An efficient synthesis of optically active trans-2-Aryl-2,3-dihydrobenzofuran-3-carboxylic acid esters via C-H insertion reaction

Article abstract of DOI:10.1055/s-2003-39316

Optically active trans-2-Aryl-2,3-dihydrobenzofuran-3-carboxylic acid esters were synthesized by intramolecular C-H insertion reaction. Upon treatment with a catalytic amount of Rh₂(R-DOSP)₄, aryldiazoester 8c possessing a chiral auxiliary underwent C-H insertion reaction to give 9c in high yield and in high selectivity (84% yield, 86% de).

Full text of DOI:10.1055/s-2003-39316

1028
LETTER
An Efficient Synthesis of Optically Active trans-2-Aryl-2,3-dihydrobenzo-
furan-3-carboxylic Acid Esters via C-H Insertion Reaction
O
ptically Active trans-2
a
-Aryl-2,3-d
t
ihydro
a
benzofura
n
r
-3-carbo
u
xylic
A
cid Esters Kurosawa, Toshiyuki Kan, Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax +81(3)58028694; E-mail: fukuyama@mol.f.u-tokyo.ac.jp
Received 24 March 2003
rivatives,4 only a handful of enantioselective syntheses are
Abstract: Optically active trans-2-Aryl-2,3-dihydrobenzofuran-3-
carboxylic acid esters were synthesized by intramolecular C-H in-
sertion reaction. Upon treatment with a catalytic amount of Rh2(R-
DOSP)4, aryldiazoester 8c possessing a chiral auxiliary underwent
C-H insertion reaction to give 9c in high yield and in high selectivity
(84% yield, 86% de).
available.5
Asymmetric C-H insertion reaction of metal-carbenoids
has been the subject of intensive investigation.6 Davies
has recently reported that a chiral rhodium-carbenoid,
derived from an aryl diazoester, undergoes inter- or in-
tramolecular asymmetric C-H insertion reaction.7,8 We
envisioned that intramolecular C-H insertion of the car-
benoid generated from 2 would provide the optically
active trans-2-aryl-2,3-dihydrobenzofuran-3-carboxylic
acid esters 1 (R1 = Ar, R2 = CO2R), the results of which
are described herein.
Key words: dihydrobenzofuran, C-H insertion, Rh2(R-DOSP)4,
chiral auxiliary, pyrrolidinyl lactamide
2,3-Dihydrobenzofuran (coumaran) 1 is a basic skeleton
found in a number of biologically interesting compounds.
Furthermore, 2-aryl-2,3-dihydrobenzofuran-3-carboxylic
acid derivatives (1: R1 = Ar, R2 = CO2R) constitute the
major frameworks of such natural products as neolig-
nans,1 serotobenine (3)2 and (–)-ephedradine A (4)3
(Scheme 1, Figure 1). Because of the unique bioactivities,
efficient methodology for the synthesis of dihydrobenzo-
furan has long been sought after. While extensive synthet-
ic efforts have been reported to date, including the
biomimetic, oxidative dimerisation of cinnamic acid de-
As shown in Scheme 2, the diazoester 8a was readily pre-
pared in a seven-step sequence from 4-bromophenol (5).
Thus, allylation of phenol 5, Claisen rearrangement, and
Scheme 1
Scheme 2 Reagents and conditions: a) Allyl bromide, K2CO3,
DMF, 60 °C (99%); b) diethylaniline, 210 °C (88%); c) K2CO3, 4-
(benzyloxy)benzyl chloride, DMF, 60 °C (95%); d) O3, CH2Cl2/
MeOH, –78 °C; Me2S, –78 °C to r.t.; e) NaClO2, 2-methyl-2-butene,
NaH2PO4·2H2O, t-BuOH/H2O (77% in 2 steps); f) CH2N2, Et2O
(81%); g) p-AcNHC6H4SO2N3, DBU, CH3CN (71%); h) Rh2(S-
DOSP)4 (5 mol%), CH2Cl2 (72%, 9a:10a = 2:3).
Figure 1
Synlett 2003, No. 7, Print: 02 06 2003.
Art Id.1437-2096,E;2003,0,07,1028,1030,ftx,en;U04703ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

LETTER
Optically Active trans-2-Aryl-2,3-dihydrobenzofuran-3-carboxylic Acid Esters
1029
subsequent introduction of a 4-(benzyloxy)benzyl group insertion reactions of 8b and 8c proceeded smoothly to af-
to the resultant phenol provided 6. Ozonolysis of the ford exclusively the trans-dihydrobenzofurans 9b and 9c
double bond in 6 followed by treatment with NaClO2 (Table 1). Presumably, the increased bulk of the ester
furnished the carboxylic acid 7. After esterification of 7, moiety is responsible for the high trans-selectivity. Fur-
diazotransfer reaction was carried out by treatment thermore, it is interesting to note that the C-H insertion
with p-acetamidobenzenesulfonyl azide and DBU.
products 9b and 9c possessed the same configuration (2S,
3S) regardless of the chirality of the catalyst (run 2 and 3).
Thus, the asymmetric induction was solely dependent on
the chiral auxiliaries and not on the catalyst.14 The highest
diastereoselectivity was attained by combination of the di-
azoester 8c and Rh2(R-DOSP)4 to afford 9c in 84% yield
and 86% de. Basic hydrolysis of 9c with Ba(OH)2 gave the
desired carboxylic acid.15
With the requisite diazoester 8a in hand, the C-H insertion
reaction by chiral rhodium catalyst was next investigated.
Upon treatment of 8a with 5 mol% of Davies’ catalyst,
Rh2(S-DOSP)4, the reaction proceeded smoothly to afford
the dihydrobenzofuran in 72% yield as a 2:3 mixture of 9a
and 10a,9 and the enantiomeric excess of the trans-isomer
was 32%.10 In order to improve the enantioselectivity, in-
corporation of a chiral auxiliary to the ester moiety of 8a In conclusion, an efficient construction of optically active
was investigated (Scheme 3).
trans-2,3-dihydro-3-benzofuran derivatives was accom-
plished by combination of Davies’ Rh catalyst and the
pyrrolidinyl (S)-lactamide chiral auxiliary. This protocol
would be amenable to large-scale preparations of the di-
hydrobenzofuran derivatives, because the reaction em-
ploys an inexpensive chiral auxiliary and proceeds at
room temperature. In fact, during the course of synthetic
study on (–)-ephedradine A (4), conversion of 8c to 9c
was accomplished on a 50 g scale. Application of this
methodology to the total syntheses of 3 and 4 is under in-
vestigation in our laboratories.16
References
(1) For a review on neolignans, see: Ward, R. S. Nat. Prod. Rep.
1999, 16, 75.
(2) Sato, H.; Kawagishi, H.; Nishimura, T.; Yoneyama, S.;
Yoshimoto, Y.; Sakamura, S.; Furusaki, A.; Katsuragi, S.;
Matsumoto, T. Agric. Biol. Chem. 1985, 49, 2969.
(3) Tamada, M.; Endo, K.; Hikino, H.; Kabuto, C. Tetrahedron
Lett. 1979, 873.
Scheme 3 Reagents and conditions: a) ROH, WSCD, DMAP,
CH2Cl2; b) p-AcNHC6H4SO2N3, DBU, CH3CN (75% for 8b and 73%
for 8c in 2 steps).
(4) For construction of dihydrobenzofuran rings by oxidative
dimerisation, see: (a) Rummakko, P.; Brunow, G.; Orlandi,
M.; Rindone, B. Synlett 1999, 333. (b) Bolzacchini, E.;
Brunow, G.; Meinardi, S.; Orlandi, M.; Rindone, B.;
Rummakko, P.; Setala, H. Tetrahedron Lett. 1998, 39,
3291. (c) Maeda, S.; Masuda, H.; Tokoroyama, T. Chem.
Pharm. Bull. 1994, 42, 2536. (d) Maeda, S.; Masuda, H.;
Tokoroyama, T. Chem. Pharm. Bull. 1994, 42, 2500.
(e) Antus, S.; Gottsegen, A.; Kolonits, P.; Wagner, H.
Liebigs Ann. Chem. 1989, 593. (f) Antus, S.; Bauer, R.;
Gottsegen, A.; Seligmann, O.; Wagner, H. Liebigs Ann.
Chem. 1987, 357.
(5) For other methods for constructing dihydrobenzofuran rings,
see: (a) Russell, M. G. N.; Baker, R.; Ball, R. G.; Thomas, S.
R.; Tsou, N. N.; Castro, J. L. J. Chem. Soc., Perkin Trans. 1
2000, 893. (b) Russell, M. G. N.; Baker, R.; Castro, J. L.
Tetrahedron Lett. 1999, 40, 8667. (c) Prakash, O.; Tanwar,
M. P. Bull. Chem. Soc. Jpn. 1995, 68, 1168. (d) Baker, R.;
Cooke, N. G.; Humphrey, G. R.; Wright, S. H. B.;
Hirshfield, J. J. Chem. Soc., Chem. Commun. 1987, 1102.
(6) For a review on asymmetric intermolecular C-H activation,
see: Davies, H. M. L.; Antoulinakis, E. G. J. Organomet.
Chem. 2001, 617, 47.
Table 1 Diastereoselectivity of the Rh-Carbenoid-Mediated
Intramolecular C-H Insertion Reaction of 8b and 8c
Run
1
Cat. Rha
9bb
7:2
5:2
7:2
9cb
3:1
Rh2(OAc)4
2
Rh2(S-DOSP)4
Rh2(R-DOSP)4
8:1
3
13:1
a All reactions were carried out in CH2Cl2 using 5 mol% of Rh
catalyst.
b Diastereoselectivity was determined by 1H NMR.
Davies reported earlier that high diastereoselectivity of in-
termolecular Rh-carbenoid-mediated cyclopropanation
was achieved by using a-hydroxy ester derivatives as the
chiral auxiliaries.11 Similarly, we have observed high dia-
stereoselectivity in the C-H insertion reaction when 8b
and 8c were employed.12 Thus, carboxylic acid 7 was cou-
pled with methyl (S)-lactate and pyrrolidinyl (S)-
lactamide13 to give, after diazo transfer reaction, the cy-
clization precursors 8b and 8c, respectively (Scheme 2).
Upon treatment with rhodium catalyst (5 mol%), the C-H
(7) Davies, H. M. L.; Grazini, M. V. A.; Aouad, E. Org. Lett.
2001, 3, 1475.
(8) Davies, H. M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem.
Soc. 2000, 122, 3063.
Synlett 2003, No. 7, 1028–1030 ISSN 1234-567-89 © Thieme Stuttgart · New York

1030
W. Kurosawa et al.
LETTER
(12) The high diastereoselectivities observed with 8b and 8c
(9) The 2,3-cis-benzofuran was readily converted to the
thermodynamically more stable trans-isomer as shown in
Scheme 4. After removal of the benzyl group, treatment of
11 with TFA resulted in the predominant formation of the
trans isomer 12. The a-position of the ester 11 was
unaffected during the transformation based on the fact that
no deuterium incorporation was observed in 12 when 11 was
treated with CF3CO2D in CD2Cl2.
indicate that the carbenoid intermediate might have strong
interaction with the carbonyl group of the chiral auxiliary as
illustrated in Scheme 5. The similar interaction was reported
in ref. 10.
Scheme 5
(13) High diastereoinduction with pyrrolidinyl (S)-lactamide as a
chiral auxiliary has been reported by Tschaen in the SN2
reaction of a-haloester derivatives, see: Devine, P. N.;
Dolling, U.-H.; Heid, R. M. Jr.; Tschaen, D. M. Tetrahedron
Lett. 1996, 37, 2683.
Scheme 4
(14) For double asymmetric induction in intramolecular C-H
insertion reactions, see: Hashimoto, S.; Watanabe, N.;
Kawano, K.; Ikegami, S. Synth. Commun. 1994, 24, 3277.
(15) The absolute configuration of the major carboxylic acid was
determined as (2R,3R) by comparison of the optical rotation
of the corresponding methyl ester 9a with the related
compound reported in ref. 5a. Furthermore, the dihydro-
benzofuran 9a was independently synthesized by utilizing
Evans’ asymmetric aldol reaction and subsequent acidic
cyclization to confirm the stereochemistry. For Evans’
enantioselective aldol reaction, see: Evans, D. A.; Bartroli,
J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127.
(16) We have recently completed the total synthesis of
(–)-ephedradine A (4). Full details of the total synthesis of 4
will be reported in due course.
(10) Recently, Hashimoto reported a similar C-H insertion
reaction with his Rh(II)-catalyst, which proceeded in high
enantio- and diastereoselectivity: Treatment of a similar
aryldiazoacetate with 1 mol% of the catalyst in toluene at
–78 °C provided the cis-benzofuran in 94% ee, see:
Saito, H.; Oishi, H.; Kitagaki, S.; Nakamura, S.; Anada, M.;
Hashimoto, S. Org. Lett. 2002, 4, 3887.
(11) Davies, H. M. L.; Huby, N. J. S.; Cantrell, W. R. Jr.; Olive,
J. L. J. Am. Chem. Soc. 1993, 115, 9468.
Synlett 2003, No. 7, 1028–1030 ISSN 1234-567-89 © Thieme Stuttgart · New York