Acid-catalyzed synthesis of methylene-bridged (S)-tyrosine - Phenol dimers

Article abstract of DOI:10.1021/jo0610863

(Chemical Equation Presented) The efficient synthesis of 2,2′-arylmethylene dimers from 3-hydroxymethyl or 3-methoxymethyl-5-halo- (S)-tyrosines and para-substituted phenols under acid-catalyzed reaction conditions using either conventional or microwave-a

Full text of DOI:10.1021/jo0610863

Acid-Catalyzed Synthesis of Methylene-Bridged
(S)-Tyrosine-Phenol Dimers
Sean P. Bew,* David L. Hughes, and Sunil V. Sharma
School of Chemical Sciences & Pharmacy, UniVersity of East
Anglia, Norwich NR4 7TJ, UK
s.bew@uea.ac.uk
ReceiVed May 26, 2006
FIGURE 1. (S)-Tyrosine-derived dimers and their starting materials.
a phenol. Critical to the overall strategy, the synthesis of our
target dimers had to be efficient, less than four synthetic steps
from readily available starting materials, and amenable to the
production of reasonable quantities of products.
The efficient synthesis of 2,2′-arylmethylene dimers from
3-hydroxymethyl or 3-methoxymethyl-5-halo-(S)-tyrosines
and para-substituted phenols under acid-catalyzed reaction
conditions using either conventional or microwave-assisted
protocols is described.
As core starting materials towards 1-6 we required efficient
synthetic routes to 7-10. Space considerations here do not
permit a lengthy discussion on our attempted application of
literature protocols for their synthesis; needless to say, the
application of seemingly straightforward procedures proved
problematic. Negating this we did develop methods that afforded
7, 9, and 10 efficiently.8 The Supporting Information contains
full synthetic procedures and the physicochemical data associ-
ated with compounds 7, 9, and 10. With reliable protocols to
core building blocks 7-10 established, their subsequent ap-
plication to dimer formation, i.e., 1-6, was initiated. Dissolving
11 (120 mg) and p-tert-butylphenol in dichloromethane contain-
ing a catalytic amount of PTSA we isolated, after microwave
irradiation at 120 °C for 30 min, a 62% yield of 1. Repeating
the reaction but on a larger scale (incorporating 800 mg of 11)
afforded a 68% yield of the desired dimer 1. Concerned that
the reaction conditions employed may epimerize the stereogenic
center on the R-amino acids of the dimers we undertook to
ascertain the stereochemical integrity of 1 using chiral HPLC
analysis (Chiralpak AD 250 × 4.6 mm). Using optically active
1 as our substrate and chiral HPLC analysis we were able to
demonstrate, when run against racemic 1, that the stereochemical
center of our product was indeed intact (see the Supporting
Information for HPLC data).
We required the previously unreported methylene-bridged (S)-
tyrosine-phenol adducts 1-6 (Figure 1). To enable their
synthesis we also required high-yielding protocols for 7 and/or
8 as well as 9 and 10. There are only a handful of reports that
detail the synthesis of tyrosine derivatives 7-10 (Figure 1). The
widespread use of tyrosine and its derivatives means that
protocols affording entities based on or similar to 1-10 are of
importance. 2,2′-Methylenebisphenols (Figure 1) are synthesized
via acid-catalyzed procedures employing o-hydroxymethylphe-
nols and phenols. Their ease of synthesis has undoubtedly
contributed to their widespread use as: Novolac resins,1 metal-
coordinating complexes,2 Salbutamol dimers,3 asymmetric
catalysts,4 calix[4]arene precursors,5 host-guest entities,6 and
anti-cancer agents.7
Our strategy toward synthesizing 1-6 included two parts:
(1) a base-catalyzed hydroxymethylation reaction between a (S)-
tyrosine derivative and formaldehyde and (2) an acid-catalyzed
reaction between the previously synthesized intermediate and
Utilizing a general procedure based on that outlined in
Scheme 1, the synthesis of 2-6 (Figure 1) was achieved in
consistent and reasonable yields (50-69%). It is worthy of note
that both electron-rich phenol-substituted dimers (1-3) and
electron-poor phenol-substituted dimers (4-6) were readily
synthesized. However, the yields of the dimers were slightly
higher when electron-rich phenols were employed. Performing
* To whom correspondence should be addressed. Tel: + 44 (0)1603 593142.
Fax: + 44 (0)1603 592003.
(1) de Bruyn, P. J.; Foo, L. M.; Lim, A. S. C.; Looney, M. G.; Solomon,
D. H. Tetrahedron 1997, 53, 13915-13932.
(2) Kamatchi, P.; Kandaswamy, M. Polyhedron 1998, 17, 1397-1405.
(3) Haddad, N.; Xu, Y.; Baron, J. A.; Yee, N. K. Tetrahedron Lett. 2002,
43, 1135-1137.
(4) Davis, T. J.; Balsells, J.; Carroll, P. J.; Walsh, P. J. Org. Lett. 2001,
3, 2161-2164.
(5) Bo¨hmer, V.; Merkel, L.; Kunz, U. J. Chem. Soc., Chem. Commun.
1987, 896-897.
(8) Banziger, M.; Kipfer, P.; Mu¨ller, W. HelV. Chim. Acta 1998, 81,
729-733. White, J. D.; Amedio, J. C., Jr. J. Org. Chem. 1989, 54, 736-
738. Lach, F.; Moody, C. J. Tetrahedron Lett. 2000, 41, 6893-6896.
Atkinson, M.; Hartley, D.; Lunts, L. H. C.; Ritchie, A. C. J. Med. Chem.
1974, 17, 248-249. Allevi, P.; Cribiu`, X.; Anastasia, M. Tetrahedron:
Asymmetry 2004, 15, 1355-1358.
(6) Sone, T.; Ohba, Y.; Yamazaki, H. Bull Chem. Soc. Jpn. 1989, 62,
1111-1116.
(7) Sanmart´ın, C.; Echeverr´ıa, M.; Mend´ıvil, B.; Cordeu, L.; Cubedo,
E.; Garc´ıa-Foncillas, J.; Font, M.; Palop, J. A. Bioorg. Med. Chem. 2005,
13, 2031-2044.
10.1021/jo0610863 CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/08/2006
J. Org. Chem. 2006, 71, 7881-7884
7881

SCHEME 1. Synthesis of (S)-Tyrosine Dimer 12 from 11
and p-Iodophenol
SCHEME 4. Synthesis of (S)-Tyrosine Dimer 1 from 17 and
p-tert-Butylphenol
SCHEME 2. Synthesis of (S)-Tyrosine Dimer 14 from 13
and p-tert-Butylphenol
test our theory, the synthesis of 1 via a PTSA-catalyzed reaction
between p-tert-butylphenol and 17 was undertaken. After flash
chromatography, a 42% and 25% yield of 1 and 17 was formed,
respectively. When a similar reaction employing microwave
irradiation was used the yield of 1 increased to 70% (Scheme
4).
When electron-rich monoprotected O-allylhydroquinone and
p-hydroxybiphenyl were employed we isolated 2 and 3 (Figure
1) in good yields (56% and 66% yields, respectively). However,
the synthesis of methylene-bridged (S)-tyrosine-phenol dimers
4-6 and 12 using 17 and electron-poor phenols, i.e., methyl
p-hydroxybenzoate, p-bromo-, p-fluoro-, and p-iodophenol all
resulted in failure (17 was returned).
SCHEME 3. Synthesis of
3-Methoxymethyl-N-Cbz-(S)-tyrosine Methyl Ester
As part of our wider strategy toward utilizing 1-6 (Figure
1), we also required a convenient synthesis of N-Cbz-3,5-bis-
(hydroxymethyl)-(S)-tyrosine alkyl ester (10, R ) CH3, Figure
1). Based on our previous experience of the difficulties in
purifying hydroxylated tyrosine derivatives, we sought an
alternative procedure. Intrigued by a report by Crisp and Turner
describing the Mannich reaction between para-substituted phe-
nols, N-morpholine, and formaldehyde affording, in good yields,
the corresponding 2,4,6-trisubstituted phenols,9 we adapted the
protocol recruiting N-Cbz-(S)-tyrosine methyl ester as the
starting material (Scheme 5). Undertaking the Mannich reaction,
we observed the complete consumption of the (S)-tyrosine
starting material. However, isolation of 18 was complicated by
its highly water-soluble nature. To obviate this procedural
problem, a one-pot protocol for the synthesis of 19 was adopted
which afforded a respectable overall yield of 80% for 19.
Verification of the identity of 19 as the expected N-Cbz-O-
acetyl-3,5-bis(acetoxymethyl)-(S)-tyrosine methyl ester was
confirmed via X-ray analysis (see Figure 1 in the Supporting
Information). Our attempts at hydrolyzing the acetyl groups on
19 using potassium carbonate in methanol (reflux, 12 h) returned
10 (R ) H, Figure 1) and not the expected N-Cbz-3,5-bis-
(hydroxymethyl)-(S)-tyrosine methyl ester. Furthermore, and
perhaps not surprisingly, when 19 was subjected to microwave
irradiation in the presence of catalytic amounts of PTSA in
methanol at 120 °C it was transformed into the 3,5-bis-
(methoxymethyl) derivative 20 in an excellent 85% yield.
Although the protocol affording 20 in a 63% overall yield
for the three steps worked well, the reaction times of 15 and 24
h for the transformations yielding 18 and 19 respectively
(Scheme 5) were not conducive to a rapid synthesis. Switching
to the original hydroxymethylation protocol reported by Mu¨ller
et al.,8 we undertook the synthesis of 10 (R ) H); however,
because of its highly polar nature, we anticipated its purification
to be a potential problem. Furthermore, the literature C-3
hydroxymethylation reaction times of 120 h were too long.
Developing a slightly modified procedure to that reported by
an acid-catalyzed microwave-irradiated condensation reaction
between 11 and p-iodophenol we isolated 12 in a 56% yield
with the majority of the mass balance (32%) being 11 (Scheme
1).
Similarly employing the corresponding 3-iodo derivative 13
and p-tert-butylphenol the efficient synthesis of the correspond-
ing (S)-tyrosine dimer 14 was undertaken. In both examples
(Schemes 1 and 2) we found no evidence of any byproducts
resulting from the decomposition of the relatively heat labile
weak carbon-iodine bond.
During our attempts to synthesize 7 we undertook the
esterification of 15 using a methanolic hydrogen chloride
solution. To our surprise a complex mixture of products resulted
from which we isolated a 48% yield of the desired methyl
carboxylate ester. Interestingly, substituting the methanolic
hydrogen chloride solution for methanol and PTSA did not
return the desired ester but instead the corresponding N-Cbz-
3-methoxymethyl-(S)-tyrosine methyl ester 16 in an excellent
90% yield. Furthermore, conducting the reaction under micro-
wave irradiation (110 °C) afforded in 30 min a quantitative yield
of 16 (Scheme 3).
Disappointed that the chemoselective esterification of 15 had
failed, we pondered the possibility that a suitable derivative of
16 may, under favorable reaction conditions, behave in a
chemically analogous manner to 11 viz a` viz dimer formation.
In that case, derivatives of 16 would be of significant interest
because of their straightforward synthesis and the fact that they
should be easier to purify than the corresponding hydroxymethyl
derivatives, e.g., 11. Therefore, utilizing derivatives of 16 as
“core” starting materials would further enhance our overall
strategy of utilizing acid-catalyzed reaction protocols for the
synthesis of methylene bridged (S)-tyrosine-phenol adducts. To
(9) Crisp, G. T.; Turner, P. D. Tetrahedron 2001, 56, 407-415.
7882 J. Org. Chem., Vol. 71, No. 20, 2006

SCHEME 5. Synthesis of 3,5-Bis(methoxymethyl)-(S)-tyrosine Derivative 20
SCHEME 6. Efficient Synthesis of 3,5-Bis(hydroxymethyl)-
or 3,5-Bis(methoxymethyl)-(S)-tyrosine Derivatives 20 and 21
acetate 5-30%) afforded 1 as a clear oil (78 mg, 62%): [R]21
D
+41.5 (c ) 3, CHCl3); IR (neat) 3314, 2953, 2360, 1692, 1507,
1206, 695 cm-1; 1H NMR (400 MHz, CDCl3) δ ) 7.34-7.31 (m,
5 H), 7.19 (s, 1 H), 7.08 (dd, J ) 8.9, 1.9 Hz, 1 H), 6.90 (d, J )
1.9 Hz, 1 H), 6.68 (s, 1 H), 6.59 (d, J ) 8.9 Hz, 1 H), 5.25 (d, J
) 8.4 Hz, 1 H), 5.10 (d, J ) 12.2 Hz, 1 H), 5.07 (d, J ) 12.2 Hz,
1 H), 4.58 (dd, J ) 8.4, 5.8 Hz, 1 H), 3.88 (s, 2 H), 3.60 (s, 3 H),
2.97 (d, J ) 5.8 Hz, 2 H), 1.26 (s, 9H) ppm; 13C NMR (100 MHz,
CDCl3) δ ) 172.1, 155.9, 150.9, 149.3, 143.9, 136.1, 131.2, 130.8,
128.7, 128.6, 128.4, 128.2, 127.9, 125.1, 125.0, 115.5, 110.7, 67.2,
60.2, 54.8, 52.3, 37.0, 33.9, 31.8, 31.5 ppm; MS (EI) m/z 569.1
(M)+; HRMS (ES) 587.1749 (M + NH4)+ (calcd for C29H36N2O6
587.1751).
Larger Scale Synthesis of 1. p-tert-Butylphenol (664 mg, 4.42
mmol), 11 (800 mg, 1.36 mmol), and PTSA (50 mg) in dichlo-
romethane (10 mL) were heated in a sealed tube in the microwave
at 120 °C for 120 min. Chromatography (hexanes-ethyl acetate
5-30%) afforded 1 as a clear oil (680 mg, 68%).
Compound 2. O-Allylhydroquinone (75 mg, 0.5 mmol), 11 (100
mg, 0.22 mmol), and PTSA (5 mg) in anhydrous dichloromethane
(4 mL) were heated in a sealed tube in the microwave at 120 °C
for 60 min. Chromatography (hexanes-ethyl acetate 5-30%)
Mu¨ller et al., we were able via a one-pot procedure, to
synthesize, in substantially shorter reaction times (3.5 h),
multigram quantities of 10 (R ) H). Refluxing an acidic
methanolic solution of 10 afforded a 54% yield of 21. Although
purification of 10 was, as predicted, problematic, its transforma-
tion into 20 using the previously outlined microwave irradiation
protocol negated this. Purification of 20 was readily undertaken
and returned the product in an overall 50% yield (Scheme 6).
Efficient protocols for the synthesis of halogenated N-Cbz-
(S)-tyrosine alkyl esters and their C-3 hydroxymethylated
analogues have been developed. The unexpected transformation
of N-Cbz-3-hydroxymethyl-(S)-tyrosine into the corresponding
N-Cbz-3-methoxymethyl-(S)-tyrosine methyl ester has been
identified. Utilizing these as starting materials, via acid-catalyzed
processes, a series of innovative methylene bridged N-Cbz-3-
bromo-(S)-tyrosine methyl ester-5-(4-substituted phenol) entities
have been assembled by conventional as well as microwave-
assisted procedures. These unique chemical entities have numer-
ous uses in synthetic, pharmaceutical, agrochemical, and material
chemistry arenas.
afforded 2 as a clear oil (82 mg, 65%): [R]21 +23.8 (c ) 1.3,
D
1
CHCl3); IR (neat) 3312, 2951, 2360, 1698 cm-1; H NMR (400
MHz, CD3OD) δ ) 7.32-7.21 (m, 5 H), 7.17 (d, J ) 1.7 Hz, 1
H), 6.90 (d, J ) 1.7 Hz, 1 H), 6.69 (d, J ) 8.6 Hz, 1 H), 6.63 (d,
J ) 3.0 Hz, 1 H) 6.58 (dd, J ) 8.6, 3.0 Hz, 1 H), 5.95 (complex
m, 1 H), 5.28 (qd, J ) 17.1, 1.6 Hz, 1 H), 5.15 (qd, J ) 10.5, 1.6
Hz, 1 H), 5.00 (m, 2 H), 4.44 (m, 1 H), 4.35 (m, 2 H), 3.85 (s, 2
H), 3.59 (s, 3 H), 2.95 (dd, J ) 13.7, 5.1 Hz, 1 H), 2.77 (dd, J )
13.7, 5.1 Hz, 1 H) ppm; 13C NMR (100 MHz, CD3OD) δ ) 172.6,
157.2, 152.4, 150.4, 148.2, 136.9, 134.1, 131.3, 130.5, 129.8, 129.6,
128.2, 127.7, 127.5, 127.4, 116.9, 116.1, 115.3, 113.4, 110.4, 69.2,
66.4, 55.7, 51.5, 36.4, 30.7 ppm; MS (EI) m/z 571.1 (M)+; HRMS
(ES) 592.0941 (M + Na)+ (calcd for C28H28NO7BrNa 592.0930).
Compound 3. A mixture of 11 (100 mg, 0.22 mmol), p-hydroxy-
biphenyl (85 mg, 0.5 mmol), and PTSA (5 mg) in dichloromethane
(4 mL) was reacted as detailed for 1 at 120 °C for 45 min. The
product was purified using flash chromatography (hexanes-ethyl
acetate, 5 to 30%) affording 3 as a clear oil (90 mg, 69%): [R]21
D
+59.4 (c ) 2.1, CHCl3); IR (neat) 3291, 2951, 2494, 2359, 1691,
1607 cm-1; 1H NMR (400 MHz, CD3OD) δ ) 7.46 (s, 1 H), 7.44
(s, 1 H), 7.31-7.15 (m, 11 H), 6.93 (d, J ) 1.8 Hz, 1 H), 6.84 (d,
J ) 8.2 Hz, 1 H), 4.92 (m, 2 H), 4.33 (m, 1 H), 3.95 (s, 2 H), 3.50
(s, 3 H), 2.92 (dd, J ) 13.8, 5.5 Hz, 1 H), 2.76 (dd, J ) 13.8, 5.5
Hz, 1 H) ppm; 13C NMR (100 MHz, CD3OD) δ ) 172.5, 157.0,
154.1, 150.5, 141.2, 136.9, 133.1, 131.2, 130.4, 129.8, 129.7, 129.1,
128.5, 128.2, 127.7, 127.4, 127.1, 126.3, 126.2, 125.8, 115.1, 110.5,
66.3, 55.7, 51.5, 36.4, 30.7 ppm; MS (EI) m/z 591.2 (M)+; HRMS
(ES) 612.0992 (M + Na)+ (calcd for C31H28NO6BrNa 612.0999).
Compound 4. Methyl p-hydroxybenzoate (60 mg, 0.4 mmol),
11 (100 mg, 0.22 mmol), and PTSA (5 mg) in dichloromethane (4
mL) were reacted as detailed for 1 (120 °C for 45 min).
Chromatography with hexanes-ethyl acetate 5-30% afforded 4
Experimental Section
Compound 1. Representative Conventional Procedure. A
mixture of 11 (120 mg, 0.26 mmol), p-tert-butylphenol (60 mg,
0.4 mmol), and PTSA (10 mg, 0.32 mmol) was dissolved in toluene
(15 mL) and heated at reflux for 18 h under argon. After cooling,
the solvent was removed in vacuo, the residue was redissolved in
ethyl acetate, washed with aqueous sodium bicarbonate, water, and
brine, dried over magnesium sulfate, filtered, and the solvent
evaporated in vacuo. Column chromatography using dichlo-
romethane-ethyl acetate (10%) afforded 1 as a clear oil (58 mg,
42%).
Representative Microwave Procedure. p-tert-Butylphenol (50
mg, 0.33 mmol), 11 (100 mg, 0.22 mmol), and PTSA (5 mg) in
dichloromethane (4 mL) was heated in a sealed tube in the
microwave at 120 °C for 30 min. Chromatography (hexanes-ethyl
as a clear oil (76 mg, 50%): [R]21.5 +31.4 (c ) 2, CH3OH); IR
D
(neat) 3347, 2951, 1692 cm-1; 1H NMR (400 MHz, CD3OD) δ )
7.69 (s, 1 H), 7.27-7.22 (m, 6 H), 7.16 (s, 1 H), 6.85 (s, 1 H),
J. Org. Chem, Vol. 71, No. 20, 2006 7883

6.80 (d, J ) 8.2 Hz, 1 H), 4.99 (m, 2 H), 4.33 (m, 1 H), 3.91 (s,
2 H), 3.75 (s, 3 H), 3.58 (s, 3 H), 2.93 (dd, J ) 13.8, 5.4 Hz, 1 H),
2.78 (dd, J ) 13.8, 5.4 Hz, 1 H) ppm; 13C NMR (75 MHz, CD3-
OD) δ ) 173.4, 168.5, 160.6, 157.9, 151.4, 137.7, 132.9, 132.0,
131.4, 130.5, 130.3, 130.0, 129.0, 128.5, 128.2, 127.9, 121.9, 115.2,
111.3, 67.1, 56.3, 52.1, 51.7, 36.9, 30.8 ppm; MS (CI) m/z 574.1
(M)+; HRMS (ES) 594.0734 (M + Na)+ (calcd for C27H26NO8-
BrNa 594.0734).
reacted as detailed for 1 (120 °C for 60 min). Chromatography
(hexanes-ethyl acetate 5-30%) afforded 12 as a clear oil (90 mg,
56%): [R]21 +57.1 (c ) 2, CHCl3); IR (neat) 3328, 2950, 2504,
D
2358, 2325, 1693 cm-1; 1H NMR (400 MHz, CD3OD) δ ) 7.30-
7.21 (m, 7 H), 7.16 (dd, J ) 9.1, 1.7 Hz, 1 H), 6.86 (d, J ) 1.7 Hz,
1 H), 6.56 (d, J ) 9.1 Hz, 1 H), 5.01 (m, 2 H), 4.34 (m, 1H), 3.83
(s, 2 H), 3.59 (s, 3 H), 2.94 (dd, J ) 13.8, 5.6 Hz, 1 H), 2.78 (dd,
J ) 13.8, 5.6 Hz, 1 H) ppm; 13C NMR (75 MHz, CD3OD) δ )
173.4, 157.9, 155.6, 151.3, 139.5, 137.7, 136.8, 132.1, 131.3, 130.8,
130.5, 129.9, 129.0, 128.5, 128.2, 117.8, 111.2, 81.5, 67.1, 56.4,
52.2, 37.0, 30.7 ppm; MS (EI) m/z 639.1 (M + H)+; HRMS (ES)
661.9639 (M + Na)+ (calcd for C25H23NO6BrI 661.9646).
Compound 5. p-Bromophenol (75 mg, 0.44 mmol), 11 (100 mg,
0.22 mmol), and PTSA (5 mg) in dichloromethane (3 mL) were
reacted as detailed for 1 (120 °C for 45 min). Compound 5 was
purified using chromatography (hexanes-ethyl acetate 5-30%)
affording a clear oil (82 mg, 53%): [R]24.5D +45.3 (c ) 2, CHCl3);
IR (neat) 3327, 2951, 1692 cm-1; 1H NMR (400 MHz, CD3OD) δ
) 7.30-7.16 (m, 6 H), 7.10 (d, J ) 2.6 Hz, 1 H), 7.08 (s, 1 H),
6.88 (s, 1 H), 6.67 (dd, J ) 9.0, 2.6 Hz, 1 H), 5.01 (m, 2 H), 4.34
(m, 1 H), 3.85 (s, 2 H), 3.60 (s, 3 H), 2.95 (dd, J ) 13.7, 5.2 Hz,
1 H), 2.78 (dd, J ) 13.7, 5.2 Hz, 1 H) ppm; 13C NMR (75 MHz,
CD3OD) δ ) 173.4, 157.9, 154.9, 151.3, 137.7, 133.4, 132.1, 131.4,
130.6, 130.3, 129.9, 129.0, 128.5, 128.2, 117.2, 111.9, 111.3, 70.9,
67.1, 56.3, 52.2, 36.9, 30.8 ppm; MS (EI) m/z 593.2 (M)+; HRMS
(EI) 590.9881 (M)+ (calcd for C25H23NO6Br2 590.9887).
Compound 6. p-Fluorophenol (61 mg, 0.5 mmol), 11 (100 mg,
0.22 mmol), and PTSA (5 mg) in dichloromethane (3 mL) were
reacted as detailed for 1 (120 °C for 45 min). Compound 6 was
purified using chromatography (hexanes-ethyl acetate 5-30%)
affording a clear oil (68 mg, 51%): [R]24D +41.1 (c ) 3, CHCl3);
IR (neat) 3324, 2952, 2495, 1691 cm-1; 1H NMR (400 MHz, CD3-
OD) δ ) 7.29-7.22 (m, 6 H), 7.18 (d, J ) 1.6 Hz, 1 H), 6.90 (d,
J ) 1.6 Hz, 1 H), 6.72 (s, 1 H), 6.69 (m, 1 H), 5.00 (m, 2 H), 4.35
(m, 1 H), 3.87 (s, 2 H), 3.59 (s, 3 H), 2.96 (dd, J ) 13.5, 5.5 Hz,
1 H), 2.78 (dd, J ) 13.5, 5.5 Hz, 1 H) ppm; 13C NMR (75 MHz,
CD3OD) δ ) 173.4, 157.9, 151.4, 151.3, 137.7, 132.1, 131.4, 130.6,
129.9, 129.0, 128.5, 128.2, 117.1, 116.8, 116.1, 116.0, 113.9, 113.6,
111.2, 67.1, 56.3, 52.1, 36.9, 31.0 ppm; MS (CI) m/z 551.1 (M +
NH4)+; HRMS (EI) 531.0687 (M)+ (calcd for C25H23NO6BrF
531.0689).
Compound 14. p-tert-Butylphenol (75 mg, 0.5 mmol), 13 (140
mg, 0.28 mmol), and PTSA (5 mg) in dichloromethane (4 mL)
were reacted as detailed for 1 (100 °C for 60 min). Chromatography
(hexanes-ethyl acetate 5-30%) affording 14 as a clear oil (102
mg, 57%): [R]22 +42.0 (c ) 2, CHCl3); IR (neat) 3279, 2954,
D
2360, 1691 cm-1; 1H NMR (400 MHz, CD3OD) δ ) 7.38 (d, J )
1.9 Hz, 1 H), 7.29-7.20 (m, 5 H), 7.14 (d, J ) 2.4 Hz, 1 H), 7.04
(dd, J ) 8.4, 2.4 Hz, 1 H), 6.95 (d, J ) 1.9 Hz, 1 H), 6.71 (d, J )
8.4 Hz, 1 H), 5.00 (m, 2 H), 4.33 (m, 1 H), 3.85 (s, 2 H), 3.54 (s,
3 H), 2.92 (dd, J ) 13.9, 5.5 Hz, 1 H), 2.76 (dd, J ) 13.9, 5.5 Hz,
1 H), 1.20 (s, 9H) ppm; 13C NMR (75 MHz, CD3OD) δ ) 172.6,
157.1, 152.9, 151.2, 143.0, 137.6, 136.9, 131.3, 130.4, 128.7, 128.3,
127.7, 127.4, 125.7, 124.3, 114.3, 85.2, 66.4, 55.8, 51.5, 36.2, 33.6,
31.4, 30.9 ppm; MS (CI) m/z 635.2 (M + NH4)+; HRMS (ES)
640.1172 (M + Na)+ (calcd for C29H32NO6NaI 640.1167).
Acknowledgment. S.P.B. and S.V.S. would like to acknowl-
edge the support of UEA, the Dove Trust (financial assistance),
the EPSRC national mass spectroscopy service and D.L.H. for
X-ray crystal studies.
Supporting Information Available: The synthesis of 7-11,
13, and 15-21 as well as the 13C NMR and HPLC data for
compounds 1-7, 12-14, 16, 17, 19, and 20. This material is
available free of charge via the Internet at http://pubs.acs.org.
Compound 12. p-Iodophenol (88 mg, 0.4 mmol), 11 (100 mg,
0.22 mmol), and PTSA (5 mg) in dichloromethane (3 mL) were
JO0610863
7884 J. Org. Chem., Vol. 71, No. 20, 2006