Synthetic Studies on Psychotrimine: Palladium-Catalysed Arylation of 2-(N -Indolyl) Amides

Article abstract of DOI:10.1055/s-0035-1560519

Through careful choice of conditions, 2-(N-indolyl) amides can be directed to undergo selectively either enolate arylation to give oxindoles or direct arylation to give indolo-fused benzodiazepines. The former chemistry facilitates the synthesis of the he

Full text of DOI:10.1055/s-0035-1560519

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2016, 27, 146–150
letter
146
E. L. Watson et al.
Letter
Synlett
Synthetic Studies on Psychotrimine: Palladium-Catalysed Aryla-
tion of 2-(N-Indolyl) Amides
R3
Emma L. Watsona
Anthony Balla
Me
Steven A. Rawb
Stephen P. Marsden*a
N
Br
R2
N
O
Boc
R2
N
R1
N
O
a Institute of Process Research and Development and School of
Chemistry, University of Leeds, Leeds LS2 9JT, UK
s.p.marsden@leeds.ac.uk
b AstraZeneca, Chemical Development, Charter Way, Silk Road
Business Park, Macclesfield SK10 2NA, UK
N
N
Pd cat.
R1
R3
N
N
Me
H
R3
divergent cyclisations
Bn
Dedicated to Professor Steve Ley FRS on the occasion of his 70th
birthday
N
N
R1
R2
O
Received: 02.10.2015
Accepted after revision: 14.10.2015
Published online: 09.11.2015
MeHN
MeHN
DOI: 10.1055/s-0035-1560519; Art ID: st-2015-d0786-l
N
1
Abstract Through careful choice of conditions, 2-(N-indolyl) amides
can be directed to undergo selectively either enolate arylation to give
oxindoles or direct arylation to give indolo-fused benzodiazepines. The
former chemistry facilitates the synthesis of the hexahydropyrrolindole
core of psychotrimine.
3a
N
1
N
3a
N
Me
H
Me
H
H
N
N
N
N
Me
H
H
N
Key words alkaloids, arylation, cyclisation, polycycles, total synthesis
MeHN
N
N
H
1
2
Me
Psychotrimine (1) is an indole alkaloid first isolated in
2004 from the leaves of the plant Psychotria rostrata (Figure
1).1 Psychotrimine is part of a wider family of cyclotrypt-
amine natural products2 but, along with the tetrameric
product psychotetramine (2),3 is structurally distinct from
the majority of the family by virtue of the N1–C3a linkage
of two tryptamine units. This structural novelty, along with
reported biological activity against Gram-positive bacteria,4
has prompted significant synthetic interest in psychotri-
mine. Takayama achieved the first racemic5 and enantiose-
lective6 total syntheses of psychotrimine, creating the fully
substituted C3a centre in an acyclic context, and then as-
sembling the core hexahydropyrrolindole skeleton by cop-
per-mediated imidation or amidation chemistry, respec-
tively. Baran reported a remarkable gram-scale synthesis of
racemic psychotrimine from commercial 7-bromotrypt-
amine in just five synthetic operations, utilising a direct ox-
idative indole–aniline coupling.7 This was subsequently
adapted to an asymmetric synthesis using a diastereoselec-
tive variant of the coupling starting from a tryptophan de-
rivative, with subsequent reductive removal of the vestigial
carboxylate functionality; the key intermediate was also
used in a total synthesis of psychotetramine.3 Formal asym-
metric syntheses based upon interception of Takayama’s in-
termediates have also been reported.8
H
Figure 1 The cyclotryptamine natural products psychotrimine (1) and
psychotetramine (2)
Our interest in investigating the synthesis of psychotri-
mine was based upon our construction of 3-amino-9 and
3-alkoxyoxindoles9b,10 by palladium-catalysed intramolecu-
lar arylation11 of protected α-amino and α-hydroxy acid
enolates.
Specifically, we envisaged that the hexahydropyrrolin-
dole core 3 of psychotrimine might be accessed by reduc-
tive cyclisation of a 3,3-disubstituted oxindole 4 bearing
both the N-linked tryptamine unit and a suitably function-
alised synthetic equivalent of a 2-aminoethyl side chain
(Scheme 1). The oxindole 4 itself would be accessed using
our enolate arylation methodology from a suitable acyclic
precursor 5. Attachment of the N-linked tryptamine to the
C7 carbon of hexahydropyrrolindole 3 would be achieved
by copper- or palladium-mediated arylation of the indole
nitrogen of a suitably protected tryptamine, as in the previ-
ous syntheses by Takayama5,6 and Baran.3,7 The C7 halide
required for such a coupling would either be carried
through the synthesis, exploiting a selective monoarylation
of a suitable 2,6-dibromoanilide (5, X = Br), or else installed
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 146–150

147
E. L. Watson et al.
Letter
Synlett
by late-stage C7 lithiation directed by a N8 carbamate, a
strategy employed by Takayama5,6 and inspired by earlier
work on C-linked cyclotryptamines by Overman.12 In this
Letter, we describe our investigations into this synthetic
strategy, culminating in the successful preparation of the
fully protected hexahydropyrroloindole core of psychotri-
mine.
amount of the indolo-fused benzodiazepinone 8a, which
arises from direct C2 arylation of the indole by the aryl ha-
lide in competition with the base-mediated enolate aryl-
ation.13,14 The indolo-fused benzodiazepine skeleton is
found in bioactive compounds including hepatitis C virus
inhibitors such as beclabuvir,15 and as a diversion we sought
to identify conditions which would promote selective for-
mation of this motif. Clearly the use of a weaker base would
disfavour or shut down the enolate arylation pathway, and
after some optimisation we found that the use of potassium
acetate along with tetrabutylammonium bromide led to an
87% yield of the desired benzodiazepinone 8a, further ex-
emplified by the successful cyclisation of analogues 8b–d
(Table 1, entries 2–5).16
MeHN
PG
N
Me
N
N
N
N
Me
H
N
H
N
O
N
Me
H
X
R3
PG
3
1
X = Br, H
MeHN
N
Br
R2
PG
R4
N
R4
Br
"N"
O
Me
N
O
N
R1
R2
X
PG
N
N
7a–f
"N"
N
+
R1
N
O
N
PG
N
R3
PG
6a–f
R3
X
Me
5
4
R4
N
Scheme 1 Retrosynthetic analysis for psychotrimine based upon palla-
dium-catalysed enolate arylation of 2-(N-indolyl) amides 5
R2
N
R1
O
We commenced our study with an investigation of the
intramolecular arylation of simple model 2-(N-indolyl)al-
kanamides 6 (Scheme 2). In our initial investigations,9a we
had shown that substrate 6a could be successfully cyclised
to the 3-(N-indolyl)oxindole 7a in 65% yield under our stan-
dard conditions using a catalyst derived from a 1:1 mixture
of palladium(II) acetate and tricyclohexylphosphine (added
as its phosphonium salt) with sodium tert-butoxide as base
in toluene under microwave irradiation (Table 1, entry 1).
The desired oxindole was also accompanied by a small
8a–f
Scheme 2 Competing enolate arylation and direct C–H arylation reac-
tions. Reagents and conditions: A: Pd(OAc)2 (10 mol%), HPCy3·BF4 (10
mol%), NaOt-Bu (3 equiv), toluene, 110 °C, microwave; B: Pd(OAc)2 (10
mol%), Ph3P (10 mol%), TBAB, KOAc, toluene, 120 °C, microwave.
Returning to the approach to psychotrimine, we were
dismayed to find that, in contrast to the successful oxindole
formation from the simple substrate 6a, variation of the N-
protecting group (Table 1, entry 6) or incorporation of a
Table 1 Competing Enolate Arylation and Direct C–H Arylation Reactions
Entry
Substrate
R1
Me
R2
Et
R3
R4
Conditions
Yield of 7 (%)
Yield of 8 (%)
1
2
3
4
5
6
7
8
6a
6a
6b
6c
6d
6e
6f
H
H
A
B
B
B
B
A
A
A
7a 65
7a 0
7b 0
7c 0
8a 3
Me
Me
SEM
SEM
Bn
Et
H
H
F
8a 87
8b 71
8c 43
8d 36
8e 60
8f 57
8g 0
H
H
Et
H
H
H
H
H
H
H
H
7d 0
7e 0
7f 0
Et
H
Me
Me
(CH2)2OTBS
(CH2)2OTBS
H
6g
(CH2)2NMe(Boc)
7g 41
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 146–150

148
E. L. Watson et al.
Letter
Synlett
more highly functionalised alkyl substituent (Table 1, entry
7) under the standard enolate arylation conditions returned
only the indolobenzodiazepinone products of direct C–H
arylation, with no oxindole being formed. Thankfully, how-
ever, the use of tryptamine-derived substrate 6g gave clean
conversion to the desired oxindole with none of the direct
arylation product observed (Table 1, entry 8). It appears
that incorporation of a C3 substituent on the indole disfa-
vours C2 arylation, presumably on steric grounds.
A successful approach to psychotrimine would require
elaboration of the hexahydropyrrolindole structure by re-
ductive cyclisation of a nitrogen nucleophile to the oxin-
dole, and also deprotection of the oxindole-derived nitro-
gen atom. We therefore developed a route to the cyclisation
precursors which would allow for late-stage incorporation
of different N-protecting groups to give maximum synthet-
ic flexibility (Scheme 3). Thus, methanolytic ring opening
of commercial 2-bromobutyrolactone (9) followed by TBS
protection of the liberated hydroxyl group gave bromoester
10, which underwent nucleophilic substitution by Boc-pro-
tected tryptamine under basic conditions to give the 2-N-
indolyl ester 11. Finally, trimethylaluminium-mediated
amidation of the ester with 2-bromoaniline gave the anilide
12, ready for appropriate N-protection.
Attention then turned to the construction of the hexahy-
dropyrrolindole skeleton. After some experimentation, we
found that the most effective method was based on the
two-step reductive cyclisation of azidolactams described by
Porter.18 Thus, azides 15a,b, prepared in three simple steps
from 14a,b, were exposed first to tributylphosphine then
lithium aluminium hydride to give the N-unsubstituted
hexahydropyrrolindoles 16a,b in moderate yield. Reductive
methylation was efficiently achieved using formaldehyde
and sodium triacetoxyborohydride, giving compounds
17a,b as the fully protected core of psychotrimine.
Br
Br
O
O
OTBS
OTBS
N
N
H
i
PG
N
N
Boc
N
Boc
Me
N
13a,b
12
ii
Me
Me
Boc
N
Boc
N
Me
N
N
N3
OTBS
O
O
iii–v
O
O
Br
OTBS
i
MeO
N
N
O
15a,b
14a,b
Br
O
PG
PG
9
10
ii
vi
Br
O
Me
OTBS
Me
N
OTBS
MeO
N
N
H
N
Boc
Boc
N
N
N
iii
vii
N
NH
Boc
N
N
Boc
N
N
Me
H
H
11
Me
12
13–17a: PG = Bn
13–17b: PG = PMB
Me
PG
PG
16a,b
17a,b
Scheme 3 Preparation of tryptamine-derived arylation precursor 12.
Reagents and conditions: i) K2CO3, MeOH, r.t., 35 min then TBSCl, imid-
azole, DMAP, DMF, r.t., 1 h (68% over 2 steps); ii) N-Boc tryptamine,
NaH, MeCN, 0 °C to r.t., 4 h (61%); iii) 2-bromoaniline, AlMe3, toluene,
60 °C, 4 h (77%).
Scheme 4 Reagents and conditions: i) NaH, BnCl or PMBCl, MeCN, 0 °C
to r.t., 4 h (PG = Bn, 84%; PG = PMB, 59%); ii) 5% Pd2(dba)3, 10% SIPr·HCl,
NaOt-Bu, toluene, reflux, 8 h (PG = Bn, 73%; PG = PMB, 58%); iii) TBAF,
THF, r.t., 2 h (PG = Bn, 85%; PG = PMB, 63%); iv) MsCl, pyridine, CH2Cl2,
r.t., 18 h (PG = Bn, 75%; PG = PMB, 98%); v) NaN3, DMSO, 60 °C, 5 h
(PG = Bn, 64%; PG = PMB, 77%); vi) PBu3, THF, r.t., 1 h, then LiAlH4, r.t., 1
h (PG = Bn, 51%; PG = PMB, 49%); vii) H2C=O (38% aq solution),
NaBH(OAc)3, MeOH, 0.5 h (PG = Bn, 99%; PG = PMB, 98%).
We progressed intermediate 12 with both benzyl and
4-methoxybenzyl protection in parallel, to facilitate differ-
ent options for deprotection towards the end-game of the
synthesis. Thus, N-alkylation of anilide 12 with the appro-
priate benzylic halide proceeded without incident to give
cyclisation precursors 13a,b (Scheme 4). Pleasingly, both
substrates cyclised efficiently under conditions we have
previously described for arylation under simple (non-mi-
crowave) heating conditions, using a palladium(0) precata-
lyst and the N-heterocyclic carbene SIPr as the ligand, giv-
ing oxindoles 14a,b in 73% and 58% yields, respectively.9c,17
Further progress towards psychotrimine would require
installation of an additional tryptamine unit linked through
the indolic nitrogen to C7 of the hexahydropyrrolindole,
which we envisaged achieving by metal-mediated C–N cou-
pling. We were attracted by the potential to directly incor-
porate a C7 bromide by the selective enolate arylation of a
2,6-dibromoanilide. To our knowledge, such substrates have
not previously been investigated in enolate arylation reac-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 146–150

149
E. L. Watson et al.
Letter
Synlett
tions, although they have been successfully employed in in-
tramolecular Heck cyclisations.19 We therefore prepared
the model dibromide 18a, but were disappointed to find
that this did not undergo cyclisation under either our mi-
crowave-based [Pd(II) precatalyst] or conventional thermal
[Pd(0) precatalyst] conditions (Scheme 5).
dergo either enolate arylation to oxindoles or direct C–H
functionalization of the indole to give indolo-fused benzo-
diazepines. The former chemistry has facilitated the syn-
thesis of the fully protected hexahydropyrrolindole core of
psychotrimine.
Acknowledgment
R
X
O
We thank the EPSRC and AstraZeneca for a studentship to E.L.W.
conditions A or B
O
N
N
Me
Y
Me
R
Y
References and Notes
19a–d
18a–d
X
18a Br
18b Br
Y
R
(1) Takayama, H.; Mori, I.; Kitajima, M.; Aimi, N.; Lajis, N. H. Org.
Lett. 2004, 6, 2945.
Br N-indolyl
(2) (a) Anthoni, U.; Christophersen, C.; Nielsen, P. H. In Alkaloids:
Chemical and Biological Perspectives; Vol. 13; Pelletier, S. W.,
Ed.; Pergamon Press: Oxford, 1999, 163. (b) Steven, A.;
Overman, L. E. Angew. Chem. Int. Ed. 2007, 46, 5488. (c) Schmidt,
M. A.; Movassaghi, M. Synlett 2008, 313. (d) Ruiz-Sanchis, P.;
Savina, S. A.; Albericio, F.; Alvarez, M. Chem. Eur. J. 2011, 17,
1388.
(3) Foo, K.; Newhouse, T.; Mori, I.; Takayama, H.; Baran, P. S. Angew.
Chem. Int. Ed. 2011, 50, 2716.
(4) Schallenberger, M. A.; Newhouse, T.; Baran, P. S.; Romesberg, F.
E. J. Antibiot. 2010, 63, 685.
Br
Cl
H
H
H
Cl
Br
18c
18d
Me
Br
O
conditions A
51%
O
N
N
Br
Me
Me
Br
20
21
Scheme 5 Behaviour of 2,6-dihalogenated N-methyl anilides under
enolate arylation and Heck conditions. Reagents and conditions: A: 10%
Pd(OAc)2, 10% HPCy3·BF4, NaOt-Bu, toluene, 110 °C, microwave. B: 5%
Pd2(dba)3, 10% SIPr·HCl, NaOt-Bu, toluene, reflux.
(5) Matsuda, Y.; Kitajima, M.; Takayama, H. Org. Lett. 2008, 10, 125.
(6) Takahashi, N.; Ito, Y.; Matsuda, Y.; Kogure, N.; Kitajima, M.;
Takayama, H. Chem. Commun. 2010, 46, 2501.
(7) (a) Newhouse, T.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 10866.
(b) Newhouse, T.; Lewis, C. A.; Eastman, K. J.; Baran, P. S. J. Am.
Chem. Soc. 2010, 132, 7119.
(8) (a) Araki, T.; Ozawa, T.; Yokoe, H.; Kanematsu, M.; Yoshida, M.;
Shishido, K. Org. Lett. 2013, 15, 200. (b) Zhang, H.; Kang, H.;
Hong, L.; Dong, W.; Li, G.; Zheng, X.; Wang, R. Org. Lett. 2014, 16,
2394.
(9) (a) Marsden, S. P.; Watson, E. L.; Raw, S. A. Org. Lett. 2008, 10,
2905. (b) Jia, Y.-X.; Hillgren, J. M.; Watson, E. L.; Marsden, S. P.;
Kundig, E. P. Chem. Commun. 2008, 4040. (c) Watson, E. L.; Raw,
S. A. Tetrahedron Lett. 2009, 50, 3318.
(10) Hillgren, J. M.; Marsden, S. P. J. Org. Chem. 2008, 73, 6459.
(11) (a) Marsden, S. P. Cross-Coupling and Heck-Type Reactions, In
Science of Synthesis; Vol. 2; Wolfe, J. P., Ed.; Thieme: Stuttgart,
2013, 565. (b) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082.
(c) Johansson, C. C. C.; Colacot, T. J. Angew. Chem. Int. Ed. 2010,
49, 676. (d) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36,
234.
(12) Lebsack, A. D.; Link, J. T.; Overman, L. E.; Stearns, B. A. J. Am.
Chem. Soc. 2002, 124, 9008.
(13) (a) Sames, D.; Brown, M. A.; Lane, B. S. J. Am. Chem. Soc. 2005,
127, 8050. (b) Bressy, C.; Alberico, D.; Lautens, M. J. Am. Chem.
Soc. 2005, 127, 13148.
(14) For a related synthesis of medium-ring-fused indoles by direct
oxidative C–H coupling, see: Pintori, D. G.; Greaney, M. F. J. Am.
Chem. Soc. 2011, 133, 1209.
(15) Gentles, R. G.; Ding, M.; Bender, J. A.; Bergstrom, C. P.; Grant-
Young, K.; Hewawasam, P.; Hudyma, T.; Martin, S.; Nickel, A.;
Reguiero-Ren, A.; Tu, Y.; Yang, Z.; Yeung, K.-S.; Zheng, X.; Chao,
S.; Sun, J.-H.; Beno, B. R.; Camac, D. M.; Chang, C.-H.; Gao, M.;
Morin, P. E.; Sheriff, S.; Tredup, J.; Wan, J.; Witmer, M. R.; Xie,
D.; Hanumegowda, U.; Knipe, J.; Mosure, K.; Santone, K. S.;
The reactions gave largely recovered starting material,
suggesting the catalytic reaction had not initiated or had
stalled. The simpler anilide 18b was also examined, but
similarly returned starting material. Concerned that the rel-
atively large bromide substituent might be inducing unfa-
vourable conformations that were preventing reaction, we
examined the corresponding dichloride 18c, again with no
success. Finally, we ruled out electronic influences of the
additional halide by examining the almost isosteric 2-bro-
mo-6-methyl anilide 18d, again recovering starting materi-
als. The successful Heck cyclisation in our hands of cro-
tonamide 20 under the standard reaction conditions in an
unoptimised 51% yield confirmed that the dibrominated
aniline function is capable of entering palladium-catalysed
pathways. The contrast between the Heck and enolate
chemistry is stark; at this stage we tentatively propose that
the Heck pathway is facilitated by a favourable coordination
of the palladium(0) to the electron-deficient alkene prior to
C–Br insertion, a pathway which is not available in the eno-
late arylation manifold. Future work towards psychotri-
mine through intermediates 17a,b will therefore focus on
directed metallation strategies for functionalization of the
C7 position.
In summary, we have examined the behaviour of 2-(N-
indolyl)amides under various palladium-catalysed aryl-
ation conditions. Through judicious choice of catalysts and
reagents, the substrates can be directed to selectively un-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 146–150

150
E. L. Watson et al.
Letter
Synlett
Parker, D. D.; Zhuo, X.; Lemm, J.; Liu, M.; Pelosi, L.; Rigat, K.;
Voss, S.; Wang, Y.; Wang, Y.-K.; Colonno, R. J.; Gao, M.; Roberts,
S. B.; Gao, Q.; Ng, A.; Meanwell, N. A.; Kadow, J. F. J. Med. Chem.
2014, 57, 1855.
This was dry-loaded onto a silica gel column and purified by
chromatography. By this procedure, amide 13a (0.10 g, 0.14
mmol) gave, after chromatography (eluent EtOAc–PE, 1:5), oxin-
dole 14a (66.8 mg, 73%) as a yellow oil; Rf = 0.31 (solvent Et2O–
PE, 1:1). IR (film): νmax = 2928, 1730, 1693, 1612, 1459, 1364,
1171, 1098 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.58–7.24 (9 H,
m, ArH), 7.10 (1 H, d, J = 7.2 Hz, ArH), 7.00 (1 H, t, J = 7.5 Hz,
ArH), 6.91 (1 H, d, J = 7.8 Hz, ArH), 6.77 (1 H, t, J = 7.7 Hz, ArH),
6.29 (1 H, d, J = 8.4 Hz, ArH), 5.04 (1 H, d, J = 15.4 Hz, NCHAHBPh),
4.87 (1 H, d, J = 15.4 Hz, NCHAHBPH), 3.74–3.46 (4 H, m, OCH2,
NCH2), 3.18–2.66 (7 H, m, NCH3, CqCH2, ArCH2), 1.43 [9 H, br s,
OC(CH3)3], 0.82 [9 H, s, SiC(CH3)3], –0.01 (3 H, s, SiCH3), –0.06 (3
H, s, SiCH3). 13C NMR (75 MHz, CDCl3): δ = 174.9 (oxindole C=O),
155.8 (Boc C=O), 142.4 (ArCq), 135.6 (ArCq), 129.8 (ArCH), 129.5
(ArCq), 128.9 (2 × ArCH), 128.7 (ArCq), 128.4 (ArCq), 128.3
(ArCH), 128.0 (ArCH), 127.5 (ArCH), 124.4 (ArCH), 123.4 (ArCH),
121.8 (ArCH), 119.5 (ArCH), 118.9 (ArCH), 113.1 (ArCq), 111.5
(ArCH), 109.7 (ArCH), 79.3 [OC(CH3)3], 64.9 (Cq), 58.2 (OCH2),
49.8 (NCH2), 44.4 (NCH2Ph), 40.1 (CqCH2), 34.4 (NCH3), 28.5
[OC(CH3)3], 25.9 [SiC(CH3)3], 23.8 (ArCH2), 18.2 [SiC(CH3)3], –5.4
[Si(CH3)2]. HRMS: m/z calcd for C39H52N3O4Si [MH+]: 654.3722;
found: 654.3720.
(16) General Procedure for the Synthesis of Indolo-Fused Benzo-
diazepinones 8
To a mixture of Pd(OAc)2 (0.1 equiv), Ph3P (0.1 equiv), TBAB (1
equiv), and KOAc (2 equiv) in a microwave vial was added
toluene (1 mL) and the mixture stirred at r.t. for 30 min. A solu-
tion of the substrate (0.5 mmol) dissolved in toluene (1 mL) was
added, the vial sealed under nitrogen, and the mixture sub-
jected to microwave irradiation [CEM Discover, variable power
mode (max 300 W), constant temperature of 120 °C] for 15 min.
The reaction mixture was cooled and filtered. The filtrate was
diluted with EtOAc and H2O. The layers were separated and the
organic layer dried (MgSO4) and concentrated under reduced
pressure to give the crude product, which was purified by chro-
matography. By this general procedure, compound 6a (200 mg,
0.54 mmol) gave the known product 8a (134 mg, 87% yield),
whose spectral data were identical to those reported in ref. 9a.
(17) General Procedure for the Synthesis of Oxindoles 14
To a mixture of Pd2(dba)3 (0.05 equiv), 1,3-bis-(2,6-diisopropyl-
phenyl)imidazolinium chloride (0.01 equiv), and NaOt-Bu (3.0
equiv) was added toluene (ca. 0.10 M). A solution of the sub-
strate (1.0 equiv) in the minimum volume of toluene was
added, and the mixture was stirred and heated to 80 °C for 8 h.
After cooling to r.t., the reaction mixture was concentrated
under reduced pressure to leave a dark brown powdery residue.
(18) Nandra, G. S.; Porter, M. J.; Elliott, J. M. Synlett 2005, 475.
(19) (a) Seo, J. H.; Artman, G. D.; Weinreb, S. M. J. Org. Chem. 2006,
71, 8891. (b) Inoue, M.; Furuyama, H.; Sakazaki, H.; Hirama, M.
Org. Lett. 2001, 3, 2863. (c) Lin, S.; Danishefsky, S. J. Angew.
Chem. Int. Ed. 2001, 40, 1967.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 146–150