Rhodium-catalyzed intermolecular reaction of alkyl azides with diazo(aryl)acetates

Article abstract of DOI:10.1055/s-0033-1340173

An efficient intermolecular interception of alkyl azides by diazo(aryl)acetates was achieved in the presence of dirhodium tetraoctanoate. The initial products were unstable α-imino esters, and overaddition of carbenoids to the C-N double bonds was avoided. After acidic workup, the corresponding α-keto esters were obtained in good to excellent yields. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340173

LETTER
▌535
lRetther odium-Catalyzed Intermolecular Reaction of Alkyl Azides with Diazo-
(aryl)acetates
Intermolecular Interception of Alkyl Azides with Diazo(aryl)acetates
Peiming Gu,*a Xiu-Ping Wu,a Yan Su,b Xue-Qiang Li,a Ping Xue,a Rui Lia
a
Key Laboratory of Energy Sources & Engineering, State Key Laboratory Cultivation Base of Natural Gas Conversion and Department of
Chemistry, Ningxia University, Yinchuan 750021, P. R. of China
Fax +86(951)2062323; E-mail: gupm@nxu.edu.cn
b
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Received: 19.09.2013; Accepted after revision: 10.12.2013
capture of an azide group by a rhodium(II) carbenoid has
been reported by Wee and co-workers,3a and confirmed by
another group.3b In this case, the intermolecular addition
of the carbenoid to the C=N bond was suppressed as a re-
Abstract: An efficient intermolecular interception of alkyl azides
by diazo(aryl)acetates was achieved in the presence of dirhodium
tetraoctanoate. The initial products were unstable α-imino esters,
and overaddition of carbenoids to the C–N double bonds was avoid-
ed. After acidic workup, the corresponding α-keto esters were ob- sult of the high potency of the intramolecular interception
tained in good to excellent yields.
of the carbenoid by the azide group.
Key words: azides, carbenoids, diazo compounds, imines, esters,
catalysis, rhodium
N3
N3
Ph
CO2Et
+
O
Ph
CO2Et
N2
Rh2(OAc)4
or Rh2(Oct)4
Ph
H
The azide group has been used extensively to facilitate the
introduction of amino groups in synthetic organic chemis-
try. In recent years, more properties and reactivities of the
organic azides have been explored.1 Among these efforts,
only a few successful conversions of free carbenes2 or
carbenoids3 into imines by reaction with alkyl azides have
been reported. Here, we present an efficient rhodium-cat-
alyzed intermolecular interception of diazo(aryl)acetates
by alkyl azides.
50–70% yield
trace
Oct = octanone
Rh(II)
a
H2O
Ph
Ph
b
a
Ph
+
b
N2
N
CO2Et
N
RhLn
+
N
–
CO2Et
CO2Et
RhLn
N2
I
Scheme 1 Rhodium-catalyzed reaction of (1-azidovinyl)benzene
with a diazo ester
In an attempt to prepare β-azidocyclopropane esters
through rhodium-catalyzed cyclopropanation of (1-azi-
dovinyl)benzene with ethyl diazoacetate (Scheme 1, path
a),4 we found that a trace of acetophenone was produced
along together with the β-azidocyclopropane ester when
dirhodium tetraacetate or dirhodium tetraoctanoate was
present. We surmised that the acetophenone was formed
through hydrolysis of ethyl [(1-phenylvinyl)imino]acetate
(I), formed through a competing reaction of a rhodium(II)
carbenoid with the nucleophilic azide group (Scheme 1,
path b).5
To the best of our knowledge, there have been no reports
of an intermolecular reaction of a rhodium(II) carbenoid
with an alkyl azide to give an α-imino ester. As a result,
the observations described above prompted us to begin
extensive research on this intermolecular transformation.
There were three principle questions to consider in eluci-
dating the nature of the intermolecular reaction. (1)
Would the intermolecular conversion of the carbenoid
with an alkyl azide proceed efficiently? (2) Would the in-
terception of the carbenoid with the azide group be pre-
ferred over C–H insertion, as the azide group has been
reported to direct C–H insertion?8 (3) Would an aziridine
be formed through overaddition of the carbenoid to the
newly formed C=N bond?
The weak nucleophilicity of the azide group has been
demonstrated in several types of Schmidt reactions of al-
kyl azides.1,6,7 The inner nitrogen atom of the azide group
can be attacked by an electrophilic free carbene to form an
imine with loss of one molecule of nitrogen.2a However,
overadditions of the highly reactive carbenes to the newly
formed C=N bonds were observed in some cases, result-
ing in the formation of mixtures of imines and aziridi-
nes.2b The azide group has been shown to be an effective
activating group in directing C–H insertion reactions of
cyclohexyl scaffolds.8 Furthermore, an intramolecular
With these three questions in mind, we examined the re-
action of ethyl diazo(phenyl)acetate (1a; 0.5 mmol) with
benzyl azide (2a; 0.6 mmol) in the presence of dirhodium
tetraacetate [Rh2(OAc)4]. NMR analysis of the crude reac-
tion mixture showed that imine 4a was, by far, the major
product, and no product from C–H insertion was ob-
served. The conversion is quite attractive, as imines have
been widely used in syntheses of natural products.1,9 Cur-
rently, the most general method for preparing an imine
from an alkyl azide involves the Staudinger reduction of
the azide followed by aza-Wittig reaction with a carbonyl
SYNLETT 2014, 25, 0535–0538
Advanced online publication: 14.01.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340173; Art ID: ST-2013-W0892-L
© Georg Thieme Verlag Stuttgart · New York

536
P. Gu et al.
LETTER
compound.10 The phosphine oxide produced in the aza- Having successful converted ethyl diazo(phenyl)acetate
Wittig reaction makes the purification procedure inconve- (1a) and benzyl azide (2a) into the ethyl oxo(phenyl)ace-
nient. Note that this conversion does not generate any or- tate (3a), we examined the reactions of two other alkyl
ganic species other than the imine.
azides: ethyl azidoacetate (2b) and heptyl azide (2c). Both
reacted with diazo(phenyl)acetate (1a) to give good yields
of the corresponding α-keto ester 3 (Table 2, entries 1–3).
Next, we explored the reactions of a series of diazo(ar-
yl)acetates 1b–m in the presence of dirhodium tetraoc-
tanoate. All the conversions gave the corresponding aryl
α-keto esters 3 (entries 4–23). Among the important fea-
tures of this reaction are the following: (1) the interception
of the diazo esters 1a–m by several types of alkyl azide
2a–c was shown to be efficient; (2) benzyl azide (2a) gave
better conversions than did alkyl azide 2b or 2c; (3) meth-
yl and ethyl diazo(aryl)acetates gave slightly better yields
of α-keto esters 3 than did the corresponding benzyl diazo
esters; (4) two molecules of nitrogen are released from the
reaction mixture; (5) the efficient reduction of the azide
group has been addressed; and, finally, (6) aryl α-keto es-
ters, which are important intermediates in synthetic
chemistry12–14 were obtained in good to excellent yields
by acidic workup of the initial interception products.
Flash column chromatography of the crude mixture from
the reaction of 1a with 2a gave a mixture of the unstable
imine 4a and ethyl oxo(phenyl)acetate (3a). To character-
ize the product better, we performed an acidic workup,
which gave keto ester 3a in 81% yield (Table 1). Increas-
ing the amount of benzyl azide (2a) improved the yield of
3a (entries 2 and 3). Among the catalysts examined,
dirhodium tetraoctanoate [Rh2(Oct)4] was found to be the
most efficient (entry 4).11 The copper(II) triflate catalyzed
reaction gave the ketone 3a in a similar yield (entry 7), al-
though the reaction had to be performed for a longer time
in refluxing dichloromethane. Note that no explicit addi-
tion of the rhodium carbenoid to the imino ester 4a took
place, even when an excess of ethyl diazo(phenyl)acetate
(1a) was used at 7 °C (entry 8). Furthermore, hydrogena-
tion of the crude mixture in the presence of ruthenium/car-
bon gave the corresponding amino ester in 75% yield (for
details, see the Supporting Information).
Table 2 Scope of the Reaction of Diazo Esters 1 with Alkyl Azides 2
Table 1 Reaction of Ethyl Diazo(phenyl)acetate (1a) with Benzyl
Azide (2a)
N2
O
N2
Rh2(Oct)4
CO2R1
CO2R1
+
R2 N3
Ar
Ar
CO2Et
acidic workup
2a: benzyl azide
2b: ethyl azidoacetate
2c: heptyl azide
O
1a
N
Ph
1
3
Rh(II) cat.
2 M HCl
+
CO2Et
CO2Et
N3
Entrya Diazo ester
Alkyl
azide
Product Yieldb
(%)
3a
4a
2a
1
1a
2a
3a
99
Ar = Ph; R1 = Et
Entrya
Catalyst
2a/1a
Time (h) Yieldb (%)
2
3
4
1a
1a
2b
2c
2a
3a
3a
3b
73
82
93c
1
2
3
4
5
6
7
8
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
1.2:1
2:1
3:1
2:1
2:1
2:1
2:1
1:3
4
81
94
93
99
94
89
99f
93g
2
1b
1
Ar = Ph; R1 = Me
c
Rh2(Oct)4
1
5
1c
2a
3c
95
Ar = 4-Tol; R1 = Et
d
Rh2(DOSP)4
3.5
1
6
7
1c
2b
2a
3c
74
99
e
Rh2(TBSP)4
Cu(OTf)2
1d
3d
5
Ar = 4-MeOC6H4; R1 = Et
Rh2(Oct)4
1
8
1e
2a
3e
92
Ar = 4-ClC6H4; R1 = Et
a A mixture of ethyl diazo(phenyl)acetate (1a; 0.5 mmol) and BnN3
(2a; 0.6 to 1.5 mmol) in CH2Cl2 (3 mL) was added slowly to a stirred
solution of the catalyst (0.003 mmol) in CH2Cl2 (1 mL) at 10–15 °C,
and the mixture was stirred for the additional time shown above.
b Isolated yield after acidic workup with 2 M aq HCl (0.5 mL) for 45
min.
9
1e
2b
2a
3e
3f
76
92
10
1f
Ar = 4-BrC6H4; R1 = Et
c Oct = octanoate.
11
12
1f
2c
2a
3f
86
87
d DOSP = 1-[(4-dodecylphenyl)sulfonyl]prolinate.
e TBSP = 1-[(4-tert-butylphenyl)sulfonyl]prolinate.
f Reaction at reflux.
1g
3g
Ar = Ph; R1 = Bn
g Reaction at 7 °C.
Synlett 2014, 25, 535–538
© Georg Thieme Verlag Stuttgart · New York

LETTER
Intermolecular Interception of Alkyl Azides with Diazo(aryl)acetates
537
Table 2 Scope of the Reaction of Diazo Esters 1 with Alkyl Azides 2
(continued)
for the conversion shown in Scheme 3. The process is ini-
tiated by the generation of rhodium carbenoid II in situ
from diazo ester 1 by loss of nitrogen. Nucleophilic attack
on the rhodium complex by the inner nitrogen atom of
azide 2 gives intermediate III. Cleavage of the Rh–C bond
releases the dirhodium catalyst, and synchronous nitrogen
extrusion gives imino ester 4, which is ultimately hydro-
lyzed to give the α-keto ester 3 under acidic conditions.
N2
O
Rh2(Oct)4
Ar
+
R2 N3
CO2R1
Ar
CO2R1
acidic workup
2a: benzyl azide
2b: ethyl azidoacetate
2c: heptyl azide
1
3
Entrya Diazo ester
Alkyl
azide
Product Yieldb
(%)
N
R1
O
N2
H+/H2O
Ar
Rh(II)
N
N2
+
13
1h
2a
3h
85
CO2R2
R1
Ar
CO2R2
Ar
CO2R2
Ar = 4-MeOC6H4; R1 = Bn
2
1
4
3
14
15
1h
2c
2a
3h
3i
87
84
– N2
Rh2L4
R1
Ar
CO2R2
– N2
1i
Ar = 4-BrC6H4; R1 = Bn
N2
N
N
N2
Rh2L4
CO2R2
III
16
17
1i
2c
2a
3i
3j
81
86
2
Rh2L4
Ar
1j
Ar = Ph; R1 = 4-BrC6H4CH2
R1
II
18
19
1j
2b
2a
3j
74
Scheme 3 Possible mechanism for the reaction
1k
3k
87c
Ar = Ph; R1 = 4-MeOC6H4CH2
Note that all the reactions gave imino esters 4 as the pri-
mary products, as identified by NMR analysis. Generally,
the alkyl azides were stable under most reaction condi-
tions, which is why the azide group was used as the pre-
cursor of an amino group. The initial crude mixture might
be amenable to further transformations of the imino es-
ters, if desired, as excess benzyl azide was the only dis-
tinct impurity.
20
21
1k
2b
2a
3k
3l
62
93
1l
Ar = 2-naphthyl; R1 = Bn
22
23
1l
2c
2a
3l
83
86
1m
3m
Ar = 1-naphthyl; R1 = Bn
a A mixture of alkyl diazo(aryl)acetate 1 (0.5 mmol) and alkyl azide 2
In conclusion, we have developed an efficient method for
(1.0 mmol) in CH2Cl2 (3 mL) was slowly added into a stirred solution intermolecular condensation of alkyl azides with diazo es-
of Rh2(Oct)4 (2.7 mg) in CH2Cl2 (1 mL) at 10–15 °C.
ters in the presence of dirhodium tetraoctanoate. The ini-
tial products were α-imino esters, formed with release of
b Isolated yield after acid workup.
c Reaction of ethyl diazo(phenyl)acetate (1a) (1.0 mmol) with BnN3
two molecules of nitrogen; no C–H insertion products or
(2a) (2.0 mmol).
aziridines from overaddition of the carbenoid were isolat-
ed. Hydrolysis of the α-imino esters with aqueous hydro-
Another example that illustrates the chemoselectivity of
the reaction is shown in Scheme 2. The conversion of ami-
no azide 5 into the imino ester 6 showed that the carbenoid
preferentially intercepts the azide group rather than under-
going N–H insertion15,16 or C–H insertion.8 The imino es-
ter 6 was sufficiently stable on silica gel to permit its
isolation in 73% yield after flash chromatography.
chloric acid gave the corresponding α-keto esters in good
to excellent yields. Currently, extensive research on this
transformation and its applications are under way in our
laboratory.
Acknowledgment
This work was supported by the National Natural Science Founda-
tion of China (Nos. 21262024, 21062014, and 21064005), the Pro-
gram for New Century Excellent Talents in University (NCET-13-
0874), the Key Project of Chinese Ministry of Education (211193),
the Scientific Research Foundation for Returned Scholars (Ministry
of Education of China), and the 211 Project of Ningxia University.
N
NHTs
N2
NHTs
Rh2(Oct)4
73%
CO2Et
+
CO2Et
N3
6
1a
5
Scheme 2 Reaction of diazo ester 1a with amino azide 5
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
copies of NMR spectra for all the reaction products, and NMR spec-
tra for the crude reaction mixture of benzyl azide (2a) with ethyl di-
On the basis of the experimental results described above
and reports in the literature,3,17 we propose the mechanism
azo(phenyl)acetate (1a).
S
Iunofpig
o
i
io
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 535–538

538
P. Gu et al.
LETTER
(2.7 mg, 0.003 mmol) in CH2Cl2 (1.0 mL), and the mixture
was stirred at 10–15 °C for 30 min. 2 M aq HCl (0.5 mL) was
added, and the mixture was kept for another 45 min. H2O
(5 mL) was then added, and the mixture was extracted with
CH2Cl2 (10 mL). The extracts were washed with H2O (10
mL), and the organic phases were combined, dried
(Na2SO4), and concentrated. The residue was purified by
flash chromatography to give a slightly yellow oil; yield: 88
mg (99%). Rf = 0.52 (EtOAc–PE, 1:10); 1H NMR (400
MHz, CDCl3): δ = 1.43 (t, J = 7.2 Hz, 3 H), 4.46 (q, J = 7.2
Hz, 2 H), 7.50–7.54 (m, 2 H), 7.64–7.69 (m, 1 H), 8.00–8.03
(m, 2 H); 13C NMR (100 MHz, CDCl3): δ = 14.1, 62.3, 128.9
(2 C), 130.0 (2 C), 132.4, 134.9, 163.8, 186.4.
References
(1) For a review, see: Organic Azides: Synthesis and
Applications; Bräse, S.; Banert, K., Eds.; Wiley: Weinheim,
2010.
(2) For intermolecular reactions of free dichlorocarbene with
alkyl azides, see: (a) Baldwin, J. E.; Patrick, J. E. Chem.
Commun. 1968, 968. (b) Szönyi, F.; Cambon, A.
Tetrahedron Lett. 1992, 33, 2339.
(3) For intramolecular reactions of diazo esters with alkyl azides
in the presence of Rh catalysts, see: (a) Wee, A. G. H.;
Slobodian, J. J. Org. Chem. 1996, 61, 2897. (b) Blond, A.;
Moumné, R.; Bégis, G.; Pasco, M.; Lecourt, T.; Micouin, L.
Tetrahedron Lett. 2011, 52, 3201.
(4) For an asymmetric cyclopropanation of α-azidostyrenes
with diazo esters developed by our group, see: Gu, P.; Su,
Y.; Wu, X.-P.; Sun, J.; Liu, W.-Y.; Xue, P.; Li, R. Org. Lett.
2012, 14, 2246.
(5) The acetophenone could also be derived from (1-azido-
vinyl)benzene. For several conversions, see: (a) Wang, Y.-
F.; Toh, K. K.; Lee, J.-Y.; Chiba, S. Angew. Chem. Int. Ed.
2011, 50, 5927. (b) Belinka, B. A. Jr. Hassner A. 1979, 44,
4712. (c) Hassner, A.; Ferdinandi, E. S.; Isbister, R. J. J. Am.
Chem. Soc. 1970, 92, 1672.
(6) For a recent review on the Schmidt reaction of alkyl azides
with carbonyl compounds, see: Wrobleski, A.; Coombs, T.
C.; Huh, C. W.; Li, S.-W.; Aubé, J. Org. React. (N. Y.) 2012,
78, 1.
(12) For selected examples of α-keto esters in synthetic
chemistry, see: (a) Petronijevic, F.; Hart, A. C.; Paquette, L.
A. Tetrahedron Lett. 2006, 47, 1741. (b) Jiang, B.; Chen, Z.-
L.; Tang, X.-X. Org. Lett. 2002, 4, 3451. (c) Ramachandran,
P. V.; Pitre, S.; Brown, H. C. J. Org. Chem. 2002, 67, 5315.
(d) Christensen, C.; Juhl, K.; Hazell, R. G.; Jørgensen, K. A.
J. Org. Chem. 2002, 67, 4875. (e) Akiyama, T.; Suzuki, M.
Chem. Commun. (Cambridge) 1997, 2357. (f) Boeykens,
M.; De Kimpe, K. A.; Tehrani, N. J. Org. Chem. 1994, 59,
6973.
(13) For preparation of aryl α-keto esters by in situ oxidation of
diazo esters, see: (a) Barrett, A. G. M.; Braddock, D. C.;
Lenoir, I.; Tone, H. J. Org. Chem. 2001, 66, 8260. (b) Ma,
M.; Li, C.-K.; Peng, L.-L.; Xie, F.; Zhang, X.; Wang, J.-B.
Tetrahedron Lett. 2005, 46, 3927.
(7) For Schmidt reactions of alkyl azides with acyl chlorides and
Schmidt reactions of aromatic aldehydes with azido amines
recently developed by our group, see: (a) Gu, P.; Kang, X.-
Y.; Sun, J.; Wang, B.-J.; Yi, M.; Li, X.-Q.; Xue, P.; Li, R.
Org. Lett. 2012, 14, 5796. (b) Gu, P.; Sun, J.; Kang, X.-Y.;
Yi, M.; Li, X.-Q.; Xue, P.; Li, R. Org. Lett. 2013, 15, 1124.
(8) Wang, P.; Adams, J. J. Am. Chem. Soc. 1994, 116, 3296.
(9) For a recent review on applications of imines in the synthesis
of alkaloids, see: Martin, S. F. Pure Appl. Chem. 2009, 81,
195; and references cited therein.
(10) For a recent review on the aza-Wittig reaction, see: Palacios,
F.; Alonso, C.; Aparicio, D.; Rubiales, G.; de los Santos, J.
M. Tetrahedron 2007, 63, 523.
(11) Ethyl Oxo(phenyl)acetate (3a); Typical Procedure
A mixture of ethyl diazo(phenyl)acetate (1a; 95 mg, 0.5
mmol) and BnN3 (2a; 133 mg, 1.0 mmol) in CH2Cl2 (3.0
mL) was added over 30 min to a stirred solution of Rh2(Oct)4
(14) For preparation of aryl α-keto esters by Rh-catalyzed
decomposition of diazo esters with H2O and DEAD in
refluxing toluene, see: Guo, Z.; Huang, H.; Fu, Q.; Hu, W.
Synlett. 2006, 2486.
(15) For an example of intermolecular N–H insertion of 4-
toluenesulfonamide, see: Buck, R.; Moody, C.; Pepper, A.
ARKIVOC 2002, (viii), 16.
(16) For selected intramolecular N–H insertions of 4-
toluenesulfonamide, see: (a) Burtoloso, A.; Correia, C.
Tetrahedron Lett. 2004, 45, 3355. (b) Burtoloso, A.;
Correia, C. J. Organomet. Chem. 2005, 690, 5636.
(c) Wang, J.; Hou, Y.; Wu, P. J. Chem. Soc., Perkin Trans.
1 1999, 2277.
(17) Nakamura, E.; Yoshikai, N.; Yamanaka, M. J. Am. Chem.
Soc. 2002, 124, 7181.
Synlett 2014, 25, 535–538
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.