α-Bromodiazoacetamides - a new class of diazo compounds for catalyst-free, ambient temperature intramolecular C-H insertion reactions

Article abstract of DOI:10.3762/bjoc.9.157

In this work, we introduce a new class of halodiazocarbonyl compounds, α-halodiazoacetamides, which through a metal-free, ambient-temperature thermolysis perform intramolecular C-H insertions to produce α-halo-β-lactams. When carried out with α-bromodiazoacetamides bearing cyclic side chains, the thermolysis reaction affords bicyclic α-halo-β-lactams, in some cases in excellent yields, depending on the ring size and substitution pattern of the cyclic amide side chains.

Full text of DOI:10.3762/bjoc.9.157

α-Bromodiazoacetamides – a new class of diazo
compounds for catalyst-free, ambient temperature
intramolecular C–H insertion reactions
Åsmund Kaupang and Tore Bonge-Hansen*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1407–1413.
Department of Chemistry, University of Oslo, P.O. Box 1033 Blindern,
NO-0315 Oslo, Norway
doi:10.3762/bjoc.9.157
Received: 13 March 2013
Accepted: 20 June 2013
Published: 11 July 2013
Email:
Åsmund Kaupang - asmund.kaupang@farmasi.uio.no;
Tore Bonge-Hansen* - tore.hansen@kjemi.uio.no
Associate Editor: B. Stoltz
* Corresponding author
© 2013 Kaupang and Bonge-Hansen; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
α-halo-β-lactam; diazo; halocarbonylcarbene; halogenation;
thermolysis
Abstract
In this work, we introduce a new class of halodiazocarbonyl compounds, α-halodiazoacetamides, which through a metal-free,
ambient-temperature thermolysis perform intramolecular C–H insertions to produce α-halo-β-lactams. When carried out with
α-bromodiazoacetamides bearing cyclic side chains, the thermolysis reaction affords bicyclic α-halo-β-lactams, in some cases in
excellent yields, depending on the ring size and substitution pattern of the cyclic amide side chains.
Introduction
Diazocarbonyl compounds are popular precursors for carbonyl- The first syntheses of α-halodiazoacetic esters, reported in the
carbenes and -carbenoids, the synthetic utility of which is thor- late 1960s, employed electrophilic diazoalkane substitution; the
oughly established through their successful employment in mercury or silver salts of ethyl diazoacetate (EDA) were reacted
cycloaddition, ylide formation, cyclopropanation and C–H with sources of electrophilic halogen (SO2Cl2, Br2 or I2). These
insertion reactions [1-3]. A generally useful modification of protocols allowed Gerhart and Schöllkopf et al. to study the
diazo compounds is the substitution of the α-hydrogen for an properties of the resulting α-halodiazoacetates and the reactiv-
electrophile. This substitution can be effected in the presence of ity of their photolytically derived carbenes [26-30]. Some ten
a base or starting from the metalated diazo compound, and years later, Regitz et al. reported the syntheses of an α-halo-
leaves the diazo function intact [4]. Among the reported trans- diazomethyl phosphonic acid dimethyl ester and an α-halo-
formations are substitutions of the diazomethyl hydrogen for diazomethyl diphenyl phosphoxide, starting from the silver salts
electrophiles based on boron [5-7], nitrogen (NO2+) [8-12], of the respective diazo compounds [10].
silicon [13-15], phosphorous [16-18], sulfur [19-21] and halo-
gens [10,22-30], as well as carbon, e.g., in aldol reactions with More recently, two novel protocols for the halogenation of
aldehydes [31,32], ketones [33,34] and imines [35,36].
diazoesters and -phosphonates have been introduced by our
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group, both employing an N-halosuccinimide as the halogen diethyl ether dispersion of the crude reaction mixture. This
source in combination with either the amidine base 1,8-diaza- modification thus allowed for gram-scale preparations of the
bicyclo[5.4.0]undec-7-ene (DBU) or sodium hydride (NaH). In desired diazoacetamides. The α-bromoacetamides were in turn
these reports, the obtained α-halodiazoacetates and α-halodiazo- prepared by the acylation of the respective secondary amines
phosphonates were successfully applied in dirhodium(II)-catal- 1a–f with bromoacetyl bromide (Scheme 1; see Supporting
ysed cyclopropanation, and C–H and Si–H insertion reactions Information File 1 for full experimental details). Among the
[37-39].
obtained diazoacetamides, 3d and 3f were not previously
reported. We therefore prepared crystals and resolved their
There are, to the best of our knowledge, no reports in the litera- structures by single-crystal X-ray diffraction. The diazoacet-
ture of α-halodiazoacetamides as a substance class. Thus, we amides 3d and 3f crystallised as their (Z)-rotamers. These data
wished to expand the substrate scope of one of our published have recently been reported [42,43].
methodologies to encompass the halogenation of diazoacet-
amides. We report herein the bromination of the diazoacet- The diazoacetamides were brominated at −5 °C with NBP in the
amides derived from a selection of cyclic secondary amines, presence of DBU and passed through a dry-ice-cooled plug of
using DBU and N-bromophthalimide (NBP), as well as an silica gel with CH2Cl2 (precooled to −15 °C), in order to
investigation of the ability of the carbenes/carbenoids derived remove the base and phthalimide. Allowing the solution to
from the resulting α-bromodiazoacetamides to form α-bromo-β- warm to ambient temperature effected the thermolysis of the
lactams.
α-bromodiazoacetamides (Scheme 2). Although we have not
determined the exact temperature at which the thermolysis takes
place, the α-bromodiazoacetamides will rapidly lose their bright
Results
The diazoacetamides 3a–f were synthesised from α-bromoacet- red colour at temperatures above 0 °C.
amides 2a–f using a protocol published by Toma et al. [40],
modified by exchanging the base employed in the original As can be seen in Table 1, the obtained yields of the α-bromo-β-
procedure (DBU) for 1,1,3,3-tetramethylguanidine (TMG). The lactams 5a–f vary significantly throughout the series. Among
use of TMG allowed for a more convenient, nonaqueous the derivatives with aliphatic amide side chains, the yields
workup, involving the near quantitative removal of the increase dramatically with ring size (Table 1, entries 1–3, prod-
produced TMG-p-toluenesulfinate salt [41] by filtration of a ucts 5a–c), whereas among the derivatives bearing 1,4-hetero-
Scheme 1: Preparation of the diazoacetamides.
Scheme 2: Bromination of the diazoacetamides 3a–f and thermolysis of the α-bromodiazoacetamides 4a–f.
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Table 1: Yieldsa of β-lactams 5a–f obtained by thermolysis of α-bromodiazoacetamides 4a–f.
Yieldsa (%)
Entry
1
Product
exo
endo
exo + endo
exo/endo
α,α’-dibromoacetamide
7b
–c
7b
n/a
7:1
34
5a
5b
5c
2
3
73
11
84
2
77
(81)d
16
(13)d
93
(94)d
5:1
(6:1)d
trace
(–)
4
34
2
36
17:1
21
5d
5e
5
6
12
14
1
3
13
17
6:1
5:1
20
12
5f
aDetermined by 1H NMR using an internal standard (see Supporting Information File 1 for details). bDecomposed in CDCl3 within 48 hours (see
Supporting Information File 1 for details). cNot detected by 1H NMR. dIsolated yield after chromatography. Bromination performed with NBS/DBU.
substituted six-membered rings as side chains, poorer yields are Supporting Information File 1). In contrast, in the lower
obtained (Table 1, entries 4–6, products 5d–f). The latter result yielding reactions, a byproduct that could be routinely identi-
could possibly be viewed as an expression of the deactivation of fied was the corresponding α,α'-dibromoacetamide, the origin of
the C–H bonds β to the N-methylene groups of the amide [44]. which remains unclear. Due to the overlap of signals from the
With the exception of the piperazine derivative 5d, the observed amide side chains in the starting materials and those of even-
diastereomeric ratio in the β-lactam products was approxi- tual dimeric products, the extent of formation of carbene dimers
mately 6:1, favouring the diastereomer in which the bromine was not possible to determine from the crude 1H NMR spectra.
atom and the ring fragment are in a trans relationship (hereafter
referred to as exo-5a–f). The stereochemistry of the obtained As can be interpreted from Table 1, the dominant reaction
β-lactams was determined based on the previously published pathway in the high-yielding reactions (Table 1, entries 2–3), is
NMR data for endo/exo-5b [45], as well as on the characteristic apparently the intramolecular C–H insertion to form a β-lactam.
magnitude of the couplings and chemical shift values of the The preferential formation of intramolecular products from
α-protons of the endo/exo stereoisomers [46-49].
N,N’-disubstituted diazoacetamides, as compared to diazo-
acetates has previously been rationalised in terms of the prox-
The high-yielding C–H insertions (Table 1, entries 2–3, prod- imity of the side chain C–H bonds to the carbene centre [50-52].
ucts 5b,c) proceed cleanly and with few byproducts (see the The greater ease with which the α-bromocarbene amide can
NMR spectra of the crude reaction mixtures containing 5b,c in insert into the C–H bonds of the larger rings (cf. the increase in
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Beilstein J. Org. Chem. 2013, 9, 1407–1413.
yields of products 5a, 5b and 5c) suggests that the proximity between the electron-donating ability of the dirhodium(II) cata-
and/or conformational flexibility of the C–H fragment is of lyst and the obtained yield of the β-lactam 5d (see Table 5.2 in
importance.
Supporting Information File 1). In our hands, the more
stabilised carbenoid afforded the best result, suggesting that the
The α-bromo-β-lactam 5b and its α-chloro-analogue have previ- intramolecular C–H insertion reaction was favoured by a less
ously been prepared by Johansson et al. in 61% [45] and reactive carbenoid. This result may provide insight into why the
53–54% yield [53,54], respectively, by the thermolysis of formation of the bicyclic system is achieved starting from the
α-dihalo(phenylmercury)acetamides in bromobenzene under α-bromodiazoacetamide 4c, but not from the α-H diazoacet-
reflux: a reaction that plausibly occurs with a free halocarbonyl- amide 3c [61] (see Discussion on the carbene-stabilising
carbene or a mercury carbenoid as intermediate [45,55,56]. In effect of halogens below) employing an electronically compa-
the case of the α-bromo-β-lactam 5b, the authors reported an rable dirhodium(II) carboxamidate catalyst (Rh2(cap)4 versus
exo-diastereoselectivity of 5.25:1. In order to compare the re- Rh2(S-MEPY)4).
activity of other halides in the α-position, we prepared and ther-
Discussion
molysed the α-chloro- and α-iodo analogues of 4d (see results
in Table 5.1 in Supporting Information File 1) [57]. In analogy Thermolysis
to the results of Johansson et al., the α-chloro analogue afforded To the best of our knowledge, only one previous account of the
a lower yield of the corresponding α-chloro-β-lactam. In the synthetic application of a thermolysis of a halodiazocarbonyl
case of the α-iodo analogue, the surprisingly low yield obtained compound can be found in the literature. In this report the ther-
may be due to decomposition during the chromatographic step, molysis of an α-bromodiazoketone was successfully employed
as indicated by a change in colour from red to purple, possibly in an intramolecular cyclopropanation reaction [62]. Histori-
owing to the formation of I2.
cally, the thermolysis of diazocarbonyl compounds has been
carried out under reflux [63-66], although examples of low
In a broader context, related examples of carbene/carbenoid temperature and ambient temperature thermolysis can be found
C–H insertions to form β-lactams exist in the literature, in in the case of more labile diazo compounds [14,22,23,67].
which the α-substituent on the carbene carbon varies (see Recent examples of thermolyses of diazocarbonyl compounds,
below). The α-phenyl analogue of β-lactam 5b has previously include the preparation of arylcyclopropanes (cyclopropanation)
been prepared by carbene C–H insertion. In these reports, the and α-arylamino esters (N–H insertion) by thermolysis of aryl-
base-promoted decomposition of a hydrazone and subsequent diazoacetates in trifluorotoluene under reflux [68,69]. In terms
thermolysis of the diazo compound in, e.g., toluene under of their application in synthesis, the need for prolonged heating
reflux, afforded the bicyclic α-phenyl-β-lactam in up to 60% may have narrowed the substrate scope of thermolysis reac-
yield (6:1/exo:endo) [58-60]. Axten et al. also prepared the tions considerably, contributing to the limited number of reports
α-phenyl-analogues of 5a, 5c and 5e, as well as an azocane of catalyst-free thermolyses of diazo compounds in the litera-
(heptamethyleneimine) derivative. The yields of the obtained ture. In comparison, the capability of the α-bromodiazoacet-
β-lactams were, however, not reported [60].
amides to thermolyse at ambient temperature without the use of
a metal catalyst, offers the reactivity of the bromocarbene
amides under genuinely mild reaction conditions.
Dirhodium(II) catalysis
Comparing with results obtained using dirhodium(II) catalysis,
Halocarbonyl carbenes and carbene/
the α-H-analogue of the azepane derivative 5c was prepared in
67% yield by Doyle et al. from 3d [61]. They could also prepare carbenoid stabilisation
the analogous azocane-derived α-H-β-lactam in 45% yield, In their ground state, the halocarbonyl carbenes derived from
accompanied by a 22% yield of the α-H-γ-lactam. Interestingly, halodiazoamides are, in analogy with those derived from halo-
the dirhodium(II)-catalysed methylene C–H insertion reactions diazoesters, predicted by theory to be singlet carbenes [70].
of the smaller cyclic derivatives 3a, 3b and 3e, were unsuc- Furthermore, in analogy to α-bromoethoxycarbonyl carbene
cessful [61]. For comparison with the thermolytic reaction, we [28,30,71], they should be electrophilic carbenes. An important
tested the performance of a small series of dirhodium(II)-cata- modulator of carbene electrophilicity is the stabilising effect of
lysts in the intramolecular C–H insertion that forms 5b. Our π-donation from a substituent on the carbene carbon into the
best result was obtained with the electron-rich dirhodium(II) vacant carbene 2p-orbital. This effect is predicted by theory, as
carboxamidate Rh2(cap)4, affording a 44% combined yield with well as observed experimentally [28,30,71-73]. The degree of
a 6:1 exo/endo ratio (versus 84% combined yield, 7:1 exo/endo, stabilisation exerted by a bromine substituent has been quanti-
in the thermolysis; see Table 5.2 in Supporting Information fied in the scale of carbenic reactivity, introduced by R. A.
File 1 for details). Furthermore, we observed a correlation Moss [71]. The increased stabilisation of α-bromocarboethoxy-
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carbene as compared to α-H-carboethoxycarbene, is apparent in insertion is conformationally favoured, the α-bromo-β-lactams
its increased propensity towards reaction with the more elec- were obtained in good to excellent yields.
tron-rich of the available reaction partners, a propensity which
has traditionally been quantified by the ratios of cyclopropana-
Supporting Information
tion of increasingly substituted ethylenes [28,30,71]. More
recently, a two-dimensional carbenic reactivity surface has been
Supporting Information File 1
established by Brinker and co-workers. Unfortunately, no halo-
carbonylcarbene has yet been included in these studies [73].
Detailed experimental procedures and physical data for the
obtained products.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-157-S1.pdf]
The donation of electron density to the vacant carbenoid 2p
orbital, has also been a topic in the paradigm of dirhodium(II)
catalysis, in which the electron-donating ability of the catalyst
ligands correlates to the observed selectivity of the
dirhodium(II) carbenoid. Thus, in analogy to the preference for
more highly substituted ethylenes, in a case where only C–H
insertion is viable, a highly stabilised dirhodium(II) carbenoid
shows increased selectivity among the possible C–H insertion
partners. For alkanes, the following order of preference is
observed: R3CH > R2CH2 > RCH3 [2,74-76]. The order of re-
activity of the C–H bonds reflects the varying abilities of the
CHn carbons to stabilise the build-up of positive charge as the
incipient electrophilic carbene/carbenoid 2p orbital attacks the
C–H σ-bonding orbital of the substrate. Consequently, C–H
bonds vicinal to heteroatoms are activated for insertion [44,77].
The observed selectivity of the more stabilised carbenoids is
attributed to the donation of electron density from the 4d
orbitals of the dirhodium(II) complex to the vacant carbenoid
2p orbital [76,78-81], which attenuates its electrophilicity. This
effect is analogous to the increased selectivity conferred by
π-donation from a halogen substituent on the carbene carbon
(see above) [28,30,71,81-84].
Acknowledgements
The authors wish to thank senior engineer Dr. Osamu Sekiguchi
for the recording of mass-spectrometry data, Professor Carl-
Henrik Gørbitz for assistance with the X-ray crystallography,
and Dr. Tor Erik Kristensen, Dr. Christian Schnaars and Dr.
Martin Hennum for their competent input and advice through-
out the preparation of this manuscript.
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