Direct Carboxylation of the Diazo Group ipso-C(sp2)-H bond with Carbon Dioxide: Access to Unsymmetrical Diazomalonates and Derivatives

Article abstract of DOI:10.1021/acs.orglett.7b03573

The direct carboxylation of the ipso-C(sp²)-H bond of a diazo compound with carbon dioxide under mild reaction conditions is described. This method is transition-metal-free, uses a weak base, and proceeds at ambient temperature under atmospheric pressure in carbon dioxide. The carboxylation exhibits high reactivity and is amenable to subsequent diversification. A series of unsymmetrical 1,3-diester/keto/amide diazo compounds are obtained with moderate to excellent yields (up to 99%) with good functional group compatibility.

Full text of DOI:10.1021/acs.orglett.7b03573

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. 2017, 19, 6756−6759
Direct Carboxylation of the Diazo Group ipso-C(sp2)−H bond with
Carbon Dioxide: Access to Unsymmetrical Diazomalonates and
Derivatives
Qianyi Liu, Man Li, Rui Xiong, and Fanyang Mo*
Department of Energy and Resources Engineering, College of Engineering, Peking University, Beijing 100871, China
S
* Supporting Information
ABSTRACT: The direct carboxylation of the ipso-C(sp2)−H bond
of a diazo compound with carbon dioxide under mild reaction
conditions is described. This method is transition-metal-free, uses a
weak base, and proceeds at ambient temperature under atmospheric
pressure in carbon dioxide. The carboxylation exhibits high
reactivity and is amenable to subsequent diversification. A series
of unsymmetrical 1,3-diester/keto/amide diazo compounds are
obtained with moderate to excellent yields (up to 99%) with good
functional group compatibility.
Scheme 1. Diazo Group as Nucleophile
ucleophilic addition reactions of diazo compounds with
Nvarious electrophiles have been known for more than a
century.1 Many of these reactions have been developed into
useful methods for organic synthesis. For example, the
Buchner−Curtius−Schlotterbeck reaction combines aldehydes
or ketones with aliphatic diazoalkanes to form homologated
ketones.2 In 1935, Arndt and Eistert reported the nucleophilic
addition of diazomethane to acyl chlorides to afford α-diazo
ketones.3 Diazo compounds are generally sensitive to acids but
are relatively stable under basic conditions. Base-promoted 1,2-
or 1,4-additions to carbonyl compounds with the diazo group
retained, as well as their asymmetric version, have been well
documented in past decades.1,4 Besides carbonyl compounds,
organoboron reagents have been found to react with diazo
compounds under mild conditions.5 This type of reaction was
pioneered by Hooz in 19686 and further developed by Wang7
and Barluenga.8 A palladium-catalyzed cross-coupling reaction
using diazo compounds as the nucleophilic partner was
developed by Wang in 2007.9
Looking through this history (Scheme 1a), the most
common and available electrophile, carbon dioxide (CO2),
surprisingly has not been used in this addition reaction. CO2, a
greenhouse gas, has attracted much attention as an inexpensive,
nontoxic, nonflammable, renewable, and abundant C1 building
block for organic synthesis.10 The carboxylation of C−H bonds
using CO2 is emerging as a straightforward and atom-economic
way to synthesize carboxylic acids and their derivatives.11
We present here an addition reaction of the diazo compound
ipso-C−H bond to CO2 under very mild reaction conditions
with the diazo group retained. The resulting α-diazo
carboxylate intermediates can be readily converted to esters
and amides in a one-pot method (Scheme 1c). From a
synthetic perspective, this method is particularly suitable for
accessing unsymmetrical diazomalonates and their derivatives
(vide infra). While these products can also be prepared via
direct diazo transfer onto activated methylenes (Scheme 1b),
the unsymmetrical malonate diester starting materials are not
Received: November 17, 2017
Published: December 6, 2017
© 2017 American Chemical Society
6756
DOI: 10.1021/acs.orglett.7b03573
Org. Lett. 2017, 19, 6756−6759

Organic Letters
Letter
readily available and often require special techniques to
prepare.12 In contrast, our method provides modular synthesis
of unsymmetrical diazomalonates.
Table 2. Carboxylation−Esterification of Diazo
a
Compounds
An electron-withdrawing group at the α position stabilizes
the diazo group, which makes the diazo compounds easy to
handle but also makes the ipso-C−H bond more acidic. The
literature contains many reports of transition-metal-free, base-
promoted additions of acidic C−H bonds to CO2.13 The
carboxylation of several representative types of acidic C−H
bonds, such as at the α position of a carbonyl compound13a−i
and at certain sites on an aromatic heterocycle,13j,m,n has been
achieved using various bases such as DBU and alkali carbonates.
Thus, we envisioned that a judicious choice of base would be
critical to promoting the desired reactivity of diazo compounds
with carbon dioxide.
We initiated our studies by investigating the carboxylation of
ethyl diazoacetate (EDA) 1a with 1 atm of CO2 in the presence
of a base and an additional electrophile (benzyl bromide 2a in
this case) to trap the newly formed carboxylate anion. A variety
of bases were examined with 3a obtained with 84% isolated
yield using Cs2CO3 as the base (Table 1, entry 5). The use of
a
Table 1. Optimization of the Reaction Conditions
b
entry
base
solvent
yield (%)
1
K2CO3
Li2CO3
KOtBu
CsF
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCM
9
2
nd
3
trace
17
4
5
Cs2CO3
DBU
84
6
trace
trace
trace
trace
30
7
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
8
1,4-dioxane
THF
a
Reaction conditions: 1 (0.5 mmol), CO2 (1 atm, closed, 50 mL
Schlenk flask, about 2 mmol, 4 equiv based on the ideal gas law at 20
°C), 2 (0.75 mmol, 1.5 equiv), Cs2CO3 (0.6 mmol, 1.2 equiv),
acetonitrile (2 mL), 50 °C, 24 h. Bromides were used unless specified
9
10
11
DMSO
DMF
79
c
b
c
12
CH3CN
trace
otherwise. Isolated yields were given. 80 °C. DMF is used as solvent.
a
For more details, see the Supporting Information.
Reaction conditions: 1a (0.5 mmol), CO2 (1 atm, closed, 50 mL
Schlenk flask, about 2 mmol, 4 equiv based on the ideal gas law at 20
°C), 2a (0.75 mmol, 1.5 equiv), base (0.6 mmol, 1.2 equiv), solvent (2
mL), 24 h, nd, not detected. Isolated yields were reported. N2
atmosphere.
addition of the diazo group to CO2, furnishing high yields of
the products (>80% in most cases). Other common alkyl
bromides were less reactive. Thus, alkyl iodides were employed
and/or the solvent was switched to DMF (3l, 3n, and 3q) to
enhance the reactivity of the esterification step. The chemo-
selectivity of this transformation was further demonstrated by
the compatibility of ketone and aldehyde functional groups in
cases 3g and 3h. α-Diazo alkyl ketones also worked well and
produced diazo β-keto esters with >80% yields (3r and 3s),
while an α-diazo aryl ketone gave a relatively low yield (3t,
45%). This carboxylation−esterification strategy was also
applied to the synthesis of α-diazo amides (3u−x) and α-
diazo phosphonate (3y) with 65−94% yields.
The utility of this methodology was further investigated by
studying the carboxylation−amidation of α-diazo compounds.
The scope is summarized in Table 3. Carboxylation of the diazo
ipso-C−H bond with CO2 generated the α-diazo carboxylate
intermediate, which reacted with methylsulfonyl chloride to
form a mixed anhydride. Finally, an amine was introduced to
deliver the final amide products. This protocol gave a range of
b
c
an organic base, DBU, was unsuccessful (entry 6). Other
solvents, such as dichloromethane, 1,4-dioxane, THF, or
DMSO, proved to be less efficient (entries 7−10), while
DMF exhibited a positive solvent effect that afforded a 79%
yield of 3a (entry 11). Since a stoichiometric amount of
carbonate salt is used as the base, the source of the carboxyl
group must be accurately identified. To this end, a control
experiment was conducted in a N2 atmosphere (i.e., in the
absence of CO2, entry 12). Not surprisingly, this reaction gave
only trace amounts of product, indicating that CO2 is the main
source of the carboxyl group for this carboxylation reaction.
These optimal reaction conditions were then used for
substrate scope studies with the results shown in Table 2.
Substituted benzyl bromides, allyl bromide, and α-bromo
carbonyl compounds were all good electrophiles for ester-
ification of the carboxylate, which was formed in situ by the
6757
DOI: 10.1021/acs.orglett.7b03573
Org. Lett. 2017, 19, 6756−6759

Organic Letters
Letter
a
a
Table 3. Carboxylation−Amidation of Diazo Compounds
Table 4. Carboxylation−Esterification of TMSCHN2
a
Reaction conditions: TMSCHN2 (0.5 mmol, 0.25 mL of 2 M in
hexane), CO2 (1 atm, closed, 100 mL Schlenk tube, about 4 mmol, 8
equiv based on the ideal gas law at 20 °C), Cs2CO3 (1.2 mmol, 2.4
equiv), alkyl bromide (3.0 mmol, 6 equiv), DMF (2 mL), rt, 24 h, then
50 °C, 24 h. Isolated yields were reported.
(6),15 O−H insertion (7),16 formal C−H insertion (8),17 the
sulfonium ylide [2,3]-sigmatropic rearrangement (9),18 and
cyclopropanation (10)19 can be efficiently performed in a single
step from the corresponding diazo starting materials (Scheme
2).
Scheme 2. Derivative Reactions of Unsymmetrical 1,3-
Dicarbonyl Diazo Compounds
a
Reaction conditions: 1 (0.5 mmol), CO2 (1 atm, closed, 50 mL
Schlenk flask, about 2 mmol, 4 equiv based on the ideal gas law at 20
°C), Cs2CO3 (0.6 mmol, 1.2 equiv), acetonitrile (2 mL), 50 °C, 24 h.
Then MsCl (0.75 mmol, 1.5 equiv), Bu4NCl (0.05 mmol, 0.1 equiv),
50 °C, 0.5 h. Amine (1 mmol, 2 equiv), 50 °C, 12 h. Isolated yields
were reported.
primary and secondary amines with the amide products
obtained with moderate to good yields (50−74%).
In addition to stable diazo compounds with an electron-
withdrawing group at the α position of the diazo group, labile
TMSCHN2 is also a competent substrate for the desired
transformation. This can be attributed to the mild reaction
conditions and the high intrinsic reactivity of the diazo C−H
addition to CO2. Thus, increasing the stoichiometry of the base
and the halide results in the carboxylation−esterification of
TMSCHN2 proceeding on both sides of the diazo group to
furnish symmetrical diazomalonates 5 with moderate to good
yields (Table 4, 5a−e, 38−68%).
The deprotonation of monosubstituted diazocarbonyls and
subsequent C−C bond formation by nucleophilic addition to
the electrophiles is well documented.1,14 Accordingly, we
propose that our reaction is also an example of deprotona-
tion−nucleophilic addition. We also performed a number of
mechanistic experiments to support the deprotonation−
addition process with the details shown in the Supporting
Information.
In summary, we have demonstrated the first use of CO2 as an
electrophile for the diazo addition reaction. The reaction
harnesses the intrinsic nucleophilicity of the diazo group, so no
strong base, no transition metal, and no harsh conditions are
needed. The resulting α-diazo carboxylate can be readily
converted to esters and amides in a one-pot method. This
method provides a new retrosynthetic disconnection for
chemists in the preparation of unsymmetrical 1,3-dicarbonyl
2-diazo compounds and their derivatives.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03573.
To demonstrate the utility of these unsymmetrical diazo
malonates/ketones/amides, several 3 and 4 products were
subjected to typical transformations via metal−carbene
chemistry. For example, reduction to the methylene group
Experiemental procedures, X-ray data for 4q, and NMR
spectra (PDF)
6758
DOI: 10.1021/acs.orglett.7b03573
Org. Lett. 2017, 19, 6756−6759

Organic Letters
Accession Codes
Letter
(11) (a) Zhang, W.; Lu, X. Chin. J. Catal. 2012, 33, 745. (b) Cai, X.;
Xie, B. Synthesis 2013, 45, 3305. (c) Liu, A.-H.; Yu, B.; He, L.-N.
Greenhouse Gases: Sci. Technol. 2015, 5, 17. (d) Yu, D.; Teong, S. P.;
Zhang, Y. Coord. Chem. Rev. 2015, 293−294, 279. (e) Sekine, K.;
Yamada, T. Chem. Soc. Rev. 2016, 45, 4524. (f) Wang, S.; Du, G.; Xi, C.
Org. Biomol. Chem. 2016, 14, 3666. (g) Wu, X.-F.; Zheng, F. Top. Curr.
Chem. 2017, 375, 4.
CCDC 1558263 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
(12) Niwayama, S.; Cho, H. Chem. Pharm. Bull. 2009, 57, 508.
(13) (a) Bottaccio, G.; Chiusoli, G. P. Chem. Commun. (London)
1966, 618a. (b) Haruki, E.; Arakawa, M.; Matsumura, N.; Otsuji, Y.;
Imoto, E. Chem. Lett. 1974, 3, 427. (c) Sakurai, H.; Shirahata, A.;
Hosomi, A. Tetrahedron Lett. 1980, 21, 1967. (d) Mori, H.; Satake, Y.
Chem. Pharm. Bull. 1985, 33, 3469. (e) Tirpak, R. E.; Olsen, R. S.;
Rathke, M. W. J. Org. Chem. 1985, 50, 4877. (f) Hisakazu, M. Bull.
Chem. Soc. Jpn. 1988, 61, 435. (g) Chiba, K.; Tagaya, H.; Miura, S.;
Karasu, M. Chem. Lett. 1992, 21, 923. (h) Abe, H.; Inoue, S. J. Chem.
Soc., Chem. Commun. 1994, 1197. (i) Flowers, B. J.; Gautreau-Service,
R.; Jessop, P. G. Adv. Synth. Catal. 2008, 350, 2947. (j) Vechorkin, O.;
Hirt, N.; Hu, X. Org. Lett. 2010, 12, 3567. (k) Dingyi, Y.; Yugen, Z.
Green Chem. 2011, 13, 1275. (l) Wang, X.; Lim, Y. N.; Lee, C.; Jang,
H.-Y.; Lee, B. Y. Eur. J. Org. Chem. 2013, 2013, 1867. (m) Banerjee, A.;
Dick, G. R.; Yoshino, T.; Kanan, M. W. Nature 2016, 531, 215.
(n) Fenner, S.; Ackermann, L. Green Chem. 2016, 18, 3804. (o) Zhang,
W.-Z.; Yang, M.-W.; Lu, X.-B. Green Chem. 2016, 18, 4181.
(14) (a) Aggarwal, V. K.; Sheldon, C. G.; Macdonald, G. J.; Martin,
W. P. J. Am. Chem. Soc. 2002, 124, 10300. (b) Jiang, N.; Wang, J.
Tetrahedron Lett. 2002, 43, 1285. (c) Matsuya, Y.; Ohsawa, N.;
Nemoto, H. J. Am. Chem. Soc. 2006, 128, 13072. (d) Xiao, F.; Liu, Y.;
Wang, J. Tetrahedron Lett. 2007, 48, 1147. (e) Draghici, C.; Brewer, M.
J. Am. Chem. Soc. 2008, 130, 3766.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: fmo@pku.edu.cn.
ORCID
Fanyang Mo: 0000-0002-4140-3020
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The project was supported by the Natural Science Foundation
of China (Grant Nos. 21502003 and 21772003). We also thank
the “1000-Youth Talents Plan” and Peking University for start-
up funds.
REFERENCES
(1) Zhang, Y.; Wang, J. Chem. Commun. 2009, 5350.
(2) (a) Buchner, E.; Curtius, T. Ber. Dtsch. Chem. Ges. 1885, 18,
2371. (b) Schlotterbeck, F. Ber. Dtsch. Chem. Ges. 1907, 40, 1826.
(c) Gutsche, C. D. Org. React. 1954, 8, 364. (d) Candeias, N. R.;
Paterna, R.; Gois, P. M. P. Chem. Rev. 2016, 116, 2937.
■
(15) Tan, Z.; Qu, Z.; Chen, B.; Wang, J. Tetrahedron 2000, 56, 7457.
(16) Davis, O. A.; Bull, J. A. Angew. Chem., Int. Ed. 2014, 53, 14230.
(17) Yu, X.; Yu, S.; Xiao, J.; Wan, B.; Li, X. J. Org. Chem. 2013, 78,
5444.
(3) Arndt, F.; Eistert, B. Ber. Dtsch. Chem. Ges. B 1935, 68, 200.
(4) (a) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091.
(b) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds: From Cyclopropanes to
Ylides; John Wiley & Sons: New York, 1998. (c) Zhang, Z.; Wang, J.
Tetrahedron 2008, 64, 6577. (d) Ford, A.; Miel, H.; Ring, A.; Slattery,
C. N.; Maguire, A. R.; McKervey, M. A. Chem. Rev. 2015, 115, 9981.
(e) Qiu, D.; Qiu, M.; Ma, R.; Zhang, Y.; Wang, J. Huaxue Xuebao
2016, 74, 472.
(18) Takano, S.; Tomita, S.; Takahashi, M.; Ogasawara, K. Chem.
Lett. 1987, 16, 1569.
(19) De Simone, F.; Saget, T.; Benfatti, F.; Almeida, S.; Waser, J.
Chem. - Eur. J. 2011, 17, 14527.
(5) Li, H.; Zhang, Y.; Wang, J. Synthesis 2013, 45, 3090.
(6) (a) Hooz, J.; Linke, S. J. Am. Chem. Soc. 1968, 90, 5936.
(b) Hooz, J.; Linke, S. J. Am. Chem. Soc. 1968, 90, 6891.
(7) (a) Peng, C.; Zhang, W.; Yan, G.; Wang, J. Org. Lett. 2009, 11,
1667. (b) Li, H.; Wang, L.; Zhang, Y.; Wang, J. Angew. Chem., Int. Ed.
2012, 51, 2943. (c) Li, H.; Shangguan, X.; Zhang, Z.; Huang, S.;
Zhang, Y.; Wang, J. Org. Lett. 2014, 16, 448.
(8) Barluenga, J.; Tomas
Chem. 2009, 1, 494.
́ ́
-Gamasa, M.; Aznar, F.; Valdes, C. Nat.
(9) Peng, C.; Cheng, J.; Wang, J. J. Am. Chem. Soc. 2007, 129, 8708.
(10) (a) Aresta, M.; Dibenedetto, A. Dalton Trans. 2007, 2975.
(b) Sakakura, T.; Choi, J.-C.; Yasuda, H. Chem. Rev. 2007, 107, 2365.
(c) Mikkelsen, M.; Jorgensen, M.; Krebs, F. C. Energy Environ. Sci.
2010, 3, 43. (d) Cokoja, M.; Bruckmeier, C.; Rieger, B.; Herrmann, W.
A.; Kuhn, F. E. Angew. Chem., Int. Ed. 2011, 50, 8510. (e) Huang, K.;
̈
Sun, C.-L.; Shi, Z.-J. Chem. Soc. Rev. 2011, 40, 2435. (f) Omae, I.
Coord. Chem. Rev. 2012, 256, 1384. (g) Tsuji, Y.; Fujihara, T. Chem.
Commun. 2012, 48, 9956. (h) Yang, Z.-Z.; He, L.-N.; Gao, J.; Liu, A.-
H.; Yu, B. Energy Environ. Sci. 2012, 5, 6602. (i) Yu, B.; Diao, Z.-F.;
Guo, C.-X.; He, L.-N. J. CO2 Util. 2013, 1, 60. (j) Aresta, M.;
Dibenedetto, A.; Angelini, A. Chem. Rev. 2014, 114, 1709. (k) Maeda,
C.; Miyazaki, Y.; Ema, T. Catal. Sci. Technol. 2014, 4, 1482. (l) Yeung,
C. S.; Dong, V. M. Top. Catal. 2014, 57, 1342. (m) Fiorani, G.; Guo,
W.; Kleij, A. W. Green Chem. 2015, 17, 1375. (n) Liu, Q.; Wu, L.;
Jackstell, R.; Beller, M. Nat. Commun. 2015, 6, 5933. (o) Yu, B.; He,
L.-N. ChemSusChem 2015, 8, 52. (p) Borjesson, M.; Moragas, T.;
̈
Gallego, D.; Martin, R. ACS Catal. 2016, 6, 6739.
6759
DOI: 10.1021/acs.orglett.7b03573
Org. Lett. 2017, 19, 6756−6759