Substrate scope in the direct imine acylation of ortho-substituted benzoic acid derivatives: The total synthesis (±)-cavidine Dedicated to the memory of Sandy McKillop - Colleague, mentor, collaborator and friend

Article abstract of DOI:10.1016/j.tet.2014.04.066

The direct imine acylation (DIA) and subsequent cyclisation of a range of imines with ortho-substituted benzoic acid derivatives is described. Variation in the coupling reagents, imine and benzoic acid were all examined. The DIA procedure was also applied in the total synthesis of (±)-cavidine.

Full text of DOI:10.1016/j.tet.2014.04.066

Accepted Manuscript
Substrate scope in the Direct Imine Acylation of ortho-substituted benzoic acid
derivatives: The total synthesis (±)-cavidine
Christiana Kitsiou, William P. Unsworth, Graeme Coulthard, Richard J. K Taylor
PII:
S0040-4020(14)00600-0
10.1016/j.tet.2014.04.066
TET 25516
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 3 April 2014
Accepted Date: 23 April 2014
Please cite this article as: Kitsiou C, Unsworth WP, Coulthard G, Taylor RJK, Substrate scope in the
Direct Imine Acylation of ortho-substituted benzoic acid derivatives: The total synthesis (±)-cavidine,
Tetrahedron (2014), doi: 10.1016/j.tet.2014.04.066.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Substrate scope in the direct imine acylation
of ortho-subtituted benzoic acid derivatives:
The total synthesis (±)-cavidine
Leave this area blank for abstract info.
Christiana Kitsiou, William P. Unsworth, Graeme Coulthard and Richard J. K. Taylor*
University of York, Heslington, York, YO10 5DD, UK

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Substrate scope in the Direct Imine Acylation of ortho-substituted benzoic acid
derivatives: The total synthesis (±)-cavidine
Christiana Kitsiou, William P. Unsworth, Graeme Coulthard and Richard J. K. Taylor*†
University of York, Heslington, York, YO10 5DD, UK
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The direct imine acylation (DIA) and subsequent cyclisation of a range of imines with ortho-
substituted benzoic acid derivatives is described. Variation in the coupling reagents, imine and
benzoic acid were all examined. The DIA procedure was also applied in the total synthesis of
(±)-cavidine.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
N-acyliminium ions
nitrogen heterocycles
molecular diversity
cavidine
evodiamine
1. Introduction
acyliminium ion 3, which is subsequently trapped by the ortho-
nucleophile in a one-pot process, driving the equilibrium towards
the formation of the desired heterocyclic product 5.
The controlled synthesis of diverse heterocycles is crucial in
both the pharmaceutical and agrochemical industries.1 Novel
methods that expedite their synthesis are therefore of great
importance, especially those which furnish a range of diverse
scaffolds whose biological activity has not previously been well-
examined. Such diversity-oriented-synthesis2 has attracted
widespread interest in recent years as a strategy to accelerate the
discovery of new therapeutically important compounds.
In order for these methods to be widely adopted by the
synthetic community, both in industry and in academia, various
conditions must be satisfied: the new methods must be reliable,
operationally simple, high yielding and crucially be capable of
generating a broad range of structures without significant
optimisation. Our research group recently reported one such
method, based on the concept of ‘Direct Imine Acylation’
(DIA).3 This methodology centres on a novel way to generate N-
acyliminium ions and their subsequent reaction with tethered
nucleophiles. The initial communication focused on the direct
coupling of a range of imines (1) with ortho-substituted benzoic
acids (2) using propylphosphonic acid anhydride (T3P)4 and
NEt(i-Pr)2 (DIPEA) to activate the benzoic acid towards
nucleophilic attack by the imine nitrogen to form the key N-
acyliminium ion 3 (Scheme 1). An accompanying mechanistic
study, in which the progress of the reaction was monitored in situ
by IR spectroscopy using ReactIRTM, shed further light on the
process. It is proposed that the N-acyliminium 3 exists only
briefly and is trapped by excess DIPEA in the reaction mixture,
affording ammonium salt 4. This process is reversible and so the
extrusion of DIPEA results in the regeneration of the N-
Scheme 1. Direct Imine Acylation
Diversity was initially examined both in terms of the imine 1
and the benzoic acid derivative 2. Most notably, the methodology
was shown to be compatible with phenols, anilines, thiols and
carbon pro-nucleophiles as the ortho-substituent on the benzoic
acid (2, X = O, NMe, S, CH(CO2Me)2). Furthermore, we more
recently disclosed preliminary results which demonstrate that
DIA is also compatible with aliphatic carboxylic acids.5 Protected
aliphatic alcohols, protected amines, thiols and a range of carbon
pro-nucleophiles can also be tethered to the carboxylic acid and
react with the N-acyliminium ion using broadly similar
conditions to those described above, dramatically increasing the
range of heterocyclic scaffolds accessible. DIA has also been
used in target synthesis; the total synthesis of evodiamine 63,6 was

2
Tetrahedron
ACCEPTED MANUSCRIPT
Table 2. Benzoic acid scope in DIA with imine 1aa
completed in high yield (95%, see later) and DIA methodology
was also used to construct the spirooxoquinolizidinone ring
system of the proposed structures of the complex marine natural
product ‘upenamide 7 (Figure 1).7
N
entry
acylating agent
product
yieldb
H
O
H
NH
Me
N
HO
O
O
N
N
7
O
6
1
2
3
4
5
6
7
8
9
2a R = H
2b R = 3-NO2
2c R = 5-NO2
2c
2d R = 5-Cl
2e R = 4-OMe
2f R = 5-OMe
2g R = 6-OMe
2h R = 4,6-OH
5a R = H
5b R = 3-NO2
5c R = 5-NO2
5c
5d R = 5-Cl
5e R = 4-OMe
5f R = 5-OMe
5g R = 6-OMe
5h R = 4,6-OH
83%*c,d
89%
Figure 1 The structure of evodiamine 6 and one of the proposed
structures of ‘upenamide 7.
91%*
90%*e
96%
82%f
60%
Herein we report extended substrate scoping studies for DIA
using benzoic acid derivatives. We also describe the application
of DIA in the total synthesis the natural product (±)-cavidine.
64%f
60%
2. Results and Discussion
In our initial communication, all of the DIA reactions reported
were performed by simply mixing the imine, carboxylic acid,
T3P and DIPEA in toluene and heating to 90 °C in most cases, or
120 °C if t.l.c. analysis indicated that the reaction was incomplete
after 20 h. All of the reagents were used as supplied, without
drying or purification, and it was not necessary to exclude air
from the reaction. We have since discovered that both CDI and
DCC may be used in place of T3P in the reaction of imine 1a
with salicylic acid 2a (Table 1, entries 1–3). The same reaction
was also tested using EDC as the coupling reagent but this failed,
most likely because of the poor solubility of EDC in toluene.
Thus, the highest yield was obtained using our original T3P
conditions, but it is important to note that other coupling reagents
can also be used, in cases where T3P is either unavailable or
unsuitable.
10
2i
5i
95%*
11
12
2j
5j
92%*
97%*
2k
5k
Table 1. Alternative coupling reagentsa
13
14
2l
5l
63%
2m
5m
96%*g
entry
coupling agent
yieldb
1
2
3
4
T3P
CDI
DCC
EDC
83%
52%
77%
0%
15
16
2n R = Me
2o R = Ph
5n R = Me
5o R = Ph
97%*c
95%
a Unless stated, reactions were performed on a 0.1–0.3 mmol scale using
imine 1a (1 equiv.), salicylic acid 2a (1.2 equiv.), coupling reagent (1.5
equiv.), DIPEA (1.85 equiv.) in PhMe at 90 ºC for 20 h.
b Isolated yields after purification by column chromatography.
The scope of the T3P-meditated DIA conditions described
above (Table 1, entry 1) was first tested with regard to the acid
coupling partner 2 (Table 2). Note that examples reported in our
prior communication are indicated with an asterisk and that the
majority of the new examples led to the formation of novel
compounds.
17
2p E = CO2Me
5p E = CO2Me
84%*c
a Unless stated, reactions were performed on a 0.1–0.3 mmol scale using
imine 1a (1 equiv.), benzoic acid 2a-p (1.2 equiv.), T3P (1.5 equiv.), DIPEA
(1.85 equiv.) in PhMe at 90 ºC for 20 h.
b Isolated yields after purification by column chromatography.
c Reaction performed in the absence of T3P gave 0% yield of product.
d Reaction performed in the absence of DIPEA gave 0% yield of product.
e Reaction performed on a 3 mmol scale under the standard conditions.

3
f Reaction performed at 120 ºC for 20 h.
and it is significant that this comparatively unstable imine is
also compatible with the standard DIA procedure.
ACCEPTED MANUSCRIPT
g Reaction performed in the absence of T3P gave 20% yield of product.
Table 3. Imine scope in DIA with benzoic acid derivativesa
*entries highlighted with an asterisk were reported in the earlier
communication (see reference 3).
Imine 1a was reacted with a wide range of salicylic acid
derivatives 2a–2h3 using the standard DIA procedure, affording
N,O-acetals 5a–5h in good to excellent yields (Table 2, entries 1–
9). All of these reactions were performed using the same
conditions with the exceptions of entries 6 and 8; in both of these
cases a higher reaction temperature (120 °C) was required in
order to achieve full conversion into the respective products 5e
and 5g. The initial N-acylation appears to be significantly slower
in these two examples, which is unsurprising as the activated
carboxylic acid is presumably less electrophilic than the other
systems tested as a result of the presence and position of the
electron-rich methoxy groups. Naphthalene and pyridine
derivatives 2i–2l are also well tolerated, affording products 5i–5l
again in good to excellent yields (entries 10–13). Clearly, ortho-
hydroxy aromatics are excellent substrates, but the real strength
of the DIA procedure is its versatility, which is demonstrated by
the similarly efficient reactions of thiosalicylic acid 2m and
anthranilic acids 2n and 2o (entries 14–16). Perhaps most
impressively, diester 2p also takes part in DIA, demonstrating
that C–C bond formation can also be achieved in very good yield
(entry 17). Crucially, all of these examples were performed using
the standard reaction conditions and are unoptimised,
highlighting the operational simplicity of the process and its
significant potential for the rapid synthesis of diverse compound
libraries for biological screening.
entry
imine
acid
product
yieldb
1
2
3
1b
1b
1b
2a
2m
2n
5q X = O
5r X = S
5s X = NMe
48%c
99%
87%*
N
4
5
6
1c
1c
1c
2a
2m
2p
5t X = O
5u X = S
5v X = CH(CO2Me)2
89%*c
97% c
69%*c
7
8
1d
1d
2a
2n
5w X = O
5x X = NMe
48%
87%
The substrate scope with respect to the imine component was
next examined (Table 3). The requisite imines 1a–1k were either
generated as described in our previous reports, were available
commercially or were made via literature methods.3,5,8,9 The basic
procedure is clearly very broad in scope, with a range of imines
compatible; DIA reactions using imines 1b–1e and benzoic acids
derivatives bearing O-, S-, N- and C-nucleophiles were tested,
affording a diverse range of products in moderate to excellent
yields (Table 3, entries 1–10). The yields for some of these
reactions are lower than for those using imine 1a, but it is
important to recognise that all of these reactions are unoptimised
and the only change made to the reaction conditions was to
increase the temperature to 120 °C if t.l.c. analysis showed that
the reaction was incomplete under the standard conditions (90
°C). We believe that the comparative stabilities of the products
may partially explain this variability in yield. For example, the
DIA of 3,4-dihydroisoquinoline 1c and acid 2a proceeded in high
yield but the analogous reaction with the dimethoxy imine 1d
proceeded in lower yield (entries 4 and 7), which may be
explained by the increased propensity for the product 5w to ring-
open (and thus regenerate the intermediate N-acyliminium ion) as
a result of the two electron-donating groups. Greater reversibility
in the cyclisation step would not only lead to an increased
reaction time, but may also lead to hydrolysis of the product
during aqueous work-up and during column chromatography.
Nonetheless, significant quantities of material were isolated in all
cases and indeed some of the yields (e.g. entries 2–5, 8) were
excellent and comparable with those reported in Table 2.
9
10
1e
1e
2m
2n
5y X = S
5z X = NMe
53%
41%
11
12
1fd
1f
2m
2n
5aa X = S
5ab X = NMe
31%
40%*
R
N
13
14
1g R = Me
1h R = Ph
2m
2m
5ac R = Me
5ad R = Ph
80%c
0%
15
16
1i
1i
2m
2o
5ae X = S
5af X = NPh
99%*
68%
17
1j
2a
5ag
60%*c
The coupling of imine 1f was examined next. This imine,
which exists primarily in its trimeric form dodecahydro-
4a,8a,12a-triazatriphenylene,9 is known to oligomerise and so
must be generated in situ. Nevertheless, it reacted with acids 2m
and 2n under the standard DIA conditions to form products 5aa
and 5ab, albeit in moderate yield (entries 11 and 12). Note that
none of the imine systems 1a–1e can tautomerise to enamines
18
1k
2n
5ah
94%*
a Unless stated, reactions were performed on a 0.1–0.3 mmol scale using
imines 1b–1k (1 equiv.), benzoic acid 2a–2p (1.2 equiv.), T3P (1.5 equiv.),
DIPEA (1.85 equiv.) in PhMe at 90 ºC for 20 h.
b Isolated yields after purification by column chromatography

4
Tetrahedron
c Reaction performed at 120 ºC for 20 h.
to inhibit DNA topoisomerase I.13 Its synthesis in 95% yield from
ACCEPTED MANUSCRIPT
d Imine 1f was generated by de-oligomerisation of dodecahydro-4a,8a,12a-
triazatriphenylene in situ.
two easily available coupling partners highlights well the
potential of DIA in target synthesis.
*entries highlighted with an asterisk were reported previously (see reference
3).
Ketimine 1g (which also is able to tautomerise to an enamine)
is compatible with DIA, reacting with thiosalicylic acid 2m,
generating product 5ac in good yield (entry 13). However, the
analogous reactions using benzoic acids substituted with O-, N-
and C-nucleophiles (2a, 2n, and 2p, not shown in the table) did
not furnish the expected products. Instead, C-acylation took place
preferentially (presumably via the enamine tautomer of the
imine), resulting in the predominant formation of Z-
enaminones.10 The analogous reaction with phenyl substituted
ketimine 1h (which cannot undergo such C-acylation) was also
screened but this imine did not react at all with thiosalicylic acid
2m (entry 14) or indeed with any of the benzoic acid derivatives
2a, 2n or 2p (not shown in the table). This result is in line with
previous studies which also found that ketimines fail to undergo
DIA with carboxylic acids bearing O-, N- or C-nucleophiles and
this is most likely because the increased steric hindrance around
the imine inhibits the requisite N-acylation reaction. The
contrasting reactivity of thiosalicylic acid 2m has intriguing
mechanistic implications and is consistent with our previous
work. Of the two successful DIA-type reactions of ketimines that
were reported previously,7 both involved thiol-substituted
carboxylic acids, indicating that an alternative mechanism most
likely operates. Thus, it seems likely that in sulfur-containing
systems the nucleophilic thiol moiety attacks the imine carbon
first, before intramolecular N-acylation takes place.7 Additional
support for this mechanism is found in the fact that partial
product formation (20 % yield) was observed in a related
example even in the absence of T3P (Table 1, entry 14).
Scheme 2 The total synthesis of evodiamine 6
Additional biologically important targets are also being
pursued, e.g. cavidine 8, a member of a large family of alkaloids
known as protoberberines14 with extremely broad biological
activity.15 Cavidine was first isolated from a Corydalis plant in
1964 by Taguchi16 and its structure was later assigned by
Manske.17 Its synthesis has been completed previously,18 but
nonetheless, we considered that DIA methodology would
expedite an efficient convergent synthesis (Scheme 3).
A significant advantage to DIA is its ability to generate
acyclic N-acyliminium ions, which are far less stable than their
cyclic analogues, particularly with respect to hydrolysis.11 This
means that N-acyliminium ion precursors are difficult to prepare
and handle, but DIA technology overcomes this by forming the
unstable N-acyliminium ions in situ, and trapping them in one
pot. This is exemplified by the formation of DIA products 5ae–
5ag in good to excellent yields from commercially available
acylic imines 1i and 1j (entries 15–17). Note also that imine 1j is
a ketimine; N-substituted ketimines has so far proven to be
incompatible with DIA but pleasingly this substituted ketimine
furnished N,O-acetal 5ag in good yield under standard DIA
conditions at 120 °C (entry 17).
Scheme 3 The total synthesis of (±)-cavidine 8
To begin, commercially available bromide 9 was converted
into the novel dimethyl malonate derivative 2q via a known
method based on the Hurtley reaction.19 Acid 2q was then reacted
with imine 1d using our standard DIA coupling conditions. We
were pleased that the DIA was successful on this more complex
system, furnishing lactam 5ai in moderate yield (39%). Previous
studies in our group have shown that, in some cases, the addition
of Lewis acids to the crude reaction mixture following N-
acylation can lead to improved yields,5 and therefore additional
optimisation reactions were performed. The most common
additive used in the DIA reactions reported to date is BF3·OEt2,
but on this system it did not improve the isolated yield of product
5ai (36%). However, by switching the additive to BCl3 (2
equivalents) allowed product 5ai to be obtained in 69% yield at
RT in chloroform.20 Importantly, the work-up for this reaction
was straightforward and this result is easily reproducible. It is
also noteworthy that no competing demethylation products were
observed.
The high yielding DIA reaction of isoquinoline 1k with
anthranilic acid 2n is significant given that it proceeded despite
the loss of aromaticity (entry 18). Unfortunately, this
dearomatising DIA reaction appears not to be general; the
analogous reactions of isoquinoline 1k with acids 2a, 2m, and 2p
under identical conditions all failed to furnish any product. Other
aromatic heterocycles containing C=N bonds (quinolone,
pyridine, DMAP, pyrimidine, pyrazine, oxazole, thiazole, N-Boc
imidazole and 1,3,5-triazine) were also examined under DIA
conditions at 120 °C with anthranilic acid 2n but no products
were isolated in any case. Note that similar dearomatising
reactions of isoquinolines have been reported,12 and that the
degree of aromaticity in the precursor is likely to crucial in the
outcome of these reactions.
The synthesis was then completed using an approach based on
that in Cushman’s route.18c Ester hydrolysis and decarboxylation
using LiOH in aqueous THF followed by reduction with LiAlH4,
afforded alcohol 10 as a single diastereoisomer following column
Finally, the formation of the natural product evodiamine 6
from dihydrocarboline 1l and anthranilic acid 2n is a particularly
noteworthy example (Scheme 2). Evodiamine is
a key
component in various weight-loss supplements and also is known

5
chromatography. Mesylation, followed by deoxygenation with
NaBH4 in refluxing ethanol21 then completed the synthesis,
affording (±)-cavidine 8, the spectral data of which were in full
accord with those previously reported (Scheme 3).14j-k, 18c
To a solution of imine (1 mmol) and acid (1.2 mmol) in dry
ACCEPTED MANUSCRIPT
toluene (10 mL) was added sequentially DIPEA (1.85 mmol) and
then T3P (1.5 mmol, 50% in THF). The resulting solution was
heated at 90 °C or 120 °C in a sealable tube for the specified
time, before cooling to RT and pouring into sat. aq. NaHCO3 (20
mL). The aqueous layer was extracted with DCM (3 × 30 mL),
concentrated in vacuo and purified by column chromatography.
Conclusion
A detailed substrate scoping study of the DIA reactions of a
range of imines and ortho-substituted benzoic acids has been
completed. The reaction has been shown to be very broad in
scope, proceeds under operationally simple conditions and
generally affords the desired product in good to excellent yield
without optimisation of the reaction conditions. This should
result in DIA being used for the construction of diverse
compound libraries for biological evaluation. The total synthesis
of (±)-cavidine was also completed; in this instance the DIA was
low yielding under the standard conditions, but could be
improved significantly by using a Lewis acid additive. The fact
that the coupling reagents (T3P and DIPEA) are compatible with
Lewis acid additives is significant as this allows such one-pot
optimisation processes to be performed easily. The success of
this example also augurs well for the similar optimisation of
other DIA reactions (especially the lower yielding cases) further
expanding its wide scope. This in turn is expected to lead to DIA
being widely used in the synthesis of other biologically important
natural product/drug targets.
6,6-Dibenzyl-4-nitro-6,7,8,9-tetrahydro-5aH,11H-pyrido[2,1-
b][1,3]benzoxazin-11-one (5b). Synthesised using the general
DIA procedure from imine 1a (56.1 mg, 0.213 mmol), acid 2b
(46.9 mg, 0.256 mmol), DIPEA (68.6 ꢀL, 0.394 mmol) and T3P
(204 mg, 0.320 mmol) in toluene (1.5 mL) at 90 °C for 20 h.
Purification by column chromatography (5:1 petrol:ethyl acetate)
afforded 5b as a colourless oil (81.1 mg, 89%); Rf 0.43 (5:1
petrol:ethyl acetate); νmax (thin film)/cm−1 1647, 1589, 1506,
1449, 1311, 1275; δH (400 MHz, CDCl3) 8.24 (1H, dd, J = 7.7,
1.7 Hz), 8.19 (1H, dd, J = 8.2, 1.7 Hz), 7.34–7.13 (11H, m, H-9),
5.31 (1H, s), 4.75–4.68 (1H, m), 3.35 (1H, d, J = 13.4 Hz), 3.17
(1H, d, J = 13.4 Hz), 2.85 (1H, d, J = 13.4 Hz), 2.53–2.42 (2H,
m), 2.18–2.05 (1H, m), 1.68–1.59 (2H, m), 1.50–1.40 (1H, m); δC
(100 MHz, CDCl3) 159.4, 150.2, 137.0, 136.4, 136.1, 133.7,
131.2, 131.0, 130.2, 128.2, 126.6, 121.0, 118.2, 90.6, 43.2,
42.2, 40.9, 35.6, 27.6, 19.6; HRMS (ESI+): Found: 429.1827;
C26H25N2O4 (MH+) Requires: 429.1809 (−4.3 ppm error).
6,6-Dibenzyl-2-chloro-6,7,8,9-tetrahydro-5aH,11H-
3. Experimental section
pyrido[2,1-b][1,3]benzoxazin-11-one (5d). Synthesised using the
general DIA procedure from imine 1a (66.9 mg, 0.254 mmol),
acid 2d (52.6 mg, 0.305 mmol), DIPEA (81.9 ꢀL, 0.470 mmol)
and T3P (242 mg, 0.381 mmol) in toluene (1.5 mL) at 90 °C for
20 h. Purification by column chromatography (5:1 petrol:ethyl
acetate) afforded 5d as a white solid (46.7 mg, 96%); m.p. 198–
201 °C; Rf 0.29 (5:1 petrol:ethyl acetate); νmax (thin film)/cm−1
1668, 1608, 1475, 1441, 1325, 1283, 704; δH (400 MHz,
CDCl3) 7.90 (1H, d, J = 2.7 Hz), 7.42 (1H, dd, J = 8.8, 2.7 Hz),
7.34–7.20 (9H, m), 7.11–7.09 (1H, m), 7.05 (1H, d, J = 8.8 Hz),
5.09 (1H, s), 4.68–4.62 (1H, m), 3.21–3.16 (2H, m), 2.86 (1H, d,
J = 13.5 Hz), 2.49–2.40 (2H, m), 2.18–2.04 (1H, m), 1.65–1.56
(2H, m), 1.42–1.31 (1H, m); δC (100 MHz, CDCl3) 161.4,
154.5, 137.0, 136.3, 134.2, 131.0, 131.0, 128.1, 128.1, 127.7,
127.3, 126.6, 126.6, 117.3, 117.2, 89.5, 42.5, 42.0, 41.4, 35.8,
27.6, 19.5; HRMS (ESI+): Found: 418.1585; C26H2535ClNO2
(MH+) Requires: 418.1568 (−3.9 ppm error).
Except where stated, all reagents were purchased from
commercial sources and used without further purification.
Anhydrous dichloromethane and toluene were obtained from an
Innovative Technology Pure Solv solvent purification system.
Anhydrous THF was obtained by distillation over sodium
benzophenone ketyl immediately before use. Flash column
chromatography was carried out using slurry packed silica gel
(SiO2), 35–70 ꢀm, 60 Å, under light positive pressure eluting
with the specified solvent system. Thin layer chromatography
(TLC) was carried out on Merck silica gel 60F254 pre-coated
aluminium foil sheets and were visualised using UV light (254
nm) and stained with either basic aqueous potassium
1
permanganate or ethanolic p- anisaldehyde as appropriate. H
NMR and 13C NMR spectra were recorded on a Jeol ECX-400
NMR or Jeol ECS400 spectrometer operating 400 MHz and 100
MHz, respectively, or on a Bruker DRX500 spectrometer,
operating at 500 MHz and 125 MHz, respectively. All spectra
was acquired at 295 K. Chemical shifts (δ) are quoted in parts per
million (ppm). The multiplicity abbreviations used are: s, singlet;
d, doublet; t, triplet; q, quartet; multiplet; br, broad or
combinations of these. Signal assignment was achieved by
analysis of DEPT, COSY, NOESY, HMBC and HSQC
experiments where required. The residual solvent peaks, δΗ 7.26
and δC 77.0 for CDCl3 were used as references. Infrared spectra
(IR) were recorded on a ThermoNicolet IR-100 spectrometer
with NaCl plates as a thin film dispersed from either CH2Cl2 or
CDCl3. High Resolution Mass Spectra (HRMS) were obtained by
University of York Mass spectrometer Service, using ionisation
(ESI) on a Bruker Daltonics, MicrOTOF spectrometer. Melting
points were measured on a Gallenkamp melting point apparatus
and are uncorrected. Compounds 1i-k, 2a-o were all purchased
from Sigma-Aldrich and used as supplied. Compounds 1a3, 1b3,
1c,8a 1d,8b 1e,8c 1f,9 1g,8d 1h,8e 1l,8f 2p,3,22 5a,3 5c,3 5d,3 5i–k,3
5m,3 5n,3 5p,3 5s,3 5t,3 5v,3 5ab,3 5ae,3 5ag,3 5ah,3 63 were
prepared using literature procedures.
6,6-Dibenzyl-3-methoxy-6,7,8,9-tetrahydro-5aH,11H-
pyrido[2,1-b][1,3] benzoxazin-11-one (5e). Synthesised using the
general DIA procedure from imine 1a (31.2 mg, 0.118 mmol),
acid 2e (23.9 mg, 0.142 mmol), DIPEA (38.0 ꢀL, 0.219 mmol)
and T3P (113 mg, 0.178 mmol) in toluene (1.5 mL) at 120 °C for
20 h. Purification by column chromatography (3:1 → 1:1
petrol:ethyl acetate → pure ethyl acetate) afforded 5e as a white
solid (40.0 mg, 82%); m.p. 158–162 °C; Rf 0.7 (ethyl acetate);
νmax (thin film)/cm−1 1635, 1593, 1562, 1473, 1423, 1381,
1352, 1257, 1181; δH (400 MHz, CDCl3) 7.85 (1H, d, J = 8.6
Hz), 7.34–7.19 (8H, m), 7.13–7.09 (2H, m), 6.63–6.56 (2H, m),
5.06 (1H, s), 4.67–4.60 (1H, m), 3.90 (3H, s) 3.24–3.19 (2H, m),
2.89 (1H, d, J = 13.7 Hz), 2.45–2.37 (2H, m), 2.16–2.03 (1H, m),
1.63–1.54 (2H, m), 1.42–1.28 (1H, m); δC (100 MHz, CDCl3)
164.8, 163.0, 157.8, 137.5, 136.6, 131.2, 131.2, 129.7, 128.2,
128.2, 126.6, 126.5, 109.5, 109.0, 100.2, 89.5, 55.8, 42.5,
41.8, 41.5, 35.9, 27.8, 19.8; HRMS (ESI+): Found: 414.2076;
C27H28NO3 (MH+) Requires: 414.2064 (−0.6 ppm error).
6,6-Dibenzyl-2-methoxy-6,7,8,9-tetrahydro-5aH,11H-
pyrido[2,1-b][1,3] benzoxazin-11-one (5f). Synthesised using the
general DIA procedure from imine 1a (37.0 mg, 0.141 mmol),
acid 2f (28.4 mg, 0.169 mmol), DIPEA (45.5 ꢀL, 0.261 mmol)
3.1 General procedure for the DIA reaction

6
Tetrahedron
ACCEPTED MANUSCRIPT
and T3P (135 mg, 0.212 mmol) in toluene (1.4 mL) at 90 °C for
2.55–2.42 (2H, m), 2.17–2.04 (1H, m), 1.64–1.56 (2H, m), 1.42–
20 h. Purification by column chromatography (4:1 petrol:ethyl
acetate) afforded 5f as a colourless solid (35.0 mg, 60%); m.p.
108–109 °C; Rf 0.7 (ethyl acetate); νmax (thin film)/cm−1 1641,
1471, 1447, 1431, 1413, 1375, 1309, 1264, 1193, 692; δH (400
MHz, CDCl3) 7.41 (1H, d, J = 2.6 Hz), 7.33–7.16 (8H, m), 7.11–
7.02 (4H, m), 5.01 (1H, s), 4.67–4.60 (1H, m), 3.81 (3H, s) 3.22–
3.18 (2H, m), 2.92 (1H, d, J = 13.9 Hz), 2.48–2.40 (2H, m),
2.17–2.05 (1H, m), 1.66–1.55 (2H, m), 1.38–1.28 (1H, m); δC
(100 MHz, CDCl3) 163.1, 154.6, 150.2, 137.3, 136.5, 131.1,
131.0, 128.1, 126.4, 126.4, 122.4, 116.9, 116.5, 109.9, 89.1,
55.9, 42.2, 41.9, 41.5, 35.9, 27.6, 19.5; HRMS (ESI+): Found:
414.2074; C27H28NO3 (MH+) Requires: 414.2064 (−2.8 ppm
error).
1.32 (1H, m); δC (100 MHz, CDCl3) 161.3, 153.6, 144.5,
136.9, 136.3, 133.7, 131.1, 131.1, 128.4, 128.3, 128.3, 126.8,
126.7, 124.3, 89.9, 42.7, 42.5, 41.5, 35.9, 27.8, 19.6; HRMS
(ESI+): Found: 385.1906; C25H25N2O2 (MH+) Requires:
385.1911 (−1.1 ppm error).
6,6-Dibenzyl-5-phenyl-5,5a,6,7,8,9-hexahydro-11H-
pyrido[2,1-b]quinazolin-11-one (5o). Synthesised using the
general DIA procedure from imine 1a (38.0 mg, 0.144 mmol),
acid 2o (36.9 mg, 0.173 mmol), DIPEA (46.4 ꢀL, 0.266 mmol)
and T3P (137 mg, 0.216 mmol) in toluene (1.4 mL) at 90 °C for
20 h. Purification by column chromatography (2:1 petrol:ethyl
acetate) afforded 5o as a white solid (63.0 mg, 95%). Rf 0.59
(ethyl acetate); m.p. 177–178 °C; νmax (thin film)/cm−1 1625,
1579, 1469, 1451, 1431, 1410, 1362, 1280, 1198, 739, 693; δH
(400 MHz, CDCl3) 8.05 (1H, dd, J = 7.7, 1.5 Hz), 7.62–7.57 (2H,
m), 7.52–7.46 (2H, m), 7.40–7.20 (5H, m), 7.13–6.92 (7H, m),
6.35 (2H, d, J = 7.3 Hz), 5.21 (1H, s), 4.94 (1H, ddd, J = 12.7,
2.1, 2.1 Hz), 3.27 (1H, d, J = 13.9 Hz), 3.02 (1H, d, J = 13.2 Hz),
2.58 (1H, d, J = 13.2 Hz), 2.52 (1H, ddd, J = 12.7, 12.7, 3.0 Hz),
2.52 (1H, d, J = 13.9 Hz) 2.15–2.04 (1H, m), 1.62–1.55 (1H, m),
1.51–1.44 (1H, m), 1.19–1.09 (1H, m); δC (100 MHz, CDCl3)
162.4, 151.2, 147.8, 137.5, 137.3, 133.2, 131.4, 131.1, 130.1,
128.9, 128.4, 128.1, 127.9, 127.0, 126.4, 126.1, 121.8, 119.8,
119.7, 81.4, 47.9, 45.1, 38.5, 36.6, 30.9, 21.4; HRMS (ESI+):
Found: 459.2436; C32H31N2O (MH+) Requires: 459.2431 (−1.2
ppm error).
6,6-Dibenzyl-1-methoxy-6,7,8,9-tetrahydro-5aH,11H-
pyrido[2,1-b][1,3] benzoxazin-11-one (5g). Synthesised using
the general DIA procedure from imine 1a (50.1 mg, 0.190
mmol), acid 2g (38.3 mg, 0.228 mmol), DIPEA (61.3 ꢀL, 0.352
mmol) and T3P (182 mg, 0.286 mmol) in toluene (1.5 mL) at 120
°C for 20 h. Purification by column chromatography (3:1 → 1:1
petrol:ethyl acetate → pure ethyl acetate ) afforded 5g as a white
solid (51.0 mg, 64%); m.p. 186–187 °C; Rf 0.29 (1:1 ethyl
acetate); νmax (thin film)/cm−1 1641, 1581, 1560, 1457, 1432,
1248, 1090; δH (400 MHz, CDCl3) 7.37 (1H, dd, J = 8.3, 8.3 Hz),
7.03-7.14 (8H, m), 7.10–7.05 (2H, m), 6.72 (1H, d, J = 8.3 Hz),
6.60 (1H, d, J = 8.3 Hz), 4.95 (1H, s), 4.67–4.60 (1H, m), 3.91
(3H, s) 3.23 (1H, d, J = 13.8 Hz), 3.19 (1H, d, J = 13.4 Hz), 2.90
(1H, d, J = 13.8 Hz), 2.47–2.37 (2H, m), 2.17–2.04 (1H, m),
1.65–1.53 (2H, m), 1.35–1.24 (1H, m); δC (100 MHz, CDCl3)
162.1, 160.7, 158.3, 137.5, 136.6, 134.3, 131.1, 128.1, 126.4,
126.3, 108.4, 109.5, 105.4, 88.4, 56.3, 42.0, 41.5, 41.4, 36.0,
27.5, 19.6; HRMS (ESI+): Found: 414.2075; C27H28NO3
(MH+) Requires: 414.2064 (−2.8 ppm error).
3,3-Dibenzyl-1,2,3,3a-tetrahydro-9H-pyrrolo[2,1-
b][1,3]benzoxazin-9-one (5q). Synthesised using general the
DIA procedure from imine 1b (33.2 mg, 0.133 mmol), acid 2a
(22.1 mg, 0.160 mmol), DIPEA (42.9 ꢀL, 0.246 mmol) and T3P
(127 mg, 0.200 mmol) in toluene (1.5 mL) at 120 °C for 20 h.
Purification by column chromatography (3:1 petrol:ethyl acetate)
afforded 5q as a yellow oil (23.7 mg, 48%). Rf 0.27 (2:1
petrol:ethyl acetate); νmax (thin film)/cm−1 2980, 1647, 1587,
1446, 1412, 1329, 1195, 1083, 1059, 693; δH (400 MHz,
CDCl3) 7.85 (1H, dd, J = 7.7, 1.7 Hz), 7.40 (1H, ddd, J = 8.2,
7.4, 1.7 Hz), 7.28–7.13 (8H, m), 7.07–7.00 (4H, m), 5.21 (1H,
s), 3.49–3.37 (2H, m), 2.95 (1H, d, J = 14.1), 2.96 (1H, d, J =
13.8 Hz), 2.89 (1H, d, J = 14.1 Hz), 2.73 (1H, d, J = 13.8 Hz),
1.81 (1H, ddd, J = 13.3, 6.7, 1.4 Hz), 1.62–1.56 (1H, m); δC (100
MHz, CDCl3) 161.3, 157.2, 137.4, 136.4, 134.0, 131.0, 130.9,
128.4, 128.4, 127.9, 126.8, 126.8, 122.7, 119.3, 116.7, 90.5,
48.0, 40.8, 40.2, 37.9, 26.4; HRMS (ESI+): Found: 370.1792;
C25H24NO2 (MH+) Requires: 370.1802 (2.7 ppm error).
6,6-Dibenzyl-1,3-dihydroxy-6,7,8,9-tetrahydro-5aH,11H-
pyrido[2,1 b][1,3] benzoxazin-11-one (5h). Synthesised using
the general DIA procedure from imine 1a (41.3 mg, 0.157
mmol), acid 2h (35.7 mg, 0.188 mmol), DIPEA (50.9 ꢀL, 0.290
mmol) and T3P (151 mg, 0.235 mmol) in toluene (1.5 mL) at 90
°C for 20 h. Purification by column chromatography (3:1 → 2:1
petrol:ethyl acetate) afforded 5h as a white solid (39.0 mg, 60%);
m.p. 135–136 °C; Rf 0.57 (1:1 petrol:ethyl acetate); νmax (thin
film)/cm−1 3269, 1619, 1589, 1491, 1471, 1441, 1293, 1257,
1137; δH (400 MHz, CDCl3) 12.10 (1H, br s), 7.35–7.20 (8H, m),
7.10–7.06 (2H, m), 6.09 (1H, d, J = 2.0 Hz), 6.01 (1H, d, J = 2.0
Hz), 5.48 (1H, br s), 4.96 (1H, s), 4.55–4.47 (1H, m), 3.18 (1H,
d, J = 13.7 Hz), 3.17 (1H, d, J = 13.4 Hz), 2.90 (1H, d, J = 13.7
Hz), 2.46–2.37 (2H, m), 2.15–2.05 (1H, m), 1.67–1.55 (2H, m),
1.37–1.22 (1H, m); δC (100 MHz, CDCl3) 167.0, 162.8, 162.8,
157.5, 137.0, 136.3, 131.0, 128.2, 128.2, 126.6, 126.5, 97.2,
95.2, 93.8, 88.9, 42.1, 41.4, 41.1, 35.7, 27.4, 19.4; HRMS
(ESI+): Found: 416.1847; C26H26NO4 (MH+) Requires:
416.1856 (2.3 ppm error).
3,3-Dibenzyl-1,2,3,3a-tetrahydro-9H-pyrrolo[2,1-
b][1,3]benzothiazin-9-one (5r). Synthesised using general the
DIA procedure from imine 1b (49.5 mg, 0.199 mmol), acid 2m
(36.7 mg, 0.238 mmol), DIPEA (64.0 ꢀL, 0.367 mmol) and T3P
(189 mg, 0.298 mmol) in toluene (1.5 mL) at 90 °C for 20 h.
Purification by column chromatography (5:1 petrol:ethyl acetate)
afforded 5r as a white solid (66.4 mg, 87%). Rf 0.80 (3:1
petrol:ethyl acetate); νmax (thin film)/cm−1 2874, 1620, 1567,
1424, 1387, 732, 694; δH (400 MHz, CDCl3) 8.00 (1H, d, J = 7.7
Hz), 7.32–7.25 (5H, m), 7.20–7.13 (7H, m), 6.98 (1H, d, J = 8.0
Hz), 4.91 (1H, s), 3.77–3.72 (1H, m), 3.67–3.60 (1H, m), 3.10
(1H, d, J = 13.6 Hz), 2.83 (1H, d, J = 14.0 Hz), 2.78 (1H, d, J =
14.0 Hz), 2.77 (1H, d, J = 13.6 Hz), 1.78 (1H, ddd, J = 12.3, 5.8,
0.9 Hz), 1.51–1.42 (1H, m); δC (100 MHz, CDCl3) 163.4, 137.1,
135.8, 134.8, 131.8, 130.9, 130.6, 129.9, 129.8, 128.4, 127.7,
126.9, 126.8, 126.0, 65.8, 49.8, 44.1, 41.1, 39.4, 27.1; HRMS
(ESI+): Found: 386.1574; C25H24NOS (MH+) Requires:
386.1573 (−0.2 ppm error).
6,6-Dibenzyl-6,7,8,9-tetrahydro-5aH,11H-dipyrido[2,1-
b:2',3'-e][1,3]oxazin-11-one (5l). Synthesised using the general
DIA procedure from imine 1a (43.0 mg, 0.163 mmol), acid 2l
(27.2 mg, 0.196 mmol), DIPEA (52.6 ꢀL, 0.302 mmol) and T3P
(156 mg, 0.245 mmol) in toluene (1.5 mL) at 90 °C for 20 h.
Purification by column chromatography (3:1 → petrol:ethyl
acetate → pure ethyl acetate → ethyl acetate, 10% MeOH)
afforded 5l as an orange oil (39.1 mg, 63%); Rf 0.23 (ethyl
acetate); νmax (thin film)/cm−1 1654, 1450, 1415, 1382, 1314,
1228, 718; δH (400 MHz, CDCl3) 8.47–8.43 (1H, m), 7.49–7.40
(2H, m), 7.34–7.19 (8H, m) 7.12–7.06 (2H, m), 5.19 (1H, s),
4.80–4.73 (1H, m), 3.25–3.17 (2H, m), 2.86 (1H, d, J = 13.7 Hz),

7
13a-Methyl-5,
13a-dihydro-6H,
8H-isoquinolino[1,2-
116.3, 73.4, 44.2, 27.6, 26.4; HRMS (ESI+): Found:
ACCEPTED MANUSCRIPT
b][1,3]benzothiazin-8-one (5u). Synthesised using the general
DIA procedure from imine 1c (37.7 mg, 0.287 mmol), acid 2m
(53.2 mg, 0.345 mmol), DIPEA (92.6 ꢀL, 0.532 mmol) and T3P
(274 mg, 0.431 mmol) in toluene (1.5 mL) at 120 °C for 20 h.
Purification by column chromatography (4:1 petrol:ethyl acetate)
afforded 5u as a white solid (74.4 mg, 97%). Rf 0.80 (2:1
petrol:ethyl acetate); νmax (thin film)/cm−1 1664, 1656, 1618,
1579, 1434, 1358, 1290, 1216, 1126, 731; δH (400 MHz,
CDCl3) 8.19 (1H, ddd, J = 7.7, 1.5, 0.6 Hz), 7.44–7.24 (7H, m),
6.24 (1H, s), 4.83–4.79 (1H, m), 3.24–3.11 (2H, m), 3.00–2.93
(1H, m); δC (100 MHz, CDCl3) 164.9, 137.8, 136.4, 131.8,
131.2, 130.8, 129.1, 128.9, 128.6, 127.7, 127.3, 127.0, 126.3,
60.7, 40.7, 29.6; HRMS (ESI+): Found: 268.0611;
C16H13NNaOS (MNa+) Requires: 290.0610 (−0.2 ppm error).
282.0958; C17H16NOS (MH+) Requires: 282.0947 (−3.8 ppm
error).
5,6,6-Trimethyl-5a,6-dihydroindolo[2,1-b]quinazolin-12(5H)-
one (5z). Synthesised using the general DIA procedure from
imine 1e (31.8 mg, 0.219 mmol), acid 2n (39.7 mg, 0.263 mmol),
DIPEA (70.6 ꢀL, 0.405 mmol) and T3P (210 mg, 0.329 mmol) in
toluene (1.5 mL) at 90 °C for 20 h. Purification by column
chromatography (19:1 petrol:ethyl acetate) afforded 5z as a
colourless oil (25.0 mg, 41%); Rf 0.64 (5:2 petrol:ethyl acetate);
νmax (thin film)/cm−1 2924, 1636, 15577, 1461, 1435, 1409,
1390, 741; δH (400 MHz, CDCl3) 8.35 (1H, dd, J = 8.0, 1.1 Hz),
8.10 (1H, dd, J = 7.8, 1.7 Hz), 7.45 (1H, ddd, J = 8.4, 7.3, 1.7
Hz), 7.31–7.27 (1H, m), 7.21 (1H, dd, J = 7.5, 1.4 Hz), 7.13 (1H,
ddd, 7.5, 7.5, 1.1 Hz), 6.96 (1H, ddd, J = 7.8, 7.3, 0.8 Hz), 6.88
(1H, d, J = 8.4 Hz), 4.98 (1H, s), 3.02 (3H, s), 1.70 (3H, s), 1.34
(3H, s); δC (100 MHz, CDCl3) 160.9, 149.5, 139.0, 138.8,
134.0, 128.6, 128.2, 124.5, 121.6, 119.3, 116.8, 116.8, 112.4,
85.2, 46.0, 34.8, 26.0, 23.3; HRMS (ESI+): Found: 279.1492;
C18H19N2O (MH+) Requires: 279.1492 (−0.1 ppm error).
2,3-Dimethoxy-5,13a-dihydro-6H,8H-isoquinolino[1,2-
b][1,3]benzoxazin-8-one (5w). Synthesised using the general
DIA procedure from imine 1d (66.6 mg, 0.348 mmol), acid 2a
(57.7 mg, 0.418 mmol), DIPEA (112 ꢀL, 0.644 mmol) and T3P
(332 mg, 0.522 mmol) in toluene (1.5 mL) at 90 °C for 20 h.
Purification by column chromatography (1:1 petrol:ethyl acetate)
afforded 5w as a white solid (51.6 mg, 48%); Rf 0.33 (ethyl
acetate); νmax (thin film)/cm−1 1641, 1587, 1494, 1446, 1394,
1247, 1209, 1095; δH (400 MHz, CDCl3) 8.03 (1H, dd, J = 7.8,
1.7 Hz), 7.48 (1H, ddd, J = 8.2, 7.3, 1.7 Hz), 7.16 (1H, ddd, J =
7.8, 7.3, 0.5 Hz), 7.08 (1H, dd, J = 8.2, 0.5 Hz), 7.03 (1H, s),
6.71 (1H, s), 6.23 (1H, s) 4.58 (1H, ddd, J = 12.8, 4.8, 3.5 Hz),
3.95 (3H, s), 3.92 (3H, s), 3.33 (1H, ddd, J = 12.8, 11.3, 3.5 Hz),
3.05 (1H, ddd, J = 15.6, 11.3, 4.8 Hz), 2.77 (1H, ddd, J = 15.6,
3.5, 3.5 Hz); δC (100 MHz, CDCl3) 163.1, 157.6, 150.0, 148.4,
134.2, 129.1, 128.7, 122.8, 122.4, 118.8, 116.6, 111.0, 110.6,
84.2, 56.2, 56.1, 38.4, 28.1; HRMS (ESI+): Found: 334.1058;
C18H17NNaO4 (MNa+) Requires: 334.1050 (−2.6 ppm error).
6,7,8,9-Tetrahydro-5aH,11H-pyrido[2,1-b][1,3]benzothiazin-
11-one (5aa).23 Synthesised using the general DIA procedure
from imine 1f (47.3 mg, 0.190 mmol), acid 2m (105 mg, 0.683
mmol), DIPEA (184 ꢀL, 0.510 mmol) and T3P (544 mg, 0.854
mmol) in toluene (2 mL) at 90 °C for 20 h. Purification by
column chromatography (5:0.5:0.5 petrol:ethyl acetate:CH2Cl2)
afforded 5aa as a white solid (39.0 mg, 31%). Rf 0.76 (ethyl
23
acetate); m.p. 52–54 °C (literature 53.5–54.5 °C); νmax (thin
film)/cm−1 3062, 2939, 2858, 1635, 1440, 1275, 1204, 920, 742;
δH (400 MHz, CDCl3) 8.16 (1H, dd, J = 7.7, 1.2 Hz), 7.35 (1H,
ddd, J = 7.7, 7.7, 1.2 Hz), 7.23 (1H, ddd, J = 7.7, 7.7, 1.2 Hz),
7.18 (1H, dd, J = 7.7, 1.2 Hz), 4.83 (1H, dd, J = 10.8, 3.8 Hz),
4.50–4.59 (1H, m), 2.98 (1H, ddd, J = 13.5, 11.8, 4.0 Hz), 2.10–
2.01 (1H, m), 2.01–1.88 (2H, m), 1.87–1.75 (1H), 1.74–1.49 (2H,
m); δC (100 MHz, CDCl3); 164.7, 134.8, 131.9, 130.6, 127.7,
126.4, 125.8, 59.0, 44.5, 31.9, 23.7, 23.1; HRMS (ESI+): Found:
220.0792; C12H14NOS (MH+) Requires: 220.0791 (−0.8 ppm
error).23
2,3-Dimethoxy-13-methyl-5,6,13,13a-tetrahydro-8H-
isoquinolino[1,2-b]quinazolin-8-one (5x). Synthesised using the
general DIA procedure from imine 1d (76.9 mg, 0.402 mmol),
acid 2n (73.0 mg, 0.483 mmol), DIPEA (130 ꢀL, 0.744 mmol)
and T3P (384 mg, 0.603 mmol) in toluene (1.5 mL) at 90 °C for
20 h. Purification by column chromatography (1:1 petrol:ethyl
acetate) afforded 5x as a colourless oil (114 mg, 87%); Rf 0.54
(ethyl acetate); νmax (thin film)/cm−1 1625, 1583, 1492, 1446,
1401, 1342, 1318, 1241, 1215, 1094, 1001, 746; δH (400 MHz,
CDCl3) 8.07–8.04 (1H, m), 7.47–7.42 (1H, m), 7.13–7.09 (2H,
m), 6.87 (1H, s), 6.67 (1H, s), 5.66 (1H, m), 4.64 (1H, ddd, J =
12.8, 5.0, 2.7 Hz), 3.89 (3H, s), 3.88 (3H, s), 3.20–3.13 (1H, m),
2.95–2.87 (1H, m), 2.78–2.71 (1H, m), 2.47 (3H, s); δC (100
MHz, CDCl3) 164.6, 151.2, 149.1, 148.3, 133.0, 129.7, 128.9,
123.7, 122.9, 122.8, 121.0, 111.0, 110.8, 71.3, 56.2, 56.0,
39.1, 36.0, 28.3; HRMS (ESI+): Found: 347.1361;
C19H21N2NaO3 (MNa+) Requires: 347.1366 (1.6 ppm error).
5,13a-Dihydro-6H,8H-isoquinolino[1,2-b][1,3]benzothiazin-
8-one (5ac). Synthesised using the general DIA procedure from
imine 1g (40.0 mg, 0.275 mmol), acid 2m (51.0 mg, 0.330
mmol), DIPEA (88.7 ꢀL, 0.510 mmol) and T3P (263 mg, 0.413
mmol) in toluene (1.5 mL) at 120 °C for 20 h. Purification by
column chromatography (5:1 petrol:ethyl acetate) afforded 5ac as
an orange oil (58.5 mg, 80%); Rf 0.34 (5:1 petrol:ethyl acetate);
νmax (thin film)/cm−1 2879, 1657, 1618, 1609, 1564, 1422,
1366, 1332, 1275, 1231, 732; δH (400 MHz, CDCl3) 8.15 (1H,
ddd, J = 7.8, 1.5, 0.5 Hz), 7.42 (1H, dd, J = 7.8, 1.6 Hz), 7.35
(1H, ddd, J = 7.7, 7.7, 1.6 Hz), 7.30–7.15 (5H, m), 5.04 (1H,
ddd, 12.6, 9.7, 1.9 Hz), 3.03 (1H, ddd, J = 15.4, 12.6, 9.7 Hz),
2.93 (1H, ddd, J = 12.6, 12.6, 2.8 Hz), 2.86 (1H, ddd, J = 15.4,
2.8, 1.9 Hz), 1.91 (3H, s); δC (100 MHz, CDCl3) 163.6, 135.8,
135.4, 134.8, 132.1, 130.9, 129.4, 128.2, 128.1, 127.3, 127.1,
126.2, 126.1, 65.9, 37.3, 29.7, 28.5; HRMS (ESI+): Found:
304.0766; C17H15NNaOS (MNa+) Requires: 304.0767 (0.3
ppm error).
6,6-Dimethyl-5a,6-dihydro-12H-indolo[2,1-
b][1,3]benzothiazin-12-one (5y). Synthesised using the general
DIA procedure from imine 1e (38.8 mg, 0.267 mmol), acid 2m
(49.4 mg, 0.321 mmol), DIPEA (86.1 ꢀL, 0.494 mmol) and T3P
(255 mg, 0.401 mmol) in toluene (1.5 mL) at 90 °C for 20 h.
Purification by column chromatography (19:1 petrol:ethyl
acetate) afforded 5y as a colourless oil (39.7 mg, 53%); Rf 0.76
(1:1 petrol:ethyl acetate); νmax (thin film)/cm−1 2918, 1625,
1572, 1457, 1369, 1310, 1269, 1143, 1078, 739; δH (400 MHz,
CDCl3) 8.35 (1H, ddd, J = 8.1, 1.0, 0.6 Hz), 8.22 (1H, ddd, J =
7.8, 1.5, 0.5 Hz), 7.44–7.28 (4H, m), 7.21 (1H, ddd, J = 7.5, 1.4,
0.6 Hz), 7.14 (1H, ddd, 7.4, 7.4, 1.1 Hz), 5.43 (1H, s, H-1), 1.53
(3H, s), 1.45 (3H, s); δC (100 MHz, CDCl3) 162.1, 140.2, 138.5,
135.1, 132.1, 130.4, 130.4, 128.3, 127.8, 126.4, 124.6, 121.8,
3-Methyl-1,2-diphenyl-2,3-dihydroquinazolin-4(1H)-one
(5af). Synthesised using the general DIA procedure from imine
1i (24.6 ꢀL, 0.200 mmol), acid 2o (51.2 mg, 0.240 mmol),
DIPEA (64.5 ꢀL, 0.370 mmol) and T3P (191 mg, 0.300 mmol) in
toluene (2.0 mL) at 90 °C for 20 h. Purification by column
chromatography (4:1 petrol:ethyl acetate) afforded 5af as a white
solid (43.0 mg, 68%). m.p. 220–223 °C; Rf 0.57 (ethyl acetate);
νmax (thin film)/cm−1 1625, 1581, 1471, 1373, 1279, 1238,

8
Tetrahedron
ACCEPTED MANUSCRIPT
1207; δH (400 MHz, CDCl3) 8.02 (1H, dd, J = 7.9, 1.2 Hz),
0.808 mmol) in THF (10 mL) and heated at 70 °C for 2 h,
7.37–7.24 (8H, m), 7.19–7.13 (3H, m), 6.96 (1H, ddd, J = 7.9,
7.9, 1.1 Hz), 6.85 (1H, dd, J = 8.2, 1.1 Hz), 5.96 (1H, s), 3.18
(3H, s); δC (100 MHz, CDCl3) 162.8, 146.1, 143.9, 139.3,
133.0, 129.8, 128.9, 128.8, 128.6, 126.5, 124.8, 123.3, 121.3,
120.5, 118.8, 80.0, 34.3; HRMS (ESI+): Found: 315.1493;
C21H19N2O (MH+) Requires: 315.1492 (−0.5 ppm error).
before it was cooled to 0 °C and quenched by the sequential
addition of water (0.031 mL), 15 % aq. NaOH (0.031 mL) and
water (0.092 mL). The resulting solids were removed by
filtration and washed with EtOAc. The solids were then
collected and refluxed in EtOAc for 2 h and filtered a second
time. The combined filtrates were dried with MgSO4 and
evaporated. Purification by column chromatography (1:1 petrol:
ethyl acetate→ EtOAc) afforded 10 as a yellow solid; (35.7
mg, 43 %); Rf 0.6 (ethyl acetate); mp: 145–147 °C (literature
193–195 °C);18c νmax (thin film)/cm−1 3261, 2924, 1609, 1516,
1462, 1360, 1257, 1232, 11209, 1138, 1044; δH (400 MHz,
CDCl3) 6.78 (2H, s), 6.64 (1H, br s), 6.61 (1H, br s), 6.01 (1H, d,
J = 1.5 Hz), 5.95 (1H, d, J = 1.5 Hz), 4.14 (1H, d, J = 15.2 Hz),
4.00 (1H, br s), 3.88 (3H, s), 3.66 (3H, s), 3.75 (1H, dd, J = 10.4,
2.0 Hz), 3.58–3.54 (1H, m), 3.53 (1H, d, J = 15.2 Hz), 3.19–3.15
(3H, m), 2.68–2.56 (2H, m); δC (100 MHz, CDCl3) 147.8,
147.8, 145.5, 143.1, 131.0, 127.9, 126.3, 120.9, 117.2, 111.5,
108.4, 107.4, 101.2, 66.0, 63.4, 56.1, 55.9, 53.0, 51.2, 43.9,
29.0; HRMS (ESI+): Found: 370.1632; C21H24NO5 (MH+)
Requires: 370.1649 (4.4 ppm error); Obtained data in accord
with those reported in the literature.18c
5-(1,3-Dimethoxy-1,3-dioxopropan-2-yl)-1,3-benzodioxole-4-
carboxylic acid (2q). Sodium hydride (60 % in mineral oil, 419
mg, 10.5 mmol) was added portionwise to a rapidly stirred cold
suspension (0 °C) of 5-bromobenzo[1,3]dioxole-4-carboxylic
acid 9 (1.00 g, 4.37 mmol), cuprous bromide (62.6 mg, 0.437
mmol) and dimethyl malonate (17.3 mL). After the addition of
the sodium hydride had been completed, the mixture was stirred
for 10 min at r.t and then for 20 h at 70 °C. The suspension,
which had turned to a solid mass, was dissolved in water (30
mL), washed with ether (3 × 80 mL) and then acidified with 10%
HCl. The acidic aqueous layer, was extracted with ethyl acetate
(3 × 100 mL), and the organic extracts were dried over MgSO4
and concentrated in vacuo. Purification by column
chromatography (5:1 → pure ethyl acetate) afforded 2q as a
colourless solid (1.01 g, 74%); Rf 0.1 (1:1 petrol:ethyl acetate);
m.p. 88–93 °C; νmax (thin film)/cm−1 2912, 2877, 1704, 1688,
1456, 1431, 1216, 1137, 1039, 1012; δH (400 MHz, CDCl3) 6.95
(1H, d, J = 8.2 Hz), 6.88 (1H, d, J = 8.2 Hz), 6.11 (2H, s), 5.53
(1H, s), 3.76 (6H, s); δC (100 MHz, CDCl3) 169.2, 149.7, 148.5,
127.1, 123.9, 111.9, 107.3, 102.5, 100.0, 54.2, 53.0; HRMS
(ESI+): Found: 319.0424; C13H12NaO8 (MNa+) Requires:
319.0424 (0.2 ppm error).
(±)-cis-2,3-Dimethoxy-8-oxo-9,10-(methylenedioxy)13-
(methanesulfoxymethyl)
tetrahydro
protoberberine.
Methanesulfonyl chloride (23.8 ꢀL, 0.308 mmol) was added
to a solution of alcohol 10 (35.5 mg, 0.096) in pyridine (1
mL). The reaction mixture was stirred at r.t. for 1.5 h and then
quenched with water (10 mL). The mixture was extracted with
Et2O (3 × 20 mL). The organic extract was dried and
evaporated. Purification by column chromatography (2:1 → 1:1
hexene:ethyl acetate → EtOAc) afforded the title compound as
a yellow oil (25.5 mg, 68 %); Rf 0.9 (ethyl acetate); νmax (thin
film)/cm−1 2936, 1517, 1462, 1353, 1334, 1172, 1142, 1041,
955, 730; δH (400 MHz, CDCl3) 6.84 (1H, d, J = 8.0 Hz), 6.75
(1H, s), 6.73 (1H, d, J = 8.0 Hz), 6.61 (1H, s), 6.00 (1H, d, J =
1.4 Hz), 5.97 (1H, d, J = 1.4 Hz), 4.22–4.08 (3H, m), 3.92–3.86
(2H, m), 3.90 (3H, s), 3.88 (3H, s), 3.56–3.52 (2H, m), 3.11–3.00
(2H, m), 2.63–2.55 (1H, m), 2.62 (3H, s); δC (100 MHz, CDCl3)
147.8, 147.4, 145.3, 142.9, 132.9, 128.1, 126.3, 1261, 123.1,
111.4, 108.5, 106.7, 101.4, 72.4, 61.5, 56.2, 56.0, 53.2, 51.2,
43.7, 36.8, 29.2; HRMS (ESI+): Found: 448.1427;
C22H26NO7S (MH+) Requires: 448.1424 (–1.3 ppm error);
Dimethyl
8,9-dimethoxy-14-oxo-11,12-dihydro-6aH-
[1,3]dioxolo[4,5-h]isoquino [2,1-b] isoquinoline-6,6(14H)-
dicarboxylate (5ai). To a solution of imine 1d (484 mg, 2.53
mmol), and acid 2q (900 mg, 3.04 mmol) in chloroform (25 mL)
was added sequentially DIPEA (0.815 mL, 4.68 mmol) and T3P
(2.42 g, 3.80 mmol, 50% solution in THF). The resulting solution
was stirred for 20 min at r.t. before BCl3 (5.10 mL, 5.10 mmol,
1.0 M solution in DCM) was added. The resulting solution was
stirred at r.t. for 20 h before it was poured into sat. aq. NaHCO3
(100 mL). The aqueous layer was extracted with DCM (3 × 100
mL), dried over MgSO4, concentrated in vacuo and purified by
column chromatography (1:1 → 1:2 petrol:ethyl acetate) to
afford 5ai as a yellow solid (819 mg, 69%); Rf 0.5 (ethyl acetate);
m.p. 152–156 °C; νmax (thin film)/cm−1 2908, 1707, 1626,
1588, 1494, 1440, 1412, 1103, 1029, 718; δH (400 MHz,
CDCl3) 6.91 (1H, d, J = 8.1 Hz), 6.81 (1H, s), 6.69 (1H, s), 6.54
(1H, d, J = 8.1 Hz), 6.22 (1H, d, J = 1.3 Hz), 6.10 (1H, d, 1.3
Hz), 5.58 (1H, s), 4.85–4.78 (1H, m), 3.88 (3H, s), 3.87 (3H, s),
3.80 (3H, s), 3.51 (3H, s), 2.92–2.87 (2H, m), 2.67–2.64 (1H,
m); δC (100 MHz, CDCl3) 170.1, 167.0, 162.0, 149.0, 148.3,
148.2, 147.1, 131.6, 130.3, 123.1, 120.1, 112.2, 111.1, 110.9,
110.7, 102.7, 65.9, 61.2, 55.9, 55.7, 53.0, 52.9, 39.3, 28.9;
HRMS (ESI+): Found: 470.1454; C24H24NO9 (MH+) Requires:
470.1446 (−1.7 ppm error).
(±)-Cavidine (8) To a solution of (±)-cis-2,3-dimethoxy-8-
oxo-9,10-(methylenedioxy)13-(methanesulfoxymethyl)
tetrahydro protoberberine (22.4 mg, 0.058 mmol) in 95% EtOH
(3.5 mL) was added NaBH4 (32.8 mg, 0.867 mmol). The
resulting mixture was heated at reflux (80 °C) for 2 h and then
poured into H2O (15 mL). The aqueous phase was extracted
with CH2Cl2 (3 × 20 mL). The organic extracts were dried
(MgSO4) and evaporated to yield the crude product.
Purification by column chromatography (5:1 hexane:ethyl
acetate) afforded cavidine 8 as a white solid (13.6 mg, 67 %);
Rf 0.4 (1:1 hexane:ethyl acetate); mp: 180–184 °C (literature
188–189 °C) νmax (thin film)/cm−1 2909, 2757, 1514, 1457,
1333, 1356, 1254, 1228, 1042, 729; δH (400 MHz, CDCl3) 6.72
(1H, d, J = 8.0 Hz), 6.68 (1H, s), 6.67 (1H, d, J = 8.0 Hz), 6.61
(1H, s), 5.97 (1H, d, J = 1.5 Hz), 5.93 (1H, d, J = 1.5 Hz), 4.09
(1H, d, J = 15.3 Hz), 3.88 (3H, s), 3.88 (3H, s), 3.73 (1H, br. s),
3.50 (1H, d, J = 15.3 Hz), 3.28–3.22 (1H, m), 3.16–3.07 (2H, m),
2.63–2.57 (2H, m), 0.94 (3H, d, J = 6.9 Hz); δC (100 MHz,
CDCl3) 147.6, 147.1, 144.6, 143.0, 135.9, 128.3, 128.3, 121.2,
116.8, 111.1, 108.5, 106.7, 101.0, 63.1, 56.1, 55.8, 53.3, 51.2,
38.5, 29.3, 18.4; HRMS (ESI+): Found: 354.1683; C21H24NO4
(MH+) Requires: 354.1700 (4.3 ppm error); Obtained data in
accord with those reported in the literature.14j-k, 18c
(±)-cis-2,3-Dimethoxy-8-oxo-9,10-(methylenedioxy)13-
(hydroxymethyl) tetrahydro protoberberine (10). To a round
bottom flask containing diester 5ai (106.5 mg, 0.227 mmol) in
THF (0.7 mL), lithium hydroxide monohydrade (28.6 mg, 0.681
mmol) in water (0.7 mL) was added at r.t. The reaction mixture
was stirred for 16 h at 90 °C. The solution was diluted with water
(10 mL), washed with DCM (10 mL) and then acidified with
10% aq. HCl. The acidic aqueous layer was then extracted with
ethyl acetate (3 × 20 mL), and the organic extracts were dried
over MgSO4 and concentrated in vacuo. The crude reaction
mixture was then added to a solution of LiAlH4 (30.7 mg,

9
16. Taguchi, H.; Imaseki, I.; Yakugaku Zasshi 1964, 84, 955.
Acknowledgements
ACCEPTED MANUSCRIPT
17. Yu, C. K.; Maclean, D. B.; Rodrigo, R. G. A.; Manske, R. H. F. Canad.
J. Chem. 1970, 48, 3673.
The authors thank the University of York Wild Fund for a
PhD bursary (C.K.), the EPSRC and the University of York for
18. (a) Ninomiya, I.; Takasugi, H.; Naito, T. Heterocycles 1973, 1, 17; (b)
Ninomiya, I.; Naito, T.; Takasugi, H. J. Chem. Soc. Perkin Trans. I,
1975, 1791; (c) Iwasa, K.; Gupta, Y. P.; Cushman, M. J. Org. Chem.
1981, 46, 4744; (d) Bhakuni, D. S.; Jain, S.; Gupta, S. Tetrahedron
1986, 42, 675.
postdoctoral
support
(W.P.U.,
EP/G068313/1;
G.C.,
EP/J016128/1) and Archimica for the generous donation of T3P.
† Dedicated to the memory of Sandy McKillop– colleague,
mentor, collaborator and friend.
19. Malamas, M. S. J. Heterocyclic Chem. 1994, 31, 565.
20. This reaction was also tested at 50 °C under otherwise identical
conditions but, as its crude 1H NMR spectra appeared to contain less of
product 5al than the analogous RT reaction, the product was not
isolated.
References and notes
21. We attempted the same reaction using LiAlH4 in THF/ether (as reported
by Cushman, see reference 18c) but this reaction was unsuccessful in
our hands.
22. Malamas, M. S.; Hohman, T. C.; Millen, J. J. Med. Chem. 1994, 37,
2043.
1. (1) (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003,
103, 893; (b) Comprehensive Heterocyclic Chemistry III; Katritzky, A.
R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K., Eds. Elsevier:
Oxford, 2008, and references therein.
2. (a) Morton, D.; Leach, S.; Cordier, C.; Warriner, S.; Nelson, A. Angew.
Chem. Int. Ed. 2009, 48, 104; (b) Spandl, R. J.; Bender, A.; Spring, D.
R. Org. Biomol. Chem. 2008, 6, 1149; (c) Lipkus. A. R.; Yuan, Q.;
Lucas, K. A.; Funk, S. A.; Bartelt III, W. F.; Schenck, R. J; Trippe, A. J.
J. Org. Chem. 2008, 73, 4443.
23. This compound is known but no NMR data were reported previously:
Rothe, M.; Steinberger, R. Tetrahedron Lett. 1970, 11, 2467.
3. Unsworth, W. P.; Kitsiou C.; Taylor, R. J. K. Org. Lett., 2013, 15, 258.
4. Wissmann, H.; Kleiner, H.-J. Angew. Chem., Int. Ed., 1980, 19, 133.
5. Unsworth, W. P.; Coulthard, G.; Kitsiou C.; Taylor, R. J. K. J. Org.
Chem. 2014, 79, 1368.
6. This synthesis later inspired the first total synthesis of the related natural
product dievodiame: Unsworth, W. P. Kitsiou C.; Taylor, R. J. K. Org.
Lett., 2013, 15, 3302.
7. (a) Unsworth, W. P.; Gallagher, K. A.; Jean, M.; Schmidt, J. P.;
Diorazio, L. J.; Taylor, R. J. K. Org. Lett., 2013, 15, 262; (b) Unsworth,
W. P.; Taylor, R. J. K. Org. Biomol. Chem. 2013, 11, 7241.
8. (a) Shi, J.; Manolikakes, G.; Yeh, C-H.; Guerrero, C. A.; Shenvi, R. A.;
Shigehisa, H.; Baran, P. S. J. Am.Chem. Soc. 2011, 133, 8014; (b)
Miyazaki, M.; Nami, A.; Keita, S.; Yuki, S.; Hiromi, F.; Takuya, K.;
Kazuhiro, N.; Yuki, O.; Kazuo, T. N.; Takashi, I. J. Org. Chem., 2011,
76, 534; (c) Liu, K. G.; Robichaud, A. J.; Lo, J. R.; Mattes, J. F.; Cai, Y.
Org. Lett. 2006, 8, 5769; (d) Rachelot, P.; Vanelle, P.; Gasquet, M.;
Delmas, F.; Crozet, M. P.; Timon-David, P.; Maldonado, J. Eur. J. Med.
Chem. 1995, 30, 503; (e) Movassaghi, M.; Hill, M. D. Org. Lett. 2008,
10, 3485; (f) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T.
Angew. Chem. Int. Ed. 2003, 42, 4077.
9. (a) Schöpf, C; Komzak, A.; Braun, F.; Jacobi, E.; Bormuth, M.-L.;
Bullnheimer, M.; Hagel, I. Liebigs Ann. 1948, 559, 1. (b) Barker, G.;
McGrath, J. L.; Klapars, A.; Stead, D.; Zhou, G.; Campos, K. R.;
O’Brien, P. J. Org. Chem. 2011, 76, 5936.
10. Dannhardt, G.; Bauer, A.; Nowe, U. J. Prakt. Chem. 1998, 340, 256.
11. Böhme, H.; Hartke, K. Chem. Ber. 1963, 96, 600.
12. Related scaffolds have been prepared previously: Sieck, O.; Ehwald,
M.; Liebscher, J. Tetrahedron Lett. 2000, 29, 5479.
13. (a) Nakasato, T.; Asada. S.; Murai. K. J. Pharm. Soc. Jpn. 1962, 82,
619; (b) Kobayashi, Y.; Nakano, Y.; Kizaki, M.; Hoshikuma, K.;
Yokoo, Y.; Kamiya, T. Planta Medica 2001, 67, 628; (c) Dong, G.;
Sheng, C. S.; Wang, S.; Miao, Z.; Yao, J.; Zhang, W. J. Med. Chem.
2010, 53, 7521.
14. (a) Gear, J.R.; Spenser, I.D. Can. J. Chem. 1963, 41, 783; (b) Beecher,
C.W.W.; Kelleher, W. J. Tetrahedron Lett. 1984, 25, 4595. (c)
Kobayashi, M.; Frenzel, T.; Lee, J.P.; Zenk, M.H.; Floss, H. G. J. Am.
Chem. Soc. 1987, 109, 6184. (d) Jendrzejewski, S. Phytochemistry
1990, 29, 135. (e) Amann, M.; Nagakura, N.; Zenk, M. H. Eur. J.
Biochem. 1988, 175, 17. (f) Kametani, T.; Takemura, M.; Ihara, M.;
Takahashi, K.; Fukumoto, K. J. Am. Chem. Soc. 1976, 98, 1956. (g)
Jeffs, P. W.; Scharver, J. D. J. Am. Chem. Soc. 1976, 98, 4301. (h)
Bhakuni, D. S.; Gusta, S.; Jain, S. Tetrahedron 1983, 39, 4003. (i)
Grycova, L.; Dostal, J.; Marek, R. Phytochemistry 2007, 68, 150. (j)
Niu, X-F.; Xu, H-B.; Liu, X.; Fan, T.; Qi, L. Chem. Nat. Compd. 2013,
49, 187; (k) Hughes, D. W.; Holland, H. L.; Maclean, D. B. Can. J.
Chem. 1976, 54, 2252.
15. (a) Vollecova, A.; Kost’alova, D.; Kettmann, V.; Toth, J. Phytother.
Res. 2003, 17, 834; (b) Hwang, J. M.; Kuo, H. C.; Tseng, T. H.; Chu, C.
Y. Arch. Toxicol. 2006, 80, 62; (c) Manshahidi, M.; Hosstinzadeh, H.
Phytother. Res. 2008, 22, 999; (d) Lo, C-Y.; Hsu, L-C.; Chen, M-S.;
Lin, Y-J.; Chen, L-G.; Kuo, C-D.; Wu, J-Y. Bioorg. Med. Chem. Lett.
2013, 23, 305; (e) Huang, Q-Q.; Bi, J-L.; Sun, Q-Y, Yang, F-M.; Wang,
Y-H.; Tang, G-H.; Zhao, F-W.; Wang, H.; Xu, J-J.; Kennelly, E. J.;
Long, C-L.; Yin, G-F. Planta Med. 2012, 78, 65; (f) Sun, H.; Zhu, L.;
Yang, H.; Qian, W.; Guo, L.; Zhou, S.; Gao, B.; Li, Z.; Zhou, Y.; Jiang,
H.; Chen, K.; Zhen, X.; Liu, H. Bioorg. Med. Chem. 2013, 21, 856.