Facile synthesis of sterically hindered and electron-deficient secondary amides from isocyanates

Article abstract of DOI:10.1002/anie.201204481

The big easy: The direct coupling of Grignard reagents to isocyanates provides a facile and robust solution for the synthesis of sterically hindered and electron-deficient secondary amides. The products are obtained in high yields without the need for excess reagents or chromatographic purification. Copyright

Full text of DOI:10.1002/anie.201204481

Angewandte
Chemie
DOI: 10.1002/anie.201204481
Amide Formation
Facile Synthesis of Sterically Hindered and Electron-Deficient
Secondary Amides from Isocyanates**
Gabriel Schꢀfer, Coraline Matthey, and Jeffrey W. Bode*
Amide bond formation is widely regarded as the most used
chemical reaction in drug discovery.[1] Despite the importance
of amides, nearly all are formed by reactions operating under
a single mechanistic approach: dehydrative condensation of
amines and carboxylic acids by the action of a coupling
agent.[2] This approach has proven to be highly suitable, albeit
often wasteful and expensive, for the majority of amides.[3] An
exception is the preparation of highly hindered and electron-
deficient amides, for which difficulty in their formation by
condensation is well known.[4] Although a number of mech-
anistically unique amide bond forming reactions have been
reported,[5] including work from our own labs,[6] none of these
new reactions addresses the challenge of preparing amides
from hindered acids or those derived from bulky or electron-
deficient amines.
As part of our research program aimed at the identifica-
tion and development of new amide-forming reactions, we
have been seeking approaches to the preparation of hindered
amides and those derived from electron-deficient amines. We
now document a rapid and simple approach to such targets by
the addition of Grignard reagents to hindered isocyanates
(Scheme 1). The reactions proceed in minutes at room
only scattered applications of this reaction have appeared.[8]
To the best of our knowledge, a general protocol for the
addition of bulky Grignard reagents to bulky or electron-
deficient isocyanates has not been reported.[9] More recently,
rhodium-catalyzed additions of organostannanes[10] and bor-
onic acids[11] to isocyanates were disclosed but—despite the
convenience of these starting materials—these methods
require an expensive rhodium catalyst and have only been
applied to unhindered substrates.
Using 1 as a model substrate, we explored the addition of
various Grignard reagents to this hindered isocyanate
(Scheme 2). We found that the reactions could be conducted
under a variety of conditions, and selected Et2O as a solvent
for further exploration of the substrate scope. Addition of the
Grignard reagent (as a solution in Et2O or THF, 1.0 equiv) to
the isocyanate (0.25m in Et2O, 1.0 equiv) at 08C followed by
warming to room temperature was found to be applicable to
nearly all substrates examined.[12] In most cases, aqueous
Scheme 1. Synthesis of sterically hindered and electron-deficient
amides by direct coupling of Grignard reagents to isocyanates.
temperature, tolerate a number of functional groups, and
provide access to hindered secondary amides not readily
prepared by standard methods.
Since the elegant work of Gilman on the titration of
organomagnesium halides through addition to isocyanates,[7]
[*] G. Schꢀfer, C. Matthey, Prof. Dr. J. W. Bode
Laboratorium fꢁr Organische Chemie, Department of Chemistry
and Applied Biosciences, ETH Zꢁrich
Wolfgang-Pauli-Strasse 10, 8093 Zꢁrich (Switzerland)
E-mail: bode@org.chem.ethz.ch
Homepage: http://www.bode.ethz.ch
[**] This work was supported by ETHIRA Grant (ETH-12 11-1). We thank
the ETH Mass Spectrometry Service for high-resolution mass
spectrometry.
Scheme 2. Grignard additions to isocyanate 1. Reaction conditions:
1 (1.0 mmol), Grignard reagent (1.0 mmol), Et2O (4 mL), 08C to RT,
30 min. [a] In situ formation of Grignard reagent from corresponding
bromide and Mg metal. [b] 3 h reaction time.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204481.
Angew. Chem. Int. Ed. 2012, 51, 1 – 4
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workup and washing of the crude material with hexanes
provided analytically pure amide products without the need
for further purifications.
high yields. Amide 15 was synthesized on a 15 mmol scale
using 2-methyl THF as a more industry-friendly solvent.[13]
The synthesis of amides from electron-deficient amines by
couplings with activated esters is often challenging due to
their decreased nucleophilicity. In contrast, electron-deficient
isocyanates are excellent substrates for the reaction with
Grignard reagents. Amide products 21–24 from bulky and
electron-deficient, aromatic isocyanates, such as 2,6-dichloro-
phenyl, 2,6-diisopropylphenyl and 2-fluoro-6-trifluoro-
methylphenyl isocyanate were accessible. Furthermore, our
conditions were applicable to the synthesis of hindered,
electron-deficient, aliphatic amides 25–27 derived from
amino-isobutyrate ester and trifluoromethyl-substituted iso-
cyanates. The a-trifluoromethyl-substituted amides could
serve as promising building blocks in medicinal chemistry.[14]
The chemoselective addition of Grignard reagents to isocya-
nates bearing ester or ketone functional groups is noteworthy;
the corresponding amides (23, 25, 26) were obtained in good
yield.
Hindered Grignard reagents including tert-butyl, mesityl
and 2-biphenyl Grignard cleanly added to the isocyanate to
give amide products 2–4 in excellent yield. Even the
extremely bulky adamantyl-, 2,4,6-trimethoxyphenyl and
2,4,6-triisopropylphenyl Grignard reagents provided desired
products 5–7 in good yield. As anticipated from these results,
several other amides derived from aromatic (8–10), hetero-
cyclic (11) and aliphatic (12, 13) Grignards were easily
prepared by this protocol. In no instance did we observe over-
reaction of the Grignard reagent with the resulting amide; this
proved to be the case even when less hindered substrates were
used.
The scope of the isocyanate was found to be equally broad
(Scheme 3). Hindered isocyanates such as tert-butyl, tert-
octyl, 1-phenylcyclopropyl, or adamantyl isocyanate were
excellent substrates and delivered amide products 15–18 in
Even the combination of the most hindered substrates
from each reaction partner gave the expected amide in good
yield, allowing for the preparation of exceptionally hindered
secondary amides 30 and 31 (Scheme 4).[15]
Scheme 4. Synthesis of sterically hindered amides 30 and 31.
The hindered isocyanate substrates are readily prepared
from either amines or carboxylic acids using well-established
methods and, if necessary, amenable to column chromatog-
raphy.[16] Two examples are shown in Scheme 5. These
isocyanates are easily handled compounds that can be
stored for months without any sign of decomposition; many
of them are commercially available. The Grignard reagents
Scheme 3. Mesityl Grignard (14) addition to various isocyanates.
Reaction conditions: isocyanate (1.0 mmol), mesityl Grignard (14,
1.0 mL of 1m solution in Et2O), Et2O (4 mL), 08C to RT, 30 min. [a]
Reaction performed on 15 mmol scale in 2-MeTHF (60 mL). [b] À788C
to RT, 30 min. [c] Isocyanate prepared in situ from 4,6-dichloropyrimi-
din-2-amine and oxalyl chloride in benzene.
Scheme 5. Synthesis of isocyanates from a) amines and b) carboxylic
acids. DPPA=Diphenylphosphoryl azide.
2
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[6] a) J. W. Bode, R. M. Fox, K. D. Baucom, Angew. Chem. 2006,
used in this study were either commercially available or
readily prepared from the corresponding organohalide and
magnesium metal. We anticipate that other methods for
Grignard formation, such as magnesium–halogen exchange[17]
or transmetalation from boron reagents,[18] will also be
suitable for this chemistry. The use of other organometallic
species, perhaps with the aid of a catalyst, is also likely to be
viable.
In summary, we have identified a convenient and rapid
approach to the synthesis of hindered and electron-deficient
amides by the direct coupling of isocyanates with Grignard
reagents. This provides a reliable solution to the preparation
of amides for which traditional, coupling reagent based
reactions generally fail to give the desired product. The
starting materials, while not as common as amines and
carboxylic acids, are readily obtained by well-known proto-
cols. We anticipate that our method will be of considerable
use for the preparation of challenging amides and will find
application in the synthesis of pharmaceuticals and materials.
118, 1270 – 1274; Angew. Chem. Int. Ed. 2006, 45, 1248 – 1252;
b) J. W. Bode, S. S. Sohn, J. Am. Chem. Soc. 2007, 129, 13798 –
13799; c) V. R. Pattabiraman, A. O. Ogunkoya, J. W. Bode,
Angew. Chem. 2012, 124, 5204 – 5208; Angew. Chem. Int. Ed.
2012, 51, 5114 – 5118; d) A. M. Dumas, G. A. Molander, J. W.
Bode, Angew. Chem. 2012, 124, 5781 – 5784; Angew. Chem. Int.
Ed. 2012, 51, 5683 – 5686.
[7] a) H. Gilman, C. R. Kinney, J. Am. Chem. Soc. 1924, 46, 493 –
497; b) H. Gilman, M. Furry, J. Am. Chem. Soc. 1928, 50, 1214 –
1216.
[8] a) H. M. Singleton, W. R. Edwards, Jr., J. Am. Soc. Chem. 1938,
60, 540 – 544; b) L. Field, J. E. Lawson, J. W. McFarland, J. Am.
Chem. Soc. 1956, 78, 4389 – 4394; c) J. W. McFarland, R. L.
Harris, J. Org. Chem. 1967, 32, 1273 – 1274; d) K. A. Parker,
E. G. Gibbons, Tetrahedron Lett. 1975, 16, 981 – 984; e) Y.
Zhang, J. Jiang, Y. Chen, Tetrahedron Lett. 1987, 28, 3815 –
3816; f) I. Stefanuti, S. A. Smith, R. J. K. Taylor, Tetrahedron
Lett. 2000, 41, 3735 – 3738; g) A. Padwa, K. R. Crawford, P.
Rashatasakhon, M. Rose, J. Org. Chem. 2003, 68, 2609 – 2617;
h) M. I. Antczak, J. M. Ready, Chem. Sci. 2012, 3, 1450 – 1454.
[9] The use of organometallic reagents for the preparation of
sterically hindered compounds is well established: a) Prepara-
tion of tetra-ortho-substituted biaryl naphthalenes with organo-
lithium species: A. C. Glass, S. Klonoski, L. N. Zakharov, S.-Y.
Liu, Chem. Commun. 2011, 47, 286 – 288; b) Bulky Grignard
reagents in the synthesis of sterically demanding ligands: A.
Labonne, T. Kribber, L. Hintermann, Org. Lett. 2006, 8, 5853 –
5856; c) Synthesis of new biarylphosphine ligands with sterically
hindered Grignard reagents: L. Salvi, N. R. Davis, S. Z. Ali, S. L.
Buchwald, Org. Lett. 2012, 14, 170 – 173.
Experimental Section
Typical procedure for the preparation of 27: In a flame-dried Schlenk-
flask under N2 1-isocyanato-1-(trifluoromethyl)cyclohexane (0.19 g,
1.0 mmol) was dissolved in dry Et2O (4 mL) and cooled to 08C.
Mesitylmagnesium bromide (14, 1.0 mL of a 1m solution in Et2O) was
added dropwise over 2–3 min and the reaction mixture was warmed to
RT and stirred for 30 min. The reaction mixture was quenched with
sat. NH4Cl solution (10 mL) and stirred for 1–2 min before EtOAc
(25 mL) was added and the phases separated. The organic layer was
washed with brine (10 mL), dried over Na2SO4, filtered and concen-
trated under reduced pressure. The obtained crude material was
washed with hexanes, the solid was collected by filtration and dried
under high vacuum to obtain the pure product 27 as a colorless solid
(0.29 g, 0.92 mmol, 92%).
[10] T. Koike, M. Takahashi, N. Arai, A. Mori, Chem. Lett. 2004, 33,
1364 – 1365.
[11] T. Miura, Y. Takahashi, M. Murakami, Chem. Commun. 2007,
3577 – 3579.
[12] For isocyanates with sensitive functional groups (ester, ketone or
carbamates) reaction was cooled to À788C and after the
addition of the Grignard reagent warmed to RT.
[13] T. Laird, Org. Process Res. Dev. 2012, 16, 1 – 2.
[14] J. M. Axten (Glaxo Group Limited), WO2004/002490A2, 2004.
[15] For rare examples of the synthesis of sterically hindered
secondary amides, see: a) Y. Rao, X. Li, S. J. Danishefsky, J.
Am. Chem. Soc. 2009, 131, 12924 – 12926; b) H. Kurata, K.
Ishibashi, K. Kojima, Synlett 1996, 517 – 518; c) P. Wipf, H.
Heimgartner, Helv. Chim. Acta 1987, 70, 354 – 368; d) K. Sasaki,
D. Crich, Org. Lett. 2011, 13, 2256 – 2259; e) M. Inoue, N.
Shinohara, S. Tanabe, T. Takahashi, K. Okura, H. Itoh, Y.
Mizoguchi, M. Iida, N. Lee, S. Matsuoka, Nat. Chem. 2010, 2,
280 – 285.
Received: June 9, 2012
Published online: && &&, &&&&
À
Keywords: amides · C C coupling · Grignard reaction ·
.
isocyanates · steric hindrance
[1] S. D. Roughley, A. M. Jordan, J. Med. Chem. 2011, 54, 3451 –
3479.
[2] E. Valeur, M. Bradley, Chem. Soc. Rev. 2009, 38, 606 – 631.
[3] D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey, J. L.
Leazer, J. Russell, R. J. Linderman, K. Lorenz, J. Manley, B. A.
Pearlman, A. Wells, A. Zaksh, T. Zhang, Green Chem. 2007, 9,
411 – 420.
[4] V. R. Pattabiraman, J. W. Bode, Nature 2011, 480, 471 – 479.
[5] a) C. Gunanathan, Y. Ben-David, D. Milstein, Science 2007, 317,
790 – 792; b) X. Li, S. J. Danishefsky, J. Am. Chem. Soc. 2008,
130, 5446 – 5448; c) H. U. Vora, T. Rovis, J. Am. Chem. Soc. 2007,
129, 13796 – 13797; d) B. Shen, D. M. Makley, J. N. Johnston,
Nature 2010, 465, 1027 – 1032; e) K. Ishihara, S. Ohara, H.
Yamamoto, J. Org. Chem. 1996, 61, 4196 – 4197; f) N. Shangguan,
S. Katukojvala, R. Greenberg, L. J. Williams, J. Am. Chem. Soc.
2003, 125, 7754 – 7755; For further references on new amide
bond forming reactions, see Ref. [4].
[16] Selected examples: a) Synthesis of isocyanates from amine
hydrochloride salts: J. H. Tsai, L. R. Takaoka, N. A. Powell,
J. S. Nowick, Org. Synth. 2002, 78, 220 – 222; b) Synthesis of
isocyanates from carboxylic acids: C. Spino, M.-A. Joly, C.
Godbout, M. Arbour, J. Org. Chem. 2005, 70, 6118 – 6121.
[17] a) A. Krasovskiy, P. Knochel, Angew. Chem. 2004, 116, 3396 –
3399; Angew. Chem. Int. Ed. 2004, 43, 3333 – 3336; b) A.
Krasovskiy, B. F. Straub, P. Knochel, Angew. Chem. 2006, 118,
165 – 169; Angew. Chem. Int. Ed. 2006, 45, 159 – 162; c) A.
Krasovskiy, F. Kopp, P. Knochel, Angew. Chem. 2006, 118, 511 –
515; Angew. Chem. Int. Ed. 2006, 45, 497 – 500.
[18] M. A. Reichle, B. Breit, Angew. Chem. 2012, 124, 5828 – 5832;
Angew. Chem. Int. Ed. 2012, 51, 5730 – 5734.
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Angewandte
Communications
Communications
Amide Formation
G. Schꢁfer, C. Matthey,
J. W. Bode*
&&&& — &&&&
Facile Synthesis of Sterically Hindered
and Electron-Deficient Secondary Amides
from Isocyanates
The big easy: The direct coupling of
Grignard reagents to isocyanates pro-
vides a facile and robust solution for the
synthesis of sterically hindered and elec-
tron-deficient secondary amides. The
products are obtained in high yields
without the need for excess reagents or
chromatographic purification.
4
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 4
These are not the final page numbers!