A general and mild copper-catalyzed three-component synthesis of protected homoallyl amines

Article abstract of DOI:10.1016/j.tetlet.2009.04.008

A mild and highly efficient copper-catalyzed, one-pot, three-component reaction is developed for the synthesis of homoallyl amines. Reaction of an aldehyde, a carbamate, and allyltrimethylsilane in the presence of 5 mol % Cu(OTf)₂ furnishes the corresponding protected homoallylic amines in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2009.04.008

Tetrahedron Letters 50 (2009) 2979–2981
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Tetrahedron Letters
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A general and mild copper-catalyzed three-component synthesis
of protected homoallyl amines
*
Kalyan Kumar Pasunooti, Min Li Leow, Seenuvasan Vedachalam, Bala Kishan Gorityala, Xue-Wei Liu
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild and highly efficient copper-catalyzed, one-pot, three-component reaction is developed for the
synthesis of homoallyl amines. Reaction of an aldehyde, a carbamate, and allyltrimethylsilane in the pres-
ence of 5 mol % Cu(OTf)2 furnishes the corresponding protected homoallylic amines in good to excellent
yields.
Received 6 February 2009
Revised 24 March 2009
Accepted 3 April 2009
Available online 8 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Lewis acid-catalyzed allylations of imines or iminium species
with allylating reagents, such as allyl silane or borane reagents
are effective methods for the introduction of an amino group into
carbon frameworks.1 In addition, homoallyl amines and their
derivatives are considered to be useful precursors in natural prod-
uct synthesis2 and in b-lactam chemistry3 and are valuable inter-
mediates in drug discovery.4 The synthesis of homoallyl amines
from aldimines and allyltrimethylsilane or allyltributylstannane,
is inefficient due to the requirement of additional synthetic trans-
formations.5,6 A one-pot, three-component reaction was first re-
ported for the preparation of homoallylamines by Panek.7
Subsequently, Veenstra reported an improved one-pot, three-com-
ponent reaction for the synthesis of protected homoallyl amines.8
The main drawback of this reaction was the use of excess Lewis
acid (BF3ÁOEt2). Yamamoto,9 Ollevier,10 Phukan,11 and
Williamson12 have demonstrated three-component syntheses of
homoallyl amines by employing various Lewis acids. All of these
methods, while offering some advantages, also suffer from disad-
vantages in terms of the use of expensive catalysts, incomplete
reactions, prior silylation of the carbamate, and limited substrate
scope. Furthermore, their scope for enantioselective synthesis
using chiral ligands is extremely limited. Hence, the development
of new methods that lead to potentially general and convenient
procedures for this transformation is still of interest.
knowledge, the copper-catalyzed three-component reaction for the
synthesis of homoallyl amines has not been studied. Herein, we re-
port a mild and efficient synthesis of homoallyl amines using cop-
per(II) triflate as an inexpensive copper catalyst.
We first optimized the reaction conditions for the copper-cat-
alyzed, one-pot, three-component allylation of in situ-generated
imines. The results are summarized in Table 1. Initially,
10 mol % of CuOTf was utilized to promote the reaction of benzal-
dehyde, benzyl carbamate (CbzNH2), and allyltrimethylsilane in
different solvents. The results were disappointing when dichloro-
methane and acetonitrile were used as solvents with yields of
only 20% and 35% being obtained, respectively (entries 1 and 2).
When 10 mol % of Cu(OTf)2 was used in acetonitrile at room tem-
perature the desired homoallyl amine was obtained in 80% yield
(Table 1, entry 3). Further investigation of the reaction conditions
revealed that acetonitrile was the best solvent and a catalyst load-
ing as low as 5 mol % could be used to afford the highest yield of
92% (entry 4).17 Changing the solvent to dichloromethane reduced
Table 1
Optimization of the copper-catalyzed one-pot, three-component allylation of in
situ-generated imines
NHCbz
O
In recent years, copper-catalyzed reactions have received con-
siderable attention as they are more affordable, highly active, less
toxic, and inexpensive in contrast to classical Lewis acids. Copper
complexes have been studied extensively by Pfaltz,13 Andrus,14
and Katsuki15 using chiral bis and tris oxazoline ligands for asym-
metric synthesis. Copper(I or II) triflates have been widely used as
catalysts for various chemical transformations.16 To the best of our
Cu catalyst
SiMe3
Cbz NH2
+
+
Ph
Ph
H
Solvent
rt, 6-12 h
1a
2a
Entry
Catalyst
mol %
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
CuOTf
CuOTf
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
10
10
10
5
5
20
CH2Cl2
CH3CN
CH3CN
CH3CN
CH2Cl2
CH3CN
24
24
12
10
24
12
20
35
80
92
40
70
* Corresponding author. Tel.: +65 6316 8901; fax: +65 6791 1961.
E-mail address: xuewei@ntu.edu.sg (X.-W. Liu).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.008

2980
K. K. Pasunooti et al. / Tetrahedron Letters 50 (2009) 2979–2981
Table 2
Synthesis of various substituted homoallyl aminesa
Entry
1
Aldehyde 1
Time (h)
10
Homoallyl amine
2b
Yield (%)
92
NHCbz
CHO
2a
NHCbz
CHO
2
8
8
6
8
8
2b
2c
2d
2e
2f
90
88
95
85
85
NHCbz
CHO
3
Br
Br
NHCbz
NHCbz
NHCbz
CHO
418
MeS
MeS
MeO
F3CO
CHO
CHO
5
MeO
619
F3CO
NHCbz
CHO
7
8
2g
2h
2i
75
76
85
78
88
82
92
O2N
O2N
NHCbz
CHO
820
12
6
MeO2C
MeO2C
NHCbz
CHO
9
NHCbz
CHO
1021
11
12
12
6
2j
O
O
NHCbz
CHO
2k
2l
NHCbz
CHO
8
NHCbz
1322
BnO
CHO
8
2m
BnO
a
Conditions: Cu(OTf)2 (5 mol %), acetonitrile, rt.
b
All products (except products 2d, 2f, 2h, 2j, and 2m) have been previously reported.8,10–12
the yield significantly to 40% (entry 5). When 20 mol % of the
copper catalyst was used, the yield dropped considerably to 70%
(entry 6).
The substrate scope for the three-component reaction of various
aldehydes, benzyl carbamate (CbzNH2), and allyltrimethylsilane
was found to be general (Table 2). In the presence of 5 mol % of

K. K. Pasunooti et al. / Tetrahedron Letters 50 (2009) 2979–2981
2981
Table 3
Saloranta, T.; Minnaard, A. J.; Leino, R. Tetrahedron Lett. 1997, 38, 997. and
references cited therein.
Synthesis of protected homoallyl amines from benzaldehyde
2. Wright, D. L.; Schulte, J. P., II; Page, M. A. Org. Lett. 2000, 2, 1847.
3. (a) Hunt, J. C. A.; Laurent, P.; Moody, C. J. Chem. Commun. 2000, 1501; (b) Ovaa,
H.; Stragies, R.; van der Marel, G. A.; van Boom, J. H.; Blechert, S. Chem.
Commun. 2000, 1501.
4. For recent applications of homoallyl amines, see: (a) Kropf, J. E.; Meigh, I. C.;
Bebbington, M. W. P.; Weinreb, S. M. J. Org. Chem. 2006, 71, 2046; (b) Pandey,
M. K.; Korapala, C. S.; Ding, H. Tetrahedron Lett. 2005, 46, 2669; (c)
Ramachandran, P. V.; Burghardt, T. E.; Bland-Berry, L. J. Org. Chem. 2005, 70,
7911.
5. (a) Billet, M.; Klotz, P.; Mann, A. Tetrahedron Lett. 2001, 38, 997; (b) Niimi, L.;
Serita, K.; Hiraoka, S.; Yakozawa, T. Tetrahedron Lett. 2000, 41, 7075. and
references cited therein.
6. Recent references on allyl stannanes: (a) Suiura, M.; Hirano, K.; Kobayashi, S. J.
Am. Chem. Soc. 2004, 126, 7182; (b) Choucair, B.; Leon, H.; Mire, M.-A.;
Lebreton, C.; Mosset, P. Org. Lett. 2000, 2, 1851; (c) Musuyama, Y.; Iwai, J.;
Onuma, Y.; Kagoshima, H. Chem. Commun. 1999, 2191; (d) Masuyama, Y.; Tosa,
J.; Kurusu, Y. Chem. Commun. 1999, 1075; (e) Larsen, S. D.; Grieco, P. A.; Fobare,
W. F. J. Am. Chem. Soc. 1986, 108, 3512.
Entry
1
Amine
Time (h)
Homoallyl amine
Yield (%)
82
NHBoc
Boc-NH2
8
NHCbz
NHTs
2
3
Cbz-NH2
Ts-NH2
10
6
92
80
Conditions: Cu(OTf)2 (5 mol %), acetonitrile, rt.
7. Panek, J. S.; Jain, N. F. J. Org. Chem. 1994, 59, 2674.
8. Veenstra, S. J.; Schmid, P. Tetrahedron Lett. 1997, 38, 997.
9. Nakamura, K.; Nakamura, H.; Yamamoto, Y. J. Org. Chem. 1999, 64, 2614.
10. Ollevier, T.; Ba, T. Tetrahedron Lett. 2003, 44, 9003.
copper(II) triflate, a variety of aldehydes were successfully trans-
formed into the corresponding Cbz-protected homoallyl amines
at room temperature. Moreover, the conditions were mild and
the reactions were rapid, and no side products were formed. First,
we chose 4-substituted aromatic aldehydes to carry out the allyla-
tion reaction. As is evident from Table 2, besides benzaldehyde (en-
try 1), other substituted aromatic aldehydes also served as good
substrates for this reaction. For example, mono-substituted benzal-
dehydes (methyl, bromo, and methylthiol) gave the desired homo-
allyl amines in excellent yields (>88%) (entries 2–4). Interestingly,
aldehydes with electron-donating groups on the phenyl ring (en-
tries 5 and 6) gave the expected products in good yields. On the
other hand, aromatic aldehydes possessing electron-withdrawing
11. Phukan, P. J. Org. Chem. 2004, 69, 4005.
12. Smitha, G.; Miriyala, B.; Williamson, J. S. Synlett 2005, 839.
13. Gokhale, A. S.; Minidis, A. B. E.; Pfaltz, A. Tetrahedron Lett. 1995, 36, 1831.
14. (a) Andrus, M. B.; Asgari, D. Tetrahedron 2000, 56, 5775; (b) Andrus, M. B.;
Asgari, D.; Sclafani, J. A. J. Org. Chem. 1997, 62, 9365; (c) Andrus, M. B.; Chen, X.
Tetrahedron 1997, 53, 16229; (d) Andrus, M. B.; Argade, A. B.; Chen, X.;
Pamment, M. G. Tetrahedron Lett. 1995, 36, 2945.
15. (a) Kohmura, Y.; Katsuki, T. Tetrahedron Lett. 2000, 41, 3941; (b) Kawasaki, K.;
Katsuki, T. Tetrahedron 1997, 53, 6337; (c) Kawasaki, K.; Katsuki, T. Synlett
1995, 1245.
16. Denmark, S. E.; Fu, J. Chem. Rev. 2003, 103, 2763.
17. General experimental procedure for the synthesis of homoallyl amines: To
stirred solution of aldehyde (1 mmol), benzyl carbamate (1.2 mmol), and
allyltrimethylsilane (1.5 mmol) in dry acetonitrile (2 mL, 0.5 M) under
a
a
nitrogen atmosphere was added Cu(OTf)2 (5 mol %) at room temperature.
The mixture was stirred until the reaction was complete as indicated by
TLC. The reaction mixture was quenched with saturated NH4Cl solution and
diluted with EtOAc. The layers were separated and the aqueous layer was
extracted twice with EtOAc, and the combined organic extract was washed
with water and brine. Drying over anhydrous sodium sulfate and
groups on the phenyl ring and a,b-unsaturated aldehydes (entries
7–9) gave the corresponding protected homoallyl amines only in
moderate yields. This methodology could be extended to a variety
of functional groups such as a long-chain aliphatic and phenyl pro-
pionaldehyde. Interestingly, benzyl-protected glycolaldehyde gave
the desired product in excellent yield, which allows an easy access
to aminoalcohols (92%, entry 13, Table 2).
To further study the scope of the reaction, we also examined the
reaction of benzaldehyde and allyl trimethylsilane with benzyl car-
bamate, tert-butyl carbamate, and para-toluene sulfonamide in the
presence of 5 mol % Cu(OTf)2. The results are summarized in Table
3. The reaction with tert-butyl carbamate went to completion to
provide the Boc-protected homoallyl amine in 82% yield. Similarly,
the benzyl carbamate and para-toluene sulfonamide reactions
afforded homoallyl amines in excellent yields (92% and 80%,
respectively).
In summary, we have demonstrated a highly efficient synthesis
of homoallylamines via a copper-catalyzed, one-pot, three-compo-
nent reaction of aldehydes, carbamates, and allyltrimethylsilane.
This method offers several advantages including mild reaction con-
ditions, a low quantity of the catalyst (5 mol %), and no formation
of by-products. The current method can be applied to numerous
functionalized substrates. Extension of this work by employing
chiral ligands is underway.
subsequent removal of the solvent under vacuum resulted in
a colorless
oily residue which was purified by column chromatography on silica gel to
give the desired product.
18. Entry 4, Table 2: Benzyl 1-[4-(methylthio)phenyl]but-3-enylcarbamate (2d): 1H
NMR (400 MHz, CDCl3): d in ppm 7.34 (br s, 4H), 7.23–7.17 (m, 5H), 5.71–5.61
(m, 1H), 5.13–5.03 (m, 5H), 4.76 (d, J = 5.6 Hz, 1H), 2.51 (s, 2H), 2.47 (s, 3H). 13C
NMR (100 MHz, CDCl3): d in ppm = 155.6, 137.3, 136.3, 133.6, 128.5, 128.1,
126.8, 118.6, 66.8, 54.1, 40.9, 15.9. IR (CHCl3):
mmax = 3016, 1716, 1500,
1215 cmÀ1. HRMS (ESI): m/z: calcd for C19H22NO2S: 328.1371 [M+H]+; found:
328.1377.
19. Entry 6, Table 2: Benzyl 1-[4-(trifluoromethoxy)phenyl] but-3-enylcarbamate (2f):
1H NMR (400 MHz, CDCl3): d in ppm 7.34–7.32 (m, 7H), 7.17 (d, J = 8.2 Hz, 2H),
5.70–5.60 (m, 1H), 5.14–5.03 (m, 5H), 4.81 (br s, 1H), 2.52 (s, 2H). 13C NMR
(100 MHz, CDCl3): d in ppm 155.6, 148.3, 136.2, 133.1, 128.5, 128.2, 127.6,
121.7, 119.1, 119.0, 66.9, 53.8, 40.9. IR (CHCl3): mmax = 3020, 1708, 1508, 1261,
1215 cmÀ1. HRMS (ESI): m/z: calcd for C19H19NO3F3: 366.1317 [M+H]+; found:
366.1324.
20. Entry 8, Table 2: Methyl 4-[1-(benzyloxycarbonylamino)but-3-enyl] benzoate
(2h): 1H NMR (400 MHz, CDCl3): d in ppm 8.00 (d, J = 8.2 Hz, 2H), 7.34–7.32
(m, 7H), 5.68–5.58 (m, 1H), 5.23 (br s, 1H), 5.13–5.02 (m, 4H), 4.85 (d,
J = 5.5 Hz, 1H), 3.90 (s, 3H), 2.52 (br s, 2H). 13C NMR (100 MHz, CDCl3): d in
ppm 166.8, 155.6, 147.2, 136.2, 133.1, 129.9, 129.2, 128.5, 128.2, 126.2,
119.0, 66.9, 54.3, 52.1, 40.8. IR (CHCl3):
mmax = 3433, 3020, 1701, 1504,
1280 cmÀ1. HRMS (ESI): m/z: calcd for C20H22NO4: 340.1549 [M+H]+; found:
340.1552.
21. Entry 10, Table 2: Benzyl 1-(furan-3-yl)but-3-enylcarbamate (2j): 1H NMR
(500 MHz, CDCl3): d in ppm 7.37–7.35 (m, 5H), 7.33–7.31 (m, 2H), 6.33 (m, 1H),
5.78–5.70 (m, 1H), 5.14–5.09 (m, 4H), 4.83 (br s, 1H), 4.83 (d, J = 6.2 Hz, 1H),
2.52 (d, J = 4.9 Hz, 2H). 13C NMR (125 MHz, CDCl3): d in ppm 155.7, 143.3,
139.1, 136.4, 133.6, 128.1, 126.4, 118.5, 109.0, 66.8, 46.8, 39.7. IR (CHCl3):
Acknowledgments
m
max = 3016, 1708, 1504, 1334, 1219 cmÀ1
C13H20NO3: 238.1443 [M+H]+; found: 238.1441.
. HRMS (ESI): m/z: calcd for
We gratefully thank Nanyang Technological University and the
Ministry of Education, Singapore for financial support.
22. Entry 13, Table 2: Benzyl 1-(benzyloxy)pent-4-en-2-ylcarbamate (2m): 1H NMR
(500 MHz, CDCl3): d in ppm 7.41–7.40 (m, 5H), 7.38–7.33 (m, 5H), 5.86–5.78
(m, 1H), 5.15–5.10 (m, 5H), 4.55 (dd, J = 12.0, 24.0 Hz, 2H), 3.95 (s, 1H),
3.55–3.53 (m, 2H), 2.46–2.39 (m, 2H). 13C NMR (125 MHz, CDCl3): d in ppm
156.0, 138.0, 136.6, 134.3, 128.5, 128.4, 128.1, 127.7, 127.6, 117.9, 73.2, 70.9,
References and notes
m
max = 3437, 3016, 1712, 1508, 1215 cmÀ1. HRMS
1. For general reviews on the allylations of imines, see: (a) Li, C.-J. Chem. Rev.
2005, 105, 3095; (b) Bloch, R. Chem. Rev. 1998, 98, 1407; (c) Kallström, S.;
66.6, 50.4, 36.4. IR (CHCl3):
(ESI): m/z: calcd for C20H24NO3: 326.1756 [M+H]+; found: 326.1751.