KIO4-mediated Selective Hydroxymethylation/Methylenation of Imidazo-Heteroarenes: A Greener Approach

Article abstract of DOI:10.1002/anie.202104503

Herein, we report a KIO₄-mediated, sustainable and chemoselective approach for the one-pot C(sp²)?H bond hydroxymethylation or methylenation of imidazo-heteroarenes with formaldehyde, generated in situ via the oxidative cleavage of ethylene glycol or glycerol (renewable reagents) through the Malaprade reaction. In the presence of ethylene glycol, a series of 3-hydroxymethyl-imidazo-heteroarenes was obtained in good to excellent yields. These compounds are important intermediates to access pharmaceutical drugs, e.g., Zolpidem. Furthermore, by using glycerol, bis(imidazo[1,2-a]pyridin-3-yl)methane derivatives were selectively obtained in good to excellent yields.

Full text of DOI:10.1002/anie.202104503

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Accepted Article
Title: KIO4-mediated selective hydroxymethylation /methylenation of
imidazo-heteroarenes: a greener approach
Authors: Marcelo Straesser Franco, Sumbal Saba, Jamal Rafique, and
Antonio Luiz Braga
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10.1002/anie.202104503
Angewandte Chemie International Edition
RESEARCH ARTICLE
KIO4-mediated selective hydroxymethylation /methylenation of
imidazo-heteroarenes: a greener approach
Marcelo Straesser Franco,[a] Sumbal Saba,[b] Jamal Rafique,*[c] Antonio Luiz Braga*[a][d]
[a]
M. S. Franco, Prof. Dr. A. L. Braga
Departamento de Química
Universidade Federal de Santa Catarina - UFSC
Florianópolis, 88040-900, SC-Brazil
E-mail: braga.antonio@ufsc.br; http://labselen.ufsc.br
Prof. Dr. S. Saba
Instituto de Química
Universidade Federal de Goiás - UFG
Goiânia, 74690-900, GO-Brazil
[b]
[c]
Prof. Dr. J. Rafique
Instituto de Química
Universidade Federal do Mato Grosso do Sul - UFMS
Campo Grande, 79074-460, MS-Brazil
E-mail: jamal.chm@gmail.com; jamal.rafique@ufms.br
Prof. Dr. A. L. Braga
[d]
Department of Chemical Sciences
Faculty of Science, University of Johannesburg,
Doornfontein, 2028, South Africa
Abstract: Herein, we report a KIO4-mediated, sustainable and
chemoselective approach for the one-pot C3(sp2)-H bond
hydroxymethylation or methylenation of imidazo-heteroarenes with
formaldehyde, generated in situ via the oxidative cleavage of ethylene
glycol or glycerol (renewable reagents) through the Malaprade
reaction. In the presence of ethylene glycol,
a series of 3-
hydroxymethyl-imidazo-heteroarenes was obtained in good to
excellent yields. These compounds are important intermediates to
access pharmaceutical drugs, e.g., Zolpidem. Furthermore, by using
glycerol, bis(imidazo[1,2-a]pyridin-3-yl)methane derivatives were
selectively obtained in good to excellent yields.
Figure 1. IP-based commercial drugs and biologically active compounds.
Traditionally, hydroxymethylation reactions involve the
addition of nucleophilic carbon-centered radicals, generated from
methanol, to protonated N-heteroarenes via the Minisci
reaction[10] or the via nucleophilic addition of organometallic
species (organolithium or Grignard reagents) to formaldehyde or
paraformaldehyde.[11] Alternatively, the reduction of carbonyl
groups, such as aldehydes, esters or carboxylic acids, also leads
to this functionality.[12-13] In addition, there are a few reports of
studies involving photoredox catalysis or the use of transition
metal catalysts.[14-15]
Despite the biological and pharmaceutical importance of the
IP core and hydroxymethylation reactions, to the best of our
knowledge, there are only two methods in the literature which
describe the hydroxymethylation of IPs: (i) the first approach
involves Vilsmeier-Haack formylation followed by reduction of the
formyl group to provide the corresponding alcohol (Scheme 1, eq.
I),[16a] and (ii) the second approach involves the reaction of IP with
excess formalin (aqueous formaldehyde solution) in a solution of
acetic acid and sodium acetate (Scheme 1, eq. II).[16b]
Introduction
N-heteroarenes are of great pharmacological, economic
and industrial importance.[1] In particular, imidazo[1,2-a]pyridines
(IPs), which are comprised of a typical and privileged scaffold, are
widely used in the pharmaceutical industry due to their diverse
biological properties.[2] Furthermore,
a
large number of
commercially available pharmaceutical drugs have IP derivatives
as an active ingredient, e.g., Zolpidem (sedative and hypnotic),
Necopidem (anesthetic), Saripidem (anxiolytic), Minodronic acid
(for the treatment of osteoporosis), SCH28080 (H+,K+-ATPase
inhibitor) and GSK812397 (potential activity for treating HIV
infections) (Figure 1). [3-5] Also, IP derivatives can be applied as
charge transporters in optoelectronics and material sciences.[6]
Therefore synthesis and functionalization of the IP core has
gained a raising attention.[2, 7-8]
On the other hand, reactions involving hydroxymethylation
are among the most important approaches in synthetic organic
chemistry, and are widely applied in the synthesis of many natural
products, pharmaceuticals and biologically active compounds.[9]
Moreover, the hydroxymethyl group (-CH2OH) is among the most
widely used intermediates to access attractive target/lead
compounds.
Both of these methodologies are of great interest. However,
a simple and straightforward approach that could be applied to a
broad range of substrates which makes use of stable bench
reagents is highly desirable.
1
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10.1002/anie.202104503
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RESEARCH ARTICLE
As part of our research interest in designing and developing
sustainable processes, as well as the C(sp2)-H functionalization
of biologically-relevant heteroarenes,[17-18] herein, we describe, for
the first time, a chemoselective and environmentally benign
protocol for the hydroxymethylation of imidazo-heteroarenes via
Malaprade oxidation. The reaction involves the use of IPs and
ethylene glycol as substrates and KIO4 as the oxidant, in water.
In addition, the reaction has been successfully applied to other
imidazo-heteroarenes (Scheme 1, eq. III). Furthermore, the use
of glycerol instead of ethylene glycol results in another interesting
class of compounds, bis(imidazo[1,2-a]pyridin-3-yl)methane
(dimeric product). In view of this, we optimized a new, more
efficient, sustainable and transition metal-free methodology for
the methylenation of IPs.
(entries 17 and 18). Decreasing the amounts of 2a and KIO4
resulted in 3a in only 59% yield (entry 19). An increase in the
stochiometric quantity of the reagents did not result in any
improvement in the yield of 3a (entry 20 vs 15).
With the best reaction parameters in hand (Table S1-ESI,
Pg S3), entry 15), the generality and scope of the
hydroxymethylation of IPs 2 were investigated (Table 1).
Initially, the mono-substituted IPs 1 with electron-donating
groups (EDGs) on the pyridyl ring as well as on the C2 aryl ring
were tested, where the corresponding hydroxymethylated
products (3a-h) were obtained in good to excellent yields (81-
96%). In the case of electron-withdrawing groups (EWGs) on the
C2 aryl ring (cyano and sulfonyl groups), the corresponding
products (3i and j) were obtained in low yields (20% and 25%,
respectively), while halogen-substituted IPs 1 resulted in the
respective products (3k-m) in moderate to good yields (42-64%).
In the case of IP where C2 was substituted with a heteroaryl group,
the desired product 3n was obtained with 63% yield while IP with
2-naphthyl group, resulted in the product 3o with 44% yield. When
di-substituted IPs 1 (substituent on the C2 aryl ring and pyridine
ring) were tested, a similar trend was observed.
Table 1. Synthesis of imidazo[1,2-a]pyridin-3-yl)methanol derivatives.[a, b]
Scheme 1. Methods for hydroxymethylation of imidazo-heteroarenes.
Results and Discussion
For the optimization of the hydroxymethylation of imidazo-
heteroarenes, 2-phenylimidazo[1,2-a]pyridine (1a, 0.3 mmol) and
ethylene glycol (2a, 1.0 molar equiv., a renewable reagent)[19]
were employed as model substrates and 0.5 mL of water was
used as a solvent.[20] Initially, the reaction was carried out at 50 °C
for a duration of 1 h in the presence of 1.0 molar equiv. oxidant
(NaIO4, KIO4, NaIO3 and KIO3, Table S1-ESI, entries 1-4). NaIO4
and KIO4 presented almost similar results, however we selected
KIO4 for further studies, considering its effectiveness, such as,
ease of handling.
In the next step, the reaction temperature was optimized
(entries 5-10) and 90 °C was found to be ideal for this
transformation, affording hydroxymethylated product 3a in 67%
isolated yield (entry 8). Increasing the temperature above 90 °C
resulted in a decrease in the yield of 3a and the formation of bis(2-
phenylimidazo[1,2-a]pyridin-3-yl)methane 4a in 9% yield (entry 4).
The formation of product 4a can be attributed to the condensation
of product 3a with substrate 1a at higher temperature.
The influence of the reaction time applied in this
transformation was then monitored (entries 11-16), and the
optimized reaction time was found to be 6 h (entry 15) for the
hydroxymethylation of 1a.
Lastly, the use of stochiometric amounts of 2a and KIO4 was
evaluated. In the absence of 2a or KIO4, no product was formed
[a] Reaction conditions: 1 (0.3 mmol), 2a (1.0 molar equiv.), KIO4 (1.0 molar
equiv.), distilled water (H2O, 0.5 mL), 90 °C, 6 h. [b] Isolated yield based on 1.
[c] Reaction time: 24 h.
2
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To further demonstrate the synthetic application of the
hydroxymethylated product, we propose the formal synthesis of
Zolpidem (commercial drug; sedative and hypnotic),[3a] Scheme
3A. This one-pot approach involves in situ transformation of the
hydroxymethylated IP 3p to the respective chloride from the
reaction with thionyl chloride (SOCl2), and subsequent reaction
with dimethylamine to give the aminomethylated IP 5 with very
good yield (82%). Compound 5 is the key intermediate in
Zolpidem synthesis, as reported by Padi and collaborators,[21]
thus, we performed its direct synthesis from IP 1p, without the
need for the preparation of 3p. In this procedure, IP 1p was
reacted with N,N-dimethyl amine under the standard conditions
(Scheme 3B). Despite omitting one step, we could obtain the key
intermediate 5 by this direct approach, although in lower yield.
In the case of EDGs, the corresponding products (3p-3r)
were obtained in good to excellent yields (83-95%), while 3s-t
were obtained in moderate yields in the case of EWG groups.
Finally, with unsubstituted IP, the desired product 3u was isolated
in excellent yield.
To verify the synthetic versatility of this methodology, the
reaction scope was further extended to structurally different N-
heteroarene compounds, i.e., substituted imidazo[1,2-
a]pyrimidines and imidazo[2,1-b]thiazoles (Table 2), under the
optimized reaction conditions. The use of imidazo[1,2-
a]pyrimidines resulted in the corresponding hydroxymethylated
products 3aa-3ac in yields of 23-45%, while imidazo[2,1-
b]thiazoles afforded 3ba-3bc in moderate to good yields (51-75%).
Table 2. Substrate scope of N-heteroarenes.[a][b]
[a] Reaction conditions: (A) 3p (0.2 mmol), CH2Cl2 (2 mL), SOCl2 (2.0 molar
equiv.), room temperature, 6 h. (II) CH3CN (2 mL), (CH3)2NH (30% w/v aqueous
solution, 1 mL), room temperature, 18 h. (B) 1p (0.3 mmol), 2a (1.0 molar equiv.),
KIO4 (1.0 molar equiv.), (CH3)2NH (30% w/v aqueous solution, 5.0 molar equiv.),
distilled water (H2O, 0.5 mL), 90 °C, 6 h. [b] Isolated yield based on 3p. [c]
Isolated yield based on 1p.
[a] Reaction conditions: 1 (0.3 mmol), 2a (1.0 molar equiv.), KIO4 (1.0 molar
equiv.), distilled water (H2O, 0.5 mL), 90 °C, 6 h. [b] Isolated yield based on 1.
[c] Reaction time: 24 h.
Scheme 3. Formal synthesis of Zolpidem.
Following
the
success
of
the
KIO4-mediated
The hydroxymethylated product could be used in the
synthesis of a number of interesting structures. To illustrate the
synthetic utility of hydroxymethylated IPs, 3a was used in the
formation of a sulfenylated product in a one-pot approach,
resulting in 7 with 97% yield (Scheme 2, eq. I). This approach
motivated us to synthesize the azide-containing product, leading
to 8 with 95% yield (Scheme 2, eq. II). Subsequently, compound
8 was used in the azide-alkyne cycloaddition (CuAAC) click
reaction (with phenyl acetylene 9) to obtain triazole 10 with 66%
yield (Scheme S9-ESI, Pg S13).
hydroxymethylation of imidazoheteroarenes, we tested different
sources of hydroxymethyl groups 2b-f (Table S2-ESI, Pg S4).
Reactions with methanol 2b or polyethylene glycol 2f
produced a mixture of products 3a and 4a, which were obtained
in low yields (Table S2-ESI, Pg S4, entries 1 and 5). Surprisingly,
when glycerol 2c was used, the product bis(2-phenylimidazo[1,2-
a]pyridin-3-yl)methane 4a was obtained with 85% yield, while the
hydroxymethylated product 3a was obtained with 7% yield (entry
2). In the case of sucrose 2d or paraformaldehyde 2e, there was
no formation of products 3a or 4a (entries 3 and 4).
This finding was of interest since, in the recent literature,
there are only a few reports that describe the synthesis of
bis(imidazo[1,2-a]pyridin-3-yl)methane 4 via methylenation of the
IP core.[22] Despite their good features, some of these methods
have limitations in terms of sustainability, such as the non-
renewable methylene sources (e.g., DMSO and DMA), use of
organic solvents, low atom economy, very high temperature and
use of a transition metal catalyst.
The results obtained (Table S2-ESI, Pg S4), entry 2)
motivated us to further explore this more sustainable approach to
the methylenation of IP derivatives 1 using 0.5 molar equiv. of
glycerol 2c (a renewable reagent)[23] as a methylene source in
water (0.5 mL), as seen in Table S3-ESI, Pg S5. For this
transformation, we selected 1a as the standard substrate.
Initially, we varied the temperature (Table S3-ESI, Pg S5,
entries 1-3) and found that 100 °C was most appropriate for this
transformation, resulting only in product 4a, with 91% yield (entry
Reaction conditions: (I) i: 3a (0.2 mmol), CH2Cl2 (2 mL), SOCl2 (2.0 molar equiv.),
room temperature, 6 h. ii: CH3CN (2 mL), 6 (2.0 molar equiv.), 75 °C, 24 h. (II)
i: 3a (1 mmol), CH2Cl2 (5 mL), SOCl2 (2.0 molar equiv.), room temperature, 6 h.
ii: CH3CN (5 mL), (CH3CH2)3N (2.1 molar equiv.), NaN3 (2.0 molar equiv.), room
temperature, 24 h. [a] Isolated yield based on 3a.
Scheme 2. Synthetic applications for hydroxymethylation products.
3
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10.1002/anie.202104503
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RESEARCH ARTICLE
2). Subsequently, reducing the reaction time was evaluated
(entries 4 and 5). However, with a shorter reaction time, a mixture
of products 3a and 4a were obtained, with 4a in lower yields.
The stoichiometry of the reagents, i.e., glycerol and
potassium periodate, was then evaluated (entries 6-8). It was
observed that increasing the amounts of 2c and KIO4 resulted
with 4a, in 63% yield, as well as 3a, with 11% yield (entry 6). In
the absence of reagents 2c or KIO4 there was no reaction (entries
7 and 8).
After ascertaining the best reaction parameters (Table S3-
ESI, Pg S5, entry 2), the generality and scope of this reaction in
the
synthesis
of
bis(imidazo[1,2-a]pyridin-3-yl)methanes
derivatives 4 from IPs 1 and glycerol 2c were investigated (Table
3). There was some influence of the electronic effect on the
reaction. In general, IPs 1 with an EDG (e.g., -CH3 and -OCH3)
afforded the desired products in excellent yields compared to the
EWG substituent. Furthermore, we also tested the heteroaryl
substituted IP; to our delight, the reaction resulted in the product
4f with 57% yield.
[a] Reaction conditions: (I) 1a (7 mmol), 2a (1.0 molar equiv.), KIO4 (1.0 molar
equiv.), distilled water (H2O, 12 mL), 90 °C, 6 h; (II) 1a (7 mmol), 2c (0.5 molar
equiv.), KIO4 (1.0 molar equiv.), distilled water (12 mL), 100 °C, 6 h. [b] Isolated
yield based on 1a.
Scheme 4. Schematic of the gram-scalable reaction.
Initially, we focused on the hydroxymethylation reaction
(Scheme 5, eq. I-V) and there was no negative effect when the
standard reaction was performed under oxygen or argon
atmosphere (Scheme 5, eqs. I and II). The results obtained
indicate that atmospheric oxygen does not actively contribute to
this transformation. A radical inhibitor did not hamper the reaction
and 3a was obtained with 85% yield (Scheme 5, eq. III). Thus, the
possibility of a radical pathway was disregarded.
Table 3. Synthesis of bis(imidazo[1,2-a]pyridin-3-yl)methane derivatives.[a, b]
[a] Reaction conditions: 1a (0.3 mmol), 2c (0.5 molar equiv.), KIO4 (1.0 molar
equiv.), distilled water (0.5 mL), 100 °C, 6 h. [b] Isolated yield based on 1.
The industrial importance and potential applications of these
greener protocols were investigated in scale-up reactions at the
gram scale (Scheme 4), using IP 1a as the reagent under the
optimized conditions. In the case of ethylene glycol, the desired
product 3a was isolated with no significant decrease in yield
(Scheme 4, eq. I). Similarly, in the case of glycerol, the
bis(imidazo[1,2-a]pyridin-3-yl)methane was obtained with 80%
isolated yield (eq. II). Thus, these protocols can be used as robust
methodologies for the gram-scale synthesis of the respective
products, which are precursors for important bioactive molecules.
Considering the interesting features of these new coupling
reactions, a number of control experiments were conducted
(Scheme 5), aimed at better understanding the mechanism
involved in the KIO4-mediated C(sp2)-H functionalization of
imidazoheteroarenes.
[a] Reaction conditions: 1a (0.3 mmol), 2a (1.0 molar equiv.), KIO4 (1 .0 molar
equiv.), distilled water (0.5 mL), 90 °C, 6 h. [b] 1a (0.3 mmol), 2c (0.5. molar
equiv.), KIO4 (1.0 molar equiv.), distilled water (0.5 mL), 100 °C, 6 h. [c] Oxygen
atmosphere. [d] Argon atmosphere. [e] TEMPO (2.0 molar equiv.). [f] NaHCO3
(1.0 molar equiv.). [g] HCO2H (1.0 molar equiv.). [h] 1a (0.15 mmol), 3a (1.0
molar equiv.), base (NaHCO3, 1.0 molar equiv.), distilled water (0.5 mL), 100 °C,
6 h. [i] 1a (0.15 mmol), 3a (1.0 molar equiv.), acid (HCO2H, 1.0 molar equiv.),
distilled water (0.5 mL), 100 °C, 6 h. -: No product detected.
Scheme 5. Control experiments.
When the standard reaction was performed in the presence
of NaHCO3 as a base (Scheme 5, eq. IV), the reaction showed
complete tolerance. Thus, the possibility of any acidic species
being involved in this transformation can be neglected. However,
when the reaction was carried out in the presence of formic acid,
the product 3a was obtained with only 19% yield. Interestingly, in
this case, the dimeric product 4a was isolated with 68% yield
(Scheme 5, eq. V), indicating that the formation of 4a is favored
4
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10.1002/anie.202104503
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RESEARCH ARTICLE
under acidic conditions. Subsequently, similar control
experiments were conducted for the methylenation reaction
(Scheme 5, eq. VI-XII). In the presence of an oxygen atmosphere
or under inert conditions, there was no significant effect (Scheme
5, eq. VI and VII), highlighting the non-relevance of atmospheric
oxygen. Similarly, the reaction proceeded normally in the
presence of TEMPO, affording the product 4a with 80% yield (eq.
VIII), indicating an ionic pathway for the reaction. Surprisingly,
when the standard reaction was carried out in the presence of 1
molar equiv. of base NaHCO3, there was complete inhibition of
the formation of product 4a; however, in this case, compound 3a
was obtained with 56% yield (eq. IX). When the standard reaction
was subsequently performed together with 1.0 molar equiv. of
formic acid, the dimeric product 4a was isolated with no significant
variation in the yield (Scheme 5, eq. X). Both these results
demonstrate that the formation of product 4a is dependent on
acidic conditions. In order to observe the role of the
hydoxymethylated product in the dimerization reaction, we
performed a standard reaction using 1 molar equiv. of 3a in the
presence of 1 molar equiv. of 1a under both basic and acidic
conditions. In the case of basic conditions (NaHCO3), there was
no formation of product 4a (eq. XI). However, when formic acid
was used, product 4a was obtained with 93% yield (eq. XII). The
results of these experiments demonstrate the importance of
formic acid in this transformation.
Based on the results of the control experiments (Scheme 5),
plausible mechanistic pathways for the hydroxymethylation and
methylenation of imidazoheteroarenes could be proposed
(Scheme 6). In the case of the hydroxymethylation of
imidazoheteroarenes (Scheme 6, Pathway A), initially, oxidative
cleavage of ethylene glycol (II) by KIO4 results in the formation of
formaldehyde (III). Subsequently, nucleophilic attack of IP (I) to
formaldehyde (III) leads to species IV, the hydroxymethylated
product (V) is obtained through intramolecular proton transfer
(IPT).
In the methylenation reaction (Scheme 6, Pathway B),
formaldehyde (III) and formic acid (VII) are generated in situ via
oxidative cleavage of glycerol (VI) by KIO4. The addition of IP (I)
to formaldehyde (III) forms the hydroxymethylated product (V).
Next, the reaction of the hydroxymethylated IP (V) with formic acid
(VII) results in the formation of the species VIII, which generates
species IX, detected during MS analysis.[24] Subsequently, the
nucleophilic attack of C3 of another IP (I) to the intermediate (IX),
results in the bis(imidazo[1,2-a]pyridin-3-yl)methane (X).
Scheme 6. Proposed mechanisms.
resulted in the methylenated products. For the methylenation
reaction, the presence of formic acid, formed during the oxidative
cleavage of glycerol catalyzes this transformation. Furthermore,
both methods could be applied for large-scale synthesis. These
new sustainable methods for the in situ generation of
formaldehyde have the potential to be applied as a C1 building
block in different transformations, including MCR. Thus, the
current report is an important contribution to the field, considering
the potential synthetic, therapeutic and industrial application of
these compounds.
Conclusions
In summary, we developed synthetically attractive, robust,
sustainable and chemoselective procedures for the
hydroxymethylation and methylenation of imidazo-heteroarenes,
providing useful products in good to excellent yields. Our synthetic
protocols involve the use of renewable reagents (ethylene glycol
and glycerol) and KIO4, which generates formaldehyde (in situ via
the Malaprade oxidation reaction) as C1 the building block. The
reactions were carried out in an air atmosphere, using water as a
solvent and easily accessible reagents. In the presence of
ethylene glycol, hydroxymethylated products were obtained.
Interestingly, the same reaction carried out with the additional
presence of dimethylamine led to the most advanced intermediate
of the drug Zolpidem, while the use of glycerol in the reaction
Acknowledgements
We gratefully acknowledge CAPES (001), CNPq, CERSusChem
GSK/FAPESP (grant 2014/50249-8) and INCT-Catálise for
5
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RESEARCH ARTICLE
13710–13717; e) B. Marianic, H. B. Hepburn, A. Grozavu, M. Dow, T. J.
Donohoe, Chem. Sci. 2021, 12, 742-746.
financial support. M.S.F would like to acknowledge CNPq for a
doctoral
fellowship.
CAPES–PrInt
Project
number
[10] a) W. Buratti, G. P. Gardini, F. Minisci, F. Bertini, R. Galli, M.
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88887.310569/2018-00 is also acknowledged. J.R. is grateful to
CNPq for funding (433896/2018-3 and 315399/2020-1). The
authors also acknowledge CEBIME for the HRMS analysis.
Keywords: imidazo-heteroarenes • KIO4 • hydroxymethylation •
C(sp2)-H functionalization • green chemistry
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ESI, Pg. S3.
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S3 ESI, Pg. 14.
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Entry for the Table of Contents
KIO4-mediated selective hydroxymethylation /methylenation: An efficient, sustainable and chemoselective procedures for the
C(sp2)-H bond hydroxymethylation and methylenation of imidazo-heteroarenes, using KIO4 has been developed. In the presence of
ethylene glycol, hydroxymethylated products were obtained in excellent yields, while the use of glycerol in the reaction resulted in the
methylenated products. The reaction allows to access the most advanced intermediate of the drug Zolpidem
Institute and/or researcher Twitter usernames: @SumbalSaba; @jamalrafique; @A_L_Braga; @ufg_oficial; @ufmsbr; @ufsc
8
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