Synthesis of 2-aryl-substituted chromans by intramolecular C-O bond formation

Article abstract of DOI:10.1055/s-0031-1290607

A synthetic route for the preparation of 2-aryl-substituted chromans from commercially available starting materials and utilizing either a palladium- or copper-catalyzed intramolecular cyclization of aryl bromides is described. Chromans with stereocontrol at C-2 can thus be obtained via a palladium-catalyzed asymmetric allylic etherification procedure utilizing a chiral indole-phosphine oxazoline (IndPHOX) ligand. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290607

LETTER
925
Synthesis of 2-Aryl-Substituted Chromans by Intramolecular C–O Bond
Formation
2
-Aryl-Substituted
uChromans Wang, Robert Franzén*
Department of Chemistry and Bioengineering, Tampere University of Technology, Korkeakoulunkatu 8, 33101 Tampere, Finland
Fax +358(3)31152108; E-mail: robert.franzen@tut.fi
Received 30 December 2011
for the preparation of diverse oxygen-containing hetero-
cyclic compounds. On the other hand, there are only a few
examples to synthesize 2-alkyl chromans,7b,d,9 and espe-
cially 2-aryl chromans9a via this approach. In this paper
Abstract: A synthetic route for the preparation of 2-aryl-substitut-
ed chromans from commercially available starting materials and
utilizing either a palladium- or copper-catalyzed intramolecular cy-
clization of aryl bromides is described. Chromans with stereocon-
trol at C-2 can thus be obtained via a palladium-catalyzed we report a new synthetic route for 2-aryl-substituted
asymmetric allylic etherification procedure utilizing a chiral indole-
phosphine oxazoline (IndPHOX) ligand.
chromans with the intramolecular cyclization of aryl bro-
mides as the key step (Scheme 1), which also enables ac-
Key words: intramolecular cyclization, chromans, chalcones, pal-
ladium, copper
cess to enantiomerically enriched chromans.
Chalcones 7a–d, prepared from commercially available
2-bromoaldehyde (5) and ketones 6a–d, were readily con-
verted to the corresponding alcohols 8a–d in quantitative
yields using sodium borohydride (Scheme 1). The follow-
ing reduction of the allylic double bond with para-tolue-
nesulfonyl hydrazide and sodium acetate trihydrate led to
the desired ortho-bromophenylpropanols 9a–d in high
yields without notable cleavage of the aryl–bromide
bond.10
Synthetic approaches towards 2-substituted chromans
(tetrahydrobenzopyrans) have attracted considerable at-
tention continuously due to the formation of a core that
exhibits biological activities in numerous natural prod-
ucts.1 A well-known example is a-tocopherol (1), a mem-
ber of the vitamin E family that serves as a radical
scavenger and lipophilic antioxidant. Moreover, the com-
pound 4¢,6-dichloroflavan (BW683C; 2) is a potent inhib-
itor of rhinovirus replication in vitro,2 and 2-(2-
piperidyl)chroman 3 and 2-(2-pyrrolidyl)chroman 4 have
shown to be promising new types of nicotine agonists
(Figure 1).3
With compounds 9a–d in hand, the intramolecular C–O
bond formation was studied. We first studied the palladi-
um-catalyzed cyclization procedure reported by Buch-
wald,7b employing the biaryl ligand 11 (Table 1).11 The
reactions with phenyl- and methyl-substituted aryl pro-
panols 9a and 9b proceeded smoothly to provide chro-
mans 10a and 10b in good yields (71% and 79%,
respectively; entry 1 and entry 2), whereas the results for
2-heteroaryl-substituted chromans (10c and 10d) were
poor. Due to the formation of the b-hydride elimination
by-product,12 the 2-furylchroman (10c) was obtained in
moderate yield (43%, entry3). After 96 hours at 90 °C we
noticed that substrate 9d reacted poorly and gave a very
low yield (16%, entry 4) of the product probably because
Cl
HO
O
O
C16H33
Cl
2
1
H
O
H
HO
O
N
N
Me
H
O
Me
H
O
10% NaOH (aq)
H2O–EtOH
NaBH4
MeOH
HO
H
R
RCOMe
+
4
3
100%
67–92%
Br
Br
Figure 1 Examples of biologically active chroman compounds
6
5
7a–d
OH
OH
NaOAc⋅3H2O
TsNHNH2
There are several synthetic studies on the construction of
the chroman core utilizing many strategies.4–6 The process
of Pd-7 or Cu-catalyzed8 intramolecular C–O bond forma-
tion using aryl halides has been successfully established
R
R
THF
79–95%
Br
9a: R = Ph
9b: R = Me
9c: R = 2-furyl
9d: R = 2-pyridinyl
Br
9a–d
8a–d
SYNLETT 2012, 23, 925–929
Advanced online publication: 15.03.2012
DOI: 10.1055/s-0031-1290607; Art ID: D82011ST
x
x.
x
x.
2
0
1
2
Scheme 1 Synthesis of 3-(2-bromophenyl)propan-1-ol derivatives
9a–d
© Georg Thieme Verlag Stuttgart · New York

926
Y. Wang, R. Franzén
LETTER
Table 1 Palladium-Catalyzed Intramolecular Cyclizationa
Pd(OAc)2 (3 mol%)
ligand 11 (3 mol%)
OH
Cs2CO3 (1.5 equiv)
P(t-Bu)2
R
toluene
O
R
Br
ligand 11
9a–d
10a–d
Entry
Temp (°C)
Time (h)
Product
10a
Isolated yield (%)
1
90
65
90
90
24
24
24
96
71
79
43
16
2b
3
10b
10c
4
10d
a See Supporting Information for details.
b See reference 7b.
Table 2 Copper-Catalyzed Intramolecular Cyclization of Compounds 9a–da
CuI (10 mol%)
2-aminopyridine (20 mol%)
NaOMe
OH
10a: R = Ph
10b: R = Me
R
10c: R = 2-furyl
10d: R = 2-pyridinyl
diglyme, 100 °C
O
R
Br
9a–d
10a–d
Entry
NaOMe (equiv)
Time (h)
Product
10a
Isolated yield (%)
1
2
3
4
1.5
2.1b
1.5
1.5
24
24
48
24
78
44
74
88
10b
10c
10d
a See Supporting Information for details.
b No reaction was observed using NaOMe (1.5 equiv).
of the palladium catalyst deactivation caused by the pyrid- sis of chromans with stereocontrol at C-2 via the
inyl group.
preparation of a chiral alcohol 8 obtained by an asymmet-
ric allylic etherification procedure.
Because of the limitation of the palladium-catalyzed
method for the cyclization, we started to investigate the Preliminary experiments were carried out for the synthe-
possibility to use an intramolecular Ullmann alkoxylation sis of chiral 2-phenylchroman (10a; Scheme 2). Starting
reaction for the cyclization of 9 instead.
from acetate 12, the catalytic reaction was performed uti-
lizing our IndPHOX ligand 13 with (E)-benzaldehyde
oxime and cesium carbonate as base in THF at 0 °C, yield-
ing a mixture of oximes 14a and 14b. After treatment with
zinc powder in AcOH–H2O,16 the linear alcohol 8a was
isolated in 43% yield with moderate enantioselectivity
(41%);17 while the branched product 15, derived from the
attack of the nucleophile to the more sterically hindered
position by SN2¢ mechanism, was obtained in good ee val-
ue (82%).17 After reduction of the double bond of alcohol
8a, followed by cyclization using CuI, the chiral chroman
10a was obtained with 44% enantioselectivity
(Scheme 2).
After a preliminary screening, we noticed that a previous-
ly reported approach using CuI and 2-aminopyridine with
sodium methoxide as base in diglyme was suitable for our
purposes (Table 2).13 Although 2-alkyl chroman 10b was
only obtained in moderate yield (44%, entry 2), the meth-
od worked well to afford 2-aryl chromans 10a, 10c and
10d in high yields (78%, 74% and 88%, respectively, en-
tries 1, 3 and 4).14
After establishing the synthetic route for racemic 2-mono-
substituted chromans, we next turned our attention to the
asymmetric synthesis of chiral chromans. Based on our
previous work with the Pd-catalyzed asymmetric allylic
substitutions using indole-phosphine oxazoline (Ind-
PHOX) ligands,15 we designed a new route for the synthe-
Encouraged by these promising results, we continued the
investigation with (E)-1,3-bis(2-bromophenyl)allyl ace-
Synlett 2012, 23, 925–929
© Thieme Stuttgart · New York

LETTER
2-Aryl-Substituted Chromans
927
Ph
Ph
[C3H5PdCl]2
ligand 13, Cs2CO3
N
O
OAc
N
O
∗
(E)-benzaldehyde oxime
+
(E)-benzaldehyde oxime
0 °C, THF
Br
Br
Br
12
14a
14b
OH
∗
OH
∗
Zn
+
AcOH, H2O
8a: 43%, ee = 42%
15: 22%, ee = 82%
Br
Br
t-Bu
O
8a
15
N
PPh2
NaOAc⋅3H2O
NH2NHTs
44% ee
N
THF
13
MeO
OH
∗
CuI, NaOMe
2-aminopyridine
∗
diglyme
44% ee
O
Ph
Br
10a
9a
Scheme 2 Synthesis of chiral chroman 10a
tate (16), which was chosen based on the following as- obtained with good enantioselectivity (89%)17 and 70%
pects: (i) to suppress regioselectivity issue in Pd-catalyzed yield (Scheme 3). The subsequent cleavage of the N–O
allylic substitution; (ii) to enhance the enantioselectivity; bond, the reduction of the double bond and the intramo-
and to (iii) afford diversity to further chroman derivatives. lecular cyclization proceeded smoothly to afford chroman
When starting material 16 was reacted with (E)-benzalde- 20,18 maintaining original enantiopurity.
hyde oxime using IndPHOX ligand 13 and cesium car-
bonate as base in THF at 0 °C for 24 hours, oxime 17 was
mined by transforming it into known chiral compound 21
The absolute configuration of compound 18 was deter-
Ph
N
OAc
O
∗
[C3H5PdCl]2
ligand 13, Cs2CO3
(E)-benzaldehyde oxime
Br Br
0 °C, THF
Br Br
70%, 89% ee
16
17
OH
∗
OH
∗
NaOAc⋅3H2O
NH2NHTs
Zn
AcOH, H2O
75%, 89% ee
THF
94%, 89% ee
Br Br
18
Br Br
19
CuI, NaOMe
2-aminopyridine
Br
∗
diglyme
60%, 89% ee
O
20
Scheme 3 Synthesis of chiral chroman 20
© Thieme Stuttgart · New York
Synlett 2012, 23, 925–929

928
Y. Wang, R. Franzén
LETTER
(Scheme 4). The reduction of 18 was performed in meth-
anol using NaBH4 in the presence of nickel(II) chloride
hexahydrate, providing chiral 21 without remarkable ra-
cemization. Comparison of the optical rotation value19 of
21 with the literature data20 revealed that the absolute ste-
reochemistry of 18 was R.
References and Notes
(1) (a) Chemistry of Heterocyclic Compounds: Chromans and
Tocopherols, Vol. 36; Ellis, G. P.; Lockhart, I. M., Eds.;
Wiley: New York, 1981. (b) Saengchantara, S. T.; Wallace,
T. W. Nat. Prod. Rep. 1986, 3, 465.
(2) Bauer, D. J.; Selway, J. W. T.; Batchelor, J. F.; Tisdale, M.;
Caldwell, I. C.; Young, D. A. Nature (London) 1981, 292,
369.
(3) Efange, S. M. N.; Tu, Z.; von Hohenberg, K.; Francesconi,
L.; Howell, R. C.; Rampersad, M. V.; Todaro, L. J.; Papke,
R. L.; Kung, M. P. J. Med. Chem. 2001, 44, 4704.
(4) For some recent examples of the racemic synthesis of
chromans, see: (a) Sugimoto, H.; Nakamura, S.; Ohwada, T.
Adv. Synth. Catal. 2007, 349, 669. (b) Yamamoto, Y.;
Itonaga, K. Org. Lett. 2009, 11, 717. (c) Batsomboon, P.;
Phakhodee, W.; Ruchirawat, S.; Ploypradith, P. J. Org.
Chem. 2009, 74, 4009. (d) Radomkit, S.; Sarnpitak, P.;
Tummatorn, J.; Batsomboon, P.; Ruchirawat, S.;
OH
∗
OH
∗
NiCl2⋅6H2O, NaBH4
MeOH
Br Br
21
87% ee
18
89% ee
Scheme 4 Determination of the absolute configuration of com-
pound 18
Ploypradith, P. Tetrahedron 2011, 67, 3904.
The adjacent 2-bromophenyl group in the structure of
chroman 20 offered various possibilities for further appli-
cations via catalytic transformations.21 As an example, we
carried out a Suzuki coupling reaction.21c–e Chroman 20
with 89% ee was reacted with phenylboronic acid (22) us-
ing Pd(PPh3)4 with sodium carbonate as base in toluene–
H2O–EtOH for 20 hours at 80 °C.
(5) For some recent examples of the asymmetric synthesis of
chromans, see: (a) Hernandez-Torres, G.; Carreno, M. C.;
Urbano, A.; Colobert, F. Eur. J. Org. Chem. 2011, 20-21,
3864. (b) Valla, C.; Baeza, A.; Menges, F.; Pfaltz, A. Synlett
2008, 3167. (c) Chandrasekhar, S.; Reddy, M. V.
Tetrahedron 2000, 56, 6339. (d) Hodgetts, K. J.
Tetrahedron 2005, 61, 6860.
(6) For a recent review on the asymmetric synthesis of
chromans, see: Shen, H. C. Tetrahedron 2009, 65, 3931.
(7) For some selected examples, see: (a) Neogi, A.; Majhi, T.
P.; Achari, B.; Chattopadhyay, P. Eur. J. Org. Chem. 2008,
2, 330. (b) Kuwabe, S.; Torraca, K. E.; Buchwald, S. L.
J. Am. Chem. Soc. 2001, 123, 12202. (c) Shelby, Q.;
Kataoka, N.; Mann, G.; Hartwig, J. J. Am. Chem. Soc. 2000,
122, 10718. (d) Torraca, K. E.; Kuwabe, S. I.; Buchwald, S.
L. J. Am. Chem. Soc. 2000, 122, 12907.
(8) For some recent examples, see: (a) Zhao, J.; Zhao, Y. F.; Fu,
H. Angew. Chem. Int. Ed. 2011, 50, 3769. (b) Niu, J. J.;
Guo, P. R.; Kang, J. T.; Li, Z. G.; Xu, J. W.; Hu, S. J. J. Org.
Chem. 2009, 74, 5075. (c) Adams, H.; Gilmore, N. J.; Jones,
S.; Muldowney, M. P.; von Reuss, S. H.; Vemula, R. Org.
Lett. 2008, 10, 1457. (d) Fang, Y.; Li, C. J. Org. Chem.
2006, 71, 6427.
(9) (a) Xu, B.; Xue, J.; Zhu, J.; Li, Y. Chem. Lett. 2008, 37, 202.
(b) Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F.
J. Org. Chem. 2002, 67, 5553. (c) Palucki, M.; Wolfe, J. P.;
Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 10333.
(10) Gan, Y.; Spencer, T. A. J. Org. Chem. 2006, 71, 5870.
(11) General Procedure for Palladium-Catalyzed
Intramolecular Cyclization: To a mixture of Pd(OAc)2 (2.4
mg, 0.0105 mmol), ligand 11 (3.1 mg, 0.0105 mmol) and
Cs2CO3 (0.17 g, 0.525 mmol), compound 9 (0.35 mmol) in
toluene (1.2 mL) was added. After stirring under 90 °C for
reported time, the reaction mixture was cooled to r.t., diluted
with Et2O, and filtered through a pad of celite. The resulting
solution was purified by silica gel chromatography (n-
hexane–EtOAc, 30:1).
The Suzuki reaction proceeded well to afford product 2222
in high yield (88%) and without loss of ee (Scheme 5).
In conclusion, we have developed a preparation route to 2-
aryl-substituted chromans from readily available starting
materials. The route gives access to enantiomerically en-
riched chromans as well. Chiral 2-phenylchroman (10a)
and 2-(2-bromophenyl)chroman (20) were obtained in
moderate and high ee values when utilizing IndPHOX
ligand 13. The further modification of 20 was investigated
by Suzuki cross-coupling affording 2-([1,1¢-biphenyl]-2-
yl)chroman (23) with preserved enantioselectivity.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
Financial support of this work was provided by the National Tech-
nology Agency of Finland (TEKES). The authors thank Matti
Vaismaa, PhD, for preliminary work performed in this paper, Mrs
Päivi Joensuu for the mass analyses, and Prof. Petri Pihko and Mr
Antti Neuvonen for the optical rotation measurements.
B(OH)2
Br
∗
Ph
Pd(PPh3)4, Na2CO3
∗
O
+
O
toluene–H2O–EtOH
88%, 89% ee
20
89% ee
22
23
Scheme 5 Suzuki coupling reaction with chroman 20 and phenylboronic acid 22
Synlett 2012, 23, 925–929
© Thieme Stuttgart · New York

LETTER
2-Aryl-Substituted Chromans
929
(12) The by-product was 1-(furan-2-yl)-3-phenylpropan-1-one,
isolated in 22% yield. For the reaction mechanism, see
reference 7b.
(13) Fagan, P. J.; Hauptman, E.; Shapiro, R.; Casalnuvo, A.
J. Am. Chem. Soc. 2000, 122, 5043.
3.10 (m, 1 H), 2.75–2.83 (m, 1 H), 2.31–2.39 (m, 1 H), 1.85–
1.94 (m, 1 H). 13C NMR (75 MHz, CDCl3): d = 155.4, 141.3,
133.0, 130.0, 129.4, 128.1, 127.8, 127.7, 122.3, 121.8,
120.8, 117.2, 77.3, 29.1, 25.5. HRMS (ESI+): m/z [M + Na]+
calcd for C15H13ONaBr: 311.0047; found: 311.0015.
(19) [a]D20 +27.7 (c = 0.5, CH2Cl2, 87% ee).
(14) General Procedure for Copper-Catalyzed
Intramolecular Cyclization: To a mixture of CuI (2.8 mg,
0.015 mmol), 2-aminopyridine (2.8 mg, 0.03 mmol) and
NaOMe (12 mg, 0.225 mmol), compound 9 (0.15 mmol) in
diglyme (0.7 mL) was added. After stirring under 100 °C for
reported time, the reaction mixture was cooled to r.t.,
quenched with H2O, and extracted with Et2O. The extracts
were washed with brine and dried over MgSO4. The solvent
was removed in vacuo and the residue was purified by
column chromatography (n-hexane–EtOAc, 30:1).
(15) (a) Wang, Y.; Hämäläinen, A.; Tois, J.; Franzén, R.
Tetrahedron: Asymmetry 2010, 21, 2376. (b) Wang, Y.;
Vaismaa, M.; Hämäläinen, A.; Tois, J.; Franzén, R.
Tetrahedron: Asymmetry 2011, 22, 524.
(16) Miyabe, H.; Matsumura, A.; Moriyama, K.; Takemoto, Y.
Org. Lett. 2004, 6, 4631.
(17) The reported ee is the average value of three entries.
(18) 2-(2-Bromophenyl)chroman (20): [a]D20 +71.2 (c = 0.95,
CHCl3, 89% ee). 1H NMR (300 MHz, CDCl3): d = 7.54–7.61
(m, 2 H), 7.36 (td, J = 7.7, 1.2 Hz, 1 H), 7.10–7.19 (m, 3 H),
6.86–6.93 (m, 2 H), 5.38 (td, J = 10.2, 2.2 Hz, 1 H), 3.00–
(20) Yasunori, Y.; Tomohiko, S.; Momoko, W.; Kazunori, K.;
Norio, M. Molecules 2011, 16, 5020.
(21) For some reviews of reactions for aromatic halides, see:
(a) Sadig, J. E. R.; Willis, M. C. Synthesis 2011, 1.
(b) Surry, D. S.; Buchwald, S. L. Angew. Chem. Int. Ed.
2008, 47, 6338. (c) Bubnov, Y. N. Heterocycles 2010, 80,
1. (d) Alonso, F.; Beletskaya, I. P.; Yus, M. Tetrahedron
2008, 64, 3047. (e) Martin, R.; Buchwald, S. L. Acc. Chem.
Res. 2008, 41, 1461. (f) Bras, J. L.; Muzart, J. Chem. Rev.
2011, 111, 1170. (g) Felpin, F. X.; Nassar-Hardy, L.;
Callonnec, F. L.; Fouquet, E. Tetrahedron 2011, 67, 2815.
(22) 2-([1,1¢-Biphenyl]-2-yl)chroman (22): [a]D20 –36.5 (c =
0.40, CHCl3, 89% ee). 1H NMR (300 MHz, CDCl3): d =
7.64–7.67 (m, 1 H), 7.25–7.46 (m, 8 H), 7.00–7.11 (m, 2 H),
6.80–6.88 (m, 2 H), 5.05–5.10 (m, 1 H), 2.71–2.78 (m, 2 H),
2.01–2.09 (m, 2 H). 13C NMR (75 MHz, CDCl3): d = 155.8,
141.2, 141.0, 139.3, 130.4, 129.8, 129.6, 128.5, 128.2,
128.0, 127.5, 127.4, 126.7, 122.2, 120.5, 117.3, 75.2, 30.1,
25.9. HRMS (ESI+): m/z [M + Na]+ calcd for C21H18ONa:
309.1255; found: 309.1263.
© Thieme Stuttgart · New York
Synlett 2012, 23, 925–929

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