Organic Letters
Letter
(11) Tozawa, T.; Yamane, Y.; Mukaiyama, T. Chem. Lett. 2005, 34,
1334−1335.
was observed in the crude reaction mixture [1H NMR (CDCl3, 400
MHz) δH 8.05−8.03 (m, 2H) and 3.91 (s, 3H) ppm]. After workup,
no methyl ester was observed, and we invoke basic hydrolysis of the
ester in the workup procedure to rationalize this. Simulated hydrolysis
of authentic methyl benzoate under the workup conditions confirmed
this. Methyl benzoate has previously shown not to react with excess
aniline neat at 140 °C Ali, Md. A.; Siddiki, S. M. A. H.; Onodera, W.;
Kon, K.; Shimizu, K.-i. ChemCatChem 2015, 7, 3555−3561. Thus, it is
to be expected that any methyl benzoate is kinetically stable under
these conditions and will not undergo conversion to the amide.
(24) The direct amidation work of Mukaiyama (refs 10−12) invokes
silyl ester intermediates but without any experimental observation
thereof. See also ref 13d.
(25) Silyl ester 13 is a known compound via InBr3 catalyzed reaction
of BzOH with HSi(OMe)3: Nishimoto, Y.; Okita, A.; Yasuda, M.;
Baba, A. Angew. Chem., Int. Ed. 2011, 50, 8623−8625. It is identified
by its characteristic resonances in its 1H NMR spectrum at 8.12−8.07
(m, 2H) and 3.74 (s, 9H) ppm in CDCl3 solution.
(26) The reaction of benzoic acid with TMOS 1 to give methyl
benzoate has previously been reported: Sumrell, G.; Ham, G. E. J. Am.
Chem. Soc. 1956, 78, 5573−5575.
(27) A related reaction has been conducted in the reverse sense with
tetraacetoxysilane and alcohols: Kopylov, V. M.; Kireev, V. V.; Ivanov,
V. V.; Astaf’ev, G. Yu.; Kozlov, Yu. V; Russ, J. Russ. J. Gen. Chem. 2001,
71, 1924−1928.
(28) Kelly, S. M.; Lipshutz, B. H. Org. Lett. 2014, 16, 98−101. See
also ref 14e.
(29) For the amidation of lithocholic acid (containing a free
secondary alcohol) a faster running component (assumed to be O-
silylated amide) could be observed by TLC (Rf 0.73, 50:50 PE/
EtOAc) after the amidation was complete. This component cleanly
converted to the product (Rf 0.33) after the addition of THF and 1 M
aqueous NaOH solution as a modification of the standard workup
procedure, and additional stirring for 16 h.
(12) Tozawa, T.; Yamane, Y.; Mukaiyama, T. Chem. Lett. 2005, 34,
1586−1587.
(13) SiCl4: (a) Chan, T. H.; Wong, L. T. L. J. Org. Chem. 1969, 34,
2766−2767. HMDS: (b) Chou, W.-C.; Chou, M.-C.; Lu, Y.-Y.; Chen,
S.-F. Tetrahedron Lett. 1999, 40, 3419−3422. PhSiH3: (c) Ruan, Z.;
Lawrence, R. M.; Cooper, C. B. Tetrahedron Lett. 2006, 47, 7649−
7651. (d) Andrews, K. G.; Summers, D. M.; Donnelly, L. J.; Denton,
R. M. Chem. Commun. 2016, 52, 1855−1858. Ph2SiH2: (e) Sayes, M.;
Charette, A. B. Green Chem. 2017, 19, 5060−5064. 9-Silafluorenyl
dichlorides: (f) Aspin, S. J.; Taillemaud, S.; Cyr, P.; Charette, A. B.
Angew. Chem., Int. Ed. 2016, 55, 13833−13837.
(14) (a) Comerford, J. W.; Clark, J. H.; Macquarrie, D. J.; Breeden, S.
W. Chem. Commun. 2009, 2562−2564. (b) Yang, X.-D.; Zeng, X.-H.;
Zhao, Y.-H.; Wang, X.-Q.; Pan, Z.-Q.; Li, L.; Zhang, H.-B. J. Comb.
Chem. 2010, 12, 307−310. (c) Komura, K.; Nakano, Y.; Koketsu, M.
Green Chem. 2011, 13, 828−831. (d) Ojeda-Porras, A.; Hernan
́
dez-
Santana, A.; Gamba-Sanchez, D. Green Chem. 2015, 17, 3157−3163.
́
(e) Tamura, M.; Murase, D.; Komura, K. Synthesis 2015, 47, 769−776.
(f) Tamura, M.; Murase, D.; Komura, K. Chem. Lett. 2016, 45, 451−
453. (g) Zakharova, M. V.; Kleitz, F.; Fontaine, F.-G. Dalton Trans.
2017, 46, 3864. (h) Ghosh, S.; Bhaumik, A.; Mondal, J.; Mallik, A.;
Sengupta, S.; Mukhopadhyay, C. Green Chem. 2012, 14, 3220−3229.
(15) Dunetz, J. R.; Magano, J.; Weisenburger, G. A. Org. Process Res.
Dev. 2016, 20, 140−177.
(16) The use of TMOS and TEOS was previously investigated by
Mukaiyama (ref 11) at rt in THF and by Sheppard in acetonitrile
solvent at 100 °C, 10 min (MW; 150 W) (ref 6a). Minimal and low
conversions respectively were reported.
(17) (EtO)4Si (TEOS, bp 168 °C) and (MeO)4Si (TMOS, bp 121
°C) are clear, colourless liquids and are commercially readily available
(TEOS ≈ US$5 per mole; TMOS ≈ US$14 per mole). These
compounds react slowly with water at neutral pH but more rapidly in
acidic conditions and even more so in basic solution. They can be
stored without special precautions and handled in air for short periods
without significant hydrolysis.
(18) For a direct comparison, see Figure 1, amide 3, footnote a. It is
our expectation that TEOS 2 would mediate all the transformations
described herein, but less efficiently.
(19) The conversions to amides 11 and 12 in refluxing toluene,
[acid] = 2.0 M, [amine] = 2.0 M, 250 mol% TMOS 1, 24 h were 53%
and 46% respectively.
(30) An attempted amidation of N-Boc-proline with benzylamine
under the standard conditions led to partial tert-butyl transfer to
benzylamine. Column chromatography provided the pure Boc-L-
proline-benzamide product in 79% yield; mp 124−125 °C (lit.6b 124−
125 °C); [α]D −80.0 (c 1.0, CH2Cl2); lit.6b [α]D −77.0 (c 1.0,
CH2Cl2).
25
25
(31) Attempted amidation of N-Fmoc-alanine with (S)-(−)-α-
methylbenzylamine under the standard conditions led to the
observation of 9-methylene-9H-fluorene as the major component in
1
the H NMR spectrum after workup.
(20) The attempted use of neat TMOS for this amidation provided
amide 12 in 30% conversion. Conditions: 250 mol% TMOS, reflux,
N2, [BzOH] = 2.7 M, [m-MeC6H4NH2] = 2.7 M, 24 h. The use of
neat TMOS for other amidations reported herein also provided no
advantage. We have also found that the use of neat TEOS 2 (bp 168−
(32) The diastereomeric purity of amide 26 was ascertained by
comparison of the product of the same amidation reaction using D-N-
Cbz-Ala (see SI for HPLC trace).
(33) A 1 mol reaction between benzoic acid and benzylamine
(reaction conditions: toluene, reflux, 250 mol % TMOS, N2; [BzOH]
= 2.0 M, [BnNH2] = 2.0 M) gave only a 51% conversion to the desired
amide after 13 h. The reaction vessel was subsequently fitted with a
fractional distillation column and takeoff head. After 3 h of subsequent
reflux, and collection of methanol, the reaction had proceeded to 100%
conversion. After workup the product was obtained pure in 99.3%
yield (210 g, PMI: 20), mp 104.2−104.9 °C; lit. mp 104−105 °C: Xu,
X.; Li, P.; Huang, Y.; Tong, C.; Yan, Y. Y.; Xie, Y. Tetrahedron Lett.
2017, 58, 1742−1746.
̊
169 C), neat HSi(OEt)3 (bp 134−135 °C), or neat B(OiPr)3 (bp
139−141 °C) at reflux for the direct amidation of benzoic acid with
aniline at [1 M] for 7 h provided the desired amide product in 55−
65% isolated yield.
(21) The attempted use of imidazole, DMAP, 1-methyl imidazole-N-
oxide, or pyridine N-oxide as activating additives for this reaction led
to lower conversions to the amide product than without. Conditions:
Toluene, reflux, N2, 10 mol% additive [BzOH] = 2.0 M, [m-
MeC6H4NH2] = 2.0 M, 250 mol% TMOS, 24 h. Conversion to amide
12: imidazole (24%); DMAP (20%); 1-methyl imidazole-N-oxide
(18%); pyridine N-oxide (28%). For the beneficial use of N,N-
dimethylaminopyridine N-oxide in conjunction with a boronic acid
catalyst for direct amidations, see ref 5l. For the beneficial use of 1-
methylimidazole-N-oxide (NMI-O) in acylation and sulfonylation and
silylation reactions of alcohols, see Murray, J. I.; Spivey, A. C. Adv.
Synth. Catal. 2015, 357, 3825−3830 and references cited therein.
(22) We have not attempted the use of xylenes or mesitylene (see
e.g., ref 5a) for these reactions, since their higher boiling points make
them difficult to remove subsequently.
(34) Fennie, M. W.; Roth, J. M. J. Chem. Educ. 2016, 93, 1788−1793
and references cited therein. The PMI for this 1 mol scale TMOS
mediated direct amidation remains unoptimized.
(35) 1H NMR and 13C NMR data are available via a data repository:
Santhakumar, G.; Braddock, D. C.; Pugh, D. Imperial College HPC
(23) In this amidation, where 2 equiv of carboxylic acid were
employed, 27% of methyl benzoate (based on % of amide product)
D
Org. Lett. XXXX, XXX, XXX−XXX