High-Temperature Boc Deprotection in Flow and Its Application in Multistep Reaction Sequences

Article abstract of DOI:10.1021/acs.orglett.6b00378

A simplified Boc deprotection using a high-temperature flow reactor is described. The system afforded the qualitative yield of a wide variety of deprotected substrates within minutes using acetonitrile as the solvent and without the use of acidic conditions or additional workups. Highly efficient, multistep reaction sequences in flow are also demonstrated wherein no extraction or isolation was required between steps.

Full text of DOI:10.1021/acs.orglett.6b00378

Letter
pubs.acs.org/OrgLett
High-Temperature Boc Deprotection in Flow and Its Application in
Multistep Reaction Sequences
Andrew R. Bogdan,*,† Manwika Charaschanya,‡ Amanda W. Dombrowski,† Ying Wang,†
and Stevan W. Djuric†
†Discovery Chemistry and Technologies, AbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States
‡Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66047, United States
S
* Supporting Information
ABSTRACT: A simplified Boc deprotection using a high-temperature flow reactor is described. The system afforded the
qualitative yield of a wide variety of deprotected substrates within minutes using acetonitrile as the solvent and without the use of
acidic conditions or additional workups. Highly efficient, multistep reaction sequences in flow are also demonstrated wherein no
extraction or isolation was required between steps.
ver the past decade, an array of new technologies has been
the pharmaceutical industry. For this reason, we sought to
Odeveloped toenable novel chemicaltransformations within accelerate reaction rates by considering the Arrhenius equation
organic synthesis.1 The major benefits of these technologies
and running the reactions at temperatures that would allow a
greater fraction of molecules to reach the activation energy
necessary for the transformation. As commercially available
microwaves have temperature, pressure, and solvent limitations,
wesoughttouseaflowreactorthatcouldhandlemoredemanding
conditions. Thus, we opted to evaluate the high-temperature and
high-pressure Phoenix flow reactor from ThalesNano (Figure 1).
This flow system is capable of reaching a maximum temperature
of 450 °C and a pressure maximum of 140 bar when equipped
with a variable back-pressure regulator (BPR).9
In medicinal chemistry, tert-butyloxycarbonyl (Boc) is by far
the most commonly used protecting group for amines.
Subsequently, the deprotection of Boc groups accounts for
>50% of amine deprotections in the literature.10 We chose to
investigate the thermal deprotection of Boc groups as this could
serve as an alternative to the widely used acidic methods. While a
few thermolytic deprotections have been reported in the
literature, these reactions are optimal when run on small scale
due to the high temperature requirements and vigorous off-
gassing of the reaction.11 A thermal deprotection would have
advantages over traditional techniques where there is functional
group incompatibility or workup complications; it would also
remove the need for expensive reagents or the use of materials in
vast excess. Compounds also would be isolated as the free amine,
not salts. Additionally, using a deprotection with no added
include increased speed, improved efficiency via simplified
purification and workup, as well as enhanced safety profiles.
Polymer-supported reagents/catalysts,2 microwave technology,3
continuous flow synthesis,4,5 and flow photochemistry6 are
examples of these tools, which have been widely used in both
academic and industrial settings to increase efficiency and to
broaden the scope of chemistry. New flow reactors are constantly
being developed due to their ability to perform safer, more
efficient, and selective chemical transformations as well as their
ability to couple multiple reaction steps into one continuous
sequence. Many advantages associated with flow reactors are
attributed to large surface area-to-volume ratios that allow rapid
heat transfer and efficient mixing, enabling reactions to be
performedinamannerthatcouldnotbereadilyobtainedinbatch.
Forcing conditions, such as elevated temperatures and pressures,
can also be readily accessed using various heat sources, such as gas
chromatograph ovens and hot plates, and back-pressure
regulators. This enables solvents to be used well beyond their
boiling points, thus, opening up the possibility of using green
solvents to replace traditional high-boiling solvents, such as
diphenyl ether, xylenes, or diglyme.
Having used high-temperature flow chemistry in 1,2,4-
oxadiazole and 1,2,4-triazole formations (175−225 °C),7 as well
as nucleophilic aromatic substitutions (225 °C),8 we began to
evaluate chemistry in a reaction space outside of what is typically
run in a chemistry laboratory (i.e., >250 °C). The ability to access
new analogues in an efficient manner is of utmost importance in
Received: February 5, 2016
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.6b00378
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Scheme 1. Substrate Scope for the High-Temperature Boc
a c
−
Deprotection in Flow
Figure 1. Schematic of the high-temperature Phoenix flow reactor.
Table 1. Thermal Deprotection of Boc-Phe-OMe 1
a
b
Isolated yield after solvent removal. The bold red nitrogen indicates
c
the amine that has been deprotected. Reactions run at 0.1 M substrate
d
unless otherwise noted. Reactions run at 0.2 M substrate.
e
f
Approximately 15% indole was observed after dry-down. Approx-
temp
entry (°C)
flow rate
(mL/min)
residence
time (min)
% conv % product 2 (MS
imately 10% indole was observed after dry-down.
(UV)
ion count)
1
2
3
4
5
6
7
200
250
300
300
300
300
200
1.0
1.0
1.0
2.0
3.0
4.0
8.0
8.0
8.0
4.0
2.7
2.0
8.0
0
49
a,b
Scheme 2. Substrate Scope for Bis-protected Compounds
>99
>99
>99
>99
0
52
68
77
80
a
a
Sample run in Biotage microwave at 200 °C for 8 min.
a
b
Isolated yield after solvent removal. The bold red nitrogen indicates
c
the amine that has been deprotected. Isolated yield after treatment
d
e
with TFA. A mixture of products was seen by 1H NMR. 10%
Figure 2. Crude 1H NMR spectra of 2.
f
piperdin-4-one was seen by 1H NMR. Isolated yield after purification
using normal-phase chromatography.
reagents would enable multistep reaction sequences to be run in
flow without any in-line extractions or workups.
analyzed using HPLC/MS. While the UV trace showed a clean
conversion to product at 300 °C, the mass trace showed
significantly more peaks, indicating that there was some
decomposition occurring when the reaction was exposed to
high temperatures for an extended period of time. For this reason,
theresidence timewasshortened byincreasing the flowrate ofthe
reactor (Table 1, entries 3−6). To our surprise, complete
Initially, we screened a range of temperatures for the
deprotection of Boc-Phe-OMe 1 using acetonitrile as the solvent
(Table 1). Starting at 200 °C for 8 min (Table 1, entry 1) afforded
no conversion to the desired product. However, increasing the
temperature up to 300 °C gave a complete conversion to the
deprotected amine (Table 1, entry 3). These reactions were
B
DOI: 10.1021/acs.orglett.6b00378
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Scheme 3. Acylation−Deprotection−Carbamate Formation Sequence Using an in-Line High-Temperature Boc Deprotection
Scheme 4. Sulfonylation−Deprotection−SNAr sequence Using an in-Line High-Temperature Boc Deprotection
conversion was still observed using the system’s maximum flow
rate of 4.0 mL/min (Table 1, entry 6), and the mass trace showed
a much higher percentage of the desired product. It should also be
noted that running the deprotection in the microwave at 200 °C
(the maximum temperature for acetonitrile) gave no conversion
to the amine 2 (Table 1, entry 7).
using only a2 minresidence time. In the case of amines 14 and 15,
oxidation to form the indole was observed after the reaction had
been concentrated. As the crude LC/MS of the samples prior to
drying indicated no trace of the indole, it was determined that this
elimination wasnotduetothe flowreactionbut thestabilityofthe
products to oxidation.
The reaction was concentrated, and a crude NMR was taken of
2 (Figure 2). The resulting 1H and 13C NMR spectra were >95%
pure with very minor baseline peaks in the 1H NMR spectrum.
This indicates that subjecting the material to the high-temper-
ature flow reactor was not causing an appreciable amount of
decomposition and that no additional workup was required to
obtain the final material. Chiral chromatography proved that the
stereochemistry of the amine is retained during the process (see
the Supporting Information). Additional green solvents, such as
ethanol, methanol, tetrahydrofuran, and 2-methyltetrahydrofur-
an, were also screened but showed impure crude NMR spectra
and LC/MS traces. In the case of ethanol, transesterification was
observed. The byproducts formed when other solvents were
tested were not characterized.
With the optimized conditions in hand, a series of Boc-
protected amines were deprotected using the flow reactor
(Scheme 1). From the substrate scope, it can be seen that this is
a general methodology for deprotecting a variety of amines. To
illustrate this, a series of primary and secondary amines were
quantitatively deprotected. Indole 3 and anilines 4, 7, 14, and 15
were also readily deprotected, as were lactam 6 and imidazole 9. A
number of functional groups were also tolerated, including
alcohols, amides, esters, aryl halides, ketones, and diamines.12 All
reported substrates achieved complete conversion, and only
concentration of the reaction solvent was required to obtain the
product.Ofnoteisthefactthatallofthereactionswerecompleted
Another set of substrates, which contained additional
protecting groups, were synthesized and subjected to the high-
temperature flow deprotection (Scheme 2). Protecting groups,
such as TBS, tosyl, and CBz, were not affected during the
deprotection and gave nearly qualitative yields of the desired
amine.Acetal19wasmoresensitivetotheconditionsbutstillgave
a good yield of the product. It is worth noting that the Boc groups
can selectively be cleaved using this protocol in the presence of
other acid-labile functional groups. When the substrates in
Scheme 2 are treated with TFA, often a mixture of products are
seen inthe crude NMRas isseen inthe case of compounds 16, 18,
19, and 21. While the Boc group has been completely cleaved,
substrates deprotected under acidic conditions showed impure
crudeNMRspectra(seetheSupportingInformation). Theability
to selectively cleave a Boc group using this acid-free, thermal
method emphasizes its potential impact on synthesis.
The ability to functionalize scaffolds orthogonally to map out
structure−activity relationship information efficiently is of crucial
importance to medicinal chemistry projects. In this context,
havingvalidatedthedeprotectionprotocolonmultiplesubstrates,
we sought to use the Phoenix in a multistep reaction sequence in
flow, in which one of the reaction steps is a Boc deprotection. The
advantages of using the high-temperature deprotection include
avoiding the use of in-line extractors to work up the reaction steps
and/or the use of excess reagents, such as TFA or HCl. We first
examined an acylation−deprotection−carbamate formation
C
DOI: 10.1021/acs.orglett.6b00378
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reaction sequence (Scheme 3). A stream of acid chloride was
mixedwithaprotecteddiamineatroomtemperatureandambient
pressure to form the amide. The reaction stream was flowed into
an injection loop and injected into the Phoenix to deprotect the
indoline to give intermediate 15. After exiting the Phoenix, the
reaction solution was mixed with a stream of 4-chlorophenyl
chloroformate and heated to 60 °C for 100 s. The entire synthesis
took ∼8 min to complete, and following concentration of the
collected solution and purification on normal-phase silica, 22 was
obtained in 91% isolated yield. It is also worth noting that
intermediate 15 could be immediately coupled in this sequence,
which prevents the indole formation that was observed if the
reaction mixture containing 15 was dried (Scheme 1, footnote f).
A sulfonylation−deprotection−SNAr reaction sequence was
also carried out using the Phoenix (Scheme 4). In this sequence, a
protected diamine was sulfonylated and mixed with an aryl halide
at room temperature and ambient pressure. The reaction stream
was once again flowed into an injection loop and loaded into the
Phoenix reactor set to 300 °C and 100 bar. In this case, the
deprotected amine was immediately coupled to the aryl halide via
a high-temperature SNAr to give 23 in 81% yield following
purification by normal-phase flash chromatography.
Both processes shown in Schemes 3 and 4 are high-throughput
methods, capable of generating grams of material in a matter of
minutes. Coupling−deprotection−coupling reaction sequences
are highly prevalent in the medicinal chemistry community, and
the overall process is greatly telescoped using this methodology.
In the cases described, where the concentration of the substrate
was not optimized, the system generates 0.4 mmol of product per
minute, indicating that these procedures are suitable for both
small-scale medicinal chemistry efforts, as well as reaction scale-
up.
The mechanism of the flow-mediated Boc deprotection
appears to be thermolytic, as the outlet of the reactor is pH
neutral when only acetonitrile is flushed through the system. As
expected, the pH of the reaction solution is slightly basic (pH ∼8)
due to the pKa of the products eluting from the system.
In conclusion, we have developed a general, high-temperature
Boc deprotection in flow using the Phoenix flow reactor.13
Removal of the solvent is the only workup required, and
subsequent reactions can be carried out without purification or
concentration. The protocol demonstrates a high functional
group tolerance and can be readily used with substrates that have
multiple protecting groups. We also demonstrate the utility of the
Boc deprotection in two different multistep reaction sequences,
showing how diverse molecular structures can rapidly be
synthesized without any intermediate extractions or purifications
within a matter of minutes.
ACKNOWLEDGMENTS
■
We thank Justin Dietrich for helpful discussions, Rick Yarbrough,
Jan Waters, and Dave Whittern for structural chemistry support,
and Erin Jordan (AbbVie) for chiral chromatography support. All
authorsareemployeesorformeremployeesofAbbVie. Thisstudy
was sponsored by AbbVie. AbbVie contributed to the study
design, research, interpretation of data, writing, reviewing and
approving the manuscript.
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ASSOCIATED CONTENT
* Supporting Information
■
S
(12) Reactions were run at either 0.1 or 0.2 M in acetonitrile, but it was
observed that higher concentrations could also be used without further
optimization. Using a 1.0 M solution of Boc-Phe-OMe gave a complete
conversion but resulted in far more vigorous off-gassing at the reactor
outlet.
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.6b00378.
Experimental procedures and full characterization (1H and
13C NMR data and spectra, MS) (PDF)
(13) When taking into account solvent recycling, no waste is generated
during this process as no reagents or workups are required. For this
reason, E-factors for this flow process would be much lower compared to
traditional batch deprotection techniques.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: andrew.bogdan@abbvie.com.
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.6b00378
Org. Lett. XXXX, XXX, XXX−XXX