Unusual cycloadditions of o-quinone methides with oxazoles

Article abstract of DOI:10.1016/j.tetlet.2005.10.168

Unusual reactions between various electron-rich oxazoles and ortho-quinone methides is described. This combination leads to some interesting adducts.

Full text of DOI:10.1016/j.tetlet.2005.10.168

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 201–204
Unusual cycloadditions of o-quinone methides with oxazoles
Christopher C. Lindsey and Thomas R. R. Pettus*
Department of Chemistry and Biochemistry, University of California at Santa Barbara, Santa Barbara, CA 93106, USA
Received 27 September 2005; revised 28 October 2005; accepted 28 October 2005
Available online 22 November 2005
Abstract—Unusual reactions between various electron-rich oxazoles and ortho-quinone methides is described. This combination
leads to some interesting adducts.
Ó 2005 Elsevier Ltd. All rights reserved.
5
Until recently, controlled low temperature access to sig-
4
PO
1
O
nificant quantities of o-quinone methide intermediates
was almost impossible,1 a problem which severely limi-
ted their use in synthesis. With the development of an
anionic generation mechanism triggered at low tempera-
tures,2 these venerable intermediates have found many
additional synthetic uses.3 These included the first exam-
ples of stereoselective inverse demand cycloadditions,4
which evolved into diastereoselective reactions and
enabled the asymmetric synthesis of chiral benzopyrans.5
In this letter, we demonstrate that the reactivity of o-quin-
one methides proves sufficient to dearomatize and
cause a reaction with various 2-amino-4-alkyl oxazoles.
However, the reaction manifold (cycloaddition vs 1,4-
conjugate addition) depends upon the electronic nature
of the 4-alkyl substituent.
R
R
R
4
3
C
O3
or
2
5
9
R'
2
R"
O
6
OP'
O
O
10
5
1
X
X
4
7
8
1
B
A
D
N
2
3
R'
Figure 1. Proposed construction of the elaborate benzopyran A by
cycloaddition of o-quinone methide B with heterocycle C or D.
with several exceedingly electron deficient symmetric
4p dienes (Fig. 2).7 The yields reported for oxazoles with
4-alkyl substituents were significantly lower than their
hydrido counterparts.
Sometime ago, we became interested in constructing
elaborate 2H-1-benzopyrans such as A, bearing alkoxy
and alkyl substituents at the 2-position, along with an
alkoxy substituent at the 3-position (Fig. 1). This
arrangement of atoms can be found in 5,6-aryloxy-spiro-
ketal of heliquinomycin. We envisioned that benzopyran
A could arise from a regioselective cycloaddition
between o-quinone methide B and the 4-substituted
dioxene C. However, there are very few methods for
the preparation of these fragile dioxenes.6 The robust
oxazole D appeared to offer synthetic equivalence for
our strategy.
5
Cl
4
Cl
Cl
O
1
R
O
Cl
Cl
Cl
Cl
N
2
3
Cl
O
N
Bn
Cl
Cl
R = H, Me
benzene
r.t.
benzene
50 ˚C
Bn
N
N
O
Cl
Cl
Cl
Cl
O
Cl
Cl
R
Cl
O
A thorough literature search revealed a single report by
Dondoni employing electron-rich 2-amino-oxazoles
R
N
Cl
Bn
Cl
Cl
O
N
R = -H (87%)
R =-Me (71%)
R = -H (87%)
R = -Me (0%)
*
Corresponding author. Tel.: +1 (805) 637 5651; fax: +1 (805) 893
5690; e-mail: pettus@chem.ucsb.edu
Figure 2. Some of DondoniÕs 1986 cycloaddition examples.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.168

202
C. C. Lindsey, T. R. R. Pettus / Tetrahedron Letters 47 (2006) 201–204
Ph
O
O
N
Ph
N
N
N
N
1.15 eq.
O
1
2
t-BuMgBr
9
Ph
Ph
OH
12
OBoc
Ph
Ph
O
O
OEt
O
[11] generated in
presence
of 2 (-78 ˚C)
N
N
N
N
O
N
4
OTBS
OBn
3
Ph
Ph
O
O
N
N
N
N
N
1.15 eq.
t-BuMgBr
O
N
O
N
OBn
OBn
H
( )-6
5
OBn
HO
10
OH
O
[13] generated in
presence
of 5 (-78 ˚C)
Figure 3. Oxazoles 1–6 examined in combination with o-quinone
methides 11 and 13.
15
OMe
14
OMe
1
Because of our experience with o-quinone methide reac-
tivity, we first examined their capacity for reaction with
commercially available 4-alkyl oxazole 1 (Fig. 3).
Deprotonation of either of the ortho-OBoc hydroxy-
methyl aromatic compounds (9 or 10,8 0.1 M in Et2O
or THF) with tert-butyl magnesium bromide leads to
–OBoc migration and subsequent b-elimination furnish-
ing the corresponding o-quinone methide intermediate
(cf. 11 and 13, Scheme 1). Although these o-quinone
methide species are exceedingly reactive, 4-methyl-oxa-
zole (1) proved ineffective as a nucleophile. Instead, o-
quinone methide intermediate undergoes self-destruc-
tion through known manifolds, such as Diels–Alder
dimerization and trimerization.
:
10
Scheme 2. Cycloadditions of oxazoles
methides 11 and 13.
2
and 5 with o-quinone
62% combined yield. In this instance, the 1,4-addition
product 1512 predominates in the mixture, and the
[4+2] cycloadduct 14 arises in small amounts (10:1).
Given the preceding result, we were surprised to find
that the silylated 4-hydroxymethyl oxazole 4 undergoes
reaction with o-quinone methide 11 generated under
similar conditions to afford in 66% combined yield a
3:1 mixture favoring the [4+2] adduct 1613 over the
1,4-conjugate addition product 1714 (Scheme 3). In addi-
tion, the carbonate protected 4-hydroxymethyl oxazole
3, undergoes cycloaddition with quinone methide 13
and affords benzopyran 1815 in 46% yield as the only
identifiable product.
Next, we examined 2-amino-4-methyl-oxazole (2) for
which Dondoni has developed an efficient synthesis.9
The initial findings, though unexpected, were encourag-
ing—the 1,4-conjugate addition adduct 1210 forms as
the sole product in a respectable 60% yield (Scheme 2).
In our past experiences with these o-quinone methides,
the conjugate addition adduct only arises with highly
polarized 2p dienophiles such as enamines. We designed
and synthesized several more elaborate oxazoles, such as
3–6.11 Generation of o-quinone methide 13 from 10 in
the presence of oxazole 5 leads to two adducts in a
It seemed that a subtle allylic stereoelectronic inductive
effect governed the outcome of the reaction (Fig. 4).
N
N
Ph
Ph
O
O
OTBS
OTBS
N
N
O
O
H
OH
1.15 eq.
H
t-BuMgBr
OH
OBoc
9
NaBH4
OBoc
[11] generated in
presence
of 4 (-78 ˚C)
R
THF/H2O
R
9
R = –OBoc
10 R = –OMe
OBoc
OBoc
17
7 R = –OBoc
8 R = –OMe
16
3
:
1
1.15 eq. t-BuMgBr
added and
N
Ph
O
OEt
O
1.15 eq.
O
N
t-BuMgBr
no desired adducts
observed
only dimerization,
trimerization, and
decomposition
H
10
O
[13] generated in
presence
of 3 (-78 ˚C)
O
R
18
generated in presence of
of oxazole 1 (-78 C)
˚
11 (R = –OBoc), 13 (R = –OMe)
OMe
and
Scheme 1. Dissatisfactory outcome between o-quinone methides 11
and 13 with oxazole 1.
Scheme 3. Cycloadditions of oxazoles
methides 11 and 13.
3
4
with o-quinone

C. C. Lindsey, T. R. R. Pettus / Tetrahedron Letters 47 (2006) 201–204
203
Ph
o-qm
o-qm
Ph
N
Ph
R = -EDG
R = -EWG
N
O
N
[4+2]
cycloaddition
[1,4]-
N
conjugate addition
O
R
N
R
H+
O
R
N
H
Figure 4. Kinetic reaction manifold (cycloaddition vs 1,4-addition)
appears R-substituent dependant.
O
OH
OR'
OR'
The 2-amino oxazoles displaying an electron rich substi-
tuent at the 4-position (R = H, Bn) underwent highly
asynchronous reactions leading to 1,4-conjugate
addition adducts, while the oxazoles displaying an
electron-withdrawing substituent at the 4-position
(R = –OTBS, –OCO2Et) underwent a synchronous
reaction affording the [4+2]-cycloadduct.
Figure 5. Thermodynamic equilibrium discovered.
addition of trace acid or by standing in CDCl3 for pro-
longed periods.
With oxazole 18 in hand, and knowledge of the acid-
mediated equilibrium, we were curious to see the out-
come upon hydrogenolysis to phenol 20.17 In principle,
the resulting phenolic benzopyran 20 might undergo
spiroketalization to 5,6-aryloxyspiroketal 24, a struc-
tural ensemble similar to that found in rubromycin
and heliquinomycin. Our initial experiments proved
disappointing. In all our attempts to induce spiroketal-
ization, the undesired tetracyclic compound 2218 forms.
We speculate that chromene 21 may precede compound
22, and that it succumbs to rapid air oxidation. How-
ever, further experiments are required to substantiate
this hypothesis (Scheme 5).
To test this supposition, we generated o-quinone meth-
ide 13 in the presence of the deprotonated oxazole
( )-6—an analog of 4-benzylated oxazole 5 that had
led almost exclusively to 1,4-conjugate addition adduct
15 (Scheme 2). In the case of the deprotonated oxazole
( )-6, however, the reaction proceeds to the cycloadduct
19 (Scheme 4).16 The fact that none of the corresponding
1,4-addition adduct is observed further substantiates
our claim—less polarized 2-amino-oxazoles proceed
through synchronous cycloadditions, while the more
polar systems resemble enamines in their asynchronous
reactivity. The stereointegrity of the reaction attests to
the kinetic preference for a single endo transition state.
Therefore, if a method was available for procuring the
hydroxyl stereocenter in oxazole 6, then the stereochem-
istry of the benzopyran would be accessible in an abso-
lute sense.
In conclusion, the unknown reactivity of some o-quin-
one methides and 2-amino-oxazoles has been revealed.
Their combination leads to an interesting assortment
of benzopyrans and oxazoles. Access to these heterocy-
clic compounds may prove to be of some therapeutic
interest in the future.
Chromatography illuminates a thermodynamic equilib-
rium between the conjugate addition and cycloaddition
adducts of the preceding schemes with mild acid
(Fig. 5). For example, if the purified oxazole 15 is sub-
jected to trace acid, a 3:1 mixture of the cycloadduct
14 and oxazole 15 forms. The purified oxazoles 12 and
18 also proceed to a mixture of [4+2] and 1,4-addition
adducts; (approximately 1:1 in both of these cases) upon
Ph
HN
H
N
O
O
N
Ph
N
OH
23
O
O
MeO
24
MeO
HO
H
Ph
2.15 eq.
O
N
N
t-BuMgBr
H
N
O
N
O
Ph
10
O
OMe
[13] generated in
presence
of ( )-6 (-78 ˚C)
H
Pd(OH)2
N
Ph
N
OH
OBn
O
19
1atm H2
MeOH
OBn
OH
18
HO
20
MeO
‡
H+
O
OR
OMe
H
Ph
O
N
H
O
O
O
N
O2
O
MgBr
O
O
3.2.1 chelate
reactive α-face
21
MeO
MeO
Bn
22
Scheme 4. Diastereoselective cycloaddition.
Scheme 5. New chromene formed.

204
C. C. Lindsey, T. R. R. Pettus / Tetrahedron Letters 47 (2006) 201–204
12. Compound 15: yellow solid. Isolated yield 55%. mp = 44–
Acknowledgements
46 °C. 1H NMR (CDCl3, 400 MHz) d 7.39–7.12 (m, 12H),
6.89–6.81 (m, 2H), 6.43 (br s, OH), 6.33–6.31 (m, 2H) 5.02
(s, 2H), 4.45 (s, 2H), 3.84 (s, 2H), 3.67 (s, 3H), 3.60 (s, 2H),
2.88 (s, 3H); HRMS (ESI) calcd for C33H32N2O4
520.236208, found 520.235058.
Research support from the University of California
Coordinating Committee on Cancer Research in the
form of two awards (19990641) and (SB010064) are
greatly appreciated along with additional support of
NSF (CHE-9971211), PRF (PRF34986-G1), NIH
(GM-64831), the UC-AIDS Initiative (K00-SB-039)
and Research Corporation (R10296). We are also
thankful for the support of our M.S. facility funded in
part by DAAD19-00-1-0026.
13. Compound 16: white solid. Isolated yield 51%. mp = 113–
114 °C. 1H NMR (CDCl3, 400 MHz) d 7.24–7.20 (m, 3H),
7.06 (d, J = 8.0 Hz, 1H), 6.87–6.82 (m, 4H), 5.25 (dd,
J1 = 3.2 Hz, J2 = 2.9 Hz, 1H), 4.34 (br s, 2H), 4.13 (d,
J = 10.7 Hz, 1H), 3.87 (d, J = 10.5 Hz, 1H), 3.03 (dd,
J1 = 15.4 Hz, J2 = 2.5 Hz, 1H), 2.90 (dd, J1 = 15.6 Hz,
J2 = 3.2 Hz, 1H), 2.71 (s, 3H), 1.56 (s, 9H), 0.90 (s, 9H),
0.11 (s, 3H), 0.09 (s, 3H); MS (ESI) m/z 555 (100.0), 500
(11.7), 499 (32.5), 413 (9.70) HRMS (ESI) calcd for
C30H42N2O6Si 555.2890, found 555.2905 (M+H).
14. Compound 17: yellow oil. Isolated yield 17%. 1H NMR
(CDCl3, 400 MHz) d 7.65 (br s, OH), 7.32–7.20 (m, 3H),
7.19–7.14 (m, 3H), 6.69 (d, J = 2.3 Hz, 1H), 6.65 (dd,
J1 = 8.2 Hz, J2 = 2.5 Hz, 1H), 4.78 (s, 2H), 4.48 (s, 2H),
3.94 (s, 2H), 2.89 (s, 3H), 1.56 (s, 9H), 0.99 (s, 9H), 0.22 (s,
6H); HRMS (ESI) 555 (100.0), 553 (46.1), 537 (22.6), 499
(19.1), 423 (20.8), calcd for C30H42N2O6Si 577.2710, found
577.2698 (M+Na).
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.10.168.
References and notes
15. Compound 18: isolated yield 46%. 1H NMR (CDCl3,
400 MHz) d 7.20–7.14 (m, 3H), 7.00 (d, 8.2 Hz, 1H), 6.75
(m, 2H), 6.66 (d, J = 2.3 Hz, 1H), 6.61 (dd, J1 = 8.1 Hz,
J2 = 2.2 Hz, 1H), 5.19 (t, J = 3.2 Hz, 1H), 4.7 (d,
J = 11.2 Hz, 1H), 4.40 (d, J = 11.1 Hz, 1H), 4.23 (q,
J = 7.2 Hz, 2H), 3.77 (s, 3H), 3.02 (dd, J1 = 15.5 Hz,
J2 = 2.5 Hz, 1H), 2.92 (dd, J1 = 15.5 Hz, J2 = 2.7 Hz, 1H),
2.71 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H); 13C (100.6 MHz) d
158.9, 155.1, 155.0, 136.9, 129.2, 128.7, 127.4, 127.2, 116.1,
109.6, 105.2, 102.6, 82.7, 71.2, 64.5, 55.5, 53.4, 29.5, 27.8,
14.5.
1. Van De Water, R. W.; Pettus, T. R. R. Tetrahedron 2002,
58, 5367–5405.
2. Van De Water, R. W.; Magdziak, D. J.; Chau, J. N.;
Pettus, T. R. R. J. Am. Chem. Soc. 2000, 122, 6502–6503.
3. (a) Jones, R. M.; Van De Water, R. W.; Lindsey, C. C.;
Hoarau, C.; Ung, T.; Pettus, T. R. R. J. Org. Chem. 2001,
66, 3435–3441; (b) Lindsey, C.; Gomez-Diaz, C.; Villalba,
J. M.; Pettus, T. R. R. Tetrahedron 2002, 58, 4559–4565.
4. Jones, R. M.; Selenski, C.; Pettus, T. R. R. J. Org. Chem.
2002, 67, 6911–6915.
5. (a) Selenski, C.; Pettus, T. R. R. J. Org. Chem. 2004, 9196–
9203; (b) Selenski, C.; Mejorado, L.; Pettus, T. R. R.
Synlett 2004, 1101–1103; For other recent examples, see:
(c) Adlington, R. M.; Rodriquez, R.; Moses, J. E.;
Cowley, A.; Baldwin, J. E. Org. Lett. 2004, 6, 3617.
6. Scharf, H. D.; Wolters, E. Angew. Chem. 1976, 88, 718.
7. Dondoni, A.; Fogagnolo, M.; Mastellari, A.; Pedrini, P.;
Ugozzoli, F. Tetrahedron Lett. 1986, 27, 3915–3918.
1
16. Compound 19: viscous yellow oil. Isolated yield 31%. H
NMR (CDCl3, 400 MHz) d 7.65 (d, 7.5 Hz, 1H), 7.45 (m,
2H), 7.35–7.16 (m, 7H), 7.02 (m, 1H), 6.90 (m, 2H), 6.72
(br s, 2H), 6.64 (d, J = 2.3, 1H), 6.56 (dd, J1 = 8.3 Hz,
J2 = 2.3 Hz, 1H), 5.72 (s, 1H), 5.23 (s, 1H), 5.10 (s, 2H),
4.36 (d, J = 15.6 Hz, 2H), 3.76 (s, 1H), 3.30 (br s, OH),
2.80 (dd, J1 = 15.2 Hz, J2 = 2.6 Hz, 1H), 2.72 (br s, 3H),
2.33 (dd, J1 = 15.2 Hz, J2 = 2.6 Hz, 1H).
1
8. Compound 10: A transparent oil. Isolated yield 71%. H
17. Compound 20: yellow solid. Isolated yield 46%. mp = 65–
67 °C. 1H NMR (CDCl3, 400 MHz) d 10.4 (br s, NH),
7.27–7.11 (m, 7H), 7.02–6.90 (m, 2H), 6.88 (td, J1 = 7.2,
J2 = 1.2 Hz, 1H), 6.77–6.61 (m, 2H), 5.10 (dd, J1 = 3.0 Hz,
J2 = 2.8 Hz, 1H), 4.4 (br s, 2H), 3.79 (s, 3H), 3.75 (d,
J = 14.0 Hz, 1H), 3.12 (d, J = 14.0 Hz, 1H), 3.04 (dd,
J1 = 15.5, J2 = 2.7 Hz, 1H), 2.95 (dd, J1 = 15.0,
J2 = 2.5 Hz), 2.77 (br s, 3H); MS (ESI) m/z 430 (23.6),
323 (23.2), 136 (43.3), 90 (100.0), 76 (10.6), HRMS (ESI)
calcd for C26H26N2O4 430.189258, found 430.189231.
18. Compound 22: yellow oil. Isolated yield 31%. 1H NMR
(CDCl3, 400 MHz) d 7.63 (dd, J1 = 4.3 Hz, J2 = 0.7 Hz,
1H), 7.58 (dd, J1 = 8.6 Hz, J2 = 0.7 Hz, 1H), 7.50 (d,
8.6 Hz, 1H), 7.35–7.35 (m, 3H), 7.09 (m, 3H) 3.90 (s, 3H).
NMR (CDCl3, 400 MHz) d 7.36 (d, 8.5 Hz, 1H), 6.81 (dd,
J1 = 8.6 Hz, J2 = 2.7 Hz, 1H), 6.70 (d, 2.5 Hz, 1H), 4.55
(d, J = 4.7 Hz, 2H), 3.81 (s, 3H), 2.06 (br s, 1OH) 1.57 (s,
9H); HRMS (ESI) calcd for C13H18O5 254.115424, found
254.115703.
9. Cockerill, A. F.; Deacon, A.; Harrison, R. G.; Osborne,
D. J.; Prime, D. M.; Ross, W. J.; Todd, A.; Verge, J. P.
Synthesis 1976, 9, 591–593.
10. Compound 12: clear oil. Isolated yield 60%. 1H NMR
(CDCl3, 400 MHz)
d 7.31–7.22 (m, 5H), 7.06 (dd,
J1 = 8.4 Hz, J2 = 2.2 Hz, 1H), 6.69–6.67 (m, 2H), 4.51 (s,
2H), 3.81 (s, 2H), 2.93 (2, 3H), 2.03 (s, 3H), 1.56 (s, 9H).
11. Lindsey, C. C.; OÕBoyle, B. M.; Mercede, S. J.; Pettus, T.
R. R. Tetrahedron Lett. 2004, 45, 867.