A formal metal-free N-arylation via the Schmidt reaction of aromatic aldehydes with an azido amine

Article abstract of DOI:10.1021/ol400213f

A formal metal-free N-arylation of aromatic aldehydes with 3-azido-N-tosylpropan-1-amine through the Schmidt process was realized in the presence of acids. TfOH was found to be a good promoter, and the exclusive 1,2-aryl migration was observed. Furthermor

Full text of DOI:10.1021/ol400213f

ORGANIC
LETTERS
2013
Vol. 15, No. 5
1124–1127
A Formal Metal-Free N‑Arylation via the
Schmidt Reaction of Aromatic Aldehydes
with an Azido Amine
Peiming Gu,* Jian Sun, Xiao-Yan Kang, Ming Yi, Xue-Qiang Li, Ping Xue, and Rui Li
Key Laboratory of Energy Sources & Engineering, State Key Laboratory Cultivation
Base of Natural Gas Conversion and Department of Chemistry, Ningxia University,
Yinchuan 750021, China
gupm@nxu.edu.cn
Received January 28, 2013
ABSTRACT
A formal metal-free N-arylation of aromatic aldehydes with 3-azido-N-tosylpropan-1-amine through the Schmidt process was realized in the
presence of acids. TfOH was found to be a good promoter, and the exclusive 1,2-aryl migration was observed. Furthermore, the conversion of an
aliphatic aldehyde to the N,N-disubstituted formamide was achieved in excellent yield.
Aromatic amines play very important roles in the phar-
maceutical, material, and dye industries,1 which are usual-
ly made from the transition-metal-catalyzed arylation of
N-nucleophiles with aryl halides,2 arylboronic acids,3 or
arenes4 under strong basic conditions. Due to their im-
portance, continuous efforts have focused on the develop-
ment of a new type of aromatic coupling partners. For
example, the aryl carboxylic acids have been used for
copper-catalyzed decarboxylative N-arylation more recently.5
To the best of our knowledge, N-arylation of amines with
aromatic aldehydes through a similar conversion has not
been achieved. The nitrogen atom insertion into the CꢀC
bond between the benzene ring and carbonyl group might
be an alternative solution. The conversion of aldehydes to
one-carbon shorter amines through the Curtius rearran-
gement of acyl azides has been reported,6 and the acyl
azides were prepared in situ by oxidation of aldehydes in
the presence of azide. The expected products of the aryl-
migration Schmidt reaction of aryl aldehydes are aryl
amines, which is a sensible option to address this issue. In
this paper, we present an efficient method for the formal
N-arylation of 3-azido-N-tosylpropan-1-amine with aro-
matic aldehydes through the Schmidt process.
(1) For recent reviews, see: (a) Fisher, C.; Koenig, B. Beilstein J. Org.
Chem. 2011, 7, 59. (b) Hili, R.; Yudin, A. K. Nat. Chem. Biol. 2006, 2,
284.
(2) For selected examples, see: (a) Louie, J.; Hartwig, J. F. Tetra-
hedron Lett. 1995, 36, 3609. (b) Guram, A. S.; Rennels, R. A.; Buchwald,
S. L. Angew. Chem., Int. Ed. 1995, 34, 1348.
(3) For selected examples, see: (a) Lam, P. Y. S.; Clark, C. G.;
Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A.
Tetrahedron Lett. 1998, 39, 2941. (b) Chan, D. M. T.; Monaco, K. L.;
Wang, R.-P.; Winteres, M. P. Tetrahedron Lett. 1998, 39, 2933.
(4) For selected examples, see: (a) Tsang, W. C. P.; Zheng, M.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 14560. (b) Thu, H.-Y.; Yu,
W.-Y.; Che, C.-M. J. Am. Chem. Soc. 2006, 128, 9048. (c) Chen, X.; Hao,
X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6790. (d)
Jordan-Hore, J. A.; Johansson, C. C. C.; Gulias, M.; Beck, E. M.;
Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 16184. (e) Brasche, G.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 1932. (f) Mei, T.-S.;
Wang, X.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 10806.
(5) For selected examples, see: (a) Cho, C.-C.; Liu, J.-N.; Chien,
C.-H.; Shie, J.-J.; Chen, Y.-C.; Fang, J.-M. J. Org. Chem. 2009, 74, 1549.
(b) Jia, W.; Jiao, N. Org. Lett. 2010, 12, 2000. (c) Ju, L.; Bode, J. W.;
Toma, T.; Fukuyama, T. Org. Synth. 2010, 87, 218. (d) Zhang, Y.; Patel,
S.; Mainolfi, N. Chem. Sci. 2012, 3, 3196.
(6) (a) Vora, H. U.; Moncecchi, J. R.; Epstein, O.; Rovis, T. J. Org.
Chem. 2008, 73, 9727–9731. (b) Marinescu, L.; Thinggaard, J.; Thom-
sen, I. B.; Bols, M. J. Org. Chem. 2003, 68, 9453–9455.
(7) For two recently reviews on the Schmidt reaction of hydrazoic
ꢀ
acid or an alkyl azide with carbonyl compounds, see: (a) Aube, J. In
Organic Azides: Synthesis and Applications; Brase, S., Banert, K., Eds.;
Wiley: Weinheim, 2009; pp 191ꢀ237. (b) Wrobleski, A.; Coombs, T. C.;
ꢀ
Huh, C. W.; Li, S.-W.; Aube, J. Org. React. 2012, 78, 1–320.
(8) For an intramolecular Schmidt reaction of alkyl azides with acyl
chloride developed in our group, see: Gu, P.; Kang, X.-Y.; Sun, J.;
Wang, B.-J.; Yi, M.; Li, X.-Q.; Xue, P.; Li, R. Org. Lett. 2012, 14, 5796–
5799.
r
10.1021/ol400213f
Published on Web 02/20/2013
2013 American Chemical Society

Much effort has been focused toward the Schmidt con-
version of carbonyl compounds.7,8 The reaction of ketones
with alkyl azides has been extensively explored and widely
utilized in the total synthesis of natural products.7,9,10 In
contrast, only a few examples of the Schmidt reaction of
aldehydes with alkyl azides11ꢀ13 have been reported
(Scheme 1). The reaction of aldehydes with HN3 generally
furnished a mixture of nitriles and formanilides resulting
from migration of the aryl group in accepted yields.14,15
However when the alkyl azides were used, no formanilides
from the migration of aryl groups were observed.
amines if the aryl migration was preferred (Scheme 2).
However, the intramolecular reaction of aryl ketones was
proven to be less reactive;9b therefore it was easy to accept
the fact that the intermolecular conversion was lacking.
Previous research had revealed that aryl aldehydes were
slightly more reactive than aryl ketones for the intermolec-
ular reaction with alkyl azides, with release of benzamides
by hydride migration.13bꢀd Aube and co-workers reported
ꢀ
that the reaction of aliphatic aldehydes in the presence of
Lewis acids gave better results, albeit in poor regioselec-
tivities (alkyl shift vs hydride shift).12
Scheme 1. Intermolecular Schmidt Reactions of Alkyl Azides
with Aldehydes
Scheme 2. Promised Products from the Intermolecular Schmidt
Reaction of Aryl Aldehydes with Alkyl Azides
Following their continuing projects on the modified
ꢀ
16
intermolecularreaction of ketones, Aube andco-workers
presented the conversion of aromatic aldehydes with azido
alcohols to heterocycles in good yields.13 The products
could be thought to be derived from the formal hydride
migration, although elimination of Hþ and N2 of the key
azidohydrin intermediate (I) was preferred by these authors
(Scheme 3).13a The strong migration aptitude of the aryl
group had been observed in the Schmidt reaction of carboca-
tions with alkyl azides;17 thus it was very interesting that no
amides from the competitive aryl migration were found in the
reactions of aryl aldehydes with alkyl azides or azido alcohols.
Theoretically, the Schmidt reaction of aromatic ketones
or aromatic aldehydes with alkyl azides would give aryl
Scheme 3. Regioselectivity of Schmidt Reactions of Aldehydes
with 1,3-Azido Alcohol
(9) For a representative intramolecular Schmidt reaction of alkyl
ꢀ
1991, 113, 8965–8966. (b) Milligan, G. L.; Mossman, C. J.; Aube, J.
azides with ketones, see: (a) Aube, J.; Milligan, G. L. J. Am. Chem. Soc.
ꢀ
J. Am. Chem. Soc. 1995, 117, 10449–10459.
(10) For an intermolecular Schmidt reaction of alkyl azides with
ꢀ
ketones, see: Aube, J.; Milligan, G. L.; Mossman, C. J. J. Org. Chem.
1992, 57, 1635–1637.
(11) For an intramolecular Schmidt reaction of aldehydes with alkyl
azides, see: ref 9b.
(12) For the normal intermolecular Schmidt reaction of aldehydes
In order to attain the N-arylation products, the Schmidt
process should be controlled through the exclusive 1,2-aryl
ꢀ
with alkyl azides, see: Lee, H.-L.; Aube, J. Tetrahedron 2007, 63, 9007–
9015.
(13) For the modified intermolecular Schmidt reaction of aldehydes
ꢀ
with azido alcohols, see: (a) Badiang, J. G.; Aube, J. J. Org. Chem. 1996,
61, 2484–2487. (b) Boyer, J. H.; Morgan, L. R., Jr. J. Org. Chem. 1959,
24, 561–562. (c) Boyer, J. H.; Canter, F. C.; Hamer, J.; Putney, R. K.
J. Am. Chem. Soc. 1956, 78, 325–327. (d) Boyer, J. H.; Hamer, J. J. Am.
Chem. Soc. 1955, 77, 951–954.
(14) For a review on a Schmidt reaction of aldehydes with HN3, see:
Koldobskii, G. I.; Ostrovskii, V. A.; Gidaspov, B. V. Russ. Chem. Rev.
1978, 47, 1084–1094.
ꢀ
(16) (a) Gracias, V.; Milligan, G. L.; Aube, J. J. Am. Chem. Soc. 1995,
ꢀ
117, 8047. (b) Gracias, V.; Milligan, G. L.; Aube, J. J. Org. Chem. 1996,
61, 10. (c) Forsee, J. E.; Aube, J. J. Org. Chem. 1999, 64, 4381. (d) Forsee,
J. E.; Aube, J. Org. Lett. 1999, 1, 495. (e) Smith, B. T.; Gracias, V.; Aube,
J. J. Org. Chem. 2000, 65, 3771. (f) Katz, C. E.; Aube, J. J. Am. Chem.
Soc. 2003, 125, 13948. (g) Sahasrabudhe, K.; Gracias, V.; Fumess, K.;
ꢀ
Sminth, B. T.; Katz, C. E.; Reddy, D. S.; Aube, J. J. Am. Chem. Soc.
ꢀ
ꢀ
ꢀ
ꢀ
2003, 125, 7914.
(17) Pearson, W. H.; Walavalkar, R.; Schkeryantz, J. M.; Fang,
W.-K.; Blickensdorf, J. D. J. Am. Chem. Soc. 1993, 115, 10183–10194.
(15) For recent examples of a chemoselective Schmidt reaction of
aldehydes with sodium azide to nitriles, see: Rokade, B. V.; Prabhu,
K. R. J. Org. Chem. 2012, 77, 5364–5370 and references cited therein.
Org. Lett., Vol. 15, No. 5, 2013
1125

migration from the azidohydrin intermediate. The inter-
molecular Schmidt reaction of aldehydes had been re-
ported to be less effective,12 so we paid more attention to
the modified procedure with the azido alcohols.13 We de-
cided to change the framework of the rearrangement in-
termediate to see if migration of the aryl group was possible.
The oxygen atom in the ring of the azidohydrin inter-
mediate (I, Scheme 3) was envisioned to be replaced with a
nitrogen unit (II, Scheme 4).
Table 1. Optimization of the Schmidt Reaction of Aldehyde 2a
with 3-Azido Amine 1a
To test our proposal, the 3-azido-N-tosylpropan-1-
amine 1 and benzaldehyde 2a were selected for the initial
investigation. As expected, the iminium cation would be
formed by dehydration of the potential hemiaminals
through a similar process of the reaction of 1,3-azido
alcohol. Then the Schmidt reaction would proceed. If the
migration of the aryl group was preferred, the N-aryl
iminium would be formed, which could be hydrolyzed to
formamide 3a.
reaction
time (h)
yieldb
(%)
entry
acid
1
2
3
4
5
6
7
8
TiCl4 (1.1 equiv)
SnCl4 (1.1 equiv)
6
13
31
14
0
6
BF3 OEt2 (1.1 equiv)
6
3
TFA (1.1 equiv)
TfOH (1.1 equiv)
TfOH (1.5 equiv)
TfOH (2.3 equiv)
TfOH (2.3 equiv)
12
1
54
64
89
91c
1
1
1
a Treatment of benzaldehyde (1.0 mmol) in DCM (5 mL) with
3-azido-N-tosylpropan-1-amine (1.0 mmol) with acids in the table.
b Isolated yield after the basic workup with 50% (w/v) aqueous KOH
solution. c Isolated yield after the basic workup with 10% (w/v) aqueous
KOH solution.
Scheme 4. Designed Aryl Migration Schmidt Reaction of Ben-
zaldehyde with 3-Azido-N-tosylpropan-1-amine
the reaction of aryl aldehydes; (2) all the aryl aldehydes
except the 4-methoxy benzaldehyde exhibit good to ex-
cellent reactivities; and (3) the methoxyl group of 4-methoxy
benzaldehyde might limit the formation of hemiaminal as
well as the attack of azide to the iminium, which seriously
affects the production of formamide (entry 9, Table 2).
Toourdelight, treatmentofbenzaldehyde2aand azide 1
with several acids followed by aqueous KOH afforded the
N,N-disubstituted formamide 3a (Table 1). Among the
acids, triflic acid (TfOH) was proven to be effective. By
increasing the amount of TfOH, the amide 3a could be
delivered in better yields (entries 6 and 7). It was believed
that the two nitrogen atoms in the product would partly
deactivate the promoter. The aqueous base workup with
10% KOH solution was slightly better than the 50% KOH
solution (entry 8 vs 7), which might be due to the trace
deformylation of 3a under the excessively basic con-
ditions.18 It should be noted that the entire 1,2-migration
of the aromatic ring happened here.
Figure 1. X-ray structure of formamide 3g.
After the opposite regioselectivity of the reaction to that
of the previous conversion was achieved, we explored the
scope of aldehydes (Table 2) with the optimal conditions
established above (in bold, Table 1). A series of aryl aldehydes
2bꢀ2l were all successfully converted to the corresponding
N-arylation amides. The structure of 3g was confirmed by
X-ray crystallographic analysis (Figure 1). Noteworthy fea-
tures of the conversion include the following: (1) the entire
migration of the aryl group over hydride is observed from
Toextendthe transformation, conversion of analiphatic
aldehyde 2m with the azido amine was also investigated
(Scheme 5), and the N,N-disubstituted formamide 3m was
successfully obtained in 91% yield with complete migra-
tion of the alkyl group.
Two alkylazides, including the benzyl azideandn-heptyl
azide, had been used to react with benzaldehyde with the
promotion of TfOH as the control experiments, but both
of them resulted in very complicated mixtures. From the
NMR analysis of the crudes, only trace signals of the
(18) For an example of deformylation of formamide under the basic
condition, see: Hengartner, U.; Batcho, A. D.; Blount, J. F.; Leimgruber,
W.; Larscheid, M. E.; Scott, J. W. J. Org. Chem. 1979, 44, 3748.
1126
Org. Lett., Vol. 15, No. 5, 2013

Table 2. Scope of the Conversiona
Scheme 5. Schmidt Reaction of the Aliphatic Aldehyde 2m with
3-Azido-N-tosylpropan-1-amine
yieldb
(%)
entry
aldehydes 2
2a, R = Ph
3
1
3a
3b
3c
3d
3e
3f
91
71
92
86
81
94
85
87
14
94
78
91
hydride was observed in the rearrangement process, with
the formal N-arylation or N-alkylation of formamides
being obtained in good to excellent yields in most cases.
Extensive research will be undertaken to understand why
the Schmidt reaction of aldehydes with the 3-azido-N-
tosylpropan-1-amine proceeds so differently from that
with azido alcohols.
2
2b, R = 4-Me-Ph
2c, R = 4-Et-Ph
2d, R = 4-iPr-Ph
2e, R = 4-F-Ph
3
4
5
6
2f, R = 4-Cl-Ph
7
2g, R = 4-Br-Ph
2h, R = 4-CN-Ph
2i, R = 4-OMe-Ph
2j, R = 3-OMe-Ph
2k, R = 1-Naphenyl
2l, R = 2-Naphenyl
3g
3h
3i
8
9
10
11
12
3j
3k
3l
Acknowledgment. This work was supported by the
National Natural Science Foundation of China (Nos.
21262024, 21062014, and 21064005), the Key Project of
Department of Education in Ningxia (2010-Preparation of
Capsaicin), the Key Project of Chinese Ministry of Educa-
tion (211193), the Scientific Research Foundation for
Returned Scholars (Ministry of Education of China), the
100 Talents Program of Ningxia, and the “211” Project in
Ningxia University.
a Reaction of the aldehyde 2 (1.0 mmol) and 3-azido-N-tosylpropan-
1-amine 1 (1.0 mmol) in DCM (10 mL) in the presence of TfOH (2.3
mmol, 2.3 equiv) for 60 min followed by treatment of 10% (w/v) aqueous
KOH solution (5 mL) for 60 min. b Isolated yield.
possible amides could be found (<5%). We tried to
separate them from the mixtures but failed. So the amino
group of 3-azido-N-tosylpropan-1-amine would be essen-
tial for the aryl- and alkyl-migration Schmidt reactions of
aldehydes based on consideration of the reaction yields
presented above.
In conclusion, we have developed anefficient conversion
of aldehydes to formamides by using 3-azido-N-tosylpro-
pan-1-amine through the Schmidt process in the presence
of TfOH. The migration of an aryl and alkyl group over
Supporting Information Available. Experimental pro-
cedures and spectroscopic data and copies of NMR
spectra for all new compounds and X-ray crystallo-
graphic data for compound 3g. This material is available
free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 5, 2013
1127