Stereospecific synthesis of alkyl-substituted vicinal diamines from the mother diamine: Overcoming the "intrinsic barrier" to the diaza-Cope rearrangement reaction

Article abstract of DOI:10.1021/ol802496r

Addition of isobutyraldehyde to 1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane (mother diamine) cleanly gives a stable, fused imidazolidinedihydro-1,3-oxazine ring complex. However, vigorous heating of the fused ring complex gives the diaza-Cope rearrangement

Full text of DOI:10.1021/ol802496r

ORGANIC
LETTERS
2009
Vol. 11, No. 1
157-160
Stereospecific Synthesis of
Alkyl-Substituted Vicinal Diamines from
the Mother Diamine: Overcoming the
“Intrinsic Barrier” to the Diaza-Cope
Rearrangement Reaction
Hyunwoo Kim, Mima Staikova, Alan J. Lough, and Jik Chin*
Department of Chemistry, UniVersity of Toronto, 80 St. George Street, Toronto,
ON, M5S 3H6 Canada
jchin@chem.utoronto.ca
Received November 4, 2008
ABSTRACT
Addition of isobutyraldehyde to 1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane (mother diamine) cleanly gives a stable, fused imidazolidine-
dihydro-1,3-oxazine ring complex. However, vigorous heating of the fused ring complex gives the diaza-Cope rearrangement product with
excellent yield and stereoselectivity. A variety of alkyl aldehydes have been used to make corresponding alkyl diamines with excellent yield
and stereospecificity. DFT computation shows that the intrinsic barrier for the rearrangement involving alkyl imines is about 7.9 kcal/mol
greater than that involving aryl imines.
The elegant synthesis of aryl-substituted meso vicinal di-
amines using the diaza-Cope rearrangement reaction was first
reported over 30 years ago by Vo¨gtle and Goldschmitt.1 More
recently, we synthesized a wide variety of aryl-substituted
chiral vicinal diamines by the rearrangement reaction (Scheme
1) from the readily available 1,2-bis(2-hydroxyphenyl)-1,2-
diaminoethane (mother diamine, 1).2 However it has been a
challenge to synthesize alkyl-substituted vicinal diamines by
the rearrangement reaction.3 While aryl-substituted chiral
vicinal diamines4 are important as ligands for a wide variety
of stereoselective catalysts,5 alkyl-substituted chiral vicinal
diamines are found in many bioactive compounds4,6 includ-
ing tamiflu,7 lorabid,8 and eloxatin.9 Here we investigate why
(1) (a) Vögtle, F.; Goldschmitt, E. Angew. Chem., Int. Ed. Engl. 1973,
12, 767. (b) Chin, J.; Mancin, F.; Thavarajah, N.; Lee, D.; Lough, A.; Chung,
D. S. J. Am. Chem. Soc. 2003, 125, 15276.
(2) (a) Kim, H.; Nguyen, Y.; Yen, C. P.-H.; Chagal, L.; Lough, A. J.;
Kim, B. M.; Chin, J. J. Am. Chem. Soc. 2008, 130, 12184. (b) Kim, H.;
Nguyen, Y.; Lough, A. J.; Chin, J. Angew. Chem., Int. Ed. 2008, 47, 8678.
(c) Kim, H.; Choi, D. S.; Yen, C. P.-H.; Lough, A. J.; Song, C. E.; Chin,
J. Chem. Commun. 2008, 1335. (d) Kim, H.-J.; Kim, H.; Alhakimi, G.;
Jeong, E. J.; Thavarajah, N.; Studnicki, L.; Koprianiuk, A.; Lough, A. J.;
Suh, J.; Chin, J. J. Am. Chem. Soc. 2005, 127, 16370. (e) Kim, H.-J.; Kim,
W.; Lough, A. J.; Kim, B. M.; Chin, J. J. Am. Chem. Soc. 2005, 127, 16776.
(3) (a) Previous attempts in our laboratory failed with alkyl aldehydes
(unpublished). (b) Attempts with alkyl ketones also failed: Vo¨gtle, F.;
Goldschmitt, E. Chem. Ber. 1976, 109, 1.
(4) (a) Kim, H.; So, S. M.; Kim, B. M.; Chin, J. Aldrichimica Acta
2008, 41, 77. (b) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem.,
Int. Ed. 1998, 37, 2580.
10.1021/ol802496r CCC: $40.75
Published on Web 12/08/2008
2009 American Chemical Society

the alkyl-substituted vicinal diamines are difficult to syn-
thesize by the rearrangement reaction10 and how these
difficulties may be overcome.
lectively in excellent yield (>99%) when the diamine is
added to 2 or more equiv of the aldehyde.11
Figure 1a shows the crystal structure of the fused imida-
zolidine-dihydro-1,3-oxazine ring (3).12 There are two new
stereogenic centers in the product (both R configuration
(Scheme 1)). One internal hydrogen bond can be seen
between the phenolic group and the secondary amine group
(O···N, 2.73 Å; H···N, 1.99 Å; O-H, 0.84 Å). The global
energy minimum structure of 313 (Figure 1b) is in excellent
agreement with the crystal structure and the solution structure
as determined by 2D 1H NMR (Figure S1, Supporting
Information). Thus the most stable of the many possible
configurational and conformational isomers of 3 is the one
that is formed.
Scheme 1
When benzaldehyde is added to 1, the corresponding
diimine (2) is formed readily followed by the rearrangement
reaction at ambient temperature.2 In sharp contrast, when
isobutyraldehyde is added to 1, a fused imidazolidine-
dihydro-1,3-oxazine ring compound (3) is formed. In prin-
ciple, 1, 2, or 3 equiv of isobutyraldehyde could add to 1 to
form one, two or three new rings, respectively. Fourteen
different products could result from the cyclization reactions
including all possible stereoisomers.11 Surprisingly, only one
major product (3) is formed stereospecifically and regiose-
Figure 1. (a) Crystal structure of 3 (50% thermal ellipsoid). (b)
Global energy minimum structure of 3.
Although 3 is stable at room temperature, it cleanly gives
the rearranged diimine (5a) when heated at 150 °C for 3 h
(Scheme 2). We propose that 3 is in equilibrium with the
diimine (4a), which rearranges to give the product (5a).
Hydrolysis of 5a gave (S,S)-1,2-diamino-1,2-diisopropyl-
ethane dihydrochloride (6a), which has been previously
synthesized by a different route for the purpose of making
NHE3 inhibitors.14 1H NMR shows that the concentration
of the diimine intermediate (4a) does not accumulate to any
observable extent during the conversion of 3 to 5a. Thus
the equilibrium appears to greatly favor 3 over 4a.
(5) (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science
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2818. (e) Funk, T. W.; Berlin, J. M.; Grubbs, R. H. J. Am. Chem. Soc.
2006, 128, 1840. (f) Kim, H.; Yen, C.; Preston, P.; Chin, J. Org. Lett. 2006,
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Laver, G.; Stevens, R. C. J. Am. Chem. Soc. 1997, 119, 681. (b) Albrecht,
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J. Org. Chem. 2008, 1839.
A variety of alkyl aldehydes may be used to make alkyl
diamines by our method (Table 1). The enantioselectivity
of the rearrangement reaction was determined by HPLC.11
(R,R)-3 gave (S,S)-5a in 93% yield with no observable loss
(12) Crystal structure of 3: C22H28N2O2, T ) 100(2) K, orthorhombic,
P2(1)2(1)2(1), Z ) 8, a ) 9.79070(10) Å, b ) 18.3356(2) Å, c ) 22.0661(2)
Å, a ) 90°, b ) 90°, g ) 90°, V ) 3961.27(7) Å3, R1 ) 0.0246, wR2 )
0.0648 for I > 2σ(I), GOF on F2 ) 1.013. Crystal structure of 5b:
C28H36N2O2, T ) 150(2) K, orthorhombic, P2(1)2(1)2(1), Z ) 4, a )
5.9303(3) Å, b ) 10.3195(7) Å, c ) 39.850(3) Å, a ) 90°, b ) 90°, g )
90°, V ) 2438.7(3) Å3, R1 ) 0.0514, wR2 ) 0.1223 for I > 2σ(I), GOF on
F2 ) 1.043. Crystal structure of 6b: C14H32Cl2.67N2O0.67, T ) 150(1) K,
cubic, I(2)1(3), Z ) 12, a ) 17.9117(6) Å, b ) 17.9117(6) Å, c )
17.9117(6) Å, a ) 90°, b ) 90°, g ) 90°, V ) 5746.6(3) Å3, R1 ) 0.0468,
wR2 ) 0.1041 for I > 2σ(I), GOF on F2 ) 1.022.
(13) Geometry optimization was performed at the B3LYP/6-31G(d) level
using Spartan 06 Windows from Wavefunction, Inc.
(14) (a) Heinelt, U.; Lang, H.-J.; Hofmeister, A.; Wirth, K. PCT Int.
Appl. WO2003053434, 2003. (b) Roland, S.; Mangeney, P.; Alexakis, A.
Synthesis 1999, 228.
(8) (a) Palomo, C.; Aizpurua, J. M.; Legido, M.; Galarza, R.; Deya,
P. M.; Dunoguès, J.; Picard, J. P.; Ricci, A.; Seconi, G. Angew. Chem., Int.
Ed. Engl. 1996, 35, 1239. (b) Misner, J. W.; Fisher, J. W.; Gardner, J. P.;
Pedersen, S. W.; Trinkle, K. L.; Jackson, B. G.; Zhang, T. Y. Tetrahedron
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881.
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Chem. 1978, 21, 1315. (b) Dullin, A.; Dufrasne, F.; Gelbcke, M.; Gust, R.
Arch. Pharm., Pharm. Med. Chem. 2004, 337, 654. (c) Boga, C.; Fiorelli,
C.; Savoia, D. Synthesis 2006, 285.
(10) (a) Roth, W. R.; Lennartz, H.-W.; Doering, W. von E.; Birladeanu,
L.; Guyton, C. A.; Kitagawa, T. J. Am. Chem. Soc. 1990, 112, 1722. (b)
Gajewski, J. J. J. Am. Chem. Soc. 1979, 101, 4393.
(11) See Supporting Information.
158
Org. Lett., Vol. 11, No. 1, 2009

Scheme 2. Diaza-Cope Rearrangement of Alkyl Diimine (4a)
in enantiopurity (>99%). The inversion of stereochemistry,
confirmed by CD spectroscopy,11 is expected from the
chairlike transition state with all equatorial substituents.2
Although the rearrangement reaction for making alkyl
diamines requires considerably harsher conditions than for
making aryl diamines, the yield and stereoselectivity remains
exceptionally high.
Figure 2. (a) Crystal structure of (R,R)-5b (50% thermal ellipsoid).
(b) Crystal structure of (S,S)-6b (50% thermal ellipsoid). Chloride
conteranion not shown.
fused ring (3) in the alkyl diamine synthesis. Another reason
may be the alkyl/aryl substituent effect in the diaza-Cope
rearrangement reaction. Detailed kinetic, stereochemical, and
computational studies support a concerted mechanism with
a chairlike transition state for the rearrangement of unsub-
stituted 1,5-hexadiene.15 Aromatic substituents have been
shown to stabilize the transition state of the [3,3]-sigmatropic
rearrangement reaction.10
Table 1. Synthesis of Alkyl Vicinal Diamines
To gain some insight into the substituent effect of the
diaza-Cope rearrangement reaction, we computed the energy
values (DFT at the B3LYP/6-31G(d) level)16 for 2, 7, 4a,
and 5a (Figure 3) along with those for the two corresponding
transition states (2q and 4aq). A chairlike transition state with
all equatorial substitutions was used in the computation of
2q and 4aq.2 Preorganized, transition-state-like structures were
used for the computation of the other four structures (2, 7,
4a, and 5a) as in our previous study.2
The two imine bonds in 4a are isolated, whereas in 5a, 2
and 7 they are conjugated with the aromatic rings. Thus the
rearrangement of 4a to 5a is expected to be thermodynami-
cally more favorable than the rearrangement of 2 to 7.
Computation shows that the rearrangement of 4a is thermo-
dynamically more favorable than for the rearrangement of 2
by about 5.5 kcal/mol. Despite the thermodynamic driving
force, the energy barrier for the rearrangement of 4a is about
5.5 kcal/mol higher than that for the rearrangement of 2. On
the basis of these calculations, the equilibrium constant for
conversion of 4a to 5a is expected to be about 104 times
greater than that for conversion of 2 to 7, but the rate of the
latter reaction is expected to be about a 104 times greater.
a Isolated yield. b Determined by HPLC using a Chiralpak AD-H
column.9 c Isolated yield starting from 3.
(15) (a) Cope, A. C.; Hardy, E. M. J. Am. Chem. Soc. 1940, 62, 441.
(b) Woodward, R. B.; Hoffmann, R. The ConserVation of Obital Symmetry;
Verlag Chemie: Weinheim/Bergstr. Germany and Academic Press: New
York, 1970. (c) Dewar, M. J. S. Angew. Chem., Int. Ed. Engl. 1971, 10,
761. (d) Wiest, O.; Black, K. A.; Houk, K. N. J. Am. Chem. Soc. 1994,
116, 10336. (e) Borden, W. T.; Davidson, E. R. Acc. Chem. Res. 1996, 29,
67.
Figure 2a shows the crystal structure of the rearranged
diimine (5b)12 formed from the reaction of 1 and cyclohexane
carboxaldehyde. Acid hydrolysis of the diimine (5b) cleanly
gives the corresponding diamine dihydrochloride (6b, Figure
2b).12
One reason why a much harsher condition is required to
make alkyl diamines than to make aryl diamines may be the
unfavorable equilibrium to form the diimine (4a) from the
(16) All calculations were carried out with Spartan 06 from Wavefunc-
tion Inc. DFT computation at B3LYP/6-31G(d) level was used to calculate
the optimized geometry and vibrational frequencies. A vibrational analysis
was performed at each stationary point to confirm its identity as an energy
minimum or a transition structure. The gas-phase enthalpy was calculated
as ∆H298) ∆ZPVE + ∆∆H0f298K + ∆E0. Zero-point vibrational energy
(ZPVE) and enthalpy change (∆∆H0f298K) from 0 to 298 K at 1 atm were
obtained from vibrational frequencies.
Org. Lett., Vol. 11, No. 1, 2009
159

Figure 3.
Energy profile for the diaza-Cope rearrangement of aryl and alkyl diimines (∆H and ∆Hq values in kcal/mol).
It is interesting to compare the two rearrangement reactions
(Figure 3) in terms of the Marcus equation.17 Although the
Marcus equation was initially derived for electron transfer
reactions, it has since been used to analyze proton transfer
reactions and other organic reactions.18 According to the
diimine, the imidazolidine, and an enamine formed between
the imidazolidine and the aldehyde).11 This mixture gives
many products upon heating. Thus the hydroxyl groups in 1
are crucial for preventing side reactions and also directing
the rearrangement reaction cleanly to completion by resonance-
assisted hydrogen bonds.2,21
q
q 2
Marcus equation (∆Gq ) ∆G0 (1 + ∆G/4∆G0 ) ), the kinetic
barrier of a reaction (∆Gq) is separated into the thermody-
namic barrier (∆G) and the so-called intrinsic barrier of the
Understanding the diaza-Cope rearrangement reaction for
making alkyl vicinal diamines is of considerable mechanistic
and synthetic interest. Harsher conditions are required for
making the alkyl diamines than for making the aryl diamines
for two main reasons. First, alkyl aldehydes form fused ring
compounds (3) with 1, whereas aryl aldehydes form diimines
(2) with 1. Second, the intrinsic barrier for the diaza-Cope
rearrangement reaction is much higher with alkyl substituents
than with aryl substituents. Remarkably, the hydroxyl groups,
in 1 not only facilitate the diaza-Cope rearrangement reaction
but also suppress side reactions in the synthesis of alkyl
vicinal diamines. Although more work is needed to show
the usefulness of the diaza-Cope rearrangement reaction in
the synthesis of complex bioactive compounds like tamiflu
and lorabid, a detailed understanding of the mechanism has
allowed the first stereospecific synthesis of alkyl-substituted
vicinal diamines by the rearrangement reaction.
q
reaction (∆G0 ; defined as the kinetic barrier in the absence
of thermodynamic influence (∆G ) 0)). By solving the
Marcus equation, the intrinsic barrier can be expressed in
terms of the kinetic barrier and the thermodynamic barrier
(∆G0q ) [-(∆G/2 - ∆Gq) + (∆Gq(∆Gq - ∆G))0.5]/2). The
value of the intrinsic barrier for conversion of 4a to 5a based
on the computed values of ∆Gq and ∆G is 26.8 kcal/mol.19
Similarly the value of the intrinsic barrier for the conversion
of 2 to 7 is 18.9 kcal/mol. Thus the alkyl/aryl substituent
effect on the kinetics of the diaza-Cope rearrangement
reaction appears to be significant (7.9 kcal/mol).
It has been shown that the diimine formed between
benzaldehyde and chiral dpen (1,2-diphenyl-1,2-diaminoet-
hane) racemizes by diaza-Cope rearrangement reaction.20 In
principle, it should be possible to make alkyl vicinal diamines
from the reaction of chiral dpen and alkyl aldehydes, since
the diaza-Cope rearrangement reaction is expected to be
thermodynamically favorable. However, 1H NMR indicates
that addition of 2 equiv of isobutyraldehyde to dpen results
in production of a mixture of compounds (including the
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada for financial
support. H.K. is grateful for the Government of Canada
Award.
Supporting Information Available: Experimental data
including crystallographic data in CIF format. This material
is available free of charge via the Internet at http://pubs.acs.org.
(17) Marcus, R. A. J. Chem. Phys. 1956, 24, 966.
(18) (a) Guthrie, J. P. J. Am. Chem. Soc. 2000, 122, 5529. (b) Guthrie,
J. P. J. Am. Chem. Soc. 2000, 122, 5520. (c) Guthrie, J. P. J. Am. Chem.
Soc. 1996, 118, 12878. (d) Murdoch, J. R. J. Am. Chem. Soc. 1972, 94,
4410. (e) Murdoch, J. R. J. Am. Chem. Soc. 1983, 105, 2159. (f) Murdoch,
J. R. J. Am. Chem. Soc. 1983, 105, 2660.
OL802496R
(19) ∆Hq and ∆H were used instead of ∆Gq and ∆G.
(20) Vo¨gtle, F.; Goldschmitt, E. Angew. Chem., Int. Ed. Engl. 1974,
13, 480.
(21) Gilli, P.; Bertolasi, V.; Ferretti, V.; Gilli, G. J. Am. Chem. Soc.
2000, 122, 10405
.
160
Org. Lett., Vol. 11, No. 1, 2009