An efficient boric acid-mediated preparation of α-hydroxyamides

Article abstract of DOI:10.1016/j.tetlet.2009.12.008

An efficient methodology for the preparation of α-hydroxyamides via boric acid-mediated addition of isonitriles onto aldehydes has been developed. The reaction of isonitriles with α-boronobenzaldehyde takes place under intramolecular catalysis conditions

Full text of DOI:10.1016/j.tetlet.2009.12.008

Tetrahedron Letters 51 (2010) 779–782
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient boric acid-mediated preparation of
a
-hydroxyamides
J. Sravan Kumar a, Subash C. Jonnalagadda b, Venkatram R. Mereddy a,
*
a Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, MN 55812, United States
b Department of Chemistry and Biochemistry, Rowan University, Glassboro, NJ 08051, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient methodology for the preparation of
a
-hydroxyamides via boric acid-mediated addition of iso-
Received 3 October 2009
Revised 25 November 2009
Accepted 1 December 2009
Available online 5 December 2009
nitriles onto aldehydes has been developed. The reaction of isonitriles with
place under intramolecular catalysis conditions to provide functionalized benzoxaboroles.
Ó 2009 Elsevier Ltd. All rights reserved.
a-boronobenzaldehyde takes
Keywords:
Multicomponent reactions
Isonitriles
Boric acid
Benzoxaboroles
1. Introduction
in general found to be more reactive and the reactions were com-
pleted in 24 h of stirring at room temperature. Aromatic aldehydes
reacted slowly and required almost 48 h of reaction time. Upon
completion, the reaction mixture was washed with water, worked
up with diethyl ether, and pure products were obtained after silica
gel column chromatography.
Boric acid is an inexpensive, nontoxic compound, and it is gen-
erally considered a green material.1 It is an excellent precursor for
the preparation of various types of organoboranes and is also used
as a mild Lewis acid catalyst for several organic transformations.2
a
-Hydroxyamides are important synthetic intermediates in organ-
We also explored the reaction with the ketones 3-pentanone
and acetophenone as representative examples. However, the reac-
tions were found to be very sluggish even with two equivalents of
boric acid and with an elevated temperature (80 °C).
ic synthesis and also serve as valuable agents in medicinal chemis-
try.3 The use of isonitriles in three or four component coupling
reactions such as Passerini and Ugi is well documented in the
literature.4 The addition of isonitriles onto carbonyl compounds
is usually catalyzed by strong protic acids or Lewis acids to provide
We then applied the methodology for intramolecular version of
the reaction starting with o-formyl phenylboronic acid 5. We
envisaged that the proximity of the boronic acid to the formyl
group in 5 could lead to a facile reaction with isonitrile under self
catalysis mode without any additional boric acid catalysis. This
reaction should provide direct access to functionalized cyclic boro-
nic acids (benzoxaboroles) 6. Indeed, the reaction of boronoalde-
hyde 5 with isonitrile 2a in DMF at room temperature took place
smoothly without boric acid to provide the product benzoxaborole
in 81% yield. Similarly, isonitriles 2b and 2c upon reaction with 5
provided the corresponding benzoxaboroles 6b and 6c, respec-
a
-hydroxyamides.5
2. Results and discussion
Owing to the aforementioned advantages, we envisaged the
utility of boric acid for the direct
aldehydes to synthesize -hydroxyamides (Table 1). For the cur-
a-addition of isonitriles onto
a
rent study, we chose benzyl, cyclohexyl, and tert-butyl isonitriles
(2a–c) and various types of aldehydes 1a–g (Table 1). We initiated
the optimization of the reaction conditions with propionaldehyde
1a with benzyl isonitrile 2a. The reaction was studied in various
solvents such as THF, CH2Cl2, EtOAc, DMF, DMSO, Dioxane, MeOH,
and water with varying amounts of boric acid (10 mol % to one
equivalent). DMF as a solvent with one equivalent of boric acid
was found to be optimal in obtaining cleaner reaction with good
yields. Aliphatic isonitriles 2b, 2c, and aliphatic aldehydes were
HO
HO
OH
O
B
B
O
H
2a-c
DMF, 25oC
RNC
N
R
H
O
5
6a
6b
, R = Bn, 81%
, R = Bu, 65%
t
6c, R = Chx, 76%
* Corresponding author.
E-mail address: vmereddy@d.umn.edu (V.R. Mereddy).
Scheme 1. Synthesis of a-amido benzoxaboroles.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.008

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J. S. Kumar et al. / Tetrahedron Letters 51 (2010) 779–782
Table 1
Boric acid-mediated addition of isonitriles and aldehydes for the synthesis of a-hydroxyamides
OH
O
2a-c
3
H
R1NC
N
B(OH)3
R
R1
R
H
DMF, 25oC
4a-u
O
1 a-g
Entry
1
Aldehyde
Isonitrile
Product
Yield (%)
78
O
OH
H
N
NC
1a
2a
4a
H
O
O
O
O
NC
OH
H
N
2
3
2b
2c
4b
4c
74
75
H
H
H
O
OH
NC
H
N
O
OH
H
N
NC
4
5
6
1b
1c
1d
2a
2b
2c
4d
4e
4f
70
71
74
O
OH
O
O
NC
H
N
H
H
O
OH
NC
H
N
O
O
OH
H
N
NC
7
2a
4g
61
H
H
O
OH
O
O
NC
H
N
8
9
2b
2c
4h
4i
64
72
O
OH
NC
H
N
H
O
O
OH
H
N
NC
10
11
12
2a
2b
2c
4j
78
74
72
H
O
O
O
C
OH
H
N
N
4k
4l
H
H
O
NC
OH
H
N
O
O
OH
H
N
NC
13
14
15
1e
1e
2a
2b
2c
4m
4n
4o
82
76
80
H
O
O
O
NC
OH
H
N
H
H
O
NC
OH
H
N
O

J. S. Kumar et al. / Tetrahedron Letters 51 (2010) 779–782
781
Table 1 (continued)
Entry
Aldehyde
Isonitrile
Product
Yield (%)
O
OH
H
N
NC
1f
16
17
18
2a
4p
65
68
67
H
O
O
O
O
O
OH
O
O
O
NC
H
N
2b
2c
4q
4r
H
H
H
O
O
O
S
NC
OH
H
N
O
OH
H
N
NC
19
20
21
1g
2a
2b
2c
4s
4t
75
72
78
S
S
S
O
OH
O
O
NC
H
N
H
H
S
S
O
OH
NC
H
N
4u
O
tively (Scheme 1). This class of boron compounds have extensive
applications in materials chemistry and synthetic chemistry as
excellent intermediates for Suzuki cross-coupling reactions.6 Sev-
eral of these compounds have also been found to exhibit important
antibacterial and antifungal properties.7
169.4, 152.3, 131.3, 130.8, 128.1, 122.9, 80.2, 51.1, 28.9; ESI-MS:
232 [(MÀH)+, 100%].
3. Conclusions
In conclusion, we have developed an efficient protocol for the
2.1. Representative procedure for the preparation of
hydroxyamide 4a
preparation of
a-hydroxyamides via boric acid mediated addition
of isonitriles onto aldehydes. The reaction in general provides good
yields of the products under very mild reaction conditions. We
have applied the methodology for an intramolecular version to
synthesize functionalized benzoxaboroles. Owing to the impor-
tance of hydroxyamides and benzoxaboroles as synthetic interme-
diates and also as medicinal agents, we believe that the current
methodology will find applications in organic and medicinal
chemistry.
To a stirred solution of propionaldehyde 1a (0.14 mL, 2.0 mmol)
in 2 mL DMF were added benzyl isonitrile 2a (0.24 mL, 2.0 mmol),
and boric acid (0.12 g, 2.0 mmol) and stirred overnight at room
temperature. Upon completion (TLC), the reaction mixture was
worked up with water and diethyl ether (3 Â 25 mL). The com-
bined organic layers were dried (MgSO4), concentrated in vacuo,
and purified by column chromatography (silica gel, hexane/ace-
tone, 4:1) to obtain 0.30 g (78%) of hydroxy amide 4a. 1H NMR
(500 MHz, CDCl3): 7.22–7.32 (m, 5H), 7.18 (bs, 1H), 4.47 (t,
J = 4.5 Hz, 1H), 4.42 (dd, J = 4.0, 15.0 Hz, 1H), 4.36 (dd, J = 4.0,
15.0 Hz, 1H),4.05–4.08 (m, 1H), 1.78–1.90 (m, 1H), 1,62–1.72 (m,
1H), 0.95 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): 174.5,
138.2, 128.9, 127.9, 127.7, 73.2, 43.3, 28.1, 9.4; ESI-MS: 216
[(M+Na)+, 100%], 194 (M+H)+.
Acknowledgments
We thank the Departments of Chemistry and Biochemistry,
Rowan University, and University of Minnesota Duluth for the
funding. Partial support for this work was provided by research
grants from the National Institutes of Health (CA129993) (VRM)
and Whiteside Institute for Clinical Research (VRM).
2.2. Representative procedure for the preparation of
benzoxaborole 6b
References and notes
1. Boric Acid General Fact Sheet-National Pesticide Information Center: http://
npic.orst.edu/factsheets/boricgen.pdf
To a stirred solution of boronoaldehyde 5 (0.3 g, 2.0 mmol) in
2 mL DMF was added tert-butyl isonitrile 2a (0.23 mL, 2.0 mmol),
and stirred overnight at room temperature. Upon completion
(TLC), the reaction mixture was worked up with water and ethyl
acetate (3 Â 25 mL). The combined organic layers were dried
(MgSO4), concentrated in vacuo, and purified by column chroma-
tography (silica gel, hexane/ethyl acetate, 3:1) to obtain 0.30 g
(65%) of benzoxaborole 6b. (Found: C, 61.53; H, 8.10; N, 6.02%;
C12H16BNO3 requires: C, 61.84; H, 6.92; N, 6.01%); 1H NMR
(500 MHz, DMSO-d6): 9.33 (bs, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.62
(d, J = 7.6 Hz, 1H), 7.36 (t, J = 7.4 Hz, 1H), 7.26 (t, J = 7.4 Hz, 1H),
6.52 (s, 1H), 5.27 (s, 1H), 1.21 (s, 9H); 13C NMR (125 MHz, CDCl3):
2. (a) Shteinberg, L. Y. Russ. J. Appl. Chem. 2009, 82, 613–617; (b) Kondaiah, G. C. M.;
Reddy, L. A.; Babu, K. S.; Gurav, V. M.; Huge, K. M.; Bandichhor, R.; Reddy, P. P.;
Bhattacharya, A.; Anand, R. V. Tetrahedron Lett. 2008, 49, 106–109; (c) Nath, J.;
Chaudhuri, M. K. Green Chem. 2008, 1, 223–230; (d) Tu, S.-J.; Zhu, X.-T.; Fang, F.;
Zhang, X.-J.; Zhu, S.-L.; Li, T.-J.; Shi, D.-Q.; Wang, X.-S.; Ji, S.-J. Chin. J. Chem. 2005,
23, 596–598; (e) Chaudhuri, M. K.; Hussain, S.; Kantam, M. L.; Neelima, B.
Tetrahedron Lett. 2005, 46, 8329–8331; (f) Maki, T.; Ishihara, K.; Yamamoto, H.
Org. Lett. 2005, 7, 5047–5050; (g) Stapp, P. R. J. Org. Chem. 1973, 38, 1433–1434.
3. (a) Schenck, H. A.; Lenkowski, P. W.; Mukherjee, I. C.; Kob, S. H.; Stables, J. P.;
Patel, M. K.; Brown, M. L. Bioorg. Med. Chem. 2004, 12, 979–993; (b) Kuduk, S. D.;
Chang, R. K.; DiPardo, R. M.; Di Marco, C. N.; Murphy, K. L.; Ransom, R. W.; Reiss,
D. R.; Tang, C.; Prueksaritanont, T.; Pettibone, D. J.; Bock, M. G. Bioorg. Med. Chem.
Lett. 2008, 18, 5107–5110.
4. (a) Banfi, L.; Riva, R. Org. React. 2005, 65, 1–141; (b) Domling, A.; Ugi, I. Angew.
Chem., Int. Ed. 2000, 39, 3168–3210.

782
J. S. Kumar et al. / Tetrahedron Letters 51 (2010) 779–782
5. (a) Yue, T.; Wang, M.-X.; Wang, D.-X.; Masson, G.; Zhu, J. Angew. Chem., Int. Ed.
2009, 48, 6717–6721; (b) Yue, T.; Wang, M. X.; Wang, D. X.; Masson, G.; Zhu, J. J.
Org. Chem. 2009, 74, 8396–8399; (c) Mihara, H.; Xu, Y.; Shepherd, N. E.;
Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 8384–8385; (d) Wang,
S.; Wang, M.-X.; Wang, D.-X.; Zhu, J. Eur. J. Org. Chem. 2007, 24, 4076–4080; (e)
Wang, S.-X.; Wang, M.-X.; Wang, D.-X.; Zhu, J. Org. Lett. 2007, 9, 3615–3618; (f)
Denmark, S. E.; Bui, T. J. Org. Chem. 2005, 70, 10190–10193; (g) Denmark, S. E.;
Fan, Y. J. Am. Chem. Soc. 2003, 125, 7825–7827; (h) Seebach, D.; Adam, G.; Gees,
T.; Schiess, M.; Weigand, W. Chem. Ber. 1988, 121, 507–517; (i) Hagedorn, I.;
Eholzer, U. Chem. Ber. 1965, 98, 936–940.
2708; (b) Nicolaou, K. C.; Li, H.; Boody, C. N. C.; Ramanjulu, J. M.; Yue, T. Y.;
Natarajan, S.; Chu, X. J.; Brase, S.; Rubsam, F. Chem. Eur. J. 1999, 5, 2584; (c) Tan,
Y. L.; White, A. J. P.; Widdowson, D. A.; Wilhelm, R.; Williams, D. J. J. Chem. Soc.,
Perkin Trans. 1 2001, 3269.
7. (a) Akama, T.; Baker, S. J.; Zhang, Y. K.; Hernandez, V.; Zhou, H.; Sanders,
V.; Freund, Y.; Kimura, R.; Maples, K. R.; Plattner, J. J. Bioorg. Med. Chem.
Lett. 2009, 19, 2129–2132; (b) Wozniack, A. A.; Cyranski, M. K.; Zubrowska,
A.; Sporzynski, A. J. Organomet. Chem. 2009, 694, 3533–3541; (c) Baker, S.
J.; Zhang, Y. K.; Akama, T.; Lau, A.; Zhou, H.; Hernandez, V.; Mao, W.;
Alley, M. R. K.; Sanders, V.; Plattner, J. J. J. Med. Chem. 2006, 49, 4447–
4450.
6. (a) Nicolaou, K. C.; Natarajan, S.; Li, H.; Jain, N. F.; Hughes, R.; Solomon, M. E.;
Ramanjulu, J. M.; Boody, C. N. C.; Takayanagi, M. Angew. Chem., Int. Ed. 1998, 37,