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DOI: 10.1055/s-0031-1290118
Remarkable Switch in the Regiochemistry of the Iodination of Anilines by N-Iodosuccinimide: Synthesis of 1,2-Dichloro-3,4-diiodobenzene
Publication History
Publication Date:
22 December 2011 (online)
Abstract
Direct iodination of anilines by NIS in polar solvents (such as DMSO) affords p-iodinated products with up to >99% regioselectivity. Switching to less polar solvents (such as benzene) in the presence of AcOH inverts this outcome toward dramatically increased or preferential generation of the o-isomers, also with up to >99% regioselectivity. This finding was exploited in the synthesis of 1,2-dichloro-3,4-diiodobenzene.
Key words
aromatic amine - electrophilic substitution - halogenation - regioselectivity - solvent effects
The electrophilic iodination of anilines has a long history, featuring a myriad of reagents. [¹] Typically, para-substitution dominates, [²] and attempts to change this selectivity have been based primarily on N-directed ortho-metallation strategies. [¹d-g] [³] However, ortho-iodination can be quite competitive, even in the case of aniline itself (see, e.g. ref. 2j), raising the question whether regiocontrol might be attained by simple alteration of reaction conditions. [4] Herein, we report a convenient, regioswitchable method for the iodination of anilines by N-iodosuccinimide (NIS).
Our work was inspired by the need to synthesize angularly (1,2- versus 3,4-) differentiated 1,2,3,4-tetrahalobenzene derivatives as building blocks for the construction of angular phenylenes. [5] With the exception of 1,2-dichloro-3,4-difluorobenzene, [6] such compounds are unknown. We therefore embarked on a synthesis of 1,2-dichloro-3,4-diiodobenzene (5), which we deemed more suitable for our purposes. An attractive route to 5 appeared to be via iodination of commercial 2,3-dichloroaniline (1a), if selective attack at the 6-position to give 2a (Scheme [¹] ) could be attained, and subsequent diazotization-iodination.
Accordingly, 1a was exposed to a variety of iodinating conditions, such as I(py)2BF4, TfOH, CH2Cl2, [²v] I2, Ag2SO4, EtOH; [²w] py, ICl, MeOH; [7] I2, KI, H2O; and NIS, AcOH, [4a] always furnishing almost exclusively the para product 3a, with the exception of the last variant, for which ¹H NMR product analysis indicated clean conversion into 2a, 3a, and 4a in the ratio 13:81:6 (isolated yields on a 2-mmol scale 6%, 59%, and 6%, respectively; Scheme [¹] ). [8]
Scheme 1 Iodination of 2,3-dichloroaniline (1a) by NIS (1.05 equiv) in AcOH
Scheme 2 Structural confirmations of 2a and 3a by their respective conversion into 5 and 6
Since the spectral data did not permit a rigorous assignment of the position of the iodine substituent in 2a and 3a, chemical structural proof was provided by conversion into the corresponding diiodides 5 and 6, in 90% and 51% yields, respectively (Scheme [²] ). Thus, the ¹H NMR spectrum of 5 shows two aromatic doublets at δ = 7.73 and 7.19 ppm, its ¹³C NMR counterpart six peaks at δ = 137.6, 137.5, 131.7, 131.0, 114.1, and 107.0 ppm. On the other hand, the symmetry of 6 is apparent by a corresponding singlet proton signal at δ = 7.44 ppm and three carbon resonances at δ = 139.0, 136.9, and 98.8 ppm.
Encouraged by the relatively sizeable quantities of 2a observed in Scheme [¹] , a number of solvents were screened to further improve this outcome (Table [¹] ). [4b] It is evident that the 2a to 3a ratio increases with decreasing solvent dielectric constant, ranging from 2:98 in DMSO to 42:58 in benzene. The only outlier is CH2Cl2 (entry 12), which performed unexpectedly well, possibly due to contamination of commercial material by acid (vide infra). Ether solvents (entries 9 and 10) failed to show measurable conversions. Interestingly, a solvent-less run (entry 1), while unsuccessful at r.t., reproduced approximately the outcome of entry 7 at 95 ºC (AcOH).
| Entry | Solventb | Dielectric constant (ε) | Conversion (%)c | 2a:3a:4a c | |||||||||||||||
| 1 | noned | - | 89 | 13:87:0 | |||||||||||||||
| 2 | DMSO | 46.7 | 92 | 2:98:0 | |||||||||||||||
| 3 | DMF | 38 | 94 | 4:96:0 | |||||||||||||||
| 4 | EtOH | 24.6 | 100 | 4:96:0 | |||||||||||||||
| 5 | acetone | 21 | 82 | 5:95:0 | |||||||||||||||
| 6 | MeCN | 37.5 | 70 | 7:93:0 | |||||||||||||||
| 7 | AcOH | 6.2 | 100 | 10:89:1 | |||||||||||||||
| 8 | EtOAc | 6.0 | 60 | 20:80:0 | |||||||||||||||
| 9 | THF | 7.5 | trace | - | |||||||||||||||
| 10 | dioxane | 2.3 | trace | - | |||||||||||||||
| 11 | toluene | 2.4 | 33 | 23:77:0 | |||||||||||||||
| 12 | CH2Cl2 | 9.1 | 78 | 40:60:0 | |||||||||||||||
| 13 | benzene | 2.3 | 49 | 42:58:0 | |||||||||||||||
|
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|
a Reaction
conditions: In a 10 mL round bottom flask, 1a (0.25
mmol) was dissolved in the solvent (5 mL), the mixture was stirred
for 5 min, and then NIS (0.25 mmol) was added. The flask was capped
and stirring was continued at r.t. for 72 h.
b The
solvents were used as received from vendors. c Determined by ¹H NMR analysis of the crude mixture. d The solid starting materials were ground to a fine powdered mixture. After 20 h at r.t., there was no appreciable conversion, hence the mixture was heated to 95 ˚C for 1 h. For solvent-free halogenations, see ref. 1b. | |||||||||||||||||||
To probe the influence of added acid on the experiments in Table [¹] , a similar screen was executed using various amounts of AcOH as co-solvent (Table [²] ). Notably, the added acid improved the efficiency of the reaction and allowed it to occur even in ether solvents. When AcOH was employed in large excess (1.5 mL, 26 mmol, ca. 100 equiv; entries 1-10), the ortho/para iodination ratios stayed unchanged from those in Table [¹] . Remarkably, however, a dramatic increase in the proportion of ortho-iodination, up to 89:11, occurred on gradual reduction of the quantity of AcOH (entries 11-14).
| Entry | AcOH amount |
Solvent (mL)b | Conversion (%) | 2a:3a c | |||||||||||||||
| 1 | 1.5 mL | DMSO (3.0) | 96 | 2:98 | |||||||||||||||
| 2 | 1.5 mL | DMF (3.0) | 98 | 2:98 | |||||||||||||||
| 3 | 1.5 mL | EtOH (3.0) | 99 | 4:96 | |||||||||||||||
| 4 | 1.5 mL | MeCN (3.0) | 98 | 7:93 | |||||||||||||||
| 5 | 1.5 mL | THF (3.0) | 96 | 15:85 | |||||||||||||||
| 6 | 1.5 mL | EtOAc (3.0) | 94 | 19:81 | |||||||||||||||
| 7 | 1.5 mL | Et2O (3.0) | 94 | 22:78 | |||||||||||||||
| 8 | 1.5 mL | dioxane (3.0) | 94 | 29:71 | |||||||||||||||
| 9 | 1.5 mL | CH2Cl2 (3.0) | 96 | 38:62 | |||||||||||||||
| 10 | 1.5 mL | benzene (3.0) | 89 | 45:55 | |||||||||||||||
| 11 | 20 equivd,e | benzene (5.0)e | 96 | 76:24 | |||||||||||||||
| 12 | 10 equivd,e | benzene (5.0)e | 96 | 80:20 | |||||||||||||||
| 13 | 5 equivd,e | benzene (5.0)e | 84 | 85:15 | |||||||||||||||
| 14 | 1 equivd,e | benzene (5.0)e | 66f | 89:11 | |||||||||||||||
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|
a Reaction
conditions: In a 10 mL round-bottom flask, 1a (0.25
mmol) and AcOH (various amounts, see column 2) were dissolved in
the solvent (various amounts, see column 3). The reaction mixture
was stirred for 5 min and then NIS (0.25 mmol) was added. The flask
was capped and stirring was continued at r.t. for 72 h.
b The
solvents were used as received from vendors unless otherwise stated. c Determined by ¹H NMR analysis of the crude mixture. d Relative to 1a. e Distilled from CaH2. The use of undried benzene reduced the ortho-selectivity by ca. 10%. f Prolonged reaction times or use of 1.3 equiv of NIS increased the conversion to >90%. | |||||||||||||||||||
With optimized conditions for the regioselective generation of 2a and 3a, respectively, from 1a in hand, the question arose to which extent this chemistry could be generalized to other anilines, especially those without sterically compensating meta-substituents, including aniline itself. Gratifyingly, the answer was largely in the affirmative (Table [³] ). Thus, aniline (1b) and NIS in DMSO gave high yields of iodoaniline with the normal para-selectivity (95%, entry b-1), a result that is repeated for the remainder of the substrates 1 under these conditions. [²] In sharp contrast, when 1b was treated with NIS in benzene-AcOH (1.05 equiv), the regiochemistry inverted to reflect preferential ortho-attack (73%, entry b-2). A similar trend is noted for the other aniline derivatives, in most cases furnishing substantial (c-2, k-2, l-2 and, o-2-q-2), if not dominant (entries e-2-i-2, m-2, and n-2), quantities of ortho-iodination products. Most remarkable is the selectivity observed for 1-naphthalenamine, which occurs in the absence of favorable statistical factors and overrides the normal preference for α attack by electrophiles (n-2). Impressive is also the regioswitch in the case of strongly deactivated 3-nitroaniline (1h; entries h-1 and h-2), although excess AcOH (20 equiv) was necessary to achieve reasonable conversion (72%) in benzene. The data indicate that encumbering the amino group appears to be detrimental to the ortho/para ratio (entries c-2-f-2, k-2, l-2, compared to entry b-2). The sensitivity of the amino function to NIS is evident in some cases, which either failed (entry j-2) or were marred by side reactions, including overiodination (entries i-2, n-2-q-2). No attempts were made to improve on these results, but in light of the data reported in Tables [¹] - [³] , such optimization should be possible and may require the development of a unique protocol for each compound of interest.
Some exploratory experiments indicate that this chemistry may be applicable to other halogenations. Thus, bromination of parent aniline (1b) with NBS under the same conditions as those employed for entry b-1 engendered the two bromoanilines with ortho/para ratio of 10:90 (>90% conversion). Switching to the conditions of entry b-2 changed this ratio to 51:49 (>90% conversion). Changing the reagent to NCS in DMSO essentially failed to convert 1b, but with AcOH in benzene provided the two chloroanilines (ortho/para = 70:30; >90% conversion). Finally, applying the respective recipes to 1j with NBS resulted in a switch of the ratios of the two tribromoanilines from ortho/para <1:>99 to 23:77, with >90% conversion in each case.
|
Solvent = DMSOa
|
Solvent = AcOH
(1.05 equiv) in benzeneb
| ||||||||||||||||||
| Aniline (1) | Entry | Conversion (%)c | 2:3 (ortho/para) (%)c | Entry | Conversion (%)c | 2:3 (ortho/para) (%)c | |||||||||||||
 | a-1 | >90 | 2:98 | a-2 | 66 | 89:11 | |||||||||||||
 | b-1 | >90 | 5:95 | b-2 | >90 | 73:27 | |||||||||||||
 | c-1 | >90 | 6:94 | c-2 | >90 | 43:57 | |||||||||||||
 | d-1 | >90 | <1:>99 | d-2 | >90 | <1:>99 | |||||||||||||
 | e-1 | >90 | <1:>99 | e-2 | 74 | 62:38 | |||||||||||||
 | f-1 | >90 | 1:99 | f-2 | >90 | 59:41 | |||||||||||||
 | g-1 | >90 | 7:93d | g-2 | >90 | 89:11d | |||||||||||||
 | h-1 | 78 | 17:83e | h-2 | 72 | >99:<1f | |||||||||||||
 | i-1 | >90 | 14:86g | i-2 | 90 | 69:31h | |||||||||||||
 | j-1 | >90 | <1:>99 | j-2 | <5 | -i | |||||||||||||
 | k-1 | >90 | <1:>99 | k-2 | 30 | 37:63 | |||||||||||||
 | l-1 | >90 | <1:>99 | l-2 | >90 | 25:75 | |||||||||||||
 | m-1 | >90 | 14:86 | m-2 | >90 | 98:2j | |||||||||||||
 | n-1 | 88 | 17:83k | n-2 | 60 | 90:10l | |||||||||||||
 | o-1 | >90 | <1:>99 | o-2 | >90 | 15:85m | |||||||||||||
 | p-1 | >90 | <1:>99 | p-2 | >90 | 22:78n | |||||||||||||
 | q-1 | >90 | <1:>99 | q-2 | >90 | 25:75o | |||||||||||||
|
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|
a Reaction
conditions: In a 25 mL round-bottom flask, 1 (0.5
mmol) in DMSO (10 mL) was stirred for 5 min, and then NIS (0.5 mmol)
was added. The flask was capped, and stirring was continued at r.t.
for 72 h.
b Reaction conditions: In a 25 mL
round-bottom flask, 1 (0.5 mmol) in a solution
of AcOH (0.525 mmol) in benzene (distilled from CaH2;
10 mL) was stirred for 5 min, and then NIS (0.5 mmol) was added.
The flask was capped, and stirring was continued at r.t. for 72
h.
c Determined by ¹H NMR
analysis of the crude mixture. The known structures were confirmed
by comparison of their ¹H NMR spectra with those
rigorously assigned in the literature, whereas new compounds were
isolated and fully characterized (see the Supporting Information
for details). d The ortho-iodo products were comprised of 5-chloro-2-iodoaniline and 3-chloro-2-iodoaniline (see Scheme [³] ). e Products consisted of 2-iodo-5-nitroaniline (10%), 2-iodo-3-nitroaniline (3%), 4-iodo-3-nitroaniline (65%), and 2,4-diiodo-3-nitroaniline (1%). f To achieve substantial conversion, 20 equiv of AcOH were necessary. Products consisted of 2-iodo-5-nitroaniline (48%), 2-iodo-3-nitroaniline (15%), and an unidentified species (9%). 4-Iodo-3-nitroaniline was not detected. g The only ortho-iodo product was 2-iodo-5-methoxyaniline. The product mixture also contained 2,4-diiodo-5-methoxyaniline (2%). h The only ortho-iodo product was 2-iodo-5-methoxyaniline. The product mixture also contained 2,4-diiodo-5-methoxyaniline (5%). i The ¹H NMR spectrum showed traces of 2,5-dibromo-4-iodoaniline and unidentified material exhibiting signals in the δ = 7.0-7.9 ppm range. j A higher amount (1.3 equiv) of NIS was employed. k The product mixture contained 2,4-diiodonaphthalen-1-amine (20%). l The product mixture contained 2,4-diiodonaphthalen-1-amine (8%). m The ¹H NMR spectrum showed the presence of 3-iodopyridin-2-amine (5%), 5-iodopyridin-2-amine (29%), and an unknown product (66%). n The mixture contained ortho- (13%), para- (46%), and an unidentified product (41%). o The mixture contained ortho- (24%), para- (70%), and a minor unidentified product (6%). | |||||||||||||||||||
In contemplation of a possible mechanistic rationale for these observations, it is interesting that the experimental and computed heats of formation of ortho- and para-iodoaniline are practically identical, [9] accenting considerations other than sterics, possibly frontier orbital, [¹0] electronic, [¹h] and H-bonding effects.
Many species have been proposed as protagonists in the electrophilic iodination of aromatics with a variety of reagents, [¹] [¹¹] most pertinently those involving acids (usually) as solvents. [²h] [i] [l] [r] [4a] [¹¹a] [c-f] [i] [j] [l] [n] To explain our increased ortho-selectivity in nonpolar solvents in the presence of equivalent amounts of AcOH, we suggest the intervention of A in Figure [¹] as a possible simplest transition state. Another option might be B, should acetic hypoiodous anhydride (AcOI) function as the attacking species. [¹¹] In polar solvents, solvation of the amino group through dipolar and H-bonding processes would then direct the electrophile to the para position. [¹²]
Figure 1 Suggested transition state for the ortho-iodination of aniline (1b) in benzene-AcOH (1 equiv)
In view of the ready switch of the regioselectivity of these iodinations with reaction conditions, it is clear that a special onus is on researchers introducing new reagents to effect such transformations to rigorously ascertain the structures of their products. This is particularly important in cases in which ¹H NMR peak multiplicity is not diagnostic, such as in the iodination of 3-mono- (e.g., 1g- 1i), 2,3-di (e.g., 1a, 1n, 1q), and 2,3,5-trisubstituted anilines. Here chemical derivatization (as, e.g., shown in Scheme [²] ) or X-ray confirmation may be required. In an attempt to reconcile the data for the known compounds listed in Table [³] with the literature (SciFinder), we encountered numerous instances of either insufficient, ambiguous, incongruous, or simply incorrect assignments (see Supporting Information).
Scheme 3 Iodination of 3-chloroaniline (1g) in AcOH, [¹6a] DMSO (Table 3, entry g-1), and benzene-AcOH (Table 3, entry g-2)
An illustrative case in point is the conversion of 3-chloroaniline (1g) into the three monoiodo derivatives 2g, 2g′, and 3g (Table [³] , entries g-1/g-2). Isomers 2g and 2g′ have been constructed unambiguously by reduction of their respective nitro derivatives, fully described, and their structures confirmed by subsequent chemistry. [¹³] [¹4] The para-iodo relative 3g was made by the iodination of 1g with benzyltrimethylammonium dichloroiodate and also fully described, in particular by its ¹H NMR spectrum. [¹5] Valgeirsson et al. purport to arrive at 2g by treatment of 1g with NIS in AcOH (70%), [¹6a] a procedure subsequently employed by Raffa et al. [¹6b] Since this result appeared at odds with ours, we repeated this preparation under the reported conditions to furnish 2g/2g′/3g/4g = 12%:0%:79%:9% (Scheme [³] ). Thus, the assignments of 2g and all compounds derived from it in these papers appear to be in error. Badri et al. use I2 and 1,4-bis(triphenylphosphonium)-2-butene peroxodisulfate to convert 1g into alleged 3g (89%), but describe spectral data that do not match any of the possible products. [¹¹b] The group of Vibhute executed this reaction with I2-HIO3, claiming the obtention of 3g (80%), [¹7] or with PyICl, suggesting the generation of 2g (89%), [¹8] or again with I2-HIO3, [¹9] but now in conjunction with microwave irradiation and alleging 2g (85%) as the product, providing ¹H NMR descriptions that are not only wrong, but incomprehensible. Bachki et al. employ I2-HgCl2 in this process and suggest para-iodination (45%), but their spectral data show 2g as the outcome. [¹¹g] A number of papers that explore new iodinating agents for arenes include 1g in their roster of test cases and propose (with two exceptions) [²i] [²0a] sole para-iodination, but do not supply retrievable spectral or chemical proof for it. [²i] [²0]
In summary, we have shown that a simple switch of the reaction medium dramatically affects the regiochemistry of the electrophilic iodination of anilines by NIS. Reactions carried out in DMSO give para-iodoanilines as the major products, but changing the conditions to anhydrous benzene in the presence of a small quantity of AcOH enhances the production of ortho-iodo products from moderately to almost quantitatively. Considering the value of both types of isomers in organic synthesis, [¹] [²¹] the reported methodology should be very useful to the practitioner in the field.
Supporting Information for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synlett.
- Supporting Information for this article is available online:
- Supporting Information
Acknowledgment
This study benefited from financial aid by the NSF (CHE-0907800).
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2g′:
Xu Z.Li Q.Zhang L.Jia Y. J. Org. Chem. 2009, 74: 6859 - 3g:
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Junne SB.Vibhute AY.Vibhute YB.Gurav VM. Int. J. Chem. Tech. Res. 2009, 1: 1005 - See, for example:
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Sun Y.-L.Zhang Y.Cui X.-H.Wang W. Adv. Synth. Catal. 2011, 353: 1174 - 21h
Shi L.Liu X.Zhang H.Jiang Y.Ma D. J. Org. Chem. 2011, 76: 4200 - 21i
Yang F.Zhang J.Wu Y. Tetrahedron 2011, 67: 2969 - 21j
Wang R.-P.Mo S.Lu Y.-Z.Shen Z.-M. Adv. Synth. Catal. 2011, 353: 713 - 21k
Xu Z.Zhang F.Zhang L.Jia Y. Org. Biomol. Chem. 2011, 9: 2512 - 21l
Kamisaki H.Nanjo T.Tsukano C.Takemoto Y. Chem. Eur. J. 2011, 17: 626 - 21m
Kaname M.Minoura M.Sashida H. Tetrahedron Lett. 2011, 52: 505
References and Notes
The structures of all new compounds (Scifinder) were in accord with their analytical and/or spectroscopic properties; see Supporting Information.
Scheme 1 Iodination of 2,3-dichloroaniline (1a) by NIS (1.05 equiv) in AcOH
Scheme 2 Structural confirmations of 2a and 3a by their respective conversion into 5 and 6
Figure 1 Suggested transition state for the ortho-iodination of aniline (1b) in benzene-AcOH (1 equiv)
Scheme 3 Iodination of 3-chloroaniline (1g) in AcOH, [¹6a] DMSO (Table 3, entry g-1), and benzene-AcOH (Table 3, entry g-2)