Planar chirality change in dediazoniation reactions of paracyclophanes and mechanistic implication

Article abstract of DOI:10.1021/ol302510t

Dediazoniation reactions of (S_p)-4-bromo-13-[2.2] paracyclophanyldiazonium fluoborate 2a through a heterolytic cleavage process gave products with partial racemization. In contrast, dediazoniation reactions of (S_p)-2a undergoing a nonheterolytic cleavage process afforded products with retention of configuration. A key intermediate, the bromonium cation B, caused the racemization. The unexpected racemization allowed the mechanisms of the dediazoniation reaction to be probed.

Full text of DOI:10.1021/ol302510t

ORGANIC
LETTERS
2012
Vol. 14, No. 21
5436–5439
Planar Chirality Change in Dediazoniation
Reactions of Paracyclophanes and
Mechanistic Implication
Fuyan He, Yudao Ma,* Lei Zhao, Wenzeng Duan, Jianqiang Chen, and Chun Song
Department of Chemistry, Shandong University, Shanda South Road No. 27,
Jinan 250100, P. R. China
ydma@sdu.edu.cn
Received September 11, 2012
ABSTRACT
Dediazoniation reactions of (Sp)-4-bromo-13-[2.2]paracyclophanyldiazonium fluoborate 2a through a heterolytic cleavage process gave products
with partial racemization. In contrast, dediazoniation reactions of (Sp)-2a undergoing a nonheterolytic cleavage process afforded products with
retention of configuration. A key intermediate, the bromonium cation B, caused the racemization. The unexpected racemization allowed the
mechanisms of the dediazoniation reaction to be probed.
[2.2]Paracyclophane, the singular framework, has deri-
vatives with unique electronic and steric properties, mak-
ing them excellent scaffolds for a range of applications.1
Some chiral [2.2]paracyclophane derivatives have been
successfully applied in hydrogenation reactions, enantio-
selective 1,2-addition, and 1,4-addition of organozinc
reagents to aldehydes and imines, etc.2 It is known that the
chiral [2.2]paracyclophane backbone is chemically and con-
figurationally stable under ambient conditions. Thermal
racemization is possible only upon cleavage of the ethano-
bridge at about 200 °C.3 Because of this, enantiopure
compounds with this backbone can be obtained by transfor-
mations of the starting optically pure [2.2]paracyclophane
derivatives under typical conditions of fine organic synthesis.
In previous studies, our group has shown that 13-amino-
4-bromo[2.2]paracyclophane is a versatile building block
for the synthesis of planar chiral [2.2]paracyclophane-
based ligands with substituents on both rings.4 The two
enantiomers of 1acan be readily obtainedby the resolution
(1) (a) Gleiter, R.; Hopf, H. Modern Cyclophane Chemistry: Wiley-
VCH: Weinheim, 2004; (b) Vc-gtle, F. Cyclophane Chemistry: Wiley:
Chichester, 1993.
(2) (a) Pye, P. J.; Rossen, K.; Reamer, R. A.; Tsou, N. N.; Volante,
R. P.; Reider, P. J. J. Am. Chem. Soc. 1997, 119, 6207. (b)Zanotti-Gerosa,
A.; Malan, C.; Herzberg, D. Org. Lett. 2001, 3, 3687. (c) Dahmen, S.;
€
Brase, S. J. Am. Chem. Soc. 2002, 124, 5940. (d) Ma, Y. D.; Song, C.; Ma,
C. Q.; Sun, Z. J.; Chai, Q.; Andrus, M. B. Angew. Chem., Int. Ed. 2003, 42,
5871. (e) Dominguez, B.; Zanotti-Gerosa, A.; Hems, W. Org. Lett. 2004,
€
€
6, 1927. (f) Brase, S.; Hofener, S. Angew. Chem., Int. Ed. 2005, 44, 7879.
€
€
(g) Lauterwasser, F.; Nieger, M.; Mansikkamaki, H.; Nattinen, K.;
€
(3) (a) Reich, H. J.; Cram, D. J. J. Am. Chem. Soc. 1967, 89, 3078.
(b) Reich, H. J.; Cram, D. J. J. Am. Chem. Soc. 1969, 91, 3517. For
photolytic racemization, see: (c) Helgeson, R. C.; Cram, D. J. J. Am. Chem.
Soc. 1966, 88, 509. (d) Delton, M. H.; Cram, D. J. J. Am. Chem. Soc. 1972,
94, 2471. For other racemization, see: (e) Zhuravsky, R. P.; Rozenberg, V. I.;
Sergeeva, E. V.; Vorontsov, E. V. Russ.Chem.Bull., Int.Ed. 2005, 54, 2702.
Brase, S. Chem.;Eur. J. 2005, 11, 4509. (h) Whelligan, D. K.; Bolm,
C. J. Org. Chem. 2006, 71, 4609. (i) Wu, X. W.; Yuan, K.;Sun, W.; Zhang,
M. J.; Hou, X. L. Tetrahedron:Asymmetry2003, 14, 107. (j) Gibson, S. E.;
Knight, J. E. Org. Biomol. Chem. 2003, 1, 1256. (k) Jiang, B.; Lei, Y.;
Zhao, X. L. J. Org. Chem. 2008, 73, 7833.
r
10.1021/ol302510t
Published on Web 10/24/2012
2012 American Chemical Society

Scheme 1. BalzꢀSchiemann Reaction of Amino
[2.2]Paracyclophanes 1aꢀc
Scheme 2. Mechanistic Details of Dediazoniation and Racemi-
zation
cation A. Because of the proximity of the two rings in
[2.2]paracyclophane,6 it was easy for the lone-pair electron
of bromine in the pseudogem position to attack the vacant
orbital of the singlet aryl cation. The bromonium cation B
carried a positive charge distributed over both rings, so it
was more stable than the singlet aryl cation A. Since the
bromonium cation B hada nonchiralstructure, the product
3a racemized when the bromonium salt reacted with the
nuclephiles (Scheme 2). The diazonium salts derived from
1b and 1c were able to generate singlet aryl cations, but,
unlike (Sp)-2a, were unable to form the nonchiral bromo-
nium cations, and the corresponding products 3b and 3c
thus obtained were not racemized remarkably (Scheme 1).
These results can be explained by the theoretical calculation
(see the Supporting Information). The bromine atom in the
of racemic 1a with (1R)-(ꢀ)-10-camphorsulfonyl chloride
((ꢀ)-CSC).4a To extend this work, we tried to synthesize
(Sp)-4-bromo-13-fluoro[2.2]paracyclophane 3a from opti-
cally pure (Sp)-1a by the BalzꢀSchiemann reaction at
60 °C (Scheme 1). To our surprise, the transformation
of (Sp)-1a gave product 3a with an er value of 73.7:26.3
by chiral HPLC analysis. However, when optically pure
12-amino-4-bromo[2.2]paracyclophane 1b and 4-amino-
[2.2]paracyclophane 1c were subjected to the Balzꢀ
Schiemann reaction under the same reaction conditions, they
afforded nearly enantiopure fluoro[2.2]paracyclophane
derivatives (3b and 3c). Thus, the observed racemization
of 3a under the same conditions as 3b and 3c clearly rules
out all reaction mechanisms that involve the cleavage of
the ethano-bridge of the [2.2]paracyclophane system. Ring
rotation without methylene bond breakage is impossible in
[2.2]paracyclophane, and an alternate mechanism without
ring rotation needed to be sought.
The racemization is highly dependent on the structures
of the substrates or the reaction intermediates. The above
results suggested that racemization of 3a during the
BalzꢀSchiemann reaction might involve a key intermedi-
ate: the bromonium cation B (Scheme 2). The thermal
decomposition of diazonium fluoborate (Sp)-2a was
based on the well-established heterolytic pathway5 and
the key step was loss of N2 to generate the singlet aryl
˚
structure A is close to the cation in the 13-position (2.40 A),
but the distance between the bromine atom and the cation
˚
in the 12-position is much greater (4.11 A).
We sought to determine whether similar partial racemiza-
tion would take place when other compounds were used as
the dediazoniation reagents. We were also interested in inves-
tigating whether an aryl radical or a cyclic concerted mechan-
ism could also lead to the racemization. The results summar-
ized in Table 1 (entries 1ꢀ6) give the details of our survey.
In both aqueous and nonaqueous solvents under acidic
conditions, the nitrogen evolution followed first-order ki-
netics, and there was a great deal of evidence that heterolytic
cleavage of the CꢀN bond was occurring.7 The partial
racemization of products 4ꢀ6 (Table 1, entries 1ꢀ3)
strongly supports the involvement of a bromonium cation
mechanism. The reduction of the diazonium ion (Sp)-2a to
4-bromo[2.2] paracyclophane 7 proceeded by a hemolytic
cleavage process (Table 1, entry 4).8 Dediazoniation with
(4) (a) Duan, W. Z.; Ma, Y. D.; Xia, H. Q.; Liu, X.; Ma, Q. S.; Sun, J.
J. Org. Chem. 2008, 73, 4330. (b) Xin, D. Y.; Ma, Y. D.; He, F. Y.
Tetrahedron: Asymmetry 2010, 21, 333. (c) Ma, Q. S.; Ma, Y. D.; Liu, X.;
Duan, W. Z.; Qu, B; Song, C. Tetrahedron: Asymmetry 2010, 21, 292.
(d) He, F. Y.; Ma, Y. D.; Zhao, L.; Duan, W. Z.; Chen, J. Q.; Zhao, Z. X.
Tetrahedron: Asymmetry 2012, 23, 809. (e) Qu, B.; Ma, Y. D.; Ma, Q. S;
Liu, X.; He, F. Y.; Song, C. J. Org. Chem. 2009, 74, 6867.
(5) Swain, C. G.; Sheats, J. E.; Harbison, K. G. J. Am. Chem. Soc.
1975, 97, 783.
(6) Cram, D. J.; Cram, J. M. Acc. Chem. Res. 1971, 4, 204.
(7) (a) DeTar, D. F.; Relyea, D. I. J. Am. Chem. Soc. 1954, 76, 1686.
(b) DeTar, D. F.; Sagmanli, S. V. J. Am. Chem. Soc. 1950, 72, 965.
Org. Lett., Vol. 14, No. 21, 2012
5437

the formation of the bromonium cation B from the singlet
aryl cation A was fast enough to compete with the reaction
between the A and a nucleophile (or solvent). Entry 1 in
Table 1 describes the solvolysis reaction of diazonium ion
in methanol.13 Because bromonium cation B gave pro-
ducts with complete racemization and singlet aryl cation
A gave products with retention of configuration, we con-
clude that, when methanol was in large excess, the relative
rate could be evaluated as rB/rX = kB ꢁ [A]/kX ꢁ [A] ꢁ
[MeOH] = kB/kX ꢁ [MeOH] = [racemic]/[excess] =
2[change]/[retention ꢀ change] = 1.01, where rB is the rate
of formation of bromonium cation B and rX is the rate of
reaction between singlet aryl cation A and methanol, while
kB and kX are the corresponding rate constants. Thus,
Table 1. Dediazoniation Reaction of 2a with Different Reagents
er (retention/ yieldb
entry solvent
reagent
product X
change)a
(%)
1
2
MeOH
DMSO
Ac2O
4, OMe
5, OH
6, OAc
7, H
74.9:25.1c
73.0:27.0
72.5:27.5
99.7:0.3
99.2:0.8
97.7:2.3d
98.6:1.4
91.5:8.5
81.9:8.1
55.6:44.4
55.1:44.9
93.2:6.8
80
84
65
61
53
76
87
85
71
55
60
52
the relative rate constant could be evaluated as kB/kX
≈
H2O
kB/kdiff = 1.01 ꢁ [MeOH] = 24.8 M at room temperature.
Substitution of the value of kdiff gives the absolute rate
constant kB as 2.48 ꢁ 1011 sꢀ1 at room temperature. The
formation of the bromonium cation B is a unimolecular
reaction, whose reaction rate (rB) is almost the same as that
of the reaction between singlet aryl cation A and methanol
(rX). So it displays high sensitivity to the singlet aryl cation A.
Moreover, as the stability of bromonium cation B is much
higher than that of singlet aryl cation A, it is expected that the
former could selectively react with different nucleophiles
while the latter could not. To summarize, the racemization
caused by bromonium cation B could act as a mechanistic
probe for the reaction leading to the singlet aryl cation.
Inorder tocheck the probe, we carried out anotherseries
of experiments (Table 1, entries 7ꢀ12). The iododediazonia-
tion reaction has been exploited for a considerable length
of time and a number of workers have proposed that the
iododediazoniation reaction proceeds through a free radical
mechanism.14 However, our results showed that the me-
chanism of the iododediazoniation reaction was not a simple
radical process but a complex blended process which was
determined by the reaction conditions. For example, under
the reaction conditions of entries 7 and 8 in Table 1, a radical
process was the predominant mechanism. A small amount
of optically pure (Sp)-2a underwent a heterolytic cleavage
through bromonium cation B to give a racemic product.
When (Sp)-2a was treated with an aqueous solution of KI
(Table 1, entry 9), the product 10 was 36% racemized. This
further confirms that the iododediazoniation reaction pro-
ceeds by two mechanisms including heterolytic and hemo-
lytic cleavage processes. When (Sp)-2a was treated with
hydroiodic acid (Table 1, entry 10), the degree of racemiza-
tion was nearly 90%, that is, a heterolytic cleavage process
was the predominant mechanism. Interestingly, the copro-
duct 5 obtained in high optical purity (er value of 93.5: 6.5 in
35% yield) indicated that the singlet aryl cation combined
mainly with water instead of hydroiodic acid. On the other
hand, the results also showed that the bromonium cation B
could selectively react with the stronger nucleophile (HI)
rather than the solvent molecule (H2O).
3
AcOH
AcONa
PhSNa
NaN3
KI
4
MeOH
DMSO
DMSO
CH3CN
CH3CN
H2O
5
8, SPh
9, N3
6
7
10, I
8
KI þ I2
KI
10, I
9
10, I
10, Ie
10
11
12
H2O
HI
CH3CN
DMSO
KSCN
KSCNþ
CuSCN
11, SCN
11, SCN
a Enantiomeric ratio was determined by chiral HPLC analysis
(Chiralpak IA column). b Isolated yield. c Compound 4 was transformed
to 5 for HPLC analysis (see the Supporting Information). d Compound 9
was transformed to 1a for HPLC analysis (see the Supporting Information).
e The coproduct was 5 with an er value of 93.5:6.5 in 35% yield.
sodium benzenethiolate in DMSO, undergoing a free radi-
cal mechanism (SRN1 reaction), afforded 13-benzene-
sulfenyl-4-bromo[2.2]paracyclophane 8 (Table 1, entry 5).9
Entry 6 in Table 1 is the dediazoniation with sodium azide
inDMSOwhich occurredthrough attack ofthe azide upon
the diazonium ion with formation of aryl pentazole and its
subsequent product 9.10 None of these products racemized
remarkably (Table 1 entries 4ꢀ6). We can conclude that reac-
tions that undergo CꢀN bond breakage through a hetero-
lytic cleavage process give products with partial racemization,
and reactions that occur by a hemolytic cleavage process
or a cyclic concerted process give products with retention of
configuration (Scheme 2).
It has been known for some time that the singlet aryl
cation is a short-lived species which is unselectively cap-
tured by a nucleophile or a solvent molecule at a diffusion-
controlled rate (its reaction rate constant kX ≈ kdiff ≈ 1 ꢁ
1010 Mꢀ1 ꢀ1).11 However, it is uncertain whether the
s
excessive reactivity of this species allowed it to be consid-
ered an intermediate in thermal reactions.12 Fortunately,
(8) DeTar, D. F.; Turetzky, M. N. J. Am. Chem. Soc. 1956, 78, 3925.
(9) Petrillo, G.; Novi, M.; Garbarino, G.; Dell’Erba, C. Tetrahedron
1986, 42, 4007.
€
(10) Brase, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew.Chem.,
Int. Ed. 2005, 44, 5188.
(11) Dichiarante, V.; Fagnoni, M.; Albini, A. J. Org. Chem. 2008, 73,
1282.
(12) Glaser, R.; Horan, C. J.; Lewis, M.; Zollinger, H. J. Org. Chem.
1999, 64, 902.
(13) DeTar, D. F.; Turetzky, M. N. J. Am. Chem. Soc. 1955, 77, 1745.
(14) Abeywickrema, A. N.; Beckwith, A. L. J. J. Org. Chem. 1987, 52,
2568.
5438
Org. Lett., Vol. 14, No. 21, 2012

Aryl thiocyanates are of interest as compounds with high
biological activity and convenient sources of thioaromatic
compounds.15 (Sp)-2a reacted with potassium thiocyanate
in acetonitrile to afford the thiocyanato[2.2]paracyclo-
phane 11 in 60% yield 10% ee (Table 1, entry 11), that
is to say, this reaction mainly underwent a bromonium
cation process. In most cases, the reaction between SCNꢀ
and aryldiazonium fluoroborates would occur without
a catalyst in extremely low yield.16 1c was also tested under
the same reaction conditions, and only a trace amount of
product could be found (<5%). This suggested again that
the bromonium cation B intermediate resulted in nearly
racemic products 11. When cuprous thiocyanate and po-
tassium thiocyanate were used together as dediazoniation
reagents as in Sandmeyer-type reactions in nitrile synthesis
(Table 1, entry 12),17 the products were only slightly
racemized in moderate yield. Obviously, the Sandmeyer
reaction in the presence of a cuprous salt was mainly a
radical process.18
It is noted that N-aromatic secondary amides can be
transformed into O-aromatic esters in high yield via
N-nitrosamide intermediates, which would thermally re-
arrange to acyloxyazoaromatics and decompose to give
O-aromatic esters and nitrogen.19 As this reaction had
similar intermediates as the dediazoniation reaction, its
mechanism could also be investigated by our probe. The
results showed that this reaction underwent a heterolytic
Scheme 3. Conversion of N-Aromatic Amides to O-Aromatic
Esters
cleavage process (Scheme 3) rather than the radical mech-
anism presented by Glatzhofer.19b
In conclusion, we discovered a novel type of partial
racemization of [2.2]paracyclophane derivatives, which is
caused by the bromonium cation B in the dediazoniation
reaction. The experimental results strongly indicate that
the partial racemization is closely related to the cleavage of
the CꢀN bond, that is, only heterolytic cleavage process
can lead to the partial racemization. The formation of
[2.2]paracyclophanylbromonium cation B provides an in-
triguing probe for future mechanistic and kinetic studies.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (Grant No.
20671059) and Department of Science and Technology
of Shandong Province is gratefully acknowledged.
(15) (a) Goldberg, J.; Jin, Q.; Ambroise, Y.; Satoh, S.; Desharnais, J.;
Capps, K.; Boger, D. L. J. Am. Chem. Soc. 2002, 124, 544. (b) Wei, Z. L.;
Kozikowski, A. P. J. Org. Chem. 2003, 68, 9116.
(16) Beletskaya, I. P.; Sigeev, A. S.; Peregudovb, A. S.; Petrovskii,
P. V. Mendeleev Commun. 2006, 16, 250.
(17) Beletskaya, I. P.; Sigeev, A. S.; Peregudov, A. S.; Petrovskii,
P. V. J. Organomet. Chem. 2004, 689, 3810.
(18) Nonhebel, D. C.; Waters, W. A. Proc. R. Soc. London A 1957,
242, 16.
Supporting Information Available. Full experimental
details and compound characterization data. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
(19) (a) White, E. H. J. Am. Chem. Soc. 1955, 77, 6011. (b) Glatzhofer,
D. T.; Roy, R. R.; Cossey, K. N. Org. Lett. 2002, 4, 2349.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 21, 2012
5439