Unexpected rearrangements of rhodium carbenoids containing a pyrrolidin-1-yl group

Article abstract of DOI:10.1016/j.tetlet.2014.02.132

Ketone- and ester-substituted diazo compounds, which contain a pyrrolidine moiety were treated with dirhodium tetraacetate generating the corresponding rhodium carbenoids. They were expected to insert into a CH bond of the pyrrolidine moiety but reacted differently. The ketone-substituted rhodium carbenoid underwent a Wolff rearrangement. The resulting ketene continued to react by lactamization and electrocyclic ring-opening and gave an acrylamide. The ester-substituted rhodium carbenoid underwent a [1.2]-shift of the (pyrrolidin-1-yl)methyl moiety, which resulted in a methacrylic ester. For each rearrangement a mechanism is suggested.

Full text of DOI:10.1016/j.tetlet.2014.02.132

Tetrahedron Letters 55 (2014) 2629–2632
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Unexpected rearrangements of rhodium carbenoids containing
a pyrrolidin-1-yl group
⇑
Julian Diehl, Reinhard Brückner
Institut für Organische Chemie, Albert-Ludwigs-Universität, Albertstraße 21, 79104 Freiburg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Ketone- and ester-substituted diazo compounds, which contain a pyrrolidine moiety were treated with
dirhodium tetraacetate generating the corresponding rhodium carbenoids. They were expected to insert
into a CAH bond of the pyrrolidine moiety but reacted differently. The ketone-substituted rhodium carb-
enoid underwent a Wolff rearrangement. The resulting ketene continued to react by lactamization and
electrocyclic ring-opening and gave an acrylamide. The ester-substituted rhodium carbenoid underwent
a [1.2]-shift of the (pyrrolidin-1-yl)methyl moiety, which resulted in a methacrylic ester. For each
rearrangement a mechanism is suggested.
Received 25 January 2014
Revised 25 February 2014
Accepted 28 February 2014
Available online 11 March 2014
Keywords:
a-Diazoketone
Ó 2014 Elsevier Ltd. All rights reserved.
a-Diazocarboxylic ester
CAH insertion
Acrylamide
Methacrylic ester
N2
Intramolecular insertions of rhodium carbenoids into appropri-
ately located CAH bonds have been employed frequently for estab-
lishing isocyclic or heterocyclic compounds of ring-sizes 4–6.1 In
particular, this is also true for converting diazocarbonyl and/or
-carboxyl compounds into azetidines,2,3 pyrrolidines,4,5 and piper-
idines.6 These substrates react with Rh2(OAc)4 or related catalysts
O
cat. Rh2(OAc)4,
benzene, reflux
O
O
O
O
O
O
O
N
N
60%
N
(ref.6)
S
S
1
2
N2
cat. Rh2(OAc)4,
CH2Cl2, rt
x
to give a carbenoid. The latter inserts into the C AH bond of a
66%
N
(ref.9)
a
x
x
x-1
(N@N@)C AÁ Á ÁAN -1AC AH moiety, wherein N
represents an
Pr
Pr
endocyclic nitrogen atom at positions N , Nd, or N , respectively.
c
e
O
O
3
4
Related ring-closures are conceivable for creating pyrrolidines7 or
1.0 eq. Cu,
benzene, 80°C
N2
x
piperidines by inserting carbenoids into the C AH bond of
O
O
N
N
N
x
x
-2- or N -3-containing chains. We wondered whether the lim-
100%
(ref.4)
O
O
N
5
6
ited precedence for pyrrolidine-furnishing syntheses based on such
a strategy lends itself to embellishment and generalization. That
would be of considerable interest for synthesizing pyrrolizidine
and indolizidine alkaloids.8
The only pyrrolidone synthesis by the mentioned approach, of
which we are aware4 is exemplified in line 3 of Scheme 1. Unless
this transformation is a multistep process, namely an Ar-SE reac-
tion, it should proceed as a 1-step insertion (and affect a Csp2AH
rather than a Csp3AH bond like in a more general illustration of
the principle). Considering the pyrrolidone formation 5?6,4 the
analogous piperidone formation 3?49 (line 2; another—at least
Rx
Rx
N2
cat. Rh2(OAc)4
N
(this work)
Ry
Ry
?
7
8
Scheme 1. Diazoketone-based CAH insertion approaches to indolizidinones and
pyrrolizidones. Enthält bei 1?2 lit.6, bei 34 lit.9 und bei 5?6 lit.4
synthesis 126 (line 1; a genuine insertion into a Csp3AH bond) alto-
gether nonetheless motivated to develop a general pyrrolidone ap-
proach by CAH insertion.
formal—insertion into
a Csp2AH bond), and the piperidone
Three specialized realizations of the carbenoid insertion ap-
proach to C@O-substituted pyrrolidines are shown in lines 1–3 of
Scheme 2, the term ‘specialized’ alluding to the bridging unit being
⇑
Corresponding author. Tel.: +49 7612036029; fax: +49 7612036100.
E-mail address: reinhard.brueckner@organik.chemie.uni-freiburg.de (R. Brückner).
http://dx.doi.org/10.1016/j.tetlet.2014.02.132
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

2630
J. Diehl, R. Brückner / Tetrahedron Letters 55 (2014) 2629–2632
tBuMe2SiO
tBuMe2SiO
tBuMe2SiO
tBuMe2SiO
O
Rh2(OAc)4,
CH2Cl2, rt
O
OR
O
N2
O
cat. Rh2(OAc)4,
CH2Cl2, rt
N2
O
OR
OR
O
O
N
N
O
N
N
95%
22
21%
26
(ref.5a
)
9
10
tBuMe2SiO
tBuMe2SiO
6.44 ppm
6.42 ppm
129 H
N ppm
129 H
N ppm
O
O
5.65 ppm
5.67 ppm
128 ppm
O
O
O
O
OR
H
H
O
O
O
O
cat. Rh2(OAc)4,
CH2Cl2, rt
N2
165 ppm
127 ppm
165 ppm
TsN
TsN
O
H
O
H
6.35 ppm
6.37 ppm
N
N
96%
27
28
(ref.5d
)
11
12
Scheme 4. Unexpected conversion of diazoketone 22 into acrylamide 28. NMR
comparison of the latter with the reference compound 27.
O
O
O
O
0.5 eq. CuOTf,
CHCl3, reflux
N2
O
51% 15
N
O
N
(ref.5d
)
8 once it would have advanced to a rhodium carbenoid. Similarly,
line 4 of Scheme 2 specifies our second speculation based on the
heterocycle-forming CAH insertions shown in lines 1–3: A CAH
insertion should transform the rhodium carbenoid derived from
diazoester 16 into the alkoxycarbonyl-substituted pyrrolizidine 17.
A diazoketone 22, which stands for the type-7 diazoketones de-
duced in Scheme 1, and a diazoester 24, which represents the type-
16 diazoesters deduced in Scheme 2, were synthesized readily
13
14
(C C)
15 (C C)
O
O
OR
Rx
Rx
N2
cat. Rh2(OAc)4
OR
N
N
(this work)
Ry
Ry
?
16
17
(Scheme 3). The N-benzylimide of L-tartaric acid was prepared as
Scheme 2. Diazoester-based CAH insertion approaches to pyrrolizidines and a
related approach from a diazoketone. Enthält bei 9?10 lit.5a und bei 11?12 lit.5d
und bei 13?15 lit.5e
described.10 O-tert-Butyldimethylsilylation followed by borane
reduction furnished the known N-benzylpyrrolidine 18,11 which
was debenzylated as described (?1911). Bromodiazoacetone
(2112)—prepared from bromoacetyl bromide (26) not with diazo-
methane12 but with (trimethylsilyl)diazomethane—and pyrroli-
dine 19 accomplished diazoketone 22 after a total of 5 steps.
configurationally locked rather than mobile. The synthesis of the
C@O-substituted pyrrolidine 10 from 95 (Scheme 2, line 1) spear-
headed a number of stereochemical studies5b,c and provided the
concept for the related insertion 11?125d (line 2). The C@O-substi-
tuted ‘pyrrolidine’ 14 must have been reached by a similar Csp3AH
insertion, that is, from 136 (line 3). However, 14 proceeded to react
by in situ oxidation, furnishing indole 15 as the only isolated cycli-
zation product.
Line 4 of Scheme 1 shows how we extrapolated the common
demoninator of the heterocycle-forming CAH bond insertions
listed in the preceding lines: We surmised that an analogous
CAH insertion allows diazoketone 7 to proceed to pyrrolizidinone
tBuMe2SiO
tBuMe2SiO
tBuMe2SiO
tBuMe2SiO
N2
N
N
O
O
22
28
+ Rh2(OAc)4, − N2
β-elimination *
tBuMe2SiO
tBuMe2SiO
tBuMe2SiO
Rh1-2(OAc)n
O
tBuMe2SiO
O
N
N
β
α
29
tBuMe2SiO
tBuMe2SiO
HO
HO
O
31a
acylation
1) BnNH2; 70% (81%10
)
tBuMe2SiO
tBuMe2SiO
O
~[1.2]
OH
OH
2) tBuMe2SiCl, imidazole; 97%
3) BH3 . THF; 93%
NR
N
O
L
-tartaric acid
1811: R = Bn
1911: R = H
30
H2, Pd(OH)2/C; 99% (100%11
)
* There seems to be no appropriate orbital overlap for a β-elimination. It is
hence suggested that ring-opening proceeds by an electrocyclic process:
tBuMe2SiO
N2
Br
σ
O
σ
O
σO
Me3SiCH=N2; 79%
N2
tBuMe2SiO
O
Br
O
O
N
σ
O
σ
O
σO
89%
Br
O
N
O
N
N
O
20
2112
22
31b (σ = tBuMe2Si)
Cf. ref.17
28a (σ = tBuMe2Si) 28
CO2Et
tBuMe2SiO
tBuMe2SiO
:
PMP
CO2Et
CO2Et
OSi(iPr)3
Br
K2CO3, MeCN; 78%
PMP
R
OSi(iPr)3
N
OSi(iPr)3
R
tBuMe2SiO
tBuMe2SiO
PMP
+
Ln(OTf)3
N
N
N
NH
(cat.)
19
23
R
Bu
Bu
Bu
LDA, then HCO2Et; 81%
OH
32
33
34
35
hydrolytic workup
PMP
tBuMe2SiO
tBuMe2SiO
tBuMe2SiO
tBuMe2SiO
N2
CO2Et
PMP
R
O
HN
O
R
N
N
N
24
25
Bu
Bu
DBU, p-AcNH-C6H4-SO2N3; 78%
36
37
Scheme 3. The synthesis of diazoketone 22 and diazoester 24. Enthält bei Schritt-
#1 lit.10, bei Verbindung 18 lit.11, bei Verbindung 19 lit.11, bei 1819 lit.11 und bei
Verbindung 21 lit.12
Scheme 5. Rationalization of the formation of acrylamide 28 from diazoketone 22
via carbenoid (carbene complex) 29 as an intermediate. Enthält im Kasten lit.17

J. Diehl, R. Brückner / Tetrahedron Letters 55 (2014) 2629–2632
2631
tBuMe2SiO
tBuMe2SiO
tBuMe2SiO
tBuMe2SiO
CO2Et
When we stirred a solution of diazoester 24 in CH2Cl2 at room
temperature the substrate was consumed within 18 h as judged
from monitoring by TLC (Scheme 6). Flash-chromatography on sil-
ica gel13 gave 45% of methacrylate 40 and none of the ester-substi-
tuted pyrrolizidine 26. This was concluded from characteristic 1H
and 13C NMR data and their analogies to the reference compound
39. Assuming that diazoester 24 reacts via the rhodium carbenoid
42 (Scheme 7) a [1.2]-shift of the (pyrrolidin-1-yl)methyl moiety
leads to the observed product 40. This is distinctly different than
how the analogous rhodium carbenoid 43 reacts. Its reaction coor-
dinate bifurcates between a CAH insertion (?41) and a [1.2]-shift
of another hydrogen atom (?44).18 Juxtaposing the respective
[1.2]-shifts it seems that the electron-donor character of the nitro-
gen atom in the pyrrolidine improves the migration ability of the
aminoalkyl moiety in comparison with the hydrogen.
In summary, the rhodium carbenoids 29 and 42 behaved in
unprecedented manners. The ketone-substituted carbenoid 29
rearranged in several steps to deliver acrylamide 28 (Scheme 5).
The ester-substituted carbenoid 42 underwent a [1.2] alkyl shift,
which provided methacrylate 40 (Scheme 6). Both rearrangements
proceeded at the expense of C,H insertions giving pyrrolizidinone
26 (Scheme 4) or the ester-substituted pyrrolizidine 10 (Scheme 6),
respectively.
Rh2(OAc)4,
CH2Cl2, rt
N2
CO2Et
N
N
45%
24
38
tBuMe2SiO
139
138
CO2Et
CO2Et
tBuMe2SiO
N ppm
H
N ppm
H
6.25 ppm
126 ppm
6.26 ppm
56 ppm
57 ppm
126 ppm
H
H
H H
H
H
5.77 ppm
5.78 ppm
3.33 ppm
3.24 and 3.40 ppm
39
40
Scheme 6. Unexpected conversion of diazoester 24 into methacrylate 40. NMR
comparison of the latter with the reference compound 39.
tBuMe2SiO
tBuMe2SiO
CO2Me
Cf. re f.18
:
Pent
N2
CO2Et
N
24
+ Rh2(OAc)4, − N2
CO2Et
41
45.5% C−H insertion
tBuMe2SiO
CO2Me
H
H
Pent
Rh1-2(OAc)n
Rh1-2(OAc)n
tBuMe2SiO
N
H
Why these peculiar rearrangements materialized and the de-
sired CAH insertions not, remains unclear. Accordingly, there is
no clue yet about how to substitute a pyrrolidine-containing diazo
compound such that it undergoes the same kinds of rearrange-
ments or subsides to our CAH insertion strategy.
42
only ~[1.2] α-aminoalkyl
tBuMe2SiO
43
47 .5% ~[1.2 ] H
CO2Me
CO2Et
tBuMe2SiO
N
Oct
40
44
Supplementary data
Scheme 7. Rationalization of the formation of methacrylate 40 from diazoester 24
via carbenoid (carbene complex) 42 as an intermediate. Enthält im Kasten lit.18
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.02.
132.
Alternatively, pyrrolidine 19 was N-alkylated with ethyl 4-bromo-
References and notes
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a-
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