Stereospecific diaza-cope rearrangement driven by steric strain

Article abstract of DOI:10.1002/anie.200801974

(Chemical Equation Presented) Bucklingunder the strain: Steric strain was used to drive the diaza-Cope rearrangement to completion (see scheme) with a high degree of stereospecificity (>99.5% ee), as evidenced by chiral-phase HPLC and crystal data. There is good agreement between the experimental and computational values for the rate and equilibrium constants for the rearrangement.

Full text of DOI:10.1002/anie.200801974

Communications
DOI: 10.1002/anie.200801974
Sigmatropic Rearrangement
Stereospecific Diaza-Cope Rearrangement Driven by Steric Strain**
Hyunwoo Kim, Yen Nguyen, Alan J. Lough, and Jik Chin*
Vögtle and Goldschmitt[1] were the first to use hydrogen
bonds to drive diaza-Cope rearrangement reactions to
completion over thirty years ago. Although many interesting
publications on the topic have since appeared,[2] no other
weak forces have been found to drive the rearrangement
reaction to completion. The diaza-Cope rearrangement is
useful for synthesizing a wide variety of chiral vicinal
diamines (Scheme 1)[3] that may be valuable for the develop-
ment of catalysts[4] and drugs.[2,5] [3,3] Sigmatropic reactions,
reaction is the first example of a [3,3] sigmatropic rearrange-
ment driven by steric strain.
We prepared (S,S)-1,2-bis(2,4,6-trimethylphenyl)-1,2-dia-
minoethane (TPEN)[10] through the diaza-Cope rearrange-
ment of the diimine formed from (R,R)-1,2-bis(2-hydroxy-
phenyl)-1,2-diaminoethane (HPEN) and mesitaldehyde.[3]
The addition of benzaldehydes (2.5 equiv) with electron-
donating or electron-withdrawing substituents to (S,S)-1,2-
bis(2,4,6-trimethylphenyl)-1,2-diaminoethane in ethanol and
subsequent stirring of the reaction mixture overnight at
ambient temperature gave the corresponding rearranged
diimines 1b–3b in good yields (80–85%). The identity of
products 1b–3b of the rearrangement reaction was confirmed
by comparing their 1H NMR spectra with those of the
diimines prepared from the corresponding diamines and
mesitaldehyde. Although the initial diimines 1a–3a were not
isolated, their clean formation (dH = 5.6 ppm for 3a, Figure 1)
Scheme 1. a)Hydrogen-bond-driven and b) steric-effect-driven diaza-
Cope rearrangement reaction.
including the Cope, Claisen, oxy-Cope, and aza-Cope reac-
tions, have received much interest on both a theoretical[6] and
a practical[7] level. The diaza-Cope rearrangement provides an
ideal platform for studying the effects of weak forces in [3,3]
sigmatropic reactions, as the systematic variation in the
structure of the starting materials that is needed for these
investigations can be achieved readily through simple syn-
thesis. It is well known that strained molecules show
remarkable reactivity.[8] Herein, we report the effect of
steric strain on the rate and equilibrium constants of the
diaza-Cope rearrangement reaction. Although ring strain has
been used to drive [3,3] sigmatropic rearrangements,[1a,9] this
Figure 1. Monitoring the conversion of 3a into 3b by 1H NMR
spectroscopy in [D6]DMSO. DMSO=dimethyl sulfoxide.
and conversion into the product diimines (dH = 4.8 ppm for
1
3b) could be monitored readily by H NMR spectroscopy.
The equilibrium constants for the rearrangement reactions in
Scheme 1 must be greater than 102, as we did not observe any
of the initial diimines by 1H NMR spectroscopy after
equilibration. We were pleasantly surprised that the steric
effect was so dramatic and complete for the rearrangement
reactions (Figure 1).
Figure 2a shows the crystal structure of 1b formed
through the rearrangement of 1a.[11] This structure is “pre-
organized”[3c] for the reversible rearrangement reaction and
resembles the computed transition-state (TS) structure for
the rearrangement of 3a (Figure 2b).[12]
[*] H. Kim, Y. Nguyen, A. J. Lough, Prof. Dr. J. Chin
Department of Chemistry, University of Toronto
80 St. George Street, Toronto, ON (Canada)
Fax: (+1)416-978-7113
E-mail: jchin@chem.utoronto.ca
We investigated the effect of steric strain on the rate and
equilibrium constants for the rearrangement of 3a to 3b by
DFT computation (B3LYP at the 6-31G* level). The differ-
ence in the computed energies of 3b and 3a (5.5 kcalmolÀ1)
[**] We thank the Natural Sciences and Engineering Research Council of
Canada for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801974.
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Scheme 2. Computed [1,3] sigmatropic shifts directed by a) a steric
effect and b) hydrogen bonding.
expected for the rearrangement of 3a. However, the destabi-
lization 3a as a result of the steric repulsion of the two mesityl
groups appears to be greater than the resonance stabilization
of the imine group.
In sharp contrast to the reactions driven by steric energy,
DFT computation showed that the rearrangement of the
“half” compound 6a for the hydrogen-bond-directed reaction
is favored by about the same amount (3.8 kcalmolÀ1) as the
rearrangement of the corresponding full compound (6.8/
2 kcalmolÀ1) after statistical correction. We showed that a
subtle difference in the strengths of the hydrogen bonds can
drive diaza-Cope rearrangement reactions to completion.[3]
The resonance-assisted hydrogen bond[15,16] (RAHB) in 6b is
expected to be a few kilocalories per mole more stable than
the regular hydrogen bond in 6a.
Figure 2. a) Crystal structure of 1b (ORTEP diagram with thermal
ellipsoids drawn at 50% probability). b) Computed structure (DFT) of
the transition state for the rearrangement of 3a to 3b. All hydrogen
atoms except those in the imine and diamine backbone have been
omitted for clarity.
translates into an equilibrium concentration ratio of about
104:1 in favor of 3b at 258C. This ratio is consistent with the
result observed by 1H NMR spectroscopy, which showed
complete conversion of 3a into 3b.
The rearrangement reactions in Scheme 1 most likely
proceed via chairlike six-membered-ring transition states
(TS) with all substituents in equatorial positions (Figure 2b).
Computation further revealed that the energy barrier for
the conversion of 3a into 3b (19.4 kcalmolÀ1) is lower than
the energy barrier (21.5 kcalmolÀ1) for the rearrangement of
the diimine 4 formed from diphenylethylenediamine (DPEN)
and benzaldehyde. Consistent with these computation results,
the experimental rate constant for the rearrangement of 3a to
3b (4.19 ” 10À5 sÀ1 at 258C) is greater than that for the
rearrangement of 4 (1.74 ” 10À5 sÀ1).[13] Our kinetic experi-
ment shows that only a small amount of the steric strain is
released at the transition state.[14]
It is not intuitively obvious how the steric effect in 3a (or
1a and 2a) manifests itself in driving the rearrangement
reaction to completion. One possibility is that the steric
repulsion between the two mesityl groups in 3a weakens the
Consistent with this hypothesis, the rearrangements of the
initial diimines 1a–3a proceed with 100% chirality transfer,
as observed for the RAHB-directed[15,16] rearrangement
reactions.[3c] HPLC on a chiral phase showed that the
stereospecificity for the conversion of 3a into 3b is excep-
tionally high (> 99.5%), even though no hydrogen bonds are
involved (see the Supporting Information).
We studied the rearrangement of 7a to 7b and the reverse
reaction (Scheme 3) in detail to compare the steric effect and
the hydrogen-bonding effect on the diaza-Cope rearrange-
ment. The same ratios of 7a to 7b were observed at
equilibrium whether we started with 7a or 7b. Diimine 7b
is favored over 7a by a ratio of about 14:1 in CDCl3 at 258C.
The solvent effect on the equilibrium is small ([D8]toluene:
17:1; [D6]DMSO: 6:1). DFT computation showed that 7b is
more stable than 7a by 1.6 kcalmolÀ1. This translates into an
equilibrium ratio of 7a to 7b of about 15:1 at 258C. Both
experiment and computation showed that 7b is more stable
À
C C bond that is cleaved in the rearrangement reaction. To
gain insight into the steric effect on the reaction (Scheme 1b),
we dissected the rearrangement by dividing 3a in two
(Scheme 2) and examined the energetics of the “half”
compound 5a. The rearrangement of the “half” compound
corresponds to a [1,3] sigmatropic shift.
Interestingly, DFT computation showed that the rear-
rangement of 5a (Scheme 2) is disfavored by about 1.9 kcal
molÀ1, whereas the rearrangement of the “full” compound 3a
is favored by about 5.5 kcalmolÀ1. We suggest that the
rearrangement of 5a is disfavored at least in part because of
=
the decease in imine conjugation. The C N bond in the imine
5a can be planar with the phenyl group, whereas that in 5b
can not be fully planar or conjugated with the mesityl group
owing to steric effects. Aloss in imine conjugation is also
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Scheme 3. Competition between steric and hydrogen-bonding effects.
than 7a. Thus, the hydrogen-bond effect appears to be
somewhat stronger than the steric effect for the rearrange-
ment reaction.
We determined the activation parameters for the inter-
conversion of 7a and 7b by measuring the rate constants of
the forward and reverse reactions at different temperatures
(60–1008C). At 608C, the rate constants for the forward and
reverse reactions are 1.1 ” 10À4 and 2.8 ” 10À5 sÀ1, respectively.
The values of the activation entropy and activation enthalpy
for the conversion of 7a into 7b are À8.2 calmolÀ1 KÀ1 and
22.9 kcalmolÀ1, respectively (Figure 3).
Figure 3. Energy profile for the interconversion of 7a and 7b (DH and
DH° values in kcalmolÀ1, DS and DS° values in calmolÀ1 KÀ1).
Scheme 4. Consecutive diaza-Cope reactions.
For the reverse reaction, these values are À0.7 calm-
olÀ1 KÀ1 and 26.3 kcalmolÀ1. Interestingly, there is a consid-
erable entropic driving force (DS = 7.5 calmolÀ1) for the
steric-effect-driven diaza-Cope rearrangement of 7b to 7a.
Thus, the equilibrium constant for the formation of 7b
increases with decreasing temperature (ÀTDS; see the
Supporting Information). The conversion of 7a into 7b is
expected to result in a favorable enthalpy change due to the
strengthening of the hydrogen bonds and an unfavorable
enthalpy change due to the increase in strain energy
associated with the steric effect. The net favorable enthalpy
change (DH = À3.4 kcalmolÀ1) indicates that more is gained
from the strong hydrogen bonds than lost because of the steric
effects. The value of this experimental enthalpy change is in
reasonably good agreement with the computed value
(À1.6 kcalmolÀ1). The change in Gibbs free energy (DG) for
the conversion of 7a into 7b is À1.2 kcalmolÀ1 (À3.4+298 ”
7.5 ” 10À3) at 258C.
it demonstrates the excellent stereospecificity of the rear-
rangement reaction with and without RHABs.
In conclusion, we have demonstrated that steric strain can
dramatically influence the equilibrium in [3,3] sigmatropic
reactions. Its effect can overcome electronic effects and
compete with the effect of resonance-assisted hydrogen
bonds. Dissection of the rearrangement reaction (Scheme 2)
provided interesting insight into the steric effect. Computa-
tion showed that the mesityl group has opposite effects on the
[3,3] and [1,3] sigmatropic reactions.
Received: April 28, 2008
Revised: August 21, 2008
Published online: October 10, 2008
Keywords: density functional calculations · diamines ·
.
sigmatropic rearrangement · stereospecificity · steric strain
Two consecutive diaza-Cope rearrangement reactions can
be used to form (R,R)-diphenylethylenediamine ((R,R)-
DPEN) from (R,R)-HPEN with exceptionally high overall
stereospecificity (Scheme 4). Although this approach does
not serve as a highly practical synthetic route to (R,R)-DPEN,
[1] a) F. Vögtle, E. Goldschmitt, Chem. Ber. 1976, 109, 1 – 40; b) F.
Vögtle, E. Goldschmitt, Angew. Chem. 1973, 85, 824 – 826;
Angew. Chem. Int. Ed. Engl. 1973, 12, 767 – 768.
8680 www.angewandte.org
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[2] a) J. Karl, R. Gust, T. Spruss, M. R. Schneider, H. Schönen-
berger, J. Engel, K.-H. Wrobel, F. Lux, S. T. Haeberlin, J. Med.
Chem. 1988, 31, 72 – 83; b) R. Gust, K. Niebler, H. Schönen-
berger, J. Med. Chem. 2005, 48, 7132 – 7144; c) L. T. Vassilev,
B. T. Vu, B. Graves, D. Carvajal, F. Podlaski, Z. Filipovic, N.
Kong, U. Kammlott, C. Lukacs, C. Klein, N. Fotouhi, E. A. Liu,
Science 2004, 303, 844 – 848; d) N. Fotouhi, G. J. Haley, K. B.
Simonsen, B. T. Vu, S. E. Webber, U.S. Patent Appl. US
20070167437, 2007; e) J. Chin, F. Mancin, N. Thavarajah, D.
Lee, A. Lough, D. S. Chung, J. Am. Chem. Soc. 2003, 125, 15276 –
15277.
[3] a) H. Kim, S. M. So, B. M. Kim, J. Chin, Aldrichimica Acta 2008,
41, 77 – 88; b) H. Kim, Y. Nguyen, C. P.-H. Yen, L. Chagal, A. J.
Lough, B. M. Kim, J. Chin, J. Am. Chem. Soc. 2008, 130, 12184 –
12191; c) H.-J. Kim, W. Kim, A. J. Lough, B. M. Kim, J. Chin, J.
Am. Chem. Soc. 2005, 127, 16776 – 16777; d) H.-J. Kim, H. Kim,
G. Alhakimi, E. J. Jeong, N. Thavarajah, L. Studnicki, A.
Koprianiuk, A. J. Lough, J. Suh, J. Chin, J. Am. Chem. Soc.
2005, 127, 16370 – 16371; e) H. Kim, C. Yen, P. Preston, J. Chin,
Org. Lett. 2006, 8, 5239 – 5242; f) H. Kim, D. S. Choi, C. P.-H.
Yen, A. J. Lough, C. E. Song, J. Chin, Chem. Commun. 2008,
1335 – 1337.
[4] a) D. Lucet, T. Le Gall, C. Mioskowski, Angew. Chem. 1998, 110,
2724 – 2772; Angew. Chem. Int. Ed. 1998, 37, 2580 – 2627; b) D.
Savoia, Top. Organomet. Chem. 2005, 15, 1 – 58; c) S. Roland, P.
Mangeney, Top. Organomet. Chem. 2005, 15, 191 – 229; d) J. A. J.
Breuzard, M. L. Christ-Tommasino, M. Lemaire, Top. Organo-
met. Chem. 2005, 15, 231 – 270.
[5] a) S. R. S. S. Kotti, C. Timmons, G. Li, Chem. Biol. Drug Des.
2006, 67, 101 – 114; b) Y.-Y. Yeung, S. Hong, E. J. Corey, J. Am.
Chem. Soc. 2006, 128, 6310 – 6311; c) Y. Fukuta, T. Mita, N.
Fukuda, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2006, 128,
6312 – 6313; d) C. Palomo, J. M. Aizpurua, M. Legido, R.
Galarza, P. M. Deya, J. Dunoguꢀs, J. P. Picard, A. Ricci, G.
Seconi, Angew. Chem. 1996, 108, 1317 – 1318; Angew. Chem. Int.
Ed. Engl. 1996, 35, 1239 – 1241; e) A. Dullin, F. Dufrasne, M.
Gelbcke, R. Gust, Arch. Pharm. 2004, 337, 654 – 667.
Chem. Int. Ed. Engl. 1971, 10, 761 – 776; f) O. Wiest, K. A. Black,
K. N. Houk, J. Am. Chem. Soc. 1994, 116, 10336 – 10337; g) W. T.
Borden, E. R. Davidson, Acc. Chem. Res. 1996, 29, 67 – 75.
[7] a) A. M. M. Castro, Chem. Rev. 2004, 104, 2939 – 3002; b) G. B.
Bennett, Synthesis 1977, 589 – 606; c) F. E. Ziegler, Acc. Chem.
Res. 1977, 10, 227 – 232.
[8] R. Hoffmann, H. Hopf, Angew. Chem. 2008, 120, 4548 – 4556;
Angew. Chem. Int. Ed. 2008, 47, 4474 – 4481.
[9] a) R. K. Hill in Comprehensive Organic Synthesis, Vol. 5 (Eds.:
B. M. Trost, I. Fleming, L. A. Paquette), Pergamon, Oxford,
1991, pp. 785 – 826; b) E. Piers in Comprehensive Organic Syn-
thesis, Vol. 5 (Eds.: B. M. Trost, I. Fleming, L. A. Paquette),
Pergamon, Oxford, 1991, pp. 971 – 998; c) T. Hudlicky, R. Fan,
J. W. Reed, K. G. Gadamasetti, Org. React. 1992, 41, 1 – 133.
[10] a) T. Ikeno, I. Iwakura, A. Shibahara, M. Hatanaka, A. Kokura,
S. Tanaka, T. Nagata, T. Yamada, Chem. Lett. 2007, 36, 738 – 739;
b) A. Kokura, S. Tanaka, A. Shibahara, T. Ikeno, T. Nagata, T.
Yamada, Chem. Lett. 2007, 36, 26 – 27; c) D. A. Watson, M. Chiu,
R. G. Bergman, Organometallics 2006, 25, 4731 – 4733; d) A.
Kokura, S. Tanaka, T. Ikeno, T. Yamada, Org. Lett. 2006, 8,
3025 – 3027; e) H. Fujii, Y. Funahashi, Angew. Chem. 2002, 114,
3790 – 3793; Angew. Chem. Int. Ed. 2002, 41, 3638 – 3641.
[11] Crystal data for 1b: C34H34N4O4, T= 150(2) K, monoclinic, C2,
Z = 4, a = 27.2150(16), b = 8.7120(3), c = 14.1740(9) ꢁ, a = 90,
b = 115.134(2), g = 908, V= 3042.4(3) ꢁ3, R1 = 0.0480, wR2 =
0.1120 for I > 2s(I), GOF(F2) = 1.009.
[12] Global-minimum-energy structures 3a and 3b were obtained by
molecular-mechanics computation. These structures and the
transition-state structure (Figure 2b) were optimized further by
DFT computation at the B3LYP/6-31G* level.
[13] F. Vögtle, E. Goldschmitt, Angew. Chem. 1974, 86, 520 – 521;
Angew. Chem. Int. Ed. Engl. 1974, 13, 480 – 482.
[14] Although the computed strain effect (21.5À19.4 = 2.1 kcal
molÀ1) on the transition state is somewhat greater than the
experimental strain effect (RTln(4.19/1.74) = 0.53 kcalmolÀ1),
the difference between the computed and experimental values is
well within computational error.
[6] a) W. R. Roth, H.-W. Lennartz, W. v. E. Doering, L. Birladeanu,
C. A. Guyton, T. Kitagawa, J. Am. Chem. Soc. 1990, 112, 1722 –
1732; b) J. J. Gajewski, J. Am. Chem. Soc. 1979, 101, 4393 – 4394;
c) A. C. Cope, E. M. Hardy, J. Am. Chem. Soc. 1940, 62, 441 –
444; d) R. B. Woodward, R. Hoffmann, The Conservation of
Orbital Symmetry, Verlag Chemie, Weinheim, 1970, p. 149;
e) M. J. S. Dewar, Angew. Chem. 1971, 83, 859 – 875; Angew.
[15] P. Gilli, V. Bertolasi, V. Ferretti, G. Gilli, J. Am. Chem. Soc. 2000,
122, 10405 – 10417.
[16] a) H. Park, K. M. Kim, A. Lee, S. Ham, W. Nam, J. Chin, J. Am.
Chem. Soc. 2007, 129, 1518 – 1519; b) K. M. Kim, H. Park, H.-J.
Kim, J. Chin, W. Nam, Org. Lett. 2005, 7, 3525 – 3527; c) J. Chin,
D. C. Kim, H.-J. Kim, F. B. Panosyan, K. M. Kim, Org. Lett. 2004,
6, 2591 – 2593.
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