A flow-based synthesis of 2-aminoadamantane-2-carboxylic acid

Article abstract of DOI:10.1021/op300084z

The development of a new, high-yielding, scalable and safe process for the preparation of 2-aminoadamantane-2-carboxylic acid (1) is described. This geminal, functionalized achiral amino acid has been reported to possess interesting biological activity as

Full text of DOI:10.1021/op300084z

Article
pubs.acs.org/OPRD
A Flow-Based Synthesis of 2-Aminoadamantane-2-carboxylic Acid
Claudio Battilocchio,*,†,‡ Ian R. Baxendale,† Mariangela Biava,‡ Matthew O. Kitching,† and Steven V. Ley†
†Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom
‡Dipartimento di Chimica e Tecnologie del Farmaco, “Sapienza” Universita
̀
di Roma, P.le A. Moro 5, Roma 00185, Italy
S
* Supporting Information
ABSTRACT: The development of a new, high-yielding, scalable and safe process for the preparation of 2-aminoadamantane-2-
carboxylic acid (1) is described. This geminal, functionalized achiral amino acid has been reported to possess interesting
biological activity as a transport mediator due to its unique physiochemical properties. We report herein on the use of various
mesoreactor flow devices to expedite the lab-scale synthesis of this molecule by simplifying the processing requirements for use of
several potentially hazardous reagent combinations and reaction conditions.
treatment of ketone 5 with a buffered solution of sodium
cyanide at elevated temperature and pressure yielded the
spirohydantoin 6 which, without purification, was hydrolysed to
the desired amino acid 1 in good overall reported yield.
In order to more readily achieve the necessary elevated
reaction temperature and pressure windows as outlined
(Scheme 1, footnote a) we transposed the chemistry to a
Biotage microwave reactor initially using sealed 20 mL reaction
vials with only minor modifications of the previous batch route
(Scheme 1, footnote b). This allowed us to perform the
chemistry safely, yielding material identical to that obtained
following the original batch conditions. (Note: this is an
important point of consideration relating to later discussion
concerning product purity.)
Although batch processing of such relatively small volumes
was straightforward when conducting optimization and test
reactions, a microwave approach can be severely limiting when
considering scale-up. It is not possible to directly scale a
microwave cavity in order to increase output equivalent to a
standard batch reactor. Physical restrictions, pertaining to the
defined penetration depth of microwaves into a reactor, limit
such an approach or certainly make reactor scaling a major
engineering challenge.12 We circumvented this issue in part by
employing a CEM stop-flow microwave.13 The adoption of
stop-flow microwave handling allowed the rapid scale-up of the
reaction sequence even though it required the processing of
heterogeneous slurries (hydantoin input reaction solution and
the resulting product mixture). Furthermore, the continuous
monitoring of temperature and pressure combined with
automatic safety cutoffs also minimized the risks associated
with scale-up. Of particular value was the automation of the
entire process which ensured reproducibility across the
consecutively conducted batch operations whilst lowering the
manual handling time necessary for a skilled chemist. In this
fashion, material could be quickly processed through the two-
step sequence on >400 mmol scale.
INTRODUCTION
■
The adamantyl cage is an important motif1 present in
numerous biologically active compounds including a number
of currently used therapeutic agents (Figure 1).2 The unique
symmetrical yet configurationally rigid geometry of the
adamantane cage is often used to influence a structure’s
physiological properties by providing a bulky lipophilic
scaffold.3 One particularly interesting adamantane derivative,
namely, 2-aminoadamantane-2-carboxylic acid (1), is an
unnatural, achiral amino acid which has been shown to possess
novel transport inhibitory properties (Figure 2).4 According to
Tager and Christensen,5 this molecule perfectly fulfills the
theoretical requirements for transport inhibition of amino acids:
(a) bulky side chain, (b) side chain apolarity, (c) catabolic
resistance for the presence of a tertiary α-carbon, and (d)
sufficient water solubility. We became interested in the
synthesis of this amino acid as part of a research program
directed towards the preparation of key probes for neurotensin
receptors 1 and 2 (NTR1 and NTR2).6a NTR1 and 2 are both
seven-transmembrane G protein-coupled receptors (GPCR’s)
with increasing relevance in several human cancers.6 In the
early 1990s, Sanofi-Aventis in a high throughput screening
campaign identified SR 45398 (2)7 as a binder of NTR in
guinea pig brains (IC50 40 μm). Through iterative lead
optimization, this was developed into the NTR1 antagonist
Merclinertant SR 48692 (3)7,8 and then a second-generation
analogue SR 142948A (4)9 capable of preferentially activating
NTR 2. In these molecules, the 2-aminoadamantane-2-
carboxylic acid residue, 1, is reported to be responsible for
key interactions allowing the selective recognition of the NTR
receptor.10
Wishing to prepare large quantities of both SR 48692 (3)
and SR 142948A (4), we required a scalable and reliable route
to this key fragment.
DISCUSSION
Unfortunately, in our hands, isolation of the pure amino acid
1 was not possible. Following either the original reported
■
Evaluating the preparative routes currently reported in the
literature we identified two main synthetic strategies. Our initial
investigations employed a Bucherer−Berg reaction as described
by Nagasawa (Scheme 1, footnote a).11 In the original report,
Received: March 27, 2012
Published: April 17, 2012
© 2012 American Chemical Society
798
dx.doi.org/10.1021/op300084z | Org. Process Res. Dev. 2012, 16, 798−810

Organic Process Research & Development
Article
Figure 1. Adamantyl-containing therapeutics in current clinical use.
Figure 2. 2-Aminoadamantane-2-carboxylic acid (1) and Sanofi-Aventis′ SR 45398 (2), Merclinertant SR 48692 (3) and SR 142948A (4).
a
recrystallisation from THF (four cycles) to yield the desired
hydantoin 6 as its monohydrate complex.
Scheme 1. Nagasawa’s route to the amino acid 1;
microwave processing conditions
b
Subjecting the purified hydantoin 6 independently to the
subsequent hydrolysis step showed that this transformation
occurred in a manner identical to that of the reactions of the
1
crude material. As monitored by H NMR of the reaction
mixture (in D2SO4), complete conversion to the amino acid 1
could be achieved by utilizing microwave heating under basic
conditions; however, frustratingly problems still persisted
regarding isolation of the amino acid. All attempts to maximize
the recovery of the product yielded material of much lower
purity (best result being 72% isolated yield corresponding to an
elemental analysis indicating only 80% purity). We were
therefore forced to consider alternative synthesis procedures.
As initially stated, a second synthetic strategy was also
originally identified in the literature. We therefore turned our
attention to this alternative pathway as inspired by Commeyr-
as15a−c and Edward15d which utilized a key Strecker reaction
(Scheme 2). Commeyras had identified a mild method of
a
Reaction conditions: i) NaCN (2 equiv), (NH4)2CO3 (1.5 equiv),
EtOH, 120 °C, 170 psi, 3 h (99%); ii) 1.25 N NaOH, 195 °C, 250 psi,
2 h (81%). Reaction conditions: i) NaCN (2.2 equiv), (NH4)2CO3
(1.5 equiv), EtOH/H2O (3:1), 150 °C, 2 h (94%); ii) 1.25 N NaOH,
175 °C, 3 h (71%).
b
procedure11 or our modified microwave protocol gave material
that was always significantly contaminated by unidentifiable
inorganic impurities as determined by microanalysis (com-
pound 1, observed range C = 37−45%, desired 67.7%).14 It also
proved extremely difficult to purify this final amino acid
product 1 due to its limited solubility. We therefore decided to
break the route down into its component steps and investigate
the individual processes in more depth.
Scheme 2. Edward route to the amino acid 1
First, confirmation of the extent of the hydantoin hydrolysis
step and determination of the level of inorganic impurities at
1
this intermediate stage were assessed by H NMR analysis (in
D2SO4). In order to facilitate rapid calibration and allow
quantification of the levels of components, each analytical
sample was doped with known quantities of p-anisidine to act
as an internal standard. From this investigation it was evident
that hydantoin 6 was being successfully and fully hydrolysed to
the corresponding amino acid 1 under the prescribed reaction
conditions. However, it was also clear that the synthesized
hydantoin material 6 possessed on average only 30−35% of the
desired material by mass. All attempts to enhance the quality of
this intermediate material by hot filtration through Celite or
glass wool, or by treatment with charcoal, Fuller’s Earth, or
montmorillonite clays surprisingly failed to significantly
improve its quality (≤45% purity by mass). Furthermore,
recrystallisation from various solvent systems proved only
moderately effective, leading to very poor recovery and only
partially purified intermediate 6 (≤80% purity). Eventually
analytically pure material was realized through repeated
catalyzing the hydrolysis of nitriles (Strecker adducts) via an in
situ generated aminol intermediate (Figure 3). Edward built
upon this concept using the presence of an α-amido moiety to
facilitate an intramolecular attack upon the adjacent nitrile,
forming the more reactive cyclic intermediate 11 which in turn
was rapidly hydrolysed to the corresponding α-aminoamide 12
and then more slowly to acid 9 (Figure 4).
Figure 3. Commeyras-assisted hydrolysis of α-amino nitriles.
799
dx.doi.org/10.1021/op300084z | Org. Process Res. Dev. 2012, 16, 798−810

Organic Process Research & Development
Article
residence time or altering the relative stoichiometries of the
reagents failed to appreciably change the resulting yield.
Eventually we discovered the cryogenic conditions were
actually detrimental to the reaction progress in flow. When
the reaction was instead carried out at a higher temperature of
40 °C using a 14 mL reactor coil on a Uniqsis FlowSyn system
under optimized conditions (0.5 M solution of 2-adamanta-
none (5) in THF at 0.18 mL min−1 and 0.5 M solution of
ethynylmagnesium bromide in THF at 0.2 mL min−1), we
obtained 2-ethynyl-2-adamantanol (13) in 80% isolated yield
on a 0.30 mol scale after standard aqueous extraction. We
prescribe this notable difference in stability of the intermediate
to the flow processing regime which means that the ionic
concentration of the reaction mixture remains relatively
constant throughout the short reaction window. This is
different from the corresponding batch scenario where, as the
reaction progresses, the concentration and consequently the
pH of the reaction media steadily increases, eventually favoring
the retro reaction. This is also consistent with observations
based upon corresponding batch reactions. It was noted that
proportionally higher relative conversion to the desired product
was achieved using lower stoichiometries of the Grignard. Also
higher final isolated yields were obtained when the reaction was
worked up immediately following Grignard addition.
As the potential liberation of acetylene constitutes a worrying
safety concern, we were very interested in evaluating the
stability of this key intermediate 13. We therefore conducted a
differential scanning calorimetry (DSC) study on this
compound (Figure 6). This highlighted an exothermic event
which indicated liberation of acetylene being accompanied with
a corresponding increase in system pressure at temperatures
above 160 °C. To confirm the identity of the suspected
degradation product as 2-adamantanone (5) we performed a
repeat scan on the same sample following cooling. The new
data obtained from the recycled sample convincingly matched
the profile obtained from authentic 2-adamantanone (5); in
conclusion, the high-temperature heating caused the de-
ethynylation of 2-ethynyladamantan-2-ol (13) (Figure 7).20
Due to the inherent reversibility of the prop-2-yn-1-olate
formation and knowledge that the acidic workup of this anion is
exothermic, we considered it to be beneficial to use flow
micromixing to prevent any overheating when conducting the
quenching step. A straightforward modification of the original
setup to incorporate an inline addition of a saturated solution of
NH4Cl was made by the incorporation of a second T-piece
(Figure 8). However, this initially proved problematic due to
the rapid precipitation of magnesium salts which accumulated
over time in the T-connector and eventually resulted in
blockage of the reactor. A simple solution to this problem was
to use pulsed sonication where the T-piece connector and a
short length (10 cm) of the subsequent tubing were submerged
in the water bath of a standard laboratory sonicator.21 This
completely eliminated buildup of precipitates, enabling steady-
state operation. The product could then be processed
Figure 4. Edward-assisted hydrolysis to give amino acid 9.
Following a minor modification of the Edward route we
obtained the required amino acid 1 in essentially comparable
overall yield (Scheme 2). The isolated product was also deemed
to be free from inorganic impurities as determined by
microanalysis. An additional benefit of this process was also
realized with regards to the ease of monitoring the final reaction
steps, owing to the presence of a UV chromaphore (the
benzamide group). Despite these apparent advantages, attempts
to scale up the process led to a marked decrease in the reaction
yields and an equivalent drop in the purity of the intermediates,
especially for the transformations of 7 and 9 which decreased
noticeably to 48% and 56%, respectively, on a 50 mmol scale
(73% and 89% previously).
We therefore decided to investigate a completely new
approach to 1 which would also be amenable to continuous
scale-up through the adoption of flow reactor technologies.16
Although the proposed route was based on a slightly longer
five-step sequence, we envisaged that each of the iterative steps
would be both individually high yielding and readily scaled
under flow conditions (Figure 5). The sequence would
commence with a Grignard reagent addition to 2-adamanta-
none (5) followed by conversion of propargylic alcohol 13 to
the acyl-propargylamide derivative 14 via a Ritter reaction. A
subsequent 5-enol-exo-dig cyclisation would furnish the oxazole
intermediate 15 on route to the azalactone 16 via ozonolysis.
This heterocyclic material 16 would represent a valuable
precursor in that it could be readily hydrolyzed to the desired
amino acid 1 but as its self possess inherent reactivity as a
masked carboxylic acid coupling partner.17
Synthetic Step 1: Grignard Addition. Initially it was
envisioned that this reaction would need to be performed at
subzero temperatures due to the well-precedented reversibility
of the Favorskii reaction under basic conditions.18 Indeed,
under batch conditions, if the propargyl alcohol anion was
allowed to warm to temperatures above −10 °C prior to
quenching, substantial quantities of the starting ketone were
isolated.
We therefore conducted the Grignard addition at −20 °C,
employing a cryo-flow reactor19 equipped with a 52 mL
perfluoroalkoxy polymer (PFA) reactor coil and two 1 mL PFA
precooling loops. A 0.5 M solution of 2-adamantanone (5) in
THF and a 0.5 M THF solution of ethynylmagnesium bromide
were delivered at a flow rate of 0.2 mL min−1 to the precooling
loops and then combined thereafter in the reactor coil via a T-
connector. Using this setup we were able to obtain an
approximate 50% yield when processing 10 mmol of the
substrate. Attempts to optimize the reaction by increasing the
Figure 5. Proposed synthesis to 2-aminoadamantane-2-carboxylic acid (1).
800
dx.doi.org/10.1021/op300084z | Org. Process Res. Dev. 2012, 16, 798−810

Organic Process Research & Development
Article
Figure 6. DSC spectrum of the ethynyl derivative: the first “negative” curve is an endothermic melting of the compound; the second “positive” curve
is related to its exothermic degradation.
Figure 7. DSC scanning of 2-adamantanone and degradation product of 2-ethynyladamantan-2-ol.
combining their results with our own experience gained
performing the fluoro Ritter reaction on styrenes23 we were
able to rapidly devise conditions for the adamantane substrate
13. We selected two different nitriles, namely, benzonitrile and
acetonitrile, since these would generate amides with differing
electronic natures thereby influencing the subsequent cyclisa-
tion and also the potential ease of their eventual deprotection.
The preliminary reaction setup employed two injection loops
(3 mL each), one filled with a mixture of the alcohol 13 and the
nitrile and the other containing neat concentrated sulfuric acid.
These were simultaneously switched into the main flow stream
(glacial acetic acid/acetic anhydride, 10:1 [v/v]) combining at a
T-piece before progressing into a 14 mL PFA continuous flow
coil (CFC). It was quickly determined that temperature was a
crucial parameter (principle component analysis, [PCA]); all
attempts to perform the reaction at temperatures exceeding 40
°C gave substantial byproduct formation, later identified as
arising from a Meyer−Schuster rearrangement followed by a
subsequent 1,2-hydride migration (Wagner−Meerwein rear-
rangement) (Figure 9). At an operating temperature of 30 °C
Figure 8. Flow scheme for the optimized Grignard addition with inline
quenching.
continuously (longest run 0.66 mol) giving an improved
isolated yield of 90%.
Synthetic Step 2: Ritter Reaction. Wirth and co-workers
have previously described the feasibility of conducting the
Ritter reaction in microfluidic flow devices.22 They convincingly
demonstrated that, even at mild temperatures ranging from 45
to 85 °C depending on the substrate, high conversions could be
realized in only a few minutes residence time (∼10 min). By
801
dx.doi.org/10.1021/op300084z | Org. Process Res. Dev. 2012, 16, 798−810

Organic Process Research & Development
Article
this product was only present in trace amounts allowing the
desired adduct to be isolated in yields of around 85% on a 3
mmol scale.
leading to 65% conversion although we were discouraged from
its use at scale due to cost. Interestingly, the use of sodium
hydroxide in a biphasic toluene/water mixture in the presence
of tetrabutylammonium chloride as a phase transfer catalyst
allowed isolation of the product 15 in a 50% yield.
Further profiling of the reaction by screening various bases,
concentrations, temperatures, and reaction times highlighted a
combination of potassium hydroxide in ethanol as an improved
media. Therefore, when a ∼3:1 molar ratio of KOH to starting
material 14 in EtOH (1.3 M) was microwave irradiated at 100
°C for 2 h, a high isolated yield of the desired product was
obtained (around 90%). At higher temperatures the reactions
produced larger quantities of an unidentified byproduct (Figure
11). Interestingly, the tailored conditions for the corresponding
Figure 9. Main product isolated at temperature above 40 °C.
Since the use of large volumes of concentrated sulfuric acid
gave workup issues, especially when scaling, we further
investigated the performance of the reaction using different
solvent compositions and additives. Ultimately, the best results
were obtained using a mixture of H2SO4/AcOH/Ac2O, 5:11:5
(v/v/v). Under these optimized conditions, a solution of
nitrile/AcOH/13 was introduced to the system at a flow rate of
1.0 mL min−1. A corresponding solution of H2SO4/AcOH/
Ac2O also at a flow rate of 1.0 mL min−1 was directed to meet
the first stream at a mixing-T piece prior to entering a 14 mL
PFA CFC maintained at 30 °C (Figure 10). The output stream
Figure 11. Temperature-dependent 5-enol-exo-dig cyclisation of 14a.
flow procedure allowed the use of an elevated temperature
window with a correspondingly shorter reaction time without
the accompanied byproduct formation (Table 1 and 2).
Table 1. Flow optimization of the acetamide derivative
cyclisation 15a
Figure 10. Ritter flow scheme for the synthesis of propargylamide 14.
residence time
(min)
temperature
conversion %
was collected into a continuously stirred tank reactor which was
continuously quenched and neutralized by an auxiliary feed line
delivering a solution of aqueous KOH (3 M). Periodically the
flask was exchanged and the solution extracted with DCM,
allowing isolation of the Ritter product 14 (Figure 10). The
lower yield obtained in the case of amide 14b is a consequence
of its problematic separation. Indeed, determination of the
entry
°C
(isolated yield %)
1
2
3
4
5
6
7
8
24
48
7
100
100
120
120
120
120
130
130
57 (57)
74 (74)
53 (53)
80 (78)
24
48
60
24
48
a
100 (91)
1
100 (85)
100 (60)
100 (45)
crude conversion to benzamide 14b indicated >95% by H
NMR and LC−MS. However, upon scale-up the excess
benzonitrile and its resulting hydrolysis byproduct (benzamide)
created considerable issues regarding efficient and clean
extraction of the product from the reaction media. Some
success was eventually realized by reducing the excess of
benzonitrile (to 1.7 equiv), and increasing the residence time,
thereby allowing isolation of an improved 85% of the amide
product 14b. Unfortunately, isolation still remained a
significant issue at larger scales (i.e., >25 g) with no satisfactory
alternative workup conditions being readily identified (see later
discussion for a solution).
Synthetic Step 3: 5-Enol-exo-dig Cyclisation. In order
to rapidly scope out the potential options for the formal 5-enol-
exo-dig cyclisation we evaluated a series of parallel batch
conditions. Attempts to catalyze the cyclisation of the
propargylamides 14 with various metal salts such as silver,
copper, or gold were only partially successful.24 The best results
were obtained using silver hexafluoroantimonate (DCM, rt)
a
No byproduct formation was detected.
In summary, the efficient flow cyclisation of the benzoyl
propargylamide derivative 15b occurred at 120 °C, with a
residence time of 24 min (1:16 molar ratio amide 14b to
KOH). The corresponding acetyl derivative 14a was less
reactive, requiring a prolonged residence time (48 min) to
achieve complete conversion to the desired product 15a under
the same reaction conditions (Figure 12). In both cases an
overall high yield of the cyclised products could be realized,
following a very trivial organic extraction of the reactor output.
This facile workup prompted us to consider a telescoped
process involving the above cyclisation step in conjugation with
the previous Ritter reaction. We anticipated that the basic
quenching step used in the Ritter process (Figure 10) could be
modified to promote the subsequent cyclisation step (Figure
802
dx.doi.org/10.1021/op300084z | Org. Process Res. Dev. 2012, 16, 798−810

Organic Process Research & Development
Article
KOH in EtOH/H2O (3 M, 40:1 [v/v]). Any minor quantities
of precipitate were directly removed by inline filtration (glass
wool), and the solution was collected into a storage vessel.
Following a suitable delay (dependent on the flow rate of the
two steps) the eluate was progressed using a second HPLC
pump through a heated PFA CFC coil (120 °C). As
anticipated, the solution from the reactor could then be readily
extracted to give the final product in good yield and excellent
purity. This abridged process proved particularly effective for
processing larger quantities of material, especially reducing the
workup burden.
Synthetic Step 4: Ozonolysis. The oxidative cleavage of
the exocyclic alkene was carried out via ozonolysis. Ozone is a
well-known oxidizing agent with a broad range of industrial
applications spanning chemical synthesis to waste treatment
and water purification. Although it has a minimal environ-
mental impact and low cost, it suffers prescriptive use based on
safety issues relating to the generation of unstable and highly
energetic ozonide intermediates.25 We and others have already
demonstrated the feasibility of conducting flow-based ozonol-
ysis procedures to expedite chemical processing and improve
the safety profile of operation.26 However, many of these
systems are not suited to direct scale-up or scale-out parallel
application. Consequently, we set ourselves the challenge to
develop a simple, high-performance and safe system for the
processing of larger quantities of substrate.
Table 2. Flow optimization of the benzamide derivative
cyclisation 15b
residence time
(min)
temperature
conversion %
(isolated yield %)
entry
°C
1
2
7
100
100
100
100
120
120
120
130
130
130
50 (50)
60 (60)
72 (72)
80 (80)
60 (60)
84 (84)
14
24
48
7
3
4
5
6
14
24
7
a
7
100 (92)
8
69 (50)
9
14
24
100 (65)
100 (50)
10
a
No byproduct formation was detected.
The first flow setup (Figure 14) used a Knauer K100 HPLC
pump to deliver a sprayed stream of the substrate (0.2 M
solution in DCM) into the gas flow (O2/O3, 500 mL min−1) via
an infusion T-piece (Figure 15b). The combined stream then
progressed through a reaction coil (20 mL, 2.5 mm i.d.) with a
residence time of 5 min (Figure 15a). The resulting output
stream was collected into a vented chamber with the excess
ozone being eliminated by gently flushing argon throughout the
solution. The expunged solution was then pumped through a
packed bed cartridge containing an excess of polymer-
supported thiourea,27 inducing reductive cleavage of the
ozonide.28 The output stream was periodically tested for
residual ozone (Ozone Test Kit OZ-2 - Camlabs part no. HH/
20644-00) and the presence of unreacted ozonide (via LC−MS
by Ph3P oxidation against an internal standard of 2,3-
dimethoxynaphthalene). The output solution was finally
evaporated under reduced pressure to give the desired
compound 16.
During the oxidative process we tried to identify the flow
pattern in order to help optimize the reaction conditions; the
very first portion of the reactor coil (5 cm) was characterized by
formation of small liquid droplets along the inner surface of the
tubing. This was accompanied by an instantaneous bleaching of
the solution (from light yellow to colourless) and a sharp drop
in temperature (rt→4 °C as detected by IR measurements at
the outer surface of the reactor). We concluded that the
endothermic process occurring was related to the “spraying
effect” (latent heat of evaporation) that occurred as the liquid
phase entered the fast moving gas flow (Figure 15b).29
Throughout the rest of the coil a wavy/annular flow pattern
was observed as shown in Figure 16. Having observed the
immediate colour change at the start of the reactor we were
interested in determining the composition of the reaction
mixture at this stage. Sampling the flow stream after only 18 cm
of tubing (1 mL internal volume) indicated total consumption
of the starting material which upon treatment with the thiourea
resin gave the desired product 16 in quantitative conversion.
Figure 12. Flow schemes for the 5-enol-exodig cyclisation of
compounds 14 to oxazolines 15.
12) as a single integrated flow process. In addition to
shortening the sequence and reducing the manual workup it
was anticipated that the basic conditions could facilitate easier
extraction of the final product. Previously, a major problem in
the Ritter step had been encountered due to the issue of
extracting and isolating the product from residual nitrile (excess
used in the Ritter) and the corresponding partially hydrolysed
byproduct amide (acetamide and benzamide). This was
particularly difficult when benzonitrile was used at scale.
However, under the strongly basic conditions and higher
reaction temperature of the cyclisation step complete hydrolysis
of the nitrile (and amide) to the carboxylate should occur
making extraction of 15 far easier. The flow reactor setup
adopted to run this sequence is shown in Figure 13.
Under the telescoped conditions, a solution of nitrile/
AcOH/13 and a corresponding mixture of H2SO4/AcOH/
Ac2O were introduced to a 14 mL PFA CFC maintained at 30
°C after mixing at a T-piece. The exiting flow stream was
further combined at a second T-connector with a solution of
Figure 13. Combined Ritter reaction and 5-enol-exodig cyclisation to
oxazolines 15.
803
dx.doi.org/10.1021/op300084z | Org. Process Res. Dev. 2012, 16, 798−810

Organic Process Research & Development
Article
Figure 14. Initial setup for ozonolysis in flow.
Therefore, wishing to take advantage of this “spraying”
phenomenon we envisaged the assembly of a short-path reactor
unit with a residence time of only 15 s. In addition to
facilitating rapid reaction processing and self-controlled cooling
the spray dispersion phenomenon would also assist flushing
excess ozone from the reaction stream by showering the output
feed into an argon (or nitrogen) blanketed purge vessel (Figure
17). At this stage a secondary pump could then be used to
advance the ozonide solution through the previously developed
resin-quenching process. This setup was readily achieved and
successfully used to process larger quantities of material.
Another useful feature of this setup was the very small
stoichiometric excess of ozone required, ranging from only
1.5−2 equiv. Under optimized conditions it was possible to
achieve a throughput of 6.6 g/h, equating to over 200 g of
product per day when processing in a continuous fashion.
Having access to gram quantities of the azalactone
intermediates 16a/b we evaluated their reactivity as coupling
agents via reaction with various nitrogen nucleophiles (Figure
18, Table 3).30 This proved an exceedingly viable trans-
Figure 15. (a) PTFE reactor-coil for ozonolysis in flow. (b) Schematic
of T-connector.
Figure 18. Flow reactions of azalactones 16a/b with nitrogen
nucleophiles.
formation, giving high yields of the coupled material following
only direct filtration of the reactor output to isolate the solid
product.
Synthetic Step 5: Hydrolytic Cleavage. Our initial
starting point for comparison purposes with the batch process
was the conditions developed by Edward et al. for the
hydrolytic cleavage of benzamide 9 (Scheme 2).15d By applying
these conditions, the phenyl derivative 16b was quantitatively
Figure 16. Wavy-annular flow pattern observed inside the PTFE
reactor coil in the ozonolysis reaction.
Figure 17. PTFE reactor-tube for ozonolysis in the optimized flow conditions.
804
dx.doi.org/10.1021/op300084z | Org. Process Res. Dev. 2012, 16, 798−810

Organic Process Research & Development
Article
T-piece before progressing into a 14 mL PFA CFC. Again,
temperature was found to be a principle parameter; reaction
temperatures below 130 °C gave substantial quantities of the N-
acylamino acid derivatives 18 and 9 (Figure 19). Likewise
increasing the flow rate beyond 0.80 mL min−1 per channel
(residence time 9 min) gave incomplete hydrolysis, resulting in
quantitative isolation of 18 and 9.
Table 3. Flow reactions of azalactones 16a/b with nitrogen
nucleophiles
Figure 19. N-Acylamino acid formed during low-temperature
processing.
The final optimized conditions used for scale-up involved
processing a solution of azalactone 16 in AcOH continuously
introduced to the system at a fixed flow rate (0.40 mL min−1 for
16a and 0.25 mL min−1 for 16b, equating to residence times of
18 and 28 min, respectively) to unite at a standard-T connector
with a solution of HCl/AcOH/H2O (9:1.8:1 [v/v/v] equal
flow rate). The combined solution was then directed into a 14
mL PFA CFC heated at an elevated temperature of 150 °C
(Figure 20). The exiting reaction mixture was collected and
Figure 20. Flow conditions for the hydrolytic deprotection to amino
acid 1.
concentrated in vacuo to obtain an off-white solid which was
triturated with hot Et2O. Bulk recrystallization from methanol
(0 °C, overnight), gave 2-aminoadamantane-2-carboxylic acid
(1) as the hydrochloride salt in very good yield (94% from 16a
and 87% from 16b). Under these optimized conditions a
throughput of 4.4 g of product (16a) per day (2.75 g for 16b)
could be realized using a single coil reactor unit which can be
easily run in a parallel reactor setup multiplying the output.
a
PBS = phosphate buffered saline, pH 7.4; Sigma Aldrich cat. no.
P4417-100TAB.
converted to the corresponding amino acid 1 after 80 h at reflux
in 70% isolated yield on a 10 mmol scale. A much faster
reaction was observed for the corresponding methyl derivative
16a which required only 28 h (96% isolated yield).
Furthermore, the workup for the amino acid 1 from the simple
acyl analogue, compound 16a, was far easier due to the
volatility of the displaced acetic acid as opposed to the resulting
benzoic acid generated from 16b. However, in each case the
product obtained as its hydrochloride salt was a perfect match
for the authentic material previously prepared and purified
(Schemes 1 and 2).
We therefore proceeded to transpose the general hydrolysis
procedure to flow. Our test setup employed two injection loops
(3 mL), one loaded with the azalactone 16 in acetic acid and
the other containing a mixture of AcOH/H2O/HCl, 9:1.8:1 (v/
v/v). The two channels were simultaneously switched into the
main flow stream of AcOH/HCl, 40:1 (v/v) and combined at a
CONCLUSIONS
■
In summary, we have developed a multistep sequence to the
title aminoacid 1 which utilizes flow-based reactor technology
to aid in the preparation and facilitate scale-up of the sequence.
The isolation at each stage of the process has been achieved
without recourse to column chromatography, in high yield and
giving quality material ready for telescoping into the
subsequent step. An overall yield for the route to the methyl
derivative 16a of 76% was achieved, whereas a slightly lower
final yield of 70% was attained for the phenyl derivative 16b.
The equipment used for the processing can be easily attained
from commercial suppliers or, in the case of the self-assembled
805
dx.doi.org/10.1021/op300084z | Org. Process Res. Dev. 2012, 16, 798−810

Organic Process Research & Development
Article
reactors, rapidly constructed without a high level of engineering
skill. We have found this approach to be highly amenable to
laboratory-based scale-up of this amino acid structure and has
allowed us to reproducibly generate several hundred grams of
final product.
Flow Synthesis of Amino Acid 1 (General Figure 5). 2-
Ethynyl Adamantan-2-ol (13). See Figure 8. A solution of
2-adamantanone (5) (100.0 g, 660 mmol, 0.5 M in THF, flow
rate 0.18 mL min−1, pump A) and a solution of ethynyl
magnesium bromide (0.5 M in THF, flow rate 0.20 mL min−1,
pump B) were combined at a T-piece using a Uniqsis Flowsyn
(residence time 37 min) and passed through a 14 mL PFA
CFC heated at 40 °C. After exiting the CFC the flow stream
was quenched with a saturated solution of NH4Cl solution
(flow rate 0.18 mL min−1, pump C) mixed at a second T-piece.
The T-piece was sonicated to avoid blockages due to formation
of insoluble magnesium salts. The combined biphasic output
was collected, and the two phases were separated; the water
phase was washed once with Et2O, and then the organic
solution obtained was dried over sodium sulfate. Evaporation of
the solvent and subsequent crystallization from hexane
furnished the desired product 2-ethynyl adamantan-2-ol (13)
as a white solid (105.5 g, 590 mmol, yield 90%, mp 101.7 °C);
EXPERIMENTAL SECTION
General Experimental Section. H NMR spectra were
■
1
recorded on a Bruker Avance DPX-400 spectrometer with the
residual solvent peak as the internal reference (CDCl3 = 7.26
1
ppm, d6-DMSO = 2.50 ppm). H resonances are reported to
the nearest 0.01 ppm. 13C NMR spectra were recorded on the
same spectrometers with the central resonance of the solvent
peak as the internal reference (CDCl3 = 77.16 ppm, d6-DMSO
= 39.52 ppm). All 13C resonances are reported to the nearest
0.1 ppm. DEPT 135, COSY, HMQC, and HMBC experiments
were used to aid structural determination and spectral
1
assignment. The multiplicity of H signals are indicated as: s
LC−MS: retention time 4.63 min, m/z [M + H]dehydrated
=
= singlet, d = doublet, t = triplet, m = multiplet, br = broad, or
combinations of thereof. Coupling constants (J) are quoted in
hertz (Hz) and reported to the nearest 0.1 Hz. Where
appropriate, averages of the signals from peaks displaying
multiplicity were used to calculate the value of the coupling
constant. Infrared spectra were recorded neat on a PerkinElmer
Spectrum One FT-IR spectrometer using Universal ATR
sampling accessories. Letters in parentheses refer to the relative
absorbency of the peak: w = weak, less than 40% of the most
intense peak; m = medium, ∼41−69% of the most intense
peak; s = strong, greater than 70% of the most intense peak.
Unless stated otherwise, reagents were obtained from
commercial sources and used without purification. Laboratory
reagent grade EtOAc, petroleum ether 40−60, and DCM were
obtained from Fischer Scientific and distilled before use. Unless
stated otherwise, heating was conducted using standard
laboratory apparatus. The removal of solvent under reduced
pressure was carried out on a standard rotary evaporator, a
Genevac EZ-2 Plus personal evaporator, or a Vapourtec V-10
evaporator. Melting points were performed on a Stanford
Research Systems MPA100 (OptiMelt) automated melting
point system and are uncorrected. High-resolution mass
spectrometry (HRMS) was performed using a Waters Micro-
mass LCT Premier spectrometer using time-of-flight with
positive ESI, or conducted by Mr. Paul Skelton on a Bruker
BioApex 47e FTICR spectrometer using positive ESI or EI at
70 eV to within a tolerance of 5 ppm of the theoretically
calculated value. LC−MS analysis was performed on an Agilent
HP 1100 series chromatography (Mercury Luna 3u C18 (2)
column) attached to a Waters ZQ2000 mass spectrometer with
ESCi ionization source in ESI mode. Elution was carried out at
a flow rate of 0.6 mL min−1 using a reverse-phase gradient of
acetonitrile and water containing 0.1% formic acid. Retention
time (Rt) is given in min to the nearest 0.1 min, and the m/z
value is reported to the nearest mass unit (m.u.). X-ray crystal
structures were determined by Dr. John Davies at the
Department of Chemistry, University of Cambridge. CIF
numbers are reported as part of compound characterization.
Elemental analyses within a tolerance of 0.3% of the
theoretical values were determined by Mr. Alan Dickerson
and Mrs. Patricia Irele in the microanalytical laboratories at the
Department of Chemistry, University of Cambridge.
159.00. FT-IR (neat, cm−1) v: 3366 (m), 3181 (m), 2898 (m),
1
2159 (w), 754 (m); H NMR (400 MHz, CDCl3): δ/ppm =
2.53 (s, 1H), 2.18−2.13 (m, 4H), 1.96−1.96 (m, 3H), 1.82−
1.77 (m, 4H), 1.70 (br s, 2H), 1.55−1.58 (m, 3H). 13C NMR
(100 MHz, CDCl3): δ/ppm = 88.51 (C), 72.70 (Csp−H), 72.50
(C), 39.31 (CH), 37.60 (CH2), 35.37 (CH2), 31.54 (CH2),
26.40 (CH), 26.23 (CH). HRMS: calculated for [C12H17O]+
177.2550, found 177.2558.
2-Ethynyl-2-acetamido Adamantane (14a). See Figure
8. Expt A (small scale). A solution of 2-ethynyl adamantan-2-ol
(13) (0.3 g, 1.7 mmol), MeCN (1.6 mL), and AcOH (2 mL),
loaded in a 3 mL injection loop (A), and neat conc. sulfuric acid
(3 mL), loaded in a 3 mL injection loop (B), were
simultaneously switched into the main flow stream of glacial
acetic acid/acetic anhydride, 10:1 (v/v) (flow rate of 1.00 mL
min−1 per channel) combining at a T-piece before progressing
into a 14 mL PFA CFC heated at 30 °C (residence time 7
min). After exiting the CFC this flow stream was quenched
with a third stream containing KOH solution (3 M, pump C at
a flow rate 3 mL min−1), and the salts formed were filtered and
washed with DCM. After separation of the two phases the
organic layer was dried over sodium sulfate and concentrated to
obtain a crude material that after trituration with hexane gave
the title compound (14a) as a white solid (0.3 g, 1.4 mmol,
yield 86%);
Expt B (scale-up). A solution of 2-ethynyl adamantan-2-ol
(13) (20.0 g, 113.6 mmol, pump A), MeCN (80 mL), and
AcOH (88 mL) and a mixture of conc. sulfuric acid (40 mL,
pump B), acetic acid (88 mL), and acetic anhydride (40 mL)
were pumped using a Uniqsis Flowsyn at a flow rate of 1.00 mL
min−1 per channel (residence time 7 min) through a 14 mL
PFA CFC heated at 30 °C. After exiting the CFC this flow
stream was quenched with a third stream containing KOH
solution (3 M, pump C at a flow rate 3 mL min−1), and the
salts formed were filtered and washed with DCM. After
separation of the two phases the organic layer was dried over
sodium sulfate and concentrated to obtain a crude material that
after trituration with hexane gave the title compound (14a) as a
white solid (21.8 g, 99.0 mmol, yield 91%, mp 147 °C); LC−
MS: retention time 4.39 min, m/z [M + H] = 218.14. FT-IR
(neat, cm−1) v: 3287 (m), 2903 (m), 2166 (w), 1645 (s), 1537
(s), 670 (m); 1H NMR (400 MHz, CDCl3): δ/ppm = 5.41 (br
s, 1H), 2.46 (s, 1H), 2.40 (br s, 2H), 2.35 (br s, 1H), 2.31 (br s,
1H), 2.01 (s, 3H), 1.82−1.77 (m, 4H), 1.70 (br s, 2H), 1.55−
Additional experimental procedures and full compound
characterizations are contained within the Supporting In-
formation.
806
dx.doi.org/10.1021/op300084z | Org. Process Res. Dev. 2012, 16, 798−810

Organic Process Research & Development
Article
1.58 (m, 3H). 13C NMR (400 MHz, CDCl3): δ/ppm = 169.12
(C), 86.18 (C), 71.73 (Csp−H), 56.47 (C), 37.64 (CH2), 35.06
(CH), 34.37 (CH2), 32.18 (CH2), 27.24 (CH), 26.76 (CH),
24.23 (CH3). HRMS: calculated for [C14H20NO]+ 218.1545,
found 218.1548.
2-Methyl-4-(adamantane-2′-spiro)-5-methylidene Ox-
azoline (15a). See Figure 12. A solution of 2-ethynyl 2-
acetylamino adamantane (14a) (9.0 g, 41.3 mmol, flow rate
0.20 mL min−1, pump A) in EtOH (400 mL) and a solution of
potassium hydroxide (13.0 g, flow rate 0.10 mL min−1, pump
B) in EtOH (200 mL) were pumped using a Uniqsis Flowsyn
(residence time 47 min) through a 14 mL PFA CFC heated at
125 °C using a 100 psi BPR. After exiting the CFC this flow
stream was collected and the solution concentrated in vacuo.
The solid obtained was quenched with distilled water (ice bath
to avoid any retroreaction) and extracted with DCM. After
drying over sodium sulfate, the solvent was evaporated and the
title compound (15a) isolated as a yellowish solid (8.2 g, 37.6
mmol, yield 91%, mp 61.5 °C).
Telescoped Procedure for the Synthesis of Oxazolines
(15a). See Figure 13. A solution of 2-ethynyl adamantan-2-ol
(13) (2.0 g, 11 mmol, pump A), MeCN (8.0 mL), and AcOH
(9 mL) and a mixture of conc sulfuric acid (4.0 mL, pump B),
acetic acid (9 mL), and acetic anhydride (4.0 mL) was pumped
using a Uniqsis Flowsyn at a flow rate of 1.00 mL min−1 per
channel (residence time 7 min) through a 14 mL PFA CFC
heated at 30 °C. After exiting the CFC the flow stream was
directed to a T-piece to meet a further solution of KOH (3 M)
in EtOH/H2O, 40:1 (v/v) (pump C, flow rate 3.0 mL min−1)
and then filtered in-line (column packed with glass wool) to
remove any precipitate (eluent collected in a filter flask). The
resultant solution was pumped into a PFA CFC and heated to
120 °C (residence time 48 min, flow rate 0.30 mL min−1). After
exiting the CFC the flow stream was collected and the solution
concentrated in vacuo. The solid obtained was quenched with
distilled water (ice bath to avoid any retroreaction), extracted
with DCM, and dried over sodium sulfate, and the solvent was
evaporated. The title compound (15a) was obtained as a
yellowish solid (2.2 g, 10 mmol, yield 91%). LC−MS: retention
time 3.70 min, m/z [M + H]protonated = 219.05; time 4.49 min,
m/z [M + H] = 218.07. FT-IR (neat, cm−1) v: 2906 (s), 1686
(s), 1654 (s), 1262 (s), 1199 (s), 1063 (s), 965 (s), 834 (s). 1H
NMR (400 MHz, CDCl3): δ/ppm = 4.79 (d, 1H, J = 2.4 Hz),
4.52 (d, 1H, J = 2.4 Hz), 2.44 (d, 2H, J = 12.4 Hz), 2.21 (d, 2H,
J = 12.4 Hz), 2.03 (s, 3H), 1.86 (br s, 3H), 1.74 (s, 2H), 1.69−
1.55 (m, 5H). 13C NMR (100 MHz, CDCl3): δ/ppm = 166.00
(C), 158.66 (C), 87.91 (CH2), 76.02, 38.70 (CH2), 37.08
(CH), 34.06 (CH2), 31.40 (CH2), 28.03 (CH), 26.76 (CH),
14.43 (CH3). HRMS: calculated for [C14H20NO]+ 218.1545,
found 218.1541. The structure was unambiguously confirmed
by single X-ray crystallography and deposited at Cambridge
University (Crystallographic Data Centre) with the unique
reference CCDC860429; space group P21/c; a = 6.6834 (2) Å,
b = 7.0945 (2) Å, c = 23.8587 (8) Å, β = 90.449 (2)°.
2-Ethynyl-2-benzamido Adamantane (14b). See Fig-
ure 10. EXPT A (small scale). A solution of 2-ethynyl
adamantan-2-ol (13) (0.3 g, 1.7 mmol), benzonitrile (0.8 mL,
7.8 mmol, 4.6 equiv) and AcOH (2.1 mL), loaded in a 3 mL
injection loop (A), and neat conc. sulfuric acid (3 mL), loaded
in a 3 mL injection loop (B), were simultaneously switched into
the main flow stream of glacial acetic acid/acetic anhydride,
10:1 (v/v) (flow rate of 1.00 mL min−1 per channel) combining
at a T-piece before progressing into a 14 mL PFA-CFC heated
at 30 °C (residence time 7 min). After exiting the CFC this
flow stream was quenched with a third stream containing KOH
solution (3 M, pump C at a flow rate 3 mL min−1), and the
salts formed were filtered and washed with DCM. After
separation of the two phases the organic layer was dried over
sodium sulfate and concentrated to obtain a crude material that
after trituration with hexane gave the title compound (14b) as a
white solid (0.38 g, 1.3 mmol, yield 77%);
EXPT B (scale-up). A solution of 2-ethynyl adamantan-2-ol
(13) (50.0 g, 280 mmol, pump A), benzonitrile (98 mL, 0.95
mol, 3.4 equiv) and acetic acid (196 mL) and a mixture of
concentrated sulfuric acid (98 mL, pump B), acetic acid (215
mL) and acetic anhydride (98 mL) were pumped using a
Uniqsis FlowSyn at a flow rate of 1.00 mL min−1 per channel
(residence time 7 min) through a 14 mL PFA CFC maintained
at 30 °C. After exiting the CFC this flow stream was quenched
with 3 M aqueous KOH solution (pump C, flow rate 3 mL
min−1) and the salts formed were filtered off and washed with
DCM. After separation of the phases the organic phase is dried
over sodium sulfate and concentrated to obtain a crude, oily
material that after trituration with hexane gave the title
compound (14b) as white solid (50.1 g, 174 mmol, yield 64%).
EXPT C (scale-up modified conditions). A solution of 2-
ethynyl adamantan-2-ol (13) (50.0 g, 0.28 mol, pump A),
benzonitrile (49 mL, 0.475 mol, 1.7 equiv) and acetic acid (196
mL) and a mixture of concentrated sulfuric acid (98 mL, pump
B), acetic acid (215 mL) and acetic anhydride (98 mL) were
pumped using a Uniqsis FlowSyn at a flow rate of 0.60 mL
min−1 per channel (residence time 11.6 min) through a 14 mL
PFA CFC maintained at 30 °C. After exiting the CFC this flow
stream was quenched with 3 M aqueous KOH solution (pump
C, flow rate 1.8 mL min−1) and the salts formed were filtered
off washing with DCM. After separation of the phases the
organic one is dried over sodium sulfate and concentrated to
obtain a crude oily material that after trituration with hexane
gave the title compound (14b) as white needles (66.5 g, 231
mmol, yield 85%, mp 189 °C); LC−MS: retention time 4.98
min, m/z [M + H] = 280.15. FT-IR (neat, cm−1) v: 3400 (m),
2-Phenyl-4-(adamantane-2′-spiro)-5-methylidene Ox-
azoline (15b). See Figure 12. A solution of 2-ethynyl 2-
benzamido adamantane (14b) (17.5 g, 63 mmol, flow rate 0.40
mL min−1, pump A) in EtOH (800 mL) and a solution of
potassium hydroxide (20.0 g, flow rate 0.20 mL min−1, pump
B) in EtOH (400 mL) were pumped using a Uniqsis Flowsyn
(residence time 24 min) through a 14 mL PFA CFC heated at
120 °C using a 100 psi BPR. After exiting the CFC this flow
stream was collected and the solution concentrated in vacuo.
The solid obtained was quenched with distilled water (ice bath
to avoid any retroreaction) and extracted with DCM. After
drying over sodium sulfate and evaporating the solvent, the title
compound (15b) was obtained as a yellowish solid (16.2 g, 53
mmol, yield 92%, mp 67 °C).
1
3281 (m), 2905 (m), 1645 (s), 1537 (s), 690 (s); H NMR
(400 MHz, CDCl3): δ/ppm = 7.96 (d, 2H, J = 6.8 Hz), 7.49
(m, 1H), 7.40 (m, 2H), 6.14 (br s, 1H), 2.56 (s, 2H), 2.49 (s,
1H), 2.40 (d, 2H, J = 11.2 Hz), 2.00 (d, 2H, J = 11.2 Hz),
1.89−1.70 (m, 9H). 13C NMR (100 MHz, CDCl3): δ/ppm =
166.26 (C), 135.27 (C), 131.47 (CH), 128.60 (CH), 126.94
(CH), 86.04 (C), 71.99 (Csp−H), 56.63 (C), 37.66 (CH2),
35.28 (CH), 34.06 (CH2), 32.01 (CH2), 26.92 (CH), 26.48
(CH). HRMS: calculated for [C19H22NO]+ 280.1701, found
280.1691.
807
dx.doi.org/10.1021/op300084z | Org. Process Res. Dev. 2012, 16, 798−810

Organic Process Research & Development
Article
Telescoped Procedure for the Synthesis of Oxazolines
(15b). See Figure 13. A solution of 2-ethynyl adamantan-2-ol
(13) (5.0 g, 28 mmol, pump A), benzonitrile (4.9 mL, 47.5
mmol, 1.7 equiv), and acetic acid (20 mL) and a mixture of
concentrated sulfuric acid (9.8 mL, pump B), acetic acid (21.5
mL), and acetic anhydride (9.8 mL) was pumped using a
Uniqsis FlowSyn at a flow rate of 0.60 mL min−1 per channel
(residence time 11.6 min) through a 14 mL PFA CFC
maintained at 30 °C. After exiting the CFC the flow stream was
directed to a T-piece to meet a further solution of KOH (3 M)
in EtOH/H2O, 40:1 (v/v) (pump C, flow rate 1.8 mL min−1)
then filtered in-line (column packed with glass wool) to remove
any precipitate (eluent collected in a filter flask). The resultant
solution was pumped into a PFA CFC and heated to 120 °C
(residence time 24 min, flow rate 0.60 mL min−1). After exiting
the CFC the flow stream was collected and the solution
concentrated in vacuo. The solid obtained was quenched with
distilled water (ice bath to avoid any retroreaction), extracted
with DCM, and dried over sodium sulfate, and the solvent was
evaporated. The title compound (15b) was obtained as a
yellowish solid (7.0 g, 25 mmol, yield 90%). LC−MS: retention
time 6.05 min, m/z [M + H] = 280.08. FT-IR (neat, cm−1) v:
P21/m: a = 6.8926 (4) Å, b = 6.5463 (4) Å, c = 12.267 (2) Å, β
= 98.997 (2)°.
2-Phenyl-4-(adamantane-2′-spiro)-oxazolin-5-one
(16b). See Figure 17. A solution of 2-phenyl-4-(adamantane-
2′-spiro)-5-methylidene oxazoline (15b) (10.0 g, 35.8 mmol,
flow rate 4.00 mL min−1, pump A) in DCM (350 mL) and a
stream of ozone (0.5 bar, flow rate 500 mL min−1) were
combined in a T-piece and directly through a 1 mL PTFE tube
reactor (180 mm, 2.5 mm i.d., ∼15 s residence time). After
exiting the tube this flow stream was collected and the excess of
ozone was blown out with argon. The solution was then
directly delivered to a scavenger cartridge containing QP-TU
(3.00 mL min −1, pump B). The collection of the output stream
and the concentration of the solution gave the title compound
(16b) as a white solid (10.09 g, 35.7 mmol, yield 99.8%, mp
109 °C); LC−MS: retention time 5.64 min, m/z [M +
H]decarboxylated = 254.12, m/z [M − H]acid = 298.05. FT-IR (neat,
cm−1) v: 2893 (s), 1796 (s), 1657 (s), 1453 (m), 1292 (s),
1
1046 (s), 961 (s), 678 (s). H NMR (400 MHz, CDCl3): δ/
ppm = 8.03 (d, 2H, J = 6.8 Hz), 7.55−7.51 (m, 1H), 7.49−745
(m, 2H), 2.59 (d, 2H, J = 14 Hz), 2.54 (d, 2H, J = 14 Hz), 1.99
(s, 2H), 1.87 (s, 2H), 1.82 (2, 2H), 1.70 (m, 4H). 13C NMR
(100 MHz, CDCl3): δ/ppm = 179.04 (C), 157.96 (C), 132.25
(CH), 128.68 (CH), 127.87 (CH), 126.64 (C), 72.79 (C),
37.81 (CH2), 35.51 (CH), 33.67 (CH2), 31.20 (CH2), 27.67
(CH), 26.39 (CH). HRMS: calculated for [C18H20NO2]+
282.1494, found 218.1484. The structure was unambiguously
confirmed by single X-ray crystallography and deposited at
Cambridge University (Crystallographic Data Centre) with the
unique reference CCDC860431; space group P21/m: a =
12.6229 (9) Å, b = 6.9172 (5) Å, c = 17.039 (2) Å, β = 109.380
(3)°.
1
2899 (s), 1666 (s), 1644 (s), 1056 (s). H NMR (400 MHz,
CDCl3): δ/ppm = 8.01 (d, 2H, J = 6.8 Hz), 7.49−7.40 (m, 3
H), 4.99 (d, 1H, J = 2.4 Hz), 4.65 (d, 1H, J = 2.4 Hz), 2.63 (d,
2H, J = 11.2 Hz), 2.29 (d, 2H, J = 11.2 Hz), 1.95 (m, 2H), 1.74
(s, 2H), 1.69−1.55 (m, 6H). 13C NMR (100 MHz, CDCl3): δ/
ppm = 166.04 (C), 157.63 (C), 131.98 (CH), 128.81 (CH),
128.12 (CH), 126.97, 88.45 (CH2), 77.14, 38.73 (CH2), 37.68
(CH), 34.14 (CH2), 31.51 (CH2), 27.96 (CH), 26.54 (CH).
HRMS: calculated for [C19H22NO]+ 280.1701, found 218.1704.
The structure was unambiguously confirmed by single X-ray
crystallography and deposited at Cambridge University
(Crystallographic Data Centre) with the unique reference
CCDC860430; space group Pbca: a = 20.3254 (3) Å, b =
12.2093 (1) Å, c = 23.7513 (3) Å.
2-Aminoadamantane-2-carboxylic Acid Hydrochlor-
ide (1). See Figure 20. Expt A. A solution of 2-methyl-4-
(adamantane-2′-spiro)-oxazolin-5-one (16a) (1.15 g, 5.25
mmol, flow rate 0.40 mL min−1, pump A) in glacial acetic
acid (150 mL) and a mixture of glacial acetic acid (90 mL),
H2O (50 mL), and hydrochloric acid (10 mL, flow rate 0.40 mL
min−1, pump B) were combined in a T-piece and reacted
through a 14 mL PFA reactor coil at 150 °C (residence time
∼18 min). After exiting the tube this flow stream was collected,
and the mixture was concentrated in vacuo. The solid obtained
was washed with hot diethyl ether (50 mL × 2) and hot
acetonitrile (50 mL × 2) to obtain the product that was
crystallised from methanol (1.10 g, 4.8 mmol, yield 94%).
Expt B. A solution of 2-phenyl-4-(adamantane-2′-spiro)-
oxazolin-5-one (16b) (1.50 g, 5.25 mmol, flow rate 0.25 mL
min−1, pump A) in glacial acetic acid (150 mL) and a mixture
of glacial acetic acid (90 mL), H2O (50 mL), and hydrochloric
acid (10 mL) (flow rate 0.25 mL min−1, pump B) were
combined in a T-piece and reacted through a 14 mL PFA
reactor coil at 150 °C (residence time ∼28 min). After exiting
the tube this flow stream was collected, and the mixture was
concentrated in vacuo. The solid obtained was washed with hot
diethyl ether (50 mL × 2) and hot acetonitrile (50 mL × 2) to
obtain the product that was crystallised from methanol (1.05 g,
4.55 mmol, yield 87%, mp >258 °C decomposition); LC−MS:
retention time 0.31 min, m/z [M + H]decarboxylated = 149.99, m/z
[M + H]deaminated = 179.05, m/z [M + H] = 196.10, m/z [M −
H] = 194.06. FT-IR (neat, cm−1) v: 3220 (w), 3168 (w), 2775
2-Methyl-4-(adamantane-2′-spiro)-oxazolin-5-one
(16a). See Figure 17. A solution of 2-methyl-4-(adamantane-
2′-spiro)-5-methylidene oxazoline (15a) (9.0 g, 41.3 mmol,
flow rate 4.00 mL min−1, pump A) in DCM (400 mL), and a
stream of ozone (0.5 bar, flow rate 500 mL min−1) were
combined in a T-piece and directly through a 1 mL PTFE tube
reactor (180 mm, 2.5 mm i.d., ∼15 s residence time). After
exiting the tube this flow stream was collected, and the excess of
ozone was blown out with argon. The solution was then
directly delivered to a scavenger cartridge containing QP-TU
(3.00 mL min −1, pump B). The collection of the output stream
and the concentration of the solution gave the title compound
(16a) as a white solid (8.7 g, 39.4 mmol, yield 95%, mp 138
°C); LC−MS: retention time 4.32 min, m/z [M + H]decarboxylated
= 192.09, m/z [M − H]acid = 236.07. FT-IR (neat, cm−1) v:
2907 (s), 1789 (m), 1693 (s), 1448 (m), 1232 (s), 1174 (s),
1
1046 (s), 971 (s), 900 (s). H NMR (400 MHz, CDCl3): δ/
ppm = 2.51 (d, 2H, J = 12 Hz), 2.35 (d, 2H, J = 11.2 Hz), 2.19
(s, 3H), 1.94 (s, 2H), 1.71−1.60 (m, 8H). 13C NMR (100
MHz, CDCl3): δ/ppm = 179.12 (C), 159.27 (C), 72.28 (C),
37.79 (CH2), 35.04 (CH), 33.61 (CH2), 31.09 (CH2), 27.48
(CH), 26.31 (CH), 15.33 (CH3). HRMS: calculated for
[C13H18NO2]+ 220.1339, found 220.1347. The structure was
unambiguously confirmed by single X-ray crystallography and
deposited at Cambridge University (Crystallographic Data
Centre) with the unique reference CCDC860432; space group
1
(s), 1725 (s), 1587 (s), 1506 (s), 1468 (s); H NMR (400
MHz, CDCl3): δ/ppm = 8.70 (s br, 3H), 2.21 (s, 2H), 2.12 (d,
2H, J = 13.2 Hz), 1.92 (d, 2H, J = 13.2 Hz), 1.75−1.80 (m,
808
dx.doi.org/10.1021/op300084z | Org. Process Res. Dev. 2012, 16, 798−810

Organic Process Research & Development
Article
4H), 1.62−1.66 (m, 2H). 13C NMR (100 MHz, CDCl3): δ/
ppm = 171.59 (C), 63.92 (C), 37.54 (CH2), 34.40 (CH), 32.24
(CH2), 31.22 (CH), 26.28 (CH). HRMS: calculated for
[C11H18NO2]+ 196.1338, found 196.1336. Microanalysis
calculated (found) for C11H18NO2Cl: C 57.02 (56.90%), H
7.83 (7.97%), N 6.04 (6.06%). The structure was unambigu-
ously confirmed by X-ray crystallography and deposited at
Cambridge University (Crystallographic Data Centre) with the
unique reference CCDC860428; space group P21/c: a =
6.3862 (2) Å, b = 11.4838 (3) Å, c = 14.9079 (4) Å, β = 95.392
(2)°.
Characterisation of Partial Hydrolysis Products from 16a
and 16b. 2-Acetylamido Adamantane-2-carboxylic Acid
(18). Off-white solid; mp 210−213 °C; LC−MS: retention
time 4.06 min, m/z [M − H] = 236.10. FT-IR (neat, cm−1) v:
3386 (m), 2907 (s), 1745 (s), 1632 (m), 1594 (s), 1248 (s),
1208 (s), 849 (m), 721 (m); 1H NMR (400 MHz, CDCl3): δ/
ppm = 12.01 (br s, 1H), 7.62 (s, 1H), 2.39 (s, 2H), 2.01 (brs,
4H), 1.82 (s, 3H), 1.73 (s, 2H), 1.62 (br s, 4H), 1.49 (m, 2H).
13C NMR (100 MHz, CDCl3): δ/ppm = 174.18 (C), 169.44
(C),63.10 (C), 38.02 (CH2), 35.80 (CH), 32.50 (CH2), 32.01
(CH2), 26.99 (CH), 26.71 (CH), 23.40 (CH3). HRMS:
calculated for [C13H20NO3]+ 238.1718, found 238.1710. The
structure was unambiguously confirmed by X-ray crystallog-
raphy and deposited at Cambridge University (Crystallographic
Data Centre) with the unique reference CCDC 874390; space
structure determination and the EPSRC for a financial
contribution toward the purchase of the X-ray diffractometer.
REFERENCES
■
(1) (a) Maison, W.; Frangioni, J. V.; Pannier, N. Org. Lett. 2004, 24,
4567−4569. (b) Papanastasiou, I.; Foscolos, G. B.; Tsotinis, A.; Olah,
J.; Ovadi, J.; Prathalingam, S. R.; Kelly, J. M. Heterocycles 2008, 75,
2043−2061. (c) Lamoureux, G.; Artavia, G. Curr. Med. Chem. 2010,
17, 2967−2978.
(2) Liu, J.; Obando, D.; Liao, V.; Lifa, T.; Codd, R. Eur. J. Med. Chem.
2011, 46, 1949−1963.
(3) (a) Nagasawa, H. T.; Elberling, J. A.; Shirota, F. N. J. Pharm. Sci.
1980, 69, 1022−1025. (b) Kovtun, V. Y.; Plakhotnik, V. M. Pharm.
Chem. J 1987, 21, 555−563. (c) Knijnenburg, A. D.; Kapoerchan, V.
V.; Spalburg, E.; de Neeling, A. J.; Mars-Groenendijk, R, H.; Noort, D.;
van der Marel, G. A.; Overkleeft, H. S.; Overhand, M. Bioorg. Med.
Chem. 2010, 18, 8403−8409.
(4) (a) Hong, F.; Zaidi, J.; Cusack, B.; Richelson, E. Bioorg. Med.
̌
Chem. 2002, 10, 3849−3858. (b) Horvat, S.; MLinaric-
Glavas-Obrovac, L.; Jakas, A.; Veljkovic, J.; Marczi, S.; Kragol, G.;
Rosc c, M.; Matkovic, M.; Milostic-Srb, A. J. Med. Chem. 2006, 49,
3136−3142.
́
Majerski, K.;
̌
́
̌
i
̌
́
́
́
(5) Christensen, H. N.; Handlogten, M. E.; Lam, I.; Tager, H. S.;
Zand, R. J. Biol. Chem. 1969, 244, 1510−1520.
(6) (a) Myers, R. M.; Shearman, J. W.; Kitching, M. O.; Ramos-
Montoya, A.; Neal, D. E.; Ley, S. V. ACS Chem. Biol. 2009, 4, 503−
525.
(7) Maffrand, J.-P.; Gully, D.; Boigegrain, R.; Jeanjean, F. Actual.
Chim. Ther. 1994, 21, 171−179. The structure of SR 45398 reported
́
group P1: a = 6.8572 (2) Å, b = 8.1043 (3) Å, c = 10.8425 (5)
̅
by Sanofi in 1994 and 1995 was drawn with the appended N-linked
phenyl group; in 1996 it was shown with the naphthyl group as shown
in Figure 2. As there are no experimental details available, the true
structure of this molecule cannot be definitively established.
(8) Boigegrain, R.; Gully, D.; Jeanjean, F.; Molimard, J. C. Eur. Pat.
0477049A1 1991 and Eur. Pat. 0477049B1, 1991.
Å; α = 90.434(2)°, β = 102.620(2)°, γ = 98.459(3)°.
2-Benzamido Adamantane-2-carboxylic Acid (9). Off-
white solid; mp 234−236 °C; LC−MS: retention time 4.28
min, m/z [M + H]+ = 322.14. FT-IR (neat, cm−1) v: 3389.7
(w), 2905.7 (m), 1740.0 (s), 1626.8 (m), 1526.3 (s); 1H NMR
(400 MHz, d6-DMSO): δ/ppm = 12.17 (br s, 1H), 8.10 (s,
1H), 7.79 (d, 2H, J = 7.2 Hz), 7.52 (t, 1H, J = 7.2 Hz), 7.44 (t,
2H, J = 7.2 Hz), 2.63 (s, 2H), 2.12 (m, 4H), 1.80 (s, 2H),
1.65−1.69 (m, 4H), 1.56 (d, 2H, J = 12.7 Hz); 13C NMR (100
MHz, d6-DMSO): δ/ppm = 173.8, 166.4, 135.1, 131.1 (CH),
128.1 (CH), 127.7 (CH), 63.1, 37.5 (CH), 33.5 (CH2), 32.8
(CH2), 31.5 (CH2), 26.5 (CH), 26.4 (CH); HRMS: calculated
for [C18H21NO3Na]+ 322.1419, found 322.1421. The structure
was unambiguously confirmed by X-ray crystallography and
deposited at Cambridge University (Crystallographic Data
Centre) with the unique reference CCDC 860427; space group
P21/n: a = 14.1635 (4) Å, b = 6.7026 (2) Å, c = 15.8379 (6) Å,
β = 99.395 (1)°.
(9) (a) Gully, D.; Labeeuw, B.; Boigegrain, R.; Oury-Donat, F.;
Bachy, A.; Poncelet, M.; Steinberg, R.; Suaud-Chagny, M. F.; Santucci,
́ ́ ́
V.; Vita, N.; Peccu, F.; Labbe-Jullie, C.; Kitagbi, P.; Soubrie, P.; Le Fur,
G.; Maffrand, J.-P. J. Pharmacol. Exp. Ther. 1996, 280, 802−812.
(b) Betancur, C.; Canton, M.; Burgos, A.; Labeeuw, B.; Gully, D.;
Rosten
(10) (a) Labbe-
́
e, W.; Pelaprat, D. Eur. J. Pharmacol. 1998, 343, 67−77.
́
Jullie, C.; Barroso, S.; Nicolas-Eteve, D.; Reversat, J.
́
́
L.; Botto, J. M.; Mazella, J.; Bernassau, J. M.; Kitabgi, P. J. Biol. Chem.
1998, 273, 16351−16357. (b) Kitabgi, P. Peptides 2006, 27, 2461−
2468.
(11) (a) Nagasawa, H. T.; Elberling, J. A.; Shirota, F. N. J. Med. Chem.
1973, 16, 823−826. (b) Nagasawa, H. T.; Elberling, J. A.; Shirota, F.
N. J. Med. Chem. 1975, 18, 826−830.
(12) (a) Baxendale, I. R.; Hayward, J. J.; Ley, S. V. Comb. Chem. High
Throughput Screening 2007, 10, 802−836. (b) Glasnov, T. N.; Kappe,
C. O. Macromol. Rapid Commun. 2007, 28, 395−410. (c) Glasnov, T.
N.; Kappe, C. O. Chem.Eur. J. 2011, 17, 11956−11968.
(13) (a) Arvela, R. K.; Leadbeater, N. E.; Collins, M. J., Jr.
Tetrahedron 2005, 61, 9349−9355. (b) Pitts, M. R.; Baxendale, I. R.
Chim Oggi 2006, 24, 41−45. (c) Moseley, J. D.; Woodman, E. K. Org.
Process Res. Dev. 2008, 12, 967−981.
ASSOCIATED CONTENT
■
S
* Supporting Information
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Alternative commercial supplies of the 2-adamantanone, sodium
cyanide, ammonium carbonate, and sodium hydroxide were obtained
and tested, but no detectable difference in the composition of the
product was obtained.
AUTHOR INFORMATION
■
Corresponding Author
*theitc@ch.cam.ac.uk
(15) (a) Pascal, R.; Tallades, J.; Commeyras, A. Bull. Soc. Chim. Fr.
1978, II, 177−184. (b) Pascal, R.; Tallades, J.; Commeyras, A.
Tetrahedron 1978, 34, 2275−2281. (c) Pascal, R.; Tallades, J.;
Commeyras, A. Tetrahedron 1980, 36, 2999−3008. (d) Paventi, M.;
Chubb, F. R.; Edward, J. T. Can. J. Chem. 1987, 65, 2114−2117.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
́
(16) For some recent examples see: (a) Munoz, M.; Alcazar, J.; de la
̃
We thank the Royal Society (I.R.B.), “Sapienza” University of
Rome (C.B.) and the BP endowment (S.V.L.) for financial
support. We also wish to thank Dr. J. E. Davies for crystal
Hoz, A.; Díaz-Ortiz, A. Eur. J. Org. Chem. 2012, 260−263. (b) Seyler,
H.; Jones, D. J.; Holmes, A. B.; Wong, W. H. H. Chem. Commun. 2012,
48, 1598−1600. (c) Ahmed-Omer, B.; Barrow, D. A.; Wirth, T.
809
dx.doi.org/10.1021/op300084z | Org. Process Res. Dev. 2012, 16, 798−810

Organic Process Research & Development
Article
ARKIVOC 2011, iv, 26−36. (d) Rasheed, M.; Wirth, T. Angew. Chem.,
Int. Ed. 2011, 50, 357−358. (e) Martin, L. J.; Marzinzik, A. L.; Ley, S.
V.; Baxendale, I. R. Org. Lett. 2011, 13, 320−323. (f) Rasheed, M.;
Elmore, S. C.; Wirth, T. In Catalytic Methods in Asymmetric Synthesis;
Gruttadauria, M., Giacalone, F., Eds.; John Wiley & Sons: New York,
2011, 345−371. (g) Ahmed-Omer, B.; Sanderson, A. J. Org. Biomol.
Chem. 2011, 9, 3854−3862. (h) Smith, C. J.; Smith, C. D.; Nikbin, N.;
Ley, S. V.; Baxendale, I. R. Org. Biomol. Chem. 2011, 9, 1927−1937.
(i) Batoul, A.-O.; Sanderson, A. J. Org. Biomol. Chem. 2011, 9, 3854−
3862. (j) Polyzos, A.; Baxendale, I. R.; Petersen, T.; Ley, S. V. Angew.
Chem., Int. Ed. 2011, 50, 1190−1193. (k) Riva, E.; Rencurosi, A.;
Gagliardi, S.; Passarella, D.; Martinelli, M. Chem.Eur. J. 2011, 17,
6221−6226. (l) Lange, P. P.; Gooßen, L. J.; Podmore, P.; Underwood,
T.; Sciammetta, N. Chem. Commun. 2011, 47, 3628−3630.
(m) Brocklehurst, C. E.; Lehmann, H.; Vecchia, L. L. Org. Process
Res. Dev. 2011, 15, 1447−1453. (n) Browne, D. L.; Deadman, B. J.;
Ashe, R.; Baxendale, I. R.; Ley, S. V. Org. Process Res. Dev 2011, 15,
693−697. (o) Mercadante, M. A.; Leadbeater, N. E. Org. Biomol.
(26) (a) Wada, Y.; Schmidt, M. A.; Jensen, K. F. Ind. Eng. Chem. Res.
2006, 45, 8036−8042. (b) Pelletier, M. J.; Fabiilli, M. L.; Moon, B.
Appl. Spectrosc. 2007, 61, 1107−1115. (c) Hubner, S.; Bentrup, U.;
̈
Budde, U.; Lovis, K.; Dietrich, T.; Freitag, A.; Kupper, L.; Jahnisch, K.
̈
̈
Org. Process Res. Dev 2009, 13, 952−960. (d) Carter, C. F.; Lange, H.;
Baxendale, I. R.; Ley, S. V.; Goode, J.; Gaunt, N.; Wittkamp, B. Org.
Process Res. Dev. 2010, 14, 393−404. (e) O’Brien, M.; Ian R.
Baxendale, I. R.; Ley, S. V. Org. Lett. 2010, 12, 1596−1598.
(f) Roydhouse, M. D.; Ghaini, A.; Constantinou, A.; Cantu-Perez,
A.; Motherwell, W. B.; Gavriilidis, A. Org. Process Res. Dev. 2011, 15,
989−996.
(27) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach,
A. G.; Longbottom, D. A.; Nessi, M.; Scott, J. S.; Storer, R. I.; Taylor,
S. J. J. Chem. Soc., Perkin Trans. 1 2000, 3815−4195.
(28) Gupta, D.; Soman, R.; Sukh, D. Tetrahedron 1982, 38, 3013−
3018.
(29) (a) Jia, W.; Qiu, H.-H. Exp. Thermal Fluid Sci. 2003, 27, 829−
838. (b) Horacek, B.; Kim, J.; Kiger, K. IEEE Trans. Device Mater.
Reliability 2004, 4, 614−625. (c) Fisenko, S. P.; Wang, W.-N.;
Lenggoro, I. W.; Okyuama, K. Chem. Eng. Sci. 2006, 61, 6029−6034.
(30) (a) Pantano, M.; Formaggio, F.; Crisma, M.; Bonora, G. M.;
Mammi, S.; Peggion, E.; Toniolo, C.; Boesten, W. H. J.; Broxterman,
Q. B.; Schoemaker, H. E.; Kamphius., J. Macromolecules 1993, 26,
1980−1984. (b) Antonova, A.; Simov., D. Khimiya Geterotsikl. Soedin.
1979, 12, 1587−1597.
́
Chem. 2011, 9, 6575−6578. (p) Bou-Hamdan, F. R.; Levesque, F.;
O’Brien, A. G.; Seeberger, P. H. Beilstein J. Org. Chem. 2011, 7, 1124−
1129. (q) Wheeler, R. C.; Baxter, E.; Campbell, I. B.; Macdonald, S. J.
F. Org. Process Res. Dev. 2011, 15, 565−569. (r) Qian, Z.; Baxendale, I.
R.; Ley, S. V. Synlett 2010, 505−508. (s) Malet-Sanz, L.; Madrzak, J.;
S.V. Ley, S. V.; Baxendale, I. R. Org. Biomol. Chem. 2010, 8, 5324−
5332. (t) Brasholz, M.; Macdonald, J. M.; Saubern, S.; Ryan, J. H.;
Holmes, A. B. Chem.Eur. J. 2010, 16, 11471−11480. (v) Wegner, J.;
Ceylan, S.; Friese, C.; Kirschning, A. Eur. J. Org. Chem. 2010, 23, 4372.
(w) Grafton, M.; Mansfield, A. C.; Fray, M. J. Tetrahedron Lett. 2010,
51, 1026−1029. (x) Tamborini, L.; Conti, P.; Pinto, A.; Micheli, C. D.
Tetrahedron: Asymmetry 2010, 21, 222−225. (y) Hopkin, M. D.;
Baxendale, I. R.; Ley, S. V. Chem. Commun. 2010, 46, 2450−2452.
(17) (a) Erlenmeyer, E. Liebigs Ann. Chem 1893, 275, 1−8.
(b) Bergmann, M.; Stern, F.; Witte, C.; Liebigs. Ann. Chem 1926,
449, 277−302. (c) Crawford, M.; Little, W. T. J. Chem. Soc. 1959,
729−731. (d) Steglich, W. Fortschr. Chem. Forsch. 1969, 12, 77−118.
(e) Cornforth, J.; Ming-hui, D. J. Chem. Soc., Perkin Trans. 1 1991,
2183−2187. (f) Combs, A. P.; Armstrong, R. W. Tetrahedron Lett.
1992, 33, 6419−6422. (g) Rasmussen, J. K.; Gleason, R. M.; Milbrath,
D. S.; Rasmussen, R. L. Ind. Eng. Chem. Res. 2005, 44, 8554−8559.
(18) Greene, T.; Wuts, P. Protection of acetylenes. In Protective
Groups in Organic Synthesis; Wiley-Interscience: New York, 1998.
(19) Browne, D. L.; Baumann, M.; Harji, B. H.; Baxendale, I. R.; Ley,
S. V. Org. Lett. 2011, 13, 3312−3315.
(20) (a) It should be noted that liberation of acetylene does not
occur upon the compound’s melting at temperatures of 101.7 °C; the
melting process is reproducible as such. (b) Due to the plastic
crystalline nature of 2-adamantanone, two main peaks were detected
when DSC scan was performed on the purchased material. Bazyleva,
A. B.; Blokhin, A. V.; Kabo, G. J.; Kabo, A. G.; Sevruk, V. M.
Thermochim. Acta 2006, 65−72.
(21) (a) Sedelmeier, J.; Ley, S. V.; Baxendale, I. R.; Baumann, M. Org.
Lett. 2010, 12, 3618−3621. (b) Battilocchio, C.; Baumann, M.;
Baxendale, I. R.; Biava, M.; Kitching, M. O.; Ley, S. V.; Martin, R. E.;
Ohnmacht, S. A.; Tappin, N. D. C. Synthesis 2012, 44, 635−647.
(22) (a) Brandt, J. C.; Elmore, S. C.; Robinson, R. I.; Wirth, T. Synlett
2010, 3099−3103. (b) Audiger, L.; Watts, K.; Elmore, S. C.; Robinson,
R. I.; Wirth, T. ChemSusChem 2011, 5, 257−260.
(23) Baumann, M.; Baxendale, I. R.; Martin, L. J.; Ley, S. V.
Tetrahedron 2009, 65, 6611−6625.
(24) (a) Kovalskaya, S. S.; Dikusar, E. A.; Kozlov, N. G.; Popova, L.
A. Russ. J. Org. Chem. 2001, 37, 1225−1227. (b) Schmidt, E. Y.;
Vasil’tsov, A. M.; Mikhaleva, A. I.; Zaitsev, A. B.; Afonin, A. V.;
Toryashinova, D. S. D.; Klyba, L. V.; Arndt, J. D.; Henkelmann, J.
ARKIVOC 2003, xiii, 35−44. (c) Hashmi, A. S. K.; Weyrauch, J. P.;
Frey, W.; Bats, J. W. Org. Lett. 2004, 6, 4391−4394. (d) Jin, C.;
Burgess, J. P.; Kepler, J. A.; Cook, C. E. Org. Lett. 2007, 9, 1887−1890.
(e) Harmata, M.; Huang, C. Synlett 2008, 1399−1401.
(25) Van Ornum, S. G.; Champeau, R. M.; Pariza, R. Chem. Rev.
2006, 106, 2990−3001.
810
dx.doi.org/10.1021/op300084z | Org. Process Res. Dev. 2012, 16, 798−810