, dt, J = 1.3, 7.4 Hz), 6.01 (1H, tdd, J = 6.6, 10.0,
16.7 Hz), 5.16–5.07 (2H, m), 3.49 (2H, d, J = 6.6 Hz), 2.85–2.82 (4H,
m), 1.75–1.69 (4H, m), 1.61–1.54 ppm (2H, m); 13C NMR (90 MHz,
CDCl3): d = 152.7 (Q), 138.0 (Q), 134.9 (CH), 129.8 (CH), 126.7 (CH),
123.1 (CH), 119.7 (CH), 115.4 (CH2), 54.0 (2C, CH2), 34.8 (CH2), 26.5
~
(CH2), 24.3 ppm (CH2); IR (film): n = 2933, 2853, 2800, 1489, 1450,
1226 cmÀ1; HRMS (EI+) calc for C14H19N ([M]+): 201.15120; found:
201.15100.
Received: March 13, 2009
Revised: May 5, 2009
Published online: June 12, 2009
Keywords: allylamines · arynes · aza-Claisen rearrangement ·
.
medium-ring compounds
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