The α-effect in iminium ion catalysis

Article abstract of DOI:10.1016/j.tet.2005.08.110

The α-effect can be used as an effective means to promote iminium ion catalysed transformations, providing acyclic scaffolds to aid in catalyst design. A thorough investigation of the structure-activity relationship of the catalyst architecture reveals optimal substituents of a disubstituted carbamate and a secondary alkyl group around a hydrazine scaffold. Molecular modelling investigations provide a mechanistic rationale to the results observed.

Full text of DOI:10.1016/j.tet.2005.08.110

Tetrahedron 62 (2006) 410–421
The a-effect in iminium ion catalysis
Julie L. Cavill,a Richard L. Elliott,b Gareth Evans,a Ian L. Jones,a James A. Platts,a,
*
Antonio M. Rudaa and Nicholas C. O. Tomkinsona,
*
aSchool of Chemistry, Main Building, Cardiff University, Park Place, Cardiff, CF10 3AT, UK
bMedicinal Chemistry, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, CM19 5AW, UK
Received 19 May 2005; revised 4 July 2005; accepted 31 August 2005
Available online 23 September 2005
Abstract—The a-effect can be used as an effective means to promote iminium ion catalysed transformations, providing acyclic scaffolds to
aid in catalyst design. A thorough investigation of the structure–activity relationship of the catalyst architecture reveals optimal substituents
of a disubstituted carbamate and a secondary alkyl group around a hydrazine scaffold. Molecular modelling investigations provide a
mechanistic rationale to the results observed.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
novel acyclic structures for future catalyst design.12 Herein,
we provide a full report on our synthetic and theoretical
investigations to gain a greater understanding of iminium
ion formation and the factors controlling this fascinating and
vibrant area of organocatalysis.
The use of secondary amines to accelerate traditional
organic transformations through LUMO-lowering has
recently caught the imagination of the synthetic community.
Although simple in both design and mechanistic rationale,
the catalysts reported to be effective in these reactions are
having a major impact on contemporary organic synthesis
and the way in which chemists think about preparing
molecules, offering practically simple ways to prepare
complex targets. The scope and number of transformations
are continuing to expand1 and now include Diels–Alder
cycloaddition,2 [3C2] cycloadditions,3 conjugate addition
reactions of pyrroles,4 indoles,5 anilines,6 nitro alkanes7 and
hydride,8 Mukaiyama–Michael reactions,9 cyclopropan-
ations10 and [4C3] cycloaddition reactions.11
The most effective catalysts in both iminium ion and
enamine catalysis share a common structure of a secondary
amine embedded within a five-membered ring (Fig. 1).13
We rationalized that this enhances the nucleophilicity of the
secondary amine, allowing effective formation of iminium
ions, and postulate that such an increase in nucleophilicity
could also be achieved by exploiting the a-effect.
We have recently become interested in the design and
synthesis of novel catalyst architectures that will allow for
the lowering of catalyst loading within these reactions.12
Based on the original proposal by MacMillan that the rate
determining step of these processes is iminium ion
formation,2b we believed that increasing the nucleophilicity
of secondary amine catalysts may well allow us to meet our
original goals. To this end, we recently reported that the
a-effect can be used as an effective platform with which to
accelerate the iminium ion catalysed Diels–Alder reaction
between a variety of dienes and dienophiles, providing
Figure 1. Effective secondary amine catalysts.
The a-effect is defined as a positive deviation of an
a-nucleophile (a nucleophile bearing an unshared pair of
electrons on an atom adjacent to the nucleophilic site) from
a Brønsted-type plot of log Knuc versus pKa constructed for a
series of normal related nucleophiles.14 More generally, it is
the influence of an atom bearing a lone pair of electrons on
the reactivity at the adjacent site. The enhanced reactivity of
a-nucleophiles was first reported in 1947, and the
phenomenon was later given its name by Edwards and
Pearson in 1962.15 The origins of the observation are of
some debate and several possible explanations have been
offered. These include the ground state of the nucleophile
Keywords: a-Effect; Iminium ion catalysis; DFT calculations.
*
Corresponding authors. Tel.: C44 29 20874950; fax: C44 29 20874030
(J.A.P.); tel.: C44 29 20874068; fax: C44 29 20874030 (N.C.O.T.);
e-mail addresses: platts@cardiff.ac.uk; tomkinsonnc@cardiff.ac.uk
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.110

J. L. Cavill et al. / Tetrahedron 62 (2006) 410–421
411
being destabilized by repulsion between the adjacent pairs
of electrons,16 stabilization of the transition state by the
extra pair of electrons,17 and the adjacent pair of electrons
reducing solvation of the nucleophile.18 It is notable that this
phenomenon is generally believed to have several origins,
and that the nature of the individual effects and the exact
conditions under which they are operative have not been
unambiguously identified. Nonetheless, the effect is genuine
and has been invoked to explain chemical reactivity.19
Within this paper we report our results on the use of the
a-effect in the acceleration of the Diels–Alder reaction with
acyclic secondary amine containing scaffolds from both a
theoretical and practical basis.
of 10 mol% catalyst, in a methanol/water mixture 19:1 and
examined the Diels–Alder reaction between trans-cinna-
maldehyde 8 and cyclopentadiene 7.
In the absence of any catalyst, or in the presence of only the
protonic acid co-catalyst, the reaction proceeded to just 7%
completion in 48 h with the endo-isomer predominating
(Table 1, entries 1 and 2). Observations by MacMillan and
others suggest that the exo-isomer of the product 10
predominates when iminium ion catalysis is occurring, as
was observed with the proline methyl ester 5 (Table 1, entry
8). The use of N,N-dimethylamine hydrochloride as the
catalyst afforded a 22% yield of adduct 8 with the exo-
isomer predominating (Table 1, entry 3), suggesting that
iminium ion catalysis was occurring, albeit sluggishly.
Significantly, the use of N,O-dimethylhydroxylamine
hydrochloride as the catalyst led to a significant increase
in the yield observed for the reaction (Table 1, entry 4),
which suggested that it would indeed be possible to
accelerate these reactions by taking advantage of the
a-effect. Extension of the reaction time further did allow
for the increased formation of the Diels–Alder adduct to
80% (Table 1, entry 5). Changing to a nitrogen based
a-heteroatom with the commercially available hydrazines—
N,N0-dimethylhydrazine (Table 1, entry 6) and N,N0-
diphenylhydrazine (Table 1, entry 7)—showed lower yield
for the transformation but did show a marked increase from
N,N-dimethylamine.
2. Results and discussion
In order to establish if the a-effect provided an effective
platform for iminium ion catalysis we conducted a series of
experiments in order to compare the aminocatalytic activity
of a pyrrolidine-type system, an acyclic secondary amine
and an acyclic secondary amine with an a-heteroatom. We
examined four commercially available acyclic secondary
amines 1–4, and compared their reactivity to proline methyl
ester 5, which has previously been reported to be effective in
catalyzing the Diels–Alder reaction and allows direct
comparison to the level of activity attainable with cyclic
amine systems (Fig. 2). The results obtained are outlined in
Table 1. We initially adopted standard reaction conditions
Having shown that the a-effect could be used to accelerate
these iminium ion catalysed transformations, we then
sought to further develop the catalyst structure to enhance
the rate of the catalytic cycle to match or increase those
displayed by cyclic secondary amines. In the search for
further modification of the catalyst architecture we made the
observation that pyrrolidine hydrochloride 6$HCl was
ineffective in catalysing the Diels–Alder reaction between
cyclopentadiene and cinnamaldehyde (Table 1, entry 9)
when compared to proline methyl ester hydrochloride
5$HCl (Table 1, entry 8). This suggested that a carbonyl-
group b- to the nucleophilic nitrogen was also involved
within the iminium ion formation. We, therefore, targeted a
series of catalysts that incorporated both the a-heteroatom
and a carbonyl functionality in the b-position to discover if
these had further effect on the reactivity of these secondary
amines.
Figure 2. Commercially available amines.
Table 1. Catalysis of the Diels–Alder reaction with commercially available
aminesa
Our initial target was the ethyl carbazate derived system 13,
easily prepared in two-steps from commercially available
starting materials via a condensation–reduction protocol in
77% overall yield (Scheme 1). Evaluation of the activity of
13$HCl under standard conditions (10 mol% cat, MeOH/
Entry
Catalyst
Time (h)
endo:exob
Yield (%)
1
None
48
48
48
48
72
72
48
48
24
64:36
63:37
38:62
34:66
34:66
68:32
38:62
29:71
32:68
7
7
2c
3c
4c
5c
6d
7d
8c
9c
NEt3$HCl
4$HCl
3$HCl
3$HCl
1$HCl
2$HCl
5$HCl
6$HCl
22
65
80
48
33
85
9
a Carried out in methanol/water 19:1 at room temperature with 10 mol%
catalyst.
b Ratio determined by 1H NMR of crude reaction mixture.
c Catalyst used as HCl salt.
d Catalyst used as bis-HCl salt.
Scheme 1. Synthesis of catalyst 13.

412
J. L. Cavill et al. / Tetrahedron 62 (2006) 410–421
H2O 19:1, room temperature, 48 h) gave the Diels–Alder
adducts in 93% isolated yield (endo:exo ratio 34:66). Thus,
introduction of a carbonyl group b- to the reactive centre
does indeed markedly increase catalytic activity, providing
a new molecular scaffold for catalyst design and
development.
Figure 4. Substitution of reactive nitrogen R1.
nitrogen (entry 2, 13$HCl, 90%) with both primary (entry
1, 14$HCl, 75%) and tertiary (entry 3, 15$HCl, 32%)
substitution providing significantly lower yields of product.
Reducing the reaction time to just 6 h with 13$HCl (entry 4)
gave the product in 74% isolated yield, and performing the
reaction in methanol led to a further dramatic increase in the
amount of isolated product (entry 5, 90%).
Having established a positive effect on activity, we set about
optimising our catalyst structure. We examined five
variables within our system (Fig. 3) to provide further
insight into the catalysts’ structure–activity relationship
(SAR), with the ultimate goal of designing a second
generation catalyst capable of accelerating these reactions
at lower catalyst loading and reaction times.
In order to ascertain whether the enhanced catalyst activity
observed was due to the a-heteroatom, the b-carbonyl, or
both, we prepared the glycine ethyl ester derived catalyst
16.20 The catalysts 17$HCl21 and 18$HCl,22 containing an
oxygen a-heteroatom and a b-carbonyl, were also syn-
thesised allowing us to compare the effects of carbon,
nitrogen and oxygen in the a-position. With oxygen as the
a-heteroatom the reactions were sluggish (Table 2, entries
8–10) providing the adducts 9 and 10 in !28% isolated
yield after 6 h. Examination of a range of solvents and
reaction conditions with these catalysts showed significantly
lower conversions, confirming that methanol appears to be
the most appropriate solvent for this class of transformation.
The glycine ethyl ester derived catalyst 16$HCl (Table 2,
entries 6 and 7) showed that the a-heteroatom is essential
for effective reactivity of our systems with the products only
being isolated in up to 5% yield. This set of results,
therefore, suggested that a synergistic effect of both the
a-heteroatom and the b-carbonyl was responsible for the
reactivity within the acyclic catalysts used (Fig. 5).
Figure 3. Variables altered for SAR of catalyst.
SAR studies on the catalyst architecture began by varying
substitution of the reactive nitrogen centre R1 with the
amines 13, 14 and 15 (Fig. 4) (see Section 5 for full details
of catalyst synthesis). These compounds contained primary,
secondary and tertiary substitution directly adjacent to the
reactive nitrogen.
The results obtained for these catalysts are outlined in
Table 2. The optimal substitution pattern proved to be a
secondary centre directly attached to the nucleophilic
Curiosity into what lay behind the need for an electron
Table 2. Iminium ion catalysed SAR studiesa
Entry
Catalyst
Solvent
Time (h)
endo:exob
Yield (%)
1
2
3
4
5
6
7
8
14$HCl
13$HCl
15$HCl
13$HCl
13$HCl
16$HCl
16$HCl
17$HCl
17$HCl
18$HCl
19$HCl
20$HCl
21$HCl
19$TFA
19$MeSO3H
19$PhCO2H
19$HBr
19$HI
MeOHc
MeOHc
MeOHc
MeOHc
MeOH
MeOH
MeOHc
MeOH
MeOHc
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
24
24
24
6
6
6
6
6
6
6
35:65
37:63
35:65
34:66
33:67
35:65
34:66
35:65
34:66
50:50
33:67
33:67
42:58
33:67
36:64
47:53
35:65
32:68
30:70
35:65
35:65
34:66
35:65
75
90
32
74
90
5
3
28
13
12
82
86
69
81
74
10
97
98
98
98
89
34
70
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
6
6
24
24
48
48
24
24
24
6
19$HPF6
22$HCl
23$HCl
24$HCl
24$HCl
6
6
24
a Diels–Alder reaction between cyclopentadiene and cinnamaldehyde at room temperature with 10 mol% catalyst.
1
b Ratio determined by H NMR of crude reaction mixture.
c Water (5%) added by volume.

J. L. Cavill et al. / Tetrahedron 62 (2006) 410–421
413
the a-heteroatom, an increase in the amount of isolated
product was observed. This was the case for both the
carbamate (entry 20) and the amide (entry 21) derivatives
leading to our most effective catalyst system observed to
date.
Figure 5. Alteration of a-heteroatom X.
withdrawing group on the a-heteroatom, led us to
synthesize a further family of compounds varying the
nature of this group (Fig. 6). The amides 19 and 20 and the
sulfonamide 21 were prepared to measure their influence
when compared to the carbamate derivative 13.
Figure 7. Nature of the acid co-catalyst HX.
Figure 6. Modification of EWG.
Figure 8. Substitution of a-heteroatom R2.
Each of these hydrazine derivatives appeared to be effective
catalysts, although they did not perform as well as the
carbamate 13$HCl. With the amides 19 and 20 the Diels–
Alder adducts were isolated in 82 and 86% yields,
respectively, (Table 2, entries 11 and 12) after just 6 h.
Although the sulfonamide performed well when compared
to the catalysts without an electron withdrawing group on
the a-heteroatom, it still returned significantly less product
when compared to the carbamates and amides, with an
extended reaction time of 24 h needed in order to obtain a
respectable yield (entry 13).
3. Theoretical calculations
Along with experimental work, theoretical calculations
were carried out on the formation of iminium ions in order
to provide a basis for further catalyst design as well as aid in
interpretation of our synthetic results. We aimed to establish
a mechanism for the formation of the active species, and
hence to understand the effect of functional groups
surrounding the reactive nitrogen centre on reactivity,
ultimately with the aim of developing a predictive scale
for amine reactivity (Fig. 8).
The next variable we addressed was the nature of acid
co-catalyst HX. Our initial work revealed that as the pKa of
the acid co-catalyst decreased, the length of time necessary
for the reaction to proceed increased (Table 2, entries
14–16). Interestingly, however, we found that with benzoic
acid as the co-catalyst, the endo:exo ratio of the products
was significantly different to the usual 2:1 ratio observed
with most other reactions (entry 16). An interesting
phenomenon of these iminium ion catalysed Diels–Alder
reactions is that with a,b-unsaturated aldehydes the exo-
isomer predominates, a complementary and potentially
synthetically significant alternative to the Lewis acid
catalysed process, which tends to give the endo-adduct
preferentially. To check the effect of counter anion size on
the geometry of the reaction products, we prepared the $HBr
and $HI salts of 19, and compared the diastereomeric ratio
of the Diels–Alder adducts (Table 2, entries 17–19).
However, in all cases the ratio of the endo and exo isomers
was 2:1, even for the non-coordinating anion PFK6 , that is,
the ratio observed for most of the systems used within this
investigation (Fig. 7).
Initially, we constructed a realistic model of the reaction
conditions used in the practical work above, namely an
ensemble including the hydrochloride salt of dimethyl-
amine, acrolein as a model electrophile, and a single explicit
water molecule, all enclosed within a spherical dielectric
approximation of methanol solvation. Optimization of this
Finally, the effect of the substituent on the a-heteroatom
was examined by preparing the methyl substituted
carbamate 22 and amide 23 as well as the more sterically
encumbered tert-butyl carbamate 24. As in the substitution
of the reactive nitrogen, catalyst reactivity is sensitive to
steric encumbrance around the a-heteroatom, the tert-butyl
derivative requiring 24 h in order to reach 70% conversion
for the reaction (Table 2, entries 22 and 23). However, we
were delighted to discover that with a methyl substituent on
Figure 9. Two optimized reaction geometries.

414
J. L. Cavill et al. / Tetrahedron 62 (2006) 410–421
Figure 10. (a) Optimised geometry of ‘pro-iminium’ and (b) iminium ion products.
reaction mixture from varying starting points revealed a
number of stable conformations of very similar energy, and
with negligible barriers to inter-conversion of each. Figure 9
shows two such starting conformations, which differ in
energy by just 2.9 kJ molK1. Addition of further explicit
water molecules to this ensemble led to the chloride
occupying a comparable position as shown in Figure 9,
that is forming a close contact with the protonated amine
obtained from relaxed potential energy surface (PES) scans.
A transition state linking the reactant and pro-iminium
product (denoted TS1) was located in this manner, with a
single imaginary frequency of 139.9i cmK1. TS1 is
110 kJ molK1 higher in energy than the reactant complex,
a sizeable barrier due largely to transfer of a proton from the
amine to chloride, accompanied by small re-orientation of
acrolein and water. A second transition state, TS2,
accompanies the elimination of water from this initial
product, again essentially a proton transfer from amine to
oxygen, mediated by the presence of chloride. TS2, with
imaginary frequency 405.6i cmK1, is ca. 90 kJ molK1 above
the pro-iminium species. Thus, the barrier associated
with initial formation of the N–C bond is rather higher in
energy than subsequent elimination of water to the final
product.
˚
(Cl/HZ1.9–2.1 A), with minor changes in other
geometrical details.
A second stable structure is found, ca. 10 kJ molK1 higher
in energy than the reactant complex, in which the N–C bond
has formed and a proton transferred from amine to carbonyl
(see Fig. 10a). Here again, the chloride ion is closely
associated with the protonated amine centre, with the water
hydrogen bonded to both ClK and OH. The N–C bond
˚
length in this ‘pro-iminium ion’ species is 1.56 A, that is,
˚
somewhat longer than a typical N–C single bond (cf. 1.46 A
In order to check whether these transition states do indeed
link the expected reactants and products, we perturbed each
TS both forwards and backwards along the imaginary
eigenvalue, then carried out geometry optimisation. This
process resulted in previously located minima from TS2, as
shown in Scheme 2. Perturbing backwards from TS1 gave
the reactant complex as expected, but forward from TS1
resulted in a new minimum structure, confirmed as such via
harmonic frequency calculation, just 32.6 kJ molK1 below
TS1. This ‘intermediate’ structure differs from the TS only
by relative rotation of the various moieties, with both
acrolein and HCl rotated towards their orientation in the
pro-iminium product.
in dimethylamine). A third low energy minimum, corre-
sponding to the iminium ion product after elimination of
water from the pro-iminium species, was located ca.
40 kJ molK1 above the reactants. This product contains
the expected N]C double bond, as evidenced by the planar
disposition of groups about N, and the N]C length of
˚
1.31 A (Fig. 10b).
Transition states connecting these minima were located
using the QST3 approach in G03, specifying reactant and
product structures along with a guess of a transition state
Scheme 2. Reaction profile of dimethylamine hydrochloride and acrolein.

J. L. Cavill et al. / Tetrahedron 62 (2006) 410–421
415
A third transition state, TS1a, separates this intermediate
from the pro-iminium structure, with a barrier of just
7 kJ molK1, that is, essentially negligible when compared to
the barriers associated with TS1 and TS2. The structure of
this transition state is interesting, as it appears the water
molecule mediates proton transfer from H–Cl to oxygen,
acting as a ‘proton shuttle’. Thus, it appears that only this
step requires the presence of an explicit water molecule, and
hence explains the frequent requirement for trace water in
the reaction mixture.
these results in terms of the electronic structure of the
relevant minima and transition states.
These results are directly relevant to those in Table 1, and
are, therefore, consistent with 0the rather small increase in
catalytic activity seen for N,N -dimethylhydrazine and the
rather larger effect found with N,O-dimethyl-hydroxyl-
amine. The reaction pathway proposed here is also
consistent with the effect of counter anion noted in
Table 2: a key step in iminium ion formation is transfer of
a proton from N to O, mediated by the counter anion. Acids
of increasing pKa should be progressively worse at
mediating such a step, and, therefore, lead to lower catalytic
activity.
In order to test this choice of theoretical method, we
re-calculated this potential energy surface (PES) using both
a larger basis set, 6-311CCG (2d,p), and a density
functional, mPW1PW91, reported to give improved barriers
for model organic reactions.26 In both cases, neither
structures nor relative energies of stationary points differed
significantly from those reported above. The larger basis set
A further interesting observation linking both synthetic and
theoretical investigations is the addition of water to some
reaction mixtures, which is only required for catalysts
lacking a b-carbonyl. This suggests the possiblity that the
carbonyl group is intimately involved with iminium ion
formation, acting as a proton shuttle in an analogous manner
to the water molecule in the calculations presented.
Introduction of the b-carbonyl may, therefore, provide an
intramolecular route for this, and hence may explain why
this functionality removes the need for water in the reaction
medium.
reduced barriers at TS1 and TS2 by 6.8 and 0.8 kJ molK1
,
respectively, while the alternative functional increased these
by 4.8 and 2.0 kJ molK1, respectively.
Therefore, we have confidence in our B3LYP/6-31CG(d)
calculations that indicate a three-step, rather than a two-step
mechanism for formation of an iminium ion from
dimethylamine hydrochloride and acrolein, albeit with one
energetically unimportant step, as shown in Scheme 2.
There is, therefore, considerable scope for electronic and/or
steric effects, through modification of the amine, to alter the
kinetics of iminium ion formation.
4. Conclusion
In summary, through a combination of both synthetic and
theoretical studies we have shown that the a-effect is an
effective platform for iminium ion catalysis. The synthetic
studies have shown an arrangement of a tertiary centre on
the reactive nitrogen together with a methyl substituent and
an ethyl carbamate on the a-heteroatom leads to a highly
effective catalyst architecture. DFT calculations have
revealed a realistic mechanistic pathway for iminium ion
formation and have shown that transition state energies can
be significantly perturbed through the incorporation of an
a-heteroatom. Of particular note is the fact that both a
counter-anion and a proton-shuttle (water) are necessary for
this process to occur. A possible reason for the counter-
intuitive need for an electron-withdrawing-group on the
Applying the same methods to two a-nucleophiles, namely
N,N0-dimethylhydrazine 1 and N,O-dimethylhydroxyl
amine 3, yields a broadly similar PES to that shown in
Scheme 2 in each case (Fig. 11). Both reaction paths show a
clear effect of the a-heteroatom, reducing the barriers at TS1
and TS2 by between 5 and 35 kJ molK1. Specific effects are
apparent in these results: the N-heteroatom reduces the
second barrier by substantially more than the first, while the
opposite is true for the O-heteroatom. Thus, there appears to
be a subtle interplay of effects at work here, consistent with
the generally accepted view that the a-effect is a complex
one. Subsequent theoretical studies will attempt to explain
Figure 11. Comparison of reaction path of three amines.

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J. L. Cavill et al. / Tetrahedron 62 (2006) 410–421
a-heteroatom may lie in the mechanism of formation of the
iminium ion. Further studies are now underway to explain
the need for a b-carbonyl within our catalyst structure and to
incorporate these fundamental findings within a chiral
catalyst for use in iminium ion catalysed transformations.
charged with hydrogen stirred for 24 h at ambient
temperature. The reaction mixture was filtered over Celitew
and the filtrate was neutralised with saturated sodium
bicarbonate solution (25 mL). The volatiles were removed
under reduced pressure and the aqueous phase was extracted
with diethyl ether (5!10 mL). The combined organic
extracts were washed with brine, dried (MgSO4) and
reduced in vacuo to give the title compound 13 (0.43 g,
85%) as a colourless viscous liquid; nmax (film)/cmK1 3314,
1701, 1529, 1266; 1H NMR (400 MHz, CDCl3) d 6.59 (1H,
s, NH) 4.13 (2H, q, JZ6.9 Hz, OCH2CH3) 3.15 (1H, sept,
JZ6.6 Hz, NCH(CH3)2) 1.24 (3H, t, JZ6.9 Hz, OCH2CH3)
1.01 (6H, d, JZ6.6 Hz, NCH(CH3)2) dC (100 MHz, CDCl3)
158.0 (C) 61.7 (CH2) 51.2 (CH) 20.9 (CH3) 15.0 (CH3); m/z
(EI) [M]C147 (21%), 131 (100), 103 (64), 85 (91), 42 (74);
HRMS (EI) (found 146.1053 [M]C; C6H14N2O2 requires
146.1055).
5. Experimental
5.1. General
1
All H and 13C nuclear magnetic resonance spectra were
recorded on a Bruker DPX-400, Bruker Avance 500 or
Bruker DPX-250 spectrometer, with 13C spectra being
recorded at 100, 125 or 62.5 MHz. Mass spectra were
obtained using a Fisons VG platform II spectrometer. High
resolution mass spectra were obtained by the EPSRC mass
spectrometry service, Swansea. Melting points were
determined on a Khofler Hot Stage Micro Melting Point
Apparatus and are uncorrected. Infrared spectra were
recorded in the range 4000–600 cmK1 using a Perkin–
Elmer 1600 series spectrophotometer as thin films or as
nujol mulls. Thin-layer chromatography (TLC) was
performed on Merck 5554 60F silica gel coated aluminium
plates and detection was effected with a solution of 10%
ceric sulfate in 10% sulfuric acid, followed by heating the
plates. Purification of compounds was achieved by medium
pressure chromatography using Merck 9385 60 silica gel.
Treatment with dry ethereal HCl gave the corresponding salt
13$HCl as a colourless solid; mp 85–87 8C; nmax (nujol)/
cmK1 3397, 2922, 2853, 1732, 1538, 1462, 1377, 1263,
1022; 1H NMR (500 MHz, CDCl3) d 10.89 (2H, br s, NH2)
9.58 (1H, br s, NH) 4.22 (2H, q, JZ7.1 Hz, OCH2CH3) 3.82
(1H, sept, JZ6.6 Hz, NCH(CH3)2) 1.39 (6H, d, JZ6.6 Hz,
NCH(CH3)2) 1.24 (3H, t, JZ7.1 Hz, OCH2CH3); 13C NMR
(100 MHz, CDCl3) d 154.7 (C) 62.4 (CH2) 55.1 (CH) 17.5
(CH3) 14.3 (CH3); m/z (APcI) [MCH–HCl]C147 (100%);
HRMS (ES) (found 147.1127 [MCH–HCl]C; C6H14N2O2
requires 147.1128).
All DFT calculations were carried out using the Gaussian03
package.23 Initial optimisations and transition state searches
were carried out at the B3LYP/6-31CG(d,p) level,24,25
within an Onsager solvent shell of methanol. Subsequent
calculations to test these methods employed the larger
6-311CCG(2d,p) basis set, as well as the mPW1PW91
functional,26 and an alternative PCM model of methanol
solvation.27 All minima and transition states were charac-
terised as such via harmonic frequency calculation and
examination of any resulting imaginary eigenvalues.
5.1.3. N0-tButylhydrazinecarboxylic acid ethyl ester 15.
tert-Butylhydrazine hydrochloride (5.00 g, 40.1 mmol,
1 equiv) was cooled to 0 8C in a suspension of dichloro-
methane (50 mL) and aqueous sodium bicarbonate solution
(50 mL). Ethyl chloroformate (4.35 g, 3.84 mmol,
40.1 mmol, 1.0 equiv) was added drop wise to the
suspension and stirring was continued at 0 8C for 30 min
and at ambient temperature overnight. The organic layer
was separated and the aqueous layer extracted with
dichloromethane (2!20 mL). The combined organics
were dried (Na2SO4) and the volatiles removed in vacuo
to give a colourless oil. Purification by flash column
chromatography eluting with ether/light petroleum 1:1
afforded the title compound 15 (662 mg, 10%) as a
colourless oil; nmax (liquid film)/cmK1 3302, 2973, 1713,
1538, 1475, 1445, 1388, 1364, 1335, 1269, 1214, 1150,
5.1.1. N0-Isopropylidenehydrazinecarboxylic acid ethyl
ester. Ethyl carbazate (2.20 g, 21.1 mmol) was stirred in an
excess of acetone (10 mL), containing acetic acid (30 mL,
0.5 mmol), for 24 h at ambient temperature. Water (20 mL)
was added and the reaction mixture extracted with
dichloromethane (3!20 mL). The combined organic
extracts were washed with brine, dried (Na2SO4) and
reduced in vacuo to afford the title compound (2.75 g, 90%)
as a colourless solid; mp 72–73 8C [lit.28 mp 75–76 8C];
nmax (nujol)/cmK1 3236, 1730, 1649, 1530, 1239; 1H NMR
(400 MHz, CDCl3) d 7.94 (1H, s, NH) 4.06 (2H, q, JZ
6.4 Hz, OCH2CH3) 1.83 (3H, s, N]CCH3) 1.71 (3H, s,
N]CCH3) 1.11 (3H, t, JZ6.4 Hz, OCH2CH3); 13C NMR
(100 MHz, CDCl3) d 154.4 (C) 151.0 (C) 61.6 (CH2) 25.4
(CH3) 16.3 (CH3) 14.5 (CH3); m/z (EI) [M]C144 (19%), 98
(93), 44 (100), 41 (69); HRMS (EI) (found 144.0898 [M]C;
C6H12N2O2 requires 144.0899).
1
1062, 1030; H NMR (400 MHz, CDCl3) d 5.97 (1H, br s,
NH) 4.10 (2H, q, JZ6.8 Hz, OCH2CH3) 1.20 (3H, t, JZ
6.8 Hz, OCH2CH3) 1.02 (9H, s, NC(CH3)3); 13C NMR
(100 MHz, CDCl3) d 158.1 (C) 61.4 (CH2) 54.9 (C) 27.0
(CH3) 14.6 (CH3); m/z (APcI) [MCH]C161 (100%);
HRMS (ES) (found 161.1285 [MCH]C; C7H16N2O2
requires 161.1285).
Treatment with dry ethereal HCl gave the corresponding salt
15$HCl as a colourless solid; mp 157–158 8C; nmax (nujol)/
cmK1 3238, 2924, 2684, 2326, 1714, 1531, 1463, 1376,
1275, 1176; 1H NMR (500 MHz, CDCl3) d 10.77 (2H, br s,
NH2) 9.38 (1H, s, NH) 4.23 (2H, q, JZ6.9 Hz, OCH2CH3)
1.41 (9H, s, NC(CH3)3) 1.26 (3H, t, JZ6.9 Hz, OCH2CH3);
13C NMR (125 MHz, CDCl3) d 156.3 (C) 63.9 (CH2) 63.3
(C) 24.8 (CH3) 14.3 (CH3); m/z (APcI) [MCH–HCl]C161
5.1.2. N0-Isopropylhydrazinecarboxylic acid ethyl ester
13. Platinum oxide (17 mg, 73 mmol) was placed in nitrogen
flushed flask with ethanol (3.4 mL) and acetic acid
(1.7 mL). N0-isopropylidene-hydrazinecarboxylic acid
ethyl ester (0.50 g, 3.5 mmol) was added, the flask was

J. L. Cavill et al. / Tetrahedron 62 (2006) 410–421
417
(100%); HRMS (ES) (found 161.1284 [MCH–HCl]C;
C7H16N2O2 requires 161.1285).
filtered over Celitew and the filtrate was neutralised with
saturated sodium bicarbonate solution (180 mL). The
volatiles were removed under reduced pressure and the
aqueous phase was extracted with diethyl ether (5!50 mL).
The combined organic extracts were washed with brine,
dried (MgSO4) and reduced in vacuo to give the title
compound 19 (2.18 g, 86%) as a colourless powder; mp
110–112 8C [lit.31 mp 115–117 8C]; nmax (nujol)/cmK1
5.1.4. N-Isopropylglycine ethyl ester 16. A solution of
isopropyl amine (13.6 g, 230 mmol, 19.6 mL, 2.3 equiv) in
toluene (100 mL) was treated with ethyl bromoacetate
(16.7 g, 100 mmol, 11.1 mL, 1.0 equiv) at ambient tem-
perature. The solution was refluxed for 2 h and subsequently
stirred at room temperature for 16 h during which time a
crystalline precipitate was formed. The solution was made
alkaline with sodium hydroxide (50% solution, 20 mL)
dissolving the precipitate. The organic layer was separated
and washed with water, brine, and dried (MgSO4). The
volatiles were removed in vacuo and the product purified by
distillation (5 mbar, 73–75 8C) [lit.29 bp 30 8C at 2.00 Torr]
to give the title compound 16 (12.3 g, 85%) as a clear
colourless liquid; nmax (film)/cmK1 3335, 2966, 1740, 1466,
1379, 1347, 1098, 1028; 1H NMR (400 MHz, CDCl3) d 4.12
(2H, q, JZ7.2 Hz, OCH2CH3) 3.34 (2H, s, NHCH2CO) 2.73
(1H, sept, JZ6.3 Hz, CH(CH3)2) 1.52 (1H, br s, NH) 1.21
(3H, t, JZ7.2 Hz, OCH2CH3) 0.99 (6H, d, JZ6.3 Hz,
CH(CH3)2); 13C NMR (100 MHz, CDCl3) d 172.7 (C) 60.8
(CH2) 48.7 (CH2) 48.3 (CH2) 22.7 (CH3) 14.2 (CH3); m/z
(APcI) [MCH]C146 (100%); HRMS (ES) (found 146.1177
[MCH]C; C7H15N1O2 requires 146.1176).
1
3289, 1640, 1537, 725, 693; H NMR (400 MHz, CDCl3)
d 7.70 (1H, s, NH) 7.69 (2H, d, JZ7.7 Hz, ArH) 7.46 (1H, t,
JZ7.7 Hz, ArH) 7.38 (2H, dd, JZ7.7, 7.7 Hz, ArH) 4.81
(1H, s, NH) 3.18 (1H, sept, JZ6.2 Hz, NCH(CH3)2) 1.05
(6H, d, JZ6.2 Hz, NCH(CH3)2); 13C NMR (100 MHz,
CDCl3) d 167.5 (C) 132.9 (C) 131.9 (CH) 128.7 (CH) 126.9
(CH) 51.4 (CH) 20.9 (CH3); m/z (EI) [M]C173 (3%), 163
(9), 122 (13), 105 (100), 77 (34); HRMS (EI) (found
178.1105 [M]C; C10H14N2O requires 178.1106).
Treatment with dry ethereal HCl gave the corresponding salt
19$HCl as a colourless solid; mp 215–218 8C; nmax (nujol
film)/cmK1 3408, 2923, 2853, 2645, 1678, 1600, 1549,
1527, 1463, 1377; 1H NMR (400 MHz, CDCl3) d 8.00 (2H,
d, JZ7.5 Hz, ArH) 7.45 (1H, t, JZ7.4 Hz, ArH) 7.31 (2H,
dd, JZ7.5, 7.4 Hz, ArH) 3.94 (1H, sept, JZ6.6 Hz,
NCH(CH3)2) 1.41 (6H, d, JZ6.6 Hz, NCH(CH3)2); 13C
NMR (125 MHz, CDCl3) d 166.8 (C) 133.5 (C) 128.7 (CH)
128.6 (CH) 128.5 (CH) 56.0 (CH) 18.0 (CH3); m/z (ApcI)
[MCH–HCl]C179 (100%).
Treatment with dry ethereal HCl gave the corresponding salt
16$HCl as a colourless solid; mp 111–112 8C; nmax (nujol)/
cmK1 3330, 2926, 2853, 2705, 2455, 1757, 1590, 1463,
1
1377; H NMR (400 MHz, CDCl3) d 9.77 (2H, br s, NH2)
5.1.7. Cyclohexanecarboxylic acid N0-Isopropylhydra-
zide 20. Platinum oxide (108 mg, 0.48 mmol) was placed in
a nitrogen flushed flask with ethanol (50 mL) and acetic acid
(25 mL). Benzoic acid isopropylidene hydrazide (4.20 g,
23.8 mmol) was added, the flask was charged with hydrogen
and stirred for 96 h at ambient temperature. The reaction
mixture was filtered over Celitew and the filtrate was
neutralised with saturated sodium bicarbonate solution
(450 mL), which caused the product to precipitate and the
suspension was extracted with diethyl ether (5!100 mL).
The combined organic extracts were washed with brine,
dried (MgSO4) and reduced in vacuo to give the title
compound 20 (2.31 g, 53%) as a colourless powder; mp
120–124 8C [lit.32 mp 122–123 8C]; nmax (nujol)/cmK1
3397, 2926, 1708, 1549, 1525, 1462, 1377, 1336, 1173,
4.21 (2H, q, JZ7.1 Hz, OCH2CH3) 3.76 (2H, s, NCH2COO)
3.56 (1H, m, NCH(CH3)2) 1.44 (6H, d, JZ6.7 Hz,
NCH(CH3)2) 1.24 (3H, t, JZ7.1 Hz, OCH2CH3); 13C
NMR (100 MHz, CDCl3) d 166.0 (C) 62.5 (CH2) 50.8
(CH) 44.2 (CH2) 18.9 (CH3) 14.0 (CH3); m/z (APcI) [MC
H–HCl]C146 (100%); HRMS (ES) (found 146.1177 [MC
H–HCl]C; C7H15N1O2 requires 146.1176).
5.1.5. Benzoic acid isopropylidene hydrazide. Benzoic
hydrazide (5.00 g, 36.7 mmol) was stirred in an excess of
acetone (22 mL, 0.3 mmol), containing acetic acid (40 mL,
0.7 mmol), for 48 h at ambient temperature. Water (30 mL)
was added and the reaction mixture was extracted with
dichloromethane (3!30 mL). The combined organic
extracts were washed with brine, dried (Na2SO4) and
reduced in vacuo to afford the title compound (5.57 g, 86%)
as a colourless solid; mp 141–143 8C [lit.30 mp 142–
143 8C]; nmax (nujol)/cmK1 3221, 1655, 1578, 1578, 1531,
1490, 718, 668; 1H NMR (400 MHz, CDCl3) d 8.70 (1H, s,
NH) 7.79 (2H, d, JZ7.1 Hz, ArH) 7.52 (1H, t, JZ7.1 Hz,
ArH) 7.44 (2H, dd, JZ7.1, 7.1 Hz, ArH) 2.15 (3H, s, CH3)
1.97 (3H, s, CH3); 13C NMR (100 MHz, CDCl3) d 164.6 (C)
156.9 (C) 134.1 (C) 132.1 (CH) 129.0 (CH) 127.6 (CH) 26.0
(CH3) 17.3 (CH3); m/z (EI) [M]C176 (8%), 161 (50), 105
(100), 77 (31); HRMS (EI) (found 176.0950 [M]C;
C10H12N2O requires 176.0950).
1
1110; H NMR (400 MHz, CDCl3) d 6.94 (1H, br s, NH)
4.61 (1H, m, NH) 3.08 (1H, m, NCH(CH3)2) 2.06 (1H, m,
Cy) 1.80 (4H, m, Cy) 1.68 (1H, m, Cy) 1.46 (2H, m, Cy)
1.25 (3H, m, Cy) 1.03 (6H, d, JZ6.4 Hz, NCH(CH3)2); 13
C
NMR (100 MHz, CDCl3) d 175.9 (C) 51.5 (CH2) 44.2 (CH2)
38.2 (CH) 29.8 (CH) 26.0 (CH3) 21.1 (CH2); m/z (APcI)
[MCH]C185 (95%) 143 (100); HRMS (ES) (found
185.1645 [MCH]C; C10H21N2O requires 185.1648).
Treatment with dry ethereal HCl gave the corresponding salt
20$HCl as a colourless solid; mp 193–194 8C; nmax (nujol)/
cmK1 3330, 2923, 1707, 1548, 1525, 1461, 1377, 1336,
1259, 1192, 1174, 1111; 1H NMR (400 MHz, CDCl3) d 5.30
(1H, s, NH) 3.81 (1H, sept, JZ6.6 Hz, NCH(CH3)2) 2.60–
2.50 (1H, m, O]CCH) 1.89–1.20 (10H, m, Cy) 1.43 (6H, d,
JZ6.6 Hz, NCH(CH3)2); 13C NMR (125 MHz, CDCl3) d
176.2 (C) 55.6 (CH2) 42.3 (CH2) 29.0 (CH) 25.5 (CH) 25.2
(CH3) 17.8 (CH2); m/z (APcI) [MCH–HCl]C185 (100%);
5.1.6. Benzoic acid N0-Isopropylhydrazide 19. Platinum
oxide (68 mg, 0.3 mmol) was placed in a nitrogen flushed
flask with ethanol (12 mL) and acetic acid (6 mL). Benzoic
acid isopropylidene hydrazide (2.50 g, 14.2 mmol) was
added, the flask was charged with hydrogen and stirred for
48 h at ambient temperature. The reaction mixture was

418
J. L. Cavill et al. / Tetrahedron 62 (2006) 410–421
HRMS (ES) (found 185.1653 [MCH–HCl]C; C10H21N2O
requires 185.1648).
distillation (110 8C) [lit.34 bp 116–118 8C] under nitrogen
affording the title compound (17.85 g, 70%); nma1x (liquid
film)/cmK1 3394, 3262, 2911, 2794, 1711, 1631; H NMR
(400 MHz, CDCl3) d 4.28 (1H, br s, NH) 2.76, (3H, s,
NHCH3) 1.88 (3H, s, N]CCH3 trans) 1.68 (3H, s, N]C–
CH3 cis); 13C NMR (100 MHz, CDCl3) d 146.4 (C) 37.9
(CH3) 25.0 (CH3) 15.5 (CH3); m/z (APcI) [MCH]C87
(100%); HRMS (EI) (found 86.0841 [M]C; C4H10N2
requires 86.0838).
5.1.8. Methanesulfonylhydrazide hydrochloride.33
Methanesulfonyl chloride (5.75 g, 50 mmol) was added
slowly to a stirred ice-cold solution of hydrazine hydrate
(2.5 g, 50 mmol) in water (7.5 mL), followed by 2 M aq
NaOH (25 mL), such that the temperature did not exceed
8 8C. On completion, hydrochloric acid (25 mL) was
added, which led to the precipitation of a small amount of
di-methanesulfonyl hydrazide, which was filtered off. The
filtrate was concentred in vacuo and the resulting residue
recrystallised twice from boiling ethanol to give the title
compound (2.0 g, 36%) as a coluorless crystaline solid; mp
152–153 8C; nmax (nujol mull)/cmK1 3440, 2652, 1953,
1461, 1376, 1146, 978; 1H NMR (400 MHz, D2O) d 3.1 (3H,
s, CH3); 13C NMR (100 MHz, D2O) d 38.4 (CH3).
5.1.12. N0-Isopropyl-N-methylhydrazinecarboxylic acid
ethyl ester hydrochloride 22$HCl. Ethyl chloroformate
(1.26 g, 1.11 mL, 11.6 mmol) was added drop wise to a
stirred solution of N-isopropylidene-N0-methylhydrazine
(1.00 g, 11.6 mmol) in dichloromethane (10 mL) and
saturated sodium bicarbonate solution (10 mL) at 0 8C.
After addition the reaction mixture was allowed to warm to
ambient temperature and stirred for 18 h. The organics were
separated and the aqueous layer extracted with dichloro-
methane (2!20 mL). The combined organics were dried
(Na2SO4) and concentrated under reduced pressure. The
organics were added to a nitrogen flushed flask, charged
with platinum oxide (132 mg, 0.58 mmol) in ethanol
(20 mL) and acetic acid (10 mL). The atmosphere was
replaced with hydrogen and the reaction stirred for 16 h at
ambient temperature. The reaction mixture was filtered over
Celitew and the filtrate was neutralised with saturated
sodium bicarbonate solution (300 mL). The single phase
solution was extracted with diethyl ether (3!50 mL) and
the combined organics were washed with brine (20 mL),
dried (MgSO4) and the volatiles were removed under
reduced pressure to give a clear oil, which was purified by
flash column chromatography eluting with ether/light
petroleum 1:1. The solvent was removed under reduced
pressure and ethereal hydrochloric acid (1 M, 58.0 mmol,
58 mL, 5 equiv) was added to the solution with swirling for
30 min at ambient temperature. The precipitate was filtered
under nitrogen affording the title compound 22$HCl as a
colourless powder (808 mg, 35%); mp 85–86 8C; nmax
(nujol)/cmK1 3399, 2921, 5852, 2612, 1729, 1562, 1503,
1462, 1378, 1332, 1312, 1202, 1122, 1018; 1H NMR
(400 MHz, CDCl3) d 4.31 (2H, q, JZ7.2 Hz, OCH2CH3)
5.48 (1H, sept, JZ6.6 Hz, NCH(CH3)2) 3.46 (3H, s, NCH3)
1.50 (6H, d, JZ6.6 Hz, NCH(CH3)2) 1.36 (3H, t, JZ7.2 Hz,
OCH2CH3); 13C NMR (125 MHz, CDCl3) d 154.2 (C) 64.1
(CH2) 54.6 (CH) 35.9 (CH3) 17.8 (CH3) 14.3 (CH3); m/z
(ES) [MCH–HCl]C161 (90%) 119 (60) 115 (100); HRMS
(ES) (found 161.1286 [MCH–HCl]C; C7H16N2O2 requires
161.1285).
5.1.9. N-Isopropylidene-N0-methanesulfonylhydrazone
hydrochloride. Methanesulfonylhydrazide hydrochloride
(400 mg, 3.5 mmol) was stirred in an excess of acetone
(20 mL) at room temperature for 24 h. The solvent was
removed in vacuo and the solid residue was recrystallised
twice from ethanol/ether to give the title compound as a
colourless solid (824 mg, 64%); mp 120 8C dec; nmax (nujol
mull)/cmK1 3410, 1977, 1672 (C]N), 1462, 1351 (SO2),
1165 (SO2), 784; 1H NMR (250 MHz, CDCl3) d 7.5 (1H, s,
SO2NH), 3.05 (3H, s, CH3), 2.0 (3H, s, CH3), 1.8 (3H, s,
CH3); 13C NMR (100 MHz, CDCl3) d 157.74 (C) 38.59
(CH3) 25.70 (CH3) 17.56 (CH3).
5.1.10. Methanesulfonic acid N0-isopropyl hydrazide
21$HCl. To a stirred solution of N-isopropylidene-N0-
methanesulfonylhydrazone
hydrochloride
(0.4 g,
2.14 mmol) in methanol (3 mL) was added a solution
NaCNBH3 in THF (1 M, 2.14 mL, 2.14 mmol) at room
temperature, followed by 2 M HCl at a rate sufficient to
maintain a pH of 2–3. After 10–15 min the pH changed less
rapidly and the mixture was allowed to stir for an additional
3 h. The pH was lowered to 1 and the volatiles were
removed under reduced pressure. The resulting residue was
taken up in water (10 mL) and the pH adjusted to 8 with
20% K2CO3 and extracted with ether (6!20 mL). The
ethereal extracts were dried (MgSO4) and concentrated to
afford an oil, which was dissolved in ether (10 mL) and the
solution was treated with 2 M HCl in ether to give a solid,
which was recrystallised from ethanol/ether to afford the
title compound 21$HCl as a colourless solid (54 mg, 13%);
mp 100–103 8C; nmax (nujol mull)/cmK1 1942, 1562, 1462,
1
1348 (SO2), 1175 (SO2), 795, 779; H NMR (400 MHz,
5.1.13. Benzoic acid N0-isopropyl-N-methylhydrazine
hydrochloride 23$HCl. Benzoyl chloride (817 mg,
5.8 mmol, 0.67 mL) was added drop wise to a stirred
solution of N-isopropylidene-N0-methylhydrazine (500 mg,
5.8 mmol) in dichloromethane (5 mL) and saturated sodium
bicarbonate solution (5 mL) at 0 8C. After addition the
reaction mixture was allowed to warm to ambient
temperature and stirred for 18 h. The organics were
separated and the aqueous layer extracted with dichloro-
methane (2!10 mL). The combined organics were dried
(Na2SO4) and concentrated under reduced pressure. The
organics were added to a nitrogen flushed flask charged with
platinum oxide (66 mg, 0.29 mmol, 5 mol%) in ethanol
D2O) d 3.42 (1H, sept, JZ6.5 Hz, CH(CH3)2), 3.1 (3H, s,
CH3), 1.14 (6H, d, JZ6.5 Hz, CH(CH3)2); 13C NMR
(100 MHz, D2O) d 54.5 (CH) 39.8 (CH3) 16.9 (CH3).
5.1.11. N-Isopropylidene-N0methylhydrazine. Methyl
hydrazine (13.6 g, 295 mmol, 15.7 mL) was added drop
wise to acetone (23.7 g, 409 mmol, 30 mL) maintaining the
reaction temperature below 35 8C. The solution was stirred
for 1 h after which the top layer was removed and allowed to
stand over potassium hydroxide (5 g) for a further 1 h. The
upper liquid was decanted from the lower aqueous layer and
allowed to stand over two successive portions of potassium
hydroxide (2!2.5 g) for 30 min each. Purification was by

J. L. Cavill et al. / Tetrahedron 62 (2006) 410–421
419
(12 mL) and acetic acid (6 mL). The atmosphere was
replaced with hydrogen and the reaction stirred for 16 h at
ambient temperature. The reaction mixture was filtered over
Celitew and the filtrate was neutralised with saturated
sodium bicarbonate solution (180 mL). The single phase
solution was extracted with diethyl ether (3!50 mL) and
the combined organics were washed with brine (20 mL),
dried (MgSO4) and the volatiles were removed under
reduced pressure resulting in a clear oil, which was purified
by flash column chromatography eluting with diethyl ether
in light petroleum 1:1. The volume of elutent was reduced
and ethereal hydrochloric acid (1 M, 13.0 mmol, 13 mL,
5 equiv) was added to the solution with swirling for 30 min
at ambient temperature. The precipitate was filtered under
nitrogen affording the title compound 23$HCl as a colour-
less solid (150 mg, 11%); mp 145–146 8C; nmax (nujol)/cmK1
3408, 2923, 2091, 1638, 1460, 1377, 1333, 1122, 1077; 1H
NMR (400 MHz, CDCl3) d 7.51 (2H, d, JZ8.0 Hz, o-Ar)
7.49, (1H, d, JZ7.1 Hz, p-Ar) 7.42 (2H, dd, JZ8.0, 7.1 Hz,
m-Ar) 3.94 (1H, sept, JZ6.6 Hz, NCH(CH3)2) 3.61 (3H, s,
NCH3) 1.51 (6H, d, JZ6.6 Hz, NCH(CH2)3); 13C NMR
(100 MHz, CDCl3) d 170.8 C) 132.3 (Ar) 130.7 (Ar) 128.9
(Ar) 128.2 (Ar) 53.7 (CH3) 38.6 (CH) 18.0 (CH3); m/z (ES)
[MCH–HCl]C193 (72%) 151 (100%); HRMS (ES) (found
193.1336 [MCH–HCl]C; C11H17N2O requires 193.1335).
(CH3) 24.5 (CH3) 19.5 (CH3) 14.6 (CH3); m/z (APcI) [MC
H]C201 (100%); HRMS (ES) (found 201.1597 [MCH]C;
C10H21N2O2 requires 201.1598).
5.1.16. N-tButyl-N0-isopropylhydrazinecarboxylic acid
ethyl ester 24. Platinum oxide (28 mg, 0.12 mmol,
5 mol%) was placed in a nitrogen flushed flask with ethanol
(6 mL) and acetic acid (3 mL). N-tert-butyl-N0-isoproyl-
idene-hydrazinecarboxylic acid ethyl ester (500 mg,
2.50 mmol) was added, the flask was charged with hydrogen
and stirring was continued for 24 h at ambient temperature.
The reaction mixture was filtered over Celitew and the
filtrate was neutralised with saturated sodium bicarbonate
solution (25 mL), which caused the product to precipitate.
The suspension was extracted with diethyl ether (5!
15 mL) and the combined organic extracts were washed
with brine, dried (MgSO4) and reduced in vacuo to give the
title compound 24 (467 mg, 93%) as a colourless oil; nmax
(liquid film)/cmK1 3314, 2971, 1702, 1467, 1396, 1367,
1308, 1250, 1223, 1168, 1081; 1H NMR (400 MHz, CDCl3)
d 4.09 (2H, q, JZ7.1 Hz, OCH2CH3) 3.80 (1H, br s, NH)
3.01 (1H, sept, JZ6.4 Hz, NCH(CH3)2) 1.28 (9H, s,
NC(CH3)3) 1.22 (3H, t, JZ7.1 Hz, OCH2CH3) 0.92 (6H,
d, JZ6.4 Hz, NCH(CH3)2); 13C NMR (100 MHz, CDCl3) d
158.3 (C) 61.2 (CH2) 58.9 (CH3) 50.6 (CH) 29.0 (CH3) 21.3
(CH3) 20.8 (CH3) 14.5 (CH3); m/z (APcI) [MCH]C203
(100%); HRMS (ES) (found 203.1756 [MCH]C;
C10H23N2O2 requires 203.1754).
5.1.14. N-tButyl-N0-isopropylidenehydrazine. tert-Butyl-
hydrazine dihydrochloride (10 g, 80 mmol, 1 equiv) was
added to acetone (4.66 g, 80 mmol, 5.89 mL, 1.0 equiv)
maintaining the temperature under 35 8C. Potassium
hydroxide (5 g) was added the mixture stirred for 1 h. The
liquid portion was decanted from the solid residue and
allowed to stand over two successive portions of potassium
hydroxide (5 g) for 1 h each. The clear colourless liquid was
purified by distillation (4 mbar, 40–41 8C) affording the title
compound (6.60 g, 64%); nmax (liquid film)/cmK1 3418,
3265, 2972, 1705, 1441, 1385, 1361, 1279, 1237, 1116; 1H
NMR (400 MHz, CDCl3) d 3.98 (1H, br s, NH) 1.70 (3H, s,
N]C(CH3)2) 1.49 (3H, s, N]C(CH3)2) 0.95 (9H, s,
NHC(CH3)3); 13C NMR (125 MHz, CDCl3) d 144.2 (C)
53.0 (C) 28.6 (CH3) 25.5 (CH3) 15.3 (CH3); m/z (APcI)
[MCH]C129 (100%).
Treatment with dry ethereal HCl gave the corresponding salt
24$HCl as a colourless solid; mp 115–117 8C; nmax (nujol)/
cmK1 2924, 2853, 1732, 1541, 1464, 1376, 1290; 1H NMR
(400 MHz, CDCl3) d 10.50 (2H, br s, NH2) 4.26 (2H, q, JZ
7.1 Hz, OCH2CH3) 3.69 (1H, sept, JZ6.6 Hz, NCH(CH3)2)
1.61 (9H, s, NC(CH3)3) 1.46 (6H, br s, NCH(CH3)2) 1.32
(3H, t, JZ7.1 Hz, OCH2CH3); 13C NMR (100 MHz,
CDCl3) d 156.0 (C) 64.4 (CH2) 62.3 (C) 57.6 (CH) 29.0
(CH3) 18.5 (CH3) 14.3 (CH3); m/z (APcI) [MCH]C203
(100%); HRMS (ES) (found 203.1753 [MCH–HCl]C;
C10H23N2O2 requires 203.1754).
5.1.17. Typical experimental procedure for catalytic
runs. trans-Cinnamaldehyde 8 (252 mg, 1.9 mmol,
0.24 mL, 1.0 equiv) was added to a solution of catalyst
(10 mol%, 0.19 mmol) in methanol (2.0 mL) at 25 8C and
the resulting mixture was stirred for 5 min to initiate
iminium ion formation. Freshly cracked cyclopentadiene 7
(323 mg, 4.9 mmol, 0.38 mL, 2.5 equiv) was added in a
single aliquot and stirring was continued for 24 h. The
volatiles were removed under reduced pressure and the
resulting organics were hydrolysed in a chloroform (2 mL),
water (1 mL) trifluoroacetic acid (1 mL) mixture over night.
Saturated sodium hydrogen carbonate solution (18 mL) was
added to neutralise the solution and the aqueous phase was
extracted with dichloromethane (2!20 mL). The combined
organics were washed with water (10 mL) and dried
(Na2SO4) prior to the removal of the volitiles under reduced
pressure. 1H NMR of the crude reaction mixture was used to
establish the conversion to the products and exo:endo ratios
through the integration of aldehyde peaks at: dH (400 MHz,
CDCl3) 9.8 (exo) 9.65 (cinnamaldehyde) 9.53 (endo). The
products were then purified by flash column chromato-
graphy eluting with 10% ethyl acetate in light petrol
5.1.15. N-tButyl-N0-isoproylidenehydrazinecarboxylic
acid ethyl ester. To a suspension of N-tert-butyl-N0-
isopropylidene-hydrazine (1.00 g, 7.80 mmol, 1.0 equiv)
in dichloromethane (10 mL) at 0 8C was added saturated
sodium bicarbonate solution (10 mL). Ethyl chloroformate
(1.02 g, 9.36 mmol, 0.89 mL, 1.2 equiv) was added drop
wise to the suspension and stirring was continued at 0 8C for
30 min and at ambient temperature overnight. The organic
layer was separated and the aqueous layer extracted with
dichloromethane (2!5 mL). The combined organics were
dried (Na2SO4) and the volatiles removed in vacuo to give a
yellow oil. Purification by flash chromatography eluting
with diethyl ether in light petroleum 1:1 afforded the title
compound (662 mg, 64%) as a colourless oil; nmax (liquid
film)/cmK1 2975, 2923, 1698, 1652, 1482, 1456, 1393,
1
1367, 1304, 1257, 1224, 1170, 1086; H NMR (400 MHz,
CDCl3) d 3.91 (2H, q, JZ7.1 Hz, OCH2CH3) 1.91 (3H, s,
NC(CH3)2) 1.71 (3H, s, NC(CH3)2) 1.21 (9H, s, NC(CH3)3)
1.04 (3H, t, JZ7.1 Hz, OCH2CH3); 13C NMR (100 MHz,
CDCl3) d 175.0 (C) 153.6 (C) 60.8 (CH2) 58.3 (CH2) 28.2

420
J. L. Cavill et al. / Tetrahedron 62 (2006) 410–421
12. Cavill, J. L.; Peters, J.-E.; Tomkinson, N. C. O. Chem.
Commun. 2003, 728.
resulting in a mixture of the exo- and endo-isomers of
3-phenyl-bicyclo[2.2.1]hept-5-ene-2-carboxaldehyde 9 and
1
10 as a pale yellow oil. H NMR, 13C NMR and IR data
13. For selected examples using these catalysts see: (a) Notz, W.;
List, B. J. Am. Chem. Soc. 2000, 122, 7386. (b) List, B.;
Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122,
2395. (c) Mangion, I. K.; Northrup, A. B.; MacMillan,
D. W. C. Angew. Chem., Int. Ed. 2004, 43, 6722. (d)
Ramachary, D. B.; Barbas, C. F., III Chem. Eur. J. 2004, 10,
5323. (e) Pulkkinen, J.; Aburel, P. S.; Halland, N.; Jørgensen,
K. A. Adv. Synth. Catal. 2004, 1077. (f) Betancort, J. M.;
Sakthivel, K.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F.,
III Synthesis 2004, 1509. (g) Saito, S.; Nakadai, M.;
Yamamoto, H. Synlett 2001, 1245.
were consistent with previously reported literature values;35
nmax (liquid film)/cmK1 1718, 1601, 1497; exo-10; 1H NMR
(400 MHz, CDCl3) d 9.85 (1H, d, JZ2.02 Hz, CHO) 7.4–
7.0 (5H, m, ArH) 6.27 (1H, dd, JZ5.63, 3.61 Hz, CH]CH)
6.01 (1H, dd, JZ5.62, 3.64 Hz, CH]CH) 3.66 (1H, dd, JZ
5.03, 3.42 Hz, CHPh) 3.25–3.05 (2H, m, CHCH2) 2.55–2.45
1
(1H, m, CHCHO) 1.65–1.45 (2H, m, CH2); endo-9; H
NMR (400 MHz, CDCl3) d 9.53 (1H, d, JZ2.16 Hz, CHO)
7.4–7.0 (5H, m, ArH) 6.36 (1H, dd, JZ5.63, 3.61 Hz,
CH]CH) 6.10 (1H, dd, JZ5.62, 3.64 Hz, CH]CH) 3.26
(1H, m, CHPh) 3.05 (1H, m, CHCH2) 3.01 (1H, m, CHCH2)
2.91 (1H, m, CHCHO) 1.49 (2H, m, CH2); m/z (EI)
[M]C198 (10%) 132 (89) 131 (100) 103 (52) 77 (21) 66
(54).
14. (a) Grekov, A. P.; Veselov, V. Y. Russ. Chem. Rev. 1978, 16,
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Acknowledgements
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The authors wish to express their gratitude to the EPSRC,
the UK Computational Chemistry Facility for a generous
grant of time on the Columbus central facility and The Mass
Spectrometry Service, Swansea for high resolution spec-
tra.This work was sponsored by EPSRC under grant ref.
GR/S69337/01.
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