Continuous-flow synthesis of 3,3-disubstituted oxindoles by a palladium-catalyzed α-arylation/alkylation sequence

Article abstract of DOI:10.1002/anie.201102401

Facilitating chemistry: Key to the success of Pd-catalyzed α-arylation of oxindoles in continuous flow involved a biphasic system, a precatalyst, and a packed-bed microreactor. Furthermore, this reaction was integrated into a two-step continuous-flow sequence for rapid, modular, and efficient syntheses of 3,3-disubstituted oxindoles. Copyright

Full text of DOI:10.1002/anie.201102401

Communications
DOI: 10.1002/anie.201102401
Continuous Synthesis
Continuous-Flow Synthesis of 3,3-Disubstituted Oxindoles by a
Palladium-Catalyzed a-Arylation/Alkylation Sequence**
Pengfei Li and Stephen L. Buchwald*
Continuous-flow reactors and their application in chemical
synthesis have been recognized as an effective alternative
strategy to the conventional batch-based regime.[1] In general,
continuous-flow multistep processes involve less manual
intervention, therefore, eliminating the handling of inter-
mediates and offering good reproducibility. Microfluidics
allow more efficient mass- and heat-transfer, which enables
precise control over the reaction parameters. In addition, the
use of microreactors provides easy scale-up, either by
increasing the dimensions of the device or by simply operating
multiple microreactors in parallel (numbering up). However,
many reactions are currently not suited for continuous-flow
microreactors because of the formation of solids during the
reaction that lead to irreversible clogging, inefficient multi-
phase mixing, slow reaction rates, and/or instability of the
preformed reagents or catalyst solutions. As part of our
ongoing work on palladium-catalyzed cross-coupling reac-
tions in continuous-flow systems,[2] we herein disclose a
continuous-flow a-arylation/alkylation sequence, in which
we are able to overcome the problems stated above
(Scheme 1).
for the synthesis of natural products and active pharmaceut-
ical ingredients (APIs).[3] Compounds containing a 3,3-
disubstituted 2-oxindole substructure comprise
a large
family of naturally occurring alkaloids, many of which display
significant biological activity.[4] As such, developing conven-
ient methods for their preparation is of considerable interest.
A
subclass of these, (spiro)pyrrolidine-3,3-oxindoles, is
regarded as a privileged structural unit in drug design.[5]
Some structurally related bioactive alkaloids, for example,
pyrroloindolines,[6] are also readily derived from 3,3-disub-
stituted oxindoles. Consequently, as a starting point for our
work on a-arylation methodology under flow conditions, we
selected 2-oxindoles 3 as the first substrate class for our
investigations.
Palladium-catalyzed a-arylation of 2-oxindoles was first
disclosed by Hartwig and Lee, and additional methods have
been reported by our group and by Willis and Durbin.[7] Our
experience (as well as Willisꢀ work) indicated that XPhos (1 in
Scheme 1) was an excellent supporting ligand. However, all of
the previous conditions reported for this process required the
use of high catalyst loadings and/or long reaction times. In
addition, these conditions inevitably proceeded as heteroge-
neous mixtures, due to either the use of sparingly soluble
inorganic bases or the salts that were produced and precipi-
tated from the reaction solution. Notably, no examples with
heteroaryl halides as coupling partners have been reported.
Based on this background information, we felt that modifi-
cations of the reaction conditions would be necessary to
develop an efficient system for this transformation in flow.
Using N-methyl-2-oxindole (3a, Table 1) as the substrate,
we initially compared a variety of conditions in a batch
process. Selected results are shown in Table 1. At 608C, and
with 1.0 mol% [Pd(dba)2] (dba = dibenzylideneacetone) and
1.5 mol% XPhos (1), very low conversion was observed with
either KHMDS (Table 1, entry 1) or LiHMDS (Table 1,
entry 2) as the base (3 min reaction time). In the case of
KHMDS, some insoluble material was generated during the
reaction. To solubilize both the organic and inorganic
materials, a biphasic system (Table 1, entry 3) was also
investigated, unfortunately with little success.[2b] At this
point, we hypothesized that a 3 min reaction time might be
inadequate for complete formation of the catalytically active
Pd0–phosphine complex. Led by our recent successes in the
Scheme 1. a-arylation of N-alkyl-2-oxindoles.
The palladium-catalyzed a-arylation reaction, during
À
which a new C C bond between the a-position of a carbonyl
and an aryl or vinyl group is formed, is an important reaction
[*] Dr. P. Li, Prof. S. L. Buchwald
Department of Chemistry, Massachusetts Institute of Technology
77 Massachusetts Ave., Cambridge, MA 02139 (USA)
Fax: (+1)617-253-3297
development and application of single-component precata-
[8]
À
À
lysts for C C and C N cross couplings, we tested pallada-
cycle 2 as a precatalyst in the a-arylation reaction, since it has
been shown to be rapidly converted to the monoligated Pd0–
XPhos complex by deprotonation and reductive elimination.
This precatalyst was prepared from commercially available
chemicals by an operationally simple one-pot process in high
E-mail: sbuchwal@mit.edu
[**] We thank Novartis International AG for funding. The 300 MHz NMR
instrument used was supported by the National Science Foundation
(Grants CHE-9808061 and DBI-9729592)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102401.
6396
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 6396 –6400

Table 1: Batch optimization of a-arylation of oxindole.[a]
denoted as solution A. Precatalyst 2 was dissolved in THF or
toluene, indicated as solution B. Due to the rapid activation of
precatalyst 2 in the presence of a base, we added 0.2 mol% of
acetic acid to prevent any base-induced decomposition.
Solution C contained aqueous KOH (with TBAB added
when toluene was used as the solvent). The three streams
passed through three check valves and were mixed in a cross.
The resulting biphasic mixture was further flowed through a
heated stainless steel packed-bed for the indicated time. After
the reactor, a back-pressure regulator (BPR) was placed to
prevent any boiling of solvent. After passing the BPR, the
reaction mixture was quenched with degassed saturated
aqueous NH4Cl and ethyl acetate, and collected in a sampler.
After variations of reaction time, temperature, amount of
KOH, and concentration, the optimal conditions for the
reaction between 3a and 4a were found as shown in Table 2.
Entry
Pd Source
Base
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
[Pd(dba)2]
[Pd(dba)2]
[Pd(dba)2]
2
KHMDS
LiHMDS
2.0m KOH
LiHMDS
2.0m KOH
2.0m KOH
2.0m KOH
2.0m KOH
2.0m KOH
2.0m KOH
THF/Tol
THF/Tol
THF/H2O
THF/Tol
THF/H2O
THF/H2O
Tol/H2O
Tol/H2O
THF/H2O
Tol/H2O
<5
12
<5
5
42
30
<5
43
88
91
2
2[c]
2
2[d]
2
2[d]
[a] Reaction conditions: A mixture of 3a (0.5 mmol), 4a (0.55 mmol),
dodecane (50 mL), catalyst (Pd 1 mol%, XPhos 1–1.5 mol%), and base
in the indicated solvent (0.5 mL THF or Tol when 1.0 mL of aq. 2.0m
KOH was used as the base, and 0.25 mL THF when 1.1 mL of 0.5m
KHMDS in Tol or 0.55 mL of 1.0m LiHMDS in Tol as the base) was
stirred at 608C for 3 min. [b] determined by GC with dodecane as internal
standard. [c] with 0.5 mol% XPhos added. [d] 5.0 mol% of tetrabuty-
lammonium bromide (TBAB) was added as phase-transfer catalyst
(PTC). [e] The reactions were run at 1008C for 3 min.
Table 2: Optimized flow conditions for a-arylation of 3a.[a]
Solvent
t [s]
Flow rate [mLminÀ1
]
Yield [%][b]
A
B
C
THF
Tol
120
80
64
89
16
22
160
224
>95
>95
[a] Reaction conditions: The volume of the packed bed was 448 mL;
Solution A: 3a (1.25m), 4a (1.28m), dodecane (0.35m) in THF or Tol;
Solution B: 2 (0.05m) and AcOH (0.01m) in THF or Tol; Solution C:
KOH (2.0m) (and 0.025m of TBAB for Tol reaction) in water.
[b] Determined by GC with dodecane as the internal standard.
yield.[8b] Using 2 as the palladium source, a variety of different
reaction conditions were compared. While the use of 2 did not
offer any improvement when LiHMDS was used as the base
(Table 1, entry 4), we observed promising results with a
biphasic, THF/aqueous KOH system (Table 1, entry 5).
Interestingly, the addition of 0.5 mol% XPhos provided no
improvement (Table 1, entry 6). We next examined a toluene/
aqueous KOH biphasic system, for which the addition of a
phase-transfer catalyst (PTC) was required to observe
significant conversion to product (Table 1, entry 7 and 8).
Among several tested PTCs, tetrabutylammonium bromide
(TBAB) was found to be superior in terms of conversion and
commercial cost. When the reactions were run at elevated
temperature (1008C) for 3 min, both THF/aqueous KOH and
toluene/aqueous KOH systems gave full conversion and
similar yields (Table 1, entry 9 and 10). To our knowledge,
these results are the first example of significantly increased
reaction rates for a-arylation in a biphasic system.[9,10] Thus,
by using palladacycle 2 as the precatalyst, and water as a
cosolvent to dissolve all inorganic salts, two efficient systems
were identified for further study under continuous-flow
conditions.
As this reaction proceeded best at 1008C, a toluene/H2O
mixture was more suitable due to the lower pressure and
slightly higher reaction rates observed in flow than that for
THF/H2O. Accordingly, in the remainder of this study, a
toluene/H2O system was employed.
Next we wanted to integrate these arylation conditions
into an a-arylation/alkylation sequence for a modular and
continuous synthesis of 3,3-disubstituted oxindoles
(Scheme 1, 3 to 6). Multistep continuous-flow reactions are
challenging due to increased complexity as compared to a
single-step flow reaction; flow rate (i.e., reaction time)
synergy, solvent compatibility, and the effect of byproducts
and impurities must be considered and optimized. Only a few
multistep continuous flow syntheses have been described.[11,1g]
Nonetheless, we felt that 3-alkyl-3-aryl-2-oxindoles could be
produced in a continuous-flow fashion by taking advantage of
the biphasic system and eliminating any intermediate workup
and purification. To examine the feasibility of this trans-
formation, we first tested the benzylation of isolated 5a under
biphasic conditions (Table 3, 5a to 6a). In batch, using TBAB
in a toluene/1.5m KOH mixture, this benzylation was
complete in less than 5 min at 1008C. Preliminary study
under flow conditions of this alkylation step indicated that
mixing efficiency was critical, as use of an open tubing reactor
led to generally lower and variable yields depending on the
flow rate employed. When a packed-bed reactor was
employed we found that the reaction was complete in 40 s.
Based on the studies described above, we constructed a
flow set-up for the continuous a-arylation/alkylation
Recently, our group has reported that a packed-bed
À
microreactor was successful in promoting biphasic C N cross-
coupling in flow because of its dramatically enhanced mixing
capacity in comparison to that observed with open tubing.[2b]
In the current a-arylation case, we observed that a packed-
bed microreactor was also required for effective mixing. Thus,
we applied our biphasic conditions in continuous-flow using a
set-up including a stainless steel packed-bed reactor (see the
Supporting Information). All liquid streams were introduced
by syringe pumps. Substrate 3a, halide 4a, and internal
standard (dodecane) were dissolved in THF or toluene,
Angew. Chem. Int. Ed. 2011, 50, 6396 –6400
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 6397

Communications
Table 3: Continuous synthesis of 3,3-disubstituted oxindoles.[a]
sequence as shown in Figure 1. The selection of the sizes of
the two packed-bed reactors depended on the approximate
reaction rates of the two reactions observed in preliminary
3-Aryloxindole 5
3,3-Disubstitutedoxindole 6[b]
(without isolation of 5)
5a, 94%, X=Cl, (1% 2),
1008C, 90 s
6a R=Bn, 93%, X=Br,
1008C, 43 s;
6a’ R=CH2CONHBn, 86%,
X=Cl, 1008C, 3 min
5b, 87%, X=Br, (1% 2),
1008C, 120 s
6b, 86%, X=Br,
1008C, 58 s
Figure 1. Flow set-up for the a-arylation/alkylation sequence.
experiments. For example, as a-arylation of 3a required
approximately 80 s and the following benzylation required
approximately 40 s, a 180 mL/90 mL combination was used for
the two-step flow. A switch valve was placed in between the
two reactors so that one can collect either the product of the
first step or of the two-step process in one experimental setup
simply by switching the valve. The three feeds A, B, and C
were identical to those described for the arylation process
with the exception that biphenyl was used instead of
dodecane as the internal standard. Benzyl bromide was
added neat as feed RX (Figure 1). With a 180 mL/90 mL set-up,
a continuous a-arylation/benzylation of 3a could be achieved
in excellent yield (isolated 93%) with a retention time of 90 s/
43 s.
5c, 86%, X=Cl, (1% 2),
1008C, 2.5 min
6c, 84%, X=Br,
1008C, 1.2 min
5d, 82%, X=Cl, (2% 2),
1108C, 10 min
6d, 74%, X=Br,
1008C, 5 min
5e, 94%, X=Br, (1% 2),
1008C, 60 s
6e, 94%, X=Br,
1008C, 120 s
With optimized conditions realized, we explored the
scope and limitations of this two-step flow system using
various oxindoles, aryl halides, and alkylating reagents. Thus,
using the set-up in Figure 1, in a single flow experiment, we
could prepare either the a-arylation product 5, or the a-
arylation/alkylation product 6 (in all cases 6 was made
without the isolation of 5). Depending on the solubility of
the materials, the concentrations of N-alkyl oxindoles in
toluene were either 1.0m or 0.6m. The results are shown in
Table 3. Generally, for the a-arylation reaction, both aryl
chlorides and bromides were excellent coupling partners.
With only 1 mol% of palladacycle 2 as the precatalyst, several
halides could be coupled with N-alkyl oxindoles at 1008C in
excellent yields in less than 4 min. Included among these were
substrates bearing an ester group (5b) and a free hydroxyl
group (5 f). Five-membered heterocycles, including a benzox-
azole (5c) and a protected indole (5e), were also good
coupling partners. Notably, MOM-protected oxindole 3b was
successfully coupled in only 60 s (94% isolated yield).
Unfortunately, heteroaryl halides, including 3-chloropyridine
5 f, 88%, X=Cl, (1% 2),
1008C, 4 min
6 f, 79%, X=OCO2Me,
1008C, 2 min
5g, 69%, X=Cl, (4% 2),
1208C, 23 min
6g, 62%, RX=BrCH2CH2Br,
808C, 23 min
[a] Reaction conditions: Using the set-up in Figure 1, all yields are based
on isolated products and calculated based on the collecting time and the
flow rates corresponding to 1.0 mmol theoretical products. [b] Yields
over two steps. MOM: methoxymethyl.
6398 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 6396 –6400

Received: April 6, 2011
Published online: June 7, 2011
and 2-chloro-6-methoxypyridine, were poor substrates and
provided lower yields under these conditions (1% Pd, 1008C,
10–20 min), making these unsuitable due to the resulting low
productivity. However, with flow systems, one can use “non-
standard” conditions, for example, temperatures higher than
the solventsꢀ boiling points, without the safety issues faced
with batch reactions. Accordingly, a 20 psi back-pressure
regulator (BPR) was placed at the end of the reactors and the
synthesis of 5d could be achieved with 2% Pd at 1108C in
10 min. Similarly, the reaction of 2-chloro-6-methoxypyridine
required 4% Pd, 1208C, and 23 min to obtain full conversion,
affording 5g in 69% isolated yield.
For the continuous a-arylation/alkylation sequence, the
alkylating reagents were introduced with an additional
syringe pump with the exception of that for synthesis of 6a’,
for which a 1.0m solution of N-benzyl-2-chloroacetamide in
1,4-dioxane was used. These flow syntheses generally pro-
duced the 3,3-disubstituted oxindoles in high yields (62–94%)
over the two steps. Allyl methyl carbonate could also be used
for a selective C- over O-allylic alkylation in the case of 6 f.
As we hoped to prepare more structurally diverse
oxindoles related to naturally occurring alkaloids, we
designed an a-arylation/C,N-double alkylation route for the
synthesis of spirocyclic oxindoles. Thus, 3-(6-methoxypyridin-
2-yl)oxindole 5g was treated at 808C with 1,2-dibromoethane
under flow conditions to yield spirocyclic pyridone 6g in a
moderate yield (62%) over two steps; the second step
included two bond-forming and one bond-breaking processes.
This strategy represents a very concise approach to this kind
of tetracyclic 3,3-spirooxindole core[4] present in natural
products such as strychnofoline.[12]
Keywords: biphasic catalysis · continuous flow ·
.
multistep reactions · oxindole · a-arylation
[1] a) Microreactors: New Technology for Modern Chemistry (Eds.:
W. Ehrfeld, V. Hessel, H. Lꢁwe), Wiley-VCH, Weinheim, 2000;
b) Microreactors in Organic Synthesis and Catalysis (Eds.: T.
Wirth), Wiley-VCH, Weinheim, 2008; c) Flash chemistry: fast
organic synthesis in microsystems (Eds.: J. Yoshida), Wiley,
Chichester, 2008; d) A. Cukalovic, J. C. M. R. Monbaliu, C.
Stevens, Top. Heterocycl. Chem. 2010, 23, 161 – 198; e) J.
Fortunak, P. N. Confalone, J. A. Grosso, Curr. Opin. Drug
Discovery Dev. 2010, 13, 642 – 644; f) A. Kirschning, Beilstein J.
Org. Chem. 2009, 5(15); g) D. Webb, T. F. Jamison, Chem. Sci.
2010, 1, 675 – 680; h) R. L. Hartman, K. F. Jensen, Lab Chip
2009, 9, 2495 – 2507; i) K. Geyer, T. Gustafsson, P. H. Seeberger,
Synlett 2009, 2382 – 2391.
[2] a) T. Noꢂl, J. R. Naber, R. L. Hartman, J. R. McMullen, K. F.
Jensen, S. L. Buchwald, Chem. Sci. 2011, 2, 287 – 290; b) J. R.
Naber, S. L. Buchwald, Angew. Chem. 2010, 122, 9659 – 9664;
Angew. Chem. Int. Ed. 2010, 49, 9469 – 9474; c) R. L. Hartman,
J. R. Naber, N. Zaborenko, S. L. Buchwald, K. F. Jensen, Org.
Process Res. Dev. 2010, 14, 1347 – 1357; d) J. P. McMullen, M. T.
Stone, S. L. Buchwald, K. F. Jensen, Angew. Chem. 2010, 122,
7230 – 7234; Angew. Chem. Int. Ed. 2010, 49, 7076 – 7080;
e) R. L. Hartman, J. R. Naber, S. L. Buchwald, K. F. Jensen,
Angew. Chem. 2010, 122, 911 – 915; Angew. Chem. Int. Ed. 2010,
49, 899 – 903; f) E. R. Murphy, J. R. Martinelli, N. Zaborenko,
S. L. Buchwald, K. F. Jensen, Angew. Chem. 2007, 119, 1764 –
1767; Angew. Chem. Int. Ed. 2007, 46, 1734 – 1737.
[3] For recent reviews of a-arylation, see: a) F. Bellina, R. Rossi,
Chem. Rev. 2010, 110, 1082 – 1146; b) C. C. C. Johansson, T. J.
Colacot, Angew. Chem. 2010, 122, 686 – 718; Angew. Chem. Int.
Ed. 2010, 49, 676 – 707.
[4] For recent reviews, see: a) F. Zhou, Y. L. Liu, J. Zhou, Adv.
Synth. Catal. 2010, 352, 1381 – 1407; b) B. Trost, M. K. Brennan,
Synthesis 2009, 3003 – 3025; c) C. Marti, E. M. Carreira, Eur. J.
Org. Chem. 2003, 2209 – 2219.
The products of this two-step continuous flow synthesis
may serve as useful synthetic intermediates towards biolog-
ically interesting molecules. To demonstrate this, compound
6a’ was transformed to a pyrroloindoline compound 8 by two
high-yielding consecutive reductions (Scheme 2).[13]
[5] C. V. Galliford, K. A. Scheidt, Angew. Chem. 2007, 119, 8902 –
8912; Angew. Chem. Int. Ed. 2007, 46, 8748 – 8758.
[6] U. Anthoni, C. Christophersen, P. H. Nielsen in Alkaloids:
Chemical & Biological Perspectives, Vol. 13 (Eds.: S. W. Pellet-
ier), Pergamon, Oxford, 1999, pp. 163 – 236.
[7] a) S. Lee, J. F. Hartwig, J. Org. Chem. 2001, 66, 3402 – 3415;
b) R. A. Altman, A. M. Hyde, X. Huang, S. L. Buchwald, J. Am.
Chem. Soc. 2008, 130, 9613 – 9620; c) M. J. Durbin, M. C. Willis,
Org. Lett. 2008, 10, 1413 – 1415; d) A. M. Taylor, R. A. Altman,
S. L. Buchwald, J. Am. Chem. Soc. 2009, 131, 9900 – 9901.
[8] a) M. R. Biscoe, B. P. Fors, S. L. Buchwald, J. Am. Chem. Soc.
2008, 130, 6686 – 6687; b) T. Kinzel, Y. Zhang, S. L. Buchwald, J.
Am. Chem. Soc. 2010, 132, 14073 – 14075.
Scheme 2. Synthesis of a pyrroloindoline from 6a’.
[9] For a single example of water as a cosolvent for a-arylation but
with decreased reaction rate see: M. Carril, R. SanMartin, F.
Churruca, I. Tellitu, E. Domꢃnguez, Org. Lett. 2005, 7, 4787 –
4789.
[10] For using small amount of water for Pd activation see: R. Martꢃn,
S. L. Buchwald, Org. Lett. 2008, 10, 4546 – 4564.
[11] a) A. Sniady, M. W. Bedore, T. F. Jamison, Angew. Chem. 2011,
123, 2203 – 2206; Angew. Chem. Int. Ed. 2011, 50, 2155 – 2158;
b) L. Malet-Sanz, J. Madrzak, S. V. Ley, I. R. Baxendale, Org.
Biomol. Chem. 2010, 8, 5324 – 5332; c) M. D. Hopkin, I. R.
Baxendale, S. V. Ley, Chem. Commun. 2010, 46, 2450 – 2452;
d) I. R. Baxendale, S. V. Ley, A. C. Mansfield, C. D. Smith,
Angew. Chem. 2009, 121, 4077 – 4081; Angew. Chem. Int. Ed.
In conclusion, a method for the palladium-catalyzed a-
arylation of oxindoles in a continuous-flow manner has been
successfully developed. Key to the success included the
implementation of a biphasic system with KOH as the base,
palladacycle 2 as the rapidly activated precatalyst, and a
packed bed as the microreactor that enables efficient mixing.
Furthermore, this reaction was integrated into a two-step
continuous-flow sequence for rapid, modular, and efficient
syntheses of 3,3-disubstituted oxindoles, providing access to
pharmaceutically interesting heterocyclic structures.
Angew. Chem. Int. Ed. 2011, 50, 6396 –6400
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 6399

Communications
2009, 48, 4017 – 4021; e) T. P. Petersen, A. Ritzen, T. Ulven, Org.
n) I. R. Baxendale, J. Deeley, C. M. Griffiths-Jones, S. V. Ley,
S. Saaby, G. K. Tranmer, Chem. Commun. 2006, 2566 – 2568;
o) I. R. Baxendale, C. M. Griffiths-Jones, S. V. Ley, G. K.
Tranmer, Synlett 2006, 427 – 430; p) S. France, D. Bernstein, A.
Weatherwax, T. Lectka, Org. Lett. 2005, 7, 3009 – 3012; q) P.
Watts, C. Wiles, S. J. Haswell, E. Pombo-Villar, Tetrahedron
2002, 58, 5427 – 5439; r) A. M. Hafez, A. E. Taggi, T. Dudding, T.
Lectka, J. Am. Chem. Soc. 2001, 123, 10853 – 10859.
Lett. 2009, 11, 5134 – 5137; f) M. Baumann, I. R. Baxendale, S. V.
Ley, N. Nikbin, C. D. Smith, Org. Biomol. Chem. 2008, 6, 1587 –
1593; g) M. Baumann, I. R. Baxendale, S. V. Ley, N. Nikbin,
C. D. Smith, J. Tierney, Org. Biomol. Chem. 2008, 6, 1577 – 1586;
h) D. Grant, R. Dahl, N. D. Cosford, J. Org. Chem. 2008, 73,
7219 – 7223; i) I. R. Baxendale, S. V. Ley, C. D. Smith, L.
Tamborini, A. F. Voica, J. Comb. Chem. 2008, 10, 851 – 857;
j) T. Gustafsson, F. Ponten, P. H. Seeberger, Chem. Commun.
2008, 1100 – 1102; k) C. M. Griffiths-Jones, M. D. Hopkin, D.
Jonsson, S. V. Ley, D. J. Tapolczay, E. Vickerstaffe, M. Ladlow, J.
Comb. Chem. 2007, 9, 422 – 430; l) H. R. Sahoo, J. G. Kralj, K. F.
Jensen, Angew. Chem. 2007, 119, 5806 – 5810; Angew. Chem. Int.
Ed. 2007, 46, 5704 – 5708; m) I. R. Baxendale, S. V. Ley, C. D.
Smith, G. K. Tranmer, Chem. Commun. 2006, 4835 – 4837;
[12] a) O. Dideberg, J. Lamotte-Brasseur, L. Dupont, H. Campsteyn,
M. Vermeire, L. Angenot, Acta Crystallogr. Sect. B 1977, 33,
1796 – 1801; b) A. Lerchner, E. M. Carreira, Chem. Eur. J. 2006,
12, 8208 – 8219.
[13] T. Kawasaki, M. Shinada, M. Ohzono, A. Ogawa, R. Terashima,
M. Sakamoto, J. Org. Chem. 2008, 73, 5959 – 5964.
6400 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 6396 –6400