C-H functionalisation of aldehydes using light generated, non-stabilised diazo compounds in flow

Article abstract of DOI:10.1039/c8cc06202a

The difficulty in accessing and safely utilising non-stabilised diazo species has in the past limited the application of this class of compounds. Here we explore further the use of oxadiazolines, non-stabilised diazo precursors which are bench stable, in direct, non-catalytic, aldehyde C-H functionalisation reactions under UV photolysis in flow and free from additives. Commercially available aldehydes are coupled to afford unsymmetrical aryl-alkyl and alkyl-alkyl ketones while mild conditions and lack of transition metal catalysts allow for exceptional functional group tolerance. Examples are given on small scale and in a larger scale continuous production.

Full text of DOI:10.1039/c8cc06202a

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C–H functionalisation of aldehydes using light
generated, non-stabilised diazo compounds in
flow†
Cite this:DOI: 10.1039/c8cc06202a
Received 30th July 2018,
Accepted 20th August 2018
a
a
a
Paul Dingwall,
Biagia Musio,
Steven V. Ley
Andreas Greb,a Lorene N. S. Crespin,
Ricardo Labes,
`
a
Jian-Siang Poh,a Patrick Pasau,b David C. Blakemorec and
a
DOI: 10.1039/c8cc06202a
*
rsc.li/chemcomm
The difficulty in accessing and safely utilising non-stabilised diazo
species has in the past limited the application of this class of
compounds. Here we explore further the use of oxadiazolines,
non-stabilised diazo precursors which are bench stable, in direct,
non-catalytic, aldehyde C–H functionalisation reactions under UV
photolysis in flow and free from additives. Commercially available
aldehydes are coupled to afford unsymmetrical aryl–alkyl and
alkyl–alkyl ketones while mild conditions and lack of transition
metal catalysts allow for exceptional functional group tolerance.
Examples are given on small scale and in a larger scale continuous
production.
Scheme 1 Synthesis and UV photolysis of oxadiazolines.
tetraacetate22 or (diacetoxyiodo)benzene23 or by electrochemical
methods24 (Scheme 1). Oxadiazolines are bench stable at room
temperature but, when exposed to UV irradiation, decompose to
form the relevant non-stabilised diazo compound and methyl
acetate.25,26 These compounds are particularly attractive for use
in flow chemistry due to the certain safety issues outlined above,
as well as the additional associated benefits that accrue under
continuous processing conditions.
The addition of a diazo compound to an aldehyde with
subsequent 1,2-hydride shift affords the corresponding ketone
product (Scheme 2).27 We have previously reported the thermally
activated insertion of diazo compounds into a formyl C–H bond
to generate unsymmetrical ketones using tosylhydrazones as
non-stabilised diazo precursors in 2014.28
Diazo compounds have a long-standing history as extremely
versatile tools for the creation of carbon–carbon and carbon–
heteroatom bonds.1–4 As a class of compounds, however, diazo
derivatives are notorious for their toxic and hazardous nature,
and associated difficulty in preparation and handling. These
difficulties are compounded when the diazo moiety is not
stabilised by either a proximal electron withdrawing group or
p-system, meaning that the chemistry of non-stabilised diazo
compounds is still a relatively underexplored area. The use of flow
techniques as an enabling technology5–8 can mitigate these classical
issues to a large extent via the in situ generation and consumption of
diazo compounds, so avoiding accumulation, allowing safer access
under reproducible process windows.9–19 Accordingly, our group
has recently published a mild method for the generation of non-
stabilised diazo compounds from oxadiazolines using UV light and
their aryl–alkyl cross-coupling with boronic acids.20
Although a ubiquitous functional group, the synthesis of
unsymmetrical ketones can still prove a synthetic challenge,
making this an active area of research. In the recent literature, a
number of methods coupling activated carbonyl substrates, such
Oxadiazolines are prepared in a one-pot, two step procedure
by the condensation of an alkyl ketone21 with acetic hydrazide
followed by cyclisation promoted by oxidants such as lead
a Department of Chemistry, University of Cambridge, Lensfield Road,
Cambridge CB2 1EW, UK. E-mail: svl1000@cam.ac.uk;
Web: http://www.leygroup.ch.cam.ac.uk
b UCB Biopharma SPRL, Chemical Research R5, Chemin du Foriest 1420,
Braine-L’Alleud, Belgium
c Medicine Design, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, USA
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c8cc06202a
Scheme 2 Mechanistic pathways available for diazo addition to an
aldehyde.
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as acetyltrimethylsilanes,29,30 acyl chlorides,31,32 amides,33–35 presumably due to decomposition of the diazo intermediate
anhydrides,36,37 phthalimides,38 or carboxylic acids,39 with various (Table 1, entry 5). Reducing the equivalents of the oxadiazolines
partners have been reported. Formation of unsymmetrical ketones relative to the aldehyde from 2 to 1.1 resulted in a decrease in
directly from aldehydes is more desirable than from activated yield and no difference was observed on change of solvent
substrates but more challenging still. Direct formyl C–H insertion to (Table 1, entries 6, 7, and 8).
create a new sp2–sp3 or sp2–sp2 carbon–carbon bond is achievable
With optimised conditions in hand we began to investigate
via Palladium,40–43 Rhodium,44,45 or Nickel46–49 catalysed processes the scope of the transformation. The in situ generation and full
as well as through NHC mediated organocatalysis50,51 or indeed consumption of diazo compounds in flow is an ideal case and
diazo chemistry27,28 (Scheme 3).
one which, when screening new reactions, may not always hold.
These existing methods afford valuable reactivity and useful Inline IR53,54 is a particularly advantageous analytical technique
chemistry. However, some drawbacks commonly encountered in diazo chemistry as diazo species have a unique IR stretch
include long reaction times, occasionally harsh conditions, (ca. 2040 cmÀ1) which, under our experimental setup, can be
necessity for a plethora of additives, the presence of up to three detected in a simple manner. As the IR is present upstream
catalysts, and relatively poor functional group compatibility from the back-pressure regulator and system outlet (Table 1) if
due to the reactivities of associated transition metal catalysts. at any time the user observes a non-trivial concentration of
In this work, we extend our original oxadiazoline methodology diazo in the output of the reactor this can be simply dealt with
and we report their very mild and rapid coupling with aldehydes through addition of an appropriate quenching agent (i.e. acetic
to form unsymmetrical alkyl–alkyl and aryl–alkyl ketones with acid) to the collection vessel prior to any diazo material exiting
excellent functional group tolerance and resulting structural the system. An additional benefit of inline IR in this methodology
diversity.
is the detection of methyl acetate, which is produced in the
Employing similar conditions to those of our previous work breakdown of the oxadiazoline (Scheme 1) and can be used to
resulted in an excellent yield of the product ketone (Table 1, observe the progress of the reaction.
entry 1).20 Removal of the DIPEA base resulted in no change to
We first sought to determine the generality of the oxadiazoline
the reaction yield (Table 1, entry 2).52 Reducing the residence component (Table 2). A variety of carbon rings were tolerated,
time to 40 minutes resulted in a decrease in yield, however from cyclopentane (1) and cyclobutane (2) to an oxadiazoline
this could be increased again by raising the temperature of the incorporating a cyclopropane moiety (3). No ring-opened product
reaction to 20 1C (Table 1, entries 3 and 4). Increasing the was observed, serving as evidence of a polar rather than a radical
temperature to 30 1C resulted in a precipitous drop of the yield, process. Tetralin (4) and methoxy naphthyl (5) were viable
substrates. An oxadiazoline derived from the macrocyclic natural
product Muscone (6) also proved viable, albeit in low yield. A
bulky adamantly group (7) reacted in good yield. Six membered
saturated heterocycles tetrahydropyran (8), tetrahydrathiopyran
(9), N-boc and N-pyrimidyl (10 and 11) piperidine reacted in
moderate to excellent yields. Five- and four-membered saturated
oxygen containing heterocycles tetrahydrofuran (12) and oxetane
(13) reacted in more moderate yields. Functional group tolerance
proved to be excellent, with examples of an epoxide (14),
primary alkyl bromide and iodide (15 and 16), terminal alkene
(17), and phosphonate ester (18) exemplifying the extremely
mild conditions of this reaction and accessing products which
would be otherwise difficult or impossible to access via metal-
catalysed methods.
Scheme 3 Methods for direct aldehyde coupling reactions to form
unsymmetrical ketones.
Table 1 Optimisation of aldehyde C–H addition reaction
We next turned our attention to the aldehyde scope. Methyl
ester (19) resulted in excellent yields while an ortho-nitrile
group (20) displayed tolerance to bulk beside the reacting
position in an aromatic system. Functional group tolerance is
again excellent with para- (21) and meta-bromo (22) benzalde-
hydes as well as the synthetically useful boron-pinacol ester (23)
which would otherwise be challenging to incorporate under
transition metal catalysis.55 However, the electron rich 4-methoxy
benzaldehyde (24) resulted in a low yield. A variety of hetero-
cyclic aldehydes were also successfully coupled. For example,
several pyridyl containing aldehydes (1, 25 and 26) as well as
thiophene (27) and isoxazole (28). We were pleased to find
that aliphatic aldehydes proceed although they appear more
challenging than aromatic aldehydes, with hexanal (29) resulting
Entry [Oxadiaz] (M) [Aldehyde] (M) tR (min) T (1C) Solvent Yielda (%)
1b
2
3
4
5
6
7
8
0.1
0.1
0.1
0.1
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
80
80
40
40
40
40
40
40
10
10
10
20
30
20
20
20
CH2Cl2 94c
CH2Cl2 93
CH2Cl2 78
CH2Cl2 91
CH2Cl2 28
CH2Cl2 72
MeTHF 70
Dioxane 70
0.1
0.06
0.06
0.06
a
b
c
GC yield unless stated otherwise. 0.1 M DIPEA. Isolated yield.
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Table 2 Metal and additive free addition of non-stabilised diazo compounds to aldehydes in flow
in a moderate yield but cyclic N-boc piperidone carboxaldehyde 311 nm) where, under our standard operating conditions the
(30) only a low yield. yield was 16% but was increased to 41% by simply halving the
When employing 4-iodobenzaldehyde (31) as the aldehyde reaction concentration and doubling the residence time.
coupling partner only decomposition to benzaldehyde was As a flow process, the methodology is eminently scalable by
observed and the use of cinnamaldehyde (32), benzothiazole simply running the reaction for longer. Without accumulation
(33), and amino (34) or nitro (35) functional groups resulted in of any diazo intermediate, a four hour run under steady state at
no reaction. In each case above, little or no conversion of the standard conditions provided 580 mg of ketone 19, corres-
oxadiazoline was observed due to the absorbance of UV irradiation ponding to a theoretical productivity of 3.48 g dÀ1, with similar
by the aldehyde. With this knowledge in hand, we found that a yield to the smaller scale run (91 to 94%) with this particular
simple test can be carried out prior to performing the reaction reactor set-up.
which allows the user to determine the feasibility and potentially
In conclusion, this work expands the scope and application
adjust conditions accordingly to maximise the yield. If the lmax of of oxadiazolines as highly effective precursors to non-stabilised
the desired aldehyde coupling partner is at or above 310 nm (the diazo compounds. Mild reaction conditions, short reaction times,
wavelength of UV irradiation employed) then the reaction is and ease of continuous operation means this methodology offers a
unlikely to proceed (see Fig. S2, ESI†). We also found that, to complementary alternative to existing literature procedures. In
some extent, this limitation can be overcome by lowering the particular, the lack of transition metals or commonly used
concentration of the reactants and increasing the residence additives such as oxidants or bases allows for the incorporation
time of the reaction. This is demonstrated in the case of of sensitive functional groups into the ketone products, laying
compound (27) (starting material aldehyde having a lmax at groundwork for their immediate further functionalisation.
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the oxadiazole during cyclisation. For further information see:
The authors kindly acknowledge funding by the H2020-
FETOPEN-2016-2017 programme of the European commission
(P. D., S. V. L., 737266-ONE FLOW), postdoctoral fellowships from
Pfizer (A. G. and L. C.), EPSRC Critical Mass Grant (EP/K009494/1)
(B. M.), Cambridge Home and EU Scholarship Scheme (J. S. P.),
and EPSRC (S. V. L., grant no. EP/K009494/1, EP/K039520/1 and
EP/M004120/1) for financial support. The authors are also grateful
to Duncan Guthrie at Vapourtec for the generous loan of a UV-150
photoreactor.
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