Scalable preparation of 4,4-disubstituted six-membered cyclic sulfones

Article abstract of DOI:10.1021/acs.orglett.0c04141

We provide an account of synthetic strategies aimed at the efficient preparation of 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (3), an important cyclic sulfone building block for medicinal chemistry. A practical and scalable protocol has been developed that readily gives access to the title compound from commercially available and inexpensive starting materials. In addition, this novel approach has enabled the synthesis of various related 4,4-disubstituted cyclic sulfone derivatives that serve as valuable structural motifs for drug discovery.

Full text of DOI:10.1021/acs.orglett.0c04141

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Letter
Scalable Preparation of 4,4-Disubstituted Six-Membered
Cyclic Sulfones
Cedric L. Hugelshofer,* Jianming Bao,* Juana Du, Eric Ashley, Wensheng Yu, Tao Ji, Bin Hu, Dejun Liu,
Ramu Rondla, Srinivas Karampuri, Vishal Sharma, Krishna Ethiraj, and Yeon-Hee Lim
Cite This: Org. Lett. 2021, 23, 943−947
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ABSTRACT: We provide an account of synthetic strategies aimed at the efficient
preparation of 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (3), an
important cyclic sulfone building block for medicinal chemistry. A practical and
scalable protocol has been developed that readily gives access to the title
compound from commercially available and inexpensive starting materials. In
addition, this novel approach has enabled the synthesis of various related 4,4-
disubstituted cyclic sulfone derivatives that serve as valuable structural motifs for
drug discovery.
piperidine derivatives due to their highly favorable pharmaco-
kinetic profiles.6
ulfones have found extensive applications as versatile
1
Sbuilding blocks in organic synthesis and in the field of
medicinal chemistry.2 Acting as ligands in a protein environ-
ment, sulfonyl groups frequently exhibit a dual character,
functioning simultaneously as hydrogen bond acceptors as well
as interacting with hydrophobic groups.2b The unique
properties of these polar, metabolically stable groups thus
renders their incorporation especially attractive in pharma-
ceuticals.3 In some cases, conformationally restrained cyclic
sulfones have been discovered to be particularly beneficial in
enhancing binding to the biological targets,4 leading to diverse
drug candidates containing this substructure being reported
(Figure 1).5 In particular, six-membered aliphatic sulfones are
frequently explored as bioisosteres of tetrahydropyran and
In an effort to enable preclinical toxicological studies in a
medicinal chemistry project, we required facile and large-scale
access to amides with an appended six-membered cyclic
sulfone of the general structure 1 (Figure 2A). A literature
survey revealed that this moiety is commonly introduced via
amide formation of a carboxylic acid with amino sulfide 2,
followed by oxidation of the thioether functionality to the
sulfone.7 For our purposes, this two-step approach was deemed
unsuitable due to the sulfide oxidation not being tolerated by
other incorporated functional groups as well as the high cost of
2. We instead were attracted to employ the more oxidized
analogue, amino sulfone 3 (Figure 2B), in the amide-coupling
step. Besides gaining access to 1 with increased synthetic
efficiency, we importantly would avoid the problematic late-
stage oxidation. To the best of our knowledge, no synthesis of
3 has been reported in the literature, and due to limited
commercial availability (at a prohibitive cost), sufficient
quantities of this key building block could not be acquired in
the short term. As such, we strove to develop a practical,
efficient, and scalable protocol that would readily give access to
decagram quantities of 3. Following consideration of various
retrosyntheses, and assessing the availability of the respective
starting materials within a short timeline, we prioritized route
scouting efforts utilizing ketone 4, amine 5, sulfide 6, and
Received: December 15, 2020
Published: January 8, 2021
Figure 1. Importance of six-membered aliphatic sulfones in medicinal
chemistry.
© 2021 The Authors. Published by
American Chemical Society
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a
Scheme 2. α-C−H Functionalization Approach
a
Reagents and conditions: (a) 10, 1,2-dichloroethane, 23 °C; (b)
CH3Li, N,N,N,N-tetramethylethyldiamine, toluene, Et2O, −78 to 23
°C (43%, two steps); (c) H5IO6, CH3CN, H2O, 0 °C; (d) acid−base
extraction (71%).
Figure 2. Retrosynthesis of amino sulfone 3.
divinyl sulfone 7 as viable, low-cost precursors.8 Herein, we
summarize the exploration of various synthetic strategies
including classical imine chemistry, α-C−H functionalization,
Ritter reaction, and nitroalkane-Michael addition to ultimately
establish an efficient and practical preparation of 3.
In an early synthetic undertaking, we envisioned that the
high oxidation state of readily available precursor ketone 4
could be leveraged for developing a concise route to amino
sulfone 3. Along these lines, we foresaw conversion of 4 to an
imine, followed by nucleophilic 1,2-addition and deprotection
of the resulting secondary amine derivative (Scheme 1). In
conditions of Corey’s seminal and bioinspired protocol for
generation of ketimines were investigated.12 In the first step,
amine 5 underwent quinone-mediated oxidation to afford
intermediate ketimine 11 as a result of condensation followed
by an in situ [1,5] H-shift. Subsequent addition of
methyllithium then furnished amine 12. We found orthoperi-
odic acid to be superior to reported oxidative hydrolytic
workup conditions (I2, aq NaOH)12d for detaching the
hydroxyarene and, following an acid−base extraction, enabling
clean isolation of amino sulfone 3. Although this outlined
synthetic route to 3 is concise, it proved problematic for scale-
up due to the necessity for a large excess of methyllithium (6
equiv) in the conversion of 11 to 12 and the poor solubility of
starting amine 5. Furthermore, the high price of 5 compared
less favorably to the other precursors (Figure 2B).
a
Scheme 1. Attempted Synthesis of Imine 8
At this stage we returned to a strategy involving imine
chemistry and it was envisioned that utilizing sulfide 6,8 rather
than the more oxidized analogue 4 (Figure 2B), might render
the corresponding imine formation feasible and obviate the
putative interference of the sulfone functionality in this step
(Scheme 3, left). Indeed, titanium(IV) ethoxide successfully
promoted condensation of 2-methyl-2-propanesulfinamide
with 6 to give imine 14, albeit in moderate yield due to the
instability of this intermediate.13 After methylmagnesium
bromide addition to 14 furnished 15, we explored installation
of the sulfone. Using m-CPBA or Oxone, we encountered
concomitant oxidation of the sulfinamide moiety, affording the
corresponding sulfone−sulfonamide product. Cleavage of the
N−S bond in this sterically encumbered sulfonamide required
harsh conditions (trifluoromethanesulfonic acid, 23 °C, 4 h)
and resulted in a very low yield (<5%) of amino sulfone 3.
Therefore, we resorted to first convert 15 to carbamate 16,
which cleanly underwent oxidation to afford the corresponding
sulfone. Finally, treatment of this intermediate with hydro-
chloric acid unveiled the α-tertiary amine and, after filtration,
provided spectroscopically pure amino sulfone salt (3·HCl).
The outlined synthetic approach proved scalable and later
allowed preparation of >350 g of 3·HCl. While serviceable, the
instability of the intermediate imine 14 was a clear drawback in
a
Selected condensation conditions investigated: toluene, 110 °C; 4 Å
molecular sieves; Ti(OEt)4; MgSO4.
practice, execution of this straightforward plan proved
unexpectedly problematic: Condensation of ketone 4 with
benzylamine9 or classical sulfinamides10 under a variety of
thermal or Lewis acid promoted conditions failed to provide
imines of type 8, and instead, we observed formation of
complex product mixtures. To avoid isolation of the
supposedly unstable intermediate 8, telescoping the reaction
mixture from the imine condensation with the ensuing
organometal addition (CH3MgBr or CH3Li) to give 9 was
also investigated, yet these attempts remained equally
unsuccessful.
In parallel to the attempted route outlined in Scheme 1, we
were drawn to a distinct approach involving conversion of
commercially available amine 511 to the title α-tertiary amine 3
by introduction of the requisite methyl group via a formal α-
C−H functionalization (Scheme 2). In this respect, modified
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a
intercepting the sulfinyl imine route. Importantly, installation
of the tert-butyl carbamate facilitated removal of the 2-
aminothiazol-4(5H)-one byproduct at this stage and enabled
facile liquid−liquid extraction of the product from the aqueous
reaction mixture in the ensuing oxidation step. The described
synthetic route proved practical and readily enabled prepara-
tion of >30 g of 3·HCl in the largest single pass conducted
(24% overall yield from 6).
Scheme 3. Sulfinyl Imine and Ritter Reaction Route
While the outlined route proved serviceable, we realized
that, due to the need for chromatographic purification, further
scalability would become unfavorable and time-consuming.
Additionally, we were drawn to the opportunity of further
simplifying the synthetic sequence and importantly gaining
modular access to novel analogues of 3. Thus, we finally turned
our attention to a distinct synthetic route starting from divinyl
sulfone 7, which based on its use as a popular cross-linking
agent is cheap and widely available in bulk quantities. We
formally aimed to stitch together this bifunctional Michael
acceptor with an ethylamine equivalent to give the desired six-
membered ring heterocycle (Figure 2B). In practice, initial
attempts of a base-mediated Michael reaction of nitroethane
with 7 led to formation of large amounts of polymeric material
and only trace amounts of nitro sulfone 19 could be detected
in the reaction mixture (Scheme 4A). A survey of inorganic
a
Scheme 4. Nitroethane−Michael Approach
a
Reagents and conditions: (a) tBuS(O)NH2, Ti(OEt)4, THF, 70 °C
(52%); (b) CH3MgBr, THF, 0 °C (36%); (c) 4 M HCl, EtOAc, 20
°C (85%); (d) (Boc)2O, NEt3, CH2Cl2, 50 °C (95%); (e) oxone,
NaHCO3, CH3CN, H2O, 0 to 20 °C (75%); (f) 4 M HCl, 1,4-
dioxane, 0 to 20 °C (96%); (g) CH3Li, THF, −78 °C (90%); (h)
ClCH2CN, H2SO4, AcOH, CH2Cl2, 0 to 20 °C (62%); (i) thiourea,
AcOH, EtOH, 80 °C; (j) (Boc)2O, 2 M aq NaOH, 1,4-dioxane, 0 to
20 °C (60%, two steps). THF = tetrahydrofuran, Ac = CH3CO, Boc =
C(O)OtBu, DME = 1,2-dimethoxyethane.
this route and a major factor affecting the low overall yield
(∼9%), thus prompting us to pursue further strategies.
As an alternative to the sulfinyl imine route, we investigated
installation of the amine functionality after introduction of the
methyl group via formal nitrogen addition to a tertiary
carbocation. Accordingly, in the first step, sulfide 6 was treated
with methyllithium to furnish tertiary alcohol 17 in 90% yield
on a 100 g scale (Scheme 3, right). Initially we pursued a Ritter
reaction14 of 17 with acetonitrile (not shown) to give the
corresponding α-tertiary acetamide. However, under various
forcing acidic, basic, or hydridic15 conditions, the ensuing N-
acetyl deprotection could not be smoothly accomplished; the
reaction resulted in either unreacted starting material or led to
nonspecific decomposition. Cognizant that haloacetyl groups
can generally be cleaved under milder conditions with
thiourea,16 we thus turned to converting tertiary alcohol 17
into the related chloroacetamide 18. Although on a small scale
(<1 g) this Ritter reaction proceeded well using standard
conditions,17 formation of a thick reaction mixture complicated
stirring upon scale-up, and the isolated yield of 18 dropped
significantly. Careful experimentation revealed that dropwise
addition of a solution of 17 and chloroacetonitrile in
dichloromethane to a mixture of sulfuric and acetic acid at 0
°C circumvented these issues, and chloroacetamide 18 could
be prepared in 62% yield on an 80 g scale. Next, removal of the
haloacetyl group was achieved in a mixture of boiling ethanol
and acetic acid in the presence of thiourea; the precipitated
amine salt was directly converted to carbamate 16, thus
a
Reagents and conditions: (a) DBU, CH2Cl2, 23 °C (80%); (b) H2
b
(50 psi), Rh/C (1 mol %), MeOH, 75 °C (95%). Active methylene
compound, divinyl sulfone, DBU, CH2Cl2, 23 °C. Yield of isolated
c
products after purification by flash chromatography on silica gel. Ar =
d
o-F-phenyl. Ar′ = p-Cl-phenyl. TMG = 1,1,3,3-tetramethylguanidine,
DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene.
and organic bases across various solvents eventually revealed
the combination of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
in dichloromethane to be uniquely effective for this trans-
formation. Under the optimized conditions (1.1 equiv DBU,
dropwise addition of 7), the undesired polymerization was
largely suppressed, and after a simple aqueous hydrochloric
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acid wash to remove the amidine base, 19 was isolated cleanly
in 80% yield (150 mmol scale). For the conversion of 19 to the
corresponding amino sulfone 3, we ultimately found hydro-
genation using Rh/C (1 mol %) to be the most efficient
reduction protocol on large scale,18 furnishing 3 in 95% yield.
The outlined two-step synthesis of the title compound stands
most favorably compared to the other synthetic routes in terms
of starting material cost, step count, and experimental
practicality.
Following the successful development of a highly concise
and scalable preparation of amino sulfone 3, evaluation of a
diverse set of other active methylene nucleophiles highlighted
that this synthetic approach proved readily amenable to the
preparation of related, valuable 4,4-disubstituted cyclic sulfones
(Scheme 4B). The established conditions successfully
promoted substituted alkyl nitro, benzylic nitro, and β-nitro
ester derivatives to undergo the double Michael reaction with
divinyl sulfone 7 and gave access to the corresponding cyclic
sulfone products (20−25) in synthetically useful yields.
Furthermore, we demonstrated that the scope of this
transformation is not limited to nitroalkane nucleophiles, but
also readily allowed preparation of functionalized sulfones
starting from β-keto ester,19 β-keto nitrile, and α-cyano amide
derivatives (26−28).
Eric Ashley − Process Research and Development, Merck &
Co., Inc., South San Francisco, California 94080, United
States; orcid.org/0000-0002-0513-3342
Wensheng Yu − External Discovery Chemistry, Merck & Co.,
Inc, Kenilworth, New Jersey 07033, United States
Tao Ji − IDSU, WuXi AppTec Co., Ltd., Shanghai 200131,
China
Bin Hu − IDSU, WuXi AppTec Co., Ltd., Shanghai 200131,
China
Dejun Liu − IDSU, WuXi AppTec Co., Ltd., Shanghai
200131, China
Ramu Rondla − GVK Biosciences Pvt, Ltd., Telangana
500076, India
Srinivas Karampuri − GVK Biosciences Pvt, Ltd., Telangana
500076, India
Vishal Sharma − GVK Biosciences Pvt, Ltd., Telangana
500076, India
Krishna Ethiraj − GVK Biosciences Pvt, Ltd., Telangana
500076, India
Yeon-Hee Lim − Department of Discovery Chemistry, Merck
& Co., Inc., South San Francisco, California 94080, United
States; orcid.org/0000-0001-5662-788X
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c04141
In conclusion, we evaluated various synthetic strategies
aimed at the preparation of amino sulfone 3 to ensure material
supply of this building block for key analogue synthesis in
preclinical safety studies. The development of a practical,
efficient, and scalable protocol was governed by commercial
availability of affordable starting materials within the necessary
timeline. Following an optimized two-step sequence involving
a double Michael addition of nitroethane to divinyl sulfone, the
target compound 3 was readily synthesized in 76% overall
yield. In addition, this novel approach has also enabled the
preparation of related 4,4-disubstituted cyclic sulfones derived
from a diverse set of active methylene nucleophiles. We
anticipate the outlined procedures and investigated synthetic
strategies will be of high value for researchers requiring not
only scalable access to 3 but also to related, functionalized
cyclic sulfone building blocks.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Faben Cruz and Rohan Merchant (from
Merck & Co., Inc., South San Francisco, CA) for insightful
discussions. We thank Melissa Lin and Chad Pickens (both
from Merck & Co. Inc., South San Francisco, CA) for
assistance with NMR spectroscopy and HRMS, respectively.
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04141.
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Experimental details and spectroscopic data (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Cedric L. Hugelshofer − Department of Discovery Chemistry,
Merck & Co., Inc., South San Francisco, California 94080,
United States; orcid.org/0000-0001-5045-8878;
Email: cedric.hugelshofer@merck.com
Jianming Bao − Department of Discovery Chemistry, Merck &
Co., Inc., South San Francisco, California 94080, United
States; Email: jianming.bao@merck.com
Authors
Juana Du − Process Research and Development, Merck & Co.,
Inc., South San Francisco, California 94080, United States
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(8) The starting material $/gram prices stated are average values for
purchase of decagram quantities from US chemical retailers available
within a two-week time period (November 2020).
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https://dx.doi.org/10.1021/acs.orglett.0c04141
Org. Lett. 2021, 23, 943−947