Asymmetric Synthesis of 2,3-Dihydrobenzofurans by a [4+1] Annulation Between Ammonium Ylides and In Situ Generated o-Quinone Methides

Article abstract of DOI:10.1002/chem.201700171

A highly enantio- and diastereoselective [4+1] annulation between in situ generated ammonium ylides and o-quinone methides for the synthesis of a variety of 2,3-dihydrobenzofurans has been developed. The key factors controlling the reactivity and stereoselectivity were systematically investigated by experimental and computational means and the energy profiles obtained provide a deeper insight into the mechanistic details of this reaction.

Full text of DOI:10.1002/chem.201700171

A Journal of
Accepted Article
Title: Asymmetric synthesis of 2,3-dihydrobenzofurans via a (4+1)
annulation between ammonium ylides and in situ generated
ortho-quinone methides
Authors: Mario Waser, Lukas Roiser, Nicole Meisinger, Uwe
Monkowius, Markus Himmelsbach, and Raphael Robiette
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To be cited as: Chem. Eur. J. 10.1002/chem.201700171
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Asymmetric synthesis of 2,3-dihydrobenzofurans via a (4+1)
annulation between ammonium ylides and in situ generated
ortho-quinone methides
Nicole Meisinger,#[a] Lukas Roiser,#[a] Uwe Monkowius,[b] Markus Himmelsbach,[c] Raphaël Robiette,*[d]
and Mario Waser*[a]
Abstract: A highly enantio- and diastereoselective (4+1)-annulation
between in situ generated ammonium ylides and ortho-quinone
methides for the synthesis of a variety of 2,3-dihydrobenzofurans was
developed. The key factors controlling the reactivity and the
stereoselectivity were systematically investigated by experimental
and computational means and the hereby obtained energy profiles
provide a deeper insight into the mechanistic details of this reaction.
annulations[11] by reacting them with different vinylogous acceptor
molecules.[4-6,12,13]
One particularly powerful methodology for the generation of
carbocyclic and heterocyclic targets in (4+n) annulation
approaches relies on the use of in situ generated ortho-quinone
methides or analogous aza-ortho-quinone methides.[14,15]
Recently, the first example of the use of in situ generated o-
quinone methides 3 (precursor 1) for (4+1) annulation reactions
with in situ generated carbonyl-stabilized sulfur ylides 4 (obtained
from sulfonium salts 2) to access 2,3-dihydrobenzofurans 5 have
been reported by Zhou et al. (Scheme 1).[5a] High yields and
excellent diastereoselectivities were obtained for different
carbonyl-stabilized sulfur ylides. However, the use of a known
camphor-derived chiral sulfonium ylide resulted in moderate
enantiocontrol only (e.r. = 69:31). In addition, Yang and Xiao very
recently reported the moderately enantioselective reaction of
achiral sulfur ylides with in situ generated ortho-quinone methides
in the presence of chiral urea catalysts.[5d]
Introduction
The 2,3-dihydrobenzofuran skeleton represents an important
motif in a variety of natural products and biologically active
molecules.[1] Accordingly the development of new methods for the
synthesis of these important target molecules has attracted
considerable recent interest and several complementary
strategies have been introduced to access them in either a
racemic or even in a stereoselective fashion.[2-6]
A
highly valuable approach to access chiral carbo- or
heterocycles is the use of onium ylides for (n+1) annulation
reactions.[7] These versatile reagents have found widespread
applications for (2+1) annulations to access (chiral) epoxides,
aziridines, and cyclopropanes.[7-10] More recently, these
compounds were also successfully employed for (4+1)
[a]
Nicole Meisinger, DI L. Roiser, Prof. M. Waser
Johannes Kepler University Linz
Institute of Organic Chemistry
Altenbergerstraße 69, 4040 Linz, Austria
E-mail: mario.waser@jku.at
[b]
[c]
[d]
Prof. U. Monkowius
Johannes Kepler University Linz
Institute of Inorganic Chemistry
Altenbergerstraße 69, 4040 Linz, Austria
Prof. M. Himmelsbach
Johannes Kepler University Linz
Institute of Analytical Chemistry
Altenbergerstraße 69, 4040 Linz, Austria
Prof. R. Robiette
Scheme 1. Zhou’s recently developed sulfur ylide 4 addition to ortho-quinone
methides 3 and targeted use of (chiral) ammonium salts 6 to control the absolute
and the relative configuration of 2,3-dihydrobenzofurans 5.
Université catholique de Louvain
Institute of Condensed Matter and Nanosciences
Place Louis Pasteur 1 box L4.01.02, 1348 Louvain-la-Neuve,
Belgium
E-mail: raphael.robiette@uclouvain.be
These authors contributed equally (in alphabetic order)
Based on our recent research focus on ammonium ylide-
mediated asymmetric annulation reactions[10] and (4+1)
annulations using ylides,[12d] we now became interested in testing
the potential of in situ generated achiral and chiral ammonium
ylides (by starting from ammonium salts 6) to access 2,3-
dihydrobenzofurans with control of both the relative and the
absolute configuration. Besides the development of the first
#
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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8
6c
6c
6c
6c
B2
B3
C
20
20
20
72
52
43
63
85
> 95:5
> 95:5
90:10
> 95:5
16:84
34:66
30:70
99:1
(highly) asymmetric ammonium ylide-based protocol which will
overcome the so far observed less satisfactory enantioselectivity
when using sulfur ylides, we also became interested in
investigating this reaction in more detail by computational means
to reveal the key-factors for this ylide-mediated (4+1) annulation
reaction.[16]
9
10
11
A2
[a] Typical conditions: 1a (0.1 mmol), 6 (0.12 mmol), Cs2CO3 (0.25 mmol) in
CH2Cl2 at r.t.; [b] Isolated yield; [c] Determined by 1H NMR of the crude product;
[d] Determined by HPLC using a chiral stationary phase and given as ratio
(2R,3R):(2S,3S); X-ray analysis of the chlorine-containing product 5f (see
Scheme 2) confirmed a (2R,3R)-configuration for this derivative and 5c was
assigned in analogy; [e] Full consumption and formation of unidentified side-
products of 1 and 6b; [f] Incomplete conversion of 6.
Results and Discussion
Development of an Enantioselective Reaction Protocol.
First attempts were made using the achiral trimethyl ammonium
salts 6a-6c to investigate the influence of the nature of the
carbonyl group on the reaction with o-quinone methide precursor
1a (Table 1). Trimethylamine was chosen as the amine group
because of its superior leaving group ability as compared to other
achiral tertiary amines.[16] In an initial screening of a variety of
different solvent/base combinations we found that the use of 2.5
eq. of Cs2CO3 in CH2Cl2 at room temperature is the most
satisfying system when using the achiral trimethylamine
containing ammonium salts 6a-6c. Under these conditions, the
ester-containing ammonium salt 6a gave the corresponding
dihydrobenzofuran 5a with high trans-selectivity, but in only
moderate yield (39%, no significant improvement by varying the
conditions or stoichiometry could be achieved). Interestingly, the
less stabilized amide-based ammonium ylide derived from 6b did
not give any product at all (just formation of unidentified side
products), while the acetophenone-based salt 6c could be used
to access 5c in an excellent 95% yield and with almost complete
trans diastereoselectivity under the optimized reaction conditions
(entries 1-3).
Having identified conditions that allowed for the high yielding and
highly diastereoselective synthesis of racemic dihydrobenzofuran
5c, we next focused on the identification of a suitable chiral amine
leaving group to develop an enantioselective protocol of this
reaction. Cinchona alkaloids are usually the chiral pool-based
tertiary amines of choice for chiral ammonium enolate-based
reactions and have proven their potential for ammonium ylide-
mediated cyclopropanations[9a,9b] or (4+1) annulations to a,b-
unsaturated imines in the past.[13b] However, these amines were
found not to be suited for ammonium ylide-mediated asymmetric
epoxidation reactions and it was only recently that we succeeded
in developing a proline-based chiral amine (structure C, Table 1)
to achieve that goal.[10f] We were thus very pleased to see that
literally the first attempt with amine A1 already gave 5c in high
enantiopurity (entry 4, Table 1). As shown in entry 5, the yield and
enantiopurity could be improved by using quinidine (A2) as the
chiral amine leaving group (e.r. = 99:1, d.r. > 95:5 and 65%
isolated yield) and we also soon realized that Cinchona alkaloids
with
a free 9-OH group (A2 and B1) allow for higher
enantioselectivities than the analogous O-alkyl derivatives (see
entries 4-9). Both enantiomers of trans-5c could readily be
obtained by using either A2 or the pseudoenantiomeric B1 but it
should be pointed out that A2 allowed for slightly higher
enantiomeric ratios than B1. Based on our positive recent
experience with compounds C,[10f] we also tested this class of
auxiliaries herein (entry 10), but it was clearly shown that these
amines are less-suited for this (4+1) annulation than the easily
available Cinchona alkaloids. Interestingly, as the conversion of
amine A2-containing ammonium salt 6c was still not complete
after 20 h reaction time (which is in sharp contrast to the use of
Me3N), longer reaction times of up to 3 days were necessary to
achieve comparable yields for the enantioselective protocol
(compare entries 11 and 3).
Table 1. Screening of different chiral and achiral ammonium salts 6 for the
synthesis of 2,3-dihydrobenzofurans 5.
Unfortunately, attempts to start from a-bromo acetophenone and
carry out an in situ ammonium salt formation and ylide generation
were not successful, neither using a catalytic, nor using a
stoichiometric amount of quinidine. As we observed mainly
decomposition of 1a in these attempts it seems likely that
ammonium salt 6c formation is slow as compared to the
generation of o-quinone methide 3 (which in the absence of a
suitable nucleophilic reaction partner undergoes aforementioned
decomposition reactions). Overall this obstacle makes a catalytic
protocol presently not feasible. However, it should be pointed out
that the amine that is liberated during the reaction can easily be
recovered after work up.
Entrya
6
Amine
t (h)
Yield
(%)b
39
trans:cisc
e.r. (trans)d
1
2
3
4
5
6
7
6a
6b
6c
6c
6c
6c
6c
Me3N
Me3N
Me3N
A1
20
20
20
20
20
20
20
> 95:5
--
--
n.r.e
95
--
> 95:5
> 95:5
> 95:5
> 95:5
> 95:5
--
37f
94:6
99:1
97:3
8:92
A2
65
A3
53
B1
62
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Having identified the optimum conditions and the best-suited
chiral amine leaving group for the first highly asymmetric and high
yielding formal (4+1) annulation procedure of onium ylides to o-
quinone methides, we next explored the application scope of this
strategy. As can be seen in Scheme 2 a variety of differently
substituted acceptors 1 and ammonium salts 6 were very well
tolerated either in a racemic fashion (using Me3N-containing
ammonium salts) or in the asymmetric protocol. In all cases the
trans products were obtained with almost exclusive
diastereoselectivity and satisfying isolated yields. The major
exception in this regard was the asymmetric synthesis of the CF3-
containing product 5h, which was achieved in a low yield of 23%
only, while the racemic protocol proceeded with 88%. We first
reasoned that this may be attributed to a decomposition reaction
between the product and the free Cinchona base that is liberated
during the reaction. However, test reactions proved that product
5h is stable in the presence of A2 and therefore the exact reason
for this striking difference remains unclear.
With respect to the influence of different aryl substituents on the
enantioselectivity two cases caught our attention. While only
subtle decreases were observed in most cases when we
introduced either substituents on the acceptor or on the donor site,
the presence of residues in position 3 of the quinone methide part
resulted in a significantly lower enantioselectivity (see products 5s
and 5t). It has been reported that the introduction of sterically
demanding groups in this position leads to a preferred formation
of the (Z)-quinone methides, while unsubstituted derivatives
mainly form the (E)-isomers.[14] We thus rationalize that this lower
selectivity may be attributed to formation of a less selective (Z)-
quinone methide (or a (E)/(Z) mixture) in these two cases. We
also tested one substrate 1 with a methyl group instead of the Ar1
substituent which performed reasonably well in the racemic
approach giving 5v in 99% but with a slightly lower d.r.. However,
the achieved enantioselectivity for the asymmetric protocol turned
out to be lower in that case. We also carried out a gram-scale
experiment for the asymmetric synthesis of 5i which was thereby
obtained with the same enantiopurity as in the 0.1 mmol scale
experiment (see Scheme 2) and in 67%
yield (compared to 81% on a smaller
scale).
Computational Studies.
In order to identify the mechanism and the
key factors controlling the reactivity and
stereoselectivity in this (4+1) annulation,
we have investigated the free energy
profile of the parent reaction between
trimethylamine containing ylide 6c (R =
Me3N; Ar2
= Ph) and the o-quinone
methide generated form 1a (Ar1 = Ph; Fig.
1). Calculations were carried out at the
B3LYP-D3/6-311+G**//B3LYP-D3/6-31G*
level of theory[18] including a continuum
description
solvent.[19]
of
dichloromethane
as
The mechanistic sequence involves two
key- steps along each of the
diastereoisomeric pathways leading to cis-
and trans-2,3-dihydrobenzofurans 5. The
first is addition of the ammonium ylide onto
the methylene position of the electron-
deficient o-quinone methide to form a
betaine intermediate (see Fig. 1).[20] This
betaine can then undergo ring closure,
with concomitant expulsion of the amine,
to
give
the
corresponding
2,3-
dihydrobenzofuran.[21]
Despite of the sterically hindered character
of the formed betaine, the initial addition
step is slightly exothermic (by 2-6 kcal.mol-1) due to the
rearomatization of the phenolic fragment. Two diastereomeric
betaines can be formed during the addition step (trans-A and cis-
A; Fig. 1). Trans-A is computed to be more stable than cis-A (-6.1
and -1.7 kcal/mol, respectively) but the latter is predicted to be
Scheme 2. Application scope for the asymmetric synthesis of 2,3-
dihydrobenzofurans 5. All reactions were run on 0.1 – 1 mmol scale. Racemic
reactions were run for 1 day and the chiral amine-based ones for 3 days to
ensure full conversion. X-ray analysis of the chlorine-containing product 5f
proved a (2R,3R)-configuration for this derivative[17] and the other products were
assigned by analogy.
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formed through a lower free energy barrier (11.6 kcal.mol-1) than
Another potential explanation involves the epimerization of the
trans-A (13.6 kcal.mol-1).
betaine intermediate
A
by
a
deprotonation/protonation
Since the SN2-type mechanism, and hence the stereospecificity,
of the cyclization step, betaines trans-A and cis-A lead to the
trans- and cis-2,3-dihydrobenzofurans 5, respectively. The free
energy barrier to ring closure is found to be similar for both
diastereomeric betaines (13-14 kcal.mol-1). In the case of trans-A,
the transition state of the ring closure lies lower in free energy than
the addition TS, thus indicating a non-reversible initial addition
step. For the cis pathway, the lower stability of cis-A induces a
partially reversible betaine formation. Indeed, the cis addition TS
and cis elimination TS are very close in terms of free energy (11.6
and 11.7 kcal.mol-1, respectively). These transition states lie
however lower than the trans addition TS, thus predicting a cis
selectivity, which is in disagreement with the observed high trans
selectivity (trans/cis > 95/5).
mechanism such as previously observed by Aggarwal et al. in
sulfur ylide-mediated cyclopropanation reactions.[22] Indeed, the
computed relative free energy of B (0.7 kcal.mol-1) indicates a
facile proton transfer, and hence epimerization, in cis-A (see SI
for full details). The observed high trans-selectivity can thus be
accounted for by selective cis-A formation followed by rapid
epimerization into trans-A, which then undergoes ring closure to
give the trans-2,3-dihydrobenzofurans (Fig. 2). This also
rationalizes why the two less enantioselective examples 5s and
5t were still obtained with very high trans-selectivities, even when
quinone methide-formation proceeds with low diastereoselectivity
only.
We reasoned that this contrast between computational
predictions and experiment could be explained by a faster cis-2,3-
dihydrobenzofuran 5c formation (kinetic selectivity) followed by
epimerization of this latter. In order to test this hypothesis, we
isolated cis-5c and put it back under reaction conditions. A slow
isomerization into the more stable trans-5c isomer was observed
by NMR which led to complete epimerization after 15 h (d.r. >
95/5). Monitoring of the (4+1) annulation reaction over time
revealed however that the >95/5 diastereomeric ratio in favour of
the trans-2,3-dihydrobenzofuran is observed throughout and even
in the first few minutes. Given its slow kinetic, epimerization of cis-
2,3-dihydrobenzofuran can thus not account by itself for the
observed high trans selectivity.
Figure 2. Mechanism and rationale for the observed high trans
selectivity in (4+1)-annulation reactions between ketone-
stabilized ammonium ylides and ortho-quinone methides
(Relative free energies are in kcal.mol-1).
Interestingly, the computed free energy profile (see
Figure 1) allows also a rationalization for the low (or
no) yield in
5 with ester- and amide-based
ammonium ylides derived from 6a and 6b,
respectively (see entries 1-2 in Table 1): Due to a
lower stabilization of the ylide, addition should be
more favoured, and more exothermic, in these
cases as compared to ketone-based ylides. But for
the elimination step, that is the reverse as the free
energy barrier is expected to be increased with
ester and amide derivatives.[23] In addition,
isomerization of betaine by deprotonation/protonation should also
be less favoured herein and the poor yields in these cases can
thus probably be explained by a longer lifetime of betaine
intermediates favouring side reactions.
Figure 1. Computed free energy profiles (kcal.mol-1) for the formation of cis-
and trans 2,3-dihydrobenzofurans 5c from ammonium ylide 6c.
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provided by the supercomputing facilities of the Université
catholique de Louvain (CISM/UCL) and the Consortium des
Équipements de Calcul Intensif en Fédération Wallonie Bruxelles
(CÉCI) funded by the Fond de la Recherche Scientifique de
Belgique (F.R.S.-FNRS) under convention 2.5020.11. The NMR
spectrometers used were acquired in collaboration with the
University of South Bohemia (CZ) with financial support from the
European Union through the EFRE INTERREG IV ETC-AT-CZ
program (project M00146, "RERI-uasb"). RR is a Chercheur
qualifié of the F.R.S.-FNRS.
Conclusions
We herein succeeded in the development of the first highly
asymmetric (4+1) annulation protocol between in situ generated
ammonium ylides and ortho-quinone methides to access chiral
2,3-dihydrobenzofuran derivatives. Key to success was the use of
an easily available Cinchona alkaloid as the chiral leaving group,
which resulted in an operationally simple and highly enantio- and
diastereoselective synthesis strategy. Detailed computational
studies support a mechanistic scenario where the high trans-
selectivity of this procedure originates from a rapid isomerization
of the cis-betaine intermediate to the trans-betaine intermediate,
thus resulting in high diastereoselectivities for a broad application
scope.
Keywords: Ylides • Quinone Methides • Stereoselectivity •
Chiral Auxiliary • DFT Calculations
1
For representative reviews please see: (a) A. Radadiya, A. Shah, Eur. J. Med.
Chem., 2015, 97, 356-376; (b) H. K. Shamsuzzaman, Eur. J. Med. Chem., 2015,
97, 483-504; (c) R. J. Nevagi, S. N. Dighe, S. N. Dighe, Eur. J. Med. Chem. 2015,
97, 561-581;
2
3
For some reviews please see: (a) F. Bertolini, M. Pineschi, Org. Prep. Proced.
Int. 2009, 41, 385-418; (b) T. D. Sheppard, J. Chem. Res. 2011, 35, 377-385.
For some recent examples employing different strategies see: (a) E. D. Coy, L.
Jovanovic, M. Sefkow, Org. Lett., 2010, 12, 1976-1979; (b) F. Baragona, T.
Lomberget, C. Duchamp, N. Henriques, E. L. Piccolo, P. Diana, A. Montalbano,
R. Barret, Tetrahedron, 2011, 67, 8731-8739; (c) A. Lu, K. Hu, Y. Wang, H. song,
Z. Zhou, J. Fang, C. Tang, J. Org. Chem., 2012, 77, 6208-6214; (d) K. X.
Rodriguez, J. D. Vail, B. L. Ashfeld, Org. Lett., 2016, 18, 4514-4517; (e) S.
Sharma, S. K. R. Parumala, R. K. Peddinti, Synlett, 2017, 28, 239-244..
For sulfur ylide-mediated (4+1) approaches with aldimines: (a) P. Xie, L. Wang,
L. Yang, E. Li, J. Ma, Y. Huang, R. Chen, J. Org. Chem., 2011, 76, 7699-7705; (b)
Y. Cheng, Y.-Q. Hu, S. Gao, L.-Q. Lu, J.-R. Chen, W.-J. Xiao, Tetrahedron, 2013,
69, 3810-3816.
Experimental Section
General details can be found in the online supporting information. This
document contains detailed synthesis procedures of starting materials and
products and analytical data of novel compounds and reaction products as
well as copies of NMR spectra and HPLC traces. The supporting
information also includes the details of the computational investigations.
4
5
General asymmetric (4+1) annulation procedure: Compound 1 (1
equiv.), ammonium salt 6 (1.2 equiv.) and Cs2CO3 (2.5 equiv.) are
dissolved in DCM (15 mL per mmol 1). The reaction mixture is stirred at
room temperature for 3 days and afterwards extracted with DCM and brine.
The combined organic phases are dried over Na2SO4, filtered and
evaporated to dryness. The crude products are purified by column
chromatography (silica gel, heptane:EtOAc). Purification by column
chromatography (gradient of heptanes and EtOAc) gives the
corresponding 2,3-dihydrobenzofurans in the reported yields and
enantiopurities.
Sulfur ylide-mediated (4+1) addition to o-quinone methides: M.-W. Chen, L.-
L. Cao, Z.-S. Ye, G.-F. Jiang, Y.-G. Zhou, Chem. Commun., 2013, 49, 1660-1662;
(b) B. Wu, M.-W. Chen, Z.-S. Ye, C.-B. Yu, Y.-G. Zhou, Adv. Synth. Catal., 2014,
356, 383-387; (c) X. Lei, C.-H. Jiang, X. Wen, Q.-L. Xu, H. Sun, RSC Adv., 2015,
5, 14953-14957; (d) Q.-Q. Yang, W.-J. Xiao, Eur. J. Org. Chem., 2017, 233-236.
6
7
For a diastereoselective (4+1)-approach using pyridinium ylides: V. A.
Osyanin, D. V. Osipov, Y. N. Klimochkin, J. Org. Chem., 2013, 78, 5505-5520.
For reviews see: (a) V. K. Aggarwal, in Comprehensive Asymmetric Catalysis,
eds. E. N. Jacobsen, A. Pfaltz and H. Yamamoto, Springer, New York, 1999, vol.
2, 679; (b) E. M. McGarrigle, E. L. Myers, O. Illa, M. A. Shaw, S. L. Riches, V. K.
Aggarwal, Chem. Rev., 2007, 107, 5841-5883.
For selected three-ring forming examples using sulfur ylides see: (a) O. Illa, M.
Arshad, A. Ros, E. M. McGarrigle, V. K. Aggarwal, J. Am. Chem. Soc., 2010, 132,
1828-1830; (b) M. Davoust, J.-F. Briere, P.-A. Jaffres, P. Metzner, J. Org. Chem.,
2005, 70, 4166-4169; (c) Y.-G. Zhou, X.-L. Hou, L.-X. Dai, L.-J. Xia, M.-H. Tang,
J. Chem. Soc., Perkin Trans. 1, 1999, 77-80; (d) V. K. Aggarwal, J. P. H.
Charmant, D. Fuentes, J. N. Harvey, G. Hynd, D. Ohara, W. Picoul, R. Robiette,
C. Smith, J.-L. Vasse, C. L. Winn, J. Am. Chem. Soc., 2006, 128, 2105-2114; (e)
F. Sarabia, S. Chammaa, M. Garcia-Castro, F. Martin-Galvez, Chem. Commun.
2009, 5763-5765; (f) O. Illa, M. Nametubi, C. Saha, M. Ostovar, C. C. Chen, M.
F. Haddow, S. Nocquet-Thibault, M. Lusi, E. M. McGarrigle, V. K. Aggarwal, J.
Am. Chem. Soc., 2013, 135, 11951-11966. (g) R. Robiette, J. Org. Chem., 2006,
71, 2726-2734.
Product 5c. Obtained as a white residue in 85% yield on 1 mmol scale
(e.r. = 99:1). [ꢀ]ꢂꢁꢃ= -8.8 (c = 0.2, DCM, e.r. = 99:1); 1H NMR (700 MHz, δ,
CDCl3, 298 K): 4.99 (d, J = 6.5 Hz, 1H), 5.82 (d, J = 6.4 Hz, 1H), 6.90 (t, J
= 7.5 Hz, 1H), 7.01 – 6.98 (m, 2H), 7.24 – 7.20 (m, 3H), 7.30 – 7.28 (m,
1H), 7.35 – 7.33 (m, 2H), 7.46 (t, J = 7.7 Hz, 2H), 7.60 (t, J = 7.3 Hz, 1H),
7.96 (d, J = 7.6 Hz, 2H) ppm. 13C NMR (176 MHz, δ, CDCl3, 298 K): 51.0,
90.7, 110.1, 121.8, 125.5, 127.6, 128.3, 128.8, 129.0, 129.1, 129.5, 133.9,
134.6, 142.4, 159.2, 194.8 ppm. HRMS (ESI): m/z calculated for C21H16O2:
323.1043 [M+Na]+; found: 323.1040. The enantioselectivity was
determined by HPLC (YMC Cellulose-SB, eluent: hexane:i-PrOH = 95:5,
0.5 mL/min, 10 °C, retention times: tmajor (2R,3R) = 15.7 min, tminor (2S,3S)
= 17.0 min).
8
9
For selected examples of ammonium ylide mediated three-ring formations by
others see: (a) C. C. C. Johansson, N. Bremeyer, S. V. Ley, D. R. Owen, S. C.
Smith, M. J. Gaunt, Angew. Chem. Int. Ed., 2006, 45, 6024-6028; (b) C. D.
Papageorgiou, M. A. Cubillo de Dios, S. V. Ley, M. J. Gaunt, Angew. Chem. Int.
Ed., 2004, 43, 4641-4644; (c) H. Kinoshita, A. Ihoriya, M. Ju-ichi, T. Kimachi,
Synlett, 2010, 2330-2334; (d) R. Robiette, M. Conza, V. K. Aggarwal, Org.
Biomol. Chem., 2006, 4, 621-623; (e) A. Alex, B. Larmanjat, J. Marrot, F. Couty,
Acknowledgements
This work was supported by the Austrian Science Funds (FWF):
Project No. P26387-N28. Computational resources have been
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O. David, Chem. Commun., 2007, 2500-2502; (f) S. Allgäuer, P. Mayer, H.
Mayr, J. Am. Chem. Soc., 2013, 135, 15216-15224.
10 For contributions by our group see: (a) M. Waser, R. Herchl, N. Müller, Chem.
Commun., 2011, 47, 2170-2172; (b) R. Herchl, M. Stiftinger, M. Waser, Org.
Biomol. Chem., 2011, 9, 7023-7027; (c) S. Aichhorn, G. N. Gururaja, M.
Reisinger, M. Waser, RSC Adv., 2013, 3, 4552-4557; (d) M. Pichler, J. Novacek,
R. Robiette, V. Poscher, M. Himmelsbach, U. Monkowius, N. Müller, M.
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Waser, Synlett, 2016, 27, 1963-1968; (f) J. Novacek, L. Roiser, K. Zielke, R.
Robiette, M. Waser, Chem. Eur. J., 2016, 22, 11422-11428; (g) J. Novacek, R.
Robiette, M. Waser, Monatsh. Chem., 2017, 148, 77-81.
11 For reviews on (4+1) reactions see: (a) C. Zhu, Y. Ding, L.-W. Ye, Org. Biomol.
Chem., 2015, 13, 2530-2536; (b) J.-R. Chen, X.-Q. Hu, L.-A. Lu, W.-J. Xiao,
Chem. Rev., 2015, 115, 5301-5365.
12 Recent examples using sulfur ylides: (a) D. Zhang, Q. Zhang, N. Zhang, R.
Zhang, Y. Liang, D. Dong, Chem. Commun., 2013, 49, 7358-7360; (b) Q.-Q.
Yang, Q. Wang, J. An, J.-R. Chen, L.-Q. Lu, W.-J. Xiao, Chem. Eur. J, 2013, 19,
8401-8404; (c) A. O. C Chagarovsky, E. M. Budynina, O. A. Ivanova, E. V.
Villemson, V. B. Rybakov, I. V. Trushkov, M.l Y. Melnikov, Org. Lett., 2014, 16,
2830-2833; (d) O. Rousseau, T. Delaunay, G. Dequirez, T. Trieu-Van, K.
Robeyns, R. Robiette, Chem. Eur. J., 2015, 21, 12899-12902; (e) X.-S. Meng, S.
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4781; (f) Q. Wang, T.-R. Li, L.-Q. Lu, M.-M. Li, K. Zhang, W.-J. Xiao, J. Am. Chem.
Soc., 2016, 138, 8360-8363.
13 Recent examples with ammonium ylides: T. A. D. Thi, Y. Depetter, K. Mollet,
H. T. Phuong, D. V. Ngoc, C. P. The, H. T. Nguyen, T. H. N. Thi, H. H. Nguyen,
M. D’hooghe, T. V. Nguyen, Tetrahedron Lett., 2015, 56, 2422-2425; (b) P.-F.
Zheng, Q. Ouyang, S.-L. Niu, L. Shuai, Y. Yuan, K. Jiang, T.-Y. Liu, Y.-C. Chen, J.
Am. Chem. Soc., 2015, 137, 9390-9399.
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18, 9160-9173; (c) L. Caruana, M. Fochi, L. Bernardi, Molecules, 2015, 20,
11733-11764.
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P. Chen, X. Wang, Y.-G. Zhou, Y. Liu, C. Li, Angew. Chem. Int. Ed., 2015, 54,
4522-4526; (b) L. Caruana, M. Mondatori, V. Corti, S. Morales, A. Mazzanti. M.
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Yan, W.-X. Huang, Y.-G. Zhou, Tetrahedron Lett., 2015, 56, 4334-4338.
16 For an analogous detailed computational study of ammonium ylide-mediated
(2+1) reactions and the influence of the nature of the amine leaving group on
such reactions please see Ref. [10f].
17 CCDC 1513613 (Cambrige Crystallographic Data Centre, www.ccdc.cam.ac.uk)
contains the supplementary crystallographic data for 5f.
18 (a) A. D. Becke, J. Chem. Phys. 1993, 98, 5648–5652; b) S. J. Grimme, Comput.
Chem. 2006, 27, 1787–1799.
19 Calculations have been carried out using Jaguar 8.5; Schrodinger, Inc.: New
York, NY, 2014. See SI for full computational details and data.
20 Addition can potentially also occur onto electrophilic positions of the quinone
ring. Calculations confirm that these latter are less favored. See SI for data.
21 The betaine can ring close according to two different pathways: by attack of
the C2 of the aromatic ring or of the phenolic oxygen to yield either a
spirocyclic cyclopropane or
a 2,3-dihydrobenzofuran, respectively. The
exclusive formation of 2,3-dihydrobenzofuran and the non-observation of
cyclopropane derivatives can, in part, be explained by the loss of aromaticity
of the phenolic fragment that formation of the latter would cause. See SI for
details.
22 S. L. Riches, C. Saha, N. F. Filgueira, E. Grange, E. M. McGarrigle, V. K.
Aggarwal, J. Am. Chem. Soc. 2010, 132, 7626-7630.
23 R. Robiette, T. Trieu-Van, V. K. Aggarwal, J. N. Harvey, J. Am. Chem. Soc. 2016,
138, 734-737.
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Entry for the Table of Contents (Please choose one layout)
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Nicole Meisinger, Lukas Roiser, Uwe
Monkowius, Markus Himmelsbach,
Raphaël Robiette*, Mario Waser*
Page No. – Page No.
Asymmetric synthesis of 2,3-
dihydrobenzofurans via a (4+1)
annulation of ammonium ylides and
in situ generated ortho-quinone
methides
The first highly enantio- and diastereoselective (4+1) annulation protocol between in situ generated ammonium ylides and ortho-
quinone methides has been developed. This protocol gives access to highly functionalized chiral 2,3-dihydrobenzofuran derivatives.
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