Regioselective lithiation of benzyl imidazole: Synthesis and evaluation of new organocatalysts for trans-diol functionalization.

Article abstract of DOI:10.1080/00397911.2019.1655766

Benzyl imidazole was successfully lithiated using n-BuLi at ?78 °C and verified by deuterium incorporation. The chemical reaction of the lithiated benzimidazole was explored with a series of different electrophiles. This approach was utilized to synthesiz

Full text of DOI:10.1080/00397911.2019.1655766

Synthetic Communications
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Regioselective lithiation of benzyl imidazole:
Synthesis and evaluation of new organocatalysts
for trans-diol functionalization.
Mohamed El-Mansy, Ankan Ghosh, Paul Ha-Yeon Cheong & Rich Carter
To cite this article: Mohamed El-Mansy, Ankan Ghosh, Paul Ha-Yeon Cheong & Rich
Carter (2019): Regioselective lithiation of benzyl imidazole: Synthesis and evaluation of
new organocatalysts for trans-diol functionalization., Synthetic Communications, DOI:
10.1080/00397911.2019.1655766
To link to this article: https://doi.org/10.1080/00397911.2019.1655766
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https://doi.org/10.1080/00397911.2019.1655766
Regioselective lithiation of benzyl imidazole: Synthesis and
evaluation of new organocatalysts for trans-diol
functionalization.
Mohamed El-Mansya,b , Ankan Ghosha, Paul Ha-Yeon Cheonga, and Rich
Cartera
b
aChemistry Department, Oregon State University, Corvallis, OR, USA; Organometallic and
Organometalloid Chemistry Department, National Research Centre, Cairo, Egypt
ABSTRACT
ARTICLE HISTORY
Benzyl imidazole was successfully lithiated using n-BuLi at ꢀ78 ꢁC
and verified by deuterium incorporation. The chemical reaction of
the lithiated benzimidazole was explored with a series of different
electrophiles. This approach was utilized to synthesize new anti and
syn diphenyl organocatalysts for trans-diol functionalization.
Received 27 June 2019
KEYWORDS
Benzimidazole; diol
functionalization; lithiation;
organocatalysis
GRAPHICAL ABSTRACT
Introduction
Imidazole derivatives are significant compounds that possess a wide array of biological
activities such as antibacterial,[1,2] anti-inflammatory, analgesic,[3,4] antitubercular,[5]
anti-depressant,[5] anti-cancer[6,7] and anti-viral activity.[8] In addition, these scaffolds
have been shown to have application in organocatalysis by Tan and coworkers for the
desymmetrization cis 1,2-diols,[9–11] which is an attractive approach over the traditional
methods for mono protection of diols.[12–14] wherein Tan’s catalyst system, an aza-
orthoformate moiety acts as substrate binding site tethered to the imidazole moiety
which acts as a base for deprotonation.
A variety of synthetic approaches have been developed to access biological and/or
catalytically relevant imidazole compounds – including lithiation of the benzylic pos-
ition of the imidazole moiety.[15–17] Herein, we report the selective lithiation of
1-methyl-2-benzyl imidazole and its subsequent reactivity with benzaldehyde and an
CONTACT Rich Carter
rich.carter@oregonstate.edu
Chemistry Department, Oregon State University, 2900
Southwest Campus Way, Corvallis 97331, OR, USA.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Oregon State University

2
M. EL-MANSY ET AL.
Ellman chiral sulfinimine for the purpose of generating new catalysts for selective func-
tionalization of trans-1,2-diols using scaffold catalysis.[9]
Results and discussion
We first set out to confirm the effectiveness of selective benzylic lithiation on our key
substrate 1 (Scheme 1). Lithiation of 1-methyl-2-benzyl imidazole[18] (1) was achieved
by using n-BuLi as a base at ꢀ78 ꢁC. The lithiated complex 2 was quenched with
CD3OD to confirm the lithiation exclusively takes place at the benzylic methylene in
compound 3 without having any reaction at the C-5 position. In this study, 87% deuter-
ium incorporation was observed as measured by integration of the residual benzyl pro-
1
tons in the H NMR spectrum.
To explore the electrophilic addition to the generated lithium complex 2, benzalde-
hyde (4) was added at ꢀ78 ꢁC allowing to warm gradually to room temperature
(Scheme 2). The reaction proceeded diastereoselectively to give the syn alcohol 5 and
anti-alcohol 6 products as the minor and major stereoisomers respectively. The relative
stereochemistries of both 5 and 6 were determined by X-ray crystallographic analysis
(Fig. 1).
With this newfound understanding of the fundamental reactivity and diastereoselec-
tivity of this carbanion 2, we became intrigued about the possibility of applying this
technology to expand the Tan catalyst systems.[9–11] These new scaffolds would contain
an additional stereogenic center and carbon spacer between the imidazole and the
orthoaminoformate (e.g., compound 10) (Scheme 3). This additional stereochemistry
and spacer found in compound 10 showed preliminary computational evidence of
expanded catalytic activity in the Tan desymmetrization/deracemization of polyols.
Initial attempts to synthesize catalyst 10 were made through the addition of lithiated
compound 2 to imine 11 (Scheme 4). Previously, imine 11 has been used for diastereo-
selective additions.[19–22] A variety of different conditions were screened – including
the use of Lewis acids such as TiCl4 and BF3ꢂEt2O. Unfortunately, we did not observe
Scheme 1. Regioselective lithiation of 1 and deuterium incorporation product (3).
Scheme 2. Addition of benzaldehyde to lithiated complex 2.

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3
successful coupling under any of these conditions – instead, the imine 11 was recovered
intact. One possible explanation for this problematic reactivity is the steric hinderance
caused by the branching on the nitrogen atom of imine 11. We speculated that place-
ment of an electron-withdrawing moiety on the imine might increase its overall reactiv-
ity and circumvent this reactivity issue.
Figure 1. ORTEP of 5 and 6.
Scheme 3. Tan’s catalyst and our modified version.
Scheme 4. Unsuccessful route.

4
M. EL-MANSY ET AL.
Scheme 5. Synthesis of anti and syn-diphenyl amines 16, 17.
Figure 2. ORTEP of 14 and 15.
The successful application of the Ellman sulfinimine.[23–25] (tert-(S)-butylsulfinimine
13) to the diastereoselective addition of the lithiated imidazole 2 is shown in Scheme 5.
Two chromatographically separable diastereomers 14 and 15 (1:1 dr) were observed in
this transformation – with a single stereochemistry at the benzylic amine position
attached to the chiral sulfinamine (denoted with an a notation on the structure) and an
equal mixture at the benzylic imidazole position (denoted with a b notation on the
structure). These diastereomers 14 and 15 were assigned based on single-crystal X-ray
crystallographic analysis (Fig. 2). Hydrolysis of 14 and 15 in methanolic hydrochloride
solution gave the corresponding amine compounds 16 and 17 (Scheme 5). The coupling
constants for the two adjacent benzylic protons in the anti-diphenyl amine 16

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SYNTHETIC COMMUNICATIONSV
5
Scheme 6. Synthesis of TBS protected ketone 20.
OH
OH
i-Pr
Ph
i-Pr
HN
HN
i) 17, Ti(i-PrO4); THF
ii) NaBH3CN; MeOH
iii) HCl, MeOH
i) 16, Ti(i-PrO4); THF
ii) NaBH3CN; MeOH
iii) HCl, MeOH
OTBS
O
Ph
N
N
N
N
Ph
Ph
i-Pr
14
Separable mixture
23 (less polar)
24 (more polar)
Separable mixture
21 (less polar)
22 (more polar)
DMF-DMA;
MeOH
DMF-DMA;
MeOH
O
i-Pr
O
i-Pr
Ph
N
O
N
O
N
Ph
N
N
Ph
N
Ph
25 (less polar)
26 (more polar)
27 (less polar)
28 (more polar)
Scheme 7. Synthesis of oxazolidine catalysts 25–28.
(J ¼ 9.2 Hz) and syn-diphenyl amine 17 (J ¼ 7.5 Hz) is consistent with the literature
data[26] and X-ray results for 14 and 15.
With the new amino imidazoles 16 and 17 now accessible, we shifted our focus to
the remainder of the scaffold needed for the potential catalyst 10 (Scheme 6).
Synthesis of the required precursor began with the known alkene 18[27] by dihydroxyla-
tion to provide aldehyde 19. Grignard addition of isopropylmagnesium bromide to alde-
hyde 19 followed by oxidation of the secondary alcohol cleanly provided the desired
ketone 20.
Combination of the amino imidazoles 16/17 with ketone 20 is shown in Scheme 7.
Reductive amination of ketone 20 with amine 16 followed by silyl deprotection resulted
in two separable alcohols 21 and 22 in an equal (1:1 dr) mixture. In a similar fashion,
reductive amination of ketone 20 with epimeric amine 17 followed by silyl deprotection
gave the corresponding alcohols 23 and 24 (1:1 dr). The identity of the newly form ster-
eocenter in compounds 21–24 from this addition was not determined. Introduction of
the aza-orthoformate moiety by the reaction of these alcohols 21–24 with DMF-DMA
gave the corresponding catalysts 25–28. As was found in Tan’s work, these compounds
proved unstable when exposed to small amounts of moisture (even air) which

6
M. EL-MANSY ET AL.
Table 1. Preliminary Exploration of Catalytic Activity of Compounds 25–28.
Entry No.
n
R
Cat. Load %
Temp. (oC)
Yield
ee%
1
2
3
4
5
6
7
8
0
1
0
1
0
1
0
0
0
0
1
1
1
1
TBS
0
0
0
0
0
0
4
4
rt
rt
4
6
25
6
72
91
86
4
47
3
TBS
TBS
TBS
Ac
Ac
4
TBS
TBS
TBS
TBS
TBS
TBS
TBS
TBS
10 mol.% 25
10 mol.% 26
10 mol.% 27
10 mol.% 28
10 mol.% 25
10 mol.% 26
10 mol.% 27
10 mol.% 28
rt
rt
rt
rt
4
4
4
ND
0
ND
ND
0
0
ND
ND
9
10
11
12
13
14
5
18
22
21
24
4
hydrolyzed the aza-orthoformate moiety. Consequently, the catalysts were used crude in
the kinetic resolution of trans-diols.
These generated catalysts were evaluated in the selective trans-diol functionaliza-
tion[11] as shown in Table 1. We first explored a selective silylation using TBSCl. We
confirmed that no appreciable yield was observed in the absence of catalysts 25–28 at
4 ꢁC (Entries 1–2). Similar behavior was observed for the 5-membered diol 7 at room
temperature (Entry 3); however, the corresponding six-membered diol 29 did provide
72% yield of the mono-protected product 30 (Entry 4). Acylation proved too reactive
on either diol, as the blank reaction proceeded easily at 4 ꢁC (Entries 5–6). With this
knowledge, we focused our catalyst screening on the silylation at 4 ꢁC with the 5-mem-
bered diol 7. Interestingly, catalyst (26) showed a differential reactivity for trans-cyclo-
pentanediol 7 over the 6-membered trans-diol 29 with 47% yield (Entry 8). No
enantioselectivity was observed in this transformation based on derivatization with
Mosher’s acid. A similar analysis of the product from the 6-membered diol 30 shown
no enantioselectivity (Entries 11 and 12).
Conclusions
In summary, a preliminary exploration into the fundamental reactivity of lithiated ben-
zyl imidazoles has been disclosed. Selective lithiation takes place using n-BuLi at ꢀ78 ꢁC
in dry THF. The electrophilic addition to benzaldehyde proceeds in low diastereoselec-
tivity (circa 2:1 dr) favoring the anti-addition product. Addition to an imine
required additional activation by a sulfinimine function. Derivatization of the imid-
azole-containing amines into Tan-like catalysts was accomplished. Modest catalytic

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7
activity was realized for selective protection for the trans-cyclopentanediol; however, no
enantioselectivity was observed.
Experimental details
General
Infrared spectra were recorded neatly unless otherwise indicated and are reported in
1
cm21. H NMR spectra were recorded in deuterated solvents and are reported in ppm
relative to tetramethylsilane and referenced internally to the residually protonated solv-
ent. 13C NMR spectra were recorded in deuterated solvents and are reported in ppm
relative to tetramethylsilane and referenced internally to the residually protonated solv-
ent. Routine monitoring of reactions was performed using EM Science DC-Alufolien sil-
ica gel, aluminum-backed TLC plates. Flash chromatography was performed with the
indicated eluents on EM Science Gedurian 230–400 mesh silica gel. Air and/or mois-
ture-sensitive reactions were performed under usual inert atmosphere conditions.
Reactions requiring anhydrous conditions were performed under a blanket of argon, in
glassware dried in an oven at 120 ꢁC or by flame, then cooled under argon. Dry THF
and DCM were obtained via a solvent purification system. All other solvents and com-
mercially available reagents were either purified via literature procedures or used with-
out further purification.
Deuterated benzylimidazole 3
To a stirred solution of benzylimidazole 1 (25 mg, 0.145 mmol) in THF (0.95 mL) at
ꢀ78 ꢁC was added sequentially n-BuLi (0.07 mL, 0.174 mmol, 2.5 M in hexanes). After
1 h, CD3OD (0.006 mL, 5.8 mg, 0.291 mmol) was added. After 2 h, the cold bath was
removed and the reaction mixture was stirred at room temperature. The reaction mix-
ture was concentrated in vacuo and the percentage of deuterium incorporation was
1
determined to be 87% using crude H NMR.
1
Supporting Information: Full experimental detail, H and 13C NMR spectra. This
material can be found through the “Supplementary Content” section of this
article’s webpage.
Acknowledgments
ꢀ
Prof. Claudia Maier (OSU) and Jeff Morre (OSU) are acknowledged for mass spectra data. Drs.
Ryne Johnston and Maduka Ogba are acknowledged for the early work on the computational
analysis of the Tan chemistry.

8
M. EL-MANSY ET AL.
Disclosure statement
No competing financial interests have been declared.
Funding
Financial support provided by the National Science Foundation [CHE-1665246] and Oregon
State University.
ORCID
Mohamed El-Mansy
http://orcid.org/0000-0001-9701-6516
Rich Carter
http://orcid.org/0000-0002-9100-1791
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