Unprecedented intramolecular nucleophilic aromatic additions of allyloxy anions to diphenylphosphinoyl-substituted benzene rings: A facile method for preparing multisubstituted benzopyrans

Article abstract of DOI:10.1055/s-2007-1000835

A new synthetic method for the preparation of multisubstituted benzopyrans that involves an intramolecular conjugate addition of allyloxy anions to diphenylphosphinoyl-substituted benzene rings is described. The intermediate anion is trapped with electrophiles providing benzopyrans that are readily oxidized with O₂ to intermediates containing a peroxide that is easily converted into benzopyran-2-ones (i.e. coumarins). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-1000835

LETTER
129
Unprecedented Intramolecular Nucleophilic Aromatic Additions of Allyloxy
Anions to Diphenylphosphinoyl-Substituted Benzene Rings: A Facile Method
for Preparing Multisubstituted Benzopyrans
A
F
acile Metho
v
d
for Prepari
u
ng Multisubs
g
tituted Benz
e
opyrans ni Gorobets, Masood Parvez, Brian A. Keay*
Department of Chemistry, University of Calgary, Calgary, AB, T2N 1N4, Canada
Fax +1(403)2841372; E-mail: keay@ucalgary.ca
Received 2 October 2007
6 thereby providing a new preparation2 of this ubiquitous
class of natural products which often display a wide range
of biological activity.2a,3 The scope and limitations of this
new reaction is described herein.
Abstract: A new synthetic method for the preparation of multisub-
stituted benzopyrans that involves an intramolecular conjugate ad-
dition of allyloxy anions to diphenylphosphinoyl-substituted
benzene rings is described. The intermediate anion is trapped with
electrophiles providing benzopyrans that are readily oxidized with
O2 to intermediates containing a peroxide that is easily converted
into benzopyran-2-ones (i.e. coumarins).
Although treatment of allyl-protected phenol 1a with
LDA (THF, –78 °C) followed by the addition of I2 gave
the expected iodinated product 7 (Scheme 2), allyl-pro-
tected phenol 1b under identical conditions provided 8.
The structure of compound 8 was initially assigned using
1H and 13C NMR spectra and MS data; however, attempts
to grow crystals of 8 under an atmosphere of air resulted
Key words: nucleophilic aromatic additions, cyclizations, ben-
zopyrans, coumarins
During studies aimed at developing new 3,3¢-disubstituted
biphenyl-2,2-diylbis(diphenylphosphine) (BIPHEP) and
1
in the formation of a new compound (by H NMR spec-
troscopy). X-ray crystallography (Figure 1) indicated the
newly formed compound contained a peroxide and had
the structure 9. Since something unique was happening
when 1b was treated with LDA followed by I2, we decided
to investigate the mechanism of this reaction.
2,2¢-bis(diphenylphosphino)-1,1¢-binaphthyl
(BINAP)
ligands,1 we discovered a new reaction involving an in-
tramolecular nucleophilic aromatic addition of an allyl-
oxy anion to diphenylphosphinoyl-substituted benzene
rings (Scheme 1). The resultant intermediate, diphen-
ylphosphinoyl-stabilized anion, can react in situ with a va-
riety of electrophiles resulting in the formation of
multisubstituted benzopyran derivatives 2–4 depending
on the substituents present in 1. Further air oxidation of 4
led to peroxide 5 that was easily converted into coumarin
Since methallyl-protected phenol 1c exhibited similar be-
havior to 1b when treated with LDA and I2 (giving 10), we
decided to study the mechanism of this reaction using 1c
since 10 was less prone to oxidation to its corresponding
peroxide (not shown). Treatment of 1c with LDA/THF at
H
R1
R2
R2
R1
O
POPh2
O
POPh2
H
R3
e
R3
a,d
a,b
4
2
R1
R2
O
POPh2
R3
1
R1
R2
R
a,c
R1
O
R2
R4
e
O
HO
O
R3
R3
f
3
R2
R4
R1
O
5 R4 = POPh2 or
CH2R
O
R3
6 R4 = POPh2 or
CH2R
Scheme 1 Reagents and conditions: (a) LDA, THF, –78 °C; (b) H+ source; (c) RCHO; (d) I2; (e) O2, r.t.; (f) Ac2O, DMAP.
SYNLETT 2008, No. 1, pp 0129–0133
x
x.
x
x.
2
0
0
7
Advanced online publication: 11.12.2007
DOI: 10.1055/s-2007-1000835; Art ID: S07907ST
© Georg Thieme Verlag Stuttgart · New York

130
E. Gorobets et al.
LETTER
–78 °C for four hours followed by the addition of H2O (or To determine if the initial site of deprotonation with LDA
D2O) gave a mixture of three compounds (3.2:2:1 ratio) of was on the methallyloxy group or the aromatic ring fol-
which the major isomer 11 crystallized and was analyzed lowed by an anionic migration to the methallyl group, 1c
by X-ray crystallography (Figure 2). Two other compo- was premixed with TMSCl5 and then treated with LDA in
nents of the mixture were identified as cis-11 and a double THF at –78 °C (Scheme 3). A mixture of four compounds
bond isomer of 11.4
was obtained with the two major isomers being assigned
12 and 13 (1:1). The other two isomers were 12 and 13
with an additional TMS group on one of the aromatic
rings of the diphenylphosphinoyl moiety. This result indi-
cated that LDA initially abstracted a proton from the
methallyl group in 1c. Further evidence to support a direct
hydrogen abstraction from the methallyl group was real-
ized when 14 (containing two deuterium atoms) was treat-
ed with LDA at –78 °C. Again a mixture of three isomers
was obtained with 15 being isolated as the major product.
Compound 15 contained the two deuterium atoms that
were present in 14 confirming that LDA was not initially
abstracting a proton from the aromatic ring in 14 (or 1c).
Based on the evidence above, we propose the following
mechanism for this new cyclization (Scheme 4). Abstrac-
tion of a methallyl proton in 1c (or allyl proton in 1b) by
LDA leads to an anion that undergoes a nucleophilic at-
tack on the aromatic ring para to the POPh2 group, result-
ing in stabilized anion 16. This anion can either pick up a
proton (or deuteron) upon workup with water to form 11
(as a mixture of configurational and double bond isomers)
or react with I2 to form intermediate 17 that eliminates HI
upon workup to regenerate the aromatic ring giving 10.
While there have been sporadic reports involving aryl an-
ions and t-BuLi adding to aromatic rings containing a
diphenylphosphinoyl moiety, these have been reported as
unwanted side reactions during various lithiation attempts
of BINAP(O),6a triphenylphosphine oxide,6b and 2-
(diphenylphosphinoyl)naphthalene.7 The steric influence
of the dimethyl acetal group must result in the diphen-
ylphosphinoyl rotating in such a way as to block abstrac-
tion of the aromatic proton at C2 in 1b and 1c resulting in
abstraction of the allylic or methallylic proton. With the
absence of the acetal group in 1a, the diphenylphosphi-
Figure 1 X-ray crystal structure of 9
Figure 2 X-ray crystal structure of 11
1) LDA, THF,
–78 °C, 1 h
1a
2) I2, THF, 15 min
O
POPh2
R1 = R2 = R3 = H
I
7 59%
OMe
OMe
POPh2
OMe
OMe
1) LDA, THF
–78 °C, 2 h
air, EtOAc
r.t., 24 h
1b
2) I2, THF,
15 min
R
R
2 = CH(OMe)2
1 = R3 = H
O
POPh2
OMe
O
O
8 64%
OH
9 44%
OMe
H
1) LDA, THF
–78 °C, 4 h
OMe
1) LDA, –78 °C
OMe
POPh2
1c
2) H2O (D2O)
3) crystallization
2) I2, THF
15 min
POPh2
H(D)
48% for 3 isomers
O
O
10 57%
11
R
R
2 = CH(OMe)2
1 = Me, R3 = H
Scheme 2
Synlett 2008, No. 1, 129–133 © Thieme Stuttgart · New York

LETTER
A Facile Method for Preparing Multisubstituted Benzopyrans
131
OMe
OMe
12
OMe
OMe
TMS
O
POPh2
1) premix with TMSCl
2) LDA, –78 °C, THF
+
TMS
OMe
O
POPh2
OMe
1c
O
POPh2
13 54% for two isomers
OMe
OMe
D
D
1) LDA, –78 °C, THF
2) H2O
OMe
OMe
O
POPh2
14
O
POPh2
H
D
D
15
Scheme 3
OMe
OMe
POPh2
OMe
OMe
POPh2
H
−
H
O
O
1c
16
N–
H2O (D2O)
I2
OMe
OMe
H
OMe
OMe
OMe
POPh2
H
OMe
POPh2
– HI
O
POPh2
H(D)
O
O
I
11
10
17
Scheme 4
noyl group acts as an ortho-lithiation director7 resulting in 18 (R = Ph) could not be isolated as it immediately
the expected abstraction of the C2 proton leading to 7 isomerized to 19a (R = Ph) during workup. The in situ
when the anion is treated with iodine.
Horner–Wittig reaction was found to be a general reac-
tion. Three other aldehydes reacted with 16 to provide
benzopyrans 19b–d in reasonable yields (58–64%) after
purification (Scheme 5).10
We then investigated whether anion 16 could be used in
situ to perform Horner–Wittig reaction8 with a variety of
aldehydes. Treatment of anion 16 (formed by treating 1c
with LDA at –78 °C in THF) with benzaldehyde at –78 °C With the above results in hand, we turned to expanding
followed by warming the mixture to room temperature re- the scope of this reaction by investigating what type of
sulted in the formation of 19a9 (R = Ph) in 62% yield after groups could be tolerated on the allyl moiety. Initially, we
workup with water (Scheme 5). Interestingly, compound investigated the effect of groups at the C2 position of the
OMe
O
OMe
H
OMe
R
H
OMe
R
16
R
THF, –78 °C to r.t.
1 h
O
O
19
18
R
Yield (%)
a Ph
b cyclohexyl
c 2-furyl
62
64
58
d CH2CH2N(Bn)Boc 62
Scheme 5
Synlett 2008, No. 1, 129–133 © Thieme Stuttgart · New York

132
E. Gorobets et al.
LETTER
OMe
OMe
OMe
OMe
3
R
1. LDA, THF, –78 °C
2. PhC(O)H
R
2
1
Ph
O
O
POPh2
R
20 H
21 Ph
22 CH2OTBS
23 CH=CH2
Yield (%)
24 67
25 63
26 63
27 59
Scheme 6
1) LDA, – 78 °C, THF
2) I2
O
POPh2
O
POPh2
Ph
Ph
77%
29
28
1) LDA, –78 °C, THF
2) I2
O
POPh2
O
POPh2
Ph
30
Ph
74%
31
OMe
OMe
R
Ac2O, DMAP
CH2Cl2, r.t., 1 h
R
O2, r.t., 48 h
acetone
OMe
Ph
OMe
Ph
O
O
O
24 R = H
25 R = Ph
32 81%
33 62%
Scheme 7
allyl group (Scheme 6). Compounds 20–23 provided 24– (Scheme 7). Stirring an acetone solution of 24 and 25 un-
27,11 respectively, with yields ranging from 59–67%. Un- der an atmosphere of O2 for 48 hours gave intermediate
fortunately, substitution of the allyl group at C1 and C3 or peroxides (not shown) that without purification12 were
just at C3 shut down the cyclization reaction in favor of treated with acetic anhydride–DMAP in CH2Cl2 to give
the LDA abstracting a proton from one of the phenyl rings benzopyran-2-ones 32 and 33 in good yield.
attached to the diphenylphosphinoyl group.
In summary, we have reported a new route towards the
The presence of the dimethylacetal group in compounds synthesis of multisubstituted benzopyrans that involves
1b, 1c and 20–23 is necessary since in its absence, LDA an intramolecular conjugate addition of allyloxy anions to
just abstracts the aromatic proton ortho to both the allyl- diphenylphosphinoyl-substituted benzene rings. The in-
oxy and the Ph2P=O groups (see 1a → 7, Scheme 2). We termediate anion can be trapped with electrophiles provid-
reasoned that the presence of a functional group between ing benzopyrans that are easily oxidized by oxygen to
the allyloxy and Ph2P=O groups might lead to a cycliza- peroxide intermediates that can be subsequently convert-
tion in the absence of the dimethylacetal group. This was ed into benzopyran-2-ones (i.e. coumarins). Extensions of
realized when compound 28 was treated with LDA at this work to determine if the dimethylacetal group is nec-
–78 °C and the resulting anion was subsequently treated essary for the cyclization, if other functional groups can
with I2 (Scheme 7) providing the expected product 29 in be tolerated and applications to the synthesis of natural
77% yield. Finally, the reaction was not restricted to sub- products are currently underway.
stituted benzene rings as naphthalene 30 cyclized as ex-
pected to give 31 (Scheme 7) thus expanding the scope of
the cyclization reaction.
Acknowledgment
We thank the Merck Frosst Center for Therapeutic Research (Cana-
da), the NSERC CRD program, and the University of Calgary for
financial support.
As noted above, benzopyran 8 was unstable in air and ox-
idized readily to peroxide 9 (Scheme 2). We took advan-
tage of this reaction to prepare some benzopyran-2-ones
Synlett 2008, No. 1, 129–133 © Thieme Stuttgart · New York

LETTER
A Facile Method for Preparing Multisubstituted Benzopyrans
133
(7) Alcock, N. W.; Brown, J. M.; Pearson, M.; Woodward, S.
Tetrahedron: Asymmetry 1992, 3, 17.
(8) Horner, L.; Hoffmann, H.; Wippel, J. H. G.; Klahre, G.
Chem. Ber. 1959, 92, 2499.
References and Notes
(1) (a) Hopkins, J. M. E.; Gorobets, E.; Wheatley, B. M. M.;
Parvez, M.; Keay, B. A. Synlett 2006, 3120. (b) Gorobets,
E.; Parvez, M.; Wheatley, B. M. M.; Keay, B. A. Can. J.
Chem. 2006, 84, 93. (c) Hopkins, J. M.; Parvez, M.; Keay,
B. A. Org. Lett. 2005, 7, 3765. (d) Gorobets, E.; McDonald,
R.; Keay, B. A. Org. Lett. 2006, 8, 1483. (e) Gorobets, E.;
Wheatley, B. M. M.; Hopkins, J. M.; McDonald, R.; Keay,
B. A. Tetrahedron Lett. 2005, 46, 3843. (f) Gorobets, E.;
Sun, G.-R.; Wheatley, B. M. M.; Parvez, M.; Keay, B. A.
Tetrahedron Lett. 2004, 45, 3597.
(9) 7-Benzyl-6-dimethoxymethyl-3-methyl-4H-chromene
(19a): To a solution of allylbenzene 1c (0.61 g, 1.45 mmol)
in THF (15 mL) was added a solution LDA over 5 min (1.74
mmol) in THF (6 mL) at –78 °C. After 4 h at this temperature
a solution of benzaldehyde (0.21 g, 2.0 mmol) in THF (3
mL) was added at –78 °C over 5 min upon which the dark
cherry color disappeared. After 15 min of stirring at this
temperature the reaction mixture was allowed to warm to r.t.
for 1 h and quenched with aq sat. NH4Cl solution (5 mL) and
H2O (5 mL) under stirring. After 10 min the organic phase
was separated and the aqueous one was extracted with
CH2Cl2 (2 × 40 mL). The combined organic extract was
washed with brine (20 mL), dried over Na2SO4 and
concentrated in vacuo. The residue was forwarded to silica
gel column chromatography (35 g, hexanes–EtOAc–Et3N,
135:15:1) to give oily 19a (0.28 g, 62% yield). Please note
19a was easily oxidized to the corresponding peroxide (like
9) if left exposed to air. 1H NMR (200 MHz, C6D6): d = 7.58
(s, 1 H, CH), 7.05–7.25 (m, 5 H, CH), 6.91 (s, 1 H, CH), 6.24
(q, J = 1.5 Hz, 1 H, CH), 5.50 [s, 1 H, CH(OMe)2], 4.10 (s,
2 H, Bn), 3.17 (s, 6 H, MeO), 3.05 (s, 2 H, CH2Ar), 1.32 (s,
3 H, Me). 13C NMR (50 MHz, C6D6): d = 151.2 (C), 140.6
(C), 138.5 (C), 135.1 (CH), 130.7 (C), 128.9 (CH), 128.4
(CH), 128.3 (CH), 125.9 (CH), 118.3 (CH), 116.8 (C), 108.3
(C), 100.9 [CH(OMe)2], 52.0 (MeO), 37.7 (CH2), 28.3
(CH2), 17.5 (Me). IR (film): 3326, 2939, 2908, 2830, 1691,
1626, 1573, 1496, 1452, 1356, 1186, 1108, 1047, 987, 956,
735, 696 cm–1. MS (EI): m/z (rel. intensity) = 165 (11), 178
(14), 231 (11), 247 (100), 277 (11), 278 (100), 310 (38)
[M+]. HRMS: m/z [M+] calcd for C20H22O3: 310.1569;
found: 310.1546.
(2) For synthetic routes to coumarins, see: (a) Ellis, G. P.;
Lockhart, I. M.; Meeder-Nyez, D. Chromenes,
Chromanones, and Chromones; Ellis, G. P., Ed.; John Wiley
& Sons: New York, 1977. (b) Borges, F.; Roleira, F.;
Milhazes, N.; Santana, L.; Uriarte, E. Curr. Med. Chem.
2005, 12, 887; and references therein. (c) Chatterjee, A. K.;
Toste, F. D.; Goldberg, S. D.; Grubbs, R. H. Pure Appl.
Chem. 2003, 75, 421. (d) Nguyen, T.; Debenedetti, S.; De
Kimpe, N. Tetrahedron Lett. 2003, 44, 4199. (e) Trost, B.
M.; Toste, F. D. J. Am. Chem. Soc. 1996, 118, 6305. (f) Jia,
C.; Piao, D.; Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara,
Y. Science 2000, 287, 1992. (g) Wu, J.; Diao, T.; Sun, W.;
Li, Y. Synth. Commun. 2006, 36, 2949.
(3) (a) Santana, L.; Uriarte, E.; Roleira, F.; Milhazes, N.;
Borges, F. Curr. Med. Chem. 2004, 11, 3239. (b) Estévez-
Braun, A.; González, A. G. Nat. Prod. Rep. 1997, 14, 465.
(c) Murray, R. D. H. Nat. Prod. Rep. 1995, 12, 477.
(d) Kostova, I.; Raleva, S.; Genova, P.; Argirova, R.
Bioinorg. Chem. Appl. 2006, 2006, 1. (e) Murray, R. D. H.
The Naturally Occurring Coumarins; Springer: New York,
2002.
(4) Interestingly, selection of a different proton source
significantly improved both selectivity of the reaction and
yield. For example, adding N-Boc-2-methylalanine methyl
ester to anion 16 instead of H2O improved the isomeric ratio
to 14:1:1.4 in favor of trans-11 and the yield from 48% to
85%.
(5) It is well known that TMSCl does not react with LDA at
–78 °C. See: Krizan, T. D.; Martin, J. C. J. Am. Chem. Soc.
1983, 105, 6155.
(6) (a) Widhalm, M.; Mereiter, K. Bull. Chem. Soc. Jpn. 2003,
76, 1233. (b) Ogawa, S.; Tajiri, Y.; Furkawa, N. Bull. Chem.
Soc. Jpn. 1991, 64, 3182.
(10) The moderate yields of this reaction were due to the products
being easily oxidized to their corresponding peroxides upon
workup.
(11) Compounds with similar structures to 24 have displayed
interesting fragrances: Demyttenaere, J.; Van Syngel, K.;
Markusse, A. P.; Vervisch, S.; Debenedetti, S.; De Kimpe,
N. Tetrahedron 2002, 58, 2163.
(12) The peroxides did not survive silica gel purification so they
were used immediately in the next reaction. The peroxide
was formed in 80–85% yield (by 1H NMR spectroscopy).
Synlett 2008, No. 1, 129–133 © Thieme Stuttgart · New York

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