Efficient synthesis of chiral 2,2′-bipyrrolidines by an anti -selective alkene diamination

Article abstract of DOI:10.1021/ol302855z

The rapid and efficient construction of complex chiral bicyclic amines is possible using a novel alkene diamination reaction. Electrophilic iodinating agents promote the intramolecular anti-selective diamination of alkenes and allow the efficient synthesi

Full text of DOI:10.1021/ol302855z

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Efficient Synthesis of Chiral
2,20-Bipyrrolidines by an
anti-Selective Alkene Diamination
€
€
Christian H. Muller, Roland Frohlich, Constantin G. Daniliuc, and Ulrich Hennecke*
€
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat, Corrensstrasse 40,
€
48149 Mu€nster, Germany
ulrich.hennecke@uni-muenster.de
Received October 17, 2012
ABSTRACT
The rapid and efficient construction of complex chiral bicyclic amines is possible using a novel alkene diamination reaction. Electrophilic
iodinating agents promote the intramolecular anti-selective diamination of alkenes and allow the efficient synthesis of chiral amines such as trans-
bipyrrolidines.
Vicinal (1,2-) diamines are important building blocks of
natural products and biologically active compounds.1
Chiral vicinal diamines are widely employed as a backbone
for the construction of reagents and catalysts in asym-
metric synthesis.2 A particularly interesting class of 1,2-
diamines are trans-2,20-bipyrrolidines, sterically demand-
ing chiral diamines with applications in organocatalysis
and asymmetric synthesis (Figure 1).3 In many cases 2,20-
bipyrrolidines have shown properties superior to the more
commonly used diamines such as trans-1,2-diamino cyclo-
hexane.4 One particularly interesting bipyrrolidine-based
ligand is the trans-bpbp ligand 1 which was shown to be the
preferred ligand for biomimetic CꢀH-bond oxidation reac-
tions.5 In iron-catalyzed asymmetric alkene dihydroxylations,
the use of a trans-bpbp derivative as a metal ligand
was again the key to reaching high enantioselectivities.6
However, despite their advantages the general use of 2,20-
bipyrrolidines as building blocks for organocatalysts and
chiral ligands has been limited most likely due to their
difficult accessibility.7 The preparation of unsubstituted
2,20-bipyrrolidine is possible by the unselective photoche-
mical dimerization of pyrrolidine followed by extensive
recrystallization to separate the isomers.7d However, reli-
able procedures for the synthesis of substituted derivatives
are missing.
(1) Kotti, S. R. S. S.; Timmons, C.; Li, G. Chem. Biol. Drug Des. 2006,
67, 101.
(2) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed.
1998, 37, 2580.
^
(3) (a) Hirama, M.; Oishi, T.; Ito, S. J. Chem. Soc., Chem. Commun.
1989, 665. (b) Oishi, T.; Hirama, M. J. Org. Chem. 1989, 54, 5834. (c)
Maa, Y.; Zhang, Y. J.; Jin, S.; Li, Q.; Li, C.; Lee, J.; Zhang, W.
Tetrahedron Lett. 2009, 50, 7388. (d) Sulzer-Moss, S.; Alexakis, A.;
Mareda, J.; Bollot, G.; Bernardinelli, G.; Filinchuk, Y. Chem.;Eur.
J. 2009, 15, 3204.
Figure 1. Important chiral diamines for asymmetric catalysis.
(4) (a) Denmark, S. E.; Fu, J.; Lawler, M. J. J. Org. Chem. 2006, 71,
1523. (b) Suzuki, K.; Oldenburg, P. D.; Que, L., Jr. Angew. Chem., Int.
Ed. 2008, 47, 1887. (c) Sergeeva, E.; Kopilov, J.; Goldberg, I.; Kol, M.
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Kol, M. Chem. Commun. 2009, 3053.
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2008, 47, 1887.
(5) Chen, M. S.; White, M. C. Science 2007, 318, 783.
r
10.1021/ol302855z
XXXX American Chemical Society

One of the most attractive routes for the synthesis of 1,2-
diamines is the direct diamination of alkenes.8 Efficient
methods for inter- and intramolecular alkene diaminations
with urea- or sulfonamide-protected precursors and stoi-
chiometric oxidants have been developed using transition
metal catalysts.9ꢀ11 These methods have in common the
fact that the amino functionalities are usually introduced
to the alkene via a formal syn-addition. Recently, transi-
tion-metal-free procedures for alkene diaminations have
emerged employing environmentally friendly hypervalent
iodine or electrophilic halogen reagents.12 Again, these
diaminations employ amines with electron-deficient pro-
tecting groups (urea, sulfonates) and proceed with syn-
selectivity. However, anti-selective diaminations are rare.13
anti-diamination of alkenes promoted by electrophilic
halogenating agents.
~
Recently, Muniz et al. reported an intermolecular anti-
diamination of styrene derivatives using hypervalent
iodine reagents.14 Herein, we present a generally applic-
able method for the synthesis of bipyrrolidines starting
from simple linear precursors using an intramolecular
Figure 2. Crystal structures of diamines 3b (left) and 3h (right).
During our investigations on asymmetric halocycliza-
tion reactions15 we observed an unusual halogen-induced
intramolecular diamination reaction. When (Z)-N,N0-
(4-bromophenyl)-1,8-diaminooct-4-ene 2b was treated with
N-iodosuccinimide (1.2 equiv) at rt a clean alkene diamina-
tion reaction to give N,N0-di(4-bromophenyl)-2,20-bipyrro-
lidine 3b was observed. The product 3b was isolated as a
single diastereomer indicating a stereospecific reaction.
Single crystal X-ray structure analysis revealed the product
to be trans-configured at the newly formed stereocenters
suggesting an anti-addition of the amino groups onto the
alkene (Figure 2).
(7) (a) Oishi, T.; Hirama, M.; Sita, L. R.; Masamune, S. Synthesis
1991, 789. (b) Kotsuki, H.; Kuzume, H.; Gohda, T.; Fukuhara, M.;
Ochi, M.; Oishi, T.; Hirama, M.; Shiro, M. Tetrahedron: Asymmetry
1995, 6, 2227. (c) Alexakis, A.; Tomassini, A.; Chouillet, C.; Roland, S.;
Mangeney, P.; Bernardinelli, G. Angew. Chem., Int. Ed. 2000, 39, 4093.
(d) Denmark, S. E.; Fu, J.; Lawler, M. J. Org. Synth. 2006, 83, 121.
(8) Reviews: (a) De Jong, S.; Nosal, D. G.; Wardrop, D. J. Tetra-
hedron 2012, 68, 4067. (b) de Figueiredo, R. M. Angew. Chem., Int. Ed.
2009, 48, 1190. (c) Cardona, F.; Goti, A. Nat. Chem. 2009, 1, 269. (d)
~
€
ꢀ
Muniz, K.; Hovelmann, C. H.; Streuff, J.; Campos-Gomez, E. Pure
Appl. Chem. 2008, 80, 1089.
(9) Leading references on transition metal catalyzed alkene diamina-
€
~
tions: (a) Streuff, J.; Hovelmann, C. H.; Nieger, M.; Muniz, K. J. Am.
Chem. Soc. 2005, 127, 14587. (b) Zabawa, T. P.; Kasi, D.; Chemler, S. R.
~
J. Am. Chem. Soc. 2005, 127, 11250. (c) Muniz, K. J. Am. Chem. Soc. 2007,
~
€
ꢀ~
129, 14542. (d) Muniz, K.; Streuff, J.; Hovelmann, C. H.; Nunez, A. Angew.
Chem., Int. Ed. 2007, 46, 7125. (e) Zabawa, T. P.; Chemler, S. R. Org. Lett.
2007,9, 2035. (f) Zhao, B.; Yuan, W.; Du, H.; Shi, Y. Org. Lett. 2007, 9, 4943.
(g) Sibbald, P. A.; Michael, F. E. Org. Lett. 2009, 11, 1147. (h) Sibbald, P. A.;
Rosewall, C. F.; Swartz, R. D.; Michael, F. E. J. Am. Chem. Soc. 2009, 131,
Table 1. Electrophilic Iodine-Induced Diamination of
(Z)-N,N0-(4-Bromophenyl)-1,8-diaminooct-4-ene 2b
~
15945. (i) Iglesias, A.; Muniz, K. Chem.;Eur. J. 2009, 15, 10563. (j)
Sequeira, F. C.; Turnpenny, B. W.; Chemler, S. R. Angew. Chem., Int. Ed.
ꢀ
~
2010, 49, 6365. (k) Iglesias, A.; Perez, E. G.; Muniz, K. Angew. Chem., Int.
Ed. 2010, 49, 8109. (l) Wang, Y.-F.; Zhu, X.; Chiba, S. J. Am. Chem. Soc.
~
2012, 134, 3679. (m) Martinez, C.; Muniz, K. Angew. Chem., Int. Ed. 2012,
ꢀ
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51, 7031. (o) Chavez, P.;Kirsch, J.;Streuff, J.;Muniz, K. J. Org. Chem. 2012,
77, 1922.
(10) For anti-selective palladium-catalyzed diaminations, see: (a)
~
€
entry
reagenta
NIS
solvent
additive
yield (%)b
Muniz, K.; Hovelmann, C. H.; Streuff, J. J. Am. Chem. Soc. 2008, 130,
€
~
763. (b) Hovelmann, C. H.; Streuff, J.; Brelot, L.; Muniz, K. Chem.
ꢀ
1
2
CH2Cl2
CH2Cl2
CH2Cl2
THF
ꢀ
82
61
63
81
70
68
40
25
∼20
~
€
Commun. 2008, 2334. (c) Muniz, K.; Streuff, J.; Chavez, P.; Hovelmann,
C. H. Chem.;Asian J. 2008, 3, 1248.
NIS
NaHCO3
c
(11) For leading references on the diamination of 1,3-dienes, see: (a)
Bar, G. L. J.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. J. Am. Chem.
Soc. 2005, 127, 7308. (b) Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc.
2007, 129, 762. (c) Du, H.; Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc.
2007, 129, 11688. (d) Zhao, B.; Peng, X.; Cui, S.; Shi, Y. J. Am. Chem.
Soc. 2010, 132, 11009. (e) Zhao, B.; Peng, X.; Zhu, Y.; Ramirez, T. A.;
Cornwall, R. G.; Shi, Y. J. Am. Chem. Soc. 2011, 133, 20890. (f)
3
NIS
NaHCO3
4
NIS
ꢀ
5
NIS
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ꢀ
c
6
I2
NaHCO3
7
ICl
ꢀ
ꢀ
ꢀ
ꢀ
8
BnMe3NICl2
NBS
NCS
~
Lishchynskyi, A.; Muniz, K. Chem.--Eur. J. 2012, 18, 2212.
9
~
€
ꢀ
(12) (a) Muniz, K.; Hovelmann, C. H.; Campos-Gomez, E.; Barluenga,
ꢀ
d
10
ꢀ
J.; Gonzalez, J. M.; Steuff, J.; Nieger, M. Chem.;Asian J. 2008, 3, 776. (b)
ꢀ
Li, H.; Widenhoefer, R. A. Tetrahedron 2010, 66, 4827. (c) Chavez, P.;
a 1.2 equiv. b Isolated yield. c Saturated solution in H2O. d Less than
5% conversion after 18 h at rt.
€
Kirsch, J.; Hovelmann, C. H.; Steuff, J.; Martınez-Belmonte, M.; Escudero-
~
ꢀ
Adan, E. C.; Martin, E.; Muniz, K. Chem. Sci. 2012, 3, 2375. (d) Kim, H. J.;
Cho, S. H.; Chang, S. Org. Lett. 2012, 14, 1424.
(13) For anti-selective halogen-induced diaminations of 1,4-dihydro-
pyridines or glycals, see: (a) Lavilla, R.; Kumar, R.; Coll, O.; Masdeu,
C.; Bosch, J. Chem. Commun. 1998, 2715. (b) Lavilla, R.; Kumar, R.;
Coll, O.; Masdeu, C.; Spada, A.; Bosch, J.; Espinosa, E.; Mollins, E.
Chem.;Eur. J. 2000, 6, 1763. (c) Kumar, V.; Ramesh, N. G. Chem.
Commun. 2006, 4952.
The reaction conditions were carefully optimized,
and the application of N-iodosuccinimide (1.2 equiv)
€
ꢀ
~
€
€
(14) Roben, C.; Souto, J. A.; Gonzalez, Y.; Lishchynskyi, A.; Muniz,
(15) Hennecke, U.; Muller, C. H.; Frohlich, R. Org. Lett. 2012, 13,
860.
K. Angew. Chem., Int. Ed. 2011, 50, 9478.
B
Org. Lett., Vol. XX, No. XX, XXXX

in dichloromethane proved to be optimal (Table 1, entry 1).
The addition of base led to significantly decreased yields
(entries 2 and 3). Iodine also induced the diamination
reaction, but lower yields were obtained (entry 6). Other
electrophilic iodine sources such as BnMe3NICl2 or ICl
proved to be inferior (entries 7 and 8). N-Bromosuccini-
mide led to a complex reaction mixture containing several
monocyclization products and only about 20% of 3b
(entry 9). Using N-chlorosuccinimide, no conversion of
the starting material could be observed (entry 10). The
reaction could be efficiently conducted in several sol-
vents, but the use of dichloromethane provided the highest
yields (entries 1, 4, and 5).
were generally good to very good, and sterically demand-
ing aryl groups with substituents at the ortho position
caused only slightly lower yields (entries 4, 5, and 7). Even
with electron-deficient substituents (ꢀCF3, ꢀNO2, ꢀCN;
entries 8, 9, and 10) selective anti-addition was observed
(crystal structure of 3h, Figure 1, and 3j, SI). With strongly
electron-donating groups (R = 4-OMe, PMP protecting
group, entry 11), a complex reaction mixture was obtained.
However, under modified conditions (I2, ꢀ78 °C) the anti-
addition product was isolated in moderate yield.16 Alkyl
substituents such as tert-butyl and benzyl groups at nitro-
gen were tolerated as well (entries 12 and 13). The efficient
cyclization of the benzyl protected diamine 2m makes the
benzyl group the protection group of choice if N,N0-
unsubstitutedbipyrrolidines are targeted. The diamination
reaction is not limited to cyclizations of unsubstituted 1,8-
diaminooct-4-enes such as 2. Diamine 4 was cyclized to
give a chiral 2,20-bipyrrolidine 5 with a tetramethyl sub-
stituted backbone (entry 14). Likewise, 1,10-diaminodec-
5-ene 6 underwent 6-exo cyclizations to yield N,N0-
(3-bromophenyl)-2,20-bipiperidine 7.
Table 2. Reaction Scope
Scheme 1. Synthesis of trans-bpbp Ligands
Probably the most important bipyrrolidine-based ligand
is the trans-bpbp ligand.5 The method presented here
allows a simple and diastereoselective synthesis of this
ligand starting from dialdehyde 8 (easily available from
1,5-cyclooctadiene by selective oxidation of one double
bond17). Reductive amination with 2-picolyl amine pro-
vided diamine 9 which upon treatment with 2 equiv of NIS
yielded the desired bpbp-ligand 1 with complete diaster-
eoselectivity and good yield (60% over two steps, Scheme 1).
Moreover, our method is also suitable for the synthesis
of backbone-substituted trans-bpbp ligands. Reductive
amination of tetraphenyl-substituted dialdehyde 10 with
2-picolyl amine yields diamine 11 which again can be cycli-
zed to give 12, a sterically demanding 4,4,40,40-tetraphenyl-
substituted trans-bpbp ligand (Scheme 1).
The unexpected anti-selectivity observed in this diami-
nation reaction is best explained by the neighboring group
a Isolated yield. b I2 (2.5 equiv) was used instead of NIS; reaction
conducted in THF at ꢀ78 °C. c 2.4 equiv of NIS were used. d Reaction
conducted at 0 °C.
(16) It seems that NIS and I2 induce the partial decomposition of 2k/
3k to unidentified oxidation products (aromatic iodination was not
observed). For the oxidative deprotection of PMP groups by NIS and I2:
Verkade, J. M. M.; von Hemert, L. J. C.; Quaedflieg, P. J. L. M.; Alsters,
P. L.; van Delft, F. L.; Rutjes, F. P. J. T. Tetrahedron Lett. 2006, 47,
8109.
Under optimized conditions the scope of the reaction
was investigated (Table 2). A wide variety of aryl groups
at the nitrogen atoms containing electron-donating and
-neutral substituents were tolerated (entries 1ꢀ7). Yields
(17) Singh, V.; Deota, P. T. Synth. Commun. 1988, 18, 617.
Org. Lett., Vol. XX, No. XX, XXXX
C

effect of the electron-rich amine after an initial halocycliza-
tion reaction.18 Upon treatment of diamine 2 with an
electrophilic iodine source, an anti-selective iodocycliza-
tion to an intermediate occurs. With electron-withdrawing
groups at the nitrogen atom such as the often used tosyl
protecting group, the reaction stops at this point and the
iodocyclization product can be isolated. However, if the
substituent on nitrogen is rather electron rich (as in this
case alkyl or aryl groups), an aziridinium ion can be
formed which is subsequently opened from the backside
leading to the anti-diamination product. The involvement
auxiliary approach is also viable for substituted bipyrroli-
dines. Cyclization of diamine 17 with a tetramethyl-
substituted carbon chain using iodine proceeded with
moderate induced diastereoselectivitiy (dr 78:22). After
column chromatography tetramethyl bipyrrolidine 18a
was isolated in 26% yield in diastereomerically pure form.
This represents the first selective synthesis of a chiral
substituted bipyrrolidine.
Scheme 2. Chiral-Auxiliary-Based Asymmetric Synthesis of
Bipyrrolidines
~
of azirdinium ions has also been suggested by Muniz in his
hypervalent iodine mediated diamination reaction to ex-
plain the observed anti-selectivity.13,14
Resolution of racemic 2,20-bipyrrolidines is in principle
possible using tartaric acid as a resolving agent, but an
asymmetric synthesis would be clearly more attractive.
One way to achieve this goal would be the use of a chiral
auxiliary at nitrogen. Diastereoselective halocyclizations
are well-known and often proceed with high selectivities.19
However, this case represents a very special situation, as
the presumed halonium ion intermediate would be a
(pseudo) meso-halonium ion and diastereoselective cycli-
zations of such meso-type intermediates are uncommon.15
As a chiral auxiliary we chose 1-(phenyl)ethylamine deri-
vatives which are easily available and well-known for high
stereoinduction.20 Reductive amination of dialdehyde 8
with 1-(phenyl)- or 1-(naphthyl)ethylamine provided the
diamines13and 14. Upon treatment withiodine(which led
to better selectivities than NIS) 13 cyclized to give the
diastereomeric products 15a and 15b as an inseparable mixture
with moderate diastereoselectivity (dr 73:27, Scheme 2). Using
the more sterically demanding 1-naphthylethyl group, much
better induced diastereoselectivities were obtained. Under
optimized reaction conditions (I2, THF, ꢀ30 °C), diamine
14 cyclized to bipyrrolidines 16a and 16b with high diaster-
eoselectivity (dr 85:15). The diastereomers 16a and 16b
were easily separable by column chromatography, and the
major diastereomer 16a was isolated in 54% yield. After
removal of the 1-(naphthyl)ethyl auxiliary, which is possi-
ble under reductive conditions (Pd(OH)2/C, HCOOH),
and acylation with benzoyl chloride, N,N0-dibenzoyl-2,20-
bipyrrolidine was obtained in diastereo- and enantiopure
form. Comparison of the optical rotation with literature
values21 established the configuration of the major diaste-
reomer 16a at the 2,20-carbon atoms to be R,R. The chiral
In conclusion, we present herein an efficient method for
the selective synthesis of substituted bipyrrolidines and
bipiperidines starting from cheap and readily available
starting materials. The method employs an intramolecular
anti-selective diamination reaction of alkenes which pro-
ceeds under very practical reaction conditions (NIS, rt)
without the need for protecting groups. This is a clear
advantage over many other diamination methods which
require amine derivatives with electron-withdrawing pro-
tecting groups (ureas, sulfonamides) that are often difficult
to remove. Our method allows for the efficient and dia-
stereoselective synthesis of substituted bipyrrolidines
which are of great interest in asymmetric synthesis and
biomimetic CꢀH oxidation reactions.
Acknowledgment. Financial support by the WWU
€
Munster and the “Fond der Chemischen Industrie” is
gratefully acknowledged. The authors thank Prof. Dr. K.
Ditrich (BASF SE) for a kind gift of chemicals.
(18) A mechanistic scheme can be found in the Supporting
Information.
(19) (a) French, A. N.; Bissmire, S.; Wirth, T. Chem. Soc. Rev. 2004,
33, 354. (b) Castellanos, A.; Fletcher, S. P. Chem.;Eur. J. 2011, 17,
5766.
Supporting Information Available. Experimental de-
tails, characterization data for all starting materials and
products, and X-ray crystallographic data. This material
is available free of charge via the Internet at http://pubs.
acs.org.
ꢀ
(20) Juriasti, E.; Leon-Romo, J. L.; Reyes, A.; Escalante, J. Tetra-
hedron: Asymmetry 1999, 10, 2441.
(21) Kotsuki, H.; Kuzume, H.; Gohda, T.; Fukuhara, M.; Ochi, M.;
Oishi, T.; Hirama, M.; Shiro, M. Tetrahedron: Asymmetry 1995, 6, 2227.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX