Radical addition reaction of brominated active methylene compounds to enol ethers using 2,2'-azobis(2,4-dimethyl-4-methoxyvaleronitrile) (V-70) as an initiator

Full text of DOI:10.1021/jo981900p

J . Org. Chem. 1999, 64, 675-678
675
Sch em e 1
Ra d ica l Ad d ition Rea ction of Br om in a ted
Active Meth ylen e Com p ou n d s to En ol
Eth er s Usin g 2,2′-Azobis(2,4-
d im eth yl-4-m eth oxyva ler on itr ile) (V-70) a s
a n In itia tor
Yasuyuki Kita,† Atsunori Sano,*,‡ Takahiro Yamaguchi,‡
Masahisa Oka,‡ Kentoku Gotanda,† and
Masato Matsugi†
Graduate School of Pharmaceutical Sciences, Osaka
University, 1-6, Yamada-oka, Suita, Osaka 565-0871,
J apan, and Tokyo Research Laboratories, Wako Pure
Chemical Industries, Ltd., 1633, Matoba, Kawagoe,
Saitama 350-1101, J apan
Sch em e 2
Received September 18, 1998
Pyrrolo[2,3-d]pyrimidine derivatives have been noted
as 7-deaza analogues of naturally occurring purines or
their nucleosides. A number of pyrrolo[2,3-d]pyrimidine
compounds are being presented for potential biological
activities, such as anticancer or antiviral.1 Therefore,
many synthetic methods for pyrrolo[2,3-d]pyrimidines
have been developed.2 Several pyrrolo[2,3-d]pyrimidine
compounds such as 7-deazaguanine (3, X ) NH2, OH)
are prepared starting from alkylated active methylene
compounds (1) having an acetal moiety via pyrimidine
intermediates (2)3 (Scheme 1). Though this synthetic
pathway has been used as the common and effective
route, severe reaction conditions or multistep sequences
are required to obtain the starting materials.3a,b
ethers seems limited, as it was reported that a radical
addition reaction of iodomethylmalononitrile to ethyl
1-propenyl ether in the presence of AIBN was unsuc-
cessful.7 The use of Lewis acid Et3B, which is known to
be an useful radical initiator at low temperature,8 seems
to be unsuitable for acid sensitive compounds.
Very recently, we reported that 2,2′-azobis(2,4-di-
methyl-4-methoxyvaleronitrile) (V-70)9 (Figure 1) serves
as an effective initiator for the addition reactions of
bromomalononitrile to various olefins including some enol
ethers at room temperature.10 In this paper, we report
the results of our further investigation on the V-70-
initiated radical addition reaction of brominated active
methylene compounds (4) to enol ethers.
We first examined the addition reactions of bromoma-
lononitrile to a â-substituted enol ethers using various
radical initiators. The results are shown in Table 1.
Treatment of 4a (1 equiv) with methyl 4-(5-methoxy-4-
pentenyl)benzoate (5a ) (1 equiv) in the presence of V-70
(10 mol %) in CH2Cl2 at room temperature for 2 h and
subsequent methanolysis afforded somewhat preferen-
tially the desired acetal adduct (1a ) (Table 1, entry 1).
Recently, Miwa and co-workers4 reported the syntheses
of pyrrolo[2,3-d]pyrimidine antifolates,5,6 a photoinduced
radical addition reaction of brominated active methylene
compounds (4) to enol ethers and subsequent alcoholysis
(Scheme 2). This photoirradiation method is performed
under mild conditions in high yields, but suffer from
practical difficulties for a large-scale production.
The use of a radical initiator such as azobisisobuty-
ronitrile (AIBN) is one effective and alternative means
to avoid the use of a photochemical reaction. However,
the applicability of AIBN in the radical addition reactions
of halogenated active methylene compounds to enol
† Osaka University.
‡ Wako Pure Chemical Industries, Ltd.
(1) (a) Lu¨pke, U.; Seela, F. Chem. Ber. 1979, 112, 3526. (b) Seela,
F.; Kehne, A. Liebigs Ann. Chem. 1983, 876. (c) Winkeler, H.-D.; Seela,
F. J . Org. Chem. 1983, 48, 3119. (d) Kazimierczuk, Z.; Cottam, H. B.;
Revankar, G. R.; Robins, R. K. J . Am. Chem. Soc. 1984, 106, 6379. (e)
Secrist, J . A., III; Clayton, S. J .; Montgomery, J . A. J . Med. Chem.
1984, 27, 534. (f) Seela, F.; Steker, H.; Driller, H.; Bindig, U. Liebigs
Ann. Chem. 1987, 15. (g) Seela, F.; Westermann, B.; Bindig, U. J .
Chem. Soc., Perkin Trans. 1 1988, 697. (h) Eger, K.; Grieb, G.; Spatling,
S. J . Heterocycl. Chem. 1990, 27, 2069. (i) Seela, F.; Muth, H.-P.; Roling,
A. Helv. Chim. Acta 1991, 74, 554. (j) Chan, X.; Siddiqi, S. M.;
Schneller, S. W. Tetrahedron Lett. 1992, 33, 2249. (k) Pecquet, P.; Huet,
F.; Legraverend, M.; Bisagni, E. Heterocycles 1992, 34, 739.
(2) Comprehensive Heterocyclic Chemistry II; Katrinzky, A. R., Lees,
C. W., Scriven, E. F. V., Eds.; Pergamon Press Ltd.: New York, 1996;
p 248-252.
(7) Curran, D. P.; Thoma, G. J . Am. Chem. Soc. 1992, 114, 4436.
(8) For a review, see: Oshima, K.; Utimoto, K. Yuki Gosei Kagaku
Kyokai Shi 1989, 47, 40.
(9) 2,2′-Azobis(2,4-dimethyl-4-methoxyvaleronitrile) (V-70) is known
as an effective initiator in the synthesis of polymers and is com-
mercially available from Wako Pure Chemical Ind., Ltd., J apan. The
abbreviation in parentheses is its trade name. This compound should
be stored below -10 °C to prevent any decomposition. Half-life data
indicates that V-70 is more unstable than AIBN in solvents. The
temperature at which half of V-70 and AIBN is decomposed in 10 h in
toluene: V-70, 30 °C; AIBN, 65 °C. V-70 is stable in a refrigerator for
a few months in a solid state.
(3) (a) Wellcome Foundation Ltd. (West, R. A.; Hinchings, G. H.)
Brit. Pat. 812,366,1959; Chem. Abstr. 1960, 5921. (b) Davoll, J . J .
Chem. Soc. 1960, 131. (c) West, R. A. J . Org. Chem. 1961, 26, 4959.
(d) Seela, F.; Lu¨pke, U. Chem. Ber. 1977, 110, 1462.
(4) Miwa, T.; Hitaka, T.; Akimoto, H. J . Org. Chem. 1993, 58, 1696.
(5) Miwa, T.; Hitaka, T.; Akimoto, H.; Nomura, H. J . Med. Chem.
1991, 34, 555.
(10) (a) Kita, Y.; Sano, A.; Yamaguchi, T.; Oka, M.; Gotanda, K.;
Matsugi, M. Tetrahedron Lett. 1997, 38, 3549. (b) Kita, Y.; Gotanda,
K.; Murata, K.; Suemura, M.; Sano, A.; Yamaguchi, T.; Oka, M.;
Matsugi, M. Org. Process Res. Dev. 1998, 2, 250.
(6) Taylar, E. C.; Kuhnt, D. J . Med. Chem. 1992, 35, 4450.
10.1021/jo981900p CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/05/1999

676 J . Org. Chem., Vol. 64, No. 2, 1999
Notes
found to proceed smoothly, providing subsequent alco-
holysis the corresponding acetal adducts (1a -f) in good
yields.
These acetal adducts were easily purified by column
chromatography on silica gel. Acetals 1a -d were identi-
fied by their spectral data. The structures of 1e,f were
confirmed by comparison with the corresponding authen-
tic samples.3a,c
F igu r e 1.
Ta ble 1. Ra d ica l Ad d ition Rea ction s of 4a to 5a Usin g
V-70 or V-70L a s a n In itia tor
Next, the conversion of 1a into pyrrolo[2,3-d]pyrimi-
dine 3b was examined in order to obtain an intermediate
for the synthesis of pyrrolo[2,3-d]pyrimidine antifolate
TNP-351 (3c,4 Scheme 3). The condensation of 1a with
guanidine hydrochloride in the presence of potassium
tert-butoxide and subsequent cyclization with hydrochlo-
ric acid afforded methyl ester 3a in 76% yield. Hydrolysis
of 3a with sodium hydroxide in aqueous methanol gave
acid 3b. Subsequent conversion of 3b to TNP-351 has
already been reported.4 In conclusion, radical addition
reactions of brominated active methylene compounds
(4a ,b) to enol ethers (5a -c) using V-70 or V-70L as
initiator smoothly proceeded at room temperature, and
acetal adducts (1a -f) were obtained in good yields by
subsequent alcoholysis. Since these acetal adducts serve
as starting materials for the synthesis of pyrrolo[2,3-d]-
pyrimidine derivatives, such as the present method,
affords a convenient and practical route to these deriva-
tives compared with the use of a photochemical reaction.
yield (%)a
initiator
(mol %)
entry
solvent
time (h)
1a
6
1
2
3
4
5
6
7
8
9
V-70 (10)
V-70 (15)
V-70 (25)
V-70L (25)
V-70 (25)
V-70L (15)
V-70L (25)
V-70L (25)
V-70L (25)
AIBN (25)
Et3B (10)
none
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
MeOH
THF
2
12
12
12
12
24
24
24
24
24
6
44
55
76
80
83
88
6
56
46
2
36
30
18
11
9
3
78
39
52
7
IPEb
CH2Cl2
CH2Cl2
CH2Cl2
10
11
12
0
0
79
89
12
Exp er im en ta l Section
a
b
Product yields were determined by HPLC. Isopropyl ether.
IR spectra were recorded using KBr disks. 1H NMR spectra
were measured in CDCl3 on 270 MHz spectrometer with tet-
ramethylsilane as the internal standard. Wakogel C-200 silica
gel (Wako Pure Chemical Industries, Ltd.) was used for column
chromatography. Wakosil 5C18 (4.6 mm × 150 mm) (Wako Pure
Chemical) was used for a high-pressure liquid chromatography
(HPLC). AIBN and V-70 were used after being dried. V-70L and
V-70H were separated from commercial V-70 according to the
procedure described in the literature.11 Methylene chloride was
used after being washed with water and dried with molecular
sieves 4A overnight. Brominated active methylene compounds
(4a ,b) were prepared by the reported methods.11,12
P r ep a r a tion of â-Su bstitu ted En ol Eth er s (5a ,b). The title
compounds were obtained from methyl 4-formylbenzoate ac-
cording to the method of Miwa.4
Meth yl 4-(5-Meth oxy-4-p en ten yl)ben zoa te (5a ): colorless
oil; IR (KBr) 1716 (CO) cm-1; 1H NMR (CDCl3, δ ppm) 7.94 (2H,
d, J ) 8 Hz), 7.24 (2H, d, J ) 8 Hz), 6.28 and 5.90 (total 1H,
each d, J ) 13 and 6 Hz), 4.71 and 4.34 (total 1H, each m), 3.89
(3H, s), 3.58 and 3.50 (total 3H, each s), 2.67 (2H, m), 2.09 and
1.95 (total 2H, each m), 1.69 (2H, m). Anal. Calcd for C14H18O3:
C, 71.77; H, 7.74. Found: C, 71.34; H, 7.38.
Meth yl 4-(4-Meth oxy-3-bu ten yl)ben zoa te (5b): colorless
oil; IR (KBr) 1716 (CO) cm-1; 1H NMR (CDCl3, δ ppm) 7.92 (2H,
d, J ) 8 Hz), 7.22 (2H, d, J ) 8 Hz), 6.26 and 5.86 (total 1H,
each d, J ) 13 and 6 Hz), 4.68 and 4.30 (total 1H, each m), 3.78
(3H, s), 3.55 and 3.46 (total 3H, each s), 2.38 and 2.21 (total 2H,
each m), 2.07 and 1.93 (total 2H, each m). Anal. Calcd for
C13H16O3: C, 70.89; H, 7.32. Found: C, 70.64; H, 7.40.
Estim a tion of P r od u ct Yield s of Ra d ica l Ad d ition Rea c-
tion s of 4a to 5a by HP LC An a lysis. Typ ica l P r oced u r e. A
mixture of 4a (0.62 g, 4.27 mmol), 5a (1.0 g, 4.27 mmol), and
V-70 (0.33 g, 1.07 mmol) in CH2Cl2 (10 mL) was stirred at room
temperature (25 °C) for 12 h under nitrogen atmosphere. The
mixture was diluted with MeOH (2 mL), stirred for 30 min, and
poured into cold water (10 mL) containing K2CO3 (1.26 g). The
resulting organic layer was separated, dried (MgSO4), and
concentrated in vacuo. The residue was analyzed by HPLC
[mobile phase, CH3CN-H2O containing 0.006 M sodium dodecyl
sulfate and 0.02 M KH2PO4 (65:35, v/v); flow rate, 1 mL/min;
detection, UV 254 nm]. The results are listed in Table 1.
The yield of 1a was improved to 76% by increasing the
amount of V-70 and extending the reaction time (Table
1, entries 1-3). V-70 is a mixture of diastereomers (V-
70L and V-70H),11 and we previously reported that V-70L
is a better initiator than V-70H.10b Therefore, we used
V-70L in the addition reactions. By using V-70L, the
yields of 1a were increased (Table 1, entries 4 and 6).
Thus, the reaction of 4a and 5a in toluene using 15 mol
% of V-70L at room temperature for 24 h gave 1a in 88%
yield (Table 1, entry 6). The influence of the solvent in
the reaction was then examined (Table 1, entries 7-9),
and methylene chloride and toluene were found to be
favorable solvents for the present radical reaction. The
reaction in methanol afforded preferentially undesired
product 6 (Table 1, entry 7), and the use of AIBN or Et3B
as initiator also gave 6 selectively (Table 1, entries 10
and 11). The reaction in the absence of an initiator
afforded only 6 (Table 1, entry 12). The undesired 6 was
obtained by methanolysis of unreacted 5a in the second
step of the reactions.
In addition, we investigated the V-70-induced radical
addition reactions of ethyl bromocyanoacetate to â-sub-
stituted or â-unsubstituted enol ethers together with
those for the reactions. The results are shown in Table
2. All of the addition reactions were carried out in toluene
or methylene chloride at room temperature and were
(11) In this paper, the isomer melting at 58 °C corresponding to
V-70L and the isomer melting at 107 °C corresponding to V-70H were
designated. The separation of these epimers is readily possible through
the difference of the solubility in diethyl ether.12 V-70L is a racemic-
form and V-70H is a meso-form.10b,12c
(12) (a) Robertson, J . A. U.S. Pat. 2,586,995, 1952; Chem. Abstr.
1952, 46, 9575c. (b) Lim, D. Collct. Czech. Chem. Commun. 1968, 33,
1122. (c) Palma, G.; Talamini, G.; Gasparini, P.; Busetti, V. Chem. Ind.
(Milan) 1970, 52, 1116.

Notes
J . Org. Chem., Vol. 64, No. 2, 1999 677
Ta ble 2. Ra d ica l Ad d ition Rea ction s of 4a ,b to 5a -c
substrate
R2
4
5
entry
R1
R3
reaction conditionsb
product 1
yielda (%)
1
2
3
4
5
6
4a CN
4b CO2Et
4a CN
4b CO2Et
4a CN
4b CO2Et
5a (CH2)3C6H4CO2Me (p)
5a (CH2)3C6H4CO2Me (p)
5b (CH2)2C6H4CO2Me (p)
5b (CH2)2C6H4CO2Me (p)
5c H
Me
Me
Me
Me
Et
A
A
A
A
B
B
1a
1b
1c
1d
1e
1f
83
67
81
71
71
61
5c H
Et
a
b
Isolated yield. (A) (i) 25 mol % V-70L, PhMe, rt, 24 h; (ii) MeOH, rt, 0.5 h. (B) (i) 10 mol% V-70, CH2Cl2, rt, 2 h; (ii) EtOH, rt, 0.5
h.
Sch em e 3a
2.36-2.20 (1H, m), 2.20-1.80 (2H, m). Anal. Calcd for
17H20N2O4: C, 64.54; H, 6.37; N, 8.86. Found: C, 64.74; H, 6.61;
N, 8.62.
Eth yl 5-[4-(Meth oxycar bon yl)ph en yl]-2-cyan o-3-(dim eth -
C
oxym eth yl) p en ta n oa te (1d ): 71% yield; diastereomeric mix-
ture (1:1); colorless oil; IR (KBr) 2250 (CN), 1720 (CO) cm-1; 1H
NMR (CDCl3, δ ppm) 7.94 and 7.93 (total 2H, each d, J ) 8 Hz),
7.26 and 7.25 (total 2H, each d, J ) 8 Hz), 4.41 and 4.31 (total
1H, each d, J ) 6 and 7 Hz), 4.25 and 4.24 (total 2H, each q, J
) 7 Hz), 3.81 (3H, s), 3.96 and 3.66 (total 1H, each d, J ) 3 Hz),
3.40 and 3.36 (total 3H, each s), 3.37and 3.31 (total 3H, each s)
2.80-2.68 (2H, m), 2.62-2.42 (1H, m), 2.18-1.76 (2H, m), 1.31
and 1.28 (total 3H, each t, J ) 7 Hz). Anal. Calcd for C19H25
-
NO6: C, 62.80; H, 6.93; N, 3.85. Found: C, 62.57; H, 6.61; N,
3.98.
Rea ction of 4a to 5a in th e Absen ce of In itia tor . A
mixture of 4a (0.62 g, 4.27 mmol) and 5a (1.0 g, 4.27 mmol) in
CH2Cl2 (10 mL) was stirred at room temperature (25 °C) under
nitrogen atmosphere for 12 h. The 1H NMR analysis of the
reaction mixture at 12 h showed that the unreacted 4a was
present in the reaction mixture (ca. 95%). The mixture was
diluted MeOH (2 mL) and stirred further for 60 min at room
temperature. Cold water (10 mL) containing K2CO3 (1.26 g) was
poured into the mixture, and the resulting organic layer was
separated, dried (MgSO4), and concentrated in vacuo. The
residue was purified by column chromatography [n-hexane-
AcOEt (4:1, v/v)] to give methyl 4-(5,5-dimethoxypentyl)benzoate
a
Key: (i) NH2C(dNH)NH2‚HCl, tBuOK, tBuOH, reflux, 2 h; (ii)
HCl, reflux, 2 h; (iii) NaOH, aqueous MeOH (50%), reflux, 2 h;
(iv) ref 4.
P r ep a r a tion of Aceta l Ad d u cts (1a -d ). Typ ica l P r oce-
d u r e. A mixture of 4a (0.62 g, 4.27 mmol), 5a (1.0 g, 4.27 mmol),
and V-70L (0.33 g, 1.07 mmol) in toluene (10 mL) was stirred at
room temperature (25 °C) for 24 h under nitrogen atmosphere.
The mixture was diluted with MeOH (2 mL), stirred for further
30 min, and poured into cold water (10 mL) containing K2CO3
(1.26 g). The resulting organic layer was separated, dried
(MgSO4), and concentrated in vacuo. The residue was purified
by column chromatography [eluent; n-hexane-AcOEt (4:1, v/v)]
to give 1a (1.17 g) in 83% yield.
(6) (1.0 g) in 89% yield as colorless oil: IR (KBr) 1720 (CO) cm-1
;
1H NMR (CDCl3, δ ppm) 7.96 (2H, d, J ) 8 Hz), 7.23 (2H, d, J
) 8 Hz), 4.36 (1H, d, J ) 5 Hz), 3.90 (3H, s), 3.30 (6H, s), 2.67
(2H, t, J ) 8 Hz), 1.66-1.50 (6H, m). Anal. Calcd for C15H22O4:
C, 67.64; H, 8.33. Found: C, 67.34, H, 8.26.
Meth yl 4-[5,5-Dicya n o-4-(d im eth oxym eth yl)p en tyl]ben -
P r ep a r a tion of Aceta l Ad d u cts (1e,f). Typ ica l P r oce-
d u r e. A mixture of 4a (1.45 g, 10 mmol), 5c (1.45 g, 20 mmol),
and V-70 (308 mg, 1 mmol) in CH2Cl2 (25 mL) was stirred at
room temperature (25 °C) for 2 h under nitrogen atmosphere.
The mixture was diluted with EtOH (5 mL) and stirred further
for 30 min. Cold water (15 mL) containing K2CO3 (2.7 g) was
poured into the mixture, and the resulting organic layer was
separated, dried (MgSO4), and concentrated in vacuo. The
residue was purified by column chromatography [eluent, n-hex-
ane-AcOEt (5:1, v/v)] to give 1e (1.25 g) in 76% yield.
2-Cya n o-4,4-d ieth oxybu tyr on itr ile (1e): colorless oil; IR
(KBr) 2220 (CN) cm-1; 1H NMR (CDCl3, δ ppm) 4.63 (1H, t, J )
8 Hz), 3.94 (1H, t, J ) 8 Hz), 3.65 (2H, m), 3.51 (2H, m), 2.21
(2H, m), 1.18 (6H, m).
zoa te (1a ): colorless oil; IR (KBr) 2255 (CN), 1719 (CO) cm-1
;
1H NMR (CDCl3, δ ppm) 7.96 (2H, d, J ) 8 Hz), 7.25 (2H, d, J
) 8 Hz), 4.31 (1H, d, J ) 5 Hz), 4.13 (1H, d, J ) 4 Hz), 3.90 (3H,
s), 3.45 (3H, s), 3.39 (3H, s), 2.73 (2H, t, J ) 8 Hz), 2.32-2.22
(1H, m), 1.95-1.60 (2H, m), 1.60-1.51 (2H, m). Anal. Calcd for
C
18H22N2O4: C, 65.44; H, 6.71; N, 8.48. Found: C, 65.78; H, 6.91;
N, 8.12.
Eth yl 6-[4-(Meth oxycar bon yl)ph en yl]-2-cyan o-3-(dim eth -
oxym eth yl) h exa n oa te (1b): 67% yield; diastereomeric mixture
(1:1); colorless oil; IR (KBr) 2250 (CN), 1720 (CO) cm-1; 1H NMR
(CDCl3, δ ppm) 7.95 and 7.94 (total 2H, each d, J ) 8 Hz), 7.24
and 7.23 (total 2H, each d, J ) 8 Hz), 4.37 and 4.25 (total 1H,
each d, J ) 6 and 7 Hz), 4.26 and 4.25 (total 2H, each q, J ) 7
Hz), 3.90 (3H, s), 3.94 and 3.56 (total 1H, each d, J ) 3 Hz),
3.40 (3H, s), 3.37 and 3.36 (total 3H, each s), 2.76-2.68 (2H,
m), 2.63-2.44 (1H, m), 1.81-1.56 (4H, m), 1.28 and 1.25 (total
3H, m). Anal. Calcd for C20H27NO6: C, 63.64; H, 7.21; N, 3.71.
Found: C, 63.78; H, 7.51; N, 3.65.
Eth yl 2-Cya n o-4,4-d ieth oxybu tyr a te (1f): 61% yield; col-
orless oil; IR (KBr) 2225 (CN), 1710 (CO2Et) cm-1 1H NMR
;
(CDCl3, δ ppm) 4.35 (1H, t, J ) 8 Hz), 4.27 (2H, q, J ) 8 Hz),
3.67 (4H, m), 3.47 (1H, m), 2.21 (2H, m), 1.34 (3H, t, J ) 8 Hz),
1.22 (6H, t, J ) 8 Hz).
Meth yl 4-[4,4-Dicya n o-3-(d im eth oxym eth yl)bu tyl]ben -
zoa te (1c): 81% yield; colorless oil; IR (KBr) 2255 (CN), 1720
(CO) cm-1; 1H NMR (CDCl3, δ ppm) 7.98 (2H, d, J ) 8 Hz), 7.29
(2H, d, J ) 8 Hz), 4.36 (1H, d, J ) 5 Hz), 4.15 (1H, d, J ) 4 Hz),
3.80 (3H, s), 3.46 (3H, s), 3.39 (3H, s), 2.88 (2H, t, J ) 8 Hz),
Meth yl Ester 3a . To a suspension of guanidine hydrochloride
(3.04 g, 31.8 mmol) in tert-BuOH (30 mL) was added tert-BuOK
(3.93 g, 35.0 mmol) under nitrogen atmosphere, and the mixture
was stirred for 15 min at room temperature. A solution of 1a
(10.5 g, 31.8 mmol) in tert-BuOH (40 mL) was then added to

678 J . Org. Chem., Vol. 64, No. 2, 1999
Additions and Corrections
the mixture and refluxed for 2 h. After being cooled to room
temperature, the mixture was poured into water (100 mL) and
extracted with AcOEt (100 mL). The extract was acidified with
concentrated HCl (3.82 g), refluxed for 2 h, and cooled to 10 °C.
The resulting precipitate was collected by filtration and dried
to give methyl 4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-
yl)propyl]benzoate hydrochloride (3a ) (8.8 g) in 76% yield as
colorless needles: mp 272-275 °C; IR (KBr) 3181 (NH2), 1718
After being cooled to room temperature, the mixture was
concentrated to a half volume in vacuo under 50 °C. The residual
mixture was acidified to pH 2 with 6 N HCl (15 mL). The
resulting precipitate was filtered off and dried to obtain 4-[3-
(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzoic acid
hydrochloride (3b) (8.9 g) in 80% yield as off-white crystalline
powder: mp 315-317 °C (dec); IR (KBr) 3175 (NH2), 1689 (CO)
cm-1; 1H NMR (DMSO-d6-D2O, δ ppm) 7.86 (2H, d, J ) 8 Hz),
7.33 (2H, d, J ) 8 Hz), 6.71 (1H, s), 2.74 (4H, m), 1.86 (2H, m).
Anal. Calcd for C16H17N5O2‚HCl‚H2O: C, 52.53; H, 5.51; N,
20.14. Found: C, 52.59; H, 5.56, N, 19.98.
(CO) cm-1 1H NMR (CD3OD, δ ppm) 7.93 (2H, d, J ) 8 Hz),
;
7.30 (2H, d, J ) 8 Hz), 6.66 (1H, s), 3.89 (3H, s), 2.77 (4H, m),
1.98 (2H, m). Anal. Calcd for C17H19N5O2‚HCl: C, 56.43; H, 5.57;
N, 19.36. Found: C, 56.39; H, 5.61, N, 19.21.
Acid 3b. A mixture of 3a (11 g, 30 mmol) and NaOH (3.6 g,
90 mmol) in 50% aqueous MeOH (50 mL) was refluxed for 2 h.
J O981900P
Additions and Corrections
Vol. 63, 1998
Da vid A. Eva n s,* Gr etch en S. P eter son , J effr ey S.
J oh n son , Da vid M. Ba r n es, Kevin R. Ca m p os, a n d Keith
A. Woer p el . An Improved Procedure for the Preparation of
2,2-Bis[2-[4(S)-tert-butyl-1,3-oxazolinyl]]propane ((S,S)-tert-Bu-
tylbis(oxazoline)) and Derived Copper(II) Complexes.
Page 4543, column 2. An error exists in the reported
1H and 13C NMR chemical shift data for 2,2-bis[2-[4(S)-
tert-butyl-1,3-oxazolinyl]]propane (1). In the 1H NMR
spectrum, the resonance at δ 3.51 should be at δ 3.85. In
the 13C NMR spectrum, the peak at δ 26.8 should be at
δ 75.4. All peak multiplicities and coupling constants are
correct as originally reported. The authors wish to thank
Dr. David W. C. MacMillan and Dr. Clayton H. Heath-
cock for bringing these errors to our attention.
J O9840271
10.1021/jo9840271
Published on Web 12/31/1998