DMF as a source of oxygen and aminomethine: Stereoselective 1,2-insertion of rhodium(II) azavinyl carbenes into the C=O bond of formamides for the synthesis of cis -diamino enones

Article abstract of DOI:10.1021/ol500723s

A new catalytic reaction in which all the atoms of a formamide are incorporated into the product through a formal stereoselective 1,2-insertion of rhodium(II) azavinyl carbenes, generated in situ from readily available N-sulfonylated 1,2,3-triazoles, into

Full text of DOI:10.1021/ol500723s

Letter
pubs.acs.org/OrgLett
DMF as a Source of Oxygen and Aminomethine: Stereoselective 1,2-
Insertion of Rhodium(II) Azavinyl Carbenes into the CO Bond of
Formamides for the Synthesis of cis-Diamino Enones
Da Jung Jung,† Hyun Ji Jeon,† Ju Hyun Kim, Youngmee Kim, and Sang-gi Lee*
Department of Chemistry and Nano Science (BK Plus), Ewha Womans University, Seoul 120-750, Korea
S
* Supporting Information
ABSTRACT: A new catalytic reaction in which all the atoms of a
formamide are incorporated into the product through a formal
stereoselective 1,2-insertion of rhodium(II) azavinyl carbenes, generated
in situ from readily available N-sulfonylated 1,2,3-triazoles, into the C
O bond of DMF and other N,N-disubstituted formamides to afford cis-
diamino enones is described.
Scheme 1. Synthesis of α-Amino Ketones from Rh(II)
Azavinyl Carbenes
N,N-Dimethylformamide (DMF) is one of the most commonly
employed aprotic polar solvents in various organic reactions.
Besides being an effective solvent, DMF has long been used as a
reagent, particularly for the introduction of a formyl group in
the Vilsmeier−Haack reaction.1,2 DMF has also been exploited
as a convenient source of various functional units such as
−CO,3 −CONMe2,4 −NMe2,5 and −H (hydride)6 in transition
metal-catalyzed reactions. More recently, it has been reported
that DMF can also act as a promising source of −CN7,8 in Pd-
or Cu-catalyzed cyanations of aryl halides, organosilanes, or in
Pd-catalyzed cyanations of aromatic and heteroaromatic
compounds through direct C−H functionalizations (Figure 1).
comopunds.11 It has been established that triazole 1, readily
prepared by the copper-catalyzed cycloaddition of a sulfonyl
azide and a terminal alkyne,12 is a convenient progenitor of
reactive electrophilic rhodium(II) azavinyl carbene A, which
reacts with weak unsaturated nucleophiles such as nitriles,10
alkynes,13 allenes,14 isocynates,15 α,β-unsaturated aldehydes,16
furans,17 indoles,18 and benzene (intramolecularly)19 to provide
numerous nitrogen heterocycles. Carbene complex A was also
shown to react with weak protic nucleophiles. For example,
Murakami and co-workers reported that the Rh(II) azavinyl
carbenes A insert into O−H bonds of H2O and allylic alcohols
to afford α-amino ketones (Scheme 1b).20
Quite recently Fokin and co-workers reported the stereo-
selective formal 1,3-insertion of carbenes A into the O−H and
N−H bonds of primary and secondary amides and carbamates
as well as carboxylic acids yielding densely functionalized (Z)-
enamides or α-amino ketones (see Scheme 1b).21 On the basis
Figure 1. Functional units from DMF incorporated in the product
from catalysis.
Despite the utility of DMF as a stable source of various
functional units of these catalytic reactions, only one of its
fragments is incorporated into the reaction product. On the
other hand, Porter and co-workers reported that a rhodium(II)-
catalyzed olefination of tertiary formamides with a silylated
diazoester afforded vinylogous carbamates, in which all units of
amides were incorporated into the product.9 Herein we report a
novel formal stereoselective 1,2-insertion of rhodium(II)
azavinyl carbenes A, derived from N-sulfonyl-1,2,3-triazoles 1,
into the formamide CO bond to afford cis-diamino enones 2,
where DMF and other N,N-disubstituted formamides are
sources of oxygen and aminomethine units (Scheme 1a).
The rhodium(II)-catalyzed denitrogenative transformation of
N-sulfonylated 1,2,3-triazoles 1, discovered by Fokin and
Gevorgyan,10 has rapidly taken its place among useful synthetic
strategies for various nitrogen-containing cyclic and acyclic
Received: March 8, 2014
Published: April 7, 2014
© 2014 American Chemical Society
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dx.doi.org/10.1021/ol500723s | Org. Lett. 2014, 16, 2208−2211

Organic Letters
Letter
of these precedents, we anticipated that the O-nucleophilic
addition of DMF at the electrophilic carbene carbon of A may
afford rhodium-iminium zwitterionic B, which could cyclize to
form 2-amino-4-oxazolines C as a product (Scheme 2). Much
Scheme 2. Plausible Mechanism for the Formation of 2a
Figure 2. X-ray structure of 2a.
may due to the unstability of N,O-hemiaminal C, which could
rearrange to aziridine D, and then afford the stable vinylogous
enamino ketone 2a via ring-opening to give the zwitterionic
species E, followed by deprotonation (Scheme 2).23
Optimization of the reaction conditions was carried out to
make this novel transformation synthetically practical, as
summarized in Table 1. Changing the catalyst to Rh2(Oct)4
and Rh2(S-DOSP)4 increased substantially the yields to 40%
(entry 2, Table 1) and 53% (entry 3, Table 1), respectively.
The yield of 2a increased further to 63% when Rh2(tBuCO2)4
was used as a catalyst (entry 4, Table 1). However, other
catalysts such as Rh2(TPA)4 and Rh2(S-PTPA)4 were not
effective (entries 5 and 6, Table 1). With 1.3 mol %
Rh2(tBuCO2)4 as a catalyst further optimization of the reaction
conditions ultimately led to an optimal protocol in which
triazole 1a is reacted with 1.4 equiv of DMF in benzene solvent
at 90 °C for 2.5 h to afford 2a in 81% yield (entry 14, Table 1).
With optimal reaction conditions in hand, we investigated
the generality of these reactions with different triazoles 1. As
shown in Table 2, the reactions with triazoles 1b−1d, prepared
from tosyl azide and phenylacetylenes bearing electron-
donating methyl at ortho-, meta-, and para-positions suggested
the reaction efficiency could be somewhat influenced by steric
forces, and thus 2b and 2c were formed in higher yields than 2d
obtained from the sterically congested ortho-methyl substituted
phenyl triazole 1d (entries 1−3, Table 2). The para-methoxy
substituted triazole 1e afforded the corresponding cis-diamino
vinyl ketones 2e in good yield (entry 4, Table 2). The triazoles
1f−1i, in which electron-withdrawing groups such as fluorine,
ketone, nitrile, and nitro are substituted on the phenyl ring,
were also tolerated under the reaction conditions and afforded
the corresponding cis-diamino vinyl ketones 2f−2i in good
yields (entries 5−8, Table 2). Alkyl-substituted triazoles 1j and
1k were also tolerated and gave the corresponding cis-diamino
vinyl ketones 2j and 2k in yields of 60 and 64%, respectively
(entries 9 and 10, Table 2).
to our surprise, when triazole 1a (R = tosyl, R1 = Ph) was
reacted with 1.4 equiv of DMF in toluene in the presence of 1.3
mol % Rh2(OAc)4, the unexpected cis-α,β-diamino vinyl ketone
2a was isolated in 38% yield (entry 1, Table 1). The structure
of 2a was unambiguously determined by spectroscopic analyses
and X-ray crystallography (Figure 2).22 A cursory inspection of
the skeletal framework of the putative carbene A and enone 2a
reveals that a stereoselective 1,2-insertion of A into the CO
bond of DMF has occurred. We reasoned that formation of 2a
a
Table 1. Optimization of Reaction Conditions
b
entry
Rh(II)
solvent
toluene
T (°C)/h
yield (%)
1
2
3
4
5
6
7
Rh2(OAc)4
100/4
100/4
100/4
100/4
100/4
100/4
120/4
120/4
120/4
72/5
38
40
53
63
10
57
71
46
62
73
57
66
<10
81
Rh2(Oct)4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CHCl3
Rh2(S-DOSP)4
Rh2(tBuCO2)4
Rh2(TPA)4
Rh2(S-PTPA)4
Rh2(tBuCO2)4
Rh2(tBuCO2)4
Rh2(tBuCO2)4
Rh2(tBuCO2)4
Rh2(tBuCO2)4
Rh2(tBuCO2)4
Rh2(tBuCO2)4
Rh2(tBuCO2)4
c
8
d
9
10
11
12
13
14
PhCl
142/2.5
90/2.5
90/2.5
90/2.5
1,2-DCE
cyclohexane
benzene
The reaction was extended to other N,N-disubstituted
formamides (Table 3). Thus, triazole 1a was reacted with
N,N-dibenzyl formamide highly efficiently to afford 2l in 91%
yield (entry 1, Table 3). The reaction with sterically congested
N,N-diisopropyl formamide could produce cis-diamino vinyl
ketone 2m in 77% yield (entry 2, Table 3). N-Aryl formamides
were also reactive, as shown with 2n obtained in 66% yield
(entry 3, Table 3). The reactions with formamides having six-
membered cyclic amine moieties such as piperidine and
morpholine proceeded smoothly to provide the corresponding
vinyl ketones 2o, 2p in high yields. Although the yield was
slightly decreased, the five-membered pyrrolidine-1-carboxalde-
a
Reaction conditions: 1a (0.3 mmol), DMF (0.42 mmol), Rh(II) (3.9
b
× 10−3 mmol), solvent (1.2 mL). Isolated yield after silica column
c
chromatography. Reaction carried out with 0.9 equiv of DMF.
d
Reaction carried out with 5.0 equiv of DMF.
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Letter
a
Table 2. Scope with Respect to Triazole 1
Table 3. Reactions of 1a with N,N-Disubstituted
Formamides
a
a
Reaction conditions: 1a (0.3 mmol), DMF (0.42 mmol),
b
Rh2(tBuCO2)4 (3.9 × 10−3 mmol), solvent (1.2 mL). Isolated yield
after silica column chromatography.
a
Reaction conditions: 1 (0.3 mmol), DMF (0.42 mmol), Rh(II) (3.9
b
× 10−3 mmol), solvent (1.2 mL). Isolated yield after silica column
chromatography.
hyde can be incorporated to give the cis-diamino vinyl ketone
2q. In sum, these results show that the reaction is highly general
with respect to the disubstituted formamides.
When the N-tosyl group of 1 was changed to benzene-
sulfonyl, the reaction efficiency remained high, providing the
corresponding cis-diamino enone 2r in 81% yield (eq 1). Under
the same reaction conditions, N,N-dimethyl benzamide was
also successfully incorporated to afford inseparable E/Z mixture
(ca. 8:1, stereochemistry is not assigned) of the trisubstituted
vinyl ketone 2s in high yields (eq 2). However, the reactions
either with N-methanesulfonyl triazoles or with a N,N-
dimethylacetamide did not proceed effectively. Finally, along
acetylene with tosylazide in the presence of CuTC (5.0 mol %,
TC = thiophene-2-carboxylate) in benzene at room temper-
ature generated triazole 1a. To this reaction mixture was added
1.4 equiv of DMF and Rh2(tBuCO2)4 (1.3 mol %) successively,
and the reaction mixture was heated to 90 °C for 2.5 h to afford
cis-diamino vinyl ketone 2a in 61% isolated yield (eq 3).
In conclusion, we have developed a new stereoselective 1,2-
insertion of Rh(II) azavinyl carbenes into the CO bond of
DMF and other N,N-dialkylsubstituted formamides to produce
the line with our continuing interest in tandem reactions,24
a
one-pot synthesis of cis-diamino vinyl ketone starting from
terminal alkyne was carried out to demonstrate the practical
convenience of the present method. Treatment of phenyl-
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Organic Letters
Letter
(12) (a) Yoo, E. J.; Ahlquist, M.; Kim, S. H.; Bae, I.; Fokin, V. V.;
Sharpless, K. B.; Chang, S. Angew. Chem., Int. Ed. 2007, 46, 1730.
(b) Raushel, J.; Fokin, V. V. Org. Lett. 2010, 12, 4952.
(13) (a) Chattopadhyay, B.; Gevorgyan, V. Org. Lett. 2011, 13, 3746.
(b) Shi, Y.; Gevorgyan, V. Org. Lett. 2013, 15, 5394. For Ni-catalyzed
tranannulation of trizoles with alkynes, see: Miura, T.; Yamauchi, M.;
Murakami, M. Chem. Commun. 2009, 1470.
cis-diamino enones, in which all the atoms of formamides are
incorporated into the product. Although more detailed studies
to elucidate the reaction mechanism are warranted, a plausible
pathway proceeds via an aziridine intermediate. Further studies
on the scope of this novel transformation and on the
applications of the cis-diamino enones are currently underway.
(14) Schults, E. S.; Sarpong, R. J. Am. Chem. Soc. 2013, 135, 4696.
(15) Chuprakov, S.; Kwok, S. W.; Fokin, V. V. J. Am. Chem. Soc.
2013, 135, 4652.
(16) Miura, T.; Tanaka, T.; Hiraga, K.; Stewart, S. G.; Murakami, M.
J. Am. Chem. Soc. 2013, 135, 13652.
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures, characterization data, and
crystal data (CIF) for 2a. This material is available free of
charge via the Internet at http://pubs.acs.org.
(17) Parr, B. T.; Green, S. A.; Davies, H. M. J. Am. Chem. Soc. 2013,
135, 4716.
(18) Spangler, J. E.; Davies, H. M. J. Am. Chem. Soc. 2013, 135, 6802.
(19) Miura, T.; Funakoshi, Y.; Murakami, M. J. Am. Chem. Soc. 2014,
136, 2272.
(20) (a) Miura, T.; Biyajima, T.; Fujii, T.; Murakami, M. J. Am. Chem.
Soc. 2012, 134, 194. (b) Miura, T.; Tanaka, T.; Biyajima, T.; Yada, A.;
Murakami, M. Angew. Chem., Int. Ed. 2013, 52, 3883.
(21) Chuprakov, S.; Worrell, B. T.; Selander, N.; Sit, R. K.; Fokin, V.
V. J. Am. Chem. Soc. 2014, 136, 195.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sanggi@ewha.ac.kr.
Author Contributions
†D. J. Jung and H. J. Jeon contributed equally to this work.
(22) For detailed data for X-ray structure of 2a (CCDC: 989567),
see the Supporting Information.
Notes
The authors declare no competing financial interest.
(23) Formation of deuterium labelled 2a-d100% from the reaction with
DMF-d7 further supports our proposed reaction pathway.
(24) For our selected recent papers on tandem reactions, see:
(a) Chun, Y. S.; Xuan, Z.; Kim, J. H.; Lee, S.-g. Org. Lett. 2013, 15,
3162. (b) Kim, J. H.; Chun, Y. S.; Lee, S.-g. J. Org. Chem. 2013, 78,
11483. (c) Lee, S.; Shin, J. Y.; Lee, S.-g. Chem.Asian J. 2013, 8, 1990.
(d) Shin, J. Y.; Jung, D. J.; Lee, S.-g. ACS Catal. 2013, 3, 525.
(e) Chun, Y. S.; Kim, J. H.; Choi, S. Y.; Ko, Y. O.; Lee, S.-g. Org. Lett.
2012, 14, 6358. (f) Kim, J. H.; Shin, H.; Lee, S.-g. J. Org. Chem. 2012,
77, 1560. (g) Chun, Y. S.; Lee, J. H.; Kim, J. H.; Ko, Y. O.; Lee, S.-g.
Org. Lett. 2011, 13, 6390. (h) Kim, J. H.; Lee, S.-g. Org. Lett. 2011, 13,
1350.
ACKNOWLEDGMENTS
■
This research was supported by the National Research
Foundation of Korea (NRF) (NRF-2011-0016344 and NRF-
2009-0083525). We thank Prof. J. Bouffard in Ewha Womans
University for comments and the Daegu branch of the Korea
Basic Science Research Center for mass spectrometric analyses.
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