Asymmetric fluorinative dearomatization of tryptamine derivatives

Article abstract of DOI:10.1039/c7cc02419c

An asymmetric fluorinative dearomatization reaction of tryptamine derivatives was developed by using a chiral anion phase transfer catalyst (PTC) system, and the preliminary results of the reaction mechanistic study were achieved. This method is characterized by a simple operation, facile introduction of a fluorine atom in a highly enantioselective manner and construction of two contiguous quaternary stereogenic centers.

Full text of DOI:10.1039/c7cc02419c

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DOI: 10.1039/C7CC02419C
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ARTICLE
Asymmetric Fluorinative Dearomatization of Tryptamine Deriva-
tives
Received 00th January 20xx,
Accepted 00th January 20xx
Xiao-Wei Liang, Chuan Liu, Wei Zhang, and Shu-Li You*
An asymmetric fluorinative dearomatization reaction of tryptamine derivatives was developed by a chiral anion phase
transfer catalyst (PTC) system, and the preliminary results of the reaction mechanistic study were achieved. This method
features simple operation, facile introduction of fluorine atom in a highly enantioselective manner and construction of two
contiguous quaternary stereogenic centers.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Fluorination reactions have witnessed tremendous tryptamine derivatives. Under the same catalytic conditions,
development due to the extreme importance of fluorine- the fluorination of 1a gave almost racemic result. 7
containing molecules in medicinal chemistry and materials
We initiated our studies by examining the reaction of
science.1 Despite catalytic asymmetric fluorination reactions tryptamine derivative 1a with Selectfluor ((1-(chloromethyl)-4-
have gained a rapid growth accompanied by the emerging of fluoro-1,4-diazoniabicyclo[2.2.2]octane)) (1.1 equiv), in the
catalytic systems,2 developing highly efficient stereoselective presence of (S)-TRIP ((S)-3,3
'-bis(2,4,6-triisopropylphenyl)-1,1
'-
fluorination is still in great demand. Catalytic asymmetric -binaphthyl-2,2
'-diyl hydrogenphosphate) (10 mol%) and
dearomatization (CADA) reactions recently have attracted sodium carbonate (1.1 equiv) in fluorobenzene (Table 1, entry
enormous research interest due to their powerfulness to 1). The fluorocyclization product 2a was given in 48% yield and
construct complex molecules from readily available aromatic 6% ee.
compounds.3 Although CADA reactions through fluorination
are undoubtedly attractive in synthesizing chiral fluorine-
containing compounds and highly desirable, successful reports
are very limited. In 2011, Gouverneur and co-workers reported
an elegant enantioselective dearomatization of indole
derivatives through cascade fluorocyclization. In general,
moderate to high levels of enantioselective control are
obtained under catalytic conditions (Scheme 1).4 Almost at the
same time, Toste and co-workers reported an enantioselective
electrophilic fluorination utilizing chiral anion phase transfer
catalyst.5
The
examples
of
dearomatization
of
benzothiophenes reported therein elucidated the potential of
CADA reactions through fluorination. Later, the same group
further advanced the asymmetric fluorinative dearomatization
reaction with phenols.6 Due to the great demand of complex
chiral fluorinated molecules and our continuous interest in
CADA reactions, herein, we report an asymmetric fluorinative
dearomatization reaction of tryptamine derivatives, providing
fluorine-containing pyrroloindolines bearing two contiguous
quaternary stereogenic centers. Ma and co-workers had
reported the chiral anion PTC strategy in bromination of
Scheme 1. Enantioselective fluorinative dearomatization reactions
of tryptamine derivatives.
a.State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Science, 345 Lingling Lu, Shanghai 200032 (China)
E-mail: slyou@sioc.ac.cn
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Encouraged by these results, various chiral phosphoric acids
(CPAs) (10 mol%) were evaluated.8 Although all reactions
proceeded to afford the desired fluorinated 6H-pyrroloindole 9
2a
,
only moderate yields could be achieved and the
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enantioselective control was not satisfactory (Table 1, entries 6). Further decreasing the reaction temperature to -60 oC
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DOI: 10.1039/C7CC02419C
1 to 7). Among all the CPAs surveyed, C6 was the optimal one afforded 2b in 64% yield with 90% ee (Table 2, entry 7). To our
to give 2a in 67% yield with 37% ee (Table 1, entry 6). To our delight, running the reaction in a higher concentration
delight, when the protecting group of tryptamine derivative
1
improved the yield to a satisfactory level (87% yield) (Table 2,
was switched from CO2Me (1a) to Boc (1b), product 2b was entry 8). Notably, 5 mol% catalyst loading gave the same
obtained in 55% ee (Table 1, entry 7).
Table 1. Evaluation of chiral phosphoric acids.
enantioselectivity (90% ee) and 66% yield (Table 2, entry 9).
Table 2. Evaluation of reaction parameters.
Entrya
solvent
time
temp
(oC)
yield
(%)b
ee (%)c
1d
2
C6H5F
8 h
rt
48
72
60
41
78
50
64
87
66
71
55
56
65
5
C6H5F
8 h
rt
entrya
CPA
C1
C2
C3
C4
C5
C6
C7
C6
1
yield (%)b
ee (%)c
3
C6H5F
16 h
11 h
10 min
10 min
16 h
16 h
18 h
18 h
0
4e
5
C6H5F
0
1
2
3
4
5
6
7
1a
1a
1a
1a
1a
1a
1a
1b
48
70
52
58
48
67
56
48
6
4
CH3CN
0
47
69
90
90
90
60
0
6
C6H5F/CH3CN
C6H5F/CH3CN
C6H5F/CH3CN
C6H5F/CH3CN
C6H5F/CH3CN
0
13
3
7
-60
-60
-60
-60
8f
9f, g
37
22
55
10d
8
a
Reaction conditions: 1b (0.2 mmol), C6 (0.02 mmol), Selectfluor
b
c
(0.22 mmol), PS (0.22 mmol) in solvent (4 mL). Isolated yield.
a
Determined by HPLC analysis. Na2CO3 instead of PS. e 4 Å MS was
d
Reactions were performed with 1 (0.2 mmol), Selectfluor (0.22
mmol), Na2CO3 (0.22 mmol), CPA (0.02 mmol) in C6H5F (4 mL) at rt. b
Isolated yield. c Determined by HPLC analysis.
used. f C6H5F/CH3CN (1:1, 2 mL). g 5 mol% C6. PS: proton sponge.
With the optimal reaction conditions in hand (Table 2, entry
8), the substrate scope was explored to test the generality of
this asymmetric fluorinative dearomatization reaction. Firstly,
the protecting group of the tryptamine was evaluated. As
shown in Table 3, in general, all the substrates with electron-
withdrawing protecting groups (CO2Me, Boc, Fmoc and Cbz)
were converted to their corresponding fluorinative
dearomatization products in satisfactory enantioselectivity
(85-90% ee, 2a to 2d) with moderate to good yields. The
substituents on the indole moiety were further explored. N-
Boc protected tryptamines with varied electron-donating
substituent (5-CH3, 5-MeO, 5-tBu) at the C5 position were well
tolerated to provide their corresponding products with good
enantioselectivity (82-90% ee) and 50-64% yields (2e to 2g),
and a methyl group at the C7 position led to only moderate
enantioselectivity (61% ee) due to the steric hindrance effect
With 1b as the model substrate, several commonly used
non-polar solvents were first screened, and fluorobenzene
proved to be the optimal one (48% yield, 55% ee). Due to the
importance of base for the anionic chiral phase-transfer
catalysis, both inorganic and organic bases were examined,
and proton sponge (PS) was found to be efficient to increase
the yield (Table 2, entry 2). When the reaction temperature
was decreased from rt to 0 oC, the reaction proceeded
smoothly with an increased enantioselectivity (56% to 65% ee)
but a prolonged reaction time was needed (Table 2, entry 3).
However, the addition of 4 Å molecular sieves (MS) led to a
complicated reaction mixture with a decreased yield and
enantioselective control (Table 2, entry 4).
Different from the phenomena that substrates treated with
Selectfluor under homogeneous conditions were converted to
a complex mixture in the chiral anion phase-transfer catalytic
system,4,5 screening polar solvents as homogeneous conditions
for this reaction afforded positive results (see SI for details).
Among tested, acetonitrile was the optimal one to provide 2b
in 78% yield, however, the enantioselectivity was decreased
slightly (Table 2, entry 5). These results encouraged us to test
mixed solvents. When mixed solvents of fluorobenzene and
acetonitrile (1:1) were utilized, the desired product 2b was
obtained in 50% yield and 69% ee within 10 min (Table 2, entry
(2h). The electron-withdrawing substituent (5-F, 5-Cl, 5-Br, 5-
CF3 and 5-CO2Et) at the C5 position of indole moiety was also
well tolerated to provide the target compounds in good
enantioselectivity (85-89% ee) and 29-89% yields (2i to 2m).
Substrates bearing a Br substituent at the different positions (4,
5, 6, 7) of the indole core underwent dearomatization
smoothly (84-92% yields) but with varied enantioselectivity
(64-97% ee). Notably, 6-Br product was obtained in 97% ee
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The reaction of 1b in gram-scale proceeded well affording
dearomative product 2b in 79% yield anDdO8I:61%0.1e03e9(/SCc7hCeCm02e4139C).
Furthermore, protection of N-H in 2b with trifluoroacetic
(
2o). Interestingly, the reactions of 4,6-dihalo-substituted
substrates proceeded in excellent enantioselectivity (96% ee,
2q 2r). Finally, the 2-substituent of the indole moiety was
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,
anhydride was carried out to give
group in could be removed by TMSOTf at -78 C (Scheme 4).
X-Ray crystallographic analysis of single crystal of
enantiopure revealed its absolute configuration as 3aR, 8aS.
4 in 88% yield, and the Boc
evaluated, and good enantioselectivity (85-89% ee) was
obtained for substrates bearing simple alkyl (2s), cyclopropyl
o
3
a
(2t), and alkenyl functional groups (2u). The reaction
3
conditions were also compatible with substrates bearing more
hindered substituent or simple H with slightly dropped
enantioselectivity (2v, 2w, 2x, 51-68% yields, 56-77% ee).
Treatment of 1b with NBS and 1,3,5-trichloroisocyanuric acid
(TCCA) led to dibromo compound 2bb (68% yield, 86% ee)
together with 32% yield of monobromo compound 2p, and
dichloro compound 2bc (66% yield, 86% ee), respectively.
Table 3. Substrate scope. a
Scheme 3. Gram-scale reaction.
Scheme 4. Transformations of product 2b.
a
Reaction conditions: 1 (0.2 mmol), C6 (0.02 mmol), Selectfluor
(0.22 mmol), base (0.22 mmol) in C6H5F:CH3CN (1:1, 2 mL) at -60 oC.
Isolated yield. Ee was determined by HPLC analysis.
Interestingly, the reaction of 3,5-dimethyl substituted
substrate 1y under the optimal reaction conditions led to the
isolation of 2yy in 72% yield and 93% ee. Likely, the
dearomatized intermediate 2y is unstable due to the
introduction of three methyl groups on the indole ring, which
facilitates the C-F bond cleavage to result in a stable benzyl
carbenium (Scheme 2).
Figure 1. Correlation between conversion of 1b with reaction time
under varied reaction conditions. The variation from the “standard
reaction conditions” (entry 8, Table 2) is denoted for each plot.
To shed light on the reaction mechanism, control
experiments were carried out to examine the effects of acid
and base additives to the reaction outcomes. The correlation
between conversion of 1b with reaction time under varied
reaction conditions were shown in Figure 1. Notably, strong
background reaction was observed. The rate of the reaction of
1b without chiral phosphoric acid catalyst or PS was similar to
Scheme 2. The fluorinative dearomatization of 1y and hydrolysis.
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47, 2558; k) Q. Ding, X. Zhou and R. Fan, Org. BiomoVl.ieCwhAermticl.e, O2n0l1in4e,
12, 4807; l) W.-T. Wu, L. Zhang and S.-LD. OYIo: u10, .1C0h3e9m/C.7CSoCc0.2R41e9vC.,
2016, 45, 1570; m) W. Sun, G. Li, L. Hong and R. Wang, Org.
Biomol. Chem., 2016, 14, 2164; n) X.-W. Liang, C. Zheng and S.-L.
You, Chem. Eur. J., 2016, 22, 11918; o) C. Zheng and S.-L. You,
Chem., 2016, 1, 857.
4 a) O. Lozano, G. Blessley, T. M. del Campo, A. L. Thompson, G. T.
Giuffredi, M. Bettati, M. Walker, R. Borman and V. Gouverneur,
Angew. Chem., Int. Ed., 2011, 50, 8105. For other examples of
fluorinative dearomatization of tryptamine derivatives, see: b) N.
Shibata, T. Tarui, Y. Doi and K. L. Kirk, Angew. Chem., Int. Ed., 2001,
40, 4461; c) T. Fujiwara, T. Seki, T. Yakura and Y. Takeuchi, J.
Fluorine Chem., 2014, 165, 7.
5 a) V. Rauniyar, A. D. Lackner, G. L. Hamilton and F. D. Toste,
Science, 2011, 334, 1681. For reviews on anionic chiral PTC
strategy, see: b) R. J. Phipps, G. L. Hamilton and F. D. Toste,
Nature Chem., 2012, 4, 603; c) M. Mahlau and B. List, Angew.
Chem., Int. Ed., 2013, 52, 518; d) K. Brak and E. N. Jacobsen,
Angew. Chem., Int. Ed., 2013, 52, 534.
6 R. J. Phipps and F. D. Toste, J. Am. Chem. Soc., 2013, 135, 1268.
For leading examples using the anionic chiral PTC strategy, see: b)
R. J. Phipps, K. Hiramatsu and F. D. Toste, J. Am. Chem. Soc., 2012,
134, 8376; c) Y.-M. Wang, J. Wu, C. Hoong, V. Rauniyar and F. D.
Toste, J. Am. Chem. Soc., 2012, 134, 12928; d) T. Honjo, R. J.
Phipps, V. Rauniyar and F. D. Toste, Angew. Chem., Int. Ed., 2012,
51, 9684; e) H. P. Shunatona, N. Frꢀh, Y.-M. Wang, V. Rauniyar
and F. D. Toste, Angew. Chem., Int. Ed., 2013, 52, 7724; f) A. J.
Neel, J. P. Hehn, P. F. Tripet and F. D. Toste, J. Am. Chem. Soc.,
2013, 135, 14044; g) J. Wu, Y.-M. Wang, A. Drljevic, V. Rauniyar, R.
J. Phipps and F. D. Toste, Proc. Natl. Acad. Sci. U. S. A., 2013, 110,
13729; h) A. D. Lackner, A. V. Samant and F. D. Toste, J. Am. Chem.
Soc., 2013, 135, 14090.
For asymmetric brominative dearomatization reactions of
tryptamines, see: a) W. Xie, G. Jiang, H. Liu, J. Hu, X. Pan, H. Zhang,
X. Wan, Y. Lai and D. Ma, Angew. Chem., Int. Ed., 2013, 52, 12924;
b) X. Feng, G. Jiang, Z. Xia, J. Hu, X. Wan, J.-M. Gao, Y. Lai and W.
Xie, Org. Lett., 2015, 17, 4428. Notably, the asymmetric
fluorination of tryptamine dearivative 1a under the same catalytic
conditions only gave moderate yield and almost racemic result
(45% yield, 5% ee).
8 For selected reviews on chiral phosphoric acid catalysis, see: a) T.
Akiyama, Chem. Rev., 2007, 107, 5744; b) M. Terada, Synthesis,
2010, 12, 1929; c) J. Yu, F. Shi and L.-Z. Gong, Acc. Chem. Res.,
2011, 44, 1156; d) M. Rueping, A. Kuenkel and I. Atodiresei, Chem.
Soc. Rev., 2011, 40, 4539; e) D. Parmar, E. Sugiono, S. Raja and M.
Rueping, Chem. Rev., 2014, 114, 9047; For pioneering
contributions, see: f) D. Uraguchi and M. Terada, J. Am. Chem.
Soc., 2004, 126, 5356; g) T. Akiyama, J. Itoh, K. Yokota and K.
Fuchibe, Angew. Chem., Int. Ed., 2004, 43, 1566.
9 For selected examples of CADA reactions of indoles, see: a) Q.-F.
Wu, H. He, W.-B. Liu and S.-L. You, J. Am. Chem. Soc., 2010, 132,
11418; b) Q.-F. Wu, C. Zheng and S.-L. You, Angew. Chem., Int. Ed.,
2012, 51, 1680; c) Q. Yin and S.-L. You, Org. Lett., 2013, 15, 4266;
d) Q. Yin and S.-L. You, Org. Lett., 2014, 16, 2426; e) Q. Cai, Q. Yin
and S.-L. You, Asian J. Org. Chem., 2014, 3, 408. f) D. Duan, Q. Yin,
S. Wang, Q. Gu and S. You, Acta Chim. Sinica, 2014, 72, 1001; g) W.
Shao, H. Li, C. Liu, D.-J. Liu and S.-L. You, Angew. Chem., Int. Ed.,
2015, 54, 7684; h) C.-X. Zhuo, Y. Zhou, Q. Cheng, L. Huang and S.-L.
You, Angew. Chem., Int. Ed., 2015, 54, 14146; i) X. Zhang, W.-B.
Liu, H.-F. Tu and S.-L. You, Chem. Sci., 2015, 6, 4525; j) L. Han, W.
Zhang, X.-X. Shi and S.-L. You, Adv. Synth. Catal., 2015, 357, 3064;
k) C. Liu, J.-C. Yi, Z.-B. Zheng, Y. Tang, L.-X. Dai and S.-L. You,
Angew. Chem., Int. Ed., 2016, 55, 751; l) R.-D. Gao, Q.-L. Xu, B.
Zhang, Y. Gu, and S.-L. You, Chem. Eur. J., 2016, 22, 11601.
that under the standard conditions (entry 8, Table 2). We
envisioned that HBF4 released from Selectfluor might
accelerate the reaction. Indeed, when 1 equiv of HBF4 was
added, the reaction becomes even faster while the reaction
becomes sluggish when 1.2 equiv of PS was employed. These
data imply that the role of PS in this reaction is to neutralize
HBF4 generated in situ and hence inhibit the racemic
background reaction.
Conclusions
In conclusion, an asymmetric fluorinative dearomatization
reaction of tryptamine derivatives was developed based on
chiral anion phase transfer strategy. The preliminary
investigations on the reaction mechanism suggested that the
reaction proceeds via a bifunctional activation by chiral BINOL-
derived phosphate anion. This method features simple
operation, facile introduction of fluorine atom in a highly
enantioselective manner and construction of two contiguous
quaternary stereogenic centers.
Acknowledgements
We thank the National Key Research and Development
Program of China (2016YFA0202900), National Basic Research
Program of China (2015CB856600), NSFC (21332009,
21361140373, 21421091), and Chinese Academy of Sciences
(XDB20000000, QYZDY-SSW-SLH012) for generous financial
support.
7
Notes and references
1 a) K. Mꢀller, C. Faeh and F. Diederich, Science, 2007, 317, 1881; b)
I. Ojima, Fluorine in Medicinal Chemistry and Chemical Biology;
Wiley-Blackwell: Oxford, U.K., 2009; c) V. Gouverneur and K.
Mꢀller, Fluorine in Pharmaceutical and Medicinal Chemistry:
From Biophysical Aspects to Clinical Applications; Imperial College
Press: London, 2012; d) P. Kirsch, Modern Fluoroorganic
Chemistry: Synthesis, Reactivity, Applications, 2nd ed.; Wiley-
VCH: Weinheim, Germany, 2013.
2 For recent reviews on catalytic asymmetric fluorination reactions,
see: a) M. C. Pacheco, S. Purser and V. Gouverneur, Chem. Rev.,
2008, 108, 1943; b) J. R. Wolstenhulme and V. Gouverneur, Acc.
Chem. Res., 2014, 47, 3560; c) J. Wu, Tetrahedron Lett., 2014, 55,
4289; d) X. Yang, T. Wu, R. J. Phipps and F. D. Toste, Chem. Rev.,
2015, 115, 826; e) T. Sugiishi, M. Matsugi, H. Hamamotob and H.
Amii, RSC Adv., 2015, 5, 17269; f) P. A. Champagne, J. Desroches,
J.-D. Hamel, M. Vandamme and J.-F. Paquin, Chem. Rev., 2015,
115, 9073.
3 For recent reviews on dearomatization reactions, see: a) A. R.
Pape, K. P. Kaliappan and E. P. Kündig, Chem. Rev., 2000, 100,
2917; b) A. Pelter and R. S. Ward, Tetrahedron, 2001, 57, 273; c) E.
P. Kündig and A. Pape, Top. Organomet. Chem. 2004, 7, 71; d) W.
D. Harman, Top. Organomet. Chem., 2004, 7, 95; e) S. Quideau, L.
Pouységu and D. Deffieux, Curr. Org. Chem., 2004, 8, 113; f) F.
López Ortiz, M. J. Iglesias, I. Fernández, C. M. Andújar Sánchez and
G. R. Gómez, Chem. Rev., 2007, 107, 1580; g) S. Quideau, L.
Pouységu and D. Deffieux, Synlett., 2008, 467; h) L. Pouységu, D.
Deffieux and S. Quideau, Tetrahedron, 2010, 66, 2235; i) C.-X.
Zhuo, W. Zhang and S.-L. You, Angew. Chem., Int. Ed., 2012, 51,
12662; j) C.-X. Zhuo, C. Zheng and S.-L. You, Acc. Chem. Res., 2014,
4 | J. Name., 2012, 00, 1-3
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