A practical approach to semicarbazone and hydrazone derivatives via imino-isocyanates

Article abstract of DOI:10.1021/ol4016089

Complex hydrazone derivatives can be accessed readily from hydrazones upon heating in the presence of nucleophiles. This reactivity likely involves imino-isocyanate intermediates, and a variety of leaving groups can be used at temperatures ranging from 20 to 150 C. Alcohols, thiols, primary, and secondary amines can be used as nucleophiles, thus providing a simple alternative to the synthesis of hydrazones via condensation on the parent carbonyl precursor and allowing late-stage derivatization.

Full text of DOI:10.1021/ol4016089

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
A Practical Approach to Semicarbazone
and Hydrazone Derivatives via
Imino-isocyanates
ꢀ
Keira Garland, Wei Gan, Charlotte Depatie-Sicard, and Andre M. Beauchemin*
Center for Catalysis Research and Innovation, Department of Chemistry, University of
Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
andre.beauchemin@uottawa.ca
Received June 7, 2013
ABSTRACT
Complex hydrazone derivatives can be accessed readily from hydrazones upon heating in the presence of nucleophiles. This reactivity likely
involves imino-isocyanate intermediates, and a variety of leaving groups can be used at temperatures ranging from 20 to 150 °C. Alcohols, thiols,
primary, and secondary amines can be used as nucleophiles, thus providing a simple alternative to the synthesis of hydrazones via condensation
on the parent carbonyl precursor and allowing late-stage derivatization.
Isocyanates (RNCO) are very important bulk chemicals
(e.g., polyurethanes) and are often used as bulding blocks
and derivatization reagents in organic synthesis.1 How-
ever, many isocyanates are toxic and workers regularly
exposed to them can develop sensitivity issues. Thus, for
selected industrial applications (e.g., paints and coatings
industries) compounds that release isocyanates in situ have
been developed. Suitable carbamates (RNHCOLG, e.g.,
LG = OPh) thus serve as blocked isocyanates.2 As part of
recent efforts toward alkene amination reactions, we be-
came interested in the reactivity of nitrogen-substituted
isocyanates.3 Surprisingly there are only a few reports on
such isocyanates in the literature.3,4
Recently, we reported intermolecular alkene aminocar-
bonylation reactivity that occurs upon heating suitable
hydrazones with alkenes (see below).3b,c Under such con-
ditions, an imino-isocyanate intermediate is generated in
situ, and complex azomethine imines possessing β-amino-
carbonyl motifs are formed from simple precursors. As
part of these efforts, we became interested in the formation
of complex hydrazones and in surveying the impact of the
nature of the leaving group on this reactivity. The synthesis
of several ketohydrazones proved challenging. First, the
condensation reactivity of carbazates (NH2NHCO2R) and
semicarbazides (NH2NHCONR0R00) was sensitive to the
steric hindrance of ketones and required heating. Not
surprisingly, some hydrazine derivatives (NH2NHCOLG)
decomposed under the reaction conditions, presumably
via generation of the amino-isocyanate NH2NCO.5 Second,
this approach inherently required the synthesis of hydrazine
derivatives that are not commercially available. These
efforts suggested that forming the hydrazone derivatives
from a common hydrazone precursor would be more
(1) (a) Ulrich, H. Chemistry and Technology of Isocyanates; J. Wiley &
Sons: Chichester, U.K., 1996. (b) Six, C.; Richter, F. In Ullmann’s Encyclopedia
of Industrial Chemistry; Wiley-VCH: 2012; Vol. 20, pp 63ꢀ82.
(2) For an entry in the blocked iscoyanate literature, see: (a) Wicks,
D. A.; Wicks, Z. W., Jr. Prog. Org. Coat. 1999, 36, 148. (b) Wicks, D. A.;
Wicks, Z. W., Jr. Prog. Org. Coat. 2001, 41, 1.
(3) (a) Roveda, J.-G.; Clavette, C.; Hunt, A. D.; Whipp, C. J.;
Gorelsky, S. I.; Beauchemin, A. M. J. Am. Chem. Soc. 2009, 131,
8740. (b) Clavette, C.; Gan, W.; Bongers, A.; Markiewicz, T.; Toderian,
A.; Gorelsky, S. I.; Beauchemin, A. M. J. Am. Chem. Soc. 2012, 134,
16111. (c) Gan, W.; Moon, P. J.; Clavette, C.; Das Neves, N.; Markiewicz,
T.; Toderian, A. B.; Beauchemin, A. M. Org. Lett. 2013, 15, 1890.
(4) For examples see: (Aminoisocyanates) (a) Wadsworth, W. S.;
Emmons, W. D. J. Org. Chem. 1967, 32, 1279. (b) Lockley, W. J. S.;
Lwowski, W. Tetrahedron Lett. 1974, 4263. (c) Kurz, M.; Reichen, W.
Tetrahedron Lett. 1978, 1433. (Imino-isocyanates) (d) Jones, D. W.
J. Chem. Soc., Chem. Commun. 1982, 766. (CONR-NCO) (e) Han, H.;
Janda, K. D. J. Am. Chem. Soc. 1996, 118, 2539. (f) Wentrup, C.; Finnerty,
J. J.; Koch, R. J. Org. Chem. 2011, 76, 6024. (Amido-isocyanates) (g) Han,
H.; Janda, K. D. J. Am. Chem. Soc. 1996, 118, 2539. For reviews, see: (h)
Reichen, W. Chem. Rev. 1978, 78, 569. (i) Wentrup, C.; Finnerty, J. J.;
Koch, R. Curr. Org. Chem 2011, 15, 1745.
(5) Teles, J. H.; Maier, G. Chem. Ber. 1989, 122, 745.
r
10.1021/ol4016089
XXXX American Chemical Society

efficient. Herein, we report on the development of this
reactivity and provide calibration on the in situ genera-
tion of imino-isocyanates and their reactivity with various
nucleophiles.
Table 2. Exchange Reaction: Nucleophile Scope Using
Hydrazones Derived from NH2NHCO2t-Bua
We thus became interested in determining the ability of
several hydrazone precursors to undergo an exchange
reaction with n-hexylamine as the nucleophile. The reac-
tivity observed with various leaving groups is presented in
Table 1.
Table 1. Exchange Reaction: Impact of Hydrazone Structure
(LG) with n-Hexylamine As Nucleophilea
entry
LG-H
temp (°C)
time
yieldb (%)
1
n-C8H17SH (1a)
n-C8H17SH (1a)
PhSH (1b)
120
100
rt
20 min
20 min
1 h
98
2
51
3
82
a Conditions: hydrazone (1.0 equiv), nucleophile (2 equiv), in PhCF3
(0.2 M), microwave irradiation; time and temperature as stated above.
b Isolated yields; NMR yield in parentheses. c PhCF3 (0.5 M). d 1.0 equiv
of hydrazone, 14 equiv of nucleophile, neat. e 5.0 equiv of nucleophile.
f 10.0 equiv of nucleophile.
4
PhSH (1b)
rt
4 h
99 (99)
92
5
t-BuNH2 (1c)
PhNH2 (1d)
morpholine (1e)
i-Pr2NH (1f)
i-Pr2NH (1f)
BnOH (1g)
120
100
100
rt
20 min
3 h
6
91
7
1 h
99
8
2 h
84 (84)
91
9
rt
4 h
10
11
12
13
14
150
120
120
100
rt
20 min
20 min
20 min
20 min
20 min
94
diisopropylamine as a leaving group under mild conditions
was inspired by a recent report by Booker-Milburn, Lloyd-
Jones et al.6 Such room temperature reactivity is also in
agreement with the pioneering work of Lubell et al. using
hydrazones with a p-nitrophenol leaving group as building
blocks for azapeptide synthesis.7 In contrast, the use of
hydrazones derived from more stable semicarbazides
(entries 5ꢀ7) and carbazates (entries 10ꢀ13) required
heating at 100ꢀ150 °C. For these substrates, the reactivity
correlates well with leaving group ability, with sterically
demanding leaving groups showing slightly increased
reactivity.
BnOH (1g)
38
t-BuOH (1h)
t-BuOH (1h)
PhOH (1i)
95
40
91 (99)
a Conditions: hydrazone (1 equiv), n-C6H13NH2 (2 equiv), PhCF3
(0.2 M); for reactions requiring heat, microwave irradiation was used.
b NMR yields using internal standard; isolated yields in parentheses
As expected, the reactivity observed with n-hexylamine
correlates well with the leaving group ability (LGH).
Encouragingly, several hydrazone precursors reacted at
room temperature [entries 3ꢀ4 (PhSH), 8ꢀ9 (i-Pr2NH),
and 14 (PhOH)]. The reactivity of these substrates with
n-hexylamine at room temperature could be consistent
with base catalysis, in agreement with the common use of
blocked isocyanates using amines as catalysts.2 The use of
After acquiring this calibration on leaving group ability,
we turned our attention to the use of various nucleophiles
(7) (a) Sabatino, D.; Proulx, C.; Klocek, S.; Bourguet, C. B.; Boeglin,
D.; Ong, H.; Lubell, W. D. Org. Lett. 2009, 11, 3650. (b) Sabatino, D.;
Proulx, C.; Pohankova, P.; Ong, H.; Lubell, W. D. J. Am. Chem. Soc.
2011, 133, 12493. For an excellent review on azapeptide synthesis, see:
(c) Proulx, C.; Sabatino, D.; Hopewell, R.; Spiegel, J.; Ramos, Y. G.;
Lubell, W. D. Future Med. Chem. 2011, 3, 1139.
ꢀ
(6) Hutchby, M.; Houlden, C. E.; Ford, J. G.; Tyler, S. N. G.; Gagne,
M. R.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Angew. Chem., Int.
Ed. 2009, 48, 8721.
B
Org. Lett., Vol. XX, No. XX, XXXX

(Table 2). As discussed above, we were particularly inter-
ested in hydrazones derived from robust carbazates since
these reagents can form hydrazones reliably even upon
condensation onto hindered ketones. Thus, the reaction
with several nucleophiles was explored on four hydrazones
derived from tert-butylcarbazate.
Scheme 1. Exchange Reaction: Synthesis of Semicarbazonesa
Gratifyingly, reaction of these robust hydrazones with
nucleophiles afforded a variety of hydrazone derivatives
upon heating at 100ꢀ150 °C (Table 2). Hydrazones de-
rived from both aldehydes and ketones proved to be
excellent substrates for this exchange reaction. The reac-
tion worked with a variety of nitrogen nucleophiles (entries
1ꢀ6, 11ꢀ13, 16, 17), thiols (entries 7ꢀ8, 15), and alcohols
(entry 9; see also Table 3). Specifically, primary amines
(entries 1ꢀ3, 11ꢀ12, 15, 17), aniline (entries 4 and 13), and
both acyclic and cyclic secondary amines proved to be
competent nucleophiles (entries 5ꢀ6). Use of n-octanethiol
(entry 7) and thiophenol (entries 8, 15) also provided
hydrazone derivatives. Only phenol proved to be a poor
nucleophile, providing only little (entries 10, 18) to no
(entry 14) conversion to the desired exchange product and
leading to recovery of unreacted starting material. Never-
theless, hydrazone 3g could be synthesized using this
approach, and crystals suitable for X-ray crystallographic
analysis were obtained (see Supporting Information for
crystal structure).
Given the importance of alcohols (especially polyols) in
the isocyanate industry, we then explored the use of several
hydrazone precursors with these nucleophiles (Table 3).
As expected, several hydrazone precursors afforded addi-
tion products upon heating in the presence of alcohols.
At 150 °C, rapid exchange was observed for the use of
carbazate based isocyanates (entries 1ꢀ2). Milder conditions
(60ꢀ80 °C) were also developed with a semicarbazide-based
hydrazone precursor (entries 3ꢀ6).6 Notably, the
reaction with 1,3-propanediol afforded the double
a Conditions: hydrazone (1 equiv), amine (5 equiv), PhCF3 (0.2 M),
microwave irradiation if heat required. LG = OPh if performed at room
temperature (rt) and LG = Ot-Bu if heating is required. Isolated yields
are reported. b Using 2.0 equiv of amine. c Using 4.0 equiv of amine. d
MeCN (0.2 M) was used as solvent. e Using heating in an oil bath.
substitution product in acceptable yield (entry 6). Concep-
tually, this result suggests that hydrazone precursors can
be used with polyols and enables further exploration of
this substitution reactivity in the isocyanate industry.2
However, additional efforts are required to indicate if
the base generated as the reaction proceeds is beneficial
to this substitution reaction (via catalysis, as previously
discussed). Further investigations are also needed to pro-
vide support for the postulated imino-isocyanate inter-
mediate and probe the likelihood of an alternative
mechanism involving a direct substitution reaction, which
could occur with activated hydrazones.
Having studied this hydrazone reactivity with several
simple substrates, leaving groups, and nucleophiles, we
then turned our attention to the synthesis of more complex
semicarbazones (Scheme 1). The scope of this reaction was
evaluated using both activated (OPh, room temperature,
six examples) and unactivated (Ot-Bu, 80ꢀ120 °C, four
examples) hydrazone precursors.
Table 3. Exchange Reaction: Impact of Hydrazone Structure
Using Alcohols as Nucleophilesa
leaving
group
temp
yield (%)b/
product
entry
R00OH
(°C)
time
1
t-BuOH
BnOH
t-BuOH
n-BuOH
n-BuOH
n-BuOH
1,3-
150
150
60
3 min (85) (1g)
3 min (80) (1h)
2
BnOH
3
(i-Pr)2NH
(i-Pr)2NH
(i-Pr)2NH
(i-Pr)2NH
3 h
65 (1l)
4c
5c
6d
80
16 h
5 h
(95) (1l)
56 (1l)
80
80
4.5 h
62(28) (1m)
propanediol
a Conditions: hydrazone (1.0 equiv), alcohol (2 equiv), in PhCF3
(0.2 M), microwave irradiation. b NMR yield using internal standard;
isolated yields in parentheses. c 5 equiv of alcohol d Hydrazone (3 equiv),
alcohol (1 equiv), MeCN (0.5M), oil bath.
Several semicarbazones were synthesized using both
primary and secondary amines (Scheme 1). As observed
previously (Table 2), hydrazones derived from aliphatic
Org. Lett., Vol. XX, No. XX, XXXX
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and aromatic aldehydes, as well as aliphatic and aromatic
ketones, were competent substrates. Double substitution
reactions were also explored (due to the importance of
diisocyanates in the preparation of polyurethanes2), and
two disubstitution products were obtained. Several func-
tional groups were also tolerated (alcohols, alkenes, esters).
Overall, this reactivity proved reliable to access complex
semicarbazone derivatives.
In summary, a variety of hydrazone derivatives were
accessed readily simply by performing an exchange reac-
tion using hydrazone precursors and amines, alcohols, or
thiols as nucleophiles. With hydrazones derived from
reactive carbazates (e.g., possessing OPh as leaving group),
exchange under mild reaction conditions is possible. This
reactivity provides a reliable alternative to the synthesis
of hydrazones via condensation on the parent carbonyl
precursor and is amenable to the formation of multiple
products from a common precursor. Development of
synthetic applications using rare nitrogen-substituted iso-
cyanate precursors are under development and will be
reported in due course.
Acknowledgment. We thank the University of Ottawa,
NSERC (Discovery Grant, Discovery Accelerator Sup-
plement, CRD and CREATE grants to A.M.B.), the
Canadian Foundation for Innovation and the Ontario
Ministry of Research and Innovation for generous fi-
nancial support. Support of this work by AstraZeneca
Canada, GreenCentre Canada, and OmegaChem is also
gratefully acknowledged. W.G. thanks the University
of Ottawa (Vision 2020 Postdoctoral fellowship). We
also thank Christian Clavette and Thomas Markiewicz
(University of Ottawa) for fruitful discussions. We also
acknowledge Amanda Bongers and Dr. Ilia Korobkov
(University of Ottawa) for assistance in determining the
structure of hydrazone 3g.
Supporting Information Available. Complete experi-
mental procedures, characterization data, and NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX