Rh2(OAc)4-mediated diazo decomposition of δ-(N-Tosyl)amino-β-keto-α-diazo carbonyl compounds: A novel approach to pyrrole derivatives

Article abstract of DOI:10.1055/s-2002-34888

(N-Tosyl)amino substituted β-keto diazo carbonyl compounds have been prepared by reaction of titanium enolate of β-ketodiazoester or -ketone with an activated N-tosylimine. Rh₂(OAc)₄-catalyzed reaction of the (N-tosyl)amino substitut

Full text of DOI:10.1055/s-2002-34888

LETTER
1913
Rh2(OAc)4-Mediated Diazo Decomposition of -(N-Tosyl)amino- -keto- -
diazo Carbonyl Compounds: A Novel Approach to Pyrrole Derivatives
S
ynthesisof Pyrro
u
les from Imin
i
e
sheng Deng, Nan Jiang, Zhihua Ma, Jianbo Wang*
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology,
College of Chemistry, Peking University, Beijing 100871, P. R. China
Fax +86(10)62751708; E-mail: wangjb@pku.edu.cn
Received 20 August 2002
The generality of the procedure is shown by the reaction
of a series of N-tosylimines with -diazo- -ketoesters and
-diazo- -ketoketones (Table 1). The condensation with
-diazo- -ketoesters gives moderate to good isolated
Abstract: (N-Tosyl)amino substituted -keto diazo carbonyl com-
pounds have been prepared by reaction of titanium enolate of -ke-
todiazoester or -ketone with an activated N-tosylimine. Rh2(OAc)4-
catalyzed reaction of the (N-tosyl)amino substituted -diazocarbo-
nyl compounds leads to the efficient formation of pyrrole deriva- yields in general, but the reaction with -diazo- -ketoke-
tives.
tone 2c gives only low yields (entries 12–14) due to the
low reactivity of the corresponding enolate and the further
aldol reaction of the products.
Key words: pyrroles, diazo compounds, Ti(IV) enolate, nucleo-
philic additions, Rh(II) carbene
O
O
TiCl4 (2.1 eq)
Et3N (1.1 eq)
HNTs O
O
Ts
H
N
Pyrrole derivatives are important heterocycles widely
used in material science and found in biologically impor-
tant natural products.1 In particular, the pyrroles bearing
functional substituents have attracted great attention
among the synthetic organic chemists, and various meth-
odologies have been developed for synthesizing these
compounds. Traditionally, pyrroles have been synthe-
sized by the condensation of primary amine with 1,4-di-
carbonyl compounds.2,3 The obvious drawback of this
approach, known as Paal–Knorr cyclocondensation, is the
accessibility of suitable 1,4-dicarbonyl compounds. In
this communication, we report a novel and highly effi-
cient two-step reaction sequence leading to the function-
alized pyrroles. This approach is based on nucleophilic
condensation of an -diazo- -ketoester or an -diazo- -
ketoketone with N-tosylimine followed by a Rh(II)-cata-
lyzed diazo decomposition.4
+
R
Ar
R
Ar
N2
CH2Cl2 ,–41 °C
N2
1
2a, R = OEt
2b, R = Ph
2c, R = Me
3a-n
Scheme 1
Table 1 TiCl4-Promoted Condensation of -Diazo- -Ketoesters 2
with N-Tosyl Imines 1a
Entry Diazo
N-Tosyl imines 1
Substrate 2 (Ar = )
Prod- Yield
uct
3a
3b
3c
3d
3e
3f
(%)b,c
1
2
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2c
2c
2c
C6H5
62 (96)
83 (98)
34 (94)
47 (96)
87 (97)
37 (92)
47 (94)
74 (99)
51 (93)
58 (96)
70 (98)
17 (37)
17 (38)
13 (33)
o-MeC6H4
p-FC6H4
3
4
p-ClC6H4
Although the aldol condensation of -diazo- -ketoester
has been developed by Calter et al.,5 the corresponding
condensation with imine is not reported. We expected the
condensation of -diazo- -ketoester 2a, and -diazo- -
ketoketones 2b, 2c with N-sulfonylimines under the simi-
lar condition as for aldol reaction would occur to give -
diazocarbonyl compounds 3a–n, which bear -(N-to-
syl)amino group (Scheme 1). Thus, titanium(IV) enolate
of -diazo- -ketoester is generated by treating the diazo
ester with TiCl4–Et3N at –41 °C in CH2Cl2. However, di-
rect reaction of N-tosylimine with the enolate did not yield
the expected condensation product. To further increase
the electrophilicity of C=N bond, N-tosylimine was acti-
vated by treating with another equivalent of TiCl4 before
reacting with the enolate. Under this condition, the ex-
pected condensation product was obtained in good yield.6
5
m-CNC6H4
p-MeOC6H4
(E)-CH=CHC6H5
2-Furyl
6
7
3g
3h
3i
8
9
2-(5-Bromo)thienyl
2-Furyl
10
11
12
13
14
3j
(E)-CH=CHC6H5
C6H5
3k
3l
m-BrC6H4
p-MeOC6H4
3m
3n
a For general experimental procedure, see ref.6
b Isolated yield.
Synlett 2002, No. 11, Print: 29 10 2002.
Art Id.1437-2096,E;2002,0,11,1913,1915,ftx,en;U05602ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
c Number in parenthesis refers to the conversion yield.

1914
G. Deng et al.
LETTER
With the -(N-tosyl)amino- -oxo- -diazo esters or ke-
tones 3a–n in hand, we proceeded to study the catalytic
reaction with Rh2(OAc)4. The diazo decomposition of 3a
(Ar = C6H5) occurred very slowly in CH2Cl2 at room tem-
perature in the presence of 1% mol of Rh2(OAc)4. Howev-
er, when it was refluxed in benzene with Rh2(OAc)4, the
diazo compound disappeared within 10 min, leading to
clean formation of a new compound. Spectroscopic data
of the isolated product confirmed its structure as 1-car-
boethoxy-2-hydroxy-5-phenylpyrrole 4a (Ar = C6H5)
(Scheme 2). The pyrrolidine derivative, which was ex-
pected to form through normal intramolecular N-H inser-
tion of the Rh(II)-carbene intermediate,7 was not observed
in this reaction. Other diazo compounds all give similar
results when reacted with catalytic Rh2(OAc)4 under the
same condition to yield corresponding pyrrole derivatives
in good yields (Table 2).8 When the diazo compounds
were decomposed with Rh2(O2CCF3)4 or Cu(acac)2 in re-
fluxing benzene, same pyrrole derivatives were obtained
in identical yields.
O
O
O
TsNH
Rh(II)
N2
O
3a
OEt
Ph
Ph
N
Ts
6
Rh
OEt
Rh(II)
TolSO2H
5
O H
[1,5] shift
O
4a
Ph
N
OEt
7
Scheme 3
tramolecular N-H insertion occurs to give 6, from which
TolSO2H is eliminated to give intermediate 7.9 Finally,
[1,5]-shift of hydrogen gives the pyrrole derivative 4a.
In summary, the nucleophilic addition of titanium (IV)
enolates of -diazo- -ketoester or -diazo- -ketoketone
to N-tosylimines was successfully promoted by the activa-
tion of TiCl4 to give -(N-tosyl)amino substituted -keto
diazo carbonyl compounds. The Rh2(OAc)4-catalyzed re-
action of these diazo carbonyl compounds gives pyrrole
derivatives in excellent yields.
O H
HNTs O
O
Rh2(OAc)4
O
Ar
R
Ar
N
H
Benzene
reflux, 10min
N2
R
3a, b, c
4a-i
Acknowledgement
Scheme 2
Table 2 Rh2(OAc)4-Mediated Diazo Decompositiona
The project is generously supported by Natural Science Foundation
of China (Grant No. 29972002, 20172002), and by Trans-Century
Training Programme Foundation for the Talents by Ministry of
Education of China.
Entry Diazo
compound 3
Product
Yield
(%)b
References
1
2
3
4
3a
4a R = OEt, Ar = C6H5
75
73
64
75
(1) Comprehensive Heterocyclic Chemistry, Vol. 2; Bird, C. W.,
Ed.; Pergamon Press: Oxford, 1996.
3b
3e
3g
4b R = OEt, Ar = o-MeC6H4
4c R = OEt, Ar = m-CNC6H4
(2) For recent examples of pyrrole syntheses based on Paal–
Knorr reaction, see: (a) Hewton, C. E.; Kimber, M. C.;
Taylor, D. K. Tetrahedron Lett. 2002, 43, 3199. (b)Takaya,
H.; Kojima, S.; Murahashi, S.-I. Org. Lett. 2001, 3, 421.
(c) Braun, R. U.; Zeitler, K.; Muller, T. J. J. Org. Lett. 2001,
3, 3297. (d) Surya Prakash Rao, H.; Jothilingam, S.
Tetrahedron Lett. 2001, 42, 6595.
(3) For recent examples of pyrrole syntheses that are not based
on Paal–Knorr reaction, see: (a) Chen, N.; Lu, Y.;
Gadamasetti, K.; Hurt, C. R.; Norman, M. H.; Fotsch, C. J.
Org. Chem. 2000, 65, 2603. (b) Katritzky, A. R.; Huang,
T.-B.; Voronkov, M. V.; Wang, M.; Kolb, H. J. Org. Chem.
2000, 65, 8819. (c) Gabriele, B.; Salerno, G.; Fazio, A.;
Bossio, M. R. Tetrahedron Lett. 2001, 42, 1339. (d) Kel’in,
A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc.
2001, 123, 2074. (e) Allin, S. M.; Barton, W. R. S.;
Bowman, W. R.; McInally, T. Tetrahedron Lett. 2001, 42,
7887. (f) Lagu, B.; Pan, M.; Wachter, M. P. Tetrahedron
Lett. 2001, 42, 6027.
4d R = OEt, Ar = (E)-
CH=CHC6H5
5
6
3h
3i
4e R = OEt, Ar = 2-Furyl
91
75
4f R = OEt, Ar = 2-(5-Bromo)
thienyl
7
8
3j
4g R = C6H5, Ar = 2-Furyl
88
94
3k
4h R = C6H5, Ar = (E)-CH=
CHC6H5
9
3n
4i R = Me, Ar = p-MeOC6H4
90
a For general experimental procedure and characterization data for
4a–i, see ref.8,
b Isolated yield.
(4) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds;
Wiley Interscience: New York, 1998.
(5) (a) Calter, M. A.; Sugathapala, P. M.; Zhu, C. Tetrahedron
Lett. 1997, 38, 3837. (b) Calter, M. A.; Sugathapala, P. M.
Tetrahedron Lett. 1998, 39, 8813. (c) Calter, M. A.; Zhu, C.
J. Org. Chem. 1999, 64, 1415.
Although the chemistry of -Diazocarbonyl compounds
have been extensively investigated, the formation of pyr-
role derivatives from -diazocarbonyl compounds bear-
ing a -(N-tosyl)amino group is unprecedented. A
possible reaction pathway is outlined in Scheme 3. In-
Synlett 2002, No. 11, 1913–1915 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of Pyrrole Derivatives
1915
(6) General procedure for the TiCl4-promoted condensation of
-diazo- -ketoester 1 with N-tosylimine: To a solution of 2a
(10.0 mmol) in anhydrous CH2Cl2 (20 mL) at –41 °C were
added dropwise TiCl4 (11.0 mmol) and Et3N (11.0 mmol).
After the resulting red-dark solution was stirred at –41 °C for
1 h, a solution of N-tosylimine (4 mmol) in anhydrous
CH2Cl2 (4 mL) was added dropwise. The reaction mixture
was stirred at –41 °C for 9 h and then was quenched with
saturated aqueous NH4Cl (5 mL). The organic layer was
separated and the aqueous layer was extracted with CH2Cl2
(2 20 mL). The combined organic layers were washed with
saturated aqueous NaHCO3 (2 20 mL), and then dried over
Na2SO4. The product was purified by flash chromatography
to yield 3a (Ar = Ph) as white solid (1.03 g, 62%). Mp 140–
142 °C; IR (KBr) 3223, 2152, 1748, 1625 cm–1; 1H NMR
(200 MHz, CDCl3) 1.32 (t, J = 7 Hz, 3 H), 2.37 (s, 3 H),
3.19 (dd, J = 15.6, 5.4 Hz, 1 H), 3.36 (dd, J = 15.6, 8 Hz, 1
H), 4.28 (q, J = 7 Hz, 2 H), 4.76–4.86 (m, 1 H), 5.69 (d, J =
7.8 Hz, 1 H), 7.14–7.20 (m, 7 H), 7.58 (d, J = 8.2 Hz, 2 H);
13C NMR (50 MHz, CDCl3) 14.2, 21.4, 46.3, 54.5, 61.6,
76.8, 126.3, 127.0, 127.4, 128.4, 129.2, 137.4, 140.1, 143.0,
161.1, 189.8; MS m/z (FAB): 416 [(M+H)+, 13], 388 (3), 344
(2), 261 (11), 245 (69), 219 (20), 181 (12), 171 (49), 139
(23), 115 (38), 91 (100), 77 (22), 59 (38), 41 (53). Anal.
Calcd for C20H21N3O5S: C, 57.82; H, 5.09; N, 10.11. Found:
C, 57.85; H, 5.09; N, 10.01.
(7) For examples of intramolecular N-H bond insertion, see:
(a) Moyer, M. P.; Feldman, P. L.; Rapoport, H. J. Org.
Chem. 1985, 50, 5223. (b) Wang, J.; Hou, Y. J. Chem. Soc.,
Perkin Trans. 1 1999, 2277.
(8) General procedure for the diazo decomposition of 3 with
catalyst Rh2(OAc)4: A solution of 3a (Ar = Ph, 1.0 mmol) in
benzene (30 mL) containing Rh2(OAc)4 (0.01 mmol) was
heated under reflux for 10 min. The solution was cooled to
room temperature and was concentrated. Purification by
flash chromatography provided 4a (Ar = Ph, 75% yield) as
white solid.
H, 4.72; N, 10.93. Found: C, 65.81; H, 4.59; N, 10.83.
4d: Mp 150–152 °C; IR (KBr) 3269, 1680, 1661 cm–1; 1H
NMR (200 MHz, CDCl3/DMSO-d6) 1.37 (t, J = 7.2 Hz,
3 H), 4.34 (q, J = 7.2 Hz, 2 H), 5.94 (d, J = 2.8 Hz, 1 H), 6.88
(d, J = 16.4 Hz, 1 H), 7.06 (d, J = 16.4 Hz, 1 H), 7.21–7.44
(m, 5 H), 7.91 (s, 1 H), 11.0 (br s, 1 H); 13C NMR (50 MHz,
CDCl3/DMSO-d6) 14.0, 58.9, 94.8, 105.2, 117.6, 125.4,
126.9, 127.9, 128.3, 133.8, 136.0, 152.6, 161.1; MS m/z (EI)
257 (M+, 100), 210 (88), 183 (11), 182 (6), 167 (8), 154 (28),
128 (46), 102 (5), 77 (6), 51 (5), 29 (5); Anal. Calcd for
C15H15NO3: C, 70.02; H, 5.88; N, 5.44. Found: C, 70.22; H,
6.08; N, 5.29.
4e: Mp 131–133 °C; IR (KBr) 3306, 1667, 1564 cm–1; 1H
NMR (200 MHz, CDCl3) 1.38 (t, J = 7.2 Hz, 3 H), 4.38 (q,
J = 7.2 Hz, 2 H), 6.06 (d, J = 2.6 Hz, 1 H), 6.45–6.47 (m, 1
H), 6.56 (d, J = 3.4 Hz, 1 H), 7.41–7.42 (m, 1 H), 7.92 (br s,
1 H), 8.59 (br s, 1 H); 13C NMR (50 MHz, CDCl3) 14.5,
60.1, 94.6, 105.4, 106.2, 111.7, 126.8, 142.0, 146.5, 154.4,
162.1; MS m/z (EI) 221 (M+, 95), 193.3 (4), 175 (100), 147
(26), 139 (2), 119 (15), 92 (52), 91 (8), 63 (15), 39 (12);
Anal. Calcd for C11H11NO4: C, 59.73; H, 5.01; N, 6.33.
Found: C, 59.65; H, 4.97; N, 6.13.
4f: Mp 129–130 °C; IR (KBr) 3502, 3289, 1677, 1574, 1539
cm–1; 1H NMR (200 MHz, CDCl3) 1.38 (t, J = 7.2 Hz, 3
H), 4.37 (q, J = 7.2 Hz, 2 H), 5.99 (d, J = 3Hz, 1 H), 6.93–
7.26 (m, 2 H), 8.08 (br s, 1 H), 8.84 (br, s, 1 H); 13C NMR
(50 MHz, CDCl3) 14.5, 60.3, 96.6, 123.7, 127.9, 129.7,
130.7, 131.9, 139.0, 144.5, 160.9; MS m/z (EI) 317 (M+,
80Br, 74), 315 (M+, 78Br, 71), 271 (100), 242 (12), 215 (9),
188 (37), 162 (76), 155 (17), 133 (14), 108 (19), 91 (40), 82
(9), 63 (14), 45 (5); Anal. Calcd for C11H10BrNO3S: C,
41.79; H, 3.19; N, 4.43. Found: C, 41.85; H, 3.26; N, 4.40.
4g: Mp 139–142 °C; IR (KBr) 3320, 1590, 1567 cm–1; 1H
NMR (200 MHz, CDCl3) 6.14 (d, J = 2.4 Hz, 1 H), 6.50
(dd, J = 3.5, 1.7 Hz, 1 H), 6.66 (d, J = 3.5 Hz, 1 H), 7.44 (d,
J = 1.7 Hz, 1 H), 7.50–7.59 (m, 3 H), 7.77–7.82 (m, 2 H),
8.26 (br s, 1 H), 10.43 (br s, 1 H); 13C NMR (50 MHz,
CDCl3) 94.8, 108.2, 112.1, 116.0, 127.5, 129.0, 129.8,
131.6, 137.7, 142.7, 145.9, 159.3, 184.0; MS m/z (EI) 253
(M+, 100), 236 (5), 224 (4), 196 (4), 176 (30), 147 (7), 120
(9), 105 (37), 92 (24), 91 (3), 77 (49), 65 (20), 51 (17), 39
(15); Anal. Calcd for C15H11NO3: C, 71.14; H, 4.38; N, 5.53.
Found: C, 70.98; H, 4.37; N, 5.46.
4h: Mp 159–161 °C; IR (KBr) 3322, 2261, 1626, 1592,
1550, 1503 cm–1; 1H NMR (200 MHz, CDCl3) 6.10 (d, J =
2 Hz, 1 H), 6.79 (d, J = 16.5 Hz, 1 H), 7.00 (d, J = 16.5 Hz,
1 H), 7.28–7.54 (m, 8 H), 7.68–7.72 (m, 2 H), 8.41 (br s, 1
H), 10.40 (br s, 1 H); 13C NMR (50 MHz, CDCl3) 96.3,
116.6, 117.3, 126.6, 127.5, 128.5, 128.8, 128.9, 131.6,
132.0, 135.9, 137.7, 138.0, 159.5, 183.8; MS m/z (EI) 289
(M+, 100), 288 (27), 270 (10), 212 (13), 156 (6), 128 (23),
105 (49), 77 (31), 51 (7); Anal. Calcd for C19H15NO2: C,
78.87; H, 5.23; N, 4.84. Found: C, 78.80; H, 5.21; N, 4.74.
4i: Mp 178–180 °C(decomposed); IR (KBr) 3272, 1614,
1585, 1534 cm–1; 1H NMR (200 MHz, CDCl3) 2.48 (s, 3
H), 3.85 (s, 3 H), 6.01 (d, J = 2.8 Hz, 1 H), 6.93 (d, J = 8.6
Hz, 2 H), 7.62 (d, J = 8.6 Hz, 2 H), 9.47 (br s, 1 H), 10.59
(br, s, 1 H); MS m/z (EI) 231 (M+, 100), 216 (93), 202 (9),
188 (5), 174 (8), 161 (15), 146 (4), 133 (18), 118 (7), 117 (8),
102 (3), 89 (12), 77 (4), 63 (6), 43 (13); Anal. Calcd for
C13H13NO3: C, 67.52; H, 5.67; N, 6.06. Found: C, 67.41; H,
5.71; N, 6.01.
4a: Mp 138–140 °C; IR (KBr) 3453, 3304, 3278, 1692
cm–1; 1H NMR (200 MHz, CDCl3) 1.37 (t, J = 7.2 Hz, 3 H),
4.37 (q, J = 7.2 Hz, 2 H), 6.16 (d, J = 3.2 Hz, 1 H), 7.25–7.79
(m, 5 H), 7.91 (br, s, 1 H), 8.76 (br, d, 1 H); 13C NMR (50
MHz, CDCl3) 14.6, 61.2, 95.9, 106.2, 124.9, 128.2, 128.6,
131.1, 136.0, 155.2, 162.0; MS m/z (EI) 231 (M+, 91), 203
(3), 185 (100), 156 (18), 129 (12), 102 (72), 77 (14), 51 (6);
Anal. Calcd for C13H13NO3: C, 67.52; H, 5.67; N, 6.06.
Found: C, 67.45; H, 5.59; N, 5.91.
4b: Mp 91–93 °C; IR (KBr) 3489, 3310, 1696, 1677 cm–1;
1H NMR (200 MHz, CDCl3) 1.37 (t, J = 7.2 Hz, 3 H), 2.43
(s, 3 H), 4.35 (q, J = 7.2 Hz, 2 H), 5.98 (d, J = 2.6 Hz, 1 H),
7.23–7.37(m, 4 H), 7.76 (br, s, 1 H), 8.11 (br, s, 1 H); 13
NMR (50 MHz, CDCl3) 14.5, 20.7, 60.0, 98.8, 105.5,
C
126.0, 128.3, 128.4, 130.9, 131.5, 135.7, 135.9, 153.7(br),
162.0(br); MS m/z (EI) 245 (M+, 100), 222 (3), 199 (93), 193
(28), 171 (12), 144 (12), 134 (12), 123 (28), 116 (63), 95 (7),
91 (6), 77 (6), 57 (6), 43 (7). Anal. Calcd for C14H15NO3: C,
68.56; H, 6.16; N, 5.71. Found: C, 68.45; H, 6.18; N, 5.61.
4c: Mp 203 °C; IR (KBr) 3501, 3337, 2227, 1669 cm–1; 1H
NMR (200 MHz, CDCl3/DMSO-d6) 1.41 (t, J = 7.2 Hz, 3
H), 4.39 (q, J = 7.2 Hz, 2 H), 6.17 (d, J = 2.8 Hz, 1 H), 7.44–
7.56 (m, 2 H), 7.89–7.95 (m, 2 H), 8.15 (s, 1 H), 10.91 (br, s,
1 H); 13C NMR (50 MHz, CDCl3/DMSO-d6) 14.1, 59.4,
95.7, 106.9, 112.0, 118.1, 128.0, 128.9, 129.9, 132.2, 132.5,
152.7, 161.4; MS m/z (EI) 256 (M+, 14), 241 (2), 210 (20),
178 (5), 171 (43), 155 (57), 127 (14), 107 (22), 91 (100), 65
(39), 57 (31), 39 (18); Anal. Calcd for C14H12N2O3: C, 65.62;
(9) p-Toluenesufinic acid was further converted to thiosulfonic
ester, which is isolated and characterized.
Synlett 2002, No. 11, 1913–1915 ISSN 0936-5214 © Thieme Stuttgart · New York