tert-Butyl isocyanide revisited as a convertible reagent in the Groebke-Blackburn reaction

Article abstract of DOI:10.1016/j.tetlet.2008.10.046

tert-Butyl isocyanide can serve as the convertible reagent in Groebke-Blackburn multi-component reactions. The effective removal of the tert-butyl group from the resulting imidazo[1,2-a]azines and -azoles is achieved on a gram scale in two steps without chromatographic purification.

Full text of DOI:10.1016/j.tetlet.2008.10.046

Tetrahedron Letters 49 (2008) 7318–7321
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
tert-Butyl isocyanide revisited as a convertible reagent
in the Groebke–Blackburn reaction
a
a
a
a
Mikhail Krasavin a,b, , Sergey Tsirulnikov , Mikhail Nikulnikov , Yuri Sandulenko , Konstantin Bukhryakov
*
a Chemical Diversity Research Institute, 2a Rabochaya Street, Moscow Region, Khimki 141400, Russia
b Department of Organic and Biological Chemistry, L. N. Tolstoy State Pedagogical University, 125 Lenin Avenue, Tula 300026, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
tert-Butyl isocyanide can serve as the convertible reagent in Groebke–Blackburn multi-component reac-
tions. The effective removal of the tert-butyl group from the resulting imidazo[1,2-a]azines and -azoles is
achieved on a gram scale in two steps without chromatographic purification.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 11 August 2008
Revised 29 September 2008
Accepted 10 October 2008
Available online 17 October 2008
Keywords:
Groebke–Blackburn multi-component
reaction
Convertible isocyanide
tert-Butyl isocyanide
Combinatorial chemistry
The Groebke–Blackburn multi-component reaction (GB-MCR)1–3
of 2-aminoazines and -azoles with aldehydes and isocyanides has
received increased attention as a powerful tool for generating large
arrays of drug-like fused imidazo[1,2-a]azines and -azoles in a
combinatorial, diversity-controlled fashion (Scheme 1).4 The
diversity in the final products, if limited by the availability of the
requisite isocyanides, can be extended further by the use of a con-
vertible isocyanide, such as 1,1,3,4-tetramethylbutylisocyanide
(Walborsky reagent5), removal of the N-isooctyl group and subse-
quent derivatization at the primary amino group via Pd-catalyzed
arylation, acylation, carbamoylation, and reductive alkylation, as
demonstrated by us6 and others7 (Scheme 2).
For preparation of combinatorial libraries of hundreds to thou-
sands of compounds based on this methodology, larger quantities
of the Groebke–Blackburn type core building blocks must be syn-
thesized, thus requiring larger quantities of the somewhat expen-
sive Walborsky reagent. Presumably, the N-isooctyl group is
removed by a strong Brønsted acid via formation of the stable (ter-
tiary) carbocation.7 Therefore, other tertiary alkyl isocyanides
(such as t-Bu) would be natural alternatives to consider. Although
t-BuNC is a much more economical alternative to the Walborsky
reagent, unfortunately, the resultant (tert-butyl)amino Groebke–
Blackburn reaction products have been shown to undergo TFA-
induced cleavage at a much slower rate (also complicated by the
R1
R3
N
H2N
R3 N+
C
R2
R1 CHO
+
R2
+
N
N
N
H
Scheme 1. Reaction of 2-aminoazines and -azoles with aldehydes and isocyanides
(the Groebke–Blackburn reaction).
trifluoroacetylation of the primary amino group) compared to
isooctylamino products.7 Herein, we report an efficient two-step
procedure for solution-phase de-tert-butylation of various Gro-
ebke–Blackburn reaction products obtained using tert-butyl
isocyanide.
The starting imidazo[2,1-b]-1,3,4-thiadiazoles 1 and imidazo-
[1,2-a]azines 2–4 were synthesized according to the recently
reported procedure using an equimolar quantity of TMSCl as the
Lewis acid promoter for the reaction (Scheme 3).8 In our prelimin-
ary experiments, Brønsted acids such as HCl in MeOH or dioxane,
glacial acetic acid, concentrated HCl or H2SO4 led to inefficient
removal of the tert-butyl group from GB-MCR products 1–4.
However, neat TFA under reflux was found to convert these
compounds in 3 h, cleanly and effectively, into the respective
trifluoroacetamides 5–8. The latter were then subjected to alkaline
hydrolysis and the corresponding primary amines 9–12 were iso-
lated in good yields after crystallization from isopropanol (Table
1).9 All of the reactions described were run on 5–10 mmol scale
resulting in the yields indicated. While derivatization of the
* Corresponding author. Tel.: +7 495 995 4944; fax: +7 495 626 9780.
E-mail address: myk@chemdiv.com (M. Krasavin).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.046

M. Krasavin et al. / Tetrahedron Letters 49 (2008) 7318–7321
7319
1
N
R
R2
H2N
N
R3 N+
convertible
isonitrile
C
R2
R1 CHO
+
+
N
H
R1
N
N
N
R
R2
O
N
i
N
H
R
N
H
ii
R2
1
removal of R3
1
N
R
R
R2
N
N
R3
N
H
H2N
iii
R1
N
R2
iv
N
O
N
R3
=
N
R1
H
R
R2
N
(Het)Ar
N
H
Scheme 2. Extended diversity in Groebke–Blackburn reaction products achieved via the use of a convertible isocyanide. Reagents and conditions: (i) RCHO, NaBH3CN, DMF–
AcOH, 25 °C, 50 h;7 (ii) RNCO, DMF, 25 °C, 24 h;7 (iii) RCOCl, DMF–pyridine, 25 °C, 24 h;7 (iv) (Het)ArX, Pd(OAc)2, BINAP, Cs2CO3, toluene, sealed tube, 100 °C, 16 h.6
primary amines 10–12 has already been described,7 newly synthe-
sized compounds 9b–g have been used to prepare a small library
H
N
of amides and ureas 13. Representative examples of such com-
N
S
N
S
N
N
pounds are given in Figure 1.10
R1
R2
R1
N
X
The inevitable intermediacy of the trifluoroacetamides in this
two-step tert-butyl group removal can be used as an advantage.
For example, we have performed a multigram synthesis of the N-
protected imidazo[1,2-a]pyridine-based amino acid 6b11 (Scheme
4) that we are now finding useful in developing solid-supported
library synthesis.12
In conclusion, we have developed an efficient two-step protocol
for tert-butyl group removal from various bicyclic imidazolyl
amines. These findings establish that readily available tert-butyl
isocyanide can serve as a more economic convertible isocyanide
alternative to Walborsky’s reagent in Groebke–Blackburn multi-
component reactions, and is suitable for multigram preparations.
General procedure: A solution of the tert-butyl amine (10 mmol)
in TFA (10 mL) was heated under reflux for 3 h. The solution was
cooled to rt, concentrated in vacuo, and the residue was dissolved
NH2
1
Y
N
Y
X
N
N
NH2
R2
N
H
2, X = Y = CH (72%)
3, X = CH, Y = N (67%)
4, X = N, Y = CH (65%)
Scheme 3. Preparation of the starting imidazo[2,1-b]-1,3,4-thiadiazoles 18 and
imidazo[1,2-a]azines 2–4. Reagents and conditions: (i) 1 equiv R2CHO, MeCN,
reflux, 2 h; (ii) TMSCl (1 equiv), MeCN/DCM, rt, 30 min; (iii) t-BuNC.
Table 1
Two-step removal of the tert-butyl group from imidazo[2,1-b]-1,3,4-thiadiazoles 1 and imidazo[1,2-a]azines 2–4
CF3
H
N
H
N
NH2
O
R2
N
S
N
S
N
S
N
N
N
R1
R2
R1
R1
R2
N
N
N
1
5
9
KOH (3 eq.)
TFA
Y
N
reflux, 3 h
MeOH-H2O (1:1)
60 oC, 8 h
Y
N
Y
N
X
X
X
N
N
N
CF3
O
R2
N
H
R2
R2
N
H
H2N
2 - 4
R1
6 - 8
10 - 12
Entry
1
Starting material
R2
Step 1 product
Yield (%)
92
Step 2 product
Yieldb (%)
46
1a
Boc
Ph
5a
9aa
N
N
2
1b
Ph
5b
89
9b
73
N
(continued on next page)

7320
M. Krasavin et al. / Tetrahedron Letters 49 (2008) 7318–7321
Table 1 (continued)
Entry
3
Starting material
R1
R2
Step 1 product
Yield (%)
Quant.
Step 2 product
Yieldb (%)
78
1c
Me
4-FC6H4
5c
9c
4
5
1d
Ph
5d
5e
92
86
9d
9e
35
65
N
O
1e
4-FC6H4
N
N
N
Cl
6
7
1f
Ph
Ph
5f
97
67
9f
58
56
N
N
1g
5g
9g
N
8
9
10
2ac
3c
—
—
—
i-Pr
i-Pr
i-Pr
6a
7
8
84
77
90
10a
11
12
55
43
57
4c
a
The product of Boc-cleavage.
Yield after crystallization from isopropanol. The actual yield may be higher.
X and Y are defined in Scheme 3.
b
c
Cl
NH
N
HN
O
HN
O
O
N
NH
N
N
N
N
N
N
N
N
N
S
S
N
S
N
13a
13c
13b
Figure 1. Representative compounds synthesized via derivatization of primary amines 9.
N
N
N
N
N
N
CF3
O
v
iv
i - iii
N
H
N
H
N
H
N
NH2
OH
OH
2c
O
2b
6b
O
O
O
Scheme 4. Large-scale preparation of 4-[3-(trifluoroacetylamino)imidazo[1,2-a]pyridin-2-yl]benzoic acid (6b). Reagents and conditions: (i) 1 equiv 4-OHCC6H4COOMe,
MeCN, reflux, 2 h; (ii) TMSCl (1 equiv MeCN/DCM, rt, 30 min; (iii) t-BuNC (i–iii, 76%); (iv) aq KOH (1 equiv), rt, 4 h (93%); (v) TFA, reflux, 3 h (88%).
in water (50 mL). The solution pH was adjusted to neutral with
NaHCO3, and the resulting precipitate collected by filtration,
washed with water, and air-dried. The solid trifluoroacetamide
was dissolved in 50% aqueous methanol (100 mL) containing
KOH (3 equiv) and the reaction mixture was stirred at 60 °C for
8 h. The precipitate that formed on cooling the reaction mixture
to rt was collected by filtration, washed with water and air-dried.
The crude product was purified by crystallization from
isopropanol.
References and notes
1. Groebke, K.; Weber, L.; Mehlin, F. Synlett 1998, 661–663.
2. Blackburn, C.; Guan, B.; Fleming, P.; Shiosaki, K.; Tsai, S. Tetrahedron Lett. 1998,
39, 3635–3638.
3. Bienaymé, H.; Bouzid, K. Angew. Chem., Int. Ed. 1998, 37, 2234–2237.
4. For the most recent examples of isocyanide-based reactions of 2-aminoazines
and -azoles see: (a) Rousseau, A. L.; Matlaba, P.; Parkinson, C. J. Tetrahedron Lett.
2007, 48, 4079–4082; (b) Shaabani, A.; Soleimani, E.; Maleki, A. Tetrahedron
Lett. 2006, 47, 3031–3034; (c) DiMauro, E. F.; Kennedy, J. M. J. Org. Chem. 2007,
72, 1013–1016; (d) Kercher, T.; Rao, C.; Bencsik, J. R.; Josey, J. A. J. Comb. Chem.
2007, 9, 1177–1187; (e) Carballares, S.; Cifuentes, M. M.; Stephenson, G. A.
Tetrahedron Lett. 2007, 48, 2041–2045; (f) Umkehrer, M.; Ross, G.; Jäger, N.;
Burdack, C.; Kolb, J.; Hu, H.; Alvim-Gaston, M.; Hulme, C. Tetrahedron Lett. 2007,
48, 2213–2216; (g) Shaabani, A.; Maleki, A.; Moghimi, R. J.; Soleimani, E. Chem.
Pharm. Bull. 2007, 55, 957–958; (h) Adib, M.; Mahdavi, M.; Noghani, M. A.;
Mirzaei, P. Tetrahedron Lett. 2007, 48, 7263–7265.
Acknowledgment
The authors are thankful to Dr. Volodymyr Kysil of ChemDiv,
Inc. (San Diego, USA) for helpful discussions regarding the
described methodology.
5. (a) Walborsky, H. M.; Niznik, G. E. J. Am. Chem. Soc. 1969, 91, 7778–7780; (b)
Walborsky, H. M.; Niznik, G. E. J. Org. Chem. 1972, 37, 187–191.

M. Krasavin et al. / Tetrahedron Letters 49 (2008) 7318–7321
7321
6. Sandulenko, Y.; Komarov, A.; Rufanov, K.; Krasavin, M. Tetrahedron Lett. 2008,
49, 5990–5993.
7. Blackburn, C.; Guan, B. Tetrahedron Lett. 2000, 41, 1495–1500.
8. Krasavin, M.; Tsirulnikov, S.; Nikulnikov, M.; Kysil, V.; Ivachtchenko, A.
Tetrahedron Lett. 2008, 49, 5241–5243.
48.1, 19.5, 11.7; LCMS (M+H+) 496; Anal. Calcd for C24H26ClN7OS: C, 58.11; H,
5.28; N, 19.77. Found: C, 58.07; H, 5.22; N, 19.73. Compound 13b—white solid,
mp = 148–150 °C; 1H NMR (300 MHz, DMSO-d6)
d 10.01 (s, 1H), 7.74 (d,
J = 7.5 Hz, 2H), 7.38 (t, J = 7.4 Hz, 2H), 7.26 (t, J = 7.4 Hz, 1H), 3.85 (m, 2H), 3.15
(t, J = 12.2 Hz, 2H), 2.13 (s, 3H), 1.54–1.70 (m, 3H), 1.30–1.65 (m, 2H), 0.97 (d,
J = 6.0 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) d 169.9, 164.4, 137.1, 133.3, 132.4,
128.4, 127.0, 125.4, 117.8, 48.7, 32.7, 29.8, 22.6, 21.5; LCMS (M+H+) 356. Anal.
Calcd for C18H21N5OS: C, 60.82; H, 5.95; N, 19.70%. Found: C, 60.79; H, 5.91; N,
19.67. Compound 13c—white solid, mp = 144–146 °C; 1H NMR (300 MHz,
DMSO-d6) d 10.40 (s, 1H), 8.07 (d, J = 7.1 Hz, 2H), 7.77 (d, J = 7.7 Hz, 2H), 7.61 (d,
J = 7.4 Hz, 1H), 7.54 (t, J = 7.5 Hz, 2H), 7.33 (d, J = 7.7 Hz, 2H), 7.19 (t, J = 7.4 Hz,
1H), 3.78 (d, J = 12.6 Hz, 2H), 3.11 (d, J = 12.6 Hz, 2H), 1.60–1.78 (m, 3H), 1.17–
1.32 (m, 2H), 0.96 (d, J = 6.3 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) d 166.3,
164.1, 137.7, 135.1, 133.9, 133.0, 132.0, 126.4, 125.3, 117.6, 95.6, 56.1, 48.5,
32.7, 29.8, 21.5, 18.5; LCMS (M+H+) 419. Anal. Calcd for C23H23N5OS: C, 66.16;
H, 5.55; N, 16.77. Found: C, 66.21; H, 5.59; N, 16.83.
9. Characterization data for selected primary amines: Compound 9b—beige solid,
mp = 153–155 °C; 1H NMR (300 MHz, DMSO-d6) d 7.77 (d, J = 7.7 Hz, 2H), 7.30
(t, J = 7.3 Hz, 2H), 7.07 (t, J = 7.7 Hz, 1H), 4.92 (br s, 2H, NH2), 3.78 (d, J = 12.0 Hz,
2H), 3.12 (d, J = 12.0 Hz, 2H), 1.60–1.75 (m, 3H), 1.16–1.30 (m, 2H), 0.94 (d,
J = 6.2 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) d 159.3, 158.7, 144.6, 133.1, 133.0,
127.7, 127.6, 114.5, 47.9, 34.3, 29.5, 20.3; LCMS (M+H+) 314. Anal. Calcd for
C16H19N5S: C, 61.32; H, 6.11; N, 22.34. Found: C, 61.39; H, 6.15; N, 22.40.
Compound 9c—pale yellow solid, mp = 178–180 °C (decomp.); 1H NMR
(300 MHz, DMSO-d6) d 7.85 (dd, J = 5.9, 8.4 Hz, 2H), 7.17 (t, J = 8.8 Hz, 2H),
5.19 (br s, 2H, NH2), 2.69 (s, 3H); 13C NMR (75 MHz, DMSO-d6) d 163.4 (d, JC–F
=
243.8 Hz), 160.5, 152.6, 143.4, 130.6 (d, JC–F = 17.0 Hz), 128.4 (d, JC–F = 6.9 Hz),
114.6 (d, JC–F = 27.3 Hz), 104.6, 15.9; LCMS (M+H+) 248. Anal. Calcd for
C11H9FN4S: C, 53.21; H, 3.65; N, 22.57. Found: C, 53.16; H, 3.59; N, 22.54.
Compound 11—brown sticky solid; 1H NMR (300 MHz, DMSO-d6) d 8.75 (d,
J = 5.9 Hz, 1H), 8.37–8.51 (m, 1H), 6.92–7.06 (m, 1H), 4.92 (br s, NH2 + bound
H2O), 3.30 (m, 1H), 1.29 (d, J = 6.2 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) d
147.5, 140.6, 133.1, 130.8, 123.6, 108.7, 95.7, 24.9, 21.9; LCMS (M+H+) 177.
Anal. Calcd for C9H12N4: C, 61.34; H, 6.86; N, 31.79. Found: C, 61.40; H, 6.91; N,
31.83.
11. Characterization data: Compound 2c—off-white solid, mp = 151–153 °C; 1H
NMR (300 MHz, DMSO-d6) d 13.20 (br s, 1H, COOH), 8.87 (d, J = 6.6 Hz, 1H),
8.26 (d, J = 8.1 Hz, 2H), 8.09 (d, J = 8.1 Hz, 2H), 7.92 (m, 2H), 7.47 (t, J = 7.3 Hz,
1H), 5.31 (s, 1H), 1.01 (s, 9H); 13C NMR (75 MHz, DMSO-d6) d 166.7, 137.5,
132.8, 132.4, 131.3, 129.5, 128.3, 128.2, 126.0, 116.1, 112.3, 56.5, 29.6; LCMS
(M+H+) 310. Anal. Calcd for C18H19N3O2: C, 69.88; H, 6.19; N, 13.58. Found: C,
69.91; H, 6.23; N, 13.62. Compound 6b—yellowish solid, mp = 135–137 °C; 1H
NMR (300 MHz, DMSO-d6) d 8.44 (d, J = 6.9 Hz, 1H), 8.07 (d, J = 8.4 Hz, 2H), 8.01
(d, J = 8.4 Hz, 2H), 7.80 (d, J = 9.1 Hz, 1H), 7.60 (t, J = 7.4 Hz, 1H), 7.22 (t,
J = 6.6 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) d 167.3, 158.5 (q, JC–F = 37.4 Hz),
139.2, 138.8, 129.4, 128.2, 127.6, 125.5, 125.0, 122.6, 116.4 (q, JC–F = 148.9 Hz),
116.5, 111.2; LCMS (M+H+) 350. Anal. Calcd for C16H10F3N3O3: C, 55.02; H,
2.89; N, 12.03. Found: C, 54.98; H, 2.83; N, 11.98.
10. Characterization data: Compound 13a—white solid, mp = 176–178 °C
(decomp.); 1H NMR (300 MHz, DMSO-d6) d 9.05 (s, 1H), 8.36 (s, 1H), 7.82 (d,
J = 7.7 Hz, 2H), 7.67 (br s, 1H), 7.35 (t, J = 7.4 Hz, 2H), 7.32 (s, 1H), 7.23 (dd,
J = 16.5, 8.1 Hz, 2H), 6.95 (d, J = 7.8 Hz, 1H), 3.45 (br s, 4H), 3.19 (m, 4H,
obscured by residual H2O signal), 2.31 (t, J = 7.1 Hz, 2H), 1.47 (m, 2H), 0.90 (t,
J = 7.3 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) d 164.1, 153.3, 141.3, 137.6, 135.7,
134.2, 133.3, 129.9, 128.1, 126.3, 125.3, 121.5, 118.1, 117.6, 116.8, 59.7, 51.6,
12. Krasavin, M.; Sandulenko, Y. J. Comb. Chem., manuscript in preparation.