Acid-catalyzed chemodivergent reactions of 2,2-dimethoxyacetaldehyde and anilines

Article abstract of DOI:10.1016/j.cclet.2020.10.033

Chemodivergent reactions of 2,2-dimethoxyacetaldehyde and anilines were described, which were established on the basis of either a C[sbnd]C bond cleavage or a rearrangement process of a reaction intermediate. These reactions proceeded in a condition-determined manner with good functional group tolerance. In the first model, 2,2-dimethoxyacetaldehyde reacted with aniline to form a new C[sbnd]N bond, in the presence of O₂, via a C[sbnd]C bond cleavage reaction. However, in the second model, by performing the reaction in the absence of O₂, Heyns rearrangement occurred and generated a new C[sbnd]O bond to form methyl phenylglycinate. Such condition-determined reactions not only offered the new way for value-added conversion of biomass-derived platform molecule, 2, 2-dimethoxyacetaldehyde, but also provided efficient methods for the synthesis of N-arylformamides and methyl phenylglycinates.

Full text of DOI:10.1016/j.cclet.2020.10.033

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Acid-catalyzed chemodivergent reactions of 2, 2-dimethoxyacetaldehyde
and anilines
Luxia Guo, Zihao Chen, Hongmei Zhu, Minghao Li, Yanlong Gu
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https://doi.org/10.1016/j.cclet.2020.10.033
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Chinese Chemical Letters
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Communication
Acid-catalyzed chemodivergent reactions of 2, 2-dimethoxyacetaldehyde and anilines
Luxia Guoa, Zihao Chena, Hongmei Zhua, Minghao Li a,*, Yanlong Gua,b,c

a Huazhong University of Science and Technology, Hubei Key Laboratory of Material Chemistry and Service Failure, Wuhan 430074, China
b State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Lanzhou 730000, China
c The Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan, Shihezi University, Shihezi 832004, China
 Corresponding authors.
E-mail addresses: klgyl@hust.edu.cn (Y. Gu), liminghaochem@hust.edu.cn (M. Li)
Graphical Abstract
Acid-catalyzed chemodivergent reactions of 2,2-dimethoxyacetaldehyde and anilines were described,
which were realized via either a C−C bond cleavage or a Heyns rearrangement of the reaction intermediate.
These reactions not only enriched the conversion method of biomass-derived platform molecule, 2, 2-
dimethoxyacetaldehyde, but also offered facile and efficient ways for the synthesis of methyl phen
ARTICLE INFO
Article history:
Received Received in revised form Accepted Available online
ABSTRACT
Chemodivergent reactions of 2,2-dimethoxyacetaldehyde and anilines were described, which were established on the basis of either a C−C bond
cleavage or a rearrangement process of a reaction intermediate. These reactions proceeded in a condition-determined manner with good functional
group tolerance. In the first model, 2,2-dimethoxyacetaldehyde reacted with aniline to form a new C−N bond, in the presence of O2, via a C−C bond
cleavage reaction. However, in the second model, by performing the reaction in the absence of O2, Heyns rearrangement occurred and generated a new
C−O bond to form methyl phenylglycinate. Such condition-determined reactions not only offered the new way for value-added conversion of biomass-
derived platform molecule, 2, 2-dimethoxyacetaldehyde, but also provided efficient methods for the synthesis of N-arylformamides and methyl
phenylglycinates.
Keywords:
Condition-determined reaction Chemodivergent reaction 2,2-Dimethoxyacetaldehyde C–C bond cleavage Heyns rearrangement
Chemodivergent reaction to selectively construct diverse compounds from readily available start materials has proven to be one of
the most important strategies in organic synthesis [1]. It attracts more and more attention and the power to develop chemodivergent
system is a longstanding challenging and an important task for organic chemists. This strategy has been used not only to develop eco-
efficient route to access novel biologically active small molecules [2], but also for creating molecular complexity to facilitate drug
discovery [3]. Many effective reaction models, such as condition-controlled [4,5], catalyst-mediated [6,7], additive-controlled [8,9],
———

directing group-enabled [10] and intermediate-dependent strategy [11,12] were all involved, and with which, a variety of molecular
frameworks were synthesized in modifying either chemo-, regio-, or stereoselectivity [13–15].
Acetals are important synthetic intermediates that are generally used as carbonyl protection in multistep synthesis reactions [16,17].
2,2-Dimethoxyacetaldehyde is a cheap and readily available biomass-derived platform molecule, because it can be synthesized from
ethylene glycol or glycerol [18,19]. This acetal is known to serve as a building block for the synthesis of a structurally diverse set of
molecules. Recently, intense research efforts have been dedicated to developing conversion pathway of valuable biomass platform
molecules [20]. In literature, 2,2-dimethoxyacetaldehyde was, simply used as a two-carbon electrophilic regent in most of the cases. For
instance, 2,2-dimethoxyacetaldehyde reacted readily with amine or methylene compound (Scheme 1, path a [21]). In most of the cases,
only the aldehyde carbonyl participated in the reaction, and the dimethoxymethylene fragment remained unaffected [22]. In some
special cases, 2,2-dimethoxyacetaldehyde contributed two of its carbons to form some heterocyclic compounds (Scheme 1, path c and
d) [23]. Although these individual examples demonstrated that the two electrophilic carbons of 2,2-dimethoxyacetaldehyde are both
reactive, the potential of this reagent in diversity-originated synthesis has not fully displayed, particularly for creating the molecular
complexity starting from the same substrates.
Scheme 1. Reactions of 2,2-dimethoxyacetaldehyde.
Direct C–C bond cleavage has attracted much attention because of the great ability to simplify the synthetic procedure [24]. Removal
of carbonyl group via oxidative cleavage is one of the typical ways [25–27], which strategically uses a carbonyl group as a temporary
activating or directing group in a number of synthetic processes. Chi and co-workers [28] reported an interesting approach, in which the
C–C bond cleavage of chiral aldehydes occurred through an in situ generated enamine intermediate, and the following oxidative
cleavage of C–C bond by oxygen allowed one molecule of N-phenylformamide to be formed. In this process, the formation of a key
hydroxyl imine intermediate provided the possibility of Heyns rearrangement, which has been widely used in carbohydrate chemistry,
and recently was extended to the synthesis of α-amino ketones [29–31]. On the basis of this unique rearrangement mechanism, methyl
phenylglycinate should be hopefully formed. Because of the fact that Heyns rearrangement occurs generally under acidic conditions,
downstream conversion of the generated N-phenylformamide product is also possible. This may allowed us to develop some new
reactions that are not possible with the previous reported alkaline conditions or metal carbene catalysts [32,33]. Out of all these
considerations, we started to use 2,2-dimethoxyacetaldehyde as a starting reagent to explore diversified reactions for organic synthesis.
Herein, we will report the successful outcome of our endeavor, in which three products including N-phenylformamide, methyl
phenylglycinate and dimethyl 2,2'-(phenylazanediyl)diacetate, were synthesized in good yield from the same substrates, 2,2-
dimethoxyacetaldehyde and aniline, and in these reactions, the product distribution can be finely tuned by changing the reaction
parameters.
To validate our hypothesis, we started our study by using 4-bromoaniline (1a) and 2, 2-dimethoxyacetaldehyde (2a) as model
substrates. Initially, the reaction was performed in 1,4-dioxane under air. No reaction occurred in the absence of catalyst (Table 1, entry
1). When strong Lewis acids, Sc(OTf)3 and AlCl3, were used as catalysts, it is difficult to initiate the reaction neither (entries 2 and 3).
When a stoichiometric amount of a weak Lewis acid, MnCl2, was added, N-(4-bromophenyl)formamide 3a was formed exclusively,
however, the yield reached only 23% after 2 h of reaction at 80 oC (entry 4). The yield of 3a can be improved to 42% by using Fe(OTf)3
as a catalyst (entry 5). PTSA exhibited excellent catalytic activity for this reaction, with which 3a can be obtained in 65% yield (entry
6). Subsequently, the effect of solvent was investigated by using PTSA as catalyst. Only trace amount of 3a was detected when toluene
was used as solvent (entry 7). The reaction proceeded hardly in acetonitrile and nitromethane (entries 8 and 9). When DMSO was
employed as solvent, 1a was converted quickly. However, three products, including 3a, methyl phenylglycinate (4aa) and dimethyl
2,2'-(phenylazanediyl)diacetate (4ba), were isolated with a product distribution in favor of the latter two (entry 10). The reaction
proceeded also smoothly in chloroform with 4ba been formed as the major product, and after 2 h of reaction, its yield reached 40%

along with simultaneous isolation of 19% of 4aa and 5% of 3a (entry 11). We next changed many other parameters in order to
maximize the yield of each reaction pathway. The uses of an excess amount of 1a and a protection with oxygen balloon were proved to
be helpful for improving the selectivity to 3a (entries 12–14). These observations guided us to find conditions A to synthesize 3a, that
are PTSA catalyst, 1,4-dioxane solvent, a 2.0/1.0 ratio of 1a/2a, protection with O2 balloon, 2 h and 60 °C. Under these conditions, 3a
can be isolated in 84% yield (entry 14). Somehow, performing the reaction at a higher temperature, 80 oC, imposed a negative effect on
the reaction (entry 15). The reaction selectivity was quite sensitive to the reaction time. When it was increased to 8 h, the yield of 3a
decreased to 32%, and the N-carboxyethylation product of aniline, 4aa, can be isolated with 38% yield (entry 16). Intriguingly, by
decreasing the ratio of 1a/2a, the reaction selectivity can also be tuned to favoring the formation of 4aa. A 74% of yield can be obtained
after 8 h in a reaction with equal amount of 1a and 2a under open-air conditions (entry 17). All these observations led us to find
conditions B to implement the N-carboxyethylation of 1a, that are PTSA catalyst, 1,4-dioxane solvent, a 1.0/1.2 ratio of 1a/2a,
protection with nitrogen balloon, 10 h and 80 °C. Under these conditions, 4aa can be isolated in 82% yield (entry 20). It should be
noted that, in this case, the yield was calculated with respect to the component with lower loading, 1a. Inspired by the observation in
performing the reaction in chloroform solvent (entry 11), conditions C for producing 4ba were also identified, which were confirmed to
be the followings: PTSA catalyst, chloroform solvent, a 1.0/2.0 ratio of 1a/2a, protection with nitrogen balloon, 60 oC, and 8 h (Table
S1 in Supporting information for detailed optimization studies). These conditions enabled us to synthesize 4ba in 79% yield (entry 21).
In conclusion, N-(4-bromophenyl)formylation (3a) was synthesized under condition A: 1a (0.6 mmol), 2a (0.3 mmol) and 20 mol% of
PTSA were added in 1,4-dioxane at 60 °C for 2 h under O2. Methyl phenylglycinate (4aa) was obtained under condition B: 1a (0.3
mmol), 2a (0.36 mmol) and 20 mol% of PTSA were added in 1,4-dioxane at 80 oC for 10 h under N2. 2,2'-(Phenylazanediyl)diacetates
(4ba) was synthesized under condition C: 1a (0.3 mmol), 2a (0.6 mmol) and 20 mol% of PTSA were added in CHCl3 at 60 oC for 8 h
under N2.
Having determined the optimized conditions A, B and C, the scope of anilines bearing various functional groups for synthesis of N-
phenylformamides, N-carboxyethylation and 2,2'-(phenylazanediyl)diacetates was then explored and the results are summarized in
Schemes 2 and 3. Upon repeating the reactions of 2a and anilines with different functional groups under the conditions A, N-
phenylformamides 3b–3v can be synthesized with yields ranging from 43% to 94%. para-Substituted anilines with a functional group,
like methyl (3c), tert-butyl (3d), methoxy (3e), halogen (3f and 3g), ethoxycarbonyl (3h) and trifluoromethyl (3i), are all tolerated the
condition A. However, 4-nitroaniline can hardly be used as substrate, and the expected product, 3k, was formed only in a trace amount.
meta-Substituted anilines are also readily participated in the N-formylation reaction, giving the expected products 3k–3o in the yields
ranging from 43% to 82%. More sterically demanding ortho-substituted anilines also engaged successfully in the N-formylation
reaction. Under the conditions A, the reactions of N-methyl-substituted anilines proceeded also very well, and the expected product, 3t
and 3u, were isolated in 78% and 81% yields, respectively. By means of a wise use of an ortho-substituted aniline, some heterocyclic
compounds can be synthesized with slight modification of the condition A. For example, o-phenylenediamine can be converted to
benzimidazole 3w in 63% of yield with the use of 3.0 equiv. of tert-butyl hydroperoxide (TBHP) as an oxidizing reagent under the
conditions A. Anthranilamide can be converted to 4-hydroxyquinazoline 3x in 73% yield under the similar conditions. Literature survey
stated that a precedent of transforming anthranilamide to 3y was established based on C–C bond cleavage, however, it involves the use
of an expensive reagent, alkynyl ketone, as substrate [34]. The combination of 2a and TPHP allowed this transformation to be realized
by a cost-effective way. Interestingly, a congener of 3x without C–C bond cleavage, 3x', can be obtained in 93% yield under N2
atmosphere in chloroform solvent. The presence of an acetal fragment adjacent to the nucleophilic aromatic ring may facilitate the
downstream conversion of this unique compound.
Scheme 2. Substrate scope of PTSA-catalyzed N-formylation reactions of anilines with 2a: 1a (0.60 mmol), 2a (0.30 mmol), PTSA (20 mol%),
1,4-dioxane (1.0 mL), under O2 atmosphere, 60 °C, 2 h, isolated yield, calculated with respect to 2a (reaction conditions A). a TBHP (3 equiv.)
as oxidant. b1a (0.30 mmol), 2a (0.30 mmol), PTSA (20 mol%), CHCl3 (1.0 mL), under N2 atmosphere, 60 °C, 2 h.
The substrates scope of the N-carboxyethylation under the condition B is shown in Scheme 3. Anilines bearing electron-
withdrawing, electron-donating, and halogen groups at the different positions all reacted smoothly with 2a, affording the N-

carboxyethylation products in moderate to good yields. The reaction could well tolerate methyl, methoxyl and halogens groups, giving
4ab to 4ah in 69-80%. It should be emphasized that, electronic effect had no obvious influence on the N-carboxyethylation reaction.
ortho-Substituted anilines were found to be less reactive than those para- or meta-substituted counterparts. The scope of the double N-
dicarboxyethylation reactions of anilines under the condition C is also examined. As shown in Scheme 3, the examined para-substituted
anilines were all compatible with this transformation, giving direct access to the corresponding 2,2'-(phenylazanediyl)diacetates (4bb–
4bd) in moderate yields (53%−62%).
Scheme 3. Synthesis of methyl phenylglycinate. 1 (0.3 mmol), 2a (0.36 mmol), PTSA (20 mol%), 1.4-dioxane (1.0 mL), under N2 at 80 oC for
10 h. Isolated yield, calculated with respect to the aniline component (reaction condition B). a 1 (0.3.0 mmol), 2a (0.60 mmol), PTSA (20
mol%), CHCl3 (1.5 mL), 60 oC, under N2 for 8 h, isolated yield, calculated with respect to the aniline (reaction condition C).
To gain the inside information of the reactions, some comparative experiments were conducted, and the result are given in Scheme 4.
Treatment of 3a with 2a in 1,4-dioxane at 80 oC in the presence of PTSA led to the formation of 4aa (Eq. 1). Although only moderate
yield was obtained, because 3a remained unreacted in the reaction system, the result in the Eq. 1 verifies the reversibility of N-
formylation of aniline [35]. Replacement of 2,2-dimethoxyacetaldehyde with either glyoxal aqueous solution or vinylene carbonate
failed to form any target product under the standard conditions (Scheme 4, Eqs. 2 and 3). With reference to literature precedent [36-38],
a plausible mechanism for the reactions is proposed as follows. In the initial stage of the reaction, aniline acted as a nucleophile to
attack the carbonyl group of 2a, leading to the formation of an intermediate I. Then, the acid catalyst activated one methoxy group of
the acetal part, increasing its leaving ability, and resulted in the formation of an intermediate II. In the presence of molecular oxygen, a
[2+2] cycloaddition occurred [28, 36-39], and the following downstream decomposition of a dioxetane intermediate III enabled the
formation of 3a. In the absence of oxygen, the intermediate II underwent a Heyns rearrangement reaction to form an intermediate 1,2-
enaminol IV [40], which was then converted to 4aa via an enol-ketone tautomerization. Compound 4ab was formed through a second
run of the N-carboxyethylation.

Scheme 4. Some control experiments and plausible mechanism.
In summary, we developed an acid-catalyzed chemodivergent method for the synthesis of N-phenylformamides and methyl
phenylglycinates by using the same starting substrates, 2, 2-dimethoxyacetaldehyde and anilines. By tuning the reaction conditions, the
product distribution can be finely changed, thus offering an effective way for maximizing the product diversity. This reaction will
provide a good example for conditions-controlled chemodivergent conversion of biomass-derived platform molecules 2, 2-
dimethoxyacetaldehyde.
Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships that
could have appeared to influence the work reported in this pape
Acknowledgments
We thank the National Natural Science Foundation of China for financial support (Nos. 2171101076 and 21872060). We are grateful
to the Analytical and Testing Centre of HUST.
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Table 1
Optimization of conditions for the reaction 4-bromoaniline and 2, 2- dimethoxyacetaldehyde. a
Yield (%)b
3a
0
0
0
Entry
Catal.
Solvent
Temp. (oC)
Time (h)
4aa
0
4ba
0
1
2
—
Sc(OTf)3
AlCl3
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Toluene
CH3CN
CH3NO2
DMSO
80
80
80
80
80
80
120
100
100
80
60
80
80
60
80
60
80
80
80
80
60
2
2
2
2
2
2
2
2
2
2
2
2
1
2
2
8
8
8
8
10
8
trace
0
0
0
3
4c
MnCl2
Fe(OTf)3
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
23
42
65
0
trace
trace
13
5
78
81
84
71
32
10
9
0
0
5
6
7
8
trace
trace
0
0
0
0
0
0
9
0
0
10
11
12d
13d,e
14d,e
15d,e
16d, e
17
18f
19g
20g, h
21h, i
25
19
21
40
0
0
0
CHCl3
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
CHCl3
trace
trace
trace
trace
38
0
0
74
0
78
0
6
7
trace
79
82
trace
trace
trace
79
Dioxane: 1,4-dioxane.
aReaction conditions: unless otherwise noted, all reactions were performed with 1a (0.30 mmol), 2a (0.30 mmol), solvent (1.0 mL) and catalyst
(20 mol%).
bIsolated yield, and the yield was calculated with respect to the component with lower loading.
cMnCl2 (1.0 equiv.).
d1a (0.60 mmol), 2a (0.30 mmol).
eO2 balloon.
f1a (0.36 mmol), 2a (0.30 mmol).
g1a (0.30 mmol), 2a (0.36 mmol).
hN2 atmosphere.
i1a (0.30 mmol), 2a (0.60 mmol).