Specific reactivity of 2,4,6-tri-tert-butylanilide anions and its application to benzylation reagent

Article abstract of DOI:10.1016/j.tetlet.2016.12.009

The reaction of methyl iodide with an anilide anion prepared from 2,4,6-tri-tert-butylanilide and NaH in CH₃CN gave N-methyl anilide (N-alkylation product) as a major product, while in the reaction of benzyl bromide with the anilide anion in DMF, O-benzyl imidate (O-alkylation product) was obtained with almost complete selectivity. The treatment of O-benzyl imidate with alcohols and carboxylic acids in the presence of trifluoromethane sulfonic acid gave benzyl ethers and benzyl esters, respectively.

Full text of DOI:10.1016/j.tetlet.2016.12.009

Accepted Manuscript
Specific reactivity of 2,4,6-tri-tert-butylanilide anions and its application to
benzylation reagent
Tomoyuki Yamada, Shiori Tsukagoshi, Osamu Kitagawa
PII:
S0040-4039(16)31638-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.009
TETL 48421
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
14 November 2016
1 December 2016
5 December 2016
Please cite this article as: Yamada, T., Tsukagoshi, S., Kitagawa, O., Specific reactivity of 2,4,6-tri-tert-butylanilide
anions and its application to benzylation reagent, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2016.12.009
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butylanilide anions and its application to
benzylation reagent
Tomoyuki Yamada, Shiori Tsukagoshi and Osamu Kitagawa*

1
Tetrahedron Letters
Specific reactivity of 2,4,6-tri-tert-butylanilide anions and its application to
benzylation reagent
Tomoyuki Yamada, Shiori Tsukagoshi and Osamu Kitagawa*
Department of Applied Chemistry, Shibaura Institute of Technology, 3-7-5 Toyosu, Koto-ku, Tokyo 135-8548, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The reaction of methyl iodide with an anilide anion prepared from 2,4,6-tri-tert-butylanilide and
NaH in CH3CN gave N-methyl anilide (N-alkylation product) as a major product, while in the
reaction of benzyl bromide with the anilide anion in DMF, O-benzyl imidate (O-alkylation
product) was obtained with almost complete selectivity. The treatment of O-benzyl imidate with
alcohols and carboxylic acids in the presence of trifluoromethane sulfonic acid gave benzyl
ethers and benzyl esters, respectively.
Available online
Keywords:
anilides
tert-butyl
imidates
benzylation
ethers
2009 Elsevier Ltd. All rights reserved.
In 1967, Chupp et al. reported that an amide bond of 2,6-
di-tert-butylanilides has a high rotational barrier (27-28 kcal
mol-1), and Z- and E-rotamers based on the amide bond can be
isolated at an ambient temperature.1 This study is noteworthy
as a rare example of a separable amide rotamer,2 while a
systematic study using anilide substrates other than -
haloacetanilides, stereoselective syntheses of anilide rotamers,
and the structural property have not been investigated in detail.
We succeeded in a highly selective stereodivergent
synthesis of Z- and E-rotamers of various N-allylated 2,4,6-tri-
tert-butylanilide derivatives via Pd(0) and Pd(II)-catalyzed N-
allylations (Scheme 1).3,4 These reactions proceed through the
formation of O-allyl imidate II followed by Pd(0)-catalyzed
intermolecular O,N-allylic rearrangement [N-allylation via -
allyl-Pd complex] or Pd(II)-catalyzed intramolecular O,N-
allylic
rearrangement
[Pd(II)-catalyzed
aza-Claisen
rearrangement] to give Z- or E-rotamer with high
stereoselectivity, respectively.3a,b
The selective formation of O-allyl imidate II (O-allylation
product) observed in the reaction of an allylic electrophile with
2,4,6-tri-tert-butylanilide anions should be noteworthy because
the reaction of allyl bromide with ordinary anilide anions
prepared from acetanilide and 2-tert-butylacetanilide gave N-
allyl anilides (N-allylation products) with almost complete
selectivity.5,6
Scheme 1. Highly stereoselective synthesis of anilide Z- and E-
rotamers via O-allyl imidate II.
On the other hand, since the reaction with alkyl halides
other than allyl bromide was not investigated, the generality on
the unique O-alkylation of 2,4,6-tri-tert-butylanilide anions was
not necessarily clear. In this Letter, we report the specific
reactivity of 2,4,6-tri-tert-butylanilide anions toward several
alkyl halides. Furthermore, the application of the obtained O-
*Corresponding author. tel: +81 3 5859 8161; fax: +81 3 5859 8101.
E-mail address: kitagawa@shibaura-it.ac.jp (O. Kitagawa)

2
Tetrahedron
benzylation products (O-benzyl imidates) to a benzylation
reagent is described.
control). In contrast, in 2,4,6-tri-tert-butylanilide anion, the N-
alkylation is prevented by the steric hindrance due to two
ortho-tert-butyl groups and an alkylation product on less
hindered oxygen atom is selectively obtained (steric control).
When small methyl iodide is used as an alkylation reagent, the
selectivity may be controlled by not only a steric factor but also
an HSAB factor to give the mixtures of N- and O-methylation
products. Since the polarity of CH3CN is slightly lower in
comparison with that of DMF, the polarization of methyl iodide
in CH3CN may be smaller than that in DMF (methyl iodide in
CH3CN may be more soft electrophile than that in DMF).7
Therefore, the reaction with methyl iodide in CH3CN may bring
about an increase in the methylation on soft nitrogen atom.
First, we investigated the alkylation with 2,4,6-tri-tert-
butylacetanilide 1a as a substrate. The results on the reaction
of several alkyl halides with the anilide anion prepared from 1a
and NaH in DMF (or CH3CN) at rt are shown in Table 1. The
N- vs O-alkylation selectivity was significantly influenced by
the bulkiness of alkyl halides. That is, similar to allyl bromide
(Scheme 1 and entry 1 in Table 1), the reaction with benzyl
bromide in DMF afforded O-benzyl imidate 4a in 83% yield
without the formation of N-benzylation product 5a (entry 2). In
the reaction with ethyl iodide, although O-ethyl imidate 6a was
obtained in a good yield (91%), the formation of a small
amount of N-ethyl anilide 7a was observed (7%, entry 3).
Meanwhile, the reaction with methyl iodide proceeded with
slight N-alkylation selectivity to give N-methyl anilide 9a and
O-methyl imidate 8a in 51% and 39% yields, respectively
(entry 4). Thus, the N-alkylation selectivity showed an
increasing tendency with a decrease in the bulkiness of alkyl
halide.
The N- vs O-alkylation selectivity in the reaction with
ethyl and methyl iodides also strongly depended on the solvent.
The reaction in CH3CN led to an increase in the N-alkylation
selectivity to give N-ethylation and N-methylation products 7a
and 9a in better yields than those in DMF (entries 7 and 8),
while in the reactions with allyl bromide and benzyl bromide,
such a solvent effect was not observed (entries 5 and 6).
Figure 1. Origin of N- and O-alkylation selectivity.
The amide rotamers in N-ethyl anilide 7a and N-methyl
anilide 9a could be separated by MPLC, while the Z- and E-
rotamers selectivity in the N-alkylation was poor (entries 3, 4, 7,
8).8
Table 1. N- vs O-alkylation selectivity in the reaction of 2,4,6-
tri-tert-butylacetanilide anion with several alkyl halides.a
Table 2. Reaction of several 2,4,6-tri-tert-butylanilide anions
with Me-I.a
entry
R-X
solvent
O-alkyl-
N-alkyl-
(Z/E)c
entry
1
R
solvent
8
8
9
9
9
ationb
ationb
(%)b
(%)b (Z/E)c
1
2
3
4
5
6
7
8
allyl-Br
Bn-Br
C2H5-I
CH3-I
DMF
DMF
DMF
DMF
2a (96%) 3a (0%)
4a (83%) 5a (0%)
6a (91%) 7a (7%)
8a (39%) 9a (51%)
-
1
2
3
4
5
6
1a
1b
CH3
DMF
DMF
DMF
8a
8b
8c
39
43
19
8
9a
9b
9c
9a
51
55
68
84
82
62
1/1.2
2
-
C2H5
7a (1/1.1)
9a (1/1.2)
-
1c CO2Me
>30
1/1.3
5
1a
1b
CH3
CH3CN 8a
CH3CN 8b
allyl-Br
Bn-Br
C2H5-I
CH3-I
CH3CN 2a (42%) 3a (0%)
CH3CN 4a (98%) 5a (0%)
CH3CN 6a (23%) 7a (13%)
C2H5
trace 9b
-
1c CO2Me CH3CN 8c
5
9c
>30
7a (1/1.3)
9a (1/1.3)
a1 (0.5 mmol), NaH (0.75 mmol), R-X (0.75 mmol), solvent (5 mL),
CH3CN
8a (8%) 9a (84%)
at rt. bIsolated yield. cThe ratio was determined by 400 MHz H-
1
a1a (0.5 mmol), NaH (0.75 or 1.15 mmol), R-X (0.75 mmol),
solvent (5 mL), at rt. bIsolated yield. cThe ratio was determined by
400 MHz 1H-NMR.
NMR.
Under the conditions shown in Table 1, the effect of acyl
substituents in the reaction with methyl iodide was further
explored (Table 2). Similar to acetanilide 1a, the reaction with
propionanilide 1b and ester anilide 1c in DMF also proceeded
with low N-methylation selectivity (O-methyl 8/N-methyl 9 =
43/55 and 19/68, entries 2 and 3). When CH3CN was used
instead of DMF, a remarkable increase in the N-methylation
selectivity was observed (entries 5 and 6).
These results can be rationally explained on the basis of a
steric factor and the hard and soft acids and bases (HSAB)
theory (Figure 1). The reactions of ordinary anilide anions with
alkyl halides (soft electrophile) preferentially occur on soft
nitrogen atom but not on hard oxygen atom to afford an N-
alkylation product with almost complete selectivity (HSAB

3
The Z- and E-rotamers selectivity in the N-methylation was
significantly influenced by the bulkiness of the acyl
substituent.3a,b The N-methylation of acetanilide 1a proceeded in
a poor E-selectivity (Z/E = 1/1.2-1/1.3, entries 1 and 4), while in
1b bearing slightly larger substituent (Et) than that (Me) of 1a,
low or moderate Z-selectivity was observed (Z/E = 2 and 5,
entries 2 and 5).8 In contrast, the reaction of 1c bearing relatively
large substituent (CO2Me) proceeded with almost complete Z-
selectivity (entries 3 and 6).3a,b
were solid (easily handleable) and can be purified without any
decomposition through extraction and column chromatography
(In trifluoroacetimidate 4d, the decomposition to 1d via
hydrolysis was observed during extraction and chromatographic
purification).12
Initially, the benzylation of 2-phenylethanol 10a with O-
benzyl acetimidate 4a as a reagent was investigated (Table 3).
After the survey of acids, solvents, and the amount of imidate
reagent 4a, it was found that the reaction with 1.3 equiv of 4a in
the presence of trifluoromethane sulfonic acid (2.0 equiv) in 1,4-
dioxane solvent provides the best result. In this case, benzyl
ether 11a was obtained at a high yield (88%, entry 6). Under the
same conditions, the benzylation with ester imidate 4c and
trifluoroacetimidate 4d completed in a shorter reaction time (5 h
and 3 h) to afford 11a in 94% and 99%, respectively (entries 7
These results can be explained as shown in Figure 2.3a,b In
substrates 1c bearing a relatively large ester group, since the
transition state TS-E9, which gives E-rotamer E-9, should be
disfavored because of the steric repulsion between the ortho-tert-
butyl groups and the R substituent, Z-9 is obtained with complete
selectivity via TS-Z9. Meanwhile, with substrates bearing a
small acyl group, the reaction proceeds not only via TS-Z9 but
also via TS-E9 to afford the mixtures of Z-9 and E-9.
and 8).
Thus, the imidate reagent bearing an electron-
withdrawing group led to an increase in the reactivity. In the
present reaction, 2.0 equiv of CF3SO3H was required to obtain a
maximum yield, while the reaction in the presence of 1.0 or 1.5
equiv of CF3SO3H resulted in a decrease in the chemical yield.
When 2.0 equiv of CH3SO3H was used as an acid, no the product
11a was obtained. In the reactions in Table 3, dibenzyl ether was
formed as a side product (In entries 6-8, dibenzyl ether side
products were obtained in 10%, 5% and 4% yields, respectively).
Table 3. Optimization of the reaction conditions in benzylation of
10a with imidate 4.a
Figure 2. Possible transition state model for Z-rotamer selectivity.
As an application of the present reaction, we next attempted
the development of a new benzylation reagent using O-benzyl
imidate products 4.9 That is, the reaction of 2,4,6-tri-tert-
butylacetanilide anion with benzyl bromide gave O-benzyl
imidate 4a in a good yield without the formation of N-benzyl
anilide 5a (entries 2 and 6 in Table 1). If such complete O-
benzylation selectivity is also observed in other 2,4,6-tri-tert-
butylanilide substrates, it should provide a facile synthetic
method of various O-benzyl imidate derivatives 4 and some of
them may work as an effective benzylation reagent.
As per our expectation, the benzylation with anions from
anilides 1c and 1d gave O-benzyl imidates 4c and 4d with
complete selectivity (Scheme 2), while in the reaction with
trifluoroacetanilide 1d, a decrease was observed in the chemical
yield due to the instability of imidate 4d.
entry
4 (equiv)
solvent
time (h) yield (%)b
1
2
3
4
5
6
7
8
4a (1.0)
4a (1.0)
4a (1.0)
4a (1.0)
4a (1.0)
4a (1.3)
4c (1.3)
4d (1.3)
1,4-dioxane
CH2Cl2
18
18
18
18
18
18
5
79
12
DMF
trace
trace
0
CH3CN
THF
1,4-dioxane
1,4-dioxane
1,4-dioxane
88
94
3
99
a10a (0.5 mmol), 4 (0.5 or 0.65 mmol), CF3SO3H (1.0 mmol) solvent
(5 mL), at rt. bThe yield was determined by 1H-NMR analysis of the
mixture of 11a and dibenzyl ether (side product).
The scope and limitation in the present benzylation were
further examined under optimized conditions (Table 4).
Although trifluoroacetimidate 4d is the most reactive benzylation
reagent, ester imidate 4c was used in the reaction provided in
Table 4 because 4d could not be prepared in a good yield
(Scheme 2). The reaction of 2-(2-chloroethoxy)ethanol 10b also
gave benzyl ether 11b in a good yield (86%, entry 2). The
present method can also be applied to the benzylation of
secondary alcohols 10c,d, while the yields slightly lowered in
comparison with those of primary alcohols 10a,b (entries 3, 4).
In the reaction of optically active ethyl lactate 10d, the
Scheme 2. Selective synthesis of O-benzyl imidates 4.
The benzylation with O-benzyl imidate products 4a, 4c, 4d
was
explored
subsequently.
Although
O-benzyl
trichloroacetimidate and trifluoroacetimidate (commercially
available) have been known as a benzylation reagent, which can
be used under the acidic conditions, these reagents are liquid
materials and difficult to store for a long time as they are
moisture sensitive.10,11 On the other hand, our imidates 4a and 4c

4
Tetrahedron
References and notes
racemization was scarcely observed. In contrast to primary and
secondary alcohols 10a-d, the reaction with tertiary alcohol 10e
gave the complex mixtures involving dehydration (alkenes) side
products and the desired benzyl ether 11e was not obtained (entry
5). The present benzylation method requires a somewhat larger
amount of CF3SO3H (2.0 equiv) in comparison with the methods
using trichloroacetimidate and trifluoroacetimidate reagents
because a chemically more stable imidate 4c is used as a reagent.
Accordingly, the tertiary carbocation from alcohol 10e as well as
the benzyl cation from 4c may be formed to result in the complex
mixtures. This is the limitation of the present benzylation.
The present method was also applied to the benzylation of
carboxylic acids. The reaction of benzoic acid 10f and 3-(2-
bromophenyl)propanoic acid 10g gave benzyl esters 11f and 11g
in 76% and 87% yields, respectively, while in these cases, 2.0
equiv of imidate 4c and the addition of MS 5A were required
(entries 6 and 7). Thus, N-(2,4,6-tri-tert-butyl)phenyl O-benzyl
imidate 4c was found to work as a benzylation reagent for
alcohols and carboxylic acids.
1.
2.
Chupp, J. P.; Olin, J. F. J. Org. Chem. 1967, 32, 2297.
Examples of separable amide rotamers: (a) Mannschreck, A.
Tetrahedron Lett. 1965, 6, 1341. (b) Toldy, L.; Radics, L.
Tetrahedron Lett. 1966, 7, 4753. (c) Staab, H. A.; Lauer, D.
Tetrahedron Lett. 1966, 7, 4593. (d) Staab, H. A.; Lauer, D.; Chem.
Ber. 1968, 101, 864. (e) Schlecker, R.; Seebach, D.; Lubosch, W.
Helv. Chim. Acta. 1978, 61, 512. (f) Seebach, D.; Wykypiel, W.;
Lubosch, W.; Kalinowski, H. O. Helv. Chim. Acta. 1978, 61, 3100.
(g) Rice C, K.; Brossi, A. J. Org. Chem. 1980, 45, 592. (h) Hay, D.
R.; Song, Z.; Smith, S. G.; Beak, P. J. Am. Chem. Soc. 1988, 110,
8145. (i) Tan, L. T.; Williamson, R. T.; Gerwick, W. H. J. Org.
Chem. 2000, 65, 419.
Papers on stereoselective synthesis of 2,4,6-tri-tert-butylanilide
rotamers (Z- and E- rotamers): (a) Ototake, N.; Taguchi, T.;
Kitagawa, O. Tetrahedron Lett. 2008, 49, 5458. (b) Ototake, N.;
Nakamura, M.; Dobashi, Y.; Fukaya, H.; Kitagawa, O. Chem. Eur. J.
2009, 15, 5090. (c) Li, X.; Curran, D. P. Org. Lett. 2010, 12, 612.
Our papers on structural property of 2,4,6-tri-tert-butylanilide
derivatives: (a) Nakamura, M.; Takahashi, I.; Yamada, S.; Dobashi,
Y.; Kitagawa, O. Tetrahedron Lett. 2011, 52, 53. (b) Ohnishi, Y.;
Sakai, M.; Nakao, S.; Kitagawa, O. Org. Lett. 2011, 13, 2840. (c)
Tsukagoshi, S.; Ototake, N.; Ohnishi, Y.; Shimizu, M.; Kitagawa, O.
Chem. Eur. J. 2013, 19, 6845.
3.
4.
5.
6.
Recent papers on alkylation of anilide and 2-tert-butylanilide anions:
(a) Hughes, A. D.; Price, D. A.; Simpkins, N. S. J. Chem. Sc. Perkin
Trans. 1, 1999, 1295. (b) De, S.; Mishra, S.; Kakde, B. N.; Dey, D.;
Bisai, A. J. Org. Chem. 2013, 78, 7823. (c) Liu, K.; Wu, X.; Kan, S.
B. J.; Shirakawa, S.; Maruoka, K. Chem. Asian J. 2013, 8, 3214. (d)
O’Sullivan, S.; Doni, E.; Tuttle, T.; Murphy, J. A. Angew. Chem. Int.
Ed. 2014, 53, 474.
It has been reported that in the reaction of 2-pyridone derivatives with
alkyl halides, the mixtures of O- and N-alkylation products are
obtained. Hao, X.; Xu, Z.; Lu, H.; Dai, X.; Yang, T.; Lin, X.; Ren, F.
Org. Lett. 2015, 17, 3382, and references cited therein.
Table 4. Benzylation of various alcohols and carboxylic acids
with imidate 4c.a
entry
10
R-OH
11
yield (%)
7.
8.
Although the reaction in other solvents (THF, 1,4-dioxane, toluene)
was also investigated, the alkylation did not proceed smoothly
because of extremely low solubility of anilide 1a.
The stereochemistries of Z- and E-rotamers were determined on the
basis of the chemical shift of -hydrogens (7a, 9a, 9b) or ester methyl
hydrogens (9c). That is, these hydrogens of E-7,9 appear in higher
field side than those of Z-7,9 because of anisotropy effect by twisted
2,4,6-tri-tert-butylphenyl group. See ref. 3.
1
10a
10b
10c
10d
10e
10f
Ph(CH2)2OH
Cl(CH2)2O(CH2)2OH
cyclohexanol
11a
11b
11c
11dd
11e
11f
94b
86c
71b
64c
0e
2
3
4f
(S)-MeCH(OH)CO2Et
Ph(CH2)2C(OH)Me2
PhCO2H
5
9.
Greene, T. W.; Wuts, P. G. M. in Protective Groups in Organic
Synthesis, 4th ed. John Wiley and Sons, New York, 2006, and
references cited therein.
6f,g
7f,g
76b
87c
10g
2-BrC6H4(CH2)2CO2H
11g
10. Typical papers on benzylation using O-benzyl trichloroacetimidate
reagent: (a) Iversen, T.; Bundle, D. R. J. Chem. Soc. Chem. Commun.
1981, 1240. (b) Ulrich, W.; Synthesis, 1987, 568. (c) Eckenberg, P.;
Groth, U.; Huhn, T.; Richter, N.; Schmeck, C. Tetrahedron 1993, 49,
1619.
11. Typical papers on benzylation using O-benzyl trifluoroacetimidate
reagent: (a) Okada, Y.; Ohtsu, M.; Bando, M.; Yamada, H. Chem.
Lett. 2007, 36, 992. (b) Tsabedze, S. B.; Kabotso, D. E. K.; Pohl, N.
L. B. Tetrahedron Lett. 2013, 54, 6983.
a10 (0.5 mmol), 4c (0.65 mmol), 1,4-dioxane (5 mL), at rt. bThe
1
yield was evaluated by H-NMR analysis of the mixtures of 11 and
dibenzyl ether (side product). cIsolated yield. dThe ee of 11d was
98%. eThe complex mixtures involving alkenes were obtained. f2.0
Equiv of 4c was used. gMS 5A was added.
In conclusion, we disclosed the specific reactivity of 2,4,6-
tri-tert-butylanilide anions with alkyl halides. The reactions with
allyl and benzyl bromides proceeded with complete O-alkylation
selectivity to give O-alkylated imidates in good yields. In the
reaction with less bulky methyl iodide, the N-methylation
products were obtained as a major product. The N- vs O-
12. Examples of moisture stable and easily handleable (solid) benzylation
reagents: (a) Poon, K. W. C.; Dudley, G. B. J. Org. Chem. 2006, 71,
3923. (b) Yamada, K.; Fujita, H.; Kunishima, M. Org. Lett. 2012, 14,
5026. (c) Yamada, K.; Tsukada, Y.; Karuo, Y.; Kitamura, M.;
Kunishima, M. Chem. Eur. J. 2014, 20, 12274.
methylation selectivity strongly depended on
a solvent.
Furthermore, O-benzyl imidate products were found to be used as
a reagent for the benzylation of alcohols and carboxylic acids.
Supplementary Materials
Experimental procedures and characterization data for all
new compounds (1d, 4a, 4c, 4d, 6a-9a, 8b-c, 9b-c), and copies
1
of H-NMR and 13C-NMR spectra of new compounds, benzyl
ethers and esters 11a-g. Supplementary data associated with
this article can be found in the online version.

5
(Highlights)
Reaction of tert-butylanilide anions with benzyl bromide gives O-benzyl imidates.
Reaction of tert-butylanilide anions with methyl iodide gives N-methyl anilides.
O-Benzyl imidates are used as a benzylation reagent of alcohols and carboxylic acids.