Rhodium-catalysed alkoxylation/acetalization of diazo compounds: One-step synthesis of highly functionalised quaternary carbon centres

Article abstract of DOI:10.1039/c5cc03903g

An intermolecular tandem reaction for the rapid build-up of densely functionalised α-alkoxy-β-oxo-esters has been developed. This novel process applies the easy to handle trimethyl orthoformate as a C1-building block in the rhodium(ii)-catalysed alkoxylation/acetalization of donor-acceptor substituted diazo compounds. The concomitant C-O/C-C bond formation reaction gives products with unique quaternary carbon centers, substituted by groups of different oxidation level (ester, protected aldehyde and alkoxide).

Full text of DOI:10.1039/c5cc03903g

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Rhodium-catalysed alkoxylation/ acetalization of diazo
compounds: One-step synthesis of highly functionalised
quaternary carbon centres
Received 00th January 20xx,
Accepted 00th January 20xx
Jola Pospech,a Alastair J. J. Lennoxa and Matthias Bellera*
DOI: 10.1039/x0xx00000x
www.rsc.org/
An intermolecular tandem reaction for the rapid build-up of catalyzed addition of
densely functionalised α-alkoxy-β-oxo-esters has been developed.
2
to 1a.
Br
Expected:
This novel process applies the easy to handle trimethyl
C(OMe)3
CO2Me
Br
orthoformate as a C1-building block in the rhodium(II)-catalysed
[RhII]
4
alkoxylation/acetalization of donor-acceptor substituted diazo
compounds. The concomitant C−O/C−C bond formaꢀon reacꢀon
gives products with unique quaternary carbon centers, substituted
by groups of different oxidation level (ester, protected aldehyde
and alkoxide).
N2
+
HC(OMe)3
Br
1a
CO2Me
OMe
OMe
2
Observed:
MeO2C OMe
3a
Rhodium(II) mediated C−C and C−X bond forming reacꢀons
Scheme 2. Upper: Multi-step synthesis of chiral α-(alk)oxy-β-oxo
esters. Lower: Synthesis of unstable α-hydroxy-β-oxo esters.
have proven to be
functionalization of organic molecules. Opportunities provided
by rhodium(II)-catalysed C C coupling chemistry have been
a
powerful approach to the
−
Hegedus (1992):
unravelled by the groups of Doyle,1 Padwa2 and Davies.3 Since
exploration in the field began, this strategy has been applied
to the synthesis of natural products and pharmaceuticals,
which has recently been extensively reviewed.4 However, with
limited exceptions,5 there remain gaps in the use of C1-
building blocks to construct functionalised molecules in a
controlled manner. Towards this end, we attempted to
implement C1-building blocks into molecular scaffolds applying
the logic of C-H bond functionalization.6 In terms of
rhodium(II)-catalysis we reasoned that an adequate C1-source
had to possess an electronically stabilised and sterically
accessible C-H bond, such as an unsubstituted acetal. We thus
considered a protocol employing trimethyl orthoformate as a
BnO
multiple
steps
S
R
OMe
OMe
CO2Me
BnO
R
S
N
hν
+
BnO
R
N
Cr(CO)5
O
5 examples,
34 - 69%
Fernandez, Lessaletta (2012):
t-Bu
tBu
carbonyl-ene
reaction
N
O
HClaq
Et2O
HO CHO
NH
N
+
N
HO
R
R
CO2Et
5 examples
yields not determined
R
CO2Et
H
H
CO2Et
the presence of a suitable Rh(II)catalyst. Having expected
direct insertion into the carbenoid, leading to orthoester
4,
potential precursor, where the insertion of
a rhodium
(Scheme 1), we were surprised to isolate
a different
compound. Full characterisation (1H- and 13C-NMR, HRMS, X-
ray crystallography7) of the resulting crystalline material
carbenoid into the isolated central C−H bond would grant
access to synthetically valuable derivatives.
We selected the readily accessible 4-bromophenyl
revealed that in place of C
−
H bond cleavage in the ortho ester,
diazoacetate
(
1a
)
as
a
model substrate. At ambient
) in
a
tandem alkoxylation/acetalization sequence occurred,
temperature, it was reacted with trimethyl orthoformate (
2
yielding a tertiary
product.
α
-alkoxy-
β-oxo-ester (3a) as the major
Scheme 1. Unexpected reaction outcome in the Rh-
Densely functionalized
α
-alkoxy-
β
-oxo-esters, such as 3a
,
are versatile and potentially important structures in synthetic
chemistry. Extensive studies and noteworthy advances have
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Table 1. Optimization of reaction conditions in the rhodium(II)- Table 2. Reaction scope in the rhodium(II)-catalyzed
catalyzed alkoxylation/acetalization (masked formylation) of alkoxylation/acetalization (masked formylation) of diazo
diazo compound 1a.
compounds (1).a,b
a
Reactions were carried out with 1a (0.2 mmol) and 2 (1.0 mmol). b Conversions
were determined by GC analysis; mesitylene was used as internal standard.
Values in parentheses indicate isolated yields. tpa := triphenylacetate;
esp := α,α,α′,α′-tetramethyl-1,3-benzenedipropionic
phenyl-sulfonyl-pyrrolidinecarboxylate;
nttl := N-(1,8-naphthaloyl)-tert-leucinate;
acid;
DOSP := dodecyl-
pttl := N-phthaloyl-tert-leucinate;
ptad := (1-adamantyl)-(N-
a
phthalimido)acetato; 2,2-DMB := 2,2-dimethylbutane.
Reaction conditions: a solution of 1 (0.4 mmol) and 2 (1.0 mmol) in CH2Cl2 (2
mL) was added dropwise (1 h) to a stirring solution of 2 (1.0 mmol) and Rh2(S-
b
been made to the synthesis of the related
α
-hydroxy-
β-the
pttl)4 (1.0 mol %) in CH2Cl2 (0.3 mL) at ambient temperature; isolated yields of
c
pure product are shown; reaction on 4.46 mmol scale with 0.5 mol % Rh2(S-
pttl)4; d PhCl at 60 °C; e PhCl at 80 °C with 10 equiv. 2; f 0.25 mmol scale.
ketone, the synthesis of tertiary α-(hydr/alk)oxy-β-oxo-esters
has been far less explored. To the best of our knowledge only
two reports extend to this composition of functionality
(Scheme 2). The earlier example, described by Hegedus and
co-workers,9 followed a chiral-pool approach to generate
optically active quaternary carbon centres using a photo-
induced addition of stoichiometric chromium-carbene
complexes to valine-derived thiazolines. Three further steps
were required to access the desired 2-methoxy-3-oxo-2-
propanoates in moderate yields and limited substrate scope.
More recently, Fernández and Lassaletta described a formal
carbonyl-ene reaction of formaldehyde tert-butyl hydrazone
with α-keto esters for the synthesis of the corresponding
C−O bond of trimethyl orthoformate, yielding 2-aryl-2-
methoxy acetate
5 as the major side product, whilst the
desired product was only formed in modest yield (entries 2-6).
Gratifyingly, C−C bond formation was more pronounced when
Rh2(esp)2 was employed as catalyst, yielding 3a in 41% isolated
yield at ambient temperature (entry 7). Further catalyst
screening revealed an enhanced activity for masked
formylation over the simple alkoxylation using Rh2(S-pttl)4
(entry 10) and Rh2(S-ptad)4 (entry 11). After other reaction
parameters were explored (entries 13-19), optimal results
were achieved using the air stable and easily prepared Rh2(S-
pttl)4 catalyst in dichloromethane (entry 17) at room
temperature. No improvement in the conversion was observed
when running the reaction at 0 °C or 40 °C. Higher yields were
recorded using an excess of the inexpensive trimethyl
orthoformate, and drop-wise addition of the diazo compound
was required to attenuate dimerization of the substrate.
Under these optimized conditions, a pure sample of 2,3,3-
trimethoxypropanoate (3a) was obtained in 84% isolated yield
after column chromatography.
carbinols.10 The unprotected
α-hydroxy-β-oxo-esters proved to
be unstable towards purification and only crude mixtures were
obtained. Thus, with protection of the aldehyde and hydroxyl,
there is lacking a straightforward and general method to
generate this type of quaternary carbon centre. Towards this
end, we report herein on the development of the first tandem
alkoxylation/masked formylation reaction via Rh(II)-catalyzed
concomitant C−O and C−C bond formaꢀon.
Experiments surveying the reaction conditions are
summarized in Table 1. The simple dirhodium carboxylate
complexes catalyzed insertion of the rhodium-carbenoid into a
With optimized reaction conditions in hand, the scope of
the tandem alkoxylation/acetalization reaction was explored
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enantiomeric excess was observed using the chiral rhodium
catalyst, pathways and can be disregarded.
(Table 2). Both methyl and ethyl esters led to the desired
product, albeit with a slight reduction in yield when using the
A
B
ethyl derivatives 1b and 1c 11
.
Halide substituted aryl substrates
were all reliably accommodated, providing valuable bromo-
3a and 3b), chloro- (3c and 3d) and fluoro (3e and 3f) bearing
Scheme 4. Possible mechanistic pathways for the alkoxylation/
acetalization (masked formylation) of diazo esters (1).
(
products in good yields. Ester, alkoxy, tosylate, mesylate and
boronic ester functionalities were also tolerated and gave
good yields of their corresponding products (3g, 3i-3l). A
modest yield was achieved in the unsubstituted substrate (3h),
which was found to improve when switching the conditions
from dichloromethane at 40 °C to chlorobenzene at 60 °C.
Competitive dimerization was more pronounced with electron-
donating substituents, nevertheless, utilizing
concentration of successfully attenuated the side-reaction
and alkoxy groups in the meta-position 3i were well
a greater
2
(
)
tolerated. We were discouraged into testing aryl moieties with
other ortho substituents, as they have been shown to give
beta lactones or undergo intramolecular cyclisation.12 Finally,
the process was found to up-scale well, as 1a was converted to
3a on a gram-scale and isolated in 86% yield using half the
normal amount (0.5 mol%) of rhodium catalyst. To our
surprise, the reaction was highly selective towards the
conversion of trimethylorthoesters, as higher analogues, such
as triethyl or tributyl orthoformates, did not serve as
competent coupling partners.
We were pleased to find that vinyldiazo acetate
6
was an
the
equally potent coupling partner in
alkoxylation/acetalization reaction.13 Hence, the dimethyl
glutaconoate derivative
(Scheme 3).
7 was obtained in 53% isolated yield
Pathways
C and D involve reversible formation of a planar
enolate,18 through which any stereochemical information
present in the ylide is lost. C−C bond formation can either
occur through a [1,2]-Stevens rearrangement or a stepwise
process involving formation of an ion pair. We initially
favoured separation of the intermediate, as three component
couplings involving interception of the ylide by external
electrophiles are well established.19 We reasoned that a simple
Scheme 3. Rhodium-catalyzed alkoxylation/acetalization of
dimethyl diazoglutaconoate (6), reaction performed on 0.2
mmol scale.
cross-over experiment employing
a
1:1 mixture of
undeuterated ([2H]0-2) and fully deuterated ([2H]10-2) trimethyl
ortho ester could elucidate this difference. Observation of
mixed products, such as D3-methoxy/dimethylacetal ([2H]3-3a
)
A
plausible mechanism for this rhodium(II)-catalyzed
masked-formylation of diazo compounds first involves the
formation of metal-carbenoid complex (Scheme 4),
and methoxy/D7-dimethylacetal ([2H]7-3a), would indicate a
separation of the catalytic intermediate into the ion pair. We
tested the reaction in four different solvents of varying
polarity, which would affect the tightness of the ion pair and
thus the degree of cross-over, and found (ESI-MS) no evidence
of any mixed products. Therefore, this strongly indicates that
a
concurrent with the observed exclusion of nitrogen gas. Rather
than the expected C−H bond insertion of the ortho ester it is
apparent that oxygen association to the electron deficient
carbenoid complex forms an oxonium ylide; a process well
known in the presence of ethers.14 We suggest this step to be
reversible, as greater concentrations of the ortho ester out-
competes irreversible dimerization of the carbenoid. When the
ylide forms from an alcohol, a proton shift occurs to displace
the metal.15 However, the clear lack of this oxygen-bound
proton in the ortho-ester opens the opportunity for
subsequent ylide rearrangement16 and C−C bond formation
the concerted pathway
D
is operational.20
There is significant potential to derivatise these
functionalised building blocks, as the orthogonal reactivity of
each functional group of the quaternary carbon can be
exploited (Scheme 5). More specifically, we showed that (a)
the acetal can be readily deprotected with I2 and acetone from
which the free aldehyde
anchor for a myriad of transformations. The ester group can be
(b) saponificated to or (c) selectively reduced to 10, a halide,
8 serves as an excellent chemical
through four possible pathways (A-D Scheme 4). A direct 1,2-
),17 would lead to product with some
Stevens rearrangement (
A
9
enantioselection. In addition, breakdown of the ylide and
subsequent stereospecific attack of the metal bound tight ion
pair (pathway B) would also lead to enantioselectivity. As no
or related functionality, attached to the phenyl moiety can be
subjected to a vast number of transformations, including (d) a
C−C cross-coupling (11). This latter reaction was further
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5
6
(a) H. M. L. Davies, Q. Jin, Org. Lett. 2004, 6, 1769
H. M. L. Davies, A. Ni, Chem. Commun. 2006, 3110
(a) A. Tlili, J. Schranck, J. Pospech, H. Neumann, M. Beller,
‒
1772; (b)
exemplified on an oestrone derivative (12) demonstrating the
ease by which the rapid build of functionality is attainable.
‒
3112.
Ang. Chem. Int. Ed. 2013, Angew. Chem. Int. Ed. 2013, 52,
Scheme 5. Upper: Useful synthetic building blocks prepared
from the derivatization of 3a; lower: Cross-coupling with an
oestrone derivative.21
6293
Neumann, M. Beller, Chem. Eur. J. 2014, 20, 3135
A. Tlili, J. Schranck, J. Pospech, H. Neumann, M. Beller,
ChemCatChem 2014, 6, 1562 1566.
−
6297; (b) J. Pospech, A. Tlili, A. Spannenberg, H.
−
3141; (c)
‒
7
8
Cambridge crystallographic database (CCDC) number for
compound 3a is 1043341.
(a) K. Mikami, M. Terada, T. Nakai, J. Am. Chem. Soc. 1989
111, 1940 1941; (b) K. Mikami, M. Terada, T. Nakai, J. Am.
Chem. Soc. 1990 112, 3949 3954; (c) K. Mikami, S.
Matsukawa, J. Am. Chem. Soc. 1993, 115, 7039 7040; (d) D.
A. Evans, C. S. Burgey, N. A. Paras, T. Vojkovsky, S. W. Tregay,
J. Am. Chem. Soc. 1998, 120, 5824 5825; (e) J. Hao, M.
Hatano, K. Mikami, K. Org. Lett. 2000, 2, 4059 4062; (f) K.
Ding, Y. Yuan, X. Zhang, Angew. Chem. Int. Ed. 2003, 42,
5478 5480; (g) G. E. Hutson, A. H. Dave, V. H. Rawal, Org.
Lett. 2007, 9, 3869 3872; (h) J. F. Zhao, H. Y. Tsui, P. J. Wu, J.
Lu, T. P. Loh, J. Am. Chem. Soc. 2008, 130, 16492 16493.
D. K. Thompson, Suzuki, N.; Hegedus, L. S.; Satoh, Y. J. Org.
Chem. 1992, 57, 1461 1467.
,
‒
,
‒
‒
‒
‒
‒
‒
‒
9
‒
10 A. Crespo-Peña, D. Monge, E. Martín-Zamora, E. Álvarez, R.
Fernández, J. M. Lassaletta, J. Am. Chem. Soc. 2012, 134,
12912‒12915.
11 In these cases, intramolecular C
‒
H bond insertion into the
ester side-chain yielding 4-membered lactones is competitive
with ylide formation. Use of a tert-butyl ester led to a
lactone side-product formed through C-H activation and
cyclisation with the rhodium carbenoid.
In summary, we have discovered a Rh(II)-catalyzed tandem
methoxylation/acetalization reaction using donor-acceptor
12 (a) 2-Methoxyphenyl diazoacetate underwent Rh(II)
catalysed C-H bond insertion and intramolecular cyclisation,
see H. M. L. Davies, M. V. A. Grazini, E. Aouad Org. Lett.,
2001, 3, 1475–1477; (b) Fu, H. Wang, H. M. L. Davies, Org.
Lett., 2014, 16, 3036–3039.
substituted diazo compounds (
1) and trimethyl orthoformate
(
2). The developed methodology represents a rare example of
an intermolecular tandem C−O bond formaꢀon and masked-
formylation, through C−C bond formaꢀon.
13 Cyclohexyl diazoacetate and TMS-ethynyl diazoacetate did
not yield the desired product.
The authors are grateful to Dr. Anke Spannenberg for the
assistance with X-ray crystallography. A. J. J. L would like to
thank the Alexander von Humboldt foundation for generous
funding.
14 Representative examples: (a) Z. Li, B. T. Parr, H. M. L. Davies,
J. Am. Chem. Soc. 2012, 134, 10942−10946; (b) Z. Li, V.
Boyarskikh, J. H. Hansen, J. Autschbach, D. G. Musaev, H. M.
L. Davies, J. Am. Chem. Soc. 2012, 134, 15497−15504; (c) S.
Kitagaki, Y. Yanamoto, H. Tsutsui, M. Anada, M. Nakajima, S.
Hashimoto, Tetrahedron Lett. 2001, 42, 6361–6364; (d) for a
similar intramolecular reaction using cyclic orthoesters see:
A. Oku, M. Numata, J. Org. Chem. 2000, 65, 1899−1906.
15 R. Paulissen, H. Reimlinger, E. Hayez, A. J. Hubert, P. Teyssié,
Tetrahedron Lett., 1973, 14, 2233–2236.
16 M. P. Doyle, J. H. Griffin, M. S. Chinn, D. V. Leusen, J. Org.
Chem., 1984, 49, 1917–1925
Notes and references
1
Reviews: (a) M. P. Doyle, M. A. McKervey, T. Ye, T. Modern
Catalytic Methods for Organic Synthesis with Diazo
Compounds; Wiley: New York, 1998. (b) M. P. Doyle, Acc.
Chem. Res. 1986, 19, 348-356; (c) M. P. Doyle, D. C. Forbes,
Chem. Rev. 1998, 98, 911‒936; (d) M. P. Doyle, R. Duffy, M.
Ratnikov, L. Zhou, Chem. Rev. 2010, 110, 704‒724; selected
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Doyle, Angew. Chem. Int. Ed. 2012, 51, 5907-5910; (f) Y.
Qian, X. Xu, X. Wang, P. J. Zavalij, W. Hu, M. P. Doyle, Angew.
Chem. Int. Ed. 2012, 51, 5900-5903; (g) X. Wang, X. Xu, P. Y.
Zavalij, M. P. Doyle, J. Am. Chem. Soc., 2011, 133, 16402–
16405
17 T. H. Eberlein, F. G. West, R. W. Tester, J. Org. Chem. 1992
57, 3479 3482.
,
−
18 Calculations have shown this process to be reversible and
that the neutral dirhodium complex is released from the
ylide easier than copper complexes, see: Y. Liang, H. Zhou, Z.-
X. Yu, J. Am. Chem. Soc., 2009, 131, 17783–17785.
19 (a) C.-D. Lu, H. Liu, Z.-Y Chen, W.-H.: Hu, A.-Q. Mi., Org. Lett.
2005, 7, 83-86; (b) H. Huang, X. Guo, W. Hu, Angew. Chem.
Int. Ed., 2007, 46, 1337–1339; (c) X. Zhang, H. Huang, X. Guo,
X. Guan, L. Yang, W. Hu, Angew. Chem. Int. Ed., 2008, 47,
2
3
4
(a) A. Padwa, S. F. Hornbuckle, Chem. Rev. 1991, 91, 263
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1996, 96, 223 270.
(a) H. M. L. Davies, R. E. J Beckwith, Chem. Rev. 2003, 103,
2861 2903. (b) H. M. L Davies, J. R. Manning, Nature 2008
451, 417 424. (c) H. M. L Davies, J. R. Denton, Chem. Soc.
Rev. 2009, 38, 3061 3071.
(4) (a) J. Egger, E. M. Carreira, Nat. Prod. Rep. 2014, 31,
‒
,
‒
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6647−6649; (d) W. Hu, X. Xu, J. Zhou, W. Liu, H. Huang, J. Hu,
L. Yang, L. Gong, J. Am. Chem. Soc. 2008, 130, 7782−7783.
See also references 2a and 13.
‒
,
‒
20 For a similar mechanistic example see: H. M. L. Davies, J.
Yang, J. Nikolai, J. Organomet. Chem., 2005, 690, 6111 6124.
21 Cambridge crystallographic database (CCDC) numbers for
compounds, 11 and are 1043342 and 1043343.
‒
−
449
45, 923
Rev. 2011, 40, 1857
−
455;(b) H. M. L.Davies, Y. Lian, Acc. Chem. Res. 2012
,
9
−
935; (c) H. M. L. Davies, D. Morton, D. Chem. Soc.
1869.
−
4 | J. Name., 2012, 00, 1-3
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