Synthesis of optically active ring-A substituted tryptophans as IDO inhibitors

Article abstract of DOI:10.1016/j.tetlet.2004.09.113

The first synthesis of optically active 7-methoxy-d-tryptophan as well as other ring-A substituted tryptophans is described.

Full text of DOI:10.1016/j.tetlet.2004.09.113

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8569–8573
Synthesis of optically active ring-A substituted
tryptophans as IDO inhibitors
Xiaoyan Li, Wenyuan Yin, P. V. V. Srirama Sarma, Hao Zhou,
Jun Ma and James M. Cook*
Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA
Received 7 July 2004; revised 14 September 2004; accepted 15 September 2004
Available online 1 October 2004
Abstract—The first synthesis of optically active 7-methoxy-D-tryptophan as well as other ring-A substituted tryptophans is
described.
Ó 2004 Elsevier Ltd. All rights reserved.
7
–10
Indoleamine 2,3-dioxygenase (IDO) is a monomeric
cytosolic enzyme that is distributed in many human tis-
sues including the lens, brain, lung, kidney, spleen, and
et al.
and suggests IDO/tryptophan catabolism plays
an important role in this process. For these reasons,
synthesis of optically active tryptophan derivatives is
necessary in the search for more potent inhibitors of
1
in macrophages. It is a heme-containing enzyme that
1
1–13
uses superoxide or oxygen to cleave the 2,3-double bond
of the pyrrole ring of L-tryptophan to yield N-formyl-
kynurenine. This is the first and rate-determining step
of the kynurenine pathway (KP), which is the major
metabolic path for the breakdown of tryptophan
IDO.
been previously reported.
Syntheses of some tryptophan analogs have
1
4–17
We wish to report the
preparation of 6-chloro-L-tryptophan 28, 5,6-dichloro-
L-tryptophan 29, 5-nitro-D-tryptophan 36, 6-nitro-D-
tryptophan 37, and 6-aza-D-tryptophan 45 as well as
the first synthesis of 7-methoxy-D-tryptophan 41 via
the Sch o¨ llkopf chiral auxiliary.
2
–4
(
catabolism).
N-Formylkynurenine is then readily
hydrolyzed to kynurenine, and subsequently converted
to a range of metabolites including quinolinic acid.
Many diseases including HIV- and AIDS-associated
dementia and wasting as well as acute/chronic immuno-
logical and inflammatory diseases have been found to be
The approach to the synthesis of these tryptophans
began with the preparation of the propargyl substituted
bislactim ethyl ether on 400g scale. Sch o¨ llkopf had ear-
lier discovered a method to prepare a variety of amino
acids based on the metallation and subsequent alkyl-
ation of bislactim ethers (Sch o¨ llkopf chiral auxiliary).
The popular Sch o¨ llkopf chiral auxiliary, bislactim ether
4 derived from D-valine and glycine, was readily availa-
ble (Scheme 1) on large scale. The TES protected
propargyl alcohol 5 required for preparation of the
alkylating agent can be obtained in 90% yield in one step
by treating triethylsilyl acetylene 7 with n-BuLi, fol-
5
associated with the elevation of IDO activity and qui-
nolinic acid. More recently, investigations by Kerr
6
18
et al. have shown that quinolinic acid (QA) production
was inhibited in a concentration dependant manner by
6
-chloro-D-tryptophan in HIV-1 infected macrophages.
1
7
In addition, Mellor et al. have demonstrated that Na-
methyl-D-tryptophan may have clinical potential for
protection of the mammalian fetus from maternal T-cell
attack and this mechanism might have wider implica-
7
–10
19
tions for the control of T-cell responses.
inhibitor, first prepared in this laboratory,
This IDO
has been
lowed by the addition of paraformaldehyde instead
17
1
1,12
of the previous three step route from propargyl alco-
hol. Activation of the hydroxyl group by the diphenyl
chlorophosphate moiety was realized in greater than
employed to study the ꢀpregnancy paradoxꢁ by Mellor
90% yield. The diphenyl phosphate that resulted was
then stirred with the anion of the Sch o¨ llkopf chiral aux-
iliary 4 (derived from D-valine) at ꢀ78°C to provide the
alkyne 6a in 90% yield with 100% diastereoselectivity.
The D-isomer 6b would originate from L-valine in the
Keywords: Optically active tryptophans; IDO; 7-Methoxy-D-
tryptophan.
*
Corresponding author. Tel.: +1 414 229 5856; fax: +1 414 229
530; e-mail: capncook@uwm.edu
5
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.113

8570
X. Li et al. / Tetrahedron Letters 45 (2004) 8569–8573
1
) NH
2
CH
2
CO
2
Et, CHCl
C
3
H
N
NH
2
O
o
O
N
triphosgene, THF
Et N, THF, -70
O
3
COOH
5-50 o
O
N
H
2) toluene, reflux
70 %
O
N
H
4
C
D-valine
00g
1
99 %
3
2
3
EtO
1
)TES
(PhO)
2) n-BuLi, THF, -78 C
freshly prepared
+
5
OH
N
N
OEt
Et
3
O BF
4
-, CH
2
Cl2, rt
2 2
POCl, KOH, Et C
O, 0 o
N
EtO
(
o
OEt
90 %
TES
9
0 %
4
6a
to L-amino acid)
05g
EtO
4
N
o
n-BuLi, THF; -78 C
TES
N
TES
H
(CH
2
O)
n
OH
OEt
TES
90%
7
5
6b (from
L-valine)
Scheme 1.
same fashion, as that illustrated in Scheme 1, to provide
alkyne 6b also in 90% yield.
ethyl ester 26. Hydrolysis of the ester 26 at 50°C with
1N aq NaOH in ethanol provided 6-chloro-L-trypto-
phan 28 in 72% yield.
Commercially available 2-nitro-4-chloroaniline 8 was
2
0
diazotized under standard conditions, followed by
treatment of the diazonium ion that resulted with KI
to give iodo derivative 9 in 94% yield. Reduction of
the nitro group was effected with acetic acid and iron
powder in refluxing ethanol to furnish the desired ortho
iodoaniline 10 in 90% yield.
For the synthesis of 5-nitro-D-tryptophan 36 and 5,6-di-
chloro-L-tryptophan 29, respectively, the required 2-
iodo-4-nitroaniline 12 and 2-iodo-4,5-dichloroaniline
16 were synthesized via standard conditions from com-
mercially available 4-nitroaniline 11 and 4,5-dichloroani-
line 15, respectively (Scheme 2). These conditions were
similar to those employed to provide 5-nitro-substituted
indole 36. The triethylsilyl group was later removed by
treatment with tetrabutylammonium fluoride. Acid-
mediated hydrolysis of the desilylated intermediate 32,
followed by saponification of the ester moiety, provided
5-nitro-D-tryptophan 36 and 5,6-dichloro-L-tryptophan
29 (Scheme 3) in good yield.
With both the TES-substituted alkyne 6a and the iodo-
aniline 10 in hand, the Larock heteroannulation was
carried out in the presence of 5% Pd(OAc) to afford
the desired indole 23 in 68% yield (Scheme 3), accompa-
nied by 10% of the 2,3-regioisomer. This byproduct may
have originated from a Heck-type coupling process.
Treatment of the indole derivative 23 with 6N aqueous
HCl in THF effected both hydrolysis of the Sch o¨ llkopf
chiral auxiliary and removal of the indole-2-silyl group
to provide the optically active 6-chloro-L-tryptophan
2
In the same manner employed to provide 5-nitro-D-try-
ptophan 36, 6-nitro-D-tryptophan 37 was synthesized in
good yield. The chemistry required for the synthesis of
NH
2
1) 50 % H SO , NaNO , 0
o
C
I
I
2
4
2
Fe, HOAc
Cl
NO
2
2) KI, RT
94 %
Cl
NO
2
EtOH, reflux
90 %
Cl
NH
2
8
9
10
O
2
N
I /CH COOAg
O
2
N
I
X
1
X
1
I
2
3
ICl
C
2
H
5
OH
NH
2
2 5
C H OH
NH
2
X
2
NH
2
X
2
NH
2
88 %
1
4. X
1
6. X
1
= H, X
2
2
= NO
2
90 %
11
12
13. X
5. X
1
1
= H, X
= Cl, X
2
2
= NO
= Cl
2
1
= Cl, X
= Cl 85%
1
NH
2
Et
3
N/CH
2
Cl
2
NHCOtBu
nBuLi/TMEDA
O
N
N
+
(
CH
3
)
3
CCCl
18
/-75 o
THF/-10 o
80 %
C
1
7
19
N
tBu
I
2
C
NHCOtBu
I
24 % H
2
SO
4
NH
2
N
N
N
C
O
heat
I
Li
Li
20
21
22
Scheme 2.

X. Li et al. / Tetrahedron Letters 45 (2004) 8569–8573
8571
EtO
N
N
CO2
CO Et
2
X1
X2
X1
X2
1 N NaOH
EtOH
X1
X2
2 N HCl
THF
NH3
NH2
N
H
OEt
N
H
N
H
2
8. X = H, X = Cl
26. X = H, X2 = Cl
25. X1 = Cl, X2 = Cl
1
2
1
2
9. X = Cl, X = Cl
27. X = Cl, X2 = Cl
6
N
1
2
1
H
C
l/
T
TBAF/THF
EtO
H
F
EtO
N
N
X1
N
N
X2
N
H
TES
OEt
X1
X2
I
OEt
TES
23. X1 = H, X2 = Cl
24. X1 = Cl, X2 = Cl
NH2
6a
5%Pd(OAc)2
X3
EtO
N
+
Na CO , LiCl
2
3
EtO
N
1
1
0. X = H, X = Cl, X = H
o
1
2
3
X1
1
00 C, DMF
N
6. X = Cl, X = Cl, X3 = H
1 2
1
1
3
2. X = NO , X = H, X3 = H
N
X2
N
H
TES
1
2
2
OEt
4. X = H, X = NO , X = H
X3
3
1
2
2
3
OEt
8. X = H, X = H, X = OCH
1
2
3
3
TES
0. X = NO , X = H, X3 = H
1 2 2
F
6b
H
T
31. X = H, X = NO , X = H
1 2 2 3
l/
C
t
r
39. X = H, X2 = H, X3 = OCH3
1
H
N
2
0 C -
0
TBAF/THF
EtO
N
CO2
CO Et
2
X1
X2
X1
X2
1
N NaOH
EtOH
X1
X2
2 N HCl
THF
N
NH3
NH2
N
H
OEt
N
H
N
H
X3
X3
X3
3
3
4
6. X = NO , X = H, X3 =H
34. X = NO , X = H, X3 = H
32. X = NO , X = H, X3 = H
1 2 2
1
2
2
1
2
2
7. X = H, X = NO , X = H
35. X = H, X = NO , X = H
33. X = H, X2 = NO , X = H
1 2 3
1
2
2
3
1
2
2
3
1. X = H, X = H, X = OCH
40. X = H, X2 = H, X3 = OCH3
1
2
3
3
1
Scheme 3.
the enantiomers (5-nitro-L-tryptophan and of 5,6-di-
1
chloro-D-tryptophan) have been previously reported.
stirred with iodine at ꢀ75°C to furnish the correspond-
ing o-iodo-(pivaloylamino) pyridine 21. This amide 21
was hydrolyzed in aqueous sulfuric acid (24%) to give
7
2
1
24,27
The 7-methoxy-D-tryptophan ethyl ester 41 was pre-
2
3-amino-4-iodopyridine 22 in 85% yield.
The 6-
2
pared (Scheme 3) via the Larock heteroannulation
2
aza-L-tryptophan ethyl ester 44 was prepared via the
Larock heteroannulation process from 3-amino-4-iodo-
pyridine 22 and the propargyl substituted Sch o¨ llkopf
chiral auxiliary 6b in the presence of Pd(OAc)2,
Na CO , LiCl in DMF at 100°C (42% isolated yield).
3
process from 2-iodo-6-methoxy-aniline 38 and the
1
7
propargyl-substituted Sch o¨ llkopf chiral auxiliary 6b
in the presence of Pd(OAc) , K CO , LiCl in DMF at
2
2
3
100°C (75% yield). This material was accompanied by
5% of a byproduct, which could be removed by chroma-
2
3
Again, a small amount (15%) of the 2,3-regioisomer
was obtained. Removal of the TES group from the in-
dole 2-position was achieved by reaction with TBAF
in THF to furnish indole 43 in 91% yield. Hydrolysis
of the Sch o¨ llkopf chiral auxiliary with 2N aqueous
HCl in THF provided optically active 6-aza-D-trypto-
phan ethyl ester 44 in 76% yield. Finally, the ethyl ester
44 was hydrolyzed to the corresponding carboxylic acid
45 with 1 N aq NaOH in ethanol in 50% yield (see
Scheme 4).
tography. The annulation could be carried out both on
small scale (100mg) and large scale (100g) in compar-
able yields. Hydrolysis of the Sch o¨ llkopf chiral auxiliary
accompanied by concomitant loss of the indole-2-silyl
group with 2N aqueous HCl in THF provided optically
active 7-methoxy-D-tryptophan ethyl ester 40 in a single
step in 92% yield. Finally, the ethyl ester 40 was hydro-
lyzed to the carboxylic acid 41 with 1N aq NaOH in eth-
anol, as illustrated in Scheme 3.
For the preparation of 6-aza-L-tryptophan, the 3-amino-
In summary, the efficient stereoselective synthesis of
optically active 6-chloro-L-tryptophan, 5-nitro-D-trypto-
phan, 6-nitro-D-tryptophan, 5,6-dichloro-L-tryptophan,
6-aza-D-tryptophan as well as the first synthesis of opti-
cally active 7-methoxy-D-tryptophan with potential
activity at IDO has been completed. These syntheses
render these tryptophans (D- or L-isomers) available in
optically active form for the study of biological proc-
esses (IDO, TDO, etc.).
4
-iodopyridine 22 (see Scheme 1) was prepared from
commercially available 2-amino-pyridine 17. This amine
was stirred with pivaloyl chloride in methylene chloride/
2
triethylamine to give pivaloylpyridine 19 in 80% yield.
5
2
8
This aminopyridine, protected as a pivaloylamide 19,
was then subjected to ortho-directed lithiation by addi-
tion of an excess of butyllithium/TMEDA to give the
2
6
lithio derivative 20 (Et O, ꢀ10°C), which was then
2

8572
X. Li et al. / Tetrahedron Letters 45 (2004) 8569–8573
EtO
EtO
N
N
5 % Pd(OAc)
2
I
TBAF/THF
N
TES
Na
2
CO
o
3
, LiCl
N
N
+
N
N
H
NH
2
OEt
OEt
100 C, DMF
TES
22
6b
42
EtO
N
CO
2
Et
CO
2
N
2
N HCl
1 N NaOH
EtOH
NH
2
NH
3
N
N
N
N
H
N
H
N
H
THF
OEt
43
44
45
Scheme 4.
Acknowledgements
21. Zhou, H.; Liao, X.; Cook, J. M. Org. Lett. 2004, 6(2), 249.
2
2
2
2. Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113,
689.
3. Kondo, Y.; Kojima, S.; Sakamoto, T. J. Org. Chem. 1997,
2, 6507.
4. Perry, C. W.; Teitel, S. US Patent 3965129 19760622,
976.
25. Turner, J. A. J. Org. Chem. 1983, 48, 3401.
6
The authors wish to thank the NIMH (MH-46851) for
generous financial support.
6
1
References and notes
2
6. Estel, L.; Marsais, F.; Queguiner, G. J. Org. Chem. 1988,
53, 2740.
1
. Yamazaki, F.; Kuroiwa, T.; Takikawa, O.; Kido, R.
Biochem. J. 1985, 230, 635.
27. Malm, J.; Rehn, B.; Hornfeldt, A.-B.; Gronowitz, S.
J. Heterocycl. Chem. 1994, 31, 11.
2
. Stone, T.; Darlington, L. Nat. Rev. Drug Disc. 2002, 1,
6
09.
28. Compound (28): 6-Chloro-L-tryptophan: mp 248–253°C,
2
5
22
3
4
5
. Stone, T. Prog. Neurobiol. 2001, 64, 185.
. Botting, N. Chem. Soc. Rev. 1995, 24, 401.
. Lestage, J.; Verrier, D.; Palin, K.; Dantzer, R. Brain
Behav. Immunity 2002, 16, 596.
. Kerr, S. J.; Armati, P. J.; Pemberton, L. A.; Smythe, G.;
Tattam, B.; Brew, B. J. J. Neurol. 1997, 49, 1671.
. Munn, D.; Zhou, M.; Attwood, J.; Bondarev, I.; Conway,
S.; Marshall, B.; Brown, C.; Mellor, A. Science 1998, 218,
½aꢁ ꢀ16.0 (c 0.15, 1M HCl) {lit. [24] ½aꢁ ꢀ15.4
D
(c 1, HOAc)}, IR (KBr) 3638, 2353, 1718, 1525,
D
ꢀ
1
1
1301cm , H NMR (300MHz, D O) d 3.13–3.21 (dd,
2
1H, J = 7.8 and 15.4Hz), 3.27–3.36 (m, 1H), 3.91 (dd, 1H,
J = 4.9 and 7.8Hz), 7.06 (dd, J = 1.8 and 8.5Hz), 7.19 (s,
6
1
3
C
1H), 7.44 (d, 1H, J = 1.7Hz), 7.56 (d, 1H, J = 8.5Hz),
7
NMR (300MHz, D O) d 26.7, 54.9, 91.2, 107.7, 111.4,
2
119.4, 119.6, 125.3, 125.5, 127.2, 136.5; MS (EI) m/e
(relative intensity) 238 (M , 7), 166 (42), 164 (100), 128
+
1
191.
8
9
. Mellor, A. L.; Munn, D. H. Immunol. Today 1999, 10, 469.
. Munn, D. H.; Shafizadeh, E.; Attwood, J. T.; Bondarev,
I.; Pashine, A.; Mellor, A. L. J. Exp. Med. 1999, 189, 1363.
(15), 101 (12), HRMS calcd 238.05 found, 238.050544.
Anal. Calcd for C H ClN O Æ1/3 H O: C, 54.13; H, 4.81;
1
1
11
2
2
2
N, 11.47. Found: C, 54.68; H, 4.62; N, 11.26.
Compound (29): 5,6-Dichloro-L-tryptophan: mp 249–
1
1
0. Mellor, A. L.; Keskin, D. B.; Johnson, T.; Chandler, P.;
Munn, D. H. J. Immunol. 2002, 168, 3771.
1. Peterson, A. C.; Laloggia, A. J.; Hamaker, L. K.; Arend,
R. A.; Fisette, P. L.; Ozaki, Y.; Will, J. A.; Brown, R. R.;
Cook, J. M. Med. Chem. Res. 1993, 3, 473.
2. Peterson, A. C.; Migawa, M. T.; Martin, M. J.; Hamaker,
L. K.; Czerwinski, K. M.; Zhang, W.; Arend, R. A.;
Fisette, P. L.; Ozaki, Y.; Will, J. A.; Brown, R. R.; Cook,
J. M. Med. Chem. Res. 1994, 4, 531.
3. Southan, M.; Truscott, R.; Jamie, J.; Pelosi, L.; Walker,
M.; Maeda, H.; Iwamoto, Y.; Tone, S. Med. Chem. Res.
26
251°C, ½aꢁ ꢀ37 (c 0.15, 1M aq HCl). IR (KBr)
D
ꢀ
1 1
3424, 1662cm . H NMR (DMSO): d 1.03 (d, 1H, J =
6.09Hz), 4.14 (s, 2H), 7.12 (s, 1H), 7.37 (s, 1H), 7.63 (s, 1H),
8.36 (s, 2H), 11.44 (s, 1H). MS (EI) m/e (relative intensity)
+
+
1
275 (M +1, 51), 273 (M +1, 100), 258 (76), 239 (29), 222
(40), 200 (27). Anal. Calcd for C H Cl N O : C, 48.37;
H, 3.69; N, 10.26. Found: C, 48.86; H, 4.21; N, 9.66.
1
1
10
2
2
2
Compound (36): 5-Nitro-D-tryptophan: mp 250–255°C,
2
5
1
½aꢁ 21.4 (c 0.14, 1M aq HCl), IR (KBr) 3411, 2363, 1635,
D
ꢀ
1 1
1587, 1330cm , H NMR (300MHz, DMSO-d ) d 3.12
6
1
996, 5, 343.
(dd, 1H, J = 7.5 and 15Hz), 3.29 (dd, 1H, J = 4.2 and
15.1Hz), 3.44 (dd, 1H, J = 4.5 and 7.4Hz) 7.44 (s, 1H),
7.51 (d, 1H, J = 9.0Hz), 7.97 (dd, 1H, J = 2.2 and 9.0Hz),
8.63 (d, 1h, J = 2.2Hz), 11.07 (s, br s, 1H); MS (EI) m/e
1
1
1
1
1
1
4. Ma, C.; He, X.; Liu, X.; Yu, S.; Zhao, S.; Cook, J. M.
Tetrahedron Lett. 1999, 40, 2917.
5. Ma, C.; Liu, X.; Yu, S.; Zhao, S.; Cook, J. M. Tetrahedron
Lett. 1999, 40, 657.
+
(relative intensity) 249 (M , 4), 175 (100), 129 (100), 102
6. Ma, C.; Yu, S.; He, X.; Liu, X.; Cook, J. M. Tetrahedron
Lett. 2000, 41, 2781.
7. Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J.; Yu, S.;
Cook, J. M. J. Org. Chem. 2001, 66, 4525.
8. Sch o¨ llkopf, U.; Groth, U.; Deng, C. Angew. Chem., Int.
Ed. Engl. 1981, 20, 798.
11 3 4 2
(30), 74 (25), Anal. Calcd for C11H N O Æ1/3 H O: C,
51.76; H, 4.60; N, 16.46. Found: C, 51.48; H, 4.43; N,
15.06.
Compound (37): 6-Nitro-D-tryptophan: mp 260–264°C,
2
5
½aꢁ 52.0 (c 0.15, 1M HCl), IR (KBr) 3449, 3182, 2366,
D
ꢀ
1 1
1623, 1334cm , H NMR (300MHz, D O) d 3.23–3.31
2
9. Jones, G. B.; Wright, J. M.; Ploudre, G. W.; Hynd, G.;
Huber, R. S.; Mathews, J. E. J. Am. Chem. Soc. 2000, 122,
(m, 2H), 3.92 (m, 1H), 7.47 (s, 1H), 7.63 (d, 1H,
J = 9.0Hz), 7.86 (dd, 1H, J = 1.8Hz and 9.0Hz), 8.28 (d,
+
1H, J = 1.9Hz), MS (EI) m/e (relative intensity) 249 (M ,
4), 175 (100), 129 (100), 102 (32), 74 (22), Anal. Calcd for
1937.
2
0. Salituro, F. G.; Tomlinson, R. C.; Baron, B. M.; Palfre-
yman, M. G.; McDonald, I. A. J. Med. Chem. 1994, 37,
C
C, 52.21; H, 4.42; N, 16.51.
11
H
11
N
3
O
4
Æ1/4 H
2
O: C, 52.07; H, 4.56; N, 16.56. Found:
334.

X. Li et al. / Tetrahedron Letters 45 (2004) 8569–8573
8573
Compound (41): 7-Methoxy-D-tryptophan: mp 234–
Compound (45): 6-Aza-D-tryptophan: mp > 300°C (dec)
2
6
25
2
1
2
5
35°C (dec), ½aꢁ 28.4 (c 0.43, H
2
O); IR (neat): 3393,
½aꢁ 27.8 (c 0.15, 1M aq HCl); IR, 2922, 1725, 1609, 1260,
D
D
ꢀ1
1
1
625, 1579, 1255, 1024cm , H NMR (300MHz, D O) d
1026, 795 H NMR (D O): d 1.25 (d, 1H, J = 6.79Hz),
2
2
.99 (dd, 1H, J = 14.6, 7.5Hz), 3.16 (dd, 1H, J = 14.6,
.1Hz), 3.61 (t, 1H, J = 6.3Hz), 3.91 (s, 3H), 6.75 (d, 1H,
2.89–3.05 (m, 2H), 6.11(s, 1H), 7.16 (d, 1H, J = 2.6Hz),
7.62 (s, 1H), 7.71 (d, 1H, J = 4.0Hz), MS (EI) m/e (relative
+
intensity) 205 (M , 8), 157 (12) 145 (45), 131 (69), 69 (55),
J = 7.7Hz), 7.05 (t, 1H, J = 7.9Hz), 7.15 (s, 1H), 7.28 (d,
1
3
1
5
1
6
H, J = 8.0Hz); C NMR (300MHz, D O) d 29.2, 55.6,
55 (100). Anal. Calcd for C H N O Æ2/3 H O: C,
2
10 11
3
2
2
6.0, 102.6, 110.4, 111.7, 119.8, 124.1, 126.3, 128.7, 145.9,
80.5. Anal. Calcd for C12
.25; N, 11.38. Found: C, 58.52; H, 6.33; N, 11.02.
55.29; H, 5.72; N, 19.35. Found: C, 55.06; H, 5.89; N,
18.97.
14 2 3 2
H N O Æ2/3 H O: C, 58.53; H,