KI Catalyzed Nitrogenation of Aldehydes and Alcohols: Direct Synthesis of Carbamoyl Azides and Ureas

Article abstract of DOI:10.1002/cjoc.201600914

An efficient KI catalyzed nitrogenation of aldehydes and alcohols for the direct synthesis of carbamoyl azides and ureas via a radical process has been developed. The simple operating procedures, the readily available starting materials including aldehydes, alcohols and amines, as well as the utility of the products all make this strategy very attractive.

Full text of DOI:10.1002/cjoc.201600914

COMMUNICATION
DOI: 10.1002/cjoc.201600914
KI Catalyzed Nitrogenation of Aldehydes and Alcohols: Direct
Synthesis of Carbamoyl Azides and Ureas
Song Song,*,a Peng Feng,a Miancheng Zou,a and Ning Jiao*,a,b
a State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University,
Beijing 100191, China
b Shanghai Key Laboratory of Green Chemistry and Chemical Processes, East China Normal University,
Shanghai 200062, China
An efficient KI catalyzed nitrogenation of aldehydes and alcohols for the direct synthesis of carbamoyl azides
and ureas via a radical process has been developed. The simple operating procedures, the readily available starting
materials including aldehydes, alcohols and amines, as well as the utility of the products all make this strategy very
attractive.
Keywords nitrogenation, aldehydes, carbamoyl azides, ureas, KI, TBHP
Introduction
The generated acyl azides by aldehydes and azides
could be easily converted into isocyanates in situ via
Curtius rearrangement.[12] The subsequent addition of
hydrazoic acids to isocyanates would generate car-
bamoyl azides (Scheme 1c). In our assumption, the util-
ity of aldehyde cross-coupling method will be further
expanded to alcohols.
Aldehydes are common and fundamental organic
units, and are conveniently transformed to various val-
ue-added chemicals.[1] Among them, the oxidative cou-
pling of aldehydes for the synthesis of other functional
compounds has attracted considerable attentions.[2] By
the employment of hypervalent iodine(III) reagents[3] or
transition-metal catalysts,[4] some novel oxidative
transformations of aldehydes have been developed.
Carbamoyl azides are versatile intermediates and build-
ing blocks in organic synthesis.[5] Several groups re-
ported the synthesis of carbamoyl azides from alde-
hydes with the employment of iodine(I) or iodine(III)
reagents which were unstable or air sensitive (Scheme
1a).[6] Thus, it is highly desirable to develop a practical
approach to realize the transformation of aldehydes to
carbamoyl azides.
Scheme 1 The synthesis of carbamoyl azides
Recently, Wan[7] and Barbas III[8] groups reported
the transformation of aldehydes to amides catalyzed by
iodine/tert-butyl hydroperoxide (TBHP) system
(Scheme 1b). With a new coupling partner, the effective
strategy expands the application of iodine/TBHP sys-
tem[9] in C－H functionalization of aldehydes. We pre-
viously reported a simple ceric ammonium nitrate (CAN)
catalyzed functionalization of ketones through double
C－C bond cleavage strategy for the synthesis of car-
bamoyl azides (Scheme 1c).[10] Inspired by the above
results and our previous nitrogenation reactions,[11]
herein, we tried to introduce the iodine/TBHP system
into the nitrogenation chemistry of aldehydes and azides.
Experimental
A dry flask with stir bar was charged with benzalde-
hyde (0.3 mmol, 31.8 mg) and KI (0.06 mmol, 9.96 mg).
*
E-mail: jiaoning@bjmu.edu.cn; Tel.: 0086-010-82805297; Fax: 0086-010-82805297
Received December 23, 2016; accepted January 25, 2017; published online XXXX, 2017.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201600914 or from the author.
In Memory of Professor Enze Min.
Chin. J. Chem. 2017, XX, 1—4
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Song et al.
COMMUNICATION
Then TMSN3 (1.2 mmol, 138 mg) and TBHP (1.2 mmol,
219 µL) in EtOAc (1 mL) was added to the flask at
room temperature. The solution was stirred at 75 ℃
under air for 24 h. After being cooled down to room
temperature, the resulting mixture was filtered and con-
centrated. The residue was purified by flash chromatog-
raphy on silica gel (eluent: V(petroleum ether)/
V(ethylacetate)＝20∶1) to afford the product.
substituted aryl aldehydes were subjected to this trans-
formation (Table 2). The results showed that aryl alde-
hydes with electron-donating groups were well tolerated
and gave the desired products in moderate to good
yields (entries 1－4, 8－9). The electron-withdrawing
group substituted aldehydes were also tolerated, but the
efficiency decreased slightly (entries 5－7). Steric hin-
drance also showed an effect in the process. For exam-
ple, the reaction of 2-methylbenzaldeyde (1i) with
TMSN3, produced the product 2i in 50% yield (cf. en-
tries 2 and 9). Moreover, heteroaryl aldehyde such as
thiophene was tolerated in this transformation and pro-
vided the corresponding product 2l in moderate yield
(entry 12). Unfortunately, the aliphatic aldehydes are
not compatible under standard reaction conditions.
Results and Discussion
We commenced our hypothesis by investigating the
reaction of benzaldehyde (1a) with trimethylsilylazide
(TMSN3) (Table 1). Firstly, a series of catalysts with
TBHP as oxidant were tested. When TBAI was em-
ployed as the catalyst, the desired product 2a was iso-
lated in 17% yield (entry 1). Subsequent research of
catalysts showed that KI was the best choice for this
transformation (entries 1－3). The other solvents in-
cluding THF, DMF, and dioxane decreased the efficien-
cy of this reaction strongly (entries 4－6). The other
oxidants such as m-CPBA or K2S2O8 could not promote
this reaction (entries 7－10). Elevating the reaction
temperature to 100 ℃ had a slight positive effect on
the yield (cf. entries 2 and 10). Only trace amount of the
desired product was obtained when sodium azide (NaN3)
was used as the azide source (entry 11). The concentra-
tion of the reaction played an important role in this pro-
cess. When the solvent was reduced to 1 mL, the desired
product was isolated in 75% yield (entry 12).
Table 2 The scope of benzaldehydesa
H
O
1
N
N3
KI (20 mol%)
R1
+
R1
H
TMSN3
R1
TBHP, EtOAc, 75 oC
24 - 36 h
O
2
Entry
Product
Yieldb/%
1
2
C6H5
2a
2b
75
76
4-Me-C6H4
3
4-tBu-C6H4
2c
76
70
61
57
55
72
50
63
61
49
4
3,4-(Me)2-C6H3
4-F-C6H4
2d
2e
2f
5
6
4-Cl-C6H4
7
4-Br-C6H4
4-MeO-C6H4
2-Me-C6H4
4-EtO-C6H4
2-naphthyl
3-thienyl
2g
2h
2i
Table 1 Optimization of the reaction conditionsa
8
9
10
11c
12
2j
2k
2l
a
b
Reaction conditions: see Table 1, entry 12. Isolated yields.
c EtOAc (3 mL) was used.
We speculated that benzylamine, phenylacetalde-
hyde, and benzyl alcohol could also be converted to
carbamoyl azide because they are easily oxidized to
benzaldehyde under oxidative conditions. As we ex-
pected, when catalyzed by KI in the presence of TBHP
at 75 ℃, the reaction of TMSN3 with benzylamine,
phenylacetaldehyde, or benzyl alcohol produced car-
bamoyl azide 2a with lower efficiencies compared to
that of benzaldehyde (Table 3). To our delight, car-
bamoyl azides (2a, 2b, 2g, 2f) were obtained in moder-
ate yields when the reaction of TMSN3 and benzyl al-
cohol was catalyzed by 20 mol% I2 in the presence of
NaOH (entries 3－6). These results indicate that a cas-
cade oxidative aldehyde generation through C－N or
C－C cleavage and the subsequent nitrogenation of al-
dehyde via C－H bond cleavage, is involved in this
process.
a Reaction conditions: The reaction mixture of 1a (0.3 mmol),
TMSN3 (4.0 equiv.), catalyst (20 mol%), and oxidant (4.0 equiv.)
in solvent (2.0 mL) was stirred under air for 48 h. b Isolated yields.
d
c TBHP (70% aqueous solution). At 100 ℃.e Sodium azide was
used instead of TMSN3. f The solvent was 1 mL and reaction time
was 24 h.
With the optimized conditions in hand, a variety of
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KI Catalyzed Nitrogenation of Aldehydes and Alcohols
Table 3 The nitrogenation of benzylamine, phenylacetaldehyde,
and benzyl alcohola
tion process (Eq. 1). When the carbamoyl azide was
treated with 0.5 equiv. of NaOAc, the 1,3-diphenylurea
(3a) could be obtained in 95% yield, which suggested
that carbamoyl azide was the intermediate in the syn-
thesis of diphenylurea (Eq. 2).[15]
Scheme 2 Transformations of phenylcarbamoyl azide
O
H
N
N
Ph
O
H
H
H
N
Ph
4a: 67%
N
N
Ph
Ph
Ph
O
O
a
4b: 68%
4e
H
N
N3
N
N
Ph
a Reaction conditions: see Table 1, entry 12. b Isolated yields.c I2
(20 mol%) was used instead of KI, NaOH (20 mol%) was added.
N Ph
HN
O
2a
PhNH2
4c: 85%
O
4d
Carbamoyl azides are easily converted to symmet-
rical ureas under basic condition. Thus, we speculate
that the aldehydes could be directly converted to ureas if
NaOAc was added to the optimal conditions. As ex-
pected, symmetrical ureas could be directly prepared
from the reaction of aryl aldehyde with azide in the
presence of 0.5 equiv. of NaOAc catalyzed by KI (Table
4).
Reaction conditions: (a) 2a (0.2 mmol), morpholine (0.4 mmol),
EtOAc (1 mL), 75 ℃, 12 h. (b) 2a (0.2 mmol), benzylamine (0.4
mmol), EtOAc (2 mL), 75 ℃, 12 h. (c) 2a (0.4 mmol), NaOH (1.0
mL, 2 mol/L), dioxane (1.0 mL), r.t., 30 min. Then HCl (1.0 mL, 6
mol/L) was added, r.t., 30 min.
Table 4 The synthesis of symmetrical ureas from aldehydea
On the basis of the above experiments and previous
studies, a proposed mechanism is shown in Scheme 3.
Firstly, tert-butoxyl radical is generated from TBHP
through the catalytic cycle, where I2 plays a role as the
catalyst.[16] Meanwhile, the substrate is attacked by the
azide to produce the intermediate A. Secondly, tert-
butoxyl radical abstracts two hydrogen atoms from the
intermediate to generate acyl azide C.[17] The acyl azide
will undergo Curtius rearrangement[12] to generate aryl
isocyanate, which reacts with another azide to produce
carbamoyl azide.
a
Reaction conditions: The reaction mixture of 1 (0.2 mmol),
TMSN3 (4.0 equiv.), KI (20 mol%), TBHP (4.0 equiv.), and
NaOAc (0.5 equiv.) in EtOAc (1 mL) was stirred under air at
75 ℃ for 36 h. b Isolated yields.
Scheme 3 Possible mechanism
Carbamoyl azide could be transformed to various
kinds of ureas via the reaction with amine nucleophiles.
Moreover, under basic environment, carbamoyl azides
would decompose to aniline. The amide would be ob-
tained by the nucleophilic attack of Grignard reagent to
carbamoyl azide.[13] Besides, it is noteworthy that car-
bamoyl azides could undergo a cyclization process to
provide tetrazole, which is an useful building block and
common biological active molecule.[14]
H
N
O
[I]/TBHP
N3
Ar
TMSN
+
3
Ar
H
2
1
O
TMSN3
tBuO
or tBuOO
tBuO
or tBuOO
OH
O
OH
Ar
N3
Ar
N3
Ar
N3
H
A
C
B
tBuOH or tBuOOH
tBuOH or tBuOOH
When 1,1-diphenyethylene (a radical scavenger) was
added under the standard conditions, the yield of car-
bamoyl azide (2a) decreased dramatically, which indi-
cated that a radical path may be involved in the azida-
Conclusions
In conclusion, an efficient KI catalyzed direct azida-
Chin. J. Chem. 2017, XX, 1—4
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Song et al.
COMMUNICATION
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azide and ureas via a radical process has been developed.
The simple operating procedures, the readily availability
of the starting materials, and the utility of the products
all make the strategy attractive. Further application of
this method and studies about the mechanism are ongo-
ing in our laboratory.
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Acknowledgement
Financial support from National Basic Research
Program of China (973 Program) (No. 2015CB856600),
the National Natural Science Foundation of China (Nos.
21325206, 21632001), National Young Top-notch Talent
Support Program, CAS Interdisciplinary Innovation
Team, and Peking University Health Science Center
(Nos. BMU20150505, BMU20160541) is greatly ap-
preciated. We thank Bencong Zhu and Ao Sun in this
group for reproducing the results of 2a and 2k.
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