Catalytic asymmetric synthesis of chromenes and tetrahydroquinolines via sequential allylic alkylation and intramolecular Heck coupling

Article abstract of DOI:10.1039/c2cc30395g

Highly enantioselective synthesis of chiral chromenes and tetrahydroquinolines is achieved by combining asymmetric copper-catalyzed allylic substitution with Grignard reagents and an efficient intramolecular Heck reaction. Moreover, the exocyclic double bond formed in the cyclisation was subjected to RCM, hydroboration and hydrogenation illuminating the synthetic versatility of these heterocycles. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc30395g

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COMMUNICATION
Catalytic asymmetric synthesis of chromenes and tetrahydroquinolines
via sequential allylic alkylation and intramolecular Heck couplingw
Valentın Hornillos, Anthoni W. van Zijl and Ben L. Feringa*
´
Received 17th January 2012, Accepted 17th February 2012
DOI: 10.1039/c2cc30395g
Highly enantioselective synthesis of chiral chromenes and tetra-
hydroquinolines is achieved by combining asymmetric copper-
catalyzed allylic substitution with Grignard reagents and an
efficient intramolecular Heck reaction. Moreover, the exocyclic
double bond formed in the cyclisation was subjected to RCM,
hydroboration and hydrogenation illuminating the synthetic
versatility of these heterocycles.
Heterocyclic compounds are indispensable structural units that are
crucial in medicinal chemistry and valuable as synthetic organic
building blocks. Among the various classes of heterocyclic
compounds, chromenes and tetrahydroquinolines are present in
a vast number of natural products and bioactive range of
substances, with wide applications.1,2 In view of their importance
in various therapeutic areas, the development of the catalytic
enantioselective synthesis of these compounds is a major goal.
Catalytic methods to prepare chiral chromenes include asymmetric
epoxidation, hydrogenation, Pd-catalyzed allylic alkylation or
chiral Brønsted acid-mediated cyclization.1 For tetrahydro-
quinolines, the Povarov reaction and various hydrogenations of
quinolines have mainly been used.2 Nonetheless, several of these
approaches show low selectivities or involve long synthetic routes.
Consequently, there is a major incentive to develop efficient
and highly enantioselective catalytic protocols toward these
important compounds.
Scheme 1 Cu-catalyzed AAA of allyl bromide.
Scheme 2 Chiral chromenes and tetrahydroquinolines via sequential
AAA and intramolecular Heck reaction.
metathesis to prepare chiral carbo-6a and nitrogen heterocycles6b
of various ring sizes and by a hetero-AAA-RCM protocol to
prepare naturally occurring butenolides.7
As shown in Scheme 2 we anticipated that combining the
Cu-catalyzed AAA with an intramolecular Heck reaction8
would be a very efficient method to prepare nitrogen or
oxygen-containing heterocycles. To the best of our knowledge
the combination of these two catalytic processes to prepare
heterocycles is unprecedented.
Our group recently reported that copper-catalyzed asymmetric
allylic alkylation (AAA) with Grignard reagents can be achieved
with excellent regio- and enantioselectivities employing Tania-
phos as a chiral ligand (Scheme 1).3,4 From a synthetic perspec-
tive, this catalytic process is especially suited for the introduction
of a methyl group using methylmagnesium bromide, one of the
most frequently encountered motifs in natural products. More-
over, a major advantage of this methodology is that it furnishes
products, which have a terminal olefin adjacent to the stereogenic
center formed that can be readily transformed into various other
functional groups.5 This double bond can also be an ideal handle
in cyclization reactions. This concept has been successfully
applied by combination of AAA followed by olefin ring-closing
Here we present a new and highly versatile catalytic enantio-
selective synthesis of chromenes and tetrahydroquinolines via
sequential Cu-catalyzed AAA/Heck reaction with excellent
enantiomeric excess (95–99% ee). The required substrates allyl
bromides 1 and 2 are readily accessible by reacting o-bromo-
phenol or tosyl protected o-bromoaniline, respectively, with
1,4-dibromo-2-butene in the presence of base (see ESIw for details).
Compounds 1 and 2, subjected to methylmagnesium bromide
in CH2Cl2 in the presence of catalytic amounts of CuBrꢀSMe2
and (R,R)-(+)-Taniaphos L1 at ꢁ80 1C, undergo substitution
to provide the products 3 and 4 in high yields, excellent
enantioselectivity (99% ee) and with almost no linear products
(branched vs. linear ratios >20 : 1) (Table 1, entries 1 and 6).
Substrates 1 and 2 can also be ethylated with high regio-
selectivity and excellent enantioselectivity (Table 1, entries 2
and 7). The use of functionalized alkene Grignard reagents gave
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4,
9747 AG, Groningen, The Netherlands. E-mail: b.l.feringa@rug.nl;
Fax: +31 50 363 4296; Tel: +31 50 363 4235
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc30395g
c
3712 Chem. Commun., 2012, 48, 3712–3714
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Table 1 Cu-catalysed enantioselective allylic alkylation of 1 and 2
with Cu/Taniaphos ((R,R)-L1) and Grignard reagentsa,b
Table 2 Intramolecular Heck reaction on chiral substrates 3 and 4a,b
Entry
Y
Product
R
Yield (%) Exo/Endoc eed (%)
Entry
Y
Product
R
Yieldc (%)
eed (%)
1
2
O
O
5a
5b
Me
Et
93
96
96 : 4
98 : 2
99
98
1
2
O
O
3a
3b
Me
Et
88
97
99
99
3e
4e
O
O
5c
5d
84
92
99 : 1
99 : 1
96
95
3
4
5
O
O
O
3c
3d
3e
86
90
94
96
95
97
5e
O
5e
89
99 : 1
99
6
7
NTs 6a
NTs 6b
Me
Et
92
93
96 : 4
98 : 2
99
99
6
7
NTs
NTs
4a
4b
Me
Et
72
99
99
99
8f
NTs 6c
87
98 : 2
97
8
NTs
4c
87
96
9f
10f
a
NTs 6d
NTs 6e
86
77
98 : 2
97 : 3
97
98
9
NTs
NTs
4d
4e
86
68
95
98
10
a
Reagents and conditions: Pd(OAc)2 (3 mol%), TBAB (1 g), TBAA
Reagents and conditions: RMgBr (1.7 eq.), CuBrꢀSMe2 (5 mol%), L1
b
(6 mol%), CH2Cl2, ꢁ80 1C, 4 h. All conversions >99% (1H-NMR).
b
(0.45 g, 1.5 mmol), 100 1C, 0.25 h. All conversions >99%
(1H-NMR). Exo/Endo rate determined by 1H-NMR. Enantio-
meric excess determined by chiral GC or HPLC (see ESI for details).
c
d
c
d
SN20 vs. SN2 > 20 : 1 (1H-NMR). Enantiomeric excess determined
by chiral GC or HPLC (see ESI for details).
e
f
Reaction time: 1.5 h. Reaction time: 1 h.
products 3c–e and 4c–e in high yields allowing for further ring-
closing metathesis after the Heck reaction (Vide infra,
Scheme 3). An important feature is that the reaction is readily
scalable to 3 mmol with similar results as observed in the
reaction of allyl bromide 1 and MeMgBr (see ESIw, compound
3a for details).
probably takes place by reaction of the chiral product
with palladium hydrides formed after b-elimination of the
Pd-intermediate.9 We studied a variety of coupling conditions
(palladium sources, phosphines, solvents and additives) but we
could not avoid this isomerization and improve the yield.
Recently Nacci et al.10 described the use of catalytic amount
of Pd(OAc)2 in a molten mixture of tetrabutylammonium
bromide (TBAB) and tetrabutylammonium acetate (TBAA)
as base under ligand-free conditions for the intermolecular
Heck coupling of a variety of chloroarenes, although this
method was not applied to chiral compounds. To our delight,
by applying these conditions to 3a and 4a we obtained the
cyclized product 5a and 6a with excellent yields (Table 2,
entries 1 and 6) while only 4% of isomerization of the double
bond to the internal position was observed. The reaction was
finished in only 15 min for both substrates. It is worth noting
that despite the reaction temperature of 100 1C the ee was not
compromised.
With the isolated AAA products 3 and 4 in hand, we turned
our attention to the study of the intramolecular Heck reaction.
When using standard conditions (catalytic amounts of Pd(OAc)2
and PPh3 and Bu4NBr as an additive in MeCN or DMF),8b
moderate yields of the bicyclic compounds 5 and 6 were
obtained (37% and 62%, respectively). The product was always
an, approximately, 70 : 30 mixture of the expected exocyclic
olefin and its isomer with the olefin in the internal position.
Since the Heck catalytic cycle can only furnish the cyclized
product with an exocyclic double bond, this isomerization
It was proposed that bromide ions from TBAB, poorly
solvated in this reaction medium, provide adequate electron
density to the palladium(0) species instead of the common
electron-rich phosphane ligands to facilitate the oxidative-
addition step.10
High isolated yields were also found for the products with
an ethyl group while improving the ratio of isomers (Table 2,
entries 2 and 7). Compounds with a longer alkyl chain
required a little more time to reach full conversion while
insignificant isomerization was found in the preparation of
Scheme 3 Ring-closing metathesis of substrates 5c, 6c, and 5d.
c
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Scheme 4 Stereoselective hydroboration of substrate 5a.
Scheme 5 Stereoselective hydrogenation of substrates 5e and 6d.
chromenes and tetrahydroquinolines (Table 2, entries 3–5
and 8–10). To ensure that racemization during the cyclisation
did not occur, the enantiomeric purity of all Heck reaction
products was determined independently by chiral GC or chiral
HPLC analysis (see ESIw for details).
bioactive substances is obtained by RCM. Moreover two
stereoselective derivatisation reactions of the exocyclic double
bond were applied to further demonstrate the synthetic versatility
of these compounds.
Financial support from The Netherlands Organization for
Scientific Research (NWO-CW) is acknowledged. V. H. is
grateful to the Spanish Ministry of Science and Innovation
(MICINN) for a postdoctoral grant.
The newly formed exocyclic double bond in position 4 of the
chromenes and tetrahydroquinolines opens a wide array of
possible transformations. To illustrate the synthetic utility of
the method, compounds 5c, 6c and 5d with an alkyl chain in
position 3 bearing a terminal double bond were subjected to
ring closing metathesis11 since the products obtained provide
core structures of natural products (Scheme 3). So 5c and 6c
were transformed to the corresponding tricyclic compounds 7
and 8 using 5.0 mol% of Hoveyda–Grubbs second-generation
catalyst in toluene providing 84% and 90% yield, respectively.
The formation of the six member ring annulated to the
chromene structure proceeded also in excellent yield from 5d.
Again, no loss of ee was observed in these transformations.
It should be noted that tetrahydroquinoline 8 is the nucleus of
many neurotransmitters targeted by membrane receptors
including calcium-activated potassium channel (BKCa), a7
nicotinic acetylcholine receptor or estrogen-activated G protein-
coupled receptor.2a On the other hand, compound 9 represents the
core structure of biologically active cannabinols.12
Notes and references
1 Chiral chromenes: (a) G. P. Ellis and I. M. Lockhart,
The Chemistry of Heterocyclic Compounds. Vol. 31: Chromenes,
Chromanones, and Chromones, ed. G. P. Ellis, Wiley-VCH, 2007,
pp. 1–1196; (b) J. D. Hepworth, C. D. Gabbutt and B. M. Heron,
in Comprehensive Heterocyclic Chemistry II: Pyrans and Their
Benzo Derivatives: Synthesis, ed. A. R. Katritzky, C. W. Rees
and E. F. V. Scriven, Pergamon Press, Oxford, 1996, vol. 5,
pp. 351–468; (c) H. C. Shen, Tetrahedron, 2009, 65, 3931–3952;
(d) M. G. Nunez, P. Garcıa, R. F. Moro and D. Dıez, Tetrahedron,
2010, 66, 2089–2109.
2 Chiral tetrahydroquinolines: (a) For a review see: V. Sridharan,
P. A. Suryavanshi and J. C. Menendez, Chem. Rev., 2011,
111, 7157; (b) Z.-X. Jia, Y.-C. Luo and P.-F. Xu, Org. Lett.,
2011, 13, 832–835 and references cited therein; (c) P. M. Dewick,
Medicinal Natural Products—A Biosynthetic Approach, Wiley,
Chichester, 2nd edn, 2001; (d) G. Satyanarayana, D. Pflasterer
and G. Helmchen, Eur. J. Org. Chem., 2011, 6877–6886.
3 (a) F. Lopez, A. W. van Zijl, A. J. Minnaard and B. L. Feringa,
Chem. Commun., 2006, 409; (b) K. Geurts, S. P. Fletcher and
B. L. Feringa, J. Am. Chem. Soc., 2006, 128, 15572.
4 For reviews on Cu-catalyzed AAA, see: (a) S. Harutyunyan, T. den
Hartog, K. Geurts, A. J. Minnaard and B. L. Feringa, Chem. Rev.,
2008, 108, 2824; (b) A. Alexakis, J. E. Backvall, N. Krause,
O. Pamies and M. Dieguez, Chem. Rev., 2008, 108, 2796.
5 (a) A. W. van Zijl, F. Lopez, A. J. Minnaard and B. L. Feringa,
J. Org.Chem., 2007, 72, 2558; (b) T. den Hartog, B. Macia,
A. J. Minnaard and B. L. Feringa, Adv. Synth. Catal., 2010,
352, 999.
6 (a) F. Giacomina, D. Riat and A. Alexakis, Org. Lett., 2010,
12, 1156; (b) J. F. Teichert, S. Zhang, A. W. van Zijl, J. W. Slaa,
A. J. Minnaard and B. L. Feringa, Org. Lett., 2010, 12, 4658.
7 B. Mao, K. Geurts, M. Fananas-Mastral, A. W. van Zijl, S. P.
Fletcher, A. J. Minnaard and B. L. Feringa, Org. Lett., 2011,
13, 948.
Another interesting transformation could be obtained via
stereoselective hydroboration–oxidation of the exocyclic double
bond directed by the stereogenic center in the a position. For
instance, compound 5a was transformed into the corresponding
alcohol by reaction with an excess of 9-BBN and subsequent
treatment with H2O2 in basic medium.5b,13 Alcohol 10 was
obtained as a single diastereoisomer in 81% yield (Scheme 4).
Finally, chromene 5e and tetrahydroquinoline 6d, both with
a terminal double bond in the alkyl chain in position 3 were
subjected to stereoselective hydrogenation of the exocyclic
double bonds in the presence of 5 mol% of Wilkinson’s
catalyst in benzene (Scheme 5).
In this case the alkyl chain in the a position to the exocyclic
double bond controls the hydrogenation to reach high selectivity
(9 : 1 and 10 : 1 for the chromene and tetrahydroquinoline,
respectively) for the cis-dialkylated product.14
8 (a) R. Imbos, A. J. Minnaard and B. L. Feringa, J. Am. Chem.
Soc., 2002, 124, 184; (b) A. B. Dounay and L. E. Overman, Chem.
Rev., 2003, 103, 2945.
9 I. P. Beletskaya and A. V. Cheprakov, Chem. Rev., 2000,
100, 3009.
10 V. Calo, A. Nacci, A. Monopoli and P. Cotugno, Angew. Chem.,
Int. Ed., 2009, 48, 6101.
11 R. H. Grubbs, Angew. Chem., Int. Ed., 2006, 45, 3760.
12 L. Minuti and E. Ballerini, J. Org. Chem., 2011, 76, 5392.
13 For a related syn-selective hydroboration–oxidation see: A. Kreier,
R. Frohlich, E. Wegelius and D. Hoppe, Synthesis, 2000, 1391.
14 T. Miura, M. Yamauchi, A. Kosaka and M. Murakami, Angew.
Chem., Int. Ed., 2010, 49, 4955.
In summary, we have demonstrated that chiral chromenes
and tetrahydroquinolines can be obtained in excellent enantio-
meric excess and high yields via sequential Cu-catalyzed AAA
and a very efficient intramolecular Heck reaction. By using a
molten mixture of TBAB and TBAA we could obtain the
cyclized products with excellent yields and without isomerization
of the exocyclic double bond. Taking advantage of this
generated olefin, the core structure of natural products and
c
3714 Chem. Commun., 2012, 48, 3712–3714
This journal is The Royal Society of Chemistry 2012