The ammonium-promoted formylation of indoles by DMSO and H2O

Article abstract of DOI:10.1039/c3ob41510d

DMSO and H₂O is an efficient combination in the NH ₄OAc-promoted formylation of indole, where DMSO serves as a C1 carbon source. The mechanism study reveals that the procedure involves a usual and unusual Pummerer reaction.

Full text of DOI:10.1039/c3ob41510d

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The Ammonium-Promoted Formylation of Indoles by DMSO and H2O
Haiyang Fei,a Jintao Yu a Yan Jiang,a Huan Guoa and Jiang Cheng*a,b
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
5
DMSO and H2O is an efficient combination in the NH4OAc-
Table 1. Screening the optimized reaction conditions.a
promoted formylation of indole, where DMSO serves as a C1
carbon source. The mechanism study reveals that the
procedure involves a usual and unusual Pummerer reaction.
The formylation reaction is an important transformation in
10 organic synthesis.1 Traditionally, the Vilsmeier-Haack
reaction is efficient for such transformation.2 However, it
requires a stoichiometric amount of POCl3, which is not
environmentally benign. The Duff reaction,3 Reimer–Tiemann
reaction,4 and Gattermann-Koch reaction,5 are also powerful
15 methods leading to formylated products. Nevertheless, some
substrates such as indoles have not been tolerated well
because of either limited substrate scope of such reactions or
strongly acidic conditions. To solve this problem, in 2011, Su
reported a mild Ru-catalyzed formylation of indoles using
20 anilines as the carbonyl source.6 Subsequently, we developed
a copper-catalyzed C3-formylation of indole C-H bonds by
tertiary amines and molecular oxygen.7 Our continuous
research on the DMSO-mediated organic reaction8 spurred us
to test the feasibility of DMSO serving as a carbonyl reagent,
25 which might open up an expedient synthetic pathway to
formylated products.
Entry
1
2
3
4
5
6
7
8
9
Metal(equiv)
CuF2(3)
Cu(OAc)2(3)
Cu(OAc)2(3)
Cu(OAc)2(3)
Additive
NH3•H2O
Yield(%)
20
23
38
44
69
74
NH3•H2O
(NH4)2CO3
HCOONH4
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
HCOONH4
NH4F
Cu(OAc)2(3)
Pd(OAc)2(0.1)
--
--
--
--
--
62
57b
79c
47c
50c
10
11
a All reactions were run with N-methyl indole 1a (0.2 mmol), ammonium
o
b
(0.8 mmol) and DMSO/H2O (1.5 mL/80 µL), 150 C, under air, 30 h.
45 Under O2. c Under N2.
With this in mind, initially, we tested the reaction of N-
methyl indole in DMSO as the model reaction. After tedious
screening, we found heating the combination of CuF2 (3
50 equiv), N-methyl indole and aqueous ammonia (4 equiv) at
o
150 C for 30 h afforded 3-formylated product in 20% yield.
Cu(OAc)2 was slightly more effective than CuF2. To our
delight, the yield dramatically increased to 69% by using
NH4OAc (4 equiv) with 3 equivalents of Cu(OAc)2. Replacing
55 Cu(OAc)2 with 10 mol % of Pd(OAc)2 afforded the formylated
product in 74% yield. Interestingly, the formylation reaction
proceeded smoothly under air in 62% yield with 4 equivalents
of NH4OAc in the absence of any transition-metal catalyst
(Table 1, entry 7). The yield increased to 79% under N2 and
60 decreased to 57% under O2. Other tested ammonium salts,
such as NH4F and HCOONH4, were inferior to NH4OAc. No
product was detected in the absence of ammonium salt. Under
standard procedure, a comparable 73% yield was obtained in
the presence of 0.2 mL of Hg(0), ruling out the possibility of
65 trace of transition-metal as the true catalyst.
With the optimized reaction conditions in hand, the
substrate scope and the limitation for this formylation reaction
studied, as shown in Figure 1. As expected, both electron-
donating and electron-withdrawing groups such as methoxy,
70 fluoro, chloro, bromo, nitro and cyano groups on the aromatic
moiety were tolerated well under this procedure. Generally,
Scheme 1. A rational strategy for formylation by DMSO and H2O.
In the Pummerer reaction, the alkyl sulfoxide is attacked by
30 a nucleophile via a thionium ion intermediate.9 We envisioned
the formed sulfide A could be oxidized to sulfoxide B in situ
after the first Pummerer reaction with DMSO in proper
reaction condition. Then, sulfoxide B is attacked by H2O as
the nucleophile in the second Pummerer reaction to afford the
35 formylation product upon hydration (Scheme 1). However,
great challenges still remain for this strategy because the
traditional Pummerer reaction requires acidic activators,
which may induce serious side reactions for indole. To solve
this problem, a Pummerer reaction under nearly neutral or
40 weakly basic conditions needs to be developed.
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

Organic & Biomolecular Chemistry
Page 2 of 3
the reaction became sluggish for those substrates possessing
product was isolated in a comparable 70% yield (Scheme 2,
an electron-withdrawing group. Thus, a longer reaction time is 35 eq 1). Replacing H2O with D2O, no deuterium atom was
View Article Online
DOI: 10.1039/C3OB41510D
required. However, moderate yields were obtained for indoles
containing electron-donating groups since serious side
reactions took place, leading to 3,3’-diindolylmethanes. It is
noteworthy that the transformation proceeded smoothly
incorporated into the formylation product (Scheme 2, eq 2).
However, heating the combination of N-methyl indole,
DMSO-d6 and H2O under 150 oC resulted in the thorough
deuteration of aldehydic hydrogen (Scheme 2, eq 2). The 3-
5
regardless of the N-substituent groups of the indoles (2o and 40 formyl N-methyl indole with 18O in the carbonyl group was
2p). Notably, the chloro and bromo functional groups
survived well under the standard procedures, offering handles
10 for further functionalization (2i–2l). Particularly, the
heteroaryl indoles, such as N-methyl-1H-pyrrolo[2,3-
the major product using the combination of DMSO and H218O
(Scheme 2, eq 2). Under the reaction leading to 3,3’-
diindolylmethane (DIM), no deuterium atom was detected in
the product from the combination of DMSO and D2O (Scheme
b]pyridine, provided the desired product 2f in 95% yield. For 45 2, eq 3). However, two deuterium atoms were incorporated in
the N-methyl indoles blocked with a phenyl group on the C-2
positions, the formylation reaction furnished the
15 corresponding product 2e in 63% yield. However, only 30%
of the 2-formylation product 2q was formed if the 3- position
the methylenyl of 3,3’-diindolylmethane by heating the
combination of d6-DMSO and H2O (Scheme 2, eq 3).
Moreover, heating the combination of N-methyl indole and
NH4OAc (4 equiv) in dry DMSO-d6 for 30 h, compound 4
of N-methyl indole was blocked with a methyl. To evaluate 50 with two deuterium atoms in the methylenyl, instead of the
the practical utility further, the reaction was conducted on a 2
mmol scale, and the desired product 2a was furnished in a
20 comparable 70% yield. Importantly, the free (NH)-indole
delivered the formylated products in acceptable yields (2r and
2s).
formylation product with aldehydic deuterium atom, was
detected by GC-MS (Scheme 2, eq. 4). According to the
experimental facts in eqs 3 and 4, an SN2 type reaction of
intermediate C in Scheme 1 attacked by nucleophile may be
55 involved in the second transformation.
O
S
Figure 1. The formylation of indoles by DMSO and H2O.a
H
C
NH4OAc (4 equiv)
O
+
+
H2O
O
S
150 oC, 30 h.
N
(sol.)
H
C
N
H
H
O
R1
, 70%
2a
(eq 1)
H2O
+
+
Potential intermediate
Y
A
S
N
R1
(sol.)
X
C
H3C
N
R2
1
NH4OAc (4 equiv)
150 oC, 30 h
2
R2
CHO
H2O
+
DMSO
+
N
CHO
CHO
CHO
N
MeO
DMSO + D2O
X = H; Y = O, , 78%
2a
1a
DMSO-d6 + H2O
DMSO + H218O
X = D (97%); Y = O,
X = H; Y = 18O, 18
77%
d-2a
(eq 2)
N
N
N
N
71%
O-2a
N
N
2a 79%, 30 h
2b 50%, 12 h
2c 57%, 16 h
CHO
2d 69%, 12 h
CHO
O
NH4HCO3 (4 equiv)
CHO
CHO
H2O
+
(sol.)
+
S
C
F
N
150 o
C
X
X
Ph
DMSO + D2O
X = H, , 70%
3a
(eq 3)
D
N
N
N
N
N
F
DMSO-d6 + H2O
AcO
X = D (96%),
76%
d-3a
O
D
+
2e 63%, 40 h
2f 95%, 48 h
CHO
2g 83%, 48 h
2h 78%, 48 h
C
D
C
CHO
CHO
CHO
O
NH4OAc (4 equiv)
Br
Cl
+
S
D3C
CD3
150 oC, 30 h
N
N
N
dry
N
N
N
N
Br
Cl
4
< 1%
2a
(eq 4)
2i 77%, 84 h
2j 75%, 84h
2k 73%, 60 h
2l 83%, 60 h
CHO
CHO
Scheme 2. Mechanism study.
CHO
CHO
O2N
NC
However, there are still two questions that remain to be
addressed. Firstly, what serves as the oxidant during the
60 transformation of thioether intermediate A to sulfoxide B
depicted in Scheme 1. We reasoned DMSO may act as an
oxidant for this transformation. However, to our surprise, no
sulfoxide was detected by heating of the potential
intermediate 3-(methylthiomethyl)-1H-indole A in DMSO at
65 150 oC for 30 h, even in the presence of 4 equivalents of
HOAc, which may act as a promoter in this oxidative
transformation.10 During the formylation reaction, a large
amount of bis(methylthio)methane was detected as byproduct
(Scheme 2, eq 4).11 However, heating the potential
70 intermediate 3-(methylthiomethyl)-1H-indole A in DMSO-d6
at 150 oC for 30 h, a species with slightly longer retention
time than CH3SCH2SCH3 and the molecular ion peak as 113,
was detected by GC-MS, which was assignable to
N
N
N
N
Ph
2o 66%, 30 h
CHO
Bn
2m 63%, 84 h
2n 84%, 60 h
2p 84%, 30 h
CHO
CHO
F
CHO
N
H
N
H
N
H
N
2q 30%, 30 h
2r 58%, 30 h
2s 70%, 48 h
2t 82%, 20 h
a
25 Reaction conditions: indole derivative 1 (0.2 mmol), NH4OAc (0.8
mmol) and DMSO/H2O (1.5 mL/80 µL), 150 oC, under N2.
Interestingly, this procedure was applicable for the
synthesis of 3,3’-diindolylmethane (DIM) 3a in 70% yield in
30 48 h by replacing NH4OAc with NH4HCO3. The presumed
intermediate 3-(methylthiomethyl)-1H-indole A in Scheme 1
was detected during the reaction by GC-MS. When it was
subjected to the standard reaction condition, the formylated
2
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Page 3 of 3
Organic & Biomolecular Chemistry
a
School of Petrochemical Engineering, Jiangsu Province Key
CH3SCD2SCD3 (see Supporting Information). In combination
with the aforementioned results, we deduced the nucleophilic
attack of the thionium ion derived from DMSO by the sulfur
Laboratory of Fine Petrochemical Engineering, Changzhou University,
Changzhou 213164, P. R. China; E-mail: jiangcheng@cczu.edu.cn
View Article Online
DOI: 10.1039/C3OB41510D
50
55
60
b State Key Laboratory of Coordination Chemistry, Nanjing University,
atom of 3-(methylthiomethyl)-1H-indole
A formed the
Nanjing 210093, P. R. China
† Electronic Supplementary Information (ESI) available: See
DOI: 10.1039/b000000x/
5
sulfonium cation 9 (in Scheme 3, R = 3-(N-methylindolyl)),12
which underwent an SN2 reaction by H2O to deliver the
hydroxymethylation product as the precusor of the
formylation product.13
1
(a) R. C. Larock, Comprehensive Organic Transformations; Wiley-
VCH: New York, 1988; (b) G. A. Olah, L. Ohannesianm and M.
Arvanaghi, Chem. Rev., 1987, 87, 671-684.
(a) A. Haack, Ber., 1927, 60, 119-122; (b) G. Jones and S. P.
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Chem., 1996, 338, 392-396; (d) G. Jones and S. P. Stanforth, Org.
React., 1997, 49, 1-330.
2
3
(a) J. C. Duff and E. J. Bills, J. Chem. Soc., 1932, 1987-1988; (b) J. C.
Duff and E. J. Bills, J. Chem. Soc., 1934, 1305-1308; (c) J. C. Duff,
J. Chem. Soc., 1941, 547-550; (d) J. C. Duff, J. Chem. Soc., 1945,
276-277; (e) L. N. Ferguson, Chem. Rev., 1946, 38, 227–254.
65 4 (a) K. Reimer and F. Tiemann, Ber., 1876, 9, 824-828; (b) H.
Wynberg, Chem. Rev., 1960, 60, 169-184; (c) H. Wynberg, Comp.
Org. Synth., 1991, 2, 769-775; (d) H. Wynberg and E. W. Meijer,
Org. Reat., 1982, 28, 1-36.
5
(a) L. Gattermann and J. A. Koch, Ber., 1897, 30, 1622-1624; (b) L.
Gattermann and W. Berchelmann, Ber., 1898, 31, 1765–1769; (c) L.
Gattermann, Ber., 1890, 23, 1218–1228; for reviews, see: (d) N. N.
Crounse, Org. React., 1949, 5, 290-300; (e) W. E. Truce, Org.
React., 1957, 9, 37-72.
70
10 Scheme 3. Proposed mechanism.
The second is how NH4OAc promotes the Pummerer
reaction. Huang reported the NH4OAc and CuBr(PPh3)3-
induced Pummerer reaction between free (NH)-indole and
DMSO leading to 3-methylthiomethyl indoles.14 Based upon
15 this and the property of DMSO, a postulated mechanism is
illustrated in Scheme 3. Firstly, NH4OAc is decomposed to
HOAc and NH3. Then, DMSO is activated by HOAc to form
intermediate 6. Secondly, the cleavage of the C-OH bond
6
W. Wu and W. Su, J. Am. Chem. Soc., 2011, 133, 11924-11927.
75 7 J. Chen, B. Liu, D. Liu, S. Liu and J. Cheng, Adv. Synth. Catal., 2012,
354, 2438-2442.
8
(a) F. Luo, C. Pan, L. Li, F. Chen and J. Cheng, Chem. Commun.,
2011, 47, 5304-5306; (b) X. Ren, J. Chen, F. Chen and J. Cheng,
Chem. Commun., 2011, 47, 6725-6727.
80 9 (a) R. Pummerer, Ber. Dtsch. Chem. Ges., 1909, 42, 2282-2291; (b)
R. Pummerer, Ber. Dtsch. Chem. Ges., 1910, 43, 1401-1412; for
reviews, see: (c) K. S. Feldman, Tetrahedron, 2006, 62, 5003-5034;
(d) S. K. Bur and A. Padwa, Chem. Rev., 2004, 104, 2401-2432; (e)
S. Akai and Y. Kita, Top. Curr. Chem., 2007, 274, 35-76; (f) L. H. S.
+
assisted by NH4 forms intermediate 7. No reaction takes
20 place without ammonium, suggesting that the ammonium is
85
Smith, S. C. Coote, H. F. Sneddon and D. J. Procter, Angew. Chem.,
Int. Ed., 2010, 49, 5832-5844; (g) A. Padwa, D. E. Gunn Jr and M.
H. Osterhout, Synthesis, 1997, 1353-1378; (h) A. Padwa and A. G.
Waterson, Curr. Org. Chem., 2000, 4, 175-203; (i) O. De Lucchi, U.
Miotti and G. Modena, Org. React., 1991, 40, 157-184; (j) A.
Padwa, S. K. Bur, M. D. Danca, J. D. Ginn and S. M. Lynch, Synlett,
2002, 851-862.
+
crucial for this transformation. The role of NH4 is likely to
facilitate the cleavage of the C-OH bond by changing the
strongly basic OH- group to NH3·H2O as a weakly basic
leaving group. Thirdly, the thionium ion 8 is formed in the
25 presence of NH3·H2O as a base. Then, it is attacked by N-
methyl indole as a nucleophile to form intermediate A.
Fourthly, the attack of sulfur atom in A to the thionium ion 8
affords sulfonium 9. Finally, the SN2 nucleophilic reaction of
intermediate 9 attacked by H2O takes place to form the
30 hydroxymethylation product, which is oxidized to the
formylation product 2 by 7 in similar with Swern oxidation.15
Meanwhile, the nucleophilic attack of 9 by another molecular
N-methyl indole produces 3,3’-diindolylmethane (DIM).
In conclusion, we have developed an NH4OAc promoted
35 procedure involving a sequential traditional and unusual
Pummerer reaction under nearly neutral conditions, leading to
3-formyl indole. This procedure uses DMSO and H2O as the
carbonyl source with good functional group tolerance. Thus, it
represents an important development in DMSO-mediated
40 transformation and the Pummerer reaction.
90
10 For the HCl-promoted oxidation of sulfide by sulfoxide, please see:
(a) U. Miotti, J. Chem. Soc., Perkin Trans. 2 1991, 617-622; (b) A.
Bovia and U. Miotti, J. Chem. Soc., Perkin Trans. 2 1978, 172-177.
95 11 A. P. Zaraiskii, N. A. Zaraiskaya, L. I. Velichko and N. M.
Anikeeva, Russ. J. Org. Chem., 2007, 43, 1728-1729.
12 For the attack of S atom of sulfide on the carbon cation of thionium
ion and the nucleophilic sustitution of the formed sulfonium, see: R.
Tanikaga, Y. Hiraki, N. Ono and A. Kaji, J. Chem. Soc., Chem.
100
Commun., 1980, 41-42.
13 For the sustitution of sulfonium by nucleophiles, please see: (a) G.
Ranieri, J. P. Hallett and T. Welton, Ind. Eng. Chem. Res., 2008, 47,
638-644; (b) R. T. Hargreaves, A. M. Katz and W. H. Saunders Jr.,
J. Am. Chem. Soc. 1976, 98, 2614-2616; (c) M. P. Friedberger and E.
R. Thornton, J. Am. Chem. Soc., 1976, 98, 2861-2865; (d) D. N.
Kevill and M. H. Ismail, J. Org. Chem., 1991, 56, 3454-3457; (e) K.
Umemura, H. Matsuyama, N. Watanabe, M. Kobayashi and N.
Kamigata, J. Org. Chem., 1989, 54, 2374-2383; (f) Y. Pocker and A.
J. Parker, J. Org. Chem., 1966, 31, 1526-1531; (g) K. R. Fountain,
D. B. Tad-y, T. W. Paul and M. V. Golynskiy, J. Org. Chem., 1999,
64, 6547-6553; (h) K. R. Fountain and K. D. Patel, J. Org. Chem.,
1997, 62, 4795-4797; (i) F. L. Roe and Jr. W. H. Saunders Jr.,
Tetrahedron Lett., 1977, 33, 1581-1585.
105
110
115
We thank the National Natural Science Foundation of China
(nos. 21272028 and 21202013), State Key Laboratory of
Coordination Chemistry of Nanjing University and Jiangsu
Key Laboratory of Advanced Catalytic Materials and
45 Technology for financial support.
14 J. Liu, X. Wang, H. Guo, X. Shi, X. Ren and G. Huang, Tetrahedron,
2012, 68, 1560-1565.
15 (a) S. L. Huang, K. Omura and D. Swern, J. Org. Chem., 1976, 41,
3329-3331; (b) T. T. Tidwell, Org. React., 1990, 39, 297-572.
Notes and references
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