Intramolecular activation of imidate with cationic gold(I) catalyst: A new benzylation reaction of alcohols

Article abstract of DOI:10.1016/j.tetlet.2020.152233

Benzylation of alcohols with benzyl (Z)-2,2,2-trifluoro-N-(2-alkynylphenyl)acetimidates 5a-f in the presence of a cationic gold(I) catalyst was investigated. Reagent 5f was the most effective, affording benzyl ethers in good yields. Our results indicate that these gold(I)-activated imidates are effective leaving groups.

Full text of DOI:10.1016/j.tetlet.2020.152233

Journal Pre-proofs
Intramolecular activation of imidate with cationic gold(I) catalyst: a new ben‐
zylation reaction of alcohols
Shintaro Ban, Tomotake Endo, Rikako Matsui, Nobuyoshi Morita,
Yoshimitsu Hashimoto, Kosaku Tanaka III, Osamu Tamura
PII:
S0040-4039(20)30700-0
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152233
TETL 152233
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
5 June 2020
4 July 2020
9 July 2020
Please cite this article as: Ban, S., Endo, T., Matsui, R., Morita, N., Hashimoto, Y., Tanaka, K. III, Tamura, O.,
Intramolecular activation of imidate with cationic gold(I) catalyst: a new benzylation reaction of alcohols,
Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.152233
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Intramolecular activation of imidate with
cationic gold(I) catalyst: a new benzylation
reaction of alcohols
Leave this area blank for abstract info.
Ph
MeO
Shintaro Ban, Tomotake Endo,
Rikako Matsui, Nobuyoshi Morita,
Yoshimitsu Hashimoto,
N
Bn O CF3
1.2 equiv
Kosaku Tanaka, III,
RO H
RO Bn
10 examples
46-82 %
Osamu Tamura*
t-Bu XPhos AuNTf2 (5 mol%)
1,4-dioxane, MS 5A
50 °C, 24 h

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Intramolecular activation of imidate with cationic gold(I) catalyst: a new benzylation
reaction of alcohols
Shintaro Ban, Tomotake Endo, Rikako Matsui, Nobuyoshi Morita, Yoshimitsu Hashimoto,
Kosaku Tanaka, III, Osamu Tamura*
aShowa Pharmaceutical University, Higashi-tamagawagakuen, Machida, Tokyo 194-8543, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Benzylation of alcohols with benzyl (Z)-2,2,2-trifluoro-N-(2-alkynylphenyl)acetimidates 5a-f in
the presence of a cationic gold(I) catalyst was investigated. Reagent 5f was the most effective,
affording benzyl ethers in good yields. Our results indicate that these gold(I)-activated imidates
are effective leaving groups.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Intramolecular activation
Imidates
Gold(I) catalyst
Benzylation
Leaving groups, such as halogens, sulfonates, etc., play vital
roles in acid-base reactions, elimination reactions and
nucleophilic substitution reactions.1 Among them, imidates are
activated by coordination of a proton or a hard Lewis acid onto
the imino nitrogen and are typically used for benzylation and
4-methoxybenzylation under acidic conditions (Scheme 1,
reaction mode A).2-4 On the other hand, 2-alkynylbenzoates are
leaving groups that are activated intramolecularly by addition
reaction of carbonyl oxygen to the alkyne moiety activated by
coordination with a soft Lewis acid, gold(I) (reaction mode B).5
These two types of leaving groups have been successfully
applied to glycosylation reactions.6 With these two reaction
modes in mind, we designed imidates that can be activated by a
soft gold(I) catalyst in a mode (reaction mode C) that is a hybrid
Reaction mode B
Raction mode A
Au
R
R
H
of reaction modes
A
and B. Thus, an N-(2-
N
O
alkynyphenyl)acetimidate could undergo coordination with
gold(I) catalyst to make the alkyne moiety highly electrophilic,
and then the imino moiety would undergo addition reaction to the
alkyne moiety to induce electrophilic activation of the imidate
moiety. To examine the feasibility of this strategy, we focused
initially on benzylation.
E
H
Nu
O
CX3
O
E
imidate
H
Nu
2-alkynylbenzoate
Raction mode C
Au
First, we synthesized the new imidates 5a-f (Scheme 2).
Sonogashira reaction of terminal alkynes 1 with 2-iodoanilines 2
gave 2-alkynyl anilines 3a-f, which were exposed to
trifluoroacetic acid under appropriate conditions for dehydration
and chlorination7 to afford chloroimines 4a-f. Finally, 4a-f were
treated with benzyl alcohol in the presence of K2CO38 as a base to
give O-benzyl imidates 5a-f.9
R
N
H
Nu
E
O
CX3
Intramolecular
activation
of acetimidate
With imidates 5a-f in hand, appropriate reaction conditions
were next examined by employing alcohol 6 and reagent 5a
(Table 1). When alcohol 6 (1.0 equiv) was treated with 5a (1.2
equiv) and Ph3PAuCl (5 mol%) in (CH2Cl)2 at room temperature,
no reaction occurred (entry 1). Use of elevated temperature
resulted in formation of only a trace of 7 (entries 2 and 3).
Scheme 1. Reaction modes of imidates (A), 2-alkynyl benzoates (B)
and the hybrid (C).

2
revealed that t-Bu XPhos AuNTf2 was more efficient, giving 7
in 64% yield (entries 10-12).
R2
I
R1
R1
With the catalyst and solvent thus identified, we next
examined the other reagents 5b-f (Table 2). A change of the
acetylenic terminal group R1 from n-butyl (5a) to phenyl (5b)
improved the yield to 72% (Table 1, entry 12 vs Table 2, entry
1), whereas 5c (R1 = 4-CF3-C6H4) and 5d (R1 = 4-MeO-C6H4)
were less effective (entries 2 and 3). As for the R2 group in the
aromatic moiety of reagent 5, an electron-donating methoxy
R2
NH2
Ph3P
Et3N
R2
2
R1
N
NH2
CCl4
TFA
Pd(PPh3)2Cl2
CuI, Et3N, rt
1
Cl
CF3
3
4
R1
5a: R1 = n-Bu, R2 = H
5b: R1 = Ph, R2 = H
R2
BnOH
K2CO2
R1
5c: R1 = 4-CF3-C6H4, R2 = H
5d: R1 = 4-MeO-C6H4, R2 = H
5e: R1 = Ph, R2 = NO2
R2
N
t-Bu Xphos AuNTf2
(5 mol%)
O
rt
OH
O
O
N
BnO
CF3
5f: R1 = Ph, R2 = MeO
MS 5A
1,4-dioxane
50 °C
5
7
BnO
CF3
6
5b-f
Scheme 2. Preparation of imidates 5a-f.
group was more efficient than an electron-deficient nitro group
(entries 4 and 5). Thus, reagent 5f efficiently benzylated alcohol
6 in the presence of t-Bu XPhos AuNTf2 and MS 5A in 1,4-
dioxane to provide product 7 in 82% yield (entry 5).
Cationic gold(I) species generated in situ by adding AgOTf
exhibited higher reactivity. Thus, 7 was not formed at room
temperature (entry 4), while the reactions at 50 °C and 80 °C
gave 7 in 42% and 50% yields, respectively (entries 5 and 6). Use
of 1,4-dioxane as a solvent improved the reactivity, and the
reaction proceeded even at room temperature to give 7 in 43%
yield although a prolonged reaction time (72 h) was required
(entry 7).10 The reaction was accelerated at higher temperatures,
and at 80 °C it was completed within 1 h to afford 7 in 59% yield
(entries 8 and 9). Next, other cationic gold(I) catalysts, JohnPhos
AuNTf2 and t-Bu XPhos AuNTf2 with MS 5A, were examined.
Comparison of JohnPhos AuNTf2 with t-Bu XPhos AuNTf2
Table 2. Gold(I)-catalyzed benzylation of 6 using 5b-f.
Time
h
Yield
%
Entry
Imidate 5
5b, R1 = Ph, R2 = H
1
2
3
4
5
42
53
16
27
25
72
42
58
10
82
5c, R1= 4-CF3-C6H4, R2 = H
5d, R1= 4-MeO-C6H4, R2 = H
5e, R1= Ph, R2 = NO2
5f, R1= Ph, R2 = MeO
Table 1. Gold(I)-catalyzed benzylation of 2-benzyloxyethanol
(6) using reagent 5a.
nBu
cat
The present gold-catalyzed benzylation is considered to
involve the highly reactive indolenium intermediate B (Scheme
3). Thus, the gold(I) catalyst coordinates with the acetylene
moiety of reagent 5 to form A, and then 5-endo-dig cyclization
occurs by attack of nitrogen of the imidate moiety on the
activated acetylene moiety to give highly activated imidate B.
Alcohol 6 reacts at the electrophilic benzyl position of B and
proton transfer takes place to afford 7 and N-acyl indole C. The
phenyl group as R1 may facilitate coordination of the cationic
gold(I) catalyst, while the methoxy group as R2 would enhance
the nucleophilicity of the imino nitrogen.
solvent
O
OH
O
O
N
temp.
time
7
BnO
CF3
5a
6
Yield
%
Entry
Conditions
1
2
3
Ph3PAuCl (5 mol%), (CH2Cl)2, rt, 24 h
Ph3PAuCl (5 mol%), (CH2Cl)2, 50 °C, 72 h
Ph3PAuCl (5 mol%), (CH2Cl)2, 80 °C, 72 h
0
2
6
Ph3PAuCl (5 mol%), AgOTf (5 mol%), (CH2Cl)2, rt,
24 h
4
5
0
Au
Ph3PAuCl (5 mol%), AgOTf (5 mol%), (CH2Cl)2, 50
°C, 48 h
Au
R1
42
50
43
57
59
30
58
64
R2
R2
Au
R1
5
Ph3PAuCl (5 mol%), AgOTf (5 mol%), (CH2Cl)2, 80
°C, 0.5 h
N
H
O
6
N
R
6
CF3
O
Ph3PAuCl (5 mol%), AgOTf (5 mol%), 1,4-dioxane,
rt, 72 h
O
CF3
7
A
B
H
Ph3PAuCl (5 mol%), AgOTf (5 mol%), 1,4-dioxane,
50 °C, 24 h
8
R2
R
O
R1
–Au
Ph3PAuCl (5 mol%), AgOTf (5 mol%), 1,4-dioxane,
80 °C, 1 h
N
9
CF3
O
JohnPhos AuNTf2 (5 mol%),a 1,4-dioxane, MS 5A,
rt, 120 h
10
11
12
7
C
JohnPhos AuNTf2 (5 mol%), 1,4-dioxane, MS 5A,
50 °C, 48 h
Scheme 3. Plausible mechanism of gold(I)-catalyzed benzylation of
alcohol 6 with imidate 5.
t-Bu XPhos AuNTf2 (5 mol%),b 1,4-dioxane, MS 5A,
50 °C, 21 h
a JohnPhos: 2-(Di-tert-butylphosphino)biphenyl
b t-Bu XPhos: 2-Di-tert-butylphosphino-2’,4’,6’-triisopropylbiphenyl

3
With the appropriate reagent 5f and conditions in hand, we
conducted gold(I)-catalyzed benzylation of various alcohols 8-14
(Table 3). Primary (entry 1), secondary (entry 2) and tertiary
(entry 3) alcohols 8-10 were benzylated to give 15-17 in 59%,
59% and 46% yields, respectively. 2-Adamantyl alcohol (11), a
highly hindered secondary alcohol, also reacted under these
conditions to afford 18 in 51% yield (entry 4). Carbamates were
tolerated, and carbamate-protected amino alcohols 12 and 13
provided benzylated compounds 19 and 20, respectively, each in
66% yield (entries 5 and 6). -Silyl alcohol is known to be
unstable under acidic conditions because of Peterson elimination,
and therefore 2-(trimethylsilyl)ethanol (14) cannot be benzylated
by acid-catalyzed benzylation with trichloroacetoimidate.11 In
contrast, alcohol 14 underwent benzylation with reagent 5f to
provide 21 in a satisfactory yield (74%) (entry 7).12
Ph
CO2H
CO2Bn
t-Bu XPhos AuNTf2
(5 mol%)
N
1,4-dioxane
MS 5A
80 °C, 1 h
61%
22
Bn
O
CF3
23
5b
Me-Ph (as a solvent)
t-Bu XPhos AuNTf2 (5 mol%)
MS 5A, 50 °C, 31 h
71%
Me
Me
o-24
44:56
p-24
Scheme 4. Ester formation of 22 and Friedel–Crafts reaction with
toluene.
Table 3. Gold(I)-catalyzed benzylation of various alcohols 8-14
using reagent 5f and t-Bu Xphos AuNTf2.a
In conclusion, we show that a new type of imidate derived
from 2-alkynylaniline can be activated by cationic gold(I)
catalyst, and can readily benzylate various alcohols. In other
words, these gold(I)-activated imidates are effective leaving
groups. Further applications of these leaving groups to other
cationic reactions, for example glycosylation, are currently under
investigation.
Ph
MeO
t-Bu XPhos AuNTf2
(5 mol%)
RO
H
RO Bn
N
1,4-dioxane
MS 5A
50 °C, 24 h
8-14
15-21
Bn
5f (1.2 eq.)
Alcohol
O
CF3
Entry
1
Yield %
Product
Acknowledgments
Bn
Ph
OH
Ph
O
59
59
8
15
This work was supported by a Grant-in-Aid for Young
Scientists from Showa Pharmaceutical University (S.B.).
Me
Me
Bn
2
3
Ph
O
Ph
OH
16
9
Me Me
OH
Me Me
References and notes
Bn
46
51
Ph
Ph
O
10
17
1.
2.
3.
For a review of leaving groups, see: Lepore, S. D.; Mondal, D.
Tetrahedron 2007, 63, 5103-5122.
For a review of imidates, see: Nakajima, N.; Ubukata, M. Sci.
Synth. 2005, 22, 343-360.
For benzyl trichloroacetimidate, see: (a) Iversen, T.; Bundle, D. R.
J. Chem. Soc., Chem. Comm. 1981, 1240-1241. For 4-
methoybenzyl trichloroacetimidate, see: (b) Nakajima, N.; Horita,
K.; Abe, R.; Yonemitsu, O. Tetrahedron Lett. 1988, 29, 4139-
4142. Both imidates are commercially available and are widely
used for benzylation and 4-methoxybenzylation. For benzyl
trifluoroacetimidate, see: (c) Nakajima, N.; Saito, M.; Ubukata, M.
Tetrahedron Lett. 1998, 39, 5565-5568. (d) Nakajima, N.; Saito,
M.; Ubukata, M. Tetrahedron 2002, 58, 3561-3577.
OH
O
Bn
4b
11
18
OH
Ph
O
Bn
N
N
5b
66
O
O
O
19
Ph
O
O
O
12
OH
O
4.
5.
6.
Triazine-based benzylation reagents can be considered as a kind of
Bn
Bn
N
N
6c
7
66
74
imidate derivatives. For
a review, see: (a) Kunishima, M.;
Yamada, K.; Fujita, H.; Kitamura, M. Synth. Org. Chem., Jpn.
2017, 75, 1023-1034. See also: (b) Yamada, K.; Fujita, H.;
Kunishima, M. Org. Lett. 2012, 14, 5026-5029. (c) Yamada, K.;
Fujita, H.; Kitamura, M.; Kunishima, M. Synthesis 2013, 45,
2989-2997. (d) Fujita, H.; Kakuyama, S.; Kunishima, M. Eur. J.
Org. Chem. 2017, 833–839.
(a) Asao, N.; Aikawa, H.; Tago, S.; Umetsu, K. Org. Lett. 2007, 9,
4299-4302. (b) Aikawa, H.; Tago, S.; Umetsu, K.; Haginiwa, N.;
Asao, N. Tetrahedron 2009, 65, 1774-1784. (c) Jean, M.; Renault,
J.; Weghe, P. V. D.; Asao, N. Tetrahedron Lett. 2010, 51, 378-
381. (d) Aikawa, H.; Kaneko, T.; Asao, N.; Yamamoto, Y.
Beilstein J. Org. Chem. 2011, 7, 648–652. See also, (e) Renault,
J.; Qian, Z.; Uriac, P.; Gouault, N. Tetrahedron Lett. 2011, 52,
2476–2479
For excellent reviews, see: (a) Yang, Y.; Zhang, X.; Yu, B. Nat.
Prod. Rep. 2015, 32, 1331- 1355. (b) Nielsen, M. M.; Pedersen, C.
M. Chem. Rev. 2018, 118, 8285-8358. See also, (c) Yu, B. Acc.
Chem. Res. 2018, 51, 507−516. (d) Li, W.; Yu, B. Chem. Soc. Rev.
2018, 47, 7954-7984. (e) Li, X.; Zhu, J. Eur. J. Org. Chem. 2016,
4724–4767.
O
13
O
20
Me3Si
Me3Si
O
OH
21
14
a Unless otherwise specified, reactions were conducted by using 5f (1.2 equiv)
and t-Bu XPhos AuNTf2 (5 mol%) at 50 °C for 24 h.
b Reagent 5f (1.5 equiv) and t-Bu XPhos AuNTf2 (6 mol%) were used at 80
°C for 4 h.
c Reagent 5f (1.8 equiv) and t-Bu XPhos AuNTf2 (7 mol%) were used at 80
°C for 5 h.
Finally, several other reactions were examined (Scheme 4).
Benzoic acid (22) was treated with reagent 5b in the presence of
a catalytic amount of t-Bu XPhos AuNTf2 and MS 5A in 1,4-
dioxane to give benzyl benzoate (23) in 61% yield.13 Reagent 5b,
on exposure to t-Bu XPhos AuNTf2 in toluene, underwent
Friedel-Crafts reaction with toluene to afford a 44:56 mixture of
o-24 and p-24 in 71% yield, indicating the generation of benzyl
cation species.
7.
8.
9.
Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe, H.; Uneyama,
K. J. Org. Chem. 1993, 58, 32-35.
Okada, Y.; Ohtsu, M.; Bando, M.; Yamada, H. Chem. Lett. 2007,
36, 992-993.
These imidates were geometrically pure, and their configurations
were tentatively assigned as (Z)-configurations because
a
trifluoromethyl group has been recognized as a very bulky

4
substituent. The bulkiness of a trifluromethyl group is estimated to
be comparable to or higher than that of an isopropyl group, see:
(a) Bott, G.; Field, L. D.; Sternhell, S. J. Am. Chem. Soc. 1980,
102, 5618-5626. (b) Nagai, T.; Nishioka, G.; Koyama, M.; Ando,
A.; Miki, T.; Kumadaki, I. Chem. Pharm. Bull. 1991, 39, 233-235.
10. Recent examples of the use of 1,4-dioxane as a solvent for gold-
catalyzed reactions, see: (a) Du, Y.; Yao, F.; Zhang, R.; Cai, M. J.
Organomet. Chem. 2020, 910, 121136-121143. (b) Furuta, M.;
Sugiyama, K.; Yamaguchi, M.; Ueda, H.; Tokuyama, H. Chem.
Pharm. Bull. 2019, 67, 872–876. (c) Cloutier, M.; Roudias, M.;
Paquin, J.-F. Org. Lett. 2019, 21, 3866−3870. (d) Zhang, X.; Sun,
X.; Fan, H.; Lyu, C.; Li, P.; Zhang, H.; Rao, W. RSC Adv. 2016, 6,
56319-56322.
11. Poon, K. W. C.; Dudley, G. B. J. Org. Chem. 2006, 71, 3923-
3927.
12. Kunishima and co-workers also succeeded in benzylation of
alcohol 14 under mild acidic conditions; see ref. 4d.
13. The requirement of higher temperature of the reaction of
carboxylic acid 22 is probably due to the lower nucleophilicity
compared to an alcohol.
Supplementary Material
1
Experimental details, H and 13C NMR spectra of all new com-
pounds are available in the Supplementary Material, at
http://dx.doi.org/10.1016/j.tetlet.