MCC/SNAr methodology. Part 1: Novel access to a range of heterocyclic cores

Article abstract of DOI:10.1016/S0040-4039(01)00920-0

The novel solution-phase syntheses of arrays of biologically relevant indazolinones, benzazepines and benzoxazepines, utilizing multi-component condensation (MCC)/S_NAr methodology is reported. Reaction of commercially available 2-fluoro-5-nitrobenzoic acid with an aldehyde, isonitrile and a primary amine tethered to a Boc-protected internal amino or hydroxyl nucleophile, affords the Ugi product in good yield. Subsequent acid treatment followed by proton scavenging promotes cyclization of internal amino nucleophiles to a variety of ring sizes. Base treatment alone is sufficient to generate benzoxazepines. Interestingly, this communication also introduces a highly efficient two-step route to benzimidazoles.

Full text of DOI:10.1016/S0040-4039(01)00920-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4963–4968
MCC/SNAr methodology. Part 1: Novel access to a range of
heterocyclic cores
Paul Tempest,* Vu Ma, Michael G. Kelly, Wyeth Jones and Christopher Hulme*
Department of Combinatorial Chemistry, AMGEN Inc., One AMGEN Center Drive, Thousand Oaks, CA 91320, USA
Received 11 December 2000; revised 16 January 2001; accepted 17 January 2001
Abstract—The novel solution-phase syntheses of arrays of biologically relevant indazolinones, benzazepines and benzoxazepines,
utilizing multi-component condensation (MCC)/SNAr methodology is reported. Reaction of commercially available 2-fluoro-5-
nitrobenzoic acid with an aldehyde, isonitrile and a primary amine tethered to a Boc-protected internal amino or hydroxyl
nucleophile, affords the Ugi product in good yield. Subsequent acid treatment followed by proton scavenging promotes cyclization
of internal amino nucleophiles to a variety of ring sizes. Base treatment alone is sufficient to generate benzoxazepines.
Interestingly, this communication also introduces a highly efficient two-step route to benzimidazoles. © 2001 Elsevier Science Ltd.
All rights reserved.
With the recent emergence of combinatorial chemistry
and high-speed parallel synthesis in the lead discovery
arena, the multi-component reaction (MCR) has wit-
nessed a resurgence of interest.1 Easily automated one-
pot reactions, such as the Ugi2 and Passerini3 reactions,
are powerful tools for producing diverse arrays of
compounds in high yield. Despite this synthetic poten-
tial, the Ugi reaction is limited by producing flexible
and peptidic-like products that are often classified as
‘non-drug-like’. Recently, several novel intramolecular
variations on the reaction have been reported where
constrained, more biologically relevant products result
from interception of the intermediate nitrilium ion
using a bifunctional input.4 An alternative approach is
to constrain the Ugi product via a post-condensation
modification by unmasking a protected amino internal
nucleophile.5,6 SNAr reactions of polymer bound 4-
fluoro-3-nitrobenzoic acid, 1, have been investigated by
several groups and have resulted in multi-step syntheses
of dihydroquinoxalinones,7 benzimidazoles,8 indoles,9
benzodiazepines,10 benzothiazepines11 and macro-
cycles,12 respectively. Thus, it was envisioned that
combining the efficiency of the Ugi condensation with a
post-condensation SNAr cyclization, via use of an inter-
nal amino or hydroxyl nucleophile, would facilitate
access to a series of biologically useful cores with
generic structure, 4 (Scheme 1). Interestingly, there are
no previous reports on the compatibility of fluoronitro
aryl derivatives with reaction conditions employed in
the Ugi-4-component reaction (U-4CR). A preliminary
investigation by reaction of 1, benzylamine, 6, 3-
phenylpropionaldehyde, 5, and cyclohexyl isocyanide,
7, gave excellent conversion (80% as judged by LC/MS
at UV215) to the desired condensation product, 8
(Scheme 2).
The reaction conditions were then modified to intro-
duce a series of mono-Boc-protected diamines, Boc-
hydrazine and amino-alcohols to investigate the
feasibility of post condensation base-catalyzed SNAr
cyclization (Scheme 3). Conditions for the initial con-
densation reaction were standardized so that each
reagent was added in the order of its participation in
the Ugi reaction.
Scheme 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00920-0

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P. Tempest et al. / Tetrahedron Letters 42 (2001) 4963–4968
Scheme 2.
Two equivalents of aldehyde (R1CHO) were employed
to promote Schiff base formation, and a one-pot dou-
11 into the benzoxazepine, 14.15 Area % (A%) purities
[LC/MS (UV220)]16 are shown in Table 1, along with
the observed molecular ion. The indazolinones, 15, 16,
17 and 18 were observed with A% purities in the range
35–63% and exhibited lower conversions than both the
benzazepines and benzoxazepines series, respectively.
The benzazepines 19, 20, 21, 22 and 23, were formed in
good to excellent yield (46–100%), with cyclization
often being complete in ca. 2 h. Cyclization also pro-
gressed satisfactorily with secondary internal amino
nucleophiles, as exemplified with 24 (A% 68%) and 25
(A% 78%), respectively. Similarly, tricyclic systems were
also accessible via the use of aminomethyl piperidines
and pyrrolidines to give 26 (A% 89%) and 28 (A%
57%), respectively. Eight-membered ring formation
was, as expected, slower than seven, often needing up
to 24 h for complete conversion. Thus, use of N-Boc-
protected 1,3-diamino-propane and aminopropanol
ble
scavenging
protocol
with
immobilized
tosylhydrazine13 and diisopropylethylamine13 removed
both the excess aldehyde and any unreacted acid, 1.
Noteworthy is the generality of the condensation reac-
tion which performs efficiently for a range of commer-
cially available aldehydes (e.g. with attached aryl,
heteroaryl, alkyl, cycloalkyl, thioalkyl, functionality)
and isonitriles (e.g. with attached alkyl, aryl, heteroaryl,
heterocycloalkyl and basic functionality). The products
9 and 10 were then subjected to treatment with TFA,
followed by proton scavenging with resin bound mor-
pholine,13 to promote cyclization to afford products 12
and 13, respectively.
Interestingly, the resin bound guanidine, PS-TBD14 was
found to be most effective for conversion of the alcohol
Scheme 3. Reagents and conditions: (i) R1CHO (0.2 M, 200 ml, MeOH), R2NC (0.1 M, 200 ml, MeOH), 1 (0.1 M, 200 ml, MeOH),
Boc-protected diamine or amino-alcohol (0.1 M, 200 ml, MeOH), rt, 48 h; (ii) PS-tosylhydrazine (3 equiv.), PS-diisopropylethyl-
amine (3 equiv.), THF:CH2Cl2 (600 ml, 1:1), 24 h; (iii) 20% TFA/CH2Cl2 (600 ml), 4 h; (iv) PS-morpholine (3 equiv.), DMF (600
ml), 36 h; (v) PS-TBD (7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene), DMF (600 ml), rt, 36 h.
Scheme 4. Reagents and conditions: (i) 39 (0.2 M, 200 ml, MeOH), 40 (0.1 M, 200 ml, MeOH), 1 (0.1 M, 200 ml, MeOH), 41 (0.1
M, 200 ml, MeOH), rt, 48 h; (ii) PS-tosylhydrazine (3 equiv.), PS-diisopropylethylamine (3 equiv.), THF:CH2Cl2 (600 ml, 1:1), 24
h; (iii) 20% TFA/CH2Cl2 (600 ml), 4 h; (iv) PS-morpholine (3 equiv.), DMF (600 ml), 36 h.

P. Tempest et al. / Tetrahedron Letters 42 (2001) 4963–4968
4965
Table 1.
Cpd c
A%a
MH+b
Cpd c
A%a
MH+
Cpd c
A%a
MH+
15
16
17
18
19
20
21
22
63
35
56
53
46
80
67
84
397
394
336
423
412
482
403
425
23
24
25
26
27
28
29
30
100
68
78
89
58
57
60
0
411
442
425
451
459
500
439
453
31
32
33
34
35
36
37
38
67
73
87
66
55
85
80
60
430
412
404
412
460
477
587
465
a Area % purities as judged by LC/MS UV220, LC/MS-HP1100 LC with LCQ, YMC-AM 4.6×150 mm column, ESI source.15
b Isolated yields: 17=50%, 22=76% 25=40%, 27=30%, 32=60%, 35=25%.
afforded 29 (A% 60%) and 38 (A% 60%), respectively.
Cyclization to the analogous nine- or ten-membered
ring benzazepine (e.g. 32) was not observed even after
prolonged treatment with base (up to 48 h). SNAr
substitution with anilines proved possible via the use of
N-Boc phenylene diamine, 42, with deprotection and
base treatment of 42 giving 27 (A% 58%) in good
overall purity (Scheme 4). Interestingly, acid treatment
of the product, 42, also gave rise to the benzimidazole,
43 (A% 34%), presumably an acid-catalyzed process
with loss of water. The analogous side reaction to
afford imidazolines17 was not observed with mono-Boc-
protected ethylene diamine, possibly due to the higher
pKa of primary alkyl amines compared to anilines.

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P. Tempest et al. / Tetrahedron Letters 42 (2001) 4963–4968
benzimidazoles. Further study of this interesting side
reaction will be reported in due course. Current efforts
are now focusing on the development of potentially
higher yielding solid-phase approaches to this method-
ology, in particular, via exploitation of nitro group
reduction and functionalization.
Acknowledgements
Figure 1.
The authors would like to thank Balan Chenara and
Vijay Gore for proof-reading this document.
References
1. For two recent excellent reviews, see: (a) Weber, L.;
Illgen, K.; Almstetter, M. Synlett 1999, 3, 366; (b) Dax,
S. L.; McNally, J. J.; Youngman, M. A. Curr. Med.
Chem. 1999, 6, 255.
Figure 2.
2. (a) Ugi, I. Angew. Chem., Int. Ed. Engl. 1962, 1, 8; (b)
Ugi, I.; Steinbruckner, C. Chem. Ber. 1961, 94, 734; (c)
Ugi, I.; Domling, A.; Horl, W. Endeavor 1994, 18, 115;
(d) Domling, A. Comb. Chem. High Throughput Screen.
1998, 1, 1; (e) Armstrong, R. W.; Combs, A. P.; Tempest,
P.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996,
29, 123.
Further study of this novel two-step benzimidazole
forming reaction will be the subject of future reports.
Several of the products were produced on a larger scale
and their isolated yields corresponded closely with
observed A% yields reported in Table 1. For example,
29 was prepared with an isolated yield of 76%.18
3. (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126; (b)
Gokel, G.; Ludke, G.; Ugi, I. In Isonitrile Chemistry;
Ugi, I., Ed.; Academic Press: New York, 1971; p. 145.
4. (a) Blackburn, C.; Guan, B.; Fleming, P.; Shiosaki, K.;
Tsai, S. Tetrahedron Lett. 1998, 39, 3635; (b) Bienayme,
H.; Bouzid, K. Angew. Chem., Int. Ed. 1998, 37, 2234; (c)
Bossio, R.; Marcaccini, S.; Paoli, P.; Pepino, R. Synthesis
1994, 672; (d) Park, S.-J.; Keum, G.; Kang, S.-B.; Koh,
H.-Y.; Kim, Y. Tetrahedron Lett. 1998, 39, 7109.
5. (a) Hulme, C.; Tang, S.-Y.; Burns, C. J.; Morize, I.;
Labaudiniere, R. J. Org. Chem. 1998, 63, 8021; (b)
Hulme, C.; Peng, J.; Louridas, B.; Menard, P.; Kro-
likowski, P.; Kumar, N. V. Tetrahedron Lett. 1998, 39,
8047; (c) Hulme, C.; Peng, J.; Morton, G.; Salvino, J. M.;
Herpin, T.; Labaudiniere, R. Tetrahedron Lett. 1998, 39,
7227; (d) Hulme, C.; Morrissette, M.; Volz, F.; Burns, C.
Tetrahedron Lett. 1998, 39, 1113.
6. (a) Keating, T. A.; Armstrong, R. W. J. Org. Chem.
1996, 61, 8935; (b) Keating, T. A.; Armstrong, R. W. J.
Am. Chem. Soc. 1995, 117, 7842–7843; (c) Rosendahl, F.
K.; Ugi, I. Ann. Chem. 1963, 666, 65; (d) Keating, T. A.;
Armstrong, R. W. J. Am. Chem. Soc. 1996, 118, 2574; (e)
Stroker, A.; Keating, T. A.; Tempest, P. A.; Armstrong,
R. W. Tetrahedron Lett. 1996, 37, 1149.
Representative scaled-up and characterized examples
for each series are included at the end of this communi-
cation.18 Encouraged with the results shown in Table 1,
the protocol was advanced to 96-well production status.
Production runs of a 320-member array of benz-
azepines and a 960-member array of benzoxazepines
were successfully completed in Whatman 96-well plates,
with reagents being dispensed using either a Quadra
96® (Tom-tech) or Rapid Plate 96® (Zymark). Scaveng-
ing with PS-TsNHNH2 (3 equiv.) and PS-diisopropyl-
ethylamine (3 equiv.) for the condensation reaction,
and either PS-morpholine or PS-TBD for SNAr cycliza-
tion was performed at the plate level, with resins added
using a Millipore® column loader. TFA solutions in
dichloromethane were dispensed using a Robbins Jet
Pipette and solutions evaporated in a SAVANT® evap-
orator. The purity distribution (A% as judged by
UV220) of the 320-member library [8 (RCHO)×4
(RNH2)×10 (RNC)] (Fig. 1) and the 960-member benz-
oxazepine library (Fig. 2) are shown.
In summary, this communication has described the first
reported post-condensation modifications of the Ugi
product, utilizing SNAr methodology, allowing access
to arrays of indazolinones, benzazepines and benzox-
azepines with a variety of accessible ring sizes. With
final products containing 3 or more points of potential
diversity and a facile and rapid production protocol,
access to thousands of diverse analogues with the afore-
mentioned core structures is now feasible. Additionally,
cyclization with aniline derived internal nucleophiles
revealed a novel two-step protocol for the synthesis of
7. Morales, G. A.; Corbett, J. W.; Degrado, W. F. J. Org.
Chem. 1998, 63, 1172.
8. (a) Phillips, G. B.; Wei, G.-P. Tetrahedron Lett. 1996, 37,
4887; (b) Tumelty, D.; Schwarz, M. K.; Cao, K.; Needels,
M. C. Tetrahedron Lett. 1999, 40, 6185.
9. Stephensen, H.; Zaragoza, F. Tetrahedron Lett. 1999, 40,
5799.
10. Lee, J.; Gauthier, D.; Rivero, R. A. J. Org. Chem. 1999,
64, 3060.

P. Tempest et al. / Tetrahedron Letters 42 (2001) 4963–4968
4967
11. Schwarz, M. K.; Tumelty, D.; Gallop, M. A. J. Org.
Chem. 1999, 64, 2219.
The following procedure was followed for the prepara-
tion of 27: A mixture of 3-phenylpropionaldehyde (0.4
M, 250 ml in MeOH), ortho-phenylene diamine tert-butyl
carbamate (0.4 M, 250 ml in MeOH), isopropyl isonitrile
(0.4 M, 250 ml in MeOH) and 2-fluoro, 5-nitro benzoic
acid (0.4 M, 250 ml in MeOH) was shaken at room
temperature for 48 h. The reaction mixture was dried,
redissolved in 1:1 DCM:THF and 5 equiv. of PS-
TsNHNH2 and PS-DIEA were added and shaken for 14
h. The reaction was filtered and the solvent evaporated. A
20% TFA/DCM solution (5 ml) was added and let stand
for 2 h and evaporated at room temperature. The result-
ing yellow oil was dissolved in DMF and 5 equiv. of
PS-DIEA and PS-TrisAmine were added and the reaction
mixture shaken for 14 h. The reaction was filtered and
the solvent evaporated in vacuo. The crude oil purified by
flash chromatography (3:1 hexane:ethyl acetate) to yield
12. Kiselyov, A. S.; Smith, L.; Tempest, P. Tetrahedron 1999,
55, 14813.
13. Purchased from Argonaut® technologies.
14. Purchased from Novabiochem® technologies.
15. Performed in a SAVANT® evaporator for 2 h.
16. LC/MS analysis was performed using a C18 Hypersil
BDS 3m 2.1×50 mm column with a mobile phase of 0.1%
TFA in CH3CN/H2O, gradient from 10% CH3CN to
100% over 15 min. HPLC was interfaced with APCI
techniques.
17. Hulme, C.; Ma, L.; Romano, J.; Morrissette, M. Tetra-
hedron Lett. 1999, 40, 7925.
18. The following procedure was followed for the large-scale
preparation of 22: A mixture of 3-phenylpropionaldehyde
(0.4 M, 250 ml in MeOH), N-Boc ethylene diamine (0.4
M, 250 ml in MeOH), tert-butyl isonitrile (0.4 M, 250 ml
in MeOH) and 2-fluoro, 5-nitro benzoic acid (0.4 M, 250
ml in MeOH) was shaken at room temperature for 48 h.
The reaction mixture was dried, redissolved in 1:1
DCM:THF and 5 equiv. of PS-TsNHNH2 and PS-mor-
pholine were added and shaken for 4 h. The reaction was
filtered and the solvent stripped. A 20% TFA/DCM
solution (5 ml) was added and let stand for 2 h and
stripped at room temperature. The resulting yellow oil
was dissolved in DMF and 5 equiv. of PS-morpholine
was added and the reaction mixture shaken for 4 h. The
reaction was filtered and the solvent was evaporated in
vacuo and purified by column chromatography to yield
1
27 (15 mg, 30%) as an oil; H NMR (400 MHz, CDCl3):
l 8.82 (1H, s), 8.20 (1H, m), 7.4–6.9 (10H, m), 4.9 (1H,
m), 2.52 (2H, m), 2.12 (2H, m), 1.24 (6H, m); 13C NMR
(100 MHz, CDCl3): l 171.0, 169.3, 156.7, 142.8, 142.4,
140.9, 130.2, 128.5, 128.4, 127.8, 127.7, 126.1, 125.5,
123.2, 121.1, 119.3, 41.8, 31.7, 29.5, 22.5. HRMS+Na:
theoretical value 481.1846; actual value 481.1843. dM/
M=0.6 ppm.
The following procedure was followed for preparation of
32: A mixture of 3-phenylpropionaldehyde (0.4 M, 250 ml
in MeOH), ethanolamine (0.4 M, 250 ml in MeOH),
isopropyl isonitrile (0.4 M, 250 ml in MeOH) and 2-
fluoro, 5-nitro benzoic acid (0.4 M, 250 ml in MeOH) was
shaken at room temperature for 48 h. The reaction
mixture was dried, redissolved in 1:1 DCM:THF and 5
equiv. of PS-TsNHNH2 and PS-DIEA were added and
shaken for 14 h. The reaction was filtered and the solvent
evaporated. The resulting yellow oil was dissolved in
DMF and 5 equiv. of PS-TBD (Nova Biochem) was
added and the reaction mixture shaken for 14 h. The
reaction was filtered and the solvent evaporated in vacuo.
The crude oil purified by flash chromatography (3:1
hexane:ethyl acetate) to yield 32 (27 mg, 60%) as an oil;
1H NMR (400 MHz, CDCl3): l 8.82 (1H, s), 8.23 (1H,
m), 7.29–7.05 (5H, m), 6.29 (1H, m), 5.13 (1H, m), 4.51
(1H, m), 4.39 (1H, m), 4.06 (1H, m), 3.81 (1H, m), 3.60
(1H, m), 2.67 (2H, m), 2.29 (1H, m), 2.03 (1H, m), 1.13
(6H, m); 13C NMR (100 MHz, CDCl3): l 170.0, 168.6,
159.0, 142.5, 140.4, 129.1, 128.3, 127.8, 126.2, 123.9,
122.3, 73.8, 57.0, 42.0, 41.6, 32.4, 31.3, 22.5. HRMS+Na:
theoretical value 434.1686; actual value 481.1674. dM/
M=2.8 ppm.
The following procedure was followed for preparation of
35: A mixture of 3-phenylpropionaldehyde (0.4 M, 250 ml
in MeOH), 2-aminophenol (0.4 M, 250 ml in MeOH),
isopropyl isonitrile (0.4 M, 250 ml in MeOH) and 2-
fluoro, 5-nitro benzoic acid (0.4 M, 250 ml in MeOH) was
shaken at room temperature for 48 h. The reaction
mixture was dried, redissolved in 1:1 DCM:THF and 5
equiv. of PS-TsNHNH2 were added and shaken for 14 h.
The reaction was filtered and the solvent evaporated. The
resulting yellow oil was dissolved in DMF and 5 equiv. of
PS-DIEA was added and the reaction mixture shaken for
14 h. The reaction was filtered and the solvent evaporated
in vacuo. The crude oil purified by flash chromatography
(3:1, hexane:ethyl acetate) to yield 35 (14 mg, 25%) as an
1
22 (32 mg, 76%) as an oil; H NMR (400 MHz, CDCl3):
l 8.85 (1H, s, C6H3), 8.02 (1H, m, C6H3), 7.28 (2H, m,
C6H5), 7.20 (3H, m, C6H5), 6.55 (1H, m, C6H3), 6.13 (1H,
s, NH)(10H, 3×m, 2×C6H5), 5.17 (1H, s, NH), 5.09 (1H,
m, CH), 3.52 (4H, 2×m, 2×CH2), 2.62 (2H, m, CH2),
1.97–2.27 (2H, 2×m, CH2), 1.34 (9H, s, C(CH3)3); 13C
NMR (100 MHz, CDCl3): l 168.77, 268.42, 162.55,
149.45, 140.74, 138.67, 131.461, 128.55, 128.40, 127.30,
126.28, 118.08, 117.31, 63.65, 57.82, 51.51, 48.71, 42.10,
36.49, 32.24, 31.46, 30.01, 28.63. HRMS: theoretical
value 425.2189; actual value 425.2203. dM/M=3.3 ppm.
The following procedure was followed for the prepara-
tion of 17: A mixture of isovaleraldehye (0.4 M, 250 ml in
MeOH), tert-butyl carbazate (0.4 M, 250 ml in MeOH),
isopropyl isonitrile (0.4 M, 250 ml in MeOH) and 2-
fluoro, 5-nitro benzoic acid (0.4 M, 250 ml in MeOH) was
shaken at room temperature for 48 h. The reaction
mixture was dried, redissolved in 1:1 DCM:THF and 5
equiv. of PS-TsNHNH2 and PS-DIEA were added and
shaken for 14 h. The reaction was filtered and the solvent
evaporated. A 20% TFA/DCM solution (5 ml) was added
and let stand for 2 h and evaporated at room tempera-
ture. The resulting yellow oil was dissolved in DMF and
5 equiv. of PS-DIEA was added and the reaction mixture
shaken for 14 h. The reaction was filtered and the solvent
evaporated in vacuo. The crude oil purified by flash
chromatography (3:1 hexane:ethyl acetate) to yield 17 (17
1
mg, 50%) as an oil; H NMR (400 MHz, CDCl3): l 8.77
(1H, s), 8.39 (1H, m), 7.35 (1H, m), 5.14 (1H, m), 3.96
(1H, m), 2.06 (1H, m), 1.69 (1H, m), 1.28 (1H, m), 1.19
(6H, m), 0.95 (6H, m); 13C NMR (100 MHz, CDCl3): l
169.6, 160.1, 147.3, 142.4, 127.0, 121.5, 115.7, 112.3, 54.9,
41.7, 40.5, 24.7, 22.8. 22.0. HRMS: theoretical value
335.1714; actual value 335.1721. dM/M=2.1 ppm.

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P. Tempest et al. / Tetrahedron Letters 42 (2001) 4963–4968
oil. 1H NMR (400 MHz, CDCl3): l 8.80 (1H, s), 8.33 (1H,
evaporated. A 20% TFA/DCM solution (5 ml) was added
and let stand for 2 h and evaporated at room temperature.
The resulting yellow oil was dissolved in DMF and 5
equiv. of PS-DIEA was added and the reaction mixture
shaken for 14 h. The reaction was filtered and the solvent
evaporated in vacuo. The crude oil purified by flash
chromatography (3:1 hexane:ethyl acetate) to yield 25 (17
m), 7.40–6.90 (10H, m), 4.90 (1H, m), 4.14 (1H, m), 2.52
(2H, m), 2.25 (1H, m), 1.91 (1H, m), 1.24 (6H, m); 13C
NMR (100 MHz, CDCl3): l 169.9, 165.1, 154.2, 145.0,
140.4, 129.0, 128.5, 128.3, 126.9, 126.1, 125., 124.5, 121.5,
120.8, 119.1, 41.8, 31.9, 29.5, 22.6. HRMS+Na: theoretical
value 482.1686; actual value 482.1675. dM/M=2.3 ppm.
The following procedure was followed for the preparation
of 25: A mixture of isovaleraldehye (0.4 M, 250 ml in
MeOH), N-Boc-N-methylene diamine (0.4 M, 250 ml in
MeOH), benzyl isonitrile (0.4 M, 250 ml in MeOH) and
2-fluoro, 5-nitro benzoic acid (0.4 M, 250 ml in MeOH)
was shaken at room temperature for 48 h. The reaction
mixture was dried, redissolved in 1:1 DCM:THF and 5
equiv. of PS-TsNHNH2 and PS-DIEA were added and
shaken for 14 h. The reaction was filtered and the solvent
1
mg, 40%) as an oil; H NMR (400 MHz, CDCl3): l 8.52
(1H, s), 8.12 (1H, m), 7.22 (5H, m), 6.73 (1H, m), 5.32 (1H,
m), 4.27–4.50 (2H, m), 3.60 (1H, m), 3.37 (2H, m), 2.88
(3H, s), 1.84 (1H, m), 1.62 (2H, m), 0.97 (6H, m); 13C
NMR (100 MHz, CDCl3): l 170.3, 169.6, 151.7, 139.9,
138.4, 129.0, 127.9, 127.8, 124.8, 116.8, 64.0, 59.4, 55.3,
43.8, 41.5, 40.9, 37.5, 25.3, 23.1, 23.0. HRMS+Na: theo-
retical value 447.2003; actual value 447.2009. dM/M=1.3
ppm.
.