Synthesis of 1,3-Aminoalcohols and Spirocyclic Azetidines via Tandem Hydroxymethylation and Aminomethylation Reaction of β-Keto Phosphonates with N-Nosyl- O-(2-bromoethyl)hydroxylamine

Article abstract of DOI:10.1021/acs.orglett.1c01091

An unprecedented tandem α-hydroxymethylation and α-aminomethylation reaction of aromatic cyclic β-keto phosphonates with N-nosyl-O-(2-bromoethyl)hydroxylamine in the presence of DBU base has been developed, affording a range of 1,3-aminoalcohols in good y

Full text of DOI:10.1021/acs.orglett.1c01091

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Letter
Synthesis of 1,3-Aminoalcohols and Spirocyclic Azetidines via
Tandem Hydroxymethylation and Aminomethylation Reaction of
β‑Keto Phosphonates with N‑Nosyl‑O‑(2-bromoethyl)hydroxylamine
Binyu Wu, Hongbing Chen, Min Gao, Xiangnan Gong, and Lin Hu*
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ABSTRACT: An unprecedented tandem α-hydroxymethylation
and α-aminomethylation reaction of aromatic cyclic β-keto
phosphonates with N-nosyl-O-(2-bromoethyl)hydroxylamine in
the presence of DBU base has been developed, affording a range
of 1,3-aminoalcohols in good yields. The resultant products could
be flexibly transformed into the spirocyclic and bispirocyclic
azetidines via one step of Mitsunobu reaction. Mechanistic study
revealed that hydroxylamine in situ generated the formaldehyde and
nosylamide, which in turn triggered the sequential Horner−
Wadsworth−Emmons, Michael, and aldol reactions.
Herein, we report that the simple N-nosyl-O-(2-
bromoethyl)hydroxylamine 2a, a stable solid, could participate
in the unprecedented tandem hydroxymethylation and amino-
methylation reactions with aromatic cyclic β-keto phospho-
nates under mild DBU basic conditions, directly affording the
α-hydroxymethyl-α-aminomethyl ketones in good yields at
room temperature (Scheme 1C). Moreover, the resultant 1,3-
aminoalcohols are versatile synthons, which could be flexibly
transformed into two types of spirocyclic- and bispirocyclic
azetidine products via one simple Mitsunobu cyclization
reaction. Notably, the latter bispirocyclic scaffold bearing two
vicinal azetidine and 1,3,4-oxadiazoline rings is synthetically
challenging, which is prepared for the first time.
Recently, we attempted to synthesize the compound 4 from
β-keto phosphonate 1a and hydroxylamine 2a in DMF under
the Cs2CO3 basic conditions. Accidentally, instead of obtaining
the target alkylation product, we isolated the 1,3-aminoalcohol
3a in 49% yield (Scheme 2). This unexpected result
immediately triggered our interest of this reaction, not only
because the α-hydroxymethyl-α-aminomethyl ketones could be
generated in such a simple way but also because the intriguing
role of the hydroxylamine played in this complicated bond
cleavage and formation process.
1,3-Aminoalcohols are a prominent motif widely employed in
synthetic and medicinal chemistry.1 As a subclass of such
compounds, α-hydroxymethyl-α-aminomethyl ketones are
exceptionally useful building blocks, because the free OH
and NH moieties as well as the carbonyl functional group
provide convenient handles for structural derivatizations. For
example, the biologically important azetidines, which are found
in many natural products and therapeutic agents,2 may be
rapidly assembled from these 1,3-aminoalcohol precursors via
an intramolecular cyclization reaction (Scheme 1A). Surpris-
ingly, although their structure looks simple, synthetic methods
for such α-hydroxymethyl-α-aminomethyl carbonyl com-
pounds are rather rare.3 The only relevant work that involved
the condensation of tetralone derivatives with paraformalde-
hyde and imidazole or triazoles to afford the α-hydroxymethyl-
α-azolylmethyl compounds was reported by Bhandari.3a
However, the reaction introduced the specific imidazole or
triazole groups into the products, thus heavily limiting their
further transformation. On the other hand, hydroxylamines
characterized by a weak N−O bond within the structure are
commonly used reagents in organic synthesis.4 Conventionally,
they were extensively exploited as amination reagent in
transition metal-catalyzed C−N bond-forming reactions.5 In
recent years, they have also been exploited as nitrogen-
centered radical precursors in photocatalytic C−N bond-
forming reactions6 (Scheme 1B). Conversely, applying
hydroxylamine derivatives as novel hydroxymethylation and
aminomethylation reagents has not been achieved to date. In
this regard, development of an efficient approach toward α-
hydroxymethyl-α-aminomethyl ketones by using hydroxyl-
amine derivatives as novel C−C bond-forming reagents will
be highly attractive.
On the basis of this initial discovery, we decided to optimize
the reaction first (Table 1). We found that the base had a
Received: March 30, 2021
Published: May 17, 2021
https://doi.org/10.1021/acs.orglett.1c01091
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4152−4157
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a
Scheme 1. Background and Our Synthetic Approach
Table 1. Optimization of the Reaction Conditions
b
entry
substrates
base
Cs2CO3
K2CO3
KOH
DBU
DBU
TEA
pyridine
DBU
DBU
DBU
DBU
DBU
DBU (3.0 equiv)
DBU (10.0 equiv)
DBU
solvent t (h) yield (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
5
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2a
2a
2a
2a
2a
2a
DMF
DMF
DMF
DMF
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
24
24
24
15
15
48
48
48
48
15
48
48
15
15
48
48
49
45
8
64
73
0
0
0
c
d
c
c
9
0
10
11
12
13
14
15
16
62
10
8
6
1a
1a
1a
1a
51
44
19
28
e
f
DBU
a
Unless otherwise noted: nucleophile (0.10 mmol), 2 (0.15 mmol),
and base (0.50 mmol) in indicated solvent at room temperature.
b
c
Isolated yield. 1a was recovered, and 2 was partially converted into
d
e
f
1,2-oxazetidine. 1a and 2a were recovered. Run at 0 °C. 1.0 equiv
of 2a was used.
Scheme 2. Initial Discovery
After establishing the optimal conditions, the scope of the α-
hydroxymethylation and α-aminomethylation reaction was
explored. As summarized in Scheme 3, a range of α-
a
Scheme 3. Substrate Scope
significant impact on the reaction. Weaker base K2CO3
provided the product 3a in 45% yield, while stronger base
KOH caused the quick decomposition of the hydroxylamine
2a. Thus 3a was obtained in very low yield (Table 1, entries
1−3). Organic base DBU turned out to be the best, which
improved the yield to 73% in DCM solvent. Other commonly
used organic bases such as TEA and pyridine were ineffective
to promote the reaction (Table 1, entries 4−7). We also
observed that both the structures of hydroxylamines and
nucleophiles affected the reaction drastically (Table 1, entries
8−12). No reaction happened when tosyl- and Boc-protected
hydroxylamines 2b and 2c were used as substrates, but the N-
nosyl hydroxylamine 2d bearing a less reactive chloro group
still delivered the product 3a in 62% yield. In addition,
replacing the phosphonate nucleophile with β-keto carboxylate
5 and tetralone 6 only afforded a trace amount of product 3.
Next, other reaction parameters such as temperature and the
amounts of base were examined, but they could not further
improve the yield (Table 1, entries 14−16). Eventually, we
determined to conduct the reaction of β-keto phosphonate 1
(1.0 equiv) and N-nosyl-O-(2-bromoethyl)hydroxylamine 2a
(1.5 equiv) in DCM at room temperature by using DBU (5.0
equiv) as base (see the Supporting Information for details).
a
Standard conditions: 1 (0.2 mmol), 2a (0.3 mmol), and DBU (1.0
b
mmol) in 2.0 mL of DCM at room temperature for 15 h. Yield for 6
mmol of 1 and 9 mmol of 2a.
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a
hydroxymethyl-α-aminomethyl ketones could be prepared in
good yields under standard conditions. Tetralone phosphonate
substrates bearing various 7-alkyl, -aryl, and -halo substituents
on the phenyl ring were well tolerated, affording the products
in 59−68% yields (Scheme 3, 3b−g). Substrates bearing
different 5- and 6-substitutents on the phenyl ring had a
slightly influence on the yield (Scheme 3, 3h−n). Hetero-
aromatic substrates such as pyridine- and thiophene-fused
cyclic ketones also reacted with hydroxylamine 2a well and
provided products 3o−p in around 53% yield. In addition,
indanone phosphonate substrates, regardless of the position
and the electronic nature of the substituents on the phenyl
ring, also produced the corresponding products in 51−62%
yields (Scheme 3, 3t−z). Moreover, other substrates such as
benzoyl, acetyl, 2-oxocyclopentyl, and 2-oxocyclohexyl phos-
phonates were also tried. However, the reactions for these
substrates were complex. Only the benzoyl and acetyl
phosphonates afforded the target 1,3-aminoalcohol products
in 24% and 20% yield, respectively.(Scheme 3, 3aa,ab). Finally,
we attempted the scalable synthesis under the standard
conditions. The reactions of 1a and 1t still performed well at
the 6 mmol scale, which furnished 1.3 g of 3a and 1.15 g of 3t
in 57% and 51% yield, respectively.
Scheme 4. Synthesis of Spirocyclic Azetidines
As mentioned above, azetidines are a class of important
heterocylces exhibiting a wide range of interesting biological
and pharmacological properties such as anti-influenza virus A
and anti-HIV activities.2 Due to the strained nature, efficient
construction of such a small ring structure remains a
challenging task.7 Especially, the synthetic approaches for
spirocyclic azetidines are currently limited.8 Considering the
pendant N-nosyl and hydroxyl functional groups that provide
convenient handles for the Mitsunobu reaction,9 we envisioned
that the above α-hydroxymethyl-α-aminomethyl ketone
products could be used for the rapid assembly of the
spirocyclic azetidines via one-step cyclization. Accordingly,
we subjected 3a to the Ph3P and diisopropyl azodicarboxylate
mixture. To our delight, the reaction smoothly furnished the
spirocyclic azetidine 7a in 80% yield at 0 °C (Scheme 4,
conditions A). This protocol was also efficient for the
construction of other spirocyclic azetidines in good yields
(Scheme 4, 7b−h). For example, pyridine- and piperidinone-
containing and indanone-fused azetidines were prepared in
56−83% yields. Impressively, by simply changing the
Mitsunobu reagent to diethyl azodicarboxylate and by
conducting the reaction at room temperature (Scheme 4,
conditions B), a series of structurally complex azetidine−1,3,4-
oxadiazoline bispiocycles could be alternatively obtained in
good yields (Scheme 4, 8a−h). To our knowledge, such
challenging structure bearing two congested vicinal spirocycles,
which was confirmed by the single crystal X-ray analysis of
compound 8c, has not been prepared previously.
a
Conditions A: 3 (0.2 mmol), DIAD (0.3 mmol), and PPh3 (0.3
mmol) in toluene at 0 °C. Conditions B: 3 (0.2 mmol), DEAD (0.48
mmol), and PPh3 (0.48 mmol) in toluene at room temperature.
should be formed via a sequential intramolecular Mitsunobu
reaction and an unusual intermolecular [4 + 1] annulation11
process (see the Supporting Information for details).
Finally, to gain insight of the α-hydroxymethylation and α-
aminomethylation reaction, we carried out the following
control experiments (Scheme 5A). We found that several
intermediates were formed at the early stage of the reaction of
Scheme 5. Mechanistic Investigations
In fact, only a few isolated examples of cyclizations of dialkyl
azodicarboxylate reagents with reactive α-ketoesters or α-
diketones to form the 1,3,4-oxadiazolines have been
reported,10 but the above double spirocyclization process of
unactivated carbonyl compounds was unprecedented. To
elucidate how the azetidine-1,3,4-oxadiazoline bicycles were
efficiently installed under such mild Mitsunobu conditions, we
examined the reaction of the tetralone 6 under the conditions
B. However, no reaction occurred at all. Instead, treatment of
spirocyclic azetidine 7a under the same conditions smoothly
generated the bispirocyclic compound 8a in 75% yield. These
results suggested that the azetidine-1,3,4-oxadiazoline product
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phosphonate 1a and hydroxylamine 2a. After quenching the
reaction at 1 h, we isolated enone 9 in 75% yield along with α-
aminomethyl phosphonate 10 and nosylamide as two minor
products (eq 1). To validate if compounds 9 and 10 were the
real intermediates of final product 3a, we resubmitted them to
the standard reaction conditions. Interestingly, enone 9 was
eventually converted into 3a in 51% yield, while compound 10
was gradually decomposed to complex mixture (eq 2). This
result indicated that enone 9 should be the intermediate of
product 3a. Thus, we speculated that this enone intermediate
might undergo the Michael addition reaction with nosylamide.
Indeed, treatment of 9 with nosylamide afforded α-amino-
methyl tetralone 11 in 55% yield in the presence of DBU base.
Moreover, we also found that compound 11 could react with
2a to produce the final product 3a (eq 3). To further
understand the role of hydroxylamine 2a in the whole process,
we just submitted 2a to the DBU basic condition. Notably, a
four-membered 1,2-oxazetidine12 intermediate 12 was rapidly
formed within 5 min of the reaction. However, this strained
compound could be decomposed to 4-nitrobenzenesulfona-
mide under DBU basic conditions. Therefore, we deduced that
the highly reactive formaldehyde and formaldimine inter-
mediates might be involved in this fragmentation process (eq
4).
On the basis of the above experiments, we proposed a
plausible pathway for the above tandem hydroxymethylation
and aminomethylation reactions (Scheme 5B). Initially,
hydroxylamine 2a was quickly cyclized to 1,2-oxazetidine 12,
followed by decomposition to the formaldehyde and N-nosyl
formaldimine in the presence of DBU base. Immediately, the
highly reactive formaldehyde intermediate was captured by
phosphonate 1 to form the enone 9 via Horner−Wadsworth−
Emmons reaction.13 Meanwhile, the formaldimine intermedi-
ate could also be partially captured by phosphonate 1, thus
giving the Mannich adduct 10 as a side product.14 However,
the N-nosyl formaldimine reagent was readily decomposed to
nosylamide for the subsequent Michael addition reaction.15
Finally, the intermediate 11 would take place the aldol reaction
with in situ generated formaldehyde to form the product 3a.
The above mechanistic study implied that hydroxylamine 2a
might be replaced by the simple nosylamide and formaldehyde
such as formalin for the tandem process. Indeed, the
multicomponent reaction of aromatic cyclic β-keto phospho-
nates (1.0 equiv), formalin (3.0 equiv), and nosylamide (1.0
equiv) could occur in the presence of DBU (5.0 equiv).
However, the reaction gave lower yields of 3, and benzoyl and
acetyl substrates provided the products in even poor yields
(Scheme 6). Meanwhile, tosylamide was also suitable for the
reaction, but BocNH2 and BnNH2 failed to produce the target
products. Overall, these results indicated that 2a was not
essential for the tandem process, which could be replaced by
the simpler and readily available formalin and nosylamide
reagents in practical synthesis.
In conclusion, we have developed an unprecedented tandem
hydroxymethylation and aminomethylation reaction of aro-
matic cyclic β-keto phosphonates with N-nosyl-O-(2-
bromoethyl)hydroxylamine in the presence of DBU base,
affording a range of α-hydroxymethyl-α-aminomethyl ketones
in good yields. Mechanistic study revealed that hydroxylamine
played a unique role in the whole process, which in situ
generated the highly reactive formaldehyde and formaldimine
reagents and in turn triggered the sequential Horner−
Wadsworth−Emmons, Michael addition, and aldol addition
reactions. Remarkably, the generated 1,3-aminoalcohols could
be flexibly converted into the biologically important spirocyclic
azetidines and azetidine-1,3,4-oxadiazoline bispirocycles via
one simple Mitsunobu cyclization reaction. In particular, the
latter products contain a challenging and novel vicinal
bispirocyclic framework, wherein the 1,3,4-oxadiazoline ring
was assembled via an unusual [4 + 1] annulation of dialkyl
azodicarboxylate with carbonyl group.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01091.
Experimental details, characterization data, NMR, and
X-ray crystallographic data (PDF)
Accession Codes
CCDC 2074010 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Lin Hu − Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, School of Pharmaceutical
Sciences, Chongqing University, Chongqing 401331, P. R.
China; orcid.org/0000-0002-8600-965X; Email: lhu@
cqu.edu.cn
Authors
Binyu Wu − Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, School of Pharmaceutical
Sciences, Chongqing University, Chongqing 401331, P. R.
China
Scheme 6. Tandem Reaction Scope with Sulfonamides
Hongbing Chen − Chongqing Key Laboratory of Natural
Product Synthesis and Drug Research, School of
Pharmaceutical Sciences, Chongqing University, Chongqing
401331, P. R. China
Min Gao − Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, School of Pharmaceutical
Sciences, Chongqing University, Chongqing 401331, P. R.
China
Xiangnan Gong − Analytical and Testing Center, Chongqing
University, Chongqing 401331, China
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the Construction of the C-N Bond. Chem. - Eur. J. 2017, 23, 2481−
2511.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01091
(6) Davies, J.; Morcillo, S. P.; Douglas, J. J.; Leonori, D.
Hydroxylamine Derivatives as Nitrogen-Radical Precursors in
Visible-Light Photochemistry. Chem. - Eur. J. 2018, 24, 12154−12163.
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Azetidines and Azetidinones. Chem. Rev. 2008, 108, 3988−4035.
(b) Couty, F.; Evano, G. Azetidines: New Tools for the Synthesis of
Nitrogen Heterocycles. Synlett 2009, 2009, 3053−3064.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from NSFC (21871032), the Natural
Science Foundation of Chongqing (cstc2020jcyjmsxmX0520),
the Fundamental Research Funds for Central Universities
(2020CDJ-LHZZ-007), and the Venture & Innovation
Support Program for Chongqing Overseas Returnees
(cx2020080) is acknowledged.
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K. O.; Coffey, S.; Fernando, D.; Hepworth, D.; Jackson, M. V.; Khot,
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C.; Saenz, J.; Stock, I. A.; Storer, G.; von Volkenburg, M.; Vrieze, D.;
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