Direct Conversion of Aldehydes and Ketones into Azides by Sequential Nucleophilic Addition and Substitution

Article abstract of DOI:10.1002/ejoc.201600856

This report describes the direct conversion of aldehydes and ketones into alkyl azides by the addition of common organometallic reagents and tandem conversion of the resulting alkoxides without isolation of the intermediate alcohols. A wide range of aldehydes and organometallic reagents (R–Li or R–MgX) are suitable participants in this process. Additional reaction telescoping beyond azide formation is demonstrated.

Full text of DOI:10.1002/ejoc.201600856

A Journal of
Accepted Article
Title: Direct Conversion of Aldehydes and Ketones to Azides via Sequential Nucleo-
philic Addition Substitution
Authors: Pratik P. Goswami; Victoria P. Suding; Angela S. Carlson; Joseph J. Topc-
zewski
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201600856
Link to VoR: http://dx.doi.org/10.1002/ejoc.201600856
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European Journal of Organic Chemistry
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COMMUNICATION
Direct Conversion of Aldehydes and Ketones to Azides via
Sequential Nucleophilic Addition & Substitution
Pratik P. Goswami,[a] Victoria P. Suding,[a] Angela S. Carlson,[a] and Joseph J. Topczewski*[a]
formation, or poor conversion. This led us to consider whether
the azides of interest could be prepared directly from readily
available carbonyl containing compounds through reaction
telescoping, which would avoid the need to isolate potentially
unstable activated intermediates. The proposed route could
involve addition of an organometallic reagent (organolithium or
Grignard) to the carbonyl, in situ trapping of the resultant
alkoxide, and nucleophilc displacement to form the azide
without isolation of the intermediate alcohol or alcohol
derivative (Equation 2).
Abstract: This report describes the direct conversion of aldehydes
and ketones to alkyl azides through the addition of common
organometallic reagents and tandem conversion of the resulting
alkoxide without isolation of the intermediate alcohol. A wide range
of aldehydes and organometallic reagents (R-Li or R-MgX) are
suitable participants in this process. Additional reaction telescoping
beyond azide formation is demonstrated.
Introduction
A major goal of modern organic synthesis is to develop
methods for the conversion of readily available feedstocks into
synthetic targets of interest while simultaneously minimizing
both the resources used and waste generated during the
synthesis. In this context, numerous formative metrics have
been developed including atom, 1 step,2 or redox economy. 3
Quantitatively, the majority of waste generated in fine chemical
synthesis is solvent and water used in isolation and purification
of products.4 As such, one straightforward way to optimize a
synthesis is to combine two or more reactions together into a
single operation, an approach known colloquially as
telescoping. 5 While conceptually appealing, practical issues
arising from reagent (in)compatibility, salt precipitation, acid-
base reactions, or side product formation increase the
challenges of telescoping relative to traditional sequential
reactions. Presented herein is a procedure to telescope the
addition of organometallic reagents to carbonyl functionality
with in situ alcohol activation and azide formation. These steps
have been routinely conducted separately,6 however they are
not commonly combined into a single procedure.
Results and Discussion
We began with 4-methoxy benzaldehyde (1) as a model
activated substrate and investigated the addition of phenyl
magnesium bromide followed by the addition of various
activating agents and azide sources (Table 1). The use of tosyl
chloride as an activating reagent followed by NaN3 addition
afforded the desired azide 2 in modest yield (81%) and the use
of TMSN3 did not afford appreciable levels of azide (not
shown). DPPA provided the highest yield in the initial
evaluation (entry 1), was the most operationally straightforward
azide source, and is generally considered to have an excellent
safety profile. Therefore, DPPA was selected for further
optimization. The process could be conducted in a variety of
solvents (entries 1 – 4) and THF was selected due to its
ubiquity. Conducting the substitution reaction to proceed at
slightly elevated temperature allowed the equivalents of
reagents to be reduced and the concentration of the reaction to
be increased (entries 5 – 8). The optimized procedure involves
the addition of the carbonyl compound to 1.2 equivalents of
Grignard reagent cooled in ice bath followed by the addition of
1.3 equivalents of DPPA, after which the reaction can be
gradually warmed to 40 °C to facilitate nucleophilic
displacement (entry 8).
We became interested in the synthesis of activated alkyl
azides, which are valuable intermediates in the synthesis of
amines and heterocycles,7 and sought an efficient and reliable
way to readily prepare these starting materials with the minimal
input of time and resources. Alkyl azides are classically
prepared by the nucleophilic displacement of alkyl halides or
activated alcohols (i.e. tosylates) with sodium azide (Equation
1).7, Additionally, various methods are known to convert
8
alcohols directly to azides through in situ alcohol activation
such as via the Mitsunobu reaction,9 through the use of base
and diphenylphosphoryl azide (DPPA),10 or the combination of
HN3 or trimethylsilyl azide and an acid promoter11 (Equation
1). In our initial efforts, we struggled to find a reliable method
to prepare some azides because the activated alkyl halides were
prone to decomposition. For example, we were unable to isolate
the tertiary bromide en route to azide 46. Many other methods
required multiple steps, resulted in alcohol dehydration, ether
[a]
Department of Chemistry
University of Minnesota
Minneapolis, Minnesota 55455
E-mail: jtopczew@umn.edu
Supporting information for this article is given via a link at the end of
the document.
Table 1. Reaction Optimization.
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European Journal of Organic Chemistry
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COMMUNICATION
Benzophenone (entry 1) and 4-methoxy acetophenone (entry 2)
afforded the target azide in modest yield. Enones (entries 3 and
4) were also compatible. Unactivated ketones (entry 5), were
less reactive to substitution of the putative tertiary phosphate
and larger quantities of elimination product(s) were observed.
Finally, phenyl benzoate (entry 6) was subjected to the reaction
conditions and a modest yield of trityl azide was obtained.
Entry
Equiv.
PhMgBr
Equiv.
DPPA
[1]/M
Solvent
°C[a]
Yield(%)[b]
Table 2. Scope of Organometallic Component.
1
2
3
4
5
6
7
8
1.5
1.5
1.5
1.5
1.5
2.0
1.0
1.2
2.0
2.0
2.0
2.0
2.0
3.0
1.1
1.3
0.2
0.2
0.2
0.2
0.2
0.7
0.7
0.7
PhMe
Et2O
DME
THF
THF
THF
THF
THF
rt
90
28
93
92
94
89
77
94
rt
rt
rt
Entry
R-M
Product
Yield (%)[a]
40
40
40
40
With optimized conditions in hand, we investigated the
nucleophilic reagent. The scope of the organometallic reagent
that participated in this process was quite broad (Table 2). 12
Organolithium and Grignard reagents provided comparable
yields (entries 1, 3, and 5 vs. entries 2, 4, and 6 respectively)
providing the user flexibility. Furthermore, aryl (entries 1, 2
and 10), alkyl (entries 3-6), vinyl (entries 7 and 8),12 cycloalkyl
(entry 9), and heteroaryl (entry 10) reagents all afforded
excellent yields in this process.
We next investigated the scope of reaction with respect to the
aldehyde (Table 3). Other electron rich (entry 1), neutral (entry
2), or deficient (entries 3 and 4) benzaldehydes afforded the
azide in high yield. It is worth noting that in the less activated
cases (entry 2-4), the nucleophilic displacement with azide was
slow and required longer reaction times, higher temperatures,
and/or the addition of exogenous azide (tetrabutylammonium
azide) to increase the yield. Heterocycle carboxaldehydes
(entries 5 and 6) as well as enals (entries 7 and 8)13 also
participated in this tandem process. Fully saturated aldehydes
(entry 9) provided trace elimination products (5% – 10%) in
addition to the azide. Chemoselective addition was possible
(enty 10). An aromatic nitro group was compatible with these
conditions and vinyl Grignard over Bartoli reaction (entry 11).
The use of m-formyl-benzoic acid did not lead to a high yield
of the desired azide due to competing acyl azide formation and
further reaction(s).14 When taken together, these data reflect a
wide scope of participating aldehydes and illustrate that this
method is of practical utility. To further illustrate the utility, the
reaction was conducted on a gram scale (Scheme 1) and the
model azide was obtained in excellent yield.
General conditions: 0.4 mmol substrate, 4.8 mmol PhMgBr, 5.2 mmol
DPPA, 0.7 M in THF, 0 °C to 40 °C, 18 – 24h [a] Isolated yields after
column chromatography. Yields are reported as the average of duplicate
trials.
The increased efficiency of this method is exemplified by
comparison to the published synthesis of azide 46 (Scheme 2).
Previously,
a
three step procedure involving Horner-
Wadsworth-Emmons condensation, selective reduction, and
azide formation has been reported in an overall yield of about
Scheme 1. Gram Scale Reaction.
,
5%.11e,15 16 Starting from the same initial precursor, the method
To further test the limits of this telescoped process, other
carbonyl compounds were investigated (Table 4). Several
activated ketones were compatible with the conditions.
reported here allows a direct synthesis, increases the overall
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European Journal of Organic Chemistry
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yield by >10 fold, and reduces the step count from 3 steps to 1
step.
Table 3. Scope of Aldehyde.
Entry
Substrate
Product
Yield (%)[a]
Scheme 2. Comparative Synthesis of Azide 46.
Table 4. Use of Ketones.
Entry
Starting Material
Product
Yield (%)[a]
General conditions: 0.4 mmol substrate, 4.8 mmol PhMgBr, 5.2 mmol
DPPA, 0.7 M in THF, 0 °C to 40 °C, 18 – 24h [a] Isolated yields after
column chromatography. Yields are reported as the average of duplicate
trials.
We next sought to expand the process beyond azide
formation. Gratifyingly, the azide could be reduced to the
benzhydrylamine derivative 47 without prior isolation (Scheme
3). This provides
a direct synthesis of non-symmetric
General conditions: 0.4 mmol substrate, 4.8 mmol PhMgBr, 5.2 mmol
DPPA, 0.7 M in THF, 0 °C to 40 °C, 18 – 24h [a] Isolated yields after
column chromatography. Yields are reported as the average of duplicate
trials. [b] 1 equiv. of TBAN3 was added and the reaction was conducted at
60 °C. [c] PhLi was used instead of PhMgBr [d] CH2CHMgBr was used
instead of PhMgBr.
benzhydrylamine derivatives from readily available precursors
in a single process. Benzhydrylamine derivatives are the key
pharmacophore present in pharmaceuticals such as Letrozole,
Cetirizine, Agispor, and Flunarizine.
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European Journal of Organic Chemistry
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COMMUNICATION
needed higher temperature and exogenous azide to complete the
nucleophilic substitution. A modified procedure was used in these cases:
Procedure II: A magnetic stir bar was added to a 50 mL or 100 mL
2- or 3-neck oven dried round bottom flask. The flask was fitted with
rubber septa, gas inlet, and connected to a Schlenk line. The flask was
evacuated and backfilled with argon (3 cycles), placed under a positive
pressure of argon, and partially submerged into an ice bath. To the flask,
THF (3 mL) and phenylmagnesium bromide (0.80 mL, 3M in Et2O, 2.4
mmol, 1.2 equiv.) were sequentially transferred via syringe. After 5 min in
the ice bath, 4-fluorobenzaldehyde (0.22 mL, 2.0 mmol, 1 equiv.) was
added dropwise via syringe. After addition of the benzaldehyde was
complete, the ice bath was removed. After an additional 10 min, the flask
was reintroduced in the ice bath and diphenylphosphoryl azide (0.57 mL,
2.6 mmol, 1.3 equiv.) was added dropwise. After an additional 10 min in
the ice bath, the ice bath was removed and the solution was heated to
60 °C. After 4h, the solution was allowed to cool to room temperature and
solid tetrabutylammonium azide (573 mg, 2.0 mmol, 1.0 equiv.) was
added to the flask. The flask was then heated to 60 °C. After 18 – 24 h
at 60 °C, the reaction was quenched by addition of water. The resulting
solution was extracted with DCM (3 x 20 mL) and the combined organic
phases were dried (MgSO4), filtered, and concentrated under reduced
pressure. Final purification by column chromatography (40 g cartridge,
gradient elution 0% - 30% EtOAc in hexanes) afforded the final product
(245 mg, 81%) as a faintly yellow oil.
Scheme 3. Further Telescoping.
Conclusions
The addition of common organometallic reagents to aldehydes
can be telescoped with azide formation. This procedure avoids
the need to isolate the intermediate alcohol and is compatible
with a wide range of aldehydes. A variety of common
organometallic reagents are suitable. Preliminary results
indicate that both ketones and esters can participate in this
cascade and further reaction telescoping is possible even
beyond azide formation.
Experimental Section
Azide Safety: Azides are known to be high energy materials and
explosions have been reported when working with azides. In the course
of this work, no issues were encountered. All of the azides synthesized in
this report have C/N ratios equal to or above the recommended guideline
of 3. Precautionary blast shields were used for all reaction using or
producing more than 1 mmol of azide. Blast shields were used both in
the fume hood and during rotary evaporation. All waste and aqueous
solution which could be contaminated with azide were kept in individually
labeled containers and were kept STRICTLY free of acid to avoid the
accidental production of HN3 – DO NOT use aqueous HCl during work up
of any of the reactions reported herein. Please read further before
repeating these experiments.17
Gram Scale reaction: A magnetic stir bar was added to a 250 mL
3-neck oven dried round bottom flask. The flask was fitted with rubber
septa, gas inlet, and connected to a Schlenk line. The flask was
evacuated and backfilled with argon (3 cycles), placed under a positive
pressure of argon, and partially submerged into an ice bath. To the flask,
THF (18 mL) and phenylmagnesium bromide (4.8 mL, 3M in Et2O, 4.5
mmol, 1.2 equiv.) were sequentially transferred via syringe. After 5 min in
the ice bath, 4-methoxybenzaldehyde (1.5 mL, 12 mmol, 1 equiv.) was
added dropwise via syringe. After addition of the benzaldehyde was
complete, the ice bath was removed. After an additional 10 min, the flask
was reintroduced into the ice bath and diphenylphosphoryl azide (3.4 mL,
16 mmol, 1.3 equiv.) was added dropwise. After an additional 10 min in
the ice bath, the ice bath was removed and the solution was heated to
40 °C. The temperature was maintained at 40 °C for 18 h. After this time,
the reaction was quenched by addition of water. The resulting solution
was extracted with DCM (3 x 20 mL) and the combined organic phases
were dried (MgSO4), filtered, and concentrated under reduced pressure.
Final purification by column chromatography (80 g cartridge, gradient
elution 0% - 30% EtOAc in hexanes) afforded the final product (2.57 g,
90%) as a faintly yellow oil.
Azide synthesis. Procedure I: A magnetic stir bar was added to a
50 mL or 100 mL 2- or 3-neck oven dried round bottom flask. The flask
was fitted with rubber septa, gas inlet, and connected to a Schlenk line.
The flask was evacuated and backfilled with argon (3 cycles), placed
under a positive pressure of argon, and partially submerged into an ice
bath. To the flask, THF (6 mL) and phenylmagnesium bromide (1.5 mL,
3M in Et2O, 4.5 mmol, 1.2 equiv.) were sequentially transferred via
syringe. After 5 min in the ice bath, 4-methoxybenzaldehyde (0.48 mL,
3.7 mmol, 1 equiv.) was added dropwise via syringe. After addition of the
benzaldehyde was complete, the ice bath was removed. After an
additional 10 min, the flask was reintroduced into the ice bath and
diphenylphosphoryl azide (1.1 mL, 4.8 mmol, 1.3 equiv.) was added
dropwise. After an additional 10 min in the ice bath, the ice bath was
removed and the solution was heated to 40 °C. The temperature was
maintained at 40 °C for 18 h – 24 h. After this time, the reaction was
quenched by addition of water. The resulting solution was extracted with
DCM (3 x 20 mL) and the combined organic phases were dried (MgSO4),
filtered, and concentrated under reduced pressure. Final purification by
column chromatography (40 g cartridge, gradient elution 0% - 30%
EtOAc in hexanes) afforded the final product (795 mg, 90%) as a faintly
yellow oil. Deactivated aryl aldehydes, including compounds 6, 8, and 10,
Acknowledgements
We thank Amy Ott for acquiring mass spectra. The ACS-PRF
(PRF# 56505-DNI1) and the University of Minnesota are
thanked for financial support. V.P.S. acknowledges UMN-UROP
support.
Keywords: azides • green chemistry • organic chemistry:
methodology and reactions
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European Journal of Organic Chemistry
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Azides
Pratik P. Goswami, Victoria P. Suding,
Angela S. Carlson, and Joseph J.
Topczewski
Page No. – Page No.
Described herein is the direct conversion of aldehydes and ketones to alkyl azides
through the addition of common organometallic reagents and tandem conversion of
the resulting alkoxide. A wide range of aldehydes and organometallic reagents are
suitable in this process. Additional reaction telescoping beyond azide formation is
demonstrated.
Direct Conversion of Aldehydes and
Ketones to Azides via Sequential
Nucleophilic Addition & Substitution
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12 The use of metal hydrides to generate the azide by tandem reduction and subsequent azide formation was not successful in preliminary experiments. Both
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