Acetic Acid Accelerated Visible-Light Photoredox Catalyzed N-Demethylation of N,N-Dimethylaminophenyl Derivatives

Article abstract of DOI:10.1002/adsc.201601108

N,N-Dimethylaminophenyl moiety is a common fragment in medicinal chemistry as several pharmaceuticals bearing this privileged motif are on the market and under clinical evaluation. Oxidative N-demethylation is generally regarded as the major metabolic pathway. However, pharmacokinetics, metabolites studies as well as the further structural modification are precluded by the impracticality of chemical synthesis. Here we report that acetic acid can significantly accelerate visible-light photoredox catalyzed N-demethylation of N,N-dimethylaminophenyl derivatives. This approach is easy for large scale reaction and even for potential industrial manufacture. (Figure presented.).

Full text of DOI:10.1002/adsc.201601108

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DOI: 10.1002/adsc.201601108
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Acetic Acid Accelerated Visible-Light Photoredox Catalyzed
N-Demethylation of N,N-Dimethylaminophenyl Derivatives
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Guolin Wu,a Yazhen Li,a Xuemei Yu,a Yu Gao,a and Haijun Chena,*
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College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, China
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E-mail: chenhaij@gmail.com
Received: October 9, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201601108
Abstract: N,N-Dimethylaminophenyl moiety is a
common fragment in medicinal chemistry as several
pharmaceuticals bearing this privileged motif are
on the market and under clinical evaluation.
Oxidative N-demethylation is generally regarded as
the major metabolic pathway. However, pharmaco-
kinetics, metabolites studies as well as the further
structural modification are precluded by the im-
practicality of chemical synthesis. Here we report
that acetic acid can significantly accelerate visible-
light photoredox catalyzed N-demethylation of
N,N-dimethylaminophenyl derivatives. This ap-
proach is easy for large scale reaction and even for
potential industrial manufacture.
Keywords: practical; visible-light; photoredox cata-
lyzed; N-demethylation
37 The amines with diverse therapeutic properties are
38 ubiquitous structures in pharmaceuticals.[1] Of all
39 privileged fragments in the medicinal chemical space,
40 the tertiary N-methylamine functional group is re-
41 garded as one of the well-known building blocks in
42 the drug discovery process.[2] The incorporation of N-
43 methylamine into drug molecules can dramatically
44 improve solubility and pharmacokinetic properties.[3]
45 Among this group, N,N-dimethylaminophenyl moiety
46 with the potential metabolic predictability is partic-
47 ularly interesting, as oxidative N-demethylation is
48 generally regarded as the major metabolic pathway.[4]
49 Due to these reasons, this functional moiety can be
50 found in a large proportion of pharmaceuticals (Fig-
51 ure 1A).[5]
Figure 1. (A) Complex pharmaceuticals containing N,N-
dimethylaminophenyl moiety as the privileged fragment. (B)
Two proposed pathways for N-demethylation of tertiary
aromatic amines in vivo. (C) Traditional N-demethylation.
(D) This work: acetic acid accelerated visible-light photo-
redox catalyzed N-demethylation of N,N-dimethylamino-
phenyl derivatives. FG=functional group.
52
During drug development, metabolites studies are
53 extraordinary important to ensure drug safety. In mechanisms including formation of carbinolamine via
54 addition, the major metabolite also can be used as a cytochrome P450 oxidation (pathway a) and gener-
55 starting point for further potential structural modifica- ation of N-oxide via flavin monooxygenation followed
56 tion.[6] It is generally believed that N-demethylation of by rearrangement (pathway b).[1a,7] Due to the inher-
57 aromatic tertiary amines proceeds by two proposed ent instability of carbinolamine, it decomposes rapidly
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Table 1. Reaction optimization.[a]
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to the demethylated product and formaldehyde (Fig-
ure 1B).[8] Traditional reagents for N-demethylation
include toxic cyanogen bromide and chloroformates.[9]
However, these reagents are not suitable for dimethy-
laminophenyl substrates bearing electron withdrawing
groups due to the intrinsic superior chemical stability
(Figure 1C).
In the past few years, there has been tremendous
progress in the field of visible light photoredox
10 catalysis.[10] However, relatively few methods can
11 provide a practical route for N-demethyl com-
12 pounds.[11] The limited photochemical procedures
13 suffered many disadvantages including slow reaction
14 time, low yield and problematic scalability.[12] In
15 addition, a broad range of substrates with electron
16 withdrawing groups were proved unsatisfactory in
17 these synthetic contexts.[13] In particular, the above
18 mentioned complex pharmaceuticals have not been
19 accessed. For this reason, a more special and general
20 method for N-demethylation of N,N-dimethylamino-
21 phenyl derivatives is in demand. Herein, we reported
22 a mild, general and practical N-demethylation (Fig-
23 ure 1D).
Entry Catalyst[b]
AcOH Time (h) Conversion[c]
(equiv.)
(Yield[d]) (%)
1
RB
0
5
3.5
3.5
3.5
3.5
3
12
72
89
98
>99
>99
< 5
< 5
97 (91)
98 (86)
>99 (79)
<5
2
RB
3
RB
10
25
50
25
25
25
25
25
25
4
RB
5
RB
RB
RB
RB
6[e]
7[f]
8[g]
9
3
24
24
3
4
1.5
4
RB
10
11
12
13
14[h]
15[i]
16[j]
17[k]
MB
Acr-Me+
24
We initiated our studies on the photochemical
[Ru(bpy)3]Cl2 25
25 oxidation by using our upgraded home-made continu-
26 ous-flow photoreactor (see Supporting Information)
27 and Rose Bengal (RB) as a meal-free photoredox
28 catalyst. Initial results showed that AcOH can signifi-
29 cantly increase the reaction efficacy (Table 1, entries
30 2–5). The reaction was run to complete conversion
31 within 3 h (entry 5), in contrast to normal condition
32 without AcOH requiring more than 24 h (entry 1).
33 Increasing amounts of AcOH led to improve effi-
34 ciency and reduce reaction time remarkably (entries
35 2–5). Notably, in the absence of O2, no conversion was
36 observed (entries 6–8). Extensive evaluation of vari-
37 ous commercially available photoredox catalysts re-
38 vealed that RB, MB (Methylene Blue) and Acr-Me+
39 are the first-class catalysts (entries 9–12, see Table S1
40 for more comprehensive data). Despite product for-
41 mation occurred to give complete conversion within
42 shorter time when using Acr-Me+ as the catalyst,
MB
RB
RB
RB
RB
0
24
3.5
3.5
3.5
3.5
<5
90
82
>98
25
25
25
25
70% + 26% of 4
[a] Selected data, see Table S1 for more comprehensive data.
[b] Reaction conditions: Step 1: substrate 1 (0.1 mmol),
AcOH, DABCO (0–5 mol%), catalyst (5 mol%), solvent
(5 mM), r.t., 34 W LEDs irradiation; Step 2: concentration,
adding MeOH and 3 N H2SO4 (aq., 10 equiv.), r.t., 12 h.
[c] Conversion determined by HNMR.
1
[d] Isolated yield of 5 (in parentheses).
[e] Reaction was carried out under O2.
[f] Under Ar.
[g] Under N2.
[h] MeOH replaced CH3CN.
[i] EtOH.
[j] Without DABCO.
43 however, the yield is a little unsatisfied. Remarkably, [k] Step 2 by using Vc (1.0 equiv.) as a hydrolytic reagent,
isolated yield.
44 no reaction took place if AcOH was omitted when
45 using MB as the catalyst (entry 13). The solvent
46 evaluation showed that CH3CN was the best solvent
47 (entries 9, 14, 15). Interestingly, the reaction without
48 DABCO also gave comparable result (entry 16).
*Unstable, detected by HRMS. DABCO=1,4-diazabicyclo
[2.2.2]octane; Acr-Me+ = N-Methyl Acridinium.
49
Monitoring the progress of the reaction revealed obtain the desired product (5) in 70% yield and
50 that one major intermediate and a small amount of formamide product (N-formyl derivative 4) in 26%
51 the desired product were detected. NMR (nuclear yield (entry 17).[15] This condition further demon-
52 magnetic resonance) and HRMS (high-resolution strated that the key intermediate is hyperoxide (2)
53 mass spectrometry) analysis revealed that this transi- and such mild condition may have more potential
54 ent major intermediate is hyperoxide (2).[14] It is worth utility for complex substrates with sensitive functional
55 noting that Vc (vitamin C, ascorbic acid) also has groups. Extensive efforts on the purification of
56 proven to be an effective hydrolytic reagent for the carbinolamine (3) were failed, further indicating that
57 final product formation, and such mild condition can
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Figure 2. Substrate scope of N-demethylation of N,N-dimethylaminophenyl derivatives. See Supporting Information for
experimental details. *EtOH replaced CH3CN as solvent and MB as catalyst. FG=functional group.
51 this intermediate is extraordinarily instable even in substrates bearing substituents at the para, meta or
52 alkaline or neutral conditions.[8]
ortho position were all worked efficiently, providing
With the optimal conditions in hand, we next the desired N-demethyl products. For example, N,N-
53
54 sought to examine the generality of this oxidative N- dimethylaminophenyl derivatives bearing ester, car-
55 demethylation by exploring the scope of N,N-dime- boxylic acid as well as amide moieties were all reacted
56 thylaminophenyl derivatives with electron-withdraw- smoothly to give the corresponding products in good
57 ing groups. As outlined in Figure 2, a wide variety of to excellent yields (7, 8, 10–17, 20–26, 29, 30). Some
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Figure 3. Application to synthesize the major metabolite of mifepristone on gram-scale (demonstrating the practicality of
visible-light photoredox catalyzed N-demethylation of N,N-dimethylaminophenyl derivatives).
15 functional groups such as aldehyde and ketone were oxide anion probe (see Supporting Information).[18]
16 compatible with this mild reaction condition (5, 6, 9, Notably, hydrogen peroxide (H2O2) was incapable of
17 19, 31). It should be noted that slight modification of being detected by in situ NMR experiment and the
18 the standard condition for some sensitive substrates starch-iodine testing, suggesting that the generation of
* À
19 might improve the yields by using milder reductive H2O2 presumptive derived from O2
may be ex-
20 hydrolytic reagent Vc (9, H2SO4 workup: 60%; Vc cluded for this N-demethylation. Furthermore, no N-
21 workup: yield up to 85%). The presence of halogen oxides were detected in the presence of hydrogen
22 substitution was also not problematic (31). In addition, peroxide and glacial acetic acid, indicating that in situ
23 the reactions of substrates bearing stronger electron- formation of peracetic acid was no involved in this
24 withdrawing substituent such as NO2 moiety pro- reaction. By analogy to prior mechanistic investiga-
25 ceeded smoothly in good yields, just requiring a longer tions of the oxidation by visible-light photoredox
26 reaction time for the reaction to reach completion (18, catalysis and our above mechanistic studies,[17,19]
27 27, 28). Moreover, the scope of the reaction was related pathway is postulated for N-demethylation.
a
28 further examined by N-demethylation of complex
A proposed mechanism for this transformation is
29 pharmaceuticals. Two representative pharmaceuticals depicted in Figure 4. Electron transfer from A to the
30 including Thioflavin T and mifepristone were effective excited state catalyst [cat]* affords cation radical B
31 in this transformation (32, 33).
32
To showcase the scalability of this process, gram-
33 scale reaction of N-demethylation of mifepristone was
34 performed (Figure 3). After a slight modification of
35 the optimized condition, we found that 5 mol% RB
36 with 100 eq AcOH remarkably reduce the reaction
37 time. It only needed 1.5 h for the reaction to reach
38 completion, while the corresponding experiment with-
39 out AcOH required more than 48 h in the same
40 condition. Gratifyingly, Vc workup afforded N-formyl
41 derivative in 22% yield, which can be hydrolyzed
42 under mildly acidic condition to provide 33 in 80%
43 yield.[16] Thus, the total yield for synthesis of 33 is up
44 to 83%. We also found that using MB as catalyst
45 afforded 33 in 69% yield.
46
To gain in sight into the reaction mechanism,
47 several mechanistic experiments were carried out.
48 Preliminary comparative experiments proved that O2
49 was very important to this reaction. Additional
50 evidence by adding H218O to the reaction without
51 detection of 18O-labled intermediates indicated that
52 oxygen atom of the key intermediate hydroperoxides
53 originated from O2.[17] In addition, the acidic condition
54 with AcOH in the reaction mixture led to a significant
55 enhancement of the production of superoxide anion
* À
Figure 4. Proposed pathway for the N-demethylation of N,N-
dimethylaminophenyl derivatives.
56 radical O2
by fluorescence measurements using
57 dihydroethidium (DHE) as a special detecting super-
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*
*
layer was further extracted with ethyl acetate. The combined
organic layers were dried over Na2SO4, filtered, and concen-
trated in vacuo to afford the crude product. The residue was
then purified by chromatography on silica gel to afford the
desired product and the formamide product.
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and [cat] . Oxidation of [cat] via electron transfer to
O2 furnishers the superoxide anion radical O2 À, while
proton and electron transfer from cation radical B to
*
* À
O2
yields hydroperoxide F. Simultaneous proton
loss from B affords a-amino radical C presumably via
AcOH-mediated deprotonation. In the presence of
oxygen, electron transfer from a-amino radical C to
O2 yields peroxyl radical D.[20] Acetic acid could
protonate the resulting peroxyl radical D to generate
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (No. 81402781), the Scientific Research
Foundation for the Returned Overseas Chinese Scholars,
Technology Development Foundation of Fuzhou University.
10 hydroperoxide radical cation E.[21] Radical cation E
11 might also facilitate single electron transfer from A to
12 afford hydroperoxide F and cation radical B, followed
13 by deprotonation of B with the acetate anion to
14 provide C.[22] At the last step, hydroperoxide F under-
15 goes tautomerization-dehydration to yield instable N-
16 hydroxymethyl derivative G* (carbinolamine) and N-
17 formyl derivative H. Both derivatives are ultimately
18 formed by the well-precedential process of dispropor-
19 tionation.[23] While, due to the inherent instability of
20 N-hydroxymethyl derivative G*, it decomposed spon-
21 taneously in the solution to furnish the demethylated
22 product and formaldehyde.
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In conclusion, we developed a practical visible-
24 light photoredox catalyzed N-demethylation of N,N-
25 dimethylaminophenyl derivatives. Given the broad
26 utility of N,N-dimethylaminophenyl moiety as one of
27 the most privileged fragments in drug development,
28 the direct N-demethylation of complex molecules with
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Experimental Section
General Procedure for Practical Visible-Light Photoredox
Catalyzed N-Demethylation of N,N-Dimethylaminophenyl
Derivatives. The round bottom flask equipped with a
magnetic stir bar was charged with RB or MB (1–20 mol%),
N,N-dimethylaminophenyl derivatives (1.0 equiv.), DABCO
(0–20 mol%). Acetonitrile or EtOH (c=4–60 mM) and
acetic acid (10–100 equiv.) were added. The resulting sol-
ution was sucked into the Home-Made Continuous-Flow
Photoreactor at one end and returned at the other (rpm=50,
flow rate is ~10 mL/min). The flow reaction was conducted
in the homemade capillary photoreactor with a pump. After
the reaction was completed (monitored by TLC analysis),
H2SO4 workup: the mixture was collected and concentrated
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49 under reduced pressure. MeOH and 3 N H2SO4 (aq., 5–
20 equiv.) were added to the residue, and the reaction
mixture was stirred at r.t. for the indicated time. Vc workup:
Vc (1.0–1.1 equiv.) was added to the solution, and the
reaction mixture was stirred at r.t. for 0.5 h. After above
mentioned workup, the mixture was concentrated under
reduced pressure. Ethyl acetate/water was added and the
solution was basified to pH 8~9 with saturated aqueous
NaHCO3. The organic layer was collected, and the aqueous
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