FeSO4·7H2O-catalyzed four-component synthesis of protected homoallylic amines

Article abstract of DOI:10.1021/jo0704558

(Chemical Equation Presented) An efficient catalytic four-component reaction of carbonyl compounds (or acetals/ketals), benzyl chloroformate (CbzCl), 1,1,1,3,3,3-hexamethyldisilazane (HMDS), and allyltrimethylsilane has been successfully developed to produce Cbz-protected homoallylic amines in the presence of 5 mol % of iron(II) sulfate heptahydrate (FeSO₄· 7H₂O), an inexpensive and environmentally friendly catalyst, at room temperature.

Full text of DOI:10.1021/jo0704558

tions of MCRs in the construction of homoallylic amines,2-5
useful intermediates in organic synthesis,6 which are commonly
synthesized by the allylation of aldimines, prepared from the
corresponding aldehydes and amines in advance using various
allylic nucleophiles.7 Among these MCRs that avoid the prior
synthesis of aldimines, the three-component reaction of alde-
hydes, carbamates, and allyltrimethylsilane to construct the
alkoxycarbonyl-protected homoallylic amines (eq 1) is particu-
FeSO4‚7H2O-Catalyzed Four-Component
Synthesis of Protected Homoallylic Amines
Qi-Yi Song, Bai-Ling Yang, and Shi-Kai Tian*
Department of Chemistry, School of Chemistry and Material
Science, UniVersity of Science and Technology of China,
Hefei, Anhui 230026, China
tiansk@ustc.edu.cn
ReceiVed March 5, 2007
larly interesting in that the protecting groups are most often
employed to handle amines in organic synthesis and can easily
undergo further conversions using well-established protective
group chemistry without affecting the double bonds.8
The replacement of the carbamate in the above three-
component reaction with N-silylcarbamate reported by Yokoza-
wa and co-workers not only allowed the reaction to proceed
under milder reaction conditions but also extended the chemistry
to a couple of simple ketones, though the yields were far from
satisfactory.2h Given that N-silylcarbamate could be easily
prepared from the corresponding alkyl chloroformate and
1,1,1,3,3,3-hexamethyldisilazane (HMDS),9 a four-component
An efficient catalytic four-component reaction of carbonyl
compounds (or acetals/ketals), benzyl chloroformate (CbzCl),
1,1,1,3,3,3-hexamethyldisilazane (HMDS), and allyltrimethyl-
silane has been successfully developed to produce Cbz-
protected homoallylic amines in the presence of 5 mol % of
iron(II) sulfate heptahydrate (FeSO4‚7H2O), an inexpensive
and environmentally friendly catalyst, at room temperature.
(3) For the three-component reaction of aldehydes, amines, and allylic
organometallics, see: (a) Das, B.; Laxminarayana, K.; Ravikanth, B.;
Ramarao, B. Tetrahedron Lett. 2006, 47, 9103. (b) Das, B.; Ravikanth, B.;
Thirupathi, P.; Rao, B. V. Tetrahedron Lett. 2006, 47, 5041. (c) Li, G.-l.;
Zhao, G. Synthesis 2006, 3189. (d) Choudary, B. M.; Jyothi, K.; Madhi,
S.; Kantam, M. L. Synlett 2004, 231. (e) Aspinall, H. C.; Bissett, J. S.;
Greeves, N.; Levin, D. Tetrahedron Lett. 2002, 43, 323. (f) Akiyama, T.;
Onuma, Y. J. Chem. Soc., Perkin Trans. 1 2002, 1157. (g) Akiyama, T.;
Iwai, J.; Onuma, Y. Kagoshima, H. Chem. Commun. 1999, 2191.
(4) For the three-component reaction of carbonyl compounds, ammonia,
and allyl boron reagents, see: (a) Dhudshia, B.; Tiburcio, J.; Thadani, A.
N. Chem. Commun. 2005, 5551. (b) Kobayashi, S.; Hirano, K.; Sugiura,
M. Chem. Commun. 2005, 104. (c) Sugiura, M.; Hirano, K.; Kobayashi, S.
J. Am. Chem. Soc. 2004, 126, 7182.
One of the most promising approaches to construct complex
organic molecules is being pursued by the development of
multicomponent reactions (MCRs) that involve the one-pot
transformation of three or more starting materials into a single
product that incorporates portions of all of the reactants.1 When
compared with the sequential synthesis of the same target by
conventional bimolecular reactions, MCRs provide significant
advantages such as the atom economical and convergent
character, the simplicity of the one-pot procedure, the possible
structural variations, and the accessible complexity of the
molecules. Recent years have witnessed a number of applica-
(5) For the three-component reaction of aldehydes, tosylamide, and
R-methylstyrene, see: Yamanaka, M.; Nishida, A.; Nakagawa, M. J. Org.
Chem. 2003, 68, 3112.
(6) For some of the recent applications of homoallylic amines in organic
synthesis, see: (a) Kropf, J. E.; Meigh, I. C.; Bebbington, M. W. P.;
Weinreb, S. M. J. Org. Chem. 2006, 71, 2046. (b) Friestad, G. K.; Korapala,
C. S.; Ding, H. J. Org. Chem. 2006, 71, 281. (c) Pandey, M. K.; Bisai, A.;
Pandey, A.; Singh, V. K. Tetrahedron Lett. 2005, 46, 5039. (d) Atobe, M.;
Yamazaki, N.; Kibayashi, C. Tetrahedron Lett. 2005, 46, 2669. (e)
Ramachandran, P. V.; Burghardt, T. E.; Bland-Berry, L. J. Org. Chem.
2005, 70, 7911. (f) Varlamov, A. V.; Zubkov, F. I.; Boltukhina, E. V.;
Sidorenko, N. V.; Borisov, R. S. Tetrahedron Lett. 2003, 44, 3641. (g)
Gille, S.; Ferry, A.; Billard, T.; Langlois, B. R. J. Org. Chem. 2003, 68,
8932. (h) Randl, S.; Blechert, S. J. Org. Chem. 2003, 68, 8879. (h) Kim,
G.; Jung, S.; Lee, E.; Kim, N. J. Org. Chem. 2003, 68, 5395. (i) Jain, R.
P.; Williams, R. M. J. Org. Chem. 2002, 67, 6361. (j) Expo´sito, A.;
Ferna´ndez-Sua´rez, M.; Iglesias, T.; Mun˜oz, L.; Riguera, R. J. Org. Chem.
2001, 66, 4206. (k) Wright, D. L.; Schulte, J. P., II; Page, M. A. Org. Lett.
2000, 2, 1847. (l) Hunt, J. C. A.; Laurent, P.; Moody, C. J. Chem. Commun.
2000, 1771.
(7) For reviews, see: (a) Puentes, C. O.; Kouznetsov, V. J. Heterocycl.
Chem. 2002, 39, 595. (b) Bloch, R. Chem. ReV. 1998, 98, 1407. (c) Enders,
D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895. (d) Yamamoto,
Y.; Asao, N. Chem. ReV. 1993, 93, 2207. For the allylation of acylhydra-
zones, see: (e) Sugiura, M.; Kobayashi, S. Angew. Chem., Int. Ed. 2005,
44, 5176. (f) Kobayashi, S.; Sugiura, M.; Ogawa, C. AdV. Synth. Catal.
2004, 346, 1023.
(1) For reviews, see: (a) Dondoni, A.; Massi, A. Acc. Chem. Res. 2006,
39, 451. (b) Do¨mling, A. Chem. ReV. 2006, 106, 17. (c) Ramo´n, D. J.;
Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602. (d) Zhu, J. Eur. J. Org.
Chem. 2003, 1133. (e) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.;
Sreekanth, A. R.; Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003, 36,
899. (f) Orru, R. V. A.; Greef, M. Synthesis 2003, 1471. (g) Do¨emling, A.;
Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. (h) Weber, L.; Illgen, K.;
Almstetter, M. Synlett 1999, 366.
(2) For the three-component reaction of carbonyl compounds, carbamates,
and allyltrialkylsilanes, see: (a) Smitha, G.; Miriyala, B.; Williamson, J.
S. Synlett 2005, 839. (b) Ella-Menye, J.-R.; Dobbs, W.; Billet, M.; Klotz,
P.; Mann, A. Tetrahedron Lett. 2005, 46, 1897. (c) Lipomi, D. J.; Panek,
J. S. Org. Lett. 2005, 7, 4701. (d) Kalita, H. R.; Phukan, P. Synth. Commun.
2005, 35, 475. (e) Phukan, P. J. Org. Chem. 2004, 69, 4005. (f) Ollevier,
T.; Ba, T. Tetrahedron Lett. 2003, 44, 9003. (g) Billet, M.; Klotz, P.; Mann,
A. Tetrahedron Lett. 2001, 42, 631. (h) Niimi, L.; Serita, K.; Hiraoka, S.;
Yokozawa, T. Tetrahedron Lett. 2000, 41, 7075. (i) Meester, W. J. N.;
Rutjes, F. P. J. T.; Hermkens, P. H. H.; Hiemstra, H. Tetrahedron Lett.
1999, 40, 1601. (j) Veenstra, S. J.; Schmid, P. Tetrahedron Lett. 1997, 38,
997.
(8) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999.
(9) Pump, J.; Wannagat, U. Monatsh. Chem. 1962, 93, 352.
10.1021/jo0704558 CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/06/2007
J. Org. Chem. 2007, 72, 5407-5410
5407

TABLE 1. Survey of Lewis Acid Catalysts and Solventsa
our delight, inexpensive and environmentally friendly FeSO4‚
7H2O was identified as a highly effective catalyst,12 with which
the reaction proceeded in 98% conversion (entry 9, Table 1).
Interestingly, FeSO4‚7H2O was found to be ineffective in
catalyzing the corresponding three-component reaction of ben-
zaldehyde (1a), CbzNH2, and allyltrimethylsilane. Further survey
of the reaction conditions revealed that acetonitrile was the
solvent of choice (Table 1), and the catalyst loading could be
lowered down without sacrificing the yield. In the presence of
5 mol % of FeSO4‚7H2O, the reaction gave product 2a in 87%
yield (vide infra). The reaction proceeded well with other alkyl
chloroformates such as PhOCOCl (74% yield) and EtOCOCl
(78% yield). However, the replacement of CbzCl with PhCOCl,
Boc2O, or TsCl led to less than 40% yield or no desired product
at all.13 In addition, using BnNH2 instead of HMDS in this four-
component reaction failed to give the desired homoallylic amine.
The substrate scope for the four-component reaction of
carbonyl compounds, CbzCl, HMDS, and allyltrimethylsilane
was found to be very general (Table 2). In the presence of 5
mol % of FeSO4‚7H2O, a variety of conjugated and unconju-
gated aldehydes were successfully transformed to their corre-
sponding homoallylic amines at room temperature (entries 1-12,
Table 2) in good yields. Importantly, acid-sensitive TBS ether
was allowed (entry 5, Table 2), and cyclic ketones (entries 13
and 14, Table 2) could also serve as suitable substrates for this
four-component reaction.14 Furthermore, this chemistry was
successfully extended to various masked carbonyl compounds
(entries 15-23, Table 2) that, stable in the air and inert to many
nucleophiles, provide significant advantages over the corre-
sponding aldehydes or ketones in synthetic manipulations. It is
notable that varied yields for the synthesis of the same Cbz-
protected homoallylic amine could be obtained from different
acetal derivatives of the aldehyde (entries 15-18, Table 2). In
addition, the use of the acetal derivative of an aldehyde with
low boiling point (e.g., acetaldehyde) could greatly facilitate
the synthesis of the corresponding Cbz-protected homoallylic
amine at room temperature (entry 22, Table 2).15
entry
catalyst
None
solvent
conversion (%)b
1
2
3
4
5
6
7
8
9
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
c
74
80
86
91
72
50
c
98
40
65
32
BiCl3
CeCl3‚7H2O
H3PMo12O40
FeCl3
FeCl3‚6H2O
FeCl2‚4H2O
Fe2(SO4)3‚5H2O
FeSO4‚7H2O
FeSO4‚7H2O
FeSO4‚7H2O
FeSO4‚7H2O
10
11
12
CH2Cl2
CHCl3
a The reaction was performed by the treatment of 1a (0.20 mmol) in
solvent (1.0 mL) at room temperature with CbzCl (1.2 equiv), HMDS (1.2
equiv), allyltrimethylsilane (1.2 equiv), and catalyst (10 mol %). b Deter-
mined by proton NMR analysis. c No or trace amount of 2a was detected
by TLC.
reaction of carbonyl compounds, alkyl chloroformate, HMDS,
and allyltrimethylsilane was envisioned to facilitate the synthesis
of the alkoxycarbonyl-protected homoallylic amines by avoiding
the prior synthesis of N-silylcarbamate (eq 2). However, to our
knowledge, there was no four-component synthesis of homoal-
lylic amines reported previously, and the presence of both two
electrophiles (carbonyl compound and alkyl chloroformate) and
two nucleophiles (HMDS and allyltrimethylsilane) in a one-
pot reaction offers a formidable challenge to drive this reaction,
as compared to the corresponding three-component reaction
where there is only one electrophile (carbonyl compound)
present, to give the desired homoallylic amine as the predomi-
nant product. Besides the possible allylation of the carbonyl
compound, one more obvious side reaction may result from
electrophilic alkyl chloroformate and nucleophilic allyltrimethyl-
silane.10 Herein we wish to report an efficient four-component
reaction of carbonyl compounds (or acetals/ketals), benzyl
chloroformate (CbzCl), HMDS, and allyltrimethylsilane to
produce Cbz-protected homoallylic amines in the presence of
5 mol % of iron(II) sulfate heptahydrate (FeSO4‚7H2O), an
inexpensive and environmentally friendly catalyst, at room
temperature.
The search for proper catalytic conditions for the four-
component reaction of carbonyl compounds, alkyl chlorofor-
mate, HMDS, and allyltrimethylsilane was launched with the
evaluation of a wide variety of commercially available solid
Lewis acids (Table 1). This catalytic four-component reaction
was performed under a “pure” MCR condition1h by adding
successively CbzCl, HMDS, allyltrimethylsilane, and Lewis acid
(10 mol %) to a stirred solution of benzaldehyde (1a) in
acetonitrile at room temperature, and the conversion of ben-
zaldehyde (1a) was determined by proton NMR analysis.11 To
Because CbzCl could quickly react with HMDS in the
absence of catalyst to generate N-silylcarbamate CbzNH(TMS)
and chlorotrimethylsilane (TMSCl),9,16 FeSO4‚7H2O itself or in
combination with TMSCl should promote the subsequent three-
component reaction of carbonyl compounds (or acetals/ketals),
CbzNH(TMS), and allyltrimethylsilane. Thus, on the basis of
the studies reported in the literature,2 we propose a reaction
pathway in which imine 4 should be generated as a key
intermediate for the formation of homoallylic amine 5, which
can be hydrolyzed to give 2, in the four-component reaction of
carbonyl compounds (or acetals/ketals), CbzCl, HMDS, and
allyltrimethylsilane (Scheme 1). In order to gain more insights
into the role played by FeSO4‚7H2O, imine 4a was prepared in
(11) The proton NMR analysis was carried out only when a significant
amount of product 2a was detected by TLC. For all entries of Table 1, the
only detectable byproduct, if any, was benzoic acid, which was taken into
account when calculating the conversion of benzaldehyde (1a).
(12) For a review on the catalysis with iron, see: Bolm, C.; Legros, J.;
Le Paih, J.; Zani, L. Chem. ReV. 2004, 104, 6217.
(13) For the reaction with TsCl, PhCHdNTs was the major product.
(14) The four-component reaction involving either cyclopentanone or
acyclic 2-heptanone proceeded in less than 30% yield.
(15) The boiling point of acetaldehyde is 21°C, and that of acetaldehyde
diethyl acetal (3h) is 103 °C.
(10) Alkyl chloroformate was reported to react with allyltrimethylsilane
in the presence of Lewis acids. See: (a) Olah, G. A.; VanVliet, D. S.; Wang,
Q.; Prakash, G. K. S. Synthesis 1995, 159. (b) Mayr, H.; Gabriel, A. O.;
Schumacher, R. Liebigs Ann. Org. Bioorg. Chem. 1995, 1583.
(16) We observed that CbzNH(TMS) was generated quickly, and its
amount was shown by TLC to decrease gradually in this four-component
reaction. CbzNH(TMS) decomposed to CbzNH2 on a TLC plate because
of its sensitivity to moisture.
5408 J. Org. Chem., Vol. 72, No. 14, 2007

TABLE 2. Iron-Catalyzed Four-Component Synthesis of Protected
Homoallylic Aminesa
SCHEME 1 . Proposed Major Reaction Pathway
TABLE 3. Allylation of Imine 4a
entry
catalyst (mol %)
additive (equiv)
yield (%)a
1
2
3
4
5
6
7
8
b
b
b
58
9.7
58
8.3
11
FeSO4‚7H2O (10)
Fe(II) (10)c
FeSO4‚7H2O (10)
FeSO4‚7H2O (10)
TMSCl (1.2)
TMSCl (0.30)
TMSCl (1.2)
TMSCl (0.30)
TMSCl (0.30) + H2O (0.15)
a Isolated yield. b No or trace amount of 2a was detected by TLC.
c Prepared from FeSO4‚7H2O and TMSCl (10 equiv) at room temperature.
and 3, Table 3), which instead could be promoted by either
TMSCl (entries 6 and 7, Table 3) or HCl (generated in situ
from TMSCl and water, entry 8, Table 3). Nevertheless, FeSO4‚
7H2O (10 mol %) itself was found to be able to catalyze the
corresponding three-component reaction of benzaldehyde (1a),
CbzNH(TMS), and allyltrimethylsilane to give product 2a in
14% yield in 48 h, and the replacement of FeSO4‚7H2O with
either TMSCl (1.2 equiv) or water (0.10-0.70 equiv to generate
HCl in situ) in the four-component reaction only gave product
2a in less than 5% yield. Taken together, FeSO4‚7H2O should
play a major role for the generation of imine 4, and TMSCl
and/or HCl generated previously should be the major promoter-
(s) for the allylation of imine 4 to generate product(s) 5 and/or
2, respectively.
In summary, we have developed, for the first time, an efficient
catalytic four-component reaction of carbonyl compounds (or
acetals/ketals), CbzCl, HMDS and allyltrimethylsilane. In the
presence of a catalytic amount of inexpensive and environmen-
tally friendly FeSO4‚7H2O, a wide variety of aldehydes, ketones,
acetals and ketals were successfully transformed to their
corresponding Cbz-protected homoallylic amines by performing
the four-component reactions under mild reaction conditions.
This protocol not only presents a novel four-component
synthesis of Cbz-protected homoallylic amines, but also adds a
synthetically useful entry into the catalysis with iron(II) salts.
Further extension of this chemistry to other catalytic MCRs is
ongoing.
a The reaction was performed by the treatment of substrate 1 or 3 (0.50
mmol) in dry MeCN (0.50 mL) at room temperature with CbzCl (1.2 equiv),
HMDS (1.2 equiv), allyltrimethylsilane (1.2 equiv), and FeSO4‚7H2O (5
mol %). b Isolated yield.
situ from benzaldehyde (1a)17 and subjected to the allylation
with allyltrimethylsilane (Table 3). Surprisingly, neither FeSO4‚
7H2O nor the iron(II) species prepared from FeSO4‚7H2O and
TMSCl18 could catalyze the allylation of imine 4a (entries 2
Experimental Section
(17) (a) Wu, T. R.; Chong, J. M. Org. Lett. 2006, 8, 15. (b) Kupfer, R.;
Meier, S.; Wurtwein, E.-U. Synthesis 1984, 688. (c) Hart, D. J.; Kanai, K.;
Thomas, D. G.; Yang, T.-K. J. Org. Chem. 1983, 48, 289.
(18) The iron(II) species was prepared by the treatment of FeSO4‚7H2O
with TMSCl (10 equiv) at room temperature for 24 h and the subsequent
evaporation under reduced pressure.
General Procedure for the Four-Component Reaction. To a
stirred solution of carbonyl compound 1 (or acetal/ketal 3, 0.50
mmol) in dry acetonitrile (0.50 mL) at room temperature were added
CbzCl (102 mg, 0.086 mL, 0.60 mmol), HMDS (96.8 mg, 0.125
J. Org. Chem, Vol. 72, No. 14, 2007 5409

mL, 0.60 mmol), allyltrimethylsiliane (68.6 mg, 0.095 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 concentrated and purified by flash column chromatography
on silica gel (eluting with 40:1 petroleum ether/EtOAc) to give
homoallylic amine 2.
purified by flash column chromatography on silica gel to give
product 2a (if any).
Acknowledgment. We are grateful for financial support from
the National Natural Science Foundation of China (no. 20672105)
and the University of Science and Technology of China.
General Procedure for the Allylation of Imine 4a. Imine 4a
was prepared in situ from benzaldehyde (1a) according to the known
procedures.17 To a stirred solution of crude imine 4a (0.25 mmol)
in dry acetonitrile (0.25 mL) at room temperature were added
allyltrimethylsilane (34.3 mg, 0.048 mL, 0.30 mmol) and catalyst
(if any, 10 mol %). The reaction mixture was stirred for 48 h and
Supporting Information Available: General information,
characterization data, and copies of 1H NMR and 13C NMR spectra
for all products. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO0704558
5410 J. Org. Chem., Vol. 72, No. 14, 2007