Ruthenium-porphyrin-catalyzed diastereoselective intramolecular alkyl carbene insertion into C-H bonds of alkyl diazomethanes generated in situ from N-tosylhydrazones

Article abstract of DOI:10.1002/anie.201408102

With a ruthenium-porphyrin catalyst, alkyl diazomethanes generated in situ from N-tosylhydrazones efficiently underwent intramolecular C(sp³)-H insertion of an alkyl carbene to give substituted tetrahydrofurans and pyrrolidines in up to 99% yield and with up to 99:1 cis selectivity. The reaction displays good tolerance of many functionalities, and the procedure is simple without the need for slow addition with a syringe pump. From a synthetic point of view, the C-H insertion of N-tosylhydrazones can be viewed as reductive coupling between a C=O bond and a C-H bond to form a new C-C bond, since N-tosylhydrazones can be readily prepared from carbonyl compounds. This reaction was successfully applied in a concise synthesis of (-)-pseudoheliotridane.

Full text of DOI:10.1002/anie.201408102

Angewandte
Chemie
DOI: 10.1002/anie.201408102
ꢀ
C H Functionalization Very Important Paper
Ruthenium–Porphyrin-Catalyzed Diastereoselective Intramolecular
ꢀ
Alkyl Carbene Insertion into C H Bonds of Alkyl Diazomethanes
Generated In Situ from N-Tosylhydrazones**
Annapureddy Rajasekar Reddy, Cong-Ying Zhou, Zhen Guo, Jinhu Wei, and Chi-Ming Che*
Abstract: With a ruthenium–porphyrin catalyst, alkyl diazo-
applications can be envisioned. Alkyl carbene complexes of
=
methanes generated in situ from N-tosylhydrazones efficiently
early transition metals feature a strong M C bond with
3
ꢀ
underwent intramolecular C(sp ) H insertion of an alkyl
a nucleophilic C atom and do not undergo electrophilic
carbene C H insertion. Although late-transition-metal
complexes, such as dirhodium(II,II) carboxylates, are well-
[2]
ꢀ
carbene to give substituted tetrahydrofurans and pyrrolidines
in up to 99% yield and with up to 99:1 cis selectivity. The
reaction displays good tolerance of many functionalities, and
the procedure is simple without the need for slow addition with
ꢀ
documented to catalyze carbene C H insertion reactions of
a-diazocarbonyl compounds,[1] to the best of our knowledge,
3
ꢀ
ꢀ
a syringe pump. From a synthetic point of view, the C H
metal-catalyzed carbene C(sp ) H insertion reactions of alkyl
insertion of N-tosylhydrazones can be viewed as reductive
diazomethanes have not been reported.[3] Recent studies
showed that Pd0/II complexes can catalyze reactions of
carbenes generated from aryl diazomethanes or alkyl diazo-
methanes to give cross-coupling products.[4]
=
ꢀ
coupling between a C O bond and a C H bond to form a new
ꢀ
C C bond, since N-tosylhydrazones can be readily prepared
from carbonyl compounds. This reaction was successfully
ꢀ
applied in a concise synthesis of (+)-pseudoheliotridane.
A major challenge in metal-catalyzed alkyl carbene C H
insertion/transfer reactions is the low stability of alkyl diazo-
methanes, which are the common source of alkyl carbenes. To
circumvent this difficulty, Morandi and Carreira reported the
in situ generation of diazomethane from a water-soluble
diazald derivative for the cyclopropanation of alkenes.[5] N-
Tosylhydrazones have been reported for the in situ generation
of the reactive alkyl diazomethanes and aryl diazome-
thanes.[4,6] Herein we describe the first example of metal-
ꢀ
M
etal-catalyzed carbene C H insertion reactions are
widely used in organic synthesis,[1] but related reactions
involving alkyl carbenes are underdeveloped. As alkyl groups
are electronically and structurally different from unsaturated
acceptor/aryl groups (Scheme 1), new reactivity and selectiv-
ꢀ
ity of C H insertion of alkyl carbenes and hence new
ꢀ
catalyzed intramolecular alkyl carbene C H insertion in
which alkyl diazomethanes generated in situ from alkyl N-
tosylhydrazones are used as the carbene source. The protocol
described herein can be used for the stereoselective synthesis
of a wide variety of substituted tetrahydrofurans[7] and
pyrrolidines.[8] The latter are commonly found in natural
products and pharmaceuticals. As alkyl N-tosylhydrazones
can be obtained by the treatment of alkyl-substituted ketones/
aldehydes with tosylhydrazine, a one-pot reaction was
ꢀ
developed for stereoselective intramolecular C C bond
formation from alkyl ketones/aldehydes.
Scheme 1. Metal–acceptor carbenes from stabilized diazo compounds
and metal–alkyl carbenes from alkyl diazomethanes. EWG=electron-
withdrawing group, Ts=p-toluenesulfonyl.
We used N-tosylhydrazone 1a to establish the optimal
reaction conditions. Treatment of the sodium salt of 1a,
generated in situ from 1a and NaOtBu, with the catalyst
[Ru(TTP)(CO)] (1 mol%) in toluene at 1108C for 5 h
afforded the 2,3-disubstituted tetrahydrofuran 2a in 78%
yield with excellent diastereoselectivity (cis/trans > 95:5;
Scheme 2). The cis configuration of the major isomer was
established by NMR spectroscopy. Other catalysts, including
[Fe(TTP)Cl], [Ru(cymene)Cl2], [Ru(salen)(CO)] (salen =
N,N’-bis(3-bromosalicylidene)-1,2-cyclohexanediamino),
[Rh2(CH3CO2)4], [Rh2(esp)2],[9] and Cu(OTf)2, gave 2a in 11–
43% yield with diastereomeric ratios of 55:45–81:19 (see the
Supporting Information). Other [Ru(Por)CO] catalysts
(H2por= porphyrin) were also effective: [Ru(TMP)(CO)]
and [Ru(F20-TPP)(CO)] afforded 2a in 65 and 53% yield,
respectively, with cis/trans ratios of around 95:5. In the
absence of a metal catalyst, 2a was obtained in 13% yield and
[*] A. R. Reddy,[+] C.-Y. Zhou,[+] J. Wei, Prof. Dr. C.-M. Che
HKU Shenzhen Institute of Research and Innovation, Shenzhen
(China); State Key Laboratory of Synthetic Chemistry and
Department of Chemistry, The University of Hong Kong
Hong Kong (China)
E-mail: cmche@hku.hk
[+] These authors contributed equally.
[**] This research was supported by grants from the National Natural
Science Foundation of China (NSFC 21272197), the National Key
Basic Research Program of China (2013CB834802), University
Development Fund of HKU. C.-Y.Z. thanks HKU for a Seed Funding
for Basic Research and a small project funding. We thank Yi Man
Eva Fung for Mass spectrometry measurements (SEG_HKU02).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201408102.
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Table 1: Ruthenium–porphyrin-catalyzed cyclization of N-tosylhydra-
zones to give tetrahydrofurans and pyrrolidines.[a]
Entry Substrate
Product
Yield
[%][b]
cis/
trans[c]
1
2
3
X=Br, 1b
X=NO2, 1c
X=OMe, 1d
2b
2c
2d
91
77
73
>95:5
94:6
>95:5
4
5
84
52
69:31
66:34
Scheme 2. [Ru(TTP)(CO)]-catalyzed cyclization of 1a to give 2a and
the structure of porphyrins used in this study.
6
94
83:17
with a cis/trans ratio of 55:45. With [Ru(TTP)(CO)] as the
catalyst, the screening of solvents and bases revealed that
a combination of K2CO3 and 1,4-dioxane led to an improve-
ment in the product yield to 88% (Scheme 2); other bases,
including Li2CO3, Na2CO3, and Cs2CO3, were less effective.
No coupling reaction of the diazo compound was observed in
the cyclization.
7
8
80
78
>95:5[d]
Various N-tosylhydrazones 1b–m derived from b-alkoxy
ketones and aldehydes underwent cyclization to give the
corresponding substituted tetrahydrofurans in moderate to
high yields and with moderate to excellent diastereoselectiv-
ity (Table 1). The reaction tolerated a variety of function-
alities, including hydroxy, halo, nitro, methoxy, acetal, and
alkene groups. The cyclization of 1b–d, with various benzyl
substituents, gave the desired products in 73–91% yield and
with excellent cis selectivity (cis/trans ꢁ 95:5; Table 1,
entries 1–3); electron-donating and electron-withdrawing
groups on the phenyl ring had a minor effect on the product
yield and diastereoselectivity. Alkyl-substituted N-tosyl-
hydrazones 1e–g were also reactive, and the aliphatic
9
79
82
>99:1
90:10[e]
>99:1
10
11
12
54
43
ꢀ
products of C H bond insertion were obtained in 52–94%
yield with cis/trans ratios of 66:34–83:17 (Table 1, entries 4–
6). For 1e and 1 f, which contain an alkene and a hydroxy
functionality, respectively, no alkene cyclopropanation or
13
14
15
R=Ph, 3a
R=Cbz, 3b
R=Me, 3c
4a
4b
4c
99
92
50
>99:1
>99:1
>99:1
ꢀ
carbene O H insertion was observed.
Under the conditions employed, insertion of the carbene
ꢀ
into tertiary C H bonds of N-tosylhydrazones gave the
corresponding products with a quaternary carbon center in
high yields (Table 1, entries 7–9). For example, the reaction of
1h gave spiroketal 2h in 80% yield and with d.r. > 95:5. The
spiroketal is a structural subunit present in a broad range of
bioactive natural products.[10] The optically active N-tosyl-
16
90
>99:1
17
18
50
94
>99:1
>99:1
ꢀ
hydrazone 1j (96% ee) underwent stereospecific C H inser-
tion to give 2j in 79% yield with complete retention of
configuration. A similar stereospecific dirhodium(II,II)-cata-
lyzed cyclization of diazocarbonyl compounds has also been
reported.[11]
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Table 1: (Continued)
underwent cyclization to give the desired products with
excellent cis selectivity (cis/trans > 99:1) and in up to 98%
yield (Table 1, entries 17–19). N-Tosylhydrazones 3h and 3i
bearing indoline and 1,2,3,4-tetrahydroquinoline moieties
were converted into the tricyclic pyrrolidines 4h and 4i in
85 and 99% yield, respectively, and with d.r. values around
70:30 (Table 1, entries 20 and 21). The N-tosylhydrazone 3k
derived from an aldehyde was also a suitable substrate and
was converted into 4k in 92% yield (Table 1, entry 23). The
formation of alkene side products derived from 1,2-hydride
migration of the carbene intermediate was detected (2–20%
yield) in the cyclization of 1a–m. However, for the cyclization
of 3a–k (except 3e) to form pyrrolidines, no alkenes were
detected. The reaction of 3e gave product 4e in 50% yield
along with an alkene side product in 45% yield. This result
with 3e can be attributed to N-substitution with Cbz, which
decreased the ability of the nitrogen atom to activate the
Entry Substrate
Product
Yield
[%][b]
cis/
trans[c]
19
98
>99:1
20
21
85
99
70:30[f]
71:29
22
23
98
92
90:10[e]
ꢀ
adjacent C H bond.
Since N-tosylhydrazones can be obtained by the treat-
ment of carbonyl compounds with TsNHNH2, we explored
the [Ru(TTP)(CO)]-catalyzed cyclization reaction directly
from carbonyl compounds in a one-pot fashion. A solution of
the carbonyl compound and TsNHNH2 in dioxane was stirred
at room temperature for 3 h, and then K2CO3 and [Ru-
(TTP)(CO)] were added, and the mixture was heated at
1058C for 10 h. Seven examples were examined, and the
corresponding cyclization products were formed in 74–94%
yield (Scheme 3). When the [Ru(TTP)(CO)]-catalyzed cycli-
zation of 1a was scaled up to a 2 g scale, 2a was obtained in
85% yield after a reaction time of 15 h.
[a] Reaction conditions: 1/K2CO3/[Ru(TTP)(CO)]=1:3 :0.01, 1058C,
10 h, N2 atmosphere. [b] Yield of the isolated product. [c] The cis/trans
ratio was determined by H NMR spectroscopy. [d] The configuration
was not determined. [e] The product was obtained with a cis–trans/cis–cis
ratio of 90:10. [f] The reaction was carried out at 908C; the product was
obtained with a trans/cis ratio of 70:30. Cbz=carboxybenzyl.
1
The reaction of the b-substituted N-tosylhyrazone 1k
furnished the 2,3,5-trisubstituted tetrahydrofuran 2k in 89%
yield with a cis–trans/cis–cis ratio of 90:10. Thus, two new
contiguous stereogenic centers were generated with a high
level of diastereoselectivity (Table 1, entry 10). The analo-
gous reaction of diazocarbonyl compounds under the catalysis
of [Rh2(CH3CO2)4] was reported to give the corresponding
tetrahydrofurans with moderate diastereoselectivity (d.r.
75:25).[12] The N-tosylhydrazones 1l and 1m derived from
a cyclic ketone and an aldehyde were also reactive and were
converted into the corresponding cyclization products in 54
and 43% yield, respectively (Table 1, entries 11 and 12). In
the reaction of 1l, a fused bicyclic tetrahydrofuran was
formed with exclusively cis selectivity.
The present catalytic method is applicable to the stereo-
selective synthesis of substituted pyrrolidines, which are
a structural motif prevalent in natural alkaloids. Although
a-diazoamides have been reported to undergo cyclization to
give four- or five-membered lactams in the presence of
a dirhodium(II,II) catalyst,[1a,c] direct access to pyrrolidines
Scheme 3. One-pot ruthenium–porphyrin-catalyzed intramolecular
ꢀ
C H insertion of ketones. The reactions were carried out with
a 1:1.05 :10 :0.01 ketone/TsNHNH2/K2CO3/[Ru(TTP)(CO)] ratio. The
yields given are for the isolated product.
ꢀ
through carbene C H insertion is unprecedented.
The treatment of N-tosylhydrazone 3a with K2CO3 in the
presence of [Ru(TTP)(CO)] (1 mol%) in 1,4-dioxane at
1058C for 9 h gave the cis pyrrolidine 4a[13] as a single isomer
in 99% yield (Table 1, entry 13). When N-tosylhydrazone 3c
To illustrate the synthetic utility of the [Ru(TTP)(CO)]-
3
ꢀ
catalyzed alkyl carbene C(sp ) H insertion, we undertook
ꢀ
was used, both insertion into a benzylic C H bond and
a short synthesis of the pyrrolizidine alkaloid (ꢂ)-pseudohe-
liotridane (Scheme 4). The N-tosylhydrazone 5 was synthe-
sized in two steps (Michael addition and condensation) from
pyrrolidine. Treatment of 5 under the aforementioned
reaction conditions gave (ꢂ)-pseudoheliotridane in 95%
yield (73% overall yield) with d.r. 91:9. Thus, this synthetic
ꢀ
insertion into a primary C H bond of the methyl group were
observed (Table 1, entry 15). In contrast to the reactions of
alkyl-substituted N-tosylhydrazones 1e–g (Table 1, entries 4–
6), which gave the corresponding tetrahydrofurans with
moderate diastereoselectivity, the amino analogues 3e–g
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Scheme 4. Synthesis of (ꢂ)-pseudoheliotridane by the [Ru(TTP)(CO)]-
catalyzed cyclization of 5.
ꢀ
Scheme 7. Proposed reaction mechanism of the alkyl carbene C H
insertion catalyzed by [Ru(TTP)(CO)].
A proposed mechanism is depicted in Scheme 7. In this
study, the reaction of [Ru(TTP)(CO)] with 1a (2 equiv) gave
2a in 81% yield with 83% of [Ru(TTP)(CO)] recovered (the
IR spectrum of the recovered catalyst showed a strong band
Scheme 5. KIE for the [Ru(TTP)(CO)]-catalyzed cyclization of 6.
ꢀ1
~
at n ¼1937 cm ), thereby lending support to [Ru(TTP)(CO)-
(CR1R2)] as a reaction intermediate responsible for intra-
ꢀ
route proved highly efficient in terms of the simplicity of the
starting materials, the high overall yield, the low number of
reaction steps, and the convenient manipulation of inter-
mediates.[14]
To gain insight into the reaction mechanism, we examined
the kinetic isotope effect (KIE) by using the monodeuterated
molecular carbene C H insertion.
To examine the effect of a trans CO ligand on the
ruthenium–alkyl carbene moiety, we undertook DFT calcu-
lations on [Ru(TPP)(CO)(C{CH3}2)] (A), [Ru(TPP)(CO)-
(C{CH3}CH2CH2OCH2Ph)] (B), and [Ru(TPP)(C{CH3}-
CH2CH2OCH2Ph)] (C). The structures of A–C were opti-
mized at the B3LYP/6-31G(d):lanl2dz level of theory, and
selected geometrical parameters are depicted in Table 2.
ꢀ
N-tosylhydrazone 6 (Scheme 5). Analysis of the C H and
ꢀ
C D insertion products (total yield: 85%) by 1H NMR
spectroscopy showed a kH/kD ratio of 2.2:1. This KIE value
is comparable to those of the dirhodium(II,II)-catalyzed
Table 2: Calculated bond distance, bond-dissociation energy (BDE), and
electrostatic potential charge of the carbene carbon atom (C(Q)) of the
ꢀ
intra- and intermolecular carbene C H insertion of diazo-
carbonyl compounds (kH/kD = (1–3.5):1)[15] and intramolecu-
=
Ru C(carbene) moiety in complexes A–C.
[16]
ꢀ
lar nitrene C H insertion of sulfamates (kH/kD = 1.9):
A
B
C
reactions generally conceived to proceed through a concerted
[1,17]
=
Ru C distance [ꢀ]
1.936
41.7
0.337
1.946
38.1
0.324
1.863
100.4
0.316
ꢀ
C H insertion pathway.
In this study, excellent stereo-
BDE [kcalmolꢀ1
]
specificity was observed (Table 1, entry 9). We next per-
formed a competitive cyclization of 1a and 1c (Scheme 6; see
also the Supporting Information) and obtained 2a and 2c in
a 1:1.5 ratio. Likewise, the competitive cyclization of 1a and
1d gave 2a and 2d in a ratio of 1.2 :1. Thus, a change in the
para substituent on the phenyl ring from an electron-with-
drawing to an electron-donating substituent has only a minor
effect on the overall transformation.[15a,18]
C(Q) [e]
Natural bond orbital (NBO)[19] and charge decomposition
analyses (CDA)[20] were used to analyze the orbital correla-
tion diagram and the carbene electrostatic potential charges
of A–C (Table 2; see also the Supporting Information,
including Figure S1).
=
The calculated Ru C distances of A–C are comparable to
those of analogous ruthenium–carbene complexes whose
structures have been determined by X-ray crystal-structure
analysis.[21] Both A and B show significantly longer Ru C
=
=
distances (1.936 and 1.946 versus 1.863 ꢀ) and lower Ru C
Scheme 6. Competition experiments: [Ru(TTP)(CO)]-catalyzed cycliza-
tion of 1a and 1c/1d.
BDE values (38.1–41.7 versus 100.4 kcalmolꢀ1) than those of
4
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C (Table 2), in line with the significant trans effect of the CO
ligand on the ruthenium–alkyl carbene moiety.[21,22] DFT
calculations on the [Ru(Por)CO]-catalyzed cyclization of 1a
ꢀ
revealed that C H insertion via B is thermodynamically and
kinetically more favorable than that via C (the activation
energy via B and C is 14.1 and 37.5 kcalmolꢀ1, respectively;
see the Supporting Information). The relatively low activation
energy via B stands in contrast to the high reaction temper-
ature of 1058C (Table 1), thus suggesting that the decom-
position of N-tosylhydrazones to generate alkyl diazome-
thanes in situ is crucial in the aforementioned [Ru(Por)(CO)]
catalysis. NBO analysis (Table 2) revealed that the carbene
carbon atom is electrophilic, as evidenced by the positive
partial electrostatic potential (ESP) charge of 0.337 e.
Are [Ru(Por)(CO)] catalysts unique? We found that
[Ru(TDCPP)(IPr)2]
(Ipr= N,N’-diisopropylimidazol-2-yli-
effective in capturing the reactive M–alkyl carbene moiety for
ꢀ
dene; see Table S1), [Ir(Por)Me], and [Co(Por)] are also
subsequent C H insertion reactions. By varying the structure
of [M(Por)X], it may be possible to tune both the reactivity
ꢀ
effective in catalyzing the alkyl carbene C H insertion
ꢀ
reactions. As shown in Scheme 8, the cyclization of 1a,g
catalyzed by [Ir(TTP)Me] and [Co(TTP)] gave 2a,g with
and selectivity of alkyl carbene C H insertion.
In summary, alkyl diazomethanes generated in situ from
N-tosylhydrazones are an effective carbene source for metal-
3
ꢀ
loporphyrin-catalyzed intramolecular C(sp ) H bond inser-
tion to give a variety of substituted tetrahydrofurans and
pyrrolidines with good diastereoselectivity. With [Ru-
(Por)(CO)] as the catalyst, good tolerance of diverse func-
tionalities was observed, and the operational procedure is
simple without the need for slow addition with a syringe
pump. The synthetic utility of the reaction was demonstrated
in a short synthesis of a pyrrolizidine alkaloid, (ꢂ)-pseudo-
heliotridane.
Received: August 8, 2014
Published online: && &&, &&&&
ꢀ
Keywords: alkyl carbenes · alkyl diazomethanes · C
H insertion · homogeneous catalysis · ruthenium
.
Scheme 8. Iridium–porphyrin- and cobalt–porphyrin-catalyzed cycliza-
tion of N-tosylhydrazones. The reactions were carried out with
a 1:3 :0.01 N-tosylhydrazone/K2CO3/([Ir(TTP)Me] or [Co(TTP)]) ratio.
The yield was determined by 1H NMR spectroscopy with 4-iodoanisole
as an internal standard. The diastereomeric ratio was determined by
1H NMR spectroscopy.
[1] For selected reviews: a) H. M. L. Davies, D. Morton, Chem. Soc.
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lower diastereoselectivity than that observed with [Ru-
(TTP)(CO)] as the catalyst. On the other hand, the [Ir-
(TTP)Me]-catalyzed cyclization of 3d to 4d and [Co(TTP)]-
catalyzed cyclization of 3a to 4a proceeded with diastereo-
selectivity comparable to that observed with [Ru(TTP)(CO)].
Catalysts [Ir(TTP)Me] and [Co(TTP)] both gave 4h with
a diastereomeric ratio of 92:8, which is higher than that
observed with [Ru(TTP)(CO)]. These two catalysts are also
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ˇ
´
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6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 7
These are not the final page numbers!

Angewandte
Chemie
Communications
ꢀ
C H Functionalization
A. R. Reddy, C.-Y. Zhou, Z. Guo, J. Wei,
C.-M. Che*
&&&& — &&&&
Ruthenium–Porphyrin-Catalyzed
Diastereoselective Intramolecular Alkyl
ꢀ
Carbene Insertion into C H Bonds of
Alkyl Diazomethanes Generated In Situ
from N-Tosylhydrazones
Nose to tail: With a ruthenium–porphyrin
a reaction that can be viewed as a reduc-
=
ꢀ
catalyst, alkyl diazomethanes generated
tive coupling between C O and C H
ꢀ
in situ from N-tosylhydrazones under-
bonds to form a new C C bond. This
3
ꢀ
went efficient intramolecular C(sp ) H
transformation was applied in a concise
insertion to give substituted tetrahydro-
furans and pyrrolidines (see scheme) in
synthesis of (ꢂ)-pseudoheliotridane.
Angew. Chem. Int. Ed. 2014, 53, 1 – 7
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!