Catalytic conversion of diazocarbonyl compounds to imines: Applications to the synthesis of tetrahydropyrimidines and β-lactams

Article abstract of DOI:10.1021/ol403427s

The synthesis of α-carbonylimines by rhodium(II)-catalyzed reactions of α-diazoesters and organic azides has been developed and applied in hetero-Diels-Alder reactions to form highly functionalized tetrahydropyrimidines and in a one-pot, multicomponent transformation between aryldiazoacetates, p-anisyl azide, and an enonediazoacetate to produce β-lactams in high yields and diastereoselectivities.

Full text of DOI:10.1021/ol403427s

Letter
pubs.acs.org/OrgLett
Catalytic Conversion of Diazocarbonyl Compounds to Imines:
Applications to the Synthesis of Tetrahydropyrimidines and
β‑Lactams
Michael D. Mandler, Phong M. Truong, Peter Y. Zavalij, and Michael P. Doyle*
Department of Chemistry & Biochemistry, University of Maryland, College Park, Maryland 20742, United States
S
* Supporting Information
ABSTRACT: The synthesis of α-carbonylimines by rhodium-
(II)-catalyzed reactions of α-diazoesters and organic azides has
been developed and applied in hetero-Diels−Alder reactions to
form highly functionalized tetrahydropyrimidines and in a one-
pot, multicomponent transformation between aryldiazoace-
tates, p-anisyl azide, and an enonediazoacetate to produce β-
lactams in high yields and diastereoselectivities.
he selective preparation of imines in organic compounds
Thaving multiple carbonyl functional groups is a daunting
task in view of the common condensation methodology
employed for imine synthesis.1 Azides are well-known to
form transition metal imido complexes ([MLn]NR) through
coordination with the metal complexes2 followed by dinitrogen
extrusion. The mechanism of this transformation has been a
subject of continuing interest.3−5 Electrophilic metal complexes
coordinate with the internal nitrogen of the azide to initiate the
elimination of dinitrogen,5 and this mechanistic pathway is
operational in catalytic metal nitrene reactions.6 However, there
are few examples for this selective transformation with ketones
or derivative functional groups, and all of them have been
intramolecular reactions. Zakarian and Pelc have employed a
Staudinger reduction of an azide with Me3P for the synthesis of
the α,γ-spirobicyclic ring system of pinnatoxins and pteriatox-
ins,7 but reaction conditions (refluxing toluene) and the modest
yield (51%) limit broader applicability. In their presentation of
metal catalyzed intramolecular reactions of indoline diazo-
amides, Wee and Slobodian reported for the first time two
examples of rhodium(II) acetate catalyzed conversion of a
diazocarbonyl compound to an imine (1→2) from the reaction
with an internal azide (Scheme 1).8 With Wee’s report as
precedent, Micouin, Lecourt and co-workers employed the
same transformation to prepare a surrogate of 2-deoxystrept-
amine 3,9 but these are the only reports for this transformation.
With the limited number of examples of this potentially
useful transformation available, we decided to investigate the
scope of the reaction with a broad selection of diazocarbonyl
compounds and azides, determine the optimum catalyst for this
transformation, and provide examples of reaction processes that
effectively utilize α-carbonylimines. The latter search has taken
us to [4 + 2]- and [2 + 2]-cycloaddition processes that employ
α-carbonylimines for the formation of tetrahydropyrimidines
and β-lactams in high yield and with a high degree of selectivity.
Initial efforts were directed toward reactions of methyl
diazoacetoacetate 4a with a stoichiometric amount of p-anisyl
azide 5a catalyzed by rhodium acetate. Because diazoaceto-
acetates, as examples of acceptor/acceptor diazo compounds,10
are relatively stable to reactions with Lewis acids and less
selective than aryl- and vinyl-diazoacetates in metal carbene
transformations, they are suitable substrates for examination of
the feasibility of the transformation. Because the product
formed in the transformation with azide is an α-ketoimine, its
formation would demonstrate a unique advantage over
traditional methods for imine formation. Reactions at room
temperature were sluggish due to imine coordination with the
moderately Lewis acidic Rh2(OAc)4, but in refluxing dichloro-
methane, imine 6a was produced in moderate yield (Table 1,
entry 1). Alternative uses of CuPF6 and Cu(OTf)2 were
examined but, although dinitrogen loss from 4a was observed,
azide 5a remained intact (entries 2−3). Lower yields of 6a were
obtained with the more soluble Rh2(oct)4 and with the less
Lewis acidic Rh2(cap)4 (entries 4−5). A reaction performed at
80 °C in refluxing DCE provided 6a in only 45% yield (entry
6). In all cases with stoichiometric 4a and 5a, a fraction of azide
5a remained. By increasing the amount of 4a to 1.2 and 1.5
Scheme 1. Previous Examples of Rhodium Catalyzed
Formation of Imines
Received: November 26, 2013
Published: January 14, 2014
© 2014 American Chemical Society
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Letter
a
yield of 6d was obtained after chromatography (entry 4). With
donor/acceptor carbene precursors,10 such as phenyldiazoace-
tate 4b, the reaction was complete within an hour and gave 6e
in 97% isolated yield (entry 5). With aryldiazoacetates 4 (R1 =
Ar) isolated yields were all above 81% (entries 5−12). When R1
= COOMe, which is less electron-withdrawing than Ac, imine
6m was obtained in 60% yield (entry 13). Diazoacetoacetate 4i
containing a remote ketone functional group gave an expected
moderate yield of imine 6n (entry 14). Enoldiazoacetate 4j,
whose metal carbene intermediate normally undergoes
nucleophilic attack at the vinylogous carbon, reacted with the
azide at the metal carbene carbon to give the corresponding
azadiene 6o in moderate yield (entry 15).
We envisioned that the highly functionalized 1-azadiene 6o
that can be accessed via the diazo-nitrene exchange method-
ology would be a good candidate for the aza-Diels−Alder
reaction. However, since 6o was only obtained in moderate
yield from enoldiazoacetate 4j, an alternative route involving
treatment of imine 6a with triethylamine and TBSOTf
generated 6o in 95% yield and only required aqueous workup
(Scheme 2).
Table 1. Optimization of Imine Formation
b
entry
catalyst (mol %)
temp (°C)
solvent
yield (%)
1
2
3
4
5
6
7
8
Rh2(OAc)4 (1)
CuPF6 (5)
40
40
40
40
80
80
40
40
DCM
DCM
DCM
DCM
DCE
59
NR
NR
43
Cu(OTf)2 (5)
Rh2(oct)4 (1)
Rh2(cap)4 (1)
Rh2(OAc)4 (1)
Rh2(OAc)4 (1)
Rh2(OAc)4 (1)
22
DCE
45
c
DCM
DCM
68
d
68
a
A solution of diazo compound (1.0 equiv) was added over 1 h via
syringe pump to a solution containing azide (1.0 equiv) and catalyst
and stirred for an additional 24 h under a nitrogen atmosphere.
Isolated yield after column chromatography. 1.2 equiv of diazo
b
c
d
compound was used. 1.5 equiv of diazo compound was used.
equiv, relative to 5a, the reaction yield improved to 68%
(entries 7−8).
Scheme 2. Alternative Route to 1-Azadiene 6o
The generality of this process was evaluated under these
optimized conditions with a selection of azides and diazo
compounds (Table 2). Product yields were sequentially lower
with phenyl azide and p-nitrophenyl azide (entries 2, 3) than
with p-methoxyphenyl azide, suggesting the importance of
azide nucleophilicity on the outcome of the reaction. The
reaction with benzyl azide produced imine 6d cleanly prior to
workup; however, 6d was prone to isomerization on silica that
formed the corresponding benzylideneimine, and only a 53%
With functionalized 1-azadiene 6o in hand we discovered
that 1,2,3,4-tetrahydropyrimidines 8 were readily formed in
high yield via a Lewis acid catalyzed [4 + 2]-cycloaddition
reaction between 6o and imines 7 (Table 3). Under optimized
a
Table 2. Reaction Scope and Limitations
a
Table 3. Synthesis of Tetrahydropyrimidines
b
entry
Ar
C6H5
8
yield (%)
1
2
3
4
5
6
7
8a
8b
8c
8d
8e
8f
91
88
90
82
82
75
72
4-BrC6H4
4-NO2C6H4
2-naphthyl
4-CH3C6H4
2-ClC6H4
4-MeOC6H4
8g
a
To a solution containing 6o (0.20 mmol) and imine 7 (0.24 mmol,
1.2 equiv) in DCM (1 mL) under a N2 atmosphere, at 0 °C, was added
Zn(OTf)2 (10 mol %), and the mixture was stirred for 36−48 h.
b
Isolated yield after column chromatography.
conditions (see Supporting Information), the reaction between
6o and imine 7a catalyzed by 10 mol % Zn(OTf)2 provided
tetrahydropyrimidine 8a in 91% yield (Table 3, entry 1).
This transformation tolerated a broad selection of aryl imines
7, including those with electron-donating, electron-withdraw-
ing, halogen, and ortho substituents (Table 3, entries 1−7). To
our knowledge, this is the first example of the aza-Diels−Alder
reaction involving imines in both the diene and dienophile.11
This methodology provides an efficient route to highly
functionalized tetrahydropyrimidines, a class of molecules
a
b
Reactions were performed as described in Table 1. Isolated yield
after column chromatography.
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whose members have anti-inflammatory and antimicrobial
properties.12
Scheme 4. One-Pot Multicomponent Synthesis of β-Lactam
10
In our efforts to form the imine product when
enonediazoacetate 4k was reacted with azides we confirmed
that this diazo compound undergoes a catalyst promoted Wolff
rearrangement, first reported by Taylor and Davies,13 to form
ketene 9 and does not react with the azide (Scheme 3). Since 9
Scheme 3. Wolff Rearrangement of 4k and [2 + 2]
Cycloaddition to β-Lactam 10a
requires highly selective and sequential dinitrogen extrusion
from the diazo compounds with initial reaction with phenyl-
diazoacetate to form the imine intermediate followed by the
Wolff rearrangement with 4k and subsequent cycloaddition.
Reaction with 4-methoxyphenyldiazoacetate 4d, also conducted
at 40 °C, cleanly provided 10c in 99% yield, and 4-
chlorophenyldiazoacetate 4e gave 10g in nearly quantitative
yield from the reaction conducted at room temperature.
In conclusion, we have developed a mild and chemoselective
process for the synthesis of imines via a formal nitrene
replacement of dinitrogen by the combination of diazocarbonyl
compounds and azides. The azadiene formed from enoldiazo-
acetate 4j undergoes highly efficient hetero-Diels−Alder
reactions with imines to form tetrahydropyrimidines. The
ketene formed catalytically from enonediazoacetate 4k under-
goes a Staudinger reaction with α-carbonylimines to yield
functionalized β-lactam derivatives. The efficiency and yield of
β-lactams formed from aryldiazoacetates were nearly quantita-
tive in multicomponent reactions with p-anisyl azide and
enonediazoacetate 4k, catalyzed by dirhodium(II) acetate.
is moderately stable under these reaction conditions, we
envisioned that subsequent treatment with imine 6e would be
possible, and, indeed, [2 + 2]-cycloaddition between 9 and 6e
yielded β-lactam 10a as a single diastereomer. Structural
assignment of 10a was confirmed by single crystal X-ray
analysis (see Supporting Information).
Other α-carbonylimines 6 formed from diazoesters were also
reacted with 9 by this application of the Staudinger
reaction,14,15 and these results are reported in Table 4. The
a
Table 4. Synthesis of β-Lactams 10
ASSOCIATED CONTENT
* Supporting Information
■
S
General experimental procedures, the X-ray crystal structure of
10a, and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: mdoyle3@umd.edu.
Notes
a
A solution containing 4k (0.43 mmol, 1.2 equiv), imine 6 (0.36
The authors declare no competing financial interest.
mmol, 1.0 equiv), and Rh2(OAc)4 (1 mol %) in 2 mL of DCM was
b
stirred for 1 h at 40 °C. Isolated yield after column chromatography.
c
Diastereoselectivity was determined by 1H NMR spectroscopic
ACKNOWLEDGMENTS
■
analysis of the unpurified reaction mixture.
The authors are grateful to the National Science Foundation
(CHE1212446) for support of this research. M.D.M. thanks the
Arnold and Mabel Beckman Foundation for a Beckman Scholar
Award.
reaction is general toward electron-donating and -withdrawing
R1 and R2 substituents on imine 6, providing high yields and
diastereoselectivities (Table 4, entries 1−4). When R1 = Ac, a
high yield of β-lactam was obtained but with essentially no
diastereoselectivity (entry 5). When R1 = silylenol 6o, 10f was
produced in 85% yield with dr >20:1, providing a highly
functionalized β-lactam (entry 6) suitable for further
elaboration.
To ascertain if the overall transformation could be performed
as a one-pot reaction, phenyldiazoacetate 4b, azide 5a,
enonediazoacetate 4k, p-anisyl azide, and rhodium acetate
were stirred at 40 °C for 2 h to give 10a in remarkably high
yield and diastereoselectivity (Scheme 4). This transformation
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