A stereoselective C7nC5x free-radical cascade route to optically pure and potentially useful tetracyclic amines

Article abstract of DOI:10.1016/j.tetlet.2008.08.013

Nucleophilic racemic amines have been synthesized utilizing a C⁷ⁿC^5x free-radical cascade reaction from a bis-allyl amine starting material. Being potentially useful organocatalytic bases as is evident from their screening in the Bay

Full text of DOI:10.1016/j.tetlet.2008.08.013

Tetrahedron Letters 49 (2008) 6111–6114
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A stereoselective C7nC5x free-radical cascade route to optically pure
and potentially useful tetracyclic amines
*
Faiz Ahmed Khan , Sarasij K. Upadhyay
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
a r t i c l e i n f o
a b s t r a c t
Nucleophilic racemic amines have been synthesized utilizing a C7n 5x free-radical cascade reaction from
C
Article history:
Received 3 July 2008
Revised 29 July 2008
Accepted 5 August 2008
Available online 8 August 2008
a bis-allyl amine starting material. Being potentially useful organocatalytic bases as is evident from their
screening in the Baylis–Hillman reaction, optically pure amines were also synthesized from optically pure
aldehydes (À) or (+)-4. Bis-allyl amides under similar radical reaction condition resulted in C7n cyclized
products.
Ó 2008 Elsevier Ltd. All rights reserved.
MeO
Br
OMe
Br
Syntheses of useful organic molecules besides naturally occur-
ring ones have gained a lot of impetus not only for the investiga-
tion of biological properties but also because of their versatile
uses in materials1 and organocatalysis.2 Naturally occurring small
molecules such as proline,3 cinchona alkaloids4 and their deriva-
tives5 obtained through judicious manipulations in their functional
groups have proven to be excellent catalysts for organocatalytic
enantioselective reactions. Optically active DABCO {2,3-bis(benzyl-
oxymethyl)-1,4-diazabicyclo(2.2.2)octane},6 pyrrolizidine7 and
bicyclic azetidine8 derivatives are some of the very few synthetic
chiral catalysts for the asymmetric Baylis–Hillman9 reaction. Not-
ing the presence of the bridged nitrogen in all three cases, it was
evident that the nucleophilicity of the amine increases with the in-
creased pyramidalization.8
MeO
H
OMe
H
MeO
Br
OMe
H
Br
Br
H
H
Br
N
H
N
N
2a
1
3
The aldehyde12 4 was condensed with allylamine and the
resulting imine was reduced with sodium borohydride in the same
pot. The mono allyl amine 5 was further allylated to give the bis-
allyl amine 3 in excellent yield (Scheme 1). Bis-allyl amine 3 was
then subjected to intramolecular radical cascade cyclization to
yield 2a and 2b13 or only 2a depending on the reaction conditions
employed (Table 1). Hydrodebromination of 2a in sodium-liquid
NH3 followed by reduction of the double bond under catalytic
hydrogenation conditions afforded 1 in 91% yield from 2a.
Initially, the radical cascade cyclization reaction was carried out
with a slow addition of 2.4 equiv of tributyltin hydride (TBTH)
through syringe pump to a dilute (0.004 M), refluxing solution of
substrate 3 in benzene over 10 h. The reaction was further refluxed
for another 2 h. Purification of the crude reaction mixture afforded
2a and 2b in 14% and 12% yields, respectively (Table 1, entry a). The
tribromo derivative 2b was transformed into 2a by bridgehead
hydrodebromination using 1.2 equiv of TBTH. The yield of 2a could
be improved to 52% by adding freshly distilled tributyltin hydride
(2.4 equiv) through syringe pump over a period of 5 h. Monitoring
the reaction (TLC) at this stage revealed the presence of a substan-
tial amount of 2b along with 2a and traces of unreacted starting
material. Addition of a further portion of 1.2 equiv TBTH and
refluxing the reaction mixture for another 2 h converted 2b into
2a. Amines are prone to decompose at higher temperature.
In view of the aforementioned literature reports, we wanted to
design a molecule bearing a tertiary nitrogen whose lone pair
would be more accessible due to increased pyramidalization by
locking the nitrogen at the bridge making it more nucleophilic
and a useful molecule for organocatalysis. Impressive examples
of complex asymmetric structures obtained through radical cas-
cade reactions have been reported in the last two decades.10
A
well-designed precursor often leads to high stereoselectivity, and
is a very desirable characteristic in synthetic organic chemistry
through radical cascade processes.11 We envisioned that the nor-
bornyl-based tetracyclic amines 1 and 2a could be expeditiously
obtained through radical cascade cyclization from bis-allyl amine
precursor 3. Herein we report a practical synthesis of racemic as
well as both the optical antipodes of highly nucleophilic tetracyclic
amines through a stereoselective 7-endo-trig followed by 5-exo-trig
radical cascade.
* Corresponding author. Tel.: +91 512 2597864; fax: +91 512 2597436.
E-mail address: faiz@iitk.ac.in (F. A. Khan).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.013

6112
F. A. Khan, S. K. Upadhyay / Tetrahedron Letters 49 (2008) 6111–6114
NH2
MeO
Br
OMe
Br
MeO
Br
OMe
Br
MeO
Br
OMe
Br
Br
4 Å MS, MeOH
18 h
K2CO3, acetone
TBTH, AIBN, PhH
Br
Br
Br
NaBH4, 0 oC-rt
4 h, 97%
Br
reflux, 4 h, 92%
Br
Br
reflux/hν
CHO
NH
N
4
5
3
MeO
Br
OMe
Br
MeO
Br
OMe
H
MeO
H
OMe
H
Na, liq. NH3
THF, -55 oC-rt
H2, Pd-C (10%)
1
+
MeOH, rt, 2 h
92%
H
H
30 min
99% from 2a
Br
H
Br
H
H
H
H
N
N
N
2b
2a
6
TBTH, AIBN, PhH
reflux, 1 h, 85%
Scheme 1.
Table 1
cyclized product 9 in 66% yield without any detectable amount
of the cascade cyclized product (Scheme 2). The pyramidal orienta-
tion of the substituents on nitrogen is essential for the cascade
cyclization to occur. While such a pyramidal orientation is feasible
for the bis-allyl amine 3, the same is not feasible for the bis-allyl
amide 8. This is because of the partial delocalization of the nitrogen
lone pair to the amide oxygen. Attempted radical cyclizations of
the mono-allyl amine 5 and mono-allyl amide 10 led to an intrac-
table reaction mixture. The ease of bridgehead cyclization in bis-al-
lyl derivatives 3 and 8 vis-a-vis the mono-allyl derivatives 5 and 10
could be because of the more probable availability of the double
bond to the bridgehead radical.
Radical cascade cyclization of 313
Entry
Reaction condition
TBTH (equiv)
Time (h)
Yield (%)
2a
2b
a
b
c
Reflux
Reflux
Reflux
2.4
3.6
3.6
2.4
12
7
3
14
52
33
14
12
—
—
d
h
m
3
—
Attempts to circumvent the decomposition of amine by reducing
the time of addition of TBTH to 3 h afforded 2a in 33% yield (Table
1, entry c). The radical reaction, when carried out under photo-
chemical conditions using a 450 W UV lamp at the same dilution,
resulted in 14% of 2a (Table 1, entry d).
The radical cascade cyclization reaction was highly stereoselec-
tive leading to only one product in which the methyl group on the
cyclopentane ring has a b-stereochemistry. If the methyl group was
There are only a few reports of 7-endo selectivity during radical
cascade processes. The molecule is organized in such a way that it
follows a C7n 5x free radical cascade16 route to a constrained amine
C
2a, whose lone pair is well exposed, making it a good candidate for
organocatalytic reactions. The mechanism for the radical cascade
cyclization of 3 to 2b involves the formation of a bridgehead radi-
to be disposed on the a-face, it would face strong steric crowding
as shown in Figure 1. Unambiguous structural proof was obtained
by single crystal X-ray analysis of 2a.14
To check the effect of an amide moiety on the radical cycliza-
tion, bis-allyl amide 8 was prepared from the acid derivative 7.15
Employing the radical cyclization on amide 8 resulted in a mono-
MeO
Br
OMe
Br
MeO
Br
OMe
Br
(1) SOCl2
(2) diallylamine
Et3N, CH2Cl2
0 oC to rt
1 h, 85%
Br
Br
Br
Br
COOH
O
N
7
8
MeO OMe
Br
H
(1) SOCl2
TBTH, AIBN
PhH, reflux
(2) allylamine
H
Br
Et3N, CH2Cl2
H
0 oC to rt, 1 h, 97%
14 h, 66%
N
2a
MeO
Br
OMe
H
MeO
Br
OMe
Br
MeO OMe
Br
H
H
Br
Br
Br
Br
H
O
H
O
N
N
H
N
10
9
Not Formed
Figure 1. Stereoselective ring formation.
Scheme 2.

F. A. Khan, S. K. Upadhyay / Tetrahedron Letters 49 (2008) 6111–6114
6113
After obtaining the optically pure amines in good yields, we em-
ployed them for the asymmetric Baylis–Hillman reaction. Using
20 mol % of the optically pure amine (À)-1 or (+)-1 along with p-
nitrobenzaldehyde and methyl acrylate in MeOH under sonication
conditions17 afforded the Baylis–Hillman adduct. While the time
required (22 h) for the formation of the adduct and the yields ob-
tained are comparable to the best conditions reported,18 the asym-
metric induction was very low (8%).
MeO
Br
MeO
Br
OMe
Br
OMe
X
Br
n-Bu3Sn
X = Br, H
Br
Br
N
N
3
In summary, we have reported a practical and expedient syn-
thesis of racemic as well as optically pure antipodes of tetracyclic
C7n
amines involving a stereoselective C7n 5x free radical cascade pro-
C
MeO
Br
MeO
Br
OMe
X
tocol. Bis-allyl amide when subjected to radical cascade conditions
resulted in C7n mono cyclized product. The optically pure and
highly nucleophilic amines were synthesized and screened for
the asymmetric Baylis–Hillman reactions.
OMe
X
Br
n-Bu3SnH
H
Br
H
C5x
H
Acknowledgements
N
N
X = H, 2a
X = Br, 2b
We thank the Department of Science and Technology (DST),
New Delhi, for financial assistance. F.A.K. acknowledges the DST
for a Swarnajayanti Fellowship. F.A.K. would also like to thank Prof.
H.-U. Reissig and the Alexander von Humboldt Stiftung for ‘Wie-
dereinladung’ for a stay at the FU Berlin during May, June-2008.
S.K.U. thanks CSIR for a fellowship.
Scheme 3.
cal by abstraction of a bridgehead bromine from 3. This is followed
by preferential cyclization with the double bond in a 7-endo-trig
fashion instead of the alternative 6-exo-trig mode, resulting in a
more stabilized secondary radical. This radical then undergoes
addition to the other double bond in a 5-exo-trig fashion to afford
the tetracyclic amines 2a or 2b (Scheme 3).
The racemic amine 2a thus obtained through the radical cas-
cade route was employed in a Baylis–Hillman reaction with p-
nitrobenzaldehyde and methyl acrylate under sonication condi-
tion17 to give the Baylis–Hillman adduct in excellent yield (81%).
A similar result was obtained by employing tetracyclic amine 1
as the catalyst. While the tetracyclic amines 2a and 1 were good
catalysts, 3 failed to catalyze the Baylis–Hillman reaction.
References and notes
1. (a) Kato, T.; Mizoshita, N.; Kishimoto, K. Angew. Chem., Int. Ed. 2006, 45, 38; (b)
Gokel, G. W.; Leevy, W. M.; Weber, M. E. Chem. Rev. 2004, 104, 2723; (c) Gokel,
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A.; Halland, N.; Jørgensen, K. A. Org. Lett. 2005, 7, 3897; (d) Austin, J. F.;
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Stavenger, R. A. J. Am. Chem. Soc. 2000, 122, 8837.
3. Reviews of the use of proline and its derivatives as organocatalysts, see: (a)
Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471; (b)
Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580; (c) List, B.
Acc. Chem. Res. 2004, 37, 548.
Pleased by the efficiency of the racemic amines 2a and 1 as cat-
alysts for the Baylis–Hillman reaction, we wanted to obtain them
in enantiomerically pure form. Attempts to resolve the amines 2a
and 1 by salt formation with various enantiomerically pure acids
met with failure as the diastereomeric mixture of the salts formed
could not be purified on repeated crystallization. Because of these
difficulties, we relied on the chiron approach to obtain the optically
active amines 2a and 1. The diastereomeric diols 11 and 12 ob-
4. For reviews, see: (a) Marcelli, T.; van Maarseveen, J. H.; Hiemstra, H. Angew.
Chem., Int. Ed. 2006, 45, 7496; (b) Tian, S.-K.; Chen, Y.; Hang, J.; Tang, L.;
McDaid, P.; Deng, L. Acc. Chem. Res. 2004, 37, 621; (c) France, S.; Guerin, D. J.;
Miller, S. J.; Lectka, T. Chem. Rev. 2003, 103, 2985; (d) Chen, Y.; McDaid, P.;
´
Deng, L. Chem. Rev. 2003, 103, 2965; (e) Kacprzak, K.; Gawronski, J. Synthesis
2001, 961.
5. For use of cinchona alkaloid derivatives as organocatalysts, see: (a) Marcelli, T.;
van der Haas, R. N. S.; van Maarseveen, J. H.; Hiemstra, H. Angew. Chem., Int. Ed.
2006, 45, 929; (b) Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B.
M.; Deng, L. Angew. Chem., Int. Ed. 2005, 44, 105; (c) Ye, J.; Dixon, D. J.; Hynes, P.
S. Chem. Commun. 2005, 4481; (d) Li, H.; Song, J.; Liu, X.; Deng, L. J. Am. Chem.
Soc. 2005, 127, 8948; (e) Liu, X.; Li, H.; Deng, L. Org. Lett. 2005, 7, 167; (f) Li, H.;
Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906.
tained from
for this task (Scheme 4).
D
-mannitol as described recently12 were employed
6. (a) Oishi, T.; Oguri, H.; Hirama, M. Tetrahedron: Asymmetry 1995, 6, 1241; (b)
Oishi, T.; Hirama, M. Tetrahedron Lett. 1992, 33, 639.
7. Barrett, A. G. M.; Cook, A. S.; Kamimura, A. Chem. Commun. 1998, 2533.
8. Barrett, A. G. M.; Dozzo, P.; White, A. J. P.; Williams, D. J. Tetrahedron 2002, 58,
7303.
9. For reviews on the Baylis–Hillman reaction, see: (a) Basavaiah, D.; Rao, K. V.;
Reddy, R. J. Chem. Soc. Rev. 2007, 36, 1581; (b) Masson, G.; Housseman, C.; Zhu,
J. Angew. Chem., Int. Ed. 2007, 46, 4614; (c) Basavaiah, D.; Jaganmohan Rao, A.;
Satyanarayana, T. Chem. Rev. 2003, 103, 811.
10. (a) Dhimane, A.-L.; A, C.; Malacria, M. Angew. Chem., Int. Ed. 2002, 41, 3284; (b)
Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237; (c) Curran, D.
P. Synthesis 1988, 417; (d) Zard, S. Z. Radicals Reactions in Organic Synthesis;
Oxford University Press: New York, 2003.
11. For recent examples of tandem radical cyclizations, see: (a) Moman, E.;
Nicoletti, D.; Mouriño, A. Org. Lett. 2006, 8, 1249; (b) Shen, L.; Hsung, R. P. Org.
Lett. 2005, 7, 775; (c) Lee, H.-Y.; Lee, S.; Kim, B. G.; Bahn, J. S. Tetrahedron Lett.
2004, 45, 7225; (d) Allan, G. M.; Parsons, A. F.; Pons, J.-F. Synlett 2002, 1431.
12. Khan, F. A.; Sudheer, Ch. Org. Lett. 2008. doi:10.1021/ol800990m.
13. Procedure for radical cascade cyclization (Table 1, entry a): Tetracyclic amine (2a)
and tetracyclic amine (2b). The radical reaction was carried out in a 500 mL
round-bottomed flask equipped with a teflon coated stirring bar and a reflux
condenser connected to a three way stopcock, one end of which was sealed
with precision seal rubber septum to which was passed the needle of the
syringe pump and other end was connected with an argon balloon. The flask
was charged with bis-allyl amine 3 (400 mg, 0.69 mmol) along with AIBN
(20 mg, 0.12 mmol). Dry, argon purged benzene (160 mL) was injected and the
MeO
Br
OMe
Br
(1) NaIO4, MeCN
H2O, 0-5 oC, 1 h
(+)-5
NH2
(2)
Br
Br
OH
4 Å MS, MeOH,18 h
(3) NaBH4, 0 oC-rt
4 h, 97%
OH
11
(-)-1
MeO
Br
OMe
Br
(+)-1
Br
Br
OH
OH
12
Scheme 4.

6114
F. A. Khan, S. K. Upadhyay / Tetrahedron Letters 49 (2008) 6111–6114
flask was placed in an oil bath on magnetic stirrer preheated to 90 °C. A
3.04–2.81 (m, 3H), 2.57 (d, 1H, J = 14.4 Hz), 2.39 (dd, 1H, J = 16.5, 7.1 Hz), 2.29–
2.16 (m, 3H), 2.04–2.01 (m, 3H), 1.12 (dd, 1H, J = 11.8, 4.9 Hz), 0.98 (d, 3H,
J = 6.8 Hz); 13C NMR (CDCl3, 100 MHz) d 128.5, 126.4, 114.6, 70.9, 65.4, 60.7,
57.0, 55.6, 52.7, 51.4, 47.5, 43.7, 40.1, 38.9, 31.7, 21.8; IR (neat) 2900, 1560,
1430, 1250 cmÀ1. Anal. Calcd for C16H22Br3NO2: C, 38.43; H, 4.43; N, 2.80.
Found: C, 38.47; H, 4.40; N, 2.78.
solution of TBTH (482 mg, 1.66 mmol) and AIBN (40 mg, 0.24 mmol) in dry,
argon purged benzene (15 mL) was injected into the reaction mixture by
syringe pump over 10 h. After being refluxed for another 2 h the reaction
mixture was cooled and the solvent was evaporated under reduced pressure.
Column chromatography using silica gel (300 mL of hexane to remove tin
impurities and then by 2 ? 4 ? 6% methanol in ethyl acetate) afforded 2a
(41 mg, 14%) as a yellowish crystalline solid and 2b (41 mg, 12%) as a viscous
liquid. 2a: mp 132 °C; 1H NMR (CDCl3, 400 MHz) d 3.46 (dd, 1H, J = 13.2,
2.2 Hz), 3.27 (s, 3H), 3.24 (s, 3H), 3.10 (ddd, 1H, J = 12.9, 8.0, 2.2 Hz), 2.87 (d, 1H,
J = 4.1 Hz), 2.84–2.79 (m, 1H), 2.63 (dd, 2H, J = 14.4, 2.9 Hz), 2.40 (dd, 1H,
J = 12.9, 7.3 Hz), 2.28 (dd, 1H, J = 14.4, 12.4 Hz), 2.19 (dd, 1H, J = 15.3, 6.4 Hz),
2.07–1.98 (m, 3H), 1.91 (ddd, 1H, J = 12.0, 8.8, 4.2 Hz), 1.02 (d, 3H, J = 6.8 Hz),
0.65 (dd, 1H, J = 11.9, 4.6 Hz); 13C NMR (CDCl3, 100 MHz) d 127.0, 124.0, 117.0,
66.9, 60.9, 58.0, 55.8, 54.5, 52.4, 50.2, 47.5, 44.0, 39.2, 30.8, 28.2, 21.7; IR (KBr)
2850, 2800, 1580, 1440, 1420, 1310, 1250 cmÀ1. Anal. Calcd for C16H23Br2NO2:
C, 45.63; H, 5.50; N, 3.33. Found: C, 45.59; H, 5.48; N, 3.30. Compound 2b: 1H
NMR (CDCl3, 400 MHz) d 3.50 (s, 3H), 3.42 (d, 1H, J = 13.1 Hz), 3.25 (s, 3H),
14. Crystallographic data (excluding structure factors) for 2a have been deposited
with the Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 693416. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk.
15. Mustafaev, A. M.; Imamaliev, A. B.; Guseinov, N. M. Zh. Org. Khim. 1989, 25,
1908.
16. (a) McCarroll, A. J.; Walton, J. C. Angew. Chem., Int. Ed. 2001, 40, 2224; (b)
McCarroll, A. J.; Walton, J. C. J. Chem. Soc., Perkin Trans. 1 2001, 3215.
17. Ultrasonic cleaner ELMA model T490 DH (350 W, 40 kHz) was used.
18. Coelho, F.; Almeida, W. P.; Veronese, D.; Mateus, C. R.; Lopes, E. C. S.; Rossi, R.
C.; Silveira, G. P. C.; Pavam, C. H. Tetrahedron 2002, 58, 7437.