A facile and general acid-catalyzed deuteration at methyl groups of N-heteroarylmethanes

Article abstract of DOI:10.1039/c7ob00062f

A facile and general Br?nsted acid-catalyzed deuteration at the methyl group of N-heteroarylmethanes was achieved through a dearomatic enamine intermediate under relatively mild reaction conditions. Both 2-methyl and 4-methyl groups in quinolines were deuterated with high deuterium incorporation. Pyridines, benzo[d]thiazoles, indoles and imines including these clinical drugs were also deuterated efficiently at the methyl groups. This reaction could be conducted on a large scale (500 mmol), showing its good potential for use in large-scale synthesis.

Full text of DOI:10.1039/c7ob00062f

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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Facile and General Acid-Catalyzed Deuteration at Methyl Groups
of N-Heteroarylmethanes
Received 00th January 20xx,
Accepted 00th January 20xx
†
†
Min Liu, Xue Chen, Tieqiao Chen* and Shuang-Feng Yin*
DOI: 10.1039/x0xx00000x
www.rsc.org/
5
A facile and general Brønsted acid-catalyzed deuteration at the medicines, the selective deuteration at the methyl group of
methyl group of N-heteroarylmethanes was achieved through a such compounds would greatly facilitate the studies on the
dearomatic enamine intermediate under a relatively mild reaction overall therapeutic and metabolic profile of a related drug.
condition. Both 2-methyl and 4-methyl groups in quinolones were Some deuterated medicines are also recognized to enhance
deuterated with high deuterium incorporation. Pyridines, the formation of active metabolites and reduce the formation
benzo[d]thiazoles, indoles and imines including those clinic drugs of toxic metabolites, thus positively impacting their metabolic
6
were also deuterated efficiently at the methyl groups. This fate. In addition, numerous efforts have been devoted to the
7
reaction could be conducted at a large scale (500 mmol), showing functionalization of methyl group in such compounds, the
good potential for large-scale synthesis.
mechanistic studies also require corresponding deuterated
compounds. However, methods for preparing those
8
-10
Deuterated compounds are widely applied in mass and NMR
1
spectroscopies. They are also recognized as powerful tools in
2
mechanistic and metabolic studies. Thus, the selective
deuterated compounds are rather limited.
Those deuterated compounds are conventionally prepared
by cross coupling between aryl halides with CD MgX catalyzed
3
8
introduction of deuterium into functional molecules has
3
attracted impressive interest. N-heteroarylmathanes usually
by a transition metal complex. Direct deuteration at the
methyl group of N-heteroarylmethanes would be an attractive
step-economic method; however current strategy usually
requires a strong base and high reaction temperature (over
occur as key core units in many natural products and
4
pharmaceutical drugs (Scheme 1).
o
9,3a
1
70 C) (Scheme 2).
In addition to the issues of safety and
CH2
N
O
manipulation, these protocols also suffer from severe
limitations of functional groups tolerance.
N
N
N
N
O
O
N
NH
previous methods: harsh conditions
cat. M
O
CH3
HO
O
O
Irinotecan
Nevirapine
Het
N
Het
N
+
3
CD MgX
OMe
X
CD
3
N
N
O
H2
C
H C
OMe
strong base
2
Het
N
Het
N
D O
MeO
MeO
N
+
2
o
over 170 C
N
NH
CD3
N
CD3
CH
3
OH
Tropicamide
O
Nevirapine(CD
inhanced eff ect
3
)
this method
Papaverine
CH3
CD3
Scheme 1. examples of pharmaceutical molecules containing N-heteroarylmethane unit.
cat. weak acid
Het
N
1
Het
+
CH
3
D O
o
o
2
8
0 C-120 C
Considering the striking effect of methyl group in clinical
N
CD3
facile and general
3
Scheme 2. Synthesis of N-heteroarylmethanes-CD
3
Herein, we report
a facile Brønsted acid-catalyzed
deuteration at the methyl group of N-heteroarylmethanes
with D2O to produce the corresponding deuterated
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1
2,13
compounds with high ratios of deuterium incorporation occur efficiently (Table 1, entries 10-12).
Scheme 2). This reaction is general, both 2-methyl and 4- O was also screened. 96% ratio of deuterium incorporation
methyl groups in various N-heteroarylmethanes including was obtained with 0.2 mL D O (Table 1, entry 14), whereas
those with functional groups are deuterated efficiently under further reducing the loading of D O would lead to the decrease
The amount of
(
D
2
2
2
the mild reaction conditions. This new transformation can be of deuteration incorporation (Table 1, entries 15 and 16). As
performed in a large scale and be applicable to some bioactive for the reaction time, it was found that the ratio of deuterium
pharmaceutical molecules, showing good industrial potential.
incorporation was D-60% at 0.5 h, D-87% at 1 h, D-91% at 2h,
D-94% at 3 h, D-96% at 4 h and D-96% at 5 h, indicating that
a
Table 1. Brønsted acid-catalyzed deuteration of 2-methylquinoline
1
3
the reaction reached equilibrium at 4 h (see SI, Figure 2).
Table 2. Brønsted acid-catalyzed deuteration at methyl groups of N-
a,b
heteroarylmethanes.
a
o
Reaction conditions: 1a (0.2 mmol), D
2
O (0.4 mL), air, 10 mL glass tube, 80 C, 4
aqueous
2
O was used. 0.1 mL D O
h. The mixture after reaction was neutralized by saturated NaHCO
3
b
1
c
d
solution. Based on H NMR spectroscopy; 0.2 mL D
2
e
2
was used. 0.05 mL D O was used.
Inspired by recent advances of acid-mediated
functionalization of methyl groups in N-heteroarylmethanes
where the methyl groups are proposed to be activated by
Brønsted acids through an enamine intermediate (Scheme
7
d,7f
2
),
methyl groups would be within reach via a similar process.
This is indeed. It was found that by heating the mixture of 2-
we envisioned that the selected deuteration at the
1
1
o
2
methylquinoline in D O at 60 C for 4 h, a trace amount of
1
deuterated compounds was produced as indicated by H NMR
spectroscopy (Table 1, entry 1). By addition of 20 mol%
benzoic acid, the ratio of deuterium incorporation was
dramatically increased to 90% under similar reaction
conditions (Table 1, entry 2). When the reaction was
o
a
2
Reaction conditions: 1 (0.2 mmol), D O (0.2 mL), benzoic acid (0.015-0.02
performed at 80 C, 97% ratio of deuterium incorporation was mmol), 10 mL glass tube, 4-8 h. The mixture after reaction was neutralized by
b
achieved (Table 1, entry 3). Further elevating the reaction saturated NaHCO
3
aqueous solution. The percent of deuterium incorporation
1
c
o
temperature to 100 C, the reaction efficiency was not
was calculated based on H NMR spectroscopy (for details, see SI). 15 mol%
d
e
benzoic acid was used. 20 mol% benzoic acid was used. 16-24 h.
improved (Table 1, entry 4). Other acids could also mediate
this reaction, despite a little low incorporation ratios were
afforded (Table 1, entries 5-9). To our delight, this reaction
could take place readily with a lower loading of catalyst and
only 7.5 mol% benzoic acid enabled this transformation to
This acid-catalyzed transformation was general; a variety of
N-heteroarylmethanes could be deuterated at the methyl
groups, producing the expected deuterated products with high
percent of deuterium incorporation (Table 2). Thus, 2-
2
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methylquinolines bearing 6-methyl, methoxy, even the easily deuterium incorporation. 91% deuterium incorporation was also
hydrolytic ester and amide groups all gave the corresponding obtained from the chloroxine derivative 5,7-dichloro-2-
4f
products efficiently under the current reaction conditions (3b
-
methylquinolin-8-ol
under
similar
reaction
conditions.
3e
and 3l). Substrates with free hydroxyl groups also produced Tropicamide was widely used in pseudomyopia treatment. The
the expected deuterated product (3f). The derivatives having corresponding deuterated product was also produced readily via
halo groups (F, Cl and Br) and electron-withdrawing groups like H/D exchange in the current system.
nitro and carbonyl groups were reactive under the reaction
conditions
(
3g
-3l).
1-Methylisoquinoline
and
2-
methylquinoxaline were also deuterated at methyl group
efficiently (3m and 3n). Neocuproine was also effective for this
reaction and both of methyl groups were deuterated readily
(
3o). In addition to methyl group adjacent to nitrogen atom,
H/D exchange could also occur readily at the 4-methyl group
exemplified as 3p under the present reaction conditions.
However, no deuterium incorporation at the methyl group
occurred when 3-methylquinoline was loaded as a substrate
(
3q). Noteworthy, by elevating the reaction temperature to
o
20 C, the pyridine derivatives could also be deuterated
1
efficiently at the methyl groups. Worth noting is that 4-methyl
group seems to be more active. For example, when 2,4-
dimethylpyridine was employed as the substrate, 92%
deuterium incorporation was achieved at 4-methyl group,
whereas only 49% of 2-methyl group was deuterated. 4-
Methylpyridine, 4-ethylpyridine and 4-benzylpyridine were
also deuterated selectively at methyl or methylene under
similar reaction conditions (3r-3u). Interestingly, other N-
heterocyclic methanes also served as good substrates.
Benzo[d]thiazoles, indoles and imines all were converted to Scheme 4. Application on deuteration of bioactive pharmaceutical molecules.
the corresponding deuterated products with high deuterium
As for the mechanism, the present H/D exchange would
incorporation (3v-3aa).
take place through an enamie intermediate (Scheme 5). It
should be noted that these results described here also
provided strong evidence for the proposed mechanism on
acid-mediated functionalization of methyl groups in N-
heteroarylmethanes that the methyl group was activated by
Practically, this reaction could be easily carried out at a
large-scale (Scheme 3). Thus, a mixture of 10 mmol 2-
o
O was stirred at 80 C for 5 h in the
methylquinoline in 6 mL D
2
presence of 7.5 mol% benzoic acid. The mixture was
neutralized with NaHCO solution (4 mL) and extracted with
ethyl acetate (5 4 mL). After being dried with Na SO and
3
7
Brønsted acid.
×
2
4
evaporated under reduced pressure, the corresponding
deuterated product 3a was given in 94% isolated yield (1.37 g)
with 95% ratio of deuterium incorporation. A similar result was
obtained at 500 mmol scale, showing its potential utility for a
large-scale preparation of such compounds (for procedure, see
SI).
CH3
CH3
CH2
CH3
H+
- H+
+
-
Het
Het
N
+
Het
N
Het
H+
H+
+
N + CH3
CH2
CH3
N
CH
3
H
H
H
Scheme 5. Proposed mechanism for the acid-catalyzed deuteration at the methyl
groups of N-heteroarylmethanes.
In summary, we have developed an efficient Brønsted acid-
catalyzed deuteration at the methyl group of N-
2
heteroarylmethanes using the simple D O as the deuterating
reagents. Quinolines, pyridines, benzo[d]thiazoles, indoles and
imines including those clinic drugs all were deuterated at the
methyl groups with high deuterium incorporation under a
relatively mild reaction condition. A scale-up experiment also
showed the possibility of large-scale synthesis. This
deuteration transformation not only provided an efficient
deuterating strategy for N-heteroarylmethanes, but also
provided a strong evidence for the proposed mechanism in the
acid-mediated functionalization of methyl groups in N-
Scheme 3. Scale-up experiments.
This Brønsted acid-catalyzed H/D exchange was applicable to
deuteration of bioactive molecules, producing the corresponding
deuterated products with high deuterium incorporation and thus
facilitating metabolic studies on related drugs (Scheme 4). For
example, papaverine, an efficient drug for treatment of the tonus
of all smooth muscle relaxation, was deuterated with 95%
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heteroarylmethanes. Detailed kinetic studies are underway in
our laboratory.
J. Med. Chem. 2014, 57, 669; (f) A. T. Bockus, J. A.
Schwochert, C. R. Pye, C. E.Townsend, V. Sok, M. A. Bednarek
and R. S. Lokey, J. Med. Chem. 2015, 58, 7409; (g) K. W.
Kuntz, J. E. Campbell, H. Keilhack, R. M. Pollock, S. K. Knutson,
M. Porter-Scott, V. M. Richon, C. J. Sneeringer, T. J. Wigle, C.
J. Allain, C. R. Majer, M. P. Moyer, R. A. Copeland and R.
Chesworth, J. Med. Chem. 2016, 59, 1556.
Partial financial supports from NFSC (21403062,
2
1373080, 21273067), HNNSF 2015JJ3039 and the
Fundamental Research Funds for the Central Universities
Hunan University) are gratefully acknowledged. The authors
(
6
7
(a) S. L. Harbeson and R. D. Tung, Medchem News, 2014,
(
T. G. Gant, J. Med. Chem. 2014, 57, 3595; (d) A. Mullard, Nat.
Rev. Drug Discov. 2016, 15, 219.
Selected examples, see (a) L.-C. Campeau, D. J. Schipper and
K. Fagnou, J. Am. Chem. Soc. 2008, 130, 3266; (b) X. Chen, C.
E. Goodhue and J.-Q. Yu, J. Am. Chem. Soc. 2006, 128, 12634;
2, 8;
b) G. S. Timmins, Expert Opin. Ther. Pat. 2014, 24, 1067; (c)
thank Dr. Qing Xu in Wenzhou University for HRMS analysis.
Notes and references
1
(a) M. C. Carrión, M. Ruiz-Castañeda, G. Espino, C. Aliende, L.
Santos, A. M. Rodríguez, B. R. Manzano, F. A. Jalón and A.
Lledós, ACS Catal. 2014, 4, 1040; (b) W. V. Ligon, Jr. and H.
(
c) J.-M Liu, X. Zhang, H. Yi, C. Liu, R. Liu, H. Zhang, K.-L. Zhuo
and A.-W. Lei, Angew. Chem. Int. Ed. 2015, 54, 1261; (d) F.-H
Xiao, S.-Q Chen, Y. Chen, H.-W Huang and G.-J. Deng, Chem.
Commun. 2015, 51, 652; (e) H. Xie, J.-H. Cai, Z.-L. Wang, H.-W.
Huang and G.-J. Deng, Org. Lett. 2016, 18, 2196; (f) Q. Li, Y.
Huang, T. Chen, Y. Zhou, Q. Xu, S.-F. Yin and L.-B. Han, Org.
Lett. 2014, 16, 3672; (g) M. Liu, T. Chen and S.-F. Yin, Catal.
Grade, Anal. Chem. 1991. 63, 255.
2
Books, see (a) Synthesis and Applications of Isotopically
Labelled Compounds, Vol. 7 (Eds.: U. Pleiss, R. Voges), Wiley,
New York, 2001; (b) T. H. Lowry and K. S. Richardson,
Mechanism and Theory in Organic Chemistry, Harper & Row,
New York, 1987; (c) A. F. Thomas, Deuterium Labelling in
Organic Chemistry, Appleton-Century-Crofts, New York,
Sci. Technol. 2016,
Tolstoluzhsky, Org. Lett. 2011, 13, 1095; (i) M. Liu, T. Chen, Y.
Zhou and S.-F. Yin, Catal. Sci. Technol. 2016, , 5792.
Synthesis via cross coupling of aryl halides with CD MgX, see
a) B. Qian, P. Xie, Y.-J. Xie and H.-M. Huang, Org. Lett. 2011,
6, 690; (h) M. Rueping and N.
1
971; Selected reviews, see (d) T. Junk and W. J. Catallo,
6
Chem. Soc. Rev. 1997, 26, 401; (e) E. M. Simmons and J. F.
Hartwig, Angew. Chem. Int. Ed. 2012, 51, 3066.
8
9
3
(
3
Selected reviews, see: (a) J. Atzrodt, V. Derdau, T. Fey and J.
Zimmermann, Angew. Chem. Int. Ed. 2007, 46, 7744; (b) Y.
Monguchi and H. Sajiki, Synlett 2012, 23, 959; Selected
examples, see (c) J.-R. Zhou and J. F. Hartwig, Angew. Chem.
Int. Ed. 2008, 47, 5783; (d) G. Erdogan and D. B. Grotjahn, J.
Am. Chem. Soc. 2009, 131, 10354; (e) S. Ma, G. Villa, P. S.
Thuy-Boun, A. Homs and J.-Q. Yu, Angew. Chem. Int. Ed.
13, 2580. The synthesis of 2-trideuteriomethyl quinoline was
described in its SI, referring to a similar procedure; see (b) K.
Tamao, S. Kodama, I. Nakajima, M. Kumada, A. Minato and K.
Suzuki, Tetrahedron 1982, 38, 3347.
o
Methods with high temperature (over 170 C), see (a) K.
Neranon and O. Ramström, RSC Adv. 2015,
Armenise, N. Tahiri, N. N. M. Eisink, M. Denis, M. J
D. Vries, M. D. Witte and A. J. Minnaard, Chem. Commun.
016, 52, 2189. Strong bases are also required in these two
5
, 2684; (b) N.
ä
ger, J. D.
2
014, 53, 734; (f) L. Neubert, D. Michalik, S. Bähn, S. Imm, H.
Neumann, J. Atzrodt, V. Derdau, W. Holla and M. Beller, J.
Am. Chem. Soc. 2012, 134, 12239; (g) S. R. Klei, J. T. Golden,
T. D. Tilley and R. G. Bergman, J. Am. Chem. Soc. 2002, 124
2
works. c) N. H. Werstiuk, and C. Ju, Can. J. Chem. 1989, 67, 5,
temperature is over 200 C in the reaction.
,
,
o
2
4
092; (h) W. J. Kerr, M. Reid and T. Tuttle, ACS Catal. 2015, 5
1
0 There is another example on CoCl
-methylquinoline with D O (only one example, 91% ratio of
deuterium incorporation, purification by column using CDCl
as an eluent), (a) Z. Jamal and Y.-C. Teo, Synlett, 2014, 25
049; see also (b) Z. Jamal, Y.-C. Teo and L.-K. Wong, Eur. J.
Org. Chem. 2014, 7343.
2
-catalyzed deuteration of
02; (i) D. Munz, M. W. Gardiner, R. Fu, T. Strassner, W. A.
, 769; (j) B.
Chatterjee and C. Gunanathan, Chem. Commun. 2016, 52
2
2
Goddard and T. B. Gunnoe, ACS Catal. 2015,
5
3
,
,
4
509; (k) Y. Ito and M. Yoshimatsu, Org. Chem. Front. 2015,
, 201; (l) T. Maegawa, Y. Fujiwara, Y. Inagaki, H. Esaki, Y.
Monguchi and H. Sajiki, Angew. Chem. Int. Ed. 2008, 47, 5394;
2
2
1
1
1
1 These reactions usually were mediated by over
stoichiometric amount of Brønsted acids, see Ref. 7.
Interestingly, this H/D exchange reaction were achieved by
only catalytic amount of benzoic acid.
2 It was deduced that the acids perhaps played dual roles in
the H/D exchange reaction: activating the methyl group
through a dearomatic enamine intermediate and increasing
(
m) L. Hu, X. Liu and X. Liao, Angew. Chem. Int. Ed. 2016, 55
743.
Selected reviews, see (a) J. P. Michael, Nat. Prod. Rep. 2004,
, 650; (b) J. P. Michael, Nat. Prod. Rep. 2008, 25, 166; (c), J.
,
9
4
2
1
P. Michael, Nat. Prod. Rep. 2007, 24, 223; Selected examples,
see (d) Y.-Y Huang, R. Narendran, F. Bischoff, N.-N Guo, Z.-H.
Zhu, S.-A Bae, A. S. Lesage and M. Laruelle, J. Med. Chem.
2
the solubility of the starting material in D O via salification.
2
005, 48, 5096; (e) V. Goncalves, J. A. Brannigan, D. Whalley,
3 The H/D exchange reaction would be accelerated by
increasing the loading of acid. For example, when a
stoichiometric amount of benzoic acid was loaded, 93%
deuterium incorporation was obtained at 0.5 h.
K. H. Ansell, B. Saxty, A. A. Holder, A. J. Wilkinson, E. W. Tate
and R. J. Leatherbarrow, J. Med. Chem. 2012, 55, 3578; (f) A.
L. Smith, K. L. Andrews, H. Beckmann, S. F. Bellon, P. J.
Beltran, S. Booker, H. Chen, Y.-A. Chung, N. D. D’Angelo, J.
Dao, K. R. Dellamaggiore, P. Jaeckel, R. Kendall, K. Labitzke, A.
M. Long, S. Materna-Reichelt, P. Mitchell, M. H. Norman, D.
Powers, M. Rose, P. L. Shaffer, M. M. Wu and J. R. Lipford, J.
Med. Chem. 2015, 58, 1426.
5
(a) E. J. Barreiro, A. E. Kummerle and C. A. Fraga, Chem. Rev.
2
2
011, 111, 5215; (b) G.-Q. Zheng, Y. Fu and C. He, Chem. Rev.
014, 114, 4602; (c) H. Schoenherr and T. Cernak, Angew.
Chem. Int. Ed. 2013, 52, 12256; (d) L. R. Vidler, P.
Filippakopoulos, O. Fedorov, S. Picaud, S. Martin, M. Tomsett,
H. Woodward, N. Brown, S. Knapp and S. Hoelder, J. Med.
Chem. 2013, 56, 8073; (e) D. Caglič, M. C. Krutein, K. M.
Bompiani, D. J. Barlow, G. Benoni, J. C. Pelletier, A. B. Reitz, L.
L. Lairson, K. L. Houseknecht, G. R. Smith and T. J. Dickerson,
4
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