Syntheses of aza and fluorine-substituted 3-(piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-ones

Article abstract of DOI:10.1016/j.tetlet.2008.11.012

A practical and expedient synthesis of the title compounds is described. They were prepared by Stille reaction of nitro halopyridines 4 or nitro fluro-halobenzenes 10, followed by Michael addition of tert-butyl 4-aminopiperidine-1-carboxylate to the resulting activated vinyl compounds 5 and 11, hydrogenation (-NO₂→-NH₂), cyclic urea formation, Boc removal, and HCl salt formation. However, N3 and F1 analogs could not be made by this general strategy. Activated vinyl compounds 5a and 5d when reacted with tert-butyl 4-aminopiperidine-1-carboxylate did not stop at the desired Michael addition stage; but proceeded to produce azaindolines 8 and 9. Michael addition did not occur to compound 11d; instead, the fluorine atom was displaced.

Full text of DOI:10.1016/j.tetlet.2008.11.012

Tetrahedron Letters 50 (2009) 386–388
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Tetrahedron Letters
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Syntheses of aza and fluorine-substituted 3-(piperidin-4-yl)-4,5-dihydro-
1H-benzo[d][1,3]diazepin-2(3H)-ones
*
Xiaojun Han , Rita L. Civiello, Stephen E. Mercer, John E. Macor, Gene M. Dubowchik
Neuroscience Discovery Chemistry, Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical and expedient synthesis of the title compounds is described. They were prepared by Stille
reaction of nitro halopyridines 4 or nitro fluro-halobenzenes 10, followed by Michael addition of tert-
butyl 4-aminopiperidine-1-carboxylate to the resulting activated vinyl compounds 5 and 11, hydrogena-
tion (–NO2?–NH2), cyclic urea formation, Boc removal, and HCl salt formation. However, N3 and F1
analogs could not be made by this general strategy. Activated vinyl compounds 5a and 5d when reacted
with tert-butyl 4-aminopiperidine-1-carboxylate did not stop at the desired Michael addition stage; but
proceeded to produce azaindolines 8 and 9. Michael addition did not occur to compound 11d; instead, the
fluorine atom was displaced.
Received 16 September 2008
Revised 4 November 2008
Accepted 5 November 2008
Available online 8 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
We have used the GPCR recognition element,1 3-(piperidin-
4
1
4
1
3
2
3
2
4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one (1), in
a
F, N
N
NH
F, N
HN
NO2
NBoc
recent medicinal chemistry program. However, the resulting com-
pounds generally have poor aqueous solubility and poor bioavail-
ability. Therefore, we hoped to improve on these by modifying
the structure of 1 (Fig. 1).
By introducing a nitrogen atom into the fused phenyl ring, we
hoped to improve both solubility and oral bioavailability of our tar-
get molecules.2 In addition, the replacement of hydrogen atom(s)
by fluorine in aromatic rings has been utilized to enhance solubil-
ity and bioavailability of pharmaceutically interesting molecules.3
For these reasons, we hoped to generate aza- and fluoro- substi-
tuted analogs of 1 with all four possible regioisomers such as
2a–d and 3a–d to explore their effects on the pharmaceutical
properties of the analogs which contain them.
N
H
O
2 and 3
III
4
4
X
3
2
3
F, N
F, N
H2N
NBoc
+
2
NO2
NO2
1
II
1
I
Figure 2. Retrosynthetic analysis.
The general retrosynthetic analysis is shown in Figure 2. Stille
coupling of halide I with Bu3SnCHCH2 would provide nitro styrene
II. Michael reaction of II with tert-butyl 4-aminopiperidine-1-car-
boxylate would afford nitro amine III. The reduction of ArNO2
group to ArNH2, and treatment of the resulting aminoethylaniline
with CDI in the presence of Et3N would afford cyclic ureas. Re-
moval of the Boc-group would then afford the desired compounds
2 and 3. In this letter, we report the successful synthesis of N1, N2,
N4, F2, F3, and F4 analogs. This general strategy, however, failed to
provide N3 and F1 analogs, as will be shown.
N
NH
N
H
O
1
4
1
4
1
The synthesis of 2a–c is summarized in Scheme 1. Stille cou-
pling4 of nitro bromide 4a and Bu3SnCHCH2 (1.2 equiv) in the pres-
ence of Pd(PPh3)2Cl2 (10%), TBAC (1.0 equiv) in MeCN at 90 °C for
2 h afforded nitro styrene 5a in 68% yield. The Michael adduct 6a
was formed by the reaction of 5a and tert-butyl 4-aminopiperi-
dine-1-carboxylate (1.5 equiv), Et3N (3.0 equiv) in EtOH at 90 °C
for 24 h;5 since some starting material was left at this point, more
tert-butyl 4-aminopiperidine-1-carboxylate (1.5 equiv) was added,
and the mixture was heated at 90 °C for 20 h to afford the final
3
2
3
2
N
N
NH
F
N
NH
N
H
N
H
O
O
2
3
Figure 1. The targeted molecules.
* Corresponding author. Tel.: +1 2036777879; fax: +1 2036777702.
E-mail address: xiaojun.han@bms.com (X. Han).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.012

X. Han et al. / Tetrahedron Letters 50 (2009) 386–388
387
NBoc
O
O
H
N
H
N
NO2
Br
NO2
NO2
N
N
N
N
N
N
N
N
NH
a
b
c, d
e
N
NBoc
N
NH
68%
48%
90%
100%
x HCl
4a
4b
4c
5a
5b
6a
7a
2a
NO2
O
O
H
N
H
N
a
b
c, d
f
NO2
NO2
NO2
N
N
N
NBoc
NBoc
N
NH
50%
81%
76%
81%
HN
6b
NBoc
NBoc
Cl
Cl
x HCl
7b
2b
NO2
O
O
H
N
H
N
N
a
b
c, d
e
NO2
N
N
NH
67%
74%
91%
88%
N
N
HN
6c
N
N
x HCl
5c
see also ref. 9
7c
2c
Scheme 1. Syntheses of N1, N2, and N4 aza analogs of 2a–c. Reagents and conditions. (a) 10% Pd(PPh3)2Cl2, 1.2 equiv Bu3SnCHCH2, 1.0 equiv TBAC, MeCN, 90 °C, 2 h; (b)
1.5 equiv tert-butyl 4-aminopiperidine-1-carboxylate, 3 equiv Et3N, EtOH, 90 °C, 24 h, then additional 1.5 equiv tert-butyl 4-aminopiperidine-1-carboxylate, 90 °C, 20 h; (c)
H2 (2 atm), 35% Pd/C (10%), MeOH, rt, 16 h; (d) 2.4 equiv CDI, 3.0 equiv Et3N, MeCN, rt 16 h; then additional 1.2 equiv CDI, 3.0 equiv Et3N, rt, 20 h; (e) (i) 20% TFA/CH2Cl2, rt,
4 h; (ii) 2 N HCl/Et2O, CH2Cl2, 30 min; (f) 4 N HCl in dioxane.
yield of 48%. The reduction of –NO2 to –NH2 was accomplished by
hydrogenation [H2 (2 atm), 35% Pd/C (10%), MeOH, rt, 16 h]. The
resulting aminoethylaniline was treated with CDI (2.4 equiv) in
the presence of Et3N (3.0 equiv) in MeCN at rt for 16 h, followed
by more CDI (1.2 equiv) and Et3N (3.0 equiv) at rt for 20 h, to afford
the cyclic urea 7a in 90% yield (two steps).6 The reaction of 7a with
20% TFA in CH2Cl2 at rt for 4 h afforded a gummy semi-solid after
removing TFA and CH2Cl2. This residue was re-dissolved in CH2Cl2
and was treated with 2 N HCl/Et2O at rt for 30 min to afford
2aꢀxHCl7 as a white solid in 100% yield. While the synthesis of
2aꢀxHCl had been reported previously,8 the method reported here-
in is more direct (four steps vs seven steps) and results in a much
higher overall yield (29.4% vs 3.7%). These same protocols were
used to convert 4b to 2bꢀxHCl (25% yield for five steps, Scheme
1), and 4c to 2cꢀxHCl (40% yield for five steps, Scheme 1).9
Bu3SnCHCH2 (1.2 equiv) in the presence of Pd(PPh3)2Cl2 (10%),
TBAC (1.0 equiv) in MeCN at 90 °C for 2 h afforded nitro styrene
5d in 94% yield. Reaction5 of 5d with tert-butyl 4-aminopiperi-
dine-1-carboxylate (1.5 equiv), Et3N (3.0 equiv) in EtOH at 90 °C
for 2 h afforded azaindoline 9 exclusively in 67% yield. We were
unable to discern whether attack of the NH2– of tert-butyl 4-amin-
opiperidine-1-carboxylate occurred first at C4 of the pyridine or at
the vinyl group. No intermediates could be detected by varying the
reaction temperature (rt, 60 °C). No reaction is observed at rt, while
slow formation of 9 occurs at 60 °C. Nitro groups on pyridines have
been reported as leaving groups in SNAr reaction by amines.11 The
procedures that are described in (Eq. 1) and Scheme 2 can be uti-
lized to prepare azaindolines (8 and 9), whose syntheses have
not been reported.
The preparation of 3a–c is summarized in Scheme 3. The Stille
coupling of nitro bromide 10a with Bu3SnCHCH2 (1.2 equiv) under
conditions described by Fu12 for ArBr [2.5% Pd(PtBu3)2, 2.5%
Pd(dba)2, PhMe, rt, 36 h] afforded the nitro styrene 11a in 99%
yield. Various reaction conditions utilizing base-catalyzed hydro-
aminations of styrene13 failed to provide the desired Michael
adduct 12a from 11a and tert-butyl 4-aminopiperidine-1-
carboxylate. We were delighted to find that the mixture of 11a
and tert-butyl 4-aminopiperidine-1-carboxylate (2.5 equiv), when
heated neat at 100 °C for 48 h, afforded Michael adduct 12a in
64% yield. Hydrogenation [5% PtO2, H2 (60 psi), MeOH, rt, 16 h]
afforded the desired reduction product (–NO2?–NH2) cleanly
without removal of fluorine. Treatment6 of the resulting aminoe-
thylaniline with CDI (1.2 equiv), Et3N (1.5 equiv) in MeCN at rt
for 16 h produced cyclic urea 13a in 96% yield (two steps). Reaction
of 13a in CH2Cl2 with 4 N HCl/dioxane produced 3a in 100% yield.
The procedures used to prepare 3a from 10a were also employed to
prepare 3b from 10b (42% yield for five steps)14 and 3c from 10c
(49% yield for five steps)15 with minor modification. The conver-
sion of 11b?12b was performed by simply mixing 11b and tert-
butyl 4-aminopiperidine-1-carboxylate (1.5 equiv) in CH2Cl2 at rt.
Then, CH2Cl2 was removed in vacuo, and the residue was stirred
at rt for 48 h to afford 12b in 85% yield after flash chromatography.
Under the reaction conditions for converting 11a to 12a [tert-butyl
4-aminopiperidine-1-carboxylate (2.5 equiv), neat, 100 °C, 48 h],
11b was converted to 12b in 21% yield along with bis-substitution
product 14 in 52% yield (Eq. 2). The conversion of 10c to 11c em-
ployed Fu conditions12 reported for ArCl [5%Pd(PtBu3)2, 1.2 equiv
Bu3SnCHCH2, 1.2 equiv CsF, dioxane, 100 °C, 24 h], since nitro chlo-
ride 10c was less reactive than nitro bromides 10a,b toward the
Stille coupling reaction.
It is interesting to note that the reaction of 5a and tert-butyl 4-
aminopiperidine-1-carboxylate under the reaction conditions used
in Scheme 1 afforded both the desired Michael adduct 6a in 48%
yield, and azaindoline 8 in 30% yield (Eq. 1). Azaindoline 8 was pre-
sumably formed via 6a, in which the nitro group acted as a leaving
group in a SNAr reaction. This indicated that the yield of 8 might be
improved by raising the reaction temperature and by increasing
reaction time, although this was not attempted.
3 eq.Et3N, EtOH, 90 ºC
1.5 eq. 62 h; 1.0 eq. 20 h
H2N
NBoc
+
N
NO2
5a
N
NO2
ð1Þ
N
NBoc
+
N
H
NBoc
N
6a
8
48% yield
30% yield
Efforts toward the synthesis of N3 aza analog 2d are summa-
rized in Scheme 2. The Stille coupling4 of nitro bromide 4d10 and
NBoc
a
b
N
NO2
N
NO2
N
N
94%
67%
Br
4d
5d
9
Scheme 2. Efforts toward synthesis of N3 aza analog. Reagents and conditions: (a)
10% Pd(PPh3)2Cl2, 1.2 equiv Bu3SnCHCH2, 1.0 equiv TBAC, MeCN, 90 °C, 2 h; (b)
1.5 equiv tert-butyl 4-aminopiperidine-1-carboxylate, 3 equiv Et3N, EtOH, 90 °C,
24 h.

388
X. Han et al. / Tetrahedron Letters 50 (2009) 386–388
O
H
N
F
F
NO2
Br
O
H
N
F
F
NO2
NO2
F
NO2
F
a
b
c, d
e
F
F
NBoc
N
NBoc
NBoc
N
NH
HCl
99%
64%
96%
100%
N
H
10a
10b
11a
11b
12a
13a
3a
3b
a
f
c, d
f
O
H
N
NO2
Br
O
H
N
NO2
NBoc
99%
85%
68%
74%
N
N
NH
HCl
F
N
H
F
12b
13b
see also ref. 14
O
H
N
O
H
N
NO2
Cl
g
b
NO2
c, d
e
NO2
NBoc
N
NH
HCl
N
NBoc
80%
99%
88%
71%
N
H
F
F
F
F
F
10c
11c
12c
13c
3c
see also ref. 15
Scheme 3. Syntheses of F2-, F3-, and F4- substituted analogs of 3a–c. Reagents and conditions. (a) 2.5%Pd(PtBu3)2, 2.5% Pd(dba)2, 1.2 equiv Bu3SnCHCH2, PhMe, rt, 36 h; (b)
2.5 equiv tert-butyl 4-aminopiperidine-1-carboxylate, neat, 100 °C, 48 h; (c) 5% PtO2, H2 (60 psi), MeOH, rt, 16 h; (d) 1.2 equiv CDI, 1.5 equiv Et3N, MeCN, rt, 16; (e) 4 N HCl/
dioxane, CH2Cl2, rt; (f) 1.5 equiv tert-butyl 4-aminopiperidine-1-carboxylate, CH2Cl2; the two reactants were formed a solution in CH2Cl2; all CH2Cl2 was removed and the
resulting oil was stirred at rt for 48 h; (g) 5%Pd(PtBu3)2, 1.2 equiv Bu3SnCHCH2, 1.2 equiv CsF, dioxane, 100 °C, 24 h.
NO2
F
F
References and notes
H
N
NO2
Cl
NO2
a
b
1. (a) Paone, D. V.; Shaw, A. W.; Nguyen, D. N.; Burgey, C. S.; Deng, J. Z.; Kane, S. A.;
Koblan, K. S.; Salvatore, C. A.; Mosser, S. D.; Johnston, V. K.; Wong, B. K.; Miller-
Stein, C. M.; Hershey, J. C.; Graham, S. L.; Vacca, J. P.; Williams, T. M. J. Med.
Chem. 2007, 50, 5564–5567; (b) Rudolf, K.; Eberlein, W.; Engel, W.; Pieper, H.;
Entzeroth, M.; Hallermayer, G.; Doods, H. J. Med. Chem. 2005, 48, 5921–5931;
(c) Müller, G. Drug Discovery Today 2003, 8, 681–691; (d) Patchett, A. A.;
Nargund, R. P. Annu. Rep. Med. Chem. 2000, 35, 289–298.
2. (a) Han, X.; Pin, S. S.; Burris, K.; Fung, L. K.; Huang, S.; Taber, M. T.; Zhang, J.;
Dubowchik, G. M. Bioorg. Med. Chem. Lett. 2005, 15, 4029–4032; (b) Han, X.;
Civiello, R.; Pin, S. S.; Burris, K.; Balanda, L. A.; Knipe, J.; Ren, S.; Fiedler, T.;
Browman, K. E.; Macci, R.; Taber, M. T.; Zhang, J.; Dubowchik, G. M. Bioorg. Med.
Chem. Lett. 2007, 17, 2026–2030.
NBoc
71%
53%
10d
11d
15
Scheme 4. Efforts toward synthesis of F1 substituted analog. Reagents and
conditions: (a) 5% Pd(tBu3)2, 1.2 equiv Bu3SnCHCH2, 1.2 equiv CsF, dioxane,
100 °C, 24 h. (b) 2 equiv tert-butyl 4-aminopiperidine-1-carboxylate, neat, 100 °C,
24 h.
NO2
NO2
NO2
NH2
3. (a) Smart, B. E. J. Fluorine Chem. 2001, 109, 3–11; (b) Bohm, H-J.; Banner, D.;
Bendels, S.; Kansy, M.; Kuhn, B.; Muller, K.; Obst-Sander, U.; Stahl, M.
ChemBioChem 2004, 5, 637; (c) Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013–
1029; (d) Kirk, K. L. Curr. Top. Med. Chem. 2006, 6, 1447–1456.
4. Sakamoto, T.; Satoh, C.; Kondo, Y.; Yamanaka, H. Heterocycles 1992, 34, 2379–
2384.
5. Tucci, F. C.; Zhu, Y.-F.; Guo, Z.; Gross, T. D.; Connors, P. J., Jr.; Struthers, R. S.;
Reinhart, G. J.; Saunders, J.; Chen, C. Bioorg. Med. Chem. Lett. 2003, 13, 3317–
3322.
H
N
H
N
Neat
100 ºC
+
+
NBoc
NBoc
N
48 h
Boc
F
F
HN
(2.5 equiv)
NBoc
11b
12b
14
21% yield
52% yield
ð2Þ
6. Mayer, P.; Brunel, P.; Chaplain, C.; Piedecoq, C.; Calmel, F.; Schambel, P.;
Chopin, P.; Wurch, T.; Pauwels, P. J.; Marien, M.; Vidaluc, J.-L.; Imbert, T. J. Med.
Chem. 2000, 43, 3653–3664.
The efforts toward synthesis of F1 analog 3d are summarized in
Scheme 4. Nitro styrene 11d was formed in 71% yield using the
conditions that were used for converting 10c to 11c. A mixture
of 11d and tert-butyl 4-aminopiperidine-1-carboxylate (2.0 equiv)
was heated at 100 °C (neat) for 24 h to afford nitroaniline 15 in 53%
yield with no desired product observed. The results of Eq. 2 and
Scheme 4 indicated that the SNAr reaction of amines with 2-F-
nitrobenzene is more facile than with 4-F-nitrobenzene, in accor-
dance with literature reports.16
In summary, aza analogs 2a–c and F-substituted analogs
3a–c of 3-(piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-
2(3H)-one (1) have been synthesized in high yields in five steps
from the corresponding nitro halides, via Stille coupling, Michael
7. x is a number between 1 and 2, as suggested by elemental analysis.
8. The synthesis of 2aꢀxHCl from 5a was previously reported in
a patent
application; however a detailed description for the synthesis of 5a was not
provided therein: Burgey, C. S.; Stump, C. A.; Williams, T. M. PCT Int. Appl.
WO2005/013894 A2, 2005.
9. Compound 5c has been prepared by the Suzuki reaction of 4c and
CH2@CHBF3K: Molander, G. A.; Rivero, M. R. Org. Lett. 2002, 4, 107–109. In
our hands, this method afforded 5c in 45% yield on
a 15-mmol scale.
Compound 5c has also been synthesized by the Stille reaction of 4c and
CH2@CHSnBu3, using Pd(PPh3)4/PPh3 as the catalyst. Li, J.; Chen, S-H.; Li, X.;
Niu, C.; Doyle, T. W. Tetrahedron, 1998, 54, 393–400.
10. Yao, J.; Blake, P. R.; Yang, J. Heterocycles 2005, 65, 2071–2081.
11. (a) Seitzberg, J. G.; Dissing, C.; Sotofte, I.; Norrby, P.-O.; Johannsen, M. J. Org.
Chem. 2005, 70, 8332–8337; (b) Abe, H.; Masuda, N.; Waki, M.; Inouye, M. J.
Am. Chem. Soc. 2005, 127, 16189–16196; (c) Shetty, R.; Nguyen, D.; Flubacher,
D.; Ruggle, F.; Schumacher, A.; Kelly, M.; Michelotti, E. Tetrahedron Lett. 2007,
48, 113–117.
addition, hydrogenation, cyclization, and Boc removal, in
a
12. Littke, A. F.; Schwarz, L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 6343–6348.
13. (a) Dale, W. J.; Buell, G. J. Org. Chem. 1956, 21, 45–48; (b) Beller, M.; Breindl, C.;
Riermeier, T. H.; Eichberger, M.; Trauthwein, H. Angew. Chem., Int. Ed. 1998, 37,
3389–3391; (c) Beller, M.; Breindl, C.; Riermeier, T. H.; Tillack, A. J. Org. Chem.
2001, 66, 1403–1412.
14. Compound 11b had been synthesized previously in 89% yield by the Stille
reaction of 10b and CH2@CHSnBu3 employing Pd(PPh3)4 as the catalyst in
PhMe at 120 °C for 7 h: Dams, G. K. J.; Vereycken, I.; Van Acker, K. L. A.; Gustin,
E. M. P. E.; Verschueren, W. G.; Ohagen, A. C. PCT Int. Appl. WO2007/113337
A1, 2007.
straightforward manner. Although the protocols developed above
cannot be applied to the synthesis of N3 and F1 analogs, some
interesting previously unreported azaindolines by-products 8 and
9 were obtained.
Supplementary data
15. Compound 11c had been synthesized previously in three steps from 2-fluoro-
6-nitrotoluene: Mundla, S. R. Tetrahedron Lett. 2000, 41, 6319–6321.
16. (a) Jamieson, C.; Congreve, M. S.; Emiabata-Smith, D. F.; Ley, S. V.; Scicinski, J. J.
Org. Process Res. Dev. 2002, 6, 823–825; (b) Gustin, D. J.; Sehon, C. A.; Wei, J.;
Cai, H.; Meduna, S. P.; Khatuya, H.; Sun, S.; Gu, Y.; Jiang, W.; Thurmond, R. L.;
Karlsson, L.; Edward, J. P. Bioorg. Med. Chem. Lett. 2005, 15, 1687–1691.
Representative experimental procedures. 1H, 13C NMR (data and
spectra), and LRMS data for representative compounds are avail-
able. Supplementary data associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2008.11.012.