Discovery of diarylpyridine derivatives as novel non-nucleoside HIV-1 reverse transcriptase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2009.07.080

Two series (4 and 5) of diarylpyridine derivatives were designed, synthesized, and evaluated for anti-HIV-1 activity. The most promising compound, 5e, inhibited HIV-1 IIIB, NL4-3, and RTMDR1 with low nanomolar EC₅₀ values and selectivity indexe

Full text of DOI:10.1016/j.bmcl.2009.07.080

Bioorganic & Medicinal Chemistry Letters 19 (2009) 5482–5485
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of diarylpyridine derivatives as novel non-nucleoside HIV-1
reverse transcriptase inhibitors
Xingtao Tian a, Bingjie Qin a, Hong Lu b, Weihong Lai d, Shibo Jiang b, Kuo-Hsiung Lee c,
Chin Ho Chen d, Lan Xie a,
*
a Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Beijing 100850, China
b Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA
c Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA
d Duke University Medical Center, Box 2926, Surgical Oncology Research Facility, Durham, NC 27710, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Two series (4 and 5) of diarylpyridine derivatives were designed, synthesized, and evaluated for anti-HIV-
1 activity. The most promising compound, 5e, inhibited HIV-1 IIIB, NL4-3, and RTMDR1 with low nano-
molar EC50 values and selectivity indexes of >10,000. The results of this study indicate that diarylpyridine
can be used as a novel scaffold to derive a new class of potent NNRTIs, active against both wild-type and
drug-resistant HIV-1 strains.
Received 2 May 2009
Revised 10 July 2009
Accepted 15 July 2009
Available online 19 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Diarylpyridine derivatives
HIV-1 NNRTIs
Drug resistance
Reverse transcriptase (RT) is one of the most important en-
zymes in the HIV-1 life cycle. Two major drug target sites in the
RT are the substrate binding site and an allosteric site that is dis-
tinct from, but closely located to, the substrate binding site.1–3
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) interact
with the allosteric binding site on HIV-1 RT to cause distortion of
the three-dimensional structure of the enzyme and to inhibit RT
catalytic function. Currently, NNRTIs approved for AIDS therapy in-
clude nevirapine, delavirdine, efavirenz, and etravirine (TMC125).
TMC125,4 TMC120,5 a previous clinical candidate, and TMC278,6
a promising new drug candidate in phase III clinical trial, (Fig. 1)
are compounds belonging to the diarylpyrimidine (DAPY) family.7
These compounds are very potent against both wild-type and
many drug-resistant HIV-1 strains. The excellent pharmacological
profile of these compounds has encouraged new research to ex-
plore a next-generation of NNRTIs with new scaffolds. Prior studies
on DAPY derivatives have revealed some pharmacophores,1,8 such
as a horseshoe binding conformation, a proper positioning of two
phenyl rings in the eastern and western wings of the NNRT binding
pockets, a para-cyanoaniline moiety in the eastern wing, and two
hydrogen bonds to K101 of HIV-1 RT. Based on this SAR informa-
tion, we initiated a program to explore new NNRTI leads with
new molecular scaffolds and high potency against wild-type and
drug-resistant viral strains. By using an isosteric replacement strat-
egy, diarylpyridine compounds were designed, synthesized, and
evaluated for anti-HIV-1 activity. Among the tested compounds,
new active leads with high potency against both wild-type and
drug-resistant HIV-1 strains were discovered. We report our prom-
ising results herein.
Compared to TMC125, our target compounds (Fig. 1) were de-
signed to retain the active para-cyanoaniline moiety, but have a
pyridine replacing the pyrimidine ring and various substituents
at the para-position of the phenoxy ring. Because the isosteric
replacement of pyridine for pyrimidine should not change the
molecular topology or flexibility, we hypothesized that the de-
signed compounds would have similar binding orientation, confor-
mation, and comparable activity to that of TMC125 and TMC278
(EC50/SI: 0.00158 lM/63,096 and 0.0005 lM/60,000, respectively,
against HIV-1 IIIB replication in the MT-4 cell line),9,10 as well as
TMC120. However, the substitution of pyridine for pyrimidine re-
sulted in the loss of an H-bond between K101 and the second nitro-
gen on the pyrimidine ring. Therefore, we incorporated a nitro or
amino group at the 3-position on the pyridine ring to provide po-
tential H-bonding with K101, as either an H-bond acceptor or
donor.
The target compounds were synthesized via the short routes
detailed in Schemes 1 and 2. The starting material 2,6-dichloro-3-
* Corresponding author. Tel./fax: +86 10 66931690.
E-mail address: lanxieshi@yahoo.com (L. Xie).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.07.080

X. Tian et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5482–5485
5483
R1
CN
NH
R
O
CN
CN
O
CN
N
NH
HN
N
N
NH
X
N
N
H-bond
H-bond
Br
NH2
TMC120,R1 = CH3
TMC278,R1 = (E)CH=CHCN
X = NO2 , NH2
Target compounds
TMC125, etravirine
Figure 1. TMC125, TMC120, TMC278, and target compounds.
Cl
N
Cl
CN
R
O
CN
R
O
CN
NO2
1
+
c
a
b
Cl
N
NH
N
NH
N
NH
NC
NH2
NO2
NO2
NH2
4
2
3
5
4a R = H
5a R = H
4b R = CH3
4c R = CH2OH
4d R = I
5b R = CH3
5c R = CH2OH
5d R = I
4e R = CN
5e R = CN
5f R = C≡ CC(OH)Me2
5g R = C≡ CH
Scheme 1. Reagents and conditions: (a) 140 °C, 4 h, N2, 73%; (b) substituted phenol, K2CO3, DMF, 120 °C, 6 h, 65–82%; (c) Na2S2O4, NH3ÁH2O, THF/H2O = 1/1 (v/v), rt, 3 h,
41–70%.
OH
I
CN
CN
CN
a
b
O
N
NH
O
N
NH
O
N
NH
NO2
NO2
NO2
4d
4f
4g
Scheme 2. Reagents and conditions: (a) 2-methyl-3-butyn-2-ol, Pd(PPh3)2Cl2, Et3N, CuI, DMF, N2, rt, 7 h, 78%; (b) NaOH, toluene, reflux, 16 h, 69%.
nitropyridine (1) is inexpensive and commercially available. React-
ing 1 with 4-aminobenzonitrile (2) at 140 °C provided 4-(6-chloro-
3-nitropyridin-2-ylamino)benzonitrile (3). Compound 3 was cou-
pled with a substituted phenol in DMF in the presence of potassium
carbonate at 120 °C for 6 h to afford the target compounds 4a–4e.
Compound 4f was prepared by Sonogashira coupling11 between
4d and 2-methyl-3-butyn-2-ol in DMF catalyzed by palladium–
copper, and was then refluxed in dry toluene in the presence of
powdered sodium hydroxide to provide 4g (Scheme 2). Finally,
the nitro group on the pyridine ring in 4a–4g was reduced to an
amino group by using sodium hydrosulfite dehydrate12 to afford
5a–5g, respectively (Scheme 1). The spectroscopic data of the 14
target compounds were consistent with the structures shown in
Scheme 1.13
The inhibitory activity of nitro-diarylpyridine (4a–4g) and ami-
no-diarylpyridine (5a–5g) derivatives on HIV-1 IIIB replication in
MT-2 cells and cytotoxicity against MT-2 cells were determined
as previously described.14 As shown in Table 1, except for 4f, most

5484
X. Tian et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5482–5485
Table 1
acceptable moiety to replace the pyrimidine ring of DAPY com-
pounds and an amino group at the 3-position of the pyridine ring
enhances anti-HIV activity against both wild-type (IIIB and NL4-
3) and multidrug resistant (RTMDR1) HIV-1 strains.
Inhibitory activity of 4a–4g and 5a–5g on HIV-1 IIIB replication in MT-2 cellsa
SId
b
c
Compds
R
CC50
(
lM)
EC50 (lM)
4a
4b
4c
4d
4e
4f
4g
5a
5b
5c
5d
5e
5f
H
CH3
CH2OH
I
110.2 0.0
503.2 5.2
115.8 14.1
148.5 31.2
50.13 2.60
8.91 0.0
1.028 0.139
0.118 0.053
0.192 0.005
2.428 0.309
0.135 0.286
23.28 10.48
0.677 0.286
0.576 0.182
0.058 0.026
0.006 0.002
0.079 0.007
0.0014 0.0023
1.578 0.097
0.424 0.282
107
4264
603
61
371
<1
Similar to TMC125, the most active new compound, 5e, has a
para-cyano group on the phenoxy ring. Compounds with methyl,
hydroxymethyl, ethynyl, iodo, and no para-substituent were also
active. However, compounds 4f and 5f with a bulky 2-methyl-
but-3-yn-2-ol [C„CC(OH)Me2] group at the para-position of the
phenoxy ring lost anti-HIV potency, although 4g and 5g with only
a simple ethynyl substituent were active. These results suggested
that substituents at this position of the phenoxy ring also directly
affect anti-HIV potency, and a bulky group might not fit well into
the hydrophobic cleft on the west wing of the NNRTI binding site.16
In summary, two series (4 and 5) of diarylpyridine derivatives
were designed, synthesized, and evaluated for anti-HIV-1 activity,
resulting in the discovery of a new class of NNRTI leads, diarylpyri-
dine-3-amine derivatives (5a–5e, 5g), with highly potent anti-HIV-
1 activity against both RTI-sensitive (IIIB and NL4-3) and -resistant
(RTMDR1) HIV-1 strains. The most promising compound was 5e,
which inhibited HIV-1 IIIB, NL4-3, and RTMDR1 with low nM
EC50 values. The results of this study indicated that diarylpyridine
could be used as a novel scaffold to derive a new class of potent
NNRTIs with activity against both wild-type and drug-resistant
HIV-1 strains. In addition, the pyridine ring replacement provides
a more convenient and shorter synthetic route, using inexpensive
commercial reagents, compared to the synthesis of DAPY deriva-
tives TMC125 and TMC278.10,17 Our current preliminary struc-
ture–activity relationship (SAR) studies have revealed that (1) the
pyridine is an acceptable isosteric replacement for the pyrimidine
ring in DAPY derivatives, (2) an amino group at the 3-position on
the pyridine is crucial for enhancing anti-HIV activity, and (3) the
R group on the phenoxy ring is also an important moiety affecting
anti-HIV activity. In light of the promising anti-HIV-1 activity of
the diarylpyridine derivatives, further structural optimization is
likely to yield novel NNRTIs with greatly improved potency.
CN
C„CC(OH)Me2
C„CH
H
CH3
CH2OH
I
CN
173.6 46.0
29.9 2.3
256
52
10.55 0.41
2.19 0.41
23.49 5.77
31.78 10.37
3.54 1.07
8.25 0.51
182
391
297
22,700
2
C„CC(OH)Me2
C„CH
5g
20
a
Compounds were tested in triplicate and the data are presented as means SD.
XTT assay was used to determine the 50% cytotoxic concentration (CC50).
ELISA was used to determine p24 production, based on which the 50% effective
b
c
concentration (EC50) for inhibiting HIV-1 replication was calculated.
d
Selectivity index (SI) = CC50/EC50
.
nitro-substituted compounds (series 4) showed significant inhibi-
tory activity against HIV-1 replication (EC50 0.12–2.4 M) and
low cytotoxicity (CC50 50–503 M), resulting in selectivity index
(SI) values of 61–4264. All the amino-substituted compounds (ser-
ies 5) displayed greater anti-HIV-1 IIIB activity (EC50 0.001–
l
l
1.58
the series 5 compounds were also more cytotoxic (CC50 2.19–
31.78 M) than the corresponding series 4 compounds. With an
lM) than the corresponding compounds in series 4. However,
l
SI of 22,700, the most promising compound was 5e.
All target compounds were further tested against HIV-1 NL4-3
and a drug-resistant strain HIV-1 RTMDR1, in comparison with
TMC120 (Table 2). In agreement with the MT-2 data, 5e was also
the most active compound and had the highest SI (13,206) against
NL4-3. The potency of 5e in this assay was comparable to that of
TMC120. Interestingly, the active compounds in both series 4 and
5 showed similar inhibitory potency against NL4-3 and RTMDR1,
which is resistant to many NRTIs and NNRTIs.15 The most potent
compound, 5e, had an EC50 value of 0.96 nM against HIV-1
RTMDR1 and 0.68 nM against HIV-1 NL4-3, a difference of only
1.4-fold. These results suggested that the pyridine ring is an
Acknowledgments
This investigation was supported by Grants 20472114 and
7052057 from the National Natural Science Foundation of China
and Beijing government, respectively, awarded to L. Xie, as well
Table 2
Inhibitory activity of 4a–4g and 5a–5g on HIV-1 NL4-3 and HIV-1 RTMDR-1 replication in TZM-bl cellsa
Compd
R
CC50
(
lM)
NL4-3
RTMDR1b
EC50
(lM)
SI
EC50
(lM)
SI
4a
4b
4c
4d
4e
4f
4g
5a
5b
5c
5d
5e
H
CH3
CH2OH
I
>55.56
>53.48
>51.28
>41.15
>51.95
>45.25
>52.08
8.14
18.63
9.34
16.72
8.98
0.234 0.058
0.0229 0.0052
0.477 0.371
0.061 0.024
0.0221 0.0061
41.346
>238
>2335
>108
>675
>2351
>1.09
>469
2025
11,156
857
2200
13,206
36
1484
>490
0.128 0.031
0.0552 0.0098
0.877 0.562
0.0943 0.009
0.0211 0.004
25.480
>433
>969
>58
>436
>2462
>1.78
>242
2153
15,525
372
3259
9354
16
1101
>1020
CN
C„CC(OH)Me2
C„CH
H
CH3
CH2OH
I
CN
0.111 0.086
0.215 0.0327
0.00402 0.00058
0.00167 0.00014
0.0109 0.0037
0.0076 0.0023
0.00068 0.00003
0.241 0.0147
0.00378 0.00134
0.00120 0.0003
0.0251 0.0081
0.00513 0.00115
0.00096 0.00027
0.531
5f
5g
TMC120
C„CC(OH)Me2
C„CH
8.73
9.94
>0.304
0.0067 0.0010
0.00062 0.00012
0.00903 0.00204
0.000298 0.00015
a
The Compounds were tested in triplicate and the data are presented as means SD.
b
HIV-1 RTMDR1 (obtained from AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH), which contains mutations in RT amino acid residues 74V,
41L, 106A, and 215Y, is resistant to AZT, ddI, nevirapine, and other non-nucleoside RT inhibitors.

X. Tian et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5482–5485
5485
mp 162–165 °C; 1H NMR (CDCl3) d 10.65 (1H, br s), 8.63 (1H, d, J = J = 8.8 Hz), 7.54
(2H, s), 7.38 (2H, d, J = 8.8 Hz), 7.21 (2H, d, J = 8.8 Hz), 6.65 (1 H, d, J = 8.8 Hz), 2.06
(6H, s); MS m/z: 487 (M+). Compound 4e: Yield 65%; yellow solid, mp 240–
241 °C; 1HNMR (CDCl3) d10.68 (1H, br s), 8.66 (1H, d, J = 8.8 Hz), 7.53 (2H, s), 7.32
(2H, d, J = 8.3 Hz), 7.19 (2H, d, J = 8.3 Hz), 6.67 (1H, d, J = 9.2 Hz), 2.16 (6H, s); MS
m/z: 386 (M+). Compound 4f: Yield: 78%; yellow solid, mp 114–116 °C; 1H NMR
(DMSO-d6) d 10.37 (1H, br s), 8.67 (1H, d, J = 8.8 Hz), 7.40 (2H, d, J = 8.8 Hz), 7.34
(2H, d, J = 8.8 Hz), 7.31 (2H, s), 6.83 (1 H, d, J = 8.8 Hz), 5.47 (1H, s), 2.00 (6H, s),
1.53 (6H, s); MS m/z: 465 (M+Na+). 4 g: Yield 69%; yellow solid, mp 186–188 °C;
1H NMR (CDCl3) d 10.66 (1H, br s), 8.63 (1H, d, J = 8.8 Hz), 7.35 (2H, d, J = 8.8 Hz),
7.34 (2H,s), 7.19 (2H, d, J = 8.8 Hz), 6.66 (1 H, d, J = 8.8 Hz), 3.17 (1H, s), 2.09 (6H,
as NIH Grants AI46221 to S. Jiang, AI33066 to K. H. Lee, and
AI65310 to C. H. Chen
References and notes
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s); MS m/z: 385 (M+). Compound 5a: Yield 51%; brown solid, mp 140–142 °C; 1
H
NMR (DMSO-d6) d 8.31 (1H, br s), 7.35 (2H, d, J = 8.8 Hz), 7.29 (2H, d, J = 8.8 Hz),
7.15 (3H, m), 7.12 (1H, d, J = 8.4 Hz), 6.40 (1H, d, J = 8.4 Hz), 4.79 (2H, br s), 2.05
(6H, s); MS m/z: 331 (M+). Compound 5b: Yield 41%; brown solid, mp 206–
208 °C; 1H NMR (DMSO-d6) d 8.32 (1H, br s), 7.39 (2H, d, J = 8.8 Hz), 7.30 (2H, d,
J = 8.8 Hz), 7.11 (1H, d, J = 8.0 Hz), 6.96 (2H, s), 6.36 (1H, d, J = 8.0 Hz), 4.78 (2H, br
s), 2.31 (3H, s), 2.00 (6H, s); MS m/z: 345 (M+). Compound 5c: Yield 70%; red solid,
mp 278–281 °C; 1H NMR (DMSO-d6) d 8.27 (1H, br s), 7.34 (4H, s), 7.11 (1H, d,
J = 8.0 Hz), 7.10 (2H, s), 6.38 (1H, d, J = 8.0 Hz), 5.22 (1H, t, J = 6.4 Hz), 4.76 (2H, br
s), 4.49 (2H, d, J = 6.4 Hz), 2.03 (6H, s); MS m/z: 361 (M+). Compound 5d: Yield
49%; brown solid, mp 186–188 °C; 1H NMR (CDCl3) d 7.50 (2H, s), 7.33 (2H, d,
J = 8.8 Hz), 7.22 (2H, d, J = 8.8 Hz), 6.98 (1H, d, J = 8.4 Hz), 6.44 (1H, d, J = 8.4 Hz),
2.09 (6H, s); MS m/z: 457 (M+). Compound 5e: Yield 66%; brown solid, mp 222–
225 °C; 1H NMR (DMSO-d6) d 8.36 (1H, br s), 7.73 (2H, s), 7.32 (2H, d, J = 9.2 Hz),
7.26 (2H, s), 7.14 (1H, d, J = 8.0 Hz), 6.49 (1H, d, J = 8.0 Hz), 4.88 (2H, br s), 2.08
(6H, s); MS m/z: 356 (M+). Compound 5f: Yield 48%; brown solid, mp 155–157 °C;
1H NMR (DMSO-d6) d 8.33 (1H, br s), 8.01 (1H, br s), 7.41 (1H, d, J = 8.8 Hz), 7.29
(4H, m), 7.23 (2H, s), 6.55 (1 H, d, J = 8.8 Hz), 4.83 (2H, br s), 2.08 (6H, s), 1.51 (6H,
5. Gruzdev, B.; Horban, A.; Boron-Kaczmarska A.; Gille, D.; Van’t Klooster, G.;
Pauwels, R. Abstr. 13, 8th Conference on Retroviruses and Opportunistic
Infections, Chicago, IL, February 4–8, 2001.
6. De Clercq, E. Int. J. Antimicrob. Agents 2009, 33, 307.
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Koymans, L.; Vinkers, M.; Guillemont, J.; Pasquier, E.; Kukla, M.; Ludovici, D.;
Andries, K.; de Bethune, M. P.; Pauwels, R.; Das, K.; Clark, A. D.; Frenkel, Y. V.;
Hughes, S. H.; Medaer, B.; De Knaep, F.; Bohets, H.; De Clerck, F.; Lampo, A.;
Williams, P.; Stoffels, P. J. Med. Chem. 2005, 48, 1901.
8. Das, K.; Lewi, P. J.; Hughes, S. H.; Arnold, E. Prog. Biophys. Mol. Biol. 2005, 88,
209.
9. Van Herrewege, Y.; Vanham, G.; Michiels, J.; Fransen, K.; Kestens, L.; Andries,
K.; Janssen, P.; Lewi, P. Antimicrob. Agents Chemother. 2004, 48, 3684.
10. Guillemont, J.; Pasquier, E.; Palandjian, P.; Vernier, D.; Gaurrand, S.; Lewi, P. J.;
Heeres, J.; de Jonge, M. R.; Koymans, L. M. H.; Daeyaert, F. F. D.; Vinkers, M. H.;
Arnold, E.; Das, K.; Pauwels, R.; Andries, K.; de Bethune, M. P.; Bettens, E.;
Hertogs, K.; Wigerinck, P.; Timmerman, P.; Janssen, P. A. J. J. Med. Chem. 2005,
48, 2072.
s); MS m/z: 413 (M+). Compound 5g: Yield 61%; brown solid, mp 79–82 °C; 1
H
NMR (DMSO-d6) d8.34 (1H, brs), 7.37 (2H, s), 7.03 (4H, m), 6.56 (1H, d, J = 8.4 Hz),
6.44 (1H, d, J = 8.4 Hz), 4.84 (2H, br s), 3.36 (1H, s), 2.02 (6H, s); MS m/z: 355 (M+).
14. Xie, L.; Guo, H. F.; Lu, H.; Zhuang, X. M.; Zhang, A. M.; Wu, G.; Ruan, J. X.; Zhou,
T.; Yu, D.; Qian, K.; Lee, K. H.; Jiang, S. J. Med. Chem. 2008, 51, 7689.
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16. Das, K.; Bauman, J. D.; Clark, A. D.; Frenkel, Y. V.; Lewi, P. J.; Shatkin, A. J.;
Hughes, S. H.; Arnold, E. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 1466.
17. Ludovici, D. W.; De Corte, B. L.; Kukla, M. J.; Ye, H.; Ho, C. Y.; Lichtenstein, M. A.;
Kavash, R. W.; Andries, K.; de Bethune, M. P.; Azijn, H.; Pauwels, R.; Lewi, P. J.;
Heeres, J.; Koymans, L. M. H.; de Jonge, M. R.; Van Aken, K. J. A.; Daeyaert, F. F.
D.; Das, K.; Arnold, E.; Janssen, P. A. J. Bioorg. Med. Chem. Lett. 2001, 11, 2235.
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12. Redemann, C. E.; Redemann, C. T. Org. Synth. 1949, 29, 8.
13. Target compound 4a: Yield 67%; yellow solid, mp 200–203 °C; 1H NMR (CDCl3) d
10.67 (1H, br s), 8.62 (1H, d, J = 8.8 Hz), 7.23 (7H, m), 6.65 (1H, d, J = 8.8 Hz), 2.12
(6H, s); MS m/z: 361 (M+). Compound 4b: Yield 72%; yellow solid, mp 167–
169 °C; 1H NMR (DMSO–d6) d 10.38 (1H, br s), 8.65 (1H, d, J = 8.8 Hz), 7.39 (4H,
m), 7.04(2H, s), 6.78 (1H, d, J = 8.8 Hz), 2.36 (3H, s), 2.00(6H, s); MS m/z:375 (M+).
Compound 4c: Yield 73%; yellow solid, mp 188–190 °C; 1H NMR (DMSO-d6) d
10.41 (1H, br s), 8.67 (1H, d, J = 8.8 Hz), 7.45 (2H, d, J = 8.8 Hz), 7.37 (2H, d,
J = 8.8 Hz), 7.19 (2H, s), 6.81 (1 H, d, J = 8.8 Hz), 5.39 (1H, t, J = 6.4 Hz), 4.55 (2H, d,
J = 6.4 Hz), 2.04 (6H, s); MS m/z: 391 (M+). Compound 4d: Yield 82%; yellow solid,