Enabling the facile conversion of acyl hydrazides into: N -acyl carbamates via metal-free ionic-based rupture of the N-N linkage

Article abstract of DOI:10.1039/c7ra04178k

Herein we report the one-pot transformation of readily synthesised/easily accessed acyl hydrazides into N-acyl carbamates via an alkylation-elimination reaction sequence. A range of N-acyl carbamates are prepared in consistent yields, including those featuring protecting groups and having alkyl & aryl N-acyl functionality. The reaction conditions also tolerate a wide variety of sensitive functional groups.

Full text of DOI:10.1039/c7ra04178k

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Enabling the facile conversion of acyl hydrazides
into N-acyl carbamates via metal-free ionic-based
rupture of the N–N linkage†
Cite this: RSC Adv., 2017, 7, 27608
a
Jack Ren and Vijay Chudasama *ab
a
Andre Shamsabadi,
´
Received 12th April 2017
Accepted 17th May 2017
Herein we report the one-pot transformation of readily synthesised/easily accessed acyl hydrazides into N-
acyl carbamates via an alkylation-elimination reaction sequence. A range of N-acyl carbamates are
prepared in consistent yields, including those featuring protecting groups and having alkyl & aryl N-acyl
functionality. The reaction conditions also tolerate a wide variety of sensitive functional groups.
DOI: 10.1039/c7ra04178k
rsc.li/rsc-advances
Acyl hydrazides have been prepared using many methods substituting the hydrazide moiety or alkylating at the acidic
through the years with a substantial increase in the number of N–H position, with the latter being used to good effect by
1
reported methodologies in the past decade. Their synthesis can exploiting the conformation of the N–N bond in ring-closing
9
now be considered to be largely optimal in view of the plethora metathesis to form medium-sized macrocycles.
of distinct routes by which they can be formed in good to
excellent yields. They represent synthetically versatile scaffolds acyl carbamates from acyl hydrazides via rupture of the N–N
In this article, we focus on developing a new method to form
1
that have been exploited for the creation of various moieties bond in a one-pot alkylation-E1cB elimination procedure
2
–5
6
6
6
such as 1,3,4-oxadiazoles, thioesters, esters, amides and (Fig. 1). Owing to the importance of N-acyl carbamates in
7
10–13
10
ketones, as well as building blocks for the creation of bioactive various bioactive compounds,
molecules such as hydroxamic acids and macrocylic enamides
Fig. 1). However, to date, all approaches have focused on ing a group in synthesis,
e.g. anti-malassezia agents,
8
9
11
12
13
insecticides, antibiotics, and pro-drugs, its use as a direct-
1
4,15
16
(
as well as phototriggers, there was
plenty of incentive to explore this chemistry. Further to this, the
synthetic strategy proposed in this article is complementary to
existing traditional approaches for the synthesis of N-acyl
carbamates, which tend to react acyl halides with carbamates or
17,18
primary/secondary amides with chloroformates.
Further-
more, the ability to cleave the N–N bond without the use of
hydrogenation, expensive catalysts and/or undesirable metals
19–24
was seen as a key aspect in itself;
this is particularly well
described in related work by Magnus et al. where conversion of
hydrazines to amines was achieved using an elegant alkylation-
elimination sequence, albeit in two distinct steps and requiring
ꢀ
23
relatively high temperatures (ca. 80 C).
Our study began with the reaction of acyl hydrazide 1a with
low-cost bromoacteate 2a with the aim of forming acyl carba-
mate 3a in a two-step one-pot procedure. Initially, the use of 1.5
eq. of ethyl bromoacetate and 3 eq. of NaH was trialled at room
temperature (Table 1, entry 1). These conditions resulted in the
formation of several entities: desired acyl carbamate 3a;
alkylated-hydrazine intermediate 4a; trans-esteried acyl
carbamate 3b; and over-alkylated product 5. Rationally, to limit
over-alkylation, the reaction was repeated with 1.1 eq. of ethyl
bromoacetate (Table 1, entry 2); this completely suppressed
formation of over-alkylated product 5. This also lowered the
yield of trans-esteried acyl carbamate 3b; suggesting that the
Fig. 1 General method for the synthesis of acyl hydrazides via
hydroacylation, how acyl hydrazides have commonly been used and
how we propose to use them in this article.
a
Department of Chemistry, University College London, 20 Gordon Street, London,
WC1H 0AJ, UK. E-mail: v.chudasama@ucl.ac.uk
b
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade
de Lisboa, Lisbon, Portugal
1
13
†
Electronic supplementary information (ESI) available: H and C NMR spectra ethoxide, which is likely to facilitate the trans-esterication
for all small molecules. See DOI: 10.1039/c7ra04178k
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Table 1 Base-mediated reaction of acyl hydrazide 1a (1 mmol) and Table 2 One-pot reaction of aryl acyl hydrazides 1a, 1c–m (1 mmol)
ꢀ
alkyl bromide 2a or 2b under a range of conditions at 25 C for 16 h
with tert-butyl bromoacetate 2b and NaH for the formation of aryl acyl
carbamates 3a, 3c–m at 25 C for 16 h
ꢀ
1
Entry
1
R ¼
Yield/%
83
2
85
3
4
5
6
7
71
70
86
76
87
a
b
Entry
R
Base
Base/eq. 3a/% 4/% 3b/% 5/%
1
2
3
4
5
6
Et (1.5 eq.) NaH
Et
Et
Bu
Bu
Bu
Bu
Bu
3
3
5
5
3
5
5
5
24
52
69
83
58
0
38
30
0
16
6
8
0
0
0
0
0
11
0
0
0
0
0
0
0
NaH
NaH
NaH
NaH
t
0
t
t
t
t
25
86
82
0
Cs
2
CO
BuOK
NaH (95%)
3
c
t
7
0
78
8
a
1
.1 eq. of alkylating agent utilised unless otherwise stated in
b
parenthesis. NaH utilised as a 60% dispersion in mineral oil unless
c t
otherwise stated in parenthesis. BuOH utilised as solvent.
process, may have been liberated from the ethyl bromoacetate
starting material under the basic conditions. Whilst the
formation of by-products 3b and 5 was suppressed by lowering
the equivalents of alkylating agent, it was coincident with
inadequate conversion of the singly alkylated intermediate 4a to
the desired acyl carbamate 3a. Most pleasingly, however, simply
increasing the equivalents of base from 3 to 5 resulted in full
conversion of the intermediate to afford acyl carbamate 3a in
8
9
72
68
6
9% yield (Table 1, entry 3). Whilst the reaction was improved,
1
1
0
1
74
80
yields were still limited by the formation of trans-esteried by-
product 3b. To circumvent the issue, we utilised tert-butyl bro-
moacetate 2b as the a-bromo acetate source; it was thought that
liberation of any tert-butoxide under basic conditions would not
result in trans-esterication. To our delight this was the case,
with complete suppression of the formation of the trans-ester-
ication product being observed (Table 1, entry 4); this resulted 12
in an 83% yield of the desired product. It is also important to
note that tert-butyl bromoacetate 2b is more readily obtained
and even more economical than its ethyl variant. Lowering the
equivalence of base to 3 once again showed incomplete
conversion of intermediate, 4b in this case, to acyl carbamate 3a
61
Having established a procedure which led to sole formation
of the desired product, the suitability of other bases was
appraised (Table 1, entries 6–8). Using Cs CO (pK ¼ 10.3), or
(Table 1, entry 5).
2
3
a
t
t
BuOK (pK ¼ 17, reaction in BuOH) only resulted in formation
a
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consistent yields being observed throughout the series. The
reaction proved to be compatible with electron rich (Table 2,
entry 5, 9), electron neutral (Table 2, entry 6) and electron poor
(Table 2, entry 1, 3, 10) moieties, irrespective of the functional
groups existing in ortho-, meta- or para-positions on the aryl
ring. Gratifyingly, even a sensitive methyl ester functionality
was tolerated in the reaction conditions (Table 2, entry 8). The
only moderate yield that was observed was when using a rather
sensitive N-methylpyrrole acyl hydrazide (Table 2, entry 12).
We also appraised the tolerance of the reaction with respect
to the use of acyl hydrazides that were synthesised from the
hydroacylation of azodicarboxylates other than DIAD (see ESI
for details on synthesis†). The optimised reaction conditions
allowed for the formation of aryl acyl carbamates with common
protecting groups, e.g. tert-butoxy carbamate (Boc), benzyloxy
carbamate (CBz) and ethyl carbamate, in high yields (Scheme 1).
These acyl carbamates can undergo facile conversion to various
Scheme 1 One-pot conversion of acyl hydrazide 1b, 1n–o to pro- species by reaction at the carbamate nitrogen atom before
tected acyl carbamates 3b, 3n–o.
27,28
cleavage of the protecting group.
Despite the majority of potent bioactive N-acyl carbamates
being aryl in their acyl character, we decided to test our protocol
on alkyl acyl hydrazides also. A selection of appropriate acyl
hydrazides (i.e. primary, secondary and tertiary alkyl examples)
were prepared using our previously described aerobic C–H
25,26,29–31
activation protocol.
Whilst reaction in our one-pot
protocol only achieved minimal yields of carbamates for the
primary and secondary alkyl acyl hydrazides 3p and 3q, a step-
wise protocol provided good yields (Scheme 2). The major
limitation on yield in all cases was elimination of the hydrazine
via deprotonation of the a-H (highlighted in red), which was
conrmed by isolation of the by-product 6 in a yield that
accounted for the mass balance. In tting with this, the absence
of an a-H acidic proton in tertiary alkyl acyl hydrazide 1r
resulted in a very good yield of carbamate 3r.
Conclusions
Scheme 2 Conversion of alkyl acyl hydrazide 1p–r to alkyl acyl
carbamates 3p–r.
In conclusion, we have shown readily accessed acyl hydrazides
to be excellent candidates for the synthesis of N-acyl carba-
mates, which have several applications in terms of their
synthetic utility and are oen inherently biologically useful (as
exemplied by the range of bioactive compounds that bear such
a motif). A robust one-pot procedure that is tolerant of a large
number of functional groups has been developed; including the
synthesis of acyl carbamates with a protecting group on the
nitrogen atom – oen a key synthetic building block – and
adaptability to alkyl & aryl N-acyl functionalities.
ꢀ
of the alkylated species 4b, suggesting that at 25 C for 16 h,
these bases were unable to facilitate E1cb elimination. Finally,
trialling of 95% NaH resulted in a slightly lower yield, 78%, than
when using a 60% dispersion in mineral oil.
With optimised conditions in hand we took the opportunity
to investigate the applicability of our protocol for the formation
of various acyl carbamates (Table 2). A range of acyl hydrazides
were trialled (1a, 1c–m) under the developed reaction condi-
tions. All starting hydrazides were prepared using our previ-
ously reported procedure for the hydroacylation of
25,26
azodicarboxylates in good yields.
To our delight, the reaction was tolerant of various func- Acknowledgements
tional groups on the aromatic acyl hydrazide motif, e.g. halo,
The authors gratefully acknowledge Prof. Alwyn Davies for
productive discussions. We also acknowledge UCL (UCL Grad-
uate Research Scholarship) for funding AS.
triuoromethyl, methoxy, ester and methyl functionalities
Table 2, entries 1–5, 7–11) were tolerated with good and
(
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