Metal-Free Cycloetherification by in Situ Generated P-Stereogenic α-Diazanium Intermediates: A Convergent Synthesis of Enantiomerically Pure Dihydrobenzooxaphospholes

Article abstract of DOI:10.1021/acs.orglett.7b00051

A metal-free tandem reaction, initiated by the generation of a diazonium cation and followed by cycloetherification, was developed. Acid-promoted de-tert-butylation of N-nitroso N-tert-butylamine was used to generate a diazonium cation in situ, demonstrating a new application of nitroso chemistry. This reaction was employed in the synthesis of substituted benzofuran-3(2H)-ones and dihydrobenzo[d][1,3]oxaphosphole 3-oxides.

Full text of DOI:10.1021/acs.orglett.7b00051

Letter
pubs.acs.org/OrgLett
Metal-Free Cycloetherification by in Situ Generated P‑Stereogenic
α‑Diazanium Intermediates: A Convergent Synthesis of
Enantiomerically Pure Dihydrobenzooxaphospholes
Shi-Guang Li,† Zhengxu S. Han,*,§ Peter Viereck,† Heewon Lee,§ Dmitry Kurouski,§
Chris H. Senanayake,§ and Youla S. Tsantrizos*,†,‡
‡
†Department of Chemistry and Department of Biochemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec
H3A 0B8, Canada
§Chemical Development, Boehringer-Ingelheim Pharmaceuticals, Inc. 900 Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut
06877-0368, United States
S
* Supporting Information
ABSTRACT: A metal-free tandem reaction, initiated by the generation of a
diazonium cation and followed by cycloetherification, was developed. Acid-
promoted de-tert-butylation of N-nitroso N-tert-butylamine was used to
generate a diazonium cation in situ, demonstrating a new application of
nitroso chemistry. This reaction was employed in the synthesis of
substituted benzofuran-3(2H)-ones and dihydrobenzo[d][1,3]oxaphosphole 3-oxides.
ihydrobenzofuran derivatives, such as benzofuran-3(2H)-
methoxyacetophenone to coumaranone under a catalytic
amount of hydrochloric acid4b and later to the conversion of 1-
[2-(allyloxy)phenyl]-2-diazoethanone to 2-allylbenzofuran-
3(2H)-one via a rhodium-catalyzed [2,3]-sigmatropic rearrange-
ment of the oxonium ylides.4 In 1991, Pirrung reported the
asymmetric total synthesis of (+)-griseofulvin using a rhodium-
catalyzed cyclization of a diazo intermediate to construct the
benzofuran-3(2H)-one core.5 Recently, Zhou and co-workers
reported a copper-catalyzed enantioselective intramolecular
insertion reaction of carbenoids into a phenolic O−H bond as
a novel strategy for the synthesis of chiral 2-carboxydihydro-
benzofurans (Scheme 1b).6 However, the inherent acute toxicity
and explosive nature of preformed diazo compounds raises
significant concerns.7 In this respect, methodologies involving in
situ generation of diazo intermediates are preferable and of wide
interest.8 For example, Carreira and co-workers reported the in
situ generation of diazomethane in a cyclopropanation cascade
reaction using a water-soluble Diazald derivative (Scheme 1c).9
Herein, we report a metal-free, tandem reaction involving acid-
promoted de-tert-butylation of N-nitroso-N-tert-butylamine to
generate a diazonium cation in situ, followed by cyclo-
etherification to give substituted benzofuran-3(2H)-ones and
P-stereogenic chiral dihydrobenzo[d][1,3]oxaphosphole 3-
oxides without erosion of chirality at the phosphorus center
(Scheme 1d).
D
ones, are important building blocks for a variety of natural
products and pharmaceuticals (Scheme 1a).1 Today, the
Scheme 1. Examples of Synthesis of Diazo Intermediates and
Applications
structurally related P-stereogenic chiral 2,3-dihydrobenzo[d]-
[1,3]oxaphospholes and their corresponding 3-oxides are
receiving significant attention due to their applications as chiral
ligands in the rapidly evolving field of asymmetric catalysis.2
Numerous methods have been reported for the construction of
the tetrahydrofuran ring of dihydrobenzofurans and benzofuran-
3(2H)-ones that describes the intramolecular C−O bond
formation via a diazo intermediate.3 The initial exploration of
this reaction can be traced back to the conversion of α-diazo-o-
Diazomethane can be generated from N-nitroso precursors
under basic conditions; examples include Diazald,9,10 nitro-
somethylurea,11 and N-nitroso-β-methylaminoisobutyl methyl
ketone.12 Mindful of these methodologies, we set out to design
an alkaline stable, N-nitroso reagent that could generate the
Received: January 6, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00051
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Organic Letters
Letter
metalated nitrosoamine and, subsequently, capture an electro-
phile to generate the key intermediate 2 (Scheme 2).
Acidification of 2 could deprotect the N-nitrosoamine to furnish
the substituted diazo intermediate in situ, which could then react
with a nucleophile.
Scheme 3. Synthesis of P-Stereogenic Chiral
Dihydrobenzoxaphospholes via in Situ Generated Diazo
Intermediates
Scheme 2. Strategy for the Synthesis of Diazo Intermediates
optimization of the reaction conditions,13 we found that this
reaction proceeded most efficiently when 4 was treated with 6
equiv of N-nitrosoamine 1 and 4 equiv of LDA in the presence of
HMPA at −78 °C, affording 5 in high to excellent yield and
enantiomeric purity (Scheme 4). Not surprisingly, the outcome
To test our strategy, the acid-promoted conversion of 2 to 3
was surveyed under various conditions (Table 1). As anticipated,
Table 1. Survey of Reaction Conditions for Diazonium-
Mediated Cycloetheration in the Synthesis of Benzofuran-
a
3(2H)-ones
Scheme 4. Synthesis of P-Stereogenic N-Nitroso α-
a
Aminophosphine Oxides 5
b
entry
2
acid
solvent
DCM
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
2a
2b
2a
2b
2a
2b
2b
2b
2b
HCl
24
24
24
24
5
0
HCl
DCM
0
TFA
DCM
0
TFA
DCM
0
TfOH
TfOH
TfOH
TfOH
TfOH
DCM
0
DCM
12
8
71 (67)
68 (60)
66
toluene
benzene
cyclohexane
8
8
23
a
All reactions were carried out with 2 (0.10 mmol) and acid (0.5
b
mmol) in solvent (1 mL) at room temperature. NMR-based
estimated yields using CH2Br2 as an internal standard, isolated yields
in parentheses.
significant reactivity differences were observed between the acid-
labile tert-butyl analogue 2b and the methyl-substituted analogue
2a (entry 5 vs 6; only decomposition products were observed in
entry 5). We did not observe any products formed with 2a,
irrespective of the reaction conditions. When 2b was used, the
desired product was obtained, but the reaction rate and yield
were highly dependent on the acid strength and the solvent (e.g.,
entry 4 vs 6). Better results were obtained when TfOH was used
as the acid in a nonpolar solvent, such as DCM, benzene, or
toluene, from which an isolated yield of 60−70% was obtained
over two steps. Encouraged by these results, we turned our
attention to the synthesis of the P-stereogenic derivatives of 6.
Previously, Han and co-workers reported the synthesis of 6
(Scheme 3, path a). Reaction of chiral phosphinates 4 with either
MeMgX or MeLi afforded the phosphine oxide 7 in high yield
and enantioselectivity.2b,c Iodination of the P-methyl followed by
demethylation of 8 provided the phenol 9, which upon treatment
with base afforded the P-chiral 2,3-dihydrobenzo[d][1,3]-
oxaphosphole 3-oxide 6.2a We presumed that the synthesis of
6 would be more straightforward if the P-chiral N-nitroso-α-
aminophosphine oxide 5 was used as an intermediate (Scheme 3;
path b).
a
All reactions were carried out with 4 (1 equiv), nitrosoamine 1 (6
equiv), LDA (4 equiv), and HMPA (10 equiv) in THF at −78 °C
unless otherwise noted (isolated yield). Stereochemistry and % ee
determined by chiral HPLC.13 Temperature at −41 °C. Nitroso-
b
c
amine 3 (8 equiv).
of this substitution reaction was modulated by the steric
hindrance around the phosphorus atom. For example, analogues
having a tert-butyl or phenanthrene substituent on the
phosphorus did not give any appreciable amount of the desired
products 5b and 5o, respectively, even after prolonged reaction
time and/or higher temperatures. Similarly, product 5j, having
two ortho-substituent phenyls on the phosphorus was obtained in
The synthesis of 5 was investigated via the reaction of 4 with
metalated nitrosoamine 1 (Scheme 3; path b). After extensive
B
DOI: 10.1021/acs.orglett.7b00051
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Organic Letters
Letter
only 33% yield and a relatively lower enantiomeric purity.
Compound 5m was also obtained in lower yield (34%), likely
due to the activated methyl on the phosphorus, which is unstable
under the strongly basic conditions. It is noteworthy that the use
of N-nitrosodimethylamine 1a gave 5 as a mixture of two
rotamers (1:1 mixture, presumably due to the high energy barrier
of the N−NO rotation or N−O inversion),14 whereas, the
products derived from 1b consisted of only one rotamer, likely
due to the steric bulk of the tert-butyl group. It is important to
note that reagent 1b and the P-chiral N-nitroso-α-amino-
phosphine oxide 5c were thermally stable up to 230 °C;13 the
latter compound may represent a unique precursor of yet
undeveloped P-chiral P,N-nitroso bidentate ligands.15
Scheme 5. Synthesis of Substituted P-Stereogenic 2,3-
Dihydrobenzo[d][1,3]oxaphosphole 3-Oxides 6
a
We subsequently focused on the synthesis of 6a to evaluate our
strategy and optimize the conditions for the tandem diazonium
generation and cycloetherification reaction (Table 2). Treatment
Table 2. Optimization for Cycloetherification Reaction
a
Isolated yield; % ee was determined by chiral HPLC.
cyclohexane at room temperature afforded 6 with lower
enantiomeric purity (method A).
The P-chiral dihydrobenzooxaphosphole 3-oxide 12 was also
prepared using the same methodology (Scheme 6). It is
a
entry
solvent
DCM
acid
temp (°C)
time (h)
yield (%)
1
2
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TFA
rt
rt
rt
rt
rt
rt
rt
rt
rt
70
4
4
4
4
4
4
4
6
6
3
65
toluene
CH3CN
THF
60
3
27
Scheme 6. Synthesis of P-Chiral 3-tert-Butyl-2,3-
dihydrobenzo[d][1,3]-oxaphospholes
4
37
5
PhCl
71
6
ODCB
C6F6
69
7
69
8
hexane
cyclohexane
77
9
81 (74)
63 (60)
10
a
Estimated yield based on 31P NMR; isolated yield in parentheses.
noteworthy that compound 12 is the precursor of many efficient
P-stereogenic chiral phosphine ligands, such as BIBOPs,17a BI-
DIME,17b,c JoshPhos,17 AntPhos,17e LalithPhos,17f BoQPhos,17f
and POP.17g The precursor compound 11 was synthesized via
nitrosation of 10, which was previously prepared by tert-
butylamination of the corresponding iodide intermediate.
Treatment of 11 with various acidic conditions13 gave the
desired product 12 in addition to the side product 13, likely due
to a competing Friedel−Crafts alkylation reaction between the
electron-rich aromatic ring and tert-butyl cation eliminated
during deprotection of compound 11. Treatment of 11 with 5
equiv of TfOH in cyclohexane favored the formation of the side
product 13 (58% isolated yield, 91.6% ee), whereas changing the
solvent to DCM gave predominantly the desired product 12 in
62% isolated yield and 99:1 er.
Intrigued by the Friedel−Crafts side reaction, we decided to
probe the mechanism of the cycloetheration step (Scheme 7). In
the presence of TfOD, compound 6a was formed without any
observable amount of the α-deuterated analogue 6a′, suggesting
that the α-diazonium cation was generated directly via “path a”
without proton exchange at the C-α position (path b).
Additionally, a model reaction with substrate 5f, lacking the
nucleophilic o-methoxy group, led mainly to the formation of
compounds 14 (40% yield), 15, and 16 (Scheme 8).
of 5c with 3 equiv of TfOH in DCM gave compound 6a in 65%
yield (based on 31P NMR) after 4 h at room temperature (Table
2, entry 1). Other nonpolar solvents (entries 2, 5, 6, and 7) gave
fairly similar yields (60−70%). However, polar solvents gave
significantly lower yields (entries 3 and 4). A longer reaction time
with highly nonpolar solvents, such as hexane and cyclohexane,
gave slightly better yields (entries 8 and 9). Interestingly, under
the latter conditions, both the starting material and the product
were mostly insoluble, and vigorous stirring of the reaction
mixture had to be maintained. It is reasonable to assume that
decreasing the polarity of the solvent, as well as the
corresponding dielectric constant, decreases the extent of
solvation of the polar transition state (diazonium cation),
leading to fewer side reactions, without any adverse effects on the
efficiency of the intramolecular cycloetherfication.16 The use of
different acids also affected the enantiomeric purity of 6a. For
example, a 97.2:2.8 er was observed with TfOH (Table 2, entry
9), whereas >99.9:0.1 er and 60% isolated yield were observed
when neat TFA was used at 70 °C for 3 h (entry 10). Under two
optimized sets of conditions (Table 2, entries 9 and 10), a
number of other structurally diverse P-stereogenic dihydroben-
zooxaphosphole 3-oxides 6 were prepared in good yield and high
enantiomeric purity as shown in Scheme 5. Although all reactions
proceeded efficiently, use of neat TFA at 70 °C for 3 h provided 6
in high enantiomeric integrity, but in slightly diminished yield
(method B). Whereas, in some cases the use of TfOH in
In summary, we developed an effective acid-promoted, metal-
free tandem reaction for the in situ generation of a diazonium
cation and subsequent cycloetherification to give a series of
substituted benzofuran-3(2H)-ones and enantiopure P-stereo-
C
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demonstrating an innovative application of classical nitroso
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considered equivalent to a carbocation and, consequently, may
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00051.
Experimental procedures and characterization details
(PDF)
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(13) Details are available in the Supporting Information.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: steve.han@boehringer-ingelheim.com.
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*E-mail: youla.tsantrizos@mcgill.ca.
ORCID
Youla S. Tsantrizos: 0000-0002-6231-7498
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the Natural Sciences
and Engineering Research Council of Canada (NSERC) and
Boehringer-Ingelheim Pharmaceuticals, Inc.
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Org. Lett. XXXX, XXX, XXX−XXX