Iron-catalyzed four-component reaction for the synthesis of protected primary amines

Article abstract of DOI:10.1002/ejoc.200700627

The first catalytic four-component reaction (4CR) of carbonyl compounds with alkyl chloroformate, HMDS and Et₃SiH has been developed to produce protected primary amines by a novel tandem nitrogen protection/direct reductive amination of carbonyl compounds. In the presence of 5 mol-% of an iron(II) salt, a wide variety of aldehydes and ketones were transformed into their corresponding protected primary amines in good to excellent yields under "pure" multicomponent reaction (MCR) conditions. This chemistry was further extended to masked carbonyl compounds such as acetals, ketals, and vinyl ethers. When compared with previous methods to prepare protected primary amines from a large excess of ammonia or ammonium salts, this 4CR not only saved at least one step of synthetic manipulation, but also utilized nearly stoichiometric nitrogen and hydrogen sources and avoided the formation of (protected) secondary amines. Additional advantages of this protocol include broader substrate scope, the use of an inexpensive and environmentally friendly catalyst, and mild reaction conditions. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700627

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200700627
Iron-Catalyzed Four-Component Reaction for the Synthesis of Protected
Primary Amines
Bai-Ling Yang[a] and Shi-Kai Tian*[a]
Keywords: Multicomponent reactions / Reductive amination / Carbonyl compounds / Acetals / Primary amines
The first catalytic four-component reaction (4CR) of carbonyl
compounds with alkyl chloroformate, HMDS and Et3SiH has
been developed to produce protected primary amines by a
novel tandem nitrogen protection/direct reductive amination
of carbonyl compounds. In the presence of 5 mol-% of an
iron(II) salt, a wide variety of aldehydes and ketones were
transformed into their corresponding protected primary
amines in good to excellent yields under “pure” multicompo-
nent reaction (MCR) conditions. This chemistry was further
extended to masked carbonyl compounds such as acetals,
ketals, and vinyl ethers. When compared with previous
methods to prepare protected primary amines from a large
excess of ammonia or ammonium salts, this 4CR not only
saved at least one step of synthetic manipulation, but also
utilized nearly stoichiometric nitrogen and hydrogen sources
and avoided the formation of (protected) secondary amines.
Additional advantages of this protocol include broader sub-
strate scope, the use of an inexpensive and environmentally
friendly catalyst, and mild reaction conditions.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
complicated by the formation of secondary and tertiary
amines and by the reduction of carbonyl compounds to
alcohols, and often requires a large excess of nitrogen and
hydrogen sources to achieve good yields. Furthermore, high
pressure and/or precious metals are used in many of these
3CRs. Due to their high reactivity, primary amines often
need an additional step of protection prior to their further
application in organic synthesis [Scheme 1 a)]. The most
widely employed protecting groups for amines are alkoxy-
carbonyl groups since they can easily undergo further con-
versions using well-established protective-group chemis-
try.[4] Alternatively, ammonia can be protected prior to the
direct reductive amination of carbonyl compounds
[Scheme 1 b)].[2,5] The incorporation of direct reductive
amination of carbonyl compounds and nitrogen-protection
into a single four-component reaction (4CR) would greatly
facilitate the manipulation to synthesize protected primary
amines [Scheme 1 c)] since it can save one step when com-
pared with a sequential 3CR and 2CR, and save two steps
when compared with three sequential 2CRs. Herein, we re-
port the first four-component synthesis of alkoxycarbonyl-
protected primary amines by tandem nitrogen protection/
direct reductive amination of carbonyl compounds (acetals,
ketals, or vinyl ethers) in the presence of 5 mol-% of an
iron(II) salt at room temperature. When compared with pre-
vious methods to prepare protected primary amines from
ammonia or ammonium salts, this four-component synthe-
sis under “pure” MCR conditions[1h] not only saved at least
one step of synthetic manipulation, but also utilized nearly
stoichiometric nitrogen and hydrogen sources and avoided
the formation of (protected) secondary amines.
Introduction
Multicomponent reactions (MCRs), which involve the
one-pot transformation of three or more starting materials
into a single product that incorporates portions of all the
reactants,[1] are powerful for the construction of complex
organic molecules. When compared with the sequential syn-
thesis of the same target by conventional bimolecular reac-
tions (2CRs), MCRs, especially those with more than three
components, exhibit much higher efficiency because they
need fewer synthetic manipulations. While most of the
MCRs discovered so far consist of three components, the
reactions with four or more components are quite rare.
Primary amines exist in many biologically important
molecules, and are also widely used as intermediates in the
synthesis of pharmaceutically active substances, dyes, and
fine chemicals. Although an amino functionality can be di-
rectly introduced into a molecule by the displacement of a
halide or sulfonate with ammonia, overalkylation of ammo-
nia is a common side reaction. A superior method is the
direct reductive amination of carbonyl compounds, a three-
component reaction (3CR) wherein the carbonyl groups re-
act with ammonia or ammonium salts in the presence of
mild reducing agents.[2,3] However, such a 3CR is also
[a] Joint Laboratory of Green Synthetic Chemistry, Department of
Chemistry, University of Science and Technology of China
Hefei, Anhui 230026, China
Fax: +86-551-3601592
E-mail: tiansk@ustc.edu.cn
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
4646
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4646–4650

Synthesis of Protected Primary Amines
Table 1. Survey of solid Lewis acid catalysts and solvents.[a]
Scheme 1. Multicomponent synthesis of (protected) primary
amines. [H] = reducing agent, Pg = protecting group, [N] = nitrogen
source.
Results and Discussion
The employment of carbamates as the nitrogen sources
in the three-component synthesis of protected primary
amines, reported by Dubé and Scholte in 1999,[5] is particu-
larly interesting in that the corresponding alkoxycarbonyl
groups serve as the protecting groups for primary amines,
[a] The reaction was performed by treatment of 1a (0.25 mmol) in
solvent (0.25 mL) at room temp. with CbzCl (0.30 mmol), HMDS
(0.30 mmol), Et3SiH (0.30 mmol), and catalyst (10 mol-%). [b] No
despite the fact that in this 3CR excessive carbamates desired product was detected by TLC.
(3.0 equiv.), triethylsilane (Et3SiH, 3.0 equiv.), and tri-
fluoroacetic acid (2.9 equiv.) were used. Realizing that N-
silylcarbamate could be easily generated from alkyl chloro-
formate and hexamethyldisilazane (HMDS),[6] we envi-
sioned a 4CR of carbonyl compounds, alkyl chloroformate,
HMDS and Et3SiH to synthesize alkoxycarbonyl-protected
primary amines by tandem nitrogen protection/direct re-
ductive amination of carbonyl compounds. However, the
presence of both two electrophiles (carbonyl compound and
alkyl chloroformate) and two nucleophiles (HMDS and
Et3SiH) in a one-pot reaction offers a formidable challenge
for this reaction to give predominantly the desired product.
The selectivity for the reactions of electrophiles with nu-
cleophiles in a multicomponent system was expected to be
attained by the choice of Lewis acids. Thus, a large number
of inexpensive solid Lewis acids were evaluated for their
ability to catalyze the 4CR of carbonyl compounds, alkyl
chloroformate, HMDS and Et3SiH (Table 1). Using benzal-
dehyde (1a) as the model substrate, this reaction was per-
formed under “pure” MCR conditions[1h] by adding suc-
cessively benzyl chloroformate (CbzCl, 1.2 equiv.), HMDS
(1.2 equiv.), Et3SiH (1.2 equiv.), and solid Lewis acid
(10 mol-%) to a stirred solution of benzaldehyde (1a) in ace-
tonitrile at room temperature. A number of common solid
Lewis acids, especially iron salts,[7] showed high catalytic
activities in this 4CR (Table 1). Importantly, the best yield
(91%) was achieved with iron(II) sulfate heptahydrate
(FeSO4·7H2O), which is inexpensive and environmentally
friendly (Table 1, Entry 10). Furthermore, this iron(II) salt
is insoluble in acetonitrile and can be removed simply by
filtration. Interestingly, FeSO4·7H2O was found to be tot-
ally ineffective in catalyzing the corresponding 3CR of
benzaldehyde (1a), CbzNH2, and Et3SiH.
A further survey of the reaction conditions revealed that
dichloromethane was the solvent of choice (Table 1, En-
try 14), and the catalyst loading could be lowered without
sacrificing the yield. In the presence of 5 mol-% of
FeSO4·7H2O, this 4CR proceeded cleanly without the for-
mation of protected secondary amine and/or benzyl
alcohol, and gave Cbz-protected primary amine 2a in 95%
yield (Table 2, Entry 1). The employment of polymethylhy-
drosiloxane (PMSH) as the hydride source in this 4CR was
also examined and found to give a much lower yield
(Table 2, Entry 2). In addition, lower yields were obtained
with many other alkyl chloroformates such as EtOCOCl
and PhOCOCl, and with acyl chloride such as PhCOCl
(Table 2, Entries 3–5).
Table 2. Survey of protecting groups for primary amines.[a]
[a] The reaction was performed by treatment of 1a (0.25 mmol) in
CH2Cl2 (0.25 mL) at room temp. with PgX (0.30 mmol), HMDS
(0.30 mmol), Et3SiH (0.30 mmol), and FeSO4·7H2O (5 mol-%). [b]
PMSH was used.
Eur. J. Org. Chem. 2007, 4646–4650
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4647

B.-L. Yang, S.-K. Tian
SHORT COMMUNICATION
Next, we investigated the substrate scope for the 4CR of
This 4CR was further extended to various masked car-
carbonyl compounds, CbzCl, HMDS, and Et3SiH since this bonyl compounds (Table 4) that, stable in air and inert to
reaction gave the best yield with CbzCl and Cbz is more many nucleophiles, offer significant advantages over the
often employed as a protecting group for a reactive amine. corresponding aldehydes or ketones in many synthetic ma-
In the presence of 5 mol-% of FeSO4·7H2O, a variety of nipulations. It is notable that good yields could be obtained
aromatic and aliphatic aldehydes, including sterically hin- using this 4CR to synthesize the same protected primary
dered ones, were transformed into their corresponding pro- amine from several different acetal derivatives of the same
tected primary amines at room temperature in good to ex- aldehyde (Table 4, Entries 1–4). In addition, the use of the
cellent yields (Table 3, Entries 1–13). Importantly, the re- acetal derivative of an aldehyde with a low boiling point
ducible nitro group and carbon–carbon double bonds, as (e.g., acetaldehyde) could greatly facilitate the synthesis of
well as acid-labile TBS ether and Boc groups were all al- the corresponding protected primary amine at room tem-
lowed in this 4CR (Table 3, Entries 3, 5–7 and 9). The reac- perature (Table 4, Entry 6).[8] Interestingly, vinyl ethers
tion of an α,β-unsaturated aldehyde was complicated by the could also serve as surrogates of carbonyl compounds in
reduction of the carbon–carbon double bond (Table 3, En- this 4CR (Table 4, Entries 11–12), though the yields were
try 14). Cyclic and acyclic ketones could also serve as suit- lower than those for the corresponding carbonyl com-
able substrates for this 4CR (Table 3, Entries 15–18), and pounds (Table 3, Entry 15).
the reaction of α-keto esters are particularly interesting
since they can be utilized to synthesize protected α-amino
esters.
Table 4. Iron-catalyzed four-component synthesis of protected pri-
mary amines from ketals, acetals, or vinyl ethers.[a]
Table 3. Iron-catalyzed 4CR of carbonyl compounds, CbzCl,
HMDS, and Et3SiH.[a]
[a] The reaction was performed by treatment of 3 (0.50 mmol) in
CH2Cl2 (0.50 mL) at room temp. with CbzCl (0.60 mmol), HMDS
(0.60 mmol), Et3SiH (0.60 mmol), and FeSO4·7H2O (5 mol-%). [b]
Isolated yield.
During the 4CR of carbonyl compounds (acetals, ketals,
or vinyl ethers), CbzCl, HMDS, and Et3SiH, we observed
that the reaction of CbzCl with HMDS proceeded quickly
to generate N-silylcarbamate CbzNH(TMS),[6] the amount
of which was indicated by TLC to decrease gradually.[9]
Thus, it is reasonable to conclude that FeSO4·7H2O itself
or in combination with chlorotrimethylsilane (TMSCl),
which is generated in situ along with CbzNH(TMS) from
CbzCl and HMDS, should promote the subsequent direct
[a] The reaction was performed by treatment of 1 (0.50 mmol) in
CH2Cl2 (0.50 mL) at room temp. with CbzCl (0.60 mmol), HMDS
(0.60 mmol), Et3SiH (0.60 mmol), and FeSO4·7H2O (5 mol-%). [b]
Isolated yield. [c] A 90:10 mixture of 2n/2k (determined by 1H
NMR analysis).
4648
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4646–4650

Synthesis of Protected Primary Amines
reductive amination of carbonyl compounds (acetals, ketals,
or vinyl ethers). On the basis of the mechanistic studies on
the direct reductive amination of carbonyl compounds,[2] we
propose for this 4CR a reaction pathway in which imine 4
should be generated as the key intermediate for the forma-
tion of 5, which can be hydrolyzed to give product 2
(Scheme 2).
Conclusions
We have developed the first catalytic 4CR of carbonyl
compounds with alkyl chloroformate, HMDS, and Et3SiH
to produce protected primary amines by a novel tandem
nitrogen protection/direct reductive amination of carbonyl
compounds. In the presence of 5 mol-% of FeSO4·7H2O, a
wide variety of aldehydes and ketones were transformed
into their corresponding alkoxycarbonyl-protected primary
amines in good to excellent yields by performing the 4CRs
under mild “pure” MCR conditions. This chemistry was
further extended to masked carbonyl compounds such as
acetals, ketals, and vinyl ethers. When compared with pre-
vious methods to prepare protected primary amines from a
large excess of ammonia or ammonium salts, this 4CR not
only saved at least one step of synthetic manipulation, but
also utilized nearly stoichiometric nitrogen and hydrogen
sources and avoided the formation of (protected) secondary
amines. Additional advantages of this protocol include
broader substrate scope, the employment of a catalytic
amount of inexpensive and environmentally friendly cata-
lyst, and mild reaction conditions. Furthermore, this study
adds a synthetically useful entry into MCRs and iron catal-
ysis.
Scheme 2. Proposed major reaction pathway.
To gain more insight into the role played by
FeSO4·7H2O, imine 4a was prepared in situ from benzalde-
hyde (1a)[10] and subjected to reduction with Et3SiH
(Table 5). Surprisingly, neither FeSO4·7H2O nor the iron(II)
species prepared from FeSO4·7H2O and TMSCl (10
equiv.)[11] could catalyze the reduction of imine 4a (Table 5,
Entries 2–3), which, instead, could be promoted by either
TMSCl (Table 5, Entries 6–7) or HCl (generated in situ
from TMSCl and water; Table 4, Entries 8–9). Nevertheless,
the replacement of FeSO4·7H2O in this 4CR with water
(0.10 or 0.70 equiv., to generate HCl), as indicated by TLC,
did not give product 2a. In addition, 10 mol-% of
FeSO4·7H2O was found to be able to catalyze the corre-
sponding three-component reaction of benzaldehyde (1a),
CbzNH(TMS), and Et3SiH to give product 2a in 40% yield,
which is significantly lower than that in the presence of
TMSCl (93% yield; Table 1, Entry 14). Taken together, the
iron(II) salt should play a major role in the generation of
imine 4 (Scheme 2), the reduction of which can be pro-
moted mainly by TMSCl and/or HCl, both of which are
generated in situ during the reaction.[12]
Experimental Section
General Procedure for the Four-Component Synthesis of Protected
Primary Amines: To a stirred solution of carbonyl compound 1
(acetal, ketal, or vinyl ether 3, 0.50 mmol) in dry dichloromethane
(0.50 mL) at room temperature were added successively CbzCl
(102 mg, 0.086 mL, 0.60 mmol), HMDS (96.8 mg, 0.125 mL,
0.60 mmol), Et3SiH (69.8 mg, 0.096 mL, 0.60 mmol), and
FeSO4·7H2O (7.0 mg, 5 mol-%). When the reaction did not proceed
further as indicated by TLC, the reaction mixture was purified by
flash column chromatography on silica gel, eluting with petroleum
ether/EtOAc (40:1 to 10:1), to give protected primary amine 2
(Tables 3 and 4).
General Procedure for the Reduction of Imine 4a: Imine 4a was pre-
pared in situ from benzaldehyde (1a) according to known pro-
cedures.[10] To a stirred solution of crude imine 4a (0.25 mmol) in
dry dichloromethane (0.25 mL) at room temperature were added
successively Et3SiH (34.9 mg, 0.048 mL, 0.30 mmol), catalyst (if
any, 10 mol-%), and additive (if any). The reaction mixture was
stirred for 24 h and purified by flash column chromatography on
silica gel to give product 2a (if any, Table 5).
Table 5. Reduction of imine 4a with Et3SiH.
Supporting Information (see footnote on the first page of this arti-
cle): Additional experimental procedures and characterization of
the products.
Acknowledgments
We are grateful for the financial support from the National Natural
Science Foundation of China (no. 20672105) and the University of
Science and Technology of China.
[1] For reviews, see: a) A. Dondoni, A. Massi, Acc. Chem. Res.
2006, 39, 451–463; b) A. Dömling, Chem. Rev. 2006, 106, 17–
89; c) D. J. Ramón, M. Yus, Angew. Chem. 2005, 117, 1628–
[a] Isolated yield. [b] No or a trace amount of 2a was detected by
TLC. [c] Prepared from FeSO4·7H2O and TMSCl at room temp.
Eur. J. Org. Chem. 2007, 4646–4650
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4649

B.-L. Yang, S.-K. Tian
SHORT COMMUNICATION
1661; Angew. Chem. Int. Ed. 2005, 44, 1602–1634; d) J. Zhu,
Eur. J. Org. Chem. 2003, 1133–1144; e) V. Nair, C. Rajesh,
A. U. Vinod, S. Bindu, A. R. Sreekanth, J. S. Mathen, L. Bala-
gopal, Acc. Chem. Res. 2003, 36, 899–907; f) R. V. A. Orru,
retti, V. Berdini, M. C. Cesta, R. Curti, L. Nicolini, A. Topai,
Tetrahedron Lett. 2001, 42, 4257–4259.
[4] T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Syn-
thesis, 3rd ed., Wiley, New York, 1999.
M. Greef, Synthesis 2003, 1471–1499; g) A. Döemling, I. Ugi, [5] D. Dubé, A. A. Scholte, Tetrahedron Lett. 1999, 40, 2295–2298.
Angew. Chem. 2000, 112, 3300–3344; Angew. Chem. Int. Ed. [6] a) J. Pump, U. Wannagat, Monatsh. Chem. 1962, 93, 352–359;
2000, 39, 3168–3210; h) L. Weber, K. Illgen, M. Almstetter,
Synlett 1999, 366–374.
[2] For recent reviews, see: a) B. Fu, N. Li, X.-M. Liang, Y.-H.
Dong, D.-Q. Wang, Chin. J. Org. Chem. 2007, 27, 1–7; b) A.-
F. Abdel-Magid, S. J. Mehrman, Org. Process Res. Dev. 2006,
10, 971–1031; c) S. Gomez, J. A. Peters, T. Maschmeyer, Adv.
Synth. Catal. 2002, 344, 1037–1057.
[3] For some recent examples on the preparation of primary
amines using the direct reductive amination of carbonyl com-
pounds, see: a) S. N. Khan, S.-Y. Bae, H.-S. Kim, Tetrahedron
Lett. 2005, 46, 7675–7678; b) T. Ikenaga, K. Matsushita, J. Shi-
nozawa, S. Yada, Y. Takagi, Tetrahedron 2005, 61, 2105–2109;
c) B. Miriyala, S. Bhattacharyya, J. S. Williamson, Tetrahedron
2004, 60, 1463–1471; d) S. Ogo, K. Uehara, T. Abura, S. Fuku-
zumi, J. Am. Chem. Soc. 2004, 126, 3020–3021; e) C. Huber,
b) Q.-Y. Song, B.-L. Yang, S.-K. Tian, J. Org. Chem. 2007, 72,
5407–5410.
[7] For a review on the catalysis with iron, see: C. Bolm, J. Legros,
J. Le Paih, L. Zani, Chem. Rev. 2004, 104, 6217–6254.
[8] The boiling point of acetaldehyde is 21 °C, and that of acetal-
dehyde diethyl acetal (3f) is 103 °C.
[9] CbzNH(TMS) decomposed to CbzNH2 on a TLC plate be-
cause of its lability to moisture.
[10] a) T. R. Wu, J. M. Chong, Org. Lett. 2006, 8, 15–18; b) R.
Kupfer, S. Meier, E.-U. Wurtwein, Synthesis 1984, 688–690; c)
D. J. Hart, K. Kanai, D. G. Thomas, T.-K. Yang, J. Org. Chem.
1983, 48, 289–294.
[11] The iron(II) species was prepared by treatment of FeSO4·7H2O
with TMSCl (10 equiv.) at room temperature for 24 h and sub-
sequent concentration under reduced pressure (15–0.1 Torr).
G. Wächtershäuser, Tetrahedron Lett. 2003, 44, 1695–1697; f) [12] When HCl serves as the promoter for the reduction of imine
C. Fava, R. Galeazzi, G. Mobbili, M. Orena, Tetrahedron:
Asymmetry 2003, 14, 3697–3703; g) V. Berdini, M. C. Cesta, R.
Curti, G. DЈAnniballe, N. Di Bello, G. Nano, L. Nicolini, A.
Topai, M. Allegretti, Tetrahedron 2002, 58, 5669–5674; h) T.
Gross, A. M. Seayad, M. Ahmad, M. Beller, Org. Lett. 2002,
4, 2055–2058; i) M. Kitamura, D. Lee, S. Hayashi, S. Tanaka,
M. Yoshimura, J. Org. Chem. 2002, 67, 8685–8687; j) M. Alleg-
4, product 2 should be generated directly. HCl can be generated
by the reaction of TMSCl, which was generated in situ along
with CbzNH(TMS) from CbzCl and HMDS, with the water
from FeSO4·7H2O or with TMSOH, which was generated in
situ during the formation of imine 4.
Received: July 9, 2007
Published Online: August 3, 2007
4650
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4646–4650