Regioselective synthesis of aniline-derived 1,3- And Ci- symmetric 1,4-diols from trans-1,4-cyclohexadiene dioxide

Article abstract of DOI:10.1021/ol902856b

[Chemical equation presented] trans-Diepoxide 1 is well-known to react with aliphatic amines and the azide ion to give exclusively the 1,3-diol products. However, we observed that by judicious choice of conditions, reaction with anilines can give predominantly the 1,3-diol (3) or the heretofore rarely seen C_i-metric 1,4-diol (4). Synthesis of an unsymmetrical 1,4-diol from two different anilines is also demonstrated. These studies demonstrate that an intramolecular anilino-NH hydrogen bond donor can direct Fuerst-Plattner epoxide opening.

Full text of DOI:10.1021/ol902856b

ORGANIC
LETTERS
2010
Vol. 12, No. 3
620-623
Regioselective Synthesis of
Aniline-Derived 1,3- and Ci-Symmetric
1,4-Diols from trans-1,4-Cyclohexadiene
Dioxide
Christopher J. Monceaux and Paul R. Carlier*
Department of Chemistry, Virginia Tech, Blacksburg, Virginia 24061
pcarlier@Vt.edu
Received December 10, 2009
ABSTRACT
trans-Diepoxide 1 is well-known to react with aliphatic amines and the azide ion to give exclusively the 1,3-diol products. However, we observed
that by judicious choice of conditions, reaction with anilines can give predominantly the 1,3-diol (3) or the heretofore rarely seen Ci-symmetric
1,4-diol (4). Synthesis of an unsymmetrical 1,4-diol from two different anilines is also demonstrated. These studies demonstrate that an
intramolecular anilino-NH hydrogen bond donor can direct Fu¨rst-Plattner epoxide opening.
Ring-opening of trans-1,4,-cyclohexadiene dioxide 1 with
aliphatic 1°- and 2°-amines,1 ammonia,1b pyrazole,2 and
Scheme 1
.
Opening of trans-Diepoxide 1 with Benzylamine 2a
and 3-Ethynylaniline 2b
azide1b,3 nucleophiles is well-known to give 1,3-diol prod-
ucts in high selectivity due to Fu¨rst-Plattner4 control of the
second ring-opening. As a case in point, reaction of 1 with
benzylamine 2a “on water”5 exclusively provides the 1,3-
diol 3a in 95% yield (Scheme 1).
In the context of a BACE1 inhibitor discovery program,6
we carried out the analogous reaction of 1 with 3-ethynyl-
aniline 2b (Scheme 1). To our surprise, a 1:1 mixture of the
(1) (a) Craig, T. W.; Harvey, G. R.; Berchtold, G. A. J. Org. Chem.
1967, 32, 3743–3749. (b) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2001, 40, 2004–2021. (c) Scheunemann, M.; Sorger, D.;
Kouznetsova, E.; Sabri, O.; Schliebs, R.; Wenzel, B.; Steinbach, J.
Tetrahedron Lett. 2007, 48, 5497–5501.
desired 1,3-diol 3b and the 1,4-diol regioisomer 4b was
obtained. The two regioisomers are easily separable on silica
gel, and their structures were assigned by 1H and 13C NMR
spectroscopy, based on the time-averaged C2 symmetry of
3b, and the instantaneous Ci-symmetry of 4b (see Supporting
Information).
Centrosymmetric 1,4-diols derived from 1 and nitrogen
nucleophiles have been characterized previously in only one
case, as a minor (<5%) byproduct in chiral Lewis acid-
catalyzed reactions with TMSN3.3c,d Aside from the interest-
(2) Barz, M.; Glas, H.; Thiel, W. R. Synthesis (Stuttg.) 1998, 1269–
1273.
(3) (a) Kavadias, G.; Droghini, R. Can. J. Chem. 1979, 57, 1870–1876.
(b) Gruber-Khadjawi, M.; Ho¨nig, H.; Illaszewicz, C. Tetrahedron: Asym-
metry 1996, 7, 807–814. (c) Clique, B.; Ironmonger, A.; Whittaker, B.;
Colley, J.; Titchmarsh, J.; Stockley, P.; Nelson, A. Org. Biomol. Chem.
2005, 3, 2776–2785. (d) Ironmonger, A.; Stockley, P.; Nelson, A. Org.
Biomol. Chem. 2005, 3, 2350–2353.
(4) Fu¨rst, A.; Plattner, P. A. HelV. Chim. Acta 1949, 32, 275–283.
10.1021/ol902856b  2010 American Chemical Society
Published on Web 01/12/2010

ing Ci-symmetry of 4b, we viewed that the complete lack
of 1,3-diol regioselectivity seen in reaction with 2b merited
further investigation. It seemed likely that electronic effects
played a significant role in the ring-opening regioselectivity.
Thus we performed reactions of 1 with five other anilines
2c-g under the same conditions (Table 1). Anilines bearing
reactions with 2b and 2e-g. A unified mechanism for
formation of both regioisomers is given in Scheme 2.
Opening of 1 with one equivalent of amine gives epoxy
aminoalcohol rac-5. According to the accepted stereoelec-
tronic requirements for epoxide opening, 5 should be formed
in the diaxial-conformation (diax-rac-5). In this conformation
it is possible for the newly installed amino substitutent at
C4 to donate a hydrogen bond to the epoxide oxygen, thereby
activating it for attack. If the second epoxide opening
proceeds directly via transition state 4*, the Fu¨rst-Plattner
effect will favor amine opening at C1, giving 1,4-diol 4. We
describe this route to 4 as “NH-directed Fu¨rst-Plattner.”
Note that a similar directing effect of a pendant cis-hydroxyl
group has been invoked in ring-opening of cyclohexene
oxides,8 and in Li+/Yb3+-catalyzed opening of cyclitol
epoxides.9 However, if 5 relaxes from its diaxial conforma-
tion to the more stable diequatorial conformation (dieq-rac-
5) prior to the second attack, the Fu¨rst-Plattner effect would
favor opening at C6 via transition state 3*, giving 1,3-diol
3. In this case, hydrogen bond assistance of the second
epoxide opening is likely provided by water.
Table 1. Reactions of 1 with Anilines 2b-g “On Water”
% yield
sigma
value7
of major
isomerb
entry
aniline
n
X
3:4a
Since aliphatic amines like 2a are poor hydrogen bond
donors relative to water, the second ring-opening is
expected to proceed via the diequatorial transition state
3*, giving 1,3-diol opening products in high selectivity.
(Scheme 1). As mentioned earlier, this standard Fu¨rst-
Plattner mechanism also accounts for the high 1,3-diol
selectivity seen in reaction of 1 with azide ion1b,3 and
pyrazoles.2 However, the substantially increased acidity of
anilines relative to amines10 should make them competent
hydrogen bond donors, rendering the 1,4-diol pathway
transition state 4* similar in energy to transition state 3*.
Furthermore, one would expect that the 1,4-pathway would
become increasingly viable with electron deficient anilines,
just as Table 1 demonstrates.
In addition, as depicted in Scheme 2, partitioning between
the 1,3- and 1,4-diol pathways also depends on the concen-
tration and competence of intermolecular hydrogen bond
donors BH (Scheme 2). In “on water” conditions, interfacial
water likely plays a dominant role in epoxide activation,5a
though dissolved water could also play a role. A logical
approach to further improve 1,4-selectivity would thus be
to perform reactions under conditions where the concentra-
tion of such intermolecular hydrogen bond donors is mini-
mized.
1
2
3
4
5
6
2c
2d
2e
2f
2b
2g
2
2
2
4
4
8
p-CH3
p-OCH3
H
p-F
m-CCH
m-Cl
-0.14
-0.12
0.0
0.15
0.21
0.37
100:0
100:0
84:16
76:24
50:50
22:78
96
90
60 (71)
62 (81)
44 (88)
56 (72)
a Crude product ratios measured by 1H NMR spectroscopy before
purification. b Chromatographed yield of the major regioisomer (note: in
entry 5, the yield of 3b is given). The value in parentheses indicates %
recovery of this isomer from the crude product mixture.
electron-donating substituents (e.g., 2c,d) gave the 1,3-diols
3c and 3d in 100% regioselectivity (entries 1 and 2).
Unsubstituted aniline 2e gave a 84:16 mixture of regioiso-
mers (entry 3), and anilines bearing electron withdrawing
substituents (e.g., 2f, 2b, 2g, entries 4-6) evidenced
increasing amounts of the 1,4-diol. As Table 1 illustrates,
selectivity for the 1,4-diol increases with the sigma value
of the substituent; m-chloroaniline 2g gives a 22:78 ratio
of the 1,3- and 1,4-diols. Finally, whereas reaction with
electron-rich anilines 2c,d was complete within 4 h at 95
°C, the electron deficient anilines required high equiva-
lency and prolonged reaction time (16 h) to give complete
conversion.
Our first attempts to achieve this goal involved running
the reactions in aprotic solvents at elevated temperatures ([1]
) 0.5 M, [2b] or [2d] ) 1 M, in acetonitrile (reflux), DMF
(95 °C), and mesitylene (150 °C)). Interestingly no reaction
was observed in any of these cases after 16 h, illustrating
the importance of hydrogen-bond assistance for the first ring-
opening to give rac-5.
On the basis of these results we reasoned that interplay of
the relatively weak nucleophilicity and enhanced hydrogen
bond donating ability of anilines (relative to aliphatic amines)
was responsible for the formation of the 1,4-diols 4 in
(5) (a) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44, 3275–3279. (b) Azizi,
N.; Saidi, M. Org. Lett. 2005, 7, 3649–3651. (c) Jung, Y.; Marcus, R. A.
J. Am. Chem. Soc. 2007, 129, 5492–502. (d) Wang, Z.; Cui, Y.-T.; Xu,
Z.-B.; Qu, J. J. Org. Chem. 2008, 73, 2270–2274.
(6) Carlier, P. R.; Monceaux, C. J.; Matsuoka, Y.; Hirate-Fukae, C.
Abstract of Papers, 236th National Meeting of the American Chemical
Society, Philadelphia, PA, August 17-21, 2008; American Chemical
Society: Washington, DC, 2008; MEDI-300.
(8) For example, cis-1,4-cyclohexadiene dioxide reacts with 2 equiv
benzylamine 2a under neat reaction conditions to give only the 1,3-diol
(see ref 1b, footnote 46).
(9) (a) Serrano, P.; Llebaria, A.; Delgado, A. J. Org. Chem. 2002, 67,
7165–7167. (b) Serrano, P.; Llebaria, A.; Va´squez, J.; de Pablo, J.; Anglada,
J. A.; Delgado, A. Chem.sEur. J. 2005, 11, 4465–4472.
(10) Bordwell, F. G.; Algrim, D. J. J. Am. Chem. Soc. 1988, 110, 2964–
2968.
(7) Carey, F. A.; Sundberg, R. J., AdVanced Organic Chemistry. Part
A, Structure and Mechanisms, 5th ed.; Springer: New York, 2007.
Org. Lett., Vol. 12, No. 3, 2010
621

Scheme 2. Proposed Mechanistic Pathways for Formation of 1,3- and 1,4-Diols (3 and 4, Respectively)
However, success was realized under neat (solvent-free)
conditions at 150 °C (16 h, Table 2). Under these
of 2b reflects competing side reactions, perhaps due to
the reactivity of the acetylene unit at 150 °C; nevertheless
high 1,4-selectivity was seen (8:92, Table 2, entry 5). The
fact that selectivity for the 1,4-diol is not absolute under
solvent-free conditions points to the participation of a
second epoxy aminoalcohol 5 and diols 3, 4 as intermo-
lecular hydrogen bond donors (BH) in the 1,3-diol
pathway.12 This competing pathway would be most
problematic in reaction with electron-rich anilines 2c-2d,
since the corresponding pendant anilino groups in 5c-5d
are poor H-bond donors relative to the alcohol groups
present in 3-5. This reasoning also accounts for the
observation that neat reaction of 1 with benzylamine 2a
(4 equiv) affords 1,3-diol 3a as the sole product (94%
yield).
Table 2. Neat (Solvent-Free) Reactions of 1 with Anilines
2b-g
To provide a further test of the key role of intramolecular
H-bonding from the pendant aniline in 1,3- vs 1,4-diol
selectivity, reactions were performed using N-methyl aniline
2h. In this case, the epoxy aminoalcohol intermediate 5h
would lack an amino hydrogen, and thus the 1,4-diol pathway
should not be viable. As hoped, these experiments confirmed
our mechanistic hypothesis: both under neat and “on water”
conditions, opening of 1 with N-methylaniline 2h exclusively
provided the 1,3-diol 3h (Table 3).
% yield
of major
isomerb
sigma
value
entry
aniline
n
X
3:4a
1
2
3
4
5
6
2c
2d
2e
2f
2b
2g
4
4
4
4
8
8
p-CH3
p-OCH3
H
p-F
m-CCH
m-Cl
-0.14
-0.12
0.0
0.15
0.21
0.37
40:60
40:60
20:80
3:97
8:92
10:90
42 (70)
51 (87)
45 (55)
74 (76)
28 (30)
84 (93)
a Crude product ratios measured by 1H NMR spectroscopy before
purification. b Chromatographed yield of the major regioisomer; the value
in parentheses indicates % recovery of this isomer from the crude product
mixture.
Table 3. Opening of 1 with N-methylaniline 2h
conditions we envision that high reactant concentrations
and hydrogen-bonding assistance from a second aniline
molecule (or trace water) initially facilitates the first ring-
opening to give the epoxy aminoalcohol rac-5.11 As hoped,
under neat conditions, all the anilines showed a predomi-
nance of 1,4-diol 4 (Table 2). Note that the 1,4-selectivity
is greatest for the electron-deficient anilines 2b, f-g and
unsubstituted aniline 2e (cf. Table 2, entries 3-7). This
observation is consistent with the expected enhanced
acidity and hydrogen-bonding ability of these anilines
(Scheme 2). The low yield seen in the solvent-free reaction
entry
aniline
regime
neat
t (°C)
3h:4ha
% yieldb
1
2
a
2h
2h
150
95
100:0
100:0
91
97
“on water”
Product ratios measured by H NMR. b Chromatographed yield.
1
622
Org. Lett., Vol. 12, No. 3, 2010

To further confirm the role of the pendant amino NH
of 5 on the regioselectivity of the second epoxide opening,
we designed two experiments to arrive at unsymmetrical
1,3- and 1,4-diols. Scheunemann has previously reported
synthesis of unsymmetrical 1,3-diols from 1 via the
intermediacy of epoxy aminoalcohols (e.g., 5a),1c but prior
to our work, preparation of the corresponding unsym-
metrical 1,4-diols had not been possible. Treatment of 1
with 0.25 equiv of anilines 2f and 2h in refluxing
isopropanol gave epoxy aminoalcohols rac-5f and 5h in
68 and 42% yield respectively (Scheme 3). By virtue of
In conclusion, we have shown that previously inacces-
sible Ci-symmetric 1,4-diols can be prepared from trans-
1,2,4,5-diepoxycyclohexane 1 and anilines. The 1,3-:1,4-
diol product ratio in reactions of 1 with anilines was found
to be sensitive to both electronic effects in the aniline,
and to the nature of the reaction conditions. Highest
selectivities for the 1,4-diol products 4 are obtained with
electron-poor anilines under neat conditions (Table 2).
Highest selectivities for the 1,3-diol products 3 are
obtained with electron-rich anilines using “on water”
conditions (Table 1). The superior hydrogen-bonding
ability of a pendant anilino group (relative to an aliphatic
amino) in the epoxy aminoalcohol intermediate 5 is
proposed to allow access to the 1,4-diol regioisomer via
intramolecular H-bond stabilized transition state 4* (Scheme
2). To the best of our knowledge, the potential of an
appropriately acidic intramolecular NH hydrogen bond
donor to direct ring-opening of cyclohexene oxides has
not previously been recognized in the literature.13 Finally,
by judicious choice of reactant order and reaction condi-
tions, it is possible to synthesize unsymmetrical 1,3- and
1,4-diols from 1 and anilines in high selectivity and yield
(Scheme 3). Further mechanistic and synthetic work is in
progress and will be reported in due course.
Scheme 3
.
Regiocontrolled Route to Unsymmetrical 1,3- or
1,4-Diols
Acknowledgment. We thank the Virginia Alzheimer’s and
Related Disease Research Award Fund (09-1) for financial
support, Ms. Jenna Templeton (Virginia Tech) for synthetic
assistance, and Professor K. Barry Sharpless (Scripps
Research Institute) for helpful discussions.
Supporting Information Available: Synthetic procedures
and analytical data. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL902856B
its pendant p-fluoroanilino group, 5f is poised to react with
an incoming aniline under solvent-free conditions to give
the 1,4-diol product. Thus rac-5f was treated with N-
methylaniline 2h, and the unsymmetrical 1,4-diol rac-4fh
was obtained in 93% yield. Conversely, epoxy aminoal-
cohol rac-5h cannot react in the 1,4-manifold, since it
lacks an intramolecular hydrogen bond donor. Thus
treatment of rac-5h with p-fluoroaniline 2f under solvent-
free conditions affords the 1,3-diol rac-3fh in 94% yield.
(11) As illustrative examples, in the case of entry 3, [1] ) 2.1 M, [2e]
) 8.3 M; for entry 6 [1] ) 0.9 M, [2g] ) 7.1 M (all reactants assumed to
have density ) 1 g/mL). These aniline concentrations are 7- to 8-fold higher
than those employed in the acetonitrile, DMF, and mesitylene reactions
described above.
(12) Autocatalysis in epoxide ring-opening under neat conditions has
been proposed by Sharpless and co-workers (refs 1b, 5a).
(13) Note, however, that this effect can explain some of the results
observed in: Kiss, L.; Forro´, E.; Martinek, T. A.; Berna´th, G.; De Kimpe,
N.; Fu¨lo¨p, F. Tetrahedron 2008, 64, 5036–5043.
Org. Lett., Vol. 12, No. 3, 2010
623