N-Isocyanodialkylamines generated in situ for the Joullié–Ugi reaction with indolenines

Article abstract of DOI:10.1016/j.tetlet.2018.08.025

N-Isocyanodialkylamines are rare isocyanide surrogates for the Ugi-type reactions. To avoid problems with instability and the obnoxious smell of these reagents, we optimized and employed a convenient protocol for in situ dehydration of N,N-dialkyl-N′-formyl hydrazines to give the respective N-isocyanodialkylamines which were utilized in the reaction with indolenines and acetic acid. The reaction was demonstrated to give modest to excellent yields of products incorporating the N-isocyanodialkylamine but not the carboxylic acid component.

Full text of DOI:10.1016/j.tetlet.2018.08.025

Accepted Manuscript
N-Isocyanodialkylamines Generated In Situ for the Joullié –Ugi reaction with
Indolenines
Pavel Golubev, Mikhail Krasavin
PII:
S0040-4039(18)31007-4
https://doi.org/10.1016/j.tetlet.2018.08.025
TETL 50200
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 July 2018
5 August 2018
13 August 2018
Please cite this article as: Golubev, P., Krasavin, M., N-Isocyanodialkylamines Generated In Situ for the Joullié –
Ugi reaction with Indolenines, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.08.025
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N-Isocyanodialkylamines Generated In Situ for the Joullié–Ugi reaction with
Indolenines
Pavel Golubev and Mikhail Krasavin*
Saint Petersburg State University, Saint Petersburg 199034 Russia.
e-mail: m.krasavin@spbu.ru
http://www.krasavin-group.org/
ORCID Mikhail Krasavin: 0000-0002-0200-4772
Abstract: N-Isocyanodialkylamines are rare isocyanide surrogates for the Ugi-type reactions. To
avoid problems with instability and the obnoxious smell of these reagents, we optimized and
employed a convenient protocol for in situ dehydration of N,N-dialkyl-Nʹ-formyl hydrazines to
give the respective N-isocyanodialkylamines which were utilized in the reaction with indolenines
and acetic acid. The reaction was demonstrated to give modest to excellent yields of products
incorporating the N-isocyanodialkylamine but not the carboxylic acid component.
Keywords: multicomponent reactions, Joullié–Ugi reaction, in situ dehydration, N-
isocyanodialkylamines, Mumm rearrangement, O-deacylation.
The Ugi multicomponent reaction (Ugi MCR)1 provides a facile entry into peptidomimetic bis-
amides 1 by allowing incorporation of the four different reagents (an amine, a carbonyl
compound, a carboxylic acid and an isocyanide) into the structure of 1 in a predictable and
efficient manner (Fig. 1).
R2
R3
O
R2 R3
O
H
HO
O
R1 NH2
N
R4
R4
N
R5
+
- H2O
R1
O
C-
N+
R5
1
Figure 1. The Ugi multicomponent reaction.
The Ugi reaction undoubtedly occupies a central place in the toolbox of combinatorial
chemistry2 and has given rise to numerous compound libraries for biomedical research.
Additionally, the use of post-condensational modifications3 of the Ugi reaction products as well

as employment of bifunctional reagents4 in the Ugi reaction itself has opened vast opportunities
for the efficient and atom-economical synthesis of unique heterocyclic scaffolds which would be
difficult or impossible to obtain otherwise.5
Replacement of either – or several – of the components of the ‘Ugi foursome’ with surrogate
reagents or reactive centers represents a productive strategy towards increasing the product
structural diversity of this powerful MCR. The amine6 and the carboxylic acid7 components are
the most frequently replaced with their reactive equivalents while the carbonyl component
replacement can be recognized, in principle, within various surrogates of the imine intermediate
through which the Ugi MCR is known to proceed; notable examples of the latter approach
include the use of activated azines.8 However, as it is evident from the literature, the isocyanide
component in the Ugi reaction has not been viewed as a candidate for surrogate replacement due
to its unique reactivity.
N-Isocyanodialkylamines 2, prepared for the first time in 1965 by dehydration of the respective
N,N-dialkyl-Nʹ-formyl hydrazines 3,9 have been employed as ligands for various metal
complexes10 as well as reagents in organic transformations as recently reviewed by Moderhack
and co-workers.11 Examples illustrating the synthetic utility of 2 are quite limited12 and include
their participation in a three-component synthesis of 1-amino-3-pyrrolin-2-ones 4,13 formation of
2-imino-1,3-oxathioles 5,14 condensation with an aniline to give hydrazine carboxamides 615 and
insertion into the N-H bond of saccharine to give formamidrazone 7.16 Interestingly, since the
first report, published in 1969, of using an N-isocyanodialkylamine in the Ugi reaction with
secondary amines,17 there has only been a single example of a similar employment of this type of
reagent – specifically, in the ‘intramolecular’ Ugi reaction toward lactam 8 as reported by
Harriman18 (Fig. 2).
However, apart from these two isolated reports, no studies involving the use of 2 in the Ugi
reaction (and isocyanide-based reactions in general) have been reported. Although the N-N
motifs are generally stigmatized as unwanted structural alerts in medicinal chemistry due to
potential toxicity of the resulting compounds,19 a hydrazide bond (such as the one present in 8)
replacing a regular amide bond in the Ugi reaction products can have significant utility in the
design of more hydrolytically stable hydrazino peptidomimetics.20 Moreover, an additional basic
nitrogen atom present in the hydrazides resulting from the use of 2 in the Ugi reaction can lead to
potentially interesting new conformations adopted by these compounds and supported via
hydrogen bonding.21 The latter have been shown to mimic various peptide turn motifs22 which
are important in protein-ligand and protein-protein interactions.23 Thus, we became puzzled by
the apparent lack of examples in the literature on the use of 2 as surrogate isocyanides in the Ugi

reaction and set off to investigate the reasons for this void as well as to expand, if possible, the
utility of this type of reagent in multicomponent chemistry. Herein, we report the results of these
findings.
R'
COCl2
O
R'
N N+ C-
N NH
R
TEA, CH2Cl2
r. t.
R
2
3
p-TolCHO
EtO2C CO2Et
N
N
O
N N+ C-
Tol-p
CO2Et
benzene
80 oC, 3 h
EtO2C
4
, 52%
OH
SNPhth
pyridine
O
S
N N+ C-
N N
toluene, 100 oC
5
, 97%
3 h
O
N
ArNH2
Ar
N
N
N
N NC
N
1,4-dioxane
80 oC, 20 h
H
H
6
OMe
N
N
N
Ar =
O
*
O
NH
O
S
O2
ether
N N+ C-
N
S
N N
O2
7
O
HO2C
Bn
O
O
N
H
N
O
N NC
N
BnNH2
MeOH, r. t., 48 h
O
8
, 61%
Figure 2. Preparation of N-isocyanodialkylamines 2 and examples of their synthetic utility.
Isocyanides in general24 and N-isocyanodialkylamines in particular9 are characterized by their
obnoxious smell, which hinders their laboratory use. Therefore, various ‘isocyanide-less’
protocols involving the generation of isocyanides in situ from practically benign precursors have
been developed. While the protocol involving the use of alkyl halides and silver cyanide
developed by El Kaim and co-workers25 would not be applicable to the preparation of N-

isocyanodialkylamines, the in situ dehydration of formamides reported recently by Dömling and
co-workers,26 in this case, appeared to be a good methodological choice. Additionally, the in situ
dehydration approach is particularly justified in the case of N-isocyanodialkylamines because the
latter are prone to rearrangement to their cyano counterparts upon standing.9 Thus, in order to
assess the prospects of using N-isocyanodialkylamines 2 as reagents for the Ugi-type reaction, in
principle, we selected indolenine 9a as an imine component (recently validated for use in the
three-component Joullié–Ugi reaction27) in combination with acetic acid and N-
(formylamino)piperidine (3a) as a precursor for the in situ preparation of isocyanamide 2a. The
results of these experiments are presented in Table 1.
Table 1. In situ dehydration of 3a to 2a and reactions of the latter with indolenine 9a.a
Cl
dehydrating
N
9a
agent, TEA
Cl
, AcOH
HN
O
N
Cl
N
NHCHO
3a
N
NC
2a
CHCl3
-15 oC, 1.5 h
N
H
Solvent
-15 oC to r. t.
Cl
10a
18 h
Entry Dehydrating
agent
Yield
Solvent
10ab
24%c,d
88%e
0%f
1
2
3
4
5
6
7
8
9
triphosgene
POCl3
POCl3
POCl3
POCl3
POCl3
POCl3
POCl3
POCl3
MeOH
MeOH
CHCl3
i-PrOH
t-BuOH
MeOH
MeOH
MeOH
MeOH
90%f
23%f
0%c,g
90%f,h
23%c,i
60%f
a Reagents and conditions: 3a (1.25 mmol), TEA (3.13 mmol), triphosgene (0.5 mmol) or POCl3
(1.38 mmol), CHCl3 (0.8 mL), then 9a (0.5 mmol), AcOH (1.5 mmol), solvent (0.2 mL);
reactions performed in a sealed vial.
1
b Determined by the relative integration of the signals for 10a in the crude H NMR spectrum
relative to the CH2Br2 internal standard.
c Incomplete conversion of 9a.
d Protocol described in ref. 26.
e Isolated yield.
f Full conversion of 9a.
g No AcOH used.
h AcOH (8 equiv.) used.
i 3a (1.5 equiv.) used.
j AcOH (1.5 equiv.) used.

The initial testing of the in situ dehydration protocol developed by Dömling and co-workers26 led
to an incomplete conversion of 9a and the formation of product 10a arising from the two-
component Joullié–Ugi reaction (i.e., without incorporation of the carboxylic acid component) in
1
24% yield, as determined by H NMR analysis of the crude reaction mixture (Entry 1).
Fortunately, the yield of the reaction improved dramatically upon replacement of triphosgene
with phosphorus(V) oxychloride; however, the acetic acid component was still absent in the
product (Entry 2).
The Ugi reaction is thought to proceed via the formation of the initial acyloxy imine adduct 11 in
which ON acyl migration (Mumm rearrangement) can take place (Scheme 1, path a) leading to
the formation of adduct 12. However, if the nucleophilicity of the nitrogen atom in question is
reduced (as is the case in 11 due to the nitrogen atom’s anilinic character as well as steric
hindrance), a competing deacylation by the nucleophilic solvent (e.g. methanol)21 can take place
(Scheme 1, path b) leading to the observed non-acylated product 10.
R1
R2
R3
R4
R3
R4
R1
N
R2
C
N
N
C
N
N
X
2
N
X
H
R5COOH
O
O
9
R5
H+
R1
R3
R4
R2
R1
R3
N
N
R2
a
HN
O
N
X
a
R4
N
H
O
X
N
O
11
R5
b
R5
12
O
ROH
- R5CO2R
b
R1
R3
R2
HN
O
N
R4
X
N
H
10
Scheme 1. Plausible mechanism for the Joullié–Ugi reaction between indolenine 9,
isocyanamide 2 and acetic acid.

We reasoned that the reaction could be forced to proceed along path a if a non-nucleophilic
(Table 1, entry 3) or less nucleophilic (Table 1 entries 4-5) solvent was used. However, in the
former case, only a complex mixture of products was observed, while running the reaction in
other alcoholic solvents either did not alter (i-PrOH) or lowered (t-BuOH) the yield of 10a but
did not lead to the formation of the respective N-acylated product 12. This indicates that the
formation of intermediate 11 did likely take place in this reaction (as no reaction was observed if
the carboxylic acid component was omitted altogether – Table 1, entry 6). However, if
intermediate 11 is not evolved via O-deacylation by a nucleophilic solvent, it gives rise to a
complex mixture of products. Increasing the amount of acetic acid (Table 1, entry 7) also did not
promote acylation while lowering the amount of either 3a (Table 1, entry 8) or acetic acid (Table
1, entry 9) led to reduction of the product yield. From these data, it was concluded that a high-
yielding two-component Joullié–Ugi reaction between 2 and 9 via in situ dehydration of 3 is
feasible in the presence of excess acetic acid, under the condition shown in Table 1, entry 2.
These conditions (Scheme 2) were employed in the preparation, with the use of formic
hydrazides 3a-g and indolenines 9a-e (Fig. 3), of an extended set of adducts 10a-r (Table 2).
R1
R2
R1
R3
R4
X
R2
N
9a-e
POCl3, TEA
HN
O
N
R4
R3
OHC
HN
X
N
CHCl3, -15 oC
1.5 h
N
H
ACOH, MeOH
-15 oC to r. t.
18 h
3a-g
10a-r
Scheme 2. Preparation of indolin-2-carboxylic acid hydrazides 10 via the two-component
Joullié–Ugi reaction.
Ph
Ph
Ph
N
NHCHO
N
NHCHO
N
NHCHO
N
NHCHO
3b
3c
3d
3a
Ph
Ph
N
N
NHCHO
NHCHO
N
NHCHO
3f
Cl
3g
3e
Cl
Cl
Cl
Cl
N
N
N
N
N
Cl
Cl
Cl
9d
9a
9e
9b
9c
Figure 3. Formic hydrazides 3a-g and indolenines 9a-e employed in this study.

As follows from the results presented in Table 2, the reaction displayed a substantial scope with
respect to N-formyl hydrazines 3 and indolenines 9 and gave the two-component reaction
adducts 10a-r in moderate to excellent yields. The reaction outcome did not seem to be affected
by steric or electronic factors, despite the observed variation in the yield. Preliminarily, it can be
concluded that a cyclic or a bulky dialkyl amino terminus in the N-formyl hydrazines 3 generally
leads to better yields in comparison with the cases when one of the terminal substituents is a
small alkyl group (as in 10f-g, 10k-o). The reaction products have been characterized by 1H and
13C NMR and high-resolution mass-spectrometry (see ESI). Additionally, the structure of a
representative compound (10m) was confirmed by single-crystal X-ray analysis (Fig. 4).
Cl
Cl
O
O
Cl
O
N
H
N
H
HN
N
HN N
N
HN
N
H
Cl
Cl
Cl
10a
10b
, 77%
10c
, 47%
, 88%
Cl
Cl
Cl
Cl
O
O
Cl
O
O
Ph
Ph
N
N
HN
N
HN N
N
H
HN
N
N
H
HN
N
H
H
Cl
Cl
Cl
10d
10e
10f
10g
, 40%
, 85%
, 84%
, 36%
Cl
Cl
O
O
O
Cl
O
Ph
Ph
Ph
Ph
Ph
Ph
N
H
HN
N
N
N
H
HN
N
HN N
N
H
HN
N
H
Cl
Ph
Cl
Cl
Cl
10h
10i
10j
10k
, 80%
, 83%
, 70%
, 40%
Cl
Cl
Cl
Cl
O
O
O
O
Ph
Ph
Ph
Ph
N
N
HN
N
HN N
N
HN
N
H
H
N
HN
N
H
Cl
Cl
H
10l
, 38%
10m
10n
, 55%
10o
, 48%
, 53%
Cl
Cl
O
Cl
O
O
N
HN
N
N
HN
N
N
HN
N
H
H
H
Cl
Cl
10p
, 68%
10q
, 52%
10r
, 87%
Table 2. Indolin-2-carboxylic acid hydrazides 10 synthesized in this work.

.
Figure 4. Single-crystal X-ray structure of compound 10m (CCDC 1835251)
Having identified indolenines 9 as suitable substrates for the AcOH-promoted reaction with N-
isocyannodialkylamines 2 generated by in situ dehydration of N,N-dialkyl-Nʹ-formyl hydrazines
3, we were curious to see if these conditions would be applicable to other variants of the Ugi
reaction. To our surprise, none of the imines tested in the reaction with 3a under the conditions
shown in Scheme 2 gave the desired product (Fig. 5). The cyclic imines 13-15 (obtained by N-
chlorination-dehydrohalogenation of the respective secondary amines28) were expected to react
similarly to indolenines 9 but only yielded complex mixtures of products. Bifunctional Schiff
base 16 - successfully employed by Harriman in the reaction with a range of isocyanides
(including one N-isocyannodialkylamine)18 – gave a similar result. Also disappointing were the
attempts to employ ‘standard’ imines 17-18 in the Ugi reaction with 2a. Finally, an attempt to
involve 2a in the Groebke-Blackburn-Bienaymé reaction29 of 2-aminopyridine-derived imine 19
did not give the expected product. Thus, it appears that indolenines 9 constitute a preferred
substrate niche for an Ugi-type reaction with N-isocyannodialkylamines 2 prepared via in situ
dehydration, as described herein.30
N
Ph
N
CO2H
N
N
N
13
14
15
16
N
Ph
Ph
N
N
MeO
O2N
19
18
17
Figure 5. Imines that failed to react in lieu of indolenines 9 with N-isocyannodialkylamine 2a
generated in situ.
In summary, we have described an in situ generation of N,N-dialkyl isocyanamides and their
employment in the two-component Joullié–Ugi reaction with indolenines promoted by acetic
acid. The latter was shown to be essential for the reaction to proceed, so is the employment of

the nucleophilic solvent methanol which most likely causes O-deacylation of the initial three-
component acyloxyimine adduct and defines the productive course for the reaction. Alternative
evolution of the latter key intermediate via an ON acyl migration (Mumm rearrangement) is
thought to be suppressed due to anilinic character and steric hindrance of the indoline nitrogen
atom. The developed protocol was extended to the preparation of 18 2-
(hydrazinocarbonyl)indoline adducts in modest to excellent yields. Efforts to expand the
substrate scope of this new variant of the Joullié–Ugi reaction as well as to achieve the three-
component outcome (with incorporation of the carboxylic acid component in the product
structure) are underway in out laboratories; the results will be reported in due course.
Acknowledgments
This research was supported by the Russian Foundation for Basic Research (grant # 16-03-
00174). We thank the Research Centre for Magnetic Resonance, the Center for Chemical
Analysis and Materials Research, and the Centre for X-ray Diffraction Methods of Saint
Petersburg State University Research Park for obtaining the analytical data.
Keywords: multicomponent reactions, Joullié–Ugi reaction, in situ dehydration, isocyanamides,
Mumm rearrangement, O-deacylation.
References and notes
1. Ugi, I.; Meyr, R.; Fetzer, U.; Steinbrückner, C. Angew. Chem. 1959, 71, 386.
2. Dömling, A. Comb. Chem. High Throughput Screen. 1998, 1, 1.
3. Marcaccini, S.; Torroba, T. Chapter 2 in: Multicomponent Reactions. J. Zhu and H.
Bienaymé, Eds.; Wiley‐VCH, 2005, pp. 33-75.
4. Ayaz, M.; De Moliner, F.; Dietrich, J.; Hulme, C. Chapter 10 in: Isocyanide chemistry –
applications in synthesis and material science. V. G. Nenajdenko, Ed.; Wiley-VCH, 2012, pp.
335-384.
5. Ivachtchenko, A. V.; Ivanenkov, Ya. A.; Kysil, V. M.; Krasavin, M.; Ilyin, A. P. Russ.
Chem. Rev. 2010, 79, 787.
6. Krasavin, M. Chapter 6 in: Isocyanide chemistry – applications in synthesis and material
science. V. G. Nenajdenko, Ed.; Wiley-VCH, 2012, pp. 195-231.
7. El Kaïm, L.; Grimaud, L. Chapter 5 in: Isocyanide chemistry – applications in synthesis and
material science. V. G. Nenajdenko, Ed.; Wiley-VCH, 2012, pp. 159-194.
8. Díaz, J. L.; Miguel, M.; Lavilla, R. J. Org. Chem. 2004, 69, 3550.
9. Bredereck, H.; Foehlisch, B.; Walz, K. Justus Liebigs Ann. Chem. 1965, 686, 92.

10. (a) Fehlhammer, W. P.; Metzner, R.; Kunz, R. Chem. Ber. 1994, 127, 321; (b) Fehlhammer,
W. P.; Metzner, R.; Sperber, W. Chem. Ber. 1994, 127, 631; (c) Bigler, R.; Huber, R.; Mezzetti,
A. Angew. Chem. Int. Ed. 2015, 54, 5171.
11. Moderhack, D. Tetrahedron 2012, 68, 5949.
12. Giustiniano, M.; Basso, A.; Mercalli, V.; Massarotti, A.; Novellino, E.; Tron, G. C.; Zhu, J.
Chem. Soc. Rev. 2017, 46, 1295.
13. Nair, V.; Mathen, J. C.; Viji, S.; Srinivas, R.; Nandakumar, M. V.; Varma, L. Tetrahedron
2002, 58, 8113.
14. Nair, V.; Mathew, b.; Vinod, A. U.; Mathen, J. C.; Ros, S.; Menon, R. S; Varma, R. L.;
Srinivas, R. Synthesis 2003, 662.
15. Kuo, M.-Y.; Lee, Y.-S.; Chen, P.; Chen, L. J.; Lu, Y. Y.; Huang, Y.-T.; Hsu, H.-Y.; Tsai, P.-
K. PCT Int. Appl. WO2011080568; Chem. Abstr. 2011, 155, 152545.
16. Müller, E.; Nespital, V.; Beutler, R. Tetrahedron Lett. 1971, 12, 525.
17. Zinner, G.; Moderhack, D.; Kliegel, W. Chem. Ber. 1969, 102, 2536-2546.
18. Harriman, G. C. B. Tetrahedron Lett. 1997, 38, 5591.
19. Sushko, I.; Salmina, E.; Potemkin, V. A.; Poda, G.; Tetko, I. V. J. Chem. Inf. Model. 2012,
52, 2310.
20. Bushkova, E.; Parchinsky, V.; Krasavin, M. Mol. Diversity 2010, 14, 493.
21. Krasavin, M.; Bushkova, E.; Parchinsky, V.; Shumsky, A. Synthesis 2010, 933.
22. Krasavin, M.; Parchinsky, V.; Shumsky, A.; Konstantinov, I.; Vantskul, A. Tetrahedron
Lett. 2010, 51, 1367.
23. Pelay-Gimeno, M.; Glas, A.; Koch, O.; Grossmann, T. N. Angew. Chem. Int. Ed. 2015, 54,
8896.
24. Dömling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083.
25. El Kaïm, L.; Grimaud, L.; Schiltz, A. Org. Biomol. Chem. 2009, 7, 3024.
26. Neochoritis, C. G.; Stotani, S.; Mishra, B.; Dömling, A. Org. Lett. 2015, 17, 2002.
27. (a) Golubev, P.; Bakulina, O.; Dar'in, D.; Krasavin, M. Eur. J. Org. Chem. 2016, 3969; (b)
Golubev, P.; Krasavin, M. Eur. J. Org. Chem. 2017, 1740.
28. Gołębiewski, W. M.; Gucma, M. Synthesis 2007, 3599.
29. Shaaban, S.; Abdel-Wahab, B. F. Mol. Diversity 2016, 20, 233.
30. General procedure for the preparation of indoline carbohydrazides 10a-r: A solution
(suspension) of formohydrazide 3 (1.25 mmol) and triethylamine (316 mg, 3.13 mmol) in CHCl3
(0.7 mL) was cooled to -15 °C (ice/salt bath). POCl3 (211 mg, 1.38 mmol) in CHCl3 (0.1 mL)
was added dropwise via syringe over 10 min and the resulting mixture was stirred at -15 °C for
90 min. Indolenine 9 (0.5 mmol) was added followed by a solution of acetic acid (1.5 mmol) in

MeOH (0.2 mL). The resulting mixture was left in the cooling bath for 18 h while slowly
warming up to room temperature. After dilution with CHCl3 (10 mL), the reaction mixture was
washed with sat. aq. NaHCO3 and water, dried over Na2SO4, filtered and concentrated in vacuo.
The residue was purified by column chromatography (silica gel, petroleum
ether/acetone/chloroform 4:1:0.5) to afford indolines 10.