Bromenium-catalysed tandem ring opening/cyclisation of vinylcyclopropanes and vinylcyclobutanes: A metal-free [3+2+1]/[4+2+1] cascade for the synthesis of chiral amidines and computational investigation

Article abstract of DOI:10.1002/chem.201103556

We present a detailed study of a [3+2+1] cascade cyclisation of vinylcyclopropanes (VCP) catalysed by a bromenium species (Br ^δ+-X^δ-) generated in situ, which results in the synthesis of chiral bicyclic amidines in a tandem one-pot operation. The formation of amidines involves the ring-opening of VCPs with Br-X, followed by a Ritter-type reaction with chloramine-T and a tandem cyclisation. The reaction has been further extended to vinylcyclobutane systems and involves a [4+2+1] cascade cyclisation with the same reagents. The versatility of the methodology has been demonstrated by careful choice of VCPs and VCBs to yield bicyclo[4.3.0]-, -[4.3.1]- and -[4.4.0]amidines in enantiomerically pure form. On the basis of the experimental observations and DFT calculations, a reasonable mechanism has been put forth to account for the formation of the products and the observed stereoselectivity. We propose the existence of a π-stabilised homoallylic carbocation at the cyclopropane carbon as the reason for high stereoselectivity. DFT studies at B3LYP/6-311+G** and M06-2X/6-31+G* levels of theory in gas-phase calculations suggest the ring-opening of VCP is initiated at the π-complex stage (between the double bond and Br-X). This can be clearly perceived from the solution-phase (acetonitrile) calculations using the polarisable continuum model (PCM) solvation model, from which the extent of the ring opening of VCP was found to be noticeably high. Studies also show that the formation of zero-bridge bicyclic amidines is favoured over other bridged bicyclic amidines. The energetics of competing reaction pathways is compared to explain the product selectivity. Copyright

Full text of DOI:10.1002/chem.201103556

FULL PAPER
DOI: 10.1002/chem.201103556
Bromenium-Catalysed Tandem Ring Opening/Cyclisation of
Vinylcyclopropanes and Vinylcyclobutanes: A Metal-Free [3+2+1]/[4+2+1]
AHCTUNGTRENNUNG
Cascade for the Synthesis of Chiral Amidines and Computational
Investigation
Venkataraman Ganesh,[a] Devarajulu Sureshkumar,[a] Debasree Chanda,[a] and
Srinivasan Chandrasekaran*[a, b]
Abstract: We present a detailed study
of a [3+2+1] cascade cyclisation of vi-
nylcyclopropanes (VCP) catalysed by a
À
to yield bicyclo
[4.3.0]-, -[4.3.1]- and
311+G** and M06-2X/6-31+G* levels
of theory in gas-phase calculations sug-
gest the ring-opening of VCP is initiat-
ed at the p-complex stage (between the
-[4.4.0]amidines in enantiomerically
pure form. On the basis of the experi-
mental observations and DFT calcula-
bromenium species (Brd+
X
dÀ) gener-
À
ated in situ, which results in the synthe-
sis of chiral bicyclic amidines in a
tandem one-pot operation. The forma-
tion of amidines involves the ring-
tions,
a
reasonable mechanism has
double bond and Br X). This can be
been put forth to account for the for-
mation of the products and the ob-
served stereoselectivity. We propose
the existence of a p-stabilised homoal-
lylic carbocation at the cyclopropane
carbon as the reason for high stereose-
lectivity. DFT studies at B3LYP/6-
clearly perceived from the solution-
phase (acetonitrile) calculations using
the polarisable continuum model
(PCM) solvation model, from which
the extent of the ring opening of VCP
was found to be noticeably high. Stud-
ies also show that the formation of
zero-bridge bicyclic amidines is fav-
oured over other bridged bicyclic ami-
dines. The energetics of competing re-
action pathways is compared to explain
the product selectivity.
À
opening of VCPs with Br X, followed
by a Ritter-type reaction with chlora-
mine-T and a tandem cyclisation. The
reaction has been further extended to
vinylcyclobutane systems and involves
a [4+2+1] cascade cyclisation with the
same reagents. The versatility of the
methodology has been demonstrated
by careful choice of VCPs and VCBs
Keywords: bromine · chirality · cyc-
lization · vinylcyclobutanes · vinyl-
cyclopropanes
Introduction
cyclohexene,[2] transition-metal-catalysed rearrangements,[3]
Lewis/Brønsted acid mediated[4] and free-radical-mediated[5]
ring-opening reactions and cycloaddition reactions.[6] Re-
cently, transition-metal-catalysed cycloaddition reactions of
VCPs have attracted enormous interest due to their utility
in the synthesis of large ring systems in a single step. There
are many reports that explore the reactivity of vinylcyclo-
propanes that involve [3+2], [5+2] and [5+2+1] cycloaddi-
tion reactions.[3,7,8] The presence of a p-bond adjacent to a
strained cyclopropane ring enables its versatility in reactivi-
ty. Due to the weak interaction between the p-orbitals of
the double bond and the s-orbital of the cyclopropane, any
reaction on the double bond has a significant influence on
Vinylcyclopropanes (VCPs) and vinylcyclobutanes (VCBs)
are versatile synthons that cover a large sphere of synthetic
applications and thus are useful in the construction of com-
plex molecular skeletons.[1] The importance of VCPs in ach-
ieving synthetic objectives and its impact on the develop-
ment of novel methodologies is evident from the literature.
A plethora of literature reports are available on the study of
thermal rearrangement of VCP to cyclopentene and VCB to
[a] V. Ganesh,+ Dr. D. Sureshkumar,+ D. Chanda,
Prof. S. Chandrasekaran
À
the cyclopropane C C bond. This can be considered an indi-
Department of Organic Chemistry
Indian Institute of Science
Bangalore, 560 012 (India)
Fax : (+91)80-2360-2423
E-mail: scn@orgchem.iisc.ernet.in
À
rect activation of the C C bond by activating the double
bond. This very nature of VCP has attracted the attention of
theoretical chemists to understand and scale the interactions
involved in its reactivity.[9]
Eschenmoser amidine,[10] 1,8-diazabicyclo
ACHTUNGTRENNUNG
[b] Prof. S. Chandrasekaran
Jawaharlal Nehru Centre for
Advanced Scientific Research
Jakkur, Bangalore, 560 064 (India)
ene (DBU) and 1,5-diazabicycloACHTNUGTRENNUNG
the benchmark examples of amidines as bases, which are
used widely in organic synthesis.[11] This family of com-
pounds is considered to be organic superbases, and a variety
of transformations[12] such as acetoxybromination, aldol-type
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103556.
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Scheme 1. General synthesis of chiral [4.3.0]-, [4.3.1]- and [4.4.0]amidines
from VCPs and VCBs.
condensation, dehydrohalogenation, the Baylis–Hillman re-
action, the Michael reaction and the Wittig reaction have
been demonstrated to be catalysed by these superbases. Var-
ious other applications in enantioselective catalysis,[11,13] as
proton sponges, in molecular recognition[14] and drug discov-
ery are prominent.[15] Despite the wide range of applications,
short and efficient synthetic methods to amidines are fairly
scarce and are quite challenging. The challenges involved in
the synthesis of chiral bicyclic amidines that employ a
simple route have been highlighted.[14c,16]
in the formation of chiral bicyclic amidines in excellent
yields (Scheme 1).
In the earlier report, we presented the reaction of 3a with
chloramine-T and phenyltrimethylammonium bromide di-
bromide (PTAB; 10 mol%) in acetonitrile to furnish the de-
sired amidine 4aa in 82% yield.[17] By using the optimised
reaction conditions, a variety of VCPs were converted to the
corresponding optically active bicyclic amidines, 4aa–4 fd
(Table 1). The reaction was shown to work efficiently even
in the case of sterically and electronically demanding sub-
Results and Discussion
Table 1. Reaction of VCP derivatives with various nitriles as solvent.[a]
In a recent communication,
we demonstrated that VCPs
under electrophilic conditions
undergo a multi-component
reaction (MCR) to yield
chiral bicyclic amidines in an
efficient manner.[17] In the
present report, we describe
comprehensive details of our
endeavour toward transition-
metal-free [3+2+1] cascade
cyclisation of vinylcyclopro-
panes toward the synthesis of
bicyclic [4.x.x]amidines and
an important extension of
this reaction to a [4+2+1]-
type cascade reaction of vi-
nylcyclobutane
derivatives
(Scheme 1). Detailed mecha-
nistic conclusions have been
derived that are strongly sup-
ported by experimental and
computational models. The
reaction conditions involve
the treatment of vinylcyclo-
propanes/vinylcyclobutanes
with chloramine-T and a hal-
ogen-based catalyst in aceto-
nitrile as solvent that results
[a] Reaction conditions: VCP (3 mmol), chloramine-T (3.3 mmol), PTAB (0.3 mmol), solvent (15 mL), 5–7 h,
RT. Yield is of the isolated product. Ts=p-toluenesulfonyl; PFP=pentafluorophenyl.
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Vinylcyclopropanes and Vinylcyclobutanes
FULL PAPER
strates. When the reaction was performed in the presence of
electron-deficient nitriles such as pentafluorobenzonitrile
(PFP-CN), it led to the expected amidine 4ad, albeit in low
yield (25%; Table 1). Successful synthesis of cyclopropyl-
and pentafluorophenyl (PFP)-substituted amidines 4ac and
4ad indicated the possibility of using cyclopropyl and fluo-
rine substituents as important pharmacophores in drug dis-
covery. The reaction of trans- and cis-4-carenes 3b and 3c,
which led to the anticipated amidines 4ba and 4ca, respec-
tively, in good yield, demonstrated the generality of this re-
action. Further, the reaction was explored with substrates
that bear common functional groups like hydroxyl and keto
groups so as to assess the scope and limitations of the reac-
tion. When 2-caren-3-ol 3d, 3-acetyl-2-carene 3e[18] and 1-
(car-2-en-3-yl)ethanol 3 f were treated with 1 and 2 in butyr-
onitrile, it resulted in the successful formation of the corre-
sponding amidines 4da, 4ea and 4 fa, respectively, in 78–
87% yields. The reaction was further extended in the pres-
ence of other nitriles to obtain amidines 4da–dd, 4ea–ec
and 4 fa–fd in excellent yields (Table 1).
from the N-chloro intermediate Id to form Ie. Intermediate
Ie undergoes intramolecular cyclisation by means of an al-
lylic substitution pathway to yield the desired amidine 4aa.
To confirm the existence of intermediate Ie, the reaction
was carried out in an EtCN/H2O mixture so as to trap inter-
mediate Ie in its protonated form (Scheme 3). Accordingly,
upon treatment with 1 and 2 in EtCN/H2O (2:1), carene 3a
led to the expected protonated compound 5a (35%), which
resulted from the proposed intermediate Ie in addition to
4af (43%).
Scheme 3. Control experiment to determine the intermediate during cyc-
lisation.
A plausible mechanistic pathway has been proposed that
would best explain the formation of product 4aa from VCP
3a (Scheme 2). On the basis of the experimental observa-
Since the key step of the reaction is presumed to involve
carbocationic intermediate Ib, the groups that stabilise the
incipient carbocation would accelerate the ring-opening
process. Hence, modifying the substituents on the cyclopro-
pane ring would have a remarkable effect in the reactivity.
Thus, to study the limitations of the methodology, we chose
a variety of vinylcyclopropanes that are electronically and
sterically diverse. The choice of the substituents is restricted
largely due to the synthetic challenges involved in arriving
at the desired VCPs. Since the dialkyl-substituted VCPs like
2-carenes 3a–f reacted with chloramine-T and PTAB in ni-
triles satisfactorily, we went one step further to explore the
effect of phenyl substitution and monoalkyl substitution on
the cyclopropane in the ring opening of VCPs. The phenyl-
substituted VCP 3g was synthesised following the procedure
reported by Davies et al.;[20] it involved the cyclopropana-
tion of 1,3-cyclohexadiene with a-phenyldiazoacetate fol-
lowed by the reduction of ester functionality with LiAlH4.[17]
Compound 3g was treated with chloramine-T and PTAB in
acetonitrile under the standard rearrangement conditions.
After 7 h, the reaction successfully yielded the desired bicy-
clic amidine 4ga in good yield (72%) and with excellent dia-
stereoselectivity
(diastereomeric
ratio
(d.r.)>95:5)
(Scheme 4). Analysis of H,1H COSY, heteronuclear multi-
ple quantum correlation (HMQC) and NOESY spectra re-
vealed a complete inversion at the phenyl-substituted cyclo-
propane carbon centre. This supports the existence of an in-
timate carbocation ion pair (or delocalised charge) rather
than a free carbocation. This observation is supported by
the pioneering work of Cram on the stereochemical course
of solvolysis in strained ring systems and number of other
reports that appeared recently.[21]
1
Scheme 2. Proposed catalytic cycle for the formation of 4aa from 3a.
tions[19a] and earlier studies reported by Sharpless et al.,[19]
we strongly believe that the reaction involves in situ genera-
À
tion of Br X (X=Cl, Br or any nucleophile) as an active
catalyst, thereby resulting in the formation of p-complex Ia
À
with the VCPs. This in turn activates the C C bond of the
cyclopropane towards ring opening regioselectively. The p-
stabilised homoallylic carbocation Ib thus formed is
quenched by acetonitrile to generate Ic followed by the
attack of chloramine-T in a domino fashion to give the N-
chloro intermediate Id. The bromide ion present in the
medium facilitates the expulsion of the chlorenium species
We were also interested in exploring the reactivity of
mono-substituted VCPs, in which the stabilisation of the
proposed incipient carbocation will be less than the gem-di-
alkyl-substituted or the phenyl-substituted cases. Mono-sub-
stituted VCPs 3h and 3i were prepared following the proce-
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S. Chandrasekaran et al.
was then extended to other nitriles (Table 2) to check the
consistency in the reactivity. As anticipated, VCP 3a gave
the corresponding amidines in good yields. Similarly, chlora-
mine-Cbz B was allowed to react with VCP 3a in cycloprop-
yl cyanide, butyronitrile and benzonitrile as solvent, and the
reaction furnished the corresponding Cbz-protected ami-
dines 4aaB–acB in good yields (73, 73 and 69%, respective-
ly).
Since amidines in the unprotected form are utilised in
enantioselective catalysis and as chiral bases, we demon-
strated the deprotection of Cbz and Boc groups under mild
conditions.[17] The deprotection of the Cbz group in 4acB
was carried out under basic conditions (40% KOH/MeOH)
and led to the formation of free amidine 7a in 63% yield.
Similarly, the Boc group from 4aaA was easily deprotected
with 50% v/v trifluoroacetic acid in CH2Cl2 (08C to RT, 7 h)
to furnish 7b in 76% yield (Scheme 5).
In the case of VCPs that bear free hydroxyl groups (3d
and 3e) under the same reaction conditions, the reagents A
and B were found to be quenched by protonation, thereby
Scheme 4. Effect of substitution on the ring-opening/cyclisation reaction
of VCPs with chloramine-T.
Table 2. Reaction of VCP derivatives with chloramines A and B.
dure reported by Guha et al.,[22] starting with the
cyclopropanation of 1,3-cyclohexadiene using
methyl diazoacetate with copper powder as catalyst
followed by reduction with LiAlH4 (see the Sup-
porting Information).[22] Surprisingly, when mono-
substituted VCPs 3h and 3i were treated with
chloramine-T and PTAB in acetonitrile, the reac-
tion led to the formation of corresponding aziri-
dines 6a and 6b as the major products and the cy-
clopropane ring was found to be intact (Scheme 4).
This can be attributed to the poor stabilisation of
the incipient carbocationic species offered by the
monoalkyl substituents. The bromonium ion formed
leads to the formation of the corresponding aziri-
dine through a classical aziridination pathway re-
ported by Sharpless et al.[19b]
À
Chiral amidines with free N H have a wide
scope as organocatalysts and chiral bases, which en-
couraged us to attempt the deprotection of the
tosyl group. Various efforts to deprotect the tosyl
(p-toluenesulfonyl) group were unsuccessful (HBr/phenol,
SmI2/Et3N). Hence, we made an effort to replace the tosyl
group with easily deprotectable groups (such as t-butyloxy-
carbonyl (Boc) and carbobenzyloxy (Cbz)) at the reagent
stage itself. Hence, chloramine-Boc A and chloramine-Cbz
B were prepared by chlorination of the corresponding car-
bamate with tBuOCl by using the procedure reported.[23]
Since the expulsion of electrophilic chlorine in chloramines
largely depend on the electron-withdrawing ability of the
groups attached to nitrogen, replacement of a sulfonyl
group with a carbamate was expected to have a profound
effect on the reactivity. Keeping this in mind, VCP 3a was
treated with chloramine-Boc A and PTAB in MeCN under
similar reaction conditions (RT, 7 h) to obtain the desired
Boc-protected amidine 4aaA in 86% yield. The reaction
Scheme 5. Deprotection of Cbz and Boc groups.
resulting in the formation of t-butylcarbamate (BocNH2)
and benzylcarbamate (CbzNH2) (Scheme 6). However, the
reaction of A was successful when the hydroxyl group of
VCP was protected as its benzyl ether (3j), which afforded
the expected amidine 4jaA in 82% yield (Table 2). Al-
though chloramine-Boc A reacts with VCPs 3a and 3j in
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Vinylcyclopropanes and Vinylcyclobutanes
FULL PAPER
has also been demonstrated with pinene derivatives (4laA
and 4laB; Table 4).
A mechanistic proposal similar to the one envisaged earli-
er has been put forth for the formation of 4la from 3l
À
(Scheme 7). Br X (X=Cl, Br or any nucleophile), the
active catalyst formed in situ during the reaction, becomes
involved in p-complexation with VCB 3l to furnish inter-
Table 3. Synthesis and reaction of five-membered fused VCP 3k with 1, A
and B.
Entry
Reactant
Solvent Reagent
Product
Yield
[%]
Scheme 6. Unexpected reactivity of chloramines A and B with VCPs.
1
MeCN
1
1
92
91
81
81
acetonitrile as expected, when treated with VCPs 3a and 3j,
chloramine-Cbz B in acetonitrile led to the unexpected for-
mation of diamine-substituted products 8a and 8b, respec-
tively (Scheme 6). This prompted us to investigate further
the mechanistic pathway towards the formation of amidines.
The reaction was then extended to the study of five-mem-
bered VCPs that were easily synthesised from 2-carene
3a.[17,24] Vinylcyclopropane 3k was treated with chloramine-
T and PTAB in acetonitrile to furnish the expected product
4ka in 92% yield. The methodology was consistent with
other nitriles such as cyclopropyl cyanide and benzonitrile
to lead to the corresponding amidines 4kb and 4kc in 91
and 81% yield, respectively. Even with chloramine-Boc and
-Cbz (A and B), in acetonitrile and cyclopropyl nitrile as
solvent the reaction successfully yielded the expected ami-
dines 4kaA and 4kbB in excellent yields (Table 3).
2
3
4
3k
3k
3k
PhCN
1
MeCN
A
5
3k
B
83
Although the stability of the incipient carbocation is the
key to the ring-opening process, the extent of ring strain is
the driving force for the ring-opening reaction. This
idea led us to explore the reactivity of vinylcyclobu-
Table 4. Reaction of vinylcyclobutane derivatives with chloramine-T and PTAB.
tanes under the same reaction conditions. From the
study, it was anticipated that bicyclic vinylcyclobu-
tanes (VCBs) such as pinenes would also undergo a
[4+2+1] cascade cyclisation under similar condi-
tions to that of 2-carene derivatives.
When a-(+)-pinene 3l was treated with chlora-
mine-T and PTAB in acetonitrile (RT, 5 h), as ex-
pected the reaction proceeded to afford bicyclo-
ACHTUNGTRENNUNG[4.3.1]amidine 4la in 45% yield and another prod-
uct 9 (15%) (which resulted from elimination)
(Table 4). Lower yields and the formation of con-
siderable amounts of eliminated products might be
due to the formation of an unfavourable [6,7]-fused
bicyclic framework. The structure of compound 4la
was confirmed by X-ray crystallographic analysis
(Figure 1). The reaction was then carried out with
various nitriles as solvent to obtain bicyclic ami-
dines (4la–le) in moderate yield. Protected deriva-
tives of myrtenol 3m and nopol 3n under similar
conditions underwent smooth ring-opening/cyclisa-
tion, thus leading to the formation of 4ma (48%),
4na (42%) and 4nb (47%), respectively. The reac-
tivity of chloramine-Boc A and chloramine-Cbz B
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S. Chandrasekaran et al.
tion of our manuscript, an article on the N-bromosuccini-
mide-initiated one-pot synthesis of imidazolines from a-
pinene by Yeung et al.[25] reported a serendipitous formation
of compound 4la and its X-ray crystal structure. But the re-
action was not explored further. In their article, 4la was re-
ported to adopt P21/c space group in the crystalline state,
thereby corroborating our observation; however, the prob-
lem of racemisation was not addressed. Here we provide
evidence for the formation of both the enantiomers of 4la
(enantiomeric ratio (e.r.) 65:35) in the case of a-pinene 3l
(chiral HPLC; see the Supporting Information). This kind
of partial racemisation was not observed in the case of vinyl-
cyclopropanes.
The problem of the partial racemisation of 4la can be ex-
plained on the basis of the reactivity of nitrogen anion IIe.
Once the nitrogen anion IIe is formed, it is capable of cyclis-
ing in two different pathways to lead to the product 4la.
The conventional “allylic substitution” of the bromide in IIe
will lead to one stereoisomer and a direct substitution of the
bromide will lead to the same product but the other enan-
tiomer. These two similar competing pathways would result
in partially racemised product 4la (Scheme 8)
Figure 1. X-ray crystal structure of compound 4la and 4ld.
This racemisation is due to the symmetry acquired during
the cyclisation of the anionic intermediate IIe by equally
feasible pathways. Hence, we studied the reactivity of simi-
lar systems that result in a secondary allylic bromide inter-
mediate IIIe but without the possibility of acquiring the
symmetry during the cyclisation (Scheme 9). Formation of
intermediate IIIe can be envisaged from VCP 3o. Cyclisa-
tion of IIIe by the allylic substitution pathway (Scheme 9,
path a) could lead to a bicyclo
substitution pathway (Scheme 9, path b) could lead to
bicyclo[4.2.1]amidine.
ACHTUNGTNER[NUNG 4.3.0]amidine and the direct-
AHCTUNGTRENNUNG
Scheme 7. Proposed catalytic cycle for the formation of 4la from 3l.
À
mediate IIa. This in turn activates the C C bond of the cy-
clobutane towards ring opening, thereby resulting in a tight
carbocation intermediate IIb. The intimate tertiary carboca-
tion IIb thus formed undergoes a Ritter-type reaction with
acetonitrile followed by the attack of chloramine-T in a
domino fashion to give the intermediate IId. The bromide
ion present in the medium facilitates the expulsion of
chlorenium ion from the N-chloro intermediate IId, thus re-
turning to the catalytic cycle as BrCl. The resulting nitrogen
anion IIe cyclises in an SN2’ pathway to form desired ami-
dine 4la.
Scheme 8. Origin of partial racemisation of compound 3l.
Although the structures of 4la and 4ld were unambigu-
ously determined by X-ray crystallography, we observed
that the products obtained from enantiomerically pure a-
(+)-pinene crystallised in P21/c, which is a centrosymmetric
space group. This indicates a possible racemisation of the
product 4la during the reaction. During the recent prepara-
Scheme 9. Allylic- versus direct-substitution pathways in five-membered
VCP 3o.
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Vinylcyclopropanes and Vinylcyclobutanes
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Compound 3o was synthesised from 3-carene by means of
a multi-step transformation (see the Supporting Informa-
tion).[26] When compound 3o was treated under the standard
rearrangement conditions (chloramine-T, 1.1 equiv; PTAB,
10 mol%) in acetonitrile at room temperature, the reaction
the open-chain amidines 11 and 12, respectively, in good
yields. These control experiments are in strong support of
the existence of the proposed intermediates. At this point
we would like to recall our earlier observation in which
VCP 3a, when treated with chloramine-Cbz, resulted in an
open-chain amidine 8a analogous to 12.
furnished bicycloACHTUNGTRENNUNG[4.3.0]amidine 4oa (Table 5) as the only
Computational methods: Calculations were per-
formed using density functional theory (DFT) with
the Gaussian 03[27] and 09 programs.[28] The geome-
tries of all the stationary states were optimised by
using hybrid density functionals, B3LYP (Beckeꢁs
three-parameter exchange with Lee–Parr–Yang cor-
relation functional)[29] and the hybrid meta-GGA
(generalised gradient approximation) functional
using M06-2X.[30] The thermochemical parameters
of the alkene-BrCl complexes were calculated using
the split-valence triple-z B3LYP/6-311+G** level
of theory at 298.15 K, which has been widely used
for these systems previously. The results were com-
pared with the split-valence double-z M06-2X/6-
31+G* level of theory. Harmonic frequencies were
calculated at the same level of theory to character-
ise the intermediates and transition states. The tran-
sition states for the ring-opening reaction were also
modelled at the B3LYP/6-311+G**//B3LYP/6-31G*
and M06-2X/6-31+G* levels of theory. The estimat-
ed geometries of the transition states were obtained
Table 5. Synthesis of bicycloACTHNUGRTNEUNG[4.3.0]amidines from 3o.
product in 90% yield, thus indicating an exclusive prefer-
ence for path a in Scheme 9. The reaction was demonstrated
in various other nitriles under similar conditions and led to
a family of bicycloACHTUNGTRENNUNG[4.3.0]amidines 4ob and 4oc in excellent
yields. The reactivity of chloramine-Boc A and chloramine-
Cbz B has also been demonstrated with this VCP skeleton
(4oaA–4ocA, 4oaB).
In addition, we performed control experiments to under-
stand thoroughly the mechanism of formation of compounds
4aa and 4la. The proposed catalytic cycle involves a Ritter-
type reaction followed by attack of the nucleophile onto the
electrophilic carbon centre (IIc) of acetonitrile to result in
intermediate IId. Subsequently, the formation of nitrogen
anion intermediate IIe that undergoes cyclisation to give
amidines was proposed. We attempted to trap this nitrogen
anion (IIe) in its protonated form. Thus, VCB 3l was treated
with chloramine-T and PTAB in a 1:1 mixture of MeCN/
H2O. Since the intramolecular cyclisation was so rapid, we
were only able to isolate the final amidine 4la as the sole
product. But when the reaction was attempted in a mixture
EtCN/H2O (2:1), the protonated form of intermediate IIe
(10) was isolated successfully in addition to amidine 4lb in
40% yield (Scheme 10).
Scheme 10. Control reactions to trap the intermediates IIc and IId.
by scanning through the bond lengths of the atoms involved
in the reaction site. The reaction profiles of various VCPs
were mapped using the polarisable continuum model (PCM)
solvation model[31] with the continuum dielectrics of acetoni-
trile (e=36.64) at B3LYP/6-311+G**. Default values for
cavitation spheres, atomic radii and the radius of the solvent
Following this, we designed an experiment to suppress the
intramolecular cyclisation by the addition of competitive nu-
cleophiles externally. When the reaction of 3l was carried
out with 1 and 2 and competitive nucleophiles such as azide
or an excess amount of chloramine-T, the reaction furnished
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S. Chandrasekaran et al.
were used as in the UAO model (simple united atom topo-
logical model) and Paulingꢁs model (with spheres explicit
for hydrogen atoms). Similarly, the cyclisation step of the re-
action was modelled at the B3LYP/6-311G** and M06-2X/6-
311G** levels of theory. For the sake of computational sim-
Alkene-halogen p-complexes have been studied exten-
sively by using both experimental[33] and computational
techniques in the literature. Kolbuszewski and Tse have
À
studied the bonding characteristics of ethylene and Br Cl
by using Dunningꢁs double-z basis.[34] Following this, Le-
noirꢁs group has modelled the gas-phase structures of p-
complexes and their charge-transfer characteristics that in-
volve alkenes at the B3LYP/6-311+G** and MP2/6-
311+G** levels of theory.[35] Since structural and thermo-
chemical parameters reported by them for the p-complex
were shown to be in good agreement with the experimental
observations, we have modelled the p-complex of VCPs at
the same level for comparison.
À
plicity, the pendant OBn group in compounds 3k and 3o
has been simplified to a methyl group.
Investigations on the mechanism: From the control experi-
ments, we were able to propose a few possible intermediates
involved in the reaction. An attempt to get a clearer picture
and quantify the feasibility of formation of the proposed in-
termediates led us to investigate further with the help of
quantum chemical calculations. The structures of vinylcyclo-
propane and vinylcyclobutane systems that were considered
for the present study are given in Figure 2.
The gas-phase geometries of complexes Int-1a–Int-4a
(Figure 3), association energies and significant bond lengths
are presented in Table 6. A comparison of the results ob-
Figure 2. VCPs and VCBs and corresponding p-complexes considered for
the computational modelling of the ring-opening steps.
p-Complexation and ring opening of vinylcyclopropanes and
vinylcyclobutane with BrCl: Under the present reaction con-
ditions, by the treatment of VCP in acetonitrile, the active
Figure 3. Energy profile for the p-complex formation followed by ring
opening of VCPs and VCB.
À
À
À
À
Br X (X may be Cl , Br , Nu ) catalyst thus formed will
eventually lead to a charge-transfer p-complex (Scheme 11).
Although various bromenium species are involved in the re-
action, the thermodynamic and kinetic factors favour the ad-
À
tained for VCP p-complexes with that of a model olefin Br
Cl (2-methylbut-2-ene) complex has been made (Table 6) to
examine the extent of perturbation caused on the cyclopro-
pane ring due to the formation of the p-complex. The asso-
À
dition of Br Cl across the double bond exclusively. Kinetic
experiments by Robertson et al. on the p-complexation of
ciation energies (DE) and bond lengths d1ACHTNGUTERNNU(G C=C···Br) (d1 =
À
various halogens and inter-halogen compounds to olefins re-
(C Br bond length)ꢂsin(bond angle A1)8) and Dd2 (elonga-
tion of C=C bond) obtained for VCPs are almost in the
range of the model alkene. However, the Dd3 values suggest
À
vealed that the reactivity of Br Cl is many times higher
than other halogen compounds.[32] Hence, the catalytic cycle
À
À
is believed to run predominantly by consuming the Br Cl
generated during the course of the reaction.
a perturbation in the C C s-bond of cyclopropane and cy-
clobutane towards ring opening; angle A1 (C3-C4-Br) illus-
trates the direction of polarisation (Scheme 12). Angle A1
shows at least 108 deviation in the cases of Int-1a and Int-2a
relative to Int-3a and Int-4a. This can be attributed to the
À
relative stability of the carbocationic centres of the Br Cl
complex (Scheme 12).
Greater stabilisation of the carbocation in the b position
from the cyclopropane relative to the a position could slow
Scheme 11. Ring opening of the vinylcyclopropane–BrCl complex.
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Vinylcyclopropanes and Vinylcyclobutanes
FULL PAPER
Table 6. Association energies of the p-complex and their significant bond lengths.
the p-complex in the gas phase revealed that the
extent of interaction between the p-orbitals and the
[a]
p-Complex
DE(ZPE)
d1
A1
[8]
Dd3
NBO energy[d]
[kcalmolÀ1
]
[ꢃ][b]
[ꢃ][c]
[kcalmolÀ1
]
cyclopropane s(C
is significant (ꢀ4.40–3.17 kcal
À
C)
Model
Int-1a
Int-2a
Int-3a
Int-4a
À6.29
À6.81
2.715
2.713
2.707
2.691
2.758
2.230
2.245
2.006
2.100
71.5
n.a.
n.a.
4.56; 4.40
4.19; 3.17
3.83; 3.86
molÀ1) as a result of complex formation. This clear-
ly shows the initiation of ring opening of cyclopro-
pane at the p-complex stage itself.
73.5
71.8
83.1
86.9
74.1
70.2
111.4
91.6
0.005
0.003
0.007
0.010
0.029
0.015
0.508
0.085
À6.72
À6.93
The estimated transition-state structures were op-
timised by using Opt=TS at the B3LYP/6-
311+G**//6-31G* and M06-2X/6-31+G* levels of
theory. The free energy of activation (DG°) and sig-
nificant bond lengths are presented in Table 7. The
transition states TS-1a to TS-4a were reached from
intermediate Int-1a to Int-4a with DG° ꢀ34 kcal
molÀ1, as predicted by B3LYP. The M06-2X func-
tional predicts parameters of TS-1a to TS-3a
À5.47
1.92; 3.38
Sol-1a[e]
Sol-2a[e]
Sol-3a[e]
Sol-4a[e]
À13.60
À12.01
À29.71
À13.54
–
–
–
–
[a] B3LYP/6-311+G**+zero-point energy (ZPE) (unscaled). [b] “Shortest” distance
between double bond and bromine, calculated as d1 =(bond length)ꢂsin(bond
À
angle)8. [c] Extent of elongation in cyclopropane C C s-bond. [d] NBO interactions
calculated at B3LYP/6-311+G**. p–s*; s–p*. [e] B3LYP/6-311+G**; SCRF=PCM;
solvent=acetonitrile.
Table 7. Relative free energies and changes in significant bond lengths at
the transition state (TS) of cyclopropane/cyclobutane ring opening.
[b]
p-Complex TS
DG°[a] [kcalmolÀ1
]
Dd3 s(CÀC)cycprop Dd4[b] Br···Cl
B3LYP
M06-2X
[ꢃ]
[ꢃ]
TS-1a
TS-2a
TS-3a
+34.30
+34.01
+30.91
+34.45
+43.91
+29.30
+26.45
+26.39
+48.54
+35.17
0.0293
À0.005
0.016
1.276
À0.003
0.840
0.970
0.664
0.294
0.451
TS-4a
Sol-TS-1a[c]
[a] B3LYP/6-311+G** and M06-2X/6-31+G* at 298.15 K. [b] Bond
lengths were obtained from B3LYP/6-311+G**-level calculations.
[c] B3LYP/6-311+G** and M06-2X/6-31+G*, PCM (acetonitrile).
(Table 7; Figures 3 and 4) suggest the occurrences of an
early transition state, since the geometry of the transition
states are more reactant-like, in which no appreciable ring
opening is observed in TS-1a to TS-3a when compared with
Int-1a to Int-3a. The transition from p-complex to the tran-
sition state is predominantly towards complete formation of
a three-membered bromonium intermediate; Dd4 represents
À
the extent of elongation of the Br Cl bond.
In the forward direction of the transition vector, the p-
complex crosses the energy barrier to result in a tight carbo-
cation–chloride complex, intermediate Int-1b1 to Int-4b1.
The expelled chloride ion migrates from one phase of the
molecular plane to the other and forms a hydrogen-bonded
complex with the acidic a-proton of the carbocation. This
kind of facial migration of the counter anion has been ob-
served several times in the context of an SN2 substitution re-
action and other reactions[36] in the gas phase; the tightly hy-
drogen-bonded complexes (cmplx-1 to cmplx-4) were shown
to be nonexistent in the solution phase.[37] To the best of our
knowledge, this kind of facial migration in the case of vinyl-
cyclopropane rearrangement in the gas phase was observed
here for the first time. To confirm this, the energy minimisa-
tion of intermediate Int-1b1 was performed by using the
PCM(MeCN) model with Pauling radii at the same level of
theory. In the solution phase, the expelled chloride ion was
found outside the molecular cavity and separated from the
carbocation entity by a distance of at least approximately
5 ꢃ from the respective hydrogen atom. The GeomView
Scheme 12. Comparison of the relative stability of the incipient carboca-
tion and factors favouring the ring-opening.
down the ring opening due to competitive equilibrium. This
phenomenon is even reflected in the Dd3 values, on account
of which the extent of ring opening is less in the case of Int-
1a and Int-2a (lower Dd3) and more in the case of Int-3a
and Int-4a. These observations can be perceived clearly
from the results obtained from the PCM(MeCN) model at the
B3LYP/6-311+G** level calculation. In a dielectric medium
of acetonitrile, for Sol-1a–4a, the complexes are more
stable and the extent of ring opening is noticeably higher
than in the gas phase.
Hence, the inhibiting effect of the stabilisation of the b-
carbocation on the ring opening can be clearly observed
from Dd3 in the case of Sol-1a and Sol-2a. Similarly, stabili-
sation of the a-carbocation that assists the ring opening can
be observed prominently (Dd3) in the cases of Sol-3a and
Sol-4a. Further, the natural bond orbital (NBO) analysis of
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S. Chandrasekaran et al.
Figure 5. Geometry of the tight carbocation intermediates Int-1b to Int-
4b.
Cyclisation of nitrogen anions Int-(1e to 4e) towards ami-
dines: According to the proposed mechanism for the reac-
tion of VCPs (Scheme 2) and VCBs (Scheme 6), the resul-
tant incipient carbocation becomes trapped by the nitriles
with the attack of chloramine-T in a domino fashion to
result in intermediate Id and IId, respectively. Expulsion of
chlorine from the N-chloro intermediates can lead to the ni-
trogen anion Ie and IIe. The key step of the reaction se-
quence is the cyclisation of anions (Ie and IIe) to the de-
sired amidines (Scheme 13). In this section, we have model-
led the reaction profile for the cyclisation of anions (Int-1e
Figure 4. Geometries of the p-complexes and transition states for the
ring-opening step in the gas phase and acetonitrile dielectric medium.
representation clearly shows
that the chloride is barely at-
tached to the carbocation entity
with the residual electron densi-
ty shared between the two spe-
cies (see the Supporting Infor-
mation). A pictorial representa-
tion of the energy profile is pre-
sented in Figure 3. The opti-
mised geometry of the tight
carbocations in the gas phase
suggested that a full carboca-
Scheme 13. Cyclisation of nitrogen anions to amidines.
tion is unlikely to be in exis-
tence due to the stabilisation
offered by the p-bond in the vicinity (Figure 5). The exis-
tence of such a tight carbocation intermediate is reflected in
the diasteroselectivity in the formation of amidines in the
case of VCPs that carry non-identical geminal substitution
on cyclopropanes (Scheme 4 presents the experimental ob-
servation of the diastereoselectivity).
to Int-4e) in an allylic substitution (SN2’) fashion to the re-
spective amidines (Prd-1 to Prd-4). The nitrogen anions
were optimised at B3LYP/6-311G**//6-31G* and M06-2X/6-
311G** levels of theory in the gas phase. The harmonic fre-
quencies and the zero-point energies obtained were recalcu-
lated at the B3LYP/6-311G** level of theory. The reaction
trajectory involves a double-well potential in the gas phase,
whereby the reactant is converted to a product complex pri-
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Vinylcyclopropanes and Vinylcyclobutanes
FULL PAPER
marily, followed by an endothermic dissociation of the com-
plex (Figure 6). This kind of potential well was observed
earlier in classic examples of SN2-substitution reactions mod-
elled in the gas phase.[36]
Figure 7. Transition-state geometry for allylic and direction cyclisation of
N-anion.
Table 8. Thermochemistry of the allylic cyclisation step.
TS
DG°[a] [kcalmolÀ1
]
Cyclisation DHcyc
Total DHtot
B3LYP
M06-2X
[kcalmolÀ1
]
[kcalmolÀ1
]
A-1e
A-2e
A-3e
A-4e
+8.95
+4.46
+8.28
+15.74
+11.79
+7.37
+12.84
+20.94
À13.77
À16.16
À10.85
À7.28
À0.5
À1.46
À1.27
+10.85
[a] B3LYP/6-311G** and M06-2X/6-311G** at 298.15 K.
Figure 6. Energy profile for allylic cyclisation of nitrogen anions a) Int-1e
and Int-4e, b) Int-2e and Int-3e.
thermic in the general case (see the Supporting Information
for the geometries of Cmplx-1 to Cmplx-4). The total en-
thalpy of cyclisation for Int-1e that results in a bicyclo-
The reaction profiles of anion Int-1e (from vinylcyclopro-
pane) were compared with Int-4e (from vinylcyclobutane,
Figure 6a) and those of Int-2e compared with Int-3e (Fig-
ure 6b) on account of their isoelectronic nature. The inter-
mediates Int-1e and Int-4e cross the energy barrier to form
the corresponding amidine through a transition state that
occurs at 9 (A-1e) and 16 kcalmolÀ1 (A-4e) above the inter-
mediate states, respectively (Figure 7, Table 8). The differ-
ence in free energies of activation (DG°) between the tran-
sition states is almost twofold. Thus, the cyclisation of anion
Int-1e to form a six-membered [4.4.0]amidine is kinetically
more favoured than the cyclisation of anion Int-4e to form
a seven-membered [4.3.1]amidine. Once the transition state
is achieved, the system results in the formation of a product
complex (Cmplx-1 and Cmplx-4); the pathway is highly exo-
A
more exothermic than the bicyclo
11 kcalmolÀ1) that results from Int-4e. Thus, formation of
bridged bicyclo[4.3.1]amidines is favoured neither kinetically
nor thermodynamically over bicyclo[4.4.0]amidines. This
ACHTUNGERTN[NUNG 4.3.1]amidine Prd-4 (+
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
might be the rationale for the surprisingly low yields and
formation of side product 35 in the case of vinylcyclobu-
tanes, whereas the vinylcyclopropanes work in an efficient
manner. Similarly, in the case of intermediate Int-2e and
Int-3e, an energy barrier of 4.5 and 8 kcalmolÀ1 need to be
crossed before reaching the product complex. The cyclisa-
tion DH for Int-2e that results in [4.3.0]amidine Prd-2 was
almost equal to the DH of [4.3.0]amidine Prd-3 from Int-3e.
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S. Chandrasekaran et al.
Figure 8. Comparison of the energy profiles of allylic cyclisation and direct cyclisation of nitrogen anions (b state calculated at lower level).
Allylic substitution pathway (SN2’) versus the direct substitu-
tion pathway (SN2)—Racemisation of 4la: The X-ray crystal
structure (Figure 1) of compound 4la revealed a possible
racemisation under the reaction conditions starting from op-
tically pure a-pinene. To explain this, we have proposed an
alternative pathway along which the cyclisation can also
happen through a direct (SN2) substitution of the bromide in
IIe with the nitrogen anion (Scheme 8). To obtain quantita-
tive evidence of the feasibility of both the pathways
tion (DHcyc) is more exothermic for allylic-substitution prod-
ucts. Hence, 4aa and 4ka are the sole products formed from
Int-1e and Int-2e. In the case Int-3e, the allylic-substitution
pathway is kinetically favoured once again, but only by a
ACTHNUTRGNEUNG
difference of 2 kcalmolÀ1 (D(DG°); Table 9).
The thermodynamic stability of the product complex
Cmplx-3 (with that of Cmplx-3d) (D
(DHcyc)=3.5 kcalmolÀ1
Table 10) and the total enthalpy for the conversion to prod-
A
;
in the case of intermediate IIe (Int-4e), the reaction
Table 9. Relative free energies for the two reaction pathways.
TS
DG°[a] allylic (SN2’) A DG°[a] direct (SN2) D
(X=A or D)
profiles of all the intermediates studied earlier (Int-
1e to Int-3e) were compared with that of Int-4e.
The energies of the anion intermediates (Int-1e to
Int-4e) calculated in the previous section were used
as such. The energies of transition states, cyclisation
enthalpies and total enthalpy for both direct- and
allylic-substitution pathways were calculated and
compared at B3LYP/6-311G** and M06-2X/6-
DACHTUNGTRENNUNG
(DG°)
B3LYP
G
B3LYP
M06-2X
B3LYP
M06-2X
X-1e
X-2e
X-3e
X-4e
+8.95
+4.46
+8.28
+15.74
+11.79
+7.37
+12.84
+20.94
+13.8[b]
n.d.
+10.04
+16.46
+22.41
n.d.[c]
+12.50
+16.86
4.80
n.a.[c]
1.76
0.72
[a] B3LYP/6-311G** and M06-2X/6-311G** at 298.15 K [kcalmolÀ1]. [b] B3LYP/6-
311G**//M06-2X/6-311G** (ZPEM06-2X) at 298.15 K. [c] n.d.=not determined, n.a.=
311G** levels of theory. The reaction profile has not applicable.
been plotted and is presented in Figure 8.
The overview of the reaction profile shows a
strong preference for the allylic-substitution path-
Table 10. Relative change in enthalpies for the two reaction pathways.
[a]
[a]
way over direct substitution. For intermediates Int-
1a and Int-2a, the direct substitution is a highly to product
Int-ne
DHcyc [kcalmolÀ1
]
DHtot [kcalmolÀ1
]
DACHTUNGTRENNUNG(DHtot)
allylic (A)
direct (D)
allylic (A)
direct (D)
[kcalmolÀ1
]
energy-demanding pathway with an energy barrier
1e
À13.77
À16.16
À10.85
À7.28
+15.40
+6.75
À7.42
À7.28
À0.5
À1.46
+0.78
+11.45
+26.20
+17.40
+8.23
27.7
18.9
7.5
of 23 kcalmolÀ1 (D-1e) relative to the allylic substi-
tution with a barrier of 9 (A-1e) and 4.5 kcalmolÀ1
(A-2e). In addition to this, the enthalpy of cyclisa-
2e
3e
4e
+11.45
0.0
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Vinylcyclopropanes and Vinylcyclobutanes
FULL PAPER
19.5 ppm; IR (neat): n˜ =2945, 1643, 1336, 1159, 1091, 813 cmÀ1; HRMS:
m/z: calcd for C19H27N2O2S [M+H+]: 347.1793; found: 347.1806; elemen-
tal analysis for C19H26N2O2S: C 65.86, H 7.56, N 8.08; found: C 65.90, H
7.47, N 8.32.
uct from Int-3e favours the allylic-substitution pathways.
From the above results, it can be inferred that the cyclisa-
tion is strongly controlled by the thermodynamic stability of
the product. However, in the case of Int-4e (IIe), the allylic
and direct substitution pathways are favored equally with
minor difference of 0.7 kcalmolÀ1 in the free energy of acti-
vation for the transition states (A-4e and D-4e). Thus, both
the pathways are equally feasible kinetically. Since the prod-
ucts obtained from the two different pathways have an
enantiomeric relationship, the difference in total enthalpy is
CCDC-849309 (4aa), -748915 (4la) and -748919 (4ld) contain the sup-
plementary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
zero (D
in the case of 4la.
ACHTUNGTRENNUNG(DHcyc)=0). This justifies the racemisation observed
Acknowledgements
We thank the CSIR, New Delhi for the Shyama Prasad Mukherjee Fel-
lowship to V.G. and the DST for the JC Bose National Fellowship to
SCN. We also thank the Supercomputer Education and Research Center
(SERC), IISc, for the computational facility.
Conclusion
To summarise, a detailed study on the reactivity of vinylcy-
clopropanes (VCP) and vinylcyclobutanes (VCB) under the
above-specified reaction conditions have been presented.
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The report demonstrates the synthesis of bicycloACTHNUTRGNEUG[N 4.3.0]-,
-[4.3.1]- and -[4.4.0]amidine skeletons in an elegant manner
by choosing the appropriate VCPs or VCBs. A convincing
mechanism for the formation of chiral bicyclic amidines has
been laid out based on the literature precedence and control
experiments. The proposed mechanism explains the selectiv-
ity in the product formation and stereoselectivity observed
in un-symmetrically substituted cyclopropanes as well. The
mechanism has been further verified with the help of DFT
studies. The study reveals that perturbation in the cyclopro-
pane ring occurs at the p-complex stage, which has been
clearly shown from the calculations performed in acetoni-
trile as solvent (PCM model). The final cyclisation step has
also been modelled in the gas phase, which explains the
preferential adoption of one of the competing pathways
(SN2 and SN2’). The product formation was found to be
strongly thermodynamically controlled. The problem of rac-
emisation in the case of the a-pinene skeleton has been
identified and it has been concluded that racemisation is not
an inherent problem in the methodology but the reactivity
of that specific skeleton.
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[a]2D5 = +93.0 (CHCl3, c=1); H NMR (300 MHz, CDCl3): d=7.73 (d, J=
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Received: November 11, 2011
Revised: March 16, 2012
Published online: && &&, 0000
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Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Vinylcyclopropanes and Vinylcyclobutanes
FULL PAPER
The ring cycle: A study of a [3+2+1]
cascade cyclisation of vinyl cyclopro-
panes (VCP) catalysed by a brome-
À
Chiral Amidines
V. Ganesh, D. Sureshkumar,
D. Chanda,
S. Chandrasekaran* .......... &&&& — &&&&
nium species (Brd+
situ, and which involves the ring-open-
X
dÀ) generated in
À
ing of VCPs with Br X followed by a
Bromenium-Catalysed Tandem Ring
Opening/Cyclisation of Vinylcyclopro-
panes and Vinylcyclobutanes: A
Metal-Free [3+2+1]/ACTHNUGTRNEUNG[4+2+1] Cascade
for the Synthesis of Chiral Amidines
and Computational Investigation
Ritter-type reaction with chloramine-T
and a tandem cyclisation, is presented
(see scheme). The reaction has been
extended to vinylcyclobutane systems.
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!