Synthesis of pyrrolo[1,3]diazepines by a dipolar cycloaddition-retro-Mannich domino reaction

Article abstract of DOI:10.1016/j.tetlet.2009.09.107

Microwave irradiation facilitated the synthesis of 4-arylthio-3-oxazolin-5-ones from ethyl cyanoformate, thiophenol, and cyclic ketones. Subsequent decarboxylation and in situ [3+2] cycloaddition provided novel 2,3,4,5-tetrahydro-1H-pyrrolo[1,2-c][1,3]diazepine scaffolds after a spontaneous retro-Mannich domino reaction.

Full text of DOI:10.1016/j.tetlet.2009.09.107

Tetrahedron Letters 50 (2009) 6810–6813
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Synthesis of pyrrolo[1,3]diazepines by a dipolar cycloaddition—retro-Mannich
domino reaction
*
Mary Liang, Cecilia Saiz , Chiara Pizzo , Peter Wipf
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Microwave irradiation facilitated the synthesis of 4-arylthio-3-oxazolin-5-ones from ethyl cyanoformate,
thiophenol, and cyclic ketones. Subsequent decarboxylation and in situ [3+2] cycloaddition provided
novel 2,3,4,5-tetrahydro-1H-pyrrolo[1,2-c][1,3]diazepine scaffolds after a spontaneous retro-Mannich
domino reaction.
Received 29 August 2009
Accepted 18 September 2009
Available online 24 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The utility of 1,4-benzodiazepines in drug discovery has been
extraordinary due to the remarkable therapeutic value of this class
of azaheterocyclic compounds.1 Benzodiazepine derivatives have
been found to possess anticonvulsant to anxiolytic activities, and
strong anti-tumor properties. Among other pharmacological func-
tions, the much less broadly studied 1,3-diazepine derivatives have
been of interest due to their inhibitory effects on HIV-1 protease,
adenosine deaminase, and guanase, as well as their NK1 recep-
tor-binding properties (Fig. 1).2,3 However, there is still a relative
dearth of synthetic methods to access fused 1,3-diazepine scaf-
folds, in particular the novel pyrrolo[1,3]diazepines.4 We have
discovered an elegant domino reaction which readily converts
1,3-oxazolin-5-ones into pyrrolo[1,3]diazepines through a mecha-
nistically intriguing cycloreversion, 1,3-dipolar cycloaddition, ret-
ro-Mannich reaction, and iminium ion addition sequence.
In this Letter, we describe a microwave-accelerated synthesis of
4-arylthio-3-oxazolin-5-ones, as well as their in situ conversion to
pyrrolo[1,3]diazepines and further functionalization of these het-
erocyclic scaffolds.
In an earlier approach, one of us had synthesized 4-arylthio-3-
oxazolin-5-ones in a ‘one-pot reaction’ from ethyl cyanoformate,
thiophenol, and carbonyl compounds in the presence of diethyl-
amine, BF3-etherate, and titanium tetrachloride.5 In an analogous
sequence, but using microwave heating in a monomode reactor,
we synthesized the piperidyl 3-oxazolin-5-one 4 from 1-benzylpi-
peridin-3-one 3 (Scheme 1). Significantly, the oxazolinone forma-
tion was thus expedited from a 12–36 h reaction time5 to 15 min
at 80 °C under microwave irradiation, and the yield was increased
to 60%.
Heating 0.5 M solution of 4 in chlorobenzene at 150 °C for
10 min in the microwave reactor released carbon dioxide to gener-
ate the intermediate nitrile ylide I1,6 which was spontaneously
trapped by the powerful dipolarophile dimethyl acetylenedicar-
boxylate (DMAD) in a 1,3-dipolar cycloaddition reaction (Scheme
2).6,7 However, rather than the expected spirocycle I2, the pyrrol-
o[1,3]diazepine 5 was isolated in good yield as the end product
of a spontaneous retro-Mannich-aminal formation pathway which
likely includes the zwitterionic I3 as yet another step along a lar-
gely unprecedented cascade process.
Ph
HO
N
H
N
OH
O
MeO
N
Ph
HO
N
NH2
O
N
N
N
HO
HN
Ph
N
NH2
HO
Figure 1. Representative examples of pharmaceutically relevant 1,3-diazepine
derivatives.
O
EtO
CN
1
PhS
O
SH
O
.
Et2NH, TiCl4, BF3 Et2O
+
N
O
CH2Cl2, 80 oC µW, 15 min
N
Ph
Ph
42-60%
N
* Corresponding author.
2
3
4
E-mail address: pwipf@pitt.edu (P. Wipf).
Present address: Laboratorio de Química Farmacéutica, DQO, Facultad de
Química, Universidad de la República, Gral Flores 2124, CC 1157, Montevideo,
Uruguay.
Scheme 1. Microwave-mediated synthesis of piperidyl 4-arylthio-3-oxazolin-5-
one 4 in the presence of diethylamine and Lewis acid catalysts.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.107

M. Liang et al. / Tetrahedron Letters 50 (2009) 6810–6813
6811
Intrigued by this domino process8 as well as the opportunity for
ready access to unusual pyrrolo[1,3]-diazepine derivatives, we
evaluated its scope with electron-deficient alkynes (Table 1). In
all cases, generation of the thio-substituted nitrile ylide was
achieved by microwave-mediated thermolysis of the oxazolinone
4 in chlorobenzene at 150 °C for 10 min. Reactive electron-defi-
cient alkyne dipolarophiles such as DMAD (entry 1) and methyl
propiolate (entry 2) gave high to moderate yields of the cascade
products 5 and 6 (77% and 47%, respectively). Interestingly, the
1,3-dipolar cycloaddition of nitrile ylide I1 with methyl propiolate
proceeded regioselectively to give diazepine 6 as a single detect-
able product, assigned by 2D NOESY analysis. The observed regi-
oselectivity in the cycloaddition suggests that the ylide carbon in
I1 is more nucleophilic than the nitrile carbon, attacking the mon-
osubstituted alkyne at the more electrophilic b-carbon. This regi-
oselectivity is in contrast to the cycloaddition of related nitrile
ylides to carbonyl compounds.6 It is also noteworthy that a previ-
ous attempt for the 1,3-dipolar cycloaddition of the cyclohexyl
analog of oxazolinone 4 to ethyl propiolate failed, leading instead
to a [1,4]H shift in the ylide to give an aza-1,3-butadiene interme-
diate, followed by the formation of a tetrahydroquinoline by way
of a Diels–Alder reaction with the propiolate.6 A possible explana-
tion for this difference in reactivity is that the presence of the
nitrogen atom in the ylide carbon substituent inductively activates
the ylide, or disfavors the [1,4]H shift sufficiently to allow a dipolar
addition to the less reactive (compared to DMAD) propiolate.
In support of an unusually high reactivity of the piperidyl nitrile
ylide I1, even the use of 2-ethynylpyridine led to dipolar cycloaddi-
tion products, albeit in a rather low overall yield of 34% (entry 3).
The regioisomers 7a and 7b were isolated as an inseparable 1.7:1
mixture. Methyl phenylpropiolate resulted in a 1.6:1 mixture of
regioisomeric adducts 8a and 8b in a combined yield of 11% (entry
4). Similarly, methyl but-2-ynoate-derived pyrrolo[1,3]-diazepines
9a and 9b were also obtained as an inseparable mixture of regioi-
somers (entry 5). In the latter three reactions, the structure of the
major regioisomer was not assigned. Due to an extensive thermal
alkyne decomposition observed by 1H NMR analysis of the crude
reaction mixture, methyl 3-(pyridin-2-yl)propiolate did not pro-
vide any desired product (entry 6). Accordingly, while the opportu-
nity for synthesizing pyrrolodiazepine derivatives 5–9 in two steps
remains intriguing, the reaction scope is still limited to moderately
to highly activated, thermally stable dipolarophiles. We intend to
CO2Me
PhS
N
PhS
O
N
Ph
Ph
CO2Me
[3+2]
-CO2
N
O
µW, 150 o
C
N
Ph
N
PhS
N
4
I1
CO2Me
PhS
PhS
CO2Me
CO2Me
N
CO2Me
N
retro-Mannich
N
N
I2
I3
Ph
Ph
PhS
CO2Me
N
CO2Me
77%
N
Ph
5
Scheme 2. Suggested mechanism for the domino process—1,3-dipolar cycloaddi-
tion of the nitrile ylide I1 derived from 4 to DMAD, retro-Mannich reaction, and
imine addition—generating the pyrrolo[1,3]-diazepine 5.
CO2Me
CO2Me
PhS
HN
PhS
CO2Me
CO2Me
Table 1
AcOH/H2O (5:1)
Domino reactions of 4 with 1,3-dipolarophiles under microwave heating conditions
N
PhS
O
N
90 °C, 2 d
85%
PhS
R1
R2
Ph
I
R1
R2
5
10
O
N
N
Ph
N
H
Ph-Cl, 150 °C µW, 10 min
N
Ph
N
Ph
PhS
HN
CO2Me
CO2Me
4
5-9
O
N
Entry Alkyne
Product R1
R2
Yield
(%)
N
N
Dioxane
100 °C, K2CO3
11
MeO2C
MeO2C
CO2Me
1
2
5
6
CO2Me
CO2Me
CO2Me
H
77
Et3N, CH2Cl2, rt
54%
Br
N
Ph
87%
47
34
N
O
12
3a
7a
7b
2-Pyridyl
H
H
N
2-Pyridyl
Me
Me
N
N
Me
Me
Me Me
4a
5a
8a
8b
Phenyl
CO2Me
CO2Me
Phenyl
11
20
MeO2C
Cl
PhS
CO2Me
CO2Me
CO2Me
PhS
Ru
Cl
Ph
P
14
N
N
CO2Me
MeO2C
EtO2C
Me
N
9a
9b
CO2Me
Me
Me
CO2Me
N
N
G2 Grubbs Catalyst
O
N
O
N
CH2Cl2 (reflux), N2
73%
13
15
6b
—
—
—
—
Ph
Ph
a
Regioisomers were not separable by chromatography on SiO2.
No desired product was observed by 1H NMR of the crude reaction mixture.
Scheme 3. Conversion of pyrrolodiazepine 5 to the free amine 10 serves as an entry
point for ring expansion to access the fused macrocyclic urea 15.
b

6812
M. Liang et al. / Tetrahedron Letters 50 (2009) 6810–6813
3. (a) Wang, L.; Hosmane, R. S. Bioorg. Med. Chem. Lett. 2001, 11, 2893–2896; (b)
Boks, G. J.; Tollenaere, J. P.; Kroon, J. Bioorg. Med. Chem. 1997, 5, 535–547.
4. The synthesis and biology of pyrrolo[1,3]diazepines remain essentially
unexplored, in spite of some previous preparative work: (a) Daich, A.; Ohier,
P.; Decroix, B. J. Heterocycl. Chem. 1995, 32, 1731–1734; (b) El-Kashef, H.;
Rathelot, P.; Vanelle, P.; Rault, S. Monatsh. Chem. 2007, 138, 469–476; (c)
Mahaffey, R. L.; Atwood, J. L.; Humphrey, M. B.; Paudler, W. W. J. Org. Chem.
1976, 41, 2963–2965.
5. (a) Wipf, P.; Heimgartner, H. Tetrahedron Lett. 1984, 25, 5127–5128; (b) Wipf,
P.; Prewo, R.; Bieri, J. H.; Heimgartner, H.; Nastopoulos, V.; Germain, G. Helv.
Chim. Acta 1987, 70, 1380–1388.
6. (a) Wipf, P.; Heimgartner, H. Chimia 1984, 38, 357–359; (b) Wipf, P.; Prewo, R.;
Bieri, J. H.; Germain, G.; Heimgartner, H. Helv. Chim. Acta 1988, 71, 1177–1190.
7. Sharp, J. T., Nitrile Ylides and Nitrile imines. In Synthetic Applications of 1,3-
Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products;
Padwa, A.; Pearson, W. H.; Eds.; Chem. Heterocycl. Compds.; J. Wiley & Sons,
Inc., 2002, Vol. 59, pp 473–538.
8. Tietze, L. F.; Modi, A. Med. Res. Rev. 2000, 20, 304–322.
Figure 2. Ball-and-stick models of force-field minimized lowest-energy conforma-
tions of cis-15 (left) and trans-15 (right).
9. For the use of azamacrocycles in diversity-oriented synthesis, see, for example:
(a) Wipf, P.; Stephenson, C. R. J.; Walczak, M. A. A. Org. Lett. 2004, 6, 3009–3012;
(b) Wessjohann, L. A.; Ruijter, E. Top. Curr. Chem. 2005, 243, 137–184.
10. Grzyb, J. A.; Shen, M.; Yoshina-Ishii, C.; Chi, W.; Brown, S.; Batey, R. A.
Tetrahedron 2005, 7153–7175.
11. Albano, V.; Gualandi, A.; Monari, M.; Savoia, D. J. Org. Chem. 2008, 73, 8376–
8381.
12. Lee, C. W.; Grubbs, R. H. J. Org. Chem. 2001, 66, 7155–7158.
develop catalytic, less harsh reaction conditions in order to expand
the scope of this novel transformation to more temperature-sensi-
tive alkynes. In contrast, we were able to showcase the possibility
for further ring conversions of pyrrolodiazepines 5–9 in the effi-
cient generation of an azamacrocyclic scaffold (Scheme 3).9
While the aminal function in the pyrrolo[1,3]diazepine 5 is suf-
ficiently resistant to hydrolysis to allow biological assays under
standard conditions, cleavage can be accomplished in a 5:1 mix-
ture of AcOH and H2O for 2 d at 90 °C. The benzylic amine 10
was isolated in 85% yield. Subsequent selective N-amidation was
affected by acyl transfer with in situ-prepared imidazolium salt
11.10 The resulting urea 12 was N-allylated in the presence of a
fivefold excess of allyl bromide and K2CO3 in dioxane at reflux to
give diene 13.11 Ring-closing metathesis with ruthenium catalyst
1412 under a nitrogen atmosphere gave the 12-membered macro-
cycle 15 in good yield as a 3:1 mixture of (Z/E)-isomers.
The formation of a mixture of cis/trans-isomers in the RCM
preparation of a macrocycle is not unexpected.12,13 We performed
conformational minimizations of the structures of cis- and trans-15
using SPARTAN 08 with the MMFF parameterization and found the
putative global minima to have essentially identical steric energies.
cis-15 displayed a half-boat-conformation of the 12-membered
ring, whereas trans-15 showed a crown-like, more rectangular con-
formation (Fig. 2). In both cases, the macrocycle minimized the
nonbonding interactions of the urea substituents.
In conclusion, we were able to apply new microwave heating
conditions to the synthesis of 4-arylthio-3-oxazolin-5-one 4. Ther-
molysis of this spirocycle revealed a mechanistically unique dom-
ino reaction, whereby expulsion of CO2 led to a nitrile ylide which
underwent in situ trapping with a 1,3-dipolarophile followed by a
retro-Mannich reaction and iminium ion cyclization, terminating in
the preparation of a pyrrolo[1,3]diazepine. Hydrolysis of the ami-
nal function, and a sequence of N-carbamoylation, N-allylation,
and RCM, provided access to the 12-membered pyrrole-fused urea
15. Pyrrole-containing natural products are known for attractive
biological properties,14 and this work provides a new access to a di-
verse set of fused pyrrole derivatives.15–17
13. (a) Hansen, E. C.; Lee, D. J. Am. Chem. Soc. 2004, 126, 15074–15080; (b) Kaul, R.;
Surprenant, S.; Lubell, W. D. J. Org. Chem. 2005, 70, 3838–3844.
14. See: Jin, Z. Nat. Prod. Rep. 2009, 26, 382–445 and references cited therein.
15. Experimental protocol and spectral data of 4: 1-Benzyl-3-piperidone: A solution of
K2CO3 (0.546 g, 2.63 mmol) in deionized water (5.0 mL) was added to 1-
benzyl-3-piperidone hydrochloride hydrate (0.600 g, 2.63 mmol) at rt. The
reaction mixture was stirred for 90 min and extracted into ethyl acetate. The
organic layer was dried (MgSO4), filtered, and concentrated to obtain 1-benzyl-
3-piperidone (free-base) as a viscous brown-oil (0.492 g, 2.60 mmol, 99%) upon
drying under high vacuum for 1 h. 7-Benzyl-3-(phenylthio)-1-oxa-4,7-
diazaspiro[4.5]dec-3-en-2-one (4): To a microwave vial containing a solution
of thiophenol (0.0689 g, 0.625 mmol) in dry dichloromethane (0.98 mL) were
added ethyl cyanoformate (0.0503 g, 0.507 mmol) and Et2NH (1 drop) at 0 °C.
The reaction mixture was stirred under an atmosphere of N2 at rt for 2 h. At
0 °C, 0.5 mL of a freshly prepared catalyst stock solution (TiCl4 (20 drops) and
BF3ÁEt2O (10 drops) in dichloromethane (3.0 mL) mixed under N2 at rt) was
added dropwise, followed by the addition of 1-benzyl-3-piperidone (0.0935 g,
0.516 mmol). The reaction mixture was heated in the microwave at 80 °C for
15 min and diluted with EtOAc and 5 M NaOH (1.0 mL). The aqueous layer was
extracted with EtOAc (3Â). The combined organic layers were washed with
brine, dried (MgSO4), filtered, and concentrated. The crude residue was purified
by chromatography on SiO2 (88% hexanes/EtOAc) to yield
4 (0.106 g,
0.301 mmol, 60%) as a light yellow-orange viscous oil. Upon refrigeration, 4
turned into an amorphous wax after several days: IR 2946, 2928, 2805, 2788,
2764, 1770, 1577, 1560, 1439, 1299, 1251, 1114, 1053, 1027, 975, 917, 900,
738, 701, 684 cmÀ1 1H NMR (CDCl3, 300 K) d 7.57–7.54 (m, 2 H), 7.41–7.39 (m,
;
3 H), 7.27–7.19 (m, 5 H), 3.60, 3.51 (AB, 2 H, J = 13.5 Hz), 2.82 (dt, 1 H, J = 11.1,
3.6 Hz), 2.51 (s, 2 H), 2.20 (app t, 1 H, J = 10.5 Hz), 2.01–1.57 (m, 4 H); 13C NMR
(CDCl3, 300 K) d 162.7, 161.5, 137.7, 133.9, 129.9, 129.5, 128.8, 128.4, 127.2,
126.4, 106.8, 62.0, 59.8, 52.1, 34.3, 22.1; TOFMS m/z 375 ([M+Na]+, 10), 365
(30), 353 ([M+H]+, 100); HRMS (ES) m/z calcd for C20H20N2O2SNa (M+Na)
375.1143, found 375.1114.
16. Experimental protocol and spectral data of dimethyl 2-benzyl-8-(phenylthio)-
2,3,4,5-tetrahydro-1H-pyrrolo[1,2c][1,3]diazepine-6,7-dicarboxylate (5): A solu-
tion of acetylenecarboxylic acid dimethyl ester (0.0745 g, 0.504 mmol) in
chlorobenzene (0.5 mL) was treated with
4 (0.0888 g, 0.252 mmol). The
reaction mixture was stirred at 150 °C for 10 min under microwave irradiation
(200 W). Without the removal of the chlorobenzene, the crude reaction mixture
was purified by chromatography on SiO2 (eluting with 100% to 80% hexanes/
EtOAc). The residue was further purified by Kugelrohr distillation (0.1 Torr,
100 °C) to yield 5 (0.0879 g, 0.195 mmol, 77%) as a light yellow oil which turned
into a yellow-orange glass upon further drying under high vacuum and extended
refrigeration: IR 2945, 1705, 1495, 1439, 1273, 1204, 1178, 1128, 1049, 1027,
738, 697 cmÀ1 1H NMR (CDCl3, 295 K) d 7.32–7.18 (m, 8H), 7.13–7.06 (m, 2H),
;
5.13 (br s, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.39 (s, 2H), 3.40–3.20 (br m, 2H), 3.01
(dd, 2H, J = 4.8, 5.1 Hz), 1.72–1.62 (m, 2H); 13C NMR (CDCl3, 300 K) d 166.2, 164.7,
143.7, 138.0, 136.4, 129.3, 128.5, 127.4, 126.4, 125.4, 120.0, 111.5, 65.6, 54.6,
52.8, 52.4, 51.6, 25.6, 22.2; TOFMS m/z 474 (3), 473 ([M+Na]+, 100), 451 ([M+H]+,
3); HRMS (ES) m/z calcd for C25H26N2O4SNa (M+Na) 473.1502, found 473.1511.
17. Experimental protocol for RCM of 13 and spectral data of dimethyl 4-benzyl-6-
methyl-5-oxo-12-(phenylthio)-1,2,3,4,5,6,7,10-octahydropyrrolo[2,1-g][1,3,8]triaz
acyclododecine-13,14-dicarboxylate ((Z)-15): A solution of diene 13 (0.0180 g,
0.0313 mmol) in dry dichloromethane (7.0 mL) was treated with 2nd
generation Grubbs catalyst 14 (0.00531 g, 0.00625 mmol), heated at reflux
for 5 h, cooled to rt, filtered through a pad of Celite/Florisil (1:1), and washed
with EtOAc. The eluent was concentrated, and the residue was purified by
chromatography on SiO2 (80% hexanes/EtOAc) to yield 15 as a colorless oil
(0.0125 g, 0.0228 mmol, 73%) and a mixture of (Z/E)-isomers (3:1). Major (Z)-
Acknowledgments
This work was supported in part by NIH grant P50-GM067082
and a gift from Boehringer-Ingelheim Pharmaceuticals, Inc. The
authors would also like to thank Dr. Kalyani Patil for assistance
in the optimization of the synthesis of 1,3-oxazolin-5-ones.
References and notes
1. See, for example: Costantino, L.; Barlocco, D. Curr. Med. Chem. 2006, 13, 65–85.
2. Dieltiens, N.; Claeys, D. D.; Allaert, B.; Verpoort, F.; Stevens, C. V. Chem.
Commun. 2005, 4477–4478.
isomer: IR 2946, 1705, 1636, 1495, 1446, 1210, 1075, 1027, 732, 701 cmÀ1
;
1H
NMR (CDCl3, 300 K) d 7.36–7.14 (m, 10 H), 5.76 (dt, 1 H, J = 7.8, 10.8 Hz), 5.15

M. Liang et al. / Tetrahedron Letters 50 (2009) 6810–6813
6813
(dt, 1 H, J = 6.6, 10.8 Hz), 4.74 (d, 2 H, J = 6.0 Hz), 4.53 (br s, 2 H), 3.94 (br s, 2 H),
3.86 (s, 3 H), 3.78 (s, 3 H), 3.24 (br s, 2 H), 2.93–2.87 (m, 2 H), 2.85 (s, 3 H),
1.70–1.60 (m, 2 H); 13C NMR (CDCl3, 300 K) d 166.2, 165.0, 163.8, 143.1, 137.8,
135.9, 133.8, 129.4, 129.1, 128.7, 127.7, 127.5, 127.3, 126.5, 125.4, 118.9, 111.5,
54.8, 52.4, 51.4, 47.0, 45.7, 42.1, 35.6, 29.7, 28.0, 22.9; MS (EI) m/z 547 (M+, 3.5),
424 (9), 91 (100); HRMS (EI) m/z calcd for C30H33N3O5S 547.2122, found
547.2141. Minor (E)-isomer: 1H NMR (CDCl3, 300 K) d 7.35–7.11 (m, 10 H), 5.85
(dt, 1 H, J = 5.7, 15.5 Hz), 5.38 (dt, 1 H, J = 6.3, 15.5 Hz), 4.76 (d, 2 H, J = 5.7 Hz),
4.38 (s, 2 H), 3.86 (s, 3 H), 3.77 (s, 3 H), 3.68–3.65 (m, 2 H), 3.12 (br s, 2 H),
2.90–2.85 (m, 2 H), 2.82 (s, 3 H), 1.78–1.69 (m, 2 H).