Discovery of redox system enabling C–N–C bonds formation: Unprecedented Aza-Cannizzaro reaction

Article abstract of DOI:10.1016/j.tetlet.2017.04.010

A novel reaction involving in situ redox conversion of glyoxylate esters to glycine is described. Simple starting materials and mild conditions for the synthesis of glycine derivatives probably indicate a pathway towards prebiotic chemistry. This proceeds analogous to Cannizzaro reaction involving ammonia therefore it can be termed as intramolecular Aza-Cannizzaro type reaction. This reaction is examined in detail with an aid of computational analysis to corroborate the proposed mechanism.

Full text of DOI:10.1016/j.tetlet.2017.04.010

Accepted Manuscript
Discovery of Redox System Enabling C-N-C Bonds Formation: Unprecedented
Aza-Cannizzaro Reaction
Abhishek Sud, Pramod S. Chaudhari, Ishu Agarwal, Amjad Bashir Mohammad,
Vilas H. Dahanukar, Rakeshwar Bandichhor
PII:
S0040-4039(17)30435-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.010
TETL 48802
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 January 2017
1 April 2017
4 April 2017
Please cite this article as: Sud, A., Chaudhari, P.S., Agarwal, I., Mohammad, A.B., Dahanukar, V.H., Bandichhor,
R., Discovery of Redox System Enabling C-N-C Bonds Formation: Unprecedented Aza-Cannizzaro Reaction,
Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.04.010
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1
Tetrahedron Letters
journal homepage: www.elsevier.com
Discovery of Redox System Enabling C-N-C Bonds Formation: Unprecedented Aza-
Cannizzaro Reaction
Abhishek Sud,a Pramod S. Chaudhari,a Ishu Agarwal,a Amjad Bashir Mohammad,a Vilas H.
Dahanukar,aRakeshwar Bandichhora*
a API R&D, IPDO Innovation Plaza, Dr. Reddy’s Laboratories Ltd. Bachupally, Hyderabad, A.P. India 500090, Fax: 9140 4434 6285; Tel: 91 40 4434 6429; E-
mail: rakeshwarb@drreddys.com;IPDO-IPM-00385
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel reaction involving in situ redox conversion of glyoxylate esters to glycine is
described. Simple starting materials and mild conditions for the synthesis of glycine
derivatives probably indicate a pathway towards prebiotic chemistry. This proceeds
analogous to Cannizzaro reaction involving ammonia therefore it can be termed as
intramolecular aza-Cannizzaro type reaction. This reaction is examined in detail with
an aid of computational analysis to corroborate the proposed mechanism.
Available online
Keywords:
Redox reaction
Cannizzaro reaction
Disproportionation
Amino acid
2009 Elsevier Ltd. All rights reserved.
DFT calculation
Introduction
In essence, this experiment (Figure 1) established emergence of
amino acids and led credence to hypothesize that complex
organic molecules can be derived from these simple building
blocks.
Thus, it was proposed that the origin of life was not from
anywhere else but from a chemical reaction that first afforded
five amino acids.1 Reanalysis of original reaction mixture of
Miller-Urey’s experiment which was performed in 2008 in fact
revealed that there were twenty amino acids synthesized in one
single experiment proves the origin of life hypothesis by
chemical evolution.2
The Miller-Urey experiment simulated probable conditions
present on early earth and demonstrated the presence of basic
building blocks of life.
Miller-Urey
In this context there are several hypotheses leading to the
synthesis of amino acid in the primordial atmospheric conditions
prevailing on early earth. Reduction of CO2 to formic acid in
aqueous solution (Figure 1) was demonstrated by Calvin et. al
that indicates one carbon source reactive species towards amino
acids.3
Calvin
Karat
HCN was also investigated and found to be a source of amino
acid due to basic hydrolysis (Figure 1).4 Few other hypotheses on
the prebiotic origin of life have been postulated by various
groups.5 Here in, we report that glyoxylic acid 1 is an amino acid
back bone which can be synthesized by nature starting from CO2
via citric acid and glyoxylate cycles or under highly energetic
conditions may be one of the sources of amino acids in prebiotic
era (Figure 1). We hypothesized that the amino acids can be
accessed via redox event on glyoxylic acid 1 leading to glycine 2
and oxalic acid 3 as shown Figure 2.
This work
Figure 1. Primordial conceived approaches for amino acids

2
Tetrahedron
Figure 2. Redox chemistry on ethyl glyoxylate and Cannizzaro
reaction
In order to validate our hypothesis we turned our focus to
understand the mechanistic aspect of Cannizzaro reaction, first
discovered in 1853, is a base induced disproportionation of an
aldehyde 4 leading to the formation of an oxidation product 6 and
its reduced counterpart 5 (Figure 2). Thus a salt of carboxylic
acid and an alcohol are obtained as the products of this reaction.
For this reaction to proceed successfully it is required that there
should not be any hydrogen atom at alpha position to the
aldehyde functionality, otherwise Aldol condensation product is
preferably obtained.6
To the best of our knowledge, there are no reports outlining the
imine taking part in these reactions instead of the carbonyl
functionality. In this report we disclose a Cannizzaro type
reaction for the first time in which the esters of glyoxylic acid
undergo an in situ disproportionation in the presence of
ammonium acetate leading to dimeric product bridged through
imine functionality as shown in Scheme 1.
Figure 3. Two different reaction pathways (a and b)
Energy barriers were ascertained by the DFT calculations
performed with the Dmol3 module of Accelrys MS using a local
density approximation, the exchange-correlation local functional
PWC.7 DMol3 uses numerical orbitals for the basic functions,
each function corresponding to an atomic orbital (AO). Double
numerical plus d-functions (DND), it is like DN with a
polarization d-function on all non-hydrogen atoms.
This is the default basic set, providing reasonable accuracy for
modest computational cost. The final energies were extrapolated
to zero smearing. Transition states (TS) of Aza Cannizzaro
reaction were located with the nudged elastic band method.8 We
calculated reaction and activation energies in gas phase. Each of
the TS structures presented was probed by a normal-mode
analysis to ensure that it indeed exhibited only one vibrational
mode with an imaginary frequency. However, there might be an
energy difference of ~ 20 – 30 kJ/mol if we change the methods
used in calculations for TS.
In the computational analysis, we considered both the following
reaction mechanism; paths a and b for this novel Aza-Cannizzaro
reaction. Path a will be a concerted [1,3]-H shift reaction when
compared to a stepwise reaction as elucidated in path b.
Calculations lead to a new intermediate stable state which is not
shown in path a, wherein we observed the formation of water
molecule, even before achieving the step 1 stable state as shown
in path a of Figure 3. Hydrogen atom (H1) located on carbon,
first forms a water molecule with an energy barrier of 257
kJ/mol, with the adjacent OH group and then dissociates from
water molecule again with approximately similar energy barrier
and adds to other carbon atom leading to step 1 as shown in path
a. Accordingly the double bond of nitrogen shifts satisfying the
valency. Final product was formed starting from intermediate
stable state (InS2) where the hydrogen of hydroxyl group attacks
nitrogen with an energy barrier of 278 kJ/mol. However, the
reaction is 142 kJ/mol exothermic and above reaction pathway
carries three transition states with ~ 250 kJ/mol barriers (Figure
5) that made us think and redesign path a leading to path b.
Different transition states of it is elucidated in Figure 6 and
energy landscape in Figure 7.
Scheme 1. Synthesis of glycine 2
Reaction proceeds through imine intermediate 7 which further
reacted with another equiv. of ethyl glyoxylate to yield atom
efficient derivative 8. There is fascinating aspect of atom
convergency in the redox event leading to the intermediate 9. In
general, imine reduction requires hydride/metal-hydrogen source
however in this case intermediate 8 undergoes oxidation of
secondary hydroxyl to ketone and the liberated hydrogen gets
accommodated in reduction of imine without any external
assistance of metal. Eventually, it was possible to access amino
acid backbone containing intermediate 9 which has further been
converted to glycine 2 and oxalic acid 3 as evocative of
Cannizzaro reaction. Although we conceived that this novel
transformation was similar to Cannizzaro reaction, we were not
assured of operating mechanism. It is being first of its kind we
attempted to probe it with an aid of computational analysis
aiming to find out which one of the two reaction pathways is
favoured from energy standpoint as shown in Figure 3.

3
a, here there has been an exothermic reaction leading to form
InS. The second step followed by overcoming a reaction barrier
of 81 kJ/mol by the hydrogen of hydroxyl attacking the carbon
next to nitrogen (see Figures 6 & 7).
Here, in the transition state, O-H bond has been elongated to 1.27
Å and whereas C-H is 1.49 Å. Rest all bond lengths & angles are
within the expected ranges. Considering energy parameters, it
can be proposed that the path b is preferred one due to its less
number of activation barriers and exothermicity. In essence,
redox event without any major external trigger is quite intriguing
that indicates one of the unprecedented pathways for prebiotic
amino acid synthesis.
Figure 4. Concerted reaction mechanism as depicted in path a.
Reaction begins from Initial state (IS) leading to the final state
(FS) passing through two intermediate states (InS1 & InS2) and
three transition states (TS1, TS2 & TS3)
Figure 7. Reaction energy landscape for path b.
Figure 5: Reaction energy landscape for path a.
Computation analysis complements the experimental results as
reaction takes place in presence of ammonium acetate (3 equiv.)
in THF as a solvent. After screening different conditions it
turned out that the best yields of 60% were obtained under reflux
in THF in 8 h of reaction time (mild conditions). When the
reaction was carried out at room temperature, a short lived imine
product was isolated which then converted to the final product on
refluxing. In addition to this, we found that one pot reaction
without isolation of imine intermediate was more efficient. After
this result, various other glyoxylates were used as substrates with
NH4OAc in refluxing THF to obtain products.
In order to establish generality of this method we embarked on
substrate scope studies. Following the typical procedure,12 it was
found that this reaction is general for varieties of alkyl esters of
glyoxylic acid 1 (a-l). Phenyl ester (1l) did not afford product 9l
in a significant quantity rather it was in trace quantity. Moreover,
the phenyl ester, 1l was consumed which may be attributed to
the reaction of resulting amine 9l to the phenyl ester (better
leaving group than alkyl esters) under refluxing conditions in
a polymerization fashion. The yields for all the products 9 (a-l)
were up to 68% (Table 1).
Figure 6. Step reaction mechanism as depicted in path b.
Reaction begins from Initial state (IS) leading to the final state
(FS) passing through two intermediate state (InS) and two
transition states (TS1, TS2)
Based on reaction energy landscape shown in Figure 6, path b is
the desired reaction pathway with lower and lesser activation
barriers. As shown in Figure 3, hydrogen (H) attacks nitrogen (N)
and forms N-H leading to an intermediate stable state (InS) by
overcoming a barrier of 220 kJ/mol and polarising nitrogen’s
double bond with neighboring carbon. In the transition state, it
was noticed that hydrogen forms a vertex of the triangle where
other two vertices were occupied by carbon and nitrogen. In the
transition state, C-H bond has been elongated to 1.44 Å and
whereas N-H is 1.23 Å. Unlike the endothermic first step of path
Table 1. Aza-Cannizzaro reaction on different alkyl esters of
glyoxylic acid
S.No. Substrate (R) Yield (%)
1
2
Ethyl (a)9
n-Propyl (b)
60
62

4
Tetrahedron
Biospheres, 1998, 28, 61; Sheng, Y. H.; Bean, H. D.; Mamajanov, I.; Hud
3
4
5
6
7
8
9
10
11
Isopropyl (c)
n-Butyl (d)10
Isobutyl (e)
t-Butyl (f)11
Cyclohexyl (g)
Hexyl (i)
Menthyl (j)
Isobornyl (k)
Phenyl (l)
68
68
65
64
60
62
65
60
trace
N. V.; Leszczynski, J. J. Am. Chem. Soc. 2009, 131, 16088; Mittapalli, G.
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Conclusion
In this communication, we discovered an unprecedented reaction,
analogous to Cannizzaro reaction which involves the in situ
disproportionation of the glyoxylates in presence of ammonium
acetate. Various glyoxylates undergo this reaction giving
respectable yields and high atom economy. Based on the
experimental observations and computational studies, we have
proposed a mechanism for this reaction. These novel reactions
have the potential to become a valuable tool in organic synthesis
to synthesize natural and un-natural amino acids and their
derivatives. Indication from computational analysis which has
been complemented by experimental outcome (under moderate
reaction conditions) prompted us to postulate a hypothesis which
could be considered as one of the pathways for prebiotic amino
acid synthesis. Further optimization and studies are underway in
our group to expand the use of these reactions in the synthesis of
amino acids.
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C. J. Chem. Educ. 1930, 7, 594; Geissman, T. A. Org. React. 1944, 1, 94;
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12. To the solution of isopropyl glyoxylate (1.28 g, 11 mmol) in THF (50
mL), ammonium acetate (3 equiv., 2.55 g, 33 mmol) was added and
refluxed for 8 h. The solvent was evaporated under vacuum and product
was obtained on purification through column chromatography on silica
W.;
Jin,
C.;
Li,
J.;
Shi,
X.;
Zhang,
G.
Acknowledgement
1
gel. Yield= 68% (0.86 g); H NMR (CDCl3, 400 MHz): δ 7.55 (br, 1H),
4.90-5.10 (m, , J = 6.28 Hz, 2H), 4.02 (d, J = 5.48 Hz, 2H), 1.40 (d, J =
6.28 Hz, 6H), 1.20 (d, J = 6.28 Hz, 6H) ppm; 13C NMR (CDCl3, 100
MHz): δ 167.3, 158.4, 155.9, 70.70, 68.8, 40.7, 20.7, 20.5; HRMS
(M+1): C10H17NO5; Calculated: 232.1185 Found: 232.1193.
We are grateful to Dr. Reddy’s Laboratories Ltd. for
encouragement and supporting this work.
Notes and references
1. Miller, S. L. Science, 1953, 117, 528; Miller, S. L.; Urey, H. G. Science,
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5. Strecker, A. Liebigs. Ann. Chem. 1850, 75, 27; Taillades, J.; Beuzelin, I.;
Garrel, L.; Tabacik, V.; Bied, C.; Commeyras, A. Origins Life Evol.

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Discovery of Redox System Enabling C-N-C Bonds Formation: Unprecedented
Aza-Cannizzaro Reaction
Abhishek Sud,a Pramod S. Chaudhari,a Ishu Agarwal,a Amjad Bashir Mohammad,a Vilas H.
Dahanukar,aRakeshwar Bandichhora*

*Highlights
Highlights
 Novel redox event without any oxidizing and reducing agent is exemplified.
 Aza-Cannizzaro as a new reaction is discovered.
 Alternate pathway for amino acid synthesis is proposed.
 Preferred operative mechanism and energy barriers are ascertained by DFT calculations.