Novel synthesis of aza-phthalimidine hydroxylactams

Article abstract of DOI:10.1080/00397910802110180

A novel and convenient synthetic route for preparing aza-phthalimidine hydroxylactams (5a-j) by N-bromosuccinimide (NBS) was developed. This method involved the substitution reactions of substrates (3a-j) with NBS via unstable intermediate bromides (4a-j) rapidly hydrolyzed into hydroxyl products in the course of the workup process. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802110180

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Novel Synthesis of Aza-
phthalimidine Hydroxylactams
Bolin Fan a , Zenglu Liu a , Mei Tang a , Yun Xu a
Xiaowei Tang a & Zhenmin Mao a
,
a School of Pharmacy, Shanghai Jiaotong University,
Shanghai, China
Published online: 12 Sep 2008.
To cite this article: Bolin Fan , Zenglu Liu , Mei Tang , Yun Xu , Xiaowei Tang &
Zhenmin Mao (2008): Novel Synthesis of Aza-phthalimidine Hydroxylactams, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 38:19, 3231-3242
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Synthetic Communications1, 38: 3231–3242, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802110180
Novel Synthesis of Aza-phthalimidine
Hydroxylactams
Bolin Fan, Zenglu Liu, Mei Tang, Yun Xu, Xiaowei Tang, and
Zhenmin Mao
School of Pharmacy, Shanghai Jiaotong University, Shanghai, China
Abstract: A novel and convenient synthetic route for preparing aza-phthalimi-
dine hydroxylactams (5a–j) by N-bromosuccinimide (NBS) was developed. This
method involved the substitution reactions of substrates (3a–j) with NBS via
unstable intermediate bromides (4a–j) rapidly hydrolyzed into hydroxyl products
in the course of the workup process.
Keywords: N-Bromosuccinimide, hydroxylactam, hydroxylation
As important structural segments in sedatives, hypnotics, and muscle
relaxants such as zopiclone,[1a] pazinaclone,[1b] and desmethylzopiclo-
ne,[1c] hydroxylactams have attracted much attention from chemists.
Hydroxylactams were also used as key intermediates for the construction
of fused heterocyclic systems.[2,3] It has been reported that hydroxylac-
tams could be synthesized by partial reduction of aza-phthalimides with
Zn=TiCl4,[4] Zn=AcOH,[5] Mg(ClO4)2=NaBH4,[6] and NaBH4.[2,7] Regior-
estriction of these methods was observed because of coordination of the
pyridine nitrogen atom with the metal ion of magnesium perchlorate or
zinc, whereby the reduction of sodium borohydride was directed to the
adjacent carbonyl group (Fig. 1). By the same cause, the reduction
usually would not happen in the 5-position. Other reported methods,[3,8]
involved 2-substituted nicotinic anilide with organolithium and dimethyl-
formamide (DMF) forming the corresponding hydroxylactam.
In consideration of the strong basic and reductive condition
employed by these reported methods, it is of great interest to develop a
Received December 2, 2007.
Address correspondence to Zhenmin Mao, School of Pharmacy, Shanghai
Jiaotong University, Shanghai 200240, China. E-mail: zmmao@163.com
3231

3232
B. Fan et al.
Figure 1. Reduction of aza-phthalimide.
new approach to hydroxylactam compounds with such a structural seg-
ment. Herein we report a mild and convenient approach to hydroxylation
of aza-phthalimidine by the N-bromosuccinimide (NBS) (Scheme 1). This
novel method could be used to prepare selectively hydroxylactam with a
hydroxyl group at the 5-position or 7-position.
To explore this new hydroxylation method, a series of aza-phthalimi-
dines (3a–j) (Table1) with different side chains were synthesized from
3-bromomethyl-pyridine-2-carboxylic acid methyl ester[9] 1 with corres-
ponding amines (2a–j) (Table 1). Hydroxylactams (5a–j) were obtained
through hydroxylation of aza-phthalimidines by NBS. The free radical
bromine substitution took place as was expected at the 5-position meth-
ene group of aza-phthalimidine.[10] A possible mechanism was that
unstable intermediate bromides (4a–j) were formed during the substi-
tution reactions of substrates (3a–j) with NBS, which rapidly hydrolyzed
into hydroxyl products in the course of workup process. In the case of
N-substituted alkyl products (5a–c) (Table 2), the yields of products
(5a–c) were moderate (42–52%) with the recovery of partial substrates
(3a–c). A chiral center was formed after introduction of newly formed
hydroxyl group into 5-position methene, so the products 5e and 5f were
the mixture of epimers under the influence of amino acid esters 3e and 3f
before hydroxylation. This was indicated in the NMR spectra of 5e and
5f; for example, the chemical shift of carbon atom connecting with a
hydroxyl group was shown as follows: 5e (dC-OH 80.873, 78.691 ppm)
and 5f (dC-OH 79.778, 79.726 ppm). As shown in the Table 2, the low yield
of the N-substituted valine aza-phthalimidine 5f was attributed to the
steric effect. No obvious side reactions occurred because most of starting
material was successfully recovered. As for the hydroxylation of
Scheme 1. Preparation of aza-phthalimidine hydroxylactam.

Aza-phthalimidine Hydroxylactams
3233
Table 1. Amines (2a–j) and aza-phthalimidines (3a–j)
Entry
1
NH2R
Aza-phthalimidines
Yield (%)
56
2
3
63
61
4
5
49
60
6
43
7
8
9
55
50
53
aza-phthalimidines 3g and 3h with NBS, it could be a free radical substi-
tution at the 5-position methene group of aza-phthalimidine or an elec-
trophilic substitution on the phenyl ring. So if the aza-phthalimidine 3g
and 1.25 equivalents of NBS were mildly refluxed in acetonitrile, the tar-
get compound 5g was given in 27% yield. When aza-phthalimidine 3h
was treated with NBS under the same conditions as 5g, however, not
hydroxylactam but bromine-substituted aza-phthalimidine 5i (Table 2,
entry 9) was isolated. When the NBS (4.0 equiv) and substrate 3h (1.0
equiv) were refluxed in acetonitrile, the compounds 5h and 5i were
afforded in 33 and 64% yields respectively.
This could be attributed to the electron-donating effect of methoxyl
group. Therefore the ortho position of methoxyl group on the phenyl ring
was more active than the 5-position methene group of aza-phthalimidine.

3234
B. Fan et al.
Table 2. Yields of products 5a–j
Entry
1
Product
Mp(ꢀC)
104–105
Yield(%)a
Yield(%)b
42
51
75–77
52
51
48
65
90
52
2
113–115
156–157
3
4
157–159
61–63
45
6
56
—
5
6
237–238c
251–252
27
33
—
—
7
8
(Continued)

Aza-phthalimidine Hydroxylactams
3235
Table 2. Continued
Entry
9
Product
Mp(ꢀC)
186–188
Yield(%)a
Yield(%)b
5i
64
—
5j
202– 205d
61
73
10
aIsolated yield by method A.
bIsolated yield by method B.
ꢀ
cRef. 8a, mp: 237–239 C.
ꢀ
dRef. 2a, mp: 203–207 C.
Further investigation with the N-benzyl aza-phthalimidine 3j indicated
that the benzyl group was intact during the substitution reaction of 3j
with NBS. The NMR spectra of the target compound 5j were identical
with those of authentic samples. This indicated that the hydroxylation
of the N-benzyl aza-phthalimidine 3j by NBS was regiospecific.
Moderate or low yield by NBS was due to the formation of aza-
phthalimides in these reactons. For example, the plausible formation
of N-alanine aza-phthalimides 8e (Scheme 2) was proposed as follows:
The fragile intermediates dibromides 6e were formed because of over-
bromination. The formation of dihydroxylactams 7e were similar to
hydroxylactams (5a–j). At the same time, the aza-phthalimides 8e were
afforded by dehydration of dihydroxylactams. Taking into account this
competitive side reaction, we handled the reaction of substrates (3a–j)
and NBS (1.0 equiv) at lower temperature (50 ꢀC) or even at room tem-
perature. Unfortunately, most of substrates were intact in these reaction
conditions. Other reagents such as Br2=CF3COOAg and N-chlorosucci-
nimide (NCS)=benzoyl peroxide (BPO) were used to improve the yield.
Scheme 2. Possible mechanism for formation of by-product 8e.

3236
B. Fan et al.
To exclude the formation of the dibromide, the substrate 3c was
handled with Br2=CF3COOAg at room temperature. Unfortunately,
the aza-phthalimide was also a major by-product. In view of these
results, reaction of the substrate 3c and NCS=BPO was treated at
60 ꢀC in chloroform. Surprisingly, the yield greatly increased from 51
to 90% (Table 2, entry 3). The substrates 3a–e and 3j were treated with
NCS=BPO under the same conditions as 5c, and the yield of corre-
sponding products improved. According to this procedure, the sub-
strates 3g and 3h were also handled at 60 ꢀC or even at the refluxing
temperature in chloroform. However, most of starting material were
kept intact.
In conclusion, a novel, convenient, and mild synthetic approach for
hydroxylactam has been developed. Compared with the conventional
methods in the pyridine heterocyclic systems, we experienced no difficulty
in getting the hydroxylactams. The hydroxylation of the other aromatic
lactam as an extension of the scope of our functionalization methodology
is under investigation in our laboratory.
EXPERIMENTAL
Melting points were determined on a RY-2 microscopic melting-point
spectrometer and are uncorrected. 1H NMR and 13C NMR spectra were
obtained on a Varian Unity 300 spectrometer. Mass spectra were
recorded on Agilent 1100 series LC-MSD and Micromass GCT. Elemen-
tal analyses were performed on a Vario EL III instrument.
Typical Procedure for Synthesis of Compounds 3a–j
3-Bromomethyl-pyridine-2-carboxylic acid methyl ester[9]
1
(2.5 g,
9.416 mmol), amines 2a–j (18.832mmol), Et3N (6.5ml, 47.08mmol), and
acetonitrile (20 ml) were stirred for 2 days at room temperature. After the
reaction was completed, the reaction mixture was concentrated under
reduced pressure. The crude product was purified by flash chromatography.
Data
ꢀ
1
Compound 3a: Yield 56%, mp: 96–98 C. H NMR (400 MHz, DMSO-
d6): d8.68 (1H, d d, J ¼ 4.4, 1.2 Hz), 8.04 (1H, d d, J ¼ 8.0, 1.2 Hz),
7.54 (1H, d d, J ¼ 8.0, 4.4 Hz), 4.47 (2H, s), 3.55 (2H, q, J ¼ 7.2 Hz),
1.17 (3H, t, J ¼ 7.2 Hz). 13C NMR (75 MHz, DMSO-d6): d166.1, 151.2,
150.7, 136.8, 132.6, 125.8, 47.2, 37.5, 13.9. Anal. calcd. for C9H10N2O
(%): C, 66.65; H, 6.21; N, 17.27. Found: C, 66.75; H, 6.43; N, 17.46.

Aza-phthalimidine Hydroxylactams
3237
Compound 3b: Yield 63%, oilresidue. 1H NMR (400MHz, DMSO-d6):
d8.68 (1H, d d, J ¼ 4.4, 1.2 Hz), 8.04 (1H, d d, J ¼ 7.6, 1.2 Hz), 7.54 (1H, d d,
J ¼ 7.6, 4.4 Hz), 4.46 (2H, s), 3.47 (2H, t, J ¼ 7.2 Hz), 1.62 (2H, m,
J ¼ 7.2 Hz), 0.837 (3H, t). 13C NMR (75 MHz, DMSO-d6): d166.4, 151.1,
150.7, 136.9, 132.5, 125.8, 47.7, 44.4, 21.6, 11.9. LC-MS (ESI): C10H12N2O
(M þ 1) 177.1, (M þ Naþ) 199.0. Anal. calcd. for C10H12N2O (%): C,
68.16; H, 6.86; N, 15.90. Found: C, 68.01; H, 6.66; N, 15.44.
Compound 3c: Yield 61%, mp: 65–66 ꢀC. 1H NMR (400 MHz,
DCCl3): d8.76 (1H, d, J ¼ 4.8 Hz), 7.83 (1H, d, J ¼ 7.6 Hz), 7.41 (1H, d
d, J ¼ 7.6, 4.8 Hz), 4.78 (1H, m), 4.34 (2H, s), 1.30 (6H, d, J ¼ 6.8 Hz).
13C NMR (75 MHz, DCCl3): d166.0, 151.4, 150.9, 135.1, 131.3, 125.0,
43.2, 42.9, 20.9, 20.9. LC-MS (ESI): C10H12N2O (M þ 1) 177.0,
(M þ Naþ) 199.0. Anal. calcd. for C10H12N2O (%): C, 68.16; H, 6.86;
N, 15.90. Found: C, 68.59; H, 6.71; N, 15.31.
ꢀ
1
Compound 3d: Yield 49%, mp: 119–120 C. H NMR (400 MHz,
DMSO-d6): d8.71–8.72 (1H, d, J ¼ 4.8 Hz), 8.07–8.09 (1H, d, J ¼ 7.6 Hz),
7.57–7.60 (1H, d d, J ¼ 7.6, 4.8 Hz), 4.53 (2H, s), 4.42 (2H, s), 3.67 (3H, s).
13C NMR (75 MHz, DMSO-d6): d170.0, 166.7, 151.0, 150.0, 137.2, 132.9,
126.3, 52.7, 48.7, 44.4. LC-MS (ESI): C10H10N2O3 (M þ 1) 207.0,
(M þ Naþ) 229.0. Anal. calcd. for C10H10N2O3 (%): C, 58.25; H, 4.89;
N, 13.59. Found: C, 57.89; H, 4.41; N, 13.79.
ꢀ
1
Compound 3e: Yield 60%, mp: 105–106 C. H NMR (400 MHz,
DMSO-d6): d8.71–8.72 (1H, d, J ¼ 4.8 Hz), 8.06–8.08 (1H, d, J ¼ 7.6 Hz),
7.57–7.60 (1H, d d, J ¼ 7.6, 4.8 Hz), 4.95–4.97 (1H, q, J ¼ 7.2 Hz), 4.46–
4.58 (2H, q, J ¼ 17.2 Hz), 3.64 (3H, s), 1.50–1.52 (3H, d, J ¼ 7.2 Hz).
13C NMR (75 MHz, DMSO-d6): d172.2, 166.4, 151.1, 150.1, 137.2,
132.9, 126.3, 52.9, 50.2, 45.5, 15.6. LC-MS (ESI): C11H12N2O3(M þ 1)
221.0, (M þ Naþ) 243.1. Anal. calcd. for C11H12N2O3 (%): C, 59.99; H,
5.49; N, 12.72. Found: C, 59.78; H,5.51; N, 12.69.
Compound3f: Yield43%, oilresidue. 1H NMR(400 MHz, DMSO-d6):
d8.80–8.81 (1H, d, J ¼ 4.8 Hz), 7.84–7.86 (1H, d, J ¼ 7.6 Hz), 7.44–7.47 (1H,
d d, J ¼ 7.6, 4.8 Hz), 4.91–4.94 (1H, d, J ¼ 10.8 Hz). 4.79–4.82 (1H, d,
J ¼ 17.2 Hz), 4.42–4.46 (1H, d, J ¼ 17.2 Hz), 3.72 (3H, s), 2.31–2.37 (1H,
m), 1.05–1.06 (3H, d, J ¼ 6.4 Hz), 0.924–0.941 (3H, d, J ¼ 6.4 Hz).
13C NMR (75 MHz, DMSO-d6): d171.8, 167.2, 151.1, 150.1, 135.7, 131.4,
125.5, 60.0, 52.0, 45.3, 29.3, 19.5, 19.3. LC-MS (ESI): C13H16N2O3(M þ 1)
249.1, (M þ Naþ) 271.1. Anal. calcd. forC13H16N2O3(%): C, 62.89;H, 6.50;
N, 11.28. Found: C, 63.30; H, 6.62; N, 11.45.
ꢀ
1
Compound 3g: Yield 55%, mp: 192–194 C. H NMR (400 MHz,
DMSO-d6): d8.75–8.76 (1H, d d, J ¼ 4.8,1.2 Hz), 8.00–8.02 (1H, d,
J ¼ 7.2 Hz), 7.90–7.93 (2H, m), 7.61–7.64 (1H, d d, J ¼ 7.2, 4.8 Hz),
7.43–7.47 (2H, m), 7.18–7.24 (1H, m), 5.03 (2H, s). 13C NMR (75 MHz,
MHz, DMSO-d6): d165.5, 151.3, 150.4, 139.9, 136.3, 132.6, 129.6, 129.6,

3238
B. Fan et al.
126.8, 125.2, 120.1, 120.1, 48.8. LC-MS (ESI): C13H10N2O (M þ 1) 211.0,
(M þ Naþ) 233.0. Anal. calcd. for C13H10N2O (%): C, 74.27; H, 4.79; N,
13.33. Found: C, 74.25; H, 4.51; N, 12.98.
ꢀ
1
Compound 3h: Yield 50%, mp: 202–204 C. H NMR (400 MHz,
DMSO-d6): d8.73–8.74 (1H, d d, J ¼ 4.8, 1.2 Hz), 8.08–8.11 (1H, d,
J ¼ 7.6 Hz), 7.78–7.80 (2H, m), 7.59–7.62 (1H, d d, J ¼ 7.2, 4.8 Hz),
7.00–7.02 (2H, m), 4.97 (2H, s), 3.76 (3H, s). 13C NMR (75 MHz,
DMSO-d6): d165.2, 157.1, 151.1, 150.6, 136.1, 133.0, 132.5, 126.5,
122.0, 122.0, 114.8, 114.8, 55.9, 49.1. LC-MS (ESI): C14H12N2O2
(M þ 1) 241.1, (M þ Naþ) 263.1. Anal. calcd. for C14H12N2O2 (%): C,
69.99; H, 5.03; N, 11.66. Found: C, 69.95; H, 5.22; N, 11.19.
Compound 3j: Yield 53%, mp: 158–160 ꢀC. 1H NMR (400 MHz,
CDCl3): d8.78–8.79 (1H, d, J ¼ 4.0 Hz), 7.73–7.75 (1H, d, J ¼ 7.6 Hz),
7.25–7.42 (6H, m), 4.86 (2H, s), 4.26 (2H, s). 13C NMR (75 MHz,
CDCl3): d166.5, 151.3, 151.0, 136.4, 135.2, 131.3, 129.1, 129.1, 128.5,
128.5, 128.1, 125.3, 47.3, 47.0. LC-MS (ESI): (M þ 1)þ 225.1,
(M þ Naþ)þ247.1. Anal. calcd. for C14H12N2O (%): C, 74.98; H, 5.39;
N, 12.49. Found: C, 74.89; H, 5.49; N, 12.35.
Typical Procedure for Synthesis of Compounds 5a–j
Method A
A solution of 3a–j (1.0 equiv), NBS (1.25 equiv), AIBN (0.0625 equiv)
in anhydrous acetonitrile was mildly refluxed for 2–5 h. It is worth to
pointing out that such a ratio gave the compound 5i with substitution
by bromine on the phenyl ring. However, when the NBS (4.0 equiv)
and substrate 3h (1.0 equiv) were refluxed in acetonitrile, the compound
5h was afforded. The resulting mixture evaporated in vacuum and was
purified by flash chromatography.
Method B
A solution of 3a–e and 3j (1.0 equiv), NCS (1.05 equiv), and BPO (0.05
equiv) in chloroform was heated to 60 ꢀC. After the substrates disap-
peared, the resulting mixture was concentrated under reduced pressure.
The crude product was purified by flash chromatography.
Data
Compound 5a: Yield 51%, mp: 104–105 ꢀC. 1H NMR (400 MHz,
DMSO-d6): d8.69–8.71 (1H, d d, J ¼ 4.8, 1.2 Hz), 8.00–8.02 (1H, d d,

Aza-phthalimidine Hydroxylactams
3239
J ¼ 7.6, 1.2 Hz), 7.54–7.57(1H, d d, J ¼ 7.6, 4.8 Hz), 6.67 (1H, d,
J ¼ 8.8 Hz), 5.87 (1H, d, J ¼ 8.8 Hz), 3.60–3.63 (1H, m, J ¼ 7.2 Hz),
3.32–3.37(1H, m, J ¼ 7.2 Hz), 1.16 (3H, t, J ¼ 7.2 Hz). 13C NMR
(75 MHz, DMSO-d6): d164.9, 151.8, 150.9, 139.7, 132.6, 126.5, 79.1,
34.5, 14.1. HRMS (EIþ): C9H10N2O2, calc. 178.0742; found 178.0735.
Anal. calcd. for C9H10N2O2 (%): C, 60.66; H, 5.66; N, 15.72. Found:
C, 60.27; H, 5.61; N, 15.80.
Compound 5b: Yield 65%, mp: 75–77 ꢀC. 1H NMR
(400 MHz,DMSO-d6): d8.70–8.71(1H, dd, J ¼ 4.8,1.6 Hz), 8.00–8.02
(1H, d d , J ¼ 7.2, 1.6 Hz), 7.54–7.58 (1H, d d, J ¼ 7.2, 4.8 Hz), 6.68
(1H, d, J ¼ 8.8 Hz, OH), 5.84 (1H, d, J ¼ 8.8 Hz), 3.53 (1H, m), 3.24–
3.26 (1H, m), 1.55–1.62 (2H, m), 0.86 (3H, t).13C NMR (75 MHz,
DMSO-d6): d165.1, 152.0, 150.7, 139.9, 132.7, 126.5, 79.3, 41.3, 21.7,
11.9. HRMS (EIþ): C10H12N2O2, calc 192.0899; found 192.0898. Anal.
calcd. for C10H12N2O2 (%): C, 62.49; H, 6.29; N, 14.57. Found: C,
62.11; H, 6.07; N, 14.98.
ꢀ
1
Compound 5c: Yield 90%, mp: 113–115 C. H NMR (400 MHz,
DMSO-d6): d8.68–8.69 (1H, d d, J ¼ 4.8, 1.6 Hz), 7.97–7.99 (1H, d d ,
J ¼ 7.2, 1.6 Hz), 7.53–7.56 (1H, d d, J ¼ 7.2, 4.8 Hz), 6.57 (1H, d,
J ¼ 9.6 Hz, OH), 5.84 (1H, d, J ¼ 9.6 Hz), 4.15–4.22 (1H, m), 1.35–1.37
(3H, d, J ¼ 6.8 Hz), 1.30–1.31 (3H, d, J ¼ 6.8 Hz). 13C NMR (75 MHz,
DMSO-d6): d164.8, 151.8, 150.8, 140.0, 132.4, 126.6, 78.9, 44.2, 22.0,
20.4. HRMS (EIþ): C10H12N2O2, calc. 192.0899; found 192.0898. Anal.
calcd. for C10H12N2O2 (%): C, 62.49; H, 6.29; N, 14.57. Found: C,
62.44; H, 6.10; N, 14.27.
ꢀ
1
Compound 5d: Yield 52%, mp: 156–157 C. H NMR (400 MHz,
DMSO-d6): d8.75–8.76 (1H, d d, J ¼ 4.8,1.6 Hz), 8.06–8.08 (1H,
d, J ¼ 7.2, 1.6 Hz), 7.61–7.64 (1H, d d, J ¼ 7.2, 4.8 Hz), 6.86–6.89 (1H,
d, J ¼ 8.8 Hz, OH), 5.86–5.88 (1H, d, J ¼ 8.8 Hz), 4.40–4.45 (1H, d,
J ¼ 18 Hz), 4.11–4.15 (1H, d, J ¼ 18 Hz), 3.66 (3H, s). 13C NMR
(75 MHz, DMSO-d6): d169.9, 165.4, 152.2, 150.0, 139.8, 133.0, 127.1,
79.8, 52.8, 41.2. HRMS (EIþ): C10H10N2O4, calc. 222.0641; found
222.0643. Anal. calcd. for C10H10N2O4 (%): C, 54.05; H, 4.54; N,
12.61. Found: C, 53.96; H, 4.66; N, 12.28.
Compound 5e: Yield 56%, colorless solid, mp: 157–159 ꢀC. 1H NMR
(400 MHz, DMSO-d6): d8.73–8.74 (1H,d, J ¼ 4.8 Hz), 8.02–8.05 (1H, d,
J ¼ 7.6 Hz), 7.59–7.63 (1H, d d, J ¼ 4.8,7.6 Hz), 6.76–6.78 (1H, d,
J ¼ 8.8 Hz ), 5.89–5.91 (1H, d, J ¼ 8.8 Hz), 4.65–4.67 (1H, q, J ¼ 7.6 Hz),
3.57 (3H, s), 1.52 (3H, d, J ¼ 7.6 Hz). 13C NMR (75 MHz, DMSO-d6):
d172.3, 165.5, 152.3, 150.3, 140.3, 132.9, 127.1, 79.7, 52.9, 49.9, 15.9.
HRMS (EIþ): C11H12N2O4, calc. 236.0797; found 236.0797. Anal. calcd.
for C11H12N2O4 (%): C, 55.93; H, 5.12; N, 11.86. Found: C, 55.74; H,
5.19; N, 11.68.

3240
B. Fan et al.
ꢀ
1
Compound 5e: Yield 32%, colorless solid, mp: 88–90 C. H NMR
(300 MHz, CDCl3): d 8.98–9.00 (1H, d d, J ¼ 1.5, 4.8 Hz), 8.173–8.202
(1H, d d, J ¼ 1.5, 7.5 Hz), 7.642–7.666 (1H, d d, J ¼ 4.8, 7.58 Hz),
5.014–5.086 (1H, q, J ¼ 7.2 Hz), 3.749(3H, s), 1.712–1.743(3H, d,
J ¼ 7.2 Hz). MS (ESI): (M þ 1) 235.0, (M þ Naþ) 257.0. Anal. calcd. for
C11H10N2O4 (%): C, 56.41; H, 4.30; N, 11.96. Found: C, 56.26; H,
3.91; N, 11.62.
ꢀ
1
Compound 5f: Yield 6%, colorless solid, mp: 61–63 C. H NMR
(400 MHz, CDCl3): d8.81–8.83 (1H, d, J ¼ 1.2, 4.8 Hz), 7.96–8.00 (1H,
d, J ¼ 1.2, 7.6 Hz), 7.48–7.52 (1H, d d, J ¼ 4.8, 7.6 Hz), 6.25 (1H, s),
4.70–4.73 (1H, d, J ¼ 10.0 Hz), 3.76 (3H, s), 2.45–2.57 (1H, m), 0.94–
1.09 (6H, d, J ¼ 6.8 Hz). 13C NMR (75 MHz, CDCl3): d175.0, 166.5,
152.6, 149.9, 138.7, 132.0, 126.6, 80.8, 61.6, 53.1, 31.0, 19.8, 19.8. HRMS
(EIþ): C13H16N2O4, calc. 264.1110, Found 264.1111. Anal. calcd. for
C13H16N2O4 (%): C, 59.08; H, 6.10; N, 10.60. Found: C, 58.84; H,
5.92; N, 10.57.
Compound 5g: Yield 27%, mp: 237–238 ꢀC [ref. 8a, mp: 237–239 ꢀC].
1H NMR (400 MHz, DMSO-d6): d8.79–8.81 (1H, d d, J ¼ 4.8,1.2 Hz),
8.12–8.14 (1H, d d, J ¼ 7.6, 1.2 Hz), 7.74–7.76 (2H, m), 7.65–7.68 (1H,
d d, J ¼ 7.6, 4.8 Hz), 7.43–7.47 (2H, m), 7.21–7.25 (1H, m), 6.92–6.95
(1H, d, J ¼ 10 Hz, OH), 6.55–6.57 (1H, d, J ¼ 10 Hz). 13C NMR(75 MHz,
MHz, DMSO-d6): d164.4, 152.6, 149.9, 139.4, 137.9, 132.7, 129.4, 129.4,
127.3, 126.1, 123.1, 123.1, 80.5.
Compound 5h: Yield 33%, colorless solid, mp: 251–252 ꢀC. 1H NMR
(400 MHz, DMSO-d6): d8.79–8.80 (1H, d d, J ¼ 4.8, 1.2 Hz), 8.10–8.13
(1H, d d, J ¼ 7.6, 1.2 Hz), 7.96 (1H, d, J ¼ 2.8 Hz ), 7.65–7.70 (2H, m),
7.20–7.22 (1H, d, J ¼ 9.2 Hz), 6.95–6.98 (1H, d, J ¼ 10 Hz, OH, D2O
Exchange), 6.46–6.49 (1H, d, J ¼ 10 Hz). 13C NMR (75 MHz, DMSO-
d6): d164.4, 153.7, 152.4, 149.7, 139.3, 132.8, 131.2, 128.1, 127.4, 124.4,
113.2, 110.7, 80.9, 57.0. HRMS (EIþ): C14H11N2O3Br (79), calc.
333.9953, found 333.9944. Anal. calcd. for C14H11BrN2O3 (%): C,
50.17; H, 3.31;N, 8.36. Found: C, 49.67; H, 2.86; N, 8.04.
Compound 5i: Yield 64%, mp: 186–188 ꢀC. 1H NMR (400 MHz,
DMSO-d6): d8.74–8.75 (1H, d d, J ¼ 4.8, 1.6 Hz), 8.21 (1H, s), 8.09–
8.11 (1H, d, J ¼ 8.0 Hz), 7.78–7.81 (1H, d), 7.59–7.62 (1H, d d, J ¼ 8.0,
4.8 Hz), 7.19–7.21(1H, m), 4.99 (2H, s), 3.85 (3H, s). 13C NMR(75 MHz,
MHz, DMSO-d6): d165.3, 153.3, 151.2, 150.4, 136.4, 134.1, 132.6, 126.7,
124.9, 120.8, 113.4, 111.2, 57.1, 49.0. LC-MS (ESI): C14H11BrN2O2
(M þ 1)319.2, (M þ Naþ) 341.0. Anal. calcd. for C14H11BrN2O2 (%): C,
52.69; H, 3.47; N, 8.78. Found: C, 52.36; H, 3.00; N, 8.33.
Compound 5j: Yield 73%, colorless solid, mp: 202–205 ꢀC [ref (2a),
ꢀ
1
mp: 203–207 C, yield 15%]. H NMR (400 MHz, DMSO-d6): d8.73–
8.74 (1H, d d, J ¼ 4.8,1.2 Hz), 8.00–8.03 (1H, d d, J ¼ 7.6, 1.2 Hz),

Aza-phthalimidine Hydroxylactams
3241
7.57–7.60 (1H, d d, J ¼ 7.6, 4.8 Hz), 7.23–7.34 (5H, m), 6.85–6.87 (1H, br,
OH), 5.71 (1H, s), 4.93 (1H, d, J ¼ 15.6 Hz), 4.42 (1H, d, J ¼ 15.6 Hz). 13
C
NMR (75 MHz, DMSO-d6): d165.1, 151.8, 150.2, 139.5, 137.8, 132.6,
128.9, 1þ28.9, 128.1, 128.1, 127.6, 126.5, 78.8, 42.8. LC-MS (ESI):
(M þ 1) 241.1, (M þ Naþ) þ263.0.
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