Synthesis and in vitro antibacterial activity of novel methylamino piperidinyl oxazolidinones

Article abstract of DOI:10.1016/j.bmcl.2007.06.075

Design and synthesis of a few novel methylamino piperidinyl substituted oxazolidinones are reported. Their antibacterial activities have been evaluated in a MIC assay against broader panel of both susceptible and resistant Gram-positive strains. (S)-N-{3-[3-Fluoro-4-(methyl-{1-[3-(5-nitrofuran-2-yl)-acryloyl]-piperid in-4-yl}-amino)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 4i has shown comparable antibacterial activity to linezolid and eperezolid in the MIC assay, additionally compound 4i showed good antibacterial activity with an in vitro MIC value of 2-4 μg/mL against linezolid resistant Staphylococcus aureus (linezolid ≥16 μg/mL).

Full text of DOI:10.1016/j.bmcl.2007.06.075

Bioorganic & Medicinal Chemistry Letters 17 (2007) 5227–5232
Synthesis and in vitro antibacterial activity of novel
methylamino piperidinyl oxazolidinonesq
Brijesh Kumar Srivastava,* Rina Soni, Jayendra Z. Patel,
Manish Solanki, Darshan Valani, Sunil Gupta, Bhupendra Mishra,
Vijay Takale, Purvi Pandya, Mukul R. Jain and Pankaj R. Patel
Zydus Research Centre, Sarkhej-Bavla N. H.8A, Moraiya, Ahmedabad 382210, India
Received 3 May 2007; revised 22 June 2007; accepted 27 June 2007
Available online 30 June 2007
Abstract—Design and synthesis of a few novel methylamino piperidinyl substituted oxazolidinones are reported. Their antibacterial
activities have been evaluated in a MIC assay against broader panel of both susceptible and resistant Gram-positive strains. (S)-N-
{3-[3-Fluoro-4-(methyl-{1-[3-(5-nitrofuran-2-yl)-acryloyl]-piperidin-4-yl}-amino)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide
4i has shown comparable antibacterial activity to linezolid and eperezolid in the MIC assay, additionally compound 4i showed good
antibacterial activity with an in vitro MIC value of 2–4 lg/mL against linezolid resistant Staphylococcus aureus (linezolid P16 lg/mL).
Ó 2007 Elsevier Ltd. All rights reserved.
Bacterial infections have been a serious concern both in
the hospital and community settings. The mortality and
morbidity caused by Gram-positive bacteria has world-
wide alarming impact on the human population. Oxazo-
lidinones have been remarkable antibacterials, which act
with a novel mechanism by inhibiting the protein synthe-
sis at the bacterial ribosomal level.1 The only drug of
oxazolidinone class linezolid (ZyvoxTM) 1 (Fig. 1) has
been approved by USFDA in April 2000.2 The multidrug
resistance is another challenge to medical fraternity.
Unfortunately the linezolid is also not spared from resis-
tance, however only few cases have been reported.3
Weidner-Wells et al. investigated 4-piperidinyloxy oxazo-
lidinone 3 (Fig. 1) with antibacterial activity against vari-
ety of susceptible as well as resistant Gram-positive
organisms.7 The results from the SAR developed by them
demonstrated that replacement of piperazinyl ring of
eperezolid 2 (Fig. 1) by 4-piperidinyloxy moiety is tolera-
ble for imparting antibacterial activity. We have devel-
oped a novel series of oxazolidinones 4a–4i, (Fig. 2)
where piperazinyl ring of eperezolid is replaced by meth-
ylamino piperidinyl system. Ranbaxy Research Labora-
tories has optimized piperazinyloxazolidinones to get
5-nitrofuryl derivative 5 (RBx-7644),5m (Fig. 2) which is
safer and currently in clinical development.8 Similarly
we have developed SAR and identified compound 6,
(Fig. 2) which bears 5-nitrofuryl on the distant nitrogen
atom of the piperazinyl ring of the eperezolid system,
show impressive in vitro MIC values against all the strains
tested.6a Looking on the promising drugability of 5-nitro-
furyl derivative, we modified methylamino piperidinyl
oxazolidinone series to get 5-nitrofuryl derivative 4i.
The oxazolidinones 1, 2, 4a–4i, 5, and 16 were evaluated
for their in vitro antibacterial activities in MIC assay by
Clinical & Laboratory Standards Institute Guidelines.9
Several pharmaceutical industries and academic institu-
tions have witnessed the pace of oxazolidinone antibac-
terial research to get efficacious and safer drug.4,5
Recently, we have disclosed our oxazolidinone antibac-
terial findings but due to unfavorable pharmacokinetic
and pharmacodynamic profile none of the compounds
could be selected for further development6.
Keywords: N-Methylamino piperidinylaryloxazolidinones; In vitro
MIC assay; Gram-positive organism; Linezolid resistant Staphylococ-
cus aureus.
q
The syntheses of methylamino piperidinyl substituted
oxazolidinones 4a–4i and 16 have been outlined in
Scheme 1 and achieved as reported in the literature.6b,10
4-Hydroxy piperidine was converted into N-Boc-4-pipe-
ZRC Communication # 226.
*
Corresponding author. Tel.: +91 2717 250801; fax: +91 2717
250603; e-mail addresses: brijeshsrivastava@zyduscadila.com,
bksri2000@yahoo.com
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.06.075

5228
B. K. Srivastava et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5227–5232
O
O
O
HO
O
O
O
O
N
N
N
N
O
N
N
NHAc
NHAc
NHAc
O
F
F
F
3
2
1
N
O
Eperezolid
Linezolid
O
R
Figure 1.
O
Me
O
N
N
NHAc
F
N
O
4a-4i
R
O2N
O2N
O
O
O
O
O
O
N
N
N
N
N
N
NHAc
NHAc
O
F
F
5
6
RBx -7644
Figure 2.
ridinol derivative 7 using tert-butoxy carbonyl anhydride,
which was reacted with methanesulfonyl chloride to
afford mesityl derivative 8. Reaction of 8 with sodium
azide gave azide derivative 9, which was further reduced
to its amino derivative 10 using triphenyl phosphine.
Reaction of 10 with 3,4-difluoro nitrobenzene was carried
out by nucleophilic substitution reaction at position 4 to
afford 11. The –NMe derivative 12 was synthesized from
11 employing methyl iodide and sodium hydride. The
nitro group of compound 12 was reduced using Raney-
Ni/hydrazine hydrate to furnish –NH2, which upon
subsequent protection with carboxy benzyloyl afforded
intermediate 13. The oxazolidinone ring was constituted
by reacting anion of 13 with (R)-glycidyl butyrate to
afford alcohol derivative 14. Compound 14 was subse-
quently converted to –NH2 derivative in the similar
manner as described for compounds 7–10 followed by
reaction with acetic anhydride to get –NHAc derivative
15. The –Boc moiety of compound 15 was deprotected
by treatment of trifluoroacetic acid to afford N-methyl
piperidinyl oxazolidinone intermediate 16. Finally
compound 16 was reacted with appropriate acrylic acid
derivatives using 1-hydroxy-benzotriazole monohydrate
and [1-(3-dimethylaminopropyl)-3-ethylcarbodiimide]
hydrochloride in the presence of triethylamine to furnish
compounds 4a–4i.
is, Staphylococcus epidermidis, Enterococcus faecalis,
and Staphylococcus aureus. The compound containing
cinnamoyl group 4a exhibited mild in vitro activity for
susceptible B. subtilis, however it did not show antibac-
terial activity for rest of the strains mentioned in Table 1.
Substitution of the phenyl ring of cinnamoyl moiety by
4-OH group 4b also did not make any notable change in
MIC values except for E. faecalis. Thus, substitution of
electron-donating group on cinnamoyl moiety is not
suitable for imparting antibacterial activities. In order
to see the effect of electron-withdrawing group on phe-
nyl ring, we substituted 4th position of the phenyl ring
with electron-withdrawing –NO2 group 4c, to our sur-
prise there was no improvement observed in antibacte-
rial activities. Furthermore, when 3 and 4 positions
were substituted as 1,2-methylenedioxy group 4d, still
no antibacterial activity was noticed. Looking on the
unfavorable antibacterial activity shown by cinnamoyl
compound 4a and its derivatives 4b–4d, we replaced
phenyl system of cinnamoyl derivative with saturated
cyclohexyl group 4e, however it exhibited MIC 4–8 lg/mL
against methicillin resistant S. aureus and there was
complete loss of antibacterial activity for rest of the
strains tested. Owing to our previous reports, where
heterocycle systems displayed significant antibacterial
activities against the similar set of Gram-positive
strains,6d further we synthesized furan derivative 4f,
which also did not show appreciable change in MIC val-
ues as compared to 4e (Table 1). Methylamino piperid-
The oxazolidinones 4a–4i and 16 were screened against
susceptible Gram-positive strains such as Bacillus subtil-

B. K. Srivastava et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5227–5232
5229
OH
N3
OH
OMs
NH2
iv
iii
ii
i
N
Boc
N
Boc
N
Boc
N
H
N
Boc
9
8
10
7
v
Me
H
N
Me
vi
NO2
N
NO2
N
NHCbz
vii, viii
F
F
F
N
N
N
13
Boc
O
12
11
Boc
Boc
ix
O
Me
Me
O
N
ii-iv, x
O
N
N
N
OH
NHAc
F
F
N
15
xi
14
N
Boc
Boc
O
O
Me
Me
O
O
O
N
N
N
N
R
OH
NHAc
NHAc
F
F
xii
HN
N
O
16
4a-4i
R
Scheme 1. Reagents and conditions: (i) Boc2O, THF, 0 °C, 3–4 h, 85%; (ii) MeSO2Cl, TEA, CH2Cl2, 0–5 °C, 1 h, 63%; (iii) NaN3, DMF, 70–80 °C,
2–3 h, 45%; (iv) PPh3, 1,4-dioxane, MeOH, NH3 aq, 27–28 °C, 30 min, 44%; (v) C6H3F2NO2, CH3CN, 75–80 °C, 1–2 h, 76%; (vi) NaH, MeI, DMF,
27–28 °C, 30 min, 23%; (vii) Raney Ni, N2H4ÆH2O, MeOH, 27–78 °C, 30 min, 50%; (viii) CbzCl, NaHCO3, (CH3)2CO, H2O, 0–27 °C, 35%; (ix)
n-BuLi (1.6 M sol. in hexane), (R)-glycidyl butyrate,THF, À78 °C, 3 h, 40%; (x) Ac2O, pyridine, 27–28 °C, 30 min, 85%; (xi) TFA, CH2Cl2, 27–28 °C,
1–2 h, 65%; (xii) EDCÆHCl, HOBtÆH2O, TEA, CH2Cl2, 27–28 °C, 0.5–1 h, (15–76%).
Table 1. In vitro MIC [minimum inhibitory concentration in lg/mL] values of novel methylamino piperidinyl oxazolidinones 4a–4i in various
susceptible Gram-positive strainsa
O
Me
O
N
N
NHAc
F
N
O
4a-4i
R
Compound
R
B.s.
S.e.
E.f.
>16
E.f. 1
S.a.
S.a. 1
8–16
S.a. 2
4–8
4a
2–4
2–4
4–8
8–16
8–16
8–16
>16
>16
>16
8–16
4b
4c
4–8
8–16
>16
>16
>16
>16
>16
HO
>16
O2N
4d
2–4
8–16
8–16
>16
8–16
>16
>16
O
O
(continued on next page)

5230
B. K. Srivastava et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5227–5232
Table 1 (continued)
Compound
R
B.s.
S.e.
>16
E.f.
>16
E.f. 1
8–16
S.a.
>16
S.a. 1
8–16
S.a. 2
8–16
4e
4f
8–16
2–4
2–4
>16
4–8
>16
>16
>16
>16
>16
>16
>16
>16
O
4g
8–16
8–16
N
H
HO
4h
4i
>16
>16
1–2
>16
2–4
>16
4–8
>16
1–2
>16
2–4
>16
1–2
O
0.5–1
O2N
O
1
1–2
2–4
2–4
2–4
ND
>16
1–2
2–4
2–4
>16
1–2
1–2
1–2
>16
2–4
2–4
1–2
>16
ND
ND
1–2
>16
2
0.5–1
0.25–0.5
>16
2–4
5
0.5–1
>16
16
a MIC were determined by broth micro dilution technique. B.s., Bacillus subtilis ATCC 6633; S.e., Staphylococcus epidermidis ATCC 12228; E.f.,
Enterococcus faecalis ATCC 29212; E.f. 1, Enterococcus faecalis ATCC 14506; S.a., Staphylococcus aureus ATCC 33591; S.a. 1, Staphylococcus
aureus ATCC 29213; S.a. 2, Staphylococcus aureus ATCC 33592; ND, not done.
inyl oxazolidinone with 3-indoyl moiety resulted in
compound 4g, which was found to be mediocre against
B. subtilis, S. epidermidis, while hydroxymethyl deriva-
tive of furan 4h showed no antibacterial activities
against susceptible strains (Table 1). The 5-nitrofuryl
derivative 4i exhibited comparable in vitro MIC values
as those of linezolid 1, eperezolid 2, and RBx-7644 5.
Replacement of piperazinyl system of compound 6 by
N-methyl piperidinyl as in 4i resulted in a slightly lesser
potent compound.6a The unmasked N-methyl piperidi-
nyl derivatives 16 were found to be inactive against all
the strains tested (Tables 1 and 2). Encouraged by
Table 2. In vitro MIC values of novel methylamino piperidinyl oxazolidinones 4a–4i in various susceptible and resistant Gram-positive strainsa
Compound
E.f. 2
E.f. 3
S.a. 3
S.a. 4
S.a. 5
S.p.
S.p. 1
S.e. 1
4a
4b
4c
4d
4e
4f
4g
4h
4i
1
8–16
8–16
>16
>16
8–16
>16
8–16
>16
1–2
4–8
8–16
8–16
>16
>16
8–16
>16
8–16
>16
2-4
>16
>16
>16
>16
>16
>16
>16
>16
2–4
8–16
4–8
8–16
8–16
>16
8–16
8–16
4–8
8–16
>16
>16
8–16
8–16
8–16
>16
1–2
8–16
8–16
>16
8–16
>16
4–8
>16
>16
>16
>16
8–16
>16
8–16
>16
8–16
2–4
>16
8–16
>16
8–16
>16
4–8
>16
>16
1–2
2–4
0.25–0.5
0.5–1
0.25–0.5
0.25–0.5
>16
0.25–0.5
1–2
ND
1–2
1–2
ND
ND
2–4
1–2
2–4
>16
>16
>16
>16
1–2
1–2
0.5–1
0.25–0.5
2–4
2
5
16
1–2
>16
1–2
>16
0.5–1
>16
0.25–0.5
>16
>16
>16
a MIC were determined by broth micro dilution technique. E.f. 2, multi-resistant Enterococcus faecalis ATCC 700802; E.f. 3, vancomycin resistant
Enterococcus faecium ATCC 700221; S.a. 3, Staphylococcus aureus ATCC 25923; S.a. 4, linezolid resistant Staphylococcus aureus NRS 119; S.a. 5,
methicillin resistant Staphylococcus aureus ATCC 700699; S.p., Streptococcus pyogens ATCC 14289; S.p. 1, multi-resistant Streptococcus pneu-
moniae ATCC 700904; S.e. 1, Staphylococcus epidermidis ATCC 155; ND, not done.

B. K. Srivastava et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5227–5232
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MIC values obtained for compound 4i, we tested all the
compounds against broader panel of susceptible and
resistant Gram-positive strains (Table 2). Compounds
4a–4h and 16 displayed similar inferior potency against
various strains mentioned in Table 2 as exhibited for
strains mentioned in Table 1 except for compound 4i,
which was found to be potent against all the strains
mentioned in Table 2.
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In the view of emerging resistance to linezolid, we tested
oxazolidinone derivatives 4a–4i against linezolid resis-
tant S. aureus strain NRS 119 (we are registered user
of Network on Antimicrobial Resistance in S. aureus,
www.narsa.net), which has G 2576T mutations in
DNA encoding the central loop of domain V of 23S
rRNA and these mutations have been reported to
develop microorganisms having linezolid resistance.3d
Compound 4i showed antibacterial activity with
in vitro MIC values in the range of 2–4 lg/mL against
linezolid resistant S. aureus (Table 2, linezolid P16 lg/mL).
Thus, appropriate substitution on oxazolidinone would
give compounds, which may even work against linezolid
resistant organisms.
In summary, replacement of piperazinyl ring of eperezo-
lid by methylamino piperidinyl system resulted in com-
pounds which were tolerable for antibacterial activity
in MIC assay. The cinnamoyl derivative 4a and different
substituents on the phenyl ring 4b and 4c are poor anti-
bacterial agents. However, the heterocyclic derivatives
4f–4i are still suitable for imparting antibacterial activity
particularly 5-nitrofuryl derivative 4i is comparable in
antibacterial MIC values to linezolid, eperezolid, and
RBx-7644. Optimization of the methylamino piperidinyl
oxazolidinone resulted in compound 4i, which was also
active against linezolid resistant strains.
Acknowledgments
Authors are thankful to NARSA, USA, for providing
linezolid resistant strains. We thank Mr. Sidhartha San-
kar Kar and Mr. Sandeep Shedage for help in the prep-
aration of the manuscript, management of the Zydus
Group for encouragement, and the analytical depart-
ment for support.
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M. J.; Grega, K. C.; Lee, C. S.; Dolak, L. A.; Seest, E. P.;
Watt, W.; Adams, W. J.; Friis, J. M.; Ford, C. W.;
Zurenko, G. E. Bioorg. Med. Chem. Lett. 2003, 13, 4235;
(l) Hutchinson, D. Curr. Top. Med. Chem. 2003, 3, 1021,
and references cited therein; (m) Rattan, A. Drugs Furture
2003, 28, 1070; (n) Tucker, J. A.; Allwine, D. A.; Grega,
K. C.; Barbachyn, M. R.; Klock, J. L.; Adamski, J. L.;
Brickner, S. J.; Hutchinson, D. K.; Ford, C. W.; Zurenko,
G. E.; Conradi, R. A.; Burton, P. S.; Jensen, R. M.
J. Med. Chem. 1998, 41, 3727; (o) Brickner, S. J. Curr.
Pharm. Des. 1996, 2, 175.
Compound 4c. 96.7% purity by HPLC; mp 153–155 °C;
IR (KBr) 3292, 1647, 1608 cmÀ1 1H NMR (300 MHz,
;
CDCl3)
d 8.23 (d, J = 8.58 Hz, 2H), 7.7–7.64 (t,
J = 8.42 Hz, 3H), 7.45–7.39 (dd, J = 14.01 and 2.01 Hz,
1H), 7.06–6.95 (m, 3H), 6.16 (bs, 1H), 4.77–4.76 (m, 2H),
4.16–4.12 (d, 1H), 4.03 (t, J = 8.95 Hz, 1H), 3.78–3.58 (m,
3H), 3.40–3.36 (t, 1H), 3.20–3.14 (bs, 1H), 2.72 (s, 3H),
2.03 (s, 3H), 1.88–1.84 (bs, 2H), 1.67–1.65 (bs, 2H); ESI-
MS: 540.2 (M+H)+.
Compound 4d. 98.4% purity by HPLC; mp 76–78 °C; IR
;
(KBr) 3292, 1643, 1595 cmÀ1 1H NMR (300 MHz,
CDCl3) d 7.58 (d, J = 15.54 Hz, 1H), 7.44–7.38 (dd,
J = 14.01 and 2.43 Hz, 1H), 7.05–6.97 (m, 2H), 6.81–6.70
(m, 1H), 6.07 (bs, 1H), 5.99 (s, 2H), 4.78–4.76 (m, 2H),
4.18–4.14 (d, 1H), 4.02 (t, J = 8.97 Hz, 1H), 3.77–3.60 (m,
3H), 3.38–3.35 (t, 1H), 3.20–3.14 (bs, 1H), 2.70 (s, 3H),
2.69–2.68 (m, 1H), 2.02 (s, 3H), 1.84–1.78 (bs, 2H), 1.67–
1.65 (bs, 2H); ESI-MS: 539.2 (M+H)+.
6. (a) Srivastava, B. K.; Jain, M. R.; Solanki, M.; Soni, R.;
Valani, D.; Gupta, S.; Mishra, B.; Takale, V.; Kapadnis,
P. Patel, H.; Pandya, P.; Patel, J. Z.; Patel, P. R. Eur. J.
Med. Chem. 2007 (doi:10.1016/j.ejmech.2007.05.003); (b)
Lohray, B. B.; Neha, G.; Srivastava, B. K.; Lohray, V. B.
Bioorg. Med. Chem. Lett. 2006, 16, 3817; (c) Lohray, B.
B.; Lohray, V. B.; Srivastava, B. K.; Gupta, S.; Solanki,
M.; Pandya, P.; Kapadnis, P. Bioorg. Med. Chem. Lett.
2006, 16, 1557; (d) Lohray, V. B.; Lohray, B. B.;
Srivastava, B. K. Pure Appl. Chem. 2005, 77, 195; (e)
Lohray, B. B.; Lohray, V. B.; Srivastava, B. K.; Gupta, S.;
Solanki, M.; Kapadnis, P.; Takale, V.; Pandya, P. Bioorg.
Med. Chem. Lett. 2004, 14, 3139; (f) Lohray, B. B.;
Lohray, V. B.; Srivastava, B. K.; Kapadnis, P.; Pandya, P.
Bioorg. Med. Chem. 2004, 12, 4557; (g) Srivastava, B. K.;
Kapadnis, P.; Pandya, P.; Lohray, V. B. Eur. J. Med.
Chem. 2004, 39, 989; (h) Gandhi, N.; Srivastava, B. K.;
Lohray, V. B.; Lohray, B. B. Tetrahedron Lett. 2004, 45,
6269; (i) Lohray, B. B.; Lohray, V. B.; Srivastava, B. K.
PCT WO 2003082864, 2003; Chem. Abstr. 2003, 139,
307798.
7. Weidner-Wells, M. A.; Boggs, C. M.; Foleno, B. D.; Wira,
E.; Bush, K.; Goldschmidt, R. M.; Hlasta, D. J. Bioorg.
Med. Chem. Lett. 2001, 11, 1829.
8. Das, B.; Rudra, S.; Yadav, A.; Ray, A.; Raja Rao, A. V.
S.; Srinivas, A. S. S. V.; Soni, A.; Saini, S.; Shukla, S.;
Pandya, M.; Bhateja, P.; Malhotra, S.; Mathur, T.; Arora,
S. K.; Rattan, A.; Mehta, A. Bioorg. Med. Chem. Lett.
2005, 15, 4261, and references cited therein.
9. National Committee for Clinical Laboratory Standards.
Methods for Dilution Antimicrobial Susceptibility Tests for
Bacteria That Grow Aerobically, 4th ed. (Approved
Standard); NCCLS Document M7-A4; NCCLS: Wayne,
PA, 1997.
Compound 4e. 97% purity by HPLC; mp 61–63 °C; IR
;
(KBr) 3292, 1652, 1604 cmÀ1 1H NMR (300 MHz,
CDCl3) d 7.43–7.38 (dd, J = 14.01 and 2.43 Hz, 1H),
7.04 (d, J = 2.43 Hz, 1H), 6.99 (d, J = 9.03 Hz, 1H), 6.85–
6.78 (m, 1H), 6.21–6.16 (dd, J = 15.24, 1.05 Hz, 1H), 6.02
(bs, 1H), 4.78–4.76 (m, 2H), 4.10–4.08 (d, 1H), 4.02 (t,
J = 8.97 Hz, 1H), 3.77–3.60 (m, 3H), 3.42–3.38 (m, 1H),
3.02–2.98 (t, 1H), 2.69 (s, 3H), 2.12–2.08 (m, 1H), 2.02 (s,
3H), 1.78–1.60 (bs, 6H), 1.58–1.54 (bs, 2H), 1.28–1.16 (m,
4H), 1.14–1.12 (m, 2H); ESI-MS: 501.2 (M+H)+.
Compound 4f. 96.9% purity by HPLC; mp 118–120 °C; IR
;
(KBr) 3292, 1647, 1600 cmÀ1 1H NMR (300 MHz,
CDCl3) d 7.47–7.38 (m, 3H), 7.05 (d, J = 2.37 Hz, 1H),
6.99 (d, J = 9.03 Hz, 1H), 6.82 (d, J = 15.12 Hz, 1H), 6.53
(d, J = 3.36 Hz, 1H), 6.45 (d, J = 3.36 Hz, 1H), 6.0 (bs,
1H), 4.79–4.75 (m, 2H), 4.12–4.08 (d, 1H), 4.02 (t,
J = 8.97 Hz, 1H), 3.77–3.60 (m, 3H), 3.42–3.36 (t, 1H),
3.08 (bs, 1H), 2.70 (s, 3H), 2.03 (s, 3H), 1.85–1.81 (bs, 2H),
1.69–1.59 (bs, 2H); ESI-MS: 485.3 (M+H)+.
Compound 4g. 93.8% purity by HPLC; mp 120–122 °C; IR
(KBr) 3269, 1635, 1573 cmÀ1; 1H NMR (300 MHz, CDCl3)
d 8.63 (bs, 1H), 7.89 (d, J = 2.61 Hz, 1H), 7.48–7.39 (m,
3H), 7.28–7.24 (m, 2H), 7.05–6.9 (m, 3H), 6.10 (bs, 1H),
4.77–4.76 (m, 2H), 4.18–4.14 (d, 1H), 4.02 (t, J = 8.97 Hz,
1H), 3.76–3.62 (m, 3H), 3.42–3.38 (t, 1H), 3.16–3.12 (bs,
1H), 2.71 (s, 3H), 2.10–2.06 (bs, 1H), 2.02 (s, 3H), 1.86–
1.82 (bs, 2H), 1.74–1.70 (bs, 2H); ESI-MS: 534.2 (M+H)+.
Compound 4h. 94.1% purity by HPLC; oil; IR (neat) 3303,
1645, 1595 cmÀ1; 1H NMR (300 MHz, CDCl3) d 7.43–7.37
(m, 2H), 7.04 (d, J = 2.16 Hz, 1H), 6.99 (d, J = 8.97 Hz,
1H), 6.82 (d, J = 15.06 Hz, 1H), 6.47 (d, J = 3.21 Hz, 1H),
6.35 (d, J = 3.37 Hz, 1H), 6.3 (bs, 1H), 4.77–4.75 (m, 2H),
4.63 (s, 2H), 4.16–4.12 (d, 1H), 4.02 (t, J = 8.97 Hz, 1H),
3.77–3.61 (m, 3H), 3.42–3.38 (t, 1H), 3.1 (t, 1H), 2.70 (s,
3H), 2.36–2.32 (bs, 1H), 2.02 (s, 3H), 1.86–1.80 (bs, 2H),
1.75–1.69 (bs, 2H); ESI-MS: 515.3 (M+H)+.
Compound 4i. 98% purity by HPLC; mp 175–177 °C; IR
(KBr) 3292, 1647, 1600 cmÀ1; 1H NMR (300 MHz, CDCl3)
d 7.46–7.40 (dd, J = 15.18 and 3.66 Hz, 2H), 7.35 (d,
J = 3.92 Hz, 1H), 7.15 (d, J = 15.21 Hz, 1H), 7.05 (d,
J = 2.47 Hz, 1H), 7.01 (d, J = 3.91 Hz, 1H), 6.69 (d,
J = 3.95 Hz, 1H), 6.0 (bs, 1H), 4.77–4.75 (m, 2H), 4.16–
4.12 (d,1H), 4.03 (t, J = 8.97 Hz, 1H), 3.78–3.58 (m, 3H),
3.42–3.36 (t, 1H), 3.16 (bs, 1H), 2.71 (s, 3H), 2.03 (s, 3H),
1.85–1.81 (bs, 2H), 1.69–1.65 (bs, 2H); ESI-MS: 530.1
(M+H)+.
10. Spectroscopic data for compounds 4a–4i:
Compound 4a. 98.8% purity by HPLC; mp 74–76 °C; IR
1
(KBr) 3292, 1751, 1647, 1598 cmÀ1; H NMR (300 MHz,
CDCl3), d 7.65 (d, J = 15.36 Hz, 1H), 7.54–7.51 (dd,
J = 7.77 and 2.34 Hz, 2H), 7.40–7.35 (m, 4H), 7.05 (d,
J = 2.46 Hz, 1H), 6.99 (d, J = 8.97 Hz, 1H), 6.90 (d,
J = 15.4 Hz, 1H), 6.02 (bs, 2H), 4.78–4.75 (m, 2H), 4.10–
4.08 (d, 1H), 4.02 (t, J = 8.95 Hz, 1H), 3.77–3.64 (m, 3H),
3.42–3.37 (t, 1H), 3.16–3.12 (bs, 1H), 2.71 (s, 3H), 2.03 (t,
3H), 1.89–1.81 (bs, 2H), 1.68–1.62 (dd, J = 11.88 and
4.41 Hz, 2H); ESI-MS: 495.2 (M+H)+.
Compound 4b. 98% purity by HPLC; mp 128–130 °C; IR
1
(KBr) 3292, 1747, 1639, 1606 cmÀ1; H NMR (300 MHz,
CDCl3) d 7.60 (d, J = 15.36 Hz, 1H), 7.42 (d, J = 8.67 Hz,
3H), 7.04–6.97 (m, 2H), 6.83 (d, J = 8.55 Hz, 2H), 6.75 (d,
J = 15.36 Hz, 1H), 6.06 (bs, 1H), 5.84 (bs, 1H), 4.78–4.75
(m, 2H), 4.16–4.12 (d, 1H), 4.02 (t, J = 8.97 Hz, 1H), 3.74–
3.60 (m, 3H), 3.35–3.28 (t, 1H), 3.12–3.08 (bs, 1H), 2.70