A Highly Stereocontrolled, One-Pot Approach toward Pyrrolobenzoxazinones and Pyrroloquinazolinones through a Lewis Acid-Catalyzed [3 + 2]-Cycloannulation Process

Article abstract of DOI:10.1021/acs.joc.5b01293

We report herein a stereocontrolled [3 + 2]-cycloheteroannulation of bis-silyl dienediolate 1 with 2-aminobenzoic acid- and 2-aminobenzamide-derived imines to furnish highly substituted pyrrolo[1,2-a]benzoxazinones 3 and pyrrolo[1,2-a]quinazolinones 4, respectively, in good overall yields. This one-pot process rapidly generates molecular complexity and comprises a Lewis acid-catalyzed, vinylogous Mannich reaction of 1 followed by an intramolecular N,O-acetal- and N,N-aminal formation, respectively, which proceeds with good to excellent stereocontrol.

Full text of DOI:10.1021/acs.joc.5b01293

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The Journal of Organic Chemistry
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A Highly Stereocontrolled, OneꢀPot Approach towards
Pyrrolobenzoxazinones and Pyrroloquinazolinones
through a Lewis AcidꢀCatalyzed [3+2]ꢀCycloannulation
Process
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Michael Boomhoff, Rostyslav Ukis, and Christoph Schneider*
Institut für Organische Chemie, University of Leipzig, Johannisallee 29, Dꢀ04103 Leipzig (Germany)
*Email: schneider@chemie.uniꢀleipzig.de
R2
R2
R1
1.) 20 mol% Sm(OTf)3
2.) 1 equivDNBSA
OTMS
OEt
O
N
+
+
R1
H
CH2Cl2/tBuOH(2:1),
H2N
O
OTMS
X
O
-20°C
EtO2C
HX
X = O
: 58-99% (19 examples)
X = NH: 62-82% (18 examples)
ABSTRACT: We report herein a stereocontrolled [3+2]ꢀcycloheteroannulation of bisꢀsilyl
dienediolate 1 with 2ꢀaminobenzoic acidꢀ and 2ꢀaminobenzamideꢀderived imines to furnish highly
substituted pyrrolo[1,2ꢀa]benzoxazinones 3 and pyrrolo[1,2ꢀa]quinazolinones 4, respectively, in good
overall yields. This oneꢀpot process rapidly generates molecular complexity and comprises a Lewis
acidꢀcatalyzed, vinylogous Mannich reaction of 1 followed by an intramolecular N,Oꢀacetalꢀ and N,Nꢀ
aminal formation, respectively, which proceeds with good to excellent stereocontrol.
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INTRODUCTION
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The rapid and stereocontrolled synthesis of novel heterocyclic scaffolds which are relevant for
biological studies and pharmaceutical applications is currently among the prime objectives in synthetic
organic chemistry.1 In the pursuit of this goal domino and sequential reactions that lead to multiple bond
forming events in a oneꢀpot operation are particularly attractive processes as they feature operational
simplicity, flexibility, and efficiency.2 In addition, such processes typically give rise to new reactive
functional groups and stereogenic centers which are ideally established with high stereoselectivity.
The benzoxazinone and dihydroquinazolinone motifs range prominent among nitrogenꢀcontaining
heterocycles due to their occurrence in a broad range of biologically active natural products,
pharmaceuticals, and agrochemicals.3 Pharmaceutical activities associated with them include
antimalarial,4 antidiabetic,5 anticancer,6 antibacterial,7 and antihypertensive properties.8 Moreover, these
structures are occasionally fused with other heterocycles and the corresponding pyrrolobenzoxazinones
and pyrroloquinazolinones stand as two representative examples.9
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The classical approach of synthesizing both the benzoxazinone and quinazolinone skeletons is based
on the acidꢀcatalyzed condensation of 2ꢀaminobenzoic acid and 2ꢀaminobenzamide, respectively, with
carbonyl compounds furnishing directly the desired target molecules.10 Moreover, the groups of List11
and Rueping12 have developed Brønsted acidꢀcatalyzed protocols to execute these reactions in a highly
enantioselective fashion and access optically highly enriched quinazolinones. In addition, copperꢀ
catalyzed protocols for the synthesis of 2ꢀaryl quinazolinones have been reported that comprise Ullmanꢀ
type couplings of amines and orthoꢀhalogenꢀsubstituted benzamides and subsequent CHꢀamidation to
effect the cyclization.13 Very recently, goldꢀcatalyzed hydroaminationꢀcyclization processes have been
added to the arsenal of synthetic chemists as well to prepare fused pyrrolobenzoxazinones and
pyrroloquinazolinones.14
We have recently described a novel threeꢀcomponent, oneꢀpot [3+2]ꢀcycloannulation process that
furnished a broad range of tetrahydropyrrolo[2,1ꢀb]benzoxazoles 2 in good yields thereby establishing
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four new σꢀbonds and two new stereogenic centers with excellent diastereoselectivity in a dominoꢀtype
fashion (Scheme 1).15a Mechanistically, this transformation was initiated by a Lewis acidꢀcatalyzed,
vinylogous Mannich reaction of the new bisꢀsilyl dienediolate 1 with orthoꢀhydroxy anilineꢀderived
imines followed by hydrolysis of the silyl enol ether moiety formed as an intermediate and finally N,Oꢀ
acetalization of the in situ formed αꢀketo ester moiety that closed the pyrrolidine ring.
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Scheme 1. The [3+2]-Cycloannulation Process towards Tetrahydropyrrolo[2,1-b]benzoxazoles 2
We reasoned that this powerful and straightforward synthesis of fused pyrrolidines could be extended
to other heterocyclic frameworks in the event that other imines with a secondary nucleophilic site would
participate in this process as well. We now report our findings on the oneꢀpot, highly diastereoselective
synthesis of related pyrrolo[1,2ꢀa]benzoxazinones and pyrrolo[1,2ꢀa]quinazolinones by application of
this strategy.16
RESULTS AND DISCUSSION
As an alternative to orthoꢀhydroxy aniline we envisioned anthranilic acid as a suitable amine
component for our threeꢀcomponent cycloannulation strategy which was expected to give rise to
pyrrolobenzoxazinones as the final products. Thus, we started our investigations with the model reaction
of anthranilic acid (1.0 equiv.), benzaldehyde (1.2 equiv.), and 1,2ꢀbis-silyldienediolate (2.0 equiv.) 1 in
tBuOH and in the presence of various lanthanide triflates (20 mol%) and H2O (1 equiv.). Waterꢀtolerant
Lewis acids such as Yb(OTf)3 and in particular Sm(OTf)3 turned out to be the most suitable catalysts for
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this transformation in terms of yield and selectivity. Thus, Sm(OTf)3 furnished
pyrrolo[1,2ꢀa]benzoxazinone 3a with 71% yield as mainly the cisꢀstereoisomer (89:11 cis/trans) after 4
h at rt while Yb(OTf)3 gave rise to the product with comparable yield but slightly reduced selectivity of
85:15 cis/trans (Scheme 2).
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Scheme 2. Preliminary Studies for the Synthesis of cis-3a
When we attempted to apply this strategy to other pyrrolobenzoxazinones we obtained the desired
products in good yields, but unfortunately with no diastereoselectivity whatsoever. Eventually, we were
able to trace this phenomenon back to a precipitation of the cisꢀstereoisomer 3a during cyclization
which led to its enrichment, but occurred only in this specific case. Therefore, other conditions were
required to obtain the pyrrolobenzoxazinones selectively.
As the diastereoselectivity of this process is determined in the cyclization, the second step of this
sequence, we attempted to add various acidic and basic additives after completion of the vinylogous
Mannich reaction in order to speed up the cyclization at potentially lower temperatures.15 However, the
use of tetraꢀnꢀbutylammonium fluoride to facilitate the desilylation gave only low yields in the solvent
mixture CH2Cl2/tBuOH (2:1), which was important to dissolve both the starting materials and the
product (Table 1, entry 1). Brønsted acids proved to be more efficient. Thus, trifluoroacetic acid
mediated the second step at rt in very good yields, albeit with no selectivity (entry 2). Lowering the
temperature to ꢀ20°C improved the selectivity slightly to 57:43 (cis/trans; entry 3). Variation of the
solvent mixture lead to undesired precipitation, no reaction or no selectivity (entries 4ꢀ7). We next
investigated the influence of the Brønsted acid on the diastereoselectivity. Among the acids
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investigated, 2,4ꢀdinitrobenzenesulfonic acid (DNBSA) gave the best result with a ratio of 85:15
favoring the cisꢀisomer and a combined yield of 61% (entries 8ꢀ13).
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We assume that the pronounced kinetic cisꢀselectivity is established during nucleophilic addition of
the pendent carboxylic acid moiety onto the in situꢀgenerated iminium ion and is most likely a result of
nonꢀbonding interactions in the transition state between the 5ꢀpyrrolidine substituent (Ph) and the
anthranylic acid moiety.
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Table 1. Optimization Studies for the [3+2]-Cycloannulation Process towards 3aa
Entry
1
Additive
TBAF
TFA
Solvent
Temp. (T)
rt
Yield [%]b
drc
50:50
50:50
57:43
66:37d
70:30 d
ꢀ
CH2Cl2/tBuOH (2:1)
CH2Cl2/tBuOH (2:1)
CH2Cl2/tBuOH (2:1)
toluene/tBuOH (2:1)
Et2O/tBuOH (2:1)
MeOH
22
88
83
84
61
ꢀ
2
rt
3
TFA
ꢀ20°C
ꢀ20°C
ꢀ20°C
ꢀ20°C
ꢀ20°C
ꢀ20°C
ꢀ20°C
ꢀ20°C
ꢀ20°C
ꢀ20°C
4
TFA
5
TFA
6
TFA
7
TFA
MeCN
79
99
99
61
64
81
50:50
55:45
63:37
85:15
83:17
71:29
8
TfOH
HCl(Et2O)
DNBSA
pTsOH
MsOH
CH2Cl2/tBuOH (2:1)
CH2Cl2/tBuOH (2:1)
CH2Cl2/tBuOH (2:1)
CH2Cl2/tBuOH (2:1)
CH2Cl2/tBuOH (2:1)
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10
11
12
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DNBA
DNBSAe
DNBSAf
DNBSAg
CH2Cl2/tBuOH (2:1)
ꢀ20°C
ꢀ20°C
ꢀ20°C
-20°C
84
62
58
83
70:30
85:15
81:19
88:12
1
2
3
4
5
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8
CH2Cl2/tBuOH (2:1)
CH2Cl2/tBuOH (2:1)
CH2Cl2/tBuOH (2:1)
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aReaction conditions: anthranilic acid (0.20 mmol), aldehyde (1.20 equiv.), bisꢀsilyldienediolate 1
(2.00 equiv.), Sm(OTf)3 (20 mol%) in 1.2 mL solvent mixture containing 1.0 equiv. H2O for 30 sec at rt,
b
additive (2 equiv.) for max. 2 h. Isolated yield of chromatographically purified material. cdr of crude
f
product determined by NMR. dcisꢀisomer precipitates. e1.00 equiv. DNBSA. 0.50 equiv. DNBSA. gstep
1 at ꢀ20°C, 1.00 equiv. DNBSA.
The amount of DNBSA could be further reduced to one equivalent with identical results and only a
slightly extended reaction time (Table 1, entry 14). The reaction is even possible with 0.5 equivalents of
DNBSA, albeit with a slightly decreased yield and selectivity (entry 15). Lowering the temperature of
the first step to ꢀ20°C further improved both the yield to 83% and the diastereoselectivity to 88:12 (entry
16) We assume that the bulky Brønsted acid DNBSA reinforces the above mentioned nonꢀbonding
interactions in the transition state of the cyclization leading to an enhanced diastereoselectivity.
With these optimal conditions in hand we studied the scope of this stereocontrolled [3+2]ꢀ
cycloheteroannulation process. It turned out that a variety of different aromatic and aliphatic aldehydes
were tolerated leading to the corresponding pyrrolobenzoxazinones 3 in generally good to excellent
yields (Table 2). The products could be obtained as single stereoisomers upon chromatographic
separation of the minor isomers. Various alkylꢀsubstituted and condensed aromatic aldehydes furnished
the products in good yields up to 96% and excellent cisꢀselectivities of up to 95:5 (entries 1ꢀ6).
Halogenated aromatic aldehydes could be successfully applied as well and delivered products 3g and 3h
in excellent yields and good diastereoselectivities (entries 7 and 8). When the electronic nature of the
aromatic system was modulated by electronwithdrawing groups, the selectivity of the process decreased
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to 72:28 (entries 9ꢀ11). Aliphatic aldehydes could be employed as well under these conditions. Thus,
cyclohexane carbaldehyde gave rise to the formation of pyrrolobenzoxazinone 3l which was obtained in
excellent yield and 94:6ꢀdiastereoselectivity (entry 12). However, subjecting pivalic aldehyde carrying a
very bulky alkyl group to this transformation produced a 1:1ꢀratio of both diastereomers in 80% yield
indicating that the tertꢀbutyl group was sterically too demanding (entry 13). Interestingly, simple flash
chromatography converted this 1:1ꢀmixture into a 26:74ꢀcis/transꢀmixture apparently through acidꢀ
catalyzed isomerization. The same effect was observed when the reaction was run directly at rt for 24 h
in the second step which almost exclusively produced the thermodynamically more stable transꢀ
stereoisomer (entry 14).
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Table 2. Substrate Scope of the [3+2]-Cycloannulation toward Pyrrolobenzoxazinones 3a
Entry Product
R1
R2
H
H
H
H
H
H
H
H
H
Yield[%]b
drc
1
2
3
4
5
6
7
8
9
Ph
83
88
87
86
88
95
94
96
90
88:12
95:5
3a
3b
3c
3d
3e
3f
2ꢀMeꢀC6H4
4ꢀMeꢀC6H4
4ꢀPhꢀC6H4
1ꢀnaphthyl
2ꢀnaphthyl
4ꢀClꢀC6H4
4ꢀBrꢀC6H4
4ꢀMeOꢀC6H4
93:7
89:11
89:11
90:10
91:9
3g
3h
3i
89:11
86:14
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4ꢀNCꢀC6H4
H
H
48
73
87
80
58
80
94
78
45
99
77:23
72:28
94:6
3j
3k
3l
1
2
3
4
5
6
7
8
3ꢀfuryl
cyclohexyl
tertꢀbutyl
tertꢀbutyl
Ph
H
H
50:50
3:97
3m
3md
3n
3o
9
H
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4ꢀMe
5ꢀMe
4ꢀOMe
4ꢀCl
5ꢀBr
94:6
Ph
89:11
88:12
86:14
89:11
Ph
3p
3q
3r
Ph
Ph
aReaction conditions: amino acid (0.20 mmol), aldehyde (1.20 equiv.), bisꢀsilyldienediolate 1 (2.00
equiv.), Sm(OTf)3 (20 mol%) in 1.2 mL solvent mixture containing 1.0 equiv. H2O for 30ꢀ50 min
b
at ꢀ20°C, addition of DNBSA for 1.5ꢀ7 h at ꢀ20°C. Isolated yield of pure material as cis/transꢀmixture;
cdr of crude product determined by NMR. d Entire reaction sequence at rt.
Variation in the anthranilic acid component was also possible and led to the formation of several
differently substituted pyrrolobenzoxazinones 3n-r (entries 15ꢀ19). Both electrondonating and
electronwithdrawing groups were tolerated in the 4ꢀ and 5ꢀposition of the heterocycle giving rise to the
products in typically good yields (45ꢀ99%) and selectivities (dr 86:14ꢀ94:6). Substitution in the 2ꢀ
position of the heterocycle led to no product formation presumably on the basis of too much steric
hindrance next to the reactive centers. The relative configuration of cisꢀpyrrolo[1,2ꢀa]benzoxazinone 3a
was unambiguously determined by Xꢀray crystallography (see Supporting Information).17
Having developed conditions for the stereoselective formation of cisꢀconfigured
pyrrolobenzoxazinones 3 under kinetically controlled conditions we wondered whether we could
effectively isomerize the N,Oꢀacetal structure and obtain a thermodynamic ratio of stereoisomers. In the
case of the tBuꢀsubstituted pyrrolobenzoxazinone 3m it had already become apparent that the
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substitution of the heterocycle affected the isomeric ratio and that large substituents rapidly shifted the
equilibrium towards the transꢀstereoisomer (Table 2, entries 13 and 14). Accordingly, we dissolved
pyrrolobenzoxazinones 3a and 3m in CH2Cl2 and treated them each with paraꢀtoluenesulfonic acid at rt
for 24 h until no further change in the isomeric ratio was observed. Whereas isomerically pure 3a (R =
Ph) produced a 1:1ꢀratio of cis/transꢀstereoisomers, the 50:50ꢀratio of cisꢀ and transꢀ3m (R = tBu) was
almost fully converted into the thermodynamically more stable transꢀisomer in quantitative yield (Table
3). These results clearly reveal that (1) an acidꢀcatalyzed isomerization process was possible and (2) that
the thermodynamic ratio of diastereomers depended on the relative steric size of the pyrrolidine
substituents.
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Table 3. Isomerization under Thermodynamic Conditions.
After having established a reliable [3+2]ꢀcycloannulation process for the synthesis of
pyrrolobenzoxazinones we wondered whether we could extend this strategy towards the synthesis of the
corresponding pyrroloquinazolinones by simply exchanging the anthranilic acid component for an
anthranilic amide. Fortunately, the formerly optimized conditions could be completely adopted and
excellent yields of the pyrroloquinazolinones 4 were obtained in this oneꢀpot process, despite the
occasional formation of quinazolinones as side products in trace amounts (<5%).11,12,18 Thus, treating
benzaldehyde, anthranilic amide, and bisꢀsilyldienediolate 1 with 20 mol% Sm(OTf)3 in CH2Cl2/tBuOH
(2:1) for 5 min at ꢀ20°C with subsequent addition of 1 equiv. of DNBSA to the intermediate vinylogous
Mannich product and stirring this mixture for 3 h at ꢀ20°C furnished pyrroloquinazolinone 4a in 70%
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isolated yield and as nearly one single diastereomer (dr > 98:2, Table 4, entry 1). Here the addition of
DNBSA was not essential for the selectivity but slightly improved the yield from 62% to 70% (entry 2).
Using this protocol a broad range of pyrroloquinazolinones 4 were obtained in this threeꢀcomponent
[3+2]ꢀcycloannulation process with typically good to excellent yields and as single stereoisomers (dr >
98:2) (Table 4). The comparably higher selectivity in the formation of pyrroloquinazolinones in contrast
to the pyrrolobenzoxazinones above appears to result from the larger steric size of the amide moiety
relative to the acid moiety and enhanced nonꢀbonding interactions in the transition state of the
cyclization accordingly.
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2
3
4
5
6
7
8
9
10
11
12
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14
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17
18
19
20
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50
51
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Table 4. Substrate Scope of the [3+2]-Cycloannulation toward Pyrroloquinazolinones 4a
Entry Product
R1
R2
H
H
H
H
H
H
H
H
H
H
Yield[%]b
1
2
4ac
4ad
4b
4c
4d
4e
4f
Ph
70
62
79
76
70
81
76
73
81
70
Ph
3
2ꢀMeꢀC6H4
3ꢀMeꢀC6H4
4ꢀMeꢀC6H4
1ꢀnaphthyl
2ꢀnaphthyl
4ꢀClꢀC6H4
4ꢀBrꢀC6H4
4ꢀFꢀC6H4
4
5
6
7
8
4g
4h
4i
9
10
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11
12
13
14
15
16
17
18
4ꢀMeOꢀC6H4
H
H
81
82
66
69
73
72
82
78
4j
4k
4l
1
2
3
4
5
6
7
8
4ꢀNCꢀC6H4
3ꢀfuryl
Ph
H
4ꢀMe
5ꢀMe
4ꢀMeO
5ꢀCl
5ꢀBr
4m
4n
4o
4p
4q
9
Ph
10
11
12
13
14
15
16
17
18
19
Ph
Ph
Ph
aReaction conditions: anthranilic amides (0.20 mmol), aldehyde (1.20 equiv.), bisꢀsilyldienediolate 1
20
21
22
23
24
25
26
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(2.00 equiv.), Sm(OTf)3 (20 mol%) in 1.2 mL solvent mixture containing 1.0 equiv. H2O for 5 min
b
at ꢀ20°C, addition of DNBSA for 1.5ꢀ7h at ꢀ20°C. Isolated yield of chromatographically pure material;
dr >98:2. cIsolation of quinazolinone 5 in 7% yield.18 dWithout DNBSA, 6h at ꢀ20°C.
Various tolyl aldehydes as well as naphthyl aldehydes were good substrates for this oneꢀpot process
and furnished the products with good yields in the range of 70ꢀ81% (Table 4, entries 2ꢀ7). Several
electrondonating and electronwithdrawing substituents in different positions around the aromatic ring
were readily tolerated and delivered the corresponding cycloannulation products with up to 82% yield
(entries 8ꢀ12). Even the 3ꢀfuryl aldehydeꢀderived pyrroloquinazolinone 4l was isolated in 66% yield as
nearly one single isomer (entry 13). Furthermore, several substituted 2ꢀaminobenzamides turned out to
be applicable to this process and reacted to produce the heterocyclic products 4mꢀ4q with up to 82%
yield (entries 14ꢀ18). The relative configuration of cisꢀpyrroloquinazolinone 4a was again verified by an
Xꢀray structure (see Supporting Information).19
CONCLUSION
In summary, we have reported a novel oneꢀpot, threeꢀcomponent, Lewisꢀacidꢀcatalyzed [3+2]ꢀ
cycloheteroannulation
process
for
the
stereocontrolled
synthesis
of
complex
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pyrrolo[1,2ꢀa]benzoxazinones 3 and pyrrolo[1,2ꢀa]quinazolinones 4. Starting from simple aldehydes,
anthranilic acid or anthranilamide derivatives, respectively, and the new bisꢀsilyldienediolate 1, a highly
efficient synthesis of a broad range of novel heterobicyclic compounds was developed. The products
were obtained in good to excellent yields and with good diastereoselectivity in the case of the
pyrrolobenzoxazinones and even as single diastereomers in the case of the pyrroloquinazolinones. It was
further shown that the N,Oꢀacetal moiety of the pyrrolobenzoxazinones could be readily isomerized
under acidic conditions. Current investigations are directed towards the development of a catalytic,
enantioselective process to furnish the products in enantiomerically enriched form.
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EXPERIMENTAL SECTION
General. Unless otherwise noted, all reactions were carried out in dry solvents under argon
atmosphere using standard vacuum line techniques. 1H and 13C NMR spectra were recorded in CDCl3 at
1
26°C. The signals were referenced to residual chloroform (7.26 ppm, H, 77.2 ppm, 13C). Chemical
shifts are reported in ppm, multiplicities are indicated by s (singlet), d (doublet), t (triplet), q (quartet), p
(pentet), m (multiplet) and brs (broad singulet). High resolution mass spectra (HRMS) were recorded
using ESIꢀFTꢀICR. Solvents were distilled from the indicated drying reagents: dichloromethane (CaH2),
tetrahydrofuran (Na, benzophenone), diethyl ether (Na, benzophenone), toluene (Na, benzophenone).
Methylꢀtertꢀbutyl ether, diethyl ether, ethyl acetate and hexane were technical grade and distilled from
KOH. Flash column chromatography was performed by using silica gel (0.040ꢀ0.063 mm). Spots were
monitored by thinꢀlayer chromatography, visualized by UV (254 nm, 366 nm) and treated with
phosphomolybdic acid staining solution. Compound 1 was synthesised according to known literature.15
General Procedure for Synthesis of Pyrrolobenzoxazinone 3a (Table 2, entry 1)
Anthranilic acid (27 mg, 0.20 mmol, 1.00 equiv.) and Sm(OTf)3 (24 mg, 0.04 mmol, 0.20 equiv.) were
dissolved in a solvent mixture of 1.2 mL tBuOH/CH2Cl2 (1:2) including 1.00 equiv. H2O (3.6 ꢀl).
Benzaldehyde (24 ꢀL, 0.24 mmol, 1.20 equiv.) was added and stirring continued for 5 min at rt. The
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reaction mixture was cooled to ꢀ20 °C and nucleophile 1 (110 mg, 0.40 mmol, 2.00 equiv.) was added
dropwise. Stirring was continued until full conversion of the intermediate was indicated by TLC
(30 min). 2,4ꢀDinitrobenzene sulfonic acid (57 mg, 0.20 mmol, 1.00 equiv.) was added in one portion
and stirring continued until full conversion of the product was indicated by TLC (4.5 h). 10 mL CH2Cl2
was added and the resulting suspension washed with 15 mL of a sat. NaHCO3 solution. The aqueous
phase was extracted several times with CH2Cl2 (10x) and the water removed by azeotropic destillation.
The crude product was dissolved in CH2Cl2, filtered through Celite® and the solvent removed under
reduced pressure (dr 88:12). Flash column chromatography (hexane/MTBE 10:1 to 6:1) gave
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pyrrolobenzoxazinone 3a (56 mg, 83%, dr 90:10) as white solid. cisꢀDiastereomer: R (hexane/MTBE
f
2:1) 0.33; mp 174 °C; 1H NMR (400 MHz, CDCl3) δ 8.00 (dd, 1H, J = 1.0, 8.0 Hz), 7.53 (d, 2H, J = 7.5
Hz), 7.41 (t, 2H, J = 7.5 Hz), 7.37–7.24 (m, 2H), 6.98 (t, 1H, J = 7.5 Hz), 6.54 (d, 1H, J = 8.0 Hz), 4.90
(dd, 1H, J = 2.5, 8.0 Hz), 4.24 (m, 2H), 2.86–2.74 (m, 2H), 2.51–2.39 (m, 1H), 2.18–2.04 (m, 1H), 1.25
(t, 3H, J = 7.0 Hz); 13C{H} NMR (100 MHz, CDCl3) δ 169.6, 163.3, 145.9, 143.3, 135.3, 130.2, 128.9,
127.6, 126.3, 122.0, 117.8, 115.3, 97.0, 69.8, 62.9, 35.6, 34.3, 14.1; IR (KBr) ν 2980, 2957, 1742, 1718,
1605, 1570, 1485, 1468, 1354, 1300, 1274, 1188, 1096, 1031, 1019, 766 cmꢀ1; MS (ESI+) m/z (M+H)+,
338.0, (M+Na)+, 360.0; Anal. Calcd for C20H19NO4: C, 71.20; H, 5.68; N, 4.15; Found: C, 71.09; H,
1
5.68; N, 4.28. transꢀDiastereomer: R
f
(hexane/MTBE 2:1) 0.23; mp 101 °C; H NMR (400 MHz,
CDCl3) δ 7.92 (dd, 1H, J = 8.0, 1.5 Hz), 7.34–7.21 (m, 6H), 6.81 (m, 1H), 6.41 (d, 1H, J = 8.0 Hz), 5.16
(dd, 1H, J = 2.5, 8.5 Hz), 4.20 (m, 2H), 2.68 (ddd, 1H, J = 13.0, 11.5, 8.0 Hz), 2.54 (ddd, 1H, J = 13.0,
13
8.0, 2.5 Hz), 2.07 (ddt, 1H, J = 12.0, 8.0, 2.5 Hz), 1.19 (t, 3H, J = 7.0 Hz); C{H} NMR (100 MHz,
CDCl3) δ 170.5, 163.6, 144.2, 141.5, 135.6, 131.1, 129.2, 127.9, 126.4, 119.9, 114.8, 112.9, 95.9, 62.8,
62.5, 34.3, 32.3, 14.2; IR (KBr) ν 3062, 2955, 2925, 2856, 1742, 1606, 1573, 1487, 1469, 1451, 1372,
1298, 1261, 1181, 1164, 1053, 1024, 761, 700, 691 cmꢀ1; MS (ESI+) m/z (M+H)+, 338.0, (M+Na)+,
360.0, (2M+Na)+,697.2; HRMS (ESI+) m/z (M+H)+ Calcd for C20H20NO4 338.13868; Found:
338.13856.
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Pyrrolobenzoxazinone 3b: dr 95:5, 62 mg (88%, dr 95:5), white solid. cisꢀDiastereomer: R
f
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(hexane/MTBE 2:1) 0.40; mp 122 °C; 1H NMR (300 MHz, CDCl3) δ 8.05–7.97 (m, 1H), 7.94–7.84 (m,
1H), 7.38–7.19 (m, 4H), 7.09–6.93 (m, 1H), 6.53 (d, 1H, J = 8.0 Hz), 5.05 (dd, 1H, J = 8.0, 2.5 Hz),
4.35–4.17 (m, 2H), 2.92–2.71 (m, 2H), 2.51–2.41 (m, 1H), 2.34 (s, 3H), 2.06–1.95 (m, 1H), 1.26 (t, 3H,
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J = 7.0 Hz); C{H} NMR (75 MHz, CDCl3) δ 169.4, 163.5, 146.2, 141.1, 135.4, 134.0, 130.8, 130.2,
127.4, 126.5, 126.2, 122.3, 118.1, 115.7, 97.3, 67.7, 62.9, 35.3, 32.7, 19.4, 14.1; IR (KBr) ν 2983, 2929,
1744, 1728, 1484, 1467, 1363, 1349, 1317, 1285, 1241, 1158, 1103, 1058, 1029, 969, 789, 765, 747,
681 cmꢀ1; MS (ESI+) m/z (M+H)+, 352.2, (M+Na)+, 374.2, (M+K)+, 390.1; Anal. Calcd for C21H21NO4:
C, 71.78; H, 6.02; N, 3.99; Found: C, 71.52; H, 6.07; N, 3.69.
Pyrrolobenzoxazinone 3c: dr 93:7, 61 mg (87%, dr 95:5), white solid. cisꢀDiastereomer: R
f
1
(hexane/MTBE 2:1) 0.40; mp 107 °C; H NMR (300 MHz, CDCl3) δ 7.99 (dd, 1H, J = 8.0, 1.5 Hz),
7.41 (d, 2H, J = 8.0 Hz), 7.33–7.25 (m, 1H), 7.22 (d, 2H, J = 8.0 Hz), 6.97 (ddd, 1H, J = 8.0, 7.5, 0.5
Hz), 6.59–6.53 (m, 1H), 4.87 (dd, 1H, J = 8.0, 2.5 Hz), 4.23 (q, 2H, J = 7.0 Hz), 2.85–2.69 (m, 2H),
2.52–2.40 (m, 1H), 2.39 (s, 3H), 2.15–2.03 (m, 1H), 1.24 (t, 3H, J = 7.0 Hz); 13C{H} NMR (100 MHz,
CDCl3) δ 169.5, 163.4, 146.0, 140.3, 137.3, 135.3, 130.2, 129.6, 126.2, 121.9, 117.8, 115.3, 97.0, 69.6,
62.9, 35.6, 34.4, 21.2, 14.1; IR (KBr) ν 2986, 2939, 1741, 1728, 1607, 1484, 1469, 1359, 1345, 1286,
1242, 1184, 1104, 1053, 1029, 962, 785, 771, 688 cmꢀ1; MS (ESI+) m/z (M+H)+, 352.2, (M+Na)+,
374.2, (M+K)+, 390.1; Anal. Calcd for C21H21NO4: C, 71.78; H, 6.02; N, 3.99; Found: C, 71.47; H,
6.25; N, 3.77.
Pyrrolobenzoxazinone 3d: dr 89:11, 71 mg (86%, dr 91:9), white solid. cisꢀDiastereomer: R
f
1
(hexane/MTBE 2:1) 0.37; mp 141 °C; H NMR (300 MHz, CDCl3) δ 8.02 (dd, 1H, J = 8.0, 1.5 Hz),
7.71–7.58 (m, 6H), 7.52 –7.43 (m, 2H), 7.42–7.29 (m, 2H), 7.07–6.97 (m, 1H), 6.63 (d, 1H, J = 8.0 Hz),
4.96 (dd, 1H, J = 2.5, 8.0 Hz), 4.37–4.19 (m, 2H), 2.93–2.75 (m, 2H), 2.54–2.43 (m, 1H), 2.23–2.12 (m,
1H), 1.27 (t, 3H, J = 7.0 Hz); 13C{H} NMR (75 MHz, CDCl3) δ 169.5, 163.4, 146.0, 142.4, 140.7,
140.6, 135.4, 130.3, 129.0, 127.6, 127.5, 127.2, 126.8, 122.1, 117.9, 115.4, 97.0, 69.6, 63.0, 35.7, 34.4,
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14.1; IR (KBr) ν 3030, 2982, 1747, 1607, 1486, 1468, 1362, 1281, 1240, 1184, 1171, 1104, 1056, 1032,
964, 764, 738, 699 cmꢀ1; MS (ESI+) m/z (M+H)+, 414.2, (M+Na)+, 436.2, (M+K)+, 452.2, (2M+Na)+,
849.4; HRMS (ESI+) m/z (M+H)+ Calcd for C26H24NO4 414.16998; Found: 414.16986.
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Pyrrolobenzoxazinone 3e: dr 89:11, 68 mg (88%, dr 91:9), white foam. cisꢀDiastereomer: R
f
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(hexane/MTBE 2:1) 0.34; mp 65 °C; H NMR (300 MHz, CDCl3) δ 8.12 (d, 1H, J = 6.5 Hz), 8.04 (dd,
1H, J = 8.0, 1.5 Hz), 8.01–7.81 (m, 3H), 7.65–7.51 (m, 3H), 7.33–7.23 (m, 1H), 7.2 (m, 1H), 6.63 (d,
1H, J = 8.0 Hz), 5.60 (d, 1H, J = 9.0 Hz), 4.30 (q, 2H, J = 7.0 Hz, 3.12–2.95 (m, 1H), 2.75 (td, 1H, J =
13.0, 7.0 Hz), 2.56–2.44 (m, 1H), 2.21 (dd, 1H, J = 11.5, 7.0 Hz), 1.30 (t, 3H, J = 7.0 Hz); 13C{H}
NMR (75 MHz, CDCl3) δ 169.6, 163.6, 146.4, 137.9, 135.5, 134.3, 130.3, 130.1, 129.3, 128.4, 126.6,
126.0, 125.8, 124.1, 123.1, 122.6, 118.3, 116.0, 97.5, 68.1, 63.1, 35.7, 33.3, 14.2; IR (KBr) ν 2980,
2959, 2926, 1747, 1607, 1485, 1468, 1364, 1348, 1288, 1244, 1157, 1145, 1103, 1056, 803, 785, 765
cmꢀ1; MS (ESI+) m/z (M+H)+, 388.2, (M+Na)+, 410.2, (M+K)+, 426.1; HRMS (ESI+) m/z (M+H)+
Calcd for C24H22NO4 388.15433; Found: 388.15424.
Pyrrolobenzoxazinone 3f: dr 90:10, 74 mg (95%, dr 92:8), white solid. cisꢀDiastereomer: R
f
(hexane/MTBE 2:1) 0.37; mp 112 °C; 1H NMR (400 MHz, CDCl3) δ 8.07–8.00 (m, 2H), 7.91 (d, 1H, J
= 8.5 Hz), 7.90–7.83 (m, 2H), 7.60 (dd, 1H, J = 8.5, 2.0 Hz), 7.52 (m, 2H), 7.28–7.23 (m, 1H), 6.99 (m,
1H), 6.58 (dd, 1H, J = 8.0, 0.5 Hz), 5.06 (dd, 1H, J = 7.5, 3.0 Hz), 4.30 (m, 2H), 2.90–2.79 (m, 2H),
2.55–2.46 (m, 1H), 2.24–2.17 (m, 1H), 1.29 (t, 3H, J = 7.0 Hz); 13C{H} NMR (100 MHz, CDCl3)
δ 169.5, 163.4, 146.0, 140.7, 135.4, 133.5, 133.0, 130.3, 129.0, 128.1, 127.9, 126.6, 126.2, 125.2, 124.4,
122.2, 118.0, 115.5, 97.1, 70.0, 63.0, 35.7, 34.2, 14.2; IR (KBr) ν 2979, 2926, 1746, 1607, 1484, 1468,
1368, 1350, 1327, 1290, 1241, 1193, 1103, 1057, 1031, 965, 822, 787, 753, 478 cmꢀ1; MS (ESI+) m/z
(M+H)+, 388.2, (M+Na)+, 410.2, (M+K)+, 426.1, (2M+Na)+, 797.3; Anal. Calcd for C24H21NO4: C,
74.40; H, 5.46; N, 3.62; Found: C, 74.21; H, 5.72; N, 3.29.
Pyrrolobenzoxazinone 3g: dr 91:9, 70 mg (94%, dr 91:9), white solid. cisꢀDiastereomer: R
f
1
(hexane/MTBE 2:1) 0.31; mp 144 °C; H NMR (400 MHz, CDCl3) δ 8.00 (dd, 1H, J = 1.5, 8.0 Hz),
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7.51–7.45 (m, 2H), 7.40–7.35 (m, 2H), 7.32 (ddd, 1H, J = 8.0, 7.5, 1.5 Hz), 7.00 (m, 1H), 6.52 (dd, 1H,
J = 8.0, 0.5 Hz), 4.86 (dd, 1H, J = 8.0, 2.5 Hz), 4.23 (m, 2H), 2.86–2.69 (m, 2H), 2.50–2.40 (m, 1H),
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2.10–2.02 (m, 1H), 1.23 (t, 3H, J = 7.0 Hz); C{H} NMR (75 MHz, CDCl3) δ 169.5, 163.2, 145.8,
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8
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141.9, 135.4, 133.5, 130.4, 129.1, 127.8, 122.3, 117.8, 115.5, 97.0, 69.2, 63.0, 35.6, 34.3, 14.1; IR
(KBr) ν 3058, 2989, 2942, 1743, 1729, 1608, 1486, 1470, 1354, 1317, 1286, 1245, 1212, 1162, 1148,
1104, 1055, 1030, 964, 790, 769 cmꢀ1; MS (ESI+) m/z (M+H)+, 372.2, (M+Na)+, 394.1, (M+K)+, 410.1,
(2M+Na)+, 765.2; HRMS (ESI+) m/z (M+Na)+ Calcd for C20H18ClNO4Na 394.08166; Found:
394.08162.
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Pyrrolobenzoxazinone 3h: dr 89:11, 80 mg (96%, dr 91:9), white solid. cisꢀDiastereomer: R
f
1
(hexane/MTBE 2:1) 0.31; mp 154 °C; H NMR (400 MHz, CDCl3) δ 8.00 (dd, 1H, J = 1.5, 8.0 Hz),
7.57–7.52 (m, 2H), 7.46–7.40 (m, 2H), 7.32 (ddd, 1H, J = 8.0, 7.5, 1.5 Hz), 7.01 (m, 1H), 6.52 (dd, 1H,
J = 8.0, 0.5 Hz), 4.85 (dd, 1H, J = 8.0, 2.5 Hz), 4.23 (m, 2H), 2.87–2.68 (m, 2H), 2.51–2.38 (m, 1H),
13
2.11–2.01 (m, 1H), 1.24 (t, 3H, J = 7.0 Hz); C{H} NMR (100 MHz, CDCl3) δ 169.5, 163.2, 145.7,
142.4, 135.4, 132.1, 130.4, 128.1, 122.4, 121.6, 117.8, 115.5, 96.9, 69.3, 63.0, 35.6, 34.2, 14.1; IR
(KBr) ν 3058, 2988, 2939, 1743, 1729, 1607, 1485, 1469, 1352, 1287, 1280, 1244, 1163, 1103, 1055,
1030, 1011, 964, 789, 768, 687 cmꢀ1; MS (ESI+) m/z (M+H)+, 416.1, 418.1, (M+Na)+, 438.1, 440.1,
(M+K)+, 454.0, 456.0, (2M+Na)+, 855.1; HRMS (ESI+) m/z (M+H)+ Calcd for C20H19BrNO4
416.04920; Found: 416.04905.
Pyrrolobenzoxazinone 3i: dr 86:14, 66 mg (90%, dr 80:20), white solid. cisꢀDiastereomer: R
f
1
(hexane/MTBE 2:1) 0.27; mp 101 °C; H NMR (300 MHz, CDCl3) δ 7.99 (dd, 1H, J = 8.0, 1.5 Hz),
7.44 (m, 2H), 7.34–7.25 (m, 1H), 7.04–6.90 (m, 3H), 6.55 (d, 1H, J = 8.0 Hz), 4.85 (dd, 1H, J = 7.5, 3.0
Hz), 4.23 (m, 2H), 3.84 (s, 3H), 2.84–2.67 (m, 2H), 2.51–2.38 (m, 1H), 2.12–2.01 (m, 1H), 1.24 (t, 3H,
J = 7.0 Hz); 13C{H} NMR (100 MHz, CDCl3) δ 169.6, 163.4, 159.2, 146.0, 135.4, 135.3, 130.3, 127.5,
122.0, 117.9, 115.3, 114.3, 97.0, 69.4, 62.9, 55.5, 35.7, 34.4, 14.1; IR (KBr) ν 2984, 2938, 2838, 1745,
1609, 1514, 1485, 1469, 1363, 1346, 1286, 1248, 1178, 1110, 1031, 835, 748, 687, 550 cmꢀ1; MS
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(ESI+) m/z (M+H)+, 368.2, (M+Na)+, 390.2, (M+K)+, 406.1; HRMS (ESI+) m/z (M+H)+ Calcd for
1
2
3
C21H22NO5 368.14925; Found: 368.14910.
4
5
6
Pyrrolobenzoxazinone 3j: dr 77:23, 35 mg (48%, dr 76:24), white solid. cisꢀDiastereomer: R
f
7
8
9
(hexane/MTBE 3:2) 0.18; mp 153°C; 1H NMR (400 MHz, CDCl3) δ 8.01 (dd, 1H, J = 8.0, 1.0 Hz), 7.71
(m, 4H), 7.34 (ddd, 1H, J = 8.5, 7.5, 1.5 Hz), 7.04 (m, 1H), 6.47 (dd, 1H, J = 8.0, 0.5 Hz), 4.93 (dd, 1H,
J = 8.5, 2.0 Hz), 4.25 (m, 2H), 2.93–2.81 (m, 1H), 2.72 (ddd, 1H, J = 13.5, 12.0, 7.0 Hz), 2.48 (ddd, 1H,
J = 13.5, 7.5, 2.5 Hz), 2.08 (ddt, 1H, J = 12.0, 7.0, 2.5 Hz), 1.24 (t, 1H, J = 7.0 Hz); 13C{H} NMR (75
MHz, CDCl3) δ 169.4, 163.0, 148.7, 145.4, 135.6, 132.8, 130.5, 127.2, 122.7, 118.7, 117.7, 115.6,
111.7, 96.9, 69.4, 63.2, 35.6, 34.1, 14.1; IR (KBr) ν 2983, 2957, 2927, 1743, 1608, 1485, 1468, 1361,
1290, 1243, 1157, 1104, 1059, 1033, 970, 762, 686, 565 cmꢀ1; MS (ESI+) m/z (M+H)+, 363.2, (M+Na)+,
385.1, (M+K)+, 401.1; HRMS (ESI+) m/z (M+Na)+ Calcd for C21H18N2O4Na 385.11588; Found:
385.11579.
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Pyrrolobenzoxazinone 3k: dr 72:28, 48 mg (73%, dr 69:31), white solid. cisꢀDiastereomer: R
f
1
(hexane/MTBE 2:1) 0.38; mp 102 °C; H NMR (300 MHz, CDCl3) δ 7.98 (dd, 1H, J = 8.0, 1.5 Hz),
7.62–7.56 (m, 1H), 7.46 (t, 1H, J = 2.0 Hz,), 7.38 (m, 1H), 7.00 (m, 1H), 6.82 (dd, 1H, J = 8.0, 0.5 Hz),
6.47 (dd, 1H, J = 2.0, 1.0 Hz), 4.82 (m, 1H), 4.20 (m, 2H), 2.80 (ddd, 1H, J = 12.5, 11.5, 7.0 Hz), 2.72–
2.57 (m, 1H), 2.47 (ddd, 1H, J = 12.5, 6.5, 2.0 Hz), 2.06 (ddt, 1H, J = 12.0, 7.0, 2.0 Hz), 1.21 (t, 3H, J =
7.0 Hz); 13C{H} NMR (100 MHz, CDCl3) δ 169.7, 163.4, 145.9, 144.2, 140.4, 135.5, 130.4, 128.5,
122.1, 117.8, 115.3, 109.0, 96.6, 63.0, 62.7, 35.8, 33.0, 14.2; IR (KBr) ν 2985, 2956, 2875, 1747, 1725,
1607, 1487, 1470, 1363, 1331, 1298, 1289, 1191, 1169, 1097, 1033, 1017, 874, 806, 764, 758, 604 cmꢀ1;
MS (ESI+) m/z (M+H)+, 328.1, (M+Na)+, 350.1, (M+K)+, 366.1, (2M+Na)+, 677.3; HRMS (ESI+) m/z
(M+H)+ Calcd for C18H18NO5 328.11795; Found: 328.11797.
Pyrrolobenzoxazinone 3l: dr 94:6, 60 mg (87%, dr 90:10), yellowish oil. cisꢀDiastereomer: R
f
1
(hexane/MTBE 2:1) 0.40; H NMR (400 MHz, CDCl3) δ 7.98 (dd, 1H, J = 8.0, 1.5 Hz), 7.51–7.40 (m,
1H), 7.06–6.93 (m, 2H), 4.14 (m, 2H), 3.56 (t, 1H, J = 7.0 Hz), 2.74 (td, 1H, J = 13.5, 7.5 Hz), 2.39 (dd,
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1H, J = 13.5, 7.5 Hz), 2.21 (tt, 1H, J = 12.5, 8.0 Hz), 2.02 (dd, 2H, J = 12.5, 7.5 Hz), 1.89–1.80 (m, 2H),
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1.78–1.71 (m, 3H), 1.32–1.20 (m, 3H), 1.16 (t, 3H, J = 7.0 Hz), 1.13–1.00 (m, 2H); C{H} NMR (75
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5
6
7
8
MHz, CDCl3) δ 169.4, 163.6, 146.5, 135.2, 130.4, 121.4, 118.1, 115.1, 96.8, 72.4, 62.6, 43.5, 36.5, 31.8,
28.6, 26.8, 26.7, 26.5, 26.4, 14.0; IR (Film) ν 2979, 2926, 2852, 1749, 1735, 1484, 1467, 1450, 1367,
1287, 1268, 1243, 1232, 1200, 1163, 1139, 1099, 1031, 973, 756, 680 cmꢀ1; MS (ESI+) m/z (M+H)+,
344.2, (M+Na)+, 366.2, (M+K)+, 382.1, (2M+Na)+, 709.4; HRMS (ESI+) m/z (M+H)+ Calcd for
C20H26NO4 344.18563; Found: 344.18556.
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Pyrrolobenzoxazinone 3m: at ꢀ20°C: dr 50:50, 51 mg (80%, dr 25:75), at rt: dr 3:97, 37 mg (58%, dr
1
3:97) yellowish oil. transꢀDiastereomer: R
f
(hexane/MTBE 2:1) 0.48; H NMR (400 MHz, CDCl3)
δ 7.87 (dd, 1H, J = 8.0, 1.5 Hz), 7.41 (m, 1H), 6.98 (d, 1H, J = 8.0 Hz), 6.87 (t, 1H, J = 8.0 Hz), 4.07 (q,
2H, J = 7.0 Hz), 4.04 (d, 1H, J = 8.0 Hz), 2.63–2.52 (m, 1H), 2.45–2.25 (m, 2H), 2.11 (dd, 1H, J = 12.5,
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7.5 Hz), 1.06 (t, 3H, J = 7.0 Hz), 0.98 (s, 9H); C{H} NMR (75 MHz, CDCl3) δ 171.2 164.5, 147.6,
134.4, 130.7, 119.8, 116.2, 114.4, 97.7, 65.9, 62.3, 38.2, 34.7, 27.9, 25.2, 14.0; IR (KBr) ν 2957, 2910,
2874, 1742, 1481, 1363, 1292, 1241, 1197, 1165, 1111, 1054, 1020, 957, 760, 696 cmꢀ1; MS (ESI+) m/z
(M+H)+, 318.1, (M+Na)+, 340.1, (M+K)+, 356.1, (2M+Na)+, 657.2; HRMS (ESI+) m/z (M+Na)+ Calcd
for C18H23NO4Na 340.15193; Found: 340.15192.
Pyrrolobenzoxazinone 3n: dr 94:6, 56.5 mg (80%, dr 96:4), yellowish solid. cisꢀDiastereomer: R
f
(hexane/MTBE 3:2) 0.38; mp 120 °C; 1H NMR (400 MHz, CDCl3) δ 7.88 (d, 1H, J = 8.0 Hz), 7.55 (m,
2H), 7.42 (m, 2H), 7.34 (m, 1H), 6.81 (d, 1H, J = 8.0 Hz), 6.35 (s, 1H), 4.88 (dd, 1H, J = 8.0, 2.5 Hz),
4.24 (q, 2H, J = 7.0 Hz), 2.86–2.68 (m, 2H), 2.47–2.39 (m, 1H), 2.18 (s, 3H), 2.14–2.04 (m, 1H), 1.25
(t, 3H, J = 7.0 Hz); 13C{H} NMR (100 MHz, CDCl3) δ 169.7, 163.5, 146.7, 146.2, 143.4, 130.2, 128.9,
127.6, 126.3, 123.5, 118.0, 112.8, 97.0, 69.8, 62.9, 35.5, 34.4, 22.1, 14.1; IR (KBr) ν 3060, 3027, 2982,
2927, 1747, 1722, 1615, 1574, 1496, 1464, 1453, 1364, 1297, 1243, 1198, 1051, 1030, 969, 773, 762,
704 cmꢀ1; MS (ESI+) m/z (M+H)+, 352.2, (M+Na)+, 374.2, (M+K)+, 390.1, (2M+Na)+, 725.2; HRMS
(ESI+) m/z (M+H)+ Calcd for C21H22NO4 352.15433; Found: 352.15468.
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Pyrrolobenzoxazinone 3o: dr 89:11, 66.0 mg (94%, dr 93:7), yellowish solid. cisꢀDiastereomer: R
f
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(hexane/MTBE 3:2) 0.53; mp 105 °C; H NMR (400 MHz, CDCl3) δ 7.81 (dd, 1H, J = 2.0, 0.5 Hz),
7.53 (m, 2H), 7.41 (m, 2H), 7.34 (m, 1H), 7.10 (ddd, 1H, J = 8.50, 2.0, 0.5 Hz), 6.45 (d, 1H, J = 8.5 Hz),
4.83 (dd, 1H, J = 8.0, 2.5 Hz), 4.23 (q, 2H, J = 7.0 Hz), 2.85–2.72 (m, 2H), 2.49–2.38 (m, 1H), 2.27 (s,
3H), 2.15–2.04 (m, 1H), 1.25 (t, 3H, J = 7.0 Hz); 13C{H} NMR (75 MHz, CDCl3) δ 169.6, 163.6, 143.7,
143.5, 136.3, 131.9, 130.0, 128.9, 127.6, 126.4, 118.2, 115.4, 97.3, 69.9, 62.8, 35.6, 34.3, 20.7, 14.1; IR
(KBr) ν 3029, 2981, 2958, 2925, 1728, 1623, 1504, 1452, 1349, 1276, 1241, 1213, 1194, 1181, 1150,
1095, 1027, 822, 758, 702 cmꢀ1; MS (ESI+) m/z (M+H)+, 352.2, (M+Na)+, 374.2, (M+K)+, 390.1,
(2M+Na)+, 725.2; HRMS (ESI+) m/z (M+H)+ Calcd for C21H22NO4 352.15433; Found: 352.15441.
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Pyrrolobenzoxazinone 3p: dr 88:12, 57.5 mg (78%, dr 92:8), yellowish solid. cisꢀDiastereomer: R
f
(hexane/MTBE 3:2) 0.26; mp 110 °C; 1H NMR (400 MHz, CDCl3) δ 7.90 (d, 1H, J = 9.0 Hz), 7.54 (m,
2H), 7.40 (m, 2H), 7.32 (m, 1H), 6.51 (dd, 1H, J = 9.0, 2.5 Hz), 5.93 (d, 1H, J = 2.5 Hz), 4.89 (dd, 1H, J
= 7.5, 4.0 Hz), 4.25 (m, 2H), 3.54 (s, 1H), 2.82–2.67 (m, 2H), 2.51–2.40 (m, 1H), 2.19–2.00 (m, 1H),
1.26 (t, 3H, J = 7.0 Hz);13C{H} NMR (100 MHz, CDCl3) δ 169.9, 165.5, 163.3, 148.0, 143.3, 132.5,
129.1, 127.8, 126.6, 109.4, 107.9, 101.5, 96.7, 69.5, 62.9, 55.4, 36.0, 34.4, 14.2; IR (KBr) ν 2976, 2952,
2904, 1747, 1721, 1614, 1570, 1497, 1471, 1323, 1291, 1273, 1252, 1227, 1212, 1183, 1129, 1096,
1026, 841, 766, 703 cmꢀ1; MS (ESI+) m/z (M+H)+, 368.2, (M+Na)+, 390.2, (M+K)+, 406.2, (2M+Na)+,
757.2; HRMS (ESI+) m/z (M+H)+ Calcd for C21H22NO5 368.14925; Found: 368.14938.
Pyrrolobenzoxazinone 3q: dr 86:14, 33.5 mg (45%, dr 91:9), white solid. cisꢀDiastereomer: R
f
1
(hexane/MTBE 2:1) 0.41; mp 125 °C; H NMR (300 MHz, CDCl3) δ 7.93 (d, 1H, J = 8.5 Hz), 7.53–
7.47 (m, 2H), 7.47–7.39 (m, 2H), 7.39–7.32 (m, 1H), 6.96 (dd, 1H, J = 8.5, 2.0 Hz), 6.51 (d, 1H, J = 2.0
Hz), 4.91 (dd, 1H, J = 8.0, 2.5 Hz), 4.26 (m, 2H), 3.54 (s, 1H), 2.86–2.70 (m, 2H), 2.53–2.39 (m, 1H),
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2.20–2.06 (m, 1H), 1.27 (t, 3H, J = 7.0 Hz); C{H} NMR (75 MHz, CDCl3) δ 169.1, 162.6, 146.8,
142.5, 141.7, 131.7, 129.1, 127.9, 126.2, 122.6, 117.5, 113.6, 96.9, 69.8, 63.1, 35.5, 34.4, 14.1; IR
(KBr) ν 2985, 2963, 2924, 1748, 1603, 1566, 1480, 1449, 1364, 1295, 1237, 1219, 1187, 1091, 1047,
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1026, 970, 858, 771, 703 cmꢀ1; MS (ESI+) m/z (M+H)+, 372.2, (M+Na)+, 394.2, (M+K)+, 410.1,
(2M+Na)+, 765.1; HRMS (ESI+) m/z (M+H)+ Calcd for C20H19ClNO4 372.09971; Found: 372.09986.
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Pyrrolobenzoxazinone 3r: dr 89:11, 82.0 mg (>99%, dr 91:9), yellowish solid. cisꢀDiastereomer: R
f
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(hexane/MTBE 2:1) 0.42; mp 148 °C; H NMR (300 MHz, CDCl3) δ 8.11 (d, 1H, J = 2.5 Hz), 7.54–
7.46 (m, 2H), 7.47–7.38 (m, 2H), 7.38–7.30 (m, 1H), 7.36 (dd, 1H, J = 8.5, 2.5 Hz), 6.41 (d, 1H, J = 8.5
Hz), 4.87 (dd, 1H, J = 8.0, 3.0 Hz), 4.26 (q, 2H, J = 7.0 Hz), 2.87–2.70 (m, 2H), 2.55–2.38 (m, 1H),
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2.21–2.06 (m, 1H), 1.27 (t, 3H, J = 7.0 Hz); C{H} NMR (75 MHz, CDCl3) δ 169.0, 162.1, 144.7,
142.8, 138.1, 132.7, 129.0, 127.9, 126.2, 119.5, 116.8, 114.5, 97.0, 69.8, 63.1, 35.5, 34.3, 14.1; IR
(KBr) ν 2980, 2962, 1746, 1601, 1481, 1451, 1423, 1356, 1281, 1235, 1176, 1158, 1125, 1058, 1028,
967, 831, 780, 743, 700 cmꢀ1; MS (ESI+) m/z (M+H)+, 416.2, 418.2, (M+Na)+, 438.2, 440.2, (M+K)+,
454.1, 456.1, (2M+Na)+, 855.0; HRMS (ESI+) m/z (M+H)+ Calcd for C20H19BrNO4 416.04920; Found:
416.04951.
General Procedure for Synthesis of Pyrroloquinazolinone 4a (Table 4, entry 1)
Anthranilic amide (27 mg, 0.20 mmol, 1.00 equiv.) and Sm(OTf)3 (24 mg, 0.04 mmol,
0.20 equiv.) were dissolved in a solvent mixture of 1.2 mL tBuOH/CH2Cl2 (1:2) including 1.00 equiv.
H2O (3.6 ꢀl). Benzaldehyde (24 ꢀL, 0.24 mmol, 1.20 equiv.) was added and stirring was continued for
5 min at rt. The reaction mixture was cooled to ꢀ20 °C and nucleophile 1 (110 mg, 0.40 mmol,
2.00 equiv.) was added dropwise. Stirring was continued until full conversion of the intermediate was
indicated by TLC (1 h). 2,4ꢀDinitrobenzene sulfonic acid (57 mg, 0.20 mmol, 1.00 equiv.) was added in
one portion and stirring was continued at ꢀ20 °C until full conversion of the product was indicated by
TLC (3 h). 10 mL CH2Cl2 was added and the resulting suspension was washed with 15 mL of sat.
NaHCO3 solution. The aqueous phase was extracted several times with CH2Cl2 (8x) and the water
removed by azeotropic destillation. The crude product was dissolved in CH2Cl2, filtered through Celite®
and the solvent removed under reduced pressure (dr >98:2). Flash column chromatography
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(hexane/MTBE 2:1 to MTBE) gave pyrroloquinazolinone 4a (47 mg, 70%, dr >98:2) as white solid. cisꢀ
(hexane/MTBE 1:4) 0.23; mp 154 °C; 1H NMR (300 MHz, CDCl3) δ 7.97 (dd, 1H, J =
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Diastereomer: R
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8.0, 1.5 Hz), 7.66–7.54 (m, 2H), 7.46–7.27 (m, 3H), 7.25–7.16 (m, 1H), 6.97–6.87 (m, 1H), 6.58–6.49
(m, 1H), 4.88 (dd, 1H, J = 8.0, 3.0 Hz), 4.20 (q, 2H, J = 7.0 Hz), 2.84–2.59 (m, 2H), 2.31–2.20 (m, 1H),
2.14–2.04 (m, 1H), 1.23 (t, 3H, J = 7.0 Hz); 13C{H} NMR (100 MHz, CDCl3) δ
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172.0, 165.5, 146.6, 144.0, 133.9, 128.7,128.3, 127.3, 126.4, 120.6, 117.5, 117.4,79.2, 70.4, 62.3, 36.4,
34.6, 14.1; IR (KBr) ν 3208, 3062, 2981, 2903, 1737, 1671, 1605, 1483, 1451, 1373, 1300, 1265, 1217,
1156, 1087, 1029, 758, 702 cmꢀ1; MS (ESI+) m/z (M+H)+, 337.2, (M+Na)+, 359.2, (M+K)+, 375.1,
(2M+Na)+, 695.3; HRMS (ESI+) m/z (M+Na)+ Calcd for C20H20N2O3Na 359.13661; Found: 359.13637.
Pyrroloquinazolinone 4b: 55 mg (79%, dr >98:2), white solid. cisꢀDiastereomer: R (hexane/MTBE
f
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1:3) 0.24; mp 149 °C; H NMR (400 MHz, CDCl3) δ 8.00 (d, 2H, J = 8.0 Hz), 7.37–7.17 (m, 5H),
6.98–6.91 (m, 1H), 6.52 (d, 1H, J = 8.0 Hz), 5.04 (dd, 1H, J = 8.5, 2.5 Hz), 4.24 (q, 2H, J = 7.0 Hz),
2.88–2.76 (m, 1H), 2.75–2.64 (m, 1H), 2.36 (s, 3H), 2.28 (ddd, 1H, J = 13.0, 7.0, 3.0 Hz), 2.02–1.93 (m,
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1H), 1.27 (t, 3H, J = 7.0 Hz); C{H} NMR (100 MHz, CDCl3) δ 172.0, 165.6, 146.9, 141.9, 133.9,
133.8, 130.7, 128.2, 127.2, 126.6, 126.5, 121.0, 117.9, 117.8, 79.4, 68.4, 62.3, 36.2, 32.9, 19.4, 14.2; IR
(KBr) ν 3195, 3061, 2975, 2925, 2903, 1739, 1670, 1607, 1483, 1375, 1302, 1282, 1263, 1159, 1083,
1034, 1026, 761, 750 cmꢀ1; MS (ESI+) m/z (M+H)+, 351.2, (M+Na)+, 373.2, (M+K)+, 389.1, (2M+Na)+,
723.3; Anal. Calcd for C21H22N2O3: C, 71.98; H, 6.33; N, 7.99; Found: C, 71.73; H, 6.27; N, 7.74.
Pyrroloquinazolinone 4c: 54 mg (76%, dr >98:2), white solid. cisꢀDiastereomer: R (hexane/MTBE
f
1:4) 0.31; mp 150 °C; 1H NMR (400 MHz, CDCl3) δ 7.97 (dd, 1H, J = 8.0, 1.5 Hz), 7.38 (d, 1H, J = 7.5
Hz), 7.35 (brs, 1H), 7.29 (t, 1H, J = 8.0 Hz), 7.25–7.19 (m, 2H), 7.12 (d, 1H, J = 7.5 Hz), 6.94–6.86 (m,
1H), 6.55 (dd, 1H, J = 8.0, 0.5 Hz), 4.85 (dd, 1H, J = 8.0, 3.5 Hz), 4.26–4.14 (m, 2H), 2.80–2.62 (m,
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2H), 2.39 (s, 3H), 2.29–2.20 (m, 1H), 2.13–2.04 (m, 1H), 1.24 (t, 3H, J = 7.0 Hz); C{H} NMR (75
MHz, CDCl3) δ 172.1, 165.6, 146.8, 144.2, 138.5, 134.0, 128.8, 128.4, 128.2, 127.1, 123.6, 120.7,
117.6, 117.5, 79.3, 70.5, 62.4, 36.7, 34.8, 21.8, 14.3; IR (KBr) ν 3208, 3064, 2979, 2905, 1738, 1673,
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1606, 1484, 1374, 1300, 1285, 1264, 1193, 1151, 1085, 1032, 787, 763, 703; MS (ESI+) m/z (M+H)+,
351.2, (M+Na)+, 373.2, (M+K)+, 389.1, (2M+Na)+, 723.3; Anal. Calcd for C21H22N2O3: C, 71.98; H,
6.33; N, 7.99; Found: C, 71.72; H, 6.33; N, 7.79.
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Pyrroloquinazolinone 4d: 49 mg (70%, dr >98:2), white solid. cisꢀDiastereomer: R (hexane/MTBE
f
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1:4) 0.34; mp 173 °C; 1H NMR (400 MHz, CDCl3) δ 7.97 (dd, 1H, J = 8.0, 1.5 Hz), 7.46 (d, 2H, J = 8.0
Hz), 7.27–7.16 (m, 3H), 7.01 (brs, 1H), 6.91 (t, 1H, J = 8.0 Hz), 6.55 (d, 1H, J = 8.0 Hz), 4.86 (dd, 1H,
J = 7.5, 3.0 Hz), 4.20 (q, 2H, J = 7.0 Hz), 2.81–2.58 (m, 2H), 2.38 (s, 3H), 2.26–2.16 (m, 1H), 2.12–
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2.02 (m, 1H), 1.24 (t, 3H, J = 7.0 Hz); C{H} NMR (100 MHz, CDCl3) δ 172.0, 165.4, 146.7, 141.0,
137.0, 134.0, 129.5, 128.3, 126.3, 120.6, 117.4, 117.4, 79.2, 70.2, 62.3, 36.7, 34.7, 21.2, 14.2; IR (KBr)
ν 3196, 3065, 2980, 2921, 2901, 1738, 1672, 1607, 1484, 1374, 1304, 1285, 1257, 1213, 1183, 1154,
1085, 1034, 1022, 755; MS (ESI+) m/z (M+H)+, 351.2, (M+Na)+, 373.2, (M+K)+, 389.1, (2M+Na)+,
723.3; Anal. Calcd for C21H22N2O3: C, 71.98; H, 6.33; N, 7.99; Found: C, 71.52; H, 6.04; N, 7.76.
Pyrroloquinazolinone 4e: 63 mg (81%, dr >98:2), white solid. cisꢀDiastereomer: R (hexane/MTBE
f
1:3) 0.21; mp 184 °C; 1H NMR (400 MHz, CDCl3) δ 8.25 (d, 1H, J = 7.0 Hz), 8.02 (dd, 1H, J = 8.0, 1.5
Hz), 7.97–7.90 (m, 2H), 7.84 (d, 1H, J = 8.0 Hz), 7.60–7.49 (m, 3H), 7.23–7.16 (m, 1H), 7.01 (s, 1H),
6.98–6.92 (m, 1H), 6.61 (d, 1H, J = 8.0 Hz), 5.58 (d, 1H, J = 8.5 Hz), 4.26 (q, 2H, J = 7.0 Hz), 3.01
(tdd, 1H, J = 12.0, 9.0, 7.0 Hz), 2.62 (td, 1H, J = 7.0, 12.5 Hz), 2.31–2.14 (m, 2H), 1.29 (t, 3H, J = 7.0
13
Hz); C{H} NMR (100 MHz, CDCl3) δ 172.1, 165.8, 147.0, 138.6, 134.1, 134.0, 130.0, 129.2, 128.2,
128.0, 126.3, 125.8, 125.7, 124.5, 123.1, 121.2, 118.2, 118.0, 79.4, 68.9, 62.4, 36.4, 33.5, 14.2; IR
(KBr) ν 3244, 3060, 2980, 2935, 1734, 1671, 1605, 1483, 1382, 1371, 1301, 1281, 1266, 1203, 1193,
1154, 1090, 1039, 1028, 803, 781, 761 cmꢀ1; MS (ESI+) m/z (M+H)+, 387.2, (M+Na)+, 409.2, (M+K)+,
425.2, (2M+Na)+, 795.3; HRMS (ESI+) m/z (M+Na)+ Calcd for C24H22N2O3Na 409.15226; Found:
409.15211.
Pyrroloquinazolinone 4f: 59 mg (76%, dr >98:2), white solid. cisꢀDiastereomer: R (hexane/MTBE
f
1:3) 0.17; mp 176 °C; 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 8.02 (dd, 1H, J = 8.0, 1.5 Hz), 7.93–
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7.84 (m, 3H), 7.63 (dd, 1H, J = 8.5, 1.5 Hz), 7.55–7.47 (m, 2H), 7.33 (s, 1H), 7.21–7.15 (m, 1H), 6.96–
6.89 (m, 1H), 6.59 (d, 1H, J = 8.0 Hz), 5.04 (dd, 1H, J = 8.0, 3.0 Hz), 4.26 (q, 2H, J = 7.0 Hz), 2.88–
2.76 (m, 1H), 2.71 (ddd, 1H, J = 13.0, 10.0, 6.5 Hz), 2.30 (ddd, 1H, J = 13.0, 7.0, 4.0 Hz), 2.22–2.13
(m, 1H), 1.29 (t, 3H, J = 7.0 Hz); 13C{H} NMR (100 MHz, CDCl3) δ 172.1, 165.5, 146.6, 141.4, 134.0,
133.5, 133.0, 128.7, 128.4, 128.1, 127.8, 126.4, 126.0, 125.2, 124.5, 120.8, 117.6, 117.5, 79.3, 70.5,
62.4, 36.6, 34.5, 14.3; IR (KBr) ν 3203, 3060, 2978, 2925, 1739, 1673, 1606, 1483, 1373, 1299, 1282,
1264, 1213, 1193, 1155, 1083, 1033, 1019, 822, 751 cmꢀ1; MS (ESI+) m/z (M+H)+, 387.2, (M+Na)+,
409.2, (M+K)+, 425.2, (2M+Na)+, 795.3; HRMS (ESI+) m/z (M+Na)+ Calcd for C24H22N2O3Na
409.15226; Found: 409.15196.
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Pyrroloquinazolinone 4g: 54 mg (73%, dr >98:2), white solid. cisꢀDiastereomer: R (hexane/MTBE
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1:4) 0.23; mp 148 °C; 1H NMR (300 MHz, CDCl3) δ 7.97 (dd, 1H, J = 8.0, 1.5 Hz), 7.53 (d, 2H, J = 8.5
Hz), 7.42–7.32 (m, 2H), 7.28–7.19 (m, 1H), 7.10 (brs, 1H), 6.98 – 6.88 (m, 1H), 6.50 (d, 1H, J = 8.0
Hz), 4.84 (dd, 1H, J = 8.0, 3.0 Hz), 4.19 (q, 2H, J = 7.0 Hz), 2.83–2.68 (m, 1H), 2.61 (ddd, 1H, J = 13.0,
10.5, 6.5 Hz), 2.24 (ddd, 1H, J = 13.0, 6.5, 4.0 Hz), 2.03 (tdd, 1H, J = 9.5, 6.5, 3.5 Hz), 1.23 (t, 3H, J =
7.0 Hz); 13C{H} NMR (75 MHz, CDCl3) δ 172.0, 165.3, 146.4, 142.6, 134.1, 133.1, 128.9, 128.4,
127.9, 121.0, 117.6, 117.3, 79.2, 69.8, 62.5, 36.6, 34.6, 14.2; IR (KBr) ν 2980, 2934, 2904, 1738, 1669,
1607, 1574, 1487, 1375, 1355, 1300, 1283, 1262, 1218, 1155, 1088, 1014, 841, 759 cmꢀ1; MS (ESI+)
m/z (M+H)+, 371.2, (M+Na)+, 393.1, (M+K)+, 409.1, (2M+Na)+, 763.2; HRMS (ESI+) m/z (M+Na)+
Calcd for C20H19ClN2O3Na 393.09764; Found: 393.09771.
Pyrroloquinazolinone 4h: 68 mg (81%, dr >98:2), white solid. cisꢀDiastereomer: R (hexane/MTBE
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1:4) 0.22; mp 157 °C; 1H NMR (300 MHz, CDCl3) δ 7.97 (dd, 1H, J = 8.0, 1.5 Hz), 7.58–7.43 (m, 4H),
7.28–7.19 (m, 1H), 7.09 (brs, 1H), 6.98–6.89 (m, 1H), 6.50 (d, 1H, J = 8.0 Hz), 4.82 (dd, 1H, J = 8.0,
3.0 Hz), 4.19 (q, 2H, J = 7.0 Hz), 2.83–2.68 (m, 1H), 2.61 (ddd, 1H, J = 13.0, 10.5, 6.5 Hz), 2.23 (ddd,
1H, J = 13.0, 6.5, 4.0 Hz), 2.09–1.98 (m, 1H), 1.23 (t, 3H, J = 7.0 Hz); 13C{H} NMR (75 MHz, CDCl3)
δ 172.0, 165.3, 146.4, 143.1, 134.1, 131.9, 128.4, 128.2, 121.2, 121.0, 117.6, 117.3, 79.2, 69.9, 62.5,
36.6, 34.5, 14.2; IR (KBr) ν 1737, 1661, 1607, 1486, 1372, 1299, 1283, 1264, 1218, 1190, 1154, 1086,
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1033, 1011, 759 cmꢀ1; MS (ESI+) m/z (M+H)+, 415.1, 417.1, (M+Na)+, 437.1, 439.1, (M+K)+, 453.1,
455.1, (2M+Na)+, 853.1; Anal. Calcd for C20H19BrN2O3: C, 57.84; H, 4.61; N, 6.75; Found: C, 57.73;
H, 4.44; N, 6.36.
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1:4) 0.22; mp 135 °C; 1H NMR (300 MHz, CDCl3) δ 7.97 (dd, 1H, J = 8.0, 1.5 Hz), 7.62–7.50 (m, 2H),
7.29–7.18 (m, 2H), 7.13–7.03 (m, 2H), 6.97– 6.88 (m, 1H), 6.51 (d, 1H, J = 8.0 Hz), 4.85 (dd, 1H, J =
8.0, 3.0 Hz), 4.19 (q, 2H, J = 7.0 Hz), 2.83–2.57 (m, 2H), 2.25 (ddd, 1H, J = 11.0, 6.5, 4.0 Hz), 2.10–
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1.99 (m, 1H), 1.23 (t, 3H, J = 7.0 Hz); C{H} NMR (100 MHz, CDCl3) δ 172.1, 165.4, 162.2 (d, J =
245.5 Hz), 146.5, 139.7 (d, J = 3.0 Hz), 134.0, 128.4, 128.0 (d, J = 8.0 Hz), 120.9, 117.6, 117.3, 115.6
(d, J = 21.5 Hz), 79.2, 69.8, 62.4, 36.5, 34.7, 14.2; IR (KBr) ν 3219, 3069, 2982, 2903, 1737, 1671,
1607, 1509, 1484, 1373, 1298, 1285, 1262, 1224, 1157, 1086, 1026, 1015, 836, 757 cmꢀ1; MS (ESI+)
m/z (MꢀCO2Et)+, 281.1, (M+H)+, 355.2, (M+Na)+, 377.2, (M+K)+, 393.1, (2M+Na)+, 731.3; Anal. Calcd
for C20H19FN2O3: C, 67.79; H, 5.40; N, 7.91; Found: C, 67.40; H, 5.39; N, 7.82.
Pyrroloquinazolinone 4j: 59 mg (81%, dr 98:2), white solid. cisꢀDiastereomer: R (hexane/MTBE 1:4)
f
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0.25; mp 148 °C; H NMR (400 MHz, CDCl3) δ 7.96 (dd, 1H, J = 8.0, 1.5 Hz), 7.51–7.45 (m, 2H),
7.24–7.18 (m, 1H), 7.17–7.01 (m, 1H), 6.96–6.88 (m, 3H), 6.55 (d, 1H, J = 8.0 Hz), 4.84 (dd, 1H, J =
7.5, 3.5 Hz), 4.19 (q, 2H, J = 7.0 Hz), 3.83 (s, 3H), 2.77–2.60 (m, 2H), 2.28–2.18 (m, 1H), 2.09–2.02
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(m, 1H), 1.23 (t, 3H, J = 7.0 Hz); C{H} NMR (75 MHz, CDCl3) δ 172.1, 165.4, 158.9, 146.7, 136.0,
133.9, 128.3, 127.5, 120.6, 117.4, 117.3, 114.1, 79.1, 69.9, 62.3, 55.4, 36.6, 34.7, 14.2; IR (KBr) ν 2981,
2934, 2904, 1733, 1666, 1608, 1513, 1483, 1373, 1300, 1282, 1249, 1176, 1086, 1034, 758, 547 cmꢀ1;
MS (ESI+) m/z (M+H)+, 367.2, (M+Na)+, 389.2, (M+K)+, 405.1, (2M+Na)+, 755.3; HRMS (ESI+) m/z
(M+Na)+ Calcd for C21H22N2O4Na 389.14718; Found: 389.14681.
Pyrroloquinazolinone 4k: 60 mg (82%, dr >98:2), white solid. cisꢀDiastereomer: R (hexane/MTBE
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1:8) 0.15; mp 179 °C; 1H NMR (300 MHz, CDCl3) δ 7.98 (dd, 1H, J = 8.0, 1.5 Hz), 7.77–7.68 (m, 4H),
7.45 (brs, 1H), 7.28–7.21 (m, 1H), 6.98–6.93 (m, 1H), 6.43 (d, 1H, J = 8.0 Hz), 4.90 (dd, 1H, J = 8.5,
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2.5 Hz), 4.19 (q, 2H, J = 7.0 Hz), 2.88–2.77 (m, 1H), 2.59 (ddd, 1H, J = 13.0, 11.0, 7.0 Hz), 2.29 (ddd,
1H, J = 13.0, 7.0, 3.5 Hz), 2.05 (ddt, 1H, J = 13.0, 6.5, 3.5 Hz), 1.22 (t, 3H, J = 7.0 Hz); 13C{H} NMR
(75 MHz, CDCl3) δ 172.0, 165.3, 149.5, 146.1, 134.1, 132.7, 128.5, 127.3, 121.3, 118.9, 117.8, 117.3,
111.3, 79.2, 70.1, 62.6, 36.5, 34.4, 14.1; IR (KBr) ν 3202, 3069, 2982, 2937, 2900, 2226, 1738, 1676,
1607, 1482, 1372, 1302, 1280, 1264, 1218, 1162, 1151, 1084, 1020, 849, 764, 565, 550 cmꢀ1; MS
(ESI+) m/z (MꢀCO2Et)+, 288.1, (M+H)+, 362.2, (M+Na)+, 384.2, (M+K)+, 400.1, (2M+Na)+, 745.3;
HRMS (ESI+) m/z (M+Na)+ Calcd for C21H19N3O3Na 384.13186; Found: 384.13179.
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Pyrroloquinazolinone 4l: 43 mg (66%, dr >98:2), white solid. cisꢀDiastereomer: R (hexane/MTBE
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1:4) 0.41; mp 132 °C; 1H NMR (300 MHz, CDCl3) δ 7.95 (dd, 1H, J = 8.0, 1.5 Hz), 7.66–7.62 (m, 1H),
7.44 (t, 1H, J = 1.5 Hz), 7.34–7.28 (m, 1H), 7.00 (brs, 1H), 6.95–6.90 (m, 1H), 6.81 (dd, 1H, J = 8.0, 0.5
Hz), 6.44 (dd, 1H, J = 1.5, 1.0 Hz), 4.83–4.77 (m, 1H), 4.15 (q, 2H, J = 7.0 Hz), 2.70–2.54 (m, 2H),
2.27–2.20 (m, 1H), 2.06–1.99 (m, 1H), 1.20 (t, 3H, J = 7.0 Hz); 13C{H} NMR (75 MHz, CDCl3) δ
172.0, 165.4, 146.5, 143.8, 140.6, 134.1, 128.8, 128.3, 120.7, 117.3, 109.0, 78.7, 63.3, 62.4, 36.8, 33.1,
14.2; IR (KBr) ν 3212, 3066, 2980, 2904, 1739, 1670, 1606, 1484, 1373, 1301, 1286, 1262, 1212, 1182,
1159, 1089, 1026, 875, 766, 601; cmꢀ1; MS (ESI+) m/z (MꢀCO2Et)+, 253.1, (M+H)+, 327.2, (M+Na)+,
349.1, (M+K)+, 365.1, (2M+Na)+, 675.3; HRMS (ESI+) m/z (M+Na)+ Calcd for C18H18N2O4Na
349.11588; Found: 349.11576.
Pyrroloquinazolinone 4m: 49 mg (69%, dr 98:2), white solid. cisꢀDiastereomer: R (hexane/MTBE
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1:4) 0.25; mp 203 °C; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, 1H, J = 8.0 Hz), 7.63–7.56 (m, 2H), 7.45–
7.37 (m, 2H), 7.36–7.27 (m, 1H), 6.75 (dd, 1H, J = 8.0, 1.0 Hz), 6.56 (brs, 1H), 6.35 (s, 1H), 4.87 (dd,
1H, J = 8.0, 2.5 Hz), 4.20 (q, 2H, J = 7.0 Hz), 2.83–2.68 (m, 1H), 2.65–2.53 (m, 1H), 2.21–2.02 (m,
2H), 2.16 (s, 3H), 1.24 (t, 3H, J = 7.0 Hz); 13C{H} NMR (75 MHz, CDCl3) δ 172.1, 165.4, 146.8, 145.0,
144.1, 128.7, 128.3, 127.3, 126.4, 122.2, 117.7, 115.0, 79.3, 70.5, 62.4, 36.7, 34.6, 22.0, 14.2; IR (KBr)
ν 3213, 2980, 2904, 1739, 1668, 1614, 1495, 1471, 1454, 1349, 1297, 1263, 1215, 1187, 1088, 1029,
1017, 778, 757, 703 cmꢀ1; MS (ESI+) m/z (MꢀCO2Et)+, 277.2, (M+H)+, 351.2, (M+Na)+, 373.2, (M+K)+,
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389.1, (2M+Na)+, 723.4; HRMS (ESI+) m/z (M+Na)+ Calcd for C21H22N2O3Na 373.15226; Found:
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1:4) 0.25; mp 154 °C; 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.61 (d, 2H, J = 7.5 Hz), 7.42 (t, 2H,
J = 7.5 Hz), 7.33 (t, 1H, J = 7.5 Hz), 7.24 (brs, 1H), 7.06 (d, 1H, J = 8.0 Hz), 6.48 (d, 1H, J = 8.0 Hz),
4.84 (dd, 1H, J = 8.0, 2.0 Hz), 4.22 (q, 2H, J = 7.0 Hz), 2.84–2.72 (m, 1H), 2.71–2.62 (m, 1H), 2.31–
2.20 (m, 1H), 2.28 (s, 3H), 2.14–2.06 (m, 1H), 1.26 (t, 3H, J = 7.0 Hz); 13C{H} NMR (75 MHz, CDCl3)
δ 172.2, 165.6, 144.5, 144.3, 134.9, 130.4, 128.7, 128.2, 127.3, 126.5, 117.8, 117.6, 79.3, 70.6, 62.3,
36.5, 34.7, 20.6, 14.2; IR (KBr) ν 3193, 3060, 1978, 2922, 2902, 1739, 1671, 1619, 1499, 1450, 1442,
1362, 1286, 1264, 1210, 1157, 1087, 1028, 822, 788, 758, 702, 541 cmꢀ1; HRMS (ESI+) m/z (M+Na)+
Calcd for C21H22N2O3Na 373.15226; Found: 373.15194.
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Pyrroloquinazolinone 4o: 53 mg (72%, dr >98:2), white solid. cisꢀDiastereomer: R (hexane/MTBE
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1:4) 0.18; mp 197 °C; 1H NMR (400 MHz, CDCl3) δ 7.89 (d, 1H, J = 8.5 Hz), 7.59–7.54 (m, 2H), 7.42–
7.35 (m, 2H), 7.32–7.27 (m, 1H), 6.70 (brs, 1H), 6.45 (dd, 1H, J = 8.5, 2.5 Hz), 5.97 (d, 1H, J = 2.5
Hz), 4.88 (dd, 1H, J = 8.0, 4.0 Hz), 4.21 (q, 2H, J = 7.0 Hz), 3.53 (s, 3H), 2.77–2.66 (m, 1H), 2.61 (ddd,
1H, J = 13.0, 9.0, 6.5 Hz), 2.25–2.17 (m, 1H), 2.12–2.04 (m, 1H), 1.25 (t, 3H, J = 7.0 Hz); 13C{H}
NMR (75 MHz, CDCl3) δ 172.3, 165.3, 164.5, 148.3, 143.9, 130.4, 128.9, 127.5, 126.6, 110.5, 107.5,
101.4, 79.3, 70.0, 62.5, 55.3, 37.0, 34.7, 14.3; IR (KBr) ν 3183, 3059, 2983, 2939, 2902, 1741, 1666,
1606, 1475, 1455, 1356, 1310, 1296, 1260, 1233, 1215, 1177, 1089, 1029, 849, 768, 759, 702 cmꢀ1; MS
(ESI+) m/z (M+H)+, 367.2, (M+Na)+, 389.2, (M+K)+, 405.1, (2M+Na)+, 755.4; HRMS (ESI+) m/z
(M+Na)+ Calcd for C21H22N2O4Na 389.14718; Found: 389.14699.
Pyrroloquinazolinone 4p: 61 mg (82%, dr >98:2), white solid. cisꢀDiastereomer: R (hexane/MTBE
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1:4) 0.35; mp 213 °C; 1H NMR (400 MHz, CDCl3) δ 7.93 (d, 1H, J = 2.5 Hz), 7.56–7.51 (m, 2H), 7.43–
7.37 (m, 2H), 7.35–7.29 (m, 1H), 7.15 (dd, 1H, J = 8.5, 2.5 Hz), 6.80 (brs, 1H), 6.46 (d, 1H, J = 8.5 Hz),
4.85 (dd, 1H, J = 8.0, 3.5 Hz), 4.22 (q, 2H, J = 7.0 Hz), 2.79–2.70 (m, 1H), 2.66 (ddd, 1H, J = 13.0,
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10.0, 6.0 Hz), 2.25–2.17 (m, 1H), 2.13–2.05 (m, 1H), 1.25 (t, 3H, J = 7.0 Hz); 13C{H} NMR (100 MHz,
CDCl3) δ 171.7, 164.3, 145.1, 143.5, 134.1, 129.0, 128.0, 127.7, 126.4, 126.2, 118.9, 118.7, 79.3, 70.4,
62.7, 36.7, 34.7, 14.3; IR (KBr) ν 3192, 3060, 2978, 2899, 1737, 1673, 1604, 1483, 1442, 1359, 1280,
1265, 1217, 1156, 1095, 1027, 756, 702 cmꢀ1; MS (ESI+) m/z (M+Na)+, 393.2, (M+K)+, 409.1,
(2M+Na)+, 763.3; HRMS (ESI+) m/z (M+Na)+ Calcd for C20H19ClN2O3Na 393.09764; Found:
393.09760.
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Pyrroloquinazolinone 4q: 65 mg (78%, dr >98:2), white solid. cisꢀDiastereomer: R (hexane/MTBE
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1:4) 0.42; mp 214 °C; 1H NMR (300 MHz, CDCl3) δ 8.08 (d, 1H, J = 2.5 Hz), 7.56–7.51 (m, 2H), 7.43–
7.37 (m, 2H), 7.35–7.29 (m, 1H), 7.28 (dd, 1H, J = 8.5, 2.5 Hz), 7.09 (brs, 1H), 6.40 (d, 1H, J = 8.5 Hz),
4.85 (dd, 1H, J = 8.0, 3.5 Hz), 4.22 (q, 2H, J = 7.0 Hz), 2.79–2.69 (m, 1H), 2.66 (ddd, 1H, J = 13.0,
10.0, 6.5 Hz), 2.24 (ddd, 1H, J = 13.0, 8.0, 4.0 Hz), 2.14–2.06 (m, 1H), 1.25 (t, 3H, J = 7.0 Hz); 13C{H}
NMR (75 MHz, CDCl3) δ 171.7, 164.3, 145.5, 143.5, 136.8, 131.0, 129.0, 127.7, 126.4, 119.1, 119.0,
113.3, 79.3, 70.3, 62.7, 36.6, 34.7, 14.3; IR (KBr) ν 3192, 3060, 2985, 2899, 1737, 1672, 1600, 1481,
1450, 1440, 1357, 1265, 1217, 1156, 1092, 1026, 987, 754, 702 cmꢀ1; MS (ESI+) m/z (M+H)+, 415.1,
417.1, (M+Na)+, 437.1, 439.1, (M+K)+, 453.0, 455.0, (2M+Na)+, 853.1; HRMS (ESI+) m/z (M+Na)+
Calcd for C20H19BrN2O3Na 437.04713; Found: 437.04710.
ACKNOWLEDGEMENT
This work was generously supported by the Deutsche Forschungsgemeinschaft (SCHN 441/10ꢀ1) and
through the generous donation of chemicals from BASF and Evonik. We thank Prof. Krautscheid
(University of Leipzig) and Prof. Sieler (University of Leipzig) for solving the xꢀray structures of 3a
and 4a.
SUPPORTING INFORMATION
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1H and 13CꢀNMR spectra data for all new compounds and crystallographic data for compounds 3a and
4a (deposition numbers: CCDC 1403682 & 1403681). This material is available free of charge via the
Internet at http://pubs.acs.org.
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