A novel reaction of gem-difluorocyclopropyl ketones with nitriles leading to 2-fluoropyrroles

Article abstract of DOI:10.1039/c3cc45456h

The CF₃SO₃H-promoted ring opening of gem-difluorocyclopropyl ketones prefers to undergo proximal bond cleavage and the subsequent cyclization with nitriles occurred smoothly to give 2-fluoropyrroles.

Full text of DOI:10.1039/c3cc45456h

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: T. Yang, J. Lin, Q. Chen and J. Xiao,
Chem. Commun., 2013, DOI: 10.1039/C3CC45456H.
This is an Accepted Manuscript, which has been through the RSC Publishing peer
review process and has been accepted for publication.
Accepted Manuscripts are published online shortly after acceptance, which is prior
Chemical Communications
www.rsc.org/chemcomm
Volume 46 | Number 32 | 28 August 2010 | Pages 5813–5976
to technical editing, formatting and proof reading. This free service from RSC
Publishing allows authors to make their results available to the community, in
citable form, before publication of the edited article. This Accepted Manuscript will
be replaced by the edited and formatted Advance Article as soon as this is available.
To cite this manuscript please use its permanent Digital Object Identifier (DOI®),
which is identical for all formats of publication.
More information about Accepted Manuscripts can be found in the
Information for Authors.
Please note that technical editing may introduce minor changes to the text and/or
graphics contained in the manuscript submitted by the author(s) which may alter
content, and that the standard Terms & Conditions and the ethical guidelines
that apply to the journal are still applicable. In no event shall the RSC be held
responsible for any errors or omissions in these Accepted Manuscript manuscripts or
any consequences arising from the use of any information contained in them.
ISSN 1359-7345
COMMUNICATION
FEATURE ARTICLE
J. Fraser Stoddart et al.
Directed self-assembly of
ring-in-ring complex
Wenbin Lin et al.
a
Hybrid nanomaterials for biomedical
applications
1359-7345(2010)46:32;1-H
www.rsc.org/chemcomm
Registered Charity Number 207890

ChemComm
Page 1 of 3Journal Name
Dynamic Article Links ►
View Article Online
DOI: 10.1039/C3CC45456H
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
ARTICLE TYPE
A novel reaction of gem-difluorocyclopropyl ketones with nitriles
leading to 2-fluoropyrroles
Tang-Po Yang, Jin-Hong Lin, Qing-Yun Chen and Ji-Chang Xiao*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
be readily cleaved in the presence of strong Brønsted acid. The
50 ringꢀopening of gemꢀdifluorocyclopropyl ketones and the
subsequent cyclization with nitriles proceeded smoothly to give
2ꢀfluoropyrroles (eq. 5).
The
CF3SO3H-promoted
ring-opening
of
gem-
difluorocyclopropyl ketones prefers to undergo proximal
bond cleavage and the subsequent cyclization with nitriles
occurred smoothly to give 2-fluoropyrroles.
Previous work
proximal bond
10 The sharp increase in the number of fluorineꢀcontaining
pharmaceuticals and agrochemicals clearly demonstrates the
exceptional importance of fluorinated compounds.1 As one of the
COR3
R2
R2
F
R1 R2
PhS-
R1
COR3
F
F
(1)
(2)
important
classes
of
fluorinated
molecules,
gemꢀ
PhS
COR3
R1
PhS
SPh
difluorocyclopropanated derivatives have attracted much
15 attention due to the unique biological activities of the gemꢀ
difluorocyclopropyl group.2 Despite the significance of this
moiety, only limited number of reports has been published about
the studies on its reactivity, especially the ringꢀopening
chemistry,3 which would be expected to be an efficient approach
20 for the synthesis of unique partially fluorinated compounds. As
part of our continuing interest in gemꢀdifluorocyclopropanes
chemistry,4 we described the regioselectivie ringꢀopening
reaction of gemꢀdifluorocyclopropyl ketones prompted by
Brønsted acid in the presence of nitrile derivatives, allowing the
25 synthesis of fluoropyrroles,5 which are valuable subunits of many
pharmacologically active compounds.6
F
F
distal bond
distal bond cleavage
O
O
F
R1
O
F
KOH
F
MeOH
R2
R2
MeO2C
R2
R1
R1
proximal bond cleavage
PentylPyr+ Br-
CF3CO2H
O
O
F
F
F
F
Ar
(3)
(4)
Br
Ar
distal bond cleavage
R4
O
R1
R4
N
F
MgI2
N
F
R1
O
R3
R2
R3
R2
distal bond cleavage
In the study on ringꢀcleavage of gemꢀdifluorocyclopropyl
ketones, the regioselectivity was found to be an interesting issue.
The ringꢀopening reaction could be promoted by nucleophiles,
30 base and acids.3aꢀb, 3dꢀe Kobayashi and coworkers found that strong
nucleophiles with low basicity would cause distal bond scission
because the carbanion intermediate could be stabilized by both
the carbonyl and βꢀdifluoromethylene groups (eq. 1, Scheme
1).3aꢀb While strong base would result in deprotonation followed
35 by defluorination and a series of transformation to lead to
proximal bond cleavage (eq. 2).3aꢀb The interesting results
disclosed some reactivity of gemꢀdifluorocyclopropanes but both
of these two routes lead to complete loss of fluorine. Dolbier et al
reported Brønsted acidꢀmediated ringꢀopening reactions with
40 ionic liquid reagent proceeding via SN2ꢀlike process to give 3ꢀ
bromoꢀ2,2ꢀdifluoropropyl ketones resulting from distal bond
scission (eq. 3).3d Soon after this report, they found that gemꢀ
difluorocyclopropyl ketones would also undergo distal bond
cleavage upon the treatment with MgI2 and further react with
45 imine to give nonꢀfluorine products (eq. 4).3e Dolbier’s results
show that distal bond prefers to cleave in the presence of acids. In
this communication, we found the regioselectivity was different
in the absence of soft nucleophiles and the proximal bond would
This work:
O
O
F
F
(5)
Ar
TfOH
F
Ar
+
RCN
NH
R
proximal bond cleavage
Scheme 1 The regioselectivity of ring-opening
55
The first attempt for the cyclization of phenyl gemꢀ
difluorocyclopropyl ketone (1a) with acetonitrile was made in the
presence of triflic acid. Acetonitrile was used as the substrate and
solvent. The reaction proceeded fast to give the desired product in
50% yield determined by 19F NMR with the use of
60 trifluoromethyl benzene as internal standard (Table 1, entry 1). A
variety of other acids including Brønsted acids and Lewis acids
were subjected to this transformation (entries 2ꢀ7). Even though
TMSOTf have been reported to be able to efficiently promote
cyclization of nonꢀfluorinated cyclopropanes with nitriles to
65 afford pyrroles,7 this Lewis acid was not effective enough to
convert gemꢀdifluorocyclopropane into 2ꢀfluoropyrrole. The
conversion of the substrate (1a) was complete in 2h but very low
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

ChemComm
Page 2 of 3
View Article Online
DOI: 10.1039/C3CC45456H
yield of product was obtained (entry 4). Yb(OTf)3 and In(OTf)2
investigated the scope of the substrates. As can be seen from
were found to be good catalysts for cyclization of nonꢀfluoroiated 40 Table 2, the yields were relatively lower for those gemꢀ
cyclopropanes with nuclephiles.8 Nevertheless, both of them
failed to mediate the desired conversion (entries 5 and 6).
CF3SO3H was proved to be the suitable acid for this reaction.
It is necessary to determine if the reaction could proceed in
difluorocyclopropyl ketones with electronꢀdonating substituent
on the para position of the phenyl ring (entry 2 and entry 3).
However, metaꢀmethoxy substituted gemꢀdifluorocyclopropyl
ketone could react well with acetonitrile to give higher yield
5
organic solvent with the use of less amount of acetonitrile (entries 45 (entry 4). In the case of halogen substituted aryl gemꢀ
8ꢀ10). It turned out that the reactions in toluene, THF or
dichloromethane became complicated and no expected product
difluorocyclopropyl ketones (entries 5ꢀ9), similar tendency was
also observed (entry 6 vs 7, 8 vs 9). Moderate yields were
obtained for other examples, such as highly electronꢀdeficient
ketone and naphthyl ketone (entries 10 and 11). Besides
10 could be detected by 19F NMR.
The amount of CF3SO3H and the reaction temperature were
next examined for optimal conditions (entries 11ꢀ17). Catalytic 50 acetonitrile, the reaction worked equally well for benzonitrile,
amount of triflic acid led to trace amount of the desired product
with much of the gemꢀdifluorocyclopropyl ketone remained even
15 prolonging the time to 2 h (entry 11). When 2 equivalents of
triflic acid were used, the yield increased slightly to 62% (entry
12). Considering that the pyrroles are prone to polymerization in
the presence of acid,9 we tried to improve the yield by decreasing
the acid concentration. However, no further improvement was
20 achieved (entries 13 and 14). To our delight, higher yield (71%)
of 2ꢀfluoropyrrole could be obtained when the reaction was
quenched at lower temperature (entry 15). When the reaction was
conducted at 0 oC, longer time was needed for the complete
conversion without increasing the yield (entry 16). The lower
25 reaction temperature resulted in sluggish reaction (entry 17).
Therefore, room temperature is the suitable temperature for the
transformation.
which means the transformation is applicable to both aliphatic
and aromatic nitriles (entry 12).
Table 2 The Reaction of gemꢀDifluorocyclopropyl Ketones with Nitrilesa
Entry
1
2
3
4
5
6
7
8
Ar
Ph (1a)
R
Product, Yieldb
2a, 64%
2b, 49%
2c, 54%
2d, 74%
2e, 60%
2f, 66%
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
4ꢀCH3C6H4 (1b)
4ꢀCH3OC6H4 (1c)
3ꢀCH3OC6H4 (1d)
4ꢀFC6H4 (1e)
3ꢀClC6H4 (1f)
4ꢀClC6H4 (1g)
4ꢀBrC6H4 (1h)
3ꢀBrC6H4 (1i)
4ꢀNO2C6H4 (1j)
Naphthyl (1k)
Ph (1a)
Table 1 Screening of The Reaction Conditionsa
2g, 57%
2h, 65%
2i, 79%
2j, 61%
2k, 52%
2l, 45%
9
10
11
12
a
55 gemꢀDifluorocyclopropyl ketone (0.2 mmol), CF3SO3H (0.4 mmol) in
RCN (1mL) at r.t. for 0.5 h under N2; quenched at ꢀ20oC; b Isolated yields.
Entry
1
2
3
4
Acid (equiv.)
CF3SO3H (1.0)
CF3COOH (1.0)
TsOH (1.0)
Time (h)
0.75
12
Yield (%)b
50%
N.R.
N.R.
28%
N.R.
N.R.
N.R.
N.D.
N.D.
N.D.
trace
62%
57%
56%
71%
71%
trace
The structure of product 2a was determined by single crystal
Xꢀray diffraction (Figure 1).10 Other structures were surmised by
analogy.
12
2
12
12
12
12
12
12
TMSOTf (1.0)
Yb(OTf)3 (1.0)
In(OTf)2 (1.0)
Cu(OTf)2 (1.0)
CF3SO3H (1.0)
CF3SO3H (1.0)
CF3SO3H (1.0)
CF3SO3H (0.1)
CF3SO3H (2.0)
CF3SO3H (2.0)
CF3SO3H (2.0)
CF3SO3H (2.0)
CF3SO3H (2.0)
CF3SO3H (2.0)
5
6
7
8c
9d
10e
11
12
13f
14g
15h
16h, i
17h, j
2
0.5
0.5
0.5
0.5
0.75
6
60
Figure 1 X-ray structure of isolated product
7, 11
Based on the above results and related reports,3dꢀf,
we
a
30 Reaction conditions: 1a (0.2 mmol), CF3SO3H (0.2 mmol) in CH3CN
proposed that the mechanism involves the partially ringꢀopening
of gemꢀdifluorocyclopropyl ketone and the stepꢀwise cyclization
65 with nitrile (Scheme 2). The protonation of ketone is favourable
for partially cleavage of the proximal bond because the resulting
carbocation could be stabilized by the fluorines. The nucleophilic
attack of the carbocation by acetonitrile followed by
intramolecular cyclization constructs the fiveꢀmembered ring A.
(1mL) at r.t. under N2; Determined by 19F NMR with the use of
b
trifluoromethyl benzene as internal standard, N.D.= not detected, N.R.=
no reaction; c 0.4 mmol of CH3CN was used in toluene (1 mL); d0.4 mmol
e
of CH3CN was used in THF (1 mL); 0.4 mmol of CH3CN was used in
35 CH2Cl2 (1 mL); f 5 mL of CH3CN was used; g 10 mL of CH3CN was used;
h Quenched at ꢀ20 oC; i The reaction was performed at 0 oC; j The reaction
was performed ꢀ10 oC.
With the optimized conditions (Table 1, entry 15) in hand, we
70 Dehydrofluorination of intermediate
A and the following
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 3 of 3
ChemComm
View Article Online
DOI: 10.1039/C3CC45456H
rearrangement affords the final product 2ꢀfluoropyrrole.
Martinez and S. L. Craig, Science, 2010, 329, 1057ꢀ1060; (j) J. M.
Lenhardt, J. W. Ogle, M. T. Ong, R. Choe, T. J. Martinez and S. L.
Craig, J. Am. Chem. Soc., 2011, 133, 3222ꢀ3225.
50
55
60
65
70
75
80
85
90
3. (a) Y. Kobayashi, T. Taguchi, T. Morikawa, T. Takase and H.
Takanashi, Tetrahedron Lett., 1980, 21, 1047ꢀ1050; (b) Y. Kobayashi,
T. Taguchi, T. Morikawa, T. Takase and H. Takanashi, J. Org. Chem.,
1982, 47, 3232ꢀ3236; (c) Y. Kobayashi, T. Morikawa and T. Taguchi,
Chem. Pharm. Bull., 1983, 31, 2616ꢀ2622; (d) W. Xu, W. Dolbier and J.
Salazar, J. Org. Chem., 2008, 73, 3535ꢀ3538; (e) W. Xu, I. Ghiviriga,
Q.ꢀY. Chen and W. R. Dolbier, J. Fluorine Chem., 2010, 131, 958ꢀ963;
(f) W. Dolbier, E. Cornett, H. Martinez and W. Xu, J. Org. Chem.,
2011, 76, 3450ꢀ3456.
Scheme 2 Proposed mechanism
The regioselectivity of ringꢀcleavage is quite different from
that reported by Dolbier and coworkers. 3dꢀ3e It might be because
the strong acid CF3SO3H (pKa ~ ꢀ14) could lead to the partially
ringꢀcleagave of gemꢀdifluorocyclopropyl ketone, while weak
acids (pKa of CF3CO2H is about ꢀ0.25) in Dolbier’s cases
couldn’t. Without the partially ringꢀcleavage, the nucleophilic
4. (a) X.ꢀC. Hang, Q.ꢀY. Chen and J.ꢀC. Xiao, Eur. J. Org. Chem., 2008,
1101ꢀ1106; (b) X.ꢀC. Hang, Q.ꢀY. Chen and J.ꢀC. Xiao, Synlett, 2008,
1989ꢀ1992; (c) X.ꢀC. Hang, Q.ꢀY. Chen and J.ꢀC. Xiao, J. Org. Chem.,
2008, 73, 8598ꢀ8600; (d) X.ꢀC. Hang, W.ꢀP. Gu, Q.ꢀY. Chen and J.ꢀC.
Xiao, Tetrahedron, 2009, 65, 6320ꢀ6324; (e) X.ꢀC. Hang, W.ꢀP. Gu,
Q.ꢀY. Chen, J.ꢀC. Xiao, W.ꢀG. Xu and S. Liu, J. Fluorine Chem., 2011,
132, 63ꢀ67.
5
10 reaction would proceed in SN2ꢀlike process.
In conclusion, we have described triflic acidꢀmediated ringꢀ
opening of gemꢀdifluorocyclopropyl ketones and the subsequent
cyclization with nitriles to give 2ꢀfluoropyrroles. The presence of
strong acid favors the cleavage of proximal bond because the two
15 fluorines could stabilize the resulting carbocation. This strategy
represents a new method for the synthesis of 2ꢀfluoropyrroles.
The study on the ringꢀopening chemistry of gemꢀ
difluorocyclopropyl ketone and the applications of this strategy to
the synthesis of other important fluorinated compounds are
20 currently underway.
5. For review, see: (a) O. Serdyuk, V. Muzalevskiy and V. Nenajdenko,,
Synthesis, 2012, 44, 2115ꢀ2137; For recent examples, see: (b) J.
Ichikawa, Y. Wada, M. Fujiwara and K. Sakoda, Synthesis, 2002,
1917–1936; (c) Y. Wang and S. Zhu, Org Lett, 2003, 5, 745ꢀ748; (d) R.
Surmont, G. Verniest and N. De Kimpe, Org. Lett., 2009, 11, 2920ꢀ
2923; (e) R. Surmont, G. Verniest, F. Colpaert, G. Macdonald, J. W.
Thuring, F. Deroose and N. D. Kimple, J. Org. Chem., 2009, 74, 1377ꢀ
1380; (f) B. M. Kim, Q.ꢀZ. San, L. R. Bhatt, S. K. Kim and K.ꢀY. Chai,
Bull. Korean Chem. Soc., 2010, 31, 31ꢀ34; (g) T. Xu, X. Mu, H. Peng
and G. Liu, Angew. Chem., Int. Ed., 2011, 50, 8176ꢀ8179.
Notes and references
6. (a) P. R. Bovy, D. B. Reitz, J. T. Collins, T. S. Chamberlain, G. M.
Olins, V. M. Corpus, E. G. McMahon, M. A. Palomo, J. P. Koepke, G.
J. Smits, D. E. McGraw and J. F. Gaw, J. Med. Chem., 1993, 36, 101ꢀ
110; (b) W. W. Wilkerson, W. Galbraith, K. GansꢀBrangs, M. Grubb,
W. E. Hewes, B. Jaffee, J. P. Kenney, J. Kerr and N. Wong, J. Med.
Chem., 1994, 37, 988ꢀ998; (c) F. C. Tucci, Y.ꢀF. Zhu, Z. Guo, T. D.
Gross, P. J. Connors Jr, R. S. Struthers, G. J. Reinhart, X. Wang, J.
Saunders and C. Chen, Bioorg. Med. Chem. Lett., 2002, 12, 3491ꢀ3495;
(d) F. Ruebsam, S. E. Webber, M. T. Tran, C. V. Tran, D. E. Murphy, J.
Zhao, P. S. Dragovich, S. H. Kim, L.ꢀS. Li, Y. Zhou, Q. Han, C. R.
Kissinger, R. E. Showalter, M. Lardy, A. M. Shah, M. Tsan, R. Patel, L.
A. LeBrun, R. Kamran, M. V. Sergeeva, D. M. Bartkowski, T. G.
Nolan, D. A. Norris and L. Kirkovsky, Bioorg. Med. Chem. Lett., 2008,
18, 3616ꢀ3621.
We thank the National Natural Science Foundation (21032006,
21172240), the 973 Program of China (2012CBA01200), Chinese
Academy of Sciences.
25 Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032 (China), Fax: (+86) 21-6416-6128; Tel:
5492-5430; E-mail: jchxiao@sioc.ac.cn
（+86）21-
‡
Electronic Supplementary Information (ESI) available: Experimental
30 procedures, characterization of data for all compounds.
1. (a) A. M. Thayer, Chem. Eng. News, 2006, 84, 15ꢀ24; (b) F. M. D.
Ismail, J. Fluorine Chem., 2002, 118; (c) K. L. Kirk, J. Fluorine Chem.,
2006, 127, 1013ꢀ1029; (d) S. Purser, P. R. Moore, S. Swallow and V.
Gouverneur, Chem. Soc. Rev., 2008, 37, 320ꢀ330; (e) X.ꢀL. Qiu, X.
Yue and F.ꢀL. Qing, in Chrial Drugs, Eds. G.ꢀQ. Lin, Q.ꢀD. You, J.ꢀF.
Cheng, John Wiley & Sons, Inc., 2011, pp. 195ꢀ251.
35
40
45
7. M. Yu and B. L. Pagenkopf, Org. Lett., 2003, 5.
2. For reviews, see: (a) W. R. Dolbier, Jr., Acc. Chem. Res., 1981, 14,
195ꢀ200; (b) T. Itoh, ACS Symp. Ser., 2005, 911, 430ꢀ439; (c) T. Itoh,
in Fluorine in Medicinal Chemistry and Chemical Biology, Ed. I.
Ojima, John Wiley & Sons Ltd., 2009, pp. 313ꢀ334; For recent
examples, see (d) R. Csuk and L. Eversmann, Tetrahedron, 1998, 54,
6445ꢀ6456; (e) F. Tian, V. Kruger, O. Bautista, J.ꢀX. Duan, A.ꢀR. Li,
W. R. Dolbier, Jr. and Q.ꢀY. Chen, Org. Lett., 2000, 2, 563ꢀ564; (f) R.
Wang, M. B. Ksebati, T. H. Corbett, E. R. Kern, J. C. Drach and J.
Zemlicka, J. Med. Chem., 2001, 44, 4019ꢀ4022; (g) C. J. Barnett, B.
Huff, M. E. Kobierski, M. Letourneau and T. M. Wilson, J. Org. Chem.,
2004, 69, 7653ꢀ7660; (h) Y. Fujioka and H. Amii, Org. Lett., 2008, 10,
769ꢀ772; (i) J. M. Lenhardt, M. T. Ong, R. Choe, C. R. Evenhuis, T. J.
8. (a) C. Carson and M. Kerr, Org. Lett., 2009, 11, 777ꢀ779; (b) A. Leduc,
T. Lebold and M. Kerr, J. Org. Chem., 2009, 74, 8414ꢀ8416.
95 9. G. F. Smith, in Adv. Heterocycl. Chem., ed. A. R. Katritzky, Academic
Press, 1963, pp. 287ꢀ309.
10. Summary of data CCDC 837294.
11. M. Yu and B. L. Pagenkopf, J. Am. Chem. Soc., 2003, 125, 8122ꢀ
8123.
100
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3