p-Methylbenzyl 2,2,2-Trichloroacetimidate: Simple Preparation and Application to Alcohol Protection

Article abstract of DOI:10.1246/CL.200303

A method for p-methylbenzyl (MBn) protection of alcohols by using MBn 2,2,2-trichloroacetimidate is described. The trichloroacetimidate can easily be prepared and isolated as a stable white powder without purification by silica gel chromatography. Catalytic use of zinc(II) triflate in diethyl ether activates the trichloroacetimidate to enable MBn protection of various alcohols.

Full text of DOI:10.1246/CL.200303

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p-Methylbenzyl 2,2,2-trichloroacetimidate:
Simple Preparation and Application to Alcohol Protection
Kazutada Ikeuchi,* Kentaro Murasawa, Tomoki Arai, and Hidetsohi Yamada
Advance Publication on the web June 4, 2020
doi:10.1246/cl.200303
© 2020 The Chemical Society of Japan
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1
p-Methylbenzyl 2,2,2-trichloroacetimidate:
Simple Preparation and Application to Alcohol Protection
Kazutada Ikeuchi,*1,2 Kentaro Murasawa,1 Tomoki Arai,1 and Hidetsohi Yamada1†
1School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda 669-1337
2Department of Chemistry, Faculty of Science, Hokkaido University, Kita 10, Nishi 8, Kita-ku, Sapporo 060-0810
E-mail: ikeuchi@sci.hokudai.ac.jp
1
2
3
4
5
6
7
A method for p-methylbenzyl (MBn) protection of
42 protection by using MBn-TCAI (1) and a catalytic Lewis
43 acid (Scheme 1b).
alcohols by using MBn 2,2,2-trichloroacetimidate is
described. The trichloroacetimidate can easily be prepared
and isolated as a stable white powder without purification
by silica gel chromatography. Catalytic use of zinc (II)
triflate in diethyl ether activates the trichloroacetimidate to
enable MBn protection of various alcohols.
(a)
NC
CN
O
O
OPMB
OMBn
OH
(NH4)2[Ce(NO3)6]
74–95% yields
Cl
Cl
R
OMBn
R
OH
OMBn
29–93% yields
8
9
Keywords: p-Methylbenzyl 2,2,2-trichloroacetimidate,
Alcohol protection, Zinc (II) triflate
(b)
This work
NH
(1)
MBnBr
base
MBnO
CCl3
R
OH
R
OMBn
R
OMBn
10
The benzyl (Bn) group and its analogues are widely
Previous work
cat. Lewis acid
11 used for alcohol protection in organic synthesis (Figure 1a).1
12 Among these protecting groups, the Bn group is the most
13 selected as a result of its stability under various conditions
14 and specific cleavage under hydrogenolytic conditions.2 The
15 Bn group is typically installed on hydroxy groups via the
16 Williamson ether synthesis (Figure 1b).3 If the substrate is
17 labile under basic conditions, acidic reaction conditions are
18 employed by using benzyl 2,2,2-trichloroacetimidate (Bn-
19 TCAI) and a Lewis acid/organic protonic acid (Figure 1b).4
20 The p-methoxybenzyl (PMB) group is also frequently used
21 for alcohol protection; the same protection method as that
22 for the Bn group can be followed,5 and the reactivity of the
23 PMB group under oxidative conditions allows its selective
24 removal in the presence of the Bn group.6 Because of such
25 advantages, further reaction methods for incorporating these
26 two groups into alcohols have been reported.7
44
45 Scheme 1. (a) Our previous report about the MBn group. (b) Methods
46 for protecting alcohols with the MBn groups.
47
MBn-TCAI (1) was prepared according to our previous
48 simple method for synthesizing various TCAIs.10 Thus, a
49 suspension of p-methylbenzyl alcohol (MBnOH) in hexane
50 was treated with trichloroacetonitrile and catalytic 1,8-
51 diazabicyclo[5.4.0]undec-7-ene (DBU) at 0 °C. Similar to
52 the appearance change that occurred in the established
53 TCAI synthesis reactions, the suspected reaction mixture
54 gradually changed to a colorless solution as the reaction
55 proceeded. Subsequent work-up process with liquid-liquid
56 extraction provided 1 in 97% yield as a white powder
57 (Scheme 2). Although the synthesis of 1 has already been
58 reported, that method requires purification by silica gel
59 chromatography.11 Our method provides 1 in high purity
60 without such purification. Synthesized 1 can be kept at room
61 temperature for a month without decomposition.
Bn/PMBX
base
(a)
(b)
R
OBn/PMB
R
OH
R
NH
R = H: Benzyl (Bn)
R = OMe: p-Methoxybenzyl (PMB)
R = Me: p-Methylbenzyl (MBn
Our method
PMB/BnO
CCl3
)
cat. acid
27
Cl3CCN (1.1 equiv.)
NH
DBU (0.1 equiv.)
OH
28 Figure 1. (a) Structures of the Bn group and its analogue. (b) General
29 method for the Bn/PMB protection.
MBnO
CCl3
hexane, 0 °C;
liquid-liquid extractiona
MBnOH
MBn-TCAI (1)
97%
30
We have recently reported that, similar to PMB groups,
Reported method11
31 p-methylbenzyl (MBn) groups installed on alcohols can be
32 removed under oxidative conditions (Scheme 1a).8
33 Furthermore, chemoselective removal of the PMB group in
34 the presence of Bn and MBn groups was demonstrated.
35 These results showed that the MBn group is a valuable
36 protecting group for alcohols, in addition to the Bn and
37 PMB groups. In the previous study, all the MBn groups in
38 the substrates were incorporated via the Williamson ether
39 synthesis because other introduction methods have not been
40 explored in detail owing to the less general use of this
41 group.9 Herein, we describe a facile method for MBn
Cl3CCN (1.2 equiv.)
DBU (0.1 equiv.)
MBnOH
MBn-TCAI (1)
95%
CH2Cl2, 0 °C to rt;
liquid-liquid extraction;
silca gel chromatography
62
63 Scheme 2. Facile synthesis of MBn-TCAI (1).
64
With MBn-TCAI (1) in hands, we turned our attention
65 to optimizing the reaction conditions for providing MBn-
66 protected compounds by using 1. Alcohol 28 possessing a

2
R = TsMeN(CH2)5
1
2
3
4
5
6
7
8
9
sulfonyl amide moiety was used for the investigation, and
the acid screening results are summarized in Table 1. The
amounts of 1 and each acid were fixed at 1.1 and 0.5
equivalents, respectively. Dichloromethane was selected as
the reaction solvent and the reaction was evaluated based on
the NMR yield of crude products. Frequently used Lewis
acids for activating Bn/PMB-TCAI, such as trimethylsilyl
RO
MeOTf
CH2Cl2
3
MBn-TCAI
(1)
Fridel-Crafts
alkylation
RO
RO
5
4a
4b
42
43 Scheme 3. Proposed mechanism for the formation of byproducts 4a and
44 4b.
trifluoromethanesulfonate
(TMSOTf),12
BF3·OEt2,13
Sc(OTf)3,14 La(OTf)3,15 and Cu(OTf)2,16 induced the
10 reaction; however, the NMR yields remained at 47%–60%,
11 indicating that these Lewis acids have no catalytic activity
12 in the reaction using 1 (entries 1–5). The use of the organic
13 protonic acid, 10-camphorsulfonic acid (CSA),17 resulted in
14 almost no reaction (entry 6). Subsequently, we used an
15 unreported catalyst for activating Bn/PMB-TCAIs. No
16 reaction occurred with the use of ZrCl4 (entry 7). Although
17 the reaction with In(OTf)3 gave the similar results to those
18 in entries 4 and 5 (entry 8), the use of MeOTf and Zn(OTf)2
19 improved the reaction conversion to give 3 in 78% and 71%
20 NMR yields, respectively (entries 9 and 10). Both reactions
21 also proceeded with similar yields when 0.1 equivalent of
22 the catalyst was used. However, MeOTf occasionally
23 produced a mixture of 4a and 4b as byproducts, in which a
24 p-xylene unit is attached to the benzene ring of the MBn
25 group of 3 (Scheme 3).18 This side reaction involves the
26 Friedel-Crafts alkylation of benzylic cation 5, derived from
27 1 in situ. Addition of a scavenger such as anisole19 and
28 pentamethylbenzene20 did not completely suppress the side
29 reaction. Therefore, we further modified the Zn(OTf)2-
30 mediated reaction system and discovered that the reaction
31 solvent was crucial for enhancing the reaction. Thus, the
32 reaction in diethyl ether proceeded smoothly with a loading
33 of 0.1 equivalent of Zn(OTf)2 to give 3 in 98% NMR yield
34 (entry 11). The use of TfOH21 instead of Zn(OTf)2
35 decreased NMR yield to 77% (entry 12), indicating that the
36 zinc (II) cation is required for efficient conversion. The
45 isolated yield of 3 under the conditions given in entry 11
46 was 94%, and no byproducts, 4a or 4b, were formed.
47
With the optimized reaction conditions established, the
48 substrate scope was investigated (Scheme 4). 3-Phenyl-1-
49 propanol (6a) and methyl (R)-3-hydroxyisobutyrate (6b)
50 reacted easily with 1 to afford 7a and 7b in 88% and 76%
51 yields, respectively. Protection of the primary alcohol in
52 serine derivative 6c resulted in a low yield (39%) because
53 the Boc group was partially damaged under the reaction
54 conditions. Secondary alcohols such as methyl lactate (6d)
55 and L-menthol (6e) formed the corresponding MBn-
56 protected compounds in 76% and 94% yields, respectively,
57 the latter using 1.5 equiv. of 1. Reaction of 1-adamantanol
58 (6f), which is classified as a tertiary alcohol, proceeded
59 smoothly with 1.5 equiv. of 1 to afford MBn ether 7f in 90%
60 yield. Using 1.1 equiv. of 1 in the reaction of 6e and 6f
61 lingered in the MBn protection to decrease the yields of 7e
62 and 7f to 73% and 66%, respectively. These results indicate
63 that the presence of excess 1 accelerated the reaction. By
64 contrast, a dramatical decrease in yield was observed when
65 more hinder alcohols such as 6g and 6h were used. In
66 particular, the secondary alcohol of 6h hardly reacted with 1
67 and provided 7h in only 19% yield. Although the reaction
68 was also attempted in the presence of excess 1, or under
69 reflux conditions, the yield of 6h was largely unchanged,
70 indicating that steric hindrance around the alcohol group
71 affects the reaction with 1. Protection of the phenolic
72 hydroxy group in methyl 4-hydroxybenzoate (6i) afforded 7i
73 with a minor C-alkylated compound with yield of 64%.
74 Notably, the enantiomeric excess of both 7c and 7d,
75 possessing a chiral center at the α-position to the carbonyl
76 moiety, was ≥98% ee. These results indicate that no
77 racemization of the chiral centers occurred under our
78 reaction conditions.
37 Table 1. Acid screening for reaction of alcohol 2 with MBn-TCAI (1).
MBn-TCAI (1) (1.1 equiv.)
Me
N
acid (0.5 equiv.)
Me
N
OH
OMBn
Ts
CH2Cl2, rt, 20–24 h
a
Ts
2
3
38
79
The functional allowance of the MBn-protected
entry
1
acid
yield (%)a
50
entry
7
acid
yield (%)a
N.R.
80 reaction was further examined. Alcohol protection using
81 TBS, Ac, and MOM groups in 6j–k was not affected under
82 the reaction conditions, thereby allowing the corresponding
83 the MBn protections in satisfactory product yields. The
84 alkyne moiety in 6m also tolerated the reaction to protect
85 the secondary alcohol, affording a yield of 89%. In contrast,
86 Weinreb amide 6n induced a side reaction triggered by
87 amide activation via Zn(OTf)2, decreasing the yield of 7n,
88 and providing inseparable byproducts. Finally, the reaction
89 conditions were applied to the protection of cholesterol (6o)
90 with a tri-substituted alkene in the tetra cyclic skeleton. The
91 reaction proceeded uneventfully, affording the MBn-
92 protected compound 7o with a yield of 77% yield.
Sc(OTf)3
BF3·OEt2
TMSOTf
La(OTf)3
Cu(OTf)2
CSA
ZrCl4
2
3
4
5
6
47
54
57
60
5
8
In(OTf)3
MeOTf
61
9
78 (77b)
71 (67b)
98 (94d)
77
10
11c
12c
Zn(OTf)2
Zn(OTf)2
TfOH
39 a NMR yield. b NMR yield with 0.1 equiv. of acid. c Reaction with 0.1
40 equiv. of acid and Et2O as the reaction solvent. d Isolated yield. Ts = p-
41 toluenesulfonyl.

3
20 Treatment of MBnOH with trichloroacetonitrile and
21 catalytic DBU in hexane produced 1 easily without
22 purification by silica gel chromatography. Activation of 1
23 with catalytic Zn(OTf)2 in Et2O enabled the MBn protection
24 of various types of alcohols in 19%–94% yields. These new
25 results and our previous report will accelerate the use of
26 MBn groups for the transformation of polyol compounds
27 with orthogonal synthetic strategies.
MBn-TCAI (1) (1.1 equiv)
Zn(OTf)2 (0.1 equiv.)
R–OH
R–OMBn
Et2O, rt
isolated yield
6a–o
7a–o
NHBoc
CO2Me
6c
OH
HO
HO
CO2Me
6a
88%
6b
76%
39% (99% ee)
28
29
This work was partly supported by JSPS KAKENHI
OH
30 (Grant numbers JP19K15549, JP18H04429, and
31 JP19H02727). We thank Dr. Yasuko Okamoto at
32 Tokushima Bunri University for measurements of the MS
33 spectra of partial compounds.
34
35
OH
CO2Me
HO
6d
76% (98% ee)
6e
6f
94%a
90%a
†Deceased on November 23, 2019. This paper is
OH
36 dedicated to the memory of Prof. Dr. Hidetoshi Yamada.
37
PMBO
HO
OBn
MeO2C
OH
38 Supporting
Information
is
available
on
O
39 http://dx.doi.org/10.1246/cl.******.
6g
43%
6h
19%
6i
64%
40 References and Notes
OH
HO
OPG
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
1
2
3
4
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6j: PG = TBS (92%)
6k: PG = MOM (81%)
6l: PG = Ac (75%)
6m
89%
H
H
O
O
H
H
HO
N
HO
6n
46%
6o
77%
1
2
Scheme 4. Substrate scope. a1.5 equiv. MBn-TCAI (1) was used.
5
3
4
5
6
7
8
9
The Zn(OTf)2/Et2O reaction system enabled the
introduction of Bn and PMB protection (Scheme 5). Thus,
treatment of 6a with Bn-TCAI or PMB-TCAI and catalytic
Zn(OTf)2 in Et2O provided the corresponding protected
compounds 8 and 9 in 81% and 87% yields, respectively.
Bn protection required reflux conditions for the reaction to
proceed efficiency. This is the first report of these reaction
6
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10 conditions for Bn/PMB protection of alcohols. Zn(OTf)2 is a
11 stable and non-fuming solid; therefore, for Bn/PMB
12 protection, the proposed method is safer and easier than
13 reactions using TfOH, which is a fuming liquid acid.7b, 7e–f, 21
Bn-TCAI (1.2 equiv.)
Zn(OTf)2 (0.1 equiv.)
OBn
Et2O, reflux, 24 h
81%
8
9
6a
8
9
K. Ikeuchi, K. Murasawa, K. Ohara, H. Yamada, Org. Lett. 2019,
21, 6638.
PMB-TCAI (1.2 equiv.)
Zn(OTf)2 (0.1 equiv.)
OPMB
There is one reaction example for alcohol protection by using
MBn-TCAI (1); however, the detail reaction conditions and the
result are not noted. See: J. W. Liebeschuetz, W. A. Wylie, B.
Waszkowycz, C. W. Murray, A. D. Rimmer, P. M. Welsh, S. D.
Jones, J. M. E. Roscoe, S. C. Young, P. J. Morgan, U.S. Pat.
Appl. US 2002/0055522, 2002.
Et2O, rt, 24 h
87%
14
15 Scheme 5. Application of the Zn(OTf)2/Et2O reaction system to Bn-
16 TCAI and PMB-TCAI.
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82 12 Selected papers for the use of TMSOTf: a) C. Dong, D. K. Reilly,
17
In summary, we established a simple preparation
18 method for MBn-TCAI (1) and developed an MBn-
19 protection method for various alcohols by using 1.
83
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3
4
5
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6
7
8
9
10
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13
14
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16
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19
20
21
22
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25
26
27
28
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31
32
33
34
35
36
Oliveira Rezende J., J.-M. Campagne, L. C. Dias, R. M. de
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37 18 Excess use of MBn-TCAI (1) often caused the side reaction.
1
38
39
Separation of 3 and by-products 4a/4b was difficult. For the H
NMR spectrum of the mixture, see the supporting information.
40 19 Y. Masui, N. Chino, S. Sakakibara, Bull. Chem. Soc. Jpn. 1980,
41
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43
45
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